awards south mrican researchers awarded r220 million research grant the project will: • evaluate an affordable hiv/aids treatment programme for adults and children in a family setting at primary care level. • test whether treatment interruption is an affordable and feasible way of controlling hiv infection in children that reduces the progression to aids. • determine the efficacy of two standard childhood vaccines (used to prevent pneumonia and meningitis) in preventing aids-related complications in infants. • evaluate the community effect of highly active antiretroviral therapy on sickness and deaths due to aids and tuberculosis. • develop simple, inexpensive methods of diagnosing hiv and monitoring treatment and drug resistance. professor james mclntyre and glenda groy. executive directors of the perinatal hiv research unit, chris hani barogwanath hospital, soweta. for further information contact: professor rob dorrington, uct centre for actuarial research tel. (021) 650-2467 or debbie bradshaw, mrc burden of disease research unit cell: 082 461 1234 ----------hhruary 2003 'low-income households in south africa carry the greatest burden of hiv!aids, experience the greatest negative effects, and have the least reserves to cope: says professor mclntyre. the new cipra grant, 'safeguarding the household: comprehensive aids research', will address hiv/aids as a problem not simply of individuals but of entire families, he explains, and all family members may participate in the studies. the cutting-edge research programme will focus on aspects of hiv treatment in adults and children, tuberculosis and affordable laboratory tests. 'this research agenda is of crucial importance to south africa and our region. it will gather essential information for the government's aids programmes in the future, and covers many of the key areas raised in the recent cabinet statement on aids; explains professor mclntyre. the grant award recognises the quality of south african aids research and will provide the opportunity to develop many more local researchers through an extensive, linked, training programme: the united states national institutes for health has announced the award of a major research grant to leading south african aids researchers. the $21.3 million (about r220 million) award over 5 years will support hiv/aids research in a family setting, a rarely tried approach to fighting the disease. this grant is the largest yet made by the comprehensive international program for research on aids (cipra). this national collaborative research effort will be led by professor james mclntyre and co-ordinated by the perinatal hiv research unit of the university of the witwatersrand. thf soutmtrn mrican journal or hiij mfdicinf making the epidemic more visible, and underscanding its dynamics through such reports is important not only in managing the impact of the epidemic but also in eventually being able to turn the tide of it. for all spheres of planning, it is essential to have an understanding of where the country stands in terms of hiv!aids. --------march 2002 11 an excellent article by professor gerald friedland, which appears in this issue of the journal, underscores the importance of adherence to antiretroviral regimens in promoting a successful outcome to therapies. it is incumbent on all doctors who prescribe therapies suggested in the society's guidelines to pay more than just lip service to adherence counselling. ongoing counselling and advice is as important for our patients as the choice of antiretrovirals. strategies to improve adherence to therapies are outlined in this very useful article. des martin editor, southern african journal of hiv medicine president, southern african hiv clinicions society will need to be reviewed on a more frequent basis than we have done in the past. it would be appropriate therefore to consider reviewing them on an annual basis, which has become the international norm. at the same meeting guidelines for the prevention and treatment of opportunistic infections were formulated, and these are published in the current issue of the journal. my thanks go to the members of the guidelines committee who gave up their valuable time to participate in this process. the issues surrounding the provision of antiretroviral therapies, in particular the provisi~n of a single dose of nevirapine to pregnant mothers and newborn infants to interrupt mother-to-child transmission [mtcn of hiv, have filled the pages of our popular press. we in the southern african hiv clinicians society believe that the time for research has passed and the time for implementation is at hand, to which end the society issued a strongly worded press release in early february 2002. in so doing we added our voice to other strident voices emanating from the medical community, particularly those of professor james mclntyre and dr glenda gray. it is with particular pride that i would like to extend my congratulations to mclntyre and gray on their receipt of the 2002 nelson mandela award for health and human rights. from the editor there are two important factors that lead to success in the use of antiretroviral (arv) therapies; firstly guidelines for the use of these therapies appropriate to our setting, and secondly adherence to the prescribed medications. to this end the society's guidelines committee met recently to review and formulate guidelines for the use of antiretroviral therapies for both adults and children. these guidelines are currently being sent to international reviewers for comment and they will be published in the june issue of the journal. it must be recognised that the formulation of guidelines is a dynamic process and in the ever-changing milieu of new drugs, prices and combinations· these guidelines the southern african journal of hiv medicine about the author(s) linda-gail bekker desmond tutu hiv centre, institute of infectious disease and molecular medicine, university of cape town, cape town, south africa benjamin brown anova health institute, johannesburg, south africa dvora joseph-davey department of epidemiology, university of california, los angeles, united states of america division of epidemiology and biostatistics, school of public health and family medicine, university of cape town, cape town, south africa kathrine gill desmond tutu hiv centre, institute of infectious disease and molecular medicine, university of cape town, cape town, south africa michelle moorhouse wits reproductive health and hiv research unit, university of the witwatersrand, johannesburg, south africa sinead delany-moretlwe wits reproductive health and hiv research unit, university of the witwatersrand, johannesburg, south africa landon myer division of epidemiology and biostatistics, school of public health and family medicine, university of cape town, cape town, south africa catherine orrell desmond tutu hiv centre, institute of infectious disease and molecular medicine, university of cape town, cape town, south africa department of medicine, university of cape town, cape town, south africa kevin rebe life vincent pallotti hospital, cape town, south africa department of medicine and infectious diseases, university of cape town, cape town, south africa w.d. francois venter ezintsha, faculty of health sciences, university of the witwatersrand, johannesburg, south africa carole l. wallis barc-sa, speciality molecular division, lancet laboratories, johannesburg, south africa how to cite this correction: bekker l-g, brown b, joseph-davey d, et al. corrigendum: southern african guidelines on the safe, easy and effective use of pre-exposure prophylaxis: 2020. s afr j hiv med. 2021;22(1), a1295. https://doi.org/10.4102/sajhivmed.v22i1.1295 note: doi of original article published: https://doi.org/10.4102/sajhivmed.v21i1.1152 correction corrigendum: southern african guidelines on the safe, easy and effective use of pre-exposure prophylaxis: 2020 linda-gail bekker, benjamin brown, dvora joseph-davey, kathrine gill, michelle moorhouse, sinead delany-moretlwe, landon myer, catherine orrell, kevin rebe, w.d. francois venter, carole l. wallis published: 08 dec. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. in the version of the article initially published, bekker l-g, brown b, joseph-davey d, et al. southern african guidelines on the safe, easy and effective use of pre-exposure prophylaxis: 2020. s afr j hiv med. 2020;21(1), a1152. https://doi.org/10.4102/sajhivmed.v21i1.1152, the orcid of the second last author was given incorrectly. the correct orcid should be https://orcid.org/0000-0002-4157-732x instead of https://orcid.org/0000-0002-6919-5171 in the ‘authors’ section. this correction does not alter the study’s findings of significance or overall interpretation of the study’s results. the authors apologise for any inconvenience caused. th!: southtrn african jou nal o~ hi mtoici!: -----------hbruary 2003 from the thank heaven that at long last we are witnessing wider use of antiretroviral therapies in south africa. there is greater acceptance of these therapies by patients, by doctors and by employer groups. the trend-setting mining giant anglo american has taken the bold step of providing antiretrovirals for its employees. regrettably government continues to drag its feet in this regard. those of us who have used antiretrovirals in our practices continue to be impressed by their beneficial effects, often rescuing patients from death's door. it is however heartening to view antiretroviral therapy lard on a larger scale by looking at evidence of its cost-effectiveness in disease management progammes. or leon regensburg presents very convincing data in the aid for aids programme regarding the cost-beneficial effects of these therapies. the latest and greatest in the hiv treatment arena, presented at the barcelona international aids conference in 2002, is described by or francois venter (p. 29) in his own inimitable style. or jean nachega has written on art in developing countries (p. 35), and this is an important focus on the unique problems and challenges of the developing world setting. art remains one of the most complex challenges facing clinicians today, and when treating a bizarre battle joep lange, president of the international aids society (ias), said at the durban 2000 aids conference that no greater ill befalls the poor than bad government, and i am afraid that there is no more unfortunate example of this than the mpumalanga provincial health department, headed up by mec sibongile manana. this lady has, in her position of power, decided to systematically ignore world health organisation recommendations, international scientific evidence and our own country's constitutional court ruling on antiretrovirals to deny the population in her province access to what is now standard practice in a number of south african provinces. hiv prophylaxis for rape victims and mother-tochild prevention programmes are becoming integrated into public sector health provision in many areas, but in mpumalanga not only is this not happening within the government, but this same government is wasting valuable aids money to fight futile court cases to stop a nongovernmental organisation that has undertaken to fill this very important service gap at its own expense! to add insult to injury the mec has taken this organisation editors patients a high index of awareness is necessary to avoid potentially fatal conditions that are associated with these therapies. all clinicians should read or jennifer pi tt's article lp. 38) on lactic acidosis in order to familiarise themselves with the clinical presentation of this potentially fatal condition. the challenge is that the initial symptoms are often vague and nonspecific. the guidelines section (p. 25) is devoted to legal and ethical issues and is presented by elsabe klinck from the south african medical assocation. these issues are as important to comply with as any other aspects of treatment the broader aspects of the ethical issues in hiv medicine are highlighted in a thought-provoking article by or dave spencer (p. 15). this issue of the journal also features an interesting case study on the immune reconstitution syndrome by or david brittain. we aim to have similar illustrative case studies in all future issues. des martin editor, southern african journal of hiv medicine president, southern african hiv clinicians saciety to court not just once but an astounding four times over the past 2 years, and has wasted tens of thousands of taxpayer rands in legal fees. tragically, a number of seemingly innocent people have lost jobs in this province as a result of the same bizarre battle. we reported some months ago in this column that or thys von mollendorf, the medical superintendent who had allowed the ngo to operate within his hospital, was suspended. i was shocked to learn from recent newspaper reports that his suspension has not been lifted and that he practises in the area from a number of private practices. it would appear that the public sector, so much in need of good people, has lost someone valuable. if the only reason for his suspension is that he has allowed an ngo to provide for his patients what the rest of the world considers to be standard levels of health care, and what our constitutional court has ruled as part of basic human rights, then the wrong person has been punished. i believe that the medical fraternity needs to find a way to say this with one voice repeatedly and forcefully. unda-gail bekker managing editar references about the author(s) gary maartens division of clinical pharmacology, department of medicine, university of cape town, cape town, south africa citation maartens g. ‘covering the tail’ after stopping efavirenz-based antiretroviral therapy. s afr j hiv med. 2020;21(1), a1036. https://doi.org/10.4102/sajhivmed.v21i1.1036 editorial ‘covering the tail’ after stopping efavirenz-based antiretroviral therapy gary maartens copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. single-dose nevirapine for the prevention of mother-to-child transmission (pmtct) was associated with the development of non-nucleoside reverse transcriptase inhibitor (nnrti) resistance mutations in a high proportion of women because of nevirapine’s low genetic barrier to resistance. the hypothesis that dual nucleoside reverse transcriptase inhibitors (nrtis) given for a short period to ‘cover the tail’ of slowly declining nevirapine concentrations would reduce the risk of emergent nnrti resistance mutations was borne out by two randomised controlled trials of a single dose of tenofovir plus emtricitabine and 4–7 days of zidovudine plus lamivudine.1,2 the practice of ‘covering the tail’ then migrated to stopping nnrti-based combination antiretroviral therapy (art) started during pregnancy for pmtct, which was ‘option b’ in world health organization (who) guidelines for women who did not qualify for long term art based on cd4 count thresholds. ‘covering the tail’ was also recommended in guidelines, for all patients stopping nnrti-based art. is there evidence that ‘covering the tail’ after stopping nnrti-based art reduces the risk of developing nnrti resistance, and is the practice relevant in the era of art for all? in this edition of the journal, ajibola et al.3 suggest that ‘covering the tail’ after stopping efavirenz-based art might reduce the risk of developing nnrti resistance (please see https://doi.org/10.4102/sajhivmed.v21i1.1023). they conducted a retrospective study of women stopping efavirenz-based art started in pregnancy as ‘option b’ in botswana and found that women who received a week of tenofovir plus emtricitabine after stopping art had less nnrti resistance. however, their study findings just failed to achieve statistical significance, likely because of the small sample size. another problem with the study is that allocation to ‘covering the tail’ was not random. because of these study limitations, we still lack good evidence that that ‘covering the tail’ after stopping nnrti-based art reduces the risk of developing nnrti resistance. the rationale for ‘covering the tail’ after stopping nnrti-based art is that efavirenz and nevirapine have longer half-lives than the older nnrtis. however, data from a pharmacokinetic study question the need for ‘covering the tail’ with a regimen of tenofovir, emtricitabine and efavirenz: the half-lives of intracellular tenofovir-diphosphate and emtricitabine-triphosphate (the active drugs) is 164 and 39 h, respectively, compared with 92 h for plasma efavirenz.4 the half-life of efavirenz is variable, largely explained by polymorphisms in cyp2b6, which encodes the main metabolising enzyme: the prevalence of the cyp2b6 slow metaboliser genotype, which results in a longer efavirenz half-life, is about 20% in south africa.5 therefore, in order to rationally ‘cover the tail’ after stopping efavirenz-based art, the cyp2b6 metaboliser genotype should be known and an additional dose or two of emtricitabine should be given; however, emtricitabine is only available in the region co-formulated with tenofovir and genotype data are almost never known. there is no good pharmacokinetic rationale for ‘covering the tail’ with a week of tenofovir plus emtricitabine, which was recommended in the botswana paper. furthermore, the time to viral rebound after stopping art in patients who have achieved virologic suppression is variable, but typically takes weeks rather than days6 and is longer with nnrti-based art.7 finally, there is rarely a medical indication to interrupt art in the current era of art for all. for these reasons, the sa hiv clinicians society guidelines on art no longer recommend ‘covering the tail’ if art is interrupted. references chi bh, sinkala m, mbewe f, et al. single-dose tenofovir and emtricitabine for reduction of viral resistance to non-nucleoside reverse transcriptase inhibitor drugs in women given intrapartum nevirapine for perinatal hiv prevention: an open-label randomised trial. lancet. 2007;370(9600):1698–1705. https://doi.org/10.1016/s0140-6736(07)61605-5 mcintyre ja, hopley m, moodley d, et al. efficacy of short-course azt plus 3tc to reduce nevirapine resistance in the prevention of mother-to-child hiv transmission: a randomized clinical trial. plos med. 2009;6(10):e1000172. https://doi.org/10.1371/journal.pmed.1000172 ajibola g, maruapula d, rowley c, et al. ‘drug resistance after cessation of efavirenz-based antiretroviral treatment started in pregnancy. s afr j hiv med. 2020;21(1), a1023. https://doi.org/10.4102/sajhivmed.v21i1.1023 jackson a, moyle g, watson v, et al. tenofovir, emtricitabine intracellular and plasma, and efavirenz plasma concentration decay following drug intake cessation: implications for hiv treatment and prevention. j acquir immune defic syndr. 2013;62(3):275–281. https://doi.org/10.1097/qai.0b013e3182829bd0 sinxadi pz, leger pd, mcilleron h, et al. pharmacogenetics of plasma efavirenz exposure in hiv-infected adults and children in south africa. br j clin pharmacol. 2015;80(1):146–156. https://doi.org/10.1111/bcp.12590 treasure gc, aga e, bosch rj, et al. brief report: relationship among viral load outcomes in hiv treatment interruption trials. j acquir immune defic syndr. 2016;72(3):310–313. https://doi.org/10.1097/qai.0000000000000964 li jz, etemad b, ahmed h, et al. the size of the expressed hiv reservoir predicts timing of viral rebound after treatment interruption. aids. 2016;30(3):343–353. https://doi.org/10.1097/01.aids.0000499516.66930.89 ---------_f---------a time of celebration south africa breathed an audible sigh of relief last month when our cabinet finally agreed to a national antiretroviral roll out programme. apparently and correctly there is a real sense of urgency to translate this into numbers of people on treatment as soon as possible. this is in keeping with the world health organisation's target, expressed on 1 december this year, of 3 million people on antiretroviral treatment by 2005. the south african approval for roll out has been dependent on the provision of a plan that would be acceptable to government. happily this plan, formulated in record time by a task force headed up by or tony mbewu and with substantial input from the c1inton foundation experts, required only a readdressing of infrastructure support before being pronounced adequate. such a national plan, which has been based on who treatment guidelines, means that there will be conformity and consistency throughout the country and streamlines a number of logistic issues such as staff training, drug procurement, laboratory needs and evaluation procedures. this conformity is ideal as long as the implementation plan is based on perfect guidelines. we all know, however, that guidelines quickly become outdated and irrelevant unless they undergo revision as new data are gathered. however, there is a real danger that as one plan is adopted the input from a diversity of protocols and projects will be lost. in south africa, as we put our energy into the rollout of a single plan, we should continue to encourage and fund pilot sites that will test new or different strategies, such as different drug regimens, adherence strategies, monitoring schedules, or even treatment strategies such as intermittent therapy. logistics such as methods of drug and data management may also be varied. with adequate evaluation and assessment. lessons learnt from these pilot sites should then be used to modify the national programme appropriately and ensure that our practice does not become outdated and ineffectual. critical to the success of the national programme is an evaluation process that will quickly identify shortcomings in the programme and enable modifications to occur. it will also need to respond dynamically to changes in the epidemic such as changes in drug sensitivity, population targets, etc. evaluation should also be sensitive enough to allow quality assessment from site to site, again enabling real-time modification and improvement. an awesome task, but one that must happen and must succeed. how appropriate in this time of celebration that zackie and tac have been nominated for a nobel prize i we are immensely proud of this activist organisation. in contrast. one remembers how destructive and obstructive the early us and european activist community was. they appeared to be passionately opposed to everyone, especially the medical community. tac has worked with the medical community towards a common goal of care and treatment for the hiv-infected. i guess this has been one good outcome of a perceived obstruction from government it has united activists and the medical community in a common mission. tac, together with the aids lew project, has rationally and cleverly used the excellent laws and constitution of this country to move this agenda forward, both in terms of government policy and in relation to the pharmaceutical industry. the recent settlement with pharmaceutical companies on the competitions lew in this country is yet another example of putting good laws to constructive use and has resulted in benefit to the country as a whole. speaking of missions, wasn't it great to be united in music at the 413664 concert recently held at greenpoint stadium in cape town] how spectacular to see south africans really caring about the plight of the hn-infected, and to see some of those old (and a few new) rockers giving up time and energy to make a difference. it wasn't about the quality of the music, but the quality of feeling. as we look back on the past year in south africa, it is as usual astounding to note the water that has flowed under the proverbial bridge. i am reminded of a line in a one-person play that i saw in new york some years ago in which it was said that more happened in a day in israel than happened in a year in norway' south africa in its young democracy is a bit like the former but to the hn community the fact that treatment is on the cards is undoubtedly the most exciting. roll on 2004, when we will actually see the treatment happen and lives and communities be changed as a result. we wish all of our readers a most wonderful holiday season, and thank the staff at sama, des and the staff at the hiv clinicians society office for all their hard work, and also all the contributors to the journals this year we look forward to a torrent of articles, papers and contributions in the new year! keep them coming! unda-gail bekker managing editor the southern african journal of hiv medicine ---------november 2003 11 hiv0304pg000 the southern african journal of hiv medicine march 2004 7 challenges ahead ‘lack of access to antiretroviral therapy is a global health emergency. to deliver antiretroviral treatment to the millions who need it, we must change the way we think and change the way we act.’ wise words spoken by lee jong-wook, director general of the world health organisation. the 3 by 5 initiative was created by who because the six million people currently infected with hiv in the developing world need access to antiretroviral therapy to survive. only 400 000 people worldwide have this access. so who has set the targets at 3 million on treatment by 2005, and time is marching on. who has developed a strategic framework for this based on five pillars: ■ global leadership, strong partnership and advocacy ■ urgent sustained country support ■ simple standardised tools for delivery ■ effective reliable supply of medicines and diagnostics ■ rapidly identifying and reapplying new knowledge and successes. we have just returned from an antiretroviral meeting in dakar, senegal, a vibrant interesting city where there is clear evidence of political leadership and support in the area of hiv. health care professionals from west and central africa were keen to share experiences and discuss standardised strategies, and hungry for new knowledge and lessons learned. very exciting developments are taking place in so many countries. even in a country as battered as zimbabwe we were told of a number of projects already enabling people to receive art, and plans are in place for expansion. indeed, as we look back at more than a year of the usapho lwethu project in gugulethu, cape town, i am so excited. it can be done — we can deliver treatment, people will take drugs faithfully, lives can be turned around and the progression of this horrible disease halted. the challenge for us all now is how to do this on a much greater scale. we need 53 sites in south africa to be up and running in the next 6 months and 1.4 million hivinfected people to be on treatment by 2007 to meet government targets. there seems to be a hive of activity, but things will never move quickly enough, to which anyone who is hiv-infected and facing aids will bear testimony. there remains concern whether roll-out is happening at the same rate in all provinces — it is well known that some provinces have more to do than others, but there is no doubt that overall there is a huge amount of work to be done. pillar five is interesting and poses some challenges, since the field of hiv medicine is an incredibly fast moving one. no sooner is a paper or concept published than it is out of date. one needs to be on the conference circuit continuously to keep one step ahead of the most recent data. some interesting nevirapine data have recently come to light. a study published in the journal of the acquired immune deficiency syndrome describes a higher rate of severe hepatotoxicity in non-hiv-infected than in hiv-infected individuals, and the rate in the latter group was higher with higher cd4 counts. the study therefore recommended that the use of post-exposure regimens containing nevirapine should be discouraged.1 montaner and colleagues2 have published findings that the risk of serious hepatotoxicity may be increased in individuals coinfected with hepatitis b and c, abnormal liver enzymes at baseline or higher cd4 counts (> 350/µl).2 a worrying paper from the paris meeting by lyons et al.3 entitled ‘nevirapine tolerability in hiv-infected women in pregnancy — a word of caution’ indicates that there is a significant risk of nevirapineassociated hepatotoxicity in pregnant women, especially those with high cd4 cell counts, and that the progression to severe hepatoxicity may be explosive and not predicted by the patient’s enzyme level at baseline. the risk of nevirapine-related hepatotoxicity and rash, which seems to be caused by an acute and idiosyncratic hypersensitivity reaction, increased with increasing cd4 cell counts. hence women with cd4 counts > 250 and men with cd4 counts > 400 or persons with recent exposure to hiv and therefore relatively normal immune responses are at particular risk.3 for these reasons, the centers for disease control recommends against the use of nevirapine as postexposure prophylaxis.4 while the ‘once dosing’ regimen used in south africa for pmtct is unlikely to cause hepatotoxicity, the data also suggest that the use of nevirapine in patients and pregnant women with high cd4 counts may be problematic and it may be necessary to measure cd4 counts before commencing a long-term nevirapine-containing regimen. linda-gail bekker managing editor 1. serious adverse cutaneous an hepatic toxicities associated with nevirapine use by nonhiv-infected individuals. j acquir immune defic syndr 2004; 35(2): 120-125. 2. montaner js, hall d, carlier h, et al. analyses of four key clinical trials to assess the risk of hepatotoxicity with nevirapine: correlation with cd4 levels, hepatitis b and c seropositivity, and baseline liver function tests. can j infect dis 2001; 12: suppl b, 31b. 3. lyons f, hopkins s, mc geary a, et al. nevirapine tolerability in hiv-infected women in pregnancy — a word of caution. 2nd international aids conference on hiv pathogenesis and treatment, paris, 13-16 july 2003. abstract lb27. 4. serious adverse events attributed to nevirapine regimens for post exposure prophylaxis after hiv exposures worldwide, 1997-2000. mmwr 2001; 49: 1139-1156. h o r i z o n s awards aids law project of south africa honoured the awards for action on hiv/aids and human rights are presented by the canadian hiv/aids legal network and human rights watch, and sponsored by the international harm reduction development program, the hilda mullen foundation, and mark gallop. the canadian hiv/aids legal network lwww.aidslaw.ca) is a national organisation engaged in education, legal and ethical analysis, and policy development, with over 250 organisational and individual members from across canada and around the world. founded in 1992, the network promotes responses to hiv/aids that respect human rights; facilitates prevention efforts and access to care, treatment and support; minimises the adverse impact of hiv/aids on individuals and communities; and addresses the social and economic factors that increase vulnerability to hiv/aids and to human rights abuses. the network is an ngo in special consultative status with the united nations economic and social council and is a partner organisation of alp of south africa. its work has received national and international recognition, and the united nations joint program on hiv/aids has included the network's activities in the unaids collection of 'best practices: note: human rights watch (www.hrw.org) is an independen~ non-governmental organisation that conducts regular, systematic investigations of human rights abuses in some 70 countries around the world. its reputation for timely, reliable disclosures has made it an essential source of information for those concerned with human rights. human rights watch addresses the human rights practices of governments of all political stripes. of all geopolitical alignments, and of all ethnic and religious persuasions. it defends freedom of thought and expression, due process and equal protection of the law, and a vigorous civil society; it documents and denounces abuses of internationally recognised human rights. its goal is to hold governments accountable if they transgress the rights of their people. human rights watch began in 1978, and today includes divisions covering africa, the americas, asia and the middle east as well as three thematic divisions on arms, children's rights, and women's rights, and special programmes on business and human rights and hiv/aids. the organisation maintains offices in new york, washington, los angeles. london, brussels, moscow, and tashkent ----------tllf soutllfrn african journal of iliv meoicine ms liesl gerntholz, representing the aids law project ofsouth africa /ieft). along with rotfjorgens, executive director af the canadian hiv/aids legal network, and joanne csete of human rights watch (right). the aids law project co-founded the treatment action campaign [tac), chaired by zackie achmat, a former alp director. alp and tac led a coalition that took the south african government to court in 2002, leading to a ruling that requires the provision of antiretroviral drugs to pregnant women for the prevention of mother-to-child hiv transmission. tac and alp are also leading players in the grassroots movement that led to the recent announcement by the south african government that it would roll out an antiretroviral treatment plan after years of resisting the very idea of treatment for aids. on 12 september 2003 in montreal, the aids law project [alp), a pioneering organisation that helps combat hiv/aids by protecting the rights of the millions affected by the disease in south africa, was the recipient of the 2003 'award for action on hiv/aids and human rights' from the canadian hiv/aids legal network and human rights watch. alp has also been on the frontlines of the battle for the right of people with aids in south africa to have access to antiretroviral drugs. 'alp has steadfastly fought the irrationality of the south african government's stance on drugs for aids, and it has helped create a movement that will eventually win this struggle: said jurgens. 'the aids law project gives the world a model for combating aids by fighting stigma, discrimination, sexual violence and other gender-related abuses that fuel the epidemic: said ralf jurgens, executive director of the canadian hiv/aids legal network. novfmbfr 2003 thf southfhn african journal o~ hiv mfolcinf ---------alp has spearheaded communications efforts to inform the south african public of its rights with respect to hiv/aids. it has provided leadership on policy and legislation related to discrimination against people with aids, to protection of women and children from sexual violence, and to protection from mandatory hiv testing, among many other issues. it has also provided technical assistance on these and many other human rights issues to activists all over africa. 'alp's outstanding leadership addresses both the aids epidemic and the epidemic of human rights abuse that fuels aids in africa: said joanne csete, director of the hiv/aids programme at human rights watch. 'alp won't rest until people with aids in south africa and those at risk can live in dignitydr wan yanhai, recipient of last year's international award [while being detained by the chinese government), as well as stephen lewis, the un special envoy for hiv/aids in africa, participated in the awards ceremony in montreal. 'south africa has one of the worst hiv epidemics in the world; said mark heywood, director of alp. 'unfortunately, the fact that having hiv also means suffering serial human rights violations is often overlooked. for a decade the aids law project, and more recently organisations such as lac, have tried to change this. we have stood up for people's rights to employment, equality, education, dignity and treatment. receiving this award means a great deal to us: alp is part of the centre for applied legal studies at the university of witwatersrand. for more information about alp, visit http://www.aidslaw.ca/maincontent/awards.htm or www.alp.org.za/. novem9fh 2003 hiv0304pg000 march 2004 the southern african journal of hiv medicine 4 4 in no other field is the role of law and ethics as crucial as in the field of hiv/aids. health care professionals are in a unique situation, as both legal and ethical rules apply to a single hiv-related situation faced by them. legal and ethical rules sometimes overlap, but sometimes differ. the south african constitution and its bill of rights complicates matters further in that it is the highest law, and even ethical rules and rulings may be challenged as being justifiable limitations to human rights principles. perhaps the most well-known rule of medical ethics is ‘do no harm’. in south africa the health professions council has issued a variety of ethical rules and its professional boards have made various rulings further concretising the application of these ethical rules. this body of rules and rulings is supplemented by policy statements, such as the guidelines for the management of patients with hiv infection or aids and the policy document on undesirable business practices, which also contains various provisions on managed care. the following human rights play an important role for people living with hiv: ■ the right to (substantive) equality and nondiscrimination ■ the right to privacy (confidentiality) ■ the right to human dignity ■ the right to security of the person (to make informed decision about one’s body) ■ the rights of access to health care and access to social security (welfare and insurance) ■ the right of access to information. these rights do, however, also entail responsibilities. the right of access to health care implies the responsibility to take care of one’s own health and to follow the instructions of one’s practitioner; the right of access to social security in the form of health care funding implies the duty not to abuse benefits awarded by schemes. preand post-test counselling form an integral part of the process of obtaining informed consent from a patient. not only does it show respect for the physical integrity and human dignity of the patient, it prepares the patient for the potential outcome of a test and issues that may arise from such an outcome. a typical pre-test counselling session could include: ■ what the test is ■ how it is done ■ all advantages and disadvantages of undertaking a test and knowing the results ■ what a positive result means ■ what a negative result means ■ the chances and implications of an incorrect result ■ appropriate support structures available, etc. concerns on funding of further health care may also be high on a patient’s list of questions and should be addressed. some of the issues raised during such sessions may indeed necessitate legal support. practitioners may find it useful to have a list of support organisations and telephone numbers available for patients. post-test counselling should revisit the above points, and, in general, serve to facilitate patients’ decision-making on future health care. the health care options and effects of each need to be discussed, as well as the ongoing and longer-term health care planning of the patient. the national health act of 2003, which is not yet in force, sets the following prerequisites for informed consent: ■ the range of diagnostic procedures and treatment options available to the patient ■ the benefits, risks, costs and consequences generally associated with each option ■ the right to refuse services, but also the implications, risks and obligations accompanying such refusal. it also sets a whole new requirement in that where health services have been provided without consent, the provincial head of a health department must be informed of such fact within 47 hours. m e d i c o l e g a l hiv/aids, law and ethics: a brief analysis of some pertinent issues elsabé klinck director: research, compliance and counselling, foundation for professional development law and ethics counselling and informed consent human rights and responsibilities the southern african journal of hiv medicine march 2004 4 5 the requirement to obtain a patient’s informed consent may be disposed of where a law so authorises or a court so orders. the national health act of 2003 also authorises treatment without consent where failure to treat the patient will result in a serious risk to public health. this clause may, albeit unjustifiably, be used in the hiv setting. another contentious section involves circumstances in which it would be justifiable for a professional not to discuss a patient’s health status with him or her, i.e. if there is substantial evidence that the disclosure would be contrary to the best interests of the user. as these sections may indeed limit the rights of patients, both should be narrowly construed and applied. although not mandatory, it is advisable to obtain written consent. a typical consent form should include that the patient received the required information (listed in the document) and has understood such information, and that the patient provides his or her informed consent for the test and/or to be informed of the results thereof and/or treatment. if the form refers to treatment, the patient has to declare that s/he understands the requirements set in terms of compliance and the effects of the failure to comply. patients may also be requested to agree to the anonymous use of their data for purposes of practice profiling, epidemiological data or files-based research projects. needle-stick injuries remain a bone of contention. however, in the absence of legislation authorising testing without consent, if is submitted that the patient’s consent should be obtained, failing which post-exposure prophylaxis (pep) should be commenced. testing in the pre-operative setting should serve to protect the health care, and especially the postoperative health care decisions, of the patient. testing solely to ‘protect other health care workers’ may result in a false sense of security and a violation of ethics (acting in the best interest of the patient) and human rights (obtaining informed consent). a third contentious area is where patients have been tested accidentally. it is advisable to discuss the circumstances with the patient and explain the importance of knowing one’s hiv status. patients who are unwilling to undergo testing also present a particular difficulty to practitioners, especially where a practitioner strongly suspects that the patient is hivpositive. the clinical signs of hiv may be explained to the patient, but it may be advisable to get to the root of this unwillingness, if necessary by means of counselling. other unresolved areas include disclosing hiv status for a known sex partner, accessing medical scheme benefits and insurance products, and access to health care in the public sector. the well-known nevirapine case provides us with a good guideline on the issue of access to treatment in that the constitutional court ruled that if a medical practitioner is of the opinion that nevirapine is clinically indicated, it should be provided to the patient. patients living with hiv and whose rights are in jeopardy may be greatly assisted if practitioners fight to retain their clinical independence. contentious issues 857 update: arv dosing chart for children and adolescents, 2012 this edition of the southern african journal of hiv medicine includes a new antiretroviral drug dosing chart for children and adolescents (2012). the chart was updated by the southern african hiv clinicians society’s arv dosing committee,* a sub-group of the society’s child and adolescent committee, and the national department of health (doh). the purpose of the chart is to provide an accurate and reliable antiretroviral therapy (art) dosing guide for south african practitioners initiating and managing art in children and adolescents. the chart is intended for doctors, nurses and pharmacists working in the south african public sector. the 2012 chart serves to update both the antiretroviral drug dosing chart for children (2009), which was incorporated into the paediatric treatment guidelines of the doh (guidelines for the management of hiv in children1 ) in 2010, as well as the antiretroviral drug dosing chart for children (2011) which was adopted in the western cape province. the 2012 chart represents national paediatric treatment policy. in this latest revision, the following principles were considered: • continued use of the standardised world health organization (who) weight bands2 • provision of target doses or dose ranges (mg/kg or mg/m2 ) • use of who weight-band dosing recommendations, differing where necessary, based on characteristics of currently available antiretroviral (arv) drug formulations in the south african public sector, or local evidence-based practice, where possible • avoidance of dosing any arv drug below 90% of the target dose or dose range, or higher than 25% above the target dose or dose range, adjusting who-recommended dosing if indicated, and taking into account that younger children (beyond the neonatal period) may frequently require relatively higher doses to achieve drug exposures similar to those of older children and adults • where evidence is available, incorporation of the option of once-daily dosing for treatment simplification, to promote adherence and support harmonisation of paediatric and adult art regimens • incorporation of flexibility, wherever practical and available formulations allow, by providing both liquid and solid formulation dosing recommendations for up to a 25 kg body weight, while retaining the principle of moving children from liquid to solid formulations whenever possible • use of one formulation (either liquid or solid) for any given dose • avoidance of different morning and evening doses for a given drug, where possible • use of fractions of tablets (no less than half) only where available tablets are scored, and warning about which tablet formulations are film-coated and must be swallowed whole (not chewed, divided or crushed). significant revisions abacavir and lamivudine • dosing in the lower weight bands (<10 kg) was considered to be too high in relation to the principles described above, and has therefore been revised slightly to recommend 2 ml twice daily (bd) in the weight band 3.0 4.9 kg, and 3 ml bd in the weight band 5.0 6.9 kg. • a liquid formulation option is provided for ≤24.9 kg of body weight. whereas lamivudine tablets may be divided and, if necessary, crushed for easier ingestion by younger children, currently available abacavir tablets are film-coated and unscored and must be swallowed whole. this has necessitated the recommendation to use only the liquid formulation (in unavoidably large volumes) for the weight band 20.0 24.9 kg. • the option of once-daily dosing is provided for 10 kg and upwards. although there are no available clinical trial data involving children initiating art with once-daily dosing of abacavir and lamivudine, the inclusion of this dosing option is supported by pharmacokinetic studies on clinically stable children aged 3 12 years with low viral loads, who were switched from twice-daily to once-daily dosing.3 , 4 , 5 no treatment-limiting toxicity was reported and there was high acceptability and a strong preference for once-daily dosing among children and caregivers. this allows for the option of a once-daily treatment regimen for those children receiving efavirenz in combination with abacavir and lamivudine. lopinavir/ritonavir • dosing in the lower weight bands (<5 kg) was considered to be too high in relation to the principles described above. taking this into account and toxicity concerns, doses have been adjusted slightly to 1 ml (80 mg) bd for 3.0 4.9 kg and 1.5 ml (120 mg) bd for 5.0 9.9 kg. • the option of tablets in the 10.0 13.9 kg weight band has been removed as it is very unlikely that many children in this group would be able to swallow whole tablets, adding to the risk that caregivers may divide or crush these tablets, which must be avoided. • the dosing for ritonavir boosting with rifampicin-based tb treatment has been adjusted accordingly and simplified to a dose of 1.5 ml (previously 1.2 ml) for the weight band 5.0 9.9 kg. efavirenz • the 2012 chart recommends using 600 mg in children weighing >40 kg (the 2011 chart allowed for use of 600 mg above 35 kg).  didanosine • once-daily dosing has been adopted. other the 2012 chart also includes 2 additional warning statements: (i) avoid kaletra® (lpv/rtv) solution in any full-term infant aged <14 days and any premature infant aged <14 days after their due date of delivery (40 weeks post conception) or obtain expert advice. (ii) currently available tablet formulations of abacavir, efavirenz, lpv/rtv (aluvia®) and azt are film-coated and must be swallowed whole and not chewed, divided or crushed.  the chart is available for download on the society’s website: http://www.sahivsoc.org. a limited number of hard copies are available. to request a copy while there are supplies, email: child_adolescent@sahivsoc.org. james nuttall paediatric infectious diseases unit red cross war memorial children's hospital and university of cape town james.nuttall@uct.ac.za laurie schowalter southern african hiv clinicians society references 1. department of health. guidelines for the management of hiv in children, 2nd ed. pretoria: doh, 2010. http://www.sahivsoc.org/upload/documents/guidelines_for_management_of_hiv_in_children_2010.pdf (accessed 23 april 2012). 1. department of health. guidelines for the management of hiv in children, 2nd ed. pretoria: doh, 2010. http://www.sahivsoc.org/upload/documents/guidelines_for_management_of_hiv_in_children_2010.pdf (accessed 23 april 2012). 2. world health organization. antiretroviral therapy for hiv infection in infants and children: towards universal access. recommendations for a public health approach. 2010 revision. geneva: who, 2010. http://www.who.int/hiv/pub/paediatric/infants2010/en/index.html (accessed 23 april 2012). 2. world health organization. antiretroviral therapy for hiv infection in infants and children: towards universal access. recommendations for a public health approach. 2010 revision. geneva: who, 2010. http://www.who.int/hiv/pub/paediatric/infants2010/en/index.html (accessed 23 april 2012). 3. bergshoeff a, burger d, verweij c, et al. plasma pharmacokinetics of onceversus twice-daily lamivudine and abacavir: simplification of combination treatment in hiv-1-infected children (penta-13). antivir ther 2005;10(2):239-246. 3. bergshoeff a, burger d, verweij c, et al. plasma pharmacokinetics of onceversus twice-daily lamivudine and abacavir: simplification of combination treatment in hiv-1-infected children (penta-13). antivir ther 2005;10(2):239-246. 4. pharmacokinetic study of once-daily versus twice-daily abacavir and lamivudine in hiv type-1-infected children aged 3 <36 months. antivir ther 2010;15(3):297-305. 4. pharmacokinetic study of once-daily versus twice-daily abacavir and lamivudine in hiv type-1-infected children aged 3 <36 months. antivir ther 2010;15(3):297-305. 5. musiime v, kendall l, bakeera-kitaka s, et al. pharmacokinetics and acceptability of onceversus twice-daily lamivudine and abacavir in hiv type-1-infected ugandan children in the arrow trial. antivir ther 2010;15(8):1115-1124. 5. musiime v, kendall l, bakeera-kitaka s, et al. pharmacokinetics and acceptability of onceversus twice-daily lamivudine and abacavir in hiv type-1-infected ugandan children in the arrow trial. antivir ther 2010;15(8):1115-1124.   *the society convened a meeting of paediatric experts on 2 december 2011, chaired by professor mark cotton and dr tammy meyers. the chart principles and major changes were agreed upon at this meeting. a subcommittee of meeting participants, co-ordinated by laurie schowalter and comprised of dr moherndren archary, dr leon levin, dr james nuttall and liezl pienaar, worked in partnership with the national doh and paediatric essential drug list committee to finalise changes post meeting. the southern african journal of hiv medicine august 2004 47 the issue of funeral and estate planning should form part of hiv counselling, but this presupposes knowledge on the part of the counsellors/social workers/health care providers of basic legal principles underpinning the field of funeral and estate planning. moreover, funeral and estate planning is often grounded in culture and religion, and perceptions of death, after-life, care of those left behind (‘legacy’, ‘inheritance’, etc.), burial and burial ceremonies, etc. this also relates to family relationships and family organisational structures and goes beyond the particular patient or client who visits a health establishment, voluntary counselling and testing (vct) service or counselling service. there may be a need for a patient/client brochure on this, possibly translated into all the official languages. people should know the difference between dying testate (with a will) and intestate (without a will) and the implications thereof. this also ties in with marital property and the recognition of the rights of people in polygamous unions. the wills act of 1953 governs wills, and is important as it sets certain prerequisites for wills to be valid, including who may draft a will, who may witness it, and who may act as executor. it also deals with the effect of divorce and annulments on wills. the intestate succession act of 1987 deals with persons who die without a will and basically provides ‘rules’ as to what will happen with a person’s property in certain circumstances (e.g. whether person is survived by a spouse and/or parents and/or children, etc.). the administration of estates act of 1965 provides for a number of issues that may also involve family members of a person planning his or her estate, such as reporting the death to the master of the high court. people should also be aware that certain financial institutions may undertake ‘estate planning’ and may draft wills of a general nature to their clients, of which the client may sometimes not even have a copy. two other factors complicate the above system, i.e. (i) inheritance in terms of traditional indigenous/cultural/ religious systems and (ii) marriage and life partnerships. the matrimonial property act of 1984, most importantly the accrual system in terms of which after divorce or death ‘of one or both of the spouses, the spouse whose estate shows no accrual or a smaller accrual than the estate of the other spouse, or his estate if he is deceased, acquires a claim against the other spouse or his estate for an amount equal to half of the difference between the accrual of the respective estates of the spouses’. people should be able to establish whether they are married in or out of community of property. people who have registered their ‘marriages’ in terms of the recognition of customary marriages act of 1998 have to take specific heed of the property consequences regulated by section 7 of this act. women who are or were joined to a customary union as the second or further wife should be aware that the property consequences of their marriage will be or are governed by a contract set after application to a court of law. cohabitation is not governed by any south african law specifically as yet (the law commission is currently working on this), but people should be advised to ‘formalise’ their life/domestic partnerships by means of wills, the appointment of a partner and/or children as beneficiaries on their pension funds, life insurance policies, and setting agreements to deal with issues such as care of children after death, etc. the maintenance of surviving spouses act of 1990 has as its objective to provide the surviving spouse in certain circumstances with a claim for maintenance against the estate of the deceased spouse, and from it some cases have been decided by our courts on who would qualify as a ‘spouse’. certain pension or provident funds make provision for funeral and/or surviving spouses/partner benefits. patients/clients should be encouraged to find out what the elsabé klinck director: research, compliance and counselling, foundation for professional development l e g a l funeral and estate planning for people living with hiv/aids some preliminary points estate planning and applicable legislation pension funds and employee benefits benefits and exclusions are in terms of hiv/aids and in terms of disability, funerals, etc. this could be done via trade union representatives, who often sit as trustees of pension/provident funds. the promotion of equality act (mentioned below) may also be applicable in cases of alleged unfairness in terms of hiv-related benefits. specific laws, such as those applicable to the police services and the military, provide for (limited and restricted) funeral assistance. the following is an extract from the sama hiv human rights and ethics guidelines. medical practitioners are often approached to fill out forms relating to a patient’s hiv status or whether he or she underwent an hiv test. the same ethical principle applies, i.e. patient information is confidential. life insurance, burial policies, etc. often become problematic when a person who has been living with hiv dies or when the company suspects that the insured person may be hiv-positive. the primary contract is between the policyholder and the insurance company. the medical practitioner may only make medical details known if the insurance company can provide the medical practitioner with a copy of a document in which the patient has provided informed consent that his/her medical details may be released to the insurer. failing that, the medical practitioner should only write ‘confidential information’ in the spaces provided and/or use the example above in relation to third-party requests as a response to the requesting company. if the insured person has died, the next of kin may consent to the disclosure of the medical information. where the policyholder and the insured person are not the same, the insured person should provide informed consent before medical details are disclosed. the medical practitioner should not take the responsibility for disclosing medical information where an insurance company has not provided sufficient safeguards to protect its own financial viability based on actuarial reasons. these safeguards should take the form of contracts with (prospective) policyholders. case law has affirmed the duty placed on an insured person to disclose ‘material facts’, based on section 59 of the long-term insurance act of 1998. the question is whether the (mis)representation would have materially affected the assessment of risk at the time of issue of the policy, objectively spoken (joubert v. absa life, 2001). many insurance companies do not provide cover if a person tests positive. insurance companies should adhere to all the principles of hiv testing, i.e. pre-test counselling, informed consent, post-test counselling and confidentiality. this becomes the duty of the medical practitioners involved in testing for insurance purposes. sama believes that blanket consent provided for insurance purposes does not conform to the principles of informed consent. the promotion of equality and prevention of unfair discrimination act of 2000 contains, inter alia, in the illustrative list of unfair. included is the insurance sector ‘unfairly disadvantaging a person or persons, including unfairly and unreasonably refusing to grant services to persons solely on the basis of hiv/aids status’. patients may approach any magistrate’s court with complaints against insurers if they suspect unfair treatment based on their hiv status. the following is an extract from the sama hiv human rights and ethics guidelines. new regulations on death notifications were passed in 1998. the new death certificate has two pages, which are detachable. it is for authorisation of burial by the department of home affairs. it is used to issue the death certificate. on this page the cause of death can only be indicated as ‘natural’ or ‘unnatural’ and no underlying causes are indicated. this is the page the family sees. this page has to be detached from the second. the second page should be placed in a sealed envelope which is then stapled to the first page before handing it to the undertaker and/or family. undertakers are empowered by law to handle these documents and bound by the same confidentiality as medical practitioners. the second page is confidential and is used by the state (department of home affairs) to collect data. on this the medical cause of death, which may include reference to hiv status, must be indicated. insurance companies have no right to demand these two pages or copies thereof. if they need a medical report, irrespective of whether it relates to a natural or an unnatural cause of death, it should be requested from the relevant doctors with the necessary supporting documents of consent. important contact numbers: • short-term insurance long-term insurance ombudsperson ombudsperson po box 30619 po box 45007 braamfontein, 2017 claremont, 7735 tel.: (011) 726-8900 tel.: (021) 674-0330 fax (011) 726-5501 fax (021) 674-0951 august 2004 the southern african journal of hiv medicine 48 long-term insurance and funeral policies death notifications abstract introduction case report discussion conclusion acknowledgements references about the author(s) bryan a. ogoti department of anaesthesia, faculty of medicine, university of nairobi, nairobi, kenya angela a. otedo department of medical services, avenue healthcare, nairobi, kenya thomas m. chokwe department of anaesthesia, faculty of medicine, university of nairobi, nairobi, kenya citation ogoti ba, otedo aa, chokwe tm. paediatric antiretroviral overdose: a case report from a resource-poor area. s afr j hiv med. 2020;21(1), a1094. https://doi.org/10.4102/sajhivmed.v21i1.1094 case report paediatric antiretroviral overdose: a case report from a resource-poor area bryan a. ogoti, angela a. otedo, thomas m. chokwe received: 23 apr. 2020; accepted: 08 may 2020; published: 21 july 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract introduction: toxic side effects from antiretroviral overdose in children have not been widely reported. antiretroviral drugs are widely used as oral medications throughout sub-saharan africa. patient presentation: we describe the clinical presentation and management of a 3-year-old male in rural kenya, who accidentally overdosed on abacavir/lamivudine combination pills. the number of pills taken was approximately 250 tablets, that is 15 g of abacavir and 7.5 g of lamivudine. he presented 24 hours later to homabay county referral hospital, with unresponsiveness, inability to feed and absence of playfulness. physical examination revealed a sick-looking, ‘unconscious’ child, responding only to voice, with tachycardia, hypertension and moderate dehydration. management and outcome: he was managed conservatively with rehydration, namely intravenous 1125 ml of 5% dextrose in 0.9% saline, and the monitoring of his neurologic status, urine output and all vital signs. he regained normal neurological function after 24 hours, and recovered uneventfully, but was lost to follow-up. conclusion: in an area endemic for hiv and where antiretroviral drug use is commonplace, there is a need for health education to ensure that parents keep drugs out of the reach of children. in the case of a suspected overdose, parents need to be reminded to seek medical attention immediately. physician awareness of the clinical presentation, management and challenges with an antiretroviral drug overdose is also important. keywords: antiretroviral; abacavir; lamivudine; poisoning; overdose; paediatrics; resource-poor. introduction antiretroviral therapy has changed infection with hiv from a fatal illness to one that is manageable.1 according to the unaids report of 2019, 61% of new hiv infections are in sub-saharan africa where the incidence in kenya is 1.02 per 1000 persons, and the overall prevalence is 4.7%. antiretroviral drugs are used by 91% of pregnant kenyan women living with hiv, 61% of infected children are on treatment and the number of aids-related deaths is now declining.2 despite the widespread use of antiretroviral drugs (arvs), paediatric overdose-related toxicity remains unreported in resource-poor settings. in 2018, van dam et al. described an adult parasuicide with dolutegravir/abacavir/lamivudine that resulted in lactic acidosis and hypokalemia. this was managed with intravenous fluids, potassium supplementation, the monitoring of drug levels and blood chemistries.3 a second adult parasuicide-overdose with dolutegravir/tenofovir/emtricitabine has also been reported.4 in this report the patient had a minor airway obstruction and required monitoring in an intensive care unit. abacavir and lamivudine are arvs that are well absorbed orally.5 abacavir is metabolised in the liver, but lamivudine is excreted unchanged in urine. nausea, vomiting, diarrhoea, cough, fever and fatigue are side effects of both drugs.5,6 we report a case of suspected abacavir/lamivudine toxicity managed conservatively in a resource-poor setting. we highlight the scarcity of information and the challenges faced. case report a 3-year-old male from rural kenya, weighing 12.5 kg, was admitted to the paediatric ward of the homabay county referral hospital. this was 24 hours after ingesting four and a half bottles of abacavir 600 mg/lamivudine 300 mg combination pills prescribed for his stepbrother. each bottle contained 60 tablets, that is, a total of 250 tablets or 15 g of abacavir and 7.5 g of lamivudine. he had been playing unattended when he ingested the tablets and afterwards appeared well and as playful as usual. he did not have a fever, rash, diarrhoea, vomiting or difficulty with breathing that would have suggested an abacavir hypersensitivity reaction. there was no report of confusion, drowsiness or seizures. he ate and slept well but the next morning was drowsy, unable to walk and feed. he arrived looking sick, lethargic and responding only to voice commands. his airway was intact and breathing and circulation were normal. there was no pallor, jaundice, cyanosis or oedema. the eyes were sunken and the skin turgor was reduced suggesting moderate dehydration. he had a tachycardia of 156/min, a respiratory rate of 27/min, spao2 of 99% – 100%, an elevated blood pressure of 131/78 mmhg. his temperature was 37.1°c. physical examination was unremarkable and all systems were normal. blood glucose and full hemogram were normal. his hiv test was negative. serum drug levels, renal and other metabolic tests were unavailable. the child was admitted to the acute room and re-hydrated as per the holliday-segar method, with 1125 ml of dextrose 5% in 0.9% sodium chloride over 24 h. vital signs and urine output were monitored hourly. activated charcoal and gastric lavage were omitted because of the late presentation. there was improvement within 24 h. he became ambulant, fed orally and his urine output normalised. he was discharged after 24 hours of observation. the child’s mother was counselled and advised on the safe handling of household poisons.the stepbrother’s prescription was refilled. she was single, uneducated and unemployed. she avoided discussions around paternity, marital status and hiv status. she provided no reliable contacts and never returned for follow-up. ethical consideration this article followed all ethical standards for research without direct contact with human or animal subjects. discussion abacavir and lamivudine are commonly used in treating children with hiv. they are well absorbed orally with short half-lives of about 2 hours. while abacavir is metabolised in the liver, lamivudine is excreted unchanged in the urine. nausea, vomiting, diarrhoea, cough, fever and fatigue are side effects of both drugs.5,6 they cause fatigue, and this patient had lethargy with altered consciousness. hypersensitivity to abacavir was absent.7 therapeutic daily paediatric doses of abacavir and lamivudine are 16 mg/kg and 10 mg/kg, not exceeding 600 mg and 300 mg per day.7 individual doses are weight-adjusted at clinics and dispensed incrementally to reduce toxicity. the doses taken in this case far exceeded the recommended upper limit. there is no known antidote for overdose. management is supportive, and ideally the patient should be admitted to a high dependency unit for continuous monitoring of urine output, neurologic status and vital signs. liver and renal function tests, with abacavir/lamivudine levels would immediately be useful to assess excretion.8,9 lamivudine is dialysable,10 but dialysis was unavailable. the two drugs are bases and urinary alkalinisation would fail. these resources were unavailable, but he nevertheless recovered well. the few reports of adult antiretroviral overdose recommend supportive management, including intensive care. although applicable to children, resources are often scarce. the temporal relationship between drug ingestion and presentation with signs and symptoms suggested overdose toxicity. the scarcity of investigational resources makes it difficult to be certain this was the cause of the patient’s clinical presentation. fatal overdoses have reduced since the introduction of child-resistant containers.9 these containers should have been used. parental education on safe storage of medications away from children can prevent such cases. inadequate maternal education likely resulted in this child’s mother being poorly informed on the proper handling of household poisons. the mother and child were lost to follow-up making it difficult to know whether the education provided to the mother had impacted on safe practices in the home. conclusion there is limited awareness of arv overdose toxicity in children, its social factors, and management options in resource-poor settings. antiretroviral drugs are supplied orally for prolonged periods, reducing mortality and hiv transmission. the potential for accidental overdosing remains and parental education must include the safe storage and handling of arvs in the home. acknowledgements the authors wish to thank dr antony gatheru and prof. otieno c.f. of the university of nairobi for taking their time to review and intellectually critique the article prior to submission. competing interests the authors declare that they have no financial or personal relationships that might have inappropriately influenced them in writing this article. authors’ contributions all authors contributed equally to this work. funding information the authors did not receive financial support for the research, authorship, or publication of this article. data availability statement data sharing is not applicable to this article, as no new data were created or analysed in this study. disclaimer the authors declare that the views expressed in the submitted article are their own and not an official position of the their affiliate institutions. references margolis am, heverling h, pham pa, stolbach a. a review of the toxicity of hiv medications. j med toxicol [serial online]. 2014 [cited 2019 aug 17];10(1):26–39. https://doi.org/10.1007/s13181-013-0325-8 joint united nations programme on hiv/aids (unaids). unaids data 2019. geneva: joint united nations programme on hiv/aids; 2019. van dam pmel, van geffen mwl, havenith tra, posthouwer d. intentional overdose of dolutegravir/abacavir/ lamivudine (triumeq) in a 26-year-old man. antivir ther. 2018;23(6):549–552. https://doi.org/10.3851/imp3229 blanch j, corbella b, garcıa f, parellada e, gatell jm. manic syndrome associated with efavirenz overdose. clin infect dis. 2001;33(2):270–271. https://doi.org/10.1086/321828 volberding pa. overview of antiretroviral therapy. in: volberding pa, sande ma, lange j, greene wc, gallant j, editors. global hiv/aids medicine. new york: elsevier saunders, 2008; p. 135–160. national aids & sti control programme. guidelines on use of antiretroviral drugs for treating and preventing hiv infection in kenya [homepage on the internet]. c2016 [updated 2016 jul; cited 2020 jan 08]. available from: https://aidsfree.usaid.gov/sites/default/files/kenya_art_2016.pdf nolan d, mallal s, reiss p. prevention, diagnosis and treatment of hiv infection. in: volberding pa, greene wc, lange jma, gallant je, sewankambo n, editors. sande’s hiv/aids medicine medical management of aids in 2012. elsevier saunders, 2012; p. 178–179. francis jd. clinical approach to the poisoned patient. in: shaw lm, kwong tc, magnani b, rosano tg, editors. the clinical toxicology laboratory: contemporary practice of poisoning evaluation. washington, dc: aacc press, 2001; p. 27–33. penny l, moriarty t. poisoning in children. bja educ [serial online]. 2009 [cited 2020 mar 15];9(4):109–113. available from: science direct electronic medicines compendium. lamivudine [homepage on the internet]. c1999 [updated 2018 jun 24; cited 2020 apr 12]. available from: https://www.medicines.org.uk/emc/product/4383/smpc hiv 852 case report acute generalised exanthematous pustulosis secondary to cotrimoxazole or tenofovir j black, r kruger, r roberts, r lehloenya, m mendelson   division of infectious diseases and hiv medicine, department of medicine, faculty of health sciences, university of cape town and groote schuur hospital, cape town j black, mb chb, fcp (sa), dip hiv man (sa) m mendelson, bsc, phd, mbbs, frcp (uk), dtm&h   division of dermatology, department of medicine, faculty of health sciences, university of cape town and groote schuur hospital, cape town r kruger, mb chb, fcderm (sa) r lehloenya, bsc, mb chb, fcderm (sa)   department of clinical laboratory sciences, division of anatomical pathology, university of cape town and national health laboratory service, groote schuur hospital, cape town r roberts, mb chb corresponding author: j black (docjohnblack@gmail.com) cutaneous adverse drug reactions are a common complication of antiretroviral therapy and of drugs used to treat opportunistic infections. we present a rare case of acute generalised exanthematous pustulosis secondary to cotrimoxazole or tenofovir. s afr j hiv med 2012;13(4):198-200. doi:10.7196/sajhivmed.852 cutaneous adverse drug reactions (cadrs) are a common complication of antiretroviral therapy (art) and of drugs used to treat opportunistic infections.1 the common clinical manifestations range from mild maculopapular eruptions to the more severe recognised spectrum of stevens-johnson syndrome (sjs), toxic epidermal necrolysis (ten) and drug reaction with eosinophilia and systemic symptoms (dress). occasionally, however, a rare manifestation of cadr occurs which presents a diagnostic dilemma. case report a 24-year-old south african woman was newly diagnosed with disseminated culture-positive tuberculosis (tb) and hiv. her cd4 count was 77 cells/mm3 and she had no prior tb history (including contacts). the patient was initiated on rifafour, and cotrimoxazole prophylaxis was started 9 days later. after a further 2 weeks, art was initiated (tenofovir (tdf), lamivudine and efavirenz). one month after art initiation, the patient presented with sudden-onset generalised, pustular, itchy rash, associated with 1 week of fatigue, nausea, vomiting and painful feet. she had renal impairment (creatinine 521 µmol/l) and was anaemic (haemoglobin 6.1g/dl). treatment with tdf, cotrimoxazole and rifampicin was ceased, and the patient was referred for further assessment. on examination, she was tachycardic but apyrexial. she had a widespread pustular rash sparing the palms and soles (fig. 1). pustules were <5 mm in size and monomorphic on an erythematous background, with areas of desquamation on the lower limbs. she had no mucous membrane involvement, but had manifested angular cheilitis and oral candidiasis. tender hepatomegaly and painful, peripheral sensory neuropathy were noted. a b fig. 1(a and b). acute generalised exanthematous pustulosis. a pus swab from one of the lesions showed neutrophils, but gram-stain and culture testing were both negative. testing of a pustule aspirate for varicella zoster virus by polymerase chain reaction (pcr) was also negative. blood, urine and sputum bacterial cultures were negative, as was syphilis serology, serum cryptococcal latex antigen test and hepatitis b serology. in addition to anaemia, the patient had a leucocytosis of 11.5 x 10^9 /l (93% neutrophils), but her platelet count was normal. she was hypo-albuminaemic (19 g/l) with mild liver dysfunction (total bilirubin 23 µmol/l, alkaline phosphatase 171 u/l, gamma-glutamyl transferase 111 u/l, alanine transaminase 34 u/l and aspartate transaminase 58 u/l). a chest x-ray showed diffuse bi-basal nodularity. necrotic lymph nodes and multiple splenic hypodensities, suggestive of abdominal tb, were evident on abdominal ultrasound. two days after admission, treatment with abacavir was started to replace tdf, and the patient was started on acyclovir, pending the results of investigations. rifampicin was re-introduced on day 4. her rash had considerably improved after 8 days and her creatinine level diminished to 303 µmol/l. renal biopsy was delayed due to the overlying skin lesions. histopathology of a skin biopsy on admission showed basket-weave hyperkeratosis, spongiosis and an intracorneal pustule, containing neutrophils and occasional lymphocytes (fig. 2). small cocci were noted within the pustule and a mild superficial perivascular lymphocytic infiltrate was present. superficial dermal vessels were mildly dilated and contained marginated neutrophils. special stains for fungi and acid-fast bacilli were negative and no granulomas, dysplastic or malignant cells were found. a histopathological diagnosis of acute generalised exanthematous pustulosis (agep) was made. multi-drug resistant tb (mdr-tb) was subsequently diagnosed on the basis of a urine culture (sampled on admission) and her tb regimen was altered. she was discharged with a clinical diagnosis of acute kidney injury secondary to tdf, disseminated mdr-tb, and agep most likely secondary to cotrimoxazole or tdf. she has had a good clinical response and, at the time of writing, remains in care 7 months post discharge. a b fig. 2. (a) intracorneal pustule (x20) containing (b) neutrophils and occasional lymphocytes (x200). discussion agep is an uncommon severe cutaneous reaction associated with drug exposure in 90% of cases. the remaining 10% of cases have been attributed to viral infections, vaccines, spider bites, heavy metal exposure, chemotherapy and radiation.2 the reaction has a mortality rate of 2%, typically occurring in the elderly with co-morbidities, and is related to septic complications.2 a wide spectrum of pustular skin diseases forms the differential diagnosis, including pustular psoriasis, sweet’s syndrome (acute febrile neutrophilic dermatosis), pustular erythema multiforme, ten, dress and bullous impetigo.2 , 3 in our patient, disseminated varicella was also considered. the combination of clinical and histological features together with appropriate drug exposure is usually enough to make the diagnosis of agep.2 , 3 to date, a single case of agep has been described in an hiv-infected patient with a cd4 count of 220 cells/mm3 , attributed to boosted darunavir, which recurred on atazanavir re-challenge.5 protease inhibitors (indinavir and boosted lopinavir) have also been implicated in agep in patients receiving post-exposure prophylaxis.6 , 7 nucleoside/nucleotide reverse transcriptase inhibitors have not been implicated as causal agents. however, there are case reports of agep following cotrimoxazole treatment in hiv-negative patients.8 , 9 the pathophysiology of agep involves drug-specific t cell activation by dendritic cells followed by t cell expansion and migration to the dermis and epidermis. the t cells are activated to produce high levels of neutrophil-attracting chemokine (cxcl8) and express a type 1 t-helper (th-1) cytokine profile (granulocyte-macrophage colony-stimulating factor, interferon gamma and tumour necrosis factor-alpha). stimulated keratinocytes recruit t cells and neutrophils to the inflamed skin. drug-specific cytotoxic cd8 t cells are responsible for killing keratinocytes and for vesicle formation, while neutrophils migrate along the cxcl8 gradient into the vesicles to form pustules.2 in the case described here, the delayed presentation following initiation of cotrimoxazole, the most likely causative agent, may have been attributed to reduced drug-specific t cell activation in advanced hiv disease. characteristic features of agep include an acute generalised cutaneous eruption of whitish non-follicular, sterile pustules <5 mm in size and on a background of erythema, which may be accompanied by a burning sensation. lesions often start on the face or intertrigenous areas, moving to the trunk and limbs within a few hours. the reaction rarely affects the palms and soles and has mucous membrane involvement in only 20% of cases. half of affected patients may report other skin symptoms. the rash lasts for a mean of 9.4 days (range 4 10), followed by desquamation. the rash is accompanied by a fever >38°c that lasts for approximately 1 week.3 the onset of rash follows 2 distinct patterns: (i) a rapid onset after drug ingestion (a few hours to 2 3 days) which is most commonly associated with antibiotics and may signify previous sensitisation; and (ii) an onset after 1 3 weeks (mean 11 days), which may result from primary sensitisation.3 , 4 a neutrophilia occurs in 90% of cases, while up to 30% have mild eosinophilia. renal dysfunction (predominantly pre-renal) occurs in one-third of cases. rarely, hypocalcaemia and a mild elevation in amino-transferases have been observed.2 , 3 the skin biopsy is characterised by spongiform subcorneal or intradermal pustules, papillary oedema and neutrophilic perivascular infiltrates.2 , 3 when there is doubt over the causal agent, and there are no alternative therapeutic agents, confirmatory tests may be performed under specialist supervision: • drug provocation testing: although the gold standard for cadr, this is contra-indicated in agep.10 • patch testing: although this has only a 50% sensitivity and 85% specificity, it is the best available test for practical reasons.2 • the lymphocyte transformation test (ltt): requires a specialised laboratory, but has an improved sensitivity of 78% with varying specificity.2 treatment of agep is symptomatic, with withdrawal of treatment with the offending drug. antibiotics are not indicated unless secondary infection occurs. corticosteroid treatment has been used, but is not required in the majority of cases.3 conclusion this case highlights a rare adverse drug reaction that can occur in hiv-infected patients and is an important differential diagnosis of a pustular eruption. antibiotics are the most common causative agents, and protease inhibitors are the most commonly implicated art drugs. early recognition and drug withdrawal are vital. if drug re-challenge is required, this should be done under specialist supervision. acknowledgments. mm receives support from the president’s emergency plan for aids relief (pepfar)/united states agency for international development (usaid) through anova healthcare. references 1. coopman sa, johnson ra, platt r, stern rs. cutaneous disease and drug reactions in hiv infection. n engl j med 1993;328:1670-1674. [http://dx.doi.org/10.1056/nejm199306103282304] 1. coopman sa, johnson ra, platt r, stern rs. cutaneous disease and drug reactions in hiv infection. n engl j med 1993;328:1670-1674. [http://dx.doi.org/10.1056/nejm199306103282304] 2. speeckaert mm, speekaert r, lambert j, brochez l. acute generalized exanthematous pustulosis: an overview of the clinical, immunological and diagnostic concepts. eur j dermatol 2010;20(4):425-433. [http://dx.doi.org/10.1684/ejd.2010.0932] 2. speeckaert mm, speekaert r, lambert j, brochez l. acute generalized exanthematous pustulosis: an overview of the clinical, immunological and diagnostic concepts. eur j dermatol 2010;20(4):425-433. [http://dx.doi.org/10.1684/ejd.2010.0932] 3. sidoroff a, halevy s, bavinck jn, vaillant l, roujeau jc. acute generalized exanthematous pustulosis (agep) – a clinical reaction pattern. j cutan pathol 2001;28:113-119. [http://dx.doi.org/10.1034/j.1600-0560.2001.028003113.x] 3. sidoroff a, halevy s, bavinck jn, vaillant l, roujeau jc. acute generalized exanthematous pustulosis (agep) – a clinical reaction pattern. j cutan pathol 2001;28:113-119. [http://dx.doi.org/10.1034/j.1600-0560.2001.028003113.x] 4. sidoroff a, dunant a, viboud c, et al. risk factors for acute generalized exanthematous pustulosis (agep) – results of a multinational case-control study (euroscar). br j dermatol 2007;157:989-996. [http://dx.doiorg/10.1111/j.1365-2133.2007.08156.x] 4. sidoroff a, dunant a, viboud c, et al. risk factors for acute generalized exanthematous pustulosis (agep) – results of a multinational case-control study (euroscar). br j dermatol 2007;157:989-996. [http://dx.doiorg/10.1111/j.1365-2133.2007.08156.x] 5. bourkia m, charlès l, lambotte o, orostegui-giron l, goujard c, ghosn j. life-threatening acute generalized exanthematous pustulosis induced by two different protease inhibitors in an hiv-1-infected patient. j antimicrob chemother 2011;66(9):2188-2189 [http://dx.doi.org/10.1093/jac/dkr227] 5. bourkia m, charlès l, lambotte o, orostegui-giron l, goujard c, ghosn j. life-threatening acute generalized exanthematous pustulosis induced by two different protease inhibitors in an hiv-1-infected patient. j antimicrob chemother 2011;66(9):2188-2189 [http://dx.doi.org/10.1093/jac/dkr227] 6. aquilina c, viraben r, roueire a. acute generalized exanthematous pustulosis: a cutaneous adverse effect due to prophylactic antiviral therapy with protease inhibitor. arch intern med 1998;158:2160-2161. 6. aquilina c, viraben r, roueire a. acute generalized exanthematous pustulosis: a cutaneous adverse effect due to prophylactic antiviral therapy with protease inhibitor. arch intern med 1998;158:2160-2161. 7. ghosn j, duvivier c, tubiana r, et al. acute generalized exanthematous pustulosis induced by hiv postexposure prophylaxis with lopinavir-ritonavir. clin infect dis 2005;41(9):1360-1361. [http://dx.doi.org/10.1086/497075] 7. ghosn j, duvivier c, tubiana r, et al. acute generalized exanthematous pustulosis induced by hiv postexposure prophylaxis with lopinavir-ritonavir. clin infect dis 2005;41(9):1360-1361. [http://dx.doi.org/10.1086/497075] 8. lee i, turner m, lee cc. acute patchy exanthematous pustulosis caused by sulfamethoxazole-trimethoprim. j am acad dermatol 2010;63(2):e41-e43 [http://dx.doi.org/10.1016/j.jaad.2009.11.008] 8. lee i, turner m, lee cc. acute patchy exanthematous pustulosis caused by sulfamethoxazole-trimethoprim. j am acad dermatol 2010;63(2):e41-e43 [http://dx.doi.org/10.1016/j.jaad.2009.11.008] 9. anliker md, wüthrich b. acute generalized exanthematous pustulosis due to sulfamethoxazol with positive lymphocyte transformation test (ltt). j investig allergol clin immunol 2003;13(1):66-68. 9. anliker md, wüthrich b. acute generalized exanthematous pustulosis due to sulfamethoxazol with positive lymphocyte transformation test (ltt). j investig allergol clin immunol 2003;13(1):66-68. 10. aberer w, bircher a, romano a, et al. drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. allergy 2003;58:854-863. [http://dx.doi.org/10.1034/j.1398-9995.2003.00279.x] 10. aberer w, bircher a, romano a, et al. drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations. allergy 2003;58:854-863. [http://dx.doi.org/10.1034/j.1398-9995.2003.00279.x] abstract introduction discussion acknowledgements references about the author(s) josephine keal empilweni services and research unit, rahima moosa mother and child hospital, department of paediatrics and child health, faculty of health sciences, university of the witwatersrand, johannesburg, south africa ahmad h. mazanderani centre for hiv and stis, national institute for communicable diseases, national health laboratory service, johannesburg, south africa nicola van dongen empilweni services and research unit, rahima moosa mother and child hospital, department of paediatrics and child health, faculty of health sciences, university of the witwatersrand, johannesburg, south africa gillian sorour empilweni services and research unit, rahima moosa mother and child hospital, department of paediatrics and child health, faculty of health sciences, university of the witwatersrand, johannesburg, south africa karl-gunter technau empilweni services and research unit, rahima moosa mother and child hospital, department of paediatrics and child health, faculty of health sciences, university of the witwatersrand, johannesburg, south africa citation keal j, mazanderani ah, van dongen n, sorour g, technau k-g. false-positive rapid diagnostic tests in paediatric and obstetric patients in south africa. s afr j hiv med. 2021;22(1), a1186. https://doi.org/10.4102/sajhivmed.v22i1.1186 research project registration: project number: r14/49 case report false-positive rapid diagnostic tests in paediatric and obstetric patients in south africa josephine keal, ahmad h. mazanderani, nicola van dongen, gillian sorour, karl-gunter technau received: 27 oct. 2020; accepted: 09 dec. 2020; published: 29 jan. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract introduction: providing easily accessible, quick and accurate human immunodeficiency virus (hiv) testing services (hts) is central to achieving the joint united nations programme on hiv/aids (unaids) 90-90-90 targets. rapid diagnostic tests (rdts) for hiv are affordable and technically easy to perform. two positive rdts from different manufacturers are required to make a diagnosis of hiv in south africa. difficulty arises when there are discordant results from the two kits. in this case report, we will discuss four instances of false-positive rdts. patient presentation: case 1 is a 10-year-old female, referred for initiation of antiretroviral treatment (art). she was diagnosed using two of the same brand rdt at her local clinic. case 2 is a 21-year-old female who presented to obstetric admissions in labour. case 3 is a 39-year-old female who was screened for hiv during a routine antenatal appointment. case 4 is a 22-year-old female who was admitted 21 days postpartum with puerperal sepsis. all four cases had discordant rdts when screened for hiv at our facility. management and outcome: the results of all the investigations conducted on all four patients confirmed hiv negative status. the reference laboratory verified the results and reran the rdts, which remained discordant. this confirmed a false-positive result in all four cases with the screening rdt. conclusion: with high numbers tested and a low yield of new cases, each individual case of discordancy may cause unnecessary distress, confusion and treatment, particularly in high-risk scenarios like pregnancy. trends of false-positive and discordant rdt results should be monitored and inform hts guidelines. keywords: hiv; rapid diagnostic test; discordant; diagnostic dilemmas; pregnancy. introduction accessible, quick and accurate human immunodeficiency virus (hiv) testing services (hts) are imperative to achieving the joint united nations programme on hiv/aids (unaids) 90-90-90 targets.1 paediatric and obstetric hts are particularly important entry points into care. correct diagnosis facilitates important decisions around maternal antiretroviral therapy (art), breastfeeding choices and infant prophylaxis. south african guidelines recommend art initiation following two consecutive hiv-detected rapid diagnostic tests (rdts), using assays from different manufacturers, at a single time-point.2 our centre uses two world health organization (who)-approved rdt kits for hiv diagnosis in all individuals older than 2 years.3 abon hiv 1/2/0 (abon biopharm, hangzhou, china) is used as the screening test (screenrdt). in the case of a positive result, a first response hiv 1–2.0 card test (premier medical corporation private, ltd., gujarat, india) is done as a confirmation test (confirmrdt). screening rapid diagnostic test has a reported specificity of 99.7%, confirmrdt has a specificity of 100%.3 as the hiv prevalence is decreasing in the tested population and the screenrdts we use do not have 100% specificity, an increasing proportion of false-positive rdt results can be expected. this is a result of the decreasing positive-predictive value of the tests used, as they are dependent on test specificity and disease prevalence. human immunodeficiency virus testing yield in south african adults has dropped over the past decade to ~5%4; thus, the expected false-positivity rate may reach 5%.5 if the national hts guidelines are not followed correctly, false positives may cause individuals to be erroneously initiated on art.6 complications can arise when screenrdt and confirmrdt are discordant, with one test indicating a reactive result and the other test a non-reactive result. if the discordant result is still present after the rdt algorithm is repeated, further tests are warranted. as per the national hts guidelines the tiebreaker test is a 4th-generation hiv enzyme-linked immunosorbent assay (elisa), such as the architect hiv-1/2 ag/ab combo assay (abbott laboratories, wiesbaden, germany) used in this case report (figure 1).2 if the elisa yields equivocal results, a qualitative hiv polymerase chain reaction (pcr) test [cobas ampliprep/taqman hiv-1, v2.0; roche molecular systems, branchburg, new jersey, united states of america (usa)] is recommended. figure 1: reflex human immunodeficiency virus laboratory testing to resolve discrepant human immunodeficiency virus rapid testing.2 in this case report, we discuss four instances of likely false-positive screenrdt to sensitise clinicians to the importance of following the hts algorithm correctly and to the unique situations, dilemmas and potential risks faced in high-risk circumstances. the tiebreaker tests are performed in central laboratories and have an expected turnaround time (tat) of less than 3 days for the hiv elisa and less than 1 week for the hiv pcr. our facility is located in an urban area and is affiliated with a university; therefore, the tat on the samples was significantly quicker than the provincial average (table 1). table 1: turnaround times for tests done and final results. all four cases discussed presented with discordant rdts – a positive screenrdt and negative confirmrdt. because of the high-risk and time-sensitive nature of the cases, point-of-care tests available on site at the time [cepheid xperttm hiv-1 vl (viral load) and xpert hiv-1 pcr, sunnyvale, california, usa] as well as tests indicated by the national testing algorithm were conducted. in addition, a western blot assay was done on all four cases after discussion with the reference laboratory. case 1 was a healthy 10-year-old female with no previous admissions or chronic conditions. her mother had been living with hiv since before client 1 was born; thus our patient was hiv exposed at birth. she had been tested three times at her local clinic according to her mother, with negative results (which we could not verify). her mother defaulted treatment when client 1 was 7 years old. efforts were made by the local clinic to invite the mother back into care. she returned and was asked to bring her children in for testing. client 1 was brought in for index testing at the time. she was diagnosed as hiv infected using two rapid tests (two screenrdt kits were used at the clinic, because of stock-out of the confirmatory kit). she was referred to our facility for treatment initiation as they did not have stock of the appropriate art. at our facility, she was found to be asymptomatic, and no history or suspicion of sexual abuse was reported. despite the referral letter requesting art initiation only, the rapid tests were repeated, yielding a screenrdt positive and confirmrdt negative results. the rdts were repeated, with discordant results again. our second case was a 21-year-old female who presented to obstetric admissions in labour at 39 weeks pregnant. as per national hts guidelines she was screened for hiv on admission. her screenrdt result was positive and confirmrdt negative. the patient had been screened at every antenatal visit (four times) prior to delivery. all prior screenrdt results were negative. she was counselled on her discordant results and the risks associated with hiv and labour and agreed to take stat doses of tenofovir-lamivudine-dolutegravir (tld) fixed-dose combination and nevirapine whilst awaiting the confirmatory tests. case 3 was a 39-year-old female in her third trimester of pregnancy. she was screened for hiv during a routine antenatal care (anc) visit, with discordant results. she had tested negative at her anc visit a month previously. she conveyed a high level of anxiety about the positive result as she, reportedly, had not been involved in any high-risk behaviour since the conception of her child. her partner had been out of the country for the past 5 months. case 4 was a 22-year-old female admitted 21 days postpartum with puerperal sepsis. the patient had tested negative four times during her pregnancy and at delivery. the positive result caused significant concern to the patient as she had been exclusively breastfeeding her child since birth. the additional investigations conducted on all four patients showed hiv-negative results. the reference laboratory confirmed the results and reran the rdts, which remained discordant. this confirmed a false-positive screenrdt result in all four cases. discussion offering accurate, accessible hts with a quick tat is imperative to realising the unaids 90-90-90 targets. with high numbers tested and a low testing yield of new cases, the positive predictive value of rdts is dropping. each individual case of discordancy is very important. discordant results create anxiety and uncertainty around a diagnosis for both the patient and the healthcare worker. this has the potential to delay treatment or cause doubt around a positive diagnosis. false-positive results run the risk of patients being incorrectly initiated on treatment, as in our first case. not only is this an unnecessary burden for the patient, but the expense of lifelong therapy or potential litigation could be significant for the state. in a study done in 2017 looking at misdiagnoses of hiv in pregnant women in south africa,6 the cost per misdiagnosis was much larger than the cost of additional confirmatory testing. human immunodeficiency virus testing services and antenatal services in lowto middle-income countries still have multiple barriers to achieving effective service delivery.7 diagnostic dilemmas in pregnancy add to the stress of delivery and pregnancy, both for the patient and the healthcare provider. it is estimated that 35% – 40% of mother-to-child transmissions occur during labour and delivery.8 women are particularly vulnerable to new hiv infection during pregnancy and the postpartum period, and recent infection may give rise to discordant rdt results.9,10 diagnostic dilemmas during labour may delay administering art in a high-risk situation. further enquiries need to be made into the screenrdt by investigating factors that may falsely trigger the kit.11 the who strategy of using three positive rdts to make a diagnosis of hiv could be considered, as it may avoid diagnostic dilemmas in pregnancy and other high-risk scenarios. it may possibly speed up the time to diagnosis, particularly in cases around delivery, where time is of the essence.4 in order to ensure appropriate management and counselling of these cases, all healthcare workers involved with hts should be trained and sensitised to the risks around discordant results. application of the south african guidelines would have sufficed in these cases. reporting and monitoring of these cases must be emphasised in order to sensitise policymakers to the true number of discordant cases and implement protocols within facilities where there is a disproportionately high number.12 acknowledgements the authors acknowledge the patients and service providers at empilweni clinic and rahima moosa hospital. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in the writing of this research article. authors’ contributions k.g.t., a.h.m. and j.k. contributed to the study conception and design; a.h.m. and k.g.t. collected the data; j.k. prepared the manuscript; k.g.t., a.h.m., n.v.d., g.s. and j.k. revised the manuscript and appraised several drafts before approving the final version submitted for publication. ethical considerations ethical clearance was obtained from the university of the witwatersrand human research ethics committee (m200677). funding information the tests run were all done as part of the national hts programme; empilweni clinic and rahima moosa hospital do receive support and funding from usaid (agreement no. 72067418ca00023). data availability statement de-identified data used for this case study is available, on reasonable request, from the corresponding author. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references unaids. 90-90-90 an ambitious treatment target to help end the aids epidemic [homepage on the internet]. 2004 [cited 2020 july 13]. available from: https://www.unaids.org/sites/default/files/media_asset/90-90-90_en.pdf hts policy [homepage on the internet]. department of health, republic of south africa; 2016. [cited 2020 july 8]. available from: https://sahivsoc.org/files/hts%20policy%2028%20july%20final%20copy.pdf the global fund. list of hiv diagnostic test kits and equipments classified according to the global fund quality assurance policy [homepage on the internet]. [updated 2020 dec 21; cited 2020 july 22]. available from: https://www.theglobalfund.org/media/5878/psm_productshiv-who_list_en.pdf consolidated guidelines on hiv testing services for a changing epidemic (p3) [homepage on the internet]. world health organization; 2019. [cited 2020 july 13].available from: https://www.who.int/publications-detail-redirect/consolidated-guidelines-on-hiv-testing-services-for-a-changing-epidemic tenny s, hoffman mr. prevalence. in: statpearls [homepage on the internet]. treasure island, fl: statpearls publishing; 2020 [cited 2020 dec 1]. available from: http://www.ncbi.nlm.nih.gov/books/nbk430867/ hsiao n-y, zerbe a, phillips tk, myer l, abrams ej. misdiagnosed hiv infection in pregnant women initiating universal art in south africa. j int aids soc. 2017;20(s6):21758. https://doi.org/10.7448/ias.20.7.21758 amnesty international. struggle for maternal health: barriers to antenatal care in south africa [homepage on the internet]. 2014 [cited 2020 dec n.d.]. available from: https://www.amnesty.org/download/documents/4000/afr530072014en.pdf ahmad n. molecular mechanisms of hiv-1 mother-to-child transmission and infection in neonatal target cells. life sci. 2011;88(21–22):980–986. https://doi.org/10.1016/j.lfs.2010.09.023 thomson ka, hughes j, baeten jm, et al. increased risk of hiv acquisition among women throughout pregnancy and during the postpartum period: a prospective per-coital-act analysis among women with hiv infected partners. j infect dis. 2018;218(1):16–25. https://doi.org/10.1093/infdis/jiy113 louie b, wong e, klausner jd, et al. assessment of rapid tests for detection of human immunodeficiency virus-specific antibodies in recently infected individuals. j clin microbiol. 2008;46(4):1494–1497. https://doi.org/10.1128/jcm.01945-07 klarkowski d, o’brien dp, shanks l, singh kp. causes of false-positive hiv rapid diagnostic test results. expert rev anti infect ther. 2014;12(1):49–62. https://doi.org/10.1586/14787210.2014.866516 kufa t, kharsany abm, cawood c, et al. misdiagnosis of hiv infection during a south african community-based survey: implications for rapid hiv testing. j int aids soc. 2017;20(s6):21753. https://doi.org/10.7448/ias.20.7.21753 summer 2009                                                          the southern african journal of hiv medicine                                                  38 the hiv/aids epidemic affects virtually every community in south africa. many people live in rural settings, and the eastern cape, in which there are a large number of rural communities, has an hiv prevalence of 29.5% among antenatal clinic attendees.1 many people are in need of antiretroviral drug therapy (art). the keiskamma aids treatment (kat) programme began in hamburg, eastern cape, in july 2004. it was established in response to community needs, identified through routine work in the local primary care clinics. both the desperate need for and total absence of arvs in the area were clearly apparent. the kat programme, in partnership with pepfar, was the first provider of antiretrovirals (arvs) in the ngqushwa (peddie) district. like the madwaleni hospital arv programme featured in this journal2 in 2006, the kat programme serves impoverished rural communities. the kat programme differs from madwaleni in some ways. the kat programme is a community-based service designed to cater for all those in need of arvs. this includes people living with hiv/aids who are too sick or too poor to access facilitybased resources, in an area where the sparse, rural distribution of villages add geographical and logistical challenges. the set-up of the kat programme and the manner in which it began functioning closely reflected the needs of these patients. arvs have only become widely available in south africa since government funding was made available in 2004.3 as a result, rural treatment programmes do not yet have many patient follow-up results available (scarce resources being concentrated on patient care rather than data collection and analysis). this study follows the progress of the first patients through the kat programme. the study period runs from july 2004 to february 2006, during which time 174 adults entered the programme. background and methods the kat programme is heavily dependent on the local communities it serves. members of these communities are employed as nursing staff, caregivers, community health workers and drivers. the kat programme utilises their access to local communities as a basis for the provision of care. the kat centre opened with the intention of serving residents of hamburg and neighbouring villages. demand for the facility increased rapidly, largely owing to lack of alternative facilities in the ngqushwa district (nompumelelo hospital in peddie received limited accreditation in march 2006 and full accreditation at the end of 2006). owing to the burden of disease and the economic limitations and geographical remoteness the keiskamma aids treatment programme: evaluation of a community-based antiretroviral programme in a rural setting original article graeme p hofmeyr, ba (anthrop) hons tom georgiou, ba (cantab) hons carol w baker, mb bch, dip child health, ba hons keiskamma aids treatment centre, hamburg, e cape this paper documents the outcomes of the first 174 patients enrolled in a recently established community-based antiretroviral (arv) treatment programme. many people are living with hiv/aids and are in need of arvs. access to arvs can pose many logistical difficulties for poor and sick persons, particularly in rural areas. this communitybased treatment programme aimed to overcome these challenges, providing transport and nursing care, as well as actively seeking persons too sick to leave their homes. this led to the inclusion of many persons with advanced hiv in the treatment population. the study used routinely collected cd4 counts, viral loads and patient observation. the results show that the majority of patients responded well to treatment. there was higher mortality among the population with advanced disease, but a considerable proportion responded well. only 4 patients were lost to follow-up. this study details how community-based arv programmes can be useful adjuncts to the facility-based system. effective treatment programmes must address the needs of the communities they serve. the keiskamma.indd 38 3/16/09 2:15:21 pm the southern african journal of hiv medicine                                                        summer 2009   39 of communities, the effective implementation of the kat programme depended on three key components: inpatient facilities, transportation, and a network of home-based care workers. the kat centre was established in an old house in hamburg, a coastal village between east london and port alfred in the region of the eastern cape previously known as ciskei. the house was made available by the department of public works. it was equipped with 20 beds and acted as a residential facility where patients too ill for ambulant care were prepared for and initiated on arvs according to the south african national antiretroviral treatment guidelines.4 patients would typically stay at the centre for 1 2 weeks or longer, during which time they would be educated about the arv regimen and the importance of adherence. many of the patients arrived in a very poor state of health, extremely weak and unable to care for themselves. a benefit of the ‘step-down’ facility meant that patients unable to cope at home could be cared for and fed in a supportive and secure environment. patients presenting with opportunistic infections were treated where possible. patients left the centre once they were prepared and established on their arv courses. the kat centre uses two bakkies (pick-up trucks) with drivers to serve the transportation needs of the programme. these fetch and deliver patients and serve as ambulances for patients referred to secondary and tertiary facilities for specialist consultation. the provision of transport by the kat programme is one of its most important elements, as it provides access to treatment for patients who are too sick to walk to facility-based care or too poor to afford transport. it is also an important means by which staff based in the kat centre can interact with the community health worker network. the network of community lay health workers act as adherence monitors in the outlying villages and provide a means by which patients can contact the kat centre. these carers visit the patients in their homes, and maintain regular cellphone contact with the kat centre. there are 19 villages in peddie south, all of which have monitors. the kat programme aims for 2 monitors per village and at the time of this study employed 32 monitors on stipends. the majority of patients are referred to the kat centre by the primary care clinics in the area. however, some patients turn up un-referred and patients have arrived from as far away as port elizabeth, king william’s town and middle drift. for patients living beyond the community health worker network, adherence monitoring is more complicated. these patients travel as a last resort, telling stories of past encounters with health care authorities that are characterised by frustration, misunderstandings and missed opportunities. in response to their acute needs and desperation, the kat programme policy is to offer effective and compassionate care for people living with hiv and aids, regardless of where they live. a high proportion of patients arrive at the kat centre very sick with concurrent tb. many had been awaiting sputum results at their local health services, and treatment for tb frequently resulted in remarkable recoveries in patients assumed to be dying of aids but who were in fact dying from tb. for the purpose of this study, which assesses the first 174 patients seen (between july 2004 and february 2006), patients were clinically classified as ambulant or bedridden, and cd4 count at treatment initiation provided a baseline measure. possible patient outcomes, as measured after 6 months of treatment, are ‘good response’ (viral load (vl) <400 copies/ml, or if not available cd4 count >250 cells/µl), ‘poor response’ (vl >400 copies/ml, or cd4 <250 cells/µl), ‘died’, ‘lost to follow-up’, ‘insufficient data’ and ‘transferred out’ (gone to other art programmes). results baseline demographics of the study population, 26% were male and 74% female; 42% of those who initiated treatment were assessed as bedridden, and the remaining 58% were ambulant. baseline cd4 counts are available for 93% of the study group. of these, 37% were in the range 0 49 cells/µl, 26% were 50 99 cells/µl, 26% were 100 199 cells/µl and 11% were in the range ≥200 cells/µl. before the treatment centre was acquired, patients needing ‘inpatient’ care were accommodated in the home of a counsellor. a staff member speaks to patients in the treatment centre. the keiskamma.indd 39 3/16/09 2:15:30 pm summer 2009                                                          the southern african journal of hiv medicine                                                  40 patient outcomes only 2 patients discontinued treatment, one for personal reasons and the other because of severe psychotic sideeffects. twenty-seven patients (16%) were transferred out to other arv programmes. unless otherwise stated, the following figures and discussion relate to the outcomes of the 145 patients (83% of the baseline population) for whom data are available. fig. 1 shows that the majority (61%, n=88) of patients had a good response, 16% (n=23) had a poor response, 21% (n=30) died and 3% (n=4) were lost to follow-up. at treatment initiation, 70 patients (41% of the baseline population) were bedridden (table i). analysis of available patient outcomes shows that 43% of the bedridden patients died, a considerably higher percentage than in the ambulant patients. of the ambulant population, 95% survived and nearly three-quarters achieved a good response. there were no significant differences between male and female patients in either group. discussion in addition to more women living in rural areas and higher infection rates in women,5 the significantly larger number of female participants may reflect difficulties in accessing male patients. the distribution of baseline cd4 counts in this population differs from what may be considered ideal for arv programme initiates. the majority of patients presented with critically low cd4 counts. the cd4 count distribution seen in this population is likely to have arisen for two principal reasons. as this was the first service to provide arv treatment in the area, a reservoir of seriously ill patients with advanced disease progression and low cd4 counts would have existed. additionally, the nature of the kat programme is likely to have meant that more patients with lower cd4 counts were included than would be found in conventional facility-based programmes. using information provided by community members, the kat programme actively seeks persons in need of arvs. this facilitated treatment for patients unable to access facility-based care. of patients with baseline cd4 counts 0 99 cells/µl, 56% were bedridden and unlikely to have accessed conventional facility-based care. because the treatment centre is recently established, it is important to review patient outcomes. it is encouraging that 80% of the study population survived or were transferred out. with time it is hoped the kat programme will pick up patients earlier, when their cd4 levels are closer to 200 cells/µl. the fact that 98% of all patients who entered the programme were successfully followed up may be attributed to the community-based system the kat programme operates. the training and involvement of community health workers appears to be a successful policy. the benefits of this system include the monitors’ intimate knowledge of local people and communities, their ability to communicate effectively, close geographical proximity to patients, and an understanding of patient cultural backgrounds. these factors will have had an important role in achieving the low number of patients lost to follow-up. although considerably more bedridden patients than ambulant patients in the programme died, outcomes in the former group can still be regarded as highly successful. these moribund patients were extremely ill at treatment initiation. it should also be noted that the majority of bedridden patients who died did so shortly after initiating treatment, before the arvs had therapeutic effect. clinical status ill/ambulant moribund total population (n=172) 102 (59%) 70 (41%) data available (n=145) 84 (58%) 61 (42%) good response 61 (73%) 27 (44%) poor response 17 (20%) 6 (10%) lost to follow-up 2 (2%) 2 (3%) died 3 (5%) 24 (43%) table i. breakdown of available patient outcomes by baseline clinical status at treatment initiation fig. 1. breakdown of known patient outcomes by baseline cd4 group in 145 patients. a health education session at the treatment centre. the keiskamma.indd 40 3/16/09 2:15:38 pm the southern african journal of hiv medicine                                                        summer 2009   41 conclusions and implications the results of this study suggest that the kat programme achieved some notable successes in its first period of operation, july 2004 february 2006. the unconventional, community-based, bottom-up approach appears to be well suited to the area and people it serves. patients in preparation for treatment initiation experienced the benefits of the ‘step-down’ inpatient facility which brought them to a level of health where arv initiation was viable. the inpatient centre also acted as an effective platform on which arv counselling and education could be conducted. the patient outcomes suggest that key issues such as regimen understanding and adherence were successfully addressed. the transport system used by the kat programme made it possible for the programme to be accessed by those most in need – the sickest and poorest. community health workers were key to the success of the kat programme. they provided an extensive support network throughout the district. the high adherence and low proportion of patients lost to follow-up are successes attributable to these workers. community health workers are also important sources of useful related local information, such as identifying other persons in need of help within their communities. effective communication and co-operation between community health workers and the kat centre has been crucial. community involvement made it possible to access bedridden patients otherwise not visible to health services. it is likely that the vast majority of these patients would have died had the kat programme operated a conventional facility-based service. this study provides evidence that no one should be regarded as too sick to enter treatment programmes, and effort and resources should be expended in order to include such patients into a treatment programme. this study provides evidence that a community-based model of arv distribution can be effective in rural settings. at the time of writing, the kat programme was integrating with recently accredited government arv providers in the district, but continued to fill the gaps where patients are unable to access government services. working within the government hiv/arv programme is important for sustainability. this must not be done at the cost of care provision to rural communities. the potential for community-based arv programmes to substantially improve rural health care exists. it is important that such programmes play a role in national hiv/arv policy. references 1. department of health. south africa. national hiv and syphilis antenatal seroprevalence survey in south africa 2005. pretoria: department of health, 2006. 2. cooke r, wilkinson l. the madwaleni hiv/arv programme. southern african journal of hiv medicine 2006; 23: 18-24. 3. department of health, south africa. operational plan for comprehensive hiv and aids care, management and treatment for south africa. pretoria: department of health, 2003. 4. department of health south africa. national antiretroviral treatment guidelines. pretoria: department of health, 2004. 5. unaids. aids epidemic update: special report on hiv/aids: december 2006. geneva: unaids, 2006. an essential part of the programme is home visits. acknowledgements: eastern cape department of health staff and facilities for collaboration in the care of the patient cohort presented. funding from pepfar and the keiskamma trust, including donations from john brown, björn rönneberg and ‘25:40’. the keiskamma.indd 41 3/16/09 2:15:43 pm paediatric art in the public sector paul roux, .\lb eke, .hph,l (biocrhics), fe? (pacd), .\fd pai!diatric hli" aids sct'i.'ic.:, groou schllut hospiral. cape tcr::::n local go t • foreign donor care workers in the public service look beyond government for funds to suppor aart for their patients. we need to engage with foreign charities, the global fund against tuberculosis, malaria and aids, and organisations like the treatment aerion campaign 0 ind ways to help our patients. because hiv infection and aids are new to our region we need new and additional sources of money and not merely a redistribution of what was an inadequate health care budget to start with. partnerships between foreign donors, local nongovernmental organisations [ngos) and public service hospitals offer a model [fig. 11 through which indigent patients can gain access to haart. the foreign donor is the source of funding. ngos administer these funds and account for expenditure to the donor. public service hospitals and clinics provide the staff and infrastructure. fig. 1. a parrnership ra deliver haart in rhe public secrar i public health service unit i t t various forms of such partnerships already exist and have enabled doctors at several public service hospitals to initiate pilot haart programmes. the benefit of these partnerships is that they hasten access to treatment and offer sites at which staff can be trained in the use of arvs. a potential harm of this model is that the pressure on government ra proviae meaningful funding for haart may be lifted. piior treatment programmes may permit aecisionantiretroviral therapy for children in the public health care sector vertical transmission of the hiv from mother to child accounts for the vast majority of hiv in'eerions seen in soutn african cnildren. prevention 0' mother-ta-child uansmission (pmtct) is highly cost-e eerive in comparison to nospital care of hiv-infec ed children,'; but the cost and cost-e'lcacy of haart in the local setting has no yet been included in this calcula ion. if pmtct programmes are rolled out efficiently and if haart becomes available for use during pregnancy, we may expect mo her,to-child transmission rates of less than 10f0. far fewer children would need haart and the overall cost may be more acceptable to many. in the absence of efficient pmtct, paediatric services countrywide have seen steep increases in admissions and outpatient visits for hiv-related infections during the past decade, even in provinces with lower rates of adult infection.' where children have reasonable access to health care, a considerable number follow a chronic disease course: require recurrent hospital admissions and present an increasing burden of cost' to the public health service. at present the right o· hiv-infeerea children to 'standard of care' rl'aragemenr, incluaing haart, is void unless health funds for arvs to treat children in the , pubuc sector because of the south african governmental health policy, which does nor permit public health service access to antireuoviral drugs (arvs), he use of these drugs has been restricted to clinical trials and to the upper tier of health care services in south africa, i.e. patients who have health care insurance or other means to purchase drugs. clinical experience with arvs has been restricted to physicians in private practice and those engaged in drug trials. since south african children have rarely been enrolled as subjects in drug trials, few local paediatricians in hospital or academic practice have been able to gain experience in using highly active antiretroviral therapy [haard. moreover, few public health care institutions, whether urban or rural, have yet developed the sort of dedicated, comprehensive clinical hiv service that is an essential precondition for the successful introduction of haart. makers to delay the roll-out of definitive services. besides their obvious benefits to infected children, haart pilot projects are useful for other reasons. while it is true that many patients with hiv infection,' and indeed simple, first-line haart regimens, could be managed at primary care level, many paediatricians and paediatricians in training feel themselves inadequate to manage infected children.' pilot programmes offer an opportunity for health care workers to set up the necessary structures to provide comprehensive care, to acquire the necessary expertise and familiarity with treatment regimens, and to gain operational insights into practical requirements for successful management with arvs. pilot programmes will provide essential information on what facilities and staff are required to prescribe, dispense and promote adherence to haart regimens in the public service. which children should be treated the updated southern african hiv clinicians society guidelines for the management of hiv infection in children list clinical category b or c disease and/or a cd4+ percentage below 20% of the age norm as indications for starting haart. these guidelines are valid for children attending public service clinics and hospitals. the cost of laboratory tests to confirm the diagnosis and time the initiation of therapy is a problem for implementing haart in the public service. a polymerase chain reaction (pcr]-based test to make a definitive diagnosis of hiv infection before starting treatment in children under 18 months old is indispensable. a correct assessment of immunosuppression is difficult without access to cd4+ counts. a recent study has shown 85% of 'stable' infected children to be moderately or severely immunosuppressed." there is some evidence for a positive correlation between cd4+ and total iymphocyte count. it would therefore seem reasonable to consider haart in any child with category b or c disease and/or a low total iymphocyte count as a candidate for haart. as is the case with adults, starting treatment is seldom an emergency in children. however, since growth and development are impaired in the majority of hiv-infected children, and since both of these problems respond to haart,'·w there seems to be more urgency to start treatment in the paediatric setting. patients with hiv infection attending public service institutions are at high risk of infection with mycobacterium tuberculosis. children who are receiving treatment for tuberculosis when first considered for haart should complete tb therapy before starting treatment with arvs if their immunity is moderately suppressed. those with severe immunosuppression should preferably complete 2 months of intensive tb therapy before starting their haart regimen. this reduces [he chances of shared the sout~frn mrican journal of hili medicine toxicity and a paradoxical worsening of tb with immune reconstitution. children who are profoundly immunosuppressed should first start and be seen to tolerate antituberculosis therapy before starting antiretroviral therap{' rationing of access to a umited treatment resource a limited number of children can be treated in charityfunded pilot programmes. the approach shared by several such programmes is to allocate haart according to a queuing system: one treats those children who meet a set of inclusion criteria (based on the hiv clinicians society guidelines) and closes admission to the programme once the full budget and all available treatment slots have been allocated. some pilot clinics have elected to treat mothers and children in pairs. the reasoning behind such a decision is clear, but because the course of hiv infection in mother and child is so often asynchronous and because the disease generally runs a faster course in children, this approach may mean that many well mothers will have to watch their children die. choice of a treatment regimen the southern african hiv clinicians society guidelines for arvs in children provide a complete list of drugs available for children and recommendations regarding the combinations to be used. a first-line three-drug regimen should include a 'backbone' of two nucleoside reverse transcriptase inhibitors (nrtls] together with either a protease inhibitor (pi) or a non-nucleoside reverse transcriptase inhibitor (nnrti). because children often have very high viral loads at diagnosis that are frequently not suppressed to undetectable levels, there is a high risk that resistant strains of virus will arise. since nnrti resistance requires a single mutation, the choice of a pi to complete a three-drug regimen may be preferable. most drugs are more expensive as paediatric suspensions than in tablet, powder or capsule form. some paediatricians, driven by cost constraints, treat children with tablets that their caregivers are required to crush and suspend in carefully measured volumes of water before administration. the unfortunate paradox is that the home environments of the poorest patients tend not to have the space or facilities for such relatively complex preparations. hence children attending public service clinics probably need the more expensive ready-made suspensions and the (also more expensive) simplest daily regimens if their caregivers are to adhere to treatment. the majority of charity-funded haart programmes have opted for relatively expensive, but simple, suspension-based regimens. ----------october 2002 adherence to haart regimens in children haart can achieve control of viral replication in hiv-linfected children who adhere to therapy" medicine that is difficult to prepare or unpalatable is less likely iq be administered to the child" if caregivers are not prepared for adherence before starting haart, or if regimens are too onerous to follow (table i), treatment is likely to fail. table i. reasons for non-adherence to paediatric haart regimens" • unpalatable medicines • difficult formulations • problems around meals • non-disclosure to others • hiding or re-labelling medicines • defaults at clinic • midday doses every effort should be made to see the burden of adherence from the caregiver's point of view. meticulous attention to detail offers the greatest likelihood of making haart a successful joint venture (table 11). the key to adherence lies in the amount of time and care the health care worker can devote to the effort of explaining the purpose and practice of adherence. table 11. strategies for the promotion of adherence to paediatric haart regimens • promote demand rather than adherence • encourage maternal self-esteem • cohort bookings to promote alliance between mothers • buddy system for 'reciprocal dots' reward for good performance • promote pride in access, therapeutic programmes. national success • access technology: 'adapracaps', syringes • training in medication • preparatory visits to the clinic • cues, reminders, diary cards • social and community support • time from health care workers monitoring the response to treatment tests to monitor immunological and viral responses to haart are becoming less expensive, though still beyond what the public service can afford. there is at least some evidence that clinical response'" is a reasonable proxy for cd4+ counts and viral loads. these findings need to be confirmed by operational research in the southern african setting. there are as yet no reports in the literature regarding the success of local paediatric programmes, and most have not been running long enough with sufficient patients for analysis. summary and conclusions current sou h african government health policy does nor permi: nerapy with antire roviral drugs in pub,ic service hospitals or clinics. given the size of the aids epidemic in south africa and the very many south african health care workers who have experienced the morbidity and mortality among their patients, it is remarkable and disquieting that there has not been more protest from the medical fraternity against government policy regarding public access to antiretroviral therapy. history will no doubt question the silence of so many. health care workers managing hiv-infected children must become more active in gaining access to haart for their patients. successful partnerships between foreign donors, local ngos and public service facilities offer models for projects to pilot haart for children and to provide experience and training for health care workers. complex regimens and problems with adherence are obstacles to the successful use of haart in children managed in the public service but can be overcome. a low-price haart regimen, if it adds complexity to administration, is not necessarily the cheapest option. government, health authorities and heads of academic departments must commit sufficient space and human resources to develop paediatric hiv!aids services so that they can become viable platforms for the delivery of haart. services should be initiated as pilot projects at all levels of health care delivery, so that units in rural areas can develop in partnership with urban and academic services that can support them. each pilot project should include elements of audit and operational research, so that in the process of implementation, all practice can be measured and assessed as services are delivered. the cost of a su"icient, dedicated and rob st health care service will be significant, but such a service must be established as soon as possible. references 1. abdullah mf, young t. bitale l., et al. public health lessons from a pilot programme to reduce mother-ta-child transmission of hn~ 1 in khayelitsha. 5afr med j 2001; 91: 579-583. 2 skordis j. nanrass n. paying to waste lives: the affordabiliry of reduc.ing motherlo-<:hild trarsmission of hiv in south africa. j healrh eron 2002; 21: 405-42l. 3. roux p, herley l corron m, eely r burden and cost of inpatient cafe for hnpositive paediatric patients-status in the cape: to ..... n metropole dunrg {ne secono ·",eel.. of march 1999. paedauic hiv census group. 5ai, mm j 2000; 90: 10081011. 4. h.j.s:s..-'"y gd, reijrhan rm, sebens am, er crl surv"val of ch eren in ca~ towr !<rown tu bevertlca _'i infected w:n hiv-1. safrmeaj 1998, 8b: 554-558. 5. lfr rinsen o. ro~'d k. glills cf. natona! iino pro'''t'cia ~ma{eo cos!s aro cos! e~ess of a p'09ramme to redj~ rro:ner-w-cr ,0 hlv uar:smission it: scutn /-yea. safrmed 12oc1j; 90: 79~7s8. 6.. m~:ril.il'i as.. z..... afer:st~'n m. ste:tr~g mh, vii!l der w ..er e. maaj1ers g, wood r. is nlv/alds a pmr;ry-cate 0 sease? apwopt a:~ eo.m of outpa:ent c;r~ ~t pa:.erts w tn hn/al3s. aids 1995; 9: 619-623. 7. frarstliir 0, mcc och m. la. es 0, hussey g. doctors' a 'twoes <:0 me care o~ en oren w tn hiv;,., scuul aitca. aids ca{~ 2000; 12: a9-9e. a. bey 55, mjgres j, po:g,e,er s. etc.lm"" ~t'o;rn;:ca mari;estatior5 o~ h n~ectec cr d'en. arn trap fcediau 1999; 19: 3-7. 9. vet,...~1 g, ..-an rossum am, hartw;g ng, et cl. trea(men 'him nignly iicrlvt iintlreuoviral therapy in "uman immunoaefic:iency virus typt i-infected chi:dren is associated him a sustained effect on growtn. ftdiacrics 2002; 109: e25. 10. mccoig c. ~strejol'i mm, castano e, et 01. effect o~ combination antireuoviral rnerapy on cerebrospinal fluid hiv rna. hn resistance, and clinical manifestations of encephalopathy. j pediau 2002; 141: 36-44. 11. 5uiit'an wj, lones be. treatment of hn-r~lated tubetcu;osis ;r: me era of effective antreuov;ral therapy. am jresoir cr,'t care mea 2001; 164: 7-12. 12. ....~30n dc, faney jj. efieacy arc aonererce to r,gl"'i' act~e: ant;reuovira tnerzpy r ch:l:!fl.'n :n~ecte!j h tfl r jmall .r"rrj~oce';;-c:er.c',' ~':n,s type: 1. fta;"otflnf~tdi51 iggs; 18: 682-689. 13. ,ar do,!!.e r8 !..et s, jotrsar g\~, ~: c. reoor:e-: ;cre'erce as a ae:errr,ran c~ tesoc~yro r:gr'l ani .. e: artire:;cr-r~ =he!a~1 ',., c'" a'et" ""t'<o jo,=ve i'~ma'" ~ .....roce"'c-er:c, .. '_s "~e:c::ci'. ,~'c:!'cs 2(,(2; 109: 1."£1. \~ hnp;jlwww.hivatis.org/trtgdln~tmlipedjatric hiv insert advice document fixed-dose combination for adults accessing antiretroviral therapy southern african hiv clinicians society corresponding author: n e c g davies (ndavies@wrhi.ac.za) this document serves to guide clinicians and programme managers on how to switch from 3 separate antiretroviral (arv) drugs to the new, single, fixed-dose combination (fdc) tablet containing tenofovir (tdf), emtricitabine (ftc) and efavirenz (efv). summary transitioning from individual drugs to an fdc tablet needs to be managed carefully, particularly regarding stock management, ordering processes, supply-chain integrity and comprehensive patient counselling. priority groups • initially, fdc supply will be insufficient to provide for all fdc-suitable patients • therefore, the national department of health (ndoh) has recommended that the following patient groups be prioritised for fdc initiation/switch: • priority group 1: all hiv-positive patients newly initiating art – adults, adolescents and pregnant women (regardless of cd4 count (amendment to the guidelines for the prevention of mother-to-child transmission of hiv (pmtct) anticipated in april 2013) – and who do not have contra-indications to the fdc component drugs • priority group 2: hiv-positive pregnant women and breastfeeding mothers currently stable on lamivudine (3tc), tdf and efv • priority group 3: virologically suppressed patients on a stavudine (d4t)-based regimen and who have normal renal function • priority group 4: stable patients receiving individual tdf, 3tc and efv and who have tuberculosis (tb) co-infection • priority group 5: stable patients receiving individual tdf, 3tc and efv and who have other co-morbidites (e.g. hypertension, diabetes) • priority group 6: patients receiving individual tdf, 3tc and efv and who request to switch to the fdc treatment • priority group 7: patients receiving individual tdf, 3tc and efv and who, after counselling, agree to switch to the fdc treatment. important: clinic staff must co-ordinate this process and only switch as many patients to the fdc tablet as stock allows. this should avoid patients being switched back and forth between fdc and individual drugs due to insufficient stock. note: the fdc tablet is not significantly larger than efv or lopinavir/ritonavir (lop/r) (aluvia); therefore, swallowing should not be problematic. s afr j hiv med 2013;14(1 suppl):41-43. doi:10.7196/sajhivmed.913 in 2012 dr aaron motsoaledi, south africa (sa)’s minister of health, announced the award of a new antiretroviral (arv) tender – worth r5.9 billion – that, for the first time since the start of the arv programme, includes a triple fixed-dose combination (fdc) tablet. the fdc tablet will contain 300 mg tenofovir (tdf), 200 mg emtricitabine (ftc) and 600 mg efavirenz (efv). this is a significant step forward for sa’s national arv programme, as it enhances cost-effectiveness and simplifies the first-line regimen. it is anticipated that over 90% of new patients will be eligible to initiate this fdc treatment. advantages of fdcs regimen and stock management simplification • arv prescribing, dispensing and stock management is simplified because the first-line regimen is reduced from 3 separate drugs to 1 combined tablet.1 • from april 2013, all pregnant women, regardless of cd4 cell count, will be initiated on triple arv therapy for the duration of pregnancy and breastfeeding, to enhance the prevention of mother-to-child transmission of hiv (pmtct) programme. the fdc tablet will simplify the rollout of this change. adherence • reducing the pill burden of the first-line regimen to 1 pill once daily may, as reported in some studies,2-4 improve adherence levels. however, the provision of intensive adherence counselling remains essential. efficacy • the efficacy of tdf/ftc/efv-based triple arv therapy has been proven in randomised controlled trials.5-7 guaranteed dosing and consistent dispensing • there is a decreased risk of incorrect dosing due to patient misunderstanding and/or prescribing/dispensing errors. • patients are unable to default single drugs to avoid certain side-effects (e.g. some patients independently discontinue efv because of dizziness or drowsiness). • there is a reduced risk of patient exposure to dual therapy during single drug stock-outs. cost the sa government negotiated a cost of r89.37 per month for the fdc treatment.8 this represents significant cost-saving compared with the old, single-drug tender. are 3tc and ftc interchangeable? the majority of patients currently accessing arvs are prescribed lamivudine (3tc). however, the fdc will contain ftc. ftc and 3tc are structurally very similar, ftc having just one additional fluorine molecule. in a recent technical update, the world health organization (who) concluded that 3tc and ftc are clinically and programmatically interchangeable.9 although few direct comparisons have been performed, 3tc and ftc appear to have comparable virological and clinical efficacy and safety. 3tc may rarely be associated with pure red-cell aplasia, which requires drug substitution, and ftc may occasionally cause palm discolouration, which is usually managed by reassuring patients. both drugs are active against the hepatitis b virus. therefore, who concludes that ‘ftc is an acceptable alternative to 3tc’ and that ‘3tc may substitute for ftc or vice versa’. both 3tc and ftc are given as a single daily dose. therefore, for those patients receiving stavudine (d4t), 3tc and efv, switching to the fdc treatment can be considered as a single drug switch from d4t to tdf because 3tc and ftc are considered to be equivalent. supply chain management it is imperative that all patients enrolled in the sa arv programme are able to access a continuous supply of arv treatment. treatment interruptions, whether of single or multiple arvs, are associated with poorer clinical outcomes, increased rates of virological failure and the emergence of drug-resistant hiv. consequently, prescription of the fdc tablet will need to be managed carefully, particularly in terms of stock management, ordering processes and supply chain integrity. a gradual, phased approach to introducing the fdc treatment to new patients, pregnant patients and those receiving d4t should help to ensure a smooth transition. district managers, facility managers, healthcare providers and pharmacy staff will need to work closely together to track how many patients are initiated on, or switched to, the fdc treatment, while also monitoring how many existing patients remain on various single drugs. changes to monthly/quarterly orders must be kept in line with the needs of each facility’s patient population. facility staff will need support to manage the transition and to communicate effectively with the national department of health (ndoh) should shortages arise (preferably before complete stock-outs occur). as the proportion of patients on ‘non-standard’ regimens decreases, it will become increasingly important for facilities to manage their single drug stocks to avoid stock-outs which disadvantage patients who are not eligible for the fdc. switching patients to the fdc sa’s fdc producers will need time to maximise production. considering that previous drug stock-outs arose when demand outstripped the manufacturers’ capacity, it is imperative that fdc rollout is undertaken in a carefully controlled, phased approach. under the january 2013 december 2014 arv tender, 30 million units of fdc will be produced for nationwide use. due to the size of sa’s arv programme, this means that fdc provision will have to be limited to specific patient groups. based on the existing tender, the ndoh has identified the following groups as eligible for fdc use. currently, the southern african hiv clinicians society recommends that clinicians adhere to these ndoh guidelines, to avoid fdc stock-outs occurring as a result of clinics over-extending beyond the anticipated maximum fdc availability during the current tender. priority patient groups (ndoh recommendations) priority group 1: all arv-naive patients newly initiating art • all hiv-infected individuals identified as eligible for art, including those with tuberculosis (tb) co-infection, should be initiated on the fdc treatment as long as there are no contra-indications to the component drugs (e.g. renal dysfunction precludes tdf use, and a recent psychotic episode precludes efv use). • this group includes new adults, adolescents and all hiv-positive pregnant women (to be initiated on triple therapy, as an fdc, regardless of cd4 count as per the new pmtct guidelines anticipated in april 2013) • women presenting in the first trimester who require urgent art initiation for their own health should be managed according to ndoh guidelines. they may not be eligible for the fdc treatment. • note: patients weighing <40 kg are unsuitable for the fdc treatment. these patients require 400 mg efv (unless concurrently receiving tb treatment). however, should they gain weight, they can switched to the fdc. priority group 2: all hiv-positive pregnant women • hiv-positive pregnant women who are already stable on 3tc, efv and tdf should be switched to the fdc treatment • breastfeeding women who are stable on individual tdf, 3tc and efv should be changed to the fdc if they agree to do so. priority group 3: established patients receiving d4t, 3tc and efv • all patients who are currently established on individual 3tc, d4t and efv should be switched to the fdc treatment. initially, while fdc stocks are built up, patients who display d4t toxicity (most commonly peripheral neuropathy or lipoatrophy) should be prioritised. • the switch to the fdc treatment should be performed as per existing guidelines. prior to the switch, clinicians must ensure that the patient has a recent (within 3 6 months) undetectable viral load and normal creatinine clearance. • the clinician is effectively switching a single drug, d4t, to tdf; therefore, it is essential to ensure that the patient is virologically suppressed before switching. • for patients with anaemia precluding azt use, plus renal dysfunction precluding tdf use, special arrangements must be made to ensure access to d4t or abacavir (abc). • patients should be counselled appropriately about the switch. • clinicians must remember to monitor creatinine clearance after 3 and 6 months, respectively, and annually thereafter. priority groups 4 and 5: stable patients with tb co-infection and other co-morbidities • there is concern that patients with co-morbidities (tb, hypertension or diabetes) may struggle with the combined pill burden. • to lessen the potential for poor adherence, such patients should be offered the fdc treatment if they are already receiving tdf, 3tc and efv. • note: multiple drug-resistant tb (mdrtb) patients are excluded as amino-glycosides and tdf have overlapping renal toxicity. rather, these patients should be initiated on azt or, if anaemic, d4t. • important: clinic staff must carefully monitor fdc prescriptions and ensure that sufficient stock is available to secure a continuous fdc supply to all patients being initiated/switched. it is critical that patients do not find themselves being switched back and forth to individual drugs due to insufficient fdc stock. what about other patient groups? as sa’s arv programme continues to expand, clinics are experiencing burgeoning populations of stable patients who are clinically well and virologically suppressed. long-term retention in care of this group is proving problematic and, increasingly, a shift to community-based, adherence club models is being advocated to streamline clinic services and improve patient retention. it is anticipated that successful implementation of such club models would be greatly facilitated by fdc availability, as this would simplify dispensing to club members. however, the ndoh has decided that clinically stable patients receiving tdf, 3tc and efv are to be prioritised below other groups during the period of this current tender. after allocating fdc stocks to new patients, pregnant patients, d4t-receiving patients and those with co-morbidities, there may not be additional fdc available for stable patients falling into priority groups 6 and 7. fdc side-effects patients taking the ftc/tdf/efv fdc tablet are expected to experience the same side-effect profile as patients taking the 3 individual drugs. patients should be counselled about potential side-effects as per usual. anecdotally, upon switching from individual drugs to other fdcs, some patients report experiencing new or different side-effects. it is uncertain whether this may be associated with the binding components within the co-formulation or due to the psychological effect of changing medication. most patients will settle with reassurance. fdc-recipient patients who develop severe adverse events necessitating discontinuation of one agent (e.g. severe efv-associated central nervous system (cns) toxicity or tdf-induced renal dysfunction) should be managed as per patients taking individual drugs. clinicians should adhere to existing guidelines when managing arv-induced adverse events. if indicated, the fdc treatment should be discontinued to remove the offending agent. the fdc should be replaced with 3 individual drugs: the 2 tolerated drugs plus an alternative to replace the offending drug. the patient must be educated carefully about their new, more complex regimen, including matters such as dosing, expected side-effects and any additional monitoring required. note: for fdc-recipient patients who develop mdr-tb, clinicians should consider switching the tdf-containing fdc for the duration of aminoglycoside use. if the patient is retained on the fdc treatment, increased renal monitoring should be instituted during the mdr-tb treatment period. patient counselling for patients, the switch from 3 tablets to 1 tablet may raise concerns about efficacy or quality. it is essential that healthcare workers educate patients about the fdc treatment. patient counselling messages • the dosage is one pill once daily, not 3 pills once daily. • although the fdc is ‘one pill once a day’, it does contain 3 different arv medications – it is easy to take, highly effective and in no way inferior to taking 3 individual drugs. • most patients initiating the fdc will not encounter problems, but if they experience any significant side-effects, they should consult their healthcare provider. • although the fdc is a large tablet, it is not significantly larger than efv or lop/r (aluvia); therefore, swallowing should not create problems. there is no liquid fdc formulation currently on the market. crushing or dissolving the fdc, which undermines bio-equivalence, should be avoided.10 • patients (especially stable patients) who are not included in the priority groups for the fdc should be counselled so that they understand why they are not being switched to an easier option. references 1. treatment action campaign (tac). include fixed-dose combinations in new arv tender. http://www.tac.org.za/community/node/3299#_ftnref1 (accessed 6 february 2013). 1. treatment action campaign (tac). include fixed-dose combinations in new arv tender. http://www.tac.org.za/community/node/3299#_ftnref1 (accessed 6 february 2013). 2. sax pe, meyers jl, mugavero m, davis kl. adherence to antiretroviral treatment and correlation with risk of hospitalization among commercially insured hiv patients in the united states. plos one 2012;7(2):e31591. [http://dx.doi.org/ 10.1371/journal.pone.0031591] 2. sax pe, meyers jl, mugavero m, davis kl. adherence to antiretroviral treatment and correlation with risk of hospitalization among commercially insured hiv patients in the united states. plos one 2012;7(2):e31591. [http://dx.doi.org/ 10.1371/journal.pone.0031591] 3. stone ve, hogan jw, schuman p, et al. antiretroviral regimen complexity, self-reported adherence, and hiv patients’ understanding of their regimens: survey of women in her study. jaids 2001;28:124-131. 3. stone ve, hogan jw, schuman p, et al. antiretroviral regimen complexity, self-reported adherence, and hiv patients’ understanding of their regimens: survey of women in her study. jaids 2001;28:124-131. 4. chesney ma. factors affecting adherence to antiretroviral therapy. clin infect dis 2000;30(s2):s171-s176. [http://dx.doi.org/10.1086/313849] 4. chesney ma. factors affecting adherence to antiretroviral therapy. clin infect dis 2000;30(s2):s171-s176. [http://dx.doi.org/10.1086/313849] 5. pozniak al, gallant je, dejesus e, et al. tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naïve patients. jaids 2006;43(5):535-540. 5. pozniak al, gallant je, dejesus e, et al. tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naïve patients. jaids 2006;43(5):535-540. 6. gallant je, dejesus e, arribas jr, et al. tenofovir df, emtricitabine and efavirenz vs. zidovudine, lamivudine, and efavirenz for hiv. n engl j med 2006;354:251-260 [http://dx.doi.org/10.1056/nejmoa051871] 6. gallant je, dejesus e, arribas jr, et al. tenofovir df, emtricitabine and efavirenz vs. zidovudine, lamivudine, and efavirenz for hiv. n engl j med 2006;354:251-260 [http://dx.doi.org/10.1056/nejmoa051871] 7. gallant je, staszewski s, pozniak al, et al. efficacy and safety of tenofovir df vs stavudine in combination therapy in antiretroviral-naïve patients: a 3-year randomized trial. jama 2004;292(2):191-201. 7. gallant je, staszewski s, pozniak al, et al. efficacy and safety of tenofovir df vs stavudine in combination therapy in antiretroviral-naïve patients: a 3-year randomized trial. jama 2004;292(2):191-201. 8. national department of health. statement issued by the minister of health dr aaron motsoaledi during the announcement of the new arv tender ahead of the world aids day. http://www.doh.gov.za/show.php?id=3834 (accessed 6 february 2013). 8. national department of health. statement issued by the minister of health dr aaron motsoaledi during the announcement of the new arv tender ahead of the world aids day. http://www.doh.gov.za/show.php?id=3834 (accessed 6 february 2013). 9. world health organization. technical update on treatment optimization: pharmacological equivalence and clinical interchangeability of lamivudine and emtricitabine: a review of current literature. http://apps.who.int/iris/bitstream/10665/70936/1/9789241503815_eng.pdf (accessed 12 february 2013). 9. world health organization. technical update on treatment optimization: pharmacological equivalence and clinical interchangeability of lamivudine and emtricitabine: a review of current literature. http://apps.who.int/iris/bitstream/10665/70936/1/9789241503815_eng.pdf (accessed 12 february 2013). 10. clayden p. poor bioequivalence with crushed and dissolved tablets. http://i-base.info/htb/10492 (accessed 6 february 2013). 10. clayden p. poor bioequivalence with crushed and dissolved tablets. http://i-base.info/htb/10492 (accessed 6 february 2013). abstract supporting the move to simplified paediatric-friendly formulations abacavir/lamivudine fixed-dose combination formulations dolutegravir future innovations for simplified paediatric-friendly formulations acknowledgements references about the author(s) moherndran archary department of paediatrics and child health, college of health sciences, university of kwazulu-natal, durban, south africa department of paediatrics, king edward viii hospital, durban, south africa riana van zyl department of paediatrics and child health, university of the free state, bloemfontein, south africa nosisa sipambo department of paediatrics and child health, university of the witwatersrand, johannesburg, south africa gillian sorour department of paediatrics and child health, university of the witwatersrand, johannesburg, south africa citation archary m, van zyl r, sipambo n, sorour g. optimised paediatric antiretroviral treatment to achieve the 95-95-95 goals. s afr j hiv med. 2021;22(1), a1278. https://doi.org/10.4102/sajhivmed.v22i1.1278 opinion paper optimised paediatric antiretroviral treatment to achieve the 95-95-95 goals moherndran archary, riana van zyl, nosisa sipambo, gillian sorour received: 21 june 2021; accepted: 14 july 2021; published: 01 sept. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract while the progress towards reaching the unaids 95-95-95 targets in south african adults seems promising, the progress in the paediatric population is lagging far behind; only 79% percent of children living with hiv know their status. of these, only 47% are on treatment, and a mere 34% of those are virally suppressed. thus, virological suppression has been attained in only 13% of children living with hiv in south africa. multiple factors contribute to the high treatment failure rate, one of them being a lack of paediatric-friendly antiretroviral treatment (art) formulations. for example, the lopinavir/ritonavir syrup, which is the current mainstay of art for young children, has an extremely unpleasant taste, contributing to the poor tolerability and lack of adherence by children using the formulation. furthermore, the lack of appropriate formulations limits the optimisation of regimens, especially for young children and those who cannot swallow tablets. switching from syrups to dispersible tablets will improve ease of administration and adherence and result in cost-saving. despite the approval of simplified paediatric-friendly formulations internationally, including other sub-saharan african countries, unnecessary delays are experienced in south africa. clinician groups and community organisations must speak up and demand that approvals be expedited to ensure the delivery of life-changing and life-saving formulations to our patients as a matter of urgency. keywords: paediatric; hiv/aids; art; 95-95-95 goals; pmtct. according to the latest global joint united nations programme on hiv and aids (unaids) estimates, 1.8 million children live with hiv worldwide, with 150 000 new infections in children aged 0–14 years contributing to 9% of the overall new infections in 2019. of these new infections, 84% occurred in sub-saharan africa, with around 95 000 hiv-related deaths in children reported in 2019.1 while south africa’s prevention of mother-to-child transmission programme has been successful in decreasing the rate of vertical transmission of hiv to 3% (from 16% in 2010), paediatric hiv treatment programmes have not been as successful.2 in 2019, hiv-related deaths in south african children declined to 4100, and the number of children living with hiv remained more or less stable at 340 000.1 as part of working towards ending the hiv pandemic by 2030, attaining and maintaining virological suppression is critical. the current south african statistics in the overall population in terms of the unaids 95-95-95 targets (diagnosis of 95% of all people living with hiv, achieving 95% on antiretroviral treatment [art] among those diagnosed and 95% virally suppressed among those being treated) are 92-75-92.1 in the paediatric population, however, the progress towards meeting the treatment cascade goals is lagging far behind. only 79% of children living with hiv know their status. of these, only 47% are on treatment, and a mere 34% of those on treatment are virally suppressed.1 treatment failure is multifactorial, but suboptimal adherence remains the most significant contributing factor. one of the reasons for non-adherence is the difficulty in obtaining treatment. the barriers to accessing treatment include physical challenges such as getting to clinics in remote areas, drug stock-outs and, recently, interrupted clinical services resulting from coronavirus disease 2019 (covid-19) restrictions. although the effect of lockdown had a more significant impact on hiv testing and the initiation of art, the provision of art was also affected.3 disruptions to hiv programmes during the covid-19 pandemic will have the most significant impact on hiv-related deaths. based on modelling studies, the interruption of art for 6 months in 50% of patients on art will result in over 296 000 estimated deaths in sub-saharan africa annually.4 in the paediatric population, adherence is dependent on the motivation and commitment of the parent or caregiver. a lack of appropriate paediatric art formulations adds to the burden of giving treatment to a child regularly enough to maintain high levels of adherence and obtain viral suppression. the classic ‘culprit’ is lopinavir/ritonavir (lpv/r) syrup: toddlers often refuse to take the treatment or vomit after the parent or caregiver administers the syrup because of the extremely unpleasant taste. in addition, the lack of fixed-dose combinations (fdc) for children results in complicated dosing regimens that negatively affect long-term adherence and retention in care. supporting the move to simplified paediatric-friendly formulations the shift away from multiple syrup formulations for children unable to swallow tablets, previously the mainstay of the paediatric hiv treatment regimens in south africa, has been delayed compared to other sub-saharan african countries. this has been because of the painstakingly slow regulatory approval of generic fdc formulations designed for children. for example, the united states food and drug administration (usfda) approved the generic fdc of abacavir (abc) and lamivudine (3tc) (120/60 mg) in 2014 (see figure 1).5 the south african product submission to the south african health products regulatory authority (sahpra), then called the medicines control council, only followed in 2016. approval, however, only occurred in 2021, 7 years later. figure 1: timelines for paediatric antiretroviral approvals are shortening, but unnecessary delays remain. the impact of optimised paediatric formulations cannot be overemphasised. for example, an 11 kg infant on abc and 3tc will require a 6 ml twice-daily dose of each syrup, or 24 ml per day, and a total monthly supply of 672 ml, compared to a child who is switched to an fdc of abc/3tc (120/60 mg) dispersible tablet (dt). switching to the fdc abc/3tc requires two tablets daily, or a bottle of 56 pills per month.7 these changes impact the patient and caregiver acceptability and adherence as well as the health system costs, including cost savings on syringes and a decrease in the required storage space. abacavir/lamivudine fixed-dose combination formulations the fdc of abc/3tc (600/300 mg) was registered for use in south africa from 2012 and was included in the paediatric and adolescent dosing guidelines soon afterwards, facilitating a once-daily nucleoside/nucleotide reverse transcriptase inhibitor (nrti) backbone in children above 25 kg.8 this film-coated tablet should be swallowed whole and not cut or crushed, preventing the use of the formulation in younger children. the new dispersible scored abc/3tc fdc (120/60 mg) allows for flexible dosing and administration. the formulation can be dissolved in liquid and administered, chewed or swallowed whole, allowing the use of the formulation from young infants to older children. the dose proportions align with the world health organization (who) dosage recommendations developed to facilitate once-daily dosing of the nrti backbone in children over 4 weeks of age and weighing 3 kg. the scored dt allows dosing in increments of 60/30 mg, which, when cut in half, allows for dosing across a wide weight range from 3 kg to 25 kg. in addition, the child-friendly flavouring of the formulation adds to the appeal. in south africa, two generic manufacturers have made this fdc available to patients in the public sector.7 dolutegravir the basis for introducing integrase inhibitors into the adult guidelines was the higher genetic barrier to resistance, improved side-effect profile and viral suppression rate associated with dolutegravir (dtg). while evidence for a potential association with neural-tube defects (ntds) and increased weight gain has slowed down the introduction of dtg, especially in women of child-bearing potential, the opening into the paediatric population has been delayed by the lack of appropriate formulations. the inclusion of adolescents early into studies such as impaact p10939,10 has allowed their concurrent access, if weighing over 30 kg, to the 50 mg formulation as per the adult formulations in the national guidelines.8 the initial registration trial for dtg included 35 mg and 25 mg doses for children weighing 20 kg – 30 kg and 15 kg – 20 kg, respectively, requiring two additional formulations of a 25 mg and 10 mg tablet. further pharmacokinetic evaluation conducted as a substudy of the odyssey trial evaluated the use of the 50 mg tablet in children between 20 kg and 30 kg.11 acceptable pharmacokinetics and side-effect profile supported the usfda registration of dtg 50 mg daily in children from 20 kg. in addition, the new dosage recommendation was added to the who and several national guidelines, including the south african national art guidelines.8 to dose children weighing below 20 kg, a 5 mg dispersible tablet of dtg (dtg dt) was developed by the originator, viiv. pharmacokinetic evaluation as part of the p1093 and odyssey trials again supported the registration of the new formulation by the usfda and european medicines agency in 2020 starting at 4 weeks of age and 3 kg in weight.12 in addition, as part of viiv’s commitment to providing early access to dtg in lowand middle-income countries (lmics), a sharing of the technical specifications with generic manufacturers has allowed the development of a scored 10 mg dtg dt.13 this has allowed dtg to be the first-line art of choice across the age spectrum from 4 weeks of age in the new consolidated who guidelines. registration of this new dispersible formulation by sahpra is eagerly awaited and will allow inclusion in the south african guidelines. the approval of dtg dt will facilitate the move away from using lpv/r syrup formulations and their associated problems. at a recent conference presentation of the results of the odyssey trial, there was no significant difference in weight gain in participants on a dtg versus non-dtg-containing regimen.14 in addition, the frequency of metabolic adverse events was lower in the dtg arm. these findings are reassuring and further support the use of dtg-based regimens in children. furthermore, with an increase in the available cohort data, the association of ntds and the use of dtg in the first trimester has decreased. the additional data support the use of dtg in women of child-bearing potential and has implications for introducing dtg in adolescent girls. tuberculosis is a common coinfection in south africa, especially in people living with hiv. co-treatment with rifampicin (rif)-containing tuberculosis treatment and dtg results in a significant decrease in the dtg plasma concentration. data in the adult population have supported 50 mg twice daily while on rif to counteract the increased hepatic metabolism. in addition, a substudy of the odyssey trial provided supportive data for this strategy in adolescents receiving rif and dtg 50 mg tablets.15 there is a lack of data on the pharmacokinetics of rif and dtg dt; however, based on the data from adults and adolescents, the usfda in the registration of dtg dt recommended twice-daily dosing of dtg dt in children receiving rif. further studies are required to confirm this strategy; however, international guidelines are likely to support this approach while awaiting more supporting data. as other global medicine regulatory authorities have extensively reviewed the formulation, advocates for the right of children to have access to the best available treatment options, clinician groups and community organisations need to be more vocal in demanding that the approval of this formulation be expedited in south africa. future innovations for simplified paediatric-friendly formulations further simplification of both treatment and prophylactic regimens for children in the future is likely to positively impact the goal of eliminating mother-to-child transmission and achieving the 95-95-95 milestone. the recent registration of long-acting injectable cabotegravir/rilpivirine (la cab/rpv) administered every 2 months in hiv-infected individuals over 18 years by the usfda highlights the direction of future treatment simplification. results from the mocha trial will support the registration of la cab/rpv in adolescents between 12 and 18 years old. while the need for refrigeration during storage of la cab/rpv may limit the use in lmics, it opens up new treatment options. this is because la cab/rpv is administered intramuscularly, where it forms a crystalline structure that slowly releases the active drug into the plasma. a planned study in protocol development (impaact 2036) hopes to explore la cab/rpv in younger children 2–12 years of age and aims to start in 2022. as we move these formulations into younger patients, the injection volumes, injection site (gluteal vs lateral thigh), changes in weight between injections and changes in the absorption and metabolism will need further evaluation. other formulations and delivery mechanisms in development include long-acting oral and implantable formulations (e.g. islatravir and lenacapavir), long-acting broadly neutralising antibodies and microarray patches. each of these formulations is likely to play a significant part in the future treatment and prevention options for children and adolescents. the scope for simplifying paediatric art regimens has vastly improved, with the potential for a once-a-day solid formulation regimen from 4 weeks of age. robust advocacy from clinicians and the community is required to ensure that these life-changing formulations are made available to our patients as soon as possible. acknowledgements the authors acknowledge leora sewnarain for formatting, language editing and proofreading the article. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions m.a., r.v.z., n.s. and g.s. read and approved the final manuscript. ethical considerations this article followed all ethical standards for research without direct contact with human or animal subjects. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references joint united nations programme on hiv/aids (unaids). unaids data 2020 [homepage on the internet]. [cited 2021 june 17]. available from: https://www.unaids.org/en/resources/documents/2020/unaids-data woldesenbet sa, jackson dj, lombard cj, et al. structural level differences in the mother-to-child hiv transmission rate in south africa: a multilevel assessment of individual-, health facility-, and provincial-level predictors of infant hiv transmission. j acquir immune defic syndr. 2017;74(5):523–530. https://doi.org/10.1097/qai.0000000000001289 dorward j, khubone t, gate k, et al. the impact of the covid-19 lockdown on hiv care in 65 south african primary care clinics: an interrupted time series analysis. lancet hiv. 2021;8(3):e158–e165. https://doi.org/10.1016/s2352-3018(20)30359-3 jewell bl, mudimu e, stover j, et al. hiv modelling consortium: potential effects of disruption to hiv programmes in sub-saharan africa caused by covid-19: results from multiple mathematical models. lancet hiv. 2020;7(9):e629–e640. https://doi.org/10.1016/s2352-3018(20)30211-3 fda approved drugs. abacavir sulfate and lamivudine no. 202381 [homepage on the internet]. [cited 2021 june 17]. available from: https://www.accessdata.fda.gov/drugsatfda_docs/pepfar/202381pi.pdf access to medicine foundation. ending the burden of hiv, malaria and tb in children: children and the ‘big three’ epidemics: despite significant advances in hiv, many children remain at risk, june 2020 [homepage on the internet]. [cited 2021 june 17]. available from: https://accesstomedicinefoundation.org/publications/ending-the-burden-of-hiv-malaria-and-tb-in-children republic of south africa department of health. antiretroviral drug dosing chart for children 2021 [homepage on the internet]. [cited 2021 june 21]. available from: https://sahivsoc.org/files/paeddosingchart_2021.pdf republic of south africa department of health. art clinical guidelines for the management of hiv in adults, pregnancy, adolescents, children, infants and neonates [homepage on the internet]. 2019 oct [updated 2020 mar; cited 2021 june 17]. available from: https://www.knowledgehub.org.za/system/files/elibdownloads/2020-05/2019%20art%20guideline%2028042020%20pdf.pdf viani rm, alvero c, fenton t, et al. p1093 study team: safety, pharmacokinetics and efficacy of dolutegravir in treatment-experienced hiv-1 infected adolescents: forty-eight-week results from impaact p1093. pediatr infect dis j. 2015;34(11):1207–1213. https://doi.org/10.1097/inf.0000000000000848 viani rm, ruel t, alvero c, et al. p1093 study team: long-term safety and efficacy of dolutegravir in treatment-experienced adolescents with human immunodeficiency virus infection: results of the impaact p1093 study. j pediatric infect dis soc. 2020;9(2):159–165. https://doi.org/10.1093/jpids/piy139 bollen pdj, moore cl, mujuru ha, et al. odyssey trial team: simplified dolutegravir dosing for children with hiv weighing 20 kg or more: pharmacokinetic and safety substudies of the multicentre, randomised odyssey trial. lancet hiv. 2020;7(8):e533–e544. https://doi.org/10.1016/s2352-3018(20)30189-2 international maternal pediatric adolescent aids clinical trials network (impaact). p1093 abstracts [homepage on the internet]. [cited 2021 june 17]. available from: https://www.impaactnetwork.org/publications/abstracts?search_api_fulltext=p1093 medicines patent pool. dolutegravir – paediatrics (dtg) [homepage on the internet]. viiv healthcare, april 2014. [cited 2021 june 17]. available from: https://medicinespatentpool.org/licence-post/dolutegravir-paediatrics-dtg/ turkova a. dolutegravir-based art is superior to nnrti/pi-based art in children and adolescents [homepage on the internet]. 28th conference on retroviruses and opportunistic infections (croi). abstract no. 174; june 3 – nov 3, 2021 | virtual [cited 2021 june 17]. available from: https://www.croiconference.org/abstract/dolutegravir-based-art-is-superior-to-nnrti-pi-based-art-in-children-and-adolescents/ waalewijn h, mujuru ha, amuge p, et al. adequate dolutegravir exposure dosed bid with rifampicin in children 6 to <18 years [homepage on the internet]. 27th conference on retroviruses and opportunistic infections (croi). abstract no. 847; mar 8–11, 2020. boston, ma. [cited 2021 june 17]. available from: https://www.croiconference.org/abstract/adequate-dolutegravir-exposure-dosed-bid-with-rifampicin-in-children-6-to/ abstract introduction methodology data collection statistical analysis results discussion limitations conclusion acknowledgements references about the author(s) mbali t. makhubo department of obstetrics and gynaecology, nelson r. mandela school of medicine, university of kwazulu-natal, durban, south africa thinagrin d. naidoo department of obstetrics and gynaecology, grey’s hospital, pietermaritzburg, south africa nelson r. mandela school of medicine, university of kwazulu-natal, durban, south africa citation makhubo mt, naidoo td.healthcare worker compliance with cervical cancer screening guidelines. an audit at district and regional level of care in the pietermaritzburg metropolitan area of kwazulu-natal. s afr j hiv med. 2020;21(1), a1104. https://doi.org/10.4102/sajhivmed.v21i1.1104 original research healthcare worker compliance with cervical cancer screening guidelines. an audit at district and regional level of care in the pietermaritzburg metropolitan area of kwazulu-natal mbali t. makhubo, thinagrin d. naidoo received: 11 may 2020; accepted: 26 june 2020; published: 02 sept. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: in south africa (sa) there are screening guidelines for cervical cancer in women living with hiv (wlwh). to our knowledge there is lack of data concerning the knowledge of health care workers (hcws) about cervical cancer screening guidelines before the initiation of antiretroviral therapy (art) in wlwh. objectives: to investigate the knowledge and familiarity of hcws regarding cervical cancer screening guidelines in wlwh. methods: a cross-sectional questionnaire-based study exploring compliance with cervical cancer screening guidelines before initiating art was conducted with 85 hcws in the antiretroviral (arv) clinics of a district and regional hospitals in kwazulu-natal, sa. data were analysed using stata v13 and a p-value of ≤ 0.05 was considered statistically significant. results: eighty-five hcws were included in the study. health care workers’ responses to knowledge about cervical cancer screening in wlwh were suboptimal and revealed significant gaps. most hcws did not know the screening intervals of wlwh. statistically significant associations were found between an hcw’s occupation and responses to the likert scale questions. conclusion: although the majority of hcws were familiar with cervical cancer screening guidelines in wlwh, the study highlights that there are deficiencies in both knowledge and practice. creating awareness among hcws regarding the current methods of cervical cancer screening is a necessary to reduce morbidity and mortality from cervical cancer in wlwh. keywords: questionnaire; likert scale; healthcare worker; cervical cancer; hiv; guidelines. introduction the ‘dual epidemics’ of the human immunodeficiency virus (hiv) and cervical cancer have been responsible for the premature deaths of thousands of women in resource-constrained countries (rccs).1 screening is a vital key to the early detection and prevention of cervical cancer. given the enormous burden of hiv and human papillomavirus (hpv) in south africa (sa), healthcare workers’ (hcws) knowledge of cervical screening and the management of both cervical cancer and hiv is vital to ensure the survival and well-being of women living with hiv (wlwh). the risk of hpv infection is increased, as are precancerous cervical lesions (risk increased by 2–12 times), in wlwh versus hiv-uninfected women.2 linking cervical screening to antiretroviral therapy(art) treatment initiation in wlwh provides hcws with a unique opportunity to diagnose and manage both viral infections. if followed properly, the screening guidelines will reduce the risk of cervical cancer in rccs.3 premalignant lesions are reportedly four to five times more likely in wlwh than in uninfected women.4 furthermore, cervical cancer in south african wlwh presents earlier (up to 18 years earlier) than hiv-uninfected peers.5 well-implemented national cervical screening guidelines and programmes significantly reduce the attributable morbidity and mortality of cervical cancer in wlwh and hiv-uninfected women.6 cervical screening is most effective when undertaken within an organised programme. in rccs, including sa, screening rates and subsequent follow-up care remain suboptimal. screening rates as low as 1% have been reported.7 screening coverage is crucial for effective prevention. the problem is compounded in rccs by poor call-back systems, weak infrastructure and inadequately skilled staff. indeed, it is unethical to offer screening without ensuring that follow-up and treatment services are available for all women. it is essential therefore that the hcws with appropriate training and skills who provide these services are familiar with the screening guidelines. to our understanding, there is a lack of data on the knowledge of hcws in this regard. this study aimed to investigate the knowledge and familiarity of hcws with cervical cancer guidelines in wlwh before initiating art. methodology this study was a cross-sectional questionnaire-based descriptive survey of 85 hcws in art clinics in the pietermaritzburg metropolitan area of kwazulu-natal province, sa. the study population was stratified by profession into three groups: interns, medical officers and professional nurses. the cohort was recruited from staff members attached to the antiretroviral (arv) clinics of the northdale (district) and edendale (regional) hospitals. the study participants were randomly selected from each group. a survey cover sheet explaining the purpose of the study was attached to the questionnaire and was signed by those who completed the questionnaire. to ensure anonymity and confidentiality, personal-subject identifiers were not used in the questionnaire itself. the principal investigator enrolled only participants who willingly and voluntarily filled in and returned the questionnaire. data collection a structured and pretested, self-administered questionnaire was used for data collection. the collected data were checked for completeness and consistency by the principal investigator and the supervisor. concerning the guidelines, experts in research methodology, obstetrics and gynaecology, and oncology confirmed the validity of the questionnaire before the pilot study commenced. the instrument was pretested on 10 study participants working in other health facilities who were not part of the actual study. findings from the pre-test were used to modify the instrument and clarify the questions. the questionnaire was divided into two parts: the first part dealt with the socio-demographic profile and professional status of the respondents and the second part dealt with knowledge about the practice of cervical cancer screening in wlwh before initiating art. the questionnaire was written in english. healthcare workers’ responses were assessed by asking them to rate each of the following statements on a five-point likert scale: all wlwh must have a yearly pap smear. a pap smear must be done at the age of 21 years irrespective of hiv status. a pap smear in wlwh is only done after the age of 30 years. cervical cancer screening in wlwh can be done anytime. cervical cancer screening in wlwh can only be done after 3 years of initiating art. if the results come back with high-grade squamous intraepithelial lesion (hsil), the patient must repeat the pap smear. if the results come back with persistent low-grade squamous intraepithelial lesion (lsil), keep the patient at the clinic without any further action. the incidence of cervical cancer in our population is very high. healthcare workers were asked to choose one of the following options for each of the statements listed above: ‘strongly agree’, ‘agree’, ‘neither agree nor disagree’, ‘disagree’ or ‘strongly disagree’. for ease of interpreting and presenting results, responses for ‘strongly agree’ and ‘agree’ and for ‘disagree’ and ‘strongly disagree’ were combined. participants’ practices were assessed by asking specific questions about practices regarding cervical cancer screening. statistical analysis a descriptive analysis of the hcw’s demographic characteristics is presented. frequencies and percentages were used to summarise categorical variables, such as the type of hcws. frequency distributions of numeric variables, such as age and years of experience, were examined for normality and means or medians used as appropriate. the outcome of the study was a knowledge score composed of the sum of the responses of each hcw to the questions posed and measured on the likert scale. subgroups were assessed by age, type of hcw and experience (years) and were compared with responses to individual questions, and an overall score was determined using the chi-square test. data were analysed using stata v13 and a p-value of < 0.05 was considered statistically significant. ethical consideration ethical clearance was obtained from the biomedical research ethics committee, the university of natal (be: 572/18), department of health and the various institutions before commencing the study. all participants provided written informed consent before enrolment. results eighty-five hcws were interviewed and enrolled in the study. demographic characteristics and professional standing of participants the majority of the hcws were 35 years old or younger (60%), women (71.8%) and black people (52.9%). professional nurses and medical officers accounted for 41.2% and 22.1% of the hcws, respectively. a total of 66% of the hcws had less than 3 years’ experience in the initiation of arv drugs and only 19 (22.4%) had formal training in hiv management. a total of 51.8% of the hcws practised at a district hospital (northdale), whereas the other half practised at the regional hospital (edendale) (table 1). of the 19 hcws who had formal training in hiv management, 7 (36.8%) had a diploma and 12 (62.2%) had a certificate in hiv management. table 1: healthcare workers’ designation and experience or training in different levels of care. awareness of cervical cancer screening guidelines and local protocols only two (2.4%) of the hcws were aware of the kwazulu-natal cervical cancer screening guidelines, and 20 (23.5%) were aware of the world health organization (who) cervical cancer screening guidelines. fifty-one (60%) of the hcws considered that the guidelines on screening wlwh provided by their health facilities were adequate (table 2). table 2: knowledge of cervical cancer screening guidelines or protocol compiled by different institutions. twenty-three (27.1%) hcws were aware of the umgungundlovu district protocol on cervical cancer screening, of which 19 were professional nurses. fifty-one (60.0%) hcws felt that patients who had abnormal pap smear results should be referred for colposcopy (33 professional nurses and 17 medical officers), and 76 (89.4%) participants believed that the health facilities where they were currently working were compliant with the cervical cancer screening programme for hiv-positive patients. only two (2.4%) participants (one first-year medical intern and one medical officer) were aware of more than one set of cervical cancer screening guidelines. the kwazulu-natal guidelines were the least known of all screening protocols. the knowledge and the implementation of cervical cancer screening guidelines the knowledge of the respondents about cervical cancer screening in wlwh was assessed on a likert scale. healthcare workers’ responses to the various statements that were designed to test their knowledge and implementation of cervical cancer screening varied (see table 3). table 3: responses of healthcare workers to statements of cervical cancer in women living with human immunodeficiency virus (n = 85).† most of the hcws were familiar with cervical cancer screening in wlwh infection in general; however, specific gaps in the knowledge were identified. some of the identified gaps included lack of knowledge about screening intervals in wlwh, when to refer a patient with an abnormal pap smear or when to repeat a smear. there was a statistically significant association betweenhcws and the awareness of the umgungundlovu district policy (only 2.1% were aware) on cervical cancer screening (p = 0.00), and the perception of oneself being compliant with the cervical cancer screening in wlwh (p = 0.00). statistically significant associations were also found between healthcare category and certain likert scale questions (table 4). table 4: association between healthcare workers and variables related to knowledge of guidelines. discussion to our understanding, this is the first study to evaluate the knowledge and implementation of cervical cancer screening guidelines by hcws in wlwh in kwazulu-natal province. the most crucial finding is that 70% of hcws knew that screening in wlwh could be done at any age, including at the time of the diagnosis of hiv infection. this is important because this differs from the previous policy that all women should be screened from the age of 30 years onwards. this finding highlights an awareness that wlwh are at a higher risk and should be managed differently. the national department of health (ndoh) guidelines were used as the yardstick. more than 80% of the hcws agreed that all wlwh must have a yearly pap smear. current south african recommendations encourage all wlwh who are at increased risk of developing cervical cancer to have yearly pap smears in high-resource settings, and 3 yearly in low-resource settings.8 similarly, canadian guidelines recommend annual pap tests for wlwh.9 one-third of the hcws agreed that a pap smear should be done at 21 years of age irrespective of hiv status. in this regard, the south african guidelines report that the pap smear must be done at the age of 25 years in hiv-uninfected women whilst in wlwh smears should be done at the time of testing hiv-seropositive.8 at present, the ndoh guidelines for the cervical cancer programme offer three cervical cytology smears per lifetime at public health facilities, starting from 30 years, and then at 10-year intervals, in hiv-uninfected women. guidelines for wlwh include more frequent cytology tests. the national department of health recommends screening for wlwh at hiv diagnosis and every 3 years then if screening is normal and yearly if abnormal (lsil). the who advocates at least one smear test (at 30–35 years of age) to be performed in a woman’s lifetime. women living with hiv who are < 21 years of age and are sexually active may have a high rate of progression of abnormal cytology.9 brogly and colleagues reported that 30% of adolescents had atypical squamous cells of undetermined significance (asc-us) or greater on their first cervical pap test.10 a small percentage of the hcws agreed that a pap smear in wlwh is only performed after the age of 30 years, whereas the ndoh guidelines state that in wlwh pap smears should be done at the time of diagnosis of the hiv infection.8 more than 40% of the hcws stated that if the results returned as hsil, the patient must repeat the pap smear. and more than 17% of hcws agreed that if the results returned as a persistent lsil, the patient should be kept at the clinic without any further action. this is not what the guidelines state. it is recommended that for a persistent lsil or worse (including asc and atypical glandular cells [agcs]) and hsil, women with abnormal pap smears should be referred for a colposcopy assessment.11,12 our study found that hcws’ responses to cervical screening in wlwh were suboptimal. most of the hcws had less than 3 years of experience in initiating arv drugs and more than 20% had formal training in hiv management, which might have negatively impacted the results. all the hcws in our study were aware of the existence of different cervical cancer screening guidelines. in sa, these guidelines are published by the ndoh. several south african provinces and hospitals have guidelines which they have adapted from the ndoh. it is concerning, however, to note that only 2.1% of kwazulu-natal hcws in this study were familiar with their provincial guidelines. this article recommends that greater attention should be given to the continuing medical education of cervical cancer screening and cervical cancer prevention. most of our hcws were in the early years of their careers. they were aware of both the ndoh and who guidelines. the former is used in all south african public sector hospitals and clinics. although two hcws answered that there were ‘separate’ kzn guidelines, this was an error. the study did not find any statistically significant association between the hcws’ category and their knowledge of the guidelines. this demonstrates the need, regardless of category, for courses in the workplace that target these concerns. on the other hand, significant differences were revealed between hcws and their awareness of district guidelines or policy, the screening intervals of wlwh and when to refer for colposcopy. although the majority of participants indicated that their facilities were compliant with the guidelines, the gaps that have been uncovered indicate the need for ongoing education in this regard. limitations the main limitations of the study are as follows: the small number of hcws: results should be interpreted with caution. the use of a questionnaire may not reflect the actual workplace competency of the participants. the answers reflect a local or specific context and therefore generalisation of the study results may be limited. an operational bias exists in the mixing of different groups of hcws with different levels of professional experience. nonetheless and surprisingly, the gaps were widespread and did not link with individual categories of hcws. conclusion healthcare workers were knowledgeable about cervical cancer screening in wlwh but displayed gaps in practice and knowledge. most of them were well informed about the recommended screening intervals. however, a certain number of hcws did not know when to refer a patient for further management. a delay in the management of precancerous lesions could lead to morbidity and mortality, particularly in wlwh. healthcare workers require guidelines customised to local contexts, in particular for the care of wlwh. recommendations emerging from this study include regular workplace refresher training that highlights the guidelines and related institutional protocols and renewed attention to the monitoring and evaluation of institutional compliance with cervical cancer screening and prevention. acknowledgements we would like to thank both facilities and staff members who participated in our study. competing interests the authors have declared that no competing interests exist. authors’ contributions both authors contributed equally o this work. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability statement data presented in this article can be available upon reasonable request to the corresponding author, provided that the source of data is acknowledged. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references figo. international federation of gynaecology and obstetrics cervical cancer and hiv [homepage on the internet]. c2018 [cited 2020 may]. available from: https://www.figo.org/news/cervical-cancer-and-hiv clifford gm, polesel j, rickenbach m. cancer risk in the swiss hiv cohort study: associations with immunodeficiency, smoking, and highly active antiretroviral therapy. j natl cancer inst. 2005;97(6):425–432. https://doi.org/10.1093/jnci/dji072 atashili j, smith js, adimora aa, eron j, miller wc, myers e. potential impact of antiretroviral therapy and screening on cervical cancer mortality in hiv-positive women in sub-saharan africa: a simulation. plos one. 2011;6(4):e18527. kafuruki l, rambau pf, massinde a, masalu n. prevalence and predictors of cervical intraepithelial neoplasia among hiv infected women at bugando medical centre, mwanza-tanzania. infect agent cancer. 2013;8(1):45. https://doi.org/10.1186/1750-9378-8-45 van bogaert lj. age at diagnosis of preinvasive and invasive cervical neoplasia in south africa hiv-positive versus hiv-negative women. int j gynecol cancer. 2011;21(2):363–366. https://doi.org/10.1097/igc.0b013e3182094d78 kamal em, el sayed ga, el behery mm, el shennawy ga. hpv detection in a self-collected vaginal swab with via for cervical cancer screening with correlation to histologically confirmed cin. arch gynecol obstet. 2014;290(6):1207–1213. https://doi.org/10.1007/s00404-014-3321-6 van schalkwyk sl, maree je, wright scd. cervical cancer: the route from signs and symptoms to treatment in south africa. reprod health matters. 2008;16(32):9–17. https://doi.org/10.1016/s0968-8080(08)32399-4 botha mh, dreyer g. guidelines for cervical cancer screening in south africa. s afr j gynaecol oncol. 2017;9(1):8–12. de pokomandy a, burchell an, salters k, et al. cervical cancer screening among women living with hiv: a cross-sectional study using the baseline questionnaire data from the canadian hiv women’s sexual and reproductive health cohort study (chiwos). cmaj open. 2019;7(2):e217–e226. https://doi.org/10.9778/cmajo.20180151 aids info. guidelines for the prevention and treatment of opportunistic in adults and adolescents with hiv [homepage on the internet]. no date [cited 2020 february 01]. available from: https://aidsinfo.nih.gov/guidelines brogly sb, watts dh, ylitalo n, et al. reproductive health of adolescent girls perinatally infected with hiv. am j public health. 2007;97(6):1047–1052. moodley j, constant d, botha mh, van der merwe fh, edwards a, momberg m. exploring the feasibility of using mobile phones to improve the management of clients with cervical cancer precursor lesions. bmc womens’ health 2019;19(1):2. https://doi.org/10.1186/s12905-018-0702-1 hiv 837 original article hiv and the urban homeless in johannesburg   g m lohrmann, b botha, a violari, g e gray   chris hani baragwanath academic hospital, johannesburg g m lohrmann, mb bch   trinity health services, johannesburg b botha, mphil   perinatal hiv research unit, chris hani baragwanath academic hospital, johannesburg a violari, md, fcpaed (sa) g e gray, mb bch, fcpaed (sa) corresponding author: g m lohrmann (graham.lohrmann@gmail.com)   background. there are few data on hiv prevalence and risk factors among inner-city homeless and marginally housed individuals in south africa. methods. we recruited 136 adults from a johannesburg inner-city homeless clinic; mean age was 32.4 years, 129 (95%) were male, and 90 (66%) were of south african nationality. participants were tested for hiv and answered a short demographic survey. descriptive statistics and uniand multivariate regression analyses were used for data analysis. results. the hiv prevalence in the cohort was 23.5%. transactional sex, relationship status, number of concurrent sexual partners, condom usage and history of previously treated sexually transmitted infections (stis), living on the street, the use of alcohol or drugs, and previous exposure to voluntary counselling and testing (vct), were not significant risk factors for hiv-positivity. statistically significant hiv risk factors on multivariate analysis included the presence of an sti (odds ratio (or) 5.6; p<0.01) and unemployment (or 6.7; p<0.01). south african nationality was a significant risk factor on univariate analysis (or 2.99; p<0.05), but not on multivariate analysis (or 2.2; p=0.17). conclusion . the hiv prevalence in the sample did not differ appreciably from hiv prevalence estimates in other at-risk populations in similar settings, suggesting that homelessness in a south african city alone may not be a significant risk factor for hiv infection. hiv prevention efforts cannot be restricted to behaviour change programmes, but must be more holistic, recognising the protective role that employment has on hiv incidence. s afr j hiv med 2012;13(4):174-177. doi:10.7196/sajhivmed.837 south africa (sa) bears a significant burden of the hiv epidemic, with an estimated 18.8% of the adult population (aged 15 49 years) infected.1 however, the prevalence of hiv within an essentially homeless population, as found in the city centre of johannesburg, is not known. research performed predominantly in developed countries suggests a substantially higher hiv and sexually transmitted infection (sti) burden among the homeless and marginally housed.2 , 3 , 4 the relationship between hiv infection, employment status and homelessness is complex. it is well documented that hiv leads to neuropsychological impairment,5 potentially leading to decreased job performance and unemployment, with up to 65% of hiv-infected individuals unemployed, even in developed countries.6 , 7 unemployment in turn leads to food insecurity, which has been associated with an increased risk of contracting hiv and lower cd4 counts.8 the homeless are also at risk of psychiatric illness and have a decreased awareness of hiv,3 both of which may affect uptake of prevention and/or treatment interventions.9 in addition, the majority of the homeless in sa urban settings are male, and hence more difficult to reach with hiv interventions.10 to gain a better understanding of these issues and to inform future hiv prevention strategies, we investigated the hiv prevalence and risk factors among urban homeless individuals in johannesburg. methods we performed a cross-sectional survey of 136 adults attending a johannesburg inner-city centre soup kitchen and clinic, operated by a local non-governmental organisation. participants were sampled conveniently and classified as homeless or marginally housed. data were collected for 1 year commencing 1 april 2010. hiv testing was performed using 2 rapid finger prick tests from separate manufacturers. a third confirmatory test was used in the case of discordant results. we also included 6 individuals who had proof of a previous hiv-positive test result. exclusion criteria included: (i) earnings in excess of r5 000/month; and (ii) residing in a house defined on the grounds of a solid permanent structure with basic amenities (water, electricity, sewerage) and that is under the ownership or rental of the participant or family (excluding anything considered to be a form of shelter). ethics approval was obtained from the human research ethics committee of the university of the witwatersrand. hiv risk factors were identified by uniand multivariate logistic regression analysis. data were represented as odds ratios (ors) with 95% confidence intervals (cis). results sample characteristics are summarised in table 1. the hiv prevalence was 23.5% (95% ci 16.4% 30.7%). mean participant age was 32.4 years with 129 (95%) of the adults being male and 46 (35%) being foreigners. the mean monthly income for the hiv-positive and -negative groups was r 485 (95% ci r176 r794) and r 863 (95% ci r540 r1 186), respectively. there was no relationship between hiv-seropositivity and relationship status, educational level, number of sexual partners, smoking or use of alcohol, illicit drugs or condoms. previous exposure to voluntary counselling and testing (vct) was not protective against hiv in this sample, as the number of previous tests was marginally higher in the hiv-positive group (1.6 v. 1.2; p>0.05). of patients who tested hiv-positive, 36.3% had had a previous positive test result elsewhere, but had never been followed up in terms of cd4 count or antiretroviral therapy (art) initiation. during post-test counselling, both hiv-positive and -negative groups reported unwillingness to disclose their status to others (59% and 50%, respectively). the results of logistic regression modelling are shown in table 2. there was a significant association between hiv-positive status and unemployment (or 6.7; 95% ci 1.8 25.6; p=0.006), and current sti (or 5.6; 95% ci 1.5 20.7; p=0.010). south african nationality was associated with hiv seropositivity on univariate analysis (or 2.2; 95% ci 1.12 7.9; p=0.028), but not multivariate analysis (or 2.2; 95% ci 0.7 7.0; p=0.17). table 1. sample characteristics characteristic n ( % ) total hiv-positive hiv-negative 136 (100) 32 (100) 104 (100) hiv test result positive negative   32 (24) 104 (76)   32 (100) 0 (0)   0 (0) 104 (100) gender male female   129 (95) 7 (5)   29 (91) 3 (9)   100 (96) 4 (4) residence street shelter informal settlement house   68 (51) 30 (22) 8 (6) 28 (21)   21 (66) 6 (19) 2 (6) 3 (9)   47 (45) 24 (23) 6 (6) 25 (24) marital status married single widowed   14 (11) 91 (73) 20 (16)   3 (10) 21 (72) 5 (17)   11 (11) 70 (73) 15 (16) nationality south african other   87 (65) 46 (35)   26 (84) 5 (16)   61 (60) 41 (40) employment status employed unemployed   55 (42) 77 (58)   7 (22) 25 (78)   52 (50) 52 (50) education level <grade 12 grade 12 tertiary   70 (62) 48 (38) 9 (7)   15 (54) 13 (46) 0 (0)   55 (56) 35 (35) 9 (9) reason for testing multiple partners partner hiv-positive or advised by family/friends feeling unwell or advised by health worker retesting (confirming hiv-positive test) curious about status partner’s behaviour or stopping condoms other   6 (4) 5 (4) 42 (31) 3 (2) 96 (71) 14 (10) 8 (6)   3 (9) 0 (0) 22 (68) 3 (9) 15 (47) 1 (3) 1 (3)   3 (3) 5 (5) 20 (19) 0 (0) 81 (78) 13 (13) 7 (7) result of most recent hiv test positive negative did not collect   12 (16) 61 (82) 1 (1)   11 (55) 8 (40) 1 (5)   1 (2) 52 (98) 0 (0) current exposures current sti cough for >1 week alcohol on most days smoking on most days recreational drug use in preceding week condom use at last sexual encounter   23 (17) 27 (20) 40 (30) 65 (48) 16 (12) 91 (51)   11 (35) 10 (32) 10 (31) 19 (59) 3 (9) 21 (44)   12 (12) 17 (17) 30 (29) 46 (45) 13 (13) 70 (53) table 1. sample characteristics (continued) characteristic n ( % ) total hiv-positive hiv-negative 136 (100) 32 (100) 104 (100) vct previous hiv testing and counselling   65 (49)   15 (50)   50 (49) exposure in preceding 12 months vaginal or anal intercourse blood transfusion or medical injection intercourse after alcohol or illicit drugs transactional sexual intercourse had oral sex sexual intercourse without a condom symptoms of an sti diagnosed with an sti   114 (84) 45 (33) 65 (48) 18 (13) 28 (21) 55 (40) 26 (19) 16 (12)   26 (81) 11 (34) 17 (50) 7 (22) 6 (19) 14 (44) 11 (34) 7 (22)   88 (85) 34 (33) 48 (46) 11 (11) 22 (21) 41 (39) 15 (14) 9 (9) sti = sexually transmitted infection; vct = voluntary counselling and testing. table 2. risk factors for hiv using logistic regression* risk factor univariate   multivariate or (95% ci) p -value   or (95% ci) p -value unemployment 3.7 (1.4 9.8) 0.009   6.7 (1.8 25.6) 0.006 south african nationality 2.99 (1.12 7.9) 0.028   2.2 (0.7 7.0) 0.170 current sti 3.7 (1.4 9.8) 0.008   5.6 (1.5 20.7) 0.010 sti = sexually transmitted infection. *statistically significant results are indicated in bold. discussion the associations between homelessness and hiv in this study contrast markedly with international literature, in terms of absolute risk and behaviour patterns. the hiv prevalence in our study was high by international standards, but not substantially greater than that of a general sa population of similar age and gender.12 furthermore, no association was found between drug use and hiv in our sample, although this is a well-documented hiv risk factor in homeless populations in europe and north america.2 , 3 , 4 hiv incidence in sa has only recently begun to plateau, with no consensus on the reason for this. it is unclear whether the successes of education and prevention programmes are finally being felt, or if increased access to art and sti treatment are at play. evidence suggests that hiv education and prevention programmes may not have had a significant effect on hiv status in our sample. for example, previous exposure to vct did not appear to be protective against hiv, and the patterns of risk behaviour were similar between hiv-positive and -negative individuals. however, the association between hiv status and unemployment was significant, because it linked unemployment to hiv risk, rather than the more simplistic factor of homelessness. overall, the results of our study suggest that the dynamics of hiv among the urban homeless in sa may be different from other settings. high levels of inequality and unemployment, especially in an urban environment, lead to a unique set of risk factors which differ from that of the developed world. in sa, simply being homeless or marginally housed may not put individuals at increased risk of hiv compared with the general population. however, unemployment needs to be addressed to mitigate the effect of the hiv epidemic in this setting. references 1. national department of health (doh). hiv & aids and sti strategic plan for south africa 2007 2011. pretoria: doh, 2008. 1. national department of health (doh). hiv & aids and sti strategic plan for south africa 2007 2011. pretoria: doh, 2008. 2. shakarishvili a, dubovskaya lk, zohrabyan ls, et al. sex work, drug use, hiv infection, and spread of sexually transmitted infections in moscow, russian federation. lancet 2005;366(9479):57-60. 2. shakarishvili a, dubovskaya lk, zohrabyan ls, et al. sex work, drug use, hiv infection, and spread of sexually transmitted infections in moscow, russian federation. lancet 2005;366(9479):57-60. 3. tynes ll, sautter fj, mcdermott be, winstead dk. risk of hiv infection in the homeless and chronically mentally ill. s afr med j 1993;86(3):276-281. 3. tynes ll, sautter fj, mcdermott be, winstead dk. risk of hiv infection in the homeless and chronically mentally ill. s afr med j 1993;86(3):276-281. 4. bangsberg dr, hecht fm, charlebois ed, et al. adherence to protease inhibitors, hiv-1 viral load, and development of drug resistance in an indigent population. aids 2000;14(4):357-366. 4. bangsberg dr, hecht fm, charlebois ed, et al. adherence to protease inhibitors, hiv-1 viral load, and development of drug resistance in an indigent population. aids 2000;14(4):357-366. 5. heaton rk, velin ra, mccutchan ja, et al. neuropsychological impairment in human immunodeficiency virus-infection: implications for employment. hnrc group. hiv neurobehavioral research center. psychosom med 1994;56(1):8-17. 5. heaton rk, velin ra, mccutchan ja, et al. neuropsychological impairment in human immunodeficiency virus-infection: implications for employment. hnrc group. hiv neurobehavioral research center. psychosom med 1994;56(1):8-17. 6. dray-spira r, gueguen a, lert f; vespa study group. disease severity, self-reported experience of workplace discrimination and employment loss during the course of chronic hiv disease: differences according to gender and education. occup environ med 2008;65(2):112-119. [http://dx.doi.org/10.1136/oem.2007.034363] 6. dray-spira r, gueguen a, lert f; vespa study group. disease severity, self-reported experience of workplace discrimination and employment loss during the course of chronic hiv disease: differences according to gender and education. occup environ med 2008;65(2):112-119. [http://dx.doi.org/10.1136/oem.2007.034363] 7. dray-spira r, lert f; vespa study group. living and working with hiv in france in 2003: results from the anrs-en12-vespa study. aids 2007;21(1):s29-s36. [http://dx.doi.org/10.1097/01.aids.0000255082.31728.52] 7. dray-spira r, lert f; vespa study group. living and working with hiv in france in 2003: results from the anrs-en12-vespa study. aids 2007;21(1):s29-s36. [http://dx.doi.org/10.1097/01.aids.0000255082.31728.52] 8. weiser sd, bangsberg dr, kegeles s, ragland k, kushel mb, frongillo ea. food insecurity among homeless and marginally housed individuals living with hiv/aids in san francisco. aids behav 2009;13(5):841-848. [http://dx.doi.org/10.1007/s10461-009-9597-z] 8. weiser sd, bangsberg dr, kegeles s, ragland k, kushel mb, frongillo ea. food insecurity among homeless and marginally housed individuals living with hiv/aids in san francisco. aids behav 2009;13(5):841-848. [http://dx.doi.org/10.1007/s10461-009-9597-z] 9. tsai ac, weiser sd, petersen ml, ragland k, kushel mb, bangsberg dr. a marginal structural model to estimate the causal effect of antidepressant medication treatment on viral suppression among homeless and marginally housed persons with hiv. arch gen psychiatry 2010;67(12):1282-1290. [http://dx.doi.org/10.1001/archgenpsychiatry.2010.16] 9. tsai ac, weiser sd, petersen ml, ragland k, kushel mb, bangsberg dr. a marginal structural model to estimate the causal effect of antidepressant medication treatment on viral suppression among homeless and marginally housed persons with hiv. arch gen psychiatry 2010;67(12):1282-1290. [http://dx.doi.org/10.1001/archgenpsychiatry.2010.16] 10. nglazi md, van schaik n, kranzer k, lawn sd, wood r, bekker lg. an incentivized hiv counseling and testing program targeting hard-to-reach unemployed men in cape town, south africa. j acquir immune defic syndr 2012;59(3):e28-e34. [http://dx.doi.org/10.1097/qai.0b013e31824445f0] 10. nglazi md, van schaik n, kranzer k, lawn sd, wood r, bekker lg. an incentivized hiv counseling and testing program targeting hard-to-reach unemployed men in cape town, south africa. j acquir immune defic syndr 2012;59(3):e28-e34. [http://dx.doi.org/10.1097/qai.0b013e31824445f0] 11. shisana o, rehle t, simbayi lc, et al. south african national hiv prevalence, hiv incidence, behaviour and communication survey. durban: human sciences research council press, 2005. 11. shisana o, rehle t, simbayi lc, et al. south african national hiv prevalence, hiv incidence, behaviour and communication survey. durban: human sciences research council press, 2005. 12. unaids/who. aids epidemic update december 2006. unaids/who 2006. http://data.unaids.org/pub/epireport/2006/2006_epiupdate_en.pdf (accessed 1 august 2012). 12. unaids/who. aids epidemic update december 2006. unaids/who 2006. http://data.unaids.org/pub/epireport/2006/2006_epiupdate_en.pdf (accessed 1 august 2012). abstract introduction methods results discussion conclusion acknowledgements references about the author(s) cleophas chimbetete newlands clinic, harare, zimbabwe tinashe mudzviti newlands clinic, harare, zimbabwe school of pharmacy, college of health sciences, university of zimbabwe, harare, zimbabwe tinei shamu newlands clinic, harare, zimbabwe institute of social and preventive medicine, university of bern, bern, switzerland citation chimbetete c, mudzviti t, shamu t. profile of elderly patients receiving antiretroviral therapy at newlands clinic in 2020: a cross-sectional study. s afr j hiv med. 2020;21(1), a1164. https://doi.org/10.4102/sajhivmed.v21i1.1164 original research profile of elderly patients receiving antiretroviral therapy at newlands clinic in 2020: a cross-sectional study cleophas chimbetete, tinashe mudzviti, tinei shamu received: 28 aug. 2020; accepted: 19 sept. 2020; published: 10 dec. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: people living with hiv (plwh) face new challenges such as accelerated ageing and higher rates of comorbidities including cardiovascular, renal and metabolic diseases as they age. objectives: to profile the demographic and clinical characteristics of elderly patients receiving hiv care at newlands clinic (nc), harare, zimbabwe, as of 01 october 2019. methods: a cross-sectional analysis was conducted using clinic data. all patients who were 50 years and older on 01 october 2019 were enrolled. descriptive statistics (medians, interquartile ranges [iqrs] and proportions) were used to describe patient demographic and clinical characteristics. results: out of 6543 patients undergoing care at nc, 1688 (25.8%) were older than 50 years. the median duration of antiretroviral therapy (art) was 10.9 years (iqr: 7.1–13). over 90% of all patients had an hiv viral load below 50 copies/ml. women were more likely than men to be overweight and obese (32% and 25% vs. 18% and 7%, respectively). hypertension (41.2%), arthritis (19.9%) and chronic kidney disease (11.6%) were common comorbidities differently distributed based on sex. the most common malignancy diagnosed in women was cervical intra-epithelial neoplasia (68% of cancer burden in women) and kaposi sarcoma was the leading malignancy in men (41% of cancer burden in men). nearly 20% of patients had at least two chronic non-communicable comorbidities and 5.6% had at least three. conclusion: a high burden of comorbidities was observed amongst hiv-positive elderly patients receiving art. age-appropriate monitoring protocols must be developed to ensure optimum quality of care for elderly hiv-positive individuals. keywords: hiv infection; elderly patients; comorbidities; art; zimbabwe. introduction effective antiretroviral therapy (art) has changed the course of human immunodeficiency virus (hiv) infection from being considered a fatal illness to a chronic manageable condition. this has enabled people to grow old living with hiv. the number of people who are more than 50 years old and living with hiv has increased globally because of the success of national art programmes and the control of new infections amongst the elderly.1 the life expectancy of people living with hiv (plwh) has increased substantially, approximating that of the general population in high-income countries.2,3 similar gains in life expectancy have also been reported in some countries in sub-saharan africa.4 it seems likely that the median age of plwh will increase with time as more and more people garner the survival benefits of effective art. it is now critical to promote healthy ageing amongst plwh, an achievement that some have described as the ‘fourth 90%’.5 as plwh age, they face many of the same health challenges as faced by older individuals in the general population. additionally, ageing plwh face new challenges such as accelerated ageing and higher rates of comorbidities including cardiovascular, renal and metabolic diseases.6 comorbidities occur at high rates at all ages amongst plwh but become increasingly important as this population ages. people living with hiv also develop geriatric syndromes and frailty earlier as compared to hiv uninfected people.7 certain art drugs such as protease inhibitors may increase cardiovascular risk because of poor metabolic profile including hyperlipidaemia compared to other drugs such as the non-nucleoside reverse transcriptase inhibitors.8 there has been a documented increase in the rate of all cancers, particularly lung, prostate, colorectal, anal, cervix, lymphomas and breast as plwh age.9 however, it is important to note that cancer rates increase with age in everyone. although there is a growing body of research on hiv and ageing, evidence from lowand middle-income countries that bear the highest burden of hiv infection is scarce.10,11 the expectations and management of elderly plwh differ from those of younger patients and may change over time. in this study, we profiled the demographic and clinical characteristics of elderly patients receiving comprehensive hiv care at newlands clinic (nc), harare, zimbabwe, as of 01 october 2019. there is evidence that the distribution of comorbidities may differ by sex12; therefore, we analysed and reported our results by sex. methods study design this study utilised a cross-sectional analysis of routinely collected electronic clinic data. study setting the study was conducted at newlands clinic, harare, zimbabwe. newlands clinic, operated by the ruedi luethy foundation, is a model public–private partnership with the ministry of health and child care. since 2004 the clinic has offered comprehensive hiv treatment and care to individuals living with hiv. operations of the clinic have been previously described.13 the clinic’s electronic database captures patient-level data on laboratory test results, diagnoses, medications and demographic variables. sampling patients ≥ 50 years were defined as elderly. all patients who were 50 years and older as on 01 october 2019 were included in the analysis. the study had no exclusion criteria for enrolment. data analysis routinely collected electronic patient data were abstracted from the clinic’s electronic database using custom structured language queries and exported to excel. records were de-identified at abstraction and assigned numeric unique identifiers. stata version 13 was used for analysis. the most recent cd4 cell count and hiv viral load (vl) were defined as the last test result documented in the patient’s clinic notes taken within the preceding year. weight categories were defined using body mass index (bmi) as follows: underweight (bmi < 18 kilogram/square meter [kg/m2]), normal weight (bmi of 18 kg/m2 – 25 kg/m2), overweight (bmi > 25 kg/m2 – 30 kg/m2) and obese (bmi > 30 kg/m2). baseline age was defined as age at the date of initiating art. descriptive statistics (medians, interquartile ranges [iqrs] and proportions) were used to describe patient demographic and clinical characteristics. diagnosis of comorbidities was conducted based on the following existing national guidelines: diabetes mellitus (dm) is defined as either fasting blood sugar ≥ 7.0 millimoles per litre (mmol/l) or random blood sugar of ≥ 11 mmol/l, if it still remains high after 3 months, then treatment is instituted. hypertension is defined as two blood pressure readings > 140/90 millimetre of mercury (mmhg) at least 6 h apart. chronic kidney disease (ckd) is defined as a serum creatinine clearance of < 60 milligrams per deciliter (mg/dl) confirmed with a second result within 3–6 months. all cancers ever diagnosed were included in the analysis and the pre-cancer conditions of vulva and cervical intra-epithelial neoplasia (vin and cin) were included as well. weight and height measurements were performed by nurses in the consulting rooms using seca 752 or seca 952 scales and wall-mounted height measure tapes, respectively. before being weighed, patients removed shoes, jackets and emptied their pockets. samples for blood glucose measurement were collected into 4-ml bd vacutainer plus plastic tubes with 10 mg sodium fluoride and 8 mg potassium oxalate additives. blood samples for creatinine measurement were collected into 4-ml bd vacutainer plus plastic serum tubes with clot activator and silicone-coated interior. glucose and creatinine measurements were conducted at the on-site laboratory on a cobas integra 400 plus instrument using the hexokinase and jaffe reaction methods, respectively. ethical consideration permission to carry out the study was granted by the newlands clinic local research board. ethical approval was granted by the medical research council of zimbabwe, approval number: a1336. participants consented to publication as part of the informed consent process. results of the 6543 patients in care at nc, 1688 (25.8%) were above the age of 50 years (table 1). the median age at analysis was 56 years (iqr: 52–61), with 72.2% of elderly patients aged between 50 and 60 years, and no difference by sex. the median duration of art was 10.9 years (iqr: 7.1–13). at enrolment into care, 51% were married, 32% widowed, 6% divorced and 11% single. there was a far lower proportion of married women than married men (31% vs. 82%). the most recent median cd4 cell count in this cohort was 464 cells/mm3 (iqr: 327–628), which was higher in females than males (526 vs. 377). over 90% of all patients were virally suppressed, with vls below 50 copies/ml. only 1.8% of patients had a vl > 1000 copies/ml. no sex differences were observed in the vl distribution. almost half of the elderly patients were either overweight or obese and 8% were underweight. women were more likely than men to be overweight and obese (32% and 25% vs. 18% and 7%, respectively). most patients (64.1%) received the fixed dose art combination of tenofovir, lamivudine and dolutegravir. table 1: demographic and clinical characteristics of elderly patients receiving antiretroviral therapy at newlands clinic in march 2020, by sex. comorbidities and pill burden hypertension, arthritis and any malignancy were common comorbidities differently distributed by sex (table 2). hypertension was the most common comorbidity, with 704 (41.2%) patients having a documented diagnosis of hypertension. a higher proportion of women as compared to men had hypertension (48.5% vs. 31.6%, respectively). arthritis was the second most common comorbidity and higher amongst women compared to men (24.5% vs. 13.1%), as was any malignancy (11.2% compared with 2.5%). other comorbidities included dm (7.2%), ckd (11.6%) and congestive cardiac failure (2.2%), which were similarly distributed in men and women. nearly 20% of patients had at least two chronic non-communicable comorbidities and 5.6% had three (figure 1). almost half of the cohort (47%) received an additional chronic medicine other than art. figure 1: distribution of comorbidities and additional chronic medicines amongst elderly patients receiving antiretroviral therapy at newlands clinic in march 2020. table 2: distribution of comorbidities amongst elderly patients receiving antiretroviral therapy at newlands clinic in march 2020, by sex. burden of malignancies ever diagnosed amongst women, the most common malignancy diagnosed was cin3, accounting for 68% of the malignancy burden (table 3). other common malignancies in women included cancer of the cervix (12%) and vin (9%). amongst men, the most common malignancy was kaposi sarcoma (41%), followed by lymphomas and penile cancer (24%). table 3: distribution of malignancies amongst elderly patients receiving antiretroviral therapy at newlands clinic in march 2020, by sex. discussion we found that a quarter of plwh receiving care at nc were older than 50 years. the majority of these elderly patients had received art for over 10 years. most men were married; the majority of women were widowed. this cohort of elderly patients had well-controlled hiv infection with evidence of good immunological status. a high prevalence of overweight or obesity was reported, particularly amongst women. comorbidities were common, notably hypertension, malignancies (far higher in women than in men) and ckd (higher in men than in women). nearly 20% of patients had at least two chronic comorbidities, and 5.6% had three. the goal of art is sustained suppression of hiv replication. our results show that elderly patients with hiv achieve high rates of viral suppression. this finding is consistent with the results from other studies.10 older patients receiving art have demonstrated good medication adherence and this plays a key role in achieving high rates of viral suppression.14,15 although only half of our patients were married at the time of enrolment into care, over 80% of men were married. the higher proportion of marriage amongst men may be because of the fact that men are more likely to remarry after the loss of a spouse or after divorce.16 older patients with hiv face a number of challenges that may affect their quality of life. loss of partners and friends may lead to social isolation, depression and poor adherence to medicines.17 additional stressors such as unemployment and poverty may further worsen the quality of life. the high number of comorbidities and pill burden may negatively affect medicine adherence. interactions between art and other medications are a major consideration amongst the ageing population. the high prevalence of chronic non-aids diseases in this cohort is consistent with the findings from other studies which have showed an increased number of comorbidities in plwh at all ages, but particularly as this population ages.6 hypertension is now recognised as an important chronic comorbid condition of plwh and is associated with increased morbidity and mortality.18 screening and optimal management of hypertension must become part of the comprehensive care of elderly plwh. the prevalence of ckd was high. numerous risk factors are involved in renal disease in plwh, such as age, black race, dm, hypertension, low cd4 counts and certain art medicines like tenofovir disoproxil fumarate.19 all hiv-positive patients especially the elderly must have annual measurements of their renal function. diabetes mellitus was far less common than hypertension. as has been previously reported, the risk of developing dm in plwh is not well-established, and studies have not consistently shown a relationship between dm and hiv.20,21 however, some studies have shown that the risk of dm increases amongst patients receiving art.22 a large number of elderly patients suffered from different forms of malignancies, which were differently distributed by sex. human papilloma virus (hpv)-related malignancies were the leading diagnosed cancers. almost 70% of the women with malignancies had hpv-related cin3. the hpv-related anogenital malignancies will remain a challenge amongst hiv-infected men and women even in the era of effective art.23 screening for high-risk hpv infection should become part of the care of hiv-positive women. the estimated cumulative incidence for other cancers such as non-hodgkin’s b-cell lymphoma, lung cancer, liver cancer and hodgkin’s lymphoma increased amongst hiv-infected patients.24 routine screening for common cancers should be part of the comprehensive care of hiv-infected elderly patients. our study was strengthened by very high levels of data completeness. however, our study was limited as we used data from a single clinic only. frailty, cognitive impairment and other geriatric syndromes that are common and important in hiv were not included in comorbidities as data on these are not routinely collected. furthermore, assessing cancers cross sectionally as we did, without consideration of those who have died of cancer prior to the data pull, underestimates the true cancer burden. we assessed all cancers ever diagnosed (historical). we acknowledge that although these data are interesting, they are potentially misleading. despite these limitations, we believe that our results are important to healthcare providers and policymakers. conclusion our data demonstrates that in africa high rates of virological suppression can be achieved amongst elderly patients on art. however, the high rates of obesity (especially amongst women) and hypertension in this population need to be addressed. the prevalence of pre-malignant cervical disease amongst elderly women is high; and hence, routine cervical cancer screening is essential for elderly women living with hiv. the time has come for hiv treatment programmes to draw on a wide range of medical disciplines and evidence-based screening procedures for the multidisciplinary care of the ageing hiv-infected population. age-appropriate monitoring protocols must be developed to ensure optimum quality of care for elderly hiv-positive individuals. acknowledgements the authors would like to acknowledge newlands clinic staff and patients. furthermore, we acknowledge morna cornell who mentored us during the writing process. competing interests the authors have no competing interests to declare. authors’ contributions all authors were involved in designing the study. t.s. and c.c. conducted the data analysis. c.c. prepared the draft manuscript. t.s. and t.m. reviewed the draft manuscript. c.c. prepared the final manuscript for publication. funding information study did not receive any funding. analysis is conducted as part of the routine clinic work. data availability statement the data sets used and/or analysed during the current study are available from the corresponding author upon request. disclaimer the views expressed in this article are those of the authors’ and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references autenrieth cs, beck ej, stelzle d, mallouris c, mahy m, ghys p. global and regional trends of people living with hiv aged 50 and over: estimates and projections for 2000–2020. plos one. 2018;13(11):e0207005. https://doi.org/10.1371/journal.pone.0207005 wandeler g, johnson lf, egger m. trends in life expectancy of hiv-positive adults on antiretroviral therapy across the globe: comparisons with general population. curr opin hiv aids. 2016;11(5):492–500. https://doi.org/10.1097/coh.0000000000000298 teeraananchai s, kerr sj, amin j, ruxrungtham k, law mg. life expectancy of hiv-positive people after starting combination antiretroviral therapy: a meta-analysis. hiv med. 2017;18(4):256–266. https://doi.org/10.1111/hiv.12421 asiki g, reniers g, newton r, et al. adult life expectancy trends in the era of antiretroviral treatment in rural uganda (1991–2012). aids. 2016;30(3):487–493. harris tg, rabkin m, el-sadr wm. achieving the fourth 90: healthy aging for people living with hiv. aids. 2018;32(12):1563–1569. https://doi.org/10.1097/qad.0000000000001870 smit m, brinkman k, geerlings s, et al. future challenges for clinical care of an ageing population infected with hiv: a modelling study. lancet infect dis. 2015;15(7):810–818. https://doi.org/10.1016/s1473-3099(15)00056-0 greene m, covinsky ke, valcour v, et al. geriatric syndromes in older hiv-infected adults. j aids. 2015;69(2):161–167. https://doi.org/10.1097/qai.0000000000000556 wing ej. hiv and aging. int j infect dis. 2016;53(1):61–68. https://doi.org/10.1016/j.ijid.2016.11.414 jilich d, sedl s, nielsen ln, et al. infection-related and -unrelated malignancies, hiv and the aging population. hiv med. 2016;17(8):590–600. agaba pa, meloni st, sule hm, et al. treatment outcomes among older human immunodeficiency virus-infected adults in nigeria. open forum infect dis. 2017;4(2):ofx031. https://doi.org/10.1093/ofid/ofx031 cornell m, johnson lf, schomaker m, et al. age in antiretroviral therapy programmes in south africa: a retrospective, multicentre, observational cohort study. lancet hiv. 2015;2(9):368–375. https://doi.org/10.1016/s2352-3018(15)00113-7 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remarriage. in: whitbourne sk, editors. the encyclopedia of adulthood and aging. hoboken, nj: john wiley & sons, 2015; p. 1–5. heestermans t, browne jl, aitken sc, vervoort sc, klipstein-grobusch k. determinants of adherence to antiretroviral therapy among hiv-positive adults in sub-saharan africa: a systematic review. bmj glob health. 2016;1(4):1–13. https://doi.org/10.1136/bmjgh-2016-000125 nguyen ka, peer n, mills ej, kengne ap. burden, determinants, and pharmacological management of hypertension in hiv-positive patients and populations: a systematic narrative review. aids rev. 2015;17(2):83–95. abraham ag, crane ah, eron j, et al. end-stage renal disease among hiv-infected adults in north america. clin infect dis. 2015;60(6):941–949. https://doi.org/10.1093/cid/ciu919 rasmussen ld, mathiesen er, kronborg g, gerstoft j, obel n. risk of diabetes mellitus in persons with and without hiv: a danish nationwide population-based cohort study. plos one. 2012;7(9):e44575. https://doi.org/10.1371/journal.pone.0044575 monroe ak, glesby mj, brown tt. diagnosing and managing diabetes in hiv-infected patients: current concepts. clin infect dis. 2015;60(3):453–462. https://doi.org/10.1093/cid/ciu779 lin sp, wu cy, wang cb, li tc, ko ny, shi zy. risk of diabetes mellitus in hiv-infected patients receiving highly active antiretroviral therapy: a nationwide population-based study. medicine (baltimore). 2018;97(36):e12268. https://doi.org/10.1097/md.0000000000012268 palefsky jm. hpv-associated anal and cervical cancers in hiv-infected individuals: incidence and prevention in the antiretroviral therapy era. curr opin hiv aids. 2017;12(1):26–30. https://doi.org/10.1097/coh.0000000000000336 silverberg mj, lau b, achenbach cj, et al. cumulative incidence of cancer among persons with hiv in north america: a cohort study. ann intern med. 2015;163(7):507–518. https://doi.org/10.7326/m14-2768 abstract introduction methods results discussion conclusion acknowledgements references about the author(s) sibusiso e. kubheka department of paediatrics and child health, college of health sciences, school of clinical medicine, university of kwazulu-natal, durban, south africa moherndran archary department of paediatrics and child health, college of health sciences, school of clinical medicine, university of kwazulu-natal, durban, south africa kevindra k. naidu maternal, child and adolescent health, school of public health, university of the witwatersrand, johannesburg, south africa citation kubheka se, archary m, naidu kk. hiv viral load testing coverage and timeliness after implementation of the wellness anniversary in a paediatric and adolescent hiv clinic in kwazulu-natal, south africa. s afr j hiv med. 2020;21(1), a1016. https://doi.org/10.4102/sajhivmed.v21i1.1016 original research hiv viral load testing coverage and timeliness after implementation of the wellness anniversary in a paediatric and adolescent hiv clinic in kwazulu-natal, south africa sibusiso e. kubheka, moherndran archary, kevindra k. naidu received: 23 july 2019; accepted: 24 aug. 2019; published: 03 feb. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the unaids 2020 global strategy to reduce the transmission of hiv includes ensuring hiv viral load (vl) testing coverage of at least 90% on all patients on antiretroviral therapy (art). routine vl monitoring has been shown to result in earlier detection of treatment failure, timely regimen switches, promotion of adherence to treatment and improved survival. we wanted to assess the introduction of the wellness anniversary in improving routine viral load monitoring. objectives: we retrospectively assessed effects of the wellness anniversary on routine vl coverage, timeliness and suppression rates. method: the month when the patient initiated art was designated as the wellness anniversary. on the anniversary month a package of care, which included a routine vl, was delivered. we conducted a retrospective chart audit to assess vl coverage and timeliness between two time periods, from january 2016 to december 2016 (pre-implementation) and from january 2017 to december 2017 (post-implementation). results: timeliness of vl testing improved from 27.5% in the pre-implementation cohort to 49.7% in the post-implementation cohort. our study showed high vl testing coverage before the implementation of the wellness anniversary with an average of 98.3% vl. there was a significant correlation between timeliness and vl suppression (vls) in the post-implementation group. conclusion: implementation of the wellness anniversary may improve timeliness of routine vl testing in settings with high vl coverage. studies looking at the effect of timeliness on vls and clinical outcomes are needed. keywords: hiv; viral load monitoring; children; paediatrics; infectious diseases. introduction south africa has the largest hiv epidemic in the world, with about 7.2 million people living with hiv in 2017.1 according to the 2016 unaids report, about 320 000 children below 15 years were living with hiv in south africa in 2016.2 while about 90% of people in south africa living with hiv knew their status, only 59% of children living with hiv in south africa had access to antiretroviral therapy (art). in 2016, approximately 78% of people on art in south africa were virally suppressed, which translates into about 47% of all people living with hiv.1,2 the unaids 2020 global strategy to reduce the transmission of hiv includes ensuring hiv viral load (vl) testing coverage of at least 90% on all patients on art.3 routine hiv vl monitoring has been shown to improve earlier detection of treatment failure, timely regimen switches, promoting adherence to treatment and survival.4 however, the effect of timeliness of routine vl monitoring on the positive effects of routine vl monitoring is unknown. the world health organization (who) guidelines from 2013 recommended hiv vl monitoring as a preferred method to monitor treatment response.5 in south africa, routine vl monitoring was rolled out in 2004. testing intervals are currently at 6 months, 12 months and every 12 months thereafter if patients are suppressed. routine hiv vl coverage in patients on art in south africa was approximately 72% prior to the implementation of the who guidelines and 75% by 2015, with 78% vl suppression (vls).6 factors that were found to contribute to low hiv vl testing coverage in lowand middle-income countries (lmic) included poor adherence to who guidelines, low levels of staff training and lack of funding.7 however, the challenges preventing increased hiv vl coverage in south africa may be different compared to most sub-saharan african countries. quality improvement projects (qip) have the potential to improve hiv vl coverage, such as qip reported by kekana et al., although the scalability of these interventions may be limited.8 sunpath et al. also showed increased vl completion after the implementation of the vl champion in lowand high-traffic arv clinics.9 improved hiv vl coverage together with active tracing has been implemented in resource-poor settings and has shown to lead towards better clinical outcomes and increased retention in care.10 viral load suppression in children from lmic is lower when compared to adults in lmic and children in high-income countries.11 hiv vls has been shown to reduce hiv transmission and improve life expectancy in people living with hiv.12 early vls in children is associated with better growth, immune and viral responses and psychosocial outcomes.13 good self-reported adherence has been associated with engaged and motivated caregivers, disclosure of child and caregiver status, knowledge of art and good patient–caregiver–healthcare provider relationships, which result in better outcomes.14 interventions that have been shown to enhance adherence include directly observed therapy by family members, personalised treatment plans, medication diaries, convenient and pleasant clinic appointments and community-based adherence support.15,16 decentralised models of art delivery may also lead to improved virologic outcomes.17 the effects of timely vl testing on treatment outcomes is unknown. there are multiple measures in place at the clinic to improve adherence to treatment and ensure timely vl testing including active tracing of defaulters, peer-led support groups and whatsapp groups supervised by social workers. we implemented the wellness anniversary to ensure delivery of an annual standardised holistic package of care. we aimed to assess the effectiveness of the wellness anniversary in improving vl testing coverage and timeliness of testing. methods study design we conducted a retrospective comprehensive chart audit to assess two time periods, from january 2016 to december 2016 (pre-implementation) and from january 2017 to december 2017 (post-implementation). the primary objective was to assess and compare the coverage and timeliness of hiv vl testing between the two time periods. secondary objectives were to describe and assess the association of vl testing coverage and timeliness with patient demographics, and to describe and assess the association of vl testing coverage and timeliness with short-term treatment outcomes. study setting the study was conducted in king edward viii hospital (keh), philani family clinic, which is a combined adult and paediatric hiv clinic in an urban area. the clinic covers a wide area which includes peri-urban and urban areas. the clinic offers both general paediatric hiv treatment services and tertiary services. the general services are provided by one permanent medical officer, a part-time medical officer and a rotating medical intern, while the tertiary service is provided by the paediatric infectious disease (id) team once a week. all routine hiv-infected children and adolescents are initiated and followed up by the general service. the tertiary service is a referral clinic for both the general clinic and a large part of kwazulu-natal province. the patients managed by the id team are referred back to the general clinic or the referring hospital with resolution of the referring problem. the audit largely focuses on the patients attending chronic follow-up in the general clinic. study population the study was conducted on all children below 19 years who attend the paediatric and adolescent hiv clinic in king edward hospital. we excluded children who were lost to follow up, children who were transferred out to other art sites, children who died in the pre-implementation period and children who turned 19 years in the post-implementation period. study sample the study sample included all the patients who were attending the hiv clinic and met the inclusion and/or exclusion criteria during the two study periods. intervention we implemented a qip at keh in june 2016 to improve the quality of care in our patients on art. this project involved introducing the concept of ‘wellness anniversary’ for patients and healthcare workers, to use the month of art initiation as an annual reminder to have their vl test taken as part of a holistic package of annual assessments which included safety laboratory tests, weight, height and developmental screening. prior to this, the clinic implemented a vl register to track vls performed and to follow up results on a weekly basis. the effectiveness of the vl register was not assessed. the project was discussed with the management, nursing staff, counsellors and social workers working at the clinic to ensure commitment from the clinic team. maternal adolescent and child health (match), a non-governmental organisation, provided the colour-coded anniversary month stickers. the nurses at the weighing station educated the patients on the aims of the wellness anniversary month. they identified the anniversary month and attached the stickers on the outpatient file and the art clinic file. the patient was also informed about when their anniversary month was. the patients who had a vl done more than 6 months before the anniversary month and were suppressed received the package of care on their anniversary month. the patients who were not suppressed were tested according to the guideline for treatment failure. the implementation was ongoing as new patients were initiated on art during the study period. data collection a list of all the participants and their folder numbers was generated from the tier.net database. files were retrieved from the filing room according to the list, file audits were performed, and data were entered in the data collection microsoft excel spreadsheet. duplication of patients’ records, patients transferred out to other sites, patients lost to follow up, and deceased patients were removed from the database. hiv vl testing was assessed by presence of results on the results sheet in the patient’s chart or the result log in the clinical chart or a specimen lab sticker in the file, or the note of the doctor’s order for the test. vl results that were not in the patient’s files were traced on the national health laboratory services trakcare system. absolute vl results were recorded to assess the outcomes. vls results were categorised as follows: ‘lower than detectable level’ (ltdl) if less than 50 copies per millilitre (cp/ml), ‘50–999 cp/ml’, ‘1000 cp/ml and above’, ‘none’ if no vl was done in the audit period, and ‘not applicable’ if a vl was not due either because the patient is on a holding regimen or has recently initiated art and 6 months on treatment has not passed by the end of the audit. outcomes and measurements viral load coverage was assessed by the proportion of patients with at least one routine vl testing performed in the 12 months within the study period. timeliness was described by how promptly the patient received testing once due for testing (i.e. 12 months after the prior vl). we considered vls which were done a month before, on or after the wellness anniversary as timely. the analysis for timeliness was performed on patients with 2 vls or performed in a 12-month period as patients needed a maximum of two vls in a period of 12 months as per the testing guidelines. patients with more than two vls were likely to have treatment failure and more frequent vl testing. short-term clinical outcomes were assessed by hiv vls. statistical analysis statistical analysis was done by looking at means, medians and standard deviations. measures for statistical significance used were pearson’s chi squared test and p-values. bias all patients were included for file review to reduce selection bias. there was no blinding to reduce bias when files were reviewed. ethical consideration ethics approval was obtained from the biostatistics research council (brec) of the university of kwazulu-natal (approval number be624/18). gatekeeper approval was obtained from king edward viii hospital and the department of health. results we reviewed 1468 patient folders. the pre-implementation dataset excluded 387 patients that were lost to follow-up, 209 patients that were transferred out and 24 patients that died. the final number of patients included for analysis was 850 in the pre-implementation group. the post-implementation dataset excluded 38 patients that turned 19 before the end of the audit, 24 patients that were lost to follow-up and 23 patients that were transferred out. we ended up with 765 patients in the post-implementation group. baseline characteristics table 1 shows baseline characteristics of the two groups. the pre-implementation group had 464 males and 386 females. the average age was 10.9 years, and the median age was 10.9 years with a standard deviation of 4.6. the post-implementation group had 422 males and 343 females. the average age was 11.9 years, and the median age was 12.1 years with a standard deviation of 4.39. age was further categorised into groups for analysis. table 1: baseline characteristics. viral load coverage the baseline vl coverage was 98.3% in the pre-implementation group and 97.8% in the post-implementation group. there was 100% coverage in the 0–3-year age group in the post-implementation audit (table 2). table 2: viral load suppression rate by age groups. viral load suppression rate viral load suppression was 86.5% in the pre-implementation group and 84.4% in the post-implementation group. the suppression rates in the 0–3-year age group were distinctly lower with 56.8% vls in the pre-implementation group and 69% post-implementation. suppression rates in the > 3–10 years were 87.7% and 85.7% in the preand post-implementation groups, respectively. viral load timeliness viral load timeliness was 27.5% in the pre-implementation group and 49.7% in the post-implementation group (figure 1). there were 164 timely vls in the pre-implementation group, of which 130 were suppressed, producing a vls rate of 79%. there was a total of 341 timely vls done post-implementation, out of a total of 723 vls, and of those only 37 were unsuppressed, producing a vls rate of 89% in that post-implementation group. there was a statistically significant association between timeliness of vl testing and vls after implementation of the wellness anniversary with a pearson’s chi square of 11.18 and p-value of 0.001 (table 3). figure 1: overall timeliness in preand post-implementation groups. table 3: timely viral load versus viral load suppression in the post-implementation group. discussion our study showed a high vl testing coverage at this urban paediatric hiv clinic before implementation of the wellness anniversary with an average of 98.3% vl coverage pre-implementation of the wellness anniversary. this was attributed to an already existing system of tracking all the patients that are due for vl testing, as well as defaulters who have not returned for their results. routine vl monitoring has been associated with better clinical outcomes.4 the wellness anniversary intervention did not have a significant positive or negative effect on the vl coverage in the clinic, with a post implementation overall coverage of 97.8%. this may be attributed to high baseline vl coverage. the patients who did not have vls done were mostly patients with anniversary months in december or january when patients return to family homes outside of the city during the holidays. timeliness of vl tests was low in our paediatric and adolescent patients with an average of 27.5% done timeously before implementation. this improved to 49.7% in patients who had suppressed vls after the implementation of the wellness anniversary. this analysis was only on patients with vls below 1000. there was particularly low timeliness in january and december in both groups which we have attributed to the holiday season. during this period the pharmacy dispenses 2 months’ supply of treatment for patients with good adherence and treatment response. some patients also go on holiday during this period. the timeliness of vl testing was expected to correlate with early detection of treatment failure and timely intervention which should lead to higher virological suppression rates and less drug resistance. however, the results did not show this, as overall suppression rates did not improve. the overall vls rate was above 80% in the pre-implementation group, which is higher than the cascaded target of 72.9% set by the unaids 2020 strategy. there was no overall improvement in suppression rates in our study. the 0–3 year age group had a particularly low suppression rate and improved after implementation. time to suppression in this group may be affected by factors such as high baseline vl, poor tolerability of syrups and caregiver-related issues.18 maternal art and early infant diagnosis are likely to improve this, with more infants with lower vls at art initiation and earlier vls. there was a statistically significant increase in vls in the patients who had timely vls in the post-implementation group. this may be attributed to the fact that patients with suppressed vls only need 12 monthly vls, which may be the bulk of patients who subsequently had timely vls. further, patients may have been better able to anticipate the date of the vl testing during the implementation and may have re-enforced adherence resulting in improved vls. studies looking at regimen switches and re-suppression as a result of timely vl testing may be more conclusive to show the effect of timely vl testing. although our study consisted of a comprehensive chart review of a large cohort of patients, limitations include that we did not record art regimens the patients were on and whether there was an increase in art regimen switches with the timely vl testing. implementation of the wellness anniversary had both patient-related and staff-related obstacles, which may be overcome easily even in lmic setting art clinics. patients were initially concerned with the possible stigma expressed by other patients because of a visible sticker on their clinical charts, which required a change in the position of the sticker so that it was less visible. the process of addressing concerns also helped with patient engagement and ownership of their treatment monitoring which may contribute to retention-in-care. once the initial phase of rolling out the wellness anniversary was completed, the responsibility of assigning the wellness anniversary and putting the stickers on the files was assigned to the doctors. patients that were transferred from other institutions often did not have detailed transfer letters, and patients could not recall the month they commenced art. the month of transfer ended up being their wellness anniversary. we would recommend that assigning the wellness anniversary should also be flexible to accommodate the patient’s and caregiver’s lifestyles such as avoiding routine monitoring in school-going children during school holiday months. we feel that these findings are generalisable to other large paediatric and adolescent clinics and offer a low-cost strategy to improve the vl testing. conclusion the implementation of the wellness anniversary in the setting of a clinic with a high vl coverage may improve timeliness of vl tests done. further studies are needed to assess the effects of timely vls on vls and clinical outcomes. acknowledgements the authors acknowledge mrs fikile nkwanyana, biostatistician, university of kwazulu-natal, for the contribution to the study. competing interests the authors have declared that no competing interests exist. authors’ contributions all authors contributed equally to this work. funding information this project was supported by the president’s emergency plan for aids relief (pepfar) through the us agency for international development (usaid) under the cooperative agreement number aid-674-a-12-00019. the contents are the sole responsibility of the authors and do not necessarily reflect the views of usaid or the us government. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references avert. hiv and aids in south africa [homepage on the internet]. 2018 [cited 2019 mar 01]. available from: avert.org unaids. unaids data 2018 [homepage on the internet]. 2018 [cited 2019 mar 01]. available from: http://www.unaids.org/sites/default/files/media_asset/unaids-data-2018_en.pdf joint united nations programme on hiv/aids (unaids). 90-90-90: an ambitious treatment target to help end the 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perinatally hiv-infected adolescents. j int aids soc. 2013;16(1):18579. https://doi.org/10.7448/ias.16.1.18579 morsheimer m, dramowski a, rabie h, cotton m. paediatric art outcomes in a decentralised model of care in cape town, south africa. south afr j hiv med. 2014;15(4):148–153. https://doi.org/10.4102/sajhivmed.v15i4.332 meyers t, yoteieng m, kuhn l, moultrie h. antiretroviral therapy responses among children attending a large public clinic in soweto, south africa. pediatr infect dis j. 2011;30(11):974. https://doi.org/10.1097/inf.0b013e31822539f6 t~e sout~ern african journal of ~iv medicine -----------hbruary 2001 platform i was subsequently leaked a 15-page follow-up letter from mbeki, and linked to the first two, i faxed it to the who, unaids and various aids scientists and researchers around the world, including dr michael gottlieb who first identified the virus. i also used it as part of a presentation i made at the cdc in atlanta in august 2000. but little in a globalised world happens in isolation. the first two lengthy letters were published in the sunday times on the eve of the world aids conference in durban in july last year in which mbeki said i was either 'brave' or had 'racist rage' in suggesting that a high incidence of rape and an out-of-control aids pandemic were fuelled by culture, tradition and religion. (regardless of the fact that the who, unaios and other bodies have increasingly pointed that oul. or that most religions are western-based.) since late 1996 pep has been given for high-risk sexual exposure in a number of locales, most commonly the usa and canada, but what has been needed are studies into its efficacy, and most particularly into rape. mbeki maintained that it was highly unlikely that hiv could be transmitted during rape, and that if it was, arvs would be ineffective. research debunks this. in late 1998 or josh bamberger, a san francisco doctor attached to its health department, began studying the impact of pep after rape on more than 200 women. by october last year (2000), the state of california issued guidelines for pep after rape based on the outcome of bamberger's study (the full text of the california guidelines can be accessed under hiv: antiretrovirals on the website www.speakout.org.za). by june 1999 a similar study was underway in france. a study presented at the durban aids conference in july charlene smith is a senior journalist and published author. she addressed the world aids conference in durban last year on post-exposlire prophylaxis (pep), and also chaired a session on women, violence and hn. she is co-author of the cdc's new guidelines on pep due out early in 2001. a large body of research emanating from france, south africa, the usa and denmark is proving that post-exposure prophylaxis (pep) taken within 72 hours of rape, a needlestick injury, high-risk sex, or a blood transfusion reduces hiv transmission by 100010. post-exposure prophylaxis there is a wealth of information to prove that arvs are not only effective, but that in populations with a high level of hiv infection their use after rape in adults and children is essential. however, the south african media has been less than exemplary in pursuing research to establish the truth. in early november last year (2000), the star published an article saying that air after rape was not effective and that no studies had been done to test that theory when senior editor, jovial rantao, was alerted to the inaccuracy, he failed to correct it. early this year (2001) the us centers for disease control (cdc) will release revised guidelines and a more comprehensive protocol for antiretrovirals (arvs) after rape to prevent hiv. the cdc move is, in part, a response to the furore that occurred in 1999 after i was raped and followed their rudimentary guidelines for arvs after sexual assault and began writing and speaking about the matter. the issue of hiv, rape and arvs began receiving international attention that was accelerated when president thabo mbeki entered the fray and not only lashed out at air in december 1999, falsely claiming that the world's most widely used arv was toxic, but then began questioning whether hiv caused aids. by june he and tony lean, leader of the opposition democratic alliance, had entered into lengthy nit-picking and often erroneous correspondence about pep after rape and issues around aids, based largely on my writings and the 28 september 1998 cdc guidelines. thf southern m ica jour al of hiv medicine -----------hhruary 200 i by scientists jean-pierre benais and a team from france had identical results of 100 rape survivors given arvs from five paris clinics since june 1999, not one had seroconverted. 'two perpetrators were known as hiv-positive and the others refused testing: data from denmark published in july 2000 in the american journol of physicions from scientists at the national university hospital rigshospitalet and state serum institute in copenhagen, showed that arv treatment given to a 13-year-old child 50 hours after receiving a blood transfusion of hiv-infec ed blood from a donor with fullblown aids, saw the child test negative for hiv for more than a year after he transfusion. the child is still clear of infection. given this research and that from the usa, most particularly california, new york and france, which showed that hiv cannot be transmitted after rape if arvs can be given, the cdc embarked on writing new guidelines for pep after rape. the cdc in atlanta, usa is considered the most authoritative aids research organisation in the world. the 1998 cdc guidelines, based on needlestick injuries, suggested that triple therapy [such as azt, 3tc and crixivan) taken soon after a rape would probably ensure that 81% of patients would not become hiv-positive. a growing body of research shows that azt or similar arvs are 100% effective after rape, and in the 28 days that a rape survivor takes those drugs she will experience minimal, if any, side-effects. no rape survivor who was hivnegative on the day of the rape, and who takes arvs after rape, develops hiv, even when it can be proved that his or her rapist or rapists were hiv-positive. research at johannesburg's sunninghill hospital involving more than 300 rape survivors shows that not one seroconverted after using azt and 3tc a quarter were gang-raped. the new cdc guidelines rely fairly significantly on the california guidelines. the california guidelines were in turn inftuenced by those from the new york state aids institute for 'hiv prophylaxis following sexual assault' which have been in place since 1997. the california guidelines note: 'pep medications taken soon after exposure to hiv can prevent hiv infection ... the cdc's hospital infections director has recommended that pep be initiated within 72 hours for individuals with recent sexual exposure to hiv and the san francisco's non-occupational pep service uses 72 hours as its cutoff. in the sexual assault context, given the delay that commonly occurs between assault and medical treatment, the advisory panel recommends setting the cut-off for treatment initiation at the outermost acceptable limit it also notes aspects of rape that increase risk: 'presence of blood; survivor or assailant with a sexual transmitted disease with inftammation such as gonorrhea, chlamydia, herpes, syphilis, bacterial vaginosis, trichomoniasis, etc.; significant trauma to survivor; ejaculation by assailant; multiple assailants or multiple penetrations by assailant(s): the cdc guidelines go into even greater detail, giving protocols for children and adolescents raped and gang-raped. in his letter to leon, mbeki relied on data on receptive vaginal intercourse. rape is non-receptive, or as i noted in my presentation to the aids conference last year where i spoke on pep: 'when i was raped last year, i was dry which meant there was greater genital injury, which facilitates infection if the rapist is hiv-positive. in the instance of a woman gang-raped in south africa which is true for 75% of women more than one of her attackers may be hiv-positive, their viral loads will tend to be high, she may be infected with more than one strain of the virus, it is likely the assailants have sexually transmitted diseases and it is unlikely they are on treatment for hiv. the raped woman or child therefore may have multiple exposure to hiv: in addition, post-traumatic stress disorder (ptsd), which all women experience after rape, depresses the immune system and gives the virus free rein. in my experience children infected with hiv as a result of rape die quickly within as little as 8 18 months. i am convinced that it is because ptsd so dramatically depresses the immune system that the child's body loses all defence mechanisms against the virus. the case of 14year-old felicia lerumo of mamelodi is an example. felicia was raped by three perpetrators on new year's day 1998. forensic evidence showed that she was a virgin at the time of the rape. the case was postponed 17 times. when felicia developed severe ftu after the rape no one tested her for hiv, nor when she developed tuberculosis. on the 17th time that she went to court, for yet another postponement she was so weak her mother carried her on her back. felicia died of aids in may 1999, 17 months after the rape, and the perpetrators were released because the courts said, 'the complainant is dead: mbeki, in his letters, said there could be no research into the relationship between rape, hiv and arvs because doctors would not allow so-called blind trials. but there were no such trials for needlestick injuries which medical staff rely on. a prominent cdc scientist noted: 'there's never going to be a randomized clinical trial to address the. issue of pep in the non-occupational setting, not only because it's not feasible uust like it was not feasible in the occupational setting), or ethical. it never happened in the hospitals, and will not happen in rape and child abuse crisis settings: in occupational exposure, mostly doctors or nurses who get so-called needlestick injuries where blood from an infected patient is splashed into an eye or accidentally transmitted to them through a cut or injection, no such trials were carried out given fears about hiv transmission, even though the risk in these instances of potential transmission is far lower than in rape. impact of pep after rape --------------ri;: sduthth wua\ jou ~a_ q~ hi, medicine mbeki pointed out that arvs do not say on package inserts that they can be used after rape. yet few drugs carry all their uses on package inserts, even those for arvs tend to be very long. the foreign scientist noted further: 'the point that the standards for recommending off-label use of a drug (using a drug that is not necessarily recommended for that use by manufacturers) should not be higher just because the indication is less or more popular. estimates (for risk) are surrounded by broad confidence inrervals and for all exposures (needlestick, sexual) and are modified by 'acmrs (such as injec ion of blood inrramuscularly, for needlesticks, bleeding or trauma, stds, for sex) associated wirn the exposure. the fairest representation of what the recommendations truly are, from all the organisations in rne usa recommending pep after rape, is that there are generally no good reasons for manufacturers m add indications for their products. guidelines in the past may have exaggerated the risks of zidovudine (azt) and minimized the potential benefits of pep and the risk to survivors, and not put into perspective the elevation of risk associated with force, bleeding and high prevalence of stds: mbeki, querying the use of pep, said, 'you might care to consider what it is that distinguishes africa from the united states, as a consequence of which millions in subin the last days of december 2000 i received a note from a rape organisation which gives antiretrovirals to say that it was considering stopping the practice because so many women are hn-positive on the night of the rape, and they hated having to tell the women that they are positive. estimates from gauteng and the western cape show that around 22% of women are hiv-positive on the day they are raped, i.e. they were infected before the rape (30% in the durban area and a claimed 66% in mpumalanga). i wrote back to the organisation as follows: 'nothing causes greater sensitivity toward the perils of hn than post-exposure prophylaxis after rape or an awareness that there are forms of treatment. i am convinced that the rape of virgins is escalating the way it is (the medical research council reported a doubling of child rape last year) on the myth that you can cleanse yourself of hiv by raping a virgin because of perceptions that there is no treatment (usually valid perceptions) and therefore people become desperate and dangerous, and our girl children carry the consequences. 'in every country where mother-ta-child transmission is treated hiv figures start dropping because people become more knowledgeable about the disease, they learn modes of transmission, and myths, they know of tests, treatment and how to cope or how to manage the virus afterwards, because everything lies in managing the virus. 'let's deal with the negative woman or child first she has survived a situation where she thought she might die, and now you are not going to do all in your power m guarantee life because some people feel squeamish about telling some people in the community that they are positive? saharan africa allegedly become hiv-positive as a result of heterosexual intercourse, while, to all intents and purposes, there is a zero possibility of this happening in the us'. in fact, the virus is moving fastest through young heterosexual hispanic and african american communities in the usa at present. in late october last year, the us house of representatives passed a bill compelling those accused of rape to be tested for hiv if the person raped requests it. a similar suggestion was put forward by the sa law commission to justice minister penuell maduna in early december 2000. pep or arvs after high-risk sex al exposure are prevalent right across the usa and are given 'ree, not only 0 those raped, but to those who might have had a high-risk sexual contact and panicked about their hiv risk in the morning. or michelle roland of the san francisco health department says they sometimes give pep to such people three or four times in a year. at the end of it all we need to have measures in place for how to help women, children and families manage hiv in those survivors who seroconvert and become positive, or who are already positive on the day of the rape (see box). 'if those involved in dealing with mother-ta-child transmission adopted the same thinking we would not now have the means to save thousands of babies. none of the mothers who have tested hiv-positive have received medication to help them, but it saves the lives of their babies. but more than that wonderful hiv-positive women, some of whom have lost their babies, have become marvellous fieldworkers and aids activists. we have had thousands of women go through trials throughout the world with mtc't and that too has led to advances in medications, treatment and awareness of how to battle this dread disease most efficiently; and it is knowledge that does not only help the babies of those brave mothers. hn-positive mothers who have taken part in trials have contributed to the knowledge that informs pep after rape and other high-risk exposure. thank god no-one became squeamish about telling those moms their status. 'i didn't want to find out after i was raped that i was positive either on the rst night or thereafter. none of us wants to be told we are facing a terminal illness at any time. but i believe, from my experience with many, many women, children and men raped that we are better able to cope with an hiv-positive prognosis in the early stages after rape than a diagnosis that follows months later at a stage when we are starting to come to terms with the effects of the rape, and then all of a sudden the woman, child or man gets another whammy months later ... in a sense they are raped all over again. the rapist/s haven't left them, they return with the diagnosis of an hiv-positive status. 'in the first days after a rape we are so numb that we can cope, but not once we thought we were leaving the rape 1\.'-= =\: ------------------:;;:=_1:,.' 'and then of course there is lots more, but meeting other people with aids, knowledge of how and what to eat the african potato and wild spinach which grow practically wild are fabulous immune boosters, people need to know this, because even the poorest can access these. 'someone needs to sit down and say, do you want to have an hiv test because there is a risk you can be infected as a result of the rape; however, you may already be infected. do you want us to do this if you are not infected already there is medication we can give you which will probably ensure you do not get hiv, but if you are already infected, there is no medicine we can give you to take away the virus ... however, if you are infected now, or if your body seroconverts later we can put you in contact with aids support groups, we will advise you on eating and lifestyle changes [this is critical and no-one is doing it because we rely too much on western notions of pharmaceuticals). 'in south africa, rape is about aids, we canno mention one sentence about rape without talking about aids; some of those women who are hiv-positive on the day they are raped, will become some of the greatest communicat-ors or fieldworkers helping others with aids or rape if you find ways to give them the opportunity: 'rape is not just about the event on the day it happens, it is not just about the medication we take for the month that follows. rape is about the rest of our lives after, how we and others help us to cope and manage our lives that is the most important gift you can give to your survivors. ir is easy 0 become fixated on the trauma and drama of the day of the rape, and ·he immediate time thereafter, but our needs after rape are far greater. the way we deal with each woman after rape impacts on entire communities, because afterward we send out [hopefully) a more informed, empowered person into the community who will, in very many instances, help orhers. 'you need to know from the time you are raped whether or not you are hiv-positive to a year after the rape that you must practise safe sex to ensure that you do not pass on hiv or any sids from the rape to a partner [i don't know of any organisation that is telling women this because in the end we tell women these things not just for them but to protect their partners now, or their partners to come, and if they want to fall pregnant at a later stage they need to know, it is a fundamental human right, not only the woman's but those she is involved with). 'let's discuss other aspects: i am not sure that the woman or child raped will be aware that the hiv-positive result predates the rape. i have found awareness of this among my sulvivors rhose educated and those not to be zilch. the dilemma you quote is very real and is felt by everyone across southern africa who is administering pep after rape, from botswana to namibia to the various locales in south africa, and indeed even in europe and north america, although obviously the incidence of hiv is far, far lower in the latter countries. 'i think you have a choice, either to give the test results 3 days later, or at a follow-up checkup at 6 weeks, or do what sunninghill has done and get the results out faster they are able to do eusas within 8 hours. this means that the result can be given to the woman on the same day or the following day. i know there are difficulties with women returning, but perhaps the test can be done first. then the forensic exam, some counselling but most importantly a place where she can clean herself, be given new clothes, shown how to take her medicines, and given the opportunity to have something to drink and to rest in a clean, comforting environment while results are produced. either way you will know what suits the woman or child best at the time. behind. it would have been far harder for me to have seroconverted at 3 months, 6 months and 1 year when i believed i had a fighting chance than on the night of the rape where i felt so battered another set of bad news would have fitted the picture; or at 6 weeks where i had strongly prepared myself for a positive result so much so that i battled to get a negative result to sink in. 'you cannot contemplate not giving pep after rape to negative women, and to isolate only children, we absolutely must save the lives of our children and teenagers by giving them pep but what of the mother raped upon whom more than one child relies? you're not going to give pep to her? 'either way, this touches on one of the most important issues in this country and southern africa, if not the continent: rhe shocking counselling preand post-test that ta es place. i had no counselling before my rest on the night i was raped at a private hospital but then again i was a difficul informed patient who wanted 0 know because i wanted arvs. doesn't matter, i still should have been counselled. i've sat in with other survivors in hospitals. clinics and elsewhere and rhe pretest counselling is grossly inadequate this is across the board, whether at private clinics, stare hospitals or ngos. maragerretlt 0: 005s'o e sex ..a . ;rt~ec:"rg an.f _se or o:r:e' "'or·occ_:a:'of1a e.xoos .. re:o ,iv, ;rc,,,,c"rg cars ce r:::: c"s re a:eo ;;0 arue:'ov"21 i"'e'20\" mmnr 1998; ~7: no, rr-17 orering hiv p(op~y ax's fa ofiing sexj,; assault: recomrrerda(o .... s '::or tre state 0" ca ·"orn"a. preo.::red ay: uro.:;r comrr j",'ry hea trio" me san fr;:rc'sco depar:r'l'er: o· pvc,:, hea ir arc tre ca ifor "2 rllv pep a=:e r se)(:...2 ass2j!t tas< force:r co<~rc"c"" .'/:" tre ca ":o'n"a sra:e q:.<'ce of ajds; lash rbarroerfer arc o:rers, qclcoer 2coo. 2000 aftler:car cal:ege o~ pnysicians. annals of in,effiol medicine 2000; 133: 31·34. cdc pub·:c healtn service guaelines for the: managerrent 0; nealm care worker exposure iq hiv ana recorrmenc-,:;tiol1$ ~or post-exoosure prophylaxis. mmwr 1998; 47: 1633. acknowledgements about the author(s) jeremy nel division of infectious diseases, department of medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa prudence ive division of infectious diseases, department of medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa carolina nel department of anatomical pathology, faculty of health sciences, university of the witwatersrand, national health laboratory services, johannesburg, south africa citation nel j, ive p, nel c. giant bacillary angiomatosis. s afr j hiv med. 2021;22(1), a1257. https://doi.org/10.4102/sajhivmed.v22i1.1257 clinical images giant bacillary angiomatosis jeremy nel, prudence ive, carolina nel received: 09 may 2021; accepted: 12 may 2021; published: 20 july 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. a 45-year-old female patient presented with a 2-month history of a progressively enlarging and ulcerating mass on her upper right chest wall, associated with weight loss of 20 kg (figure 1a). the mass measured 12 cm in diameter and had become gradually more painful as the lesion expanded. the patient was newly diagnosed with hiv-1 infection, with a baseline cd4+ t-cell count of 10 cells/mm3 and a viral load of 38 000 copies/ml. initially a diagnosis of non-hodgkin’s lymphoma was considered, but a biopsy revealed that the lesion consisted of a proliferation of capillaries lined by plump endothelial cells. a warthin–starry stain highlighted bacilli morphologically in keeping with bartonella species (figure 1b, arrows). an indirect immune fluorescence antibody assay for bartonella henselae immunoglobulin g was strongly positive (> 1:256), and the biopsy sample tested positive for bartonella by polymerase chain reaction, confirming the diagnosis of bacillary angiomatosis. oral azithromycin therapy resulted in rapid improvement, with abatement of the pain within two days and regression of the lesion to half its original size within two weeks. antiretroviral treatment was commenced simultaneously. complete resolution of the lesion was accomplished after nine weeks of therapy, leaving only mild residual scarring (figure 1c). to the best of our knowledge, this 12-cm lesion is the largest described in the literature to date. figure 1: (a) the 20 cm ulcerating bacillary angioma. (b) warthin-starry stain highlighting clumps of bacilli in keeping with bartonella species. (c) resolution of the lesion following 9 weeks of therapy. acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions j.n. drafted the manuscript. p.i. and c.n. reviewed the manuscript. ethical considerations ethical approval for this study was obtained from the university of the witwatersrand’s human research ethics committee (clearance number: m1909103). funding information the authors received no financial support for the research or authorship of this article. data availability data sharing is not applicable to this article. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. 189 sajhivmed december 2013, vol. 14, no. 4 c p d q u e s t io n a ir e cpd questionnaire vol. 14, no. 4 regarding the effect of antiretroviral therapy (art) on preg­ nancy outcomes: 1. studies from europe and north america have suggested that in utero exposure to art may be associated with prematurity, and this association appears particularly likely with nucleoside reverse transcriptase inhibitors (nrtis). 2. women initiating art during pregnancy consistently appear to have lower birth weight infants than women who conceive after art initiation. regarding patients failing second­line art: 3. for art to be effective, adherence rates must be at least 70%. 4. studies show that the vast majority of cases of confirmed viraemia on second-line art regimens are the result of antiretroviral resistance. 5. for patients receiving second-line regimens who have evidence of viraemia, further adherence counselling is unlikely to be helpful, and referral for genotypic testing and/ or third-line art is the only option. 6. a targeted adherence counselling intervention can lead to resuppression in individuals who appear to be failing second-line regimens. regarding human papillomavirus (hpv) infection in men: 7. hiv is a strong risk factor for hpv acquisition in men. 8. anogenital hpv in men is not associated with significant pathology. 9. compared with women, men have shorter-term persistence of infection and lower rates of re-infection of hpv. 10. the new hpv vaccine being rolled out in south africa (sa) is not necessary for hiv-positive men. regarding queries from nurses working in art services: 11. in many parts of sa, nurse-initiated management of antiretroviral therapy (nimart) underpins public sector art services. 12. the interpretation of laboratory results before initiating patients on art is a common knowledge gap among nimart nurses. regarding hiv self­testing in children: 13. self-testing for hiv infection is being seen as a new way of reaching under-tested populations. 14. in line with key legal norms, children above the age of 12 years could consent to such a self-test. 15. there are already relatively high rates of health-facilitybased hiv testing among children. regarding mental illness in hiv­positive individuals: 16. ‘common’ mental disorders such as depression or anxiety occur less commonly in hiv-positive individuals than in the general population. 17. a primary care practitioner can often identify significant men tal illness with a few simple screening questions. 18. in starting antidepressants, the governing principle is to start at low doses and escalate dosing gradually over time. 19. efavirenz has psychotropic properties and is absolutely contra indicated in individuals with serious mental disorders such as schizophrenia. 20. the approach to medication to treat anxiety disorders (such as post-traumatic stress disorder) parallels that of depressive disorders, and serotonin-norepinephrine reuptake inhibitors (snris) such as venlafaxine are the firstline treatment in most circumstances. five cpd points are awarded for the correct completion and submission of the questions below. cpd questionnaires must be completed online via www.cpdjournals.co.za. after submission, you can check the answers and print your certificate. this programme is available free of charge to members of the sa hiv clinicians society and sama only. instructions 1. read the journal. all the answers will be found there. 2. go to www.cpdjournals.co.za to answer the questions. accreditation number: mdb001/011/01/2013 (clinical) http://www.cpdjournals.co.za http://www.cpdjournals.co.za thf souther.n african jour.nal of hiv medicine -----------from the editor combination counselling one wonders how much influence the iraqi war and planned re-building of that country will have on deflecting and redirecting international focus and funding away from the war against hiv/aids in subsaharan africa. we have already seen the impact the war has had on the travel plans of scientists from the developed world (the united kingdom and the united states of america). as gerald friedland said at the recent boston retrovirus conference, 'perhaps more progress would be made if hiv were declared a weapon of mass destruction: highlights of the boston conference included impressive presentations on antiretroviral therapy in resource-poor settings, covered in more detail in an article in this issue. at last, feasible, punitive obstacles sudi as adherence issues were shown not to be the bogeymen that we have all been led to believe. patients in southern africa are as adherent as anywhere else in the world. good but careful attention to counselling to obtain commitment to lifelong treatment is required and ongoing counselling regarding other associated issues is essential. in other words, the message here is for doctors not simply to write scripts but to counsel patients on side-effects and toxicities [shortand longterm), because once patients understand these issues they are more than willing to commit to lifelong therapy. we are constantly told that directly observed therapy (dots) for tuberculosis treatment has not been a huge success in the developing world. but, once again, we believe that not enough attention is given to counselling around the tuberculosis treatment issue. it simply is no good just to give patients the drugs and leave them to thei r own devices. so the new catchword is not combination treatment so much as combination counselling. that combination is: time, effort, and culturally appropriate counselling. des martin editor, southern african journal af hiv medicine president, southern african hiv clinicians saciety may 2003 abstract introduction research methods and design results discussion conclusion acknowledgements references about the author(s) bianca sossen department of medicine, faculty of health sciences, university of cape town, cape town, south africa wellcome centre for infectious diseases research in africa, institute of infectious disease and molecular medicine, university of cape town, cape town, south africa amanda ryan town 2 clinic, cape town city health department, cape town, south africa joanna bielawski cape town city health department, cape town, south africa riana greyling matthew goniwe clinic, cape town city health department, cape town, south africa gillian matthews matthew goniwe clinic, cape town city health department, cape town, south africa sheetal hurribunce-james town 2 clinic, cape town city health department, cape town, south africa rené goliath wellcome centre for infectious diseases research in africa, institute of infectious disease and molecular medicine, university of cape town, cape town, south africa judy caldwell cape town city health department, cape town, south africa graeme meintjes department of medicine, faculty of health sciences, university of cape town, cape town, south africa wellcome centre for infectious diseases research in africa, institute of infectious disease and molecular medicine, university of cape town, cape town, south africa citation sossen b, ryan a, bielawski j, et al. urine lipoarabinomannan for rapid tuberculosis diagnosis in hiv-infected adult outpatients in khayelitsha. s afr j hiv med. 2021;22(1), a1226. https://doi.org/10.4102/sajhivmed.v22i1.1226 original research urine lipoarabinomannan for rapid tuberculosis diagnosis in hiv-infected adult outpatients in khayelitsha bianca sossen, amanda ryan, joanna bielawski, riana greyling, gillian matthews, sheetal hurribunce-james, rené goliath, judy caldwell, graeme meintjes received: 09 feb. 2021; accepted: 22 mar. 2021; published: 26 apr. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: decreasing tuberculosis (tb) mortality is constrained by diagnostic and treatment delays. the world health organization (who) recently actively recommended the point-of-care alere determine lipoarabinomannan ag assay (alerelam) to assist in the diagnosis of tuberculosis in specific hiv-infected outpatients. objectives: the primary objective of this study was to compare time to ambulatory tb treatment in hiv-infected adults with cd4 ≤ 100 cells/μl before and after (‘primary comparison groups’) availability of alerelam. in pre-specified subgroups, we prospectively assessed alerelam-positive prevalence. method: clinicians prospectively performed alerelam in hiv-infected adults with tb symptoms and either cd4 ≤ 100 cells/μl or ‘seriously ill’ criteria. in a retrospective arm of equal duration, clinicians retrospectively collected data on hiv-infected adults with cd4 ≤ 100 cells/μl who initiated tb treatment. results: a total of 115 prospectively eligible adults (of whom 55 had cd4 ≤ 100 cells/μl) and 77 retrospectively eligible patients were included. in the primary comparison groups, the retrospective and prospective arms had similar age and sex distribution. with availability of alerelam, the time to tb treatment decreased from a median of 4 to 3 days (p = 0.0557). with availability of alerelam, same-day tb treatment initiation rose from 9.1% to 32.7% (p = 0.0006). in those with cd4 ≤ 100 only, those with ‘seriously ill’ criteria only, and in those meeting either, or both, of these criteria, alerelam was positive in 10.5%, 21.9%, 34.8% and 48.4% respectively. conclusion: availability of alerelam led to more patients initiating same-day tb treatment. using both cd4 ≤ 100 and ‘seriously ill’ criteria gave the greatest yield. results of this study have informed local policy design. keywords: tuberculosis; lipoarabinomannan; ambulatory; outpatient; point-of-care; urine; hiv; diagnostic. introduction in 2019, there were an estimated 10.0 million cases of tuberculosis (tb) worldwide.1 those who had co-infection with hiv were at a disproportionately higher risk of death, despite tb being a curable disease. the world health organization (who) has highlighted that continued high rates of tb mortality relate to gaps in detection and diagnosis of this disease, as well as in poor linking of patients with care and treatment once tb is diagnosed. while sputum-based diagnostics have been the mainstay of tb diagnosis for decades, they have lower yield in people living with hiv (plhiv) and are currently not able to provide a rapid answer at the bedside or in the clinic. lipoarabinomannan (lam) is a component of the mycobacterial cell wall and has been assessed as a potential biomarker for active tb diagnosis in samples such as urine, sputum and serum – both with complex laboratory-based assays and in simple point-of-care devices.2 the alere determine tb lam ag assay (alerelam; abbott, chicago, il, usa) is a lateral-flow rapid assay, which can provide a diagnosis within 30 min at the bedside on an easily collected urine sample. in unselected plhiv in a recent cochrane meta-analysis representing data from 3365 patients with 13% tb prevalence, alerelam had an estimated diagnostic sensitivity of 62% in patients who were hospitalised, and 31% in outpatients against a microbiological reference standard.3 in this same meta-analysis, alerelam had a specificity of 84% in inpatients compared to 95% in outpatients – also against a microbiological reference standard. while sputum-based diagnostics typically lose diagnostic yield in patients with lower cd4 counts, alerelam is consistently associated with greater sensitivity in this group, including in cohorts from similar settings as this study.4 furthermore, in randomised, multi-country controlled trials at hospital level, availability of alerelam led to improved rates of survival in severely ill plhiv.5,6 despite the expanded antiretroviral access in south africa, the proportion of patients presenting with advanced hiv disease (ahd; defined in adults as cd4 ≤ 200 cells/µl or who stage 3/4 disease) has remained unchanged in recent years at 32% – 35%,7 including in 2019–2020 at approximately 34.6% (city of cape town data; personal communication). furthermore, in resource-constrained settings, patients who qualify for hospital-level care where alerelam could be available might not always access this because of hospital bed shortages or difficulties in travelling to centralised care. since 2019, the who has recommended that alerelam should be used to assist in the diagnosis of active tb in outpatient settings for plhiv with cd4 ≤ 100 cells/µl and in those with either ‘seriously ill’ criteria or signs and symptoms of tb.8 while sensitivity is low in outpatient settings, the who has motivated that making alerelam available to all qualifying plhiv presenting for care at any level of the health system would be a step towards ensuring earlier tb diagnosis and reducing mortality in those at greatest risk.1 when new point-of-care tests are recommended and become available, the uptake and assessment of impact in real-world settings is not always straightforward.9,10 in early 2018, we began a pragmatic study with a before-after design to assess the impact of alerelam availability in the outpatient setting in three primary health care (phc) clinics in khayelitsha, cape town. we assessed whether giving clinicians access to alerelam could decrease the time to initiate tb treatment by allowing for greater same-day treatment initiation; we prospectively measured the prevalence of alerelam positivity in pre-specified subgroups and assessed how this introduction affected other diagnostic practices in a complex, demanding setting. this study was designed to assist with local alerelam policy development for the outpatient setting. research methods and design the study was initiated at three phc clinics in two sub-districts of cape town, where there are high rates of hiv and tb. because of staffing changes and an unfortunate fire that led to temporary closure of one of the clinics, the study could not be completed at one of the three initial clinics. we compared prospective and retrospective arms before and after alerelam was made available to clinicians. eligibility criteria for this study were designed to reflect the who guidelines for patients qualifying for alerelam.8 in the prospective arm, eligible patients were consenting adults (≥18 years) with hiv, in whom a diagnosis of tb was suspected (based on who symptom screen) and who had either a cd4 ≤ 100 cells/µl (within 6 months) and/or met criteria for being ‘seriously ill’ (as defined by any of respiratory rate > 30 breaths/min, heart rate > 120 beats/min, body mass index [bmi] ≤ 18.5 kg/m2, systolic blood pressure < 90 mmhg or being unable to walk unaided). in the retrospective arm, eligible patients were similarly adults (≥18 years) with hiv, who had a cd4 ≤ 100 cells/µl (within 6 months) and were initiated on tb treatment. in both the retrospective and prospective arms, patients were excluded if they initiated tb treatment as inpatients, as this group would have already had access to alerelam in our setting. of note, individual patients could only contribute to the data set once and a decision was made a priori to only include the first eligible presentation, even if an individual had presented on multiple occasions. before the start of the prospective arm, a training session was held where clinicians were taught how to perform and interpret the assay. the study had a pragmatic design and thereby did not systematically perform any additional tb testing, but training included the importance of performing additional tests irrespective of the alerelam result, for confirmation of mycobacterium tuberculosis and for drug susceptibility testing. there are no on-site x-ray facilities at these clinics, but x-ray is accessible offsite approximately once on a weekly basis. in the prospective arm, clinicians invited consent from eligible patients and recruitment continued until the minimum sample size was reached across all clinics. retrospective data were collected through folder reviews of a period of equal duration to the prospective arm. clinicians took 1 month to gain experience in performing the assay at their clinic, and to minimise the overlap of presenting periods between the retrospective and prospective arms (i.e. march 2018). the alerelam was performed by treating clinicians in their consulting rooms according to the manufacturer’s instructions. briefly, 60 µl of urine was applied to the sample pad and after 25 min test strips were read using the test’s reference scale card for grading with any band equal or greater in intensity than grade 1 deemed as positive. patients in both retrospective and prospective arms were followed up for 6 months. in both arms, all patients who had longer than 6 weeks between their presentation and tb treatment were excluded from the primary analysis as it would not be possible to delineate whether patients were presenting as part of the same or different clinical ‘episode’. the primary objective was to compare the time to initiation of tb treatment between the retrospective and prospective arms in those patients who were initiated on treatment at phc level and limited to those with cd4 ≤ 100 cells/µl. the primary objective could only compare those meeting the cd4 criteria, in each arm, rather than those meeting ‘seriously ill’ criteria, in order to avoid introduction of misclassification bias with retrospective data collection. a secondary objective estimated the prevalence of alerelam positivity in the following groups in the prospective arm: those with cd4 ≤ 100 cells/µl, those who met ‘seriously ill’ criteria and in those with either or both cd4 ≤ 100 cells/µl and criteria for being ‘seriously ill’. the sample size calculation was done for the primary objective. we assumed that access to alerelam would decrease the mean time from presentation to treatment from 6 to 4 days. to ensure at least 80% statistical power with an alpha rate of 0.05, we required 63 participants per arm. ethical considerations this study was initiated after approval from the faculty of health sciences human research ethics committee (hrec) (reference: #102/2018). written informed consent was obtained from all the patients in the prospective arm. the hrec gave permission for clinicians to record data for the retrospective arm through folder reviews. results in the 9-month period from june 2017 to february 2018, 126 patients received tb treatment and had a cd4 ≤ 100 cells/µl at two phc clinics in khayelitsha (figure 1). of these, 25 (19.8%) were excluded from the study because of having initiated tb treatment in hospital, 15 (11.9%) had already received tb treatment in the 3 months prior to presentation and eight (6.3%) could not be included in the study because of medical records being misplaced – leaving 78 patients in the retrospective arm of this study. one of these 78 was started on tb treatment beyond the pre-specified 6-week cut-off period and therefore was not included in the primary analysis. a total of 61/77 (79.2%) had a known cd4 count on the day that tb treatment was initiated. figure 1: flow diagram of patients. between april and december 2018, 123 eligible patients with tb symptoms gave written consent to take part in the study (figure 1). within the prospective arm, 56 had cd4 ≤ 100 cells/µl and were treated for tb and 27 had cd4 ≤ 100 cells/µl but were not started on tb treatment. one of these 56 was started on tb treatment beyond the pre-specified 6-week cut-off period and therefore was not included in the primary analysis. a further 32 in the prospective arm had cd4 > 100 but met the criteria for being ‘seriously ill’. a total of 36/55 (65.5%) patients in the prospective arm had a known cd4 count on the day that alerelam was performed. the 77 patients in the retrospective arm were compared with the 55 patients in the prospective arm with cd4 counts ≤ 100 cells/µl, for the primary objective of this study. they had a similar age distribution (retrospective: median 36 years; prospective: median 35 years) and sex distribution (retrospective: 46.8% female; prospective: 50.9% female) (table 1). there were more new hiv diagnoses in the retrospective (32.5%) group than in the prospective (10.9%) group. the retrospective arm had more plhiv who were antiretroviral therapy (art)-naïve (46.8%) compared to the prospective arm (16.4%). there were more patients meeting the criteria for being ‘seriously ill’ in the prospective (87.3%) group than in the retrospective (50.6%) group. table 1: baseline characteristics of the study population. once alerelam had become available (i.e. prospective arm), there was a median of 1 day (interquartile range [iq]): 0–5 days) between presentation and clinicians performing the alerelam. before alerelam availability, patients were initiated on tb treatment at a median of 4 days (iqr: 2–7 days) after presentation compared to a median of 3 days once alerelam had become available (iqr: 0–6 days) (p = 0.0557) (figure 2). figure 2: histogram of the number of patients initiating tb treatment per day, over days 0–42 in the study, in (a) the prospective arm meeting criteria for inclusion in primary analysis and (b) the retrospective arm. orange dashed line represents the median. a total of 7/77 (9.1%) and 18/55 (32.7%) of patients were initiated on tb treatment on the same day as presentation before and after alerelam availability, respectively (p = 0.0006). before and after the introduction of alerelam, patients had a similar number of microbiological tests for m. tuberculosis (p = 0.8535) and a similar proportion had chest x-rays performed (p = 0.5143) as part of their work-up for tb (table 2). at the time of tb treatment initiation, 54.5% of patients in the retrospective arm were initiated on this treatment based on clinical and/or radiological features only and this empiric treatment declined to 30.9% in the prospective arm (p = 0.0071). before alerelam availability, 85.7% (66/77) of patients had a rapid test performed on sputum (i.e. genexpert or smear) compared to 66.1% (76/115) after alerelam became available. non-alerelam urine tb tests became more common after alerelam became available, with 14.3% (11/77) having urine sent for mycobacterial culture before alerelam availability compared to 32.2% (23/115) after alerelam availability. of note, genexpert testing on urine is not currently routinely available in this setting. table 2: tuberculosis diagnostic tests done before and after the introduction of alerelam in the primary comparison groups. in the prospective arm, irrespective of eventual tb treatment, the prevalence of alerelam positivity in those with cd4 ≤ 100 cells/µl and not meeting ‘seriously ill’ criteria was 10.5% (n = 2/19) (figure 3). in those who met the ‘seriously ill’ criteria but had cd4 > 100 cells/µl, the prevalence of alerelam positivity was 21.9% (n = 7/32) and in this group the median cd4 was 148 cells/µl, with a range from 103 cells/µl to 469 cells/µl. by including those who met either cd4 ≤ 100 cells/µl or ‘seriously ill’ criteria, this yielded an alerelam positive prevalence of 34.8% (n = 40/115). the highest yield for alerelam positive prevalence was in those plhiv meeting both cd4 ≤ 100 cells/µl and ‘seriously ill’ criteria at 48.4% (n = 31/64). figure 3: alerelam-positive prevalence in (a) patients with cd4 ≤ 100 but not meeting ‘seriously ill’ criteria, (b) those with ‘seriously ill’ criteria but cd4 > 100, (c) those with either cd4 ≤ 100 or ‘seriously ill’ criteria, and (d) those meeting both cd4 ≤ 100 and ‘seriously ill’ criteria. in both the retrospective and prospective arms, patients were not eligible for the study if their tb treatment initiation was at hospital level. within the 6-month follow-up period, risk of hospitalisation that did not include tb treatment initiation was similar in the retrospective (22/78; 28.2%) and prospective (38/115; 33.0%) arms (p = 0.4761). four patients (4/78; 5.1%) in the retrospective arm and eight patients (8/115; 7.0%) in the prospective arm died during the 6-month follow-up period (p = 0.7649). in the prospective arm where alerelam was available, 3/40 (7.5%) of alerelam-positive patients died and 5/75 (6.7%) of alerelam-negative patients died. discussion in a high-burden tb and hiv setting, the availability of alerelam at ambulatory level meant that more patients with both hiv and tb who were presenting for care with low cd4 counts were initiated on tb treatment on the same day as presentation, and the proportion initiating tb treatment empirically was nearly halved. importantly, the study found that the greatest yield in detecting alerelam-positive patients was when the combination of cd4 and ‘seriously ill’ criteria was used, emphasising the importance of implementing the full set of criteria for alerelam, especially when cd4 counts might not be known on the day of presentation. while the findings of this study have been used to inform local policy design, there are a number of key limitations to consider. firstly, this study was conducted in clinics in khayelitsha, cape town and the results might not be generalisable to other areas that have different burdens of tb and hiv. secondly, there could have been patients in the prospective arm of this study who were eligible for alerelam but were missed because of oversight or having already been initiated on tb treatment empirically before they were known to be eligible for alerelam. however, this would have likely meant that we underestimated the effect of alerelam on decreasing time to treatment initiation in comparison to the retrospective arm, rather than overestimated it. furthermore, our sample size was too small to make robust conclusions regarding the exploratory analyses of associations with the clinical outcomes of hospitalisation and death. while a before-after study design comes with inherent limitations in comparison to the gold standard of a randomised controlled trial, the former allowed for policy-informing evidence to be accurately generated within a short time and with limited resources. other studies have been performed to assess the impact of alerelam on time to initiation of tb treatment in an outpatient setting.11,12,13 the multi-centre tb-neat trial performed alerelam on biobanked urine samples and concluded that alerelam results would have no impact on decreasing time to initiation of tb treatment if chest x-ray facilities are available on-site and where rates of empiric tb treatment are high.13 despite a high burden of tb in our study’s community and generally higher healthcare resources in south africa than some other comparable high-burden settings, the clinics in this study do not have access to on-site chest x-ray. with availability of alerelam, we saw that the rates of empiric tb treatment decreased significantly, and the number of patients being initiated on tb treatment on the same day as presentation tripled. based on cohorts recruited in south africa and other african countries, modelling studies have estimated that implementation of alerelam within tb diagnostic algorithms is also cost-effective.14,15 simplifying the criteria for alerelam as far as possible would likely improve its uptake and implementation, but this needs to be balanced against diagnostic yield of the criteria considered, which in turn impacts cost-effectiveness. in comparison to our study, others have reported on alerelam-positive prevalence in ambulatory plhiv irrespective of cd4 or ‘seriously ill’ criteria and estimated this prevalence to be much lower (from 13.0%16 to 16.9%11). our higher alerelam-positive prevalence (34.8%) is likely because of selecting patients who had either cd4 ≤ 100 cells/µl or criteria for being ‘seriously ill’. while cd4 criteria are informed by the greater diagnostic sensitivity in this group, cd4 counts might not always be available on the day of presentation for care. however, the criteria for being ‘seriously ill’ rely on vital signs that can be performed in any setting and our study showed that implementing the combination of these criteria had the greatest yield. the effects of introducing a point-of-care diagnostic test into a new complex setting and diagnostic environment are important to consider. with the limited sensitivity of alerelam and its inability to diagnose drug resistance, further diagnostic work-up is critical, with the current recommendation being that alerelam should be performed in conjunction with a sputum genexpert.8 once alerelam became available to clinicians, they performed a similar number of microbiological tests and chest x-rays overall but tended to perform fewer sputum rapid tests (i.e. genexpert or smear) and a similar proportion of sputum mycobacterial cultures, but double the number of mycobacterial cultures on urine. noting that urine is an easier sample to collect and clinicians had already collected this sample for the alerelam, this might have been the reason as to why they performed more mycobacterial cultures on urine. however, the yield of mycobacterial culture of urine for pulmonary or extra-pulmonary tb diagnosis is very low (< 10%).17,18 furthermore, it is preferable to perform a genexpert test and not a mycobacterial culture alone as it takes several weeks before a culture result becomes available and this could lead to significant delays in tb or rifampicin resistance diagnosis. this pragmatic study’s findings highlight the importance of clear guidelines regarding further diagnostic work-up, whether a patient’s alerelam result is positive or negative. in line with the who’s guidance to make alerelam accessible as a means to decrease tb mortality in plhiv, alerelam should be made available to all patients meeting criteria for testing in outpatient settings. this pragmatic study highlights the potential benefits and consequences when rolling out this point-of-care test in a new setting that should be considered by both policymakers and clinicians. conclusion with the availability of alerelam, the percentage of patients being initiated on tb treatment on the same day as presentation rose from 9.1% to 32.7% and the median time for initiation of tb treatment was 3 days compared to 4 days. using cd4 ≤ 100 cells/μl and ‘seriously ill’ testing criteria gave the highest yield of alerelam-positive patients. these findings highlight the utility of this rapid point-of-care tb test at phc clinics for ill patients with hiv who are at high risk of mortality from tb. acknowledgements the authors would like to acknowledge and thank all the patients for taking part in this study. the authors would also like to thank thumeka londile, a tb nurse, who supported this study at her clinical site. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions j.c. and g.me. conceived of the study. b.s., a.r. and g.me. developed the study protocol and design. b.s. and r.go. coordinated the various study sites under the supervision of g.me. a.r., j.b., r.gr., g.ma., s.h.-j. carried out the study protocol, collected data and performed point-of-care tests at their study sites. b.s. managed the databased and performed the analysis, with review from g.me., j.c., a.r., j.b., r.gr. b.s. wrote the first version of the manuscript, with input and review from all other authors. funding information the authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article. g.me. was supported by the wellcome trust (098316, 214321/z/18/z, and 203135/z/16/z), and the south african research chairs initiative of the department of science and technology and national research foundation (nrf) of south africa (grant no. 64787). the funders had no role in the study design, data collection, data analysis, data interpretation or writing of this report. the opinions, findings and conclusions expressed in this article are only those of the authors. data availability the data that support the findings of this study are available from the corresponding author, b.s., upon reasonable request. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references world health organization. global tuberculosis report 2020. geneva: world health organization; 2020. bulterys ma, wagner b, redard-jacot m, et al. point-of-care urine lam tests for tuberculosis diagnosis: a status update. j clin med. 2019;9(1):111. https://doi.org/10.3390/jcm9010111 bjerrum s, schiller i, dendukuri n, et al. lateral flow urine lipoarabinomannan assay for detecting active tuberculosis in people living with hiv. cochrane database syst rev. 2019;(10):cd011420. 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https://doi.org/10.1186/s12879-015-0967-z reddy kp, gupta-wright a, fielding kl, et al. cost-effectiveness of urine-based tuberculosis screening in hospitalised patients with hiv in africa: a microsimulation modelling study. lancet glob health. 2019;7(2):e200–e208. https://doi.org/10.1016/s2214-109x(18)30436-4 yakhelef n, audibert m, ferlazzo g, et al. cost-effectiveness of diagnostic algorithms including lateral-flow urine lipoarabinomannan for hiv-positive patients with symptoms of tuberculosis. plos one. 2020;15(1):e0227138. https://doi.org/10.1371/journal.pone.0227138 drain pk, losina e, coleman sm, et al. clinic-based urinary lipoarabinomannan as a biomarker of clinical disease severity and mortality among antiretroviral therapy-naive human immunodeficiency virus-infected adults in south africa. open forum infect dis. 2017;4(3):ofx167. https://doi.org/10.1093/ofid/ofx167 bentz, r, dimcheff d, nemiroff m, tsang a, weg j. the incidence of urine cultures positive for mycobacterium tuberculosis in a general tuberculosis patient population. am rev respir dis. 1975;111(5):647–650. monkongdee p, mccarthy kd, cain kp, et al. yield of acid-fast smear and mycobacterial culture for tuberculosis diagnosis in people with human immunodeficiency virus. am j respir crit care med. 2009;180(9):903–908. https://doi.org/10.1164/rccm.200905-0692oc abstract introduction methods results discussion conclusion acknowledgements references about the author(s) nické theron department of paediatrics and child health, faculty of health sciences, university of the free state, bloemfontein, south africa gina joubert department of biostatistics, faculty of health sciences, university of the free state, bloemfontein, south africa bertram d. henderson division of clinical genetics, faculty of health sciences, university of the free state, bloemfontein, south africa citation theron n, joubert g, henderson bd. neural tube defects in the free state province from 2012 to 2016. is there an increase? s afr j hiv med. 2020;21(1), a1134. https://doi.org/10.4102/sajhivmed.v21i1.1134 original research neural tube defects in the free state province from 2012 to 2016. is there an increase? nické theron, gina joubert, bertram d. henderson received: 14 july 2020; accepted: 03 aug. 2020; published: 25 sept. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: neural tube defects (ntds) are anomalies of the central nervous system caused by the defective closure of the neural tube during early embryogenesis. a significant decline in the incidence of ntds after folic acid fortification of food in south africa was previously shown. recently, clinical geneticists have voiced concerns that there is a possible resurgence in the number of ntds. objectives: the aim of this study was to determine the incidence of ntds at a south african hospital from 2012 to 2016. methods: this is a retrospective cross-sectional study where all babies with ntds born in, or referred to universitas hospital were included as study participants. information was collected for both the mother and the baby from hospital records and data forms. results: seventy-seven cases of ntds were captured from 2012 to 2016. the incidence of ntds was 0.34/1000 births in the free state province, and 1.21/1000 births if only the data for babies born in universitas hospital and pelonomi hospital were used. further analysis showed a male: female ratio of 1:1. open spina bifida was the most common defect at 71.4%. conclusion: the incidence of ntds in the free state province was low compared to other south african and international studies. the incidence for the metropolitan hospitals is comparable to that of previous studies. this discrepancy is a marker of poor data recording and will impact healthcare planning. a statistically significant increase in ntds could not be proven. keywords: neural tube defects; birth defects; data collection; free state province; south africa; antiretroviral treatment. introduction neural tube defects (ntds) are severe anomalies of the central nervous system caused by the defective closure of the neural tube during early embryogenesis.1 an estimated minimum of 300 000 neonates are affected worldwide each year.2 according to unicef and the south african burden of disease study in 2000,3 numerous different congenital defects are ranked in the first 20 specific-causes of under-five childhood mortality in south africa (sa). the specific disorders were congenital heart disease (8th), ntds (12th), chromosomal defects (18th) and congenital disorders of the gastrointestinal tract (19th). despite many studies and growth in the knowledge of neural tube embryology, this multifactorial disorder and the complex genetic and environmental factors interactions that cause or prevent it remain poorly understood.4 neural tube defects are classified as open or closed (membrane-covered) lesions. the type of lesion determines the clinical impact. open lesions affecting the brain such as anencephaly (absence of major part of the brain, skull and scalp) and craniorachischisis (anencephaly and ntds that extend to the neck) are lethal antenatally or shortly after birth. the morbidity of encephalocoeles (protrusion of either brain tissue, its covering membranes or both through a defect in the skull) depends on the extent, position and contents of the protrusion. spina bifida is an ntd that is restricted to the caudal portion of the neural tube. its morbidity depends on the extent and level of the lesion and the degree of neurological impairment below that level.5 spina bifida can be divided into three common types. spina bifida occulta results from the failure of vertebral fusion and has no opening on the back (also called a closed ntd). there might be a clue to the defect in the form of a tuft of hair or a dimple in the overlying skin. this is the mildest form and usually does not cause any disability. a protruding sac filled with fluid that does not involve the spinal cord is called a meningocoele. myelomeningocoele is the most common and severest form. this involves incomplete vertebral and neural tube closure and thus exposure of the spinal cord and meninges which may be open or closed.6 this necessitates early surgical treatment of the lesion and the associated complications (such as hydrocephalus) and requires long-term rehabilitation and follow-up.7 numerous risk factors have been identified for ntds, including both genetic and environmental factors. maternal vitamin b12 deficiency has been shown to increase the risk of ntds.2 maternal exposure to teratogens, such as methotrexate, valproic acid, other anticonvulsants and aminopterin, as well as hyperthermia early in pregnancy, low socioeconomic status, maternal obesity, pre-gestational diabetes and genetic predisposition are factors that increase the risk.4 neural tube defects can also occur as part of genetic syndromes as one of the multiple congenital malformations.1,2 since the seminal work of czeizel and dudás,8 folic acid (vitamin b9) has become the accepted norm for primary prevention of ntds.4,7 sustainable progress has been made in the primary prevention of ntds resulting from folic acid supplementation/food fortification. one of the first studies to support this was done in china from 1993 to 1995.9 the daily intake of folic acid during the periconceptional period was found to reduce a woman’s risk of having a foetus or infant with an ntd. the effect of this fortification was greatest in the high-prevalence rural regions. in 2003, sa legislated a programme of folic acid fortification of staple foods. an ecological study in the country, from 2002 to 2005, confirmed a significant decline in the incidence of ntds post fortification, together with a reduction in the related financial and health burden.10 there are no current studies on the incidence or prevalence of ntds in sa. ncayiyana conducted a study from 1980 to 1984 in a rural transkei district that showed an incidence of 6.1 ntds/1000 births.11 a lower prevalence was found in urban regions such as cape town, namely 1.3/1000 births.12 according to sayed et al.,10 the prevalence between january 2003 and june 2004 (pre-fortification) was 1.41/1000 births and between october 2004 and june 2005 (post-fortification) was 0.98/1000 births. this is comparable to the 1.67/1000 prevalence in lowand middle-income countries reported between 2000 and 2013.2 since the study of sayed et al.,10 there have been many changes in sa’s healthcare. clinical geneticists ‘have the impression’ that there has been a resurgence of ntds in recent years: christianson al, personal communication, johannesburg, sa, may 2016. the sayed study10 took place in an environment of high hiv infection rates. the slow rollout of antiretroviral treatment (art) in the region is unlikely to have influenced the study findings. antiretroviral treatment protocols have changed numerous times in the past 11 years. if an increase in ntds is demonstrated, a causal relationship will need to be investigated. the sa-national art programme was launched in april 2004. adult regimens comprised of two nucleoside/tide reverse transcriptase inhibitors (nrtis) and one non-nucleoside reverse transcriptase inhibitor (nnrti): initially stavudine and lamivudine (nrtis) and efavirenz/nevirapine (nnrtis).13 in 2010, first-line art was changed to tenofovir and lamivudine/emtricitabine with nevirapine still preferred in women of child-bearing age.14 by 2013, the guideline was changed to tenofovir, emtricitabine/lamivudine and efavirenz for all adults, irrespective of gender or pregnancy.15 this is generally given as a fixed-dose combination tablet as recommended in the 2015 national guidelines.16 an analysis in 2013 found no evidence of an increased risk of central nervous system congenital anomalies associated with first-trimester exposure to efavirenz in lowand middle-income countries.17 the incidence of ntds was low and similar to that of the general population in this systematic review and meta-analysis. since 7 october 2003, sa legislation namely, the foodstuffs, cosmetics and disinfectants act number 54, has required any person who manufactures, imports or sells bread, wheat-flour and maize-meal, to fortify it with vitamins and minerals.18 the included vitamins are vitamin a, thiamine (vitamin b1), riboflavin (vitamin b2), niacin (vitamin b3), folic acid (vitamin b9) and pyridoxine (vitamin b6). the included minerals are iron and zinc. the regulations also stipulate that a miller should keep monthly records and store the fortification mixture under hygienic conditions. contravention of these conditions may result in a fine.19 environmental health practitioners were trained and mobilised to carry out routine inspections of mills to ensure compliance with food fortification regulations. the success of this fortification programme depends on a multitude of factors as outlined in ‘a reflection of the south african maize meal and wheat flour fortification program (2004–2007)’.19 aim and objectives this study aimed to determine if there was an increase in the incidence of ntds in live and stillbirths in the free state province (fs) from 2012 to 2016 as reflected by universitas hospital’s (uh) records. specific objectives: the incidence of ntds found in this study was compared with the incidence of ntds found in the fs in 2005 by sayed et al.10 data were collected to identify recurrent factors that could be used in further research studies as possible risk factors. to determine the incidence of cranial versus spinal ntds. methods this was a retrospective cross-sectional study set at uh, bloemfontein, which is the referral hospital in the fs for the treatment of all ntds as well as antenatal diagnoses of congenital defects. all babies with ntds (including stillbirths, late terminations and live births) from pregnancies reaching viability born in uh or referred to uh from 2012 to 2016 were included in this study. at uh, viability is defined as later than 28 weeks’ pregnancy duration or more than 800 g birth weight. the department of health information systems (dhis) defines a delivery later than 28 weeks as a birth, and not a miscarriage. early miscarriages or termination of pregnancy before 28 weeks’ gestation were excluded to enable comparison with the sayed et al. study.10 patients referred from outside the fs were also excluded. measurement neural tube defect cases were identified and data were collected retrospectively from the following sources: surveillance of birth defects reporting forms – uh. meditech records: the electronic system for patient data capturing at uh. hospital records from the neonatal unit and obstetric unit, including admission registers as well as the records-archive of uh. number of births in the fs for 2012 to 2016 – dhis. the birth data for uh and pelonomi hospital (ph) were collected from the specific maternity wards and calculated separately to that from the rest of the fs. once the ntd cases were identified, data from their summaries on meditech as well as hospital files were collected and entered into a data collection sheet. each case was given a unique research number for the information of the mother and the baby to maintain the confidentiality of the patients. the data collection sheets were then entered into an excel® spreadsheet. the first three cases were used for the pilot study to test the data collection sheet. the data-sheet was adapted to include the gender and the weight of the baby. these three cases were included in the study. analysis of data the university analysed the data. the results were summarised as frequencies, percentages (categorical variables) and medians (numerical variables due to skew distributions). ninety five per cent confidence intervals (95% ci) and appropriate hypothesis testing were used for comparison with other studies. ethical consideration approval to undertake this study was obtained from the health sciences research ethics committee of the university of the free state (hsrec 53/2016) and permission to conduct this study was also obtained from the free state province department of health. the information of each patient was managed with strict confidentiality. the hospital numbers of each patient and mother and the date of birth were transcribed onto a separate list and a specific research number was allocated for each mother and baby (e.g. m1, b1). on the data-sheet and the excel spread-sheet, only these research numbers were used to ensure confidentiality. these data-sheets were kept in a locked cabinet at the department of paediatrics. results in total, 77 cases of ntds were captured from 2012 to 2016 at uh. the number of cases per year indicated that most were born in 2013 and 2014, with 10 in 2012, 19 in 2013, 19 in 2014, 15 in 2015 and 14 in 2016. see figure 1. figure 1: number of neural tube defect (ntd) cases per year at universitas hospital. twenty-six (26; 33.8%) of the cases were born in uh, and 51 in other hospitals. the highest number of referrals was from the mangaung area (32.7%). this is displayed in figure 2. figure 2: referrals from outside of universitas hospital (%) by municipal district20 and population in 2011.20 the incidence of ntds was calculated using the number of births in the fs per year as well as the number of ntds per year, as shown in table 1. thus, over the 5 years, the incidence of ntds was 0.34/1000 births. table 1: birth statistics and incidence of neural tube defects in the free state province from 2012 to 2016. data for uh and ph were calculated separately from data of the rest of the fs as both had been sentinel sites for the sayed et al. study.10 there were 27 222 births from 2012 to 2016 and 33 cases born at these hospitals. the incidence for ntds was 1.21/1000 births for babies born in ph and uh, which represents the metropolitan areas of the fs. the relative risk of an ntd from 2012 to 2016 in comparison to the sayed et al. study is 1.18 (95% ci 0.52–2.68, p = 0.69). there is no significant increase. the demographics of the ntd cases revealed a male: female ratio of 1:1 with the gender known in 68 (88.3%). fifteen of the cases were firstborn (15; 22.4%), 20 were second-born (29.9%) and 15 third-born (22.4%). the birth order was known in 67 (87.0%). sixty-two (62; 80.5%) of the ntd cases were live births and 15 (19.5%) were late terminations or stillbirths. all the different types of ntds were represented in these cases. open spina bifida (meningocoele or myelomeningocoele) was the most common at 71.4%, 2.6% had spina bifida occulta, 13% had anencephaly and 9.1% had an encephalocoele. some babies were reported to have more than one ntd as identified by the examining doctor: 1.3% had both anencephaly and an encephalocoele, and 2.6% had both an encephalocoele and open spina bifida. see figure 3. figure 3: distribution of types of neural tube defects (ntds). other congenital defects were identified in addition to the ntd in many cases. these were classified as part of the ntd sequence (found in 55.8% of cases) or part of other syndromes and associations (found in 16.9% of cases). open spina bifida is often associated with other central nervous system anomalies, such as chiari type 2 malformation, hydrocephalus and club feet. these are considered as a sequence. isolated ntds occurred in 27.3% of cases. see figure 4. figure 4: associated congenital abnormalities. the other specific syndromes or patterns of congenital abnormalities most frequently associated with ntds were vacterl association (30.8%) and trisomy 18 (15.4%). see figure 5. figure 5: specific syndromes or patterns of congenital abnormalities. the data collected from the maternal files were analysed to identify risk factors that might play a role in the development of ntds. the maternal age showed a skewed distribution with a median of 28.5 years. the maximum age was 43 years and the minimum was 16 years. the maternal age was known in 76 cases (98.7%). teratogen exposure was known for 63 mothers (81.8%) and 15 (23.8%) were exposed to teratogens. three mothers were on anti-epileptic treatment, all used valproate. the epilepsy history of 67 (87.0%) mothers was known. twelve mothers (15.6%) were exposed to other medications or toxins during their pregnancy including alcohol (n = 1), smoking (n = 1), antihypertensive treatment (n = 6), penicillin (n = 3) and traditional medicine (n = 1). one mother was diagnosed with diabetes mellitus during pregnancy. the hiv data were captured for most mothers (94.8%). the prevalence of hiv-positive mothers in this study was 34.3% (25/73). the 95% ci for the prevalence of hiv in this study was 24.4% – 45.7%, which encapsulates both the fs and national prevalence. there is, therefore, no statistically significant difference in the hiv status of mothers who delivered babies with ntds and the general population. of the mothers who were living with hiv, most were taking antiretroviral drugs (arvs) (n = 23), one mother was not on arvs during pregnancy and the treatment status of one mother was unknown. see figure 6. figure 6: antiretroviral (arv) treatment of mothers who are hiv positive. family history, including previous pregnancy outcomes, was available for 34 cases (44.2%). one mother had a previous pregnancy-related ntd. neural tube defects in the extended family were absent in the 17 cases where the data were recorded. one mother of seven with known data had used folic acid during her pregnancy. it was unknown whether any of the mothers used folic acid during the peri-conception period. discussion this study determined the incidence of ntds in the fs from 2012 to 2016 and looked at the maternal and foetal profiles of the babies with these defects. according to the authors’ knowledge, this is the first study to determine the incidence of ntds in the fs. other available data in sa are for rural transkei (6.1 ntds/1000 births in 1980–1984)11 and cape town (1.3/1000 in 1994)12. sayed et al.10 used only the number of births at uh and ph, and the number of babies with an ntd born in these sentinel sites to obtain an incidence of 1.03/1000 for the fs and an incidence of 0.98 for sa using sentinel sites in three other provinces. compared to the above incidences, the fs incidence of 0.34/1000 found in this study is low. as only the cases referred to uh were captured, it can be postulated that this incidence is a false representation of the actual situation. babies may die before referral or not been referred to as in the case of anencephaly, or the cases with spina bifida occulta may have been missed. an attempt was made to supplement the data with data from the dhis where the causes of death are captured. this was unsuccessful. the entries were either not made or wrongly entered as searches indicated one death per year due to ntds. comparing the incidence for uh and ph to the sayed et al.10 data indicated an increase in the incidence of ntds from 1.03/1000 in 2004/2005 (shortly after food fortification with folic acid was introduced) to 1.21/1000 in 2012 to 2016. this tends to support the impression that there is a resurgence in the number of ntd cases in the fs, but this was not statistically significant. the referrals from outside uh were classified according to the municipal healthcare districts where the baby was born. most referrals were from the mangaung area as expected from the population distribution of the fs.20 see figure 2. the demographics of the ntd cases in this study contradicted most of the other studies done in sa. both the study performed in cape town over 20 years ago12 and a study performed in gauteng21 that looked at the profile of ntd cases showed that it was more prevalent in females than males, whereas this study had an equal female to male ratio. the birth order also differed from the study performed in gauteng21 where the firstborn and lastborn infants were more at risk of ntds, whereas it was the second-born infants who were mostly affected in this study. a possible explanation for the contradictions would be our small sample size. the distribution of the type of ntd is in keeping with other studies.2,10,11,22 a study performed in tunisia22 also showed that spina bifida was the most common defect, followed by anencephaly. the difference between the two was much smaller, however, (38.9% for spina bifida, 22.8% for anencephaly) and this can be accounted for by the fact that most anencephaly patients are probably not referred from the peripheral hospitals due to the poor prognosis. when interpreting the maternal data, it is important to note that the data available for the mothers were poor. they were collected from the neonatal and obstetric summaries found in the electronic data-keeping system as well as the uh admission books, which were often incomplete. most of the summaries regularly did not include the family history of ntds or whether the mother used supplements before or during pregnancy. the data for the mother’s medication history and other chronic diseases (e.g. diabetes mellitus) that could be risk factors were also poorly represented. it is, thus, not possible to draw definitive conclusions. if the data were not recorded in the summaries, these were probably not considered whilst the patient was admitted to the hospital and the mother was, thus, also not properly counselled regarding recurrence and prevention in future pregnancies. this should be addressed by the different departments to optimise patient care. the hiv data were captured for most mothers. hiv status was known for 94.8%. the prevalence of hiv-positive mothers in this study was 34.3%. this is higher than the prevalence in pregnant females in the fs from 2009 to 2013 which ranged between 29.8% (2013) and 32.5% (2011) according to ‘the 2013 national antenatal sentinel hiv prevalence survey south africa’.23 the overall hiv prevalence in pregnant females in sa in 2013 was 29.7%, which is also lower than the prevalence found in this study. these differences were, however, not statistically significant. the type of arvs and the duration of arv use were also poorly captured in the data sources. it is, therefore, not possible to say whether a specific type of arv or a certain treatment regimen contributed to a higher rate of ntds. on 21 may 2018, after the completion of this study, the fda issued a warning that women treated with dolutegravir in the first trimester of pregnancy are at higher risk for ntds.24 this report also indicated that the national institutes of health has launched an international study to compare the safety and efficacy of three arv treatments for pregnant women with hiv. a recent study highlights the need for proper data surveillance and recording of congenital disorders to accurately demonstrate the contribution thereof to the burden of disease on our health care system.25 the congenital disorder surveillance was already implemented in sa in 1980 with several changes to the system in 2001 namely, the birth defect notification tool of the national department of health, and a coding classification added in 2006. it was found in the study performed by lebese et al.25 that the implementation of these systems was poor. when compared to expected congenital disorder notifications, there was an underreporting of more than 99%. kwa-zulu natal recorded the highest number of congenital disorders per year (total of 7219 over 9 years) whilst the fs only recorded 744 cases during the same period. this highlights the need for training of healthcare providers as well as coordinators to report congenital defects so that relevant health policies can be developed. the poor data availability in this study highlighted the same limitations and issues. conclusion there is a clinical impression that the incidence of ntds is increasing. the data obtained in this study appear to support this impression, but no significant statistical difference could be proven. a major finding of this study was, however, the poor data capturing and recording in the fs, which will impact the planning and funding for the healthcare of congenital defects in the fs and sa as a whole. the incidence for ntds in the fs was found to be 0.34/1000 births, which is low compared to other south african and international data.1,2,10,11,12,22 the discrepancy between the incidence of ntds in the fs and the metropolitan hospitals serves as a marker of the poor data recording. the incidence for uh and ph for 2012 to 2016 (1.21/1000 births) is comparable to the incidence found in the sayed et al. study.10 no specific correlation could be drawn between known risk factors and the ntd cases. a prospective study in this field, with a larger study population, will be required to confirm or refute the clinical impression that there is an increase in the incidence of ntds in the fs and to identify possible explanations, if so. acknowledgements the authors would like to thank ms. a steinhobel, operational manager, universitas hospital, and her staff at the neonatal high care for filing all the congenital abnormality report forms and permitting access to them, and ms. t mulder, faculty of health sciences, ufs, for reviewing the document and editing it for publication. this research was conducted for the fulfilment of the mmed in paediatrics (nt) and supervised by bdh. competing interests the authors have declared that no competing interest exists. authors’ contributions all authors contributed equally to this work. funding information the research was funded from the research funds of the department of paediatrics and child health, ufs, and the division clinical genetics, ufs. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references public health agency of canada. congenital anomalies in canada 2013: a perinatal health surveillance report [homepage on the internet]. c2013 [cited 2015 mar 17]. available from: http://publications.gc.ca/collections/collection_2014/aspc-phac/hp35-40-2013-eng.pdf lo a, polšek d, sidhu s. estimating the burden of neural tube defects in lowand middle-income countries. j glob health. 2014;4(1):010402. https://doi.org/10.7189/jogh.04.010402 bradshaw d, bourne d, nannan n. what are the leading causes of death among south african children? mrc policy brief no 3 [homepage on the internet]. c2003 [cited 2016 feb 07]. available from: 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proven aids drugs for africa. the world health organization was formed in 1948 and its constitution drafted then included the elimination of substandard pharmaceutical production and improving the quality and safety of health care infrastructure in developing countries throughout the world. this letter questions quality and safety of pharmaceutical standards and implementation of guidelines in general of the who in recent times. it asks for a clearer plan from the who on exactly how 3 million people should be treated with antiretroviral (arv) therapy by 2005, claiming that the present plan is vague on medical supervision and follow-up. it also highlights the concerns around the who’s recommendation for fixed-dose combination (fdc) arv drugs. while fixed-dose drugs are attractive in simplifying therapy and promoting adherence, they should undergo stringent human bioequivalence testing verified by a rigorous regulatory body. the pre-qualification system employed by the who, which is not a regulatory agency, does not mean that adequate quality control has been performed on these drugs. the generic fdcs are also attractive for reasons of cost. however, it should not always be assumed that generics and fdcs are cheaper than patent drugs — the latest price comparisons done by médecins sans frontières show that in many cases single-component patented drugs are cheaper than the equivalent generics. sobering lessons learnt in treating malaria are that cheaper copies may not be as effective and may thus lead to more morbidity and mortality than before. thompson ayodele, director for public policy analysis in lagos, nigeria, makes the following salient statement: ‘the extent of the hiv epidemic and the emergence of resistant strains makes the need for testing more, not less acute. hiv medicines, whether original or generic, should meet the most stringent rigorous clinical and testing reviews. if the proposed drugs are rejected by pharmacies in brussels, geneva, london, tokyo or washington, accepting the use of the same drugs in africa, with little resources and lack of equipment to do proper clinical and scientific evaluation, may further compound the woes of hiv/aids victims.’ another factor that may well have a negative impact on adherence, and thus the success of the ‘3 by 5 initiative’, is the high rates of alcohol use in communities also needing widespread implementation of art. alcohol abuse has been associated with poor adherence to highly active antiretroviral therapy (haart). the relationship between adherence to haart and alcohol consumption at baseline and over a 6-month follow-up was investigated by the care unit in boston.1 in this group of 267 hiv-infected participants, alcohol consumption was the most significant predictor of adherence, with better adherence associated with recent abstinence from alcohol compared with at-risk level use (or = 3.6) or moderate use (or = 3.0). the study concluded that any alcohol use in hiv-infected persons with a history of alcohol problems is associated with worse art adherence, and surmised that addressing alcohol use may improve clinical outcomes. in a further study by ena et al.2 from spain, which looked at risk and determinants of developing severe liver toxicity during therapy with nevirapineand efavirenz-containing regimens in hiv-infected patients, multivariate analysis showed the association of severe liver toxicity with hepatitis c antibody positivity (rr = 7.64), combination of non-nucleoside reverse transcriptase inhibitor with a protease inhibitor (rr = 3.07) and alcohol intake greater than 40 g/d (rr = 3.09). the study concludes that alcohol should be avoided during art therapy. two good reasons why we need more support for our communities where art programmes are happening. in any of these communities, shebeens, beer halls and bottle stores far outnumber alcohol support groups such as alcoholics anonymous. in one of the communities where we work there is not a single ngo devoted to alcohol support, yet alcohol use continues to be one of the big social problems cited by our therapeutic counsellors, who often consider it a significant factor in possible non-adherence. as the national arv programme rolls out, perhaps sanca needs to be looking at a parallel ‘roll-out’ of services throughout south africa. linda-gail bekker managing editor 1. samet jh, horton nj, meli s, freedberg ka, palepu a. alcohol consumption and antiretroviral adherence among hiv infected persons with alcohol problems. alcohol clin exp res 2004; 28: 572-577. 2. ena j, amador c, benito c, fenoll v, pasquau f. risk and determinants of developing severe liver toxicity during therapy with nevirapineand efevirez-containing regimens in hivinfected patients. int j std aids 2003; 14: 776-781. ----------1_--------in defence of the vulnerable 'manto, aids drugs do work after rape: headlines from the mail et guardian of 18 january this year reflect the frustration felt by both lay and professional people in trying to convince our government that there is impressive evidence for the benefit of antiretroviral (arv) drugs. the government continues to object to the administration of these agents from state hospitals. recently the lay press has reported two very disturbing accounts of medical travesties. the first report concerns rob ferreira hospital superintendent, or thys von mollendorf, who was found guilty of gross insubordination by a government tribunal last week. his crime was to allow volunteer workers to facilitate the provision of free arvs to rape survivors. these volunteers, working for the organisation 'grip' (the greater nelspruit rape intervention project), provided counselling, clothes, toiletries and legal advice to the traumatised survivors. the mpumulanga health mec, sibongile manana, accused or von mollendorf of embarrassing government and told provincial legislature 'that any non-profi~ non-government or volunteer organisations that continued to defy provincial policy would be frozen out of the public health sector: using 'catch 22' logic she states that the reason for deferring roll-out of the mother-ta-child transmission (mtcn prevention programmes is lack of resources, including counselling, yet she bans voluntary organisations such as grip that are stepping into the breach and supplying these services. the second episode involves kimberley hospital in the northern cape, where the health mec of that province castigated the hospital staff and suspended one doctor for administering arvs as hiv post-exposure prophylaxis to tshepang', the 9-monthold baby who was sodomised and raped last november. these reports highlight the failure of state health services to provide life-saving interventions to vulnerable populations, and the more sinister implication is the undermining of ethical and professional autonomy of doctors working in the state sector. the value of arvs to prevent mtct has been demonstrated unequivocally in randomised controlled trials. in rape, where such trials in this vulnerable group are not ethically possible, the risks of hiv transmission are even higher. in africa the risk of hiv transmission due to rape is significant. the world health organisation has reported that two-thirds of hiv-positive women in rwanda have become infected as a result of rape. in south africa, where more than 1.6 million rapes occur annually, it has been estimated that the resulting risk of hiv infection may be as high as 40'¥0 because of high hiv prevalence rates and the frequency of gang rape. a local study reported by or adrienne wulfsohn at the 2001 idsa conference in stellenbosch described the 2-year follow-up of 1 ()()() rape survivors. wulfsohn reported that no rape survivor who received arvs within 72 hours of the rape had be<::ome hiv-positive, and that prophylaxis was well tolerated. the findings of this important south african study have influenced the forthcoming centers for disease control guidelines on hiv prophylaxis after rape and cannot be ignored by health care providers; they should be incorporated into health care policy as a matter of extreme urgency by our state health department. it is understandable and correct that the doctor facing a woman who has survived the devastation of rape will do whatever it takes to administer arv prophylaxis to prevent the added death sentence of hiv infection. not to do so would be to fail one of the most vulnerable sectors of our society. when these responsibilities are not met, the health profession must step in to advocate for these sectors. those of our colleagues who do so and in so doing jeopardise their positions and face punishment by the state must be supported and championed by the rest of the profession. 11 march 2002 ----------the southern african journal of hiv meoicine the world medical association declaration on physician independence and professional freedom of october 1986 states that 'physicians must have the professional freedom to care for their patients without interference. the exercise of the physician's professional judgement and discretion in making clinical and ethical decisions in the care and treatment of patients must be preserved and protected: the south african medical association human rights, law and ethics committee adopted the following resolutions in july 2001: 'the committee affirms its strong support for the rights of medical practitioners to clinical independence and autonomy. this includes the right to treat patients without undue infiuence, pressure or victimisation from employers or government institutions. medical practitioners are under an ethical duty to act in the best interest of their patients, who form an exceptionally vulnerable group in south african society. the committee also supports the rights of patients to receive necessary treatment, always with their informed consent this was further endorsed by a recent statement put out by the colleges of medicine of south africa on the controversy about the preventive treatment of hiv infection, which stated among other things that the colleges believe it unethical and against medical principles to penalise doctors in the public sector who obtain and administer nevirapine to their patients (for mother-to-child transmission prevention) in the proper manner. indeed we are in serious trouble when south african doctors can no longer exercise professional judgement in providing the best perceived care for their patients without government or other interference. the legacies of the past should have taught us this lesson. when political ideology, political party lines or other governmental infiuences override the ethical and professional obligations of medical practitioners, indefensible acts are committed or basic medical care omitted by this same profession, and the memory of or steve 8iko will bear testimony to that. l1nda-gall bekker managing editor th!: southfrn african journal of hiv mtoicin!: ----------march 2002 11 hiv0304pg000 the southern african journal of hiv medicine march 2004 5 sexual violence — the neglected epidemic south africa is thought to have one of the highest incidences of sexual assault in the world. about 50 000 rapes were reported in 2001 alone, although it is thought that this is just a small percentage of the total number. one of the main reasons that rape is so prevalent in south africa is that the justice system is so ineffective in dealing with it. most rapists walk free. of 50 000 reported cases in 2001 only about 5 000 resulted in convictions. similar statistics were reported by the south african police service in 2002, but a very worrying statistic is that more than 40% of survivors of sexual assault who reported their cases to the police between february 2002 and march 2003 were girls under 18, with 14% being 12 years or younger. this would mean that pre-teens and teenagers are at much higher risk of sexual assault than the population as a whole. in 2000 and 2001 the reported incidence of rape and attempted rape of children increased, even as the incidence among adults began to stabilise. far too many girls have no safe haven from sexual violence, and many girls are coerced to have sex and subjected to sexual harassment by male relatives, boyfriends, schoolteachers and male classmates.1 in 2002, a government study once again found that only 7.7% of reported rape cases resulted in convictions and that a large number of cases were still being withdrawn after having been registered, despite police instructions not to do so. the causes put forward by sociologists in an attempt to explain the high incidence of sexual assault are many and varied. they include societal attitudes in a male-dominated and patriarchal society, lack of empowerment of women, the culture of violence as a legacy of the apartheid years, and a number of ‘rape myths’, among the most hideous of which is that sex with a virgin is a cure for aids. an important component of this neglected epidemic is sexual violence against both men and young boys. between september 2000 and april 2003 a private hospital group that provides post-exposure prophylaxis (pep) for survivors of sexual violence treated 67 male patients out of a total of 1 465 (4.5%).2 other private clinics have reported similar statistics. in the 2003 annual report by judge hannes fagan (the inspecting judge of prisons) he said that south africa has one of the highest proportions of prisoners for its population in the world, possibly the highest in africa. four out of every 1 000 south africans are in jail and prisons hold 70% more people than they were designed to accommodate, which is known to contribute to the spread of hiv/aids. during the jali commission (investigating corruption in prisons) rape was said to be most prevalent among awaiting-trial prisoners because of overcrowding and the fact that there are no separate holding facilities for people who have been accused of different classifications of crime. compounding these circumstances, most male prisoners do not report rape and awaiting-trial prisoners have no access to social workers or other professionals. during the commission interviews, police inspectors reported that they could not recall any prosecutions involving cases of sodomy in prison. the hiv clinicians society has over the years been very concerned about this largely neglected field of patient management. the society receives calls on a regular basis from members seeking guidance on how to deal with victims of sexual assault. we believe that to deal with the epidemic the justice system needs to be strengthened in order that more cases are brought to court and more rapists convicted of this heinous crime. we as doctors, however, have to play our part in providing the required evidence in a proper manner which will make the prosecutors’ task so much easier. the other issue at stake is the provision of pep for survivors of sexual assault. we believe that the article by dr adrienne wulfsohn on p. 21 both addresses the issue of appropriate management of a case of sexual assault and also provides guidelines as to how forensic specimens should be obtained. this will empower doctors to deal more adequately with patients who have been sexually assaulted and play their part in combating this neglected epidemic. des martin editor, southern african journal of hiv medicine president, southern african hiv clinicians society 1. see, e.g. human rights watch, scared at school: violence against girls in south african schools (new york: human rights watch, 2001). 2. human rights watch interview with mandé toubkin, johannesburg, 19 may 2003: mandé toubkin, ‘rape: a social responsibility project. can it be managed in the private health care environment?’, power point presentation, 2003. f r o m t h e e d i t o r make up june issue nicky june 2005 the southern african journal of hiv medicine30 we describe lessons learned from independent evaluations of nine home-based care (hbc) projects in lesotho, south africa and swaziland. projects were funded through bristol-myers squibb's secure the future (stf) initiative and evaluated through the stf monitoring and evaluation unit (meu) at yale university. the objectives of this study were to: assess the management capacity of the hbc organisations reviewed, concentrating on monitoring and supervision mechanisms identify innovations in responding to the challenges of delivering care in resource-poor settings, and explore the nature of linkages between hbc projects and governments. specific strategies to assure quality are discussed, as are policy changes necessary to provide system-wide improvements in quality and the integration of hbc. these are particularly important as governments seek ways to use existing resources to make antiretroviral (arv) roll-outs successful. more than 25 million people were hiv positive in sub-saharan africa at the end of 2004, and during 2004 alone, 2.3 million people died of aids.1 the hiv/aids pandemic is affecting the welfare of nations, communities and families, but its impact begins with the suffering of the infected individual. before dying, most will experience opportunistic infections, functional and psychological morbidity, and alarmingly under-treated pain. most often, family members are left to carry the burden of this morbidity. structured and effective care is not consistently available for all who need it. the first hbc programmes in africa for aids patients were established in the late 1980s in zambia and uganda.2,3 the world health organization (who) describes hbc as placing informal and formal caregivers in the home to ‘promote, restore, and maintain a person's maximum level of comfort, function, and health including care toward a dignified death’ (p. ix).4 in place of acute-care hospitalisation and long-term care institutionalisation, it draws on families and communities to provide hope, support, and high-quality care to ill people in the home including physical, psychosocial, palliative and spiritual activities. the goals of hbc overlap with those of palliative care, as both incorporate spiritual and psychosocial support. however, the latter typically includes care outside as well as within the home, and places a stronger emphasis on pain relief. in southern africa, common pain control medications such as morphine are not available for patients cared for at home, as inadequate numbers of personnel are qualified to administer such drugs. in many african countries hbc programmes are being implemented by non-governmental organisations (ngos) and faith-based organisations (fbos) to provide services unavailable through health care institutions. in south africa, for example, the government developed a national hbc strategy because of the lack of hospital beds, inadequate numbers of health professionals, lack of resources for treatment, an emphasis on curable conditions in existing institutions, and cost.5 research has shown that many people prefer to receive care in familiar environments close to family and friends.6,7 furthermore, effective home care has been shown to improve the quality of life of patients as well as their primary caregivers. for families, hbc may prove more convenient and less expensive than transporting sick family members to the hospital. hbc also provides opportunities for hiv/aids education, particularly important for more isolated communities.8 several investigations have expressed the need for more comprehensive evaluative reports of hbc and clearer guidelines on the development, implementation, monitoring and evaluation of hbc programmes in developing countries.9-11 there is an abundance of related literature, particularly on palliative care, but most of this focuses on europe and north america. as hbc has emerged as a key strategy in the aids c o m m u n i t y improving home-based care in southern africa: an analysis of project evaluations alana rosenberg, mph1 zonke mabude, rn/rm, ma2 kari hartwig, drph1 sahar rooholamini, mph1 dede oracca-tetteh, mph1 michael merson, md1 1yale university school of medicine, new haven, ct, usa 2university of the witwatersrand, johannesburg, south africa make up june issue nicky 5/30/05 2:19 pm page 30 the southern african journal of hiv medicine june 2005 3 1 pandemic in africa, it is important to build a body of work that includes case studies, lessons learned, and best practices unique to sub-saharan africa. the available literature reveals severe challenges for hbc in sub-saharan africa. studies cited lack of programme funding,12 lack of pain control medication,6,13 reliance on volunteers,14 the difficulty of providing care in the context of poverty,15 the need to increase coverage of hbc programmes,16,17 and ensuring that these programmes are of high quality and effective. increases in the number of hiv clients often overshadow the number of accessible caregivers, thus creating a shortage of care and overworked caregivers. underlying all of these challenges is the lack of integration of hbc programmes into government health care provision.16-19 in a 2003 survey of 48 hbc programmes in 14 sub-saharan african countries, 85% of programme management reported government endorsement, but almost all also reported absent or problematic palliative care national strategies.18 the purpose of this paper is to provide lessons learned from independent evaluations of nine hbc projects in lesotho, south africa and swaziland supported by the secure the future (stf) project. the magnitude of the hiv/aids pandemic in subsaharan africa makes the expansion and improvement of hbc a necessity. using external evaluations from nine diverse hbc project evaluations, this study explores issues relevant to assuring quality of hbc projects in southern africa. the specific objectives of the study were to: assess the management capacity of the hbc organisations reviewed, concentrating on monitoring and supervision mechanisms identify innovations in responding to the challenges of delivering care in resource-poor settings, and explore the nature of linkages between hbc projects and governments. our hope was that the results of this study would provide guidance for the implementation of the arv roll-outs underway or planned in these countries. specific strategies to assure quality at the project level are discussed, as are policy changes necessary to provide system-wide improvements in quality and the integration of hbc. we analysed the content of nine hbc final evaluation reports sponsored by the bristol-myers squibb (bms) foundation's stf initiative and overseen by the monitoring and evaluation unit (meu) of stf at yale's center for interdisciplinary research on aids (cira). all evaluations were analysed with permission from the project leadership. while 14 hbc projects were funded by bms, 4 had not been evaluated by the meu at the time of the analysis, and for 1, permission to use the report was not obtained. the meu was established through a grant from bms to provide evaluation services and training in monitoring and evaluation for stf grantees. regional consultants from a variety of disciplines conducted the evaluations using a participatory approach aimed to meet the needs of project staff and bms management. initial planning sessions with project staff were followed by a site visit of 3 5 days. document review, key informant interviews, and focus groups were main data sources. evaluation reports reviewed the project's strengths, weaknesses and gaps, and provided recommendations and lessons learned. the length of funding for projects was 15 months (2 projects), 2 years (4 projects), or 3 years (3 projects). evaluation reports were read by four coders who searched key words (e.g. ‘volunteers,’ ‘networks,’ ‘stipends’, etc.) and themes (e.g. organisational structure, relationship with government, etc.) relevant to our research questions. these keywords and themes were then integrated into a preliminary coding tree. we then defined each code and used findings from the reports to inform our consolidation of codes into larger categories. the four coders individually coded the same 14-page segment of a report and compared respective results to establish inter-coder reliability. with high levels of agreement, authors then coded reports by hand. the project evaluations were carried out in south africa (7), swaziland (1) and lesotho (1) (see table i). three of the 9 were implemented by an organisation that identified itself as faithbased. all 9 provided medical care and psychosocial support, and many mentioned that they provided nutritional support (7), information education and communication (6), referrals to other services if needed (6), income-generating activities (5), support for orphans and vulnerable children (5), and skills training (5). less common were projects that offered spiritual support (2), regular material assistance (2), and voluntary counselling and testing (1). three organisations had some form of inpatient facility. those receiving care were in rural, urban and peri-urban areas. while most organisations aimed to provide direct hbc services, one was an oversight body for hbc and another was an economic development model implemented in partnership with hbc providers. organisational capacity management all the evaluations found areas of management needing improvement. management challenges included a lack of good governance practices (2), inadequate capacity of the management staff (4), unclear lines of communication and chains of command (2), lack of formal policies and procedures (2), and insufficient management or administrative infrastructure (6). however, some projects excelled in these same areas, with clear staff roles and responsibilities, procedures manuals, dedicated and skilled management staff, methods results make up june issue nicky 5/30/05 2:19 pm page 31 june 2005 the southern african journal of hiv medicine32 faith rural/ trained caregiver site country based urban in hbc model compensation 1 south africa no rural 60 ngo collaborates with local monthly stipend hospital for referrals. hbc representatives sit on local management committees in all areas being served 2 south africa yes rural and 110 fbo collaborates with churches. none urban volunteers trained through ministers and counsellors of their church. caregivers form groups and are supported by hbc co-ordinator and consultant social workers 3 south africa no rural and 214 fbo collaborates with area clinics to monthly stipend urban support caregivers and refer clients. caregivers form groups and are supported by hbc manager (nurse) 4 swaziland yes rural and 120 implementing ngo collaborates some volunteers urban volunteer with international partner that and nurses receive caregivers, fundraises and provides allowances 30 parish medication and technical expertise. nurses retired nurses attached to parishes conduct home visits and provide professional support to volunteers 5 lesotho yes rural 90 national ngo aims to train none professionals on effective hbc who then train lay counsellors. project activities support the national hbc programme, which forms part of the existing primary health care programme 6 south africa no urban 25 freestanding ngo has sites in city monthly stipend hospitals and community centers for collaboration and referrals 7 south africa no peri-urban 47 academic hospice provides monthly stipend management and leadership role to local hospice. service area divided into subsections. a professional nurse supervises caregivers in each subsection 8 south africa no rural 1 046 joint undertaking between the monthly stipend provincial health department, ngos, and co-ordinating bodies to design and institute an integrated strategy and governance structures at the provincial and district levels 9 south africa no peri-urban na consortium implementing an honoraria economic development model that aims to enable households to generate and acquire resources to pay for their care requirements, and subsidise care for those unable to pay through local enterprise activities. *information based on status of project at time of evaluation. table i. description of the 9 hbc projects evaluated* make up june issue nicky 5/30/05 2:19 pm page 32 the southern african journal of hiv medicine june 2005 3 3 and open communication within the organisation cited as strengths. in 4 projects, strategic planning, financial management, policy issues, work plans and monitoring were handled by an administrative structure separate from the service delivery structure. in all these projects, local management capacity was cited as weak and therefore many management tasks went to consortia or more capable partners. however these partners were further removed, both in distance and focus, from actual service delivery. evaluators identified a lack of community and unity between administrative and service delivery structures. they recommended improvements in local service delivery structures to make them able to manage and sustain their own work more effectively. monitoring monitoring of project process and output indicators needed improvement among all 9 projects evaluated. seven of the evaluations called for improvements in the monitoring of services; 2 noted that projects had plans in place for implementing a new or improved monitoring system. for different projects, evaluators stated the need for monitoring for a cost-benefit analysis; a quality assurance mechanism; verification that activities being carried out were the planned activities funded; data on which to base management decisions; and an evaluation of the impact of caregivers on the well-being of patients. several benefits of strong monitoring were observed. through documentation and monitoring of increased activities, one organisation was able to prove the demand for services and thus secured additional funding for the programme. for 2 projects, needs assessments proved useful; one assisted in allocating appropriate numbers of volunteers per village, and the other helped to revise the project according to gaps identified. the integration of an efficient monitoring system also aided the supervision of caregivers in more than one case. linking the collection of monitoring data with the disbursement of stipends was one effective strategy employed. two organisations had useful partnerships with agencies that provided monitoring and evaluation support. one received assistance from a consultant who developed, through the participation of relevant staff and volunteers, an appropriate set of monitoring tools and then trained staff on how to use the forms. another organisation partnered with a university to conduct a needs assessment and create a monitoring framework. supervision successful monitoring often went hand in hand with effective supervision of caregivers. supervision was integral to the success of the projects evaluated, and those that made it a main activity were more successful at assuring quality. supervision by a professional nurse ensured high-quality monitoring at 2 organisations evaluated. several other successful mechanisms for supervision were reported: regular supervision meetings with caregivers; adequate numbers of nurses to supervise volunteers, described by a staff member as ‘the glue that holds the entire operation together’ in one project; initiation visits by a nurse to a new patient's home to plan care; and follow-up visits to homes to ask about satisfaction with care offered. one project used retired nurses both to conduct home visits themselves and to support volunteer caregivers, tapping into an available, local, skilled group. too often, evaluators found inconsistent supervision. specific problems included irregular attendance at supervision meetings, especially among volunteers not being compensated adequately; supervision meetings by caregiver request rather than regularly; and a lack of transportation for supervisors to follow up with caregivers and families in rural areas. in one project, the evaluator recommended that further caregivers should not be trained because the organisation did not have the capacity to supervise them adequately. livelihood options for caregivers and clients all hbc projects reviewed operated in resource-poor settings, and both caregivers and clients often faced the day-to-day challenge of surviving with limited access to livelihood. evaluation reports captured the ways in which projects responded to the income needs of both caregivers and clients. caregivers the number of caregivers trained in projects ranged from 25 to 1 046 individuals. caregivers were described in many instances as dedicated and ambitious individuals who felt a deep sense of responsibility toward their clients, often as a result of having known or cared for someone who had been ill in the past. the majority of caregivers were young women (under 30 years of age) with little or no previous training in care giving or health care. only 4 evaluations mentioned criteria for caregivers; 1 programme screened individuals for commitment during a trial period. one evaluator noted marked gender disparities within the hbc programme structure: while the leadership was mostly male, staff and caregivers were mostly female. one evaluator noted that diversifying caregivers by age and gender may make older, male hbc clients feel more at ease. in all projects, caregivers were volunteers; 7 of these provided some form of financial compensation to caregivers. some received allowances for meals and transport and/or hbc kits with essential supplies (gloves, linens, medicines, etc.), including clothing and boots. stipends and allowances were often reported to be insufficient to cover work-related costs and were not regularly disbursed to all caregivers. of those evaluation reports that specifically reported the stipend amount, the highest stipend mentioned was zar500, less than us$100, per month. hbc kits were reported to be in short supply, and in one programme, kits were entirely missing. make up june issue nicky 5/30/05 2:19 pm page 33 june 2005 the southern african journal of hiv medicine34 some hbc projects tried to address the emotional, professional and practical needs of their caregivers. two provided counselling for caregivers. one offered a unique solution to the common problem of heavy workload by forming caregiver networks that could be used as a resource for finding help, replacements and greater flexibility with work schedules. promotion structure and the opportunity for permanent employment in the community were cited as important incentives for caregivers. in a few projects, caregivers were matched with a professional health care provider in the community to gain knowledge, experience and advice about career development. in another, a promotion structure was created to allow outstanding volunteers to advance (see fig. 1). all hbc projects offered some form of training to caregivers, and caregivers valued ongoing training, accreditation and skills development programmes. clients in responding to the holistic needs of clients, the majority of hbc projects recognised the need for food security and poverty alleviation projects. eight projects offered material assistance to the neediest families being served, and 3 offered assistance accessing government grants. five engaged in igas with clients and 5 offered skills training. four of the igas made up a significant component of the project, and 1 did not dedicate enough resources to its igas and was therefore very limited. three had dedicated staff or volunteers who received a stipend working specifically on igas. two evaluations noted that igas were intended for people living with aids (plwas), but ended up benefiting community members more generally. three provided financial assistance to igas for start-up materials such as bakery equipment, gardening equipment, and seeds. evaluators identified 3 iga components of projects as achieving ‘limited success’, 1 as achieving some success, and 1 as a successful aspect of the overall hbc project (see fig. 2 for project details). igas thus presented a challenge for 4 hbc projects. projects that had dedicated staff and allocated funds for igas met with more success than those that did not. partnerships with governments a majority of projects described the potential for government involvement in the administration of hbc. two evaluations of projects, one in south africa and one in lesotho, praised the governments' efforts to provide access to best-practice models, training and capacity building opportunities, and financial support. four projects reported representatives of departments of health or social development on their boards of directors and advisory boards. not all agencies reported government involvement. however, when evaluations addressed the issue, all noted that hbc project leadership expressed the need for the government to assume more responsibility on different levels, including the provision of financial assistance, accreditation of training, strengthening the institutional capacity of hbc, and creating a political climate conducive to the efforts of hbc initiatives. while all nine projects analysed here were implemented within southern africa, they were undertaken in vastly different contexts. the mountain villages of lesotho and the inner city neighbourhoods of johannesburg would appear to have little in common. despite major differences in locations, populations served, and national contexts, all projects had the same basic mission: to provide quality home care for plwas through trained caregivers in resource-poor and under-served settings. our findings from these nine diverse projects in three southern african countries illuminate how hbc has been conceived and implemented in the region, obstacles faced in assuring high quality, and how projects have worked to overcome them. the following discussion highlights these findings and recommends policy changes at the funder and national level that could help achieve high-quality, integrated hbc. building the capacity of organisations as the need grows, programme funders and implementers will look to expand hbc to cover larger geographical areas and participants: women and elderly mechanisms: iga officers hired allocated funds village committees successes: cumulative savings personal empowerment donations to households with orphans facilitating factors: group unity and cohesion market opportunities targeted flexibility in project spending for igas (more than double expected) fig. 2. successful gardening and candlemaking igas at a rural site in lesotho (site 6). at an urban programme in johannesburg (site 7), a ‘career path’ for volunteers was created as a response to limited funds for stipends. volunteers started out as unpaid befrienders in hospitals, and were promoted as funds became available if commitment and competence were demonstrated. befriender unpaid volunteer counsellor stipend hbc honorarium fieldworker team leader paid staff → fig. 1. creating a ‘career path’ for volunteers. discussion make up june issue nicky 5/30/05 2:19 pm page 34 the southern african journal of hiv medicine june 2005 3 5 more patients. however, to do so will require careful attention to the capacity of often new hbc organisations' abilities to effectively manage such expansion, at the local level. at the project level, we have noted that a sustainable hbc programme requires adequate governance, effective communication between partners, access to material resources, institutional support, financial assistance, committed and informed caregivers, and community involvement. partnerships and consortia may be good solutions to build the capacity of organisations doing hbc, but ultimately funders should realise that success will depend on the ability of projects to increasingly manage their own projects, including financially. organisations whose finances are managed by parent institutions or other partners may be vulnerable and left with no capacity to manage their own funding should they become independent. hbc projects must put in place adequate monitoring, evaluation and supervision mechanisms. collaboration with organisations that have the capacity to provide technical monitoring and evaluation support was a successful strategy in some of the projects evaluated. funders should seek ways of training management and staff in monitoring and evaluation skills. information obtained in the process of programme monitoring can be linked to the disbursement of stipends for caregivers. pre and post evaluations and the development of impact level indicators will help programmes measure effectiveness. for supervision, projects must ensure they have adequate skilled managers or nurses to conduct all supervision, and that regular supervision meetings are held with caregivers. furthermore, transportation for supervision should be a programme priority. programmes should not expand beyond their capacity to supervise caregivers in the field. enhancing livelihood options for caregivers and clients effective hbc cannot be delivered without making poverty alleviation for both clients and their caregivers a priority. while volunteers frequently offer their time despite the lack of regular incentives, programme planners, donors and governments should consider the ethics and appropriateness of not adequately compensating people who often come from disadvantaged backgrounds and accept heavy responsibilities of caregiving for the terminally ill. hbc projects that provide caregivers opportunities for advancement to paid positions within the programme and beyond are serving the community in two ways – providing quality hbc and developing marketable skills. hbc should allow for financial incentives, transportation, medical kits and their re-supply, and provide accessible caregiver support mechanisms in order to boost the morale of caregivers and staff who often face difficult physical and emotional work conditions. remuneration guidelines should be clearly explained to all volunteers and staff from the outset. all the projects reviewed faced the tremendous challenge of attempting to provide care in the context of food insecurity and household poverty of clients. most projects were able to provide some form of material assistance for food security to their most needy clients. while add-on income-generating projects were attempted by many projects, few were economically successful or sustainable. hbc has been sited as a mechanism to reach a community's most vulnerable. those planning hbc programmes should consider forming partnerships with agencies able to offer economic development possibilities to households in need. in addition, hbc programmes should adequately budget for the start-up funds and external expertise needed if they plan to incorporate an iga. finally, a key part of any hbc programme is an efficient medical and social service referral system and assistance in accessing government grants. stronger integration of hbc into government health care provision the governments of south africa, swaziland, and lesotho have recognised the importance of hbc and sought to provide guidance and support to those engaged in hbc. however, hbc needs stronger government co-ordination, integration, and monitoring and evaluation in order to increase quality and coverage. if embedded into a country's national hiv/aids plan and adequately linked to the national health care system, hbc will more likely be viewed as a more viable option and funding can be systematically set aside as is the case for other health service areas. additionally, an established commitment from governments gives projects the firm foundation that may make outside donors more inclined to partner. one important area for government policy development is accreditation for hbc training to assure the quality of instruction and subsequent care in the field. the incorporation of palliative care through the provision of pain control drugs such as morphine is another essential aspect of care that hbc programmes could begin to offer if the supply of drugs could be stabilised through government support. finally, governments should assess the implications of their remuneration policies for caregivers, or the lack of such policies, to assure fair wages for this necessary service. given the high demand for hbc and governments' inability to meet this demand, external donors should prioritise hbc when assisting governments to implement their national hiv/aids strategies. the integration of hbc into government health programmes is particularly important as governments begin to roll out arvs. ngos in general, and hbc programmes specifically, have a natural role to play owing to the experience they have gained caring for aids patients in their homes over the past decades. their potential contributions include providing drug education, adherence follow-up, and complementary support, such as food security and counselling to patients on arvs. policy makers and those implementing arv roll-outs should partner with hbc projects and build their capacity accordingly, as they represent an invaluable resource. the community-based treatment programmes currently being piloted through partnerships between bms stf and five southern african governments are seeking to do this in an effective manner. make up june issue nicky 5/30/05 2:19 pm page 35 june 2005 the southern african journal of hiv medicine36 the following evaluation reports from the bristol-myers squibb secure the future monitoring and evaluation unit (yale university) were analysed in the current review: archdiocese of cape town caring network final evaluation report. august 2002; bambisanani hiv/aids project final evaluation report. august 2003; caritas swaziland parish nurse programme final evaluation report. august 2003; christian health association of lesotho home based care project final evaluation report. november 2004; community aids response final evaluation report. september 2003; living with hope and meaning in the face of illness, death, and dying: sth consortium final evaluation report. march 2002; naledi hospice home based care programme final evaluation report. june 2003; port elizabeth catholic diocese hiv/aids education programme final evaluation report. august 2002. references 1. unaids. 2004 report on the global aids epidemic. geneva: unaids, 2004. 2. panos. 1996. home-based care, not home based neglect. http://www.aegis.com/news/panos/1996/ps960701.html (accessed february 2005). 3. victor b. what are the lessons learned from the past 15 years of home based care in developing countries? 14th international aids conference, barcelona, july 2002 (abstract wepef6642). 4. world health organization. home based care and long term care: home care issues at the approach of the 21st century from a who perspective: an annotated bibliography. geneva: who, 1999. 5. department of health, republic of south africa. national guidelines on home-based care/community-based care. pretoria: doh: 2001. 6. kikule e. a good death in uganda: survey of needs for palliative care for terminally ill people in urban areas. bmj 2003; 327: 192-194. 7. uys l. aspects of the care of people with hiv/aids in south africa. public health nursing 2003; 20: 271-280. 8. world health organization. aids home care handbook. geneva: who, 1993. 9. ndaba-mbata r, seloilwe e. home-based care of the terminally ill in botswana: knowledge and perceptions. international nursing review 2000; 47: 218-223. 10. singer p, bowman k. quality care at the end of life: should be recognized as a global problem for public health and health systems. bmj 2002; 324: 1291-1292. 11. olenja j. assessing community attitude towards home-based care for people with aids (pwas) in kenya. community health 1999; 24: 187199. 12. johnson b, khanna s. community health workers and home-based care programs for hiv clients. j natl med assoc 2004; 96: 496-502. 13. murray s, grant e, grant a, kendall m. dying from cancer in developed and developing countries: lessons from two qualitative interview studies of patients and their carers. bmj 2003; 326: 368. 14. akintola o. a gendered analysis of the burden of care on family and volunteer caregivers in uganda and south africa. durban: health economics and hiv/aids research division, 2004. 15. fox s. integrated community-based home care in south africa: a review of the model implemented by the hospice association of south africa. cape town: centre for aids development, research and education (cadre) on behalf of the policy project, 2001. 16. unaids. reaching out, scaling up: eight case studies of home and community care for and by people with hiv/aids. geneva: unaids, 2001. 17. fru nsutebu e, walley j, mataka e, fikansa c. scaling up hiv/aids and tb home-based care: lessons from zambia. health policy and planning 2001; 16: 240-247. 18. harding r, stewart k, marconi k, o'neill j, higginson i. current hiv/aids end-of-life care in sub-saharan africa: a survey of models, services, challenges and priorities. biomed central public health 2003; 3 (33). 19. walker, m, aceng e, tindyebwa d, nabyonga j, ogwang p, kiiza p. an assessment of home-based care programs in uganda: their strengths and weaknesses. www.hsph.harvard.edu/takemi/rp213.pdf (accessed june 2004). we extend our appreciation to sarah hanck and alim manji for assistance in conducting the literature searches; to all project directors who permitted the use of project evaluation reports for this analysis; and to the consultants who conducted these evaluations. make up june issue nicky 6/1/05 11:14 am page 36 about the author(s) maren kummerow julius global health, julius center for health sciences and primary care, university medical center utrecht, utrecht university, utrecht, the netherlands erica j. shaddock division of pulmonology, department of internal medicine, charlotte maxeke johannesburg academic hospital, johannesburg, south africa faculty of health sciences, university of the witwatersrand, johannesburg, south africa kerstin klipstein-grobusch julius global health, julius center for health sciences and primary care, university medical center utrecht, utrecht university, utrecht, the netherlands division of epidemiology and biostatistics, school of public health, faculty of health sciences, university of the witwatersrand, johannesburg, south africa roos b. barth department of internal medicine and infectious diseases, university medical center utrecht, utrecht university, utrecht, the netherlands diederick e. grobbee julius global health, julius center for health sciences and primary care, university medical center utrecht, utrecht university, utrecht, the netherlands w.d. francois venter wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, johannesburg, south africa charles feldman department of internal medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa alinda vos julius global health, julius center for health sciences and primary care, university medical center utrecht, utrecht university, utrecht, the netherlands department of internal medicine and infectious diseases, university medical center utrecht, utrecht university, utrecht, the netherlands wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, johannesburg, south africa citation kummerow m, shaddock ej, klipstein-grobusch k, et al. erratum: unexpected low frequency of respiratory symptoms in an hiv-positive urban sub-saharan population compared to an hiv-negative control group. s afr j hiv med. 2021;22(1):1180. https://doi.org/10.4102/sajhivmed.v22i1.1180 note: doi link to the original article: https://doi.org/10.4102/sajhivmed.v20i1.1010 correction erratum: unexpected low frequency of respiratory symptoms in an hiv-positive urban sub-saharan population compared to an hiv-negative control group maren kummerow, erica j. shaddock, kerstin klipstein-grobusch, roos b. barth, diederick e. grobbee, w.d. francois venter, charles feldman, alinda vos published: 19 apr. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. in the version of this article initially published, kummerow m, shaddock ej, klipstein-grobusch k, et al. unexpected low frequency of respiratory symptoms in an hiv-positive urban sub-saharan population compared to an hiv-negative control group. s afr j hiv med. 2019;20(1):a1010. https://doi.org/10.4102/sajhivmed.v20i1.1010, the name of the sixth author was given incorrectly. the correct name should be w.d. francois venter instead of francois d.f. venter in the ‘authors’ section. this correction does not alter the significance of the study findings or the overall interpretation of the study results. the publisher apologises for any inconvenience caused. introduction specific guidelines changes breastfeeding conclusions acknowledgements references about the author(s) jeannette wessels research centre for maternal, fetal, newborn and child health care strategies, university of pretoria, pretoria, south africa gayle sherman department of paediatrics & child health, faculty of health sciences, university of the witwatersrand, johannesburg, south africa centre for hiv & sti, national institute for communicable diseases, division of the national health laboratory services, johannesburg, south africa lesley bamford child, youth, and school health chief directorate, national department of health, pretoria, south africa school of health systems and public health, university of pretoria, pretoria, south africa manala makua communicable and non-communicable diseases branch, national department of health, pretoria mathilda ntloana communicable and non-communicable diseases branch, national department of health, pretoria james nuttall department of paediatrics and child health, red cross war memorial children’s hospital, university of cape town, cape town, south africa yogan pillay communicable and non-communicable diseases branch, national department of health, pretoria ameena goga health systems research unit, south african research council, cape town, south africa department of paediatrics and child health, university of pretoria, pretoria, south africa hiv prevention research unit, south african medical research council, cape town, south africa ute feucht research centre for maternal, fetal, newborn and child health care strategies, university of pretoria, pretoria, south africa department of paediatrics and child health, university of pretoria, pretoria, south africa tshwane district health services, gauteng department of health, tshwane, south africa maternal and infant health care strategies research unit, south african medical research council, pretoria, south africa citation wessels j, sherman g, bamford l, et al. the updated south african national guideline for the prevention of mother to child transmission of communicable infections (2019). s afr j hiv med. 2020;21(1), a1079. https://doi.org/10.4102/sajhivmed.v21i1.1079 guideline the updated south african national guideline for the prevention of mother to child transmission of communicable infections (2019) jeannette wessels, gayle sherman, lesley bamford, manala makua, mathilda ntloana, james nuttall, yogan pillay, ameena goga, ute feucht received: 24 feb. 2020; accepted: 03 may 2020; published: 08 july 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. introduction south africa has made great strides in reducing the vertical transmission of human immunodeficiency virus (hiv) in the first two months of life from 23% (2003) to 0.7% (2019), despite a persistently high antenatal hiv prevalence of around 30%. improving access to antiretroviral therapy during antenatal care has significantly contributed to this success, but has led to an increase in the relative proportion of vertical transmissions due to breastfeeding in the first six months post-delivery. yet, due to the shortand long-term benefits of breastfeeding and risks associated with not breastfeeding, mothers need to be supported to breastfeed their infants for the longest duration possible, while maintaining virological suppression to reduce the vertical transmission risk. the new south african national guideline for the prevention of mother to child transmission of communicable infections (2019) outlines three major strategies for programme improvement. these are 1) prevention of primary hiv infection and unintended pregnancies in women of childbearing potential, 2) improvement of maternal viral suppression rates at delivery and in the post-delivery period through potent, well-tolerated antiretroviral regimens, strategic use of maternal viral load monitoring, linking of mothers to post-delivery hiv care and integration of mother-infant health care, and 3) provision of enhanced prophylaxis to infants of mothers with elevated hiv viral loads in the breastfeeding period, while every effort is made to regain maternal viral suppression. rigorous implementation of this guideline can potentially move south africa closer to the goal of eliminating mother-to-child transmission and making an hiv-free generation a reality. south africa’s (sa) programme of prevention of mother-to-child transmission (pmtct) of hiv has achieved remarkable successes in recent years in ensuring good outcomes for pregnant women living with hiv and reducing the risk of vertical hiv transmission to their children.1 the most critical intervention to prevent vertical transmission is the maintenance of the undetectable maternal hiv viral load (vl) levels through effective antiretroviral therapy (art).2 this has necessitated a considerable scale-up of hiv testing services (hts) within antenatal care to identify women living with hiv (wlwh). the pmtct ‘option b plus’, namely the provision of lifelong art irrespective of cd4 count or clinical disease severity, was implemented in south africa in january 2015, and significantly improved access to art for pregnant women in the public sector.3,4 as a result, more than 95% of women with unknown hiv status are currently tested for hiv during antenatal care, and more than 90% of wlwh are on art.5 vertical transmission rates within the first two months of life dropped dramatically from 23% in 20036 to 0.7% in 2019.7 whilst the achievements in reducing hiv transmission at birth are noteworthy, the global plan target1 of elimination of vertical transmission will remain elusive due to sa’s high hiv prevalence rates. this brings into stark focus the need for primary prevention of hiv in all women of reproductive potential, before, during, and after pregnancy, as well as the urgent need to intensify measures to prevent unintended pregnancies. according to data published in 2016, the cumulative vertical transmission rate by 18 months of age is 4.3%.8 the largest proportion (> 80%) of these transmissions occur during the first six months of the breastfeeding period,8 when women may experience pronounced challenges to adherence and retention in care, impacting negatively on viral suppression.9,10,11,12 at the same time, breastfeeding remains a key strategy to ensure that south african children survive and thrive. the evidence indicates that the benefits of breastfeeding outweigh the risks of not breastfeeding, regardless of the maternal hiv status.13,14,15 as the hiv epidemic matures, it is clear that the breastfeeding period must be one of the main priorities in the prevention of vertical transmission of hiv. new innovative strategies are required to achieve and maintain maternal viral suppression in the period after birth, whilst simultaneously promoting breastfeeding as a major child survival strategy. in addition, sustained maternal viral suppression will allow the realisation of the longer-term advantages of ‘option b plus,’ including improved maternal health, viral suppression in subsequent pregnancies, and reduced hiv transmission to sexual partners. to this end, the south african department of health has revised the guideline for the prevention of mother to child transmission of communicable infections (2019). this standalone guideline also forms part of the revised national consolidated guidelines for the management of hiv in adults, adolescents, children and infants and for the prevention of mother-to-child transmission (2019). the guideline incorporates new evidence, both scientific and operational, to ensure that south africa’s hiv pmtct programme remains relevant, practical, and evidence-based. a concerted effort has been made to ensure alignment between these guidelines and other national guidelines, including the standard treatment guidelines and essential medicines list for south africa. it includes a strong focus on the prevention of hiv and unintended pregnancies in women of childbearing potential, maternal viral suppression, preventing mtct during the breastfeeding period, and care integration for the mother-infant pair. a summary of the major changes in the guideline is illustrated in table 1, together with the rationale for major changes for wlwh, being provided in the text. table 1: summary of the main changes in the south african 2019 prevention of mother-to-child guideline. specific guidelines changes antiretroviral therapy during pregnancy and the breastfeeding period the risk of vertical hiv-transmission correlates strongly with maternal hiv vl levels.16,17 for every additional week on suppressive art during antenatal care, the risk of mtct is reduced by 10%.2 therefore, the prescription of antiretroviral drugs that rapidly and safely achieve and sustain maternal viral suppression during pregnancy and the breastfeeding period is of greatest importance to the prevention of vertical transmission. in this regard, the newly introduced integrase inhibitor dolutegravir (dtg) offers improved tolerability, few drug interactions, and the reduced risk of viral drug resistance.18 the time to viral suppression is approximately halved by dtg when compared to the currently administered drug efavirenz (efv).18 recent data from botswana indicates that dtg may increase the risk of neural tube defects (ntds).19 the absolute risk is low, currently documented at 0.3% for mothers conceiving on a dtg-containing art compared to a risk of 0.1% for mothers conceiving on alternative regimens.20 whilst the world health organization (who) has recommended dtg as the preferred first-line option for all populations (weight ≥ 20 kg) without exceptions, south africa has opted for a more conservative approach, and recommends that dtg should be used with caution in women wanting to conceive, and be avoided in the first six weeks of pregnancy, that is, following her last menstrual period and before closure of the foetal neural tube approximately four weeks after conception. however, recent evidence indicates that dtg is likely to have health and cost benefits over efv even in women who intend pregnancy,21 providing further confirmation for the who’s more inclusive approach. whilst south africa’s position on dtg is likely to change as evidence evolves, confusion around the use of dtg in women of childbearing potential has resulted in the suboptimal uptake of effective art in the women who need it most. as a positive consequence, the current dtg recommendations will require that family planning services be better integrated into art care. health care workers should regularly discuss issues of childbearing and contraception with their clients in order to understand current fertility intentions and contraceptive needs. all women require appropriate counselling on the risks and benefits of dtg and should make an informed choice (box 1). women may choose to use dtg; for those women who choose not to use dtg, efv remains a safe, efficacious and cost-effective option. concurrent use of effective contraception is recommended for all non-pregnant women not currently desiring a pregnancy. box 1: use of dolutegravir in women of childbearing potential. regimen switches during pregnancy a single drug switch from an efv-containing regimen to a dtg-containing regimen should only be considered if the client has a suppressed vl (in the last six months), irrespective of pregnancy status. therefore, pregnant women already on art should continue their current art regimen, pending the result of their hiv vl at entry into antenatal care. if the vl is below 50 copies/ml, and the woman has progressed past the initial six weeks of pregnancy, that is, six weeks since her last normal menstruation, switching to a dtg-containing regimen may be offered. appropriate counselling as outlined in box 1 should precede the use of dtg in any women of childbearing potential. antiretroviral therapy for women with previous antiretroviral exposure women presenting during pregnancy and breastfeeding who are not on art but with previous exposure to art present a unique dilemma, given the urgency for maternal vl suppression. they may already have developed viral resistance, with the potential of delayed viral suppression on the re-starting of efv-containing regimens. for this reason, women known to be living with hiv who are currently not on art, but who are art-exposed, for example previous pmtct, or previous loss-to-follow-up on art, should initiate a dtg-containing regimen. the fixed-dose combination of tenofovir (tdf), lamivudine (3tc), and dtg, known as tld, is recommended with previously documented vl suppression on art. without proof of prior viral suppression (with previous vl results either not suppressed or not available), zidovudine (azt), 3tc and dtg should be initiated, due to the higher likelihood of concomitant resistance to both the tdf and efv components of their first-line fixed-dose combination regimen. antiretroviral therapy for women presenting in labour for women initiating art around the time of labour and delivery, earlier guidelines recommended one dose of nevirapine (nvp) and tdf/emtricitabine (ftc), together with three-hourly azt during labour.25 this has been replaced with a single dose of nvp, together with a dose of tld (see table 1, row 7: art for the mother presenting in labour). the dose of nvp is retained due to existing evidence.26 previously, in the era where not all women were eligible for art post-delivery, the tdf/ftc combination was used to ‘cover the tail’ and reduce the risk of viral resistance. however, all women now qualify for art. the tld given in labour provides the first dose of lifelong art and removes the need for both tdf/ftc and three-hourly azt during labour. antiretroviral therapy is to be continued the following day after understanding the woman’s fertility intentions and appropriate counselling on the risk of dtg-associated ntds for her subsequent pregnancies. the recommended regimen in the period after birth is tld. concurrent use of effective contraception is recommended for all women at discharge from labour wards. table 2: infant hiv post-exposure prophylaxis given at birth. maternal human immunodeficiency virus viral load monitoring potent art regimens are most effective when coupled with hiv vl monitoring to confirm good adherence and viral suppression or to allow the timely detection of factors that may negatively affect viral suppression (e.g. suboptimal treatment adherence, drug interactions, intercurrent infections, etc.). importantly, vl monitoring can only be effective if coupled with a response to the test results, and women with detectable vl results (vl > 50 c/ml) must be followed up for urgent intervention, directed to ensure immediate viral suppression. accurate national surveillance of maternal vl suppression will require a means to distinguish between vls done during antenatal care, at delivery, and after birth. within the public sector this will be achieved through the use of electronic gatekeeping codes submitted on national health laboratory service (nhls) requisition forms (code c#delivery applied to vls at delivery, and c#pmtct applied to vls during the antenatal and postpartum periods). of great importance, colleagues in the private sector may wish to discuss with their laboratory service the value or feasibility of implementing such a coding system in their practice. viral load monitoring during the antenatal period women initiating or re-initiating art in pregnancy should have their first vl measured three months after starting art. if suppressed, the vl should be repeated at delivery. for wlwh and who are already on art, the vl should be measured at the first antenatal care visit, as per previous guidelines. if suppressed, the vl is repeated at delivery, unless subsequent vl non-suppression is suspected. accurate recording, of antenatal maternal vl testing data in the maternity case record, is crucial to ensure communication and continuity of care between antenatal and delivery services. women initiating art at any time after 28 weeks gestation will have a vl measurement done at delivery and repeated three months after delivery. if the mother-infant pair is receiving integrated care, this vl should be aligned to the 10-week well-child immunisation visit. viral load monitoring at delivery and six months after delivery previous implementation of vl monitoring in the pmtct programme has been suboptimal. thus, the vl monitoring schedule, that had been linked to the art history and timing of anc booking, has been changed to fixed time points linked to the pregnancy itself. a vl at delivery has, therefore, been introduced for all wlwh. much debate has ensued with regard to the best timing of a vl around the time of delivery. whilst results of a vl done at 36 weeks’ gestation would be available by the time of delivery, a significant proportion of women, including those with premature labour, those with uncertain gestational age, and un-booked deliveries, would not receive a vl at 36 weeks’ gestation. additionally, antenatal care usually occurs at a different facility from delivery, and antenatal vl results may not be available at the delivery site. a vl done at the actual time of delivery has the following advantages: high in-facility birth rates, and previous rapid uptake and high coverage of infant birth pcr testing within labour wards, infer the possibility of near-universal coverage of the delivery vl. uniformly performed vls at time-point of delivery will enable the health system to monitor and better enforce the coverage of maternal vl testing. viral load testing at delivery allows for placing of the reference to the maternal laboratory testing into the infant’s road-to-health booklet to provide a potential link for pmtct interventions, promoting integrated care for the mother-infant pair and ensuring consideration of maternal laboratory results during infant health care provision. it provides a means of epidemiological surveillance of vertical transmission risk at delivery. given that more than half of vertical transmissions now occur after delivery,8,27 linked to postpartum challenges to adherence and retention in care,9,10,11,12 a maternal vl should be done at six months after delivery for all wlwh, aligned to the six-month well-child immunisation visit, regardless of breastfeeding status. as the maternal vl impacts directly on the care required for the infant, breastfeeding mothers who are not receiving integrated care as a mother-infant pair and who are receiving care at a separate art clinic face a significant challenge. general art services have, to date, not effectively identified breastfeeding mothers, nor monitored their vls at six-monthly intervals. if breastfeeding is to be protected by providing enhanced infant antiretroviral prophylaxis in mothers who have detectable vls, much will need to be done to improve the identification of breastfeeding mothers and their infants, vl monitoring, and communication with providers caring for their infants. clinical interventions alone will not improve postpartum viral suppression. health workers, supported by community engagement and media campaigns, should empower mothers with knowledge regarding the importance of continued viral suppression for both maternal and child health benefits. women need to be equipped to anticipate adherence challenges in the postpartum period, including disrupted routines, sleep deprivation, and postnatal depression. linkages to available resources should occur, for example community health workers, mentor mothers, momconnect, or other support groups and clubs. a concerted effort should be made by all in the care team to ensure that the mother is retained in care, adherent to art, maintains vl suppression and has access to effective contraceptive services. management of an elevated maternal human immunodeficiency virus viral load viral load suppression across the south african art programme is now defined as a vl of < 50 copies/ml. any vl ≥ 50 copies/ml implies viral replication and risk to the mother and infant. if the mother is on art and her vl is detectable, drug resistance must be considered. but such a situation needs to trigger a thorough assessment, for example evaluation of adherence, a check of medication dosages, a review of potential drug-drug interactions and the exclusion of intercurrent infection. a cause needs to be identified and corrected. an elevated maternal vl of ≥ 1000 copies/ml at delivery or during the breastfeeding period warrants initiating, extending, or re-starting high-risk infant art prophylaxis (see below). the threshold for virological failure and switch to second-line art is influenced by the treatment regimen, namely an efv or a dtg-containing regimen, and the prior duration of art. the definition of virological failure whilst on an efv-based regimen remains a vl of ≥ 1000 c/ml on two consecutive occasions ideally not longer than three months apart, despite attention to adherence issues. the definition of failure on a dtg-based regimen requires at least three vls ≥ 1000 copies/ml over a two-year period together with a focused effort to improve the patient’s adherence. women failing to suppress on secondor third-line art warrant expert discussion or referral. these clients are likely to be experiencing complex clinical and psychosocial challenges and will likely benefit from an individualised approach to maternal management, infant prophylaxis, and recommendations for possible breastfeeding cessation and the prescription of infant formula. infant post-exposure prophylaxis to be provided at birth the delivery vl will determine the infant’s hiv transmission risk category. however, many mother-infant pairs will be discharged after birth but before the delivery vl results are available. then the most recently available vl result, that is, within the last 12 weeks, will determine the infant’s risk category prior to discharge at birth. the laboratory barcode sticker or similar indicator of the delivery vl, clearly labelled ‘maternal’ to distinguish it from the infant’s hiv pcr barcode sticker, should be placed in the infant’s patient records, together with the road-to-health booklet, to ensure access to both maternal and infant birth-pcr results at the 3–6-day postnatal visit. adjustments can then also be made to the infant prophylaxis regimen, as appropriate. low-risk infants, namely infants born to mothers with a suppressed vl within the last 12 weeks of delivery, or at delivery, should receive nvp daily for six weeks. high-risk infants identified at birth, namely no recent vl available in the last 12 weeks of pregnancy or maternal vl ≥ 1000 copies/ml, should receive high-risk prophylaxis: nvp daily for a minimum of 12 weeks and azt twice daily for six weeks. a persistently elevated maternal vl in the breastfeeding period is a further risk for hiv acquisition in the infant.16,17 for this reason, nvp should only be stopped after 12 weeks post-delivery if the maternal vl is < 1000 copies/ml. otherwise nvp should be continued until a maternal vl of < 1000 copies/ml is achieved or until four weeks after breastfeeding cessation. table 2 provides a summary of infant post-exposure prophylaxis to be given at birth, based on the infant’s risk profile for hiv transmission and chosen feeding method. infant human immunodeficiency virus testing infant hiv pcr testing at birth is recommended in all hiv-exposed infants, to identify intra-uterine transmission. wherever possible, birth hiv pcr tests should not be submitted with the mother’s name and details such as ‘baby of’. mothers should be counselled during antenatal care to provide the permanent name and surname of the child at delivery. correct identification information for the child will allow the birth pcr to be linked to later test records, and will facilitate registration of the birth with home affairs before discharge. hiv pcr testing at age 10 weeks is recommended to identify perinatal hiv transmission. this remains part of the standard schedule of testing for hiv-exposed infants (table 3). however, the hiv pcr test at 18 weeks, previously performed in infants who received high-risk prophylaxis, has been discontinued due to inadequate uptake and non-alignment with any child immunisation visit. instead, all hiv-exposed infants, both low and high risk, are to receive an hiv pcr test at the six-month integrated well-child visit. over 80% of infants who acquire hiv do so by six months of age, highlighting the importance of this six-month hiv pcr test.8 however, the risk of infant hiv acquisition may shift to more than 20% after six months of age if longer periods of breastfeeding are achieved. breastfed infants who test hiv negative, particularly those on antiretroviral prophylaxis, should not be assumed to be uninfected until after the age-appropriate post-weaning hiv test has been performed. table 3: time points for routine hiv testing in hiv-exposed and hiv-unexposed children. at six months of age, the hiv status of all infants not already known to be hiv-exposed should be established by offering an hiv test to the mother. this maternal hiv test should fall into the routine three-monthly hiv testing schedule for all breastfeeding mothers who are not yet known to be living with hiv. if a maternal hiv test is not feasible, consent should be obtained to perform a rapid test on the child. care that is provided in an integrated manner to the mother-infant pair greatly facilitates this process of (1) identifying a women as breastfeeding, (2) identifying those women who require hiv testing, and (3) determining the care required by the infant as informed by the mother’s results. breastfeeding mothers who are not receiving integrated care face a significant challenge with regard to repeat hiv testing. much will need to be done to ensure that breastfeeding mothers are able to access hiv testing services within family planning clinics and other general health services, and that her infant receives the appropriate care according to her test results. an hiv antibody test (hiv rapid or elisa [enzyme-linked immunosorbent assay] test) is used as a screening test above 18 months of age. however, in a small percentage of children the maternal antibodies persist beyond 18 months of age, potentially resulting in false-positive hiv diagnoses and inappropriate initiation of lifelong art.22 therefore, hiv pcr testing is now recommended as confirmatory testing in all hiv-positive hiv rapid or elisa tests in children under two years of age. a summary of initial and confirmatory hiv testing is outlined in table 4. table 4: hiv tests for initial and confirmatory testing in children according to age: 2019 prevention of mother-to-child transmission guidelines. at the clinician’s discretion, the hiv pcr may be replaced by a vl test, which has the advantage of both confirming the hiv diagnosis and providing a baseline vl for monitoring the child’s response to art. diagnostic difficulties, for example indeterminate hiv pcr test results, require urgent expert advice. breastfeeding due to the expanded access to art in south africa, the country-level recommendations for breastfeeding are now the same whether or not the mother is living with hiv.15,28 these recommendations include exclusive breastfeeding for the first six months, the introduction of appropriate complementary foods thereafter, and continued breastfeeding for two years or longer. given the numerous benefits of breastfeeding for the health and well-being of all children, it is imperative that mothers are supported to breastfeed their infants for the longest possible duration whilst maintaining viral suppression and reducing the risk of hiv-transmission through breastmilk exposure. to reduce hiv transmission during breastfeeding, the guideline outlines two major strategies. the first is to improve viral suppression rates in the period after birth by (1) providing potent and well-tolerated art regimens – including dtg, (2) outlining mechanisms for linking mothers back into appropriate hiv care post-delivery, (3) integrating services for mother-infant pairs to promote adherence and retention in care, and (4) using vl monitoring strategically for the timely detection of, and response to, elevated hiv vls. whilst maternal viral suppression remains the gold standard, elevated hiv vls will occur in selected women in the breastfeeding period. the second strategy is to provide enhanced infant prophylaxis whilst every effort is made to regain maternal viral suppression. prophylaxis for infants of breastfeeding mothers with an elevated human immunodeficiency virus viral load an elevated maternal hiv vl during breastfeeding can occur either at the time of a new hiv diagnosis or because of an unsuppressed vl on art. regardless of the cause, an elevated hiv vl in a breastfeeding mother requires urgent clinical intervention and more frequent vl monitoring. with pre-treatment resistance to non-nucleoside reverse transcriptase inhibitors documented to be on the increase, and the high likelihood (up to 40%) of viral resistance in the mother with an elevated vl on art,29,30 these infants should receive high-risk prophylaxis consisting of azt twice daily for six weeks, and nvp daily for a minimum of 12 weeks, with infant nvp only stopped after confirmed maternal hiv vl < 1000 c/ml, or breastfeeding cessation. consolidated hiv pcr and vl results for action reports, generated daily or weekly from the nhls data warehouse, can be used to fast track high-risk clients, including pregnant women with high vls and hiv-infected infants. reports for the public sector can be accessed by registering at http://www.nicd.ac.za. conclusions whilst much progress has been made in preventing vertical transmission of hiv, much remains to be done. overcoming the ‘next frontier’ and preventing vertical hiv transmission during the breastfeeding period may well be the most challenging phase yet. in response, the new 2019 pmtct guideline outlines strategies that focus strongly on maintaining maternal hiv viral suppression, strengthening and integrating care for mother-infant pairs, and supporting and protecting breastfeeding as a major child survival strategy. creating an environment that enables the rigorous implementation of this guideline will move south africa closer to the goal of eliminating vertical hiv transmission and making an hiv-free generation a reality. the guideline for the prevention of mother to child transmission of communicable infections is available at http://bit/ly/2019-pmtct-guidelines. acknowledgements the authors would like to acknowledge the national department of health prevention of mother-to-child transmission (ndoh pmtct) technical working group, and all experts and health care workers who provided inputs into the guideline. competing interests the authors have declared that no competing interests exist. authors’ contributions u.d.f. conceptualised the paper and provided strategic guidance to j.w. as lead author, j.w. synthesised all drafts, managed input and prepared the paper in final form. u.d.f. reviewed all drafts and provided editorial support. a.g., g.s., l.b. and j.n. provided strategic inputs and contributed to all drafts. all authors read and commented on drafts and approved the final version. ethical consideration this article followed all ethical standards for carrying out research without direct contact with human or animal subjects. funding information this paper received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. data availability statement data sharing is not applicable to this article as no new data were created or analysed in preparation of this manuscript. disclaimer the information presented in these guidelines conforms to the current medical, nursing and pharmaceutical practice. contributors and editors cannot be held responsible for errors, individual responses to medicines, and other consequences. references unaids. 2015 progress report on the global plan [homepage on the internet]. geneva: unaids; 2015 [cited 2019 oct 17]. available from: https://www.unaids.org/sites/default/files/media_asset/jc2774_2015progressreport_globalplan_en.pdf townsend cl, byrne l, cortina-borja m, et al. earlier initiation of art and further decline in mother-to-child hiv transmission rates, 2000–2011. aids. 2014;28(7):1049–1057. https://doi.org/10.1097/qad.0000000000000212 kim mh, ahmed s, abrams ej. pediatric hiv: progress on prevention, treatment, and cure. curr pediatr rep. 2015;3(3):219–229. https://doi.org/10.1007/s40124-015-0087-7 myer l, phillips tk. beyond ‘option b+’. jaids. 2017;75(suppl 2):s115–s122. https://doi.org/10.1097/qai.0000000000001343 massyn n, peer n, english r, padarath a, barron p, day c. district health barometer 2015/16 [homepage on the internet]. durban: health systems trust; 2016 [cited 2019 oct 17]. available from: https://www.hst.org.za/publications/district%20health%20barometers/district%20health%20barometer%202015_16.pdf sherman gg, lilian rr, bhardwaj s, candy s, barron p. laboratory information system data demonstrate successful implementation of the prevention of mother-to-child transmission programme in south africa. s afr med j. 2014;104(3):235. https://doi.org/10.7196/samj.7598 moyo f, haeri mazanderani a, barron p, et al. introduction of routine hiv birth testing in the south african national consolidated guidelines. pediatr infect dis j. 2018;37(6):559–563. https://doi.org/10.1097/inf.0000000000001840 goga a, jackson c. highest risk of mother-to-child transmission of hiv or death in the first 6 months postpartum: results from 18-month follow-up of an hiv-exposed national cohort, south africa [homepage on the internet]. presented at: aids 2016 conference, 2016 [cited 2019 dec 13]. available from: https://programme.aids2016.org/abstract/abstract/6477 gertsch a, michel o, locatelli i, et al. adherence to antiretroviral treatment decreases during postpartum compared to pregnancy: a longitudinal electronic monitoring study. aids patient care stds. 2013;27(4):208–210. https://doi.org/10.1089/apc.2013.0005 nachega jb, uthman oa, anderson j, et al. adherence to antiretroviral therapy during and after pregnancy in low-income, middle-income, and high-income countries. aids. 2012;26(16):2039–2052. https://doi.org/10.1097/qad.0b013e328359590f haas a, msukwa m, egger m, et al. adherence to antiretroviral therapy during and after pregnancy: cohort study on women receiving care in malawi’s option b+ program. clin infect dis. 2016;63(9):1227–1235. https://doi.org/10.1093/cid/ciw500 henegar ce, westreich dj, maskew m, miller wc, brookhart ma, van rie a. effect of pregnancy and the postpartum period on adherence to antiretroviral therapy amongst hiv-infected women established on treatment. jaids. 2015;68(4):477–480. https://doi.org/10.1097/qai.0000000000000501 nieuwoudt sj, ngandu cb, manderson l, norris sa. exclusive breastfeeding policy, practice and influences in south africa, 1980 to 2018: a mixed-methods systematic review. doherty t, editor. plos one. 2019;14(10):e0224029. https://doi.org/10.1371/journal.pone.0224029 rollins nc, bhandari n, hajeebhoy n, et al. why invest, and what it will take to improve breastfeeding practices? lancet. elsevier bv; 2016;387(10017):491–504. https://doi.org/10.1016/s0140-6736(15)01044-2 who, unicef. guideline: updates on hiv and infant feeding [homepage on the internet]. world health organisation; 2016 [cited 2019 oct 17]. available from: https://apps.who.int/iris/bitstream/10665/246260/1/9789241549707-eng.pdf myer l, phillips t, mcintyre ja, et al. hiv viraemia and mother-to-child transmission risk after antiretroviral therapy initiation in pregnancy in cape town, south africa. hiv med; 2016;18(2):80–88. https://doi.org/10.1111/hiv.12397 ewing ac, ellington sr, wiener jb, et al. predictors of perinatal hiv transmission among women without prior antiretroviral therapy in a resource-limited setting. pediatr infect dis j. 2019;38(5):508–512. https://doi.org/10.1097/inf.0000000000002220 khoo s. dolphin-1: randomised controlled trial of dolutegravir (dtg)-versus efavirenz (efv)-based therapy in mothers initiating antiretroviral treatment in late pregnancy [homepage on the internet]. presented at: aids 2018 [cited 2019 oct 18]. available from: https://programme.aids2018.org/abstract/abstract/13144 zash r, holmes l, diseko m, et al. neural-tube defects and antiretroviral treatment regimens in botswana. new engl j med. 2019;381(9):827–840. https://doi.org/10.1056/nejmoa1905230 who. update of recommendations on firstand second-line antiretroviral regimens [homepage on the internet]. 2019 [cited 2019 sept 29]. available from: https://www.who.int/hiv/pub/arv/arv-update-2019-policy/en/ phillips an, bansi-matharu l, venter f, et al. updated assessment of risks and benefits of dolutegravir versus efavirenz in new antiretroviral treatment initiators in sub-saharan africa: modelling to inform treatment guidelines. lancet hiv. elsevier bv; 2020;7(3):e193–e200. https://doi.org/10.1016/s2352-3018(19)30400-x who. policy brief: updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of hiv [homepage on the internet]. geneva: world health organisation; 2018 [cited 2019 sept 28]. available from: https://www.who.int/hiv/pub/guidelines/en/ mofenson l. web annex c. safety of dolutegravir in pregnancy and breastfeeding [homepage on the internet]. in: updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of hiv: interim guidelines. supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection. world health organisation; 2018 [cited 2019 sept 28]. available from: https://apps.who.int/iris/handle/10665/276491 waitt c, orrell c, walimbwa s, et al. safety and pharmacokinetics of dolutegravir in pregnant mothers with hiv infection and their neonates: a randomised trial (dolphin-1 study). mofenson lm, editor. plos med. 2019;16(9):e1002895. https://doi.org/10.1371/journal.pmed.1002895 sandoh. national consolidated guidelines for the prevention of mother-to-child transmission of hiv (pmtct) and the management of hiv in children, adolescents and adults [homepage on the internet]. south africa national department of health; 2015 [cited 2018 may]. available from: https://www.health.gov.za/index.php/2014-03-17-09-09-38/policies-and-guidelines/category/230-2015p?download=937:national-art-guidelines-2015final abrams ej, myer l. can we achieve an aids-free generation? perspectives on the global campaign to eliminate new pediatric hiv infections. jaids. 2013;63(suppl 2):s208–s212. https://doi.org/10.1097/qai.0b013e3182986f55 myer l, phillips tk. beyond ‘option b+’. jaids; 2017;75(1):s115–s122. https://doi.org/10.1097/qai.0000000000001343 bispo s, chikhungu l, rollins n, siegfried n, newell m-l. postnatal hiv transmission in breastfed infants of hiv-infected women on art: a systematic review and meta-analysis. jias. 2017;20(1):21251. https://doi.org/10.7448/ias.20.1.21251 mancinelli s, galluzzo cm, andreotti m, et al. virological response and drug resistance 1 and 2 years post-partum in hiv-infected women initiated on life-long antiretroviral therapy in malawi. aids res hum retroviruses. 2016;32(8):737–742. https://doi.org/10.1089/aid.2015.0366 fogel j, li q, taha te, et al. initiation of antiretroviral treatment in women after delivery can induce multiclass drug resistance in breastfeeding hiv-infected infants. clin infect dis. 2011;52(8):1069–1076. https://doi.org/10.1093/cid/cir008 m southtrn mrican journal o~ hiv mtoicint -----------july 2002 something to offer unoa-gail bekker managing editor encouraging it is that more than just an isolated few are talking of expanded access to highly active antiretroviral therapy (haarn for the people of africa i the w9rld health organisation conservatively estimates that some 6 million people in developing countries are in need of lifesustaining antiretrovirals right now, in the year 2002, yet only 230 000 have access, and most live in one country brazil. in april 2002 the who came up with guidelines on scaling up antiretroviral therapy in resource-limited settings, the global fund is being mobilised and local activist organisations are shifting their emphasis on mother-to-child (mtcn prevention programmes to include general access to haart. not that the pressure on the need for mtct prevention and improved mtct programmes should abate for even a moment. fourteen weeks ago i had the awesome experience of giving birth to a wonderful little boy who has subsequently turned our lives around and filled us with such joy. but along with the joy i have been struck by how much anxiety, both rational and irrational, goes with the whole experience. i have feared for his safe delivery, his state of health, my ability to feed him, our coping with him and his acceptance of us, and so on and on. and then i tried to imagine what it must be like to be a young mother who suspects or discovers her positive hiv status, and must await with trepidation the possible additional calamity that her infection has passed to her child. such anxiety must be intolerable, yet in this country many brave young women face it daily. as a medical profession we have something that can be offered to them. our present mtct strategies are not a panacea and will not save all, but giving a mother the opportunity to do as much as she can for her unborn child may compensate for some of the anxiety. it is two years since the publication of the hiv clinicians society's first antiretroviral guidelines. the current issue of the journal is devoted entirely to the issues surrounding antiretroviral therapies. the eagerly awaited revised guidelines have seen changes brought about due to the availability of new drugs and the dramatic price decreases in drugs. the who recommendations have been borne in mind, as have the recommendations of our international reviewers (ias, prof. stefano vella/prof. joep lange; iapac, jose zuniga usa; uk prof. brian gauard; australia prof. oavid cooper; and argentina praf. pedro cahn). des martin editor, southern african journal ofhiv medicine president, southern african hivclinicians society i would like to take this opportunity to thank the guidelines committee ior des martin, or mark cotton, prof. gary maartens, or oave spencer, or mark andrews, or francois venter and prof. robin wood) who met in march 2001 under the chairmanship of or steven miller. these guidelines represent a good balance between the standard of care and the economic resources available to provide this optimal care. it is to be noted that the guidelines concentrate on firstand second-line therapies and that thirdand fourth-line therapies and salvage therapies should be managed by clinicians who have expertise in dealing with such failures. it is recommended that clinicians access the society's treatment network for help and advice in this regard. this edition also sees an update in review form of the various issues that impact on the use of antiretroviral therapies and provides an insert that should prove useful as a quick desktop reference guide for clinicians in their daily practices. from the editors http://www.sajhivmed.org.za open access page 1 of 1 reviewer acknowledgement acknowledgement to reviewers in an effort to facilitate the selection of appropriate peer reviewers for the southern african journal of hiv medicine, we ask that you take a moment to update your electronic portfolio on https:// sajhivmed.org.za for our files, allowing us better access to your areas of interest and expertise, in order to match reviewers with submitted manuscripts. if you would like to become a reviewer, please visit the journal website and register as a reviewer. to access your details on the website, you will need to follow these steps: 1. log into the online journal at https:// sajhivmed.org.za 2. in your ‘user home’ [https://sajhivmed.org. za/index.php/hivmed/ user] select ‘edit my profile’ under the heading ‘my account’ and insert all relevant details, bio statement and reviewing interest(s). 3. it is good practice as a reviewer to update your personal details regularly to ensure contact with you throughout your professional term as reviewer to the southern african journal of hiv medicine. please do not hesitate to contact us if you require assistance in performing this task. publisher: publishing@aosis.co.za tel: +27 21 975 2602 tel: 086 1000 381 the editorial team of the southern african journal of hiv medicine recognises the value and importance of peer reviewers in the overall publication process – not only in shaping individual manuscripts, but also in shaping the credibility and reputation of our journal. we are committed to the timely publication of all original, innovative contributions submitted for publication. as such, the identification and selection of reviewers who have expertise and interest in the topics appropriate to each manuscript are essential elements in ensuring a timely, productive peer review process. we would like to take this opportunity to thank the following reviewers who participated in shaping this volume of the southern african journal of hiv medicine. we appreciate the time taken to perform your review(s) successfully. adri williams anandan a. moodley andrew black ashraf h. coovadia brian g. williams busisiwe nkala-dlamini busisiwe nkosi candice fick carolina e. nel catherine orrell christopher gilpin clara schutte cleophas chimbetete cloete van vuuren coceka n. mnyani colin menezes corinna m. walsh david boulware david moore david stead eitzaz sadiq francois venter gary maartens gary reubenson gert van zyl gillian hunt gillian sorour herculina s. kruger india butler jade c. mogambery james j.c. nuttall janan j. dietrich jeremy s. nel joana woods joel francis jonathan stadler julia turner kagiso motse kapila hari karen koch karl technau katherine m. gill kathleen m. powis kerry gordon kim roberg lee fairlie leigh f. johnson leon levin lucas hermans maia lesosky mark cotton matthew f. chersich michael t. boswell michelle venter michelle wong mitch matoga moeketsi mathe moira beery myra taylor naomi hill nataly woollett nathan geffen nelly sharpley nicola wattrus nicolette du plessis nicolette p. naidoo nomathemba chandiwana nontokozo langwenya nosisa sipambo pauline howell philip j. smith phumla sinxadi prudence ive rachael rawlinson rannakoe lehloenya remco peters renate strehlau samanta lalla-edward samantha potgieter sarah e. hill shafiya coovadia shenaaz pahad shobna sawry siphamandla gumede sipho dlamini siraaj adams sudhir sharma susan j. randall talitha crowley tammy meyers theresa m. rossouw thozama dubula tim tucker tivani p. mashamba-thompson tom h. boyles tshegofatso maimela violet m. awori virginia zweigenthal http://www.sajhivmed.org.za� https://sajhivmed.org.za� https://sajhivmed.org.za� https://sajhivmed.org.za� https://sajhivmed.org.za� https://sajhivmed.org.za/index.php/hivmed/user https://sajhivmed.org.za/index.php/hivmed/user https://sajhivmed.org.za/index.php/hivmed/user mailto:publishing@aosis.co.za summer 2009                                                          the southern african journal of hiv medicine                                                  44 primary pulmonary tuberculosis (tb) in children typically forms a ghon complex visible on the chest radiograph as perihilar or paratracheal lymphadenopathy with or without an area of parenchymal infiltrate (ghon focus). cavitation or breakdown of lung parenchyma is significantly more common in hiv-infected than hivuninfected children. the determinants of cavitation in children are not well defined. in adults, cavitary disease is common and is thought to be due to a delayed hypersensitivity response to the tb bacilli. new or worsening cavitation has been described as a presenting feature of tb-related immune reconstitution inflammatory syndrome (tb-iris) in adults after starting highly active antiretroviral therapy (haart). we present a case of cavitation of the ghon focus in a 7month-old girl started on haart at 2 months of age. we explore the pathogenesis of her cavitation, particularly focusing on two possibilities: an exaggerated immune response such as tb-iris, or an inadequate immune response due to incomplete immune reconstitution. case report the patient’s mother was identified as hiv-infected through participation in the prevention of mother to child transmission program in the western cape, south africa. despite the mother having received antenatal zidovudine (zdv) for 4 weeks, the infant’s hiv dna polymerase chain reaction (pcr) test was positive at 6 weeks of age. the viral load at that time was 43 200 (log 4.64) copies per ml. the infant received haart (zdv, lamivudine and lopinavir/ritonavir) from 8 weeks of age through participation in the children with hiv early antiretroviral therapy (cher) trial. compliance was confirmed with monthly pharmacy calculations. the baseline cd4 count was 908 cells/μl (cd4% 22.9%), rising to 1 214 cells/μl (31.4%) after 3 months on haart. five months after initiating haart (i.e. at 7 months of age) the patient was hospitalised for an acute respiratory illness. although she had no known tb contact, her weight had dropped significantly over the preceding month (fig. 1). her cd4 count had dropped acutely to 762 cells/μl (23.6%). a chest radiograph showed hilar lymphadenopathy with left lower lobe opacification, and a single large cavity in the same region (fig. 2). these changes were not present on baseline chest radiographs done at 2 months of age. mycobacterium tuberculosis, fully susceptible to isoniazid and rifampicin, was cultured from a gastric aspirate. she was started on a standard three-drug tb regimen (isoniazid, rifampicin and pyrazinamide) with additional ritonavir added to her antiretroviral treatment, and thereafter displayed good catch-up growth (fig. 1). a plasma hiv rna level done at 14 months of age was below detectable limits, confirming adherence to haart. the left lower lobe cavity had resolved completely after 9 months of tb treatment (i.e. at 16 months of age). discussion the subject’s immune reconstitution had been reasonably successful. three months after starting haart (i.e. at 5 months of age) her cd4 count had risen from a baseline of 908 cells/μl (22.9%) to 1 214 cells/μl (31.4%), cavitation of the ghon focus in an hiv-infected infant who acquired tuberculosis after the initiation of haart paediatric case study s innes1, mb bch, mrcpch h s schaaf2, mb chb, mmed (ped), dcm, md (ped) m f cotton1,2, mb chb, mmed, phd, fcpaed, dtm&h, dch (sa) 1kid-cru (children's infectious diseases clinical research unit), tygerberg academic hospital, tygerberg, w cape 2department of paediatrics and child health, tygerberg academic hospital and stellenbosch university, tygerberg tuberculosis immune reconstitution inflammatory syndrome (iris) may present as new or worsening cavitation. we present an hiv-infected infant in whom tb infection and subsequent cavitation of the ghon focus appeared to coincide with immune reconstitution due to highly active antiretroviral therapy (haart). tb-iris in response to infection that occurs after starting haart has not previously been described. cavitation of the.indd 44 3/16/09 2:18:14 pm summer 2009                                                          the southern african journal of hiv medicine                                                  46 equivalent to the fifth centile for absolute cd4 counts among healthy black hiv-negative children between 3 and 6 months of age in europe (1 200 cells/μl).1 however, it is possible that her immune response may have been marginally impaired since, although at the lower limit of normal, her absolute cd4 count was well below the median for age (2 500 cells/μl). the clinical evidence in this case suggests that tb infection occurred after the initiation of haart. according to the growth curve, failure to thrive began 1 month before presentation (i.e. 4 months after the initiation of haart). wallgren documented that the development of the hypersensitivity response to tb in normal children (as shown by a positive tuberculin skin test or erythema nodosum) and the clinical manifestations of primary tb occur between 5 and 6 weeks after infection, although in exceptional cases, this may occur up to 8 weeks after infection.2 therefore, according to wallgren’s ‘timetable of tuberculosis’ it is very unlikely that the manifestation of primary tb would have been delayed by 4 months. in adults, new or worsening cavitation may be a presenting feature of tb-iris. antimycobacterial activity is usually restored within 6 months of haart in highly immunocompromised hiv-infected children.3 consequently, clinical deterioration due to tb-iris generally occurs within 6 months of starting haart.3 in this case, acknowledgements drs helena rabie and heather jaspan, professors peter donald and ben marais of stellenbosch university, and dr stephen lawn of the university of cape town are thanked for constructive criticism and advice. financial support for cher trial: national institute of allergy and infectious diseases (niaid) of the us national institutes for health (nih), through the comprehensive international program of research on aids (cipra) network, grant number u19 ai53217. the departments of health of the western cape and gauteng, south africa and glaxosmithkline plc provided additional support. the content of this publication does not necessarily reflect the views or policies of niaid, nor does mention of trade names, commercial projects, or organisations imply endorsement by the us government. the study was also conducted as an investigational new drug (ind) number: ind 71,494 under the supervision of the food and drug administration. contribution of authors: dr steve innes prepared the manuscript. professors mark cotton and simon schaaf personally supervised the development of the material. fig. 1. growth chart. fig. 2. anteroposterior chest radiograph at 7 months of age. cavitation of the.indd 46 3/16/09 2:18:23 pm summer 2009                                                          the southern african journal of hiv medicine                                                   symptoms began 4 months after starting haart. this case satisfied the paediatric iris working group consensus criteria for the diagnosis of tb-iris in children.4 currently two forms of tb-iris have been described: acute unmasking of pre-existing tb infection, and paradoxical worsening of known pulmonary tb disease.4 both ‘unmasking’ and ‘paradoxical’ iris occur in response to tb bacilli present in the lung parenchyma before the initiation of haart. the pathogenesis of iris is poorly understood but is related to the recovery of the th-1 immune response following successful suppression of viral replication by haart.5 the newly reconstituted th-1 system then reacts aggressively to antigens of dead and living organisms accumulated during immune suppression. this exaggerated (or possibly dysregulated) immune response causes local tissue damage, resulting in the typical manifestations of iris. there is some evidence that the recovery of m. tuberculosis-specific th-1 cells occurs more slowly than the recovery of other specific th-1 responses.6 this may result in a delay in the manifestation of tb-iris after the initiation of haart. in our case, tb infection most likely occurred after the initiation of haart. therefore our case cannot definitively be included in either the paradoxical or the unmasking category of tb-iris. we question whether this case may represent a third, previously unrecognised form of tbiris where exposure to a new pathogen may result in an exaggerated immunological response due to dysregulated immune recovery in the early phase of haart. in young infants, it is possible that prior exposure to bacille calmette-guérin immunisation at birth may prime the immune system for an iris-like response on exposure to m. tuberculosis during the early phase of haart.3 references 1. european collaborative study. age-related standards for total lymphocyte, cd4 and cd8 t-cell counts in children born in europe. pediatr infect dis j 2005; 24: 595600. 2. wallgren a. the timetable of tuberculosis. tubercle 1948; 29: 245-251. 3. kampmann b, tena-coki gn, nicol mp, levin m, eley b. reconstitution of antimycobacterial immune responses in hiv-infected children receiving haart. aids 2006; 20(7): 1011-1018. 4. boulware dr, callens s, pahwa s. pediatric hiv immune reconstitution inflammatory syndrome. curr opin hiv aids 2008; 3: 461-467. 5. ulrichs t, moody db, grant e, kaufmann sh, porcelli sa. t-cell responses to cd1presented lipid antigens in humans with mycobacterium tuberculosis infection. infect immun 2003; 71(6): 3076-3087. 6. schluger nw, perez d, liu ym. reconstitution of immune responses to tuberculosis in patients with hiv infection who receive antiretroviral therapy. chest 2002; 122(2): 597-602. the south african red cross shows a siyayinqoba educational video about tb and hiv to a family in khatlehong. there are eight people living in the home. their father died of tb last year after being infected for the third time. the daughter currently has mdrtb and is on antiretrovirals. she was bedridden but is starting to feel better and able to walk around the house. her brother is also showing symptoms of tb, and during this visit the red cross managed to convince him to be tested. 48 cavitation of the.indd 48 3/16/09 2:19:05 pm arv rollout helen schneider, centre for hea1lh policy~ school of puhli£ heabh, univemly of che wu'wgtetstand, joho.nnesburg jadles mc::intyre, perinatal mv research unii, chin hani baragwa7uuh hospi.raj, sowew, gauteng novfmhfr 2003 are implemented in a manner that benefits the health system as a whole and builds equity. a programme of arv access also has to grapple with the challenge of ensuring that people take drugs several times a day, every day, for the rest of their lives. poor adherence rapidly leads to the emergence of drug resistance and treatment failure at the individual level. if resistance develops on a wide scale, this will have broader public health implications. obligations on the part of individuals to adhere have to be matched by obligations on the part of the health system to ensure continuous access to uninterrupted supplies of drugs, skilled providers and laboratory support able to maximise the safety and efficacy of drugs, and a supportive environment for adherence. unfortunately, the margin for learning through failure is narrow. thf southfrn african journal of hiv mfoicinf ---------this article reflects the outcomes of a seminar hosted by the school of public health and perinatal hiv researdh unit, university of the witwatersrand, 0!1 friday 1 august 2003. summary of proceedings challenges were discussed from all these perspectives during the course of the seminar, with the purpose of specifically addressing the health systems challenges. the seminar deliberately did not address two key aspects of the scaling up procurement: provision of affordable drugs, and the mobilisation of financial resources for the implementation of a programme, as these were being debated in other fora. scaling up the use of antiretrovirals in the public sector: what are the challenges? on 1 august 2003 the wits school of public health and perinatal hiv research unit hosted a l-day seminar on the challenges to scaling up access to antiretroviral therapy (arv or art) in south africa. highly active antiretroviral therapy (haart, also referred to as art or arvs) makes a dramatic difference to the survival and health of people living with hiv. at present only about 1 000 public sector users in south africa have access to arvs through a series of small-scale projects across the country. greater access to arvs could change the lives of millions of people. it could also bring with it large new investments in the health system that, if properly planned, could address systemic weaknesses as well as strengthen less resourced areas. it is imperative that these investments the meeting was attended by 130 people, representing a wide variety of backgrounds and including such diverse role players as people involved in pilot programmes successfully delivering antiretrovirals in poor communities (including a neighbouring country) and those involved in the roll-out of the mother-to-child transmission prevention [pmtct) programme and the national tuberculosis programme, and the implementation of the termination of pregnancy act a number of projects have shown that these challenges can be confronted on a small scale within the public sector, such that the benefits of arvs far outweigh the risks associated with them. south africa has a health care infrastructure that has proved that it is capable of providing chronic disease care, most notably for tuberculosis. scaling up access to arvs through this system is not outside the bounds of imagination. however, the tb programme and the implementation of the termination of pregnancy act and pmtct programme provide evidence highlighting the fact that a programme of universal access to arvs will require performance from our health system at a level and scale far higher than at present. it means addressing key weaknesses, such as the inadequate staffing and support of primary health care facilities, demoralisation and flight of health care workers from the public sector, inequities in access to facilities, drugs and other forms of infrastructure, and poor relations between users, communities and the health system. the experience from neighbouring botswana is that the challenges to scaling up lie in two areas: health system capacity (particularly human resources) on the one hand, and stigmatisation and inadequate demand for services on the other. the need for communication and community mobilisation emerged as a key theme across all presentations at the seminar. ultimately, to be successful, an arv programme must face the complexity of transforming relationships it must appreciate its role as one of innovation, of 'thinking out of the box: it can only do so by mobilising all available expertise and energies across the country, both inside and outside government. given its significance, it is imperative that all south africans participate in the process of discussion and debate about how to implement an arv programme. proposed principles for scaling up access to arvs 1. a policy on widespread access to arvs can only succeed if it fully mobilises the existing health system. it should form an integral part of the continuum of hiv care through the public primary health care and hospital system, coordinated by district, provincial and national management structures. this does not preclude a degree of 'exceptionalism' and vertical programme arrangements, under very specific conditions; nor does it exclude the possibility of co-ordinated action between public and private sectors where this is deemed relevant at local level. 2. an arv programme integrated into the health system, however, will not succeed if it is regarded as a simple 'addon' to the multiple functions and activities already performed by the health system. additional resources must november 2003 ---------be provided, particularly in the range and numbers of skilled personnel at facility level, but also in support systems. new ways of managing existing resources need to be developed. 3. the massive additional investment in health systems brought about by an arv programme provides a unique opportunity to strengthen the health system as a whole. improvements in systems, such as drug supplies, access to laboratory services, referral, and staff training and support, should be structured to strengthen quality and access for all health conditions. an arv programme should be seen as an opportunity to address fundamental problems, such as the public sector human resource crisis and provider attitudes and values. it should not be implemented at the cost of other essential health programmes. 4. an arv programme should not deepen the inequities in our health system. ultimately, it must be judged by whether it succeeds in reaching the most remote and disadvantaged areas of the country. this may mean special measures to build the 'capacity to benefit' from an arv programme in disadvantaged areas. this would require investment in basic systems and infrastructure upon which a continuum of hiv care, including arvs, can be built. 5. existing public health and hiv treatment initiatives in south africa provide useful models for the design of an arv programme. experiences with the procedures, systems and infrastructure of the national tb control programme can inform an arv programme. they include standardisation of treatment, registers, monitoring and evaluation processes and the particular combination of vertical support and horizontal implementation. existing arv projects suggest that an arv programme integrated into a broader hiv care treatment service can be configured in the same way as other chronic disease programmes, as nurse-based follow-up with adequate doctor support 6. alternatives to the main approach to tuberculosis care, namely 'directly observed therapy', however, are needed if the stringent adherence requirements of arvs are to be achieved. the evidence from pilot projects is that high levels of adherence stem from a new kind of contract between providers and clients. this contract is premised on very high levels of understanding or treatment literacy on the part of users. it requires the establishment of explicit support systems for users and community mobilisation and advocacy processes that promote the rights of people living with hiv/aids. the responsibility for adherence is given to the client him/herself, but occurs within a clear framework of empowerment, a period of treatment preparedness and the building of trusting relationships with providers. this is very different to the traditional paternalistic and passive relationship between health care workers and patients, and the sduthfrn african journal of hiv medicine making the change represents the key innovation challenge of an arv programme. central to this relationship are the front-line providers, who have to be won over to the purpose, content and process of an arv programme. 7. how an arv programme is implemented is as important as the whotof the programme. to build the levels and scale of performance required of an arv programme necessitates an innovative approach to implementation. task teams developing guidelines and procedures at national level alone will not achieve the rapid buy-in and change required at all levels of the system. political management, in the sense of actively building common visions, is as important as technical design. we therefore propose a set of sub-principles to govern the implementation process: • the planning process should be as inclusive as possible. it is important that the voices of all stakeholders with insight and an interest in the implementation of an arv programme be represented in defining the vision and principles of the programme. these include line and programme managers at national, provincial and local/district levels; clinicians and others involved in pilot arv programmes or who have shown that they can provide good quality hiv care in the public sector; front-line providers, ngos and activist groupings involved in community mobilisation; and researchers who can support monitoring and evaluation. donors and external consultants, while clearly important stakeholders, should not dominate the process. the roles and responsibilities of all these role players need to be discussed and agreed upon. • the process of implementation needs to be supported by a rigorous and creative communication strategy aimed at preparing and ensuring the buy-in of all who will be implicated in the process of implementation. its aim would be to develop a common vision and understanding, as the foundation for action. • top-down planning should be combined with bottomup processes that harness local energy and stimulate initiative. the need for defining clear outcomes and standardisation must be balanced with flexibility in programme implementation at local level. it also requires designing an implementation strategy that involves constant engagement with the periphery in iterative processes of learning and problem solving, of learning by doing. • district and facility actors are much more likely to take up the challenge of an arv programme if they can witness it being done in other districts and by other actors. horizontal processes of interaction will lead to more effective learning tr.an instructions from the top. a key aspect of implementation must be to promote novfmber 2003 ---------networking between actors already involved in hiv treatment programmes and those wishing to develop programmes in their areas. • an incremental, step-wise process of building capacity for arvs needs to be defined. building blocks such as the establishment of a good follow-up, 'wellness' service for people with hiv, evidence of community mobilisation and support groups, voluntary counselling and testing and laboratory infrastructure need to be spelt out support strategies need to involve not only training but also mechanisms for developing infrastructure and systems at facility and district levels. • while certain aspects of implementation need to be standardised, local people should be given some choice and flexibility in the content and pace of implementation. this includes front-line providers, users and community members who are the ultimate implementers of policy. we propose, in the first instance, a process of voluntary accreditation, in which facilities and their community and district level counterparts apply for the right to distribute arvs. the onus will rest on them to prove their ability to do so and will be formally assessed through an accreditation process where clear criteria are spelt out these districts could then form learning partnerships with others in the process of horizontal learning described above. obviously, such a process would require co-ordination and management to ensure that equity is maintained. • an arv programme is one necessary and important component of a wider social response to hiv/aids in south africa. the hiv epidemic represents both a crisis and an opportunity for the country currently in the midst of profound and dynamic transformation. in this context, a commitment to scale up the introduction of arvs must be viewed alongside a measured and multidimensional approach to hiv one founded on a renewed commitment to prevention and to a broader social response· to the structural conditions that influenc'e vulnerability to hiv. final comment south africa has the potential to generate a model approach to the introduction of arvs that has relevance and application to the wider sub-saharan region. as unprecedented external funds are made available to support and facilitate this process, effective co-ordination and providing clear direction around the care components of the arv-health systems approach is essential. in this context, there is a need to balance effective partnerships and the generation of creative responses on the ground with a comprehensive vision for the systems required to sustain such an ambitious intervention in the long term. thf southern ahlican journal of hiv mfolcinf abstract background methods results discussion acknowledgements references appendix 1 appendix 2 about the author(s) sisanda gaga beyond zero, east london, south africa nokuzola mqoqi beyond zero, east london, south africa raymond chimatira centers for disease control and prevention, pretoria, south africa singilizwe moko eastern cape provincial department of health, bisho, south africa jude o. igumbor school of public health, faculty of health sciences, university of the witwatersrand, johannesburg, south africa citation gaga s, mqoqi n, chimatira r, moko s, igumbor jo. continuous quality improvement in hiv and tb services at selected healthcare facilities in south africa. s afr j hiv med. 2021;22(1), a1202. https://doi.org/10.4102/sajhivmed.v22i1.1202 review article continuous quality improvement in hiv and tb services at selected healthcare facilities in south africa sisanda gaga, nokuzola mqoqi, raymond chimatira, singilizwe moko, jude o. igumbor received: 27 nov. 2020; accepted: 26 feb. 2021; published: 12 may 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: continuous quality improvement (cqi) is essential for hiv and tuberculosis (tb) services. similarly, a thorough understanding of the requirements and impact of cqi is critical to its successful institutionalisation. however, this is currently lacking. objectives: the objective of this study is to describe the cqi implementation process and examine its effect on hiv and tb service delivery at selected primary healthcare facilities in two south african districts. method: we used a separate sample, preand post-test, quasi-experimental study design based on data collected from the clinical audit of patient cohorts seen in 2014 and 2015 respectively. quality was measured based on the extent to which prescribed services were provided. tailored cqi interventions were implemented based on service delivery gaps identified by the 2014 cqi audit. data were summarised and analysed using a combination of univariate and multivariate analysis. results: the services identified as low quality were related to opportunistic infections management and laboratory practices. compliance to prescribed service items in antiretroviral treatment initiation and monitoring, pharmacy and laboratory management, exceeded 70% across study sites. over 80% of low quality service delivery items were optimised in less than six months with targeted quality improvement support. conclusion: the observed improvements signal the effectiveness of the cqi approach, its capacity to rapidly improve under-performance, its high replicability and the need to provide quality maintenance support to sustain or improve healthcare facilities performing well. the study strongly underscores the need to improve the management of opportunistic infections and complications, particularly tb. keywords: continuous quality improvement; interventions; hiv/aids; services; outcomes; south africa. background continuous quality improvement (cqi) is a management approach used to enhance an organisation’s processes based on its measured performance.1,2,3 continuous quality improvement processes use performance data to inform an iterative and incremental transition towards an optimally performing system by building on successes and improving sub-optimum activities and outputs.4 continuous quality improvement processes are proactive. they are able to identify and remediate latent or future programme challenges and requirements.5 the world health organization’s (who) health systems strengthening (hss) framework6 reemphasises the critical value of cqi models. the framework depicts the quality as a bridge between the building blocks of the healthcare system and their desired outcomes. thus, an effective hss model relies on functional cqi processes. this reasoning is in line with the established linkages between cqi implementation and improved health system efficiency, access and outcomes.7,8,9 the characteristic value of cqi approaches is their ability to measure process and outcome indicators, with the aim of targeting the implementation of change in the smallest replicable unit within the health system.10 the growing number of people living with hiv (plwhiv) has necessitated the increasing demand for quality care. this means that sub-quality hiv and tb programmes may fail to meet their targets. this scenario and the ‘chronicity’ of the hiv epidemic and its manifestations, could result in the following challenges: insufficient screening of high-risk individuals, failure to adequately link people to care, inability to retain people on treatment, deficiency in re-engaging lost patients, and an increase in patients’ morbidity and mortality. these factors are key drivers of hiv transmission; they increase the costs of care and diminish the programme’s sustainability and outcomes.11,12 in order to address these concerns, the systematic approach of cqi models can be applied to yield and optimise the epidemiologic impacts and cost-effectiveness of interventions.11 globally, cqi initiatives have reported varied and remarkable success in the fight against hiv.13 efforts to standardise the hiv programme for cqi processes have, for the most part, been observed in developed countries where the epidemic and context are different from those in africa.8,10,11 the usefulness of cqi processes in lowand middle-income countries (lmics) remains to be seen, in particular, its potential to accelerate progress towards achieving epidemic control.1 continuous quality improvement was introduced in two districts of south africa (sa) in 2014 by the centers for disease prevention and control (cdc), the implementing partner that funded the hiv programmes. little is known about how the cqi programme was implemented or the success of this intervention to improve the delivery of hiv and tb services. in this research article, we describe the cqi implementation process and examine its effect on the delivery of hiv and tb services at selected primary healthcare (phc) facilities in two districts of sa. methods study design a separate sample, preand post-test quasi-experimental study design was adopted based on routine programme data from two districts supported by the president’s emergency plan for aids relief (pepfar) funded hiv/tb programme in sa. the data were collected from the medical records of patients through a retrospective clinical audit of data collected during routine service delivery at two time points: july to december 2014 and july to december 2015. the cqi intervention was implemented for 6 months between the two time points (january–june 2015). the clinical audits focused on the following five service delivery areas: adult antiretroviral therapy (art), hiv counselling and testing (hct), tb case finding and management, and pharmacy and laboratory service delivery areas, which were aligned with various inter-related targets. such targets are contained in the joint united nations programme on hiv and aids (unaids) 90-90-90 strategy,14 the district implementation plan (dip) and in the routine pepfar/south african national department of health (ndoh) monitoring and evaluation plan. several questions or items in each service delivery area were designed to identify gaps in the quality of services. the list of questions or items assessed is appended to the document displayed in appendix 1. study population and sampling the clinical audits were conducted in 90 supported healthcare facilities in the two districts of sa: district a and district b. ninety-three per cent of the facilities included were phc facilities, and the rest of them were community health centres (chcs). seventy-one per cent of the healthcare facilities were from district b. about 60% of the facilities were located in rural areas and 40% were in urban areas. prior to the implementation of the cqi project in 2014, most of the performance indicators of the health system in both the districts required improvement, as most programme targets were unmet. at the start of the project, district a ranked amongst the 10 worst-performing districts in sa on indicators, such as management of inpatients.15 the worst performing indicators for district b included the management of phc facilities, inpatients, human resources, tb case findings and tb treatment outcomes.15 the healthcare facilities included in this evaluation were high-volume sites or those having at least 800 people regularly on art at the healthcare facility. this is otherwise referred to as total remaining on art (troa). high-volume sites are designated by the department of health based on the monthly facility headcount, catchment population size, health facility utilisation rate and disease burden. there were 90 study sites purposively selected using the criteria of high hiv or tb burden. all the healthcare facilities with the availability of patients’ folders, in all the five service delivery areas, were eligible for this study. the first cohort consisted of all records of patients initiated on art from july to december 2014. the second cohort consisted of all records of patients initiated on art from july to december 2015. a maximum of 20 patient service records and folders per facility were selected and audited. the 20 folders consisted of the records of tb and/or hiv patients from the five service areas that were assessed (see appendix table 1 for the list of items assessed in each service area). a systematic sampling method was used to select the files to be audited. the interval between audited files was calculated based on the total number of eligible files at the site. all available folders were audited for facilities with < 20 folders. with 20 patient folders selected per healthcare facility, a minimum sample size of 1800 patient folders were audited. the proposed sample size was intended to detect a 95% power and a 5% margin of error. from the sample calculation, it was assumed that there were approximately 72 000 patient folders in the 90 healthcare facilities based on a troa of about 800. by systematic random sampling, the sampling interval (k) of 40 was calculated by dividing troa (800) by the required sample per facility (20). using a random starting point (x), we were able to establish every kth folder to be selected until the number of 20 folders was reached. incomplete files were replaced with the next kth folder. study intervention the study intervention included the cqi audits and tailored support provided by a roving team of multidisciplinary healthcare providers. the roving cqi audit teams consisted of nurse mentors, information officers, monitoring and evaluation advisors, pharmacy assistants and at least one technical specialist. the multidisciplinary audit teams provided comprehensive and integrated support to the audited healthcare facilities. the audit teams were trained on cqi processes, reporting protocols and problem remediation mechanisms using a standard operating procedure that was developed for the audits. clinical practitioners with research and health system strengthening experience provided training to the roving teams. this was performed to ensure quality and implementation consistency amongst all teams. each audit involved patient file reviews and scoring by the team. thereafter, the overall facility performance report was provided to the respective healthcare facility managers. red flags (bottlenecks), as well as improvement plans, were discussed with the health facility manager. the focus of the intervention was on how to improve the activities and indicator element that was not performing well, that is, < 50% compliance to prescribed service items. based on identified needs, the cqi plans with specific interventions varied between healthcare facilities. the interventions ranged from activities to improve drug procurement and dispensary procedures to clinical skills development, mentorship and supportive supervision. they also included improvements in monitoring and evaluation, and information utilisation for decision-making, targeted service improvement, service delivery campaigns and community engagement activities, support with patient flow management and human resource management support. the use of tailored interventions to respond to prevailing service delivery gaps during quality improvement has been found to be efficient and effective.16,17 data collection tool a service audit tool was used to assess the quality of hiv and tb services provided. the data audit tool was adapted from the standardised data audit tool developed by the ndoh for routine monitoring of health programmes. the audit tool was developed through an extensive consultative process with inclusive multidisciplinary healthcare teams who were selected from participating healthcare facilities before the first audit in july 2014. the finalised tool was pretested in two randomly selected healthcare facilities. these pilot sites were excluded from the main study. responses on the tool were coded: 1 = yes and 0 = no. the number of ‘yes’ responses, divided by the total number of audit items or questions per service area, determined the total facility score per service area. the formula was adjusted to exclude ‘not applicable’ in the final facility score. three cut-off points were used to categorise the performance of healthcare facilities in each of the service areas. green represented facilities that scored ≥ 85%, amber for facilities that scored between 50% and 84%, and red signified poor-performing facilities scoring < 50% in an item measured or service area. additionally, health facility capacity and performance indicators were obtained from the district health information system (dhis) database. the collected information included facility aggregates reported as percentages and ratios. the indicators collected from the national indicator data set (nids) included health facility utilisation rate, nurse and doctor workloads, number of individuals initiated for treatment prior to and during the audit period, number of patients remaining in care during the period, and patient headcount. the list of health facility capacity and performance indicators is available in appendix 2. with this additional data, we were able to compare the average facility performance based on the routine dhis indicator 3 months before (april – july 2014) and 3 months after (august – october 2015). these time points are before and after the implementation of the tailored cqi interventions developed by the cqi team and the respective health facility managers. the additional analysis of nids data was to triangulate the findings of the record review, and to explore for possible confounders and explanatory variables of the study outcomes. data analysis the audit data on hiv-tb services were analysed to describe the overall performance of the healthcare facilities’ programme implementation and service quality in the 2014 and 2015 cohorts. all data were analysed using stata (version 13.0, statacorp). the inter-item correlations and cronbach’s alpha of the respective scales’ service areas were also calculated to assess the reliability of the audits tools. apart from the original laboratory services audit tool, the rest of the audit tools were reliable, with cronbach’s alpha at or exceeding the recommended 0.7 mark (table 1). the reliability of the laboratory services audit tool was improved by deleting items with low inter-item and squared multiple correlations. this analysis was conducted before basic descriptive analysis to determine whether we can create reliable measurement scales using service area quality items. table 1: reliability of audit tools used to assess the quality of hiv and tuberculosis services. inter-item and squared multiple correlation analyses are used to explain the extent to which the performance of one item on a scale is affected by the scores of other items in the respective scales. therefore, we used this analysis to identify items, the presence or absence of which were affected by the combined presence or absence of the rest of the items in the respective tools. meaning, if a quality requirement (item) is met, it is highly likely that the rest of the quality requirements (items) in the audit tool are met. the items also had the highest loading in the principal component analysis and communality. we further carried out stepwise regression analysis to identify the strongest predictors of the particular item. we used this analytical approach to identify possible precursors and covariates to target during routine quality maintenance audits with fewer items. factor analysis was performed to assess the validity of the tools and to explore the possibility of reducing each service area’s tool to fewer clinically and statistically significant questions or items that can be used routinely. after establishing the validity of the items and scales, we used descriptive analysis in the form of counts and percentages to present variables collected from the clinical audit and nids indicators. differences in cohorts were determined using chi-square or fisher’s exact test for sparse data. correlations were performed between the extent of programme implementation and the quality of services provided at the two time points. using linear regression analysis, the quality improvement measures and categories were adjusted against standard health systems performance indicators from nids of their respective service areas. the facility performance in 2014 and 2015 cohorts was compared using chi-square tests for categorical outcomes. continuous variables were compared with either mann–whitney u-test or analysis of variance (anova) test. we also calculated comparisons between districts, phc facilities and chcs. ethical considerations ethics approval to conduct the study was obtained from the university of the witwatersrand’s human research ethics committee (no. m161025) and from the associate director of science in the centre of global health, cdc. we conducted a secondary analysis of anonymised data that did not require individual patient consent. consequently, our ethics approval was a waiver to use secondary data sources. this research article presents aggregate and summary data of all participants, and hence, consent to publish is not required. results service area audit scores services areas, such as pharmacy and hct, reported the highest scores in the 2014 and 2015 audits, whereas tb case finding and management recorded the lowest quality scores in both years, showing a marginal improvement in 2015 (table 2). the highest percentage differences in the two audits were recorded for the hct (9%) and laboratory service areas (9%). table 2 further shows that in 2015, district a reported the highest hct and adult hiv quality scores. in the same year, the highest pharmacy score was recorded in district b, and tb case finding and management quality audit scores were relatively low in district a (66.7%) and district b (65.2%). concurrently, district b retained the highest pharmacy score (89.8%), and district a retained the highest adult art score (84.3%). the highest improvement was reported in laboratory indices in district b (12.2%). the differences in cohorts were considered to be statistically significant (p < 0.001), except for district a where a marginal improvement was observed because of its good performance in the previous audit. table 2: percentage performance in the service areas by districts and cohorts. in 2015, fewer (n = 18) healthcare facilities were red flagged for intensive quality improvement in all the service areas compared with those red flagged in 2014 (n = 41; figure 1). the quality audit scores for the red-flagged facilities were < 50% in the respective service areas. figure 1: number of healthcare facilities with red-flagged service areas following the 2014 and 2015 audits. best and worst performing items table 3 shows the worst and best performing items in the tb case finding and management service area based on the 2014 audit. tuberculosis case findings recorded the highest number of quality items that attained low audit scores. the performance of the respective service areas represents general improvements in 2015. this observation is against the backdrop that the tb service area has recorded relatively low overall quality scores. table 3: best and worst performing items in the tuberculosis case finding and management and adult antiretroviral therapy service areas. items measuring the tb laboratory test turnaround time (tat) recorded the lowest scores, particularly in district b. the provision of line probe assay (lpa) to non-converters and isoniazid (inh) prevention therapy (ipt) to eligible contacts was consistently low in both districts. investigation of conversion just before 3 months (at 11 weeks) in line with tb guidelines was relatively poor in both the districts. the cryptococcal antigen (crag) testing item of the adult art service areas was equally poor in both districts. the low proportion of patients positive for tb symptoms with appropriate further investigation was of concern under the adult art service area. however, the adult art service area reported relatively high overall quality audit scores compared with all other service areas. a relatively low documentation of lost or rejected specimens was observed in the performance of laboratory service area of district a. urban–rural differences in service area audit scores when compared with the urban healthcare facilities, the rural healthcare facilities consistently performed better in raw audit scores for the tb case finding and management and laboratory service areas in both the 2014 and 2015 audits (figure 2). notwithstanding the apparent similarity in the performance of urban and rural healthcare facilities at both audits in the adult art service area, rural healthcare facilities performed slightly better. the respective locations, however, recorded significant improvements in the 2015 cohort (p < 0.001). the urban healthcare facilities performed better in the pharmacy service area. the highest improvement (12%) was recorded by rural health facilities in the hct area. a notable improvement was observed in both the urban and rural areas for the laboratory service area, with a statistical difference observed in 2015 in both locations compared with their performance in the 2014 audit (p < 0.001). figure 2: urban and rural quality audit scores in 2014 and 2015 (preand post-continuous quality improvement interventions). predictors of items with the highest loading in principal component analysis the strength of the loading in principal component analysis is an indication of the relationship between a variable and items in the scale or, in this case, the service areas.18 the adult art service area audit item – ‘patient screened negative for any tb symptom and initiated for inh’ – was a predictor of patients remaining on art 6 months after treatment initiation (r2 = 0.5). the predictors of received laboratory result recorded in the shipping list/specimen book included the following items: ‘rejected or lost results documented’, and ‘facility documenting samples on daily basis in shipping list/specimen book’ (r2 = 0.5). more predictions can be found in the tabular form (table 4). table 4: quality assessment items with the highest squared multiple correlation in each service area using the july 2014 baseline audit data. performance of selected national indicator data sets based on the dhis data, the 90 audited facilities varied in capacity and performance. district a reported a high healthcare facility utilisation rate, nurse workload and performed well in terms of hiv testing coverage (table 5). the table also depicts the relatively high hiv prevalence rate in district b, despite the relatively low hiv testing coverage. table 5: average district capacity and performance as of july 2014 based on national indicator data set. the average facility performance based on routine dhis indicators in the 3 months before (april – july 2014) and 3 months after (august – october 2015) cqi implementation was compared (figure 3). these time points are before and after the implementation of the tailored cqi interventions. the highest improvements were observed in hiv testing coverage (11%) and tb acid fast bacillus (afb) sputum results turnaround time of < 48 h (6%). the observed differences were also statistically significant (p < 0.001). in addition to information shown in figure 3, the data revealed that tb case findings significantly increased by approximately 50% from 1.9 to 2.8 (p < 0.001). figure 3: performance of facilities by district health information system indicator pre-and post-continuous quality improvement intervention (april 2014 and october 2015). relationship between service area quality scores and national indicator data set weak to moderate associations existed between service area quality scores and the national indicator data set (table 6). the strongest correlation was observed between the tb case finding and management audit score and the nids, measuring the proportion of hiv-positive patients screened for tb rates. similarly, there were positive associations between the hct service area score and the nids indicator, measuring the proportion of hiv-positive patients screened for tb and hiv testing coverage. the prevalence rate of hiv reported in the nids consistently demonstrated a negative relationship with the service areas quality scores to the extent that the higher the hiv prevalence rate the lower the quality scores. the laboratory service areas quality score showed associations with more nids indicators. healthcare facilities with a higher utilisation rate and workload performed better in the laboratory service area, whilst healthcare facilities with a higher hiv prevalence and higher tb screening rate performed poorly in the laboratory service area. table 6: correlations between service area scores and routinely collected national indicator data set. table 6 also suggests that healthcare facilities that performed better in the tb case management (in terms of the service area score) might not have performed very well with the screening of new hiv-positive patients for tb (and vice versa). the facilities with better tb case management also had a lower doctor workload. figure 4 shows the correlation coefficients of the average hiv-positive patient screened for tb rates and the tb case finding and management categories in both years and districts. healthcare facilities that were performing relatively better than the other healthcare facilities in the tb case finding and management service area reported significantly less hiv-positive patients screened for tb rate compared with those in the poor and good categories. figure 4: average hiv + patient screened for tuberculosis rate by the tuberculosis case finding and management service area quality category. discussion this report provides evidence of improvements in processes and outcomes in all service areas following the cqi intervention. this observation is informed by the significant decline in the number of healthcare facilities with red-flagged audit scores (< 50% compliance with prescribed services), as well as the observed improvements in most service areas across districts amongst the 2015 cohort in comparison with the 2014 cohort. whilst marginal improvements may be observed in scores aggregated in both the districts, the magnitude of effect varies across service areas and districts. this may be attributed to the varying demand or supply ratios (e.g. patient load vs. human resources) across facilities and service areas, as well as other factors unique to service areas, districts and facilities. furthermore, the inverse relationship observed between the quality and volume of services provided suggests that the poor quality observed in some healthcare facilities may be because of a high volume of work. consequently, increasing the supply and efficiency of human resources may improve the quality scores in such facilities. further research is, however, needed to explore this relationship. a marked improvement was observed in hct and laboratory samples and test results management. this may be because of implementing partner’s generic interventions to improve both components at all its supported sites. implementing partner’s focus on these service areas is over and above the site-specific interventions that were developed and implemented during the cqi project. during this assessment, it was found that the hct recorded the most marked reduction in the number of facilities red flagged between the 2014 and 2015 audits. a positive association observed between quality scores for hct service area and nids indicators related to hiv and tb supports other research studies and policy documents, which suggest that a synergistic approach to hiv or tb management will result in better service outcomes.21 the integration of these services is, however, not without systemic challenges. insufficient stakeholder consultations, poor leadership and political will are common bottlenecks to the implementation of integrated hiv and tb policy in parts of sa.22 a similar study carried out in uganda reported integration constraints in addition to other factors, such as poor planning and coordination, as well as inadequate provider knowledge of interpreting tb laboratory results.23 the health system governance bottlenecks may account for the differential improvement rates observed, particularly in district a, which had the most marked quality improvement audit scores in this service area. interestingly, whilst both districts scored high with respect to ensuring that patients are diagnosed with the genexpert®24 system, ensuring a 48-h turnaround time for the results was suboptimal. the implication is that whereas clients may be getting the needed services, there is a need to further improve implementation fidelity of service processes. even though the genexpert® test for tb is reputed to deliver results in 2 h under ideal conditions, operational barriers commonly affect this turnaround time in real-world settings. piatek et al.24 identified the following barriers: inadequate human resources, practices of batching specimens, and inefficient specimen referral and transport networks. thus, addressing these issues as part of this cqi initiative may improve the quality of genexpert® services, including the turnaround time. we also found that healthcare facilities with high quality scores for the tb case finding service area also had lower smear positive rates. this may imply that available healthcare workers were unable to meet the demand for screening services, and thus, there were trade-offs between the quality of services and meeting the quantity of demand for services at the healthcare facilities. these trade-offs are not unique to the south african context. a recent study in the neighbouring country lesotho also identified inadequate workforce as a major reason for poor adherence to tb control guidelines.25 the observed pattern could be because of the discretionary power of frontline health workers in determining how to implement the guidelines and policies.26 in this scenario, the decision to trade quality of services for volume is likely to result from reactionary discretion of the healthcare workers, when faced with work overload, irrespective of policies and guidelines. walker and gilson27 studied the attitudes of frontline nurses in sa, and found that personal views and values influence healthcare workers’ discretion to adhere to policies and guidelines. thus, in order to minimise the impact of frontline discretionary power on quality-of-service delivery, efforts should be made to ensure adequate distribution of healthcare workers. furthermore, healthcare workers require continuous and/or ongoing training on guidelines, with emphasis on the importance of adherence to quality. enhanced supportive supervision may also limit the discretionary space of frontline healthcare workers. specific activities that require further attention include ensuring that line probe assays are performed for non-converters, ipt is initiated for eligible contacts, and the turnaround time for afb and genexpert® results is improved. limitations of the study whilst this research study provides useful insights into the effect of a cqi process in enhancing the delivery of hiv and tb services in parts of sa, notable study limitations should be highlighted. the quality of care reported in the study did not include patient valuation of services provided despite its importance in quality measurement. however, we focused on the process of care delivery, which is one of the intermediaries of the six elements of care improvement proposed by the institute of medicine.28 the six elements included patient-centred care and satisfaction, timeliness, safety, equity, efficiency and effectiveness. we did not compare our study sites with non-intervention sites to fully substantiate the impact and ascertain the efficacy of the intervention or if it translated to patient health outcomes. nonetheless, the short duration of the intervention, the high number of healthcare facilities covered and the significant improvement in districts with a long history of poor performance15 may give credence to our cqi intervention. the study’s heavy reliance on routine health services data that are prone to incompleteness should also be noted. furthermore, the study did not measure the long-term durability and sustainability of the cqi process. however, this investigation strongly demonstrates the extent to which intended services are provided. such information is essential to gauge and promote adherence to evidence-based clinical guidelines whilst relying on appropriate measures to address other limitations. conclusion and recommendations this research study revealed overall improvement in the quality of adult art services between 2014 and 2015 in both districts. the adult art service area had relatively high overall quality scores compared with all the other service areas. however, whereas quality scores were very high with respect to screening and treatment services, more attention should be paid to improving screening for opportunistic infections, such as crag, as well as strengthening clinical integration of tb or hiv services. for example, a significant proportion of eligible clients did not have crag performed before the commencement of art. whilst the cause of this observation may be beyond the scope of this study, a study in the western cape singled out forgetfulness to order the test by providers as the major cause of this implementation gap.29 other authors have recommended a reflex laboratory testing approach as a more effective alternative to provider-induced testing. reflexed tests automatically result in the order of one or more secondary tests based on predetermined criteria applied to the primary test.30 ultimately, targeting and improving poor performing items could improve any service area’s overall quality score. this research study contributes to empirical evidence of the effectiveness of the cqi intervention on service delivery processes and outcomes in sa. our claim stands on the significant improvement in service area outcomes following our cqi intervention. various types of cqi methods have been widely adopted in healthcare with numerous reports of success.8 this assessment corroborates existing studies, which found the use of cqi both feasible and acceptable with respect to hiv or tb case findings and management.22 it has also been reported, elsewhere, that the success of cqi initiatives depends on frontline health workers’ involvement, as well as strong organisational support.19 therefore, we recommend adequate capacitation and distribution of healthcare workers to match the demand for services. strategies, such as improving supportive supervision of health workers at service delivery points and strengthening clinical governance, will ensure compliance with service delivery guidelines and enhance positive organisational behaviour. the adoption of available technological solutions to help to minimise errors may also improve quality and human resource efficiency. finally, strengthening integrated service delivery, particularly the tb and hiv interphase, should be prioritised to promote human and material resource efficiency. acknowledgements the authors would like to acknowledge all those who contributed directly and indirectly to this project, including pepfar funding through the cdc, eastern cape department of health and beyond zero staff. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions s.g., n.m., r.c. s.m. and j.o.i. were involved in the conception of the research, including selection of the research questions, and developing the protocol. s.g., n.m. and j.o.i. supervised the data collection; j.o.i. undertook data analysis and drafted the initial paper. all authors read, edited and approved revisions and the final submitted version of the manuscript. funding information this cqi project was supported by the cdc of the us department of health and human services (hhs) under the cooperative agreement no. nu2ggh001143 with 100% of the project funded by cdc/hhs. data availability the data that support the findings of this study are available from the last author, j.o.i., upon reasonable request. disclaimer the contents of this report are the responsibility of the authors and do not necessarily reflect the views of cdc/hhs or the united states government. references yotebieng m, behets f, kawende b, ravelomanana nlr, tabala m, okitolonda ew. continuous quality improvement interventions to improve long-term outcomes of antiretroviral therapy in women who initiated therapy during pregnancy or breastfeeding in the democratic republic of congo: design of an open-label, parallel, group randomized. bmc health serv res. 2017;17(1):306. https://doi.org/10.1186/s12913-017-2253-9 goldstone j. the role of quality assurance versus continuous quality improvement. j vasc surg. 1998;28(2):378–380. https://doi.org/10.1016/s0741-5214(98)70180-6 green dk. quality improvement versus quality assurance? top health rec manage. 1991;11(3):58–70. merry af, cooper jb, soyannwo o, wilson ih, eichhorn jh. an iterative process of global quality improvement: the international standards for a safe practice of anesthesia 2010. can j 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care: relevance and applications. pediatr crit care med. 2005;6(3):264–269. https://doi.org/10.1097/01.pcc.0000160592.87113.c6 vallabhaneni s, longley n, smith m, et al. evaluation of a public-sector, provider-initiated cryptococcal antigen screening and treatment program, western cape, south africa. j acquir immune defic syndr. 2016;72(2):e37–e42. https://doi.org/10.1097/qai.0000000000000976 rajasingham r, meya d, boulware d. integrating cryptococcal antigen screening and preemptive treatment into routine hiv care. j acquir immune defic syndr. 2012;59(5):85–91. https://doi.org/10.1097/qai.0b013e31824c837e appendix 1 table 1-a1: list of items used for quality of care audit. appendix 2 list of indicators and data requested from the national department of health all data requested are health facility level aggregate data and has no patient unique data. they include: hiv prevalence health facility utilisation rate nurse and doctor workloads number of people initiated on treatment during the audit period number of patients remaining in care during the period patient headcount during the audit period number of hiv and tb deaths reported during the audit period introduction background quick facts on oral pre-exposure prophylaxis conclusion acknowledgements references footnote about the author(s) linda-gail bekker desmond tutu hiv centre, institute of infectious disease and molecular medicine, university of cape town, cape town, south africa benjamin brown anova health institute, johannesburg, south africa dvora joseph-davey department of epidemiology, university of california, los angeles, united states of america division of epidemiology and biostatistics, school of public health and family medicine, university of cape town, cape town, south africa kathrine gill desmond tutu hiv centre, institute of infectious disease and molecular medicine, university of cape town, cape town, south africa michelle moorhouse wits reproductive health and hiv research unit, university of the witwatersrand, johannesburg, south africa sinead delany-moretlwe wits reproductive health and hiv research unit, university of the witwatersrand, johannesburg, south africa landon myer division of epidemiology and biostatistics, school of public health and family medicine, university of cape town, cape town, south africa catherine orrell desmond tutu hiv centre, institute of infectious disease and molecular medicine, university of cape town, cape town, south africa department of medicine, university of cape town, cape town, south africa kevin rebe life vincent pallotti hospital, cape town, south africa department of medicine and infectious diseases, university of cape town, cape town, south africa w.d. francois venter ezintsha, faculty of health sciences, university of the witwatersrand, johannesburg, south africa carole l. wallis barc-sa, speciality molecular division, lancet laboratories, johannesburg, south africa citation bekker l-g, brown b, joseph-davey d, et al. southern african guidelines on the safe, easy and effective use of pre-exposure prophylaxis: 2020. s afr j hiv med. 2020;21(1), a1152. https://doi.org/10.4102/sajhivmed.v21i1.1152 guideline southern african guidelines on the safe, easy and effective use of pre-exposure prophylaxis: 2020 linda-gail bekker, benjamin brown, dvora joseph-davey, kathrine gill, michelle moorhouse, sinead delany-moretlwe, landon myer, catherine orrell, kevin rebe, w.d. francois venter, carole l. wallis received: 14 aug. 2020; accepted: 14 aug. 2020; published: 10 dec. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. introduction pre-exposure prophylaxis (prep) with antiretroviral agents to prevent human immunodeficiency virus (hiv) acquisition is now a standard of care in many countries. after more than a decade of research and dozens of randomised trials, it is clear that prep is both safe and efficacious. oral prep is thus a key component of an hiv prevention package and should be offered to anyone who may be exposed to hiv, whether sexually or through other means. with the highest hiv incidence in the world, prep use in the south african population remains unacceptably low and insufficient to reach its full impact as an hiv control measure. to realise the full value of this prevention tool, prep must become more accessible. therefore, the updated 2020 prep guidelines have (1) broadened eligible groups to include pregnant and breastfeeding women, (2) reduced clinical and health system barriers to simplify prep initiation and administration (e.g. same-day prep), (3) broadened prep delivery to include on-demand prep in men who have sex with men and transgender women, (4) provided updates of adverse events and relevant drug–drug interactions and (5) suggested parameters with which to measure prep rollout and success. background the first southern african hiv clinicians society pre-exposure prophylaxis (prep) guidelines were published in the southern african journal of hiv medicine in 2012 following labelling approval by the federal drug administration (fda) in the united states of america.1 the results of three clinical trials underpinned those guidelines: the global iprex study in men who have sex with men (msm) and transgender (tg) people, the partners prep study in discordant couples in uganda and kenya and the tenofovir disoproxil fumarate (tdf) 2 study in heterosexual men and women from botswana.2,3,4,5 since then a further seven randomised controlled trials (rcts) and numerous open label demonstration studies have led to the registration of combination therapy, with tenofovir and emtricitabine or related variations thereof as effective tools in the prevention of human immunodeficiency virus (hiv) transmission to uninfected persons.6,7,8,9,10,11,12,13,14,15,16,17,18,19 the world health organization (who) set a target of 3 million prep users worldwide by 2020. with 240 000 incident hiv infections per year in south africa, which is equivalent to almost 15% of all new infections globally,20 a significant portion of those effective prep users should be in this country. however, despite the research, demonstration projects and existing guidelines, prep use remains low and insufficient to effectively reduce south african hiv incidence rates, with only an estimated 45 000 people using prep as of june 2020.21 people who have been offered prep and have integrated it into their daily lives describe how they have felt more in control of their circumstances, more free of worry and able to once again enjoy their sexual intimacies in ways that have not been possible for decades given south africa’s very high hiv prevalence. in foreign cities such as london and san francisco and regions such as new south wales in australia where universal test and treat strategies have been coupled with extensive scale-up for prep, the rates of new hiv infections have dropped precipitously.22 it is expected that with the assistance of these guidelines, further prep scale-up will soon be possible in south africa with similar positive outcomes. the 2012 prep guideline was last updated in 2016. the current (2020) guideline provides further options regarding drug use and the practice of oral prep,1 including (1) broadened eligible groups to include pregnant and breastfeeding women, (2) reduced clinical and health system barriers to simplify prep initiation and administration (e.g. same-day prep), (3) broadened prep delivery to include on-demand prep in msm and tg women, (4) provided updates of adverse events and relevant drug–drug interactions and (5) suggested parameters with which to measure prep rollout and success. we also introduce alternative oral antiretroviral (arv) agents and new modalities on the horizon. we present an updated lexicon for prep clients and users in figure 1. figure 1: pre-exposure prophylaxis introduces a new lexicon. quick facts on oral pre-exposure prophylaxis at this time, prep is the daily use by the hiv-uninfected of oral tdf or tenofovir alafenamide (taf)/emtricitabine (ftc) co-formulated with emtricitabine (tdf/ftc or f/taf) or variations of this, for example, tdf on its own or co-administered with lamivudine (3tc) to prevent hiv acquisition (transmission). the most commonly used preparation and the one licensed in south africa for oral prep is tdf/ftc. pre-exposure prophylaxis has been shown to be effective amongst a wide range of hiv-negative populations. there are other drugs and other routes of administration under investigation, for example, a topical dapivirine vaginal ring and long-acting injectable cabotegravir. the registration of taf is currently under review in south africa. these guidelines will be updated as new data become available21: pre-exposure prophylaxis has a long history of effectiveness in the setting of preventing vertical hiv transmission. protective in utero foetal arv drug levels are optimised prior to delivery (exposure).23 consistent adherence to prep reduces the risk of hiv transmission from sex by > 95%.2 for those at risk, daily prep has been confirmed to be effective in the prevention of sexual and injecting drug use hiv transmission. where adherence is suboptimal, prep is less effective (unreliable) as protective drug (arv) levels at the time and site of exposure may be too low. daily use is the most dependable way to ensure effectiveness.24 condom use is still recommended as prep does not protect against other sexually transmitted infections (stis), such as syphilis, chlamydia and gonorrhoea. pre-exposure prophylaxis has no contraceptive effect. the drugs used in prep do not interact with hormonal contraception. pre-exposure prophylaxis is safe to take when pregnant or breastfeeding.19,25 on-demand prep (for msm and tg women only): two pills are taken 2–24 h before sex. if sex occurs, the individual who is or is presumed to be hiv-uninfected follows up with one pill per day for 2 days after sex.26 pre-exposure prophylaxis is generally well tolerated. occasional side effects include nausea, bloating and/or headaches in approximately one in 10 users. whilst tdf/ftc is available for all populations, taf/ftc has so far only been shown to be efficacious in men and tg women. studies in cisgender women are planned. pre-exposure prophylaxis at this time is in the form of oral pills only, but topical rings and long-acting injectables are under investigation.27 who is pre-exposure prophylaxis for? pre-exposure prophylaxis is an effective prevention option for any sexually active person who might be exposed to hiv through contact with hiv-infected body fluids (genital and blood). pre-exposure prophylaxis is suitable for people of any sex, gender and sexual orientation. the who recommends that prep should be scaled up for populations where the incidence of hiv is 3% or greater.24 although risk is unevenly distributed across sub-populations and geographic areas in southern africa, a very large number of sexually active people are exposed to this degree of risk. whilst many prep efforts have focused on specific ‘high-risk’ or key population groups, at an individual client level, anyone who reports that he or she is at risk of hiv infection might benefit from prep. in these cases, prep education should be provided and intervention should be offered. on the contrary, the use of a risk scoring tool is not recommended but rather that an accurate sexual history is elicited from clients to identify sexual behaviours that justify consideration of improved or enhanced hiv prevention strategies. this is because risk scores fail when risk is not well judged and individual risk levels are dynamic; in addition, no single risk score has been validated for generalised use. given the high ongoing rates of hiv transmission in south africa and low current prep demand and no saturation in both the private and public sectors,21 people seeking prep should be encouraged to initiate prep, provided that they are sexually active and there is a reasonable risk that they might be exposed to hiv (see table 1). table 1: populations for pre-exposure prophylaxis consideration. differing pharmacokinetic (pk) data play a role in different recommendations for dose frequency in different populations. tissue drug concentrations in genital and anal mucosa vary with higher levels and steady states reached more rapidly in anal compared with vaginal mucosa.28 pharmacokinetic modelling studies have suggested that fewer doses may be required to reach effective concentrations in anal compared with vaginal mucosa. this has led to three recommendations that depend on whether exposure is via vaginal (heterosexual sex) or anal mucosal routes: pre-exposure prophylaxis where the hiv exposure is via vaginal mucosa should be dosed daily. pre-exposure prophylaxis where the hiv exposure is via vaginal mucosa may require up to 7 days of dosing before being fully effective. on-demand prep is not recommended where exposure is via vaginal mucosa. when should pre-exposure prophylaxis not be offered? pre-exposure prophylaxis should not be offered to anyone who is suspected or confirmed to be hiv-positive. providing prep to an individual who is hiv-positive or acutely seroconverting is sub-optimal treatment for hiv and could lead to antiviral drug resistance. individuals who refuse to hiv test should be counselled and prep should not be offered. pre-exposure prophylaxis should be delayed in anyone with an acute viral illness that could be because of hiv seroconversion. there is considerable overlap in symptoms and signs caused by viruses; therefore, any potential prep client presenting with fever, myalgia, arthralgia, rash, headache, and oral or genital ulcers might be hiv-positive but in the window period. other hiv prevention options, like condoms, should be discussed, repeat testing should be arranged for 2 weeks later, with prep offered then if repeat test is negative. tenofovir-based prep should not be offered to anyone with pre-existing renal dysfunction (estimated glomerular filtration rate i [egfr] < 50 ml/min). clients can return in 1–3 weeks to re-test egfr to re-assess eligibility. individuals < 35 kilograms (kg) should not be given oral prep. simplifying pre-exposure prophylaxis to improve access and optimise use pre-exposure prophylaxis is safe, well tolerated and easy to administer step 1: check client desirability of pre-exposure prophylaxis: the aims of initiation consultations for prep are: understanding and insight of potential prep user: to ensure that the prep user understands what prep is and the protection it provides, and has a personal plan for its effective use human immunodeficiency virus-negative status of user: to ensure that the prep user is confirmed to be hiv-negative (rapid hiv testing acceptable) suitability and safety of prep for user: to assess the suitability and safety of prep in those with renal and/or other potential contraindications. step 2: test for human immunodeficiency virus status: human immunodeficiency virus testing is required at initiation and at least 3 monthly whilst on pre-exposure prophylaxis to confirm hiv-negative status follow hiv testing guidelines. elicit a medical history and conduct a targeted examination to exclude acute exposure (symptoms suspicious of acute infection may be followed with repeat testing after 2 weeks to confirm hiv-negative status). human immunodeficiency virus testing is advised 3–6 monthly whilst on prep to ensure breakthrough infection has not occurred. human immunodeficiency virus self-testing may be used as an alternative whilst on prep. inconclusive hiv test results should be referred for confirmatory testing. pre-exposure prophylaxis should be stopped immediately in anyone with a positive or indeterminate hiv test result. should an interruption in prep occur, then initiation testing should be performed (as above) prior to restart. step 3: check general well-being: clinical assessment: a clinical assessment for stis should be performed at initiation, 6 monthly or when indicated. appropriate sti screening is recommended and aetiologic testing and treatment should be provided when available. this should include nucleic acid antigen testing for chlamydia trachoma and neisseria gonococcus and serology for treponema pallidum. syndromic sti screening and management is otherwise recommended. viral hepatitis b screening is recommended at prep initiation and screening if status is unknown. hepatitis b vaccination is recommended if available or if screening serology test is negative. step 4: check for contraindications: renal function: a baseline assessment of renal function should be performed (creatinine and egfr) in patients who are above 40 years of age, have co-morbidities or are on concomitant medication. pre-exposure prophylaxis should not be used in people with a baseline egfr of < 50 ml/min. renal function may be checked annually and more frequently as dictated by an underlying renal problem or comorbidity. step 5: plan follow-up visits: assess how pill-taking is going for prep user. interactions should be supportive and affirming. identify a motivator to support effective pill-taking. provide prep education regarding effective use and effectiveness of prep. identify barriers to effective use. provide realistic strategies to address barriers. discuss use of other hiv prevention measures that are relevant to situation. review need for prep and any change in sexual risk. step 6: package of prevention: providers can provide prep on the same day as counselling, following hiv testing. pre-exposure prophylaxis alone provides high levels of hiv prevention; however, additional benefits are likely to accrue if it is offered as part of a package of combination prevention that includes: counselling on effective use, starting and stopping prep. agreement for follow-up hiv testing. human immunodeficiency virus testing and counselling of sex partners (including hiv self-screening) commodities such as condoms and sexual lubricants. sexual health screening, including sti symptom check, aetiological sti testing if available and treatment either syndromically or as per laboratory results. discussions on reproductive intent and provision of contraception as needed. active safer conception counselling and guidance should be offered to women and couples who wish to conceive (see safer conception guidelines). gender affirming counselling and treatment for tg populations. immediate access to antiretroviral therapy (art) for potential prep users who screen hiv-positive and require treatment. a prescription for prep (or prep medication) should be provided for a 3-month start. adolescents and younger users or those who have identified pill-taking difficulties may be invited to return after 1 month to troubleshoot adherence difficulties. telephonic contact may help with mild side effect management and difficulties with establishing pill-taking routines. a follow-up visit for clinical monitoring, counselling on persistence at 3 months, and then every 6 months or as required. again, younger users may benefit from more regular contact. tips to support pre-exposure prophylaxis pill-taking schedule medication taking time to correspond with the client’s daily routine activities (e.g. brushing teeth, eating breakfast and going to bed). take pills at night if worried about side effects (e.g. in pregnant women). use reminders, for example, cell phone, alarms, beepers and calendars. use pillboxes to ensure daily use. review disclosure issues to identify those who can support the client’s intentions to take their pills or barriers to pill-taking because of lack of disclosure or privacy at home. join an online support group, for example, facebook: prep rethinking hiv prevention. other considerations stopping and starting pre-exposure prophylaxis: unlike taking art, prep is not a lifelong intervention and individuals should be encouraged to ascertain risk and gauge their own need for prep. different types of prevention may also be preferred at different times, for example, a holiday away versus busy working period at home. individuals should be instructed how to begin and stop daily use prep. this is different from ‘on-demand’ prep, which is described in more detail below. tenofovir disoproxil fumarate/ftc can only prevent hiv if provided at sufficient levels in the tissues at the time of hiv exposure. the need for loading doses has been controversial and largely informed by pk modelling studies. the current research suggests that as many as 7 days of oral doses may be required in the case of vaginal mucosal exposure to ensure that sufficient tissue levels have been reached. however, clinical use in cis-males and trans-women suggests that high levels of protection can be achieved with dosing just before exposure. if a prep user’s risk changes, that is, declines, or one wishes to stop prep for any reason, it should be affirmed that prep is not a lifelong intervention and that it is fine to stop. it is advised to take prep for up to 28 days after the last potential exposure to hiv (although this is not based on clinical evidence and alternative hiv prevention advice and commodities should be discussed). clients should be invited to return to discuss prep at any point in future. risk disinhibition: pre-exposure prophylaxis is highly efficacious and therefore it is unlikely even with more condomless sex that hiv infection will occur. most studies have shown that increased access to care has resulted in less risky sex but in practice prep may result in more stis and unintended pregnancies. for effective prep services, sti screening, appropriate treatment and prevention as well as contraception should be offered as part of an integrated sexual and reproductive health service at each prep clinical consultation. sexually transmitted infections and pre-exposure prophylaxis: where feasible, a sexual history and a targeted examination is recommended to guide further screening and management, taking into account that stis occur at all anatomic sites including oral, vaginal, penile and anal sites. the frequency of screening should be individualised and guided by the sexual history. we recommend that sti screening should occur at least annually and more frequently (6 monthly) in key populations such as msm,36,37 pregnant women38,39,40 and sex workers. high rates of asymptomatic chlamydia trachomatis (ct) are occurring amongst young women and msm in the region. for this reason, where possible, nucleic acid amplification test (naat) testing for gonorrhoea and ct are highly recommended, but these tests are expensive and not always available. syndromic sti screening and management should be offered as an alternative. post-exposure prophylaxis to pre-exposure prophylaxis: individuals who frequently require post-exposure prophylaxis (pep) for hiv exposure may benefit from prep. on completion of 28 days of triple arv pep therapy, oral prep may be continued with ongoing maintenance as before. individuals who have a break between pep and prep initiation should initiate as recommended above. broaden pre-exposure prophylaxis modalities to include on-demand pre-exposure prophylaxis in men who have sex with men and transgender women on demand pre-exposure prophylaxis there is now robust evidence from the intervention préventive de l’exposition aux risques avec et pour les gays (ipergay), and intervention préventive de l’exposition aux risques avec et pour les gays (ipergay) open label extension (ole) and prevenir studies26,41 that on-demand (i.e. sex or coital based dosing of prep) is effective for msm and tg women and can be used as an alternative to daily dosing. on-demand prep involves the so-called ‘2:1:1 strategy’. prep users are advised to take two pills of tdf-based prep (i.e. a double dose) 2–24 h before sex. if sex occurs, they should follow up with one pill per day for the following 2 days after sex. this strategy allows minimisation of unnecessary prep doses when hiv exposure is unlikely (no sex) and therefore might decrease the risk of cumulative side effects. the strategy might suit individuals who do not want to take pills daily, allowing prevention doses to be focused around the time of hiv exposure risk. should someone initiate on-demand prep, they should be counselled on the strategy and similar initiation precautions and investigations should be done. human immunodeficiency virus status should be confirmed as negative, they should be considered for renal function testing and should attend their health provider regularly for sti screening and repeat hiv testing. new prescriptions should be administered as often as required. newer pre-exposure prophylaxis options a recently added arv shown to be effective for oral prep is a tenofovir (tfv) pro-drug called taf that is approved in combination with other arv agents for the treatment of hiv-1 infection in adults and paediatric patients. tenofovir alafenamide has pk properties that distinguish it from tdf, resulting in clinically meaningful benefits that improve safety and increase the efficacy of taf over tdf in prep. the lower levels of circulating tfv have consistently been associated with improved measures of renal and bone safety laboratory markers. emtricitabine + taf fixed dose combination pill (f/taf) was shown in the recently published emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for hiv pre-exposure prophylaxis (discover) trial to be non-inferior to f/tdf and has thus been licensed by the fda for oral prep use in men and tg women.42 an equivalent trial is being designed for cisgender women in which taf use in pregnancy will also be explored. long-acting cabotegravir which is a depot injectable integrase prep agent has just been shown to be non-inferior to oral tdf/ftc in a randomised clinical trial of msm and tg women (hptn 083).43 the companion study of cabotegravir long acting in african women is still underway (hptn 084, the life study, nct03164564).i finally, the topical dapivirine vaginal ring has just been recommended by the european medical agency as a prep intervention for women unable to safely utilise oral prep. this preventive tool was shown to reduce hiv acquisition by about 30% in women at risk of hiv acquisition in two rcts conducted in africa.44 updates to adverse events and drug–drug interactions adverse events tenofovir disoproxil fumarate and taf are safe and well-tolerated drugs. side effects do not occur in 90% or more clients who start prep. initial minor side effects including headache and gastrointestinal upset (i.e. diarrhoea, nausea and loss of weight) may be experienced in up to 10% of people taking prep, but are self-limiting, with resolution within 2–3 weeks.3 these can be managed symptomatically. tolerance improves over time. renal toxicity: a creatinine clearance (crcl) test is recommended at the time of prep commencement to exclude asymptomatic renal disease but is not essential in well individuals under the age of 40 years and should not delay prep start. tenofovir may cause a 5 ml/min – 6 ml/min reduction in crcl in the first few months of use and if this prompts a prep pause, prep may be re-introduced in most cases without further problems. in pregnant women, individuals > 40 years of age, those with a chronic disease and those using concomitant medications, creatinine should be drawn the same day as prep start (results can be communicated later) and repeated at months 6 and 12. more frequent monitoring of renal function may be required for people with chronic diseases such as hypertension and diabetes, as per the plan for that comorbidity. tenofovir disoproxil fumarate should not be commenced if the crcl is < 50 ml/min, and should be stopped if the crcl declines below 50 ml/min. the client can re-test within 1 month to establish if their crcl changes and can start prep then. where renal toxicity is an issue, taf/ftc may be considered as an alternative agent because of its renal sparing properties (see table 2). table 2: creatinine monitoring with tenofovir disoproxil fumarate pre-exposure prophylaxis. bone mineral density: there is evidence for bone density loss with long-term use of tdf. for those with risk factors for reduced bone mineral density (bmd) (e.g. adolescents, people using recreational drugs such as amphetamines, people > 60 years of age, with known low bmd, postand peri-menopausal women and those with a history of fragility fractures), the use of taf or episodic tdf (to reduce exposure) could be considered. hepatitis b: tenofovir disoproxil fumarate is also an antiviral treatment for hepatitis b. for this reason, screening for hepatitis b surface antigen is recommended prior to starting prep, but should not prevent prep start. hepatitis b infection is also not a contraindication for prep use in individuals who would benefit. caution when stopping prep may be required in those who are hepatitis b surface antigen positive. rebound of hepatitis b virus resulting in liver injury has been described in the setting of art and not prep but remains a theoretical concern. hepatitis b vaccination is recommended for those who are hepatitis surface antigen negative. drug resistance: drug resistance mostly occurs when prep is initiated at a time when the client is acutely hiv infected and is seroconverting. during these times, viral replication occurs rapidly in the blood. pre-exposure prophylaxis drug concentrations are still suboptimal. clients who seroconvert should stop prep use immediately and initiate art as soon as possible. monitoring of art should follow adult treatment guidelines. drug–drug interactions transgender women on feminising hormonal treatment were thought to be in danger of drug–drug interactions with reduced efficacy of prep; however, a recent study has shown this is not the case.45 tenofovir disoproxil fumarate is largely eliminated by the kidneys. there are few drug interactions of note, but tdf should be used with caution with medications that cause renal toxicity (see table 3). table 3: drug interactions with tenofovir disoproxil fumarate. conclusion we expect guidelines to be updated on a regular basis in line with ongoing research on vaginal rings, new drugs (including taf), new regimens and injectable prep. south africa is involved in several clinical trials. longer term and, on-demand modalities are compelling alternatives for individuals who either do not want to take a daily pill and, or want to take prep intermittently. emerging modalities such as vaginal films, microneedles and subdermal implants have numerous advantages but are still in early stages of development. oral prep is a discreet, user-dependent, safe and effective prevention modality which is now part of the south african standard of hiv prevention. adolescents and adults who deem themselves to be at risk of acquiring hiv can be offered this modality to enable safer sexual activity and worry-free intimate relationships. these guidelines will help simplify prep delivery to ensure that prep is available to all who need it. acknowledgements competing interests the authors have declared that no competing interest exists. authors’ contributions all authors contributed equally to this work. ethical consideration this article followed all ethical standards for research without direct contact with human or animal subjects. funding information d.j.d. received funding from fogarty international center (k01tw011187). l.m. and d.j.d. received funding from national institute of mental health (nimh) (r01mh116771). data availability statement data sharing is 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prophylaxis in men at high risk for hiv-1 infection. n engl j med. 2015;373(23):2237–2246. https://doi.org/10.1056/nejmoa1506273 hare b. the phase 3 discover study: daily f/taf or f/tdf for hiv preexposure prophylaxis. conference on retroviruses and opportunistic infections; croi 2019 march 4-7; seattle, washington, usa. hiv prevention trials network. a phase 2b/3 double blind safety and efficacy study of injectable cabotegravir compared to daily oral tenofovir disoproxil fumarate/emtricitabine (tdf/ftc), for pre-exposure prophylaxis in hiv-uninfected cisgender men and transgender women who have sex with men [homepage on the internet]. 2020 [cited 2020 jul 06]. https://www.hptn.org/news-and-events/press-releases/hptn-083-study-demonstrates-superiority-cabotegravir-prevention-hiv vaginal ring to reduce the risk of hiv infection for women in non-eu countries with high disease burden [homepage on the internet]. ema press release. [cited 2020 aug 09]. available from: https://www.ema.europa.eu/en/news/vaginal-ring-reduce-risk-hiv-infection-women-non-eu-countries-high-disease-burden grant rm, pellegrini m, defechereux pa, et al. sex hormone therapy and tenofovir diphosphate concentration in dried blood spots: primary results of the ibreathe study. clin infect dis. ciaa1160. https://doi.org/10.1093/cid/ciaa1160 footnote i. with regard to long-acting single-agent injectable antiretroviral cabotegravir in the pre-exposure prevention (prep) of hiv infection/transmission to hiv-uninfected women (study hptn 084) and men (study hptn 083), both demonstrate superior efficacy versus standard oral prep. in the hptn 084 study, cabotegravir given every two months was 89% more effective than daily pills at preventing hiv acquisition. london, 9 november 2020. https://clinicaltrials.gov/ct2/show/nct03164564. (htpn 084); https://clinicaltrials.gov/ct2/show/nct02720094. (htpn 083). editor’s comment: note that this data will still require approval from international and local agencies. cabotegravir is not currently registered for use in south africa. aid for aids l 0 regensberg, lwb chb, mrcp m s hislop, msc aid/or aids pry (lcd), private bag xi003, claremolll, 7735 a report back on more than four years of hiv/aids disease management in southern africa the major challenge facing the acceptance of the programme was the high cost of art. negotiations with representatives from pharmacy groups resulted in art being made available at cost plus a dispensing fee of r50 per line item. even so, the cost of the cheapest combination was still very high, and concerns were raised as to the viability of the programme and the ability of medical schemes to sustain these costs on an on-going basis. our belief was that the drug costs would eventually come down, and that highly active antiretroviral therapy [haarn would become the standard of care. fortunately, this has proved to be the case [table i). however, only some manufacturers have reduced art prices substantially and only a limited range of haart can be made available. consoudation and growth the subsequent 4 years has seen a phenomenal growth in afa [fig. 1), from a handful of contracted medical schemes to 38, from dealing with south african medical schemes only to providing the programme to multinational companies throughout africa, and from offering only a disease management programme to offering a comprehensive risk management solution for corporates. providers outside the country are able to register patients by internet and interact with clinical staff electronically. around the country. the reasons for the scepticism were twofold. firstly, afa was recommending art only when the cd4 count was less than 350!~1 or an aids-defining illness was present. this was the era of 'hit early and hit hard', and delaying therapy to the extent recommended was considered close to heresy by the majority of experts. equally unacceptable to many was the use of dual therapy, which was known to be inferior to triple therapy at the time. however, dual therapy was all that was affordable for most medical schemes and, although sub-optimal, had clearly been shown to provide benefit for patients. patients were urged to buy the third drug themselves in order to obtain the full benefit of art, but few were able to afford this. -----------h9ruary 2003 aid for aids (afa) was based on the premise that the major cost driver in managing hiv!aids was hospitalisation for aids-related conditions and that art, although costly, would be effective in terms of slowing progression of the disease, reducing morbidity and improving survival' it was felt that making art available by way of a disease management programme with careful monitoring, coupled with education of patients and meaningful clinical support of providers, would be cost-effective and benefit both the funders of health care and, more importantly, those beneficiaries who were living with hiv!aids. the first clinical guidelines, now in a substantially revised and expanded 4th edition, were presented to a somewhat sceptical medical profession in a series of workshops prior to 1998 and the implementation of the medical schemes act, beneficiaries of medical aid schemes who were living with hiv or aids were at a considerable disadvantage. not only was risk rating permitted, but hivseropositive individuals could be excluded from membership. as a result, fraudulent claims were common, and few individuals had access to effective antiretroviral therapy (art). the problem was compounded by the high cost of the drugs, minimal benefits and, at the time, lack of experience in using art on the part of many primary health care doctors. early days the aims and objectives of afa were published shortly after it was launched in 1998.' in essence, afa was to be a comprehensive and confidential disease management programme with a strong telephonic patient education and support component and managed access to art and related drugs, prophylaxis and monitoring tests. clinical support of providers was through well-trained clinical staff and a 'hands-on' clinical advisory committee drawn from both the academic and the private sectors. emphasis was placed on regular monitoring of cd4 counts and viral loads and collection of both clinical and claims data. the southhln african journal o~ hiv medicine table i. change in the cost of haart between the inception of alo for aids and the present (cost price including van 1.6%1.2%0.8%0.4% mtct outcomes r 1 693 r 929 r 824 i i i i i i i i tj i • • . • ~ ~ ~ g ~ ~ ~ ~ ~ ~ ~ ~0 ~ • ~ ~ re g ~ ~ ~ ~ ~ ~ ~ • ~ age band (ye3l$) l~ ~ hi,i. .i 0.0% gauteng umpopo free state north west mpumalanga eastern cape westemcape northern cape kwazulu-natal • 3.5% ! 3.0% 3 2.5% ! 20%.. ,,% li • 1.0% ~ m% # 0.0% fig. 3. aid for aids en raiment by region {% total lives covered}. forward out of fear of disclosing status to the main member. enrolment by region shows that the rate of uptake is highest in kwazulu{natal (1.55%), and lowest in the western cape (0.15%), with more than a tenfold difference between these regions (fig. 3). the rate of enrolment per region will be infiuenced by the underlying hiv prevalence in the medical scheme membership in that region, as well as localised factors, such as the level of stigmatisation, which determine the probability of disclosure. fig. 2. aid for aids enralment by age {% total lives covered}. cost/month afa currently has polymerase chain reaction [pcr) results for 962 infants where complete mother-to-child transmission [mten prophylaxis was provided, mostly the southern african journal of hiv medicine 1 jun. 199b 1 dec. 2002 r 3 692 r 3 626 r 1 471 haart combinations retrovir + 3tc + viramune zerit + videx + crixivan* air + 3tc + norvir -riii rff111t111111 0 i i 0 i i i i ~ • i 8 0;; ~ ~ ~ £ ! ~ ~ adult adult paediatrict • 800 mg 3 times a day. t child agro 1 ym. • '"""'j--------------:rrrl i i: 150001--------------,"" 1100001----------=<'<f1i •~ 5000 1------=fill fig. 7. cumulative enralment ofpatients onto the aid far aids pragramme. well over 20 000 people have been registered on afa to date, and some 12000 are on ongoing art [mostly haarn. cover is provided to over 2 million beneficiaries. the staff complement has grown from 6 to 36 people, and now includes a dedicated management team, 2 full-time doctors and 12 nurses and pharmacists, as well as it and administrative staff. ,,""',------------------, some interesting trends have emerged from the enrolment data. most striking is the patient gender distribution, with 61% females and 39% males. this is higher than expected from aids demographic modelling [the prevalence for the country as a whole is estimated to be marginally higher in adult women than men),' and may be due in part to increased awareness of hiv status in pregnant women through voluntary counselling and testing [vct). to date, some 20% of female patients have been pregnant at registration. another factor behind male under-enrolment may be a greater level of denial in males, as this group remains under-represented even if pregnancy is taken into account. the age distribution of patients shows that enrolment is greatest between 25 and 45 years, with 74% of patients in this age group (fig. 2). in total, 93% of patients are older than 19. there is a surprisingly large difference between enrolment in 15 19-year-olds and in 20 24-year-olds [0.14% v. 0.70010), as well as between the latter and 25 29year-olds [0.70% v. 207%). this may be because the majority of the younger patients are dependants 100% and 85<\'0 in 15 19and 20 24-year-olds respectively, compared with 30% in 25 29-year-olds. there may therefore be a reluctance in these age groups to come february 2003 ----------3 6 9 12 15 18 ~ ~ ~ ~ ~ ~ months post art commencement cd4 count at registration rr ~m rl cd4 (cells/~1) % > 499 15 350 499 15 200 349 26 50 199 29 < 50 15 the future table ill. cd4 count distribution at enrolment on the aid for aids programme fig. 5. hospital admissions relative to commencement ofari months relative to art commencement hospitalisation the aim of any disease management programme (dmp) is evidence-based case management with continual evaluation of clinical and economic outcomes, in order to optimise the use of increasingly scarce health care resources, limit disease progression and improve overall health. our outcomes show that access to art reduces the need for hospitalisation and provides significant reduction in viral load over 3 years despite starting with sub-optimal . ~ 180 § 160 :::: 140 ~ 120 ~ 100 ~ ao ~ 60.. =a. 40 ~ 20 o the hospitalisation data illustrate that admission is frequently the event which precipitates afa registration (fig. 5). were all patients to commence art at the optimal time, we would not expect to see a peak in admissions around the enrolment period. the programme has been monitoring admission rates after commencement of art for over 4 years. it has been heartening to see that once patients have commenced therapy, the admission rate has stabilised. this is particularly notable considering that the majority of patients enrolled at a relatively late stage of the disease. effectively this has translated into a stable postregistration cost scenario rather than a steady upward trend in subsequent years. 200 ~ ~ 0 3 6 9 12 15 18 ~ ~ ~ pregnant female patients have enrolled with a cd4 count < 200 cells/~l, in comparison with 50% of males. preliminary results point to entry cd4 count as being a strong determinant of survival. in particular, patients with a cd4 count < 50 cells/~1 appear to have a substantially higher probability of death within 24 months of enrolment. ----------h8ruary 2003 94.7 5.3 911 51 total virological response table 11. mkt pcr results negative positive per fig. 4. viro/ogicol response to ontiretroviral therapy in aid for aids patien 15. the virological response of afa patients to antiretroviral therapy is shown in fig. 4. most patients started on dual therapy then switched to haart. the mean baseline viral load of patients at commencement of antiretroviral therapy was 5.01 log 10' it is interesting to note the improved response to therapy from 27 months onwards. this is attributed to a greater proportion of patients with data at these time points having had therapy intensified to haart. the virological response at one year (1 10glo reduction) is associated with a 90% reduction in disease progression in patients on dual therapy.' the southern african journal o~ hiv medicine the cd4 count at registration provides a useful measure of whether patients have enrolled late [table ill). ideally, patients should register well before their cd4 count reaches 200 cells/~1 so that art can be commenced at the optimal time. it is of concern that a large percentage of patients enter the programme with a cd4 count < 200 cells/~1. this is either because patients are ignorant of their hiv status until they are admitted to hospital for an opportunistic infection, or because they are in denial. it is interesting that on average, women (excluding those who are pregnant at registration) tend to enrol at an earlier cd4 stage than their male counterparts. to date, 43% of non0.0 tr-n--.rrt-rr-rtn-r.-rr-r-rttn-n 0.2 :5 0.4 l 0.6 ~ 0.8 l 1.0 c 1.2 ~ 1.4 1.• 1.8.'-------------------' short-course zidovudine for the mother, 6 weeks of zidovudine for the child, and milk substitutes for 6 months (table 11). most babies were delivered by caesarean section. the transmission rate of 5.3% is similar to the rate reported in an earlier study.' over the past year the use of shortcourse haart has been recommended, and the reduction in mtct is expected to improve further. therapy. we aim to assess the impact of cost reductions in increasing access to haart on survival and hope to present these data in due course. the programme also offers a valuable education and awareness opportunity for beneficiaries and employees of contracted medical schemes and companies, as well as clinical support for those doctors who require it. we have identified a number of challenges. these include communicating more effectively with patients, maintaining adherence to therapy, and, in common with other hiv dmp,' addressing the relatively low level of enrolment of earlier stage patients. we would like to reverse the current situation where some patients only join the programme after they are hospitalised for an aids-related condition. it is crucial for all health care workers, including doctors, to encourage as many people as possible to know their status and if positive, to join their scheme or company's hiv dmp long before they are likely to develop an opportunistic condition. continuing to provide optimal therapy within the available benefit remains an on-going problem as medical schemes come under increasing pressure from spiralling health care inflation. this will become even more critical as patients move on to more complex salvage regimens after a number of years and the need for sophisticated investigations such as resistance testing increases. after more than 4 years afa has demonstrated that it is possible to manage hiv costs effectively, and despite the challenges we have identified, there is no reason why hiv disease management cannot be extended to far larger numbers of people. references 1. palella fj, delaney km, moorman ac, e't 0/_ declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. n fngl j m~ 1998; 338: 853-860. 2 r~ensberg lo, cowlin jr, waiters l.., ramsay g. affordable management of hn infection in the private sector. safr med j 1998; 88: 945-948. 3_ oorringron re, bradshaw 0, budh=:nder o. hfv/aids profijeof the provinces ofsouth africa indicators for 2002 cape town: centre for actuarial research, m~ical r~arch council and actuarial society of south africa, 2002. 4. regensberg l.., pead c, mahumapelo j, canon m. prevention of vertical transmission of human immunoddiciency type 1 virus in a managed c<lfe sening_ 5 afr med j 2000; 90: 1092-1093. 5. kalzenstein oa, hammer sm, hughes md. et al. the relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in hiv-infected adults with 200 to 500 (04 cells p« cubic millimeter. aids clinical trials group study 175 virology study team. n englj mro 1996; 335: 1091-1098. 6. stein a, mcleod h, achmat z. the cover provided for hiv/aids benefits in medical schemes in 2002. uct-care/tac industry survey: care monograph 10, july 2002 hbruary 2003 ----------the southern african journal of hiv medicine hiv 875 scientific letter stavudine dosage reduction: effect on symptomatic hyperlactataemia and lactic acidosis in patients at dr george mukhari hospital, pretoria to the editor: a range of studies have demonstrated that symptomatic hyperlactataemia and lactic acidosis are associated with antiretroviral combinations containing stavudine.1 , 2 the hiv treatment programme in khayelitsha, cape town, which began using stavudine as a first-line therapy in 2003, reported approximately 10% of patients switching from stavudine to the alternative drug after 12 months due to hyperlactataemia.3 following a meta-analysis showing that lower doses of stavudine are safer and as effective, the world health organization (who) issued a statement that only a low dose of stavudine (30 mg) should be used.4 this retrospective review included patients treated at the adult hiv clinic at dr george mukhari hospital, pretoria, south africa. the study was approved by the medunsa research ethics committee (reference mp 156/2005). the records of 86 patients (aged 27 59 years) initiated on stavudine-containing antiretroviral therapy regimens between 2004 and 2006 were analysed: 66 females (29 received 40 mg stavudine; 37 received 30 mg stavudine) and 20 males (7 received 40 mg stavudine; 13 received 30 mg stavudine). lactate levels were not routinely determined for all patients (only when a clinician suspected lactic acidosis or symptomatic hyperlactataemia on the basis of clinical symptoms). a serum lactate level >2.0 mmol/l was considered to be elevated. lactic acidosis was defined by persistently increased blood lactate levels (>5 mmol/l) in association with acidosis (ph <7.35) and a bicarbonate level ≤ 20 mmol/l.5 among female patients, elevated lactate levels developed in 18/29 (62%) treated with 40 mg stavudine, but only 13/37 (35%) treated with 30 mg of stavudine (range 2.3 9.8 mmol/l). among male patients, elevated lactate levels developed in 2/14 (14%) treated with 30 mg stavudine and 2/7 (29%) treated with 40 mg stavudine. thirty-five patients (41%) had elevated lactate levels with signs or symptoms that obliged clinicians to cease treatment. the relative odds of developing elevated lactate levels when commencing treatment were 2.92 times higher in the group receiving 40 mg stavudine than in the group receiving 30 mg stavudine (95% confidence interval 1.10 2.51). the relative risk (rr) ratio was higher for female patients, with a greater risk for developing hyperlactataemia than males (rr 2.17 for 40 mg stavudine; rr 2.28 for 30 mg stavudine) (table 1). table 1. elevated lactate level in patients receiving 30 mg or 40 mg stavudine 40 mg stavudine 30 mg stavudine or (95% ci) female, n (%) 3.02 (1.10 8.29) elevated lactate levels 18 (27) 13 (20) normal lactate levels 11 (17) 24 (36) total 29 (44) 37 (56) male, n (%) 2.20 (0.24 20.00) elevated lactate levels 2 (10) 2 (10) normal lactate levels 5 (25) 11 (55) total 7 (35) 13 (65) or = odds ratio; ci = confidence interval. the onset of the first symptoms of elevated lactate levels occurred from 2 to 18 months following treatment initiation. of the 35 patients with elevated lactate levels, 43% (n=15) were obese and 4 (11%) died due to complications of lactic acidosis. this analysis demonstrated that stavudine dose reduction increased the odds of patients being more stable on treatment with fewer reported side-effects. stavudine-containing regimens should be avoided in obese female patients. low-dose stavudine (20 mg) may offer alternative solutions in poor or resource-limited settings, with a lower associated risk of toxicity and side-effects; however, virological non-inferiority to the first-line treatment option should be established. m nlooto e osuch w du plooy department of pharmacology and therapeutics, school of medicine, university of limpopo, medunsa campus corresponding author: e osuch (elzbieta.osuch@ul.ac.za) references 1. menezes c, maskew m, sanne i, crowther n, raal f. a longitudinal study of stavudine-associated toxicities in a large cohort of south african hiv infected subjects. bmc infect dis 2011;11:244. [http://dx.doi.org/10.1186/1471-2334-11-244] 1. menezes c, maskew m, sanne i, crowther n, raal f. a longitudinal study of stavudine-associated toxicities in a large cohort of south african hiv infected subjects. bmc infect dis 2011;11:244. [http://dx.doi.org/10.1186/1471-2334-11-244] 2. hernández pérez e, dawood h. stavudine-induced hyperlactatemia/lactic acidosis at a tertiary communicable diseases clinic in south africa. j int assoc physicians aids care (chic) 2010;9(2):109-112. [http://dx.doi.org/10.1177/1545109710361536] 2. hernández pérez e, dawood h. stavudine-induced hyperlactatemia/lactic acidosis at a tertiary communicable diseases clinic in south africa. j int assoc physicians aids care (chic) 2010;9(2):109-112. [http://dx.doi.org/10.1177/1545109710361536] 3. wood r. 2006. the role of stavudine in the south african public sector antiretroviral programme: should the perfect be the enemy of the good? southern african journal of hiv medicine 2006;7(2):5-8. 3. wood r. 2006. the role of stavudine in the south african public sector antiretroviral programme: should the perfect be the enemy of the good? southern african journal of hiv medicine 2006;7(2):5-8. 4. hill a, ruxrungtham k, hanvanich m, et al. systematic review of clinical trials evaluating low doses of stavudine as part of antiretroviral treatment. expert opin pharmacoter 2007;8(5):679-688. [http://dx.doi.org/10.1517/14656566.8.5.679] 4. hill a, ruxrungtham k, hanvanich m, et al. systematic review of clinical trials evaluating low doses of stavudine as part of antiretroviral treatment. expert opin pharmacoter 2007;8(5):679-688. [http://dx.doi.org/10.1517/14656566.8.5.679] 5. southern african hiv clinicians society. guidelines for the prevention, diagnosis and management of nrti-associated symptomatic hyperlactataemia and lactic acidosis. southern african journal of hiv medicine 2006;7(1):8-15. 5. southern african hiv clinicians society. guidelines for the prevention, diagnosis and management of nrti-associated symptomatic hyperlactataemia and lactic acidosis. southern african journal of hiv medicine 2006;7(1):8-15. s afr j hiv med 2013;14(1):34-35. doi:10.7196/sajhivmed.875 abstract introduction and background aim method results discussion conclusion acknowledgements references about the author(s) talitha crowley department of nursing and midwifery, faculty of medicine and health sciences, stellenbosch university, cape town, south africa elizabeth mokoka forum of university nursing deans of south africa (fundisa), pretoria, south africa nelouise geyer nursing education association, pretoria, south africa department of nursing education, university of the witwatersrand, johannesburg, south africa citation crowley t, mokoka e, geyer n. ten years of nurse-initiated antiretroviral treatment in south africa: a narrative review of enablers and barriers. s afr j hiv med. 2021;22(1), a1196. https://doi.org/10.4102/sajhivmed.v22i1.1196 review article ten years of nurse-initiated antiretroviral treatment in south africa: a narrative review of enablers and barriers talitha crowley, elizabeth mokoka, nelouise geyer received: 13 nov. 2020; accepted: 24 dec. 2020; published: 11 mar. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the roll out of nurse-initiated and managed antiretroviral treatment (nimart) was implemented in 2010 by the national department of health (ndoh) in south africa in response to the large numbers of persons living with hiv who needed treatment. to enable access to treatment requires shifting the task from doctors to nurses, which had its own challenges, barriers and enablers. objectives: the aim of this narrative is to review content on the implementation of nimart in south africa over the period 2010–2020, with a focus on enablers and barriers to the implementation. method: a comprehensive search of databases, namely, pubmed, google scholar and cumulative index to nursing and allied health literature (cinahl), yielded qualitative, quantitative and mixed-method studies that addressed various topics on nimart. inclusion and exclusion criteria were set and 38 publications met the inclusion criteria for the review. results: training, mentorship, tailored tuberculosis (tb) and hiv guidelines, integration of services and monitoring and support have enabled the implementation of nimart. this resulted in increased knowledge and confidence of nurses to initiate patients on antiretroviral treatment (art) and decreased time to initiation and loads on referral facilities. barriers such as non-standardised training, inadequate mentoring, human resource constraints, health system challenges, lack of support and empowerment, and challenges with legislation, policy and guidelines still hinder nimart implementation. conclusion: identifying barriers and enablers will assist policymakers in implementing a structured programme for nimart in south africa and improve access, as well as the training and mentoring of professional nurses, which will enhance their competence and confidence. keywords: nurse-initiated; nimart; south africa; antiretroviral treatment; enablers; barriers. introduction and background the implementation of nurse-initiated and managed antiretroviral treatment (nimart) was a direct response to the high rate of persons living with hiv and requiring treatment. initially, antiretroviral treatment (art) was provided in hospitals and initiation was performed by doctors. with more patients requiring treatment, as hiv infections soared and doctors’ capacity exceeded, a task shifting model was implemented, with nurses in the public sector having to initiate art to scale up hiv treatment and increase access for more south africans living with hiv.1 poor socio-economic conditions and distances that patients had to travel to access care brought the need to decentralise hiv management services to primary healthcare (phc) facilities. this, in turn, increased pressure to have more nurses trained to initiate art and manage stable patients following national guidelines.2 the evidence that task-shifting may improve health outcomes, quality of care and patient satisfaction,3,4 together with the additional benefits of decentralisation of treatment5 and the growing numbers of persons living with hiv in south africa, necessitated the wide-scale implementation of nimart training. the world health organization recommendations and guidelines for task-shifting6 advocate that task-shifting should be implemented alongside efforts to increase the skilled workforce, health systems reorganisation and an enabling regulatory framework. continued quality of care can only be maintained with standardised competency-based training, supportive mentoring and effective referral systems.6 whilst there has been evidence that nimart-trained nurses can initiate and manage patients successfully, researchers cautioned that we may not know enough about key patient-, providerand organisational-level enablers and barriers of wide-scale implementation.7 it has been 10 years since the initial nimart implementation in south africa in 2010. human immunodeficiency virus treatment and management guidelines have been revised several times since the art implementation, and hiv care has been integrated into various other services such as general phc,8 tuberculosis (tb) management9 and antenatal care.10 nurse-initiated and managed art has also expanded to include the management of children and patients with virological failure.11 with such wide-scale implementation and the evolving role of nurses in the context of nimart and hiv management, it is inevitable that there may be challenges. recent reviews that have summarised the enablers and barriers of the implementation of nimart in the context of south africa could not be found in the literature. it therefore became critical to search the literature in order to identify enablers and barriers and to make recommendations that will improve nimart implementation. aim the aim of the article is to review published literature on nimart in south africa, with particular focus on the enablers and barriers to implementation. method in order to provide a comprehensive synthesis of the evidence and a broad perspective on nimart, articles on the topic, its history and development were searched and presented in a narrative format.12 a narrative overview or review is a non-systematic narrative synthesis of previously published literature.12 search strategy and study selection pubmed, cinahl and google scholar databases were searched for relevant south african articles published between january 2010 and june 2020. different search strategies were applied, using the mesh term combinations. in pubmed and cinahl, we used boolean operations such as ([‘nurse-initiated’] and nimart) and ‘south africa’) and in google scholar we used a string (nimart south africa). we identified additional records by reviewing master’s or phd e-theses, conference abstracts and published studies known to the authors. relevant grey literature, such as department of health documents, was also included. one of the authors and a research assistant screened the abstracts for relevancy. articles were included if they met the following criteria: published in english, between january 2010 and june 2020 and reported studies conducted in south africa. records were excluded if the results did not relate directly to nimart or if the study was not conducted in south africa. data extraction and evidence appraisal data on the study aim, methods, sample and key enablers and barriers were extracted in tabular format. the quality of evidence was appraised using the john’s hopkins evidence level and quality guide.13 ethical consideration this article followed all ethical standards for research without direct contact with human or animal subjects. results a total of 479 records were identified: 7 from pubmed and cinahl, 475 from google scholar and 15 through the authors of this article. after removing duplicates and excluding studies not relevant to the topic, 38 publications were included in our narrative literature review. the review includes qualitative, quantitative and mixed-methods studies and literature reviews that reported on evidence related to the nimart implementation in south africa. almost all the studies were classified as level iii, b (non-experimental studies of good quality).13 most of the quantitative and qualitative studies were descriptive in nature. however, the studies had sufficient sample sizes and provided reasonably consistent results and recommendations. the studies’ findings are presented narratively under the headings ‘enablers’ and ‘barriers’ to nimart implementation. a summary of the included studies is provided in annexure 1. a summary of the enablers and barriers is depicted in table 1. table 1: summary of enablers and barriers to the implementation of nurse-initiated and managed antiretroviral treatment in south africa. enablers to nurse-initiated and managed antiretroviral treatment implementation the streamlining tasks and roles to expand treatment and care for hiv (stretch) trial, conducted before the official implementation of nimart in 2010, reported on key enablers in the south african setting.14 key components of effective implementation included tailored guidelines, training and support to build the clinical confidence of nurses and health services reorganisation.14 since then, several other studies have highlighted similar enablers. we identified key enablers of nimart implementation as being: (1) training and mentorship; (2) hiv and tb management guidelines; (3) integration of services; and (4) monitoring and support. training and mentorship in order to enable nimart implementation, nurses need additional training. nurses undergoing nimart training have to complete hiv training covering various topics, clinical guideline training (practical approach to lung health and hiv/aids in sa [palsa plus] and integrated management of childhood illnesses [imci]), and complete a portfolio of evidence (poe) containing a range of competencies. nurse-initiated and managed antiretroviral treatment nurses are required to initiate and follow up a minimum number of patients in various age groups, including adults and children.15 only after the successful completion of the poe, nurses receive a certificate of competence to initiate nimart. in some settings, nurses’ competence are formally tested through objective structured clinical examinations (osce).15 with the introduction of the department of health’s clinical mentoring manual for integrated services,16 mentorship was formally introduced to enhance clinical expertise. the model advocates a clinical proficiency pathway starting with didactic training accompanied by clinical practice, assessment and continuous mentoring to ensure clinical expertise. doctors or nurses can become clinical mentors, provided that they undergo mentoring training.17 many non-governmental organisations (ngos) and other private organisations rose to the task of assisting the national department of health (ndoh) with training and mentoring. these courses included, for example, the clinical competency in antiretroviral and tuberculosis (ccart) course developed by the university of stellenbosch in collaboration with john’s hopkins university and the united states agency for international development (usaid),18 a course presented by the foundation of professional development (fpd)19 and a course developed by the university of kwazulu-natal.2 across the courses, various challenges were reported such as difficulty to complete assignments, dispensing certificates and poes for art initiations.18 success stories included improvement in pre-and post-course knowledge and confidence and increased rates of poe completion because of a team of roving mentors.2,18,19 adequate training results in improved knowledge of hiv management, greater confidence and clinical competence, particularly if accompanied by mentoring.14,20,21,22 a study conducted in an urban and rural district in the western cape found that the majority of nimart-trained nurses had adequate hiv management knowledge and were very confident to manage adult patients.22 the survey was specific to adult hiv management as nurses are only involved to a limited extent in the management of children in the western cape. nurse-initiated and managed antiretroviral treatment training leads to feelings of empowerment because of expanded roles.20 appropriate training and support can lead to increased quality of patient care, confidence and professional development.17 nurses may experience work satisfaction because of the difference they are making in patients’ lives.23 in the north west province, the ability to work independently boosted nurses’ self-esteem and self-worth.24 in venda, some nurses reported that they felt proud that they were contributing to the nimart programme.25 in johannesburg, the training of nurses in nimart increased access to art as shown by an increase in the number of monthly initiations. it also resulted in reduced workloads at referral facilities.26 a qualitative study in johannesburg reported that referrals to tertiary hospitals were significantly reduced after the introduction of nimart. nurses observed an improvement in the quality of life of their patients and the retention of patients in care, which they felt reflected the success of nimart.27 similarly, in kwazulu-natal, a cross-sectional study revealed that in 98% of the primary care clinics in one district, nurses initiated patients on art. the majority of nurses also indicated that children were initiated in their clinics, with only some still being initiated by a doctor.28 accelerating nimart in paediatric patients, coupled with mentoring and support were considered enablers in the provision of art in infants and children living with hiv in the eastern cape.29 clinical exposure further contributes to knowledge and confidence as was found in a study conducted in the western cape where a higher caseload of hiv patients was associated with higher knowledge and confidence.22 in the north west province, effective placement, specifically at community health centres, contributed to poe completion.24 the mentoring of nurses had a positive effect on patient care by improving the clinical skills of professional nurses and by raising the standard of hiv care in the eastern cape.30 in khayelitsha, cape town, a mentoring programme led to improvements in the quality of care nurses provided and their knowledge and confidence.17 nurses initiated 77% of art-eligible patients after completing a mentorship programme and improvements in their art management were observed.17 if the majority of persons living with hiv are managed by nurses, doctors can attend to the more complicated cases, which, in turn, may result in better overall patient outcomes. another study in the western cape found that a 2-week mentoring period was associated with greater hiv confidence compared with other periods. a period of 2 weeks of ‘dedicated mentoring-time’ with a mentor may be sufficient to complete competencies.22 jobson et al.31 conducted a qualitative study, evaluating the role of mentoring in the support of the scale-up of art across three provinces of south africa. the study explored the role of targeted mentoring using a needs-based approach to support nimart, pharmacy management and data management.31 the study adopted a two-stage approach, which they classified as proactive and reactive mentoring. for nimart-trained nurses, the proactive approach entailed having nurse mentors accompanying them during patient consultations, which provided support in transferring skills learnt during training to actual implementation when providing care. participants stated that they had gained knowledge after training and mentoring, which empowered them to up-scale services through nimart. the reactive role required the mentor (nurse) to be a problem solver and a source of support, as required at various stages during hiv care and management. this type of support is important for nimart-trained nurses who were starting to initiate and manage patients on art. mentorship strengthened skills and knowledge transfer, allowed mentees to develop their own skills and provided a source for psychosocial support as mentees became confident and felt empowered to take on new responsibilities in providing hiv care.31 hiv and tb management guidelines the introduction of tailored guidelines such as the practical approach to care kit (pack) was critical to assist nurses to implement nimart.14 a mixed-methods study conducted in the limpopo province found that nurses practiced rational prescription and followed art guidelines, with lower patient mortality (below 1%) and loss-to-follow-up rates compared with that of surrounding hospitals. in addition, 91.1% of nimart-managed patients had undetectable viral loads after 1 year on treatment. patients also reported high levels of satisfaction.32 a study conducted in the north west province found that nurses preferred guidelines to be user-friendly, easy to follow and keep on their person and available in all consulting rooms.33 nurses also wanted to be supported and supervised until they are familiar with applying the guidelines in practice. they preferred continuous training and education about guidelines. organisational and structural changes such as manageable workloads and improved communication were thought to enable adherence to art and tb treatment guidelines.33 integration of services initially, nimart was implemented as a vertical programme. now it is increasingly being integrated into a range of primary care services.8 the integration of hiv care into phc services is reported as a structural facilitative factor for the implementation of nimart.27 the integration of hiv care into antenatal care and the introduction of option b+ meant that all pregnant women living with hiv needed to be initiated on art. a retrospective record analysis conducted in the gauteng province comparing time to initiation of art amongst antenatal clients before and after nimart implementation showed no significant reduction in the time to initiation on art.10 however, the study was conducted in the early stages of nimart training and not all midwives may have been trained; therefore, they could only initiate clients on certain days. contrary to this, a study conducted in kwazulu-natal, soon after nimart implementation in 2011, found that 97% of women were initiated on art in antenatal care settings, illustrating a shift in care from art clinics to nurse-managed antenatal clinics. this also resulted in reduced time to art initiation from 38 to 4 days.34 one study evaluated the effectiveness of the nimart programme in the waterberg district of the limpopo province and found the number of patients initiated in the hospital dropped as did the number lost-to-follow-up, after the introduction of nimart in primary care.35 monitoring and support a study conducted in the western cape found that regular feedback about clinic and personal performance was associated with higher hiv management knowledge,22 with a study in limpopo highlighting that support from visiting doctors and management were viewed as very helpful, even if management could not resolve all their problems.23 support amongst nurses is a further enabler to the implementation of nimart.25 supportive teamwork (ongoing support from facility managers and colleagues), motivation and support from mentors were found to be key contributors to poe completion in the north west province.24 barriers to nurse-initiated and managed antiretroviral treatment implementation the implementation of nimart may have been too hasty, not providing enough time for crucial capacity-building interventions such as mentoring and systems reorganisation.20 barriers identified in this review include: (1) non-standardised training and inadequate mentoring, (2) human resources constraints, (3) health system challenges, (4) lack of support and empowerment, (5) challenges with legislation, policy and guidelines and (6) patient-related factors. non-standardised training and inadequate mentoring inadequate or non-standardised training and the lack of continuous clinical mentoring and supervision by clinic managers were mentioned in most studies as barriers to the implementation of nimart.19,20,23,24,25,27,28,35,36,37 as mentioned before, nimart training was, and is being conducted by various ngos, the ndoh and private training providers. one of the challenges is that training is not standardised, ranging from a few days to a few weeks or even months, which makes it difficult to evaluate its effectiveness or quality. each provider determined their own programme’s content, duration, instruction methods and assessment strategies. this limits the ability to set guidelines for structured training and mentoring. in some cases, nurses initiated patients even before attending or successfully completing nimart training.19 the process of submitting poe’s and doing an additional course in dispensing was found to be dysfunctional as many nurses could not complete it.15,18,38 in the north west, prerequisites such as pack training and imci were barriers to the completion of poes.24 in rural north west province, challenges relating to nimart training included the lack of a standardised curriculum, lack of involvement of quality assurance bodies, nursing colleges and universities and inadequate continuous professional development (cpd).39 another barrier identified in the north west province was disorganisation at the level of the regional training centre (not receiving poe’s directly after the training) and at the level of the trainee (lack of planning).24 this partly defeated the aims of nimart, which was meant to be an intervention intended to improve healthcare access and equity, ideally without compromising the quality of care and a key strategy for expanding access to hiv treatment at phc level. there is a lack of evidence in south africa regarding the effectiveness of different nimart training programmes and the impact on patient outcomes.2 one should also question the sufficiency of a once-off nimart training and further explore the role of continuing education and cpd. a study conducted in the western cape found that nimart nurses with recent training on guidelines (less than 3 years) had better knowledge compared with nurses who reported to be trained more than 3 years ago.22 in general, nimart-trained nurses identified the need for continuing education.2,19,20,21,35,39 whilst nimart training enabled access, a lack of mentoring following training was a barrier in terms of the gap between the number of nurses who received training and those who could initiate treatment. despite the large-scale training to upskill nurses, not all nurses initiated art after receiving training. a study conducted in rural north west province found that although nimart increased access to care, there was no steady increase in the initiation of adults, children and pregnant women on art. initiation was especially low amongst children. this was despite the fact that 75% of nurses in 99% of healthcare facilities were nimart trained.40 facilities were also performing below the targets for retention in care and viral load completion and suppression rates, indicating poor quality of care and non-compliance to guidelines. another study conducted amongst nimart-trained nurses across 7 provinces found that of the 126 nurses sampled, only 79 initiated treatment and only 9 initiated treatment in children.19 factors contributing to low initiation rates include inadequate training, lack of confidence and lack of mentoring and supervision. a study conducted in the western cape amongst 77 nimart nurses working across 29 healthcare facilities on factors influencing the knowledge and confidence of professional nurses prescribing hiv treatment concluded that training, mentorship and clinical practice experience were associated with confidence and knowledge.22 a qualitative study conducted in johannesburg found that a lack of mentoring was likely to have contributed to a lack of nurses’ confidence to initiate art. they recommended a nurse-mentor model where experienced nurses can supervise and support colleagues; as well as access to telephonic support.20 nurse-initiated and managed antiretroviral treatment-trained nurses in venda reported that because of the limited 1-week didactic training, they ended up learning most of the competencies at work, highlighting the need for mentoring support.25 the need for supportive mentoring was underscored by the fact that only 63% of the nurses who completed a training course in kwazulu-natal felt confident enough to initiate art following the training.2 with the escalating number of persons living with hiv requiring treatment, it became crucial to nationally upskill the nurses who were not initiating as a result of a lack of mentorship and standardised training. whilst some of the ngos had a mentorship programme as part of their training, this was not a norm across all trainings. the ndoh subsequently developed a national clinical mentorship programme, which was aimed at providing practical on-site support to nimart-trained nurses and ensure a competent and confident workforce. a manual was developed, with didactic content and practical tools that could be used to design, implement and evaluate a clinical mentorship programme at facility level and following clinical guidelines on hiv care. of importance was that the manual could also be used by pharmacists, medical officers and other members of the multidisciplinary team providing hiv care services.16 however, even with this clinical mentorship programme in place, challenges with regard to mentoring exist. one of these challenges include that during proactive mentoring, it often happened that the mentors ended up delivering the actual service themselves and were sometimes not available when needed because of being responsible for several facilities.31 there is also no standardised time or method for clinical mentorship and it varies from a minimum of 40 h in the western cape17 to targeted mentoring in other settings.15,31 several studies identified key knowledge and confidence gaps amongst nimart-trained nurses, further indicating a need for improved training and mentoring. a lack of confidence to manage children was identified in a study in the north west province.39 naude21 similarly found low levels of competency in certain areas of hiv management, particularly for art initiation and follow-up in children, in the north west province. in venda and limpopo, nurses reported that they faced problems in performing certain tasks such as obtaining blood from children.25,41 mashudu35 also found that few children were initiated on art in limpopo. low initiation rates amongst children should be investigated further. it may be that the policy in many provinces, such as the western cape, is that children must be managed by doctors or that paediatric nimart training and mentoring is not sufficient. in a study to explore the experiences of healthcare professionals regarding the provision of art for children in phc settings in nelson mandela bay health district in the eastern cape, the need for training, mentoring and debriefing was expressed as one of the challenges related to providing decentralised art to children. nurses were apprehensive to work with children and noticed incongruence in the interpretation of art side effects in children.29 an analysis of nurses’ queries to the national hiv and tb health worker hotline showed that 66% of the queries received were from nimart-trained nurses and most were related to art initiation and adverse drug reactions. the most common knowledge gap identified was on the interpretation of blood results before initiation of art,42 which was also confirmed by rasalanavho.25 in the study conducted in the western cape, low confidence was reported in prescribing for concurrent illnesses and in identifying the signs and symptoms of immune reconstitution inflammatory syndrome. nurses had less than optimal knowledge of virological failure and drug–drug interactions.22 in kwazulu-natal, most nimart nurses knew the correct art regimens, art eligibility criteria and when blood for cd4 count and viral load should be taken, although worrying gaps were identified.28 human resources constraints human resources constraints, increased workloads and administrative duties such as paperwork, were cited in many studies as negatively influencing the implementation of nimart,14,19,20,21,23,25,27,32,35,39 with doctors reportedly not fully supporting the nimart programme.25 excessive workloads also interfere with the completion of mentorship programmes.24 in one study, 55% of nurses reported seeing more than 30 patients a day and 30% saw more than 40 patients a day.21 as a result of integration of hiv management in primary care, nimart-trained nurses also have other tasks to perform.22,25 nurses reported the inability to delegate tasks to lower cadres and also reported having to do non-nursing tasks such as collection of drugs from depots27 or using their own transport to collect drugs.25 despite human resource challenges, nimart nurses display resilience. in the western cape, even though 44.4% of nurses felt that their workload was unacceptable, and 48.1% were dissatisfied with their work environment, salary and work hours; 88.3% were nonetheless still motivated to work.22 the challenge of high workloads was mitigated by nurses in venda through problem-solving and innovative strategies such as allocating different times for collecting tablets and reviews as well as group counselling.25 the growing number of patients on art necessitates looking at decentralising art care further and utilising chronic care models for stable patients on art to decongest clinics.20 several studies mentioned the utilisation of lower cadres of healthcare workers such as lay workers to trace patients,27 the education of the community, increased community management of hiv and addressing poverty and stigma, as crucial to the continued success of the hiv programme in south africa.23,43 health systems challenges although integration of services can be an enabling factor, it is not without challenges. high hiv–tb co-infection rates and high antenatal hiv prevalence rates in south africa necessitate integration of hiv into tb and antenatal care. this means that primary care nurses and midwives have to expand their competencies to include nimart. these changes also have an effect on the scope of practice and the training of nurses. it may also impact the quality of care that can be provided to other patient populations in primary care and women’s healthcare settings. a study conducted in the free state to evaluate patients’ perceptions of the effect of the integration of nimart into primary care on quality of care showed that there was no decrease in patient satisfaction with staff. this was despite increases in patient numbers. however, satisfaction scores were lower for child health and chronic care patients (except tb), suggesting that there may be a knock-on effect on other services.44 a study in the limpopo province on the views of registered nurses of the prevention of mother-to-child transmission (pmtct) programme revealed considerable challenges to integrate nimart into antenatal and postnatal care.43 these challenges related particularly to having to spend more time with patients when initiating art during the antenatal period; the additional workload was not accompanied by additional support. integration of services should be accompanied by the provision of adequate resources and reorganisation of services.14 however, several studies reported inadequate infrastructure and resources such as consultation rooms, inadequate workspace compromising patient privacy and confidentiality, as well as the lack of resources such as stationery, drugs, equipment needed for blood collection, telephones, electronic drug ordering systems, information systems and slow turnaround times of blood investigations.15,19,21,23,25,27,32,33,35,41,43 poor data management, including lack of compliance with standard operating procedures, incomplete records and inadequate audits hampered performance.23 nurses also experience poor referral feedback systems.27 there is a necessity for quality improvement teams to ensure quality of care.20 lack of support and empowerment health system issues and lack of managerial support was identified in several studies.20,23,25,33 in venda, nurses reported a lack of support from doctors and refusal to see complicated cases requiring expert management.25 naude,21 through a mixed-methods study, explored empowerment amongst nimart-trained nurses. quantitative findings revealed that nurses were only moderately structurally empowered. with regard to psychological empowerment, professional nurses felt that they only minimally influenced their work environment. management and organisational processes were identified as being central to the empowerment of nimart nurses.21 in the eastern cape, barriers to paediatric nimart implementation included ineffective management, disharmony and non-conducive work environments.29 a negative attitude towards the management of hiv and tb patients was identified by mboweni and makhado.38 negative attitudes and discrimination from non-nimart-trained nurses and refusal to manage hiv positive patients was also reported in a study conducted in venda. nurses reported that patients questioned their ethical values to keep information confidential and had negative attitudes towards the nimart programme.25 a study conducted in the limpopo province found that nurses also had fears of infecting themselves with hiv,41 indicating that there may be a lack of workplace-based support. challenges with legislation, policy and guidelines the lack of enabling legislation and regulations,45,46 the lack of clear guidelines and standard operating procedures,37 unclear roles or scope of practice – nurses sometimes perform the roles of medical practitioners and pharmacists,21 and salary or remuneration challenges were also reported.32 provincial governments and the ndoh were mandated to maintain records of all nurses authorised to prescribe art and to communicate this to the south african nursing council. anecdotal reports suggest that this has not happened. there is no formal scope of practice for nimart-trained nurses and they do not receive additional remuneration for expanded roles. some studies reported the lack of updated guidelines, particularly in rural areas.28 a study in kwazulu-natal and north west provinces revealed that nurses may not be following hiv and tb guidelines. barriers to adhering to guidelines included a lack of agreement with the guidelines or guidelines not being clear or understandable; insufficient knowledge as a result of not being updated or involved in guideline development; frequent guideline changes; poor motivation; and lack of supportive supervision.9 continuous revision of guidelines requires frequent updated training, but training programmes are not always communicated timeously to ensure that staff can attend.43 patient-related factors many studies also highlighted patient-related factors hindering the implementation of nimart such as poverty, stigma, lack of transport and non-adherence to treatment.25,27 however, the discussion of patient factors is beyond the scope of this review and could perhaps be a focus for future studies. discussion it has been 10 years since the implementation of nimart in south africa. evidence from observational studies indicates that there are several enablers and barriers to implementation. based on the evidence presented here, we discuss implications for practice, education and research. implications for practice the narrative review identified two frameworks developed from rigorous research that could be implemented in practice to strengthen nimart training and implementation and empower nimart-trained nurses.21,37 the conceptual framework for strengthening nimart training and implementation developed by mboweni and makhado39 outlines structural attributes that advocates for adequate resources, infrastructure, supportive legislation and policy, effective training strategies and a supportive healthcare system culture.37 this is supported by the framework of naude21 who outlined the following elements of structural empowerment: training and mentoring (knowledge, technical skills and professional growth); resources (human, equipment and supply chain); support (clinical supervision, guidance from managers and feedback); communication (information, protocols and guidelines) and power (formal in the form of role clarification and decision making and informal in the form of team acceptance and remuneration).21 many of these infrastructural and resource inadequacies may be addressed by investing in and improving the leadership and management of phc services. implications for education mboweni and makhado’s framework identified that effective nimart education and implementation requires (1) an integrated curriculum and effective training strategies for inand pre-service education and (2) a healthcare system culture that includes support through mentoring or coaching, discipline, communication and referral systems.37 although nimart training is still being provided by ngo’s and various private organisations, there is now a greater effort to incorporate comprehensive hiv training, including nimart, in undergraduate pre-service programmes.2,46,47,48 evidence suggests that pre-service nurses still have inadequate hiv management knowledge.47 some researchers advocate for specialisation programmes for the management of chronic conditions, including hiv and tb.21 one study recommended future research regarding the role of the postgraduate diploma in primary care nursing in the implementation of nimart as nurses felt that those who had the qualification were better equipped to manage patients on art.27 however, in the same study, as reported in other studies,2,19 the majority of nimart nurses did not have a qualification in primary care (health assessment, diagnosis, treatment and care). more research is needed to explore if a primary care qualification is important for nimart implementation2 or whether nimart competencies should be integrated in the undergraduate programme or the postgraduate diploma in primary care nursing. nonetheless, there is a need to standardise ‘in-service’ types of nimart training across provinces, aligning them to the competencies outlined in the clinical mentorship manual for integrated services,16 as well as ensuring formal competency assessment. implications for research further research is needed on the standardisation and effectiveness of nimart training and mentoring programmes and the long-term impact on patient outcomes towards attaining national and international targets for hiv care and management. evidence-based guidelines for the integration of nimart into primary care services and continuous monitoring and support are urgently needed. strengths and limitations the search strategy was not comprehensive and some relevant studies may have been excluded. however, the authors are confident that we have provided an exhaustive description of barriers and facilitators to nimart implementation in south africa. conclusion although training, mentorship, guidelines, integration of services and monitoring and support have enabled the implementation of nimart, several barriers such as non-standardised training, inadequate mentoring, human resource constraints, health system challenges, lack of support and empowerment, and challenges with legislation, policy and guidelines still hinder its effectiveness. various key role players such as the ndoh, the south african nursing council, training providers and researchers need to work together to standardise training and provide evidence-based guidelines for mentoring, integration of services and continuous monitoring and support. acknowledgements the authors would like to acknowledge eveline kabongo for conducting the initial literature search. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this review article. authors’ contributions t.c., e.m. and n.g. reviewed the literature and provided feedback on the manuscript. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. 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from: https://researchspace.ukzn.ac.za/bitstream/handle/10413/15808/xaba_pearl_2016.pdf?sequence=1&isallowed=y williams m, van rooyen drm, ricks ej. provision of antiretroviral therapy for children in nelson mandela bay: health care professionals’ challenges. african j prim heal care fam med. 2018;10(1):1–11. https://doi.org/10.4102/phcfm.v10i1.1490 jones m, stander m, van zyl m, cameron d. recall of lost-to-follow-up pre-antiretroviral therapy patients in the eastern cape: effect of mentoring on patient care. samj. 2012;102(9):768–769. https://doi.org/10.7196/samj.5957 jobson g, mabitsi m, railton j, et al. targeted mentoring for human immunodeficiency virus programme support in south africa. south afr j hiv med. 2019;20(1):1–6. https://doi.org/10.4102/sajhivmed.v20i1.873 visser ca, wolvaardt je, cameron d, marincowitz gjo. clinical mentoring to improve quality of care provided at three nim-art facilities: a mixed methods study. african j prim heal care fam med. 2018;10(1):1–7. https://doi.org/10.4102/phcfm.v10i1.1579 makhado l, davhana-maselesele m, lebese r, maputle s. factors facilitating trained nimart nurses ’ adherence to treatment guidelines: a vital matter in the management of tb/hiv treatment in south africa. bmc nursing. 2020;19:77. https://doi.org/10.1186/s12912-020-00470-6 nozulu n, gaede bm. antiretroviral initiation of pregnant women and antenatal care booking practices in ethekwini district, kwazulu-natal, south africa. afr j prm health care fam med. 2018;10(1):a1606. https://doi.org/10.4102/phcfm.v10i1.160 mashudu m. an evaluation of the effectiveness of the nurse-initiated-and-managed antiretroviral treatment (nimart) programme, waterberg district, limpopo province. university of venda; 2015. mangi ng, goon d ter, yako em. self-efficacy and clinical performance of nurses initiated and management of antiretroviral therapy: narrative review. open publ health j. 2019;12:86–93. https://doi.org/10.2174/1874944501912010086 mboweni sh, makhado l. conceptual framework for strengthening nurse-initiated management of antiretroviral therapy training and implementation in north west province. healh sa gesondheid. 2020;25:1–10. https://doi.org/10.4102/hsag.v25i0.1285 stellenbosch university. art2scale final technical report update 25 nov. 2010. mboweni sh, makhado l. challenges influencing nurse-initiated management of antiretroviral therapy training and implementation in ngaka modiri molema district, north west province. heal sa gesondheid. 2020;25:1–11. https://doi.org/10.4102/hsag.v25i0.1174 mboweni sh, makhado l. impact of nimart training on hiv management in ngaka modiri molema district, north west province. int j africa nurs sci. 2019;11(january):100170. https://doi.org/10.1016/j.ijans.2019.100170 sekatane pt. a protocol for professional nurses regarding the management of nurse initiated management of antiretroviral therapy (nimart) in the ehlanzeni district, mpumalanga province, south africa. university of limpopo; 2014 [cited 2020 apr 7]. available from: http://ulspace.ul.ac.za/handle/10386/1377 swart am, chisholm bs, cohen k, workman lj, cameron j, blockman m. analysis of queries from nurses to the south african national hiv & tb health care worker hotline. south afr j hiv med. 2013;14(4):179–182. https://doi.org/10.7196/sajhivmed.948 hanrahan ba, williams a. prevention of mother-to-child transmission of hiv guidelines: nurses’ views at four primary healthcare facilities in the limpopo province. s afr j hiv med. 2017;18(1):1–6. https://doi.org/10.4102/sajhivmed.v18i1.690 rawat a, uebel k, moore d. patient responses on quality of care and satisfaction with staff after integrated hiv care in south african primary health care clinics. j assoc nurses aids care. 2018;29(5):698–711. https://doi.org/10.1016/j.jana.2018.04.014 ford p. nurse initiated and managed anti-retroviral treatment: an ethical and legal analysis in south africa. msc med (bioethics health law). johannesberg; 2013 [cited 2020 apr 7]. available from: http://wiredspace.wits.ac.za/bitstream/handle/10539/14413/research_report_nimart__final_submission_with_amendments-20-07-13.pdf?sequence=1 zuber a, mccarthy cf, verani ar, msidi e, johnson c. a survey of nurse-initiated and -managed antiretroviral therapy (nimart) in practice, education, policy, and regulation in east, central, and southern africa. j assoc nurses aids care. 2014;25(6):520–531. https://doi.org/10.1016/j.jana.2014.02.003 lekhuleni me, kgole jc, mbombi mo. knowledge of student nurses in nurse initiated and management of antiretroviral therapy at the university of limpopo, south africa: tb, hiv/aids and other diseases. african j phys heal educ recreat danc. 2015;21(october):53–61. modeste rm, adejumo o. strengthening the preparation of student nurses to participate in the provision of nurse initiated and monitored antiretroviral (nimart) in south africa [homepage on the internet]. 2016 [cited 2020 oct 07]. available from: https://hdl.handle.net/10755/603007 colvin cj, fairall l, lewin s, et al. expanding access to art in south africa: the role of nurse-initiated treatment. samj. 2010;100(4):210–211. annexure 1: summary of included studies. annexure 1 (continues…): summary of included studies. annexure 1 (continues…): summary of included studies. annexure 1 (continues…): summary of included studies. ----..--,----1_------a crack in the dam wall i feel optimistic! i think that there is at last light at the end of the tunnel, and art access for all the hiv-infected people of south africa may just be coming into view. we have a lot to do! to date, despite the world health organisation call for expanded access, the south african public sector has had very limited access to antiretroviral agents. for art to have an impact on the south african epidemic, where it is estimated that 5 million people may already be infected, it will be necessary to establish care structures in the communities that carry most of the disease burden. implementation of a national hiv treatment programme is likely to require a variety of reproducible delivery models to senice areas with different levels of care and infrastructure. there is an urgent need to investigate the various models of art delivery available in public sector settings in south africa in order to estimate our national human resource, training and infrastructure requirements more accurately. this operational research is an amazing opportunity to inform not just ourselves but our continent and the rest of the world. there is real recognition that while there are lessons to be learnt from the developed world our situation in the developing world is different. and we need to find out what is applicable in africa, culturally and logistically time is running out in order to carry out this type of research it is often necessary to provide art to a group of research volunteers or people recruited onto programmes for a defined period of time. however, researchers find that drug supply for such research poses a catch-22 situation. a recent editorial in science describes the difficulty that has become central to the ongoing funding of operational research, about which a debate has been raging in the usa. funders have previously not provided the drugs or the finance to purchase art. the us national institute of health has recently encouraged research on the best ways to deliver art to developing countries, but it is concerned that the cost of drugs for such studies would swamp its research budget a draft policy from niaid, the aids division of the institute, states that the cost of purchasing drugs would severely restrict the institute's research capacity by limiting the number, scope, duration and focus of its international hiv-related research activities. the institute is also concerned that it would be unethical to stop treatment when the trial ends. the editorial in science quotes professor bruce walker from massachusetts general hospital in boston as saying that a limited period on drugs is better than none, that the niaids policy is less than visionary, and that it is stifling research since it is obviously a tall order to expect the researchers to come up with the drugs themselves. the policy has resulted in long waiting periods before these projects can be undertaken, while pharmaceuticals and ngos are wooed into supplying drugs. south africa has a number of internationally approved grants, where building infrastructure and implemen ation costs are paid for but funding for art remains outstanding. most of these projects involve innovative research that will teach us much abou art delivery models and operational issues around drug delivery. researchers are now trying a variety of well-worn avenues to obtain drugs so that· their research can go forward. it was refreshing and encouraging to hear recently that at least one major funder, secure the future from bristol myers squibb, is calling for operational research proposals investigating art provision and that they will provide treatment let us hope that others will overcome the difficulties and follow suit. obtaining these drugs and initiating these projects will be instrumental in breaking down some more of the obstacles to a national art roll-out in..': . south africa. l1nda-gail bekker managing editor th!: southtrn african journal of hi m!:oicin!: -----------may 2003 11 introduction antiretroviral therapy procurement strategies in egypt national treatment policies and recommendations the global effect of coronavirus disease on medication supply chain national response during coronavirus disease 2019 africa between the hammer of hiv and the anvil of coronavirus disease 2019 the african medicine agency treaty conclusion acknowledgements references about the author(s) heba elsayed national aids program, ministry of health and population, cairo, egypt mohamed hassany tropical medicine department, national hepatology and tropical medicine research institute, cairo, egypt ministry of health and population, cairo, egypt citation elsayed h, hassany m. antiretroviral therapy under the wing of the covid-19 epidemic: one look, and different solutions. s afr j hiv med. 2020;21(1), a1167. https://doi.org/10.4102/sajhivmed.v21i1.1167 scientific letter antiretroviral therapy under the wing of the covid-19 epidemic: one look, and different solutions heba elsayed, mohamed hassany received: 06 sept. 2020; accepted: 02 oct. 2020; published: 15 dec. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. introduction dear editors, we read with great interest the editorial ‘antiretroviral therapy optimization in the time of covid-19: is it really different in north and south africa?’ by cordie et al.1 and we find it an excellent opportunity to address some critical issues. with the detection of the first case of the human immunodeficiency virus (hiv) in egypt in 1986, the ministry of health and population (mohp) established the national aids program (nap) as the entity responsible for combating the hiv epidemic in the country. this task has included prevention and the care and treatment of people living with hiv (plhiv) and coordinating the efforts of stakeholders such as the united nations (un) and civil society organizations (csos).2 antiretroviral therapy procurement strategies in egypt antiretroviral (arv) drugs were first introduced in egypt in 2008. from 2008 to 2014, these were funded from the global fund to fight aids, tuberculosis and malaria (gfatm). in 2014, the mohp took the step to start covering arv drugs from domestic funding and succeeded from 2017 until now to cover 100% of egypt’s needs from the domestic funds. this has been with a view to ensure arv-sustainability and avoid the risk of stockouts. this is considered a unique initiative amongst all countries in the region.3,4 egypt has given attention to the procurement and supply management of art. clinic pharmacists were provided with a comprehensive medication policy and capacity-building standards through international experts. the latter were recruited by unicef, the agency that assists the government in the procurement of unregistered arvs. this provides art clinics with a unique stock management system.5 in 2018, the mohp encouraged local pharmaceutical companies to register all first-line arvs. this covers approximately 97% of the drugs needed by plhiv. the remaining unregistered arvs are procured via unicef.5 national treatment policies and recommendations national aids program has expanded the treatment options for plhiv in accordance with the world health organization’s (who’s) guidelines and the national context. the most recent egyptian national care and arvs guidelines were published in 2015. these were followed in 2017 by a summary update. this adopted a ‘test and treat/treat all’ approach that supplies arvs to all plhiv regardless of their cd4 count or viral load level. this update included the introduction of dolutegravir (dtg) as an alternative first-line option to efavirenz (efv) as per the who recommendations.6 tenofovir disoproxil fumarate + emtricitabine (tdf + ftc) is the preferred nucleoside reverse-transcriptase inhibitor (nrti) first-line art backbone. as per our national guidelines, tdf + ftc + efv is the currently preferred first-line regimen. an alternative nrti backbone is the combination of zidovudine (azt) and 3tc, which is registered and manufactured locally.7 the global effect of coronavirus disease on medication supply chain with the evolution of the coronavirus disease 2019 (covid-19) pandemic, all countries have taken measures to control the spread of the infection. as a result of the lockdown and the interference with international flights, global health systems have faced the potential of medicine stock-outs. seventy-three countries reported such a risk of arv stockouts.8 based on a recent unaids study that explores challenges facing global hiv programmes, reduced production and availability of active pharmaceutical ingredients (apis) and issues with transportation have negatively affected dependent regions.9 remedial action has been required by countries and stakeholders. national response during coronavirus disease 2019 the egyptian nap has taken steps to support plhiv during the covid-19 epidemic. these include prolonging arv-dispensing intervals beyond a month, strengthening teleconsultation services, ensuring ongoing follow-up of covid-19-infected plhiv and assisting with their admission to isolation hospitals and subsequent care. since the start of the pandemic and the confirmation of egypt’s first covid-19 case in february 2020,10 a ‘partial-lockdown’ model has allowed continued access to medication via a medicines stockpile, the government’s cargo fleet and airline support. these measures protect egypt from exposure to a significant stockout or delayed arv access. africa between the hammer of hiv and the anvil of coronavirus disease 2019 africa has a large hiv burden: ongoing new hiv infections, approximately 500 000 hiv-related deaths in 2018 and at least a third of plwh still not accessing art.11 multiple factors have undermined the continent’s ability to end the hiv epidemic. some of these factors are persisting civil wars, tribal conflicts, natural disasters, poor health systems and weak infrastructure.12 these factors have created an art coverage-gap of 59% in eastern and southern africa, 79% in western and central africa and 89% in north africa.13 this situation has worsened subsequent to the covid-19 epidemic. nonetheless a number of north african countries have low hiv prevalence rates, namely less than 0.1% and have been ‘protected’ from these covid-19-related art problems.14 at the end of september 2020, the number of covid-19 cases in africa has approached a million and a half with nearly 35 000 deaths.15 a who modelling study projects that the number of covid-19 cases in the first year of the pandemic in africa will reach between 29 and 44 million and of this between 190 000 and 290 000 will die.16 these data suggest a continuous reappraisal of the effects of covid-19 by african government and the possible art shortages. key challenges (figure 1) overlapping challenges that may affect the arvs supply chain: countries’ lockdown measures economic challenges because of the reduction or stoppage of all the economic activities the subsequent decrease in api and intermediate pharmaceutical ingredients’ production capacities lead to increased api costs slow shipments and reduced access to medicines. figure 1: challenges and solutions in the medication supply chain under coronavirus disease 2019 pandemic. key solutions with the easing of the lockdown measures the following solutions are surfacing: alternative procurement sources and long-term forecasting plans to enhance drug stocking manipulating different ways of shipping resource mobilisation and the waiving of national taxes to maintain stable pricing levels support from global funding agencies and concerned un agencies. the african medicine agency treaty the establishment of the african medicine agency (ama) treaty may assist countries in africa cope with covid-19 and hiv.17 this coincides with activities of the third specialised technical committee on health, population and drug control (stc-hpdc-3) held in cairo in august 2019. sixteen african countries (algeria, benin, chad, ghana, madagascar, mali, morocco, rwanda, saharawi arab democratic republic, senegal, tunisia, seychelles, niger, guinea, sierra leone and burkina faso) officially signed the treaty. the ama is considered to be the first continental initiative to integrate the regulations of medicines and medical products thereby ensuring the provision of safe and effective drugs and medical products to the people. the treaty also aims to strengthen africa’s capacity to produce medicines by utilising available production capacity and unifying standards and product registration across the continent. such a treaty will allow drugs manufactured or registered in one african country to be deployed elsewhere on the continent without further regulatory constraints. this will in turn widen the availability and variety of drugs and augment competition amongst api providers to ensure that medicines can be offered at an optimum and affordable price. conclusion the covid-19 pandemic requires both a shortand long-term strategy to overcome the anticipated shortages of hiv-related healthcare services at national level. in parallel with this, multisectoral international solidarity and collaboration with global stakeholders needs to be continued and fostered to achieve the 90-90-90 unaids hiv-elimination goals and manage covid-19 successfully. acknowledgements competing interests the authors have declared that no competing interests exist. authors’ contributions all authors contributed equally to this work. ethical consideration this article followed all ethical standards for research without direct contact with human or animal subjects. funding information this research received no specific grant from any funding agency in public, commercial or not-for-profit sectors. data availability statement data sharing does not apply to this article, as no new data were created. disclaimer the mentioned opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references cordie a, el-kotamy m, esmat g. antiretroviral therapy optimisation in the time of covid-19: is it really different in north and south africa? s afr j hiv med. 2020;21(1):a1118. https://doi.org/10.4102/sajhivmed.v21i1.1118 shawky s, soliman c, kassak km, oraby d, el-khoury d, kabore i. hiv surveillance and epidemic profile in the middle east and north africa. j acquir immune defic syndr. 2009;51(suppl 3):s83–s95. https://doi.org/10.1097/qai.0b013e3181aafd3f haakenstad a, moses mw, tao t, et al. potential for additional government spending on hiv/aids in 137 low-income and middle-income countries: an economic modelling study. lancet hiv. 2019;6(6):e382–e395. https://doi.org/10.1016/s2352-3018(19)30038-4 global aids monitoring 2019, country progress report, egypt [homepage on the internet]. [cited 2020 sept 26]. available from: https://www.unaids.org/sites/default/files/country/documents/egy_2019_countryreport.pdf explore hiv/aids programme, unicef egypt website [homepage on the internet]. [cited 2020 sept 26]. available from: https://www.unicef.org/egypt/hivaids who updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of hiv, interim guidance [homepage on the internet]. [cited 2020 sept 26]. available from: https://www.who.int/hiv/pub/guidelines/arv2018update/en/ who update of recommendations on firstand second-line antiretroviral regimens [homepage on the internet]. [cited 2020 sept 26]. available from: https://www.who.int/hiv/pub/arv/arv-update-2019-policy/en/ who newsroom, access to hiv medicines severely impacted by covid-19 as aids response stalls [homepage on the internet]. [cited 2020 sept 26]. available from: https://www.who.int/news-room/detail/06-07-2020-who-access-to-hiv-medicines-severely-impacted-by-covid-19-as-aids-response-stalls unaids press release, covid-19 could affect the availability and cost of antiretroviral medicines, but the risks can be mitigated [homepage on the internet]. [cited 2020 sept 26]. available from: https://www.unaids.org/en/resources/presscentre/pressreleaseandstatementarchive/2020/june/20200622_availability-and-cost-of-antiretroviral-medicines hassany m, abdel-razek w, asem n, abdallah m, zaid h. estimation of covid-19 burden in egypt. lancet infect dis. 2020;20(8):896–897. https://doi.org/10.1016/s1473-3099(20)30319-4 afro who health topics [homepage on the internet]. [cited 2020 sept 26]. available from: https://www.afro.who.int/health-topics/hivaids martial np, sieleunou i. an appeal for large scale production of antiretroviral drugs in africa. pan afr med j. 2016;25(261):18. https://doi.org/10.11604/pamj.2016.25.18.10658 access to antiretroviral therapy in africa, status report on progress towards the 2015 targets [homepage on the internet]. [cited 2020 sept 26]. available from: https://www.unaids.org/sites/default/files/media_asset/20131219_accessartafricastatusreportprogresstowards2015targets_en_0.pdf africa development information [homepage on the internet]. [cited 2020 sept 26]. available from: http://www.afri-dev.info covid-19 worldmeter [homepage on the internet]. [cited 2020 sept 26]. available from: https://www.worldometers.info/coronavirus/ gaye b, khoury s, cene cw, et al. socio-demographic and epidemiological consideration of africa’s covid-19 response: what is the possible pandemic course? nat med. 2020;26(7):996–999. https://doi.org/10.1038/s41591-020-0960-y african medicine agency (ama) treaty [homepage on the internet]. [cited 2020 sept 26]. available from: https://au.int/en/pressreleases/20200205/african-medicine-agency-ama-treaty hiv_nov04 the southern african journal of hiv medicine november 2004 3 with the national arv roll-out underway, despite being somewhat slower than was hoped, antiretrovirals (arvs) are now recognised as the standard of care for appropriately staged hiv-infected south africans in both the private and public health care sectors. as american and local experts point out in their article ‘managing hiv as a chronic disease’ (p. 7), highly active antiretroviral therapy (haart) results in significantly better survival rates but requires a streamlined system, a multidisciplinary approach, accurate data collecting and statistical analyses, and the full support of clinics and the community. clearly the public hospitals cannot carry on taking the brunt of the pandemic, as shown in research conducted at red cross children’s hospital in cape town (p. 32) confirming that current admission policies regarding inpatient treatment of hiv/aids appear unsustainable. this is of great concern, as the hiv prevalence in the western cape lags behind that of other provinces and sub-saharan africa. with finite resources (including money, health care workers and hospital beds) this is another compelling reason to speed up the arv roll-out in all provinces, i.e. to reduce the present high admission rates for opportunistic infections and terminal care. in developing countries there is a huge need to incorporate hiv/aids into the health care system as another chronic disease, as opposed to creating parallel structures for hiv infection, which is time consuming and unnecessary. optimal use of human resources and appropriate division of labour, coupled with adequate training in the long-term management of hiv infection, is essential. this means the full continuum, from voluntary counselling and testing (vct) through the early (pre-art) stages, to haart and eventually terminal care. with this in mind, a society guidelines committee met in johannesburg recently to formulate pre-art guidelines to assist health care workers through the phases before hivpositive patients require haart (p. 18). any comments on this document would be welcomed. approximately 90% of patients will develop one or more skin diseases during the course of their infection. kzn dermatologist, dr ncoza dlova, shares her experience and visuals of hiv-associated dermatological conditions with us in a series of articles. in part 1 (p. 12), dr dlova points out that the course of cutaneous manifestations is completely different in patients on antiretroviral therapy and those who are not, generally being less severe and chronic in patients on haart. another compelling reason to hope for a stepping up of the provision of arvs at approved public sector sites. constant talk about arvs in both the private and the public sector is certainly not all that is on our minds. reduction of transmission is a vital part of any successful hiv/aids plan. two articles in this issue deal with different aspects of this problem, which seems to confound us in south africa. in the first, steve andrews and marilyn keegan address the wellknown role of transport workers in global and national spread of hiv in a novel way. they stress the importance of interventions at rest places, lending credence to the importance of the place method (which aims to improve prevention programme coverage at geographical sites at which hiv transmission is most likely to occur). another prevention of transmission issue, the breast-feeding debate, is addressed in an article and a letter to the editor, so read on … des martin editor, southern african journal of hiv medicine president, southern african hiv clinicians society f r o m t h e e d i t o r about the author(s) david c. spencer division of infectious diseases, department of medicine, helen joseph hospital, university of the witwatersrand, johannesburg, south africa citation spencer dc, editorial. s afr j hiv med. 2019;20(1), a1037. https://doi.org/10.4102/sajhivmed.v20i1.1037 editorial editorial david c. spencer copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. dear members of the southern african hiv clinicians’ society and readers of the southern african journal of hiv medicine. this is an update of articles published in the sajhivmed between may and july 2019. we hope that by going through this summary you will visit the journal and look at the published material yourself. the articles address contemporary and regional issues in hiv medicine. the topics speak to all aspects of the epidemic: epidemiology, public health, prevention, clinical medicine, tuberculosis and opportunistic diseases, management guidelines, opinion pieces, editorials and case reports. for the teachers, trainers, healthcare managers and administrators among us, there is a wealth of local information in these papers. please acknowledge our talented researchers by reading what they write. i am sure you will want to thank the authors, our reviewers and our publishers (aosis). i wish you an enjoyable read with the southern african journal of hiv medicine. may 2019 aigbodion sj, motara f, laher ae. occupational blood and body fluid exposures to human immunodeficiency virus post-exposure prophylaxis. south afr j hiv med. 2019;20(1):a958. https://doi.org/10.4102/sajhivmed.v20i1.958 recommended reading: this is a must-read for all practising in the southern african region and for final-year medical students in particular who will soon become interns and nurses who are already working on the wards of our hospitals. this is a well-written, descriptive (anonymous questionnaire), cross-sectional study reflecting the experience over 2 years of interns exposed to hiv-positive blood or body fluids in four large gauteng public hospitals affiliated to the university of the witwatersrand. the study data were collected at the end of 2017 from 175 doctors aged 24–30 years who collectively provided n = 182 incidence reports of occupational exposure to hiv, served as the sample for the study. the prevalence of exposure was more or less identical whether the intern was gaining experience in surgery, obgyn or medicine. more than a fifth (n = 30, 22%) had more than one exposure. while most initiated post-exposure therapy within 24 h (79% on first-exposures, and 89% on their third exposure) only two-thirds viz. 63% (first exposure) and 62.5% (third exposure) completed the 28-day antiretroviral (art) course. (how many started art within 2–4 h?) taking all exposures into account, the full 28-day course was completed by only n = 51 (36.2%). a third took only two antiretrovirals (arvs) as post-exposure prophylaxis (pep). a total of n = 33 (18%), were unaware of alternative treatment options. two (1.1%) seroconversions are reported and documented. are the number of arvs used in pep important? ‘there is no evidence to suggest that a three-drug regimen is superior to a two drug regimen’. the authors do not seem to think so. they have a point. but not all arvs are equal in potency nor do all offer the same level (barrier) to viral resistance. three-drug regimens, usually boosted protease inhibitor (bpi) based, reflect a time when arvs were generally less potent or more toxic than now and when regimens that combined different classes of arv demonstrated greatest efficacy. the authors acknowledge limitations: the cross-sectional and retrospective nature of the data, the limited range of the questions and insufficient data on exposure to art-resistant virus. pep studies cannot be randomised controlled trials nor can they be placebo-controlled. these studies are therefore important despite their limitations. ps: the 2019 southern african hiv clinicians’ pep guidelines are under preparation and will be available in this journal early in 2020. if i was a prospective intern, i would be hoping that my senior in the unit would give me complimentary copies of these two articles before i started work! nb the society’s last pep guidelines were formulated in 2015. a more up-to-date edition is recommended. 2. mndzebele s, matonyane lg. sexual behaviours, awareness and perceptions towards voluntary medical male circumcision among students in dr kenneth kaunda district, south africa. south afr j hiv med. 2019;20(1):a846. https://doi.org/10.4102/sajhivmed.v20i1.846 editor’s comment: this cross-sectional, questionnaire-based, descriptive study on attitudes of young male south african college students towards medical male circumcision revealed that the 351 participants had high levels of knowledge and understanding of the procedure and its benefits. many of the students were themselves circumcised viz. 77.6%, and had chosen to have mmc (78.2%). is this a changing trend in sa? 3. edet a, akinsola ha, bessong pa. virologic and immunologic responses of patients on highly active antiretroviral therapy in a rural community health centre in limpopo, south africa: a retrospective study. south afr j hiv med. 2019;20(1):a818. https://doi.org/10.4102/sajhivmed.v20i1.818 editor’s comment: recommended reading – a study that ought to be read by all. this retrospective analysis records data spanning 12 years (2004–2016) and asks the question, ‘what are the long-term immunologic (cd4) and virologic (viral load) consequences of art in a rural region of south africa’. ‘is (rural) sa on the road to achieving the joint united nations programme on hiv and aids (unaids) 90-90-90 goals?’ ‘will universal art in this rural region offer the reward of “treatment as prevention,” that is long-term viral suppression and no further viral transmission?’ the study is well set-out and very easy to follow. a total of 1247 patients were followed. all had to have been on art for a minimum of 6 months. the analysis suggests that achieving the 90-90-90 goal is unlikely: viral suppression at < 50 cp/ml after 6 months, 12 months, 24 months, 36 months and 132 months after starting art is 64%, 70%, 70%, 69% and 94%, respectively. the last percentage can be ignored as only 16 patients were available to be assessed at 12 years. n = 882 (59%) recorded two or more consecutive viral loads < 50 cp/ml? but only 14% had persistent viral load suppression at < 50 cp/ml for the initial 54 months of the study. will rural sa reach the unaids 90-90-90 goal by 2020? will viral transmission come to an end any time soon? the answers are all too obvious after reading this intelligent and readable article. ps. if you teach hiv medicine, this is a useful study to have in your repertoire. 4. essa r, maharaj s, hari k, motakef s. tonsil histopathology in hiv-infected versus hiv-uninfected adults. south afr j hiv med. 2019;20(1):a936. https://doi.org/10.4102/sajhivmed.v20i1.936 editor’s comment: this is a retrospective histological review covering 10 years (2005–2015) of adult tonsillectomies in the department of otorhinolaryngology (ent)/head and neck surgery at the university of the witwatersrand in johannesburg. although the results are divided into two categories, viz. hiv-infected (n = 84) and hiv-uninfected (n = 74), the study is largely descriptive and there is no attempt to link findings with patient demographics, cd4 results, viral loads and the clinical details of the cases. statistical and comparative data are, for the most part, left unexplored. although reactive lymphoid hyperplasia was the most frequent histological finding in both arms viz. 77% in hiv-positive and negative, no data are provided to explain the cause of the reactive hyperplasia in the hiv-uninfected group. were other viruses, for example, ebv, cmv, hpv, hhv8 and others implicated? 5. moorhouse m, cohen k. the role of rilpivirine in southern africa. south afr j hiv med. 2019;20(1):a825. https://doi.org/10.4102/sajhivmed.v20i1.825 editor’s comment: recommended reading. this is a comprehensive review of the role of rilpivirine (rpv) in the context of art, pre-exposure (prep) and pep in public sector programmes of low-and middle-income countries (lmics). the authors address regional art-issues that will impact on rpv use viz. irregular or unavailable viral load testing, rpv’s loss of efficacy in the context of high (baseline) viral loads, rifampicin and rpv (tuberculosis therapy), rpv and dolutegravir (dtg), other drug–drug interactions and long-acting rpv in future prep and pep programmes. the findings are quite interesting and relevant. ps: for those who are writing exams later this year or in early 2020, this is a must-read. but for all of us, this is a nuts-and-bolts review that deserves to be read. june 2019 6. manjengwa pa, mangold k, musekiwa a, kuonza lr. cognitive and behavioural determinants of multiple sexual partnerships and condom use in south africa: results of a national survey. south afr j hiv med. 2019;20(1):a868. https://doi.org/10.4102/sajhivmed.v20i1.868 editor’s comment: recommended reading. this is another well-crafted paper. it is a cross-sectional and descriptive report that draws upon the third national hiv survey of 2012. the researchers ask why south africans continue to take risks. two high-risk groups are defined: those with multiple sexual partners (msps) and those who do not use condoms consistently viz. non-condom users (ncu). the parent survey included 10 034 people. this study employs a sample of 6061 people who provided information about sexual behaviour in the preceding 12 months. thirteen per cent (n = 744/6061) were msps and 53% (n = 3158/6039) were ncus. respondents in the msp group indicated that ‘perceived benefits’ (adjusted odds ratios, aor = 2.16) and a related issue, intergenerational sex (aor = 2.14), and non-susceptibility to hiv, that is irrational beliefs like ‘it won’t happen to me’, lay behind their actions. similar reasoning defined the responses of the ncus: perceived benefits (aor = 1.25), non-susceptibility to hiv (aor = 1.6) and my ‘personal belief’ (aor = 1.35). these irrational and dangerous responses jeopardise attempts to bring the epidemic to an end. i recommend this paper for further reading. is our community aware of these data? and would that make any difference? 7. sharp j, wilkinson l, cox v, cragg c, van cutsem g, grimsrud a. outcomes of patients enrolled in an antiretroviral adherence club with recent viral suppression after experiencing elevated viral loads. south afr j hiv med. 2019;20(1):a905. https://doi.org/10.4102/sajhivmed.v20i1.905 editor’s comment: patients at high risk of treatment failure (n = 165) were enrolled in an adherence club rather than being retained in their parent treatment facility viz. ubuntu clinic, khayelitsha, western cape, sa. most of the patients (81.8%) were women. enrolment started in 2012–2014 and the study ended in mid-2015. data were analysed retrospectively. the target population had demonstrated difficulty with art adherence prior to their integration into the study. the outcomes with regard to both retention in care viz. 98% (6 months), 95% (12 months) and 89% (18 months) and viral suppression viz. < 400 cp/ml, 90% (6 months), 84% (12 months) and 75% (18 months) are comparable with those of clinic-based adherence studies elsewhere. this is a clearly written article with an important message: with commitment from patients and the caregiver, high-risk patients can be accommodated within a ‘differentiated’ model of art delivery. limitations? i would watch the 18-month numbers down the line and would want data that are more inclusive of men in the western cape. despite the absence of a control group, the retrospective nature of the study and the incomplete tracing of those lost to follow-up, it nevertheless is a good read. 8. coetzee m, delport sd. peripartum hiv infection in very low birth weight infants fed ‘raw’ mother’s own milk. south afr j hiv med. 2019;20(1):a912. https://doi.org/10.4102/sajhivmed.v20i1.912 editor’s comment: an important paper to read. this is another retrospective study that identified 80 very low birth weight (< 1500 g) infants born to hiv-infected mothers between 2010 and 2013. the authors are paediatricians from kalafong hospital in pretoria. two (2.5%) of the 80 infants tested hiv-positive after birth. neither mother had been on art during pregnancy. sixty-three infants (79%) had been exposed to maternal art during pregnancy. none tested positive at the 4–6 week follow-up clinic visit. the two infants who were infected belonged to a group of 17 art-naïve mothers. all the newborns received nevirapine prophylaxis. all were given mother’s milk – ‘raw mother’s milk’. a small group (n = 21/80, 26%) required additional breast milk given by donors. when did the two acquire infection? was the ‘raw’ breast milk the source of virus or infection? the authors argue not. both children developed clinical signs of ‘acute’ hiv seroconversion shortly after birth. they tested hiv-polymerase chain reaction (pcr) positive on day 9 and day 20 respectively. neither had been tested at birth. the authors did a good job of taking the reader through the complicated evolution of mother-to-child hiv prevention in the last decade in south africa. current goal posts viz. birth testing of all exposed infants and universal hiv testing and treatment of all, ought to pre-empt the loop-holes identified in this study. this paper is an important read. very low birth weight newborns are at-risk people who require focused care. 9. lazarus e, otwombe k, dietrich j, et al. vaginal practices among women at risk for hiv acquisition in soweto, south africa. south afr j hiv med. 2019;20(1):a866. https://doi.org/10.4102/sajhivmed.v20i1.866 editor’s comment: this is a observational study spanning a period of 3 months (august 2014 – april 2015) and involving 50 hiv-uninfected sowetan women aged between 18 and 25 who provided questionnaire-directed answers investigating the frequency and nature of post-coital vaginal ‘cleansing’ practices. do vaginal practices increase the risk of hiv acquisition, that is by causing low-level, but recurrent trauma to the genital tract? the aim of the study was to describe local practice. the authors note that south africa’s overall hiv prevalence among 20–24 year-olds is 16% and in gauteng where this study was performed, prevalence in the general population is 18%. exposure to infection was high. on average, the study group recorded having sex 15.3 times per month with their main partner, having casual sex 10 times per month and having sex with a ‘new’ casual partner 3.6 times per month. condom use was rare. however, this increased over the course of the study viz. 2% at baseline to 20% (main partner) and to 56% (casual partner) by the end of the study. no hiv infections occurred. cleansing practices included washing the vagina with water (44%) and using fingers to facilitate cleaning (48%) and were more likely practised after inconsistent condom use or sex with a casual partner, p = 0.001. these practices decreased over the course of the study. despite being asymptomatic, 40%, n = 20 women had positive baseline lab tests for a genital tract infection. 10. kateule e, kumar r, mwakazanga d, mulenga m, daka v, chongwe g. a cross-sectional study of the factors associated with male circumcision status among college youth in ndola, zambia. south afr j hiv med. 2019;20(1):a952. https://doi.org/10.4102/sajhivmed.v20i1.952 editor’s comment: this report discusses the knowledge, attitudes and perceptions of 136 male zambian students with regard to male circumcision and voluntary medical male circumcision (vmmc) in particular. a total of 63% of the students had been circumcised and most (96%) had taken the formal medical route viz. vmmc. this study has several limitations: cohort-bias, the observational nature of the data, self-reporting by the students and ‘predictable’ results, for example the circumcised students viewed the procedure as safe (aor = 5.13, ci = 2.09–14.82), and effective in reducing viral transmission from infected women to uninfected men (aor = 3.65, ci = 3.12–11.67). (note the wide confidence intervals). the 2012–2015 national coverage of vmmc in zambia was only 54% while the adult prevalence of hiv was 12.3% (zamphir fact sheet, december 2016). what is it that makes adult men complacent in the face of this epidemic? this study does not provide the answer but certainly begs the question. 11. chakalisa u, wirth k, bennett k, et al. self-reported risky sexual practices among adolescents and young adults in botswana. south afr j hiv med. 2019;20(1):a899. https://doi.org/10.4102/sajhivmed.v20i1.899 editor’s comment: recommended reading. this is an important substudy of a cross-sectional, cluster-randomised combination prevention project based in botswana: the ‘yatsie project’. the aim of the parent study is to evaluate the impact of interventions on the prevention of hiv in that country. the aim of the substudy was to identify and characterise the risk-taking sexual activities that promote viral transmission. the findings of the substudy are not surprising: self-reported risk-taking sexual behaviour of adolescents and young adults differs between males and females. subjects were aged 16–24 years. of the 3380 study participants, n = 2311 reported being sexually active viz. women (65%) and men (35%). enrolment took place from october 2013 to november 2015. univariate and multivariate data underline the importance of the following markers of risk among women: inconsistent condom use, intergenerational sex (with male partners > 10 years older) and transactional sex among the poor. on the other hand, women were less likely than men to report being sexually active before 15 years, to use alcohol at or during intercourse and to report ≥ 2 (multiple) sexual partners in the preceding 12 months. men living close to urban areas and those with internet access were at greater risk of being hiv-positive. this paper is a must-read for health workers and administrators across southern africa. success of hiv prevention has been elusive in this age group. treatment as prevention will take us far. but papers such as this provide tools that communities can use to facilitate change. 12. mukumbang fc, van wyk b, van belle s, marchal b. ‘at this [adherence] club, we are a family now’: a realist theory-testing case study of the antiretroviral treatment adherence club, south africa. south afr j hiv med. 2019;20(1):a922. https://doi.org/10.4102/sajhivmed.v20i1.922 editor’s comment: ‘how successful are adherence clubs actually?’ this paper examines two adherence clubs associated with a provincial public health facility in the western cape (facility y) and provides a theoretic explanation (‘realist evaluation’) as to how and why clubs work. the authors remind us that ‘only 62.3% of all people living with hiv (plhiv) in south africa are virally suppressed’, (www.hsrc.ac.za/uploads/pagecontent/9234/finalpresentationsfor17julylaunch.pdf.) and that only 63.3% of infected south africans are retained in the national south african hiv healthcare programme (fox et al. plos med 2018;15:30–43) without a cure in sight, south africa needs a long-term programme that delivers stronger numbers. although much of the paper is taken up with providing a coherent thesis, the discussion and case evaluation provide practical steps to assist with improving outcomes from adherence clubs. figure 4 in the article is a useful summary of the thesis. 13. bisschoff c, coulon j, isaacs z, et al. hiv testing at birth. are we getting it right? south afr j hiv med. 2019;20(1):a951. https://doi.org/10.4102/sajhivmed.v20i1.951 editor’s comment: this is a brief retrospective, descriptive, file-audit of births to hiv-positive mothers at the mangaung university community health centre, bloemfontein, south africa, during 2016. a third of all the mothers treated at the clinic in 2016 tested hiv-positive. a total of 428 babies were born to these mothers. out of the infected mothers 7.3% were teenagers. testing at birth (pcr) was conducted in 87.6% of the hiv-exposed infants of whom four (1.1%) were positive. while birth pcr testing levels are commendable, only n = 157 (36.7%) of exposed infants had the recommended 10-week follow-up hiv-pcr test. almost all exposed infants (n = 427, 99.8%) were given nevirapine prophylaxis. did any of the infected children start on art? ‘no records were kept’. while prevention of mother-to-child transmission (pmtct) has been a great success, gaps in care still exist. a third of the mothers in 2016 were hiv positive…!? ouch!! july 2019 14. solomons dj, van der merwe a, esterhuizen tm, crowley t. factors influencing the confidence and knowledge of nurses prescribing antiretroviral treatment in a rural and urban district in the western cape province. south afr j hiv med. 2019;20(1):a923. https://doi.org/10.4102/sajhivmed.v20i1.923 editor’s comment: nimart stands for nurse-initiated and (nurse) managed antiretroviral treatment. this is a cross-sectional survey conducted among 77 nimart nurses recruited from 29 healthcare centres in the western cape province of sa. the study covered both urban and rural nurses and aimed to identify factors influencing the nurses’ knowledge base and managerial or clinical confidence. important limitations are noted by the authors: the cross-sectional and retrospective design, the small cohort, the large numbers of nurses who despite being nimart ‘authorised’, nonetheless refused to participate in the study viz. n = 18 (25%) rural nurses and n = 22 (33%) urban nurses. potential biases, for example the ‘self-completing’ of the questionnaires, may have led to further limitations. nonetheless, many nurses (50%) indicated high levels of confidence with regard to the nursing aspects of hiv patient management and examination. but importantly, only 14% felt themselves to be expert enough in the day-to-day interaction with patients, and in particular, with the switching and stopping of art. contact with a ‘clinical mentor or clinician’ was limited for almost half (n = 36/77, 47%): once a week (n = 19), once a month (n = 14) and annually (n = 3). the replies of some are worrying: ‘no’ (n = 34, 44%), when asked ‘do you feel your workload is acceptable?’, and ‘no’ (n = 37, 48%), when asked ‘are you satisfied with your work conditions’. not surprisingly, the study found that training, personal feedback, mentoring and seeing or caring for lots of patients had positive results with respect to knowledge and confidence. the small print is what worries me. nimart-trained nurses are a precious asset to south africa’s hiv response. i am worried because of those nimart nurses who refused to participate and those who did, yet expressed unhappiness with their situation. how widespread are these attitudes and views? 15. chateau av, dlova nc, dawood h, aldous c. outcomes of stevens–johnson syndrome and toxic epidermal necrolysis in hiv-infected patients when using systemic steroids and/or intravenous immunoglobulins in pietermaritzburg, south africa. south afr j hiv med. 2019;20(1):a944. https://doi.org/10.4102/sajhivmed.v20i1.944 editor’s comment: this retrospective study involving 36 hiv-positive patients reports the outcome of stevens–johnson syndrome (sjs), toxic epidermal necrolysis (ten) and the sjs–ten ‘overlap’ syndrome during the 18-month period, january 2010–july 2011. short-term (3-day) oral steroids and intravenous immunoglobulins (ivig) were used in all. active debridement of bullae, de-roofing of blisters among others, was avoided in favour of careful skin cleansing. out of the 36 patients 32 were female. sixteen were pregnant. almost all (93.8%) were on nevirapine at the time of admission and the mean cd4 count of the group was 267 cells/mm³ (sd 60.6). ten (27.8%) were also taking anti-tuberculosis drugs, isoniazid (n = 2) and rifafour (n = 8). one pregnant patient died. no adverse steroid-related events were identified. unfortunately, the study has not provided more recent data. i would love to know if the disappearance of nevirapine from most art programmes has resulted in the disappearance of these life-threatening skin conditions? nevirapine is no longer a regular part of local and international art guidelines. (meintjes g, moorhouse ma, carmona s, et al. adult antiretroviral therapy guidelines 2017. s afr j hiv med. 2017;18(1):a776. https://doi.org/10.4102/sajhivmed.v18i1.776) 16. munderi p, were e, avihingsanon a, et al. switching at low hiv-rna-1 rna into fixed-dose combinations: tdf/ftc/ rpv is non-inferior to tdf/ftc/efv in first-line suppressed patients living with hiv. south afr j hiv med. 2019;20(1):a949. https://doi.org/10.4102/sajhivmed.v20i1.949 editor’s comment: highly recommended. this paper details the results of the salif study (salif = switching at low hiv-1 rna into fixed-dose combinations). the study was conducted between august 2012 and october 2015 in five sub-saharan countries viz. cameroon, kenya, senegal, south africa and uganda and one asian country, thailand. it is a phase 3b, randomised, open-label, non-inferiority first-line art switch-study that introduced rpv to virologically suppressed (hiv-rna < 50 cp/ml) patients who had completed ± 12 months of either efavirenz (55%) or nevirapine (45%). the backbone nucleoside reverse transcriptase inhibitors (nrti) component of the regimen was tenofovir (tdf) + emtricitabine (ftc) before and after the switch. the rpv switch required the following: virological suppression (viral load < 50 cp/ml), cd4 count > 200 c/mm³, a normal baseline electrocardiograph (ecg) and the absence of concurrent tuberculosis (tb) therapy. of the total cohort of 426 subjects, half (n = 211), that is the comparator arm, either continued with tdf+ftc+efv throughout the study or switched to efv from nevirapine (nvp) after an initial ± 12 months on tdf + ftc + nvp. the rpv arm, n = 213, switched to rpv + tdf + ftc having completed an initial 12 months on tdf + ftc + efv. both drug combinations were administered as single-tablet combination regimens (strs). the rpv arm met the 48 week efficacy viz. ≥ 10% non-inferiority criteria and rate of virological failure requirements viz. viral suppression (< 400 cp/ml); rpv arm, n = 200/213 (93.8%) and efv arm, n = 203/211 (96.2%). more subjects discontinued the study in the rpv arm (8%) as compared to the efv arm (4.7%), (n = 27). this appeared to have been driven by an increase in adverse events (3.3% vs. 0.5%) in the rpv arm and an unanticipated closure of one of the study sites. the number of discontinuations is small. the increase in adverse events has not been previously reported in similar rpv versus efv studies. dr moorhouse and dr cohen provide an opinion piece on rpv use in south africa in the sajhivmed of the 29th may this year. (see item no. 5 discussed earlier). moorhouse et al. focus on the limitations of rpv in first-line art in sa viz. baseline viral loads are unchecked in the public sector, many needing to start art in sa present with low cd4 counts < 200 c/mm³, many in sa are already undergoing tb (rifampicin) therapy and the recording of baseline qt-intervals in south africans initiating art is not routine. nevertheless, munderi’s paper suggests that a novel role for rvp, for example first-line switch studies, remains an option in those who satisfy the criteria. this is a thoughtful and well-written paper. 17. lilian rr, rees k, mabitsi m, mcintrye ja, struthers he, peters rph. baseline cd4 and mortality trends in the south african human immunodeficiency virus programme: analysis of routine data. south afr j hiv med. 2019;20(1):a963. https://doi.org/10.4102/sajhivmed.v20i1.963 editor’s comment: highly recommended. this paper reviews hiv changes viz. in mortality and cd4 numbers at presentation, in south africa from 2004 to 2016. the tables and figures provide a very clear window as to what is happening in this region. the university of cape town’s tier.net database provided the n = 203,131 and n = 101,814 anonymised patient records of the respective johannesburg (jhb) and mopani (mpi, limpopo, rural) regions analysed. the paper focuses on mortality in relation to cd4 counts < 200 c/mm³. it also draws attention to the post-2013 decline in art initiations in both regions – despite the fact that neither has yet achieved the 90-90-90 goals of the unaid and the world health organization (who). in both regions, it is women who outnumber men with regard to art initiations viz. 63–67% jhb and 68% mpi. in their analysis of the meaning of a low baseline, that is, cd4 count < 200 c/mm³ at art initiation, this is the group with the highest early mortality after starting art and over a 5-year period. the data are significant (p < 0.001) whether urban or rural. the risk is still present in the 2016/2017 data. the percentage of those initiating art at these low levels remains high at this time viz. ± 40% in jhb and 35% in mpi. who are the ones who are at greatest risk of initiating art at low cd4 levels? men, the elderly, the hospitalised. the authors make the point – not new – that these citizens of sa are not invisible to society. this is a very thought-provoking study. for those among us who teach medicine, this paper has robust data, excellent tables and figures and a great deal to talk about. this paper is a must-read for all our hiv clinicians’ society members. 18. rossouw tm, van dyk g, van zyl g. rapid emergence of resistance to antiretroviral treatment after undisclosed prior experience: a case report. south afr j hiv med. 2019;20(1):a965. https://doi.org/10.4102/sajhivmed.v20i1.965 editor’s comment: this is a short case report of a 43-year-old female whose prior exposure to first-line art (2012–2013) was revealed following failure of what had been believed to be the patient’s first exposure to art in july 2014. genotype testing at the commencement of art in july 2014 failed to reveal viral mutations. however, these emerged after the (re)start of antiviral therapy. this report is a reminder that failure to suppress hiv after first-line therapy must trigger the possibility of prior exposure to arvs in addition to inadequate adherence. a comprehensive medical history must always include questions about prior art exposure. tht southtrn african journal of hiv mtolcint -----------hhruary 200 i prevention if taken within 2 hours of occupational exposure, post-exposure prophylaxis (pep) reduces the risk of seroconversion by approximately 800/0. it is now recommended that health care workers take pep within 72 hours following needlestick injury. no reliable data exist for pep in rape victims, but trials done in san francisco' and france' suggest that effectiveness may be as high as 10001o if pep is taken within 72 hours of the incident. unfortunately, it took a tragic incident in which a 15year-old girl was gang-raped after the intruders had murdered both her parents, for me to realise how inadequate the system was. in march 1998 the sunninghill hospital rape crisis centre was opened. after extensive literature research and discussions with experts nationally and internationally, basic protocols and guidelines were drawn up. at antenatal clinics were infected with hiv. the various statistics are endless and horrifying as medical professionals what are we doing to alleviate the problem? overview of medical management of victims of sexual abuse a h wulfsohn, mb bch head, sunninghil1 hospital accident and emergency unit, and medical director, albertina sisulu rope crisis centre, johannesburg statistics from unisa (march 1999) show that one in two south african women will be raped.' in 1999 childline showed that 1 in 4 girls and 1 in 5 boys under the age of 16 years will have been sexually molested.' in may 2000 the department of health showed that 20010 of girls aged between 13 and 19 years and seen as general medical practitioners, few of us have seen and managed rape victims on a regular basis. a major reason for this is that until recently only district surgeons saw and treated rape victims. however, if one takes the time to read the various provincial health departments' medica-legal services guidelines, all experienced registered health care workers may see and manage these 'types of patients'. a sexual assault occurs once every 6.4 minutes in the usa, where 1 in every 6 women will be raped during her lifetime. although a woman is four times more likely to be assaulted by someone she knows than by someone she does not know, the majority of these crimes go unreported, even though rape is seen to be a felony in the united states"" february 2001 -----------m southern african journal of hiv medicine management of a rape survivor can be conveniently regarded under the following headings, which comprise guidelines used at sunninghill hospital and the other sexual assault crisis centre clinic within netcare: medical management at sunninghill hospital, johannesburg it is important to remember that a rape survivor is a patient like any other, though with special needs. therefore, the basics of clinical medicine apply: good history taking, clinical examination, special investigations and appropriate management. 1. every patient is seen and managed in a comfortable and compassionate environment. 2. should the patient be a priority 1 (code red immediate life-threatening injury) or a priority 2 (code yellow -limb/potential life-threatening injury), then the patient is managed in the resuscitation room according to advanced trauma life support protocols. 3. if the patient is a priority 3 (code green non-limb or life-threatening injury) then the patient is treated in a private dedicated room. 4. a registered nurse and a medical doctor start taking a medical history as well as details of the actual rape. 5. all staff have undergone basic counselling training and have been trained in general medico-iegal procedures. 6. once a history has been taken the procedures are explained in detail to the patient. 7. if the patient has decided to lay a charge the appropriate medico-iegal examination will take place. s. at this and other similar units the appropriate crime kits for the medica-legal examination are available. often the investigating south african police officers may not have easy access to the specific kits. 9. for this reason a co-operative positive working relationship with the relevant police officers is vital. 10. all injuries are attended to within the unit. the patient should not be transferred unless procedures not routinely provided for in the unit are necessary. 11. specialist treatment may be required, e.g. a child with vaginal tears should be sutured under general anaesthetic administered by a specialist anaesthetist. 12. if the patient requires x-rays, admission to hospital or other specific medical treatment will be done. this alleviates any further secondary traumatisation for the patient. 13. antibiotic prophylaxis is prescribed where necessary. 14. following completion of the full medica-legal examination, a facility where the patient can shower/bath and change into clean clothing should be made available. 15. the patient is followed up at 6-weekly, 3-monthly and 6-monthly intervals and annual intervals. 16. the patient is free to attend the unit for any ongoing medical condition or counselling and for regular annual follow-up visits. post-exposure prophylaxis (pep) 1. part of the initial history-taking involves pre-hiv test counselling. 2. information regarding pep guidelines is given to the patient. 3. informed consent for the baseline hiv ellsa test is obtained. 4. information is given and consent obtained with regard to further management. 5. if the patient is under age, then consent should be provided by the appropriate parent/guardian. if they are not available, then attending police officers will assist. 6. a quick turnaround time is required for the hiv ellsa results which are returned within 3 hours by ampath laboratories. 7. only patients who attend the unit within 72 hours of the incident will be offered pep should the baseline ellsa test be negative. 8. if the baseline hiv ellsa is positive, counselling is carried out and referrals are made to appropriate centres for hiv-aids care. 9. other baseline tests include: a full blood count (fbc), liver function (lf) and urea and creatinine estimation. 10. a pregnancy test will be performed if necessary. 11. the patient will be followed up by the unit for other medical problems as well as for ongoing counselling. 12. if the patient attends the unit 72 hours after the incident, counselling is carried out and the blood tests mentioned above are offered. 13. no pep is offered to patients attending after 72 hours."'" 14. all patients who present within 72 hours of the incident and are hiv-negative are offered a 28-day course of air 200 mg bd and 3tc 150 mg tds. 15. of the> 450 patients who have been seen at the sunninghill hospital rape crisis centre, only 2 patients have been given indinavir sulphate (crixovan). (one of the patients was a health care worker who requested the therapy, and the second was a code red assault.) results to date 1. approximately 18% of patients attending the unit are hiv-positive. 2. of the patients who were hiv-negative at baseline (this is the majority of patients) and who took pep within 72 hours of the rape and completed the course, none has seroconverted. 3. in one case, pep was given more than 72 hours after the incident (supplied by an external source). this patient tested positive at the 6-week visit. (this patient was negative at baseline; however, she was tested 4 days after the incident.) 4. severe side-effects were rare and only noted in 2 patients. 5. compliance is not a problem with pep in the context of sexual assault whereas compliance for pep in the case of needlestick injuries among health care workers has been problematic because of sideeffects. 6. the follow-up rate is satisfactory until the third month (approximately 68%), but falls away dramatically after the 6-month visit to as low as 35%. other medications 1. where appropriate, the patient is also given antibiotic prophylaxis: • penicillin 2 million units imi or 2 g ciprofioxacin stat • metronidazole 2 g po slat or metronidazole 500 mg ivi (should the patient be vomiting or nauseous) • tetracyclines 500 mg qid for 10 days. 2. children allergic to penicillin are given erythromycin. 3. a 'morning after pill', e.g. levonorgestrel 0.25 mg and ethinylestradiol 0.05 mg or a higher dose norgestrel/ethinyl oestradiol combination (two tablets stat and then two 12 hours later in both formulations mentioned the dosage is the same) is supplied if necessary. 4. vaginal douches are supplied for patients to take home. 5. anti-emetics are prescribed if necessary. 6. analgesia/anti-infiammatory agents are also provided if necessary. hhruary 2001----------counselung 1. trained counsellors are called in to counsel every rape patient. support is provided to the family, friends, spouse and patient during the acute event and follow-up counselling, tailored to the patient's needs, is provided on a regular basis. 2. the unit's experience is that it is imperative that a counsellor see the patients at their first visit. this facilitates regular follow-up for the patients and their families. 3. should patients wish to lay a charge, they may do so with the attending police officer. (police officers accompany less than 48% of the patients who come to the unit; however, the unit's figures show that over 70% of patients actually lay charges.) 4. if a police officer is not in attendance during the initial admission then the appropriate police services must be called should the patient wish to lay a charge. when formulating guidelines and protocols for this disastrous medical emergency it is important for medical practitioners to remember that every patient is an individual and that management of the patient and family needs to be individualised. it is also necessary to bear in mind that both the physical and emotional injuries may need therapy for several months and ongoing support will need to be provided for a considerable period of time. in common with pep guidelines in other settings, it is recognised that in this context revision may need to occur as and when new therapies and new testing methods become available. references 1. petter w, whitehill dl management of female sexual assault am farn physician 199b. 2. statisrical absrracr of rhe uniced stares' 996, 116th ed. 3. swart l. gilchrist a, butchard a, seedat m, martin l ra~ surveillance through district surgeon's offices in johannesburg, 1996 1998: evaluation and prevention implications. pretoria: institute of social and health sciences. uni\lersity of south africa. match 1999. 4. bamberger jd, waldo ca, et af. post ol:posure prophylaxis for hn infection following sexual assault am j med 1999; 106: 323-3265. beino! jp, et al. an inv~stigation of rape and post exposure prophylgxis in eight p'arisian clinics. paper presc:nted at the: durban world aids conf~r~nc~. jun~ 2000. 6. gerberding jl prophylaxis for qctupationaj o:posur~ to hiv. aim intern med 1996; 125: 497-501. further reading • case-eontrol study of hiv seroconversion in health·care workers after percutaneous exposure to hiv infected blood: france, uk, and usa, january 1988 august 1994. mmwr 1995; 44: 929-933. • centres for disease control and prev~ntion. guid~lines for treatment of sexually transmitted diseases. mmwr 1998; 47: 109-111. • gostin lo. lazzarini z. alexander d, et al. hiv testing, counseling, and prophylaxis aher sexual assault lama 1994; 271: 1436-1444. • katz mh. gerberding jl post exposure treatment of people exposed to the hiv through sexual contact of injection-drug use.. n engl jmed 1997; 336: 1097-1100. the southern mrican journal of hiv medicine 865 message from the editor the 20th international aids conference was recently held in july in washington, dc, usa. south africa, generally, and the southern african hiv clinicians society, specifically, were well represented, with prominent presentations by senior academics and policy makers. indeed, following the conference, i have heard several colleagues from around the country comment that ‘south africans were presenting everywhere’ at the meeting. the conference theme, ‘turning the tide together’, reflected a sense of renewed hope in the fight against the hiv epidemic. research towards a cure for hiv disease received a great deal of attention, while discussions of antiretroviral-based prevention strategies shifted from trials for determining efficacy towards grappling with the practical issues of implementation. although most of us could not attend the meeting, luckily much of the conference content is downloadable from the website: http://www.aids2012.org. at the meeting, the international aids society (ias) inducted a new governing council, including professor linda-gail bekker from the university of cape town (a former editor of the southern african journal of hiv medicine). congratulations to linda-gail on this significant achievement. we look forward to hearing from her on international developments at the ias in future editions of the journal. closer to home, the society is preparing for its inaugural conference, to be held in cape town from 25 28 november 2012. the conference will cover the latest local research on key topics in hiv medicine and service delivery, and a panel of international speakers will present current 'state-of-the-art' in clinical practice. for the conference programme and information on how to register, see: http://www.sahivsoc2012.co.za. we hope to publish conference abstracts and related outputs in an edition of the journal in early 2013, for those who cannot attend this exciting meeting. this edition of the journal features the latest guidelines from the society on the use of antiretroviral therapy in adults (an update to previous guidelines from 2008). as with many of the society’s recommendations, these guidelines seek to balance best clinical practice with what is realistic and feasible in the range of healthcare settings across the country. following this, evans and colleagues1 present an analysis of the prescribing of abacavir in public facilities across gauteng province. their results provide an interesting real-world counterpoint to the guidelines for art use – a pause for reflection on how the best-intended guidelines may be translated into clinical practice. also from gauteng, a study by page-shipp2 demonstrates the challenges of integrating tb-hiv services in primary care. this article also shows the important insights that can be generated from routinely collected service delivery data. hopefully, we will see more submissions of this kind of valuable operations research to the journal. in addition, moosa3 assesses the effect of treating depression on art adherence, with results suggesting that effective therapy (whether pharmacological or psychotherapeutic) can help to improve hiv outcomes over time. this edition also features two interesting case reports. this first, a report by patel4 from botswana, gives rise to discussion of long-term non-progressors in sub-saharan africa – a group of patients who may go undetected and sub-optimally managed in many settings. in the second report, kibirige5 presents a case of likely hiv-associated addison’s disease from uganda, highlighting the difficulty in arriving at a definitive diagnosis where resources for investigation are limited. finally, this issue of the journal includes as a loose insert: a revised dosing chart for paediatric antiretrovirals from the society. with an accompanying description by nuttall and schowalter,6 this chart is an invaluable resource for clinicians on the ground, and is sure to be a hot commodity. additional copies are available on request from the society. happy reading. landon myer associate professor, school of public health & family medicine university of cape town landon.myer@uct.ac.za   1. evans d, maskew m, heneger c, sanne i. estimated use of abacavir among adults and children enrolled in public sector antiretroviral therapy programmes in gauteng province, south africa. southern african journal of hiv medicine 2012;13(3):134-137. [http://dx.doi.org/10.7196/sajhivmed.822] 1. evans d, maskew m, heneger c, sanne i. estimated use of abacavir among adults and children enrolled in public sector antiretroviral therapy programmes in gauteng province, south africa. southern african journal of hiv medicine 2012;13(3):134-137. [http://dx.doi.org/10.7196/sajhivmed.822] 2. page-shipp l, voss de lima y, clouse k, et al. tb/hiv integration at primary care level: a quantitative assessment at 3 clinics in johannesburg, south africa. southern african journal of hiv medicine 2012;13(3):138-143. [http://dx.doi.org/10.7196/sajhivmed.833] 2. page-shipp l, voss de lima y, clouse k, et al. tb/hiv integration at primary care level: a quantitative assessment at 3 clinics in johannesburg, south africa. southern african journal of hiv medicine 2012;13(3):138-143. [http://dx.doi.org/10.7196/sajhivmed.833] 3. moosa myh, jeenah fy. treating depression in hiv-positive patients affects adherence. southern african journal of hiv medicine 2012;13(3):144-149. [http://dx.doi.org/10.7196/sajhivmed.782] 3. moosa myh, jeenah fy. treating depression in hiv-positive patients affects adherence. southern african journal of hiv medicine 2012;13(3):144-149. [http://dx.doi.org/10.7196/sajhivmed.782] 4. patel p, brooks m, anabwani g, tolle ma. control and non-progression of hiv-1 infection in sub-saharan africa: a case and review. southern african journal of hiv medicine 2012;13(3):152-155. [http://dx.doi.org/10.7196/sajhivmed.848] 4. patel p, brooks m, anabwani g, tolle ma. control and non-progression of hiv-1 infection in sub-saharan africa: a case and review. southern african journal of hiv medicine 2012;13(3):152-155. [http://dx.doi.org/10.7196/sajhivmed.848] 5. kibirige d, ssekitoleko r, mutebi e. persistent dizziness and recurrent syncope due to hiv-associated addison’s disease: case report from a resource-limited setting. southern african journal of hiv medicine 2012;13(3):150-151. [http://dx.doi.org/10.7196/sajhivmed.847] 5. kibirige d, ssekitoleko r, mutebi e. persistent dizziness and recurrent syncope due to hiv-associated addison’s disease: case report from a resource-limited setting. southern african journal of hiv medicine 2012;13(3):150-151. [http://dx.doi.org/10.7196/sajhivmed.847] 6. nuttall j, schowalter l. update: arv dosing chart for children and adolescents, 2012. south african journal of hiv medicine 2012;13(3):110-112. [http://dx.doi.org/10.7196/sajhivmed.857] 6. nuttall j, schowalter l. update: arv dosing chart for children and adolescents, 2012. south african journal of hiv medicine 2012;13(3):110-112. [http://dx.doi.org/10.7196/sajhivmed.857] the sou lrifrn a~rican journal o~ hiv medicine -----------march 2002 clinical guideline hiv clinicians society of southern africa corresponding author: g maartells, ["tedious diseases unit, department of medicine, university of cape town all dosages are acceptable, but lower dose regimens are better tolerated. there is scanty evidence for lower dose regimens against toxoplasmosis and strongest evidence for higher-dose regimens. dose of co-trimoxazole prophylaxis indications for co-trimoxazole prophylaxis primary prophylaxis co-trimoxazole intolerance is common in late disease and usually presents as a maculopapular rash. many intolerant patients may continue to receive co-trimoxazole with the addition of an antihistamine unless there are systemic symptoms or mucosal involvement. if co-trimoxazole therapy is discontinued, desensitisation or rechallenge appear to be safe unless there are systemic symptoms or mucosal involvement. because co-trimoxazole reduces the incidence of many opportunistic infections, rechallenge or desensitisation should be considered. studies have demonstrated that desensitisation and rechallenge appear safe. both rechallenge and desensitisation should be done under antihistamine cover starting the day before. rechallenge should be done with co-trimoxazole 480 mg and the patient observed for several hours. several desensitisation regimens exist; one of the simplest uses coco-trimoxazole intolerance tuberculosis preventive therapy was covered in the februory 2001 issue of the sa journal of hiv medicine. all the following regimens are equally efficacious against pneumocystis carinii pneumonia (pcp): • 960 mg daily • 960 mg three days/week • 480 mg daily. • who clinical stage 3 or 4 • cd4 count < 200 • total iymphocyte count < 1.25 x 10'/1 (should only be used when cd4 count unavailable may miss 25% of patients c04 < 200). the prevention and treatment of opportunistic infections in hiv-infected adults the best method of preventing opportunistic infections in hiv-infected individuals is to use highly active antiretroviral therapy, which leads to partial immune reconstitution. however, even if antiretroviral therapy is available a substantial proportion of patients will either present with severe immune suppression or remain severely immune-suppressed despite antiretroviral therapy. many opportunistic infections can be prevented in these patients by using primary prophylaxis (see below) or vaccination (see below). relapses are common after initial treatment of many opportunistic infections and maintenance therapy (also known as secondary prophylaxis see table l) is necessary while patients remain immunesuppressed. the following delegates attended the opportunistic infections guideline workshop of the sa hiv clinicians society, held in cape town on 9 march: or mark cotton, professor gary maartens, or steve andrews, or steve miller, or dave spencer, or des martin, or francois venter, and pofessor robin wood. a number of lengthy and comprehensive articles and guidelines exist with regard to the treatment and prevention of opportunistic infections, but this guideline is designed to be easy and simple for a practitioner to use. it is presented in a simplified format. the guideline is supported by evidence-based studies and adapted to be appropriate to the local situation. it should be noted that only the drugs that are licensed in south africa have been recommended and in addition, at all times, the most cost-effective regiments) have been endorsed. alternative regiments) have been listed where appropriate, but these are not exhaustive. a practitioner dealing with a more complex problem may find it necessary to consult with a colleague or refer to more comprehensive material. table i. treatment and secondary prophylaxls of opportunistic infecnons in adults standard adult doses have been given. every effort has been made to check doses. but readers should check other sources. usual duration of therapy has been given, but longer courses may be needed in individual cases. infection treatment options duration se<:ond,ry prophylaxis' herpes simplex valacidovir 500 mg bid 7 days not usually recommended acyclovir 400 mg tid (acyclovir 400 mg bid) famcidovir 125 mg bid tuberculosis standard short-eourse therapy 6 months not recommended candida oesophagitis ruconazole 100 mg daily 14 28 days not recommended itraconazole 200 mg daily ketoconazole 400 mg daily pneumocystis codnii co-trimoxazolej 3-4 tabs qid 14-21 days pneumonia1 dapsone 100 mg daily plus co-trimoxazole' 2 tabs daily trimethoprim 300 mg tid dapsone 100 mg daily clindamycin 450 mg tid plus primaquine 15 mg daily toxoplasmosis co-trimoxazolej 4 tabs bid 4 weeks cotrimoxazole' 2 tabs daily then 2 tabs bid 12 weeks c1indamycin 600 mg qid plus 6 weeks pyrimethamine' 50 mg daily cytomegalovirus gancielovir 5 mglkg bid iv then 14 days n/a ganciciovir 5 mglkg/day iv ufelong! 5 days/week or 19tidpo atypical mycobacteriosis clarithromycin 500 mg bid plus ufelong' n/a ethambutol 800 mg daily salmonella bacteraemia ciprofloxacin 500 mg bid 6 weeks not recommended lsosporiasis co-trimoxazole' 4 table" bid 4 weeks co-trimoxazole' 2 tabs pyrimethamine' 25 mg daily daily pyrimethamine' 75 mg daily cryptosporidiosis none available (anti motility drugs) n/a n/a bacterial pneumonia cefuroxime 750 mg 1.5 g tid iv' 5 10 days not recommended ceramandole 1 2 9 qid iv' ceftriaxone 1 2 9 daily iv' cefotaxime 1 2 9 bid iv' co-amoxielav 1.2 9 tid iv' moxifloxacin 400 mg daily gatifloxacin 400 mg daily cryptococcal meningitis amphotericin b 0.7 mg(kg'lv daily 7-14days auconazole 100 200 mg then fluconazole 400 mg daily 8 10 weeks daily' herpes zoster [shingles! acyclovir 800 mg 5 times/day 7 days not recommended valacielovir 1 9 tid famciclovir 250 mg tid microsporidiosis a1bendazole 400 mg bid' 21 days not recommended 1. prophylaxis or lifelong therapy can be discontinued if the cd4 count increases to > 200 on antiretroviral therapy. 2. adjunctive corticosteroids are indicated in hypoxic patien" [oral prednisone 40 mg bid followed by taper after 5 10 days). 3. single-strength (480 mg) table". 4. folinic acid (nor. folic acid) should be used to treat or prevent bone marrow suppression. 5. therapy should be completed with oral antibiotics (amoxicillin, co-amoxiclav, moxifloxacin or gatifloxacin are recommended). these antibiotics are recommended in the south african thoracic society guidelines on community-acquired pneumonia (in pressl. 6. a test dose of 1 mg should be given over 30 minutes if this is tolerated then half the daily dose can be infused over 4 hours with the full dose given the next day. many experts omit the test dose. 7. only certain species [notably encephalitozoon intestinalis) respond well to albendazole. the southern african journal of hiv meoicine ----------march 2002 march 2002 ------------'ht southh1n mrican journal o~ hv mtd cint trimoxazole syrup [240 mg/5 ml): day 1 1.25 ml daily day 2 1.25 ml bid day 3 1.25 ml tid day 4 2.5 ml bid day 5 2.5 ml tid day 6 one tablet [480 mg) daily llnurg gs. stqnford jf. e'ora;;no mf,~;: a. trirrethoprim-sj.tgrretnoxaro e (tmp-sml) dost~ arion 'versus d" 'et{ retn" en;e ~r preurrocysls ca{l"!ii pnejmo" a propn, axis in nljp';4j'1 immuncxf(:""ciercy ... ·rus in=~:m pal~is w'rn pre-w ous al:herse reac:.on to tmp·sml. j in=ect dis 2001; 184: 992-997l the alternative to co-trimoxazole if co-trimoxazole cannot be tolerated, dapsone 100 mg daily should be substituted. dapsone is as effec ive as cotrimoxazole for prophylaxis against pcp but does not prevent other opportunistic infections, e.g. toxoplasmosis, isosporiasis and bacterial infections. vaccination aerosolised pentamidine is not cost effective in the local setting. live vaccines should generally be avoided in adults. yellow fever vaccine may be safe if the cd4+ count is > 200. when the c04+ count is < 200 antigenic responses tend to be poor and short-lived for all types of vaccinations. a transient increase in viral load, experienced following vaccination, can be discounted. • influenza vaccination should be administered annually. • the present 23 polyvalent pneumococcal vaccine should be avoided as there is strong evidence that it is harmful. further trials on other pneumococcal vaccines are awaited. • hepatitis b vaccine should be administered to hepatitis b surface antigen-negative patients. hiv 1002 human papillomavirus infection and disease in men: impact of hiv s delany-moretlwe,1 mb bch, phd, dtm&h; a chikandiwa,1 mb bch, mph; j gibbs,1,2 mb chb, mrcp, msc 1 wits reproductive health and hiv institute, university of the witwatersrand, johannesburg, south africa 2 london school of hygiene and tropical medicine, london, united kingdom corresponding author: s delany-moretlwe (sdelany@wrhi.ac.za) there is growing evidence of a significant burden of human papillomavirus (hpv) infection and associated disease in men. high rates of hpv infection have been observed in men from sub-saharan africa where hiv prevalence is high. hiv infection increases hpv prevalence, incidence and persistence and is strongly associated with the development of anogenital warts and anal, penile and head and neck cancers in men. despite increasing access to antiretroviral therapy, there appears to be little benefit in preventing the development of these cancers in hiv-positive men, making prevention of infection a priority. new prevention options that are being introduced in many african countries include male circumcision and hpv vaccination. however, more data are needed on the burden of hpv disease in men before boys are included in hpv vaccination programmes. s afr j hiv med 2013;14(4):183-188. doi:10.7196/sajhivmed.1002 human papillomavirus (hpv) is a common sexually transmitted infection (sti) affecting both men and women.1 hpv infections can be classified as either low(lr) or high-risk (hr). 2 hr-hpv infections have been associated with cancer of the anogenital and oropharyngeal tissues. while the majority of hpv infections are transient and clear spontaneously, persistent infection with hr-hpv is associated with the development of pre-neoplastic and neoplastic lesions in these areas (fig. 1). while much is known about the natural history of hpv infection in cervical cancer in women, less is known about the development of hpv-associated disease in men. emerging evidence points to a significant role for hiv infection in promoting hpv prevalence, incidence and persistence. this review provides an update on current evidence regarding the epidemiology of hpv infection and disease in men, the effects of hiv on hpv infection and disease in men in sub-saharan africa (ssa), and the prospects for prevention in this setting. fig. 1. natural course of genital hr-hpv infection (source: stanley 82 ). global burden of hpv hpv infection is ubiquitous in men. a systematic review of 62 studies using reliable methods of hpv dna detection and conducted prior to 2009, representing 14 800 men in 23 countries, showed that anogenital hpv dna prevalence is generally high in sexually active men. the review highlighted considerable variation in estimates by region, from 1% to 84% in lr men, to 2% to 93% in hr men.3 compared with studies in women, peak prevalence spanned a wide range of ages, suggesting that men have the potential for longer-term persistence of infection or higher rates of re-infection.3 type-specific hpv seroprevalence studies are better indicators of lifetime exposure to hpv infection, although they may underestimate cumulative hpv exposure, given that not all infections lead to seroconversion.4 recent population-based studies have estimated the prevalence of antibodies to vaccine-preventable hpv types 6, 11, 16 and 18. among men aged 14 59 years in the usa, 12.2% of men were seropositive for any vaccine type, with a peak prevalence of 18% among men aged 50 59 years.5 in a similar population-based study in australia, peak prevalence of any vaccine type was 31.5% among men aged 40 49 years;6 and a study from the netherlands estimated that the seroprevalence of any hr-hpv in men aged ≥14 years was 20%.7 there is some evidence that seroprevalence appears to be rising as a result of changes in sexual behaviour and earlier age of sexual debut. in a related study from the netherlands comparing serosurveillance rates of hr-hpv in the periods 1995 1996 and 2006 2007, overall hr-hpv seroprevalence rates were significantly higher in the later survey, compared with the earlier survey across all age groups.8 burden of infection in ssa a recent global review of 117 studies worldwide suggests that the seroprevalence of hpv is even higher in ssa, although data on men in ssa are sparse.4 in a small study of tanzanian genital ulcer disease (gud) patients, pregnant women and male blood donors, the prevalence of antibodies to hr-hpv ranged from 77% in male gud patients to 15% in male blood donors. in this study, the prevalence of antibodies to hpv types 16, 18, 51 and 52 was considerably higher in hiv-positive patients with gud.9 although data on anogenital hpv dna prevalence in men in ssa are also limited,3 overall reported prevalences in men are high, ranging from 19% to 78%.10-15 in most, but not all studies, the most prevalent type was hpv-16.15 the observed heterogeneity in estimates can be attributed to differences in age distribution, sexual behaviour and hiv prevalence within the different populations. emerging data suggest that the incidence of hr anogenital hpv infection in men is also high, ranging from 35.7/100 person years in south african men to 40/100 person-years in east african men participating in male circumcision (mc) trials.16-18 in both settings, the risk of hpv acquisition was doubled in hiv-positive men. these incidence rates are much higher than those previously observed else­where.19 , 20 factors associated with hpv infection hpv seroprevalence rates are consistently lower in men than in women,[6,21 ,22] with men also producing lower antibody titres than women. 23 there are several plausible bio­logical explanations for differences in antibody responses between men and women. men may experience a higher frequency of transient infections, a lower viral load, or produce less robust immunological responses than women. 24 it has been argued that the site of infection and/or type of epithelium influence antibody responses, with men experiencing a higher proportion of infections in more keratinised tissues (e.g. penile shaft) than women (e.g. anal canal or cervix). thicker, more keratinised epithelium may present a barrier to infection, and if infected, may be less likely than mucosal surfaces to induce an immune response, given the relative distance from draining lymphatics and lymph nodes. 23 , 25 recent data from a study comparing type-specific hpv antibody pre­valence with the corresponding prevalence of hpv dna detected in the external genitalia and anal canal in heterosexual men and men who have sex with men (msm) support this notion. higher hpv-6 and -16 seroprevalence rates were observed in men that had a same hpv-type infection in the anal canal, than in those with the same hpv-type infection in the external genitalia only. higher seroprevalence rates were also observed in msm compared with heterosexual men.26 the association between hpv infection and age is somewhat inconsistent, with fairly flat prevalence curves reported in populations where hiv prevalence is relatively low. 3 , 27 data emerging from africa, present a simi­larly mixed picture. a study among kenyan fishermen showed a lower risk for hpv infection in older age groups,10 while data from kenyan men participating in an mc trial showed little variation in prevalence with age.28 a more recent study in men from tanzania demonstrated an association between increasing age and hpv prevalence, but that this association was driven by hiv-positive men.15 two recent incidence studies confirmed that increasing age is associated with a lower risk for hpv infection.16 , 17 combined, these data tend to suggest that the association between hpv infection and age in men in ssa is related to patterns of sexual activity, but confounded by hiv status, which may promote the persistence of hpv infection. sexual behaviour is an important risk factor for anogenital hpv infection. more recent publications have highlighted the importance of age of sexual debut,8 marital status,29 high number of lifetime sexual part­ners,5 , 30 , 31 number of recent sexual partners,30 longer history of sexual activity,30 route of exposure,26 , 30 , 32 and having sex with men32-34 as risk factors for anogenital hpv infection. similar observations about sexual risk behaviour and an association with hpv have been made in studies of men in ssa.10 , 17 , 28 while the data on the protective effects of condoms are somewhat mixed,35 evidence from african studies in men show a reduced risk of genital hpv infection associated with condom use.10 , 28 , 36 , 37 evidence from randomised controlled trials (rcts) of mc has conclusively demonstrated the protective benefits of mc in reducing the risk of hpv prevalence and incidence.[17,36, 38,39] related findings from the trial in kenya have highlighted less frequent bathing as a risk factor for hpv infection, which may be associated with poor genital hygiene in uncircumcised men.18 , 28 stis are independently associated with the risk of hpv infection, particularly chla­mydia,19 , 30 herpes simplex virus (hsv)-2,34 and hepatitis b.40 while they may share a common mode of transmission, stis are thought to increase the risk of hpv infection by facilitating access to the basal epithelium through micro-abrasions in the skin.35 recent reports on male populations in africa point to a higher risk of penile hpv in men co-infected with laboratory-diagnosed chlamydia tracho­matis or neisseria gonorrhoeae, and those who are hsv-2-seropositive.28 interestingly, hr-hpv clearance was recently shown to shown to be higher in hiv-negative men co-infected with syphilis or hsv-2, suggesting that other genital tract infections may also create an inflammatory cytokine milieu that may facilitate the clearance of hpv.17 hiv is a strong risk factor for hpv infection in men. while studies of anal hpv infection in msm from europe and the americas first identified an increased risk for infection in hiv-positive men,24 there is now a growing body of evidence from studies of men in ssa that shows that prevalent and incident ano­genital hpv infection is more common in hiv-positive men.[15,16, 37] multiple infections, particularly with hr-hpv, are more common in hiv-positive men.13 , 41 prevalence of infec­t­ion increases with declining cd4+ count.42 partner hiv status has also been shown to increase the risk of hpv detection in men.14 , 43 anogenital warts anogenital warts (agws) are the most common clinical manifestation of hpv infec­tion.44 caused mainly by infection with hpv-6 and -11,45 they are highly infectious. an esti­mated 65% of people whose sexual partner has genital warts will develop warts themselves. 46 the estimated incubation period from hpv infection to genital wart development is 2 weeks 8 months.47 while approximately 20 30% of genital warts will spontaneously regress,48 recurrence is common, resulting in significant psychological morbidity and high medical costs for repeated treatment. these costs are not insignificant when compared with costs for treatment of cervical cancer in women.49 two recent reviews estimated the prevalence and incidence of agws in the general adult population worldwide45 and in ssa,50 respectively.. worldwide, the overall prevalence of agws, based on genital examinations, ranged from 0.2% to 5.1%, with higher prevalence rates observed in males. data suggest that prevalence has increased in recent decades, possibly as a result of changes in sexual behaviour. studies in male populations in ssa suggest much higher prevalence rates than in high-income countries, possibly as a result of higher hiv prevalence rates. highest rates of 4.8 12.2% have been observed in hr men from central and south africa, a region of high hiv prevalence. lack of circumcision and hiv infection have been identified as risk factors for agws in men.12 importantly, hiv-positive men with agws may also be at risk for infection with hr-hpv. in a small study in johannesburg among hiv-positive men with penile warts, 85% were found to have hr-hpv as well. hpv-16 and -18 were most frequently detected.41 these high rates of hr-hpv detection in men with hiv suggest that they are at significant risk for the future development of pre-neoplastic and neoplastic lesions, emphasising the importance of target­ing screening programmes for hiv-positive men with agws. anal cancer while relatively uncommon, the incidence of anal cancer in men appears to be rising.51 a systematic review examined these trends, and found that age-adjusted incidence rates for anal cancer have increased in several high-income countries, with hpv infection identified as the most important associated aetiological factor.52 besides increasing age, smoking, receptive anal intercourse and hiv infection were the most important risk factors for anal cancer, with the highest incidence rates observed in hiv-positive msm. while anal cancer incidence is highest in hiv-positive msm, it should be noted that receptive anal intercourse is not a prerequisite for anal hpv infection, pre-cancer lesions or anal cancer. piketty et al.53 demonstrated high rates of anal infection and squamous intraepithelial lesions in hiv-positive men with no previous history of anal intercourse – an observation made subsequently in other studies.54 in such instances, anal hpv infection is thought be transferred to the anal canal through transiently infected fingers or toys, as well as by shedding from other infected genital sites. anal cancer is considered to be biologic­ally similar to cervical cancer. like cervical cancer, it is thought to be preceded by a spectrum of intraepithelial changes and anal intraepithelial neoplasia (ain), which can be graded similarly to cervical cancer. while there is strong supportive evidence that high-grade ain is a precursor to invasive cancer, there is no consensus regarding the prevalence or significance of ain, nor on the rate of ain progression to cancer. almost all of the natural history data come from studies in msm, with few data on heterosexual, hiv-negative or african populations. a recent meta-analysis of anal hpv and associated lesions in msm found that hiv-positive men were consistently more likely to be infected with hpv, to have associated lesions, and to have higher rates of anal cancer, although the excess in hiv-positive men was smallest for high-grade ain, and was not statistically significant for that category. while there were no data on progression rates of ain to cancer, estimates from this analysis suggest that rates of progression are significantly lower than those observed in cervical cancer.55 despite significant heterogeneity in the data, and a lack of prospective data, it remains plausible that high-grade ain lesions regress more frequently than high-grade cervical lesions. 56 while the prevention of anal cancers in high-risk hiv-positive men is a priority, these findings raise doubts about the utility of anal cancer screening programmes at present. until further evidence of benefit for screening in terms of reductions in anal cancer incidence and mortality become available, anal cancer screening programmes for men are likely to be controversial. despite immune reconstitution associated with highly active antiretroviral therapy (haart), there appears to be little evidence that this therapy has a preventive effect on the development of anal cancer. the recent meta-analysis and other analyses of temporal trends in anal cancer incidence have highlighted the continuing high incidence of anal cancer, despite the widespread introduction of haart. 55 , 57 , 58 these data suggest that prolonged survival afforded by haart initiation may allow more time for ain to progress to cancer, thus leading to higher anal cancer rates. penile cancer penile cancers are relatively rare. in 2008, of the estimated 22 000 new penile cancer cases, half were attributable to hpv, with much higher rates observed in regions with a low human development index.59 data from zimbabwe suggest that southern africa has higher incidence rates,60 and a recently published report of hpv detection in cancerous and pre-cancerous penile lesions from men in south africa demonstrated multiple hpv infections, with high rates of hpv-16.61 risk factors for penile cancer include: a lack of mc; phimosis and/or poor genital hygiene; agws; and hiv infection. hiv-positive men have an eight-fold increased risk of penile cancer, which may be associated with higher hpv infection rates.62 other risk factors for penile cancer that have been reported include current smoking, early age of first sexual intercourse, high lifetime number of female sexual partners, lack of condom use, chronic inflammatory conditions including balanitis and lichen sclerosus, and treatment with ultraviolet photochemotherapy for psoriasis.63 head and neck squamous cell carcinomas head and neck cancer commonly refers to squamous cell carcinomas (sccs) arising in the upper aerodigestive tract (oral cavity, nasopharynx, hypopharynx and larynx). traditionally, most head and neck cancers were associated with tobacco and alcohol exposures and presented after the age of 60 years. more recently, a shift in the epidemiology of oropharyngeal scc has been observed, with a rising incidence, particularly in the palatine tonsils and base of the tongue, occurring in younger age groups and in people who have never smoked. 64 like the cervix and anus, there is an epithelial transition zone within the oropharynx which is prone to hpv infection, dysplasia and the development of sccs. in a systematic review of studies involving histological specimens of head and neck sccs, in 36% hpv dna was detected, and hpv-16 was the most common hpv type associated with head and neck scc.65 hiv-infected individuals have a 1.5 four-fold higher risk of oropharyngeal or tonsillar cancer than the general population. although the proportion of oropharyngeal cancers is unknown, hiv-positive individuals appear to be at moderately increased risk of hpv-associated head and neck scc compared with the general population.66 d’souza et al.67 showed convincing evidence that oral cavity hpv dna infection was related to sexual behaviour, including oral sex. there is evidence that hiv-positive individuals have a higher prevalence of oral hr-hpv, even after controlling for sexual behaviour,68 and that the risk for infection appears to be higher among those with a declining cd4+ count.69 while there are limited data on the natural history of oral hpv infection, the majority of infections clear within two years,70 although persistence appears to be associated with a cd4+ count <500 cells/μl.71 there do not appear to be benefits for haart on either the persistence of hpv infection or the clearance of oral lesions, but more evidence is needed in this regard.66 data on oral hpv and hpv-associated head and neck scc in african populations is currently scarce, although one study from senegal,72 which included 117 invasive head and neck cancer histology specimens, mainly from men with a mean age of 52 years, found only four cases to be positive for hpv dna. the authors remarked that larger studies are needed to confirm these findings and explore other potential risk factors specific to the region.72 prevention of hpv-associated infection and disease in men evidence for the benefit of several strategies to prevent hpv infection and subsequent disease in men has emerged in recent years. studies have shown a greater protective effect of condoms in the prevention of hpv acquisition in men. analysis of data from a multi-national cohort study in men showed a two-fold lower risk of hpv acquisition in men with no steady partner and who always used condoms. in addition, the probability of clearing an oncogenic infection was 30% higher in men who consistently used condoms with non-steady partners.73 consistent condom use has also been associated with the regression of penile lesions in men.74 recent rcts in africa provide strong evidence that mc is protective against hpv infection. in these trials, mc has been associated with reductions in the incidence, prevalence and persistence of hpv infection in men. in hiv-negative men, mc has also been shown to reduce hr-hpv transmission to female partners.75 recent data suggests that decreased penile shedding of hr-hpv observed in hpv-infected circumcised men may help to explain the protective effects observed for female partners.38 mc has also been associated with a lower prevalence of flat penile lesions in men.39 vaccines are the ideal form of primary prevention for infectious diseases, and have been successful in the control of many other infectious diseases. having been shown to be efficacious in women, hpv vaccine studies have now demonstrated evidence of benefit in men. an rct involving 4 065 men from 18 countries aged 16 26 years showed that the quadrivalent vaccine was 90% effective in preventing infection with vaccine-specific types in the per protocol analysis, and 89% effective in preventing agws in the same population.76 in 602 msm aged 16 26 years, the quadrivalent vaccine was 77.5% effective in preventing hpv-6-, -11-, -16 and -18-associated ain.77 the bivalent vaccine is not currently registered for use in men. hpv vaccination has been shown to be safe and highly immunogenic in hiv-1 infected men.78 modelling studies predict benefits of vaccination for boys, when high levels of vaccine coverage are achieved in girls,79 and data emerging from countries where national vaccination programmes have been introduced confirm this. even though vaccination was restricted to girls, in australia, there has been an 82% decline in agws in men aged <21 years since the introduction of the vaccine.80 in denmark, a 50% decline in agws in young men aged <19 years was observed only three years post vaccine introduction. 81 however, these benefits may not translate to all men, particularly msm who may not benefit from herd immunity. australia is the first country to extend vaccination to men. while several countries in africa have recently introduced hpv vaccination programmes, these school-based programmes do not include boys. further evidence is needed of the hpv-associated burden of disease in men, and the potential effects of hiv on hpv-associated disease in men before the vaccination of boys can be considered in lower-resource settings. conclusion hpv infection and associated disease are common in men in ssa. while data on the burden of disease are limited, studies suggest that infection with hpv is common, particularly in the context of hiv. there is also growing evidence to suggest that hiv infection enhances hpv persistence – a precursor for the development of cancer. given expanding access to haart in africa, there is now potential for significant morbidity and mortality from hpv-related cancers in men in the future. while mc and hpv vaccination programmes are being rolled out in many african countries where the burden of hiv is high, more data are needed on the natural history and burden of hpv-associated disease in men in africa to inform the development of prevention programmes. references 1. international agency for research on cancer. monographs on the evaluation of carcinogenic risks to humans 2007;90. 1. international agency for research on cancer. monographs on the evaluation of carcinogenic 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measurements are often necessary, and there are no fixed dose combinations for children yet. as children are growing, frequent re-adjustment of dosing is necessary. viral dynamics: perspectives in children viral loads in children are far higher in the first year of life than those in adults and only decline to adult values by 5 6 years of age. by 2 months of age, most hiv-infected infants have viral loads above 100 000 rna copies/ml of plasma, ranging from undetectable to 10 million rna copies/ml. the mean viral load in the first year of life is 185 000 copies/ml. generally, the higher the viral load, the more rapid the disease progression, although there is considerable variability. viral load assays are of value in assessing the efficacy of the regimen. a combination of viral load assay and cd4+ percentage is most predictive of mortality, although there is a stronger correlation with mortality for cd4 than viral load (fig. 1). the prognostic value of cd4+ percentage is agedependent, with a higher value having a worse prognosis at a younger age than relatively low values at an older age. goals of therapy the goals of therapy are: ■ maximal and durable suppression of viral load ■ restoration or preservation of immunological function (usually measured with cd4+ count) ■ improvement in clinical symptoms ■ reduction in morbidity and mortality. the overall objective of therapy is to enhance the quality and quantity of life and to promote physical, social and intellectual development of the child within a functional family setting. a practical goal is to avoid hospitalisation by minimising the impact of intercurrent disease, thus keeping the child with his/her family. finally, the well-being of a child impacts positively on the parents, and a healthy parent is vital. in addition to antiretrovirals (arvs), the following strategies are essential to the child: ■ prevention of opportunistic infections ■ aggressive treatment of intercurrent infections fig. 1. cd4% v. probability of death (a) and aids (b) in 12 months, and viral load v. probability of death (c) and aids (d) in 12 months (source – lancet 2003; 362 1605-1611). g u i d e l i n e s antiretroviral therapy in children southern african hiv clinicians society the paediatric sub-committee of the southern african hiv clinicians society comprises paediatricians from the private and public sectors. these guidelines are the result of reviewing all the available paediatric treatment guidelines, consulting with international experts and drawing from their clinical experience. they differ from those of the national department of health (doh), the world health organization (who) and other international guidelines (penta, etc). we encourage all treaters to consult the other guidelines, and make an informed decision for treating children. websites of other guidelines can be found below under ‘recommended reading’. for the benefit of those working in the state sector, a summary of the doh guidelines can be found in this journal on page 33. november 2005 the southern african journal of hiv medicine hiv november new 13/12/05 12:43 pm page 18 the southern african journal of hiv medicine november 2005 1 9 ■ nutritional support ■ good supportive care. combination therapy there is no role for monoor dual therapy. a combination of at least three drugs is mandatory. the higher viral loads in children may make suppression of plasma hiv rna to below the limits of detection more difficult to achieve than in adults. however, with the potent combinations available today, plasma hiv rna suppression should be achievable in the vast majority of patients. while triple therapy is the most common regimen, quadruple therapy in children under 1 year of age and with high viral loads may have a role, especially when unboosted protease inhibitors (pis) or non-nucleoside reverse transcriptase inhibitors (nnrtis) are used as part of the regimen. the rationale for therapy is to suppress viral replication below detectable limits in the plasma, thereby minimising the possibility of viral resistance. however, even partial viral suppression is usually accompanied by an improved clinical outcome. adherence adherence to art is vital for a successful outcome. the factors that impact on adherence include: ■ affordability. before initiating therapy, treaters should ascertain the affordability of a proposed regimen over a prolonged period of time. anyone not being able to afford therapy should be referred to the state sector. ■ motivation and commitment of caregiver/parent to the child's lifelong therapy. adherence involves administering every dose of medication usually twice daily, every day of every year. weekends away, schooling and other parental obligations need to be anticipated and planned for. ■ parental/caregiver understanding that poor adherence is the single most important factor leading to drug failure and resistance, and implies loss of future therapeutic options. ■ acceptance. address any social issues as appropriate. ■ liquid formulations are problematic in that they are invariably more expensive than tablets/capsules, often have an unpleasant taste, and in some cases involve administration of large volumes of liquids. ■ additional issues which can enhance adherence include: • as far as possible children should be taught to swallow pills/capsules. this can be done using appropriately sized sweets. • disclosure at home is also to be encouraged to enhance the treatment support in the home environment. • the caregiver should identify one other person who can help with treatment (treatment buddy) as a back-up. • syringes for liquid formulations should receive special attention. make sure that the caregiver draws up the correct volume and expels excess air. category characteristics n no signs or symptoms related hiv infection or only 1 condition listed in a a two or more conditions listed below but none from b or c: (mild) ■ lymphadenopathy (≥ 0.5 cm at more than 2 sites; bilateral = 1 site) ■ hepatomegaly ■ splenomegaly ■ parotitis ■ dermatitis ■ recurrent or persistent upper respiratory tract infections, sinusitis, or otitis media b symptomatic conditions other than from a or c and (moderate) attributed to hiv infection; including but not limited to: ■ anaemia (< 8 g/l), neutropenia (< 1 � 109/l), thrombocytopenia (< 100 � 109/l) – persisting ≥ 30 days ■ bacterial meningitis, pneumonia or sepsis (single episode) ■ candidiasis, persisting > 2 months in children > 6 months of age ■ cardiomyopathy ■ cytomegalovirus (cmv) infection, onset < 1 month of age ■ diarrhoea – recurrent or chronic ■ hepatitis ■ herpes simplex virus (hsv) stomatitis > 2 episodes within a year ■ hsv bronchitis, pneumonitis or oesophagitis with onset < 1 year of age ■ herpes zoster (shingles) ≥ 2 episodes or > 1 dermatome ■ leiomyosarcoma ■ lymphoid interstitial pneumonitis (lip) or pulmonary lymphoid hyperplasia complex ■ nephropathy ■ nocardiosis ■ persistent fever (> 1 month) ■ toxoplasmosis, onset < 1 month of age ■ varicella, disseminated c ■ serious bacterial infections, multiple or recurrent (at any of the least 2 culture-confirmed episodes within a 3-year following: period) of: (severe) septicaemia, pneumonia, meningitis, bone or joint infection, or abscess of an internal organ or body cavity ■ candidiasis (oesophageal or pulmonary) ■ disseminated fungal infections (coccidioidomycosis, histoplasmosis, cryptococcosis) ■ cryptococcal meningitis ■ cmv disease with onset at age > 1 month (at site other than lymph nodes, spleen, liver) ■ encephalopathy ■ hsv causing mucocutaneous ulcer persisting > 1 month, or bronchitis, oesophagitis, pneumonitis, oesophagitis in a child > 1 month ■ kaposi's sarcoma ■ lymphoma: primary in brain, burkitt's, immunoblastic, large cell, b cell or unknown ■ mycobacterium tuberculosis (disseminated or extrapulmonary) ■ mycobacterium avium complex or mycobacterium kansasii (disseminated) ■ pneumocystis jiroveci pneumonia (pcp) ■ progressive multifocal leukoencephalopathy ■ cerebral toxoplasmosis with onset > 1 month of age ■ wasting syndrome in the absence of illness other than hiv that could explain the following: persistent weight loss > 10% of baseline, or downward crossing of at least 2 of the following percentiles on a weight-for-age chart (95th, 50th, 25th, 5th) in a child ≥ 1 year of age; or < 5th centile weight for height on 2 consecutive measurements ≥ 30 days apart plus (1) chronic diarrhoea (≥ 2 loose stools per day ≥ 30 days); or (2) documented fever ≥ 30 days intermittent or constant source: mmwr 1994; 43: rr1-12. table i. clinical categories for children with hiv infection hiv november new 13/12/05 12:43 pm page 19 november 2005 the southern african journal of hiv medicine20 • dosages of liquid formulations should be rounded up to a convenient volume for administering. note: ■ emphasise good adherence at each visit. it is useful to compare art with therapy for diabetes and hypertension, both requiring lifelong therapy and where poor adherence is associated with disease progression. ■ the treater should be aware that the doses need adjustment at each visit as the child grows. ■ it is useful to dispense the antiretroviral drugs oneself or else to have them delivered to one’s rooms to keep track of those patients who do not collect their medications on time. this could alert you to a potential adherence problem. classification of hiv in children the centers for disease control have utilised both clinical and immunological parameters for paediatric practice (tables i and ll). indications for starting art in children indications for starting art in children are set out in table iii. starting highly active antiretroviral therapy (haart) is never an emergency. it may be beneficial to wait until adherence can be assured and the family has been adequately counselled and are ready for the rigours of art. initiation of therapy first 1 2 visits a full clinical examination should be performed, including accurate baseline weight, height, and head circumference measurement for children aged under 2 years. blood samples should be taken for hiv viral load and cd4+ count. counselling and information. topics to be covered include: ■ hiv prognosis ■ treatment ■ adherence ■ drug formulations ■ taste issues (including taste test where appropriate) ■ initiate prophylaxis as indicated. ensure that family/caregivers have contact details for treating staff in case of any questions/adverse events. next visit if therapy is indicated and if the family is adequately counselled and able to maintain adherence, dispense drugs. graphically illustrate the drugs and how and when to take them, preferably with actual drugs or samples. you may want to consider observing administration of the drugs. if the family are not ready yet, continue counselling and work on barriers to adherence. day 2 a quick phone call to make sure that everything is in order is a good idea. 1 2 weeks later a phone call to the caregiver/parent is recommended to discuss tolerance and adherence issues. the government rollout programme recommends a visit 2 weeks after starting treatment where adherence is discussed and medication technique is checked. one month after starting treatment the clinician should conduct a general examination and draw blood to monitor drug toxicity. age of child < 12 months 1 5 years 6 12 years immunological category cd4+/µl cd4+% cd4+/µl cd4+% cd4+µl cd4+% 1. no immunosuppression > 1 500 ≥ 25 ≥ 1 000 ≥ 25 ≥ 500 ≥ 25 2. moderate immunosuppression 750 1 499 15 24 500 999 15 24 200 499 15 -24 3. severe immunosuppression < 750 < 15 < 500 < 15 < 200 < 15 source: mmwr 1994; 43: rr1-12. table ll. immunological categories for children with hiv infection infants less than 1 year of age* ■ clinical category b or c or ■ cd4% < 30 35% children 1 3 years old ■ selected category b diseases† or ■ category c or ■ cd4% < 20% children 4 12 years old ■ selected category b diseases† or ■ category c or ■ cd4% < 15 20% adolescents > 13 years ■ follow adult guidelines *infants under a year of age are most at risk for disease progression. clinical and laboratory parameters are notoriously unreliable in predicting which infants will be rapid progressors. this explains the high cd4 cut-offs for initiating art in this age group. †selected category b diseases: persistent candida infection (> 2 months in children > 6 months old), cardiomyopathy, chronic diarrhoea, disseminated herpes simplex virus, leiomyosarcoma, lymphoid interstitial pneumonitis (lip) or pulmonary lymphoid hyperplasia complex, nephropathy, disseminated varicella. note: bronchiectasis is seen commonly but is not addressed in the classification. art should begin prior to development of bronchiectasis. pulmonary tuberculosis should be regarded as category b. table iii. indications for starting art in children hiv november new 13/12/05 12:43 pm page 20 the southern african journal of hiv medicine november 2005 2 1 tolerance and adherence issues should be discussed. it may be useful to ask how many doses have been missed in the last 3 days, and how many in the last month. three months after starting treatment the clinician should conduct a general examination and draw blood to monitor drug toxicity. check weight and alter doses accordingly. blood should be taken for hiv viral load and cd4+ count. adverse effects, tolerance and adherence issues should be discussed with the caregiver. three-monthly thereafter the clinician should conduct a general examination and draw blood to monitor drug toxicity, hiv viral load and cd4+ count. check weight and alter doses accordingly. if the patient's results remain stable, clinical examinations and blood tests can be carried out 6-monthly, but children aged under 2 years need to be seen at least 3-monthly to adjust drug doses according to growth. discuss adverse effects, tolerance and adherence issues with caregiver at every visit. monitoring: special considerations for children viral load historically the percentage of children on triple therapy achieving and maintaining a plasma viral load of below 400 copies/mi was 25 75%. with our currently available regimens and attention to adherence, children should be achieving viral load suppression equivalent to that possible in adults. recent cohort data suggest that we can achieve undetectable viral loads in over 80% of treatment-naïve children. therapeutic options for children are limited. the decision to switch therapy because of suboptimal response must therefore be made thoughtfully, and balanced against the risk of accumulating additional resistance by maintaining a nonsuppressive regimen. many clinicians switch arvs when the cd4% or count consistently drops or definite evidence of clinical failure has occurred. such evidence includes: ■ growth failure ■ neurodevelopmental deterioration ■ disease progression. although there is no consensus, a growing number of international experts advise aggressively achieving and maintaining viral suppression. note: ■ viral suppression of < 10-fold (1 log) at 8 12 weeks after starting art may be inadequate. ■ in children who have responded with durable but not absolute viral suppression, a reproducible increase > 3-fold (0.5 log) in children ≥ 2 years and 5-fold (0.7 log) in infants < 2 years may be an indication to change arvs. ■ a repeat test is recommended whenever a routine measurement yields an unexpected result. it is usually not worth doing routine plasma hiv rna levels during an intercurrent event. additional non-routine testing may be indicated if the clinical condition changes. ■ two measurements should be performed 1 month apart before instituting changes. ■ viral loads can be temporarily raised for up to a month after intercurrent infections or vaccinations. ■ patients should be sequentially tested using the same method and the same laboratory. cd4+ lymphocyte counts and cd4+ percentages the cd4+ count should be measured whenever the viral load is determined, except when the viral load is repeated to verify an unexpected result. cd4+ lymphocyte counts are much higher in infancy than adulthood but the cd4+ percentage remains relatively more constant, although this is also higher in children < 2 years. cd4+ percentages may be easier to work with, but cd4+ counts should also be used and knowledge of normal values for age is a prerequisite. a cd4+ percentage below 15% should be viewed in the same light as a cd4+ count < 200/µi in adults (refer table il). lymphopenia and lymphocytosis may overor understate cd4 percentages or counts. cd4+ counts/percentages are useful for monitoring response to arvs. cd4+ counts can be temporarily lowered due to intercurrent infections or vaccinations and can take up to a month to recover. although there is a strong association between cd4+ depletion and opportunistic diseases, pneumocystis pneumonia may occur in the first year of life despite 'normal' counts for age. all hiv-infected or exposed children under 1 year of age should receive co-trimoxazole prophylaxis from 6 weeks of age. if the child is hiv infected, this can be stopped at 1 year if the cd4+ percentage is > 20%, or once there has been immune recovery to > 20% on art. if the child is hiv negative, co-trimoxazole can be stopped at 6 months of age as long as the mother is not breastfeeding. height and weight the 'road to health' chart is a valuable tool for monitoring the well-being of children. failure to maintain growth is suggestive of progressive hiv disease or superimposed infection such as tuberculosis. recommended arv regimens antiretroviral drugs (tables iv vi) a 4-drug regimen may be more effective than the standard 3 drugs in young infants because of extremely high viral loads, hiv november new 13/12/05 12:43 pm page 21 november 2005 the southern african journal of hiv medicine22 but should only be contemplated if parental commitment is obtained. this regimen will have long-term financial impact, as costs will increase dramatically as the child grows. the efficacy of downscaling to a 3-drug regimen awaits further studies. consult the sa hiv clinicians society for suitable regimens. current national department of health recommendations regimens currently recommended by the department of health are set out in table vii. it is recommended that children in the private sector receive the same regimens as children in the state sector to facilitate moving to the state sector in the event of the patient no longer being covered by health insurance. dosages of arvs in children and side-effects see tables viii and ix. drug interactions of note there are multiple opportunities for serious drug interactions. clinicians are advised to scrutinise package information and seek advice if uncertain. ■ rifampicin reduces levels of indinavir, nelfinavir, saquinavir (protease inhibitors) and nevirapine and should not be used with any of these drugs. ■ efavirenz causes reduced levels of clarithromycin, but not azithromycin. ■ ritonavir should not be given with numerous drugs. ■ of the antiepileptic drugs, sodium valproate is the safest to use with arvs. ■ ritonavir inhibits cyp p450 3a4 in the gut. this prevents the breakdown of inhaled steroids, leading to systemic absorption with resultant cushing's syndrome. rather use a nnrti-containing combination if the patient is on inhaled or nasal steroids. the following drugs are metabolised by cytochrome p450 (cyp3a4), hence there is the possibility of multiple interactions: pis ■ saquinavir ■ ritonavir ■ nelfinavir ■ indinavir ■ lopinavir. preferred nrti backbone d4t + 3tc zdv + 3tc zdv + ddl abc + 3tc abc + zdv avoid d4t + ddi if possible contraindicated d4t + zdv ddi + ddc d4t + ddc preferred nnrtis < 3 years nvp > 3 years efv or nvp there are no data on efv dosing for children < 3 years of age preferred pi lopinavir/ritonavir (lpv/rtv) (kaletra®) table v. preferred arvs preferred regimens 2 nrtis + efv or nvp (1 each from categories i, ii and ill) (or 3tc + abc + iii) 2 nrtis + 1 pi (1 each from categories i, ii and iv (or 3tc + abc + iv)) note: resistance to efv and nvp develops rapidly if undetectable viral loads are not achieved. some experts feel they should only be used when viral loads are < 150 000 copies/ml or where good adherence can be assured. only in special circumstances: 1 nrti + efv or nvp + 1 pi (1 each from categories i or ii, + ill + iv) note: although very potent, this regimen leaves few alternatives for future use and should only be considered in special circumstances (toxicity or salvage). abc + zdv + 3tc note: adult data indicate that this regimen is not as potent as other triple regimens, so should be avoided. * to be read in conjunction with table iv. table vi. recommended arv regimens* 6 months up over 3 years to 3 years* and > 10 kg 1st line stavudine (d4t) stavudine (d4t) lamivudine (3tc) lamivudine (3tc) kaletra® efavirenz 2nd line zidovudine (azt) zidovudine (azt) didanosine (ddi) didanosine (ddi) nevirapine/efavirenz† kaletra® *since there is now a pharmacokinetic study on kaletra in infants < 6 months of age, these infants can now receive the same regimens as children from 6 months to 3 years (see table viii for dosages). † efavirenz if the child is over 3 years and nevirapine if < 3 years. table vii. national doh art drug choices for children category i stavudine (d4t)* nrti – thymidine base zidovudine (zdv)* category ii didanosine (ddi)* nrti – other lamivudine (3tc)*† abacavir (abc)* ntrti tenofovir (tdf)‡ category iii nevirapine (nvp)† nnrti efavirenz (efv)†§ category iv ritonavir (rtv)* pi nelfinavir (nfv)* lopinavir/ritonavir (lpv/rtv)* saquinavir (sqv) soft gel indinavir (idv) *available in paediatric formulations. †require single mutation for development of resistance and therefore some experts only use them in regimens with a good chance of attaining undetectable viral loads. ‡not yet available in paediatric formulation. paediatric dosage still uncertain. requires section 21 authorisation from the medicines control council. §efavirenz (efv) is only available in capsule form. there are no data for children under 3 years of age. nrti = nucleoside reverse transcriptase inhibitor; ntrti = nucleotide reverse transcriptase inhibitor; nnrti = non-nucleoside reverse transcriptase inhibitor; pi = protease inhibitor. table iv. antiretroviral drugs hiv november new 13/12/05 12:43 pm page 22 the southern african journal of hiv medicine november 2005 2 3 nnrtis ■ nevirapine ■ efavirenz. additional practical points nucleoside analogues resistance to nucleoside analogues is slow to develop, with the exception of 3tc. resistance to 3tc is selected within weeks when part of a non-suppressive regimen, but this is not generally a problem if there is good adherence to a 3-drug combination. 3tc resistance may, however, sensitise hiv to the antiviral activity of zdv, d4t and tdf, but the durability of this effect is uncertain. also, hiv with the characteristic mutation for 3tc resistance, m184v, is less pathogenic. all nucleoside analogues have been associated with lactic acidosis, a rare but potentially life-threatening complication of treatment. the pathogenesis is believed to involve druginduced mitochondrial damage. practical dosing advice although paediatric dosages are calculated using the child's weight or surface area, one must consider the practicalities of the dose. a dose of 1.75 ml, for example, is very difficult to measure accurately, so a more practical dose would be 1.8 ml (generally round upwards). certain arv solutions, e.g. lpv/rtv (kaletra®) or rtv (norvir), are highly concentrated, so dosages do need to be calculated to the nearest one-tenth of a millilitre (but it is not necessary to calculate to the nearest one-hundredth). others, e.g. zdv, 3tc, nvp (viramune®) or abc (ziagen®) solutions, can quite safely be rounded up to the nearest millilitre. when using stavudine capsules dissolved in water, dosages can be rounded up to the nearest 5 mg. every effort should be made to switch to tablets or capsules as soon as possible. haart after failed mtct prophylaxis 1. when nevirapine was used as a single dose in mtct prophylaxis. in the hivnet 012 study, up to 45% of hivinfected infants had resistance mutations against nnrtis after 1 dose of nvp to the mother and the infant for prevention of mother-to-child transmission (mtct). there are emerging data in adults and children suggesting reduced efficacy of future nnrti-containing regimens. it is therefore advisable to avoid nevirapine and efavirenz as part of first-line therapy in this situation. 2. if azt monotherapy was used in mtct prophylaxis. data support the use of azt as part of combination therapy in infected infants. resistance has, however, been described. 3. if azt and 3tc were used as dual therapy for mtct prophylaxis, avoid 3tc only if the mother had a prolonged course of treatment without adequate viral suppression. however, in the usual short courses used for mtct (< 4 weeks), it would be acceptable to use 3tc in the hivinfected infant. 4. if the mother was on triple combination therapy, where possible avoid the drugs the mother was taking, especially if she had a detectable viral load. if unavoidable, it is advisable to get resistance testing done on the infant first and only use those drugs to which the virus is sensitive. if the mother had a undetectable viral load, it is probably acceptable to use the same agents in her hivinfected baby. tb treatment and haart in children as a result of the interaction between rifampicin and the pis and nnrtis, one needs to modify the tuberculosis treatment or the art or both. other factors to take into consideration are overlapping toxicities of tb drugs and arvs, and immune reconstitution inflammatory syndrome (iris). options: ■ ideally delay initiation of art until after the course of tb treatment. (allow 2 weeks for the effects of rifampicin on the liver to ‘wash out’.) ■ if the cd4 count at the start of tb treatment indicates the need for art, then delay the initiation of art for 1 2 months of tb treatment. this reduces the likelihood of immune reconstitution disease and enables identification of the likely causative drugs if toxicities develop. use standard tb treatment together with arvs compatible with rifampicin, i.e. 2 nrtis + either ritonavir or efavirenz (children > 3 years). the efavirenz dose should be increased by 30%. in practical terms, just adding an additional 50 mg capsule of efv to the child's calculated dose is probably adequate (currently under investigation in a pk study in cape town). ■ use rifabutin instead of rifampicin (difficult to obtain and very expensive); ritonavir should not be used with rifabutin. ■ in adults, extra rtv can be added to lpv/rtv (kaletra®) to overcome the effects of the rifampicin. unfortunately there is, as yet, no paediatric recommendation. this is currently under investigation in a pharmacokinetic study in cape town. please discuss with an expert in this matter. specific issues for adolescents ■ adult guidelines are appropriate for post-pubertal adolescents (tanner stage v) (tables x and xi). ■ for adolescents in early puberty (tanner stages i and ii) use paediatric guidelines). ■ for intermediate puberty, use paediatric guidelines but monitor closely for toxicity. ■ non-adherence is problematic and strategies should be introduced to promote adherence, including more frequent visits and intensive counselling. ■ disclosure of the child's diagnosis is an important issue in ensuring adherence in adolescents. disclosure is a process hiv november new 13/12/05 12:43 pm page 23 november 2005 the southern african journal of hiv medicine24 table viii. dosage and frequency of arvs in children susp: 10 mg/ml caps: 100 mg, 250 mg tabs 300 mg susp: 10 mg/ml tabs: 25 mg, 50 mg, 100 mg, 150 mg enteric-coated didanosine (ec) 250 mg, 400 mg susp: 1 mg/ml caps: 20 mg, 30 mg, 40 mg susp: 20 mg/ml tabs: 300 mg susp: 10 mg/ml tabs: 150 mg susp: 10 mg/ml tabs: 200 mg caps: 50 and 200 mg (suspension available from manufacturer) neonates: 4 mg/kg/dose until 29 days paediatric: 180 240 mg/m2 neonates: 50 mg/m2/dose paediatric: 90 120 mg/m2 neonates < 29 days: 0.5 mg/kg/dose paediatric: 1 mg/kg/dose all ages: 8 mg/kg/dose neonates: 2 mg/kg paediatric: 4 mg/kg neonates: 5 mg/kg/ day od x 14 days then 120 mg/m2/dose bd x 14 days then 200 mg/m2/dose bd paediatric: 120 200 mg/m2 start at 120 mg/m2 daily for 14 days and increase to bd dosage if no rash or severe side-effects 10 <15 kg: 200 mg 15 < 20 kg: 250 mg 20 < 25 kg: 300 mg 25 < 32.5 kg: 350 mg 32.5 < 40 kg: 400 mg > 40 kg: 600 mg 2 2 2 2 can give total daily dosage x 1 2 2 2 2 2 2 1 room temperature refrigerate suspension refrigerate suspension room temperature room temperature room temperature room temperature half h pre-meals or 1 h after meal use single daily dose if necessary for adherence. needs to be separated from pi by 1 2 h (depending on which pi) ec ddi still needs to be taken on empty stomach but can be given together with pi ec ddi capsules can be opened and sprinkled on food capsules stable in water suspension for 24 hours at room temperature watch for hypersensitivity reaction. do not rechallenge after hypersensitivity reaction skin rash usually occurs in 1st 6 weeks; do not increase dosage until rash resolves watch for liver toxicity try to maintain dosage >150 mg/m2/ dose bd no data < 3 yrs and < 10 kg. give at night to avoid cns side-effects. capsules can be opened & given with food. anticipate cns sideeffects (frequently nightmares) – potential source of early poor adherence zidovudine (zdv) retrovir® didanosine (ddi) videx® stavudine (d4t) zerit® abacavir ziagen® lamivudine (3tc®) nevirapine viramune® efavirenz stocrin® drug formulations dosage (per dose) frequency storage comments nucleoside reverse transcriptase inhibitors (nrtis) non-nucleoside reverse transcriptase inhibitors (nnrtis) hiv november new 13/12/05 12:43 pm page 24 the southern african journal of hiv medicine november 2005 2 5 ` table viii. dosage and frequency of arvs in children (continued) susp: 80 mg/ml caps: 100 mg susp: 50 mg/1 g spoon and 200 mg per teaspoon tabs: 250 mg oral solution: 80 mg lopinavir (lpv) & 20 mg ritonavir (rtv) per ml capsules: 133 mg lpv/33 mg rtv hard gel capsules (hgc): 200 mg (only use together with rtv) > 1 month: start at 250 mg/m2/dose and increase by 50 mg/m2 every 2 3 days up to 400 mg/m2 1 month to 2 years: 450 mg/m2 neonates: 55 75 mg/kg/dose paediatric: < 1 year 75 mg/kg/ dose > 1 year 55 60 mg/ kg/dose (adolescent: 750 mg tds or 1 250 bid) infants < 6 months: 300 mg lpv component/m2 patients not taking nvp or efv: 230 mg lpv component/m2 (max 400 mg lpv = adolescent dose) in the light of low levels of lpv found in children esp < 2 years of age, some experts would use the higher dose of kaletra below in all children patients taking nvp or efv or art experienced: 300 mg lpv component/m2 (max 533 mg lpv = adolescent dose) dual pis: sqv 50 mg/kg rtv 100 mg/m2 adolescent: sqv 1 000 mg rtv 100 mg 2 2 2 2 2 2 2 2 2 2 2 capsules should be refrigerated. oral solution can be kept at room temperature. room temperature oral solution and capsules should be refrigerated can be kept at room temperature up to 25ºc if used within 2 months room temperature take with food bitter; coat mouth with peanut butter or give with chocolate milk take 2 h apart from ddi. can be taken together with ec ddi give 2 h before or 1 h after ddi. can be taken together with ec ddi. best with light meal do not use with rifampicin powder is 5% active drug and the rest is carrier powder. most experts prefer to crush the tablets and suspend in milk or water or sprinkle on pudding administer with food. high-fat meal increases absorption, especially of the liquid preparation if co-administered with ddi, ddi should be given 1 hour before or 2 h after lopinavir/ritonavir kaletra can be taken together with ec ddi administer within 2 h of a full meal to increase absorption sun exposure can cause photosensitivity reactions; therefore, sunscreen or protective clothing is recommended ritonavir norvir® nelfinavir vira-cept® lopinavir/ ritonavir kaletra® saquinavir (sqv) invirase® – hard gel capsule drug formulations dosage (per dose) frequency storage comments protease inhibitors (pis) body surface area (m2) = √height (cm) � weight (kg) � 3600 hiv november new 13/12/05 12:43 pm page 25 november 2005 the southern african journal of hiv medicine that should begin from 7 years of age taking into account the child's cognitive ability. changing therapy ■ in case of toxicity or intolerance, a simple substitution can be made. do not reduce dosage unless the reduced dose is still in the therapeutic range. ■ for failure of a regimen: • first-line therapy. if the viral load is detectable even at a low rate, check and encourage adherence. also check dosages or other ‘technical problems’ such as for vomiting or spitting out medications or not receiving medications on time. if the viral load is persistently > 10 000 copies/ml on 2 or 3 occasions despite good adherence and resolved technical problems, consider changing regimens. be sure to resolve the adherence problems before changing therapy, otherwise the second regimen will also be doomed to failure. • second-line or subsequent regimens – consult an expert. ■ when failure is due to viral resistance, at least two drugs should be changed. consider resistance testing (see below). ■ since future options are limited, whether to change and choice of new regimen should only be made by an experienced clinician. ■ consult the southern african hiv clinicians society. resistance testing at present only genotypic resistance testing is available in south africa. genotyping is still an expensive option. genotyping will only tell about resistance to drugs the patient is currently taking but not necessarily about resistance to previous arvs the child may have been exposed to. for this reason, genotyping needs to be interpreted in conjunction with a detailed arv drug history. the interpretation is complicated and should be done by an expert in the field. generally genotyping is reserved for patients who have failed their second regimen because of the cost involved. however in paediatrics, because of the practice of continuing with a regimen that is failing virologically yet not immunologically or clinically, there may be a place for genotyping after failing a first regimen. there may also be a place for infants infected despite maternal haart. contact the southern african hiv clinicians society for further information on when to perform and on interpreting genotyping. stage pubic hair penis testes 1 none pre-adolescent pre-adolescent 2 scanty, long, slight enlarged slightly pigmented enlargement scrotum, pink texture altered 3 darker, starts longer larger to curl, small amount 4 resembles adult, larger, glans larger, scrotum less than adult and breadth dark increase size 5 adult distribution adult adult spread to medial surface of thighs table x. tanner staging for boys stage pubic hair breasts 1 pre-adolescent pre-adolescent 2 sparse, lightly breast and papilla elevated pigmented, straight, as small mound; areola medial border labia diameter increased 3 darker, beginning breast and areola to curl, increased enlarged, no contour amount separation 4 coarse, curly, areola and papilla form abundant but less secondary mound than adult 5 adult feminine mature; nipple projects, triangle, spread to areola part of general medial surface of breast contour thighs table xi. tanner staging for girlstable ix. side-effects of arvs in children class drug side-effects nrti zdv anaemia, granulocytopenia (retrovir®) myopathy, lactic acidosis ddi common: abdominal pain, nausea and vomiting (videx®) uncommon: pancreatitis, peripheral neuropathy, lactic acidosis stavudine common: headache, rash, gastrointestinal (zerit®) uncommon: lipoatrophy, pancreatitis, peripheral neuropathy, lactic acidosis abacavir hypersensitivity reaction (with or without (ziagen®) rash) – fever, rash, fatigue, nausea, vomiting, diarrhoea, pharyngitis, dyspnoea and cough, elevated alt, creatinine or cpk lymphopenia lactic acidosis lamivudine common: headache, fatigue and abdominal pain (3tc®) uncommon: lactic acidosis nnrti nevirapine skin rash, sedative effect and diarrhoea. liver (viramune®) toxicity efavirenz skin rash (stocrin®) cns – sleep disturbance, confusion, abnormal thinking teratogenic in primates and humans pi ritonavir nausea, vomiting, diarrhoea (norvir®) hypercholesterolaemia and hypertriglyceridaemia, lipodystrophy nelfinavir diarrhoea (vira-cept®) can exacerbate chronic liver disease hypercholesterolaemia and hypertriglyceridaemia lopinavir/ nausea, vomiting, diarrhoea ritonavir hypercholesterolaemia and (kaletra®) hypertriglyceridaemia, lipodystrophy 28 hiv november new 13/12/05 1:42 pm page 28 the southern african journal of hiv medicine november 2005 2 9 switching from a pi-containing to an nnrti-containing regimen numerous adult and one paediatric study have shown the feasibility of switching from a pi to an nnrti where viral loads are < 50 copies/ml on a pi-containing triple regimen. this would help prevent some of the long-term adverse effects of the pis. where the mother and/or baby had been given a single dose of nvp to prevent mtct, this practice should be avoided. interrupting therapy when stopping or interrupting a regimen containing an nnrti, be aware that the long half-life of the nnrti will cause subtherapeutic levels to persist for up to several weeks. some experts favour either continuing the nrtis for a week after stopping the nnrti or switching to a pi to avoid developing resistance to the nnrti. selected adverse effects of arvs in children arvs are generally well tolerated in children. a few more serious adverse effects are mentioned here. for other adverse effects contact the southern african hiv clinicians society. lactic acidosis lactic acidosis is a serious, life-threatening complication of nrti therapy, especially ddi and d4t. fortunately it is rare. symptoms include nausea and vomiting, abdominal pain, tachypnoea and dyspnoea, weight loss and fatigue. it may also cause neurological symptoms including a guillain barré-like picture. there is no value in routine measurement of lactate levels. clinicians should be aware of the symptoms and diagnose the condition timeously. diagnosis is confirmed with a serum lactate level of > 5 mmol/l, metabolic acidosis and a raised anion gap. liver enzymes may also be increased. in patients with a lactate level >10 mmol/l or > 5 mmol/l and metabolic acidosis, art should be discontinued and supportive therapy instituted. treatment (usually in an intensive care unit) consists of intravenous fluids and ensuring oxygenation of tissues with respiratory support, as needed. some reports suggest that alkalinising the blood with bicarbonate might improve prognosis, but this remains controversial. thiamine (vitamin b1), riboflavin (vitamin b2) and l-carnitine may be useful (there are no data to show efficacy). following an episode of lactic acidosis, it may take several months for lactate levels and liver enzymes to normalise. nrtis should generally not be used again. contact the society for assistance in designing a new regimen after lactic acidosis. haematological toxicity the two major agents implicated in causing haematological toxicity in hiv-infected patients are zidovudine and cotrimoxazole (usually only high-dose co-trimoxazole used in treating pcp, but occasionally prophylactic doses. it is reversible with folinic acid – not folic acid). patients on zdv should have their full blood counts (fbcs) monitored monthly for the first 3 months and 3-monthly thereafter. the main bone marrow toxicities from zdv are anaemia and neutropenia. anaemia may be due to hiv infection itself, aids-related conditions such as disseminated mycobacterium avium complex (mac), cytomegalovirus, or lymphoma, or it may be nutritional, e.g. iron or folate deficiency, or drug related. it is most commonly caused by zdv but may be related to other arvs. management depends on the options available and the extent of the problem. it is reasonable to switch to a drug that causes fewer haematological side-effects, e.g. switch from zdv to d4t. a haemoglobin level below 7 8 g/dl warrants investigation and treatment. nutritional deficiencies, especially of iron, should be addressed as well. neutropenia is quite common in children with hiv and in those on haart. unless severe, < 0.25 � 109/l, it often resolves spontaneously (provided there are no associated signs such as persistent fever or localised infection) and a repeat fbc should simply be done a week later. if neutropenia is severe, < 0.25 � 109/l, the offending agent should be replaced if feasible. rashes most rashes following arvs are mild to moderate and resolve spontaneously with drug continuation. most rashes are maculopapular or urticarial. the most severe rashes include stevens-johnson syndrome, toxic epidermal necrolysis, abacavir (abc) hypersensitivity reaction rash, and the drug rash with eosinophilia and systemic symptoms (dress) reported with nnrtis. the highest incidence of drug rashes occurs with the nnrtis (more severe and more frequent with nvp). rash usually occurs in the first 2 4 weeks of treatment. the rash is usually maculopapular and erythematous. nvp is given daily for the first 2 weeks and only increased to twice daily once the rash has resolved. mild to moderate rashes will often resolve spontaneously but need to be closely monitored. oral antihistamines can be used. in children who develop severe rash, cutaneous bullae or target lesions, mucosal lesions or systemic symptoms, nvp should be permanently discontinued. if nvp is discontinued because of mild or moderate rash, restarting nvp after the rash has resolved may be considered with close monitoring. cross-reactivity among nnrtis may occur. therefore avoid efv in children with a severe rash. however, in children with mild or moderate rash without mucosal involvement or systemic symptoms, substitution of efavirenz (efv) may be done with caution. rashes may occur in children receiving efv. these rashes are usually less severe than in those with nvp, and resolution of the rash during treatment continuation is common. however, hiv november new 13/12/05 1:42 pm page 29 november 2005 the southern african journal of hiv medicine if efv-associated rash is severe, or is accompanied by mucosal or systemic symptoms, efv should be permanently discontinued. hypersensitivity syndrome abacavir and nevirapine are most commonly implicated in hypersensitivity syndrome. abc causes a systemic illness characterised by fever, rash, nausea, vomiting, diarrhoea, fatigue, myalgia and arthralgia. respiratory symptoms, such as pharyngitis, cough, or dyspnoea may be present. the skin rash occurs in about 70% of cases and is often maculopapular or urticarial. the abc hypersensitivity reaction occurs in 4 8% of patients, but it may be less common in black africans. it usually occurs in the first 6 weeks after starting abc. it is characterised by multisystem involvement and worsening of symptoms with each dose. abc hypersensitivity reaction is fully reversible on discontinuing abacavir, and is never fatal on first exposure to the drug. patients must never be rechallenged with abc after a hypersensitivity reaction as deaths from hypotension have occurred. a hypersensitivity reaction has been described for nvp. systemic symptoms such as fever, myalgia, arthralgia, hepatitis and eosinophilia may occur. it usually occurs in the first 8 weeks of treatment. nvp should be permanently discontinued after a nvp hypersensitivity reaction and efv should be avoided as well. hepatotoxicity all three classes of arv drugs currently in use in sa have been implicated. liver dysfunction in hiv infection may be caused by hiv itself, co-infection with hepatitis b or c viruses or opportunistic infections, malignancies, drug interactions or drug-induced hepatotoxicity. nrti-associated hepatotoxicity is primarily due to mitochondrial toxicity. nnrtis are associated with asymptomatic elevations in liver enzymes and hypersensitivity reaction with hepatitis. nvp is associated with more hepatotoxicity than efv. pi-associated elevations in liver enzymes can occur at any time during the course of therapy. patients with chronic hepatitis b or c may experience an increase in liver enzymes after starting haart as part of an immune reconstitution disease. also, after discontinuing drugs such as 3tc or tdf (which are used to treat hepatitis b) there may be an increase in liver enzymes. children do seem to get less hepatic dysfunction on haart than adults. patients on nvp should have liver function tests (lfts) done 2weekly for the first two months, then 3-monthly thereafter. lfts should be monitored routinely 3 4-monthly in patients on other haart regimens. if transaminases are elevated < 10 times the upper limit of normal (uln) there is no need to interrupt haart. patients with clinical hepatitis or severe hepatotoxicity (> 10 � uln) should have a work-up for other causes of hepatitis, e.g. hepatitis a, b or c, and haart should be interrupted. patients on nvp with clinical hepatitis should discontinue nvp and have their haart regimen changed. rechallenge with nvp or abc after acute hepatitis is not recommended. patients with hepatitis b co-infection may need to continue with 3tc if their haart regimen is changed to prevent a flare-up in their hepatitis b. lipodystrophy lipodystrophy typically involves accumulation of visceral fat in the abdomen (central obesity), dorsocervical area (buffalo hump) and breasts. there may also be loss of subcutaneous fat in the face, extremities and buttocks (lipoatrophy). the pis have been implicated in causing the fat accumulation, whereas the nrtis, especially stavudine, have been implicated in lipoatrophy. there are no data in children, but adult data suggest that switching from d4t or zdv to abc will partially reverse lipoatrophy but not the visceral fat accumulation. there are also limited data indicating that switching to a regimen containing a pi and an nnrti only will also reverse lipoatrophy. hyperlipidaemia the pis (especially rtv and lpv/r) are the main arvs implicated in causing hyperlipidaemia. however, both stavudine and efavirenz have also been implicated. while pi therapy in adults is associated with increased risk of cardiovascular disease, there is currently no evidence of an association between elevated cholesterol levels in children and an increased risk of premature death, as in adults. as a result, there has been no experience with lipid-lowering agents in children and there is no consensus in this regard. cholesterols and triglycerides should be measured 6 12-monthly in children on pis. a random cholesterol and triglyceride is probably adequate, but if these are raised a fasting level should be done. referral to a dietician and encouraging exercise are the first interventions. if these are unsuccessful, consult the southern african hiv clinicians society. options available include observation, arv agent switching (e.g. from a pi to an nnrti) or lipid-lowering agents. statins are metabolised by cytochrome p450 resulting in either toxicity or diminished effect when used with ritonavir, so these agents should be used with caution and only on the advice of an expert. recommended reading 1. centers for disease control and prevention. guidelines for the use of antiretroviral agents in paediatric practice. mmwr 1998; 47: 1-43. published and updated regularly on www.aidsinfo.nih.gov 2. sharland m, castelli g, ramos jt, blanche s, gibb dm. on behalf of the penta steering committee. penta guidelines for the use of antiretroviral therapy in paediatric hiv infection www.ctu.mrc.ac.uk/penta/ 3. world health organization guidelines www.who.int 4. national department of health guidelines www.doh.gov.za/ 30 hiv november new 13/12/05 1:42 pm page 30 with the development of the society's two previous paediatric antiretroviral therapy (art) guidelines in 2000 and 2002 there were no other guidelines available in south africa (sa), so our guidelines had to accommodate all children in sa. these guidelines were used both for children in the private sector and those in the state sector whose parents were funding their own therapy. however, since 2003 the department of health (doh) has published excellent guidelines for treating children with art in the state sector. these guidelines are more than sufficient for patients in the state sector who require art, and are summarised in this journal on page 33. it is important to remember to consult the latest version of the doh guidelines as previous versions are still in circulation, which are very cumbersome and impractical to use. the paediatric sub-group's dilemma when designing their guidelines was to whom they should be targeted. clearly there was no need to have extra guidelines for patients in the state sector. there are, however, no good guidelines for patients who have access to more resources and have more choice with regard to antiretroviral drugs and regimens and when to start art. there are still quite a considerable number of patients on art in the private sector. in addition, these patients may have been on therapy for a number of years now and some might already be on their second or third regimens. for this reason, a guideline was needed that took into account those choices that are available in the private sector. this guideline would need to introduce concepts such as genotyping for changing therapy, which may not be available to those patients in the state sector. these guidelines are in no way intended to undermine the doh guidelines and are generally to be used only by those patients in the private sector who have access to other resources. it is my fervent hope that by the time the society's paediatric antiretroviral guidelines are next updated there will be no need for separate guidelines for the state and private sectors. we are making a concerted effort to work towards having only one guideline, but in the meantime people in the state sector are encouraged to use state sector guidelines and those in the private sector are encouraged to use these guidelines below. the most important issue is not which guidelines we follow but that we treat these children. so many children out there need art and are not receiving treatment. even more devastating is the fact that a large number of children are dying from aids who should not be dying from what is clearly a controllable chronic disease. children should be living with hiv and not dying from it. i would like to thank the members of my committee for their contributions to these guidelines and for the effort and time they put into this endeavour. i would also like to thank our overseas reviewers, not only for critically reviewing these guidelines but for the contribution they are making to the advancement of paediatric art in south africa. leon levin chairman, southern african hiv clinicians society's paediatric sub-committee november 2005 paediatric antiretroviral therapy – how many guidelines? guidelines for antiretroviral therapy in children november 2005 version chairman dr leon levin expert panel members prof mark cotton, prof glenda gray, dr leon levin, prof james nuttal, dr helena rabie, dr paul roux and dr avye violari international reviewers prof stephane blanche, dr elaine abrams, dr ann melvin, dr andrew pavia and dr gareth tudor-williams we acknowledge the assistance of dr lucille blumberg in the section on tb treatment and haart in children. disclaimer: specific recommendations provided in this document are intended only as a guide to clinical therapy, based on expert consensus and best current evidence. recommended drugs and dosages are based on current available data and may differ from dosages recommended by manufacturers. treatment decisions for patients should be made by their responsible clinicians with due consideration for individual circumstances. the most current version of this document should always be consulted. the southern african journal of hiv medicine november 2005 3 1 hiv november new 13/12/05 1:42 pm page 31 hiv 878 message from the editor this edition of the southern african journal of hiv medicine is coming out slightly earlier than scheduled, timed to coincide with the first southern african hiv clinicians society conference in cape town. the conference features an exciting line-up of leading local researchers, as well as international experts. during 2013, the journal will carry some of the reports and papers from the meeting; therefore, if you can’t attend the conference, you will still be able to keep up to date on the latest trends and developments in hiv medicine and clinical care. in this issue we feature a number of pieces related to the management of hiv-infected pregnant women. some researchers, clinicians and policy makers see the prevention of mother-to-child transmission (pmtct) of hiv as rather straightforward, and i’ve sat in on more than a few meetings where pmtct is described by colleagues (both south african and international) as important yet ‘boring’. quite to the contrary, pmtct interventions and policies are currently a hotbed of debate at the intersection of science, service delivery and policy-making. along with other pieces in the journal over the last few months, several of the contributions in this edition help to demonstrate why this is so. firstly, martin and black1 discuss the role of isoniazid preventive therapy (ipt) for tuberculosis in hiv-infected pregnant women. they suggest that given the relative health of hiv-infected pregnant women, even with low cd4 cell counts, routine use of ipt during pregnancy may not be the best use of resources to promote the health of hiv-infected mothers and their children. in addition, the choice of antiretrovirals (arvs) during pregnancy can be controversial, with particular local concern surrounding arv-related toxicities in pregnancy. usually these concerns focus on fetal development and potential teratogenicity, but the choice of non-nucleoside reverse transcriptase inhibitors (nnrtis) also has implications for maternal health. in this issue, bera et al.2 report two cases of apparent nevirapine (nvp) toxicities in pregnant women initiating art. while case reports are rarely suitable evidence for making clinical or policy decisions, the authors point out that the evidence against the use of efavirenz in pregnancy comes mostly from case reports of teratogenicity – so perhaps these cases of nvp toxicity help to balance the scales somewhat. arguably the most contentious issue in pmtct today regards the choice of prophylactic regimens for women with higher cd4 cell counts (e.g. >350 cells/mm3). there is little debate that pregnant women with advanced hiv disease require rapid initiation of lifelong antiretroviral treatment (art). however, the best arv intervention for women with higher cd4 cell counts is unclear. currently, south africa and many other countries implement zidovudine prophylaxis during pregnancy for women with high cd4 cell counts (referred to as pmtct ‘option a’ in the world health organization (who) 2009 guidelines), while in europe, brazil and north america, triple-drug prophylaxis during pregnancy (who ‘option b’) is commonplace. to date, these prophylactic strategies appear roughly equivalent in their effectiveness for pmtct, and a randomised controlled trial comparing them is underway, with several sites in south africa. recently there has been a call for universal initiation of lifelong art for all hiv-infected pregnant women, regardless of cd4 cell count or who stage. this approach (sometimes referred to as who ‘optional b+’) is the focus of a commentary in this issue by besada and colleagues3 from médecins sans frontières (msf). the who ‘optional b+’ approach is being promoted heavily by who, the united states president’s emergency plan for aids relief (pepfar), and a range of international agencies, and – as presented here – there are strong hypothetical arguments for the idea of universal art for pregnant women. on the other hand, there are also significant concerns raised by any strategy that calls for universal art for all hiv-infected individuals. yet, throughout these discussions about ‘optional b+’, there is a striking absence of substantive evidence, and the knowledge base that could help inform a policy decision to implement universal initiation of lifelong art for all hiv-infected pregnant women is astonishingly thin. in particular, there is as yet no meaningful evaluation of a programme that attempts to provide lifelong art to all hiv-infected pregnant women. without such evidence, national policy decisions regarding patient management can be leveraged by individual opinions, institutional agendas and donor priorities. in this context, we eagerly anticipate a decision by the national department of health on the future strategies for pmtct in south africa. hopefully, along with the other pmtct-related contributions in this issue, this debate helps to demonstrate that this is a topic that is anything but boring. happy reading.   landon myer associate professor school of public health & family medicine faculty of health sciences university of cape town landon.myer@uct.ac.za   1. martin ce, black v. tuberculosis prevention in hiv-infected pregnant women in south africa. southern african journal of hiv medicine 2012;13(4):182-184. [http://dx.doi.org/10.7196/sajhivmed.789] 1. martin ce, black v. tuberculosis prevention in hiv-infected pregnant women in south africa. southern african journal of hiv medicine 2012;13(4):182-184. [http://dx.doi.org/10.7196/sajhivmed.789] 2. bera e, naidoo d, williams m. maternal deaths following nevirapine-based antiretroviral therapy. southern african journal of hiv medicine 2012;13(4):196-197. [http://dx.doi.org/10.7196/sajhivmed.869] 2. bera e, naidoo d, williams m. maternal deaths following nevirapine-based antiretroviral therapy. southern african journal of hiv medicine 2012;13(4):196-197. [http://dx.doi.org/10.7196/sajhivmed.869] 3. besada d, van cutsem g, goemaere e, ford n, bygrave h, lynch s. the case for option b and optional b+: ensuring that south africa’s commitment to eliminating mother-to-child transmission of hiv becomes a reality. southern african journal of hiv medicine 2012;13(4):178-181. [http://dx.doi.org/10.7196/sajhivmed.864] 3. besada d, van cutsem g, goemaere e, ford n, bygrave h, lynch s. the case for option b and optional b+: ensuring that south africa’s commitment to eliminating mother-to-child transmission of hiv becomes a reality. southern african journal of hiv medicine 2012;13(4):178-181. [http://dx.doi.org/10.7196/sajhivmed.864] m southtrn mrican journal o~ hiv mtoicint -----------july 2002 something to offer unoa-gail bekker managing editor encouraging it is that more than just an isolated few are talking of expanded access to highly active antiretroviral therapy (haarn for the people of africa i the w9rld health organisation conservatively estimates that some 6 million people in developing countries are in need of lifesustaining antiretrovirals right now, in the year 2002, yet only 230 000 have access, and most live in one country brazil. in april 2002 the who came up with guidelines on scaling up antiretroviral therapy in resource-limited settings, the global fund is being mobilised and local activist organisations are shifting their emphasis on mother-to-child (mtcn prevention programmes to include general access to haart. not that the pressure on the need for mtct prevention and improved mtct programmes should abate for even a moment. fourteen weeks ago i had the awesome experience of giving birth to a wonderful little boy who has subsequently turned our lives around and filled us with such joy. but along with the joy i have been struck by how much anxiety, both rational and irrational, goes with the whole experience. i have feared for his safe delivery, his state of health, my ability to feed him, our coping with him and his acceptance of us, and so on and on. and then i tried to imagine what it must be like to be a young mother who suspects or discovers her positive hiv status, and must await with trepidation the possible additional calamity that her infection has passed to her child. such anxiety must be intolerable, yet in this country many brave young women face it daily. as a medical profession we have something that can be offered to them. our present mtct strategies are not a panacea and will not save all, but giving a mother the opportunity to do as much as she can for her unborn child may compensate for some of the anxiety. it is two years since the publication of the hiv clinicians society's first antiretroviral guidelines. the current issue of the journal is devoted entirely to the issues surrounding antiretroviral therapies. the eagerly awaited revised guidelines have seen changes brought about due to the availability of new drugs and the dramatic price decreases in drugs. the who recommendations have been borne in mind, as have the recommendations of our international reviewers (ias, prof. stefano vella/prof. joep lange; iapac, jose zuniga usa; uk prof. brian gauard; australia prof. oavid cooper; and argentina praf. pedro cahn). des martin editor, southern african journal ofhiv medicine president, southern african hivclinicians society i would like to take this opportunity to thank the guidelines committee ior des martin, or mark cotton, prof. gary maartens, or oave spencer, or mark andrews, or francois venter and prof. robin wood) who met in march 2001 under the chairmanship of or steven miller. these guidelines represent a good balance between the standard of care and the economic resources available to provide this optimal care. it is to be noted that the guidelines concentrate on firstand second-line therapies and that thirdand fourth-line therapies and salvage therapies should be managed by clinicians who have expertise in dealing with such failures. it is recommended that clinicians access the society's treatment network for help and advice in this regard. this edition also sees an update in review form of the various issues that impact on the use of antiretroviral therapies and provides an insert that should prove useful as a quick desktop reference guide for clinicians in their daily practices. from the editors abstract introduction methods results discussion limitations conclusion acknowledgements references about the author(s) preyanka pillay department of internal medicine, greys hospital, pietermaritzburg, south africa school of clinical medicine, college of health sciences, university of kwazulu-natal, durban, south africa somasundram pillay department of internal medicine, edendale hospital, pietermaritzburg, south africa department of internal medicine, king edward hospital, durban, south africa nobuhle mchunu department of biostatistics, faculty of statistics, south african medical research council, durban, south africa department of statistics, school of mathematics, statistics and computer science, university of kwazulu-natal, pietermaritzburg, south africa citation pillay p, pillay s, mchunu n. the spectrum of electrolyte abnormalities in black african people living with human immunodeficiency virus and diabetes mellitus at edendale hospital, pietermaritzburg, south africa. s afr j hiv med. 2020;21(1), a1095. https://doi.org/10.4102/sajhivmed.v21i1.1095 original research the spectrum of electrolyte abnormalities in black african people living with human immunodeficiency virus and diabetes mellitus at edendale hospital, pietermaritzburg, south africa preyanka pillay, somasundram pillay, nobuhle mchunu received: 26 apr. 2020; accepted: 07 june 2020; published: 23 july 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: serum electrolyte abnormalities in black african people living with human immunodeficiency virus (hiv) and diabetes mellitus (plwh/dm) is unknown. objectives: the aim of this study was to analyse serum electrolytes (sodium, potassium, calcium and phosphate) and factors associated with electrolyte abnormalities in black african plwh/dm versus hiv-uninfected patients with dm. methods: we conducted a retrospective case-control study in 96 black african plwh/dm (cases) and 192 hiv-uninfected patients with dm (controls), who were visiting the edendale hospital dm clinic, from 01 january 2016 to 31 december 2016. pearson’s correlation, multivariate linear and logistic regression analyses were utilised. results: hypocalcaemia was the most frequent electrolyte abnormality in plwh/dm and hiv-uninfected patients with dm (31.25% vs. 22.91%), followed by hyponatraemia (18.75% vs. 13.54%). median (iqr) corrected serum calcium levels were significantly lower in plwh/dm compared with hiv-uninfected patients with dm (2.24 [2.18–2.30] mmol/l vs. 2.29 [2.20–2.36] mmol/l; p = 0.001). for every per cent increase in glycated haemoglobin, the odds of hyponatraemia significantly increased in both plwh/dm (odds ratio [or]: 1.55; 95% confidence interval [ci]: 1.19 –2.02; p = 0.003) and hiv-uninfected patients with dm (or: 1.26; 95% ci: 1.04 –1.54; p = 0.009). conclusion: hypocalcaemia and hyponatraemia were the most frequent electrolyte abnormalities and occurred more frequently in plwh/dm compared with hiv-uninfected patients with dm. people living with hiv and dm have significantly lower corrected serum calcium levels compared with hiv-uninfected patients with dm. furthermore, hyponatraemia is a marker of impaired glycaemic control. keywords: hiv; diabetes mellitus; electrolytes; sodium; potassium; calcium; phosphate; black african. introduction lowand middle-income countries account for 80% of the global diabetes mellitus (dm) burden.1 the international diabetes federation (idf) estimates that africa will experience the greatest global upsurge of dm by 2045.1 in 2015, dm was the second leading cause of mortality in south africa after tuberculosis.2 moreover, south africa has the highest prevalence of human immunodeficiency virus (hiv) globally and recorded 7.06 million people living with hiv (plwh) in 2017, with kwazulu-natal province having the majority of these cases.3,4 following the introduction of antiretroviral therapy (art), the prevalence of comorbid hiv and dm is on the rise because of an increase in life expectancy and the adverse metabolic effects of art.5 a study in the united states of america (usa) determined that the prevalence of dm in plwh was 10.3%, and the prevalence of dm was 3.8% higher in plwh compared with the general population.6 electrolytes play a vital role in maintaining homeostasis and are paramount in mediating enzymatic reactions, cellular function and electrical gradients.7 patients with hiv or dm are predisposed to electrolyte abnormalities because of multifactorial pathophysiological factors.8,9 the risk of nephropathy, with subsequent electrolyte abnormalities, increases in the setting of comorbid hiv and dm. furthermore, the black african population has distinct electrolyte physiology and a predisposition to chronic kidney disease and hiv-associated nephropathy (hivan).10 in addition, the use of tenofovir (tdf) increases the risk of proximal tubular dysfunction and subsequent hypokalaemia and hypophosphataemia.11 the atherosclerosis risk in communities (aric) study concluded that african american patients had an approximately twofold greater incidence of type 2 dm compared with white patients.12 although this racial disparity is multifactorial, lower vitamin d13 and serum potassium levels14 in the black population are being explored as possible contributory factors. importantly, the prevalence of vitamin d deficiency in type 2 dm is disproportionately elevated in african american people compared with other ethnic groups in the usa.15 electrolyte abnormalities are associated with increased morbidity and mortality, even if they are chronic or of mild severity and may remain clinically silent until an advanced stage.8,9 however, there is a paucity of data from africa regarding electrolyte abnormalities in hiv or dm. furthermore, there are no studies assessing electrolyte abnormalities in black african people living with hiv and diabetes mellitus (plwh/dm). determining and understanding the spectrum of electrolyte abnormalities in black african plwh/dm are of crucial significance, particularly in south africa, which has a large burden of hiv and dm and is undergoing an epidemiological transition in a resource-limited setting. the objective of this retrospective case–control study was to determine, compare and identify associated factors regarding serum electrolyte abnormalities (sodium, potassium, calcium and phosphate) in black african plwh/dm versus black african hiv-uninfected patients with dm who attended the edendale hospital dm clinic from 01 january to 31 december 2016. methods this quantitative retrospective case–control study was conducted in 96 black african plwh/dm (cases) and 192 black african hiv-uninfected patients with dm (controls) attending the edendale hospital dm clinic, pietermaritzburg, kwazulu-natal, south africa, over 1 year from 01 january to 31 december 2016. records of patients attending the dm clinic were analysed retrospectively from datasheets. electrolytes were measured during routine outpatient visits at the edendale hospital dm clinic. black african plwh/dm included in the study could have either type 1 or type 2 dm, be on art or antiretroviral-naïve, have any degree of renal function that was determined by the estimated glomerular filtration rate (egfr) and be on medication for comorbidities. patients with incomplete records were excluded from the study. sample sizes were determined by applying a power analysis in g*power, which used an alpha of 0.05, a power of 0.80 and a medium effect size of 0.4. the ratio of cases and controls was 1:2, and participants were selected by random sampling, matched by egfr. estimated glomerular filtration rate was stratified by the kidney disease outcomes quality initiative (kdoqi) classification. data were anonymised with reference numbers. variables analysed included the following: age (years) sex hiv status type of dm duration of dm (years) duration of hiv (years) duration of art (years) type of art egfr (ml/min/1.73m2) levels of serum sodium, potassium, corrected calcium and phosphate (mmol/l) levels of glycated haemoglobin (hba1c) (%). the following serum electrolyte reference ranges, as per the national health laboratory services (nhls), were utilised: sodium: 136 mmol/l – 145 mmol/l potassium: 3.5 mmol/l – 5.1 mmol/l calcium: 2.20 mmol/l – 2.55 mmol/l phosphate: 0.78 mmol/l – 1.42 mmol/l any electrolyte values below the lower limit of normal were considered hypo-electrolyte abnormalities, whilst those above the upper limit of normal were considered hyper-electrolyte abnormalities. corrected serum calcium levels were utilised and calculated as follows: measured total calcium (mmol/l) + 0.02 (40 [g/l] – serum albumin [g/l]). the 2017 society for endocrinology, metabolism and diabetes of south africa (semdsa) guidelines advocate for an hba1c ≤ 7% to prevent microand macro-vascular complications. therefore, in this study, adequate glycaemic control was defined as hba1c ≤ 7%. estimated glomerular filtration rate was calculated by using the modification of diet in renal disease (mdrd) formula. serum electrolytes, egfr and hba1c were measured by using the siemens dimension® analyser. statistical analysis data were captured by using microsoft excel, version 2016 (microsoft, usa). statistical analyses were conducted by using statistical analysis software (sas), version 9.4 (sas institute inc., cary, nc, usa). continuous variables were expressed as medians with interquartile ranges (iqrs). categorical variables were expressed as frequencies and percentages. continuous variables were compared by using the wilcoxon rank-sum test as data were asymmetrically distributed. categorical variables were compared by using either the chi-square test or fisher’s exact test if there were less than five observations in any cell. pearson’s correlation coefficient assessed the correlation between hba1c and electrolytes. multinomial logistic regression assessed factors associated with electrolyte abnormalities. linear regression analyses assessed the effect of measured covariates on electrolytes. multivariable models were stratified by hiv status and were adjusted for gender, age, use of tdf, type of dm, duration of dm, duration of hiv, hba1c and egfr. a two-tailed value of p < 0.05 was considered to indicate statistical significance. ethical consideration ethical approval to conduct the study was obtained from the biomedical research and ethics committee (brec) of the university of kwazulu-natal (reference number be576/18). permission was obtained from edendale hospital to utilise the dm clinic datasheet for data collection. results descriptive data ninety-six black african plwh/dm (cases) and 192 black african hiv-uninfected patients with dm (controls) were reviewed. people living with hiv and dm were significantly younger than hiv-uninfected patients with dm (median [iqr]: 46.5 [39–53.5] years vs. 56 [47–64] years; p < 0.001) (table 1). hiv-uninfected patients had a significantly longer duration of dm compared with plwh/dm (median [iqr]: 7 [3–13] years vs. 5 [2–9] years; p = 0.006). people living with hiv and dm had a median (iqr) duration of hiv of 7 (3–10) years and 86 (89.58%) patients were on art, which included 65 (67.7%) patients on tdf (table 1). eighty-four (87.5%) plwh/dm and 172 (89.58%) hiv-uninfected patients had type 2 dm. seventy-three (76.0%) plwh/dm and 153 (79.7%) hiv-uninfected patients with dm had an hba1c > 7%, which was considered uncontrolled. the median (iqr) hba1c amongst plwh/dm and hiv-uninfected patients with dm was 9.45% (7.1% – 11.45%) and 9.70% (7.35% – 11.5%), respectively (p = 0.836). an egfr less than 60 ml/min/1.73m2 was present in 12 (12.5%) plwh/dm and 24 (12.5%) hiv-uninfected patients with dm, respectively (table1). table 1: demographic and clinical characteristics of people living with human immunodeficiency virus and diabetes mellitus, and human immunodeficiency virus-uninfected patients with diabetes mellitus. analysis of electrolytes sodium hyponatraemia was the second most frequent electrolyte abnormality, which occurred in 18 (18.75%) plwh/dm and 26 (13.54%) hiv-uninfected patients with dm (table 1). serum sodium was the only electrolyte significantly negatively correlated with hba1c in both plwh/dm (r = −0.34; p = 0.001) and hiv-uninfected patients with dm (r = −0.28; p < 0.001) (table 2). adjusted multinomial logistic regression analysis amongst plwh/dm suggests that for every per cent increase in hba1c, the odds of hyponatraemia significantly increased by 55% (odds ratio [or]: 1.55; 95% confidence interval [ci]: 1.19–2.02; p = 0.003), whilst in hiv-uninfected patients with dm the odds of hyponatraemia significantly increased by 26% (or: 1.26; 95% ci: 1.04–1.54; p = 0.009) (table 3). multivariate linear regression showed significant associations between serum sodium and hba1c. amongst plwh/dm, for every per cent increase in hba1c, serum sodium decreased by 0.51 mmol/l (β = −0.51; p = 0.004), and for every per cent increase in hba1c amongst hiv-uninfected patients with dm, serum sodium decreased by 0.45 mmol/l (β = −0.45; p < 0.001) (table 4). table 2: correlation of electrolytes and glycated haemoglobin in people living with human immunodeficiency virus and diabetes mellitus, and human immunodeficiency virus-uninfected patients with diabetes mellitus. table 3: adjusted and un-adjusted odds ratio estimates for the associations of electrolyte abnormalities with glycated haemoglobin in people living with human immunodeficiency virus and diabetes mellitus, and human immunodeficiency virus-uninfected patients with diabetes mellitus. table 4: linear regression analysis for the associations of electrolytes with clinical factors in people living with human immunodeficiency virus and diabetes mellitus, and human immunodeficiency virus-uninfected patients with diabetes mellitus. potassium the duration of hiv was not significantly associated with hypokalaemia on adjusted multinomial logistic regression analysis (or: 0.85; 95% ci: 0.59–1.23; p = 0.645). furthermore, the odds of hypokalaemia in plwh using tdf compared with non-tdf-based art were not significant (or: 0.87; 95% ci: 0.06–13.12; p = 0.766). adjusted multinomial logistic regression determined that the duration of dm was significantly associated with potassium abnormalities. in plwh/dm, for every year increase in the duration of dm, the odds of hypokalaemia increased by 97% (or: 1.97; 95% ci: 1.13–3.43; p = 0.025). however, in hiv-uninfected patients with dm, the odds of hyperkalaemia increased by 10% (or: 1.10; 95% ci: 1.02–1.19; p = 0.048). multivariate linear regression also showed significant associations between serum potassium levels and the duration of dm. for every year increase in the duration of dm, serum potassium decreased by 0.04 mmol/l amongst plwh/dm (β = −0.04; p = 0.018) and increased by 0.01 mmol/l amongst hiv-uninfected patients with dm (β = 0.01; p = 0.042) (table 4). calcium serum-corrected calcium was the only electrolyte with median (iqr) levels significantly lower in plwh/dm compared with hiv-uninfected patients with dm (2.24 [2.18–2.30] mmol/l vs. 2.29 [2.20–2.36] mmol/l; p = 0.001). furthermore, the most frequent electrolyte abnormality in plwh/dm and hiv-uninfected patients with dm was hypocalcaemia (31.25% vs. 22.91%) (table 1). adjusted multinomial logistic regression in plwh/dm and hiv-uninfected patients with dm found no factors significantly associated with hypocalcaemia or hypercalcaemia. however, multivariate linear regression analysis in hiv-uninfected patients with dm showed that for every year increase in age, serum calcium decreased by 0.01 mmol/l (β = −0.01; p = 0.031) (table 4). phosphate adjusted multinomial logistic regression in plwh/dm and hiv-uninfected patients with dm found no factors significantly associated with hypophosphataemia or hyperphosphataemia. notably, the use of tdf was not significantly associated with hypophosphataemia in plwh/dm (or: 1.69; 95% ci: 0.20–14.12; p = 0.800). multivariate linear regression in plwh/dm determined that for every year increase in age, serum phosphate decreased by 0.01 mmol/l (β = −0.01; p = 0.033). moreover, on average, serum phosphate was 0.09 mmol/l higher in women than in men amongst hiv-uninfected patients with dm, and all other variables were constant (β = 0.09; p = 0.006) (table 4). discussion sodium serum sodium abnormalities in dm vary depending on the degree of water and sodium change.9 serum glucose is an osmotically active substance; therefore, hyponatraemia in dm is mostly attributed to hyperglycaemia-induced hyper-osmolality, resulting in a dilutional effect or osmotic diuresis with hypovolemic hyponatraemia.9 hypernatraemia may occur if water loss exceeds sodium loss.9 our study identified serum sodium to be the only electrolyte significantly associated with hba1c levels in both plwh/dm and hiv-uninfected patients with dm. furthermore, elevated hba1c levels significantly increased the odds of hyponatraemia, with the odds being greater in plwh/dm compared with their hiv-uninfected counterparts. although pseudo-hyponatraemia in dm is common, hyponatraemia could be utilised as a marker of impaired dm control. our finding regarding the association between hba1c and serum sodium levels is comparable with that of a study conducted in india, which determined that mean (standard deviation [s.d.]) serum sodium levels were significantly lower in patients with dm compared with non-dm controls (127.92 [0.45] mmol/l vs. 135.82 [0.34] mmol/l; p = 0.0001) and that hba1c was significantly inversely correlated with serum sodium levels (r = 0.640; p = 0.0001).7 however, no regression analysis was performed in the study conducted in india.7 other causes of hyponatraemia in dm include side effects of drugs such as diuretics, diabetic nephropathy and the syndrome of inappropriate antidiuretic hormone secretion (siadh).9 our study demonstrated that plwh/dm had a higher frequency of hyponatraemia compared with hiv-uninfected patients with dm (18.75% vs. 13.4%). the increased frequency of hyponatraemia in plwh/dm could be attributed to the additive effect of hiv on sodium homeostasis. hyponatraemia is a common electrolyte disorder in plwh and a possible marker of hiv severity, as patients with hyponatraemia have significantly lower cd4 counts, higher viral loads and an increased prevalence of acquired immunodeficiency syndrome (aids).16 in plwh, the main causes of hyponatraemia include opportunistic infections which predispose to siadh, adrenal insufficiency, diarrhoea and vomiting.17 furthermore, dysfunction of the thick ascending limb of the loop of henle secondary to hiv and inflammation results in impaired free water clearance and dilutional hyponatraemia.8,18 people living with hiv and dm may be at a higher risk of hyponatraemia because of contributory factors from both hiv and dm. furthermore, hyponatraemia in the black african population may indicate a greater degree of sodium imbalance compared with other ethnic groups as the black population physiologically have increased sodium retention with lower plasma renin and aldosterone levels.19,20 potassium hyperkalaemia is common in dm.7,21,22 conversely, studies conducted in nigeria and saudi arabia found a predominant hypokalaemia and no significant association between serum potassium levels and glycaemic control, respectively.23,24 similarly, our study found no significant association between hba1c and serum potassium levels. common causes of hyperkalaemia in dm and hiv include hyporeninaemic hypo-aldosteronism, acidosis, renal impairment and drugs such as angiotensin-converting enzyme (ace) inhibitors, potassium-sparing diuretics and beta-blockers8,9 hypokalaemia in dm is frequently caused by insulin administration, malabsorption, osmotic diuresis and hypomagnesaemia.9 in plwh, hypokalaemia is commonly caused by vomiting, diarrhoea and proximal tubular dysfunction secondary to tdf.25,26,27 however, in our study, tdf was not significantly associated with hypokalaemia. this could be attributed to our study having relatively young plwh that were on art for a median duration of 6 years and only 12.5% of plwh having an egfr < 60ml/min/1.73m2, which may reduce the risk of tdf induced nephrotoxicity. notably, our study determined that for every unit increase in dm duration, the odds of hypokalaemia significantly increased by 97% in plwh/dm. this could be attributed to patients with comorbid hiv and dm developing a greater degree of insulin resistance, as both conditions progress,28 and therefore require higher doses of insulin to achieve glycaemic control with a propensity for hypokalaemia. this possible contributory factor needs to be explored further as our study did not evaluate the use of insulin. in hiv-uninfected patients with dm, the likelihood of hyperkalaemia significantly increased by 10% for every unit increase in dm duration. this could be attributed to dysautonomia in long-standing dm which impairs the conversion of prorenin to renin and predisposes to hyporeninaemic hypo-aldosteronism and associated hyperkalaemia.29 calcium calcium homeostasis is strongly regulated by parathyroid hormone and vitamin d. factors contributing to hypocalcaemia in hiv and dm include vitamin d deficiency, hypoparathyroidism and hypomagnesaemia.9,30 our study identified hypocalcaemia as the most common electrolyte abnormality in both plwh/dm and hiv-uninfected patients with dm. furthermore, serum calcium was the only electrolyte with median levels significantly lower in plwh/dm compared with hiv-uninfected patients with dm. similarly, keuhn et al. identified mean serum calcium levels to be significantly lower in hiv-infected patients compared with controls (p < 0.0001), irrespective of serum albumin levels.30 hypocalcaemia is also common in patients with dm, with a study in sudan showing significantly lower mean serum calcium levels in patients with dm compared with controls (p < 0.05).31 furthermore, vitamin d deficiency in the elderly is common despite consistent vitamin d intake and may predispose to hypocalcaemia.32 notably, our study demonstrated a significant inverse association between serum calcium and age in hiv-uninfected patients with dm. a significant association between serum calcium and age may have not been detected in plwh/dm as they were significantly younger. the degree of sunlight exposure was not documented in this study. although plwh/dm were significantly younger than hiv-uninfected patients with dm, clinically this difference in age should not usually result in a greater proportion of hiv-uninfected patients being housebound. therefore, the significant inverse association between serum calcium levels and age in hiv-uninfected patients may be influenced by factors besides sun exposure. the mechanism of vitamin d deficiency in hiv is multifactorial and involves the inhibitory effect of pro-inflammatory cytokines that reduces renal 1-α hydroxylation of vitamin d and the consumption of vitamin d by macrophages and lymphocytes.33 furthermore, vitamin d has a significant immunomodulatory role, and deficiencies in plwh are associated with lower cd4 cell counts, higher viral loads, hiv progression and an increased risk of opportunistic infections.34 moreover, studies have suggested that vitamin d deficiency and low calcium levels result in impaired insulin synthesis and secretion with subsequent glucose intolerance and insulin resistance.15 the european aids clinical society (eacs) has vitamin d supplementation recommendations and reports that the prevalence of low vitamin d levels was up to 80% in hiv cohorts and was associated with an increased risk of osteoporosis, type 2 dm, mortality and aids events.35 this is in contrast to south african hiv and dm guidelines, which do not have vitamin d deficiency recommendations despite our susceptible population.36,37 consequently, the presence of comorbid hiv and dm in the black african population potentially increases the risk of vitamin d deficiency and hypocalcaemia, which might negatively impact hiv and dm control. the role of vitamin d in the pathogenesis and control of hiv and dm and the effect of vitamin d supplementation need to be further explored, particularly in the black african population. phosphate the risk of tdf-induced nephrotoxicity with isolated hypophosphataemia, proximal tubular dysfunction or fanconi syndrome increases in the presence of renal impairment.38 this is of particular concern in patients with comorbid hiv and dm, advancing age, lower cd4 cell counts and elevated baseline creatinine levels.38 our study did not find tdf to be significantly associated with hypophosphataemia or serum phosphate levels in plwh/dm. this could be attributed to the fact that our study had only 12.5% of plwh/dm with an egfr <60 ml/min/1.73m2, patients were using art for a median duration of only 6 years and plwh/dm were relatively young. a study by day et al. observed the frequency of hypophosphataemia in tdf recipients to be higher than non-tdf art recipients (31% vs. 22%). however, no independent association was found between tdf use and the frequency or severity of hypophosphataemia.39 the recognition that hypophosphataemia in plwh on tdf is multifactorial must be considered to avoid unnecessary tdf cessation in a resource-limited setting. current guidelines this study determined that electrolyte abnormalities in black african plwh/dm are common, with hypocalcaemia and hyponatraemia being the most frequent electrolyte abnormalities. however, the current semdsa guidelines only recommend that serum potassium needs to be measured at diagnosis and monitored annually.37 furthermore, south african hiv guidelines only recommend the monitoring of serum potassium and phosphate in high-risk patients and patients with features of tubular wasting.36 limitations the limitations of this study included cd4 count and viral load not being documented for a majority of patients as management and monitoring of hiv occurs at designated hiv clinics. therefore, the association between hiv control and electrolyte abnormalities could not be determined. possible tdf-induced proximal tubular dysfunction and electrolyte loss were not assessed with urine electrolytes as they were not routinely performed in the dm clinic. patients in this study could have been on medication or could have comorbidities which may affect electrolytes. however, by including these patients the study was more representable and reproducible as the majority of patients suffering from dm were usually part of a metabolic syndrome which requires chronic treatment to improve outcomes. in addition, the use of oral antidiabetic medication or insulin and the respective doses were not included. this could have been used to compare the dm treatment requirements in plwh/dm and hiv-uninfected patients as both groups had similar hba1c levels. lastly, because of the retrospective nature of the study, causality could not be determined. however, this is a newly explored topic, and this study is useful in providing preliminary data for future prospective studies. conclusion serum electrolyte abnormalities in black african plwh/dm are common. hypocalcaemia and hyponatraemia were the most frequent electrolyte abnormalities and occurred more frequently in plwh/dm compared with hiv-uninfected patients with dm. serum calcium levels were significantly lower in black african plwh/dm compared with hiv-uninfected patients with dm. importantly, hyponatraemia is a potential marker of impaired glycaemic control as elevated hba1c levels significantly increased the odds of hyponatraemia in both groups; however, the odds were greater in plwh/dm. ultimately, black african plwh/dm are highly vulnerable to electrolyte abnormalities because of multifactorial pathophysiological factors. further large prospective studies regarding electrolyte abnormalities in black african plwh/dm will assist in identifying contributory factors and implementing tailored guidelines that could facilitate prevention, earlier detection, closer monitoring and appropriate intervention to reduce associated adverse effects in this high-risk population, particularly in the south african context. acknowledgements this study contributes towards the master of medical science degree of dr preyanka pillay, which is supervised by dr somasundram pillay. competing interests the authors declare that they have no competing interests. authors’ contributions p.p. contributed to the conception and design of the study as well as the collection, analysis and interpretation of the data. p.p. wrote and edited the manuscript. s.p. contributed to the conception and design of the study and critically reviewed and edited the manuscript. n.m. contributed to the statistical analysis and interpretation of data; she also critically reviewed and edited the manuscript. all authors gave final approval of the version to be published. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability statement data are available upon request from the corresponding author. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references international diabetes federation. idf diabetes atlas, 8th ed. 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[cited 2019 mar 03]. available from: www.eacsociety.org/files/2018_guidelines-9.1-english.pdf meintjes g, moorhouse m, carmona s, et al. adult antiretroviral therapy guidelines 2017. s afr j hiv med. 2017;18(1):a776. https://doi.org/10.4102/sajhivmed.v18i1.776 semdsa 2017 guidelines for the management of type 2 diabetes mellitus. semdsa type 2 diabetes guidelines expert committee. jemsda [serial online] 2017 [cited 2019 mar 03];22(1):1–196. available from: https://www.semdsa.org.za/images/647-4385-1-pb.pdf tourret j, deray g, isnard-bagnis c. tenofovir effect on the kidneys of hiv-infected patients: a double-edged sword? j am soc nephrol. 2013;24(10):1519–1527. https://doi.org/10.1681/asn.2012080857 day s, leake date h, bannister a, hankins m, fisher m. serum hypophosphatemia in tenofovir disoproxil fumarate recipients is multifactorial in origin, questioning the utility of its monitoring in clinical practice. jaids j acquir immune defic syndr. 2005;38(3):301–304. abstract introduction methodology results discussion conclusion acknowledgements references about the author(s) juliet c.y. nyasulu division of community paediatrics, faculty of health sciences, university of the witwatersrand, johannesburg, south africa health systems strengthening, afriquip, johannesburg, south africa innocent maposa department of epidemiology and biostatistics, faculty of health sciences, university of the witwatersrand, johannesburg, south africa centre for hiv and sti’s, national institute for communicable diseases, johannesburg, south africa bernard p. sikhakhane jhb health district: monitoring and evaluation, gauteng provincial department of health, johannesburg, south africa himani pandya division of community paediatrics, faculty of health sciences, university of the witwatersrand, johannesburg, south africa citation nyasulu jcy, maposa i, sikhakhane bp, pandya h. access to hiv services and viral load suppression among children during the 90-90-90 strategy implementation in south africa: a time series analysis. s afr j hiv med. 2021;22(1), a1187. https://doi.org/10.4102/sajhivmed.v22i1.1187 original research access to hiv services and viral load suppression among children during the 90-90-90 strategy implementation in south africa: a time series analysis juliet c.y. nyasulu, innocent maposa, bernard p. sikhakhane, himani pandya received: 29 oct. 2020; accepted: 13 dec. 2020; published: 17 mar. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: during the era of the millennium development goals (mdg), children were shown to have less access to human immunodeficiency virus (hiv) services than their adult counterparts; hence the call to prioritise children in the implementation of the sustainable development goals (sdgs). however, south african (sa) national data in 2019 indicated that almost 3 years into the implementation of the 90-90-90 strategy, only 59% of children living with hiv had been tested for hiv compared to 90% of adults. objectives: to evaluate the access of children to hiv services and record the viral load (vl) suppression rates during the implementation of the 90-90-90 strategy in the city of johannesburg (coj), south africa. methods: this study applied a quasi-experimental interrupted time-series (its) design using the monthly district health information system (dhis) and national health laboratory services (nhls) databases spanning the period from 2015 to 2020, that is, before and after the implementation and roll-out of the 90-90-90 strategy. data were extracted from these databases into ms excel 2010 spreadsheets and analysed with stata 15 software from stata corp using a two-tailed t-test at a 5% level of significance. results: overall, a significant increase was observed in the number of individuals tested for hiv, n = 757, p = 0.0086, and retained in care n = 2523, p = 0.001 over the whole period of analysis beginning in april 2015. adult hiv testing, antiretroviral treatment (art) initiation and retention in care had been decreasing in absolute numbers over a 10-month period before the intervention. an increase in these three data elements was observed following the implementation of the 90-90-90 program. on the other hand, children aged 0–15 years had demonstrated a significant increase in absolute numbers tested for hiv, n = 171, p = 0.001, but an insignificant increase in number of art initiations, n = 14.33, p = 0.252, before implementation but a decrease after this. the overall vl suppression rates for children were lower than those of adults. conclusion: although the coj has recorded progress in adult hiv testing, art initiation and retention, children living with hiv aged 0–15 years continue to experience less access to hiv services and lower vl suppression than youths and adults of ≥ 15 years. therefore, to ensure that the 90-90-90 targets are achieved across different age groups, children must be prioritised so that they can equally access these services with adults. keywords: 90-90-90 strategy; implementation; hiv testing; art initiation; retention in hiv care; hiv care access by children. introduction in the era of the sustainable development goals (sdg’s), the unaids set countries, the ambitious ‘90-90-90’ target of eradicating global infection with hiv by 2030. this required that by 2020, 90% of people living with hiv would know their status, 90% of whom would be on antiretroviral treatment (art) and 90% of the latter, would be virally suppressed.1 the underlying principle behind these goals is the rapid scale-up of access to treatment for all plwh, irrespective of their cd4 count. the primary target are cities as the risk of hiv and tuberculosis (tb) is greater in urban than rural areas. more than 200 cities and municipalities across the globe signed the united nations declaration pledging commitment to these goals.1,2 some progress was made: by 2018, 79% (range, 67–92%) of global plwh knew their status. of these, 78% (range 69–82%) were accessing art and 86% (range, 72–92%) of the latter were virally suppressed. targets for children and adolescents lagged behind.1 a total of 7.9 million south africans are plwh. of these, ± 4.9 million are on art.3 the city of johannesburg (coj), together with 19 other south african (sa) cities and metropolitans, endorsed these 90-90-90 strategic goals.1,2 whilst testing and treatment ‘scale-up’ in the coj had been rapid in the preceding decade, the required ‘doubling of effort’ by 2020, could not be met.4 nonetheless, progress had been made. ninety per cent of sa-plwh knew their status, 62% had been initiated on art and 54% were virally suppressed, that is, 90-62-54%.3,5 all was not good news, though. in 2019, only 63% of 0–15-year-olds living with hiv were reported to be on art.5 compared with adults, hiv testing of children < 15 years has been suboptimal. the 2019 sa-90-90-90 progress report indicated that only 59% of children living with hiv knew their status, and though 96% of those tested had been initiated onto art, only 67% were virally suppressed; too few children are tested.6 this is despite the 2016–2030 sdg’s strategy to prioritise children and the young.7,8 although the national hiv statistics show a decline in the number of infected children and an increase in adults with hiv, the extent of the problem in the coj has not been reported.3 this study evaluates the access of children < 15 years to hiv services and the rates of viral load (vl) suppression during the implementation of the 90-90-90 strategy in the city. methodology study design this was a quasi-experimental study that aimed to establish the impact of the implementation of the 90-90-90 strategy on hiv testing, art initiation, retention in care and viral suppression amongst plwh in the coj using an interrupted time series (its) analysis of data from the district health information system (dhis) and the national health laboratory service (nhls). to strengthen the internal validity of the study, other factors that would impact hiv testing, art usage and retention in care during the study period are explored and explained. study participants the study included all individuals who tested positive for hiv and were initiated onto art and who remained on art in the coj and on the dhis database over the study period. in line with the dhis age-categories, children were grouped into those < 59 months of age and from 5 to < 15 years. those above 15 years were categorised as adults. all vl tests performed by the nhls during the study period were included. study setting data were collected from the coj, gauteng province, south africa. the city has seven regions (a–f), and a total population of ± 5.6 million. this accounts for 36% of the gauteng and ± 10% of the national population.3 one hundred and twenty-one primary healthcare (phc) facilities offer hiv-services in the coj and cater for ± half-a-million plwh.9 the 90-90-90 strategy intervention the 90-90-90 strategy was conceptualised in 2015 and introduced to the coj in january 2016. the district program implementation team identified indicators that would assist in attaining these targets. these indicators focused on the four pillars of hiv-care cascade, namely (1) prevention, (2) case identification, (3) treatment initiation, and (4) retention and success of treatment. those indicators performing below target were described together with their root causes. activities were proposed to address the gaps in the 90-90-90 district strategy implementation plan (dip).7 responsible personnel and the measures required to track progress were identified. for example, one of the gaps in the district was poor access to services by youth and by men. as a result, social mobilisation and communication that targeted men and youth, key populations and vulnerable groups was implemented. the dip was rolled out in january 2016.7 data collection data were collected from monthly reports of facilities captured in the dhis database. all who were initiated on art had a vl test – a measure of viral suppression and a proxy of adherence and retention in care – after 6 months and annually thereafter. more frequent vl monitoring is recommended where vl suppression is not achieved.10 viral suppression is defined as vl < 50 copies/ml as per the 2019 south african national department of health (sandoh) guidelines.10 the nhls database provided viral suppression data. data from the dhis program was collated from april 2015 until march 2019 (48 months) and included the 9 months to january 2016 (before) and the 38 months after strategy implementation in january 2016. in addition, all vl suppression nhls data from january 2015 to february 2020 (62 months) are included in this study. the proportion of virally suppressed ‘test-results’ has been calculated on a monthly basis throughout the 62 months for both adults and children. outcome measures the study outcome measures included the number of individuals tested, initiated on art, retained in care and virally suppressed in the coj facilities before and after the january 2016 roll-out. statistical analysis data preparation was done in ms excel 2010 and analysed with stata 15(stata corp). we used a two-tailed test at a 5% level of significance throughout the analysis. continuous data were expressed as the means (standard deviation, sd) or medians (interquartile range, iqr). categorical data are presented as frequencies and percentages. the durbin-watson statistic was used to test for autocorrelation. we modelled the its data using segmented regression analysis which, as suggested by wagner et al., has the advantage of adjusting for baseline level and trend, in this case, the hiv test-and-treat policy changes.11 for hiv testing, art initiation and retention in hiv care, we compared the time series pattern 9 months before and after january 2016 when the 90-90-90 strategy implementation was rolled out in the coj to assess differences. in addition, average monthly vl suppression rates from 12 months (january–december 2015) before were compared to 50 months (january 2016–february 2020) after strategy implementation roll-out. the trends before and after this intervention were analysed to assess whether the passage of time was associated with an increase or a decrease in the number of hiv tests, initiations and retention in care as well as viral suppression. the specific model is: where yt is the total number of those hiv tested, art initiated and remaining in care or vl suppression rate in a month in johannesburg, which are response variables in this model; xt is a count time variable indicating time in months from the start of the observation period to intervention; intervention is an indicator i(t ≥ t0) variable for time t occurring before (i(t ≥ t0) =0) or after (i(t ≥ t0) = 1) 90-90-90 strategy roll-out, which was implemented at month t0 in the series; and representing time after intervention is a count variable for the number of months after the intervention at time t0 = 10 when assessing 90-90-90 indicators and t0 = 13 when assessing suppression rates computed from nhls data. suppression was defined as having a vl below 50 copies/ml. in this model, β0 is the estimate of baseline level of the outcome, being the average number of patients tested for hiv, initiated on art and virally suppressed at time zero; β1 estimates the mean change in total number or rate that occurred in each month before 90-90-90 strategy intervention; β2 estimates the level of change in the average number of patients tested for hiv, initiated on art and virally suppressed during the intervention month; and β3 estimates the change in the trend in the mean monthly number of patients tested for hiv, initiated on art and virally suppressed after the 90-90-90 strategy intervention implementation. the error term et at time t represents the random variability not accounted for by the model. ethical considerations ethical approval for this study was obtained on 01 october 2018 from the university of the witwatersrand human research ethics committee (project research number: r14/49 and ethical clearance number: m180640). results numbers for hiv testing, art initiation and those remaining in care before and after the implementation roll-out. pre-intervention or pre-implementation all values are presented as medians with interquartile range [iqr]. the total number tested monthly for hiv in the pre-intervention period viz. april–december 2015 was a median of n = 64 379 (iqr, 58 425–66 374). adults numbered 49 650 (iqr, 47 644–52 092) of whom 6592 (iqr, 6328–6808) were in antenatal care (anc). under-5 years numbered 544 (iqr: 0–786) and 5 to < 15-year-olds numbered 681 (iqr, 25–917). overall, the total number initiated monthly onto art in the pre-intervention period was 4431 (iqr: 4375–4513). n = 101 (iqr, 89–112) were children < 15 years. the number of adults was 4327 (iqr: 425–4388). the total number of plwh retained in antiretroviral (art) care monthly in the pre-intervention period was 256 278 (iqr: 254 111–257 452). n = 10 775 (iqr, 10 704–10 832) were children < 15 years of age. youths and adults in care numbered 245 509 (iqr: 243 392–246 620). post-intervention or post-implementation all values are presented as medians with interquartile ranges [iqr]. the total number tested monthly for hiv during the 38 months post-intervention period was 75 162 (iqr: 71 015–84 736). youths and adults numbered 57 027 (iqr, 51 831–64 825) of whom 7085 (iqr, 6725–7461) were in anc care. the number of under-5 years was 1065 (iqr: 893–1194) and 5 to < 15 years was 1449 (iqr, 1174–2097) monthly. the total number initiated monthly onto art post-intervention was 5288 (iqr, 4796–6053). n = 129 (iqr: 103–173) were children < 15 years. the youths and adults numbered 5134 (iqr: 4659–5925). the total number of plwh retained on art monthly in the 38 months after intervention was 312 360 (iqr, 284 296–338 008). the monthly numbers of children < 15 years were 8688 (iqr, 8266–10 048). the median monthly number of all youths and adults retained in care was 303 596 (iqr, 274 060–329 767). number of viral load tests conducted before and after intervention a total of 2 040 018 vl tests were performed during the 62-month (5 years) period of the study on 23 193 children < 5 years, 58 563 children 5 to < 15 years and 1 958 262 youths and adults (table 1). each newly diagnosed client had a vl at 6 and 12 months then annually thereafter and intermittently if clinically indicated. follow-up tests number more than the total number of individual patients. table 1: number of viral loads captured annually in the city of johannesburg before and after the intervention. hiv testing, antiretroviral treatment initiation and retention in care before and after the intervention hiv testing before and after the intervention in the 10 months of 2015 that preceded the implementation of the 90-90-90 roll-out strategy, there was a non-significant monthly average decline in the number tested for hiv, p = 0.57. however, categorised by age, hiv testing of adults did appear to decline significantly, p < 0.001; whilst testing of children increased, 19 months to < 5 years, p = 0.008 and ≥ 5 to < 15 years, p = 0.001 (table 2, item 1). after controlling for autocorrelation, at the time of the roll-out-strategy intervention in january 2016 (month 10) a non-significant, monthly-average increase of 1448 people tested for hiv, p = 0.27 was recorded. categorised by age, this testing showed a significant increase amongst adults (p < 0.001) and a significant decrease amongst children, 19 to < 5 years, p = 0.008, and those 5 to < 15 years, p = 0.001. nevertheless, in the period 2015–2019, a significant overall average increase of 757 persons was recorded in the monthly average tested for hiv, p = 0.009. table 2: the monthly average change in hiv testing and art initiation of youths and adults (> 15yrs) and of children (< 15yrs) before (9 months) and after (38 months) the 90-90-90 implementation or intervention. post-intervention or post-implementation a non-significant increase in hiv testing was observed in the total adult group and the anc attendees, though not significantly different from the baseline. on the other hand, significant declines in hiv testing amongst under-5 years (< 59 months) and 5 to < 15 year groups were observed at the same time: n = -101; p = 0.021 and n = -171; p < 0.001, respectively. overall trend throughout the study period as shown in table 2, overall, there was a significant increase in hiv testing amongst adults and under-5 years children (< 59 months): n = 622; p = 0.025 and n = 14; p = 0.002, respectively, with no significant change from baseline for the 5 to < 15-year-old group. antiretroviral treatment initiation for those who are hiv positive pre-implementation, the average numbers of monthly art initiations amongst adults declined non-significantly by about 65 persons, p = 0.349, but increased by ± 14 persons amongst children < 15 years, p = 0.252. after implementation, an increase was observed in adults and a slight decrease in children < 15 years. overall, the trend throughout the study period suggests an insignificant increase in art initiation amongst adults and an insignificant decrease amongst children < 15 years. retention on antiretroviral treatment for 9 months before implementation, there was a non-significant total monthly average loss from hiv care of 462 plwh, p = 0.515. after january 2016, at the time of the strategy intervention, after controlling for autocorrelation, there was a monthly average increase of retention in care of 2985 plwh, p < 0.001. overall, from 2015 to 2018, there was a significant monthly average increase of 2523 plwh retained in art care, p < 0.001. pre-intervention or pre-implementation as shown in table 2, the average number of adults in art care declined by about 418 persons, p = 0.536, monthly and in children (the < 15-year group) by ± 49 persons monthly, p = 0.302 (table 2). post-intervention or post-implementation there was an increase in adults and a decrease in children < 15 years retained on art care (table 2). overall trend throughout the study period there was a significant increase in numbers of adults on art and a significant decrease in children < 15 years. overall hiv testing and antiretroviral treatment initiation trends over the study period figure 1 shows the overall increasing monthly hiv testing trends over the study period and the consistent declines in update of hiv testing over the festive months of december and january. figure 1: overall average monthly increase or decrease in human immunodeficiency virus testing in the city of johannesburg. figure 2a and 2b depicts the increasing numbers of those retained on art amongst adults centrally to a continuous drop amongst children over the months. to note is the fact that adult and children retention in hiv care trends had some consistent drops during the festive season months of december to january. figure 2: (a) trends in adults monthly retention on antiretroviral treatment and (b) trends in < 15 years monthly retention on antiretroviral treatment. viral load suppression rates before and after the strategy roll-out as shown in figure 3, the number of vl tests conducted during january 2015 to february 2020 indicates a higher suppression rate for adults compared to children through the 5 years preand post-implementation and roll-out. throughout the period, a seasonal drop in vl suppression is observed between december and january of each year. figure 3: proportions of those virally suppressed before and after the 90-90-90 strategy implementation. discussion this was a quasi-experimental study that utilised an its analysis to establish the effect of the 90-90-90 strategy implementation on hiv testing, art initiation and retention in care amongst hiv positive individuals in the coj. overall, a significant increase was observed in the number of individuals tested for hiv, initiated on art and retained in hiv care after the implementation. adult hiv testing, art initiation and retention in hiv care had decreased significantly before implementation but was followed by a significant increase over time in all three aspects once the strategy was rolled out. on the other hand, all three measures in children aged 0–15 years had been increasing before implementation but decreased significantly thereafter. throughout the study period, rates of viral suppression were less in children than in adults, though trends were similar (table 3). rates of hiv testing, art initiation, retention in care and vl suppression declined in december and january – each ‘festive season’ – throughout the study period. table 3: viral load suppression rate before and after the 90-90-90 strategy implementation amongst children and adults. viral load defined at vl< 50 copies/ml. hiv testing, antiretroviral treatment initiation and retention in care for adults our data indicate that the implementation of the 90-90-09 strategy in the coj has had a positive effect amongst adults accessing hiv services in the city. other studies support this assessment.12,13 the roll-out of ‘universal test and treat’ (utt) in september 2016 would have contributed to this outcome as this removed the cd4 count ‘barrier’ to care.14,15 furthermore, the roll-out of the 90-90-90 strategy was accompanied by hiv testing campaigns that raised awareness in the community.7 hiv testing, antiretroviral treatment initiation and retention in care for 0–15 year-olds a concern is the apparent decline of hiv testing amongst children aged 0–15 years. this followed an increase in testing in the pre-implementation phase. the most recent sandoh implementation progress-report noted that only ± 59% of children living with hiv (clwh) are being diagnosed. although 96% of those who test positive are initiated onto art, only 66% are retained in care. in reality, this means that only about 38% of clwh achieve retention on art.6 furthermore, the hiv screening strategy amongst the 0–15 year-olds during the study period missed a large number of clwh, especially children infected postnatally via breastfeeding practices, or perinatally with delayed seroconversion post-delivery.16 birth pcr tests on all exposed infants are now helping to close this gap.17,18 additional failures occur during or at the end of breastfeeding, or when birth results are not checked and when follow-up and linkage to care are not established.19 point-of-care infant testing may assist in the prevention of some gaps.20 current south african infant-testing guidelines recommend testing at birth, 10 weeks and upon ending breastfeeding.14 nonetheless, data from tshwane district report that only a third of hiv-exposed children repeat the hiv test at 18–24 months and only a quarter at the end of breastfeeding.21 although early infant diagnosis using pcr at birth and 10 weeks has impacted infant hiv testing,22 gaps remain. consequently, the current testing of children is suboptimal compared to adults.6 the system is failing children. greater effort must be made to trace and test exposed children, especially post-breastfeeding as these 18-month rates are extremely low.6,23 our study found that art initiation rates in < 5-year-old children have declined. in part, this results from the country’s excellent prevention of mother-to-child transmission of hiv (pmtct) rate of 0.9% and the coj’s 1%.24 fewer children are now needing to be initiated on art. however, our study also found that fewer children are being tested. gaps and opportunities are being missed.6 innovative approaches are still needed in support of this population group.20,25 the testing, initiation and retention in care data of the 5 to < 15-year-old cohort changed from an increase in 2015 to a significant decline after the implementation of the 90-90-90 strategy. a possible explanation is that at the end of the implementation phase of the millennium development goals (mdg) goals (2014–2015), it was clear that children were being missed and a special call was made to reverse this situation with the implementation of the sdgs. a concerted effort was made to prioritise hiv testing and art initiation in this age group.8 although the coj had a 2016–2020 dip which covered activities to reach youths, it did not prioritise those aged < 15 years.8,26 reports in the sdg implementation era still document the inadequate provision of services to children and youth; something that must be rectified in the 2020/2030 targets.13,23 concerning children and youths, the nhls database indicated that throughout the reporting period, the younger the individual, the lower the vl suppression rate. whilst children aged < 5 years and 5 to < 15 years showed a small but significant increase in the overall vl suppression over the 5-year study period, this was still below that of the adults. the suboptimal performance of children triangulates with the dhis database and is similar to other studies.6 innovative solutions are needed to assist in ensuring that more children are tested, initiated and adhere to art. five years into the implementation of sdg goals, our children lag behind their adult counterparts. urgent action is called for. of interest is the ‘lapse’ in the performance indicators across all age groups in the december to january festive period. not much has been documented regarding patients’ access and adherence to care during this time. however, we speculate that the lower rates of performance at these times reflect the annual migration of city-dwellers to ancestral homes in south and southern africa – appointments are missed and treatment adherence impaired and vl suppression rates fall.3 it is critical to establish whether this is the case and what mechanisms are needed to mitigate the problem. for example, the provision of more than one repeat of medication to cover the holiday duration. and the scheduling of the coj’s hiv testing campaigns to avoid the holiday seasons. study limitations include the retrospective nature of the data and our inability therefore to link cause and effect. caution is suggested when interpreting sensitivity data where numbers of our children analysed were extremely low. the study also records that the coj was not able to fulfil the unaids 90-90-90 target by 2020. the databases and data recorded in healthcare facilities were at times incomplete. however, we applied quality tracing to our resources and are confident that the outcome in this study reflects that data. the strength of the study is in the large cohort size and the reproducibility and integrity of the data over a prolonged 5-year assessment period. conclusion this study highlights the suboptimal level of access to hiv services and vl suppression of children compared to adults during the 90-90-90 strategy implementation in the coj. serious consideration is recommended to ensure that children and their guardians enjoy equity with adults in accessing healthcare services in the coj if 90-90-90 targets are to be met. plans must be implemented to mitigate the loss of hiv care and control that appears to be occurring during the holiday season. acknowledgements the authors would like to acknowledge the support from the city of johannesburg team for provision of data and information on the 90-90-90 strategy implementation progress. in addition, the help from prince dulaze of anova health, the implementation partner, is also greatly appreciated. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this research article. authors’ contributions j.c.y.n. conceptualised the research project and drafted the first version of this article. i.m. and b.p.s. analysed the data and drafted the results section. j.c.y.n., i.m., b.p.s. and h.p. read, revised the drafts and approved the final manuscript. j.c.y.n. is the guarantor of the manuscript. funding information the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. data availability data analysed for this study will be made available when the need arises. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references unaids global aids update 2019. communities at the centre: defending rights, breaking barriers, reaching people with hiv services [homepage on the internet]. 2019 [cited 2020 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[monograph]. johannesburg: university of the witwatersrand; 2016 [cited 2020 july 10]. available from: http://wiredspace.wits.ac.za/handle/10539/21246 johnson l, dorrington r, moolla h. progress towards the 2020 targets for hiv diagnosis and antiretroviral treatment in south africa. s afr med j. 2017;18(1):a694. https://doi.org/10.4102/sajhivmed.v18i1.694 wessels j, sherman g, bamford l, et al. the updated south african national guideline for the prevention of mother to child transmission of communicable infections (2019). south afr j hiv med. 2020;21(1):1079. https://doi.org/10.4102/sajhivmed.v21i1.1079 mnyani c, tait cl, peters rph, et al. implementation of a pmtct programme in a high hiv prevalence setting in johannesburg, south africa: 2002–2015. s afr j hiv med. 2020;21(1):a1024. https://doi.org/10.4102/sajhivmed.v21i1.1024 phiri na, lee hy, chilenga l, et al. early infant diagnosis and outcomes in hiv-exposed infants at a central and a district hospital, northern malawi. public health action. 2017;7(2):83–89. https://doi.org/10.5588/pha.16.0119 spooner e, govender k, reddy t, et al. point-of-care hiv testing best practice for early infant diagnosis: an implementation study. bmc public health. 2019;19(1):731. https://doi.org/10.1186/s12889-019-6990-z moloko sm. factors associated with the hiv transmission rate in 18 to 24 month-old children enrolled in the prevention of mother-to-child transmission programme at the city of tshwane clinics [homepage on the internet]. pretoria: university of south africa [cited 2020 aug 14]. available from: http://hdl.handle.net/10500/13817 technau k, kuhn l, coovadia a, carmona s, sherman g. improving early identification of hiv-infected neonates with birth pcr testing in a large urban hospital in johannesburg, south africa: successes and challenges. j int aids soc. 2017;20(1):21436. https://doi.org/10.7448/ias.20.01/21436 davies m, pinto j. targeting 90-90-90 – don’t leave children and adolescents behind. j int aids soc. 2015;18(suppl 6):20745. https://doi.org/10.7448/ias.18.7.20745 goga a, chirinda w, ngandu n, et al. closing the gaps to eliminate mother-to-child transmission (mtct) of hiv in south africa: understanding mtct case rates, factors that hinder the monitoring and attainment of targets, and potential game-changers. s afr med j. 2018;108(3 suppl 1):s17–s24. https://doi.org/10.7196/samj.2017.v108i3b.12817 kellerman s, essajee s. hiv testing for children in resource-limited settings: what are we waiting for? plos med. 2010;7(7):e1000285. https://doi.org/10.1371/journal.pmed.1000285 sherman g, lilian r, bhardwaj s, candy s, barron p. laboratory information system data demonstrate successful implementation of the prevention of mother-to-child transmission programme in south africa. s afr med j. 2014;104(suppl. 1):235–258. https://doi.org/10.7196/samj.7598 848 control and non-progression of hiv-1 infection in sub-saharan africa: a case and review   p patel, m brooks, g anabwani, m a tolle   botswana-baylor children’s clinical centre of excellence, princess marina hospital, gaborone, botswana p patel, md, msc g anabwani, mb chb   botswana-baylor children’s clinical centre of excellence, princess marina hospital, gaborone, botswana, and ohio university school of medicine, athens, ohio, usa m brooks   baylor college of medicine children’s foundation, bugando medical centre, mwanza, tanzania, and department of pediatrics, retrovirology and global health section, texas children’s hospital, baylor college of medicine, houston, texas, usa m a tolle, md, mph corresponding author: m a tolle (tolle@bcm.edu) elite and viraemic controllers represent unique subsets of hiv-infected patients who may also be long-term non-progressors (ltnps). lntps constitute an estimated 1 15% of the total hiv-positive population in the usa and europe, but less is known about their epidemiology in sub-saharan africa. though the exact mechanisms for long-term non-progression appear to be numerous and are still under investigation, research on elite controllers may hold the key to new therapeutics and vaccine development. the clinical management of such patients can be challenging, as there are no standard guidelines for treatment, particularly in resource-limited settings. we describe the case of an hiv-infected botswanan man who is likely an elite or viraemic controller. s afr j hiv med 2012;13(3):152-155. doi:10.7196/sajhivmed.848 in 2005, a 54-year-old motswana male with no known history of medical problems, travel outside botswana, or hiv risk exposure to persons beyond botswana, was diagnosed with hiv (rapid test). he was asymptomatic upon presentation, his baseline cd4 was 989 cells/mm3 (35%) and baseline hiv viral load was <400 copies/ml (assay limit of detection: 400 copies/ml). in 2006, a subsequent rapid hiv-test was also positive, as was qualitative hiv-pcr, although quantitative viral load remained <400 copies/ml. from diagnosis to date of this report, the patient remained asymptomatic with a robust cd4 cell count (fig. 1) and undetectable viral load, without antiretroviral therapy (art). fig. 1. cd4 cell count of the patient over time. the patient’s wife was diagnosed with hiv in 2003 at the age of 37 years. she was severely immunosuppressed at presentation (cd4 count of 40 cells/mm3 ). she was initiated on art and remained virologically suppressed (unclear baseline viral load). the couple’s daughter was diagnosed with hiv in 2005 at the age of 9 years (cd4 count – 254 cells/mm3 ; baseline viral load – 144 000 copies/ml). at the time of the report, she was virologically suppressed with robust immune response on art. discussion hiv-infected individuals who take longer than 10 years to progress to aids have historically been called long-term non-progressors (ltnps). the study of ltnps has revealed much about the natural history of hiv infection. most infected individuals who are not treated with art advance to aids over approximately a decade.1 since first investigated in the late 1990s, it has been shown that not all elite controllers follow the same natural history; some control the virus but eventually progress and others control the virus without progression.1 , 2 whether hiv elite controllers are ‘ultra-slow progressors’ or totally non-progressive remains to be determined. little is known about the epidemiology of ltnps in sub-saharan africa (ssa). a ugandan study found rates of long-term non-progression and elite control among 9% and 1%, of the total hiv-seropositive population, respectively.3 in the few studies demonstrating the existence thereof in ssa, the cohorts have been very small, the viral and host genetics have not been explored and, in some cases, the cohorts have used significantly different definitions of long-term non-progression.3 , 4 , 5 therefore, the mean progression of elite controllers or ltnps without art in ssa is largely undefined, especially with regard to hiv subtype c. multiple attempts have been made to define and classify hiv disease by clinical progression. the hiv controller consortium has defined 2 groups of hiv-infected patients: elite controllers with viral loads off art <50 hiv rna copies/ml for at least 1 year, and viraemic controllers who maintain viral loads of 50 2 000 copies/ml without treatment for at least 1 year.1 , 6 casado and colleagues further differentiated groups into elite controllers, ‘classic’ lntps (viraemic controllers v. viraemic non-controllers depending on the viral load), chronic progressors and rapid progressors (who progress to aids within 3 years of diagnosis).7 they defined elite controllers as patients with a positive hiv test, who have viral loads consistently lower than the assay detection level for longer than 10 years.   features unique to botswana and southern africa in resource-limited settings, the differentiation of elite controllers from viraemic controllers may be complicated. though modern assays can detect viraemia >50 copies/ml, older assays – widely used in botswana’s national hiv programme – have a minimum detection level of 400 copies/ml. even though 95% of all hiv patients do eventually show signs of progression, without highly specialised testing for protective and progressive factors, it is difficult to practically categorise and predict disease progression.8 viral suppression is correlated with certain practical clinical outcomes, including partner and mother-to-child transmissibility, and aids-free survival.9 in botswana’s national art programme, where patients qualify for art at a cd4 count <350 cells/mm3 , baseline viral loads are not performed, without which the practitioner cannot differentiate between an ltnp, who has a higher probability of progression of aids, and an elite controller. there are case reports of elite controllers progressing after super-infection with 2 different hiv subtypes,10 , 11 heightening the importance of secondary prevention strategies in counselling patients. some limitations of our case merit further discussion. the lack of subtype analysis is notable; this was neither available nor cost-effective for the patient, given the constraints of botswana’s hiv programme, and the lack of value that this would add to clinical management under current national hiv guidelines. the patient’s viral load was repeated at 3-monthly intervals and remained <400 copies/ml. however, viral loads were performed with the standard roche amplicor hiv-1 monitor test, which is not designed to detect non-m-group hiv (such as group o) or hiv-2.12 , 13 though hiv-2 and group o hiv-1 could not be ruled out, the patient was presumed to have hiv-1 subtype c. hiv epigenetics of southern africa, and botswana in particular, show that the majority of hiv-infected patients are infected with hiv-1 subtype c.12 , 13 , 14 a 2005 study found a 98.6% prevalence of hiv-1 subtype c among randomly selected samples of hiv-infected patients from 22 health districts in botswana.15 cases of subtype a, b, f1, g, u and ch recombinant have been confirmed in south africa,13 while isolated cases of group o have been noted in zambia.12 regional prevalence of hiv-2 is very low in southern africa, with most cases reported in angola and mozambique.12 the prevalence of hiv-2 is highest in west africa, with hiv-1 group o being more prevalent in west and central africa, particularly cameroon, guinea and gabon.12 while the possibility that our patient acquired hiv from a different source cannot be excluded, the patient denied travel outside of botswana or to any of the aforementioned regions, as well as sexual relations with commercial sex workers and intravenous drug use. the hiv status of the wife and child also served to support the patient’s diagnosis of hiv-1 subtype c; the child was perinatally infected and all members were presumed to have the same strain of hiv. the child had a detectable baseline viral load and both the wife and child experienced immune decline to aids, necessitating highly active art (haart). 
this case is particularly interesting because little is known about the rate of the clinical progression of subtype c, compared with other subtypes. moreover, the epigenetics of subtype c in southern africa may not be conducive to ltnps. one study of hiv-1 subtype c in botswana showed a potentially higher median viral load for extended periods of time.14 prior to that in a senegalese study, hiv-1-infected patients with subtype c, d or g were at higher risk of developing aids than their subtype a counterparts.16 this case of a likely elite or viraemic controller ltnp in botswana illuminates gaps in our knowledge of the molecular mechanisms and clinical management of such patients. most research on elite controllers and ltnps has been confined to the basic sciences to elucidate the immune mechanisms involved, in hope of providing the basis for new therapeutics and vaccine development.17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 complex host factors appear to be implicated in the control of hiv viral replication as well as viral dynamics. our case highlights the importance of the host immune response. the patient’s daughter was unable to halt hiv progression and the wife had progressive immune decline, despite questionable viral suppression at baseline. both were presumed to be infected with the same strain of hiv-1 as our patient.   important knowledge gaps elite controllers are an area of ongoing research and discovery. numerous viral factors have been posited as the aetiology of elite control. some studies have confirmed infection with an attenuated replication-incompetent hiv virus in some patients.8 in particular, mutations in specific hiv genes such as nef, rev, tat, vif, vpr and vpu have been implicated.18 , 19 , 31 however, the majority of elite controllers have been found to be infected with replication-competent hiv,7 , 32 , 33 leaving the interaction with complex host immune mechanisms as the predominant explanation for the existence of most elite controllers. the transmission of hiv from a patient with aids to an elite controller has been described34 as well as a case of continued viral suppression in the face of super-infection with a pathogenic hiv-1 strain.35 however, the exact viral factors and associated roles in the development of elite controllers is still unknown. proposed host immune mechanisms are numerous and have been reviewed elsewhere.6 , 8 , 31 , 32 , 33 briefly, roles for both adaptive and innate immune mechanisms have been elucidated.31 hla class alleles have been implicated: one study showed the expression of allele hla b*57 in half of their elite controller cohort;6 however, other studies did not detect this in the majority of their cohort.9 , 29 natural killer responses and high hiv-specific cd4 and cd8 activation may also be involved.32 , 33 studies evaluating the presence and titres of anti-hiv antibodies have yielded conflicting data, but may have uncovered a potential mechanism in some elite controllers.21 , 26 , 27 , 32 with continued basic science research, perhaps a greater understanding of the interactions between host and viral factors will become clearer.   approach to management as elite controllers appear to comprise less than 1% of the total population of hiv-infected individuals,31 there is a paucity of data on the mortality, natural progression and optimal management of these individuals.1 historically, studies have enrolled a relatively small number of elite controllers, lacked the further differentiation and unified definitions of ltnp and/or elite controllers, evaluated data from subsets from larger studies, and focused on immune mechanisms instead of clinical progression.1 , 8 , 9 , 36 though the majority of elite controllers maintain high and stable cd4 cell counts for longer than 10 years with low rates of clinical progression,37 , 38 a minority of patients eventually require treatment as a result of a loss of viral control or progressive immune decline despite continued viral suppression.1 , 11 the exact mechanisms, though unknown, may involve low levels of viral replication or factors independent to viral load, such as immune and t-cell activation and pro-inflammatory markers.1 , 37 , 39 in a trial of hiv-1 seroconverters with spontaneous viral suppression, 6.7% of patients progressed to an aids-defining illness with 3 patients developing progressive disease in the face of continued viral suppression.38 , 40 however, given that the dynamics and clinical progression of elite controllers may differ from other ltnps (such as viraemic controllers), the lack of differentiation of these groups limits the utility of many older studies.1 , 36 though a system based on clinically distinct classifications is advocated by graber et al., casado and colleagues support clinical definitions based on viral and host factors.7 , 36 though there is no standard consensus, more recent studies have capitalised on our evolving knowledge of the different classifications of ltnps. okulicz and colleagues have recently shown a decreased risk of aids-defining illnesses,1 stable cd4 and longer duration of cd4>350 cells/mm3 in elite controllers than in viraemic controllers.1 there is also conflicting evidence regarding the rate of recovery after the initiation of antiretroviral therapy (art) in ltnps. okulicz et al. showed that the ltnp elite controllers appear to reconstitute t-cells more slowly than other patients, while mckinnon and colleagues found that only cd4 nadir, and not elite controller status, was associated with slower rates of immune reconstitution.1 , 5 , 41 the clinical management of elite controllers is not discussed in the world health organization (who) hiv/aids guidelines, but is briefly touched upon in the united states department of health and human services (dhhs) and international aids society (ias) guidelines. the dhhs guidelines mention ltnps with high viral loads and elite controllers with immune or clinical failure and state that: ‘although therapy may be theoretically beneficial for patients in either group, clinical data supporting therapy for non-progressors and elite controllers are lacking.’42 the ias hiv guidelines state that art should be considered for patients with cd4<500 cells/mm3 , ‘unless the patient is an elite controller or has stable cd4 with low level viraemia.’43 though most expert consultants commence art in elite controllers based on the same criteria as for hiv progressors, optimal management is unknown. there has been some suggestion that elite controllers may benefit from art, in decreasing immune activation, which appears to play a central role in immune decline over time40 and in non-aids complications such as cardiovascular and neurological disease. conclusion this case of an elite or viraemic controller illustrates the limitations of national health guidelines, such as those in botswana, which do not specifically address treatment strategies for elite controllers and/or ltnps. the case also emphasises how further classification of ltnp types may guide strategies in the future, particularly in the developing world where assays are generally not as sensitive. the omission of lntp subsets, such as elite or viraemic controllers, from the national guidelines of most african countries is not surprising given that they comprise a very small minority of patients, and emphasis has historically been on preventing and treating opportunistic infections and aids. further research should be devoted to assessing the prevalence, natural history, morbidity and mortality of elite controllers and ltnps in sub-saharan african, to create consensus on rational and optimal management. references 1. okulicz jf, marconi vc, landrum ml, et al. clinical outcomes of elite controllers, viremic controllers, and long-term nonprogressors in the us department of defense hiv natural history study. j infect dis 2009;200:1714-1723. 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[http://dx.doi.org/10.1001/jama.2010.1004] hiv0304pg000 the southern african journal of hiv medicine march 2004 2 1 1. introduction (a) it is important to remember that survivors of sexual assault are patients like any other patients but with special needs. the basics of good clinical medicine should therefore apply including good history taking, clinical examination, special investigations and appropriate management. (b) every patient should be seen and managed in a comfortable and compassionate environment. (c) the appropriate crime kits for the medico-legal examination should be available in hospitals and doctors’ rooms, as south african police service (saps) personnel do not always have easy, quick access to the kits. this is one of the many reasons why a positive and co-operative working relationship with the relevant local saps is vital. (d) all health care staff should undergo basic training in counselling and should have been trained in general medico-legal procedures regarding rape/sexual assault. 2. procedures (a) if the patient is a priority 1 (immediate life-threatening injury = code red) or priority 2 (limb/potential lifethreatening injury = code yellow) they should be managed in the resuscitation room according to advanced trauma life support protocols. (b) if the patient is a priority 3 (non-limb or lifethreatening injury = code green) they should be treated in a dedicated, private room. (c) a registered nurse and a medical doctor should commence by taking the medical history and details of the actual sexual assault. (d) once the history has been taken, the medical procedures that will be necessary should be explained to the patient in detail. (e) if the patient decides to lay a charge, the appropriate medico-legal examination should be explained in detail. (f) if the patient is treated in a hospital, all injuries should be attended to, and patient transferral should be kept to a minimum. (g) however, referrals may be necessary in certain circumstances, e.g. a child with vaginal tears requiring suturing under general anesthesia by a specialist surgeon. (h) if the patient requires special investigations, e.g. x-rays, or requires admission for specialised medical treatment, this should be carried out. (i) where appropriate antibiotic prophylaxis should be commenced, as soon as possible. (j) if possible, a facility should be made available where the patient can shower/bath and change their clothing on completion of the full medico-legal examination. (k) follow-up examinations should take place at 6 weeks, 3 months and 6 months after the assault. the choice of whether to attend for regular annual follow-up visits should be left to the patient. 3. counselling (a) a trained counsellor should be called in for every case of sexual assault. he or she would be in a position to assist the family, friends, spouse and victim throughout the entire procedure and then provide follow-up counselling on a regular basis, according to the patient’s needs. (b) the patient has a right to lay a charge against the perpetrator(s). this should be facilitated with the relevant saps. statistics from one large johannesburg hospital trauma unit show that less than 48% of patients are accompanied to casualty by a member of the saps. it may therefore be necessary to call in a saps officer for unaccompanied patients wishing to lay a charge. data indicate that over 70% of sexual assault patients lay g u i d e l i n e s medical management of a survivor of sexual assault/abuse including post-exposure prophylaxis and the forensic kit adrienne wulfsohn, mb bch private medical practitioner i. medical management march 2004 the southern african journal of hiv medicine 2 2 charges against the perpetrator(s), with appropriate treatment and explanations. (c) experience has shown that patients who see a counsellor at the initial event have improved follow-up rates for themselves and their families. (a) a component of the initial history taking should include pre-test counselling for an hiv test. (b) consent for the management and procedures to be undertaken should be obtained. (c) informed consent for the baseline hiv enzyme-linked immunosorbent assay (elisa) should be obtained. if the patient is under age the appropriate parent/guardian should be approached. if they are unavailable the attending saps officer will assist. if reliable rapid tests are available these may be used. (d) the hiv elisa results should be available within 3 hours. (e) in circumstances where the results of conventional hiv elisa tests may be delayed the use of rapid antibody tests is endorsed. a positive rapid test result would need to be confirmed by the use of a conventional elisa test. (f) every patient should be told about pep. (g) if the elisa test is negative, patients seen within 72 hours of the sexual assault should be offered antiretroviral (arv) pep. this should consist of a 28-day course of azt and 3tc (combivir), one tablet twice daily. children and the elderly, who may find capsules difficult to swallow or require a lower dosage than provided by combivir, can be given azt/zidovudine (retrovir) and 3tc/lamivudine syrup. (h) patients presenting more than 72 hours after the sexual assault should be counselled and offered routine blood testing, counselling and follow-up for hiv/aids and the rape incident. (i) if the patient’s hiv elisa is positive, he or she should be counselled and referred to relevant centres for hiv-aids treatment. (j) a pregnancy test should be done if necessary. (k) adherence to pep does not appear to be problematical among survivors of sexual assault. (l) the follow-up rate is excellent within the first 3 months and may only decline thereafter. (m) the unit should provide patient follow-up for other medical problems, as well as counselling. other concomitantly prescribed medication prophylactic antibiotics. in addition to the arvs the patients should be given prophylactic antibiotics for other sexually transmitted infections: ■ penicillin 2 million units intramuscularly (im) or ciprobay 2 g stat. ■ flagyl 2 g p.o. stat or flagyl 500 mg intravenously (iv) should the patient be vomiting or nauseous. ■ zithromax 1 g p.o. stat or tetracyclines 500 mg q.i.d. for 10 days. patients who are allergic to penicillin should be given erythromycin. other medication to consider: ■ the ‘morning after’ pill should be given if appropriate and necessary. this should be given at least 1 hour before giving the antibiotic prophylaxis. ■ a vaginal douche should be provided to take home. ■ anti-emetics should be prescribed if necessary. ■ analgesia/anti-inflammatory medication should be prescribed if necessary. the following steps should help you to understand the kit and make it easier to work with. general (a) it is imperative that from the commencement to the completion of the medical examination, a correct chain of events (evidence) is adhered to. (b) it is therefore desirable that a second health care professional is present during the course of the forensic examination. the crime kit the new crime kit consists of: 1. the evidence collection form and 2. the crime kit itself, which contains 7 sections. (not all 7 sections will necessarily be used in all rape cases.) 1. the evidence collection form (a) the form (1 page) needs to be completed in triplicate. (b) the first section of the document requests all of the particulars of the examining doctor. ii. post-exposure prophylaxis (pep) iii. the forensic kit — directions for use march 2004 the southern african journal of hiv medicine 2 4 (c) the second section asks the patient when he/she last had consensual intercourse. it is vital that this question be asked, although it may prove difficult, because if consensual intercourse has taken place within 5 7 days before the assault semen from the consenting partner may still be present. this can make the forensic examination difficult to interpret. (d) should consensual intercourse have taken place within 5 7 days before the assault the justice system may request a blood sample, for dna testing of the initial consenting partner, prior to going to court (e) the third section requests all of the patient’s details. this is a vital part of the form that must be completed, as it is the only piece of documentation showing the patient’s name and details, since these cannot be reflected on the outside of the forensic collection box. (f) the fourth section requests the doctor or examiner to list the specimens that have been taken. (g) the doctor and patient both need to sign the form. (h) the first copy of the form should be placed in the crime kit box. (i) the doctor retains the second copy in the patient’s file for medico-legal purposes should the case go to court. (j) the third copy, together with the forensic evidence bag, is handed to the member of the family crime and sexual violence unit (fcs) unit or saps unit who collects the kit. 2. the crime kit a. section 1. the oral swab this is used to detect any seminal fluid present in the buccal cavity if the patient has been forced to perform oral sex . the kit contains the following: ■ a swab box ■ a swab ■ an evidence seal. nb: the swab must not be moistened. procedure: swab the following areas with the same swab: ■ under the tongue ■ along the inner, outer, upper and lower gum line ■ the cheek ■ the palate. there are extra swabs if necessary. then: ■ place the swab in the box ■ fold as instructed ■ seal with an evidence seal. b. section 2. collection of underwear the kit contains the following: a brown paper bag for the panties (or panties and/or pad) worn during or immediately after the assault. nb: sanitary pads attached to panties should be left attached. procedure: the instructions request: ■ collection of the patient’s panties and/or sanitary pad that she may have been wearing during or immediately after the assault. ■ if the pad is separate from the panties, cover the adhesive (outside) side of the pad with the wax strip provided. ■ if the victim is a man or boy, the underpants must be collected. ■ place all items in the bag. ■ seal the bag by removing the self–adhesive backing from the bag. ■ place the evidence sticker where the lip and the body of the bag meet. ■ if the patient was wearing a tampon, see section 7 (tampon collection). c. section 3. collection of other evidence from the patient’s body this section provides for the correct removal of evidence from the patient’s body. there are two steps (c.1 and c.2) to this part of the kit. c.1. collection of evidence from the patient’s body, e.g. foreign debris and/or dried secretions the kit contains the following: ■ sterile swabs ■ sharp-pointed sterile swabs (2) ■ sterile water ■ ruler ■ box for swabs ■ a catch paper for reference samples. procedure: ■ look for any areas on the body on which there may be dried secretions, and also ask the patient if they feel any area(s) of dried and/or caked secretions on their body. ■ to identify secretions, ask the patient if she/he knows where they might be. ask the patient if the perpetrator kissed, licked or bit her/him anywhere. those areas should be swabbed. ■ to prevent destroying any evidence, one evidence source should be swabbed at a single time. march 2004 the southern african journal of hiv medicine 2 6 ■ this means one ‘stain’ per swab. this is to prevent mixing evidence if there was more than one attacker. ■ the swab should be moistened with the sterile water provided before swabbing the body area. ■ if the patient reports having scratched the perpetrator, fingernail scrapings must be taken. before swabbing under the fingernail(s) loosen the debris with a sterile blade (2 swabs with sharp points are provided in the kit) which can be used to swab under the nail(s). the swab must be moistened with the sterile water provided. ■ any bruise(s)/bite mark(s) should be measured with the ruler provided. ■ pack the swabs in the box provided. ■ break off the ends and close with an evidence seal. c.2. collection of evidence from the patient’s hair the kit contains the following: ■ a comb ■ a catch paper for the head combings ■ a catch paper for reference samples. hair combing procedure: ■ place the catch paper under the patient’s head. ■ comb the hair so that any loose hair or debris fall onto the catch paper marked ‘head hair combing’. ensure that there are sufficient samples. ■ comb hair in a downward direction to ensure that any foreign debris falls onto the catchment paper. ■ you may use your fingers to ruffle the hair to loosen any debris that may be stuck in the hair. ■ fold the paper with the comb inside it . ■ place in pack. ■ seal the pack with an evidence sticker. reference head hair: ■ pull at least 5 hairs from the top, back, front, left and right side of the head. ■ place the hair on the catch paper marked pulled ‘reference head hair’. ■ fold the paper and seal with an evidence seal. d. section 4. collection of debris that will link the patient to the location of the assault the kit contains the following: ■ catch paper marked ‘debris a’ for matted hair from the head or body which might indicate blood/semen ■ catch paper marked ‘debris b’ for debris taken from the body. procedure for collecting samples: debris a: ■ look for matted hair on the head and/or body that may indicate blood/semen. ■ cut the hair over the catch paper marked ‘debris a’. ■ fold the paper and seal with the evidence seal. debris b: ■ collect any debris such as soil, leaves, grass and hair that may be present during the examination. ■ use a spatula and remove the debris from the patient's body. ■ place it on the catch paper marked ‘debris b’. ■ fold the paper. ■ seal with the evidence seal. e. section 5. collection of pubic hair and reference hair this is done to attempt to identify the perpetrator. this section contains two sub-sections: e1 for samples of pubic hair and e2 for reference hair. the kit contains the following: ■ a comb ■ catch paper marked ‘pubic hair combing’ ■ catch paper marked ‘reference pubic hair’. e.1. pubic hair combing procedure for collecting pubic hair combings: ■ place the catch paper marked ‘pubic hair combing’ under the patient’s buttocks. ■ comb the hair in a downward direction over the catch paper. ■ comb with your fingers to assist in loosening debris. ■ if matted hair is noted, cut it off over the catch paper. ■ fold the paper. ■ seal with evidence seal. e.2. reference hair procedure for collecting reference pubic hair combings: ■ this is needed for microscopic screening ■ with the patient’s consent, pull out about 10 pubic hairs. ■ place the hair into the catch paper marked ‘reference pubic hair’. ■ fold. ■ seal with the evidence seal. f. section 6. collection of anal samples (used in anal rape) nb. the ano-rectal examination should be carried out before the vaginal examination to prevent crosscontamination of evidence. the kit contains the following: ■ two swabs ■ an amp of sterile water ■ racks marked ‘a’ and ‘b’. the southern african journal of hiv medicine march 2004 2 7 procedure for collecting samples from the external anal area and the rectum: external anal area: ■ put the patient into a comfortable position, e.g. left lateral position. ■ moisten the swab with the sterile water provided. ■ swab the external anal area, extending slightly into the anal canal. ■ place the swab in the rack marked ‘a’. rectum: ■ apply gentle lateral tension to the peri-anal area for about 3 minutes to dilate the anal sphincter. ■ after dilatation has taken place, use one swab to swab the rectal canal. ■ place the swab in the rack marked ‘b’. ■ fold pack. ■ close with evidence seal. g. section 7. collection of vaginal swabs (used in vaginal rape) the kit contains the following: ■ three swabs ■ an amp of sterile water ■ racks marked ‘a’, ‘b’ and ‘c’ ■ box marked ‘tampon’. procedure for collecting vaginal biological material for dna testing that may identify the perpetrator: (nb: swabs are taken of three areas: external genital area, vagina and cervix). external genital area swab: ■ moisten the swab with the sterile water provided. ■ swab the external and internal surface of the labia majora and minora including the clitoris, peri-urethral area and fosse navicularis. ■ place the swab in the rack marked ‘a’. vaginal swab: ■ this must be done before the internal clinical examination. ■ insert an unlubricated speculum ■ swab the anterior and posterior vaginal fornices ■ place the swab in the rack marked ‘b’. cervical swab: ■ swab the inside of the cervical os. ■ collect as much of the mucous plug as possible. ■ place the swab in the rack marked ‘c’. ■ fold. ■ seal the box with the evidence seal. ■ place sellotape around the box. tampon collection: if a tampon was present during the rape or inserted after the rape, it should be retained for evidence. the procedure for collection is: ■ remove the tampon ■ place in the box marked ‘tampon’ ■ seal the box with the evidence seal. additional items collection of reference dna specimen — which need not be included in the kit. ■ this provides the forensic laboratory with a sample of the patient’s blood. ■ once the blood has been taken and put in the purplecapped tube, insert the cannula provided. ■ press the cannula onto the cassette. ony one drop of blood is needed. ■ place the cassette in the bag provided. ■ seal with an evidence seal. box closure ■ once all the specimens have been taken, place them in the box. ■ leave the unused packs in the box. ■ the front page of the evidence collection form is placed on top of the specimens. ■ on the outside of the box is a space to write the police station and case number. ■ there are three stickers with numbers on, on the upper left corner of the box. ■ one sticker goes onto the j88 form. ■ the second sticker goes onto the retained copy of the form which is stapled onto the inside cover of the patient file. ■ the third sticker stays on the box. ■ the box is then sealed with the evidence sticker provided. ■ place sellotape around the box to keep it closed. focus hiv/aids profile in the provinces of south mrica, 2002 insights, sapped our energies and dispirited our determination to act. and, most significantly, they have silenced all too many voices among those who are experiencing the epidemic in their own bodies and their own families and in their own communities. the deniers have re-created shame, and reimposed silence, in an epidemic where the struggle for twenty years has been to create voices and to defeat shame. the denial of the facts about aids is not only an outrage against the truth. it is a profound insult to those south africans who are living with and dying from the effects of the virus. they deny us the dignity of our suffering. they deny us the dignity of our struggle for life against the workings of a viral agent. most importantly, they deny us the dignity of the truth, and the power and hope, and the opportunities for action, that acceptance of the truth brings. in countless villages and townships and cities and settlements in south africa, where the virus is taking its toll a booklet entitled hiv/aids profile in the provinces of south africa: indicators for 2002 has recently been released. it makes provincial trends and statistics on the hiv/aids epidemic available to government officials at all levels, as well as to business people, non-governmental organisations (ngos) and the public the report gives readers a sense of the magnitude of the numbers involved, and will allow them to benchmark other information about the epidemic as it becomes available. the booklet can be down loaded from www.mrc.ac.za or www.assa.org.za/aidsmodel.asp or www.commerce.uct. ac.za/care, and is also available from the university of cape town (uct)'s centre for actuarial research at r30 per copy (tel. (021) 650-2475). the estimates provided are not new in fact. they have been available for the last year on the actuarial society of south africa's website but it is the first time they have been compiled into one publication for ease of access. the indicators are based on a model constructed by the actuarial society of south africa (assa). while there is ~ehruaily 2003 -----------of health and life among our people, the terrible truth about aids is being born and lived and died. our people are being born, are living with, and dying from that truth. they are living that truth in the rising fevers, the wasting of flesh and the slow, agonised cessation of bodily functions that result from the virus. their suffering is being increased and is being prolonged incalculably by the deniers. but, as we have seen today, from the terrible grief of those affected by the virus a terrible determination arises: a determination to defeat untruth and misrepresentation and distortion, and to assert hope. that is the ultimate significance of the unforgettable images of this exhibition: that untruth and inaction are the greatest crimes of all. let us take an angry inspiration, and a deep determination, from that. reference 1. hlongwan(" c. caravans, ears, g~st', foot & mouth ana srarisrics hn/alds and the struggle for the humani~tioi1 of the african. anc document, distributed april 2002 always a degree of uncertainty surrounding such estimates, models can provide an invaluable tool for giving a sense of possible future scenarios. the assa model is continuously being improved as more data become available and our understanding of the dynamics of the epidemic improve. some of the information available in the report • the extent of the epidemic, with 6,5 million people (14,2'1'0 of the population) infected with hiv by july 2002. • of these, over 95% (6.1 million) are in the age group 18 64 years (labour force age). • the prevalence is highest [25.9%) among young women of childbearing age this, in turn, has implications in terms of numbers of orphans. • the prevalence of hiv/aids (among all ages) in each of the provinces is as follows: kwazulu-natal 18.4% eastern cape 11.3% free state 16.7% limpopo 11.0% mpumalanga 16.5'1'0 northern cape 7.9% gauteng 16.qoio western cape 4.2'1'0 north west 15.1 % the southern african journal of hiv medicine awards south mrican researchers awarded r220 million research grant the project will: • evaluate an affordable hiv/aids treatment programme for adults and children in a family setting at primary care level. • test whether treatment interruption is an affordable and feasible way of controlling hiv infection in children that reduces the progression to aids. • determine the efficacy of two standard childhood vaccines (used to prevent pneumonia and meningitis) in preventing aids-related complications in infants. • evaluate the community effect of highly active antiretroviral therapy on sickness and deaths due to aids and tuberculosis. • develop simple, inexpensive methods of diagnosing hiv and monitoring treatment and drug resistance. professor james mclntyre and glenda groy. executive directors of the perinatal hiv research unit, chris hani barogwanath hospital, soweta. for further information contact: professor rob dorrington, uct centre for actuarial research tel. (021) 650-2467 or debbie bradshaw, mrc burden of disease research unit cell: 082 461 1234 ----------hhruary 2003 'low-income households in south africa carry the greatest burden of hiv!aids, experience the greatest negative effects, and have the least reserves to cope: says professor mclntyre. the new cipra grant, 'safeguarding the household: comprehensive aids research', will address hiv/aids as a problem not simply of individuals but of entire families, he explains, and all family members may participate in the studies. the cutting-edge research programme will focus on aspects of hiv treatment in adults and children, tuberculosis and affordable laboratory tests. 'this research agenda is of crucial importance to south africa and our region. it will gather essential information for the government's aids programmes in the future, and covers many of the key areas raised in the recent cabinet statement on aids; explains professor mclntyre. the grant award recognises the quality of south african aids research and will provide the opportunity to develop many more local researchers through an extensive, linked, training programme: the united states national institutes for health has announced the award of a major research grant to leading south african aids researchers. the $21.3 million (about r220 million) award over 5 years will support hiv/aids research in a family setting, a rarely tried approach to fighting the disease. this grant is the largest yet made by the comprehensive international program for research on aids (cipra). this national collaborative research effort will be led by professor james mclntyre and co-ordinated by the perinatal hiv research unit of the university of the witwatersrand. thf soutmtrn mrican journal or hiij mfdicinf making the epidemic more visible, and underscanding its dynamics through such reports is important not only in managing the impact of the epidemic but also in eventually being able to turn the tide of it. for all spheres of planning, it is essential to have an understanding of where the country stands in terms of hiv!aids. hiv 833 tb/hiv integration at primary care level: a quantitative assessment at 3 clinics in johannesburg, south africa l page-shipp, y voss de lima, k clouse, j de vos, l evarts, j bassett, i sanne, a van rie   right to care, johannesburg l page-shipp, mb bch i sanne, mb bch, fcp (sa)   clinical hiv research unit, university of the witwatersrand, johannesburg i sanne, mb bch, fcp (sa) y voss de lima, msc k clouse, mph   department of epidemiology, university of north carolina, chapel hill, nc, usa k clouse, mph a van rie, md, phd   geomed, stellenbosch j de vos, msc (eng)   public health leadership program, university of north carolina, chapel hill, nc, usa l evarts, mph   witkoppen health and welfare centre, johannesburg j bassett, mb chb corresponding author: l page-shipp (liesl.pageshipp@gmail.com) background. in 2004 the world health organization (who) released the interim policy on collaborative tb/hiv activities. according to the policy, for people living with hiv (plwh), activities include intensified case finding, isoniazid preventive therapy (ipt) and infection control. for tb patients, activities included hiv counselling and testing (hct), prevention messages, and cotrimoxazole preventive therapy (cpt), care and support, and antiretroviral therapy (art) for those with hiv-associated tb. while important progress has been made in implementation, targets of the who global plan to stop tb have not been reached. objective. to quantify tb/hiv integration at 3 primary healthcare clinics in johannesburg, south africa. methods. routinely collected tb and hiv data from the hct register, tb ‘suspect’ register, tb treatment register, clinic files and hiv electronic database, collected over a 3-month period, were reviewed. results. of 1 104 people receiving hct: 306 (28%) were hiv-positive; a cd4 count was documented for 57%; and few received tb screening or ipt. in clinic encounters among plwh, 921 (15%) had documented tb symptoms; only 10% were assessed by smear microscopy, and few asymptomatic plwh were offered ipt. infection control was poorly documented and implemented. hiv status was documented for 155 (75%) of the 208 tb patients; 90% were hiv-positive and 88% had a documented cd4 count. provision of cpt and art was poorly documented. conclusion. the coverage of most tb/hiv collaborative activities was below global plan targets. the lack of standardised recording tools and incomplete documentation impeded assessment at facility level and limited the accuracy of compiled data. s afr j hiv med 2012;13(3):138-143. doi:10.7196/sajhivmed.833 hiv-associated tuberculosis (tb) continues to pose a considerable global public health threat. in 2010, 1.1 million (13%) of the 8.8 million new tb cases globally were among people living with hiv (plwh) and hiv accounted for 25% of the 1.4 million tb deaths. south africa ranked third in the number of incident tb cases in 2010 with an estimated 61% of tb patients infected with hiv. despite important efforts to curb the tb epidemic, south africa (sa) was the only high-burden country where the tb burden continued to rise in 2010.1 to address the hiv-associated tb epidemic, in 2004 the world health organization (who) published the interim policy on collaborative tb/hiv activities.2 to decrease the burden of tb in plwh, the guidelines recommend intensified tb case-finding (icf), isoniazid preventive therapy (ipt) and infection control in healthcare and congregate settings. in 2008, these activities were packaged as the ‘3is’. to decrease the burden of hiv in tb patients, the guidelines promote hiv counselling and testing (hct) and hiv prevention methods for all tb patients, and cotrimoxazole preventive therapy (cpt) and hiv/aids care and support including antiretroviral therapy (art) for those co-infected. in 2006, the stop tb partnership launched the ‘global plan to stop tb 2011 2015’, providing a roadmap for scaling up prevention and treatment and research and development.3 the plan outlined specific tb/hiv collaboration targets, providing a framework for measuring who tb/hiv collaborative activities. despite an increasing body of evidence on the effectiveness and feasibility of collaborative tb/hiv activities and recent improvements in tb/hiv integration, implementation remains below targets.1 , 3 in 2010, key global indicators included merely 12% of eligible patients initiating ipt, and only 34% of tb patients were reported to know their hiv status.1 we reviewed routine tb and hiv data to quantify tb/hiv integration, measured against who and global plan targets,1 , 3 at 3 primary healthcare clinics in johannesburg, sa. methods study setting and population three primary healthcare clinics in the johannesburg metropolitan area were purposefully selected to represent different geographical catchment areas and non-governmental and department of health (doh) clinics. all clinics provided tb diagnosis and treatment services, hct, pre-art care, and continuation of art for stable patients. two sites also served to initiate art. tb and hiv services were performed vertically in different areas of the clinic by different staff who self-identified as either ‘tb’ or ‘hiv’ staff. hiv counselling and testing was performed in those who requested this service, and provider-initiated hct was offered to pregnant women and clients with aids symptoms, including tb and sexually transmitted diseases. cpt was indicated in plwh with a cd4 count <200 cells/mm3 , as well as in symptomatic hiv disease and in all tb patients.4 plwh were eligible for art if their cd4 count was <200 cells/mm3 and/or they met the who criteria of stage 4 disease.5 plwh were eligible for ipt if they were asymptomatic for tb and had a positive tuberculin skin test (tst), or they were a tb contact.4 clinic clients with cough persisting for longer than 2 weeks were considered tb suspects, independent of hiv status. the first-line diagnostic for tb was smear microscopy. smear-negative tb suspects were assessed further by culture (sputum analysis performed by the centralised national health laboratory service) and chest x-ray (performed at nearest hospital).4 all clients who presented to 1 of the 3 selected clinics between 19 august and 19 october 2009 and who received tb and/or hiv services were included for analysis. eligible clients were identified by review of relevant data sources, including the paper sa national doh hct register, tb case identification and follow-up register, tb treatment register, and an electronic hiv database (therapyedge) (table 1). records of all eligible individuals were reviewed 2 months after their clinic visit to allow sufficient time for activities to be performed and results to be captured. infection control was assessed using a standardised risk assessment tool based on national tb infection control guidelines.6 table 1. definition of study participants, data sources and activities reviewed   definition source tb and hiv activities performed reviewed (n) hct clients clinic clients with record of hiv test hct register medical file intensified tb screening staging by cd4 count 1 104 plwh encounters clinic visits by plwh electronic hiv database tb case identification register intensified tb screening referral for tb investigation (if symptomatic) 6 157 tb suspects clinic client with record of diagnostic sputum investigation tb case identification register hct register medical file diagnostic assessment of tb suspect hct cpt and art (if eligible) 602 tb patients starting tb treatment clinic client with tb start date during the study period tb treatment register tb clinic file hct cpt staging by cd4 count art if eligible 208 hct = hiv counselling and testing; plwh = people living with hiv; cpt = cotrimoxazole preventive therapy; art = antiretroviral therapy; tb = tuberculosis. individuals were categorised as: ‘hct clients’ if they received hct during the study period; ‘tb suspect’ if they had a diagnostic sputum investigation recorded; and ‘tb patient’ if they were started on tb treatment during the study period. as the who guidelines recommend symptom screening at every clinic visit, we included all plwh encounters, including multiple encounters by individual plwh that occurred during the specified time period. clinic records of clients who were newly tested hiv-positive were reviewed for documentation of tb symptom screening. names were cross-checked with the ‘tb detection and follow up sputum register’ to assess if a sputum specimen was obtained. data on plwh were extracted from the therapyedge database. for every encounter registered, recorded symptoms and signs were reviewed. for every plwh with recorded cough, night sweats, weight loss, axillary nodules or fever, the ‘tb detection and follow up sputum register’ was cross-checked to assess if a sputum specimen had been obtained. files of clients entered into the tb case identification and follow up register and/or the tb register were reviewed for hiv testing, cd4 count, cpt status and art status. all data from standardised national doh registers and therapyedge were entered for analysis in an electronic tb/hiv clinic and patient management program (emum®). descriptive statistics were used to characterise the study population. statistical analyses were performed with sas software (version 9.2). the global plan targets3 were used as the standards against which the implementation of these activities was measured. the study was approved by the human research ethics committee of the university of the witwatersrand, the institutional review board of the university of north carolina, the city of johannesburg health department, and facility managers. results activities to reduce the burden of tb among plwh hct clients were young (median age of 27 years) and the majority were female (75%). of the 1 104 clients tested, 306 (28%) were hiv-positive. only 57% of hiv-positive patients had a cd4 count result recorded, with a median count of 336 cells/mm3 (iqr 152 502). the proportion of clients newly diagnosed with hiv who were screened for tb symptoms could not be determined, as this activity was not systematically recorded. based on review of the tb case identification register, only 2/306 (0.6%) hiv-positive hct clients were assessed by smear microscopy at the time of their hct visit. there were 6 157 clinic encounters for 4 079 individual plwh. the majority (79%) were for patients receiving art (table 2). the proportion of individuals with any recorded tb symptom of any duration was slightly higher for pre-art than art visits (17% v. 14%; p=0.04). in both populations, coughing was the most frequently recorded symptom (85% and 70%, respectively). of the 921 clinic encounters with documented tb symptoms, only 91 (10%) resulted in sputum collection, with similar proportions of pre-art and art suspects being investigated (12% and 9%, respectively, p=0.20). among the 91 tb suspects investigated, 8 smear-positive pulmonary tb cases and 9 smear-negative culture-positive tb cases were diagnosed. a culture result was missing or contaminated in 27% (22/83) of smear-negative tb suspects. table 2. intensified tb case finding during 6 157 clinic encounters among 4 079 individual plwh at 3 primary care clinics in johannesburg   all n (%) pre-art n (%) art n (%) p-value total, n (%) 6 157 (100) 1 274 (21) 4 883 (79)   any tb symptom recorded,* n (%) 921 (15) 214 (17) 707 (14) 0.04 cough 678 (74) 181 (85) 497 (70)   weight loss 138 (15) 38 (18) 100 (14)   night sweats 169 (18) 27 (13) 142 (20)   lymphadenopathy 79 (9) 14 (7) 65 (9)   fever 58 (6) 14 (7) 44 (6)   investigated for tb (if symptomatic), n (%) 91 (10) 26 (12) 65 (9) 0.20 smear-positive 8 (9) 2 (8) 6 (9)   smear-negative, culture-negative 52 (57) 17 (65) 35 (54)   smear-negative, culture-positive 9 (10) 1 (4) 8 (12)   smear-negative, culture missing/contaminated 22 (27) 6 (23) 16 (25)   *patients may have reported more than one symptom. the clinics did not collect information on ipt in an ipt register, pre-art register or in the electronic hiv system, making an accurate estimate of the number of people receiving ipt difficult. according to the clinic directors, a small number of plwh received ipt in 1 clinic; the other 2 clinics did not provide ipt. an infection control plan existed in 2 sites, and posters on cough hygiene were displayed in all 3 facilities. staff training was ad hoc; management reported that an effort was made to educate staff on tb and encourage them to know their hiv status and seek appropriate care. there was no triage system or fast-tracking of patients with coughing. environmental controls were inconsistently used, 30% of windows remained closed. one site had ultraviolet germicidal irradiation in the tb clinic area. personal protection for staff interacting with patients in the form of n95 respirator or surgical masks was available at one clinic, but use was not enforced. tb disease in healthcare workers was not documented.   activities to reduce the burden of hiv among tb patients among the 602 tb suspects, 173 (29%) were known hiv-positive before their suspect visit but only half were documented as receiving hiv care (table 3). among the 429 tb suspects with unknown hiv status, 217 (51%) had a record of hct offer. of these, 110 (51%) were hiv-positive, 43 (20%) were hiv-negative, and 64 (29%) refused hiv testing. overall, hiv status was recorded in 54% of tb suspects; 73% (95% ci 0.83 0.90) were hiv-infected. table 3. hiv activities recorded among 602 tb suspects at 3 primary care clinics in johannesburg, south africa hiv counselling and testing, n (%)   known hiv-positive before tb suspect visit 173 (29) referred from pre-art care 26 (15) referred from art clinic 65 (38) no documentation of hiv care 80 (46) hct at time of tb suspect visit (if unknown hiv status), n (%)   record of hiv counselling and/or testing 217 (51) hiv-positive 110 (51) hiv-negative 43 (20) hiv testing offered but refused 64 (29) no record of hiv counselling or testing 212 (49) tb suspects with documented hiv status at end of tb suspect visit 326 (54) hiv prevalence rate among tb suspects with recorded hiv status, % (95% ci) 73 (0.83 0.90) staging by cd4 count   recorded cd4 count, n (%)   known hiv-positive before tb suspect visit 132 (76) newly diagnosed hiv infection at time of tb suspect visit 90 (82) median cd4 count, cells/mm3 (iqr)   known hiv-positive before tb suspect visit 190 (90 351) newly diagnosed hiv infection at time of tb suspect visit 183 (61 289) a cd4 cell count was documented in 78% (222/283) of hiv-positive tb suspects. the proportion of suspects staged by cd4 count and the median cd4 count did not differ significantly between those with known status at time of presentation and those tested on the day of the tb suspect visit (76% v. 82%, respectively; p=0.27; and 190 (iqr 90 351) v. 183 (iqr 61 289) cells/mm3 , respectively). among the 602 tb suspects, 143 (24%) were diagnosed with active tb: 80 (56%) with smear-positive tb, 25 (17%) with smear-negative culture-positive tb, 27 (19%) based on clinical and/or radiological criteria and 11 (8%) with extrapulmonary tb. among the 494 smear-negative tb suspects, a culture was requested in 345 (70%). the culture was positive for mycobacterium tuberculosis in 5%, negative in 48%, and had missing results in 17%. tb treatment was initiated in only 81% (65/80) of tb suspects who were positive on smear microscopy and 26% (7/27) of smear-negative suspects with a positive culture. during the 3-month study period, 208 patients received tb treatment – the majority (81%) for pulmonary tb. the proportion of tb patients aware of their hiv status increased from 39% before tb diagnosis to 66% at time of tb treatment initiation, and to 75% during tb treatment (fig. 1). among the 155 tb patients with known hiv status, 90% were hiv-positive. a cd4 count was documented for almost all hiv-positive tb patients (88%). the median cd4 count was 131 cells/mm33 (interquartile range (iqr) 60 235), and the vast majority (107/123; 87%) had a cd4 count <350 cells/mm3 . there was no documentation of hiv prevention and counselling for hiv-positive or -negative patients, but condoms were freely available at all 3 clinics. according to the staff, most hiv-positive tb patients received cpt, but the proportion receiving such therapy could not be quantified as it was not documented in the tb register, nor consistently recorded in patient files. art status was not consistently recorded, and patients receiving tb treatment at a clinic not accredited for art initiation might have initiated art in another facility, making accurate reporting of the proportion receiving art impossible. fig 1. hiv counselling and testing among 208 tb patients registered at 3 primary care clinics in johannesburg, south africa. discussion in this quantitative evaluation of collaborative tb/hiv activities at 3 primary healthcare clinics, we confirmed the magnitude of the tb/hiv epidemic and observed strengths and gaps in the fight against tb/hiv at primary care level. however, our analysis was challenged by weaknesses in the routine data required to report on who core indicators developed to monitor tb/hiv activities. the most important strength observed was the high rate of hiv and cd4 testing achieved among tb patients (75% and 88%, respectively). important gaps included the lack of full tb/hiv integration despite availability of all services at one facility. firstly, art coverage among patients with tb could not be ascertained as art was not documented in the tb register or on the tb treatment card. secondly, integration of tb services into pre-art care was poor. patients newly diagnosed with hiv were not routinely screened for tb, even though a simple tb symptom screen could successfully have been integrated.7 people newly diagnosed with hiv were not offered ipt, even though most might have been eligible considering that the median cd4 count was 336 cells/mm3 (higher than the median cd4 count of 111 cells/mm3 recorded in large art cohorts in sub-saharan africa).8 thirdly, tb screening for people enrolled in hiv care was suboptimal. a formalised tb symptom screen was not performed and the tb screening outcome was not recorded as ‘no signs’, ‘suspect’, ‘on treatment’ or ‘not assessed’, as per who recommendations.9 consequently, healthcare workers rarely acted upon the information. only 10% of those presenting with symptoms of tb were assessed by microscopy, and ipt was initiated in only a few asymptomatic plwh. the ‘proportion of symptomatic plwh assessed for tb’ may be a useful additional indicator. finally, while some steps were taken towards tb infection control, this was not formally documented. the use of a standardised tb infection control risk assessment tool on a quarterly basis could facilitate monitoring. given the lack of monitoring at facility level, it is not surprising that global data are lacking on the proportion of healthcare facilities providing services for plwh that have tb infection control practices (indicator b.3.1) and the proportion of healthcare workers who develop tb (indicator b.3.2).9 we also observed shortcomings in non-integrated services. with regard to tb services, only 67% of patients with a microbiological diagnosis of tb initiated treatment, indicating important initial default of patients. culture results were missing for 17% of specimens sent, resulting in poor service quality and a waste of resources. this could be improved by the introduction of more sensitive tb diagnostic tools with potential for use at point-of-care – such as the xpert mtb/rif10 test and the lipo-arabinomanna (lam)11 assay. with regard to hiv services, a cd4 count was recorded for only 56% of people newly diagnosed with hiv, again suggesting a failure to engage and retain patients in care. the scarcity of data hampered a comparison of our findings with those observed in other settings. many have discussed the challenges of tb/hiv integration;7 , 12 , 13 , 14 however, most data are aggregated at country level and accurate reporting is complicated by the existence of 2 vertical programmes.15 coverage of the different components at facility level is not well described. only 2 other quantitative assessments at facility level have been published: in 2000 2002, coetzee et al. 16 observed many missed opportunities for tb and hiv prevention, diagnosis and management at primary care clinics in khayelitsha; and in 2006, scott et al. 17 audited tb/hiv integration at 16 clinics in cape town, using a rapid (2 hours per clinic) audit tool and found poor capacity and weaknesses in quality and continuity of care.17 despite our comprehensive review of data on a large number of clinic clients, our study suffered limitations. to assess routine care, data collection was retrospective; consequently, activities that were performed but not recorded could not be assessed. furthermore, clients may have received care at other clinics, but we were unable to verify this due to the high number of clinics in the city of johannesburg (n=90). data were only reviewed on adult clinic clients; an assessment of tb/hiv activities in children would have been complementary. finally, sa underwent significant policy changes regarding collaborative tb/hiv since the review was undertaken. art eligibility criteria changed to a cd4 count <350 cells/mm3 for tb patients and pregnant women, and art is currently indicated for all multi-drug resistant tb patients, regardless of cd4 count. the revised ipt guidelines removed the need for tst and included patients with previous tb and those on art. conclusion despite the existence of effective interventions, clear policies and guidelines, the tb/hiv epidemic continues to rage. it is encouraging that most tb/hiv activities were implemented at the primary care clinics, but unfortunately, at coverage levels well below the global plan targets (table 4).1 this highlights the vast number of opportunities to improve tb control and hiv care as we move towards meaningful tb/hiv integration. the poor quality of routine data was of concern, especially given that primary care clinics are expected to compile data from these sources to report to district and national levels for aggregation, analysis, dissemination and management of the tb and hiv programmes. collection of tb/hiv collaborative data can be complicated by privacy concerns,18 the need to share data between 2 vertical programmes, and the lack of investment in monitoring and evaluation tools.15 accurate monitoring of tb/hiv activities at all levels (facility, district, national and global) requires rationalisation and standardisation,18 19 with appropriate treatment cards, registers, cohort reporting forms, and supportive supervision.9 , 19 the implementation of integrated tb/hiv electronic data collection and clinic management tools has the potential to galvanise tb/hiv integration at primary care level. we need to ensure that every action is properly recorded and that every loop is closed from diagnosis to treatment of tb and hiv, to result in fully integrated patient care. table 4. coverage of tb/hiv activities compared with 2010 estimates for sa 1 and the global plan to stop tb targets 3 indicator 9 global plan target (2011 2015) sa three primary care clinics in johannesburg percentage of hiv-positive patients screened for tb in hiv care and treatment settings (indicator b.1.1) 100% 758 837 • not recorded at hct • 100% of plwh in care screened for tb symptoms • 10% of tb suspects assessed by smear microscopy percentage of new hiv-positive patients starting ipt (indicator b.2.1) 100% 124 059 (12%) • 0% at 2 clinics • small proportion at 1 clinic proportion of healthcare facilities providing services for plwh that have infection-control practices including tb control (indicator b.3.1) target not set but 100% implied nr none satisfied the requirements of indicator b.3.1 proportion of healthcare workers employed in facilities providing care for plwh who developed tb (indicator b.3.2) equal to background rate nr nr proportion of tb patients with known hiv status (indicator c.1.1) 100% 54% 75% proportion of all registered tb patients with documented hiv status who are hiv-positive (indicator c.1.2.1) na 60% 90% availability of free condoms at tb services (indicator c.2.1) 100% nr 100% proportion of hiv-positive tb patients who receive cpt (indicator c.3.1) 100% 74% high according to healthcare worked, but poorly documented proportion of hiv-positive tb patients enrolled in hiv care services during tb treatment (indicator c.4.1) 100% nr poorly documented proportion of hiv-positive registered tb patients given art during tb treatment (indicator c.5.1) 100% 54% poorly documented na = not available; nr = not recorded acknowledgements. the authors acknowledge cassidy henegar for help at the initial stages of the study, the city of johannesburg senior management, regional directors and clinic management, and the witkoppen health and welfare centre senior management and staff. funding. the project was supported by funding from the united states president’s emergency plan for aids relief (pepfar) in a grant by usaid to right to care and the institution (674-a-00-08-00007-00). research training for l page-shipp was supported by dhhs/nih/fic 5 u2r tw00737-04. references 1. world health organization. global tuberculosis control. geneva: who, 2011. http://www.who.int/tb/publications/global_report/2011 (accessed 10 november 2011). 1. world health organization. global tuberculosis control. geneva: who, 2011. http://www.who.int/tb/publications/global_report/2011 (accessed 10 november 2011). 2. world health organization. interim policy on collaborative tb/hiv activities. geneva: who, 2004. http://whqlibdoc.who.int/hq/2004 (accessed 1 october 2009). 2. world health organization. interim policy on collaborative tb/hiv activities. geneva: who, 2004. http://whqlibdoc.who.int/hq/2004 (accessed 1 october 2009). 3. world health organization. global plan to stop tb 2011-2015. geneva: who, 2010. http://whqlibdoc.who.int/publications/2010 (accessed 2 april 2011). 3. world health organization. global plan to stop tb 2011-2015. geneva: who, 2010. http://whqlibdoc.who.int/publications/2010 (accessed 2 april 2011). 4. department of health. national tuberculosis management guidelines. pretoria: doh, 2008. 4. department of health. national tuberculosis management guidelines. pretoria: doh, 2008. 5. department of health. national antiretroviral treatment guidelines 2004. pretoria: doh, 2004. http://www.doh.gov.za/docs/misc./2004 (accessed 3 november 2007). 5. department of health. national antiretroviral treatment guidelines 2004. pretoria: doh, 2004. http://www.doh.gov.za/docs/misc./2004 (accessed 3 november 2007). 6. department of health. national tb infection control guidelines. pretoria: doh, 2007. http://www.doh.gov.za/docs/policy/2007/ipc-policy.pdf (accessed 8 may 2008). 6. department of health. national tb infection control guidelines. pretoria: doh, 2007. http://www.doh.gov.za/docs/policy/2007/ipc-policy.pdf (accessed 8 may 2008). 7. howard aa, el-sadr wm. integration of tuberculosis and hiv services in sub-saharan africa: lessons learned. clin infect dis 2010;50:s238-s244. [http://dx.doi.org/10.1086/651497] 7. howard aa, el-sadr wm. integration of tuberculosis and hiv services in sub-saharan africa: lessons learned. clin infect dis 2010;50:s238-s244. [http://dx.doi.org/10.1086/651497] 8. may m, boulle a, phiri s, et al. prognosis of patients with hiv-1 infection starting antiretroviral therapy in sub-saharan africa: a collaborative analysis of scale-up programmes. lancet 2010;376(9739):449-457. [http://dx.doi.org/10.1016/s0140-6736(10)60666-6] 8. may m, boulle a, phiri s, et al. prognosis of patients with hiv-1 infection starting antiretroviral therapy in sub-saharan africa: a collaborative analysis of scale-up programmes. lancet 2010;376(9739):449-457. [http://dx.doi.org/10.1016/s0140-6736(10)60666-6] 9. world health organization. a guide to monitoring and evaluation for collaborative tb/hiv activities. geneva: who, 2009. http://whqlibdoc.who.int/publications/2009 (accessed 6 march 2010). 9. world health organization. a guide to monitoring and evaluation for collaborative tb/hiv activities. geneva: who, 2009. http://whqlibdoc.who.int/publications/2009 (accessed 6 march 2010). 10. boehme cc, nicol mp, nabeta p, et al. feasibility, diagnostic accuracy, and effectiveness of decentralised use of the xpert mtb/rif test for diagnosis of tuberculosis and multidrug resistance : a multicentre implementation study. lancet 2011;6736(11):1-11. 10. boehme cc, nicol mp, nabeta p, et al. feasibility, diagnostic accuracy, and effectiveness of decentralised use of the xpert mtb/rif test for diagnosis of tuberculosis and multidrug resistance : a multicentre implementation study. lancet 2011;6736(11):1-11. 11. lawn sd, kerkhoff ad, vogt m, et al. diagnostic accuracy of a low-cost, urine antigen, point-of-care screening assay for hiv-associated pulmonary tuberculosis before antiretroviral therapy: a descriptive study. lancet infect dis 2012;12(3):201-209. [http://dx.doi.org/10.1016/s1473-3099(11)70251] 11. lawn sd, kerkhoff ad, vogt m, et al. diagnostic accuracy of a low-cost, urine antigen, point-of-care screening assay for hiv-associated pulmonary tuberculosis before antiretroviral therapy: a descriptive study. lancet infect dis 2012;12(3):201-209. [http://dx.doi.org/10.1016/s1473-3099(11)70251] 12. harries ad, zachariah r, lawn sd. providing hiv care for co-infected tuberculosis patients : a perspective from sub-saharan africa. int j tuberc lung dis 2009;13(1):6-16. 12. harries ad, zachariah r, lawn sd. providing hiv care for co-infected tuberculosis patients : a perspective from sub-saharan africa. int j tuberc lung dis 2009;13(1):6-16. 13. dong k, thabethe z, hurtado r, et al. challenges to the success of hiv and tuberculosis care and treatment in the public health sector in south africa. j infect dis 2007;196:s491-s496. [http://dx.doi.org/10.1086/521111] 13. dong k, thabethe z, hurtado r, et al. challenges to the success of hiv and tuberculosis care and treatment in the public health sector in south africa. j infect dis 2007;196:s491-s496. [http://dx.doi.org/10.1086/521111] 14. perumal r, padayatchi n, stiefvater e. the whole is greater than the sum of the parts: recognising missed opportunities for an optimal response to the rapidly maturing tb-hiv co-epidemic in south africa. bmc public health 2009;9:243-250. [http://dx.doi.org/10.1186/1471-2458-9-243] 14. perumal r, padayatchi n, stiefvater e. the whole is greater than the sum of the parts: recognising missed opportunities for an optimal response to the rapidly maturing tb-hiv co-epidemic in south africa. bmc public health 2009;9:243-250. [http://dx.doi.org/10.1186/1471-2458-9-243] 15. gunneberg c, reid a, williams bg, et al. global monitoring of collaborative tb-hiv activities. int j tuberc lung dis 2008;12:2-7. 15. gunneberg c, reid a, williams bg, et al. global monitoring of collaborative tb-hiv activities. int j tuberc lung dis 2008;12:2-7. 16. coetzee d, hilderbrand k, goemaere e, et al. integrating tuberculosis and hiv care in the primary care setting in south africa. trop med int health 2004;9(6):a11-a15. [http://dx.doi.org/10.1111%2fj.1365-3156.2004.01259.x] 16. coetzee d, hilderbrand k, goemaere e, et al. integrating tuberculosis and hiv care in the primary care setting in south africa. trop med int health 2004;9(6):a11-a15. [http://dx.doi.org/10.1111%2fj.1365-3156.2004.01259.x] 17. scott v, chopra m, azevedo v, et al. scaling up integration: development and results of a participatory assessment of hiv/tb services. health res policy syst 2010;8:23-34. [http://dx.doi.org/10.1186%2f1478-4505-8-23] 17. scott v, chopra m, azevedo v, et al. scaling up integration: development and results of a participatory assessment of hiv/tb services. health res policy syst 2010;8:23-34. [http://dx.doi.org/10.1186%2f1478-4505-8-23] 18. loveday m, zweigenthal v. tb and hiv integration: obstacles and possible solutions to implementation in south africa. trop med int health 2011;16(4):431-438. [http://dx.doi.org/10.1111%2fj.1365-3156.2010.02721.x] 18. loveday m, zweigenthal v. tb and hiv integration: obstacles and possible solutions to implementation in south africa. trop med int health 2011;16(4):431-438. [http://dx.doi.org/10.1111%2fj.1365-3156.2010.02721.x] 19. harries ad, zachariah r, corbett el, et al. the hiv-associated tuberculosis epidemic – when will we act? lancet 2010;29(375):1906-1919. [http://dx.doi.org/10.1016%2fs0140-6736%2810%2960409-6] 19. harries ad, zachariah r, corbett el, et al. the hiv-associated tuberculosis epidemic – when will we act? lancet 2010;29(375):1906-1919. [http://dx.doi.org/10.1016%2fs0140-6736%2810%2960409-6]   make up june issue nicky june 2005 the southern african journal of hiv medicine42 p a e d i a t r i c c a r e botswana-baylor children’s clinical centre of excellence the role of a paediatric centre of excellence in assuring the prioritisation and quality of paediatric care within a developing national hiv care programme elizabeth d lowenthal, md1 gabriel m anabwani, mb chb, mmed, msc1 haruna b jibril, mb bs, pmcpaed, msc2 beth barr, mph1 opelo m rankopo, rn, bn, mn1 mark w kline, md1 1baylor college of medicine, baylor international pediatric aids initiative, botswana-baylor children’s clinical centre of excellence 2princess marina hospital, botswana the hiv/aids epidemic is having a devastating global impact on children and families. in 2004, an estimated 640 000 children became newly infected with hiv and about 2.2 million children were living with the virus. more than half a million children worldwide died of hiv-related illnesses in 2004. ninety-five per cent of hiv/aids-associated deaths occur in the developing world and about 70% of infected individuals reside in subsaharan africa.1 worldwide, hiv is threatening child survival and reversing development gains of past decades. globally, hiv/aids now accounts for about 4% of all deaths among children under 5 years of age; in southern africa, hiv/aids may account for 30 50% of all such deaths. where paediatric hivrelated care and treatment services are not available, it is estimated that more than half of infected children die before reaching their second birthday.2 when comprehensive care, including highly active antiretroviral therapy (haart), is available to children, these grim statistics can be reversed. survival rates are significantly better among children and adolescents treated with haart.3-5 growth is normalised6,7 and children thrive in normal school environments.8 in a resource-poor setting it has been demonstrated that haart can be administered safely and effectively.6,9 despite the great potential for children to thrive within childfocused treatment programmes in both highand low-resource settings, ‘children are for the most part ignored’10 within international hiv resource planning initiatives. when their care is included in programme planning, children are most commonly ‘treated as an “add on” to the adult response’.10 children represent a disproportionate share of those individuals infected with hiv who do not have access to treatment.11,12 contributing to the limited availability of paediatric care is the lack of health professionals with expertise or experience in treating children infected with hiv, including the provision of therapy, dosing, administration and monitoring. worldwide, health care providers at all levels have limited skills to identify children living with hiv; to provide them with antiretroviral (arv) treatment and other care services; to monitor their progress; and to provide psychosocial support. most health care professionals in countries hard-hit by hiv lack formal training in paediatric hiv/aids treatment. formal research training and infrastructure for the performance of paediatric-focused hiv/aids clinical research are also lacking. the creation of paediatric clinical centres of excellence facilitates the prioritisation of paediatric hiv care services within and around countries hard-hit by the hiv epidemic and assures that highquality paediatric-focused health care education is available. in botswana, nearly 40% of all pregnant women are infected with hiv.13 standard surveillance does not include children, so exact paediatric numbers are unknown. it is thought, however, that thousands of batswana children under the age of 15 are hiv-infected. because of a strong nationwide commitment, led by the president of the republic of botswana, his excellency mr festus mogae, botswana became the first country in subsaharan africa to establish a national arv treatment programme. in 2000, the government of botswana entered the african comprehensive hiv/aids partnership (achap),14 in order to establish a sustainable response to the country’s epidemic. in 2001, the government of botswana made an unprecedented commitment to provide free haart to all qualifying citizens through its national arv programme. for paediatric patients, arv medications became available through the public sector in botswana in may 2002. in the year before that, children in need of arv therapy were able to obtain necessary medications through a clinical trial managed jointly by staff of the princess marina hospital and baylor college of the botswana experience make up june issue nicky 5/30/05 2:20 pm page 42 the southern african journal of hiv medicine june 2005 4 3 medicine. theoretical and practical training was also performed jointly to prepare available staff to lead the nation in the provision of excellent care and treatment to hiv-infected children. an exchange programme was established to allow botswana-based faculty to obtain further practical training in research and patient care in the usa and to allow us-based health professionals to work in the clinic in botswana. in 2001, an adult infectious disease care clinic was established as a pilot at princess marina hospital. this clinic formed the backbone of the national antiretroviral programme for adults beginning in january 2002. space for the care of paediatric patients was available at the site for half a day each week, beginning in june 2002. to better address the unique needs of the paediatric population, a centre dedicated to providing comprehensive, state-of-the-art care and treatment to hivinfected children was established on the princess marina hospital campus. the botswana-baylor children’s clinical centre of excellence (coe) was opened and officially dedicated by his excellency mr festus mogae on 20 june 2003. this facility, the first of its kind on the african continent, provides state-of-the-art care and treatment to hiv-infected children and families from gaborone and across botswana. the centre is a product of a partnership between the baylor international pediatric aids initiative at baylor college of medicine (houston, texas, usa), the princess marina hospital in gaborone and the government of botswana. the centre was made possible by a landmark $6 million grant from the bristol-myers squibb secure the future programme. the centre is supported by additional funding to baylor from the fogarty international center of the us national institutes of health and the us centers for disease control and prevention global aids program. the coe is based on a model first piloted in constanta, romania, another resource-poor setting with a significant paediatric hiv epidemic.6,9 staffed collaboratively by us and botswana health professionals, the botswana-baylor children’s clinical centre of excellence (coe) provides services that are comprehensive in scope, encompassing the primary and specialty medical care and social service needs of hiv-infected infants, children and families. the centre includes ten outpatient clinic rooms, a pharmacy, a laboratory, a classroom, offices and a conference room. health professional education and clinical research are integral to the centre’s mission. by prioritising health professional educational activities, the centre catalyses the decentralisation and expansion of paediatric care throughout botswana and the region. the heart of all initiatives organised through the coe is the provision of outstanding care and treatment to hiv-infected children. paediatric care in gaborone had been initiated at the princess marina hospital about a year before and was transferred to the coe at the time of its opening in june 2003. even as the national programme services expanded to include children throughout the country, the coe remained the focal point of paediatric care nationwide currently, the majority of patients receiving care through the coe are enrolled in the botswana national antiretroviral programme. at the coe, the national paediatric antiretroviral programme is jointly administered by the paediatric staff of the princess marina hospital and the coe. children enrolled in the programme at the coe receive comprehensive care including primary paediatric care, antiretroviral therapy and monitoring, psychosocial support and nutritional surveillance from a dedicated and multidisciplinary staff. a family care model clinic has also been established to provide care to caretakers along with their children. at the coe, paediatricians are available to care for children and adult patients receive treatment from a physician specialist. in nonspecialist centres throughout the country, it is anticipated that families will similarly receive their care together using the family care model. as the availability of comprehensive care for hiv-infected children extends to the rest of the nation, most children and families will be treated by more generally trained medical officers. the botswana baylor children’s clinical centre of excellence will remain as a referral centre for the most challenging paediatric cases as well as for ongoing training of health care providers in optimal treatment strategies for children. as is true for most of sub-saharan africa, botswana has a very limited number of paediatric specialists. the majority of all specialists work at the two national referral hospitals in francistown and gaborone. general practitioners in the national arv programme are frequently hesitant to screen and treat children for hiv. in order to address this issue, the coebased staff from both the baylor programme and princess marina hospital conduct week-long training courses at the ‘arv roll-out sites’ around botswana. these trainings focus on issues related to paediatric hiv care and antiretroviral treatment and are both didactic and practical. these educational programmes are funded by the us centers for disease control and prevention (cdc) botswana-usa (botusa) project. the coe also collaborates with the elizabeth glazer pediatric aids foundation (egpaf) to provide training for a number of health professionals from countries throughout the region. the training serves to strengthen the capacity to provide arvs to children throughout the country and the region. following the formal training, practitioners from the remote sites frequently consult with the coe-based specialists for guidance with their difficult paediatric cases. trainees attend clinic and didactic sessions at the coe, or at their home sites with coe-based visiting preceptors, in order to increase their skills in treating paediatric hiv. african countries benefiting from these training activities have included south africa, swaziland, zambia, nigeria and tanzania. the topics patient care education make up june issue nicky 5/30/05 2:20 pm page 43 the southern african journal of hiv medicine june 2005 4 5 covered in the paediatric training programmes include those shown in fig. 1. training is inclusive of a number of health professional groups including students, nurses, doctors and pharmacists. a curriculum on paediatric hiv/aids for health professionals has also been developed to allow for the wider dissemination of practical knowledge.15 this teaching tool is available in several languages and has been disseminated to health care workers in more than 50 countries. the long-term provision of care and treatment to hiv-infected children worldwide will be limited by the relative lack of data regarding the safest and most effective employable options for children.16 in order to address the knowledge gap regarding the unique needs of children infected with hiv, the coe provides infrastructure, expertise and staffing to conduct high-quality, high-impact, highly ethical paediatric clinical research. currently enrolment is underway for the botswana/baylor antiretroviral assessment trial 2 (bana02), an analysis of cd4positive t-lymphocyte count-based structured treatment interruptions in children. with targeted enrollment of 600 children, bana 2 will be the largest paediatric arv clinical trial to have been performed on the african continent. (bana means children in setswana. bana 2 is the second large study dedicated to expanding the knowledge related to arv therapy options for children in botswana.) research organised through the coe also addresses barriers to paediatric arv adherence, disclosure of hiv status to children and adolescents, and the comprehensive needs of high-risk paediatric populations. in order to facilitate the extension of high-quality paediatric care to the broader community, the coe has initiated a number of outreach programmes. these programmes share a common focus on improving the access to high-quality medical care for children, including orphans and vulnerable children (ovcs). the methods employed through outreach programmes mirror others organised through the coe, stressing the provision of high-quality medical care, psychosocial support and training. the coe staff, supported by a separate grant from secure the future, also provide on-site support to health care professionals in bobonong, botswana. with over 70% of women of childbearing age testing positive for hiv in the bobirwa subdistrict, the people of this area suffer from one of the highest prevalence rates of hiv infection of any community in the world. before the coe’s involvement there, no patients were receiving arv treatment through this site. because of the outreach work at this site, patients are being started on therapy more rapidly and the prioritisation of paediatric care is consistently stressed. closer to the coe, another outreach programme is working in collaboration with community-based organisations (cbos) to perform health assessments of more than a thousand ovcs living in three densely populated villages within 50 km of gaborone. the coe is taking the lead in botswana in the area of home-based testing. children connected to orphan programmes in the community are visited in their homes, and all family members are counselled and offered age-appropriate hiv testing. adults and children over 18 months of age can receive immediate at-home rapid-testing. children who are found to be hiv-infected or to have other special needs are then appropriately referred, many directly to the coe for arv treatment. as of 1 april 2005, 3 937 batswana children had been screened for hiv infection at the botswana baylor children’s clinical centre of excellence. of these, 1 353 children (34.4%) were hivpositive, and 1 159 paediatric patients have begun haart at the coe. only 61 patients are known to have died since testing positive for hiv at the coe. most of these deaths occurred within a short time of the children’s coming to the coe, in patients who presented with advanced disease. twenty of the children died before they could be started on arv medications. the first 214 children to complete 12 months of follow-up within the coe-based national programme have been systematically evaluated with respect to medication adherence, clinical condition, cd4% and viral load values. at the time of entry into the programme, 121 (56.5%) were in cdc category c3, indicating a severe clinical state. owing to the exceptional commitment of the patients’ families, complemented by intensive psychosocial support, overall medication adherence (based on pill count and liquid medication measurements) was 95% during the initial year of follow-up. of the patients 85% achieved complete virological suppression (viral load < 400). mean log viral load values at entry, 3 months, 6 months, and 12 months of follow-up are demonstrated in fig. 2. fig. 3 • epidemiology & pathophysiology of hiv infection • prevention of mother to child transmission of hiv • diagnosis of hiv in infants and children • clinical manifestations in hiv-infected children • opportunistic infections in children • paediatric antiretroviral treatment and monitoring • development of resistance to antiretroviral medications • primary care of the hiv-infected child • nutrition management of the hiv-infected child • communicating with children: disclosure and counselling • ethical, legal, and human rights issues in paediatric hiv fig. 1. paediatric hiv training modules. research outreach outcomes make up june issue nicky 5/30/05 2:20 pm page 45 june 2005 the southern african journal of hiv medicine46 illustrates the patients’ mean cd4% during the same time period. an excellent clinical, immunological and virological response to arv therapy was achieved. the creation of dedicated paediatric centres of excellence is transforming the face of paediatric hiv/aids, providing treatment for the first time to large numbers of infected children, building essential capacity and infrastructure, and promoting the acquisition of knowledge that will enhance hiv/aids care and treatment globally. we credit the early success of the botswana-baylor children’s clinical centre of excellence to a variety of factors: a commitment to comprehensive medical, psychosocial, and community support; well-trained multidisciplinary staff; dedicated collaborative partners; highly motivated children and caregivers; and attention to family-centred care. the botswana government’s commitment to sustainability of the national arv programme and to the treatment of children has ensured that our efforts to prioritise paediatric care have received consistent support. the baylor college of medicine’s early partnership with the princess marina hospital has allowed for ongoing sharing of resources, essential to the daily function of the coe. the necessity for treatments that focus on children has been recognised and honoured by all coe partners, leading to consistent prioritisation and a high quality of care for a growing number of botswana’s children. currently, additional paediatric clinical centres of excellence for the care and treatment of hiv-infected children are being built based on the success of botswana’s programme. centres in swaziland and lesotho, also funded by the bristol myers squibb secure the future programme, are scheduled to open in december of 2005. references 1. unaids. 2004 report on the global aids epidemic. http://www. unaids.org/wad2004/report.html (accessed 2 april 2004). 2. newell ml, coovadia h, cortina-borjam, et al. mortality of infected and uninfected infants born to hiv-infected mothers in africa: a pooled analysis. lancet 2004; 364: 1236-1243. 3. mcconnell ms, byers rh, frederick t, et al. trends in antiretroviral use and survival rates for a large cohort of hiv-infected children and adolescents in the united states, 1989-2001. jaids 2005; 389(4): 488494. 4. gortmaker sl, hughes m, cervia j, et al. effect of combination therapy including protease inhibitors on mortality among children and adolescents infected with hiv-1. n engl j med 2001; 345: 1522-1528. 5. de martino m, tovo p, balducci p, et al. reduction in mortality with availability of antiretroviral therapy for children with perinatal hiv-1 infection. jama 2000; 284: 190-197. 6. kline mw, matusa rf, copaciu l, et al. comprehensive pediatric human immunodeficiency virus care and treatment in constanta, romania. implementation of a program of highly active antiretroviral therapy in a resource-poor setting. pediatr infect dis j 2004; 23: 695-700. 7. verweel g, van rossum am, hartwig ng, wolfs tf, scherpbier hj, groot r. treatment with highly active antiretroviral therapy in human immunodeficiency virus type 1-infected children is associated with a sustained effect on growth. pediatrics 2002; 109: e25. 8. wilfert cm, kline mw, futterman d, et al. education of children with human immunodeficiency virus infection. pediatrics 2000; 105: 13581360. 9. kline mw. no greater gift than hope. seminars in pediatric infectious diseases 2003; 14: 309-313. 10. unicef. reaching out to children in the who ‘3 by 5’ initiative: paediatric hiv care and treatment summary report. 11. unicef/who technical consultation. improving access to appropriate paediatric arv formulations. 3 4 november 2004. http://www.who. int/3by5/en/finalreport.pdf (accessed 2 april 2005). 12. united nations children’s fund. the state of the world’s children 2005. unicef, 2004. 13. botswana national aids coordinating agency. 2003 second generation hiv/aids surveillance technical report. gaborone: botswana national aids coordinating agency, 2003. 14. ramiah i, reich mr. public-private partnerships and antiretroviral drugs for hiv/aids: lessons from botswana. health affairs 2005; 24: 545-551. 15. baylor international pediatric aids initiative. hiv curriculum for the health professional. houston: baylor college of medicine, 2003. 16. world health organization. hiv medicines. 3 by 5 strategy: improving access to paediatric hiv medicines. who drug information 2004; 18: 288fig. 2. mean log viral load during first year of therapy. fig. 3. mean cd4% during first year of therapy. discussion the work at the botswana baylor children’s centre of excellence would never have been realised without the support of the botswana ministry of health, princess marina hospital, baylor college of medicine and the bristol myers squibb secure the future programme. we also wish to acknowledge the contributions of cdc-botusa, the elizabeth glaser pediatric aids foundation, the fogarty international center of the us national institutes of health, the kgalagadi beverages trust and debswana. the ongoing dedicated work of the staff of the coe and princess marina hospital, our patients, and their families, ensure the continued success of these programmes. make up june issue nicky 5/30/05 2:21 pm page 46 abstract introduction methods results discussion limitations conclusions acknowledgements references about the author(s) jacques d. du toit hiv outpatient department, zithulele hospital, mqanduli, south africamrc/wits rural public health and health transitions research unit, school of public health, university of the witwatersrand, johannesburg, south africa koot kotze hiv outpatient department, zithulele hospital, mqanduli, south africanuffield department of primary healthcare sciences, university of oxford, oxford, united kingdom helene-mari van der westhuizen hiv outpatient department, zithulele hospital, mqanduli, south africanuffield department of primary healthcare sciences, university of oxford, oxford, united kingdom taryn l. gaunt hiv outpatient department, zithulele hospital, mqanduli, south africa citation du toit jd, kotze k, van der westhuizen h-m, gaunt tl. nevirapine-induced stevens-johnson syndrome in children living with hiv in south africa. s afr j hiv med. 2021;22(1), a1182. https://doi.org/10.4102/sajhivmed.v22i1.1182 original research nevirapine-induced stevens-johnson syndrome in children living with hiv in south africa jacques d. du toit, koot kotze, helene-mari van der westhuizen, taryn l. gaunt received: 22 oct. 2020; accepted: 09 dec. 2020; published: 23 feb. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: although adverse drug reactions resulting from the use of nevirapine (nvp) are well described in adults (estimated frequency of 6% – 10%), it has previously been considered less common in children (0.3% – 1.4%). stock-outs of antiretroviral agents occur frequently in south africa and result in interruptions in therapy and drug substitutions. objectives: to report on a case series of paediatric patients who suffered cutaneous drug reactions to nvp at rates not previously described in children. method: we describe a retrospective observational case series of six children living with hiv who developed stevens-johnson syndrome (sjs) following exposure to nvp because of a prolonged stock-out of efavirenz 200 mg tablets in south africa. results: of the 392 paediatric patients receiving antiretroviral therapy at the institution, 172 were affected by the efavirenz stock-out. of these, 85 children were changed to nvp of which six developed nvp-induced sjs (7.1% incidence rate). the median time between initiating nvp and developing symptoms was 27 days (range 12–35 days). all patients responded well to nvp cessation and symptomatic treatment. one patient was referred for specialist care. two patients were successfully rechallenged with efavirenz after developing sjs and three continued lopinavir/ritonavir. conclusions: this is the second largest case series of nvp-induced sjs in children to date and raises the possibility that the incidence of sjs in children may be higher than previously described. further research is required to explore the risk factors associated with nvp-induced sjs in children. this case series highlights the negative impact of drug stock-outs on patient health outcomes. keywords: nevirapine; stevens-johnson syndrome; toxic epidermal necrolysis; paediatric; hiv; stock-outs. introduction stevens-johnson syndrome (sjs) and its severe form, toxic epidermal necrolysis (ten), are mucocutaneous reactions associated with significant morbidity and mortality.1 stevens-johnson syndrome/toxic epidermal necrolysis may be caused by a wide range of medications and infections, and in many cases, it may be difficult to definitively establish the causative agent.2 stevens-johnson syndrome and ten are thought to be delayed hypersensitivity reactions resulting from interactions between the drug and the adaptive immune system via specific human leukocyte antigen (hla) subtypes and t-cell receptors.3 these drug metabolites likely result in immune mediated apoptosis of keratinocytes and eventual epidermal detachment.4 the time between exposure to a causative agent and onset of symptoms is estimated to be between 4 and 28 days.2 it has also been hypothesised that human immunodeficiency virus (hiv) infection itself may increase the risk of developing sjs/ten.1,5 the non-nucleoside reverse transcriptase inhibitor (nnrti) nevirapine (nvp) is a well-established cause of sjs/ten in adults but is thought to be uncommon in children.3 we accessed nine reports of sjs/ten in children exposed to nvp describing 29 patients in total.6,7,8,9,10,11,12,13,14 although nvp hypersensitivity has been associated with higher cd4 cell counts in adults (> 250 cells/µl in females and > 400 cells/µl in males), the above case reports show sjs and ten occurring at any stage of immune suppression in paediatric populations.8 it has been suggested that the paucity of cases reporting on the association between nvp in children and sjs/ten may be a result of prescribing behaviour rather than an actual decreased risk compared with adults.2 however, there is widespread use of nvp in infants as part of prevention of mother-to-child transmission (pmtct) programmes and we could only find reference to two cases of children below 1 year developing sjs following exposure to nvp.8 the reasons for this remain unclear, although greater immune tolerance in neonates may play a role. it is estimated that 6% – 10% of adults exposed to nvp will develop some form of drug-induced hypersensitivity, which may be grouped into one of five phenotypes: nvp-induced rash, hypersensitivity syndrome, sjs, toxic epidermal necrolysis, and drug-induced liver injury.15 the estimated risk for sjs/ten in drug safety profile studies in adult and paediatric patients with hiv on nvp-containing regimens was previously thought to be approximately 0.3%.16 this contrasts with the estimated 1.4% incidence encountered by the largest case series of nvp associated sjs/ten in pediatric patients to date.8 the national consolidated guidelines for pmtct and the management of hiv in children, adolescents and adults, published by the department of health of south africa in 2015 lists efavirenz (efv) as the preferred nnrti in children (> 4 weeks old) and adults, but allows for the use of nvp in first line regimens in neonates and in adolescents where efv is contraindicated. it does not specify cd4 cell counts or percentages at which the use of nvp in antiretroviral (arv) regimens of children is contraindicated.17 the updated 2019 guideline recommends switching children to dolutegravir-based regimens in south africa and does not provide recommendations on the use of nvp.18 a nvp-containing regimen is still recommended when initiating art during the neonatal period and further information about potential risks and benefits for its use in children are important, as drug stock-outs lead to clinicians making individualised treatment decisions based on available arvs. stock-outs of antiretroviral treatment, defined by the world health organization as the complete unavailability of a specific drug at a delivery or storage point for at least 1 day, are common in south africa’s antiretroviral therapy (art) programme and may lead to worse health outcomes and virological failure.19,20 stock-outs disrupt hiv care programmes and pose challenging treatment decisions when the preferred drug is not available. after an adverse event, it is also difficult to decide whether a drug in the same class can be re-introduced; although it has been shown that it is safe to restart efv in patients who had sjs because of nvp.21 in this article we describe sjs that developed in children after switching to nvp during an efv stockout. methods background during february to may 2018 there was a prolonged stock-out of 200 mg efv tablets at a rural hospital in the eastern cape, south africa. a strategy was developed by the acting clinical manager and head pharmacist in conjunction with a paediatric infectious disease specialist to limit the effects on patient care. children were switched to the best possible alternative treatment regimens, taking drug stock levels and individual case details into account. a viral load cut-off was used to split the large cohort of children into those who were fully or partially suppressed and those who had a higher level of viraemia. a viral load of 400 copies/ml was used as this was the lowest level of viral suppression that the laboratory could accurately measure in the period preceding the stock-out. there were also limited supplies of efv 50 mg tablets and lopinavir/ritonavir (lpv/r), so it was not possible to transition the entire cohort to these alternatives. children with a viral load deemed acceptable given the circumstances (< 400 copies/ml in the preceding 6 months) were switched to either nvp or dispensed the required efv dose using 50 mg tablets. as a result of the the concern of rapidly depleting the efv 50 mg tablet supply and further disrupting treatment in younger children, older children were preferentially changed to nvp. if children were not adequately virally suppressed (> 400 copies/ml in the preceding 6 months), they were changed to second line therapy and thus received lpv/r. children who were on 400 mg efv were switched to 400 mg immediate release (ir) nvp nocte and those on 300 mg efv were switched to ir nvp 200 mg in the morning and 100 mg in the evening based on local institutional practice. study design this study is a retrospective observational case series describing the clinical course of a cohort of children living with hiv who developed an adverse drug reaction after substitution of their antiretroviral drugs. the researchers had no prior intention to evaluate the effects of nvp in this population preceding the substitution and the decision to write up the cases was made retrospectively. clinical and drug prescription information was extracted from routinely collected hiv service programmatic data and paediatric ward admission notes. contextual information regarding the hiv programme and treatment history was obtained through the idart (intelligent dispensing of art) electronic record keeping system. there are no universally accepted diagnostic criteria for sjs/ten. a minimum of two of the following clinical features with the history of new exposure to nvp were used as inclusion criteria for this case series: prodrome of acute-onset febrile illness and malaise; painful rash that progresses rapidly; erythematous macules, targetoid lesions, vesicles, or bullae; positive nikolsky sign; and mucosal involvement.22 total body surface area (tbsa) percentage involvement was documented using the lund and browder chart to distinguish between sjs (< 10%), sjs/ten overlap (10% – 30%), and ten (> 30%)23. ethical consideration ethical approval was granted from the human research committee at walter sisulu university’s faculty of health sciences postgraduate education, training, research and ethics unit (ref: 022/2019). permission for the study was attained from the relevant institutions and the eastern cape health research committee (ref: ec_201907_013). written consent was obtained from the primary caregivers of children included in this case series. results the efv 200 mg tablet stock-out affected 172 children. this represented 44% of the total paediatric population (age < 15 years) collecting arv treatment in the hospital catchment area at that time (n = 392). eighty-five patients were switched from efv to nvp, with the remaining patients either receiving efv in 50 mg tablets (34 patients), lpv/r (45 patients), sourcing efv 200 mg tablets elsewhere (3 patients), or were lost to follow-up (5 patients). six cases of sjs/ten (incidence rate = 7.1%, 95% ci: 1.6% – 12.5%) were reported. five of the six patient’s caregivers consented to link clinical records with this case series, and this review will discuss details of those children. based on these notes, no other new medication had been prescribed surrounding the introduction of nvp and sjs/ten was the most likely clinical diagnosis. the mean age of the participants was 10.4 years (sd: 2.9) and the mean weight was 26.8 kg (sd: 4.9) (table 1). five of the children were receiving abacavir (abc)/lamivudine (3tc)/efv before the drug switch. one child had confirmed prior exposure to nvp through the pmtct programme. all children were reportedly healthy preceding their exposure to nvp, with no concurrent treatment initiation recorded. table 1: case information of patients with stevens-johnson syndrome/toxic epidermal necrolysis. the median time between initiating nvp and developing symptoms was 27 days (range 12–35 days). all patients responded well to nvp cessation, symptomatic treatment, and eye care if applicable. one patient was referred for tertiary care. two patients were successfully rechallenged with efv after developing sjs/ten and the other three continued lpv/r. discussion prior to this case series, few cases of sjs/ten in children after exposure to nvp have been described in the literature, with some experts believing that nvp associated sjs/ten is uncommon in children living with hiv.6,7,8,9,10,11,12,13,14 our case series showed an incidence rate of 7.1% of sjs/ten after exposure to nvp because of a stock-out of efv 200 mg tablets. this was higher than previously estimated (0.3% and 1.4%), however, given the small number of cases, the 95% confidence interval is wide (1.6% – 12.5%), and the true incidence in a larger population may be lower than what we found and closer to these estimates. our result, and the true estimate, may however be higher than previously estimated and instead be congruent with the estimated incidence of nvp hypersensitivity in adults.8,16 we postulate that the reasons for the higher than expected incidence rate may be related to a genetic predisposition to developing nvp-induced sjs/ten in this cohort of patients. increasing bodies of literature are describing strong associations between hla alleles and severe cutaneous adverse reactions with certain drugs.24 although there are limited studies on sjs/ten in sub-saharan africa, there is some evidence linking specific hla subtypes (such as hla-cw*04) to nvp-induced sjs in populations from these regions.15,25 adverse events relating to nvp have also been shown to strongly associate with single nucleotide polymorphisms in genes known to influence the rate of plasma clearance of nvp.25 we were unable to perform an analysis to investigate the influence of cd4 cell count on the incidence of sjs in our dataset, and further research could help clarify whether this is a contributing factor in children, as it is a known risk factor for adverse reactions to nvp in adults.26 the nvp tablets used were an ir formulation as the 400 mg extended release formulation was not available. whilst some participants received this formulation as two divided doses, others received this as a single dose. based on this and sjs being an immunological, dose independent reaction,27 we are uncertain of the contribution of this to a higher than expected incidence of sjs in this cohort. the demographic characteristics of the patients in this case series are similar to those described in the literature. the time to onset of symptoms was similar to that seen in previously described cases of sjs/ten (4–28 days), with a median of 27 days (range 12–35 days) amongst the patients treated in this series. the most severe case of ten in our series had the longest interval between switching to nvp and presenting with symptoms (35 days). this could be because of delays in accessing healthcare in a rural setting, rather than an actual extended time before onset of symptoms. this case series also demonstrates the difficulty of safely managing drug stock-outs, especially in rural healthcare settings. given the difficulty of switching a large group of patients to a single alternative and the potential for triggering further stock-outs in other medications in a ‘knock-on’ effect, individualised substitutions had to be made in consultation with paediatric hiv experts. unfortunately, and possibly because of a combination of the given contributing factors, the incidence of nvp associated sjs/ten in our setting was far greater than previously reported in the literature. knowledge of this case series may influence risk-benefit assessments in future similar scenarios and assist clinicians in selecting safer alternative regimens for children living with hiv. although we as authors advise against the use of nvp in this type of patient, stock-outs are an unfortunate reality and nvp may be the only available alternative. if a clinician has exhausted all other options as outlined in their national guidelines (such as the use of dolutegravir or lpv/r) and a drug holiday is not appropriate, we advise the following approach: the patient and their responsible guardian be counselled regarding the potential risks and early warning signs of sjs. increase monitoring frequency (approximately a 2and 4-week follow-up). avoid addition of other new medication. limitations information for this case series was collected retrospectively and not all desired data were available. furthermore, most of the patients were managed by different clinicians, resulting in differences in diagnostic criteria used and drug histories. the authors made every effort to ensure that the data collected was accurate despite these difficulties. as a result of the mobility of patients using health services in the region of the study, it is also possible that there were more cases of sjs/ten or other adverse reactions in the nvp-substitution cohort. these patients may have presented for healthcare elsewhere, although only one patient was lost to follow-up in the nvp-substitution cohort. conclusions the risk of nvp-induced sjs/ten in children living with hiv may be significantly higher than previously documented. medication shortages have a negative impact on hiv care, and strategies to prevent stock-outs should be a key part of health system strengthening. national directives should be made available to assist healthcare workers in safely caring for patients when shortages occur. acknowledgements we would like to thank dr jennifer minnaar for her assistance in planning the initial stages of the research and her support in starting the data collection. we are grateful for associate professor angela dramowski for her valuable feedback on this article. we would like to thank the zithulele arv team and catherine young for their assistance in data collection. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions j.d.d.t. completed data extraction, t.l.g. obtained informed consent from caregivers, j.d.d.t., t.l.g., k.k. and h.m.v.d.w. contributed equally to the conceptualisation and writing of this manuscript. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability the manuscript is a case series and thus there are no publically available datasets to refer to. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references levi n, bastuji-garin s, mockenhaupt m, et al. medications as risk factors of stevens-johnson syndrome and toxic epidermal necrolysis in children: a pooled analysis. pediatrics. 2009;123(2):e297–e304. https://doi.org/10.1542/peds.2008-1923 dodiuk-gad rp, chung w-h, valeyrie-allanore l, shear nh. stevens-johnson syndrome and toxic epidermal necrolysis: an update. am j clin dermatol. 2015;16(6):475–493. https://doi.org/10.1007/s40257-015-0158-0 ferrandiz-pulido c, garcia-patos v. a review of causes of stevens-johnson syndrome and toxic epidermal necrolysis in children. arch dis child. 2013;98(12):998–1003. https://doi.org/10.1136/archdischild-2013-303718 roujeau j-c, stern r. severe adverse cutaneous reactions to drugs. n engl j med. 1994;331(1):1272–1285. 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efavirenz challenge in patients with nevirapine induced stevens-johnson syndrome. s afr j infect dis. 2016;31(4):119–121. https://doi.org/10.1080/23120053.2016.1156874 high wa, roujeau j-c. stevens-johnson syndrome and toxic epidermal necrolysis: pathogenesis, clinical manifestations, and diagnosis. up-to-date [homepage on the internet]. waltham, ma: uptodate; 2018 [cited 2020 apr 20]. available from: https://www.uptodate.com french le. toxic epidermal necrolysis and stevens johnson syndrome: our current understanding. allergol int. 2006;55(1):9–16. https://doi.org/10.2332/allergolint.55.9 cheng c-y, su s-c, chen c-h, chen w-l, deng s-t, chung w-h. hla associations and clinical implications in t-cell mediated drug hypersensitivity reactions: an updated review. j immunol res. 2014;2014:565320. https://doi.org/10.1155/2014/565320 yuan j, guo s, hall d, et al. toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of african, asian, and european descent. aids. 2011;25(10):1271–1280. https://doi.org/10.1097/qad.0b013e32834779df kesselring am, wit fw, sabin ca, et al. risk factors for treatment-limiting toxicities in patients starting nevirapine-containing antiretroviral therapy. aids. 2009;23(13):1689–1699. https://doi.org/10.1097/qad.0b013e32832d3b54 mockenhaupt m, viboud c, dunant a, et al. stevens-johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. the euroscar-study. j invest dermatol. 2008;128(1):35–44. https://doi.org/10.1038/sj.jid.5701033 abstract case presentation discussion acknowledgements references about the author(s) kairoonisha mahomed private practice, johannesburg, south africa carole l. wallis department of molecular pathology, barc-sa and lancet laboratories, johannesburg, south africa liezl dunn aid for aids management (pty) ltd, cape town, south africa shavani maharaj aid for aids management (pty) ltd, cape town, south africa gary maartens department of medicine, faculty of health sciences, university of cape town, cape town, south africa graeme meintjes department of medicine, faculty of health sciences, university of cape town, cape town, south africa citation mahomed k, wallis cl, dunn l, maharaj s, maartens g, meintjies g. case report: emergence of dolutegravir resistance in a patient on second-line antiretroviral therapy. s afr j hiv med. 2020;21(1), a1062. https://doi.org/10.4102/sajhivmed.v21i1.1062 case report case report: emergence of dolutegravir resistance in a patient on second-line antiretroviral therapy kairoonisha mahomed, carole l. wallis, liezl dunn, shavani maharaj, gary maartens, graeme meintjes received: 19 dec. 2019; accepted: 02 mar. 2020; published: 02 july 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract introduction: the integrase strand transfer inhibitor dolutegravir (dtg) has a high genetic barrier to resistance. only rare cases of resistance to dtg have been reported when it is used as a component of antiretroviral therapy regimens in treatment-experienced patients unless there was prior use of a first-generation integrase inhibitor. patient presentation: a 38-year-old woman diagnosed with tuberculosis was switched to a second-line antiretroviral regimen of zidovudine, lamivudine and dolutegravir 50 mg 12-hourly together with rifampicin-based tb treatment. based on treatment history and a previous resistance test there was resistance to lamivudine but full susceptibility to zidovudine. the patient did not suppress her viral load on this regimen and later admitted to only taking dolutegravir 50 mg in the morning because of insomnia. management and outcome: a second resistance test was performed which showed intermediate level of resistance to dolutegravir. her regimen was changed to tenofovir, emtricitabine and ritonavir-boosted atazanavir with rifabutin replacing rifampicin for the remainder of her tb treatment. she achieved viral suppression on this regimen. conclusion: to our knowledge this is the first case report from south africa of emergent dolutegravir resistance in a treatment-experienced, integrase inhibitor-naïve patient. factors that may have contributed to resistance emergence in this patient were that there was only one fully active nucleoside reverse transcriptase inhibitor in the regimen and lower exposure to dolutegravir because of the reduced dosing frequency while on rifampicin. keywords: hiv drug resistance; antiretroviral therapy; regimens; dolutegravir; rifampicin; case presentation a 38-year-old woman started antiretroviral therapy (art) in 2007 with zidovudine (azt), lamivudine (3tc) and efavirenz. her baseline human immunodeficiency virus (hiv) viral load and cluster of differentiation 4 (cd4) cell count results were not available. in september 2009, she experienced virological failure (this hiv viral load result is not available), and a genotypic antiretroviral resistance test showed a thymidine analogue mutation (tam, k219ke [i.e. mixed population of mutant and wild type at that codon]), m184m/v and three non-nucleoside reverse transcriptase inhibitor (nnrti) mutations (a98g, e138a and k238t) (see table 1). table 1: cd4 count and hiv viral load results available. based on this genotype, her regimen was changed to tenofovir (tdf), emtricitabine (ftc) and ritonavir-boosted atazanavir. she then transitioned from hiv care in the private sector to the public sector where she was changed to abacavir (abc), 3tc and ritonavir-boosted lopinavir. when she returned to private sector care in may 2017, she reported severe diarrhoea, resulting in poor adherence to art. her medication was switched to abc, 3tc and ritonavir-boosted atazanavir and the diarrhoea settled. in june 2017, she was diagnosed with tuberculosis (tb) and was started on a rifampicin-based tb treatment. her hiv viral load at this time was 345 406 copies/ml. as she already had significant diarrhoea on standard dose ritonavir-boosted lopinavir, it was felt that double-dose ritonavir-boosted lopinavir during tb treatment would not be tolerated. given that azt was still fully susceptible at the time of first-line failure, it was thought that azt would still be susceptible and therefore providing one active nucleoside reverse transcriptase inhibitor (nrti) to accompany dolutegravir (dtg). the patient was therefore switched to azt, 3tc and dtg 50 mg 12-hourly. the patient informed her doctor in july 2017 that she was experiencing insomnia on this regimen. she was reassured and advised to continue until she had completed tb treatment. there were regular pharmacy claims for treatment from june 2017 until november 2017 when her viral load was 2800 copies/ml. a resistance test was performed in february 2018, and the following mutations were observed: three integrase mutations (t66ti, g118r and e138ek) resulting in high-level resistance to raltegravir and elvitegravir and intermediate resistance to dtg (based on the stanford score), m184v and two nnrti mutations (a98g and e138a). a sample was also collected for phenotypic testing at monogram and the results showed that there was a 21-fold reduction in dtg susceptibility. furthermore, all the other available integrase inhibitors had reduced susceptibility (3.92; 32and 24-fold reduction to bictegravir, elvitegravir and raltegravir, respectively). she then admitted to only taking dtg 50 mg in the morning because she had experienced insomnia with twice daily dosing, which resolved if she skipped the evening dose. based on the resistance test result, her art regimen was changed to tdf, ftc and ritonavir-boosted atazanavir in february 2018 with rifabutin replacing rifampicin for the remaining months of tb treatment. an hiv viral load performed 3 months after the change was 230 copies/ml, and subsequent viral loads have been below 20 copies/ml for about 12 months. discussion the integrase strand transfer inhibitor dtg has a high genetic barrier to resistance. in clinical trials evaluating dtg as a component of triple drug therapy in art-naïve patients, no emergence of resistance to dtg has been reported. only rare cases of emergence of resistance to dtg have been reported when it has been used as a component of art regimens in treatment-experienced patients, unless there has been prior use of the first-generation integrase inhibitors, raltegravir and elvitegravir.1 in the case reported here of a treatment-experienced patient, dtg resistance was detected after 8 months on a regimen of azt, 3tc and dtg. based on the patient’s treatment history and resistance test results, this patient’s virus (at the time of starting this regimen) had resistance to 3tc (through the m184v mutation, which also re-sensitises the virus to azt in the presence of tams), but was fully susceptible to azt. the stanford score for azt on the 2009 resistance test was 0 (the one tam that was present, k219e, results in potential low-level resistance to azt, but is counteracted by the re-sensitising effect of m184v) and between 2009 and 2017, the patient received only tdf/ftc and abc/3tc as nrtis. these nrti combinations typically do not select for tams, the mutations that may compromise azt. in addition, there were no tams found on the 2018 resistance test. based on the dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with hiv-1 infection in whom first-line therapy has failed (dawning) trial results, it would be predicted that her regimen of dtg with two nrtis, one of which (azt) was fully active, should be effective. the dawning trial evaluated dtg with nrtis in second-line art and demonstrated that when there was at least one fully active nrti accompanying dtg, then this regimen was superior to ritonavir-boosted lopinavir combined with nrtis: at week 48, 84% in the dtg arm achieved viral suppression compared with 70% in the lopinavir arm.2 whilst no protease inhibitor mutations were detected in patients in the ritonavir-boosted lopinavir arm, 2/283 patients in the per-protocol analysis and in the dtg arm developed integrase resistance mutations (11 patients in the dtg arm who met virologic withdrawal criteria had a resistance test performed). one patient developed h51hy, g118r, e138ek and r263k mutations and the other patient developed the g118r mutation. like these two cases in dawning, the patient reported here developed dtg resistance on second line despite there being a fully active nrti in the regimen. another factor that may have contributed to the development of dtg resistance in this patient was the drug interaction with rifampicin. rifampicin is a potent inducer of ugt1a1 and cyp3a4, the enzymes that metabolise dtg and thereby reduces concentrations of dtg (the trough dtg concentration is reduced by 85%).3 studies in healthy volunteers and patients with hiv and tb have shown that this reduction can be compensated by increasing the frequency of dtg dosing from 50 mg daily to 50 mg 12-hourly in patients on rifampicin, which results in trough concentrations similar to patients taking dtg 50 mg daily without rifampicin, and resulted in adequate virological responses in patients with hiv and tb in the inspiring trial.4,5 our patient decreased the dtg dose to 50 mg daily whilst on rifampicin because of insomnia, which would have resulted in considerably lower exposure to dtg and may have contributed to the emergence of resistance. a case has been reported in which dtg resistance emerged in a patient on dtg-containing first-line regimen who was taking rifampicin for treatment of a staphylococcal infection. the dtg was increased to 50 mg twice daily, but despite this, the patient had unexpectedly lower dtg concentrations.6 it is important to note that the need for this dose adjustment of dtg with rifampicin is currently being investigated. because dtg was shown to have antiviral efficacy at doses as low as 10 mg daily in phase 2 trials,7,8 it is possible that a dose increase is not required in patients on first-line dtg-based art and rifampicin. this is supported by a recent pharmacokinetic study in healthy volunteers that showed that in patients taking dtg 50 mg once daily with rifampicin, all had dtg trough concentrations above the protein-adjusted ic90.3 a recent observational study from botswana reported similar virologic outcomes in patients on rifampicin taking dtg 50 mg 12-hourly versus 50 mg daily.9 the radiant-tb trial is being conducted in cape town and is enrolling patients on tb treatment and starting first-line art who are being randomised to tdf/ftc/dtg 50 mg 12-hourly versus tdf/ftc/dtg 50 mg daily (https://clinicaltrials.gov/ct2/show/nct03851588). until data from this trial are available, we recommend dtg be dosed at 50 mg 12-hourly in all patients on rifampicin. whilst very few cases of dtg resistance have been reported in patients taking dtg as part of a triple-drug first-line art regimen in routine clinical practice, one feature of the cases reported has been a high baseline viral load.6,10,11 this may also have been a contributing factor in the patient described in this case report. in conclusion, although there is a very low risk of dtg resistance when used as part of the first-line combination therapy, dtg resistance is not uncommon after monotherapy and when used in patients previously exposed to raltegravir or elvitegravir therapy. however, apart from the dawning and dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with hiv (sailing) trials,2,12 there is limited data on the risk of dtg resistance in treatment-experienced, integrase inhibitor-naïve patients, especially in routine clinical practice, with concomitant usage of rifampicin and variable adherence and when used long term. to our knowledge, this is the first case report from south africa of dtg resistance emerging in a patient who was integrase inhibitor-naïve when starting dtg. factors that may have contributed to resistance emergence in this patient were that there was only one fully active nrti in the regimen in a treatment-experienced patient (based on population-based genotyping) and the lowered exposure to dtg because the patient reduced the dtg dosing frequency from 50 mg 12-hourly to 50 mg daily against her doctor’s advice whilst on rifampicin because of insomnia. acknowledgements competing interests the authors have declared that no competing interest exists. authors’ contributions all authors contributed equally to this work. ethical consideration this article followed all ethical standards for carrying out a research without direct contact with human or animal subjects. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references rhee sy, grant pm, tzou pl, et al. a systematic review of the genetic mechanisms of dolutegravir resistance. j antimicrob chemother. 2019;74(11):3135–3149. https://doi.org/10.1093/jac/dkz256 aboud m, kaplan r, lombaard j, et al. dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with hiv-1 infection in whom first-line therapy has failed (dawning): an open-label, non-inferiority, phase 3b trial. lancet infect dis. 2019;19(3):253–264. https://doi.org/10.1016/s1473-3099(19)30036-2 wang x, cerrone m, ferretti f, et al. pharmacokinetics of dolutegravir 100 mg once daily with rifampicin. int j antimicrob agents. 2019;54(2):202–206. https://doi.org/10.1016/j.ijantimicag.2019.04.009 dooley ke, sayre p, borland j, et al. safety, tolerability, and pharmacokinetics of the hiv integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. j acquir immune defic syndr. 2013;62(1):21–27. https://doi.org/10.1097/qai.0b013e318276cda9 dooley ke, kaplan r, mwelase n, et al. dolutegravir-based antiretroviral therapy for patients co-infected with tuberculosis and hiv: a multicenter, noncomparative, open-label, randomized trial. clin infect dis. 2020;70(4):549–556. pena mj, chueca n, d’avolio a, zarzalejos jm, garcia f. virological failure in hiv to triple therapy with dolutegravir-based firstline treatment: rare but possible. open forum infect dis. 2018;6(1):ofy332. https://doi.org/10.1093/ofid/ofy332 min s, sloan l, dejesus e, et al. antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in hiv-1-infected adults. aids. 2011;25(14):1737–1745. https://doi.org/10.1097/qad.0b013e32834a1dd9 van lunzen j, maggiolo f, arribas jr, et al. once daily dolutegravir (s/gsk1349572) in combination therapy in antiretroviral-naive adults with hiv: planned interim 48 week results from spring-1, a dose-ranging, randomised, phase 2b trial. lancet infect dis. 2012;12(2):111–118. https://doi.org/10.1016/s1473-3099(11)70290-0 modongo c, wang q, dima m, et al. clinical and virological outcomes of tb/hiv coinfected patients treated with dolutegravir-based hiv antiretroviral regimens: programmatic experience from botswana. j acquir immune defic syndr. 2019;82(2):111–115. https://doi.org/10.1097/qai.0000000000002126 fulcher ja, du y, zhang th, sun r, landovitz rj. emergence of integrase resistance mutations during initial therapy containing dolutegravir. clin infect dis. 2018;67(5):791–794. https://doi.org/10.1093/cid/ciy228 lübke n, jensen b, hüttig f, et al. failure of dolutegravir first-line art with selection of virus carrying r263k and g118r. n engl j med. 2019;381(9):887–889. https://doi.org/10.1056/nejmc1806554 cahn p, pozniak al, mingrone h, et al. dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with hiv: week 48 results from the randomised, double-blind, non-inferiority sailing study. lancet. 2013;382(9893):700–708. https://doi.org/10.1016/s0140-6736(13)61221-0 abstract introduction methods results discussion conclusion acknowledgements references about the author(s) aditi rao department of international health, johns hopkins bloomberg school of public health, baltimore, united states of america caitlin kennedy department of international health, johns hopkins bloomberg school of public health, baltimore, united states of america pamela mda nelson mandela academic clinical research unit, mthatha, south africa thomas c. quinn department of medicine, johns hopkins university school of medicine, baltimore, united states of america division of intramural research, national institutes of allergy and infectious diseases, national institutes of health, bethesda, united states of america david stead department of medicine, frere and cecilia makiwane hospitals, east london, south africa department of medicine, faculty of health sciences, walter sisulu university, east london, south africa bhakti hansoti department of international health, johns hopkins bloomberg school of public health, baltimore, united states of america department of medicine, johns hopkins university school of medicine, baltimore, united states of america citation rao a, kennedy c, mda p, quinn tc, stead d, hansoti b. patient acceptance of hiv testing services in rural emergency departments in south africa. s afr j hiv med. 2020;21(1), a1105. https://doi.org/10.4102/sajhivmed.v21i1.1105 original research patient acceptance of hiv testing services in rural emergency departments in south africa aditi rao, caitlin kennedy, pamela mda, thomas c. quinn, david stead, bhakti hansoti received: 15 may 2020; accepted: 02 june 2020; published: 22 july 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: south africa faces the highest burden of hiv infection globally. the national strategic plan on hiv recommends provider-initiated hiv counselling and testing (hct) in all healthcare facilities. however, hiv continues to overwhelm the healthcare system. emergency department (ed)-based hct could address unmet testing needs. objectives: this study examines the reasons for accepting or declining hct in south african eds to inform the development of hct implementation strategies. method: we conducted a prospective observational study in two rural eds, from june to september 2017. patients presenting to the ed were systematically approached and offered a point-of-care test in accordance with national guidelines. patients demographics, presenting compaint, medical history and reasons for accepting/declining testing, were recorded. a pooled analysis is presented. results: across sites, 2074 adult, non-critical patients in the ed were approached; 1880 were enrolled in the study. of those enrolled, 19.7% had a previously known positive diagnosis, and 80.3% were unaware of their hiv status. of those unaware, 90% patients accepted and 10% declined testing. the primary reasons for declining testing were ‘does not want to know status’ (37.6%), ‘in too much pain’ (34%) and ‘does not believe they are at risk’ (19.9%). conclusions: despite national guidelines, a high proportion of individuals remain undiagnosed, of which a majority are young men. our study demonstrated high patient acceptance of ed-based hct. there is a need for investment and innovation regarding effective pain management and confidential service delivery to address patient barriers. findings support a routine, non-targeted hct strategy in eds. keywords: hiv counselling and testing; south africa; emergency department; patient acceptance; implementation research; linkage to care. introduction south africa (sa) faces the highest burden of hiv infection globally, with 7.7 million people living with hiv (plwh) and prevalence ranging from 12.6% to 27% across the country.1,2 in 2018, sa had 240 000 new hiv infections and 71 000 aids-related deaths.1 the joint united nations programme on hiv/aids (unaids) adopted the ambitious treatment target of 90-90-90, wherein by 2020 90% of all plwh would know their status, 90% of whom would be receiving sustained antiretroviral therapy (art), of whom 90% would have achieved viral suppression.3 currently, in sa, an estimated 90% of plwh know their status, of whom 68% are accessing art, and 87% of these have achieved viral suppression.1 over the past two decades, numerous steps have been taken by the government to deliver evidence-based interventions focusing on hiv prevention, treatment, and retention. these efforts include the expansion of condom distribution, a national voluntary medical male circumcision program, prevention of mother-to-child transmission, as well as initiatives to increase knowledge and awareness of hiv/aids in communities utilising healthcare, in educational infrastructures and social media.2,4 however, despite sustained efforts and innovative measures, critical coverage gaps remain, with an estimated 10% of hiv-positive south africans unaware of their status5 and with 15% of new global infections occurring in the country.2 the first critical step to meeting the 90-90-90 target is hiv testing. early detection of undiagnosed hiv infection followed by effective linkage to care and treatment extends life expectancy, improves the quality of life, and reduces hiv transmission.6 since 2015, the south african national strategic plan on hiv, sexually transmitted infections and tuberculosis has recommended provider-initiated hiv counselling and testing (hct) to all persons attending healthcare facilities as a standard component of medical care, including trauma, casualty, and specialty clinics.6,7 nonetheless, the provision of hct in healthcare facilities is often hindered by the lack of standardised training and by competing clinical care priorities that prohibit effective service delivery.5,7 in addition, resources for hct have largely been directed to primary healthcare centres and antenatal clinics or are focused on high-risk populations such as sex workers, men who have sex with men, injection drug users, and prisoners.8,9 as a result, individuals who do not interact with the healthcare system through these channels, such as young men, often miss being tested. in sa, 90% of the population accesses healthcare through the public sector. for 28%, the emergency department (ed), a setting that provides high-volume care, is their only point of contact.10 in the united states of america, the ed is recognised by the centers for disease control and prevention to be a crucial venue in implementing the national hiv testing strategy.11 seminal studies have not only quantified the burden of hiv infection in eds but also have been critical to shaping the us national strategy for hiv; they could similarly address unmet testing needs in sa.11,12,13,14 in lowand middle-income countries (lmics), hiv prevalence in eds may be high, for example, 19% in papua new guinea and 50% in uganda.15,16 provision of hiv testing in the ed could thus be a critical intervention in curbing the epidemic. its acceptance in acute care settings, however, has not been widely evaluated in sub-saharan africa. studies have primarily focused on rates of acceptance, without exploring the reasons behind patients’ decisions. ascertaining the perspectives of patients, especially of those who decline testing, enables the identification of barriers to service delivery and the development of effective strategies to increase hiv diagnosis and linkage to care. in this exploratory observational study, to determine the feasibility of expanding an ed-based hiv testing strategy in sa, we investigated patient perspectives on accepting or declining hct and quantified the burden of hiv infection in the ed while implementing the nationally recommended hct programme. this study will assist policymakers and healthcare providers to inform the integration of hct in the clinical care pathway and optimise hct service delivery in this venue, resulting in early engagement in care and treatment initiation, ultimately reducing hiv-associated morbidity and mortality. methods the walter sisulu infectious diseases screening in emergency departments (wise) study was a prospective observational study. hiv counselling and testing was implemented in the eds of the nelson mandela academic hospital (nmah) and the mthatha regional hospital (mrh) in the eastern cape province, from 27 june to 03 september 2017. study site the study was conducted in mthatha, a rural town in the south african province of the eastern cape, a region that supports 12.6% of the country’s population.10 the area faces a disproportionate burden of acute injuries and illnesses with high rates of hiv and tuberculosis.7 it is also one of sa’s poorest provinces and is a key priority area for hiv research and capacity building.7 both hospitals are affiliated with the walter sisulu university. nelson mandela academic hospital is a large tertiary-care referral centre with 24-h trauma services, seeing only patients requiring specialty or surgical interventions referred from other district-level facilities. mthatha regional hospital is a district-level facility that provides care to walk-in patients and referrals from adjacent maternal and childcare facilities. the eds provide 24-h coverage and see 100–150 patients daily from the surrounding 100-km catchment area. both sites are relatively low-resourced and not equipped with an electronic medical record (emr) system, patient tracking system or standardised triage processes. furthermore, there are no providers specialising in emergency medicine at these sites. study population patients presenting to the ed who were aged 18 years and older and clinically stable (defined as the south african triage scale designation of ‘non-emergent’) were included in the study. triage scores were assigned by trained study staff, based on the south african triage scale (sats).17 patients younger than 18 years, not able to provide informed consent (i.e. patients with a depressed level of consciousness or mentally altered) or undergoing active resuscitation were excluded. recruitment and sampling all patients presenting to the ed during the study period who met the inclusion criteria were approached by trained hct staff, informed of the ongoing study and offered a point-of-care hiv test. written informed consent was sought for testing and participation in a survey that asked about reasons for accepting or declining the test. patients with a known hiv-positive diagnosis were asked if they had access to an antiretroviral (arv) clinic, if they were on regular treatment and whether they were aware of having developed aids or being virally suppressed. data were also collected on patient demographics, presenting complaint, presenting symptoms and past medical history. hiv counsellors approached all eligible patients in a large waiting room after they underwent initial triage and administrative processes. patients consenting to the study were escorted to a private room for testing if possible, whereas patients assigned a bed were tested at the bedside with curtains drawn where possible. given the lack of an emr or patient tracking system, hct staff placed a small dot on the folders of all patients who were approached and offered hct. every 4 h, the study supervisors audited the folders of patients located within the ed to ensure that all eligible patients had been approached. based on recent survey data from the 2017 south african national hiv prevalence study, hiv prevalence amongst south africans of all ages was estimated at 14%.2 our study aimed to recruit a sample size of 700 patients at each site. this would present a large enough sample to capture the variation in testing preferences in the study setting, allowing us to detect a difference of greater than 5% from the baseline estimate of 14%, assuming a two-sided α of 0.05 and 80% power, for a period of 7 weeks at each site. intervention patients were offered point-of-care hiv testing following the south african national hiv testing guidelines.7 patients who consented to the test provided a blood sample obtained through a lancet finger prick. following the recommended testing algorithm, patients were first tested using the advanced quality anti-hiv 1&2 rapid test (intec products, inc., fujian, china). non-reactive samples were reported as an hiv-negative result. reactive samples were confirmed with an hiv 1/2/o tri-line hiv rapid test (abon biopharm, hangzhou, china). confirmed reactive samples were reported as an hiv-positive result, and patients were provided with a referral letter to a local arv clinic. confirmed non-reactive samples were reported as an indeterminate result, and patients were counselled to repeat the test in 4–6 weeks. counselling preceded and followed all tests and included education on hiv transmission, prevention, and management. results were available within 10–15 min of testing, whereas counselling required an additional 10–15 min, depending on the hiv test result. data collection ten local research assistants were hired and trained in rapid point-of-care hct, good clinical practice and data collection, and were familiarised with the study protocol before the start of the study. research assistants and study staff worked in shifts to ensure 24-h coverage of the ed. in tandem with offering hiv testing, hct staff administered a brief survey. patient responses to questions about their gender, past medical history, mode of arrival, reason for visit, presenting complaint, and symptoms were recorded as pre-determined binary or categorical options, age was recorded as free text, and reasons for accepting or declining testing were captured via pre-determined categorical options derived from the literature or as free text. data were recorded on case report forms. these forms were scanned and uploaded onto idatafax (df/net research, inc., seattle, wa, usa) by trained study staff. following validation and cleaning, data were exported into excel v.16.9 (microsoft, inc., redmond, wa, usa), and then imported into stata v.14 (statacorp, tx, usa) for analysis. the outcome of interest, declining hct, was measured as a binary variable (‘no’ = 0 and ‘yes’ = 1). the independent variables measured were age (18–30, 31–50, 51–70, 70+), sex (male, female), presenting complaint (trauma, medical), south african triage score (death, routine visit, urgent, very urgent, emergent), access to primary care (yes, no), past medical history (hypertension, coronary artery disease, tuberculosis, diabetes, asthma, chronic obstructive pulmonary disorder, cancer), visit time (within regular operating hours, 9 am to 5 pm, or out of regular operating hours), visit reason (new complaint, return visit, referral), mode of transport (self-transport, ambulance, police), presenting symptoms (pain, fever) and disposition (death, intensive care unit admission, general admission, emergent surgery, transfer, discharge, absconded). data analysis and statistics analysis was conducted on patients unaware of their status, to examine the relationship between the outcome of interest and all other independent variables. chi-square tests were used to explore individual variable associations with declining hct. logistic regression analysis was conducted to assess the contribution of each variable to declining hct. bivariate analysis was conducted to estimate the association between the outcome and each predictor variable, as well as multivariate analysis to estimate the independent effect of each predictor variable, adjusting for all others. all variables were included in the final model, following checks for collinearity and goodness of fit and performing a best-subsets variable selection. sub-group analysis was completed on the top reasons for accepting and declining hct by gender. a reference level was selected for categorical variables with multiple responses, and other levels were accordingly compared. associations were assessed using odds ratios (ors), 95% confidence intervals (cis) and p-values. a p-value of ≤ 0.05 was regarded as statistically significant. a pooled analysis of data collected from both sites is presented; no significant differences were observed between the two sites (table 1). table 1: characteristics of emergency department patients at nelson mandela academic hospital and mthatha regional hospital. ethical consideration the study was approved by the johns hopkins university school of medicine institutional review board (reference number irb00105801), the human research ethics committee from the university of cape town (mrec reference number 856/2015), the human research committee of walter sisulu university (reference number 069/2015) and the eastern cape department of health. written consent was obtained from all participants who enrolled in the study and was required for the collection of demographic data, hct and a follow-up call for newly diagnosed patients, separately. results a total of 1010 patients presented to the nmah ed between 27 june and 13 august 2017. of these, 727 (72%) patients were approached by hct staff, and 622 (61.6%) were enrolled in the study. a total of 3245 patients presented to the mrh ed between 24 july and 03 september 2017; of these, 1347 (41.5%) patients were approached by hct staff, and 1258 (38.8%) were enrolled in the study (table 1). across both sites, 2074 patients were approached by the hct staff, and 1880 (90.6%) were enrolled in the study. patients enrolled were slightly female predominant (966, 51.4%), with a median age of 33 years (interquartile range [iqr]:24–59). most patients presented with medical complaints (1278, 67.9%), received a triage designation of ‘urgent’ (1269, 67.5%) and reported having access to primary care services (1696, 90.2%; table 1). of the 1880 patients enrolled, 465 (24.7%) patients were aware of their hiv status (defined as a known hiv-positive diagnosis [371, 19.7%] or tested hiv negative within the last 12 months [94, 5%]), and 1415 (75.3%) patients were unaware of their hiv status. of patients with a known hiv-positive diagnosis, 351 (94.9%) said they were regularly accessing an arv clinic. of patients who were regularly accessing an arv clinic, 23 (6.5%) reported being virally suppressed, 46 (13.1%) reported not being virally suppressed and 282 (80.3%) were unsure (figure 1). in addition, 20 (5.4%) patients who had a known hiv-positive diagnosis wanted to get retested to confirm if they were truly/still hiv positive. figure 1: flow diagram demonstrating study enrolment and outcomes. of the 1415 patients unaware of their status, 141 (10%) declined hct, and 1274 (90%) accepted. of the patients who accepted hct, 159 (12.5%) were diagnosed as hiv positive, 1102 (86.5%) were diagnosed as hiv negative and 13 (1%) had an indeterminate result. the overall prevalence of hiv in the study population was 28.1%. patients declining and those accepting hct both largely presented with medical complaints (912, 64.5%), received a triage designation of ‘urgent’ (954, 67.4%), had stated access to primary care services (1255, 89.2%), had no past medical history (929, 65.7%), visited the ed outside of regular hours (799, 56.5%), had a new complaint (878, 62.4%), used self-transport (881, 62.7%), had symptoms of pain (790, 55.8%), had no symptoms of fever (1388, 98.1%), were ultimately discharged from the ed (718, 53.9%) and were aged 18–30 years (629, 44.5%; table 2). table 2: characteristics of emergency department patients and association of factors with declining hiv counselling and testing. the top reasons for accepting hct were ‘has not tested in the past year’ (451, 35.4%), ‘has never been tested’ (242, 18.9%) and ‘test is rapid and free’ (237, 18.6%) (figure 1). patients accepting testing were largely male (672, 52.7%). the top reasons for declining hct were ‘does not want to know status’ (53, 37.6%), ‘in too much pain’ (48, 34%) and ‘does not believe they are at risk’ (28, 19.9%; figure 1). patients declining testing were largely female (85, 60.3%). sub-group analysis of the reasons for accepting and declining hct by gender showed slight differences between men and women in the reported reasons (table 3). the primary reason for accepting hct for both men and women was ‘has not tested in the past year’, 35.8% and 34.9%, respectively, followed by ‘has never been tested’ (21.4%) for men and ‘test is rapid and free’ (20.3%) for women. the primary reason for declining hct given by men was ‘does not want to know status’ (66.1%) and ‘in too much pain’ for women (22.4%), followed by ‘in too much pain’ for men (42.9%) and ‘does not believe they are at risk’ (17.6%) for women. table 3: reasons for accepting or declining hiv counselling and testing by gender. univariate analysis showed that compared with male patients, female patients were more likely to decline hct associations were assessed using odds ratio (or: 1.7; 95%) confidence intervals (ci:1.2–2.4). patients who complained of pain compared with patients who did not (or: 1.7; 95% ci: 1.2–2.5) and those arriving at the ed by ambulance compared to self-transport or with the police (or: 1.4; 95% ci: 1.1–2.1) were also more likely to decline hct. in addition, patients presenting with traumatic injuries compared with medical complaints (or: 1.6; 95% ci: 1.1–2.2) were more likely to decline hct. other factors including age, triage score, access to primary care, past medical history, visit time, visit reason and final disposition did not show a statistically significant correlation with declining hct (table 2). multivariate analysis showed that patients who complained of pain compared with patients who did not (or: 1.6; 95% ci: 1.1–2.6) were slightly more likely to decline hct. other variables did not show a statistically significant correlation with declining hct (table 2). discussion we found acceptance of hct services in the ed to be reassuringly high. our study revealed that 90% of patients who were unaware of their hiv status accepted hiv testing. this was observed despite patients being in a clinical environment where hiv testing is not routinely offered and where patients present with acute injury or illness and are often in pain or moderate distress.11,18 these findings are consistent with results from other lmics. in kenya and guyana, it was found that 97.7% and 75.5% of non-critical patients accepted hct in the ed, respectively.19,20 our results also highlight a substantial burden of undiagnosed hiv: 8.5% of enrolled patients were newly diagnosed as hiv positive. these patients presented to the ed for various clinical complaints, and a positive diagnosis of hiv was an incidental finding. the two most common reasons for accepting hct in the ed were ‘has not tested in the past year’, followed by ‘has never been tested’. this positively implies the need for hct in acute care settings, to cover the existing testing gap, as we are able to capture patients who are currently missed by other testing venues within the healthcare system. recently, novel approaches for hct – such as home-based, community-based and couples testing – have been added to traditional facility-based hct delivery systems, with good acceptance rates.21,22 a systematic review of hct strategies in sub-saharan africa reported an acceptance rate of 70% for home-based testing and 76% for community-based testing.21 however, despite the variety of testing strategies and venues, a testing gap remains, particularly amongst young adults and men.23,24 considering that 44.1% of all patients accepting testing were young adults (18–30 years) and 52.7% were male, our study demonstrates that the ed is an opportune venue to capture this missed population. another factor leading to testing acceptance, reported by a fifth of patients accepting hct, was ‘the test is rapid and free’. this measure combines both cost and ease/limited time lost to testing. while it is hard to separate the two and determine which is a more significant factor, ensuring that both are addressed is a likely key to maintaining high acceptance of hct in a fast-moving environment such as the ed. this is supported by a study in uganda, where 25% of ed patients reported not knowing their hiv status because of the lack of access to free testing services.16 at present, hct services are offered free of cost in all government healthcare facilities in sa; however, maintaining free services can be burdensome for the government, especially if testing services are to be further expanded. furthermore, ensuring that testing and counselling are not time-consuming and are part of routine clinical care in the ed might address the barrier of having to seek out testing as a discrete task in itself. acceptance, however, was not universal. in our study population, women were significantly more likely to decline to test, whereas men were more likely to accept. similar findings were observed in other studies examining the acceptability of testing in eds, in both highand low-resource settings.20,25 this might be because women are aware of having access to testing services during antenatal visits, through preventing mother-to-child transmission (pmtct) programmes or through family planning services, and hence do not need to test in the ed.1 this is supported by the finding that more women were already aware of their hiv status; 71.6% of the patients with a known hiv-positive diagnosis were women. in addition, a significant proportion of women presenting to the ed in our context were diagnosed with pregnancy complications or injury wounds, likely justifying ‘in too much pain’ as the primary reason reported for women to decline hct. on the contrary, though women were more likely to decline hct, a majority still accepted testing when offered. while it is difficult to generalise individual motivations, factors including lack of social support and fear of stigma or rejection if tested hiv positive, especially in the presence of their partner or family accompanying them to the ed, may otherwise underlie the greater tendency of women to decline hct.25 the top reasons reported for declining hct in our ed, ‘does not want to know status’ and ‘does not believe they are at risk’, are interestingly established findings from high-income countries and lmics, across healthcare settings.16,20,26,27,28,29 it could be that patients prefer uncertainty rather than facing the psychosocial consequences of an hiv-positive diagnosis, especially considering the imaginable stigma attached to such a diagnosis.30 this could be tackled through targeted preand post-counselling efforts. on the contrary, it is also possible that the small proportion of patients who declined to be tested are not at risk of contracting hiv and were accurately perceiving their risk. we did not include any risk measures in our survey and are thus unable to precisely indicate individuals who should have been tested. a significant barrier to hct in the ed and other healthcare facilities frequently described in the literature are stigma and the lack of confidentiality.20,26,31 this finding is supported by contextual knowledge, wherein anthropological studies exploring cultural perceptions and practices around hiv in mthatha have reported pervasive stigma attached to hiv/aids, resulting in multiple forms of exclusion based on sexism, racism and homophobia,30 the national hiv prevalence survey indicated that 26% of people would not be willing to share a meal, 18% were unwilling to sleep in the same room and 6% would not speak to plwh.2 yet, none of the patients declining testing in our study reported reasons implying real or perceived stigma or the lack of confidentiality. the studies supporting this notion conducted in-depth interviews or had one-on-one conversations with patients, which likely allowed for deeper exploration of patient perspectives on hct services, whereas given the patient volumes, high turnover and the lack of any coordinated processes in our study setting, it is possible that patients were less likely to report stigma as a reason for declining testing. pain was a notable justification for declining testing in this context and showed significant correlation through bivariate and multivariate analysis. the second most common reported reason, ‘in too much pain’, was not surprising, as a high proportion of cases presented with acute traumatic injuries. in addition, traumatic injuries and arriving at the ed in an ambulance, which are critical proxies to pain and the seriousness of a patient’s condition, were positively correlated with declining testing. this finding is specific to declining hct in the ed and has not been previously reported as a barrier in other testing venues. to address this barrier, the integration of pain management before hct is recommended. if a patient’s presenting complaint has been addressed by providers, and appropriate action taken, patients might be more likely to accept testing. linkage to care is the next critical step following testing. as part of our study, all newly diagnosed patients were counselled extensively on the importance of seeking follow-up care and were given a referral letter. given that both nmah and mrh see patients from a 100-km radius, it was challenging to ensure linkage to care, as it would depend on the area individuals came from and the presence and ease of access to an art clinic. for patients who were local to mthatha, we were able to direct them to the gateway clinic – an art centre – located within the same campus as the hospital. with the consent of all patients who were newly diagnosed as hiv positive, we collected their names and contact details to conduct follow-up calls after 1 month, 6 months and a year. the follow-up calls will allow us to assess whether individuals have been able to link to care and/or what challenges they are facing in doing so. results from the follow-up calls will be collated and analysed post-completion. despite these challenges, 94.9% of patients with a known hiv-positive diagnosis presenting to the eds reported having access to an art clinic, and 85.4% of those individuals reported regularly accessing the clinic. these rates are commendable and imply a willingness of patients in this setting to seek follow-up care. however, these are self-reported statistics and could be inflated as a result of social-desirability bias. another interesting finding was that a small proportion of patients with a known hiv-positive diagnosis (20, 5.4%) requested a repeat test to confirm their diagnosis. patients stated that they wanted to confirm whether they were truly hiv positive and/or if they were still hiv positive. upon retesting, all 20 patients were hiv positive. the desire to retest when an opportunity presented could likely be a result of mistrust in the healthcare system or a result of the low health literacy in the region, which are both potential barriers to achieving high rates of testing and sustained linkage to care.30,31 there are several study limitations to consider. the protocol was to approach every patient presenting in the ed who met the inclusion criteria. however, the lack of infrastructure, systematic medical record-keeping or a patient tracking process made it challenging to retain all patients who presented to the ed. many patients were missing from the records, whereas others were entered multiple times, making it difficult to keep count of the total number of patients. hiv counselling and testing services were provided 24 h a day, yet we were only able to approach 48% of patients who presented for care. we believe this is, in part, a result of the high volumes of patients and the quick turnaround time, as well as the time-consuming nature of counselling. patients enrolled in the study may be a biased subset of the ed population, namely, easier to approach, spoke the same language as the hct counsellors, had milder injuries or conditions and presented at times when the patient volume was lower. maintaining confidentiality was challenging given the limited space – the eds in both hospitals were in essence one big room, with beds lined up against each other. lastly, the study was human-resource intensive. we had a team of four dedicated hct staff at all times. nevertheless, greater staff numbers would have allowed the capture of more study subjects. such a situation would be difficult to sustain in a low-resource setting such as mthatha. to optimise our strategy and accurately capture data, given the lack of organisation and clear processes, our data were collected prospectively, whereby we relied less on recorded data and were able to capture most of it in real time. as the ed is busy and sees high patient volumes, we attempted to collect as much data as efficiently as possible, using a survey format with mostly ‘yes’ and ‘no’ questions. however, to have had a better understanding of patient perspectives, the study might have been enhanced by in-depth telephone interviews with a smaller number of patients after they had left the ed. conclusion our study demonstrated high patient acceptance of the nationally recommended hct strategy in an ed setting. the overall adult prevalence of hiv in the ed was high at 28.1%. patients who were male, young and not in pain or critically injured were more likely to accept hct, critically supporting the provision of hct in acute care settings, as it successfully captured an important demographic that has generally been missed through other testing venues. in addition, the lack of significant correlation in demographic or clinical characteristics and hct uptake argues for a routine, non-targeted strategy in the ed. our study further reveals the need for continued investment to ensure that hct is widely available, with provision to effectively identify and manage pain and trauma. finally, critical to embedding hct in the routine clinical care offered in the ed will be the confidential conduct of hct that permits stigma around hiv infection and testing to be appropriately addressed – something that will require further innovation and implementation research. acknowledgements the authors acknowledge the staff in the nelson mandela academic hospital and mthatha regional hospital emergency departments for making this research possible and the hiv counselling and testing team for their dedication and hard work during the study. the authors also acknowledge the contributions of nomzamo mvandaba for her assistance as a study coordinator for the wise study and those of victoria chen and kathryn clark in data collection and data validation. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions b.h. conceived the original idea for the parent study and designed the protocol. a.r., p.m. and b.h. coordinated the study and data collection. a.r. carried out data analysis and prepared the manuscript. c.k., t.c.q., d.s. and b.h. provided substantial edits and revisions. funding information this research was supported by the south african medical research council, the division of intramural research, the national institute of allergy and infectious diseases, national institutes of health, and the johns hopkins center for global health. data availability statement the data that support the findings of this study are available on request from the corresponding author, a.r. the data are not publicly available because they contain sensitive information that could compromise the privacy of research participants. disclaimer all views expressed in the submitted article are the authors’ own and not an official position of the institutions represented or the funders. references unaids. unaids data 2019. unaids, geneva, switzerland; 2019. simbayi lc, zuma k, zungu n, et al. south african national hiv prevalence, incidence and behaviour, and communication survey, 2017. cape town: 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2014;32(9):1109–1112. https://doi.org/10.1016/j.ajem.2014.05.034 christopoulos ka, weiser sd, koester ka, et al. understanding patient acceptance and refusal of hiv testing in the emergency department. bmc public health. 2012;12(1):3. https://doi.org/10.1186/1471-2458-12-3 gazimbi mm. a multilevel analysis of the determinants of hiv testing in zimbabwe: evidence from the demographic and health surveys. hiv/aids res treat open j. 2017;4(1):17. http://doi.org/10.17140/hartoj-4-124 leclerc-madlala s, simbayi lc, cloete a. the sociocultural aspects of hiv/aids in south africa. in: hiv/aids in south africa 25 years on: psychosocial perspectives. 2009; p. 13–25. nombembe c. music-making of the xhosa diasporic community: a focus on the umguyo tradition in zimbabwe. cape town: university of witwatersrand, faculty of humanities, wits school of music in cape town; 2013. hiv0304pg000 march 2004 the southern african journal of hiv medicine 3 4 pilot studies conducted in south africa, uganda, cameroon, cote d’ivoire, kenya, malawi, senegal and india demonstrate the feasibility and effectiveness of highly active antiretroviral therapy (haart) in a range of resource-poor settings with limited evidence of resistance. there is little evidence outside of these small studies. positive outcomes (good adherence, decreased viral load, increased cd4+ count, decreased opportunistic infections and side-effects) from the pilot studies compare favourably with rich countries. patient commitment has been shown to be strengthened by careful counselling of both patients and families before commencement of therapy, ongoing support; local government and community support, and recovery from aids illnesses. patients on haart do better than those who because of cost considerations are given dual nucleoside therapy. dual therapy has limited durability and may promote more rapid emergence of drug resistance. effects of haart on mortality differ. in brazil, where there is universal access, there has been a 50% decrease in hiv-related deaths since 1996 and a median survival increase from 18 to 58 months. improvements have been recorded at sites in most countries with the exception of the médecins sans frontières (msf) homa bay site in kenya, where late presentation played a major role. art has decreased the risk of tuberculosis (tb) by as much as 80% in brazil and south africa. in brazil, the positive impact of haart includes a decrease in health a r t i n r e s o u r c e p o o r s e t t i n g s provision of antiretroviral therapy in resource-limited settings – a review up to august 2003 world health organisation (who) and department for international development, uk précis by penny penhall. improved prospects for expanded access to antiretroviral therapy (art) in resource-poor settings are the result of reduced costs of antiretroviral drugs (arvs), increased availability of cheaper generics and access to funds such as the global fund to fight acquired immunodeficiency syndrome (aids), tuberculosis and malaria (gfatm), private foundations, non-government organisations (ngos), corporate initiatives, government budgets and other multilateral and bilateral donors, with the prospect of additional funding from the united states millennium challenge account. increased affordability together with the political will has seen a rapid increase in the number of countries introducing or scaling up art programmes. the paper aims to elucidate the requirements for art programmes in resource-poor settings by using existing pilot experience and lessons learnt with particular regard to: ■ the feasibility of art in resource-poor settings. ■ the different approaches being taken to delivery of art. ■ the issues to be considered in scaling up art provision. feasibility and impact of art in resource-poor settings the southern african journal of hiv medicine march 2004 3 5 service expenditure, where an estimated 358 000 hospital admissions were avoided between 1996 and 2002, saving us$2.2 billion. two years after introducing a comprehensive hiv/aids programme with art, a cote d’ivoire private sector company noted a fivefold increase in company-based voluntary counselling and testing (vct), a 94% decrease in absenteeism, an 81% decrease in hivrelated hospitalisation, a 78% decrease in new aids cases, and a 58% decrease in hiv-related mortality. the company saved approximately us$750 000 in health care, funeral costs and absenteeism. debate on the impact of haart on risk behaviour and implications for the spread of disease continues, but in brazil no increase in unsafe behaviour has been reported. in cote d’ivoire it was found that unprotected sex was associated with not being on art treatment. south africa’s khayelitsha project confirmed this finding, with increased condom use in those on treatment. national plans and strategies brazil, thailand and botswana have national art programmes, and mozambique, malawi and kenya have developed strategic plans for scaling up (as has south africa). focus has differed from country to country; some have concentrated on service delivery and access to art rather than on strategic planning, and others are reviewing their legal and policy framework. experience in african countries indicates that clear goal setting and integrating art programmes into national hiv/aids strategic plans, with multisectoral national review, helps to define priorities for scale-up. a review of national hiv strategic plans in five sub-saharan countries identified a number of weaknesses in national plans and priority setting processes: ■ unrealistic resource allocation — designed for resource mobilisation. ■ priority setting by donors instead of by considerations of cost-effectiveness. ■ the balance between prevention and care being determined arbitrarily. the key issue being, not whether to include art or not, but the balance between prevention and care and different care interventions. many large organisations suggest that hiv/aids programmes be included or considered in poverty reduction strategies, as they believe that addressing the epidemic is central to poverty reduction. this is not always easy in practice as organisations are not always aligned, poverty reduction programmes do not always identify hiv/aids strategies, and there is concern that combining projects may distort planning and budgeting processes. models of delivery many countries have a wide variety of arv providers and programmes within one country, which operate in different settings, and have different financing, logistical and clinical structures. this makes it difficult for policy makers to evaluate coverage, quality of services and equity impact. experience indicates that scaling up is best achieved through co-ordination and collaboration with the existing operational mix of providers, e.g. private sector (private health care facilities, private physicians, company schemes) combined with ngos, and local and international organisations including mission hospitals, religious networks and community organisations. systems need to be appropriate to the national context and the health system. a literature review indicates that in most countries the public sector uses one or a combination of three models, i.e. ■ provincial and regional hospital delivery ■ district level delivery ■ community clinic or community-based delivery. public health sector most countries in sub-saharan africa are using public sector hospitals in a phased, scale-up approach beginning with selected regional or provincial hospitals, e.g. ghana began with 2 hospitals, botswana with 4 sites and nigeria with 25. a number of countries use district facilities for counselling, testing, treatment of opportunistic diseases, prevention of mother-to-child-transmission (pmtct) and monitoring and as referral points, and major public hospitals (often teaching hospitals) as the entry point for arv treatment, e.g. ghana, senegal, botswana and nigeria. a second phase, comprising inclusion of all regional hospitals, is then undertaken. mozambique is to make arv available through multi-purpose integrated health networks (ihns). non-government and community organisations in some countries ngos are at the forefront of the provision of arv treatment through pilot schemes and community programmes. a number of ngos, e.g. msf and aids healthcare foundation, run such pilot programmes in a number of african countries including south africa. faith-based networks also play a role. the number of patients treated varies from as few as 50 60 through to 300 or more. approaches to delivery of art march 2004 the southern african journal of hiv medicine 3 6 community-based organisations (cbos) are being considered in some countries e.g. uganda (through taso and cdc) as a result of the successful, perhaps best-known, haiti cbo, documented by farmer in 2002, which provides haart through directly observed therapy (dot) to approximately 60 patients. the importance of good information and adequate art training has been shown to be essential for ngos and cbos. private sector even in very poor countries art has been available through the private health care sector for some time at a range of (mostly) high prices. high prices are not a guarantee of quality, as doctors sometimes prescribe according to patient affordability and local availability of arvs. some studies have shown that prescribing is consistent with international standards and others that drug regimens and frequency of monitoring are sub-standard. concerns include monotherapy, resistance development, poor adherence, and unreliable drug supply leading to intermittent treatment and regimen switching. multinationals providing arvs to their staff include softdrinks manufacturers (coca-cola), breweries (heineken), car manufacturers (daimler chrysler, ford) and mining companies in botswana and south africa (e.g. anglo american). electricity companies in south africa (eskom) and cote d’ivoire also provide art. some evidence from africa suggests a cost saving for companies providing arv, although studies suggest that affordability is more important than cost saving in influencing the initiation of the provision of art. a trend towards shifting the burden to households and to government through cost-sharing models including preemployment screening and restructuring of employee benefits, has been identified. selection of beneficiaries coverage in december 2002, the world health organisation (who) estimated that < 1 in 18 people in middleand low-income countries, thought to be in need of art, were on treatment. nearly two-thirds of these were in latin america and the caribbean. in sub-saharan africa, only 50 000 of 4.1 million needing art were on treatment. eligibility criteria who guidelines for resource-poor settings recommend treatment for the following categories of hiv-positive people: ■ diagnosed with aids ■ with a cd4+ count of < 200/µl, or fulfilling the guidelines based on clinical diagnosis where cd4+ testing is not available. in countries with inadequate resources to treat all people requiring art, additional criteria are required in the decision-making process. clearly defined economic, social and biomedical criteria are required to determine eligibility for free treatment to ensure equitable access. communities need to be made aware of these criteria. msf in south africa has established clear criteria which include living in the geographical catchment area, number of dependants, health status, income, disclosure and activism. equity and priority target groups scale-up programmes should be informed by equity issues and consideration given to the poor, different geographical regions, rural v. urban populations, specific population groups, gender and children. socio-economic determinants for free and subsidised arvs need to be carefully defined to ensure equitable access. experience has shown that many of the poor may not be able to afford art even if it is heavily subsidised as the lowest cost of triple therapy can be as much as twice the average monthly formal sector wage, e.g. in mozambique. in cost sharing systems, levels of charging, means testing and waiver systems need to be addressed. countries’ objectives differ. some aim to achieve the widest possible geographical coverage while others target key groups which vary by country, e.g. hiv-positive people with serious immune system damage, continued treatment of hiv-positive mothers identified in pmtct strategies and their male partners, post-exposure prophylaxis (pep) for health care workers, patients with tb, and victims of sexual assault. inclusion and free access criteria need to be flexible and evolve in accordance with changes in drug prices, availability and financial resources. health systems systems strengthening there is limited information on the impact of hiv/aids on already constrained health systems of developing countries. scaling up has the potential to strengthen systems and improve outcomes for non-hiv-related conditions if investment is used to address infrastructure, human resources and logistical weaknesses, e.g. in thailand. improving clinical services can boost staff morale, e.g. in haiti. conversely art programmes could issues in scaling up art provision the southern african journal of hiv medicine march 2004 3 7 weaken poor health systems without appropriate investment in systems strengthening. situational assessments of regional and district facilities to identify needs and gaps and system strengthening requirements have been undertaken by certain countries, e.g. kenya. integration of services it is generally accepted that art needs to be delivered as part of a comprehensive approach to prevention, care and support services including voluntary counselling and testing (vct), pmtct, diagnosis and treatment of opportunistic infections (ois) and other hiv-related illnesses. integration and co-ordination of services is advised by who as opposed to setting up new parallel structures. lower levels of the system can act as entry points to regional treatment centres offering art, or vct and tb programmes can act as entry points. infrastructure limited infrastructure is a major constraint to scaling up of art. there is a lack of clarity regarding the minimum infrastructure requirement, its costs and efficiencies of scale. laboratory, pharmacy and clinical facilities are required for successful art delivery. kenya is one of the few countries to have conducted a comprehensive situational assessment of public health facilities. human resources staff shortages are a major constraint to scaling up and in many of the worst-affected countries the health sector is facing a crisis in skilled human resources due to migration to the private sector and other countries and exacerbated by hiv/aids-related attrition. innovative ways to address lack of human capacity include lay counsellors, reduced frequency of visits for stable and adherent patients, prescribing of arvs by district hospitals but collection of drugs and monitoring at satellite health centres using simplified clinical review guidelines and simple but effective record keeping and drug monitoring systems. training for clusters of doctors, nurses and other health care workers is critical, as is a common approach and message. training strategies and methods need rethinking in order to incorporate responsive continued education given the rapidly evolving nature of art. improved staff management (capacity to co-ordinate, supervise and monitor the scaling up process at all levels) would substantially increase staff productivity within the broader contexts of decentralisation and health sector reform. drugs and supplies effective art programmes require regular and timely supplies of competitively priced quality drugs, laboratory reagents and related supplies, and drugs for ois. this requires buffering against uncertainties in funding to minimise risks of interrupted supplies and prevent resistance. countries planning a scale-up need clear drug procurement, storage and distribution policies to prevent misuse. secure supply chains and storage systems need strict monitoring to prevent leakage from public programmes. some drug registration processes may be slow and complex and procurement hampered by lack of drug information and corruption. import taxes and duties add to the cost of arvs and reagents, so local production (as in brazil, india, thailand, china) and the use of generics (kenya, mozambique, south africa, ethiopia and ghana) are preferred options. assessment of challenges recent research has identified the following challenges in countries wishing to scale up art: weak public sector management of essential drugs, poor storage facilities, weak transportation systems, problematic customs processes, diversion of products, inadequate training, lack of information systems, inaccurate quantification and forecasting (often based on consumption rather than morbidity data). the trend towards decentralisation requires support for district level planning and informed decision-making and drug budgeting. key logistics management issues key management issues listed by who/unaids include the role of public v. private sector, supportive policies and legal environment, harmonised or standardised procurement, quality assurance and control, criteria for quantification and forecasting, standard treatment guidelines and inclusion in essential drug lists (edls), inventory control systems, secure transportation and storage, monitoring of prescribing patterns, dispensing patterns and stock levels. logistics management information systems need to be user-friendly and a minimal burden to health workers, to provide timely data, and to respond flexibly to consumption and regimen changes and drug substitution. clinical management standard guidelines guidelines reduce treatment complexity and the cost of treatment and monitoring, and increase access to art, march 2004 the southern african journal of hiv medicine 3 8 especially in resource-poor countries. in addition, local guidelines simplify eligibility criteria for initiating therapy and standardise firstand second-line therapy. some research in zambia and mexico indicates that lack of enforcement of guidelines, cost of triple therapy, and poor training of prescribers can lead to poor prescribing habits. alternative treatment regimens despite price decreases, haart remains expensive relative to many other treatment modalities and remains complex in spite of the introduction of treatment regimens. simpler and more affordable regimens are being sought and studied, including structured treatment interruption, which appears the most promising option at present. clinical and laboratory monitoring laboratory monitoring is essential for the accurate assessment of the outcomes of art and requires adequate facilities and well-trained staff to conduct accurate cd4+, viral load, and basic safety tests for side-effects. in most resource-poor countries laboratory services require strengthening. while the price of art has decreased, the price of tests has not (though in south africa there have been reductions). reduced prices for tests and reagents need to be negotiated, cheaper generic alternatives sourced, and new technologies and assays developed. simplified and less frequent monitoring methods (e.g. one cd4+ every 6 months) and the use of low-cost alternatives to cd4+ tests are being studied. these require more reliance on clinical markers such as weight and early detection of any deterioration in health, e.g. ois. it has been suggested that viral load testing be confined to monitoring of resistance at national referral centres. alternatives to the present cd4+ testing methods include dynabeads and cytospheres (counts measured by flow cytometry and non-flow cytometry), but their disadvantages include being labour intensive and requiring trained technicians, limiting the number that can be processed per day. the who recommends further studies before any recommendations are made for developing countries. alternatives to polymerase chain reaction (pcr)based and bdna-based viral load assays are also being evaluated. drug resistance the development of drug resistance is a commonly cited concern regarding rapid scale-up programmes in resourcepoor settings, although a world bank meeting in june 2003 concluded that there was no empirical evidence that it is more problematic in developing countries than developed countries. they concluded that concerns should not delay programmes but recommended the promotion of rational drug use and good patient adherence. most developing countries cannot afford resistance testing for individual patients and most laboratories are not equipped to perform resistance tests. the who and various partners are working towards a global hiv drug resistance surveillance programme to record prevalence, identify contributory factors and strategise to minimise and limit the spread of resistant organisms. demand and adherence uptake of art availability and lowered cost of art does not guarantee access, as uptake is influenced by financial, organisational, physical and social factors. as many people are unaware of their hiv status, providing and improving access to vct is an initial and vital step in increasing uptake. a study conducted in kampala, uganda, found that despite decreased arv prices, uptake did not increase because of the limited knowledge and negative attitudes to arvs of health care workers and patients. subsequent training of health care workers and the use of people taking arvs to educate others increased the number of patients. arv availability and usage in pmtct programmes has increased uptake of vct in certain settings such as south africa and haiti. the provision of free-of-charge diagnosis, drugs and monitoring improves uptake, although payment for ois may remain an obstacle. where patient co-payments are required, assessments on willingness to pay, ability to pay and impact of payments on households should be undertaken. in households in which more than one person is infected, cost is even more problematical. people with private health insurance may not wish to claim for reimbursement due to fear of disclosure and discrimination. barriers to access include lack of transport, fear of disclosure, stigma and discrimination. there is however evidence that art availability increases uptake of services, changes community perceptions of aids and reduces discrimination. community education is essential in improving uptake and successful implementation of programmes. adherence concerns regarding patient adherence to art in resourcepoor settings have been proved unfounded, programmes such as the msf pilot programme in khayelitsha, south the southern african journal of hiv medicine march 2004 3 9 africa, having demonstrated adherence of > 95% after 3 months of treatment. the programme combines patientcentred education with individual, peer and practical support. brazil attributes high rates of adherence to affordability, fixed-dose combinations, community participation, involvement of civil society organisations and adherencesupport groups and support houses. other factors promoting adherence include affordability, disclosure of status to partners and family and regimens with limited numbers of pills. poor clinical management and side-effects can adversely affect adherence. more research is required and a study to identify the main determinants of adherence, barriers to adherence and the identification of effective interventions, is being undertaken in mombasa, kenya. community involvement experience indicates that uptake and adherence are improved in communities that have been adequately prepared for scaling-up programmes (highlighted at a who/unaids meeting recently). planning and budgeting for health care provider training and capacity building in communities is critical to the success and sustainability of expanded art programmes. in brazil and south africa civil society organisations have played a key role in advocacy and community mobilisation, e.g. the treatment action campaign. in countries in which art is not universally available, community involvement is becoming increasingly important in ensuring that decisions are made in a transparent and equitable manner. affordability and financing arv prices increased competition and generics have substantially decreased arv prices, enabling more governments to provide art through the public sector. in may 2003 the least expensive brand name combination recommended by the who for low-income countries cost approximately us$675 per person per year and the least expensive generic combination just under us$300 per person per year. in resource-poor countries, local manufacture and imported generics from brazil, india and thailand have made significant contributions to increased affordability. costing and sustainability developing countries with a high hiv incidence face or anticipate considerable difficulties regarding cost of public programmes. most governments will continue to require external aid to provide free or highly subsidised art for some time to come. only 7 of 19 accelerating access initiative (aai) countries have been able to fully subsidise arv therapy. geffen et al. recently reported that a fully comprehensive hiv/aids response was feasible in south africa, including arv drugs, training and improvement in infrastructure (subsequently the price of arvs has decreased and locally produced generics are soon to be made available). there is significant potential for arv costs to be offset by reductions in hospitalisation and treatment of ois (us$400 million in 2001 — national treasury of the republic of sa, 2001). financing mechanisms long-term funding of programmes through the public sector is unrealistic in most resource-poor countries and multi-funding approaches are needed. a range of such strategies include drug and laboratory cost reduction, graduated cost sharing with the assistance of ngos and private sector enterprises (based on ability to pay), national government exchequer funds, employer treatment schemes, health insurance scheme coverage of art, social insurance funds, and donor support. monitoring and evaluation art programme monitoring and evaluation (m&e) m&e will assist in the identification of challenges and speed up the application of lessons learned. they need to identify inefficiencies, obstacles and adverse effects and address feasibility and cost issues and consider art within the context of comprehensive care. in addition to clinical outcomes m&e will need to include equity, quality of care, and impact on risk behaviour issues. methods of patient and drug monitoring differ by country but include paper-based identity or photo cards, health facility registers, smart cards, finger-print readers, barcoded drug packaging and electronic databases and sophisticated computer technology and fixed and mobile telephone-based links to central monitoring points. journal 15 will contain a précis of the ‘review of experience’ section of the original report prepared by the health systems resource centre for the uk department for international development in collaboration with the world health organisation. abstract introduction south africa’s policy related-progress and response to the hiv epidemic changes in the hiv epidemic over the past decade: estimates from the thembisa model conclusion acknowledgements references about the author(s) yogan pillay clinton health access initiative, south africa leigh johnson centre for infectious disease epidemiology and research, school of public health and family medicine, university of cape town, cape town, south africa citation pillay y, johnson l. world aids day 2020: reflections on global and south african progress and continuing challenges. s afr j hiv med. 2021;22(1), a1205. https://doi.org/10.4102/sajhivmed.v22i1.1205 review article world aids day 2020: reflections on global and south african progress and continuing challenges yogan pillay, leigh johnson received: 18 dec. 2020; accepted: 29 jan. 2021; published: 10 mar. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: reflecting on progress and challenges in meeting global human immunodeficiency virus (hiv) targets is often done ahead of world aids day. this article reflects on progress and the continuing challenges in meeting targets in south africa (sa). objective: to review policy and implementation related progress and continuing challenges towards eliminating hiv as a public health threat by 2030. method: policy analysis and review of modeling data from thembisa 4.3. results: south africa has made significant progress in the adoption of policies with two exceptions. while there are gaps in reaching the 90-90-90 implementation targets, progress has been made in the past decade. conclusion: while progress has been made in the past decade towards the global targets, much work remains to ensure that hiv transmission is curtailed and those that require treatment are initiated on treatment and are virally suppressed. keywords: hiv; prevention; treatment; viral suppression; prep. introduction south africa (sa) recently commemorated world aids day 2020. at the start of 2021, we reflect on areas ‘done well’ and those ‘yet to show progress’. three recent documents provide independent data with which sa can achieve this and rededicate healthcare workers to eliminating human immunodeficiency virus (hiv) as a public health threat by 2030. these articles are, the world aids day report 2020: ‘prevailing against pandemics by putting people at the centre’, published by the joint united nations programme on hiv/aids (unaids),1 the 2020 global hiv policy report: policy barriers to hiv progress2 and current south african estimates as described in the ‘thembisa 4.3 model’, a report published by the university of cape town.3 the annual unaids world aids day report1 focuses on progress in meeting targets and on areas of ongoing concern. of the estimated 38 million people living with hiv (plwh) globally, 12 million are not on treatment. in addition, in 2019, 1.7 million people were newly infected and 690 000 died of acquired immunodeficiency syndrome (aids)-related causes. although the target was to have at least 30 million people worldwide on treatment by december 2020, actual numbers were 4 million off this goal! in september 2020, unaids reported a shortfall in achieving its 90-90-90 global targets. by the end of 2019, these were only 81-67-59! furthermore, the target of having ≥ 73% of all plwh on antiretrovirals (arvs) and exhibiting viral suppression by the end of 2020, is said to be ‘unlikely’.4 even before the coronavirus disease 2019 (covid-19) pandemic, the world health organization (who) had indicated that the global hiv response ‘was stalling’!5 coronavirus disease 2019 has negatively impacted the international hiv response. unaids reports major disruptions in hiv-testing and access to antiretroviral therapy (art).1 access to hiv prevention services for men who have sex with men (msm) was interrupted in cambodia, honduras, jamaica, sa and togo. in addition, the number initiating art continued to decline through to september 2020, in the dominican republic, kyrgyzstan, lesotho, sierra leone and sa. figure 1 indicates a rebound in testing in uganda and sa between march/april and august/september 2020, but persistently poor testing rates in sierra leone and lesotho. figure 1: change in the number of human immunodeficiency virus tests and results returned per month compared with baseline of selected countries in 2020. the unaids report1 also noted several positive initiatives prior to and in response to the covid-19 pandemic. these include adopting new dispensing policies for stable hiv patients such as multi-month dispensing in burundi, the dominican republic, ethiopia, mozambique, papua new guinea and sa. this reduced the need for clinic visits to collect arv treatment. in botswana, kenya, rwanda and sa, voluntary medical male circumcision (vmmc) has restarted since the imposition of strict lockdowns. despite these initiatives, there is widespread concern about the disruption of essential services by covid-19. south africa’s policy related-progress and response to the hiv epidemic implementation of interventions to prevent hiv and get people onto treatment as soon as they are diagnosed starts with good policies. south africa has long been feted as having exemplary policies. the 2020 global hiv policy report2 shows that amongst countries in eastern and southern africa – countries with the largest burden of hiv – sa has the highest overall policy-adoption score. the report suggests that sa has yet to make progress in the following three areas. the use of national laws to take advantage of the flexibilities in the agreement on trade-related aspects of intellectual property rights (trips) to procure medicines at more affordable prices, the decriminalisation of sex work and the personal possession and/or use of drugs. south africa has used its large volumes and tender-pricing system to drive down national and global prices but has not utilised provisions of trips such as compulsory licensing and parallel importation. although the former deputy president mr. c. ramaphosa publicly launched an hiv programme for sex workers and declared that ‘sex work is work’, this has not stopped police harassing sex workers.6 with respect to the legalisation of drug-use, to date only the private use of marijuana is legal but not its sale. however, drug use by the more than 75 000 injecting-drug users continues to be criminalised in sa, a situation that fuels both hiv and hepatitis transmission.7 south africa must move more rapidly to a clearer policy on the decriminalisation of sex work and of injecting-drug use. in addition, the sa government must give greater consideration to the flexibilities of trips where medicine prices are not being reduced to affordable levels. changes in the hiv epidemic over the past decade: estimates from the thembisa model in this report, we have used estimates from the thembisa 4.3 model, an integrated hiv/demographic mathematical model developed for sa. this assesses the impact of different hiv programmes at a national and provincial level. estimates from the thembisa 4.3 model were released in november 2020 ahead of world aids day 2020. prevalence of hiv the estimate is that there are 7.64 million people in the country living with hiv (plwh: 4.84 million females ≥ 15 years, 2.49 million males ≥ 15 years and 310 000 children < 15 years). the total number of plwh has increased from 5.9 million in 2010, an increase of 1.7 million between 2010 and 2019. incidence of hiv with respect to new hiv infections, there were 201 000 new hiv infections in 2018–2019: 121 000 in women, 67 000 in men and 11 600 infections from mother-to-child-transmission (mtct). the majority of the latter (69%) occurred during the breastfeeding period. the total number of new infections in 2009–2010 was 412 000 – which implies a 51% decline in new infections over the 2010–2019 period. however, it is more meaningful to assess changes in hiv incidence rates in 15–49-year-olds. changes in population growth and the population age distribution affect the absolute numbers of new infections. using this metric, hiv incidence rates in sa declined by 55% over the 2010–2019 period, with the decline being greatest in kwazulu-natal (kzn) (61%) and least in the province of the western cape (34%). this decline in hiv incidence in kzn was confirmed in population-based surveillance studies.8 in terms of the drivers of these declines in kzn, high coverage of vmmc and greater access to arvs have been suggested as contributory and recommended to be scaled up in other provinces.9 the highest thembisa-model hiv incidence-rates are in msm (2.60%) and female sex workers (fsws) (5.50%). however, there have been significant declines in these cohorts. the incidence in msm has declined from 5.69% and in fsws from 10.96% in 2010. although these are encouraging estimates, they largely reflect the impact of general hiv prevention and treatment programmes.10 interventions such as pre-exposure prophylaxis (prep), which has been provided to fsws and msm, still have low uptake and retention rates. the model estimates a 2019 prep coverage rate of 3% and 1% in fsws and msm, respectively. these groups require special attention with respect to prevention and significantly increased access to treatment. over the past decade, there has been concern about hiv-infection in adolescent girls and young women (agyw) aged 15–24 years. the thembisa model estimates that the incidence rate in this cohort has declined from 2.98% in 2008 to 1.30% in 2018. these reductions are largely because of increased hiv testing, arv coverage and high levels of condom use. whilst still unacceptably high, this decline is important. human immunodeficiency virus-incidence rates in adolescent boys and young men (abym) are lower in both 2008 and 2018 periods: 1.03% and 0.33%, respectively.10 gender inequalities and transmission of hiv from older men to agyw are posited as the main drivers of the incidence-differences between agyw and abym.11,12 new infections at birth have declined from 18 300 in 2010 to 3600 in 2019: a decline of 80%. this is a consequence of the greater proportion of infected mothers on art during pregnancy and at delivery, 32% in 2010 and 97% in 2019. however, the decline in new infections related to breastfeeding has been less dramatic: 22 000 (2010) to 8000 (2019) – a 63% decline. breastfeeding mothers need greater support from healthcare professionals and their families/communities. pre-exposure prophylaxis in pregnant and breastfeeding mothers can reduce vertical transmission by 40%.13 pre-exposure prophylaxis is safe in breastfeeding – with minimal infant-drug exposure.14 the use of prep as part of a comprehensive package of interventions in countries with a high hiv prevalence is endorsed by the who in both antenatal and postnatal care.15 prevention of hiv prevention starts with knowing one’s status. a combination of interventions accounts for prevention successes of the past decade. but greater effort is needed. test and treat the thembisa ‘ever-tested-for-hiv’ model estimates the percent of adults tested increased from 47.3% in 2010 to 76.3% in 2019. a total of 81% of sa women compared with 72% of men had ever-tested by 2019. condom use despite the provision of free male and female condoms by the sa government, their use at last sexual encounter increased marginally from 23% (2010) to 29% (2019) amongst women aged 25–49 years. only 27% of 15to 24-year-old females used a condom at their last sexual encounter. (note that the thembisa estimates are lower than self-reported rates as they are adjusted for social desirability-bias in self-reported data). as the most effective barrier method for the prevention of sexually transmitted infections (stis) and unplanned pregnancies, more attention needs to be paid to convince south africans of their value. circumcision south africa, supported by pepfar and the global fund, launched a large vmmc roll-out around 2008. the proportion of men aged 15–49 years who are circumcised has increased from 36.4% in 2010 to 57.5% in 2019. pre-exposure prophylaxis the national sa-prep programme was introduced in 2016 and provided oral prep to sex workers. the programme was expanded in 2017 to include college and university students at onsite health clinics. since 2018, prep has been provided in public health clinics. deaths associated with hiv the 2018–2019 estimate of hivand aids-related deaths in sa is 74 000 plwh: 31 000 deaths in women, 39 000 in males and 3900 in children. the higher number of male deaths follows men presenting late to facilities, fewer men knowing their status, fewer men on treatment. deaths have declined from 2009 to 2010 when it was estimated that there were 183 000 deaths – a 60% decline. as plwh live longer, they are likely to need care for comorbidities such as diabetes, hypertension and cardiovascular diseases.16 antiretroviral coverage thembisa 4.3 estimates that arv coverage increased from n = 530 877 (9.4%) in 2008 to n = 4 723 950 (62.7%) in 2018. whilst this is a large increase in arv coverage, males ≥ 15 years lag behind, increasing from 8.0% in 2008 to 57.2% by 2018. women’s art coverage was 9.9% in 2008 and 66.2% in 2018. performing worst of all are children < 15 years of age: from 11.3% in 2008 to 53.2% in 2018. increasing access and improving adherence to arvs for growing numbers of south africans means accessing the latest, safest and best-tolerated arvs at lowest cost. the newest (november 2019) of fixed-dose combinations in the sa public health sector is tld: tenofovir (tdf), lamivudine (3tc) and dolutegravir (dtg). whilst there are concerns about the long-term consequences of weight gain – greater in women than men, the combination is well tolerated and presents the virus with a high-barrier to resistance. paediatric-dtg in a dispersible tablet is an important advance for infants and children living with hiv who are ≥ 4 weeks of age and weigh at least 3 kilograms (kg). despite being endorsed by the who, paediatric-dtg has not as yet been registered for use in sa.17 meeting the unaids 90-90-90 targets how did sa do in the light of the unaids’ 90-90-90 targets? the thembisa estimates for adult women, males and children are presented separately to illustrate the variation across these groups (table 1). adult women in sa had reached 94-74-92 in 2019; adult males, 91-67-92 and children fared worst, 79-70-72. table 1 indicates a great deal of provincial variation. kwazulu-natal is the best performing province: 95% of adult kzn-women know their hiv status, 77% are on art and 95% of these are estimated to be virally suppressed. the worst performing provinces with respect to women living with hiv are gauteng (92-69-88) and north west (92-64-91). the latter does ‘better’ with children at 82-70-70, compared with the worst performing province, limpopo at 72-58-63. table 1: progress towards the 90-90-90 targets in 2019. conclusion at the beginning of each december since 1988, the global aids community and partners reflect on progress made in turning the tide on the hiv epidemic and consider the challenges as well as the work that remains to eliminate hiv as a public health threat. the year 2020 was especially challenging given the impact of the covid-19 pandemic on individuals, families, and the local and global community. health and social services were disrupted in many parts of the world making it difficult for people to access services. there is now a need for recovery and a reset to ensure that the gains made in the hiv programme, in sa and globally, are not lost and that we can accelerate towards the new targets that unaids18 has proposed – of achieving the expanded 95-95-95 targets by 2025, as well as removing punitive laws, decreasing stigma and discrimination, and decreasing gender inequality and violence. acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions y.p. conceptualised and wrote the first draft; l.j. provided the south african estimates and revised the draft. ethical consideration this article followed all ethical standards for research without direct contact with human or animal subjects. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability all data are secondary data, which are publicly available and referenced. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references unaids. prevailing against pandemics by putting people at the centre [homepage on the internet]. geneva; 2020 [cited n.d.]. available from: https://www.unaids.org/sites/default/files/media_asset/prevailing-against-pandemics_en.pdf hiv policy lab. 2020 global hiv policy report: policy barriers to hiv progress [homepage on the internet]. 2020 [cited n.d.]. available from: https://www.hivpolicylab.org/documents/reports/2020globalreport/2020%20hiv%20policy%20lab%20executive%20summary%20 johnson lf, dorrington re. thembisa version 4.3: a model for evaluating the impact of hiv/aids in south africa [homepage on the internet]. 2020 [cited n.d.]. available from: https://www.thembisa.org/ unaids. 90–90–90: good progress, but the world is off-track for hitting the 2020 targets [homepage on the internet]. 2020 [cited n.d.]. available from: https://www.unaids.org/en/resources/presscentre/featurestories/2020/september/20200921_90-90-90 world health organization. world aids day 2020: global solidarity and resilient hiv services [homepage on the internet]. 2020 [cited n.d.]. available from: https://www.who.int/news-room/events/detail/2020/12/01/default-calendar/world-aids-day-2020?utm_source=global+health+now+main+list&utm_campaign=f33aef1be0-email_campaign_2020_11_30_02_11&utm_medium=email&utm_term=0_8d0d062dbd-f33aef1be0-2890801 human rights watch. why sex work should be decriminalized [homepage on the internet]. 2019 [cited n.d.]. available from: https://www.hrw.org/news/2019/08/07/why-sex-work-should-be-decriminalized scheibe a, shelly s, versfeld a. prohibitionist drug policy in south africa – reasons and effects. int dev policy. 2020; pt 3(12). https://doi.org/10.4000/poldev.4007 vandormael a, cuadros dc, kim h-y. the state of the hiv epidemic in rural kwazulu-natal, south africa: a novel application of disease metrics to assess trajectories and highlight areas for intervention. int j epidemiol. 2020;49(2):666–675. https://doi.org/10.1093/ije/dyz269 vandormael a, akullian a, siedner m, et al. declines in hiv incidence among men and women in a south african population-based cohort. nature. 2019;10(1):5482. https://doi.org/10.1038/s41467-019-13473-y johnson l, meyer-rath g, dorrington r et al. the effect of hiv programmes in south africa on national hiv incidence trends, 2000–2017. poster presentation at the 23rd international aids conference. san francisco, ca: international aids society; 2020 july 6–10. birdthistle i, tanton c, tomita a, et al. recent levels and trends in hiv incidence rates among adolescent girls and young women in ten high-prevalence african countries: a systematic review and meta-analysis. lancet glob health. 2019;7(11):e1521–e1540. https://doi.org/10.1016/s2214-109x(19)30410-3 de oliverira t, kharsany abm, graf t, et al. transmission networks and risk of hiv infection in kwazulu-natal, south africa: a community-wide phylogenetic study. lancet hiv. 2017;4(1):e41–e50. https://doi.org/10.1016/s2352-3018(16)30186-2 davey dlj, bekker l-g, gomba y, et al. modelling the potential impact of providing preexposure prophylaxis in pregnant and breastfeeding women in south africa. aids. 2019;33(8):1391–1395. https://doi.org/10.1097/qad.0000000000002221 mugwanya kk, hendrix cw, mugo nr, et al. pre-exposure prophylaxis use by breastfeeding hiv-uninfected women: a prospective short-term study of antiretroviral excretion in breast milk and infant absorption. plos med. 2016;13(9):e1002132. https://doi.org/10.1371/journal.pmed.1002132 world health organization. preventing hiv during pregnancy and breastfeeding in the context of prep: technical brief [homepage on the internet]. 2017 [cited n.d.]. available from: https://www.who.int/hiv/pub/toolkits/prep-preventing-hiv-during-pregnancy/en/ mathebula rl, maimela e, ntuli ns. the prevalence of selected non-communicable disease risk factors among hiv patients on anti-retroviral therapy in bushbuckridge sub-district, mpumalanga province. bmc public health. 2020;20(1):247. https://doi.org/10.1186/s12889-019-8134-x who. who welcomes fda approval of new formulation of dolutegravir for young children living with hiv [homepage on the internet]. 2020 [cited n.d.]. available from: https://www.who.int/news/item/18-06-2020-who-welcomes-fda-approval-of-new-formulation-of-dolutegravir-for-young-children-living-with-hiv unaids. 2025 aids targets: putting people living with hiv and communities at risk at the centre [homepage on the internet]. geneva; 2020 [cited n.d.]. available from: https://aidstargets2025.unaids.org/ about the author(s) david c. spencer division of infectious diseases, department of medicine, helen joseph hospital, university of the witwatersrand, johannesburg, south africa citation spencer dc. the editor’s review of articles published from august to december 2019 in the southern african journal of hiv medicine. s afr j hiv med. 2020;21(1), a1120. https://doi.org/10.4102/sajhivmed.v21i1.1120 editorial the editor’s review of articles published from august to december 2019 in the southern african journal of hiv medicine david c. spencer copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. august 2019 1. woods j, moorhouse m, knight l. a descriptive analysis of the role of a whatsapp clinical discussion group as a forum for continuing medical education in the eastern cape, south africa. s afr j hiv med. 2019;20(1):a982. https://doi.org/10.4102/sajhivmed.v20i1.982 editor’s comment: in the year following my internship (1976), i worked at mseleni hospital, then a small 120-bed hospital in a remote corner of kwazulu-natal (kzn) province, south africa. for much of the time, i was the only doctor. one of the highlights was the thursday night radio call-in to discuss cases with colleagues at manguzi and bethesda, similar rural hospitals in northern kzn. i was a rookie. darryl hackland and pat garde (bethesda) and cliff allward (manguzi) were my lifeline. another was the periodic weekend fly-in of durban-based university of kzn academics who would assist with surgery and walk through the wards with me. this observational study of the role of a whatsapp group gives that story of a 21st-century twist. the goal of the authors was to assess the educational value of a whatsapp group of 166 experienced and inexperienced doctors in rural public hospitals and clinics in the eastern cape province of south africa and to ask whether the whatsapp discussion was helpful and whether informed consent and privacy rules were breached. all the patients had complicated human immunodeficiency virus/tuberculosis (hiv/tb) co-infection. the study was undertaken between january 2016 and july 2017. the whatsapp groups were given a short questionnaire and asked to submit answers anonymously. although 86% of respondents replied that the group had given them ‘improved confidence and ability in managing sick patients’, and 52% said they used the guidance they had received ‘all the time’, many in the whatsapp group (n = 74/166; 45%) never actually posted a response. moreover, whilst answers such as ‘i use the guidance to manage patients’, ‘i refer to previous whatsapp cases’, ‘i gained new clinical insights’ and so on reached statistical significance, that is, suggesting that clinical confidence had been increased, high odds ratios and wide confidence intervals suggest important limitations (table 3 in the article). does posting patient data risk a breach of doctor–patient ethics? eighty-nine per cent of respondents agreed with the fact that informed consent would be required before posting patient-related data; however, in reality only 52% did this. and what about those registered on the programme who never appeared to participate? was this a valuable learning experience for them? perhaps, an analysis of the differences between the 50% who did not post cases and the 3% who did so frequently might answer this question. 2. mugusi sf, mopei n, minzi o. adherence to combination antiretroviral therapy among orphaned children in dar es salaam, tanzania. s afr j hiv med. 2019;20(1):a954. https://doi.org/10.4102/sajhivmed.v20i1.954 editor’s comment: adherence to antiretroviral therapy (art) is examined in this cross-sectional study of 216 tanzanian orphans aged 2–14 years. all the children were hiv-positive and had been on nevirapine (nvp)-based art for a minimum of 6 months. the study was conducted from june to september 2015. adherence was measured in three ways: a 3-day recall of pill-taking behaviour (caregiver questioned), the historical regularity/reliability of clinic attendance and the monitoring of nvp-blood levels on study entry. viral load levels are not supplied. likely not available. on recall, 79.6% of children had not missed any doses, and 82.9% gave a history of regular clinic attendance. yet, therapeutic levels of nvp, namely ≥ 3 µg/ml, were detected in only 72.2% of patients. on multivariate analysis, higher nvp levels were protective of unreliable clinic attendance (unadjusted odds ratios [uor] 0.45, 95% confidence interval [ci] 0.21–0.95, p = 0.04) and linked positively to higher cd4 levels, namely > 25% and counts >500 cells/mm³, p = 0.001. orphans missing both parents were at greater risk of low nvp blood levels, namely, uor 1.37, 95% ci 0.69–2.68. sub-therapeutic nvp levels were less likely amongst those orphans who were aware of their hiv status, that is, had experienced full disclosure (uor 0.65, 95% ci 0.34–1.24). the limitations of this study are important: the cross-sectional design, the absence of an age-matched ‘non-orphan’ comparator-arm, reliance on caregiver ‘self-reporting’ and the wider lack of applicability of blood nvp levels to adherence management in africa. the fact that viral loads are still not routinely available everywhere in sub-saharan africa is an inescapable subtext to this study. is therapeutic nvp monitoring needed in africa? it added value to this study. however, a wider role will be limited by costs and accessibility. 3. vujanovic m, brkic-jovanovic n, ilic d, et al. associations of visceral fat thickness and anthropometric measurements with non-alcoholic fatty liver development in male patients mono-infected with human immunodeficiency virus. s afr j hiv med. 2019;20(1):a968. https://doi.org/10.4102/sajhivmed.v20i1.986 editor’s comment: in this article from serbia, 88 hiv-positive men on antiretroviral therapy (art) were enrolled in a study evaluating a link between visceral fat thickness (vft) as measured with abdominal ultrasound and the routine anthropometric measurements of obesity, cardiovascular risk and non-alcoholic steatohepatitis (nash). the study took place over 18 months between september 2016 and april 2018. the average age of the men was 39.9 ± 9.9 years and the following anthropometric measurements were taken: waist and hip circumference (wc, hc), waist–hip and waist–height ratios (w/hipr, w/htr) and the body mass index (bmi). hepatic steatosis was diagnosed on sonography. those with steatosis were more likely to have elevated random blood glucose levels, raised bmi and raised wc, hc, w/hipr and w/htr in addition to elevated vft (p < 0.001). age ≥ 38.5 years was associated with an increased risk of the condition; 90.6% of those aged > 38.5 years with a vft > 31.98 mm had hepatic steatosis. the authors discuss these results in the context of lowand middle-income countries where access to reliable non-invasive tests for hepatic steatosis is limited. the study limitations include its cross-sectional design, the absence of women and children and the lack of detailed information on antiretrovirals used by the men and the duration of their treatment. 4. diana ne, feldman c. measles in adults: a comparison of hospitalised hiv-infected and hiv-uninfected patients. s afr j hiv med. 2019;20(1):a877. https://doi.org/10/4102/sajhivmed.v20i1.877 editor’s comment: south africa experienced an unusually large outbreak of measles between 2009 and 2011. in this descriptive study from the wards of the charlotte maxeke johannesburg academic hospital, the authors present data on hiv-positive adults with laboratory-confirmed measles. thirty-three adults with measles were identified, of whom 24 underwent hiv testing. of the 24 tested for hiv, 18 (75%) were hiv-positive and six were hiv-negative. the remainder of the adult measles group (n = 9) were not tested. most of the hiv-positive were women (13/18; 72%). although the authors remarked that demographics, clinical findings and laboratory data between the hiv-positive and hiv-negative patients were similar, serious disease, for example, pneumonia and respiratory failure, was more frequent in the hiv-positive (or 5.0, 95% ci 0.48–51.8, p = 0.34). the duration of hospital stay for the hiv-positive patients was significantly longer (p = 0.03), and of the three adult measles deaths, all were in the hiv-positive (or 2.9, 95% ci 0.13–65.3, p = 0.56). the median cd4 count of the hiv-positive patients was 109 cells/mm³. unfortunately, the authors do not provide further analysis, for example, individual cd4s, viral loads, antiretroviral therapy used and microbiology of the secondary infections. do hiv-positive adults exposed to measles require re-vaccination or vaccination if this was missed in childhood? this is not addressed in this article, which is an important question. according to loevinsohn (2019:836–844, in suggested reading below), ‘the measles vaccine should be given to potentially susceptible but asymptomatic hiv-positive adults and be considered for those with symptomatic hiv infection even if not severely immunosuppressed’. suggested additional reading loevinsohn g, et al. measles seroprevalence and vaccine responses in human immunodeficiency virus-infected adolescents and adults: a systematic review. clin infect dis. 2019 aug 16;69(5):836–844. https://doi.org/10.1093/cid/ciy980. moss wj. measles. seminar. lancet. 2017;390:2490–2502. https://doi.org/10.1016/s0140-6736(17)31463-0 measles vaccination: a who position paper. april 2017. recommendations. vaccine. 2019 jan 7;37(2):219–222. https://doi.org/10.1016/j.vaccine20178.07.066). 5. van elsland sl, peters rph, grobbelaar c, et al. disclosure of human immunodeficiency virus status to children in south africa: a comprehensive analysis. s afr j hiv med. 2019;20(1):a884. https://doi.org/10.4102/sajhivmed.v20i1.884 editor’s comment: recommended reading. in this cross-sectional study from the western cape, the authors ask the following questions: how many children know their hiv status and what factors assist our understanding of non-disclosure? it is a well-written report with data that deserve a wide audience. the total cohort was 185. all were on antiretroviral therapy and their ages ranged from 3 to 14 years. most (145; 76.3%) had not experienced full disclosure, whilst 17 (8.9%) had experienced. a further 28 (14.7%) received ‘partial’ disclosure. the cross-sectional nature of the study, the small number of ‘disclosed’ children and the dependence on questionnaires, clinic records and caregiver’s reports would have introduced limitations but the take-home messages are worth noting: disclosure was more likely to have occurred amongst older children and those whose caregivers were more highly educated. the latter were more likely to be men, although less than 10% of the study’s caregivers were men. indeed, disclosure was less likely if the caregiver was a woman, if children had detectable viral loads and if the child was still taking ‘syrup’ formulations of the antiretrovirals , namely, a younger group, if the child was noted by the caregiver to be non-adherent and if the child was on protease inhibitors, stavudine (d4t) and/or didanosine (ddi). this article provides the readers with credible information. figure 1 in this article will also give hiv educators a useful outline to the important associations that promote disclosure/non-disclosure. 6. schutz c, ward a, burton r, et al. false rifampicin results using xpert mtb/rif on urine samples in hospitalised hiv-infected patients. s afr j hiv med. 2019;20(1):a978. https://doi.org/10.4102/sajhivmed.v20i1.978 editor’s comment: recommended reading. this study is from colleagues in cape town. urine samples were collected prospectively from hiv-positive patients with microbiologically proven active tb in two independent cohorts between 2012 and 2016. multiple samples from each patient – including sputum, blood, tissue and urine – were subjected to culture, gene xpert (including xpert ultra) and line probe analysis (lpa). a total of 1704 urine xpert results were available from 1171 patients. four hundred and sixteen (24.4%; 95% ci 22.4–26.5) of the urine xpert results were positive for mycobacterium tuberculosis (mtb) and 43/413 (10.4%) were rifampicin resistant on xpert analysis. of the latter group, 30/41 were confirmed to be truly rifampicin resistant, yielding a positive predictive value of 73.2% (95% ci 57.1–85/8). urine tests from patients not on tb therapy at the time of assessment gave more true-positive rifampicin-resistant xpert results (85.7%, 95% ci 67.3–96.0) than the urine of those on tb treatment (53.8%, 95 ci 25.1–80.8). about 11/43 urine results were falsely positive for rifampicin resistance (25.6%, 95% ci 13.5–41.2). three patients in the urine xpert rifampicin-resistant group were found to have concurrent rifampicin-sensitive tb on alternative specimens tested simultaneously, that is, ‘hetero-resistant tb’. this article is a stimulating read and feeds the reader’s mind – a compulsory reading for clinicians, particularly infectious diseases colleagues, fellows and registrars!! 7. ekermans p, de gama r, kock c, et al. an unusual case of abdominal mycobacterial infection: case report and literature review. s afr j hiv med. 2019;20(1):a993. https://doi.org/10.4102/sajhivmed.v20i1.993 editor’s comment: highly recommended. in this case report, dr ekermans and colleagues describe an hiv-positive 8-year-old’s experience of acquired immunodeficiency syndrome in south africa. the author does a great job of describing the difficulties in confirming the diagnosis and isolating the organism. the histological and radiographic plates are superb: clear and compelling. the author tells this story with compassion and respect for his subject. the art and science of medicine shine on these pages. this is how we learn medicine, and how we become better doctors. i loved this read and recommend it to all who read this journal. 8. atuhaire c, taseera k, spoor c, cumber ry, cumber sn. knowledge and perceptions of male immigrants in leeds (uk) towards male circumcision as an hiv-prevention strategy. s afr j hiv med. 2019;20(1):a823. https://doi.org/10.4102/sajhivmed.v20i1.823 editor’s comment: whilst the estimated prevalence of hiv infection in the united kingdom (uk) is low, namely, ≤ 1.5 per 1000 persons, that of uk immigrants from eastern and southern africa is far higher, namely, 25–50 per 1000 persons. would medical male circumcision (mmc) be considered by these immigrants as a means of preventing hiv transmission? only 10 persons were interviewed in a snowball recruitment study of contacts from a local church in leeds, uk. the participants expressed little or no knowledge of circumcision as an hiv-preventive tool. instead and despite the group’s roots from the epicentre of the epidemic, circumcision is still merely a ‘rite of passage’. whilst the study limitations are obvious, it begs the question of the universality of hiv dogma. in the west, ‘treatment as prevention’ has replaced mmc. with current dogma promoting universal ‘test and treat (utt)’ and ‘immediate art for all’, should we be talking about mcc in high-income countries? and what of its future in middleand low-income regions in the face of more effective preventive measures? and how effectively has mmc changed attitudes to hiv prevention in eastern and southern africa? september 2019 9. manickchund n, du plessis c, john m-a, et al. case report. emtricitabine-induced pure red cell aplasia. s afr j hiv med. 2019;20(1):a983. https://doi.4102/sajhivmed.v20i1.983 editor’s comment: in this article, the authors report a female patient with pure red-cell aplasia. she was 35 years of age in 2014, pregnant, anaemic at baseline (haemoglobin [hb] = 8.2 g/dl) and had a low cd4 count (83 cells/mm3). two months after starting first-line art, namely, tenofovir + emtricitabine (ftc) + efavirenz, she was found to be severely anaemic: hb = 2.2 g/dl, normocytic normochromic. her hiv infection was under control. workup included a bone marrow examination, which revealed a pure red cell aplasia and a positive parvovirus b-19 polymerase chain reaction (pcr). the patient received intravenous immune globulin (ivig) for 5 days and packed red cells. over the next 11 months, she required multiple transfusions and six more courses of ivig. her art was changed and the ftc stopped: tenofovir + abacavir + efavirenz, after which the anaemia resolved. however, the patient’s parvovirus b19-pcr remained positive (2017). a role for lamivudine (3tc) and emtricitabine in pure red cell aplasia has been suggested by multiple reports over the past two decades. this report is a reminder of this rare drug-related toxicity. suggested additional reading tsukamoto t. hematopoietic stem/progenitor cells and the pathogenesis of hiv/aids. front cell infect microbiol. 2020 feb 21;10:60. https://doi.org/10.3389/fcimb.2020.00060 durandt c, potgieter jc, mellet j, et al. hiv and haematopoiesis. s afr med j. 2019 sep 10;109(8b):40–45. https://doi.org/10.7196/samj.2019.vi09:8b.13829 knuesel sj, sawalla guseh j ii, karp leaf r, ciaranello al, eng gm. case 6-2018: a 35-year-old woman with headache, subjective fever, and anemia. n engl j med. 2018;378:753–760. https://doi.org/10.1056/nejmcpc1712223 10. cloete cm, hampton j, chetty t, et al. evaluation of a health system intervention to improve virological management in an antiretroviral programme at a municipal clinic in central durban. s afr j hiv med. 2019;20(1):a985. https://doi.org/10.4102/sajhivmed.v20i1.985 editor’s comment: ‘what are the gaps in service delivery that allow for clinical failure/poor viral control?’ this is a detailed, prospective clinic-based study undertaken between 2011 and 2015. the investigators divided the study into three periods: pre-intervention, intervention and post-intervention. the intervention required checking every 10th patient file (n = 1538) with (1) an in-depth file review, (2) recording of viral loads (vl) and the ‘retention-in-care’ status of the client and (3) an assessment of the ‘viral load-management process’. gaps were identified and interventions were implemented. outcome measurements improved over the 4 years of the study, namely, the number of appropriate vl tests and the filing of results increased from 78% to 92% (p = 0.0009), the number of patients who accessed their vl result increased from 59% to 86% (p < 0.0001) and fewer patients, from 81% to 27%, required changes to antiretroviral therapy (art) following the intervention. the detailed description in this report suggests a huge commitment from the clinic staff and the research team. sustainable? the study required outside funding and the salaries of additional staff. sustainable? gaps are noted: continuing high patient volumes, the ongoing and urgent priority of art-initiation, the need for and absence of dedicated pharmacists in hiv clinics and so on. the authors point out that the third unaids 90 or (95)% goal is achievable, that is, reliable long-term vl suppression by 2030. this sounds optimistic. ‘is this effort reproducible on a large scale?’ 11. kummerow m, shaddock ej, klipstein-grobusch k, et al. unexpected low frequency of respiratory symptoms in an hiv-positive urban sub-saharan population compared to an hiv-negative control group. s afr j hiv med. 2019;20(1):a1010. https://doi.org/10.4102/sajhivmed.v20i1.1010 editor’s comment: this is a cross-sectional study of 547 adults living in johannesburg between july 2016 and november 2017. two-thirds of the patients were people living with hiv (plwh) (n = 347, 63%). the remainder were hiv-negative matched controls. the median age of the patients was 37 years. two-thirds (62%) were women. recruits were asked about cough, cough accompanied by mucus or phlegm, breathlessness, wheeze and so on. the participants were also examined, had their blood tested (hiv status confirmed, hiv viral load [vl] and cd4 cell count) and completed a ‘quality of life’ questionnaire. the plwh were subdivided into three groups: ‘the antiretroviral therapy (art)-naïve’ (26%), ‘on first-line art’ (24%) and ‘on second-line art’ (50%). those on art were recruits from randomised controlled trials (rcts) and demonstrated a high level (> 90%) of viral suppression. their cd4 levels (median) were largely normal: namely, first-line art, cd4 = 413.5 (range: 278.5–574.3) and second-line art, cd4 = 619 (range: 429–798) cells/mm3, respectively. those ‘initiating’ therapy, that is, naïve to art when tested, also demonstrated relatively preserved median cd4 levels, namely, cd4 = 281 (range: 191–400.8) cells/mm3. moreover, indeed, the authors note that ‘the frequency of respiratory symptoms did not differ by hiv status after adjustment for age and sex’. ‘breathlessness (however) was associated with older age, female sex, obesity, a previous history of respiratory infection and airway hyper-reactivity (asthma)’. chronic lung disease has been described in africans living with hiv. the participants in this study were young and most had accessed reliable art for several years, exhibited immune (peripheral cd4 cell) reconstitution and reliable viral suppression. how should hiv clinicians be monitoring the health of our patients’ respiratory tract? will the coronavirus disease 2019 (covid-19) pandemic require a rethink of our patients’ respiratory safety? suggested additional reading desai sr, nair a, rylance j, et al. human immunodeficiency virus-associated chronic lung disease in children and adolescents in chest radiographic and high-resolution computed tomographic findings. clin infect dis. 2018;66(2):274–281. https://doi.org/10.1093/vid/cix778 shaddock ej, richards ga, murray j. lung fibrosis in deceased hiv-infected patients with pneumocystis pneumonia. s afr j hiv med. 2012;13(2):64–67. 12. bharuthram n, feldman c. the diagnostic utility of bone marrow examination in an infectious diseases ward. s afr j hiv med. 2019;20(1):a974. https://doi/org/10.4102/sajhivmed.v20i1.974 editor’s comment: this is a retrospective review of consecutive bone marrow aspirate and trephine (bmat) examinations of 327 patients admitted to the infectious diseases ward of a large academic hospital in johannesburg from 2012 to 2014. most of the patients (314;96%) were people living with hiv (plwh). ‘what is the utility of bmat in the context of hiv infection?’ a peripheral white blood cell (wbc) cytopenia of ≤ 4 × 109/l predicted a ‘unique’ diagnosis (odds ratio [or] 2.38, 95% ci 1.37–4.14, p = 0.002) and the likelihood of a mycobacterial infection (or 2.11, 95% ci 1.28–4.41, p = 0.005). ‘unique’ diagnoses mean diagnoses found only on bmat despite extensive alternate investigation or achieved before the results of other tests were available or known. unique diagnoses occurred in 77 (23.5%) patients and were mycobacterium tuberculosis (mtb) in 17/77 (22%) and mycobacterium avium complex (mac) in another three patients. three bmats each provided ≥ 1x ‘unique’ diagnosis, for example, tb and cancer. proven or suspected mycobacterial disease accounted for 57 bmats with granulomas, culture-proven mtb without supportive histology in 50 and mtb confirmed with granulomas in 32 patients. the limitations of this study include its retrospective format, inherent case selection bias and, sadly, the absence of newer diagnostic tools such as sputum and urine mtb-rif-resistance gene-xpert, gene-xpert ultra and urine lipoarabinomannan (lam). the latter is particularly disappointing as these molecular diagnostics are currently changing the face of clinical medicine. 13. mehta uc, van schalkwyk c, naidoo p, et al. birth outcomes following antiretroviral exposure during pregnancy: initial results from a pregnancy exposure registry in south africa. s afr j hiv med. 2019;20(1):a971. https://doi/org/10.4102/sajhivmed.v20i1.971 editor’s comment: recommended reading. although international first-line art guidelines have replaced nevirapine (nvp) and efavirenz (efv) with dolutegravir (dtg), concerns remain regarding the safety of art in pregnancy. dolutegravir is teratogenic in the first trimester of pregnancy. women living with hiv and planning a family and those diagnosed with hiv in the first trimester should not use dtg. this article addresses the safety of nvp and efv in pregnancy in a cohort of pregnant south african (sa) women. in 2013, the sa national department of health promoted the introduction of a birth-outcomes registry amongst pregnant women and their infants exposed to arvs. the authors report on the first 12 months of this programme (2013–2014). two outcomes were assessed: major congenital malformations (cms) following arv exposure in the first trimester of pregnancy. adverse birth outcomes (abos), namely, foetal death, preterm delivery, low birth weight, small for gestational age and neonatal death, following arv exposure at any time during pregnancy. data were collected at the prince mshiyeni memorial hospital in umlazi, durban, south africa. a total of 10 417 pregnancies and 10 517 birth outcomes were captured. the overall prevalence of hiv infection was 4013/10 417 (38.5%). a higher prevalence was noted in women > 35 years (640/1100; 58%) and in multigravida versus primigravid women (49.2% vs. 21.9%), respectively. the numbers of major cms were small. about one-third of cases were in infants of mothers who were on art (11/27; 29.7%). compared to hiv-negative pregnant women unexposed to arvs, first-trimester exposure to efavirenz in hiv-positive women did not increase the risk of cm (risk ratio [rr] 0.87, 95% ci 0.12–6.4, p = 0.895). however, first-trimester nvp exposure may increase the risk: rr 9.2, 95% ci 2.27–37.94, p = 0.002. this finding may have been influenced by confounders (e.g. small numbers) and thus requires more data or confirmation. the risk of abos was greater in infants of mothers with exposure to art at any time throughout pregnancy versus hiv-uninfected mothers (rr 1.23, 95% ci 1.14–1.31, p < 0.001) but particularly where efv or nvp use had started before the pregnancy. this report is published at a time when guidelines are changing. the non-nucleoside reverse transcriptase inhibitors (nnrtis) are being phased out of first-line regimens. but women unable to take dtg are likely to be given efv or perhaps nvp. this is a high-end paper that is informative and supports the long-term role of efv in women for whom dtg is contraindicated. suggested additional reading zash r, holmes l, diseko m, et al. neural tube defects and antiretroviral treatment regimens in botswana. n eng j med. 2019 aug;381(9):827–840. https://doi.org/10.1056/nejmoa1905230 the national department of health, the republic of south africa. 2019 antiretroviral treatment guidelines for the management of hiv in adults, pregnancy, adolescents, children, infants and neonates. october 2019. dolutegravir overview, art initiation, p. 8. available from: https://www.health.gov.za october 2019 14. cele ma, archary m. acceptability of short text messages to support treatment adherence among adolescents living with hiv in a rural and urban clinic in kwazulu-natal. s afr j hiv med. 2019;20(1):a976. https://doi.org/10.4102/sajhivmed.v20i1.976 editor’s comment: this article reports the results of a small, questionnaire-based, cross-sectional, pilot study of 100 adolescents (aged 12–19 years) from two clinic sites – one urban (n = 50) and the other rural (n = 50) in kwazulu-natal, south africa. poor retention in care and unreliable treatment adherence challenge the success of antiretroviral therapy (art) in this group of patients. will text messaging remedy the problem? the authors confirm the widespread use (88%) of mobile devices amongst rural and urban respondents. although two-thirds of participants were willing to receive their health information messages through mobile devices, others were unwilling or undecided. higher education was found to be linked with greater mobile device usage. but who are those – people living with hiv – who are unwilling or undecided? did the potential breach of privacy and the risk of unsanctioned disclosure via their smartphone inform the negative response? forty-eight per cent of the cohort had never sent health-related short message services (smss) to or received (fewer) such messages from their clinic or health professionals. who are these 12–19-year-olds who are unwilling or undecided? are these the ones who will be lost to care and fail adherence? how do we ensure these also become confident, understand their rights and are assisted to adhere to art? 15. van wyk b, davids l-a. challenges to hiv treatment adherence among adolescents in a low socio-economic setting in cape town. s afr j hiv med. 2019;20(1):a1002. https://doi.org/10.4102/sajhivmed.v20i1.1002 editor’s comment: this is a descriptive record of challenges faced by 15 adolescents (aged 10–19 years) living with hiv since birth, and receiving support from a primary care clinic in the greater cape town district. the participants were interviewed in 2016 and had been on antiretroviral therapy for a minimum of 6 months. group and individual discussion focused on barriers to and facilitators of adherence. the themes identified by the authors are not new: the conflict between school and clinic, the need for greater ‘hiv-competency’ of households and the provision of adolescent-friendly health services. limitations are acknowledged: small numbers, incomplete data saturation and the absence of a wide spectrum of views including that of defaulters. however for me, the strength of this study includes the verbatim comments of the participants. for a brief moment, the reader hears what it is like to be young and stigmatised and shamed by hiv and aids. this is why adherence is so difficult. it is not simply a matter of healing our youth; it is rather about society and the ongoing wider response to people living with hiv. 16. moodley k, bill pla, patel vb. motor lumbosacral radiculopathy in hiv-infected patients. s afr j hiv med. 2019;10(1):a992. https://doi.org/10.4102/sajhivmed.v20i1.992 editor’s comment: this is a short report of 11 young (median age = 29 years) people living with hiv naïve to antiretroviral therapy (art), who experienced a slowly progressive, bilateral and symmetrical, isolated, lower motor neurone weakness of the lower limbs. the latter were areflexic and flaccid. the remainder of the neurological examination, including higher function, sensation and sphincter control, were normal. a diagnosis of subacute motor lumbosacral radiculopathy was made. the mean duration of symptoms was 6.5 months (interquartile range [iqr] 3–7.5 months). six were female patients. cerebrospinal fluid (csf) was notable for an elevated protein and the presence of mononuclear cells. tests for malignancy and various infecting organisms were negative. the group’s median cd4 cell count was 327 cells/mm3 (iqr 146 cells/mm3 – 457 cells/mm3). unfortunately, serum and csf hiv viral load levels were not drawn. on magnetic resonance imaging (mri), gadolinium enhancement was visible in the lumbar ventral roots. electromyography (emg) confirmed abnormal activity of the lumbar and lower limb muscles. all the patients were treated for up to 4–6 weeks, with large amounts of oral prednisone (1.5 mg/kg/day). steroids were sometimes given for longer periods. no steroid toxicity and no intercurrent (opportunistic) infection (e.g. tb and fungal) were reported. antiretroviral therapy was not started immediately and no patient was on arvs at the time of diagnosis. ninety-one per cent of patients recovered within 3.4 months. all except one with mild residual weakness were ‘normal’ at the final 18-month follow-up visit. the authors – from the neurology department of the university of kwazulu-natal (ukzn), durban, south africa – discuss the differential diagnosis and point out that since the rollout of ‘universal test and treat’ in 2017, few additional cases have been reported. 17. laughton b, naidoo s, dobbels efmt, et al. neurodevelopment at 11 months after starting antiretroviral therapy within 3 weeks of life. s afr j hiv med. 2019;20(1):a1008. https://doi.org/10.4102/sajhivmed.v20i1.1008 editor’s comment. recommended reading. this is an important, prospective, observational study of 29 infants born to mothers living with hiv (mlwh). all infants were started on antiretroviral therapy (art) within 21 days of their birth. twenty-four of the mothers (83%) were on art at the time of delivery. twenty-three (79%) infants were females. infant viral load (vl) level at birth was 3904 (the median infant vl level at birth was 3904 (range, 259-16,022) copies/ml. viral suppression (vl < 400 copies/ml) on art occurred at 19.1 weeks (median, range 15, 36) of age. the global griffiths mental development scales (gmds), an early neurodevelopmental assessment tool, found the infant’s developmental scores to be normal at 11.5 ± 0.8 months. this was despite the fact that 9/29 (31%) infants had a detectable bloodstream vl at the time. of the five central nervous system (cns) domains assessed, locomotor skills scored the lowest and hearing and language the highest. the authors acknowledge that this study is small and the results are preliminary. nonetheless, these data suggest that art started at this extremely young age is safe and beneficial. the authors inform us that a larger study is already underway. this article is another milestone along the way to beating the virus and to the well-being of future generations, 18. archary m, fairlee l, slogrove a. opinion piece. current perspectives on paediatric hiv management from the mexico international aids society conference, 2019. s afr j hiv med. 2019;20(1):a1027. https://doi.org/10.4102/sajhivmed.v20i1.1027 editor’s comment: recommended reading. this is a summary of presentations and discussions held at the following meetings: the 11th international workshop on pediatric hiv and the 5th workshop on children and adolescents hiv-exposed and uninfected, and the international aids society (ias) conference in mexico, july 2019. the authors remark that despite general success in controlling vertical transmission, there were 160 000 new global paediatric hiv infections in 2018. they further add that ‘sub-saharan africa is struggling with meeting unaids 90-90-90 goals for children and adolescents living with hiv’. this is nevertheless an optimistic report that focuses on antiretroviral treatment and the prevention of vertical transmission of hiv. new antiretrovirals and a new delivery system: gs-6207 is the first of the capsid-inhibitor arv class but currently no paediatric studies have been reported. adult trials are promising. treatment = long-acting, s/c administration every 3 months. mk-8591, the first nucleoside reverse transcriptase translocation-inhibitor. no paediatric data but adult studies = prolonged intracellular half-life and low once a week dosing. no cross-resistance to other nucleoside-reverse transcritpase inhibitors (nrtis). an adult fixed-dose combination (fdc) in trials: mk-8591+doravirine. a paediatric formulation is possible. tenofovir alafenamide (taf) in children, a new nrti with lower renal and bone demineralisation risk and an fdc formulation for children aged > 6 years and weighing ≥ 25 kg: taf/ftc/elvitegravir+cobicistat. of a variety of novel drug delivery systems, the adult transdermal adhesive micro-needle skin patches that deliver monthly cabotegravir offer new therapeutic or prevention options with potential for paediatric application. antiretroviral drug efficacy and safety: birth defects. the risk of neural tube defects in infants exposed to dolutegravir (dtg) during periconception (first-trimester of pregnancy) appears to be confirmed with updated data from botswana’s tsepamo birth surveillance study. nevertheless, the world health organization recommends dtg-based antiretroviral therapy (art) for all women of child-bearing potential who are living with hiv. women who are not pregnant must be counselled regarding contraception. and counselling of all women must ensure that the decision for either a dtg or an efavirenz (efv)-based art is a fully informed decision and decided ahead of the start of art. children who are hiv-exposed but uninfected (cheu) enrolled in the international antiretroviral pregnancy registry (apr) had lower birth weightand length-for-age compared to unexposed, uninfected children. zimbabwe’s shine study also reported stunting and mortality risk to cheu (see comment summary 13 above). metabolic effects of art. exposure of adults to art (the south african advance study) uncovered significant weight gain in all study arms but especially those given both dtg+taf/ftc. what drug-related toxicity is emerging and what does this mean for children on these drugs? public health, art and children. paediatric retention in care and viral load (vl) suppression rates are suboptimal in southern africa. adolescent mortality and morbidity risk is too high. according to the international epidemiologic databases to evaluate aids – southern africa (iedea-sa) collaboration data 2004–2017, ‘children lag behind’. readers are encouraged to check out this ‘opinion piece’ for themselves. its background is the success of the prevention of mother-to-child transmission of hiv. its reality is the day-to-day management of young people living with hiv. 19. dunlop jl, slemming w, schnippel k, et al. breast abnormalities in adolescents receiving antiretroviral therapy. s afr j hiv med. 2019;20(1):a1017. https://doi.org/10.4102/sajhivmed.v20i1.1017 editor’s comment: this is a retrospective report of abnormal breast development in adolescents aged 10–19 years. all were on antiretroviral therapy (art). the article reflects january–december 2014 clinical records of 631 johannesburg-based adolescents living with hiv (alwh). of the patients, 37 (5.9%) had ‘abnormal’ breasts. of those with abnormal breasts, most (24; 65%) were men (p = 0.043). median duration of art was 4.9 years. the older adolescents (p < 0.0005) and those on efavirenz (efb)-based art (p = 0.016) were more likely to have breast problems. ninety-two per cent (34/37) were on efv, whilst the remaining 8% were on lamivudine (3tc) monotherapy, that is, they were likely to have been on efv previously. (the prevalence of efv use amongst those with normal breasts – the comparator group – was lower, namely n = 384/594;74.3%). the use of boosted-protease inhibitors, such as lopinavir or ritonavir, atazanavir and darunavir, was not associated with breast changes. although lipodystrophy was recorded in 46.3% and gynecomastia in 29% of those with breast changes, body mass index-confirmed overweight or obesity was found in only eight (19.5%) participants. more than 70% had viral suppression (vl < 50 copies/ml) and immune reconstitution (cd4 count ≥ 500 cells/mm3). most of the 37 adolescents took their pills. the file review indicated that clinic physicians ‘corrected’ the problem by replacing efv with nevirapine (nvp). this hardly solved the problem. the authors remark that few were referred for additional breast care. and of the three who were referred, none received any definitive intervention. this article has also limitations. retrospective studies have a tendency to accumulate data gaps with the passage of time. did the breast abnormalities ever resolve? the use of efv is widespread in sub-saharan africa. are these toxicities still being seen? is anyone culpable? after all, these are iatrogenic adverse events. 20. govender np, meintjes g, mangena p, et al. southern african hiv clinicians society guideline for the prevention, diagnosis and management of cryptococcal disease among hiv-infected persons: 2019 update. s afr j hiv med. 2019;20(1):a1030. https://doi.org/10.4102/sajhivmed.v20i1.1030 editor’s comments: i recommend this guideline paper to all. it is a must-read and is up there with the best. 21. spencer dc, krause r, rossouw t, et al. palliative care guidelines for the management of hiv-infected people in south africa. s afr j hiv med. 2019;20(1):a1013. https://doi.org/10.4102/sajhivmed.v20i1.1013 editor’s comment: this is a guideline paper and i thank the colleagues who helped me with this one. if you are interested in this field of hiv medicine, please contact the hiv clinicians society. we are eager to start an interest group to develop the field further. 22. kaplan s, nteso ks, ford n, boulle a, meintjes g. loss to follow-up from antiretroviral therapy clinics: a systematic review and meta-analysis of published studies in south africa from 2011 to 2015. s afr j hiv med. 2019;20(1):a984. https://doi.org/10.4102/sajhivmed.v20i1.984 editor’s comment: recommended reading. this review article provides a meta-analysis of public sector south african antiretroviral therapy (art) studies that address loss to follow-up (ltfu) and mortality data. this is an important article and will inform the epidemiology and practice of art in south africa in the years ahead. the data are derived from 48x adult, 15x paediatric and 4x pregnancy studies completed between january 2011 and october 2015. the study limitations are acknowledged: non-homogeneous data sources, namely, clinics, hospitals, rural and urban sites; and non-standardised definitions of ltfu across sources. when is a client lost to follow-up? after 3, 6 or 12 months since their last visit? the initiation of art itself was in flux at the time: baseline cd4 counts varied and treatment varied between private and state providers. were ‘silent transfers’ excluded from the ltfu data, that is, clients who move between clinics without informing staff and who are not truly ltfu? the median cohort study size was 3737 persons. median adult age and baseline cd4 count at art initiation were 35.8 years and 121 cells/mm3, respectively. the median age of art initiation in children was 4.2 years. the ‘defined’ follow-up time varied from 9 weeks to 5 years and the meta-analysis indicated no difference in ltfu estimates at 3-, 6or 12-month census. the overall median mortality at 1 year was 7.9% (iqr 4.1–11.4; range 0% – 26%) and the median ltfu at 1 year was 12.8% (iqr 7.9% – 22.0%, range 0.2% – 43.1%). aggregate meta-analysis ltfu estimates at 1 year were 11.6% (95% ci 11.4% – 11.7%) in the adult studies, 30.0% (95% ci 28.7% – 37.4%) for the pregnant cohorts and accounted for 7.5% (95% ci 6.7% – 8.2%) of the paediatric data. the 5-year ltfu estimate was 25% (95% ci 24.8% – 25.4%) based on three adult studies. in their concluding remarks, the authors indicate their support for the standardisation of the ltfu definition to 180 days (6 months). thank you for reading through this summary of articles published in the southern african journal of hiv medicine august–december 2019. similar summaries are available for the first half of 2019. if you have suggestions and improvements, please contact me at editor@sajhivmed.org.za. dr david spencer editor-in-chief southern african journal of hiv medicine medicine and the media richard delate manager,alds development research and evaluation (adre) anton harber, caxton professor of journalism at the university of the witwatersrand, points out that newsrooms increasingly have 'fewer experienced journalists and more and more green generalists', which impacts negatively on the quality of coverage. indeed nowhere is this more apparent than in the realm of media reporting on hiv/aids. south africa does have some specialist reporters covering the topic reporters who have educated themselves on the science of hiv/aids. but even these specialist journalists face constraints in covering the epidemic. they are expected to be experts in the bio-medical science of the epidemic, the demographic and economic impact, treatment, vaccines and social dimensions. as the epidemic unfolds and advances are made in addressing it, these journalists are required to keep abreast of current developments and for this they need resources to undertake research and access to experts who can provide them with insight to enable an in-depth and critical analysis of the issues as they unfold. quality of coverage the southern african journal of hiv medicine however, harber notes that newsrooms are under-staffed, meaning that fewer journalists are available to cover more issues. in the case of hiv/aids, specialist reporters are also required to cover all issues relating to health. in some instances they have the added burden of covering other areas as assigned by the newsroom. harber highlights that the competitive nature of the industry and the need to demonstrate profits for shareholders and owners are resulting in cutbacks, including limiting the access of staff to the internet and closing down internal libraries. these are the basic tools required by a journalist, and the cutbacks limit the ability of even specialist journalists to keep abreast with latest scientific developments. furthermore, editorial decision making has a great impact on the quality of coverage given to the epidemic. peet kruger, an editor with bee/d, indicated that at one point bee/d took the decision to cut down on the amount of reporting on hiv/aids owing to research that % of coverage 32.5 25.3 20 4.5 17.7 hiv/a1ds issue treatment prevention social/political impact economic effects other the south african media are often accused of not giving enough attention to hiv/aids. research by media tenor undertaken from 1 january to 31 december 2002 in which 148 056 reports were analysed from selected south african media found that hiv/aids received just under 30/0 of all media coverage, representing more coverage than issues such as education, health and even the environment but less than business, crime and politics. hiv/a1ds issues reported upon by the sa media in 2002 warren parker and kevin kelly of the centre for aids development research and evaluation (cadre) pointed out at a recent presentation to the south african national editors forum (sanef) that media reporting has intensified over time and has tended to follow the important emerging themes in south africa. these include following political debates, tracking issues such as prevention of mother-tochild transmission, introduction of drug therapies, relating the epidemic to economic issues, impacts and responses at family and community level, and critical reporting on various fronts. these trends are reflected in the research done by media tenor, which shows that in 2002, 32.50/0 of media articles on hiv/aids were related to treatment, of which 450/0 were concerned with nevirapine. prevention received 25.30'\) of the coverage but the predominant topic in this category, 650/0, concerned the social and political will to confront the epidemic. while statistics are important in giving us a picture of the commitment of the media to covering the epidemic, and what issues the media are covering, they do not provide a good indication of the quality or depth of media reporting on the topic. closing the gap: understanding media reporting on hiv/aids novfmhfh. 2003 6 o¥---==================-./ media coverage of hiv/aids, 2002 (source: media tenor. south africa, 1lan 31 dee 2002 www.mediatenor.co.za). november 2003 o finance week.d the citizen o business day • financial mail []the...., lie-tv o the star • the sunday times 11 the sunday independent o the pretoria news 11 city press • the sowetan • sunday wof1d • mail and guardian it is interesting to note that media tenor's research concluded that civil society had a significant voice (34.5%) in the coverage of hn/aids. of these reports 7.9"10 were by ngos including the tac, 4% by south african doctors, and 3.2% by people living with hiv/aids. in the lourn-aids survey, almost all respondents pointed out that the tac was particularly effective in their media outreach. the reasons for this, according to the respondents, were that the tac is pro active in communicating with the media, spokespersons were available at all times, and the tac bought into the media logic and provides information to journalists that is packaged through the use of 'sound bytes'. one of huge 'mistrust between government and particularly the ministry and the minister, and the media: in addition, a lourn-aids survey of media experiences of spokespersons found that in most instances journalists revealed that government spokespersons were not responsive to requests for information, and would discuss issues only as long as these were off the record. however, the participants indicated that they also understood the constraints under which spokespersons operated, including the lack of clarity concerning government policy and the workload with which government spokespersons were burdened. this 'mistrust' has resulted in journalists deemed to be critical not being invited to press events, invitations being passed on to other journalists who are less likely to challenge the speakers, and complaints to the editors. a journalist from mpumalanga says, 'when you do write anything, the flurry of denials, of press releases, the questioning of racial and political motivations of journalists who write about it so there's a fair bit of tension.' 2 4 3 5 the southtrn ahtican journal of hiv medicine ---------demonstrated 'audience fatigue with the topic: robyn chalmers of business day says that their publication took the decision that reporting should focus on the relevance of the issue for business. beyond the newsroom it appears that hiv/aids is still confined to the specialist health reporter, and as such is viewed by the south african media as a health issue rather than a critical challenge that is at the centre of all economic and social development in the country. as such, it is imperative that reporters covering other beats should integrate hiv/aids into their own portfolios. these editorial decisions limit the range of reporting and challenge journalists to find new and creative means of telling the story in the context of the editorial policy. but, as claire bisseker of the finoncial mail highlights, 'how many times can one report on the potential impact of hiv/aids on the workforce, or the successful elements of workplace programmes, or the fact that it pays to treat with antiretrovirals?' the relationship between government and the media with regard to reporting on hiv/aids has broken down to the extent that a journalist in kwazulu-natal described it as beyond the newsroom, there are many challenges confronting journalists that impact negatively on the quality of hiv/aids reporting, especially in relation to fairness and accuracy. the washington post's code of ethics defines fairness as portraying both sides of the argument, while the african women's media centre moves beyond this, saying that when it comes to hiv/aids journalists should also indicate which side carries more weight and why. this indicates that news does not happen in a vacuum it is informed through bringing issues to the attention of the media. it is not possible for one journalist to be aware of all the issues that can be reported on, so a proactive partnership between media and ngos is called for, one in which ngos are proactive in bringing issues to the attention of the media. however, this is not to say that media themselves should be less proactive in looking for areas to cover. journalist and activist charlene smith argues that journalists 'should be doing more research, relying less on the internet and more on going out into the field and meeting the researchers and scientists, and people infected and affected~ in relation to health, social workers and ngos, smith argues that they should be more proactive in inviting the media to visit their projects and provide them with good information. however, many organisations and indeed government are not proactive when it comes to dealing with the press. many organisations do not understand what constitutes news, how decisions are made within the newsroom, or the newsgathering process. many do not have a media strategy in place, or dedicated staff and personnel to work with the media. often experts are reluctant to speak or take a 'belligerent' stance towards the media, rather than one that encourages reporting. in part this appears to be due to past experience, including being 'misquoted'. how can we demand analytical, fair and accurate reporting if government. organisations and experts do not play an active role in communicating with the media? sensationalism sells another aspect that speaks to the quality of reporting on hiv/aids is that of sensationalism. indeed, ngos and activists are quick to point to the media as sensationalising the issue. yet, as indicated, the media in south africa rely to a great extent on sources such as press releases and events that inform their reporting. this is not to deny thot there is not a degree of sensationalism in the south african media that seeks to sell newspapers but there is also no shortage of critics, researchers and hiv/aids organisations who habitually make use of sensationalism and are then quoted in the media. a number of organisations and government employ public relations tactics with a view to 'selling the story to the media: indeed, just as we should demand that the media pursue and present the truth, so should we demand that organisations and agencies present us with factual and unbiased information, based on identifiable and verifiable information. it does not necessarily follow that a singlesourced press release should be published without novfmllfr 2003 ---------alternative viewpoints, comments or perspectives being reported. as parker and kelly argue, reporters need to interrogate the information that they receive through developing a wider network of sources and commentators that can add different perspectives and insights to the claims that are being made. innovative approaches in south africa the media have adopted a number of innovative approaches in response to the epidemic. the soweton has been the most proactive in this regard. the paper has incorporated the aids red ribbon as part of its masthead. it has a regular columnist, lucky mazibuko, who is living with hiv/aids. the popularity of lucky's column is indicated by a number of letters from readers looking for advice or support. other papers such as the daily news and the natal witness also carry the red ribbon and aids helpline telephone number, together with their titles. the independent newspapers group prints a number of hiv/aids-related numbers with stories on hiv/aids, providing a point of reference if readers are looking for additional information. in addition the group has concluded a partnership agreement with 10velife for the production of the thetanathi, a weekly youth supplement in a similar vein the sunday times has also concluded a partnership agreement with 10velife for the production of s'camto print the sabc has a long tradition of partnering with ngos for the production of programmatic content on hiv/aids. these include soul city and 10velife. the sabc also commissions programming that is produced by consortia that include hiv/aids ngos, while e-tv has worked with the tac for the production of beat-it. which combines personal documentary accounts of people living with hiv/aids with expert advice and explanation on strategies for living with hiv. similarly, a number of organisations are working to inform media reporting on hiv/ai ds. health-e is dedicated to producing news and analysis for print and electronic media regarding health policy and practice in south africa. the agency employs some health journalists particularly experienced in reporting on hiv/aids. articles are available through weekly newsbriefs and on the organisation's website www.health-e.org.za. more recently wits university together with the perinatal research unit at chris hani baragwanath hospital has started a research fellowship programme that undertakes research on media reporting on the epidemic, as a means to inform editorial decision making and projects working to improve media coverage. the southern african journal of hiv medicine thf southfrn ahlican journal of hiv mfoicinf ---------the south african aids vaccine initiative (saavi) has been engaged in a process of providing workshops for journalists in an effort to improve the understanding of vaccine research and to facilitate more informed reporting on this topic. a research-based intervention, joum-aids, is being undertaken by the centre for aids development research and evaluation (cadre). it seeks to inform media reporting to ensure in-depth, accurate and critical reporting on hiv/aids. this is achieved through the development of information resources for journalists and the support of dialogue between journalists and those working in the area of hiv/aids. joum-aids also provides in-newsroom training for journalists reporting on hiv/aids (endorsed by the south african national editors forum sanef) in partnership with a range of ngds working in the area of hiv/aids. in summary, this article outlines the complexity surrounding reporting on issues related to hiv/aids and the new approaches that have been undertaken by the media in this regard. references 8eamish j. r~poning on hn/ajd5 in africa: a manuol senegal: african women's media centre. delate r. mroia reporting on hiv/alds in south africa going behind the statistics. joum-ald5 2003. delate r. hiv/ajos and the media: a discussion papo-. online itcme for the university of natal and wishingtllfl, bothdl (www.joum-aids.ory]' hajber a hjmalism in the age of the market 4th harold wolpe memorial lttture, 26 sqlternber 2002. kdly i(, p"..rker w. writing ~ epidemic: the roit of the south african media in shaping ~ to hiv/alds.. 2001. kdly i(, ?-..rttr w. hl\iialds aod ma:ili r~: taking the ~d. ?r~tition to the south african nal;ion,l editors forum, 2003 lwww.journ-aids.org). manson h. madiba ~ds nation on hn/alds is:sul=:s: coyerc;ge of hiv/a1ds in the south african media:january december 2002. media ttnol sa reseorchjoumo~ 2003; 10 141. mansen h. hn/alds and the sa media: charlene smith tak.es media to task over hiv/aids covffilg~ supplied by media tenor, south africa, 2003. washington fbst media bias cattgorir:s (www.~nthepost.org/biu. a~ 22 april 2ooji. novfmhfil 2003 hiv 789 forum tuberculosis prevention in hiv-infected pregnant women in south africa c e martin, v black   wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, johannesburg c e martin, mb chb, dip hiv man, dtm&h v black, bsc, mb chb, dip hiv man, dtm&h corresponding author: c e martin (cmartin@wrhi.ac.za) the high burden of hiv and tuberculosis (tb) among pregnant women in south africa contributes to a high maternal mortality rate. isoniazid preventive therapy (ipt) is recommended for the prevention of active tb in hiv-infected individuals, including pregnant women. however, there are few data regarding ipt use in the latter, with concern regarding the concurrent use of ipt with nevirapine in pregnancy, as both treatments are hepatotoxic. the benefit and safety of ipt in hiv-infected pregnant women has not been established. we recommend a simplification of hiv and tb interventions by providing triple antiretroviral therapy to all hiv-infected pregnant women. s afr j hiv med 2012;13(4):182-184. doi:10.7196/sajhivmed.789 maternal deaths in south africa (sa) continue to rise, despite the target of the fifth millennium development goal (mdg) of a 75% reduction in maternal mortality by 2015. this target cannot be addressed without an appreciation of the effect of hiv and tuberculosis (tb) on maternal mortality in the country: the antenatal hiv sero-prevalence stands at 29.4%,1 and hiv is the most common contributory condition to maternal mortality.2 a number of studies have confirmed the contribution of hiv in maternal mortality and morbidity.3 , 4 , 5 the prevalence of tb in hiv-infected pregnant women in sa is similar to that of the general population: approximately 795/100 000.6 in 2009, the prevalence of active tb in hiv-infected women attending antenatal care in soweto, gauteng province, was found to be 688/100 000; higher than the prevalence in hiv-uninfected women (201/100 000).7 these findings were comparable with data from durban, kwazulu-natal, where prevalence rates of active tb between 1996 and 1998 were 774/100 000 hiv-infected pregnant women; 10 times higher than the prevalence for hiv-uninfected pregnant women.8 it is well established that tb and hiv are closely linked. an estimated 70% of adults presenting with new cases of tb in sa are co-infected with hiv, with tb being the most common cause of morbidity and mortality in hiv-infected individuals.9 tb is a leading cause of maternal mortality and morbidity, causing 15% of all maternal mortality in high hiv prevalence settings, and 15 34% of indirect obstetric maternal mortality.10 in sa between 2008 and 2010, tb accounted for 27% of deaths in women who died of aids-related complications during pregnancy, childbirth or the puerperium.2 the findings of a study in durban revealed a 3-fold higher maternal mortality ratio (mmr) among hiv-infected women with tb (12 170/100 000 live births) compared with tb-infected hiv-uninfected women (3 850/100 000 live births) in the absence of antiretroviral therapy (art).11 of the women diagnosed with tb, 79% were co-infected with hiv.11 similarly high mmrs in tb/hiv-co-infected women have been observed in a number of studies in sub-saharan africa.4 , 12 , 13 , 14 the challenge of tb diagnosis in hiv-infected pregnant women although diagnostic approaches to tb are similar for hiv-infected pregnant women as they are for hiv-uninfected and non-pregnant women, there are major challenges to the diagnosis of tb in the former. the symptoms of tb may be non-specific in pregnancy, or even absent, mimicking physiological changes. weight loss associated with tb disease may be masked by normal weight gain in pregnancy.15 the disease may only present post delivery in either the mother or infant.16 furthermore, clinical signs of hiv may overlap with those of tb and there may be a wide differential diagnosis.16 hiv-infected adults may also have a high prevalence of subclinical tb disease,17 with hiv-infected pregnant women also less likely to be sputum acid-fast bacilli smear-positive than hiv-uninfected pregnant women with tb disease.7 , 18 barriers to accessing care may contribute further to the under-diagnosis of tb in these women.7 tb prevention strategies in the context of hiv tb prevention, diagnosis and treatment in hiv-infected pregnant women should be integrated into routine maternal healthcare services. key strategies adopted by the world health organization (who) to decrease the effect of tb on people living with hiv include the 3 i’s: intensified tb case finding, isoniazid preventative therapy (ipt); and infection control for tb.19 it has been established that the use of ipt reduces the risk of active tb in hiv-infected individuals. however, this is more pronounced in those with a positive tuberculin skin test (tst).20 , 21 the most recent meta-analysis of the treatment of latent tb infection (ltbi) in hiv-infected individuals encompassed 12 trials and 8 578 hiv-infected participants.20 overall, the treatment of ltbi reduced the risk of active tb by 32% (risk ratio (rr) 0.68; 95% confidence interval (ci) 0.54 0.85). this benefit was stronger in tst-positive individuals (rr 0.38; 95% ci 0.25 0.57) than in tst-negative individuals (rr 0.89; 95% ci 0.64 1.24). isoniazid (inh) monotherapy was found to reduce mortality only in those who were tst-positive. however, overall, there was no evidence that preventive therapy reduced all-cause mortality.20 a randomised controlled trial (rct) of 6v. 36-month ipt for tb in hiv-infected adults in botswana also found a benefit of ipt in tst-positive individuals, but no benefit for those who were tst-negative.21 the use of art in hiv-infected adults also reduces the incidence of tb. in a meta-analysis of 9 observational cohort studies, a 67% reduction in tb incidence across a range of cd4 cell counts and who disease stages was reported.22 tb risk reductions with art occur irrespective of tst reactions.22 , 23 although the greatest absolute risk reduction of tb is observed in individuals with the most advanced immunodeficiency at baseline,22 patients starting art earlier, at higher cd4 cell counts, have a 2-fold lower risk of tb compared with those initiating art at lower cd4 cell counts.23 , 24 hiv-infected individuals starting art with low cd4 cell counts remain at high risk of tb until cd4 cell count recovery has occurred.23 studies have suggested that there may be additional benefit to concurrent ipt and art.21 , 25 , 26 in a recent rct in khayelitsha, a 37% reduction in the risk of tb was evident in individuals receiving ipt and art compared with patients receiving art only (rr 0.63; 95% ci 0.41 0.94). however, the risk of stopping inh or placebo due to grade 3 or 4 elevation of alanine transaminase (alt) was twice as high in the patients receiving ipt compared with those receiving placebo and, overall, there was no evidence of mortality benefit.27 the effect of timing of ipt v. art initiation has not been determined. experts recommend not initiating ipt at the same time as art, but rather delaying initiation until stabilisation on art, at approximately 3 months.22 , 28 the safety of ipt in pregnant women current national and international guidelines recommend the use of ipt for 6 months for all hiv-infected adults asymptomatic for tb, including pregnant women.9 , 29 who advises that, although not a requirement for ipt initiation in hiv-infected individuals, tsts may identify those who would benefit most from ipt. the american thoracic society (ats) recommends a tst for the diagnosis of ltbi in pregnant women with a specific risk factor for ltbi or who are at risk for progression to tb disease. this includes women who are hiv-infected or who have a recent tb case contact. although ats acknowledge that treatment for ltbi in pregnancy is controversial, they do recommend such treatment for cases of recent tb or hiv infection where there is an increased risk of haematogenous spread of organisms to the placenta, as well as in situations with a high risk of progression of ltbi to disease.30 guidelines do indicate that ipt can be administered during pregnancy, but it is unclear when and if ipt should be given if the pregnant woman is receiving art. there is little evidence available on ipt use in hiv-uninfected pregnant women in general. furthermore, to our knowledge, there is no evidence available of the effectiveness of ipt in reducing tb risk in hiv-infected pregnant women. in a study which modelled the cost-effectiveness and outcomes of different treatment strategies for ltbi in pregnancy, antepartum ipt was anticipated to result in the fewest cases of tb and be more cost-effective than no treatment or delaying treatment until postpartum.31 anteand postpartum ipt was predicted to be less costly and result in a higher life expectancy than no treatment, despite a higher mortality rate due to hepatitis in the antepartum group.31 however, hiv infection and the use of art were not taken into account. inh is not teratogenic, even if given during the first trimester,32 but it has a number of known adverse effects which include neurological toxicity, skin rash and hepatotoxicity. reported rates of inh-associated clinical and biochemical hepatitis range from 0% to 5%.28 in a systematic review of the risk of age-related hepatotoxicity in ltbi treatment, a median hepatotoxicity rate of 1.8% was reported. studies with close monitoring of hepatotoxicity reported lower rates of hepatotoxicity than those without monitoring. in studies with available information, there was only one reported case of hospitalisation and no reported cases of mortality.33 a comparison of treatment with rifampicin for 4 months v. inh for 9 months found rates of hepatotoxicity of 1.4 5.2% in the latter.34 although it is not conclusive whether the side-effects of inh are worsened by pregnancy, 2 studies have suggested that pregnant or postpartum women may be at higher risk of hepatotoxicity.30 pyridoxine supplementation is recommended in hiv-infected and pregnant individuals taking inh to prevent neurological toxicity.30 the rate of inh-associated hepatitis in hiv-infected individuals appears to be similar to that of the general population.35 in a brazilian study of hiv-infected patients receiving ipt (with or without art), 1.2% of participants had adverse reactions leading to discontinuation of ipt.36 in a study of 1 762 hiv-infected individuals receiving ipt in botswana, 1.1% developed hepatitis, and one death was reported.28 in khayelitsha, a hepatitis risk of 2.9% was reported in patients receiving ipt and art.27 some antiretroviral drugs are known to be associated with significant adverse effects, including hepatotoxicity. a 4.4% prevalence of grade 3 4 hepatotoxicity and 7% prevalence of grade 1 2 hepatotoxicity have been associated with nevirapine (nvp) use in hiv-infected pregnant women. the rate of nvp side-effects is higher in women with cd4 counts >250 cells/mm3.37 nvp is part of the first-line regimens used to treat hiv-infected pregnant women with cd4 counts ≤350 cells/ mm3  or who clinical stage 3 or 4 conditions in sa. increased rates of inh-associated hepatitis have been reported in patients receiving nvp-containing art regimens compared with those receiving efavirenz (efv)-containing regimens. in a previous study, the use of art by 480 patients was not associated with inh-hepatitis, although those receiving nvp had a higher rate of hepatitis (2%) than those receiving efv (0.9%). interestingly, a cd4 cell count <200 cells/mm3 was associated with inh hepatitis (rr 2.80; 95% ci 1.13 6.84).28 conclusion there is a high burden of hiv and tb among pregnant women in sa, contributing to a high mmr. despite art availability in the country, the recent maternal mortality survey showed that the majority of women who died from hiv did not access art. if we are to progress towards the mdg targets, interventions need to be safe, easy to implement and simplified to maximise early nurse initiation of art. ipt initiation after art in pregnancy adds additional steps to antenatal care, which is currently under-resourced. this may further burden the programme and compromise other areas of care, for a benefit apparently limited to tst-positive individuals and that, to date, has no evidence of efficacy in pregnancy. screening all pregnant women for tb and hiv is imperative. those with tb disease should be treated accordingly, with contact tracing and screening of household contacts. although not currently stipulated in guidelines, all hiv-infected pregnant women should be considered for initiation onto combination art. with this approach, ipt initiation may be better deferred until the postpartum period. triple art for all hiv-infected pregnant women will reduce mother-to-child hiv transmission, adverse pregnancy outcomes, maternal mortality, horizontal transmission to uninfected partners and, specifically, the incidence of tb disease. references 1. national department of health (doh). the national antenatal sentinel hiv and syphilis prevalence survey in south africa. pretoria: doh, 2010. http://www.health-e.org.za/documents/85d3dad6136e8ca9d02cceb7f4a36145.pdf (accessed 2 november 2011). 1. national department of health (doh). the national antenatal sentinel hiv and syphilis prevalence survey in south africa. pretoria: doh, 2010. http://www.health-e.org.za/documents/85d3dad6136e8ca9d02cceb7f4a36145.pdf (accessed 2 november 2011). 2. national committee on confidential enquiries into maternal deaths. saving mothers 2008 2010: fifth report on confidential enquiries into maternal deaths in south africa. http://www.doh.gov.za/list.php?type=maternal%20and%20child%20health (accessed 30 may 2012). 2. national committee on confidential enquiries into maternal deaths. saving mothers 2008 2010: fifth report on confidential enquiries into maternal deaths in south africa. http://www.doh.gov.za/list.php?type=maternal%20and%20child%20health (accessed 30 may 2012). 3. coutsoudis a, england k, rollins n, coovadia h, newell m-l, bland r. women’s morbidity and mortality in the first 2 years after delivery according to hiv status. aids 2010;24(18):2859-2866. [http://dx.doi.org/10.1097/qad.0b013e32834041b7] 3. coutsoudis a, england k, rollins n, coovadia h, newell m-l, bland r. women’s morbidity and mortality in the first 2 years after delivery according to hiv status. aids 2010;24(18):2859-2866. [http://dx.doi.org/10.1097/qad.0b013e32834041b7] 4. zvandasara p, hargrove jw, ntozini r, et al. mortality and morbidity among postpartum hiv-positive and hiv-negative women in zimbabwe: risk factors, causes, and impact of single-dose postpartum vitamin a supplementation. j acquir immune defic syndr 2006;43(1):107-116. [http://dx.doi.org/10.1097/01.qai.0000229015.77569.c7] 4. zvandasara p, hargrove jw, ntozini r, et al. mortality and morbidity among postpartum hiv-positive and hiv-negative women in zimbabwe: risk factors, causes, and impact of single-dose postpartum vitamin a supplementation. j acquir immune defic syndr 2006;43(1):107-116. 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[http://dx.doi.org/10.1016/s0140-6736(11)60204-3] 22. lawn sd, wood r, de cock km, kranzer k, lewis jj, churchyard gj. antiretrovirals and isoniazid preventive therapy in the prevention of hiv-associated tuberculosis in settings with limited health-care resources. lancet infect dis 2010;10(7):489-498. [http://dx.doi.org/10.1016/s1473-3099(10)70078-5] 22. lawn sd, wood r, de cock km, kranzer k, lewis jj, churchyard gj. antiretrovirals and isoniazid preventive therapy in the prevention of hiv-associated tuberculosis in settings with limited health-care resources. lancet infect dis 2010;10(7):489-498. [http://dx.doi.org/10.1016/s1473-3099(10)70078-5] 23. lawn sd, harries ad, williams bg, et al. antiretroviral therapy and the control of hiv-associated tuberculosis. will art do it? int j tuberc lung dis 2011;15(5):571-581. 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[http://dx.doi.org/10.1164/rccm.200911-1783oc] 29. world health organization (who). guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with hiv in resource-constrained settings. geneva: who, 2011. http://whqlibdoc.who.int/publications/2011/9789241500708_eng.pdf (accessed 21 november 2011). 29. world health organization (who). guidelines for intensified tuberculosis case-finding and isoniazid preventive therapy for people living with hiv in resource-constrained settings. geneva: who, 2011. http://whqlibdoc.who.int/publications/2011/9789241500708_eng.pdf (accessed 21 november 2011). 30. american thoracic society, centers for disease control and prevention. targeted tuberculin testing and treatment of latent tuberculosis infection. am j respir crit care med 2000;161(3):s221-s247. 30. american thoracic society, centers for disease control and prevention. targeted tuberculin testing and treatment of latent tuberculosis infection. am j respir crit care med 2000;161(3):s221-s247. 31. boggess ka, myers er, hamilton cd. antepartum or postpartum isoniazid treatment of latent tuberculosis infection. obstet gynecol 2000;96(5):757-762. 31. boggess ka, myers er, hamilton cd. antepartum or postpartum isoniazid treatment of latent tuberculosis infection. obstet gynecol 2000;96(5):757-762. 32. bothamley g. drug treatment for tuberculosis during pregnancy: safety considerations. drug saf 2001;24(7):553-565. 32. bothamley g. drug treatment for tuberculosis during pregnancy: safety considerations. drug saf 2001;24(7):553-565. 33. kunst h, khan ks. age-related risk of hepatotoxicity in the treatment of latent tuberculosis infection: a systematic review. int j tuberc lung dis 2010;14(11):1374-1381. 33. kunst h, khan ks. age-related risk of hepatotoxicity in the treatment of latent tuberculosis infection: a systematic review. int j tuberc lung dis 2010;14(11):1374-1381. 34. ziakas pd, mylonakis e. 4 months of rifampin compared with 9 months of isoniazid for the management of latent tuberculosis infection: a meta-analysis and cost-effectiveness study that focuses on compliance and liver toxicity. clin infect dis 2009;49(12):1883-1889. [http://dx.doi.org/10.1086/647944] 34. ziakas pd, mylonakis e. 4 months of rifampin compared with 9 months of isoniazid for the management of latent tuberculosis infection: a meta-analysis and cost-effectiveness study that focuses on compliance and liver toxicity. clin infect dis 2009;49(12):1883-1889. [http://dx.doi.org/10.1086/647944] 35. saukkonen jj, cohn dl, jasmer rm, et al. an official ats statement: hepatotoxicity of antituberculosis therapy. am j respir crit care med 2006;174(8):935-952. [http://dx.doi.org/10.1164/rccm.200510-1666st] 35. saukkonen jj, cohn dl, jasmer rm, et al. an official ats statement: hepatotoxicity of antituberculosis therapy. am j respir crit care med 2006;174(8):935-952. [http://dx.doi.org/10.1164/rccm.200510-1666st] 36. durovni b, cavalcante sc, saraceni v, et al. the implementation of isoniazid preventive therapy in hiv clinics: the experience from the tb/hiv in rio (thrio) study. aids 2010;24(5):s49-s56. [[http://dx.doi.org/10.1097/01.aids.0000391022.95412.a6] 36. durovni b, cavalcante sc, saraceni v, et al. the implementation of isoniazid preventive therapy in hiv clinics: the experience from the tb/hiv in rio (thrio) study. aids 2010;24(5):s49-s56. [[http://dx.doi.org/10.1097/01.aids.0000391022.95412.a6] 37. mckoy jm, bennett cl, scheetz mh, et al. hepatotoxicity associated with longversus short-course hiv-prophylactic nevirapine use: a systematic review and meta-analysis from the research on adverse drug events and reports (radar) project. drug saf 2009;32(2):147-158. 37. mckoy jm, bennett cl, scheetz mh, et al. hepatotoxicity associated with longversus short-course hiv-prophylactic nevirapine use: a systematic review and meta-analysis from the research on adverse drug events and reports (radar) project. drug saf 2009;32(2):147-158. 'he souther african jour al of hii' meoici e-----------march 2002 legal matters elsabe klinck legal adl.riser, sollth africall medical association human rights, lml' qlld ethics u"it (b) unfair discrimination in the provision of benefits, facilities and services related to insurance. (cl unfairly disadvantaging a person or persons, including unfairly and unreasonably refusing to grant services to persons, solely on the basis of hiv/aids status: aggrieved individuals or the family members of deceased persons may approach their nearest magistrate's court to enforce these statutory rights. insured persons should also be aware that insurers may contest pay-outs or insurance claims on the basis of the non-disclosure of material facts, and such claims may even be made against a deceased person's estate. insurance companies aim to be profitable and work on collective risk. with the coming inro operarion of the promorion of equality and prevention of unfair discrimination act larer this year, insurance companies may be required to justify hiv exclusions. hiv status is a socalled 'additional prohibited ground' of discrimination and the schedule to the act lists the following as illustrations of unfair practices: is something that has to be contractually agreed berween the insurer and the insured when the policy is taken out. '(al unfairly refusing on one or more of the prohibited grounds to provide or to make available an insurance policy to any person. hiv/aids, human rights and insurance some indicators every patient has a constitutional righr to privacy and every doctor has an ethical duty to maintain patient confidentiality. the principle is that any rhird party such as an insurance company can only access information to which a patient (the insured) has provided informed consent. informed consent means that the person is aware of the consequences of his/her consent. therefore the south african medical association does not regard blanket consent or consent obtained years ago as informed consent. in insurance law, a person (the insured) has to disclose all material facts that may affect the insurance to the insurer. the relationship is between the insurer and the insured, and unless the insured has consented to the medical practitioner making medical information known on his/her behalf, the practitioner is bound to preserve confidentiality. the family of a deceased person may consent to an insurer requesting information from the practitioner in terms of the promotion of access to information acr of 2000. the regulations to the act must be used to request the information. medical practitioners may be requested to complete forms in which they have [q indicate their suspicions in relation to a patient's htv s a us. if the doctor does not know a deceased person's hiv starus, ir cannot be revealed, because one cannot reveal what one does nor know. if disclosure of medical facts [or indicators) is required ex post facto, companies and orhers may require a range of tests to be per armed on deceased persons, but again that hiv 869 case report maternal deaths following nevirapine-based antiretroviral therapy e bera, d naidoo, m williams department of obstetrics and gynaecology, university of the witwatersrand and rahima moosa mother-and-child hospital, johannesburg e bera, fcog (sa) d naidoo, fcog (sa) m williams, mb chb corresponding author: e bera (drebera@hotmail.com) we report 2 cases illustrating that it is too simplistic to link nevirapine (nvp) toxicity exclusively to individuals with immune preservation. not enough is known about the mechanism of hepatotoxicity or cutaneous eruption to predict these events. this type of hypersensitivity reaction occurs rarely among hiv-exposed infants taking nvp prophylaxis or antiretroviral therapy (art)-experienced adults with complete plasma viral load suppression. conversely, hiv-uninfected adults and art-naive pregnant women appear to be disproportionately affected by the adverse effects of nvp. s afr j hiv med 2012;13(4):196-197. doi:10.7196/sajhivmed.869 over the last decade, south africa (sa) has made major progress in the prevention of mother-to-child transmission (pmtct) of hiv. pmtct uptake among women known to be hiv-infected increased from 65% in 2006 to >90% in 2010,1 , 2 and the most recent national mother-to-child transmission rate at 6 weeks postpartum (2.7%) is the lowest recorded to date.1 at the same time, maternal mortality-related hiv has continued to increase despite the increasing availability of antiretroviral therapy (art). data from the national confidential enquiry into maternal deaths show that 28% of all maternal deaths in 2008 2010 were aids-related, compared with an estimated 20% in 2002 2004.3 the most recent report included a new category of maternal deaths, attributed to art-related toxicity. the majority of the 73 deaths in this category were attributed to acute liver failure and stevens-johnson syndrome (sjs). although relatively uncommon, the occurrence of art-related toxicity deaths was twice as high during 2010 than in previous years. this increase coincided with the release of the 2010 sa pmtct guidelines4 that promoted nevirapine (nvp)-based art for pregnant women with world health organization (who) clinical stage 3 or 4 disease, regardless of cd4 cell count, hepatitis b infection, the presence of abnormal liver transaminases, or the need for tuberculosis co-treatment. recently, who noted its support for the expanded use of efavirenz (efv) in pregnancy, based on growing evidence for the lack of efv teratogenicity in the first trimester.5 still, many health professionals remain at odds over the choice of non-nucleoside reverse transcriptase inhibitors (nnrtis) – efv and nvp – particularly for pregnant women in the case of advanced immune suppression or during the first trimester. case reports are of limited value to the practice of evidence-based medicine, but they can illustrate the potential effect of clinical decisions. previous recommendations to avoid efv use in pregnancy were based largely on 5 case reports of birth defects in humans, 3 of which (myelomeningocele) resembled those from animal studies.6 a recent case report of cleft palate and micropthalmia following efv use at conception7 is likely to re-ignite the debate around the safety and wider use of the drug in pregnancy. although the handful of cases of birth defects that may be associated with efv use are widely discussed, much less attention has been given to reports of much more common toxicities associated with nvp use. we report 2 recent cases of maternal deaths at our institution, both from liver failure, following initiation of nvp-based art. case 1 a 22-year-old hiv-infected woman in her second pregnancy was commenced on tenofovir (tdf), lamivudine (3tc) and nvp at 31 weeks’ gestation. her nadir cd4 cell count was 201 cells/µl and alanine transaminase (alt) was 14 iu/l at baseline. she was assessed as who clinical stage 1. after 2 weeks, the dose of nvp was doubled to 200 mg 12-hourly. apart from haematinics, she received no other medication. six weeks following art initiation, she presented in labour with restlessness, jaundice, confusion, and an intra-uterine fetal death. her alanine transaminase (alt) was 462 iu/l, aspartate transaminase (ast) 134 iu/l and international normalised ratio (inr) >10. she delivered a fresh stillborn weighing 2.7 kg. she bled profusely following delivery, during which time she experienced a convulsion. the patient’s capillary glucose was 2.4 mmol/l. although she was adequately resuscitated and scheduled for exploration under anaesthesia, she had a cardiorespiratory arrest en route to theatre. she was declared dead after an hour of resuscitation. the woman’s family declined a postmortem examination. case 2 a 29-year-old woman with nadir cd4 count 119 cells/µl was commenced on tdf, 3tc and nvp (initially 200 mg daily) at a peripheral clinic. she was 26 weeks pregnant. no baseline alt measurement was performed and no other medication was prescribed. the patient presented a month later with a generalised rash and fulminant liver failure. by the time of referral to our facility, she was jaundiced, hypotensive, breathless, oliguric and had an altered level of consciousness. her haemoglobin was 9.2 g/dl, white cell count 32.9 x 109 /l, platelets 207 x 10^9 /l, urea 8.8 mmol/l, creatinine 202 µmol/l, ast 548 iu/l and inr 4.47. results of screening for malaria and viral hepatitis were negative. the patient was ventilated and received inotropic support. ultrasound examination confirmed an in utero fetal death. a computed tomography scan of her brain was normal. she delivered a fresh stillborn after induction of labour. postpartum, she developed grade 4 hepatic encephalopathy, persistent hypotension non-responsive to inotropic support, and worsening liver dysfunction (ast 568 iu/l, alt 412 iu/l and inr 5.53), and required continued ventilation. the patient demised the following day. discussion these cases are typical of the maternal deaths due to art-related toxicity that are occurring with increasing frequency across sa. while the cases are not definitive and key investigations of interest (e.g. liver biopsy) are lacking, they provide a useful counterpoint to the case reports regarding efv teratogenicity that have had a strong influence on sa policy. not enough is known about the mechanism of hepatotoxicity or cutaneous eruption related to nnrtis to enable a reliable prediction of these events in people taking nvp. this type of hypersensitivity reaction occurs rarely among hiv-exposed infants taking nvp prophylaxis, or art-experienced adults with complete plasma viral load suppression.8 conversely, hiv-uninfected adults and art-naive pregnant women appear to be disproportionately affected by the adverse effects of nvp.9 severe adverse events following nvp-based art among pregnant women are relatively common. in a cohort of pregnant women from kenya, severe hepatotoxicity and severe rash occurred in 8% and 6%, respectively.10 although the pharmacogenetic basis of nvp hypersensitivity is not well understood, there is some support for hla-drb*1 allele and hla-cw8 expression in its pathogenesis.11 , 12 a group of investigators recently identified nvp-derived adducts (haptens) with the n-terminal valine of haemoglobin, in 12/13 individuals receiving nvp-based art.13 drug bio-activation to reactive metabolites, capable of forming protein adducts and binding to self-proteins, is believed to be the trigger behind these idiosyncratic allergic reactions. the detection of this adduct may provide a clue to the molecular mechanisms underlying nvp hypersensitivity. the current british hiv association guidelines recommend either efvor nvp-based art for pregnant women with a cd4 count <250 cells/µl.14 the sa national confidential enquiry into maternal deaths has recommended efv to replace nvp when initiating art in pregnancy from the second trimester onwards.3 although a cochrane review suggested the equivalence of efv and nvp for efficacy endpoints in the treatment of hiv disease, efv may be safer, notably for the development of raised liver transaminases and neutropenia.15 given that the united states food and drug administration assigned efv to pregnancy category d (indicating evidence of human fetal risk), it is unsurprising that there are no trials comparing nvp and efv in pregnant women.6 however, in the absence of head-to-head data on the choice of nnrti in pregnancy, decision-making on the basis of case reports and series has led to conclusions that may not be in the best interests of the public’s health. our view is that efv should be recommended to all pregnant women in need of art for their own health. apart from regimen simplicity across all cd4 cell counts, there are a number of conditions unique to pregnancy (including pre-eclampsia; the haemolysis, elevated liver enzymes and low platelet (hellp) syndrome; and acute fatty liver) that may mimic nvp toxicity, leading to inappropriate withdrawal of art. conversely, these conditions may delay diagnosis of nvp toxicity, with progression to overt liver failure. although the evidence for efv teratogenicity is equivocal, given the labelling of efv, art should be delayed until around 12 weeks’ gestation to enable neural tube closure and embryogenesis of the face to be completed.16 generally, there is a clear and urgent need for more evidence to inform the choice of nnrti during pregnancy. we support calls for the development of a register of art exposure during pregnancy, with particular focus on the first trimester. given that the background prevalence of neural tube defects in some regions of sa is as high as 3.55/1 000 live births,17 approximately 3 000 4 000 first-trimester efv exposures would be required to identify (or rule out) the teratogenicity of efv with some confidence. until more useful data are available on the safety of efv use around conception, the drug’s use in the first trimester will remain a vexing issue. references 1. goga a, dinh th, jackson d, et al. impact of the national prevention of mother to child transmission of hiv (pmtct) program on perinatal mother-to-child transmission of hiv (mtct) measured at 6 weeks postpartum, south africa (sa): results of the first year of implementation of the 2010 pmtct guidelines recommended by the world health organization (who). iac conference, pretoria, 26 july 2012. 1. goga a, dinh th, jackson d, et al. impact of the national prevention of mother to child transmission of hiv (pmtct) program on perinatal mother-to-child transmission of hiv (mtct) measured at 6 weeks postpartum, south africa (sa): results of the first year of implementation of the 2010 pmtct guidelines recommended by the world health organization (who). iac conference, pretoria, 26 july 2012. 2. doherty t. pmtct indicators. the district health barometer 2007/8. pretoria: health systems trust, 2008. http://www.hst.org.za (accessed 20 january 2010). 2. doherty t. pmtct indicators. the district health barometer 2007/8. pretoria: health systems trust, 2008. http://www.hst.org.za (accessed 20 january 2010). 3. national committee for confidential enquiry into maternal deaths. saving mothers 2008 2010. fifth report on the confidential enquiries into maternal deaths in south africa. pretoria: department of health, 2012. 3. national committee for confidential enquiry into maternal deaths. saving mothers 2008 2010. fifth report on the confidential enquiries into maternal deaths in south africa. pretoria: department of health, 2012. 4. national department of health (doh). clinical guidelines: pmtct (prevention of mother-to-child transmission) 2010. pretoria: doh, 2010. 4. national department of health (doh). clinical guidelines: pmtct (prevention of mother-to-child transmission) 2010. pretoria: doh, 2010. 5. ford n, vitoria m, shaffer n. technical update on treatment optimization. use of efavirenz during pregnancy: a public health perspective. geneva: world health organization, 2012. 5. ford n, vitoria m, shaffer n. technical update on treatment optimization. use of efavirenz during pregnancy: a public health perspective. geneva: world health organization, 2012. 6. lewis-hall fc. important change in sustiva (efavirenz) package insert – change from category c to d. rockville: bristol-myers squibb company, 2005. http://www.fda.gov (accessed 19 april 2008). 6. lewis-hall fc. important change in sustiva (efavirenz) package insert – change from category c to d. rockville: bristol-myers squibb company, 2005. http://www.fda.gov (accessed 19 april 2008). 7. schanske al. bilateral oblique facial clefts and extremity anomaly in an infant after intrauterine efavirenz exposure and review of its teratogenic risk. aids 2012 (in press). [http://dx.doi.org/10.1097/qad.0b013e328356467a] 7. schanske al. bilateral oblique facial clefts and extremity anomaly in an infant after intrauterine efavirenz exposure and review of its teratogenic risk. aids 2012 (in press). [http://dx.doi.org/10.1097/qad.0b013e328356467a] 8. de lazzari e, leon a, arnaiz ja, et al. hepatotoxicity of nevirapine in virologically suppressed patients according to gender and cd4 cell counts. hiv med 2008;9:221-226. [http://dx.doi.org/10.1111/j.1468-1293.2008.00552.x] 8. de lazzari e, leon a, arnaiz ja, et al. hepatotoxicity of nevirapine in virologically suppressed patients according to gender and cd4 cell counts. hiv med 2008;9:221-226. [http://dx.doi.org/10.1111/j.1468-1293.2008.00552.x] 9. mckoy jm, bennett cl, scheetz mh, et al. hepatotoxicity associated with longversus short-course hiv-prophylactic nevirapine use: a systematic review and meta-analysis from the research on adverse drug events and reports (radar) project. drug saf 2009;32(2):147-158. [http://dx.doi.org/10.2165/00002018-200932020-00007] 9. mckoy jm, bennett cl, scheetz mh, et al. hepatotoxicity associated with longversus short-course hiv-prophylactic nevirapine use: a systematic review and meta-analysis from the research on adverse drug events and reports (radar) project. drug saf 2009;32(2):147-158. [http://dx.doi.org/10.2165/00002018-200932020-00007] 10. peters pj, polle n, zeh c, et al. nevirapine-associated hepatotoxicity and rash among hiv-infected pregnant women in kenya. j int assoc physicians aids care 2012;11:142-149. [http://dx.doi.org/10.1177/1545109711423445] 10. peters pj, polle n, zeh c, et al. nevirapine-associated hepatotoxicity and rash among hiv-infected pregnant women in kenya. j int assoc physicians aids care 2012;11:142-149. [http://dx.doi.org/10.1177/1545109711423445] 11. vitezica zg, milpied b, lonjou c, et al. hla-drb1*01 associated with cutaneous hypersensitivity induced by nevirapine and efavirenz. aids 2008;22(4):540-541. [http://dx.doi.org/10.1097/qad.0b013e3282f37812] 11. vitezica zg, milpied b, lonjou c, et al. hla-drb1*01 associated with cutaneous hypersensitivity induced by nevirapine and efavirenz. aids 2008;22(4):540-541. [http://dx.doi.org/10.1097/qad.0b013e3282f37812] 12. gatanaga h, yazaki h, tanuma j, et al. hla-cw8 primarily associated with hypersensitivity to nevirapine. aids 2007;21(2):264-265. [http://dx.doi.org/10.1097/qad.0b013e32801199d9] 12. gatanaga h, yazaki h, tanuma j, et al. hla-cw8 primarily associated with hypersensitivity to nevirapine. aids 2007;21(2):264-265. [http://dx.doi.org/10.1097/qad.0b013e32801199d9] 13. caixas u, antunes amm, marinho at, et al. evidence for nevirapine bioactivation in man: searching for the first step in the mechanism of nevirapine toxicity. toxicology 2012 (in press). [http://dx.doi.org/10.1016/j.tox.2012.06.013] 13. caixas u, antunes amm, marinho at, et al. evidence for nevirapine bioactivation in man: searching for the first step in the mechanism of nevirapine toxicity. toxicology 2012 (in press). [http://dx.doi.org/10.1016/j.tox.2012.06.013] 14. de ruiter a, taylor gp, palfreeman a, et al. british hiv association guidelines for the management of hiv infection in pregnant women 2012: consultation draft. http://www.bhiva.org/documents/guidelines/pregnancy/pregnancy_guidelines_for_consultation120125.pdf (accessed 1 february 2012). 14. de ruiter a, taylor gp, palfreeman a, et al. british hiv association guidelines for the management of hiv infection in pregnant women 2012: consultation draft. http://www.bhiva.org/documents/guidelines/pregnancy/pregnancy_guidelines_for_consultation120125.pdf (accessed 1 february 2012). 15. mbuagbaw lce, irlam jh, spaulding a, rutherford gw, siegfried n. efavirenz or nevirapine in three-drug combination therapy with two nucleoside-reverse transcriptase inhibitors for initial treatment of hiv infection in antiretroviral-naive individuals. cochrane database of systematic reviews 2010;12. 15. mbuagbaw lce, irlam jh, spaulding a, rutherford gw, siegfried n. efavirenz or nevirapine in three-drug combination therapy with two nucleoside-reverse transcriptase inhibitors for initial treatment of hiv infection in antiretroviral-naive individuals. cochrane database of systematic reviews 2010;12. 16. moore kl, persaud tvn, eds. the developing human: clinically orientated embryology. 5th ed. philadelphia: wb saunders, 1993:205-225. 16. moore kl, persaud tvn, eds. the developing human: clinically orientated embryology. 5th ed. philadelphia: wb saunders, 1993:205-225. 17. robertson hl, steyn np, venter pa, christianson al. neural tube defects and folic acid: a south african perspective. s afr med j 1997;87:928-931. 17. robertson hl, steyn np, venter pa, christianson al. neural tube defects and folic acid: a south african perspective. s afr med j 1997;87:928-931. abstract introduction methodology search strategy study inclusion criteria study selection and data extraction quality evidence assessment and risk of bias results discussion concerns and barriers related to community-based antiretroviral therapy initiation knowledge gaps and future directions conclusion acknowledgements references about the author(s) raymond chimatira department of public health, school of public health and nursing, university of kwazulu-natal, durban, south africa andrew ross department of family medicine, school of public health and nursing, university of kwazulu-natal, durban, south africa citation chimatira r, ross a. a rapid review and synthesis of the effectiveness of programmes initiating community-based antiretroviral therapy in sub-saharan africa. s afr j hiv med. 2020;21(1), a1153. https://doi.org/10.4102/sajhivmed.v21i1.1153 review article a rapid review and synthesis of the effectiveness of programmes initiating community-based antiretroviral therapy in sub-saharan africa raymond chimatira, andrew ross received: 16 aug. 2020; accepted: 10 sept. 2020; published: 05 nov. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: community-based antiretroviral therapy initiation (cb-arti) has the potential to reduce attrition by increasing access to care, reducing patient costs, decongesting clinics and ensuring improved uptake of art. there is a paucity of research that identifies successful implementation of cb-arti in sub-saharan africa (ssa). objectives: the aim of the study was to review and describe the evidence on the effectiveness of cb-arti programmes that start art in communities in comparison with the current standards of care in ssa. methods: a rapid review of grey and published peer-reviewed literature between january 2009 and july 2019, by using pubmed, pdq-evidence, google scholar, clinical trial databases and major hiv (human immunodeficiency virus) conference websites, was conducted. search terms used included ‘community-based’, ‘home initiation community models’, ‘antiretroviral therapy’, ‘clinical outcomes’, ‘viral suppression’, ‘retention in care’, ‘loss to follow-up’, ‘hiv’ and ‘sub-saharan africa’. results: the search yielded 90 articles and reports following the removal of duplicates. after initial screening and full-text screening, six articles remained and were included in the qualitative narrative synthesis. this included four randomised control trials and two cohort studies of specific interventions comparing cb-arti with the standard of care in ssa. there is evidence that cb-arti can increase access to hiv-testing services, linkage to art, retention in care and viral suppression rates and is possibly not inferior to facility-based healthcare. conclusion: cb-arti has the potential to increase access to hiv services to people living with hiv in ssa. the results mentioned previously suggest that cb-arti models could prove to be equal and possibly not inferior to facility-based ones and warrant further investigation. keywords: community-based art; hiv; interventions; art initiation; retention; attrition; viral suppression; sub-saharan africa. introduction sustainable human immunodeficiency virus (hiv) epidemic control requires that a large percentage of people living with hiv (plhiv) must initiate antiretroviral therapy (art) early, regardless of their cd4 t-cell count or clinical stage, and remain in care, adhere to treatment and achieve viral suppression.1 to this end, the joint united nations programme on hiv and aids (unaids) set the ambitious 95–95–95 treatment targets that by 2030, 95% of all plhiv will know their hiv status, 95% of all those diagnosed as hiv-positive will receive sustained art and 95% of all those receiving art will achieve viral suppression.1 however, the achievement of the 95-95-95 targets in sub-saharan africa (ssa) is challenged by a weak hiv care cascade, with plhiv being lost at each step as a result of barriers to getting tested, linkage to and staying in care, and starting or adhering to art.2 many studies from ssa report that rates of linkage to care and initiation of art in individuals who tested hiv-positive are lower than 50%.2,3 successful strategies to address the high rates of patient attrition at every stage of the hiv care cascade include rapid art initiation and differentiated care models with community art distribution for stable patients on art. community-based hiv programmes that include dispensing art have contributed significantly to decongesting the traditional healthcare services, and improved adherence and retention in care.2,3,4 other interventions identified through systematic reviews and meta-analyses include community-based hiv testing, facilitated referrals for art initiation, education, treatment supporters and active adherence reminder devices such as mobile phone text messages. however, these have shown mixed results, with each intervention also being found not to produce significant effects in some settings.5 despite this, interest is increasing in the role of out-of-facility or community-based art initiation (cb-arti) as an essential approach for universal access to hiv care. community-based art initiation has the potential to reduce attrition by increasing access to care, reducing patient costs, decongesting clinics and ensuring improved uptake of art.3,6,7 there is a need for the updating of the status of evidence that supports the implementation of cb-arti models. such evidence should include its impact on the clinical and behavioural outcomes such as retention in care and viral suppression amongst patients initiating art in ssa. the objective of this article is to review and describe the evidence of the effectiveness of cb-arti programmes that start art in communities in comparison with the current standard of care in ssa, namely the initiation of art in traditional facility-based hospitals and clinics. methodology this rapid review used a streamlined systematic method to capture the evidence from current community-based approaches to the initiation of art in ssa. there were two research questions. (1) what are the essential elements of evidence-based models of cb-arti that inform policy in ssa? (2) how do the reported clinical outcomes, for example, retention in care and viral suppression, amongst patients initiating art in community-based settings compare with traditional standards of care in ssa? the rapid review approach streamlines traditional systematic review methods to gain efficiency and accelerate the review process, whilst still aiming to produce valid conclusions.8 we focussed on a narrow topic, used a limited rather than an exhaustive range of search terms and restricted the analysis and synthesis. we also restricted the search of grey literature (material written for professionals and disseminated outside of peer-reviewed journals) to key websites and only considered studies published in english since january 2009. furthermore, we performed single (vs. dual) screening of titles and abstracts by using rayyan, a web-based semi-automated screening software (https://rayyan.qcri.org/welcome). search strategy studies were identified through bibliographic searches of pubmed and pdq-evidence publication databases by using the following terms and variations: ‘community based’; ‘home initiation’; ‘community models’; ‘home care services’; ‘health facility’; ‘clinic’; ‘antiretroviral therapy’; ‘antiretroviral’; ‘clinical outcomes’; ‘patient adherence’; ‘patient compliance’; ‘viral load’; ‘viral suppression’; ‘retention’; ‘retention in care’; ‘loss to follow-up’; ‘attrition’; and ‘hiv’. the search strategy was limited to studies conducted in ssa and published in english from january 2009 through july 2019. the pubmed search strategy is summarised in box 1. box 1: pubmed search string. we also conducted a grey literature search that was limited to abstracts from the following major hiv-related conferences: conference on retroviruses and opportunistic infections (croi), the international aids conference, international conference on aids and stds in africa (icasa), southern african hiv clinicians’ society conference and the south african aids conference. in addition, we searched clinical trial databases for planned or ongoing research via the u.s. national library of medicine register of clinical trials (clinicaltrials.gov) and the who (world health organisation) international clinical trials registry platform (ictrp). three technical experts on hiv care and treatment were also contacted by e-mail for comment on the appropriateness of the identified literature and additional articles. study inclusion criteria studies were included in the review if they: (1) reported on community-based models of art initiation; (2) measured clinical outcomes (e.g. linkage to care, adherence, reported stigma, retention in care and virologic suppression) of patients initiated on art in the community compared with patients receiving the current standard of care; and (3) used observational and experimental methods with primary data within randomised controlled trials (rcts), cross-sectional or cohort (prospective and retrospective) designs. we excluded articles that did not meet all three criteria from the review. study selection and data extraction all references captured by the search engine were uploaded to rayyan and duplicates were identified and removed. the eligibility of the articles was assessed in two steps, the first entailing all titles and abstracts being assessed by the primary reviewer. in the second step, full texts for all the articles deemed relevant to the research questions were read in full and analysed to confirm their eligibility. the primary reviewer extracted data from all eligible articles by using a standard data collection form to collect information about the publication date, study setting, design and interventions, patient population and outcome measures. the secondary reviewer reviewed all the extractions for accuracy. quality evidence assessment and risk of bias the quality of evidence and risk of bias (rob) of the studies included in the final review was assessed by one reviewer by using the mcmaster university’s quality assessment tool (https://merst.ca/ephpp-tools/) from the effective public health practice project (ephpp). the secondary reviewer verified the quality of evidence and the rob assessment. ethical consideration this article followed all ethical standards for research without direct contact with human or animal subjects. results study selection and characteristics of included studies the process of study identification and selection concluded with 90 citations being identified after removing duplicates (figure 1). after screening the titles and abstracts, six full-text articles were selected for critical review (table 1). these consisted of four completed studies and two ongoing rcts (table 2). four studies were included for the qualitative synthesis of patient outcomes, which varied between studies, and included case finding (hiv seropositive yield), linkage to art initiation, art adherence, retention in care and viral suppression (table 3). figure 1: preferred reporting items for systematic reviews and meta-analyses (prisma) flow for study selection. table 1: description of studies included in the review. table 2: comparative summary of community antiretroviral therapy initiation models identified. table 3: effectiveness of community antiretroviral therapy initiation models identified. we excluded all studies that did not report on art initiation in the community (out-of-facility). interventions were implemented in lesotho, malawi, nigeria, south africa, tanzania and uganda. the four completed studies were assessed by using the mcmaster university’s quality assessment tool, and individual studies ranged in quality from 1 (strong) to 3 (weak), with the overall average being 2. the two ongoing rcts included in the model description were not assessed for quality as they had not been completed at the time of reporting. models of community-based antiretroviral therapy initiation community-based art initiation modalities include home, mobile and workplace as part of an hiv-testing campaign. the review identified two main models of cb-arti, with some variations across countries (table 2): (1) on-site art initiation and community-based art monitoring and resupply7,9,10 and (2) a hybrid model with on-site community art initiation and referral to local clinics for art monitoring and resupply.3,4,11 in addition, the review identified key activities addressing seven areas of cb-arti service delivery, namely (1) demand creation, (2) patient access for htc, (3) provider roles, including task shifting, (4) laboratory and clinical evaluation, (5) adherence preparation, (6) place and time of art initiation and (7) follow-up care.3,4,9 examples of these cb-arti programme activities, including summaries of information on the purpose of the activity, populations targeted and strategies used, are provided in table 2. effects on clinical outcomes two completed rcts,3,4 one quasi-experimental prospective cohort study9 and one retrospective interrupted time series cohort study11 were included for the qualitative synthesis of patient outcomes. two of the studies reported on hiv test uptake and case finding, all four on linkage to art initiation, three on retention in care and one on viral suppression (table 3). human immunodeficiency virus test uptake and case finding one rct reported on hiv test uptake, whilst one rct and one retrospective interrupted time series cohort study reported on hiv case finding as an outcome. in urban slums in malawi, macpherson et al.4 reported that there was no significant difference in the uptake of hiv-self-testing (hivst) kits between offering optional home initiation of hiv care after self-testing (home group) compared with hivst followed by facility-based services only (facility group). however, participants in the home group were more likely to report a positive hivst result (6.0%) compared with the facility group (3.3%). in addition, the median cd4 t-cell count at art initiation was higher amongst home (219 cells/µl) than facility initiators (154 cells/µl). oladele et al.14 found that introducing two models of community art delivery services resulted in more hiv-positive individuals being identified per 100 000 population in 14 high-burden local government areas in nigeria in the 12 months after the models were introduced compared with the 12 months before. model a (immediate on-site initiation) identified 11 374 versus 5352 per 100 000 population, whilst model b (hiv diagnosis up to baseline evaluation and referral for art) identified 907 versus 152 per 100 000 population. furthermore, preliminary data from the delivery optimization for antiretroviral therapy (do art) study13 suggest that 80% (320/398) of persons testing hiv positive in rural uganda were eligible for same-day art initiation, with men accounting for more than half the persons eligible (169/320; 53%). linkage to antiretroviral therapy initiation four studies reported on linkage to art initiation as an outcome. the study by macpherson et al.4 in urban slums in malawi found that the cumulative incidence of art initiation was significantly higher in the home (2.2% of residents) compared with the facility group (0.7% of residents). labhart et al.3 found that linkage to art within 90 days after enrolment was higher in the same-day home-based art initiation group (94/137; 68.6%) than in the facility-based care group (59/137; 43.1%) in rural lesotho. tun et al.11 found that at 6 months, 256/256 (100%) of the community-based intervention group and 181/253 (71.5%) of the facility-based comparison group self-reported as being linked to care and on art amongst sex workers in tanzania. oladele et al.14 found that both model a (on-site initiation) and model b (immediate referral) clusters had more hiv positives initiated on art per 100 000 population in the 12 months after the models were introduced compared with the 12 months before (model a: 7347 vs. 2181; and model b: 499 vs. 152). for model a clusters, 59.6% of hiv positives identified in health facilities were linked to art compared with 69.1% of hiv positives identified in the community. for model b clusters, 80.9% of hiv positives identified in health facilities were linked to art compared with 31.6% of hiv positives identified in the community. retention in care and loss to follow-up three studies reported on retention in care or loss to follow-up as an outcome. macpherson et al.4 found that at 6 months, 52/181 (28.7%) of the home group and 15/63 (23.8%) of the facility group were lost to follow-up. in addition, the rate of loss to follow-up was higher amongst the home group (63.4/1000 person-months) than in the facility group (53.5/1000 person-months) in unadjusted analysis. labhardt et al.3 found that at 12 months, 12/137 (8.8%) of the same-day community-based group and 10/137 (7.3%) of the facility-based care group were lost to follow-up. retention in care since enrolment was significantly higher in the same-day community-based group (p = 0.009). tun et al.11 found that at 6 months, 254/254 (100%) of the intervention group and 171/180 (95%) of the comparison group remained in care and on art. viral suppression one rct reported on viral suppression as an outcome. labhardt et al.3 reported that art-naïve participants who were assigned to the same-day home-based art initiation were more likely to remain in care at 12 months and achieve vl suppression. the authors reported that in the 11 to 14-month window after enrolment, 69/137 (50.4%) of the same-day group and 47/137 (34.3%) of the facility-based care group achieved documented viral suppression (vl < 100 copies/ml). in each group, 14/137 (10.2%) had no documented vl, whilst the remaining patients did not attend the health facility within that time frame. effects on behaviour two studies measured self-reported medication adherence, whilst one measured self-reported internalised stigma and an ongoing one reported on patient acceptability. medication adherence macpherson et al.4 found that, based on clients completing an adherence questionnaire (at 2–4 weeks, 3 months and 6 months), 19/164 (11.6%) and 3/60 (5.0%) art initiators in the home and facility groups, respectively, self-reported missing at least one dose of art in the past 4 days at any assessment point (p = 0.14). tun et al.9 found that medication adherence was not significantly different amongst those with a completed adherence questionnaire, with 37/214 (17.3%) and 25/152 (16.4%) self-reported missing at least one dose of art in the past 7 days, and 2/214 (0.9%) of the same-day group and 9/159 (5.7%) of the usual care group self-reported stopping taking art for more than 30 days continuously (p = 0.008). internalised stigma and acceptability tun et al.9 used a validated six-item scale to assess participants’ feelings of shame and guilt as a result of living with hiv and found that a community-based intervention group was less likely to report high levels of internalised stigma compared with the facility-based group (26.6% vs. 39.9%; p = 0.001). this supports the findings by wyatt et al.6 who reported that amongst 50 do art study participants in uganda, home initiation was associated with decreased concerns about disclosure risk at facilities. the authors also reported that other participants perceived home initiation and community follow-up to have many advantages compared with facility-based care, including being convenient, saving time and money otherwise spent on travel to clinics, and being responsive to individual needs. additional benefits reported include reaching hard-to-reach populations, for example, fsws,9 men at trading posts and those only available in the evenings and at weekends.3,6,13 cost analysis macpherson et al.4 reported that the average cost of the home-based art services was us$97.11 per patient assessed. in comparison, the average cost per patient initiated on art was us$172.46. data on estimated cost per participant from the do art study in uganda and south africa are still pending.7 discussion summary of the evidence a rapid review method was used to quickly capture the current evidence on the essential elements of evidence-based models of community-based (out-of-facility) art initiation and the reported outcomes amongst patients initiating art in community-based settings in ssa. we searched two databases, five conference websites and two registers of clinical trials for intervention studies evaluating cb-arti models, with four completed and two ongoing studies being included in this review. the review identified heterogeneity in interventions, study design, location and definition of outcomes measured as a major obstacle to interpreting and synthesising the data on cb-arti. for example, some of the authors report on retention in care and loss to follow-up at 6 months4,9 versus 12 months,3 and linkage to care at 3 months3 versus 6 months.9 these differences are highlighted in tables 1 and 2. however, despite the limitations noted above, the existing data suggest that cb-arti could be more effective in increasing the uptake of hiv testing and improving case finding at a population level4,11 than in facility-based art initiation. other advantages include improved linkage to art initiation,3,4,9,11 which results in similar rates of viral suppression.3 one study conducted before the universal test and treat (utt) era reported a higher rate of loss to follow-up amongst the home group,4 and two other studies conducted in the utt era reported significantly higher retention in care rates in the same-day group.3,9 in addition, two studies found that there was no difference in self-reported medication adherence,3,9 and one reported low self-reported internalised stigma.9 the above results suggest that cb-arti models are equal and certainly not inferior to facility-based healthcare. strengths and benefits of community-based antiretroviral therapy initiation community-based hts are an essential pillar towards reaching hiv epidemic control. however, it is estimated that almost two-thirds of patients are lost in the process from community-based hiv testing to facility art initiation without specific interventions, with higher loss to follow up (ltfu) rates amongst african cohorts.14 hence, many authors and technical experts believe that cb-arti has considerable potential to address the gap between hiv diagnosis and art initiation.3,9,10,11 the strengths of the cb-arti models noted in the literature include reducing the structural barriers, such as cost of transport to the clinic, time saved otherwise spent on travel to clinics, flexibility of hours and location of service delivery and addressing stigma associated with traditional healthcare (especially for key populations), which in turn appear to result in better access to art initiation for ‘hard-to-reach’ populations, such as men, fsws and other key populations.3,6,11,14 concerns and barriers related to community-based antiretroviral therapy initiation there are concerns that cb-arti may shift scarce resources and art initiations from healthcare facilities, which may result in their being unsustainable.4,9 however, cb-arti identified patients with higher median cd4 cell counts, which in turn may influence cost-effectiveness favourably through reduced morbidity and mortality.4 in addition, studies in malawi and nigeria both reported that the rates of facility-based art initiations remained stable, whilst community-based initiations provided extra numbers.4,11 another issue raised in the literature relates to the potential for increased rates of loss to follow-up,4,11 which means that additional adherence support measures should be put in place as cb-arti moves from small pilot studies to programmatic scale-up. concerns have also been expressed about the perceived lack of confidentiality, especially in smaller communities.4 however, participants from uganda and tanzania reported cb-arti to be an acceptable option that is perceived to have many advantages compared with facility-based care.6,9,13 knowledge gaps and future directions the purpose of this rapid review was to synthesise and describe what is currently known on the topic of cb-arti. based on the findings, several considerations for future research and practice in the field of cb-arti are evident. firstly, it is essential to consider the fit of cb-arti initiatives within the context of the local epidemic conditions to ensure that they complement existing healthcare systems. this includes addressing existing facility-level barriers, such as long waiting times and poor staff attitudes, to increasing uptake of art. secondly, given the results, which suggest that cb-arti models are possibly not inferior to facility-based ones, it is crucial to revisit existing policies on decanting stable virally suppressed patients to community art distribution models after 12 months. this is especially important for key and other priority populations, such as men, adolescents and young people whose retention in care is often hindered by facility-level barriers. thirdly, it is important to consider the needs of the population by developing partnerships with community leaders and community-based organisations to overcome potential barriers related to lack of confidentiality, and widespread stigma and discrimination. in addition, designing cb-arti initiatives that are integrated into general health campaigns can also address the potential lack of confidentiality. community-based art initiation models should therefore include assessments for non-communicable diseases, screening for sexually transmitted infections and tuberculosis (tb), hiv pre-exposure prophylaxis (prep) and other hiv prevention services, family planning services, as well as alcohol and drug rehabilitation services. finally, further research is needed regarding the impact and estimated costs, as well as the cost-effectiveness of cb-arti models. limitations our results and conclusions might be susceptible to the bias related to the limits of a rapid review. these include restricting the search to literature published in english language and two electronic databases (although we used the pubmed database that contains by far the most significant number of health and medical journals). the search was also complemented by grey literature searches from major hiv-related conferences, clinical trial databases and brief technical expert consultations. a second limitation is that only one author screened and selected the titles and abstracts from the total set of documents retrieved, extracted data from all eligible articles and assessed the quality of evidence and rob. however, this author is knowledgeable about the content area. the second author checked all the extractions for accuracy and verified the quality of evidence and rob assessment. as a result of the heterogeneity in intervention, study design, location and definition of outcomes measured, we were not able to combine the results to estimate overall intervention effect or draw conclusions on the relative effectiveness of community-based versus facility-based art initiation. varying definitions of the outcomes of interest also impacted the comparability of the results. this major obstacle has been highlighted by rosen et al.15 who have proposed standardised primary and secondary outcomes for research on accelerating art initiation. finally, some of the studies assessed are still incomplete, and the final results with higher numbers of participants (higher statistical power) may differ significantly from some of the preliminary findings presented. conclusion this rapid review identified a small but rich set of information on the topic of cb-arti. however, after weighing the existing evidence, it appears that there is evidence that cb-arti can increase access to hts, linkage to art, retention in care and viral suppression rates, and is possibly not inferior to facility-based healthcare. the results reached earlier suggest that cb-arti models could prove to be equal and possibly not inferior to facility-based ones and warrant further investigation. the apparent promise and pitfalls of cb-arti and the increasing interest of policymakers in its potential as a strategy to increase linkage to care and art uptake in the era of utt indicate that careful monitoring of the evidence base is warranted. acknowledgements competing interests the authors have declared that no competing interests exist. authors’ contributions r.c. conceptualised the project, the main conceptual ideas, and drafted the first manuscript. both r.c. and a.r. contributed to the final version of the manuscript. a.r. supervised the project. funding information this research was funded by the university of kwazulu-natal through a phd studentship bursary awarded to r.c. by the college of health sciences. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references joint united nations programme on hiv/aids (unaids). fast-track: ending the aids epidemic by 2030. geneva: joint united nations programme on hiv/aids; 2014. fox mp, rosen s, geldsetzer p, barnighausen t, negussie e, beanland r. interventions to improve the rate or timing of initiation of antiretroviral therapy for hiv in sub-saharan africa: meta-analyses of effectiveness. j int aids soc. 2016;19(1):20888. https://doi.org/10.7448/ias.19.1.20888 labhardt nd, ringera i, lejone ti, et al. effect of offering same-day art vs usual health facility referral during home-based hiv testing on linkage to care and viral suppression among adults with hiv in lesotho: the cascade randomized clinical trial. j am med assoc. 2018 mar;319(11):1103–1112. https://doi.org/10.1001/jama.2018.1818 macpherson p, lalloo dg, webb el, et al. effect of optional home initiation of hiv care following hiv self-testing on antiretroviral therapy initiation among adults in malawi: a randomized clinical trial. j am med assoc. 2014 jul;312(4):372–379. https://doi.org/10.1001/jama.2014.6493 nachega jb, adetokunboh o, uthman oa, et al. community-based interventions to improve and sustain antiretroviral therapy adherence, retention in hiv care and clinical outcomes in lowand middle-income countries for achieving the unaids 90-90-90 targets. curr hiv/aids rep. 2016;13(5):241–255. https://doi.org/10.1007/s11904-016-0325-9 wyatt ma, pisarski e, krows b, et al. community-based art initiation, delivery and monitoring in rural southwest uganda: participant experiences of a differentiated model of hiv care delivery. 9th ias conference on hiv science, 23–26 july 2017, ias: paris, france; 2017 [cited n.d.]. 2929992. barnabas r v. delivery optimization for antiretroviral therapy (the do art study) [homepage on the internet]. washington, dc: clinicaltrials.gov; 2016 [cited 2018 feb 27]. p. 1–7. available from: https://clinicaltrials.gov/ct2/show/nct02929992 tricco ac, langlois e, straus se, world health organization. rapid reviews to strengthen health policy and systems: a practical guide. geneva: world health organization; 2017. tun w, apicella l, casalini c, et al. community-based antiretroviral therapy (art) delivery for female sex workers in tanzania: 6-month art initiation and adherence. aids behav. 2019;23(suppl 2):142–152. https://doi.org/10.1007/s10461-019-02549-x amstutz a, lejone ti, khesa l, et al. vibra trial – effect of village-based refill of art following home-based same-day art initiation vs clinic-based art refill on viral suppression among individuals living with hiv: protocol of a cluster-randomized clinical trial in rural lesotho. trials. 2019;20:522. https://doi.org/10.1186/s13063-019-3510-5 oladele ea, badejo oa, obanubi c, et al. bridging the hiv treatment gap in nigeria: examining community antiretroviral treatment models. j int aids soc. 2018;21(4):e25108. https://doi.org/10.1002/jia2.25108 labhardt nd, ringera i, lejone ti, et al. same day art initiation versus clinic-based pre-art assessment and counselling for individuals newly tested hiv-positive during community-based hiv testing in rural lesotho – a randomized controlled trial (cascade trial). bmc public health. 2016;16:329. https://doi.org/10.1186/s12889-016-2972-6 asiimwe s, van rooyen h, schaafsma tt, et al. community-based hiv testing and assessment for same-day art reaches men for hiv care. oral abstracts of the 22nd international aids conference, 23–27 july 2018, amsterdam, the netherlands. j intern aids soc, 21:78. https://doi.org/10.1002/jia2.25148 rosen s, fox mp. retention in hiv care between testing and treatment in sub-saharan africa: a systematic review. plos med. 2011;8(7):e1001056. https://doi.org/10.1371/journal.pmed.1001056 rosen s, fox mp, larson ba, et al. accelerating the uptake and timing of antiretroviral therapy initiation in sub-saharan africa: an operations research agenda. plos med. 2016;13(8):1–13. https://doi.org/10.1371/journal.pmed.1002106 the southern african journal of hiv medicine ------------may 200 i managed health care leighton mcdonald, mb ellb, doh mx health institute, centurion, south africa all of the aforementioned factors will ultimately place downward pressure on the economy, since hiv/aids has introduced additional costs to an economy ill-equipped to deal with this load. investor confidence may be affected as economic costs employee benefits the cost of maintaining employee benefits is set to rise dramatically as the health of the workforce deteriorates. benefits affected to the greatest degree include pension, disability and health care cover. in the face of this scenario it is likely that employees will increasingly offer a finite package to employers and pass the responsibility for pension and health care cover on to the employees. while this will achieve the objective of capping the risk for the employer, it is unlikely to benefit the employee who will be tempted to utilise the full package for immediate material needs rather than pension and health care. social and community costs the consequences of a high burden of dead and dying patients will affect every aspect of the community, from the increased responsibility of caring for the ill and the overburdening of the extended family in absorbing children orphaned by the epidemic through to the relative chaos caused by the loss of a traditional social structure. training additional training will be required, not only for new employees but in order to increase the range of skills held by employees in order to equip them to deal with a wider variety of occupations where necessary. loss of productivity productivity will be affected not only by absenteeism but by the fact that ill employees and those who are concerned about ill family members are less likely to be fully productive and are more likely to have accidents in the workplace. recruitment costs of recruitment will increase as employees need to be replaced. legislation excludes pre-employment hiv testing in areas of high prevalence it is possible that a significant percentage of new recruits will themselves be hiv-infected. diagnostic and monitoring antiretroviral, prophylaxis and treatment of opportunistic infections management of opportunistic infections hospitalisation these are widely quoted as they are often the most tangible evidence of the impact of the condition. included are the costs of: consultations investigations medication counselling the above are costs which can be directly attributable to hiv/aids; they are not exhaustive and do not include the indirect costs associated with increased utilisation of general health care services that may occur as a result of ill health. employer costs the employer is exposed to costs in a range of areas, including: absenteeism in the form of sick leave for infected employees, but also for employees who are caring for infected family and for those attending the increasing number of funerals. hiv/aids has a financial impact on all aspects of south africa. the costs can be categorised as follows: medical costs hiv and aids is having, and will continue to have, a significant effect on the private health care industry in south africa. a number of clinical, financial, legislative and ethical questions need to be addressed in deciding on an effective and sustainable response to the challenge posed by the epidemic. the maturation of the epidemic from an hiv to an aids epidemic has resulted in increased health care costs for employers, medical schemes and individuals. this increased expenditure has not always resulted in a favourable outcome and there is an urgent need to address the funding of hiv/aids management in a rational way to ensure optimal utilization of scarce resources treatment of hiv/aids in the managed care setting costs of hiv/a1ds t~e sout~ern african journal of ~iv meoicine ------------may 200 i effect on medical schemes this can be explained by means of simple graphs (figs 1and 2). affordabillty of medication using a simple calculation for a scheme of 20 000 lives and assuming an average antiretroviral medication cost of r2 500 per month, the ann~al cost for antiretroviral therapy is as follows: • 2% prevalence 400 patients x r2 500 x 12 months ~ r12 000 000 • 5% prevalence 1 000 patients x r2 500 x 12 months ~ r30 000 000 • 10% prevalence 2 000 patients x r2 500 x 12 months ~ r60 000 000 provision of an hiv/aids benefit the promulgation of the medical schemes act [act 131 of 1998) outlined certain responsibilities for medical schemes with regard to hiv/aids management. these are stipulated in section 29 (1) of the act and refer to a set of prescribed minimum benefits [pmb) which any entity carrying out the business of a medical scheme is compelled to fund. antiretroviral medication, despite the recent price cuts, is not inexpensive and the fact that at least two antiretroviral drugs are required in combination adds significant expenses to medical schemes. the pmb stipulates hospital inpatient care for a range of conditions including: diagnosis hiv-associated disease treatment medical and surgical treatment of opportunistic infections and localised malignancies the act does not enforce the use of antiretroviral therapy for the management of hiv-infected medical scheme members, but an argument has been raised that the use of these drugs [and the funding thereon would maintain the health status of the patient and prevent costs associated with advanced hiv disease. is the management of hiv/aids with antiretroviral therapy cost-effective in the south african private health care setting? while it would appear to be common sense to provide optimal therapy initially to control the disease (as with other chronic conditions such as asthma and diabetes mellitus), hiv presents some unique problems. the scenario outlined above has necessitated a review of the funding of hiv/aids management. with the advent of hiv/aids an additional cost burden has been introduced and, since this is an illness that hits hardest in the young, healthy population, the health care costs of these individuals have escalated and the portion of these contributions which previously subsidised the treatment of the elderly and the sick is no longer available for this purpose i.e. the monetary requirement represented by (2) is now in excess of the monetary surplus represented by (1). average cost ,/ "2 average contribution age (years) ...............'" /' average cost age (years) ""~'"--_._------------------~--~'"'average contribution eo,,,,, health care (r) costo! health care (r) to understand the effect that hiv/aids has on the funding of health care it is useful to revisit the economic principle upon which the funding of medical schemes is based, namely cross-subsidisation. traditionally a contribution has been made to a medical scheme, whether use was made of the benefits or not. in this way those who paid more than they used were subsidising those who used more than they paid provided the total claimed from the scheme was lower than total contributions, the scheme was financially viable. hiv/aids has increased costs for medical schemes, and as a result the cost of contributions for employers and individuals has risen. it must be noted that hiv/ai ds is only one of a number of factors that has caused an escalation in health care costs. the competitiveness of south african business is compromised. the numbers of unemployed persons may increase as a result of the demise of marginal businesses. fig. 1. health core costs by age of member (before hiv/aiosj. 1 ~ money received (by means of the average contribution) and not paid out in health cofe claims; 2 = money required (over and above the average contribution) to pay health care claims. fig. 2. health core costs by age of member (with hiv/aiosj. 1~ money received (by means of the average contribution) and not paid out in health care claims; 2 = money reql.:ired (over and above the overage contribution) to pay health care claims. before the advent of hiv/aids the average health care costs of members were related to age, largely owing to an increase in the incidence of age-related conditions (heart disease, cancer, stroke, etc.) in the elderly. the costs of managing the conditions were met from contributions, since there was a young, healthy sector of the membership who were not experiencing high health care expenses, i.e. provided the monetary value represented by (1) was greater than that represented by (2), the scheme was financially viable. conclusion innovative treatment plans treatment guidelines need to be tailored for specific clinical and financial circumstances. possibilities include: delayed treatment while it is accepted that treatment should not be initiated above a cd4+ count of 350 cells/ml, there may be some value in lowering this value to 250. research is ongoing. interrupted treatment this implies 'treatment holidays', e.g. two months on treatment followed by a month off, which effectively reduces the cost of treatment by one third. stepped treatment regimens a narrow range of robust treatment should be utilised initially with access to more complex (and expensive) combinations restricted to specialist use. curtailed treatment an end-point could be set beyond which a decision is made to curtail arv and provide palliative care only. disease management the complexity of the condition and its management make it essential that any medical scheme providing a benefit for hiv management ensures that a disease management programme is in place to support the patient and the treating practitioner. decisions on treatment should always be evidence-based to promote a favourable health outcome. elements of a disease management programme include: • comprehensive patient assessment • treatment guidelines/protocols • critical pathways [which investigations/interventions need to be carried out and at which time intervals) • patient education, support and counselling • health status monitoring • outcomes measurement (health status, quality of life, economic). the treating practitioner should be assisted, where necessary, in the selection of the most appropriate medication and the patient should be empowered with information to manage the disease optimally [e.g. compliance, lifestyle changes, etc.). perceived discrimination the provision of an additional financial benefit for the management of hiv-infected members may be seen as unfairly discriminating against members of the scheme who have other health care requirements that are not funded by the scheme, e.g. an asthmatic patient whose chronic medication benefit is insufficient for full coverage of required chronic medication. the provision of antiretroviral therapy does not guarantee a large decrease in hospitalisation costs, for the following reasons: • treatment failure will occur in a percentage of cases, either due to viral resistance or to sub-optimal compliance. • patients presenting with advanced disease may require periodic hospitalisation despite antiretroviral therapy. terminal care may be required in end-stage disease. possiblie solutions the spend on antiretroviral medication is an additional cost for the scheme and will ultimately need to be covered by way of increased member contributions. hospitalisation continues costs will obviously be dependent on the scheme's hiv prevalence, the rate at which patients present for treatment and the protocols used for therapy. the scheme should assess the potential liability prior to deciding on a benefit. the provision of an additional benefit for hiv treatment also translates into higher member contributions for all members. all these 'actors, along with other costs of managing hiv, need to be considered in the compilation of the annual medical scheme benefits (and budget). there are a number of measures that can be taken by the scheme to optimise the benefits offered to hiv-positive members. secure additional funding in closed, employer-based medical schemes 'top-up' funding should be secured from the employer who stands to gain from the maintenance of the health status of employees. increasingly, employers are realising the benefits of providing a benefit for the management of hn-positive employees and this represents an opportunity for cooperation between the employer and the medical scheme. discounted medications the cost of antiretroviral medications has been falling, but there is further scope for medical schemes to negotiate favourable pricing with pharmaceutical companies. this is particularly valid for large medical schemes where volumebased discounts are feasible. the costs associated with hiv/aids and its complications represent a large threat to the financial viability of medical schemes. ignoring the problem will exacerbate the threat and schemes need to strive to find solutions that are nondiscriminatory, ethical and sustainable. ongoing measurement of financial, clinical and quality outcomes needs to be accurately carried out for purposes of policy review should this be necessary. may 200 i ------------the southern african journal o~ hiv meoicine 770 case report varicella zoster virus infection causing urinary retention in a child with hiv infection s wessels, c f heyns   department of urology, stellenbosch university and tygerberg hospital, western cape s wessels, mb chb c f heyns, mb chb, mmed (urol), phd, fcssa (urol) corresponding author: c f heyns (cfh2@sun.ac.za) an 11-year-old boy receiving antiretroviral therapy for hiv infection and antibacterial therapy for pulmonary tuberculosis presented with urinary retention due to varicella zoster virus infection involving the sacral nerves, confirmed on serological testing. the perineum over dermatomes s2 s4 on the left was involved with a vesicular and superficially erosive rash. a transurethral catheter was inserted and the patient was treated with acyclovir (300 mg 6-hourly for 5 days). at follow-up 4 weeks later, the perineal skin lesions had healed, the catheter was removed and the patient was able to pass urine. s afr j hiv med 2012;13(4):202-203. doi:10.7196/sajhivmed.770 varicella zoster virus (vzv) of the human herpes virus family causes childhood chickenpox, becomes latent in sensory ganglia and re-activates years later in immunocompromised and elderly persons to produce shingles (herpes zoster). the annual incidence of herpes zoster in children aged <10 years is reported to be 0.74 per 1 000 children per year.1 the association of vzv infection and neurogenic bladder dysfunction is rare and mostly seen in adults, with only one reported case in a child.2 severe and debilitating zoster-associated dermatological, ophthalmological and neurological complications may occur in patients with hiv infection.3 we describe the case of an hiv-positive child who presented with acute urinary retention secondary to vzv infection. case description an 11-year-old boy was referred with urinary retention. he complained of difficulty passing urine, lower abdominal discomfort, and a painful rash over the perineum for 5 days. his mother had noticed that he had lower abdominal swelling. the patient was hiv-positive and receiving treatment accordingly (300 mg zidovudine twice daily, 250 mg didanosine daily and 200 mg/50 mg lopinavir/ritonavir twice daily). he was also receiving treatment for pulmonary tuberculosis, diagnosed 6 months prior (300 mg rifampicin and 150 mg isoniazid daily). the boy had no previous history of chickenpox. on examination, the patient was pyrexial (temperature 39°c) and appeared acutely ill. his bladder was distended, easily palpable and mildly tender. his penis, scrotum and perineum over dermatomes s2 s4 on the left were involved with a vesicular and superficially erosive rash. severe swelling of the prepuce caused the appearance of phimosis (fig. 1). on digital rectal examination, his anal tone was normal. the bulbocarvernosus reflex was not tested due to severe tenderness in the perineal area. no abnormalities were found on neurological examination of his lower limbs. fig. 1. blistering and superficially erosive skin lesions due to varicella zoster virus infection involving the sacral nerves (s2 s4) on the left side. an 8f foley catheter was inserted transurethrally and 1 500 ml of clear urine was drained. the boy was admitted to hospital and treated with 300 mg acyclovir 6-hourly (intravenous), 4 drops of oral tilidine 6-hourly and 1 000 mg paracetamol 8-hourly. urine dipstick testing showed a trace of blood. urine microscopy showed leukocytes <1 000 cells/mm3 and erythrocytes <1 000 cells/mm3, and was negative for bacterial cultures. the patient’s absolute cd4 count was 159×106 /l with a cd4% of lymphocytes of 9.42% and cd45 positive white cell count of 6.18×109 /l. blood tests revealed 136 mmol/l sodium, 4.3 mmol/l potassium, 2.8 mmol/l urea, 32 µmol/l creatinine, a 5.9×109 /l white cell count, 11.5 g/dl haemoglobin and 303×109 /l platelets. serological tests were igg-positive and igm-negative for human simplex virus (hsv) types 1 and 2, and igg-positive and igm-positive for vzv. smears for viral culture were negative for hsv 1 and 2 and negative for vzv; however, the smears were taken after the blisters had ruptured and there was already scab formation. due to the clinical picture and the serology results, treatment for herpes zoster was continued. the boy was discharged after 7 days with the transurethral catheter in situ. at follow-up one week later, the preputial swelling had resolved but phimosis was present due to scarring. circumcision was performed under general anaesthesia. a trial without catheter was attempted. after 3 hours the bladder was palpable, but he had no urge to urinate. a 12f foley catheter was re-inserted and 600 ml of urine was drained. at follow-up 2 weeks later, the perineal skin had healed and a trial without catheter was repeated. he was able to urinate 250 ml with a post-void residual volume of 124 ml urine on ultrasound. he appeared well and was urinating without difficulty at last follow-up 2 months later. discussion the prevalence of hiv infection in children aged 2 14 years in south africa is approximately 2.5%.4 the incidence of herpes zoster in children aged <10 years is approximately 0.74 per 1 000 per year.1 this incidence is higher in hiv-positive children (164 per 1 000 per year) and possibly even higher in children with a low cd4 count.5 bladder dysfunction secondary to herpes zoster is uncommon, affecting 3.5 4.2% of people with vzv infection, but occurs more often when the lumbosacral dermatomes are involved (28.6%).5 voiding dysfunction caused by herpes zoster may be classified as cystitis-associated, neuritis-associated or myelitis-associated.5 neuritis-associated dysfunction leads to an acontractile bladder and hypoesthesia. in cystitis-associated bladder dysfunction, the neurological examination is normal, whereas overflow incontinence and neurological abnormalities occur with myelitis-associated dysfunction, according to the level of spinal involvement. it is important not to ascribe urinary retention to the pain of genital ulceration.5 the prognosis is favourable with acyclovir therapy and intermittent or indwelling catheterisation. the usual time to recovery of voiding function is 8 weeks. antiviral therapy decreases the duration and number of vesicles, but there is no evidence that it reduces the duration of neuropathic bladder dysfunction.6 , 7 it is uncertain whether starting acyclovir therapy after the vesicles have formed alters the outcome. viruses associated with neurological complications that affect bladder function are hsv types 1 and 2 (most common), vzv, cytomegalovirus and epstein-barr virus. radiculomyelitis causing transient urinary retention and sensory lumbosacral symptoms is known as elsberg syndrome.8 the most common diagnostic pitfall with vzv is its confusion with hsv infection. hsv lesions may appear in a dermatomal pattern, especially when involving the thighs or buttocks. the major difference between the two diseases (when hsv occurs in belt-like patterns) is the significantly higher re-activation frequency of hsv. laboratory tests may be required to differentiate hsv from vzv. a definitive diagnosis is made by isolation of the virus in cell cultures inoculated with body fluids. polymerase chain reaction techniques may be used to detect viral dna in the cerebrospinal fluid. heterologous antibody responses to hsv and vzv may occur in some patients because the two viruses share common antigens. in our patient, the clinical picture was in keeping with vzv rather than hsv infection, and the serological tests were compatible with a diagnosis of acute vzv infection.   acknowledgement. written informed consent was obtained from the patient’s mother to take clinical photographs of the perineal skin lesions at presentation and follow-up.     references 1. vafai a, berger m. zoster in patients infected with hiv: a review. am j med sci 2001;321(6):372-380. [http//dx.doi.org/10.1097/00000441-200106000-00003] 1. vafai a, berger m. zoster in patients infected with hiv: a review. am j med sci 2001;321(6):372-380. [http//dx.doi.org/10.1097/00000441-200106000-00003] 2. pandhi d, reddy b. childhood herpes zoster complicated by neurogenic bladder dysfunction. ped dermatol 2004;21(3):279-280. [http://dx.doi.org/10.1111/j.0736-8046.2004.21324.x] 2. pandhi d, reddy b. childhood herpes zoster complicated by neurogenic bladder dysfunction. ped dermatol 2004;21(3):279-280. [http://dx.doi.org/10.1111/j.0736-8046.2004.21324.x] 3. gnann jw. varicella-zoster virus: atypical presentation and unusual complications. j infect dis 2002;186(suppl 1):s91-s98. [http://dx.doi.org/10.1086/342963] 3. gnann jw. varicella-zoster virus: atypical presentation and unusual complications. j infect dis 2002;186(suppl 1):s91-s98. [http://dx.doi.org/10.1086/342963] 4. human sciences research council (hsrc). the south african national hiv survey. pretoria: hsrc, 2008. http://www.hsrc.ac.za/document-3238.phtml (accessed 22 june 2011) 4. human sciences research council (hsrc). the south african national hiv survey. pretoria: hsrc, 2008. http://www.hsrc.ac.za/document-3238.phtml (accessed 22 june 2011) 5. dinh a, salomon j, schoindre y, et al: acute urinary retention due to viral co-infections (hiv, hbv, vzv). jiapac 2010;9(1):20-22. 5. dinh a, salomon j, schoindre y, et al: acute urinary retention due to viral co-infections (hiv, hbv, vzv). jiapac 2010;9(1):20-22. 6. gershon aa, mervish n, larussa p, et al. varicella-zoster virus infection in children with underlying human immunodeficiency virus infection. j infect dis 1997;176(6):1496-1500. [http//dx.doi.org/10.1086/514147] 6. gershon aa, mervish n, larussa p, et al. varicella-zoster virus infection in children with underlying human immunodeficiency virus infection. j infect dis 1997;176(6):1496-1500. [http//dx.doi.org/10.1086/514147] 7. petursson g, helgason s, gudmundsson s, et al. herpes zoster in children and adolescents. pediatr infect dis j 1998;17(10):905-908. [http//dx.doi.org/10.1097/00006454-199810000-00011] 7. petursson g, helgason s, gudmundsson s, et al. herpes zoster in children and adolescents. pediatr infect dis j 1998;17(10):905-908. [http//dx.doi.org/10.1097/00006454-199810000-00011] 8. eberhardt o, küker w, dichgans j, et al. hsv-2 sacral radiculitis (elsberg syndrome). neurology 2004;63(4):758-759. [http//dx.doi.org/10.1212/01.wnl.0000134652.51657.10] 8. eberhardt o, küker w, dichgans j, et al. hsv-2 sacral radiculitis (elsberg syndrome). neurology 2004;63(4):758-759. [http//dx.doi.org/10.1212/01.wnl.0000134652.51657.10] abstract background methods results discussion limitations conclusion acknowledgements references appendix 1 about the author(s) alex e. fischer ezintsha, faculty of health science, university of the witwatersrand, johannesburg, south africa mothepane phatsoane ezintsha, faculty of health science, university of the witwatersrand, johannesburg, south africa mohammed majam ezintsha, faculty of health science, university of the witwatersrand, johannesburg, south africa luke shankland aviro health, cape town, south africa musaed abrahams aviro health, cape town, south africa naleni rhagnath ezintsha, faculty of health science, university of the witwatersrand, johannesburg, south africa samanta t. lalla-edward ezintsha, faculty of health science, university of the witwatersrand, johannesburg, south africa citation fischer ae, phatsoane m, majam m, et al. uptake of the ithaka mobile application in johannesburg, south africa, for human immunodeficiency virus self-testing result reporting. s afr j hiv med. 2021;22(1), a1197. https://doi.org/10.4102/sajhivmed.v22i1.1197 original research uptake of the ithaka mobile application in johannesburg, south africa, for human immunodeficiency virus self-testing result reporting alex e. fischer, mothepane phatsoane, mohammed majam, luke shankland, musaed abrahams, naleni rhagnath, samanta t. lalla-edward received: 17 nov. 2020; accepted: 28 dec. 2020; published: 22 feb. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: human immunodeficiency virus self-testing (hivst) can reduce facility-based hiv testing barriers; however, no proven applications exist with widespread uptake for self-reporting or linkage to care. mobile health (mhealth) applications (apps) have shown high usability and feasibility scores, so ithaka was developed for south africans to self-report hivst results outside clinical settings. objectives: this study investigated the use of ithaka as a support tool for hivst users, specifically the ability to self-report results. method: this cross-sectional study was conducted from november 2018 to june 2019. at existing hivst distribution sites, individuals were given hivst kits and then invited to use ithaka. participants could test at home and report their results through the app anytime. ithaka tracked when people logged-on, registered, received counselling and reported results. post-study surveys on user experience were also conducted. results: of 751 participants, 531 (70.7%) logged onto the app, 412 (54.9%) registered, 295 (39.3%) received counselling and 168 (22.4%) self-reported results. participants strongly agreed that ithaka was useful and that it was easy to upload results. forty-one participants completed a post-test survey, and 39/41 (95.1%) completed the app journey. most participants (36/41;87.8%) had no challenges, although 2/41 (4.9%) cited perceived data costs, 2/41 (4.9%) difficulty uploading results and 1/41 (2.4%) language, as challenges. conclusion: despite the small sample size, this study has shown that hivst participants under pragmatic conditions were willing and able to self-report results via the app, whilst also identifying areas of improvement for scaling up. keywords: hiv; hiv self-test; self-reporting; mobile app; mhealth; monitoring and evaluation. background human immunodeficiency virus self-testing (hivst) can reduce barriers associated with conventional facility-based hiv testing, and since its introduction in 2012, more than 6.5 million hivst kits have been distributed globally.1,2 in 2018, south africa integrated hivst into its national hiv strategy as a way to expand testing beyond standard healthcare facilities to meet the unaids 90-90-90 target.3,4 these targets state that 90%, 81% and 73% of the total population should know their hiv status, be linked to antiretroviral treatment (art) and experience viral suppression, respectively.5 despite the benefits of hivst, there are some gaps associated with its use, as it is hard to track and is only classified as tests for triage, which should not be considered diagnostic.6 furthermore, south africa does not have an appropriate system for users to self-report their results, or be linked to care, and this lack of reporting makes it difficult for public health stakeholders to conduct monitoring and evaluation on the uptake and effectiveness of hivst, especially at the population level.7 over the last decade, lowand middle-income countries have experienced an increase in mobile coverage and smartphone use, which has qualified the introduction of mobile health (mhealth) interventions in these regions.8,9,10 there is a strong body of evidence supporting the use of mhealth interventions to enhance patient outcomes for a broad spectrum of health conditions, including hiv. in low-income settings specifically, different interventions have targeted various stages of the hiv care cascade, including text message campaigns, telephone hotlines and mobile applications (apps).6,11,12,13,14 south africa has been investigating the use of mhealth interventions to accompany hivst for users to self-report their results, and in a recent study, 9.8% of participants self-reported their results by using an interactive voice response telephone hotline.15 feasibility studies have also been done on the hivsmart! app and the aspecttm app; both mobile apps guide self-testers through the testing and reporting process. these apps were both tested in a clinical setting, under the observation of healthcare workers (hcws), and whilst both the apps reported high usability and acceptability, they did not investigate the reporting of results in a non-clinical setting as an outcome.16,17,18,19 the ithaka app (aviro health, cape town, south africa) has been developed to close this gap by providing untrained hivst users a mobile platform to self-report their hivst results independent of a formal clinical setting, whilst also removing the potential for observational bias. the objective of this study was to investigate the use of ithaka as an hivst support tool for individuals, specifically the ability to report self-results outside a clinical environment. methods study design this was a cross-sectional evaluation conducted from november 2018 to june 2019 with a random sample of 751 consenting adults from the general population of inner-city johannesburg, south africa. people who received an hivst kit were invited to participate in the study. as per the hivst programme, requirements to receive an hivst kit were if they had willingness to perform an hivst, had not tested for hiv in the previous 3 months, had a mobile phone compatible with the app, were 18 years or older, were able to read english and were able to provide written informed consent. participants were excluded if they were known to be living with hiv, were a practising hcw or if they were taking drugs that could affect the sensitivity of the test, such as pre-exposure prophylaxis, art or an experimental hiv vaccine. before the study, a 2-week pilot period that included 41 people was used to improve operational issues, refine the content and user experience of the app and confirm the linkage between the data collection and data analysis datasets. app development the ithaka self-test support tool is a mobile phone-based tool to support users through self-testing and eventual confirmatory testing. it is a progressive web app (pwa), which is accessible as a reverse-billed mobi-site, where the provider pays any data costs, rendering the tool free to end users. the ithaka platform provides users with a tailored journey to encourage user retention, reporting and linkage to care, as well as gamification to boost user engagement. ithaka guides the patients through the various testing steps and will prompt the users to report back on their status, progress, emotional state, information comprehension and user satisfaction. before conducting the self-test, users must complete a brief counselling component that explains the test process, and what to expect after obtaining the results; however, if users want more information, they can access integrated chat-based help at any time, or request a call back from a call centre. in the event of a positive hiv result, the study participant is referred for clinical treatment and care, whilst participants who test negative will be counselled and encouraged to seek confirmatory testing at 3 months. the ithaka platform is secure, with unique user profile logins and encrypted back-end databases to ensure data security and patient anonymity in line with the protection of personal information (popi) guidelines.20 furthermore, stakeholders can receive real-time data on how users are engaging with the materials and platform. screenshots of ithaka are presented in figure 1. figure 1: ithaka screenshots. data collection hiv self-testing africa (hstar) is an hivst distribution and research programme that supplies free oraquick® rapid hiv self-test (orasure technologies, bethlehem, usa) to people in region f of johannesburg, south africa, through fixed-point distribution sites. these sites were also used to recruit participants for the ithaka study. to collect a random sample and minimise disruption to the regular hstar programme (since recruitment was being performed by the distribution team), one random day each week was used to recruit participants for the ithaka study. after an individual received their self-test, peer educators invited them to participate in the ithaka study. no additional log was maintained to document individuals who declined to participate. if an individual showed interest, the peer educator provided detailed information on the ithaka study and obtained a written informed consent prior to administering the pre-survey questionnaire. the peer educator helped the participant log into and register on the app on the participant’s phone, which was available through a uniform resource locator (url). data were collected from three sources as follows: pre-study survey: an in-person survey was conducted by peer educators to capture demographic information, including age, education, shared phone, gender and location. ithaka platform: the app tracked user engagement marked by logging on, registering, receiving counselling and reporting results. post-study survey: a telephone survey was conducted to obtain user feedback on the app, which included likert-scale questions ([1] strongly disagree; [2] disagree; [3] neither agree nor disagree; [4] agree; [5] strongly agree) and open-ended questions. the likert scale was used to understand the user experience of ithaka (asking ratings on usefulness, ease of use, empowering, trustworthiness, ease of understanding and reliability), and whether it decreased barriers to report results, find a clinic, read frequently asked questions (faqs), get reminders and make referrals. participants were asked open-ended questions regarding their discontinued usage of the app, challenges using the app and if they would recommend it to a friend (appendix 1). all participants were invited to participate in the post-study survey via a phone call to the number they had provided. participants were eligible to participate if they provided consent and had completed the app journey, making it to the final reporting results stage, and answered all survey questions. data analysis data from the surveys and ithaka database were cleaned in excel (microsoft, seattle, usa) and then exported to stata v.14 (statacorp, college station, usa) for analysis. demographic information and questions about app usage were described with frequency and percentages. user flow through the app was tracked and then presented with frequency and percentage through each stage. likert scores were averaged and presented as a number between 1 and 5, with numbers approaching five representing favourable outcomes. ethical consideration and approval ethics approval was obtained from the human research ethics committee of the university of the witwatersrand, reference number: 180708. all participants provided written informed consent. the app was made available as a reverse-billed site, so participants did not incur data costs, but participants were provided no reimbursements for their time in the study. results demographics a total of 751 people participated in the study. nearly half of the participants, 340 (45.3%), were between the ages of 26 and 35 years, a third were 25 years old or below, 231 (30.8%) and about a quarter above were 35 years of age, 175 (23.3%). four hundred and thirty-one (57.4%) participants were female, and 634 (84.4%) did not share mobile phones with anyone. only 3 (0.4%) participants had a primary school education, 444 (59.1%) had a secondary school education and 203 (27.0%) had a tertiary school education, or higher. the complete demographic characteristics are presented in table 1. table 1: demographic characteristics. ithaka use figure 2 shows the cascade of ithaka use from the point of enrolment to reporting hiv results. approximately, three quarters, 531 (70.7%), logged on to the app. more than half the enrolled participants, 412 (54.9%), completed the registration process, 295 (39.3%) enrolled participants completed the pre-test counselling and the how-to-test instructions and 168 (22.4%) enrolled participants self-reported their results. of the 168 participants who self-reported their results, 14 (8.3%) reported as hiv positive. figure 2: user journey through ithaka: november 2018 to june 2019. ithaka user experience of the 336 participants who were successfully contacted for the post-test telephone survey, consent to participate was provided by 190 (56.5%) participants, although only 112 (33.3%) were eligible for the post-study survey, and 41 (37.3%) completed the entire survey. to quantify the user experience, mean likert scores approaching five represented strong agreement with the statement, whereas scores approaching one represented strong disagreement with the statement. the two statements, ithaka made it easy to upload results and ithaka made it easy to find a clinic had mean likert scores of 3.8 (sd = 1.6) and 4.2 (sd = 0.9), respectively. all other user experience statements were strongly agreed with, receiving ratings that were above or equal to 4.5 (sd = 0.5–0.7). the mean likert scores are presented with standard deviations (sds) in table 2. table 2: mean likert scores for user experience. when participants were asked why they had stopped using the app, 39/41 (95.1%) respondents stated that they used the app to completion, whilst two (4.9%) stated that they stopped because they were unable to upload their hivst results. all 41/41 (100.0%) participants who responded stated that they would recommend the app to someone else, with respondents citing ease of use 12/41 (29.3%), liking the app 4/41 (9.8%) and privacy 2/41 (4.9%) as the main reasons for why they would recommend it to someone else. most of the respondents, 36/41 (87.8%) stated that they did not experience any challenges or difficulties whilst using the app; however, 2/41 (4.9%) respondents cited data costs as a challenge, 2/41 (4.9%) respondents stated that they had difficulty uploading results and 1/41 (2.4%) respondent stated that he or she had experienced challenges because of the app languages. all user experience questions are presented in table 3. table 3: open-ended user experience questions. discussion to our knowledge, this is the first study in south africa to evaluate the use of an mhealth app to self-report hivst results as an outcome, independent of observation in a clinical setting. previous feasibility studies have shown high acceptance of mhealth apps for the monitoring and evaluation of hivsts; however, they only evaluated usability in the presence of hcws and did not evaluate any reporting outcomes through the app.16,17,18,19 similar to these previous studies, the ithaka app showed high self-reported usability amongst those interviewed, whilst also confirming that participants under real-world conditions were willing and able to self-report their results via the app. the self-reporting of results by logged on participants through the ithaka app was 22.4%, which is acceptable, considering that it is common for apps to lose up to 80% of their active users in the first week.21 furthermore, the percentage of hivst results reported through ithaka was more than twice that of a previous tele-health intervention in south africa, which only led to 9.8% of participants self-reporting.15 despite this increase in self-reporting and high usability likert scores, 43.1% of participants who received counselling (a proxy for completing the self-test) still did not self-report their hivst results, which leaves opportunity for improvement. although field testing of ithaka followed a 3-month human-centred design (including personal and journey mapping) and a 2-week pilot testing, a percentage (12.2%) of surveyed participants did experience challenges with the ithaka platform. this not only suggests that users may need more than a brief introduction from a peer educator but also suggests that the technology development phase requires several iterations with greater consideration for pragmatic value propositions and testing of varied content or messaging before inclusion. going forward, focus group or follow-up interviews with participants who did not complete the app journey could be conducted to further identify areas of improvement that caused participants to cease activity on the app. similar to reports of other south african digital health interventions, for users to completely embrace ithaka and realise its full use, marketing campaigns can be used to create awareness, followed by a more comprehensive onboarding to motivate users.22 although practical reasons for stopping the use of the app, such as forgetting to log back in or not using the test yet, should be mitigated with text message reminders, which have been shown to improve the user responsiveness of other mhealth apps,23,24,25 we did not find this in our study in which registered participants received reminder messages on day 1 and day 7. some participants cited data costs and network issues as challenges to the app, and these are well-documented barriers for any mhealth app to enter into the south african market;6,22 however, ithaka was a reverse-billed online platform that removed the barrier of data costs. as a reverse-billed platform, any and all data costs for using the platform are paid for by the service provider (ithaka), and the end-users do not incur any costs, nor do they use any of their own data whilst on the platform. there may have been some confusion by study participants regarding the meaning of reverse-billing, and this beneficial feature should be sufficiently explained to users in the future, so they know that no costs are incurred on their end whilst using the platform. in south africa, there is currently no endorsed platform for users to self-report their hivst results, or be linked to care following a positive test,6 which makes the monitoring and evaluation very ineffective for the government and associated public health stakeholders.7 this study has shown that as a proof-of-concept, hivst users are willing and able to self-report their hivst results via the ithaka app, and this sharing of information on a national scale could greatly improve hivst monitoring and evaluation. whilst this study focussed on self-testing, which directly addresses the gap between the first 90 and the 85% of hiv-positive south africans who know their status, it does not address the country’s largest deficit, as only 71% of people who are eligible for art are actively receiving treatment.26 ithaka could continue to increase active users by sending out reminders to encourage the self-reporting of results and keep users engaged by promoting linkage to care opportunities. to improve accessibility and usability, the ithaka platform has since been extended to whatsapp and to support blood-based tests. the ithaka platform has also undergone a number of processes and content changes that were implemented as a way to continue improving on the hivst reporting rate. in addition, extensions to the tool to support and confirm linkages to care and improve initiation and viral load suppression are currently undergoing piloting and development. limitations this study presented some limitations. participants were recruited through existing hivst distribution points, so individuals may have had previous exposure to hivst studies, and potential study fatigue may have influenced their willingness to participate. because of this exposure, participants may have a greater base-level background knowledge of hivst than the general population. the ithaka app was only available to individuals with mobile phones capable of running the current iteration of the app and does not include individuals who could not access the app because of different operating systems or memory capacity. furthermore, a peer educator helped participants log into and register on the app, which may have influenced the ease of use and initial components of the cascade. the use of only one hivst kit means that these results also cannot be generalised across all hivst kits. additionally, only 8.3% of participants self-reported an hiv-positive result, which is much lower than the national prevalence of 13.1%, and this may be because of a selection or reporting bias, where individuals who may be hiv positive did not participate or report their positive results. the views presented of the user experience responses may not represent the views of the study population as only participants who completed the app journey and answered all questions were included in the post-study survey results. the low completion rate for some of the survey questions represents a minority of the group and a larger minority in relation to the general population. lastly, the post-test survey was conducted via voice call, which may have attributed to this low completion rate. conclusion millions of hivst kits have been distributed globally; however, there is currently no universally accepted platform for users to self-report their hivst results, health behaviour and outcomes in line with the hiv care cascade. this study has shown that hivst users outside the clinical setting were willing and able to self-report their results via the app. this could be used on a national level to improve the monitoring and reporting of hivst programmes, leading to the optimisation of kit distribution, and targeted marketing and support. the use of an app introduces the possibility to promote and improve linkage to care, counselling and follow-up for newly tested hiv-positive users. this, together with exploring other popular channels for making digital services available such as whatsapp, needs to be explored further to ultimately enable the development of an app that is user friendly, cost efficient and beneficial to hiv programmes. acknowledgements the authors would like to acknowledge all study participants. competing interests l.s. and m.a. work for aviro health and were involved in the design of the ithaka hivst app. authors’ contributions l.s., m.a., n.r., m.p. and m.m. designed the study. l.s., m.a., n.r. and m.p. collected data, l.s., n.r., m.p., s.t.l.-e. and a.e.f. were involved in the data cleaning and analysis and a.e.f., s.t.l.-e., m.p. and l.s. wrote the initial draft of the manuscript. all authors critically reviewed and approved the final draft. funding information this study was funded by the bill and melinda gates foundation (grant number opp1189095) and unitaid star (grant number unitaid-2017-17-sfh-star). data availability the data that support the findings of this study are available from the corresponding author, a.e.f., upon reasonable request. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references wong v, jenkins e, ford n, ingold h. to thine own test be true: hiv self-testing and the global reach for the undiagnosed. j int aids soc. 2019;22(s1):e25256. https://doi.org/10.1002/jia2.25256 figueroa c, johnson c, verster a, baggaley r. attitudes and acceptability on hiv self-testing among key populations: a literature review. aids behav. 2015;19:1949. https://doi.org/10.1007/s10461-015-1097-8 unitaid, world health organization. market and technology landscape: hiv 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https://doi.org/10.2196/10258 mcgill university health centre foundation. hiv smart app [homepage on the internet]. 2016 [cited 2020 mar 18]. available from: https://www.muhcfoundation.com/current-projects/hiv-smart-app/ gous n, fischer a, rhagnath n, phatsoane m, majam m, lalla-edward st. feasibility and acceptability of a mobile application to support hiv self-testing in johannesburg, south africa: a pilot study. s afr j hiv med. 2020;21(1):a1088. https://doi.org/10.4102/sajhivmed.v21i1.1088 republic of south africa. government gazette, act no 4 of 2013: protection of personal information act, 2013. cape town: the south african government; 2013. sigg s, lagerspetz e, peltonen e, nurmi p, tarkoma s. sovereignty of the apps: there’s more to relevance than downloads. cornell university: comput soc. 2016:arxiv:1611.10161. seebregts c, dane p, parsons an, et al. designing for scale: optimising the health information system architecture for mobile maternal health messaging in south africa (momconnect). br med j glob health. 2018;3(suppl 2):e000563. https://doi.org/10.1136/bmjgh-2017-000563 mugo pm, wahome ew, gichuru en, et al. effect of text message, phone call, and in-person appointment reminders on uptake of repeat hiv testing among outpatients screened for acute hiv infection in kenya: a randomized controlled trial. plos one. 2016;11(4):e0153612. https://doi.org/10.1371/journal.pone.0153612 arora s, peters al, agy c, menchine m. a mobile health intervention for inner city patients with poorly controlled diabetes: proof-of-concept of the text-med program. diabetes technol ther. 2012;14(6):492–496. https://doi.org/10.1089/dia.2011.0252 fischer ae, sebidi j, barron p, lalla-edward st. the momconnect nurses and midwives support platform (nurseconnect): a qualitative process evaluation. jmir mhealth uhealth. 2019;7(2):e11644 https://doi.org/10.2196/11644 human sciences research council. the fifth south african national hiv prevalence, incidence, behaviour and communication survey, 2017: hiv impact assessment summary report [homepage on the internet]. 2018 [cited 2020 apr 5]. available from: https://www.aidshealth.org/wp-content/uploads/2018/08/hsrc-survey-2018-summary.pdf appendix 1 programme monitoring robin wood, bsc, b.\!, dt.hi:-h, .ihid, fcp (s.4) linda·gai! beller, .iib chb, fcp (sa), dt.hi:-h, phd hiv research l.:nit, departme711 of .\ledicine, c.;nit:ersity of cape to'c.:n a proposed register documenting entry criteria and recording arv scheduled therapy would allow an overall audit of programme performance in a similar fashion iq that of tne tb register. incorporation of the national id number in conjunction with national death registration data would allow calculation of the sunival of patients entering the programme on an 'intention to treat' basis [fig. 1). there is a urgent need to establish a minimum data set required to allow evaluation and comparison of arv projects in africa. programme will need to be of a similar magnitude to that of the tb treatment programme and will face similar challenges as high levels of adherence to potentially toxic drugs are required for a prolonged period of time. the tb control programme utilises a standard two-scheduled approach to drug therapy, which simplifies the operational implementation necessary for a large national programme. art treatment register the national tb register allows performance assessments to be made of individual clinics and ultimately the programme as a whole. similarly, an art scheduled approach would simplify training and education of medical personnel and would result in predictable patterns of toxicity and of resistance. a predetermined standardised sequence of drug combinations would also limit the number of drugs to be procured and managed. comparison of these data with modelled survival of patients determined by baseline characteristics at entry to the programme would allow calculation of life-years gained by the programme. a national art programme would utilise large quantities of relatively expensive drugs, and the financial burden of poor drug accountability could seriously undermine such a programme. the arv treatment affordable national haart programme examples of highly successful arv programmes in countries at a comparable stage of developmen to sout ern african countries, and with similar socioeconomic challenges, are the arv (haart) programmes incorporated into tne brazilian public health care system' and the pilot projm instituted in rural haiti, the poores country in the western hemisphere: a concern that widespread, unregulated access to antiretroviral (arv) drugs in sub-saharan africa could lead to the rapid emergence of resistant viral strains, spelling doom for the individual, curtailing future treatment options, and leading to transmission of resistan' virus, has been voiced.' this pessimistic perception 0' the outcome of haart programmes in resource-poor settings is not inevitable, if a well-organised national treatment plan is developed. highly active antiretroviral therapy (haart) has greatly improved the prognosis of hiv-infected individuals in a' uent countries, resulting in a marked drop in aidsrelated mortality'·' in order to extend the benefits to resource-poor countries, the world health organisation [who) has called for expanded access to art.' des ~lartin, .ifb chb, .i'l\!,d, dt.i!&h, dph uni',:mio' oj tlu 1f'il"..::acmtand and hiv clnlu;i.ans societ)' penny penhall hw clinicians s0ci2ty perceptions of southern african and other resource-poor sffilngs national antiritroviral treatment register a necessity? wi:n 360 000 estimated aids cases in south afcca·' an art in ongoing discussions surrounding the roll-out of arvs by the state, cost is often mentioned as one of the 'problems: in fact, a costing model of a rationed national haart programme has recently been shown to be affordable within present south african budgetary constraints' and elements of civil society are now demanding increased access to haart in the puolic health sector.; ~ i \ ~ ... ~" . '1' =j .... : '5: ~ <u o o '"" ~ :i= ch en o c:: ~ :i= ch ;0 = :>,., ::= r> :> = co c:: ;0 = :> ~ =,., :i= <: '5: ch = r> =~ p.aujintlnf. ge....'fnlprmtdpn sjlbo<l~~1lii.jlae<ij cllan\1&a wuhln 8chqdultl1 sjlbo<lulti.lermwt.jn!llbl1jlf.liii'ijl) ..--n_ 'comliliiiiiii •rfjqno whooll__ , .. • 0816,tarted ~ da" from to reasoo date 8larted i:::::j """ fmm to rn.on ""..imll 11 :r:dilojioilt 1-20 changa 1 12111102 b2 bl 1 change 1 81_""•.,~iona i dill diiqf\011i ~~ 11/10f02 al-azt 81 .. nvp change 2 07/01103 a3 a 2 "'1.azt ct.nfv 01 .. ka!elra, chang.2 'il"an"'rrtdi a2 .. 3tc 82 .. efv change 3 04/23103 a6 a2 1 1.2 .. 3to c2 _ino 02 .. sqvlr change 3 ::10 loiiow·upid no check co. 00lli1l ib 1211102 a3 .. d4t chango 4 a3 .. d4t chsav 03.inojr chilnge .. i ivlfiliold 1 11 a4 .. dd! change 5 m.ddl c" .amp d1-amp/r chanoe is a5·ddc chanoe 6 a.6. c1dc chbi)ot 6 ~~ ~ a6 .. abc ao. "bc "dmghlllory rea lion lor change 1 .. intoloranca mfar curranl therapy 2 .. laboratory tolllclty r"alon lor change 1 .. intolerance -"iazf 131c invp i 3 .. vlrallallure current thlrlpv 2 .. laboratory toxlcltvnb if vlrojoglcm failure proceed to ichedul6 2 3 .. failurti.. c other 4. other heano who ciin.., '''110 ' ... 3 dat6 startod ~ nb" vlroiogica!!~lurep~ 10 s;'!!eduled~ oala ~l.rted ~ "".. from to reason 0...imf' 21 8lqlno dlag..." '·eo chonge 1 ~ chang.l 12/12103 cl dl 3 """"-idno lli.. oi*_ 11101101 al. an 81. nvp chof'108 2 a1.all c1. nfv 01 .i<alelra change 2 -...i i .... a2.3tc 82. efv change 3 a2 • 3tc ci:. ino 02. sowr change 3 ...~~idna check i c04_ 30 110 101 a3 .. d4t chaf'1084 a3 -d4t c3·sav 03.indlr cl'lang84 """i v1ii1 !old 3.45 11101101 m.dd1 chrnne 5 a4. ddl c4. amp 04. amp/r chang.6a5. lidc chongs 6 a,5·ddc change & a6. abc 'aa-aac 0"'11_ •• raabon lor chango 1 • intolorance2 '" laboratory toxlcuy rellcn for change 1 • intoleranceloltar 3 • vlrallallure cl.lrrenltrr 2 '" laboralory 1000101ly.,nb "vlrojog/cal 'allure proceed 10 sclllk/uie 2 ikoiolra i 3. 'allureiazt a 4. other 4. oiher liko who ll!nioii.... 1-4 ~ date 8tarted ~ dat. from to reason dele ,tarted i:::::j da" fmm to r...o' §3: ="== :. changb 1 1102 a3 a4 1 ch.nge 1 --:~ 0910 1 al. an 91. nvp change 2 a1-azt cl. nfv 01 • kaletl'8 ch.nge 2 ~---a;;; a2 _ 3tc 62 • efv chango 3 a2-3tc c2.ind 02 .. sqwr change 3id no check cq~11 1 a3 _ dh change 4 a3.d4t ca. sqv 03.ino/r change 4t ' n~ " ,,-", i villlioici 4.45 11/01 1 a4 • ddl change 6 m-ddl c4. amp 04. amp'r change 5 a5. ddc change 6 ab. ddc chang.6a6 _ abc m.abo ~ *s rea80n for change 1 • inlolerallce ~ 1i!1li~ current therrp 2 • laboratory loxlclty a.aaonlor change 1 -intolerance [ddl ijt iefv i 3 • vlrallallure 2 _laboratory 1000lcltv.,ns if v/rolqglctll failure procfhki to sclloollle 2 3. fallura 4", other 4 .0ihe!:r reqno -m:=r~ dale alerted c:::=:::j dat. from to r.."", d.la a18rttd c:::j 0.1t from to ""'''''' 0iiti '=--= change 1 12/11102 al a3 , cila""" , 12/12103 al a3 --~ujno a1.azt b1.nvp change 2 at"all c,_npv 01 _ kalltll1 change 2 -,.,i i a2 • 3tc 82 • efv change 3 a2.3to 02. ino 02. sovlr ch8noe 3 =to 1oi1c1woup . .;ip no ctlbck i 004 .....' '"," " a3 • d4t change 4 a3 .. o4t c3·sqv 03. tndlr change 4 i a4 • ddl ch&noe 5 a4" ddl c4 _ amp d4 _amp/r chanoe 5y1l"11ta1d no a5 • ddc change 6 a6 .. dele chl1'lq86 a6.abc ~.a8c reason tor change 1 " inlolerance drug h!.1ofy ~~ ~ current thorap 2 • laborolory toxicity aeaaon iqr change 1 "lnlolel1nca ""war i dlil i jl !nvp i 3 .. viral laliure oii1pv 2 " laboratory loxlally>1whk nb /f ",irolog/csl failure proceed to scflodule 2 ! i 3. falfura 4", other 4" oiher fig, 1, proposed web-based art register. tilt soutlltrn mrican journal of iiiv medicine -----------register at any institution could be reconciled against drug purchases by that institution for drug accountability purposes and to identify and avoid 'drug seepage: specific questions such as impact of prior exposure to mother-tochild transmission preventive therapy on subsequent response to art could be answered by analysis of the register database. blood sampled at the time of failure of the first schedule could also be stored for national viral genotyping surveys, which could give information on patterns of viral resistance, which in turn would allow scientifically based changes in scheduled drug choices. an art register would need to be a standardised form that could be in either paperor web-based formats. as art will be provided at health care facilities other than tb clinics the administration of the register would need to be the responsibility of organisations such as the national or provincial aids directorates. outcomes the major outcomes of a successful art programme would be a decrease in aids morbidity and mortality. while cd4 cell counts, clinical stage and viral load determine prognosis of untreated patients, effective viral suppression by art is the major determinant of outcome on treatment" national and international art guidelines have been developed and published, which give clear initiation criteria and recommended therapy combinations and could be used as a basis for scheduled drug choice.'·" lessons from the tb control programme to encourage the correct usage of art, it has been suggested that the art programme be closely linked to and managed within the tb control programmes of subsaharan africa.' art canno~ however, be isolated from the wider comprehensive approach to hiv and aids patient care, including management of the psychosocial and other medical complications, such as prophylaxis and treatment of opportunistic infection.'·' it would not be practical or prudent to burden the tb control programme with this heavy responsibility. a scheduled art approach could be a useful method to enable wider, more equitable access to art within our existing health infrastructure, and an art register would be a tool to monitor the overall performance of such an expanded access programme. while expanded access to art should not be the responsibility of the tb clinics, there may be important lessons to be learned from the programmatic methodological approaches of the national tb control programme. protocol outune the proposed register would be web-based with passwordprotected access from registered pcs only. entry of the individual national identity number would lead to an allocated site registration number, which would be used in all future communications. the proposed format of the register is shown in fig. 1, and all data entry will be by 'point and click' menus. baseline data will be entered including age, sex, who stage and staging conditions, baseline cd4 count and the initial treatment schedule chosen by the practitioner. subsequent changes in treatment regimens would be categorised as due to toxicity, drug intolerance or viral failure together with dates of changes. the present drug regimen will be shown in an automatically updated regimen box. blood samples for genotyping will be stored at each change of therapy triggered by viral failure. automatic e-mail requests for patient status will be generated to confirm whether subjects are still actively followed up or lost to follow-up. funding has been sought to perform genotyperesistant pattern at the time of first failure of the second regimen. it is intended that these data be made available to the clinician for clinical decision-making. register outputs the register is intended to act as a pilot audit of current arv clinical practice and to develop a tool for monitoring increasing widespread access to haart. the primary aim is to assess the overall prognosis of subjects initiating haart treatment in south africa by establishing 'intention to treat' survival. secondary end points include length of time on first non-nucleoside reverse transcriptase inhibitor (nnrti)-based regimen in clinical practice, time to first virological failure and comparative tolerability of different starting regimens. initial viral resistance genotype data will be made available for longitudinal population surveillance of circulating pre-treatment resistant mutations. subsequent genotypic data will reflect viral response to present drug pressure and aid clinicians' therapeutic choices after failure of the protease inhibitor (pi)-based regimen. participation it is envisaged that members of the sa hiv clinicians society who are experienced treaters participate in the programme by entering the password-protected internet site from registered pes. as indicated above, the entry of the individual national identity number would lead to an allocated site registration number, which would be used in all communications. participating medical practitioners would be required to recruit drug-naive patients and be willing strictly to follow the current hiv clinicians society guidelines. the initial regimen would be an nnrti-based regimen and the may 2003 guidelines gayle g sherman, me bch, dch (sa), dtm&h, mmed (haem) department of molecular medicine and hamullofggy.johannesburg hospiuzl. nazional health labararory service and university of cbe wi",,,,umand, ]oiuznmjlnng infant hn diagnostic guidelines to facilitate adoption !>errings: guidelines for a public health approach. geneva: who, 20025. harries ad, nyangu1u os. hargreaves nj, kaluwa 0, salaniponi fm. pr~enting antiretroviral anarchy in sub-saharan africa lancet 2001; 358: 410-414. 6. lrli gc, vitoria ma. fighting against aids: tn/:' brazilian ~jence. aids 2002; 16: 2373~238j. 7. farmtt p, ~nd(e f, mukherjee 15, ~r al community-based approach~ to hiv uea!metlt in (~urct·poor settings.. lona:r200l; 358: 404-409. a soulle a. kenyan c. skordis j, wood r. rationing haart part i: an ~iotation of the rosts of a limited public sector antiretroviral ueatmem programm~ in south africa. saf, mn)2002; 92: 811-817. 9. bredeu consetlsus statement on the irrperative to expand acttss to antireuoviraj medicin~ fur adults and o1ildren with hfv{a1ds in south africa. noveffloo2001. national tret1tmenr congress resourct docum~nr numb~r 12. cape town: treatment action campaign. 10. report on the global hivialds epidemic. joint united nations programme on hn!alds (una/osj. geneva: unaids, july 2002. 11. egger m, may m, chene g, et al. prognosis of hiv-1-infe<:ted patients starting highly active antiretroviral tilerapy: a collaborative analysis of prospective studies. lancer 2002; 360: 119-129. 12. southern african hiv clinicians society. clinical guidelines: antiretroviral therapy in adults. june 2002 vtrsion. sourhern african journal of hn medicine 2002; july (issue 8): 22~29. the qualitative hiv polymerase chain reaction (pcr) test is highly specific for hiv infection, but sensitivity varies with the age of the infant' the per identifies approximately 50% of infected infants at or just after birth and> 95% at 3 6 months of age" more recent evidence suggests that hiv pcr tests performed at ~ 1 month of age have a sensitivity of ~ 95% and specificity of > 99<\'0.' the roche amplicor kit (roche molecular systems, somerville, nj) ------------the southern african journal of hiv medicine 1. morcroft po, \/tlla 5, benfield n.. eta/' changing mortality across europe in patients infected with hn-1. lancet 1998; 352: 17251730. moore ro, chaisson re. natural history of hiv infection in the era of combination antiretroviral therapy. aids 1999; 13: 1933-1942 3. palella fj, dejaney km, moorman ac, er 01. declining morbidity and mortality among patients with advanced human immunodeficiency virus in~tion. n englj mm 1998; 338: 853-860. 4 world health organisation. scaling up anrirecrovirol therapy in r~itt-lim;red subsequent or second-line regimen would be pi-based. references any interested treaters who would like to participate should e-mail the managing editor of the southern african journal of hiv medicine at igbekker@cormack.uctac.za, expressing the number of patients likely to be treated at their site in the next year. south africa is currently estimated to have 300 000 hiv/aids orphans, and the figure is likely to increase to 2 million by 2015.' facilitating adoption of children affected by hiv provides a highly effective strategy for addressing the hiv/aids orphan crisis, albeit on a very small scale. the legal and ethical issues surrounding hiv testing of abandoned children for the purposes of adoption are not addressed here. these guidelines were contributed to and are endorsed by: or ashraf h coovadia department of fljediorrics, coronation hospital, and university of the witwatersrand or mark f cotton fljediatric infectious disease unit tygerberg children's hospito( university ofste/lenbosch or glenda e gray perinatal hiv research unit chris hani-barogwanath hospital and university of the witwatersrand professor gregory 0 hussey school of child and adolescent health, university of cape town or leon j levi n puediatn·cian in pfnate practice or tammy m merers department of fljediatrics, chris hani-baragwanath hospital and university of the witwatersrand professor lynn morris aids unit national institute for communicable diseases and university of the witwatersrand or adrian j puren national institute for communicable diseases and university of the witwatersrand or wendy 5 stevens department of molecular medicine and haematology. national health laborotory service and university of the witwatersrond or lynne m webber department ofmedical virology, university of pretoria may 2003 th~ author (middle) wich colfeogut::5.. may 2001-------------the southern african journal of hiv medicine in rural areas far removed from the main cities and towns where public hospitals and clinics have established hiv/aids programmes, referral is usually restricted by financial and other constraints, e.g. nowhere for the patient to stay while accessing treatment, absenteeism from work and family responsibilities. organisations (ngos) and/or church groups. at present there is a glaring lack of co-ordination or common approach by the main stakeholders ngos, government, business, traditional healers and medical practitioners. the redeployment of existing health personnel trained in hiv management from the major public medical service providers to heavily populated rural areas (in the manner of china's 'barefoot doctors') would go some way towards alleviating personal and family suffering. prevention rural realities /t is common know/edge thot in order to be effective, hiv/aids progrommes need to include the following components: • prevention ospects • care options, and • personol ond community support. this article addresses same of the issues which impact on attempts by medial professianals to deliver 0 meaningful level of care to locol rurol communities. bonaventure nyathi, mb chb, amp (mbsj . lomnkgale medical centre, namnkgale, northem prcmillce news and views unemployment and resultant poverty in many rural parts of south africa dictate that most people live from hand to mouth, with their main objectives being to fill empty bellies and ensure a roof over their heads. a desire to learn about a dread disease shrouded with uncertainty and social stigmatisation is near the bottom of their list of basic human needs. poverty, together with a high level of illiteracy, results in ignorance, which in turn is compounded by the fact that most educational resources are not easily accessible iclinics/hospitals distance from the community), or in the local language. community counsellors need to be trained in the vernacular. mentorship of these programmes would probably be most successfully organised by local non-government the southern african journal or hiv medicine -------------may 200 i inadequaie or non-exisieni laboraiory faciliiies coupled wiih ihe high cosi of iescs (especially cd4 couni and viral load) make definiiive diagnosis, siaging and moniioring of hiv disease difficuli if noi impossible, pariicularly in paiienis wiih iuberculosis. even if aniireiroviral drugs for ihe preveniion of moiher-to-child iransmission are available, which moihers would you give ihe aniireiroviral io? the pool of infeciion simply geis larger. the majoriiy of rural paiienis wiih hiv and aids-relaied condiiions are unemployed and can hope io receive ai mosi rudimeniary home-based care. those who are employed are seldom on medical aid, and earn comparaiively small wages. this impacis on ihe exieni of provision of even 'cheap' prophylaciic ireaimeni for opporiunisiic infeciions. to ihose rural people living wiih aids (plwa) who do undersiand ihe posiiive impaci of aniireiroviral therapy on lengih and qualiiy of life, ii remains an almosi unobiainable luxury. support despiie media inierest in fosier care and adopiion of aids orphans, none of ihese often-reporied programmes! aciiviiies appear visible and iherefore accessible io mosi rural privaie praciiiioners or, for ihai mauer, io families decimated by ihe virus. souih africa is a couniry crying oui for skilled workers and in need of such basic faciliiies as rudimeniary home siruciures, safe running waier and home grown-producis, bui ihere seems io be no auempi io harness ihe manpower offered by people living wiih hiv who are siill in good healih. there is a dire need for a sysiem enabling funciional neiworking wiih naiional and iniernaiional organisaiions io promoie rural educaiion, iraining and funding of projecis. perhaps research projecis focusing on prevalence, subiypes and managemeni opiions need io be encouraged io include communiiy aspecis in iheir budgeis. drug irials and vaccine developmeni programmes should noi be sanciioned unless ihey include elemenis of communiiybased service and social responsibiliiy. solutions siraiegically placed cenires for chronic disease managemeni wiih special emphasis on hiv!aids managemeni should be esiablished in rural communiiies, wiih iniiial preference given io those wiih a high incidence of people living wiih aids. these cenires should be partnerships beiween governmeni and ihe private secior. such insiiiuiions could co-ordinaie all ihe various aciiviiies and programmes iaking place in iheir immediaie viciniiy wheiher privaiely funded or oiherwise, and wheiher local or iniernaiional. relaied organisaiions, including ihose run by religious groups, iradiiional healers and treaimeni aciion campaigners, should be housed iogeiher in ihis hub. this approach should go a long way iowards avoiding duplication of services and wasiage of finiie resources. ideally, ihis kind of cenire should offer educaiion, iraining and counselling for healih care and educaiional professionals as well as inieresied communiiy members. awareness and preveniion communicaiion campaigns could be run from ihese cenires wiih a sirong emphasis on communiiy ouireach projecis and social neiworking. laboraiory and research faciliiies could be run and coordinaied from ihese local esiablishmenis io save on building and iranspori cosis. the inclusion of social and welfare suppori programmes, e.g. adopiion and foster care services; basic skills iraining and employmeni programmes for people living wiih aids and lawyers for human rig his, would faciliiaie access and undoubiedly impaci on ihe communiiy incidence of infeciion, by becoming ihe cenire of local aciion againsi aids. a co-ordinaied conceried effori, as opposed io numerous fragmenied and cosily duplicaiions of minor services, would seem io be ihe besi long-ierm siraiegic approach. the muliipliciiy of ihe services offered by such a cenire would also iend io desiigmaiise ihe disease, owing io ihe enormous role ii would play in ihe lives of rural dwellers. existing physical structures this approach io finding some sort of rural soluiion io ihe challenges of ihe hiv!aids pandemic is noi aboui putting up cosily new siruciures ihe proverbial re-inveniing of ihe wheel bui about uiilising exisiing faciliiies, e.g. iribal auihoriiies, church buildings, schools or hospiial clinics. the physical siruciure would simply function as a visible focal poini, accessible io ihe communiiy for co-ordinaiing of ihe muliipliciiy of available services. there has never before been such a great opportunity far the health core community to commit itself to its responsibility and far humanity to take care of its kind. we miss this opportunity at our awn peril. abstract introduction methodology results discussion conclusion acknowledgements references about the author(s) brian e. van wyk school of public health, faculty of community and health sciences, university of the western cape, cape town, south africa lee-ann c. davids school of public health, faculty of community and health sciences, university of the western cape, cape town, south africa citation van wyk be, davids l-ac. challenges to hiv treatment adherence amongst adolescents in a low socio-economic setting in cape town. s afr j hiv med. 2019;20(1), a1002. https://doi.org/10.4102/sajhivmed.v20i1.1002 original research challenges to hiv treatment adherence amongst adolescents in a low socio-economic setting in cape town brian e. van wyk, lee-ann c. davids received: 26 june 2019; accepted: 24 july 2019; published: 28 oct. 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: despite the successful rollout of anti-retroviral therapy (art) and steep declines in hiv incidence in south africa, this has not been the case for adolescents (10–19 years). adolescents on hiv treatment have lower rates of viral load suppression and adherence compared to adults and children. objectives: this article reports on the adherence challenges faced by adolescents receiving art in a primary health care clinic in a low socio-economic urban setting in cape town. method: an exploratory qualitative design was employed where data were collected through four focus group discussions with adolescents (n = 15) who received art at a primary health care clinic in a low socio-economic urban setting in cape town and followed up with eight individual, semi-structured interviews with two adolescents from each focus group. two key informant interviews were conducted with health workers at the clinic. audio data were digitally recorded and transcribed verbatim. data were analysed using content analysis. results: school commitments, strained teacher–learner relationships, negative household dynamics and ill treatment by non-biological caregivers were reported as major barriers to adherence. in addition, poor service delivery, missing or misplaced files and long waiting times came under major criticism. fear of unintended disclosure of hiv status, stigma and discrimination, treatment fatigue and having unstructured lives negatively influenced adherence. having a strong social support system and having life goals and ambitions were motivators to remain adherent. conclusion: this study highlighted the complexity of art adherence in the midst of juggling school, home life and personal life goals and aspirations. interventions to improve adherence should address psychosocial factors such as treatment fatigue, disclosure and family and household dynamics, in addition to streamlining service delivery between the school and clinic. keywords: hiv; aids; adolescents; youth; adherence. introduction background globally, there are 2.1 million adolescents (10–19 years) estimated to be living with hiv in 2016, which accounts for 6% of all people living with hiv.1 the successful scale-up of antiretroviral therapy (art) and prevention of mother to child transmission (pmtct) programmes has led to the improved survival of perinatally infected children – who are now the ‘first generation’ of children with hiv entering adolescence.2 despite improved access to art and steep declines in hiv incidence and hiv-related mortality globally, hiv-related mortality amongst adolescents (15–19 years) has increased by about 50% between 2005 and 2012.3,4 in 2015, hiv was the second leading cause of mortality amongst adolescents globally and the leading cause of mortality in sub-saharan africa.5 the world health organization (who) argues that the reason for this statistic is partly because of insufficient prioritisation of adolescent health in national health programmes, poor provision of appropriate hiv testing and counselling (hct) services and substandard follow-up care for adolescents who test hiv positive and who require art.4 further, it is widely reported that even when adolescents do access art, adherence and retention in care and treatment outcomes are poorer compared to adults.6 poor adherence to art is one of the most significant challenges in ensuring patients achieve and maintain viral load suppression.6 factors associated with poor adherence have been categorised as patient-related, structural, provider-related, disease-related, medication-related or psychological barriers.7 for adolescents, the transitional life period is characterised by physiological, psychological and intellectual development, which poses very unique challenges to art adherence.8 the management of adolescents on art, therefore, has to take cognisance of the complexity of biological and psychosocial changes which take place in the life of adolescents and its effects on adherence.9,10,11 research problem it is posited that, amongst others, the reason for the poor adherence amongst adolescents (15–19 years) is because the transition from paediatric to adult hiv care programme is not well managed.3 however, there is a paucity of behavioural research to give insights into what the challenges and barriers are that adolescents with hiv face when receiving treatment in the adult art programme.10 research aim the aim of the study was to describe challenges to living with hiv and adherence to art amongst school-going adolescents who receive art at a public primary health care clinic in 2015–2016 in a low economic urban setting in the western cape province of south africa. methodology study setting this study took place at a municipal primary health care clinic in an urban residential area (township) in the greater cape town area, where the participants received hiv treatment services. the township is home to a predominantly african community.12 during the previous political regime (apartheid), this community was largely marginalised and exploited. the area spans 13.46 km2 and has a total population of 64 269, of which 96.3% are african people, 2.7% are mixed race people and 0.2% are white people. it is part of the cape town metro that carries the heaviest burden of hiv disease in the western cape with a prevalence of 5.2% in 2012.12 the clinic provides immunisation services, care for sick babies, tb treatment for drug susceptible and drug-resistant tb and hiv care for adults and children (wellness care and art). it also provides antenatal care and family planning services. the clinic is open monday to friday from 07:30 to 16:30. the clinic is staffed by a pharmacist, two resident doctors, nurses, admin staff and a psychologist who comes to the clinic once a week. no dedicated adolescent services are provided. the majority of the youth who access this facility come from the high school and primary school that are adjacent to the facility and utilised the clinic facilities before or after school. the number of adolescents who access the clinic for art and hiv care is not known because routine hiv data are reported for paediatric (under 15 years) and adult (15 years and older) patients. the study was conducted from february to april 2016. study design an exploratory qualitative design13 was employed, because art adherence is considered a very complex phenomenon and requires an in-depth understanding of the socio-cultural as well as the biological environment in which the behaviour occurs. study population and sampling adolescents between 10 and 19 years who were registered to receive art at the primary health care clinic in 2015–2016 and who were on art for at least 6 months constituted the target study population and were subjected to purposive sampling. the inclusion criterion of 6 months on art was chosen, because we wanted to explore participants’ adherence behaviour and experience on art. twenty-six participants were identified as eligible for inclusion to the study from their clinic files. however, only 15 participants were reachable and consented to participate in the study. socio-demographic characteristics such as age and sex, clinical characteristics such as indications of adherence and initiation date of art were extracted from patient folders to identify eligible participants. a summary of characteristics of adolescent participants is presented in table 1. participants’ adherence was identified as ‘poor’ or ‘good’ from the doctor’s notes in the patient folder. all participants in the study were perinatally infected. table 1: characteristics of adolescent participants (n = 15). data collection data were collected through four focus group discussions (fgds) and eight individual interviews in a language of the participants’ choice, that is, english or isixhosa. all data were digitally recorded and transcribed verbatim. the researcher (ld) facilitated the fgds and individual interviews and was assisted by an isixhosa-speaking interpreter. isixhosa transcriptions were translated to english. the researcher (ld) was a medical doctor, who worked in the hiv programme in city health and conducted the current research towards her master’s degree. the focus groups were divided according to gender and age as follows: females, 10–14 years old – 3 participants males, 10–14 years old – 4 participants females, 15–19 years old – 6 participants males, 15–19 years old – 2 participants. focus groups were age and gender aggregated, to allow free sharing within the group with a similar demographic or peer group. the fgds were held in a meeting room in the facility. two participants from each fgd, who were identified to be willing to share more valuable insights, were approached for follow-up individual interviews. in the case of fgd 4, both participants agreed to be interviewed. the interviews and fgds were semi-structured, with open-ended questions and prompts. an interview guide was compiled for this purpose in order to ensure standardisation across focus groups. in addition, two key informant interviews were conducted with nurses who worked in the hiv programme in the clinic. data analysis the interviews were analysed manually making use of content analysis.13 analysing the data started with reading and re-reading the transcripts several times. this was performed concurrently with reading the field notes, personal reflections and reading entries from my research diary. on reading a transcript for the third time, the researcher (ld) made pencil notes in the margin of all the main issues that relate to adherence to treatment which came out from the text. the researcher was as inclusive as possible and also considered the things which were not being said such as suggestive statements and links between statements in different parts of the interview. then, the list of all codes was transferred onto a separate page. in the next step, the researcher re-wrote the list of codes, but this time highlighting codes which were duplicated or emphasised by the participants. similar codes were then grouped together, and in the last step, themes were developed. a consensus was reached between the researchers (ld and bvw) on the themes and codes. trustworthiness we followed lincoln and guba’s criteria for credibility, transferability, dependability and confirmability to enhance the trustworthiness of our study.13 the researchers held several meetings to debrief during data collection and analysis of interviews. transcripts were shared amongst the researchers to check for quality and to check coding and formulation of themes. disagreements were discussed until consensus on themes was reached. an independent person was used to transcribe the interviews and fgds. translation from isixhosa to english was done by a first language speaker in isixhosa, with master’s level qualification in public health. ethical considerations ethics clearance for the study was provided by the university of the western cape biomedical research ethics committee (registration number: 15/7/254) and approved by city health (id number: 10537). all information was treated confidentially, and all participants’ anonymity maintained. participation in the research was voluntary, and upon obtaining informed consent from all participants, and parents or guardians (if adolescent was younger than 18 years). results in this study, several barriers and one facilitator of adolescents’ art adherence were identified. a presentation of these factors follows below. barriers to adherence the reported barriers to adherence were school, social, health services, treatmentand patient-related factors. school factors school factors such as school (work) commitment, communication with school teachers and negative teacher attitudes were found to play a deterring role in accessing the clinic, disclosure and adherence to art. participants often expressed feeling conflicted between school commitments and the need to attend clinic appointments. even though there was a school adjacent to the clinic, many participants attended school elsewhere: ‘it would be nice for us to come at our own time, so that we do not have to miss our school work. that way we can be able to balance our life. your school work doesn’t suffer because of the clinic appointments, and vice versa.’ (group 4, male, 18) in addition, the need to communicate attending regular clinic visits to teachers posed a significant barrier to attending regular clinic follow-ups as they feared unintended disclosure which may potentially lead to stigma and discrimination: ‘okay my life orientation teacher is not a friendly person. she likes to shout, beat and [is] always angry. when she is angry, she says a lot of things out of anger; imagine now if you tell her about your status, and when she is angry she burst out in front of everyone. the best way is to keep this to myself.’ (group 4, male, 16) ‘it does not sit well with me, because people will be suspicious, they will have questions about my frequent visits to the clinic. that does not make me feel right.’ (group 4, male, 18) social factors a lack of financial support was reported to have a negative impact on art adherence, as participants often did not have money to pay for public transport to the clinic: ‘oh … maybe i can use it [financial support] for a taxi fare to collect my medication.’ (group 4, male, 18) participants cited negative relationships with non-biological caregivers as a barrier to adhering to art with some orphans even saying they defaulted art in an attempt to end their lives and be with their deceased biological parents: ‘yoh, when i am feeling bad, i stop taking my pills. for example, when i have quarrelled with my mother, sometimes she says things that are not so nice. like saying she never infected me. my mother is not my biological mother mos. my biological parents are dead. so when she talks like that i feel lonely and i feel bad, i stop taking the pills because i also want to die.’ (group 4, male, 18) furthermore, adolescence is characterised by a desire to fit in. some respondents reported feeling like outcasts amongst their immediate family because they were the only ones who were hiv positive: ‘i would not feel different from them [if i was hiv negative]; now i feel like an outcast. i am the only person with this thing [hiv] and i do not belong here. i feel like staying away from them … i wish i could stop taking medication [art] and be like them.’ (group 4, male, 18) health services factors long waiting times at the health facility were mentioned by all participants as a deterrent to adhering to clinic appointments (picking up medications), as these interfered with attending school that day: ‘… sometimes if you come here at half past 8 and the doctor doesn’t attend you. … doctors can make you wait for a very long time before they can attend you. you can come here at 8am and they only start to attend to you at 9. mind you, you will go home at 4 that is why i get bored.’ (group 1, female, 13) in addition, participants feared that the flow of patients at this health facility may lead to unintended disclosure of their hiv status, because the area in which you waited in the clinic gave clear indication of the services you were coming for: ‘one time i came to fetch my medication and i saw my neighbour. now she knows [i am hiv positive] because it’s obvious that people who wait this side are hiv positive.’ (group 4, male, 16) missing and misplaced files also served as a major barrier to adhering to art as adolescents would be told by clinic staff to return to the clinic on a different day to collect their medication: ‘i do go home without help, they keep losing my folder and sending me home and ask me to come back tomorrow. when i come again, they will say it is you again, and they are not keen to help me. mind you i ran out of medication.’ (group 3, female, 15) differential treatment and verbal abuse by health care workers towards patients who had defaulted or missed appointments deterred adolescents from returning to the clinic to re-start treatment: participant is that i am scared because it’s been a while since i came to the clinic. facilitator and what are you scared of? participant like the doctor is going to shout at me facilitator anything else? participant the doctor will shout at me, and i will have to wait at the clinic since they will start with the non-defaulters. that makes me angry. (group 4, male, 18) a key informant admitted that often the unique attributes of adolescents were not completely understood by health care workers and that this impacted on service delivery to this group and resultant adherence. they were of the opinion that the health care system should be set up in such a way so as to focus on the unique needs of adolescents: ‘i don’t think we have systems in place yet because there is nothing that focuses on them (adolescents). they are just in another group of adults taking arvs so there is nothing focusing specifically on assisting them so i would say we do not have a system that really supports them maybe if we could establish something that really focus on them because [they] are just dumped among the adults because they are just part of the whole group who is taking the arvs.’ (nurse) treatment-related factors treatment fatigue was mentioned as a profoundly significant barrier to adherence by all participants: ‘i sometimes feel that this thing that i have to take the pills every day does not sit well with me, i just get bored and feel like i could just throw them in the bin.’ (group 1, female, 13) ‘because it has been a while since i started taking the pills, i started when i was staying in mandela at worcester, but i was not used to them by then. i always ask mom and my sister, when i will ever stop taking these pills and my sister says, you will take them till you die. so that is why i do not like them.’ (group 1, female, 13) participants in this study found the treatment routine associated with art extremely rigid and were frustrated by the fact that apparently no leniency was allowed: ‘yah, i also miss them sometimes. i am a playful person. so at times i miss my time and i do not want to take them after that time because i do not know if they will have negative effects after.’ (group 4, male, 16) patient-related factors the dynamics of disclosure played a pivotal role in art adherence amongst these participants. the majority of participants preferred selective disclosure where they chose to disclose their hiv status to some people but not to others. many participants feared rejection, stigma and discrimination if their status is known. therefore, participants chose not to disclose their hiv status or that they are on treatment to friends, even when they sleep over: ‘i don’t want to disclose my [hiv] status to my neighbour or to my friends. i want to disclose my status only to my family.’ (group 3, female, 17) furthermore, some of the younger participants did not disclose their status because their parents forbade them to do so. this may be because if an adolescent discloses their hiv status they may also indirectly be disclosing their parent’s hiv status: ‘because my mother told me that i must not tell anyone [about my hiv status].’ (group 1, female, 10) ‘they [my parents] prohibit us from talking about it [our hiv status].’ (group 2, male, 14) many participants felt that no harm would come to them if they miss taking their medication on occasions. they would rather have fun with friends and have unplanned sleepovers following parties than come home to take their medication. the participants reported that they do not make provision to take their medication with them in the event of social functions: ‘there are times when there is a party somewhere and my friends will be attending and i also have to go with them. in those instances we come home the following day, and i will miss my pills. those gatherings are fun, i can’t leave fun mos.’ (group 4, male, 18) ‘sometimes, like holiday like december like its few party. and so like if i was at a party with friends, like maybe i am whatever place with my friends but my friends did not know i was hiv positive. so when it was 9 o’clock it was difficult to just leave. so i would just think argh, so what if i don’t take them, nothing will change i will just take them on another day.’ (group 3, female, 15) some participants reported feelings of being alone and not normal or dirty because they were hiv positive and have to take medication: ‘to be like a normal person, when i am taking these arvs i don’t feel like a normal person because everybody does not drink these pills. i feel like i am the only one here that drinks these pills.’ (14-year-old male) ‘… it is me alone at my home that is drinking the medication and that it makes me … it makes me feel very lonely.’ (14-year-old male) ‘not now like last year a lot because i feel bored and i feel no future. i am dirty i feel like i take the pills to the toilet and flush [the pills].’ (group 3, female, 15) facilitators of adherence receiving social support from family members, particularly siblings, and friends encouraged participants to remain adherent to their art: ‘okay we are four, it’s me, my mom, and my two sisters. but i am close to my mom. me and my big sister we quarrel a lot, even out of nothing. she knows about my treatment but when we have fights she doesn’t say anything about it, even when i am tired of taking it they encourage me to continue. they always check if i take my treatment and they will notice that i am not taking it. we are such a close family but i am closer with my mother.’ (group 4, male, 16) ‘yah because i feel like i am free, even when he [my friend] visits my place or i visit his place i feel free to take my medication. when i am sleeping over at his place, when i say i am going to take my pills he understands and even remind me some days.’ (group 4, male, 18) discussion the findings of our study indicate three extended themes, namely the conflict between the school and clinic, the need for hiv-competent households and adolescent-friendly hiv services. conflict between school and clinic the importance of keeping adolescents living with hiv in school has been expressed by researchers and social activists, because education reduces the vulnerability of girls and instils hopefulness for the future in all adolescents.14,15,16 it is thus concerning that this study reports conflicted commitments to school attendance and making clinic appointments. in addition, the need to communicate attending regular clinic visits to teachers posed a significant barrier to attending regular clinic follow-ups as they feared unintended disclosure which may potentially lead to stigma and discrimination. the findings of the study are in keeping with the literature which suggests that mainstream schooling may not necessarily always have a positive impact on adherence. in this study, the routine of schooling also made clinic visits difficult and some participants felt that their frequent absences may lead to unintended disclosure of their hiv status. it is well documented that if adolescents disclose their status to a trustworthy person or people, they are more likely to receive help in the form of knowledge and resources to help them cope with a hiv diagnosis and to access and remain in hiv care.4,5 we recommend that educators should be sensitised – hiv competent – to handle hiv disclosure of learners with sensitivity and understanding. hiv-competent households a lack of financial support and negative household dynamics were found to have a negative impact on art adherence. the findings of the study are thus in keeping with the literature on the positive effects of financial support and/or income security of households on adherence amongst adolescents.4,15 in our enquiry, negative household dynamics had a detrimental effect on reported art adherence. some participants reported feeling like outcasts in their family as a result of being the only family member who was hiv positive and on treatment. this was also the reason they gave for sometimes feeling like ending their lives by not taking their medication. the findings are in keeping with the literature that identifies parenting and family dynamics as playing a pivotal role in facilitating adherence to art.4,17,18 adolescent-friendly hiv services our study found health systems barriers to art adherence in the form of long waiting times and missing or misplaced files, and the risk of inadvertent disclosure of hiv status. these barriers have been reported previously and are not unique to adolescents.19,20,21,22 literature recommends the integration of youth-friendly services such as evening clinics, adolescent clinic days and youth-friendly waiting areas within art programmes.23 reconciling adolescence and taking medicine all participants reported treatment fatigue as a barrier to adherence. participants in this study were frustrated that the treatment routine was extremely rigid and that no leniency was allowed. this is in keeping with the literature that identified treatment fatigue as a major factor impacting on older adolescents’ ability to remain adherent to a treatment regimen.24 there was a suggestion from the older adolescents in this study that having art-free weekends would greatly improve their adherence.25 the nature of disclosure remains a pivotal role in art adherence as also reported in this study. the participants in this study preferred selective disclosure where they chose to disclose their hiv status to some people but not to others, which is in line with the current who guidelines.4 our study found that participants reported improved adherence once their hiv status had been disclosed to them and they have disclosed their hiv status to supportive friends. these findings are congruent with the literature that says if adolescents disclose their status to a trustworthy person or people, they are more likely to receive help in the form of knowledge and resources to help them cope with a hiv diagnosis and to access and remain in hiv care.4,26 our study found indications of depressive symptoms through participants reporting feelings of being alone and dirty (self-stigma) and contemplating ending their lives. this finding is consistent with the literature that reports higher prevalence of emotional and behavioural problems amongst adolescents living with hiv compared to other high-risk groups.27,28 a meta-analysis reports that patients with depressive symptoms were 42% less likely to achieve optimal adherence to art regimen.29 conclusion this study highlighted the complexity of art adherence in the midst of juggling school, home life and personal life goals and aspirations amongst a sample of school-going adolescents on art in a low socio-economic urban township in the western cape. whereas it was encouraging that the adolescents were all in school, the lack of collaboration between the education sector and the health sector in the interest of the adolescent and learner’s adherence to treatment is of great concern. more research is needed to unpack the complexity of this intersection and to develop guidelines for integration and collaboration between these two sectors that could be mirrored at implementation level between the school and the clinic. interventions to improve adherence should address psychosocial factors such as treatment fatigue, depressive symptoms, disclosure and family and household dynamics amongst adolescents. in other facilities in the western cape province, family clinics and youth clubs have been implemented to boost adherence. future studies should seek to explore how these initiatives could be mainstreamed across all facilities in the province. limitations of the study this study is of limited scope, because it was conducted towards the fulfilment of requirements for a master’s degree with coursework. the sample size was relatively small, and data saturation was not achieved. the sample was drawn from adolescents who were still in care; therefore, some measure of adherence was present. valuable lessons about adherence challenges might be missed because those who defaulted from treatment were not included in the study. acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions l.-a.c.d. conducted the research and wrote the first draft. b.e.v.w. supervised the research, revised subsequent drafts and finalised the manuscript. all authors approved the final version of the manuscript. funding this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors only. references unicef. current status and progress: turning the tide against aids will require more concentrated focus on adolescents and young people [homepage on the internet]. 2017[cited 2017 aug 18]. available from: https://data.unicef.org/topic/hivaids/adolescents-young-people/# cotton m, jaspan h, li r, nattrass n, o’brien 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https://doi.org/10.1016/j.childyouth.2016.09.039 hoare j. the adolescent brain: understanding how youth perceive risks and healthcare needs. 21st international aids conference, durban, july 18–22, 2016. mellins ca, brackis-cott e, leu cs, et al. rates and types of psychiatric disorders in perinatally human immunodeficiency virus-infected youth and seroreverters. j child psychol psychiatry. 2009;50(9):1131–1138. https://doi.org/10.1111/j.1469-7610.2009.02069.x uthman o, magidson j, safren s, nachega j. depression and adherence to antiretroviral therapy in low-, middle-and high-income countries: a systematic review and meta-analysis. curr hiv/aids rep. 2014;11(3):291–307. https://doi.org/10.1007/s11904-014-0220-1 abstract introduction background methods results discussion conclusion acknowledgements references about the author(s) hanlie myburgh desmond tutu tb centre, department of paediatrics and child health, faculty of medicine and health sciences, stellenbosch university, cape town, south africa remco p.h. peters anova health institute, johannesburg, south africa theunis hurter anova health institute, johannesburg, south africa cornelius j. grobbelaar anova health institute, johannesburg, south africa graeme hoddinott desmond tutu tb centre, department of paediatrics and child health, faculty of medicine and health sciences, stellenbosch university, cape town, south africa citation myburgh h, peters rph, hurter t, grobbelaar cj, hoddinott g. transition to an in-facility electronic tuberculosis register: lessons from a south african pilot project. s afr j hiv med. 2020;21(1), a1025. https://doi.org/10.4102/sajhivmed.v21i1.1025 original research transition to an in-facility electronic tuberculosis register: lessons from a south african pilot project hanlie myburgh, remco p.h. peters, theunis hurter, cornelius j. grobbelaar, graeme hoddinott received: 26 aug. 2019; accepted: 30 sept. 2019; published: 16 jan. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: south africa has one of the highest incidences of tuberculosis (tb) globally. high co-morbid hiv prevalence complicates tb management and treatment outcomes. growing evidence suggests that integrating the tb and hiv programmes will improve the overall results. objectives: to describe how tb programme staff at various levels of the south african health system responded to the transition from a paper-based to an electronic register of tb data integrated with hiv programme data. method: three primary health service facilities in the cape winelands district, western cape province, south africa served as pilot sites for implementation. semi-structured interviews were conducted with 21 tb programme staff purposively selected at facility, sub-district, district and provincial levels of the health system, based on their involvement in implementing electronic tb data. an objective-driven thematic frame was used to analyse the data. results: fears about the transition included reductions in data quality, changes to the status quo and a lack of computer literacy. participants acknowledged benefits of reduced workloads, speed of accessing patient-level data and click-of-a-button reporting. three factors influenced the ease of adopting the new system: firstly, implementation challenged the vertical position of the tb programme, tb data and staff’s conventional roles and responsibilities; secondly, perceptions of the paper-based register as functional and reliable made the transition to electronic seem unnecessary; and thirdly, lack of a process of change management challenged staff’s ability to internalise the proposed change. conclusion: a process of change management is critical to facilitate the efficiency and effectiveness with which the electronic in-facility tb register is implemented. keywords: tb programme; systems integration; monitoring and evaluation; roles and responsibilities; hiv. introduction south africa has one of the highest burdens of tuberculosis (tb) globally.1,2 in 2017, the estimated incidence of drug-susceptible tb (ds-tb) was 567 per 100 000 persons, and there were approximately 78 000 deaths from tb-related causes.3,4 the close relationship between tb and hiv (> 60% of tb patients are also living with hiv) further complicates tb management and treatment outcomes.2,5,6 growing evidence suggests that integrating the tb and hiv programmes will improve overall outcomes and reduce mortality.1,6,7,8 background in south africa, tb and hiv programmes and health information systems are implemented as vertical and siloed systems and have largely retained this separation.1,2,5 since 1995, the national tb programme has been supported by a central standardised recording system to monitor tb case rates and treatment outcomes. this system comprises paper-based registers at facility level. an electronic tb register (etr.net) for ds-tb at sub-district, district, provincial and national levels was added in 2005.1,9,10,11 in 2014, the national department of health of south africa took a decision to integrate the tb and hiv information systems at facility level into a single non-networked electronic system called tier.net.12 since 2010, tier.net has been serving as the primary monitoring platform for the national antiretroviral treatment (art) programme13 and was incrementally expanded to include hiv testing and pre-art data modules. tier.net is used to capture patient-level hiv information at facility level and is integrated with the district health information system (dhis) for reporting various programme data from sub-district to national levels. in contrast, tb programme data remained separate from other health programmes, where tb nurses capture patient information into facility level paper-based tb registers (figure 1). pages from the paper-based registers are sent to the sub-district administrative level where they are captured into etr.net. tb coordinators validate the captured data and refer queries back to the facilities. they also provide quarterly feedback to facilities and tb managers, and submit a dispatch of the data to the district level, from where it is sent to province, and finally to national level to generate annual reports. with the integration of tb and hiv programme data, a specially developed tb module for tier.net would supplant the paper-based tb register at facility level. in theory, this would allow tb programme staff at facility level immediate and easy access to individual and aggregated tb data. the introduction of the tb module is also the first step in decentralising tb programme data. specifically, introduction of the tb module would shift the programme from one that performs surveillance only to one that uses real-time data for patient management and is integrated with the dhis used for overall health programme reporting. figure 1: the data flow of tb and hiv programme data before and after the implementation of the tb module in tier.net.12 prior to implementation, the tb and hiv programme comprised two separate systems (tier, etr), each maintained on separate hardware with its own support structure; co-infected patients were tracked separately. the tb system emphasises data reporting with the use of paper registers, and facility level staff depend on sub-district tb coordinators for programme feedback; the hiv system (tier.net) combines immediate, real-time access to individual and aggregated hiv data for patient management and programme reporting, and is integrated with the dhis. after implementation, tb and hiv programme data flow up through tier.net and are consolidated into one database. tb and hiv programme data are available at all levels of the health system for querying and reporting (national through to facilities) and is integrated with the webdhis system. in this qualitative study, we retrospectively describe how tb programme staff working at various levels of the south african health system responded to the transition from a paper-based to an electronic tb data system at facility level prior to its widespread adoption and implementation. we consider the need to prioritise change management in health services implementation and the unique challenges posed by the history of the tb programme for data and service integration. methods study design and setting the department of health identified three primary health service facilities in the cape winelands district in the western cape province, south africa, to serve as pilot sites for implementing electronic tb data at facility level. the sites were each located in different sub-districts and differed with respect to tb caseload, tb staff component and programmatic services offered. this qualitative evaluation was conducted independently from the implementation process. sampling and data collection data were collected between july and september 2016, one year after implementation had started. participants were purposively selected as key informants at facility, sub-district, district and provincial levels of the provincial health system based on their involvement in the implementation process of the tb module in tier.net in a decision-making, managerial and/or implementation capacity. participants included: managers at facility, sub-district, district and provincial levels of the health system (n = 12) who were involved in the tb programme and health information in a managerial and decision-making capacity administrative staff at facility level (n = 2) who were responsible for electronically capturing health information for various health programmes, including the tb programme clinical tb staff or nurses at facility level (n = 6) who had experience using the paper tb registers and implementing the tb module in tier.net in each facility, including capturing tb data into the electronic register an implementing partner from the anova health institute (n = 1) who provided extensive support to facility and sub-district level staff during implementation in all three pilot sites. to maintain their anonymity all manager-participants are referred to as tb managers in the results regardless of their position in the health system. discussions were conducted in participants’ preferred language by two bilingual (afrikaans and english) researchers using a semi-structured discussion guide. interviews were audio recorded and ranged from 20 min to 90 min. interview questions were about participants’ recollections of their experiences of tb programme data with the paper-based system, the transition to an electronic system and their current experiences with the electronic system. the evaluation of the pilot project was funded by the anova health institute, which was the implementing partner at the time of the study. to mediate potential desirability bias in participants’ responses during interviews, the researchers conducting the interviews were external to the organisation. data analysis audio recordings were summarised and transcribed by the researchers. an objective-driven thematic frame was used to explore the data – namely aspects of the health information system that could be influenced by transition from a paper-based to an electronic tb patient register (e.g. resources, data flows, decision-making and accountability)14,15, as well as contextual health systems factors that could influence transition to the electronic tb register. key ideas from the data were grouped into: contextual factors process-related changes during the transition recommendations for facilitating efficiency and effectiveness. these findings were discussed amongst the authors, who drew on their experiences of implementing the tb programme and health information systems to interpret the data. ethical onsiderations ethical clearance for this study was obtained from the university of stellenbosch’s health research ethics committee, and an informed consent process was followed with each participant (ethical clearance no. n16/02/024). results participants shared conflicting feelings about the transition to an electronic in-facility tb register, describing not only their anxieties around the transition but also acknowledging its benefits. specifically, participants expressed fears over reduction in data quality, uncertainty over changes to the status quo and, for some facility level staff, insecurity regarding their ability to use an unfamiliar and electronic system. participants referred to such challenges while describing positive experiences, such as significantly reduced workloads, speed of accessing patient-level data and click-of-a-button reporting. our results report on three key contextual factors emerging from our interviews that gave rise to the conflicting sentiments that influenced the ease of adopting the facility level electronic tb register: (1) the position of tb programme and programme data, (2) perceptions about the new and old systems and (3) how acceptance of the new system was facilitated. position of the tuberculosis programme and tuberculosis programme data at the facility the historically siloed nature of the tb programme and data flow in south africa enabled tb clinicians and managers careful control of programme data for surveillance purposes using paper-based registers. tb programme staff positioned themselves as ‘tb champions’, that is, as custodians of tb data, which they entered, tallied and then appropriated, and this led to them having a vested interest in the status quo of ‘their’ paper-based system. the transition to an electronic in-facility register signalled a shift in how the tb programme would be controlled, allowing more involvement of facility level staff in data entry and maintenance, and signalling a loss of control as the data would be available to a much broader audience. excerpts from interviews illustrate the shift in power with introduction of the register: ‘there is one person in the clinic who completes the [paper] register; there is one person in the clinic who understands tb data. and all of a sudden [with introduction of the electronic tb register], the clerk must become involved, and more than one clerk, and more than one staff member.’ (participant 19, female, tb manager, 13 september 2016) ‘in the olden days you felt like those old sisters lording over everything – they can ask you anything, you know everything, you understand everything. and [with the electronic tb register] i don’t know it.’ (participant 7, female, nurse, 09 september 2016) the electronic register would allow facilities to query and clean their own data before submission in upward data flow, with sub-district tb coordinators taking on a less hands-on oversight role than they had before. this role change and the perceived effects of the transition on data quality raised anxieties: ‘eighty percent of [tb coordinators’] work was etr, was tb data. data, data analysis, and data validation. now we come and say that there is a possibility that we’ll take the etr away because we want to do better patient management. that’s the anxiety – what about us now? what is our role? they don’t understand, they’ll still have a role in data. the role just needs to be clarified.’ (participant 20, male, tb manager, 15 september 2016) ‘i kicked against the [electronic] system…because i felt that i was … a safety net [for data quality].’ (participant 11, female, tb manager, 05 august 2016) in one instance, fears over reduction in data quality caused a manager to undermine the register’s implementation: ‘[the tb manager] didn’t want us to spend time on the computer [and implement the register], just wanted the paper. we decided that we’re going to continue [to implement], we’re going to show them it works. show them how we print reports, how quick it is.’ (participant 1, female, clerk, 01 july 2016) to allay fears over tb case registration and maintenance of data quality, all three facilities kept parallel paper-based and electronic registers at the start of implementation and monthly data audits were conducted throughout. while some tb managers continued to hold apprehensions over data quality, they also saw the potential of the electronic register to increase ownership of tb data at facility level: ‘i hope and trust that ownership [of the data] will be better because the data is not going far away to someone who captures it, the data is here in my clinic and i capture it myself.’ (participant 13, male, tb manager, 25 august 2016) prior to the transition to the electronic register, using tb data for patient management required manual interrogation of patient folders to identify patients who missed sputum collection or who were experiencing treatment interruptions. this was labour and time-intensive and could not be regularly conducted by the three facilities without support. yet, the notion that the electronic tb register offered click-of-a-button in-facility access to data for patient management and improved reporting was not realised at initial introduction: ‘[the implementing partner] told us everything that we see now: ”you will easily see that patients are late.“ we said ”we won’t, we’ll still have to go through the folders.” everything he said is [true/we were wrong].’ (participant 6, female, nurse, 19 august 2016) perceptions about the ‘new’ electronic and ‘old’ paper-based register participants across all levels of the health system expressed familiarity with and confidence in the etr.net surveillance system and the paper-based registers that support it: ‘you can go to anyone in the department of health in the western cape and they will tell you that the only reliable data is tb data. with all the mistakes in the systems [of other health programmes] the only reliable data is tb data.’ (participant 19, female, tb manager, 13 september 2016) ‘it was difficult for [the nurses] to let go of those papers. they were clinging to their register, ”don’t take my register away!“’ (participant 9, female, tb manager, 23 august 2016) accordingly, when the electronic in-facility tb register was introduced, some participants felt that it was an unnecessary change as it replaced a working system. despite their apprehensions, managers in the tb programme recognised the transition to an electronic in-facility register as a logical progression in management of tb data. this related to the integration of tb programme data with general health information management, and to the broader notion that the tb programme should move with the time: ‘anyone looking for tb data in the country must get data from the tb programme (and not from health information management like with all other programmes). integrated systems is the answer.’ (participant 19, female, tb manager, 13 september 2016) ‘all other [programmes] are on [electronic] systems. that’s why tb must move away from paper-based. it might get resistance from some of the clinics, but usually it’s because people don’t understand.’ (participant 13, male, tb manager, 25 august 2016) some participants expressed serious concerns about the integration of tb data with the existing hiv data infrastructure, tier.net. for some, their siloed work had given them little to no experience with the tier.net software, while others’ concerns were informed by the gaps they perceived in tier.net’s hiv and art modules, which negatively influenced confidence in the new system’s ability to effectively maintain tb data: ‘we have a lot of work to do on the quality of capturing [hiv programme data] on tier.net, now we add the additional burden of tb … how can you go from point a to point b if your point a things aren’t correct yet?’ (participant 11, female, tb manager, 05 august 2016) this first pilot implementation of the electronic in-facility tb register highlighted some flaws in the software, producing erroneous reports on key tb indicators. this caused some participants to question the integrity of the new programme, and tb coordinators felt that they were responsible for resolving technical issues despite first and foremost being clinicians. despite these challenges, regular meetings of tb programme stakeholders during implementation and training of in-facility staff (clerks and clinicians) on the electronic tb register kept momentum for implementation. how acceptance of the ‘new’ system was facilitated in preparing facilities as implementation sites, efforts focussed largely on coalface implementers. managers were primarily involved to follow due consultative process rather than as advisors and decision-makers in the implementation process. department of health implementers and implementing partners supported the transition by training clerks and tb clinicians on the electronic register and completion of clinical stationery, resource allocation (computers and additional staff during back-capturing active tb clients) and continuous feedback meetings during implementation. while some participants felt that these processes were sufficient, others expressed anxieties about how the decision to pilot the electronic facility level tb register was taken, discussions on how this change would be implemented and the broader implications for the tb programme and their roles: ‘it’s a paradigm shift, how we used to work in the past, and now we don’t work like that anymore. it’s tough, because many colleagues don’t trust the process; they’re used to a different process. it is our responsibility as senior managers to turn those heads.’ (participant 20, male, tb manager, 15 september 2016) given the breadth of the proposed change that some participants felt the electronic facility level tb register ushered in, participants at sub-district and district management levels spoke about the need for change management: ‘when introducing something, come with change management to enable the people to grasp it and to internalise it. you get it today, and tomorrow must implement it. and that’s why people put up these walls. resistance, resistance.’ (participant 14, female, tb manager, 05 august 2016) for staff at facility level, one of the most challenging aspects of implementation was related to their historic use of paper-based registers and subsequent underexposure and distrust of technology. some participants also voiced concerns over the safety of electronic data during power outages, in case of computer theft and possible system failures. as such, computer literacy at facility level was a consistent concern of participants at all levels of the health system: ‘i think one of the shortcomings [in rolling out further] will be that colleagues aren’t excited about technology or that they are not ready to embrace computers.’ (participant 12, male, tb manager, 23 august 2016) the question ‘who is best-placed to capture tb data?’ divided tb stakeholders into two camps: those advocating for tb clinicians to continue to capture data and those advocating for the responsibility to be handed over to clerks as is the practice in the hiv programme. in the two facilities with smaller patient numbers, the tb clinicians had quickly become adept at capturing tb data into the electronic register and drawing reports. at the time of the evaluation, clinicians in all three facilities were either responsible for or assisting with capturing tb data and were regularly accessing reports on the system. discussion there are numerous factors that influence transition from paper to electronic records and information systems in health services.13,16,17 these include organisational culture, for instance, readiness of the organisation and its end users to adopt a new technology,18,19 the ability of the innovation to integrate with existing, conventional workflows or to require changes to it,19,20,21 and more practical aspects such as computer literacy of staff which may influence how confident they feel to successfully implement the innovation.15 as such, even a seemingly simple replacement of a paper-based register with an electronic one may bring about important shifts in power for different users by requiring adapted skillsets, resulting in complex changes to the status quo. these factors ultimately shape the response of those affected by the proposed change.22 while the introduction and potential of electronic tb data at facility level can be considered an important step forward for the tb programme, many of the participants recounted strong initial reactions and resistance towards the proposed change that affected the efficiency and effectiveness of implementation. these anxieties and resistances were concerned with: firstly, the vertical position of the tb programme and tb programme data which ushered in changes to staff’s conventional, familiar roles and responsibilities; secondly, with perceptions about the ‘new’ electronic register as deleterious and unnecessary and the ‘old’ paper-based register as functional and reliable; and thirdly how adoption of the new register would be facilitated, which participants felt lacked a process whereby they could internalise the proposed change. we make three recommendations for facilitating the transition to an electronic tb register at facility level in south africa and for moving to integrated electronic systems in general. firstly, implementers must invest in a process of change management alongside the transition to electronic facility level tb data in south africa. kuhn and giuse define change management as ‘the process of assisting individuals and organizations in passing from an old way of doing things to a new way of doing things’.23 to be successful, a change management process should involve the management of the practical aspects of the change (e.g. resources and training), and should address how the change might challenge the sense of security, confidence and identity that individuals associate with the conventional or old way of doing things.24,25 in the south african example, such a change management process must endeavour to achieve buy-in across all levels of the healthcare system by identifying the individuals or groups who will be affected by the change, and creating a space in which their anxieties can be voiced, acknowledged and addressed. this process could be facilitated by showcasing experiences and outcomes from pilot sites and providing practical examples of how challenges can be mediated and resolved. in other tb treatment contexts, such a change management process should involve prior formative research, which can include desk research, to establish the health and political context within which the tb programme is required to transition. in particular, this involves establishing how existing tb programmes and systems function, the relational nuances between people and programmes that might affect implementation (as is the case between the hiv and tb programmes in south africa) and people’s loyalties to particular ways of operating within the tb programme. secondly, individuals driving implementation should include individuals from within the tb programme in order to bring expert knowledge of the existing system and to lend credibility to the proposed change. implementers should directly address the potential challenges of transitioning, work with staff to set realistic expectations of individuals’ roles and responsibilities and how these may change with implementation, and ensure that they are communicated effectively. at each facility, staff should be allowed to tailor some elements of implementation to their local contexts, for instance, the decision about who is best placed to capture tb data, and provide support to develop sustainable plans for maintaining the data. the following aspects of implementation should be addressed: the rationale for the transition, in particular, the limitations of maintaining separate programme data and the possibilities opened up for improving tb patient management and programme outcomes with decentralisation and integration of tb data with those of other health programmes; anticipate implementers’ potential distrust and discomfort with the introduction of the electronic tb register, potential fears about losing data quality, and their familiarity with and trust in the functionality of the paper-based register and the etr.net system. also pre-emption and discussion of the process of identifying and reporting flaws and compatibility issues in the software, and detailing of the support that is available if such issues were to arise. thirdly, it must be recognised that data use and analysis by facility managers and tb nurses will take time to cultivate; it is necessary to understand that the electronic register frees up the hands of sub-district level tb coordinators to provide health systems strengthening support to facilities by, for instance, using data in real-time to check progress against targets. through highlighting key issues to address during implementation, our study contributes to informing wide-scale implementation of electronic tb data in south african health facilities, and can inform the implementation of electronic health information systems in favour of paper-based systems globally. there are two limitations to the study. firstly, the study uses interviews with participants a year after the pilot project began to report on implementation, thus asking participants to recall their experiences rather than documenting their experiences in real-time. secondly, this study was also limited by its focus on pilot sites in one health district in the western cape province which is not necessarily representative of other settings within and outside of south africa. conclusion south africa is one of the first countries to pilot electronic tb data at facility level for programme monitoring. in order to facilitate the efficiency and effectiveness with which the register is implemented, it is critical that a process of change management occur alongside its continued rollout. this process must address the shift from a vertical to integrated health information system for the tb programme on one level, and on another, its particular integration with tier.net, the health information system used for monitoring and evaluating the south african hiv programme. while our findings in this study are largely context-specific, there are significant similarities across tb programmes as vertical or siloed surveillance programmes that could extend our findings’ relevance beyond south africa, particularly to contexts with comparatively high hiv and tb burdens. acknowledgements the authors thank the study participants for availing their time in helping to provide information for this research. competing interests the authors have declared that no competing interests exist. authors’ contributions h.m., r.p.h.p., t.h. and g.h. conceived and designed the analysis. h.m. collected the data, synthesised findings and produced the first draft of this article. r.p.h.p., t.h., c.j.g. and g.h. provided analytic support, expert insights into interpreting data and multiple revisions of the manuscript. funding information this study is made possible by the generous support of the american people through the us president’s emergency plan for aids relief (pepfar) through the united states agency for international development (usaid) under cooperative agreement number aid-674-a-12-00015, entitled systems strengthening for better hiv/tb patient outcomes, and cooperative agreement number 72067418ca00023 for the accelerating program achievements to control the epidemic (apace) activity in south africa to the anova health institute. data availability statement data sharing is not applicable to this 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organizations: systematic review and recommendations. milbank q. 2004;82(4):581–629. https://doi.org/10.1111/j.0887-378x.2004.00325.x kuhn ka, giuse da. from hospital information systems to health information systems: problems, challenges, perspectives. methods inf med. 2001;40(4):275–287. https://doi.org/10.1055/s-0038-1634170 kotter j, cohen d. the heart of change: real life stories of how people change their organization. boston, ma: harvard business school press; 2002. campbell rj. change management in health care. health care manage. 2008;27(1):23–39. https://doi.org/10.1097/01.hcm.0000285028.79762.a1 abstract background methods results discussion conclusion acknowledgements references about the author(s) tinashe mudzviti school of pharmacy, university of zimbabwe, harare, zimbabwe newlands clinic, harare, zimbabwe anesu dhliwayo school of pharmacy, university of zimbabwe, harare, zimbabwe byrone chingombe population services international, harare, zimbabwe bernard ngara department of community medicine, college of health sciences, university of zimbabwe, harare, zimbabwe tsitsi g. monera-penduka school of pharmacy, university of zimbabwe, harare, zimbabwe charles c. maponga school of pharmacy, university of zimbabwe, harare, zimbabwe population services international, harare, zimbabwe center for integrated global biomedical sciences, university at buffalo, new york, united states gene d. morse center for integrated global biomedical sciences, university at buffalo, new york, united states translational pharmacology research core, university at buffalo, new york, united states citation mudzviti t, dhliwayo a, chingombe b, et al. perspectives on oral pre-exposure prophylaxis use amongst female sex workers in harare, zimbabwe. s afr j hiv med. 2020;21(1), a1039. https://doi.org/10.4102/sajhivmed.v21i1.1039 original research perspectives on oral pre-exposure prophylaxis use amongst female sex workers in harare, zimbabwe tinashe mudzviti, anesu dhliwayo, byrone chingombe, bernard ngara, tsitsi g. monera-penduka, charles c. maponga, gene d. morse received: 22 oct. 2019; accepted: 11 jan. 2020; published: 19 feb. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: pre-exposure prophylaxis (prep) could provide protection from human immunodeficiency virus (hiv) infection in sexually active persons at risk. limited data are available in zimbabwe with regard to the perceptions about prep amongst female sex workers (fsws). objectives: the aim of this study was to evaluate the knowledge levels of oral prep and the likelihood of its use amongst fsws. method: this was a cross-sectional study in the peri-urban areas of harare, zimbabwe. human immunodeficiency virus-negative fsws were interviewed to assess their awareness of and likelihood to use prep. the relative importance index was used to evaluate the levels of knowledge and the likelihood of, and barriers to, prep use. a set of 10 questions was designed and validated that evaluated participants’ understanding of prep. a bivariate logistic regression model was utilised to identify predictors of prep use. results: a total of 131 fsws with a median age of 25 years (interquartile range: 21–31) participated in this study. of the 71 (54%) fsws who had heard about prep, 46 (35%) participants had adequate knowledge of its use. a total of 102 (78%) participants revealed that they would be willing to continuously use prep if it was provided free of cost. increasing age of the participants was associated with an increase in the likelihood of using prep (r = 0.0033, p = 0.038). more knowledge about prep increased the likelihood of its use (r = 0.21, p = 0.0153). this likelihood increased amongst participants with an unprotected sexual intercourse encounter in the preceding 3 months (r = 0.0448, p = 0.026). conclusion: knowledge of prep amongst fsws was low. to increase the uptake of prep, there is a need to further sensitise fsws about this intervention. programmes should also promote awareness training in fsw subgroups that are less likely to use prep. keywords: female sex workers; hiv; pre-exposure prophylaxis; barriers; truvada. background whilst the adult prevalence of human immunodeficiency virus (hiv) in the general population of zimbabwe is 15%, the prevalence in key populations is higher.1 in populations of female sex workers (fsws), the hiv prevalence in 2013 was 50% – 70% in different parts of zimbabwe.2 in many settings, key populations are hidden and stigmatised, and their representation in national surveillance data is limited. it has been cited that key populations and their sex partners not only make up the largest proportion of people living with hiv (plwh) but also represent a significant proportion of new infections in sub-saharan africa.3 pre-exposure prophylaxis (prep) can become a female-controlled hiv prevention method for fsws and others who are unable to negotiate condom use. the ministry of health and child care (mohcc) has developed a prep framework policy that prioritises access for ‘at-risk’ populations. groups that need to be offered prep include female and male sex workers; serodiscordant couples, that is, the hiv seronegative partner; adolescent girls and young women; pregnant women in relationships with men of unknown status and high-risk men, for example, men who have sex with men (msm); prisoners; long-distance truck drivers; and transgender people.4 a fixed-dose regimen of either tenofovir 300 mg and emtricitabine 200 mg (tdf/ftc) or tenofovir 300 mg and lamivudine 300 mg (tdf/3tc) has been recommended for once-daily oral administration during the period an individual is at risk of contracting hiv infection.4 zimbabwe has adopted the joint united nations programme on hiv and aids 90-90-90 global goals to help reduce new infections and end the hiv pandemic.5 this target will be difficult to reach without reducing transmission amongst high-incidence populations. although it is well established that effective prep could provide an additional safety net to sexually active persons at risk,6 limited data are available in zimbabwe regarding the knowledge and the likelihood of prep use amongst fsws. there is a need to understand both the acceptability of prep amongst fsws and the factors likely to determine uptake. most research efforts to date have focussed on clinical aspects of prep. little attention has been focussed on the factors that influence fsws’ willingness to take it. it is estimated that there are 40 000 (plausibility bounds [pbs] 28 000–59 000) active fsws in zimbabwe, that is, 1.23% (pb: 0.86% – 1.79%) of the adult female population. a total of 20 000 (50%) are in harare and bulawayo.7 this study was conducted to assess the levels of knowledge, barriers to and likelihood of oral prep use amongst fsws as a preventative method in reducing the risk of acquiring hiv in harare, zimbabwe. methods study design and setting this was a cross-sectional study of fsws in seven peri-urban areas of harare province, zimbabwe. these sites were specifically chosen because they are high-density areas, and apart from the central business district, they are areas from which fsws frequently operate.8 study population and recruitment this cross-sectional study was conducted between december 2016 and february 2017 in partnership with a local private voluntary organisation (pvo) that offers prep services. the pvo had been offering prep using tdf/ftc (truvadatm) tablets as an hiv prevention method in six zimbabwean districts since august 2016. this was a demonstration project introduced to inform people of the new hiv prevention strategy of the mohcc. the primary target populations included adolescent girls and young women aged 15–24 years, fsws, msm and serodiscordant couples.9 human immunodeficiency virus–negative fsws were defined as those who had been tested for hiv in the previous 3 months and had tested negative or those who perceived themselves to be hiv-negative. the prep intervention that is defined for the purpose of this study refers to oral prep with truvada, which is indicated for ‘at-risk’ individuals with a laboratory-confirmed hiv-negative result. none of the participants was already receiving prep from the pvo. snowball sampling was used to locate and enrol fsws from the peri-urban harare sites. a peer referral system whereby ‘seed’ subjects previously identified by the pvo and ‘queens’ (the leaders of a significant group of sex workers based on their location in a certain area) provided referrals to enable further recruitment and mobilisation of other fsws. this technique was utilised because of laws and policies that criminalise sex work in zimbabwe. female sex workers were also identified during community outreach hiv testing and counselling activities by the pvo. once identified, fsws were asked to provide written consent and to complete a 48-item questionnaire. the questionnaire was administered by the interviewer. the questionnaire had sections enquiring about socio-demographic factors, sexual behavioural characteristics, hiv testing, prep knowledge, perceptions, barriers and the likelihood of its use. sexual behavioural characteristics were investigated to determine the hiv acquisition risk profile of the fsws. the interviews were conducted in the language that the participant was most comfortable with. ‘sufficient knowledge’ was judged by means of an initial self-report and an additional nine technical questions designed to test the level of knowledge. these technical questions included the participant’s knowledge that prep is used by hiv-negative individuals, the dosing frequency, potential drug interactions and whether there are other reproductive health benefits. once the level of knowledge was ascertained, the participants were then educated about prep use. the perceived barriers that were evaluated included stigma, cost of prep and the side-effects of truvada. data management and statistical analysis research electronic data capture (redcap) was used to manage data. this was hosted by the college of health sciences of the university of zimbabwe. the contribution of each factor, namely, age, cost of prep and drug side-effects, with regard to improving prep uptake amongst fsws was examined. the importance of each factor as perceived by the respondents was assessed by computing the relative importance index (rii). the rii is a statistical measure recorded on a scale of 0 < rii ≤ 1, where ‘0’ or any value close to ‘0’ is defined as a poor knowledge of prep use, the participant is less likely to use prep or barriers associated with prep are likely to affect uptake. if the rii score was ‘1’ or close to ‘1’, it means that participants were knowledgeable about prep, were more likely to use prep and that barriers associated with prep use were unlikely to affect its uptake. the rii was computed using the equation , where scorei was the score for each question given by the participants and ranged from 0 to 4 (where ‘0’ was ‘very much disagree, strongly disagree or never’ and ‘4’ was ‘strongly agree, very much agree or almost always’). k was the maximum possible score and n was the total number of questions. according to johnson and lebreton,10 rii is the proportionate contribution each predictor makes to r2 (where r2 is the extent to which the dependent variable can be predicted by the predictor variables), considering both its direct effect (correlation with the dependent variable) and its effect when combined with other variables. all data analysis was performed using stata version 13 (statacorp lp, tx, usa) software package. bivariate linear regression was used to determine if there was a relationship between the rii scores of knowledge, likelihood and barriers (klbs) and exploratory factor variables that were collected in the study. to identify the relationship between klb rii scores, a matrix of spearman correlation coefficients was used. ethical consideration prior to conducting the survey, the study protocol including the data collecting tool was reviewed and approved by the joint research ethics committee of the university of zimbabwe and the parirenyatwa group of hospitals (jrec/328/16). all participants provided written informed consent before participating in the study. results a total of 131 presumed hiv-negative, adult fsws were recruited to participate in this study, and their demographic characteristics are shown in table 1. all study participants were self-identified as residents of the harare province. table 1: demographic characteristics of study participants (n = 131). participant’s characteristics – sexual risk factors and human immunodeficiency virus testing the median number of sexual encounters by the participants was five [interquartile range (iqr): 3–6] partners per day. half of the participants (50%) did not know their partner’s hiv serostatus and only 42% of the fsws would talk about hiv with their clients or partners. all participants perceived the use of condoms as a necessary tool when engaging in sexual activity with their partners or clients, 86% used condoms with the last three partners they encountered and 44% reported having ever had a condom burst at least once during sexual intercourse. the variables affecting hiv acquisition risk are depicted in table 2. table 2: variables affecting risk of human immunodeficiency virus acquisition. pre-exposure prophylaxis knowledge of the 131 participants, 71 (54%) had heard about prep and of those only 46 (35%) had sufficient knowledge about prep (rii > 0.5). participants mostly heard about prep from non-governmental organisations (59%), from friends (35%) and only 6% of the participants had heard about prep through clinics. likelihood of pre-exposure prophylaxis use the participants’ responses when asked about the likelihood of prep use are shown in table 3. regardless of a likelihood to use prep, potential barriers were cited, such as stigma, costs, side-effects associated with the prep tablet and poor knowledge, as shown in table 3. table 3: likelihood of pre-exposure prophylaxis use and perceived barriers (n = 131). relative importance index on a scale of rii, the median score for prep knowledge was ‘0’, indicating that participants had limited knowledge about prep. participants perceived the use of prep as an important component in the ideal hiv prevention strategy once educated about it. in relation to the likelihood of prep use, the median score for the likelihood of prep use was 0.89 ranging from 0.48 to 1. therefore, the likelihood of prep use amongst the participants was high. the rii median score for barriers associated with prep use was 0.29 (iqr: 0–0.63). this indicated that the barriers associated with prep uptake were less likely than knowledge to affect participants’ use of prep. results that were statistically significant in the bivariate analysis are shown in table 4. table 4: relationship between predictor variables and dependent variable. an increase in the number of dependents was associated with a reduced knowledge about prep, as shown in table 4. there was a statistically significant association between age and likelihood of prep use. as participants became older, there was an increase in the likelihood of prep use. this increased amongst participants who had unprotected sex in the last 3 months. there was, however, no statistically significant association between knowledge rii with age, marital status, education, change in place of residence, income and years of practice as a sex worker (p > 0.05). considering the likelihood of prep use amongst the participants, there was no association noted between the likelihood rii score and the number of dependents, marital status, education, change in place of residence, income and years of practice as a sex worker (p > 0.05). spearman’s rank correlation coefficient was computed to identify and test the strength of the relationship between knowledge and barriers with the likelihood of prep use. table 5 shows the spearman correlation coefficients for the relationship between rii scores of klbs associated with prep use. table 5: spearman correlation coefficients for the relationship between relative importance index scores of knowledge, likelihood and barriers associated with pre-exposure prophylaxis use. considering likelihood and knowledge rii scores, there was a positive correlation whereby more knowledge about prep moderately increased the likelihood of prep use (r = 0.21, p = 0.0153). there was a negative correlation between barriers and the likelihood rii score, that is, as barriers associated with prep use decreased, the likelihood of prep use moderately increased (r = 0.23, p = 0.0074). discussion in a real-world setting, the effectiveness of prep will depend on its acceptability, adoption and sustained use by high-risk populations. pre-exposure prophylaxis medication will have little impact in reducing hiv infections if these components are not addressed.11 findings from this study indicate that fsws continue to engage in risky sexual behaviours. in the last 3 months, 53 (40%) of the participants reported having unprotected sexual intercourse with a casual partner. in our study, 54% of fsws had heard of prep before participating. in spite of having little knowledge of prep, the majority of fsws were willing to use prep (median rii = 0.89; range 0.48–1) to reduce their risk of contracting hiv infection. in a similar study conducted in china, only 16.5% had heard of prep before participation, and only 1.4% had used prep before.12 nevertheless, 69% and 95% of the respective fsw populations of china and india reported a willingness to use prep.12,13 these estimates were consistent with our findings that 89% of the participants were willing to use prep. educating hiv-uninfected fsws about prep is likely to support the uptake of prep and assist in decreasing the incidence of hiv in zimbabwe. pre-exposure prophylaxis programmes have been incorporated into sexually transmitted disease clinics, reproductive health programmes and genitourinary medicine clinics in high-income countries.14,15,16,17 findings from this study indicated that there was a significant association between the likelihood of prep use, age and unprotected sexual intercourse in the preceding 3 months. older participants were more likely to adopt prep as an hiv prevention strategy. this suggests that those who perceive themselves to be at a higher risk of hiv infection are more likely to adopt prep as an hiv intervention. elmes et al. evaluated condom use by fsws in eastern zimbabwe and reported that older participants were less likely to request condom use from partners.18 older fsws may therefore be at a higher risk of acquiring hiv and should be prioritised for prep access. in spite of the high levels of interest in prep, potential barriers were cited including cost, side-effects and poor knowledge of prep use. whilst prep had to be bought, 46% of the participants strongly agreed that lack of money would pose a challenge to prep uptake. many participants felt that prep ought to be provided free in view of the severity of the hiv epidemic in zimbabwe. the high cost of prep is undoubtedly a major barrier to its uptake worldwide, particularly in high-income countries where only branded tdf/ftc is available.19 in low-income countries that have established prep programmes, cost is not identified as a barrier to access because the medicines are free. in the kenyan setting, fsws were more concerned about the stigma of being tested for hiv and the barrier posed by the test with regard to the success of the intervention.20 in our study, stigma was not identified as a possible barrier to taking prep. this contrasted with the kenyan setting and is a distinct finding for the zimbabwean fsws. with a reduced fear of stigmatisation, there is scope for improved acceptability of prep in fsws. our results indicate that participants were generally willing to accept prep and adopt it as soon as it was made available. information emerging from trial projects and open-label extensions where prep has been offered free of charge by knowledgeable providers suggests that uptake may be high in settings where cost and provider-related barriers had been removed.15,16,21 our results showed that participants were willing to take prep even when reminded of potential side-effects. participants cited that the side-effects of prep could have an impact on one’s quality of life but that would not hinder taking prep. only 9% of the fsws strongly expressed that side-effects would affect their lifestyle and possibly prevent prep use. sex workers in mombasa, kenya, voiced concerns about the potential negative side-effects of prep. in this qualitative study, a minority of participants were deterred from using prep because of the side-effects.22 women from six us cities where female hiv infection is highly prevalent viewed prep as an important prevention option, provided that side-effects and cost to the consumer were minimal.23 the feasibility of oral prep implementation in zimbabwe has been proven in ongoing and completed demonstration projects and clinical trials. by the end of 2017, a total of 3073 clients were initiated on prep in zimbabwe. ninety per cent of the clients initiated on prep were women, with the majority of them in the 25–49 years age group. the majority (52%) of the clients initiated on prep were fsws. the accessibility of prep outside of demonstration projects has been limited.9 whilst the sample size recruited for participation in this study was small, the information generated provides a foundation in the development of further programming for prep implementation in fsws. the information was also generated from peri-urban, high-density areas in harare (the capital city of zimbabwe). perceptions and knowledge levels might differ across other diverse geographical locations in zimbabwe, and more studies need to be conducted. because of the legal status of sex work in zimbabwe, we used a snowball sampling technique in order to reach fsws who might otherwise have been unwilling to participate in the study for fear of litigation. this sampling technique has the potential to introduce selection bias. the zimbabwean mohcc has considered addressing the knowledge gap about prep in the general population through different channels whilst at the same time raising awareness to increase risk perception, especially amongst adolescent girls and young women. these considerations have been made as part of an implementation plan for prep in zimbabwe between 2018 and 2020 (inclusive). our study provides guidance on the progress made on addressing the knowledge gap about prep. conclusion we set out to evaluate the knowledge levels of prep and the likelihood of its use amongst fsws. whilst the knowledge level was low, the majority of fsws would be willing to use prep for the purpose of hiv/aids prevention. non-governmental organisations are playing a major role in sensitising fsws about prep. the local clinics need to increase their visibility as information dissemination institutions for prep. the clinics are strategically positioned to enlighten key populations about prep and to prescribe medication to those who might need it. successful dissemination of information can be achieved if prep programmes are incorporated into other programmes within the clinics. acknowledgements the authors thank all the team members, field officers and fsws who participated in the study. competing interests the authors have declared that no competing interests exist. authors’ contributions t.m., a.d., c.c.m. and b.c. provided leadership for the project. t.m., a.d. and b.c. were responsible for conceptualisation of the study. a.d., b.n. and b.c. were responsible for data collection. t.m., c.c.m., b.n., t.g.m.-p. and a.d. were responsible for data analysis. g.d.m., t.g.m.-p. and c.c.m. provided technical expertise. t.m. and b.c. provided clinical expertise for the project. all authors contributed to the writing of the manuscript and approved the final version for publication. funding information this research was made possible through core services and support from the university of rochester center for aids research, a programme (p30 ai078498) funded by the national institutes of health (nih). the content is solely the responsibility of the authors and does not necessarily represent the official views of the nih. data availability statement data sets are available from the corresponding author upon request. disclaimer the views and opinions expressed in this article are those of the authors and 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united nations programme on hiv/aids (unaids). 90-90-90 an ambitious treatment target to help end the aids epidemic, geneva: unaids; 2014. desai m, field n, grant r, mccormack s. state of the art review: recent advances in prep for hiv. bmj. 2017;359:j5011. https://doi.org/10.1136/bmj.j5011 cowan fm, chabata st, musemburi s, et al. strengthening the scalep and uptake of effective interventions for sex workers for population impact in zimbabwe. j int aids soc. 2019;22 (suppl 4):e25320. https://doi.org/10.1002/jia2.25320 chiyaka t, mushati p, hensen b, et al. reaching young women who sell sex: methods and results of social mapping to describe and identify young women for dreams impact evaluation in zimbabwe. plos one. 2018;13(3):e0194301. https://doi.org/10.1371/journal.pone.0194301 gwavava e. understanding the uptake and retention patterns of prep users in zimbabwe by subpopulation. aids 2018. amsterdam: international aids society; 2018. johnson jw, lebreton jm. history and use of 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use and the determinants of the price of sex among female sex workers in eastern zimbabwe. j infect dis. 2014;210 (suppl 2):s569–s578. https://doi.org/10.1093/infdis/jiu493 wilton j, senn h, sharma m, tan dh. pre-exposure prophylaxis for sexually-acquired hiv risk management: a review. hiv aids. 2015;7:125–136. https://doi.org/10.2147/hiv.s50025 mack n, odhiambo j, wong cm, agot k. barriers and facilitators to pre-exposure prophylaxis (prep) eligibility screening and ongoing hiv testing among target populations in bondo and rarieda, kenya: results of a consultation with community stakeholders. bmc health serv res. 2014;14:231. https://doi.org/10.1186/1472-6963-14-231 heffron r, celum c, mugo n, et al., editors. high initiation of prep and art in a demonstration project among african hiv-discordant couples. 21st conference on retroviruses and opportunistic infections; 2014 march 03–06; boston, ma: international aids society; 2014. restar aj, tocco ju, mantell je, et al. perspectives on hiv preand post-exposure prophylaxes (prep and pep) among female and male sex workers in mombasa, kenya: implications for integrating biomedical prevention into sexual health services. aids educ prev. 2017;29(2):141–153. https://doi.org/10.1521/aeap.2017.29.2.141 auerbach jd, kinsky s, brown g, charles v. knowledge, attitudes, and likelihood of pre-exposure prophylaxis (prep) use among us women at risk of acquiring hiv. aids patient care stds. 2015;29(2):102–110. https://doi.org/10.1089/apc.2014.0142 guidelines elsabe klinck legal advisor, south aftuan medical associanon post-test counselling has long been recognised as imperative, in view of the nature of the pandemic, the role that positive hiv status plays in continued health care decisions, and the necessity of behavioural changes following a positive (and negativel) test result. the requirement to obtain informed consent before any test, treatment, diagnosis or intervention has been part of south african medical ethics and law since 1912. the human right of freedom and security of the person lends further support to this principle. it has two aspects: sufficient information, and an understanding of that information and its implication for the patient. the courts judge this from the perspective of the patient, and not from the perspective of the health care professional. pre-test counselling forms part of the process of obtaining informed consent. by not addressing these aspects, a health care professional may be found not to have obtained informed consent. ----------hhruary 2003 pre-test counselling the patient knows why an hiv test has to be done (e.g. insurance purposes, continued medical care, ./ pregnancy, solving the 'puzzle' of recurring infections, etc.), and why knowing one's hiv status is important opportunity is provided for the patient to express concern and uncertainty, and these concerns have ./ been addressed. the patient knows what an hiv test is and how it will be done. ./ the patient knows how long it will take before s/he will have the result. ./ the patient knows who the result will be provided to (e.g. his/her gp or the sister at the local clinic) and that s/he is responsible for getting those results from that health care professional. ./ the patient has been prepared to think about what a positive or a negative result may mean for him ./or her, specifically in relation to continued health care and the reason why the test has been commissioned in the first place. the patient has been provided with sufficient opportunity to ask questions and to think about the ./ possibility/necessity of a test. the patient has been provided with details of where counselling and support services can be ./ obtained. hiv legal and ethical issues a comprehensive set of guidelines is available from the south african medical association at (02l) 530-6528, or e-mail emacdonald@samedical.org. the guidelines include all relevant legislation, ethical rules and policy documents pertaining to hiv/ai os. the southern african journal of hiv medicine a very important ethical principle that underpins doctors' conduct in dealing with the pandemic is that of patient advocacy. patients often do not know that they have certain legislative protection. ill-informed perceptions often underlie a refusal to be tested or a refusal to disclose hiv-positive status. non-exhaustive checklists are provided in this article to guide doctors through the general processes. when dealing with hiv, doctors have to address a number of ethical and legislative requirements, or where they do not have the time or experience to provide, for example, comprehensive counselling, they must see to it that patients have undergone this. many of the principles involved are no different from those applicable to testing for or treatment of any disease. however, the stigma attached to hiv and the politicisation of the pandemic have magnified the importance of doctors adhering to these rules. in terms of legislation, specific mention is made of hiv in certain laws, and doctors have to be aware of these. post-test counselling the meaning of a positive or negative result has been discussed, including, depending on the type .i of test used, the possibility of a false-negative result. how a patient should protect him/herself against infection or reinfection and how s/he should .i protect others from getting infected, including, where applicable, the issue of breast-feeding. various treatment options (antiretroviral therapy (arn. post-exposure prophylaxis (pep), treatment .i for opportunistic infections), effects and demands in terms of regularly taking medication and costs (including implications for medical scheme funding) have been discussed. how hiv status will affect future medical care. .i dealing with the issue of possible disclosure to significant others, (potential) sex partners, family members, employers, other health care workers, etc.; as well as the obstacles and opportunities the .i patient sees in this regard. issues of religion, culture and beliefs that may influence the patient's choices and behaviour have .i been recognised and addressed in a positive and constructive manner. possible lifestyle changes and preparation for these. .i addressing issues such as death, surviving children and care or adoption, families, concerns about .i insurance and funeral policies, etc. where continued counselling is impossible for the particular health care worker, the patient has .i been referred to an appropriate counsellor or counselling facility. testing for hiv (informed consent) the patient understands that an hiv test is to be performed and has indicated such understanding .i clearly, if necessary through the assistance of an interpreter. the patient knows what the implications of the test might be, e.g. that insurance cover may be .i denied, or that a baby may be born hiv-positive, and/or that medication would have to be prescribed. the patient has signed [or refused to sign) an informed consent form, indicating such .i understanding. in the case of a refusal, no tests may be performed. the informed consent form included: .i • the full names and identity number of the patient. • reference to the person who informed the patient about the aspects found in the consent form. • that the patient has been informed about the nature, conduct, benefits, risks and implications involved in undertaking an hiv test and/or treatment and/or intervention. • that the patient has received information on hiv, the test and/or treatment and has had an opportunity to ask questions. • that the patient has been provided with an opportunity to consider whether s/he wants the test to be performed. • the patient freely and voluntarily agrees to the performance of the test/treatment/intervention. • that the test concerns the drawing of a blood sample and the performance of an hiv antibody or hiv test on that sample. • that the patient agrees to the utilisation of such a result in an anonymous format for purposes of research and/or data collection. • that the results will remain confidential, unless the patient has provided informed consent to a disclosure. • that the patient knows that s/he is at any stage free to withdraw such consent. where the patient is a child, that the provisions of the child care act have been complied with (le. .i independent. informed consent for those 14 years of age and older for medical treatment). where the patient is mentally incapable of consenting, that relevant legislative requirements are .i met, e.g. the mental health care act. that the patient has provided the laboratory conducting the test with the name of a gp or health .i care facility to whom the results could be made available and who would be able to discuss future health care options with the patient. ff8ruary 2003 ----------thf southfrn african journal of hiv mfoicinf confidentiality as a cornerstone principle in medical ethics is found in a number of important sources, such as the hpcsa's ethical rules, the promotion of access to information act, the bill of rights in the south african constitution, the regulations to the medical schemes act and proposed legislation such as the national health bill. doctors are often faced with particular situations placing them in a difficult position, where they may experience a conflict between the requests made by third parties, and the interests of their patients. health care professionals may unknowingly assist third parties in unlawfully obtaining an hiv test, for example. it is therefore imperative that health care professionals are knowledgeable about the basic legislative requirements applicable to these situations. confidentiality the patient has been assured of the health care professional's duty to .i preserve confidentiality. the patient has been informed if disclosure has to be made in terms of a .i consent form s/he has signed (e.g. with an insurance company) or a managed care agreement with the patient's medical practitioner in terms of the regulations to the medical schemes act the patient has been advised of the desirability of disclosure to sex partners .i and significant others and an offer has been made to assist the patient in such a disclosure. if the medical practitioner intends to breach confidentiality, s/he is aware of .i and takes full responsibility for the legal and ethical implications of such a step. s/he should be convinced that there is an identifiable third party facing a real risk and the patient has been informed of the intended breach. where an employer or any third party has paid for the hiv test, no disclosure of the .i results of the test has been made to such employer or person, unless the patient has provided his/her informed consent for such a disclosure. the patient has been informed that s/he does not have to disclose to such entities or persons. the patient's informed consent has been .i obtained for disclosures to subsequent health care professionals to whose treatment they have been referred, after issues such as the impact of hiv on postoperative care or health care treatment options have been explained. hhruary 2003 ----------legislative requirements occupational injuries and diseases: • health care professionals have been informed of the relevant protocols in their workplaces that deal with pep after possible exposure to hiv. • the source patient has not been tested without his/her informed consent • the health care professional has access to free testing, pep and counselling. • the employer has started proceedings under the compensation of occupational injuries and oisease act so as to ensure the payment of compensation to the health care professional. employment: • the employer who has requested the hiv test has obtained a court order from the labour court authorising testing. • the provisions set out in the court order have been complied with. • no test results have been made available to the employer without the relevant employee's informed consent • employees have not signed any document in which they waive their rights in terms of the employment equity act of 1998. • employees have been assured that there may be no discrimination based on their hiv status and no reduction in terms of employment benefits would take place. insurance: • the patient/insured is aware of the exclusions found in his/her policy document • the patient is aware that section 59 of the long-term insurance act compels him/her to disclose all material medical facts at the time of applying for a policy. • the patient is aware of the implications of the medical records consent form signed at the particular insurance company. • the patient has been informed of specific hiv products offered by insurers. medical schemes: • the patient knows the limits of his/her medical scheme benefits. • the patient knows which treatment would be paid for as being part of the prescribed minimum benefits. • the patient has considered the financial implications of hiv art or treatment for opportunistic infections. the patient has reached a decision to either pay for it him/herself, seek participation in programmes that do provide art and/or to apply for assistance at the medical scheme or other financing mechanism. • the patient has been requested to provide the health care professional with clear instructions in terms of (non)disclosure to the scheme, particularly in the absence of a managed care agreement between the scheme and the health care provider. discrimination and patient empowerment: • the patient knows that s/he may not be discriminated against and may challenge any decision pertaining to his/her health care, insurance, benefits, employment, ete at an appropriate forum. • relief exists in the utilisation of the promotion of equality and prevention of unfair discrimination act, or by approaching ngos or the human rights commission, with particular complaints. t~f sout~trn african journal of hiv mtdlcint the southern african journal of hiv medicine november 2005 33 g u i d e l i n e s guidelines for the management of hiv-infected children (national department of health, south africa 2005) a summary of antiretroviral treatment guidelines tammy meyers, fcpaed (sa) harriet shezi children's clinic, chris hani baragwanath hospital, johannesburg brian eley, fcpaed (sa) red cross children's hospital, cape town national guidelines for the management of hiv-infected children in south africa have been developed as a consensus document by practising hiv clinicians around the country. guidelines for antiretroviral (arv) management of children appear in a booklet distributed by the national department of health (doh) since mid-2004 (national antiretroviral treatment programme guideline for carers, national department of health, south africa, 2004). a comprehensive booklet on management of hiv-infected children has also been produced for the doh which includes recommendations on management with antiretroviral (arv) therapy. the south african national paediatric guidelines are based on the recommendations provided by the world health organization (who) (scaling up antiretroviral therapy in resource limited settings; treatment guidelines for a public health approach who 2003). it is important to note that who are updating their recommendations. based on this some amendments, e.g. the staging system, have already been incorporated into the final version of the south african national guidelines. other recommendations are more recent and have yet to undergo broader review. these have therefore not formed part of the printed version of the south african guidelines. it is anticipated that a process of updating the guidelines needs to be put in place urgently. the national guidelines are available on the government website (www.health.gov.za), and clinicians are advised to update themselves regularly at this website for any amendments that may be made to the guidelines. it is essential that clinicians involved with management of hivinfected children in both the private and the public sector are familiar with national recommendations for treatment. the majority of hiv-infected children will access care in the public sector and many move between private and public sector. treatment choices made by private clinicians should take into account what is available in the public service, particularly if the patient is likely to access care from both sectors. owing to the scale of the hiv epidemic, and in order to reach all those who need care, people need to have access to comprehensive hiv care at health care facilities as close as possible to their homes. uncomplicated cases, both adult and paediatric, should be managed at primary care facilities. the south african national guidelines are designed for clinicians practising at all levels of care. in many cases primary health care nurses may need to commence and manage children and adults on arvs. since arv treatment is uncomplicated in most cases, this should be well within the scope of practice of appropriately clinically trained nurses. goals of antiretroviral therapy the goals of arv therapy for children are to increase survival, improve quality of life and decrease hiv-related morbidity and mortality. ■ the child's cd4 count should rise and remain above the baseline count. ■ the child's viral load should become undetectable (< 400 copies/ml) and remain undetectable on arv therapy, although in some children a suppressed though detectable viral load, with sustained elevation in cd4 count and absence of intercurrent and/or opportunistic infection, may be the best achievable goal. eligibility for antiretroviral therapy patients must satisfy clinical and social criteria before being accepted for treatment. clinical criteria 1. confirmation of diagnosis of hiv infection. 2. recurrent (> 2 admissions per year) hospitalisations for hiv complications or prolonged hospitalisation for hiv (> 4 weeks), or 3. the patient satisfies the provisional who citeria for stage iii/iv disease (see interim revised who staging of disease) or 4. for relatively asymptomatic patients, one can consider starting arv if the cd4 percentage is < 20% (age under 18 months) or < 15% (age over 18 months). november 2005 the southern african journal of hiv medicine34 social criteria these criteria are extremely important for the success of the programme and need to be adhered to. the principle is that adherence to treatment must be at least probable. 1. at least one identifiable caregiver who is able to supervise the child for administering medication (orphans and vulnerable children (ovc) should not be discriminated against and all efforts should be made to ensure that their psychosocial circumstances be addressed so that they too can receive treatment). 2. disclosure to another adult living in the same house is encouraged (but not mandatory), so that there is someone else who may assist with the child's art. 3. nb: treatment of mother/caregiver/other family members ■ always ask about the caregiver's health, and the health of other members of the family. ■ ensure that mothers and other family members access medical care timeously, including art if needed. ■ where possible, hiv-positive mothers and caregivers requiring medical attention should be attended to at the same time as their children in order to decrease the number of clinic visits and associated costs and time away from work. what to start? antiretroviral drug choices for children are set out in table i. general comments ■ all infants under 6 months of age who require arv therapy should preferably be started on treatment under specialist supervision. ■ stavudine solution requires refrigeration. if no fridge is available, stavudine capsules may be opened and dissolved, and the required amount administered to the child. the rest can be discarded. if the caregiver experiences difficulty with stavudine capsules, zidovudine suspension may be used instead. ■ switch to tablets or capsules from syrups or solutions as soon as possible. ■ lopinavir/ritonavir (kaletra®) needs to be kept cool (< 25°c). ■ didanosine (ddl) must be taken alone, on an empty stomach, at least an hour before (or 2 hours after) a meal. tablets should be dissolved in at least 30 ml of water. it is important to use 2 tablets of didanosine to obtain sufficient antacid buffering, e.g. if the child needs 100 mg prescribe 2 x 50 mg tablets. ■ children may occasionally need to change from a drug in the first-line regimen to one from the second-line regimen, because of intolerance or a serious adverse reaction. swapping limits the patient's second-line treatment options. the decision to swap must be made by a doctor with arv experience. swapping of one drug should only be done if there is full viral suppression, failing which the whole regimen may need to be altered. if intolerance develops to ritonavir or lopinavir/ritonavir (kaletra®), switch to nelfinavir. abacavir may be used if adverse events on other nucleoside reverse transcriptase inhibitors (nrtis) occur. ■ drugs not listed in the firstand second-line regimens but mentioned in the guidelines, e.g. ritonavir, nelfinivir, saquinavir, abacavir and nevirapine, should be available at all tertiary care centres. ■ doh guidelines have incorporated a dosing table that has been based on weight bands in order to facilitate ease of prescribing paediatric formulations (table ii). adverse events the adverse event profile of arvs is similar in adults and children. most side-effects of treatment are minor if they occur, but on occasion severe adverse events may require urgent referral to centres with expertise and arvs may need to be stopped. such events include severe hepatitis, stevensjohnson syndrome, pancreatitis, lactic acidosis (presenting with severe gastrointestinal symptoms, pain, vomiting and/or decreased level of consciousness). refer to 'guidelines for management of the hiv-infected child' (www.health.gov.za) for more detailed information regarding adverse events. children on stavudine may, like adults, develop peripheral neuropathy and/or lipodystrophy/lymphoatrophy. these may be subtle or more difficult to diagnose in children. nevertheless, a high index of suspicion may result in more adverse events being detected in children in general. switching from stavudine to abacavir may be helpful if the child has viral suppression. remember that all adverse events should be notified to the medicines control council (mcc). a copy of the yellow form that is required to be completed may be found in the full guidelines and/or is obtainable from the mcc offices. adherence adherence greater than 95% will ensure a good virological response and prevent the emergence of viral resistance. good adherence can be achieved with regular education and support. adherence may be monitored using diary cards, medication check and other measures. all efforts should be made to encourage this level of adherence. 6 months up to 3 years > 3 years and > 10 kg 1st line stavudine (d4t) stavudine (d4t) lamivudine (3tc) lamivudine (3tc) kaletra® efavirenz 2nd line zidovudine (azt) zidovudine (azt) didanosine (ddi) didanosine (ddi) nevirapine/efavirenz* kaletra® * efavirenz if the child is over 3 years and nevirapine if < 3 years. table i. antiretroviral drug choices for children t h e s o u t h er n a fr ic a n jo u r n a l o f h iv m ed ic in e n o v em b er 2 0 0 5 3 5 table ii. paediatric arv and trimethoprim/sulfamethoxazole dosing chart for use in resource-constrained settings trimethoprim/ sulfamethoxazole stavudine lamivudine zidovodine didanosine nevirapine tmp/smz weight abacavir (zerit® (epivir®, (retrovir®), zdv, (videx®, (virammune®, nvp) efavirenz lopinaviriritonavir nelfinavir indinavir septran, bactrim®, (kg) (ziagen®) d4t) 3tc) azt ddi) and trimethoprim sulphamethoxazole (stocrin®, sustiva®, efv) (kaletra®) (viracept®) (crixivan®) various) induction maintenance dose < 15 kg = 12 mg � 4 mg / kg dose: lop/kg once daily 4 mg / kg ≥ 15 kg = 10 mg (for prophylaxis once daily lop/kg against opporfor first 14 < 8 yrs ≥ 8 yrs twice daily tunistic illnesses. 8 mg / kg 1 mg / kg 4 mg / kg 240 mg/ m2 120 mg / m2 days, then 7 mg / kg 4 mg / kg dose as shown (iop = iopinavir; 60 mg / kg 500 mg/m2 doses for treattwice daily twice daily twice daily twice daily twice daily give twice daily twice daily once daily r = ritonavir) twice daily every 8 hours ment of bacterial maintenance and protozoal dose infections are higher than listed here) liquid tablet capsules liquid tablet liquid capsule chewable liquid tablet liquid tablet liquid tablet liquid capsules liquid capsules single20 300 15, 20, 30 10 150 10 100 tablets 10 200 10 200 10 200 30 50, 80 mg 133.3/33.3 tablet capsule liquid strength mg / ml mg mg mg / ml mg mg / ml mg 25, 50, 100 mg mg / ml mg mg / ml mg mg / mg mg / ml 200 mg lopinavir/ mg 250 mg 200 mg 8 mg / ml (ss) tablet ml ml9 lop/r 80 mg tmp/ 400 mg smz 5 6.9 2 ml 2 ml 7 ml 2 ml 4 ml 2 tabs 1 cap 3 ml 7 9.9 3 ml 15 mg 3 ml 9 ml 1 cap 25 mg + 3 ml 6 ml 1.5 ml 2 tabs 1 cap 4 ml � 1 2 � ss tab 25 mg 10 11.9 4 ml 15 mg (or 4 ml 12 ml 1 cap 25 mg + 4 ml 8 ml � 1 2 � tab 9 ml 200 mg 2 ml 2 tabs 1 cap 5 ml � 1 2 � ss tab 20 mg) 25 mg 12 14.9 5 ml 15 mg (or 5 ml 14 ml 1 cap 50 mg + 5 ml 9 ml � 1 2 � tab 9 ml 200 mg 2 ml 3 tabs 1 cap 7 ml 1 ss tab 20 mg) 25 mg 15 16.9 6 ml 15 mg (or 6 ml � 1 2 � tab 15 ml 2 caps 50 mg + 6 ml 10 ml � 1 2 � tab 10 ml 200 mg + 2.5 ml 1 cap 3 tabs 2 caps 8 ml 1 ss tab 20 mg) 25 mg 50 mg 50 mg + 1 tab 200 mg + 17 19.9 7 ml � 1 2 � tab 20 mg 7 ml � 1 2 � tab 17 ml 2 caps 50 mg 7 ml 13 ml a.m.+ 10 ml 50 mg 2.5 ml 2 caps 4 tabs 2 caps 9 ml 1 ss tab � 1 2 � tab p.m. 50 mg + 1 tab 200 mg + 20 24.9 9 ml � 1 2 � tab 20 mg 9 ml � 1 2 � tab 20 ml 2 caps 50 mg 9 ml � 1 2 � tab 16 ml a.m. + 9 ml � 1 2 � tab 12 ml 2 x 50 mg 3 ml 2 caps 5 tabs 2 caps 11 ml 1 ss tab � 1 2 � tab p.m. 25 11 � 1 2 � tab 27.9 ml 3 caps or kg 300 mg 100 mg + 200 mg + 25 29.9 28 12 30 mg 11 ml 1 tab 24 ml tab 25 mg 11 ml � 1 2 � tab 20 ml 1 tab 11 ml � 1 2 � tab 15 ml 3 x 50 mg 3.5 ml 2 caps 5 tabs 2 caps 14 ml 2 ss tabs 29.9 ml 1 tab kg 3 caps or 100 mg + 1 tab 30200 mg + 30 34.9 13 ml 1 tab 30 mg 13 ml 1 tab 27 ml 300 mg 25 mg 13 ml 1 tab 13 ml a.m.+ 32.9 15 3 x tab �1 2 � tab kg ml 50 mg 4 ml 3 caps 5 tabs 3 caps 17 ml 2 ss tabs p.m. 3317 200 mg + 34.9 ml 200 mg kg 3 caps or 100 mg + 1 tab a.m. 200 mg + 35 40 15 ml 1 tab 30 mg 15 ml 1 tab 30 ml 300 mg 25 mg 15 ml 1 tab 15 ml + � 1 2 � tab p.m. 17 ml 200 mg 5 ml 3 caps 5 tabs 3 caps 20 ml 2 ss tabs tab november 2005 the southern african journal of hiv medicine36 it is not possible for health care providers to reliably predict which caregivers or individuals will ultimately be adherent to their treatment plan, as adherence does not correlate with gender, cultural background, socioeconomic or education level, or language barriers between provider and patient. it is therefore essential to provide all caregivers with a comprehensive plan to support adherence. several strategies need to be applied and all members of the health care team, as well as family and possibly even community-based support groups, need to be involved. experience has shown that adherence decreases as time progresses. monitoring and support of adherence is therefore essential. some factors affecting adherence to paediatric art are listed below. a trusting relationship between the patient and caregiver and members of the health care team is essential. optimal adherence requires full participation by the health-care team. every interaction with the patient and caregiver provides an opportunity for reinforcing the absolute need for adherence. some important factors diminishing adherence in children ■ unanticipated drug side-effects and adverse events. ■ intercurrent illness. ■ caregiver illness/death or otherwise occupied. ■ patient resistance to taking medicines – ritonavir, singly or in combination with lopinavir, has a very bitter taste. ■ change or absence of patient's nurse or doctor. ■ frequent daily doses – e.g. twice or three times per day. nb: every effort should be made to ensure that every child who needs arv can access this regardless of home circumstances. if necessary involve counsellors, social workers or even the school to ensure that the child may be adherent to his/her arv therapy. in even the worst social circumstances a creative solution can and must be found. switching to second-line therapy reasons for switching to second-line therapy are set out in table iii. n.b.: changing from firstto second-line arv is a decision that is undertaken only after careful consideration. it is not something that one would rush into before considering possible improvements in managing therapy at home. first check adherence: if it is not possible to improve adherence, attempt directly observed therapy (dot) with a health care worker or the trusted 'other' family member or friend identified under 'social criteria' above. it is essential that switching arv regimens is done in consultation with a paediatrician with arv experience. concomitant tuberculosis tuberculosis occurs commonly with hiv. there are two scenarios to consider: 1. child presents with tuberculosis before commencing arv therapy. ■ complete tb therapy if possible before commencing arv therapy or delay art for at least 2 months (in severe cases it may be necessary to commence arvs even sooner). ■ if the child has failed the nevirapine vertical transmission programme or is less than 3 years old or weighs < 10 kg, use ritonavir as the third drug. ■ if the child was not on the nevirapine vertical transmission programme and is more than 3 years old and weighs more than 10 kg, use efavirenz as the third drug (monitor alanine transaminase (alt) monthly). 2. child develops tuberculosis while on arv therapy. ■ if the child is on lopinavir/ritonavir or nelfinavir, then switch to ritonavir. ■ if the child is on nevirapine, and is less than 3 years old or weighs less than 10 kg, switch to ritonavir. ■ if the child is on nevirapine and is more than 3 years old and weighs more than 10 kg, switch to efavirenz. ■ if the child is unable to tolerate the large number of drugs, clinical immunological virological lack of growth or confirmed return of rebound of viral decline of growth in cd4 percentage load to baseline. a child showing (repeated within 1 (a detectable initial response month) to baseline viral load may to treatment or below before be tolerated in starting therapy children, loss of neuroin the absence of providing that developmental mileconcurrent illness growth and stones or developto explain cd4 elevated cd4 ment of hiv decline count are encephalopathy sustained.) more than 50% decline new evidence of in cd4 percentage stage iii/iv disease from peak (confirmed (not immune within 1 month) reconstitution in the absence of syndrome: see concurrent illness to below) explain cd4 decline recurrence of prior opportunistic infections, e.g. oral candidiasis that is refractory to treatment note: 1. short episodes or isolated events of lower respiratory tract infection and gastroenteritis should not necessarily be regarded as clinical failure. 2. presentation with tuberculosis or other opportunistic infections may be a sign of immune reconstitution inflammatory syndrome (iris). this will usually be associated with a cd4 count and/or percentage which have improved over time. this is not an indication to switch to second-line therapy. table iii. reasons to move to second-line arv therapy in children the southern african journal of hiv medicine november 2005 37 arv therapy may have to be interrupted until tb therapy has been completed (always discuss this with an experienced paediatric hiv clinician). ■ monitor alt monthly. note: discuss all cases with a paediatrician with arv experience, before interrupting therapy. monitoring see table iv. clinical staging see table v. clinical stage 1 asymptomatic persistent generalised lymphadenopathy clinical stage 2 hepatosplenomegaly papular pruritic eruptions seborrhoeic dermatitis extensive human papillomavirus infection extensive molluscum contagiosum fungal nail infections recurrent oral ulcerations lineal gingival erythema (lge) angular cheilitis parotid enlargement herpes zoster recurrent or chronic respiratory tract infections (otitis media, otorrhoea, sinusitis) clinical stage 3 moderate unexplained malnutrition not adequately responding to standard therapy unexplained persistent diarrhoea (14 days or more) unexplained persistent fever (intermittent or constant, for longer than 1 month) oral candidiasis (outside neonatal period ) oral hairy leukoplakia acute necrotising ulcerative gingivitis/periodontitis pulmonary tuberculosis severe recurrent presumed bacterial pneumonia unexplained anaemia (< 8 g/dl), and/or neutropenia (< 500/mm3) and/or thrombocytopenia (< 50 000/mm3) for more than 1 month chronic hiv-associated lung disease including bronchiectasis symptomatic lymphoid interstitial pneumonitis (lip) clinical stage 4 unexplained severe wasting or severe malnutrition not adequately responding to standard therapy pneumocystis pneumonia recurrent severe presumed bacterial infections (e.g. empyema, pyomyositis, bone or joint infection, meningitis, but excluding pneumonia) chronic herpes simplex infection (orolabial or cutaneous of more than 1 month's duration) extrapulmonary tb kaposi's sarcoma oesophageal candidiasis cns toxoplasmosis (outside the neonatal period) hiv encephalopathy cytomegalovirus infection (cmv retinitis or infection of organs other than liver, spleen or lymph nodes; onset at age 1 month or more) extrapulmonary cryptococcosis including meningitis any disseminated endemic mycosis (e.g. extrapulmonary histoplasmosis, coccidiomycosis, penicilliosis) cryptosporidiosis isosporiasis disseminated non-tuberculous mycobacterial infection candida of trachea, bronchi or lungs visceral herpes simplex infection acquired hiv-associated rectal fistula cerebral or b-cell non-hodgkin’s lymphoma progressive multifocal leukoencephalopathy (pml) hiv-associated cardiomyopathy or hiv-associated nephropathy *for persons aged under 15 years with confirmed laboratory evidence of hiv infection; hiv antibody if aged 18 months and above; virological or p24 antigen testing if aged under 18 months. table v. interim revised who clinical staging of hiv/aids for infants and children* we would like to acknowledge all hiv clinicians around the country who assisted with the development of the above guidelines. regimen test frequency d4t/3tc/ cd4% and/or staging, 6-monthly lopinavir cd4 count + ritonavir vl baseline, 6-monthly (kaletra®) random cholesterol baseline, 6-monthly random glucose baseline, 6-monthly alt and fbc baseline, 6-monthly d4t/3tc/efv cd4% and/or staging, 6-monthly cd4 count vl baseline, 6-monthly alt and fbc baseline 6-monthly ddi/azt/ cd4% and/or staging, 6-monthly nevirapine cd4 count vl baseline, 6-monthly fbc baseline, then monthly for 3 months, then 6-monthly (with cd4 and vl) thereafter alt baseline, week 2, 4 and 8, thereafter 6-monthly ddi/azt/efv cd4% and/or cd4 count 6-monthly fbc baseline, then monthly for 3 months, then 6-monthly (with cd4 and vl) thereafter alt 6-monthly ddi/abc/efv cd4% and/or cd4 count 6-monthly alt 6-monthly fbc 6-monthly (with vl and cd4 + count) *if the random cholesterol is elevated, perform fasting cholesterol and fasting triglycerides. staging = initial testing (screening) for all patients when being referred for antiretroviral therapy; baseline = testing for art eligible patients, at initiation of art; vl = viral load; alt = alanine transaminase; fbc = full blood count. it is at the discretion of the initiator of art to decide whether monitoring for efficacy or toxicity be done outside of the routine schedule. n.b.: for all regimens a baseline serum lipase is useful. this may be repeated if there is clinical indication to do so. table iv. paediatric arv regimens and routine monitoring during treatment obituary dr dennis sifris: in memorium in memorial: dr dennis sifris *1945–+2020 author: david c. spencer1 affiliation: 1division of infectious diseases, department of medicine, helen joseph hospital, university of the witwatersrand, johannesburg, south africa corresponding author: david spencer, editor@sajhivmed.org.za how to cite this article: spencer dc. dr dennis sifris: in memorium. s afr j hiv med. 2020;21(1), a1143. https://doi.org/10.4102/sajhivmed.v21i1.1143 note: photo of dr dennis sifris provided by lauren jankelowitz. republished with permission from andré van bassen of lifesense disease management. copyright: © 2020. the author. licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. dr dennis sifris, a pioneer in the field of hiv in south africa, died in july 2020 of colonic cancer. he was 75 years old. in 1984, dennis and the late professor reuben sher established south africa’s first hiv clinic at the johannesburg hospital (now the charlotte maxeke johannesburg academic hospital). the hiv pandemic had come to the attention of the medical community three years earlier because of the deaths of a large number of young men in the united states of america (usa). homosexuality was banned and prosecuted in south africa in that era. dennis and reuben made it their business to identify the infected and to provide them with care and support. it was at a time when the clinicians faced ridicule or censure from colleagues for their support of homosexuals and the hiv infected. the lives of multiplied thousands were saved. health workers have been trained. medical students have become professors. the practice of hiv medicine has been influenced by south african scientists and researchers who were trained in the clinic. this too, is dennis’ legacy. dennis was loud. he was visible. he had marched with larry kramer in new york and los angeles and witnessed the birth of the gay men’s health crisis movement in that country. [larry died in new york in may this year]. dennis’ activism was a catalyst in this process. others such as the aids law project, the treatment action campaign, the stop stock-outs project, and the southern african hiv clinicians’ society, followed this process. perhaps our combined action in 2002 and 2003 ensured antiretroviral treatment for all south african citizens and helped to end a denialist presidency. for much of dennis’ career, he ran a large private practice in johannesburg. in 1999, he joined a south african healthcare management company (lifesense hiv disease management) as chief medical officer. private practice ‘had taken its toll’, he said. in this new position he oversaw the care of more than 120,000 people living with hiv. more recently, he moved with his partner (jamie) to the usa. dennis is a cofounder of the sa hiv clinicians’ society and was active in local hiv-conferences and despite his recent ill health, maintained an interest in all things related to hiv in his patients in south africa. dennis, how should we measure your time with us? thank you for friendship, for colouring our lives with laughter and for me – surprise. for being impossible (embarrassing) when that was needed. thank you for caring for the sick. thank you for the lives you saved. thank you for accepting graciously my criticism of your clinic notes – not enough detail! ooh! – when i was chief. dennis, thank you for giving a human face to hiv and aids, and for being yourself. from all of us in the clinicians’ society, “ti sei perso”. (you are missed). and to jamie, our heartfelt condolences. dc spencer, editor-in-chief abstract introduction fungal infections bacterial infections viral infections helminthic infections conclusion acknowledgements references about the author(s) reena mohanlal department of anatomical pathology, faculty of health sciences, university of the witwatersrand, johannesburg, south africa national health laboratory services, chris hani baragwanath academic hospital, johannesburg, south africa denasha l. reddy division of infectious diseases, department of internal medicine, chris hani baragwanath academic hospital, university of the witwatersrand, johannesburg, south africa citation mohanlal r, reddy dl. spectrum of hiv-associated infectious diseases: a case series through the eyes of the histopathologist. s afr j hiv med. 2020;21(1), a1087. https://doi.org/10.4102/sajhivmed.v21i1.1087 case report spectrum of hiv-associated infectious diseases: a case series through the eyes of the histopathologist reena mohanlal, denasha l. reddy received: 20 mar. 2020; accepted: 23 apr. 2020; published: 29 june 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: human immunodeficiency virus (hiv) infection increases the risk of infection by a host of other opportunistic pathogens. the clinical presentations of these co-infections in immunocompromised patients are often atypical; therefore diagnosis is delayed in the absence of investigations such as tissue biopsy. infection may involve sites that are difficult to access for biopsy and, as a consequence, there is limited diagnostic tissue available for analysis. the histopathologist, aided by ancillary tests, is relied upon to make a timeous and accurate diagnosis. objectives: to illustrate key histological features of hiv-associated infectious diseases encountered in a histopathology laboratory and to highlight, with the aid of literature, the relevance of histopathology in diagnosis. method: a retrospective descriptive case series of biopsies histologically diagnosed with hiv-associated infectious diseases over four years (2015–2019) was performed at the chris hani baragwanath academic hospital national health laboratory services histopathology department. these cases have been photographed to illustrate microscopic aspects and will be accompanied by a literature review of opportunistic infections in the context of hiv infection. results: this article highlights aspects of fungal, parasitic, viral and selected bacterial infections of people living with hiv for whom the histopathological examination of tissue was an essential component of the clinical diagnosis. histological features are noted on routine slides and accompanied by diagnostic features revealed with histochemical and immunohistochemical stains. conclusion: medical practitioners working in areas of high hiv endemicity should be familiar with the variety of infectious diseases that are encountered and with the diagnostic importance of the histopathologist in clinical management. keywords: infectious diseases; histology; hiv; opportunistic infections; diagnosis. introduction people living with human immunodeficiency virus (hiv) are at risk from multiple infective pathogens. the clinical presentation of these infections is often atypical. this can result in costly diagnostic and therapeutic delays. adequate tissue is sometimes inaccessible for re-biopsy, is of limited quantity, or may have been fixed in formalin and is therefore useless for routine microbiological culture. what the histopathologist has may be all the material there is. in the absence of a confirmatory microbiological ‘answer’, the histopathologist must maintain a high index of suspicion for infectious diseases, perform special stains and exclude multiple pathogens even after one has been identified.1 there is limited exposure to histopathology in undergraduate medical training in south africa (sa) and clinicopathological meetings for postgraduate teaching are mostly confined to large academic centres. this article highlights aspects of fungal, parasitic, viral and selected bacterial infections encountered in the context of hiv infection and immunosuppression. a series of cases diagnosed with the aid of the histopathology laboratory of the national health laboratory service (nhls) of the chris hani baragwanath academic hospital (chbah) in soweto, sa, has been collected to demonstrate the importance of the histopathologist to the hiv clinician and infectious diseases specialist. fungal infections case 1 a bone marrow trephine biopsy from an hiv-positive man with bi-cytopaenia was received. intracellular fungal yeasts were noted on special stains (figure 1). a diagnosis of fungal infection was made and correlation with fungal culture was advised. figure 1: bone marrow trephine biopsy with intracellular fungal yeasts (arrow) that are periodic acid schiff positive with alcian blue periodic acid schiff stain (original magnification × 400). case 2 a skin punch biopsy was submitted from a 32-year-old woman with umbilicated skin lesions. cryptococcal latex antigen on serum and cerebrospinal fluid (csf) were positive and csf fungal culture revealed cryptococcus neoformans. her cd4 count was 1 cell/µl. numerous extracellular yeasts were seen on haematoxylin and eosin stained section (figure 2). the capsules and cell walls were highlighted on alcian blue periodic acid schiff (abpas) special stain (figure 2, inset) and the diagnosis of cryptococcosis was made. figure 2: skin biopsy with numerous extracellular yeasts on haematoxylin and eosin (original magnification × 200), the inset shows the yeasts with blue capsules and pink cell walls on alcian blue periodic acid schiff stain (original magnification × 400). comment: the histopathologist is often relied upon to make a timeous diagnosis of a fungal infection as tissue may not have been submitted for fungal culture or an ‘extended’ culture may be required, leading to a longer diagnostic turnaround time. although fungal culture remains the gold standard, the diagnosis of a fungal infection can be reliably made on histological examination by identifying fungal yeasts (see figure 1) or hyphae using histochemical stains such as grocott and periodic acid schiff (pas). histological features of fungal infection that should prompt special staining for fungal elements include granulomatous inflammation, neutrophilic micro-abscesses, foamy histiocytes, ulceration, pseudoepitheliomatous hyperplasia and suppurative inflammation.2 some morphological clues may point towards a specific fungus; for example cryptococcus yeasts, which are extracellular and variably sized. the typical staining on abpas special stain, as was noted in case 2 (see figure 2), is supportive of the diagnosis. pneumocystis jirovecii is typically present within a foamy exudate, the organisms are grocott positive and appear as collapsed ‘helmets’ with a central dot. in a south african cohort of patients from the western cape, emergomycosis (previously emmonsiosis) was the most common systemic mycoses, followed by sporotrichosis and histoplasmosis.3 it is not possible to distinguish emergomycosis from other fungi on histological examination.4 serum β-d-glucan and urine histoplasma capsulatum antigen testing can be used as adjuncts when a fungal infection is clinically suspected. it is worthwhile remembering that urine h. capsulatum antigen can be positive in patients with emergomycosis due to cross-reactivity.3,4 once the histological diagnosis of a fungal infection is made, further material should be submitted for fungal culture or polymerase chain reaction (pcr). although further confirmatory investigations were not performed in case 1, definitive identification of fungal species by these methods is critical as they will impact the choice and duration of antifungal therapy. bacterial infections mycobacterial infection case 3 a 40-year-old hiv-positive woman had bi-cytopaenia on full blood count. histological examination of the bone marrow trephine biopsy showed an infiltrate of foamy histiocytes. numerous, clumped intracellular acid-fast bacilli were noted on ziehl neelsen (zn) stain (figure 3). culture yielded growth of a non-tuberculous mycobacterium and pcr confirmed mycobacterium avium complex. figure 3: bone marrow trephine biopsy showing histiocytes (arrows) (original magnification × 200) with acid fast bacilli in clumps on ziehl neelsen stain (inset) (original magnification × 400). comment: the synergy between the mycobacterium species and hiv is well documented. patients with hiv have progressive and disseminated mycobacterial diseases, and, in turn, mycobacterial infection increases hiv replication.5 the histological presentations of mycobacterial infection are varied. the prototypic feature noted on microscopic examination is granulomatous inflammation. however, with advanced immunosuppression, granulomas are usually absent and neutrophilic infiltration and necrosis are prominent.6 mycobacterial spindle cell pseudotumour is another manifestation of mycobacterial infection seen more commonly in lymph node biopsies. this entity is characterised by a proliferation of spindled histiocytes and fibroblasts and positive zn stain. it may mimic a host of mesenchymal tumours due to the spindled appearance of the cells, thus leading to misdiagnosis.6,7 bacille calmette-guérin (bcg) infection may manifest as regional (bcgitis) or systemic disease (bcgosis) following bcg vaccination.8 in addition, bcgitis may occur after commencement of antiretroviral therapy (art) as part of immune reconstitution. this should be borne in mind, especially when children present with lymphadenitis involving axillary or supraclavicular nodes and granulomatous inflammation is noted on histological examination.8,9 testing for mycobacterium bovis is indicated in this setting.8 tuberculids such as erythema induratum are hypersensitivity reactions to mycobacterial antigens and no acid-fast bacilli are demonstrated in tissue biopsies from these lesions.10 although definitive mycobacterial species identification is not possible on histological examination, the finding of sheets of foamy histiocytes containing zn and pas-positive bacilli are suggestive of mycobacterium avium complex as noted in case 3 (see figure 3). acid-fast bacilli with a long beaded appearance may indicate infection with mycobacterium kansasii.5 in cases where granulomatous inflammation morphologically in keeping with mycobacterial infection or acid-fast bacilli are noted on histological examination, samples should be submitted for mycobacterial culture and sensitivity, and when appropriate – molecular testing. it should be noted that there may be false positives on zn stain due to laboratory contamination that occurs during preparation. histopathologists are always sensitised to this possibility and contaminants are recognised as such as they lie on a different plane, are clumped or are free-lying, away from the tissue section.5 bartonella infection case 4 a 34-year-old man on art presented with a fungating mass on the right foot. he had a cd4 count of 21 cells/µl. features of bacillary angiomatosis were noted on routinely stained skin biopsy and warthin-starry stain confirmed the presence of bacilli; pcr was not requested. comment: histologically, bacillary angiomatosis comprises a lobular proliferation of vascular spaces with plump endothelial cells and neutrophilic debris.11 the bacilli in bacillary angiomatosis are noted as basophilic clumps in the tissue stroma where they proliferate (figure 4). the bacteria induce endothelial anti-apoptosis and a pro-inflammatory state which accounts for the histological features that are noted.12 warthin-starry special stain or pcr for bartonella genus can be used to confirm the diagnosis. the microscopic differential diagnosis includes a pyogenic granuloma or kaposi sarcoma. while bartonella infection manifests most commonly as bacillary angiomatosis in immunocompromised patients, it may also cause peliosis in the liver, endocarditis, osteomyelitis and cat-scratch disease.12 figure 4: a proliferation of capillaries is noted with basophilic clumps of bacteria, indicated by arrows, characteristic of bacillary angiomatosis (original magnification × 400). syphilis case 5 a 32-year-old woman who was recently commenced on art presented to the dermatology clinic with a generalised maculopapular rash involving her palms and soles. her cd4 count was 219 cells/µl. a lichenoid lymphoplasmacytic infiltrate was noted on haematoxylin and eosin stained section (figure 5, inset). numerous spirochaetes were identified on treponema pallidum immunohistochemistry, confirming the diagnosis of secondary syphilis (figure 5). serum t. pallidum antibody was positive and rapid plasma reagin test was reactive with a titer of 1024. figure 5: numerous spirochaetes are identified on t. pallidum immunohistochemistry performed on the skin biopsy (original magnification × 400). a lichenoid lymphoplasmacytic infiltrate is noted on haematoxylin and eosin (inset) (original magnification × 200). comment: the prevalence of syphilis is increasing. in canada, the united states and the united kingdom, an increasing incidence is noted in men who have sex with men. skin lesions are the most amenable to biopsy in suspected syphilis. papulosquamous lesions with palmo-plantar involvement are the typical clinical findings but atypical presentations such as alopecia, pustular lesions, annular rash and nodules have also been described. patients with hiv infection are more likely to have atypical presentations and secondary syphilis at the time of diagnosis.13 histopathological findings in secondary syphilis include epidermal hyperplasia and a moderate to dense lymphoplasmacytic infiltrate as were noted in case 5 (figure 5, inset). the t. pallidum immunohistochemical stain (figure 5) is more sensitive than a silver stain. the sensitivity of immunohistochemistry was 64% compared to 9% for the silver stain, in detecting spirochaetes in one study. the same study also showed that patients with cd4 counts less than 250 cells/ml had more organisms (> 100 treponemes in 10 high power fields) demonstrated on skin biopsy than those with cd4 counts above 250 cells/ml.14 viral infections case 6 a 32-year-old woman presented with a one-month history of a perianal lesion. she had a cd4 count of 18 cells/µl. herpes simplex virus (hsv) and cytomegalovirus (cmv) inclusions were both present in the perianal biopsy (figure 6). no serological testing for hsv or cmv were performed. figure 6: perianal biopsy showing herpes simplex virus and cytomegalovirus inclusions (inset) in the same biopsy (both original magnification × 400). comment infection with hsv2 typically presents as genital ulcers. there is a strong association between hiv and hsv2 infection.15 individuals infected with hsv2 have sixfold higher odds of hiv infection compared with those uninfected with hsv2, and 68% of patients with genital ulcers caused by hsv2 were found to be co-infected with hiv. locally, hsv2 remains the leading cause of pathogen detectable genital ulcer disease.16 histologically, cells infected with hsv2 show intranuclear inclusions with a glassy appearance, margination of chromatin and multinucleation. infected keratinocytes are best demonstrated at the ulcer edge (figure 6). however, in hypertrophic or tumourous hsv2 lesions, the dense inflammatory cell infiltrate may obscure the viral inclusions. careful search of multiple levels through the tissue block and immunohistochemistry may be required to identify the virally infected cells. sparse infected cells within the deep dermis derived from ruptured hair follicles may be seen. it has been postulated that the florid inflammation noted in these hypertrophic lesions is due to immune reconstitution.17 tissue may be submitted for drug resistance testing in those cases not showing clinical response to standard therapy. cells infected with hsv and varicella-zoster virus show identical features on histological examination. immunohistochemical stains are available to help distinguish among them. characteristic intracytoplasmic and intranuclear cmv inclusions were also seen in case 6 (figure 6, inset) but atypical histological features are well documented.18 immunohistochemistry can also be used in those cases that are densely inflamed. the role of cmv that is detected in mucocutaneous lesions is controversial. it is thought by some that the virus does not cause the lesion but is merely a bystander and signifies that there is generalised cmv infection. its presence in genito-anal lesions may be as a result of autoinoculation of virus shed in faeces. possible re-activation of latent virus in endothelial cells or haematogenous spread of the virus to granulation tissue is also postulated.19 cytomegalovirus gastrointestinal tract disease can manifest as ulceration or polyps endoscopically and can show co-infection with other organisms such as cryptosporidium.20 viral load testing for cmv may be useful in confirming disease and in monitoring treatment response. case 7 a bone marrow trephine biopsy was submitted from a 29-year-old hiv-positive woman known to have pulmonary tuberculosis and a cd4 count of 80 cells/µl. her red cell count was 2.31 × 1012/l, her reticulocyte count was 7.41% and her haemoglobin was 7.0 g/dl. numerous parvovirus inclusions were noted on microscopic examination (figure 7). figure 7: bone marrow trephine biopsy with numerous parvovirus inclusions (arrows) (original magnification × 400). comment parvovirus b19 infection of the bone marrow can manifest as a transient aplastic crisis or persistent infection with pure red cell aplasia. on microscopic examination of a bone marrow trephine biopsy with parvovirus infection, erythroid precursors are absent and giant pro-normoblasts21 are seen (figure 7). morphologically suspicious cases can be confirmed with immunohistochemistry. while pcr testing for parvovirus b19 is very sensitive, detection of parvovirus b19 dna in the blood does not equate to acute infection.22 parvovirus b19 dna has also been detected in asymptomatic, parvovirus b19 igm negative individuals in solid organs such as skin, myocardium, synovium and bone marrow.23 no pcr or viral load testing was performed in our case. helminthic infections case 8 a fallopian tube was excised for an ectopic pregnancy and submitted for histology. schistosomal ova were noted incidentally within the fallopian tube on microscopic examination (figure 8). figure 8: fallopian tube with products of conception and an incidental finding of schistosomal ova (arrow) (original magnification × 100) and inset (original magnification × 400). comment schistosomiasis is diagnosed on histology in biopsy specimens from the urinary bladder, cervix, fallopian tube, appendix, liver and colon. the ova are elliptical in shape and may be calcified (figure 8). a schistosoma haematobium ovum has a terminal spine, while a schistosoma mansoni ovum has a lateral spine. this distinguishing feature is difficult to apply in histology due to variability in the plane of sectioning. schistosoma mansoni ova are positive with a zn stain while s. haematobium ova are negative. the ova elicit a granulomatous or eosinophilic inflammatory response. haemazoin pigment, a fine black non-refractile pigment, is another useful clue to the presence of schistosomiasis. it is formed by digestion of haemoglobin present in the worm gut following ingestion of red blood cells.24 schistosomiasis is thought to increase susceptibility to hiv infection by disrupting the mucosal barrier and increasing vascularisation and recruitment of cd4 positive t cells.25 although treatment kills the adult worms, the lesions may persist. tissue diagnosis in female genital schistosomiasis is crucial as it is thought to impact fertility.26 stool and urine microscopy are the gold standard to assess for infection but suffer from a lack of sensitivity as the eggs are not always detectable in the urine.27 bladder biopsies are usually submitted to the laboratory with the clinical information of the characteristic ‘sandy patches’ appearance noted on cystoscopy. in other sites, however, the diagnosis is often rendered incidentally in biopsies submitted for other pathologies such as in case 8. other helminthic infections that can be readily diagnosed by the histopathologist are neurocysticercosis and hydatid disease. hiv-positive individuals with neurocysticercosis may present with multiple parenchymal lesions and co-infection with hiv has been reported in almost a third of cases of neurocysticercosis.28 on microscopic examination, the cysts have three layers, including outer cuticular, middle cellular and inner reticular layers.29 hydatid disease is caused by species of the echinococcus genus.30 histologically proven cases of hydatid disease have increased and may be due to the increase in hiv prevalence. lungs and liver are the more commonly affected organs.31 the cyst wall appears thin, smooth and white macroscopically, and on histological examination appears eosinophilic, acellular and lamellar. cytological examination of the cyst fluid shows refractile hooklets and scolices.30 while hiv is a risk factor for infection with strongyloides stercoralis, hyperinfection with autoinfection and disseminated disease that is associated with immunosuppression are rarely reported in hiv-positive patients.32 the histopathologist plays a limited role in the diagnosis of strongyloidiasis as stool samples are usually submitted for confirmation. an eosinophilic infiltrate with microabscess formation and degranulation on histological examination of mesenteric lymph nodes may be a clue to the presence of strongyloides infection.33 conclusion histopathology plays an important role in the diagnosis of infectious diseases as many have characteristic histological features. pathologists practising in areas with a high hiv prevalence are attuned to the importance of investigating inflamed tissue biopsies for an underlying infectious agent with special and immunohistochemical stains and liaising with clinicians to initiate timeous therapy. correlation with relevant investigations such as pcr, culture and sensitivity, is advised in all cases to inform treatment decisions. with the aid of this case series and accompanying histology images, some key features of infections encountered in practice are conveyed to demonstrate the relevance of histopathology. acknowledgements mr eric liebenberg for his assistance with photography, members of the histopathology department at nhls chris hani baragwanath academic hospital and the staff at the chris hani baragwanath academic hospital who work tirelessly under challenging circumstances. competing interests the authors have declared that no competing interests exist. authors’ contributions r.m. and d.l.r. conceived the design, r.m. collected and photographed cases and drafted the manuscript, and d.l.r. revised the manuscript. ethical consideration ethics approval was obtained from the human research ethics committee (medical) of the university of the witwatersrand (clearance certificate number m190484). specific histology slides were retrieved from the archives of the histopathology department at chbah nhls and photographed. a literature review was conducted using pubmed. funding information this research received no specific grant from any funding agency in the public, commercial or not for profit sectors. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or any affiliated agency of the authors. references grayson w. recognition of dual or multiple pathology in skin biopsies from patients with hiv/aids. patholog res int. 2011;2011:398546. https://doi.org/10.4061/2011/398546 fernandez-flores a, saeb-lima m, arenas-guzman r. morphological findings of deep cutaneous fungal infections. am j dermatopathol. 2014;36(7):531–556. https://doi.org/10.1097/dad.0b013e31829cc6f3 schwartz i, kenyon c, lehloenya r, et al. aid-related endemic mycoses in western cape, south africa and clinical mimics: a cross sectional study of adults with advanced hiv and recent onset widespread skin lesions. open forum infect dis. 2017;4(4):1–7. https://doi.org/10.1093/ofid/ofx186 schwartz i, govender n, corcoran c, et al. clinical characteristic, 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pathol. 2006;10(4):209–214. https://doi.org/10.1016/j.anndiagpath.2005.11.008 hiv0304pg000 march 2004 the southern african journal of hiv medicine 4 0 as the epidemic has developed, issues relating to children and the impact of hiv have begun to gain prominence. the two cases described below illustrate some of the complexities involved in children’s rights and hiv/aids. the right to equality in access to education the buccleuch montessori nursery school case garnered much publicity when it was argued in september 2002. the case concerned the right of tholakele nkosi, then 3 years old, to attend the private nursery school. the applicant in the case, karen perreira, tholakele’s foster mother, had elected to disclose tholakele’s hiv status to the school, believing that it was in the child’s best interest for the school to be aware of her medical condition. the response of the school was extraordinary in the context of a severe aids epidemic well into its second decade — fears were expressed about the risks of transmission as a result of biting, scratching insect bites and sharing sweets. the school also indicated that it did not consider itself equipped to admit a child with hiv as none of its teachers had received any training in this regard. in order to counter these allegations, expert affidavits dealing with the risks of hiv transmission in the school setting, evidence regarding the non-discrimination policy of the department of education and international case law were put before the court. a dispute existed between the parties as to whether tholakele’s application for admission was actually rejected. according to the school’s own version, however, it conceded that a recommendation had been made to defer the application until such time as the school considered itself ready to admit children with hiv and until tholakele was ‘past the biting stage’. it was argued that this conduct, on its own, constituted unfair discrimination against tholakele. judgment was handed down more than a year later, in september 2003. disappointingly, judge lucy mailula found that since the school had not made a final decision m e d i c o l e g a l an overview of some of the key legal developments in hiv/aids and the law — 2003 liesl gerntholtz, ba, llb head, legal unit, aids law project, and centre for applied legal studies, university of the witwatersrand, johannesburg south africa has a strong legal framework that offers a high level of protection to people living with hiv/aids. although the constitution does not explicitly refer to hiv/aids, it does prohibit unfair discrimination on the grounds of disability. international jurisprudence has developed a broad definition of ‘disability’, which goes beyond so-called functional disability and has successfully accommodated hiv-related discrimination cases in australia, canada and the usa. it is likely that south african courts will ultimately do the same. employment legislation does refer specifically to hiv-related discrimination and prohibits unfair discrimination on the grounds of hiv status in the workplace. pre-employment and employment hiv testing is prohibited, unless the permission of the labour court is obtained before to testing takes place. there are other laws, dealing with the provision of medical aid services, access to education and health care, that also prevent hiv-related discrimination. despite this, however, people with hiv/aids continue to suffer high levels of discrimination and prejudice. the disclosure of hiv status remains a fearful experience for many south africans and may well be accompanied by violence and economic and social deprivation. this article examines some of the most important cases that have come before the courts and other tribunals in 2003 and have sought to establish the rights of people with hiv/aids to live lives of dignity without fear. children march 2004 the southern african journal of hiv medicine 4 2 to exclude tholakele, its conduct did not amount to unfair discrimination. the judge did not deal with the implications of the recommendation to defer tholakele’s admission and the discrimination inherent in such conduct and dismissed the application with costs. in my view, the judgment is a dangerous one as it allows a school to effectively exclude a child with hiv as long it ‘defers’ the application, rather than rejects it outright. the judgment provides no guidance as to the basis on which such a deferral may take place, how long the application may be deferred and what steps a school should take to accommodate children with hiv. the judgment may also serve as a precedent for other settings where service providers wish to exclude people with hiv. the judgment is currently being appealed. children and consent to hiv testing and treatment south african law requires that parental consent be obtained before any medical treatment can be given to a child below the age of 14 years. the child care act 74 of 1983 permits the minister of social development to consent to the treatment in the absence of consent from a parent or legal guardian, and a medical superintendent may consent in urgent cases. the high court, as the upper guardian of all children, may also be approached to provide consent. the wits paediatric hiv working group (wphwg) provides treatment and care to children in the public sector and to children and infants in children’s homes. increasing numbers of children with hiv who require treatment and care are presenting at hospitals without parents or legal guardians. for these children, there is no person who is legally capable of providing consent to treatment and hiv testing. a similar situation has arisen in children’s homes, where there are significant numbers of children, particularly newborn babies, who have not been lawfully placed in the custody of the homes. the wphwg wished to provide a high level of treatment and care to these vulnerable children and was extremely concerned about how the requirement of consent could be dealt with. it was the view of the wphwg that consent plays a crucial role in empowering patients and their caregivers to participate in decisions about their health and also protects the health worker. three cases were brought in 2003, dealing with consent. the first two merely sought permission from the court for five orphans without legal guardians to commence antiretroviral treatment. although both applications were successful, it was clear that it would be difficult, timeconsuming and expensive to approach the high court for each child in respect of whom consent could not be obtained. attempts were then made to use the mechanism created by the child care act that allowed for ministerial consent to be obtained where parental consent could not. the minister of social development responded promptly to the first request and gave his permission for the children named in the letter to receive treatment. however, he failed to respond to any further requests and a third court application was then brought. the third application attempted to create a mechanism that would facilitate the care of these children, without eroding the need to obtain consent, and was much broader in scope than the first applications. the order granted by the court permits the doctors associated with the wphwg to obtain consent from the person who has daily care of the child, once they have certified that the test or treatment is in the best interests of the child. this approach is in line with the current proposals in the children’s bill (a draft act that has not yet been enacted), which gives limited legal recognition to caregivers and allows them to consent to medical treatment. although the case represents an important victory for children, its application is limited to the wphwg and it will not assist other doctors. it is unlikely that the children’s bill will become law in the near future and it is therefore extremely important that the issue of consent be dealt with in the interim period. if it is not, doctors who treat children with hiv will be forced to either exclude children without legal guardians, or to act without consent. neither situation is desirable. vrm v. the hpcsa a key case dealing with the role of the health professions council of south africa (hpcsa) in regulating the medical profession was finalised in 2003. the case concerned a pregnant woman with hiv who was tested during her pregnancy without her consent. the doctor who performed the test did not disclose the results of the test to his patient and failed to advise her of the steps she could take to reduce the risk of perinatal hiv transmission. the patient subsequently delivered a stillborn baby and was advised that she had hiv shortly after the birth. a complaint was referred to the hpcsa, and although the doctor conceded that he had tested the patient without her informed consent and had not disclosed her test result, the hpcsa declined to convene a disciplinary hearing. its health care the southern african journal of hiv medicine march 2004 4 3 committee of preliminary enquiry accepted the version of the doctor, that he had acted ‘out of compassion’, and declined to take the matter any further. the judgment on appeal criticised the failure of the hpcsa adequately to consider the facts of the case and indicated that the procedures of the committee of preliminary enquiry were flawed. the judgment examined the role of this committee and indicated that it did not have the power to merely accept the version of the doctor over that of the patient, which it routinely does, unless the evidence provided by the doctor is corroborated. the matter has been referred back to the hpcsa for proper consideration. several other complaints, which the hpcsa had also failed to deal with properly, will also be reconsidered in light of the judgment. a civil claim for damages against the doctor is pending. access to affordable antiretroviral medicines in september 2002, a complaint was lodged with the competition commission against two major pharmaceutical companies, glaxosmithkline and boehringer ingelheim, on behalf of various applicants, including four people living with hiv, the treatment action campaign, cosatu and the aids consortium. the complaint alleged that the two companies were acting unlawfully by charging excessive prices for certain antiretroviral drugs. the complaint stated that the prices charged were directly responsible for the ‘premature, predictable and avoidable deaths of women, men and children living with hiv/aids’. in october 2003, the commission announced that it had decided to refer the complaint to the competition tribunal for adjudication. on 9 december 2003, a landmark agreement was reached between the two companies and the activists. the terms of these agreements will open the market to generic competition. the companies have agreed to license four additional companies to manufacture or import generic azt and lamivudine products, with three companies being licensed to manufacture and/or import generic nevirapine products. the agreements will have the effect of allowing government to procure antiretroviral drugs from a range of generic manufacturers without having to issue compulsory licences or negotiate voluntary licences first and will have a significant impact on prices. gazi v. the minister of public service dr gazi, a medical practitioner in the eastern cape and the then spokesperson for health for the pan african congress (pac), was found guilty of misconduct after he made various negative comments regarding the failure of the first minister of health to put an pmtct programme in place. dr gazi appealled against the finding as well as the sentence, which amounted to a reprimand. the case has important implications for the rights of doctors who work in the public sector to speak out in the public interest and in the interests of their patients. the case was argued in 2003 and a judgment is expected in 2004. a number of important cases will be heard in 2004. these cases will, it is hoped, continue to develop the law relating to hiv/aids and also empower people with hiv/aids to use the law to redress unfair discrimination. negligence three important cases dealing with medical negligence in the context of hiv are likely to be finalised in 2004. one case deals with the transplantation of a kidney from an infected person to a recipient without hiv. despite requesting that hiv testing be conducted on both parties, medical practitioners preformed the transplant without confirming the hiv status of the donor. a claim for damages is pending against the hospital. a second case concerns a newborn baby who was infected in hospital. a claim for damages, including access to antiretroviral therapy, is currently underway. the third case concerns the failure of medical practitioners to ensure that hiv test results were communicated to a couple who were attempting to conceive a child. one partner was positive and subsequently inadvertently infected his partner, who was negative at the time of the test. south african national defence force the sandf continues to conduct pre-employment hiv testing and to exclude job applicants with hiv. the sandf is excluded from the employment equity act, which prohibits hiv testing in the workplace. it is our view that such testing is unlawful and unconstitutional, and a case challenging the requirement that new recruits are hiv negative will be argued in 2004. outstanding cases a preview of 2004 clive evian, me bch~ l\1.med (community health) aids management and supporrilifeu.'ot'ksj hon. lecrurer. deparrmenr of community health, university of rhe 'wittratersrand november 2003 .. ".. fig. 2. age-specific hiv prevalence amang pregnant wamen in the public health services in sauth africa, 2000 2002. the southern african journal of hiv medicine ---------i'" i'" i'" "t-----------,ca-----------l3lt---f:t---'"." " hiv prevalence u--------' ':~ 1990 lis1 1992 1993 1994 1995 1996 11;91 1998 1999 2000 2001 2002 15 ·19 yis zl-24)l'1(;1 .. tlii ~ ·29l"'1(; .. ll:jll·~\'is(;"'ll35·]ill"5ip'*tl hgyr5(p. tl 1!12!xil 112lx1 c! 200'< fig. 1. hiv prevalence among pregnant women in the public health services in south africa, 1990 2002. why the latest antenatal hiv prevalence survey results are still bad news if the essential dynamics of the epidemic are understood i think they may lead to adifferent conclusion, and this issue needs more exploration and expert opinion. it will be seen that in actual fact the recent hiv antenatal surveillance survey shows that the epidemic is clearly still very much out of control (at the very least among women in the pregnancy age group). the charts and data below show the overall hiv prevalence in pregnant women from 1990 to 2002 (fig. 1) and the age-specific hiv prevalence from 2000 2002 (fig. 2). after the minister of health delayed releasing the 2002 antenatal hiv survey to the south african public for many months, the report on the 2002 antenatal survey results' was somewhat misleading in giving the impression to the public that the epidemic is 'stabilising' and coming under control. is this spin another example of the national denial recently so well propagated by president mbeki ('personally i do not know anyone who has died of aids')? when the epidemic began in the late 19805 (see fig. 1), almost 100'\'0 of the population was hiv-negative. the epidemic took a few years to establish itself, because hiv is a poorly transmitted virus and it therefore took some time to build up a critical pool of infected people (le 1989 1992). once the pool was large enough, i.e. 1 2% of sexually active adults (extrapolating to many tens of thousands of people], the epidemic started to grow exponentially (1993 1997). at this stage each new infection added one more to the prevalence and the rate of increase was very high (1992 1998). after some time [because hiv is a long chronic infection), many people are repeatedly reinfected; these reinfections do not add to the prevalence, and the epidemic appears to slow down (1998 2001]. in addition, at this more mature phase of the epidemic, most very vulnerable people have now acquired hiv (except for the youngest age bands), and a 'saturation' of a sort may be reached. also people have started dying from the disease [7 10 years after infection], and if the number of deaths equals the number of new infections, the prevalence will remain the same (you cannot contribute to prevalence if you are no longer around to be tested). clearly the epidemic is not under control yet for us to claim control, the hiv prevalence must be on the decline and decline consistently over a number of years. not only is the prevalence not declining, but it is inclining (2001 2(02). while this incline may not be statistically significant there is a very strong hint of a rise. any continued rise in the presence of a maturing epidemic is very bad news. even more serious than the evidence from the overall epidemic are the facts arising out of the age-specific hiv prevalence among pregnant women (see fig. 2). firstly, if one looks at the prevalence in the 15 19-year age group, it is falling slightly. however, the mere fact that approximately 15% of teenage girls are hiv-infected is terrible. it means that in the space of about 2 3 years teenage girls are going from almost zero prevalence (in the 10 14-year age group) to a striking 15%. this is alarming even if the figure is decreasing slightly. a high proportion of these infections must be arising out of sexual contact with older men (from whom the infection must originate]. also, the age band most sensitive to change is the 15 19-year band (prevalence in older age bands will take longer to show declining trends over time owing to the chronic nature of hiv infection], as young people enter the november 2003 sexually active phase of their lives. if the prevalence in this band is indeed being maintained at high levels it is very bad news. now, to go one step further, note how steep the increase in hiv infection is between the 15 19 age band and the 2024 band almost a doubling of the prevalence, le approximately a 100% increase. this indicates not only that are prevention strategies failing, but they are failing with distinction. this upward trend is being carried through to the 25 29and 30 34-year age bands as well, where there has been a significant increase in hiv prevalence from 2001 to 2002. the above data are revealing concerning both the upward trend in prevalence in the 20 34-year bands and the fact that this is taking place in a time period where the epidemic is maturing. the rate of new infections, or of people being reinfected, may be as bad now as it was 5 6 years ago (assuming that there is also an attrition of hiv-positive people through death). the 101 of hiv prevention is to face up to the reality of the epidemic. this cannot be achieved if the department of health is not fully informed and fully understanding of the true dynamic of the epidemic and its implications. and it cannot be achieved if the public are not fully informed of the implications of the results of such an important survey. the latest antenatal data are indeed very worrying and suggest that the national strategy (if it exists] is failing. failure is one thing, and it may be inevitable, but not to recognise it is a possibly even more worrying failure. it is also high time that the ministry of health expands its hiv surveillance to include more than just pregnant women in their surveillance, le. men, all age groups, and various other social demographic strata. president mbeki is the world leader in hiv denial, and by spinning the antenatal data the department of health may now be collaborating with this denial. leadership around this epidemic is the most critical factor in the true stabilisation of the epidemic in some countries north of south africa. when will the leadership of this country wake up7 1f not now when? 1. oepartment of h~th. notioooj hn and syphilis~knce sufl.'e)'of women attmding public antenaml oinits in south africa. pretoria: ikpartmmt of ~ith. 2002 the southern african journal of h'iv meoicine hivmed_20(1)_2019_contents.indd http://www.sajhivmed.org.za open access table of contents i opinion paper current perspectives on paediatric hiv management from the mexico international aids society conference, 2019 mohendran archary, lee fairlie, amy slogrove southern african journal of hiv medicine | vol 20, no 1 | a1027 | 31 october 2019 case report cutaneous tuberculosis in hiv-infected individuals: lessons learnt from a case series vhudzani tshisevhe, nontombi mbelle, remco p.h. peters southern african journal of hiv medicine | vol 20, no 1 | a895 | 12 march 2019 case report a case report of untreatable hiv infection in harare, zimbabwe cleophas chimbetete, linda chirimuta, margaret pascoe, olivia keiser southern african journal of hiv medicine | vol 20, no 1 | a885 | 27 june 2019 case report rapid emergence of resistance to antiretroviral treatment after undisclosed prior exposure: a case report theresa m. rossouw, gisela van dyk, gert van zyl southern african journal of hiv medicine | vol 20, no 1 | a965 | 30 july 2019 case report an unusual case of abdominal mycobacterial infection: case report and literature review pieter ekermans, rene de gama, celeste kock, ebrahim hoosien, tomas slavik, terry marshall, craig corcoran, jakko van ingen southern african journal of hiv medicine | vol 20, no 1 | a993 | 28 august 2019 case report emtricitabine-induced pure red cell aplasia nithendra manickchund, camille du plessis, melanie-anne a. john, thandekile c. manzini, bernadett i. gosnell, richard j. lessells, yunus s. moosa southern african journal of hiv medicine | vol 20, no 1 | a983 | 23 september 2019 editor's choice 66 71 74 78 editor's choice 81 87 editorial david c. spencer southern african journal of hiv medicine | vol 20, no 1 | a1037 | 02 december 2019 guideline southern african hiv clinicians society guideline for the prevention, diagnosis and management of cryptococcal disease among hiv-infected persons: 2019 update nelesh p. govender, graeme meintjes, phetho mangena, jeremy nel, samantha potgieter, denasha reddy, helena rabie, douglas wilson, john black, david boulware, tom boyles, tom chiller, halima dawood, sipho dlamini, thomas s. harrison, prudence ive, joseph jarvis, alan karstaedt, matamela c. madua, colin menezes, mahomed-yunus s. moosa, zaaheera motlekar, amir shroufi, sarah lynn stacey, merika tsitsi, gilles van cutsem, ebrahim variava, michelle venter, rachel wake southern african journal of hiv medicine | vol 20, no 1 | a1030 | 08 november 2019 guideline palliative care guidelines for the management of hiv-infected people in south africa david c. spencer, rené krause, theresa rossouw, mahomed-yunus s. moosa, selma browde, esnath maramba, lauren jankelowitz, muhangwi b. mulaudzi, mpho ratishikana-moloko, oluwarotimi f. modupe, adam mahomed southern african journal of hiv medicine | vol 20, no 1 | a1013 | 13 december 2019 review article loss to follow-up from antiretroviral therapy clinics: a systematic review and meta-analysis of published studies in south africa from 2011 to 2015 samantha kaplan, katleho s. nteso, nathan ford, andrew boulle, graeme meintjes southern african journal of hiv medicine | vol 20, no 1 | a984 | 18 december 2019 opinion paper the role of rilpivirine in southern africa michelle a. moorhouse, karen cohen southern african journal of hiv medicine | vol 20, no 1 | a825 | 29 may 2019 1 editor's choice 7 editor's choice 23 editor's choice 49 editor's choice 59 page i of iv table of contents i vol 20, no 1 (2019) issn: 1608-9693 (print) | issn: 2078-6751 (online)southern african journal of hiv medicine epidemiology and prevention original research targeted mentoring for human immunodeficiency virus programme support in south africa geoffrey jobson, moyahabo mabitsi, jean railton, cornelis j. grobbelaar, james a. mcintyre, helen e. struthers, remco p.h. peters southern african journal of hiv medicine | vol 20, no 1 | a873 | 14 february 2019 original research knowledge about male circumcision and perception of risk for hiv among youth in harare, zimbabwe kudzaishe mangombe, ishmael kalule-sabiti southern african journal of hiv medicine | vol 20, no 1 | a855 | 30 april 2019 editor's choice 90 96 original research ‘we must treat them like all the other people’: evaluating the integrated key populations sensitivity training programme for healthcare workers in south africa zoe duby, francisco fong-jaen, busisiwe nkosi, benjamin brown, andrew scheibe southern african journal of hiv medicine | vol 20, no 1 | a909 | 30 april 2019 original research sexual behaviours, awareness and perceptions towards voluntary medical male circumcision among students in dr kenneth kaunda district, south africa sam mndzebele, lebogang g. matonyane southern african journal of hiv medicine | vol 20, no 1 | a846 | 22 may 2019 105 112 http://www.sajhivmed.org.za open access table of contents ii original research evaluation of a health system intervention to improve virological management in an antiretroviral programme at a municipal clinic in central durban christie m. cloete, jane hampton, terusha chetty, thando ngomane, elizabeth spooner, linda m.g. zako, shabashini reddy, tarylee reddy, nozipho luthuli, hope ngobese, gita ramjee, anna coutsoudis, photini kiepiela southern african journal of hiv medicine | vol 20, no 1 | a985 | 26 september 2019 original research acceptability of short text messages to support treatment adherence among adolescents living with hiv in a rural and urban clinic in kwazulu-natal mthokozisi a. cele, moherndran archary southern african journal of hiv medicine | vol 20, no 1 | a976 | 03 october 2019 original research challenges to hiv treatment adherence amongst adolescents in a low socio-economic setting in cape town brian e. van wyk, lee-ann c. davids southern african journal of hiv medicine | vol 20, no 1 | a1002 | 28 october 2019 original research knowledge and perceptions of male immigrants in leeds (uk) towards male circumcision as an hiv prevention strategy catherine atuhaire, kabanda taseera, chris spoor, rosaline y. cumber, samuel n. cumber southern african journal of hiv medicine | vol 20, no 1 | a823 | 31 october 2019 163 171 177 184 original research cognitive and behavioural determinants of multiple sexual partnerships and condom use in south africa: results of a national survey patience g. manjengwa, kerry mangold, alfred musekiwa, lazarus r. kuonza southern african journal of hiv medicine | vol 20, no 1 | a868 | 10 june 2019 original research outcomes of patients enrolled in an antiretroviral adherence club with recent viral suppression after experiencing elevated viral loads joseph sharp, lynne wilkinson, vivian cox, carol cragg, gilles van cutsem, anna grimsrud southern african journal of hiv medicine | vol 20, no 1 | a905 | 11 june 2019 original research a cross-sectional study of the factors associated with male circumcision status among college youth in ndola, zambia, 2016 ernest kateule, ramya kumar, david mwakazanga, modest mulenga, victor daka, gershom chongwe southern african journal of hiv medicine | vol 20, no 1 | a952 | 20 june 2019 original research self-reported risky sexual practices among adolescents and young adults in botswana unoda chakalisa, kathleen wirth, kara bennett, etienne kadima, kutlo manyake, tendani gaolathe, pam bachanas, tafireyi marukutira, refeletswe lebelonyane, scott dryden-peterson, lisa butler, mompati mmalane, joseph makhema, michelle e. roland, molly pretorius-holme, max essex, shahin lockman, kathleen m. powis southern african journal of hiv medicine | vol 20, no 1 | a899 | 26 june 2019 original research ‘at this [adherence] club, we are a family now’: a realist theory-testing case study of the antiretroviral treatment adherence club, south africa ferdinand c. mukumbang, brian van wyk, sara van belle, bruno marchal southern african journal of hiv medicine | vol 20, no 1 | a922 | 26 june 2019 118 127 134 editor's choice 141 149 page ii of iv basic science (microbiology) clinical hiv and antiretroviral therapy (art) original research false rifampicin resistant results using xpert mtb/rif on urine samples in hospitalised hiv-infected patients charlotte schutz, amy ward, rosie burton, mark p. nicol, liz blumenthal, graeme meintjes, andrew d. kerkhoff southern african journal of hiv medicine | vol 20, no 1 | a978 | 28 august 2019 editor's choice 190 original research hiv status and mortality of surgical inpatients in rural zimbabwe: a retrospective chart review pascal migaud, michael silverman, paul thistle southern african journal of hiv medicine | vol 20, no 1 | a812 | 24 january 2019 original research hiv-associated cavernous sinus disease cait-lynn d. wells, anand a. moodley southern african journal of hiv medicine | vol 20, no 1 | a862 | 20 march 2019 200 206 original research comparison of non-invasive methods of assessing liver fibrosis in combination art-experienced zimbabweans brenda nherera, kudakwashe mhandire, tinashe k. nyazika, alfred makura, cuthbert musarurwa, prichard t. mapondera, babill stray-pedersen, hilda t. matarira southern african journal of hiv medicine | vol 20, no 1 | a844 | 11 april 2019 original research correlation of hair and plasma efavirenz concentrations in hiv-positive south africans jenna johnston, lubbe wiesner, peter smith, gary maartens, catherine orrell southern african journal of hiv medicine | vol 20, no 1 | a881 | 29 april 2019 213 219 http://www.sajhivmed.org.za open access table of contents iii original research occupational blood and body fluid exposures and human immunodeficiency virus post-exposure prophylaxis amongst intern doctors sunday j. aigbodion, feroza motara, abdullah e. laher southern african journal of hiv medicine | vol 20, no 1 | a958 | 22 may 2019 original research virologic and immunologic responses of patients on highly active antiretroviral therapy in a rural community health centre in limpopo, south africa: a retrospective study aniekan edet, henry akinsola, pascal o. bessong southern african journal of hiv medicine | vol 20, no 1 | a818 | 22 may 2019 original research tonsil histopathology in hiv-infected versus hiv-uninfected adults ridwaan essa, shivesh maharaj, kapila hari, shahpar motakef southern african journal of hiv medicine | vol 20, no 1 | a936 | 28 may 2019 original research factors influencing the confidence and knowledge of nurses prescribing antiretroviral treatment in a rural and urban district in the western cape province deborah j. solomons, anita s. van der merwe, tonya m. esterhuizen, talitha crowley southern african journal of hiv medicine | vol 20, no 1 | a923 | 02 july 2019 original research outcomes of stevens–johnson syndrome and toxic epidermal necrolysis in hiv-infected patients when using systemic steroids and/or intravenous immunoglobulins in pietermaritzburg, south africa antoinette v. chateau, ncoza c. dlova, halima dawood, colleen aldous southern african journal of hiv medicine | vol 20, no 1 | a944 | 04 july 2019 original research switching at low hiv-1 rna into fixed dose combinations: tdf/ftc/rpv is non-inferior to tdf/ftc/efv in first-line suppressed patients living with hiv paula munderi, edwin were, anchalee avihingsanon, pascale a.m. mbida, lerato mohapi, samba b. moussa, marjolein jansen, ceyhun bicer, perry mohammed, yvon van delft southern african journal of hiv medicine | vol 20, no 1 | a949 | 23 july 2019 original research baseline cd4 and mortality trends in the south african human immunodeficiency virus programme: analysis of routine data rivka r. lilian, kate rees, moyahabo mabitsi, james a. mcintyre, helen e. struthers, remco p.h. peters southern african journal of hiv medicine | vol 20, no 1 | a963 | 24 july 2019 editor's choice 225 231 238 243 250 258 editor's choice 268 original research a descriptive analysis of the role of a whatsapp clinical discussion group as a forum for continuing medical education in the management of complicated hiv and tb clinical cases in a group of doctors in the eastern cape, south africa joana woods, michelle moorhouse, lucia knight southern african journal of hiv medicine | vol 20, no 1 | a982 | 01 august 2019 original research associations of visceral fat thickness and anthropometric measurements with non-alcoholic fatty liver disease development in male patients mono-infected with human immunodeficiency virus miloš vujanović, nina brkić-jovanović, dalibor ilić, zorka drvendžija, biljana srdić-galić, vesna turkulov, snežana brkić, daniela marić southern african journal of hiv medicine | vol 20, no 1 | a968 | 07 august 2019 original research measles in adults: a comparison of hospitalised hiv-infected and hiv-uninfected patients nina e. diana, charles feldman southern african journal of hiv medicine | vol 20, no 1 | a877 | 13 august 2019 original research unexpected low frequency of respiratory symptoms in an hiv-positive urban sub-saharan population compared to an hiv-negative control group maren kummerow, erica j. shaddock, kerstin klipstein-grobusch, roos b. barth, diederick e. grobbee, francois d.f. venter, charles feldman, alinda vos southern african journal of hiv medicine | vol 20, no 1 | a1010 | 26 september 2019 original research the diagnostic utility of bone marrow examination in an infectious disease ward nirvana bharuthram, charles feldman southern african journal of hiv medicine | vol 20, no 1 | a974 | 30 september 2019 original research motor lumbosacral radiculopathy in hiv-infected patients kaminie moodley, pierre l.a. bill, vinod b. patel southern african journal of hiv medicine | vol 20, no 1 | a992 | 28 october 2019 original research breast abnormalities in adolescents receiving antiretroviral therapy jackie l. dunlop, wiedaad slemming, kathryn schnippel, caroline makura, leon j. levin, sarah rayne, marnie vujovic, cynthia firnhaber southern african journal of hiv medicine | vol 20, no 1 | a1017 | 06 november 2019 278 287 293 298 305 312 318 page iii of iv paediatric hiv original research peripartum hiv infection in very low birth weight infants fed ‘raw’ mother’s own milk melantha coetzee, suzanne d. delport southern african journal of hiv medicine | vol 20, no 1 | a912 | 19 june 2019 original research hiv testing at birth: are we getting it right? chanté bisschoff, jasmine coulon, ziva isaacs, lavinia van der linde, linley wilson, riana van zyl, gina joubert southern african journal of hiv medicine | vol 20, no 1 | a951 | 27 june 2019 325 332 original research adherence to combination antiretroviral therapy among orphaned children in dar es salaam, tanzania sabina f. mugusi, nassoro mopei, omary minzi southern african journal of hiv medicine | vol 20, no 1 | a954 | 06 august 2019 original research disclosure of human immunodeficiency virus status to children in south africa: a comprehensive analysis sabine l. van elsland, remco p.h. peters, cornelis grobbelaar, patiswa ketelo, maarten o. kok, mark f. cotton, a. marceline van furth southern african journal of hiv medicine | vol 20, no 1 | a884 | 22 august 2019 337 editor's choice 345 http://www.sajhivmed.org.za open access table of contents iv page iv of iv original research birth outcomes following antiretroviral exposure during pregnancy: initial results from a pregnancy exposure registry in south africa ushma c. mehta, cari van schalkwyk, prineetha naidoo, arthi ramkissoon, otty mhlongo, niren r. maharaj, niree naidoo, karen fieggen, michael f. urban, shaun krog, alex welte, mukesh dheda, yogan pillay, neil f. moran southern african journal of hiv medicine | vol 20, no 1 | a971 | 30 september 2019 355 female and maternal hiv original research neurodevelopment at 11 months after starting antiretroviral therapy within 3 weeks of life barbara laughton, shalena naidoo, els f.m.t. dobbels, michael j. boivin, anita janse van rensburg, richard h. glashoff, gert u. van zyl, mariana kruger, mark f. cotton southern african journal of hiv medicine | vol 20, no 1 | a1008 | 30 october 2019 367 original research sexually transmitted infections, the silent partner in hiv-infected women in zimbabwe sara lowe, tinashe mudzviti, ardele mandiriri, tinei shamu, petronella mudhokwani, cleophas chimbetete, ruedi luethy, margaret pascoe southern african journal of hiv medicine | vol 20, no 1 | a849 | 23 january 2019 original research hiv viraemia during pregnancy in women receiving preconception antiretroviral therapy in kwadukuza, kwazulu-natal vuyokazi ntlantsana, richard j. hift, wendy p. mphatswe southern african journal of hiv medicine | vol 20, no 1 | a847 | 10 april 2019 375 381 original research vaginal practices among women at risk for hiv acquisition in soweto, south africa erica lazarus, kennedy otwombe, janan dietrich, michele p. andrasik, cecilia a. morgan, james g. kublin, glenda e. gray, abby j. isaacs, fatima laher southern african journal of hiv medicine | vol 20, no 1 | a866 | 20 june 2019 reviewer acknowledgement southern african journal of hiv medicine | vol 20, no 1 | a1050 | 12 december 2019 389 396 abstract introduction state of the global epidemic hiv epidemiology in esa challenges for achieving 95-95-95 in esa the impending challenge of acute hiv infections disproportionate impact of new hiv infections on key and vulnerable populations recommendations for research priorities conclusion acknowledgements references about the author(s) erica parker faculty of health and medical sciences, the university of western australia, perth, australia melinda a. judge faculty of health and medical sciences, the university of western australia, perth, australia eusebio macete manhiça health research centre, manhiça, mozambique tacilta nhampossa manhiça health research centre, manhiça, mozambique jienchi dorward nuffield department of primary care health sciences, university of oxford, oxford, united kingdom centre for the aids programme of research in south africa (caprisa), university of kwazulu-natal, durban, south africa denise c. langa department of surveillance, instituto nacional de saúde, maputo, mozambique caroline de schacht friends in global health, maputo, mozambique aleny couto national sti, hiv/aids programme, ministry of health, maputo, mozambique paula vaz fundaçao ariel glaser contra o sida pediátrico, maputo, mozambique marco vitoria department of hiv/aids, world health organization, geneva, switzerland lucas molfino médecins sans frontières, maputo, mozambique rachel t. idowu center for global health, centers for disease control and prevention, maputo, mozambique nilesh bhatt elizabeth glaser pediatric aids foundation, maputo, mozambique denise naniche manhiça health research centre, manhiça, mozambique barcelona institute for global health (isglobal), spain peter n. le souëf faculty of health and medical sciences, the university of western australia, perth, australia citation parker el, judge ma, macete e, et al. hiv infection in eastern and southern africa: highest burden, largest challenges, greatest potential. s afr j hiv med. 2021;22(1), a1237. https://doi.org/10.4102/sajhivmed.v22i1.1237 opinion paper hiv infection in eastern and southern africa: highest burden, largest challenges, greatest potential erica parker, melinda a. judge, eusebio macete, tacilta nhampossa, jienchi dorward, denise c. langa, caroline de schacht, aleny couto, paula vaz, marco vitoria, lucas molfino, rachel t. idowu, nilesh bhatt, denise naniche, peter n. le souëf received: 02 mar. 2021; accepted: 01 apr. 2021; published: 28 may 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the burden of hiv is especially concerning for eastern and southern africa (esa), as despite expansion of test-and-treat programmes, this region continues to experience significant challenges resulting from high rates of morbidity, mortality and new infections. hard-won lessons from programmes on the ground in esa should be shared. objectives: this report summarises relevant evidence and regional experts’ recommendations regarding challenges specific to esa. method: this commentary includes an in-depth review of relevant literature, progress against global goals and consensus opinion from experts. results: recommendations include priorities for essential research (surveillance data collection, key and vulnerable population education and testing, in-country testing trials and evidence-based support services to improve retention in care) as well as research that can accelerate progress towards the prevention of new infections and achieving ambitious global goals in esa. conclusion: the elimination of hiv in esa will require continued investment, commitment to evidence-based programmes and persistence. local research is critical to ensuring that responses in esa are targeted, efficient and evaluated. keywords: hiv epidemiology; public health; risk factors; vulnerable populations; prevention and control; early diagnosis. introduction in the decades since hiv-1 first emerged, the response has been marked by strong global commitments, extensive education campaigns and the development of improved tests and life-saving antiretroviral treatments (art) that are reaching more and more individuals.1 with evidence-based prevention and treatment strategies available, nations have united to set goals, with the end of the hiv epidemic potentially attainable by 2030.2 one hallmark concept in the fight against hiv has been the ‘know your epidemic, know your response’ approach to deliver programmes in different settings.3 more than 70% of persons living with hiv (plwh) reside in sub-saharan africa (ssa), where resources for healthcare are disproportionately limited. eastern and southern africa (esa), in particular, continues to record the highest rates of hiv-1 prevalence and incidence worldwide.4 in this region, knowing where and among whom the infection is spreading has been challenging, and key populations are only recently being highlighted. a second hallmark of the fight against hiv has been the joint united nations programme on hiv/aids (unaids) ‘fast-track’ targets, whereby 90% of plwh should know their status, 90% of those diagnosed should receive art and 90% of those on art should achieve viral suppression by 2020 (‘90-90-90’).5 despite remarkable progress towards these targets in esa, the sheer scale of the epidemic in this region leaves much to be done.6 in the next decade, efforts must be redoubled for raised targets of 95-95-95 by 2030.7 programmes on the ground have identified region-specific challenges to be overcome and lessons that should be broadly shared with esa and potentially with many communities globally. an important barrier preventing progress in esa is the timely detection and treatment of acute hiv infections.the earliest stage of hiv infection is characterised by high viral loads and a high potential for onward transmission, but it is typically missed using existing testing algorithms.8 as art coverage improves, the proportion of transmissions attributable to undiagnosed acute hiv infection increases.9 furthermore, new hiv infections disproportionately affect key populations.10 affordable testing solutions for acute hiv detection in high-prevalence, resource-limited settings are needed.9 as the 2020 deadline passed, trends indicated that the 90-90-90 targets were not reached across most of esa.2 renewed efforts looking ahead to the 2030 unaids targets of 95-95-95 will be required. to this end, a group of regional experts was invited to collate their expertise, with a view to addressing the local challenges that prevent the achievement of global goals. state of the global epidemic according to unaids, there were an estimated 38 million plwh worldwide at the end of 2019, with 1.7 million new infections and 690 000 aids-related deaths that year (figure 1).10 a successful vaccine and functional cure for hiv are yet to be developed, and lifelong art remains the cornerstone of management. figure 1: (a) worldwide distribution of new hiv infections identified by unaids in 2019. (b) distribution of people living with hiv infection in esa in 2019. (c) prevalence of hiv infection per 100 000 population among countries in esa. (d) incidence of hiv infection per 1000 population among countries in esa. the 2020 unaids report highlights a ‘prevention crisis’.10 programmes aiming to prevent new hiv infections (such as education, barrier contraception, voluntary male medical circumcision and pre-exposure prophylaxis [prep]) must be a priority alongside test-and-treat programmes and must appropriately target key populations and their partners, who comprise 62% of new hiv infections globally.10 hiv epidemiology in esa regional hiv epidemics look markedly different across the world and require tailored responses. in esa, there are 20.7 million adults and children living with hiv (54% of global hiv prevalence),10 and in 2019 44% of all new infections occurred here.10 key populations make up an estimated 28% of new infections in esa.10 in some areas, reasonable progress has been made towards the fast-track targets (e.g. eswatini, namibia and zambia); in other areas, progress is more limited (e.g. mauritius and south sudan). an estimated 87% of plwh in esa are aware of their status (the ‘first 90’; figure 2); however, this figure ranges from 15% to 98% between countries.10 figure 2: data on the esa 90-90-90 goals in all ages by country from the unaids data 2020 report.10 (a) first 90; (b) second 90; (c) third 90. of those diagnosed with hiv in esa, approximately 83% have commenced art (the ‘second 90’).10 this figure ranges from 37% to 98% between countries,10 highlighting deep inequities within and across countries. of those on treatment, 90% have achieved viral suppression (the ‘third 90’); this figure ranges from 68% to 97% between countries, with 2 of 21 countries unable to provide estimates. combatting the epidemic in esa is a multifaceted challenge, and progress must occur within a broader context of socio-economic development. despite some successes, the 2020 milestones were not achieved in many countries across esa, and the greatest challenges persist as the focus shifts to achieving the new 95-95-95 targets. challenges for achieving 95-95-95 in esa the first 95 in high hiv prevalence settings, obtaining accurate measures of the first 95 is challenging. in esa, hiv care commonly takes place in rural settings, utilising paper-based records.11 to estimate the first 95, the denominator is typically the number of people testing positive for hiv during randomised household or community-based serosurveys and/or at antenatal clinics; the numerator is those among them known to have previous positive results (either disclosed to surveyors or identified in medical records).12 rates of non-disclosure can be high.13 when people are retested in southern mozambique, non-disclosure of previous results occurs in over one-third of people, but the rate is higher for tests performed in a community setting (38.9%) or initiated by the provider (29.4%) than in those presenting for voluntary testing (13%).13 similar findings have been described in tanzania and malawi.14,15 cross-checking survey responses against medical records is impossible in many countries where hiv testing is performed anonymously.11 the high percentage of hiv-positive people who do not disclose, and are thus repeatedly deemed recently infected, leads to an overestimation of new hiv cases and an underestimation of progress towards the first 95. in mozambique, non-disclosure resulted in underestimation of the first 95 by around 8.5%.13 improving testing coverage to achieve the first 95 is feasible but must be accompanied by interventions that support the whole care cascade. in the treatment as prevention (tasp) trial of universal test-and-treat in kwazulu-natal, south africa, repeated rounds of home-based testing increased the proportion of people knowing their hiv status to 91.5%.16 however, only 58.0% of these individuals commenced art; many did not link to care.16 this suggests that to reach 95-95-95, all three targets must be understood and addressed in parallel.17 the second 95 the second 95 is more readily measured, as countries (or their health facilities and non-governmental organisations) generally have stronger records on the number of people receiving art. according to world health organization recommendations, early art commencement has reduced hiv/aids-related mortality, with some models showing an estimated 75% fewer deaths per annum.18 test-and-treat strategies recommending commencement of art within 14 days of a positive diagnosis (independent of the cd4+ t-cell count) are relatively recent in most of ssa,19 and uptake has been commendable.20 broader implementation is limited not only by the political will but also by the resources required to upskill staff and provide a sustainable treatment supply. given the scale of the epidemic in esa, the rollout of any advances in treatment regimens to the front lines can present a formidable challenge. the system’s fragility has been highlighted by covid-19 over the past year, with reports of delays in the delivery of treatment stock from international suppliers, depleted national stockpiles and periods of lockdown limiting individuals’ access to hiv medications.21 based on country guidelines, in 2014–2015, of those eligible for art in manhiça, mozambique, 83.7% started art within 3 months.22 in july 2016, mozambique phased in the implementation of test-and-treat and undertook qualitative research into the patterns of art initiation or refusal.23,24 the acceptance of treatment depends on the availability and accessibility of services, as well as appropriate and considered explanations following diagnosis.25 linkage to care is improved by the desire to live, family support and subjective illness.23,24 barriers to linkage to care include the fear of dissemination of one’s hiv status, feeling subjectively healthy, migration, health system issues and fears of discrimination.23,24,26 the third 95 achieving viral suppression requires retention in care, maintenance of art and regular testing of the hiv viral load. retention in care is improved by feeling better after art initiation, confidence in the health system and support from family and providers.27 communication about continuing treatment despite feeling better also helps.24 barriers to retention include provider authoritarianism, which limits patient autonomy and engagement in their healthcare, and the adverse effects of art.27 men across the region are a hard-to-reach group; they test less, and more abandon art after initiation.22 there are additional complexities related to paediatric care, such as the health literacy of parents and their confidence in managing hiv. for children, retention is highest when both mother and child register concurrently.28 innovative strategies to improve testing uptake and support early art initiation and nutritional supplementation can improve retention.29,30 before the introduction of the universal test-and-treat programme, there were concerns that commencing art among people with high cd4+ t-cell counts would overburden the health system and that those feeling healthy would not adhere to treatment.31 however, of the plwh in kwazulu-natal with cd4+ t-cell counts of > 500 cells/µl, 78% accepted art,32 86% were adherent33 and 96% achieved viral suppression.34 furthermore, retention in care and viral suppression were similar among people who initiated art with cd4+ t-cell counts of > 500 cells/µl compared to those with lower cd4+ t-cell counts.35 measuring the third 95 requires country-wide laboratory systems capable of processing large volumes of viral load requests and returning results; thus, many esa countries score poorly.10 for example, in mozambique, only 45% of plwh achieve documented viral suppression10; however, viral load testing is available to few, particularly in rural settings.36,37 under-developed laboratory systems also delay diagnoses of virological failure, leading to increased transmission, illness progression and treatment resistance.38 point-of-care (poc) viral load testing improved viral suppression, retention in care and the communication of results to patients in kwazulu-natal,39 and it proved feasible and cost-effective in botswana and zambia.40,41 further development of centralised, high-throughput laboratory-based testing alongside decentralised poc testing will be crucial to ensure adequate monitoring of viral suppression throughout esa. the impending challenge of acute hiv infections acute hiv infection is commonly defined as the period prior to seroconversion, between 3 and 12 weeks in duration.42,43 gene expression is vastly upregulated in the initial months, driving inflammation, immune responses and cell turnover.44 this correlates with a substantial peak in viral load, meaning the risk of onward transmission during acute hiv is 8–25 times higher than during chronic infection.45,46,47 the estimated prevalence of acute hiv infection in esa is 1% – 3%.48,49,50,51 undiagnosed acute hiv is particularly concerning for the following: pregnant and breastfeeding women who have poorer health outcomes as well as increased perinatal transmission risk52,53,54,55; people who received blood transfusions screened for hiv serology but not viral load56,57; and those who started prep when already infected, as this may confer an increased risk of drug resistance mutations.58 the earliest time period that an acute hiv infection can be detected is 5–14 days by nucleic acid amplification.59 this is not feasible in low-resource settings, so other options include viral load poc testing (gene xpert60 and alereq61), p24 antigen testing (if developed into rapid tests),62 non-viral immune response biomarkers (e.g. ip-10)63 or a symptom/risk score.8,64 rapid testing and art for all hiv-seropositive individuals remains the priority; however, a focus on this alone will miss seronegative hiv-infected individuals. as art coverage increases, the proportion of hiv transmission attributable to acute hiv will increase. affordable rapid tests for p24 or non-viral immune markers combined with a risk score may be the best way to identify acutely infected individuals in high-hiv-burden, low-resource settings. disproportionate impact of new hiv infections on key and vulnerable populations of the 1.7 million new hiv infections in 2019, 62% occurred in key populations and their sexual partners.6 key populations include men who have sex with men,65 people who inject drugs,66 female sex workers67 and transgender people.6 vulnerable populations at increased hiv risk in esa include prisoners,6,68 long-haul truck drivers,69 mobile mining workers,70 migrants71 and serodiscordant couples.6 also at disproportionately high risk of hiv infection are young women,72 who are 2–3 times73,74 more likely to be newly infected than their 15–24-year-old male counterparts. pregnant and breastfeeding women and their infants are an often-overlooked vulnerable population.52 infants of mothers who acquired hiv during pregnancy or postpartum are at increased risk of hiv transmission compared to infants of chronically hiv-infected mothers.52 approximately 45% of new global infections in 2019 were in esa.6,10 no country in esa has sufficient data to describe the size of their key populations,10,75 although several have commenced population-specific mapping (table 1).76 control of hiv in these populations will contribute to the deceleration of the hiv epidemic in the general population. national surveys of key populations biennially are recommended, as knowing the epidemic is the first key to design the response. table 1: prevalence of hiv among certain key and vulnerable populations in esa. recommendations for research priorities promote and expand local prevention research, including programme and policy evaluations. investigate and implement methods to improve the accessibility of hiv education and testing, including routine surveillance, particularly for key populations. support in-country trials of viral load and cd4 t-cell count poc testing and the surrounding services required to improve art adherence, clinical management and retention in care. conclusion the road to hiv elimination in esa requires continued strong and sustained national and international investment, commitment to evidence-based programmes and persistence. the region contains over half of the world’s population of plwh and continues to have major challenges to achieving 90-90-90, let alone the looming target of 95-95-95. the priority must remain diagnosing, treating and virally suppressing all existing hiv infections. however, in high-prevalence settings, the prevention of new infections and early diagnosis of acute infections remain important goals. research must ensure that responses in the region are targeted, efficient and evaluated. in particular, esa will benefit from strengthened surveillance and key and vulnerable population research, in-country development and validation of hiv tests, and supported rapid transition to new art regimens to ensure sustainable progress towards important global goals. acknowledgements the authors thank eva kiwango, the unaids country director for mozambique, for the contribution to this article. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions e.p. and m.j. are co-first authors and have contributed equally to the article. e.p., m.a.j., e.m., t.n., d.n. and p.n.l.s. planned and organised the collaboration; all authors contributed region-specific knowledge and expertise. e.p., m.a.j., d.n. and p.n.l.s. wrote the manuscript, with review and revision by all authors. ethical considerations this article followed all ethical standards for research without direct contact with human or animal subjects. funding information this study was supported by the manhiça foundation, mozambique, and a research impact grant (ra/1/2799/40) from the university of western australia. data availability publicly available data sets were accessed from https://www.unaids.org/sites/default/files/media_asset/2020_aids-data-book_en.pdf (associated with figures 1 and 2) and https://population.un.org/wpp/ (associated with figure 1). disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references ford n, ball a, baggaley r, et al. the who public health approach to hiv treatment and care: looking back and looking ahead. lancet infect dis. 2018;18(3):e76–e86. https://doi.org/10.1016/s1473-3099(17)30482-6 the joint united nations programme on hiv/aids (unaids). seizing the moment. geneva: unaids; 2020. report no.: jc2991. wilson d, halperin dt. “know your epidemic, know your response”: a useful approach, if we get it right. lancet. 2008;372(9637):423–426. https://doi.org/10.1016/s0140-6736(08)60883-1 the joint 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activities related to hiv/aids. maputo, mozambique: misau; april 2018. swannet s, decroo t, de castro smtl, et al. journey towards universal viral load monitoring in maputo, mozambique: many gaps, but encouraging signs. int health. 2017;9(4):206–214. https://doi.org/10.1093/inthealth/ihx021 petersen ml, tran l, geng eh, et al. delayed switch of antiretroviral therapy after virologic failure associated with elevated mortality among hiv-infected adults in africa. aids. 2014;28(14):2097–2107. https://doi.org/10.1097/qad.0000000000000349 drain pk, dorward j, violette lr, et al. point-of-care hiv viral load testing combined with task shifting to improve treatment outcomes (stream): findings from an open-label, non-inferiority, randomised controlled trial. lancet hiv. 2020;7(4):e229–e237. https://doi.org/10.1016/s2352-3018(19)30402-3 moyo s, mohammed t, wirth ke, et al. point-of-care cepheid xpert hiv-1 viral load test in rural african communities is feasible and reliable. j clin microbiol. 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2016;388(10050):1215–1227. https://doi.org/10.1016/s0140-6736(16)30578-5 the joint united nations programme on hiv/aids (unaids). unaids key population atlas geneva [homepage on the internet] [cited 2021 mar 31]. available from: https://kpatlas.unaids.org/dashboard nalá r, cummings b, horth r, et al. men who have sex with men in mozambique: identifying a hidden population at high-risk for hiv. aids behav. 2015;19(2):393–404. https://doi.org/10.1007/s10461-014-0895-8 augusto âdo r, young pw, horth rz, et al. high burden of hiv infection and risk behaviors among female sex workers in three main urban areas of mozambique. aids behav. 2016;20(4):799–810. https://doi.org/10.1007/s10461-015-1140-9 semá baltazar c, horth r, boothe m, et al. high prevalence of hiv, hbsag and anti-hcv positivity among people who injected drugs: results of the first bio-behavioral survey using respondent-driven sampling in two urban areas in mozambique. bmc infect dis. 2019;19(1):1022. https://doi.org/10.1186/s12879-019-4655-2 baral s, trapence g, motimedi f, et al. hiv prevalence, risks for hiv infection, and human rights among men who have sex with men (msm) in malawi, namibia, and botswana. plos one. 2009;4(3):e4997. https://doi.org/10.1371/journal.pone.0004997 heijnen m, mumtaz gr, abu-raddad lj. status of hiv and hepatitis c virus infections among prisoners in the middle east and north africa: review and synthesis. j int aids soc. 2016;19(1):20873. https://doi.org/10.7448/ias.19.1.20873 united nations, department of economic and social affairs, population division. new york, world population prospects 2019 [homepage on the internet] [cited 2020 aug 16]. available from: https://population.un.org/wpp/ abstract twin pandemics: coronavirus disease 2019 and hiv development of the hiv online provider education programme the hiv online provider education programme looking ahead acknowledgements references about the author(s) efeose a. airewele infectious disease division, department of medicine, massachusetts general hospital, boston, massachusetts, united states of america harvard university center for aids research, boston, massachusetts, united states of america henry sunpath department of infectious diseases, nelson r. mandela school of medicine, university of kwazulu-natal, durban, south africa mahomed-yunus s. moosa department of infectious diseases, nelson r. mandela school of medicine, university of kwazulu-natal, durban, south africa rajesh t. gandhi infectious disease division, department of medicine, massachusetts general hospital, boston, massachusetts, united states of america harvard university center for aids research, boston, massachusetts, united states of america citation airewele ea, sunpath h, moosa m-ys, gandhi rt. importance of global communication to combat global pandemics: lessons from the hiv online provider education programme. s afr j hiv med. 2021;22(1), a1281. https://doi.org/10.4102/sajhivmed.v22i1.1281 opinion paper importance of global communication to combat global pandemics: lessons from the hiv online provider education programme efeose a. airewele, henry sunpath, mahomed-yunus s. moosa, rajesh t. gandhi received: 22 june 2021; accepted: 21 july 2021; published: 31 aug. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract in many ways, the coronavirus disease 2019 (covid-19) pandemic mirrors the challenges, lessons and opportunities of the hiv pandemic. in this article, we argue that global pandemics such as covid-19 and hiv require a global response. we highlight the hiv online provider education (hope) programme as an example of the importance of global communication when combating a pandemic. from both the covid-19 and hiv pandemics, we have learned that to optimise health worldwide, it is necessary to have effective and efficient means of swiftly sharing experiences, expertise, best practices and guidelines. to prepare for the next public health emergency, clinicians and researchers must put in place and promote effective programmes for global communication. keywords: hiv; aids; covid-19; covid; pandemic; communication; collaboration; global health; public health. twin pandemics: coronavirus disease 2019 and hiv when the novel coronavirus emerged in late 2019, much was unknown about its transmission, treatment and trajectory. in response to the rapidly growing case numbers and global spread, the world health organization declared the coronavirus disease 2019 (covid-19) outbreak a public health emergency of international concern on 30 january 2020.1 at the time, there was widespread uncertainty and fear about the mode of spread of severe acute respiratory syndrome coronavirus 2 (sars-cov-2), leading to hysteria and responses such as washing down groceries and other measures that were ultimately discarded. early on, there were no known treatments for covid-19, and in many places around the world, medications that ultimately proved ineffective – like hydroxychloroquine – were frequently administered out of desperation.2,3 in addition, it soon became clear that covid-19 was disproportionately affecting key populations such as racial and ethnic minorities in the united states (us) and other countries and the poor all around the world. in many ways, these early responses to covid-19 were eerily reminiscent of the world’s first tentative responses to hiv/aids (box 1). box 1: parallels between the hiv and coronavirus disease 2019 pandemics. similar to the covid-19 pandemic, when the first patient with aids was identified in the early 1980s, there was widespread fear of a new, unknown virus. because of uncertainties about how hiv was spread, people were shunned and stigmatised. in addition, people with hiv then – and now – often belonged to the most vulnerable and marginalised communities. the parallels between hiv and covid-19 treatments are also telling. as with covid-19, early treatments for hiv were largely ineffective and often harmful. by 1987, the united states (us) food and drug administration had approved the first antiretroviral medication, zidovudine, but it soon became evident that single-drug therapy had serious limitations. since then, significant progress has been made in developing well-tolerated, highly effective combination antiretroviral treatments (art), resulting in dramatic reductions in both morbidity and mortality. despite the similarities, there are also vast differences between covid-19 and hiv. the former is primarily a respiratory viral infection transmitted by droplets and through the airborne route, with the majority of patients recovering spontaneously. the latter is a sexually transmitted and blood-borne viral disease that causes immunodeficiency and opportunistic conditions and is usually fatal if not treated. the former has had an unprecedented impact on the global economy, in part because of its rapid trajectory necessitating widespread lockdowns. nevertheless, the parallels summarised above, and the global nature of both pandemics, highlight the critical need for global communication in our response. a prime example of global communication to advance health occurred during the roll-out of hiv treatment throughout the world. the largest number of people with hiv reside in sub-saharan africa, specifically south africa. in the early days of art, management of hiv was rapidly evolving, and it was critically important to keep clinicians abreast of the latest in the treatment of this disease. it was in this context that the hiv online provider education (hope) programme was developed and now serves as an important example of how a global communication network can be utilised to advance health in disparate parts of the world. development of the hiv online provider education programme the hope programme was established in 2003, around the time of the launch of the president’s emergency plan for aids relief (pepfar). the hope programme was developed by three collaborators: dr rajesh gandhi, director of hiv clinical services and education at massachusetts general hospital, professor of medicine at harvard medical school and, at the time, director of the harvard university center for aids research clinical core; dr henry sunpath, then chief of medicine at mccord hospital; and dr yunus moosa, chief of infectious diseases at the king edward viii hospital, university of kwazulu-natal. from the beginning, hope and a face-to-face yearly conference called the annual workshop on advanced clinical care – aids, or awacc – were joint projects of the mccord hospital, the university of kwazulu-natal, massachusetts general hospital and the harvard university center for aids research. as a result of drs sunpath and moosa’s collaborative activities with the kwazulu-natal department of public health, there were frequent discussions and dynamic exchanges of ideas between the conference organisers and public health officials. most importantly, unlike some educational activities that have originated in the global north and spread to the global south, hope was in its essence a joint and highly collaborative project – a digital ‘two-way street’ – that fostered global communication around the treatment of people with hiv. the early interactions between researchers and clinicians in south africa and the us exemplify the collaborative nature of the hope programme and affiliated activities. in 2002, before the national art roll-out strategy began in south africa, mccord hospital was one of the largest centres providing dedicated hiv care in south africa, where aids denialism existed for many years. early on, clinicians struggled with developing treatment guidelines to manage adverse events, treatment failure and coinfections within the constraints of a limited art formulary and laboratory support. in 2003 clinicians and researchers from the us, including prof. gerald friedland from yale and prof. bruce walker from harvard medical school, reached out to leaders at mccord hospital, resulting in joint site visits by senior infectious disease specialists. jointly and collaboratively, clinicians and researchers developed clinical algorithms to manage a broad array of diagnostic and therapeutic problems. the infectious diseases unit at the university of kwazulu-natal also participated in the joint working group with colleagues from the us and mccord and participated in case-based discussions as the art programme grew to about 3500 patients. as word of the success of the work at mccord hospital spread in the community, many clinicians from kwazulu-natal and throughout south africa were keen to collaborate with us to develop art programmes. in 2004, pepfar came on board to support the mccord hospital programme, and the numbers of patients on art expanded significantly. in addition, many surrounding clinics sent healthcare workers to our regular continuing medical education meetings. the department of health was also interested in working with us to develop treatment protocols and training programmes. with the leading roles of prof. gandhi and our team in durban, we started the first awacc in 2006. the meeting was widely acclaimed as a most relevant exchange of expertise in hiv care in resource-limited settings in africa. the hiv online provider education programme the hope programme focuses on topics relevant to the care of people with hiv in resource-limited settings. through regular internet-based conferences, the hope programme serves as an opportunity for continuing education and the sharing of best practices in hiv medicine for clinicians worldwide. in addition to a programme focused on physicians, a parallel conference was designed specifically for nurses.4 during the early years of the hope programme, clinicians in the us had more experience treating patients with art. because of this, hope conferences were primarily case based and followed the ‘mentoring the mentor’ model to support south african, zimbabwean, us, haitian, dominican and indian clinicians. it was realised early on that clinicians learned best when clinical problems were constructed around a real-life clinical case, and this led to a case-based as opposed to a didactic approach to teaching. initially, because of the toxicities of the available antiretroviral medications, much of the focus was on managing the complications arising from treatment. in particular, the unavoidable reliance on antiretroviral agents such as stavudine and didanosine led to a rise in complex metabolic complications such as lactic acidosis, pancreatitis, lipodystrophy and peripheral neuropathy.5 through the hope programme, clinicians gained familiarity with the adverse events commonly associated with art and developed confidence in identifying and managing these conditions using locally available resources. physicians in the us offered advice based on years of clinical experience with similar toxicities and often influenced discussions and policies in south africa. the hope conferences and in-person conferences like awacc also served as opportunities for clinicians to advocate for access to better-tolerated and less toxic medications, like tenofovir. eliminating stavudine and didanosine from the art formulary in south africa took approximately 6 years, during which time physicians worked collaboratively to develop guidelines to manage toxicities. in addition to toxicities, antiretroviral drug resistance emerged as a significant threat to the impact of these medications in reducing morbidity and mortality. a 2008 study from two clinics in durban, south africa, demonstrated that > 83% of patients with virological failure had a least one major resistance mutation, and, of particular concern, mutations resulting in resistance to at least two classes of drugs were present in more than half of those tested.6 the hope conference served as a critical forum for clinicians to discuss and develop management strategies for patients with drug-resistant hiv. again, these discussions influenced policies related to the management of virological failure. attending the hope conferences in real time served as an opportunity for the immediate exchange of knowledge while simultaneously facilitating networking with physicians around the world. through the hope programme, physicians in the us and south africa have been able to connect and engage in collaborative research. the potential to serve as a networking platform was an unexpected beneficial outcome of the real-time nature of the hope conferences. for those unable to join the conferences live, recordings, references and slide presentations have been made available at no cost on the hope website after each conference. what has been the utilisation of and response to hope? when hope first started, 2000–3000 users logged in annually. in recent years, this number has increased at least threefold to around 9000 attendees per year. since tracking began in 2012, almost 20 000 users have viewed the conferences, with almost 95 000 conference page views. about 60% of those accessing conferences are medical doctors, 20% are nurses, 10% are nurse practitioners and 10% are medical students. in terms of geographic distribution, visitors are most frequently from the us, south africa, dominican republic, canada and argentina. surveys of hope conference attendees reveal that 95% of the participants report the content is relevant to their practice and that a similar proportion report that there is an appropriate mix of didactic and interactive material. in its early years, attendees asked for additional content relevant to nurses, which led to the development of a parallel hope nurses’ conference. the cost of the programme has mainly been the time and effort of the organisers who arrange the speakers and discussants, as well as the project coordinator for the programme, whose time and effort has been supported by the harvard university center for aids research as a component of its training mission. the hope conference itself is free of charge for all participants. over time, as south african clinicians gained experience in the care of patients with hiv, they themselves evolved into experts in their own right, and the hope programme shifted focus to summarising the latest in hiv research and innovation. these conferences now serve as an important platform to keep providers in the us, south africa and other parts of the globe up to date with the latest advances in the field. of late, the hope programme has pivoted to incorporating content geared towards confronting the latest global pandemic, covid-19. one such recent conference described the impact of the b.1.351 (beta) variant of sars-cov-2, which was instrumental in alerting us clinicians to the challenges ahead. looking ahead through the hope programme, we can see how global communication positively impacts health education internationally. by expanding and developing other programmes like hope, clinicians can position themselves to mount an effective global response to health threats like hiv and covid-19. interactive online clinical discussions are one of many ways in which the global medical community can bridge the gap in medical education to promote better health outcomes for people everywhere. to reach the joint united nations programme on hiv/aids targets for 2030, it is of the utmost importance that collaborative educational initiatives that started at the turn of this century expand and continue. acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions all authors contributed to the conception of the presented work. e.a.a. and r.t.g. wrote the original manuscript with support from m.-y.s.m. and h.s. all authors contributed to the final manuscript and approved of the version to be published. ethical considerations this article followed all ethical standards for research without direct contact with human or animal subjects. funding information r.t.g. received grant funding from the harvard university center for aids research (nih p30 ai060354) and the aids clinical trials group (nih/niaid 2 umai069412-09). data availability data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references world health organization. statement on the second meeting of the international health regulations (2005) emergency committee regarding the outbreak of novel coronavirus (2019-ncov) [homepage on the internet]. 2020 [cited 2020 jan 30]; [updated 2020 jan 30]. available from: https://www.who.int/news/item/30-01-2020-statement-on-the-second-meeting-of-the-international-health-regulations-(2005)-emergency-committee-regarding-the-outbreak-of-novel-coronavirus-(2019-ncov) siedner mj, gandhi rt, kim ay. desperate times call for temperate measures: practicing infectious diseases during a novel pandemic. j infect dis. 2020;222(7):1084–1085. https://doi.org/10.1093/infdis/jiaa209 airewele e, gandhi rt. trials and therapeutics: important lessons from the covid-19 pandemic. harvard health pol rev [serial online]. 2021 [cited 2021 apr 30]. available from: http://www.hhpronline.org/articles/2021/4/30/trials-and-therapeutics-important-lessons-from-the-covid-19-pandemic kiviat ad, geary mc, sunpath h, et al. hiv online provider education (hope): the internet as a tool for training in hiv medicine. j infect dis. 2007;196(suppl 3):s512–s515. https://doi.org/10.1086/521117 murphy ra, sunpath h, kuritzkes dr, venter f, gandhi rt. antiretroviral therapy-associated toxicities in the resource-poor world: the challenge of a limited formulary. j infect dis. 2007;196(suppl 3):s449–s456. https://doi.org/10.1086/521112 marconi vc, sunpath h, lu z, et al. prevalence of hiv-1 drug resistance after failure of a first highly active antiretroviral therapy regimen in kwazulu-natal, south africa. clin infect dis. 2008;46(10):1589–1597. https://doi.org/10.1086/587109 make up june issue nicky the southern african journal of hiv medicine june 2005 1 1 n a t u r a l h i s t o r y the spectrum and prognosis of aidsdefining illnesses in cape town m badri, msc med gary maartens, fcp linda-gail bekker phd robin wood, fcp desmond tutu hiv centre, institute of infectious diseases and molecular medicine, and department of clinical pharmacology, faculty of health sciences, university of cape town objectives. to describe the incidence, spectrum and prognosis of aids-defining illnesses (adi) in patients without access to antiretroviral therapy (art). design. prospective cohort study. subjects. 1 215 hiv-infected patients attending adult hiv clinics affiliated to the university of cape town in the new somerset and groote schuur hospitals from 1992 to 2000. main outcome measures. incidence rate (ir) of adis and survival after the development of adi. results. during follow-up, 430 adis occurred (ir = 21.3 cases per 100 patient-years (pys)). ir varied according to cd4 count, with 38.8, 17.0 and 8.52 cases/100 pys in patients with cd4 counts < 200 cells/µl, 200 350 cells/µl and > 350 cells/µl, respectively. tuberculosis (tb) was the commonest adi, followed by candidiasis of the oesophagus/trachea/bronchi. irs for chronic herpes simplex ulcers, hiv wasting, pneumocystis carinii pneumonia and kaposi's sarcoma were > 1.00 cases/100 pys. tb was diagnosed in all cd4 strata, and was the only illness to occur commonly above 200 cells/µl. the median cd4 counts within 6 months of diagnosis of adi ranged from 138 cells/µl for tb to 17 cells/µl for cryptococcosis. overall, median time to death from date of diagnosis was 18 months, and ranged from 24.1 months for patients diagnosed with tb to 6 months for those diagnosed with cytomegalovirus. conclusions. hiv-infected patients with no access to art in cape town are at high risk of aids-defining illnesses. this study provides useful data for designing therapeutic interventions for preventing these infections. hiv infection is characterised by progressive immune suppression, which eventually results in the development of opportunistic diseases.1-3 the spectrum of these infections varies across the world, and is partially determined by the organisms that are prevalent in the community. the spectrum of severe hiv-related diseases in sub-saharan africa is characterised by an abundance of virulent pathogens such as mycobacterium tuberculosis, streptococcus pneumoniae and salmonella spp.4,5 pneumocystis carinii pneumonia (pcp) is uncommon, and avirulent organisms such as cytomegalovirus (cmv) and m. avium complex are seldom found.4,5 tuberculosis (tb), bacterial infections and malaria are the leading causes of hiv-related morbidity across sub-saharan africa. in studies reporting cd4 count, the range of cell counts at the time of diagnosis of severe hiv-related diseases is wide.4,5 while the spectrum of severe hiv-related diseases in industrialised countries is well described, few published studies exist describing the incidence and prognosis of hiv-related diseases in africa, and the level of immune suppression at which these diseases occur. most existing studies are of crosssectional design, and is difficult to compare them owing to differences in referral patterns, study population, criteria for hiv testing, diagnostic methods, and the disease reported.6 sound incidence data on severe hiv-related events are important for designing preventive or curative therapeutic intervention. the objectives of this analysis were to estimate the incidence of aids-defining illness (stratified by cd4 count and who clinical stage) and survival after the development of aids-defining illness, and to describe the distribution of the cd4 count within 6 months of the onset of aids-defining illnesses in hivinfected patients with no access to antiretroviral therapy (art). the analysis was based on the cape town aids cohort (ctac), which comprises patients from the wide socio-demographic methods make up june issue nicky 5/30/05 1:18 pm page 11 june 2005 the southern african journal of hiv medicine12 spectrum of the western cape. ctac is based on patients attending public sector hiv health care services at new somerset hospital (nsh) and groote schuur hospital (gsh), which are affiliated to the university of cape town. for the purpose of this analysis, patients presenting with an aidsdefining illness at their initial clinic visit or receiving any form of art were excluded. data on the ctac patients were collected prospectively from 1992. routine demographic, clinical and laboratory data were collected using a standard computerised format. patients presented to the clinic approximately 3 6-monthly or more frequently if clinically indicated. at each visit, patients were examined for manifestations of hiv/aids-related illness and staged using the world health organization (who) criteria.7 hiv diagnosis was confirmed by enzyme-linked immunosorbent assay (elisa) and confirmed with western blot (or subsequently a second elisa) on two different blood specimens. the cd4 count was measured approximately bi-annually, using flow cytometry (beckman coulter®, miami, fla, usa). vital status data were acquired from the inpatient records, via notification by family or the patient's general practitioner, or by reviewing local death registries. the analysis was carried using epi info (version 6.0; cdc, atlanta, ga, usa) and statistica (release 6.6, tulsa, oklahoma, usa). aids-free survival and risk of death from onset of aids the kaplan-meier method was used to plot aids-free survival curves by who stage and cd4 count from the initial clinic visit date to the date of onset of an aids-defining illness. the same method was used to measure risk of death from the onset of aids. the analysis was further stratified by specific illness. cd4 count was measured ± 6 months from the initial clinic visit, if not available at the date of the initial clinic visit. cd4 count was categorised as < 200, 200 350 and > 350 cells/µl. incidence of aids-defining illnesses the incidence rate (ir) for each diagnosis was calculated by dividing the number of new diagnoses of the aids-defining illness that occurred after entry into the cohort by the total number of the person-years (pys) of the cohort. the analysis was further stratified by baseline cd4 count. the time spent in each cd4 count stratum was summed, yielding pys by cd4 count stratum, and the incidence rate of each aids-defining illness was calculated as the number of new cases occurring while in a given cd4 count stratum, divided by the total number of pys of observation in that cd4 count stratum. for each aidsdefining illness the distribution of cd4 counts (within ± 6 months of the diagnosis of the condition) was examined. allcause mortality was estimated for each aids-defining illness using the kaplan-meier method. follow-up was continued until death, date last seen in the clinic or end-point of the study (31 december 2000). in this analysis, all sites of tb diagnosis (pulmonary, extrapulmonary or disseminated) were included in one group. study sample the study included 1 215 patients who did not use art during follow-up and had no aids-defining illness before the initial clinic visit. the baseline characteristics of these patients are described in table i. the cohort consists mostly of young indigent patients with a wide clinical and immune suppression spectrum. approximately 50% of these patients received prophylactic cotrimoxazole at some point of their follow-up. aids-free survival median time to occurrence of an aids-defining illness varied according to baseline cd4 count (ranging from 63 months for patients with cd4 count > 350 cells/µl to 18 months in those with cd4 count < 200 cells/µl) and who stage (ranging from 56 months for patients with who stage i to 18 months in those with who stage iii) (fig. 1). incidence of aids-defining illnesses during a median 1.66 years of follow-up, 430 aids-defining illnesses occurred (ir = 21.3 cases per 100 pys, 95% confidence interval (ci) 19.6 23.2) (table ii). of these illnesses, 255 occurred in patients with cd4 count < 200 cells/µl (ir = 38.8 cases per 100 pys, 95% ci 35.0 42.6), 108 illnesses in patients with cd4 count 200 350 cells/µl (ir = 17.0 cases per 100 pys, 95% ci 14.2 20.2), and 59 in patients with cd4 count > 350 cells/µl (ir = 8.52 cases per 100 pys, 95% ci 6.6 10.9). eight illnesses occurred in 30.1 pys of follow-up in patients with unknown cd4 count (ir = 26.7, 95% ci 12.3 45.9 cases per 100 pys). incidence ranged from 10.6 cases per 100 pys for tb to 0.05 cases per 100 pys for endemic mycosis. age (mean ± sd) (yrs) 31.3 (± 8.89) cd4 count < 200 cells/µl 415 (34.2%) 200 350 cells/µl 319 (26.3%) > 350 cells/µl 446 (36.7%) not done 35 (2.8%) median (interquartile range) 276.5 (143.5 437.0) who stage stage i 547 (45%) stage ii 210 (17.3%) stage iii 458 (37.7%) use of cotrimoxazole 644 (53.0%) gender female 634 (52.2%) male 581 (47.8%) socioeconomic status low 872 (71.8%) high 343 (28.2%) sd = standard deviation. table i. baseline characteristics of the cohort results make up june issue nicky 5/30/05 1:18 pm page 12 june 2005 the southern african journal of hiv medicine14 cd4 count at diagnosis of aids-defining illnesses at (or ± 6 months of) the date of diagnosis, median cd4 counts ranged from 138 cells/µl for tb cases to 17 cells/µl for cryptococcosis (fig. 2). survival following diagnosis of aids-defining illnesses overall, median time to death from date of diagnosis was 18 months. median survival ranged from 24.1 months for patients diagnosed with tb to 6 months for those diagnosed with cmv (table iii). this study reported high rates of aidsdefining illnesses among hiv-infected patients living in cape town with no access to highly active antiretroviral therapy (haart). the ir of these illnesses was high at low cd4 cell strata, particularly in the < 200 cells/µl stratum. tb was the commonest illness, followed by candidiasis of the oesophagus/ trachea/bronchi or lungs. herpes simplex virus (hsv) infection, wasting, pneumocystis carinii pneunomia (pcp) and kaposi's sarcoma had an ir > 1.00 cases per 100 pys. disseminated mycosis, progressive multifocal leukoencephalopathy and lymphoma were rare. tb was diagnosed in all cd4 strata, and was the only illness to occur commonly above 200 cells/µl. this study is one of only a few that have assessed the incidence of the aids-defining illnesses in africa, stratified both by cd4 count and who clinical stage. however, the preponderance of tb and the level of immune suppression at which it occurs, and the overall spectrum of illnesses, is consistent with other reports from the region.5,8-10 of note is the fact that most of the illnesses diagnosed in this cohort are preventable or are amenable to treatment. the incidence estimates and time to aids according to baseline cd4 count and who stage, and survival following the onset of each aidsmedian aids-free survival (months) cd4 > 350 cd4 200 350 cd4 < 200 stage 1 stage 2 stage 3 63 41 18 56 39 18 overall < 200 cells/µl 200 350 cells/µl > 350 cells/µl illness (2014.8 pys) (657.5 pys) (635.1 pys) (692.1 pys) n/a no. incidence no. incidence no. incidence no. incidence 1 tuberculosis 214 10.6 111 16.88 62 9.76 39 5.64 2 2 candidiasis of o/t/b/l 57 2.83 40 6.08 13 2.05 2 0.29 2 3 hsv 27 1.34 19 2.89 7 1.10 1 0.14 0 4 wasting 27 1.34 15 2.28 6 0.94 6 0.87 0 5 pcp 24 1.19 15 2.28 6 0.94 3 0.43 0 6 kaposi's sarcoma 23 1.14 17 2.59 2 0.31 3 0.43 1 7 cryptococcosis 13 0.65 9 1.37 2 0.31 1 0.14 1 8 encephalopathy 11 0.55 5 0.76 4 0.63 1 0.14 1 9 cryptosporidiosis 10 0.50 8 1.22 0 0 1 0.14 1 10 disseminated atypical mycobacteria 8 0.40 5 0.76 3 0.47 0 0 0 11 cmv 6 0.30 4 0.61 1 0.16 1 0.14 0 12 lymphoma 4 0.20 4 0.61 0 0 0 0 0 13 toxoplasmosis 3 0.15 3 0.46 0 0 0 0 0 14 pml 2 0.10 0 0 2 0.31 0 0 0 15 mycosis 1 0.05 1 0.15 0 0 0 0 0 total 430 21.34 256 38.94 108 17.01 58 8.38 8 incidence = per 100 py; candidiasis of o/t/b/l = candidiasis of the oesophagus, trachea, bronchi or lungs; pml = progressive multifocal leukoencephalopathy. table ii. incidence of aids-defining illnesses in 1 215 hiv-infected patients with no access to haart (1992 2000) by cd4 count strata fig. 1. kaplan-meier probabilities of aids-free survival according to baseline cd4 count category and who stage. discussion make up june issue nicky 5/30/05 1:19 pm page 14 june 2005 the southern african journal of hiv medicine16 defining illness calculated in this study, are useful data for designing and assessing the outcome of therapeutic interventions for preventing and treating these infections. survival after aids in africa may be shorter than in industrialised countries. this may be due to high prevalence of virulent pathogens in the environment and lack of access to health care. in a recent review, holmes et al.5 observed that in sub-saharan africa, tb and bacterial infections are the major cause of morbidity and mortality among hospitalised patients. bacteraemia, particularly caused by non-typhoid salmonellae and s. pneumoniae, and associated with cryptosporidia and isospora belli, are the most frequently isolated pathogens. nontyphoid salmonellae and shigella species are also commonly isolated when stool cultures are performed. cerebral toxoplasmosis, and meningitis due to cryptococcus neoformans, tuberculosis and bacterial pathogens, are the most frequent neurological infections. infections with atypical mycobacteria, pneumocystis carinii and cmv are rare.5 they also found that, compared with industrialised countries, death occurs at a higher range of cd4 counts, although still in the range consistent with advanced disease. the findings of this study have important implications for health care management of hiv-infected patients. very few infections preventable by cotrimoxazole occurred at cd4 counts > 200 cells/µl. this suggests a limited beneficial effect for prophylactic cotrimoxazole in patients with cd4 counts at this level. the high incidence of tb across the different cd4 count strata indicates that preventive therapy with isoniazid should be considered early in the course of hiv disease. this study had the following limitations. cause of death was not ascertained, and therefore all-cause mortality was reported. as such, we are unable to exclude non-hiv-related causes of death. median follow-up of 19.9 months is relatively short and reflects the difficulty of maintaining long follow-up in this setting. it is therefore possible that the actual incidence rate of the various infections reported among this cohort might have been underestimated. in conclusion, in hiv-infected patients without access to haart in cape town, the overall risk of aids-defining illnesses is high and increases with lower cd4 counts and more advanced who clinical stage. early prevention and treatment of these infections will result in large health benefits. guidelines for therapeutic interventions for prevention of aids-defining illness, including art, in this region should be tailored according to the spectrum and epidemiology of these infections. references 1. masur h, michelis ma, greene jb, et al. an outbreak of communityacquired pneumocystis carinii pneumonia, initial manifestations of cellular immune dysfunction. n engl med 1981; 305: 1431-1438. 2. gottlieb ms, schroff r, schanker hm et al. pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men. n engl j med 1984; 305: 1425-1431. 3. siegal fp, lopez c, hammer gs, et al. severe acquired immunodeficiency in male homosexuals manifested by chronic perianal ulcerative herpes simplex lesions. n engl j med 1984; 305: 1439-1444. 4. maartens g. opportunistic infections associated with hiv infection in africa. oral dis 2002; 8: 76-79. 5. holmes cb, losina e, walensky rp, yazdanpanah y, freedberg ka. review of human immunodeficiency virus type 1-related opportunistic infections in sub-saharan africa. clin infect dis 2003; 36: 652-662. 6. grant ad, kaplan je, de cock km. preventing opportunistic infections among human immunodeficiency virus-infected adults in african countries. am j trop med hyg 2001; 65: 810-821. 7. world health organization. acquired immunodeficiency syndrome (aids): interim proposal for a who staging system for hiv infection and disease. wkly epidemiol rec 1990, 65: 221-224. 8. mukadi y, perriens jh, st. louis me, et al. spectrum of immunodeficiency in hiv-1-infected patients with pulmonary tuberculosis in zaire. lancet 1993; 342: 143-146. 9. grant a, sidibe k, domoua k, et al. spectrum of disease among hivinfected adults hospitalised in a respiratory medicine unit in abidjan, cote d'ivoire. int j tuberc lung dis 1998;11: 926-934. 10. corbett el, churchyard gj, charalambos s, et al. morbidity and mortality in south african gold miners: impact of untreated disease due to human immunodeficiency virus. clin infect dis 2002; 34: 1251-1258. condition all tb was ks hsv pcp cryps cand enc lymph crypo atyp cmv median 18.1 24.1 22.2 17.8 17 14 13.9 9.5 8.6 7.6 6.5 6.4 6.1 survival table iii. kaplan-meier probabilities of survival following diagnosis. this study was funded by an academic research grant from secure the future, bristol-myers and squibb, and partially funded by cipra-sa (national institutes of health, usa). the authors acknowledge invaluable assistance in data acquisition from desmond tutu hiv research centre staff, dr r kirsten (medical superintendent), m goliath, r solomons and j preez of somerset hospital, and m hassan and j daniels of the cape town metropolitan council. tb = all forms of tb; enc = hiv encephalopathy; pcp = pneumocystis carinii pneumonia; toxo = toxoplasmosis; hsv = herpes simplex virus; ks = kaposi's sarcoma; was = hiv wasting syndrome; crys = cryptosporidiosis with diarrhoea > 1 month; cand = candidiasis of the oesophagus, trachea, bronchi or lungs; atyp = disseminated atypical mycobacteriosis; cmv = cytomegalovirus; lym = lymphoma; cryb = extrapulmonary cryptococcosis. fig. 2. cd4 count distribution at (or ± 6 months of) the date of diagnosis. make up june issue nicky 5/30/05 1:20 pm page 16 acknowledgements references footnotes about the author(s) rahma mohamed endemic medicine department, kasr alainy school of medicine, cairo university hospitals, cairo, egypt heba wanis third world network, cairo, egypt sonia zebachi clinical epidemiology and aging team (cepia), mondor institute for biomedical research (inserm u955), créteil, france public health services, henri-mondor hospital, assistance publique-hôpitaux de paris, paris-est créteil university, créteil, france menna-t-allah el-kotamy egyptian patent office, academy of scientific research and technology, cairo, egypt gamal esmat endemic medicine department, kasr alainy school of medicine, cairo university hospitals, cairo, egypt ahmed cordie endemic medicine department, kasr alainy school of medicine, cairo university hospitals, cairo, egypt citation mohamed r, wanis h, zebachi s, el-kotamy m, esmat g, cordie a. covid-19 crisis effect on hiv service delivery in egypt: hard times or blessings in disguise? s afr j hiv med. 2020;21(1), a1170. https://doi.org/10.4102/sajhivmed.v21i1.1170 editorial covid-19 crisis effect on hiv service delivery in egypt: hard times or blessings in disguise? rahma mohamed, heba wanis, sonia zebachi, menna-t-allah el-kotamy, gamal esmat, ahmed cordie copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. coronavirus disease 2019 (covid-19) continues to disrupt the health system globally. nevertheless, such adversity has urged us to rethink the way healthcare is delivered, based on a recommendation and a lesson learnt which we wish to highlight in the following paragraphs. in our previous editorial published on 30 july 2020, we recommended the use of locally manufactured tenofovir disoproxil fumarate (tdf)/lamivudine (3tc) for the treatment of people living with hiv (plhiv) in egypt, as an alternative to the imported originator’s tdf/emtricitabine (tdf/ftc) 2-in-1 combination, the importation of which was hindered by covid-19 restrictions, making it inaccessible.1 available data about the interchangeability between tdf/3tc and tdf/ftc are not limited to their use for treatment only, but include their use for prevention as well. evidence shows similar distribution of 3tc and ftc in cervicovaginal fluid and in semen, with a lack of data on 3tc rectal concentration in humans. in the meantime, the human mucosal pharmacokinetic profile suggests pharmacological equivalence of ftc and 3tc for pre-exposure prophylaxis (prep).2 in 2015, the world health organization (who) recommended that any person at substantial risk of human immunodeficiency virus (hiv) should be offered oral prep containing tdf as part of a combination hiv prevention programme.3 in 2017, the who essential medicines list was updated to include prep drugs, specifically tdf, tdf/ftc and tdf/3tc.4 in most countries that have adopted prep, tdf/ftc is the most commonly recommended prep therapy. six countries recommend tdf/3tc for prep in addition to tdf/ftc, namely, kenya, namibia, pakistan, south sudan, zambia and zimbabwe, whilst lesotho’s guidelines recommend exclusively tdf/3tc.5 pre-exposure prophylaxis is a ‘game changer’ for hiv prevention. when taken consistently and correctly, it is very effective and reduces the chances of hiv infection to near-zero.6 despite this, the cost of prep remains an important limiting factor to its wide use, particularly in lowand middle-income countries. egypt has the fastest growing hiv rate in the middle east and north africa region, where the epidemic is concentrated in key populations. case load has increased annually by 25% – 35% for the past 10 years, and yet egypt has not adopted the who’s oral prep recommendations at this time.7 both tdf and 3tc are locally manufactured in egypt and are available at affordable prices because of the absence of patent protection on either of them. the growing evidence on tdf/3tc as an effective prep option, availability of locally produced generic tdf/3tc and the urgent need to control the trajectory of the hiv epidemic should all motivate the egyptian national aids programme (nap) to start providing prep services and to recommend its use for prevention within the national guidelines. such a step will encourage more generic pharmaceutical companies to join the growing market, increasing competition and thus further lowering costs. during the covid-19 pandemic, as a mitigation measure to patients’ movement restriction, the nap implemented multi-month dispensing (mmd) of antiretroviral therapy (art) covering 2–3 months, which has had a positive impact on the adherence of plhiv. in a pilot study conducted on 40 egyptian patients attending one of the clinics affiliated to kasr al-aini hiv and viral hepatitis fighting group1, the six-item morisky medication adherence scale8 was administered twice using a standard telephone script, first in mid-march and then in mid-august. the number of plhiv with high motivation and high knowledge was significantly higher in mid-august (36 vs. 27 and 36 vs. 28, respectively, p < 0.001). multi-month dispensing because of covid-19 pandemic was the most commonly reported factor (90%) amongst those with high motivation. it would be fair to conclude that it is necessary to move towards mmd for medically stable patients on art, whilst managing the stock and supply line, in order to save healthcare service costs and improve patients’ adherence and retention in care. multi-month dispensing can be provided through community-based models of care that require the engagement of community health workers, common in rural parts of egypt, who provide peer support to patients and help improve their adherence, retention and viral suppression. besides, the covid-19 pandemic has accelerated the implementation of telemedicine in many countries, but not so much in egypt.9 the use of telemedicine services for hiv prevention and management represents an innovative and a possibly more effective way of providing hiv services and for implementation of mmd in egypt. whilst covid-19 has placed pressures on our healthcare system, it has been a blessing in disguise. the above lessons learnt can certainly guide us into reshaping our healthcare system by endorsing more resource-savvy and patient-oriented strategies. acknowledgements competing interests g.e. is a speaker, advisory board member and investigator for gilead science, gsk and abbvie. all other authors declared no competing interests with respect to this study. authors’ contributions the concept for this editorial was developed by a.c. and g.e. m.e. developed the first draft. s.z. performed the statistical analysis. h.w. and r.m. prepared the final version. all authors revised and approved the final version of the article. ethical consideration this article followed all ethical standards for research without direct contact with human or animal subjects. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability statement data analysed in this study are available if needed for revision without disclosing the confidential details of our patients. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references cordie a, el-kotamy m, esmat g. antiretroviral therapy optimisation in the time of covid-19: is it really different in north and south africa? s afr j hiv med. 2020;21(1):a1118. https://doi.org/10.4102/sajhivmed.v21i1.1118 world health organisation. appropriate medicines: options for pre-exposure prophylaxis [homepage on the internet]. geneva: world health organisation; 2018 [cited 2020 aug 20]. licence: cc by-nc-sa 3.0 igo. available from: https://www.who.int/hiv/pub/journal_articles/3tc-ftc-interchangeable/en/ world health organization (who). policy brief: who expands recommendation on oral pre-exposure prophylaxis of hiv infection (prep) [homepage on the internet]. geneva, switzerland: world health organisation; 2015 [cited 2020 sept 5]. available from: https://apps.who.int/iris/bitstream/handle/10665/197906/who_hiv_2015.48_eng.pdf world health organization. who model list of essential medicines: 20th list (march 2017) [homepage on the internet]. geneva: world health organization; 2017 [cited 2020 jul 13]. available from: http://apps.who.int/iris/bitstream/handle/10665/273826/eml-20-eng.pdf?ua=1 hodges-mameletzis i, dalal s, msimanga-radebe b, rodolph m, baggaley r. going global: the adoption of the world health organization’s enabling recommendation on oral pre-exposure prophylaxis for hiv. sex health. 2018;15(6):489–500. https://doi.org/10.1071/sh18125 fonner va, dalglish sl, kennedy ce, et al. effectiveness and safety of oral hiv preexposure prophylaxis for all populations. aids (london, england). 2016;30(12):1973. https://doi.org/10.1097/qad.0000000000001145 unaids. miles to go – closing gaps, breaking barriers, righting injustices: global aids update 2018 [homepage on the internet]. geneva: joint united nations programme on hiv/aids; 2018 [cited 2020 sept 05]. p. 233. available from: https://www.unaids.org/en/resources/documents/2018/global-aids-update vural b, acar ot, topsever p, filiz tm. reliability and validity of turkish version of modified morisky scale. j turk fam phys. 1999;3(4):17–20. khorshid m, bakheet n, abdallah s, essam m, cordie a. covid-19: a strong call for remote medicine in ibd. j dig dis. 2020;21(10):597–599. https://doi.org/10.1111/1751-2980.12935 footnotes 1. kasr al-aini hiv and viral hepatitis fighting group is a group of clinical leads in the field of infectious diseases at cairo university hospitals, working in collaboration with different egyptian universities to provide high-quality care to people living with hiv and viral hepatitis, with a special focus on continuous medical education and research. new horizons i m sanne, fep (sa), dtm&h wo francois, fep (sa), dtm&h w f ven'"" fep (sa), dtm&h cl;'lical hiv research ullit, ullirm-sity of the witu7tlfmrand, /ohnmresbllrg new horizons in the treatment of hiv infection the southfrn african journal of hiv mtolcinf the susceptibility of the two commonly available nnrtls to single resistance mutations remains a major challenge. the drugs are commonly used as firs -line therapy because they are potent, easy to take and, despite significant shortterm toxicities, have good long-term tolerance. currently, the acquisition of the common mutations occurs rapidly if the drug is incorrectly taken. the mutations confer highlevel resistance, and generally mean that the entire class of drugs is not available for future use. furthermore, the mutation does not result in less 'fit' virus, which can occur with nucleoside analogue mutations. usually requires refrigeration, the formulation can be kept for up to 2 months at room temperature (22 0 cl. abbott has already announced that the drug will be available at access pricing to members of the hiv clinicians society. atazanavir, a once-daily pi which has been tested extensively at several sites in south africa over the last 3 years, also appears to have a good safety profile, with limited triglyceride and cholesterol changes. a major benefit in africa is that it is heat-stable at high temperatures, a property not shared by other pis. in vitro evidence of antiviral efficacy of atazanavir to viral isolates resistant to two more pis supports the current research programme in salvage therapy. the drug is not yet available internationally, but is due for evaluation by the food and drug administration (foal soon. tipranavir is another pi in development, and is currently being evaluated in salvage regimens. development has been hampered by an initial massive pill burden, similar side-effects to other pis, and the fact that the drug has been handed from one pharmaceutical company to the next. it is the first nonpeptide pi, which accounts for its unique resistance profile, but licensing is unlikely to occur in the next 2 years. a precursor to amprenavir is currently in phase 3 studies, with the hope of decreasing the pill burden and tablet size. non-nucleoside reverse transcriptase inhibitors [nnrtis) new drug development in nnrns includes emivirine, which has now completed phase 3 tes ing, including in south protease inhibitors (pis) new compounds and formulations of existing drug classes the prospect of patients being on lifelong and lifesaving medication has been a considerable inducement for pharmaceutical companies to develop safer and better tolerated drugs. a huge amount of research into new drugs, new uses for older drugs, and completely new strategies to assist in mobilising the body's immune defences, is being undertaken. clinicians working with hiv-infected patients have witnessed near-miraculous clinical benefits with antiretroviral therapy. in the space of a few years, an almost universally fatal disease has been transformed into a chronic, manageable outpatient condition. however, the downsides of the drugs were almost immediately apparent. tolerability, clinical and metabolic side-effects, lack of convenient dosing schedules, viral genetic resistance and cost make the disease very challenging to treat. the recognition of drug toxicities, particularly of the protease inhibitors, has led to a more tempered approach to the previous practice popular in affluent countries of simply putting patients on treatment early on in their disease. the rapid rise of viral resistance in poorly adherent patients has led to the quest for drugs easier to take, and with higher or new resistance barriers. most of the recent developments have been with existing classes of drugs, and with entry inhibitors. the search for pis that are easy to take and have fewer side-effects continues. about to enter the south african market is the lopinavir/ritonavir combination, marketed as kaletra, which has been tested in clinical trials locally. this drug is administered twice daily, is better tolerated than many of its predecessors, and has a high resistance barrier. it is very useful in salvage regimens, and daily dosing is being investigated. despite comaining ritonavir, which july 2002 thf southfrn african journal of hi mfoicinf -----------africa. possible benefits of emivirine include reduced hepatotoxicity, and absence of skin rash, but commercial viablility of the drug is limited because efficacy appears to be similar to currently registered medication. investigators in south africa felt that emivirine did provide good clinical response and treatment efficacy, but its future will depends on the commercial viability. second-line nnrtls, which have resistance profiles different to the two currently available options, are being assessed. ope 083 is biochemically very similar to efavirenz, but is more potent with fewer neuropsychiatric side-effects. very early trials have been encouraging, but the drug has a long development road ahead. another experimental nnrti, tmc 125, may also benefit patients with nnrti resistance mutations, and has shown remarkable efficacy in drug-naive patients. again early data are very encouraging, but larger trials are awaited. a third nnrtl, capravirine, was already in phase 3 development in 2001, when its continued testing on humans was interrupted after animal studies showed vasculitis at dosing levels in excess of the human dose. there are indications from the current patent holder pfizer that the drug will continue in development, with phase 3 clinical trials planned for 2002. in vitro activity of capravirine includes nnrtl-resistant viruses. nucleoside analogues these drugs continue to form the 'backbone' of the vast majority of antiretroviral combinations. odl (videx) is an inexpensive and potent nucleoside analogue, commonly used in southern africa. monotherapy studies indicate that ddl can reduce viral loads by up to -2.0 log. a new enteric-coated formulation called videx ec is being investigated, with improved palatability, improved gastrointestinal tolerability, and potentially less peripheral neuropathy. the original ddl, as well as the new formulation, can be used in once-daily dosing. the new enteric-coated formulation still is recommended for dosing on an empty stomach. overall the benefits of videx ec and once-daily dosing will lead to increased use of this nucleoside in first-line therapy. 04t is also being assessed in an extended-release form (lerit xr), including trials in south africa. the only real benefit will probably be once-daily dosing, as early data suggest no difference in side-effects. with ongoing concerns about lipoatrophy, mitochondrial toxicity, peripheral neuropathy and lactic acidosis, 04t is being spared internationally in first-line therapy. clinicians in south africa cannot afford to ignore this potent nucleoside analogue in view of the access pricing iniliatives of bristol myers squibb. emtricitabine (he) is a potent, well-tolerated nucleoside analogue derivative of 3tc with similar dosing, efficacy and side-effects. while resistance mutations m184v are associated with resistance to ftc, additional potency of ftc in a triple-therapy regimen is associated with 50% less m184 mutation than a triple-therapy regimen containing 3tc in patients with demonstrated virological failure. it has been extensively used in south african research sites. the fda is currently reviewing its registration. glaxosmithkline is following its hugely successful combivir (the combination of azt and 3tc) with trizivir, abacavir (liagen) added to combivir, in a single tablet, given twice daily. the drug combination is widely used in the usa, and will be released soon in south africa. the benefit of a triple nucleoside combination is that two further classes of drugs are available if the drug fails, and the ease of administration is very attractive. concerns have been raised that abacavir-containing regimens have less efficacy in the face of very high viral loads (> 100 000 copies/mo, a common problem in south africa, where patients often present late and symptomatic. abacavir's peculiar resistance profile means that the drug should probably be used as the first-line choice, as its efficacy in salvage is poor. the potentially fatal hypersensitivity of abacavir is a side-effect of concern, especially as inexperienced doctors may use the combination drug more readily, as it is easy to prescribe, but miss the hypersensitivity reaction. the cost of this triple therapy combination tablet is limiting its widespread use in resource-poor settings. tenofovir was recently approved by the fda. the drug is a much safer derivative of the ill-fated adefovir, which had significant renal toxicity and was denied approval by the fda. in the new product the nephrotoxicity has been resolved, with no significant tubular abnormality noted in clinical studies. experience in south africa is limited, as its major role has been in drug-experienced patients, although trial results in treatment na'ive-patients should be available later this year. the drug is remarkably well tolerated, very potent and easily administered, with resistance to 3tc paradoxically reversing the infrequent tenofovir resistance mutations. mitochondrial toxicity does not seem to be a problem. it is hoped that it will be licensed for use in south africa soon. its place in a future once-daily single combination pill is being explored. once-daily treatlment regimens once-daily treatment regimens, with their potential for improved adherence, have been the aim of treatment research. of the currently available medications only efavirenz is registered for once-daily use. early studies demonstrate that 3tc can be administered once daily. both he pharmacokinetic pro-le and clinical research evidence july 2002 suggest that ftc can be used once daily, but it needs to be passed by the registration committees. atazanavir, videx ec and zerit xr have all been specifically developed for oncedaily treatment, and once-daily dosing of kaletra is currently being studied. novel targets the life cycle of the virus throws up multiple potential drug targets. the most advanced group of drugs is the so-called entry inhibitors, which are about to be assessed in phase 3 trials. entry inhibitors hiv entry into the host cell is mediated initially by the cd4 molecule, and then either the ccrs or cxcr4 protein. the virus then fuses with membrane using the viral gp-41 envelope protein. sch c (schering c, as the drug is being developed by schering-plough) is an oral ccrs antagonist, blocking the second step where the virus binds to the ccr5 receptor. initial trials showed marked antiviral effects, but possible cardiotoxicity. dose-ranging studies seem to have addressed this, but more results should be available later this year. other companies are working on ccr5-blockers, but less is known about the stages of development oral drugs that block cxcr4 are currently being developed, but these are in early development. an intravenous formulation, amd-3100, has had some antiviral success, but development has been halted because of its toxicity and poor pharmacokinetics. the 'fusion inhibitors' stop the final binding of the virus to the cell. several drugs are in development, including t-20, t-1249 and bms 806. t-20 and t-1249 are only available in injectable form. bms 806 is available in orally administered form, and recent data are encouraging. combinations of the entry inhibitors may be synergistic and are under investigation. integrase inhibitors integrase is the enzyme that integrates viral dna into the host cell's dna, and drug development targeted at the enzyme has been taking place for years. however, prior candidate drugs have been limited by toxicity. two new compounds are about to enter clinical development, through phase 1 and 2 trials, but clinical use is at best years away. generics with the recent pharmaceutical industry court case and initiatives from the department o' health, generic july 2002 manufacture of medications and their importation from other countries have been initiated. companies that are not bound by patent protection laws are manufacturing combination tablets, using drugs from different drug companies. these are starting to filter into south africa illegally, as cheap alternatives to available patented products. these products may be granted approval by the south african government in he future. clinicians should be wary when using these products, as quality assurance is variable with smaller companies. only limited bioequivalence data and no results of clinical trials are available from generic manufacturers. cipla, a longestablished indian company which has manufacturing processes approved by the fda, the medicines control council (south africa) and the world health organisation, is producing a combination tablet of d4t, 3tc and nevirapine (triomune), and other companies will probably follow suit. strategies around treatment new horizons do not just relate to the new drugs themselves. treatment strategies for use of the drugs, especially in the resource-constrained environment, continue to develop. structured treatment interruptions the realisation that a patient can stop taking antiretrovirals without routine development of resistance has made it possible to develop a number of new treatment strategies to evaluate the efficacy and limit the toxicity of antiviral therapy. scientists have postulated that stop-starting therapy in patients with chronic hiv may allow the body's immune system to 'see' the virus in a controlled way, allowing cellmediated and humoral immune responses to hiv to be reacquired. if the body's immune system can be 'autovaccinated' often enough, it may ultimately control the virus without antiretroviral therapy. initial results have been disappointing in this regard, and the strategy is still being evaluated in trials. however, this strategy may find a place on the basis of savings on drug costs and significantly lower toxicity alone. there is evidence that structured treatment interruptions (511) during seroconversion may be beneficial. current evidence demonstrates that early treatment of hiv followed by treatment interruption during seroconversion leads to improved immune responses to hiv, and is associated with changes in viral and cd4+ set-point after treatment interruption. south african and other guidelines sugges treating these patients, although the specifics of how and for how long is unclear. un ortunately these patients are difficult to diagnose, so treatment during this the southern african journal or hiv medicine -~f sou'hf!1. africa jour al de ~i ivl£o c t ------------stage is unlikely to be a useful strategy in the vast majority of patients, even if it is found to be effective. therapeutic vaccination this approach is similar to the sti thinking. it is hoped that vaccinating a patient against hiv while they are on hiv treatment may harness more of the immune system in helping to control the virus. the sti experience has tempered enthusiasm for this approach. early evidence has shown some immunological benefit, but clear clinical benefit is still awaited. a variety of candidate therapeutic vaccines have been tried, without clear evidence of benefit. therapeutic drug level monitoring drug level testing is extensively used in clinical medicine, and includes testing for medicines as widely used as digoxin, the aminoglycosides, lithium, antiepileptics, and cyclosporin. however, the reasons for doing these tests vary some are used to monitor adherence, others to confirm efficacy, and others to minimise toxicity. techniques to measure most commercially available pis and nnrtls are now well established [the nnrtl's effective levels are intracellular, and therefore cannot be measured). however, the role of drug testing is still unclear. assessing adherence may be useful, but the steady state of these drugs is such that simply taking the drug once be'ore an appointment may mean that the patient has a therapeutic level when tested. toxicity may be related to excessive dosing for some patients, in particular with ritonavirboosted pis, and may be avoided through therapeutic drug level monitoring. drug levels of some of the pis seem to correlate with the side-effect profile, and reducing the dose decreases side-effects without loss of efficacy. complex drug-drug interactions in patients requiring polypharmacy can be monitored, so that the drug level does not become toxic or subtherapeutic. thi, information remains limited, but a lot of research is being pursued. one of the difficulties is that most drugs are taken twice daily, making trough and peak interpretations more difficult. the tests are easy for laboratories to do, and will probably be clinically available soon. genotype and phenotype resistance testing these tests are also finding their way into routine clinical practice in the assessmen of the 'failing' patient, and as a means of understanding which drugs are less useful, and which can be retained in future regimens. in most cases treatment failure is due to non-adherence with wild-type virus. genotype testing involves isolation of genetic sequences conferring resistance to drugs. different mutations confer varying levels of resistance and crossresistance to di"erent drugs. the rest is expensive, but relatively quick to do. expert assessment of the results in conjunction with current and past drug regimens is essential. initial cynicism about genotype testing results (and occasional frank disregard) still persists. an expert 'guess' based on knowledge of the patient's past regimens was initially shown to be almost as good a predictor of future success as the test itself. however, the enthusiasts pressed on, and trials now show that interpreting genotyping results in conjunction with expert opinion gives better results than expert opinion alone. genotype testing sophistication continues to grow as new resistance mutations are discovered and the clinical significance of other mutations become apparent. expanded access to the tests is limited by the cost and availability of expertise in assessment of results. phenotype resistance testing is not yet generally available, but conceptually is more like a routine mic (inhibitory concentration) for the virus, with growth assessed at different concentrations of the drug. clinical experience remains limited, it is prohibitively expensive, and the test takes much longer than genotype resistance testing. however, it assesses more than just the most prevalent virus, is easier to interpret, and may give more accurate information about resistance. its future role is uncertain. virtual phenotype' testing uses the results of genotype resistance testing and compares them against a database of phenotype resistance testing on existing similar viruses. it can predict the viral behaviour against di' erent drug combinations. as a sophisticated and constantly evolving interpretation of genotype testing, it has an exciting role. current guidelines for resistance testing are limited to treatment-adherent patients demonstrating virological failure. testing treatment-naive patients, or patients who are the source of needlestick or other exposure-related injuries, may be indicated before starting antiretrovirals, but is currently controversial. , identlrcatlon and t1reatlment of side-effects the short and long-term side-effects of the antiretrovirals have attracted much unfavourable a ention. as all the multi-drug regimen choices are similar in terms of efficacy and dosing schedule, cost and side-effect profile are increasingly defining drug choices. upodystrophy, a complex clinical and metabolic syndrome that has an array of presentations, remains an enigma. the syndrome is seen primarily with the pis. the increase in visceral fat, abnormal lipid profiles, hypertension and insulin resistance suggests a cardiovascular time-bomb wailing to go off. interestingly, a massive retrospec ive july 2002 book review jljli 2002 ------------sixty colour photographs and x-rays of common dermatological, oral, respiratory and haematological problems provide a useful reference, and a resource page of national and international hiv-related websites and call-lines ensures access to current developments in hiv therapy, research and sociopolitical issues. tht sou,;jtf aplhn journal of hi mtolci t conclusion the immediate horizons promise new and betterformulated drugs for south africans infected with hiv. the role of monitoring of drug levels and resistance patterns is still being determined, and the identification and treatment of side-effects con inues to evolve. huge amoums of research dollars are being poured into the disease, and research appropriate to our region is required. genetically determined. however, routine hla typing is impractical and expensive, and simpler tests are required to predict this serious complication. the prospect of a daily, relatively safe, single combination tablet appears to be on the horizon. in the absence of a cure, making hiv infection an easily managed chronic disease remains a priority. treatment cost and infrastructure requirements need to be addressed in the resource-poor setting. drugs in primary care clinics, and home-based care and community liaison. highlights include chapters on antiretroviral therapy, oral medicine, nutrition, counselling, the prevention of motherto-child transmission of hiv, infant feeding and palliative care. a chapter dealing with the ethical issues surrounding hiv care explores many of the dilemmas faced by health care professionals on a daily basis. this handbook is endorsed by the southern african hiv clinicians society and is sure to prove an indispensable aid in improving the care of people with hiv in both hospital and community settings in southern africa and the rest of the developing world. ruth cornick infectious disease clinical reosearch unit ucr lung institute cape town study recently showed no increase in cardiovascular mortality in patients treated with antiretrovirals, despite the fact that they lived significantly longer. however, the endothelial dysfunction responsible for strokes and myocardial infarction occurs over many years, and we may yet see an epidemic of treatment-related mortality. treatment of the metabolic parameters is still challenging, as it is not clear whether there is an actual risk. early indications of metabolic complications in black patients in south africa indicate that lipodystrophy is associated with diabetes and hypertension rather than lipid changes in this population. identifying life-threatening complications before they become serious remains a challenge. hyperlactataemia has a high mortality if symptomatic, but can be subtle and nonspecific for the unwary clinician. studies looking at 'safety' parameters to identify patients early are being undertaken. abacavir hypersensitivity appears in part to be handbook of hiv medicine. by douglas wilson, sudeshni naidoo, linda-gail bekker, mark cotton, gary maartens. pp. 600. cape town: oxford university press, 2002. the oxford hondbook of hiv medicine for developing countries is a long-overdue addition to the 'oxford handbook' series. it is aimed at all those concerned with the health care of people with hiv, including medical students, nurses, newly qualified doctors, primary care practitioners and hospital doctors, and serves as a practical guide to the assessment and management of hivrelated problems. compiled with the expertise of more than 50 authors, this concise yet comprehensive handbook covers a broad range of topics including diagnostic and management approaches to the common manifestations of hiv in both adults and children, overviews of the virology, immunology and south african epidemiology of hiv, and the holistic care of the hiv-infected person. throughout the handbook there is a strong emphasis on the primary care managemem of the patient with hiv in a resource-limited sening. this is covereo in more detail in the chapters on primary care approach, commonly useo ff9ruary 200 i-----------the southern african journal of hiv medicine the issue of post-exposure prophylaxis following sexual assault is addressed by charlene smith and the experiences in a rape crisis centre are described by or wulfson. the insights provided by these contributions are invaluable to our clinicians, many of whom have expressed their inadequacy when having to deal with this medical emergency. the sunninghill hospital protocol will go a long way towards helping in this regard. the clinicians society would urge the state to consider providing post-exposure prophylaxis to survivors of sexual assault at no charge. this will help to allay the tremendous emotional devastation and fear of acquiring disease that these individuals live through. des martin editor, southern african journal ofhiv medicine presiden~ southern african hiv clinicians society. zidovudine was approved for use as an antiretroviral agent in 1987. it was used, at that time, as a single agent to treat patients with hiv infection. the therapeutic effect of this monotherapy was, however, of short duration due to the rapid development of viral resistance to the drug. subsequently the use of two drugs (dual therapies) became the standard of care. their antiretroviral effect was more pronounced and of a longer duration, but regrettably viral resistance once again limited the therapeutic effects. following the international aids conference in vancouver in 1996 triple combination therapies (haart) were endorsed and proved to be effective in the majority of patients treated, as evidenced by profound and durable suppression of viral loads and an impressive rise in cd4 counts. from the editor it is only now, 5 years later, that clinicians who treat hiv are encountering some of the long-term side-effects and toxicities associated with these therapies. the proceedings of a workshop examining the metabolic disturbances associated with certain of the therapies is highlighted in this issue of the journal. flowing from this workshop it was evident that there is a clear need to formulate guidelines for monitoring drug-associated metabolic disturbances in our populations. there may be distinct differences in the frequency and patterns of these disturbances. the intriguing question of structured treatment interruptions (sti) is reviewed by sanne and colleagues and may represent one strategy to minimise these toxicities. . acknowledgements about the author(s) michael t. boswell department of internal medicine, school of medicine, faculty of health sciences, university of pretoria, pretoria, south africa department of internal medicine, steve biko academic hospital, pretoria, south africa liam robinson department of oral pathology and oral biology, school of dentistry, faculty of health sciences, university of pretoria, pretoria, south africa nelesh govender centre for hais, amr and mycoses, national institute for communicable diseases, johannesburg, south africa faculty of health sciences, university of the witwatersrand, johannesburg, south africa citation boswell mt, robinson l, govender n. skin and mucosal manifestations of an aids-related systemic mycosis. s afr j hiv med. 2021;22(1), a1198. https://doi.org/10.4102/sajhivmed.v22i1.1198 clinical images skin and mucosal manifestations of an aids-related systemic mycosis michael t. boswell, liam robinson, nelesh govender received: 23 nov. 2020; accepted: 09 dec. 2020; published: 28 jan. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. a human immunodeficiency virus (hiv)-positive male from cameroon who had recently started antiretroviral therapy presented with a new rash, night sweats and loss of weight. on examination, erythematous to flesh-coloured papules were noted on the trunk (a). intraoral examination revealed granular-appearing lesions of the hard and soft palate, with areas of pigmentation in keeping with hiv-associated mucosal hyperpigmentation (b). a full blood count showed a pancytopenia, with a moderate neutropenia. he had a severe lymphopenia, and his cd4+ t-cell count was 46 cells/microlitre (µl). serum (1-3)-β-d-glucan and ferritin levels were markedly elevated at > 500 picograms per millilitre (pg/ml) and 5533 micrograms per litre (µg/l), respectively. periodic acid–schiff with diastase (pas-d) and grocott-gomori histochemical stains of a skin punch biopsy showed numerous small, round intracytoplasmic organisms within histiocytes, consistent with histoplasmosis (c and d) (see figure 1). a pan-fungal polymerase chain reaction (pcr) assay confirmed infection with either histoplasma capsulatum or emergomyces africanus. this pcr assay cross-reacts with blastomyces species; however, the yeast phase of this pathogen has a different histological appearance. figure 1: (a) erythematous to flesh-coloured papules on the trunk; (b) granular-appearing, pigmented lesions involving the hard and soft palate; (c) pas-d and (d) grocott-gomori stained sections highlighting the intracytoplasmic organisms (original magnification × 200). acknowledgements the authors would like to thank theresa rossouw, tarryn jacobs and glynn dale buchanan for their help on earlier versions of this manuscript and input on the management of this case. competing interests the authors have declared that no competing interests exist. authors’ contributions all authors contributed to the case management and drafting of this manuscript. funding information this research did not receive any specific grant from funding agencies in the public, commercial or not-for-profit sectors. data availability statement data sharing is not applicable to this article, as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. hiv 981 perceived adherence barriers among patients failing second-line antiretroviral therapy in khayelitsha, south africa w barnett,1 mph; g patten,2 msc; b kerschberger,2 md, mph; k conradie,2 mb chb, dch (sa), diphivman (sa); d b garone,2 mb chb, md; g van cutsem,2,3 md, dtm&h, mph; c j colvin,3 phd (anthropology), mph 1 school of public health and family medicine, university of cape town, south africa 2 médecins sans fronti ères, khayelitsha, cape town, south africa 3 centre for infectious disease epidemiology and research, school of public health and family medicine, university of cape town, south africa corresponding author: g patten (gpatten@gmail.com) background. the recent scale-up of antiretroviral therapy (art) coverage in resource-limited settings has greatly improved access to treatment. however, increasing numbers of patients are failing firstand second-line art. objective. to examine factors affecting adherence to second-line art from the perspective of clinic staff and patients, assessing both individual and structural perceived barriers. methods. research was conducted at a large primary care tuberculosis (tb)/hiv clinic in khayelitsha, a peri-urban township in cape town, south africa. participants were drawn from a médecins sans frontières-run programme to support patients failing second-line art. a qualitative research approach was used, combining multiple methodologies including key informant interviews with staff (n=11), in-depth interviews with patients (n=10) and a photovoice workshop (n=11). responses and photographs were coded by content; data were transformed into variables and analysed accordingly. results. staff identified drinking, non-disclosure, not using condoms and pill fatigue as barriers to art adherence, while patients identified side-effects, not using condoms and a lack of understanding concerning medication timing. with respect to service delivery, staff identified a need for continued counselling and educational support following art initiation. patients were concerned about missing medical records and poor staff attitudes in the clinic. conclusion. these findings identify discrepancies between provider and patient perceptions of barriers to, and facilitators of adherence, as well as of service delivery solutions. this highlights the need for on-going counselling and education following art initiation, improved quality of counselling, and improved methods to identify and address specific barriers concerning medication adherence. s afr j hiv med 2013;14(4):170-176. doi:10.7196/sajhivmed.981 in 2010, the world health organization esti­mated that 34 million people were living with hiv/aids (plwha) – of whom more than 30 million were living in lowand middle-income countries.1 around 9.7 million were receiving antiretroviral therapy (art) in 2012, more than a 30-fold increase in ten years.2 with an increased number of people receiving art, firstand second-line treatment failure has become more common.1 , 3 treatment failure results in increased morbidity and mor­tality for plwha, with larger numbers requiring more ex­pen­sive secondand third-line treatment, and an increased risk of hiv transmission, including drug-resistant strains. 3 for art to be effective, adherence rates must be between 90%4 , 5 and 95%.6 , 7 studies also indicate that many failures are the result of suboptimal adherence, rather than due to the development of antiretroviral (arv) resistance, suggesting a potential for continued efficacy with improved adherence, especially on protease inhibitor (pi)-based regimens.8-10 patients failing second-line regimens have no further treatment options available in the public sector in sub-saharan africa, as third-line regimens are too costly.11 there is an escalating need to mitigate failure rates and improve the effectiveness of art within existing public health structures.12 we sought to investigate: (i) major barriers to, and facilitators of art adherence in this population; and (ii) areas of art service delivery that shape patient behaviour. we examined the experiences of patients who failed both firstand second-line art, identified through routine viral load (vl) testing. the most commonly cited barriers to adherence included: side-effects; regimen complexity; socio-cultural factors such as complex dosing schedules, alcohol and substance abuse; economic factors; and patient-provider relationships.13-17 no studies specifically addressing barriers to, or facilitators of adherence in patients with multiple episodes of treatment failure and re-adherence were identified. the majority of patients in this study achieved successful re-suppression following second-line art failure. further work is needed to better understand the successful re-suppression of hiv in these patients.8 methods setting this study was conducted at ubuntu clinic, a public sector primary care hiv/tb clinic in khayelitsha, a peri-urban township in cape town, south africa (sa). khayelitsha, with more than 500 000 residents, has one of the highest burdens of hiv infection nationally and worldwide, with an antenatal hiv prevalence of >26% in 2010.18 arvs have been available since 2001 and currently there are more than 20 000 plwha in the area receiving art. 19 ubuntu clinic serves the biggest and oldest cohort of art patients in khayelitsha. by the end of 2011, 6 296 patients were receiving art, of whom 463 (7.4%) were receiving second-line treatment. currently, 20 new patients per month are starting second-line art.18 treatment success is assessed through vl testing. provincial guide­lines recommend that a vl test is performed at four and 12 months after treatment initiation and on a yearly basis thereafter.11 after an initial high vl (defined as >1 000 copies/ml), patients attend adherence counselling and a follow-up vl is taken three months thereafter. two consecutives vls >1 000 copies/ml confirm virological failure, after which patients should be switched to a second-line art regimen. at ubuntu clinic, after five years of receiving art, an estimated 14% of patients experienced virological failure and 12% were switched to a second-line regimen.20 , 21 previous studies have found second-line failure rates in sa to be as high as 33%22 and 40%,25 respectively. the latter study conducted viral genotyping at ubuntu clinic and found that only two of 37 second-line failure patients had developed drug resistance.23 médecins sans frontières (msf) is an international non-governmental organisation that has worked closely with the western cape department of health during the scale-up of art coverage in khayelitsha. in 2010, msf, in collaboration with ubuntu clinic staff, developed and implemented a patient-centred model of care for patients failing second-line art. the programme provides a dedicated space, and individual and group counselling support. at the time of this study (august 2011), 49 patients were enrolled in the second-line failure clinic. this population allowed a first look at a small, but growing group of patients with multiple treatment failures in a setting with one of the highest hiv burdens worldwide. study population patients in msf’s second-line failure programme (patients with at least one vl >1 000 copies/ml) were approached to participate in the study. of the 49 patients meeting these criteria, 12 were included based on availability and willingness to participate. nurses, counsellors and doctors were selected from both the msf programme and ubuntu clinic staff as key informants; they were purposively sampled to include those with the most exposure to patients receiving second-line art. data collection this study used multiple methods including in-depth patient and key informant interviews and a photovoice workshop.24 semi-structured interviews were developed with input from all co-investigators on the project. key informant interviews focused on staff perspectives regarding reasons for treatment failure and barriers in healthcare delivery. patient interviews focused on individual reasons for treatment failure and perceptions of clinic service delivery. patients also engaged in a photovoice workshop, a participatory quali­tative research method where participants are given disposable cameras to take photographs of predetermined themes, and then en­­gage with each other around the meanings and experiences behind the photographs.24 participants took part in two day-long workshops. the first introduced photovoice and, with the participants, developed themes to explore the relationship between treatment and the people, places and ideas in their daily lives. participants were then given two weeks to take photographs and return the cameras to the research team for development. in the second workshop, participants chose three of their photographs to share, and researchers facilitated discussion and the identification of themes. twelve patients consented to be in the study, all took part in the photovoice workshop; however, two could not be found for in-depth interviews following multiple attempts. one had relocated from the area, and another could not be located. data analysis interviews were conducted in english (n=3) and isixhosa (n=7), de­pend­ing on participant preference, with the aid of a translator. inter­views and photovoice sessions were tape-recorded and transcribed; each was conducted by one of two separate investigators. interview content and photographs were analysed to identify recurring themes. the initial analysis was done by a single investigator, and the review of themes identified was performed by all co-investigators. a process of coding and categorisation of data content assisted in bringing meaning to the responses and photographs.25 , 26 data were transformed into variables, with interviews and photovoice data analysed separately. ethical approval the study was approved by the human research ethics committee and institutional review board of the faculty of health sciences, university of cape town. each participant gave written consent for their involvement in the study, including consent to publication of their photographs. results sample characteristics of the 10 patients interviewed, nine were female and one was male. all lived in khayelitsha. the patients received first-line art for a mean of 32 months (range 13 63) and second-line art for a mean of 38 months (range 10 72). after being switched to second-line art, patients experienced their first elevated vl (>1 000 copies/ml) at a mean of 12 months (range 4 41). of the 11 key informant interviews, three were nurses, four were counsellors and four were doctors. staff had worked a mean of 66 months (range 6 168) in the clinic. barriers and enablers to adherence patient-cited barriers no patient responded that a single barrier caused their treatment failure and the majority (n=6) stated that they had made an active decision to stop taking their medication due to the barriers identified. the top reasons for art failure (each cited by 3 patients) were side-effects, not using condoms, a lack of understanding around medication timing, didanosine (ddi) time delay between medication and food intake, and large pill size (table 1). key-informant-cited barriers the main adherence barriers cited by staff were patient drinking (n=9), non-disclosure (n=8), not using condoms (n=6), pill fatigue (n=5) and forgetting to take medication (n=5) (table 1). side-effects one-third of patients identified side-effects as a reason for treatment failure, citing nausea, vomiting, stomach pains and cramping: ‘i have this diarrhoea in my stomach and it’s cramping … it started my viral to go up and up and up because i skip now because i’m scared that maybe i’m going to the church and my stomach maybe want to run.’ (p06) ‘patients are not taking three of the tablets, taking two because one has got side-effects.’ (ki02) another patient on second-line art stopped because she did not realise her vl would go up quickly and was surprised when it became detectable. one-third of key informants also identified side-effects as a barrier. not condomising one-third of patients blamed their failure on not using condoms: ‘i had a boyfriend and didn’t condomise with the boyfriend. after that i … failed and was changed to second-line.’ (p04) not using condoms also emerged as a central theme in the key informant interviews, with six of 11 respondents citing it as a reason for non-adherence. key informants did appear to understand this risk to treatment success as a consequence of transmission of resistant strains. however, they seemed to inflate the risk of this occurring. one key informant described a tendency of staff to defer to an ‘easy’ explanation for treatment failure. timing of medication at the time of art initiation, counsellors instructed patients to take their pills twice daily at exactly the same time in the morning and evening. this is laid out as one of the ‘rules’ of art adherence and is presented in a concrete format, allowing very little scope for the patients when times clashed with their schedules: ‘to keep the time is too difficult. i take my pills at 7 but sometimes wake up at 8 and the time has passed.’ (p05) one patient (p04) stated that she often missed doses because of her work schedule. another blamed his counsellor for not telling him to take his medication twice daily, e.g. at 07h00 and 19h00. one-third of patients indi­cated that they had defaulted on first-line art due to such strict parameters: ‘before they said to us, if you used to take your tablets at 8 o’clock in the morning or night you can’t take it at 9 o’clock because it’s too late. but [msf counsellors] said it’s not late, you must take the tablets. if you forget, maybe it’s two hours or one hour, you can take your tablets.’ (p02) many patients cited this increased latitude around timing as helpful to becoming re-­adherent, allowing them more freedom to adjust timing around their schedules. only one key informant mentioned timing of medication as a barrier to patient adherence. ddi time delay until 2009, sa guidelines recom­mended ddi as part of its second-line art regimen. this required patients to take the medication one hour before eating. this time-delay was identified by one-third of patients and one key informant as a reason for treatment failure. ‘you must leave [medication] for the hour and then you forget to take other tablets after that. you take it maybe at 6 o’clock; you have to run at 7 o’clock for the train … you think okay that time is past, so you have to drink at night. that’s why your viral load is so grown.’ (p06) ‘we picked up that they were having the problem with the ddi delay and for­getting.’ (ki01) pills too large one-third of patients stated that they had difficulty taking their medication because of the large pill size. two of these patients discontinued taking their second-line regimen for this reason: ‘it was getting so difficult to take second-line. it was a big pill and i decided to stop.’ (p04) pill size was not noted in the key informant interviews as a reason for non-adherence. patient drinking one patient identified drinking as a factor in her treatment failure. in the key informant interviews, however, alcohol use emerged as the most cited reason for failure (cited by 9). staff said that this affected adherence in two ways: firstly, patients often forget to take their medication when drinking. secondly, staff reported that, as with the timing of medication, patients understood that they could not drink and take their arvs literally and stopped treatment altogether: ‘[the patient] sees that he is much better and he will start to drink again. it’s whereby most of them are failing because when they are drinking, they don’t take their medication, they stop their medication.’ (ki02) non-disclosure one patient identified non-disclosure as a barrier, citing the difficulty of maintaining art without support at home where she felt she had to hide her medication: ‘some of them they don’t tell their partners that they are positive and are on treatment. they need to disclose to friends, to partners.’ (ki10) eight of the 11 key informants indicated that non-disclosure was problem­atic. many of their patients felt the need to hide their medication and would often not take it when travelling or if others were present at work or at home. pill fatigue one patient identified pill fatigue as a reason for defaulting, noting: ‘i just keep getting tired sometimes. to take treatment everyday is not nice.’ (p03); ‘second-line patients are more likely to have problems because of pill fatigue.’ (ki09) five of the 11 key informants identified pill fatigue as a barrier. forgetting five of the 11 key informants identified patients forgetting to take their pills as a barrier. this was often cited with various reasons, ranging from patients being busy with work or family obligations, travelling without medication, and the lack of a plan for treatment adherence (alarm or friend/family to remind them). two of 10 patients identified forgetting as a barrier. service delivery barriers patient-cited clinic obstacles interviews with patients revealed difficulties with healthcare delivery at ubuntu clinic, with some patients citing missing medical records (n=6) and clinic staff shouting at patients (n=6). few, however, cited these problems in response to questions on defaulting or suboptimal adherence. rather, many seemed to view them as an expected part of clinic attendance; two patients stated that clinic problems affected their adherence or their attendance at the clinic: ‘sometimes they will shout you if you ask something … shouting at the top of their voices. you feel not happy and you go home and feel unhappy. and next time you say i’m not going to this clinic anymore.’ (p02) key-informant-cited clinic obstacles staff identified a lack of continued counselling support following art initiation (n=8) and insufficient education for patients (n=3) as key obsta­cles. one counsellor noted: ‘the point where we are failing is to really find out exactly why [the patient] is failing and try to fix the thing that makes them to fail first-line … there is no time to focus on the problem, instead we are just providing the medication without support.’ (ki09) staff also highlighted the need for increased follow-up to catch adherence issues earlier on. one clinician identified counselling as a critical but under-utilised component: ‘there is so much pressure for roll-out of getting more patients onto arvs, getting nurses dishing out arvs … counsellors are being overlooked but they are a critical part of the whole process.’ (ki08) three of the 11 key informants responded that there was no need for improvement and seven did not think that the clinic needed more time or resources for patients. these staff felt that patients should engage better with the healthcare system, that many obstacles faced by patients are difficult for the clinic to solve, or that current resources could be managed better. patient perspectives on the msf programme patients cited feeling more comfortable and free to share problems (n=7), shorter wait times (n=6), seeing the same staff (n=4) and support groups (n=2) as reasons why they preferred msf’s programme to the larger clinic: ‘i feel free now that on this side of the clinic. i can share everything … when i come here i feel at home because before when i was taking medicine on that side [larger clinic], i was afraid whether i had done right or done wrong.’ (p04) a more patient-centred environment enabled more open discussion of barriers to adherence and facilitated the resolution of issues. photovoice patient perspectives the photovoice component of the study elicit­ed a different patient perspective on treatment compared with the interviews. the photographs and the workshop discussion became a plat­form for sharing successes and sources of strength. each patient chose three pictures to share (table 2). of 33 total photographs shared, only nine illustrated negative aspects of patients’ lives, such as poor living conditions, difficulty remembering treat­ment, poor clinic service and not having family support. yet, when presented by patients, these negative aspects were often treated as barriers overcome or obstacles to get past. the remaining photographs (24/33) showed supportive family and friends (n=11) (fig. 1), the importance of treatment (n=5), gratitude towards the msf clinic staff (n=3) (fig. 2), religion as a source of strength (n=2), and over­­coming drinking problems (n=2) (fig. 3). there was a notable difference in the themes presented by patients as part of the photovoice analysis and those that emerged in the interviews. this is likely due to the difference in methodology and format. photo­voice involved individual presentation to the full group; patients seemed to experience this format as a type of support group with a focus on sharing positive experiences, often to encourage others in the group by describing facilitators to adherence and sources of support: ‘i believe in tablets, because it’s my life and i will be taking treatment for life. not for me, but for the kids too.’ (p04) fig. 1. the daughter of a patient reminds her mother to take her medication. fig. 2. a counsellor explaining medication parameters to a patient. fig. 3. a patient who struggled with an alcohol abuse problem depicts herself pouring out the remaining alcohol in her home. discussion south africa’s national strategic plan on hiv, stis and tb: 2012 2016 calls for 80% of plwha to be receiving art by 2016,27 expanding from the 56% of those eligible who were receiving art in 2009.28 however, this focus on initiating patients on treatment has largely ignored the rising numbers of patients failing treatment.11 , 29 we aimed to identify barriers and facilitators to long-term art adherence in the context of second-line treatment failure from the perspective of staff and patients. interview themes most frequently identified as barriers to treatment adherence differed between patients and staff. staff identified drinking, non-disclosure, not using condoms, pill fatigue and forgetting to take medication as barriers to adherence, while patients identi­fied side-effects, not using condoms and a lack of understanding around medication timing. with respect to service delivery, staff identified a need for continued counselling and educational support following art initiation. patients were concerned about missing medical records and poor staff attitudes in the clinic. patients as well as staff had a tendency to blame treatment failure on factors that were external to themselves and their role in treatment adherence. this is consistent with previous findings in a similar setting, where art patients who adhered tended to ascribe this to internal strength, whereas when they failed, external factors were identified.30 in the current study, the princi­pal patient-identified barriers were side-effects, not condomising, ddi, large pills and not understanding medi­cation – all but condomising point toward obstacles external to the patient; whereas, staff identified patient drinking, not disclosing, not condomising and pill fatigue most frequently – all of which focus more on patient behaviour. in the principal obstacles identified, the only one common to both patients and staff was not using a condom. when staff were questioned further on this topic, it became clear that they seemed to understand not condomising as contributing to the spread of resistant hiv strains within the population. however, given the small numbers of those failing second-line art, the likelihood was very low of any patients in this sample contracting a resistant strain rather than failure resulting from non-adherence. given the complexities involved in identifying behaviours that contribute to non-adherence, one explanation is that both patients and staff found not condomising a factor that is easily identifiable and relatively easily addressed, causing both to over-emphasise its role. this over-emphasis adds to the knowledge gap patients experience in understanding the reasons for treatment failure, reducing their ability to address and identify actual adherence issues. for some patients, art failure resulted from a lack of understanding around the parameters of their medication. for others, the issues were psychosocial in nature, involving bad living environments or a lack of support at home. yet, some patients made an active decision to stop taking medication and became re-adherent when issues such as side-effects, pill size or time delay were addressed. patients enrolled in the second-line failure clinic receive patient-centred support with individual and group counselling. unpublished data show a high vl re-suppression rate among those enrolled in the programme. this is likely due to improved access to staff, continuity of staff and more supportive clinic environment, allowing for quicker follow-up and more open discussion of issues affecting adherence. this is consistent with findings from similar studies where strong and open relationships between patients and healthcare providers facilitate adherence.30 there is currently an information gap between patients experiencing difficulties with treatment and clinic staff addressing those issues. there are personal and structural reasons for this, stemming from patients not informing staff when experiencing difficulties, not understanding which behaviours will lead to raised vls and not feeling comfortable with staff. the most patient-cited clinic obstacle was staff shouting at patients; however, some patients also highlighted the benefit of feeling open and able to share their issues with the msf programme staff. this serves to emphasise the importance of trust and communication be­tween patients and staff, particularly between patients and counsellors; patients’ difficulties with treatment remained unresolved until the clinic environment changed, allowing for open discussion and management of those issues. though previous research has shown similar barriers to adherence including poor patient-staff relationships, untimely addressing of adherence issues and inadequate counselling following initiation of art,31 the patient population in this study showed that improving these issues within service delivery can lead to improved adherence and vl suppression. many staff responded that there was no need for an improvement in service delivery and that the clinic had sufficient resources to serve its patient population, highlighting a tendency among some staff not to be critical of the status quo or look for methods to improve current service delivery. the present focus on increasing art coverage and the relatively few patients who are failing treatment has concentrated efforts to increase the number of patients receiving art, leaving little time to focus on the increasing rate of art failure. study limitations interviews conducted in isixhosa were translated during the interview in real time by msf staff, which may have influenced patient response, either limiting patient openness due to the presence of clinic staff or limiting the interviewer interaction because of the language barrier. the high proportion of female respondents limited the generalisability of the study findings, suggesting that our results may only be appropriate to a female population failing second-line art. though the proportion of females attending the second-line art clinic at the time was 68%, participation of males was low due to difficult schedules and willingness to participate. only one male participated in the study, making it difficult to determine whether responses were gender-biased. the study population comprised a small group of patients who had a very specific context of care delivery within a programme separate from standard government clinical care. thus, their experiences within a more ade­quately resourced environment than public clinical care is certain to have affected their perspectives on service delivery as well as their high level of re-adherence. moreover, because of the relatively low numbers of patients failing second-line art, the large bulk of staff experience is with patients receiving first-line art. as the number of patients failing second-line art increases, so will staff experience with these patients, offering a future opportunity to assess staff perspectives on barriers to, and facilitators of adherence. study significance this study focused on a patient population that included among the first patients in sa who have experienced virological failure on second-line art medication. yet, many of these patients have been able to suppress their vls within the msf-run programme. this success highlights the importance of both counsellors and clinicians providing the necessary patient support – to ensure that patients are adequately equipped to initiate art successfully and to serve as the front line for identifying problems as they arise. many of the patients who became re-adherent benefitted from open relationships with clinic staff, enabling discussion and management of adherence issues. prioritising patient-staff relationships and strengthening support mechanisms to identify adherence issues early on offers an opportunity for the current system of art initiation and support to improve patient outcomes. the largely positive themes elicited by photovoice illustrate that many multiple-failure patients feel positively about their treatment and lives and, with improved support mechanisms, this can translate into improved adherence and outcomes. although some patients did make an active decision to stop taking art, all continued to attend the clinic and engage with the healthcare system, demonstrating an opportunity for clinic staff to reduce failure rates in a patient population with no treatment option following failure of a second-line art regimen. recommendations the frequency with which not using condoms was cited as a factor contributing to art failure should be examined further at the staff and patient level to ensure that messaging is not misleading and that patients address all behaviours affecting adherence. continued follow-up, especially with regards to easily altered behaviour or misunderstood medication parameters (e.g. timing, missed doses, forgetting) should be explored to identify how best to equip patients for art regimens. continuity of care and patients’ comfort with staff is another area that could be explored to identify whether and how that may have contributed to improved patient outcomes in this group. though few patients were found to have resistant hiv strains following genotyping at ubuntu clinic, the incidence of primary or secondary infection with resistant strains should be explored. this is likely to become an increasingly important aspect of art failure as the prevalence of resistant strains increases. acknowledgements. we acknowledge the dedicated staff at ubuntu clinic and the participants who were involved in this study. the data and findings from this study will be made available upon request. references 1. world health organization. antiretroviral therapy. http://www.who.int/hiv/topics/treatment/en/index.html (accessed 26 may 2012). 1. world health organization. antiretroviral therapy. http://www.who.int/hiv/topics/treatment/en/index.html (accessed 26 may 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[http://dx.doi.org/10.1097/qai.0b013e31820dc0cc] 24. wang c, burris ma. photovoice: concept, methodology, and use for participatory needs assessment. health educ behav 1997;24:369-387. 24. wang c, burris ma. photovoice: concept, methodology, and use for participatory needs assessment. health educ behav 1997;24:369-387. 25. pope c, mays n. qualitative research: reaching the parts other methods cannot reach: an introduction to qualitative methods in health and health services research. bmj open 1995;311:42-45. 25. pope c, mays n. qualitative research: reaching the parts other methods cannot reach: an introduction to qualitative methods in health and health services research. bmj open 1995;311:42-45. 26. elo s, kyngäs h. the qualitative content analysis process. j adv nurs 2008;62:107-115. [http://dx.doi.org/10.1111/j.1365-2648.2007.04569.x] 26. elo s, kyngäs h. the qualitative content analysis process. j adv nurs 2008;62:107-115. [http://dx.doi.org/10.1111/j.1365-2648.2007.04569.x] 27. south african national aids council. national strategic plan on hiv, stis and tb: 2012 2016. http://www.doh.gov.za/docs/stratdocs/2012/nspfull.pdf (accessed 1 june 2012). 27. south african national aids council. national strategic plan on hiv, stis and tb: 2012 2016. http://www.doh.gov.za/docs/stratdocs/2012/nspfull.pdf (accessed 1 june 2012). 28. us agency for international development. usaid south africa hiv/aids profile. http://transition.usaid.gov/our_work/global_health/aids/countries/africa/southafrica.html (accessed 20 july 2012). 28. us agency for international development. usaid south africa hiv/aids profile. http://transition.usaid.gov/our_work/global_health/aids/countries/africa/southafrica.html (accessed 20 july 2012). 29. cornell m, grimsrud a, fairall l, et al. temporal changes in programme outcomes among adult patients initiating antiretroviral therapy across south africa, 2002 2007. aids 2010;24:2263-2270. [http://dx.doi.org/10.1097/qad.0b013e32833d45c5] 29. cornell m, grimsrud a, fairall l, et al. temporal changes in programme outcomes among adult patients initiating antiretroviral therapy across south africa, 2002 2007. aids 2010;24:2263-2270. [http://dx.doi.org/10.1097/qad.0b013e32833d45c5] 30. sharada p, wasti, simkhada p, et al. barriers to and facilitators of antiretroviral therapy adherence in nepal: a qualitative study. j health popul nutr 2012;30:410-419. 30. sharada p, wasti, simkhada p, et al. barriers to and facilitators of antiretroviral therapy adherence in nepal: a qualitative study. j health popul nutr 2012;30:410-419. 31. sanjobo n, frich jc, fretheim a barriers and facilitators to patients’ adherence to antiretroviral treatment in zambia: a qualitative study. sahara j 2008;5:136-143. 31. sanjobo n, frich jc, fretheim a barriers and facilitators to patients’ adherence to antiretroviral treatment in zambia: a qualitative study. sahara j 2008;5:136-143. abstract introduction methods results discussion acknowledgements references about the author(s) oda e. van den berg julius center for health sciences and primary care, university medical center utrecht, utrecht, the netherlands erica j. shaddock charlotte maxeke johannesburg academic hospital, division of pulmonology and critical care, school of clinical medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa sarah l. stacey charlotte maxeke johannesburg academic hospital, division of pulmonology and critical care, school of clinical medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa charles feldman charlotte maxeke johannesburg academic hospital, division of pulmonology and critical care, school of clinical medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa roos e. barth department of internal medicine and infectious diseases, university medical center utrecht, utrecht, the netherlands diederick e. grobbee julius center for health sciences and primary care, university medical center utrecht, utrecht, the netherlands willem d.f. venter ezintsha, university of the witwatersrand, johannesburg, south africa kerstin klipstein-grobusch julius global health, julius center for health sciences and primary care, university medical center utrecht, utrecht, the netherlands alinda g. vos julius center for health sciences and primary care, university medical center utrecht, utrecht, the netherlands ezintsha, university of the witwatersrand, johannesburg, south africa citation van den berg oe, shaddock ej, stacey sl, et al. the influence of hiv infection and antiretroviral treatment on pulmonary function in individuals in an urban setting in sub-saharan africa. s afr j hiv med. 2021;22(1), a1312. https://doi.org/10.4102/sajhivmed.v22i1.1312 original research the influence of hiv infection and antiretroviral treatment on pulmonary function in individuals in an urban setting in sub-saharan africa oda e. van den berg, erica j. shaddock, sarah l. stacey, charles feldman, roos e. barth, diederick e. grobbee, willem d.f. venter, kerstin klipstein-grobusch, alinda g. vos received: 08 sept. 2021; accepted: 06 oct. 2021; published: 15 nov. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: with the roll-out of antiretroviral treatment (art), the life expectancy of people with hiv and, hence, morbidity from non-communicable diseases, including pulmonary diseases, have increased. objectives: this research study aims to investigate whether hiv infection and art use are associated with pulmonary function, given the high frequency of pulmonary infections, including tuberculosis (tb), associated with hiv. method: adults living with hiv (art-naïve, on firstor second-line art), and age and sex matched hiv-negative controls were included in a cross-sectional study in johannesburg, south africa. spirometry was performed to determine lung function, measuring the forced expiratory volume in one second (fev1), the forced vital capacity (fvc) and the fev1/fvc ratio before (pre), and after (post), short-acting bronchodilator. the association of hiv infection and art use with pulmonary function was analysed using linear regression models, adjusting for age, gender, body surface area (bsa), employment, education, smoking and tb. results: overall, 548 participants (62% women) were included with a mean age of 38 (standard deviation [s.d.] 9.5) years. no effect of hiv or art on post-fev1 was observed in adjusted analysis. additional adjustment for tb resulted in a higher post-fev1 in participants on art compared with hiv-negative participants, whereas tb was associated with a lower fev1. no effect of hiv and art on post-fev1/fvc was observed. conclusion: hiv infection and art use were not associated with reduced pulmonary function in this urban african population. tuberculosis showed a mediating effect on the association between hiv, art and pulmonary function. keywords: hiv; antiretroviral therapy; tuberculosis; spirometry; sub-saharan africa; obstructive lung disorder; copd; asthma; pulmonary function. introduction approximately 70% of all people with hiv infection live in sub-saharan africa (ssa), with south africa constituting the largest hiv epidemic profile in the world.1 before the roll-out of antiretroviral therapy (art) programmes, the most frequent complications of hiv infection included pulmonary infections, which were a major cause of morbidity and mortality rates.2 the widespread use of art for the treatment of hiv has contributed to an increased life expectancy among people living with hiv (plhiv), which is subsequently associated with increases in non-communicable diseases in plhiv.2,3 among non-communicable diseases, obstructive lung disorders (olds) constitute a major class.4 the burden of chronic respiratory diseases is generally increasing across the globe, and asthma and chronic obstructive pulmonary disease (copd) are among the main causes of mortality and morbidity.5 whilst risk factors, such as smoking and opportunistic infections, contribute to this increased risk, the literature suggests that hiv infection and art use may be associated with the development of olds.6,7 viral suppression resulting from art could contribute to the preservation of lung function.7 however, some studies suggest that there is a direct negative effect of art on pulmonary function.8,9,10 potential explanations include a direct toxic effect of art on the lungs, a renewed response to subclinical pulmonary infections because of the restoration of the immune system and/or the development of autoimmunity. in south africa, the adult art coverage is 73%.1 patients failing first-line art, consisting of non-nucleoside reverse-transcriptase inhibitor-based (nnrti) regimens, are switched to second-line art, including a protease inhibitor.11 to date, there have been no data on potential differential effects of distinct art classes on lung function, and the results from studies carried out in high-income countries cannot be generalised to ssa because of differences in socio-demographic characteristics of the hiv population and the differences in the burden of infectious respiratory diseases.3 tuberculosis (tb) remains a major health challenge among hiv-positive people in south africa. within the first year of hiv infection, the risk of active tb doubles.12 tuberculosis is thought to mediate the effect of hiv and art on olds, as hiv increases the susceptibility to tb, which is strongly related to adverse pulmonary function.12,13,14 however, only a few studies on the influence of hiv on pulmonary function have taken into account the possible contribution of tb. this study aims to investigate the influence of hiv, first-line art and second-line art on pulmonary function in an urban african population, taking into account the role of tb. methods a four-arm comparative, cross-sectional study was performed, including people aged ≥ 18 years between july 2016 and november 2017. the study site was located at the charlotte maxeke johannesburg academic hospital, central johannesburg, south africa. the methods have been described previously.15 in line with the inclusion criteria of the randomised controlled trials (rcts) from which the participants were selected, four different groups consisting of plhiv but not yet or less than 8 weeks on art (hiv+, art–), plhiv and on first-line tenofovir-containing art regimens for at least 2.5 years (hiv+, art1), and those on second-line art for at least 6 months (hiv+, art2) and hiv-negative controls (hiv–) were identified. three ongoing rcts, conducted by the wits reproductive health and hiv institute (wits rhi),14 were used for the recruitment of participants. the hiv+, art– patients were recruited from an ongoing open-label rct investigation of dolutegravir and two different prodrugs of tenofovir as first-line art in people newly diagnosed with hiv, and were recruited from routine hiv services in local clinics in central johannesburg.16 patients were approached for participation in this study at any time from their enrolment in the rct up to a follow-up duration of 36 weeks. none of the hiv+, art– participants was on art for more than 8 weeks upon enrolment in this study. participants in the hiv+, art1 group were recruited from a rct completed in 2016, which investigated low-dose stavudine versus tenofovir in first-line art regimens. these participants were recruited from the same clinic.17 only participants to receive tenofovir were asked to participate in this study by phone in a random order until the required number of participants was reached. the hiv+, art2 group was selected from an open label randomised study comparing two second-line protease-inhibitor-based art regimens.18 participants were approached for enrolment in this study during baseline or one of the follow-up visits. the main exclusion criteria for all rcts were impaired kidney and/or liver function, hepatitis b infection and pregnancy. for recruitment of the hiv–group, participants living with hiv were asked to refer an uninfected family member or a friend or contact with unknown hiv status of the same sex and age (±5 years) to participate in the study. all participants without a known hiv-positive status were tested for hiv on enrolment, according to national testing guidelines.19 if a participant tested positive for hiv without a history of art use, they were assigned to the hiv+, art– group and referred to a local clinic to start art. however, if a participant tested positive for hiv and was found to be on art already, they were assigned to the hiv+, art1 or hiv+, art2 group depending on their art regimen. data were collected during a single visit through questionnaires, physical examination and spirometry. a modified version of the who step instrument was used to assess information on demographics, ethnicity, medical history, concomitant drug use, exposure to harmful liquids, gases or material and a family history of pulmonary disease.20 the respiratory questionnaire was based on the british medical research council respiratory questionnaire,21,22 the ats-dld-78-a,23 the world health survey24 and questionnaires used in other publications.25,26 tuberculosis was defined as self-reported history of tb or pneumonia. spirometry, with preand post-bronchodilator measurements, was performed by trained researchers using a hand-held carefusion 2009 spirometer and spida 5 software. the participants were seated when performing the manoeuver. in order to obtain sufficient spirometry results, three acceptable manoeuvers were needed in which the two largest values for forced expiratory volume in one second (fev1) and forced vital capacity (fvc), respectively, were at maximum 150 ml apart. in addition, efforts were considered acceptable if the individual performed the maneuver with maximum inspiration, a good start, a smooth continuous exhalation and maximal effort, without evidence of early termination, inconsistent effort, leak or an obstructed mouthpiece. if the results were not sufficient, the measurements were repeated up to a maximum of eight times. after obtaining the first measurements, a bronchodilator was administered (400 µg salbutamol) to the participant using an aerochamber. after 15 min, post-bronchodilation spirometry was performed using the same method as described above. all calibrations and tests were performed in accordance with the american thoracic society (atsiii) and european respiratory society recommendations,27 and only tests that met the above-mentioned criteria were included in the analysis. in cases where participants had only one or two reproducible post-bronchodilator flow volume curves, but these were comparable with the pre-bronchodilator flow volume curves, the post results were used for analysis. the respiratory parameters measured were as follows: fev1, fvc and the fev1/fvc ratio before (pre) and after (post) short-acting bronchodilator. the highest post-bronchodilator fev1 and fvc values were used for analysis. spirometry results that revealed the presence of disease were reviewed by a pulmonologist. the highest post-bronchodilator fev1 and fvc values were used for analysis. for the current study, olds were defined as the presence of copd according to the lower limit of normal (lln) cut-off and reversible airflow obstruction. as the gold standard definition of copd, fev1/fvc < 0.70,28 overestimates airflow obstruction in the elderly and underestimates airflow obstruction in the young,29 we chose to include an lln to define olds. the lln is defined as a fev1/fvc ratio below the fifth percentile of the predicted value. the global lung initiative equation category ‘afro-american’ was used to define normal values.30 the predicted values of fev1 percentage were used to classify copd severity.28 according to the national heart, lung and blood institute, reversible airflow obstruction is present when the fev1 increases by 12% and 200 ml after inhalation of the bronchodilator, which may indicate the presence of asthma.31,32 continuous descriptive data are presented as means and standard deviations (s.d.) or, in the case of non-normality, as medians and interquartile ranges (iqr) and nominal data with frequency count (percentage [%]). the uncorrected post-bronchodilator spirometry results are presented per group. data analysis demographic and clinical characteristics of the population were presented using mean and s.d., or median with iqr in the case of non-normality, for continuous data. nominal data were presented using frequency counts (percentage, [%]). in table 2, the uncorrected post-bronchodilator spirometry results were presented for the four different groups. outcomes included the number of people with a fev1/fvc < lln (copd), a fev1/fvc < 0.70, an increase in fev1 of 12% and 200 ml (asthma), and old based on the lln. table 1: characteristics of the study population. table 2: post-bronchodilator spirometry results. next, post-fev1 and post-fev1/fvc were compared across the groups by linear regression analysis, with the hiv-negative group as reference, as presented in table 3. stratification for tb was not feasible because of the small sample size within the stratum of tb-positive, hiv-negative. the first model included all groups with no adjustments; the second model was adjusted for age, sex and body surface area (bsa) calculated by mosteller’s formula.33 the third model was adjusted for age, sex, bsa, smoking, employment and education. smoking is a known confounder in the relation between hiv and pulmonary function. employment and education were added as proxy for socio-economic status (ses). the fourth model was additionally adjusted for tb. table 3: hiv and antiretroviral therapy status on mean (a) post-forced expiratory volume in 1 s and (b) post-forced expiratory volume in 1 s/forced vital capacity. multicollinearity was tested using a correlation matrix and the variance inflation factor. in the sensitivity analysis, participants with less than three post-bronchodilator blows were excluded from the analysis. participants with incomplete spirometry were no different from those with complete spirometry data, and as we had sufficient power, listwise deletion of participants without spirometry results was performed. all analyses were performed using statistical package for social sciences (spss) version 25 (spss, chicago, il, united states [us]). a two-sided p-value of < 0.05 was considered to be statistically significant. results of the 548 participants enrolled, 531 participants (97%) were included in the analysis. nine participants were excluded because of missing spirometry results and eight with poor-quality spirometry. furthermore, eight participants had an insufficient post-bronchodilator test and, therefore, their results could not be used to assess asthma. the characteristics of the four different groups are discussed in this study, as shown in table 1. the majority were female participants (n = 329, 62%) with the mean age of 38 (s.d. 9.5) years. almost all participants were black africans (97.7%). hiv-positive participants were more often women and older compared with the hiv-negative participants (p < 0.01 for both comparisons). hiv-negative participants were more often current smokers than hiv-positive participants (37% vs. 14%, p < 0.001). employment rate varied significantly between the groups, with the lowest employment rate reported for the hiv-negative group and the highest employment rate for the hiv+, art1 group (33% vs 85%, p < 0.001). hiv-positive participants were much more likely to have had tb (30% vs 4%, p < 0.001). the median cd4 cell count was 470 among hiv-positive participants (iqr = 395). the further analysis included 524 participants (96%) as 24 participants did not undergo a spirometry or had a spirometry that did not meet the quality criteria. these 24 participants had a similar demographic profile to those who completed the spirometry. the frequency of old was 8.3% (n = 44) in total (table 2). for reversible airflow obstruction, it was 6.3% (n = 33) and for copd, according to the lln, it was 3.1% (n = 16) (table 2). following adjustment for age, gender and bsa, no effect of hiv and art on post-fev1 was observed (table 3a, model 2). age was associated with a significantly lower fev1 (β = −0.03 l, p < 0.001), and male gender and bsa were associated with a significantly higher fev1 (β = 0.89 l and 0.36 l, respectively, p < 0.001). additional adjustment for smoking, employment and education did not change the results (table 3a, model 3). after further adjustment for tb (model 4), hiv-positive participants on first-line and on second-line art had a significantly higher post-fev1 compared with hiv-negative participants, whereas tb was associated with a lower fev1 (β = −0.236 l, p < 0.001). no effect of hiv and art on the post-fev1/fvc was observed (table 3b). each variable of interest consisted of less than one percent missing. therefore, multiple imputations were assumed to provide no benefit. in a sensitivity analysis, the above-described analyses were repeated whilst excluding 32 participants with only one or two reproducible post-bronchodilator flow volume curves. the magnitude and direction of the results were the same. discussion in this study, we sought to determine whether hiv and art were independently associated with pulmonary function, taking tb into account. in this urban african population, the frequency of old was 8.3%. hiv and art were associated with a significantly higher fev1, but only following adjustment for tb, whilst tb was associated with a lower fev1. this indicates a mediating effect of tb in the association of hiv and art with pulmonary function as assessed with fev1. no effect on the fev1/fvc ratio was observed. the frequency of 3% for copd in this study population is lower compared with that of previous studies from south africa, with a prevalence rate of up to 22%.34,35 these studies, however, included older participants and more smokers. the reversible airflow obstruction frequency of 9% among hiv-positive participants in this study was slightly higher compared with the 7.3% found by gingo et al.36 in the united states using the same definition. limited available data regarding the prevalence of asthma complicates a comparison with earlier studies. in addition, most of these studies were performed with children and based on self-reported wheeze or previous diagnosis of asthma,37,38 or used a challenge test,39 both shown to diagnose asthma more frequently compared with using a bronchodilator test to measure reversible airflow obstruction.40,41,42,43 asthma is typically diagnosed early in life and could have preceded inclusion in this study with a minimum age of 18 years. consistent with the low frequency of old, this cohort has a surprisingly low frequency of respiratory complaints, as was previously described by kummerow et al.44 previous studies support an increased frequency of respiratory symptoms2,10 and incidence of olds among hiv-positive people using art.6,45,46,47 crothers et al.6 stated that hiv infection is an independent risk factor for copd. however, these findings were based on the patient’s self-report and did not include women, a group that constitutes the largest proportion of the hiv population in ssa. drummond et al.7 found that hiv independently contributes to an accelerated pulmonary function decline whilst taking into account respiratory infections. however, participants in that study were intravenous drug users, which is an independent risk factor for copd.2 both studies also reported a much higher smoking frequency compared with our study. as such, these studies are most likely not generalisable to ssa populations. a recent study in a rural african population found that pulmonary function was impaired in plhiv compared with hiv-negative participants; however, the impairment may have resulted from co-infection with tb.14 the current study confirms this finding by showing a mediating effect of tb in the relationship between hiv, art and lung function. studies have shown contradictory results on the effect of art on pulmonary function. crothers et al.6 concluded that the use of art was associated with a lower risk of copd. contrasting these findings, two cross-sectional studies have shown that the use of art is associated with an increase in the prevalence of copd and a decline in the post-fev1/fvc ratio.2,10 the current study showed no effect of using art on the pulmonary function in plhiv. these conflicting findings suggest that environmental and occupational factors, such as exposure to open fire, air pollution and the use of personal protection at dusty jobs, may vary between populations; however, it is also likely that methods of data collection, diagnosis and vital statistics are not directly comparable between studies.48,49 no effect of smoking on post-fev1 and post-fev1/fvc was observed, which may be because of irregular smoking habits depending on financial resources or lack of information on pack-years in current smokers, resulting in misclassification of smoking habits.50 an additional explanation could be that the study population is relatively young, and that the effect of smoking only appears later in life. furthermore, hiv-positive participants might remember their medical history better, and social desirability bias could have occurred because of smoking stigma in hiv-positive people. the finding that hiv is associated with an increase in fev1 was surprising. there could be unmeasured variables associated with airway obstruction that were not considered in the current study, which could explain a lower fev1 in the control group. however, most previously reported variables associated with pulmonary obstruction were included and tested. furthermore, those on firstor second-line art had a higher prevalence of tb. therefore, the mediating effect of tb is larger in these groups, which was reflected by model 3. another challenge lies in defining the clinical relevance of the study findings, as there is a small decline in fev1 initially, and the impact of this decline on a patient depends on various factors.48 because of the relatively young population in the current study, clinically relevant effects might not have occurred yet, but could still occur later in life. strengths of this study include the standardised data collection, including questionnaires and spirometry testing, and the use of an hiv-negative control group. to account for differences between the groups, the analyses were corrected for smoking, a known confounder in the relation between hiv and pulmonary function, and employment and education were added as a proxy for the ses. furthermore, although participants were recruited from rcts, we feel that they represent the general hiv-positive community. participants in the rct were recruited at public hiv treatment clinics in the inner city of johannesburg. randomised controlled trials in this setting tend to attract the general population because of the conveniences in logistics (such as travel reimbursement, personal attention and shorter waiting times at the clinics). a limitation of the study includes its cross-sectional design, limiting any causal inference. in order to assess the real burden of pulmonary impairment, a follow-up study would be more suitable. moreover, it might be that the control group of this study is not completely representative of the general hiv-uninfected population. this study data showed that employment rates were much lower in the hiv-negative group. this might reflect that unemployed family members or friends were more eager to participate than employed relatives. this could have introduced selection bias despite adjustment for socio-demographic factors as there might have been unmeasured confounding. in addition, a history of tb was combined with a history of pneumonia, as we deemed this self-reported information not accurate enough to distinguish between both entities. this could have led to the overdiagnosis of tb. in conclusion, the findings in this study suggest that hiv infection and art use are not associated with a reduction in pulmonary function. however, hiv remains the main risk factor for acquiring tb and the data did show a reduced pulmonary function in relation to tb. this emphasises the important role of tb in this population. future research studies should be targeted at eliminating tb, and an investigation of whether those living with hiv and a history of tb would benefit from screening tests to detect olds. in daily hiv care, healthcare providers should be aware that a history of tb can contribute to an impaired pulmonary function. acknowledgements the authors acknowledge boehringer ingelheim the netherlands for lending the spirometry equipment. a warm thanks as well to sir j.w. van den bos, senior advisor at boehringer ingelheim the netherlands, for his practical support and advice regarding the use of the spirometry software. besides that, the authors thank pt-medical b.v. for sponsoring the disposable spirometry filters. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions o.e.v.d.b was responsible for conceptualisation, data curation, formal analysis, methodology, project administration, visualisation, writing of the original draft, writing and editing of the article. e.j.s. assisted with conceptualisation, investigation, methodology, resources, writing and editing. s.l.s. assisted with conceptualisation, methodology, resources, writing and editing. c.f. assisted with conceptualisation, methodology, resources, writing and editing. r.e.b. assisted with conceptualisation, methodology, co-supervision, writing and editing. d.e.g. assisted with conceptualisation, methodology, main supervision, writing and editing. w.d.f.v. assisted with conceptualisation, methodology, writing and editing. k.k.-g. assisted with conceptualisation, methodology, co-supervision, writing of the original draft, writing and editing. a.g.v. assisted with conceptualisation, data curation, formal analysis, funding acquisition, investigation, methodology, project administration, co-supervision, writing of the original draft, writing and editing. ethical considerations this study was approved by the human ethics research committee of the university of the witwatersrand (ethics clearance number: m160130) and conform to ethical norms and standards of the declaration of helsinki. all participants provided written, informed consent prior to participation. funding information pt-medical b.v. offered the spirometry filters with a discount. boehringer ingelheim the netherlands sponsored the purchase of the spirometry filters with a once-off grant of €1700.00. none of the companies was involved in the protocol development, conduct of the study, analysis of the data or writing of the report. data availability the authors confirm that the data supporting the findings of this study are available within the article. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references unaids. global hiv & aids statistics fact sheet. aidsinfo; 2020 [cited 2019 dec]. available from: http://aidsinfo.unaids.org. gingo mr, george mp, kessinger cj, et al. pulmonary function abnormalities in hiv-infected patients during the current antiretroviral therapy era. am j respir crit care med. 2010;182(6):790–796. https://doi.org/10.1164/rccm.200912-1858oc unaids. report on the global hiv/aids epidemic. geneva: 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the prevalence of copd in africa: a systematic analysis. copd. 2015;12(1):71–81. gingo mr, wenzel se, steele c, et al. asthma diagnosis and airway bronchodilator response in hiv-infected patients. j allergy clin immunol. 2012;129(3):708.e8–714.e8. https://doi.org/10.1016/j.jaci.2011.11.015 braman ss. the global burden of asthma. chest. 2006;130(1):4s–12s. https://doi.org/10.1378/chest.130.1_suppl.4s adeloye d, chan ky, rudan i, campbell h. an estimate of asthma prevalence in africa: a systematic analysis. croat med j. 2013;54(6):519–531. poirier cd, inhaber n, lalonde rg, ernst p. prevalence of bronchial hyperresponsiveness among hiv-infected men. am j respir crit care med. 2001;164(4):542–545. https://doi.org/10.1164/ajrccm.164.4.2010019 hunter cj, brightling ce, woltmann g, wardlaw aj, pavord id. a comparison of the validity of different diagnostic tests in adults with asthma. chest. 2002;121(4):1051–1057. https://doi.org/10.1378/chest.121.4.1051 gjevre ja, hurst ts, taylor-gjevre rm, cockcroft dw. the american thoracic society’s spirometric criteria alone is inadequate in asthma diagnosis. can respir j. 2006;13(8):433–437. martins p, rosado-pinto j, do céu teixeira m, et al. under-report and underdiagnosis of chronic respiratory diseases in an african country. allergy. 2009;64(7):1061–1067. https://doi.org/10.1111/j.1398-9995.2009.01956.x schneider a, gindner l, tilemann l, et al. diagnostic accuracy of spirometry in primary care. bmc pulm med. 2009;9(1):31. https://doi.org/10.1186/1471-2466-9-31 kummerow m, shaddock ej, klipstein-grobusch k, et al. unexpected low frequency of respiratory symptoms in an hiv-positive urban sub-saharan population compared to an hiv-negative control group. south afr j hiv med. 2019;20(1):1–7. foster sb, paul me, kozinetz ca, macias cg, shearer wt. prevalence of asthma in children and young adults with hiv infection. j allergy clin immunol. 2007;119(3):750. https://doi.org/10.1016/j.jaci.2007.01.002 gutin f, butt a, alame w, thomas 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guidelines the 2012 southern african arv drug resistance testing guidelines by the southern african hiv clinicians society   f conradie, d wilson (chairpersons of the resistance testing guidelines committee), a basson, t de oliveira, g hunt, d joel, m papathanasopoulos, w preiser, j klausner, d spencer, w stevens, f venter, c van vuuren (expert panel members), l levin, g meintjes, c orrell, h sunpath, t rossouw, g van zyl (reviewers) corresponding author: f conradie (fconradie@witshealth.co.za) disclaimer: specific recommendations provided here are intended only as a guide to clinical therapy, based on expert consensus and best current evidence. treatment decisions for patients should be made by their responsible clinicians, with due consideration for individual circumstances. the most current version of this document should always be consulted. following the rapid scale-up of the programme for universal access to antiretroviral therapy (art) in southern africa, resistance to antiretroviral medications will occur. a detectable viral load must be treated as an emergency and should trigger intensive patient tracking and adherence counselling. in contrast to the developed world, the incidence of transmitted resistance is still low in most areas in the region. therefore, in this consensus statement we do not recommend resistance testing in hiv-infected adults upon diagnosis or art initiation. however, baseline resistance testing is recommended for children who have been exposed to art for prevention of mother-to-child-transmission therapy and subsequently become hiv-infected. resistance testing is also recommended after virological failure of firstand second-line art regimens. s afr j hiv med 2012;13(4):162-167. doi:10.7196/sajhivmed.874 1. opening statement antiretroviral therapy (art) has converted hiv infection from an almost universally fatal illness to a chronic manageable disease. adherence to therapy is essential for full viral suppression and optimal immune reconstitution. if antiretroviral (arv) drug levels are suboptimal, the risk of developing arv drug resistance is high due to the high rate of hiv replication and the lack of proofreading capacity in the viral reverse transcriptase enzyme. continuation of a failing art regimen can affect both the treated individual and the community, as resistant viral strains can be transmitted to other persons. resistance can be minimised by uninterrupted supply of medication, scientifically sound prescribing practices, long-term adherence support, viral load (vl) monitoring, and rapid responses to demonstrated virological failure with timeous changes of therapy.1 we developed consensus guidelines for hiv resistance testing that consider international best practice and the financial constraints encountered in southern africa. the guidelines, presented here, are based on the levels of resistance in the community as reported in the 2012 world health organization (who) hiv drug resistance report.2 the north american and british resistance testing guidelines,3 , 4 , 5 although ideal, are not affordable nor applicable in most southern african situations. these guidelines are aimed at southern african clinicians who manage individuals with hiv infection in both the private and public sectors in our region. appropriate, affordable resistance testing needs to be incorporated strategically into national guidelines relevant to southern africa. in late 2012, the south african national department of health sanctioned the formalisation of a national hiv drug resistance working group. all relevant stakeholders were identified and a steering committee was formed. the working group has 4 clear pillars: (i) a clinical stream; (ii) a national database development team; (iii) a laboratory team (national health laboratory service (nhls) and national institute for communicable disease (nicd)); and (iv) an epidemiology stream. the presence of a vl >1 000 copies/ ml in an individual who has been receiving art for >6 months constitutes an adherence emergency, and should trigger a vigorous response from the healthcare provider, including increased adherence support, before the vl measurement is repeated. 2. recommendations for arv drug resistance testing 2.1 the diagnosis of hiv in children aged <2 years genotyping at baseline to detect resistance mutations should be performed for all hiv-infected infants who have been exposed to any form of art taken by the mother or infant for the prevention of mother-to-child transmission (pmtct) of hiv, or who have unknown exposure to pmtct. infants and children are a challenging group to treat with art, especially in resource-constrained healthcare settings. children and their mothers are likely to have been exposed to arv medications in pmtct programmes. approximately 52.6% (95% confidence interval (ci) 37.7 67.0) of children who fail pmtct therapy have at least one non-nucleoside reverse transcriptase inhibitor (nnrti) mutation after single-dose nevirapine (sdnvp), and about 16.5% (ci 8.9 28.3) after sdnvp combined with antepartum, postpartum or postnatal zidovudine (azt) with or without lamivudine (3tc).6 these mutations will generally have disappeared, or may not be detectable by routine resistance testing, 2 years after the last dose of prophylactic art. children aged <3 years are treated with a boosted protease inhibitor (pi) regimen, but it is important to document nnrti resistance, as this will have implications in the choice of second-line regimens.7 resistance mutations in children failing art seem to be more common than in adults.8 results from baseline resistance testing will ensure the most appropriate selection of arv drugs. further research on appropriate drug regimens in paediatric and adolescent populations is, critically, an unmet need.   2.2 failure of arv regimens resistance testing is recommended for all patients (children and adults) failing first-line nnrti-based arv regimens, with failure defined as two vl measurements >1 000 rna copies/ml, with adherence and other issues addressed in the interval (see section 5). the accumulation of resistance mutations can be minimised by repeating the vl measurement within 3 months.9 , 10 , 11 if the first-line regimen is fully effective, then the vl should have fallen by 1.0 log10 copies/ml within 4 weeks or be undetectable by 3 months (or <1 000 rna copies/ml in patients whose initial vl was very high).4 resistance tests serve two purposes: (i) a fully sensitive pattern may imply that the patient is not adhering to treatment or has completely interrupted art; and (ii) if resistance mutations are present, then the clinician, preferably together with an expert, can decide on the most appropriate second-line regimen. in patients on a stavudine (d4t)or azt-containing nnrti-regimen, or on a tenofovir (tdf)-containing regimen, the importance of excluding resistance to tdf is crucial. tdf may be required as part of the nucleoside reverse transcriptase inhibitor (nrti) backbone in second-line art, or for treatment of hepatitis b virus (hbv)/hiv co-infection in combination with 3tc.12 resistance testing is recommended for all patients (children and adults) failing a pi-based arv regimen. failure is defined as two vl measurements >1 000 rna copies/ml, with measurements taken 3 6 months apart and with adherence and other issues addressed in the interval. an absence of pi mutations during pi-based therapy strongly suggests non-adherence to treatment.13 children on any pi regimen are at high risk for pi resistance if co-treated with rifampicin (for tuberculosis). repeated vl measurements and resistance testing are recommended for patients failing long-term pi regimens with a concurrent decline in cd4 count.   2.3 acute infection recent hiv infection in adults is rarely documented; however, viral genotyping at this time may give valuable public health insights into currently circulating strains. resistance testing recommendations for specific acute infection scenarios are shown in table 1. table 1. recommendations for hiv resistance testing patient group recommendation comments recent infection infected infants aged <2 years exposed to pmtct or infected children aged >2 years who stopped taking daily nvp less than 2 years previously recommended as soon as hiv infection is diagnosed infants aged <2 years where exposure to pmtct is uncertain recommended as soon as hiv infection is diagnosed documented acute infection* (seroconversion) recommended possible public health surveillance function hiv diagnosis     patients without documented seroconversion presenting for routine clinical care not recommended background prevalence of transmitted resistance is low and time since infection is likely to be long, decreasing the likelihood of detecting resistance mutations arv initiation children aged >2 years about to start first-line art not recommended unless within 2 years of stopping daily nvp pregnant women about to start first-line art not recommended pregnant women should have a vl measurement 3 months after art initiation. detectable viraemia >1 000 rna copies/ml should be treated as an adherence emergency. adults about to start first-line art not recommended background prevalence resistance is very low and the time since infection is likely to be long, decreasing the likelihood of detecting resistance mutations. failure of nnrti-based art adults and children with two vl measurements >1 000 rna copies/ml† and/or at least a <2 log10 drop in vl while on nnrti-based art (measurements at least 4 weeks, preferably 3 months, apart) recommended adherence‡ issues should be addressed comprehensively between the 2 measurements. resistance testing should be performed while the patient is on the failing regimen or within 4 weeks of discontinuation. failure of a boosted pi-based regimen     adults and children with two vl measurements >1 000 rna copies/ml† and/or a <2 log10 drop in vl while on pi-based art (measurements 3 6 months apart) recommended failure on pi regimens is almost always due to poor adherence. adherence‡ issues should be addressed comprehensively between the 2 measurements. resistance testing should be performed while the patient is on the failing regimen or within 4 weeks of discontinuation.   pmtct = prevention of mother-to-child transmission; nvp = nevirapine; art = antiretroviral therapy; rna = ribonucleic acid; nnrti = non-nucleoside reverse transcriptase inhibitor; pi = protease inhibitor; vl = viral load. *some or all of the following features: high fever, generalised lymphadenopathy, oral ulcers, pharyngitis, maculopapular rash, lymphopenia, thrombocytopenia, and transaminases, in combination with a history suggestive of hiv exposure. †definition of virological failure may vary between southern african countries. a persisting vl of 500 1 000 copies/ml could be considered for resistance testing, with access to sensitive in-house assays. ‡see section on arv adherence (section 5). 3. scenarios where arv resistance testing is not recommended 3.1 hiv diagnosis in adults and adolescents at the current level of transmitted resistance in the community, performing resistance testing in all individuals who are diagnosed with hiv infection is not cost-effective. for pregnant women, although we do not recommend routine resistance testing, we do recommend hiv vl testing 3 months after initiating triple arv therapy (for cd4 counts <350 cells/mm3 ) or at the time that pregnancy is confirmed in women already receiving art. a vl >1 000 rna copies/ml at this point should be regarded as an emergency, and should lead to intensive adherence support and screening for drug interactions or other reasons for failure (section 5), to minimise fetal transmission risk. the vl measurement should be repeated after 4 weeks, and, if >1 000 copies/ml, hiv resistance testing and an immediate switch to a second-line art regimen must be performed.   3.2 arv initiation in adults and children aged >2 years children aged >2 years who stopped taking prophylactic nvp during breastfeeding more than 2 years previously do not need a resistance test prior to arv initiation. in such cases, resistance, if present, is very unlikely to be detected by genotyping. while super-infection with a resistant viral strain is a theoretical possibility, it is considered to be so rare that performing resistance tests would not be cost-effective.   3.3 treatment interruptions without documented failure patients who have interrupted therapy for reasons other than proven virological failure should not have hiv genotype testing performed upon presentation for subsequent art.14 rather, the previous art regimen should be re-started, and vl should be measured after 3 months. resistance mutations generally disappear rapidly in the absence of drug pressure and a reliable resistance test result may not be obtained during treatment interruptions. if the vl is not suppressed after adherence intervention, a resistance test can be obtained to document resistance, and an appropriate second-line regimen can be selected.15 4. national integration of public sector laboratories in the public sector in south africa, the nhls has five centralised facilities capable of conducting sequence-based resistance testing. currently, only two of these facilities perform routine genotyping for patient care on a large scale (tygerberg and johannesburg). laboratories focus on genotyping assays, most using in-house assays, with backup from commercial assays such as viroseq or trugene. national surveillance is conducted at the nicd. as the arv programme expands and patients receive treatment for longer periods of time, the capacity for resistance testing will need to be expanded. currently, phenotyping capabilities for resistance are available, largely for research purposes, at several academic centres. numerous research projects are underway to develop and assess more affordable and accessible approaches to resistance testing (e.g. sequencing short regions of the reverse transcriptase gene). the southern africa treatment and resistance network (saturn) has integrated the efforts of laboratories, researchers and clinicians to monitor hiv resistance patterns and advise on the clinical management of patients failing art. the saturn drug resistance database systems are freely available and include two of the best public drug resistance databases in the world: the stanford hiv drug resistance database and the regadb clinical management database. saturn databases are used to deliver an approach to virological failure, delivering resistance genotyping, interpretation and clinical management to remote primary healthcare clinics without elaborate computer systems or infectious diseases specialists at each clinic. for each case, all laboratories (non-governmental, public and private) generate a report that includes clinical and resistance data. this report is sent to hiv specialists for review and feedback, to advise management at the primary clinic. meaningful interpretation of the results of genotypic resistance tests requires a detailed knowledge of the patient’s full arv history, including drug regimens used, vl and cd4 test results, any previous resistance test results, co-occurrence of other infections, and timelines. this information needs to be provided by the clinician/nurse upon submitting the resistance test. 4.1 surveillance of arv drug resistance the ongoing monitoring of arv drug resistance is a critical public health activity, particularly in settings where individualised arv drug resistance testing (genotyping) is not routinely performed prior to art initiation. the success of empiric art regimens depends on the regular and timely knowledge and review of the epidemiology of arv drug resistance. recommended systems for surveillance include prevalence monitoring of hiv genotype results at sentinel sites among populations who have recently acquired infection: e.g. recent seroconverters, hiv-infected pregnant women aged ≤21 years, infants infected despite arv exposure and those with acute hiv infection. there may also be additional value in prevalence monitoring at sentinel sites of arv drug resistance among those newly initiating therapy. 4.2 monitoring and evaluation the proportion of art-treated patients on first-line, second-line and subsequent therapy should be monitored routinely. because a detectable plasma vl while on art requires immediate intervention, national monitoring of the proportion of patients with detectable plasma vls is recommended. thresholds for response should be determined at the public health level. for example, a facility or geographic area with >20% detectable plasma viraemia in patients on arv who were previously undetectable, should urgently be investigated. analyses should be performed according to demographic and geographic characteristics, and reported quarterly to national hiv treatment programmes. the evaluation of the effect of hiv genotype testing on the selection of arv regimens and clinical outcomes should be supported through networks of clinical programmes. indicators to monitor the use of hiv genotype resistance assays should include: the number of assays per specified time period; the proportion of assays performed in adults, children and pregnant women; and the prevalence and type of resistance (including class of resistance and specific mutations). as the surveillance of arv resistance and clinical use of hiv genotyping increases, additional monitoring and evaluation activities may be required. most settings require increased capacity for monitoring and evaluation. resources to sustain adequate data management and interpretation are a public health priority. the net cost of incorporating resistance testing, for surveillance as well as patient management, needs to be evaluated carefully in arv programmes in southern africa.16 5. non-adherence: causes and interventions the adherence requirements of art are onerous, necessitating adherence rates >90% for first-line nnrti-based regimens. the best biological marker of adherence is an undetectable vl in patients on art. the regularity of pharmacy pick-ups is also a good marker of adherence. other strategies, including pill counts, have limited practical utility in busy clinics, and are often inaccurate.17 pill boxes and treatment supporters may be useful in selected individuals.18 a detectable vl in patients on art should be treated as a medical emergency, with immediate intervention, prompt evaluation by an experienced clinician and appropriate support staff (e.g. social workers, psychologists, and counsellors), and frequent follow-up. in the case of first-line virological failure, up to 50% of patients can re-suppress their vl,7 , 8 if virological failure is identified timeously, and if adherence can be improved. in patients failing second-line therapies, and where expensive third-line options are being evaluated, newer measures such as the use of electronic pill boxes (e.g. medication event monitoring system (mems) caps) and hair pi levels may be used, if available. in a significant minority of cases, patients will have no resistance on resistance testing. data from south africa reveal that this can be as high as 15 20% where patients have been genotyped.19 , 20 this means the patient is missing a large number of doses, consequently resulting in insufficient drug pressure to induce or select out existing resistance. these patients have a poorer prognosis, paradoxically, than patients with established resistance,21 , 22 as their poor adherence is often difficult to remedy, and may persist into subsequent regimen choices. such patients often require the intervention of a psychologist or experienced counsellor. common causes of poor adherence (sections 5.1 5.12) are often complex and linked to social issues. 5.1 inadequate treatment literacy most hiv programmes have extraordinary adherence rates when compared with other chronic diseases – largely due to efforts by clinic staff to ensure that patients understand hiv infection and art. if a patient fails therapy, then some examination of the pre-art counselling may be merited. 5.2 side-effects side-effects are a very common reason for patients to default therapy. a careful history of often subtle but distressing side-effects (bad dreams, sleepiness, poor concentration, nausea, loss of appetite), in conjunction with a work history (shift work in particular) may allow for drug substitutions. subtle signs of lipo-atrophy due to nrtis are often not taken seriously by healthcare providers. regular enquiry and immediate drug substitutions should form part of every healthcare worker encounter. single drug substitutions should only be performed if the vl is undetectable. 5.3 depression and mental illness undiagnosed or under-treated depression and other mental illnesses are often overlooked. the frequency of major depression is twice as high in hiv-infected patients as in matched hiv-negative patients.23 patients with depression usually respond well to treatement with an antidepressant in combination with other non-pharmaceutical interventions. patients who respond to antidepressant medication should be treated accordingly for at least 6 months. 5.4 poverty and food insecurity both poverty and food insecurity have been related to poor adherence and an increased frequency of missed clinic visits. patients often lose their jobs due to ill health in the period leading up to art initiation. patients should be encouraged to return to the job market as soon as is feasible, or to seek support. the need to seek work may cause patients to move away from the current clinic; therefore, referral must be facilitated. access to available grants, social support and employment ngos may provide additional support. 5.5 work-related issues work-related issues, including shift work and an inability to attend clinic visits on weekdays, are a major cause of poor adherence. long clinic waiting times and monthly medication pick-ups, may make holding down a job untenable, especially with an unsympathetic employer. 5.6 substance use alcohol use may cause significant problems with adherence. in addition, other recreational drugs may cause problems in certain parts of the country. use may fluctuate according to availability and peer pressure. 5.7 social problems social problems that affect adherence include stigma, both external and internal, and poor social support networks. perceived stigma is correlated with poor adherence. this may manifest in: a fear of tablets being found; an inability to solicit family or partner support; fear around visiting the clinic or pharmacy; or anxiety regarding an employer, neighbours or a community. social support groups may assist in this regard. 5.8 denial art initiation in ambivalent, conflicted patients is unlikely to have a successful outcome. the involvement of family members and partners may be an effective mechanism for addressing denial. 5.9 pill burden pill burden is less of an issue with current regimens, but must be considered in patients who are failing treatment. pill burden due to treatment for other conditions, such as hypertension or diabetes, should also be addressed. dosing simplification, such as provision of fixed-dose combination regimens, where possible, should be a major part of advocacy within public programmes. 5.10 altered fertility intentions hiv-discordant or -concordant couples may spontaneously decide to cease their art regimen with the intent to begin a family. empathetic fertility counselling during art initiation should prevent this from occurring. 5.11 conflict of opinions conflict of opinions on the use of arvs occurs frequently between healthcare providers, certain alternative health providers and churches. this is best addressed with an honest and non-judgmental conversation. 5.12 other drug doses should be checked, especially in patients referred from the private sector or inexperienced sites. drug interactions (e.g. rifampicin with a pi), absorption issues and primary acquisition of resistant virus may also result in failure. 6. laboratory objectives 6.1 recommendations and requirements a meaningful interpretation of genotypic resistance test results requires detailed knowledge of the patient’s full arv history, including drug regimens used, vl and cd4 test results, any previous resistance test results, and timelines. it is desirable that national databases be built, using unique patient identifiers (e.g. id numbers), to allow the easy retrieval of information for patients who have been cared for at different clinics and tested by different laboratories. besides improving patient care and easing clinical workload, this approach is cost-effective, as it prevents unnecessary repeat testing. all resistance test results (including clinical information and sequences obtained) should be entered into a central database, such as the one maintained by saturn, to enable research and surveillance. 6.2 genotypic arv resistance testing: practical issues testing requires ethylenediaminetetra-acetic acid (edta) whole blood or edta plasma (purple-top tubes). alternatively, where established, dried blood spots (dbss) may be used. to ensure sample integrity, whole-blood and plasma samples must be maintained and shipped cooled (4°c – fridge temperature) and reach the laboratory within 48 hours. for longer delays, whole-blood specimens must be centrifuged and the plasma stored at -20°c (frozen). repeat freeze-thaw cycles must be avoided. dbss can be maintained at room temperature for up to 4 weeks, and must be frozen at -20°c if the delay is longer than 4 weeks. current commercial tests have been licensed for specimens with a vl value of at least 1 000 rna copies/ml. if dbss are used, then the minimum usable vl is 2 000 5 000 rna copies/ml. nevertheless, many in-house assays can detect vls of 500 1 000 rna copies/ml. the probability of harbouring resistance in the vl range of 500 1 000 rna copies/ml is only marginally less than in the 1 000 10 000 copies/ ml range.24 the acquisition of additional mutations is not necessarily associated with incremental increases in vl.25 once a failing art regimen has been discontinued, most resistant viral variants quickly become undetectable. samples must therefore be obtained while the patient is still on the failing regimen or very shortly after discontinuation (to a maximum of 4 weeks). current test methods do not detect minority resistant viral variants (quasi-species present at less than approximately 20% of the total population) or archived resistance.26 even in the best hands, the rate of failure to amplify virus is 5 10%, so not all samples submitted to the laboratory will have a genotype result. 6.3 genotypic arv resistance assays currently available genotype tests evaluate only the viral reverse transcriptase and protease genes. mutations in the genes encoding these enzymes underlie resistance to the nrtis, nnrtis and pis. raltegravir (ral),27 , 28 the first of the integrase strand-transfer inhibitors (istis), is now registered in south africa. currently, no entry inhibitors – e.g. maraviroc (a ccr5 co-receptor inhibitor) or enfuvirtide (a fusion inhibitor ) – have been registered. future genotype tests will also need to incorporate these drug classes. current resistance testing is performed by means of polymerase chain reaction (pcr) amplification and sequencing/genotyping of the hiv-1 protease and reverse transcriptase genes, using commercial or validated in-house assays. the turnaround time of these assays is approximately 2 weeks. current united states food and drug administration (fda)-approved commercial assays, including viroseq and trugene, can be performed at a cost of approximately r5 000 per assay. in-house assays are about 50% cheaper. results can provide data on the presence or absence of resistance mutations, with resistance mutations interpretable by drug resistance algorithms, many of which are available online. 7. research priorities 7.1 resistance assays the main thrust of research activities remains the need to develop rapid, affordable, accessible resistance assays, including: • advocacy to drive down current commercial assay costs • the evaluation of innovative new testing approaches, e.g. the use of more cost-effective strategies such as allele-specific assays (e.g. m184v) to determine adherence • improved logistics using creative approaches such as dbs technology • national standardisation of technology and reporting across the country • continual review to ensure the incorporation of new drug classes into assays • integrase assays • tropism assays for ccr5 inhibitors • the constant evaluation of new testing platforms, e.g. ultra-deep sequencing strategies • the suitability of assays for relevant local hiv subtypes. 7.2 operational research activities 7.2.1 laboratory-based activities laboratory-based activities should include: • the upgrading and up-scaling of infrastructure, human resource skills, interpretation skills, and improved emergency reporting within and by the laboratory • national data flow and reporting • a monitoring and evaluation framework to evaluate the effect of the intervention • ongoing cost-effectiveness modelling and analyses to assess cost-effectiveness • ensured support for strengthened national surveillance activities (i.e. increased numbers processed in realtime). 7.2.2 clinical activities clinical activities must include: • strategies to develop a hierarchy of specialist support for interpretation, e.g. failure clinics • resistance testing to support ongoing clinical research and guideline development • strategising for the components of an appropriate standardised third-line regimen. 7.2.3 basic research questions future work should address: • the contribution of detecting minority variants and their effect on patient outcome (including ultra-deep sequencing) • the significance and role of pi mutations in the local population • the development of a national reference facility that conducts phenotyping and other sophisticated assays to support and develop a strong scientific agenda for resistance testing. 8. closing comment these guidelines reflect the current status quo in terms of levels of hiv resistance in southern africa in late 2012, and will be reviewed every few years. implementation of the recommendations herein will require a drastic expansion of the laboratory capacity in the region. conflict of interest. all expert panel members and reviewers have completed and submitted conflict of interest disclosure forms. disclosure information represents the previous 3 years (updated 13 october 2012) and pertains to relationships with pharmaceutical companies and medical aids. f conradie has received research support from bristol-myers squibb, gilead, glaxosmithkline and tibotec. she is also a consultant for discovery health. l levin has received honoraria from abbott, aspen, novagen, optipharm and viiv healthcare for speaking engagements, and served as a consultant to optipharm and discovery health. g meintjes has received honoraria from sanofi-aventis for speaking engagements and is a consultant to aid for aids. c orrell received funding support from merck sharp & dohme (msd) to attend a workshop, and received honoraria from abbott for a speaking engagement. t rossouw received honoraria from abbott for a speaking engagement, and serves as a consultant to discovery health. d spencer has received honoraria from abbott, adcock ingram, aspen, msd and janssen for speaking engagements. h sunpath received research support from gilead sciences. g van zyl has received honoraria from abbott for speaking engagements. f venter has received support from adcock ingram to attend conferences and honoraria from johnson and johnson, merck and tibotec for speaking engagements. a basson, t de oliveira, g hunt, d joel, m papathanasopoulos, w preiser, j klausner, w stevens, c van vuuren and d wilson have no conflicts of interest to declare.   acknowledgement. this work was supported and funded by the southern african hiv clinicians society through an educational grant from atlantic philanthropies. the authors wish to acknowledge lynsey isherwood for her assistance in the development of this document. references 1. kantor r, shafer rw, follansbee s, et al. evolution of resistance to drugs in hiv-1-infected patients failing antiretroviral therapy. aids 2004;18(11):1503-1511. 1. kantor r, shafer rw, follansbee s, et al. evolution of resistance to drugs in hiv-1-infected patients failing antiretroviral therapy. aids 2004;18(11):1503-1511. 2. world health organization (who). hiv resistance report, 2012. geneva: who, 2012. http://www.who.int/hiv/pub/drugresistance/report2012/en/index.html (accessed 9 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[http://dx.doi.org/10.1002/14651858.cd001442.pub2] 20. rosen s, long l, sanne i, stevens ws, fox mp. the net cost of incorporating resistance testing into hiv/aids treatment in south africa: a markov model with primary data. j intl aids soc 2011;14:24. 20. rosen s, long l, sanne i, stevens ws, fox mp. the net cost of incorporating resistance testing into hiv/aids treatment in south africa: a markov model with primary data. j intl aids soc 2011;14:24. 21. marconi vc, sunpath h, lu z, et al. prevalence of hiv-1 drug resistance after virologic failure of first-line antiretroviral therapy (art) in a resource-limited setting: initial results of the south africa resistance cohort study (sarcs). cid 2008;46:1589-1597. 21. marconi vc, sunpath h, lu z, et al. prevalence of hiv-1 drug resistance after virologic failure of first-line antiretroviral therapy (art) in a resource-limited setting: initial results of the south africa resistance cohort study (sarcs). cid 2008;46:1589-1597. 22. orrell c, harling g, lawn sd, et al. conservation of first-line antiretroviral treatment regimen where therapeutic options are limited. antivir ther 2007;12(1):83-88. 22. orrell c, harling g, lawn sd, et al. conservation of first-line antiretroviral treatment regimen where therapeutic options are limited. antivir ther 2007;12(1):83-88. 23. nakasujja n, skolasky rl, musisi s, et al. depression symptoms and cognitive function among individuals with advanced hiv infection initiating haart in uganda. bmc psychiatry 2010;10:10-44. 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[http://dx.doi.org/10.1016/s0140-6736(09)60918-1] guidelines gayle g sherman, me bch, dch (sa), dtm&h, mmed (haem) department of molecular medicine and hamullofggy.johannesburg hospiuzl. nazional health labararory service and university of cbe wi",,,,umand, ]oiuznmjlnng infant hn diagnostic guidelines to facilitate adoption !>errings: guidelines for a public health approach. geneva: who, 20025. harries ad, nyangu1u os. hargreaves nj, kaluwa 0, salaniponi fm. pr~enting antiretroviral anarchy in sub-saharan africa lancet 2001; 358: 410-414. 6. lrli gc, vitoria ma. fighting against aids: tn/:' brazilian ~jence. aids 2002; 16: 2373~238j. 7. farmtt p, ~nd(e f, mukherjee 15, ~r al community-based approach~ to hiv uea!metlt in (~urct·poor settings.. lona:r200l; 358: 404-409. a soulle a. kenyan c. skordis j, wood r. rationing haart part i: an ~iotation of the rosts of a limited public sector antiretroviral ueatmem programm~ in south africa. saf, mn)2002; 92: 811-817. 9. bredeu consetlsus statement on the irrperative to expand acttss to antireuoviraj medicin~ fur adults and o1ildren with hfv{a1ds in south africa. noveffloo2001. national tret1tmenr congress resourct docum~nr numb~r 12. cape town: treatment action campaign. 10. report on the global hivialds epidemic. joint united nations programme on hn!alds (una/osj. geneva: unaids, july 2002. 11. egger m, may m, chene g, et al. prognosis of hiv-1-infe<:ted patients starting highly active antiretroviral tilerapy: a collaborative analysis of prospective studies. lancer 2002; 360: 119-129. 12. southern african hiv clinicians society. clinical guidelines: antiretroviral therapy in adults. june 2002 vtrsion. sourhern african journal of hn medicine 2002; july (issue 8): 22~29. the qualitative hiv polymerase chain reaction (pcr) test is highly specific for hiv infection, but sensitivity varies with the age of the infant' the per identifies approximately 50% of infected infants at or just after birth and> 95% at 3 6 months of age" more recent evidence suggests that hiv pcr tests performed at ~ 1 month of age have a sensitivity of ~ 95% and specificity of > 99<\'0.' the roche amplicor kit (roche molecular systems, somerville, nj) ------------the southern african journal of hiv medicine 1. morcroft po, \/tlla 5, benfield n.. eta/' changing mortality across europe in patients infected with hn-1. lancet 1998; 352: 17251730. moore ro, chaisson re. natural history of hiv infection in the era of combination antiretroviral therapy. aids 1999; 13: 1933-1942 3. palella fj, dejaney km, moorman ac, er 01. declining morbidity and mortality among patients with advanced human immunodeficiency virus in~tion. n englj mm 1998; 338: 853-860. 4 world health organisation. scaling up anrirecrovirol therapy in r~itt-lim;red subsequent or second-line regimen would be pi-based. references any interested treaters who would like to participate should e-mail the managing editor of the southern african journal of hiv medicine at igbekker@cormack.uctac.za, expressing the number of patients likely to be treated at their site in the next year. south africa is currently estimated to have 300 000 hiv/aids orphans, and the figure is likely to increase to 2 million by 2015.' facilitating adoption of children affected by hiv provides a highly effective strategy for addressing the hiv/aids orphan crisis, albeit on a very small scale. the legal and ethical issues surrounding hiv testing of abandoned children for the purposes of adoption are not addressed here. these guidelines were contributed to and are endorsed by: or ashraf h coovadia department of fljediorrics, coronation hospital, and university of the witwatersrand or mark f cotton fljediatric infectious disease unit tygerberg children's hospito( university ofste/lenbosch or glenda e gray perinatal hiv research unit chris hani-barogwanath hospital and university of the witwatersrand professor gregory 0 hussey school of child and adolescent health, university of cape town or leon j levi n puediatn·cian in pfnate practice or tammy m merers department of fljediatrics, chris hani-baragwanath hospital and university of the witwatersrand professor lynn morris aids unit national institute for communicable diseases and university of the witwatersrand or adrian j puren national institute for communicable diseases and university of the witwatersrand or wendy 5 stevens department of molecular medicine and haematology. national health laborotory service and university of the witwatersrond or lynne m webber department ofmedical virology, university of pretoria may 2003 hiv diagnostic protocol for adoptlon purposes 6 weeks of age hiv eusa to assess hiv exposure at birth [omit if the hiv eusa of the mother is eonfirmed positive) oualitative hiv pcr if the hiv eusa of the infant (or the mother) is reactive 3 months of age qualitative hiv pcr to eonfirm result of pcr at 6 weeks of age notes 1. clinical examination to assess for stigmata of hlv infection should be performed at 6 weeks and 3 months of age.. the 6-week clinical examination, when stigmata of hiv infection may be less evident, is likely to be less helpful than the 3-rnonth o:amination. 2. at 6 weeks of age, blood should be taken for both hiv eusa and per tests and the per analysed only if the hiv eusa test result is reactive. 3. postnatal transmission of hiv infection is likely to be evident by 6 weeks after termination of breast-feeding; nevertheless it is recommended that the final qualitative hiv per test be performed 3 months after breast-feeding has ceased. interpretation two concordant qualitative hlv per results in an appropriate clinical context confirm the hiv status of the child. discrepant per results require further investigation. ------------the southern mrican journal of hi mfoicinf references all abandoned neonates estimated to be,.; 72 hours of age should be given post-exposure prophylaxis. if logistics are in place for obtaining hn test results quickly, only hivexposed neonates should be treated. it is theoretically possible for an hn-exposed child to have a non-reactive hiv ellsa if the mother seroconverted late in pregnancy or, less plausibly, if she was terminally ill towards the end of the pregnancy. both situations are associated with a high viral load and increased propensity for vertical transmission of hiv. the suggested diagnostic guidelines would not detect neonates exposed to hiv under these circumstances unless they presented with clinical stigmata. despite the high prevalence of hiv in south africa, it is expected to be rare for an hn-exposed child to have a non-reactive hiv ellsa test, so qualitative hiv pcr testing of every child being investigated for adoption is not warranted. 1. johtl5ofl l. dooington r the impact of aids on orphanhood in south africa: a quanorativ(' analysis.. centre fut actuarial r~rch: monograph no. 4. 2001. isbn 0799220892. www.commerce.uct.ac.za/care/monographs/monographs/monoo4.pdf (accessed 22 may 2ooj}. 2. working group on antirecroviral therapy: narional pediatric hiv resource cent{'/". antiretroviral therapy and medical management of the human immunodeficiency virus-infected child. pediatr infecedisj 1993; 12: 513-522 j. (enters for disease control. 1995 r~sed guiddines for prophylaxis against pneumocystis rorinii pneumonia for children infecred with or ~narally &posed to human immunodeficiency virus. mmwr morbid motrol wily r~ 1995; 44(rr-4i: 1-11. 4. &njamin ok, mill{'/" we, fiscus sa. eeol rational resting of the hn-exposed inf.int peaiorric:s 2001; 10s{ti: ej. 5. american acaaemy of fled.attics. eva1udtion ana mttiicaj treatmer.r of the hnexposed infant. pediatnes 1997; 99{6): 909-917. adoptive parents need to be aware of the fact that despite comprehensive general medical examinations and testing, there is no guarantee of a completely healthy child. in the context of hiv testing, this applies to the possibility of a negative hiv ellsa in an hiv-exposed child, as well as the recommendation to do the final hiv pcr test at 3 months instead of the exceptionally expensive and extreme recommendation of an hiv eusa at 24 months of age."" performing additional hn tests is unlikely to yield different results from those achieved using the diagnostic guidelines suggested above. current hiv diagnostic guidelines for perinatally exposed infants recommend that hiv infection be confirmed by 2 positive hiv pcr tests performed on different samples. negative hn infection status is established if 2 hiv pcr tests, the first at ~ 1 month of age and the second at ~ 4 months, are negative in a non-breast-fed infant. to determine definitively that the child is not infected, seroreversion should be demonstrated by 2 negative hiv enzyme-linked immunosorbent assay (eusa) tests, the final one performed at 24 months of age.'-s version 1.5, which has shown excellent sensitivity and specificity in the south african setting, is the recommended qualitative (dna) pcr test there are no published hiv diagnostic guidelines for facilitating adoption. such guidelines require a balance between making an accurate diagnosis of the child's hiv infection status and doing so as early in life as possible, factoring in practicalities and cost considerations. the second pcr test is done to confirm the first pcr result and to guard against technical or sample mix-up errors. this could be achieved by re-testing as soon as possible after the first pcr test result is known," but performing the second pcr at an older age increases the sensitivity of the test by detecting the < 5% of infants who will test positive for the first time after 1 month of age. the recommended hn diagnostic protocol for adoption purposes is explained in the box above the possibility that antiretroviral therapy used in prevention of mother-to-child transmission (pmtcn programmes may affect the timing of the pcr testing in infancy has not been substantiated.' local data on clinical stigmata of hiv at 6 weeks and 3 months of age and the sensitivity and specificity of qualitative hiv pcr as well as the influence of nevirapine for pmtct on the timing of pcr testing are expected shortly. these diagnostic guidelines are likely to evolve as new data and technical improvements in testing become available.' may ~003 40 sajhivmed march 2013, vol. 14, no. 1 cpd questionnaire vol. 14, no. 1 true (a) or false (b): regarding hiv-related lipodystrophy: 1. the lipodystrophy syndrome is most commonly characterised by lipohypertrophy with lipomatosis. 2. in terms of the effect of antiretroviral therapy (art) on lipodystrophy, an increase in trunk fat has been observed with efavirenz-, protease-inhibitorand raltegravir-containing regimens, and a clear causal relationship has been established. 3. the metabolic complications of lipodystrophy are fully reversible through treatment modification. regarding partner concurrency and hiv: 4. it is widely accepted that partner concurrency (having more than one sexual partner in a given period of time) is a major determinant of the spread of hiv in south africa. 5. across south african language groups, multiple partners per year, point concurrency and lower condom utilisation rates are all associated with increased hiv prevalence by language group. 6. the spread of hiv is driven by the degree of connectedness of the sexual network. regarding stavudine dosing: 7. obesity, female gender, age and duration of treatment are the risk factors increasing the possibility of severe hyperlactataemia and lactic acidosis when patients are on stavudine-containing art regimens. 8. following a meta-analysis showing that lower doses of stavudine were safer and just as effective, the world health organization (who) issued a statement that only a low dose of stavudine (30 mg) should be used. regarding screening for hiv-associated neurocognitive disorders (hands): 9. hands are commonly diagnosed by comparing neuropsychological scores with normative data using standard deviation as an indicator of impairment. 10. using general scores from african samples is appropriate when placing people in categories of impairment using standard deviation from normative scores. 11. figures from south africa suggest that up to 25% of hivpositive individuals may display cognitive impairment. regarding adolescent hiv treatment services: 12. the transition for young people living with hiv from paediatric/adolescent hiv healthcare providers to adult hiv healthcare providers is a major challenge. 13. a large number of healthcare programmes are tailored specifically for behaviourally infected adolescents and young adults with hiv in sub-saharan africa. this group represents one of the few demographic groups adequately served by the various healthcare systems. 14. adjusting to the concept of adult healthcare, adult-oriented clinic environments as well as a perceived sense of stigma are key challenges faced by young people transitioning into adult care services. regarding gender inequality in art: 15. in african cohorts, women have higher mortality while receiving art than men. 16. disproportionately more women than men have accessed art in south africa – 60 % of eligible women were receiving art by mid-2011 compared with 40% of eligible men. regarding the prevention of mother-to-child transmission (pmtct) of hiv: 17. there is overwhelming global consensus that all hivpositive pregnant women should be started immediately on lifelong art regardless of cd4 cell count. 18. there is clear evidence that exposure to art has no effect on pregnancy outcomes such as preterm delivery and low birth weight. regarding who guidelines for adult art: 19. who currently recommends that adults living with hiv start art when their cd4 counts fall below 500 cd4 cells/ µl. 20. there are clear benefits to individual patient health associated with art initiation above 350 cells/µl. c p d q u e s t io n a ir e five cpd points are awarded for the correct completion and submission of the questions below. cpd questionnaires must be completed online via www.cpdjournals.co.za. after submission, you can check the answers and print your certificate. this programme is available free of charge to members of the sa hiv clinicians society and sama only. instructions 1. read the journal. all the answers will be found there. 2. go to www.cpdjournals.co.za to answer the questions. accreditation number: mdb001/011/01/2013 (clinical) abstract introduction patients and methods results discussion conclusion acknowledgements references appendix about the author(s) eric h. decloedt division of clinical pharmacology, department of medicine, faculty of medicine and health sciences, stellenbosch university, cape town, south africa division of clinical pharmacology, department of medicine, faculty of health sciences, university of cape town, cape town, south africa phumla z. sinxadi division of clinical pharmacology, department of medicine, faculty of health sciences, university of cape town, cape town, south africa lubbe wiesner division of clinical pharmacology, department of medicine, faculty of health sciences, university of cape town, cape town, south africa john a. joska department of psychiatry and mental health, health sciences, groote schuur hospital, university of cape town, cape town, south africa david w. haas department of medicine, vanderbilt university medical center, vanderbilt university, nashville, tennessee, united states department of internal medicine, meharry medical college, nashville, tennessee, united states gary maartens division of clinical pharmacology, department of medicine, faculty of health sciences, university of cape town, cape town, south africa citation decloedt eh, sinxadi pz, wiesner l, joska ja, haas dw, maartens g. pharmacogenetics of tenofovir and emtricitabine penetration into cerebrospinal fluid. s afr j hiv med. 2021;22(1), a1206. https://doi.org/10.4102/sajhivmed.v22i1.1206 original research pharmacogenetics of tenofovir and emtricitabine penetration into cerebrospinal fluid eric h. decloedt, phumla z. sinxadi, lubbe wiesner, john a. joska, david w. haas, gary maartens received: 22 dec. 2020; accepted: 09 mar. 2021; published: 28 apr. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: blood-cerebrospinal fluid (csf) barrier transporters affect the influx and efflux of drugs. the antiretrovirals tenofovir and emtricitabine may be substrates of blood-brain barrier (bbb) and blood-csf barrier transporters, but data are limited regarding the pharmacogenetics and pharmacokinetics of their central nervous system (cns) penetration. objectives: we investigated genetic polymorphisms associated with csf disposition of tenofovir and emtricitabine. method: we collected paired plasma and csf samples from 47 hiv-positive black south african adults who were virologically suppressed on efavirenz, tenofovir and emtricitabine. we considered 1846 single-nucleotide polymorphisms from seven relevant transporter genes (abcc5, abcg2, abcb1, slco2b1, sclo1a2, slco1b1 and abcc4) and 782 met a linkage disequilibrium (ld)-pruning threshold. results: the geometric mean (95% confidence interval [ci]) values for tenofovir and emtricitabine csf-to-plasma concentration ratios were 0.023 (0.021–0.026) and 0.528 (0.460–0.605), respectively. in linear regression models, the lowest p-value for association with the tenofovir csf-to-plasma ratio was abcb1 rs1989830 (p = 1.2 × 10−3) and for emtricitabine, it was abcc5 rs11921035 (p = 1.4 × 10−3). none withstood correction for multiple testing. conclusion: no genetic polymorphisms were associated with plasma, csf concentrations or csf-to-plasma ratios for either tenofovir or emtricitabine. keywords: pharmacokinetics; pharmacogenetics; tenofovir; emtricitabine; cerebrospinal fluid. introduction tenofovir and emtricitabine are part of the current first-line antiretroviral therapy (art) regimens for hiv-positive adults in resource-limited settings and both are widely used in high-income countries.1 infection of the central nervous system (cns) by hiv-1 occurs early in infection and its clearance is reliant on adequate cns antiretroviral concentrations.2 however, there are limited data regarding determinants of cerebrospinal fluid (csf) penetration by tenofovir and emtricitabine. data from small cohorts indicate that csf concentrations of tenofovir and emtricitabine are 5% and 50% of plasma concentrations, respectively.3,4,5 however, higher csf tenofovir concentrations and lower emtricitabine concentrations have been reported, which may be explained by polymorphisms in drug transporters or altered blood–brain barrier (bbb) permeability.4,5 transporters in the bbb and blood–csf barrier (bcb) affect the influx and efflux of drugs, including tenofovir and emtricitabine.3,6,7 multidrug resistance protein-5 (mrp-5, encoded by abcc5) is ubiquitous and mediates the efflux of nucleoside reverse transcriptase inhibitors.8 lower csf emtricitabine exposure in females compared to males is hypothesised to reflect differential expression of mrp transporters at the bbb and bcb.3 in vitro, tenofovir is a substrate of the breast cancer resistance protein (bcrp, encoded by abcg2), mrp-4 (encoded by abcc4) and p-glycoprotein (encoded by abcb1).9,10,11 a polymorphism in abcg2 rs2231142 has been associated with 1.5-fold increased plasma tenofovir exposure and thai patients carrying abcc4 3463 ag or gg (rs1751034) had an 11% greater tenofovir clearance compared with aa.12,13 loss-of-function abcc4 polymorphisms have been associated with reduced clearance of tenofovir.11,14 in genome-wide analyses, slc17a1 rs12662869 was associated with an increase in tenofovir clearance.15 it is possible that genetic polymorphisms that affect transporter function will affect tenofovir or emtricitabine csf penetration. the pharmacogenetics of csf penetration of tenofovir and emtricitabine have not been described. africans are the most genetically diverse population worldwide.16 south africa has the world’s largest art programme, with most patients currently receiving efavirenz-based regimens that include the nucleos(t)ides tenofovir and emtricitabine.17 we previously reported on the pharmacogenetics of csf penetration of efavirenz in black south africans.18 here, we characterise the associations between transporter gene polymorphisms and csf penetration of tenofovir and emtricitabine in the same cohort. patients and methods participants adults (≥ 18 and ≤ 70 years of age) from a randomised control trial (pactr201310000635418) that investigated lithium for hiv-associated neurocognitive impairment were invited to participate in the present study.19 we also invited participants who were screened for that trial but were excluded based on cognitive impairment criteria. all participants provided written informed consent. this study was approved by the university of cape town human research ethics committee (hrec 071/2013). pharmacokinetic sampling we collected paired plasma and csf samples for tenofovir and emtricitabine assays. participants recorded the dosing time the night before and were admitted in the morning for pharmacokinetic sampling. whole blood was collected within 45 min of csf sampling and centrifuged within 1 h of collection. plasma and csf aliquots were stored at −80 °c until analysis. tenofovir and emtricitabine measurement the analytical laboratory in the division of clinical pharmacology at the university of cape town quantified total tenofovir and emtricitabine in plasma and csf using validated liquid chromatography tandem mass spectrometry assays. the lower limits of quantification (llqs) for plasma tenofovir and emtricitabine were 10.0 ng/ml and 37.5 ng/ml, respectively. for csf, the llqs for total tenofovir and emtricitabine were 0.5 ng/ml. concentrations below the limits of quantification were treated as missing data. characterisation of genetic polymorphisms we extracted dna from the buffy coat using the qiasymphony kit. genotyping was performed using the infinium® expanded multi-ethnic genotyping array (megaex; illumina, san diego, ca, usa). polymorphisms that were not genotyped were imputed. polymorphisms were extracted from seven genes ±50 kb: abcb1 (301 polymorphisms), abcc4 (630 polymorphisms), abcc5 (225 polymorphisms), abcg2 (164 polymorphisms), slco1a2 (406 polymorphisms) and slco2b1 (118 polymorphisms). polymorphisms were excluded for genotyping efficiency less than 99%, minor allele frequency less than 5% and hardy-weinberg equilibrium p-values less than 0.00001. we also genotyped slco1b1 521t→c (rs4149056) and slco1b1 (rs4149032) using the massarray iplex® gold system (sequenom, inc., san diego, ca, usa). all genotyping was performed at vanderbilt technologies for advanced genomics (vantage), by laboratory personnel with no knowledge of clinical data. all samples were genotyped in duplicate. the final dataset included 1846 polymorphisms from 47 participants. pharmacokinetic statistical analysis pharmacokinetic data were not normally distributed so were expressed as median and interquartile ranges (iqrs) and geometric means (95% confidence interval [ci]). pearson’s r correlation was used to assess the correlations between plasma and csf concentrations. we performed statistical analysis using stata version 15.0 (statacorp, college station, tx, usa). graphs were created using graphpad prism version 7.03 for windows (graphpad software, la jolla, ca, usa). genetic associations associations with pharmacokinetic parameters were assessed by univariable analysis. pharmacokinetic data were log10 transformed for association analyses. we used ratios of total concentrations without correcting for protein binding. cerebrospinal fluid-to-plasma concentration ratios were calculated using raw concentrations and then log10 transformed. we performed genetic association analyses using plink version 1.9.20 for primary analyses, we conducted linkage disequilibrium (ld) pruned with an r2 threshold of 0.95 within a 50-kb window at 5-kb increments. the final analysis included 782 polymorphisms that met the ld-pruning threshold. we used bonferroni correction to adjust for multiple testing (p = 0.05 divided by 782 polymorphisms). we generated an ld plot using haploview (https://www.broadinstitute.org/haploview/haploview). we previously reported ld plots for these polymorphisms.18 ethical considerations all participants provided written informed consent. this study was approved by the university of cape town human research ethics committee (hrec 071/2013). results we studied 47 participants who self-identified as black south africans (isixhosa speaking), of whom 41 were female. all were virologically suppressed and were receiving efavirenz, tenofovir and emtricitabine (n = 43) or efavirenz, tenofovir and lamivudine (n = 4). the median (iqr) values of the baseline characteristics were age 36 (iqr = 32–43) years, a cd4 t-cell count of 470 (iqr = 384–586) cells/mm3, a time on art of 38 (iqr = 18–54) months and a body mass index (bmi) of 25.6 (iqr = 22.7–29.3) kg/m2. the concentrations of tenofovir (plasma and csf) and emtricitabine (plasma and csf) are presented in table 1. the plasma and csf concentrations of tenofovir and emtricitabine were each correlated (p < 0.0001, r2 = 0.53 and p < 0.0001, r2 = 0.45; respectively) (appendix figure 1a and 1b). there was no statistically significant association of csf-to-plasma ratios versus time after dosing (appendix figure 2). table 1: concentrations of tenofovir and emtricitabine in plasma and cerebrospinal fluid. genetic polymorphisms amongst the 47 participants, 1846 polymorphisms were successfully genotyped. only slco1b1 rs4149056 was monomorphic (i.e. no minor alleles). the remaining 1845 polymorphisms were in hardy–weinberg equilibrium based on a bonferroni-adjusted p-value threshold of 6.4 × 10−5; 56 had unadjusted bonferroni p-values of < 0.05. minor allele frequencies for all polymorphisms are provided in appendix table 1. genetic associations with tenofovir and emtricitabine cerebrospinal fluid penetration in univariable linear regression analyses (table 2), the tenofovir csf-to-plasma ratio was best predicted by a model that included abcb1 rs1989830 (β = −0.12; 95% ci = −0.19 – –0.05; p = 1.2 × 10−3). the emtricitabine csf-to-plasma ratio was best predicted by a model that included abcc5 rs11921035 (β = −0.32; 95% ci = −0.50 – –0.14; p = 1.4 × 10−3), as shown in table 3. no association achieved significance after correcting for multiple testing. univariable linear regression analyses and polymorphisms with p-values below 0.01 for tenofovir and emtricitabine csf-to-plasma ratios are shown in tables 2 and 3, respectively. for absolute plasma and csf tenofovir concentrations, 10 polymorphisms in abcg2, abcc5, slco1a2 and abcc4 for plasma and six in abcb1, abcg2, abcc5, slco1a2 and abcc4 for csf had p-values less than 0.01 (data not shown). for absolute plasma and csf emtricitabine concentrations, six polymorphisms in abcc5, slco1a2, abcc4 and slco2b1 for plasma and 12 in abcb1, abcg2, abcc5, slco1a2 and abcc4 had p-values less than 0.01 (data not shown). no associations with slco1b1 rs4149032 were found. table 2: genetic associations with detectable log10-transformed cerebrospinal fluid-to-plasma tenofovir concentrations in 43 black south african adults. table 3: genetic associations with detectable log10-transformed cerebrospinal fluid -to plasma emtricitabine concentrations in 39 south african adults. discussion we characterised the associations between 782 genetic polymorphisms and csf disposition of tenofovir and emtricitabine in black south african adults. the lowest p-value for tenofovir csf-to-plasma ratio was abcb1 rs1989830 (p = 1.2 × 10−3), and for emtricitabine was abcc5 rs11921035 (p = 1.4 × 10−3). none were significant after correcting for multiple testing. in addition, we found no significant associations with absolute csf or plasma concentration after correcting for multiple testing. associations with tenofovir pharmacokinetics and genetic polymorphisms were found in other populations. an increase in tenofovir plasma concentrations were independently associated with abcc4 4131t→g (genotype tg or gg) in 150 thai hiv-infected adults.14 abcb1 rs3213619 was associated with increased tenofovir bioavailability in a predominantly african-american patient population (n = 45) and thought to be a result of decreased p-glycoprotein function.21 a genome-wide and candidate gene association analyses with tenofovir pharmacokinetics showed that slc17a1 rs12662869 was associated with an increase in tenofovir clearance (p = 7.1 × 10−9) but failed to show significant associations in candidate genes (including abcc4, abcc10, abcb1, abcc2, slc22a11, ak2 and ak3) after correction for multiple comparisons.15 our study has limitations. with our sample size, we were underpowered to detect associations with small effect sizes. we could only detect associations with relatively frequent polymorphisms and with large effect sizes. therefore, these data should be regarded as exploratory. polymorphisms not genotyped in our study may be associated with tenofovir or emtricitabine disposition into csf. whilst we did not adjust for creatinine clearance, this should not be a confounder that affects drug disposition into csf. we included 33 (70%) participants with mild to moderate neurocognitive impairment, as previously reported.18 we may therefore have introduced a selection bias. conclusion in conclusion, we found no significant associations between any of the 782 polymorphisms and plasma concentrations, csf concentrations or csf-to-plasma ratios for either tenofovir or emtricitabine in univariate linear regression models after correcting for multiple testing. acknowledgements the authors are grateful to the study participants. the study team in alphabetical order includes laura comrie (clinical support), carla freeman (clinical support), shahieda isaacs (viral sequencing), pam jordan (data capturer), teboho linda (neuropsychology technician). nozipho mawisa (study nurse), queen maswana (recruiter), rasmita ori (clinical support), kareema poggenpoel (administration support) and shireen surtie (study coordinator). the authors are also grateful to cara sutcliffe and the vantage team at vanderbilt. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions e.h.d. was responsible for the study concept and design, data acquisition, data analysis and interpretation of data, drafting and revising the manuscript for content, study supervision and obtaining funding. p.z.s. contributed to data analysis and interpretation of data and drafted and revised the manuscript for content. l.w. conducted the sample analysis and revised the manuscript for content. j.a.j. contributed to the study concept and design, revised the manuscript for content and supervised the study. d.w.h. conducted the sample analysis and data analysis, interpreted the data and revised the manuscript for content. g.m. contributed to the study concept and design and revised the manuscript for content. funding information this work was supported by the south african medical research council and the european and developing countries clinical trials partnership (sp.2011.41304.065). the drug assays analysed at the university of cape town were supported in part by the national institute of allergy and infectious diseases of the national institutes of health (um1 ai068634, um1 ai068636, um1 ai106701 and u01 ai068632), the eunice kennedy shriver national institute of child health and human development (nichd) and the national institute of mental health (ai068632). d.w.h. is supported by national institutes of health grants ai077505, ai069439 and tr002243. data availability the data that support the findings of this study are available from the corresponding author, e.h.d., upon reasonable request. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references world health organization (who). first-line art for adults [homepage on the internet]. 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http://apps.who.int/gho/data/node.main.626?lang=en2017 decloedt eh, sinxadi pz, van zyl gu, et al. pharmacogenetics and pharmacokinetics of cns penetration of efavirenz and its metabolites. j antimicrob chemother. 2019;74(3):699–709. https://doi.org/10.1093/jac/dky481 decloedt eh, freeman c, howells f, et al. moderate to severe hiv-associated neurocognitive impairment: a randomized placebo-controlled trial of lithium. medicine. 2016;95(46):e5401. https://doi.org/10.1097/md.0000000000005401 purcell s, neale b, todd-brown k, et al. plink: a tool set for whole-genome association and population-based linkage analyses. am j hum genet. 2007;81(3):559–575. chen j, akhtari fs, wagner mj, et al. pharmacogenetic analysis of the model-based pharmacokinetics of five anti-hiv drugs: how does this influence the effect of aging? clin transl sci. 2018;11(2):226–236. https://doi.org/10.1111/cts.12525 appendix figure 1-a1: pearson correlation plots for log10-transformed plasma and cerebrospinal fluid (csf) concentrations emtricitabine and tenofovir. panel a: relationship between csf and plasma tenofovir concentrations. panel b: relationship between csf and plasma emtricitabine concentrations. all concentrations are log10 transformed. figure 2-a1: cerebrospinal fluid (csf)-to-plasma concentration ratios of detectable pairs of plasma and csf samples versus time after dosing. the lines are linear regression lines and were not statistically significant. table 1-a1: minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. table 1-a1 (continues...): minor allele frequencies for 1846 polymorphisms in 43 black south africans. abstract introduction methods results discussion strengths and limitations of the study conclusion acknowledgements references about the author(s) mildred lusaka department of nursing and midwifery, faculty of medicine and health sciences, stellenbosch university, cape town, south africa talitha crowley department of nursing and midwifery, faculty of medicine and health sciences, stellenbosch university, cape town, south africa citation lusaka m, crowley t. administering human immunodeficiency virus post-exposure prophylaxis: challenges experienced by mothers in lusaka, zambia. s afr j hiv med. 2021;22(1), a1183. https://doi.org/10.4102/sajhivmed.v22i1.1183 original research administering human immunodeficiency virus post-exposure prophylaxis: challenges experienced by mothers in lusaka, zambia mildred lusaka, talitha crowley received: 22 oct. 2020; accepted: 16 dec. 2020; published: 27 jan. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: mothers living with human immunodeficiency virus (hiv) should be guided to practise safe childbirth, provide appropriate infant feeding, return infants for repeat hiv testing and administer for the required period, protective antiretroviral (arv) medication (post-exposure prophylaxis [pep]) to their infants. although several studies have explored challenges related to the prevention of mother-to-child transmission (pmtct), no studies were found that focused specifically on the mother and pep. objectives: to explore and understand the challenges experienced by mothers in lusaka, zambia, whilst providing their children with pep. methods: this study utilised a qualitative methodology and a descriptive design. fifteen semi-structured individual interviews were conducted with mothers who gave pep to their infants. study evaluation made use of creswell’s six steps of data analysis. results: women experienced numerous challenges. challenges of an individual and social nature included ‘negative’ emotions, misconceptions and a lack of understanding of pep. post-exposure prophylaxis was sometimes burdensome and partner involvement often limited. cultural, religious practices and stigma deterred some women from continuing pep. healthcare challenges included time-consuming appointments and protracted waiting periods. clinic organisation was often inefficient and complicated by stock-outs of essential medication such as nevirapine. healthcare workers were at times stigmatising towards mothers living with hiv and their infants. the counselling support provided by the healthcare workers was felt to be inadequate in the face of the burden of pep. conclusion: post-exposure prophylaxis as part of the pmtct programme is key to eliminating mother-to-child transmission of hiv. postnatal support for women administering pep to their children can be enhanced through counselling that is personand family-centred is culturally sensitive and offers differentiated services that include pep, integrated mother-and-child healthcare and access to support groups. keywords: mother-to-child transmission of hiv; post-exposure prophylaxis; prevention of mother-to-child-transmission of hiv; challenges. introduction approximately 90% of new human immunodeficiency virus (hiv) infections of children and most acquired immunodeficiency syndrome (aids)-related paediatric deaths occur in africa.1,2 in 2019, 150 000 children globally were ‘newly infected’ with hiv.1 most acquire hiv infection vertically, that is, from their mothers. the unaids target of eliminating mother-to-child transmission in africa by 2030 is still a long way off.2 numerous randomised clinical trials (rcts) have confirmed the efficacy of antiretroviral (arv) drugs both as treatment and as prevention of hiv.3 the widespread and consistent use of arvs in prevention, antiretroviral treatment (art) and infant–mother post-exposure prophylaxis (pep) provides africa with its most accessible means to end hiv-related infant morbidity and mortality.1,4 most african countries have implemented prevention of mother-to-child transmission (pmtct) programmes since 1999.5 in 2016, zambia adopted the option b+ plan that provides all pregnant and breastfeeding women (mothers) living with hiv (wlwh) lifelong art, regardless of their cd4 count or clinical stage.6 these wlwh protect their infants by taking maternal art throughout pregnancy and breastfeeding, and by giving their hiv-exposed infant arvs immediately after birth and until 28 days following the end of breastfeeding. maternal viral load (vl) monitoring measures the protective efficacy of the programme.7 the use of arvs in this way is infantpep and is an important component of the pmtct programme in zambia. prevention of mother-to-child transmission programmes prevent infant hiv infections and deaths.2 nevertheless, women participating in these programmes in malawi, mozambique and south africa report individual and socio-economic challenges, such as a lack of knowledge about infant art, transportation costs, inadequate spousal or family support and a fear to disclose because of hiv/aids-related stigma and discrimination.8,9,10,11,12,13 the poor quality of postnatal services in africa’s generally weak healthcare systems and the challenges faced by individual women and their socio-economic circumstances compromise pmtct retention rates.2,14 few pmtct programmes provide support, treatment and ongoing care for the infant after discharge.14 in zambia and india, reported inadequacies include a lack of information and professional support, a lack of hiv-testing kits and shortages of arvs and infant nevirapine (nvp).15,16 women on art during pregnancy experience a unique postpartum transition from receiving care for themselves and the baby simultaneously, whilst the infant is, in utero, to receiving separate infant and maternal care after delivery.11 in addition, the infant’s medication (pep) must be given as medically prescribed. there is therefore a particular need to support wlwh whilst in the postnatal and breastfeeding period.2,17 although several studies have explored the experiences of women engaged in pmtct with some focusing on the postnatal period, none has focused specifically on the challenges that mothers experience in providing pep to their infants after birth. the administration of pep to infants is a key pillar of the pmtct programme. this has made it imperative to explore the challenges that mothers experience when administering pep to their infants. methods study design a qualitative approach with an explorative-descriptive design was used. administering pep to a baby by a mother living with hiv is a complex and multi-faceted phenomenon. a qualitative design was selected to gain a detailed in-depth understanding of these challenges. setting the study was conducted at the university teaching hospital (uth) in lusaka, the capital city of zambia. the uth is the principal training centre for healthcare workers of different categories and the main referral hospital of the country. population and sampling the target population was adult mothers living with hiv who had been caring for an infant since birth and had experience of administering pep within the 3 months prior to data collection. a purposive sample of 15 women who attended their 6 weeks postnatal visit was drawn to participate in the study. purposive sampling aimed to include women from various settings around lusaka, different language and socio-economic backgrounds, those with prior experience in providing pep and those without, to ensure maximum variability of experiences.18 the study focused on adult mothers because there may be specific challenges unique to adolescent mothers. the hospital staff first obtained permission from possible participants before referring them to the researcher. data saturation was reached when the 15th interview yielded no new information. data collection in-depth interviews were undertaken in august and september 2016 using a semi-structured interview guide. the first author, who was not personally known to the participants or involved in their care, conducted one-on-one interviews at a place convenient for the participants. she was trained in conducting individual interviews, which was done in the women’s home language, nyanja or bemba; some participants spoke english in-between the conversation. interviews took place in a separate room within the uth building but in another department to maintain privacy. open-ended questions were asked in an informal, conversational manner, in order to allow the participants to talk freely about their experiences. interviews lasted between 35 and 45 min, were audio-recorded and field notes were taken. as member-checking was done in the interviews by means of summarising and clarifying information, and data saturation was achieved, no follow-up interviews were required. data analysis data analysis was performed simultaneously throughout data collection. the first author listened to the recordings and transcribed the participants’ recorded interviews verbatim. this was then translated into english. data were analysed manually, organised and interpreted using creswell’s six-step technique of data analysis for qualitative research.19 all information collected from the participants through interviews were analysed by both authors by way of gathering and generating the collected data into themes. discrepancies were resolved through consensus. trustworthiness was maintained through adhering to the principles of credibility, transferability, conformability and dependability.19 credibility was ensured through selection of those participants who met the inclusion criteria and by following the interview guide. assurance regarding the truth of data collected was established through the techniques of peer debriefing and member checks. transferability was pursued during data collection until data saturation occurred and a description was provided of the study setting. conformability was established through the recorded data that substantiated the findings and that agreed that the interpretation was a genuine reflection of the participants’ experiences. dependability is supported by a step-by-step ‘audit trail’. ethical consideration ethical approval to conduct the research study was obtained from the health research ethics committee (hrec) of the faculty of medicine and health sciences, stellenbosch university (su), south africa (sa), reference number s16/04/062. in addition, approval was obtained from the permanent secretary, ministry of health in zambia, the institution and head of department of the university teaching hospital in lusaka, zambia. further ethical approval was obtained from the biomedical health research ethics committee (bhrec), university of zambia (unza), reference number 001-07-16. written informed consent was obtained from all participants. confidentiality was maintained throughout the study to protect the hiv status of participants by using identification numbers in lieu of personal identification. these identification numbers were also used when transcribing the interviews. results participant characteristics fifteen participants were enrolled in the study. the participants were mothers from peri-urban and urban areas around lusaka city who were administering art to their infants at the time of the study. nine participants were married (9/15 = 60%), two were divorced, one was separated from her partner and three were single mothers. the participants’ age ranged from 20 to 42 and they had two to four children. three participants were employed and 12 were unemployed (see table 1). table 1: participant characteristics. themes seven themes with several sub-themes were identified as depicted in table 2. table 2: themes and sub-themes. emotional responses participants expressed several emotional responses towards living with hiv, the possibility of transmitting the virus to the infant, providing pep and breastfeeding. for some participants, it brought apprehension, fear, worry and a sense of guilt realising that it would be their fault if their child became hiv-positive. yet, they tended to manage these emotions alone: ‘i am fearful of losing my baby even if i am giving nevirapine.’ (participant 2, 31 years old, married) some participants were worried about the side effects of nvp, the drug given to the infant for pep and the potential harm that it could cause to their infants. the awareness that high level of adherence was needed in order to prevent hiv transmission made participants worry when their babies did not swallow all the medication: ‘the baby doesn’t swallow all the medication … it is scary to keep waiting for the results when you know that the baby never swallows all the medication at times. i don’t want to be told that the baby is positive.’ (participant 1, 20 years old, single) some participants expressed feelings of guilt and self-blame as they felt responsible for the suffering of the infant. feelings of guilt and self-reproach also emanated from experiences of not adhering to the advice of healthcare workers during previous pregnancies: ‘help was offered to me, but i chose to ignore it. i did not want others to know, it was so foolish of me. i should have composed myself enough to do the right thing … i lost my three babies probably because of being hiv-positive or because of not following what the nurses told us from the antenatal clinics.’ (participant 6, 38 years old, married) knowledge and understanding some of the participants were sceptical about the efficacy of pep. the reasons for their doubt appeared to be a lack of knowledge and understanding, as well misconceptions about the need for providing pep and its benefits. some participants were misinformed about breastfeeding and they expressed ignorance of safe breastfeeding practices. many of these misconceptions were because of conflicting information received from different sources. participants received information from their church pastors, mother-in-law’s, family members, friends and healthcare workers: ‘i hear from friends that the medication results in complications.’ (participant 9, 22 years old, single) some participants had inadequate information because of fear of asking healthcare workers if they do not understand: ‘i was scared of being scolded at by health professionals. the instructions are scribbled on the bottle. at times the amount changes and is not visible enough to read.’ (participant 11, 27 years old, single) the perceptions of some participants were that pep was unnecessary because their infants were healthy. one participant believed that as her baby looked healthy, there was no need to give the drug: ‘the baby looks healthy, why give the nevirapine?’. (participant 2, 31 years old, married) in some instances, the administration of nvp was believed to be associated with cancer and diarrhoea. these misconceptions influenced the willingness of the mothers to give nvp to their babies: ‘i am told by friends that these drugs cause cancer of the liver, these drugs are so strong, and ward 6 has a number of children with cancer.’ (participant 9, 22 years old, single) post-exposure prophylaxis administration practices participants who had disclosed their hiv status were less likely to report having problems administering nvp. for some, giving nvp to their infants was a burden because the act of giving medication was a constant reminder of hiv infection. many of the participants admitted that they chose to hide the administration of pep from their family members, friends and partners. this was done by removing the medicine label from the bottle or by waiting until they were alone: ‘at first, i would remove the label from the bottle and i would give the medicine to the baby when i was alone.’ (participant 6, 38 years old, married) participants found it difficult to adhere to treatment and postnatal appointments when they continued hiding the administration of nvp to their infants from family and friends. the constant thought of having to give nvp was expressed as a burden and remembering to give the medication on a daily basis or making arrangements when the mother was not available to give the medication was a concern: ‘i had challenges telling her the truth. there are times when i would want my stepchild to give the medication to the baby. and i would just instruct her and not tell her what it was. she is a grown-up girl. one day i told her that it was medicine for diarrhoea, please give the baby when she wakes up. i was the only one who could give the medication.’ (participant 10, 29 years old, married) healthcare appointments some participants mentioned being unhappy with hospital appointments and complained that time was wasted whilst waiting for services. inefficient organisation and the long waiting times at the facilities and when obtaining hiv test results were barriers to accessing postnatal care: ‘there were long queues – baby still too small, those that were to receive vaccines and results were put in the same line, takes time to have one’s turn. babies who were successfully immunised and whose hiv tests were done for the first time still go back to line up for supply of nvp.’ (participant 12, 27 years old, single) working mothers found it difficult to get permission from work to attend hospital appointments, especially because the healthcare appointments for herself and her baby were separate: ‘it was not easy to get permission from work. i used to get permission for myself and now i have to get permission for me and the baby … not easy to get permission from work to go for hospital.’ (participant 5, 32 years old, married) drug stock-outs contributed further to the time being spent on healthcare appointments: ‘only medicine for 4 days was given at times and i was required to get permission twice within a week to get back to the hospital for more medicines.’ (participant 3, 26 years old, married) participants perceived some healthcare workers as uncaring, non-sympathetic and unapproachable. stigmatising behaviour by healthcare workers was a challenge mentioned by some participants: ‘nurses would give each other signs, a certain way of communication among themselves referring to hiv-positive mothers.’ (participant 3, 26 years old, married) partner involvement some participants feared abandonment if they disclosed their hiv status to their partners, while others mentioned that their partners refused to test for hiv and did not support them emotionally: ‘i did not know how to tell my husband. as such i was in constant fear because i could not guess how he was going to react. i kept quiet and pretended that everything was fine.’ (participant 7, 29 years old, married) ‘it is really unfortunate, that my husband was in a position not to listen … i think he knew that he was positive, that was why he was so defensive, and you know he knew that he was positive even before we got married.’ (participant 6, 38 years old, married) cultural and religious influences in the zambian context, the family plays a pivotal role in the culture of child nurturing. the influence of the extended family, including grandmothers and the mother-in-law, played a significant role in the decisions made by participants to attend healthcare appointments for pep. moving around in public with a baby below the age of 3 months is considered unacceptable in some zambian cultures and motivating to attend appointments without disclosing their hiv status was a challenge for women: ‘but my mother-in-law believes in staying indoors until the baby is 3 months old.’ (participant 6, 38 years old, married) ‘i didn’t go for the 1-week appointment. i was told the baby was too young … my mother-in-law escorted me when the baby was 6 weeks. she told me that the baby was too young to be moving around with her in public.’ (participant 11, 20 years old, single) participants appeared to have different personal beliefs about the administration of nvp and the impact that it would have on their infants. some indicated that they believed in traditional medicine or spiritual healing. in some instances, they expressed fear and mistrust of pep, which was also negatively associated with demons. participants proved that they were not demon-possessed by seeking spiritual intervention. these negative beliefs led some participants not to administer nvp to their infants whilst they were seeking spiritual intervention: ‘we used to go for overnight prayers and believed that the anointing water and oil were going to cure us.’ (participant 3, 26 years old, married) stigma and discrimination stigma and discrimination were identified as a continuous challenge. it was very obvious that stigma and discrimination were widespread in families and communities. this forced women to avoid practices that revealed their hiv status. much of the stigma was associated with misconceptions about hiv and the administration of nvp to the infants. stigma and discrimination led participants to make decisions to either continue or to discontinue treatment. a lack of privacy and confidentiality in healthcare settings was a concern. some participants felt uncomfortable because they were told about nvp administration and hiv results within the hearing distance of others: ‘at the clinics, you are told to sit in a waiting space before being given the results. when you are many, a counsellor would come out and call out names, giving the papers carrying the negative results and after that she tells them to go. an announcement will be made for those remaining not to leave but to remain seated until results were given.’ (participant 10, 29 years old, married) discussion several individual, social and healthcare system challenges were identified that were related to the administration of pep to infants born to wlwh. individual challenges included emotional responses such as worry and fear, a lack of knowledge and understanding as well as misconceptions regarding pep. some reported that they did not know how to read the instructions provided. others felt that instructions were unclear and that specific issues such as drug administration times and what to do in case of vomiting or spitting were unclear. information about pep administration was communicated through group counselling as well as preand post-test counselling. yet, time constraints resulted in the information being given hastily and with little opportunity for questions and clarification. similar anxiety about the infant’s hiv diagnosis has been identified in a south african study on pmtct.11 reports from malawi, ethiopia, tanzania and ghana also confirm that mothers lack knowledge of infant art, feeding and how to care for their infants.8,20,21,22,23,24 social challenges mainly related to cultural and religious influences, limited partner involvement, a lack of disclosure and support. mothers in the current study were obliged to follow the advice of grandmothers, mothers and mothers-in-law.20 various religious practices and the fear of stigma influenced the administration of pep: all reported in other studies.8,21,24 additional studies from sub-saharan africa provide a wide socio-economic backdrop of poverty, migration, transport costs and the failure of families to provide adequate support to ensure the effectiveness of infant pep.9,24,25 the organisation of healthcare services caused inefficiencies and hindered the clarification of essential information. participants experienced stigma, a lack of confidentiality and uncaring behaviour from healthcare staff. indeed, the healthcare system itself was often a challenge to overcome rather than a supportive asset to these young mothers.24,26,27 these findings indicate the need for person or family-centred counselling that focuses on the evaluation of and solution to individual barriers and enablers of pep. counselling should also be culturally sensitive and assist women to incorporate their cultural and spiritual beliefs in a meaningful way into the care of their infants. family-counselling interventions and peer support groups could be a solution and facilitate family, peer and partner support.28 although facility-based, mother-support groups in zimbabwe failed to improve the retention in care of hiv-exposed infants at 12 months, it may still have a role in certain contexts and amongst high-risk groups.28 integration of pep into routine child healthcare visits or the combining of mother-and-child care may reduce the burden of multiple appointments. providing differentiated care such as fast-tracking women, who need pep refills only or providing community pep refills, should be considered. a recent report suggests that the provision of correct education, family and partner involvement, addressing health systems gaps, linking the clinic with the community and the provision of income generation support is key to promoting adherence within pmtct programmes.24 more qualitative and quantitative research is needed to explore pep-related behaviours and to understand the factors that influence pep administration over longer periods of time. this may be required during high-risk exposures. strengths and limitations of the study to the best of our knowledge, this is the only qualitative study to focus specifically on the experiences of wlwh whilst providing pep to their infants. the literature focuses on factors influencing maternal art adherence and less so on pep administration, which is an equally important component of the pmtct programme. there are several study limitations: the study was conducted at only one hospital and clinic, the uth, and included only mothers who attended postnatal visits, which may limit transferability to other settings. at the time of the study, there was limited availability to published literature on the challenges of mothers administering pep to their infants. conclusion the administration of pep as part of the pmtct programme is key to ensuring the goal of zero mother-to-child transmission. the findings indicate that women who administer pep to their infants have to overcome a variety of individual, social and healthcare system challenges. postnatal support for these women can be enhanced through person or family-centred, culturally sensitive counselling, providing differentiated services for pep, integrated mother-and-child healthcare and access to support groups. acknowledgements the authors would like to express sincere thanks to all participants that shared their experiences. competing interests the authors have declared that no competing interest exists. authors’ contributions m.l. wrote the proposal, conducted the study as part of her master of nursing degree and reviewed the article, providing substantial feedback. t.c. supervised the study. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability statement data sharing is not applicable to this article. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references ngarina m, tarimo eam, naburi h, et al. women’s preferences regarding infant or maternal antiretroviral prophylaxis for prevention of mother-to child transmission of hiv during breastfeeding and their views on option b+ in dar es salaam, tanzania. plos one. 2014;9(1):e85310. https://doi.org/10.1371/journal.pone.0085310 unicef. elimination of mother-to-child transmission [homepage on the internet]. 2020 [cited 2020 dec 12]. available from: 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nursing research, appraisal, synthesis and generation of evidence. 7th ed. st louis, mo: saunders; 2013. creswell jw. research design. qualitative, quantitate, mixed methods approaches. 4th ed. washington, dc: sage; 2014. de schacht c, lucas c, mboa c, et al. access to hiv prevention and care for hiv-exposed and hiv-infected children: a qualitative study in rural and urban mozambique. services for hiv-exposed children for essential preventive care. bmc publ health [serial online]. 2014 [cited 2016 dec 15];14(1):1240. available from: http://www.biomedcentral.com/1471-2458/14/1240 boateng d, kwapong dokuaa g, agyei-baffour p. knowledge, perception about antiretroviral therapy (art) and prevention of mother-to-child-transmission (pmtct) and adherence to art among hiv positive women in the ashanti region, ghana: a cross-sectional study. bmc women health [serial online]. 2013[cited];13(2):1472–6874. available from: http://www.biomedcentral.com/1472-6874/13/2 tesfaye g, tufa b, likisa j, alebachew m, temesgen g, dinsa h. knowledge, attitude and practice towards pmtct of hiv among women attending ambo hospital anc clinic, west ethiopia. aids clin res. 2014;6:1. https://doi.org/10.4172/2155-6113.1000407 falnes ef, tylleskarl t, manuela m, manongi r, engebretsen im. mothers’ knowledge and utilization of prevention of mother to child transmission services in northern tanzania. j int aids soc [serial online]. 2010 [cited 2017 sep 27];13:36. available from: http://www.jiasociety.org/content/13/1/36 king r, matovu jn, rujumba j, et al. pmtct option b+ 2012 to 2018 – taking stock: barriers and strategies to improve adherence to option b+ in urban and rural uganda. afr j aids res. 2020;19(2):135–146. https://doi.org/10.2989/16085906.2020.1760325 kalembo fw, zgambo m. loss to follow up: a major challenge to successful implementation of prevention of mother-to-child transmission of hiv-1 programs in sub-saharan africa. isrn aids. 2012:589817. https://doi.org/10.5402/2012/589817 nuwagaba-biribonwoha h, mayon-white rt, okong p, carpenter lm. challenges faced by health workers in implementing the prevention of mother-to-child hiv transmission (pmtct) programme in uganda. j publ health. 2007;29(3):269–274. https://doi.org/10.1093/pubmed/fdm025 kweyamba m, buregyeya e, kusiima j, kweyamba v, mukose ad. loss to follow-up among hiv positive pregnant and lactating mothers on lifelong antiretroviral therapy for pmtct in rural uganda. adv publ health. 2018;article id 7540587:1–9. https://doi.org/10.1155/2018/7540587 foster g, orne-gliemann j, font h, et al. impact of facility-based mother support groups on retention in care and pmtct outcomes in rural zimbabwe: the epaz cluster-randomized controlled trial. acquir immune defic syndr. 2017;75(2):s207–s215. https://doi.org/10.1097/qai.0000000000001360 hiv 861 original article risk factors for discordant immune response among hiv-infected patients initiating antiretroviral therapy: a retrospective cohort study b p muzah, s takuva, m maskew, s delany-moretlwe   wits reproductive health and hiv institute, clinical hiv research unit, department of internal medicine, school of clinical medicine, and school of public health, faculty of health sciences, university of the witwatersrand, johannesburg b p muzah, mb chb, msc   clinical hiv research unit, department of internal medicine, school of clinical medicine, faculty of health sciences, university of the witwatersrand, johannesburg s takuva, mb chb, msc   clinical hiv research unit, and health economics and epidemiology research office, department of internal medicine, school of clinical medicine, faculty of health sciences, university of the witwatersrand, johannesburg m maskew, mb bch, msc   wits reproductive health and hiv institute, university of the witwatersrand, johannesburg s delany-moretlwe, mb bch, phd corresponding author: b p muzah (bmuzah@wrhi.ac.za)   background. the therapeutic goal of antiretroviral therapy (art) is sustained immune recovery and viral suppression. however, some patients experience poor cd4 cell count responses despite achieving viral suppression. such discordant immune responses have been associated with poor clinical outcomes. objective. we aimed to determine the prevalence of discordant immune response and explore associated factors in a retrospective cohort of patients attending 2 large public sector clinics, during the 6 months following art initiation. methods. data were analysed from 810 hiv-infected adults initiated on first-line haart at 2 clinics in johannesburg, between 1 november 2008 and 31 december 2009. multivariate logistic regression models were used to estimate adjusted odds ratios (aors) to determine associations between discordant immune response and clinical and demographic factors. results. at art initiation, 65% (n=592) of participants were female, with a mean age of 38.5 years. median baseline cd4 cell count was 155 cells/mm3 , 70% (n=645) of patients had a haemoglobin level >11 g/dl and 88% (n=803) were initiated on stavudine-lamivudine-efavirenz/nevirapine (d4t-3tc-efv/nvp). six months after art initiation, 24% (n=220) of patients had a discordant immune response and 7% (n=67) a discordant virological response. on multivariate analysis, baseline cd cell count ≥200 cells/mm3 (aor 3.02; 95% confidence interval (ci) 2.08 4.38; p<0.001) and moderate anaemia (8.0 9.4 g/dl) at baseline (aor 2.30; 95% ci 1.25 4.59; p=0.007) were independently associated with the development of discordant immune response, after adjustment for education level, world health organization (who) clinical stage and art regimen. conclusions. discordant immune response following art initiation was common and associated with baseline anaemia and cd4 cell count in our cohort. intensive monitoring of at-risk individuals may improve clinical outcomes. s afr j hiv med 2012;13(4):168-172. doi:10.7196/sajhivmed.861 hiv infection is typically associated with progressive cd4 cell depletion and consequent immunodeficiency.1 , 2 , 3 the introduction of antiretroviral therapy (art) has seen a decline in the morbidity and mortality associated with hiv infection.4 this is a consequence of the ability of art to suppress hiv viraemia to undetectable levels and allow immune restoration, resulting in an increase in circulating cd4 cells.5 in clinical practice, however, not all patients receiving art achieve the desired concordant response of viral suppression with cd4 cell count increase.6 as many as 20 40% of patients on art do not show a significant increase in cd4 cell count despite viral suppression.6 this phenomenon is referred to as discordant immune response and is associated with an increased risk of developing an aids event or death.6 , 7 , 8 , 9 discordant immune response may arise either as a result of failed immune reconstitution or the excessive destruction of cd4 cells.10 the reconstitution of peripheral cd4 cells is a biphasic process with an initial rapid increase of memory cd4 cells, succeeded by a slow increase in naive cd4 cells.11 , 12 the second rise in cd4 cells may be due to cellular expansion or sustained cell survival in the periphery, as well as the central regeneration of cells by the thymus.10 despite the relative frequency of discordant immune response following art initiation, data on the prevalence of this phenomenen and associated factors are still limited in south africa (sa), as well as in other lowand middle-income countries, where treatment is primarily nucleoside reverse transcriptase inhibitor (nrti)-based.13 in these settings patients often initiate treatment at advanced stages of immunosuppression and have co-morbidities that compromise treatment response.14 the lack of knowledge about this subgroup may contribute to inadequate clinical management, as current hiv treatment guidelines do not provide specific applicable guidance. in this retrospective study we describe the prevalence of, and factors associated with, discordant immune response in a cohort of patients from 2 large public sector clinics in sa in the first 6 months after art initiation. methods we retrospectively analysed data from 810 hiv-infected patients aged >16 years who initiated art at 2 district comprehensive care management and treatment centres in ekurhuleni, gauteng province, from 1 november 2008 to 31 december 2009. ekurhuleni, the largest district in the province, has a population of nearly 3 million people, and an hiv prevalence of 31.5%.15 patients were included in the study if they were art-naive at the time of treatment initiation, and were maintained on a standard first-line art regimen16 for at least 3 months following treatment initiation. ethical approval and study permission were obtained from the human research ethics committee of the university of the witwatersrand and the ekurhuleni ethical panel. data collection patient demographics and contact information were recorded at the commencement visit to the clinic. at ensuing visits, the patients’ weight, reports of any symptoms and new diagnoses were recorded. data were collated by trained data capturers after each visit. results of cd4 cell count, plasma hiv viral load (pvl), full blood count and liver function tests (lfts) were recorded upon receipt. all data were maintained in the patient health management database therapy-edge. stata software (version 11) was used for data analysis. socio-demographic characteristics (age, gender, education level, occupation status and alcohol use/smoking), medical history including prior pulmonary tuberculosis (tb) and art information were extracted from therapy-edge, as were physical examination findings such as body mass index (bmi), liver function and haemoglobin (hb) values. hb, lfts and cd4 cell count were measured at art initiation (i.e. baseline) and at 6 months post-art initiation, with only pvl measured at 6 months.  outcome assessment viral suppression was defined as a pvl <400 copies/ml at 6 months after art initiation.16 immune reconstitution was defined as an absolute increase in the cd4 cell count value of 50 cells/mm3 at an average of 6 months after art initiation. a discordant immune response was defined as a failure of immune reconstitution (increase in cd4 cell count <50 cells/mm3 ) within 3 6 months of art initiation, in the presence of viral suppression (pvl <400 copies/ml). measurements within 3 6 months of art initiation were used, in accordance with the 6-month follow-up recommended in national guidelines.16 statistical methods descriptive statistics, using means and standard deviations for continuous variables, and frequencies for categorical variables, were used to report sample characteristics. associations between the main outcome and potential explanatory factors were assessed using variate logistic regression, using odds ratios (ors) and 95% confidence intervals (cis) to express the measure of association. factors that were significant at p≤0.2 in univariate analysis were considered for inclusion in multivariate logistic regression models. final models were derived using forward selection and backward elimination techniques. the final model was adjusted for education level, world health organization (who) clinical stage, baseline cd4 cell count, and art regimen, and adjusted ors (aors) were presented. baseline who clinical stage was included in the final model regardless of statistical significance in the univariate analysis because of the link between hiv clinical disease and outcome. these models were tested using the hosmer-lemeshow goodness-of-fit test. interactions between all significant variables in the model were also investigated. collinearity was tested in all the regression models. a sensitivity analysis to demonstrate the robustness of the study findings to variation in definition of cd4 cell count response was also conducted using a 30% increase from baseline cd4 cell count as the desired response. results a total of 6 460 adults enrolled in the art programme at the 2 clinics; 4 581 (80%) were excluded due to an absent baseline/6-month follow-up cd4 cell count and/or pvl, and a further 962 were excluded due to a lack of additional information (e.g. art regimen or baseline laboratory values). of the remaining 917 eligible, 810 were included for analysis. the remainder were excluded as they had discordant virological responses (i.e. immune reconstitution in the absence of viral suppression) or were non-responders (no change in cd4 cell count or pvl). prevalence of discordant immune response on art within the cohort, 220 (24%) experienced a discordant immune response within 6 months of art initiation. at baseline, the mean cd4 cell count in the discordant group was 218 cells/mm3 (sd ±168), compared with 137 cells/mm3 (sd ±85) in the group with a concordant response to treatment. factors associated with a discordant immune response baseline characteristics of discordant and concordant immune responders were compared (table 1). compared with concordant immune responders, patients with discordant immune responses were more likely to be older, to have initiated art at a higher baseline cd4 cell count, to have been initiated onto zidovudine or tenofovir-containing art regimens, and to have significantly different hb levels and moderate anaemia at the start of art. no significant differences were observed between the groups in terms of gender, occupational status, education level, history of tuberculosis, smoking or alcohol use, bmi, who clinical stage, or aspartate transaminase (ast) and alanine transaminase (alt) levels. table 1. cohort characteristics with logistic regression analysis of factors associated with discordant v. concordant immune response characteristic total ( n =810) discordant response n (%)* or (95% ci) p -value ‡ aor (95% ci) p -value ‡ age (years), mean (±sd) 220 39.5 (±8.9) 1.02 (1.00 1.04) 0.028 1.02 (1.00 1.04) 0.031 gender female male   138 82   138 (63) 82 (37)   1 1.18 (0.85 1.66)     0.323     art d4t-3tc-nvp/efv azt-3tc-nvp/efv tdf-3tc-nvp/efv   188 27 5   188 (86) 27 (12) 5 (2)   1 1.91 (1.14 3.20) 0.78 (0.29 2.15)     0.014 0.639     baseline cd4 cell count (cells/mm3 ) <200 >200   122 98   122 (55) 98 (45)   1 2.90 (2.08 4.03)     0.0001   1 3.02 (2.08 4.38)     0.001 who clinical stage 1 2 3   164 4 52   164 (75) 4 (2) 52 (23)   1 2.12 (0.56 7.98) 0.91 (0.63 1.31)     0.268 0.616     hb (g/dl) normal ( ≥11) mild anaemia (9.5 10.9) moderate anaemia (8 9.4) severe anaemia (≤7.9)   162 31 23 2   162 (74) 31 (14) 23 (11) 2 (1)†(2)   1 0.76 (0.49 1.19) 1.55 (0.90 2.68) 0.20 (0.05 0.88)     0.230 0.117 0.032   1 0.88 (0.54 1.45) 2.30 (1.26 4.19) 0.36 (0.08 1.63)     0.629 0.007 0.188 history of tb no yes   192 28   192 (87) 28 (13)   1 1.26 (0.78 2.04)     0.335     smoking no yes   147 38   147 (79) 38 (21)†(35)   1 0.99 (0.65 1.50)     0.948     alcohol no yes   139 41   139 (77) 41 (23)†(40)   1 1.11 (0.73 1.67)     0.630     bmi normal (18.50 24.99) underweight (<18.50) overweight (25.00 29.99) obese (≥30.00)   93 15 34 30   93 (54) 15 (9) 34 (20) 30 (17)†(48)   1 0.94 (0.50 1.79) 0.58 (0.37 0.91) 0.88 (0.54 1.41)     0.854 0.017 0.594     occupation status unemployed employed   128 71   128 (64) 71 (36)†(21)   1 1.25 (0.88 1.76)     0.210     education level illiterate primary secondary tertiary   9 33 149 1   9 (5) 33 (17) 149 (78) 1 (1)†(28)   1 0.48 (0.18 1.24) 0.49 (0.20 1.19) 0.10 (0.01 0.93)     0.124 0.116 0.043     ast (iu/l) normal above normal   136 77   136 (64) 77 (36)†(7)   1 1.16 (0.83 1.61)     0.379     alt (iu/l) normal above normal   209 10   209 (95) 10 (5)†(1)   1 0.83 (0.40 1.71)     0.605     art = antiretroviral therapy; d4t = stavudine; 3tc = lamivudine; efv/nvp = evafirenz/nevaripine; azt = zidovudine; tdf = tenofovir; who = world health organization; hb = haemoglobin; tb = tuberculosis; bmi = body mass index; alt = alanine aminotransferase; ast = aspartate transaminase. *data are expressed as n (%) for categorical variables and mean (±sd) for continuous variables. †missing values. ‡ p-values were obtained using χ2 test and student’s t-test. in the final model, a discordant immune response was found to be associated with increasing age (aor 1.02; ci 1.00 1.04; p=0.031), initiating treatment at a cd4 cell count >200 cells/mm33 (aor 3.02; ci 2.08 4.38; p<0.0001), and the presence of moderate anaemia (hb 8.0 9.4 g/dl) (aor 2.3; ci 1.26 4.19; p=0.007), after adjusting for baseline education, who clinical stage, cd4 cell count and art regimen (table 1). no significant interactions were found between the significant variables in the final model, which was deemed adequate using the hosmer-lemeshow goodness-of-fit test (p=0.416). the results of the sensitivity analysis, conducted by considering a 30% increase from baseline cd4 cell count as the desired response, are summarised in table 2. the univariate analysis produced similar findings to those in the primary analysis. only baseline hb level failed as a significant factor in the development of discordant response using the modified outcome definition. table 2. uni and multivariate analysis for sensitivity of factors associated with discordant immune response at 6 months after art initiation   or (ci) p -value aor (ci) p -value age (years) 1.02 (1.00 1.04) 0.0590 1.02 (1.00 1.04) 0.0300 baseline cd4 cell count (cells/mm3 ) <200 >200   1 5.51 (3.91 7.77)     0.0001   1 5.31 (3.71 7.61)     0.0001   or = odds ratio; aor = adjusted odds ratio; ci = confidence interval. discussion despite an adequate virological response, 24% of patients did not achieve an adequate immune response at 6 months after art initiation. increasing age, initiating art at a cd4 cell count >200 cells/mm3 , and initiating art with moderate anaemia were associated with failure to achieve optimal immune restoration. no associations between discordant immune response and gender, bmi or art regimen were observed, although these were identified as risk factors in other studies.17 , 18 the findings concerning age were consistent with findings from other studies, where increasing age was associated with poor immune recovery.5 in the north american aids cohort collaboration on research design (na-accord) study, data from 19 cohorts and 12 196 participants showed that increasing age was associated with a lower chance of achieving an increase in cd4 cell count >100 cells/mm3 at 24 months following art initiation.19 this has been linked to the observation that thymus activity, which is largely responsible for immune restoration, decreases with ageing.10 the literature is conflicting regarding the association of baseline cd4 cell count with discordant immune response outcome. findings similar to ours emerged from a cohort of 4 810 patients initiating art in the antiretroviral therapy in low-income countries (art-linc) study.20 the association between art initiation with a baseline cd4 cell count >200 cells/mm3 and the development of discordant immune response can be explained by the nonlinear nature of cd4 cell count increases after art initiation across the different baseline cd4 cell count strata:4 starting treatment at higher cd4 cell counts limits the scope for further increases.21 these findings are important as treatment programmes increase the cd4 cell count threshold for art initiation. in contrast to our findings, several studies conducted in resource-rich settings have shown that low baseline cd4 cell count is associated with discordant immune response.4 this is biologically plausible given that a low nadir pre-treatment cd4 cell count is thought to be suggestive of more extensive depletion of cd4 cells in the gut-associated lymphoid tissue during acute hiv infection, and may be delayed or refractory to reconstitution with art.22 genetic variability has been investigated as a possible modulator of immunological recovery, and may explain the divergent associations in the existing literature. these data suggest that moderate anaemia at baseline is associated with failure to achieve immune recovery at 6-month follow-up – an association that has not been documented previously. the aetiology of anaemia in hiv infection is multifactorial, but is commonly due to underproduction of erythrocytes by the bone marrow stem cells.23 these stem cells are also responsible for the production of cd4 cells through the myeloid precursor cell.24 poor production of myeloid precursor cells can therefore result in decreased production of both cd4 cells and erythrocytes. in addition, the erythrocytes of hiv-infected individuals may experience membrane changes which result in decreased pliability and premature destruction.25 the same applies to cd4 cells.25 these mechanisms of reduced stem cell activity and membrane changes could explain the association between anaemia when starting art and a subsequent discordant immune response. however, this finding should be interpreted with caution, as it was not significant in the sensitivity analysis when the definition of immune response was altered. study strengths and limitations although the sample size was relatively small, it was likely to be representative of patients in routine clinical care in gauteng province. the validity of the results may have been limited by the high proportion of missing data. patterns in missing data could have resulted in non-differential misclassification of patients, as a consequence of inaccurate measuring of outcomes and subsequent bias. however, such errors could have been evenly distributed among the groups and data were noted to be missing at random (analysis not shown). the outcomes were measured between 3 and 6 months after art initiation; it is therefore possible that factors associated with discordant immune response may have varied with longer periods of treatment. conclusion the findings of this study suggest that a significant proportion of patients initiating art in sa do not achieve an optimal 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[http://dx.doi.org/10.1089/aid.2008.0098] 14. holmes cb, losina e, walensky rp, yazdanpanah y, freedberg ka. review of human immunodeficiency virus type 1-related opportunistic infections in sub-saharan africa. clin infect dis 2003;36(5):652-662. 14. holmes cb, losina e, walensky rp, yazdanpanah y, freedberg ka. review of human immunodeficiency virus type 1-related opportunistic infections in sub-saharan africa. clin infect dis 2003;36(5):652-662. 15. national department of health. 2008 national antenatal sentinel hiv and syphilis prevalence survey. pretoria: doh, 2008. 15. national department of health. 2008 national antenatal sentinel hiv and syphilis prevalence survey. pretoria: doh, 2008. 16. national department of health. national antiretroviral therapy guidelines. pretoria: doh, 2004. 16. national department of health. national antiretroviral therapy guidelines. pretoria: doh, 2004. 17. mocroft a, philips an, gatell j, ledergerber b, fisher m. normalisation of cd4 counts in patients with hiv-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study. lancet 2007;370:407-413. 17. mocroft a, philips an, gatell j, ledergerber b, fisher m. normalisation of cd4 counts in patients with hiv-1 infection and maximum virological suppression who are taking combination antiretroviral therapy: an observational cohort study. lancet 2007;370:407-413. 18. patterson k, napravnik s, eron j, keruly j, moore r. effects of age and sex on immunological and virological responses to initial highly active antiretroviral therapy. hiv med 2007;8:406–410. 18. patterson k, napravnik s, eron j, keruly j, moore r. effects of age and sex on immunological and virological responses to initial highly active antiretroviral therapy. hiv med 2007;8:406–410. 19. althoffa kn, justiceb ac, gangea sj, et al. virologic and immunologic response to haart, by age and regimen class. aids 2010;24:2469-2479. 19. althoffa kn, justiceb ac, gangea sj, et al. virologic and immunologic response to haart, by age and regimen class. aids 2010;24:2469-2479. 20. tuboi sh, brinkhof mw, egger m, et al. discordant responses to potent antiretroviral treatment in previously naive hiv-1-infected adults initiating treatment in resource-constrained countries: the antiretroviral therapy in low-income countries (art-linc) collaboration. j acquir immune defic syndr 2007;45(1):52-59. 20. tuboi sh, brinkhof mw, egger m, et al. discordant responses to potent antiretroviral treatment in previously naive hiv-1-infected adults initiating treatment in resource-constrained countries: the antiretroviral therapy in low-income countries (art-linc) collaboration. j acquir immune defic syndr 2007;45(1):52-59. 21. gilson rj, man sl, copas a, et al. discordant responses on starting highly active antiretroviral therapy: suboptimal cd4 increases despite early viral suppression in the uk collaborative hiv cohort (uk chic) study. hiv med 2010;11(2):152-160. 21. gilson rj, man sl, copas a, et al. discordant responses on starting highly active antiretroviral therapy: suboptimal cd4 increases despite early viral suppression in the uk collaborative hiv cohort (uk chic) study. hiv med 2010;11(2):152-160. 22. brenchly jm, schaker tw, ruff le. cd4+ t cell depletion during all stages of hiv disease occurs predominantly in the gastrointestinal tract. j exp med 2004;200:749-759. 22. brenchly jm, schaker tw, ruff le. cd4+ t cell depletion during all stages of hiv disease occurs predominantly in the gastrointestinal tract. j exp med 2004;200:749-759. 23. moore rd, forney d. anemia in hiv-infected patients receiving highly active antiretroviral therapy. j acquir immune defic syndr 2002;29:54-57. 23. moore rd, forney d. anemia in hiv-infected patients receiving highly active antiretroviral therapy. j acquir immune defic syndr 2002;29:54-57. 24. calles nr, evans d, terlounge d. pathophysiology of the human immunodeficiency virus. hiv curriculum for health professionals 2009:13. 24. calles nr, evans d, terlounge d. pathophysiology of the human immunodeficiency virus. hiv curriculum for health professionals 2009:13. 25. martins-silva j, nuno c, santos m. changes in blood cells membrane properties in hiv-type 1infected patients. aids res hum retroviruses 2006;22:849-853. 25. martins-silva j, nuno c, santos m. changes in blood cells membrane properties in hiv-type 1infected patients. aids res hum retroviruses 2006;22:849-853. contents executive summary scope and purpose audience methods 1. introduction 2. informed consent 3. primary care 4. non-medical gender-affirming practices 5. psychosocial care 6. hormone therapy 7. surgery 8. institutions 9. voice and communication 10. key terms acknowledgements references appendix 1: the role of health professionals in change of gender marker at home affairs: act 49 appendix 2: client information and consent form for feminising hormone therapy appendix 3: client information and consent form for masculinising hormone therapy about the author(s) anastacia tomson my family gp, cape town, south africa shemah koleinu, cape town, south africa chris/tine mclachlan kwazulu-natal department of health, pietermaritzburg, south africa department of psychology, college of human sciences, university of south africa, pretoria, south africa professional association for transgender health south africa, cape town, south africa psychological society of south africa, johannesburg, south africa camilla wattrus southern african hiv clinicians society, johannesburg, south africa kevin adams professional association for transgender health south africa, cape town, south africa department of plastic surgery, faculty of health science, university of cape town, cape town, south africa ronald addinall professional association for transgender health south africa, cape town, south africa department of social development, faculty of humanities, university of cape town, cape town, south africa southern african sexual health association, cape town, south africa rutendo bothma wits reproductive health institute, johannesburg, south africa lauren jankelowitz southern african hiv clinicians society, johannesburg, south africa elliott kotze psychologist, independent practice, cape town, south africa zamasomi luvuno school of nursing and public health, centre for rural health, university of kwazulu-natal, durban, south africa nkanyiso madlala department of psychology, college of human sciences, university of south africa, pretoria, south africa professional association for transgender health south africa, cape town, south africa psychological society of south africa, johannesburg, south africa savuka matyila gender dynamix, cape town, south africa anil padavatan gender dynamix, cape town, south africa mershen pillay professional association for transgender health south africa, cape town, south africa department of speech-language therapy, faculty of health sciences, university of kwazulu-natal, durban, south africa department of speech-language therapy, faculty of health sciences, massey university, auckland, new zealand mmamontsheng d. rakumakoe professional association for transgender health south africa, cape town, south africa quadcare, johannesburg, south africa mathilde tomson-myburgh shemah koleinu, cape town, south africa willem d.f. venter ezintsha, faculty of health sciences, university of the witwatersrand, johannesburg, south africa elma de vries professional association for transgender health south africa, cape town, south africa cape town metro health services, cape town, south africa school of public health and family medicine, faculty of health science, university of cape town, cape town, south africa citation tomson a, mclachlan c, wattrus c, et al. southern african hiv clinicians’ society gender-affirming healthcare guideline for south africa. s afr j hiv med. 2021;22(1), a1299. https://doi.org/10.4102/sajhivmed.v22i1.1299 guideline southern african hiv clinicians’ society gender-affirming healthcare guideline for south africa anastacia tomson, chris/tine mclachlan, camilla wattrus, kevin adams, ronald addinall, rutendo bothma, lauren jankelowitz, elliott kotze, zamasomi luvuno, nkanyiso madlala, savuka matyila, anil padavatan, mershen pillay, mmamontsheng d. rakumakoe, mathilde tomson-myburgh, willem d.f. venter, elma de vries received: 13 aug. 2021; accepted: 17 aug. 2021; published: 28 sept. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. contents executive summary scope and purpose audience methods introduction informed consent 2.1. the process 2.2. hormone therapy and surgery 2.3. children and adolescents 2.4. intellectual and developmental disability primary care 3.1. the importance of the primary care provider 3.2. comprehensive care 3.2.1. violence 3.2.2. mental health 3.2.3. substance use 3.2.4. fertility and contraception 3.2.5. cancer 3.2.6. sexual health 3.2.7. sexually transmitted infections 3.2.8. hiv 3.2.9. physical examination non-medical gender-affirming practices 4.1. binding 4.2. tucking 4.3. padding and packing psychosocial care 5.1. the role of the mental healthcare provider 5.2. children 5.3. adolescents 5.4. adults 5.5. the meso and macro context hormone therapy 6.1. background 6.2. indications 6.3. feminising therapy 6.4. masculinising therapy 6.5. adolescents 6.6. mature clients surgery 7.1. preoperative considerations 7.2. peri-surgical care institutions 8.1. care facilities 8.2. correctional facilities 8.3. work facilities 8.4. educational facilities voice and communication key terms acknowledgements references appendix 1: the role of health professionals in change of gender marker at home affairs: act 49 appendix 2: client information and consent form for feminising hormone therapy appendix 3: client information and consent form for masculinising hormone therapy executive summary we support an affirming approach to managing the transgender and gender diverse (tgd) client, centering on the individual’s agency, autonomy and right to self-determination, as opposed to practices that pathologise and stigmatise transgender identity, imposing barriers to accessing healthcare services. transgender and gender diverse individuals have long faced discrimination on multiple axes, both globally and in south africa. although south africa enshrines the protection of human rights in its constitution, tgd individuals continue to face marginalisation, prejudice and threats to their safety. challenges, including homelessness, unemployment, poor social support, bullying, harassment and violence, persist, indicating failures of policy development, practice implementation and a disregard for the human rights of individuals in the tgd community. this guideline has been developed primarily with the intention of centering and amplifying voices of tgd individuals in order to facilitate access to healthcare that is sensitive, skilled and respectful. we recognise that there are significant gaps in the knowledge and skills of healthcare providers, and there is a lack of understanding of the unique experiences faced by tgd persons. the prevailing sentiment that many healthcare providers hold around tgd individuals, informed by ignorance and conditioning within social and societal structures, are malevolent towards this community, and often include harmful assumptions and generalisations. we believe that healthcare providers have an ethical obligation to interrogate these notions, and we promote an attitude of respect for diversity that upholds human rights. it has been well established that access to competent and dignified gender-affirming healthcare (gahc) is not only safe but also plays a significant role in improving measurable outcomes for tgd clients. it has also been well established that pathologising approaches and practices that limit access to care can be damaging and harmful. finally, we recognise that tgd individuals have historically endured being undermined, condescended to and pitied by the healthcare system and its providers. we affirm a commitment to upholding a strength-based perspective that values and respects the experiences of tgd clients and celebrates their individual identity rather than merely accepting or tolerating it. this guideline, which no doubt will require ongoing revision, reflection and refinement in consultation with tgd communities and healthcare providers, represents a first step made in good faith towards creating a practical tool founded in robust scientific evidence, lodged within a human rights framework, and is intended to facilitate access to skilled and sensitive care that will yield tangible benefits to this unique and important group. scope and purpose provide evidence-informed best practice recommendations in order to enable south african healthcare providers, including psychosocial and allied healthcare professionals, to offer quality, affirming services to tgd clients. the term ‘client’, for the purposes of this guideline, includes service users, patients and participants. provide support to tgd clients when accessing healthcare services. note: this publication is a summary version of an expanded guideline, which can be accessed here: https://sahivsoc.org/subheader/index/sahcs-guidelines. audience this includes all healthcare providers, particularly those working in a primary care setting, public or private, or that care for tgd clients. methods the guideline development committee comprised 17 people, chaired by dr anastacia tomson and rev. chris/tine mclachlan, which was inclusive, with representation of providers, advocates and civil society organisations in the tgd space, and many with personal experience as a tgd client. development was predicated on the necessity to amplify the voices of those within the tgd community in order to better meet their needs, rather than presuming that healthcare providers can address those needs alone. this guideline was informed by evidence-based research studies, as well as provider experience from within the field. the committee worked from a gender-affirming, non-gatekeeping, depathologising perspective using a participatory approach that centres on the tgd client’s agency and humanity, and upholds their dignity.1,2,3 strict values underpin this guideline, as shown in table 1. in order to ensure applicability to the south african context, focused effort was made to review local research studies. resources from the global south were then accessed, and only key resources from the global north were incorporated. an extensive, external peer review process was conducted, which included both health provider and community reviews. guideline development and publication were supported by the southern african hiv clinicians’ society (sahcs) through dr camilla wattrus and dr lauren jankelowitz. table 1: values underpinning this guideline. 1. introduction i don’t think we really know what freedom is in south africa. what will it take for me to have the freedom and safety to stand up in public and say, ‘i am gender fluid’? i don’t just feel marginalised, i feel like there is no space for me at all. (personal communication with client, durban, south africa. 2020) south africa is a country with a progressive constitution and bill of rights that provide for dignity, equality and access to healthcare services.7 this is echoed by the south african health professions act and general ethical rules for health professionals18, social service professions,19 the constitutions of the professional association for transgender health in south africa20 and psychological society of south africa21, and the department of health’s batho pele principles.22 despite this, many transgender and gender diverse (tgd) individuals struggle to access gender-affirming healthcare (gahc) services in south africa. gender-affirming healthcare attends holistically to a tgd individual’s mental, physical and social well-being, and health needs, whilst respecting their self-identified gender.23 each individual has unique needs, and the gender-affirming process is rarely linear. this process may include social and medical elements, or none at all. a client with a non-binary identity may have unique and specific treatment goals: because for me, my transitioning is more spiritual than physical. i live as a woman every day. my nieces and my nephews, they call me mom, and finding peace within myself and being able to fight for them to have a representation of what love looks like makes me feel fulfilled. your womanhood is within you more than what is here on the physicality.24 it is important to note that as a healthcare provider, withholding or delaying treatment is not a neutral action. it can have an impact on the client’s mental health conditions and, in adolescents, may have implications on what medical or surgical treatment is required later in life. gatekeeping (delaying treatment until the healthcare provider feels a particular subjective degree of certainty) is potentially harmful.11 2. informed consent 2.1. the process informed consent (ic) in gahc is complex and nuanced.25,26 the ic process should empower the individual by upholding their autonomy and maintaining their integrity.11 even in a supportive and affirming environment, there is often an unequal power relationship between the client and the healthcare provider.27 this can be distressing to the client and have a negative impact on their care.28 the client and healthcare provider should be collaborative partners in decisionmaking.1,29 the healthcare provider should inform the client of the risks and benefits of the various treatment options, thus enabling the client to make an informed decision about their own healthcare.30 2.2. hormone therapy and surgery a healthcare provider wanting to prescribe hormone therapy (ht) does not require a letter from a mental health provider (mhp) in order to do so, and they may perform the psychosocial assessment themselves if comfortable.6,26 for gender-affirming surgery, a documented process of thorough ic is essential and, ideally, should be performed together with a multidisciplinary team that includes a mhp. if the client is able to consent, their autonomy should be respected and facilitated,6 and it is recommended that in the case of an mhp writing a referral letter to a surgeon, this be written in collaboration with the client.2 we note that the world professional association for transgender health (wpath) standards of care 76 states that a client should have two independent psychological evaluations prior to surgery. however, it has been convincingly argued that this is not necessary for all clients.31 2.3. children and adolescents the children’s act states: a child may consent to medical treatment if over 12 years and the child is of sufficient maturity and has the mental capacity to understand the benefits, risks, social and other implications of the treatment.32 the term ‘medical treatment’ is understood to be a manifestation of the right to health as provided for in section 27 of the constitution of the republic of south africa,7 and includes access to psychosocial and mental healthcare services.33 if an adolescent desires puberty blocking medication, ht or surgery, the ic process requires involvement of a multidisciplinary team, including both mental health and medical or surgical providers.34 it is recommended that both parents and legal guardians be included in this process wherever possible,5 as improved family support is associated with better mental health outcomes in tgd adolescents.35,36 2.4. intellectual and developmental disability individuals living with intellectual or developmental disability have the right to access healthcare services.37 this includes tgd individuals who may have limited capacity to consent to gender-affirming treatment. where fully ic cannot be provided, shared decision-making practices should be adopted, in which the client’s autonomy in the process is upheld.38 3. primary care 3.1. the importance of the primary care provider the tgd population is a marginalised group that faces many barriers in accessing healthcare services.39 currently, there are few facilities, resources and targeted programmes to cater for this population’s specific sexual and reproductive health needs.40 in order to enable broader access, the provision of gahc services needs to move away from specialist clinics and into primary care.41,42 gender-affirming healthcare should be integrated into existing primary care services, as has been done with hiv care in south africa. primary care nurses are in a key position to ensure that tgd clients receive better care and experiences within healthcare facilities.43 delivery of ht by primary care providers using the ic model can be performed safely and effectively for adult clients, with specialist endocrinologist care needed only for complex cases.44 specialist involvement may also be of great value for an adolescent client; however, case-by-case decisions should be made within a multidisciplinary team context.5 in addition, a sex-positive approach by the primary care provider is important. it recognises that each individual’s sexuality is unique and multifaceted, and emphasises the importance of sexual pleasure, freedom and diversity.45 3.2. comprehensive care screening is part of prevention and providing comprehensive primary care. when caring for a tgd client, specific attention needs to be paid to the following areas: 3.2.1. violence transgender and gender diverse persons experience a disproportionately high level of violence39 and, therefore, a trauma-informed primary care approach is essential.46 the world health organization (who) recommends the lives approach to violence (listen, enquire, validate, enhance safety and provide support).47 a client who has experienced sexual violence needs timely access to appropriate care, including post-exposure prophylaxis (pep), sexually transmitted infection (sti) prevention and, if necessary, emergency contraception.48 3.2.2. mental health comprehensive care should include screening for mental health conditions, as well as consideration of the possible negative impact of gender dysphoria on the client’s mental health, and the potential positive impact that gender-affirming treatment may have.49,50 in a south african study, it was found that transgender adults had an incidence of anxiety of 25.9%, of substance use 21.0%, of eating disorders or psychotic disorders 2.3%, and a lifetime prevalence of mood disorder of 21.2%.51 assessment should include that of the client’s existing support structure, and support and psychoeducational needs related to their care. a tgd client should always be offered mental health support,5,6 and continued support should be encouraged and facilitated, regardless of the client’s mental health status.29 a mental health condition is not a contra-indication to initiating ht, and it can be managed concurrently.6 referral to a mhp is required if there is a concern about decision-making capacity or if a mental health condition needs to be addressed. whilst the presence of some mental health disorders (particularly those with manic or psychotic features) may have an impact on an individual’s capacity to provide ic, a recent meta-review showed that most clients with a severe mental disorder made appropriate decisions regarding their healthcare.52 an australian study30 revealed that general practitioners needed to refer only 8% of their tgd clients to a mental health professional prior to ht initiation and most of these clients had either schizophrenia or post-traumatic stress disorder (ptsd). over half (56%) of tgd clients in this study had a mental health condition, such as depression, anxiety, attention-deficit-hyperactivity-disorder, autism-spectrum disorder or bipolar disorder; however, this did not have an impact on their capacity to consent to ht.30 3.2.3. substance use nearly half of transgender women (48%) and transgender men (49%) consume alcohol at hazardous, harmful or dependent levels.39 these harmful drinking practices are associated with a lifetime experience of physical or sexual violence.39 in addition, tobacco, alcohol and drug use can be used as coping mechanisms,53 and tobacco use in combination with oestrogen therapy is associated with an increased risk for venous thromboembolism;5 thus, screening is essential. a sensitive, client-centred approach within a harm reduction framework is recommended.54 3.2.4. fertility and contraception reliable contraception options must be explored in an assigned-female-at-birth (afab) client that has a uterus and ovaries, as pregnancy is still possible, even if the client is on testosterone.55 the client’s reproductive preferences should be thoroughly assessed, especially in the context of initiating ht. a transgender man who desires children may consider pregnancy56 and chest feeding.57 in a transgender woman who wishes to breastfeed, lactation can be induced by expression and medications (such as domperidone) with no adverse effects on the infant.57,58 3.2.5. cancer cancer screening is based on what anatomy (body part or organ) is present and whether the client meets the criteria for screening based on risk factors and/or symptoms. relevant screening should be carried out regardless of ht use,59 and there is no evidence for increased risk of cancer as a result of ht.59 in a tgd client with cervical tissue, cervical screening, human papillomavirus (hpv) testing and hpv vaccination are essential.60 in south africa, cervical cancer ranks as the highest cause of cancer-related deaths in persons afab61, and screening should be performed regardless of the sexual orientation or comorbidities.62 this can be performed with a pap smear or a vaginal hpv swab test. a self-collected vaginal swab is an option for a client who is reluctant to have a vaginal examination.63 in a tgd client with breast tissue, recommendations for breast cancer screening should be followed as for a cisgender person.64 prostate cancer has been documented in transgender women, although the prevalence is lower in transgender women than in cisgender men.64 screening should follow guidelines as for cisgender men; however, if a prostatic-specific antigen (psa) test is carried out in a transgender woman with a low testosterone level, the upper limit of normal should be reduced to 1.0 ng/ml (rather than 2.0 ng/ml as in cisgender men).65 3.2.6. sexual health in a client taking feminising ht, changes to libido and sexual response cycle are usually observed within 1–3 months of initiation of treatment.66 in a client taking masculinising ht, an increase in sexual desire and activity is often reported66, and clitoral enlargement is likely to occur.67 vaginal atrophy may occur because of the hypoestrogenic effect that testosterone has on vaginal tissues68 and can be ameliorated with lubricants. a tgd client on ht may experience a shift in sexual orientation over time.69 3.2.7. sexually transmitted infections transgender and gender diverse clients are not a single category. epidemiologic differences, such as the prevalence of gonorrhoea, require different responses for reducing infection and delivering appropriate sexual healthcare.70 a client may engage in high-risk behaviour, and a detailed sexual history should aid screening and examination. assumptions about the client’s sexual orientation and behaviour should be avoided, and rather discussed in a -non-judgmental way. it is also important to note that in african culture, the thought of sex as taboo limits the range of acceptable terms when discussing a sexual history.71 the use of culturally respectful language can enable the reporting of truthful facts and minimise ambiguity or shame.72 this can be performed jointly with visual aids or a bilingual lexicon when necessary.73 table 274 provides recommendations for how to take a sexual history and the isinguni alternatives provided in the table acknowledge respect and personhood-principles, that are largely characterised and embraced by southern african ethno-cultural populations. table 2: gender-inclusive language for taking a sexual history. 3.2.8. hiv transgender and gender diverse persons are disproportionately burdened by hiv and have a greater risk of acquiring the virus, with the prevalence rate of hiv being 46% amongst transgender women in south africa.75 as such, all tgd clients should be offered pre-exposure prophylaxis (prep).76 prep has no impact on the concentration of oestradiol or testosterone levels and can be safely prescribed in a client on ht.77 hiv testing and counselling services should address tgd-specific needs, and options, such as hiv self-screening, index testing and partner notification, should be offered.59 modern antiretroviral treatment (art) and the use of an integrase inhibitor are recommended for a tgd client with hiv, as there are no contraindications to ht.78 a dolutegravir-containing regimen is preferred over an efavirenz-containing regimen because it is generally better tolerated (fewer neuropsychiatric, hepatic and metabolic effects) and has a very high resistance barrier.79 if the tgd client is on both spironolactone and cotrimoxazole, serum electrolytes and renal function need to be frequently monitored because of a possible drug interaction, which may lead to hyperkalaemia, severe illness and even death.80 particularly close attention should be paid to the client if they are elderly.80 transgender women with hiv are less likely to access hiv treatment or engage in care because of barriers, such as poverty, violence, stigma and unemployment. as such, there are lower rates of virologic suppression and higher hiv-related mortality rates in this group.81 adherence to art and prep should be emphasised. social media platforms and other information communication technologies should be used to encourage retention in hiv care services.82 3.2.9. physical examination it is important to note that a physical examination may cause the tgd client distress. box 1 provides an affirming approach to a physical examination.59 box 1: an affirming approach to a physical examination. 4. non-medical gender-affirming practices it is important to understand non-medical practices and to establish which strategies the client may use. these strategies are used by tgd individuals to modify their gender presentation, and include binding, tucking, padding and packing.83,84 these strategies may alleviate gender dysphoria and can address the need to ‘pass’ as cisgender in a particular context.84 it is important to understand associated risks and benefits, and provide the client with information on how to perform them safely. 4.1. binding chest binding is used to flatten chest tissue. specialised compression garments, bandages or duct tape may be used. although this can be safely performed, risks may include back and shoulder pain, shortness of breath, and skin and soft tissue problems. recommend ‘off-days’ from binding, encourage good skin hygiene, and advise the client to avoid elastic bandages, duct tape and plastic wraps.85 4.2. tucking tucking is used to present a flat pelvic area using a gaff (a specialised tight garment, often homemade), tape or tight briefs.86 the testicles are pushed into the inguinal canal, and the penis is taped between the legs.87 although this can be safely carried out, risks may include testicular and penile pain, and skin problems such as a rash and itching.86 recommend tucking for shorter periods or less tight tucking, and good skin hygiene is encouraged.59 4.3. padding and packing padding involves the use of prosthetics or padding under the clothes to give the appearance of breasts and/or phenotypic female curves. packing is the use of prosthetics or padding under the clothes to give the appearance of a penis and phenotypic male pelvic bulge.83 both padding and packing carry little to no health risk. 5. psychosocial care the term ‘mental healthcare provider (mhp)’ has been used, and refers to the broad spectrum of providers who may assist the client with their psychosocial needs.5,89 these include clinical, counselling, educational and industrial psychologists; clinical, school and other social workers; psychiatrists; psychological and registered counsellors, and occupational therapists. 5.1. the role of the mental healthcare provider a life-course approach alongside understanding the impact of minority stress, stigma and prejudice on the client’s psychosocial well-being is recommended.2,88,89 the concerns of the individual, as well as their broader socio-economic-cultural context, should be addressed. the term ‘mental healthcare provider (mhp)’ has been used, which refers to the broad spectrum of providers who may assist the client with their psychosocial needs.5,89 the mhp has many important roles in aiding gender-affirming care, as displayed in table 3. table 3: the role of the mental healthcare provider. 5.2. children a child can present as early as 2 or 3 years of age with persistent and consistent indicators of gender diversity.5,94 the mhp needs to ‘get to know’ the tgd child, and gender incongruence must be determined together with the child and their caregiver(s).5,6,94 social transition is the recommended intervention for a tgd child, where it is their expressed need to do so6, and this can be facilitated by the mhp.97 5.3. adolescents the prospect of puberty and developing secondary sexual characteristics in conflict with experienced gender identity is often daunting and even traumatic for a tgd adolescent. the mhp should work with the adolescent and their caregiver(s) and, if appropriate, facilitate access to puberty pausing treatment.5,6,94,98,99 5.4. adults the mhp should offer an affirming and supportive space to enable tgd adults to come to an understanding and acceptance of their gender identity and its possible implications.3,100 any trauma experienced as a consequence of the client’s gender identity should be addressed. a client who has begun transitioning within adulthood may require support with ‘coming out’ to their intimate partner(s), family, friends and work colleagues; and managing the resulting relational outcomes.6,101,102 for an elderly client who may have specific challenges, such as an increased risk of isolation or loneliness, the mhp should help to identify sources of strength and resilience.103 the mhp may need to assist in finding a safe and affirming living space with adequate medical and psychosocial care. 5.5. the meso and macro context a mhp working with a tgd client (child, adolescent or adult) may need to engage with the client’s broader family, learning institution or community to help to establish safe and affirming spaces for the client. this could include supportive counselling, psychoeducation, community education, resource development and linkage, offering a support space and advocacy actions.3,5,6,94 6. hormone therapy 6.1. background gender-affirming hormones have been shown to be safe104,105 and effective,11 and were listed as essential medicines by the south african national essential medicine list committee (nemlc) in 2019, for tertiary level of care106. the goal of ht is to affirm the client’s experienced gender.17 in a non-binary client, it is particularly important to understand their desired outcome before deciding on treatment.107 provision of ht should be based on the principle of ic, rather than on the specific diagnostic criteria that have previously, and often harmfully, been applied.11 6.2. indications in south africa, the indications for accessing ht are as follows: a desire to use ht. persistent gender incongruence between one’s experienced and assigned gender. capacity to make a fully informed decision and consent to treatment. if the client is an adolescent, consult with a multidisciplinary team to confirm gender incongruence and mental capacity to provide ic.108 if a significant medical or mental health concern is present, ensure that it is managed concurrently, without delaying ht.30 gender dysphoria and real-life experience (a period of time in which a tgd individual has lived full-time in their identified gender role) are not prerequisites for the initiation or maintenance of ht.6 figure 1 shows a visual representation of the recommended process to follow when providing ht. figure 1: recommended process for provision of hormone therapy. 6.3. feminising therapy the aim of therapy is to promote the development of feminising sexual characteristics and to suppress the masculinising effects of endogenous testosterone.109 the cornerstone of treatment is administration of exogenous oestrogen. the addition of an androgen receptor antagonist may be required to achieve full suppression of testosterone110; however, recent evidence suggests that this may not be essential to reduce testosterone levels to cisgender female ranges, as was previously thought.111 for conditions that may be exacerbated by oestrogen administration, such as oestrogen-sensitive malignancies, coronary artery disease and cerebrovascular disease, careful evaluation should be done prior to ht initiation66 and ht individualised. in a client with a history of venous thromboembolism (vte), transdermal oestrogen may be considered after an ic discussion.59,112 feminising treatment options are shown in table 4, and effects and reversibility of treatment are shown in table 5126. baseline screening is recommended prior to ht treatment, as shown in figure 2127. figure 2: suggested baseline screening prior to hormone therapy initiation.baseline sex hormone levels are generally unnecessary. table 4: feminising hormone therapy and antiandrogens. table 5: timeline and reversibility of feminising hormone therapy. a client’s experience on treatment should be the primary guiding factor in dose titration and maintenance, and treatment may still be provided in resource-constrained settings where laboratory measurement of hormonal levels is not available. however, when these investigations are accessible, they can provide helpful guidance in optimising the dose. recommended laboratory monitoring is shown in table 659. table 6: laboratory monitoring for feminising and masculinising therapy. 6.4. masculinising therapy the goal of masculinising therapy is to promote the development of testosterone-induced secondary sexual characteristics.128 suppression of oestrogen and ovulation will almost always occur108 and, thus, oestrogen antagonists are not required. exogenous testosterone can be administered by intramuscular or subcutaneous injection or as a topical transdermal preparation. oral testosterone should be avoided as it is hepatotoxic.67 a client with severe hypertension, sleep apnoea or untreated polycythaemia (haematocrit above 55%) requires management prior to treatment initiation, as these conditions may be exacerbated by testosterone.66 testosterone treatment options are shown in table 766,129, whilst effects and reversibility of treatment are shown in table 866,109. baseline screening and monitoring are recommended, as indicated in figure 2 and table 6, respectively. table 7: masculinising hormone therapy. table 8: timeline and reversibility of masculinising hormone therapy. 6.5. adolescents whilst ht is not required for prepubertal tgd children, pubertal suppression to halt the progression of physical changes may significantly reduce distress in a tgd adolescent,94,108 which, in turn, has been shown to improve mental health conditions and decrease suicidality.130 puberty can be suppressed with gonadotrophin-releasing hormone agonists (gnrha) once tanner stage 2 of puberty has been reached.94 gonadotrophin-releasing hormone agonists available in south africa include leuprolide and goserelin, both of which are administered every 12 weeks via intramuscular or subcutaneous injection.131 it is recommended that a paediatric endocrinologist oversees this care,5,108 and that fertility preservation is discussed prior to ht initiation.132 the timing of ht initiation should be individualised, and should consider family support, likely time on gnrha, potential impacts on height, risks of delaying ht and the adolescent’s ability to consent.94 the inclusion of an mhp and, ideally, the parents or legal guardians are recommended when deciding on the appropriateness of ht.5 6.6. mature clients hormone therapy is indicated as a long term treatment, as some body changes may reverse if it is stopped.59 there is no age recommendation for the reduction or termination of ht, and individual cardiovascular risk in the mature tgd client needs to be considered and discussed with the client.59 7. surgery 7.1. preoperative considerations it is important to note that there is diversity in the surgery requested by tgd clients.133 a client may desire for chest or facial or genital surgery only, or a combination of these. a non-binary client’s request for surgery should be specifically individualised.134 tables 9 and 10 show, respectively, the available feminising and masculinising surgical options. hormone therapy is usually recommended prior to surgery; however, a client may be unable to or prefer not to take ht prior to surgery.6 in south africa, a documented process of thorough ic is essential prior to surgery. table 9: feminising surgery. table 10: masculinising surgery. 7.2. peri-surgical care post-surgical care is vital to recovery, and should include psychological care and physiotherapy. it is important to note that the continuity of gender-affirming care does not end with the surgical procedure(s), and ongoing support should be provided. the tgd community can play a significant role in perioperative care, both through peer and organisational support groups.140 satisfaction following surgery is usually high, with less gender dysphoria, reduced psychological distress and better integration into society.141 8. institutions 8.1. care facilities providing a safe, welcoming, and culturally appropriate healthcare environment is essential to ensure that a tgd client not only seeks care but also returns for follow-up.59 the following are recommendations for care facilities, including healthcare facilities,142,143 old-age homes103 and shelters144: ensure that staff are trained to care for a tgd client, and that anti-discrimination and anti-harassment policies are in place. limit language as a barrier by ensuring that there is staff competency to present information in more than one of south africa’s 11 official languages and, if required, basic south african sign language. ensure that the client’s gender identity and treatment information are kept confidential and protected under the protection of personal information act (popia). ensure registration records and intake forms reflect the client’s name-in-use, legal name and surname (if relevant and in consultation with the client), pronouns and gender. practise discretion with billing information in terms of differentiating between the client’s legal name and name-in-use, and consult with the client directly to avoid any breaches of confidentiality. respect a person’s name and pronouns, regardless of the appearance, history or sex assigned at birth. assign the person to a bed or room or ward based on their self-identified gender. ensure the client’s equal and fair access to bathroom facilities that are aligned with their self-identified gender (including fully private, non-binary or gender-neutral bathrooms). ensure that the client has access to personal items that facilitate their gender expression (this may include items, such as makeup and shaving equipment, and items used to bind, pack or tuck). ensure residents in shelters are able to choose their clothing, residential allocation (e.g. in single-gender settings)144 and are protected from gender-identity discrimination.103 8.2. correctional facilities the following are specific recommendations for tgd offenders: ensure that all correctional staff are trained on gender identity and diversity, and that all in-house health providers are trained in gahc.145 ensure safe and secure detention and incarceration, with appropriate section placement to reduce victimisation.146 assign the offender to a single cell, if this is their preference, but recognise that this protective placement might in itself result in victimisation.147 facilitate access to ht.148 ensure that the offender has access to sexual healthcare (provision of condoms, pep and prep), given their increased exposure to hiv and stis.146 8.3. work facilities inclusion begins before a tgd staff member’s social transition within the workplace. collaboration between leadership and human resources is needed for the implementation of clear guidance to support tgd staff.149 healthcare providers can play an advisory role in needs assessment, intervention design and implementation, and policy development and employee benefits. 8.4. educational facilities in accordance with south african legislation, all schools, whether private or public, mixed or single gender, must ensure an inclusive, non-discriminatory and diversity-affirming environment.150,151,152 this supports basic human rights, actualisation of potential, human dignity, equality, right to education, protection from physical and emotional harm, and is in the best interest of the learners. healthcare providers can assist schools with the development of relevant policies and guidelines, as well as staff sensitisation.3 9. voice and communication it is helpful to understand how sex and gender influence voice and communication, and that a speech-language therapist (slt) can play an important role in this regard.6 voice and communication are often closely connected to gender identity or expression, and the tgd client may want to sound more feminine, more masculine or gender neutral. masculinising ht can contribute to a desired voice change but may not be sufficient to achieve the client’s goals. feminising ht is unlikely to result in a desired voice change. the tgd client, therefore, may benefit from referral to a qualified slt with experience in providing gender-affirming care.6 the main strategy for voice care is related to the alteration of one’s speaking fundamental frequency, intonation and resonance.153,154 the slt should perform a voice and communication assessment, which includes a quality of life measure,155,156 and can provide both voice and communication interventions, as shown in table 11. it is important to acknowledge south africa’s multilingual communication landscape, and that communication requires an individualised approach and specialist intervention. table 11: voice and communication interventions. 10. key terms table 12 shows important key terms used within the field of gahc. table 12: key terms. acknowledgements the authors would like to acknowledge the contributors involved in the peer review process: casey blake, pierre brouard, marli conradie-smit, jenna-lee de beer-procter, diana dickinson, jenny durandt, kerry frizelle, gerhard grobler, naomi hill, kim lithgow, adele marais, sakhile msweli, lavanya naidoo, tammy nash, juan nel, simon pickstone-taylor, suntosh pillay, alicia porter, ian ross, andrew scheibe, jireh serfontein, ariane spitaels, liesl theron, john torline, leigh ann van der merwe, niel victor and lee-anne walker. a special note of thanks also goes to valencia malaza from sahcs for administrative support. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this research article. authors’ contributions all authors contributed equally to this work. ethical consideration to the fullest extent permitted by law, the southern african hiv clinicians’ society (sahcs) and the authors of this study cannot be held liable for any aspect of healthcare administered using this information or any other use, including any use that is not in accordance with any guidelines or (mis-)use. specific recommendations provided here are intended only as a guide to clinical management based on expert consensus and best current evidence at the date of first publication. management decisions for clients should be made by their responsible clinicians, with due consideration for individual circumstances and various contexts. the information provided in this document should not be considered as a substitute for such professional judgement. the most current version of this document should always be consulted. funding information the authors received no financial support for the research, authorship or publication of this article. data availability data sharing is not applicable to this article, as no new data were created or analysed in this study. disclaimer this research article followed all ethical standards for research without any direct contact with human or animal subjects. references mclachlan c. gender-affirming healthcare: our 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sj. unpacking the gender system: a theoretical perspective on gender beliefs and social relations. gend soc. 2004;18(4):510–531. https://doi.org/10.1177/0891243204265269 sutherland c, roberts b, gabriel n, struwig j, gordon s. progressive prudes: a survey of attitudes towards homosexuality & gender non-conformity in south africa. pretoria: department service delivery, democracy and governance, human science research council; 2016. iranti-org. ending pathological practices against trans and intersex bodies in africa [homepage on the internet]. johannesburg: iranti-org; 2016 [cited 2021 aug 12]. available from: https://www.iranti.org.za/wp-content/uploads/2019/04/national-intersex-dialogue.pdf births and deaths registration act no 51 of 1992. republic of south africa: government gazette; 1992. appendix 1: the role of health professionals in change of gender marker at home affairs: act 49 south african legislation allows a transgender and gender diverse (tgd) person to change his or her gender marker, as well as his or her forename. transgender and gender diverse people can apply to change their sex description in the birth register in terms of the alteration of sex description and sex status act 49 of 2003. section 2(1) states: any person whose sexual characteristics have been altered by surgical or medical treatment … resulting in gender reassignment … may apply to the director-general of the national department of home affairs for the alteration of the sex description on his or her birth register.96 in terms of section 2(2)(b), an application must include two reports by medical practitioners, the examples of which are provided below. the act does not make gender reassignment surgery compulsory. hormonal treatment is sufficient.96 application for forename change can be made as per section 24 of the births and deaths registration act and does not require any letter.161 a helpful resource that details the process for clients is available at https://www.betrue2me.org/resources/be-true-2-me-guideline-legal-gender-marker-and-forename-change/ figure 1-a1: suggested letter in support of application to department of home affairs for change in gender marker – medical doctor. figure 2-a1: suggested letter in support of application to department of home affairs for change in gender marker – surgeon (following feminising surgery). figure 3-a1: suggested letter in support of application to department of home affairs for change in gender marker – clinical psychologist or counselling psychologist or educational psychologist or clinical social worker. appendix 2: client information and consent form for feminising hormone therapy many tgd clients choose to seek gender-affirming care in the form of hormone therapy (ht). the decision to start on ht rests with you, the client, and not with your healthcare provider. the informed consent model of treatment provides you agency over this decision – it is the role of your doctor to support and guide you through this process safely and effectively. you may have read up, or heard from other tgd people, about ht. some of the information that you may have come across could potentially be out of date or inaccurate. if you have any questions or concerns at any time, you should always feel free to raise these concerns with your healthcare provider. please remember that every client is unique and will respond differently to medication, and that one client’s treatment programme might differ substantially from another because of a variety of physiological and medical factors. try not to compare the treatment you are receiving with that of anyone else – your journey is your own. if you have concerns about the efficacy of your treatment, make a point to discuss this with your provider at your next appointment. before starting on ht, there are a few points that are worth considering. this informed consent document will draw your attention to some of these points, as well as outline the expected effects, side effects and risks that are associated with ht to make sure that you have all the information you need to make the best decision about your body and your health. the role of psychotherapy in transgender and gender diverse clients visiting a psychologist is not a requirement for initiating ht. whilst previously some healthcare providers required a letter of diagnosis or referral, this is no longer necessary under international best practice. your doctor will ask you some questions to determine that you have a good support structure as you move forward. this is not because going on ht itself necessitates this but rather because for many clients of tgd experience, navigating the world is already difficult, and ht, although often resulting in many positive and beneficial changes, can also lead to some emotional lability. a solid support structure looks different for everyone; however, this may include friends, families, support groups, therapists or counsellors. your doctor might suggest or offer you referrals to support groups and therapists, if you indicate that you might benefit from these. the role of endocrinologists and other specialists hormone therapy does not need to be prescribed or monitored by an endocrinologist. prescribing ht is well within the realm of a suitably skilled general practitioner (gp) or family physician. not all gps, nor all endocrinologists, have experience in managing gender-affirming ht, and the expertise of the clinician should be the guiding factor in determining who prescribes and monitors your ht. you may benefit from visiting other allied healthcare professionals, such as speech therapists, or from medical specialists, such as plastic surgeons. not every tgd client will necessarily want to pursue these options, and you should discuss your individual goals with your prescribing doctor. home affairs and gender marker if you wish to update your gender marker on your birth certificate and id document, the department of home affairs requires two letters from healthcare professionals, which state that you have undergone medical or surgical gender reassignment. either of these is sufficient; you do not need to have had surgery to update your gender marker. unfortunately, at present, gender markers in south africa are binary; thus, an id document can reflect either female or male gender; there is no unspecified or non-binary marker. your prescribing doctor can write one of your letters for the department of home affairs and should be able to refer you to another healthcare provider to write the second letter. if you wish to change your name, this process should be undertaken separate to updating your gender marker (either before or after). this does not require supporting letters from healthcare providers. other important aspects to explore: potential challenges with legal documents: some tgd persons have trouble with banking, registration as a student and writing examinations, registration of motor vehicles, and so on whilst they are waiting for their new documents. some are accused of potential fraud because they do not look the same as the photograph in their identity document or their name may be different from the name on their qualification certificates. changing one’s gender marker and names will take a while. you may want to consider how you will deal with it in the interim. you also may want to consider whether you need to change other documentation, for example your matric certificate. potential impact on emotions: the impact of hormones can be very diverse and individualised. your mood may fluctuate. for example, some tgd women may experience being more moody or tearful at times. potential impact on relationships with family and significant others: have you thought about the possible impact on your relationship with significant others? if you are in an intimate relationship, this may change when you start on hormones, and relationship roles may need to be renegotiated. a partner may grieve the loss of aspects of who you were and the way the relationship used to be. what possible impacts can it have on your family and how will you be able to deal with your family’s response? have you considered the impact of the change of gender role in your family? have you considered the impact of potential loss of fertility? are there children that may be impacted and are the children prepared? potential change in sexual orientation: it is possible that your sexual orientation may remain constant or shift, either temporarily or permanently (e.g. shift in attraction or choice of sexual partners, widened spectrum of attraction and shift in sexual orientation identity). potential impact on safety: in some settings, the physical changes in hormones may have an impact on your safety, with people who do not fit into society’s expectations of male or female being at increased risk of violence. potential impact on employment: some tgd persons experience discrimination in the workplace or struggle to obtain employment. this may be more difficult when your legal documents (e.g. identity document) and your appearance do not match. potential grief and loss: some tgd people experience a sense of loss, for example a tgd woman may be treated differently by society when she is read as a female person. a tgd woman may also experience that she has become physically weaker. taste changes: some tgd persons experience a change in their taste sensations, and their likes and dislikes of certain foods. body odour change: some tgd persons experience a change in their body odour on hormone treatment. appetite and sleeping patterns: often the tgd person will experience an increase of appetite, which, in turn, could lead to weight gain. sleeping patterns may also be affected. feminising hormone therapy feminising ht is prescribed for assigned-male-at-birth clients who wish to feminise. the backbone of feminising ht is oestrogen therapy. anti-androgens (spironolactone, cyproterone acetate or bicalutamide) are sometimes used, although many clients can achieve testosterone suppression using oestrogen therapy alone. the biggest concern with oestrogen therapy is the risk of clot formation, which can lead to deep venous thrombosis (dvt), or life-threatening pulmonary emboli. it is this risk that limits the amount of oestrogen we can safely give clients. oral oestrogen (e.g. estrofem or premarin) carry a higher risk of these adverse events than parenteral (i.e. administered outside the digestive tract) oestrogen. your doctor will discuss with you the various options for ht that are available and help you to decide which form of treatment is best for you. costs of hormone therapy it is important to remember that not only do different clients have different needs in accessing ht but also that prices for medication may vary between different pharmacies, and that these prices may fluctuate over time. the majority of clients can expect to spend approximately r300–r500 per month on ht. this does not include monitoring blood tests or doctor’s visits. changes that occur when using hormone therapy the changes you will experience on ht often take some time to fully develop. some of these changes are reversible, and will disappear should you discontinue ht. others are irreversible and will persist even if you stop taking your hormones. the timeline for these changes to begin is variable; however, most of them will only reach their maximum degree after 3–5 years on ht. reversible changes loss of muscle mass and decreased strength changes in body fat distribution, possibly associated with weight gain (increased fat deposition in breasts, buttocks, hips and thighs) softer and thinner skin reduced acne lighter and thinner body and facial hair cessation of male-pattern balding, possible scalp hair regrowth changes in sex drive (usually a decrease initially, followed by an increase together with a change in sexual response cycle) changes in the strength and frequency of erections, and changes in the amount and consistency of ejaculate changes in mood and emotional response. irreversible changes breast development; whilst the size of breast tissue may fluctuate, ht will cause permanent development of breast structures, which will remain even if ht is withdrawn testicular atrophy infertility changes in bone density. limitations of hormone therapy it is important to understand that there are certain features that ht cannot alter, which include the following: presence of facial hair – although ht may make the hair thinner, or cause it go grow more slowly, ht will not eliminate facial hair pitch of the voice bone structure of the face presence of thyroid cartilage (adam’s apple). important risks associated with hormone therapy as with any medication, ht carries with it certain risks. some of these risks can be mitigated or reduced by lifestyle factors, whilst others are independent risks that cannot be altered. it is important to be fully aware of the risks associated with ht before starting your treatment. blood clots are the most prominent risk factor associated with feminising ht. a blood clot can lead to dvt, pulmonary embolism (a blood clot in the lungs), heart attacks or strokes. these conditions may be severely debilitating or even fatal: cardiovascular disease nausea or vomiting migraines or other headaches gallstones and other diseases of the gallbladder. elevated levels of prolactin can rarely occur in clients on feminising ht because of the development of a prolactinoma, a benign (non-cancerous) tumour of the pituitary gland, which may interfere with vision. these can require surgical management, depending on the nature of the lesion. some of the risks mentioned are modified by other factors. notably, cardiovascular and clot risk are worse in clients who are above the age of 45 smoke use alcohol have pre-existing medical conditions, such as diabetes, high blood pressure and high cholesterol. some clients will experience a reduction in their blood pressure and improvements in their cholesterol levels on ht. this is not a guarantee and is not a replacement for positive lifestyle changes. fertility although not all clients become infertile on ht, and some might regain fertility if they stop ht, many may become irreversibly infertile. hormone therapy is not a replacement for effective and responsible contraceptive use. all clients considering starting on ht should consider using a cryobank to preserve genetic material, in case they wish to conceive genetically related children at a later stage. even if this is not a priority for you at this stage in your life, please consider the possibility that your perspectives might change with time, and that it is ideal to store material before starting ht rather than trying to regain fertility once you are already on hormone treatment. your doctor can refer you to facilities that can assist in cryopreservation. monitoring and follow up your doctor will advise and guide you in monitoring your safety while you are on ht. usually, this will involve regular check-ups and physical examinations, as well as certain blood tests. at the outset, it is not uncommon for these evaluations to be performed monthly, whilst you are still achieving the correct hormonal balance for you. later, once you are stable on treatment, these intervals might be extended to 6-monthly, or perhaps even annually. this schedule is different for every client. if you decide to stop your ht, you should discuss this decision with your doctor. it can be dangerous to abruptly withdraw ht without adequate medical supervision. more information please remember that you can discuss any questions or concerns with your doctor at any time. information on self-injection technique can be found at: https://fenwayhealth.org/wp-content/uploads/2015/07/com-1880-tgd-health_injection-guide_small_v2.pdf informed consent for feminising hormone treatment i confirm that i have read and understand the information above. i confirm that my doctor has told me about the effects of feminising hormone treatment, including the more common or serious risks and side effects as mentioned above. i understand that some of these effects may be permanent. i understand that as part of my treatment plan, i shall take my medication as prescribed and have check-ups, including blood tests as required. my doctor has offered me adequate opportunity to ask any questions that i have regarding feminising hormone therapy. i hereby agree that my doctor starts/continues treating me with feminising hormone therapy. appendix 3: client information and consent form for masculinising hormone therapy many tgd clients choose to seek gender-affirming care in the form of ht. the decision to start on ht rests with you, the client, and not with your healthcare provider. the informed consent model of treatment provides you agency over this decision – it is the role of your doctor to support and guide you through this process safely and effectively. you may have read up, or heard from other tgd individuals, about ht. some of the information that you may have come across could potentially be out of date or inaccurate. if you have any questions or concerns at any time, you should always feel free to raise these concerns with your healthcare provider. please remember that every client is unique and will respond differently to medication, and that one client’s treatment programme might differ substantially from another’s because of a variety of physiological and medical factors. try not to compare the treatment you are receiving with that of anyone else – your journey is your own. if you have concerns about the efficacy of your treatment, make a point to discuss this with your provider at your next appointment. before starting on ht, there are a few points that are worth considering. this informed consent document will draw your attention to some of these points, as well as outline the expected effects, side effects and risks that are associated with ht to make sure that you have all the information you need to make the best decision about your body and your health. the role of psychotherapy in transgender and gender diverse clients visiting a psychologist is not a requirement for initiating ht. whilst previously some healthcare providers required a letter of diagnosis or referral, this is no longer necessary under international best practice. your doctor will ask you some questions to determine that you have a good support structure as you move forward. this is not because going on ht itself necessitates this, but rather because for many clients of tgd experience, navigating the world is already difficult, and ht, although often resulting in many positive and beneficial changes, can also lead to some emotional lability. a solid support structure looks different for everyone; however, this may include friends, families, support groups, therapists or counsellors. your doctor might suggest or offer you referrals to support groups and therapists, if you indicate that you might benefit from these. the role of endocrinologists and other specialists hormone therapy does not need to be prescribed or monitored by an endocrinologist. prescribing ht is well within the realm of a suitably skilled gp or family physician. not all gps, nor all endocrinologists, have experience in managing gender-affirming ht, and the expertise of the clinician should be the guiding factor in determining who prescribes and monitors your ht. you may benefit from seeing other allied health professionals, such as speech therapists, or from medical specialists such as plastic surgeons. not every tgd client will necessarily want to pursue these options, and you should discuss your individual goals with your prescribing doctor. home affairs and gender marker if you wish to update your gender marker on your birth certificate and id document, the department of home affairs requires two letters from healthcare professionals, which state that you have undergone medical or surgical gender reassignment. either of these is sufficient; you do not need to have had surgery to update your gender marker. unfortunately, at present, gender markers in south africa are binary – thus, an id document can reflect either female or male gender; there is no unspecified or non-binary marker. your prescribing doctor can write one of your letters for the department of home affairs and should be able to refer you to another healthcare provider to write the second letter. if you wish to change your name, this process should be undertaken separate to updating your gender marker (either before or after). this does not require supporting letters from healthcare providers. potential challenges with legal documents: some tgd persons have trouble with banking, registration as a student and writing examinations, registration of motor vehicles, and so on whilst they are waiting for their new documents. some are accused of potential fraud because they do not look the same as the photograph in their identity document or their name may be different from the one on their qualification certificates. changing one’s legal gender marker and names will take a while. you may want to consider how you will deal with it in the interim. you also may want to consider whether you need to change other documentation, for example your matric certificate. other important aspects to explore: potential impact on emotions: the impact of testosterone can be very diverse and individualised. your mood may fluctuate. for example, often a tgd man may struggle to cry, and their emotions may become less intense. some also experience increased irritability. potential impact on relationships with family and significant others: have you thought about the possible impact on your relationship with significant others? if you are in an intimate relationship, this may change when you start on hormones, and relationship roles may need to be re-negotiated. a partner may grieve the loss of aspects of who you were and the way the relationship used to be. what are the possible impacts it can have on your family and how will you be able to deal with your family’s response? have you considered the impact of the change of gender role in your family? have you considered the impact of potential loss of fertility? are there children that may be impacted and are the children prepared? potential change in sexual orientation: it is possible that your sexual orientation may remain constant or shift, either temporarily or permanently (e.g. shift in attraction or choice of sexual partners, widened spectrum of attraction and shift in sexual orientation identity). potential impact on safety: in some settings, the physical changes in hormones may have an impact on your safety, with people who do not fit into society’s expectations of male or female being at increased risk of violence. potential impact on employment: some tgd persons experience discrimination in the workplace or struggle to obtain employment. this may be more difficult when your legal documents (e.g. identity document) and your appearance do not match. potential grief and loss: some tgd persons experience a sense of loss. a tgd man may lose certain gender roles in the family. taste changes: some tgd persons experience a change in their taste sensations, and their likes and dislikes of certain foods. body odour change: some tgd persons experience a change in their body odour on hormone treatment. appetite and sleeping patterns: often the tgd person will experience an increase of appetite. this could lead to weight gain. sleeping patterns may also be affected. masculinising hormone therapy masculinising ht is prescribed for assigned-female-at-birth clients who wish to masculinise. the backbone of masculinising ht is testosterone therapy. no additional medications are necessary to suppress oestrogen, as testosterone is able to do this alone. the biggest concern with testosterone therapy is the risk of liver and cardiovascular disease. testosterone use can adversely affect the liver, which is an organ vital to detoxifying the blood, and metabolising medications and dietary nutrients. changes in testosterone levels have also been found to increase low-density lipoprotein (commonly known as ‘bad’) cholesterol and decrease high-density lipoprotein (commonly known as ‘good’) cholesterol. these changes in the metabolic profile can increase a client’s risk of heart attacks or strokes to levels similar to those seen in cisgender men. your doctor will discuss with you the various options for ht that are available and help you to decide which form of treatment is best for you. additional medications for clients who wish to achieve suppression of menstruation, but have not performed so on testosterone alone, progesterone may be added. some clients will use topical minoxidil in order to achieve fuller facial hair growth. costs of hormone therapy it is important to remember that not only do different clients have different needs in accessing ht but also that prices for medication may vary between different pharmacies, and that these prices may fluctuate over time. the majority of clients can expect to spend between r200 and r600 per month on ht. this does not include monitoring blood tests or doctor’s visits. changes that occur when using hormone therapy the changes you will experience on ht often take some time to fully develop. some of these changes are reversible and will disappear should you discontinue ht. others are irreversible and will persist even if you stop taking your hormones. the timeline for these changes to begin is variable; however, most of them will only reach their maximum degree after 3–5 years on ht. reversible changes gain of muscle mass and increased strength changes in body fat distribution, possibly associated with weight gain (increased fat deposition in the abdomen, and decreased fat in breasts, buttocks and thighs) coarser and thicker skin increased acne coarser and thicker body hair increased red blood cell count increase in sex drive changes in mood and emotional response (often initially an increase in irritability, amongst other emotions) cessation of menses and ovulation, and dryness of the genital tissues. irreversible changes hair loss or male pattern baldness may occur facial hair growth deepening of the voice enlargement of the clitoris infertility. limitations of hormone therapy it is important to understand that there are certain features that ht cannot alter, which include the following: presence of breast tissue – ht can reduce fat deposition in the breasts and make them smaller; however, it will not result in a loss of actual breast tissue bone structure – ht will not change the structure of your pelvis or make you grow taller important risks associated with hormone therapy as with any medication, ht carries with it certain risks. some of these risks can be mitigated or reduced by lifestyle factors, whilst others are independent risks that cannot be altered. it is important to be fully aware of the risks associated with ht before making the decision to start your treatment: high cholesterol or blood fats increased red blood cell count high blood pressure. all of the above can lead to or worsen cardiovascular disease, or lead to strokes. these conditions can be life threatening. liver disease psychiatric symptoms include mood disturbances, anxiety or psychosis, especially if there are pre-existing mental health conditions. if you have been diagnosed with a mental health condition and/or use psychiatric medication, you need to discuss the starting of ht with your doctor. the use of hormones can interact with various medications and may have an impact on your mental health conditions. some of the risks mentioned are modified by other factors. notably, cardiovascular and clot risks are worse in clients who smoke use alcohol have pre-existing medical conditions, such as diabetes, high blood pressure and high cholesterol. fertility although not all clients become infertile on ht, and some might regain fertility if they stop ht, many may become irreversibly infertile. hormone therapy is not a replacement for effective and responsible contraceptive use. all clients considering starting on ht should consider using a cryobank to preserve their genetic material, in case they wish to conceive genetically related children at a later stage. even if this is not a priority for you at this stage in your life, please consider the possibility that your perspectives might change with time, and that it is ideal to store genetic material before starting with ht rather than trying to regain fertility once you are already on ht. your doctor can refer you to facilities that can aid in cryopreservation. monitoring and follow-up your doctor will advise and guide you in monitoring your safety whilst you are on ht. usually, this will involve regular check-ups and physical examinations, as well as certain blood tests. at the outset, it is not uncommon for these evaluations to be performed monthly, whilst you are still achieving the correct hormonal balance for you. later, once you are stable on treatment, these intervals might be extended to 6-monthly, or perhaps even annually. this schedule is different for every client. if you decide to stop your ht, you should discuss this decision with your doctor. it can be dangerous to abruptly withdraw ht without adequate medical supervision. more information please remember that you can discuss any questions or concerns with your doctor at any time. information on self-injection technique can be found at: https://fenwayhealth.org/wp-content/uploads/2015/07/com-1880-tgd-health_injection-guide_small_v2.pdf informed consent for masculinising hormone treatment i confirm that i have read and understand the information above. i confirm that my doctor has told me about the effects of masculinising hormone treatment, including the more common or serious risks and side effects as mentioned above. i understand that some of these effects may be permanent. i understand that as part of my treatment plan, i shall take my medication as prescribed and have check-ups, including blood tests, as required. my doctor has offered me adequate opportunity to ask any questions that i have regarding masculinising hormone therapy. i hereby agree that my doctor starts/continues treating me with masculinising hormone therapy. abstract introduction case report discussion acknowledgements references about the author(s) somasundram pillay department of internal medicine, faculty of health sciences, university of kwazulu-natal, durban, south africa nombulelo magula department of internal medicine, faculty of health sciences, university of kwazulu-natal, durban, south africa citation pillay s, magula n. a trio of infectious diseases and pulmonary embolism: a developing world’s reality. s afr j hiv med. 2021;22(1), a1192. https://doi.org/10.4102/sajhivmed.v22i1.1192 case report a trio of infectious diseases and pulmonary embolism: a developing world’s reality somasundram pillay, nombulelo magula received: 05 nov. 2020; accepted: 11 dec. 2020; published: 28 jan. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract introduction: human immunodeficiency virus (hiv), tuberculosis (tb) and coronavirus disease (covid-19) infections independently possess the ability to trigger formation of venous thromboembolism (vte) and pulmonary embolism (pe). to the authors’ knowledge, this is the first case report describing the presence of pe in a patient with all three aforementioned infectious co-morbidities. presentation: a patient living with hiv with virological failure secondary to defaulting antiretroviral therapy (art) presented with hypoxia, clinical and radiological features suggestive of community-acquired pneumonia (cap) with raised inflammatory markers and d-dimer levels. management: she was commenced on prophylactic anticoagulation, supplemental oxygen and empirical antibiotics targeting cap and pneumocystis jiroveci pneumonia, swabbed for covid-19 infection and had sputa sent for gene xpert® tb testing. a day later, covid-19 results returned positive and the patient was transferred to isolation and added onto dexamethasone and therapeutic anticoagulation. sputa returned positive for mycobacterium tb a day later, and anti-tuberculosis therapy was added. she remained persistently hypoxic, with a well’s score of 3 placing her at moderate risk for pe, which prompted for a computed tomography pulmonary angiogram (ctpa) being ordered, which demonstrated left lower lobe subsegmental pe. warfarin was added to her regimen. she was discharged on day 18 with a therapeutic international normalised ratio (inr) and not requiring oxygen therapy. conclusion: this scenario is relevant in low to middle-income countries. the utilisation of a raised d-dimer in the setting of all four coexisting conditions in arriving at a definite diagnosis remains uncertain. we noted that despite our index patient being on thrombo-prophylaxis, she developed pe highlighting the need for increased vigilance in all covid-19 patients, even those on prophylactic anticoagulation. keywords: hiv; tuberculosis; covid-19; pulmonary embolism; middle-income countries. introduction coronavirus disease (covid-19) infection is associated with increased prevalence of venous thromboembolism and pulmonary embolism (pe).1,2,3,4,5 pulmonary embolism carries a high morbidity and mortality burden, and a high index of suspicion for underlying pe must be maintained in all covid-19 infected patients. hypercoagulability in covid-19 infection occurs either because of altered haemostasis, severe inflammation, endothelial dysregulation or disseminated intravascular coagulation.1 the risk of venous thromboembolism (vte) in patients living with hiv (plhiv) is increased in patients who are antiretroviral therapy (art)-naïve, those with a low cluster of differentiation (cd4) counts and virally unsuppressed.6 dentan and colleagues showed that tuberculosis is significantly associated with vte. they, however, found no link between tb and pe but postulated that the occurrence of pe in patients with tb (pwtb) could be explained by hypercoagulability.7 reports of pe in pwtb in africa are scarce. kwas et al. have described three cases of tb associated with pe in patients from tunisia,8 whilst ekukwe and colleagues described another case of bilateral pe in a pwtb.9 clinical and therapeutic challenges exist in plhiv presenting with community-acquired pneumonia (cap). depending on the patient’s art compliance, viral load, certain differentials arise – especially if the patient is viral unsuppressed where in addition to covid-19 pneumonia, one considers pneumocystis jiroveci pneumonia (pjp) and/or pulmonary tb as differentials. empirical therapy is commenced with an antibiotic (containing a combination of trimethoprim and sulfamethoxazole) plus corticosteroid therapy for pjp with amoxicillin-clavulanic acid and azithromycin for cap.10 we describe the following typical patient encountered in clinical practice to demonstrate the need for maintaining a high level of clinical vigilance for pe in patients with coexistent hiv, tb and covid-19 infection. no data exists, describing the occurrence of pe in such a patient co-infected with all three infectious conditions. case report miss b.n.s., a 44-year-old female living with hiv since 1997, had defaulted art since 2012 and was virologically unsuppressed (viral load of 23 358 copies/ml, cd4 = 66 cells/µl). she presented on 22/09/2020 with a 1-week history of constitutional symptoms (poor appetite, night sweats and easy fatigability) associated with a non-productive cough and shortness of breath. no symptoms of fever, sore throat, anosmia or dysgeusia were elicited. clinical examination revealed a chronically ill-looking patient, tachycardia (133 beats/min), tachypnoea (22 breaths/min) and hypoxic at room air (oxygen saturation of 88%). chest auscultation revealed crepitations in the mid and lower zones of her right lung. chest radiograph (figure 1) showed bilateral central and peripheral ground-glass opacification (ggo), greater involvement of the right lung. figure 1: chest radiograph (postero-anterior view). blood investigations revealed results as per table 1. based on the patient’s history, clinical, radiological and biochemical findings, a diagnosis of cap was made, and she was started empirically on amoxicillin-clavulanic acid, azithromycin, oral trimethoprim/sulfamethoxazole, prednisone and prophylactic clexane® 60 mg daily. nasopharyngeal swab and sputa were sent for covid-19 and tb polymerase chain reaction (pcr). a day later, the covid-19 pcr result returned as positive. she was initiated onto dexamethasone, vitamin d, zinc, thiamine, ascorbic acid and therapeutic anticoagulation (enoxaparin 60 mg bd). whilst in the ward she remained hypoxic requiring 100% rebreather mask to maintain an oxygen saturation of over 90%. the sputa tb pcr test returned positive on 24/09/2020, and the patient was initiated onto anti-tuberculosis treatment (rifafour® 3 tablets with pyridoxine 25 mg daily). table 1: results of laboratory investigations. however, despite being on treatment for pjp, pulmonary tb and cap, the patient remained hypoxic with a wells’ score of 3 (heart rate > 100 bpm and prolonged immobilisation) putting her at moderate risk of developing a pe.11 a ctpa was ordered and revealed bilateral ggo and left lower lobe subsegmental pulmonary emboli (figure 2). figure 2: computed tomography pulmonary angiogram showing filling defect in left lower lobe subsegmental pulmonary artery. no evidence of deep vein thrombosis was found. warfarin 5 mg daily was added to her existing anticoagulation regimen. the final diagnosis made in miss b.n.s. was that of a plhiv, virologically unsuppressed, who defaulted art with a cd4 of 66 with confirmed: severe covid-19:12,13,14 pulmonary tuberculosis pulmonary embolism pneumocystis iirovecii pneumonia (clinical diagnosis plus a positive serum b-d-glucan). she remained hypoxic needing prolonged oxygen supplementation until day 17 post-admission. on day 18, she was transferred to a step-down facility off oxygen to continue with her anticoagulation and tb treatment with a view to restarting art in 6–8 weeks. discussion individually, hiv, tb and covid-19 can predispose to thromboembolism. this case report describes the presence of pe in a patient with all aforementioned infectious diseases and the complexities associated with diagnosis in a developing country. no literature could be found on the combination of hiv, tb, covid-19 and the development of pe in a single patient. daily clinical patient re-evaluation is a necessity even in the times of covid-19. this is often neglected as clinical staff are afraid of their well-being and resort to making notes without careful patient re-examination. together with clinical examination, review of blood investigations and patient’s oxygen consumption needs, a management plan could be formulated. the plasma d-dimer test has a low specificity and can be raised in a multitude of conditions including hiv-infection, tb, vte, pe, covid-19, pneumonia and increased age.15,16,17,18 this limited its use in differentiating between the four coexistent medical conditions in our patient, all of which are known to cause elevations in d-dimer levels. this highlights the complexity of diagnosing pe in the context of hiv, tb and covid-19 infection. the debate on the use of thromboprophylaxis in patients hospitalised with covid-19 is ongoing with most studies currently advocating for its use.19,20,21 prophylactic anticoagulation has long been recommended for at-risk in-patients with medical conditions such as hiv and/or tb.22,23 despite being on prophylactic enoxaparin, our patient still developed a pe. this is similar to what klok et al. and tang et al. showed in their studies.9,24 pulmonary embolism remains a great masquerader and clinicians must maintain a level of vigilance for diagnosing this life-threatening medical condition, more especially during the covid-19 infection era. acknowledgements competing interests the authors have declared that no competing interest exists. authors’ contributions the principal author (s.p.) made substantial contributions to conception and design of the work, writing of the article and final approval and agreed to be accountable for all aspects of the research. the co-author (n.m.) made substantial contributions to conception of the work, critically reviewed and edited the draft and final approval and agreed to be accountable for all aspects of the research. ethical consideration approval was obtained from the patient, king edward viii hospital and the kwazulu-natal department of health. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references allen, f. & michaely, r., 2003, ‘payout policy’, in g.m. constantinides, m. harris & r.m. stulz (eds.), handbook of the economics of finance, vol. 1, pp. 337–429, elsevier, amsterdam. alzahrani, m. & lasfer, m., 2012, ‘investor protection, taxation, and 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companies: transparent or not?’, journal of accounting in emerging economies 10(3), 465–486. https://doi.org/10.1108/jaee-02-2020-0040 van der linde, k., 2008, ‘aspects of the regulation of share capital and distributions to shareholders’, phd thesis, university of south africa, pretoria. venter, s., 2014, ‘the impact of the introduction of dividends tax in south africa on foreign and local investors’, master’s thesis, university of pretoria, pretoria. wesson, n. & hamman, w.d., 2012, ‘the repurchase by a holding company of treasury shares held by subsidiaries: a south african perspective’, south african journal of business management 43(4), 33–44. https://doi.org/10.4102/sajbm.v43i4.480 wesson, n., hamman, w.d. & bruwer, b.w., 2015, ‘share repurchase and dividend payout behaviour: the south african experience’, south african journal of business management 46(3), 43–54. https://doi.org/10.4102/sajbm.v46i3.100 wesson, n., smit, e., kidd, m. & hamman, w.d., 2018, ‘determinants of the choice between share repurchases and dividend payments’, research in international business and finance 45, 180–196. https://doi.org/10.1016/j.ribaf.2017.07.150 williams, l.j. & abdi, h., 2010, ‘fisher’s least significant difference (lsd) test’, in n. salkind (ed.), encyclopedia of research design, pp. 840–853, sage, california. world bank, 2020, world development indicators – gdp growth (annual %), viewed 18 may 2020, from https://databank.worldbank.org/source/world-development-indicators. march 2002 -----------the souththn africa journal or hiv medicine legal issues the coming crime wave? aids, orphans and crime in south africa orphans run greater risks of being malnourished and stunted than children who have parents to look after them.' they are also the first to be denied education when extended families cannot afford to educate all the children of the household. this lack of schooling, often combined with poor nutrition, makes it particularly difficult for orphans to escape poverty.' poverty and urbanisation orphans and crime a number of studies have been conducted on the plight of orphans and their caretakers in various african countries. it has been shown that families that foster children in kenya usually live below the poverty line, and that orphan households in tanzania have more children, are larger, and have less favourable dependency ratios than non-orphan households.' however, the large number of anticipated aids orphans has led the united nations international children's emergency fund (unicef) to conclude that africa's age-old social safety net for such children in the form of deep-rooted kinship systems and extended family networks is unable to cope with the strain of aids and soaring numbers of orphans in the most affected countries: 'capacity and resources are stretched to breaking point, and those providing the necessary care in many cases are already impoverished, often elderly and might themselves have depended financially and physically on the support of the very son or daughter who has died:' the many orphaned south african children who will grow up under extreme levels of poverty will be sorely tempted or even obliged for the sake of their physical survival to commit a range of property-related crimes. these crimes will include the theft of food and clothing by shoplifting and residential burglary, or the theft of other items which can be sold or traded for food, clothing or other necessities. older orphans in their early teenage years might resort to mugging and robbery to make ends meet. children or on the growing proportion of elderly people. martin schonteich institl/te for seclln·ty studies, pretoria introduction as the aids epidemic progresses 'here will be fewer adults of normal parenting age to care for the children they leave behind. the burden of care will increasingly fall on other south africa has the largest population of hiv-positive people in the world. it is estimated that 6 million south africans will die from the epidemic by 2010.' in contrast to most infectious diseases, which target the elderly and the very young, hiv/aids takes its greatest toll among young adults. the expected wholesale death of young adults in south africa is producing orphans on a scale unprecedented in the country's history. in addition, hiv/aids will detrimentally affect the criminal justice system's effectiveness. with an increasing number of police officers, prison wardens and court personnel falling ill and dying, the state's ability to fight crime, and punish and rehabilitate offenders will be undermined. crime levels in south africa are likely to increase over the next two decades because of the hiv/aids epidemic. the epidemic will result in an unprecedented increase in the country's orphan population. growing up without parents, and badly supervised by relatives and welfare organisations, this growing pool of orphans will be at greater than average risk of engaging in criminal activity. many orphans will also be vulnerable to victimisation. nearly 1 million south african children under the age of 15 years will have lost their mother or both parents to aids by 2005. the department of health [doh) estimates that this figure will increase to over 2 million by 2010.' overwhelming caregivers historically, large-scale orphaning has been a sporadic, short-term problem caused by war, famine or disease. the hiv/aids epidemic has transformed it into a long-term chronic problem that will extend at least through the first third of the twenty-first century.' this is because the increase in orphan rates lags behind hiv infection levels by about 10 years, the time it takes the average person who contracts the virus to die from full-blown aids. [ht sou"hhl afr.ica jour.nal ot hl\ afo cl t ----------march 2002 the migration of children to urban centres has long been observed in developing countries, including south africa, because of high rural unemployment and poverty levels' this 'rend is li ely to increase as the epidemic escalates and leaves large numbers of orphans in its wake. a significant number of child migrants flocking to their nearest ci will increase the already high numbers of street children in south africa. street children are both the cause and victims of a range of crimes. petty thefts, muggings, burglaries and theft out of motor vehicles are crimes commonly associated with street children. many such children are assaulted, abused, raped and drawn into prostitution rings. a large influx of orphaned children into the urban slums surrounding many south african cities will exacerbate soda-economic conditions, thereby creating a vibrant breeding ground for a variety of social ills such as crime. moreover, certain types of crime, such as gang-related crimes, vehicle thefts, robberies and burglaries, are higher in cities than in rural areas, with the rate generally increasing according to city size. moreover, most factors associated with high crime rates characterise cities to a greater extent than small towns or rural villages. population density, for example, is thought to be associated with crime in that greater concentrations of people lead to competition for limited resources, greater stress and increased con ic. faclors that characterise urbanisation such as overcrowding and increased consumer demands and expectations are lhemselves believed to be associated with high crime rates. high levels of gang activity and the availability of firearms are also mainly evident in urban areas and are known to be related to criminal activity.' psychological trauma children who lose a parent to aids suffer loss and grief like any other orphan. however, their loss is exacerbated by prejudice and social exclusion, and can lead to the loss of education and health care:' that is, the shame, 'ear and rejection that often surrounds people affected by hiv/aids can create additional stress and isolation for children, both before and after the death of their parent or parents. the psychological impact on a child who witnesses his or her parent dying of aids can be more intense than for children whose parents die from more sudden causes. according to unaids: 'hiv ultimately makes people ill but it runs an unpredictable course. there are typically months or years of stress, suffering or depression before a patient dies. and in developing countries, where the epidemic is concentrated, effective pain or symptom relief is often unavailable lo alleviate a parent's suffering:" moreover, for a child living with a parent who has aids, the disease is especially cruel as hiv is sexually transmitted. consequently, once one parent is infec ed, he or she is likely to pass it on to the other parent. children who lose a parent to aids are therefore at considerable risk of losing their remaining parent as well. children consequently have to take on the role of mother, father or both, doing housework, farming and caring for their siblings and their ill or dying parents, 'bringing on stress that would exhaust even adults'." a report prepared for unicef identifies a set of experiences commonly affecting most aids orphans: • trauma associated with losing a parent, which is in most cases exacerbated by the threat of losing the second parent • witnessing the parent's physical deterioration, pain and death • caring for a parent in his or her terminal phase and often being blamed for causing pain • anxiety about source of livelihood and ability to retain the family home after the parent's death" research commissioned by the nelson mandela children's fund found that south african aids orphans are being ostracised by their communities and exploited financially by relatives who had taken them in, primarily to receive a state grant. emotionally, the orphans were found to be suffering as a result of he deprivation of parental guidance, emotional trauma as a result of loss, and the problem of having to cope with adult responsibilities prematurely. the research found that orphans were also vulnerable to physical and sexual abuse by neighbours and relatives:' delinquency and crime a south african doh publication," which looks at the impact of aids in south africa, predicts that children orphaned because of aids could be at risk of engaging in delinquent behaviour: 'as [orphaned] children under stress grow up without adequate parenting and support, they are at greater risk of developing antisocial behaviour and of being less productive members of society:" ashraf grimwood of the national aids coalition in south africa argues that the increasing number of aids orphan~ who grow up without parental support and supervision, will turn to crime: 'crime will increase because of the disintegration of the fabric of our society. it will be made worse by the lack of guidance, care and support for hivpositive people, including children. children orphaned by aids will have no role models in the future and they will resort to crime to survive:" a review of the backgrounds of a large sample of children who have killed or committed other grave (usually violenr) crimes in rhe uk found thar 57% had experienced the oearh, or loss 0 contact, o~ someone importam such as a parent" a 1998 inrerview swdy of young men serving jail senrences, or involved in crime, by rhe centre for the study of violence ana reconciliarion (in soutn a'ricaj found thar mast of the interviewees were 'abandoned or kicked aut of their homes, or... had to live with a stepfather or mother who rejected them. many expressed feelings of being unloved:" the absence a' a father figure early in the lives of young males rends to increase the incidence of delinquency larer on.'; moreover, such an absence will directly affect a bay's ability to develop self-conrrol. the secure attachmenr or emotion a invesrment process [a farher figure providesl 'acilirates t e cnild's abili a develop and demonstrate bath emparhy and self-control. by exrension, an insecure attachment will lead to lower levels of empathy and selfcontrol, and to an increase in violent behaviour." since the early 1990s reports from government commissions, research reports, and syntheses produced by national crime prevention organisations have identified a number of common factors associated with delinquency, violence and insecurity:" • poverty and unemployment deriving from social exclusion, especially far youth • dysfuncriona families wim uncaring and inconsistent paren al attitudes, violence or parental conflict • discrimination and exc'usion deriving from one or other form of oppression • degradation of urban environments and social bonds • social acceprance of a culture of violence • presence of exacerbating factors such as firearms and drugs. all of the above factors apply to a large proportion of aids orphans in south africa. such orphans grow up impoverished, end to be socially excluded, are not properly cared 'or because of the lass of their parenr!s), are often discriminated against, ana grow up in an environment where socia bands are falling apart beca se of me high aids-re ateo morta i rates among all segments of society. if would appear rhar tne kind of psyc ological rrauma and lack of parenral affection and supervision experienced by aids orphans is a goad predictor of subsequent delinquency and violent criminal behaviour. insufficienr research has been done an the extent of the risk aids orpnans face of engaging in antisocial and via ent behaviour 'a[er'1 me'r ives. however, given tnar :here will be same 2 i ion aids orpha s in soum a'rica ay 2010, it \ ...'. .:.:is conceivable that there will be a significant increase in violent interpersonal crime such as murder, rape and assault, violent property crime such as robbery, and violenr cri e against property such as malicio s injury to properry. orphans as victims the hiv/aids epidemic can also lead to crime in more direct ways, with orphans and other vulnerable children becoming victims. the belief that sex with avirgin can cure hiv!aids appears to be widespread." in south africa, 25% of young people do not know that this is a myth." moreover, rapists are also targeting young girls in the belief that being less sexually active, they are less likely to have hiv or aids." a study conducted among urban south african township youtn in 1996 found ha far the youth the knowledge that hey were in'ec ed wirh hiv, or merely believed that they might be infected, 'was accepted not only as a death sen ence but also as a passport to sexual licence:" tnat is, same youths argued thar they would actively spread the hiv virus among as many people as passible if they themselves were infected with hiv a philosophy of 'infect one, infect all: young women expressed a general fear that men would respond to an hiv-positive diagnosis by raping women." weakening criminal justice system unexoectedly, and largely unrecognised by criminal justice policy makers, hiv/aids could signiicanrly impact an the criminal justice sys em's effectiveness. ir is likely that the administration a justice will suffer under the onslaught of the epidemic. as mare people fall ill and die of aids, fewer criminal trials will be finalised. presently it takes about 6 months far a trial to be finalised in the country's magistrates' courts. within the coming decade, when one in five south africans will be infected and ill with the virus many trials will be delayed or will have to be stopped altogether because the accused, his witnesses, the state's witnesses or one of ne court o~lcials is likely to be ill, dying or dead because of he disease. as rhe wheels of justice turn even mare slowly than rhey 00 now, and as justice will often not be done because of rhe non-comp etion of trials, further impetus could be gi,en to vigilante organisations wim rheir promise of swift and effective 'justice: the epidemic will affect the south african police service and the department of correctional services particularly badly as many of their operational staff are young adults who are in the high-risk group when it comes to infection. already undersraffed, these services will 'unction even less op(mally :ran rhey do raoay as absenree'sm oecause a' _... " march 2002 -----------illness, and high mortality rates among staff members, increase. over the next decade the political pressure on the government to devote more resources to health and welfare services will increase. thi~ and the negative effect the epidemic will have on the economy generally, is likely to curtail state spending on the criminal justice system. under-resourced and operating with a high number of ill personnel, some operational ac ivities of the criminal justice system could stop functioning altogether. conclusion south africa's growing number of aids orphans are likely to be significant contributors to future crime levels. governmental policy makers would be well advised to brace themselves for an increase in juvenile crime as the number of orphaned juveniles increases over the next two decades. traditional methods of fighting crime, such as tougher laws, more police officers, and more prisons will do little to counter this. what is required is a programme of action that will involve not only key government departments comprising the criminal justice system (police, justice, and corrections), but also departments such as health, welfare, and education. moreover, relevant non-governmental organisations (ngos) and organs of civil society need to get involved to develop strategies to combat the anticipated increase in crime committed by aids orphans effectively. adequately staffed and resourced juvenile detention centres, rehabilitation and diversion programmes for young offenders, and an effective children's court system will have to feature more prominently on governments' list of priorities in the future. references 1. shell r. half.nay to the holocaust: the economic. demographic and 50(-011 impiications of the aids pandemic to the year 2010 in the southern african r~ion. o«:asional papers. june 2000. johann~bufg: konrad adenauer sti'wng; n 2. kinghorn a, steinberg m. hiv/aids in south afriro: the impact and the priorirj~ oepar-tltlen! of health, 1999: 14. 3. hunter s. wijliamson 1. children on the brink. updated e5cimou:s and recommendociof15 for inte,..enaotl executive summary. wasnington. dc: usaid. 2000: 1. 4. nitl:(j nations international children's emergency fund. children orphonro by aids. fronc-line r~nses from ea5!ern cnd southern africa. new york: uniuf, 1999: 3 5. mysfk wd, fr~an a, s!awski j. implications of aids for the southern african populoition ~ge profi,e:. sourhern african journalafgeroncology 1997; 6(2}: 6. 6. a wor'd &nk policy research report confrontir.g aids. pubfic priorities in cl g/obel epidffllic new york: oxford univ~ty pr~ 1999: 223-224. 7. a wor d bank policy research report confrontir.g aids. public priorities in a global epideitjc. new york: oxfora univer5lty press" 1999: 225-227. 8. m:c:hoid k. urdermj:oing me urban impact of hiv/alds-associate1j orphanhood, in aids orphans in africa. bui'cing an urban respons(.lohannesburg: cewe for policy studies, 2001: 25. 9. gloifiz l south african cities '~nder s·ege. durban: fndicaror crime and conflict, no. 2, 1995: 17. 10. fne orphoins of aids: breaking the vicious circ e. <hnptlwww.ura;ds.orgj unaids/nenrslwadjl997/orphansofaids.h:mi>. 11. chilcren orphaned by aids. <hnpj/www.unads.org/una;ds!e:vents/wad! 1997jorpharjitm>. 12. unit~ nations children's emergency fund. children orphon~ by aids. fronr~jine responses from eastern cnd southern africa. new york: unicef, 1999: 5. 13. l.oening-vovsty h, wilson t. approaches to caring for children orphaned by aids and other vulnerable children. johannesburg: institute for uroan primary health care,2oot. 14. thompson c. aids orphans in dire need. the citizen 2001; 25 june. 15. kinghorn a, steinberg m. hfii!aids in south africa: the impact and rhe priorities. pretoria: department of health, 15, 16. mackay mm. aids will spur on crime, say l:)lperts. 5arurdayargus 1999; 9 january. 17. why do children become ~iolent? innocenti digesr, children and violence, no. 2. aorence: unicef international child development centre, 15. 18 se:gal l, pe:lo j, rampa p. asicamtheni magents let's talk, magents. youm attitudes towards crime. crime and conflicr, no. 15, autumn 1999. durban: university of natal: 24. 19. bawlby 1. forry-four juvenile thieves: their characters and home life. london: bailliere, tindall and cox. 1947. 20. kiln rs. building the foundation for a side-by-side ~planatory model: a general theory of crime, the age-graded life-rours( the1jry, and attachment the1jry. western criminology review, 1999; 1(21: online: <hnptlwc:r.sonoma.edul vln2!kalz.html> (5 may 1999). 21. crime prevention digest 11. comparative analysis ofsucressful community sofety. montregl: irternational cerue for the prevention of crime. 1999: 20-21. 22 l.eclerc-mad1a!a s. crime in an epidemic: the case of rape and aids. acro crimino!ogiro, vol 9, no 2. pretoria: criminological society of south africa, 1996: "23. tovelife, hot ptospecrs, cold facts. johannesourg: colorpress, solf"jl africa, 2/xxl. 24. l.eclerc-madla a s. crime in an epidemic: the cas( of rape and aids. acro oimin%gico, vo. 9, no 2. pretoria: criminolog:cal society of sojth a..~ca, 1996: 35-3625. l.eclerc-mad!a a s. crime in an epidemic: the case of rape and aids. acta criminalog·ro, vo 9, no 2. pretora: crift7ino1og·cal society of south africa, 1996: 32 26. lederc-mad;a a s. crime j1 an eo;demic· the case of rape ar.d aids. acre criminalogica, vo 9, no 2. pretoria· crift7nolog ca! society of south africa, 1996: 33-34. thf southtrn african journal or hiv mfoicinf hiv0304pg000 march 2004 the southern african journal of hiv medicine 2 8 two previously published reports provided guidelines for managing the pharmacological interactions that can result when patients are treated with protease inhibitors (pis) or non-nucleoside reverse transcriptase inhibitors (nnrtis) for human immunodeficiency virus (hiv) infection together with rifamycins for tuberculosis (tb).1,2 this article presents current data pertaining to interactions between these agents, with recommendations for their use from a group of centers for disease control (cdc) scientists and outside expert consultants; these include initial recommendations for the pis lopinavir/ritonavir, atazanavir, and fosamprenavir (a phosphate ester prodrug of amprenavir). the principal locus of these drug-drug interactions is the cytochrome p450 (cyp) system in the intestinal wall and liver, specifically the iso-enzyme cyp3a4.3 rifamycins are antituberculosis agents that induce the activity of cyp3a4 and may thereby substantially decrease serum concentrations of pis and nnrtis. the available rifamycins differ in potency as cyp3a4 inducers, with rifampin (rifampicin) being the most potent, rifapentine being intermediate, and rifabutin being the least potent inducer.4 as such, rifabutin can be safely used with most pis and nnrtis, except saquinavir and delavirdine (see table ii). unlike rifampin (rifampicin) and rifapentine, however, rifabutin is also a substrate for cyp3a4; its serum concentration is therefore affected by the degree to which cyp3a4 is inhibited or induced by pis and nnrtis. rifapentine, a long-acting rifamycin, is not recommended for the treatment of tb in hiv-infected persons because of its association with acquired rifamycin resistance in such patients.5 g u i d e l i n e s updated guidelines for the use of rifamycins for the treatment of tuberculosis in hiv-infected patients taking protease inhibitors or non-nucleoside reverse transcriptase inhibitors centers for disease control and prevention national center for hiv, std and tb prevention division of tuberculosis elimination mechanisms of rifamycins-antiretroviral drug interactions the southern african journal of hiv medicine march 2004 2 9 among the available antiretroviral (arv) agents, ritonavir has the highest potency in inhibiting cyp3a4, a quality that increases the serum concentrations of other coadministered pis,6 although it can also increase concentrations of rifabutin and a rifabutin metabolite to toxic levels.7 initial guidance from the cdc stated that use of rifampin (rifampicin) was contraindicated for persons taking nnrtis and pis.1 subsequent data, however, have supported the use of rifampin (rifampicin) with certain combinations of arv agents. these include: ■ ritonavir with nucleoside/tide reverse transcriptase inhibitors (nrtis)8 ■ efavirenz with nrtis.9-11 alternative, less supported, arv combinations for use with rifampin (rifampicin) include: ■ ritonavir (400 mg twice daily) and saquinavir (400 mg twice daily) with nrtis12 ■ ritonavir (400 mg twice daily) and lopinavir (400 mg twice daily) with nrtis (when the current coformulated lopinavir/ritonavir combination is supplemented with additional ritonavir, see table i)13 ■ nevirapine with nrtis14-17 (and boehringer ingelheim, viramune product information, 2002) ■ triple nrtis.1,2 it is noteworthy that the ritonavir dose typically used for pharmaco-enhancement of co-administered pis (i.e. 100 mg or 200 mg twice daily),19 though less likely to produce adverse events than higher doses, still results in net cyp3a4 induction when used with rifampin (rifampicin)13 (and bms virology, reyataz package insert, 2003). data are lacking for other pis co-administered with rifampin (rifampicin) and ritonavir 400 mg twice daily. the use of nevirapine and nrtis with rifampin (rifampicin) is of particular importance in countries with limited resources where rifabutin may not be available, and for pregnant patients, in whom efavirenz cannot be used. despite pharmacokinetic data showing a significant reduction in nevirapine concentrations when co-administered with rifampin (rifampicin),14-17 two small studies demonstrated a favourable clinical and virological response.16,18 nonetheless, until additional data are available, rifampin (rifampicin)and nevirapine-containing arv regimens rifampin (rifampicin) and antiretroviral therapy (table i) march 2004 the southern african journal of hiv medicine 3 0 should only be used when no other options are available and close clinical and virological monitoring can be performed. rifabutin can be used with most pis, including atazanavir and fos-amprenavir, provided the dose of rifabutin is reduced (abbott laboratories, kaletra package insert, 2003 revised). use of rifabutin with saquinavir alone is not advised given the significant decrease in saquinavir concentration; however, rifabutin may be used with saquinavir if co-administered with ritonavir. other pi/ ritonavir combinations, including lopinavir/ritonavir, can be safely co-administered with rifabutin as long as the dose of rifabutin is decreased.20 conversely, as a cyp3a4 inducer efavirenz can reduce concentrations of rifabutin, necessitating an increase in the dose of rifabutin.21 rifabutin and antiretroviral therapy (table ii) antiretroviral rifampin (rifampicin) single pis dose change dose change* comments ritonavir none none ritonavir auc ↓ by 35%; no change in (600 mg/d) rifampin (rifampicin) concentration amprenavir rifampin (rifampicin) and amprenavir should amprenavir auc ↓ by 82%, cmin ↓ by 92% not be used together fos-amprenavir rifampin (rifampicin) and fos-amprenavir see amprenavir should not be used together atazanavir rifampin (rifampicin) and atazanavir should interaction studies not performed, but marked not be used together decrease in atazanavir concentrations predicted indinavir rifampin (rifampicin) and indinavir should indinavir auc ↓ 89% not be used together nelfinavir rifampin (rifampicin) and nelfinavir should nelfinavir auc ↓ 82% not be used together saquinavir rifampin (rifampicin) and saquinavir should saquinavir auc ↓ 84% not be used together recommended change recommended change in dose of in dose of rifampin dual pi combinations antiretroviral drug (rifampicin) comments saquinavir / ritonavir saquinavir 400 mg + none limited clinical experience12 ritonavir 400 mg (600 mg/day) twice/day phamaco-augmented lopinavir/ritonavir lopinavir/ritonavir none limited clinical experience. increased (kaletra®) (kaletra®) – 3 capsules (600 mg/day) hepatotoxicity from ritonavir is likely13 note: additional ritonavir required + 300 mg ritonavir twice/day lopinavir/ritonavir (kaletra®) rifampin (rifampicin) and lopinavir/ritonavir lopinavir auc ↓ by 75 % & cmin ↓ by 99% (kaletra®) should not be used together. if kaletra® is used with rifampin (rifampicin), additional ritonavir is required (see above) non-nucleoside reverse recommended change recommended change transcriptase inhibitors in dose of in dose of rifampin antiretroviral drug (rifampicin) comments efavirenz ↑ to 800 mg/day† none efavirenz auc ↓ by 22%; no change in rifampin (600 mg/day) (rifampicin) concentration nevirapine 200 mg twice daily none nevirapine auc ↓ 37% 58% and cmin ↓ 68% with ( 600 mg/day) 200 mg 2x/day dose14-16 (and boehringer ingelheim viramune product information). limited, though favorable data for efficacy of 200 mg bid dose, although should only be used if no other options exist and clinical and virological monitoring possible.16,17 may consider 300 mg bid only if close biochemical monitoring feasible; however, no clinical, pharmacokinetic, or safety data available for 300 mg bid dose delavirdine rifampin (rifampicin) and delavirdine should delavirdine auc ↓ by 95% not be used together *references proved for combinations with either inconclusive or limited data. †may ↓ to 600 mg/day if 800 mg dose not easily tolerated. table i. recommendations for co-administering protease inhibitors and non-nucleoside reverse transcriptase inhibitors with rifampin (rifampicin) — united states, 2004* the southern african journal of hiv medicine march 2004 3 1 further study is needed regarding the co-administration of other complex arv combinations (e.g. the concurrent use of cyp3a4 inducer and inhibitor, such as efavirenz and a pi) with rifabutin and rifampin (rifampicin). one observational study found that the use of rifabutin with such complex arv regimens was associated with low serum concentrations of rifabutin, particularly when the rifabutin dose was reduced to 150 mg twice weekly for use with ritonavir-containing regimens.21 the nrtis, which include zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine, are not metabolised by cyp3a4, so nrtis and rifampicins may be co-administered without dose adjustments. however, arv therapy consisting exclusively of nrtis appears to have reduced potency compared with regimens that contain either a pi or an nnrti, and current guidelines recommend nrti-based regimens only if pibased or nnrti-based regimens cannot be used.22 as with nrtis, in vitro and pharmacokinetic data suggest that cyp3a4 is not involved in the metabolism of either the nrti tenofovir or the fusion inhibitor enfuvirtide, and each is therefore considered safe to use with any of the rifamycins23 (and gilead sciences inc., viread package insert, 2002). rifamycin resistance has developed during the treatment of tb in hiv-infected persons, and has been associated with all rifamycins, particularly with highly intermittent administration (once or twice weekly). rifapentine, which can be administered once a week, is not recommended for hiv-infected patients because of their risk of developing other drug interaction issues single protease antiretroviral dose rifabutin dose inhibitors change change* comments amprenavir none ↓ to 150 mg/day rifabutin auc ↑ by 193%; no change in or 300 mg 3x/week amprenavir concentration. fos-amprenavir none ↓ to 150 mg/day comparable to amprenavir. or 300 mg 3x/week atazanavir none ↓ to 150 mg every other day or 150 mg 3x/week† rifabutin auc ↑ by 250% indinavir ↑ to 1 000 mg q 8 h ↓ to 150 mg/day or 300 mg 3x/week rifabutin auc ↑ by 204%; indinavir auc ↓ by 32%. nelfinavir ↑ to 1 000 mg q 8 h ↓ to 150 mg/day or 300 mg 3x/week rifabutin auc ↑ by 207%; nelfinavir auc ↓ by 32% ritonavir none ↓ to 150 mg every other day rifabutin auc ↑ by 430%; no change in or 150 mg 3x/week ritonavir concentration saquinavir rifabutin and saquinavir should not be used together saquinavir auc ↓ by 43% dual protease inhibitor antiretroviral dose rifabutin dose comments combinations change change* lopinavir / ritonavir none ↓ to 150 mg every other day rifabutin auc ↑ by 303%; (kaletra™) or 150 mg 3x/week 25-o-des-acetyl rifabutin auc ↑ by 47.5-fold ritonavir (any dose) with none ↓ to 150 mg every other day saquinavir, indinavir, or 150 mg 3x/week amprenavir, fos-amprenavir, or atazanavir non-nucleoside reverse antiretroviral dose rifabutin dose transcriptase inhibitors change change† comments efavirenz none ↑ to 450 mg/day or 600 mg rifabutin auc ↓ by 38% 3x/week effect of efavirenz + protease inhibitor (s) on rifabutin concentration has not been studied nevirapine none 300 mg/day or 300 mg 3x/week rifabutin and nevirapine auc not significantly changed delavirdine rifabutin and delavirdine should not be used together delavirdine auc ↓ by 80%; rifabutin auc ↑ by 100% *if cd4 count is greater than 100 cells/µl, may consider twice weekly administration of rifabutin with amprenavir, fos-amprenavir, indinavir, nelfinavir, efavirenz, and nevirapine. †recommendation as per package insert. table ii. recommendations for co-administering protease inhibitors and non-nucleoside reverse transcriptase inhibitors with rifabutin — united states, 2004 acquired rifamycin resistance march 2004 the southern african journal of hiv medicine 3 2 rifamycin resistance.5 in addition, rifamycin resistance has developed in patients who have advanced hiv disease (i.e. cd4 count < 100 cells/µl) and are receiving rifampin (rifampicin) or rifabutin twice weekly.24-26 to prevent acquired rifamycin resistance in persons with advanced hiv infection and tb, more frequent therapy (thrice weekly or daily) with either rifampin (rifampicin)or rifabutin-based tb regimens is recommended. as new arv agents and additional pharmacokinetic data become available, recommendations for the use of these agents during the treatment of tb are likely to be revised and updated. more general information on arv drug interactions can be obtained at http://www.aidsinfo.nih. gov/guidelines and http://www.hiv-druginteractions. org. references 1. centers for disease control. prevention and treatment of tuberculosis among patients infected with human immunodeficiency virus: principles of therapy and revised recommendations. mmwr 1998; 47 (no. rr-20). 2. centers for disease conrol. updated guidelines for the use of rifabutin or rifampin (rifampicin) for the treatment and prevention of tuberculosis among hiv-infected patients taking protease inhibitors or nonnucleoside reverse transcriptase inhibitors. mmwr 2000; 49: 185-189. 3. burman w, gallicano k, peloquin c. therapeutic implications of drug interactions in the treatment of hiv-related tuberculosis. clin infect dis 1999; 28: 419-430. 4. li a, reith m, rasmussen a, et al. primary human hepatocytes as a tool for the evaluation of structure-activity relationship in cytrochrome p450 induction potential of xenobiotics: evaluation of rifampin (rifampicin), rifapentine, rifabutin. chemico-biological interactions 1997; 107: 17-30. 5. vernon a, burman w, benator d, et al. acquired rifamycin monoresistance in patients with hiv-related tuberculosis treated with once-weekly rifapentine and isoniazid. lancet 1999; 353: 1843-1847. 6. kempf d, marsh k, kumar g, et al. pharmacokinetic enhancement of inhibitors of the human immunodeficiency virus protease by co-administration with ritonavir. antimicrob agents chemother 1997; 41: 654-660. 7. sun e, health-chiozzi m, cameron d, et al. concurrent ritonavir and rifabutin increases risk of rifabutin-associated adverse events. xith international aids conference, vancouver, canada, 1996: abstract mob171. 8. moreno s, podzamczer d, blazquez r, et al. treatment of tuberculosis in hivinfected patients: safety and antiretroviral efficacy of concomitant use of ritonavir and rifampin (rifampicin). aids 2001; 15: 1185-1187. 9. lopez-cortes l, ruiz-valderas r, viciana p, et al. pharmacokinetic interactions between efavirenz and rifampin (rifampicin) in hiv-infected patients with tuberculosis. clin pharmacokinet 2002; 41: 681-690. 10. patel a, patel k, patel j, et al. to study the safety and antiretroviral efficacy of rifampicin and efavirenz in antiretroviral-naïve tuberculosis co-infected hiv-1 patients in india. xth conference on retroviruses and opportunistic infections, boston, ma, 2003: abstract 438. 11. pedral-samapio d, alves c, netto e, et al. efficacy of efavirenz 600 mg dose in the arv therapy regimen for hiv patients receiving rifampicin in the treatment of tuberculosis. xth conference on retroviruses and opportunistic infections, boston, ma, 2003: abstract 784. 12. veldkamp a, hoetelmans r, beijnen. ritonavir enables combined therapy with rifampin (rifampicin) and saquinavir. clin infect dis 1999; 29: 1586. 13. la porte c, colbers e, bertz r, et al. pharmacokinetics of two adjusted dose regimens of lopinavir/ritonavir in combination with rifampin (rifampicin) in healthy volunteers. 42nd interscience conference on antimicrobial agents and chemotherapy, san diego, ca, 2002: abstract a-1823. 14. robinson p, lamson m, gigliotti m, et al. pharmacokinetic interactions between nevirapine and rifampin (rifampicin). xiith international aids conference, geneva, switzerland, 1998: abstract 60623. 15. dean g, back d, de ruiter a, effect of tuberculosis therapy on nevirapine trough plasma concentration (correspondence). aids 1999; 13: 2489-2490. 16. ribera e, pou l, lopez rm, et al. pharmacokinetic interaction between nevirapine and rifampicin in hiv-infected patients with tuberculosis. j acquir immune defic syndr 2001; 28: 450-453. 17. olivia j, moreno s, sanz j, et al. co-administration of rifampin (rifampicin) and nevirapine in hiv-infected patients with tuberculosis (correspondence). aids 2003; 17: 637-642. 18. cooper c, van heeswijk, gallicano k, et al. a review of low-dose ritonavir in protease inhibitor combination therapy. clin infect dis 2003; 36: 1585-1592. 19. justesen u, andersen a, klitgaard n, et al. pharmacokinetic interaction between rifampin (rifampicin) and the twice-daily combination of indinavir and low-dose ritonavir in hiv-infected patients. xth conference on retroviruses and opportunistic infections, boston, ma, 2003: abstract 542. 20. hollender e, stambaugh j, ashkin d, et al. the concomitant use of rifabutin and efavirenz in hiv/tb coinfected patients. xth conference on retroviruses and opportunistic infections, boston, ma, 2003: abstract 785. 21. spradling p, drociuk d, mclaughlin s, et al. drug-drug interactions in inmates treated for human immunodeficiency virus and mycobacterium tuberculosis infection or disease: an institutional tuberculosis outbreak. clin infect dis 2002; 35: 1106-1112. 22. us department of health and human services. guidelines for the use of antiretroviral agents in hiv-1-infected adults and adolescents. november 10, 2003. http://aidsinfo.nih.gov 23. boyd m, ruxrungtham k, zhang x, et al. enfuvirtide: investigations on the drug interaction potential in hiv-infected patients. xth conference on retroviruses and opportunistic infections, boston, ma, 2003: abstract 541. 24. el-sadr w, perlman d, matts j, et al. evaluation of an intensive intermittentinduction regimen and duration of short-course treatment for human immunodeficiency virus-related pulmonary tuberculosis. clin infect dis 1998; 26: 1148-1158. 25. cdc acquired rifamycin resistance in persons with advanced hiv disease being treated for active tuberculosis with intermittent rifamycin-based regimens. mmwr 2002; 51: 214-215. 26. nettles r, mazo d, alwood k, et al. tuberculosis relapse and acquired rifamycin resistance in hiv-1 infected persons is associated with low cd4 count, but is not more common with rifabutin than rifampin (rifampicin). xth conference on retroviruses and opportunistic infections, boston, ma, 2003: abstract 137. significant contributions to the review of this document were made by the following persons: william burman, denver public health department; philip spardling, cdc; paul weidle, cdc; jonathan kaplan, cdc; alice pau, nih; andrew vernon, cdc; harold jaffe, cdc; m elsa villarino, cdc; richard o’brien, cdc; kenneth castro, cdc; michael f lademarco, cdc; timothy sterling, vanderbilt university; susan ray, emory university; lisa goozé, university of california, san francisco; jean nachega, johns hopkins university; joseph burzinski, new york city department of health and mental hygiene; sonal munsiff, new york city department of health and mental hygiene/ cdc. this document (updated 20 january 2004) is on the cdc division of tuberculosis elimination website at www.cdc.gov/nchstp/tb/tb_hiv_drugs/toc.htm education da"id l woods, md, frcp, ocr di'i.;ision of l\"«maral meduinc, school of child and adokjant health, univerriry afcape tol."1t a novel approach to perinatal hiv/aids training for doctors and nurses in south africa m southern african journal of hiv medicine the standard pep course consists of two training manuals, one on maternal and the other on newborn care. each manual has 15 units, addressing important or common clinical problems. a manual usually requires a year to complete. groups of 5 10 students study the programme together. they elect a group leader who manages the course and arranges a meeting of participants every 3 weeks. a formal tutor is not required. the course material from one unit at a time is studied by each participant at home and then discussed at the group meetings, thus introducing the concept of peer tuition. group members encourage, support and teach each other in a spirit of cooperative learning. participants complete and mark their own multiple choice tests, enabling them to monitor their own progress through the course. the responsibility of learning is therefore placed squarely on the shoulders of question is asked and then the appropriate answer is given. utilising this method, participants are led from the most basic facts to more complex concepts. case studies are also used to place the information into clinical context. participants find this method of outreach education simple, easy and enjoyable. flow diagrams are used to summarise diagnostic and management protocols while a multiple choice test, before and after each unit, allows the participants to monitor their own progress. skills workshops include simple line drawings and step-by-step instructions to master clinical skills. widespread consultation with colleagues and comment by course participants has transformed pep into a consensus statement of maternal and newborn care that has helped to standardise the provision of perinatal care in south africa. the large number of children presenting with aids in south africa is a wake-up call for urgent attention to be paid to reducing the risk of mother-to-child transmission of hiv. this requires an innovative method of training the thousands of nurses and doctors who provide perinatal care, especially in rural areas with limited opportunities for ongoing education. the perinatal education programme is a self-help method of learning which has been very successful in enabling nurses and doctors to take responsibility for their own distance training. a recent perinatal hiv/aids supplement to the programme provides a novel and appropriate means of meeting this training need. as the hiv epidemic sweeps across south africa, many of the aids victims are young children infected by their mothers in the perinatal period. while these children unfortunately bear the brunt of the early epidemic, many of them could have been spared the horrors of aids if more attention had been paid to reducing the risk of vertical transmission. screening during pregnancy, short-course antiretroviral prophylaxis, modification of the management of labour and delivery, and exclusive breastor formulafeeding promise to significantly reduce the rate of motherto-child transmission of hiv and therefore the incidence of childhood aids. however, to introduce these essential changes in management large numbers of nurses and doctors will require additional training. this is problematic due to the lack of funding, few available tutors and the impracticality of moving staff to regional centres for training courses. traditional methods of centralised teaching with tutors training small groups of students in teaching hospitals are expensive and no longer appropriate or applicable. what is required is an innovative method of enabling nurses and doctors to manage their own continuing education. this need is particularly urgent with staff caring for pregnant women who are hiv-infected and their hiv-exposed infants. the perinatal education programme (pep) offers a cheap and practical means of addressing the problem.' pep is a self-help distance learning course that aims at improving the care of pregnant women and their newborn infants, especially in rural areas. it is presented in the form of training manuals that use a problem-orientated, patientbased approach. a question-and-answer method of problem solving is used as the basic learning model: first a february 2003 ----------each participant. the group leader invites an appropriate medical or nursing colleague to attend the pep meeting in order to demonstrate the clinical skills attached to the unit being studied. in this way local resource personnel are encouraged to share their clinical abilities, and solve the seemingly insurmountable problem of skills instruction in rural areas. a formal multiple-choice examination is offered to participants on completion of each manual. regional health care services manage their own examination. certificates are awarded to successful candidates and a graduation ceremony is arranged that acknowledges the considerable effort of the participants, and encourages other colleagues to join a pep group. participants buy their own manuals from the perinatal education trust at r1s0 each. this payment allows the trust, which produces the programme, to be financially self-sufficient. through the generosity of a private donor, nurses from the public sector who pass the pep examination may apply for a retrospective bursary that repays the cost of their course. this system rewards success and enables most practising midwives in south africa to join the project. because each group takes ownership of their course, the pride and sense of achievement is theirs. to date more than 30 000 pep manuals have been distributed and over 10000 certificates awarded to nurses and medical practitioners, as well as undergraduate nursing and medical students, who have successfully completed the course in southern africa. a field study and two prospective controlled trials of the maternal care and newborn care pep manuals have documented a significant improvement in cognitive knowledge, clinical skills, attitudes and patient care practices of midwives in south africa.'" in the prospective trials, either the maternal or newborn care manual was introduced into a district hospital and its primary care clinic while the pep was withheld from the neighbouring district, which was used as a control. midwives in both the intervention and control districts were objectively assessed at the start and again at the end of the study. the midwives using pep managed their own course over 12 months without a trainer. this is the first study to have documented that groups of midwives can be empowered to enhance their own clinical knowledge and skills and improve their attitudes and standard of patient care without the infrastructure of a formal training institution. midwives using pep reported that they felt more confident in their clinical abilities, experienced less stress at work, and achieved a greater degree of job satisfaction. perhaps the awareness and appreciation of self-growth is one of the most important achievements of this method of distance education. recently a supplementary pep manual on perinatal the southern african journal of hiv medicine hiv/aids has been developed. it allows groups of professional health care workers to learn about all aspects of perinatal hiv infection. the five units address the following topics: • a general introduction to hiv infection and aids. • management of hiv-infected women during pregnancy. • management of hiv-infected women during labour and delivery. • management of hiv-exposed infants. • counselling hiv-positive women. the learning material provides the reader with the basic theoretical knowledge of hiv infection and aids, an approach to diagnosis and management of mother and infant, and counselling principles to support the mother and family. thirteen experts in the field of perinatal hiv in south africa contributed to the development of the training manual. the layout and method of learning is the same as the two basic pep manuals. the cost of the perinatal hiv/aids manual is rso, inclusive of vat, postage and packaging, and the end-of-course examination. a certificate is awarded to candidates who successfully complete the 4-month course and pass the final multiplechoice examination. the course offered by the perinatal hiv/aids manual is recognised for 10 cpd points provided the doctor successfully completes the examination. both the standard manuals and the supplementary manual on perinatal hiv/aids are available in either english or afrikaans. in a small field trial in kwazulu/natal, midwives studied the perinatal hiv/aids manual. an assessment of their knowledge of the subject, before and after they conducted their own self-help course, showed a significant improvement from 64% to 94%. this result is similar to the more exhaustive assessments of the two basic pep manuals. over the past year, 1 000 perinatal hiv/aids manuals have been distributed and well received by doctors and nurses working in both hospitals and clinics. the perinatal education programme offers a cheap and appropriate means of bringing on-site training to the many thousands of professional health care workers who are struggling to provide adequate care to hiv-positive women and their newborn children, especially in rural areas. the cost of the course is minimal compared with that of traditional training methods, and no formal teaching infrastructure is needed. provisional results suggest that the perinatal hiv/aids manual is as effective in providing appropriate knowledge as the rest of the perinatal education programme. what is required is a concerted national and provisional plan to promote this form of educational opportunity to all who could benefit. with well-trained midwives and doctors, and a simple, appropriate protocol of managing pregnant women who ----------hbruary 2003 industry news 2. woods dl theran ga the impacr of the perinatal education programmf' on cognitivt: knowledge in midw~ 5afrmroj 1995; 85: 150-153. 3. theron gb. improved cognitivt knowledge of midw~ practicing in the e4srern ca~ p(ovin~ of the republic of south africa through study of cl self educational manual. midwifery 1999; 15: 66-71. 4. tneron gb. lmprovro practical skills of midw~ praeticing in the eastern province of the republic of south a'"cc; through me study of a self-tducation manual. jpmnaro!2lxxj; 3: 18418a 5. theran gb. the effect of the maternal care manual of the ptrinatal etiucdtion programml:' on the attitude of midw~ towards ih~r work. curorionis 1999; dettmber: 63~67. 6. rneron gb. the effe<:t of the maternal ci!!:' manual from the perinatal educ;;tion programme on the quality of ;nte+ and inuapa/1um care rendered by miowives. safr m~j 1999; 89: 336-341 7. gr~nfietd oh. evaluation of the use of the neonalal manual of the perirlaral educ;;tion programme. in: proceedings of rh~ 7th world iamaneh conf~~nce. pretoria: university of pretoria, 1999: 229-231. tllf southfrn african journal of hiv mfoicinf ms lmackenzie (bms anti-infective franchise monoger), mr i strochan (ceo of bms), prof. cfeldman. or 0 mwanthembe, prof. grichards, or m sussmon. 1. woods dl an innovativl:' programme for training in maternal and newborn care. ~min neonotol 1999; 4: 209-216. are hiv-positive, the present high rate of mother-ta-child transmission can be reduced, with a resultant drop in the numbers of children suffering from and dying of aids in south africa. for further information visit the perinatal education trust website at www!pepcourse.co.za or contact the trust by phone or fax at (021) 671-8030. references the castle in kyalami was the ideal venue for bristol-myers squibb to introduce the newly formed anti-infective franchise in both grandeur and style on 3 december 2002. the sovereign feast and dancing were enjoyed by all until well into the night introduction of the bristol-myers squibb anti-infective franchise bristol-myers squibb have a wealth of knowledge in the anti-infective market with products including tequin, maxipime, prozef, fungizone, cefril, cefril-a, cefacidal and azactam in their anti-infective franchise. in addition, bristol-myers squibb has a strong antiretroviral franchise in zerit and videx, which are supplied below cost to the south african market mrs and prof. de ksommers, ms rcoetzee (prozef product manager), or a brink. hhruar 2003----------865 message message from the executive i am not sure if i am the only one who feels this way, but sometimes i feel we are fighting a losing battle. it seems that the numbers and the challenges are overwhelming. but, something happened in the last few weeks that reminded me never to give up in fighting for the healthcare rights of all south africans. michelle moorehouse, a member of our board, was incensed by an advertisement for pre-sex gel. this clearly unregistered product was being manufactured and sold by a doctor in port elizabeth. michelle did not want anyone to buy this gel and to think that they were protected from hiv. she drafted a passionate letter that was sent off to a number of key stakeholders, including the registrar of medicine. the medicines control council (mcc) visited the doctor’s rooms, withdrew the product and stopped all sales. who knows how many lives have been saved as a consequence? well done to michelle. we need to fight each battle that comes our way with the same dedication. on the real prevention front, there has been some good news. the united states food and drug administration (fda) has registered truvada for pre-exposure prophylaxis for men and women. much media frenzy has surrounded this announcement, with the common question: ‘does this mean we can abandon condoms?’ there is not going to be a one-size-fits-all for hiv prevention, but each new intervention will contribute in some way. to all members, members' friends and potential members, please remember that the first southern african hiv clinicians society conference will be held in cape town at the end of this year. please put the dates 25 28 november 2012 into your diaries, register for the conference, and make travel arrangements accordingly. francesca conradie president southern african hiv clinicians society johannesburg references about the author(s) carey pike desmond tutu health foundation, faculty of health sciences, university of cape town, cape town, south africa connie celum department of global health, university of washington, seattle, united states of america department of medicine, university of washington, seattle, united states of america department of epidemiology, university of washington, seattle, united states of america linda-gail bekker desmond tutu health foundation, faculty of health sciences, university of cape town, cape town, south africa citation pike c, celum c, bekker l-g. adolescent healthcare: i’m lovin’ it. s afr j hiv med. 2020;21(1), a1147. https://doi.org/10.4102/sajhivmed.v21i1.1147 editorial adolescent healthcare: i’m lovin’ it carey pike, connie celum, linda-gail bekker copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. the field of adolescent health is motivated by the potential to deliver healthcare interventions that could have long-term prevention and health promotion benefits.1 in south africa (sa), adolescents (aged 10–24 years) are the largest growing demographic and yet show sub-optimal health outcomes, particularly those related to sexual and reproductive health (srh).2 interventions to facilitate risk awareness and access to testing and screening programmes reduce sexually transmitted infection (sti) rates and avoid unintended pregnancies, yet adolescents continue to face real and perceived barriers whilst accessing services.3 modern adolescents differ from previous generations in mindset and behaviour. driven by technological advances and urbanisation, the igeneration (born between mid-1990s and mid-2000s) has heightened expectations of speed, functionality and choice. whilst these characteristics are known and capitalised on by commercial enterprises, they are underutilised by healthcare platforms. understanding the adolescent perspective can illuminate ways healthcare delivery can be adapted to promote adolescent access. here we compare the delivery of adolescent srh services to that of fast-food outlets, which constitute a well-utilised service with competitive global revenues and a large adolescent clientele. we consider eight potential reasons fast food is popular amongst adolescents and how these concepts could be extended to optimise healthcare delivery and increase uptake. are we there yet? long waiting times at healthcare facilities, influenced by patient–nurse ratios, type of service and time of arrival, are a barrier to healthcare services.4 while the average waiting time in a sa clinic is 116 min, the average fast-food client would only wait 255 seconds (just over 4 min).5 although not directly comparable, the efforts that fast-food outlets undertake to promote fast service are relevant. the fast-food systems are signposted and easy to navigate, with available services clearly displayed to facilitate informed decision-making immediately from the queue. clear healthcare information strategies, including appropriate infographics, inside and outside the clinics could similarly streamline visits.3 the fast-food production is optimised by efficient, automated machinery; the healthcare analogy is the point-of-care diagnostic systems and the same-day treatment, which would increase clinic efficiency, treatment initiation and retention. an example of a popular consumer-friendly healthcare model that provides convenient, rapid sti/hiv services with improved patient outcomes is the dean street express clinic in london.6,7 a similar model could be adapted for adolescents. location, location and location. a convenient geospatial location is a high priority for fast-food outlets who prioritise foot traffic and proximity to transport routes, which are positively associated with increased uptake.8 decentralisation of healthcare services through mobile clinics and school health programmes that provide screening services, medication collection and basic treatment with onward referrals could increase spatial access and decongest facilities. off-site centres that provide quick, easy access may be particularly desirable to adolescents.9 the fast-food industry has further found that home delivery services are the easiest way to decongest their outlets. medication delivery for chronic care patients could provide the health equivalent to ubereats – a platform that adolescents are very familiar with. convenient operating hours also allow fast-food outlets to accommodate a broad range of schedules. public health facilities that cater to the same broad population are sometimes inconveniently located and often operate solely during working hours, requiring patients to miss work or school. extending operating hours into the early morning, late evening, and weekends to accommodate patients could promote uptake. tell me what’s out there. each year, the average american child will view over 250 mcdonalds’ advertisements exclusively tailored for their age group.8 marketing for fast-food products is pervasive, which normalise the product being advertised and provide continuous reminders to access them. advertising campaigns for hiv products that make use of multiple media platforms could accelerate public knowledge and normalise use.9 different adverts are needed to target diverse population groups differentiated by age. to target health promotion media for youth, social media adverts and influencers (users who have an established audience and are able to promote products because of their perceived authenticity) could raise awareness of health interventions and normalise their use.10 life tastes good: this was originally a 2001 campaign slogan for coca cola. this phrase captures the fast-food industry’s main message: this tastes good and by eating it your life will be good too. the message is gain framed, with an emphasis on the reward. biomedical products for hiv such as antiretroviral therapy, oral pre-exposure prophylaxis (prep), voluntary male medical circumcision (mmc) and condoms have many positive benefits, yet are often offered within a negative framework that focuses on risk aversion and the negative consequences of not using the product. hiv, sti and pregnancy prevention might benefit from gain-frame messages such as the ‘do what you want. do it with love, respect, and condoms’ slogan employed by youth-led youth against aids organisation.11,12 fast food is cheap, as are public healthcare services in sa. however, indirect costs such as transport to the facility and opportunity costs for missing work or school constitute real barriers to access. these costs could be circumvented through decentralised healthcare services that operate at flexible hours. fast-food outlets are places to socialise. outlets benefit when customers are happy to be seen there. building positive social associations with attendance is a way in which clinics could attract healthy individuals and patients into the space. this can be achieved by making the healthcare spaces attractive and adolescent friendly, normalising visits and offering linkage to in-person or virtual peer support linkages. health promotion is supported by regular health visits, which are more accessible when quick, delivered by friendly, non-judgemental staff, and provided an overall positive experience.3 providing choice: fast-food outlets offer menus that can be tailored to preferences and specific dietary requirements. the hiv response is well-positioned to offer choice, particularly around prevention options. choices can be tailored to provide an ‘adolescent menu’ of oral prep, condoms and mmc or a menu for sexually and gender diverse persons, including condoms, lubricant oral prep, mmc and, when they become available, effective rectal microbicides. choices can change as your risk or preference changes. promoting choice supports long-term engagement in the service. keep up. the fast-food industry is constantly evolving to meet customers’ dynamic demands. as the proportion of the population identifying as vegetarian has increased, the fast-food outlets have adapted to offer vegetarian meals. responsiveness to customer feedback and popular trends is prioritised, with a focus on user-driven product development. conversely, within healthcare a pathogenic focus can overshadow user-demand considerations. although biomedical and behavioural interventions take years to move from concept to market, reducing their ability to be responsive, healthcare promotion and delivery can adapt to meet users’ needs and preferences. among adolescents, healthcare is one of many competing priorities. this makes it easy to put off clinic visits and regular health checks. as sub-saharan africa continues to develop and secure access to low-cost, fast services, the modern african adolescent may not only demand but start to expect healthcare delivery systems that fit their faster environment. references patton gc, sawyer sm, santelli js, et al. our future: a lancet commission on adolescent health and wellbeing. lancet (london, england). 2016;387(10036):2423–2478. joint united nations programme on hiv/aids (unaids). global aids update. seizing the moment: tackling entrenched inequalities to end epidemics. 2020. geneva; unaids. smith p, marcus r, bennie t, et al. what do south african adolescents want in a sexual health service? evidence from the south african studies on hiv in adolescents (sasha) project. s afr med j. 2018 jul 25;108(8):677–681. https://doi.org/10.7196/samj.2018.v108i8.13013 egbujie ba, grimwood a, mothibi-wabafor ec, et al. impact of ‘ideal clinic’ implementation on patient waiting time in primary healthcare clinics in kwa-zulu natal province, south africa: a before and after evaluation. samj. 2018;108(4):311–318. https://doi.org/10.7196/samj.2018.v108i4.12583 qsr magazines. the 2019 qsr drive-thru study: speed of service [homepage on the internet]. [cited 2020 aug 05]. available from: https://www.qsrmagazine.com/drive-thru/fast-food-drive-thrus-got-20-seconds-slower-2019 girometti n, mccormack s, devitt e, et al. evolution of a pre-exposure prophylaxis (prep) service in a community-located sexual health clinic: concise report of the prepxpress. sex health. 2018 nov;15(6):598–600. https://doi.org/10.1071/sh18055 whitlock gg, gibbons dc, longford n, harvey mj, mcowan a, adams ej. rapid testing and treatment for sexually transmitted infections improve patient care and yield public health benefits. int j std aids. 2018 apr;29(5):474–482. https://doi.org/10.1177/0956462417736431 athens jk, duncan dt, elbel b. proximity to fast-food outlets and supermarkets as predictors of fast-food dining frequency. j acad nutr diet. 2016;116(8)1266–1275. https://doi.org/10.1016/j.jand.2015.12.022 ahmed n, pike c, bekker lg. scaling up pre-exposure prophylaxis in sub-saharan africa. curr opin infect dis. 2019; 32(1):24–30. https://doi.org/10.1097/qco.0000000000000511 pixless. instagram influencer: definition [homepage on the internet]. [cited 2020 jul 20] available from: https://www.pixlee.com/definitions/definition-instagram-influencer youth against aids [homepage on the internet]. [cited 2020 jul 20]. available from: https://www.youth-against-aids.org/ morton jf, myers l, gill k, et al. evaluation of a behavior-centered design strategy for creating demand for oral prep among young women in cape town, south africa. gates open res. 2020 jul 3;4:29. https://doi.org/10.12688/gatesopenres.13103.2 hiv_nov04 november 2004 the southern african journal of hiv medicine1 8 g u i d e l i n e pre-art guidelines amended november 2004 introduction as southern africa has finite medical resources and the public sector roll-out of antiretrovirals (arvs) is in its infancy, it is incumbent on medical practitioners to attempt to preserve the immune status of the patient for as long as possible so as to delay the initiation of antiretroviral therapy (art). these guidelines attempt to address the factors which are important in the holistic approach to patient management and which could also influence the progression and outcome of disease, including: ■ natural history of hiv infection ■ primary prophylaxis and immunisations ■ nutrition ■ support and counselling. south african hiv clinicians society expert committee most morbidity and mortality in hiv-infected patients is the result of opportunistic infections (ois). primary prophylaxis and immunisation can reduce the risk of these occurring. secondary prophylaxis is given to prevent recurrences of ois. progressive immunosuppression is associated with a wide variety of ois, but some ois can occur when the cd4+ cell count is relatively high, e.g. 500 cells/µl. as these guidelines address pre-art issues, only conditions that occur at cd4+ above 200 cells/µl will be discussed, as patients with cd4+ counts of 200 cells/µl or with a slightly higher cd4+ count and the presence of an oi(s) are likely to be on antiretroviral therapy. primary prophylaxis co-trimoxazole co-trimoxazole markedly reduces hospitalisation and mortality and provides protection against: ■ pneumocystis jiroveci (formerly known as p. carinii pneumonia (pcp) ■ toxoplasmosis ■ many bacterial infections, and ■ diarrhoea caused by isospora belli or cyclospora species. indications ■ all hiv-infected adults who are immunosuppressed, i.e. world health organization (who) stages 3 & 4 and/or cd4+ count < 200 cells/µl or total lymphocyte count of < 1.25 x 109/l. ■ co-trimoxazole can be discontinued in patients on art when the cd4+ count has risen above 200 cells/µl and has remained above that level for 3 months or more. dosage co-trimoxazole 960 mg/d. this dosage is the best-studied and the only regimen used in randomised controlled trials conducted in africa. lower dose regimens (480 mg/d or 960 mg 3 times per week) have been shown to have equivalent efficacy to the 960 mg/d with less toxicity, but all these studies were conducted in developed countries. side-effects the commonest side-effect of co-trimoxazole is maculopapular rash. treatment may be continued in the presence of mild rash or interrupted and then rechallenged with antihistamine cover. treatment should not be continued in the presence of fever, hepatitis or mucous membrane lesions, e.g. stevens-johnson syndrome. neutropenia is a rare side-effect of prophylactic cotrimoxazole — routine blood count monitoring is not necessary. primary prophylaxis and immunisation november 2004 the southern african journal of hiv medicine2 0 alternative drug dapsone 100 mg/d. note: dapsone does not provide protection against bacterial infections and provides only limited protection against toxoplasmosis. drugs to prevent tuberculosis (tb) isoniazid (inh) given at a dose of 300 mg/d for 6 months is the most studied of the prophylactic regimens and recommended in south african department of health (doh) guidelines. notes: ■ before commencement of preventive tb treatment, active tb should be excluded by using current doh guidelines. further investigations to exclude tb must be done if any of the following symptoms are present: • cough > 2 weeks • drenching night sweats or fever for > 2 weeks • observed weight loss > 1.5 kg/month. if any of the above symptoms are present, two sputum smears and one sputum for tb culture should be sent to the laboratory. it is not necessary to do a screening chest x-ray before initiating preventive therapy. ■ preventive therapy reduces the risk of active tb by about 60% in hiv-infected patients with a tuberculin skin test (mantoux test) reaction of ≥ 5mm. ■ there is no significant benefit in giving prophylaxis to patients with a negative skin test unless they fall into a high-risk category, i.e.: • people who have been in contact with tb including health care workers • underground miners and prisoners. ■ in communities with a high tb prevalence the benefit of prophylaxis does not extend beyond about 2 years. it is therefore recommended that hiv-infected health care workers should not work in areas with a high risk for tb. ■ tb preventive therapy should not be administered at tb clinics, as hiv-infected patients may be exposed to multidrug-resistant tb. in addition, the capacity of tb clinics is limited. ■ it is essential to monitor for symptoms of hepatotoxicity on a monthly basis. patients must immediately report any symptoms of nausea, vomiting, abdominal pain and jaundice. ■ pyridoxine 10 50 mg daily must be given concomitantly with isoniazid (inh) to prevent neuropathy (25 mg tablets are available in the public sector). as other supplements and multivitamin preparations may also contain pyridoxine, patients should be warned not to take over 100 mg per day. hiv infection is associated with a multifaceted suppression of both humoral and cell-mediated immune response, which may impair the response to vaccinations, reducing their efficacy. the safety of vaccination is also modified by hiv infection and the live vaccines of varicella, rotavirus and oral polio are contraindicated. hiv infection increases susceptibility to the diseases immunisation can protect against. therefore hiv infection alters both the risks and benefits of vaccination. while the aim of vaccination is to prevent clinical disease, trials of vaccine efficacy frequently rely on the surrogate marker of antibody titre. the antibody titres required to prevent disease are not always well established for immune-competent individuals and may differ in hiv-infected people. particularly if severe, immune suppression is associated with impaired responses to subunit, toxoid and killed vaccines. the efficacy of vaccination is therefore lowest in those most susceptible to the disease against which protection is sought. the decision to use a vaccine must be based on best assessment of risks and benefits. response to vaccination when the cd4+ count is < 200 cells/µl is very poor. it is mandatory to report all suspected vaccine-related adverse events and vaccine failures. pneumococcal vaccination although pneumococcal vaccination is recommended routinely and as early as possible by the centers for disease control and prevention (cdc) for patients who are hivseropositive, this is not currently recommended in south africa. the recommendation by the cdc was not based on studies but on the premise that while efficacy is not proven, the potential benefit and safety of the vaccine justify its use in this situation. there is currently insufficient evidence to support this recommendation. plasma hiv levels have been found to be transiently elevated in some studies in hiv-seropositive individuals following pneumococcal vaccination. the significance of these elevated levels is uncertain. the polyvalent pneumovax® has been shown to be ineffective and in fact increased the risk of pneumonia in a large ugandan study of patients not on art, and is therefore not advised.1 influenza vaccination the southern african influenza vaccine recommendations for 20042 recommend that people with mild to moderate immunosuppression should be vaccinated because of the greater liability to complications associated with secondary adult immunisations the southern african journal of hiv medicine november 2004 2 1 infection. however, because of the poor efficiency of the vaccine in severely immunosuppressed persons, i.e. those with cd4+ counts < 200 cells/µl, there is little point in immunising them. instead one would need to rely on chemoprophylaxis with either amantidine or (preferably) the newer neuraminidase inhibitor drugs, zanamavir or oseltamavir, for protection against influenza. limited data are available with regard to the effects of influenza on the hiv-infected individual but there is some evidence that symptoms may be prolonged and complications more common, and severe, at least in some cases. transient (2 4-week) increases in replication of hiv-1 in the plasma or peripheral blood mononuclear cells of hiv-infected persons after influenza vaccination have been noted in some studies. these increases are of uncertain significance. responses are sub-optimal if cd4+ counts are very low.2 travel and other special situations ■ hepatitis a and b vaccination can be given to all hivpositive patients if necessary. ■ yellow-fever vaccination can be given to patients with early hiv infection (who stage 1 or 2) and patients who have a cd4+ cell count of > 200 cells/µl, but is contraindicated in patients with symptomatic hiv infection (who stage 3 or 4 disease) and if the cd4+ count is less than 200 cells/µl. ■ rabies vaccination should be given to hiv-infected people working with animals and at game parks. immunoglobulins should be used in the event of a significant exposure. ■ cholera. no role other than for health care workers involved in an epidemic. ■ typhoid and oral polio vaccination is endorsed (inactivated polio vaccine (salk) should be given if this is available). malaria most cases of malaria in sub-saharan africa are due to plasmodium falciparum, the most severe and only lifethreatening form of malaria. all the remarks that follow apply to this species. south africans are generally at increased risk of developing severe malaria as they do not develop protective immunity because transmission is of low intensity, and is seasonal. falciparum malaria has higher mortality rates and is more common in hivinfected persons, especially those people with low cd4+ lymphocyte counts. pregnant women in areas of high transmission of malaria are at risk of severe forms of the disease, generally when they are primigravidas, but all gravidities of hiv-infected women are at risk. there is evidence that placental infection by malaria increases the risk of mother-to-child transmission of hiv. preventing malaria ■ avoiding mosquito bites. all hiv-infected individuals living in malaria transmission areas should be protected by adequate vector control. malaria control programmes in these areas are responsible for vector control, particularly spraying the interior of dwellings with residual insecticides, the use of larvicides, and reducing standing water. at an individual level, the simplest and most cost-effective way to minimise mosquito bites is by using insecticide-impregnated bed nets, and ensuring that these are regularly reimpregnated. the use of topical insect repellents is also effective, provided that 10 20% diethyltoluamide (deet) preparations are used (other preparations have minimal or no effect). repellents should be applied to all exposed skin (sparing the face) especially between dusk and dawn. travellers should also use mosquito coils or plugs. ■ chemoprophylaxis. all hiv-infected travellers to malaria transmission areas should be given chemoprophylaxis, according to national department of health guidelines for the prevention of malaria in south africa. either mefloquine or doxycycline is recommended. the combination of atovaquone and proguanil (malanil) is also effective, but is expensive and there are potential drug interactions with arvs that do not apply to either mefloquine or doxycycline (see below). malaria chemoprophylaxis should be offered to hivinfected pregnant women living in malaria endemic areas, irrespective of their gravidity. chemoprophylaxis must be accompanied by the non-drug measures to avoid mosquito bites. mefloquine is the agent of choice in pregnancy (as doxycycline is contraindicated), but its safety in the first trimester is still unclear. ■ the role of mefloquine or doxycycline chemoprophylaxis outside of pregnancy in adults living in endemic areas is unclear. hiv-infected patients with cd4+ lymphocyte counts < 200 cells/µl are at highest risk of malaria. these patients should all receive cotrimoxazole, which has been shown to reduce the risk of malaria in several studies of hiv-infected groups in sub-saharan africa. however, resistance to sulfadoxine-pyrimethamine (fansidar) has become widespread among p. falciparum in southern and eastern africa. co-trimoxazole has the same mechanism of action as fansidar and it is therefore likely that it will have limited chemoprophylactic efficacy in most areas. treating malaria since hiv-infected individuals are at increased risk of severe or fatal malaria it is essential that the diagnosis is november 2004 the southern african journal of hiv medicine2 2 made early. hiv-infected patients living in or travelling to malaria transmission areas should be encouraged to present to a health care facility where they can be tested immediately should they develop fever or flu-like symptoms. falciparum malaria in the hiv-infected patient should be treated with the most effective antimalarial available, i.e. either quinine (combined with doxycyline or clindamycin) or artemesinin-based combination therapy (in south africa artemether-lumefantrine (coartem) is the only available product). fansidar resistance is now so widespread in sub-saharan africa that this agent should no longer be used alone to treat malaria in patients at high risk of severe malaria — this includes all those with hiv infection. there are potentially significant interactions between arvs and quinine and coartem (see arv guidelines). in all stages of hiv infection emphasis on nutrition is very important and should focus on recommending a normal, healthy eating pattern and a balanced diet. the objective is to maintain a healthy body weight by eating a wide variety of healthy foods and exercising regularly. moderate exercise is recommended but intensive/vigorous exercise should be avoided as it may increase the metabolic rate and thus accelerate wasting. owing to the large number of people living in poor socioeconomic conditions in southern africa, health care practitioners treat many underweight individuals. malnutrition itself compromises immunity, which in turn affects hiv-related immune deficiency. the pathogenesis of malnutrition in hiv is multifactorial. reduced food intake because of socio-economic factors, anxiety, depression and oral or oesophageal thrush, and diarrhoea (in the later stages of hiv infection), are associated with acute periods of weight loss because of malabsorption of nutrients and an increased metabolic rate due to opportunistic infections. measuring nutritional status/body cell mass nutritional status, specifically the maintenance of protein stores (body cell mass) does impact on the ability to survive the ravages of hiv. body weight fluctuates within 3% over time in stable healthy adults. physical performance has been shown to decline after a weight loss of >10% of initial body mass, and weight loss of > 20% is associated with increased hospitalisation. at a level of 54% of normal body cell mass, death is likely to occur regardless of the presence or absence of ois. a depletion of the intracellular component of mass — the body cell mass — has been linked to shortened survival, increased risk of ois and poorer quality of life, independent of the level of immune depletion (cd4+ cell count). at each visit the nutrition status should be assessed and the following recorded: ■ body weight. ■ weight loss indicators (who): • < 10% unintentional weight loss (who clinical stage 2) • > 10% unintentional weight loss (who stage 3). ■ in the absence of reliable previous weight, the body mass index (bmi) can be calculated by dividing the patient’s weight (kg) by height squared (m2). a bmi of ≤ 18.5 is associated with a high mortality risk. in the absence of a stadiometer, height can be measured by measuring the distance between the tip of one middle finger to mid-sternum and multiplying this by two. ■ additional screening criteria: • changes in dietary intake • assessment of clinical status (wasting) • medication regimen (drug-nutrient interactions) and • exercise habits. hiv-related wasting syndrome there are two types of hiv-related wasting syndrome: ■ starvation-related wasting resulting from food deprivation (voluntary/involuntary) in clinically stable patients who have not yet presented with ois. the macronutrient status reflects the total body mass and the micronutrient status the body’s cellular functioning. micronutrient deficiency may exist without macronutrient deficiency, but macronutrient deficiency is almost always associated with micronutrient deficiency. these people respond well to nutritional support and feeding which usually reverses the starvation. ■ cachexia-related wasting is a disproportionate depletion of lean body mass (lbm) as a result of alterations in metabolism. in fighting disease, metabolic output is redirected to energy requirements and substrate needed to fuel the body’s response instead of normal maintenance of the body mass. in the long term this leads to protein (especially skeletal muscle) loss. feeding is not a sufficient intervention to reverse the effects of cachexia. food security in the african setting, household food security and the ability to implement food safety measures should be considered as important determinants of the development of aids wasting syndrome. large and small food donations require appropriate storage facilities and an efficient distribution network. nutrition the southern african journal of hiv medicine november 2004 2 3 further studies on the impact of malnutrition and food supplementation are urgently needed. there are no data to support the routine use of supplements in hiv-infected individuals with no evidence of nutritional deficiencies. evidence does, however, suggest that micronutrient deficiencies are common in patients with hiv and are associated with disease progression. regarding vitamin supplementation in poor, developing countries: ■ use of the following vitamins and minerals has been demonstrated to help slow disease progression: • vitamin b complex, c and e. a recent study by fawzi et al.3 conducted on 1 078 pregnant women in dar es salaam, tanzania, compared the following regimens: vitamin a alone; a multivitamin (vitamin b complex, c and e) alone, vitamin a plus the multivitamin; and placebo. the results showed that multivitamins (vitamin b complex, c and e) helped to slow down disease progression, but that the addition of vitamin a actually reduced the benefit at the end point.3 vitamin b complex had been shown to be useful in earlier studies.4-6 • selenium. little work has been conducted on selenium apart from willumsen’s work in 20037 and more work is required to confirm that selenium may reduce the incidence of ois, improve immune function and slow disease progression. ■ benefit demonstrated in identified deficiency: • vitamin a8 (note: not more than 20 000 iu/4 000 µg re — increased disease progression). • zinc9 (note: > 20 mg/d = increased disease progression; ≥ 14 mg/d = decreased survival.) ■ vitamins and minerals not recommended in hivinfection — associated with possible worsening of the condition: • vitamin a10 • iron: no published reports of iron supplementation studies. where possible all patients should be on multivitamins that include the nutrients in dosages indicated in table i. a supplement which provides 100% to 150% of the recommended dietary allowances (rdas) of current dietary reference intakes (dris) is advisable since it is most unlikely dietary supplements maximum dose for toxic on higher dose rda (range supplementation (upper limit (ul) — do not nutrient for female and male) in hiv/aids exceed) vitamin e (mg te) 15 25 α-te* 1 000 te selenium (µg) 55 100 400 folate (µg) 400 400 800 1 000 niacin b3 (mg) 14 -16 25 35 thiamin b1 (mg) 1.1 1.2 5.5 6.0 none riboflavin b2 (mg) 1.1 1.3 5.5 6.8 none vitamin b6 (mg) 1.3 6.8 100 vitamin b12 (mg) 2.4 5 10 none vitamin c (mg) 75 90 250 2 000 β-carotene (mg) no rda 15 mg magnesium (mg) 280 200 350 chromium (mg) 25 35 µg 25 µg a-lipoic acid no rda 10 15 mg 100 mg glutathion 10 mg 50 mg none α-te = α-tocopherol equivalents or mg of rrr-α-tocopherol; dri = dietary reference intakes, which has four categories: ear (estimated average requirements – needed to set rda), rda (recommended dietary allowances), ai (adequate intakes), ul (tolerable upper limits). notes: ■ patients receiving rifampicin treatment may require additional vitamin d supplementation. ■ patients receiving isoniazid therapy should receive 10 15 mg pyridoxine (vitamin b6) to prevent peripheral neuropathy. pyridoxine has monoamine oxidase inhibitor (maoi)-like activity. avoid high tyramine or histamine foods:8 • foods that must be avoided (high content of tyramine, dopamine, histamine, phenylethylamine): aged cheese (e.g. cheddar, blue); aged meat (e.g. dry sausage, salami, biltong); soy sauce; fermented soy beans, soybean paste; tofu; sauerkraut; tap beer; concentrated yeast extract (marmite); banana peel; all casseroles made with aged cheese. • foods that may be used with caution: red or white wine 60 120 ml per day; coffee, cola; pizza (homemade or gourmet pizza may have higher content); bottled beer, 2 x 350 ml bottles maximum; alcohol-free beer, 2 x 350 ml bottles maximum. • foods not limited (based on current analyses): unfermented cheese (cream, cottage, processed); smoked white fish, salmon, anchovies, pickled herring; fresh meat, poultry or fish; canned figs, raisins; fresh pineapple; beetroot, cucumber; sweetcorn, mushrooms; salad dressings, tomato sauce; worcestershire sauce; baked raised products, plain cookies; boiled egg, yoghurt, ice cream; avocado, figs, banana, raspberries; brewer’s yeast (vitamin supplements); curry powder; peanuts, chocolate. all packaged processed meats, e.g. hot dogs, bologna, liverwurst, should be stored in refrigerator immediately and eaten as soon as possible. histamine content is highest in improperly stored or spoiled fish, e.g. tuna. table i. dietary supplements november 2004 the southern african journal of hiv medicine2 6 that a person with hiv/aids will be able to meet the requirements for vitamins and minerals with diet alone owing to poor appetite and/or possible financial constraints. food choice advice in hiv-infected people, the emphasis is on ensuring adequate energy and protein intake to maintain body weight and, more specifically, lean body tissue. this advice should commence early in the infection and include (where the patient can afford it): ■ food variety. ■ plenty of fruit and vegetables. ■ starch as the basis of all meals. ■ daily portions of meat and dairy products. ■ sugars, fats and oils should be included in the diet, especially following periods of weight loss. ■ regular intake of dried beas, peas, lentils, peanuts or soya. ■ salt should be used sparingly (as in south africa there is a high prevalence of hypertension and stroke). ■ alcohol should be avoided. ■ during times of loss of appetite and/or nausea, small frequent meals should be advised. the patient should avoid lying down after a meal, and should eat foods at room temperature. ■ when symptoms of sore mouth or throat appear, soft foods moistened with margarine or gravy can be advised and sticky, spicy and acidic foods should be avoided, e.g. peanut butter, dry rough foods, citrus fruits. ■ when diarrhoea or vomiting is present advise isotonic fluids (see box), diluted fruit drinks, and avoidance of caffeine products (coffee, cola drinks), dairy products (although fermented dairy, e.g. maas, may be tolerated) and high-fat foods. encourage high soluble fibre foods, e.g. bananas, oats porridge. ■ intake of lots of clean, safe water. ■ as much physical activity as possible. the food pyramid the food pyramid (fig. 1) illustrates the above dietary guidelines.11 ■ choose at least 1 portion (or more) from the last 3 levels of the pyramid for each meal as indicated in example meal plans (see below). ■ eat at least 6 meals (where possible) — 3 main meals and 3 snacks in between meals. ■ use fats, sweets and alcohol sparingly (top level). example meal plans choose foods from the different levels of the pyramid within the financial constraints of the given individual, including culturally accepted foods. morning meal • porridge (1 cup)/2 slices wholewheat bread with sugar/jam (2 t) • milk (1 cup)/cheese (30 g)/1 egg/cooked beans (1/2 c)/ meat or fish (30 g cooked) • fruit/vegetable — raw/cooked/juice (1 portion) mid-morning snack • cottage cheese (2 tbsp) + 1 slice wholewheat bread or • cheddar cheese (30 g) + 3 crackers or • yoghurt, low fat, fruited (175 ml) lunch/light meal • porridge/rice/samp (1 2 cups)/2 3 slices wholewheat bread with sugar/jam (2 3 t) • milk (1 cup)/cheese (60 g)/eggs (1 2)/1/2 c cooked beans/30 60 g cooked meat or fish • fruit/vegetable — raw/cooked/juice (1 portion) mid-afternoon snack • cottage/gouda cheese (125 ml) + 1/2 banana or • pudding (175 ml) or • bean/egg filling + 1 slice wholewheat bread oral rehydration solution (ors) • 1 litre clean, safe water • add 8 level teaspoons sugar • add half teaspoon salt • mix well • store in clean and covered container • keep in cool place • make fresh solution every day this suffices if nothing else is available, but contains no potassium. ors with potassium is on the primary care edl. fig. 1. the food pyramid. the southern african journal of hiv medicine november 2004 2 7 dinner/main meal • meat/fish/poultry/cooked dry beans or lentil dish (one 60 90 g portion cooked) • samp/rice/porridge/potato/sweet potato (1 2 cups) • vegetables (cooked and/or raw) (1 2 cups) and/or • fruit 1 2 portions late evening meal • 1 slice wholewheat bread + filling or • fruit yoghurt (175 ml) or • fruit raw/cooked/juice + milk/maas nutritional benefits of herbs and other unconventional treatment strategies more information on unconventional treatment strategies is available on www.sun.ac.za/nicus. ■ garlic. no human studies to date have consistently and conclusively documented that garlic can improve immunity or the immune response. various deleterious side-effects are associated with the use of garlic supplements. ■ virgin olive oil. although the substitution of saturated fat or polyunsaturated fat with extra-virgin olive oil may have health benefits for people living with hiv/aids, there is no convincing or consistent scientific evidence that virgin olive oil boosts immunity or alters the course of hiv/aids, adversely or beneficially. for financially insecure patients the purchase of a relatively expensive product such as virgin olive oil may limit the purchase of other affordable wholesome foods. ■ african potato (hypoxis hemerocallidea corm). hiv/aids patients should avoid any supplements containing african potato or the hypoxis plant. it is a rich source of phytosterols, but it has been found to be a toxic agent causing bone marrow toxicity and worsening immune suppression in hiv-infection as well as in feline immunodeficiency virus infection. this agent should therefore be avoided. ■ onion. onions are a food source of phytochemicals such as flavonoids and organosulphur compounds. in terms of safety the ingestion of large quantities of onions is known to cause gastrointestinal discomfort and distension and they should be used with caution by individuals with chronic diarrhoea and gastrointestinal discomfort. ■ spirulina. this extract of blue-green algae has some immunomodulatory activity: • inhibits mast cell-mediated allergic reactions • increases the activity of macrophages • increases phagocytosis • increases the concentration of interleukin-1 (il1). blue green algae extracts can be contaminated with toxic species (microcystis aeruginosa) that are hepatotoxic. heavy metal contamination has also been reported. a protein (cyanovirin-n) with anti-hiv properties has been isolated from another species (nostoc ellipsosporum) by the national cancer institute, usa. research is needed to confirm efficacy in humans. ■ sutherlandia frutescens. this traditional herbal remedy is widely used in south africa. animal studies conducted by the medical research council failed to show any significant toxicity. no published studies exist on human toxicity or use for any indication. ■ immune modulators (e.g. phytosterols) a mixture of the plant sterols (phytosterols) betasitosterol and its glycoside, moducare, is widely promoted as an ‘immune booster’ in hiv infection. studies conducted by researchers at the university of stellenbosch have shown several effects on immunity in vitro: • lymphocyte proliferation in response to mitogenic stimulation is enhanced • increased lytic ability of natural killer cells • increased th1 immune response and unchanged or inhibited th2 response • inhibition of the pro-inflammatory cytokines, interleukin 6 and tnf-α. effects are therefore both stimulatory and inhibitory. it is more accurate to call it an immune modulator rather than an immune booster. the net effects in hivinfected individuals are difficult to predict. the stimulatory effects (e.g. on lymphocyte proliferation) could be harmful, leading to increased hiv replication. a small unpublished feline study has shown that cd4+ cell counts remain higher during treatment. an uncontrolled unpublished human study claimed reduced viral load but provides no specific figures. researchers stated that moducare has no antiviral effects and ascribed the reduction in viral load to reduced immune activation. a small controlled human trial carried out in adults with tuberculosis showed no improvement in sputum conversion rates, but subjects gained weight. elevated eosinophil counts were noted in the treatment arm, which could indicate hypersensitivity. there are therefore grounds for believing that the product might be beneficial but equally a concern that it could be harmful. further randomised controlled trials need to be conducted. ■ other alternative diet therapies and supplements. these diets have not been subjected to formal clinical research and many of these diets may imply, or result in, some ill-advised food elimination and/or restriction. it is best to eat a varied diet, within the financial constraints of the given individual, and include culturally accepted energyand protein-rich foods. november 2004 the southern african journal of hiv medicine2 8 the importance of the role comprehensive counselling plays in the management of patients living with hiv/aids cannot be overemphasised. such counselling has a demonstrably beneficial effect upon the subsequent quality of life of people living with the virus.12 the aim of counselling is to provide each individual with sufficient information to manage his/her condition well and to access the support required to deal with all aspects relating to their infection: medical, social, psychological and emotional. in this context counselling may be termed a ‘structured conversation aimed at facilitating a client’s (patient’s) quality of life in the face of adversity’.13 counselling is performed by a suitably trained health care professional or counsellor. the latter may be someone from the client’s own community.14,15 additional care may be given in a ‘support group’ where overall supervision remains in the hands of a trained and accountable member of the group. counsellors too require access to support for the purpose of processing and debriefing sensitive information and feelings. burnout and emotional fatigue are common problems among workers in the health field.16-18 specific forms of counselling voluntary counselling and testing (vct) and pre-test counselling vct is a voluntary programme that provides confidentiality and ease of access to the hiv test and result. pre-test counselling focuses on the value of knowing one’s hiv status and the consequent lifestyle and social change that such knowledge will bring. the possibility of a positive test result is discussed together with the consequent need to inform (sexual) partner(s) and to disclose one’s hiv status to significant others such as family members. how would i respond to such news? how will i inform my partner? how do i deal with stigma and rejection? the counsellor anticipates the patient’s responses and aims to provide sufficient support to enable the patient to cope. a downside to testing positive is coping with societal restrictions and personal shame: exclusion from or ‘loading’ of insurance policies and home loans, retrenchment or harassment in the workplace, the curtailing of emigration and restrictions on international travel, the banning of blood and organ donation, rejection from family and friends. however ‘forewarned is also forearmed’. knowing one’s hiv status is a ‘first’ step in preventing viral transmission and in ensuring good health in the future. wise counsel will assist the patient to manage his/her personal affairs and make provision for the long-term care of dependants. a return date for obtaining the result is set at the initial visit. the actual blood or saliva test may be done at or after the counselling has been completed. the test measures the presence of antibodies in the patient and is usually an hiv elisa and/or western blot test. some centres are able to perform ‘rapid’ hiv-antibody tests: the patient can be given his/her result almost immediately. pre-test counselling is regarded as a prerequisite to performing an hiv test. persons doing the test without the patient’s consent are liable to prosecution in south africa. the patient must give his/her consent to the test.19-21 post-test counselling in this context the patient has had an hiv test but has not yet received the result. it presupposes that pre-test counselling has been performed. the counsellor assists the patient in understanding his/her test result. the patient must be shown his/her result. the test result will be either negative or positive. an ‘indeterminate’ result means that the test needs to be repeated. if it is persistent over subsequent follow-up, an alternative means of verifying infection is indicated. where the result is negative, both truly negative and falsely negative results are possible. test results that are falsely negative occur either soon after exposure, mostly within 6 weeks — the so-called ‘window period’ — or late in the course of hiv infection. in both situations the patient’s level of anti-hiv antibodies is below the limit of detection by the laboratory. repeat antibody testing where the suspicion of infection is very high or the use of an alternative means of detecting the virus — by measurement of the p24 antigen, or directly measuring the virus with a viral polymerase chain reaction (pcr) test (a ‘qualitative’ viral load) — and the practice of ‘safe sex’ until clarification of status are indicated. false-negative tests are rare and seldom a cause of anxiety to either the patient or the counsellor. in 2000, an average of 24.5% of south african antenatal clinic attenders tested hiv-positive. prevalence rates in the community as a whole are in excess of 11 17%.22,23 this is sufficiently high to make false-positive hiv-antibody tests unusual. the patient who tests hiv-positive but who is uninfected is not difficult to differentiate from those who are truly infected and whose tests are truly positive. falsepositive tests occasionally result from technical or laboratory errors. where uncertainty exists the test must be repeated. alternative tests, if required, will clarify the patient’s status. where the patient tests positive, instill hope. deal with immediate feelings, particularly where he/she has been poorly prepared. it is always good to have a close friend or family member with the patient or in the waiting room outside. in africa, the involvement of the family and support and counselling the southern african journal of hiv medicine november 2004 2 9 sometimes community members is a cultural norm and may be requested by the patient. review the ‘hows’ with the patient: how to notify partners and/or family, how to practise safe sex, and how to introduce the use of condoms into a relationship when these were previously taboo. recall the ways in which the virus can be spread and indicate what to do when blood spills occur in the home. there is no need for social isolation. young patients wishing to have a family will need advice regarding pregnancy. encourage the patient to plan for the future. detail the support that is available to him/her. access to art has altered the previously bleak picture. patients can expect to live for many years after starting arv drugs. even in resource-poor settings, patients show a response to arv drugs that is similar to that in highly developed communities.24,25 post-test counselling is always done in private and never ‘over the telephone’. do not leave test results on an answering machine or cell phone. never give results to a ‘friend’ or a third party. post-test counselling is generally not repeated unless the patient requests further assistance. the latter is most frequently given in the form of ‘life-skills’ counselling. life-skills, crisis intervention and family planning counselling growing the skills to meet the challenges of life is a longterm necessity we all face. those who are hiv infected encounter these challenges when least prepared. they are young. sexual relationships and the nuclear family are incomplete. permanent employment and financial security are many years away. peer pressure and a culture that is itself in transition, drive youth — like lemmings — into the web of an epidemic that offers little chance of escape. patients express shame, guilt, anger, betrayal, blaming, denial, depression, bargaining, loss. what do i do with myself? how do i deal with my feelings? how do i mend the relationships that have been broken? how do i change? can i accept my situation and move on? who am i? time and listening skills are needed but seldom available in busy clinics and practices. suicidal thoughts must be taken seriously, although suicide remains rare. nevertheless suicide is more frequent in the hiv infected and particularly around the time of diagnosis.26,27 the counsellor assists the patient in setting goals and encourages him/her to implement these. the virus must not be allowed to define who the patient is.28 have sexual partners been notified? do these partners need assistance and are they supportive of the patient? is the patient employed and are there work-related problems: unlawful dismissal, hiv testing without consent or with coercion, undue absenteeism, inability to work and the need to procure pension benefits and/or disability grants? from time to time patients or their families will ask for legal assistance: with physical and other forms of abuse in the home, advice regarding separation or divorce, workrelated issues, problems with the payout of funeral benefits or insurance cover. obtaining bank loans and insurance remains difficult for many patients. support groups are often very helpful in this long-term form of counselling. patients learn from one another. family planning may need to be addressed. infected parents want an hiv-negative baby. ideally both partners should be counselled together and each encouraged to take personal responsibility for his/her own sexual health. discussion on contraception must include barrier methods, particularly condom use, and the role of injectable and oral hormonal contraceptives. condom use is recommended at all times, even where both partners are already hiv infected. super-infection with ‘new’ hiv strains has been recorded in such circumstances.29,30 nonetheless those who plan to become pregnant need to be listened to sympathetically and assisted where possible. discordant couples (where one is hiv-negative and the other positive) may question why one remains uninfected. such couples need clear scientific advice and must be encouraged to persist in condom use. life-skills and crisis counselling usually takes place in a situation where privacy and time are available to the counsellor and the patient. where time and opportunity do not permit, the physician must refer to an appropriately skilled caregiver. severe depression, suicidal talk, domestic violence, and psychotic and irrational behaviour, must be regarded seriously. patients and their families must be assisted with obtaining the help they need.31 management-related counselling patients often ask the difference between being hivpositive and having the acquired immunodeficiency syndrome (aids). the various staging systems — who or centers for disease control (cdc) — can be explained briefly in a non-technical manner. the art of counselling ■ empathy. indicate concern, be non-judgemental and accepting. where possible sit alongside the patient and not on the other side of the desk, and at the same height as the client. avoid emotional and physical distance. ■ trust. maintain confidentiality at all times, keep (brief) notes/records of the interview. keep the interview private and attempt to prevent interruptions, e.g. cellphone calls. where feasible, ensure that the same november 2004 the southern african journal of hiv medicine3 0 counsellor and patient/client meet during follow-up visits. ■ listen. be an informed and an attentive listener. when information is needed, provide scientific knowledge in a manner that can be understood by the client. provide information on the costs involved and the accessing of affordable medicines. encourage long-term budgeting. listen to the patient – attempt to hear what is being said behind the words. ■ sensitivity. be client-centred. attempt to understand the culture and belief system. encourage family or partner involvement. enquire about feelings: what need is being expressed? what emotion is being experienced? provide a sense of hope and indicate the next step – what can be done. deal with specific medical problems without delay. ‘how are you coping?’ ■ right questions. ‘why do you want to know your hiv status?’ encourage the patient to voice his/her concerns and questions. avoid ‘closed-ended’ questions: e.g. ‘do you ..., did you ..., have you ….’ use instead ‘open-ended’ questions that allow for interaction between the client and yourself. begin the discussion with ‘why ..., what ..., when ..., how ..., describe …’. education: providing patients with knowledge the counsellor needs to be able to address the following topics comprehensively and clearly: ■ scientific data about hiv and the effects of infection on the human system. • what is a virus? the natural history of the virus (hiv) and where it has come from. • how is hiv infection contracted? through contact with blood, sexual contact and mother-to-child transmission. how can viral transmission be prevented? • how does the virus damage the human body/ immune system? the viral life cycle within the human lymphocyte, i.e. within the immune system of the host. • survival data as they relate to the patient. the control of the virus by the host immune system, medication, and lifestyle modification. ■ laboratory monitoring of the infection and the effects of medication. • the cd4 cell count: measuring the immune system. aim: to build up the cd4 cell count and to maintain it within the normal range indefinitely. the normal cd4 cell count is between 500 and 2 000 cells/µl. • the viral load: measuring the virus itself. aim: to ensure tight control of the virus to minimise the damage to the human body/immune system. • other laboratory tests, e.g. full blood count (fbc). • cost and frequency of tests. aim: where possible, to ensure an affordable and reliable source of scientific information on the patient’s progress. ■ the medical management of the patient. • the diagnosis of hiv and aids. the taking of a medical history and the examination of the patient. confirmatory blood (saliva) tests. • follow-up visits and blood tests. emphasise adherence with the follow-up schedule. follow-up visits offer the opportunity to ensure that the viral infection is under control. ■ the role of lifestyle and diet (nutrition) in maintaining health. • a healthy diet and lifestyle makes good sense and should be encouraged. • there is, however, little supportive evidence-based data for the use of special diets and nutritional supplements. these can prove very expensive to the consumer. • where documented or anticipated deficiencies of vitamins or trace elements exist, these can be replaced. • it is possible that a mixture of vitamins b, c and e may be of benefit. (see section on nutrition.) conclusion adequate counselling requires time and commitment. this is often difficult in a busy or understaffed clinic or medical practice. many successful hiv practices have delegated much of the counselling to trained nursing staff or willing and skilled community members. to view the hiv epidemic purely as a plague that requires the adoption of health precautions and drugs is to miss the point. the epidemic continues to grow each year despite scientifically appropriate messages. lifestyles are not changing. for the latter to occur significant changes in relationships between people must occur. in an article on concurrent relationships as a reason for the high rate of hiv infections in africa, the authors comment: ‘as soon as one person in a network of concurrent relationships contracts hiv, everyone else in the network is placed at risk. by contrast, serial monogamy traps the virus within a single relationship for months or years.’30 we need a more caring society. the hiv epidemic offers that opportunity. good counselling helps to open that door. references 1. adult influenza and pneumococcal vaccination guidelines. s afr med j 1999; 89: 1215-1230 (part 2). 2. schoub bd. vaccine advisories: influenza vaccine recommendations. communicable diseases surveillance bulletin. 2004; march: page 1. 3. fawzi w, msamanga gi, spiegelman, et al. a randomized trial of multivitamin supplements and hiv disease progression and mortality. n engl j med 2004; 35: 23-32. 4. baum m, cassetti l., bonvehi p, shor-posner g, lu y, sauberlich h. inadequate dietary intake and altered nutrition status in early hiv-1 infection. nutrition 1994; the southern african journal of hiv medicine november 2004 3 1 10: 16-20. 5. baum mk, shor-posner g, lu y, et al. micronutrients and hiv-1 disease progression. aids 1995; 9: 1051. 6. tang am, graham nm, saah a.j. effects of micronutrient intake on survival in human immunodeficiency virus type 1 infection. am j epidemiol 1996; 143: 12441256. 7. willumsen j. the role of nutrition interventions in the prevention of hiv infection and progression of hiv/aids. technical review 2003; feb. 8. semva rd, tang am. micronutrients and the pathogenesis of human immunodeficiency virus infection. br j nutr 1999; 81: 181-189. 9. kupka r, fawzi w. zinc nutrition and hiv infection. nutr rev 2002; 60(3): 69-79. 10. rothman kj, moore ll, singer mr, nguyen u-sdt, manninno s, mulinsky a. teratogenicity of high vitamin a intake. n engl j med 1995; 333: 1369-1373. 11. mahan escott-stump, eds. krause’s food, nutrition and diet therapy. 11th ed. 2004; 459. 12. van dyk a. counseling in a traditional african society. in: hiv/aids care and counselling. a multidisciplinary approach. 2nd ed. cape town: maskew miller longman, 2001: 227-236 13. johnson p. basic counseling skills: applications in hiv/aids counseling. unpublished manuscript, unisa centre for applied psychology, pretoria, 2000, p. 3. quoted in van dyk a (above), p. 200. 14. farmer p, leandre f, makherjee js, et al. community-based approaches to hiv treatment in resource poor settings. lancet 2001; 358: 404-409. 15. behforouz hl, farmer pe, mukherjee js. from directly observed therapy to accompagnateurs: enhancing aids treatment outcomes in haiti and in boston. clin infect dis 2004; 38: s429-s436. 16. allwood cw, freidland ir, karstaedt as, mcintyre ja. aids – the baragwanath experience. part iv. counselling and ethical issues. s afr med j 1992; 82: 98-101. 17. miller d. stress and burnout in hiv/aids carers. aids 1996; 10: suppl a, s213-s221. 18. schulz r, mendelsohn ab, naley we, et al., for the resources for enhancing alzheimer’s caregiver health (reach) investigators. end-of-life care and the effects of bereavement on family caregivers of persons with dementia. n engl j med 2003; 349: 1936-1942. 19. grinstead oa, gregorich se, choi k-h, coates t, and the voluntary hiv-1 counselling and testing efficacy study. positive and negative life events after councelling and testing: the voluntary hiv-1 counselling and testing efficacy study. aids 2001; 15: 1045-1052. 20. the voluntary hiv-1 counseling and testing efficacy study group. efficacy of voluntary hiv-1 counselling and testing in individuals and couples in kenya, tanzania, and trinidad: a randomized trial. lancet 2000; 356: 103-112. 21. fenton ka, peterman ta. hiv partner notification: taking a new look. aids 1997; 11: 1535-1546. 22. hosegood v, vanneste a-m, timaeus im. levels and causes of adult mortality in rural south africa: the impact of aids. aids 2004; 18: 663-671. 23. dorrington r, bourne d, bradshaw d, laubscher r, timaeus im. the impact of hiv/aids on adult mortality in south africa: technical report. http://www.mrc.ac.za/bod/dob.htm 24. egger m, may m, chene g, et al. lancet 2002; 360: 119-129. 25. coetzee d, hilderbrand k, boulle a, et al. outcomes after two years of providing antiretroviral treatment in khayelitsha, south africa. aids 2004; 18: 887-895. 26. van dyk a. counselling the infected and the affected. in: hiv/aids care and counselling: a multidisciplinary approach. 2nd ed. cape town: pearson education, 2001: 278-282. 27. maris rw. suicide. lancet 2002; 360: 319-326. 28. cassel ej. the nature of suffering and the goals of medicine. n engl j med 1982; 306: 639-645. 29. goulder jr, walker bd. hiv-1 superinfection – a word of caution. n engl j med 2002; 347: 756-758. 30. jost s, bernard m-c, kaiser l, et al. a patient with hiv-1 superinfection. n engl j med 2002; 347: 731-736. 31. halperin dt, epstein h. concurrent sexual partnerships help to explain africa’s high hiv prevalence: implication for prevention. lancet 2004; 364: 4-6. to the editor: the article in this issue of the southern african journal of hiv medicine by anna coutsoudis entitled ‘breast feeding and hiv: an update’ (p. 45), illustrates that there is still a great deal of debate in south africa around this topic. coutsoudis correctly points out in her article that the randomised controlled trial of breast versus formula feeding carried out in kenya had limitations; in particular an intent-to-treat analysis was performed that would have underestimated transmission in the breast-feeding and over-estimated transmission in the formula-feeding populations. this given, why would it be unethical to repeat this trial with prevention of mother-to-child transmission (pmtct) antiretroviral prophylaxis in the intrapartum period? there is ethical equipoise, since most women still breast-feed in south africa and formula feeding is not without risk. this paper also cites a suggested 4% assumed risk of transmission for every 6 months of breast-feeding, and this high transmission rate must beg the question of the circumstances under which breastfeeding is justified and when it is feasible to avoid this risk. there should be an analysis of risk benefit — what are child survival risks in south africa if infants are not breast-fed, compared with survival in those infants who become infected with hiv? francois dabis has reported from cote d’ivoire on the use of triple regimens such as azt/3tc/nvp to reduce intrapartum as well as breast-milk transmission and other strategies such as the regimen used by lallemant in thailand which have shown a large reduction in transmission. since south africa and thailand share similar infrastructure and socio-economic status, perhaps a similar regimen should be adopted here. coutsoudis also does not comment on the local pmtct programmes and the fact that breast-milk substitutes are available. she does not comment on whether high rates of exclusive breast-feeding are feasible, and indeed whether high rates have been attained in a variety of communities in south africa. finally, the paper does not give formula feeding as a option in pmtct strategies and yet does not clarify why not or the conditions under which it should be considered. glenda gray perinatal hiv research unit university of the witwatersrand letter • letter • letter • letter • letter chairperson of the pre-art guidelines committee: dr des martin. expert panel members: professor gary maartens, dr dave spencer, dr lynne webber, dr leighton mcdonald, professor andre dannhauser, professor derick veldman, dr francois venter, professor robin wood and dr steve andrews. these guidelines pertain to the republic of south africa. the sduthhln african journal of hiv medicine ----------february 200 i horizons free diflucan here! the southern africa regional dffice of iapac (the international association of physicians in aids care) has been given the responsibility to facilitate the training of health care workers on the best practices relating to using diflucan and for managing cm and oc. this training will take place in a phased approach that initially targets the institutions in each province where the drug is to be made available. fact sheets that summarise these best practices have been published. in addition, modular training materials for nurses, doctors and patients are being developed and will be available from iapac. iapac's 'aids care faculty', a network of experienced health professionals through which ongoing training activities will take place, is seen as a regional asset that will facilitate the cascade of information fiow and professional education relating to hiv/aids best practices and lead to a growth in both the numbers and capacity of trained health care workers managing the disease appropriately. careful procedures have been put in place to regulate the dispensing of donation stock to ensure that it is used only for the indications allowed and to prevent stock diversion, although the ministry of health has confirmed that no patient will be refused access to this treatment, even if they are referred from the private sector. patients presenting with cm have a poor longer-term survival prognosis and here are particular challenges to managing aids patients with cm and also important opportunities not to be missed in identifying vulnerable households of patients that will benefit from social interventions, such as planning for orphan care. clinicians are encouraged to actively participate in training activities where these are offered and to ensure that patients are identified early and referred to participating institutions to make the most of this intervention. the diflucan parnership programme offers an important opportunity to impact on the care of aids patients, but its success will depend on how well the drug is used and how many patients are identified and referred for treatment. iapac is facilitating a toll-free difiucan hotline on the number 08003435821 for any enquiries relating to where the drug is available, how it should be used and how to access training and other resources. the diflucan partnership programme website (www.dpp.org.zo) is on additional source of resources, information and training materials. the diflucan partnership programme is therefore seen as an important catalyst for improving how aids patients are treated and cared for. world aids day (december 1st) at the end of last year saw the signing of a groundbreaking public-private partnership agreement between pfizer pharmaceuticals and the south african ministry of health. the memorandum of understanding that defines the conditions of pfizer's 2-year donation of free difiucan to south africa (estimated at a market value of r375 million) was the culmination of months of negotiations to ensure that south africa benefits appropriately from the offer. pfizer has made a significant additional commitment to support the development of knowledge and skills in implementing the diflucan partnership programme through funding professional training that is part of the department of health's broader strategy to build the capacity of all healthcare workers managing the epidemic, providing training for guideline-supported best practices. through this process, which has been severely criticised by the treatment action campaign as creating unacceptable delays to making this treatment accessible, the department of health has achieved agreement on expanding the indications for using the donated drug to include both cryptococcal meningitis and oesophageal candidiasis. pfizer also committed to making the offer available to other sadc countries, in compliance with the sadc health ministers' stated strategy for taking on international pharmaceutical offers as part of a regional response. the implementation of this initiative is being overseen at a top level by a ministerial working group, which has already held a number of strategy meetings to ensure that the intervention is made widely available as soon as possible. the agreement has been cited as an important example of what can be achieved through enabling partnerships that add value and scope to the care that is delivered to hivaffected populations. it is hoped that this will encourage similar initiatives that are able to bring more hope to aids sufferers in the region. for south africa, this is important as the first treatment access programme to result from challenging the pharmaceutical multinationals to make hiv medications more generally available to hiv-affected populations in developing countries. in mid february, the mcc fast-tracked its registration of the donation formulation (which differs from the commercially available capsule in that it is a blue 200 mg tablet), and it is anticipated that institutions should have stock available for prescription before the end of march. abstract introduction methods results discussion conclusion acknowledgements references about the author(s) ardele m. mandiriri newlands clinic, harare, zimbabwe department of epidemiology, faculty of epidemiology and population health, london school of hygiene and tropical medicine, london, united kingdom margaret j. pascoe newlands clinic, harare, zimbabwe tinei shamu newlands clinic, harare, zimbabwe institute of social and preventive medicine, university of bern, bern, switzerland sara lowe newlands clinic, harare, zimbabwe department of medicine, college of health sciences, university of zimbabwe, harare, zimbabwe citation mandiriri am, pascoe mj., shamu t., lowe s. cervical human papillomavirus prevalence, risk factors and outcomes in a cohort of hiv-infected women in harare, zimbabwe. s afr j hiv med. 2020;21(1), a1123. https://doi.org/10.4102/sajhivmed.v21i1.1123 original research cervical human papillomavirus prevalence, risk factors and outcomes in a cohort of hiv-infected women in harare, zimbabwe ardele m. mandiriri, margaret j. pascoe, tinei shamu, sara lowe received: 06 july 2020; accepted: 30 aug. 2020; published: 05 nov. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: human papillomavirus (hpv) associated invasive cervical cancer (icc) is common in zimbabwe, disproportionately affecting women living with hiv (wlhiv). understanding high-risk hpv (hrhpv) infection in relation to cervical disease is important for icc prevention amongst wlhiv. objectives: to describe the prevalence of cervical hrhpv, type distribution, associated risk factors and icc screening outcomes in an urban cohort of zimbabwean women. methods: in this cohort study, wlhiv were tested for hrhpv infection using the cepheid xpert® hpv assay and followed up for incident cervical disease. follow-up assessments were done by visual inspection with acetic acid (via). descriptive statistics and logistic regression were used to describe hrhpv burden and association between hrhpv and potential risk factors. incidence rates (ir) and rate ratios of cervical disease by hrhpv infection status were also calculated. results: amongst 321 wlhiv recruited, hrhpv prevalence was 24.9% (n = 80). fifty-two of these women (65%) were positive for hrhpv types other than 16 or 18/45. younger age (22–29 years), early sexual debut (13–16 years) and antiretroviral therapy (art) regimen (second-line art) were independently associated with hrhpv positivity. positive via ir ratio between hrhpv-positive and -negative women was 12.57 (95% confidence interval [ci]: 4.14–38.19). only women with hrhpv infection had incident cervical disease (ir: 6.41/100 person-years, (95% ci: 3.33–12.32). there were no icc cases by the end of the 2-year follow-up. conclusion: there was a high prevalence of hrhpv infection other than 16 and 18/45 in this cohort. integrating hpv testing in cervical cancer screening programmes may increase screening intervals in hrhpv-negative women, reducing costs for programmes. we recommend further research into cross protectivity of the bivalent and quadrivalent hpv vaccines against these other hrhpv types. keywords: cervical cancer screening; hpv infection in wlhiv; hrhpv prevalence; visual inspection with acetic acid; hpv vaccine cross protection. introduction zimbabwe is one of the countries with the highest human immunodeficiency virus (hiv) burden in sub-saharan africa. in 2018, the hiv prevalence was estimated at 12.7% amongst adults aged 15 to 49 years, with a higher prevalence in women (15.4%) than in men (10.0%).1 women living with hiv (wlhiv) have higher rates of infection with high-risk human papillomavirus (hrhpv) genotypes. high-risk human papillomavirus co-infection with hiv is associated with decreased clearance, increased hpv persistence and progression to precancerous lesions and cervical cancer.2,3,4,5 invasive cervical cancer (icc) is the most common female malignancy in zimbabwe and is the leading cause of female cancer-related deaths with an age-standardised mortality rate of 46 per 100 000 women per year.6 the current recommended cervical cancer screening method in low resource settings such as sub-saharan africa is visual inspection of the cervix after application of acetic acid (via).7,8,9 the who 2013 cervical cancer guidelines recommend primary hpv testing as the preferred method where resources are available, as hpv testing is more sensitive and effective in identifying women at high risk for precancerous and cancerous lesions.10,11 this modality of screening has not been rolled out in the region because of the prohibitive cost of the test. the diagnostic landscape is changing, and as cost-effective point-of-care hpv dna tests are becoming more accessible, countries have commenced hpv screening as the preferred primary cervical cancer screening method.12,13 the zimbabwean government partnering with gavi, the vaccine alliance in 2018, rolled out a national hpv vaccination programme, as its cervical cancer primary prevention method. the programme targeted the countries’ 800 000 girls aged 10–14 using the bivalent vaccine, which confers protection to hrhpv subtypes 16/18/45.14 this, however, has raised questions on the cross protective effect of other hrhpv subtypes, which have been reported to be prevalent amongst women in zimbabwe.15,16 sub-saharan african studies investigating hpv prevalence in wlhiv have shown a wide variability across different countries from 24% to 64%.17,18,19,20,21,22 in 2017, a zimbabwean study showed a hrhpv prevalence of 33% in a rural cohort of 123 wlhiv. types 35, 52 and 58 were found to be amongst the highly prevalent types, in addition to types 16 and 18.15 these geographical differences in hpv burden and type distribution highlight the need to assess the zimbabwean urban context independently. in this cohort study, we investigated the prevalence of hrhpv, the associated risk factors and via outcomes during 2 years of follow-up. methods study design and setting this analytic cohort study was conducted amongst wlhiv at newlands clinic (nc), in harare, zimbabwe. the nc was established in 2004 in partnership with the ministry of health and child care (mohcc) and provides comprehensive hiv care to approximately 6500 men, women and children.23 sexual reproductive health services form an integral component of hiv care at nc and include cervical cancer screening, diagnosis and treatment of sexually transmitted infections (stis), and the provision of shortand long-acting reversible contraceptive methods. an hpv vaccination programme was also introduced at the clinic in 2015. in this year alone, 517 adolescents and youth 12–22 years old (312 females and 205 males) were vaccinated using the quadrivalent hpv vaccine. the vaccination of children, adolescents and young adults still continues to date at the clinic as part of the clinic’s effort to prevent a potential burden of hpv-related cancers in these young people as they mature. women registered in care at nc attend routine annual cervical cancer screening where the via method is used as guided by the zimbabwean ministry of health. the procedure is performed by a team of three nurses who have been trained in this technique. women with a positive via screen are treated with either cryotherapy, loop electrical excision procedure (leep) or referred for specialist management depending on the type and extent of the cervical lesion. visual inspection with acetic acid and cryotherapy are conducted by the nurses. the leep procedure is performed by a gynaecologist, and the excised tissue is sent to an external laboratory for histological examination. study procedure we invited women attending cervical cancer screening between 01 september 2017 and 21 november 2018 to participate in the study. sexually active, hiv-positive women above the age of 18 years who consented to participate in the study were recruited. potential participants with a positive pregnancy test were excluded. baseline information including sexual history and demographic information were collected and stored in a microsoft access database. at the baseline visit, we screened participants using via, the study nurses collected endocervical swabs for the hpv dna tests. women who screened positive by via were reviewed six monthly, and those who screened negative, annually. for the hpv dna tests, we collected endocervical swabs using the cervexbrush25 and deposited the samples into preservcyt50 transport medium. we used xpert® hpv kits for testing on the genexpert machine located at the onsite nc laboratory. the test detected 14 high-risk hpv with callouts for hpv 16, hpv 18/45 and ‘other hrhpv’. amongst the ‘other hrhpv’ subtypes are hpv 31, 33, 35, 39, 51, 52, 56, 58, 59, 66 and 68. the 14 hpv types are detected in five fluorescent channels, each with individual parameters for target detection and validity; channel 1: hpv16, channel 2: hpv18/45, channel 3: hpv31/33/35/52/58, channel 4: hpv51/59, channel 5: hpv 39/56/66/68. for channels in which more than one type is detected, the xpert® hpv test does not distinguish between types.24 positive hrhpv results during the study period did not alter via follow-up intervals which were determined by via results only. we followed up participants with via screening for a median of 26 months (interquartile range [iqr]: 24–28), which was up to april 2020. participants with incident hpv-related disease as high-grade vulva intraepithelial neoplasia (vin3) were censored from further follow-up. we collected additional patient data including antiretroviral therapy (art) medication history, via screening results and laboratory results from the clinic’s electronic database. none of the women in the study cohort had an hpv vaccination history. statistical analysis we used stata 13.1 (college station, texas) for data cleaning and analysis. we used proportions and medians for descriptive statistics, logistic regression and the associated wald test for measures of association between hrhpv test and potential risk factors, and wilcoxon rank-sum (mann whitney) test differences between continuous variables. we assessed all potential risk factors in univariate and multivariable logistic regression models to determine independent associations. our final logistic regression model did not include via data as hpv infection is known to precede via status. incidence rates (ir) and ir ratios for cervical disease defined as via positivity, high-grade squamous intraepithelial neoplasia (hgsil) and cervical cancer were assessed with the follow-up data. all statistical tests were two-tailed with p < 0.05 considered significant and 95% confidence intervals [ci] used. in summary, our descriptive, univariate and multivariate analysis were based on all data 100% (n = 321). follow-up data was based on 96% (n = 308) women with hrhpv test results and without incident cervical disease. ethical consideration the study was approved by the newlands clinic research team and the medical research council of zimbabwe (approval mrcz/a/1980). results we recruited 321 women with a median age of 44 years (iqr: 38–50). one hundred and thirty-eight (43.0%) women were married and 29.6% (n = 95) were widowed. two-thirds of the women (63.9%, n = 205) were educated to high-school level (at least 8 years of formal education). most women (64.5%, n = 207) reported sexual debut between 17 and 21 years, and 13.4% (n = 43) were 16 years or below at sexual debut. regarding duration on art, 233 (70.8%) had been on art for more than 5 years (median art duration = 7.8 years, iqr: 4.4–10.8 years). in total, 252 (78.5%) were on a first-line art regimen (1 non-nucleoside reverse transcriptase inhibitor [nnrti] + 2 nucleoside/nucleotide reverse transcriptase inhibitor [nrti]) and had a median cd4 count of 525 cells/mm3 (iqr 366–687 cells/mm3. one-third (33.7%, n = 108) reported that they were unaware of their partner’s hiv status and 15.6% (n = 50) were in hiv sero-discordant relationships. amongst the 310 women who had hiv viral load results, 91.2% (n = 283) had undetectable viral loads (below 50 copies/ml) and 2.9% (n = 9) had a viral load above 1000 copies/ml (table 1). table 1: socio-demographic characteristics and risk factors of participants at baseline (n = 321). all the 321 women had a successful hpv test, 80 (24.9%; 95% ci: 20.2% – 29.7%) were positive for any hrhpv. human papillomavirus 16 positivity without other coinfections was in 9 (11.2%) women, 10 (12.5%) were positive for hpv 18/45 alone, 52 (65%) for other hrhpv. a small proportion, four (5%) had hpv 16 and other hrhpv coinfections, and five (6.3%) had hpv 18 and other hrhpv. there were no co-infections with hpv 16 and hpv 18/45. data for specific channels positive for other hrhpv-positive samples were available for 56/61 samples (91.8%). amongst these 56 samples, 40 (71.4%) were positive in channel 3 (hpv31/33/35/52/58), 5 (7.1%) in channel 4 (hpv51/59) and 15 (26.8%) in channel 5 (hpv 39/56/66/68). one was positive in both channels 3 and 4, whilst two were positive in both channels 3 and 5 (figure 1). of the 80 women with a positive hrhpv test, 6 (7.5%) had a concurrent via positive result. of these women, two were positive for hpv type 16 only, one for hpv 16 and other types (channel 5) and three tested positive for other hrhpv types (2 were channel 3 positive and the other had missing channel data). figure 1: distribution of high-risk human papillomavirus infection in women living with human immunodeficiency virus (n = 80) as determined by five channel xpert® human papillomavirus. in the univariate analysis shown in table 2, women aged 22–29 years (or 3.0, 95% ci: 1.2–7.9, p = 0.02), women with a positive via within 2 years prior to hpv screening (or 6.1, 95% ci: 2.9–12.8, p < 0.001), women on second-line art (or 2.38, 95% ci: 1.3–4.4) and those with a positive via at time of hpv screen (or 6.6, 95% ci: 1.6–27.6, p < 0.001) were more likely to test positive for hrhpv. having a detectable viral load at the time of screening and sexual debut between the age of 13 and 16 years were also significantly associated with hrhpv positivity (or: 2.3, 95% ci: 1.01–5.3, p = 0.04, or:3.2, ci: 1.3–7.9, p < 0.01). however, no statistical significance for hrhpv positivity was observed for cd4 count < 200 cells/mm3 (or 1.2, ci: 0.4–4.0). in the multivariate analysis, only younger age (22–29 years), (adjusted odds ratio [aor] 2.9; 95% ci: 1.0–8.8, p = 0.05), art regimen (aor 2.1; 95% ci: 1.1–4.0, p < 0.05) and early sexual debut at ages 13–16 years (aor 4.0, 95% ci: 1.4–11.5, p < 0.05) showed evidence of association with hrhpv positivity (table 2). table 2: univariate and multivariate analysis of patient characteristics associated with high-risk human papillomavirus positivity. visual inspection with acetic acid follow-up outcomes after high-risk human papillomavirus testing three hundred and eight (96%) participants with negative via at the time of hrhpv screen were followed up for a median of 2 years (645 total person-years of follow-up). follow-up was made to determine incident via positivity, incident hgsil and incident cervical cancer (confirmed by leep biopsy) by hpv infection status at baseline. the via positivity ir in hrhpv-negative women was 0.79 per 100 person-years (95% ci: 0.30–2.11). in hrhpv-positive women, the via positivity ir was 9.97 per 100 person-years (95% ci: 5.90–16.83). incident rate ratio between the two groups of women was 12.57 (95% ci: 4.14–38.19). there was no evidence of incident cervical disease (hgsil) in women who tested negative for hrhpv infection. amongst women with hrhpv infection, the ir of hgsil was 6.41 per 100 person-years (95% ci: 3.33–12.32). during the follow-up period, there was no incident of cervical cancer regardless of hrhpv infection status (figure 2). figure 2: visual inspection with acetic acid follow-up outcomes after baseline high-risk human papillomavirus testing. of the 14 incident via-positive women at follow-up, eight (57%) at baseline were positive for other hrhpv subtypes (four being channel 3 subtypes and the others having missing channel data), two were positive for hpv16, one was positive for hpv 16 and other hrhpv subtypes (channel 5). two were positive for hrhpv 18/45 only and one for hrhpv 18/45 and other (channel 3). none of the women had 16/18/45 coinfections at baseline. none of the women with positive channel 4 subtypes had incident cervical disease at follow-up. discussion we detected hrhpv infection in 24.5% of wlhiv attending routine cervical screening. the prevalence of types 16 and 18/45 was relatively low, with a predominance (65%) of the non-16/18/45 hpv subtypes. our observed overall hrhpv prevalence is similar to the 33% prevalence reported in a cohort of wlhiv in rural zimbabwe,15 but lower than that observed in other regional studies from malawi, burundi, kenya and south africa, which range from 45% to 64%.19,20,25,26 the difference in reported prevalence rates between studies may be because of several factors including the heterogeneity of the study populations. our study describes prevalence in an urban cohort of women with well-controlled hiv (95% vl < 1000 copies/ml). the majority of the women were receiving their first-line art regimen for a median of 7 years and had previous cervical cancer screening. globally, hpv types 16 and 18 predominate and are responsible for most anogenital hpv-related cancers in women.27 in our study, 35% of women with hrhpv had either hpv 16 or 18/45, whilst 65% had ‘other’ high-risk types. these findings are consistent with data from other studies in the region, including a world regional hpv survey, which describes an increased probability amongst wlhiv to harbour other hrhpv types such as 31, 33, 35, 52 and 58, often in the absence of cervical disease (hgsil or icc).22,28,29,30. cumulative risk and annual rate of progression to cancer varies depending on hpv type in immunocompetent women.31 in a longitudinal study of 11 573 hiv-negative, hrhpv-positive women, demarco et al. reported that 21.5% of women at kaiser permanente in northern california, united states of america, with baseline hpv 16 had progressed to precancer/cancer at 7 years and women with hpv 33 also showing high cumulative risk with 18.4% progression at 7 years.31 our study’s limited follow-up time inhibits us from making comments on the progression potential of the observed non-16/18/45 hrhpv subtypes. wlhiv with hrhpv are, however, at an increased risk of rapid progression to cervical disease.2,3,4,5 more robust epidemiological data in wlhiv are required to clearly define this risk according to hrhpv type with longer follow-up periods, in order to inform and optimise cervical screening programmes in wlhiv. human papillomavirus vaccination programmes are a key component of primary prevention to reduce cervical cancer-associated morbidity and mortality. the who currently recommends both bivalent and quadrivalent vaccines, which confer protection against hrhpv types 16 and 18.32 cross protection from the bivalent vaccine for other non-vaccine high-risk types as in our cohort has been demonstrated. van de weele et al. noted significant reductions in incident and/or persistence of certain types (hpv 31, 33, 35 and 45), following exposure to the bivalent vaccine in a cohort of young dutch women.33 in view of the dominance of subtypes other than hpv 16 or hpv 18/45, it is unclear whether the bivalent vaccine currently being administered in the zimbabwe national programme will provide cross protection against these subtypes. an understanding of the degree of cross protection from context-specific data is warranted. this can be achieved through country-specific vaccine evaluation studies in the vaccinated cohort. early sexual debut and younger age were significant predictors of hrhpv infection in our cohort. women with an early sexual debut (13–16 years) were at least three times more likely to test positive for hrhpv when compared with those whose sexual debut was after 21 years. in keeping with these findings, a cohort analysis of 1445 urban women in south africa showed a peak in hrhpv prevalence in women younger than 25 years and a gradual decrease of hrhpv infection with increasing age of women.34 van aardt et al. postulate that the higher hrhpv prevalence in younger women may be partially explained by the lack of natural immunity in the initial stages of sexual activity.35 literature also provides evidence that over 35% of women contract hpv within the first 2 years of sexual debut8 and that early sexual debut is also associated with a greater number of sexual partners and an increased risk of sti infection.36,37 research to further elucidate clearance and progression to cervical dysplasia in younger women is also necessary. despite most women in our study being on first-line art and 95% having viral load (vl) < 1000 copies/ml, women on second-line therapy were twice as likely to test positive for hrhpv. in a systematic review of the association between hpv infection and art, menon et al. indicate that severe immuno-suppression of cd4 counts < 200 cells/mm3 increases the risk of hrhpv infection.38 in our context, women on second-line art often have a history of severe immunosuppression necessitating the switch to second-line art. after a median of 2 years follow-up, the incident rates for both via positivity and hgsil were significantly higher in the women with hrhpv infection. no cases of hgsil were observed in hrhpv-negative women. these data are consistent with findings from large longitudinal studies. data from the kaiser portland cohort of over 20 000 women and more than 15 years of follow-up demonstrate a low risk of precancer or cancer in hiv-negative women with a single negative hrhpv result. the high negative predictive value of hpv dna testing is now well established, hence the adoption by many global cervical screening programmes as the primary screening tool.10,39 in low-income countries, less-frequent cervical cancer screening, once every 3 years, for hrhpv-negative wlhiv will have both the potential to reduce costs and divert scarce resources to hrhpv-positive women who are at higher risk of developing cervical cancer and in women who have never been screened. this resource optimisation may translate to greater screening potential in settings where coverage is still low like in zimbabwe.8 however, a key component of the potential success of this screening programme that utilises hpv testing is the development and availability of low-cost hpv assays. as reported in the methodology, the use of the xpert® hpv kits limited our ability to describe individual hrhpv types in the cohort apart from hpv 16. secondly, the duration of follow-up was short and because of the nature of the pathogenesis of hpv infection, there was limited time for disease progression to occur. thirdly, hrhpv infection was only assessed at baseline, therefore questions of hpv persistence and clearance could not be addressed. despite these limitations, the information from this study can be used to provide background data for prospective cohort studies to ascertain persistence of hpv infections in women with controlled hiv infection. conclusion our study highlights key epidemiological information on hrhpv infection in an urban cohort of hiv-infected women in zimbabwe. there was a lower than expected overall prevalence of hrhpv infection in the study cohort, but a higher prevalence of hrhpv subtypes other than hpv 16 or 18/45. this raises some important vaccine effectiveness questions regarding the current roll-out of the prequalified bivalent and quadrivalent hpv vaccine, particularly regarding the level of cross-protection against other hrhpv types, which are prevalent in our setting. our follow-up data highlights the potential benefits of integrating primary hpv testing, in cervical cancer screening programmes amongst wlhiv, which may lead to reduced screening intervals in hrhpv-negative women and potentially result in cost reduction. acknowledgements the authors are grateful to sr petronella mudhokwani, sr grace dambanemweya and sr adelaide mawora, for their work in data collection. the authors are also grateful to prof. ruedi luethy, for his support and guidance in this work. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions a.m.m. was responsible for drafting the manuscript, managing the study data and follow-up of patients. m.j.p. was responsible for study conception, supervising the research process and contributed to the analysis of the data and write-up. s.l. was responsible for the conception of the study and supervising the drafting of the manuscript and analysis of data. t.s. conducted the data analysis and results write-up and assisted with study conception. all the authors revised the draft critically and gave final approval of the version to be published. all authors read and approved the final manuscript. funding information the study was financed through the newlands clinic operational budget. data availability statement data are available upon request from the corresponding author. disclaimer the views expressed in this article are the authors’ and not necessarily reflect the official policy or position of any affiliated agency of the authors. references zimbabwe | unaids [homepage on the internet]. 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antiretroviral therapy and the presence of hpv, premalignant and malignant cervical lesions in sub-saharan africa: a systematic review: current evidence and directions for future research. bmj open. 2017 aug 04;7(8):e015123. https://doi.org/10.1136/bmjopen-2016-015123 schiffman m, glass ag, wentzensen n, et al. a long-term prospective study of type-specific human papillomavirus infection and risk of cervical neoplasia among 20,000 women in the portland kaiser cohort study. cancer epidemiol biomarkers prev. 2011;20(7):1398–1409. https://doi.org/10.1158/1055-9965.epi-11-0206 m_sajhiv_n20_a2.pdf 5the southern african journal of hiv medicine september 2005 h o r i z o n s hiv/aids: the mirror in south africa’s face let us open with nkosi johnson’s words of wisdom: ‘i want people to understand about aids – to be careful and respect aids – you can’t get aids if you touch, hug, kiss, hold hands with someone who is infected. care for us and accept us – we are human beings. we are normal. we have hands. we have feet. we can walk, we can talk, we have needs just like everyone else – don’t be afraid of us – we are all the same!’ why would an 11-year-old child have to make such an impassionate plea in the south africa of 2000? is this not a society that has committed itself to the fundamental human rights enshrined in the un charter? is this not a society that prides itself in adhering to the african value system of ubuntu? is this not a country with a government that has explicitly stated that its governance principles are based on ‘batho pele’ (people first)? what has gone wrong? hiv/aids is a mirror in the face of our society. it forces us to examine the contours of our face as it really is, not as we would like to see it. like any face, ours bears the scars of the past, the impact of the realities of today and indications of how the future is likely to shape up for us. let us take each in turn. hiv/aids and the past the old adage ‘the chickens are coming home to roost’ has a particularly cruel twist to it for south africa as a society. there are just too many chickens coming home to roost on our fragile democratic edifice. we were dealt too bad a hand by history. just think of the legacy we have to cope with which has contributed to our vulnerability to the hiv/aids pandemic. that legacy also undermines our capacity to address the pandemic decisively. first, the foundations of our society are built on conquest that undermined the structure and socioeconomic fabric of indigenous people and constrained their ability to adapt and evolve to meet the challenges of modernity. adherence to cultural and customary practices that may be in conflict with the values of science in areas where universally accepted practices save lives, might be seen as the only way to protect and defend the dignity of a wounded people. we have elements of this way of thinking in our society. second, the migrant labour system and its disruptive impact on family life over generations have undermined the dignity of people housed in migrant labour hostels. this system is a major contributor to the size and shape of the hiv/aids pandemic in our society. denial of the rights of migrants to dignified lives with their families made them vulnerable to sexually transmitted diseases. it turned men into conduits of the infection to their families. third, the pressures of the struggle against apartheid and the brutal suppression of the liberation movement forced many into exile. life in exile made many vulnerable to contact with and infection by the virus, which had its early manifestations in some of the frontline states where many of the heroes of the struggle lived. it is indeed a cruel irony that returning heroes should have been conduits of this deadly virus. fourth, the illegitimacy of the apartheid state made it unwilling or unable to tackle the hiv/aids pandemic in its infancy in the 1980s when it could have been nipped in the bud. we know from experiences of much poorer countries that implementation of a comprehensive care and treatment programme at a stage when the infection rate was low contained its spread, to less than 3% to date in senegal, for example. hiv/aids is one of the many costs of the legacy of apartheid. apartheid was an expensive experiment. it demonstrated beyond doubt that inequality is expensive, not just for those discriminated against, but for society as a whole. hiv/aids and the present the ideals we signed up for as a post-apartheid society are enshrined in our constitution. the gap between those ideals and our practices as a society is large. ours is a constitution second to none in enunciating commitments to the fundamental rights of everyone. the rights of the child. equality between men and women. and the responsibility of the state to ensure that the basic socioeconomic rights of citizens are enabled. there are a number of reasons for this large and in some areas growing gap. first of these is the difficulty of overcoming the a highlight of the 2nd south african aids conference was the first nkosi johnson memorial lecture, delivered by dr mamphela ramphele. nkosi johnson, young man that he was, warmed all our hearts when he courageously spoke out against discrimination at the world aids conference in durban 2000. this lecture will be a consistent feature of the sa hiv conference, to mark this young man’s role in ridding south africa of hiv-related discrimination. dr ramphele, a notable academic, activist and fine south african, gave a stirring and thought-provoking lecture that really set the tone for the conference. unity and accountability demands that we take stock and examine ourselves critically and honestly. it is our pleasure to publish the first nkosi johnson memorial lecture as delivered on 7 june 2005. 7 legacy of inequality. policy commitments are often not followed through into implementation, monitoring and evaluation. much of the problem comes from the weak implementation capacity of the government machinery at all levels of government, as acknowledged by the president in his state of the nation address earlier this year. there are notable exceptions. denial of opportunities for management training and experience in the past, and the failure to acknowledge and correct deficits since 1994, have left us in a weak position to live out our commitments. second, there is the ‘shouting silence’ that xoliswa’s documentary speaks to. xoliswa was moved by her personal loss of her own mother to the pandemic to document the harrowing lives of young people left to fend for themselves following the deaths of their mothers from hiv/aids. the loneliness of children walking the streets in search of love and care is forcefully brought home to us. the heroic efforts of grandmothers who come out of their retirement to become both mothers and fathers to their orphaned grandchildren are captured sensitively in this documentary. we know of many more poor women all over our country who are rising to the challenge in the face of great adversity. but why the deafening silence from the rest of us? why did we have to be reminded by nkosi to ‘care for us and accept us – we are human beings’? where is ubuntu of the whole society in the face of the estimated more than 5 million south africans living with hiv/aids under the cloud of stigma? where was ubuntu when many of the 300 000 people who died in 2004 from hiv/aids did so without the comfort of loved ones because of the shame they felt? where is ubuntu when close to 1 000 people in the prime of their lives (15 49 years of age) die miserable deaths each day, shielding from the sting of stigma that still pervades our society and constrains our response to the pandemic? where is ubuntu when the caregivers of orphans and vulnerable children are not able to access child support grants because of uncaring and corrupt officials? where is ubuntu when children are sexually assaulted by their fathers and other close relatives? where is ubuntu when babies are raped in the vain hope of cleansing infected men of hiv/aids? we are all challenged by the level of pain and suffering of people living with hiv/aids and their caregivers to stop paying lip service to the values and precepts enshrined in our constitution. the quality of our society will be judged by how we treat the most vulnerable among us. we are not at the moment doing well on that score. third, part of the reason for the silence is our embarrassment about acknowledging the reality of hiv/aids, given its links to sexuality. we are a socially conservative society. all the cultures we bring into the new south africa are prudish about talking about sex. we just do it. but we have to talk about sex as president museveni of uganda did, and made it part of the responsibility of government officials to do the same. captains of industry and commerce must also step up and lead aids campaigns with the same passion they devote to profits. aids affects the bottom line by undermining the quality of our human capital. combating hiv/aids has to involve a comprehensive approach that includes changing behaviours, including the practices that make men and women more vulnerable to infection. fourth, the clash between customs that create a breeding ground for sexually transmitted diseases, including hiv/aids, and the demands of combating the pandemic have to be acknowledged and challenged. polygamy and multiple sexual partners, inheriting widows, unprotected sex, non-sterile initiation rites etc. all have to give way to safer practices. there is just too much at stake for us to let customs continue to put people at risk. finally, there is a cruel irony in that of all african countries affected by hiv/aids south africa has the greatest ability to combat the disease, yet we are under-performing. why? how do we explain brazil’s better performance with more or less the same level of scientific proficiency and economic development? we have a serious problem of mistrust in our society that prevents us from acknowledging our problems and using the resources we have to address them. take the case of the causation of hiv/aids. why did it take so long to have clarity infusing our policy responses? we have the depth of scientific know-how and economic resources to have been a front-runner in comprehensive care and treatment and deal a mortal blow to the disease, as brazil did. but the scientists were largely white, male, urban based, and outside the policy-making domain of government. mistrust of the racist system that denied the majority of south africans scientific literacy and proficiency, constrained evidence-based policy-making. to add insult to injury, the same racist system had over centuries in many parts of the world stigmatised black male sexuality as dangerous and driven by uncontrollable lust. unless we acknowledge the pain of those so stigmatised, we are unlikely to overcome our mistrust and build a better life for all. but those wounded by the past also need to transcend the past and take ownership of shaping a future of dignity for all. ‘the reconstruction of the soul’, as former president mandela reminds us, is still unfinished business in south africa. scientists must stand up more and often to say no to those bent on misleading the public. this is particularly important in a society with such low levels of literacy, numeracy and understanding of established basic scientific facts including how our bodies function. confusing advice to those already overwhelmed by the trauma of hiv/aids should not be permitted. the highest ethical standards should be upheld in the care and treatment of hiv/aids-affected people and in clinical trials involving them. the medical profession needs to play the role of watchdog for poor and vulnerable people. the south african medical association should be at the forefront of the protection campaign. silence makes all of us accomplices. how can we the southern african journal of hiv medicine september 2005 allow confusion between the role of specific treatment with antiretrovirals on one hand, and the benefits of good nutrition and supplementary nutritional agents such as vitamins for any health care process on the other? it sounds so medieval. remember the sanatoria of pre-industrial europe where many died of tuberculosis before the advent of antimycobacterial remedies? remember that those early tb drugs too had toxic side-effects – but they were better than placebos? toxicity diminished with better drugs invented later with the benefit of better knowledge. why are we not drawing on rich medical history to help our society cope with this present challenge? the way forward the best way of honouring the memory of nkosi johnson and many other children who met premature deaths at the hands of hiv/aids is to end denialism now. our democracy is over ten years old now; we need to take ownership of shaping our country’s future and create a better life for all. blaming apartheid has its limits, just as blaming one’s parents for one’s failures has its limits too. we need to transcend our past and build a better future by playing to our strengths and minimising our weaknesses. we need to promote a rights-based value system in our society at all levels. the president and his cabinet should lead the charge on this. no government official should be allowed to undermine the rights of citizens without being held accountable. official acts of omission or commission and institutional arrangements that infringe on the rights of people should be tackled urgently. for example, overcrowded prisons and failing public services undermine what our society stands for. education and training programmes for all public officials is of key importance, and public education programmes, including school-based ones, should be vigorously promoted too. men need to be educated about the difference between manhood and male dominance. real men do not need to violate the rights of women and children to assert their manhood. women need to be part of the teaching and learning of husbands, sons, brothers and significant others about gender relationships in a human rights culture. it is only when a critical mass of citizens is confident enough to demand their rights that a human rights culture will flourish. in such a flourishing human rights culture, accountability of public officials will be better enforced. we need to enforce the rights of citizens, especially the vulnerable ones. it is a sad reality that law enforcement agencies do not yet see human rights violations as a crime. domestic violence is still treated as a private affair even as the rights of women and children are violated. recent reports of the epidemic of violence against women and children add urgency to this issue. training and linking incentives to enforcement of rights is urgently needed in our law enforcement system. there must also be penalties for failure to perform in this area. those citizens who are enlightened have a responsibility not only to demand their rights, but also to ensure that the rights of the least in our society are respected and protected. only then can we call ourselves a civilised country. only then will we have honoured the memory of nkosi. mamphela ramphele 7 june 2005 i~f sour frn african jdu nal of ~iv mfdici f ------------dctohfr 2002 from the antiretroviral therapy is at last receiving more attention. such is the scale of hiv morbidity that every health care worker will need to gain expertise in this area. children are our future, and it is appropriate that their needs and those of their parents are adequately addressed. the concept of family therapy should now be emphasised, as paediatric hiv reflects hiv infection of the parents as well. for those tens of thousands of children needing therapy, their caregivers' health is integral to survival. this concept of family therapy represents a unique opportunity orphaned by aids recently a young tb researcher visiting us from new york went shopping at the greenpoint sunday market and was accosted by some thugs who relieved her of her bag. she put up a brave struggle and her screams alerted some good samaritans, who gave chase. one of the thugs was apprehended and the bag, with some contents, recovered. the samaritans put it into their car while they dealt with the miscreant they returned to their car just in time to see some street children making off with the now tvlicestolen handbag, and all the other contents of the car! it was just the weekend after, in the independent of 6 october, that i read the most disturbing article entitled the aids orphans time bomb': the pandemic 'will rob three million children of parents in the next ten years, bringing spectre of social chaos and even higher crime rate: the reporter quoted the institute for security studies as saying that the burgeoning orphan population will grow up under extreme levels of poverty and will be sorely tempted, and even obliged for its physical survival, to turn to crime, drugs, gangs and the sex trade. a staggering 300 000 children have already lost their mothers to aids. pre aids, 2.5% of the popula 'on in developing countries were orphaned, and is proportion is expected to increase to 17% in south africa by 2010. it is estimated that 10 000 children currently live or work on south africa's streets. a stop at any city traffic lights will bear testimony to this, and the number is set to rise dramatically in the near future. the traditional african safety net, the extended family, will probably not be able to absorb overwhelming numbers of orphans. research has also shown that households with one or more members who have hiv/aids are much poorer than others. when the breadwinner dies the economic impact on the children left behind is drastic. orphans identified their priority needs as the most immediate basics: food, clothing and education. editors to southern african family physicians to develop strategies to treat and strengthen families. the concepts of antiretroviral therapy in children are relatively easy and the principles are similar to those for adults. important differences include more use of liquid formulations, surface area dosing for some medications, the need to increase medication with growth, and the importance of caregivers in maintaining adherence. mark canon guest editor. southern africon journal of hiv medicine this problem must provide yet another most compelling reason to implement countrywide antiviral treatment debbie bradshaw from the medical research council is quoted as saying 'a large number of people are already infected with hiv and will progress to aids, illness and death. unless something is done to prevent this, they are going to die and not be around to look after their kids: according to an mrc report published in may, orphaned children are 'not only traumatised by the loss of parents, they lack the necessary parental guidance through crucial life-stages of identity formation and socialisation. psychosocial effects will be worsened by accompanying threats to the basic survival and security frequently experienced by orphans: innovative solutions are called for. one example is the non-governmental organisation called big brother, big sister, south africa, which screens, recruits and trains adult volunteers to mentor assigned orphans. the initial commitment is only one hour per orphan per week, but one can see how, as bonds grow, this time will increase. the idea is that the orphan will have an adult who takes an interest in his or her daily life and becomes a role model during important stages of development the story brought home to me once again the depths and complexities of the aids pandemic, especially in a continent like africa. we really do have to find a way to take that first step to national arv treatment three cheers for the south african medical associa 'on, who with kgosi le lape at its helm has fearlessly moved headlong into mobilisation for a national treatment plan and a bold plan it is too. using the mandela children's fund as a channel for collecting funds and backed by a number of important south africans, letlape looks set to pull it off. unda-gail bekker managing editor acknowledgements about the author(s) mithra john department of health, internal medicine, helen joseph hospital, johannesburg, south africa stacey norsworthy department of health, internal medicine, helen joseph hospital, johannesburg, south africa lauren richards department of health, internal medicine, helen joseph hospital, johannesburg, south africa citation john m, norsworthy s, richards l. cutaneous lesions in the setting of disseminated cryptococcus neoformans infection. s afr j hiv med. 2021;22(1), a1315. https://doi.org/10.4102/sajhivmed.v22i1.1315 clinical images cutaneous lesions in the setting of disseminated cryptococcus neoformans infection mithra john, stacey norsworthy, lauren richards received: 09 sept. 2021; accepted: 21 sept. 2021; published: 29 oct. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. a 38-year-old hiv-positive south african man presented with a 3-week history of headache and worsening widespread cutaneous lesions. he had recently started antiretroviral treatment (art), was virologically suppressed and had a cd4 t-lymphocyte count of 21 cells/µl. clinically, the patient had ulcerated, centrally necrotic plaques and papules found mainly on the face and scalp, with lesser involvement of the torso and limbs. the largest lesion was noted to be on his left cheek and measured 4 cm in diameter (figure 1a). additionally, the patient displayed signs of meningitis and a right cranial nerve vi palsy on neurological examination. figure 1: (a) a 4-cm, centrally necrotic plaque on the patient’s left cheek with a smaller papule adjacent to it; (b) significant improvement of the same lesions following 5 weeks of therapy; (c) periodic acid–schiff and (d) grocott–gomori stained sections showing numerous fungal organisms with a large clear capsule, in keeping with cryptococcus neoformans (original magnification, 40×). a diagnosis of disseminated cryptococcus neoformans infection was made based on a positive serum and cerebrospinal fluid cryptococcus antigen and a skin punch biopsy. histological evaluation of the skin biopsy specimen revealed numerous fungal organisms with a large clear capsule and narrow-based budding on both periodic acid–schiff and grocott–gomori’s methenamine silver staining in keeping with c. neoformans (figure 1c and 1d). this was further confirmed on fungal culture of the biopsy specimen. the patient received amphotericin b deoxycholate and flucytosine for 7 days, as well as daily therapeutic lumbar punctures to relieve raised intracranial pressure. he was then transitioned to oral fluconazole, and art was reintroduced 5 weeks later. the patient responded well to treatment, with significant improvement to his skin lesions (figure 1b). acknowledgements the authors thank dr j. nel and dr l.p. mekoa for their input in producing this manuscript. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions m.j. drafted the manuscript. l.r and s.n. reviewed the manuscript. ethical considerations permission was obtained from the human research ethics committee (medical), university of the witwatersrand, johannesburg (protocol number m210756). funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability data sharing is not applicable to this article, as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. hiv 834 impact of antiretroviral therapy on pregnancy outcomes c d aniji,1 fcog (sa); o a towobola,1 phd; m e hoque,2 msc; t j mashamba,1 mb chb; s monokoane,1 fcog (sa) 1 department of obstetrics and gynaecology, university of limpopo, medunsa campus, pretoria, south africa 2 graduate school of business and leadership, university of kwazulu-natal, westville campus, durban, south africa corresponding author: m e hoque (muhammad.ehsanul@gmail.com) background. the majority of hiv-positive women in south africa are of reproductive age, and pregnancies among women using antiretroviral therapy (art) are common. however, there are mixed data regarding the impact of art on pregnancy outcomes. objective. to examine the impact of art on pregnancy outcome according to the timing of initiation of treatment. methods. a retrospective cohort study was conducted among women delivering at a tertiary hospital from 1 october 2008 to 31 march 2009. results. a total of 245 mothers were receiving art: 76 mothers (31%) started art pre-conception and 169 mothers (69%) started art after the first trimester. no significant differences were observed in the rates of preterm delivery and low birth weight (lbw) between the pre and post-conception groups (21% v. 24% and 21% v. 25%, respectively). conclusion. in this cohort of women receiving art in pregnancy, timing of art initiation did not have any adverse effect on the measured pregnancy outcomes such as preterm delivery and lbw. s afr j hiv med 2013;14(4):176-178. doi:10.7196/sajhivmed.834 south africa (sa), like many countries in sub-saharan africa, has a high hiv disease burden. according to 2008 reports by the world health organization (who) and the joint united nations programme on hiv and aids (unaids), an estimated 6 million adults and children were living with hiv in sa by the end of 2007, including approximately 3.2 million (54%) women aged ≥15 years. 1 , 2 this has a significant impact on vertical transmission and maternal mortality. the fourth report on confidential enquiries into maternal deaths in south africa 2005 2007 showed that pregnancy-unrelated infections, mostly hiv/aids, were res­ponsi­­ble for 43.7% of all reported maternal deaths.3-5 varied results have been reported on the risk of adverse pregnancy outcomes in hiv-positive women treated with antiretroviral therapy (art). several studies from europe have suggested that the initiation of art during pregnancy may be associated with an increased risk of preterm delivery, particularly with protease inhibitor (pi)-containing regimens. 6-8 however, these findings have been contradicted by studies from brazil and north america showing no association between maternal art use and pregnancy outcomes.9-12 in africa, there have been some studies that evaluated the impact of art on pregnancy outcomes. in a cote d’ivoire study13 it was highlighted that art in pregnant women with advanced hiv disease substantially reduced mother-to-child transmission, but was associated with low birth weight (lbw). a matched case-control study conducted in nigeria14 found that hiv-positive women were significantly more likely to have intrauterine growth restriction, preterm labour and lbw babies than hiv-negative women. given the large number of hiv-positive pregnant women in sa, and the importance of art use for promoting maternal and child health in this population, it is pertinent to investigate any effects that art may have on pregnancy outcomes. the aim of this study was to investigate the impact of art on pregnancy outcome, according to the timing of initiation of treatment, in a cohort of hiv-positive pregnant women at dr george mukhari hospital (dgmh) in ga-rankuwa, sa. methods we performed a retrospective medical record review of hiv-positive pregnant women who delivered at dgmh from 1 october 2008 to 31 march 2009. dgmh has a large academic obstetric unit with approximately 8 500 deliveries per annum. the study included hiv-positive pregnant women who booked at the antenatal clinic at dgmh and had either been receiving art before pregnancy (pre-conception art group) or started art after the first trimester of pregnancy (post-conception art group). women with multiple pregnancies and those who defaulted art and/or antenatal clinic visits were excluded from the analysis. data on demographic and obstetric characteristics and art use were collected from the labour ward delivery register, patients’ antenatal cards and/or hospital records. data were analysed using spss (version 17.0). term delivery was defined as birth at a gestational age of ≥37 weeks, where ultrasound was used to date the pregnancy before 20 weeks’ gestation; or a birth weight of ≥2 500g in cases where pregnancy was not dated with ultrasound before 20 weeks’ gestation. all statistical tests were performed using two-sided tests at the p≤0.05 level of significance. ethical approval for the study was obtained from the medunsa research and ethics committee of the university of limpopo. results a total of 245 mothers were receiving art during the study period; 76 (31%) were receiving art pre-conception and 169 mothers (69%) started art post conception after the first trimester. the average age of the participants was 31 and 29 years in the preand post-conception groups, respectively (p=0.003). significantly more women in the post-conception group were primigravidae than in the pre-conception group (18% v. 5%, respectively; p=0.003). the rate of caesarean sections was similar in the preand post-conception groups (table 1). in the pre-conception group, 73 women were on a regimen of two nucleoside reverse transcriptase inhibitors (nrtis) with a non-nucleoside reverse transcriptase inhibitor (nnrti), while 3 women were on pi-containing regimens. the duration of treatment prior to conception ranged from 4 to 60 months. all the women in this group were in relatively good health, with sustained viral suppression prior to conception. in the post-conception group, 161 women were using two nrtis with an nnrti, while 8 women were on pi-containing regimens. all women in this group had cd4+ counts <200 cells/µl per the national art guidelines at the time of the study. the duration of treatment before delivery ranged from 2 to 22 weeks. table 2 compares pregnancy outcomes between the two groups. results indicated that preterm delivery rates were similar between the preand post-conception groups (p=0.348). with regards to lbw, the rate was slightly lower (21%) in the pre-conception group than in the post-conception group (24%), but the difference was not significant (p=0.945). discussion we investigated the effect of art on pregnancy outcomes according to the timing of initiation of treatment. accordingly, we did not find any negative impact of this therapy on pregnancy outcomes, regardless of the timing of treatment initiation. those women who were receiving art prior to conception, irrespective of the duration of treatment, had a similar rate of preterm delivery compared with those who commenced art after the first trimester of pregnancy. a study conducted in the usa10 also reported a non-significant difference in the rate of preterm delivery between preand post-conception art groups. it would seem that in this study population, the use of antiretrovirals did not have any effect, whether positive or negative, on the rate of preterm deliveries. it is important to point out that the use of illicit drugs, alcohol abuse and cigarette smoking – all important causes of preterm labour – were negligible in this setting. however, our results are in contrast to the findings of some other studies conducted in europe, cote d’ivore and nigeria, which concluded that patients who were receiving art prior to conception had an increased risk of preterm delivery compared with those who commenced art post conception.8 , 12-14 with regards to lbw in our study, the rates were similar: 17.1% and 20.7% in the preand post-conception groups, respectively. this result is in line with other studies conducted in brazil and the usa,11 , 15 both of which did not find any association between birth weight and the use of art. however, contrasting results from europe, cote d’ivore and nigeria indicated higher rates of lbw among women receiving art.8 , 13 , 14 study limitations this was a retrospective study that focused on women delivering live infants in health facili­ties and did not account for early pregnancy loss or home deliveries, thus constituting an important potential bias. several other factors with known influence on pregnancy outcome including other infectious diseases, socioeconomic information of the mothers (e.g. educational level and employment status) were not measured and could not be evaluated in this study. conclusion in summary, the results of this study suggest that art initiated before or during pregnancy does not have any adverse effect on measured pregnancy outcomes such as preterm delivery and lbw. acknowledgement. we thank all members of staff in the labour ward for their efforts in entering data into the maternity records, and the clerks in the records department who assisted with patient file retrieval. references 1. unaids/who epidemiological fact sheets on hiv and aids, 2008 update. http://apps.who.int/globalatlas/predefined reports/efs2008 (accessed 28 march 2011). 1. unaids/who epidemiological fact sheets on hiv and aids, 2008 update. http://apps.who.int/globalatlas/predefined reports/efs2008 (accessed 28 march 2011). 2. national department of health. national antenatal sentinel hiv and syphilis prevalence survey in south africa 2009. http://www.doh.za/docs (accessed 28 march 2011). 2. national department of health. national 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[http://dx.doi.org/10.1111/j.1468-1293.2008.00520.x] 8. thorne c, patel d, newell ml. increased risk of adverse pregnancy outcomes in hiv-infected women treated with highly active antiretroviral therapy in europe. aids 2004;18(17):2337-2379. 8. thorne c, patel d, newell ml. increased risk of adverse pregnancy outcomes in hiv-infected women treated with highly active antiretroviral therapy in europe. aids 2004;18(17):2337-2379. 9. carceller a, ferreira e, alloul s, lapointe n. lack of effect on prematurity, birth weight and infant growth from exposure to protease inhibitors in utero and after birth. pharmacotherapy 2009;29(11):1289-1296. [http://dx.doi.org/10.1592/phco.29.11.1289] 9. carceller a, ferreira e, alloul s, lapointe n. lack of effect on prematurity, birth weight and infant growth from exposure to protease inhibitors in utero and after birth. pharmacotherapy 2009;29(11):1289-1296. [http://dx.doi.org/10.1592/phco.29.11.1289] 10. patel k, shapiro de, brogly sb, livingston eg, stek am, bardeguez ad. prenatal protease inhibitor use and risk of preterm birth among hiv-infected women initiating antiretroviral drugs during pregnancy. j infect dis 2010;201(7):1035-1044. [http://dx.doi.org/10.1086/651232] 10. patel k, shapiro de, brogly sb, livingston eg, stek am, bardeguez ad. prenatal protease inhibitor use and risk of preterm birth among hiv-infected women initiating antiretroviral drugs during pregnancy. j infect dis 2010;201(7):1035-1044. [http://dx.doi.org/10.1086/651232] 11. szyld eg, warley em, freimanis l, et al. maternal antiretroviral drugs during pregnancy and infant low birth weight and preterm birth. aids 2006;20(18):2345-2353. [http://dx.doi.org/10.1097/01.aids.0000253362.01696.9d] 11. szyld eg, warley em, freimanis l, et al. maternal antiretroviral drugs during pregnancy and infant low birth weight and preterm birth. aids 2006;20(18):2345-2353. [http://dx.doi.org/10.1097/01.aids.0000253362.01696.9d] 12. machado es, hofer cb, costa tt, et al. pregnancy outcome in women infected with hiv-1 receiving combination antiretroviral therapy before versus after conception. sex transm infect 2009;85(2):82-87. [http://dx.doi.org/10.1136/sti.2008.032300] 12. machado es, hofer cb, costa tt, et al. pregnancy outcome in women infected with hiv-1 receiving combination antiretroviral therapy before versus after conception. sex transm infect 2009;85(2):82-87. [http://dx.doi.org/10.1136/sti.2008.032300] 13. ekouevia dk, coffiea pa, becquet r, et al. haart, antiretroviral therapy in pregnant women with advanced hiv disease and pregnancy outcomes in abidjan, cote d’ivoire. aids 2008;22(14):1815-1820. 13. ekouevia dk, coffiea pa, becquet r, et al. haart, antiretroviral therapy in pregnant women with advanced hiv disease and pregnancy outcomes in abidjan, cote d’ivoire. aids 2008;22(14):1815-1820. 14. olagbuji bn, ezeanochie mc, ande ab, oboro vo. obstetric and perinatal outcome in hiv positive women receiving haart in urban nigeria. arch gynecol obstec 2010;281(6):991-994. [http://dx.doi.org/10.1007/s00404-009-1186-x] 14. olagbuji bn, ezeanochie mc, ande ab, oboro vo. obstetric and perinatal outcome in hiv positive women receiving haart in urban nigeria. arch gynecol obstec 2010;281(6):991-994. [http://dx.doi.org/10.1007/s00404-009-1186-x] 15. schulte j, dominguez k, sukalac t, bohannon b, fowler mg. declines in low birth weight and preterm birth among infants who were born to hiv-infected women during an era of increased use of maternal antiretroviral drugs: pediatric spectrum of hiv disease, 1989-2004. pediatrics 2007;119(4):e900-e906. [http://dx.doi.org/10.1542/peds.2006-1123] 15. schulte j, dominguez k, sukalac t, bohannon b, fowler mg. declines in low birth weight and preterm birth among infants who were born to hiv-infected women during an era of increased use of maternal antiretroviral drugs: pediatric spectrum of hiv disease, 1989-2004. pediatrics 2007;119(4):e900-e906. [http://dx.doi.org/10.1542/peds.2006-1123] abstract acknowledgements references about the author(s) leon j. levin department of paediatrics, right to care, johannesburg, south africa juliet l. horak department of paediatrics, dora nginza hospital, gqeberha, south africa james nuttall department of paediatrics, faculty of health sciences, university of cape town, cape town, south africa citation levin lj, horak jl, nuttall j. looking back at paediatric hiv treatment in south africa. my, how we have grown! s afr j hiv med. 2021;22(1), a1283. https://doi.org/10.4102/sajhivmed.v22i1.1283 opinion paper looking back at paediatric hiv treatment in south africa. my, how we have grown! leon j. levin, juliet l. horak, james nuttall received: 28 june 2021; accepted: 01 aug. 2021; published: 16 sept. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract antiretroviral treatment has undergone major changes in the last 20 years, from monotherapy, to dual therapy and finally to triple therapy. lately, more focus has been placed on better, more well-tolerated combinations and formulations. as in most other disciplines in medicine, the development of paediatric hiv dosages and formulations always tends to lag behind adult research. twenty years ago, it could take several years before data were available to enable the use of life-saving antiretrovirals in children. paediatricians, being ever resourceful, were not prepared to let their paediatric patients suffer despite the lack of data or formulations and so made a plan. this article describes some of the trials and tribulations that we went through trying to make sure that our paediatric hiv patients not only survived but thrived. clinicians treating paediatric patients today have it so much easier because of what our colleagues and their patients went through in those early days. keywords: hiv; paediatric hiv; paediatric antiretroviral treatment; south africa; history. it is hard to convey the sense of helplessness felt by those of us who worked in the pre-antiretroviral treatment (art) era when faced with a sick hiv-infected child and mother. we had little to offer except the treatment of opportunistic infections and co-trimoxazole prophylaxis. we have come a long way since then. in the mid-1990s, when hiv treatment had evolved only as far as dual nucleoside reverse transcriptase inhibitors (nrtis), an article appeared in the new england journal of medicine suggesting that didanosine (ddi) monotherapy was as good as the combination of zidovudine (azt) and ddi and better than azt alone.1 at the time, viral load monitoring was unavailable, and the less useful marker of hiv disease progression and/or death was used in clinical trials. because ddi monotherapy was quite affordable (r80.00 a month for a baby), a few patients in the state sector were able to afford ddi monotherapy, and this did provide a brief respite from the ravages of the disease. in 1998, two developments spurred the cause of paediatric hiv treatment in south africa. the first was the launch of stavudine (d4t) in south africa. we now know that this is a very toxic drug, but in those days, it was heralded as a new, very potent nrti. however, no matter how low the required paediatric dosage, d4t remained expensive and often unaffordable, at approximately r1000.00 a month. to help our patients, one of us would purchase a month’s supply of the adult 40 mg capsules costing r1000.00 and have a chemist split the contents of the capsule into two and put each half back into another capsule. that way, the 20 mg capsules were made available at half price. stavudine powder for reconstitution with water to form a suspension of 1 mg/ml and dosed at 1 mg/kg per dose twice a day was subsequently released but required refrigeration and the administration of relatively large volumes of liquid medication to young children. to get around these problems, many clinicians treating children unable to swallow capsules or in whom a lower dose was required used a technique of opening d4t capsules, dispersing the powder contents in water and administering an appropriate weight-based dose. some years later, pharmacological and pharmacokinetic evaluations using high-performance liquid chromatography confirmed the accuracy of the off-label opened-capsule dosing method for stavudine and showed that plasma drug exposure after stavudine administration as a solution in this way was bioequivalent to intact capsule administration.2,3 however, arvs were still very expensive, and few individuals could afford them. they were not available in the state sector, and medical aids were generally not paying for them, either. in 1998, aid for aids (afa) was launched to assist medical insurance schemes to manage hiv in the private sector. it was revolutionary, but there was a limit – adult patients could only receive dual therapy and not triple therapy. one of the researchers (l.j.l.) approached afa (dr leon regensburg) and asked if it would be possible for paediatric patients to receive triple therapy, because they could get three drugs for the same price as two drugs in adults. afa did, as a result, allow paediatric patients triple therapy; this is why some paediatric patients in the private sector received triple therapy as early as 1998. although many were on d4t/ddi/ritonavir (rtv) – not a great regimen in anybody’s book – many survived and are alive and well today. while paediatric arv experience was evolving in the private sector, nothing was available in the state sector. hydroxyurea, a cheap drug used in oncology and believed to be synergistic with ddi, was tried. because of its low cost, patients, including children, were treated with the combination.4,5 however, its toxicity – lactic acidosis, often with fatal consequences – was quickly recognised, and this therapy ended. from 2000, things changed for the better. the aids 2000 conference was a watershed moment, as was the launch of the southern african journal of hiv medicine. in the early 2000s, very limited access to paediatric art in the public sector was mostly via international humanitarian non-governmental organisations such as médecins sans frontiers (doctors without borders) and donor-supported hospital-based programmes.6,7 on 01 april 2004, the national arv roll-out began.8 this was wonderful, but paediatric formulations were far from optimal. children were given d4t/lamivudine (3tc) combined with lopinavir/r (lpv/r) if they were under 3 years of age or efavirenz if they were over 3 years. besides the problem of the terrible taste and poor tolerability of lpv/r, it was not used in children under 6 months in the absence of data on its use in this age group. so, any child under 6 months was given full-dose rtv, as were any patients on concurrent rifampicin-containing antituberculosis treatment. besides the bad taste of rtv, this protease inhibitor (pi) presents hiv with a low genetic barrier to resistance, resulting in many children developing pi resistance.9 several years later, the nrti backbone was changed to abacavir and 3tc, a safer combination and one that allowed for once-daily dosing – a big help in terms of adherence. one of the obstacles to achieving widespread coverage of paediatric art has been the simplification of the prescribing process for non-paediatricians, including doctors and nurses who are more familiar with prescribing art for adults but who are also involved in treating children, particularly at the primary care level. calculating individualised doses of separate and mostly liquid oral arv formulations for an infant or young child at each clinic visit using the current weight or body surface area is complicated and time-consuming. the development and updating of an integrated weight-based arv dosing chart for children based on world health organization guidelines and adapted for the arv formulations available in south africa has contributed to building confidence amongst prescribing clinicians and pharmacists and helped facilitate children’s access to art. however, issues of arv tolerability and access to formulations appropriate for children remain. the lpv/r formulation is very unpleasant to taste, and whilst young babies tend to tolerate it when their taste buds are still undeveloped, as they grow older, they often spit or vomit it out. only in 2020 did the lpv/r pellets become available both in the state and private sectors. however, in the state sector, it may only be prescribed for patients over 6 months of age who are not tolerating the lpv/r solution.10 in the 2019 national guidelines, tenofovir/3tc/dolutegravir fixed-dose-combination tablets can be used from 10 years of age and 35 kg upwards,11 making a well-tolerated single-tablet regimen available for the first time to these adolescents. another issue that is still a problem is adolescent disclosure, because very few healthcare workers feel comfortable disclosing to their adolescent patients, and parents are obviously petrified to do so because of feelings of guilt and worries that the children may be angry with them. this and other adolescent issues are resulting in very low rates of adolescent viral suppression.12 in south africa, hiv viral resistance testing first became available in the early 2000s. at the time, a prevailing practice was to keep children with high viral loads on the same art regimen as long as the cd4 count was acceptable. this was a pragmatic approach because of the limited treatment options available and the restricted access to resistance testing but is likely to have contributed to the accumulation of progressive resistance mutations in some children, thereby limiting future treatment options. a national third-line art expert committee was established in 2013, focusing on patients with virological failure on a pi-based art regimen. new-generation pis and the integrase strand transfer inhibitor (insti) class of arv drugs became accessible, though on a limited basis. this has provided real hope for treatment-experienced adults and children and their clinicians in achieving better long-term treatment outcomes. alongside the changes in paediatric art, the reduction in mother-to-child transmission (mtct) resulting from maternal art has been dramatic. between 2009 and 2015, new paediatric infections decreased by 84% as a result of our national prevention of mtct guidelines evolving rapidly,13 culminating in january 2015 in the provision of lifelong triple art for all pregnant and breastfeeding women. whilst fewer children are acquiring hiv through vertical transmission, we are finding these children particularly challenging to deal with. pregnant women who know their hiv status and are able to take art rarely transmit hiv to their babies. of course, some mothers acquire hiv for the first time during their pregnancy or whilst breastfeeding and have unfortunately already transmitted the infection to their baby before they are aware of their status. however, the majority of infected babies in the era of art are born to mothers who for complex social reasons have defaulted on their art or take it inconsistently. poverty, stigma, and drug and alcohol abuse are all contributory factors. unfortunately, many of these mothers in turn find it difficult to give arvs to their children and to access treatment for them. many of the children who acquire hiv now are born into families with the least ability to deal with it. the hopelessness we felt in the pre-art era is now replaced by the heartbreak and frustration of having life-saving treatment that is not taken. in summary, paediatric art in south africa has come a long way: monotherapy, dual therapy, toxic regimens with d4t, ddi, and rtv. however, a universally available, well-tolerated, single formulation available from birth to adolescence still eludes us. whilst advocating for new, simpler and better-tolerated paediatric regimens, an underlying constraint remains – that of improving the support of vulnerable patients, especially pregnant and breastfeeding mothers, so that they are able to take art consistently and ensure the protection of the next generation of south africans. acknowledgements competing interests l.j.l. has received honoraria from abbvie, cipla medpro and johnson and johnson for serving on advisory boards and delivering lectures. authors’ contributions l.j.l. wrote the first draft. j.l.h. and j.n. added to the article and reviewed and edited it. ethical considerations this article followed all ethical standards for research without direct contact with human or animal subjects. funding information the article processing fee was sponsored by the southern african hiv clinicians society. data availability data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references englund ja, baker cj, raskino c, et al. zidovudine, didanosine, or both as the initial treatment for symptomatic hiv-infected children. n engl j med. 1997;336:1704–1712. https://doi.org/10.1056/nejm199706123362403 innes s, smuts m, cotton m, seifart h, rosenkranz b. comparative study of different brands of stavudine capsules for the off-label ‘opened capsule’ dosing method recommended for hiv-infected infants and children in resource-limited settings. sajch. 2009 jul;3(2):44–47. innes s, norman j, smith p, et al. bioequivalence of dispersed stavudine: opened versus closed capsule dosing. antivir ther. 2011;16(7):1131–1134. https://doi.org/10.3851/imp1876 zachary kc, davis b. hydroxyurea for hiv infection. aids clin care. 1998 apr;10(4):25–26, 32. sanne i, smego ra. systematic review of combination antiretroviral therapy with didanosine plus hydroxyurea: a partial solution to africa’s hiv/aids problem? int j infect dis. 2001;5:43–48. reddi a, leeper s, grobler a, et al. preliminary outcomes of a paediatric highly active antiretroviral therapy cohort from kwazulu-natal, south africa. bmc pediatr. 2007;7:13. https://doi.org/10.1186/1471-2431-7-13 eley b, nuttall j, davies m-a, et al. initial experience of a public sector antiretroviral treatment programme for hiv-infected children and their infected parents. s afr med j. 2004;94(8):643–646. simelela np, venter wdf. a brief history of south africa’s response to aids. s afr med j. 2014;104(3 suppl 1):249–251. van zyl gu, van der merwe l, claassen m, et al. protease inhibitor resistance in south african children with virologic failure. pediatr infect dis j. 2009 dec;28(12):1125–1127. national department of health circular. notice: availability of lopinavir/ritonavir oral pellets to children on antiretroviral treatment, version 2021 [homepage on the internet]. reference 2021/22/02/edp/02. [cited 2021 jun 22]. available from: https://drive.google.com/file/d/1uflsckm0iwgeeuhxjkeccl9hfpznesjj/view?usp=sharing south african national department of health. national consolidated guidelines for the management of hiv in adults, adolescents, children and infants and prevention of mother-to-child transmission [homepage on the internet]. 2020 [cited 2021 jun 22]. available from: https://www.knowledgehub.org.za/system/files/elibdownloads/2020-07/national%20consolidated%20guidelines%2030062020%20signed%20print%20v7.pdf nglazi m, kranzer k, holele p, et al. treatment outcomes in hiv-infected adolescents attending a community-based antiretroviral therapy clinic in south africa. bmc infect dis. 2012;12:21. https://doi.org/10.1186/1471-2334-12-21 joint united nations programme on hiv/aids (unaids). on the fast-track to an aids-free generation. the incredible journey of the global plan towards the elimination of new hiv infections among children by 2015 and keeping their mothers alive. geneva: joint united nations programme on hiv/aids; 2016. th!: southtrn african jou nal o~ hi mtoici!: -----------hbruary 2003 from the thank heaven that at long last we are witnessing wider use of antiretroviral therapies in south africa. there is greater acceptance of these therapies by patients, by doctors and by employer groups. the trend-setting mining giant anglo american has taken the bold step of providing antiretrovirals for its employees. regrettably government continues to drag its feet in this regard. those of us who have used antiretrovirals in our practices continue to be impressed by their beneficial effects, often rescuing patients from death's door. it is however heartening to view antiretroviral therapy lard on a larger scale by looking at evidence of its cost-effectiveness in disease management progammes. or leon regensburg presents very convincing data in the aid for aids programme regarding the cost-beneficial effects of these therapies. the latest and greatest in the hiv treatment arena, presented at the barcelona international aids conference in 2002, is described by or francois venter (p. 29) in his own inimitable style. or jean nachega has written on art in developing countries (p. 35), and this is an important focus on the unique problems and challenges of the developing world setting. art remains one of the most complex challenges facing clinicians today, and when treating a bizarre battle joep lange, president of the international aids society (ias), said at the durban 2000 aids conference that no greater ill befalls the poor than bad government, and i am afraid that there is no more unfortunate example of this than the mpumalanga provincial health department, headed up by mec sibongile manana. this lady has, in her position of power, decided to systematically ignore world health organisation recommendations, international scientific evidence and our own country's constitutional court ruling on antiretrovirals to deny the population in her province access to what is now standard practice in a number of south african provinces. hiv prophylaxis for rape victims and mother-tochild prevention programmes are becoming integrated into public sector health provision in many areas, but in mpumalanga not only is this not happening within the government, but this same government is wasting valuable aids money to fight futile court cases to stop a nongovernmental organisation that has undertaken to fill this very important service gap at its own expense! to add insult to injury the mec has taken this organisation editors patients a high index of awareness is necessary to avoid potentially fatal conditions that are associated with these therapies. all clinicians should read or jennifer pi tt's article lp. 38) on lactic acidosis in order to familiarise themselves with the clinical presentation of this potentially fatal condition. the challenge is that the initial symptoms are often vague and nonspecific. the guidelines section (p. 25) is devoted to legal and ethical issues and is presented by elsabe klinck from the south african medical assocation. these issues are as important to comply with as any other aspects of treatment the broader aspects of the ethical issues in hiv medicine are highlighted in a thought-provoking article by or dave spencer (p. 15). this issue of the journal also features an interesting case study on the immune reconstitution syndrome by or david brittain. we aim to have similar illustrative case studies in all future issues. des martin editor, southern african journal of hiv medicine president, southern african hiv clinicians saciety to court not just once but an astounding four times over the past 2 years, and has wasted tens of thousands of taxpayer rands in legal fees. tragically, a number of seemingly innocent people have lost jobs in this province as a result of the same bizarre battle. we reported some months ago in this column that or thys von mollendorf, the medical superintendent who had allowed the ngo to operate within his hospital, was suspended. i was shocked to learn from recent newspaper reports that his suspension has not been lifted and that he practises in the area from a number of private practices. it would appear that the public sector, so much in need of good people, has lost someone valuable. if the only reason for his suspension is that he has allowed an ngo to provide for his patients what the rest of the world considers to be standard levels of health care, and what our constitutional court has ruled as part of basic human rights, then the wrong person has been punished. i believe that the medical fraternity needs to find a way to say this with one voice repeatedly and forcefully. unda-gail bekker managing editar references about the author(s) david c. spencer division of infectious diseases, department of medicine, helen joseph hospital, university of the witwatersrand, johannesburg, south africa citation spencer dc. editorial. s afr j hiv med. 2020;21(1), a1199. https://doi.org/10.4102/sajhivmed.v21i1.1199 editorial editorial david c. spencer copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. greetings to all readers of the southern african journal of hiv medicine (sajhivmed) and members of the southern african hiv clinicians’ society! this has been a long year and one that will not be forgotten easily. coronavirus disease 2019 (covid-19) has reshaped our world. thank you to our nurses and doctors who stand by the bedside of the sick, placing life and future on the line for others. you have done a great job, and we are proud of you. thank you too, to researchers, laboratory staff and industry colleagues for your backroom work. without the goodwill of all, the sick are easily abandoned. thankfully, effective vaccines are emerging. but the pandemic is not over. will lowand middle-income countries (lmics) access these therapeutics? time will tell. clearly, this is an issue that we will closely watch. thank you to our authors. your vision of human immunodeficiency virus (hiv) in africa is important to us: current, authentic and compelling. you have allowed science/truth to do the talking. thank you for your submissions. articles are already being allocated to our 2021 edition! if you too have hiv-related research based in lmics, especially in africa, please consider submitting to the sajhivmed. thank you to our reviewers. thank you for saying yes. for returning reviews on time and ensuring we meet international publication standards and timelines! you are the backbone of our success and we are very much in your debt. if you are taking a break over the december holidays, we invite our readers to do some catch-up journal reading. this year we have shared 60 articles with you. the majority were the product of ‘original’ research. a small number included reviews, case reports and letters. five are new guidelines. i will restrict my comments to these. but please do not forget the remaining 55 articles. these papers reflect this changing epidemic on our doorstep. stay up to date. the 2020 updated art guideline is essential reading.1 this is high-end contemporary science with a strong clinical appeal. a lot about dolutegravir. but with many ‘insights’ and ‘tips’ not found elsewhere. a very special guideline, it deserves your attention. dr jeremy nel and his co-authors have also given us an african ‘first’, the guidelines for solid-organ transplantation in persons living with hiv (plwh).2 this is a collaboration of local and international hiv clinicians and senior transplant surgeons. relevant to africa? yes. transplant organs are needed by hiv-infected and uninfected all over africa. this article rewards the reader with accessible immunology and a practical approach to complex patient care. human immunodeficiency virus-prevention is addressed in two guidelines. the updated south african national guideline for the prevention of mother to child transmission of communicable infections (2019) and the southern african guideline on the safe, easy and effective use of pre-exposure prophylaxis (prep): 2020.3,4 the former is an update of the 2019 national prevention of mother-to-child transmission (pmtct) guidelines. its underlying concern is the relative increase in viral transmission in the first 18 months of life: 0.7% at birth (2019) but 4.3% at 18 months (2016). (more recent 18-month data are clearly needed). quo vadis re. breastfeeding? children in africa remain at risk of hiv infection. these guidelines set out the rules, the goalposts. please read and implement these guidelines. this is an extraordinary report.5 the authors comment, ‘to our knowledge, no pmtct data of this magnitude has been published from a low-income, high hiv-prevalence setting’ before! this is a 14-year review of the pmtct in a large cohort of sowetan women and their children. over this period 360,751 pregnant women were managed in 13 clinics in soweto, south africa. the proportion of pregnant women living with hiv who attended these clinics rose from 14.3% in 2009 to 45% in 2015 (p < 0.001)! prevalence rates of hiv in pregnancy during the period were high: 28.9% in 2002, 33.1% in 2009 and 27.4% in 2015. nevertheless, the clinic staff clinics and the project funders -overseas and local (sa government) – managed to reduce the mother-to-child transmission rate at 6 weeks of life from 7.0% in 2007 to < 1.6% in 2013-2015, p < 0.001. the report is astonishing. the south africa of recent decades has not been easy to live in particularly for the poor. more so for those living with hiv. the authors acknowledge limitations to their work. these do not detract from the body of the work or lessen its impact. prof. bekker’s ‘safe, easy and effective use of prep’ paper comes on the heels of data confirming the superior efficacy of two-monthly injections of cabotegravir as against oral long-term prep in 3223 african women (study hptn 084) and men who have sex with men (msm) and transgender women (study hptn 083). https://clinicaltrials.gov/ct2/show/nct03164564. (htpn 084), https://clinicaltrials.gov/ct2/show/nct02720094. (htpn 083). human immunodeficiency virus prevention is of critical importance to south africa (sa). the current population of sa is ± 59.62 million; ± 7.8 million are plwh and ± 18.7% of our 15–49-year-olds are living with hiv.6 i recommend this prep guideline to every healthcare worker. these numbers demand action. although only oral prep is available in sa at this time, injectables will come. we need to get young people in particular thinking new thoughts about their sexual health. a companion article speaks to the ethics and legalities of adolescent prep.7 this is particularly helpful for family physicians and parents who wish to protect sexually active children. the fifth guideline has broad application in sub-saharan africa. the southern african hiv clinicians’ society guideline for harm reduction focuses on drug addiction in plwh.8 justice edwin cameron provides a wise and considered response. please read it.9 the guideline is long but comprehensive. the writers are experts in the field. throughout, a human rights understanding is followed and a compassionate yet evidence-based approach to illicit drug use is outlined. addiction is increasing in africa. many also live with hiv. new thoughts and new approaches are needed. this is a timely but sober read. if you care for your patients, do not sidestep the issue. i have left you with another 55 articles to explore in the days ahead. many of these can stand with the best in the field. take a look at this year’s volume. this year marks the 20th anniversary of the ‘birth’ of the southern african journal of hiv medicine.10 it was the brainchild of the then president-elect of the society, prof. des martin, and others on the executive committee. we published the first issue to coincide with the 13th international hiv conference in durban (sa) in july of 2000. the first journal is a brief read but provided colleagues and the south african nation with its first ever ‘national’ antiretroviral (art) guideline. thank you, des. thank you, colleagues. we have come a long way since then. the lives of thousands have been rescued. words cannot measure the success. references nel j, dlamini s, meintjes g, et al. south african hiv clinicians’ society guidelines for antiretroviral therapy in adults: 2020 update. s afr j hiv med. 2020;21(1):a1115. https://doi.org/10.4102/sajhivmed.v21i1.1115 nel js, conradie f, botha j, et al. southern african clinicians’ society guidelines for solid-organ transplantation in human immunodeficiency virus: an evidence-based framework for human immunodeficiency virus-positive donors and recipients. s afr j hiv med. 2020;21(1):a1133. https://doi.org/10.4102/sajhivmed.v21i1.1133 wessels j, sherman g, bamford l, et al. the updated south african national guideline for the prevention of mother to child transmission of communicable infections (2019). s afr j hiv med. 2020;21(1):a1079. https://doi.org/10.4102/sajhivmed.v21i1.1079 bekker l-g, brown b, joseph-davey d, et al. southern african guideline on the safe, easy and effective use of pre-exposure prophylaxis (prep): 2020. s afr j hiv med. 2020;21(1):a1152. https://doi.org/10.4102/sajhivmed.v21i1.1152 mnyani cn, tait cl, peters rph, et al. implementation of a pmtct programme in a high hiv prevalence setting in johannesburg, south africa: 2002–2015. s afr j hiv med. 2020;21(1), a1024. https://doi.org/10.4102/sajhivmed.v21i1.1024 diego i, munthree c. south african mid-year population estimates [homepage on the internet]. 2020 [2020 nov 20]. available from: www.statssa.gov.za strode a, slack cm, essack z, toohey jd, bekker l-g. be legally wise: when is parental consent required for adolescents’ access to pre-exposure prophylaxis (prep)? s afr j hiv med. 2020;21(1):a1129. https://doi.org/10.4102/sajhivmed.v21i1.1129 scheibe ap, sibeko g, shelly s, et al. southern african hiv clinicians’ society guideline for harm reduction. s afr j hiv med. 2020;21(1):a1161. https://doi.org/10.4102/sajhivmed.v21i1.1161 cameron e. introduction to the southern african hiv clinicians’ society harm-reduction guideline. s afr j hiv med. 2020;21(1):a1179. https://doi/org/10.4102/sajhivmed.v21.i1.1179 martin d. editorial. s afr j hiv med. 2000;1(1):a489. https://doi.org/10.4102/sajhivmed.v1i1.489 hiv 871 original article overview of hiv-related lipodystrophy t m rossouw, m e botes, f conradie department of family medicine, faculty of health sciences, university of pretoria t m rossouw, mb chb, mphil, mph, phd private practice, pretoria m e botes, mb chb department of clinical medicine, faculty of health sciences, university of the witwatersrand, johannesburg f conradie, mb bch, dip hiv man, dip tropical medicine and hygiene corresponding author: t m rossouw (theresa.rossouw@up.ac.za) lipodystrophy is a well-recognised adverse effect of hiv and antiretroviral therapy, with certain antiretrovirals, specifically thymidine analogues, implicated in the aetiology and pathogenesis. lipodystrophy is often accompanied by metabolic complications, such as hyperlipidaemia and insulin resistance, which increase risk for cardiovascular disease. there are limited data on the effect of treatment modification, pharmacological interventions and surgical management on this condition. here we summarise the latest data on lipodystrophy, with the aim of facilitating informed decision-making in managing this condition. in light of the absence of cost-effective measures to treat lipoatrophy and lipohypertrophy, prevention remains the best option; we recommend targeted annual screening. healthcare workers should be sensitised to early detection in patients on thymidine-based regimens, and affected patients should be switched to an appropriate regimen as soon as feasible. there is no evidence to support the use of new-generation arvs, except in patients with significant hypercholesterolaemia, where atazanavir and raltegravir may present better options. s afr j hiv med 2013;14(1):29-33. doi:10.7196/sajhivmed.871 the lipodystrophy syndrome is a well-recognised phenomenon in hiv-1-infected patients receiving antiretroviral therapy (art). the syndrome is characterised by body habitus changes, most commonly a combination of lipoatrophy (la) (loss of peripheral subcutaneous adipose tissue (sat), usually in the face, limbs and buttocks) and lipohypertrophy (lh) (visceral adipose tissue (vat) accumulation, gynaecomastia and, in some cases, lipomatosis, especially in the dorsocervical area, known as a ‘buffalo hump’). even though the aetiology remains unclear, the following factors have been implicated in the development of lipodystrophy: hiv itself, older age, female sex, genetic parameters and art. 1 there seems to be consensus that peripheral la and central lh have the same causes (hiv and art), but are likely to be related to different fat depot physiologies.2 it is speculated that la is linked to severe mitochondrial dysfunction, oxidative stress and inflammation, while hypertrophy is related to mild mitochondrial dysfunction and cortisol activation, promoted by inflammation. importantly, both la in the lower part of the body and abdominal lh have been associated with metabolic changes akin to the metabolic syndrome, particularly dyslipidaemia and insulin resistance.3 recent reports in the popular press have highlighted the psychological and social distress that patients experience as a result of lipodystrophy. often, patients are left on offending regimens for too long, causing extreme and often irreversible body changes. it is imperative that healthcare workers familiarise themselves with this entity and understand the treatment options available to patients. here we summarise the latest data on the topic, with the aim of facilitating informed decision-making in managing this condition. role of art data on the effect of art on lipodystrophy exist for the older nucleoside reverse transcriptase inhibitors (nrtis) and unboosted protease inhibitors (pis), but seem to be conflicting for the non-nucleoside reverse transcriptase inhibitors (nnrtis) and newer pis, and are mostly unavailable for the new drug classes. many studies have implicated stavudine (d4t) and zidovudine (azt) in the development of lipodystrophy and this is generally uncontested. abacavir (abc) and tenofovir (tdf) have been shown to have minimal effect.6 initial studies did not reveal a role for efavirenz (efv) in lipodystrophy, but the recent actg a5142 study6 found that la was indeed more relevant in efv-treated patients when compared with boosted lopinavir (lpv/r)-treated patients. another study, however, found only a minimal difference between efv and another pi, atazanavir (atv).7 taken together, these studies suggest that in terms of the development of la, lpv may have a slight advantage over efv when combined with tdf (up to 96 weeks) in treatment-naive patients. in terms of lipodystrophy, atv may have a marginal advantage over efv when combined with azt (up to 48 weeks) in treatment-naive patients. importantly, atv is known to have a better lipid profile than efv and lpv/r and an argument could therefore be made for its preferential use in patients at high risk for cardiovascular disease. the 2011 united states department of health and human services art guidelines state that an increase in trunk fat has been observed with efv-, pi-, and raltegravir (ral)-containing regimens, but that a causal relationship has not been established.4 there are very few data on the entry inhibitors and integrase inhibitors, although some early data indicate the possibility of an improved metabolic and lipid profile. there are currently no systematic reviews or meta-analyses comparing the effects of different antiretrovirals (arvs) on lipodystrophy. the comparison of studies is complicated by different measurement standards for lipodystrophy, the use of different race and ethnic groups, and a general lack of control groups. table 1 summarises the current knowledge about the effect of different arvs on lipodystrophy, lipids and glucose metabolism. table 1. the effects of different arv drugs on fat and metabolism* drug la lh dyslipidaemia insulin resistance stavudine (d4t) +++ ++ ++ ++ zidovudine (azt) ++ + + ++ didanosine (ddi) +/ +/ + + lamivudine (3tc) 0 0 + 0 abacavir (abc) 0 0 + 0 tenofovir (tdf) 0 0 0 0 emtricitabine (ftc) 0 0 0 0 efavirenz (efv) +/ +/ ++ hdl + nevirapine (nvp) 0 0 + hdl 0 ritonavir (rtv) +/ + +++ ++ indinavir (idv) +/ + + +++ lopinavir (lpv) +/ + ++ ++ saquinavir (sqv) +/ + +/ +/ atazanavir (atv) 0 ++ +/ 0 darunavir (drv) 0 + +/ +/ enfuvirtide (inn) insufficient data insufficient data 0 0 maraviroc (mvc) insufficient data insufficient data 0 0 raltegravir (ral) insufficient data insufficient data 0 0 la = lipoatrophy; lh = lipohypertrophy. *adapted from caron-debarle et al.2 it is important to note that the number of patients changing art regimens because of lipodystrophy appears to be decreasing over time. the swiss hiv cohort study5 followed 5 777 participants who started art between 2000 and 2006, and compared rates of lipodystrophy between 2000 and 2002, and 2003 and 2006. the findings revealed that 4% of patients had changed art regimens due to lipodystrophy during 2000 2002, whereas only 1% of patients changed during 2003 2006. this reduction was attributed to the decreased use of azt (88% v. 64%) and d4t (4.2% v. 0.7%) and the increased use of tdf (0% v. 30%) over this time.5 the differential metabolic effects of the nnrtis, nrtis and pis are depicted in fig. 1. there is currently not enough long-term information on entry inhibitors and integrase inhibitors to allow for categorisation. fig. 1. metabolic impact of art classes and individual drugs. 8 nntri = non-nucleoside reverse transcriptase inhibitor; nrti = nucleoside reverse transcriptase inhibitor; pi = protease inhibitor. metabolic consequences of lipodystrophy lipodystrophy is well known to cause significant psychological distress and has been identified as a risk factor for art non-adherence.9 , 10 there are, however, other consequences that may warrant treatment modification, especially metabolic complications. fig. 2 shows that increased central fat and decreased limb fat are implicated in the development of metabolic complications. the basic pathology is postulated to be an increased release of cytokines and free fatty acids (ffas) which, together with decreased adiponectin production by adipose tissue, lead to insulin resistance and triglyceride (tg) deposition in tissues such as the liver, skeletal muscle and heart. it seems that active lipolysis in sat, combined with impaired fat storage capacity in the subcutaneous depot, drives the deposition of lipids in ectopic sites such as the viscera and other non-adipose sites. this leads to hepatic steatosis and increased lipid content in skeletal muscle, which contribute to systemic metabolic alterations, especially insulin resistance. the high levels of ffas may also affect pancreatic function and thus contribute to impaired insulin release and a pre-diabetic state. fig. 2. metabolic consequences of lipodystrophy. vat = visceral adipose tissue; sat = subcutaneous adipose tissue; tnf = tumour necrosis factor; il-6 = interleukin-6; ffas = free fatty acids; nash = non-alcoholic steatohepatitis. these metabolic changes ultimately result in impaired glucose tolerance and dyslipidaemia with decreased high-density lipoprotein cholesterol (hdl-c) and increased tgs. metabolic complications are therefore responsible for increased cardiovascular and hepatic disease risks. these changes have also been linked to premature ageing. the hypothesis has been put forward that chronic hiv infection, combined with the use of some arvs and lipodystrophy, may accelerate the normal ageing processes and lead to the early development of age-related co-morbidities.2 management of lipodystrophy changing art lipoatrophy the only art modification that has been shown to partially reverse sat loss is switching from d4t or azt to abc or tdf.11 , 12 one small study comparing the effect of three abc substitution approaches over 48 weeks showed that fat mass in the arms and legs improved significantly (41% and 52%, respectively) when d4t was replaced with abc. there was, however, no improvement when treatment with a pi or nnrti was stopped in favour of abc.13 on average, an estimated 400 500 g fat can be regained per year, but it is important to bear in mind that some patients may fail to demonstrate significant improvement due to possible exhaustion of the fat mesenchymal stem-cell pool. furthermore, treatment modification may introduce risks associated with the new art regimen, such as abc hypersensitivity and tdf-associated nephrotoxicity; therefore, adequate monitoring should be in place. in light of the ongoing controversy regarding abc and cardiovascular risk, abc may best be avoided in patients with established cardiovascular disease (cvd). an alternative strategy is to switch to an nrti-sparing regimen. this approach has also been shown to increase total limb fat by approximately 400 500 g per year, but has the disadvantage of possible increased dyslipidaemia (with all pis except atv). furthermore, data on its long-term virological efficacy is limited.8 , 14 lipohypertrophy weight gain is an expected consequence of successful art. weight reduction – or even better, avoidance of weight gain – through healthy diet and exercise may decrease vat deposition and possibly improve insulin sensitivity and the lipid profile. there is, however, no information about the sufficient amount of diet and exercise needed to maintain this effect, and it may even aggravate la. there are limited data on the effect of an art regimen change on lh. in a trial of 201 hiv-infected patients with abdominal fat accumulation and viral suppression, a switch from a twice-daily ritonavir-boosted pi regimen to once-daily ritonavir-boosted atv led to a non-significant difference in limb fat loss at 48 weeks.15 some anecdotal data do, however, hint that atv may have some effect: a very small case series of three patients described regression of central fat accumulation after nelfinavir (nfv) was replaced with atv.16 in a recent study by lake et al.,17 39 virologically controlled women receiving tdf-ftc/abc-3tc and either nnrtior pi-based art, with lh, were randomised to immediate or delayed switch of the nnrti or pi component to ral. after 24 weeks, no statistically significant changes in vat or sat, anthropometrics, body mass index (bmi), glucose or c-reactive protein (crp) were observed, but there were significant improvements in total and low-density lipoprotein (ldl) cholesterol (p=0.04).17 there is therefore insufficient evidence to suggest that a change to the newer classes of drugs, such as integrase and entry inhibitors, may reverse la or lh. the complexity of the data highlights the controversy of changing a treatment regimen for clinical and aesthetic reasons in the face of maximal virological suppression. novel treatment strategies lipoatrophy trials of the thiazolidinediones have shown that this drug class has very modest, if any, effect on lipoatrophic sat. although these drugs improve insulin sensitivity, they are known to induce harmful effects on blood lipids.18 in a randomised controlled trial, pioglitazone was shown to increase the number and function of mitochondria and partially reverse peripheral fat loss in patients without thymidine nrtis. this effect was, however, not noticeable to the patients.19 uridine, a pyrimidine nucleoside, has been postulated to protect fat cells from the adverse effects of thymidine analogues. after initial promising results, however, the drug failed to demonstrate improvement in limb fat in a subsequent multicentre clinical trial of 165 participants.20 pravastatin, a lipid-lowering 3-hydroxy-3-methyl-glutaryl-coa (hmg-coa) reductase inhibitor that is thought to have anti-inflammatory properties, was shown to partially reverse lipodystrophy in 33 hypercholesterolaemic men.21 however, it failed to show a beneficial effect in a randomised trial of men who had discontinued thymidine nrtis.22 lipohypertrophy growth hormone (gh) has been shown to decrease vat, but it may worsen subcutaneous la and insulin resistance.8 tesamorelin, a gh-releasing factor analogue, has been used to restore gh levels and has demonstrated a significant reduction in vat hypertrophy. it has also been shown to improve the levels of tgs, hdl-c, adiponectin and insulin-like growth factor 1 (igf-1), although a small but statistically significant worsening of glucose profiles was also evident. based on these data, the us food and drug administration (fda) approved tesamorelin for the treatment of excess abdominal fat in hiv-infected patients in november 2010. the drug may only be used in patients without active malignancy and its widespread use is complicated by cost, the need for frequent monitoring of igf-1 and glycosylated haemoglobin (hba1c), and the lack of safety data beyond one year of use. therapy should not be continued for longer than six months in the absence of a favourable treatment response, as assessed by a decrease in waist circumference.23 metformin is known to decrease vat, especially in the presence of insulin resistance. it may, however, worsen subcutaneous la and should not be used in patients with a low bmi. there are, however, not enough data to recommended its use in patients without diabetes mellitus (dm) at this stage. anabolic steroids have not shown a beneficial response in the presence of normal blood testosterone levels and can also not be recommended at present. overall, in light of the high cost of these treatments, limited data showing minimal improvement, an absence of clear long-term benefits and the possibility of new complications of the therapy, none of these drugs can be recommended for the routine treatment of lipodystrophy at this stage. role of surgery lipoatrophy various surgical interventions have been proposed for the management of facial la. there are, however, limited long-term data on the different approaches, and inadequate comparisons thereof. polylactic acid (pla) is a re-absorbable filler that is immunologically inert and causes only limited inflammation. most patients report a good response after three to four injections. it is, however, prohibitively expensive. hyaluronic acid and collagen produce equally favourable results, but the effects are less durable. transplanting autologous harvested fat cells is becoming increasingly topical, but costs, the invasiveness of the technique and the requirement of general anaesthesia and hospitalisation limit its use.24 polyalkylamide (bio-alcamid) is a permanent filler and has been used with good effect, especially in cases of severe la. permanent fillers do not, however, have long-term safety data and have the disadvantage that, if la progresses, then the edges of the filler may become visible. conversely, if fat mass increases, the permanent filler may over-correct the original defect and hence become obvious and unsightly.24 lipohypertrophy surgical interventions have been used for localised forms of lh, such as lipomas and buffalo humps. options include standard surgical removal and liposuction. the duration of effect is, however, variable and up to half of the patients with dorsocervical disease experience a recurrence after 1 2 years. surgery can also be considered when significant fat has accumulated around the breast tissue. breast reduction surgery is invasive, requires anaesthesia and hospitilisation, and has a similar risk of fat return, especially if the patient cannot be established on a pi-sparing regimen. surgery is not an option for patients with abdominal lh. screening for and managing metabolic complications suggested approach prevention of hiv-related lipodystrophy is the best strategy and all hiv-infected persons should be screened at regular intervals for a history of metabolic disease, dyslipidaemia, dm, hypertension and alteration of body composition (table 2). interventions to prevent cvd should vary in intensity according to a patient’s absolute risk of ischaemic heart disease. a comprehensive, multi-disciplinary approach is preferred. this should start with lifestyle interventions – counselling to stop smoking, modified diet and regular exercise – and be followed with a change of art if needed, and the use of lipid-lowering medication in high-risk patients. the prevention and management of type 2 dm and hypertension should be in accordance with guidelines used in the general population. when pharmacological interventions are considered, care should be taken to avoid detrimental pharmacokinetic interactions, such as between statins and pis.24 table 2. suggested annual screening for metabolic complications history • family or personal history of cvd, dm or ht • concomitant treatment for dm, ht or dyslipidaemia • concomitant use of medication with risk for dm or dyslipidaemia • lifestyle: smoking, alcohol, exercise, diet • patient perception of change in body composition examination • body composition • bmi • waist circumference • waist:hip ratio • clinical signs of lipodystrophy • blood pressure • cardiovascular risk assessment bloods • lipids: fasting total cholesterol, tgs, ldl-c and hdl-c • glucose (fasting) • liver enzymes: alt, ast, ggt, alp • renal function: egfr special investigations • ecg: men aged >40 years and women aged >50 years cvd = cardiovascular disease; dm = diabetes mellitus; ht = hypertension; bmi = body mass index; tgs = triglycerides; ldl-c = low-density lipoprotein cholesterol; hdl-c = high-density lipoprotein cholesterol; alt = alanine transaminase; ast = aspartate transaminase; ggt = gamma-glutamyl transpeptidase; alp = alkaline phosphatase; egfr = estimated glomerular filtration rate; ecg = electrocardiogram. conclusion lipodystrophy remains a challenge in the long-term management of hiv-infected patients receiving art, and should be regarded as part of a more pervasive pathology. we recommend approaching the condition with targeted annual screening. in light of the absence of cost-effective measures to treat la and lh, prevention remains the best option. healthcare workers should be sensitised to the early detection of lipodystrophy in patients on thymidine-based art regimens. furthermore, affected patients should be switched to an appropriate regimen as soon as is feasible. there is currently no evidence to support the use of new-generation arvs, except in patients with significant hypercholesterolaemia, where atv and ral may present better options. references 1. grinspoon s, carr a. cardiovascular risk and body-fat abnormalities in hiv-infected adults. n engl j med 2005;352:48-62. 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[http://dx.doi.org/10.1097/qai.0b013e318042e204] 14. tebas p, zhang j, yarasheski k, et al. switching to a protease inhibitor-containing, nucleoside-sparing regimen (lopinavir/ritonavir plus efavirenz) increases limb fat but raises serum lipid levels: results of a prospective randomized trial (aids clinical trial group 5125s). j acquir immune defic syndr 2007;45(2):193. [http://dx.doi.org/10.1097/qai.0b013e318042e204] 15. moyle gj, andrade-villanueva j, girard pm, et al. a randomized comparative 96-week trial of boosted atazanavir versus continued boosted protease inhibitor in hiv-1 patients with abdominal adiposity. antivir ther 2012;17(4):689. [http://dx.doi.org/10.3851/imp2083] 15. moyle gj, andrade-villanueva j, girard pm, et al. a randomized comparative 96-week trial of boosted atazanavir versus continued boosted protease inhibitor in hiv-1 patients with abdominal adiposity. antivir ther 2012;17(4):689. [http://dx.doi.org/10.3851/imp2083] 16. haerter g, manfras bj, mueller m, kern p, trein a. regression of lipodystrophy in hiv-infected patients under therapy with the new protease inhibitor atazanavir. aids 2004;18(6):952-998. 16. haerter g, manfras bj, mueller m, kern p, trein a. regression of lipodystrophy in hiv-infected patients under therapy with the new protease inhibitor atazanavir. aids 2004;18(6):952-998. 17. lake je, mccomsey ga, hulgan tm, et al. a randomized trial of raltegravir replacement for protease inhibitor or non-nucleoside reverse transcriptase inhibitor in hiv-infected women with lipohypertrophy. aids patient care stds 2012,26(9):532-540. [http://dx.doi.org/10.1089/apc.2012.0135] 17. lake je, mccomsey ga, hulgan tm, et al. a randomized trial of raltegravir replacement for protease inhibitor or non-nucleoside reverse transcriptase inhibitor in hiv-infected women with lipohypertrophy. aids patient care stds 2012,26(9):532-540. [http://dx.doi.org/10.1089/apc.2012.0135] 18. sutinen j. the effects of thiazolidinediones on metabolic complications and lipodystrophy in hiv-infected patients (review). ppar research 2009:373524. [http://dx.doi.org/10.1155/2009/373524] 18. sutinen j. the effects of thiazolidinediones on metabolic complications and lipodystrophy in hiv-infected patients (review). ppar research 2009:373524. [http://dx.doi.org/10.1155/2009/373524] 19. slama l, lanoy e, valantin m-a, et al. effect of pioglitazone on hiv-1-related lipodystrophy: a randomized double-blind placebo-controlled trial (anrs 113). antivir ther 2008;13(1):67-76. 19. slama l, lanoy e, valantin m-a, et al. effect of pioglitazone on hiv-1-related lipodystrophy: a randomized double-blind placebo-controlled trial (anrs 113). antivir ther 2008;13(1):67-76. 20. mccomsey g, o’riordan ma, choi j, et al. a 48-week randomized study of uridine supplementation vs. switch to tdf on limb fat, mitochondrial function, inflammation and bone mineral density in hiv lipoatrophy. 17th conference on retroviruses and opportunistic infections, san francisco, ca, usa, 2010;342. 20. mccomsey g, o’riordan ma, choi j, et al. a 48-week randomized study of uridine supplementation vs. switch to tdf on limb fat, mitochondrial function, inflammation and bone mineral density in hiv lipoatrophy. 17th conference on retroviruses and opportunistic infections, san francisco, ca, usa, 2010;342. 21. mallon pwg, miller j, kovacic jc, et al. effect of pravastatin on body composition and markers of cardiovascular disease in hiv-infected men a randomized, placebo-controlled study. aids 2006;20(7):1003-1010. [http://dx.doi.org/10.1097/01.aids.0000222072.37749.5a] 21. mallon pwg, miller j, kovacic jc, et al. effect of pravastatin on body composition and markers of cardiovascular disease in hiv-infected men a randomized, placebo-controlled study. aids 2006;20(7):1003-1010. [http://dx.doi.org/10.1097/01.aids.0000222072.37749.5a] 22. calmy a, bloch m, wand h, et al. no significant effect of uridine or pravastatin treatment for hiv lipoatrophy in men who have ceased thymidine analogue nucleoside reverse transcriptase inhibitor therapy: a randomized trial. hiv med 2010;11(8):493-501. [http://dx.doi.org/10.1111/j.1468-1293.2009.00817.x] 22. calmy a, bloch m, wand h, et al. no significant effect of uridine or pravastatin treatment for hiv lipoatrophy in men who have ceased thymidine analogue nucleoside reverse transcriptase inhibitor therapy: a randomized trial. hiv med 2010;11(8):493-501. [http://dx.doi.org/10.1111/j.1468-1293.2009.00817.x] 23. falutz j, mamputu jc, potvin d, et al. effects of tesamorelin (th9507), a growth hormone-releasing factor analog, in human immunodeficiency virus-infected patients with excess abdominal fat: a pooled analysis of two multicenter, double-blind placebo-controlled phase 3 trials with safety extension data. j clin endocrinol metab 2010; 95:4291. [http://dx.doi.org/10.1210/jc.2010-0490] 23. falutz j, mamputu jc, potvin d, et al. effects of tesamorelin (th9507), a growth hormone-releasing factor analog, in human immunodeficiency virus-infected patients with excess abdominal fat: a pooled analysis of two multicenter, double-blind placebo-controlled phase 3 trials with safety extension data. j clin endocrinol metab 2010; 95:4291. [http://dx.doi.org/10.1210/jc.2010-0490] 24. gazzard bg; bhiva treatment guidelines writing group. british hiv association guidelines for the treatment of hiv-1-infected adults with antiretroviral therapy 2008. hiv med 2008;9(8):563-608. 24. gazzard bg; bhiva treatment guidelines writing group. british hiv association guidelines for the treatment of hiv-1-infected adults with antiretroviral therapy 2008. hiv med 2008;9(8):563-608. abstract introduction methods results discussion conclusion acknowledgements references about the author(s) saskya claasens division of dermatology, department of medicine, faculty of medicine and health sciences, stellenbosch university, cape town, south africa susanna m.h. kannenberg division of dermatology, department of medicine, faculty of medicine and health sciences, stellenbosch university, cape town, south africa henry f. jordaan division of dermatology, department of medicine, faculty of medicine and health sciences, stellenbosch university, cape town, south africa karis moxley research development and support division, faculty of medicine and health sciences, stellenbosch university, cape town, south africa rhodine smith division of dermatology, department of medicine, faculty of medicine and health sciences, stellenbosch university, cape town, south africa division of epidemiology and biostatistics, department of global health, faculty of medicine and health sciences, stellenbosch university, cape town, south africa johann de wet division of dermatology, department of medicine, faculty of medicine and health sciences, stellenbosch university, cape town, south africa willem i. visser division of dermatology, department of medicine, faculty of medicine and health sciences, stellenbosch university, cape town, south africa citation claasens s, kannenberg smh, jordaan hf, et al. the prevalence and spectrum of mucocutaneous disease in south african people living with hiv and accessing care at a district-level hospital. s afr j hiv med. 2020;21(1), a1154. https://doi.org/10.4102/sajhivmed.v21i1.1154 original research the prevalence and spectrum of mucocutaneous disease in south african people living with hiv and accessing care at a district-level hospital saskya claasens, susanna m.h. kannenberg, henry f. jordaan, karis moxley, rhodine smith, johann de wet, willem i. visser received: 16 aug. 2020; accepted: 04 sept. 2020; published: 10 dec. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: although the association between human immunodeficiency virus (hiv) and mucocutaneous diseases has been well studied within south african specialist centres, there is limited data from district-level hospitals. available data may, therefore, fail to reflect the prevalence and full spectrum of dermatoses seen in people living with hiv (plwh). objectives: to determine the prevalence and spectrum of dermatoses seen in plwh. method: we conducted a cross-sectional, descriptive study of 970 plwh (men and women, ≥ 18 years old) accessing care at karl bremer hospital, a district-level hospital located in the western cape province, south africa, between 01 september 2016 and 28 february 2017. results: the prevalence of mucocutaneous disease in this sample was 12.7% (95% confidence interval [ci] 0.11–0.15). non-infectious dermatoses comprised 71.0% of the disorders. pruritic papular eruption (20.0%) and seborrheic dermatitis (6.0%) were the most common non-infectious dermatoses. tinea corporis (8.0%) and oral candidiasis (6.0%) were the most prevalent infectious dermatoses. there was no significant association between skin disease category (infectious or non-infectious dermatoses) and patient demographics (gender and ethnicity) or hiv-disease characteristics (cd4+ cell count, viral load and duration of antiretroviral therapy [art]). conclusion: this study provides valuable scientific data on the prevalence and spectrum of mucocutaneous disease in plwh attending a south african district-level hospital. prospective studies conducted in other district-level centres across the country are required to determine the lifetime prevalence and spectrum of dermatoses in plwh in the art era. keywords: mucocutaneous disease; hiv; district-level hospitals; art; south africa. introduction the skin serves as an important clinical tool in the diagnosis and staging of patients with human immunodeficiency virus (hiv) and may be a marker of disease progression. skin diseases are common and well described in the hiv-positive population and may affect up to 90% of individuals during the course of their illness.1,2 although many skin and mucosal diseases are not unique to people living with hiv (plwh), these patients can present with atypical features and dual or triple pathology.3 furthermore, infective and inflammatory dermatoses in plwh tend to be more severe and slower to respond to treatment when compared with the hiv-negative population.4 antiretroviral therapy (art) has altered the natural progression of hiv infection, leading to immune reconstitution through the suppression of viral replication and the recovery of the cd4+ cell count. as a result of art, plwh are living longer and healthier lives with a near-normal life expectancy.5 several of the hiv-associated dermatoses have declined during the art era, but certain drug reactions and inflammatory skin conditions have increased.4,6 management of plwh in the art era includes addressing common non-infectious dermatoses in addition to rare opportunistic infections and infection-associated malignancies.5 of the 7.2 million plwh residing in south africa, an estimated 61% were accessing art in 2017.7 south african studies performed before the roll-out of art described the cutaneous manifestations of hiv.8,9,10 following the launch of art, studies placed more emphasis on severe cutaneous adverse drug reactions and dermatoses that occur in the setting of tuberculosis (tb) co-infection.11,12 although the existing body of literature provides valuable insights into dermatoses more likely to occur at advanced stages of immunosuppression, it does not sufficiently describe the full spectrum and prevalence of all mucocutaneous diseases occurring in plwh. this is because most prior studies were performed at specialist and tertiary-level hospitals, and there is limited data available from district-level hospitals. this limitation may have biased current knowledge and understanding regarding the spectrum and prevalence of dermatoses amongst plwh. for example, studies performed at tertiary referral centres are more likely to include dermatoses that warrant inpatient management, such as inflammatory dermatoses, erythroderma and severe cutaneous drug reactions.9,13 furthermore, most plwh are cared for at primary and district-level healthcare facilities where they may present with common skin diseases that can be diagnosed and treated at the primary healthcare level. overall, data from studies performed at tertiary referral centres could overestimate certain dermatoses and fail to represent the full spectrum of dermatoses seen in the majority of plwh attending non-specialist centres. this oversight may have important implications for the prescribed standard of care for plwh at a district level. therefore, to ensure that appropriate prevention and treatment strategies are implemented, there is a need to fully describe cutaneous diseases being treated at this level. therefore, this study aimed to determine the prevalence and spectrum of hiv-related skin diseases at a south african primary healthcare facility. we additionally aimed to assess any possible associations between patient characteristics and dermatoses. methods study design this descriptive and cross-sectional study was conducted at the adult hiv clinic at karl bremer hospital (kbh), cape town, south africa, between 01 september 2016 and 28 february 2017. study setting karl bremer hospital is a publicly funded district-level hospital. it serves a heterogeneous patient population of lowto middle-income status. the hiv clinic is a division of the outpatient department and is operated by a nurse, two counsellors and a medical officer. patients who require specialist dermatology care are referred to tygerberg hospital, which is a tertiary hospital in the vicinity. study sample all plwh (men and women, ≥ 18 years old) seeking routine care at the hiv clinic at kbh were eligible to participate in the study. we included patients receiving art and those awaiting art commencement. we estimated an appropriate sample size using data provided in a previous study that reported the prevalence of cutaneous manifestations of hiv at a tertiary dermatology outpatient centre in kwazulu-natal (before the roll-out of art).10 herpes zoster was the most common cutaneous manifestation (19%) and opportunistic fungal infections were reported to be least prevalent conditions (3%). using openepi software (www.openepi.com), an expected prevalence of 10%, a 2% level of precision and a confidence interval (ci) of 95%, we calculated the required sample size to be 864. we considered this number to be sufficient to describe the spectrum of skin diseases in patients attending the hiv clinic with a high level of precision. during the 6-month study period, 970 patients were screened, of which 123 had skin disease and thus they were invited to participate in the study. the final sample comprised 100 patients who provided informed consent. procedure a data collection sheet was completed by the medical officer (author s.c.) working at the hiv clinic for all participants who signed informed consent. data recorded included demographics, body mass index (bmi), recent (within the preceding 6 months) cd4+ cell count (recorded as either < 200 cells/µl or ≥ 200 cells/µl), viral load (recorded as undetectable or detectable) and art regimen (type and duration). antiretroviral therapy was defined as a regimen consisting of two nucleoside reverse transcriptase inhibitors (nrtis) in combination with a non-nucleoside reverse transcriptase inhibitor (nnrti) or a ritonavir-boosted protease inhibitor (pi). the medical officer recorded a description of cutaneous disease found on routine clinical examination. before the study commenced, the medical officer was trained to describe the duration, distribution and morphology of skin lesions of all participants in a standardised format. where the dermatological diagnosis remained unclear after clinical examination, consent was obtained for taking the clinical photographs of skin lesions. additional consent was obtained for the publication of clinical photographs. clinical photographs were taken for a total of 45 participants. new cases were discussed weekly with dermatologists based at tygerberg hospital to verify the diagnosis of all skin conditions. to assist with diagnosis and management of the patient, skin biopsies were performed when it was clinically indicated. the spectrum of skin diseases was broadly grouped into either infectious or non-infectious dermatoses. infectious dermatoses were further divided into bacterial, viral and fungal infections and insect bite reactions. dermatoses in the non-infectious group were separated into inflammatory, neoplastic, drug-related and other conditions. these characteristics were grouped based on clinically significant cut-off points and published data.14,15,16,17,18,19,20 data analysis continuous variables were summarised as mean and standard deviation (s.d.), whilst nominal variables were summarised as counts and percentages. pearson’s chi-square test was used to assess the possible association between skin disease category and patient demographics (gender and ethnicity) or hiv disease characteristics (cd4+ cell count, viral load and duration of art). data were analysed using stata (version 15; stata corp., college station, texas, usa) and statistical significance was set at p < 0.05. ethical consideration ethical approval was obtained from the health research ethics committee of stellenbosch university (n16/05/071). the study was also approved by the management of karl bremer hospital. participation was voluntary and all participants provided written informed consent to take part in the study. all data were anonymised to ensure the privacy and confidentiality of participants’ personal information and each participant was assigned a unique identifier. results we observed mucocutaneous disease in 123 patients out of a total of 970 who were screened, which is equivalent to a prevalence of 12.7% (95% ci 0.11–0.15). the demographic and clinical characteristics of the sample (n = 100 patients who provided informed consent) are summarised in table 1. the mean age (± s.d.) was 40.4 (± 10.1) years. there were slightly more women (59%) than men (41%). most participants were black people (75%), had a cd4+ cell count ≥ 200 cells/µl (69%) and were on art (74%). of those participants on art (n = 74), most (n = 65; 87.8%) were on an nnrti-based regimen, whilst nine (12.2%) participants were on a pi-based regimen. most patients (n = 45; 60.8%) had been on art for more than a year. one-third of the sample (35%) had a normal weight (bmi 18.5–24), 24% were overweight (bmi 25–30) and 14% were obese (bmi > 30). very few patients (7%) were classified as being underweight (bmi < 18.5). we were unable to calculate the bmi for 20 patients because of missing weight or height statistics in patient folders. table 1: demographic and clinical characteristics of human immunodeficiency virus-positive patients with skin disease (n = 100). a total of 121 dermatoses were identified in 100 study participants. the number of participants who presented with dual and triple pathology was 20 and 1, respectively. the spectrum of dermatoses in this sample is summarised in table 2. table 2: spectrum of dermatoses recorded for human immunodeficiency virus-positive patients (n = 100). infectious dermatoses affected half of the participants in the sample. fungal infections were the most prevalent (n = 28, 28.0%), followed by viral (n = 14, 14.0%) and bacterial infections (n = 8, 8.0%). fungal infections included oral candidiasis (n = 6), pityriasis versicolor (n = 4), intertriginous candidiasis (n = 1) and a spectrum of dermatophytosis (n = 17), namely, tinea corporis (n = 8), onychomycosis (n = 5) (figure 1), tinea pedis (n = 3) and tinea faciei (n = 1). overall, tinea corporis (8.0%) and oral candidiasis (6.0%) were the most prevalent of all infectious conditions. bacterial infections included ecthyma (n = 3), folliculitis (n = 2), cellulitis (n = 1), impetigo (n = 1) and secondary syphilis (n = 1), whilst viral infections included condylomata acuminata (n = 4), herpes zoster (n = 2), molluscum contagiosum (n = 2), orolabial herpes simplex (n = 2), anogenital herpes simplex (n = 1), generalised verrucosis (n = 1), oral hairy leukoplakia (n = 1) and viral exanthem (n = 1). figure 1: proximal onychomycosis affecting four digits. non-infectious dermatoses affected 71.0% of the sample. of the non-infectious dermatoses, inflammatory dermatoses were the most common (n = 50) and included pruritic papular eruption (ppe) (n = 20) (figure 2), seborrheic dermatitis (n = 6), angular cheilitis (n = 4), atopic dermatitis (n = 4), contact dermatitis (n = 4), insect bite reaction (grouped urticarial papules on exposed sites such as the head, neck and distal extremities) (n = 4), dermatitis not otherwise specified (n = 3), chronic paronychia (n = 2), eosinophilic folliculitis (n = 2) and acne vulgaris (n = 1). neoplastic conditions (n = 5) included actinic keratosis (n = 1), anal squamous cell carcinoma in situ (n = 1), basal cell carcinoma (n = 1) (figure 3), cutaneous squamous cell carcinoma (n = 1) and seborrheic keratosis (n = 1). drug-related dermatoses (n = 2) included steroid-induced rosacea (n = 1) and zidovudine-induced mucocutaneous hyperpigmentation (n = 1). other dermatoses (n = 14) included post-inflammatory hyperpigmentation (n = 4), xerosis (n = 4), keloids (n = 3), vitiligo (n = 2) and palmoplantar keratoderma (n = 1). figure 2: pruritic papular eruption with post-inflammatory hyperpigmentation. figure 3: pigmented basal cell carcinoma involving the medial canthus. pearson’s chi-square test showed no significant association between skin disease category (infectious and non-infectious diseases) and patient demographics (gender, p = 0.36; ethnicity, p = 0.31; bmi, p = 0.61) or hiv disease characteristics (cd4+ count, p = 0.82; viral load [vl], p = 0.32; art, p = 0.21; duration of art, p = 0.28). discussion this study contributes novel information regarding the prevalence and spectrum of mucocutaneous diseases at a district-level hospital in south africa. we estimated the prevalence of hiv-associated mucocutaneous disease to be 12.7%. our search of the literature revealed that there appears to be a lack of south african and district-level data with which we can compare our findings. nevertheless, our estimate is far below that recorded in other literature. cross-sectional studies conducted in the art era at specialist centres in china and south india recorded mucocutaneous disease in 62.9% and 69.41% of hiv-infected patients, respectively.14,21 this difference in prevalence estimates between specialist and district-level centres may be because of the impact of art on mucocutaneous disease in the study population. previous studies have found mucocutaneous disease to be less prevalent in patients who had received art compared with those without art.14,17 calista et al. highlighted that a change in both the prevalence and type of cutaneous disorders is likely to be observed with the introduction of art.17 this effect is likely because of immune restoration following sustained art. kore et al. found that the proportion of hiv-infected patients having dermatoses increased with immunological worsening and that the average number of skin disorders per patient was significantly higher in patients with a cd4+ cell count less than 200 cells/µl.20 although we did not record the clinical stage of our study participants, the demographic data suggest a recovering immune profile in our study population. most of our participants were taking art (74%) and had a cd4+ cell count above 200 (69%) at the time of the study. non-infectious dermatoses were the most common group of mucocutaneous manifestations in our study. inflammatory dermatoses were the predominant non-infectious dermatoses. inflammatory dermatoses in the setting of hiv tend to be chronic, atypical and difficult to treat and, therefore, frequently warrant referral to specialist centres where the prevalence might be overestimated. this could explain why inflammatory dermatoses related to hiv (namely, seborrheic dermatitis, psoriasis, drug eruptions and erythroderma) were the most common dermatologic cause of admission in a south african study performed in the pre-art era.9 however, studies in the art era have persistently shown the spectrum of skin diseases shift from infectious to non-infectious dermatoses.17,18,22 in our study, the increased prevalence of inflammatory dermatoses was mainly attributed to ppe (20%) and seborrheic dermatitis (6%). the reported prevalence of ppe in the literature ranges from 11% to 46%.5,23,24 two ugandan studies have suggested that ppe may be related to an exaggerated immunological reaction to arthropod bites.23,25 the prevalence of ppe in our study may be attributed to its chronicity, its association with increased levels of immunosuppression (one-third of our study population had a cd4+ cell count below 200) and poor socio-economic conditions, which predispose patients to arthropod bites.5,18,21 seborrheic dermatitis (6%) was the second most common inflammatory dermatosis in our study. the prevalence of seborrheic dermatitis has been reported to be 40% in hiv-positive patients and as high as 80% in acquired immunodeficiency syndrome (aids) patients in comparison with 3% in the hiv-negative population.26 studies from china, india and the united states of america performed in the art era have reported low prevalence rates of seborrheic dermatitis at 1.21%, 1.8% and 10.6%, respectively.14,21,27 likewise, the prevalence of seborrheic dermatitis in our study is similar to that of the hiv-negative population and may be attributed to the influence of art. neoplastic conditions were recorded in 5% of the study population. since the introduction of art, the incidence of aids-defining cancers (kaposi’s sarcoma, non-hodgkin’s lymphoma and cervical cancer) has decreased, whereas the relative frequency of non-aids-defining cancers has increased.28 basal cell carcinoma and squamous cell carcinoma comprise the keratinocyte carcinomas and are the most common malignancies worldwide in both the general population and plwh.5,29 the spectrum of neoplastic conditions observed in this study comprised benign epidermal neoplasms and keratinocyte carcinomas. condylomata acuminata were observed in four patients, one of whom had concomitant anal squamous cell carcinoma in situ. anal cancer (a human papillomavirus-related cancer) has been associated with the duration of both immunodeficiency and viral replication.29 as a result of increased life expectancy, cancer-specific screening programmes in hiv-infected patients should be extended to include non-aids-defining cancers such as anal cancer and keratinocyte cancer. drug-related dermatoses were observed in 2% of our study population and included steroid-induced rosacea and zidovudine (azt)-induced mucocutaneous hyperpigmentation. in this study, no patients presented with severe cutaneous adverse drug reactions such as steven–johnson syndrome, toxic epidermal necrolysis or drug hypersensitivity syndrome. international studies in the art era have reported a prevalence of drug eruptions between 10% and 17%.14,17,18 a study performed in a tertiary hospital in cape town, south africa, found that most severe skin reactions resulting in admission occurred during the first 2 months after combination art initiation. nevirapine and pregnancy are also known to be strongly associated with severe skin reactions.13 most of the participants receiving art had been on treatment for more than 1 year and all those receiving an nnrti-based regimen were taking efavirenz and not nevirapine. this could explain the absence of severe cutaneous adverse drug reactions in our study. none of the female participants was pregnant at the time of the current study. lastly, patients presenting with severe skin reactions mostly necessitate inpatient management and referral to tertiary institutions and may not present directly to a district-level health facility. infectious dermatoses were observed in half of our study population and were encountered less frequently than non-infectious dermatoses. tinea corporis (8%) and oral candidiasis (6%) were the two most common conditions in the infectious dermatoses group. dermatophytosis (including tinea corporis, tinea faciei, tinea pedis and onychomycosis) is common in the setting of hiv and tends to occur as an early manifestation of immunosuppression at higher cd4+ cell counts.30 dermatophytosis was recorded in 17% of our patients, which is in line with other studies performed in the art era reporting a prevalence between 11.9% and 17.6%.16,20,21 although oral candidiasis was one of the most common dermatoses recorded in our study, its prevalence is low compared with previous studies. the incidence of candidiasis has been shown to increase with a cd4+ cell count below 200.14,15 kore et al. and han et al. demonstrated a significant decline in candidiasis in their study population after the initiation of art (20.8% vs. 11.5% and 64.04% vs. 16.6%).14,20 the majority of participants in our study were on art and had a cd4+ count above 200. these factors, together with an increased awareness and early treatment of oral candidiasis, could likely explain its low prevalence. the mean age of our study participants was 40 years, which is approximately 6 years older than that previously recorded in south african studies evaluating cutaneous manifestations of hiv in the pre-art era.9,10 in general, plwh in the art era are increasingly older and have a near-normal life expectancy.5,31 our findings are similar to those in a recent study performed at a specialised tb hospital in the western cape, which reported a mean age of 37 years in patients co-infected with tb and hiv.12 historically, art eligibility criteria in south africa allowed for pregnant women to be initiated on art at higher cd4+ cell counts compared with the general adult hiv-positive population.32 the routine surveillance of hiv during antenatal care may explain the increased proportion of females in this study as maternal services form an important referral pathway for art services. our study has some limitations. firstly, we emphasise that the accurate diagnoses of dermatoses can be challenging in hiv-positive patients because of the atypical presentation of skin disorders. secondly, because of the cross-sectional nature of the study, the true prevalence of skin conditions in this study population may be underestimated. long-term follow-up studies, as opposed to cross-sectional studies, are required to understand the true lifetime prevalence and spectrum of dermatoses in hiv-positive patients in the art era. thirdly, there could be an underestimation of dermatoses because none of the patients were examined by a dermatologist. having a dermatologist see the patients primarily or using clinical photographs to verify the diagnosis of all skin conditions would have provided a more accurate presentation of dermatoses. fourthly, our findings could be limited by self-report bias. patients may be reluctant to mention minor skin complaints that do not interfere with daily functioning or cause cosmetic concern to avoid unnecessary time spent at the clinic. conclusion this study provides valuable scientific data on the prevalence and spectrum of mucocutaneous disease seen in plwh attending a district-level hospital in south africa. these findings could guide the development of training opportunities for primary healthcare workers to better manage the most prevalent hiv-associated dermatoses. this, in turn, may help to decentralise health services and improve the quality of care at primary and district levels. more studies performed outside tertiary-level hospitals are needed to provide insights into the true spectrum and prevalence of dermatoses affecting plwh in the art era. acknowledgements competing interests the authors declare that they have no competing interests. authors’ contributions s.c. and s.m.h.k. conceptualised and designed the study. s.c. was responsible for data collection and drafting of the manuscript. r.s. contributed to the statistical analysis and interpretation. s.m.h.k., h.f.j., k.m., j.d.w. and w.i.v. provided critical revisions of content. all authors reviewed the draft versions and approved the final version of the manuscript. funding information this study was funded by the john moche research grant, dermatology society of south africa. data availability statement the authors confirm that the data supporting the findings of this study are available within the article. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references coldiron bm, bergstresser pr. prevalence and clinical spectrum of skin disease in patients infected with human immunodeficiency virus. 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[cited 2018 nov 05]. available from: http://www.unaids.org/sites/default/files/media_asset/unaids-data-2018_en.pdf abdulla eak, jordaan hf. skin diseases in human immunodeficiency virus infected patients. m. med (derm) [dissertation]. tygerberg academic hospital, university of stellenbosch, 1999. (unpublished data). mosam a, irusen em, kagoro h, aboobaker j, dlova nc. the impact of human immunodeficiency virus/acquired immunodeficiency syndrome (hiv/aids) on skin disease in kwazulu-natal, south africa. int j dermatol. 2004;43(10):782–783. https://doi.org/10.1111/j.1365-4632.2004.02187.x morar n, dlova nc, mosam a, aboobaker j. cutaneous manifestations of hiv in kwazulu natal, south africa. int j dermatol. 2006;45(8):1006–1007. https://doi.org/10.1111/j.1365-4632.2006.02753.x lehloenya rj, kgokolo m. clinical presentations of severe cutaneous drug reactions in hiv-infected africans. dermatol clin. 2014;32(2):227–235. https://doi.org/10.1016/j.det.2013.11.004 mclachlan i, visser wi, jordaan hf. skin conditions in a south african tuberculosis hospital: prevalence, description, and possible associations. int j dermatol. 2016;55(11):1234–1241. https://doi.org/10.1111/ijd.13355 stewart a, lehloenya r, boulle a, de waal r, maartens g, cohen k. severe antiretroviral-associated skin reactions in south african patients: a case series and case-control analysis. pharmacoepidemiol drug saf. 2016;25(11):1313–1319. https://doi.org/10.1002/pds.4067 han j, lun wh, meng zh, et al. mucocutaneous manifestations of hiv-infected patients in the era of haart in guangxi zhuang autonomous region, china. j eur acad dermatol venereol. 2013;27(3):376–382. https://doi.org/10.1111/j.1468-3083.2011.04429.x fernandes ms, bhat rm. spectrum of mucocutaneous manifestations in human immunodeficiency virus-infected patients and its correlation with cd4 lymphocyte count. int j std aids. 2015;26(6):414–419. https://doi.org/10.1177/0956462414543121 boushab bm, malick fall fz, ould cheikh mohamed vadel tk, et al. mucocutaneous manifestations in human immunodeficiency virus (hiv)-infected patients in nouakchott, mauritania. int j dermatol. 2017;56(12):1421–1424. https://doi.org/10.1111/ijd.13737 calista d, morri m, stagno a, boschini a. changing morbidity of cutaneous diseases in patients with hiv after the introduction of highly active antiretroviral therapy including a protease inhibitor. am j clin dermatol. 2002;3(1):59–62. https://doi.org/10.2165/00128071-200203010-00006 goh bk, chan rk, sen p, et al. spectrum of skin disorders in human immunodeficiency virus-infected patients in singapore and the relationship to cd4 lymphocyte counts. int j dermatol. 2007;46(7):695–699. https://doi.org/10.1111/j.1365-4632.2007.03164.x mbuagbaw j, eyong i, alemnji g, mpoudi n, same-ekobo a. patterns of skin manifestations and their relationships with cd4 counts among hiv/aids patients in cameroon. int j dermatol. 2006;45(3):280–284. https://doi.org/10.1111/j.1365-4632.2004.02529.x kore sd, kanwar aj, vinay k, wanchu a. pattern of mucocutaneous manifestations in human immunodeficiency virus-positive patients in north india. indian j sex transm dis. 2013;34(1):19–24. https://doi.org/10.4103/0253-7184.112865 prabhakaran n, jaisankar tj, hamide a, malathi m, kumari r, thappa dm. effect of antiretroviral therapy on mucocutaneous manifestations among human immunodeficiency virus-infected patients in a tertiary care centre in south india. indian j sex transm dis. 2015;36(2):166–173. https://doi.org/10.4103/0253-7184.167160 punyaratabandhu p, prasithsirikul w, jirachanakul p. skin manifestation of thai hiv infected patients in haart era. j med assoc thai. 2012;95(4):497–504. resneck js, van beek m, furmanski l, et al. etiology of pruritic papular eruption with hiv infection in uganda. jama. 2004;292(21):2614–2621. https://doi.org/10.1001/jama.292.21.2614 boonchai w, laohasrisakul r, manonukul j, kulthanan k. pruritic papular eruption in hiv seropositive patients: a cutaneous marker for immunosuppression. int j dermatol. 1999;38(5):348–350. https://doi.org/10.1046/j.1365-4362.1999.00694.x chua sl, amerson eh, leslie ks, et al. factors associated with pruritic papular eruption of human immunodeficiency virus infection in the antiretroviral therapy era. br j dermatol. 2014;170(4):832–839. https://doi.org/10.1111/bjd.12721 cedeno-laurent f, gómez-flores m, mendez n, et al. new insights into hiv-1-primary skin disorders. j int aids soc. 2011;14(1):5. https://doi.org/10.1186/1758-2652-14-5 zancanaro pcq, mcgirt ly, mamelak aj, nguyen rhn, martins cr. cutaneous manifestations of hiv in the era of highly active antiretroviral therapy: an institutional urban clinic experience. j am acad dermatol. 2006;54(4):581–588. https://doi.org/10.1016/j.jaad.2005.12.030 guiguet m, boué f, cadranel j, lang jm, rosenthal e, costagliola d. effect of immunodeficiency, hiv viral load, and antiretroviral therapy on the risk of individual malignancies (fhdh-anrs co4): a prospective cohort study. lancet oncol. 2009;10(12):1152–1159. https://doi.org/10.1016/s1470-2045(09)70282-7 cameron mc, lee e, hibler bp, et al. basal cell carcinoma epidemiology; pathophysiology; clinical and histological subtypes; and disease associations. j am acad dermatol. 2019;80(2):303–317. https://doi.org/10.1016/j.jaad.2018.03.060 vasudevan b, sagar a, bahal a, mohanty ap. cutaneous manifestations of hiv – a detailed study of morphological variants, markers of advanced disease, and the changing spectrum. armed forces med j india. 2012;68(1):20–27. https://doi.org/10.1016/s0377-1237(11)60122-6 johnson lf, mossong j, dorrington re, et al. life expectancies of south african adults starting antiretroviral treatment: collaborative analysis of cohort studies. plos med. 2013;10(4):e1001418. https://doi.org/10.1371/journal.pmed.1001418 stinson k, goemaere e, coetzee d, et al. cohort profile: the khayelitsha antiretroviral programme, cape town, south africa. int j epidemiol. 2017;46(2):e21. https://doi.org/10.1093/ije/dyw057 from the editor when i look back and take stock of what has happened over the last year the highlights include the success of the dira sengwe conference in durban; the commencement of antiretroviral therapy by zackie achmat and his nomination for the nobel peace prize; the emergence of meaningful corporate antiretroviral rollouts; the lowering of many antiretroviral prices to not-for-profit levels, and the government's vacillation over the provision of antiretrovirals (arvs), hastily followed by their announcement of an arv rollout planned to begin at pilot sites early next year. at society level, the increase in membership and initiatives has been harci to keep pace with. from 300 members in april 2000 we have burgeoned to nearly 6 000 members, more than half of whom have successfully completed the society/foundation for professional development hiv management course. in addition, about two dozen people have also sar the examinarions for the colleges of medicine's diploma in hiv management. the society has employed a database manager to capture not only members' contact details, but also their continuing medical educarional achievements 50 that maximum use can be made of the darabase as a referral tool and doctor network of trained and experienced practirioners. the governmenr would be well advised to partner with rhe sociery in its rollout and make use of rhe sociery's rrained hiv/aids marers and mulriaisciplinary experts, some wirh 15 years' experience. access programmes have always been embraced by rhe society in order to meet the organisation's core objective of providing state-of-the-art medical care lo those infected and affected by hiv/aids. recently the society entered into an agreement with gsk's global access programme to obtain gsk anriretrovirals for members' unfunded and 'under-funded' patients whose hiv medical aid benefits are insufficient to fund 12 months of trearment. to date, approximately 200 members have registered on the programme and as a result, a significanr number of patienrs are benefiring from far more affordable treatmenr. for more details about the programme, ring the society's new special projects manager, mrs berry prentice, on (011) 4535066. i would like to take this opportuniry to recognise the voluntary work undertaken by many members of the society involved in a large variety of humanitarian organisations and programmes. they give selflessly of their time and skills in an to attempr to combat the ravages of hiv/aids in our country. let's hope their generous efforts will be assisted by the government's programme and planned rollout of antiretrovirals. on a final note, i would like to wish you all a peaceful and restful holiday season. des martin editor, southern african journal ofhivmedicine president, southern africon hiv clinicians society abstract background methods results discussion acknowledgements references about the author(s) philasande mkoko department of medicine, division of cardiology, faculty of health sciences, university of cape town, cape town, south africa department of medicine, dora nginza hospital, port elizabeth, south africa jessica du preez department of medicine, dora nginza hospital, port elizabeth, south africa senlika naidoo department of medicine, dora nginza hospital, port elizabeth, south africa department of medicine, livingstone hospital, port elizabeth, south africa citation mkoko p, du preez j, naidoo s. intracranial pressure management in patients with human immunodeficiency virus-associated cryptococcal meningitis in a resource-constrained setting. s afr j hiv med. 2020;21(1), a1171. https://doi.org/10.4102/sajhivmed.v21i1.1171 original research intracranial pressure management in patients with human immunodeficiency virus-associated cryptococcal meningitis in a resource-constrained setting philasande mkoko, jessica du preez, senlika naidoo received: 25 sept. 2020; accepted: 20 oct. 2020; published: 18 dec. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: cryptococcal meningitis (ccm) is the leading cause of meningitis in people living with hiv (plwh) in sub-saharan africa (ssa). the mortality and morbidity associated with ccm remain high. combination of antifungal therapy, diligent management of intracranial pressure (ip) and the correct timing of the introduction of antiretroviral therapy (art) minimise the risk of mortality and morbidity. the absence of spinal manometers in many healthcare centres in ssa challenges the accurate measurement of cerebrospinal fluid (csf) pressure and its control. objectives: we hypothesised that four lumbar punctures (lps) in the first week of the diagnosis and treatment of ccm would reduce ip such that in-hospital mortality and morbidity of hiv-associated ccm (hiv/ccm) would be significantly reduced. methods: we conducted a retrospective study to assess whether receipt of four or more lps in the first week of the diagnosis and treatment with combination antifungal therapy of hiv/ccm would be associated with the reduction of in-hospital mortality in adult plwh. results: from 01 january 2016 to 31 december 2016, 116 adult patients were admitted to the dora nginza district hospital in zwide, port elizabeth, south africa. after exclusion of 11 (two were younger than 18 years, two had missing hospital records and seven demised or left the hospital before 7 days of hospitalisation), 105 patients were included in the analysis. the mean age was 39.4 (standard deviation [s.d.] ± 9.7) years, 64.8% were male. all were plwh. a total of 52.4% had defaulted art and 25.7% were art naïve. forty-three patients received four or more lps (mean = 4.58 [± 0.96]) in the first week of hospitalisation with an associated in-hospital mortality of 11.6% (n = 5/43) compared with 62 patients who received less than four lps (mean = 2.18 [± 0.80]) with an in-hospital mortality of 29% (n = 18/62) and a relative risk of 0.80 (95% ci, 0.66–0.97), p = 0.034. conclusion: in the current study of adult plwh presenting to hospital with hiv/ccm, four or more lps in the first 7 days following admission and the initiation of treatment were associated with a 17.4% reduction in absolute risk of in-hospital mortality and a 20% reduction in relative risk of in-hospital mortality. this mortality difference was noted in patients who survived and were in hospital at the time of the 7-day study census and persisted until the time of hospital discharge. keywords: cryptococcal meningitis; hiv; antifungal therapy; antiretroviral therapy; in-hospital mortality; adult plwh. background cryptococcal meningitis (ccm) accounts for up to 60% of meningitis in adult persons living with hiv (plwh) in many african countries including south africa (sa).1,2 those with cd4 cell counts < 100 cells/µl are particularly at risk.3 mortality is high – reaching levels of 70% in sub-saharan africa (ssa).3 altered mental state at presentation, older age, high cerebrospinal fluid (csf) fungal burden and high peripheral white cell count predict mortality in antiretroviral therapy (art) naïve patients.4 although the availability of art has led to a decrease in hiv-associated ccm (hiv/ccm) in high-income countries,5 the condition remains responsible for 10% – 20% of hiv-related deaths in ssa.6 notwithstanding improved access to art, many remain outside of care or on failing treatment and at risk of opportunistic disease.7 the initial (induction phase) management of hiv/ccm requires the following: (1) combination antifungal therapy including iv amphotericin b and oral flucytosine (first week only) and high-dose oral fluconazole 1200 mg daily (second week), after that an 8-week consolidation phase of oral fluconazole 800 mg daily, (2) control of raised intracranial pressure (rip) with therapeutic lumbar punctures (lps) to maintain the ‘opening-pressure’ (csf-op) at < 25 cm of water and (3) minimising the risk of immune reconstitution inflammatory syndrome (iris) by delaying the initiation of art until 4 to 6 weeks after the start of antifungal therapy.8,9,10,11,12 in the absence of a spinal manometer, the sa guidelines for the prevention, diagnosis and management of ccm recommend performing an lp to remove 20 ml – 30 ml of csf if the symptoms and signs of rip are present.12 however, in clinical practise only 23% – 30% of ccm patients with signs and symptoms receive ‘therapeutic’ lps.13,14 a symptom guided approach has the potential to miss asymptomatic patients who might benefit from therapeutic lps. we hypothesised that four or more lps in the first 7 days of treatment could facilitate csf drainage and reduce in-hospital mortality in plwh and hiv/ccm in a resource constrained setting where there are no spinal manometers. we, therefore, conducted a single centre retrospective cohort study to determine the impact on in-hospital mortality of four or more lps in the first 7 days of antifungal therapy compared with plwh/ccm who received fewer than four lps. methods study design the study was designed as a retrospective cohort review of plwh/ccm admitted to the department of medicine at the dora nginza hospital from 01 january 2016 to 31 december 2016. the dora nginza hospital is a district hospital located in the zwide township of the nelson mandela bay municipality (port elizabeth), sa. the nelson mandela bay region has a population of 1 152 115 and an unemployment rate of 36.6%.15 the internal medicine department consists of a 120-bed unit without access to intensive or high care services and with limited access to radiological imaging apart from plain chest radiography. study population clinical notes, discharge summaries and death notification registries were reviewed to identify patients who received a primary or secondary diagnosis of ccm. data collection a standardised data collection form was prepared. this included patient demographic details, comorbidities, history of previous ccm, data of concurrent tuberculosis (tb) and details of the index admission. patients’ folders were checked for the results of therapeutic lps and to document the indications for the procedure. the national health laboratory services (nhls) computer records were accessed for admission bloods, cd4 count, hiv viral load (vl) and csf results. identifying patient material was anonymised at the time of the collection and storage of data. statistical analysis continuous variables are reported as mean (± standard deviation, [s.d.]) when normally distributed and as median (interquartile range, iqr) when not normally distributed. discrete data are presented as number and percentages. pearson’s chi-square test and corresponding 95% confidence intervals (ci) were used to calculate the mortality difference between the study and comparator groups. a p-value of < 0.05 defined significance. patients who died or left hospital within the first 7 days were excluded from the mortality analysis. statistical analyses were performed by using ibm spss statistics for macintosh version 24.0. ethical consideration approval to conduct the study was obtained from walter sisulu university human research committee. ethical clearance number: 027/2018. results clinical characteristics of the study population from 01 january 2016 to 31 december 2016, a total of 116 patients received a diagnosis of ccm. after exclusion of 11 (two were younger than 18 years, two had missing hospital files/records and seven demised or left the hospital before 7 days of hospitalisation), 105 patients were available for study analysis (figure 1). figure 1: flow diagram showing patients enrollment in the study. the mean age of patients was 39.4 (s.d. ± 9.7) years. a total of 65.2% were male. all the patients were plwh and had a median cd4 count = 37 (iqr, 13–77) cells/µl. human immunodeficiency virus infection was newly diagnosed on the index admission in 25.7%. default from previous art was recorded in 52.4% of patients (table 1). table 1: baseline characteristics. a total of 17.1% of patients gave a history of previous ccm. headache was the most prevalent presenting symptom (91.4%) followed by a low glasgow coma scale (32.4%) (table 2). a total of 9.5% of patients had a focal neurological deficit, namely an abducent (cranial nerve 6) palsy, suggesting possible rip at presentation. the diagnosis of ccm was based on a positive csf-cryptococcal antigen (crag) in all patients, a positive csf india ink in 80% and a positive csf culture for cryptococcus neoformans in 94.3%. one hundred and three (n = 103) patients received local guideline-based therapy consisting of a combination of amphotericin b and fluconazole. two patients did not receive fluconazole: one had acute hepatitis b and the other, a drug-induced liver injury (dili) resulting from tb therapy. table 2: clinical features and cerebrospinal fluid findings. therapeutic lumbar punctures and hospital mortality a total of 496 lps were performed. each patient received a mean of 4.62 (s.d. ± 2.30) therapeutic lps (all patients). the mean duration of hospitalisation of the entire group was 19.4 (s.d. ± 8.3) days. a total of n = 23/105 (21.9%) patients died during the index hospitalisation. patients who received ≥ 4 lps in the first 7 days had an in-hospital mortality rate of 11.6% (n = 5/43), whereas those with < 4 lps in the first 7 days had in-hospital mortality of 29% (n = 18/62). this represents a 17.4% absolute risk reduction of in-hospital mortality and a relative risk of 0.80 (95% ci, 0.66–0.97, p = 0.034), namely a 20% relative risk reduction of in-hospital mortality (figures 2 and 3). patients who received four or more lps in the first 7 days received a mean of 4.58 (s.d. ± 0.96) lps in the first week of treatment. figure 2: clustered bar chart depicting in-hospital mortality and receipt of ≥ 4 lumbar punctures versus < 4 lumbar punctures in the first 7 days of combination antifungal therapy. figure 3: kaplan-meier estimate of survival amongst patients who received four or more lumbar punctures in the first 7 days of combination antifungal therapy compared with those who received less than four lumbar punctures in the first 7 days of combination antifungal therapy. discussion in this retrospective study of patients with hiv/ccm, receipt of four more lps in the first week of diagnosis and treatment was associated with reduced in-hospital mortality. these findings inform the recorded 98.2% compliance of hospital staff with local guideline-based treatment of ccm with combination antifungal therapy. raised intracranial pressure develops in most plwh with hiv/ccm and portends a poor prognosis if not adequately treated.16 lumbar punctures and csf drainage have been shown to be effective in managing ccm related rip.17 alternatives such as acetazolamide or corticosteroids have no role in the management of hiv/ccm.18,19 despite the increased prevalence of rip, therapeutic lps are seldom instituted even when symptoms and signs of rip are present.13,16 in a clinical audit by adeyemi and ross, only 23% of patients with ccm related headaches received therapeutic lps despite 82% of patients receiving analgesia for their pain.13 similarly, rolfes et al. report that only 30% of the 248 patients in their cohort received therapeutic lps.14 this was despite the fact that therapeutic lps were associated with a 69% improvement in survival.14 in our study we report a 17.4% absolute risk reduction of in-hospital mortality following intervention with four or more lps in the week of diagnosis and treatment. spinal manometers are recommended for the measurement of rip. in resource limited settings spinal manometers are seldom available. instead, guidelines recommend using tubing from intravenous giving-sets.20 a small single centre study by meda and colleagues has confirmed a correlation between spinal manometer and intravenous giving set use in determining csf-op in the setting of ccm. however, this study consisted of only 35 subjects and reported technical shortcomings in the reliability of the measurements.21 in a recent study, mogambery et al. found that the use of an intravenous giving set considerably underestimated csf-op when compared with that of a spinal manometer, mean 16.2 (s.d. ± 10) cm h2o versus 22.7 (s.d ± 10) cm h2o, p < 0.001.22 a schedule of at least four lps with csf drainage of 20 ml – 30 ml12 in the first week of diagnosis and treatment could be life-saving in settings with no access to spinal manometers. the optimal management of ccm consists of a triad of (1) combination antifungal therapy, (2) intracranial pressure (ip) management with csf drainage and (3) immune reconstitution with art after completion of 4 to 6 weeks of combination antifungal therapy to avoid ccm-iris.12 this study provides evidence that rip in hiv/ccm can be managed without recourse to spinal manometers. the limitations of this study include it’s retrospective and single centres design. also, we do not have data on the volume of csf removed and survival beyond the index hospitalisation. in conclusion, this study shows that plwh/ccm can be effectively managed in centres with limited access to spinal manometers. we have shown that ≥ four lps with csf drainage in the first 7 days of hospitalisation improves early survival. acknowledgements we would like to thank professor graeme meintjes for his insight and advice. competing interests the authors have declared that no competing interest exists. authors’ contributions p.m. designed the study and collected the data. j.d. and s.n. collected the data. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability statement data are available on request. disclaimer data sharing is not applicable to this article as no new data were created or analysed in this study. references durski kn, kuntz km, yasukawa k, virnig ba, meya db, boulware dr. cost-effective diagnostic checklists for meningitis in resource-limited 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18]. available from: https://www.statssa.gov.za/?page_id=1021&id=nelson-mandela-bay-municipality graybill jr, sobel j, saag m, et al. diagnosis and management of increased intracranial pressure in patients with aids and cryptococcal meningitis. clin infect dis. 2000;30(1):47–54. https://doi.org/10.1086/313603 sun h-y, hung c-c, chang s-c. management of cryptococcal meningitis with extremely high intracranial pressure in hiv-infected patients. clin infect dis. 2004;38(12):1790–1792. https://doi.org/10.1086/421272 day j, imran d, ganiem ar, et al. cryptodex: a randomised, double-blind, placebo-controlled phase iii trial of adjunctive dexamethasone in hiv-infected adults with cryptococcal meningitis: study protocol for a randomised control trial. trials. 2014;15:441. https://doi.org/10.1186/1745-6215-15-441 beardsley j, wolbers m, kibengo fm, et al. adjunctive dexamethasone in hiv-associated cryptococcal meningitis. n engl j med. 2016;374(6):542–554. https://doi.org/10.1056/nejmoa1509024 abassi m, boulware dr, rhein j. cryptococcal meningitis: diagnosis and management update. curr trop med rep. 2015;2(2):90–99. https://doi.org/10.1007/s40475-015-0046-y meda j, kalluvya s, downs ja, et al. cryptococcal meningitis management in tanzania with strict schedule of serial lumber punctures using intravenous tubing sets: an operational research study. j acquir immune defic syndr. 2014;66(2):e31–e36. https://doi.org/10.1097/qai.0000000000000147 mogambery ta, moodley a, connolly c. is the intravenous giving set a reliable alternative to the spinal manometer in measuring cerebrospinal fluid opening pressure? s afr med j. 2018;108(10):865–869. https://doi.org/10.7196/samj.2018.v108i10.13176 southern african mv clinicians society clinical guidelines antiretroviral therapy in adults june 2002 version 3. classes of antiretrovlral agents and their mechanisms of action the sour rifq afr,ca jour al o~ hi meoici 'f 2. standard of care maximally suppressive antiretroviral regimens (highly active antiretroviral therapy haard should be used whenever possible in order to obtain the best clinical results and to prevent resistance. • single-drug regimens (monotherapy) monotherapy should not be used in the treotment of hiv infection; however, it continues to play a very important role in the prevention of mother-to-child transmission [mtcd. • dual-drug regimens dual therapy is moderately effective, but is unlikely to produce long-term durable benefit in most patients. it is not the standard of care, but is considerably better than no therapy and should be considered in patients unable to afford haart. this should only be applied to patients who have already developed aids. in this setting, dual 'herapy is better than no therapy; otherwise resistance is a major concern if dual nucleoside therapy is prescribed to asymptomatic patients. the efficacy of two-drug combinations [dual therapy) is greater than that of monotherapy, potentially achieving a 1.5 1.8 log reduction in viral load. note that triple combinations are the standard of care. • triple combinations the combination of three synergistic antiretroviral agents remains the standard of care; substantial reductions in medication prices continue to make triple-drug regimens more affordable. currently available antiretroviral agents [table i) inhibit one of two key viral enzymes required by hiv for intracellular viral replication: • reverse transcriptase, which is essential for completion of the early stages of hiv replication, and • protease, which is required for the assembly and maturation of fully in'eetious viral progeny. 1. goals of therapy the magnitude of hiv infection in southern africa and the number of impoverished people who desperately need antiretroviral therapy [ard but will never receive it is overwhelming, and unparalleled in the history of infectious diseases. lifetime costs associated with antiretroviral therapy and political intransigence remain the most important obstacles to adequate management of hn infection in many countries, including south africa, where the availability of finance determines access to therapy. while the southern african hiv clinicians society endorses the right of all hiv-infected adults and children to receive standard of care, it also acknowledges the serious limitations infiuencing the individual's access to effective therapy. the southern african hiv clinicians society endorses the right of all hiv-infected adults and children to receive an optimal standard of care and supports all initiatives that improve access to effective therapy. as knowledge and understanding of the use of antiretroviral therapies is still evolving and new therapeutic agents are becoming available, guidelines are reviewed and updated regularly. the most current version should always be consulted. this is achieved by suppressing viral replication as intensely as possible for as long as possible by using tolerable and sustainable treatment for an indefinite period of time. by doing so, the impact of hiv on the immune system may be minimised and the morbidity and mortality associated with hiv infection can be improved. the primary goals of antiretroviral therapy are: • maximal and durable suppression of viral load • restoration and/or preserva ion of immunological function • improvement of quality of life, and • reduction of hiv-related morbidity and mortality. effective therapy has been shown to reduce the number of new cells infected by hiv and to impede the ability of the virus to evolve drug resistance. july 2002 ------------table i. classes and mechanisms of acnon of antiretrovlral agents qassification of enzyme antiretrovil'3l agent abrev. inhibited specific action nucleoside reverse nrtls reverse mimics the normal transcriptase inhibitors transcriptase building blocks of hiv dna non-nucleoside reverse nnrtls reverse directly inhibits transcriptase inhibitors transcriptase reverse transcriptase protease inhibitors pis protease inhibits late stages of hlv replication thf southtrn mrican journal of hiv mfoicinf protease inhibitors yes yes unknown· no yes yes no yes no no rare nrti nnrti yes no yes yes yes no yes no rare, but yes potential for anaphylaxis with abacavir yes unknownyes no unknownyes unknownyes: efavirenz no no no yes: efavirenz myelosuppression gi intolerance pancreatitis peripheral neuropathy allergic reaction side-effect i complication [jpoatrophy lactic acidosis [jpodystrophy raised cholesterol and triglyceride insulin resistance neuropsychiatric manifestations 7. indications for starting antiretroviral therapy • attack the virus at multiple anatomical sites using drugs that can penetrate different cellular and body compartments. • malt:' darn miuir~ efavirmz {stocrinl is teratogt:'flic and shou.ld be: avoidt:'d in womm of chijd~ring potential unlt:'ss they art:' using aot:'qllatt:' imramuscu!ar progt:'stogens and oarrit:'! rontraetp~ and only wht:'ft:' no other antirt:'trovirals art:' ava~ablt. 5tavudint:' (zt:'rit) and didanosint:' (vidod art contraindicattti in pregnancy and lactation. faraliti~ dut to lactic acidosis have been reportro. table ill. side-effiffi and compucations of antlretrovlral agents drug therapies that do not sufficiently suppress viral replication invariably allow the emergence of resistant viral strains. resistant virus compromises future therapy for the patient and poses a significant public health challenge as it may be disseminated into the community. antiretroviral therapy should be deferred until patients are prepared to commit themselves to long-term treatment and to maintaining good adherence to the therapy. all infected individuals. including those on effective antiretroviral therapy, should be viewed as potentially infectious. adequate counselling about safer sex practices must be provided to encourage prevention of new in ections and reinfection. generic name trade name class of drug zidovudine (azt) retrovir· nrti didanosine (ddl) videx" nrti zalcitabine (ddcj hivid nrti lamivudine (3tcj 3tc" nrti stavudine (md zerir nrti abacavir ziagen" nrti nevirapine viramuneo nnrti efavirenz stocrin nnrti nelfinavir vira-cept" pi indinavir crixivan pi ritonavir norvir· pi saquinavir (hard~el invi-rase pi formulation) saquinavir (soft-gel forto-vase pi formulation] amprenavir predir· pi lopinavir/ritonavir kaletra pi • ava~ablt:' in ~atric foonutations.. table 11. antiretroviral agents currently available in south africa 5. major side-effects and compucations of classes of antiretroviral agents 4. antlretroviral agents currently available in south africa 6. standard of care note: always refer to the most current version of the guidelines as new treatments regulorly become ovoiloble for clinical use (see table if). the tolerability of antiretroviral regimens remains one of the important determinants of treatment success. some of the more common currently recognised side-effects and complications of these agents are listed in table ill. the consequences of changing antiretroviral therapy need to be carefully considered before substituting or stopping specific agents. effective combination therapy should enable the following: • additive or synergistic antiviral activity. • the delay in, or prevention of. emerging drug-resistant viruses. july 2002 art interactions with rifampion 8. laboratory monitoring notes on concomitant tuberculosis assay dynamic range volume required quantiplex hn1 < 50 > 500000 5 ml edta tube rna 3.) bona [purple top) ampiclor pcr < 400 > 750 000 200 ~i edta plasma hn-l ,1.5 < 50 > 75000 500 ~i edta plasma lcx hiv rna at 50 1 000 000 200 ~i edta plasma 178 5000000 500 ~i eota plasma nuclisens at 400 10 000 000 200 ~i edta plasma 40 10000000 500 ~i edta plasma the soumqn ahlcan jour al of hiv medicine 9.1 criteria for treatment success • a decline in viral load of at least 1 log from pretreatment levels by 6 8 weeks after initiating art. • a decline in viral load to < 400 rna copies/m i by 24 weeks after commencemen of therapy. 9. outcomes of art 10. initial antlretrovlral regimens for the previously untreated patient • nuclisens, and • lcx. note: inadequote patient odherence to the prescribed regimen remains one of the most common reasons for treatment foi/ure. note: a sustained viral load of < 50 rna copies/ml is associated with the most durable viro/ogicol benefit. ---------~~--------assayrubes the article on p. 38 covers anomalies. monitoring of viral load and cd4+ cell count is covered in full in the article on p. 38. comparable results are obtained with the first three methods; experience is currently more limited with the lcx assay. it is recommended that the same method be used for sequential testing in an individual patient. 9.2 criteria indicative of treatment failure these guidelines define virological failure as: • a sustained increase in viral load > 5 000 copies/m!. • a decline in viral load of less than 1 log within 6 8 weeks after commencing antiretroviral therapy. • a sustained increase in viral load of> 0.6 log from its lowest point or a return to 50'¥0 of pretreatment value. several 'actors can infiuence the measure men of hiv viral load. i is strongly recommended that the decision to alter therapy should be based on the results of at least two consecutive viral load measurements performed at least 1 week apart. initial regimens for treatment-natve patients should comprise combinations of drugs that are expected to treatment recommended treatment treatment recommended monitor cd4+ count and commence treatment if the cd4 annual decline is in excess of the expeered 20 80 cells/year. or if the cd4 count approaches 200/~1 defer treatment treatment treatment recommended symptomatic patient presence of hn-related symptoms, current or previous hiv-associated disease" primary infection t asymptomatic patient c04+ count < 2ooj~1 c04+ count 200 350/~1 cd4+ count > 350/~1 nrtls no in eractions efavirenz mild reduction in efavirenz levels some experts increase the dose to 800 mg nevirapine moderate reduction in nevirapine levels limited experience ritonavir (full dose) no significant interaction ritonavir + no significant interac ·on saquinavir (both 400 mg bid) all other pis marked reduction in pi levels avoid ~ include a1ds-<ie:'ining iun~ {except tumrutosis see box belowj. unexptain~ w~gh[ toss > 10l1j of body weight, unexplain~ dlarrh~ lasting> 1 month, oral candidiasis or oral hairy kukoplakia. tprimary infection. haart startro early in primary infection t!:'ads to virat suppr~sion which appears to maintain hiv-spttific immunity in a significant proportion of cases, who b«om!:' slow pr09r~fs with a jow yiral toad after discontinuing hmrt. th!:' duration of treatment is uncertain at the present time• tb should always be managed by public sector tb clinics. • if the patient is already on antiretroviral therapy the regimen should if possible be changed to be compatible with rifampicin. • if the patient's cd4+ count is > 200/~1, commence antiretroviral therapy after completing tuberculosis therapy (provided the patient fulfils the criteria above). • if the cd4+ count is < 200/~1 delay antiretroviral therapy until after the intensive phase of tuberculosis therapy (2 months) unless the patient has other serious hn-related illness or has a very low cd4+ count, in which case antiretroviral therapy should be introduced only once the patient is stabilised on tuberculosis therapy. four laboratory methods are available for determining viral load: • ampiclor pcr • brancheo dna july 2002 'teratogenic should be avoided in womtn of chil~rin9 potential unl~ using adequate: intramuscular ptclgl!stogens and barrier col1tra~tives. and only where no other antireuovirals are av.;ilable.. table iv. antiviral regimens for the previously untreated patient c.tegory iii ab.c.vir (abcl c.tegory v nelfin.vir (npv) indin.vir (!dv) ritonavir [ri\/) saquinavir [sqv) [soilgel formulation) lopinavirjritonavir combination new agent stavudind zidovudinet lamivudine or zalcitabine didanosine· or zalcitabine· abacavir, sravudine or zidovudine or other as determined by resistance testing determined by resistance testing c.tegory iv nevir.pine (nvp) ernvirenz (ef\/)' zidovudine stavudine didanosine lamivudine zalcitabine initial agent abacavir 9.2 changing non-nucleoside reverse transcriptase inhibitors (category iv) 'may exhibit reductd activity dut: to croshesimnce with lamivudine 13tc1. tmay exhibit cross-resistan~ 9.1 changing nucleoside reverse inhibitors (categories i, 11 and ill) (table v)) table v. changing nucleoside reverse transcriptase inhibitors there is broad cross-resistance between the currently available nnrtls. resistance to one nnrti precludes the use of another, unless there are resistance test data to the contrary. individuals in whom an nnrti-containing regimen fails may be candidates for an abacavir-containing triple-nucleoside combination (if the viral load is < 55000 rna copies/ml) or a protease-inhibitor containing regimen. resistance to one agent of this class effectively results in cross-resistance to all members of drugs in this category (that are currently available in south africa). sequential use of these drugs is not recommended. the southfrn mrican journal of hiv mfoi'i'e changing protease inhibitors (category v) a major reason for failure of regimens that contain pro ease inhibitors is suboptimal pharmacokinetics and inadequate drug exposure as a result of poor adherence (often due to intolerance). this needs to be considered carefully before deciding to introduce an alterna ive picontaining regimen. second-line protease inhibitor alternatives may exhibit reduced activity due to extensive cross-resistance within this class of drugs. pharmacological boosting of protease blood levels can be achieved by combining amprenavir, saquinavir and indinavir with low category 11 did.nosine (ddl) lalcit.bine (ddc) lamivudine [3tc) c.tegory i st.vudine (d4d zidovudine (alt) for initiation of art therapy prescribe two nrtls and an nnrti (one drug from category i, one from category 11, and one from category iv). if the viral load is < 55 000 copies/ml a third nrti (from category ill) may be considered as par of a triple nrti regimen. in accordance with who and unaids recommendations, these guidelines endorse the use of nrtls and nnrtls as first-line therapy. the importance o' adherence must be clearly explained to the patient and reinforced at every visit. institution of antiretroviral therapy is never an emergency in the setting of established infection. practitioners should take sufficient time and care to prepare themselves and the patient for an intenention that may be lifelong. treatment should only be changed as soon as possible in the following situations: • patient intolerance despite adequate and appropriate intenention • significant side-effects • treatment failure, as defined in 9.2 above. achieve the abovementioned treatment goals. these are shown in table iv. 12. options for changing therapy particular consideration should be given to those factors that may affect patient adherence, such as the regimen's pill burden, dosing frequency, food requirements, convenience, toxicity and drug interaction profile. 11. indications for changing therapy table v contains recommendations for changing therapy when drug resistance emerges; the caveats listed above apply. when virological failure occurs it is essential to change at least two of the drugs in the patient's regimen when possible, the clinician may choose to be guided by genotypic or phenotypic resistance testing. july 2002 chairperson of adult guidelines committee or steven miller expert panel members steven andrews, mark cotton, gary maartens, des martin, steven miller, robin wood, dave spencer, francois venter international reviewers pedro cahn, david cooper, brian gazzard, stefana vella t~e sout~trn africa journal or ~iv medicine -----------july 2002 disclaimer: specific recommendations pravided in this dacument are intended only as a guide to clinical therapy, based on expert cansensus and best current evidence. treatment decisions for patients shauld be made by their responsible clinicians, with due consideration for individual circumstances. the most current version af this document should always be consulted. 13. treatment decision support doses of ritonavir. experience with these combinations is limited and advice on dosing should be sought. for specific advice and assistance in using these guidelines, please contact the southern african hiv clinicians society bye-mail: sahivsoc@iafrica.com abstract international paediatric hiv workshop international aids society conference fifth workshop on children who are hiv-exposed and uninfected conclusion acknowledgements references about the author(s) mohendran archary department of infectious diseases, university of kwazulu-natal, durban, south africa department of paediatrics & child health, university of kwazulu-natal, durban, south africa lee fairlie wits reproductive health and hiv institute (wrhi), university of the witwatersrand, johannesburg, south africa amy slogrove department of paediatrics and child health, stellenbosch university, cape town, south africa citation archary m, fairlie l, slogrove a. current perspectives on paediatric hiv management from the mexico international aids society conference, 2019. s afr j hiv med. 2019;20(1), a1027. https://doi.org/10.4102/sajhivmed.v20i1.1027 opinion paper current perspectives on paediatric hiv management from the mexico international aids society conference, 2019 mohendran archary, lee fairlie, amy slogrove received: 30 aug. 2019; accepted: 11 sept. 2019; published: 31 oct. 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract while acknowledging the great achievements in getting 23 million people living with hiv to access antiretroviral treatment (art) globally, there is still more to do in order to close the hiv treatment gap between the paediatric and adult art programmes, with only 54% of children accessing art compared to 62% of adults. furthermore, while tremendous global gains have been made in preventing perinatal and postnatal hiv acquisition, hiv-exposed and uninfected children are still not achieving early childhood developmental outcomes comparable to hiv-unexposed children. in this article, we present highlights from two pre-conference meetings (11th international workshop on hiv pediatrics and 5th workshop on children and adolescents hiv exposed and uninfected) and the international aids society (ias) meeting held in mexico in july 2019. keywords: 2019 paediatric art conferences; international aids society; management of pregnant and breastfeeding women; paediatric/adolescent hiv; treatment update. international paediatric hiv workshop the global scale-up of antiretroviral treatment (art) and prevention of mother-to-child transmission (pmtct) strategies has resulted in a dramatic reduction in new paediatric infections. despite this, globally there were 160 000 new paediatric infections in 2018. this annual meeting provides a good summary of the current and future directions in the prevention and treatment of paediatric and adolescent hiv and co-infections. the key findings presented at this meeting can be categorised into the following: (1) treatment and management of paediatric and adolescent hiv; and (2) management of pregnant and breastfeeding women and pmtct. treatment and management of paediatric/adolescent hiv difficulties in administering medication to children and attendant adherence issues have resulted in poorer virological suppression rates in children than adults.1 several advances in drug formulations and delivery methods were presented at the meeting. two of the notable new molecules with a potential impact on management of children in the future are gs-6207 and mk-8591. gs-6207 is the first in the class of capsid inhibitors and is unique in that it acts on various sites of the hiv lifecycle including capsid disassembly on viral entry and capsid assembly and maturation during production of new viral particles. initial data on subcutaneous administration in adults support 3-monthly administration. no paediatric studies have been conducted.2 the second (mk-8591) also has an unique mechanism of action as a nucleoside reverse transcriptase translocation inhibitor that lacks cross-resistance with other nucleoside reverse transcriptase inhibitors (nrtis). in addition, the formulation has a very long intracellular half-life that potentially allows for administration of very low dosages and the possibility of being given once weekly. adult data from a fixed-dose combination of mk-8591/doravirine were presented at the main conference. animal studies suggest that an implantable formulation may support once-a-year administration.3 no paediatric data are available on these new formulations. other notable new treatment options included cabotegravir/rilpivirine and extended release broadly neutralising antibodies.4 tenofovir alafenamide (taf) as the optimal background regimen in children was discussed. the advantage of taf compared to tenofovir diproxil fumarate (tdf) in paediatrics is the potentially lower incidence of renal toxicity and decreases in bone mineral density. a pooled analysis of paediatric taf studies showed high rates of virological suppression (> 90%) with no emergence of resistance when combined with an integrase inhibitor.5 in addition, results from a study using taf/ftc/elvitegravir/cobicistat fixed drug combination (fdc) in children over 6 years and 25 kg had no serious adverse events (grade 3/4 aes) with high rates of viral suppression between 90% and 100%. of note is the lack of data on using taf with rifampin-based therapy in paediatrics; data in adults suggest twice daily administration may overcome this interaction.6 novel delivery methods of art for treatment and prevention of hiv hold exciting promise for children. long-acting subcutaneous infusions, injections and implants have shown promise in adults and are moving rapidly into the paediatric arena. transdermal drug delivery using an adhesive patch with micro-needles was described with data in adults achieving acceptable cabotegravir concentrations with once-monthly application.7 this drug delivery method holds several advantages for use in children by allowing flexibility to alter doses in a growing child together with easy application and removal, if required. achieving the goals of 90:90:90 requires improved paediatric case finding which was addressed in a plenary talk and several oral abstract presentations. traditional health facility-based testing does not identify hiv-infected children before the onset of symptoms. community-based screening and index case testing were suggested as an alternative case finding strategy for early identification.8 untested children often have siblings or parents that have been previously tested, with failure to link other family members into care. effective community engagement and participation is necessary to facilitate case finding.9 in settings with high burden of infections, early infant diagnosis together with testing during immunisation visits was cost-effective.10 getting children to start art and maintaining viral suppression in order to achieve the last two 90s is challenging, especially in hiv-infected newborns, young infants and adolescents. stratifying intensity of follow-up, counselling and the package of care based on virologic response to therapy was found to be feasible even in rural settings.11 silent transfers of patients (self or poorly documented transfers) between facilities accounted for 65% of patients that were labelled as being lost to follow-up in a cohort from the western cape province, highlighting the challenges with linkage of patients.12 improved data management systems and unique identifiers to track patients were recommended by the authors. management of pregnant and lactating women and prevention of mother-to-child transmission eagerly awaited results from the botswana tsepamo birth surveillance study on the risk of neural tube defects (ntd) in infants born to mothers receiving dolutegravir (dtg) peri-conception were presented indicating a reduction in the risk from that previously reported, but still above the background ntd risk. in addition, data from the international antiretroviral pregnancy registry (apr) showed an overall risk of ntd following peri-conception art exposure of 0.03%.13 in the registry, there were only 248 peri-conception dtg exposures with 1 ntd, limiting the ability to make definitive conclusions. it was noted that the majority of data for the registry was obtained from the united states/canada (75%), with only 7% from africa, and an appeal was made to report peri-conception art exposure to local pharmacovigilance structures (national department of health, national pharmacovigilance centre) and international pregnancy registries (www.apregistry.com or https://globalbirthdefects.tghn.org). apart from birth defects, infants exposed in utero to hiv and art had poorer weight-for-age (waz) and length-for-age (haz) z-scores compared to hiv-unexposed infants.14 overall, the workshop highlighted major gains that have been achieved in preventing new paediatric infections and treating hiv-infected children and adolescents. however, to achieve the 90:90:90 goals, new clinicaland community-based strategies are needed to find and treat patient populations that have poor health seeking behaviour and disruptive social networks that make consistent adherence to a treatment regimen difficult. international aids society conference the main ias conference covered numerous tracks including basic science, clinical science, prevention science and social, behavioural and implementation science. in this article, we provide feedback on aspects of the main conference that related to children, adolescents and pregnant women, with a focus on optimised hiv treatment and pmtct. optimised maternal antiretroviral treatment and prevention of mother-to-child transmission in addition to the eagerly awaited tsepamo data, presented in the workshop, additional data were presented from the botswana ministry of health and wellness, showing a prevalence of 0.66% (95% confidence interval [ci] 0.02–3.69) in women conceiving on dtg-based art.15 although only one additional child enrolled in the tsepamo trial was noted to develop an ntd when following all trial participants up until conclusion of their pregnancies, this prevalence remains higher than reported in women conceiving on any other art regimen and hiv-negative women.16 data from brazil, where 384 women conceived on dtg, showed no ntds (95% ci 0–0.003).17 these updated findings prompted slight wording changes within the world health organization (who) guidelines, now recommending dtg-based art as the preferred regimen for all hiv-infected patients, although in women of child-bearing age, an informed decision regarding their regimen and contraception must be made before deciding on a dtgor efavirenz-based regimen.18 the advance study randomised 1053 adolescents and adults to receiving a dtg-based regimen with either taf or tdf and emtricitabine (ftc), compared to standard of care efavirenz/ftc/tdf. the study reported non-inferiority for dtg-based regimens at 48 weeks, with the primary endpoint of viral load (vl) < 50 copies/ml in an intention to treat analysis. toxicity was low overall across the study arms; however, significant weight gain particularly in black south african women occurred in those receiving dtg/taf/ftc (median 10 kg increase), compared to dtg/tdf/ftc (median 5 kg increase) and efv/tdf/ftc (median 3 kg increase)19 were randomised to dtg/tdf/ftc versus efv(400 mg)/tdf/ftc.20 although this weight gain or the implications thereof are currently not well understood, further evaluation of this finding is warranted. however, as participants enrolled were relatively well, this raises concern regarding long-term risks for cardiovascular disease in women receiving dtg and taf combination art. sixty-five women conceived on the study with no increased risk for adverse pregnancy outcomes in women receiving dtg at conception. a study in johannesburg and tshwane, south africa, offered point-of-care maternal vl and early infant diagnosis hiv testing around the time of delivery only during ‘office hours’. of 1762 valid vls, around 36.4% were unsuppressed at delivery with a vl > 50 copies/ml). fortunately, infant hiv infection rates were low (65/4333; 1.5%); however, this highlights gaps in optimised maternal art coverage and uptake of vl testing at delivery, with potential risk of hiv transmission.21 hiv treatment and treatment outcomes in children and adolescents as guidelines move to a universal regimen for all hiv-positive persons, children lag behind in the era of dtg. data were presented from the odyssey trial, regarding the pharmacokinetics (pk) of 5 mg dtg dispersible tablets in 28 children weighing 6 kg to < 20 kg (in three weight bands: 6 kg to < 10 kg, 10 kg to < 14 kg and 14 kg to < 20 kg) from zimbabwe and uganda. in the weight bands between 10 kg to < 14 kg and 14 kg to < 20kg, pk data were similar to the published data in adults, older children and younger children. however, as in the 6 to < 10 kg group, some children had low trough concentration (ctrough) levels with high inter-participants variability; further pk data are required for this group and children weighed between 3 kg and < 6 kg, highlighting complexities of hiv treatment in younger age groups.22 a study from zimbabwe analysed results of genotypic resistance testing in 160 of 185 children with virological failure on first and second line regimens, and calculated a total genotypic susceptibility score (tgss) for a switch to protease inhibitor (pi)or dtg-based regimens, respectively.23 the tgss demonstrated that therapy with the tenofovir–lamivudine–dolutegravir (tld) combination tablet may result in dtg monotherapy, due to dual nrti resistance with associated risks of virologic failure and future dtg resistance.23 data from the international epidemiologic databases to evaluate aids southern africa collaboration (iedea-sa) showed that between 2004 and 2017 perinatally hiv-infected children and adolescents had suboptimal retention in care, suboptimal vl suppression rates and mortality, with particular risk for those who initiate art at older ages and more severe immunosuppression. adolescents, especially those at high risk, require additional support and follow-up to prevent morbidity and mortality.24 fifth workshop on children who are hiv-exposed and uninfected the fifth workshop on children who are hiv-exposed and uninfected (cheu) was themed around the first 1000 days of life (conception to age 2 years), with presentations spanning basic and clinical science, policy, programmatic and research considerations. according to the joint united nations programme on hiv and aids (unaids) estimates, globally there were 14.8 million cheu (age 0–14 years) in 2018, with 3.5 million (24%) living in south africa. the prevalence of cheu exceeded 20% in four southern african countries: eswatini (32%), botswana (27%), south africa (22%) and lesotho (21%).25 the hiv-exposed in utero environment untangling the mechanisms of adverse birth outcomes in pregnant women living with hiv (pwlhiv) and the role that hiv, specific antiretroviral drugs or other maternal factors play is crucial to securing optimal outcomes for cheu. in pwlhiv cohorts on non-pi-based art in cape town, timing of art initiation either preconception or during pregnancy had no influence on placental pathology. however, t-regulatory cells were significantly lower at birth in cheu than children hiv unexposed and uninfected (chuu).26 in a canadian cohort of pwlhiv, pi-based art was associated with lower progesterone and prolactin levels, altered placental morphology and inefficient or over-worked placentas compared to pwlhiv on non-pi-based art and pregnant women without hiv.27 in a mouse model, normal placental spiral artery remodelling and trophoblast invasion, controlled by progesterone and prolactin, were inhibited by lopinavir/ritonavir but not atazanavir/ritonavir or darunavir/ritonavir.27 further work is needed to determine whether these endocrine and placental alterations are associated with preterm birth and intrauterine growth restriction in pwlhiv. solutions to children who are hiv-exposed and uninfected vulnerabilities in early childhood in a belgian cohort of cheu compared to hiv-unexposed children, neonatal immune parameters as well as infectious morbidity risk differed by timing of initiation of maternal art.28 infants of mothers on preconception art had immune and infectious morbidity profiles similar to hiv-unexposed infants, whereas infants of mothers on pregnancy-initiated art showed alterations in cellular and humoral immunity at birth, predictive of and associated with a threefold higher risk for infectious-cause hospitalisations. in the zimbabawean shine trial, conducted in the context of universal maternal art and high sustained breastfeeding, cheu had an almost 50% increased risk of stunting at 18 months than hiv-unexposed children (rr 1.48; 95% ci 1.34–1.64) and mortality at 18 months in children born to wlhiv was almost 40% higher than hiv-unexposed children (rr 1.39; 95% ci 1.02–1.89).29 there were also significant deficits in gross motor, fine motor and language development at 24 months in cheu compared to hiv-unexposed children, with normalisation of neurodevelopment in the cheu group randomised to both a water/sanitation/hygiene and an infant and young child feeding intervention.30 zambia is rolling out a ‘smartcare’ system that is optimising electronic medical records held on an individual patient ‘smart card’ to facilitate confidential communication and availability of hiv-related information for all people living with hiv and all children who are hiv-exposed.31 south africa is supporting early childhood development through the ‘side-by-side’ campaign built around the five pillars of nutrition, love, protection, healthcare and extracare. with almost 25% of children in south africa being cheu, a dedicated service and monitoring of cheu is unfeasible and undesirable.32 there is a need however to identify the subset of cheu at highest risk for poor outcomes and requiring linkage to the fifth pillar of extracare and support. globally, two policy agendas are converging with synergies between the start free stay free aids free agenda and the nurturing care framework that can be optimised to achieve improved early childhood development outcomes for all children affected by hiv.33 conclusion remarkable success has been achieved to ensure an hiv-free start to life for over 1 million children born each year to women with hiv. however, investment in more detailed research is required to understand why cheu are not surviving and thriving as well as children born to women without hiv and how to support families affected by hiv to achieve optimal outcomes for their children. for children who are infected with hiv, improvements in art and art drug delivery mechanism hold the promise of simplified treatment regimens. acknowledgements the authors would like to acknowledge the child and adolescent committee of the southern african hiv clinicians society for the review of the manuscript. competing interests the authors have declared that no competing interest exists. authors’ contributions all authors contributed equally to this work. ethical consideration this article followed all ethical standards for research without direct contact with human or animal subjects. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references davies ma, moultrie h, eley b, et al. virologic failure and second-line antiretroviral therapy in children in south africa – the iedea southern africa collaboration. j acquir immune defic syndr. 2011;56(3):270–278. https://doi.org/10.1097/qai.0b013e3182060610 sager je, begley r, rhee m, et al. safety and pk of subcutaneous gs-6207, a novel hiv-1 capsid inhibitor [homepage on the internet]. abstract no. 141. croi conference; 2019 mar 4–7; seattle, wa. [cited n.d.]. available from: http://www.croiconference.org/sessions/safety-and-pk-subcutaneous-gs-6207-novel-hiv-1-capsid-inhibitor. barrett s, teller r, forster s, et al. extended-duration mk-8591-eluting implant as a candidate for hiv treatment and prevention. antimicrob agents chemother. 2018;62(10):1–13. https://doi.org/10.1128/aac.01058-18 rajoli rkr, back dj, rannard s, et al. in silico dose prediction for long-acting rilpivirine and cabotegravir administration to children and adolescents. clin pharmacokinet. 2018;57(2):255–266. https://doi.org/10.1007/s40262-017-0557-x cox s, porter d, white k, graham h, pikora c, callebaut c. tenofovir alafenamide-based regimens: a pooled resistance analysis in pediatric participants [homepage on the internet]. oral abstract presentations no. 4. 10th international aids society conference on hiv science; 2019 jul 21–24; mexico city. [cited n.d.]. available from: http://regist2.virology-education.com/presentations/2019/hivped/04a_cox.pdf. rakhmanina n, natukunda e, kosalaraksa p. safety and efficacy of e/c/f/taf in virologically suppressed, hiv infected children through 96 weeks [homepage on the internet]. short oral poster presentations no. 22. 10th international aids society conference on hiv science; 2019 jul 21–24; mexico city. [cited n.d.]. available from: http://regist2.virology-education.com/presentations/2019/hivped/04a_cox.pdf. rajoli rkr, curley p, back d. in silico drug interaction of long-acting rilpivirine and cabotegravir with rifampin [homepage on the internet]. abstract no. 485. croi conference; 2018 mar 4–7; boston, ma. 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[cited n.d.]. available from: https://www.virology-education.com/wp-content/uploads/2019/07/11ped_-program.pdf. ciaranello a. the clinical impact and cost-effectiveness of routine hiv screening and testing at infant immunization visits in côte d’ivoire (ci), south africa, and zimbabwe [homepage on the internet]. short oral poster presentation no. 21. 10th international aids society conference on hiv science; 2019 jul 21–24; mexico city. [cited n.d.]. available from: https://www.virology-education.com/wp-content/uploads/2019/07/11ped_-program.pdf. shava a. retention and viral suppression of children and adolescents in hiv care, zimbabwe [homepage on the internet]. poster walk no. 52. 10th international aids society conference on hiv science; 2019 jul 21–24; mexico city. [cited n.d.]. available from: https://www.virology-education.com/wp-content/uploads/2019/07/11ped_-program.pdf. nyakato p, boulle a, wood r, et al. outcomes of children and adolescents living with hiv considered lost to follow up at iedea-sa cohorts in the western cape: linkage to western cape provincial health data centre records [homepage on the internet]. oral abstract presentation no. 28. 10th international aids society conference on hiv science; 2019 jul 21–24; mexico city. [cited n.d.]. available from: http://regist2.virology-education.com/presentations/2019/hivped/28a_nyakato.pdf. mofensen l, vannappagari v, scheuerle ae, et al. periconceptional antiretroviral exposure and central nervous system (cns) and neural tube birth defects – data from antiretroviral pregnancy registry (apr) [homepage on the internet]. oral abstract presentation no. 12. 10th international aids society conference on hiv science; 2019 jul 21–24; mexico city. [cited n.d.]. available from: http://regist2.virology-education.com/presentations/2019/hivped/12a_mofenson.pdf. nyemba dc, kalk e, hlengiwe m, et al. lower birth weight-for-age and length-for-age z-scores in infants with in utero hiv and arv exposure: a prospective study in cape town, south africa [homepage on the internet]. oral abstract presentation no. 15. 10th international aids society conference on hiv science; 2019 jul 21–24; mexico city. [cited n.d.]. available from: http://regist2.virology-education.com/presentations/2019/hivped/15a_chiwoniso.pdf. zash r, holmes l, diseko m, et al. neural tube defects by antiretroviral and hiv exposure in the tsepamo study, botswana [homepage on the internet]. oral abtract presentation no. moax0105lb. 10th international aids society conference on hiv science; 2019 jul 21–24; mexico city. [cited n.d.]. available from: http://programme.ias2019.org/abstract/abstract/4822. raesima mm, forhan s, thomas v, et al. addressing the safety signal with dolutegravir use at conception: additional surveillance data from botswana [homepage on the internet]. oral abtract presentation no. moax0106lb. 10th international aids society conference on hiv science; 2019 jul 21–24; mexico city. [cited n.d.]. available from: http://programme.ias2019.org/abstract/abstract/5089. pereira g, kim a, jalil e, et al. no occurrences of neural tube defects among 382 women on dolutegravir at pregnancy conception in brazil [homepage on the internet]. oral abtract presentation no. moax0104lb. 10th international aids society conference on hiv science; 2019 jul 21–24; mexico city. [cited n.d.]. available from: http://programme.ias2019.org/abstract/abstract/4991. world health organisation. update of recommendations on firstand second-line antiretroviral regimens – policy brief [homepage on the internet]. [cited n.d.]. available from: https://www.who.int/hiv/pub/arv/arv-update-2019-policy/en/. venter wf, moorhouse m, sokhela s, et al. the advance trial: phase 3, randomized comparison of taf/ftc/dtg, tdf/ftc/dtg or tdf/ftc/efv for first-line treatment of hiv-1 infection [homepage on the internet]. oral abtract presentation no. weab0405lb. 10th international aids society conference on hiv science; 2019 jul 21–24; mexico city. [cited n.d.]. available from: https://onlinelibrary.wiley.com/doi/10.1002/jia2.25327. hill a, venter wf, delaporte e, et al. progressive rises in weight and clinical obesity for taf/ftc/dtg and tdf/ftc/dtg versus tdf/ftc/efv: advance and namsal trials. oral abtract presentation no. moax0102lb [homepage on the internet]. 10th international aids society conference on hiv science; 2019 jul 21–24; mexico city. [cited n.d.]. available from: https://onlinelibrary.wiley.com/doi/10.1002/jia2.25327. moyo f, haeri mazanderani a, murray t, et al. characterizing viral load burden among hiv positive women around time of delivery: findings from four tertiary obstetric units in gauteng, south africa [homepage on the internet]. oral abtract presentation no. tuab0104. 10th international aids society conference on hiv science; 2019 jul 21–24; mexico city. [cited n.d.]. available from: https://onlinelibrary.wiley.com/doi/10.1002/jia2.25327. waalewijn h, bollen pdj, moore c. pharmacokinetics of dolutegravir 5 mg dispersible tablets in children weighing 6 to < 20 kg dosed using who weight bands [homepage on the internet]. oral abtract presentation no. weab0401lb. 10th international aids society conference on hiv science; 2019 jul 21–24; mexico city. [cited n.d.]. available from: https://onlinelibrary.wiley.com/doi/10.1002/jia2.25327. kouamou vm, manasa j, mcgregor a, et al. dolutegravir containing regimens may need optimization for african youth failing art [homepage on the internet]. oral abtract presentation no. weab0203. 10th international aids society conference on hiv science; 2019 jul 21–24; mexico city. [cited n.d.]. available from: https://onlinelibrary.wiley.com/doi/10.1002/jia2.25327. tsondai pr, braithwaite k, fattii g. describing the characteristics and long-term outcomes of adolescents living with perinatally acquired hiv in the iedea-southern africa collaboration: 2004 to 2017 [homepage on the internet]. oral abtract presentation no. weab0201. 10th international aids society conference on hiv science; 2019 jul 21–24; mexico city. [cited n.d.]. available from: https://onlinelibrary.wiley.com/doi/10.1002/jia2.25327. joint united nations programme on hiv/aids. 2019 unaids estimates [homepage on the internet]. [cited n.d.]. available from: http://aidsinfo.unaids.org. gray c. the impact of maternal hiv infection on placental and neonatal immunology among children hiv exposed uninfected [homepage on the internet]. oral presentation. 5th workshop on children and adolescents hiv exposed and uninfected; 2019 jul 21–24; mexico city. [cited n.d.]. available from: https://www.iasociety.org/hiv-programmes/programmes/paediatrics-cipher/5th-hiv-exposed-uninfected-child-and-adolescent-workshop. serghides l. arv exposure and placental morphology/function [homepage on the internet]. oral presentation. 5th workshop on children and adolescents hiv exposed and uninfected; 2019 jul 21–24; mexico city. [cited n.d.]. available from: https://www.iasociety.org/hiv-programmes/programmes/paediatrics-cipher/5th-hiv-exposed-uninfected-child-and-adolescent-workshop. marchant a. maternal determinants of immunity in children hiv exposed and uninfected [homepage on the internet]. oral presentation. 5th workshop on children and adolescents hiv exposed and uninfected; 2019 jul 21–24; mexico city. [cited n.d.]. available from: https://www.iasociety.org/hiv-programmes/programmes/paediatrics-cipher/5th-hiv-exposed-uninfected-child-and-adolescent-workshop. evans c. child mortality growth and early childhood development – comparing children who are hiv exposed and uninfected and children hiv unexposed in the shine trial [homepage on the internet]. oral presentation. 5th workshop on children and adolescents hiv exposed and uninfected; 2019 jul 21–24; mexico city. [cited n.d.]. available from: https://www.iasociety.org/hiv-programmes/programmes/paediatrics-cipher/5th-hiv-exposed-uninfected-child-and-adolescent-workshop. prendergast a. infant feeding and wash interventions among children hiv exposed uninfected in shine [homepage on the internet]. oral presentation. 5th workshop on children and adolescents hiv exposed and uninfected; 2019 jul 21–24; mexico city. [cited n.d.]. available from: https://www.iasociety.org/hiv-programmes/programmes/paediatrics-cipher/5th-hiv-exposed-uninfected-child-and-adolescent-workshop. mulenga p, mutanga j. follow-up of children hiv exposed uninfected through routine child health services: zambian perspective [homepage on the internet]. oral presentation. 5th workshop on children and adolescents hiv exposed and uninfected; 2019 jul 21–24; mexico city. [cited n.d.]. available from: https://www.iasociety.org/hiv-programmes/programmes/paediatrics-cipher/5th-hiv-exposed-uninfected-child-and-adolescent-workshop. bamford l, feucht u. providing care for children hiv exposed uninfected through routine child health services: south african perspective [homepage on the internet]. oral presentation. 5th workshop on children and adolescents hiv exposed and uninfected; 2019 jul 21–24; mexico city. [cited n.d.]. available from: https://www.iasociety.org/hiv-programmes/programmes/paediatrics-cipher/5th-hiv-exposed-uninfected-child-and-adolescent-workshop. penazzato m. integrating children hiv exposed and uninfected into the nurturing care framework [homepage on the internet]. oral presentation. 5th workshop on children and adolescents hiv exposed and uninfected; 2019 jul 21–24; mexico city. [cited n.d.]. available from: https://www.iasociety.org/hiv-programmes/programmes/paediatrics-cipher/5th-hiv-exposed-uninfected-child-and-adolescent-workshop. make up june issue nicky the southern african journal of hiv medicine june 2005 3 7 s o c i a l s u p p o r t effectiveness of the non-profit organisation, ‘grandmothers against poverty and aids’ – a study kathleen brodrick, msc ot, director, gapa mandisa mafuya, ba, project manager, gapa grandmothers against poverty and aids, khayelitsha,w cape arising out of and based on a pilot intervention project of the albertina and walter sisulu institute of ageing in africa, a nonprofit organisation called grandmothers against poverty and aids (gapa) was formed.1 gapa has been operating in khayelitsha since october 2001. in that time the number of grandmothers participating in gapa activities, namely workshops and psychosocial support groups, has been growing steadily. anecdotal evidence suggests that the grandmothers are developing the capacity to cope with the effects of the aids crisis and are becoming empowered members of their communities. the intervention strategy of gapa is a two-pronged approach. firstly grandmothers are invited to attend a workshop series which cover topics such as aids education, home care, nutrition, elder abuse, human rights, food gardening, drawing up wills, accessing social grants and business skills. these workshops are for a maximum of 30 grandmothers and are held over 3 days each month. the workshop facilitators are local experts in their field and some are grandmothers who have been trained by gapa. all workshops are conducted in the local language, isixhosa. since may 2002, 250 grandmothers have attended a series of workshops at some time. the number of grandmothers attending continues to grow by 30 each month. the second approach has been to invite grandmothers who are directly affected by hiv/aids in their families to join a support group in their neighbourhood. the support groups, consisting of between 5 and 10 members, are activity-based. meetings are held in group leaders’ homes once a week. education, problem solving and handicraft manufacture is carried out in the groups. the groups form autonomous units under the guidance and leadership of the group leader. home groups as a support strategy were started in july 2002 to accommodate the growing number of grandmothers who wanted to join the existing psychosocial support group. grandmothers who had been trained in the pilot intervention phase held between august and november 2001, had developed sufficient confidence in their own knowledge of hiv/aids and handicraft skills to lead others. an added benefit of the home groups was the eradication of the problem of transport costs incurred by grandmothers getting to the venue. setting up groups in their neighbourhoods meant that grandmothers could now walk a short distance to attend their group. the logistical problems of feeding a growing and fluctuating number of attendees were also removed with the formation of home groups. the group leaders were given a cash allowance to provide food for the groups from their kitchens. in july 2002 there were 3 groups. this grew to 6 by august 2002 and to 9 by february 2003. in july 2003 there were 12 groups. monitoring of the groups began in earnest in july 2003 with the employment of a project manager. continuous monitoring of the groups led to the eradication of fictitious attendance books and the dissolution of one group. with the improved system, new groups were formed in new areas and some new group leaders were brought on board. in february 2004 there were 13 groups led by 8 group leaders. in december 2004 there were 19 groups held in 6 suburbs of khayelitsha and run by 13 group leaders. three groups were formed in the eastern cape in november 2003. in order to evaluate the effectiveness of gapa’s presence as an agent in the fight against poverty and aids in grandmotherheaded households in khayelitsha, a qualitative and quantitative study was conducted from july 2004 to december 2004. a questionnaire was administered to all grandmothers who attended one of the home support groups. items on the questionnaire covered demographic details of the group the study instruments make up june issue nicky 5/30/05 2:20 pm page 37 june 2005 the southern african journal of hiv medicine38 attendee, her family’s status with regard to hiv/aids, the number of grandchildren living with her, details of membership of gapa, and economic gains as a member. additional items asked respondents to articulate what the best and the worst aspects of belonging to a group were. the questionnaire was administered in isixhosa or english, and was completed by 163 grandmothers. the second investigation was a phenomenological study investigating the meaning of membership of gapa and how this membership had impacted on grandmothers’ lives. in order to elicit the meaning of membership of gapa, an ‘indaba’ was held each month to which all group members were invited. the sampling method was that of voluntary participation. provision was made in the programme of events for grandmothers who wished to participate to address the gathering about what being a member of gapa had meant to them. ages of group members ages of gapa members ranged from 40 to 90 years (n = 163). the age distribution is shown in fig. i. membership of gapa is defined as grandmothers aged 50 years and older. of the respondents, 45% were aged 60 years and older. at 60 women are eligible for social assistance of r740 per month. eighteen per cent of the group members were aged between 40 and 49 years. in these cases the group leaders had used their judgement and allowed the younger women to join because they were grandmothers and were in need of psychosocial support. thirty-seven per cent of the grandmothers were aged between 50 and 59 years. hiv-infected grandmothers eight respondents reported that they were hiv positive. these grandmothers were aged 42, 44, 47, 50, 51 (2), 56 and 57 years. in all, these 8 women cared for 24 children under the age of 21 years, 12 of whom were grandchildren. one of the 51-year-old grandmothers cared for 7 children under the age of 21 years, 3 of whom were grandchildren. only 1 of the grandmothers (one of the 51-year-olds) had a cohabiting husband who was also hiv positive. recent deaths of the grandmothers 82% reported that they had experienced recent deaths in their families (fig. 2). deaths were considered to be recent if they had occurred within the last 5 years and were still a source of sorrow for the participant. causes of death were not specifically asked about. however, most deaths were thought by the subjects to be the result of opportunistic diseases due to aids. some participants indicated that at the time of the death they were unaware of hiv/aids and in hindsight realised that hiv infection had been the root cause of the person’s untimely death. family hiv status the respondents were asked if they knew any family members who were hiv positive, and 64% reported that they had living family members who were known to be hiv positive (fig. 3). children who live with grandmothers one hundred and fifty-five respondents reported that children under the age of 21 years lived in their homes. these respondents cared for a total of 515 children, of whom 366 were grandchildren. the other 149 children were either their own children, foster children or children of close relatives for whom they were responsible. benefits received due to gapa membership in response to the question ‘have you made any money for yourself from being a member of gapa?’ 65% of respondents said that they had made some money. responses were vague, ranging from ‘a little’ to ‘a lot’. in less than 23% of cases was an actual monetary value given. two respondents were definite that they made r100 and r25 per month, respectively. the range was from r10 to r2000. others who gave a monetary value did not specify over what time period they had made the money. of the grandmothers 64% reported that they had benefited from being a member of gapa by receiving school fees (81%) and food (57%). four respondents said that they had received materials with which to do handicraft. however, all grandmothers received fabric and other handicraft materials in their groups as well as a meal. what grandmothers had learned as members of gapa all participants reported that they had learned something from being involved with gapa. the responses fell into the following categories: • acceptance – ‘to be able to help a person with hiv and to teach others how to accept them.’ • home nursing – ‘you can support the hiv positive person without becoming sick.’ • practical skills – ‘how to grow vegetables and how to sew.’ 60 69 (28%) 50 59 (37%) 40 49 (18%) 80+ (2%) 70 79 (15%) fig. 1. group membeers by age. results and discussion make up june issue nicky 5/30/05 2:20 pm page 38 the southern african journal of hiv medicine june 2005 3 9 • income generation – ‘how to make extra income.’ • peer support – ‘co-operation and love brings success.’ what was the best thing about being in a group? participants’ responses fell into the following categories: • stress alleviation – ‘we have a chance to relieve stress.’ • income generation – ‘financial security because of the sewing.’ • companionship – ‘not sitting at home being unhappy and alone.’ • safety – ‘you feel free to communicate your feelings to other people.’ • problem solving – ‘problems regarding hiv/aids are shared.’ what was the worst thing about being in a group? ninety percent of the respondents said that there was nothing negative that could be said about being in a group. those who did report something negative generally complained about arguments within the group and (in 2 cases) about the unfair distribution of goods within the group. community intervention by grandmothers the responses to the question ‘how can you help people who have hiv/aids in their families?’ fell into the following categories: • referral – ‘by referring them to the nearest group of gapa.’ • tolerance – ‘by asking them to accept the child so that he/she can accept the disease’. spouse son daughter nephew niece brother sister grandchild other 0 5 10 15 20 25 30 35 n u m b e r o f d e a th s 12 4 30 30 15 10 9 7 17 fig. 2. grandmothers’ family members who had recently died. spouse son daughter nephew niece brother sister grandchild other 2 10 32 8 15 6 6 7 16 0 5 10 15 20 25 30 35 n u m b e r in fe c te d fig. 3. grandmothers’ family members who were hiv positive. make up june issue nicky 5/30/05 2:20 pm page 39 june 2005 the southern african journal of hiv medicine40 • education – ‘to teach them how to look after people who have aids and not just to throw them away’. • destigmatisation – ‘teach them not to hide it, look after herself honestly. this is not the end of the world.’ • practical help – ‘i can help the person to bath the hivpositive person, i can cook for them and comfort them.’ • counselling – ‘counselling, giving hope, it’s not the end of the world to be hiv-positive.’ every month from july 2004 to december 2004 all members of gapa were invited to attend an indaba at the gapa centre in khayelitsha. the average monthly attendance was 90 grandmothers. the programme of the gathering followed a similar format each month. it included a talk about hiv/aids by one of the group leaders, prayer and song, and an hour during which grandmothers were invited to address the group about what belonging to gapa meant to them. by giving them an open topic to talk about, the researchers discovered what the grandmothers felt to be most important issues in their relationship with gapa. their testimony was recorded and transcribed from isixhosa into english for later analysis. the testimony by individual grandmothers caused the atmosphere of the gathering to be emotionally charged and there were frequent outbursts of crying and wailing by grandmothers who were overcome by emotion. after each grandmother’s testimony there would a short spiritual song or a prayer by the whole group. these sessions were therapeutic for the individual speaking out as well as for others who could relate to their stories. the data gathered were rich and multitudinous. the researchers sorted the data into broad categories based on issues that were repeatedly brought up when the grandmothers were addressing those present at the indabas. their testimony dealt with subjects such as their health and their interactions between their families and their communities. direct quotes from what the grandmothers said at the indabas capture the essence of what they considered to be the most important issues surrounding the aids epidemic and their interaction with gapa. grandmothers’ health many of the grandmothers said that being left on their own to cope with death and illness in the family caused them to suffer from stress and ill health. ‘before i heard that my daughter was hiv positive i had nothing wrong with my health. no high blood pressure, no diabetes, but when she fell sick with tb and i was told it was hiv, i was devastated, i became sick myself. when i met the people who were attending the gapa group i felt better. even when she died leaving a 5-year-old baby i was stronger than before.’ family dynamics grandmothers spoke of being isolated from their communities because of the stigma associated with the unknown. in some cases grandmothers revealed that their family members had kept their conditions secret and denied being infected even though they were very ill. ‘i am very thankful to gapa. where would we be today without these groups? we are here because of our children. they are driving us crazy. i don’t have a good life myself. my grandson is on drugs. always he steals everything he sees. at the same time my daughter is sick with hiv but does not want to accept. i am so glad that mrs f has given us this opportunity to share our burdens and get support from you. with the help and support of gapa i am sure i will be able to survive difficulties and help my daughter come back to her senses.’ the value of being in a support group was described as providing education about the disease and providing emotional support which gave them strength to speak openly about aids. ‘it is good to talk about hiv to protect it from being a scary thing.’ ‘our lives have been touched by gapa. it taught us to accept hiv as other diseases. i am staying at home with my daughter who is hiv+ but sometimes forgets she has that disease. that is the way gapa made me accept hiv. i am at peace with the disease.’ grandmothers who received preschool fees for their grandchildren expressed relief that children who otherwise would be kept at home had somewhere safe to go to during the day. ‘we have grandchildren with whom we were sitting alone at home. i am no longer with sorrows because my granddaughter is at preschool paid for by gapa.’ ‘now my grandson attends a preschool and is paid for by gapa because i don’t have any money to pay for him.’ interaction with others in the group some grandmothers described how when a gapa group leader invited them to join a support group in their area they went along to the group with scepticism. however they soon realised the benefits of the knowledge, understanding and emotional support they received from their peers. joining the psychosocial groups gave them a feeling of togetherness and acceptance with others in their group. ‘when i entered mrs m’s house (group leader) i could feel the acceptance in the women that she was working (sewing) with. now even if people talk about aids i no longer get the monthly indabas make up june issue nicky 5/30/05 2:20 pm page 40 the southern african journal of hiv medicine june 2005 4 1 anxious thinking that they mean the aids in my family. i have learned to accept all situations and sicknesses through gapa.’ furthermore, they learned new practical skills such as sewing and gardening. they were very proud to discover that they were able to make useful household articles that they could sell or use in their own homes. planting their own vegetables was also a source of pride to them. ‘i gained a lot from gapa. i now eat vegetables, cabbage and spinach grown in my garden.’ results of this research project are very encouraging and show conclusively that gapa is making a positive contribution to the lives of grandmothers and their families. the information that grandmothers receive in workshops, from group leaders and their peers equips them with some practical skills to cope with their daily lives. food gardens have been started, financial aid in the form of government grants has been accessed, handicraft groups have been started to increase household income, and small children have been sent to preschool. grandmothers have found strength from one another to speak out about the stigma that existed around families that had hiv-positive members, and have been able to lean on each other in times of family deaths and crises. gapa has bred a group of grandmothers who are well informed and concerned for their families and communities in an atmosphere of ignorance and fear of hiv/aids. grandmothers indicated time and again that with one another’s support they were willing to share knowledge with their communities. furthermore, they acknowledged that a problem shared became less of a problem and resolved to encourage families to disclose their hiv status so that they too could benefit from community support. to sum up, hiv/aids is killing the younger people of south africa and it is the grandparents who will be left with much of the burden of bringing up future generations of south africans. the problem has been succinctly put by a grandmother at an indaba: ‘elderly women are crying on their own with no one to talk to. it has turned from them expecting to be buried by their children, now elderly women bury their children. that is not nice, we need to comfort each other under this umbrella (gapa).’ conclusion make up june issue nicky 6/1/05 11:13 am page 41 abstract introduction materials and methods results discussion conclusion acknowledgements references about the author(s) bhaveshan reddy department of virology, faculty of health science, university of the witwatersrand, johannesburg, south africa national health laboratory service, johannesburg, south africa naseem cassim national health laboratory service, johannesburg, south africa department of haematology and molecular medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa florette treurnicht department of virology, faculty of health science, university of the witwatersrand, johannesburg, south africa national health laboratory service, johannesburg, south africa zinhle makatini department of virology, faculty of health science, university of the witwatersrand, johannesburg, south africa national health laboratory service, johannesburg, south africa citation reddy b, cassim n, treurnicht f, makatini z. factors influencing the high rejection rates of hiv 1/2 serology samples at charlotte maxeke johannesburg academic hospital and the cost implications. s afr j hiv med. 2022;23(1), a1326. https://doi.org/10.4102/sajhivmed.v23i1.1326 original research factors influencing the high rejection rates of hiv 1/2 serology samples at charlotte maxeke johannesburg academic hospital and the cost implications bhaveshan reddy, naseem cassim, florette treurnicht, zinhle makatini received: 05 oct. 2021; accepted: 12 nov. 2021; published: 11 jan. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: hiv enzyme-linked immunosorbent assay (elisa) is one of the most requested test sets within virology and forms an essential part of patient management. assessment of the rejection criteria is a key quality indicator, crucial for improving laboratory services and efficiency to ensure accurate and reliable results. objectives: the aim of this study was to identify the factors that influence the hiv 1/2 serology rejection rates (rr) at charlotte maxeke johannesburg academic hospital and to evaluate the associated costs. methods: a retrospective study was conducted (june to december 2019) to identify the rr and rejection criteria of hiv serology samples throughout the total testing process. descriptive analysis using percentages and frequencies was used to analyse the rr by phase, health establishment, ward and healthcare professional. a cost analysis incorporating minor and major costs was modelled in each phase of testing, and the total cost of rejections was calculated. results: a total of 6678 tests were received, and 738 were rejected (rr = 11.1%). the pre-analytical phase contributed significantly to the overall rr, with the requirement of a separate sample (57.44%) the most common reason for rejection. the total cost per rejected test was $2.47, which amounted to a total rejection cost of $197.55, of which $158.18 was caused by the pre-analytical rejection criteria. conclusion: high rr of hiv tests were noted, resulting in significant cost wastage. identification and analysis of rejections must be implemented across all laboratories to improve the efficiency of testing, provide a cost-saving benefit and maintain high laboratory standards. keywords: hiv; rejection rates; cost analysis; laboratory; diagnostics. introduction hiv remains a leading cause of increased morbidity and mortality, especially in southern africa. despite active measures to control the course of this disease, over 7 million individuals are living with hiv in south africa.1 the joint united nations programme on hiv/aids (unaids) 95-95-95 goals highlight the role of diagnostic testing as one of the main strategies in controlling this pandemic.2 providing accurate and reliable results timeously has proven to have positive outcomes in the management of hiv-infected individuals.3 in line with the 95-95-95 targets, south africa adheres to the universal test and treat strategy. as such, the laboratory has a responsibility to provide quality results to promote patient safety. a constant increase in test demand results in increased workload, which leads to inefficiencies within the laboratory and healthcare facility. as a result, laboratory accountability for patient safety has been highlighted in recent studies and should include the monitoring and analysis of key quality indicators such as rejection rates (rr).4 this can be tailor-made to accommodate different laboratories; however, when doing so, pre-existing limitations such as laboratory design, infrastructure, personnel and operating processes must be considered. the rejection of a sample has detrimental consequences for the laboratory, health facility and individual tested. this can be reflected in delayed turnaround times, reduced efficiency, poor workflow, cost implications, missed or delayed diagnostic opportunities and loss to follow-up.5,6 a rejected test caused by laboratory error or an hiv test that is incorrectly requested in a setting such as the early infant diagnosis (eid) programme can be a major pitfall in achieving targets that aim to reduce new paediatric infection rates (0–24 months). several studies reported that a significant number of rejected tests are not repeated (once-off occurrence) and can account for up to a 12% increased chance of inappropriate patient care.7 a projected error rate of this magnitude in the south african context can apply tremendous pressure to the already financially constrained and resource-burdened public health sector, especially in key age categories such as the paediatric population. recent literature reports several factors contributing to increased rr throughout the total testing process, including haemolysis, the mislabelling of samples and inappropriate sample collection.8 the total testing process consists of three phases – (1) pre-analytical, (2) analytical and (3) post-analytical – with the majority of rejections occurring in the pre-analytical phase.9 with the rise in the burden of diseases and the emergence of novel pathogens, there has been an increased need for diagnostic testing; however, this need has not been met with the necessary financial resources. to support the increase in testing, there is a need to review cost-saving strategies and how they will benefit the laboratory as well as the patient. a costing analysis that used the markov probability model suggested a total loss of $357.15 per hospital patient.10 similarly, a number of studies have estimated pre-analytical rr costs to range between $160.00 and $225.00 per month.10,11 these substantial costs can have a significant impact on the total hospital budget. the primary aim of this study was to assess the hiv serology rr and reasons in the department of virology, national health laboratory service (nhls), charlotte maxeke johannesburg academic hospital (cmjah). the secondary aim was to undertake a costing analysis to illustrate the financial implications of these rejections in a typical south african health laboratory. materials and methods study setting this retrospective study was conducted for the period 01 june 2019 to 31 december 2019 in the department of virology of the nhls based at cmjah (johannesburg, south africa). the department provides a dedicated 24-h diagnostic service to cmjah, a tertiary-level hospital, surrounding primary healthcare (phc) facilities and both regional and district level hospitals. specimen registration for hiv serology test requests, samples were registered on the laboratory information system (lis) following standard operating procedures to capture all demographic, clinical and test request details provided on the laboratory request form. the test results are automatically downloaded to the lis, and all laboratory data are stored in the nhls corporate data warehouse (cdw). test rejections and rejection criteria all rejection codes and descriptions were defined by the local laboratory and the nhls expert committees. electronic gatekeeping of samples was included as a rejection criterion in this study, defined as any hiv serology sample requested before the minimum request interval time had elapsed. the pre-analytical phase included all processes from sample collection to receipt at the cmjah nhls receiving office. all processes that pertained to the performance of the test were assigned to the analytical phase, whereas the post-analytical phase involved the analysis, interpretation and authorisation of the test results. lookup table for each rejection, a rejection code is entered into the lis to indicate to the requesting healthcare practitioner the reason for not performing the test, for example ‘specimen insufficient’ (spins). because of the vast number of rejection codes reported, a lookup table was developed using microsoft excel (redmond, california, united states) to assign the rejection status (rejected/not rejected) and phase of testing (pre-analytical, analytical or post-analytical). lookup tables were then used to group assigned codes of large data sets with similar information, avoiding manual coding (table 1). table 1: example of some rejection codes and rejection reasons used to assign the rejection status and rejection phase values in a lookup table for hiv serology samples. data analysis an nhls-specific test code for hiv serology was used to extract data from the cdw for the 6 months (01 june to 31 december 2019). all rejected tests and the reasons for rejection were captured on the lis and downloaded to the cdw database. the data extract also included the following variables: (1) age, (2) facility name, (3) referring healthcare professional, (4) rejection code, (5) rejection reason description, (6) date of collection, (7) date of rejection, (8) ward code and (9) ward description. age was stratified into three categories – infants and toddlers (0–24 months), children and adolescents (2–18 years) and adults (> 18 years) – and the total number of rejections per age group was calculated. we used the facility name to assign the health establishment type (phc facility or hospital). similarly, we used ward descriptions to assign the following ward types: (1) medical, (2) trauma and casualty, (3) surgical, (4) intensive care unit (icu), (5) paediatrics, (6) obstetrics and gynaecology and (7) antiretroviral (arv) clinic. experts read the ward description and assigned the ward type; for example ‘area 165 medical casualty cas’ was assigned as the trauma and casualty ward. requisitioner information, which included the healthcare practitioner’s name and professional society registration details (south african nursing council [sanc] or health professions council of south africa [hpcsa]), was used to assign the following professional types: (1) nurse, (2) medical intern (in) and (3) medical practitioner (mp). for example, requisitioner details that included sanc, in and mp numbers were assigned as a nurse, intern and medical practitioner, respectively. data that did not include the rejection reason description could not be categorised and were excluded from this study. rejection rate calculations the rr were calculated using the formula: and reported as a percentage. the rr were analysed by process phase, health establishment, ward and healthcare professional. cost analysis the cost analysis was performed to determine the cost per rejection for each phase of testing. all costs were obtained in south african rands (zar) and converted to united states dollars (usd) using an exchange rate of 14.60/$1.00. the accounting stance was assumed to be the provider of diagnostic services, and costs associated with overheads and laboratory management were excluded. for the pre-analytical phase, data generated from a local study that conducted a top–down costing of historical expenditure data for the 2019–2020 financial period for the cmjah receiving office were used ($0.77 per registration). a pre-analytical cost per test was calculated using the assumption that on average 3.5 tests are requested per registration. for the analytical phase (pre-analytical cost + analytical cost), the cost per test associated with the analyser, staffing, reagents and test consumables was determined. these costs were obtained from the oracle enterprise resource planning (erp) system of the nhls (box 1). the roche cobas 8000 modular analyser (module e602; roche diagnostics, basel, switzerland) was provided through a service placement agreement, and thus the costs associated with the outright purchase, maintenance and servicing of the instrument are included in the reagent cost. all costing data were captured in microsoft excel for analysis. box 1: itemised list of resources within the analytical phase of testing. for staffing costs (medical technologist – c2 grade), given the short sample preparation time, the time to perform the test (in minutes) was multiplied by the annual cost per minute, based on the assumption that hiv serology testing is offered on a 365-day running cycle (annual cost / 365). similarly, for the post-analytical phase, the average time (3 min) for a registrar (d1 grade) to review and authorise the result on the lis was used. all staff salaries were based on the nhls cost to company (ctc) salary scales. to calculate the total cost of rejection, the cost per test was multiplied by the total number of hiv serology rejections. corporate warehouse data were provided as a csv file used for preliminary analysis in microsoft excel. descriptive analysis was conducted using tibco statistica version 13.5.0 analytical software (california, united states). ethical considerations the study was approved by the human research ethics committee, university of the witwatersrand (clearance certificate number m201117). results a total of 6678 hiv serology samples were received for the study period, of which 738 samples were rejected (11.1%). among the rejected group, a mean age of 32 years was reported (standard deviation: 20.57), with the majority attributed to the adult population (560/738; 75.88%). within the age group of 0–24 months, there were 106 rejected samples (14.36%). there were 671 (90.92%) and 67 (9.08%) rejected samples from hospitals and phc facilities, respectively (figure 1). figure 1: rejection rates and criteria throughout the total testing process for hiv serology samples performed at the department of virology, national health laboratory service, charlotte maxeke johannesburg academic hospital, south africa, between 01 june 2019 and 31 december 2019. the majority (719/738; 97.4%) of rejections occurred in the pre-analytical phase, where most samples (413/719; 57.4%) were rejected because of the requirement for a separate sample (figure 1). this was followed by rejections as a result of electronic gatekeeping (13.6%), spins (10%), requiring a clotted sample (9.9%) and specimen not received (3.9%). other (5.1%) reasons for sample rejection in the pre-analytical phase included mislabelling, incomplete healthcare worker or patient information, and unsuitable samples. eighteen (2.43%) samples were rejected in the analytical phase because of a number of laboratory errors, such as poor sample integrity, and one (0.13%) in the post-analytical phase because of a non-reportable result. based on the ward type, the medical unit had the highest number of rejections (239/738; 32%) followed by trauma and casualty (136/738; 19%), surgical (104/738; 14%) and icu, which accounted for 11% (77/738) (figure 2). the requirement of a separate sample was the most common reason for rejection across all departments, health facilities and age groups. within this criteria, hospital samples accounted for 375/413 (90.80%) and clinics for 38/413 (9.20%) rejections. transport of samples was a rejection criterion associated with clinic samples only (3/67; 4.47%). figure 2: pie chart displaying the percentage of hiv serology sample rejections by ward type at the department of virology, charlotte maxeke johannesburg academic hospital, south africa between 01 june 2019 and 31 december 2019. the intensive care unit metric includes both the adult and paediatric age categories. further analysis by health establishment and healthcare profession type revealed that, at hospitals, the majority of rejections were requested by medical practitioners (543/671; 80.92%). in contrast, interns, nurses and clinical associates accounted for the remaining 19%. for phc facilities, 79.1% of rejections were requested or collected by nursing staff (table 2). table 2: number of hiv serology samples rejected, by health establishment and healthcare professional type. table 3 summarises the itemised costs for hiv serology by testing phase. the total cost per sample for the pre-analytical phase was calculated to be $0.22. the bulk of the pre-analytical costs was for staff, at $0.13 per sample. for the analytical phase, a cost per test of $1.83 was reported. the hiv reagent pack contributed $1.04, compared to $0.50 for buffer and waste consumables. the staff cost contributions for the analytical and post-analytical phases were $0.29 and $0.42, respectively (table 3). table 3: itemised cost per sample for each phase of testing for hiv serology rejections. the total cost per sample was calculated to be $2.47 across the three phases of testing. the total cost of rejections was $197.55 (table 4). the pre-analytical phase contributed 82.6% of the total cost of rejections ($158.18), followed by the analytical phase, with 17.2% ($36.90). given the single post-analytical rejection, the total cost for that phase of testing was $2.47. table 4: determining the total cost of rejections for hiv serology testing across the three phases of testing. discussion in this study, we assessed the rates, reasons and cost of rejections for hiv serology tests at the department of virology at an academic hospital in south africa over 6 months in 2019. overall rr of 3.6% were reported for all test requests received during 2019 (cmjah nhls statistics, unpublished). this is consistent with other studies that reported similar average rr (0.1% – 3.49%).12,13 however, the hiv serology rr of 11.1% reported in this study are significantly higher than reported rates and not aligned with the accepted internal test rr of < 5% set for virology. in the laboratory setting described, multiple reasons for rejection throughout the total testing process were noted. as reported in other studies, the pre-analytical phase was identified as the main phase of rejection, where 1 in 10 patients had a missed or delayed diagnosis, predominantly as a result of the requirement for a separate sample. this criterion is consistently noted as the most common reason for rejection in the data described here and highlights a gap in training on hiv serology sample collection for healthcare practitioners. in addition, despite current eid guidelines, which recommend that an hiv dna polymerase chain reaction (pcr) test be done from birth to 18 months of age, 14% of rejected tests fell within this age group. our data identified that hiv serology tests are incorrectly requested within this age group, indicating a need for clinical training on guidelines and laboratory requirements for testing. it further underlines the importance of routine monitoring and analysis of the rejection criteria as a key quality indicator for continuous improvement. this study also illustrates the laboratory’s acceptability criteria and how strictly they are adhered to. within the receiving laboratory, all staff are guided by the standard operating procedures for registration of a sample and the criteria for rejection. a large number of rejection criteria also fall within the clinical domain, over which the laboratory may not necessarily have influence and which requires tighter control with regard to the collection and requisition of samples by clinical departments. other studies have shown similar findings, in that a large number of errors (pre-analytical) occur outside the laboratory and are caused by actions predominantly by the healthcare workers.14 this is attributable to frequent staff rotation and substandard training. it is clear from the data of this study which healthcare personnel requested or drew samples that led to rejections and would benefit from additional training. all these aspects are clearly described in the nhls handbook provided to hospitals and clinics. as such, these errors could have easily been avoided, subsequently eliminating a large percentage of rejections. it is important to note that the rejected tests originate mainly from the medical, trauma and casualty, and surgical wards, where timeous and accurate hiv results are important for clinical management of patients because of the high burden of hiv in south africa. in response to these findings, despite the lack of standardised rejection criteria amongst laboratory networks, appropriate corrective and preventative actions can be implemented, monitored and assessed. these include regular staff training and routine competency assessments directed towards key receiving office staff and healthcare workers. these training mechanisms will provide the greatest outcome in terms of rr reduction but should also be extended to all healthcare and laboratory workers. laboratory manuals targeting key issues such as requesting a separate sample for hiv testing can avoid delays in turnaround time and patient management. training on the current hiv and eid guidelines, as well as providing itemised rejections for a specific test set by ward, may also aid in the regular monitoring and evaluation of procedures, which will ensure good diagnostic practices. reduced rr may lead to improved patient care.15 the impact of rejecting samples also has financial implications. the current study findings assessed the cost implications of these rejections. for one laboratory, an annual cost of $383.03 was reported.16 when these data are extrapolated for national hiv serology testing across the nhls for the 2019–2020 financial period (assuming 11.1% rr), the total cost of rejections amounts to $122 295. this signifies a substantial cost burden to the health system that could be avoided. furthermore, the cost of rejections must be seen as a contributing loss within the broader healthcare system. improving the efficiency of testing will have a twofold benefit, firstly providing a significant contribution to healthcare resource savings and secondly improving a key quality indicator that plays a pivotal role in maintaining high laboratory standards.17,18 as the rejections occurred primarily within the pre-analytical phase in this study, it affirms that measures put in place through detailed rejection criteria by the nhls also served to reduce the costs associated with performing unnecessary test or tests with compromised quality through the use of shared samples.19 the study limitations included a small number of unspecified rejection reasons from the data extract, as well as the rejection reasons being grouped into similar categories. this may have resulted in non-specific rejection codes being used that therefore did not necessarily accurately describe the rejection. the data from this study only take into consideration hiv laboratory-based testing and exclude a large volume of point-of-care testing performed at other health establishments. however, because of the availability of such data, this study recognises an opportunity to improve the analysis of rr if the data are managed properly and categorised in a more user-friendly manner. this will allow for laboratories to monitor their data over shorter time intervals and will lead to the timely identification of problem areas. this will encourage proactive measures to be implemented in order to reduce the overall number of rejections. conclusion there are substantial data to suggest that inappropriate test use, rejections and repeat testing contribute to increased laboratory expenditure and unfavourable patient outcomes. identification of the key rr is an additional tool to monitor laboratory efficiency, improve service delivery and identify areas in the testing process that need intervention through corrective actions. limiting rejections in the laboratory will save significant costs and time and improve the clinical utility of diagnostic tests, which will benefit the laboratory, patients and the healthcare system. acknowledgements the authors acknowledge and thank the department of virology and staff who assisted in the processing of samples. the nhls is acknowledged for granting access to the data used in this study. competing interests the authors acknowledge no financial or personal relationships that may have inappropriately influenced them during the write-up of this article. authors’ contributions b.r. and z.m. conceptualised the study. b.r. executed the research and data analysis. the first draft was reviewed by z.m. n.c. provided input into the cost model and addition of key resources. z.m, n.c and f.t reviewed the subsequent drafts, provided critical revision and feedback, and contributed to the overall standard of work. funding information the authors received no financial support for the research, authorship, and/or publication of this article. data availability the raw data were generated by the national health laboratory services corporate data warehouse. derived data supporting the findings of this study are available from the corresponding author, b.r., upon suitable 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2010;20(2):147–153. https://doi.org/10.11613/bm.2010.014 847 persistent dizziness and recurrent syncope due to hiv-associated addison’s disease: case report from a resource-limited setting d kibirige, r ssekitoleko, e mutebi department of medicine, makerere university college of health sciences and infectious diseases unit, mulago national referral and teaching hospital, kampala, uganda d kibirige, mb chb, mmed (int med) r ssekitoleko, mb chb, mmed (int med)   department of medicine, makerere university college of health sciences and endocrine unit, mulago national referral and teaching hospital, kampala, uganda e mutebi, mb chb, mmed (int med), msc (ceb) corresponding author: d kibirige (davouirek@yahoo.co.uk) addison’s disease or primary adrenal insufficiency is a well-recognised fatal endocrine condition among hiv-infected patients. hiv infection is associated with adrenal gland destruction and profound disruption of the hypothalamic-pituitary adrenal axis. we describe a case of hiv-associated addison’s disease in a 58-year-old newly diagnosed hiv-seropositive male patient, highlighting its occurrence in this era of the hiv/aids pandemic. s afr j hiv med 2012;13(3):150-151. doi:10.7196/sajhivmed.847 addison’s disease, or primary adrenal insufficiency, is a chronic disorder of the adrenal cortex resulting in inadequate production of glucocorticoids and mineralocorticoids. it is an often-missed and potentially lethal condition associated with increased mortality if untreated.1 addison’s disease typically presents with nonspecific vague symptoms of an insidious onset, such as fatigue, malaise, abdominal pain, weight loss, nausea and vomiting. physical signs include orthostatic hypotension or shock, and hyperpigmentation, while biochemical indicators include hyponatraemia, hyperkalaemia and hypoglycaemia.1 , 2 causes of addison’s disease include: autoimmune adrenalitis; chronic infections such as tuberculosis (tb), cytomegalovirus (cmv) infection; adrenal haemorrhage or infiltration; and genetic and idiopathic causes.1 addison’s disease has also been documented among hiv-infected patients.3 the potential pathophysiological mechanisms of adrenal dysfunction include direct destruction of the adrenal glands caused by hiv or opportunistic infections such as cmv or tb, neoplastic infiltration, and the effects of pro-inflammatory cytokines. the disease may also be drug-induced, e.g. by ketoconazole and rifampicin.3 , 4 case description a 58-year-old newly diagnosed hiv-seropositive antiretroviral therapy (art)-naive male patient presented with a 3-month history of progressive darkening of the palms of his hands, persistent postural dizziness, fatigability, profound general body weakness, syncope and recurrent episodes of fasting hypoglycaemia. he did not report a history suggestive of tb, fever, headaches, convulsions or chronic glucocorticoid use. physical examination revealed mild pallor of the mucous membranes, generalised hyperpigmentation involving the face, oral mucosa and the palmar creases, and absence of peripheral lymphadenopathy. small volume tachycardia (110 beats/min) with postural hypotension (supine blood pressure 90/50 mmhg, sitting blood pressure 70/40 mmhg) was noted on cardiovascular examination. there were no signs of cmv retinitis or papilloedema on fundoscopy. an extensive clinical evaluation did not reveal any underlying neoplasm. laboratory tests revealed a mild normocytic normochromic anaemia (10.6 g/dl; range 12.0 16.0), a cd4 count of 17 cells/mm3, random blood sugar of 2.6 mmol/l (3.5 7.0), hyponatraemia (128 mmol/l; 135 150), mild hyperkalaemia (5.8 mmol/l; 3.5 5.5), raised creatinine (137 µmol/l; 0 106) and a low 8 am cortisol level (151.2 nmol/l). results were normal for serum cryptococcal antigen (crag), liver function, serum albumin and corrected calcium level tests. an electrocardiogram and echocardiography, performed to rule out any structural heart lesion, were normal. results of a chest x-ray and abdominal ultrasound were also normal. due to financial constraints, an 8 am serum adrenocorticotrophic hormone (acth) test, specific adrenal auto-antibody test and computed tomography (ct) scan of the adrenal gland were not performed. a diagnosis of probable hiv-associated addison’s disease and severe immunosuppression was made. the patient received a slow bolus of intravenous 50% dextrose, intravenous fluids and hydrocortisone. he was later maintained on oral prednisolone (5 mg in the morning and 2.5 mg in the evening) and art was initiated (emcitrabine, tenofovir and efavirenz). oral fludrocortisone and hydrocortisone were not used as they are not readily available in the country. the patient was discharged following remarkable improvement, and was fully counselled about his condition. no opportunistic infection has been discovered at subsequent follow-up visits. discussion this case demonstrates that hiv-associated addison’s disease occurs especially with severe immunosuppression. an 8 am cortisol level <165 nmol/l (6 µg/dl) is highly suggestive of addison’s disease,1 as demonstrated in our patient. however, most patients require further assessment with a synthetic acth test (250 µg synacthen) for confirmation of the disease. notably, this test is not readily available in most resource-limited settings. an increase in the serum cortisol level 1 hour after the synacthen injection to >500 nmol/l (18 µg/dl) confirms the absence of the disease.1 , 2 hiv has a direct independent destructive effect on the adrenal glands and disrupts the hypothalamic-pituitary-adrenal axis, producing subclinical to overt features of addison’s disease. co-existing opportunistic infections, such as tb and cmv, among hiv-infected patients increase the risk of developing addison’s disease.3 , 4 biochemical evidence of primary adrenal insufficiency is more common in the late stages of hiv infection and with severe immunosuppression, as in this case.5 , 6 european studies of hospitalised patients with advanced hiv infection reported a 17 22% prevalence of addison’s disease.6 , 7 however, a varying prevalence has been documented in africa. meya et al. 8 reported a prevalence of 19% among 113 critically ill hiv-infected ugandan patients. the majority of these patients had tb, kaposi sarcoma and cryptococcal meningitis as the main underlying co-morbidities.8 none of the patients had advanced hiv infection as the sole clinical diagnosis. in contrast, studies by soule9 and ross et al. 10 among south african patients reported no hiv/aids-related addison’s disease. the management of addison’s disease is focused mainly on the correction of hypovolaemia and electrolyte imbalances with adequate amounts of intravenous fluids, the correction of hypoglycaemia, long-term glucocorticoid and mineralocorticoid replacement and the management of underlying causes.1 , 2 a ct scan of the adrenal glands is significant in cases secondary to infections such as tb, as well as in post-sepsis adrenal haemorrhage and neoplastic infiltration. in particular, tb of the adrenal glands revealed by ct imaging presents initially with bilateral adrenal enlargement; calcifications develop later in the disease.1 ct imaging is costly, however, and not readily available in most resource-limited settings. in cases of hiv-associated addison’s disease, extensive screening for occult opportunistic infections prior to art initiation and timely initiation of art are highly recommended. conclusion as demonstrated by this case, clinicians should have a high index of suspicion of addison’s disease in hiv-infected patients presenting with typical electrolyte abnormalities or unexplained hypotension. the disease should be managed instantly and appropriately to reduce the risk of mortality. references 1. arlt w, allolio b. adrenal insufficiency. lancet 2003;361:1881-1893. 1. arlt w, allolio b. adrenal insufficiency. lancet 2003;361:1881-1893. 2. ross i, levitt n. diagnosis and management of addison’s disease: insights gained from a large south african cohort. journal of endocrinology, metabolism and diabetes of south africa 2011;16:86-92. 2. ross i, levitt n. diagnosis and management of addison’s disease: insights gained from a large south african cohort. journal of endocrinology, metabolism and diabetes of south africa 2011;16:86-92. 3. janet l, grinspoon s. adrenal function in hiv infection. curr opin endocrinol diabetes obes 2010;17:205-209. 3. janet l, grinspoon s. adrenal function in hiv infection. curr opin endocrinol diabetes obes 2010;17:205-209. 4. evangelia z, george c. dysfunction of the hypothalamic-pituitary-adrenal axis in hiv infection and disease. hormones 2008;7:205-216. 4. evangelia z, george c. dysfunction of the hypothalamic-pituitary-adrenal axis in hiv infection and disease. hormones 2008;7:205-216. 5. hoshino y, yamashita n, nakamura t, et al. prospective examination of adrenocortical function in advanced aids patients. endocr j 2002;49:641-647. 5. hoshino y, yamashita n, nakamura t, et al. prospective examination of adrenocortical function in advanced aids patients. endocr j 2002;49:641-647. 6. membreno l, irony i, dere w, et al. adrenocortical function in acquired immune deficiency syndrome. j clin endocrinol metab 1987;65:482-487. 6. membreno l, irony i, dere w, et al. adrenocortical function in acquired immune deficiency syndrome. j clin endocrinol metab 1987;65:482-487. 7. casado j, piedrola g. adrenal insufficiency in patients with aids: when to suspect it and how to diagnose it. aids patient care stds 1997;11:339-343. 7. casado j, piedrola g. adrenal insufficiency in patients with aids: when to suspect it and how to diagnose it. aids patient care stds 1997;11:339-343. 8. meya d, katabira e, otim m, et al. functional adrenal insufficiency among critically ill patients with human immunodeficiency virus in a resource-limited setting. afr health sci 2007;7:101-107. 8. meya d, katabira e, otim m, et al. functional adrenal insufficiency among critically ill patients with human immunodeficiency virus in a resource-limited setting. afr health sci 2007;7:101-107. 9. soule s. addison’s disease in africa a teaching hospital experience. clin endocrinol (oxf) 1999;50:115-120. 9. soule s. addison’s disease in africa a teaching hospital experience. clin endocrinol (oxf) 1999;50:115-120. 10. ross i, boulle a, soule s, et al. autoimmunity predominates in a large south african cohort with addison’s disease of mainly european descent despite long-standing disease and is associated with hla dqb*0201. clin endocrinol (oxf) 2010;73:291-298. 10. ross i, boulle a, soule s, et al. autoimmunity predominates in a large south african cohort with addison’s disease of mainly european descent despite long-standing disease and is associated with hla dqb*0201. clin endocrinol (oxf) 2010;73:291-298. http://www.sajhivmed.org.za open access page 1 of 1 reviewer acknowledgementpage 1 of 1 reviewer acknowledgement acknowledgement to reviewers in an effort to facilitate the selection of appropriate peer reviewers for the southern african journal of hiv medicine, we ask that you take a moment to update your electronic portfolio on https:// sajhivmed.org.za for our files, allowing us better access to your areas of interest and expertise, in order to match reviewers with submitted manuscripts. if you would like to become a reviewer, please visit the journal website and register as a reviewer. to access your details on the website, you will need to follow these steps: 1. log into the online journal at https:// sajhivmed.org.za 2. in your ‘user home’ [https://sajhivmed.org. za/index.php/hivmed/ user] select ‘edit my profile’ under the heading ‘my account’ and insert all relevant details, bio statement and reviewing interest(s). 3. it is good practice as a reviewer to update your personal details regularly to ensure contact with you throughout your professional term as reviewer to the southern african journal of hiv medicine. please do not hesitate to contact us if you require assistance in performing this task. publisher: publishing@aosis.co.za tel: +27 21 975 2602 tel: 086 1000 381 the editorial team of the southern african journal of hiv medicine recognises the value and importance of peer reviewers in the overall publication process – not only in shaping individual manuscripts, but also in shaping the credibility and reputation of our journal. we are committed to the timely publication of all original, innovative contributions submitted for publication. as such, the identification and selection of reviewers who have expertise and interest in the topics appropriate to each manuscript are essential elements in ensuring a timely, productive peer review process. we would like to take this opportunity to thank the following reviewers who participated in shaping this volume of the southern african journal of hiv medicine. we may have omitted a reviewer’s name in error and for this we do apologise and thank that esteemed colleague. we appreciate the time taken to perform your review(s) successfully. abdullah e. laher abdulsalam m. yakasai aditi rao alvin munsamy anandan a. moodley andrew ross anthony a. oyekunle ava avalos bianca da costa dias brian eley busisiwe nkala-dlamini cait-lynn d. wells carolina e. nel catherine orrell cathy van rooyen christen r. lahner cleophas chimbetete corinna m. walsh david p. moore david b. meya david boulware dickman gareta dirk blom eckhart j. buchmann eitzaz sadiq emma kalk farai k. munyayi frasia oosthuizen gary maartens godfrey m. rwegerera graeme hoddinott hannes p. mouton helena rabie herculina s. kruger huibrecht c. lion-cachet james j.c. nuttall joana woods john s. lambert johnny mahlangu jonathan j. stadler joram l. nyandat juan jansen van vuuren juliane hiesgen june fabian karl-gunter technau kate braithwaite katherine m. gill kim roberg kudzaishe mangombe lauren jennings lee fairlie linda rogers louise j. gilbert lucas hermans marcelle myburgh mareike rabe mark w. sonderup mark j. siedner melanie nicol melinda a. judge micah oyaro michael t. boswell michelle venter mina hosseinapour moherndran archary natasha davies nnabuike c. ngene nondumiso s. makhunga-ramfolo nosisa sipambo patrick m. masokwane pieter ekermans prudence ive regina osih remco p.h. peters sarah a. van blydenstein shaun d. maasdorp shayne a. loubser siphamandla b. gumede sipho dlamini susan j. randall suzanne mccluskey talitha crowley tammy meyers theresa t. rossouw tim tucker tinashe mudzviti violet m. awori willem d.l. venter http://www.sajhivmed.org.za� https://sajhivmed.org.za� https://sajhivmed.org.za� https://sajhivmed.org.za� https://sajhivmed.org.za� https://sajhivmed.org.za/index.php/hivmed/user https://sajhivmed.org.za/index.php/hivmed/user https://sajhivmed.org.za/index.php/hivmed/user mailto:publishing@aosis.co.za abstract introduction methods discussion conclusion acknowledgements references about the author(s) billy m. tsima department of family medicine and public health, faculty of medicine, university of botswana, gaborone, botswana precious moedi princess marina hospital, dental department, gaborone, botswana joyce maunge botswana upenn partnership, gaborone, botswana kitso machangane botswana upenn partnership, gaborone, botswana martha kgogwane botswana upenn partnership, gaborone, botswana tebogo mudojwa botswana upenn partnership, gaborone, botswana joseph bastian department of psychiatry, perelman school of medicine, university of pennsylvania, philadelphia, united states of america warren bilker department of biostatistics, epidemiology and informatics, perelman school of medicine, university of pennsylvania, philadelphia, united states of america rebecca ashare department of psychiatry, perelman school of medicine, university of pennsylvania, philadelphia, united states of america robert schnoll department of psychiatry, perelman school of medicine, university of pennsylvania, philadelphia, united states of america robert gross department of medicine (id), perelman school of medicine, university of pennsylvania, philadelphia, united states of america citation tsima bm, moedi p, maunge j, et al. feasibility of implementing a novel behavioural smoking cessation intervention amongst human immunodeficiency virus-infected smokers in a resource-limited setting: a single-arm pilot trial. s afr j hiv med. 2020;21(1), a1075. https://doi.org/10.4102/sajhivmed.v21i1.1075 research project registration: project number: hpdme 13/18/1 original research feasibility of implementing a novel behavioural smoking cessation intervention amongst human immunodeficiency virus-infected smokers in a resource-limited setting: a single-arm pilot trial billy m. tsima, precious moedi, joyce maunge, kitso machangane, martha kgogwane, tebogo mudojwa, joseph bastian, warren bilker, rebecca ashare, robert schnoll, robert gross received: 05 feb. 2020; accepted: 08 mar. 2020; published: 24 june 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: tobacco use is prevalent amongst individuals infected with human immunodeficiency virus (hiv). in resource-constrained settings, pharmacological smoking cessation interventions are unfeasible because of their high cost. there is a need to develop and evaluate behavioural interventions to address the unique challenges of tobacco use in the hiv-infected populations in these settings. objectives: the authors aimed to assess the feasibility and acceptability of the behavioural activation/problem solving for smoking cessation (baps-sc) intervention programme to determine whether it should be tested in an adequately powered randomised controlled trial. method: the authors merged behavioural activation therapy (bat) with the principles of problem-solving therapy to create a novel five-session counselling model to address the unique challenges of tobacco cessation amongst those infected with hiv. feasibility measures included the rate of enrolment amongst those eligible and the retention rate and descriptive analysis of intervention acceptability. the authors’ secondary outcome was 7-day point smoking prevalence abstinence, confirmed with breath carbon monoxide. results: a total of 128 individuals were screened over 8 weeks with 50 deemed eligible and 40 enrolled (80%). retention at week 12 was 53% (21/40). the 7-day point prevalence abstinence, co-confirmed, at week 12 was 37.5% (15/40). all respondents indicated that they would recommend baps-sc to other smokers who want to quit, and would be willing to participate in the programme again up to the point of exit if they did not stop smoking. conclusion: a full-scale randomised control trial comparing baps-sc with usual practice is warranted to evaluate the efficacy of this novel intervention in these settings. keywords: smoking cessation; tobacco; behaviour activation; problem solving; hiv. introduction the human immunodeficiency virus (hiv) epidemic in sub-saharan africa has resulted in a large-scale transformation of healthcare delivery in heavily affected countries such as botswana.1 unfortunately, other health threats such as cardiovascular disease and cancer have emerged amongst people living with hiv/aids (plwha) partly because of the chronic inflammation of hiv that is compounded by high rates of smoking in this population.2 as such, addressing modifiable cardiovascular risk factors amongst those with hiv infection, including tobacco use, has become a critical priority.3,4 indeed, continued smoking amongst those with hiv infection can result in serious adverse effects, including reduced effectiveness of antiretroviral (arv) therapy.5 controlling for medication adherence and comorbid illicit drug use, hiv-infected smokers on arv have a significantly lower likelihood of achieving a viral response and a greater chance of viral or immunologic failure compared with their non-smoking counterparts.6 persistent smoking amongst hiv-infected individuals may also increase progression to acquired immunodeficiency syndrome (aids).7 pulmonary tuberculosis, a major public health crisis in sub-saharan africa, occurs at higher rates in smokers compared with non-smokers.8 overall, the mortality gains of arv treatment and the associated improved quality of life amongst those with hiv infection are being jeopardised by the cardiovascular and neoplastic diseases attributable to tobacco use in this population.9 although interest in quitting smoking is high amongst plwha,10,11,12 particularly when hiv treatment is initiated13 and when tobacco use treatment is integrated with hiv care,14 remarkably little research has focussed on developing and testing smoking cessation interventions for plwha.11 unfortunately, in low-income and developing countries, the costs of pharmacotherapy for nicotine addiction make pharmacological treatments currently inaccessible for plwha and further emphasise the importance of novel behavioural strategies. depressive symptoms are common in hiv-infected populations, often comorbid with smoking, and associated with poor smoking cessation rates.15 behavioural activation therapy (bat), rooted in a behavioural economic framework, has been effective at treating depression, and preliminary data in the united states of america (usa) suggests that it may also effectively address smoking.16 behavioural activation therapy aims to increase engagement in healthy rewarding activities (i.e., alternative reinforcers) by reducing patterns of avoidance, withdrawal and inactivity, and to decrease activities that enhance the rewarding aspects of smoking (i.e., complementary reinforcers). additionally, problem-solving approaches have been used with plwha to improve medication adherence and decrease depressive symptoms.17 behavioural activation therapy and problem-solving approach may help smokers select and implement activities that will replace smoking, thereby reducing smoking rates. the authors developed a novel counselling model incorporating elements of behavioural activation and problem solving to address the unique challenges of tobacco cessation amongst those with hiv infection. they aimed to assess the feasibility and appeal of behavioural activation/problem solving for smoking cessation (baps-sc) intervention to determine whether it should be tested in an adequately powered clinical trial. methods participant enrolment the authors conducted a single-arm pilot trial of the baps-sc intervention in botswana amongst hiv-infected individuals aged 18–65 years who smoked ≥ 5 cigarettes/day, on average, at four outpatient hiv clinics. the target accrual goal was 40 participants. this was based on the assumption that at least five participants would be enrolled per week, thus ensuring that the recruitment of human subjects into the trial is timely as this is vital to the success of the trial.18 the authors excluded participants if they reported current untreated and unstable alcohol dependence; current use or discontinuation within last 14 days of smoking cessation medications; current diagnosis of unstable and untreated major depression or current or past diagnosis of psychotic disorder; use of chewing tobacco, snuff or snus; current participation in a smoking cessation programme; or plans to use nicotine substitutes or smoking cessation treatments in the next 7 months. the restriction to 7 months was based on the anticipated period to conduct the trial so as to avoid contamination of the intervention with other smoking cessation modalities not under investigation. a trained recruiter approached each patient in clinic to ascertain smoking status. those acknowledging smoking were asked to participate in a questionnaire related to their smoking and offered participation in the pilot trial. those who agreed were referred to the research assistant who arranged to meet with them to determine eligibility and administer informed consent. design of intervention the authors merged bat with the principles of problem-solving therapy to create a novel five-session counselling model to address the unique challenges of tobacco cessation amongst plwha (baps-sc). members of the team created a formal treatment manual, which was evaluated for cultural appropriateness by botswana co-investigators, including assessment of translation and back translation and pre-pilot testing using videoconferencing to role play. key components of baps-sc include activity monitoring and rewarding activity scheduling, assessment of personal goals and values, assessment and altering of avoidance behaviour and other maladaptive coping strategies, and contingency management. behavioural activation/problem solving for smoking cessation focuses on reducing stress pile-up and loss of pleasure that accompanies the cessation process and on identifying and establishing environmental/social changes to promote abstinence. behavioural activation/problem solving for smoking cessation addresses smoking as a behaviour that prevents and restricts opportunities for contact with healthy rewarding behaviours. these changes are achieved through altering daily routines previously associated with smoking in ways that increase pleasure and mastery across life domains, reducing rumination and increasing behavioural skills to prevent return to smoking as a means of avoiding stressors. a pre-quit session (session 1) introduces participants to: (1) self-monitoring of mood and behaviour; (2) assessment of personal values to refine the treatment plan; and (3) scheduling of substitute rewarding activities that align with their abstinence goal. at the target quit date (tqd) session (session 2), participants’ experiences with abstinence are reviewed and functional analysis of behaviour is introduced, especially as it relates to smoking and avoidance patterns. information obtained is used to help generate a tailored behavioural activation plan by using the problem-solving framework to increase rewarding activities and relationships, reduce avoidant responses to distressing experiences and facilitate successful implementation of smoking trigger management strategies. sessions 3–5 incorporate strategies to address avoidance patterns, especially those involving smoking, and replace them with adaptive coping strategies, again by using problem solving. sessions were conducted by telephone over a 12-week period (with the first session lasting 1 h and subsequent sessions lasting 30–45 min on average) and involved weekly homework assignments. data collection and management collected data included information related to smoking behaviour (including nicotine dependence measured by the fagerström test for nicotine dependence19), anhedonia [using the snaith–hamilton pleasure scale (shaps)20] and feasibility (e.g., rate of accrual and retention and appeal of the intervention). participant accrual rate was defined as the number of participants enrolled over 8 weeks. retention was calculated as a proportion of participants enrolled who were available at week 12 contact session. study staff not acting as interventionists interviewed participants at baseline, week 6 and week 12 to determine if they were still smoking and whether they implemented the suggested intervention strategies. the timeline follow-back procedure assessed daily smoking between measurement time points.21 additionally, the amount of carbon monoxide (co) in participants’ breath was tested to confirm self-reported abstinence from tobacco. data were collected on paper and transferred to an electronic redcap database for analysis. data analysis the authors used descriptive statistics to characterise the sample. feasibility measures included the rate of enrolment and retention and descriptive analysis of intervention acceptability (e.g., whether the participants would have enrolled in the intervention had they known what the experience would be like and whether they would refer a friend who wanted to quit smoking). the primary efficacy outcome was 7-day point prevalence abstinence at week 12 (12 weeks post-tqd), defined as self-reported abstinence for 7 days prior to the assessment and breath co <8 ppm.22 this approach is in line with the recommendations of the working group of the society for research on nicotine and tobacco based on literature review of abstinence measures used in trials of smoking cessation intervention.23 ethical consideration ethical approval was obtained from the botswana ministry of health (health research unit, reference number: hpdme 13/18/1). results characteristics of the sample are described in table 1. a total of 128 individuals were screened over 8 weeks with 50 deemed eligible and 40 enrolled (80%), as shown in figure 1. retention at week 12 was 52.5% (21/40). figure 1: participant flow diagram. table 1: demographic characteristics. the 7-day point prevalence abstinence at week 12 was 37.5% (15/40). notably, all respondents indicated that they would recommend baps-sc to other smokers who want to quit and would be willing to participate in the programme again up to the point of exit if they did not stop smoking. when a more stringent threshold of exhaled co ≤ 4 ppm was used as the criterion for success, the quit rate in this pilot was 9/40 (22.5%). discussion the authors conducted a single-arm pilot trial of the baps-sc intervention programme, a novel behavioural smoking cessation intervention for plwha in a high-hiv-burden sub-saharan country wherein all 40 participants received the intervention. this design is ideal for studies aiming to determine if a novel intervention is appealing and feasible in the setting and warrants a full-scale clinical trial.24 the results of the co monitoring and exit interviews suggest that baps-sc is likely to be efficacious. this study’s results of a high degree of smoking cessation success with baps-sc suggest a potentially highly impactful smoking cessation programme given that behavioural smoking cessation programmes rarely yield quit rates higher than 10% – 15%.25 there is no comparable trial that tested the intervention developed by the team of the authors with an hiv-negative cohort of smokers. two comparisons are worth noting, and both indicate a substantial benefit from authors’ intervention. firstly, meta-analyses of behavioural interventions (without medications) for smoking cessation rooted in classic cognitive-behavioural theory show that they yield quit rates of generally less than 15% at the end of treatment.26 secondly, macpherson et al. (2010), in their pilot test of bat for smoking cessation, reported an end-of-treatment quit rate of 17%.27 the authors used a higher threshold of co to determine smoking cessation as opposed to a more stringent cut-off in the range of 3 ppm – 4 ppm recently proposed by other researchers.28 however, 8 ppm is the cut-off used in most smoking cessation clinical trials for plwha, so the authors chose this cut-off to compare their results to the current literature. with regard to past behavioural smoking cessation treatments for plwha, a cell phone-based intervention was found to be associated with significantly higher initial quit rates compared with usual care.29 other studies including a group-based tailored intervention, motivational interventions and a web-based intervention (vs in-person or self-help) have not yielded significant increases in quit rates.30,31,32,33,34,35,36 two pilot studies of behavioural treatments that address negative affect (depression and anxiety) show promise for plwha.37,38 the baps-sc trial proved feasible. firstly, the target sample size of 40 participants was reached within 8 weeks of recruitment, a rate of enrolment that would make large trials feasible. the authors’ findings indicated that a large-scale clinical trial would be feasible to determine the efficacy of the baps-sc programme in this setting where hiv prevalence is relatively high. furthermore, smoking prevalence in the setting of their pilot study was estimated to be as high as 51% for male candidates and 6% for female candidates with hiv infection.39 there were proportionately fewer female candidates enrolled in the present study consistent with data from demographic and health surveys in sub-saharan africa.40 although these smoking rates appear to be comparatively lower than reports from north america and europe, these rates are projected to increase in the african continent whilst they are falling in other parts of the world.40,41 given the limited behavioural health infrastructure in low middle income countries (lmics) such as botswana, the authors leveraged hiv clinical care sites and telephone-delivered counselling to extend the reach of skilled practitioners. the authors found this strategy to be effective and acceptable by the participants in the pilot trial. smoking is a major cause of morbidity and mortality, yet smokers find it very difficult to quit. if individuals quit because of this intervention, they will reduce their risk of cardiovascular disease, chronic obstructive pulmonary disease and cancers, particularly lung cancer. this will be of direct benefit to the individual participant. further, if the authors are able to mount a full-scale trial based on the results of this pilot trial, high hiv burden lmics such as botswana may benefit because the intervention may become standard of care in the country, reducing disease burden caused by tobacco use. being a behavioural intervention without pharmacological intervention, the cost is expected to be substantially less with the baps-sc compared with a pharmacological intervention. a formal cost-effective analysis will be needed to be undertaken following the roll out of the programme. results of the exit questionnaires to evaluate the acceptability of the baps-sc trial indicate that hiv-infected smokers in botswana find the programme to be appealing and acceptable. the results indicate a lower-than-expected retention rate with slightly over half of the participants remaining in the study after a 12-week follow-up period. the retention rates across most smoking cessation trials generally exceed 75%.42 this may be improved by asking participants to provide contact numbers of associates such as friends and family members who can be contacted if the participant is unreachable after a number of attempts and increasing incentives to complete follow-ups. from an evidence-based medicine perspective, if efficacy of the intervention is determined to be high, implementation science methods would need to be employed in the clinical care setting to incorporate the intervention into hiv programmes. the intervention leverages the existing hiv care infrastructure and will likely facilitate scale-up in sub-saharan african settings where hiv is common and smoking continues to emerge as a threat to hiv-positive individuals’ health and survival. limitations this pilot study evaluating the feasibility of baps-sc amongst hiv-infected smokers in botswana has notable limitations. this was a single-arm trial, and therefore the results indicate only preliminary evidence of efficiency of the intervention and do not confirm efficacy. however, the authors’ main aim was to evaluate feasibility of implementing the intervention. the planned full clinical trial informed by these results will be powered to address efficacy. additionally, the follow-up period was of only 12 weeks as the aim was to evaluate feasibility of the novel intervention. thus, the follow-up period was not long enough to assess long-term abstinence. however, this was a pilot study to inform a future clinical trial. conclusion the results of this single-arm pilot trial demonstrate the feasibility of leveraging hiv clinical infrastructure for implementing baps-sc as a smoking cessation intervention programme amongst hiv-infected smokers in a resource-limited setting with high hiv burden. a full-scale clinical trial comparing baps-sc with standard counselling is thus warranted to evaluate the efficacy of this novel intervention in these settings. acknowledgements the authors would like to thank all the participants who volunteered to participate in the study. competing interests the authors have declared that no competing interest exists. authors’ contributions b.m.t., r.s. and r.g. designed the study and provided scientific oversight. k.m., j.m., m.k. and t.m. conducted interviews and worked on informed consent and data management. p.m., j.b., w.b. and r.a. contributed to the design of the measures and interpretation of findings. b.t. conducted the primary analysis. b.m.t., r.s. and r.g. drafted the manuscript and incorporated authors’ comments. all authors critically reviewed and edited the manuscript. the final manuscript for submission was approved by all authors. funding information this study was supported by national institutes of health (nih) grants that include hiv clinical epidemiology training for botswana (d43 tw00978), penn center for aids research (p30 ai045008) and penn mental health aids research center (p30 mh097488). data availability statement the data used for this analysis are available from the authors upon reasonable request. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references eyawo o, franco-villalobos c, hull mw, et al. changes in mortality rates and causes of death in a population-based cohort of 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aids programme of research in south africa (caprisa), university of kwazulu-natal, durban, south africa nuffield department of primary care health sciences, university of oxford, oxford, united kingdom nivashnee naicker centre for the aids programme of research in south africa (caprisa), university of kwazulu-natal, durban, south africa farzana osman centre for the aids programme of research in south africa (caprisa), university of kwazulu-natal, durban, south africa siphesihle gumede centre for the aids programme of research in south africa (caprisa), university of kwazulu-natal, durban, south africa yukteshwar sookrajh prince cyril zulu communicable disease centre, ethekwini municipality, durban, south africa paul drain department of global health, schools of medicine and public health, university of washington, seattle, united states department of medicine, school of medicine, university of washington, seattle, united states department of epidemiology, school of public health, university of washington, seattle, united states nigel garrett centre for the aids programme of research in south africa (caprisa), university of kwazulu-natal, durban, south africa department of public health medicine, school of nursing and public health, university of kwazulu-natal, durban, south africa citation mthembu n, dorward j, naicker n, et al. low cd4 count and educational status predict abnormal cervical smears amongst hiv-positive women initiating antiretroviral therapy in south africa. s afr j hiv med. 2020;21(1), a1045. https://doi.org/10.4102/sajhivmed.v21i1.1045 project research number: nct03066128 scientific letter low cd4 count and educational status predict abnormal cervical smears amongst hiv-positive women initiating antiretroviral therapy in south africa nondumiso mthembu, jienchi dorward, nivashnee naicker, farzana osman, siphesihle gumede, yukteshwar sookrajh, paul drain, nigel garrett received: 18 nov. 2019; accepted: 22 jan. 2020; published: 30 mar. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. introduction cervical cancer is common amongst human immunodeficiency virus (hiv)-positive women in lowand middle-income countries. in south africa, more than 7500 cases are diagnosed annually and over 50% result in death, making cervical cancer the leading cause of cancer mortality.1 south africa’s high hiv prevalence contributes to this high burden, because hiv-positive women are more likely to have persistent human papilloma virus (hpv) infection and precancerous cervical changes.2 cervical cancer is preventable either through hpv vaccination of girls before sexual debut, which was rolled out in south africa from 2014, or screening and treatment of precancerous cervical lesions. south african guidelines recommend cervical screening for all hiv-positive women at hiv diagnosis and then every 3 years.1 antiretroviral therapy (art) causes immune reconstitution and may reduce the risk of cervical cancer amongst hiv-positive women by lowering hpv acquisition, increasing hpv clearance and slowing the progression to precancerous lesions.2 however, these effects may be diminished for women who initiate art at low cd4 counts.3 since 2016, when universal test and treat (utt) was introduced in south africa, women began initiating art at cd4 counts > 500 cells/mm3 (early initiators) and may therefore be protected against precancerous cervical abnormalities and cancer.3 in this study, we aimed to assess whether early initiators of art had a lower risk of abnormal cervical smears when compared to late initiators (women with a cd4 ≤ 500 cells/mm3), after introduction of utt in south africa. methods study design we performed a cross-sectional analysis at enrolment into the simplifying hiv treatment and monitoring (stream) study, a randomised trial assessing point-of-care viral load testing amongst people living with hiv receiving art (nct03066128).4,5 participants and setting the stream study was conducted at the prince cyril zulu communicable disease centre (pcz cdc), a large public clinic in central durban, south africa. at pcz cdc, all women who test hiv-positive are referred for art initiation and have cd4 cell count and papanicolaou cervical smear testing performed using routine national health laboratory services (nhls). we enrolled non-pregnant, hiv-positive adults aged 18 years or older who were clinically stable on first-line art for 6 months, and randomised them to receive point-of-care viral load monitoring and task-shifting to an enrolled nurse or standard laboratory monitoring and professional nurse care.4 all participants had been initiated on art after the introduction of utt. cervical smear results were checked using nhls records for all women at screening. women with abnormal cervical smear results of high-grade squamous intraepithelial lesion (hsil) who needed referral for colposcopy did not meet the stream study eligibility criteria of being clinically stable (as they required active care by a physician) and were excluded from stream, and therefore from this analysis.4 those without a baseline cervical smear result had a smear test after entry into the study and continued follow-up, even if a high-grade lesion was detected. data source and data management at enrolment, we recorded socio-demographic, laboratory and clinical information using a nurse-administered questionnaire and by retrospective review of clinical notes and nhls records. we used the following validated questionnaires: audit-c to assess alcohol use, patient health questionnaire 2 (phq2) for depression and world health organization violence against women for intimate partner violence. we captured data in the secure, password-protected idatafax system (df/net research, inc., seattle, wa, usa) and performed three rounds of data quality checks consisting of source document review, internal quality audits and weekly quality reports. statistical analysis we assessed socio-demographic and clinical exposure variables including age, educational status, having a stable partner, parity, contraceptive use, time from diagnosis to art initiation, previous tuberculosis, intimate partner violence, alcohol use or depression and cd4 count. the primary outcome for this analysis was the absence or the presence of an abnormal cervical smear, which included atypical squamous cells of undetermined significance (ascus), low-grade squamous intraepithelial lesion (lsil) and hsil. we used descriptive statistics to summarise socio-demographic and clinical variables and missing data. associations between socio-demographic and clinical exposures, and the outcome of an abnormal cervical smear result were assessed using bivariable and multivariable poisson regression models with robust variance. we included covariates with a p-value of < 0.15 in the bivariable analysis into the multivariable model. we used sas version 9.4 (sas institute inc., cary, nc, usa) for the statistical analysis. results a total of 390 participants were enrolled into the stream study, of whom 235 (60.3%) were women, with a median age of 30 years (interquartile range [iqr] 26–37 years) and a median cd4 count of 401/cells/mm3 (iqr 215–608 cells/mm3). eight women who had hsil at art initiation were not eligible for enrolment and thus were excluded from the stream study. of the 235 women, 176 (74.9%) women with a conclusive cervical smear result were included in this analysis (table 1), and of the 176 women included, 66 (37.5%) had abnormal cervical smears. amongst the women with abnormal cervical smears, 62 women (35.2%) had lsil, three (1.7%) had hsil and one (0.6%) had ascus. women with a cd4 count < 200 cells/mm3 had the highest proportion of abnormal cervical smears (20/40, 50.0%). of the 59 women with no cervical smear test result available, eight (13.6%) tests were performed but no test result was available, 13 (22.0%) were inadequate for evaluation and 38 (64.4%) had no record of testing. median cd4 count amongst women with no smear result was 405 (iqr 244–608), compared to 401 (iqr 207–611) amongst those with a smear result (p = 0.498). table 1: baseline characteristics of women with cervical smear results available (n = 176).5 in bivariable analysis, women with an initiation cd4 count of ≤ 500 cells/mm3 had a higher risk of abnormal cervical smears, compared to women with a cd4 count > 500 cells/mm3 (risk ratio 1.84, 95% confidence interval [ci] 1.04–3.28, table 2). women who had not completed secondary education also had a higher risk of abnormal cervical smears. time from diagnosis to art initiation, having a stable partner, previous tuberculosis, contraceptive use, intimate partner violence, alcohol use or depression were not associated with abnormal cervical smear results. table 2: associations between socio-demographic variables, initiation cd4 count and abnormal cervical smear results (n = 176).5 in multivariable analyses, late initiators of art had a higher risk of abnormal cervical smears when compared to early initiators (adjusted risk ratio [arr] 1.71, 95% ci 1.04–2.80). furthermore, independent of cd4 count, women with a lower educational status also had a higher risk of abnormal cervical smears (arr 1.48, 95% cl 1.02–2.14). discussion in this cohort of women initiating art after implementation of utt, there was a high prevalence of abnormal cervical lesions, affecting over a third of all women successfully screened. women who initiated art at lower cd4 thresholds and those who did not reach secondary education had a higher risk for abnormal cervical lesions. our findings are similar to a systematic review, including studies mainly from europe and north america, which found that women with lower cd4 counts had consistently higher incidence of abnormal cervical lesions.6 this review also showed an increased risk of progression of cervical lesions with declining cd4 count.6 a cross-sectional analysis of 1140 nigerian women showed that both lowand high-grade cervical lesions were detected almost four times more frequently in women with cd4 < 200 cells/mm3.7 therefore, earlier initiation of art at higher cd4 counts may have a protective effect on the development and progression of abnormal cervical lesions in this setting.2,3,8 of note, in spite of the implementation of utt, the majority of women in this study presented with cd4 counts ≤ 500 cells/mm3, meaning that further efforts are needed to diagnose and initiate art earlier amongst women living with hiv. similar to our finding, a cross-sectional study from zambia, analysing data in over 14 000 women from a national cervical screening programme, showed that women having at least secondary education were less likely to develop abnormal cervical lesions, compared to women with no formal education.9 the protective effect of attaining a higher level of education may be explained by increased awareness of the disease, delayed sexual debut and greater access to healthcare, including cervical screening services. while the recent roll-out of hpv vaccination to south african school girls through a public health initiative has somewhat created renewed awareness of cervical cancer, gaps remain in knowledge and prevention of the disease and access to screening services for secondary prevention.1,10 limitations of our study included the cross-sectional design and a relatively small sample size, which means that the analysis may not be sufficiently powered to rule out weak associations between other exposure variables and abnormal smears. furthermore, we excluded women with hsil without a conclusive negative colposcopy result from the study. even in this large hiv clinic, a quarter of women did not have the recommended cervical smear result available at art initiation. a strength of our study is that we were able to assess the prevalence of abnormal cervical lesions in women initiating art at higher cd4 thresholds in the era of utt in a public health setting. while hpv vaccination for young women has now been introduced in south africa, the long-term impact on cervical cancer is still uncertain. in the meantime, cervical cancer screening remains a priority. here, we highlight that early art initiation and ensuring frequent cervical screening for those with lower cd4 counts and lower educational background should be prioritised. universal test and treat will help reduce cervical abnormalities, but other measures, such as scaling up of existing screening services, better colposcopy and treatment provision, as well as the implementation of high-risk hpv screening strategies, are necessary to reduce the burden of this preventable disease. acknowledgements the authors are grateful to the study participants and the staff at the prince cyril zulu communicable disease centre and centre for the aids programme of research in south africa (caprisa) ethekwini clinical research site. competing interests the authors report no real or perceived vested interests related to this article that could be construed as a conflict of interest. ethical consideration ethical approval to conduct the study was obtained by the university of kwazulu-natal biomedical research ethics committee (bfc296/16) and the university of washington institutional review board (study00001466). authors’ contributions n.m., j.d., n.n., p.d. and n.g. conceived the study. n.m., j.d., n.n., s.g. and y.s. collected the data. f.o. performed the statistical analysis. n.m. and j.d. drafted the manuscript. all authors critically reviewed and edited the manuscript and gave their consent for publication. funding information the simplifying hiv treatment and monitoring (stream) study was funded by the us national institutes for health (nih) (ai124719). the nih had no role in the study design and manuscript submission, or collection, management, analysis or interpretation of study data. data availability statement the data that support the findings of this study are available from the corresponding author (j.d.) upon reasonable request and subject to caprisa data availability policies. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references the south african national department of health. cervical cancer prevention and control [homepage on the internet]. pretoria; 2017 [cited 21 jan 2020]. available from: http://www.health.gov.za/index.php/2014-08-15-12-53-24?download=1393:cervical-cancer-policy-pdf liu g, sharma m, tan n, et al. hiv-positive women have higher risk of human papilloma virus infection, precancerous lesions, and cervical cancer. aids. 2018;32(6):795–808. https://doi.org/10.1097/qad.0000000000001765 kelly h, weiss ha, benavente y, et al. association of antiretroviral therapy with high-risk human papillomavirus, cervical intraepithelial neoplasia, and invasive cervical cancer in women living with hiv: a systematic review and meta-analysis. lancet hiv. 2018;5(1):e45–e58. https://doi.org/10.1016/s2352-3018(17)30149-2 dorward j, garrett n, quame-amaglo j, et al. protocol for a randomised controlled implementation trial of point-of-care viral load testing and task shifting: the simplifying hiv treatment and monitoring (stream) study. bmj open. 2017;7(9):e017507. https://doi.org/10.1136/bmjopen-2017-017507 drain pk, dorward j, violette lr, et al. point-of-care hiv viral load testing combined with task shifting to improve treatment outcomes (stream): findings from an open-label, non-inferiority, randomised controlled trial. lancet hiv. 2020. https://doi.org/10.1016/s2352-3018(19)30402-3. epub ahead of print. denslow sa, rositch af, firnhaber c, et al. incidence and progression of 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of vhembe district in limpopo province, south africa. afr j reprod health. 2018;22(3):111–119. https://doi.org/10.29063/ajrh2018/v22i3.12 the southern aflllcan joullnal of hiv medicine ----------hhllually 2003 remarks a broken landscape crucially, these deniers also reject the most signal truth in the aids epidemic. this is that the destructive activity of the virus within the human body can be completely contained by carefully administered and properly monitored antiretroviral medications. the deniers revile those speaking the truth about aids for engaging in 'scare-mongering: they attack them as agents of an 'omnipotent apparatus' engaged in 'a massive political-commercial campaign to promote antiretroviral drugs: they condemn those speaking the truth about aids for a supposed campaign 'to medicalise poverty and underdevelopment:' this third crisis in aids had been engendered by those in our country who deny the facts about aids. there are those who deny that aids has introduced disturbingly new patterns of disease and dying to our sub-continent. they deny that these new patterns are the result of an infectious agent a virus, one that is mostly sexually transmitted; one that enters the human body, and attacks the immune system, and destroys it through retroviral activity, rendering it vulnerable to attack by a host of infections. the cost is immeasurable. the acts and words of the deniers have at every level paralysed our national response to the epidemic. they have confused our planning and befuddled our strategies. they have con ounded our known for more than six centuries. on the other hand that crisis is one of leadership and management a challenge to every person with power and resources and skills to use them to alleviate and obviate suffering and death on this scale. they depict the facts about aids as a monstrous plot against africans because they are black. in this the denial of aids represents the ultimate relic of apartheid's racially imposed consciousness, and the deniers achieve the ultimate victory of the apartheid mindset. but most importantly, and most tragically, in our nation that crisis is also one of truth-telling. the most fundamental crisis in the aids epidemic is our nation's struggle to identify and confront and act on the truth about aids. his depiction of that reality is astonishing in its power, in its graphic truth, in its respectful distance and in its searing intimacy. what does it mean to say that an artist (or an art gallery) 'shows commitment'7 it means that he or she brings not only an engagement to the subject of the display, but an involvement in it that transcends mere observation or representation. 'a broken landscape', an exhibition of photographs by gideon mendel at the south african national gallery, cape town, closed on saturday 13 april 2002. mr justice edwin cameron, of the supreme court of appeal, gave the following address. this is plain from gideon mendel's 'a broken landscape: the photographer has shown an imaginative and respectful engagement with his topic. but he has done infinitely more than that. he has aligned himself unmistakably with the reality that confronts his subjects and those around them. this exhibition has been a remarkable event its presence here represents a major commitment by the south african national gallery to people living with hiv and aids. the work on display itself shows deep commitment. in achieving this, neither the artist nor his exhibition has been static. as events have moved, he has included them the court battle about the provision of antiretroviral medication to pregnant mothers, the claim to life of those who for the first time are now gaining access to longerterm drug therapy. in all of this the artist is depicting a truth. but his work also makes a call to action. the exhibition challenges those who view it to take a position on the lives and the deaths of those it represents. he places before us images that shock us with their force and closeness. the reason is that he has involved himself with the extremity of his subjects' struggle, who are at the very edge of life. he shows us the inexpressible complexity, the terrible simplicity, and the dignity of that state. that call to action echoes the most urgent current question in our national life. it is true that we have a 'crisis of aids' in our country. on the one hand that crisis is one of illness and suffering and dying dying on a larger scale and in conspicuously different patterns from before; on a scale globally that dwarfs any disease or epidemic the world has focus hiv/aids profile in the provinces of south mrica, 2002 insights, sapped our energies and dispirited our determination to act. and, most significantly, they have silenced all too many voices among those who are experiencing the epidemic in their own bodies and their own families and in their own communities. the deniers have re-created shame, and reimposed silence, in an epidemic where the struggle for twenty years has been to create voices and to defeat shame. the denial of the facts about aids is not only an outrage against the truth. it is a profound insult to those south africans who are living with and dying from the effects of the virus. they deny us the dignity of our suffering. they deny us the dignity of our struggle for life against the workings of a viral agent. most importantly, they deny us the dignity of the truth, and the power and hope, and the opportunities for action, that acceptance of the truth brings. in countless villages and townships and cities and settlements in south africa, where the virus is taking its toll a booklet entitled hiv/aids profile in the provinces of south africa: indicators for 2002 has recently been released. it makes provincial trends and statistics on the hiv/aids epidemic available to government officials at all levels, as well as to business people, non-governmental organisations (ngos) and the public the report gives readers a sense of the magnitude of the numbers involved, and will allow them to benchmark other information about the epidemic as it becomes available. the booklet can be down loaded from www.mrc.ac.za or www.assa.org.za/aidsmodel.asp or www.commerce.uct. ac.za/care, and is also available from the university of cape town (uct)'s centre for actuarial research at r30 per copy (tel. (021) 650-2475). the estimates provided are not new in fact. they have been available for the last year on the actuarial society of south africa's website but it is the first time they have been compiled into one publication for ease of access. the indicators are based on a model constructed by the actuarial society of south africa (assa). while there is ~ehruaily 2003 -----------of health and life among our people, the terrible truth about aids is being born and lived and died. our people are being born, are living with, and dying from that truth. they are living that truth in the rising fevers, the wasting of flesh and the slow, agonised cessation of bodily functions that result from the virus. their suffering is being increased and is being prolonged incalculably by the deniers. but, as we have seen today, from the terrible grief of those affected by the virus a terrible determination arises: a determination to defeat untruth and misrepresentation and distortion, and to assert hope. that is the ultimate significance of the unforgettable images of this exhibition: that untruth and inaction are the greatest crimes of all. let us take an angry inspiration, and a deep determination, from that. reference 1. hlongwan(" c. caravans, ears, g~st', foot & mouth ana srarisrics hn/alds and the struggle for the humani~tioi1 of the african. anc document, distributed april 2002 always a degree of uncertainty surrounding such estimates, models can provide an invaluable tool for giving a sense of possible future scenarios. the assa model is continuously being improved as more data become available and our understanding of the dynamics of the epidemic improve. some of the information available in the report • the extent of the epidemic, with 6,5 million people (14,2'1'0 of the population) infected with hiv by july 2002. • of these, over 95% (6.1 million) are in the age group 18 64 years (labour force age). • the prevalence is highest [25.9%) among young women of childbearing age this, in turn, has implications in terms of numbers of orphans. • the prevalence of hiv/aids (among all ages) in each of the provinces is as follows: kwazulu-natal 18.4% eastern cape 11.3% free state 16.7% limpopo 11.0% mpumalanga 16.5'1'0 northern cape 7.9% gauteng 16.qoio western cape 4.2'1'0 north west 15.1 % the southern african journal of hiv medicine h o r i z o n s can we involve adolescents in hiv vaccine trials can we afford not to? more than half of the world’s population is under 25 years of age – the largest population of young people the world has ever seen. in south africa, 54% of the population is under 24 years of age. all are at risk for hiv infection. unaids reports that in 2004 there were 14 000 new infections daily. almost 100% of these were in the developing world, 1 200 were in 14 25-year-olds, and half of these were in females. two-thirds of the infections in this age group occurred in sub-saharan africa. an hiv prevalence survey carried out in nearly 12 000 young south africans and recently reported in aids showed a prevalence rate of 2.3% in boys and 4.1% in girls at age 15, increasing steadily to 5.9% in boys and a staggering 31.2% in girls by age 21.1 so what are the risk factors for infection in these young people? almost universally sex, with numbers most driven by heterosexual sex in young women in sub-saharan africa. other risk factors include homosexual sex, while intravenous drug use is an increasing problem, especially in eastern europe and central asia. women comprise three-quarters of infections among young heterosexual people in africa. this is because hiv transmission is more efficient from men to women. a number of factors contribute to this, e.g. young women are having sex with older men (trans-generational), putting them at more risk of encountering positive partners, but education and coercion also play a part. biological reasons include cervical ectopy, hormonal influences, pregnancy-related infection and concomitant sexually transmitted infections.2 in addition, youth may be vulnerable in their decision making around sexual practices owing to inexperience, a transitional emotional state, drug and other substance abuse, marginalised activities, economic forces and coercion. all of these factors make heterosexual youth in resource-poor settings, intravenous drug-using youth in other communities and young men who have sex with men in many countries at increased risk of hiv infection. sexual behaviour surveys have been carried out extensively in south africa, with at least 35 published articles on hiv knowledge and 75 papers on sexual behaviour and risk. these studies confirm that south african youth have an early sexual debut (< 15 years) and indulge in relatively high-risk behaviour. this has made aids the leading cause of death. yet research in adolescents is fraught: they have not reached the age of legal majority, they are undergoing hormonal upheavals, and they are in a transitional phase of social development. anyone who has had teenagers in their household will know the quest for identity, autonomy and control, the distrust of hierarchy and establishment, the strong effects of peer pressure and social norms, and a strong element of invincibility or risk taking. participation in research is complicated by the requirement for consent from a legal guardian, the need to accommodate school hours and homework, mobility in terms of future plans, and reliance on public transport to get to clinic appointments. information on sexual risk can be difficult to get and may have questionable reliability. while adolescents are unsophisticated and in their formal operational phase of data processing, they are trainable.4 why then even consider adolescents for clinical vaccine trials? the argument comes down to a risk/benefit one. on the one hand we have the problem of conducting ‘non-therapeutic’ research in vulnerable minors, but on the other we have a lifethreatening pandemic of unprecedented proportions that is especially targeting youth in developing countries. there is scientific justification for the argument that immune responses may be adversely affected by the huge hormonal shifts occurring at this age, but other vaccine trials have indicated that age may play a positive part in responses, e.g. hepatitis b (better responses with half the dose used for 11 19-year-olds compared with 20 30-year olds), while in hpv trials the geometric mean titres were 2-fold higher in the 10 15-year age group compared with 16 23 years. another reason to involve adolescents in vaccine clinical testing at this stage is that regulatory bodies will almost certainly require adolescent experience for licensure and we certainly don’t want to lag in implementation of a vaccine in teenagers should one look promising. finally, the actual rollout and distribution of an effective vaccine will be a monumental task worldwide and we should be prepared for this. involvement of adolescents now may prepare the way. the early age of sexual debut and risk for hiv acquisition indicates that our window of opportunity to implement a preventive vaccine occurs before the age of 14 years. our feasibility studies in cape town have shown that there is adolescent interest in participation and that motivation is largely altruistic. since the adolescent hiv epidemic is such a serious problem for south africa, and we have the expertise and apparently the enthusiasm here to overcome the obstacles, it seems to me that south africa must lead the way in getting adolescents involved as soon as possible. this article was derived from presentations delivered by jared baeten, university of washington, seattle, and linda-gail bekker at the 2005 aids vaccine conference, montreal. linda-gail bekker managing editor 1. pettifor, et al. aids 2005; 19: 1525-1534. 2. plourde, et al. j inf dis 1994; 170: 313-317. 4. l swartz, et al. jaipac 2005 (in press). 7 august 2004 the southern african journal of hiv medicine 6 things to think about well, the national antiretroviral roll-out is rolling — and we’re hearing about activity in just about every province, which is very good news indeed. this journal should be a barometer for how things are going, and perhaps we will undertake to devote half a page or so to monitor progress right across the country. also we welcome papers on lessons learnt, successes and difficulties from all parts of south africa — as we share our experiences we will improve our services and make more of an impact. i know in the western cape our aids directorate is very pleased with how things are going, with numbers in current sites increasing weekly and more sites being added monthly. the challenge as initial roll-out takes place is to think one step ahead and anticipate the problems of the future. just three such problems immediately come to mind, though there are many more to think about and plan for. the first is recognition that most of the resources are being put into outpatient care. this makes sense when we need to treat many thousands of people, as in our national tuberculosis programme. however, a truly comprehensive health service must offer primary, secondary and tertiary care. while we are treating the sickest of the sick, which will continue for some time as the criteria for starting antiretroviral therapy are aids or a markedly reduced cd4 count, we can expect fairly significant mortality and morbidity in the early days of therapy. aggressive and expert inpatient care for recognition and treatment of the immune reconstitution syndromes, including difficult-to-diagnose tb (often requiring diagnostics not available at primary or even secondary levels), and other opportunistic infections, will enable more people to make it through those troublesome first three months and then have as good a stab as anyone at longer and better lives. and don’t forget the small proportion of really adherent patients who develop late side-effects that may need an effective multispecialist approach to get these ‘excellent’ patients back to their busy lives. the other area we are going to have to address as arv programmes mature is the fact that a large proportion of our patients (70% at hanan-crusaid in gugulethu) is female and that as viral loads are suppressed and young people begin to feel better, issues around sexuality, fertility and reproduction are raised. a female star on ‘isidingo’ has in recent episodes been grappling with just these issues while living with hiv infection. as a health profession we are going to have to work through this one and formulate some appropriate responses. of course people have a right to children, and i don’t think we will be able to decide otherwise! the first prize will be to work with our patients and ensure that they understand all benefits and all risks and make their decisions with cool heads and with full knowledge. a challenge in a busy arv clinic! again, i don’t think we are going to be able to have enough doctor and nurse time for these important discussions, so we will need to equip our therapeutic counsellors, foot soldiers, treatment buddies or peer counsellors with the relevant facts so that we get the right messages out there. what an exciting time to be a health practitioner! hiv and the provision of art have really brought to the fore patient autonomy and the need for a proper and equal patientpractitioner relationship. a challenge for many of us who haven’t experienced this before, but oh! so refreshing! finally, andrew boulle and helen meintjies highlighted a very important third issue to think about as a consequence of the aids epidemic and treatment in the 27 august edition of mail and guardian. they remind us that we have the largest hiv epidemic in the world and will soon have the largest art programme too. the foster care grant (r530 per month) and the disability grant (r740) have the fastest increase in uptake, and this is a direct consequence of the hiv epidemic. although not intended to do so, in the absence of adequate social security alternatives each of these grants currently plays a critical role in alleviating poverty in households throughout south africa. yet, as boulle and meintjies point out, it is discriminatory to provide grants to orphans to the age of 18 years without providing at least equal support to the many other impoverished children whose parents are alive. the child care grant (r170) is of much lower monetary value and only eligible to the age of 11 years. until the introduction of a national arv program where hopefully all eligible hiv-infected persons will be treated with art, a disability grant awarded to a person with advanced hiv disease was effectively a ‘grant for life’. patients on art will not sicken to the same extent and therefore never be eligible for the grant, or else may improve significantly, leading to grant withdrawal. in communities where the low employment rate is more of an obstacle to gainful employment than the hiv epidemic, this may have dire effects on the family and indeed on allowing the individual to remain in care. people may delay testing and enrolment in care until they qualify for a disability grant, and then not have the incentive to adhere to therapy once on treatment. boulle and meintjies conclude that a possible solution is extension of the child support grant to all children up to 18 years and the implementation of a basic income grant. they argue that it is only with such comprehensive social security that south africans will be equitably supported through the hiv epidemic. linda-gail bekker managing editor h o r i z o n s hivmed_21(1)_2020_contents.indd http://www.sajhivmed.org.za open access table of contents editorial the editor’s review of articles published from august to december 2019 in the southern african journal of hiv medicine david c. spencer southern african journal of hiv medicine | vol 21, no 1 | a1120 | 24 august 2020 3editorial david c. spencer southern african journal of hiv medicine | vol 21, no 1 | a1199 | 21 december 2020 1 page i of iv table of contents vol 21, no 1 (2020) issn: 1608-9693 (print) | issn: 2078-6751 (online)southern african journal of hiv medicine 2020 guidelines and editorial comment: southern african hiv clinicians society (sahcs) adolescent healthcare and pre-exposure prophylaxis harm reduction epidemiology and prevention guideline the updated south african national guideline for the prevention of mother to child transmission of communicable infections (2019) jeannette wessels, gayle sherman, lesley bamford, manala makua, mathilda ntloana, james nuttall, yogan pillay, ameena goga, ute feucht southern african journal of hiv medicine | vol 21, no 1 | a1079 | 08 july 2020 guideline southern african hiv clinicians society guidelines for antiretroviral therapy in adults: 2020 update jeremy nel, sipho dlamini, graeme meintjes, rosie burton, john m. black, natasha e.c.g. davies, eric hefer, gary maartens, phetho m. mangena, moeketsi t. mathe, mahomed-yunus moosa, muhangwi b. mulaudzi, michelle moorhouse, jennifer nash, thandeka c. nkonyane, wolfgang preiser, mohammed s. rassool, david stead, helen van der plas, cloete van vuuren, willem d.f. venter, joana f. woods southern african journal of hiv medicine | vol 21, no 1 | a1115 | 16 september 2020 editor's choice 11 editor's choice 19 editorial adolescent healthcare: i’m lovin’ it carey pike, connie celum, linda-gail bekker southern african journal of hiv medicine | vol 21, no 1 | a1147 | 21 october 2020 74 editorial introduction to the southern african hiv clinicians society harm reduction guidelines edwin cameron southern african journal of hiv medicine | vol 21, no 1 | a1179 | 17 december 2020 editor's choice 81 editorial antiretroviral therapy optimisation in the time of covid-19: is it really different in north and south africa? ahmed cordie, menna-t-allah el-kotamy, gamal esmat southern african journal of hiv medicine | vol 21, no 1 | a1118 | 30 july 2020 118 guideline southern african hiv clinicians society guidelines for solid organ transplantation in human immunodeficiency virus: an evidence-based framework for human immunodeficiency virus-positive donors and recipients jeremy s. nel, francesca conradie, jean botha, harriet etheredge, june fabian, leon levin, ahmad h. mazanderani, michelle moorhouse, elmi muller, caroline tiemessen, david thomson, julia turner southern african journal of hiv medicine | vol 21, no 1 | a1133 | 15 october 2020 guideline southern african guidelines on the safe, easy and effective use of pre-exposure prophylaxis: 2020 linda-gail bekker, benjamin brown, dvora joseph-davey, kathrine gill, michelle moorhouse, sinead delany-moretlwe, landon myer, catherine orrell, kevin rebe, w.d. francois venter, carole l. wallis southern african journal of hiv medicine | vol 21, no 1 | a1152 | 10 december 2020 editor's choice 58 editor's choice 66 original research be legally wise: when is parental consent required for adolescents’ access to pre-exposure prophylaxis (prep)? ann strode, catherine m. slack, zaynab essack, jacintha d. toohey, linda-gail bekker southern african journal of hiv medicine | vol 21, no 1 | a1129 | 10 november 2020 editor's choice 76 guideline southern african hiv clinicians society guidelines for harm reduction andrew scheibe, goodman sibeko, shaun shelly, theresa rossouw, vincent zishiri, willem d.f. venter southern african journal of hiv medicine | vol 21, no 1 | a1161 | 17 december 2020 editor's choice 84 editorial covid-19 crisis effect on hiv service delivery in egypt: hard times or blessings in disguise? rahma mohamed, heba wanis, sonia zebachi, menna-t-allah el-kotamy, gamal esmat, ahmed cordie southern african journal of hiv medicine | vol 21, no 1 | a1170 | 09 december 2020 120 http://www.sajhivmed.org.za open access table of contentspage ii of iv hiv-related epidemiology and prevention basic science hiv diagnostics original research perspectives on oral pre-exposure prophylaxis use amongst female sex workers in harare, zimbabwe tinashe mudzviti, anesu dhliwayo, byrone chingombe, bernard ngara, tsitsi g. monera-penduka, charles c. maponga, gene d. morse southern african journal of hiv medicine | vol 21, no 1 | a1039 | 19 february 2020 original research knowledge, attitudes and behaviours towards people with hiv and aids among private higher education students in johannesburg, south africa natasha khamisa, maboe mokgobi, tariro basera southern african journal of hiv medicine | vol 21, no 1 | a991 | 24 march 2020 original research sexual function after voluntary medical male circumcision for human immunodeficiency virus prevention: results from a programmatic delivery setting in botswana jillian c. pintye, kathleen e. wirth, conrad ntsuape, nora j. kleinman, lisa spees, bazghina-werq semo, shreshth mawandia, jenny ledikwe southern african journal of hiv medicine | vol 21, no 1 | a1042 | 20 april 2020 original research sexual risk compensation following voluntary medical male circumcision: results from a prospective cohort study amongst human immunodeficiency virus-negative adult men in botswana lisa p. spees, kathleen e. wirth, shreshth mawandia, semo bazghinawerq, jenny h. ledikwe southern african journal of hiv medicine | vol 21, no 1 | a1157 | 14 december 2020 125 131 138 146 review article future approaches to clearing the latent human immunodeficiency virus reservoir: beyond latency reversal alexander m.l. hayes southern african journal of hiv medicine | vol 21, no 1 | a1089 | 12 august 2020 174 original research evaluation of a mobile application to support hiv self-testing in johannesburg, south africa natasha gous, alex e. fischer, naleni rhagnath, mothepane phatsoane, mohammed majam, samanta t. lalla-edward southern african journal of hiv medicine | vol 21, no 1 | a1088 | 30 june 2020 180 original research evaluation of the impact of delayed centrifugation on the diagnostic performance of serum creatinine as a baseline measure of renal function before antiretroviral treatment chemedzai e. chikomba, carolyn j. padoa, donald tanyanyiwa southern african journal of hiv medicine | vol 21, no 1 | a1056 | 16 july 2020 187 scientific letter antiretroviral therapy under the wing of the covid-19 epidemic: one look, and different solutions heba elsayed, mohamed hassany southern african journal of hiv medicine | vol 21, no 1 | a1167 | 15 december 2020 122 original research tobacco smoking and associated factors in human immunodeficiency virus-infected adults attending human immunodeficiency virus clinics in the western cape province, south africa muyunda mutemwa, nasheeta peer, anniza de villiers, mieke faber, andre-pascal kengne southern african journal of hiv medicine | vol 21, no 1 | a1072 | 21 april 2020 original research feasibility of implementing a novel behavioural smoking cessation intervention amongst human immunodeficiency virus-infected smokers in a resource-limited setting: a single-arm pilot trial billy m. tsima, precious moedi, joyce maunge, kitso machangane, martha kgogwane, tebogo mudojwa, joseph bastian, warren bilker, rebecca ashare, robert schnoll, robert gross southern african journal of hiv medicine | vol 21, no 1 | a1075 | 24 june 2020 original research depression, sleep quality and condom use amongst iranian people living with human immunodeficiency virus marzieh mahboobi, arezu najafi, amin nakhostin-ansari, parvin afsar kazerooni, matin bazargani, fatemeh navaiian, samaneh akbarpour southern african journal of hiv medicine | vol 21, no 1 | a1150 | 15 december 2020 155 163 169 http://www.sajhivmed.org.za open access table of contents original research patient acceptance of hiv testing services in rural emergency departments in south africa aditi rao, caitlin kennedy, pamela mda, thomas c. quinn, david stead, bhakti hansoti southern african journal of hiv medicine | vol 21, no 1 | a1105 | 22 july 2020 202 review article the evolution and adoption of world health organization policy guidelines on antiretroviral therapy initiation in sub-saharan africa: a scoping review sabina m. govere, moses j. chimbari southern african journal of hiv medicine | vol 21, no 1 | a1103 | 30 september 2020 review article a rapid review and synthesis of the effectiveness of programmes initiating community-based antiretroviral therapy in sub-saharan africa raymond chimatira, andrew ross southern african journal of hiv medicine | vol 21, no 1 | a1153 | 05 november 2020 scientific letter drug resistance after cessation of efavirenz-based antiretroviral treatment started in pregnancy globahan ajibola, christopher rowley, dorcas maruapula, jean leidner, kara bennett, kathleen powis, roger l. shapiro, shahin lockman southern african journal of hiv medicine | vol 21, no 1 | a1023 | 27 january 2020 editorial ‘covering the tail’ after stopping efavirenz-based antiretroviral therapy gary maartens southern african journal of hiv medicine | vol 21, no 1 | a1036 | 27 january 2020 scientific letter cd4 testing after initiation of antiretroviral therapy: analysis of routine data from the south african hiv programme rivka r. lilian, natasha davies, louise gilbert, james a. mcintyre, helen e. struthers, kate rees southern african journal of hiv medicine | vol 21, no 1 | a1165 | 14 december 2020 original research transition to an in-facility electronic tuberculosis register: lessons from a south african pilot project hanlie myburgh, remco p.h. peters, theunis hurter, cornelius j. grobbelaar, graeme hoddinott southern african journal of hiv medicine | vol 21, no 1 | a1025 | 16 january 2020 original research changes in the incidence and prevalence of human immunodeficiency virus or acquired immunodeficiency syndrome in the south african medical schemes environment: 2005–2015 floidy wafawanaka, martha s. lubbe, irma kotzé, marike cockeran southern african journal of hiv medicine | vol 21, no 1 | a1007 | 29 june 2020 original research characteristics and outcomes of older people on antiretroviral therapy in tlokwe clinics, south africa mareike rabe, huibrecht c. lion-cachet, melaku a. eyassu southern african journal of hiv medicine | vol 21, no 1 | a1066 | 07 july 2020 220 231 240 244 editor's choice 246 250 257 265 original research the spectrum of electrolyte abnormalities in black african people living with human immunodeficiency virus and diabetes mellitus at edendale hospital, pietermaritzburg, south africa preyanka pillay, somasundram pillay, nobuhle mchunu southern african journal of hiv medicine | vol 21, no 1 | a1095 | 23 july 2020 original research understanding adherence in virally suppressed and unsuppressed human immunodeficiency virus-positive urban patients on second-line antiretroviral treatment siphamandla b. gumede, willem d.f. venter, samanta t. lalla-edward southern african journal of hiv medicine | vol 21, no 1 | a1107 | 11 august 2020 original research feasibility of implementing same-day antiretroviral therapy initiation during routine care in ekurhuleni district, south africa: retention and viral load suppression nolundi mshweshwe-pakela, bhakti hansoti, tonderai mabuto, deanna kerrigan, griffiths kubeka, elizabeth hahn, salome charalambous, christopher j. hoffmann southern african journal of hiv medicine | vol 21, no 1 | a1085 | 20 august 2020 original research effects of hiv and non-communicable disease comorbidity on healthcare costs and health experiences in people living with hiv in zimbabwe laston gonah, indres moodley, khumbulani hlongwana southern african journal of hiv medicine | vol 21, no 1 | a1102 | 04 september 2020 original research capacity of antiretroviral therapy sites for managing ncds in people living with hiv in zimbabwe laston gonah, indres moodley, khumbulani hlongwana southern african journal of hiv medicine | vol 21, no 1 | a1113 | 04 september 2020 original research human immunodeficiency virus, diabetes mellitus and thyroid abnormalities: should we be screening? somasundram pillay, davashni pillay, deepak singh, romashan pillay southern african journal of hiv medicine | vol 21, no 1 | a1116 | 09 november 2020 original research profile of elderly patients receiving antiretroviral therapy at newlands clinic in 2020: a cross-sectional study cleophas chimbetete, tinashe mudzviti, tinei shamu southern african journal of hiv medicine | vol 21, no 1 | a1164 | 10 december 2020 275 editor's choice 283 editor's choice 293 299 307 314 322 original research the influence of haemodialysis on cd4+ t-cell counts in people living with human immunodeficiency virus with end-stage kidney disease melanie pretorius, estee benade, june fabian, denise lawrie, elizabeth s. mayne southern african journal of hiv medicine | vol 21, no 1 | a1125 | 21 december 2020 211 clinical hiv medicine and antiretroviral therapy (art) page iii of iv http://www.sajhivmed.org.za open access table of contents original research the prevalence and spectrum of mucocutaneous disease in south african people living with hiv and accessing care at a district-level hospital saskya claasens, susanna m.h. kannenberg, henry f. jordaan, karis moxley, rhodine smith, johann de wet, willem i. visser southern african journal of hiv medicine | vol 21, no 1 | a1154 | 10 december 2020 327 original research implementation of a pmtct programme in a high hiv prevalence setting in johannesburg, south africa: 2002–2015 coceka n. mnyani, carol l. tait, remco p.h. peters, helen struthers, avy violari, glenda gray, eckhart j. buchmann, matthew f. chersich, james a. mcintyre southern african journal of hiv medicine | vol 21, no 1 | a1024 | 23 march 2020 scientific letter low cd4 count and educational status predict abnormal cervical smears amongst hiv-positive women initiating antiretroviral therapy in south africa nondumiso mthembu, jienchi dorward, nivashnee naicker, farzana osman, siphesihle gumede, yukteshwar sookrajh, paul drain, nigel garrett southern african journal of hiv medicine | vol 21, no 1 | a1045 | 30 march 2020 editor's choice 339 editor's choice 346 original research hiv viral load testing coverage and timeliness after implementation of the wellness anniversary in a paediatric and adolescent hiv clinic in kwazulu-natal, south africa sibusiso e. kubheka, moherndran archary, kevindra k. naidu southern african journal of hiv medicine | vol 21, no 1 | a1016 | 03 february 2020 original research the effects of teen clubs on retention in hiv care among adolescents in windhoek, namibia farai k. munyayi, brian van wyk southern african journal of hiv medicine | vol 21, no 1 | a1031 | 03 february 2020 original research adolescent human immunodeficiency virus self-management: associations with treatment adherence, viral suppression, sexual risk behaviours and health-related quality of life talitha crowley, anita van der merwe, martin kidd, donald skinner southern african journal of hiv medicine | vol 21, no 1 | a1054 | 29 april 2020 original research impact of routine birth early infant diagnosis on neonatal hiv treatment cascade in ethekwini district, south africa vidya kalawan, kevindra naidoo, moherndran archary southern african journal of hiv medicine | vol 21, no 1 | a1084 | 02 june 2020 original research empowering parents for human immunodeficiency virus prevention: health and sex education at home taygen edwards, ntombizodumo mkwanazi, joanie mitchell, ruth m. bland, tamsen j. rochat southern african journal of hiv medicine | vol 21, no 1 | a970 | 29 june 2020 363 368 377 388 393 original research healthcare worker compliance with cervical cancer screening guidelines. an audit at district and regional level of care in the pietermaritzburg metropolitan area of kwazulu-natal mbali t. makhubo, thinagrin d. naidoo southern african journal of hiv medicine | vol 21, no 1 | a1104 | 02 september 2020 original research cervical human papillomavirus prevalence, risk factors and outcomes in a cohort of hiv-infected women in harare, zimbabwe ardele m. mandiriri, margaret j. pascoe, tinei shamu, sara lowe southern african journal of hiv medicine | vol 21, no 1 | a1123 | 05 november 2020 350 355 original research intracranial pressure management in patients with human immunodeficiency virus-associated cryptococcal meningitis in a resource-constrained setting philasande mkoko, jessica du preez, senlika naidoo southern african journal of hiv medicine | vol 21, no 1 | a1171 | 18 december 2020 editor's choice 334 page iv of iv female and maternal health paediatric and adolescent hiv original research late diagnosis of human immunodeficiency virus infection is linked to higher rates of epilepsy in children in the eastern cape of south africa isabel a. michaelis, maryke nielsen, craig carty, markus wolff, caroline a. sabin, john s. lambert southern african journal of hiv medicine | vol 21, no 1 | a1047 | 30 june 2020 original research retention in care for adolescents who were newly initiated on antiretroviral therapy in the cape metropole in south africa brian van wyk, ebrahim kriel, ferdinand mukumbang southern african journal of hiv medicine | vol 21, no 1 | a1077 | 22 july 2020 original research neural tube defects in the free state province from 2012 to 2016. is there an increase? nické theron, gina joubert, bertram d. henderson southern african journal of hiv medicine | vol 21, no 1 | a1134 | 25 september 2020 obituaries dr dennis sifris: in memorium david c. spencer southern african journal of hiv medicine | vol 21, no 1 | a1143 | 27 august 2020 reviewer acknowledgement southern african journal of hiv medicine | vol 21, no 1 | a1195 | 22 december 2020 editor's choice 406 412 420 427 428 abstract introduction methods results discussion limitations conclusions acknowledgements references about the author(s) natasha gous systemone, llc, weltevreden park, south africa alex e. fischer ezintsha, wits reproductive health and hiv institute, university of the witwatersrand, johannesburg, south africa naleni rhagnath ezintsha, wits reproductive health and hiv institute, university of the witwatersrand, johannesburg, south africa mothepane phatsoane ezintsha, wits reproductive health and hiv institute, university of the witwatersrand, johannesburg, south africa mohammed majam ezintsha, wits reproductive health and hiv institute, university of the witwatersrand, johannesburg, south africa samanta t. lalla-edward ezintsha, wits reproductive health and hiv institute, university of the witwatersrand, johannesburg, south africa citation gous n, fischer ae, rhagnath n, phatsoane m, majam m, lalla-edward st. evaluation of a mobile application to support hiv self-testing in johannesburg, south africa. s afr j hiv med. 2020;21(1):a1088. https://doi.org/10.4102/sajhivmed.v21i1.1088 original research evaluation of a mobile application to support hiv self-testing in johannesburg, south africa natasha gous, alex e. fischer, naleni rhagnath, mothepane phatsoane, mohammed majam, samanta t. lalla-edward received: 25 mar. 2020; accepted: 23 apr. 2020; published: 30 june 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: human immunodeficiency virus self-testing (hivst) reduces barriers associated with facility-based testing; however, no formal mechanism exists for users to self-report results or link to care. the aspecttm hivst mobile application (app) was developed for use in south africa. objectives: this study evaluated the acceptability and feasibility of the aspecttm hivst app for individuals from the inner city of johannesburg. method: this cross-sectional pilot, with a convenience sample of 300 adults, was conducted in july 2018. participants were provided an oraquick hivst kit and a smartphone preloaded with the app, then asked to follow the in-app instructions for use (ifu) to complete the hivst and upload results. trained healthcare workers (hcws) observed and recorded any deviations from the ifu, and conducted a post-test survey to assess acceptability. feasibility was evaluated by the number of participants who agreed to participate, completed the self-test, and uploaded all information onto the app correctly. results: most participants (98.7%) found the app easy to use. to reduce difficulties related to the ifu (26; 8.7%), participants suggested multimedia supplements (4; 1.3%), additional languages (4; 1.3%) and simplified instructions (5; 1.7%). all individuals approached, agreed to participate, 267 (89.0%) correctly completed all steps and 210 (78.7%) successfully captured all information on the app. most errors (26; 8.7%) were testing errors and 1 (0.3%) was from the app sequence. twelve (4.5%) errors were with test strip imaging and 72 (27.0%) discordances were with demographic information. conclusion: despite some challenges with ifu interpretation and data capture via the app, this pilot showed that the aspecttm hivst app is an acceptable way to upload mobile hivst results and demographic information to a central database. keywords: hiv self-test; digitisation; mobile app; monitoring and evaluation; digital health. introduction in 2012, the oraquick advance rapid hiv-1/2 antibody test (orasure technologies inc, bethlehem, usa) was the first hiv self-test (hivst) approved for sale in the united states as an over-the-counter hivst rapid diagnostic test (rdt) for individuals with no prior hiv testing experience.1 since then, over 2.5 million hivst kits have been sold globally and more than 4 million have been distributed through donor funded programmes.2 the world health organization (who) strongly recommends that hivst be utilised as a way to complement existing hiv services3 as self-testing may reduce barriers associated with traditional facility-based testing, like travel, wait times and privacy concerns.4,5 based on this growing body of evidence, south africa became one of over 40 countries to have incorporated hiv self-testing into their national hiv policies,6,7 with self-testing introduced as a way to help close the gap between the 84.9% of adults living with hiv who know their hiv status and the 90% target of the unaids 90-90-90 initiative.5,8,9,10 the introduction of hivst programmes will improve access to further hiv diagnostic services, prompting an increase in testing uptake and frequency, which could lead to earlier diagnosis.11 there are, however, several concerns related to hivst, as there is no formal pipeline for users to self-report their results or be linked to care following the self-test. these hivst kits are not diagnostic, but rather considered tests for triage, and all positive results should prompt the user to seek confirmatory testing by a trained healthcare professional.12 furthermore, the independence of hivst presents considerable challenges surrounding the monitoring and evaluation (m&e) of hivst programmes, which are required by public health stakeholders to understand the uptake and effectiveness.13 strong mobile phone penetration in lowand middle-income countries (lmic)14,15 has led to the development of a variety of mobile health (mhealth) interventions to complement hivst. these include telephone hotlines, short message service interventions, internet-based platforms and mobile applications (apps).16,17,18,19,20 a brazilian study conducted in 2019 showed that an internet-based intervention targeting men who have sex with men led to 21.4% of online participants self-reporting, whilst an interactive voice response telephone line in south africa was found to link 9.8% of participants to care.21 whilst these platforms have shown varied success, the introduction of mhealth interventions for linkage to care and m&e are in line with the south african national department of health mhealth strategy (2015), and should be explored further.22 despite data concerns in lmics,23 recent trends are towards the development of downloadable apps due to their agility and scalability.24 the app interface also provides developers with a malleable platform that can be tailored to individual users, allowing them to curate a collection of hivst information, resources and guidance for testers, whilst also capturing the hivst result data.19,20 recently, hivsmarttm, a canadian app, was developed to guide users through the testing process, link them to care, and store the hivst result data. preliminary evaluations in key canadian populations, as well as healthcare workers in south africa have shown the app to be feasible and acceptable; however, neither hivsmarttm, nor any other app, has been developed or tested for the general population in lmics.9,20,25 south africa has shown previous acceptance of hiv-related mhealth interventions with smartlink, an app that improved linkage to care for clinic-based hiv testing in participants under 30 years of age.26 another successful mhealth intervention, momconnect, has been used by over 2 million pregnant south african women with information regarding their pregnancy, whilst also creating a national pregnancy registry.27,28 the aspecttm hivst app was developed to help strengthen and complement hivst programmes by supporting self-testers through testing, facilitating linkage to care and digitising the reporting of hivst results through an operational dashboard for m&e. the specific objective of this pilot study was to evaluate the acceptability and feasibility of the aspecttm hivst app for individuals from the inner city of johannesburg, in order to advise further scale-up. we present the findings from this pilot. methods study design this evaluation was a cross-sectional pilot study that ran for four weeks in july 2018. a convenience sample of 300 consenting adults was recruited from inner-city johannesburg, south africa. recruitment was based around the hillbrow health clinic by trained healthcare workers (hcw) who went into the surrounding communities and spoke to the public about the current study. those interested were screened against inclusion/exclusion criteria, then brought to the hillbrow clinic to provide consent and complete the study. participants were included if they owned a mobile phone (feature phones, or higher, for app compatibility) and could provide a valid mobile phone number, were 18 years or older, able to read english and able to provide written informed consent. participants were excluded if they did not meet the inclusion criteria, were currently on a pre-exposure prophylaxis (prep) regime or any hiv treatment medication, could not provide valid identification or had any condition that may have interfered with the testing process (such as intoxication or poor vision). development of the aspecttm hiv-self-testing mobile app the aspecttm hivst app was designed for android and deployed by systemone, llc (northampton, ma, usa), a diagnostic connectivity and disease intelligence company. the aspecttm hivst app was designed to be integrated with the existing aspecttm software platform, a system designed to integrate directly with diagnostic instruments in order to collect digital results for real-time monitoring and reporting via an operational dashboard. the aspecttm api can also communicate with redcap, an existing south african healthcare database, and this application is already being used for reporting hiv viral load results and early infant hiv diagnosis (eid). the aspecttm hivst app was developed using dimagi commcare (washington, usa), a common data-gathering platform. the app was structured to allow the self-tester to collect their own demographic information, provide the tester with instructions on how to perform self-testing, input their interpretation of the test result, and capture a photo of the hivst strip (figure 1). demographic data were collected with one question per page and included the self-tester’s age, gender, mobile number, education level and whether they had self-tested before. the instructions, which were developed in english, provided the tester with step-by-step guidance, presented pictorially with simple wording taken directly from the hivst kit manufacturer’s instruction sheet, so that self-testing could be performed independently of a clinical setting. figure 1: screenshots of the aspecttm hiv-self-testing mobile app.29 all data gathered by the app was automatically uploaded via a secure server to the aspecttm data management platform for viewing and review by the research team. data collected in aspecttm was presented in aggregate form on a data dashboard that could be configured to display any relevant statistics for the research team. the app security was implemented with privacy by design methodology as per protection of personal information (popi) guidelines30 with patient data encrypted in transit and at rest, and also followed best practice guidelines in accordance with general data protection regulation recommendations.31 data collection trained hcws obtained voluntary informed consent from the participant in a private room, then uploaded the participant’s unique study identification number on the app. once uploaded, the participant was handed a samsung j5 smartphone, preloaded with the aspecttm hivst app, and an accompanying hivst kit. the sealed test kit contained an english brochure with instructions for use (ifu) as part of the standard packaging; however, the participant was requested to perform the hivst by following the ifu included in the hivst kit and the digital version of the ifu provided on the app. obtaining the sample takes 5–8 min when using the ifu (either paper or digital), followed by a 20 min incubation period. the oraquick hivst kit (orasure technologies inc., bethlehem, usa) was used for the study as it had already undergone full evaluation and was approved for use in south africa.32 in a private room at a clinic, participants were asked to navigate the app and perform the hivst with no assistance, whilst the hcw observed the process and recorded any deviations from the app instructions. following the test, the hcw asked the participant a number of questions to obtain feedback on the app design and willingness to use an app for hivst in future. after the 28 min test was completed, the participant returned the phone to the hcw, who then uploaded their professional interpretation of the hivst result on the app. regardless of the hivst result, the hcw performed confirmatory testing using a commercial hiv rapid test (advanced quality, intec products, inc., xiaman, china). if the participant’s self-test and hcw confirmatory tests were discordant, a third test was performed (abon 1/2/o tri-line, abon biopharm hangzhou co., hangshou china). the hcw uploaded all results, as applicable, on the app for reporting purposes. participants with hiv-positive results (based on the confirmatory testing) were referred to a clinic as per standard of care.7 evaluation of hiv-self-testing and mobile app usage acceptability outcomes the evaluation of mobile apps may provide challenges to researchers due to the nature of their varied users, objectives, interfaces and mobility.33 in many cases, app developers and researchers develop data collection tools that are app-specific, in order to explore concepts exclusive to their app.34,35 for this pilot study, a survey was developed to advise on the preliminary scale-up of the app, which looked at general acceptability and asked a set of closed-ended (yes/no) and open-ended questions, similar to the methodologies found in other mhealth app evaluations.21,36 the survey collected participant demographic information and included questions on whether the app was easy to use; which steps, if any, were difficult to understand; would they use the app again; would they be willing to download this app in the future and if they had any suggestions to improve the app. the demographic information collected by the survey and recorded by the hcw was also used to reference the accuracy of data capture on the app. feasibility outcomes similar to acceptability, there is no universal measure for determining the feasibility of an app; however, the generally accepted formula for feasibility includes three criteria: the participant’s acceptance of using the app, the ability of the participant to complete tasks on the app and the ability of the app to perform the required tasks.37 these variables inevitably change based on the functionality of the app and its intended users, and for this pilot the feasibility criteria were as follows: user acceptance of the app: the number of participants who agreed to use the app. successful test completion using the app: the number of participants who completed the testing through the app without error (i.e. experiencing difficulties or asking the hcw for assistance). success of data capture through the app: the number of participants who captured their demographic information (when compared to the original records collected by the hcw), uploaded their interpreted test result and captured their test-strip images correctly. the final feasibility score is then presented as a percentage of the final criteria.37 data analysis all data extracted from the survey questionnaire (paper based) were entered into an access controlled excel spreadsheet. the quantitative data captured on aspecttm were extracted into a separate access controlled excel spreadsheet. quality control checks involved a 10% randomised check comparing paper-based tools against data on the spreadsheet. this was performed by the quality control officer on a daily basis. all data were coded and then exported to stata version 15.1 (statacorp, usa) for descriptive analysis. data were grouped into categories to define demographic characteristics, then presented as frequency counts and percentages. ethical consideration ethics approval was obtained from the university of the witwatersrand human research ethics committee (reference number 180504). all participants provided informed consent and were compensated zar150 for their time. results demographics of the 300 participants, over two-thirds (211; 70.3%) were younger than 36 years old, there were 134 (44.7%) female participants and 231 (77.0%) participants who were educated up to at least high school level. only 35 (11.7%) participants indicated that they had previously self-tested. this information is presented in table 1. table 1: demographic characteristics. sample size = 300. hiv test outcomes forty-two (14%) participants interpreted their self-test result as hiv positive; however, there were 5 (1.7%) discordant interpretations between participants and hcws (table 2). three (1.0%) results were interpreted as positive by the hcw but were interpreted as either invalid (1; 0.3%) or negative (2; 0.7%) by the participant, and 2 (0.7%) results were interpreted as negative by the hcw but interpreted as either indeterminate (1; 0.3%) or positive (1; 0.3%) by the participant. manual review of these discordant test result images, on the aspecttm dashboard by a senior researcher, confirmed the hcw interpretation in all discordances. the confirmatory testing of all participants conclusively diagnosed 43 (14.3%) as hiv positive, all of whom were referred to care by the hcw. table 2: human immunodeficiency virus (hiv) testing outcomes. sample size = 300. acceptability nearly all participants (296/300; 98.7%) found the aspecttm hivst app easy to use, when surveyed; however, 26 (8.7%) participants experienced some difficulty working through the testing steps as outlined in the app (table 3). almost all of the difficulties were related to the self-testing procedures, as 18 (6.0%) participants had difficulty sliding the tube into the stand, eight (2.7%) had difficulties swabbing their gums and three (1.0%) stated that the instructions were not clear. another four (1.3%) participants had difficulty taking and uploading the picture of the test to the app. when asked for suggestions to make the app easier to use, five (1.7%) participants recommended that the instructions and steps be clarified, whilst four (1.3%) participants specifically suggested adding a multimedia component to the instructions. another four (1.3%) participants suggested that the app be available in local languages and two (0.7%) participants stated that the phone memory requirements should be decreased. all but one (299/300; 99.7%) participants were willing to use the app again and only two (0.7%) participants stated that they would not be willing to download the app in the future. table 3: acceptability outcomes. sample size = 300. feasibility the final feasibility score was 70.0%. all 300 individuals approached for this study agreed to participate in the evaluation of the aspecttm hivst app (table 4). of the 300 participants, 267 (89.0%) successfully completed the hivst by following all of the steps on the app without error. the majority of errors (26; 8.7%) came from participants performing the testing procedures incorrectly, after reading the instructions on the app, which included sliding the tube into the stand (18; 6.0%) and swabbing the gums (8; 2.7%). another four (1.3%) participants had difficulties with the language of the instructions, whilst eight (2.7%) participants made errors interpreting their hivst results and one participant (0.3%) could not properly navigate the pages of the app. table 4: feasibility outcomes. of the 267 participants who completed the testing (table 4), 210 (78.7%) participants successfully captured all information on the app. the most erroneous variable was previous testing history, where 34 (12.7%) participants submitted information that did not correlate with what they stated to the hcw during the survey. the variables of age and highest level of education each had 12 (4.5%) participants who exhibited discordance and there were also two (0.7%) discordances with gender compared with hcw-recorded data. twelve (4.5%) participants also uploaded an illegible image of the hivst strip to the app. discussion this pilot study is the first investigation of an mhealth app to enhance monitoring and evaluation of hivsts for individuals from the inner city of johannesburg, and the findings from this pilot have established that participants showed high acceptability of the intervention, whilst also identifying challenges that can be targeted for improvement as the platform scales up. the high acceptability was similar to that of the hivsmarttm app and a brazilian internet-based intervention; however, these studies only evaluated the feasibility of using the app to link patients to care or increase testing uptake, respectively.9,20,21,37 the aspecttm hivst app, instead, aimed to guide participants through the testing process, then upload the results to a central server for m&e, and this additional layer of complexity has introduced more opportunities for user error. the majority of errors, however, were not as a result of the app functionality, but rather test usability and the ifu that guided the self-testing process. errors stemming from the ifus have been well documented in a number of hivst studies, including ones from south africa.38,39,40 suggestions like clarifying the instructions, incorporating video or voice notes, and offering additional languages should all be taken into consideration, especially as more hivsts, each with specific ifus, become available to the market. some of these suggestions have already been implemented by other platforms, as the hivsmarttm app is already available in both of canada’s national languages, and provides supplemental video content.20 there were a number of discrepancies between hcw-recorded and app-captured data on participant demographic information. there were also some difficulties in the uploading of the test strip photo via the app. a simple summary page, similar to that seen on a banking app, before completing a transaction, could provide the user with an opportunity to review their information before submitting it through the app. this additional checkpoint should help prevent any data entry errors. one variable, however, previous hiv testing history, had 34 (12.7%) discordant entries between what the hcw recorded and what the app captured; all 34 entries reported never having hiv tested to the hcw, but were captured in the app as having previously tested. it is possible that privacy of the app has revealed an interviewer bias, where some participants may not have felt comfortable sharing sensitive information with the hcw, but felt free to do so through the app. previous mhealth studies have also found that self-administered tools may decrease interview bias;41 however, further evaluation of this app and its users would be required before stating that the app is responsible for removing or decreasing this interviewer bias. some participants also had difficulty understanding how to take a picture of the test strip. when test images were reviewed on the aspecttm dashboard, the images were quite variable in terms of quality. the purpose of this functionality was to allow a third party to manually review test images and flag potential discordant results for follow-up. however, similarly to other studies,20,42 we had high concordance between participant and hcw interpretation of the self-test and, thus, this step may not even be necessary if lay persons are able to interpret results as accurately as trained hcws. in low bandwidth environments, the requirement to upload images may also incur additional data charges and may not be cost effective. with the number of countries adopting hivst policies being on the rise, the m&e of these programmes poses a unique set of challenges12 and measurement of uptake and effectiveness becomes difficult. the aspecttm hivst app facilitated the capture of hivst data directly to an operational dashboard, namely aspecttm. this dashboard was developed by systemone and is currently being used to report tuberculosis and hiv viral load results from over 3000 diagnostic instruments across 43 countries.29 for this study, the dashboard displayed very basic summary hiv statistics, a list of individual test results and also supported the downloading of automated reports. this could allow a programme manager to remotely monitor indicators such as uptake, demographics of the testing population, hiv positivity rates, invalid rates and improve reporting against key performance indicators. the functionality of the dashboard also allows for the pushing of automated sms notifications directly to the tester based on their hiv result, which could be used to promote confirmatory testing and help link them to care.43 this is especially important for hivst, as one of the problems with home testing is that people receiving a positive diagnosis are suddenly faced with a serious diagnosis and no immediate access to information, counselling or treatment resources.11 the feasibility of these dashboard features should be considered for future research. data concerns are also an important issue in south africa, with previous mhealth studies highlighting data costs and phone memory as a barrier to entry.26,44 future app development should focus on keeping storage requirements minimal to ensure that the app is available for as many individuals as possible. furthermore, the necessity to upload images may also incur additional data charges and may not be affordable for all users. limitations the study had several limitations. convenience sampling from one sub-district from inner-city johannesburg was used to recruit participants limiting the generalisability of the findings, and the compensation of participants may have accounted for the very high participation rate. furthermore, the majority of participants were under 35 years old, which may have made it easier for them to navigate a mobile app as they may be more tech-savvy than older age groups. the aspecttm hivst app was only available in english. it was also only tested on a samsung phone, and it may not reflect the usability of the app on other phones owned by the general population, especially across different operating systems and memory capacities. the discordance between hcw-recorded and app-captured demographics may reflect an interviewer bias, whilst the process of testing in front of a hcw may have increased the number of forced errors due to the pressures of being observed. performing the hivst with the app in a clinic, with a hcw present, may also present bias, as the app is intended to be used independently of a clinic setting. another limitation of the pilot process was that the hcws did not record the participants’ interpretation on paper and, thus, results discordance could not be verified, as was done for the other variables. although recent studies have introduced validated data collection tools for mhealth usability,45 at the time of this study, there were also no validated data collection tools to measure the acceptability and feasibility of mhealth apps for hivst, hence the study-specific questions may not be used to reproduce these results in similar settings. similarly, the use of only one hivst kit and its accompanying ifu means that these results cannot be generalised across all hivsts, especially since many of the errors were related to the interpretation of the ifu. conclusions with millions of hivst kits distributed worldwide without adequate tracking, the need for m&e of these kits is ever increasing. on an individual level, this may lead to better linkage to care and follow-up with patients and, on a national level, tracking can identify areas of need to optimise kit distribution, marketing and supplementary information. despite some challenges with ifu interpretation and data capture via the app, this pilot study has shown that the aspecttm hivst app is an acceptable way to upload mobile hivst results and demographic information to a central database. acknowledgements the investigators would like to thank the study implementation team and the study participants. competing interests n.g. works for systemone and was involved in the design of the aspect hivst app. authors’ contributions n.g., n.r., m.p. and m.m. designed the study. n.g., n.r. and m.p. collected data, n.g., n.r., m.p. and a.e.f. were involved in the data cleaning and analysis; a.e.f., s.t.l.-e. and n.g. wrote the initial draft of the manuscript. all authors critically reviewed and approved the final draft. funding information funding to carry out the research project has been obtained through a gates grand challenges award to systemone (grant number: opp1182240) and grand to wits rhi received from the bill and melinda gates foundation (grant number opp1132929). data availability statement data are available upon reasonable request. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references richter m, venter wd, gray a. enabling hiv self-testing in south africa. s afr j med. 2016;13(4):186–187. https://doi.org/10.7196/sajhivmed.858 unitaid, world health organization. market and technology landscape: hiv rapid diagnostic tests for self-testing. 4th ed. geneva: unitaid; 2018. wong v, jenkins e, ford n, ingold h. to thine own test be true: hiv self-testing and the global reach for the undiagnosed. j int aids soc. 2019;22(s1):e25256. https://doi.org/10.1002/jia2.25256 figueroa c, johnson c, verster a, baggaley r. attitudes and acceptability on hiv self-testing among key populations: a literature review. aids behav. 2015;19(11):1949. https://doi.org/10.1007/s10461-015-1097-8 makusha t, knight l, taegtmeyer m, et al. hiv self-testing could ‘revolutionize testing in south africa, but it has got to be done properly’: perceptions of key stakeholders. plos one. 2015;10(3):e0122783. https://doi.org/10.1371/journal.pone.0122783 world health organization. number of countries adopting hiv self-testing policies rises sharply [homepage on the internet]. 2020 [updated 2017 jul 25; cited 2020 jan 15]. available from: https://www.who.int/hiv/mediacentre/news/hiv-self-testing-increases/en/ national department of health south africa. national hiv self screening guidelines 2018. pretoria: department of health republic of south africa; 2018. aids. global aids update. unaids [homepage on the internet]. 2020 [cited 2020 feb 1]. available from: http://www.unaids.org/en/resources/documents/2017/%202017_data_book pai np, behlim t, abrahams l, et al. will an unsupervised self-testing strategy for hiv work in health care workers of south africa? a cross sectional pilot feasibility study. plos one. 2013;8(11):e79772. https://doi.org/10.1371/journal.pone.0079772 human sciences research council. the fifth south african national hiv prevalence, incidence, behaviour and communication survey, 2017: hiv impact assessment summary report. pretoria: human sciences research council; 2018. ritchwood d, selin a, pettifor a, et al. hiv self-testing: south african young adults’ recommendations for ease of use, test kit contents, accessibility, and supportive resources. bmc public health. 2019;19(1):123. https://doi.org/10.1186/s12889-019-6402-4 venter f, majam m, jankelowitz l, et al. south african hiv self-testing policy and guidance considerations. southern afr j hiv med. 2017;18(1):775. https://doi.org/10.4102/sajhivmed.v18i1.775 fionet: mobile diagnostics integrated with cloud information services. usaid mhealth compendium, volume 2; pp. 62–63 [homepage on the internet]. 2017 [cited 2019 nov 13]. available from: http://www.africanstrategies4health.org/uploads/1/3/5/3/13538666/fionet_-_mobile_diagnostics.pdf gsma. the mobile economy sub-saharan africa. london: gmsa; 2017. wedderburn cj, murtagh m, toskin i, peeling rw. using electronic readers to monitor progress toward elimination of mother-to-child transmission of hiv and syphilis: an opinion piece. int j gynecol obstet. 2015;130(s1):s81–s83. https://doi.org/10.1016/j.ijgo.2015.04.006 mokgatle mm, madiba s. high acceptability of hiv self-testing among technical vocational education and training college students in gauteng and north west province: what are the implications for the scale up in south africa? plos one. 2017;12(1):e0169765. https://doi.org/10.1371/journal.pone.0169765 majam m, quaife m, phatsoane m, et al. high self-reporting of hiv self-test results through an interactive voice response telephone line in inner city johannesburg. poster session presented at: ias conference on hiv science, mexico; 2019 jul 21–24. de boni rb, lentini n, santelli ac, et al. self-testing, communication and information technology to promote hiv diagnosis among young gay and other men who have sex with men (msm) in brazil. j int aids soc. 2018;21(5):e25116. https://doi.org/10.1002/jia2.25116 janssen r, engel n, esmail a, et al. alone but supported: a qualitative study of an hiv self-testing app in an observational cohort study in south africa. aids behav. 2020;24(2):467–474. https://doi.org/10.1007/s10461-019-02516-6 pai pn, smallwood m, desjardins l, et al. an unsupervised smart app-optimized hiv self-testing program in montreal, canada: cross-sectional study. j med internet res. 2018;20(11):e10258. https://doi.org/10.2196/10258 de boni rb, veloso vg, fernandes nm, et al. an internet-based hiv self-testing program to increase hiv testing uptake among men who have sex with men in brazil: descriptive cross-sectional analysis. j med internet res. 2019;21(8):e14145. https://doi.org/10.2196/14145 national department of health, south africa. mhealth strategy 2015–2019. pretoria: national department of health; 2015. researchictafrica.net. cape town: research ict africa; 2017. state of prepaid market in south africa: submission to parliament of south africa on the cost to communicate in south africa [homepage on the internet]. 2016 [cited 2019 dec 8]. available from: https://www.ellipsis.co.za/wpcontent/uploads/2016/09/cost_to_communicate_research_ict_africa.pdf gough a, hunter rf, ajao o, et al. tweet for behavior change: using social media for the dissemination of public health messages. jmir public health surveill. 2017;3(1):e14. https://doi.org/10.2196/publichealth.6313 mcgill university health centre foundation. hiv smart app [homepage on the internet]. 2016 [cited 2020 jan 12]. available from: https://www.muhcfoundation.com/current-projects/hiv-smart-app/ venter wdf, fischer a, lalla-edward st, et al. improving linkage to and retention in care in newly diagnosed hiv-positive patients using smartphones in south africa: randomized controlled trial. jmir mhealth uhealth. 2019;7(4):e12652. https://doi.org/10.2196/12652 seebregts c, dane p, parsons an, et al. designing for scale: optimising the health information system architecture for mobile maternal health messaging in south africa (momconnect). bmj glob health. 2018;3(s2):e000563. https://doi.org/10.1136/bmjgh-2017-000563 praekelt. momconnect for nurses and midwives programme status report (quarter 2) 1 april 2017–30 june. johannesburg: praekelt; 2017. systemone. aspect, see what matters [homepage on the internet]. 2020 [cited 2020 mar 24]. available from: https://systemone.id/aspect republic of south africa. government gazette, act no 4 of 2013: protection of personal information act, 2013. cape town: the south african government; 2013. the eu general data protection regulation (gdpr) (regulation (eu) 2016/679). european parliament and council [homepage on the internet]. 2016 [cited 2019 nov 3]. available from: http://www.eugdpr.org/ ingold h, mwerinde o, ross al, et al. the self-testing africa (star) initiative: accelerating global access and scale-up of hiv self-testing. j int aids soc. 2019; 22(s1):e25249. https://doi.org/10.1002/jia2.25249 baharuddin r, singh d, razali r. usability dimensions for mobile applications – a review res. j. appl sci eng technol. 2013;5(6):2225–2231. https://doi.org/10.19026/rjaset.5.4776 reynoldson c, stones c, allsop m, et al. assessing the quality and usability of smartphone apps for pain self-management. pain med. 2004;15(6):898–909. https://doi.org/10.1111/pme.12327 jake-schoffman de, silfee vj, waring me, et al. methods for evaluating the content, usability, and efficacy of commercial mobile health apps. jmir mhealth uhealth. 2017;5(12):e190. https://doi.org/10.2196/mhealth.8758 birkhoff s, cantrell ma, moriarty h, lustig r. the usability and acceptability of a patient-centered mobile health tracking app among a sample of adult radiation oncology patients. ans adv nurs sci. 2018;(41)3:243–259. https://doi.org/10.1097/ans.0000000000000202 pai np, bhrgava m, joseph l, et al. will an unsupervised self-testing strategy be feasible to operationalize in canada? results from a pilot study in students of a large canadian university. aids res treat. 2014;2014(747619):1–8. https://doi.org/10.1155/2014/747619 simwinga m, kumwenda mkrd, kayira l, et al. ability to understand and correctly follow hiv self-test kit instructions for use: applying the cognitive interview technique in malawi and zambia. j int aids soc. 2019;22(s1):e25253. https://doi.org/10.1002/jia2.25253 smith p, wallace m, bekker lg. adolescents’ experience of a rapid hiv self-testing device in youth-friendly clinic settings in cape town south africa: a cross-sectional community based usability study. jias. 2016;19(1):28406597. https://doi.org/10.7448/ias.19.1.21111 majam m, mazzola l, rhagnath n, et al. usability assessment of seven hiv self-test devices conducted with lay-users in johannesburg, south africa. plos one. 2020;15(1):e0227198. https://doi.org/10.1371/journal.pone.0227198 kim h, xie b. health literacy and internetand mobile app-based health services: a systematic review of the literature. proc assoc info sci tech. 2015;52(1):1–4. https://doi.org/10.1002/pra2.2015.145052010075 bwana p, ochieng l, mwau m. performance and usability evaluation of the insti hiv self-test in kenya for qualitative detection of antibodies to hiv. plos one. 2018;13(9):e0202491. https://doi.org/10.1371/journal.pone.0202491 siedner m, santorino d, lankowski a, et al. an sms intervention to improve hiv linkage to care: a randomized, comparative effectiveness trial. 2014 presented at: 21st conference on retroviruses and opportunistic infections; 2014 march; boston, ma. fischer ae, sebidi j, barron p, lalla-edward st. the momconnect nurses and midwives support platform (nurseconnect): a qualitative process evaluation. jmir mhealth uhealth. 2019;7(2):e11644. https://doi.org/10.2196/11644 zhoe l, bao j, setiawan ma, saptono a, parmanto b. the mhealth app usability questionnaire (mauq): development and validation study. jmir mhealth uhealth. 2019;7(4):e11500. https://doi.org/10.2196/11500 hiv 858 forum enabling hiv self-testing in south africa m l richter, w d f venter, a gray   african centre for migration and society, university of the witwatersrand, johannesburg, and international centre for reproductive health, department of obstetrics and gynecology, ghent university, belgium m l richter, ba (hons) ma llm   wits reproductive health and hiv institute, university of the witwatersrand, johannesburg w d f venter, fcp (sa)   discipline of pharmaceutical sciences, university of kwazulu-natal, durban a gray, msc (pharm), fps corresponding author: m l richter (marlise.richter@gmail.com) in a south african context, we consider the implications of the united states food and drug administration’s recent approval of the oraquick hiv self-testing kit. we argue that current law and policy inhibit the roll-out of accurate and well-regulated self-testing kits, and create a loophole for sale in supermarkets, but not pharmacies. s afr j hiv med 2012;13(4):186-187. doi:10.7196/sajhivmed.85   in july 2012, the food and drug administration (fda) approved the oraquick test (orasure technologies) as the first hiv self-testing kit in the usa.1 this over-the-counter test, retailing at approximately us$35 40 (r245 280), uses saliva from a mouth swab and provides a result within 20 40 mins. orasure has established a consumer support centre that provides telephonic support and referrals.2 in a recent study of new york-based men who have sex with men (msm) who were provided with the self-testing kit, few experienced problems performing the test.3 studies by the integration of tb in education and care for hiv/aids (iteach) in rural kwazulu-natal, south africa (sa), are showing equally promising results (k dong, personal communication). it would seem that, with appropriate support, self-testing is poised to revolutionise hiv-testing. sa has made immense strides in improving hiv testing coverage, at least partly owing to direct intervention by the minister of health.4 however, average cd4 counts at initiation of hiv treatment remain low, suggesting that late diagnosis may still be a problem for a sizeable proportion of the population. new, more convenient ways to test for hiv may increase the proportion of individuals who know their hiv status, and help to identify infected individuals earlier in the course of disease. a recent lancet editorial notes: ‘ironically, the lack of mandatory counselling with oraquick may help decrease the stigma around testing’.5 previously, we examined the arguments against self-testing and showed that critics’ objections to its roll-out in sa were based largely on vague fears with little supporting evidence.6 similar conclusions in support of self-testing have been drawn by others.7 , 8 there are a wide range of self-tests currently available in pharmacies and supermarkets in sa, including tests for pregnancy, prostate cancer, ovulation, recreational drugs and breathalysers for alcohol. few objections have been raised against the availability of these tests, and their distribution is not regulated. we have argued that self-testing in sa may have an enormous positive effect on hiv testing uptake and early diagnosis. self-testing could extend to groups that have been traditionally hard to reach with general public health campaigns, and would be in line with the spirit of the patients’ rights charter and the national health act, urging people to take responsibility for their own health.6 yet, sa’s legal and policy frameworks do not facilitate the dissemination of hiv self-tests. self-tests are classified as ‘medical devices’ under the medicines and related substances control act (act no. 101 of 1965, as amended), but there is no regulatory system in place yet for medical devices. this means, for example, that the manufacturers of the oraquick test would be able to market it in sa – as long as the kit, ironically, is not available in pharmacies. the only legally binding restriction on the distribution of self-testing hiv kits is provided by the good pharmacy practice (gpp) standards issued by the south african pharmacy council.9 the 4th edition of the gpp, last updated in 2010, prevents pharmacists from selling the test or administering it in a pharmacy. section 2.13.5.5 of the gpp states that ‘only rapid tests which use a blood sample may be performed in a pharmacy’. section 2.13.5.8(h) adds that ‘pharmacists must not sell hiv tests for patients to perform at home.’ interestingly, this restriction does not apply to any other tests. nor does the gpp apply to general supermarkets or corner cafes, creating a loophole for distribution. while the fda stamp of approval means that the public need not be concerned about the accuracy of oraquick if it were to become available locally, this would not necessarily hold true for other hiv self-tests that are currently obtainable at community pharmacies, and are left unregulated. although implementing an effective regulatory system for medical devices is challenging, unjustified restrictions such as those in the gpp could easily be addressed. a recent civil society consensus statement on strategies to improve hiv testing and counselling highlighted these and other challenges of hiv-testing policies, paradigms and legal frameworks in sa.10 the statement endorsed self-testing ‘if accompanied by the same essential components of any hiv testing service, including easy access to accurate information’ and linkages to care. these are indeed vital components of the goal to enable everyone in sa to test for hiv regularly, and to do so when and where they choose.   useful websites: • ‘the first in-home oral hiv test’: http://www.oraquick.com/home • ‘oraquick in-home hiv test’: http://www.cvs.com/shop/product-detail/oraquick-in-home-hiv-test?skuid=896631   references 1. british broadcasting corporation (bbc) news. us approves first over-the-counter hiv home-use test. london: bbc news, 2012. http://www.bbc.co.uk/news/world-us-canada-18700121 (accessed 3 july 2012). 1. british broadcasting corporation (bbc) news. us approves first over-the-counter hiv home-use test. london: bbc news, 2012. http://www.bbc.co.uk/news/world-us-canada-18700121 (accessed 3 july 2012). 2. food and drug administration (fda). first rapid home-use hiv kit approved for self-testing. silver spring, md: fda, 2012. http://www.fda.gov/forconsumers/consumerupdates/ucm310545.htm (accessed 24 october 2012). 2. food and drug administration (fda). first rapid home-use hiv kit approved for self-testing. silver spring, md: fda, 2012. http://www.fda.gov/forconsumers/consumerupdates/ucm310545.htm (accessed 24 october 2012). 3. carballo-diéguez a, frasca t, balan i, ibitoye m, dolezal c. use of a rapid hiv home test prevents hiv exposure in a high risk sample of men who have sex with men. aids and behavior 2012;16(7):1753-1760. [http://dx.doi.org/10.1007/s10461-012-0274-2] 3. carballo-diéguez a, frasca t, balan i, ibitoye m, dolezal c. use of a rapid hiv home test prevents hiv exposure in a high risk sample of men who have sex with men. aids and behavior 2012;16(7):1753-1760. [http://dx.doi.org/10.1007/s10461-012-0274-2] 4. mbengashe t. the national hiv counselling and testing campaign and treatment expansion in south africa: a return on investments in combination prevention. xix international aids conference, 26 july 2012, washington dc. 4. mbengashe t. the national hiv counselling and testing campaign and treatment expansion in south africa: a return on investments in combination prevention. xix international aids conference, 26 july 2012, washington dc. 5. arnold c. at-home hiv test poses dilemmas and opportunities. lancet 2012;380(9847):1045-1046. 5. arnold c. at-home hiv test poses dilemmas and opportunities. lancet 2012;380(9847):1045-1046. 6. richter m, venter wd, gray a. home self-testing for hiv: aids exceptionalism gone wrong. s afr med j 2010;100(10):636-642. 6. richter m, venter wd, gray a. home self-testing for hiv: aids exceptionalism gone wrong. s afr med j 2010;100(10):636-642. 7. gardner j. hiv home testing – a problem or part of the solution? south african journal of bioethics and law 2012;5(1):15-19. 7. gardner j. hiv home testing – a problem or part of the solution? south african journal of bioethics and law 2012;5(1):15-19. 8. bayer r, stryker j, smith md. testing for hiv infection at home. n engl j med 1995;332(19):1296-1299. 8. bayer r, stryker j, smith md. testing for hiv infection at home. n engl j med 1995;332(19):1296-1299. 9. south african pharmacy council. good pharmacy practice in south africa. fourth edition. arcadia: south african pharmacy council, 2010. 9. south african pharmacy council. good pharmacy practice in south africa. fourth edition. arcadia: south african pharmacy council, 2010. 10. southern african hiv clinicians society, treatment action campaign, section27, et al. joint statement – how we can improve hiv testing and counselling. http://www.sahivsoc.org/newsroom/society-news (accessed 30 july 2012). 10. southern african hiv clinicians society, treatment action campaign, section27, et al. joint statement – how we can improve hiv testing and counselling. http://www.sahivsoc.org/newsroom/society-news (accessed 30 july 2012). medical insurance leighton mcdonald, mb chb e-cecutive manager, quaisa hr-ms, johannesburg the addition of a chronic disease list (col), covering 25 chronic illnesses, to the prescribed minimum benefits will have cost implications for most medical schemes, with schemes having to fund the diagnosis, medical management and investigation as well as medication for listed diseases. these costs may not be subject to copayments and may not be funded from the savings account portion of a member's benefits. while many medical schemes have in the past provided benefits for chronic medication, the costs of out-of-hospital management of these conditions will pose an additional risk to many schemes. the southern african journal of hiv medicine prescribed minimum benefits government has announced its intention to have all public senice employees covered by one medical scheme, with effect from january 2005. this will have the following effects: • an increase in the number of people being treated in the private health care sector • standardisation of benefits provided to employees • economies of scale for management of the scheme • increased buying/negotiating power with suppliers of services. public service employee medical scheme this should result in tighter management and increased affordability of health care benefits. in addition, the public health care sector should be able to allocate current budgets to fewer patients. making sense of medical insurance in south africa today on 5 october 2003 the sunday times ran a feature on the medical scheme industry, to update readers on a number of changes that are currently taking place, primarily as a result of new legislation. a range of topics was covered in separate articles, and are summarised below. the public service currently employs approximately 900 000 people, of whom only 500 000 are members of a large range of medical schemes. the balance rely on public facilities for their health care requirements. the tender to be issued for the administration of this medical scheme will be a catalyst for the required increase in black economic empowerment of the medical scheme industry and address some of the imbalances currently experienced in this sector. eighty per cent of white south africans currently enjoy medical scheme cover, while only 20% of the black population do so (a total of 18% of the south african population is covered). alterations made to the regulations of the medical schemes act have made it compulsory for medical schemes to provide funding for the management of chronic illnesses from january 2004. november 2003 m southern af ican journal of hiv mfoicinf ---------schemes most at risk will be those with poor clinical risk profiles, primarily those with a pensioner ratio above the average. these schemes will face additional costs next year that will need to be funded from increased contributions or at the expense of other benefits that may be reduced to subsidise this requirement the risk equalisation fund (ref), planned for introduction in 2005, will address the problems posed by variances in risk profiles across schemes. all schemes will pay into the ref, which will be distributed to schemes based on their risk profile, larger disbursements going to those assessed as having higher risk. concern has been expressed at the asynchronous timing of legislative changes the implementation of expanded prescribed minimum benefits a full year before that of the ref will put higher-risk medical schemes at a disadvantage during this window period. risk equausatlon fund january 2005 sees the implementation of an ref for the medical scheme industry. the objective of this fund is to 'level the playing fields' with regard to risks that medical schemes are exposed to. a uniform contribution will be made by all medical schemes and disbursements will be made to schemes depending on their level of risk (calculated by analysing membership profile), with higherrisk schemes receiving larger payouts. the implementation of the ref will lead to a greater level of premium contribution standardisation for a set of health care benefits. as contribution rates are currently used as a competitive parameter by schemes, this will lead to greater competition based on service rather than cos~ which will have positive effects on the industry. one of the objectives is the protection of affordability of health care cover this will need to be closely monitored along with the effects of other legislative changes. management of fraud in the medical scheme industry , the issue of fraud in the medical scheme industry continues to be of great concern and is now being addressed through a collaborative effort the board of healthcare funders, a body representing member medical schemes, has initiated a fraud unit by bringing together industry roleplayers in an information sharing initiative. it is widely reported that 10 20% of the r40 billion spent in the medical scheme industry can be attributed to fraudulent practices, including: • members receiving benefits to which they are not entitled (sharing membership cards) • providers claiming for services which are included in benefits after providing services which are not included in benefits after providing services (spectacles claimed for after dispensing sunglasses) • providers claiming from medical schemes for nonhealth care services (cash, pots, cookware, audio equipment, etc.l • providers claiming for patients when no services were delivered. the commitment shown by the roleplayers, primarily the large administrators, will increase the effectiveness of this initiative. information will be shared across schemes to track providers and/or members who have unusual claims patterns. providers found to have submitted fraudulent claims to one scheme will be investigated in other schemes in order to strengthen legal cases. a register of these providers will also be kept for use by medical schemes. employer-funded hiv treatment initiatives it appears that legislation is preventing employers from providing treatment to hiv-infected workers. the council for medical schemes, the body responsible for enforcing medical scheme legislation, has indicated that employers who provide treatment benefits for hiv-infected employees are effectively carrying out the business of a medical scheme and need to comply with all aspects of the medical schemes ac~ including provision of cover for the extensive prescribed minimum benefits. this is based on a technicality where employers outsource the management of this benefit to companies providing hiv/aids disease management services. since employers who wish to offer this benefit feel they are offering a valuable service to their workforce, it has always been expecled that the council for medical schemes would grant exemptions to facilitate the process. the council has indicated that it will not be doing so. one spokesperson has gone as far as to say 'those companies that are complaining would have had their employees on medical aid if they were genuinely concerned: neil kirby of werksman attorneys points out that most companies involved in this issue do not want to fall foul of the law and the council for medical schemes. this issue may only be resolved when a company follows the legal route (possibly through the constitutional court) to address the situation. ~ovfm9fr 2003 hiv 991_in.indd o r ig in a l a r t ic l e original article management of cryptococcal meningitis in adults at mthatha hospital complex, eastern cape, south africa o o sogbanmu,1 mb chb, pgdip (hivmgt), mmed (fam med); m a john,2,3 mb chb, fcpath (micro), dip hiv man (sa), dtmh, cert infectious disease (sa); u lalloo,2 mb chb, fcp, doh, md 1 cecilia makiwane hospital, eastern cape department of health, east london, south africa 2 enhancing care initiative, nelson r mandela school of medicine, university of kwazulu-natal, durban, south africa 3 infectious diseases department, nelson r mandela school of medicine, university of kwazulu-natal, durban, south africa corresponding author: m a john (johnm@ukzn.ac.za) background. cryptoccocal meningitis (cm) remains prevalent in hiv-infected individuals across south africa (sa). early diagnosis and management, aided by the existing southern african hiv clinicians society (sahivsoc) 2007 guidelines on management of cm, could reduce the mortality associated with this condition. objective. to review the management of adult patients with cm and adherence to the sahivsoc 2007 guidelines in a district hospital. methods. a retrospective chart review of patients admitted with cm from december 2011 to may 2012 was performed. the following key recommendations of the guidelines were evaluated: measurement of cerebrospinal fluid (csf) opening pressure at the first lumbar puncture (lp), prescription of amphotericin b (amb)/fluconazole therapy, intravenous prehydration preceding administration of amb, monitoring of renal function and performance of serial lps to manage raised intracranial pressure (icp). results. a total of 57 patient charts were reviewed, of which 40 (70%) were of females. the mean age (range) of the cohort was 36 (21 60) years. fifty-two (91%) patients presented with headache. confusion was recorded in 30 (53%) and vomiting in 26 (46%). the major signs observed were fever (n=29 (51%)) and neck stiffness (n=34 (60%)). fifty-five (96%) patients were hivinfected at presentation, with a median (range) cd4+ count of 77 (13 90) cells/µl. none of the patients had a csf opening pressure measured at first lp. amb was used as an induction agent in 51 (89%) patients, of whom 47 (92%) completed 2 weeks of amb. of these 51, only 20 (40%) were prehydrated and 10 (18%) had two repeat lps performed 1 week apart. renal function was monitored in only 27 (53%) of the patients receiving amb. this was done at baseline and twice weekly, and was consistent with the guidelines. no abnormality in renal function was recorded in these cases during the study. the mortality rate was 30% in the first 10 days of admission. conclusion. this chart review showed inadequate adherence to the recommendations of the 2007 sahivsoc guidelines in the majority of cases except for the use of amb as a first-line antifungal agent. control of icp and monitoring for drug toxicity were not done as per guidelines and may impact on clinical care and outcome. despite this, the early 30% mortality is comparable with published reports from other regions in sa, but is higher than in developed health systems. s afr j hiv med 2014;15(3):104-107. doi:10.7196/sajhivmed.991 worldwide, the burden of cryptoccocal meningitis (cm) is estimated to be 0.04 12% per year among persons with hiv, resulting in nearly 625 000 deaths.[1] sub-saharan africa has the highest yearly burden with 720 000 cases (range 144 000 1.3 million).[1] in sub-saharan africa, mortality is estimated to be 50 70%, compared with 12% in the usa and other developed nations.[2] cryptococcus neoformans infections are very rare in healthy people, with a yearly incidence of 0.4 1.3 cases per 100 000 in the general population.[2] in a population-based surveillance of cryptococcosis in gauteng, south africa (sa), the overall incidence rate was 15.6/100 000 among both hiv-positive and -negative individuals.[3] among hiv-positive persons, the rate was 95/100 000, and among persons living with aids, 14/1 000.[3] in hiv-positive individuals, cm may present with headaches, unexplained fever, nausea, vomiting, neck stiffness, confusion, seizures, abnormal behaviour, and new onset of psychiatric symptoms, altered level of consciousness, focal neurological signs, diplopia, unexplained blindness and sometimes coma.[4] headache is the predominant symptom and was observed in 100% of cases in a study done by baradkar et al.[5] neck stiffness may be absent in some patients with cm.[6] the presentation of cm may be acute, sub-acute (over 2 4 weeks), or chronic (>4 weeks).[4] despite the availability of highly active antiretroviral treatment (haart), the mortality from cm has not changed from the pre-haart era. however, cm immune reconstitution inflammatory syndrome (iris) is implicated in the ongoing high mortality.[7] it is also not uncommon to have other opportunistic infections together with cm that contribute to mortality.[8] elevated intracranial pressure (icp) results in increased mortality and morbidity. up to 40% of cm deaths occurring during weeks 3 10 of treatment were associated with elevated icp. visual loss was also observed as a consequence of elevated icp.[9] a high index of suspicion is needed for the diagnosis of cm, especially in sub-saharan africa, where there is a dearth of standard laboratory facilities and expertise. therefore, the role 104 sajhivmed september 2014, vol. 15, no. 3 o r ig in a l a r t ic l e september 2014, vol. 15, no. 3 sajhivmed 105 of a detailed history and physical examination cannot be overemphasised.[10] the definitive diagnosis involves cerebrospinal fluid (csf) microscopy, cryptococcal antigen (crag) detection in csf and/or serum, and the culture of c. neoformans.[11] if an indian ink stain is negative, crag remains a reliable test (95% sensitivity, 95% specificity). the crag latex agglutination system (meridien bioscience, us) is commonly used and correlates well with the fungal burden.[11] in a retrospective study conducted in durban, sa, the significantly higher indian ink positivity rate and significantly higher mean crag titre reflected the greater fungal load in hiv-positive patients.[12] culture of c. neoformans in csf is also beneficial in the diagnosis of subsequent episodes of cm where both crag and indian ink tests are not useful.[13] the only guideline for the management of cm in our setting, prior to 2012 when this study was conducted, was published by the sahivsoc in 2007.[6] this guideline was updated in 2013. the initial guideline highlighted the role of amphotericin b (amb) as the antifungal agent preferred during the induction phase of treatment. treatment with amb (1 mg/kg body weight (bw)/day) for 2 weeks, followed by fluconazole (400 mg/day) as a consolidation agent for 8 weeks was recommended. a dose of 200 mg fluconazole daily is indicated for secondary prophylaxis until the cd4+ t-lymphocyte count is >200 cells/µl for at least 6 months and the most recent hiv-1 viral load is suppressed; this applies to patients with a first episode of cm.[6] patients with relapse are treated with 1 mg/kg bw amb for 2 4 weeks or until the csf is sterile. consolidation and maintenance options in relapse depend on the fluconazole minimum inhibitory concentration and include high-dose fluconazole with or without weekly amb infusions, or voriconazole. [6] amb is often unavailable in our centres, hence high-dose fluconazole (800 1 200 mg) is often used. the latter is suboptimal at these doses. [14] for resource-limited settings where amb is unavailable, high-dose fluconazole (1 200 mg) is recommended as an induction agent by the world health organization (who).[15] similar to the sahivsoc guidelines, tronconso et al.[16] highlighted the role of monitoring renal function while patients are undergoing the induction phase with amb. if creatinine increases by twofold, the amb dose is omitted and prehydration with 0.9% normal saline, 1 l 8-hourly, is recommended. amb should be stopped if the creatinine fails to decrease after this intervention.[6] in june 2013, the sahivsoc updated the guideline for the prevention, diagnosis and management of cm in hiv-positive persons to be compatible with who guidelines. a major change from the 2007 version is the role of both amb and fluconazole during the induction phase. the revision also highlighted timing of haart initiation.[13] methods the study was a descriptive, retrospective chart review conducted at the mthatha general hospital in the eastern cape (ec), sa, between december 2011 and may 2012. the majority of patients with cm in the or tambo district of the ec are managed as inpatients in this facility. the hospital serves as a referral centre and has 100 medical beds. the inclusion criteria were adult patients >18 years of age with a first episode of cm diagnosed on lumbar puncture (lp) as part of routine care of patients with clinical features of meningitis. patients were managed by a team of doctors that included an intern, medical officer/registrar and a family physician. the researcher did not interact with the patients. for data collection, a researcher searched the ward register daily for cases diagnosed as cm and admitted to any of the medical wards. data were collected from respective patient case note files. the medical records of all patients identified with cm from the ward register were available for data collection and were verified by positive laboratory results. the data of interest were: measurements of csf opening pressure at the first lp; whether amb/fluconazole therapy was used; whether prehydration was administered before the receipt of amb; and whether monitoring of renal function (rising urea and creatinine only) and icp were done according to the recommendations of the sahivsoc 2007 cm guidelines. the time of commencement of amb was documented in the prescription/drug chart of each patient and the time of admission was recorded on the admission chart and the nurses’ charts. the renal function of each patient was determined from the laboratory report in the case notes. data were analysed using spss version 18.0 (ibm, south africa). descriptive data were presented using frequency tables. ethical approval was obtained from the biomedical research ethics committee of the university of kwazulu-natal (number be058/12). results a total of 57 charts were reviewed over the 6-month study period, representing all patients who were admitted to the medical wards with cm in this time period. however, some patients may have died in casualty before ward admission and hence would not have been captured in the ward admission charts. the mean age (range) of the patients was 36 (21 60) years, and 40 were women (70%). table 1 shows the presenting complaints, signs and their frequency of occurrence. of the 57 patients, 52 (91%) presented with headache. confusion was recorded in 30 (53%) and vomiting in 26 (46%) of subjects. the major signs observed were fever in 29 (51%), and meningeal signs in 34 (60%). all patients had an initial lp for csf laboratory analysis that included biochemistry, indian ink stain, crag assay and fungal culture. a computerised tomography (ct) scan was done in only two patients with table 1. presenting symptoms and signs of patients admitted with cryptococcal meningitis (n=57) presenting complaints n % headache 52 91 confusion 30 53 psychotic features 11 19 seizures 13 23 vomiting 26 46 signs fever 29 51 neck stiffness 34 60 kernig’s and brudzinski’s signs 34 60 focal signs (hemiparesis) 1 2 cranial nerve deficit 1 2 o r ig in a l a r t ic l e 106 sajhivmed september 2014, vol. 15, no. 3 focal signs and cranial nerve deficits, showing a mass lesion in both cases, suggestive of cryptococcoma. there was no record of the measurement of csf opening pressure at lp in any of the charts reviewed. the diagnosis of cm was made within 24 hours of presentation (range 3 8 hours) in 70% of the patients. this was calculated from the time the lp was performed to the time the microscopy result was obtained. all 57 cases were positive for microscopy and culture for c. neoformans, while crag was positive in 51 (89%) cases. hiv infection was diagnosed for the first time in 7 (12%) of these patients. the remaining 50 (88%) were known to be hiv-positive. all had features of immunosuppression. the most frequent infections were oropharyngeal candidiasis and tuberculosis (tb) (table 2). the median (range) cd4+ count was 77 (51 100) cells/µl. twenty-two (39%) of the 57 patients were on haart. thirteen (23%) patients had been on arvs for less than 6 months and the remaining 9 (16%) patients had been on arvs for 7 12 months. all patients were on tenofovir, lamivudine and efavirenz and were documented to be adherent to treatment. tenofovir was continued even when amb was commenced. thirty-two (56%) of the patients had co-infection with pulmonary tb. ten of these patients were diagnosed on sputum microscopy for acid-fast bacilli, while the remainder were diagnosed clinically and on chest radiography. ten patients had tuberculous meningitis co-infection based on csf lymphocytosis and raised protein. amb (1 mg/kg bw) was used as the induction agent for the management of cm in 51 (89%) of the patients, while the remaining 6 (11%) had intravenous fluconazole (800 mg) because amb was out of stock. among the 51 patients who had amb as an induction agent, the drug was initiated in 50 (98%) cases, within 24 hours of the attending doctor writing the script. the time of commencement of amb was documented in the prescription/drug chart by the nurse administering the dose and the time of admission was recorded on the patient chart. only 20 (39%) patients receiving amb had documentation of adequate prehydration. forty-seven (92%) patients completed the 2-week course of amb. renal function was monitored in 27 (53%) of the patients receiving amb. this was done at baseline and twice weekly, and was consistent with the guideline. results were obtained from the case files and the normal ranges for urea and creatinine were 2.1 7.1 mmol/l and 64 104 µmol/l, respectively. no abnormalities in serum urea and creatinine were recorded in these cases during the study. ten patients (18%) who experienced worsening headache in the ward had two repeat lps performed for the management of raised icp. these lps were performed 1 week apart. forty patients (70%) were discharged, with the average (range) hospital stay being 21 (16 28) days. the in-hospital mortality rate within the first 1 10 days of hospital admission was 30%. fluconazole 400 mg was dispensed on discharge for 1 week of the consolidation phase and patients were referred to a local clinic to continue treatment. data on patients prescribed haart were not obtained. discussion there are few data on management and outcome of cm from a non-research district hospital setting in a resource-limited health system where operational challenges may have a significant impact. this study was limited by the retrospective, descriptive nature. although all patient charts were found, documentation in the clinical notes was poor and missing data compromised this chart review. the mthatha complex manages 6 10 cases of cm in aids patients per month. some cases of cm could have been missed in this review if patients died in casualty and hence were not captured in the ward admission file. this retrospective chart review of adult patients found that the management was not consistently in line with national guidelines. unlike other studies where the incidence of cm was similar in both sexes, or higher in men,[1] we found that the disease was three times higher in women. the reason for this may be the migrant nature and different health-seeking behaviour of men in this community and warrants further investigation. all patients were hiv-positive with a median cd4+ count of 77 cells/µl, consistent with the results in other studies. [1,3] an interesting observation is that 88% of patients were known to be infected with hiv prior to the diagnosis of cm. the mortality of 30% was less than that reported in a ugandan study in a similar patient population and healthcare system, where mortality was between 40% and 50%.[7] the mortality was similar to that in other centres in sa.[17] many patients already diagnosed with hiv infection were not on arvs at the time of presentation. this is of concern as it is likely that cm may have been preventable in the majority. this observation highlights the need for a more intensive rollout of arv treatment. our study also highlighted the occurrence of cm in the first 6 months of haart, which may represent iris or reflect ongoing immunosuppression during early haart. headache was the most common symptom. vomiting, fever, confusion and psychosis were also noted. however, meningeal signs were absent in 40% of the patients. this may be owing to poor inflammatory response attributed to severe immunosuppression. the study found that co-infections, particularly tb, were extremely high in these cm patients. this is not surprising, because of profound immunosuppression and the high prevalence of tb in our setting. many cases of tb were diagnosed on clinical or radiological features, or suggestive csf microscopy and biochemistry. since these are not specific diagnostic tests, overdiagnosis of tb was possible. the csf crag was found to be an extremely important test; 77% of the patients were diagnosed within 24 hours of presentation using this assay. the crag test should be routinely performed by the laboratory if the india ink stain is negative. the effect of early diagnosis on morbidity and mortality is well documented. [18] it was also demonstrated that patients who presented with features of neurological deficit received a ct scan as recommended by the guideline.[6] none of the patients admitted had an opening csf pressure measured during the lp and fundoscopy was not done, which is of concern. documentation and management of icp was also not done. this was presumably because the hospital does not stock manometers. drug treatment aspects of the 2007 sahivsoc guidelines were followed in most table 2. concurrent opportunistic infections and comorbidities in patients with cryptococcal meningitis (n=57) opportunistic infections n % pulmonary tuberculosis 32 56 oropharyngeal candidiasis 57 100 seborrhoeic dermatitis 12 21 oral hairy leukoplakia 8 14 tuberculous meningitis 10 23 o r ig in a l a r t ic l e september 2014, vol. 15, no. 3 sajhivmed 107 patients who received amb as the induction agent, and all were discharged on fluconazole, 400 mg daily, as a consolidation agent.[6] prehydration and renal toxicity monitoring advised by the guideline were not followed, and it is surprising that more renal complications were not observed. however, documentation of fluid administration is poor in our facility. early mortality rates may have improved if these measures had been implemented. conclusion we recommend that an in-service workshop on common opportunistic infections in hiv should be provided for healthcare providers within the district hospital setting. a commitment by the department of health to provide necessary diagnostic tools, including manometers, and an uninterrupted drug supply would improve the management and outcome of the disease at a district level. references 1. park bj, wannemuehler ka, marston bj, govender n, pappas pg, chiller tm. estimation of the current global burden of cryptococcal meningitis among persons living with hiv/ aids. aids 2009;23(4):525-530. [http://dx.doi.org/10.1097/qad.0b013e328322ffac] 2. centers for disease control and prevention. c. neoformans cryptococcosis. http//:www. cdc.gov/fungal/crptococcosis-neoformans/statistics.html (accessed 27 july 2013). 3. mccarthy km, morgan j, wannemuehler ka, et al. population-based surveillance for cryptococcosis in an antiretroviral-naive south african province with a high hiv seroprevalence. aids 2006;20(17):2199-2206. [http://dx.doi.org/10.1097/ qad.0b013e3280106d6a] 4. bicanic t, harrison ts. cryptococcal meningitis. br med bull 2004;72(1):99-118. [http://dx.doi.org/10.1093/bmb/ldh043] 5. baradkar v, mathur m, de a, kumar s, rathi s. prevalence and clinical presentation of cryptococcal meningitis among hiv seropositive patients. indian j sex transm dis 2001;30(1):19-22. [http://dx.doi.org/10.4103/0253-7184.55474] 6. mccarthy k, meintjes g, arthington-skaggs b, et al. guidelines for the prevention, diagnosis and management of cryptococcal meningitis and disseminated cryptococcosis in hiv-infected patients. s afr j hiv med 2008;3(25):25-35. http:// sajhivmed.org.za/index.php/sajhivmed/article/view/92 (accessed 6 june 2013). 7. kambugu a, meya d, rhein j, et al. outcomes of cryptococcal meningitis in uganda before and after the availability of haart. clin infect dis 2008;46(11):1694-1701. [http://dx.doi.org/10.1086/587667] 8. skiest dj, hester lj, hardy rd. cryptococcal immune reconstitution inflammatory syndrome: report of four cases in three patients and review of the literature. j infect 2005;51(5): e289-e297. [http://dx.doi.org/10.1016/j.jinf.2005.02.031] 9. van der horst cm, saag ms, cloud ga, et al. treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. national institute of allergy and infectious diseases mycoses study group and aids clinical trials group. n engl j med 1997;337(1):15-21. 10. lightowler jvj, cooke gs, mutevedzi p, et al. treatment of cryptococcal meningitis in kwazulu-natal, south africa. plos one 2010;5(1):e8630. [http://dx.doi. org/10.1371/journal.pone.0008630] 11. tanner dc, weinstein mp, fedorciw b, joho kl, thorpe jj, reller l. comparison of commercial kits for detection of cryptococcal antigen. j clin microbiol 1994;32(7):16801684. 12. moosa mys, coovadia ym. cryptococcal meningitis in durban, south africa: a comparison of clinical features, laboratory findings, and outcome for human immunodeficiency virus (hiv)-positive and hiv-negative patients. clin infect dis 1997;24(2):131-134. 13. southern african hiv clinicians society. the guideline for the prevention, diagnosis and management of cryptococcal meningitis among hiv-infected persons: 2013 update. s afr j hiv med 2013;2(4):76-86. [http://dx.doi.org/10.7196/sajhivmed.930] 14. pukkila-worley r, mylonakis e. epidemiology and management of cryptococcal meningitis: developments and challenges. expert opin on pharmacother 2008;9(4):551-560. [http://dx.doi.org/10.1517/14656566.9.4.551] 15. world health organization. rapid advice: diagnosis, prevention and management of cryptococcal disease in hiv-infected adults, adolescents and children. geneva: world health organization, 2011:4-44. http://whqlibdoc.who.int/ publications/2011/9789241502979_eng.pdf (accessed 2 january 2014). 16. troncoso a, fumagalli j, shinzato r, gulotta h, toller m, bava j. cns cryptococcoma in an hiv-positive patient. j int assoc physicians aids care (chic) 2002;1(4):131-133. 17. lessells rj, mutevedzi pc, heller t, newell ml. poor long-term outcomes for cryptococcal meningitis in rural south africa. s afr med j 2011;101(4):251-252. 18. dhana a. diagnosis of cryptococcosis and prevention of cryptococcal meningitis using a novel point-of-care lateral flow assay. case reports in medicine 2013;2013(article id 640216):4 pp. [http://dx.doi.org/10.1155/2013/640216] i~f sour frn african jdu nal of ~iv mfdici f ------------dctohfr 2002 from the antiretroviral therapy is at last receiving more attention. such is the scale of hiv morbidity that every health care worker will need to gain expertise in this area. children are our future, and it is appropriate that their needs and those of their parents are adequately addressed. the concept of family therapy should now be emphasised, as paediatric hiv reflects hiv infection of the parents as well. for those tens of thousands of children needing therapy, their caregivers' health is integral to survival. this concept of family therapy represents a unique opportunity orphaned by aids recently a young tb researcher visiting us from new york went shopping at the greenpoint sunday market and was accosted by some thugs who relieved her of her bag. she put up a brave struggle and her screams alerted some good samaritans, who gave chase. one of the thugs was apprehended and the bag, with some contents, recovered. the samaritans put it into their car while they dealt with the miscreant they returned to their car just in time to see some street children making off with the now tvlicestolen handbag, and all the other contents of the car! it was just the weekend after, in the independent of 6 october, that i read the most disturbing article entitled the aids orphans time bomb': the pandemic 'will rob three million children of parents in the next ten years, bringing spectre of social chaos and even higher crime rate: the reporter quoted the institute for security studies as saying that the burgeoning orphan population will grow up under extreme levels of poverty and will be sorely tempted, and even obliged for its physical survival, to turn to crime, drugs, gangs and the sex trade. a staggering 300 000 children have already lost their mothers to aids. pre aids, 2.5% of the popula 'on in developing countries were orphaned, and is proportion is expected to increase to 17% in south africa by 2010. it is estimated that 10 000 children currently live or work on south africa's streets. a stop at any city traffic lights will bear testimony to this, and the number is set to rise dramatically in the near future. the traditional african safety net, the extended family, will probably not be able to absorb overwhelming numbers of orphans. research has also shown that households with one or more members who have hiv/aids are much poorer than others. when the breadwinner dies the economic impact on the children left behind is drastic. orphans identified their priority needs as the most immediate basics: food, clothing and education. editors to southern african family physicians to develop strategies to treat and strengthen families. the concepts of antiretroviral therapy in children are relatively easy and the principles are similar to those for adults. important differences include more use of liquid formulations, surface area dosing for some medications, the need to increase medication with growth, and the importance of caregivers in maintaining adherence. mark canon guest editor. southern africon journal of hiv medicine this problem must provide yet another most compelling reason to implement countrywide antiviral treatment debbie bradshaw from the medical research council is quoted as saying 'a large number of people are already infected with hiv and will progress to aids, illness and death. unless something is done to prevent this, they are going to die and not be around to look after their kids: according to an mrc report published in may, orphaned children are 'not only traumatised by the loss of parents, they lack the necessary parental guidance through crucial life-stages of identity formation and socialisation. psychosocial effects will be worsened by accompanying threats to the basic survival and security frequently experienced by orphans: innovative solutions are called for. one example is the non-governmental organisation called big brother, big sister, south africa, which screens, recruits and trains adult volunteers to mentor assigned orphans. the initial commitment is only one hour per orphan per week, but one can see how, as bonds grow, this time will increase. the idea is that the orphan will have an adult who takes an interest in his or her daily life and becomes a role model during important stages of development the story brought home to me once again the depths and complexities of the aids pandemic, especially in a continent like africa. we really do have to find a way to take that first step to national arv treatment three cheers for the south african medical associa 'on, who with kgosi le lape at its helm has fearlessly moved headlong into mobilisation for a national treatment plan and a bold plan it is too. using the mandela children's fund as a channel for collecting funds and backed by a number of important south africans, letlape looks set to pull it off. unda-gail bekker managing editor cpd questionnaire vol. 13, no. 4 204 sajhivmed november 2012, vol. 13, no. 4 c p d q u e s t io n a ir e true (a) or false (b) – click on the correct answer: regarding the urinary tract manifestations of varicella zoster virus 1. the mechanism through which varicella zoster virus causes urinary retention is almost always related to pain of genital ulceration. regarding tuberculosis (tb) prevention in pregnant women 2. the sensitivity of typical tb symptoms (e.g. weight loss) in diagnosing tb in hiv-infected pregnant women is similar to other hiv-infected adults. 3. isoniazid is not known to be teratogenic. regarding hiv in homeless populations in south africa 4. in settings of low hiv prevalence, homelessness is a wellestablished socioeconomic risk factor for hiv infection. regarding cutaneous reactions to cotrimoxazole 5. acute generalised exanthematous pustulosis is the second most common cutaneous adverse drug reaction caused by bactrim. regarding immunological responses after art initiation 6. less than 5% of individuals initiating art will have poor immunological responses as measured by cd4 cell count. 7. poor immunological responses on art occur more commonly in older adult patients. regarding self-testing for hiv infection 8. although self-testing kits are available from chemists, there is, as yet, no fda-approved testing kit. regarding resistance testing in hiv infection 9. according to the new south african art resistance testing guidelines, all infants newly diagnosed with hiv infection should have hiv genotyping, with particular concern related to non-nucleoside reverse transcriptase inhibitor (nnrti)-resistant mutations. 10. according to the new south african art resistance testing guidelines, all adults newly diagnosed with hiv infection should have hiv genotyping, with particular concern related to protease inhibitor (pi)-resistant mutations. 11. in any patient on first-line therapy with first-time detectable viraemia (>1 000 copies/ml), non-adherence is the most likely explanation, and intensive adherence counselling and support are required before repeating viral load testing. 12. in adults, resistance testing is recommended for any patient failing first-line therapy; the nucleoside reverse transcriptase inhibitor (nrti) of greatest interest here is lamivudine (3tc). 13. genotypic testing is required following any treatment interruption before re-starting therapy. 14. failure to achieve viral suppression on a pi-containing regimen is almost always due to resistance. regarding the prescribing of psychotropic medication in individuals on art 15. although not commonplace, several nrtis can have central nervous systems manifestations that warrant consideration in patients with known mental illness. 16. after excluding organic causes and delirium, hiv-infected adults who require antipsychotics should ideally be started on haloperidol, as extrapyramidal side-effects are less common in hiv-infected patients than in uninfected patients. 17. promethazine and amitriptyline are suitable choices for patients on art who report sleep disturbances. 18. commonly used antipsychotic medications (such as haloperidol) do not interact with most antiretroviral drugs. 19. commonly used mood-stabilising medications, such as carbamazepine and valproate, do not typically interact with most antiretroviral drugs. regarding nevirapine toxicity in pregnancy 20. in the context of pregnancy, nevirapine toxicity occurs more commonly at low cd4 cell counts. five cpd points are awarded for the correct completion and submission of the questions below. cpd questionnaires must be completed online via www.cpdjournals.co.za. after submission, you can check the answers and print your certificate. this programme is available free of charge to members of the sa hiv clinicians society and sama only. instructions 1. read the journal. all the answers will be found there. 2. go to www.cpdjournals.co.za to answer the questions. accreditation number: mdb001/028/10/2011 (clinical) abstract introduction methods results discussion conclusion acknowledgements references about the author(s) dorsaf saadouli department of ophthalmology, la rabta hospital, faculty of medicine of tunis, university of tunis el manar, tunis, tunisia lamia ammari department of infectious diseases, la rabta hospital, faculty of medicine of tunis, university of tunis el manar, tunis, tunisia khaoula ben mansour department of ophthalmology, la rabta hospital, faculty of medicine of tunis, university of tunis el manar, tunis, tunisia yosra yahyaoui faculty of medicine of tunis, university tunis el manar, tunis, tunisia sameh aissa department of infectious diseases, la rabta hospital, faculty of medicine of tunis, university of tunis el manar, tunis, tunisia el afrit mohamed ali department of ophthalmology, la rabta hospital, faculty of medicine of tunis, university of tunis el manar, tunis, tunisia salem yahyaoui faculty of medicine of tunis, university tunis el manar, tunis, tunisia hanene tiouri department of infectious diseases, la rabta hospital, faculty of medicine of tunis, university of tunis el manar, tunis, tunisia citation saadouli d, ammari l, ben mansour k, et al. ocular manifestations of people living with hiv in tunisia. s afr j hiv med. 2021;22(1), a1193. https://doi.org/10.4102/sajhivmed.v22i1.1193 original research ocular manifestations of people living with hiv in tunisia dorsaf saadouli, lamia ammari, khaoula ben mansour, yosra yahyaoui, sameh aissa, el afrit mohamed ali, salem yahyaoui, hanene tiouri received: 06 nov. 2020; accepted: 02 dec. 2020; published: 19 mar. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: ocular involvement is a common complication of human immunodeficiency virus (hiv). knowledge about this topic in tunisia is limited. objective: to investigate ophthalmic manifestations in patients living with hiv in tunisia. method: this was an observational study, performed between january 2007 and december 2016. we included patients with ocular disorders related to hiv. the data were recorded retrospectively from chart review. results: amongst 98 people living with hiv (plwh), 36 participants (55 eyes) had ocular manifestations. the mean age was 32.2 ± 5.6 years. twenty-four patients were men and 12 were women. the mean value of cd4+ t-cell count was 156.5 ± 4.2 cells/µl. bilateral lesions were found in 19 eyes. best corrected visual acuity was better than 6/12 in 36 eyes. the most common ocular finding was dry eye syndrome (22%), cotton-wool spots (20%) and retinal haemorrhage (16%) followed by cytomegalovirus (cmv) retinitis (9%), anterior uveitis (7%), toxoplasmosis (4%) and tuberculosis retinochoroiditis (7%) herpetic keratitis (5%), herpes zoster ophthalmicus (2%) and syphilitic chorioretinitis (2%). papilledema was found in three eyes (5%). panuveitis was observed in four eyes (7%): three of them were associated with chorioretinal toxoplasmosis, syphilitic chorioretinitis and cmv retinitis. the fourth was attributable to immune recovery uveitis. a cd4+ t-cell count of ≤ 200 cells/µl was found to be an independent risk factor for developing posterior segment manifestations. conclusion: various ophthalmic manifestations were observed in plwh. the most common lesion was retinopathy. ocular involvement can be serious leading to poor visual prognosis, which requires close collaboration between the ophthalmologist and infectious disease physician. keywords: acquired immunodeficiency syndrome; human immunodeficiency virus; ocular manifestation; uveitis; immune recovery uveitis; cytomegalovirus retinitis. introduction human immunodeficiency virus (hiv) is a major global public health problem.1 immunodeficiency caused by the virus results in increased susceptibility to opportunistic infections and neoplasms.2 by increasing access to antiretroviral drugs, this disorder changed from a high-mortality disease to a manageable chronic disease, which may affect every organ system.3 in tunisia, hiv prevalence was 0.016% and patients were mainly infected with hiv-1.4,5 ocular complications often reflect systemic disease and have become more common and occur in approximately 70% – 80% of people living with hiv (plwh).1 it has been shown that the prevalence of ocular problems in plwh is higher than in uninfected patients.6,7 however, the clinical features of these ocular manifestations differ between countries, especially between high-income and low to middle-income countries.8 this is because of improved accessibility to healthcare and to antiretroviral therapy (art), which has shifted the spectrum of the disease from infectious to non-infectious affections. most ocular manifestations respond well to treatment, so it is important to recognise them in order to establish an early diagnosis and to start an adequate management programme. knowledge about this topic in tunisia, a north african country, is limited.9 here, we aimed to investigate ophthalmic manifestations in plwh in the tunisian population. methods this retrospective study was carried out in the ophthalmology department of la rabta hospital of tunis over a period of 10 years between january 2007 and december 2016. the median year that most of the participants presented (9 patients) was 2013. it included patients with ocular disorders related to hiv. patients were referred from the department of infectious diseases, which is an hiv reference centre. human immunodeficiency virus classification was determined according to the centers for disease control and prevention (cdc) and world health organization (who) staging systems.2,10 patients with other causes of immunodeficiency and those with additional medical problems that may overlap with ocular manifestations were excluded from our study. data extracted retrospectively from the chart reviews, included: age, gender, corrected visual acuity (va) (measured with a snellen chart), anterior segment slit-lamp examination, intraocular pressure (iop) with goldmann applanation tonometry, dilated fundus examination and fluorescein angiography if appropriate. antiretoviral treatment status and cd4+ t-cell counts were also collected. the diagnosis of cytomegalovirus (cmv) retinitis (fulminant or indolent form) was based on clinical characteristics of a necrotic retinitis with irregular borders with or without haemorrhage and small adjacent dot-like, white satellite lesions.8,11 immune recovery uveitis was diagnosed when non-infectious uveitis occurred in patients with inactive cmv retinitis who showed a substantial elevation in cd4+ t-cell count by 50 cells/µl or more to a level of 100 cells/µl or more with highly active antiretroviral therapy (haart).11 all statistical analyses were performed using spss 20. comparison of continuous data was performed with the independent samples of student’s-t test, the mann–whitney test or the wilcoxon signed-rank test. categorical data were analysed with the chi-squared test or the fisher exact test. we conducted a logistic regression analysis in descending order, to identify factors independently associated with posterior segment involvement. statistical significance was defined as p < 0.05. ethical consideration ethical approval was obtained from stellenbosch university health research ethics committee, reference number: s19/06/109. results of the 98 patients living with hiv who underwent an ophthalmic examination, 36 cases (55 eyes) (36.7%.) had ocular manifestations (table 1). twenty-four patients were men and 12 were women, the sex ratio was 2. the age of the patients with ocular manifestations ranged from 18 to 56 years with mean age of 32.2 ± 5.6 years (table 2). seventy per cent of patients were in the age group of 30–39 years. most patients (86%) were on art. tenofovir + emtricitabine + efavirenz combination-therapy has been prescribed since 2011. however, before this period patients were treated with individual drugs, zidovudine + lamivudine and efavirenz. those who did not receive art were: one new case with first diagnosis, poor compliance with treatment because of depression (1 patient) and tuberculosis infection, which resulted in the delay of the antiretroviral therapy (3 patients). systemic opportunistic infections at the time of ophthalmic examination were noted in six patients. they included pulmonary tuberculosis (three patients), pneumocystis pneumonia (two patients), cryptococcal meningitis (one patient) and candidiasis (one patient). fifty-five per cent of cases were in the who clinical stage 3 of hiv disease. of these, five patients did not receive antiretroviral therapy. table 1: ocular manifestations in patients living with hiv (n = 36). table 2: baseline demographic characteristics of the study participants listed. slightly more than half of the patients (55%) had cd4+ t-cell counts < 200 cells/µl. the mean value of the cd4+ t-cell count was 156.5 (sd ± 4.2 cells/µl); the median value was 172 cells/µl, range: 23–359 cells/µl. the four cases with cmv retinitis had cd4+ t-cell counts below 50 cells/µl, with a mean value of 36.4 ± 5.2 cells/µl. various ocular manifestations were noted. bilateral lesions were found in 19 eyes. twenty-nine of the eyes (53%) had a best corrected visual acuity (bcva) better than or equal to 6/12, whilst 11 eyes (20%) had a bcva between 6/60 and 6/12 and 15 eyes (27%) had a bcva acuity lower than 6/60. the main manifestations were decreased and/or blurred vision (20 eyes) followed by redness (eight eyes) and floaters (five eyes). nine cases (11 eyes) did not show this manifestation. anterior segment manifestations were noted in 36.4% of cases. most were not specific: dry eye syndrome found in 12 eyes (22%), and complicated by bilateral corneal ulcer in one. others were opportunistic viral infections: herpes keratitis in three eyes: (5.4%) and herpes zoster ‘ophthalmicus’ in one (2%). anterior uveitis was found in four eyes (7%), which was attributed to the toxic effects of the hiv protease inhibitor indinavir in all cases. posterior segment involvement was seen in 32 eyes of 23 patients (58%). the most common manifestation was retinal microvasculopathy observed in 20 eyes (36%) of 13 patients. the manifestations were characterised by cotton-wool spots noted in 11 eyes (20%) and intra-retinal haemorrhages noted in nine eyes (16%). the other posterior segment manifestations included toxoplasmosis in 2 (4%) and tuberculosis retinochoroiditis in 7 (9%) eyes, syphilitic chorioretinitis in one eye (2%) and cmv retinitis involving five eyes (9%). panuveitis was observed in four eyes (7%): three with chorioretinal toxoplasmosis, syphilitic chorioretinitis and cmv retinitis each. the fourth had a paradoxical worsening of intraocular inflammation after starting art, which was attributed to immune recovery uveitis. the neuro-ophthalmic manifestations observed included bilateral disc oedema secondary to cryptococcal meningitis in one patient and unilateral optic neuropathy in one patient. the ocular manifestations observed in the five patients who did not receive art were as follows: tuberculosis retinochoroiditis (3 cases) and cmv retinitis (2 cases). a cd4+ t-cell count of < 200 cells/µl was found to be an independent risk factor for developing posterior segment disease, adjusted or = 3.2, ci 95%, 1.1–3.2, p = 0.01. however, the number of samples was too small to do a comparison of male versus female and art treated versus art-naïve patients. discussion during the course of the disease, the prevalence of ophthalmic manifestations in plwh ranged from 19% to 70%.2,12 it differs by geographic region, which is related to regional hiv prevalence.12 although it has been considerably reduced by the introduction of art, it may still be high, especially in areas with high hiv prevalence such as sub-saharan africa.12,13,14 this may be because of an increase in the survival of these patients.12,13,14 in the present study, the prevalence of ocular involvement was 36.7%, which is comparable to other african studies.13,15 however, ocular manifestations in this study might be under-reported because most of the plwh do not receive routine ophthalmic screening. previous studies have found demographic patterns similar to that of our study, such as male preponderance likely related to the greater risk-taking sexual behaviour of men.16 in addition, our most susceptible age group with ocular complications of hiv, namely those in their 30s, was also described in a ghanaian study.17 the ocular manifestations are varied. almost all the structures of the eye may be affected. it has been demonstrated that the cd4+ t-cell count may help to predict the occurrence of ocular manifestations in plwh. indeed, the risk of developing ocular disease in plwh is increased when the cd4 count is < 200 cells/µl.2,13 this is consistent with our findings. although sufficient care is generally provided in our country, patients often do not adhere to treatment and to follow-up. this may explain the relatively low value of the mean cd4+ t-cell count in the present study. moreover, based on a french study comparing the clinical features of north african and french plwh, the difference concerned only the adherence to care, which could be related to a problem of acceptability of the disease.7 the ocular manifestations may be classified as opportunistic infections, retinal microangiopathy, neoplasms, neuro-ophthalmic lesions and immune reconstitution inflammatory syndrome (iris).18 antiretroviral therapy has improved the length and quality of life by decreasing opportunistic infections.19 consequently, the prevalence of anterior segment complications and adnexal disorders compared with posterior segment manifestations has increased.19 its prevalence ranged from 7% to 33.9%.18,19,20 these disorders were 36.4% in the present study. anterior segment disorders can lead to ocular morbidity and so affect the quality of life of patients. dry eye, blepharitis and uveitis are the most common anterior segment complications. this finding is consistent with our study that noted a predominance of dry eye syndrome (22%), possibly contributed to, by the region’s climate. ophthalmic herpes zoster, noted in one eye in our series, can be considered a possible indicator of hiv-infection, especially in young adults (< 50 years of age).21 moreover, it has been shown that anterior uveitis was less frequent than posterior uveitis.18 drug induced and immune recovery uveitis and herpetic uveitis were the main causes reported by singalavanija.18 in our study anterior uveitis was related to indinavir therapy in all cases. the low prevalence of anterior uveitis mentioned in the present study (7%) suggests a delayed consultation, which could lead to a serious issue. neoplasms of the eyelid or the conjunctiva, in plwh are not rare. kaposi’s sarcoma may affect up to 10%.19 however, we did not encounter anyone with this neoplasm.19 as reported in previous african data the most common ocular involvement in plwh was retinopathy that is characterised by cotton-wool spots or associated with intra-retinal haemorrhages.14,15,22 patients having such manifestations are usually asymptomatic.14,15 posterior segment manifestations include, in addition to retinopathy, opportunistic infections of the retina and the choroid. the introduction of art has led to a decrease in the incidence of these disorders.7,21 various opportunistic pathogens can be associated with hiv infection. cytomegalovirus retinitis was the most common ocular opportunistic infection and was most often associated with cd4+ t-cell count < 50 cells/µl. however, ocular syphilis is considered as undiscriminating and does not associate with cd4+ t-cell count. several studies showed that panuveitis is the most common ocular presentation in plwh.21,23,24,25 this is consistent with the clinical presentation of our only patient who presented with syphilitic panuveitis. the results of this study are similar to the findings of other african studies. although the incidence of ocular complications in hiv infection has declined since the advent of art, it remains the main cause of visual loss in patients with aids in developing countries because of limited medical resources, which can lead to a poorer systemic management. in the present study, 27% of patients had a bcva < 6/60. so the management of such patients represents a macro-issue of public health in our country. the early detection of ocular involvement in plwh is highly recommended in order to prevent severe vision loss or at least minimise it. the limitation of our retrospective study is the internal validity because of the selection bias. in addition, male predominance may be a possible bias. we propose a prospective study with a larger sample size with systematic screening examinations, comparing uninfected people with ophthalmic disorders to plwh. this would show if there is an increase in cases or severity because of hiv. conclusion ophthalmic manifestations in tunisian plwh are varied. the most common lesion was retinopathy. however, ocular involvement in plwh can be serious leading to poor visual prognosis, especially in developing countries. although the introduction of art has decreased the incidence and the severity of opportunistic ocular infections, newer manifestations such as drug induced and immune recovery uveitis have emerged as a cause of visual loss. therefore, the collaboration between ophthalmologists and infectious disease physicians is strongly recommended in the diagnosis and management of these patients. acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions s.d. is the corresponding author and assisted in writing, reviewing and editing the article. b.m. was involved in writing the original draft. a.l., t.h. and a.s. provided care and follow-up of the patient. m.a.e.a, y.y. and s.a. assisted in data curation. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability the data that support the findings of this study are available from the corresponding author, s.d., upon reasonable request. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references canidate s, hart m. the use of avatar counseling for hiv/aids health education: the examination of self-identity in avatar preferences. j med internet res. 2017;19(12):e365. https://doi.org/10.2196/jmir.6740 saini n, hasija s, kaur p, kaur m, pathania v, singh a. 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tangmonkongvoragul c. anterior segment and external ocular disorders associated with hiv infections in the era of haart in chiang mai university hospital, a prospective descriptive cross sectional study. plos one. 2018;13(2):e0193161. https://doi.org/10.1371/journal.pone.0193161 purushottam j, thakur a, choudhary m, sharma s, shah d. ocular manifestations in hiv positive and aids patients in nepal. int j clin med. 2012;3(1):14–21. laovirojjanakul w, thanathanee o. opportunistic ocular infections in the setting of hiv. curr opin ophthalmol. 2018;29(6):558–565. https://doi.org/10.1097/icu.0000000000000531 kestelyn pg. aids and the eye in developing countries. in: lightman s, editor. hiv and the eye. london: imperial college press; 2000; pp. 257–623. mandelcorn ed. infectious causes of posterior uveitis. can j ophthalmol. 2013;48(1):31–39. https://doi.org/10.1016/j.jcjo.2012.11.013 hughes eh. syphilitic retinitis and uveitis in hiv-positive adults. clin experiment ophthalmol. 2010;38:851–856. https://doi.org/10.1111/j.1442-9071.2010.02383.x tran th. syphilitic uveitis in patients infected with human immunodeficiency virus. graefes arch cli exp ophthalmol. 2005;243(1):863–869. https://doi.org/10.1007/s00417-005-1137-6 abstract introduction research methods and design results discussion limitations conclusion acknowledgements references about the author(s) sadiyya sheik department of global health, faculty of health systems and public health, stellenbosch university, cape town, south africa bart willems department of global health, faculty of health systems and public health, stellenbosch university, cape town, south africa citation sheik s, willems b. estimating qualification and factors associated with third-line antiretroviral therapy referral in the western cape. s afr j hiv med. 2021;22(1), a1184. https://doi.org/10.4102/sajhivmed.v22i1.1184 original research estimating qualification and factors associated with third-line antiretroviral therapy referral in the western cape sadiyya sheik, bart willems received: 22 oct. 2020; accepted: 08 dec. 2020; published: 28 jan. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: south africa’s antiretroviral therapy (art) programme is the largest globally and the universal test-and-treat policy is expected to increase the numbers on art. this may have implications for treatment failure rates implying a greater future need for third-line regimens. south africa initiated a third-line programme in 2013. however, there is little evidence quantifying the third-line need in this setting and the programme itself has not been formally evaluated. objectives: the study evaluated the third-line art referral process in the western cape. method: routinely collected data were analysed to derive an estimate of patients meeting criteria for third-line referral and compared with patients who were referred. factors associated with referral were identified. results: in the study period, 947 patients met criteria for third-line referral and 167 patients were referred. comparison revealed a poor overlap of only 42 patients. in multivariate analysis, factors associated with referral included receiving care at a hospital rather than a primary healthcare facility (adjusted odd ratios [aor] = 2.15, 95% confidence interval [ci] 1.1–4.2), a higher number of viral load [vls] ≥ 1000 copies/ml whilst on a protease inhibitor (pi) (aor = 1.2, 95% ci 1.01–1.42) and a greater number of years on a pi (aor = 1.25, 95% ci 1.07–1.46). patients with a 6-month gap in dispensing were less likely to be referred (aor = 0.37, 95% ci 0.17–0.81). conclusion: this study adds to a limited body of knowledge regarding third-line art programmes. the findings indicate missed opportunities for and inappropriate referral of patients. factors associated with referral were largely health system related. clinician awareness and compliance with referral remain unknown and may be contributory. keywords: third-line art; resistance; public health; hiv; western cape. introduction human immunodeficiency virus (hiv) is a major contributor to morbidity and mortality in south africa and remains a prominent part of the country’s burden of disease landscape – despite gains in life expectancy linked to large scale roll-out of antiretroviral therapy (art).1 public sector art has been available in south africa for more than a decade and there are more than 5.2 million people receiving art in the country2 making the south african art programme the largest in the world. in 2016, south africa adopted a universal test-and-treat policy, making art accessible to all people living with hiv regardless of cd4 count. this has increased the number of south africans on art but may have additional implications for rates of treatment failure and drug resistance as a result of increasing exposure to art. in the future, there may be an amplified need for second and third-line art in the country. the south african national department of health (ndoh) initiated the world’s first public sector third-line art access programme in april 2013. unlike the first and second-lines, which are pre-defined regimens following a public health approach, there is no standard third-line regimen. the choice of individual drugs included in a third-line regimen is made on a case-by-case basis considering the patient history and results of genotype resistance testing. third-line therapy can only be accessed via a referral process in which clinicians motivate to a central third-line committee first to obtain genotype testing for patients who meet the defined referral criteria and subsequently third-line art depending on the outcome of the genotype testing. third-line programmes are in their infancy worldwide and there is little evidence quantifying the need for third-line therapy in the south african setting. in addition, the referral process by which third-line art is accessed has not been formally evaluated and predictors of referral are not known. thus, there exists a critical need to evaluate third-line art programmes in this setting. we evaluated a third-line art referral process in the western cape province of south africa by estimating qualification for referral to the provincial third-line art committee, comparing the estimate with actual referrals and identifying factors associated with referral. research methods and design setting the study was conducted in the western cape province of south africa. there is one metropolitan and five rural districts in the western cape. approximately two-thirds of the population reside in the cape town metro district. in 2015, the antenatal hiv prevalence was 17.6% in the province and district prevalence varied from 11.6%3 in the central karoo to 18.9% in the cape town metro. in 2015, approximately 60% (180 769) of the estimated hiv-infected population were on art.4 western cape third-line antiretroviral therapy referral criteria and process clinicians motivate to a provincial third-line committee for genotype testing and third-line art for a defined group of patients who are failing second-line therapy. a panel of experts reviews each case to decide whether genotype resistance testing is warranted. if genotype testing is warranted, the panel then makes recommendations regarding the need for third-line therapy informed by a resistance score derived from the genotype results. both genotype testing and third-line therapy are not routinely available outside of this access programme. adult patients (15 years and older) may be referred to the third-line art committee if they have been receiving a protease inhibitor (pi) based regimen for ≥2 years and have virological non-suppression – defined as three viral loads ≥ 1000 copies/ml at least 8–12 weeks apart.5 in addition, good adherence should be verified objectively by pharmacy refill records. clinicians are required to complete a formal application form, collating the patient’s clinical history and an adherence assessment form, which is completed together with the patient (see online appendix). clinicians submit the necessary documentation via email and a decision regarding genotype testing and third-line therapy is made based on this documentation. study design the study was designed in three-steps in relation to the primary objectives of the research. figure 1 is a graphic representation of the three-step study design and each of the steps is discussed in further detail. figure 1: graphic representation of study design. step 1: estimating qualification for referral the aim of the first step of the study was to identify all adult patients who met the criteria for referral to the third-line art committee in the study period (01 october 2014–30 september 2016). criteria for referral to the committee included: age ≥ 15 years, receiving a pi-based regimen for at least 2 years and virological non-suppression defined as at least three viral load measurements of ≥ 1000 copies/ml (≥ log 3) 8–12 weeks apart. routinely collected data for patients aged 15 years and older receiving pi-based art during the study period was requested from the newly established provincial health data centre (phdc). the centre curates data from a number of stand-alone primary information systems and incorporates an inter-operability component that allows for the linkage of patient level data from each individual system using the patient master index (pmi), which uniquely identifies individuals. data were derived from four sources. pharmacy records were obtained from three sources: tier.net (an electronic register used for managing the hiv programme, jac (a pharmacy management system) and the chronic dispensing unit (cdu, a dispensing system used for chronic medication) as no one system was able to provide a complete dispensing history. jac and cdu were considered preferred sources of dispensing data because the recording of data is automated and less prone to error than that derived from tier.net, which requires manual capturing by information clerks. the fourth data source was the national health laboratory service (nhls) for data pertaining to viral load records. data from these sources were cleaned and analysed to identify patients meeting the criteria for referral to the third-line art committee in the study period. step 2: comparison with actual referrals in the second step of the study, a database of actual referrals to the third-line art committee was obtained and analysed. the database was cleaned and records occurring outside the study period were excluded. this database was then matched with the estimate of patients meeting the criteria for referral (i.e. the output of step 1) and based on the matching process, patients were classified into three categories: ‘met criteria and referred’, ‘met criteria and not referred’ and ‘did not meet criteria and referred’. in order to strengthen the matching process in the case of patients with multiple folder numbers, patient folder numbers from the database of actual referrals were first matched with an identification table provided by the phdc, which identified a dominant identification number that grouped together multiple folder numbers from the same patient. step 3: factors associated with referral in the third step of the study, a comparative analysis of the groups ‘met criteria and referred’ and ‘met criteria and not referred’ was undertaken with the aim of identifying factors associated with referral. comparator variables were obtained from routinely collected data and two categories of variables were collected, that is, demographic (e.g. age, sex and facility type) and clinical (e.g. time on pi) data. variables were selected based on findings from literature pertaining to switch from first to second-line therapy. notably, certain patient-level and facility-level variables were excluded because of non-feasible data collection. (see discussion). data analysis data were analysed using stata version 13.1 (statacorp texas 2013) and a p-value of < 0.05 was considered statistically significant. continuous variables were described using relevant summary statistics depending on the distribution of the data. further analysis involved the testing of hypotheses to determine if each variable was independently associated with the outcome, that is, referral, using either chi-squared, fischer’s exact or the wilcoxon rank sum test depending on the distribution of data. following univariate analysis, all variables were entered into a logistic regression model and a backward stepwise selection procedure was used to eliminate non-significant variables. findings are presented as crude and adjusted odds ratios with 95% confidence intervals (ci). we performed additional analyses on the group ‘did not meet criteria and referred’. whilst this group was not the focus of the study, further analysis of the patients in this group was relevant to a comprehensive evaluation of the third-line art referral process. in addition, in the absence of a validation method for estimating qualification for referral, we conducted sensitivity analyses to determine the impact of varying certain data parameters on the estimate. ethical consideration ethical approval to conduct the study was obtained from the health research ethics committee of stellenbosch university (reference no. s16/09/162). results step 1: estimating qualification for referral of the 13 791 adult patients who were on a second-line regimen for at least 2 years, 947 (6.9%) met the criteria for referral to the third-line art committee in the period 01 october 2014 to 30 september 2016. figure 2 illustrates the data cleaning and analysis process undertaken to derive the estimate of patients meeting the criteria for referral. table 1 provides descriptive characteristics for this cohort. figure 2: estimating qualification for referral: data cleaning and analysis process. table 1: descriptive characteristics by group. step 2: comparison with actual referrals a total of 167 adult patients were referred to the third-line art committee in the period 01 october 2014 to 30 september 2016 (table 1). comparison of the two groups indicated that 42 patients met the referral criteria and were referred; 905 patients met the referral criteria and were not referred and 125 patients did not meet referral criteria but were referred (figure 3 and table 2). figure 3: overlap between patients who met the criteria and those who were referred. table 2: descriptive characteristics by group. step 3: identification of predictors in univariate analysis, several factors were associated with referral: receiving art at a hospital rather than a primary healthcare (phc) facility (odd ratios [or] = 2.15, 95% ci 1.1–4.0), greater number of years on a pi (or = 1.22, 95% ci 1.07–1.39), greater number of viral loads taken whilst on the pi (or = 1.23, 95% ci 1.13–1.34) and greater number of high viral loads (i.e. ≥ 1000 copies/ml) whilst on the pi (or = 1.37, 95% ci 1.18–1.59). factors associated with non-referral were receiving art care in a rural district (or = 0.4, 95% ci 0.35–0.46) and the presence of a 6-month gap in dispensing (or = 0.43, 95% ci 0.22–0.83). in multivariate analysis, independent determinants of referral included receiving care at a hospital rather than a phc facility (adjusted odd ratios [aor] = 2.15, 95% ci 1.1–4.2), a higher number of vls ≥ 1000 copies/ml whilst on a pi (aor = 1.2, 95% ci 1.01–1.42) and a greater number of years on a pi (aor = 1.25, 95% ci 1.07–1.46). patients with a 6-month gap in dispensing were less likely to be referred (aor = 0.37, 95% ci 0.17–0.81). the final model in the multivariate logistic regression analysis was highly statistically significant (p = 0.0000) (table 3). table 3: predictors of referral. univariate and multivariate analysis. did not meet criteria and referred of the 125 patients who were referred despite not meeting the criteria for referral in the study period, 107 patient records were identified for further analysis using the folder number provided in the referral documentation. where present, the folder number allowed for the identification of the pmi, which facilitated linkage with records in the study dataset. figure 4 demonstrates the reasons why these patients were not included in the estimate of patients meeting the criteria for referral to the committee. an important finding is that 36 of the 125 patients in this group did actually meet the criteria for referral and that they were eventually excluded from the estimate because they had met the referral criteria prior to and not in the study period. the implication of this finding is explored further in the sensitivity analysis. figure 4: further analysis: ‘did not meet criteria and referred’ group. sensitivity analysis a sensitivity analysis was undertaken because of two main concerns relating to the procedure used in step 1 to derive an estimate of patients meeting the criteria for referral to the third-line art committee in the study period. the first of these concerns related to the impact of patient adherence to therapy on the outcome, that is, referral. adherence data were not captured by routine information systems and therefore could not be incorporated into the estimate. as clinical knowledge of adherence may impact on the referral decision, it is likely that the number of patients meeting criteria for referral was overestimated. in the sensitivity analysis, the presence of gaps between dispensing events was utilised as a proxy measure for non-adherence. twelve and 6 month gaps in dispensing were considered. the second concern pertains to the time period in which the criteria for referral were met. the study undertook to identify only those patients who had met the criteria in the period 01 october 2014 to 30 september 2016. however, prior to april 2013 no third-line art referral system was available to patients failing second-line regimens. it is therefore plausible that patients who met the criteria for referral prior to the start of this period would be referred once the referral process and committee was established. this hypothesis is supported by the analysis of the ‘did not meet criteria and referred’. for this reason, variation in the time period of meeting the criteria for referral was analysed. patients meeting the referral criteria from 2012, 2013 and 2014 were considered. in order to further the analysis, a combination of the two factors (i.e. adherence estimate and time period) was considered. for this analysis, we allowed for inclusion of patients meeting criteria for referral from 2012 until the end of the study period and excluded patients with a dispensing gap of 12 months. the resultant estimate was 1079 patients meeting the criteria for referral to the third-line art committee. revision of the estimate improved the match of patients who met the criteria and were actually referred from 42 to 55; however, the number of patients meeting criteria and not referred was also substantially higher having increased from 947 to 1024 (data not shown). it is likely that the match may have been higher had actual referrals prior to 2013 been included. in multivariate analysis, following a backward stepwise selection procedure with variables removed from the model at p > 0.05, only the number of vls ≥ 1000 copies/ml whilst on a pi remained independently associated with the outcome, that is, referral. for each additional high vl, patients had 1.2 times the odds of being referred (95% ci 1.09–1.34, p = 0.000). discussion the study found that in 2 years, 947 patients met the criteria for referral to the western cape third-line art committee – to be evaluated for genotype resistance testing as a precursor for consideration for third-line art. this estimate, obtained from the analysis of routinely collected data, was far larger than the number of patients actually referred to the committee in the same period (n = 167). a comparison of the two groups identified only a small overlap in patients (n = 42) indicating both a large proportion of missed opportunities for referral and a considerable proportion of referrals that did not meet the referral criteria. the study found that 6.9% (947 of 13 791) patients receiving second-line art care for at least 2 years in the western cape should have been evaluated for third-line art in a 2-year time period. as far as the author is aware, this is the first study to enumerate the need for third-line referral in this setting. this information is particularly useful for public health planning and may be considered a proxy for evaluation of second-line programmes. the study found a poor match between individuals meeting the criteria for referral and those who were referred – indicating both a large number of missed opportunities and inappropriate application of the referral criteria. missed opportunities for referral have considerable public health implications resulting in patients remaining on a failing regimen for a longer duration, accumulating further resistant mutations and potentially compromising future treatment options.6 in addition, delays in referral may facilitate transmission of resistant virus. comparative analysis identified that factors independently associated with referral included receiving care at a hospital rather than a phc facility, receiving a pi for a greater number of years and having a higher number of viral load tests whilst on the pi. patients who had at least a 6-month gap between dispensing records were less likely to be referred than those without. in our study, for every additional year on a pi after the 2-year referral criterion, patients had 1.25 times the odds of being referred. one similar study in a south african cohort also identified that time on second-line therapy prior to the availability of third-line treatment was a strong predictor of switching to third-line therapy amongst patients with significant viraemia.7 another study which looked at switching from first to second-line therapy found a decreased likelihood of switching in patients who started art in a more recent calendar year.8 as clinicians are likely to first attempt adherence interventions prior to referral, this finding may reflect the referral of patients for whom adherence interventions were unsuccessful. we also found that the number of high viral loads whilst on the pi was independently associated with referral, indicating that even with the length of time receiving a pi held constant, patients who had more viral load tests done were more likely to be referred. frequent viral load testing suggests clinician awareness of treatment failure and most likely reflects frequent review of adherence intervention efforts. we also found that patients who were receiving care in a hospital were more than twice as likely to be referred than those who were receiving care at a phc facility. this finding is not supported by a study analysing predictors of switching from first to second-line regimens, which did not find a significant difference in rates of switching between treatment providers, including providers in both hospital and phc settings.9 however, variation in rates of treatment switch between clinics has been described previously.10 it is possible that the higher rate of referral from hospitals in our study reflects differences in the art programme and patient profile in these settings. patients in hospital-based art centres may have more complicated treatment histories and may be more likely to be seen by doctors and therefore more likely to be referred. in addition, the higher proportion of referrals from hospitals may be masking prior up-referral from phc to hospital-based art centres because of treatment failure. clinician awareness and compliance with the referral procedure has not been investigated; however, differences in clinician awareness and influence between these settings may also explain some of the findings. our study found that patient non-adherence (evaluated by the presence of a 6-month gap in dispensing as a proxy measure) resulted in patients being less likely to be referred. this finding is supported by others who have found that in the context of switching from first to second-line therapy, patients who missed visits11 and those who had no clinic contact for 4 months12 were less likely to switch from first to second-line art. other studies looking at predictors of treatment switch have indicated magnitude of the viral load result as a significant factor, with values greater than log 4 more likely to result in switch.11,12 in our study, however, viral load magnitude at the third of the three high viral loads and at the last recorded viral load was not significantly associated with the referral outcome. selection of these time points may explain why the study did not find an association between viral load magnitude and referral. it is possible that the findings may have differed if more sophisticated analysis were conducted by selecting the viral load result closest to the date of meeting referral criteria instead. parameters not evaluated in this study include cd4 count magnitude and rate of decline, which were found to be predictors of switching from a first to second-line regimen.8,9,10,11,12 in addition, the study did not investigate the impact of clinician knowledge of the referral criteria and process. limitations the estimate of patients meeting criteria for referral is subject to a number of limitations. firstly, the estimate was derived from primary data sources, which may have been prone to data error. the tier.net information system in particular is less robust than other sources of pharmaceutical dispensing data because of its reliance on manual data capture by information clerks. unfortunately, tier.net was a vital data source to the estimate enabling calculation of the duration of time an individual had been receiving a pi. other sources of pharmaceutical dispensing data (jac, cdu) have only been established in recent years and did not have wide facility and patient coverage. secondly, there is potential for missed or incomplete linkage of records using the pmi. thirdly, whilst every attempt was made to model the estimate around the criteria for referral to the third-line art committee, some parameters could not be established. for example, the referral criteria specified three consecutive high viral loads (≥ 1000 copies/ml) 8–12 weeks apart. the estimate was able to identify patients who had three consecutive high viral loads but did not determine the duration of time between each result. furthermore, the three consecutive high viral load results may have occurred at any point in the patient’s history of receiving a pi, meaning that patients identified as meeting the criteria for referral may have achieved virologic re-suppression and therefore would not have been referred. in an attempt to mitigate this, the estimate excluded patients who achieved virologic suppression at the last recorded viral load in the study period. the referral criteria also specified objective verification of adherence by pharmacy refill records and the completion of an adherence assessment. this could not be incorporated reliably into the estimate and was therefore excluded. this is likely to have resulted in an overestimate of patients meeting the criteria for referral. an attempt was made to address this limitation by undertaking sensitivity analyses, which looked at the impact of dispensing gaps (as a proxy for poor adherence) on the estimate. however, further analysis of patients who were actually referred revealed a high proportion of patients with dispensing gaps 12 months or longer. based on the information at hand and because of the inability to validate the estimate it is unclear whether this finding relates to poor quality of the pharmaceutical dispensing data, which were utilised to determine gaps in dispensing. clinicians may have a better view of adherence than what can be gleaned from pharmaceutical records and may choose not to refer patients based on their assessment. in addition, whilst genotype resistance testing is not routinely available outside of this access programme, clinicians may have been able to access genotype testing via alternate means, for example, via research procedures – 8.4% of patients referred to the third-line committee did already have a genotype test at the time of referral (table 1). it is possible that patients who might otherwise have been referred to the committee for genotype testing were not referred as a result. an additional consideration (supported by both the sensitivity analyses and further analysis of the group of patients who were referred despite not meeting the criteria for referral) is that of a delay between meeting the criteria and actual referral. it is also important to acknowledge that referral of patients who did not meet the referral criteria may have been appropriate under certain special circumstances such as virological failure in pregnancy or virological failure because of incorrect pi dosing in the setting of concomitant tuberculosis. the inability to validate the estimate is an important limitation of the study. no single data source could be used as a gold standard to verify the key clinical criteria utilised to derive the estimate. folder review formed part of the initial study design for the purposes of validation and collection of additional data. however, following a pilot exercise, this aspect of the study was abandoned because of reasons of non-feasibility. this impacted both on the ability to verify the estimate and on the collection of data pertaining to explanatory variables. despite these limitations, this exercise demonstrated the use of routine data on a population level to identify patients requiring further intervention. in the future, widespread permeation of pharmaceutical information systems and improved data usage and quality may allow this exercise to prompt clinicians to refer patients appropriately. similarly, this exercise may allow programme managers to evaluate the effectiveness of the second-line art programme on provincial, district and sub-district levels. conclusion this study evaluated a third-line art referral process in the western cape province of south africa – the country with the largest art programme in the world and the first public sector third-line access programme. this work adds to a limited body of knowledge pertaining to the need for third-line art in south africa, providing information that is valuable for public health planning and health programme evaluation. the study identified missed opportunities for referral and inappropriate referral of patients to the third-line art committee, which have significant public health implications. the estimate of patients meeting the referral criteria was subject to a number of limitations and could not be reliably validated. however, with ongoing data usage, improved data quality and more sophisticated analysis, this method of identifying patients meeting the referral criteria could be used to prompt referral. future work should focus on refining the methods used to identify patients meeting the criteria for referral and determining the validity of the method. in addition, clinician awareness of the referral criteria and procedure should be evaluated to give a comprehensive view of the referral process and guide future intervention. acknowledgements the authors would like to acknowledge professor andrew boulle for guidance and assistance with data access via the phdc, ms jacqueline voget for contextual information regarding the third-line art programme in the western cape and the biostatistics unit at the centre for evidence based healthcare (cebhc), stellenbosch university for assistance with the development of a data analysis plan. competing interests the authors have declared that no competing interests exist. authors’ contributions s.s. wrote the study protocol, collected and analysed the data and compiled the report. b.w. supervised all aspects of the research project and reviewed the final manuscript. funding information s.s. received a discovery foundation academic award in 2017 for this research project. data availability statement the data that support the findings of this study are available from the provincial health data centre (phdc), western cape government: health. restrictions apply to the availability of these data, which were used under licence for this study. data are available with the permission of the phdc, western cape government: health. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references johnson lf, may mt, dorrington re, et al. estimating the impact of antiretroviral treatment on adult mortality trends in south africa: a mathematical modelling study. plos med. 2017;14(2):e1002468. https://doi.org/10.1371/journal.pmed.1002468 unaids. country factsheets south africa 2019 [homepage on the internet]. 2019 [cited 2020 oct 08]. available from: https://www.unaids.org/en/regionscountries/countries/southafrica. western cape antenatal survey report 2015. draft report. cape town: western cape government: health; 2016. annual performance plan 2016/2017 [homepage on the internet]. cape town: western cape government: health; 2016. [cited 2020 oct 08]. available from: https://www.westerncape.gov.za/assets/departments/health/app2016-2017.pdf third line art regimens in adults and children. hast directorate. circular 158/2014. cape town: western cape government: health; 2014. rawizza he, chaplin b, meloni st, et al. accumulation of protease mutations among patients failing second-line antiretroviral therapy and response to salvage therapy in nigeria. plos one. 2013;8(9):1–8. https://doi.org/10.1371/journal.pone.0073582 evans d, hirasen k, berhanu r, et al. predictors of switch to and early outcomes on third-line antiretroviral therapy at a large public-sector clinic in johannesburg, south africa. aids res ther. 2018;15(1):1–12. https://doi.org/10.1186/s12981-018-0196-9 palombi l, marazzi mc, guidotti g, et al. incidence and predictors of death, retention, and switch to second-line regimens in antiretroviral-treated patients in subsaharan african sites with comprehensive monitoring availability. clin infect dis. 2009;48(1):115–122. https://doi.org/10.1086/593312 fox mp, van cutsem g, giddy j, et al. rates and predictors of failure of first-line antiretroviral therapy and switch to second-line art in south africa. j acquir immune defic syndr. 2012;60(4):428–437. https://doi.org/10.1097/qai.0b013e3182557785 johnston v, fielding kl, charalambous s, churchyard g, phillips a, grant ad. outcomes following virological failure and predictors of switching to second-line antiretroviral therapy in a south african treatment programme. j acquir immune defic syndr. 2012;61(3):1–19. https://doi.org/10.1097/qai.0b013e318266ee3f rohr jk, ive p, robert horsburgh c, et al. marginal structural models to assess delays in second-line hiv treatment initiation in south africa. plos one. 2016;11(8):1–11. https://doi.org/10.1371/journal.pone.0161469 ssempijja v, nakigozi g, chang l, et al. rates of switching to second-line antiretroviral therapy and impact of delayed switching on immunologic, virologic, and mortality outcomes among hiv-infected adults with virologic failure in rakai, uganda. bmc infect dis. 2017;17(1):582. https://doi.org/10.1186/s12879-017-2680-6 abstract introduction methods findings financial resources discussion strengths and limitations conclusion acknowledgements references about the author(s) laston gonah health outcomes research unit, discipline of public health medicine, school of nursing and public health, college of health sciences, university of kwazulu-natal, durban, south africa indres moodley health outcomes research unit, discipline of public health medicine, school of nursing and public health, college of health sciences, university of kwazulu-natal, durban, south africa khumbulani hlongwana health outcomes research unit, discipline of public health medicine, school of nursing and public health, college of health sciences, university of kwazulu-natal, durban, south africa citation gonah l, moodley i, hlongwana k. capacity of antiretroviral therapy sites for managing ncds in people living with hiv in zimbabwe. s afr j hiv med. 2020;21(1), a1113. https://doi.org/10.4102/sajhivmed.v21i1.1113 original research capacity of antiretroviral therapy sites for managing ncds in people living with hiv in zimbabwe laston gonah, indres moodley, khumbulani hlongwana received: 11 june 2020; accepted: 06 july 2020; published: 04 sept. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: there are marked inconsistencies in prevalence data for human immunodeficiency virus and non-communicable disease (hiv-ncd) comorbidity in zimbabwe. objectives: to explain these discrepancies, we investigated the capacity of antiretroviral therapy (art) sites in managing hypertension (htn) and diabetes mellitus (dm) in people living with hiv (plwh) in gweru district, zimbabwe. method: this was a qualitative research design in which key informant interviews were conducted with eight health managers, and 12 focus group discussions (fgds) were conducted with 72 plwh concurrently diagnosed with htn and/or dm. thematic data analysis was performed in nvivo version 12®. results: routine screening for htn and targeted screening for dm were often interrupted by dysfunctional machines and intermittent supply of necessary consumables, impacting negatively on the capacity of the sites to monitor and screen for the ncds. erratic hypertensive and diabetic medication availability at study sites were also reported, forcing patients to turn to other treatment options (medication rationing or overdose or sharing, use of home remedies and traditional medicines, and reliance on faith and traditional healers). conclusion: findings demonstrate that the quality of observed incidence and prevalence data for htn and dm in lmics is a function of the capacity of health centres to screen for ncds. given the ageing population of plwh in sub-saharan africa, coupled with increasing trends in the prevalence of ncds in hiv-infected people, hiv programmes have not evolved with the changing needs of plwh. attention to the holistic management of plwh is long overdue. keywords: hypertension; diabetes mellitus; hiv-ncd comorbidity; ncd management protocols; ncd screening and treatment. introduction unprecedented global improvement in enabling access to antiretroviral therapy (art) by people living with human immunodeficiency virus (plwh), contributing to increased viral suppression and increased survival in plwh, is well documented.1 by the end of 2018, more than 61% of the 37.9 million plwh, globally, were accessing art, which is a substantial increase from 45% in 2010.1 over the same period, acquired immunodeficiency syndrome (aids)-related deaths decreased by about 45%,1 thereby demonstrating the significant contribution of art to increased survival in plwh. while there is empirical evidence showing the positive contribution of art to improved survival in plwh, new threats associated with non-communicable diseases (ncds) co-existing with human immunodeficiency virus (hiv) in plwh have emerged.2 this co-existence is likely to impact negatively on the gains already achieved in controlling hiv, especially in many lowto middle-income countries (lmics) where the majority of plwh on art live and where health care systems are known to be fragile.2 the real effects of ncds co-existence with hiv in plwh in many settings may be undermined by the lack of accurate data to understand this phenomenon fully. for example, there are marked inconsistencies in the zimbabwean prevalence data for hiv-ncd comorbidity.3,4,5 these epidemiological discrepancies can be best explained by studying the capacity of art sites to manage ncds in plwh, that is, the screening, diagnosis, treatment and data management. limited capacity to screen and diagnose diseases or conditions may compromise the quality of the prevalence data generated. in zimbabwe, more robust and consistent evidence exists for the management of tuberculosis (tb) – a well-known leading cause of death in plwh.6,7 contrary to the worldwide situation with tb, which is well integrated into hiv care allowing active tb case finding and better case management, there is limited evidence on how hiv-ncd comorbidity is being managed in zimbabwe.6,7 against this background of discrepancies as reported in the current literature, a qualitative study was conducted in gweru district of zimbabwe among healthcare workers and plwh. the study sought to explore the treatment of hypertension (htn) and diabetes mellitus (dm) in plwh attending art sites and to assess the current capacity of these sites to manage htn and dm. we also investigated the challenges faced by plwh diagnosed with htn and/or dm in accessing care at the study sites and their ways of coping up with the challenges. gweru district is one of the unique districts in zimbabwe in the sense that it comprises both urban and rural populations, a phenomenon different from the other major metropolitan provinces such as harare and bulawayo, which consist of urban populations in their entirety. gweru district is in the midlands province, where the prevalence of hiv is relatively higher than some other provinces.8 methods design and setting this was an exploratory, qualitative study utilising data collected from key informant interviews and focus-group discussions (fgds). six high-volume public art sites situated at primary healthcare clinics were selected for the study. these were those with the highest number of plwh (≥1000 plwh) registered for art in the gweru district. four sites were situated in the urban part. the remaining two sites were in the rural sector. sampling and data collection key-informant interviews were conducted with the district medical officer (dmo), the city health director and a nurse-in-charge of each of the six art sites. each of the key informants had special expertise and experience in managing ncds and hiv in the district. a total of eight key-informant interviews were conducted in the english language, using a key-informant interview guide. the guide was designed to assess how htn and dm were being managed at the art sites and to assess the capacity of the sites to manage plwh with these comorbidities. each interview lasted an average of 50 minutes. where necessary, observations were conducted with key informants to corroborate data. the english language was used given its status as the official language of the workplace. focus group discussions were conducted among plwh with htn and/or dm. a standard fgd guide was used to elicit care perspectives on comorbid disease care and experiences and/or challenges encountered while accessing care at the art centres. we also enquired about the coping strategies employed in dealing with the identified challenges. purposive sampling criteria were used to identify the fgd participants.9 these were art-registered plwh who had htn and/or dm and had reported for care at least once a month for the previous 3 months prior to the study – confirmed by patient site records. the average time taken to complete each fgd was 65 minutes. the data collection tools, namely the interview guide and the fgd guide, were validated by (1) having them separately checked for appropriateness by three doctorate holders, who had particular experience in health sciences research, (2) pilot testing the interview guide among health managers from another district and (3) pilot testing the fgd guide among other potential participants who were later excluded from the final study. the data collection tools were modified according to pilot test responses before being used in the final data collection. written informed consent was sought from potential participants. age (30–49; and >50 years), gender (male and female) and geographical background (rural and urban) were considered as key characteristics that could influence free and natural discussion. therefore, homogeneity of characteristics (similar age group, gender and geographical background) within fgds was ensured to promote unrestricted group member participation. heterogeneity of participants in terms of age, gender and geographic background was ensured across all fgds to capture diverse perspectives. each fgd was composed of six participants. all fgds were conducted in local languages (shona and/or ndebele) using an fgd guide. translation of fgd data to the english language was performed in consultation with three experts of english, shona and ndebele languages during data transcription. both interviews and fgds were conducted by the principal investigator who has some training in qualitative research methods. furthermore, the co-author who guided the research process had experience as a qualitative researcher. notes were taken during interviews, and fgds, whereas session summaries and debriefing notes were produced from each interview and fgd conducted. all interview and fgd sessions were recorded using two audio recorders. analysis and data collection were iterative, with interviews and fgds continuing until code saturation, that is, until no new codes were emerging.10 when the last nurse-in-charge was interviewed at the sixth clinic, it was found that no new themes or information had emerged and that code saturation had been reached with the eight interviews. no further interviews were conducted with additional employees. as for fgds, 12 fgds (six participants per one fgd) were conducted before reaching the saturation point. data management and analyses data from the interviews and fgds were stored as audio-recordings, interview notes, fgd notes, session summaries and debriefing notes. audiotapes were transcribed verbatim onto a word-processing programme. analyst triangulation was achieved through the two researchers independently analysing all emerging codes and issues across interviews and fgds, and later discussing them to ensure that the results were grounded on data rather than the researchers’ perceptions. thematic analysis of qualitative data was performed in nvivo version 12®, involving familiarisation with the data, generation of initial codes, searching of themes within the codes, reviewing, defining and naming themes. findings were presented according to emerging themes, using verbatim quotes to illustrate and support the analysis. findings participant characteristics a total of eight interviews were conducted with key informants, whereas 12 fgds were conducted with plwh concurrently diagnosed with htn and/or dm (table 1). the basic requirement for a nurse-in-charge is a diploma, whereas that for a dmo and/or city health director is a degree. table 1: interview and focus group discussion participants’ characteristics. findings from key informant interviews key themes that emerged from key-informant interviews pointed on issues to do with how htn and dm were being managed, and the capacity of art sites to screen, diagnose and treat htn and dm. the themes and subthemes emerging from each fgd are summarised in table 2. table 2: saturation grid of themes and subthemes emerging from key informant interviews. management of hypertension and diabetes mellitus findings from key informants consistently concurred on how screening services for htn and dm were being offered: ‘ministry [of health] regulations require vital observations (including blood pressure, pulse rate, weight, and temperature measurements) to be done at every consultation as part of routine screening, to all patients regardless of hiv status …. however, the regulations require targeted screening for diabetes mellitus where random blood sugar (rbs) measurements are done only when a patient presents with signs and symptoms suggestive of diabetes mellitus.’ (male, 45 years old, health executive) it was found that both bp and rbs measurements were being offered as part of the consultation process at all art sites, where hiv-negative people pay a consultation fee equivalent to usd$1, and plwh do not pay any consultation fee in urban sites. in rural sites, both hiv negative and plwh do not pay any consultation fee. nurses-in-charge for all the study sites consistently mentioned existence of community art review groups (cargs): ‘there are cargs, of 7–10 plwh per group. through cargs, only one group member collects medication on behalf of other group members, thereby reducing transport cost for collection of art medication. this is useful especially when the patient does not require other services like viral load measurements, htn/dm screening or other consultation services.’ (female, nurse-in-charge, with over 10 years’ experience) the capacity of antiretroviral therapy sites to screen, diagnose and treat non-communicable diseases with regard to the capacity of art sites to manage htn and dm, the availability of human, financial and material (equipment and drugs) resources for screening, diagnosis and treatment was assessed at each art centre. human resources all key informants confirmed that the general nurses present at all art sites were capable of screening for htn and dm, even though they lacked at least one speciality, namely training in endocrinology. however, the lack of equipment remained a leading challenge: ‘all the art sites are manned by nurses who can screen for hypertension and diabetes mellitus if they have the required equipment. however, we do not have specialised endocrinology nurses for ncd care at any of art sites in the district.’ (male, district health executive, with over 6 years’ experience) material resources (equipment and drugs) screening for htn requires a blood pressure (bp) machine, whereas screening for dm requires a random blood sugar (rbs) machine and glucostrips. some bp machines used in the study sites were battery-powered, while others were electric-powered. random blood sugar machines at all study sites were battery-powered. all sites had at least one bp and rbs machine. interview findings from all study sites consistently found that availability of screening services for htn and dm was generally limited and periodically interrupted by various challenges. these included running out of machine batteries without timely replacement for htn screening and frequent electrical power cuts that affected the use of electric-powered bp machines: ‘…. yes, we have a bp machine here. but we have not been using it for the past 2 months, because it doesn’t have batteries.’ (female, nurse-in-charge, at a rural art site) another reported challenge was the dysfunctional bp machines caused by the machine breakdowns. in three (two urban and one rural site) of the six study sites, the availability of only one bp machine was insufficient to service all clinic departments, including the outpatients and the maternity departments. for targeted screening for dm, all the sites reported that the service was generally not available, largely because of non-availability of glucostrips: ‘the major challenge affecting screening for diabetes mellitus is the unavailability of glucostrips. there is a general shortage of glucostrips in our health centres, so patients might not have their blood glucose levels checked when they require the service …. for hypertension screening, some health centres do not have functional bp machines due to issues like machine breakdowns, electricity power cuts, and unavailability of batteries, among other reasons.’ (male, district health executive, with 5 years’ experience) concerning the availability of drugs for htn and dm, the interview findings revealed the partial availability of htn drugs and the general non-availability of dm drugs. there was a convergence of views from all the study sites in that some hypertensive patients usually on hydrochlorothiazide (hct) drug sometimes had access to the drug. however, hypertensive patients may need more than one type of drug, where some combinations might not include hct. none of the key informants reported having any diabetic medication in stock: ‘stock-outs for hypertensive and diabetic medication are generally common due to limited funding for ncds. most patients usually get hct from most of our health centres.’ (male, health executive, with over 6 years’ experience) while patients are unable to access screening services or medication for either htn or dm or both, they are usually referred to private pharmacies where they must pay transportation costs, and the cost of the screening service and/or the medication costs: ‘if they can’t get medication here, we write them a prescription to purchase in town [in private pharmacies] if they have the funds.’ (male, nurse-in-charge, with over 15 years’ experience at an urban art site) financial resources responses pointed to limited financial resources for ncd management. interviewees consistently reported that funding was inadequate to meet the needs of people at risk of or living with ncds: ‘the main source of funds for ncd management is the government of zimbabwe (goz). unlike the integrated hiv and tb care programmes, which receive additional funding from non-governmental organizations (ngos) like the global fund and usaid, ncd programmes are funded largely by the government, where the funding is usually limited. funding is required for maintenance of equipment, procurement of equipment, drugs and medical sundries, … even training and re-training of our healthcare workers on ncd management.’ (male, health executive, with 5 years’ experience) focus group discussion findings from patients a total of 12 fgds (consisting of six participants each) were conducted. more fgds (n = 8) were conducted among female participants than among male participants (n = 4). other characteristics of fgd participants are shown in table 3. table 3: characteristics of focus group discussions of people living with human immunodeficiency virus and comorbid non-communicable diseases (n = 72).† challenges faced by patients in accessing non-communicable diseases care and related coping mechanisms the analysis of data generated from the fgds revealed the non-availability of bp and rbs measurement services, the non-availability of htn and dm medication at art sites, the unaffordable cost of medication at private pharmacies and the challenges of transportation costs when seeking medical care or medication, as common challenges faced by patients in accessing care for htn and dm. the saturation grid for themes and subthemes emerging from the fgds is presented in table 4. the fgd findings at both urban and rural sites were consistent with those from the key informant interviews. table 4: saturation grid of themes and subthemes emerging from focus group discussions. challenges in accessing healthcare there was consensus across all fgds that bp and rbs measurement services were not always available at all study sites. participants pointed to repeated power cuts affecting the electric-powered bp machines, the battery-powered machines running out of batteries or service non-availability because of use of the machine in other clinic departments: ‘…. as for me, my bp was only checked once this year. most of the time i come here there will be no electricity so the bp machine will not be working. sometimes you come here, and you are told the machine is being used in the maternity ward. as for sugar [diabetes mellitus], i don’t even know whether the machine is here or not because i have never received the service here.’ (female, 55 years old, participant with htn & dm) the other commonly emerging subtheme from all fgds was of medication availability for htn and dm. participants from all the art sites confirmed that hct is the only medication for htn, which some might access. however, some hypertensive patients are not prescribed hct, while others take more than one variety of medicine, none of which can be accessed at the clinic. none of the patients from all the 12 fgds reported to have accessed dm medication: ‘sometimes they give hct, but it is not everyone who gets it. again, some of us do not take hct, i take 4 other drugs for hypertension. for sugar [diabetes mellitus], i have never received medication from this clinic.’ (male, 62 years old, participant with htn and dm) when they cannot get medication from the clinic, participants reported getting prescriptions to purchase the required medication from private pharmacies, where the main challenge is the high cost of medication and transportation: ‘they give a prescription for you to buy in the [private] pharmacies in town. there drugs are very expensive and some of us cannot even afford them. to go there you need transport fare again. it’s really not easy.’ (female, 68 years old, participant with diabetes mellitus) coping mechanisms common coping subthemes included taking multiple doses to compensate for missed doses, sharing and rationing the medication. furthermore, the use of home remedies, traditional herbs and consultation of traditional and faith healers emerged as coping strategies to deal with the identified challenges in managing htn and dm. it emerged that when patients do not have enough medication to last the whole month, there was a general consensus that they ration the medication by only taking medication when they experience serious illness. also reported was that patients often took multiple doses of hct to complement the missing medication, which would not have been purchased, or when they perceive symptoms to be associated with their hypertension: ‘you go to the clinic and they give you only hct. apart from hct, i need 3 more types of bp drugs. so when it gets serious, i take 4 hct pills at once to relieve the pain, and it works.’ (male, 57 years old, participant diagnosed with htn 10 years ago) others reported borrowing medications when they run out of medication: ‘last time i fell seriously ill and i could feel i was dying. i did not have the medication and transport fare to go to the clinic either. i ended up borrowing the medication from my neighbour, that is how i got saved. we always help each other that way.’ (female, 68 years old, participant diagnosed with htn and dm) concerning home remedies, the use of ginger, garlic, cassia abbreviata (murumanyama in local shona language) and smashed avocado seeds commonly reported remedies used to manage htn. diabetic patients often used ginger, boiled black-jack and diet monitoring as remedies or alternatives for managing dm when they could not access medication: ‘i rely a lot on those [remedies]… especially garlic, murumanyama [cassia abbreviata] and [smashed] avocado seeds to manage my [high] bp … ginger and boiled black-jack also works for sugar [dm]… what can we do?… i can’t afford these [allopathic] medicines.’ (female, 57 years old, participant diagnosed with htn and dm) patients also reported that they relied on faith and traditional healers for the management of htn and dm. most participants across all fgds mentioned that faith and traditional healers play an important role in managing their htn and dm. although all generally believed that allopathic medicines were more effective, they reported resorting to faith and traditional healers because they were cheaper alternatives. participants also reported that these faith and traditional healers provided ‘spiritual-uplifting’ in the absence of medical drugs: ‘i know that [prescribed] drugs are effective… but one needs money to buy them. prophets, traditional healers … and home remedies are cheaper or even free, … so i can’t watch myself die when these options are there.’ (male, 61 years old, participant with dm) in some worst-case scenario, some reported avoiding formal healthcare for fear of what they called ‘unnecessary costs’: ‘i do not even go to the [provincial] hospital, because when i go there, sometimes they tell me my [blood] sugar [level] is very high and give me bed-rest, but not the medication. the next day, they give me a huge bill to pay for the bed-rest when i did not have medication. better i rest at home.’ (female, 48 years old, participant with dm) discussion this study assessed the capacity of art sites to manage htn and dm in plwh, from the perspectives and experiences of key healthcare workers and affected patients in the gweru district of zimbabwe. also assessed were patients’ experiences on the challenges they face in accessing care and the coping mechanisms they employ in dealing with the challenges. several important findings emerged: (1) art sites had limited capacity to screen for htn and dm in plwh, together with non-availability of htn and dm medication, because of limited funding available for ncds care; (2) plwh who have htn and/or dm are deterred from accessing healthcare for htn and dm at public art sites, mainly because of frequent unavailability of screening and treatment services and the high costs of medication in private pharmacies; (3) coping strategies employed in addressing encountered challenges include taking multiple doses to compensate for missed doses, sharing medication with others, medication rationing, the use of home remedies and traditional herbs, and the consultation of traditional or faith healers. in this study, htn screening was found to be integrated into routine screening as part of vital measurements which should be performed at every clinic consultation regardless of hiv status. in principle, this is a strategic arrangement to increase chances of hypertensive case finding as well as reducing stigma associated with screening only one group of patients.7 for dm, the zimbabwean ministry of health’s regulations require targeted screening where rbs measurements are taken from patients presenting with signs and symptoms suggestive of high blood sugar levels.7 while the protocols and cost of screening for htn and dm could promote active case finding, in this study, effective implementation of the process was threatened by non-functional equipment secondary to limited funds. interrupted provision of screening services can negatively affect diagnosis of new cases and ultimately result in lower than actual incidence and prevalence rates being observed for htn and dm, as has been found in other studies.11 erratic availability of htn and dm medication at art sites was reported as another common challenge faced by patients, as observed in other similar studies.4,12,13 for the majority of patients who could not afford medication from private pharmacies, alternative approaches were taken. the reported options included medication rationing or sharing or overdose, for example, multiple doses to compensate when the medication became available and the use of home remedies and herbs. these options do not offer effective treatment for htn and dm because they are not regulated, nor is their effectiveness subjected to empirical research.7 if htn and dm are not managed well in plwh, the survival and wellness gains of art will be sacrificed. the unprecedented scale-up of art in sub-saharan africa (ssa) has resulted in more plwh achieving virologic suppression and increased survival.14 therefore, the incidence of diseases associated with ageing such as hiv-htn, dm, chronic kidney and heart disease will also increase.2,14,15,16,17,18 a study conducted in malawi revealed that the lack of screening equipment and services, and medication stock-outs were frequent challenges to the care of plwh and htn/dm.19 other studies conducted in ssa focused more on the feasibility of integrating hiv/aids programme with ncd care, and key findings point to the existence of challenges in screening for htn and dm compared to those for hiv/aids care.17 there is limited research into the capacity of ssa to manage the future challenges faced by the long-term survivors of hiv. strengths and limitations use of purposive sampling based on set criteria to identify participants; involvement of more than one experienced qualitative researcher to reduce the chances of subjective bias; and attempts to attain code saturation in data collection represent methodological strengths of the study. the weakness of the study was the use of cross-sectional study design that prevents long-term follow-up of participants and the absence of ‘hard’ clinical end points – actual bp, glucose monitoring and viral load suppression of the study cohort over time – to support the contention that the care of this group of zimbabwean patients is being compromised. conclusion findings from this study demonstrate that the observed incidence and prevalence of htn and dm among plwh in gweru district is a function of the capacity of its healthcare system to screen for and adequately manage ncds. given the ageing population of plwh in ssa, coupled with the growing prevalence of ncds in this group, hiv programmes require strengthening. while the social and economic problems of zimbabwe are dire, this study gives voice to some of its plwh. we feel that this is a voice that others need to hear too. acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this research article. authors’ contributions all authors contributed equally to this work. ethical consideration ethical approval for this study was obtained from the university of kwazulu-natal biomedical research ethics committee (ethical clearance number: be086/19) and the ministry of health and child care head office in harare. participation in the study was voluntary. written informed consent was sought from potential participants, and confidentiality was maintained throughout the study by removal of personal identifiers after entry into the electronic database and use of non-identifiable coded numbers. all data were password-protected and stored in the electronic participant database. funding information the research received funding from university of kwazulunatal, under phd research grant. data availability statement because of the private nature of the data, data for the study will be available only upon request and approval of authorising ministry of health. disclaimer the views and opinions expressed in this article are those of the authors and not necessarily reflect the official policy or position of any affiliated agency of the authors. references joint united nations programme on hiv/aids (unaids). global hiv & aids statistics – 2018 fact sheet [homepage on the internet]. unaids; 2018. available from: https://www.unaids.org/en/resources/fact-sheet world health organization. working group on the inclusion of ncds in other programmatic areas: who global coordination mechanism on the prevention and control of non-communicable diseases (working group 3.1, 2016–2017). geneva: world health organization; 2018. magodoro im, esterhuizen tm, chivese t. a cross-sectional, facility based study of comorbid non-communicable diseases among adults living with hiv infection in zimbabwe. bmc res notes. 2016;9(1):379. https://doi.org/10.1186/s13104-016-2187-z mutede br, magure t, gombe nt, bangure d, tshimanga m. prevalence and factors associated with hypertension among anti-retroviral therapy patients aged 15 years and above in makonde district, zimbabwe, 2012: an analytic cross sectional study. world j cardiovasc dis. 2015;5(9):266. https://doi.org/10.4236/wjcd.2015.59030 smit m, olney j, ford np, et al. the growing burden of non-communicable disease among persons living with hiv in zimbabwe. aids. 2018;32(6):773. https://doi.org/10.1097/qad.0000000000001754 lazarus jv, olsen m, ditiu l, matic s. tuberculosis – hiv co-infection: policy and epidemiology in 25 countries in the who european region. hiv med. 2008;9(6):406–414. https://doi.org/10.1111/j.1468-1293.2008.00567.x ministry of health and child care (mohcc). the national health strategy for zimbabwe (2016-2020): equity and quality in health: leaving no one behind. harare: ministry of health and child care; 2016 [cited no date]. available from: https://malariaelimination8.org/wp-content/uploads/2017/02/national%20health%20strategy%20for%20zimbabwe%202016-2020.pdf zimbabwe population-based hiv impact assessment: zimphia 2015–2016, final report [homepage on the internet]. icap at columbia university. 2019 [cited 2020 feb 5]. available from: https://phia.icap.columbia.edu/wp-content/uploads/2019/08/zimphia-final-report_integrated_web-1.pdf marshall mn. sampling for qualitative research. family prac. 1996;13(6):522–526. https://doi.org/10.1093/fampra/13.6.522 hennink mm, kaiser bn, marconi vc. code saturation versus meaning saturation: how many interviews are enough? qual health res. 2017;27(4):591–608. https://doi.org/10.1177/1049732316665344 aschengrau a, seage gr. essentials of epidemiology in public health. sudbury, massachusetts: jones & bartlett publishers; 2013. mungati m, manangazira p, takundwa l, et al. factors affecting diagnosis and management of hypertension in mazowe district of mashonaland central province in zimbabwe: 2012. bmc cardiovasc disord. 2014;14(1):102. https://doi.org/10.1186/1471-2261-14-102 peltzer k. utilization and practice of traditional/complementary/alternative medicine (tm/cam) in south africa. afr j tradit complemen altern med. 2009;6(2):175. chamie g, kwarisiima d, clark td, et al. leveraging rapid community-based hiv testing campaigns for non-communicable diseases in rural uganda. plos one. 2012;7(8):e43400. https://doi.org/10.1371/journal.pone.0043400 chhoun p, tuot s, harries ad, et al. high prevalence of non-communicable diseases and associated risk factors amongst adults living with hiv in cambodia. plos one. 2017;12(11):e0187591. https://doi.org/10.1371/journal.pone.0187591 coetzee l, bogler l, de neve jw, bärnighausen t, geldsetzer p, vollmer s. hiv, antiretroviral therapy and non-communicable diseases in sub-saharan africa: empirical evidence from 44 countries over the period 2000 to 2016. j int aids soc. 2019;22(7):e25364. https://doi.org/10.1002/jia2.25364 mc conalogue d, nxumalo b, busawa-la f, sharp a, walley j. implementation of a non-communicable disease (ncd) screening programme in a rural african hiv clinic. hiv/aids res treat open j. 2017;4(1):32–39. patel p, speight c, maida a, et al. integrating hiv and hypertension management in low-resource settings: lessons from malawi. plos med. 2018;15(3):e1002523. https://doi.org/0.1371/journal.pmed.1002523 pfaff c, scott v, hoffman r, mwagomba b. you can treat my hiv-but can you treat my blood pressure? availability of integrated hiv and non-communicable disease care in northern malawi. afr j prim health care fam med. 2017;9(1):1–8. march hiv issue 1-16 the southern african journal of hiv medicine march 2005 looking back, looking forward more than any other field of medicine, hiv medicine is evol-ving rapidly. not only are new drugs, new drug targets and new strategies being discovered, but also guidelines must be reviewed continually as new information about how to use them comes to light. the recent flood of controversy in the world media surrounding nevirapine highlights this, and also illustrates the benefit of this sort of information being digested by experts and repackaged for local consumption. there is a need for health care workers to have regular and reliable access to new infor-mation, updates and continuing medical education. the number of new companies and organisations offering continuing medical education bears testimony to the growing industry and has markedly increased the number and variety of updates currently available to the medical health worker in south africa today. the southern african journal of hiv medicine is the official journal of the south african hiv clinicians society, and as such is sent to every member of the society (currently more than 8 000). it has become an important way for guidelines to be dispersed and for locally relevant information to reach the most rural areas, including other countries in africa. since inception of the journal in july 2000 an impressive list of guidelines has been compiled and peer reviewed by local experts (see the table below). this year will also see the journal launched on line, increasing accessibility of previous guidelines and journal articles. the journal is published quarterly and all submitted articles are peer reviewed. we are reliant on a steady supply of diverse, good-quality and relevant material, especially as we try to continually h o r i z o n s guideline edition number adult management july 2000 1 paediatric management november 2000 2 tb preventive therapy february 2001 3 mtct prevention may 2001 4 perinatal hiv diagnosis august 2001 5 palliative care december 2001 6 opportunistic infection management march 2002 7 adult management (1st revision) june 2002 8 paediatric management (1st revision) november 2002 9 legal and ethical february 2003 10 infant testing may 2003 11 blood product handling august 2003 12 sexual assault, february 2004 13 tb treatment with art patient confidentiality june 2004 14 pre-art management november 2004 15 adult management (2nd revision) march 2005 16 7 march hiv issue 1-16 4/16/05 9:56 am page 7 march 2005 the southern african journal of hiv medicine 8 improve readability and content into the new year. any suggestions, contributions or new ideas are welcome! the second 46664 aids awareness concert will be held at fancourt this month and hopefully with the hasselplattners bankrolling it, it will raise not only awareness but also funds this year. mr mandela’s enigmatic influence once again sees an impressive line-up of international and national artists contributing to this now annual event hosted by the nelson mandela foundation. my vintage means that some artists are unknown to me, although the ageing rockers that make up queen are a strong pull for me to invest and find a way to get down to george! i wonder how different things would have been for this awesome rock band if freddie mercury had not been struck down by aids at the age of 45. despite the fact that he was already very ill with hiv he appeared with the spanish diva montserrat caballe at the la nit festival and sang the song he had written for montserrat and barcelona called ‘barcelona’. that was his last stage performance. freddie mercury disclosed his hiv-positive status the day before he died in london in 1991. following this, his disclosure has been important for hiv awareness, although earlier disclosure might have been even more powerful. speaking of great musicians, south africa can really hold its own. one new and refreshing band that i had the pleasure of hearing was ‘freshly ground’ at the recent opening of the first dedicated public sector antiretroviral clinic in south africa, the hanan-crusaid clinic in gugulethu. they are an ‘afro-fusion’ band and packed with talent — they had western cape’s premier rasool dancing in such a way that madiba would have been proud! what a terrific occasion. other talent in the news recently has been the south african film industry — anant singh’s film ‘yesterday’ was up for an oscar. while it unfortunately did not win the foreign film category, it certainly brought the south african hiv epidemic some international coverage. the story is of a young woman in kwazulu-natal who discovers she is hiv infected and alone with her child. her one wish is to live long enough to see her child go to school. the film will be viewed at the south african hiv conference in durban — just one of the highlights in a conference that promises lots of interest. if you haven’t yet registered for this conference, you should do so! there are more than 5 000 delegates already signed up and it should be a great three days of networking and updates. see you there! linda-gail bekker managing editor march hiv issue 1-16 tib 4/21/05 1:03 pm page 8 abstract introduction research methods and design results discussion limitations conclusion acknowledgements references appendix 1 about the author(s) luize muller department of radiology, faculty of health sciences, university of kwazulu-natal, pietermaritzburg, south africa tanusha sewchuran department of radiology, faculty of health sciences, university of kwazulu-natal, pietermaritzburg, south africa miranda durand department of radiology, faculty of health sciences, university of kwazulu-natal, pietermaritzburg, south africa citation muller l, sewchuran t, durand m. prevalence of incidental premature cardiac calcifications in an hiv-infected south african population using conventional computed tomography chest radiography. s afr j hiv med. 2021;22(1), a1241. https://doi.org/10.4102/sajhivmed.v22i1.1241 original research prevalence of incidental premature cardiac calcifications in an hiv-infected south african population using conventional computed tomography chest radiography luize muller, tanusha sewchuran, miranda durand received: 04 mar. 2021; accepted: 30 mar. 2021; published: 13 may 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: international literature reported an increased prevalence of cardiovascular disease in persons living with hiv (plwh), inferring an association with accelerated coronary atherosclerosis and plaque formation. few local studies of hiv-related cardiac disease have confirmed this. early identification of cardiac plaques would assist clinicians with risk stratification and implementation of treatment strategies to reduce morbidity and mortality. in resource-limited settings the use of conventional computed tomography (ct) may have a role in identifying at-risk individuals. objectives: this hypothesis-generating study was aimed at determining the contribution of hiv to accelerated vascular aging by assessing cardiac calcifications, incidentally detected on conventional ct chest imaging, in a young hiv-positive population. method: a retrospective quantitative analysis was performed at a tertiary hospital in kwazulu-natal, south africa, over a 5-year period. young patients (18–45 years) who underwent ct chest imaging for varied indications were included, further sub-categorised by immune status, the presence, absence and location of calcifications. patients with unknown hiv statuses were excluded. results: an increased probability of cardiac calcification with increasing age, independent of the hiv status, was established. no statistically significant difference could be demonstrated between the cohorts. in the pre-contrasted subcategory, a lower p-value suggested an ‘imminent’ statistical significance. contrast may have obscured some calcifications. the failure to record the immune status in a large number of patients resulted in their exclusion and limited the study. conclusion: the increased prevalence of incidentally detected cardiac calcifications in young hiv-infected individuals warrants further evaluation and cardiovascular risk stratification. keywords: hiv; coronary calcification; atherosclerosis; ct; premature vascular aging; coronary plaques. introduction the life expectancy of hiv-infected individuals has dramatically increased as a result of advances in treatment, as well as in the prevention and management of opportunistic infections. despite an improvement in immunological status and suppressed viral load, an increased risk of chronic cardiovascular disease has been documented, specifically acute coronary syndromes, cerebral vascular accidents and atherosclerosis.1 the exact pathophysiology is still unclear. the proposed mechanisms include insulin resistance, dyslipidaemia, endothelial dysfunction, inflammation and the direct invasion of the vessel wall by hiv.2,3 this increase of chronic vascular disease in an hiv-infected population will contribute to the overall morbidity and mortality, and place additional pressure on financial and operational resources. early identification and management could result in timely intervention, the reduction of complications and improved patient outcomes, particularly in resource-poor environments where access to tertiary healthcare is limited. guaraldi et al.1 postulate that hiv causes premature vascular ageing and cardiovascular disease. an indicator of this is the ‘unexpected’ presence of atherosclerotic plaque in youth and young adults when usually only encountered in those aged ≥ 50 years. radiographic imaging and evaluation of the characteristics of the plaque assist with determining the overall severity.1 many international studies have demonstrated an increased incidence of coronary plaque in persons living with hiv (plwh), mostly uncalcified and often associated with poorer clinical outcomes.1,3,4,5,6,7,8 little of this data is available from africa, despite sub-saharan africa being severely affected by hiv. the finding of an increased prevalence of premature cardiac calcifications in south africans (sa) living with hiv will inform the need for early detection, intervention and prevention to reduce long-term cardiovascular-related morbidity and mortality. valvular calcifications have also been linked to vascular ageing and accelerated atherosclerosis.9,10,11 lange et al.9 determined that both mitral annular and coronary artery calcifications were amplified in plwh. the authors surmised that the concomitant presence of mitral and coronary artery calcifications was associated with morbidity and mortality.9 a more recent analysis from the multicentre aids cohort study11 found that combined mitral and aortic valvular calcifications were more prevalent in their hiv-infected cohort. of particular note was the high incidence of uncalcified plaques in the coronary arteries of patients who presented with aortic valve (av) calcifications (figures 1 and 2). this finding suggests that despite conventional computed tomography (ct) not being able to reveal uncalcified coronary plaque, the presence of av calcifications suggests that additional investigation is warranted.11 figure 1: axial (a) and coronal (b) precontrasted images through the mediastinum depicting dense calcium deposition on the aortic valve as indicated by the arrows. figure 2: axial (a) and sagittal (b) contrasted images of the heart demonstrating coarse mitral valve celcifications as indicated by the arrows. both coronary artery plaque and valvular calcification, which are considered objective indicators of atherosclerosis, can be evaluated with imaging. previous studies examined the relationship between atherosclerotic plaque and hiv with the use of electrocardiogram (ecg)-gated cardiac ct and coronary angiograms. the plaque burden was quantified using the agatston calcium score.2,4,6,12 this method requires dedicated and specialised hardware and software not readily available in all hospitals, particularly in resource-constrained centres. in most developing countries, where the disease burden is often the highest, conventional spiral ct is usually a more accessible and affordable alternative. a study conducted by chandra et al. made use of the weston score as an alternative for calcium scoring.13 the weston score does not rely on specialist equipment or contrast. coronary plaques are identified on non-contrasted images obtained by conventional ct, and a scoring system is used to classify the type of calcification. while the weston score is more subjective, because it relies on the interpreters’ visual identification and requires good quality unenhanced imaging, it can be used as a possible alternative to detect calcifications with similar outcomes.13 south africa has a high prevalence of hiv infection principally in adolescents and young adults, aged 15–49 years. in view of the improved life expectancy of sa-lwh, many of whom were infected at an early age, we investigated the prevalence of premature cardiac calcifications (coronary and valvular) incidentally detected in groups of young sa-lwh and using a control group of hiv-negative individuals of similar age for comparison. by evaluating patients younger than 50 years, the traditional risk factors associated with vascular ageing are less likely to be active. we further recommend and support the use of conventional spiral ct chest (contrasted or non-contrasted) as an alternative to ecg-gated ct in a resource-constrained setting, to screen for incidental cardiac calcifications. research methods and design our study was based on the hypothesis that hiv prematurely accelerates cardiac ageing. we performed a retrospective quantitative analysis of all patients between the ages of 18 and 45 years who underwent a chest ct scan during a 5-year period (01 january 2014 – 31 december 2018) at a tertiary hospital in kwazulu-natal. these scans were not dedicated cardiac cts, simply because in resource-limited settings such as ours, we do not routinely perform ecg-gated chest imaging. indications for ct chest were therefore varied, included both medical and surgical and were not specifically cardiac in nature. patients seen during normal working hours and after hours were included. no specific patient preparation, such as the use of a beta blocker, was administered to alter the cardiac rate or reduce motion artefacts. patients were scanned on a somatom sensation 64-slice cardiac ct scanner using standardised imaging parameters. images were accessed from the picture and archiving communication system (pacs). the ct imaging protocol included pre-contrast only or both preand post-contrast, plus a routine 100-ml bolus of omnipaque 300 contrast at a flow rate of 3 ml/s. the date of the scan, age, gender and hiv status were collected retrospectively from the ct request forms. in the event that the patient’s hiv status was not provided on the request form, laboratory confirmation was sought from the national health laboratory service (nhls) database. two board-certified radiologists, with a specialist interest in cardiothoracic imaging and with 5 and 10 years of experience, reviewed the preselected and anonymised studies and recorded, with the aid of a data collection tool, the presence or absence of cardiac calcifications in patients referred for imaging (appendix 1). where interobserver variability occurred, the images were reviewed and consensus was sought. the exact location of the calcifications (coronary and valvular) and the imaging technique (preor post-contrast chest ct) were available for evaluation. the evaluated vascular sites included the left marginal artery (lma), left anterior descending artery (lad), right coronary artery (rca), and left coronary artery (lca). the valvular sites included the mitral valves (mv) and av. the radiologists were blinded to the patient’s hiv status. patients were excluded from the study if their hiv status was unknown or if the ct scan was considered non-diagnostic, for example, if a significant artefact obscured the anatomical regions of interest. descriptive statistics were used to differentiate the demographic and clinical characteristics of the patients, sub-categorised into hiv-positive and hiv-negative. these included specific age categories and gender. furthermore, a statistical analysis was performed on the pre-contrasted studies only in order to determine the estimated probability of developing cardiac calcifications. the presence of cardiac calcifications between the two groups was compared using a chi-square test. the effects of age and gender were adjusted by using a logistic regression model. a p-value of 0.05 or less was regarded as statistically significant, with a confidence interval of 95%. ethical considerations ethical approval was obtained from the research ethics committee of the faculty of health sciences, the department of health and the medical manager of the hospital where the research was conducted. all images were captured using grey’s radiology pacs with the permission of the medical manager, ethics committee and head of the department of radiology. results a total of 1050 patients underwent ct of the chest during the 5-year period (01 january 2014 – 31 december 2018). four hundred and twenty-five patients were excluded because their immune status was not documented or because of non-diagnostic scans with poor image quality. a total of 625 patients with a documented hiv status were included in the final study sample. of the 438 patients who were hiv positive, 53 (12.1%) patients demonstrated cardiac calcifications. in the hiv-negative sample, consisting of 187 patients, 19 (10.2%) had documented cardiac calcifications (figure 3). the difference in the percentage of hiv-positive and hiv-negative participants with calcifications was not statistically significant (p = 0.487). the discrepancy in the overall size of the respective populations limits statistical accuracy but suggests the need for further prospective analysis. figure 3: diagrammatic representation of the results. an increased probability of calcification with increasing age was noted, independent of hiv status (p = 0.00006). in any multiple regression model where the independent variables are mutually uncorrelated, the estimated coefficients associated with the independent variables relate to those variables only. because calcification was not significantly correlated to hiv status in our limited study, we can claim that any conclusion referring to whether a patient shows calcification is not affected by that patient’s hiv status. no statistically significant difference was noted between gender, hiv status and the probability of developing calcification (logistic regression, p = 0.281 and p = 0.952) (table 1). the median age of the patients in the hiv-negative group was 31 years and in the hiv-positive group, it was 36 years. table 1: estimated probability of calcification as a function of age, gender and hiv status. regarding the anatomical location of the calcifications, no statistical significance was noted between the hiv-positive and hiv-negative groups, particularly in the lad coronary artery, where the majority of calcifications were detected, likely because of its anatomical visibility (p = 0.40502) (figure 4). figure 4: post-contrasted axial images (a & b) at different levels showing calcifications along the left anterior descending coronary artery as indicated by the arrows. in the av, 2.1% of the hiv-negative sample compared to 0.7% of the hiv-positive sample demonstrated calcifications, with a difference of 1.4%, which was not statistically significant (p = 0.13699) (figure 5, table 2). figure 5: demonstrates an increased probability to develop cardiac calcifications with an increase in age. table 2: comparison of the probability to develop cardiac calcification between hiv positive and hiv negative cohort groups. in total, 619 patients had pre-contrasted chest imaging. within this subdivision, 95 patients with visible cardiac calcifications were hiv-positive, and 51 were hiv-negative, a percentage difference that was not statistically significant (p = 0.1409). the lower p-value provides some weak evidence that increasing age also increased the probability of an affirmative when assessing the pre-contrasted images only. this is suggestive but inconclusive evidence that hiv status might have an effect. the dense contrast may obscure soft calcifications and implies that further investigation is warranted. a noticeable numerical variance was seen in the incidence of cardiac calcifications between the hiv-positive and hiv-negative cohorts, when evaluating the different age categories, specifically seen in the age group of 31–35 years (figure 6). figure 6: demonstrates the numerical variance, in percentage, in the incidence of calcifications in the different age categories according to immune status. discussion atherosclerotic plaques are a strong indicator of vascular ageing, a finding commonly seen in individuals over the age of 50 years. however, it has been well documented internationally that the long-term effects of hiv in plwh, who now have improved life expectancy, include coronary ageing at an accelerated pace.1 the burden of hiv and aids in southern africa has an earlier influence on the population, with the likelihood of an increase in premature vascular ageing. in an attempt to rule out the effects of normal vascular ageing and other comorbidities associated with advanced age, a younger population was chosen, with a median age of 31 in the hiv-negative and 36 in the hiv-positive patients. fitch et al. demonstrated an association between accelerated cardiovascular ageing and the immune status of the hiv-infected patient.5 the presence of cardiac calcifications in a much younger population (< 50 years) signifies premature vascular ageing in hiv-infected individuals. even though the percentage of participants with calcifications was not significantly different between the groups, the mere presence of calcifications in the younger age group is concerning for the development of premature atherosclerotic changes. by assessing the probability of developing calcifications in the two study groups on the pre-contrasted images only, there was weak but inconclusive evidence that hiv might have an effect. this suggests that by eliminating the effect of contrast artefacts, the visibility of calcifications would be increased, yielding more conclusive data. furthermore, rezaeian et al. proved a higher incidence of non-calcified atheromatous plaques in an hiv population, a finding that cannot be demonstrated with conventional ct.11 by looking at calcifications only as a measure of vascular ageing, we excluded patients with non-calcified atheromatous plaques by default, making it difficult to assess the true extent of vascular ageing in our study sample. using ecg-gated cardiac ct would have improved the detection of non-calcified plaques and would also have reduced motion artefacts, which could further improve identification. in combination, the above-mentioned findings do not exclude a link between hiv status and the development of premature cardiac calcifications. the possibility remains and warrants further investigation, as does the prevalence of uncalcified plaque in this population – an entity that has been internationally recognised with growing concern. our study further incidentally emphasises the known association of increasing age with the development of cardiac calcifications and underscores that their presence can be used as an objective indicator of vascular ageing. limitations our study aimed to assess the effect of hiv on premature cardiac ageing, observed as incidentally detected valvular and coronary calcifications in young patients. the retrospective review of ct chest scans performed for other indications in patients younger than 45 years of age, in whom comorbidities are thought less likely, limited diagnostic accuracy. furthermore, the lack of preparation for imaging, such as the use of beta blockers, and the relatively small sample size are further considerations. while our sample size is small, the positive findings in the hiv-infected group are concerning and warrant further investigation. we unfortunately did not take into account the viral load, cd4 status, time since diagnosis or the use and type of antiretroviral drugs in our patient population. this is an important limiting factor as certain treatment regimens have been found to contribute to vascular ageing.3 furthermore, the time since hiv diagnosis, as some patients may have seroconverted shortly before imaging, may result in less time to develop calcified plaques or even non-calcified atheromatous plaques. lastly, the unavailability of immune status proved a significant limiting factor. a large number of patients in our initial sample size had no documented hiv status on the referral letter, with no serological test results available on the nhls system. because of this, a significant number of patients were excluded from the study, resulting in a mismatch in numbers between the cohort groups. conclusion our hypothesis of increased cardiac calcifications in young hiv-infected individuals, incidentally detected on ct chest radiography, shows distinct promise and definitely warrants further imaging, best with a prospective study detailing cardiovascular risk stratification in this select population, which will positively impact patient outcomes. acknowledgements the author (l.m.) wishes to express her sincere thanks and appreciation to the following people: dr t. sewchuran (her supervisor), department of radiology, greys hospital, for guidance with regard to the research fundamentals as they relate to the field of clinical imaging sciences, encouragement to uphold high standards of professional conduct, critical and constructive commentary on the study design and interpretation of results; and dr m. durand, head of the department of radiology, greys hospital, for assisting in the data analysis and guidance. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions l.m. is the main author who was responsible for the literature review, study protocol, data collection, data analysis, write-up and discussion. t.s. acted as the primary supervisor and was responsible for the study guidance, protocol review and data analysis. m.d. acted as the co-supervisor and assisted with the protocol review and data analysis. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references guaraldi g, zona s, alexopoulos n, et al. coronary aging in hiv-infected patients. clin infect dis. 2009;49(11):1756–1762. https://doi.org/10.1086/648080 tawakol a, lo j, zanni mv, et al. increased arterial inflammation relates to high-risk coronary plaque morphology in hiv-infected patients. j acquir immune defic syndr. 2014;66(2):164–171. https://doi.org/10.1097/qai.0000000000000138 calza l, manfredi r, pocaterra d, chiodo f. risk of premature atherosclerosis and ischemic heart disease associated with hiv infection and antiretroviral therapy. j infect. 2008;57(1):16–32. https://doi.org/10.1016/j.jinf.2008.02.006 d’ascenzo f, cerrato e, calcagno a, et al. high prevalence at computed coronary tomography of non-calcified plaques in asymptomatic hiv patients treated with haart: a meta-analysis. atherosclerosis. 2015;240(1):197–204. https://doi.org/10.1016/j.atherosclerosis.2015.03.019 fitch kv, srinivasa s, abbara s, et al. noncalcified coronary atherosclerotic plaque and immune activation in hiv-infected women. j infect dis. 2013;208(11):1737–1746. https://doi.org/10.1093/infdis/jit508 lo j, abbara s, shturman l, et al. increased prevalence of subclinical coronary atherosclerosis detected by coronary computed tomography angiography in hiv-infected men. aids. 2010;24(2):243–253. https://doi.org/10.1097/qad.0b013e328333ea9e mikhail ij, purdy jb, dimock ds, et al. high rate of coronary artery abnormalities in adolescents and young adults infected with human immunodeficiency virus early in life. pediatr infect dis j. 2011;30(8):710–712. https://doi.org/10.1097/inf.0b013e31820f6575 post ws, budoff m, kingsley l, et al. associations between hiv infection and subclinical coronary atherosclerosis. ann intern med. 2014;160(7):458–467. https://doi.org/10.7326/m13-1754 lange dc, glidden d, secemsky ea, et al. mitral annular and coronary artery calcification are associated with mortality in hiv-infected individuals. plos one. 2015;10(7):e0130592. https://doi.org/10.1371/journal.pone.0130592 owens ds, budoff mj, katz r, et al. aortic valve calcium independently predicts coronary and cardiovascular events in a primary prevention population. jacc cardiovasc imaging. 2012;5(6):619–625. https://doi.org/10.1016/j.jcmg.2011.12.023 rezaeian p, miller pe, haberlen sa, et al. extra-coronary calcification (aortic valve calcification, mitral annular calcification, aortic valve ring calcification and thoracic aortic calcification) in hiv seropositive and seronegative men: multicenter aids cohort study. j cardiovasc comput tomogr. 2016;10(3):229–236. https://doi.org/10.1016/j.jcct.2016.02.002 kingsley la, deal j, jacobson l, et al. incidence and progression of coronary artery calcium in hiv-infected and hiv-uninfected men. aids. 2015;29(18):2427–2434. https://doi.org/10.1097/qad.0000000000000847 chandra d, gupta a, leader jk, et al. assessment of coronary artery calcium by chest ct compared with ekg-gated cardiac ct in the multicenter aids cohort study. plos one. 2017;12(4):e0176557. https://doi.org/10.1371/journal.pone.0176557 appendix 1 clinical.html forum clinical case study programme regina osih, md, mph corresponding author: r osih (regina.osih@gmail.com) the southern african hiv clinicians society’s online clinical cases are geared at providing excellent continuing medical education for members of the society. this activity has been created to offer clinicians working in the hiv area access to online education. cases are written by experienced hiv specialists and can range from general adult hiv/tb through specialist paediatric cases to other related infectious diseases encountered when managing patients with hiv. cases can be marked with one, two or three stars. one-star cases are basic cases directed towards clinicians who are new to the practice of hiv or who intend to start providing hiv care. they are also appropriate for clinicians who have more experience but who do not see hiv-positive patients on a routine basis and would like to refresh their knowledge around the management of key hiv-related conditions. cases marked with two stars are meant for clinicians who work daily with hiv-positive patients but would not consider themselves experts in the field. cases marked with three stars are meant for clinicians who currently provide comprehensive hiv care and/or are specialists in the field of hiv and infectious disease. each activity is accredited for four cpd points through the health professions council of south africa. while the activity is open to all users of the website, only members of the society can redeem cpd points for successfully completing the activity. box 1 provides an abbreviated example of a case from the case library. this particular case illustrates the complex interaction between viral hepatitis b and hiv in mode of transmission, diagnosis and treatment. it also explores reasons why an hiv-1 viral load could be below the level of detection in this patient, or in an untreated patient in general. other case studies focus on art complications, paediatric hiv treatment and ethical issues. case studies will be added on a regular basis to form a library of resources available to all society members. for more information, please visit our website case library at http://www. sahivsoc.org/case-studies/overview. regina osih is a public health consultant in private practice in johannesburg. box 1. summary of clinical case study: hepatitis b a 24-year-old man presents to the clinic with a history of hepatitis b, treated at another hospital a year go. he had presented with acute hepatitis a few years ago, and on follow-up at 6 months was found to be hepatitis bsag positive and treated for 1 year with 3tc (lamivudine). he presents to a new clinic after 1 year of 3tc treatment (which has just been discontinued) for further management. this patient was not tested for hiv at the time of his first presentation. an hiv test is done at this presentation, and it is positive – but with an undetectable hiv-1 viral load. hiv 862 guidelines for antiretroviral therapy in adults by the southern african hiv clinicians society graeme meintjes, gary maartens (chairpersons of the adult guidelines committee), andrew boulle, francesca conradie, eric goemaere, eric hefer, dave johnson, moeketsi mathe, yunus moosa, regina osih, theresa rossouw, gilles van cutsem, ebrahim variava, francois venter (expert panel members), dave spencer (reviewer), on behalf of the southern african hiv clinicians society corresponding author: g meintjes (graemein@mweb.co.za)   these guidelines are intended as an update to those published in the southern african journal of hiv medicine in january 2008. since the release of the previous guidelines, the scale-up of antiretroviral therapy (art) in southern africa has continued to grow. cohort studies from the region show excellent clinical outcomes; however, art is still being started late (in advanced disease), resulting in relatively high early mortality rates. new data on antiretroviral (arv) tolerability in the region and several new arv drugs have become available. although currently few in number, some patients in the region are failing protease inhibitor (pi)-based second-line regimens. to address this, guidelines on third-line (or ‘salvage’) therapy have been expanded. s afr j hiv med 2012;13(3):114-133. doi:10.7196/sajhivmed.862 disclaimer: specific recommendations provided here are intended only as a guide to clinical therapy, based on expert consensus and best current evidence. treatment decisions for patients should be made by their responsible clinicians, with due consideration for individual circumstances. the most current version of this document should always be consulted. 1. underlying principles while many art guidelines are available internationally, these guidelines have been written to address issues relevant to southern africa. the following general principles underpinned the writing process: • south africa is a middle-income country whereas certain other countries in the region are low-income countries; therefore, affordability was taken into account. • only treatment and diagnostic options available in southern africa were included. • we recognised the need to bridge the gap in treatment recommendations between public and private sector programmes, considering that many patients transition between the 2 sectors for treatment. • the guidelines are intended to reflect ‘best practice’ – while it is acknowledged that certain recommendations are aspirational for poorly resourced settings, the unavailability of diagnostic/monitoring tests should not be a barrier to providing art to those in need. • there has been a shift to view treatment as a means of hiv prevention. the evidence base for this exists for serodiscordant couples; recommendations in this regard are included in these guidelines and additional data from community studies are awaited. • references for key new recommendations were included to address the need for supporting evidence. 2. goals of therapy the primary goals of art are to: • improve quality of life • reduce hiv-related morbidity and mortality • provide maximal and durable suppression of viral load • restore and/or preserve immune function. these goals are achieved by completely suppressing viral replication for as long as possible using well-tolerated and sustainable treatment. with prolonged viral suppression, the cd4 lymphocyte count usually increases, which is accompanied by partial restoration of pathogen-specific immune function. for most patients, this results in a dramatic reduction in the risk of hiv-associated morbidity and mortality. it is still unclear whether immune function ever returns to full normality. long-term cohorts will provide answers, but for now, and for practical purposes, clinicians should treat patients who adhere to art with the anticipation of a near-normal life expectancy. 3. standard of care maximally suppressive art regimens should be used to obtain the best results and to prevent resistance. in the region, non-suppressive regimens such as mono/dual nucleoside reverse transcriptase inhibitor (nrti) therapies have historically been used. the initiation of such therapies is now strongly discouraged. however, non-suppressive regimens have a role in the prevention of mother-to-child transmission (pmtct) and in post-exposure prophylaxis (pep) for healthcare workers following occupational exposure. furthermore, they are probably effective following sexual exposure. for further guidance: southern african hiv clinicians society. post-exposure prophylaxis. southern african journal of hiv medicine 2008;9:36-45. 4. classes of arv agents and their mechanisms of action the most commonly used arv agents in the region inhibit 1 of 3 key hiv enzymes that are required by the virus for intracellular replication (table 1): • reverse transcriptase – essential for completion of the early stages of hiv replication • protease – required for the assembly and maturation of fully-infectious viral progeny • integrase – required for the integration of proviral dna into the host chromosomal dna. table 1. classes of arv agents class abbreviation mechanism of action specific action nucleoside and nucleotide reverse transcriptase inhibitors nrtis and ntrtis   reverse transcriptase inhibition nucleic acid analogues that mimic the normal building blocks of dna, preventing transcription of viral rna to dna non-nucleoside reverse transcriptase inhibitors nnrtis reverse transcriptase inhibition small compounds shaped to fit into the genomic hiv binding site of reverse transcriptase and directly inhibit its action protease inhibitors pis protease inhibition inhibit the final maturation stages of hiv replication, resulting in the formation of non-infective viral particles entry inhibitors* entry inhibition bind to viral gp41 or host cell cd4 or chemokine (ccr5) receptors integrase inhibitors (also termed integrase strand transfer inhibitors) instis inhibit viral integration prevent the transfer of proviral dna strands into the host chromosomal dna * not yet available in southern africa. arv = antiretroviral; dna = deoxyribonucleic acid; rna = ribonucleic acid. 5. arv agents currently available in southern africa (table 2) 5.1 notes different fixed-dose drug combinations are increasingly being made available. the oldest combination is zidovudine (azt)/lamivudine (3tc), but a number of other 2 3 fixed-dose combinations are now available in southern africa. these reduce the burden of multiple pills and improve adherence. however, side-effects remain as described in table 2. table 2. dose and common adverse drug reactions of arv agents available in southern africa generic name class of drug* recommended dosage common or severe adverse drug reactions† zidovudine (azt) nrti 300 mg 12-hourly   bone marrow suppression, gastro-intestinal (gi) upset, headache, myopathy, hyperlactataemia/steatohepatitis (medium potential), lipo-atrophy didanosine (ddi) nrti 400 mg daily (250 mg daily if <60 kg) taken on an empty stomach (enteric coated formulation preferred) peripheral neuropathy, pancreatitis, nausea, diarrhoea, hyperlactataemia/steatohepatitis (high potential) lamivudine (3tc) nrti 150 mg 12-hourly or 300 mg daily anaemia (pure red cell aplasia) (rare), hyperlactataemia/steatohepatitis (very low potential) stavudine (d4t) nrti 30 mg 12-hourly note: higher doses for >60 kg no longer recommended due to toxicity peripheral neuropathy, lipo-atrophy, hyperlactataemia/steatohepatitis (high potential), pancreatitis, hiv-associated neuromuscular weakness syndrome (hanws) (rare), dyslipidaemia abacavir (abc) nrti 300 mg 12-hourly or 600 mg daily hypersensitivity reaction, hyperlactataemia/steatohepatitis (very low potential) tenofovir (tdf) ntrti 300 mg daily   renal failure, tubular wasting syndrome, reduced bone mineral density, hyperlactataemia/steatohepatitis (very low potential) emtricitabine (ftc) nrti 200 mg daily   palmar hyperpigmentation, hyperlactataemia/steatohepatitis (very low potential) nevirapine (nvp) nnrti 200 mg daily for 14 days then 200 mg 12-hourly rash, hepatitis efavirenz (efv) nnrti 600 mg at night central nervous system symptoms (vivid dreams, problems with concentration, confusion, mood disturbance, psychosis), rash, hepatitis, gynaecomastia etravirine (etv) nnrti 200 mg 12-hourly rash, hepatitis indinavir (idv) (rarely used) pi 800 mg 12-hourly with 100 mg ritonavir 12-hourly no food restrictions maintain high fluid intake kidney stones, unconjugated hyperbilirubinaemia (visible jaundice in minority of patients), gi disturbances, hair loss, hyperglycaemia, headache, dyslipidaemia atazanavir (atv) pi 400 mg daily (only if art-naive) or 300 mg with ritonavir 100 mg daily (preferable) with tdf 300/100 mg daily and with efv 400/100 mg daily unconjugated hyperbilirubinaemia (visible jaundice in minority of patients), dyslipidaemia (low potential), renal stones (rare), hepatitis   lopinavir/ritonavir (lpv/r) boosted pi 400/100 mg 12-hourly or 800/200 mg daily (only if pi-naive). gi upset, dyslipidaemia, hepatitis darunavir (drv) pi 600 mg 12-hourly with 100 mg ritonavir 12-hourly or 800/100 mg daily (only if pi-naive) gi upset, rash, dyslipidaemia, hepatitis contains sulphonamide moiety (use with caution in patients with sulpha allergy) saquinavir (sqv) (hard gel formulation, rarely used) pi 1 000 mg with 100 mg ritonavir 12-hourly, or 1 600 mg with 100 mg ritonavir daily (only if pi-naive) take with a fatty meal, or up to 2 hours after meal gi disturbance (mild), hepatitis, hyperglycaemia, dyslipidaemia raltegravir (ral) insti 400 mg 12-hourly rash (rare), headache, gi upset *all protease inhibitors (pis) may be associated with cardiac conduction abnormalities (especially pr prolongation). this seldom results in clinically significant effects, but caution should be taken when co-prescribing other drugs that cause delayed cardiac conduction, such as macrolides. †life-threatening reactions are indicated in bold. nrti = nucleoside reverse transcriptase inhibitor; ntrti = nucleotide reverse transcriptase inhibitor; nnrti = non-nucleoside reverse transcriptase inhibitor; pi = protease inhibitor; insti = integrase inhibitor (integrase strand transfer inhibitor). low-dose ritonavir is used to ‘boost’ the concentration of other pis. it is always used with lopinavir (lpv) (fixed-dose combination) and saquinavir (sqv) and is strongly encouraged with other pis. the following pis are recommended for use: lpv/ritonavir (lpv/r), atazanavir/ritonavir (atv/r) and darunavir/ritonavir (drv/r). patients receiving older pis (e.g. sqv and indinavir) should be switched to these (consult an expert if the patient’s viral load is not suppressed). we recommend against regimens containing dual ritonavir-boosted pis, as there is no evidence for superior efficacy1 and significant side-effects are likely. combinations to be avoided include: (i) azt plus d4t (antagonism); (ii) tenofovir (tdf) plus didanosine (ddi) (associated with poorer virological and immunological responses and increased toxicity); and (iii) d4t plus ddi (associated with a very high risk for mitochondrial toxicities such as lactic acidosis and peripheral neuropathy). 6. indications for starting art indications for art initiation are summarised in table 3. art initiation is never an emergency, unless used for pep or pmtct. however, patients with profound immunosuppression are at significant risk of opportunistic illnesses, and should be assessed rapidly and initiated on art as soon as adherence is assured. the following investigations are recommended prior to initiating art: • alanine transaminase (alt) • full blood count (fbc) • serum creatinine and calculate creatinine clearance: avoid tdf if creatinine clearance is <50 ml/min; other nrtis, except abacavir (abc), require dose adjustment if creatinine clearance is <50 ml/min (see the modified cockgraft-gault equation – table 9) • urinalysis for proteinuria • hepatitis b surface antigen • cd4 count. table 3. indications for art* clinical diagnoses (irrespective of cd4 count)   who clinical stage 3 and 4† art recommended other severe hiv-related disorders, e.g.:‡ immune thrombocytopenia thrombotic thrombocytopenic purpura polymyositis lymphocytic interstitial pneumonitis art recommended non hiv-related disorders:§ malignancies (excluding localised malignancies) hepatitis b¶ hepatitis c any condition requiring long-term immunosuppressive therapy art recommended       art recommended     cd4 counts   <350 cells/µl art recommended >350 cells/µl defer art     hiv-infected partner in serodiscordant relationship   regardless of cd4 count or clinical diagnoses offer art and discuss safe sex (discussion must involve both partners) *note that either listed clinical diagnoses or cd4 strata would be an indication for art. †see appendix. ‡specialist input required. note that this list is not exhaustive – any other severe hiv-related disorder should be considered an indication for art. §specialist input required. other disorders that may benefit from improvement in immune function should also be considered as an indication to start art. also, given that untreated hiv appears to be a risk factor for vascular disease, patients with symptomatic vascular disease or diabetes mellitus can be considered for earlier art. ¶hepatitis b that qualifies for specific anti-hepatitis b therapy (see section 13.5 for criteria and recommended art regimens). where feasible, a serum or plasma cryptococcal antigen test should be performed in patients starting art with a cd4 count <100 cells/μl, to screen for early cryptococcal disease and to initiate pre-emptive treatment if needed. in addition, a baseline hiv viral load should be performed where feasible. art should be deferred until patients are prepared to commit to long-term treatment and maintaining good treatment adherence. however, efforts should be made to avoid lengthy indecision that may result in avoidable clinical deterioration and death. 6.1 rationale for these guidelines 6.1.1 cd4 threshold a randomised trial in haiti demonstrated reduced mortality and incident tuberculosis (tb) in patients starting art at a cd4 threshold <350 cells/µl (compared with patients waiting to start therapy at <200 cells/μl).2 some observational data suggest that reduced morbidity and mortality are associated with starting art even earlier (at cd4 thresholds of 500 cells/μl or above that).3 , 4 , 5 , 6 however, these data are derived from retrospective studies with methodological issues and probable residual confounding. if there is benefit to patients starting art at cd4 counts >350 cells/μl, the benefit is likely to be small, since hiv-related events at high cd4 counts are rare. a randomised controlled trial (rct) (hptn052) showed reduced morbidity but not mortality associated with starting art at a cd4 count of 350 550 cells/µl (compared with <250 cells/μl).7 however, again, the absolute benefits were small. definitive evidence regarding earlier art initiation is awaited from an ongoing rct, the start study (http://clinicaltrials.gov/ct2/show/nct00867048). 6.1.2 treating who stage 3 many observational studies have shown that tb (the most common world health organization (who) stage 3 condition associated with hiv) accelerates hiv disease progression and increases mortality.8 we advise that an episode of hiv-associated tb (i.e. tb diagnosed at the time of seropositive hiv test) is a sufficient criterion for art, but not remote episodes of tb when the patient’s hiv status was unknown. 6.1.3 serodiscordant couples the hptn052 trial showed that treating the hiv-infected partner in a serodiscordant relationship with art was associated with a 96% reduction in transmission risk to the uninfected partner.7 6.2 starting art in patients with tb decisions regarding the timing of art in patients with tb should be made on the basis of the cd4 count: • cd4 count ≤50 cells/µl: art should be regarded as urgent, and the aim should be to start therapy after 2 weeks of tb treatment. three rcts9 , 10 , 11 have demonstrated that this approach reduces aids progression and mortality. it is advised to commence art after it is clear that the patient’s tb symptoms are improving and that tb therapy is tolerated. • cd4 count >50 cells/µl: art should be delayed until after the intensive phase of tb treatment (2 months) unless the patient has other serious hiv-related conditions (e.g. kaposi’s sarcoma or hiv encephalopathy). the longer delay before commencing art in this group is expected to reduce the risk of shared toxicity (as the patient will then be receiving fewer tb drugs) and to reduce the risk of the immune reconstitution inflammatory syndrome (iris) (section 15). the rcts did not show a higher risk of aids progression/mortality in this group when art initiation was delayed until 2 months after starting tb treatment.9 , 10 , 11 • there are important drug interactions and shared side-effects when art is co-administered with tb therapy (section 13.1). • when art is commenced, patients should be warned that tb symptoms or signs may temporarily worsen and new features may occur in the first 3 months as a result of tb-iris. • unless contra-indicated, cotrimoxazole prophylaxis should be initiated in patients with hiv-associated tb. • patients with tb meningitis (tbm) starting art immediately or at 2 months following diagnosis were shown to have similar high mortality, with more complications in the former.12 we recommend starting art 2 8 weeks after tbm diagnosis. 6.3 starting art in patients with other opportunistic diseases/infections for patients with cryptococcal meningitis (cm), the optimal time to start art is currently unclear. the high risk of mortality prior to art and the mortality risk associated with intracranial cryptococcal iris need to be balanced, and published studies have shown conflicting results.13 , 14 the cryptococcal optimal art timing (coat) trial was recently stopped early by the data and safety monitoring board because of excess mortality in patients who started art in hospital 1 2 weeks after cm diagnosis compared with those starting 5 6 weeks after diagnosis. the final results of this trial are awaited. in the interim, we recommend starting art around 4 weeks after antifungal treatment (preferably amphotericin b-based) is started. in patients with other infections (e.g. pneumocystis pneumonia or bacterial pneumonia) and who have a cd4 count <200 cells/μl, clinicians should aim to start art within 2 weeks of starting treatment for that infection. in patients with severe kaposi’s sarcoma and lymphoma, art counselling should be expedited and art should be started as soon as possible. refer to supplementary material: ‘starting art in hospital’ and ‘high-risk patients’. 6.4 patient readiness for art patient readiness for therapy is as important as the medical indications for commencing therapy. • the patient must demonstrate insight and must have established the ability to attend reliably. • conventionally, art is not started at the first visit. usually, 2 3 visits staggered closely together are required before art is started, to accommodate counselling. prolonged delays in starting art should be avoided. art should be delayed only if concerns about adherence are severe enough to outweigh the risk of hiv disease progression. • the patient should be provided with information on the following: • art is life-long therapy • the importance of 100% adherence • art side-effects and what to do and who to contact if serious side-effects occur. • active depression or substance abuse should be dealt with. • a personal treatment plan should be formulated for each patient, specifying drug storage, strategies for missed doses and how to integrate taking medication into daily routine. the patient must be made aware of scheduling in terms of clinical follow-up. • disclosure of hiv status (to a partner and/or other household members) should be strongly encouraged. this has been shown to be an important determinant of treatment adherence and assists in the provision of patient-directed support. disclosure also identifies exposed contacts for screening and support. this issue needs to be handled sensitively in situations where disclosure may have harmful consequences, particularly for women. • the patient should be encouraged to join a support group and/or identify a treatment ‘buddy’. however, neither disclosure nor support group participation are prerequisites for good adherence in all patients. • clinicians should ensure that they have the contact details of each patient and their treatment ‘buddy’. • counselling should cover safe-sex practices and address issues related to reproductive health (i.e. family planning, contraception, condom use, pregnancy and pmtct). refer to supplementary material: ‘common misconceptions regarding art’ and ‘adherence interventions’. 6.5 art in primary infection there is insufficient evidence to recommend art for primary infection. there are compelling reasons to defer therapy, including lack of proven efficacy, drug toxicity, and the potential for drug resistance. patients with severe primary infection progress more rapidly, which is an indication for careful follow-up. art in primary infection should be considered in a properly conducted research study, or in the presence of very severe symptoms (e.g. meningo-encephalitis), which are rare. consultation with an expert treater is advised. 7. initial arv regimens for the previously untreated patient in accordance with international recommendations, we recommend the use of a non-nucleoside reverse transcriptase inhibitor (nnrti) and 2 nrtis (a safe dual nrti combination) as the first-line art regimen. in comparison with pis, nnrtis are better tolerated in the long term and are at least as potent when combined with an appropriate dual nrti combination.15 we do not recommend pi or integrase inhibitor (integrase strand transfer inhibitor (insti)) use in first-line therapy, unless dictated by intolerance or nnrti contra-indications. either nvp or efavirenz (efv) may be selected as the nnrti. efv is the preferred nnrti. nvp should be selected for women in the first trimester of pregnancy or those who intend to fall pregnant (section 13.2). owing to its neuropsychiatric side-effects, efv should be avoided in those with active psychiatric illness, shift workers and those operating heavy machinery or vehicles. nvp should be avoided in women with a cd4 count >250 cells/μl and men with a cd4 count >400 cells/μl initiating art for the first time, because of the increased risk of rash-associated hepatitis. it should be noted, however, that this side-effect can occur at any cd4 count. clinicians should consider avoiding nvp in patients who may encounter difficulties getting rapid medical attention should rash or hepatitis symptoms occur. nvp should also be avoided in patients with pre-existent liver disease. when both nvp and efv are contra-indicated, raltegravir (ral) or a pi could be substituted. any patient starting an nnrti should be told to report a rash, jaundice or symptoms of hepatitis immediately. any of the following 2-drug nrti combinations are recommended for use with the nnrti: • 3tc plus tdf, azt or abc • emtricitabine (ftc) – a cytidine analogue very similar to 3tc – that is combined with tdf in a fixed-dose combination or with the addition of efv as a triple-drug combination pill. tdf is the favoured nrti to use with 3tc (or ftc). selection will depend on affordability and co-morbidity (e.g. patients with a creatinine clearance <50 ml/min should not start tdf). if tdf is unavailable or contra-indicated, azt should be used, provided that haemoglobin (hb) is >10 g/dl. a large clinical trial comparing abcv. tdf-containing first-line regimens showed lower rates of virological suppression with abc in patients with a baseline viral load >100 000 copies/ml.16 similar findings were demonstrated in a second study,17 but not confirmed in another.18 abc is more costly and unavailable in most public sector programmes and has been associated with an increased risk of myocardial infarction (mi) in some, but not all, cohort studies.19 , 20 the association with mi was not confirmed in a meta-analysis of rcts.21 nevertheless, caution is recommended when considering abc for patients at significant risk of ischaemic heart disease or with established ischaemic heart disease. abc is an option to consider in chronic renal failure where tdf and azt (because of anaemia) cannot be used. d4t is a cheaper option than tdf, azt and abc, but it is considerably more toxic. most public sector programmes in southern africa have discontinued d4t in first-line art. nonetheless, there is still a role for d4t in selected patients, when it is used in the short term in patients with contra-indications to other nrtis. a common example is a patient with renal dysfunction and anaemia at baseline who could be started on d4t for 3 6 months and then switched to azt or tdf depending on resolution of the anaemia and/or renal dysfunction. in addition, if there is a need for concomitant nephrotoxic medications, e.g. aminoglycosides to treat multidrug resistant (mdr)-tb, d4t (or azt or abc) is preferable to tdf during the period of exposure to the other nephrotoxic medication. patients usually tolerate short-term d4t well. severe d4t side-effects, such as hyperlactataemia, lipo-atrophy and other mitochondrial toxicity, typically occur after 4 6 months, although peripheral neuropathy can develop earlier. we favour regimens that include fixed-dose combinations and allow once-daily dosing (refer to table 2 for doses and common side-effects). 8. laboratory monitoring for art efficacy 8.1 viral loads viral loads should be performed: • at baseline (before commencing art, where possible) • at 3 months after the commencement of art (this early viral load is desirable to detect adherence problems early before resistance develops. a small number of patients who start with a very high viral load may not be fully suppressed at 3 months despite 100% adherence, but such patients would have had a >2 log drop in viral load from baseline; therefore, the 3-month result should be interpreted in relation to the baseline viral load. all patients who have a detectable viral load at 3 months should receive additional adherence interventions.) • at 6 months thereafter and then every 6 months (in patients who are virologically suppressed (undetectable viral load) for longer than 12 months and who demonstrate reliable adherence and follow-up, it may be acceptable to reduce the frequency of viral load monitoring to annually) • if viral load is >50 copies/ml, then repeat measurement in 3 months, after an adherence intervention. 8.1.1 notes (i) a viral load >50 copies/ml while receiving art should be an indication for urgent action to improve adherence. a subsequent art change must be considered if there is not complete viral suppression at the subsequent 3-month follow-up viral load (see section 10 'indications for changing art'). (ii) viral load monitoring is key to the success of art. decisions to change art made on the basis of virological failure, rather than on clinical or immunologic failure alone, result in better patient outcomes. if the viral load is undetectable, then the virus cannot mutate and develop resistance. a sustained viral load of <50 copies/ml is associated with the most durable virological benefit. 8.2 cd4+ counts cd4 counts should be performed every 6 months. in patients being monitored with viral loads once the cd4 count is >200 cells/μl, provided that the viral load is suppressed, routine cd4 testing could be stopped as it adds little to management. this is expert opinion rather than being evidence-based. however, if virological or clinical failure occurs, then a cd4 count should be repeated as it may influence management decisions. 9. defining art failure in resource-limited settings where viral loads are unavailable, the who has devised criteria for defining art failure on the basis of cd4 count responses or clinical disease progression. studies have shown that switching art regimens using these criteria results in a significant proportion of patients switching very late (with progressive accumulation of resistant mutations) and switching inappropriately (as the cd4 count response may be poor, despite optimal virological suppression).22 9.1 virological criteria for treatment success treatment success is defined by: • a decline in viral load of at least 2 log from pre-treatment levels 3 months after initiating art • a decline in viral load to <50 rna copies/ml within 6 months of commencing art and sustained thereafter. 9.2 virological criteria for treatment failure treatment failure is defined by a confirmed hiv viral load of >1 000 copies/ml in 2 measurements taken 1 3 months apart. several factors can influence the measurement of hiv viral load. the decision to alter art should therefore be based on the results of repeat testing after 1 3 months following intensive adherence counselling. inadequate patient adherence to the prescribed regimen remains the most common reason for treatment failure. other important causes include: prior use of single-dose nvp for pmtct, especially when art is initiated within 6 months of the pmtct dose; drug interactions that decrease art concentrations; and transmitted drug resistance, which is currently uncommon in the region (<5%).23 9.3 cd4 response typically, the cd4 count increases rapidly in the first month of art, by approximately 75 100 cells/μl, with a more gradual rise thereafter (50 100 cells/μl/year).24 most, but not all, patients achieve a cd4 count >500 cells/μl after several years of art, provided that the viral load remains suppressed.25 , 26 , 27 however, cd4 responses are highly variable and may fail to increase despite virological suppression, in about 10 20% of patients.28 , 29 such patients have a delayed or absent cd4 response to art despite viral suppression, which is termed an ‘immunological discordant response to art’. certain studies suggest that older patients are at higher risk. there is no evidence that such patients benefit from a change in art regimen; therefore, the same regimen should be continued. cotrimoxazole prophylaxis should be continued if the cd4 count remains <200 cells/μl and isoniazid (inh) prophylaxis should be considered. there is evidence that the prognosis of such patients is worse than in those who have a cd4 response, but better than that of patients not receiving art. if such patients are clinically unwell, tb or lymphoma should be considered as the cause of persistent cd4 lymphopaenia. cd4 counts may continue to rise or remain stable in the presence of incomplete viral suppression (which will result in the emergence of drug resistance) until the viral load is high (approximately 10 000 copies/ml and above).30 10. indications for changing art individual art drugs may be substituted in the event of toxicity (section 14), provided that the viral load is suppressed or art was initiated within the preceding 6 months. changing the first-line art regimen to a second-line regimen is a major step. the drugs used in second-line regimens are often not as well tolerated and are more expensive, usually with limited options for subsequent treatment owing to cost. for this reason, clinicians tend to switch to second-line art after a prolonged period of virological failure, which will cause a progressive increase in the accumulation of resistant mutations. this reduces the efficacy of second-line and subsequent regimens. if the viral load is >1 000 copies/ml, it is essential to step up adherence interventions, as discussed above. once the viral load is confirmed on a second specimen to be >1 000 copies/ml despite adherence, the patient should be switched to a second-line regimen without undue delay. in summary, we advise a switch to a second-line regimen when 2 viral load measurements have been >1 000 copies/ml, preferably with the measurements taken 3 months apart with at least 4 weeks of an intensified adherence intervention in between. in patients with low cd4 counts (<100 cells/μl), this process should be expedited. some patients have persistently detectable viral loads at low levels (200 1 000 copies/ml). if patients have low level viraemia for a prolonged period (>1 year) or persistently low cd4 counts (<100 cells/μl) together with low-level viraemia despite adherence interventions, they should be switched to second-line art. 10.1 second-line art the following ritonavir-boosted pis are recommended in conjunction with 2 nrtis (table 2): • atv/r • lpv/r • drv/r (it is preferable to save this drug for third-line therapy, further discussed below). indinavir (idv) is significantly more toxic than other pis. sqv is less robust in terms of resistance than the 3 options listed. idv and sqv confer no benefit over other options, and are therefore not recommended. boosting involves the addition of low-dose ritonavir, which inhibits pi metabolism, thereby boosting pi plasma concentration and prolonging its half-life. lpv is co-formulated with ritonavir in a heat-stable tablet (aluvia) and is the best option in patients without a refrigerator (other pis require ritonavir boosting with a separate ritonavir capsule that ideally requires refrigeration, although ritonavir capsules are stable at room temperature for 30 days). we recommend against the use of unboosted pis. if a patient was receiving a first-line combination of 2 nrtis and a pi (boosted or unboosted), it is best to discuss the choice of second-line regimen with an experienced treater and consider a genotype resistance test. second-line nnrti plus nrti regimens are often not effective in such patients because of nrti mutations, while boosted pi regimens in second-line art may remain effective. decisions are therefore best guided by resistance testing. 10.2 selecting second-line dual nrtis because boosted pis are robust drugs (i.e. resistance develops slowly) in pi-naive patients, it is very likely that virological suppression will be achieved with good adherence, even if the 2 nrtis used in second-line are partially compromised by nrti resistance mutations (tables 4 and 5).31 table 4. mutations selected by first-line nrti combinations* first-line nrtis nrti mutations selected 3tc or ftc select for m184v, which compromises both 3tc and ftc, and slightly impairs the activity of abc and ddi, but increases susceptibility to azt, d4t and tdf azt selects for thymidine analogue mutations (tams) which may compromise all nrtis† d4t selects for tams which may compromise all nrtis in a minority of patients, d4t may select for k65r which compromises tdf, abc and ddi, but increases susceptibility to azt tdf selects for k65r which compromises tdf, abc and ddi, but increases susceptibility to azt abc selects for l74v which compromises abc and ddi may also select for k65r which compromises tdf, abc and ddi, but increases susceptibility to azt selects for y115f which decreases its susceptibility *these mutations accumulate with time – the longer the patient has virological failure, the more of these mutations are likely to be selected. †the presence of ≥3 tams, including m41l and l210w, confer intermediateto high-level tdf resistance. tams = thymidine analogue mutations; nrti = nucleoside reverse transcriptase inhibitor; 3tc = lamivudine; ftc = emtricitabine; azt = zidovudine; d4t = stavudine; tdf = tenofovir; abc = abacavir. table 5. choice of second-line nrtis in relation to first-line nrtis used first-line nrtis used second-line nrti combination advised azt plus 3tc tdf plus 3tc* d4t plus 3tc tdf plus 3tc* (preferably genotype first, given the increased risk of k65r on d4t in subtype c)32 tdf plus 3tc* azt plus 3tc abc plus 3tc azt plus 3tc *3tc is interchangeable with ftc. nrti = nucleoside reverse transcriptase inhibitor; azt = zidovudine; 3tc = lamivudine; d4t = stavudine; tdf = tenofovir; abc = abacavir; ftc = emtricitabine. certain nrti combinations are contra-indicated for toxicity reasons (e.g. d4t plus ddi, or tdf plus ddi). tdf plus abc is not recommended for second-line art, as these agents share several resistance mutations. nrti combinations advised for second-line regimens include either azt plus 3tc, or tdf plus 3tc (ftc can be substituted in place of 3tc), depending on the likely mutational profile selected during the patient’s first-line nrti combination. even if 3tc (or ftc) is used in a failed first-line regimen and may, therefore, have selected for the m184v mutation which confers resistance to the agent, 3tc (or ftc) can be re-used in second-line therapy because of the capacity of the m184v mutation to partially restore susceptibility to azt, d4t and tdf in the presence of thymidine analogue mutations (tams), and to partially restore susceptibility to tdf in the presence of the k65r mutation. the m184v mutation also reduces the replicative capacity of the virus. ideally, a resistance test should be performed at first-line failure to ensure that the patient does indeed have resistance (and the virus is not ‘wild-type’) and to guide choices of second-line and future regimens. however, in many settings in the region, this is unaffordable and/or unavailable. 11. patients who return after defaulting therapy we recommend restarting the same regimen if patients return to care after defaulting therapy and repeating hiv viral load measurements after 3 months; switching to a second-line regimen should be considered if the viral load is not suppressed at this point. if a patient is receiving first-line therapy, azt could be substituted for d4t. however, we do not recommend substituting tdf, because, if the patient has pre-existing nnrti and 3tc resistance, tdf resistance may rapidly result compromising its efficacy in second-line therapy. if a patient has multiple episodes of interruption, and, particularly, if they are beyond the first year of art, then many clinicians would consider switching the patient to a second-line regimen, making the assumption that the multiple interruptions resulted in first-line resistance. reasons for defaulting should be addressed and adherence support increased. performing a resistance test after the patient has been off art for longer than 4 weeks is of limited value as many resistance mutations are overtaken by wild-type when art is stopped. 12. drug interactions there are many important drug interactions between arv agents and other medications, as well as between certain arv agents themselves. these interactions occur because of metabolism of arv drugs by cytochrome p450 in the liver and intestine and induction or inhibition by arvs of this and other enzyme systems and drug transporters. certain of these drug interactions are discussed in these guidelines (e.g. the interaction between rifampicin and nnrtis, pis and ral). the list of all potential drug interactions is, however, very long and therefore beyond the scope of this document. knowledge of drug interactions is constantly evolving. clinicians are advised to consult the package inserts of arv agents and concomitant medication to assess for drug interactions and the following websites, which provide up-to-date information on drug interactions and the actions required to account for them: • university of liverpool drug interactions charts: http://www.hiv-druginteractions.org • university of cape town medicines information centre arv interactions table: http://www.mic.uct.ac.za/?page_id=47 we advise that clinicians assess for potential drug interactions whenever patients start or switch to a new arv drugs or regimens, and start new concomitant medications. in addition, herbal medications may also have interactions with arvs. 13. art in special populations 13.1 tb the art regimen should be modified if necessary for compatibility with rifampicin – a critical component of the tb regimen that substantially reduces the risk of relapse after completing tb treatment. efv is the preferred nnrti for use with rifampicin. nvp is an alternative in patients with contra-indications for efv (e.g. psychosis), but it carries a higher risk of hepatitis and virological failure when used with rifampicin. the plasma concentrations of all boosted pis are reduced to sub-therapeutic ranges with rifampicin. dose adjustment of some pis can overcome this induction (table 6), but there is a risk of hepatotoxicity. the patient will require counselling and alt should be monitored frequently. an alternative approach is to replace rifampicin with rifabutin. however, rifabutin is expensive and not currently available at public sector tb clinics. also, rifabutin is not co-formulated with other tb drugs such as rifampicin, and the evidence base for rifabutin in the treatment of tb is much less substantial than that for rifampicin.33 there is also uncertainty regarding the optimal dose of rifabutin with boosted pis; current guidelines recommend 150 mg on alternate days. rifabutin may be considered in patients not tolerating co-treatment with art and rifampicin-based antitubercular therapy (e.g. patients unable to tolerate the increased lpv/r dose) or in art-experienced patients on an art regimen that is not compatible with rifampicin (e.g. those on third-line art with drv/r). rifabutin doses may require adjustment (table 8). if rifabutin is unavailable and adjusted doses of pis are poorly tolerated in patients on second-line art, double-dose ral (800 mg 12-hourly) may be substituted for the pi or triple nrti therapy may be considered. triple nrti art is, however, inferior to conventional art and ral is less robust than a pi in second-line therapy. nevertheless, short-term use over 6 months is probably preferable to treating tb without rifampicin, which has a high risk of failure or relapse. art and tb medication share many side-effects (table 7). table 6. art interactions with rifampicin and recommendations for co-administration class arv agent interaction dose of art drug with rifampicin nrtis all in class no significant pharmacokinetic interactions no dose adjustment required nnrtis efv mild reduction in efv concentrations in some patients, efv concentrations may increase no dose adjustment required (600 mg nocte) nvp moderate reduction in nvp concentrations use standard dosing, but omit the lead-in dose phase and start 200 mg nvp 12-hourly etv marked reduction in etv concentrations do not prescribe concomitantly pis lpv/r lpv plasma concentrations significantly decreased the preferable strategy is to double the dose of lpv/r to 800/200 mg 12-hourly alternatively, add 300 mg ritonavir 12-hourly to standard dose of 2 tablets 12-hourly of lpv/r there is an increased risk of hepatotoxicity with these strategies these dose adjustments can be made gradually over 1 2 weeks* sqv/ r sqv concentrations are significantly decreased 400 mg sqv plus 400 mg ritonavir 12-hourly increased risk of hepatotoxicity all other pis marked reduction in pi concentrations do not prescribe concomitantly insti ral marked reduction in concentrations double the dose of ral to 800 mg 12-hourly *the double dosing regimen is preferred as it is better tolerated. dose adjustments should be continued for 2 weeks after rifampicin is stopped. art = antiretroviral therapy; arv = antiretroviral; nrti = nucleoside reverse transcriptase inhibitor; nnrti = non-nucleoside reverse transcriptase inhibitor; pi = protease inhibitor; insti = integrase inhibitor (integrase strand transfer inhibitor); efv = efavirenz; nvp = nevirapine; lpv = lopinavir; lpv/r = lopinavir/ritonavir; sqv = saquinavir; sqv/r = saquinavir/ritonavir; ral = raltegravir. table 7. shared side-effects of tb treatment and art side-effects art tb treatment nausea azt, ddi, pis pyrazinamide, ethionamide hepatitis nvp, efv, pis (nrtis can cause steatohepatitis) rifampicin, isoniazid, pyrazinamide and many second-line drugs including quinolones peripheral neuropathy d4t, ddi isoniazid, ethionamide, terizidone/cycloserine renal impairment tdf aminoglycosides rash nvp, efv, ral rifampicin, isoniazid, pyrazinamide, ethambutol, streptomycin and many second-line drugs including quinolones neuropsychiatric efv terizidone/cycloserine, quinolones, isoniazid azt = zidovudine; ddi = didanosine; pis = protease inhibitors; nvp = nevirapine; efv = efavirenz; nrtis = nucleoside reverse transcriptase inhibitors; d4t = stavudine; tdf = tenofovir. table 8. dosing of arvs and rifabutin when prescribed concomitantly arv arv dose change rifabutin dose efv none increase to 450 mg/day nvp none 300 mg/day atv or ritonavir-boosted pis none decrease to 150 mg every second day arv = antiretroviral; efv = efavirenz; nvp = nevirapine; atv = atazanavir; pis = protease inhibitors. 13.2 pregnancy aids is the most frequent cause of death in pregnant women in many southern african countries,34 and is a significant cause of morbidity and mortality in children born to hiv-infected women. even where children are born hiv-negative, their mortality is significantly increased. traditionally, the focus on hiv and pregnancy has centred on the transmission of hiv to children. this has lead to complex regimens to address concerns about efficacy and resistance. these guidelines attempt where possible to simplify this approach, to decrease transmission in both pregnant and breastfeeding mothers, and facilitate the continuum of care. 13.2.1 nnrti and pi choice in pregnancy • efv has been shown to be teratogenic in primates, resulting in craniofacial abnormalities in exposed offspring. there have been isolated human case reports of myelomeningocele (neural tube defects) in infants following intra-uterine exposure to efv. the drug is classified by the united states food and drug administration (fda) as a category d drug, meaning that ‘there is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g. if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).’ • it should be noted, however, that data supporting this classification are not definitive. the incidence of neural tube defects and all congenital abnormalities among women exposed to efv in the first trimester is similar to that of the general population, but insufficient numbers have been studied to state definitively that the drug is safe.35 most experts are willing to prescribe efv for use in the second and third trimester, because the neural tube is formed in the first 4 weeks of pregnancy. if a woman expresses the desire to fall pregnant, we suggest starting an alternative to efv or switching from efv to an alternative. however, if a woman falls pregnant on efv we suggest continuing it (the neural tube forms in the first 4 weeks). in a pregnant woman not yet receiving art, we suggest starting art after the first trimester so that efv can be used, unless the patient has advanced immunosuppression, in which case nvp can be started in the first trimester. recent guidance from who is that efv can be used throughout pregnancy; their review of current data on efv safety and risk of teratogenicity was reassuring and, from a public health perspective, the need for simplicity and the toxicity associated with nvp were considered to outweigh concerns regarding unproven risks associated with efv.36 • nvp-based art is the preferred regimen for women in the first trimester of pregnancy. initiating nvp at a cd4 count >250 cells/μl is associated with a much higher risk of rash-associated hepatitis. it should be noted that switching to nvp in women who plan to fall pregnant with cd4 counts that have increased to >250 cells/μl on art is not associated with this increased risk. nevertheless, a background risk of rash and hepatitis remains. • in women who are wanting to fall pregnant if the cd4 count is >250 cells/μl, or if there is intolerance to nvp, a boosted pi regimen can be used instead of nvp. studies have shown that lpv concentrations are significantly reduced in pregnancy, but are adequate provided that lpv is the first pi that has been used. once-daily dosing of lpv/r should not be used in pregnancy. similarly, concentrations of boosted atv are reduced in pregnancy, and the dose of atv should be increased to 400 mg daily with 100 mg ritonavir daily. unboosted atv is not recommended in pregnancy. 13.2.2 general points • fertility choices in the context of hiv treatment are complex. clinicians should check these choices at every patient visit to minimise risks. adequate access to safe and effective contraception should be provided. for further guidance: southern african hiv clinicians society. guideline on safer conception in fertile hiv-infected individuals and couples. southern african journal of hiv medicine 2011;12:31-44. • clinicians should be aware that women may fall pregnant unintentionally, but that the response may still vary from welcoming the pregnancy to wanting a termination. • in general, far too few women in the southern african region receive prophylaxis for pmtct. every effort must be made to ensure rapid ascertainment of hiv status and access to appropriate pmtct and art. • south african data suggest that most hiv transmissions to babies occur from hiv-positive mothers with cd4 counts <350 cells/μl. rapid art initiation for the mother at this level will have a large effect on both maternal and child health. • all pregnant women of unknown hiv status or who were previously hiv-negative should be offered an hiv test, irrespective of previous sexual activity, marital status, social group or perceived hiv risk status. ideally, testing should be repeated in the last trimester, as some studies have suggested a greater hiv acquisition risk during pregnancy. • mother-to-child transmission is a rapidly evolving field, and international guidelines should be monitored for major changes. 13.2.3 recommendations for women who are pregnant and not receiving art, the following is recommended as best standard of care in situations where resources are available: • all pregnant women should be initiated on triple-drug art, if adequately prepared, irrespective of cd4 cell count and viral load. • hiv testing and staging must be done quickly and art adherence counselling should be accelerated, with the aim to put women on treatment within 2 weeks of first visit (and more rapidly in the third trimester of pregnancy). women who are being initiated onto art for pmtct should ideally be initiated after the first trimester, but women with a cd4 count <200 cells/μl or with severe hiv morbidity should be started in the first trimester. • women with baseline cd4 counts <350 cells/μl should have their art continued indefinitely. • women who elect to breastfeed and have a baseline cd4 count >350 cells/μl should continue art until weaning has occurred. • art should be stopped after delivery in women with baseline cd4 counts >350 cells/μl, provided that they are formula feeding. • if a woman presents during labour and is not receiving art, single-dose nvp should be given to mother and baby, with additional azt and 3tc for 1 week or single-dose tdf/ftc to the mother to reduce the risk of nnrti resistance developing (nvp has a very long half-life). • refer to pmtct guidelines for recommended regimens for the baby. 13.3 arv dosages in renal failure (table 9) renal function is estimated either by the modified cockgraft-gault equation (see table 9) or the modification of diet in renal disease (mdrd) method, which most laboratories report as ‘e-gfr’. the results of these formulae differ slightly, but either can be used for clinical management. for peritoneal dialysis, the dose given with a creatinine clearance <10 should be given daily. for haemodialysis, the dose given with a creatinine clearance <10 should be given daily, but must be given after dialysis on dialysis days, to prevent the drug from be dialysed out. table 9. arv dosage adjustments in renal failure   creatinine clearance drug 10 – 50 <10 azt unchanged 300 mg daily ddi >60 kg body weight: 200 mg daily <60 kg body weight: 150 mg daily >60 kg body weight: 100 mg daily <60 kg body weight: 75 mg daily 3tc 150 mg daily 50 mg daily d4t 15 mg 12-hourly 15 mg daily abc unchanged unchanged tdf avoid avoid pis unchanged unchanged nnrtis unchanged unchanged *source: bartlett jg. medical care of patients with hiv infection 2010, and the sanford guide to antimicrobial therapy 2010. azt = zidovudine; ddi = didanosine; 3tc = lamivudine; d4t = stavudine; abc = abacavir; tdf = tenofovir; pi = protease inhibitor; nnrti = non-nucleoside reverse transcriptase inhibitor. the modified cockgraft-gault equation: creatine clearance* = [(140 age) x ideal weight] / serum creatinine *for women, multiply the total by 0.85. 13.4 arv dosages in liver impairment unlike in renal impairment, there is no blood test that can accurately quantify liver impairment. child-pugh class c may require dose adjustment for the relevant arvs listed in table 10. in general, the combination of tdf with 3tc (or ftc) and efv (or ral) is regarded as the least hepatotoxic. if the patient has active hepatitis b, discontinuation of arvs that have activity against hepatitis b (tdf, 3tc and ftc) can cause severe flares of hepatitis (see section 13.5). 
 table 10. prescribing arvs in liver impairment class drug prescribing notes nrtis abc reduce adult dose to 200 mg bd for significant liver impairment contra-indicated in severe hepatic impairment ddi use with caution: recent reports implicate use as a risk factor for the development of hepatic decompensation in patients being treated for cirrhosis due to hepatitis c ftc in patients with chronic hepatitis b, there is a risk of rebound hepatitis when ftc is discontinued or if hepatitis b resistance to ftc develops 3tc in patients with chronic hepatitis b, there is a risk of rebound hepatitis when 3tc is discontinued or if hepatitis b resistance to 3tc develops d4t use with caution and never combine d4t and ddi in patients with liver disease tdf in patients with chronic hepatitis b, there is a risk of rebound hepatitis when tdf is discontinued azt decrease dose by 50% or double dosage interval if significant liver disease nnrtis efv caution should be exercised in administering efv to patients with liver disease therapeutic drug monitoring should be done if available nvp avoid if significant hepatic impairment or active hepatitis b or c pis atv avoid in severe hepatic impairment idv reduce unboosted adult dose to 600 mg 8-hourly if significant hepatic impairment lpv/r lpv is highly metabolised in the liver and concentrations may be increased in patients with hepatic impairment therapeutic drug monitoring should be done if available drv use with caution or avoid if significant liver disease sqv avoid: there have been reports of worsening liver disease and development of portal hypertension after starting sqv in patients with severe liver disease nrtis = nucleoside reverse transcriptase inhibitors; abc = abacavir; ddi = didanosine; ftc = emtricitabine; 3tc = lamivudine; d4t = stavudine; tdf = tenofovir; azt = zidovudine; nnrtis = non-nucleoside reverse transcriptase inhibitors; efv = efavirenz; nvp = nevirapine; pis = protease inhibitors; atv = atazanavir; idv = indinavir; lpv/r = lopinavir/ritonavir; drv = darunavir; sqv = saquinavir. 13.5 hepatitis b co-infection hepatitis b is a common co-infection in southern africa with hiv, with significant implications for progression to cirrhosis, as well as for treatment options. clinicians are encouraged to support current efforts in the region to vaccinate all children for hepatitis b, and to extend coverage to eligible adults. access to vaccination, laboratory resources and treatment options are all limited to some extent in southern african countries, and the recommendations below should each be considered in the light of the local context. all hiv-infected patients should be screened for active hepatitis b (limiting screening to those with liver function abnormalities will miss many cases as liver enzymes are often normal in hepatitis b infection). hepatitis b surface antigen is an appropriate screening test. hepatitis b dna viral load correlates with disease progression and may be used to monitor anti-hepatitis b therapy, but it is expensive and availability is limited. hepatitis b/hiv co-infection is associated with: • an increased risk of chronic liver disease • a higher hepatitis b viral load • diminished responses to hepatitis b vaccine • poorer responses to interferon-alpha treatment • an increased incidence of drug-induced hepatotoxicity (particularly with nvp) • a flare of hepatitis within 3 months of commencing art (due to hepatitis b-iris, which is difficult to differentiate from drug hepatotoxicity). drugs directed against hepatitis b that have no or minimal anti-hiv activity (e.g. entecavir and telbivudine) are largely unavailable or extremely expensive in our region. for practical purposes, the only available therapy is to use arvs that also have anti-hepatitis b activity (tdf, 3tc and ftc). as with hiv, these drugs suppress hepatitis b, but do not eradicate it. effective treatment prevents or slows progression to cirrhosis. indications for specific hepatitis b treatments37 include any one of the following: • a positive test for hepatitis b e antigen • raised alt (>2x the upper limit of normal (uln)) • evidence of fibrosis on biopsy or on appropriate imaging • a hepatitis b viral load >10 000 copies/ml (or 2 000 iu/ml). if any of the above criteria are met, then art should be commenced irrespective of the cd4 count. the art regimen should include tdf and 3tc (or ftc). using 3tc without including tdf leads to hepatitis b resistance in 80 90% of patients after 5 years of treatment. if patients meet criteria for switching to a second-line art regimen (to treat their hiv), this combination (tdf and 3tc/ftc) should be continued to suppress hbv infection, as interruption of tdf and/or ftc/3tc has been associated with life-threatening hepatitis flares. the second-line art regimen should be shaped around these 2 drugs in discussion with an experienced treater. nvp should be avoided in patients with hepatitis b co-infection. in patients with hepatitis b and renal dysfunction, the use of tdf may be considered with dosing frequency adjustment based on creatinine clearance (see package insert) and more frequent creatinine monitoring. if renal dysfunction is severe or renal function deteriorates with tdf, 3tc monotherapy (with or without pegylated interferon-alpha) should be considered. pegylated interferon-alpha is very costly. for further guidance: southern african hiv clinicians society. management of hiv-hepatitis b co-infection. southern african journal of hiv medicine 2011;12:27-33. 13.6 malaria there are several drug interactions between antimalarials and arvs: • artemether-lumefantrine (coartem) can be safely administered with nvp. there are no data yet on interactions with efv, but the combination is likely to be safe. boosted pis dramatically increase the plasma concentrations of lumefantrine, but a dose reduction is not recommended, as the toxicity threshold of lumefantrine seems to be high. close monitoring for toxicity is recommended when co-administering artemether-lumefantrine with art. • quinine concentrations are significantly decreased by lpv/r, probably due to induction of metabolism by ritonavir. it is likely that quinine concentrations will also be reduced by efv and nvp; therefore, quinine should be avoided in patients receiving pis or nnrtis. patients with severe malaria should receive artesunate and those with milder malaria should be treated with artemether-lumefantrine. • among drugs used for chemoprophylaxis, there are no clinically significant pharmacokinetic interactions between arvs and mefloquine or doxycycline. however, mefloquine and efv both cause frequent neuropsychiatric side-effects; therefore, doxycycline is the preferred chemoprophylactic agent for patients receiving efv. • there are several interactions with atovaquone-proguanil (malanil). atovaquone concentrations are reduced by pis and efv. it is also likely that nvp decreases atovaquone concentrations. proguanil concentrations are also reduced by pis and efv. use of atovaquone-proguanil is therefore best avoided in patients receiving pis or nnrtis. 14. arv toxicity monitoring and management currently used art is generally well tolerated. many adverse drug reactions are mild and occur only in the first few weeks of therapy. if toxicity does not resolve or is severe, then the offending drug should be substituted as indicated below. it is important to ensure that the viral load is suppressed before substituting a single drug, otherwise resistance may develop to the new drug, consequently compromising future regimens. single drug substitutions can be performed safely in the first 6 months of art without measuring the viral load. it is rarely necessary to stop the entire art regimen due to toxicity. it is advised to switch only the culprit drug and continue the rest of the art regimen. in certain life-threatening situations (e.g. hepatitis with liver failure, lactic acidosis), it may be necessary to cease use of all arvs. in patients with severe nnrti-related toxicity, a pi should be substituted. if this is undesirable (e.g. in a patient receiving tb therapy), use of the nnrti should be stopped and 2 nrtis should be continued for 1 week to reduce the risk of resistance developing to nnrtis, which have a long half-life. 14.1 haematological toxicity cytopaenias occur commonly in hiv infection without exposure to art. patients receiving azt, d4t or cotrimoxazole may experience abnormalities in their fbcs. significant bone marrow toxicity from cotrimoxazole generally only occurs with high doses used for treating opportunistic infections. patients receiving prophylactic cotrimoxazole uncommonly develop isolated neutropaenia. fbc monitoring is necessary with azt; this should be performed monthly for 3 months, then after 6 months of therapy and thereafter if clinically indicated (it is unusual to see haematological toxicity occurring after 6 months). the main problem arising from azt use is anaemia and neutropaenia; platelet counts generally rise with use of the drug. management guidelines are provided in table 11. macrocytosis is usual with d4t and azt therapy; there is no need to measure vitamin b12 and folate concentrations, unless there are other indications that these may be deficient. pure red cell aplasia, which presents with severe anaemia and low reticulocyte index, has rarely been associated with 3tc. a bone marrow examination should be performed to confirm the condition. parvovirus b19 infection should be excluded (a polymerase chain reaction (pcr) test should be requested on blood sent in an ethylenediaminetetra-acetic acid (edta) tube). table 11. guidelines for managing haematological toxicity (mainly azt-induced)           hb >8 g/dl monitor 7.0 7.9 repeat 4 weeks reduce azt 200 mg bd or consider switching azt 6.5 6.9 repeat 2 weeks consider switching azt <6.5 switch azt neutrophils 1 1.5x109 /l repeat 4 weeks 0.75 1.0 repeat 2 weeks 0.50 0.75 repeat 2 weeks consider switching azt <0.5 switch azt hb = haemoglobin; azt = zidovudine. 14.2 hepatotoxicity • liver function tests (lfts) should be performed at art initiation and measurement interval should be tailored thereafter to individual drug regimens. the full panel of lfts is expensive; therefore, it is recommended that only alt is monitored, as this is the most sensitive indicator of drug-induced liver injury. the full lft profile should be requested in patients with symptoms suggestive of hepatitis.
all arv classes have been associated with hepatotoxicity – most commonly nnrtis. the nrtis very rarely present with acute hepatitis. mild alt elevations occur very commonly and usually transiently with many drugs in general. alt elevations >5xuln are significant. • ideally, in patients starting nvp, alt should be monitored at 2, 4, 8 and 12 weeks after initiation. if monitoring is performed, a system should be in place to obtain the result and contact the patient; routine alt monitoring makes little sense in settings where the result will only be available when the patient is seen in 2 4 weeks, or where the patient cannot be contacted. it is essential to educate all patients starting nvp about the symptoms of hepatitis (nausea, vomiting, anorexia, malaise, jaundice and right upper quadrant pain) and drug rash, which is frequently associated with hepatitis. if such symptoms develop, alt should be determined urgently. • hepatotoxic drugs should be discontinued at high levels of lft abnormality (table 12) or at lower levels if any symptoms of hepatitis appear. rechallenge may be considered in selected cases; a specialist should be consulted. if hepatitis occurs together with a rash or fever, or with other systemic involvement, then rechallenge with nnrtis, abc or cotrimoxazole should not be attempted. table 12. guidelines for managing hepatotoxicity uln* <2.5 x uln 2.5 5 x uln >5 x uln alt monitor repeat at 1 week discontinue relevant drug(s) alp monitor repeat at 2 weeks ultrasound consider biopsy bilirubin repeat at 1 week discontinue relevant drug(s) discontinue relevant drug(s) *any elevations with symptoms of hepatitis (nausea, vomiting, right upper quadrant pain) should be regarded as an indication to stop relevant drugs. uln = upper limit of normal; alt = alanine transaminase; alp = alkaline phosphatase. • prolonged use of nrtis, especially d4t and ddi, may cause fatty liver. typically, alt concentration is more signficantly elevated than ast, and the concentration of cannalicular enzymes (ggt and alkaline phosphatase (alp)) is more significantly elevated than the transaminases. non-tender hepatomegaly may be present. ultrasound or computed tomography (ct) imaging may show decreased hepatic density. the condition is not benign and fibrosis has been reported with long-term ddi use. patients should be advised to avoid alcohol. patients receiving d4t or ddi should be switched to safer nrtis. • in patients with severe hepatitis or jaundice, the international normalised ratio (inr) should be assessed, as well as features of hepatic encephalopathy (i.e. features of hepatic failure). • if the concentration of cannalicular enzymes is more significantly elevated than alt, or if conjugated bilirubin is elevated, an ultrasound of the liver should be conducted to exclude biliary obstruction. • isolated unconjugated hyperbilirubinaemia (drug-induced gilbert’s syndrome) is associated with certain pis (idv and especially atv). although this is a benign condition, it is often cosmetically unacceptable to patients. • patients with underlying hepatitis b or c infection frequently experience a ‘flare’ of hepatitis when art is commenced, as a consequence of iris. hepatitis b can also flare when arvs that have activity against hepatitis b (tdf, 3tc and ftc) are discontinued or when hepatitis b resistance develops. • many other drugs can cause hepatotoxicity, notably anti-tb agents (including prophylactic isoniazid) and azoles. cotrimoxazole is a rare cause of hepatitis, usually with a cholestatic picture. 14.3 hyperlactataemia • this side-effect has become less common with fewer patients starting art with d4t and with the use of lower doses. however, clinicians should remain vigilant in patients receiving d4t and be aware that this side-effect can occur with all other nrtis, although very rare with abc, tdf, 3tc and ftc. mildly elevated lactate is not uncommon in patients treated with nrtis, but is generally asymptomatic. asymptomatic elevated lactate does not predict the development of lactic acidosis; it is therefore unnecessary to monitor levels in asymptomatic patients. • lactic acidosis is a serious, rare, potentially fatal side-effect of nrtis, most commonly associated with d4t, particularly when combined with ddi. symptomatic hyperlactataemia without acidosis is more common, but seldom seen with the safer nrtis recommended. • the combination of d4t and ddi is associated with a high risk of symptomatic hyperlactactaemia or lactic acidosis (particularly in pregnancy). this combination should therefore be avoided. • symptoms are non-specific and include nausea and vomiting, abdominal pain, dyspnoea, fatigue and weight loss. • risk factors for hyperlactataemia include: • female gender • obesity • the use of nrtis for >6 months • the development of nrti-induced peripheral neuropathy or fatty liver. • a raised lactate of >5 mmol/l together with metabolic acidosis confirms the diagnosis of lactic acidosis. low serum bicarbonate (<20 mmol/l) is the most sensitive marker of acidosis. associated abnormalities include elevated ast and alt, lactate dehydrogenase and creatinine kinase. treatment is supportive. high-dose riboflavin (50 mg) and l-carnitine may be used (no evidence for either intervention). management depends on the lactate and bicarbonate concentrations: • lactate <5 mmol/l and bicarbonate >20 mmol/l and minor symptoms. nrtis should be switched to agents less associated with hyperlactataemia: tdf or abc (if these are unavailable, then azt could be used) plus ftc or 3tc. symptoms and serial lactate should be monitored for several months (lactate levels decrease slowly over weeks). • lactate >5 mmol/l and bicarbonate >15 mmol/l. nrtis should be discontinued and the patient should be admitted. if the patient is on an nnrti regimen, a boosted pi should be added. if the patient has already failed an nnrti and is on a boosted pi, ral and/or etravirine (etv) should be added, if available, or the patient should be continued on the boosted pi only. when lactate has normalised, the patient should be switched to tdf or abc with 3tc or ftc, as above. • lactate >5mmol/l and bicarbonate <15 mmol/l. nrtis should be discontinued and the patient should be admitted, preferably to an intensive care unit. if the patient is on an nnrti regimen, a boosted pi should be added. if the patient has already failed an nnrti regimen and is receiving a boosted pi, ral and/or etv should be added, if available, or the patient should be continued on a boosted pi only. bicarbonate replacement is controversial, but most experts would use this strategy to partially correct severe acidosis. broad-spectrum antibiotics are recommended as sepsis can mimic nrti-induced lactic acidosis (this can be discontinued if procalcitonin is normal). on recovery, all nrtis should be avoided in future regimens (some experts would be prepared to use safer nrtis, as above). for further guidance: southern african hiv clinicians society. guidelines for the prevention, diagnosis and management of nrti-associated symptomatic hyperlactataemia and lactic acidosis. southern african journal of hiv medicine 2006;7:8-15. the potential of nrtis to cause elevated lactate varies (from most likely to least likely): stavudine/didanosine > zidovudine > tenofovir/emtricitabine/lamivudine/abacavir 14.4 dyslipidaemia • pis, with the exception of unboosted atv, can cause fasting hypertriglyceridaemia and elevated ldl-cholesterol. boosted atv is associated with less severe dyslipidaemia. d4t can cause mild hypertriglyceridaemia. pis are associated with the most marked elevation of triglycerides. efv can cause elevated total cholesterol and mild hypertriglyceridaemia. • diet and lifestyle modification should always be advised. diet is more effective for controlling hypertriglyceridaemia than hypercholesterolaemia. other cardiovascular risk factors should be addressed. • if patients receiving pis develop dyslipidaemia that warrants lipid-lowering therapy, they should be switched to boosted atv, if possible, rather than adding therapy for the dyslipidaemia. switching the pi to ral is another option, because ral has a favourable lipid profile. however, ral should only be used in a regimen with 2 other fully active drugs. • marked hypertriglyceridaemia (>10 mmol/l) can cause pancreatitis and requires urgent treatment with diet, fibrates and switching to boosted atv (fibrates can be stopped after 1 month followed by reassessment). indications for statin therapy in hiv-infected patients should be the same as in uninfected patients, according to the framingham heart disease risk score. many statins have interactions with pis that can lead to potentially toxic statin concentrations, with the exception of pravastatin and fluvastatin, which can be used without dose adjustment. atorvastatin concentrations are significantly raised by pis, but lower doses (e.g. 10 mg daily) can be used. lovastatin and simvastatin should not be co-administered with pis, as their concentrations are dramatically increased and severe rhabdomyolysis has been reported. • we suggest assessing lipids after 3 months on a pi regimen. if normal at this stage, the assessment should be performed annually only in those with other cardiovascular risk factors. 14.5 lipodystrophy • long-term art use may cause chronic lipodystrophic changes, with a change in body fat distribution. this can present with fat accumulation (visceral obesity, breast enlargement, ‘buffalo hump’ or lipomata) or fat loss (lipo-atrophy, presenting as facial, limb and buttock wasting) or with both. • the thymidine analogue nrtis (azt and especially d4t) are associated with fat loss. • previously, pis were thought to be the cause of lipohypertrophy. however, more recent studies have shown that all classes of arvs are associated with fat gain to the same extent. furthermore, longitudinal studies comparing hiv-uninfected people with hiv-infected people on long-term art have demonstrated that the extent and distribution of fat gain are similar. these data suggest that fat gain is a consequence of treating hiv. the appearance of the fat gain is particularly unsightly when accompanied by subcutaneous fat loss. • the re-distribution of body fat may be cosmetically unacceptable to the patient, resulting in discontinuation of art. • lipo-atrophy improves when d4t/azt is substituted with tdf or abc, but resolution is very slow and usually incomplete; therefore, it is important to recognise lipo-atrophy early or, better still, to use nrtis that are not associated with the condition. • there is no good evidence to support the switching of arvs in patients with fat accumulation. exercise is of some assistance in reducing abdominal fat. surgery should be considered in selected cases with focal fat gain (e.g. those with prominent ‘buffalo humps’). metformin modestly reduces weight and improves insulin resistance in patients with the metabolic syndrome or isolated dysglycaemia. • visceral fat accumulation is associated with insulin resistance and dyslipidaemia. other cardiovascular risk factors should be addressed in all patients. 14.6 hypersensitivity • rash with nnrtis is common (more severe and frequent with nvp) in the first 6 weeks of therapy. if the rash is accompanied by systemic features (e.g. fever, elevated alt or hepatitis), mucosal involvement or blistering, the nnrti should be discontinued immediately and rechallenge must not be performed. if the rash is mild and occurs without these features, the nnrti can be continued and the rash can be treated symptomatically with antihistamines and, possibly, topical steroids. systemic steroids should not be used. • in patients who develop rashes during the low-dose nvp ‘lead in’ phase (200 mg daily), the dosage must not be increased to 200 mg 12-hourly until the reaction has completely resolved. this ‘treat-through’ approach is only acceptable if the patient can carefully be observed, otherwise nvp should be substituted. • there is a possible cross-reaction between nvp and efv, although most studies report no evidence of this. it is acceptable to substitute efv for nvp in the event of hypersensitivity, unless the reaction was severe. there are hardly any data on substituting nvp for efv in the event of hypersensitivity; therefore, this substitution is not recommended.38 • abc hypersensitivity is primarily a systemic reaction occurring within the first 8 weeks of therapy in approximately 3% of cases. fatalities may occur on rechallenge. therapy must be discontinued and never re-introduced. the manifestations of hypersensitivity include fever, rash, fatigue and abdominal or respiratory symptoms. if there is any doubt concerning the diagnosis (e.g. if the patient has a cough with fever), then the patient should be admitted for observation. symptoms progress if hypersensitivity is present. the hypersensitivity reaction has been shown to occur on a genetic basis, being virtually confined to the hla-b*5701 allele, which is very uncommon in africans. if affordable and available, this allele should be excluded prior to using abc in populations where the allele occurs. 14.7 nephrotoxicity analysis for serum creatinine and urine proteinuria must be performed at baseline in all patients to detect sub-clinical renal disease, as there is an increased risk of renal failure in hiv infection due to a variety of causes. the dose of nrtis needs to be adjusted in renal failure (table 9). in a minority of patients, tdf may cause a tubular wasting syndrome (including wasting of phosphate and potassium). if patients receiving tdf develop muscle weakness or other muscle symptoms, then potassium and phosphate levels must be assessed. tdf can also cause acute renal failure, but this is uncommon. tdf should be discontinued immediately in patients with acute renal failure; it can be recommenced when the renal failure has resolved only if an alternative cause of renal failure is established. it is essential to estimate the creatinine clearance before commencing tdf, which should not be used if the clearance is <50 ml/min. for patients receiving tdf, creatinine should be monitored at 3 months, 6 months and then 6-monthly. in high-risk patients (particularly those with co-existent hypertension or diabetes), creatinine should also be checked at 1 and 2 months. long-term use of tdf with other nephrotoxic agents (e.g. aminoglycosides or nsaids) should be avoided. in patients in whom tdf is avoided because creatinine clearance is <50 ml/min at baseline, it may be possible to switch to tdf at a later point if renal function improves. this is often the case if patients had chronic diarrhoea or other opportunistic infections at the time of art initiation. 14.8 neuropsychiatric toxicity azt and ral frequently cause headaches when started, but this usually resolves. efv frequently causes neuropsychiatric effects in the first few weeks of therapy, typically presenting with insomnia, vivid dreams and dizziness. both dysphoria and euphoria may occur. fortunately, these features subside in the majority of patients within the first 4 6 weeks. psychosis may occasionally occur. if the neuropsychiatric effects of efv are not tolerated, then the patient should be switched to nvp or another alternative. 14.9 dysglycaemia the older pis, notably idv, may cause diabetes. however, the newer pis (atv, drv and lpv) do not. visceral fat gain, which occurs to a similar extent with all arv classes, is associated with insulin resistance. blood glucose should be assessed serially in these patients as part of a cardiovascular risk assessment. 14.10 gynaecomastia gynaecomastia involves the development of breast tissue in men. this is not related to lipodystrophy. it may be bilateral or unilateral. serum testosterone should be measured and replacement therapy given if this is low. gynaecomastia is most consistently associated with efv, so patients should be switched to nvp or another alternative. 15. immune reconstitution inflammatory syndrome (iris) approximately 10 20% of patients who start art with advanced immunosuppression experience clinical deterioration during the first months due to iris. two forms are recognised: unmasking iris occurs in patients who have an unrecognised opportunistic infection when art is started and who then present with an exaggerated inflammatory features of that infection during early art due to it being ‘unmasked’ by recovering immunity; paradoxical iris occurs in patients who are being treated for an opportunistic infection when they start art, but who develop an immune-mediated worsening or recurrence of features of that infection after starting art. iris is most frequently described in association with tb and cm. skin conditions such as molluscum contagiosum and kaposi’s sarcoma may also worsen due to iris. the diagnosis of iris can be difficult, mainly because there is no confirmatory diagnostic test. diagnosis relies on recognition of the characteristic clinical presentation, ensuring that opportunistic infection(s) are correctly diagnosed, and excluding alternative causes for deterioration such as drug resistance (e.g. mdr-tb). case definitions for tb and cryptococcal iris have been published.39 , 40 it is important to ensure that the underlying opportunistic infection is treated appropriately. art should be continued, unless iris is life-threatening (e.g. neurological involvement in tb-iris with depressed level of consciousness). corticosteroids have been shown to reduce morbidity and improve symptoms in paradoxical tb-iris,41 and can be used in mycobacterial and fungal forms of iris when other causes for deterioration have been excluded, and particularly when iris features are severe.42 practical guidelines for tb-iris management have recently been published.43 16. third-line art third-line art (also referred to as ‘salvage’ therapy) is used when a patient has experienced virological failure on drugs from the nrti, nnrti and pi classes (with documented pi resistance). before considering third-line therapy, adherence interventions should be intensified and, if there is still no viral suppression, a resistance test must be performed to confirm the presence of resistance to the pi being used in second-line therapy. this test is very expensive and the patient must be on the failing art at the time, as ‘wild-type’ hiv is more fit and outgrows the resistant mutant population which therefore cannot be detected within some weeks/months after cessation of art. however, third-line regimens are also extremely expensive and are not justified if the patient does not have resistance necessitating such a switch. data show that currently most patients failing second-line regimens in sa are infected with an hiv virus without pi mutations. in these patients, improved adherence is required rather than third-line regimens. the decisions regarding treatment choices in third-line therapy are complex and need to be guided by resistance patterns found on resistance testing. it is essential that resistance tests are interpreted in conjunction with a full art history by an expert. current international guidelines promote the idea that virological suppression is a realistic goal for third-line therapy. this is certainly true with the availability of several new classes of arv agents (entry inhibitors and instis) together with newer pis (drv and tipranavir) and nnrtis (etv).44 as these drugs become available in the region for patients who require them, they provide the possibility of effective suppression with third-line therapy. drv, etv and the insti ral are now registered in south africa. no firm recommendations for a generic third-line regimen can be made and regimen choice should be individualised. an expert treater should always be consulted. a few guidelines regarding third-line art regimens are further discussed: • there is a need for specific adherence counselling in patients preparing to start third-line art, with a frank discussion that this regimen is likely to be their last option for the foreseeable future. • first-generation nnrtis (nvp and efv) have no place in third-line therapy as they do not impair viral fitness. • a boosted pi with the broadest resistance profile should be selected (this is currently drv).45 drv must be used twice daily in this context (600 mg 12-hourly with 100 mg ritonavir 12-hourly). lpv may be used if the drug is still active based on a resistance test (e.g. if the patient failed second-line atv therapy). • the addition of 3tc (or ftc) is recommended as the m184v mutation that it selects for impairs viral replication. other nrtis (the most active based on resistance testing) should also be added. • consideration of the addition of other salvage drugs (e.g. ral46 and/or etv47 , 48 ) will depend on genotype resistance test result and cost issues. ral is preferred because it belongs to an entirely new class with no risk of cross-resistance from prior art exposure in firstand second-line therapy. because most patients are not receiving an nnrti at the time of failing second-line therapy when a genotype resistance test is typically performed, prior nnrti mutations related to first-line nnrti failure may be archived at this time. therefore, it is difficult to be certain from this genotype as to whether etv is compromised; however, data from south africa suggest that the majority of patients who have failed nvp or efv are still susceptible to etv.49 • we advise against double ritonavir-boosted pis.1 • if viral suppression is not achieved on salvage therapy, there is still benefit in continuing failing art because of the residual partial activity and ‘crippling’ effect of such art. ‘crippling’ describes the fact that mutant viruses often have less replicative capacity. provided that the viral load can be maintained below 10 000 copies/ml, the cd4 count will usually be maintained or even increase.30 for further guidance, the southern african hiv clinicians society will be publishing art resistance guidelines in late 2012. 17. support and counselling 17.1 art-related counselling many patients are afraid of starting art. the patient should be reassured that the drugs work and that side-effects are usually minor and transient, or manageable. the patient should be given a treatment plan, specifying the reasons for commencing therapy and the drugs to be used (with names and details including the appearance of each drug, when and how they are to be taken, and a brief indication of anticipated side-effects and toxicity). adherence in the order of 95 100% is required for virological suppression. poor adherence results in the development of drug resistance. the desire to stop therapy or alter the number or timing of the drugs must be avoided. the patient must be encouraged to discuss drug-related issues with his/her clinician before any changes are made. 17.2 lifestyle, nutrition, traditional medication and supplements a healthy lifestyle is recommended, including a balanced diet, plenty of exercise, giving up smoking, moderating alcohol and having a positive outlook on the future. various adjuncts to therapy are widely used in the community. these include specific diets, food/nutritional supplements, vitamins and so-called immune ‘boosters’. scientific evidence to support the use of these is largely absent. some herbs and high doses of trace elements and fat-soluble vitamins may cause harm and ought to be discouraged. there are also potentially important drug interactions between some herbal remedies and arvs. for further guidance: southern african hiv clinicians society. nutrition and hiv/aids: nutritional guidelines for hiv-infected adults and children in southern africa: meeting the needs. southern african journal of hiv medicine 2007;8:22-32. southern african hiv clinicians society. nutrition and hiv/aids: nutritional guidelines for hiv-infected adults and children in southern africa: meeting the needs. southern african journal of hiv medicine 2008;9:34-59. 17.3 immunisations hiv infection is associated with a suppression of both humoral and cell-mediated immune response, which may impair the response to vaccinations reducing their efficacy, especially if the cd4 count is <200 cells/μl. the safety of live attenuated vaccination is also modified by hiv-infection and live vaccines are contra-indicated in symptomatic hiv disease or if the cd4 count is <200 cells/μl. the decision to use a vaccine must be based on best assessment of risks and benefits. travellers to areas endemic for malaria and yellow fever need to be cautioned. the forested regions where contact with the mosquito vector and the virus is possible must be avoided. yellow fever vaccination poses a risk to hiv-positive travellers whose cd4 count is <200 cells/μl. such persons should be encouraged to make alternative arrangements or to travel with documentation that permits travel without prior vaccination. 17.4 opportunistic infections the use of appropriate prophylaxis (primary or secondary) is essential in patients initiating art. in general, prophylaxis can be discontinued once the cd4 count has increased to 200 cells/μl (but certain minimal durations of prophylaxis apply for secondary prophylaxis – local and international guidelines should be consulted). funding and support. this work is supported and funded by the southern african hiv clinicians society through an educational grant from atlantic philanthropies. conflict of interest. all expert panel members have completed and submitted conflict of interest disclosure forms. disclosure information represents the previous 3 years (updated 17 august 2012) and includes relationships with pharmaceutical companies and medical aids: dr francesca conradie has received support from abbott to attend conferences, and research support from tibotec. she has also received honoraria for speaking engagements from abbott and msd. dr hefer has received support to attend conferences from abbott, adcock ingram, aspen and msd. he owns shares in lifecell and has received honoraria for speaking engagements from abbott, aspen and msd. dr johnson has received research support from bristol myers squibb (bms), msd, tibotec and schering-plough. he has also received honoraria for speaking engagements from abbott. professor graeme meintjes has received honoraria for speaking engagements from sanofi aventis and serves as a consultant for aid for aids. professor yunus moosa has received support to attend conferences from abbott and honoraria for speaking at conferences/seminars from abbott, aspen, msd and pfizer. dr theresa rossouw serves as a consultant for discovery health. dr ebrahim variava receives support for clinical trials from outsuka. professor francois venter has received support to attend conferences from adcock ingram and msd; honoraria for speaking engagements from msd; and has served as a consultant for abbott, johnson and johnson and tibotec. dr eric goemaere, professor gary maartens, dr moeketsi mathe, dr regina osih and dr gilles van custem report no conflicts of interest. references 1. petersen ml, wang y, van der laan mj, rhee sy, shafer rw, fessel wj. virologic efficacy of boosted double versus boosted single protease inhibitor therapy. aids 2007;21(12):1547-1554. 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[http://dx.doi.org/10.1016/s0140-6736(07)61048-4] 49. stevens ws, wallis cl, sanne i, venter f. will etravirine work in patients failing nonnucleoside reverse transcriptase inhibitor-based treatment in southern africa? j acquir immune defic syndr 2009;52(5):655-656. [http://dx.doi.org/10.1097/qai.0b013e3181ba1b00] 49. stevens ws, wallis cl, sanne i, venter f. will etravirine work in patients failing nonnucleoside reverse transcriptase inhibitor-based treatment in southern africa? j acquir immune defic syndr 2009;52(5):655-656. [http://dx.doi.org/10.1097/qai.0b013e3181ba1b00]   appendix: who stage 3 and 4 conditions (2006 revision) who stage 3 conditions • unexplained severe weight loss (over 10% of presumed or measured body weight) • unexplained chronic diarrhoea persisting for longer than 1 month • unexplained persistent fever (intermittent or constant for longer than 1 month) • persistent oral candidiasis • oral hairy leukoplakia • pulmonary tb (current) • severe bacterial infections (e.g. pneumonia, empyema, pyomyositis, bone or joint infection, meningitis, bacteraemia, severe pelvic inflammatory disease) • acute necrotising ulcerative stomatitis, gingivitis or periodontitis • unexplained anaemia (<8 g/dl), neutropaenia (<0.5x109 /l) and/or chronic thrombocytopenia (<50x109 /l). who stage 4 conditions • hiv wasting syndrome • pneumocystis pneumonia • recurrent severe bacterial pneumonia • chronic herpes simplex infection (orolabial, genital or anorectal of more than 1 month’s duration or visceral at any site) • oesophageal candidiasis (or candidiasis of trachea, bronchi or lungs) • extrapulmonary tb • kaposi’s sarcoma • cytomegalovirus infection (retinitis or infection of other organs) • central nervous system toxoplasmosis • hiv encephalopathy • extrapulmonary cryptococcosis including meningitis • disseminated non-tuberculous mycobacteria infection • progressive multifocal leukoencephalopathy • chronic cryptosporidiosis • chronic isosporiasis • disseminated mycosis (extrapulmonary histoplasmosis, coccidiomycosis) • recurrent septicaemia (including non-typhoidal salmonella) • lymphoma (cerebral or b cell non-hodgkin) • invasive cervical carcinoma • atypical disseminated leishmaniasis • symptomatic hiv-associated nephropathy • symptomatic hiv-associated cardiomyopathy. supplementary material 1. starting art in hospital starting art in eligible patients in an inpatient setting can be considered in certain circumstances, and should be strongly considered during prolonged hospitalisation, where adherence, toxicity management and other support can be directly provided. however, limited data have shown what many experienced clinicians predicted – that patients who are initiated on art within the hospital have high default rates. this may be due to several factors – patients who wait to become severely ill and enter hospital may still have high levels of denial; they may be too ill to take in adherence counselling; and discharge may not be managed well. the clinician must carefully weigh up the high risk of deferring art in terms of mortality and morbidity, and the risk for the individual patient of default which cannot easily be predicted.  if a patient is considered for initiation in hospital, the following should be attended to: in hospital • before discharge, the patient must understand the reasons for initiation of art • if the patient is too ill/not mentally competent, a caregiver and/or family member who will act as a directly observed therapy supporter should be involved • care should be exercised regarding art drug interactions with concomitant medication. on discharge • give very clear art clinic directions, with a referral letter and details of documentation needed by the clinic • patients should be encouraged to attend the art clinic as soon as possible for an appointment and should be informed of reasonable clinic appointment waiting times • sufficient medication must be provided to last to the art clinic visit • these patients are often discharged on newly initiated tb treatment; few programmes as yet offer integrated tb/art clinical services, and the need for separate clinical visits should be carefully explained • discharging patients directly into the care of adequately counselled family members can be invaluable. 2. high-risk patients patients who are at high risk for early mortality, iris and art side-effects include: • patients with a low bmi, anaemia and low albumin levels • patients with newly diagnosed opportunistic illness, especially tb and cm • patients with low cd4 counts. these patients should be initiated on art as quickly as possible after any underlying opportunistic illnesses have been addressed (note the specific guidelines regarding art timing in tb and cm in the guidelines), and should be counselled about the risk of iris, which may be misinterpreted as art side-effects. ideally, patients should have access to rapid referral systems, in the events of experiencing complicated iris or side-effects. in addition, patients with any of the following are at high risk of default or inadequate adherence: • uncontrolled depression • poverty • ambivalence about their hiv status • distrust of the formal health sector • lack of home support or high levels of community stigma • alcohol or other substance abuse • post-partum women. adherence issues are addressed in the southern african antiretroviral resistance treatment guidelines, and include attention to treating mental illness and substance use, giving access to support groups, addressing potential workplace related issues including drug toxicity issues, additional counselling if denial is an issue, honest discussions about alternative health providers and churches that may undermine adherence, better post-partum integration of women/child hiv services, and actively linking poorer patients to poverty alleviation programmes. 3. common art misconceptions • you cannot take art if you do not have food available. none of the commonly used firstand second-line options have meaningful food restrictions. patients should be warned that their appetite may return and that this may even be uncomfortable. however, food insecurity should be managed actively through rapid referral, and this should never be a reason to delay art initiation. • doses need to be taken at precisely the same time each day. this myth was especially prevalent in the earlier days of art, with anecdotes of patients returning to clinic in despair, after having interrupted their therapy for several weeks after missing a dose due to oversleeping by an hour. encouraging patients to establish a routine helps with adherence, but delayed dosing is rarely a problem, even if out by many hours. most of the drugs have long half-lives, and patients should be told simply to take their dose once they remember to do so. • you must never drink alcohol again. heavy alcohol use may affect adherence, and may potentiate the hepatic toxicity of art and other hepatic pathology. however, data do not support the commonly held notion that alcohol speeds up the progression to aids, nor is there any evidence that moderate alcohol use has any negative effect on the health of hiv-positive individuals. local guidelines for the general population around responsible alcohol use should be followed; prohibition is not advocated. • disclosure is a prerequisite for art. this myth probably followed early experiences with highly rationed art, where all possible adherence strategies were aggressively pursued to optimise outcomes, and bringing in a ‘treatment buddy’ was required to access art. however, it became a form of punishment by some unsophisticated counsellors and clinicians, often under the pretext of preventing transmission, through making hiv status public. this tactic is almost certainly illegal and certainly unethical, and while disclosure may assist patients with support and adherence, this should be suggested and based on the patient’s individual circumstances. forced disclosure can result in violence at the hands of a partner or community, and undermines confidence in confidentiality within the entire health system. patients should be counselled about the pro’s and cons of disclosure, and assisted through the process as needed. • unprotected sex causes virological failure. this myth probably emerges from a convoluted understanding of the transmission of resistant virus. theoretically, unprotected sex with someone who is failing art may allow for the passage of resistant virus, but this is unusual. patients should be counselled about safe sex, however, unprotected sex itself will not result in virological failure. 4. adherence interventions causes of poor adherence are often complex and linked to social issues. common causes include: • inadequate treatment literacy. most hiv programmes have extraordinary adherence rates when compared with other chronic diseases; this is largely due to effort being made to ensure patients understand hiv. if a patient fails therapy, some examination of the pre-art counselling may be merited. • side-effects. side-effects are a very common reason for patients to default therapy. a careful history of often subtle but distressing side-effects (bad dreams, sleepiness, poor concentration, nausea, loss of appetite, change of body shape), in conjunction with a work history (shift work in particular) may allow for drug substitutions. subtle lipo-atrophy changes from d4t and azt are often not taken seriously by healthcare providers, until disfiguring. regular enquiry and immediate drug substitutions where possible should form part of every healthcare worker encounter. • depression and other mental illnesses. undiagnosed or under-treated depression and other mental illness (the frequency of major depression is 2 times higher in hiv-positive subjects than in matched hiv-negative subjects) may undermine adherence. patients with depression usually respond well to an anti-depressant medication in combination with non-pharmaceutical interventions. if they do respond it should be given for at least 6 months. • poverty and food insecurity. both of these have been related to poor adherence and increased missed clinic visits. patients often lose their jobs due to ill health during the period leading up to art initiation, and should be encouraged to return to the job market as soon as feasible or to seek support. this may lead to moving away from the art clinic, and referral must be facilitated. access to available grants, social support and employment non-governmental organisations (ngos) may provide additional support. • work-related issues. these include shift work and ability to attend clinic visits on weekdays. they are a major cause of poor adherence. long clinic waiting times, including monthly pick-ups, may make holding down a job untenable, especially with an unsympathetic employer. clinicians should try to encourage clinics to be flexible, run smoothly for healthy patients, and provide 3 6-monthly pharmacy refills. • substance use. excessive alcohol use may cause significant problems with adherence. in addition, other recreational drugs may cause problems in certain parts of the country, and use fluctuates according to availability and fad. • social problems. stigma and poor social support networks. perceived stigma is correlated with poor adherence; this may manifest in a fear of tablets being found, an inability to solicit family or partner support, or anxiety regarding an employer, neighbours or a community. social support groups may assist. • denial. initiation of ambivalent, conflicted patients on art is unlikely to have a successful outcome. involvement of family members and partners may be an effective mechanism for addressing denial. • pill burden. this is less of an issue than previously, but must be considered in patients who are failing treatment. dosing simplification should be a major part of advocacy within public sector programmes. • altered fertility intentions. hiv-discordant or -concordant couples may spontaneously decide to cease their art regimen as they intend to begin a family; sympathetic and facilitatory fertility counselling during art initiation counselling, should prevent this. • conflict of opinions. conflict of opinions on the use of arvs occurs frequently between healthcare providers, certain alternative health providers and churches. this is best addressed with an honest and non-judgmental conversation practical adherence tools tools such as pillboxes, diaries and setting alarms may help patients to remember to take their medication. having an emergency supply of a single dose on hand (e.g. in the handbag or workbag) may be useful for situations when patients have unexpected delays in getting home. medicine formulations and trade names may change, and patients should be educated to recognise the generic name of their current regimen to avoid confusion. acknowledgements references about the author(s) edwin cameron judicial inspectorate of correctional services, pretoria, south africa citation cameron e. introduction to the southern african hiv clinicians society harm reduction guidelines. s afr j hiv med. 2020;21(1), a1179. https://doi.org/10.4102/sajhivmed.v21i1.1179 editorial introduction to the southern african hiv clinicians society harm reduction guidelines edwin cameron copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. lawyers have done much damage in south africa. apartheid was enforced, minutely and brutishly, through the law. its central weapon, viciously wielded, was the criminal law. that legacy looms large over our still-new, still-nascent constitutional democracy. it is particularly painful in the case of people who use drugs. for more than 50 years, the criminal law has waged war on people who use drugs. the consequences have been deadly. criminalising people who use drugs is not only vicious, as apartheid’s laws were. it is stupid, and ineffective. it does nothing to diminish the use of drugs. prisons rarely advance rehabilitation, and indeed prison is no place where someone dependent on drugs could hope to resolve their dependence or find ‘rehabilitation’. globally, leaders and institutions, including the united nations, have conceded this. they now acknowledge that criminalising people who use drugs is not an appropriate solution and that treating them as criminals inflicts significant harm on society. in south africa, the debate has been muted. current policies rely on a criminal justice response to drug use. so far, this has attracted little public criticism, although former president motlanthe has recently added his considerable stature to the call to decriminalise drug use: he has spoken out strongly against prohibition, repression, harsh penalties and prison for drug-related offences.1 it is notable and timely that in june 2019 the southern african hiv clinicians society (sahcs) published a position paper supporting decriminalisation of drug use. like sex, the pursuit of mind-altering substances is part of being human.2 this seemingly radical statement is in fact an inoffensive truism. and hence, as with sex, the ‘just say no’ message is futilely misplaced in reducing transmission of human immunodeficiency virus (hiv) between people who use drugs. furthermore, research has established that people who use drugs are not a homogeneous group, and the drug experience is mediated by not only the pharmacology of the drug but also individual vulnerabilities and mindsets, in addition to the context in which the drugs are used.3 the majority of people who use drugs will not suffer harmful consequences. however, misguided application of the criminal law inflicts harm, disastrously. people who are marginalised, excluded and stigmatised are far more likely to suffer harm from their drug use, as well as become addicted to drugs.4 recent years have seen an increase in the use of drugs in south africa, as well as in the numbers of people dependent on heroin. the use of drugs like nyaope, whoonga and unga is increasing, as is the injecting of heroin and stimulant drugs.5 this calls, imperatively, for harm reduction services, including providing sterile injecting equipment. but they are absent. this invites an increase in blood-borne infections. the prevalence of hiv amongst people who inject drugs is 21%, and the rate of hepatitis c is 55%. the joint united nations programme on hiv/aids (unaids) warns, if south africa does not take action now, it will never reach the 2020 fast track targets for hiv reduction that we missed.6 here, history grimly repeats itself. the barriers people with and at risk of hiv and acquired immunodeficiency syndrome (aids) faced are strikingly similar to those people using drugs face now: fear, exclusion, stigma, prejudice, disregard of human rights, science and compassion. instead, there is the terribly misplaced invocation of the criminal justice system. there is an underlying and deep-rooted belief that deviance must be punished. the crude remedies that inflicted apartheid are reassigned to persecute people who use drugs (the same is true in the case of sex workers and people not conforming to traditional gender constructs). criminalising people who use drugs is a damaging distraction from the most effective means we have to reduce the consequences of drug use: harm reduction. harm reduction is a practical and rights-informed approach to assist people in reducing drug-related harms and to support them in changes they seek to make. conceived in the 1980s, from the imperative to stop the rapid spread of hiv amongst people who use drugs, the harm reduction movement has been fostered by hiv activists and hiv clinicians. therefore, it is fitting that sahcs leads. these harm reduction guidelines embody empirically indicated and rights-respecting doctrine in both decriminalising drug use and adopting best clinical practice to reduce the spread of hiv and other blood-borne viruses amongst people who use and inject drugs. the guidelines make sound sense. not only do they build on the statement supporting the decriminalisation of the use of certain drugs, but they also take a public health approach rather than an abstinence and recovery-focused approach. also, they take into account the context, that is, what components drive the dependent and habitual use of drugs? valuable lessons we learned from the response to hiv apply to people who use drugs. whilst people who use drugs may need health services, pathologising them inflicts significant stigma and exclusion. we fail in our response to people who use drugs by simplistically depicting them as either prisoners or patients. they are first and foremost people, who have the constitutionally enshrined right to be treated with dignity and to receive the highest standard of care available. the lessons are clear. countries that have embraced the principles of harm reduction have seen a reduction in the rates of hiv infection. they have benefited from lower overdose deaths and reductions in the adverse health, social and economic consequences from the use of drugs.7 of course, harm reduction is not without its critics, even within the medical community. the counter-arguments proceed principally from moral axiom. the belief that people should be abstinent from drugs is as misguided as the belief that hiv can be prevented by teaching people to abstain from sex. to deny people harm reduction services echoes the damage that refusing to make condoms available futilely inflicted. the policy landscape in south africa has shifted, and for the first time, harm reduction is described in the national drug master plan. however, this needs to be backed by political determination. we must replace the misplaced abstinence-based approach with an approach proven to help reduce the consequences of using unregulated drugs. without addressing the underlying motivators, addressing drug use in isolation will seldom help. the guidelines are, therefore, more than a simple set of algorithms or treatment regimens. they describe the reasons why people may develop problematic drug use, the systemic and contextual issues, psychosocial and biomedical intervention and evidence-based approaches for more vulnerable populations. even amongst clinicians, there are gaps in understanding people who use drugs and their medical needs. the guidelines are timely and well-directed, in supporting clinicians who engage with and treat people who use drugs. it is imperative that they are used and disseminated widely. south africa is burdened in many areas by shame, including internalised shame and stigma.8 these hobble the power of people to act fully as citizens; they isolate people and allow anger and fear to amass. the notion that all people who use drugs are selfish, dishonest or powerless risks becoming self-fulfilling. these guidelines counter internalised stigma by including the voices of people who use drugs. this step is not radical. it is elementary. and essential. these guidelines are most welcome. they afford an essential scientific, pragmatic and effective patient-centred resource for clinicians. they fill a critical gap in our response to hiv. their sound professionalism and evidence-based wisdom will contribute to the policy shifts we critically need, if south africa’s response to people who use drugs is to meet the standards of the constitution. acknowledgements the author would like to thank shaun shelly for assistance in conducting this research. competing interests the author declares that no competing interest exists. authors’ contributions i declare that i am the sole author of this research article. ethical consideration this article followed all ethical standards for research without direct contact with human or animal subjects. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions presented in this article are those of the author alone and do not necessarily reflect the official policy or position of any affiliated agency of the author. references let’s admit we were wrong (with former president olusegun abasanjo of nigeria) [homepage on the internet]. [cited 2020 oct 02]. available from: https://idpc.net/alerts/2020/09/drugs-let-s-admit-we-were-wrong siegel r. intoxication: the universal drive for mind-altering substances. rochester, vermont: park street press; 2005. zinberg n. drug, set and setting: the basis for controlled intoxicant use. new haven, ct: yale university press; 1984. alexander bk. the globalisation of addiction. a study in poverty of spirit. oxford, united kingdom: oxford university press; 2008. dada s, harker n, jodilee b, et al. phase 44. cape town: sa medical research council; 2019. unaids. south africa [homepage on the internet]. [cited no date]. available from: https://www.unaids.org/en/regionscountries/countries/southafrica harm reduction international. the global state of harm reduction 2018. 6th ed. london: harm reduction international; 2018. cameron e. how we internalise shame and stigma [homepage on the internet]. 2018 [cited 2020 oct 02]. available from: https://www.groundup.org.za/article/how-we-internalise-stigma-and-shame/ abstract adolescent human immunodeficiency virus risk and pre-exposure prophylaxis the public health and human rights imperative to ensure adolescent access to pre-exposure prophylaxis the current legal framework for child consent to health interventions establishing the meaning of a statutory term implications of pre-exposure prophylaxis falling within the scope of medical treatment for adolescent consent approaches conclusions and recommendations acknowledgements references about the author(s) ann strode school of law, college and law and management sciences, university of kwazulu-natal, pietermaritzburg, south africa hiv/aids vaccines ethics group, school of applied human sciences, college of humanities, university of kwazulu-natal, pietermaritzburg, south africa catherine m. slack hiv/aids vaccines ethics group, school of applied human sciences, college of humanities, university of kwazulu-natal, pietermaritzburg, south africa zaynab essack school of law, college and law and management sciences, university of kwazulu-natal, pietermaritzburg, south africa center for community-based research, human and social capabilities division, human sciences research council, pietermaritzburg, south africa jacintha d. toohey school of law, college and law and management sciences, university of kwazulu-natal, pietermaritzburg, south africa linda-gail bekker the desmond tutu hiv centre, university of cape town, cape town, south africa citation strode a, slack cm, essack z, et al. be legally wise: when is parental consent required for adolescents’ access to pre-exposure prophylaxis (prep)?. s afr j hiv med. 2020;21(1), a1129. https://doi.org/10.4102/sajhivmed.v21i1.1129 original research be legally wise: when is parental consent required for adolescents’ access to pre-exposure prophylaxis (prep)? ann strode, catherine m. slack, zaynab essack, jacintha d. toohey, linda-gail bekker received: 13 july 2020; accepted: 20 aug. 2020; published: 10 nov. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: south african adolescents (12–17 years) need an array of prevention tools to address their risk of acquiring the life-long, stigmatized condition that is hiv. prevention tools include pre-exposure prophylaxis (prep). however, service providers may not be clear on the instances where self-consent is permissible or when parental consent should be secured. aim: to consider the legal norms for minor consent to prep using the rules of statutory interpretation. setting: legal and policy framework. results: we find that prep should be interpreted as a form of ‘medical treatment’; understood broadly so that it falls within the ambit of one of consent norms in the children’s act. when prep is interpreted as ‘medical treatment’, then self-consent to prep is permissible for persons over 12 years, if they have the mental capacity and maturity to understand the benefits, risks, social and other implications of the proposed treatment. currently, prep is only licensed for persons over 35 kg. reaching the age of 12 years is a necessary but not sufficient criteria for self-consent and service-providers must ensure capacity requirements are met before implementing a self-consent approach. decisional support and adherence support are critical. conclusions: we recommend that service-providers should take steps to ensure that those persons who meet an age requirement for self-consent, also meet the capacity requirement, and that best practices in this regard be shared. we also recommend that policy makers should ensure that prep guidelines are updated to reflect the adolescent consent approach articulated above. it is envisaged that these efforts will enable at-risk adolescents to access much needed interventions to reduce their hiv risk. keywords: parental consent; self-consent; hiv; prevention; minors’ capacity. adolescent human immunodeficiency virus risk and pre-exposure prophylaxis globally young people are especially vulnerable to human immunodeficiency virus (hiv).1,2,3,4 human immunodeficiency virus prevalence amongst adolescents and young adults in south africa remains skewed. in 2017, the hiv prevalence amongst females was higher than their male counterparts (5.8% vs. 4.7% amongst 15–19 year olds and 15.6% vs. 4.8% amongst 20–24 year olds).5 in the same year, 66 000 new hiv infections occurred amongst adolescent girls and young women in south africa.5 likewise, young men having sex with men (msm) in south africa are highly vulnerable to hiv infection.5 there is now good evidence that oral pre-exposure prophylaxis (prep) taken daily, as part of a combination prevention package, can protect hiv-negative adults against hiv acquisition.6,7,8,9 the us federal drug administration has, based on safety data, licensed oral combination of tenofovir (tdf)/emtricitabine (ftc) for hiv prevention for at-risk adolescents with body weights above 35 kg (bekker, personal communication, 9 jun 2020). the south african health products regulatory authority (sahpra) has similarly approved a fixed-dose combination of tenofovir disoproxyl fumarate and emtricitabine for prep (for adults and adolescents > 35 kg).7 in addition to oral prep, which is proven and registered for use as hiv prevention, there are additional prep options that have different routes of administration and less frequent dosing including long-acting injectable prep and vaginal rings. these are at various stages in the development pipeline, with the dapivirine vaginal ring furthest along also currently under review by regulatory agencies. this means adolescents may soon have more choices about the form of prep available to them (bekker, personal communication, 9 jun 2020). providing at-risk populations with access to prep is described as a key objective within the south african national strategic plan on hiv, tuberculosis (tb) and sexually transmitted infections (stis): 2017–2022.9 initially, the department of health operationalised this objective by targeting sex workers and msm, but this has now been expanded to include other at-risk populations such as university students and young women.10 to date public sector roll-out has lagged, and prep is mostly available through demonstration projects, clinical research sites and the private healthcare sector.11,12 however, south africa is now in the process of expanding access, with 3000 facilities being able to provide oral prep. within this community-based approach, self-presenting adolescents who are > 35 kg and are deemed to be at risk of hiv acquisition will be eligible to access oral prep. although prep is registered for use in persons > 35 kg, there is no policy that deals with consent to this product by persons under 18 years. for example, the current south african hiv clinicians guidelines do not address the consent approach for adolescent access to prep. these guidelines are currently being updated, and it is understood that the new version which will be published in november 2020 will include a recommended consent approach for persons under 18 years.12 the unintended consequences of this lack of policy on adolescent consent to prep is that it is unclear whether adolescents can self-consent or require parental consent for access to prep. in this article, we describe the current legal framework for adolescent consent to health interventions including ‘medical treatment’. we examine whether adolescents can consent independently for prep in terms of the current legal framework. we conclude with our position on an appropriate consent strategy and recommend that the department of health revise current prep policies to provide certainty on this issue. it should be noted that although this article focusses on adolescent consent to prep, it has a broader application. as described here, a key issue in the current legal framework is whether the term ‘medical treatment’ in the children’s act, 200513 is broad enough to encompass prevention interventions such as vaccines. this has implications for adolescent consent to the human papillomavirus (hpv) vaccine and other non-therapeutic health interventions. the public health and human rights imperative to ensure adolescent access to pre-exposure prophylaxis it is both a human rights and public health imperative to ensure that adolescents have access to tools to minimise their hiv risk.4 access requires an evaluation of barriers, including legal barriers in the form of parental consent requirements.2 research from the united states of america has shown that parental consent may act as a legal barrier to adolescents accessing sexual and reproductive health services.14 one study indicated that up to one-fifth of adolescents who were surveyed did not want their parents to be involved in the consent process.15 other studies have shown, for example, that a greater number of adolescents volunteered for services such as hiv testing once they were able to provide independent consent.15 furthermore, many adolescents are deterred from accessing abortion and contraception services by parental consent because they fear parental disappointment, sanction or retaliation.15 similarly, there are concerns that parental consent might impede access to hiv prevention packages for adolescents for similar reasons.4,16 the current legal framework for child consent to health interventions self-consent to specified health interventions the children’s act states that full legal capacity is attained at 18 years; however, persons below this age may, in certain circumstances, legally self-consent to a range of specified health services, as we have noted elsewhere.2,3,16 sections 12 and 129–135 of the children’s act13 deal with the consent requirements for medical treatment, surgical operations, hiv testing, male circumcision and contraceptives.2,3 the children’s act refers expressly to three current forms of hiv prevention, namely male circumcision, condoms (under contraceptives) and hiv testing, and sets ages at which adolescents may self-consent to the intervention. as set out in earlier articles, consent to ‘medical treatment’ is a general category in the act that covers a range of non-specified health interventions.13 section 129 provides that a child may consent independently to ‘medical treatment’ if they are older than 12 years and they have the ‘mental capacity to understand the benefits, risks, social and other implications’ of the proposed treatment.2,3 if a child is below the age of 12 years or lacks capacity, proxy consent must be provided by a parent, guardian or care-giver amongst others.2,3 self-consent to non-specified health interventions whilst the children’s act provides clarity on consent to most medical interventions for children under 18 years, it does not directly address the age at which adolescents might self-consent to non-specified preventive interventions such as prep. there are two implications of this lacuna. firstly, if the children’s act or any other legislation does not set an age of independent consent to a health service or if the child is below the age specified in law for independent consent, then parental or guardianship consent will be required.2,3 or, secondly, if the intervention is not listed, one could examine any of the other specified health interventions and establish whether they could encompass it. in this instance, the only broad health service that an adolescent can self-consent to is ‘medical treatment’. thus, one must ask whether something that is not directly therapeutic in nature falls within the ambit of term ‘medical treatment’. establishing the meaning of a statutory term where the breadth of a statutory term is unclear, it requires a process of interpretation to establish its scope. there are various approaches to statutory interpretation. firstly, one can use internal aids such as definitions in the act. the children’s act does not contain a definition of ‘medical treatment’ nor does it list a gamut of the therapies that may fall under its umbrella. furthermore, there is no definition of the term in other legislation. if we use external aids to statutory interpretation such as a dictionary, there are variations in the way they define ‘medical treatment’. some recognise medical treatment as an ‘action or manner of treating a patient medically or surgically’.17 ‘medically’ is further defined as ‘a way that relates to medicine’,18 and others define the term around the objectives of the treatment, for example ‘the use of drugs, exercises, etc. to improve the condition or an ill, injured person, or to cure disease’.19 neither definition refers expressly to medical treatment including preventing an illness that a healthy person is at risk of contracting. where there is limited assistance from internal or external aids the general principles of statutory interpretation must be used. in the constitutional court judgement of cool ideas 1186 cc v hubbard and another, the court identified three interconnected elements of statutory interpretation.20 firstly, an examination of the purpose of the provision.21 secondly, a review of its legislative context.20 thirdly, identifying a meaning, which is consistent with the values underlying the constitution.20 the constitution also provides in section 39 that courts may consider foreign law when interpreting rights.19 firstly, if we apply the principles established in the cool ideas case, one must establish the purpose of the provision. the term is used within chapter 7 of the children’s act, which is headed ‘protective measures relating to health of children’.13 as stated here, this section deals largely with consent to a range of health interventions. in the preamble to the act, one of its stated purposes is to ‘make provision for structures, services and means for promoting and monitoring the sound physical, psychological, intellectual, emotional and social development of children’ and ‘to promote the protection, development and well-being of children’.13 it is submitted that in the light of this discussion, the primary purpose of the consent provisions are to protect children from being treated without informed consent and to ensure their physical well-being is promoted. secondly, regarding the context of the provision within the act the term is used in a chapter on the protection of the health rights of children.13 the historical context of the consent provisions were documented in the south african law reform commission’s review of the child care act: final report.21 this report noted that the previous approach to consent to ‘medical treatment’ served as a barrier to children obtaining appropriate medical care as the age of consent was set at the older age of 14 years and only a limited number of persons could provide proxy consent.21 a further contextual issue is that (as we have set out in earlier articles) adolescents are able to consent to various other specified health prevention interventions, such as contraceptives and hiv testing.13 with regard to both contraceptives and hiv testing, adolescents from the age of 12 are able to access them without parental consent. it is submitted that in this instance the context indicates that the legislator recognised that adolescents did have the capacity to consent to certain preventative health interventions. it would, therefore, be consistent with this approach if medical treatment was interpreted broadly to include other non-specified prevention interventions. the last consideration from the cool ideas case is when interpreting a statutory provision one must find an interpretation that is consistent with the constitutional values of human dignity, equality and freedom.19 the constitutional court has held that the recognition of a child’s dignity requires an acceptance that they have their own, independent and distinctive personalities.22 as such, it is argued that a child’s right to inherent dignity requires a recognition of their other rights such as the rights of access to basic healthcare services in section 28 of the constitution.19 a narrow interpretation of the term ‘medical treatment’, which restricts it to therapeutic interventions, would undermine an adolescent’s access to various preventative interventions such as the hpv vaccine or prep. this is not consistent with the constitutional value of dignity as it undermines fundamental rights. finally, a factor to consider is the approach in foreign jurisdictions. here, there is limited assistance. a recent review by taggart et al. found that at present, the only country to explicitly include prep as falling within the definition of medical treatment is france.23 we submit that based on the interpretation principles described here, it is possible to argue that ‘medical treatment’ ought to be understood broadly as meaning the treatment of a person for a current or a future condition that they may be at risk of contracting. just as, for example, counselling an obese child on the need for a healthier diet and exercise programme could be seen as preventative treatment to reduce their future risk of type 2 diabetes. we submit that this interpretation is consistent with the purposes and context of the children’s act and is also consistent with constitutional values. implications of pre-exposure prophylaxis falling within the scope of medical treatment for adolescent consent approaches based on the given reasoning, we submit the term ‘medical treatment’ should be interpreted to encompass interventions to prevent an at-risk person from acquiring a disease. this means that the term would cover both therapeutic and preventative health interventions. it would also include but not be limited to, for example, the provision of antiretrovirals to prevent hiv acquisition (prep). we submit that this is in line with a careful statutory interpretation of the term and it reflects its ordinary practical meaning. as suggested here, many practitioners already provide preventative interventions within the scope of medical treatment such as contraceptive counselling, advice about the hpv vaccine and assistance with healthy diets. in short, this broad interpretation of medical treatment enables doctors to provide more holistic healthcare independently for qualifying adolescents. with regard to the implication for prep being viewed as a form of ‘medical treatment’, there are two requirements for adolescent self-consent. firstly, they must be ≥ 12 years old, and secondly they must have ‘capacity’. capacity is the law’s recognition of a person’s ability to perform a juristic act – any action that has legal consequences – such as consenting to medical treatment requires capacity. a person will have capacity if he or she is able to exercise their judgement based on an understanding of the nature and consequences of the decision.2,5 in this context the children’s act provides that a child will have capacity to consent if he or she can understand three elements of the proposed treatment; its ‘benefits, risks, social and other implications’.2,3,13 if we apply these factors to consent for prep we recommend that in order for an adolescent to self-consent the following criteria should be met, the adolescent would need to be: at risk of hiv infection weigh more than 35 kg 12 years or older able to understand the benefits of using prep to reduce their risk of hiv, relative to other hiv prevention tools mature enough to understand and accept that there are risks attached to using prep informed that there may be social or other implications associated with taking prep such as stigmatisation for being in an ‘at-risk’ category able to understand the need for adherence and how this will be integrated into their lives, including the possible need for parental or other support to ensure adherence. this means that qualifying adolescents will be entitled to privacy regarding their medical treatment choice of hiv prevention.24 given the evolving capacity of adolescents it will be easier for older children to meet these criteria. with younger children, additional decisional supports will need to be put in place to ensure that they are able to exercise sound judgement regarding this form of hiv prevention. if they do not meet these capacity requirements, consent for prep will have to be provided by a parent, guardian or caregiver. regarding adherence for adolescents, there is not yet robust evidence on effective adherence interventions specifically tailored for adolescents; however, the early demonstration projects have provided some lessons. access to refills should be as easy as possible, enhanced by regular provider-contact, during and between visits, for example, with a navigator or counsellor. support from family and close friends including an intimate partner can be positive, but disclosure of prep use has also resulted in social harms such as intimate partner violence. providers should advise adolescents to seek counselling on safe disclosure. short-term incentives to maintain drug levels and plasma drug level feedback have also been studied with varying levels of effectiveness (bekker, personal communication, 9 jun 2020). further implementation research is warranted before this is widely adopted. conclusions and recommendations south african adolescents need an array of hiv prevention tools to address their risk of acquiring the life-long, stigmatised condition, that is hiv.1 this public health crisis requires us to consider current legal norms for consent to prevention tools by adolescents and ensure that service providers are clear on the instances where self-consent is permissible or when parental consent should be secured. we recommend that prep should be interpreted as being a form of ‘medical treatment’ so that it falls within the ambit of one of consent norms in the children’s act. this recommendation is consistent with earlier recommendations for self-consent for adolescents over 12 years to hpv vaccination from tathia and colleagues27 and builds on recommendations from vawda and colleagues28 that the term ‘medical reasons’ is broad enough to include hiv prevention.28 we elaborate on earlier recommendations by outlining and using tools of statutory interpretation to justify it. following this interpretation, self-consent to medical treatment – understood broadly to include prep – is permissible for persons over 12 years only when they have the mental capacity to understand the benefits, risks, social and other implications’ of the proposed treatment.2,3 we recommend that service providers should take steps to ensure that those persons who meet the age and capacity requirement for self-consent have access to prep. we also recommend that policy makers should ensure that prep guidelines are updated to reflect the adolescent consent approach articulated here. hopefully these efforts will enable at-risk adolescents to access much needed interventions to reduce their risk of hiv. acknowledgements competing interests there were no competing interests in the development of this article. authors’ contributions a.s. and j.d.t. developed the legal section of the article. z.e. and c.m.s. drafted the background and context and assisted with the analysis. l.-g.b. added the specialist information on prep. all authors contributed to the editing and analysis of the article. ethical consideration this article followed all ethical standards for a research without direct contact with human or animal subjects. funding information this article was made possible by funding from award number 1ro1 a1094586 from the national institutes of health (nih) entitled choices for adolescent methods of prevention in south africa (champs). data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the content is solely the responsibility of the authors and does not necessarily represent the official views of the nih. it does not necessarily represent the views of any council or committee with which the authors are affiliated. references bekker l, gill k, wallace m. pre-exposure prophylaxis for south african adolescents: what evidence? s afr med j. 2015;105(11):907–911. https://doi.org/10.7196/samj.2015.v105i11.10222 strode a, essack z. facilitating access to adolescent sexual and reproductive health services through legislative reform: lessons from the south african experience. s afr med j. 2017;107(9):741–744. https://doi.org/10.7196/samj.2017.v107i9.12525 strode a, slack c, essack z. child consent in south african law: implications for researchers, service providers and policy-makers. s afr med j. 2010;100(4):247–249. https://doi.org/10.7196/samj.3609 pettifor a, nguyen nl, celum c, cowan fm, go v, hightow-weidman l. tailored combination prevention packages and prep for young key populations. j int aids soc. 2015;18(2 suppl 1):19434. https://doi.org/10.7448/ias.18.2.19434 simbayi l, zuma k, zungu n, et al. south african national hiv prevalence, incidence, behaviour and communication survey, 2017. cape town: hsrc press; 2019. world health organisation (who). who expands recommendation on oral pre-exposure prophylaxis of hiv infection (prep). policy brief. geneva: world health organisation; 2015. bekker l-g, rebe k, venter f, et al. southern african guidelines on the safe use of pre-exposure prophylaxis in persons at risk of acquiring hiv-1 infection. s afr j hiv med. 2016;17(1):455. https://doi.org/10.4102/sajhivmed.v17i1.455 jiang j, yang x, ye l, et al. pre-exposure prophylaxis for the prevention of hiv infection in high risk populations: a meta-analysis of randomized controlled trials. plos one. 2014;9(2):e87674. https://doi.org/10.1371/journal.pone.0087674 south african national aids council. national strategic plan on hiv, tb and stis 2017–2022 [homepage on the internet]. 2017 [cited 2018 feb 4]. available from: http://nsp.sanac.org.za/ mbatha jn, taylor m, kleppa e, et al. high-risk human papillomavirus types in hiv-infected and hiv-uninfected young women in kwazulu-natal, south africa: implications for vaccination. infect dis. 2017;49(8):601–608. https://doi.org/10.1080/23744235.2017.1312513 mbatha t. spotlight [homepage on the internet]. 2017 [cited 2019 aug 11]. available from: https://www.spotlightnsp.co.za/2017/12/17/state-prep-access-sa/ bekker lg, rebe k, venter f. southern african guidelines on the safe use of pre-exposure prophylaxis in persons at risk of acquiring hiv-1 infection. s afr j hiv med. 2016;17(1):455. https://doi.org/10.4102/sajhivmed.v17i1.455 republic of south africa. children’s act, no. 38 of 2005. 2005. government gazette, cape town, south africa. jackson s, hafemeister tl. impact of parental consent and notification policies on the decisions of adolescents to be tested for hiv. j adolesc health. 2001;29(2):81–93. https://doi.org/10.1016/s1054-139x(00)00178-6 delany-moretlwe s, cowan fm, busza j, bolton-moore c, kelley k, fairlie l. providing comprehensive health services for young key populations: needs, barriers and gaps. j int aids soc. 2015;18(2 suppl 1):19833. https://doi.org/10.7448/ias.18.2.19833 strode a. a critical review of the regulation of research involving children in south africa: from self-regulation to 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[cited 2018 march 14]. available from: http://www.merriam-webster.com/medical/treatment. cambridge dictionaries online [homepage on the internet]. [cited 2019 march 22]. available from: http://dictionary.cambridge.org/us/dictionary/english/treatment. republic of south africa. constitution of the republic of south africa. 1996. government gazette, cape town, south africa. cool ideas 1186 cc v hubbard and another 2014 (4) sa 474 (cc) south african law reform commission. review of the child care act 2002 [homepage on the internet]. [cited 2020 jun 9] available from: http://www.justice.gov.za/salrc/reports/r_pr110_01_2002dec.pdf south african law reform commission. review of the child care act 2002. [cited 2020 june 09]. available from: http://www.justice.gov.za/salrc/reports/r_pr110_01_2002dec.pdf. taggart t, bond kt, ritchwood td, smith jc. getting youth prepared: adolescent consent laws and implications for the availability of prep among youth in countries outside of the united states. j int aids soc. 2019;22(7):e25363. https://doi.org/10.1002/jia2.25363 strode a, slack c. child privacy rights: a ‘cinderella’ issue in hiv-prevention research. s afr j hiv med. 2013;14(3):108–110. https://doi.org/10.7196/sajhivmed.897 tathiah n, naidoo m, moodley i. human papillomavirus (hpv) vaccination of adolescents in the south african private health sector: lessons from the hpv demonstration project in kwazulu-natal. s afr med j. 2015;105(11):954. https://doi.org/10.7196/samj.2015.v105i11.10135 vawda ya, maqutu ln. neonatal circumcision – violation of children’s rights or public health necessity?. s afr j bioethics law 2011;4(1):36–41. https://doi.org/10.7196/sajbl.119 strode a, toohey j, slack c. addressing legal and policy barriers to male circumcision for adolescent boys in south africa. s afr med j. 2016;106(12):1173–1176. https://doi.org/10.7196/samj.2016.v106.i12.11215 reddy dm, fleming r, swain c. effect of mandatory parental notification on adolescent girls’ use of sexual health care services. jama. 2002;288(6):710–714. https://doi.org/10.1001/jama.288.6.710 j _ 2~r:2 --------------counselling oplions should include abstinence, monogamy (mutual faithfulness) and the correct use of condoms. in the absence of a test, emergency treatment may not be withheld. in certain well-defined high-risk or exposureprone procedures, the patient should be informed and asked to consent. if the patient declines, s/he should be managed as if positive. before testing, the health professional should: • check for legislative processes that may regulate hiv testing, e.g. prisons, schools, work place, insurance policies, etc. • confirm ihat there is a clinical indication. • ensure that pretest counselling has been done adequately, or do so personally. • ensure that the client has been fully informed and thereafter consented. • be in a position to ensure confidentiality. the health professions council of south africa and the south african medical association recommend that since an hiv test interferes with a person's rights to freedom and securiry of person and privacy, a person may only be tested • at his/her own request • after s/he has given informed consent, preferably written • he/she may otherwise be tested when authorised by legislation or a couri order. probably the most common reason for health professionals to counsel south africans today is in the context of hiv testing. a general poster in ihe ward or clinic room that 'all patients will be tested for hiv' does not constitute informed consent nor should a patiem just be presenred with a leafcr or referred to another organisalion for informarion. testing as part of research is permitted only with tile candidate's free and informed consent. testing an existing blood sample can only be done if the patiem consents. unlinked and anonymous resting is permitted by the department of health if done by a national or local health authority. proper ethical guidelines should be adhered to and there should be security safeguards for confidentiality. the hiv epidemic more than any other has brought with it the need for health care workers to have counselling skills. the life-changing nature of an hiv diagnosis requires that all persons are fully informed of the consequences of a positive result before they are tested (pretest counselling) and thereafter be told the result and given support if it is positive (post-test counselling). there are a number of other situations in the context of hiv where counselling is required, e.g. bereaved family members, loss of reproductive capability, ete. it is therefore in the best imerests of the health care professional not only to know the resources to call upon for more advanced counselling support but also to develop some personal basic counselling skills. unda-gall bekker, .hb glib, fe?, phd infectious disease clinical r<!search unit, [let lung 11l5tiwre.. cap!! tcn~'11 this article has been adapted by unda-gail bekker from a chapter by carroll jacobs in the handbook of hiv medicine (reviewed elsewhere in this issue). it is recommended that ihe full chapter in the handbook be referred to. counselling in a health care setting consists of a supportive relationship in a structured environment where one person helps another person to: • know more about a situation/ illness/diagnosis. • contain his/her emotions. • explore and define his/her feelings, thoughts and actions around the diagnosis. • find solutions to problems that he/she will encounter. • develop coping skills for the future. hiv counselling hiv counselling aims to: • provide a supportive environment. • help clients manage their problems and issues. • explore coping skills they have used before and develop new ones. • empower clients to become self -sufficient in dealing with emerging issues/problems. • counsel hiv-negative clients so that they know how to remain negalive. • counsel hiv-positive cliems on how to avoid crossinfection and how to prevem infecting others. • explore options with the client that will help them id bring about necessary changes in behaviour. these pretest counselling checklist for pretest counselling: • assure the client that both counselling and testing are confidential procedures. • be sure that if more than one session is required it can be offered. • provide information about hiv infection and transmission and its links to aids, sexually transmitted infections and tuberculosis. • provide information on the technical aspects of testing, ihe 'window period' and its implications and the meaning of the terms 'posiiive' and 'negative: • discuss the implications of a positive or negative diagnosis. • provide information about the client's legal rights in terms of who to tell (sexual partner/si or not to tell (e.g. the employer, third parties, etc.). clients are not obliged to tell anyone apart from their sexual partners. • evaluate risk behaviour: find out why the individual wants to be tested, and the nature and extent of previous and present high-risk behaviour, and discuss the steps that they should take to prevent future infection or transmission. • determine the client's coping resources and support systems in the event of a positive result. • contain ihe client's emotions as they deal with issues about relationships. • determine whether the client wishes to be tested that day or not, and whether they would like to receive the result that day or not. • assure [he client that you respect their decision. • provide a sense of support and hope for the client. a person who has tested hiv-positive may never have the same quality of life again. hiv-positive people who are properly and appropriately counselled not only feel better following the support. but also are better able to talk about their fears and feelings, and to plan their future. with ongoing emotional and psychological support [he hivpositive person can change his or her behaviour from destructive living to positive living. both preand post-test counselling are very important. it is dangerous to compromise the counselling process and take short cuts in the counselling room. post-test counselling post-lest counselling helps ihe client to work through the crisis and other issues that may arise as a result of being wld [heir hiv starus. giving the results. • give the results as soon as they are receivea. do not prolong the suspense with inane conversation. • give the results face to face, never telephonically and never through third parties. • the person who conducted the pretest counselling should wherever possible also give the result and posttest counselling. • let the client choose whether they want the result that day or not. people may need more time to consider the impact of a possible hiv-positive result on their lives before they receive the result. • if the result is positive, do not give it unless you or a back-up support can see the client the following day. if the hiv result is negative: • discuss the window period. • reinforce the message of prevention and safer sexual practices. • pick up on any oiher issues ihat may have been raised in the pretest counselling session. • discuss referral if necessary, especially if there are ongoing risk factors. hiv positive result: initially: • concentrate on managing the resultant crisis and addressing the client's immediate concerns. • be careful of information overload in the first encounters. later [often at a follow-up appointment the next day, if possible) • continue to comain the client's emotions. • answer any questions. • remind the client of the need for partner notification though they may still need some time and support for this. • introduce concepls such as: • the need for medical assessment and where to get it • safer sex • the cost and availability of antiretroviral therapies (art) and drug trials • the importance of a well-balanced diet. resi and exercise • the need to eliminate alcohol, smoking or drugs. ongoing counselling helps the client [q deal with issues such as partner notification, relationship difficulties, queries about health and treatment and disclosure to others. with wrinen permission, the counsellor may liaise with other caregivers. develop a good working relationship with them, as you may be able to share contacts and referral sources. july 2002 message from executive.html message from the executive in late march 2012, all the elected members of the board of the southern african hiv clinicians society met for the first time under my leadership to discuss the way forward. we decided that our objectives would now include partnering with governments to implement optimal hiv programmes and policies. for south africa, this means doing all we can to assist the government to achieve the goals of national strategic plan 2012 2016. in line with this objective, we faced the following challenge in the ensuing weeks: we received reports from a number of sites that there were some medication stock-outs, including tenofovir. concerned healthcare workers wanted to know how they could provide for their patients. knowing that treatment interruptions have long-term consequences in terms of resistance as well as other complications, many healthcarers were not sure how to handle drug shortages. some patients can have treatment substitutions, so we convened a virtual ad hoc committee of the brains trust of the society. within a matter of days, we drafted a consensus statement that was sent to the director-general of health (and is included in this issue). as we went through this process, i was struck by the depth of experience we have in the society. our brains trust must be unequalled anywhere in the world. to now assist the department of health, we are implementing an sms stock-out line for healthcare workers to report drug shortages. all reports will be submitted to the department of health every second week of each month. we will monitor shortage trends and the progress towards resolution. enclosed is a stock-out report form that includes details of applicable drugs and information on how to report shortages. another area we have agreed to focus on is the improvement of tb diagnosis, care and prevention within the context of the hiv epidemic. we have made many remarkable achievements in the diagnosis, care and treatment of hiv infection, and we need to repeat this for tb. the overlap between the two epidemics is very substantial. for the first time in my career, there have been some new and exciting developments. the genexpert technology has been adopted in a bold move for the diagnosis of tb. the department of health has announced that art should be provided for all hiv-infected individuals who get tb, irrespective of their cd4. it seems to me that we are now at a stage in the tb epidemic where we were about 10 years ago in the hiv epidemic. we are on the brink of new interventions and there is renewed drive within the department to tackle the problems. but the task ahead is huge. about 1% of south africans contract tb every year. will we achieve the nsp goal of a reduction of this incidence rate by half within 5 years? to my mind, we can only do so if we apply the same determination that we did in the hiv arena. tb is our next battle, and looming behind that is the ever-increasing burden of drug-resistant tb. finally, please don’t forget that we have a conference coming up at the end of the year in cape town from 25 28 november. entitled ‘striving for clinical excellence’, this is a conference that i think all southern african hiv clinicians should attend. there is no better way to spend the last week in november than in the mother city – rubbing shoulders with the best extant hiv healthcare workers. francesca conradie president southern african hiv clinicians society johannesburg message august 2004 the southern african journal of hiv medicine 4 the rate of co-infection with hiv and tuberculosis (tb) leaves local doctors in no doubt as to the importance of secondary preventive therapy against tuberculosis. gavin churchyard’s study, described in this issue, showed that isoniazid reduced the incidence of recurrent tb in miners by 55% compared with no prophylaxis. he suggests that international guidelines be expanded to include recommendations for secondary preventive therapy in settings where tb prevalence is high, such as in south africa. a lot has been said about the bangkok conference particularly regarding the prevention of mother-to-child transmission and the related issue of resistance when nevirapine is used as a single agent. neil martinson and steven miller cover this topic thoroughly and eloquently in two separate articles, followed by an informative overview of the entire conference by francois venter, who hopes that papers presented at the 2006 toronto conference will offer more analysis of raw data as opposed to anecdotal experience. beset by problems, including disclosure on birth certificates, trends in aids mortality are difficult to determine, but sudeshni naidoo and francis mburu studied hiv/aids mortality among inpatients at motebang hospital in lesotho and found that over a 15-year period aids had modified the mortality trend by raising the death rate of younger adults, thereby deviating from the natural trend. almost 70% of all deaths at the hospital were due to communicable diseases, maternal, perinatal and nutritional conditions, of which 70 80% were due to aids-related conditions. the researchers believe that their data will serve as a basis on which to evaluate the impact of current and future interventions, e.g. the proposed provision of antiretroviral drugs. bloemfontein researchers studied supplementary infant feeding as an important vector of disease transmission and determined the level of microbial contamination in bottle feeds given to infants living in mangaung. nearly 85% of bottle feeds tested were classified as unfit for human consumption, leading fredrick veldman and jaco brink to underline the need to address the content of feeding literacy programmes. two interesting case studies are presented in this issue ,followed by a legal opinion on the importance of funeral and estate planning by elsabé klinck. much work still needs to be done in southern africa to improve the treatment and care of hiv-infected people and their families and communities. it is hoped that the national antiretroviral roll-out will gain momentum and give hope, better health and longer lives to those people who qualify for treatment according to the national guidelines (cd4+ count < 200 cells/µl irrespective of who stage, or who stage iv disease irrespective of cd4+ count). in the interim, a national guideline committee of society experts from both the private and public sectors has compiled a guideline for the management of hiv-infected people not yet requiring or qualifying for antiretroviral treatment. it is hoped that this will assist health care professionals in maintaining the health of infected people for as long as possible prior to the need for antiretroviral therapy. it will be published shortly. des martin editor, southern african journal of hiv medicine president, southern african hiv clinicians society f r o m t h e e d i t o r abstract introduction methods results discussion acknowledgements references appendix about the author(s) sarah heany department of psychiatry, faculty of health sciences, university of cape town, cape town, south africa nicole phillips department of psychiatry, faculty of health sciences, university of cape town, cape town, south africa landon myer department of epidemiology and biostatistics, faculty of health sciences, university of cape town, cape town, south africa heather zar department of paediatrics and child health, faculty of health sciences, university of cape town, cape town, south africa dan stein department of psychiatry, faculty of health sciences, university of cape town, cape town, south africa jacqueline hoare department of psychiatry, faculty of health sciences, university of cape town, cape town, south africa citation heany s, phillips n, myer l, zar h, stein d, hoare j. physical development and mental health in south african perinatally hiv-positive adolescents on antiretroviral therapy and their caregivers with and without household food insecurity. s afr j hiv med. 2021;22(1), a1316. https://doi.org/10.4102/sajhivmed.v22i1.1316 original research physical development and mental health in south african perinatally hiv-positive adolescents on antiretroviral therapy and their caregivers with and without household food insecurity sarah heany, nicole phillips, landon myer, heather zar, dan stein, jacqueline hoare received: 10 sept. 2021; accepted: 26 oct. 2021; published: 15 dec. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: perinatally acquired hiv-infected (phiv+) adolescents have shown impairments in neurocognitive function and mental health problems compared with their peers. the contribution of food insecurity to such impairments has not been explored. objectives: the aim of this report has been to explore the contribution of food insecurity to neurocognitive impairment and mental health problems in adolescents with perinatally-acquired hiv infection. method: a total of 248 phiv+ adolescents and healthy controls aged between 9 and 12 years completed a neuropsychological battery, the childhood behaviour checklist (cbcl) and the becks youth inventory. head circumference, body mass index (bmi), height for age (haz), tanner pubertal staging, albumin, haemoglobin, cd4 and viral loads were also measured. participants’ caregivers were interviewed about their mental health and household food security. t-tests were used to assess for differences in food secure and food insecure households. results: caregivers of phiv+ adolescents reported higher levels of depressive symptoms and household food insecurity. increased food insecurity was associated with more behavioural problems in adolescents, as well as lower haemoglobin and albumin levels, faster processing speed and increased tanner staging in boys. body mass index and haz were not affected by food insecurity. conclusion: these findings suggest that household food insecurity is associated with some altered behavioural, physical and physiological outcomes, which could complicate and compound the existing difficulties in phiv+ households. keywords: hiv; caregiver depression; behavioural problems; hunger risk; food security; poverty. introduction adolescents with perinatally acquired hiv infection (phiv+) have worse outcomes in general cognitive development and mental health compared with age-matched hiv-negative peers,1,2,3,4,5 with the socioeconomic status as a potential cofounder.6 these include a poorer function in cognitive domains, such as working memory, executive function and processing speed,2 and a higher prevalence of attention deficit hyperactivity disorder (adhd) symptoms, depressive symptoms, anger, disruptive behaviour, self-concept or functional competence.4 both physiological and socio-environmental conditions have been implicated in these associations, in youth and adolescents, specifically with increased stress or mental ill health in their caregivers.7 a south african study8 found that depression amongst caregivers was strongly associated with problematic adolescent behaviour, more so than the hiv status. cognitive and behavioural problems in youth are also aggravated in situations of poverty.9 food insecurity specifically has been associated with increased cognitive and behavioural problems in children and adolescents. both externalising and internalising subscales of the childhood behaviour checklist (cbcl),10,11 as well as behaviour reports from teachers,12 have been associated with food insecurity. in addition, food insecurity has been associated with lower antiretroviral therapy (art) adherence in rural ugandan hiv-affected households.13 south african phiv+ adolescents also often experience high rates of orphanhood and living with extended family, often in unstable living environments.14 studies examining problematic or disruptive behaviour in phiv+ adolescents are sparse.15 in addition, the impact of food insecurity on measures of cognition, affect, and behaviour may play a moderating role in the developing mental health of adolescents, but such findings have not been reported in the existing literature. in this study, we investigated the effects of household food insecurity on mental health conditions of adolescents and caregivers. methods participants and setting this is a cross-sectional analysis of enrolment data from a neuropsychiatric sub-study of the cape town adolescent antiretroviral cohort (ctaac), a study of phiv+ adolescents on art in a large city in south africa. the neuropsychiatric sub-study recruited phiv+ adolescents from art services across the municipality. these adolescents were eligible to participate if they were aged 9–12 years, were on art for > 6 months and knew their hiv status. hiv-negative healthy controls (hcs) were frequency matched with phiv+ participants on age, sex and ethnicity. all adolescents screened for the hc cohort underwent rapid hiv testing to confirm their negative status. the exclusion criteria for both groups were as follows: (1) an uncontrolled medical condition, such as diabetes mellitus, epilepsy and tuberculosis (tb) requiring hospital admission; (2) an identified central nervous system (cns) condition, including meningitis (tb or bacterial), cerebrovascular accident, lymphoma, history of head injury with loss of consciousness greater than 5 min or any radiological evidence of skull fracture, history of perinatal complications, including hypoxic ischaemic encephalopathy or neonatal jaundice requiring exchange transfusion, or neurodevelopmental disorder not attributed to hiv. the primary caregiver of each participant provided written informed consent prior to participation, and each participant provided his or her assent for participation. all data were obtained from 204 phiv+ and 44 hc participants between 2013 and 2015. measures adolescents had a clinical examination, including tanner staging and anthropometry. a blood sample for measuring albumin, cd4 and viral load (vl) was taken. weight was measured in kilograms on a scales 2000 calibrated digital scale to the nearest 0.1 kg. the standing height was measured in centimetres using a stadiometer with a moveable headboard to the nearest 0.1 cm.16 body mass index (bmi) was calculated from the measured height and weight as weight/height^2 (kg/m^2). in order to assess for stunting, height for age z scores (haz) were calculated separately for girls and boys using the 2007 who growth reference for school-aged children and adolescents (available at http://www.who.int/growthref/tools/en/). weight for age z scores are not recommended for children over the age of 10 years. adolescents completed the following measures: beck youth inventories17 was used to assess depression, anxiety, anger, disruptive behaviour and self-concept. each participant was assessed using a battery of standardised neuropsychological tests, including measures of processing speed and working memory, as used in paediatric assessment and research in south africa.2 antiretroviral therapy adherence was recorded using a self-report questionnaire. tests were administered in the adolescents’ home language. caregivers completed the following measures regarding the adolescents’ behaviour: the cbcl18 to assess their adolescents’ behavioural and emotional problems and psychopathology using four subscales: total problems, total competence, internalising behaviour and externalising behaviour. conners parent rating scale19 was used to assess adhd symptoms. adolescent art adherence was also reported on by the caregivers. caregivers completed the following measures regarding their own experiences: caregiver depression was measured using the center for epidemiological studies-depression (ces-d).20 the community childhood identification project hunger index (cchip) food security scale, as used in the south african national health and nutrition examination 2012,21 was used to assess household food security. scores were obtained via an eight-point self-reported questionnaire as completed by the legal guardian of the adolescent (see appendix 1). a score of 0 indicates food secure and a score of > 1 indicates food insecure. center for epidemiological studies-depression, cbcl, household poverty, cognitive performance, and tanner staging (indicating pubertal development), were assessed at baseline. food security data were collected at a 6-month follow-up. albumin and haemoglobin (hb) levels were recorded 12 months after the baseline. statistics differences in mental health, cognition and behaviour in the adolescents, as well as depression of the caregiver, were assessed between the food security groups (food secure and food insecure). these tests were carried out in the combined sample (phiv+ and hc together) and in the phiv+ group alone. the tests were not carried out in the hc group alone as there were not enough hc participants in the food insecure category to facilitate comparative tests. mean measures of albumin, hb and physical development were assessed between the food secure and food insecure groups. differences in the above measures were also assessed between the phiv+ and hc groups. the art adherence scores were tested for differences based on food security levels. the different measures of disruptive behaviour (becks disruptive behaviour [bdb] and cbcl subscales) were tested for correlations. statistical tests were conducted using statistical package for the social sciences (spss) for windows, version 26 (ibm corp., armonk, new york, united states). for all tests of interval data, t-test was used. for tests of categorical data (tanner staging, home language and repeated grades), chi-square tests were used. levene’s test for equality of variances was assessed for each t-test to determine whether a mann–whitney test was required. in post hoc and sensitivity testing, some behavioural and affective measures were assessed for correlations using pearson’s correlation coefficients. ethical considerations this study was approved by the university of cape town’s faculty of health sciences human research ethics committee (hrec ref 051/2013) and is in accordance with the declaration of helsinki. all data were obtained from 204 phiv+ and 44 hc ctaac participants between 2013 and 2015. results overall results in the full sample the mean annual income was just under $350.00, on average, for both phiv+ and hc households, classified as extreme poverty (< $1.90 per day) by the world bank.22 the median age of the sample (including phiv+ and hc) was 10.8 years. tanner staging was higher in girls than boys. a total of 225 adolescent caregivers provided food security scores, with 50 indicating food insecurity. the average age of art onset in the phiv+ group was 3.4 years, with a standard deviation of 2.53. in the phiv+ group, the median cd4 count was 903 cells/mm3, and the mean was 957 cells/mm3. about 17% of the phiv+ group had detectable vl levels of over 50 copies/ml. the findings as well as differences between the phiv and hc groups have been listed (table 1). table 1: baseline demographic and clinical characteristics of the cohort, comparing perinatally acquired hiv infection and healthy controls groups. differences between perinatally acquired hiv infection and healthy controls groups levels of poverty were well-matched between the phiv+ and hc groups. despite matched poverty levels, 26% of phiv+ households experience food insecurity, whilst only 5% of hc households reported food insecurity. the number of repeated grades differed between the groups, with 59% of the phiv+ group and 42% of the hc group having repeated a grade. albumin levels were lower in the phiv+ group. body weight, height, haz, bmi and female tanner scores were all lower in the phiv+ group. the median haz score in the phiv+ group was –2 and in the hc group was –1.9. caregiver depression and food insecurity were higher in the phiv+ group. in the phiv+ group, 203 caregivers provided ces-d scores, 94 of whom are considered at risk for depression (a score of ≥ 16).23 in the hc group, 44 parents completed the ces-d, 13 of whom had a score of ≥ 16. affect and cognitive scores by food insecurity (table 2) in the combined sample (phiv+ and hc group), hb and albumin levels were lower in the food insecure group. problem behaviour, as measured by cbcl total problems (cbcl-tp), was higher in the food insecure group (t = 2.05(220), p = 0.042). cognitive domains and bmi did not differ according to food insecurity in the combined sample. the bdb measure of disruptive behaviour almost differed (p = 0.078), whilst depression, anxiety and anger did not differ. a test correlating bdb scores with cbcl scores showed that bdb was correlated with cbcl tp (r = 0.23, p < 0.001), but not with the other cbcl subscales (externalising behaviour, internalising behaviour and total competence). tanner stage in boys was slightly higher in the food insecure group, although boys’ ages were very closely matched (10.7 years in the food secure group and 10.8 years in the food insecure group). when the subscales of the cbcl were compared between the food secure and food insecure groups, only cbcl-tp was significantly different. table 2: baseline demographic and clinical characteristics of the cohort, comparing food insecure and food secure. affect and cognitive scores by food insecurity amongst perinatally acquired hiv-infected adolescents when the phiv+ group was investigated on its own, problem behaviour as measured by cbcl-tp was no longer significantly different between the food security group (t = 1.82(180), p = 0.07). it should be mentioned that this change in p-value from 0.04 to 0.07 (along with a change in t-score from 2.05 to 1.82) may be because of the smaller n in this test of this subsample. amongst the cognitive domains, only processing speed differed amongst the food security groups, with food insecurity being associated with faster processing speed. we noted that processing speed was not different between the food secure and food insecure groups when the phiv+ and hc were combined (t = –0.53, p = 0.60), only within the phiv+ sample, as shown in table 2. there was no difference in reported art adherence between the food secure and food insecure groups. discussion this study of the ctaac adolescent cohort found that food insecurity was associated with problem behaviour, as measured by cbcl-tp. in addition, processing speed was faster in phiv+ adolescents who experience household food insecurity. we also found that food insecurity was not associated with working memory, cbcl total competence or conners adhd scale. becks inventory scores of depression, anxiety, anger and disruptive behaviour were also not significantly associated with food security, although the data trended towards the food insecure groups having higher scores in each of these inventory domains. in the whole sample (phiv+ and hc combined), lower hb and albumin levels were associated with food insecurity. perinatally acquired hiv infection households were more likely to have food insecurity and caregiver depression. lower height, weight, bmi and albumin levels were also related to phiv status. problem behaviour differed according to level of household food insecurity. becks disruptive behaviour and cbcl-tp also correlated strongly. it is, therefore, possible that both being phiv+ and having food insecurity in the home may compound adolescent problem behaviour. a longitudinal study conducted in the united states found that whilst there are higher rates of problem behaviour in hiv+ children, demographic factors such as level of parental education may be a stronger cause of problem behaviour than hiv diagnosis.24 a study on a south african cohort of phiv+ children and adolescents also found that problem behaviour was not directly linked to hiv status, but instead was more associated with caregiver depression.8 this study adds to these findings by including household food insecurity and shows that it may have a modulating effect on problem behaviour in adolescents. overall, the literature points to a complex interaction of social and demographic factors that influence problem behaviour in phiv+ and healthy adolescents. interestingly, a study from atlanta, georgia, on hiv+ children and adolescents (97% perinatally infected) and controls showed that whilst psychological maladjustment was high in the hiv+ group, it was even higher in the control group, specifically with regard to internalising behaviour.25 problem behaviour, particularly problematic conduct, has previously been associated with decreased art adherence in phiv+ children and adolescents in the united states.26 food insecurity has also been associated with lower art adherence in rural ugandan hiv+ households.13 whilst this may have severe implications for the ongoing health and hiv+ population, our phiv+ sample did not show any differences in reported adherence in relation to food insecurity. in our cohort, height, weight, bmi, haz and tanner staging in girls were all lower in the phiv+ group, indicating stunted growth; however, these growth biomarkers were not related to food insecurity. a study in tanzanian adolescents has previously associated food insecurity with undernutrition and lower bmi, although mental health was not measured.27 alternately, in the north american populations, food insecurity has been associated with an increased risk of obesity and metabolic syndrome in both adults and adolescents.28,29,30,31 this inconsistency in published results may be because of different lifestyle norms and factors of poverty in each studied population. a review focussing on western countries found that food insecurity had deleterious consequences of emotional, cognitive and behavioural outputs in children and adolescents.32 a uk-based study found that cognitive differences in food insecurity groups could be explained by poverty levels, and behavioural development could be explained by environmental and parental treatment in the home; emotional problems were, however, ascribed to food insecurity alone.33 this study tries to piece these different factors together; however, more longitudinal data are required. there are some limitations to this study. one is the cross-sectional design; however, follow-up analyses with this cohort are underway. the food security data, household income, mental health, and problem behaviour measures in this study were all self-reported by parents or legal guardians, which leaves some room for error, given that answers rely on recall. responses to measures, such as the food security questionnaire, are vulnerable to biased reporting from participants. this bias can depend on the participants’ comfort and familiarity with the data collection team, and may be influenced by inhibition or alternately a tendency towards expected responses when facing many questions about experienced difficulties. another limitation here is the small size of the hc group; however, the group was well matched. different measures of food insecurity are used in research studies across the world because of different living conditions and norms; however, this currently seems necessary, given differing socio-cultural contexts. in order to clarify the associations between problem behaviour, hiv status, poverty indicators, nutrition, development and mental states, the effects of specific family and household dynamics of affected children and adolescents should be studied further, especially using objective food security measures and with research designs that facilitate understanding of causal pathways. in conclusion, phiv+ adolescents suffer delays in physical development, including bmi, haz, pubertal development and lower circulating albumin levels. household food insecurity further affects albumin and hb levels and increases the likelihood of behavioural problems in phiv+ adolescents. acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions s.j.h. carried out the statistical analyses and wrote the first draft of the manuscript. n.p. coordinated and supervised data collection and entry, and critically reviewed the manuscript. j.h. was the principal investigator of this study, and critically reviewed and approved the manuscript before submission. h.j.z. was the principal investigator on cape town adolescent antiretroviral cohort (ctaac), and critically reviewed the manuscript. d.j.s. and l.m. assisted in study conceptualisation, advised on statistical analysis and critically reviewed the manuscript. all authors read and approved the final manuscript. funding information j.h. has received support from medical research council (mrc) of south africa. h.j.z. and d.j.s. are supported by the nrf and the mrc of south africa. s.j.h has received support from the oppenheimer memorial trust. this research work was supported by nichd under grant number 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https://doi.org/10.1016/j.amepre.2010.10.028 rose d, bodor jn. household food insecurity and overweight status in young school children: results from the early childhood longitudinal study. pediatrics. 2006;117(2):464–473. https://doi.org/10.1542/peds.2005-0582 shankar p, chung r, frank da. association of food insecurity with children’s behavioral, emotional, and academic outcomes: a systematic review. j dev behav pediatr. 2017;38(2):135–150. https://doi.org/10.1097/dbp.0000000000000383 belsky dw, moffitt te, arseneault l, melchior m, caspi, a. context and sequelae of food insecurity in children’s development. am j epidemiol. 2010;172(7):809–818. https://doi.org/10.1093/aje/kwq201 appendix appendix 1: the community childhood identification project hunger index food security scale. hiv 1065_in.indd c a s e r e p o r t 110 sajhivmed september 2014, vol. 15, no. 3 case report the diagnostic value of lymph node biopsy to detect castleman’s disease p soma,1 mb chb, msc (clinical epidemiology); s kara,2 mb chb 1 department of physiology, faculty of health sciences, university of pretoria, south africa 2 department of internal medicine, faculty of health sciences, university of pretoria, south africa corresponding author: p soma (prashilla.soma@up.ac.za) hiv is not indicated in the aetiology of castleman’s disease. however, it impacts on the prevalence and natural history of this disease and signi� cantly on the disease progression. castleman’s disease is a unior multicentric disease of the lymph node with or without polyclonal proliferation of b-cells. it is a morphologically distinct form of lymph node hyperplasia and is characterised by signi� cant architectural changes in all lymphatic compartments. histopathologically, the disease is classi� ed into two major subtypes: the hyaline-vascular type and the plasma-cell type. a mixed type is also identi� ed, as there are frequent transitions between the types. � e diagnosis of castleman’s disease needs to be made histologically. treatment modalities include surgery, which is curative for unicentric disease, and systemic therapy, which is needed for multicentric disease. � is case highlights the diagnostic value of lymph node excision biopsy in hiv-infected patients.  s afr j hiv med 2014;15(3):110-111. doi:10.7196/sajhivmed.1065 a 49-year-old male patient presented to our emergency department with a 5-day history of a non-productive cough, fever, chills, shortness of breath and lower abdominal pain with associated nausea and vomiting. his background history was that of longstanding diabetes mellitus and hypertension, but he did not report an hiv diagnosis or antiretroviral use. upon examination, the patient did not appear chronically ill. his vitals included a blood pressure of 163/73 mmhg, a respiratory rate of 25 breaths per minute and a temperature of 37.5°c. generalised lymphadenopathy was also detected, especially in the cervical and right axillary areas. � e lymph nodes were hard, non-tender, mobile and measured 1 2 cm in diameter. examination of the heart and lungs revealed no abnormalities. palpation of the abdomen con� rmed splenomegaly, suprapubic tenderness and right renal angle tenderness. abnormal laboratory findings included haematuria, haemoglobin at 9.2 g/dl (normal range 14.3 18.3 g/dl), and microscopic examination of the urine-cultured klebsiella. an hiv enzyme-linked immunosorbent assay was positive, and the initial cd4+ was 233 × 106/l. three specimens of nasogastric aspirates were negative for tuberculosis. a lymph node biopsy was done and the histological findings confirmed features that were in keeping with early human herpesvirus type 8 (hhv8)-associated multicentric castleman’s disease. also present was predominantly sinusoidal vascular proliferation in keeping with kaposi’s sarcoma. in addition, the surrounding lymphoid tissue showed against the background of what appeared to be preceding follicular hyperplasia features of marked folliculolysis, and increased plasmacytoid cells and plasma cells were also seen populating some of the follicles. other features of castleman’s disease included the ‘onion skin’ arrangement of the surrounding lymphocyte (fig. 1). discussion multicentric castleman’s disease (mcd) is an uncommon, aggressive lymphoproliferative disorder with an increased prevalence in people living with hiv.[1] it was � rst described in a case report by castleman and towne in 1954.[2] classi� cation of disease types is based on histopathological features, and two major subtypes are identi� ed: the hyaline-vascular type and the plasma-cell type. a mixed type is also identi� ed, as there are frequent transitions between the two types.[3] based on clinical features, castleman’s disease can be divided into solitary and multicentric types. common sites for the solitary type are in the mediastinum, neck, lung, mesentery, axillary lymph nodes, fig. 1. histology reveals small lymphocytes arranged in a concentric onion-skin pattern. these morphological features are characteristic of castleman’s disease.[3] c a s e r e p o r t september 2014, vol. 15, no. 3 sajhivmed 111 c a s e r e p o r t peritoneum, so� tissues and nasopharynx, where a mass forms. �e dominant histopathological type, in over 90% of cases of the solitary type, is the hyaline-vascular type. �e plasma-cell type is found mostly in the multicentric or systemic form of the disease. in the hyaline-vascular type, a�ected lymph nodes are characterised by follicular and interfollicular vascular proliferation. a wide variety of follicle sizes have been identi�ed, and most of them contain small hyalinised blood vessels that penetrate the germinal centres in an outward concentric fashion from the perifollicular area, giving it the characteristic appearance shown in fig. 1. numerous capillaries and cells, especially lymphocytes, admix with some plasma cells, and in rare cases, immunoblasts �ll the interfollicular areas. in contrast, in the plasma-cell type, the main features are sheets of plasma cells with large and hyperplastic follicles.[4] in a study by o’leary et al.,[5] researchers looked at 16 patients with castleman’s disease and examined the correlation between hhv-8 and castleman’s disease lymph node angiogenesis. of the study sample, five mcd and two solitary castleman’s disease biopsies were positive for hhv-8. this represented 43% of the patients, a small proportion that may suggest a reactivation of latent hhv-8 infection in patients with castleman’s disease. detailed analysis confirmed that hhv-8 was identified in 10% of the b-lymphocytes in the endothelial cells and in subcapsular spindle cell proliferations. a mechanism implicated in the pathogenesis of angiogenesis in castleman’s disease is via the production of hhv-8 viral interleukin 6 (il-6).[5] to facilitate risk stratification, prognosis and choice of treatment, staging of the disease is recommended. three crucial aspects need to be addressed: (i) extent of the disease, which can be evaluated by imaging; (ii) the histopathological classification, as this has implications regarding therapy; and (iii) viral aetiology, determined by blood tests to clarify hiv status, serology to establish presence of epsteinbarr virus, and immunostaining to detect viral il-6.[3] even though clinical presentation is usually nonspecific, symptoms fall into four categories: (i) local compression effects caused by enlarged lymph nodes; (ii) systemic symptoms such as fever, weight loss, night sweats, weakness and fatigue caused by b-cell involvement and related cytokine activation; (iii) fluid retention-associated symptoms such as oedema, ascites and pleural effusion; and (iv) clinical features as a result of associated complication, e.g. lymphoma.[3] as a general rule, when local compression symptoms are present, it is likely to be unicentric hyaline-vascular castleman’s disease, while when systemic symptoms are present, multicentric plasma-cell type should be considered. specific clinical parameters have been identified by oksenhendler[6] to increase the rate of diagnosing castleman’s disease in hiv-positive individuals, including fever, diffuse lymphadenopathy, splenomegaly, severe cytopenia, high serum c-reactive protein levels, elevated hhv-8 dna levels in peripheral blood mononuclear cells, extreme plasmacytosis in lymph nodes or bone marrow, nasal obstruction, respiratory symptoms, kaposi’s sarcoma lesions, a previous similar episode with spontaneous resolution, positive coombs’ test and haemophagocytic syndrome. castleman’s disease is also associated with kaposi’s sarcoma, non-hodgkin lymphoma, paraneoplastic pemphigus and poems syndrome (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin signs).[3] modality of treatment is strongly guided by clinical classification, in particular whether a patient has unicentric or multicentric disease. unicentric type is usually cured by surgical removal of the affected lymph nodes or local radiotherapy for sites that are unresectable; multicentric disease necessitates systemic therapy.[3] in patients who are hiv-negative, multicentric disease is often symptomatic. the treatment regimen for the hiv-negative group included: (i) treating underlying infection such as hhv-8 (with drugs such as ganciclovir, valganciclovir or foscarnet); (ii) decreasing cytokine acceleration with tocilizumab (a monoclonal antibody that blocks the il-6 receptor) or corticosteroids (not a popular choice in view of its side-effects); (iii) reducing proliferation of b-cells; and (iv) shrinking tumour mass. chemotherapeutic agents in combination or single agents such as cyclophosphamide, vinblastine and etoposide can be prescribed for systemic disease.[3] a study by mylona et al.[7] illustrated that life expectancy in multicentric disease appears to have improved, with the fatality rate among patients receiving antiretroviral therapy (art) at 29% compared with the fatality rate of 75% among pre-art patients. another significant finding in their study was that patients on art at the time of diagnosis of mcd had a better immunological profile and were less likely to have concurrent kaposi’s sarcoma than those commencing art after the diagnosis of mcd was made. despite the clinical differences between the patients receiving and those not receiving art, their mortality rates did not vary significantly.[7] the administration of monoclonal antibodies also forms part of treatment options. rituximab, an anti-cd20 monoclonal antibody, has been tried and a good response has been documented.[1,3,7] the safety of rituximab as a single therapeutic agent demands ongoing studies.[3] conclusion taking into consideration the high prevalence of hiv in south africa (sa), a high clinical index of suspicion should be held when patients present with lymphadenopathy accompanied by nonspeci�c systemic signs, as this will increase the likelihood of diagnosing castleman’s disease. a critical aspect is careful examination so that diseases with similar clinical presentation are excluded. �is case highlights the need for lymph node biopsy especially in our sa setting. as described, mcd can be associated with serious medical conditions; prompt diagnosis is thus essential. more research is needed to establish the optimal therapy for this rare disease, particularly in the context of hiv infection. references 1. waterston a, bower m. fi�y years of multicentric castleman’s disease. acta oncol 2004;43(8):698-704. [http://dx.doi.org/10.1080/02841860410002752] 2. castleman b, towne vw. case records of the massachusetts general hospital; weekly clinicopathological exercises; found by richard c cabot. n engl j med 1954;251(10):396-400. [http://dx.doi.org/10.1056/nejm195409022511008] 3. schulte km, talat n. castleman’s disease: a two compartment model of hhv 8 infection. nat rev clin oncol 2010;7(9):533-543. [http://dx.doi.org/10.1038/ nrclinonc.2010.103] 4. keller ar, hochholzer l, castleman b. hyaline-vascular and plasma-cell types of giant lymph node hyperplasia of the mediastinum and other locations. cancer 1972;29(3):670-683. 5. o’leary j, kennedy m, howells d, et al. cellular localisation of hhv-8 in castleman’s disease: is there a link with lymph node vascularity? mol pathol 2000;53(2):69-76. 6. oksenhendler e. hiv-associated multicentric castleman disease. curr opin hiv aids 2009;4(1):16-21. [http://dx.doi.org/10.1097/coh.0b013e328319bca9] 7. mylona ee, baraboutis ig, lekakis lj, georgiou o, papastamopoulos v, skoutelis a. multicentric castleman’s disease in hiv infection: a systematic review of the literature. aids rev 2008;10(1):25-35. abstract introduction methods data collection data analysis results discussion acknowledgements references about the author(s) maren kummerow julius global health, julius center for health sciences and primary care, university medical center utrecht, utrecht university, utrecht, the netherlands erica j. shaddock division of pulmonology, department of internal medicine, charlotte maxeke johannesburg academic hospital, johannesburg, south africa faculty of health sciences, university of the witwatersrand, johannesburg, south africa kerstin klipstein-grobusch julius global health, julius center for health sciences and primary care, university medical center utrecht, utrecht university, utrecht, the netherlands division of epidemiology and biostatistics, school of public health, faculty of health sciences, university of the witwatersrand, johannesburg, south africa roos b. barth department of internal medicine and infectious diseases, university medical center utrecht, utrecht university, utrecht, the netherlands diederick e. grobbee julius global health, julius center for health sciences and primary care, university medical center utrecht, utrecht university, utrecht, the netherlands francois d.f. venter wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, johannesburg, south africa charles feldman department of internal medicine, faculty of health sciences, university the of witwatersrand, johannesburg, south africa alinda vos julius global health, julius center for health sciences and primary care, university medical center utrecht, utrecht university, utrecht, the netherlands department of internal medicine and infectious diseases, university medical center utrecht, utrecht university, utrecht, the netherlands wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, johannesburg, south africa citation kummerow m, shaddock e.j, klipstein-grobusch k, et al. unexpected low frequency of respiratory symptoms in an hiv-positive urban sub-saharan population compared to an hiv-negative control group. s afr j hiv med. 2019;20(1), a1010. https://doi.org/10.4102/sajhivmed.v20i1.1010 original research unexpected low frequency of respiratory symptoms in an hiv-positive urban sub-saharan population compared to an hiv-negative control group maren kummerow, erica j. shaddock, kerstin klipstein-grobusch, roos b. barth, diederick e. grobbee, francois d.f. venter, charles feldman, alinda vos received: 12 july 2019; accepted: 22 july 2019; published: 26 sept. 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: chronic respiratory illnesses and respiratory infections are common in hiv-positive populations. it seems reasonable that hiv-positive people experience more respiratory symptoms, such as coughing and breathlessness, than those who are hiv-negative. objectives: this study aims to determine the frequency of respiratory symptoms in an urban african hiv-positive population. method: a cross-sectional study was conducted in johannesburg, south africa, in 2016–2017. four groups of participants were included: hiv-positive participants (1) not yet on antiretroviral therapy (art), (2) on first-line art, (3) on second-line art and (4) ageand sex-matched hiv-negative controls. data were collected on socio-demographics, respiratory risk factors and respiratory symptoms. a logistic regression analysis was performed to determine if respiratory symptoms differed between groups and to identify determinants associated with symptoms. results: overall, 547 participants were included, of whom 62% were women, with a median age of 37 years. of these patients, 63% (347) were hiv-positive, 26% were art-naïve, 24% were on first-line art and 50% were on second-line art. cough and/or productive cough was reported by 27 (5%), wheezing by 9 (2%) and breathlessness by 118 (22%) of the participants. the frequency of these symptoms did not differ by hiv status after adjustment for age and sex. breathlessness was associated with age, female sex, obesity, a history of respiratory infection and a history of airway hyper-reactivity. conclusion: the frequency of respiratory symptoms was low in our study population except for breathlessness. hiv-positive participants, whether or not on art, did not experience more symptoms than hiv-negative participants. keywords: respiratory complaints; cough; hiv; art; sub-saharan africa. introduction in the last two decades, the introduction of antiretroviral therapy (art) has substantially improved life expectancy of hiv-positive patients. patients who are adequately treated with art have a near-normal lifespan compared to the general population and, as a consequence, hiv has become a chronic disease.1 one of the reasons for the increase in life expectancy in hiv-positive patients on art is the lower frequency of severe and life-threatening opportunistic lung infections, such as tuberculosis and bacterial pneumonia.2 however, non-communicable chronic respiratory illnesses, such as chronic obstructive pulmonary disease (copd), are more frequently seen in people living with hiv (plhiv) compared to people without hiv.3 studies have shown that plhiv report more respiratory symptoms, such as coughing, productive cough and shortness of breath.4 this is of interest when considering that plhiv are ageing and respiratory symptoms are more frequent in an older population.5 however, most of the literature related to respiratory symptoms in hiv infection emanate from north america. there are insufficient data on the extent of this problem in lowand middle-income countries (lmic) where the majority of plhiv reside and where the burden of tuberculosis and bacterial pneumonia is higher than in high-income countries (hic) like north america. we studied the frequency of respiratory symptoms in plhiv whether or not on art in an urban area in south africa in comparison to an hiv-negative control group, as well as the determinants of respiratory symptoms. methods we conducted a cross-sectional study in johannesburg, south africa, from july 2016 to november 2017. we recruited four groups of participants from the johannesburg area: hiv-positive participants not yet on art, hiv-positive participants on first-line art, hiv-positive participants on second-line treatment and hiv-negative control participants. the hiv-positive participants were recruited from past or ongoing randomised controlled trials (rcts) comparing different art regimens in a governmental hiv care facility in central johannesburg.6,7 the control group was recruited by hiv-positive participants who invited their family or friends with a negative or unknown hiv status with the same age range (+/−5 years) and sex to participate in the study. all control participants underwent hiv counselling and testing according to the south african department of health guidelines.8 if a control participant tested hiv-positive and there was no history of art use, they were counted in the first group (hiv-positive, art-naïve) and referred to a local clinic to initiate art. if they were on art already, they were included in the group on firstor second-line art, depending on their current art regimen. data collection data were collected during a single visit. information on demographics and smoking was assessed with a modified version of the who steps instrument9. information on medical history, respiratory symptoms, working and living circumstances and occupational exposure to potentially harmful agents was obtained using following questionnaires: the british medical research council (mrc) respiratory questionnaire,10,11 the mrc dyspnoea scale,12 the world health survey,13 the ats-dld-78-a14 and questions used in other publications15,16. respiratory symptoms evaluated in this study were ‘cough’, ‘bringing up phlegm’, ‘breathlessness’ and ‘wheezing or whistling’ according to the mrc respiratory questionnaire and the ats-dld-78. a questionnaire also included ‘cough’ and ‘bringing up phlegm’ as symptoms which were evaluated separately (table 1). table 1: questions to assess respiratory symptoms. a physical examination was performed, which included measurements of height and weight. blood sample was collected for measurement of hiv viral load and cd4-cell count (hiv-positive participants only). for participants who were recruited from one of the rcts, laboratory data were retrieved from the rct visit closest to our study visit. data analysis outcomes were described as median with interquartile range for continuous variables (all non-normally distributed) and count with percentage for categorical variables. differences in continuous variables across the four groups were tested using a mann–whitney u test and categorical variables using a fisher’s exact test. the frequency of respiratory symptoms across the four groups was displayed in bar charts. we combined the four respiratory symptoms in a composite outcome ‘any respiratory symptom’ that was defined as the occurrence of at least one of the respiratory complaints, namely coughing, bringing up phlegm, shortness of breath and/or wheezing or whistling. we first analysed if the frequency of respiratory symptoms differed according to hiv or art status in three logistic regression models using ‘any respiratory symptom’ as outcome. in the first model, we assessed the unadjusted association between hiv and art status and the occurrence of any respiratory symptom using the hiv-negative group as the reference group. the second model was adjusted for sex and age, and the third model additionally adjusted for body mass index (bmi), ever smoking, passive smoking, respiratory infections in the past (pneumonia and/or tuberculosis) and bronchial hyper-reactivity. to investigate the influence of hivand art-related characteristics, we repeated the models described above including the hiv-positive participants only and using the art-naïve group as the reference group. in the third model, hiv viral load and cd4+ cell counts were added. finally, we analysed which determinants were associated with any respiratory symptom. the following factors were considered in univariable analysis: hiv status, age, sex, bmi, ever smoking and passive smoking, respiratory illnesses in the past such as tuberculosis and pneumonia, history of bronchial hyper-reactivity and environmental factors (worked in the mining industry or worked in a dusty job or exposure to gas, chemical fumes or pesticides in work). all factors with a p-value of < 0.2 in univariate analysis as well as age and sex were then included in multivariable analysis using forced entry. a p-value < 0.05 was considered to be statistically significant. for the statistical analyses, we used the statistic programme ‘ibm spss statistics’ version 24.0 (ibm spss statistics for windows, version 24.0. ibm corp., armonk, ny). ethical considerations ethical permission was obtained from the human research ethics committee of the university of the witwatersrand (hrec number m160131). all participants provided written informed consent prior to participation. results of the 548 participants, 547 were included in the study. one participant was excluded as there was no information on hiv status. almost all participants were black africans (99.6%), 341 (62%) were women, 394 (72%) were hiv-positive, and the median age was 37 years (table 2). of the hiv-positive group, 103 (26%) were art-naïve, 94 (24%) were on first-line treatment and 197 (50%) were on second-line treatment (table 2). table 2: characteristics of the study population. the hiv-positive group on second-line treatment had a higher percentage of women (73%, p < 0.001) and was older compared to the other groups (42 years, p < 0.001). the control group and the art-naïve group had a high percentage of current daily smokers (37% and 26%, respectively). thirty-four per cent hiv-positive participants reported a history of a respiratory infection such as tuberculosis or pneumonia. the numbers were especially high in the group on second-line treatment (51%). occupational exposure was uncommon, with only 26 participants (5%) reporting any exposure. almost all participants used gas or electricity for cooking (99.5%) and heating (99%). cough was reported by only six (1%) participants. bringing up phlegm was reported by 12 (2%) participants and 9 (2%) participants reported both. wheezing occurred in 9 (2%) participants and breathlessness in 118 (22%) participants (figure 1). figure 1: frequency of respiratory symptoms by hiv status, (a) cough ≥ 2 weeks (n), (b) bringing up phlegm (n), (c) medical research council dyspnoea scale ≥ 2 (n), wheezing or whistling (n). in total, 143 participants (26%) reported at least one respiratory symptom of which 128 participants (90%) reported one symptom, 11 (8%) reported two symptoms, 3 (2%) reported three symptoms and only one participant reported all symptoms. in the unadjusted comparison across the four groups, the hiv-positive group on second-line art had significantly more respiratory symptoms compared to the hiv-negative group (odds ratio [or] 2.5, 95% confidence interval [ci] 1.5–4.1) (table 3). however, after adjustment for sex and age, there was no difference in the frequency of respiratory symptoms related to hiv or art status. further adjustment for respiratory risk factors did not change this finding. table 3: any respiratory symptom for all participants. when we restricted the analysis to the hiv-positive participants, the same crude trend was observed with participants on second-line art having more respiratory symptoms than the other participants in the unadjusted analysis. this result disappeared after adjustment for sex and age. additional adjustment for cd4-cell count and viral load did not change the findings. the occurrence of any respiratory complaint was associated with age, female sex, bmi and a history of bronchial hyper-reactivity (table 4). when limiting the analysis to breathlessness, age, female sex, bmi, bronchial hyper-reactivity and a history of pulmonary infection were the associating factors (table 5). table 4: factors associated with any respiratory symptom. table 5: factors associated with breathlessness. discussion the frequency of respiratory complaints in our study was surprisingly low when compared to what has been reported in the literature in studies from both hic and lmic. for coughing, a frequency of 17%17 – 40%18 has been reported in hic and 7% – 48%19,20,21,22,23 in lmic. in contrast, only 3.3% of the participants reported cough in our study. bringing up phlegm was reported by 30% of hiv-negative and 42% of plhiv in studies conducted in hic,18,21,24 whereas this was reported by only 2% of the participants in our study. both coughing and bringing up phlegm were reported to happen more in plhiv than in hiv-negative participants.18,21,24 wheezing and whistling have only been evaluated in two studies from hic. no difference was found between plhiv and hiv-negative participants.24,25 in contrast, breathlessness was a frequently expressed complaint with 22% of the participants in our study, indicating that they experienced breathlessness. this is in line with the literature, mostly from hic, reporting that between 1.4% and 42% of the population experience breathlessness. people living with hiv were found to experience breathlessness more often than hiv-negative individuals,18,25,26 a finding that we could not confirm in our study. the following reasons should be considered to understand the low number of respiratory complaints, except for breathlessness, noted among the participants in our study compared to previous studies. firstly, our study population differed from study populations in hic. people living with hiv from hic represent a particular group with specific health risk behaviour, such as men having sex with men (msm) or intravenous drug users with a higher percentage of smokers than the hiv-negative population.27 in our study cohort, plhiv smoked significantly less than the hiv-negative population (15.2% of plhiv versus 36.8% of hiv-negative participants, p < 0.01). secondly, with regard to lmic, most of the studies from the african countries reported that the use of wood fire was still common and responsible for a high burden of respiratory disease and symptoms,28,29 whereas in our study household air pollution because of open fires for cooking and heating was hardly present among the participants. thirdly, heterogeneity in interpretation of definitions may have confounded results among the different studies from hic and lmic. finally, most of the studies conducted previously in africa had a low percentage of participants on treatment with art,21,30 whereas 74% of plhiv in our study were on art. uncontrolled hiv infection, and hence inflammation and a high risk of pulmonary infections, would likely result in an increased incidence of respiratory symptoms. despite these possible explanations for our findings, it is still particularly surprising that hiv-positive, art-naïve participants in our study hardly reported respiratory symptoms. a possible explanation could be the fact that the art-naïve group was still young and had not had the chance to develop symptoms yet. additionally, they had a median cd4 count of 281 cells/mm3 and therefore were still at low risk for opportunistic infections.31 this is supported by the low prevalence of a history of tuberculosis in the art-naïve group compared to the group on firstand second-line art, which might indicate that art-naïve participants had not had uncontrolled viremia for a long period of time. another unexpected finding of our study was that despite the high burden of respiratory infections in the past in plhiv, this did not result in a higher frequency of respiratory symptoms except for breathlessness. it may be the case that, given the relatively young age of the population, there was still enough pulmonary reserve capacity to limit complaints in daily life. clearly, the next step to clarify the relationship between respiratory infections in the past, particularly tuberculosis, and current pulmonary function would be to include lung function testing in the analysis. limitations of this study include the recruitment process of the study population which may influence the generalisability of our results. participants were not randomly sampled from the general hiv-positive population but were recruited from rcts. however, we think that the participants were representative of people with the same hiv and art status as they were all recruited from routine local hiv diagnostic services. furthermore, it is possible that the control group experienced more breathlessness as a result of the high percentage of smokers in this group. this could have reduced the contrast between the hiv-positive and hiv-negative participants. lastly, although we tried to define respiratory complaints clearly, there may still be uncertainty around the definition. future studies should seek to standardise the definition of respiratory symptoms more strictly and it would be helpful if all studies used the same definitions. in conclusion, the results of this study among a large group of hiv-positive and -negative patients do not support the view that respiratory symptoms are more common among patients with hiv. acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions a.v. was responsible for the study design and coordination of data collection. e.j.s. was involved in data collection. m.k. performed the data analyses and was responsible for interpretation of results under the supervision of a.v. m.k. and a.v. wrote the article. e.j.s., k.k.-g., r.b.b., d.e.g., f.d.f.v. and c.f. critically revised the article. all authors gave final approval for the version to be published. funding no funding was received for this project. data availability statement the authors confirm that the data supporting the findings of this study are available within the article or its supplementary materials. disclaimer the views and opinions expressed in this article are the authors’ own and do not reflect an official position of the authors’ institutions. references bor j, herbst aj, newell ml, barnighausen 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https://doi.org/10.1097/qai.0b013e3182a9215a frazier el, sutton my, brooks jt, shouse rl, weiser j. trends in cigarette smoking among adults with hiv compared with the general adult population, united states – 2009–2014. prev med. 2018 jun;111:231–234. https://doi.org/10.1016/j.ypmed.2018.03.007 buist a, mcburnie m, vollmer w. international variation in the prevalence of copd (the bold study): a population-based prevalence study. lancet. 2007(370):741–750. https://doi.org/10.1016/s0140-6736(07)61377-4 van gemert f, kirenga b, chavannes n, et al. prevalence of chronic obstructive pulmonary disease and associated risk factors in uganda (fresh air uganda): a prospective cross-sectional observational study. lancet glob health. 2015 jan;3(1):e44–e51. https://doi.org/10.1016/s2214-109x(14)70337-7 norrgren h, da silva zj, andersson s, et al. clinical features, immunological changes and mortality in a cohort of hiv-2-infected individuals in bissau, guinea-bissau. scand j infect dis. 1998;30(4):323–329. https://doi.org/10.1080/00365549850160585 phair j, munoz a, detels r. the risk of pneumocystis carinii pneumonia among men infected with human immunodeficiency virus type 1. n engl j med. 1990(322):161–165. https://doi.org/10.1056/nejm199001183220304 m_sajhiv_n20_a14.pdf the southern african journal of hiv medicine september 2005 45 the legal framework for hiv testing the constitution provides that every person has the right to bodily integrity and privacy (s 12 and s 14, constitution of the republic of south africa act, no. 108 of 1996). these rights give individuals control over their bodies and enable them to make autonomous decisions (de waal et al.,2 p. 262). these rights are also well-established principles in our common law.3 more recently the national health act (no. 61 of 2003) has codified these rights, stating that no health service may be provided to a user without their consent (s 7, national health act). in other words, patients must give their consent to medical treatment including hiv testing (dada and mcquoid mason,4 p. 8). accordingly, they may also refuse to be treated or undergo a diagnostic test.5 the requirements for valid consent include: the patient must have knowledge of the nature and extent of the harm or risk involved, appreciate and understand the nature of the harm or risk and consent to the harm or assume the risk.6 rights are not absolute, and the constitution provides that they may be limited if this is reasonable and justifiable in an open and democratic society based on human dignity, equality and freedom (s 36, constitution of the republic of south africa act). the constitutional court has held that this requires a proportionality analysis which examines the purpose, effects and importance of the legislation and the nature and the extent of the limitation of rights. the more substantial the inroad into individual rights the more compelling the ground for justification must be (currie et al.,7 p. 341). framing the debate de cock and colleagues, who kicked off the routine testing debate in their 2002 article in the lancet,8 framed the issue as public health v. human rights. given the increasing availability of arvs, an 'exceptionalist' insistence relying primarily on d e b a t e s scaling up hiv testing in resourceconstrained settings: debates on the role of vct and routine ‘opt-in or opt-out’ hiv testing ann strode, faculty of law, university of kwazulu-natal heidi van rooyen, human sciences research council mark heywood, aids law project, university of the witwatersrand quarraisha abdool karim, caprisa, university of kwazulu-natal, and department of epidemiology, columbia university, new york scaling up of the numbers of people voluntarily undergoing hiv testing has become vital, especially in resource-constrained settings, where the need for knowledge of hiv status for both prevention and care is critical. the reality is that for most people in africa, access to hiv testing and to voluntary counselling and testing (vct) has been very limited, and this has human rights implications – missing the opportunity to be diagnosed with a disease that is now well understood, manageable and treatable means certain death. the key challenge in our current context is how scaling up of hiv testing should be done. in responding to this challenge, we are guided by gruskin and loff,1 who state that ‘a human rights approach mandates that any public strategy, whether or not rights are to be restricted, be informed by evidence and widely debated. this approach protects against unproved and potentially counterproductive strategies, even those motivated by the genuine despair in the face of overwhelming public health challenges.’ this article describes the arguments and discussion raised during a session on models for increasing access to hiv testing at the 2nd national conference on hiv/aids held in durban in june 2005. it describes the legal framework for hiv testing in south africa, frames the issues at the heart of the debate, and describes and discusses the various models of hiv testing, routine hiv testing, vct and mandatory or compulsory hiv testing, within the context of hiv prevention and care. it concludes with recommendations. september 2005 the southern african journal of hiv medicine 46 informed consent, sometimes described as a western medical importation, has been the main deterrent to the uptake of hiv testing. accordingly, de cock et al. state that: ‘routine testing should not require consent or pre-test counselling provided that all clients are informed that routine testing is part of the package of services for which they are voluntarily attending’ (p. 70). when framed in this manner the debate centres around whether a human rights-based approach to hiv is impeding our public health response to the epidemic this assumes that the debate is whether a public health or a human rights-based approach is more effective. we argue that this is an artificial polarisation that detracts from the key issues. this debate centres on the slow uptake of hiv testing in resourceconstrained settings, and it should be framed around a problem analysis based on the following questions: why is the uptake of hiv testing slow? is uptake influenced by the nature of current models for hiv testing? what is the legal framework and how does it influence policy decisions regarding models for hiv testing? what are the gender implications of the various models of hiv testing? could adopting new models for hiv testing influence uptake of hiv testing and access to arvs? models for hiv testing there are currently three models for hiv testing in a south african context. they are not mutually exclusive and could all play different roles within a broader public health strategy to combat hiv/aids. routine hiv testing there are many forms of routine hiv testing currently being discussed and implemented in a somewhat ad hoc manner. however, it appears that a routine offer of hiv testing during any encounter with the health care services, with the option of ‘opting in’ or ‘opting out’ of testing, is increasingly being implemented. does the law allow routine hiv testing? there is no legal obstacle to the state introducing a policy of routine hiv testing provided that the testing process continues to meet the requirements for lawful informed consent. a key issue would be whether a routine offer of hiv testing with the option of opting in or out of testing enables patients to act voluntarily. consent may not be induced by fear, force, threats, duress, coercion, compulsion, deceit, fraud, undue influence, perverse incentive or financial gain (van oosten,9 p. 29). in this regard, careful consideration must be given to gender issues, power imbalances and other subtle factors that may affect patient autonomy. arguments for routine hiv testing there are several reasons why it could be argued that routine testing is merited. firstly, the unprecedented scale of the hiv epidemic and the generalisation of vulnerability to hiv infection necessitates more traditional health measures to capture those who are vulnerable – but do not view themselves as at risk. secondly, the advent of treatment and the fact that hiv testing is a 'gateway' to access to treatment necessitates this move. and lastly, there is the reality that in most high-prevalence and resource-constrained countries, arv treatment only reaches a fraction of those who qualify for it. according to clinical guidelines reaching vulnerable populations remains a major imperative for the scale-up of testing. routine testing will ‘enable a greater number of hiv infected individuals to know their status, be motivated to change their behaviour and prevent transmission, and seek available care, support and treatment . . .’ .10 arguments against routine hiv testing de facto routine testing of only certain populations can lead to new stigma against those populations. for example, the implementation of routine testing among populations at risk who are either captive (such as prisoners) or depend on access to health care services because of their gender (such as pregnant women) could, instead of destigmatisation of hiv through its de-exceptionalisation, do the opposite. routine testing is open to the possibility of abuse of patients – there is the possibility that if no clear guidelines and procedures are put in place, patients may be coerced into taking an hiv test without full knowledge of the procedure and its impact. in practice, it may be difficult for patients to refuse testing at any stage of the process. for example, in botswana organisations like the botswana network on ethics law and hiv (bonela) argue that the ‘opt-out’ policy has evolved into a policy of routine testing with minimal counselling and subtle coercive pressures to deter people from opting out. although the policy might be reaping short-term benefits by identifying people in need of treatment, its longerterm consequences are likely to be poor adherence to treatment as well as continued misunderstandings about hiv. many developing countries do not yet have the means effectively to apply new strategies like routine or opt-out testing, in which health care workers make a point of offering (and providing) more hiv tests. taking the ‘v’ and ‘c’ out of vct limits the prevention and risk reduction outcomes that are critical within hiv and aids. furthermore, there is little empirical evidence to support the belief that removing the voluntary informed consent and counselling components of vct will lead to greater uptake of arvs in developing contexts. gender is an important dimension of the hiv pandemic.11,12 the stark social, economic and political power imbalances between men and women are a major factor influencing hiv risk.13,14 policies promoting routine testing may fail to recognise the supportive role of counselling. this could undermine important gains made in prevention of mother-tochild transmission (pmtct) programmes. the southern african journal of hiv medicine september 2005 47 voluntary counselling and testing vct is a combination of two activities, counselling and testing, into a service that amplifies both. the objectives of vct are the prevention of hiv transmission and the provision of emotional support of those who wish to consider hiv testing – to help the person make a decision about whether or not to be tested, and to provide support and facilitate decision making following testing. does the law require vct before hiv testing? the law does not specifically state that patients should undergo vct before hiv testing. however, the counselling process involved in this model of hiv testing does ensure that the key elements of lawful informed consent are met, namely the provision of information, understanding, appreciation and unequivocal agreement to be tested. arguments for vct the rationale for hiv counselling and testing as a pivotal response in the hiv/aids pandemic is well established. hiv/aids is primarily a social phenomenon arising from a compelling disease15 that gives rise to a range of behavioural, psychological and social consequences for both those infected with and those affected by the hiv. vct provides a significant prevention opportunity for dissemination of accurate information about hiv/aids, for risk assessment and risk reduction counselling (regardless of serostatus), for counselling about options to reduce hiv (mtct), and for information and referral to medical services specific to treatment of such associated infections as sexually transmitted diseases or such opportunistic infections as tuberculosis. vct has been shown to be a demonstrably effective secondary prevention strategy that assists hiv-positive individuals and serodiscordant couples reduce the risk of infecting others or of re-infecting themselves.16-19 its role as a primary prevention strategy for hiv-negative people as well as the long-term effects of vct are less clear.16,17 despite these apparent limitations of vct, a recent comprehensive review concluded that most vct studies reveal significant benefits to persons following vct.19 with regard to the supportive goal of vct, there is growing research evidence to suggest that vct plays an important role in assisting people to cope with a range of psychosocial sequelae associated with an hiv-positive diagnosis.19,20-23 there is therefore demonstrable research evidence that vct works on both prevention and support levels. for example, a recently completed study highlights the fact that good counselling is integral to pmtct implementation and effectiveness.24,25 the study showed that supportive counselling was vital in helping women manage potentially negative reactions of spouses or family members, but also in encouraging partner support, co-counselling and hiv testing. further, knowledge of hiv status and counselling was a major means of empowering women to enforce their individual choices surrounding, for example, infant feeding and protected sexual intercourse. the lack of utilisation of vct is due to its limited availability. this reflects the starving of health care services of financial and human resources and the reticence of governments to deal with the hiv/aids epidemic properly from a health perspective. other reasons for the slow uptake of vct could be widespread fear of taking the test; concerns that confidentiality will be breached; stigma and discrimination; and the costs associated with the service. arguments against vct many argue that where vct was once the first point of service to a range of services that people might need, it now acts as a bottleneck to enabling rapidly increased access to treatment.10 there is a growing perception that it is the ‘v’ and ‘c’ in vct that creates this bottleneck. mandatory or compulsory hiv testing mandatory or compulsory hiv testing occurs when laws limit the rights of individuals to bodily integrity by requiring hiv testing. failure to comply could have legal implications. does the law allow mandatory hiv testing? there is no legislation (as yet) that specifically provides for mandatory hiv testing in south africa. however there are two areas in which legislation could be developed: the national health act (no. 61 of 2003) allows the minister of health to issue regulations regarding communicable diseases (s 90(1)(j), national health act). in terms of similar powers provided in the previous health act (no. 63 of 1977) the apartheid government in 1987 issued the regulations relating to communicable diseases and the notification of notifiable medical conditions (government notice r 2438 in government gazette 11014 of 30 october 1987). these regulations allowed for mandatory medical examinations (which could include hiv testing) in a number of circumstances. they were widely criticised26 and were apparently never implemented.27 to date no regulations have been issued in terms of the new national health act. in our criminal law there are currently no provisions for mandatory hiv testing. however the south african law reform commission has in its fourth interim report on aspects of the law relating to aids27 recommended that parliament adopt its proposed compulsory testing of sexual offenders bill which would allow the victim of any sexual offence to apply to a magistrate for an order compelling the alleged offender to be tested for hiv. arguments for mandatory testing it is argued that mandatory testing promotes public health goals and the public good. mass testing programmes could enable the early identification and treatment of large numbers of persons, thus reducing the number of new infections.28 it is also seen to be a justifiable infringement of an individua’s right to bodily integrity and privacy (in certain circumstances) september 2005 the southern african journal of hiv medicine 48 as the benefits to the individual and society outweigh the individual cost.29 finally, it enables hiv treatment to be provided to vulnerable and marginalised groups. arguments against mandatory testing protecting the human rights of persons infected and affected by hiv serves to promote public health goals rather than undermine them. where persons are at risk of hiv infection they need to be able to access public health services. where persons are coercively tested or may face stigma and discrimination following testing they are unlikely to access such services and are often driven underground.29 furthermore, infringing rights such as the rights to privacy, dignity and bodily integrity is not justifiable30 and compulsory testing frequently results in increased vulnerability for such groups.31 for example, compulsory testing of sex workers who use health care services may simply further stigmatise this group and act as a barrier to their accessing health services. conclusion in this rapidly changing context of an evolving epidemic and new interventions to reduce hiv transmission and alter the natural history of infection, we need to critically examine the problems with current approaches and look at how we can improve a range of interventions. vct depends on the voluntary entrance of at-risk groups to the health service. in the absence of public health strategies that loudly encourage vct among the population generally, it is bound to have limited impact. however, its real benefit has been for the small numbers of people who chose and then were able to access the service. routine testing, on the other hand, is presenting itself as a new public health strategy, a necessary measure to allow health care services to identify much greater numbers of those who are already infected. increasing access to treatment is a critical intervention in the epidemic, but should not be at the expense of preventing further transmission of the virus. we need both. public health and human rights can have common goals. thus, we argue that this debate should centre on how to ensure more v, more c and more t – to leave any part out of the equation either has human rights or public health implications. testing without voluntarism is most definitely a human rights and a public health violation. testing without counselling will not have the beneficial impact on either prevention or treatment that it seeks; for routine testing to succeed as a either a prevention or treatment strategy, it will still depend upon the quality of counselling that accompanies it. finally, in conclusion we submit that there is some synergy between the models for hiv testing. a routine offer of hiv testing could be used to promote access to vct. accordingly we argue that a routine offer of hiv testing should be made to those considered at risk for hiv, e.g. those attending sexually transmitted infection clinics, pregnant women, and those presenting to health services with signs and symptoms of advancing hiv disease including tuberculosis. the routine offer of hiv testing in public health facilities should continue to create opportunities for patients to make an informed, confidential decision to test or not. clients should be encouraged to disclose their hiv status and to encourage others in their lives to test too. a routine offer of hiv testing should not undermine vct but rather promote access to it. further, we recommend that in making public health policy decisions on models for hiv testing we should be: cognisant of the context. not compromise many gains we have made over the years with regard to human rights. foster evidence-based decision-making which requires the establishment of the relationship between hiv testing and prevention outcomes; determines the relationships between vct and arv uptake and hiv testing and arv uptake; and identifies whether the ‘v’ and the ‘c’ are really causing the bottleneck to testing. ensure that hiv testing is expanded to those who are asymptomatic. understand and address the reasons for the low uptake of vct in developing contexts. based on a thorough gender analysis. compare the different models of hiv testing being provided to establish uptake through each, and understand better the decision-making process in each setting, the role of different levels of coercion or voluntariness on decisions to test, and the consequences thereof. references 1. gruskin s, loff l. do human rights have a role in public health work? lancet 2002; 360: 1880. 2. de waal j, currie i, erasmus g. the bill of rights handbook. 4th ed. cape town: juta, 2001: 246-264. 3. stoffberg v elliot 1922 cpd 148, p. 148. 4. legal aspects of medical practice. in: dada m, mcquoid mason dj, eds. introduction to medico-legal practice. durban: butterworths, 2002: 3-32. 5. c v minister of correctional services 1996 (4) sa 292 (tpd), 301 b. 6. lambert v hefer, no. 1955 (2) sa 507 at 507 g-h. 7. currie i, de waal j, de vos p, govender k, klug h. the structure of the bill of rights. in: the new constitutional and administrative law. cape town: juta, 200: 317-344. 8. decock km, mbori-ngacha d, marum e. shadow on the continent: public health and hiv/aids in africa in the 21st century. lancet 2002; 360: 67-72. 9. van oosten f. the law and ethics of information and consent in medical research. tydskrif vir hedendaagse romeins-hollandse reg 2000; 63: 29. 10. unaids global reference group on hiv/aids and human rights. issue paper: current debates on hiv testing and counselling. geneva: unaids, 2003: 2. 11. tallis v. aids a crisis for women. agenda 1998; no. 39, 6-14. 12. abdool karim q. women and aids the imperative for a gendered prognosis and prevention policy. agenda 1998; no. 39, 15 25. 13. weiss e, gupta rg. bridging the gap: addressing gender and sexuality in hiv prevention. findings from the women and aids research program. international centre for research on women, 1998. 14. wingood gm, diclemente rj. application of the theory of gender and power to examine hiv-related exposures, risk factors, and effective interventions for women. health educ behav 2000; 27(5): 539-565. 15. richter l., van rooyen h, solomon v, griesel r, durrheim k. putting hiv/aids counselling in its place. society in transition, 2001; 32 (1): 148-153. 16. wolitski r.j, macgowan r.j, higgins dl, jorgensen cm. the effects of hiv counselling and testing on risk-related practices and help-seeking behaviour. aids educ prev 1997; 9: 52-67. 17. weinhardt l, carey m, johnson b, bickham n. effects of hiv counselling and testing on sexual risk behaviour: a meta-analytic review of published research, 1985-1997. am j public health 1999; 89: 1397-1405. 18. voluntary hiv-1 counselling and testing efficacy study group. efficacy of voluntary hiv-1 counselling and testing in individuals and couples in kenya, tanzania and trinidad: a randomised trial. lancet 2000; 356: 103-112. 19. unaids. the impact of voluntary counselling and testing: a global review of the benefits and challenges. geneva: unaids, 2001. 20. lie g, biswalo. p. perception of appropriate hiv/aids counsellors in arusha and kilimanjaro regions of tanzania: implications for hospital counselling. aids care 1994; 6 (2): 139-151. 21. lie gt, biswalo pm. hiv-positive patients choice of a significant other to be informed about the hiv test result: findings from an hiv/aids counselling programme in the regional hospitals of arusha and kilimanjaro, tanzania. aids care 1996; 8: 285-296. 22. baggeley r. fear of knowing: why 9 in 10 couples refused hiv tests in lusaka, zambia. abstract no. e.1266. 10th international conference on aids and stds in africa, abidjan, 7-11 december 1997. 23. kraabendum aa, kuijper b, wolffers in, drew r. the impact of counselling on hiv-infected women in zimbabwe. aids care 1998; 10 (1): s25-s37. 24. chopra m, jackson d, ashworth a, doherty t. an evaluation of the quality of counselling provided to mothers in three pmtct pilot sites in south africa. world health organisation, january 2004. 25. perez p, orne-gliemann j, mukotekwa t, et al. prevention of mother to child transmission of hiv: evaluation of a pilot programme in a district hospital in rural zimbabwe. bmj 2004; 329: 1147-1150. 26. cameron e, swanson e. public health and human rights – the aids crisis in south africa. south african journal of human rights 1992; 8: 200-233 (at p. 213). 27. south african law reform commission. fourth interim report on aspects of the law relating to aids: compulsory testing of sexual offenders. pretoria: south african law reform commission, 2001. 28. holbrooke r, furman r. a global battle’s missing weapon. new york times 2004; 10 february. 29. south africn law reform commission. second interim report on aspects of the law relating to aids: pre-employment hiv testing. pretoria: south african law reform commission,1998. 30. women’s legal centre. submission in response to draft regulation no. r 485 relating to aids notification as contained within government gazette dated 23rd april 1999. cape town: women's legal centre, 1999. 31. heywood m. the implications of 'aids notification' for human rights and hiv/aids prevention in south africa. johannesburg: aids law project, 1999. http://www.sajhivmed.org.za open access page 1 of 1 reviewer acknowledgementpage 1 of 1 reviewer acknowledgement acknowledgement to reviewers in an effort to facilitate the selection of appropriate peer reviewers for the southern african journal of hiv medicine, we ask that you take a moment to update your electronic portfolio on https:// sajhivmed.org.za for our files, allowing us better access to your areas of interest and expertise, in order to match reviewers with submitted manuscripts. if you would like to become a reviewer, please visit the journal website and register as a reviewer. to access your details on the website, you will need to follow these steps: 1. log into the online journal at https:// sajhivmed.org.za 2. in your ‘user home’ [https://sajhivmed.org. za/index.php/hivmed/ user] select ‘edit my profile’ under the heading ‘my account’ and insert all relevant details, bio statement and reviewing interest(s). 3. it is good practice as a reviewer to update your personal details regularly to ensure contact with you throughout your professional term as reviewer to the southern african journal of hiv medicine. please do not hesitate to contact us if you require assistance in performing this task. publisher: publishing@aosis.co.za tel: +27 21 975 2602 tel: 086 1000 381 the editorial team of the southern african journal of hiv medicine recognises the value and importance of peer reviewers in the overall publication process – not only in shaping individual manuscripts, but also in shaping the credibility and reputation of our journal. we are committed to the timely publication of all original, innovative contributions submitted for publication. as such, the identification and selection of reviewers who have expertise and interest in the topics appropriate to each manuscript are essential elements in ensuring a timely, productive peer review process. we would like to take this opportunity to thank the following reviewers who participated in shaping this volume of the southern african journal of hiv medicine. we appreciate the time taken to perform your review(s) successfully. abdulsalam m. yakasai admire t. chikandiwa adri williams alex welte anandan a. moodley ashraf hassen coovadia ava avalos bianca da costa dias billy m. tsima brian van wyk busisiwe nkosi candice fick carolina e. nel catherine orrell cleophas chimbetete cloete van vuuren coceka n. mnyani david moore evan shoul francois venter frasia oosthuizen gary maartens gert van zyl gillian hunt gillian sorour godfrey m. rwegerera hannes mouton india butler jade c. mogambery janan j. dietrich jeremy s. nel joana woods jonathan stadler kagiso motse kapila hari karl technau katayoun tayeri katherine m. gill kathleen m. powis kerusha govender kim roberg lauren jankelowitz lauren jennings lee fairlie leigh f. johnson leon levin louise gilbert lucas hermans mark cotton matthew f. chersich michael t. boswell michelle venter mina hosseinapour naomi hill nicolette p. naidoo pauline howell pieter ekermans pooja balani prudence ive rachael rawlinson rannakoe lehloenya rubeshan perumal saajida mahomed sarah e. hill sean wasserman shaun barnabas shayne loubser shenaaz pahad shobna sawry siphamandla b. gumede stuart a. ali susan j. randall talitha crowley tammy meyers thozama dubula tom h. boyles vhudzani tshisevhe violet m. awori virginia zweigenthal zainab mohamed http://www.sajhivmed.org.za� https://sajhivmed.org.za� https://sajhivmed.org.za� https://sajhivmed.org.za� https://sajhivmed.org.za� https://sajhivmed.org.za/index.php/hivmed/user https://sajhivmed.org.za/index.php/hivmed/user https://sajhivmed.org.za/index.php/hivmed/user mailto:publishing@aosis.co.za about the author(s) kate rees anova health institute, johannesburg, south africasouth africa and department of community health, faculty of health sciences, university of the witwatersrand, johannesburg, south africa melanie bisnauth anova health institute, johannesburg, south africa cara o’connor anova health institute, johannesburg, south africa tshifhiwa ramvhulela anova health institute, johannesburg, south africa nomzamo vali anova health institute, johannesburg, south africa citation rees k, bisnauth m, o’connor c, ramvhulela t, vali n. understanding patients reinitiating antiretroviral therapy in two south african districts. s afr j hiv med. 2022;23(1), a1380. https://doi.org/10.4102/sajhivmed.v23i1.1380 conference abstracts understanding patients reinitiating antiretroviral therapy in two south african districts kate rees, melanie bisnauth, cara o’connor, tshifhiwa ramvhulela, nomzamo vali received: 09 feb. 2022; accepted: 16 feb. 2022; published: 14 apr. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. antiretroviral treatment (art) coverage is south africa’s biggest obstacle to 90-90-90 achievement. many people living with hiv who are not on art have started but experienced interrupted treatment. a major programmatic challenge is how to return them to care. we aim to describe patients reinitiating art in two districts to inform these efforts. as part of evaluating a campaign to return patients to care (welcome back campaign), we asked lay counsellors to collect data on all patients reinitiating art. data collection started in august 2021 and we report data through september 2021 for two districts, one metropolitan and one district municipality. two hundred and seventeen forms were completed, 120 from cape town and 97 from sedibeng. fifty-eight percent (n = 126) of reinitiating patients were women. thirty-two percent (n = 68) had interrupted treatment for three months or less, while 40% (n = 85) had interrupted treatment for more than 12 months. the commonest reported reason for interruption in cape town was relocation or mobility (27%; n = 32), followed by difficulty getting time off work (15%; n = 17) and disclosure issues (9%; n = 11). in sedibeng the top reasons were difficulty getting time off work (21%; n = 20), relocation (18%; n = 17) and long waiting times (12%; n = 12). women were more likely to report disclosure issues and being scared to come back to the clinic as a reason for interrupting, while men were more likely to cite staff attitude. reasons for returning to care included worry about being off art (38%; n = 82), feeling sick (15%; n = 34) and tracing (12%; n = 27). men were more likely to report illness and improved accessibility as a reason for seeking care, while women were more likely to report media messaging. it is critical that health services are supportive of patients reinitiating art after interruptions, and that more enabling systems for patients moving between clinics are developed. nudges should be developed to encourage people already worried about having interrupted treatment to reinitiate it. the authors would like to thank the sedibeng and cape town departments of health. ethical considerations: this study was approved by the human sciences research council human research ethics committee, reference: rec 3/22/08/18. funding information: this research is made possible by the generous support of the american people through the united states agency for international development (usaid) and the president’s emergency plan for aids relief (pepfar) under cooperative agreement number 72067418ca00023 to the anova health institute. hiv 893 abstracts ‘striving for clinical excellence’: southern african hiv clinicians society conference, cape town, 25 28 november 2012 a selection of the best abstracts from the first southern african hiv clinicians society conference, held in november 2012, is provided here. presentations from the conference may be viewed online (http://www.sahivsoc2012.co.za). s afr j hiv med 2013;14(1):36-39. [http://dx.doi.org/10.7196/sajhivmed.893] first place salivary mucin muc5b inhibits hiv-1 subtypes a and c in an in vitro pseudoviral assay j peacocke, 1 z lotz 1 , j dorfman 2 , d kahn 1 , p roux 1 , a mall 1 1. university of cape town; 2. international centre for genetic engineering and biotechnology (icgeb), university of cape town category: clinical laboratory science background. sub-saharan africa is the world’s most hiv/aids-affected region. more interventions to manage this pandemic are urgently required. transmission of the virus through saliva exchange is rarely known to occur. using an in vitro pseudoviral assay, we sought to further describe findings that crude saliva and its purified mucins inhibit hiv-1. a robust assay is key to the identification of the mechanism involved in the inhibition of the virus by mucins. it could also help to identify a peptide sequence in mucins that could be used as a basis for the development of a microbicide. methods. mucus was extracted in 4.0 m guanidinium hydrochloride and a cocktail of protease inhibitors (ph 6.5). sepharose 4b gel filtration was used to separate muc5b and muc7 in saliva, and mucins were purified by density-gradient ultra-centrifugation in caesium chloride. sodium dodecyl sulphate-polyacrylamide gel electrophoresis (sds-page) analysis and western blotting were used to determine the size, purity and identity of the mucins. the inhibitory activity of crude saliva and purified muc5b and muc7, from hiv-negative (n=20) and hiv-positive (n=20) donors, was tested by their incubation with subtypes a and c hiv-1 pseudovirus and infection of susceptible epithelial tumour cells (genetically modified tzm-bl cells). results. crude hiv-negative and hiv-positive saliva inhibited hiv-1 in an in vitro pseudoviral assay in a dose-response nature. salivary muc5b neutralised hiv-1 subtype c pseudoviruses cap45 (kzn) and du422 (durban) and q168a.2 (kenya) of subtype a, when purified from hiv-negative and hiv-positive individuals. the neutralisation capability of muc5b appeared greater than that of muc7 for the hiv-negative group. conclusion. crude saliva and its purified mucins from uninfected controls and hiv-positive individuals inhibited hiv-1 in an in vitro pseudoviral assay. the different inhibitory capabilities are postulated to be due to altered glycosylation of the mucins. further work using liquid chromatography-mass spectrometry (lc-ms), to analyse glycosylation between mucin groups, is anticipated to reveal such differences. second place a randomised controlled trial of two sputum sample acquisition methods in persons with smear-negative or sputum-scarce tuberculosis in primary care practice j g peter, g theron, a pooran, j thomas, m pascoe, k dheda lung infection and immunity unit, division of pulmonology and uct lung institute, department of medicine, faculty of health sciences, university of cape town category: hiv complications background. sputum obtained either through dedicated healthcare-worker-provided instruction or sputum induction can improve tuberculosis (tb) case detection. however, the optimal initial sputum sampling strategy for adults with smear-negative or sputum-scarce tb in high-hiv-prevalent primary care practice is unknown. methods. adults with suspected tb from 3 primary care facilities in cape town, south africa, who were sputum-scarce or smear-negative, underwent open-labelled randomisation to receive induction (n=268; hiv-infected n=96) or healthcare-worker-provided instruction (n=213; hiv-infected n=75) to obtain sputum samples. an intention-to-treat analysis was undertaken and the primary outcome measure was time to treatment initiation. the study is registered with clinicaltrials.gov (http://www.clinicaltrials.gov) (nct01545661). results. although a sputum sample >1 ml was acquired in a higher proportion of induced v. instructed participants (90% v. 76%; p<0.001) and culture-based tb case detection was higher in induced v. instructed participants (22% v. 14%; p=0.03), case detection was similar in both arms using either smear-microscopy or xpert-mtb/rif. however, given higher empirical treatment rates in instructed v. induced participants (62% v. 43%; p=0.04), a similar proportion in each group initiated tb treatment during the study (30% v. 29%), and at 10 days post-enrolment, a greater proportion of instructed v. induced participants had commenced treatment (75% v. 56%; p=0.03). differences between groups were unchanged if the analysis was restricted to hiv-infected participants only, with the exception that culture-based case detection and empirical treatment rates were similar in instructed v. induced participants. the per-procedure sampling cost was lower for instructed than induced patients (us$2.14 v. us$7.88). conclusions. healthcare-worker-provided instruction is the preferred initial sputum sampling strategy in primary care practice for adult participants with sputum-scarce or smear-negative tb, irrespective of hiv status. runners up (alphabetical according to first author) viral re-suppression in the presence of hiv-1 drug resistance mutations a e basson 1 , c j hoffmann 2,3 , s charalambous 2 , l morris 1 1. centre for hiv & sti: hiv virology, national institute for communicable diseases, johannesburg; 2. the aurum institute, johannesburg; 3. johns hopkins university, school of medicine, usa category: antiretroviral therapy background. hiv-1 drug resistance mutations present the most common reason for loss of antiviral activity and frequently herald a regimen change. however, small studies have demonstrated re-suppression without a switch in regimen, even in the presence of specific drug-resistance mutations. we aimed to identify the hiv genotypic background of patients who re-suppressed while remaining on the same regimen after initial failure. methods. patients were enrolled in a prospective workplace hiv cohort (aurum cohort) with routine hiv rna and cd4 monitoring. suppression (hiv rna <400 copies/µl), failure (viral load (vl) >1 000 copies/µl), and subsequent re-suppression were identified from serial hiv rna values. first-line regimens were lamivudine (3tc) plus efavirenz (efv)/nevirapine (nvp) with either stavudine (d4t) (75%) or zidovudine (azt) (21%). population-based sequencing was performed using plasma rna and resistance mutations were identified with the stanford hiv database. results. a total of 71 failing patients who re-suppressed on the same regimen were included. the average vl at failure was log10 4.6 and the average time to re-suppression was 31.8 weeks. at failure, 31/71 (44%) patients had resistance-associated mutations, including m184v (58%), k103n (52%) and v106m (29%). both the m184v and k103n mutations occurred in 9/31 (29%) of the re-suppressors. the prevalence of tams and other resistance mutations was <3%. the median vl at the time of genotyping was log10 3.9 among those with resistance mutations and log10 4.3 among those without mutations (p=0.02). conclusion. while the majority of patients who re-suppressed after virological failure were infected with wildtype virus, 44% had one or more drug-resistance mutations. further work is needed to explore the long-term virological outcomes of patients who re-suppress despite resistance mutations. high rate of virological re-suppression among patients failing second-line art: a model of care to address adherence in a resource-limited setting in khayelitsha k conradie, g patten, b kerschberger, d garone, g van cutsem médecins sans frontières category: operational research background. the rapid scale-up of antiretroviral therapy (art) coverage in the last decade has improved access to treatment; however, it has coincided with an increasing number of patients failing treatment. in the public sector, patients failing their second-line regimens cannot access costly third-line drugs. treatment failure may be due to poor adherence, rather than drug resistance. an intervention to improve adherence in patients failing second-line art was introduced at a primary care clinic in khayelitsha. methods. the intervention included counsellor-led support groups and adherence-focused clinical consultations. it aimed to identify and overcome practical and psycho-social barriers to adherence. support groups allowed patients with similar difficulties to share experiences and solutions. the consultations were individual, addressing each patient’s particular barriers. a descriptive analysis of patients’ viral load history during july 2010 and december 2011 was undertaken using routinely collected data. results. a total of 69 patients were enrolled in the programme, 25 patients were excluded due to insufficient follow-up time. four patients enrolled with known pi resistance and were switched to a third-line regimen. of the remaining 40 patients: 27 (68%) went on to achieve virological suppression during 9 months of follow-up time and 5 patients left the programme (2 to death, 2 were lost to follow-up and 1 transferred). seven patients (18%) continued to experience viraemia, either with known adherence problems or known to be treatment-sensitive following genotyping. one patient was resistant on genotype and switched to third-line treatment. conclusion. poor adherence was the primary reason for virological failure among patients failing second-line art. identification of virological escape followed by simple, targeted adherence support can reduce treatment failure, improve treatment outcomes and decrease the need for costly and inaccessible third-line art. characteristics, sexual behaviour and risk factors of female, male and transgender sex workers in south africa m richter 1,2 , m f chersich 1,3 , m temmerman 1 , s luchters 4 1. international centre for reproductive health, department of obstetrics and gynaecology, ghent university, belgium; 2. african centre for migration & society, university of the witwatersrand, johannesburg; 3. centre for health policy, school of public health, faculty of health sciences, university of the witwatersrand, johannesburg; 4. centre for international health, burnet institute, australia & school of public health and preventive medicine, monash university, australia category: women’s health background. information on the characteristics, sexual behaviour and health needs of sex workers in south africa is limited. current social, legal and institutional factors impede a safe working environment for sex workers and their clients. objectives. to describe the characteristics and sexual behaviour of female, male and transgender sex workers, and assess risk factors for unprotected penetrative sexual intercourse. methods. repeat cross-sectional surveys among sex workers were conducted in hillbrow, sandton, rustenburg and cape town. sex workers were interviewed once and those reporting a re-interview were excluded from the analysis. unprotected sex was defined as any unprotected penetrative vaginal and/or anal sexual intercourse with the last two clients. results. a total of 1 799 sex workers were interviewed between may 2010 and september 2010. sex work was a full-time profession for most participants. participants who reported daily or weekly binge-drinking were 2.1-fold more likely to have unprotected sex than those who reported never binge drinking (adjusted odds ratio (aor), 95% ci 1.2 3.7; p=0.011). compared with females, male sex workers were 2.9-times more likely (aor, 95% ci 1.6 5.3; p<0.001) and transgender people were 2.4-times more likely (aor, 95% ci 1.1 4.9; p=0.021) to have unprotected sex. sex workers in hillbrow, where the only sex-work-specific clinic was operational, were less likely to have unprotected sex than those in other sites. conclusion. tailored sex-work interventions should: explicitly include male and transgender sex workers and sex-work-specific clinics; focus on the risks of unprotected anal sex; and include interventions to reduce alcohol harms. high rate of abacavir resistance in children limits the choice of nrti used in second-line art h sunpath 1,2 , p winternheimer 1 , s cohen 3 , i tennant 4 , r murphy 5 , m gordon 6 , d kuritzkes 8 , v marconi 9 1. mccord hospital, durban; 2. infectious disease unit, university of kwazulu-natal, durban; 3. albert einstein medical school, new york university, usa; 4. university of edinburgh medical school, united kingdom; 5. médecins sans frontières; 6. university of kwazulu natal; 7. hasso plattner laboratory, germany; 8. harvard medical school, usa; 9. emory university school of medicine, atlanta, usa category: children and adolescents background. since 2010, initial antiretroviral therapy (art) for hiv-infected children in south africa has consisted of abacavir (abc), lamivudine (3tc), and efavirenz (efv), while second-line art has comprised zidovudine (azt), didanosie (ddi) and ritonavir-boosted lopinavir (lop/r). we sought to determine the rate of virological failure (vf) and describe prevalent drug-resistance mutations among clade c-infected children. methods. at the sinikithemba clinic at mccord hospital in durban, a retrospective chart review was performed to identify children who initiated abc/3tc/efv or were switched to this treatment without interruption between april 2010 and january 2012. children receiving abc/3tc/efv for at least 24 months and with no prior history of vf (viral load >1 000 copies/µl following at least 6 months of art) were included. characteristics at art initiation, virological outcomes and genotypic resistance patterns (using trugene assay and the stanford database) were recorded with a standardised instrument. results. a total of 221 children receiving abc/3tc/efv were identified; 154 (69.7%) were initiated on this treatment and 67 (30.3%) underwent an uninterrupted switch. fourteen (6%) children experienced vf following a median treatment duration of 11 months (interquartile range (iqr) 8 13). ten patients underwent genotyping: 4 (40%) had the k65r mutation, 4 (40%) had the l74v mutation and 1 (10%) had the l74i mutation. nine (90%) patients had major non-nucleoside reverse transcriptase inhibitor (nnrti)-resistance mutations. conclusion. among children failing abc/3tc/efv treatment, a high level of resistance to abc and nnrtis was observed. importantly, resistance mutations (l74v, k65r and l74i) are likely to reduce the activity of didanosine (ddi) in the second-line regimen. based on these initial data, in the absence of resistance testing and following failure of abc/3tc/efv, we recommend that second-line art comprises azt/3tc/lpv/r in south africa. the recycling of 3tc in the second-line regimen will help to minimise side-effects and preserve azt hyper-susceptibility, and is likely to result in a reduction of viral fitness. retention in care among hiv-infected patients with mental illness in johannesburg, south africa t wagner 1 , g jonsson 2 1. case western reserve university, usa; 2. chris hani baragwanath academic hospital category: antiretroviral therapy background. retention in care is required for optimal clinical outcomes in patients with hiv infection. reasons for loss to follow-up are not well understood, especially with regard to hiv-infected individuals with mental illness. methods. a retrospective analysis was conducted among adult patients with a history of mental illness at an urban hiv clinic in johannesburg, south africa, between july 2010 and september 2011. patients discontinuing follow-up for at least 6 months were identified and traced through home visits to determine health status and reasons for discontinuing care. results. of the 561 adult patients evaluated, 139 (24.8%) discontinued follow-up during the study period. of those discontinuing follow-up, 48 were successfully traced by home visits. among this group, 21 (43.8%) were not engaged in care, 12 (25%) had transferred care, 9 (18.8%) were deceased, 3 (6.2%) had relocated, and 3 (6.2%) were missing. characteristics associated with death in those receiving art were lower baseline cd4 cell counts (median 59 v. 133 cells/µl; p=0.036), lower most recent cd4 cell counts (median 147 v. 285 cells/µl; p=0.022), and higher most recent hiv rna viral loads (median 151 828 v. 557; p=0.015). a significantly higher proportion of those who died had a history of tuberculosis compared with those who were living when traced (p=0.022). the most frequently cited reasons for discontinuing follow-up were: transportation costs and distances; conflicts with work or school schedules; and confusion regarding when to return for care. conclusion. nearly 1/4 patients receiving care at luthando neuropsychiatric hiv clinic over the 14-month review period had discontinued follow-up. however, one-quarter of the patients traced by home visits were engaged in care elsewhere, with the majority still receiving art. tracing patients through home visits proved to be an effective means by which to confirm the magnitude of patients lost to follow-up, ascertain their outcomes, and elucidate their reasons for discontinuing care. profile of young children developing tuberculosis after initiation of antiretroviral therapy e walters 1 , j duvenhage 1 , s van wyk 1 , h rabie 2 1. desmond tutu tb centre, stellenbosch university; 2. tygerberg children’s hospital, cape town category: children and adolescents background. young age and hiv co-infection interact to substantially increase the risk of developing tuberculosis (tb) among children from tb endemic settings. the effect of antiretroviral therapy (art) on incidence and the clinical manifestations of tb in young children requires better description. methods. we retrospectively reviewed clinical and laboratory data of children aged <2 years who initiated art at tygerberg children’s hospital infectious disease clinic, cape town, south africa, from january 2003 to june 2010. tb immune reconstitution (tb-iris) and incident tb were defined as tb treatment episodes within or following 3 months, respectively, of art initiation. the observation period ended when children exited the hospital system for any reason. time spent in trials of novel art agents and prolonged isoniazid prevention therapy were reasons for exclusion from the observation period. results. art was initiated in 531 children including 254 (48%) males. the median age was 7.9 months (interquartile range (iqr) 3.6 31.5) and median cd4 cell count (percentage) was 17.5% (iqr 11.5 26.2). the median follow-up time was 11.4 months (iqr 3.6 31.5). fifty-one (9.6%) of the children died. art was initiated during tb treatment in 125 (23%) children. seventy-one new tb episodes (29 tb-iris) were recorded after art initiation: 58 pulmonary, 5 miliary, 4 tb meningitis, 3 lymphadenitis, and 1 osteo-articular tb. nine (13%) episodes were bacteriologically confirmed. the incident tb rate was 4.6 episodes/100 person years of follow-up. among children who developed tb, the median age and cd4 percentage at art initiation was 6.3 months (iqr 4.5 12.2) months and 18.0% (12.9 25.3), respectively. baseline demographic and immunological characteristics were similar between children with tb-iris v. incident tb. conclusion. young hiv-infected children remain at high risk of tb disease, including disseminated forms, despite a reduction in tb incidence with early art initiation. effective preventive strategies and improved diagnostic methods for tb in this vulnerable group could improve clinical outcomes. safety of sutherlandia fructescens in hiv-seropositive south african adults: an adaptive, double-blinded, randomised, placebo-controlled trial d wilson 1 , k goggin 2 , k williams 2 , m gerkowicz 2 , n gqaleni 3 , j syce 4 , p bartman 1 , q johnson 4 , w folk 2 1. department of medicine, edendale hospital, pietermaritzburg; 2. university of missouri, usa; 3. university of kwazulu-natal, durban; 4. the international center for indigenous phytotherapy studies, university of the western cape, cape town category: hiv complications background. sutherlandia fructescens is widely used as a traditional medication by hiv-seropositive adults living in south africa; however, the safety of the use of the plant has not been studied objectively. an adaptive 2-stage randomised double-blind placebo-controlled study was used to evaluate the use of s. fructescens in healthy hiv-seropositive adults with a cd4 t-lymphocyte count >350 cells/µl. methods. fifty-six participants were randomised in stage 1 of the study to receive 400, 800 or 1 200 mg of s. fructescens twice daily or matching placebo for 24 weeks. no adverse events related to the consumption of s. fructescens were detected; subsequently an additional 77 participants were randomised to 1 200 mg s. fructescens or placebo. data from stages 1 and 2 were combined so that a total of 106 participants were analysed with 53 in each arm, comparing 1 200 mg s. fructescens against placebo. results. s. fructescens was well tolerated; biochemical, haematological and electrocardiographic parameters remained within normal limits for the duration of the study. the changes in hiv viral load and cd4 t-lymphocyte count were similar in the two arms at 24 weeks (p>0.3). the questionnaire scores for physical vitality and energy were similar over the study period between the two arms (p>0.1). the burden of infection (boi) (defined as the number of days of infection-related events experienced by each participant) was greater in the s. fructescens arm: mean 5.0 (5.5) v. 9.0 (12.7) days (p=0.045), and median 9.0 (12.7) v. 18.2 (25.4) days (p=0.065). conclusion. the implications of greater boi observed in the s. fructescens arm need further evaluation. no other safety issues were identified in this cohort relating to the consumption of high-dose s. fructescens. march hiv issue 1-16 the southern african journal of hiv medicine march 2005 55 even after five years of intensive activity by the society, and an increase of membership from 300 to 8 600 health care professionals, i am still frequently asked what it means to be a member of the southern african hiv clinicians society. well, apart from the camaraderie of the executive committee and members, engendered by a collective effort to provide appropriate diagnosis and treatment to southern africa’s hivinfected and affected, the obvious advantages are: quarterly publications: • the southern african journal of hiv medicine • transcript (newsletter containing regional and country branch meeting information and the latest antiretroviral (arv) drug prices) • website*: society structure; executive committee information; latest hiv/aids news; locally produced guidelines; up-to-date private sector arv prices; back issues of journals, and branch meeting information. courses: courses are provided in collaboration with other organisations, e.g. the foundation for professional deve lopment (fpd): • hiv management course (3-day course) • refresher course (1-day course for alumni of the hiv management course). courses are aimed at providing training for health care professionals at different levels of interest, the end-point of which would be to sit the diploma of hiv management, run bi-annually for the last 3 years by the colleges of medicine of south africa and held in various centres throughout south africa and selected cities in other countries. examinations are set and marked by the society executive committee (exco). access to not-for-profit priced antiretrovirals: through agreements with pharmaceutical companies, paid-up members of the society may enroll on access programmes, e.g. glaxo smithkline’s global access programme. guidelines: locally produced guidelines on a large variety of hiv/aids diagnostic, treatment and care topics are compiled by specialist guidelines committees. they are published in the journal and updated on an on-going basis. this issue of the journal contains updated adult art guidelines. current guidelines are in the process of being loaded onto the website. consultancy: a daytime consultancy service for doctors needing specialist advice on difficult cases is provided (currently as a free service) by highly experienced members of the society. advocacy: the exco takes up advocacy issues on the society’s behalf, for example access to treatment, post-exposure prophylaxis (occupational and sexual assault) and other topics, to try to improve the rendering of adequate and appropriate hiv/aids medical services in southern africa. this is aimed at making medical hiv/aids care a more rewarding experience. networking: the society’s database (of 8 600 members) provides an efficient networking and referral tool. health care professionals who need to refer patients to doctors in their towns/centres ring the society offices and are provided with lists of four to five doctors who have completed an hiv management course, together with their contact details. recently the society concluded a three-year memorandum of understanding with the international association of physicians in aids care (iapac) in which the two organisations broadly agreed to collaborate in the areas of expanding medical education; advocacy; and the development of appropriate training materials based on sahcs guidelines. included in this co-operation is an agreement that the society will distribute jiapac (iapac’s quarterly journal) together with the southern african journal of hiv medicine every quarter. another reason to belong! des martin editor, southern african journal of hiv medicine president, southern african hiv clinicians society f r o m t h e e d i t o r if you are not receiving full services from the society, please make sure that you have provided the database manager with your current contact details by e-mailing mr pat solan at: patsolan@global.co.za. * please note: although the society’s upgraded and fully functional website is available to members with access to the web, members who wish to continue to receive journals in hard copy, by post, will do so. members who wish to receive transcript via e-mail or post please send an e-mail to sahivsoc@sahivsoc.org or ring ms samantha klusener at: (011) 453-5066 or fax a note to: (011) 4535059. march hiv issue 1-16 4/16/05 11:06 am page 5 introduction molecular workup results discussion acknowledgements references about the author(s) johannes c. botha department of medical virology, faculty of medicine and health sciences, stellenbosch university, cape town, south africa kim steegen department of molecular medicine and haematology, faculty of health sciences, national health laboratory service, johannesburg, south africa department of molecular medicine and haematology, faculty of health sciences, university of the witwatersrand, johannesburg, south africa mariam edoo department of medicine, helen joseph hospital, johannesburg, south africa jeremy nel department of medicine, helen joseph hospital, johannesburg, south africa department of medicine, university of the witwatersrand, johannesburg, south africa gert u. van zyl department of medical virology, faculty of medicine and health sciences, stellenbosch university, cape town, south africa department of molecular medicine, national health laboratory service, cape town, south africa citation botha jc, steegen k, edoo m, nel j, van zyl gu. low-level viraemia despite emergence of dolutegravir-resistant variants. s afr j hiv med. 2022;23(1), a1398. https://doi.org/10.4102/sajhivmed.v23i1.1398 scientific letter low-level viraemia despite emergence of dolutegravir-resistant variants johannes c. botha, kim steegen, mariam edoo, jeremy nel, gert u. van zyl received: 03 may 2022; accepted: 30 june 2022; published: 30 sept. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. introduction dolutegravir (dtg), an integrase strand transfer inhibitor (insti)-based hiv-1 therapy, is widely recommended in first-line and second-line regimens.1,2 integrase strand transfer inhibitor resistance mutations associated with dtg-containing regimens have been well described, most often occurring after dtg monotherapy or in insti-experienced patients.3although rare, emergence of these mutations has also been described in patients on dtg-containing triple-drug regimens4 and insti-naïve patients.5,6 the r263k mutation is commonly associated with the emergence of dtg resistance but reduces viral fitness and dna integration.7,8 here we describe a case of very slow viral decline (~42 months) in a treatment-experienced, insti-naïve patient on a dtg-based triple therapy regimen. case a 43-year-old man was diagnosed with hiv-1 in 2012 and commenced on an antiretroviral treatment (art) regimen consisting of tenofovir disoproxil fumarate (tdf), emtricitabine (ftc) and efavirenz (efv). initial poor adherence to treatment and virologic failure was reported for 2012–2015 (viral load range 14 269 copies/ml – 173 455 copies/ml), and due to concerns of having possibly acquired resistance to this regimen, treatment was empirically switched according to national guidelines to lamivudine (3tc), zidovudine (azt) and lopinavir/ritonavir (lpv/r). he remained on this regimen with his family practitioner from 2015 until early 2018, when he was referred back to our hospital for persistently high hiv viral loads. he admitted to poor adherence secondary to lpv/r-associated diarrhoea, and was subsequently switched to 3tc, azt and dtg. patient clinical data and treatment history are shown in table 1. after initial viral load decline to 6500 copies/ml the viral load returned to 11 700 copies/ml and non-adherence was suspected. although admitting poor adherence during 2012–2018 the patient claimed perfect adherence since starting his dtg regimen. adherence was confirmed initially by means of directly observed therapy, and then by unannounced random (same-day unscheduled clinic visit requests) 3tc and dtg drug concentration testing on two and four occasions (3tc 1.24 μg/ml – 4.45 μg/ml, dtg 0.583 μg/ml – 1.354 μg/ml in plasma). drug resistance testing on multiple occasions (figure 1) identified m184v which, results in resistance to 3tc and increases susceptibility to azt; k65r was also detected and also increases azt susceptibility.9 integrase sequencing indicated susceptibility to dtg from january 2018 until september 2019 (21 months), after which resistance to dtg (n155h and r263k) was detected (january 2020) in a single sample. follow-up insti drug resistance testing could not confirm dtg resistance. even though dtg resistance was detected at one time point, the viral load continued to decline (figure 1) despite the patient remaining on a dtg-based regimen. plasma samples from three time points and cells (buffy coat/peripheral blood mononuclear cells [pbmcs]) from two time points were collected (s1, s2 & s3) for further investigation (table 1 and figure 1). all samples used in this study were collected after dtg initiation, with the relevant regimen over sampling period s1 and s2 being 3tc/azt/drv/r and s3 being 3tc/azt/dtg. figure 1: patient viral load (blue) and cd4 data (orange) graph displayed in months since dolutegravir initiation indicating samples available for further investigation (black dots) (s1, s2 & s3). routine drug resistance testing performed on multiple occasions are indicated by red dots. table 1: patient clinical data and treatment regimens. molecular workup pbmcs were isolated from freshly collected whole blood ethylenediaminetetraacetic acid specimens according to the hiv/aids network coordination cross-network peripheral blood mononuclear cell processing standard operating procedure (www.hanc.info/labs/labresources/procedures/pages/pbmcsop.aspx). cell-associated dna and rna were isolated from pbmcs and viral rna was isolated from plasma as reported by hong et al.10 single genome amplification products covering the p6-protease-reverse transcriptase (p6prrt) region were generated and sanger sequencing was performed as described previously.11 additionally, single genome amplicons covering the entire polymerase region were analysed for drug resistance mutations. population and single genome nucleotide sequences were analysed for drug resistance mutations. ethical considerations ethical approval was obtained from the university of the witwatersrand, where the patient was enrolled. written informed consent was obtained from the patient. results patient p6prrt nucleotide sequences from s1 (plasma rna and buffy coat dna), s2 (plasma rna) and s3 (plasma rna, cell-associated dna and rna) indicate drug resistance mutation m184v (table 2). table 2: patient p6-protease-reverse transcriptase nucleotide sequences obtained from various sources for each sample with drug resistance mutations detected. mutations n155k and r263k were only detected once in s3 and were confirmed with single genome sequencing (table 3). drug resistance analyses of integrase population and single genome amplicons from plasma rna indicate two distinct populations: insti resistant and insti non-resistant (table 3). these two integrase populations are reflected in phylogenetic analysis (figure 2). figure 2: neighbour joining p-distance phylogenetic tree of integrase nucleotide sequences generated from population and single genome amplicons. table 3: integrase population and single genome sequences indicating associated drug resistance mutations. at the time insti resistance was definitively confirmed, the patient’s hiv viral load had already declined to 50 copies/ml. after much discussion with the patient, the patient elected to continue on his current regimen (rather than switch to a non-dtg-based regimen) with regular hiv viral load monitoring. discussion we report a patient with viral load suppression despite a mixed viral population that includes insti-resistant variants with n155h and r263k. the patient was treatment experienced but insti naïve when initiated on a dtg-based regimen. dtg-resistant mutations n155h and r263k were first detected 24 months after dtg initiation; however, despite this the hiv-1 viral load continued decline to 50 copies/ml after 42 months. it is unclear why the dtg-resistant variants did not outcompete dtg-susceptible variants, but the low viral fitness could have contributed. mutations r263k, m184v and k65r are all associated with decreased viral fitness and here occurred on the same viral variant. the slow but continued viral load decline could be due to the remaining activity and hyper-susceptibility to azt, in the presence of the m184v and k65r mutations.12,13,14,15 moreover cd4+ cell recovery and associated improved cytotoxic t-cell responses could have contributed to immune reconstitution to hiv and resulting viral load decline. although previously thought to be rare, several cases of virological failure as a result of dtg resistance in insti-naïve patients have been described.4,16,17 the factors associated with dtg resistance are poorly understood. whereas dtg resistance when used in first-line therapy is exceedingly rare, it is not unusual when dtg is administered to treatment-experienced patients,1,6 even when previously insti naïve. it is interesting that six of the nine cases of treatment-experienced, insti-naïve cases in the nadia study1 with drug resistance received the same regimen as this patient, albeit that in our case this was given as a third-line regimen in contrast to nadia where the patients received dtg in second-line treatment. reported clinical risk factors associated with emergence of dtg resistance include poor treatment adherence, drug interactions and hiv factors such as a high baseline viral load.6 in this case we report good adherence but the high viral load (> 100 000 copies/ml) prior to dtg initiation could be a contributing risk factor, even though insti resistance was only detected after 24 months. the combination of n155h and r263k is associated with virologic failure on dtg-based regimens,4,18,19 in spite of the fitness cost of r263k.7 even though n155h partially compensates for the r263k viral fitness cost, development of compensatory mutations to the n155h, r263k strain may be unlikely or slow despite drug pressure.20 no additional risk factors were identified in this case. the presence of dtg resistance only partially explains the viraemia in this patient but offers no clarity on the susceptible sub-population. the detectable viraemia could be the result of intermittent adherence or compartmentalised replication or clonal viraemia.11,21,22 random unannounced drug concentration testing on various occasions suggest that intermittent adherence is an unlikely cause of the viraemia. both compartmentalised replication and clonal viraemia could explain the relatively high viral load for an extended period of time. we investigated clonal viraemia in this case as described by halvas et al.,11 but we were not able to find a matching proviral clone to the monotypic plasma virus population (data not shown); further investigation could be performed to shed light on this. this case report provides further evidence that dtg is not impervious to drug resistance, especially when used in treatment-experienced patients. it also suggests that patients with dtg resistance may not present with immediate viral rebound due to the fitness cost of mutations and could present with delayed viral load suppression or low-level viraemia. it is not known whether this patient’s hiv viral load will continue to remain low or whether additional compensatory mutations might allow the drug-resistant variant to regain fitness resulting in rebound. continued vigilance is required when using dtg in treatment-experienced patients and sensitive drug resistance assays may be needed to detect drug resistance at low viral load levels. acknowledgements the patient for participating in this study. the funding body that allowed us to investigate this case. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions patient enrolment and sample collection was done by m.e. and j.n. j.c.b. and g.u.v.z. designed the study. data collection was performed by j.c.b. and k.s. j.c.b., k.s., j.n. and g.u.v.z. analysed the data. j.c.b. wrote the article and all authors reviewed it. supervision of the project was done by g.u.v.z. funding information the assay development was supported by the united states (us) national institutes of health and south african medical research council through its us–south africa program for collaborative biomedical research (national cancer institute grant no. u01ca200441). the funding body had no involvement in study design, data collection or manuscript writing. data availability all figures and data are available within the article. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references paton ni, musaazi j, kityo c, et al. efficacy and safety of dolutegravir or darunavir in combination with lamivudine plus either zidovudine or tenofovir for second-line treatment of hiv infection (nadia): week 96 results from a prospective, multicentre, open-label, factorial, randomised, non-inferiority trial. lancet hiv. 2022;9(6):e381–e393. https://doi.org/10.1016/s2352-3018(22)00092-3 world health organisation. consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection [homepage on the internet]. who; 2016 [cited 2020 sep 28]. available from: https://www.who.int/publications/i/item/9789241549684. rhee s-y, grant pm, tzou pl, et al. a systematic review of the genetic mechanisms of dolutegravir resistance. j antimicrob chemother. 2019;74(11):3135–3149. https://doi.org/10.1093/jac/dkz256 cahn p, pozniak al, mingrone h, et al. dolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with hiv: week 48 results from the randomised, double-blind, non-inferiority sailing study. lancet. 2013;382(9893):700–708. https://doi.org/10.1016/s0140-6736(13)61221-0 pena mj, chueca n, d’avolio a, zarzalejos jm, garcia f. virological failure in hiv to triple therapy with dolutegravir-based firstline treatment: rare but possible. open forum infect dis. 2019;6(1):ofy332. https://doi.org/10.1093/ofid/ofy332 cevik m, orkin c, sax pe. emergent resistance to dolutegravir among insti-naïve patients on first-line or second-line antiretroviral therapy: a review of published cases. open forum infect dis. 2020;7(6):ofaa202. https://doi.org/10.1093/ofid/ofaa202 mesplède t, quashie pk, osman n, et al. viral fitness cost prevents hiv-1 from evading dolutegravir drug pressure. retrovirology. 2013;10:22. https://doi.org/10.1186/1742-4690-10-22 mesplède t, leng j, pham ht, et al. the r263k dolutegravir resistance-associated substitution progressively decreases hiv-1 integration. mbio. 2017;8(2):e00157–17. https://doi.org/10.1128/mbio.00157-17 liu tf, shafer rw. web resources for hiv type 1 genotypic-resistance test interpretation. clin infect dis. 2006;42(11):1608–1618. https://doi.org/10.1086/503914 hong f, aga e, cillo ar, et al. novel assays for measurement of total cell-associated hiv-1 dna and rna. j clin microbiol. 2016;54(4):902–911. https://doi.org/10.1128/jcm.02904-15 halvas ek, joseph kw, brandt ld, et al. hiv-1 viremia not suppressible by antiretroviral therapy can originate from large t cell clones producing infectious virus. j clin invest. 2020;130(11):5847–5857. https://doi.org/10.1172/jci138099 larder b, kemp s, harrigan p. potential mechanism for sustained antiretroviral efficacy of azt-3tc combination therapy. science. 1995;269(5224):696–699. https://doi.org/10.1126/science.7542804 melikian gl, rhee s-y, taylor j, et al. standardized comparison of the relative impacts of hiv-1 reverse transcriptase (rt) mutations on nucleoside rt inhibitor susceptibility. antimicrob agents chemother. 2012;56(5):2305–2313. https://doi.org/10.1128/aac.05487-11 stephan c, dauer b, bickel m, et al. intensification of a failing regimen with zidovudine may cause sustained virologic suppression in the presence of resensitising mutations including k65r. j infect. 2010;61(4):346–350. https://doi.org/10.1016/j.jinf.2010.06.008 wu nc, de la cruz j, al-mawsawi lq, et al. hiv-1 quasispecies delineation by tag linkage deep sequencing. plos one. 2014;9(5):e97505. https://doi.org/10.1371/journal.pone.0097505 lepik kj, harrigan pr, yip b, et al. emergent drug resistance with integrase strand transfer inhibitor-based regimens. aids. 2017;31(10):1425–1434. https://doi.org/10.1097/qad.0000000000001494 aboud m, kaplan r, lombaard j, et al. dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with hiv-1 infection in whom first-line therapy has failed (dawning): an open-label, non-inferiority, phase 3b trial. lancet infect dis. 2019;19(3):253–264. https://doi.org/10.1016/s1473-3099(19)30036-2 blanco jl, rojas j, paredes r, et al. dolutegravir-based maintenance monotherapy versus dual therapy with lamivudine: a planned 24 week analysis of the dolam randomized clinical trial. j antimicrob chemother. 2018;73(7):1965–1971. https://doi.org/10.1093/jac/dky093 quashie pk, mesplede t, han y-s, et al. characterization of the r263k mutation in hiv-1 integrase that confers low-level resistance to the second-generation integrase strand transfer inhibitor dolutegravir. j virol. 2012;86(5):2696–2705. https://doi.org/10.1128/jvi.06591-11 anstett k, fusco r, cutillas v, mesplède t, wainberg ma. dolutegravir-selected hiv-1 containing the n155h and r263k resistance substitutions does not acquire additional compensatory mutations under drug pressure that lead to higher-level resistance and increased replicative capacity. j virol. 2015;89(20):10482–10488. https://doi.org/10.1128/jvi.01725-15 marras d, bruggeman la, gao f, et al. replication and compartmentalization of hiv-1 in kidney epithelium of patients with hiv-associated nephropathy. nat med. 2002;8:522–526. https://doi.org/10.1038/nm0502-522 li jz, gallien s, ribaudo h, heisey a, bangsberg dr, kuritzkes dr. incomplete adherence to antiretroviral therapy is associated with higher levels of residual hiv-1 viremia. aids. 2014;28(2):181–186. https://doi.org/10.1097/qad.0000000000000123 hiv november new november 2005 the southern african journal of hiv medicine14 14. starr se, fletcher cv, spector sa, et al.; pactg 382 study team. pediatric aids clinical trials group. efavirenz liquid formulation in human immunodeficiency virus-infected children. pediatr infect dis j 2002; 21: 659-663. 15. saez-llorens x, violari a, deetz co, et al. forty-eight-week evaluation of lopinavir/ritonavir, a new protease inhibitor, in human immunodeficiency virusinfected children. pediatr infect dis j 2003; 22: 216-224. 16. chadwick eg, rodman j, palumbo p, et al. pactg 1030 study team. a prospective evaluation of pharmacologic, virologic, and immunologic parameters for lopinavir/ritonavir for hiv-1 infected infants < 6 months of age (abstract). in: 12th conference on retroviruses and opportunistic infections, february 2005, boston, ma. 17. pau ak, capparelli ev, holland d, fomundam h, matchaba gu, moodley nk. instability of lopinavir/ritonavir capsules at ambient temperature in subsaharan africa: relevance to who antiretrovirals. aids 2005; 19: 1233-1234. 18. krogstad p, wiznia a, luzuriaga k, et al. treatment of human immunodeficiency virus 1-infected infants and children with the protease inhibitor nelfinavir mesylate. clin infect dis 1999; 28: 1109-1118. 19. schuster t, linde r, wintergerst u, et al. nelfinavir pharmacokinetics in hivinfected children: a comparison of twice daily and three times daily dosing. aids 2000; 14: 1466-1468. 20. hoody dw, fletcher cv. pharmacology considerations for antiretroviral therapy in human immunodeficiency virus (hiv)-infected children. semin pediatr infect dis 2003; 14: 286-294. 21. capparelli ev, mirochnick m, danker wm, et al. pactg study 331 team. pharmacokinetics and tolerance of zidovudine in preterm infants. j pediatr 2003; 142: 47-52. 22. mirochnick m, fenton t, gagnier p, et al. pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. pediatric aids clinical trials group protocol 250 team. j infect dis 1998; 178: 368-374. 23. capparelli e, blanchard s, aweeka f, acosta e. population pharmacokinetics of nevirapine in infants and children – the impact of body size, age, and concomitant therapies (abstract). in: 6th international workshop on clinical pharmacology of hiv therapy 2005, quebec city, ca. 24. litalien c, fay a, compagnucci a, et al. paediatric european network for treatment of aids excecutive committee. pharmacokinetics of nelfinavir and its active metabolite, hydroxy-tert-butylamide, in infants perinatally infected with human immunodeficiency virus type 1. pediatr infect dis j 2003; 22: 48-55. 25. hazra r, balis fm, tullio an, et al. single-dose and steady-state pharmacokinetics of tenofovir disoproxil fumarate in human immunodeficiency virusinfected children. antimicrob agents chemother 2004; 48: 124-129. hiv infection is a multisystem disease characterised by progressive immunodeficiency and increasing susceptibility to common and opportunistic pathogens. progressive disease is characterised by reversible and then permanent end-organ dysfunction due to hiv itself or co-pathogens, and also an increased risk of malignancy. the hallmark of immunodeficiency is cd4+ lymphocyte depletion, although other elements of the immune system are also deranged. children with hiv are classified according to clinical and immunological criteria. both systems are useful for individual patient management, and together are more useful than either parameter individually. classification into mutually exclusive categories allows standardisation of this complex multisystem disease process, facilitating case management and informing the clinician of both the extent of clinical progression and prognosis. because of the varied prevalence of pathogens in different geographical areas, disease manifestations may differ. some pathogens, such as pneumocystis jiroveci and cytomegalovirus (cmv), will cause the same disease manifestations in any location. others, such as mycobacterium tuberculosis, are more prevalent in sub-saharan africa than elsewhere. a classification system should take cognisance of this variability. decisions to initiate antiretroviral therapy (art) or to change therapy because of regimen failure are based on an understanding of disease progression. lastly, the classification system allows for surveillance, facilitating planning by ministries of health for adequate resources and equitable access to care. differences between adults and children as children are growing and developing, many clinical manifestations may be unique to children. both the immunological system and organs grow and develop in children but are static in adults. the cd4 percentage stays relatively constant, but there is a decline in cd4+ t-cell numbers as children mature. cd4 cells may be functionally immature, most graphically illustrated by the finding of a high s t a g i n g classification of hiv disease in children – towards pragmatism? mark f cotton, mb chb, mmed (paed), phd, fcpaed (sa), dtm&h, dch (sa) kid-cru and paediatric infectious diseases unit, tygerberg children’s hospital, faculty of health sciences, stellenbosch university hiv november new 13/12/05 12:43 pm page 14 prevalence of pneumocystis pneumonia (pcp) in young infants with far higher cd4 counts or percentages than would occur in adults. age is an important determinant for rapid progression in infants. conditions such as lymphoid interstitial pneumonitis (lip) are recognised more commonly in children than adults. differences in disease manifestation between adults and children are shown in fig. 1 (a and b). in infants, young age and immunological immaturity are probably the most important determinants of disease. the centers for disease control and prevention classification the centers for disease control (cdc) classification was first introduced in 1987 and modified in 1994.1,2 it comprised clinical and immunological components, recognising that there could be discordance between the two. such discordance has been shown in south african children.3 clinical categories range from asymptomatic (n) to mild symptoms and signs (a), moderate severity (b) and severe (c) (table i). immunological stages range from no cd4+ depletion (stage 1) to moderate depletion (stage 2) and severe depletion (stage 3) (see table ii in the paediatric art guidelines, p. 20). the classification is well accepted and has shown excellent predictive value, especially in north american and european children. for example, in an analysis for the pediatric spectrum of diseases project, barnhart and colleagues could differentiate between the different stages of disease (table i).4 in an african setting, although the classification is useful, it is sometimes difficult to fit symptomatic children into the classification system. for example, in a study from malawi, because of high mortality by 3 years of age only 10% of children were in stage b or c as the majority had already died.5 inconsistencies there are a number of inconsistencies in the classification. for example, two episodes of bacterial infection within a 2-year period, responding well to antibiotics, and lymphoma are both classified in c. leiomyosarcoma is in b, but kaposi’s sarcoma is in c. congenital cmv or toxoplasmosis are in b, but if of later onset are in c. congenital or early infection may be even more devastating than later onset as it may be acquired from an immunosuppressed mother, facilitating the transfer of large numbers of pathogens to a fetus. for stage b, some conditions have a worse prognosis than others. galli et al. found that anaemia, candidiasis, diarrhoea, cardiomyopathy, hepatitis and persistent fever had a worse prognosis than other events.6 hiv-associated nephropathy leads to renal failure and death, yet is also in b, while a chronic herpetic ulcer that may respond to acyclovir is in c. many conditions seen in africa are inadequately addressed. failure to thrive occurs commonly in an african setting and is an independent risk factor for mortality.3 in the cdc classification, wasting must be accompanied by either chronic diarrhoea or fever for at least 30 days to be classified in c. tuberculosis is especially common in hiv-infected children.7-9 only disseminated tuberculosis is addressed in the cdc the southern african journal of hiv medicine november 2005 stage time in category time to stage c percentage reaching percentage 5-year median survival (months) (years) stage c in 5 years survival (years) n 10 6.6 50 75 8 a 4 5.7 58 67 7.1 b 65 5.4 60 65 6.8 c 34 17 1.9 table i. disease stages in hiv-infected children in the usa, 1982 1993, prior to highly active antiretroviral therapy 1 5 fig. 1. relationship between cd4 cells, disease and time in adults (a) and children (b). a b hiv november new 13/12/05 12:43 pm page 15 november 2005 the southern african journal of hiv medicine16 classification. a child with multiple episodes of pulmonary tuberculosis may therefore not be adequately classified. disseminated bacillus calmette-guérin disease is an emerging problem with an extremely poor prognosis yet is also not addressed.10 chronic lung disease, especially bronchiectasis, is seen commonly in children who have not had access to art, but is not addressed in the cdc system. lip is classified in b and is considered to have a relatively good prognosis.11 the differentiation between lip and bronchiectasis is not easy, and many children with bronchiectasis may be misdiagnosed as having lip, therefore possibly not receiving art as they are not considered sick enough. rectovesical and rectovaginal fistulas are also not addressed but have an extremely poor prognosis.12 world health organization classification the world health organization (who) developed a four-stage classification system for adults in 1994.13 the staging system has proved useful in africa and elsewhere.14-16 a three-stage paediatric classification was introduced in 2002.17 while superficially easy to use, it did not address many conditions seen in hiv-infected infants. in 2004, after a period of deliberation with paediatricians experienced in treating hivinfected children, a revised four-stage system was introduced (table ii).18 it was felt that a four-stage system would be less confusing for health care workers, especially those also dealing with adults, and in addition would assist the transition of children to adulthood when care might be transferred to an adult clinic. stage 1 is asymptomatic. stage 2 includes mainly minor mucocutaneous disorders. hepatomegaly, hepatosplenomegaly and splenomegaly were placed in stage 2 rather than stage 1 as their presence has been associated with more rapid progression.19,20 stages 3 and 4 include conditions seen with progressive disease, stage 4 being more serious and more likely to result in early death. pulmonary tuberculosis is in stage 3. despite this, tuberculosis is not an automatic indication for art; rather, the clinical situation should be evaluated for each child. the who recommends art for both stages 3 and 4. malnutrition is better addressed, with moderate being a stage 3 and severe a stage 4 event. bronchiectasis has been included in stage 3 and rectovesical or rectovaginal fistula in stage 4. aspects of the classification system still need to be refined. the separation of minor mucocutaneous disorders into a separate stage may be artificial. wananukul has found increasing frequency of these disorders with increasing disease severity.21 areas that need to be addressed include multiple episodes of tuberculosis and whether prognosis worsens with cumulative acquisition of staging criteria. malnutrition has been integrated into the classification in a way that is understandable to south african health care workers, with underweight for age allowing classification in stage 3 and marasmus allowing classification in stage 4. pneumonia occurs commonly and is easily treated with stage 1 asymptomatic persistent generalised lymphadenopathy (pgl) hepatosplenomegaly stage 2 recurrent or chronic upper respiratory tract infections (otitis media, otorrhoea, sinusitis) papular pruritic eruptions seborrhoeic dermatitis extensive human papillomavirus infection extensive molluscum infection herpes zoster fungal nail infections recurrent oral ulcerations lineal gingival erythema (lge) angular cheilitis parotid enlargement stage 3 conditions where a presumptive diagnosis can be made using clinical signs or simple investigations unexplained moderate malnutrition† not adequately responding to standard therapy (< 3rd centile) unexplained persistent diarrhoea (14 days or more) unexplained persistent fever (intermittent or constant, for longer than 1 month) oral candidiasis (outside neonatal period) oral hairy leukoplakia acute necrotising ulcerative gingivitis/periodontitis pulmonary tuberculosis‡ severe recurrent presumed bacterial pneumonia conditions where confirmatory diagnostic testing is necessary lymphoid interstitial pneumonitis (lip) unexplained anaemia (< 8 g/dl), neutropenia (< 1 000/mm3) or thrombocytopenia (< 50 000/mm3) for more than 1 month chronic hiv-associated lung disease including bronchiectasis stage 4 conditions where a presumptive diagnosis can be made using clinical signs or simple investigations unexplained severe wasting or severe malnutrition§ not adequately responding to standard therapy (< 60% expected body weight) pneumocystis pneumonia recurrent severe presumed bacterial infections (e.g. empyema, pyomyositis, bone or joint infection, meningitis, but excluding pneumonia) chronic herpes simplex infection (orolabial or cutaneous of more than 1 month’s duration, visceral of any duration) extrapulmonary tuberculosis kaposi’s sarcoma oesophageal candidiasis cns toxoplasmosis (outside the neonatal period) hiv encephalopathy conditions where confirmatory diagnostic testing is necessary cmv infection (cmv retinitis or infection of organ other than liver, spleen, or lymph nodes, onset at age 1 month or more) cryptococcal meningitis (or other extrapulmonary disease) any disseminated endemic mycosis (e.g. extrapulmonary histoplasmosis, coccidiomycosis, penicilliosis) cryptosporidiosis isosporiasis disseminated non-tuberculous mycobacteria infection candida of trachea, bronchi or lungs acquired hiv-related rectal fistula cerebral or b-cell non-hodgkin's lymphoma progressive multifocal leukoencephalopathy (pml) hiv-related cardiomyopathy or hiv-related nephropathy stage on art *interim africa region version, for use in those under 15 years with confirmed laboratory evidence of hiv infection; hiv antibody where age >18 months, virological or p24 ag testing where age < 18 months. †moderate malnutrition: defined as very low weight for age – http://www.who.int/childadolescent-health/publications/child_health/who_fch_cah_00.1. htm or http://www.who.int/nut/documents/manage_severe_malnutrition_eng.pdf ‡tb is particularly difficult to diagnose in infants and young children. §severe malnutrition: defined as very low weight or visible severe wasting or oedema of both feet – http://www.who.int/child-adolescent-health/publications/child_health/ who_ fch_cah_00.1.htm table ii. revised who clinical staging of hiv for infants and children* hiv november new 13/12/05 12:43 pm page 16 the southern african journal of hiv medicine november 2005 1 7 antibiotics. for this reason pneumonia has been separated from other causes of bacterial sepsis and is in stage 3. this is of special relevance to children already on art, in whom intercurrent pneumonia, responding to antibiotics, occurs commonly. in many parts of africa, although hiv antibodies can be tested easily in infants below 18 months, virological confirmation is either not possible or takes too long. for these circumstances, the who has developed criteria for presumptive stage 4, where art is indicated (table iii). for the first time this recognises that hiv manifests as a symptom complex rather than just a single staging condition. it also provides justification for starting art in symptomatic infants without virological confirmation. a few inconsistencies remain. for example, diarrhoea persisting for > 30 days should be classified in stage 4 regardless of whether a pathogen such as cryptosporidium parvum is identified. conclusion the who classification has acknowledged conditions commonly seen in africa and should help with management of children. a revision has been scheduled for 2006. clinicians working with children have an opportunity for input in improving the classification. references 1. centers for disease control and prevention. classification system for human immunodeficiency virus (hiv) infection in children under 13 years of age. mmwr morb mortal wkly rep 1987; 36: 225-230. 2. centers for disease control and prevention. 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age. mmwr morb mortal wkly rep 1994; 43: rr1-12. 3. van kooten niekerk nk, knies mm, howard j, et al. the first 5 years of the family clinic for hiv at tygerberg hospital: family demographics, survival of children and early impact of antiretroviral therapy. j trop pediatr 2005; 9 june. 4. barnhart hx, caldwell mb, thomas p, et al. natural history of human immunodeficiency virus disease in perinatally infected children: an analysis from the pediatric spectrum of disease project. pediatrics 1996; 97: 710-716. 5. taha te, graham sm, kumwenda ni, et al. morbidity among human immunodeficiency virus-1-infected and -uninfected african children. pediatrics 2000; 106(6): e77. 6. galli l, de martino m, tovo pa, gabiano c, zappa m. predictive value of the hiv paediatric classification system for the long-term course of perinatally infected children. int j epidemiol 2000; 29: 573-578. 7. schaaf hs, geldenduys a, gie rp, cotton mf. culture-positive tuberculosis in human immunodeficiency virus type 1-infected children. pediatr infect dis j 1998; 17: 599-604. 8. jeena pm, pillay p, pillay t, coovadia hm. impact of hiv-1 co-infection on presentation and hospital-related mortality in children with culture proven pulmonary tuberculosis in durban, south africa. int j tuberc lung dis 2002; 6: 672-678. 9. kiwanuka j, graham sm, coulter jb, et al. diagnosis of pulmonary tuberculosis in children in an hiv-1 endemic area, malawi. ann trop paediatr 2001; 21: 5-14. 10. hesseling ac, schaaf hs, hanekom wa, et al. danish bacille calmette-guerin vaccine-induced disease in human immunodeficiency virus-infected children. clin infect dis 2003; 37: 1226-1233. 11. hussey gd, reijnhart rm, sebens am, burgess j, schaaf s, potgieter s. survival of children in cape town known to be vertically infected with hiv-1. s afr med j 1998; 88: 554-558. 12. wiersma r. hiv-positive african children with rectal fistulae. j pediatr surg 2003; 38(1): 62-64; discussion 62-64. 13. who case definitions for aids surveillance in adults and adolescents. wkly epidemiol rec 1994; 69(37): 273-275. 14. aylward rb, vlahov d, munoz a, rapiti e. validation of the proposed world health organization staging system for disease and infection in a cohort of intravenous drug users. aids 1994; 8: 1129-1133. 15. post fa, badri m, wood r, maartens g. aids in africa – survival according to aids-defining illness. s afr med j 2001; 91: 583-586. 16. kassa e, rinke de wit tf, hailu e, et al. evaluation of the world health organization staging system for hiv infection and disease in ethiopia: association between clinical stages and laboratory markers. aids 1999; 13: 381-389. 17. world health organization. scaling up antiretroviral therapy in resource limited settings: guidelines for a public health approach. 22-04-02 2002. 18. world health organization. interim who clinical staging of hiv/aids and hiv/aids case definitions for surveillance african region. available at: whqlibdoc.who.int/hq/2005/who_hiv_2005.02.pdf (accessed 18 september 2005). 19. tovo pa, de martino m, gabiano c, et al. prognostic factors and survival in children with perinatal hiv-1 infection. the italian register for hiv infections in children. lancet 1992; 339: 1249-1253. 20. diaz c, hanson c, cooper er, et al. disease progression in a cohort of infants with vertically acquired hiv infection observed from birth: the women and infants transmission study (wits). j acquir immune defic syndr hum retrovirol 1998; 18: 221-228. 21. wananukul s, thisyakorn u. mucocutaneous manifestations of hiv infection in 91 children born to hiv-seropositive women. pediatr dermatol 1999; 16: 359363. ■ hiv seropositive infant less than 18 months symptomatic with 2 or more of following: oral thrush, +/severe pneumonia, +/severe wasting/malnutrition, +/severe sepsis, severe immunosuppression should be suspected and arv treatment is indicated ■ cd4 values where available may be used to guide decision making, cd4% below 25 requires arv treatment ■ other factors that support diagnosis of clinical stage 4 hiv infection in an hiv-seropositive infant are recent maternal death or advanced hiv disease in mother ■ confirmation of the diagnosis of hiv infection should be sought as soon as possible table iii. presumptive stage 4 hiv infection in infants below 18 months of age where virological confirmation is not possible hiv november new 13/12/05 12:43 pm page 17 commencing paediatric art tammy meyers, fcpaed (sa) paediatric hiv cliuic, chris halli baragwallath hospital. johannesburg when to start antiretrovlral therapy in hiv-infected children children over 12 months of age 1. always start art if: • clinical stage cor o cd4 < 15'lb 2. consider art if: • clinical stage b+ or o cd4 <2mb or -vl> slog 3. defer art if: • stage n or a disease, and o cd4 > 2ql1b and o iowvl< 5 log who paediatric classification of hiv/aids stage i o asymptomatic o generalised lymphadenopathy stage 11 • unexplained chronic diarrhoea • recurrent severe bacterial infection • oral candidiasis beyond neonatal period (severe persistent or recurrent) • persistent fever stage iii • aids opportunistic infection • severe failure to thrive • progressive encephalopathy • recurrent septicaemia • malignancy recently draft guidelines have also been published by the world health organisation (who).; the who recommends offering art to hiv-infected infants with virologically proven infection and who paediatric stage iii disease (aids) or who paediatric stage i and ii hiv disease and a cd4% < 200/0. for children >18 months who are hiv antibody-positive, the who recommends art if they have category a, b, c) children and those with any immune suppression [immune category 2 or 3, cd4% < 25%). the pediatric european network for the treatment of aids (penta) group have updated treatment guidelines that adopt a less aggressive approach' (table i). -----------octolltr 2002 table i. recommendation on when to start art infants 1. always start if any of: o clinical stage c o cd4 < 2ql1b o rapidly falling cd4'lb (irrespective of value), and lor o vl persistently> 10' copies/m i 2. consider art in any infant irrespective of clinical or immunological stage • somt authors rroxrunmd starting if dinic:al stagt b. but~ is no c'of'iso"isljs vl viral1oad. thf southtrn african journal of hiv mfoici f guideunes the right time to start antiretroviral therapy (art) in adults and children is currently a topic of much discussion. delaying the initiation of art in children until absolutely necessary is of compelling importance for several reasons. experience in the usa and europe shows that achieving adequate long-term adherence in children remains a major challenge. poor adherence is responsible for the emergence of resistant strains of hiv, resulting in treatment failures. prolonged art in children also exposes them to the increased risk of toxic side-effects. metabolic complications (lactic acidosis, lipodystrophy) of art have been well documented in adults and are now being described in children." importantly, in settings where resources are limited, delayed initiation of treatment could be a mechanism for reducing the cost of management. adult guidelines from both europe and north america now advocate that therapy be initiated when the cd4 count is 200 350 cells/~1. historically, art has always been recommended for use in almost all children, regardless of the clinical staging of the disease. the recently updated guidelines from the centers for disease control (cdc) still advocate initiation of art for all infants less than 1 year of age.' the guidelines also continue to debate the initiation of art in older, mildly affected children, but advocate early commencement of therapy for all symptomatic [clinical months since enrolment 130 23.8 62 25.8 60 73.3 no. of children 'lb mortality 31 16 44 deaths 1.0 hili cd4% 8 l i i 30+l.-.6 \ 20-29 15--19 .4 , l 10-14.2 0-9 0.0 0 6 12 18 24 30 36 thf southern african journal of hiv mfoicinf cd4'lb > 25 15-25 <15 table 11. correlation of cd4 cellofo wffil mortauty clinically and have annual tests for virological and immunological deterioration. survival to 3 years by kaplanmeier methods was significantly associated with higher cd4% and higher weight-for-age at enrolment (figs 1 and 2)." children with cd4% < 10% had the worst outcomes, with no significant difference between the groups at higher levels. those with weight-for-age z-scores less than -2 sd also had a significantly poorer outcome than the others. viral load at baseline was not a useful predictor of outcome over the 3 years. clinical status at enrolment predicted 88% of the deaths. data from a north american study of 254 untreated children with mild to moderate symptoms of hiv show similar outcomes. mean cd4% was 25% and there was a mean observation period on study of 5.1 years. survival statistics demonstrated dramatic thresholds at a cd4% of> 15% (table 11)." fig. 7. survival by cd4% at baseline. fig. 2. survival by weight-for-age z-score at boseline. months since enrolment 1.0 .8 .6 ~ < oi .4 weight-far-age <-250 .2 >=-250 0.0 0 6 12 18 24 30 36 who stage iii hiv disease (aids) regardless of cd4 percentage. in children over 18 months of age with who stage i or 11 hiv disease, art is recommended if the cd4 percentage is <15ofo (who clinical staging for children). the south african guidelines printed in this journal advocate in itiation of treatment in the following situations: • clinical category 8 (except for a single episode of bacterial sepsis or a single episode of zoster) or c, or • cd4%< 20%. the rationale for the aggressive therapeutic approach in north america stems from the belief that initiating highly active antiretroviral therapy [haart) may attenuate the severity of hiv infection and improve immune recovery. while there is some evidence that 'hitting hard' may be of benefit in early infection.' whether this is true once infection is established needs further investigation. there are no data at present showing that early initiation of therapy is associated with an improved long-term clinical outcome. the benefits of early therapy in infants also need to be weighed against the long-term exposure of the child to relatively toxic drugs. which guideunes? a cohort of 51 hiv-infected children at chris hani baragwanath hospital has been followed up over 3 years. children selected were age-matched according to clinically defined mild (n ~ 26) or severe (n ~ 25) disease (median age 4 years). these children have been followed up what criteria for treatment deferral are safe for children? deciding when to start therapy can become complex given all these different guidelines. clearly, where resources are limited it is almost impossible to adopt such an aggressive approach if we are to treat thousands of hiv-infected children. delaying art for a few years would certainly be one way of sparing some of the expense of treatment. there is evidence that delaying initiation of art is a reasonable approach in some children. it has been reported that 40 50% of vertically hivinfected children survived to around 10 years of age without art.'"' mortality in a cohort of hiv-infected children in malawi demonstrated 55% survival to 3 years of age" in the penta 1 trial, no added benefit was demonstrated for starting zidovudine early over deferring until the development of symptoms." in adults, immune recovery appears to be independent of the baseline cd4 count as long as art is started before the cd4 count falls below 200" in addition, although art can markedly reduce viral replication, it has become clear that it does not 'eliminate the virus. october. 2002 ----------references -----------octoefr 2002 combination antirwoviral merapy. j pros 2001; 138: 5. 3. fne working group on anoretrdviraj tnerapy and medical management of hivinfected children. guidclin~ for the u~ of antireuoviral agents in pediatric hiv infection, 2001 www.hivatis..org 4. sharland m, gattinara di zub gc, rames jt. et al. penta gjidelin~ for the us(: of antireuoviral therapy in pcediauic hili inf~on. hfv m~icjne 2002; 3: 3. 5. scaling up antireuovirdl tnerapy in resourct·limit~ settings. guicelin~ for a pubiic hta1ttj approach. exec~tive summary, who, april 2002. 6. luzugl.ria k. mcmanus m, car<ilir1a m, er al early therapy of vertical human immunodeficiency virus lylj('-l ih -i} irfection:conuol of viral replication ami absence of persistent hlv-i 5p('cific immune r5ponses.. ) viroj 2ocxj; 74: 69846991. 7. towo pa. dt marino m, gab:ano c. etaj. prq9nostic faetol'5 and survival in children with perinatil hlv-l inftttion. i..an~t 1992; 339: n~9·1253. 8. european collabor,ane study. natura history of vtt'ticajy acquired human immunodeficiency virw; 1 ir,'"ection. fh!iauics 1994; 94: 815-819. 9. b,anche s, tardieu m, d![tge am, et al ldngirudinal srudy of 94 symptomatic infants with perinarahy acquired human immunodeficiency virus infection: evidence of a bimodal expr~on of dinical and biological symptoms.. am) dis child 1990; 144: 121()..1215. 10. taha le, kum..... enda ni, broaaliead rl, er al. mortality ai'ter trle first year of life among human immunoceficiency virus type-l infected childrerl pediou infect dis j 1999; 18: 689-694. it paaiiatric european networ'( for treatment of aids (penial. fm year follow up of vertically infected cildren in a randomized double blind controlled trial o' immediate versus deferrec zidov'.idine: the penta 1 trial atch dis child 2001; 84: 23()'-236. 12. franco jm, leon-leal la, lea! ja. et aj. c04+ and c08+ iymphocyte regeneration ai'ter antireuoviral therapy in hlv-i infected children and adult patients. oin exp immuno/2cxxl; 119: 493-498. 13. meyers t, kuhn l neddo"ns-tayfor 5, etol ddayed antiretroviral therapy iarn in a drug naive hlv symptomatic paediatric population, when should it be staned? 14th international aids conf('(enct", barcelona labstract moorbl131). 14. mofenson lm, korelitz j, meyer wa, r:tol. the relationship !le:twetn serum human immunodeficiency virus type 1 (hiv1) rna levd, c04lymphocyte percent and long·term mortafity risk in hlv-l-infected children. national institute of child health and human devefopment intravenous immunoglobulin oinical trial study group.) infect dis 1997; 175: 1029-1038. 1. jaquet d. l.evine m, orte9a-rodriguti e. et ol oinical and mmbolic presentation of the lipodysuophic syndrome in hn inf~ted children. aids20c<l; t4: 2123-2128. 2. church ja, mitchell wg, gonzalez-gomez i, et al. mitochondrial dna depletion, near-fatal metabolic acidosis, and liver failurl:' in ..n hiv-infected child treated with it is hoped that the guidelines presented in this journal will provide a wide safety net for the initiation of therapy. in the south african context, where facilities are available for those who are on medical aid or who are able to pay for medication, it seems prudent to offer this wide safety margin. if art becomes more widely accessible in the public sector, implementation of the who guidelines may be a more affordable option. deferring treatment should not, however, preclude continued and regular monitoring. if it is decided that a child does not require therapy at the initial visit the patient should be monitored at regular intervals (3 6-monthly) for clinical and immunological deterioration so that treatment can be started timeously. continued monitoring ensures that the risks of delaying therapy are minimised as much as possible. the concern remains whether delaying therapy will ultimately affect immune recovery, thereby compromising the long-term outcome, and this needs further research. rh southfrn mrican journal of hiv mfoicinf abstract introduction methods results discussion conclusion acknowledgements references about the author(s) lisa p. spees department of health policy and management, gillings school of global public health, university of north carolina at chapel hill, chapel hill, nc, united states of america lineberger comprehensive cancer center, university of north carolina, chapel hill, nc, united states of america kathleen e. wirth department of biostatistics, faculty of health sciences, harvard t.h. chan school of public health, boston, ma, united states of america botswana international training and education center for health (i-tech), gaborone, botswana shreshth mawandia department of health policy and management, faculty of medicine, botswana international training and education center for health, gaborone, botswana department of global health, university of washington, seattle, wa, united states of america semo bazghina-werq department of global health, university of washington, seattle, wa, united states of america independent global health consultant, washington, dc, united states of america jenny h. ledikwe department of health policy and management, faculty of medicine, botswana international training and education center for health, gaborone, botswana department of global health, university of washington, seattle, wa, united states of america citation spees lp, wirth ke, mawandia s, bazghina-werq s, ledikwe jh. sexual risk compensation following voluntary medical male circumcision: results from a prospective cohort study amongst human immunodeficiency virus-negative adult men in botswana. s afr j hiv med. 2020;21(1), a1157. https://doi.org/10.4102/sajhivmed.v21i1.1157 original research sexual risk compensation following voluntary medical male circumcision: results from a prospective cohort study amongst human immunodeficiency virus-negative adult men in botswana lisa p. spees, kathleen e. wirth, shreshth mawandia, semo bazghina-werq, jenny h. ledikwe received: 19 aug. 2020; accepted: 21 oct. 2020; published: 14 dec. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: circumcised men may increase sexual risk-taking following voluntary medical male circumcision (vmmc) because of decreased perceptions of risk, which may negate the beneficial impact of vmmc in preventing new human immunodeficiency virus (hiv) infections. objectives: we evaluated changes in sexual behaviour following vmmc. method: we conducted a prospective cohort study amongst sexually active, hiv-negative adult men undergoing vmmc in gaborone, botswana, during 2013–2015. risky sexual behaviour, defined as the number of sexual partners in the previous month and ≥ 1 concurrent sexual partnerships during the previous 3 months, was assessed at baseline (prior to vmmc) and 3 months post-vmmc. change over time was assessed by using inverse probability weighted linear and conditional logistic regression models. results: we enrolled 523 men; 509 (97%) provided sexual behaviour information at baseline. at 3 months post-vmmc, 368 (72%) completed the follow-up questionnaire. at baseline, the mean (95% confidence interval) number of sexual partners was 1.60 (1.48, 1.65), and 111 (31% of 353 with data) men reported engaging in concurrent partnerships. at 3 months post-vmmc, 70 (23% of 311 with data) reported fewer partners and 19% had more partners. amongst 111 men with a concurrent partnership at baseline, 52% reported none post-vmmc. amongst the 242 (69%) without a concurrent partnership at baseline, 19% reported initiating one post-vmmc. after adjustment for loss to follow-up, risky sexual behaviour post-vmmc (measured as mean changes in a number of partners and proportion engaging in concurrency) was similar to baseline levels. conclusion: we found no evidence of sexual risk compensation in the 3 months following vmmc. keywords: circumcision; hiv prevention; botswana; sexual behaviour; risk-taking; prospective studies. introduction three randomised controlled trials (rcts) from sub-saharan africa showed that voluntary medical male circumcision (vmmc) reduced human immunodeficiency virus (hiv) transmission from females to males by up to 60%.1,2,3 mathematical models suggest that hiv incidence will decrease in circumcised men, and subsequently in women and uncircumcised men, as the uptake of vmmc increases.4,5,6 botswana has the fourth highest hiv prevalence in the world, with one in five adults infected.7 whilst 83% hiv-positive individuals are receiving treatment, hiv incidence remains high.7 in 2018, 8500 new hiv infections were diagnosed.7 in botswana, it is estimated that expanding vmmc coverage would avert 4900 new hiv infections through 2030.8 there are concerns that circumcised men may be more likely to engage in risky sexual behaviours following surgery because of their perception of the reduced risk of hiv acquisition conferred by circumcision. this phenomenon, known as risk compensation or behaviour disinhibition, may reduce the effectiveness of vmmc in preventing new hiv infections. although rcts conducted in kenya and uganda indicated that risk compensation behaviour did not increase following circumcision,9 a rct conducted in south africa documented a higher number of sexual contacts amongst circumcised men compared with uncircumcised men in the control group.1 however, amongst recent cross-sectional surveys conducted in south africa, uganda and kenya, there was no evidence that circumcised men’s behaviour was riskier than uncircumcised men’s behaviour.10,11,12 men circumcised in non-clinical trial settings may also encounter different experiences and behave differently. however, little is known about how sexual behaviour changes in real-world settings, as there have been only two studies that examined men’s sexual behaviours before and after undergoing vmmc.13,14 although the two studies, both conducted in south africa, found minimal or no evidence of risk compensation, no studies have examined risk compensation in botswana, where the rate of multiple and concurrent sexual partnerships is particularly high. recently published findings from a large population-based sample found that 31% of sexually active adults in botswana had concurrent sexual partners in the past year.15 we conducted a prospective cohort study amongst men aged 18–49 years undergoing vmmc in botswana to evaluate the changes, if any, in the frequency of high-risk sexual behaviour following vmmc, including the total number and timing of sexual partnerships during the previous 3 months. methods study design this clinic-based prospective cohort study was designed to assess (1) the frequency, type and severity of adverse events immediately following vmmc; (2) the prevalence and correlates of re-initiation of sexual activity and (3) changes in risky sexual behaviour following vmmc. the current analysis reports on the third primary objective. the study was conducted by the international training and education center for health (i-tech), a collaboration with the university of washington and the university of california, san francisco. recruitment and enrolment of study participants occurred before undergoing vmmc, but after individuals completed group education and individual counselling with clinic staff (including hiv testing) and provided written, informed consent for the procedure. neither the pre-procedure activities described above nor the procedure itself was performed by study staff. the overall objective of botswana’s national safe male circumcision programme is to reach a male circumcision prevalence rate of 80% amongst 0–49-year-old hiv-negative males. a complete description of the programme, including details on the procedure itself, can be found elsewhere.16 study setting and participants adult men undergoing vmmc through the national safe male circumcision programme were enrolled between november 2013 and april 2015 at two government-run clinics providing free circumcision services in gaborone, the capital city of botswana. participant eligibility criteria included: age ranging 18–49 years, residence within 25 km of gaborone, ever had sexual intercourse and documented hiv-negative test result. all participants provided written informed consent for participation in the study in addition to the consent obtained by clinic staff for the circumcision procedure. sample size for study planning purposes, we computed sample size requirements (and corresponding power) based on the dichotomous outcome and engagement in concurrent sexual partnership(s) during the previous 3 months. we used mcnemar’s test for two correlated proportions to determine the number of participants enrolled and the corresponding power to detect the smallest, clinically meaningful difference in the proportion of men who report engaging in a concurrent sexual partnership between baseline and 3 months post-circumcision.17 figure 1 shows the summary of the proportions associated with all possible responses under this framework. figure 1: contingency table used for calculating power based on mcnemar’s test of two correlated proportions. specifically, pb and pfu represent the total proportion of individuals reporting high-risk sexual behaviour at baseline and follow-up, respectively; p01 and p10 represent the proportion of individuals who increase or decrease their high-risk sexual behaviour between baseline and follow-up, respectively. we explicitly chose to test a one-sided alternative that high-risk sexual behaviour increases at follow-up (as opposed to the two-sided alternative of any change) to reflect the conceptual definition of risk compensation. thus, assuming a baseline prevalence of sexual concurrency (pb) of 19%,18 10% were unable to undergo vmmc because of medical or other contraindications and 20% were lost to follow-up, power was estimated to be > 80% to detect a 5% increase in the proportion of men who engage in high-risk sexual behaviour at 3 months post-circumcision (relative to baseline) based on a sample size of 523 participants. power was estimated to be 99% for a 10% increase at 3 months post-vmmc. measures in addition to the primary endpoints, the baseline questionnaire also collected information on demographics (age, current relationship status and religious affiliation), socioeconomic indicators (education, employment status, electricity in household, refrigerator in household and use of wood as cooking fuel), frequency and intensity of alcohol consumption, age at sexual initiation and history of transactional sex. we also collected information on the primary reason for getting circumcised (i.e. protecting against hiv, personal hygiene or other), whether the participant believed circumcision would have a negative, positive or no impact on the quality of sex, and administered a four-question scale developed in south africa to assess attitudes towards condom use, monogamy and hiv risk in the context of circumcision.19 lastly, we constructed two indicators evaluating the accuracy of participants’ knowledge regarding the effect of vmmc on female-to-male and male-to-female hiv transmission. specifically, we classified men as having correct knowledge if they indicated that vmmc partially protects a man from getting hiv from a woman but does not affect a woman’s chances of getting hiv from a man. data collection before undergoing circumcision, all study participants were asked to complete a baseline sexual behaviour questionnaire through an audio computer-assisted self-interviewing (acasi) tool in a private office room at the study site. this interviewing technique circumvented social desirability bias by allowing the participant to complete the questionnaire in a standardised format without having to share their responses with study personnel directly. however, if the participant was unable or preferred not to use the acasi tool, the study nurse was available to administer the questionnaire. the tool, available in both english and the local language, setswana, was developed by using questionnaire development system (qdstm) questionnaire and survey development software adapted for low literacy and computer naïve populations (nova research company, silver spring, md). after circumcision, post-procedure visits at 2 days, 7 days, 6 weeks and 3 months were scheduled as outlined by the botswana ministry of health (moh) guidelines for adult vmmc. at each visit, participants completed the follow-up survey through acasi during their clinic appointment. a follow-up visit at 12 months was planned to coincide with annual hiv testing as per standard of care in botswana. each study participant was provided with a wallet-size reminder card noting the date of each follow-up visit. participants received bwp100 (approximately usd$8 at study initiation) at each post-operative visit as compensation for their time and travel costs. the current analysis is restricted to data collected at baseline and the 3-month follow-up visit when the sexual behaviour questionnaire was repeated. study data were collected and managed by using research electronic data capture (redcap), a secure, web-based application designed to support data capture for research studies hosted at the institute for translational health sciences at the university of washington.20 outcomes the primary outcomes of the current analysis were (1) the number of sexual partners in the previous 1 month and (2) one or more concurrent sexual partnerships during the previous 3 months. in accordance with the joint united nations programme on hiv/aids (unaids) recommendations, we defined a concurrent sexual partnership as ‘overlapping sexual partnerships in which sexual intercourse with one partner occurs between two acts of intercourse with another partner’.21 concurrency was then assessed by using the following three questions (based on unaids recommendations for data collection), each of which was asked of participant’s three most recent sexual partners: ‘how long ago did you first have sexual intercourse with this person?’ ‘when was the last time you had sexual intercourse with this person?’ and ‘are you still having sex with this person?’ to evaluate the change in the number of sexual partners and engagement in concurrent sexual partnerships before and after undergoing vmmc, we constructed change scores for each endpoint, which subtracted participants’ baseline response from that reported at the 3-month follow-up interview. statistical analyses for the continuous outcome, the number of sexual partners (past 1 month), we fit an intercept-only inverse-probability weighted linear regression model to estimate the mean change in the number of partners at 3 months post-vmmc (compared to baseline). for the dichotomous outcome, engagement in concurrent sexual partnerships (past 3 months), we fit an inverse-probability weighted conditional logistic regression model (stratified on the participant) to estimate the change in the proportion of participants reporting sexual concurrency at 3 months post-vmmc (compared with baseline). inverse probability weighting was used to adjust for potential selection bias because of non-trivial (anticipated to be 20% before study start) loss to follow-up.22,23,24 inverse-probability weighting adjusts for loss to follow-up by empirically breaking the association between observed predictors (collected at baseline) and participation at follow-up, allowing for unbiased estimation in the weighted sample, provided a regression for participation is correctly specified and no unobserved correlates of non-participation and risky sexual behaviour exist. inverse probability weights for participation at follow-up were constructed from a multivariable logistic regression model, which considered the following 24 potential covariates based on subject-matter knowledge: age, relationship status, religious affiliation, education, employment status, household assets or characteristics, reason for circumcision, correct knowledge of circumcision benefits, beliefs about circumcision, alcohol use, age at first sex, number of sexual partners (past 1 month, 1 year and lifetime) and transactional sex. we also created 117 two-way interaction terms by taking the cross-product of each demographic and socioeconomic covariates with each knowledge, belief and behavioural covariate. to build the multivariate logistic regression model required by inverse-probability weighting, we used a stepwise, forward selection procedure to identify covariates from the list of candidate predictors listed above. the entry and exit criteria were set to a p < 0.2. we included missing indicators for each selected variable to maximise the number of cases included in the final models and to maintain a constant sample size across analyses. in post-hoc analyses, we sought to identify attitudes, beliefs and/or behaviours reported at baseline that may be predictive of engagement (irrespective of what the participant reported at baseline [i.e. pre-circumcision]) in high-risk sexual behaviour at 3 months post-vmmc. specifically, we fit separate univariableand multivariable-adjusted modified poisson regression models (weighted by the inverse of the probability of participation at follow-up) for each of our primary outcomes (with the number of sexual partners in the past 1 month dichotomised at two or more) for each of the following covariates: alcohol consumption, reasons for circumcision, correct knowledge of circumcision benefits, beliefs about circumcision, age at first sex and transactional sex. all multivariable models were adjusted for potential confounding by the following demographic and socioeconomic covariates (all assessed at baseline): age, relationship status, religious affiliation, education, employment and household use of wood as cooking fuel. all analyses were conducted by using sas software version 9.4 (sas institute, cary, nc). ethical consideration ethical approvals were obtained from the health research and development committee at the botswana ministry of health (moh) (#00699) and the university of washington institutional review board (#42047). results between november 2013 and october 2015, research staff screened 577 men preparing to undergo vmmc for study participation (figure 2). a total of 528 (92%) participants were determined to be eligible for participation and 523 (91%) subsequently enrolled. reasons for ineligibility included not sexually active (4%), residence outside of the area (5%), hiv infection (< 1%) and age < 18 years or > 49 years (< 1%). four individuals who met study eligibility criteria and consented to study participation were not circumcised because of medical contraindications that were identified before the procedure. amongst the 509 circumcised participants who completed the baseline sexual behaviour questionnaire, 368 (72%) attended the follow-up visit and completed the sexual behaviour questionnaire at 3 months post-circumcision. because of missing data on specified outcomes, 353 were included in the analysis examining the number of sexual partners in the past month, and 311 were included in the sexual concurrency analysis. figure 2: consolidated standards of reporting trials (consort) diagram illustrating screening, eligibility, enrolment and follow-up of men undergoing voluntary medical male circumcision in gaborone, botswana, 2013–2015. table 1 shows the summary of the baseline characteristics of the study population according to the availability of sexual behaviour data at 3 months post-circumcision. men who either did not complete the follow-up visit (n = 105) or refused the sexual behaviour questionnaire (n = 36) were more highly educated (odds ratio [or]: 1.72; 95% confidence interval [ci]: 1.13–2.61) and underwent circumcision for personal hygiene reasons (or: 1.66; 95% ci: 1.07–2.57) compared with respondents at 3 months post-vmmc. in contrast, non-respondents were less likely to live in larger households (or: 0.59; 95% ci: 0.36–0.97). no other baseline characteristics were significantly associated with the response at 3 months post-vmmc. table 1: distribution of baseline characteristics of n = 509 hiv-negative, sexually active adult men who underwent voluntary medical male circumcision according to the availability of sexual behaviour data at 3 months post-voluntary medical male circumcision and association of these characteristics with data availability. figure 3 shows the summary of the change in the number of sexual partners and engagement in concurrent sexual partnerships at the 3-month follow-up visit (relative to baseline). amongst the 368 men who attended the follow-up visit at 3 months, 57 (15%) did not provide information on the number of partners during the past 1 month at either baseline and/or follow-up. data on engagement in concurrent sexual partnerships were available for 353 (96%) of the 368 men who attended follow-up. figure 3: summary of change in the number of sexual partners (past 1 month) and engagement in concurrent partnerships at 3 months amongst men undergoing voluntary medical male circumcision in gaborone, botswana, 2012–2015. at baseline, the mean (95% ci) number of sexual partners (past 1 month) was 1.60 (1.48, 1.65). although the majority (59% of n = 311 with available data) of men reported the same number of partners at 3 months post-vmmc, 70 (23%) reported fewer partners and 59 (19%) had more partners (figure 3). for concurrency (past 3 months), at baseline, 111 (31% of n = 353 with available data) reported engaging in one or more concurrent sexual partnerships. by 3 months post-vmmc, 58 (52% of 111) had ended the concurrent partnership. in contrast, amongst the 242 (69%) who did not report any concurrent sexual partnerships at baseline, 47 (19% of 242) had initiated a concurrent partnership at 3 months (figure 3). after adjustment for possible selection bias because of loss to follow-up at 3 months, we found no evidence of sexual risk compensation following vmmc: mean change in number of partners was -0.04 (95% ci: -0.15, 0.08; p = 0.61) and the proportion engaging in concurrency was 0.04 (95% ci: -0.05, 0.14; p = 0.38). tables 2 and 3 present the results of post-hoc analyses aimed at identifying predictors of any engagement (irrespective of change from baseline or pre-circumcision) in high-risk sexual behaviour at 3 months post-vmmc. in multivariable-adjusted models (simultaneously adjusted for potential selection bias because of loss to follow-up), alcohol consumption (table 2; risk ratio [rr]: 1.72; 95% ci: 1.19, 2.49) and transactional sex (rr: 1.77; 95% ci: 1.13, 2.77) were positively associated with reporting two or more partners (past 1 month) at follow-up. alcohol consumption was also positively associated with concurrency at 3 months post-vmmc (table 3; rr: 2.30; 95% ci: 1.45, 3.66). in contrast, older age at first sexual intercourse (21 years and older) was negatively associated with multiple sexual partners (table 2; rr: 0.50; 95% ci: 0.30, 0.84) at follow-up. no other attitudinal or behavioural covariates were significantly associated with either outcome in either univariableor multivariable-adjusted analyses. table 2: univariableand multivariable-adjusted attitudinal and behavioural predictors of multiple sexual partners (past 1 month) at 3 months amongst men undergoing voluntary medical male circumcision in gaborone, botswana, 2012–2015. table 3: univariableand multivariable-adjusted attitudinal and behavioural predictors of concurrent sexual partnerships (past 3 months) at 3 months amongst men undergoing voluntary medical male circumcision in gaborone, botswana, 2012–2015. discussion in this prospective cohort study of adult men undergoing circumcision within an urban, public-sector clinic in botswana, we found no evidence of sexual risk compensation in the 3 months following the procedure. although most participants did not alter their behaviour between baseline and follow-up, amongst those whose behaviour did change, a larger proportion of men reduced, rather than increased, their engagement in risky sexual behaviour as assessed by both the total number and timing of sexual partnerships. our overall findings are consistent with previous reports from south africa showing little to no evidence of risk compensation following vmmc.13,14 alcohol consumption was the strongest predictor of subsequent engagement in risky sexual behaviour following vmmc. previous studies of hiv prevention interventions conducted amongst hiv-negative and hiv-positive persons in the region have yielded similar results. data from the sustainable east africa research in community health (search) study, a cluster-randomised test-and-treat trial conducted in rural uganda and kenya, identified alcohol use as a significant predictor of hiv acquisition in developing an hiv risk score.25 additionally, in a subset of search participants also evaluated for tuberculosis acquisition, alcohol users were twice as likely to become infected with tuberculosis compared with non-drinkers, irrespective of hiv status or presence of an infected household contact.26 in botswana, qualitative in-depth interviews conducted with sexually active young adults presenting for care for urogenital complaints cited alcohol use as contributing to inconsistent and/or incorrect condom use.27 most of the existing data around risky sexual behaviour and vmmc relies on cross-sectional surveys (i.e. collected at a single point in time) in which the sexual behaviours of circumcised and uncircumcised men are compared.10,11,12 in contrast, we employed a pre–post intervention design in which sexual behaviour was assessed before and after participants underwent vmmc. this is important because men who choose to undergo circumcision may differ systematically from men who do not in ways that are related to risky sexual behaviour but are not easily measured. in our study, each participant served as his own control over time enabling us to control for bias resulting from fixed, systematic differences regardless of whether they are recorded by research staff. a second key strength of our results is the use of acasi to collect sexual behaviour information. given the sensitive and private nature of participation in sexual activities, individuals may underestimate or in some cases overestimate engagement in risky sexual behaviour. indeed, multiple studies have shown that this type of information bias is particularly prevalent in studies on sexual behaviour, which utilise face-to-face interviewing techniques.28,29 misreporting of high-risk sexual behaviour amongst men undergoing vmmc may underestimate prevalence, hindering the effectiveness and safety of circumcision programmes. to mitigate this potential form of information bias, we used acasi, an interviewing technique that allows the participant to complete the questionnaires privately and without directly sharing their responses with study staff. our study is subject to limitations. firstly, 28% of men either did not return for follow-up at 3 months post-vmmc and/or did not provide information on risky sexual behaviour post-vmmc. adjustment for selection bias because of this sub-optimal retention relies on the assumption that, conditional on a set of observed covariates, men who did and did not return for follow-up are exchangeable, and its appropriateness depends on our ability to identify, measure and control for all covariates associated with loss to follow-up. based on subject-matter knowledge, we considered 24 demographic, socio-economic and behavioural covariates and 117 two-way interaction terms in the multivariable model required by the inverse probability weighting procedure. however, as with any observational study, bias because of unmeasured factors is possible. conclusion despite these limitations, our results provide reassurance that men undergoing vmmc in botswana are unlikely to be systematically engaging in risk compensation. such behaviour, if practised widely, has the potential to undermine the public health benefits of vmmc. instead, we found that in the 3 months following vmmc, both the overall number and timing of sexual partners were similar to pre-circumcision levels. botswana’s circumcision programme continues to provide hiv prevention through the circumcision procedure itself and is not being jeopardised by the perception of reduced risk of hiv acquisition. acknowledgements competing interests all authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions l.p.s. and k.e.h. conceived of the presented idea and performed the analysis and wrote the manuscript. s.m. and s.b. verified the analytical methods and edited the final manuscript. j.h.l. supervised the findings of this work and edited the final manuscript. all authors discussed the results and contributed to the final manuscript. funding information this publication was made possible by grant number u91ha06801 from the u.s. department of health and human services, health resources and services administration, hiv/aids bureau’s global health systems branch and grant number ul1tr000423 from the national center for research resources, national institutes of health. its contents are solely the responsibility of the authors and do not necessarily represent the official views of the government. data availability statement the computing code and an anonymised analytic data set used to produce the results contained in this manuscript are available upon request from the corresponding author. disclaimer views expressed in the submitted article are our own and do not necessarily reflect the official policy or position of our institutions or funders. references auvert b, taljaard d, lagarde e, sobngwi tambekou j, sitta r, puren a. randomized, controlled intervention trial of male circumcision for reduction of hiv infection risk: the anrs 1265 trial. plos med. 2005;2(11):e298. https://doi.org/10.1371/journal.pmed.0020298 gray rh, kigozi 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randomised controlled trial comparing computer-assisted with face-to-face sexual history taking in a clinical setting. sex transm infect. 2007;83(1):52–56. https://doi.org/10.1136/sti.2006.020776 abstract introduction methods results discussion acknowledgements references appendix 1 about the author(s) annelotte e. sussenbach julius global health, julius center for health sciences and primary care, university medical center utrecht, utrecht, the netherlands sjors w.l. van gijzel julius global health, julius center for health sciences and primary care, university medical center utrecht, utrecht, the netherlands samanta t. lalla-edward ezintsha, faculty of health sciences, university of the witwatersrand, johannesburg, south africa willem d.f. venter ezintsha, faculty of health sciences, university of the witwatersrand, johannesburg, south africa erica shaddock division of pulmonology, department of internal medicine, charlotte maxeke johannesburg academic hospital, johannesburg, south africadivision of pulmonology, faculty of health sciences, university of the witwatersrand, johannesburg, south africa charles feldman division of pulmonology, department of internal medicine, charlotte maxeke johannesburg academic hospital, johannesburg, south africadivision of pulmonology, faculty of health sciences, university of the witwatersrand, johannesburg, south africa kerstin klipstein-grobusch julius global health, julius center for health sciences and primary care, university medical center utrecht, utrecht, the netherlandsdivision of epidemiology and biostatistics, school of public health, faculty of health sciences, university of the witwatersrand, johannesburg, south africa alinda g. vos julius global health, julius center for health sciences and primary care, university medical center utrecht, utrecht, the netherlandsezintsha, faculty of health sciences, university of the witwatersrand, johannesburg, south africa citation sussenbach ae, van gijzel swl, lalla-edward st, et al. the influence of smoking and hiv infection on pulmonary function. s afr j hiv med. 2022;23(1), a1329. https://doi.org/10.4102/sajhivmed.v23i1.1329 original research the influence of smoking and hiv infection on pulmonary function annelotte e. sussenbach, sjors w.l. van gijzel, samanta t. lalla-edward, willem d.f. venter, erica shaddock, charles feldman, kerstin klipstein-grobusch, alinda g. vos received: 12 oct. 2021; accepted: 29 nov. 2021; published: 21 feb. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: prevalence of hiv, smoking, and pulmonary infections in south africa are high. objectives: we investigated the role of smoking and hiv status on lung function. methods: this is a secondary analysis of a cross-sectional study conducted in south africa. data included demographics, pulmonary risk factors and a spirometry test to obtain the forced expiratory volume in one second (fev1) and the ratio of fev1/forced vital capacity (fvc). in the initial multivariable regression analysis, the effect of smoking on pulmonary function in hiv-positive adults was assessed. the analysis was repeated, assessing the influence of hiv status on lung function in both hiv-negative and hiv-positive smokers. the models were adjusted for age, sex, body mass index (bmi), time since hiv diagnosis, antiretroviral treatment (art) use, occupational hazards, history of tuberculosis or pneumonia, indoor smoking and the presence of an indoor fireplace during childhood. results: this study included 524 people living with hiv (plwh, 66.7% female, mean age 40.9 years [s.d.; 9.4]) and 79 hiv-negative smokers (77.2% male, mean age 34.4 years [s.d.: 12.1]). of the plwh, 118 (22.5%) were past or current smokers and 406 (77.5%) were non-smokers. smoking was not associated with changes in the fev1 or fev1/fvc ratio in multivariable regression analysis. in the second analysis, hiv status was also not associated with reduced pulmonary function following adjustment for confounders. conclusion: neither smoking nor being hiv-positive was associated with decreased pulmonary function in this relatively young population. these findings should be confirmed in a longitudinal study, including an older population. keywords: hiv; lung function; plwh; south africa; spirometry; sub-saharan africa. introduction hiv has infected over 75 million people, with over 32 million deaths reported worldwide since its emergence in the 1980s.1 even though there is no cure for hiv infection, the use of antiretroviral treatment (art) has resulted in a near normal life expectancy for people living with hiv (plwh).2,3 this increased life expectancy has resulted in an increase in age-related comorbid diseases, such as cardiovascular diseases, diabetes mellitus and cancers.2,3 untreated hiv is associated with an increased vulnerability to pulmonary infections, such as pneumonia and pulmonary tuberculosis (tb), resulting from the immune dysfunction caused by the virus.2,4,5,6 although art restores immune function in plwh, immunity does not return to normal levels and chronic immune activation persists. this low-grade immune activation is also manifested in the immune cells that reside in the lungs and may be responsible for hiv-related lung damage.7 furthermore, art and hiv might be independently associated with a decline in pulmonary function.8,9 although smoking rates are decreasing globally, about 80% of smokers live in lowand middle-income countries (lmics), which also have the highest prevalence of hiv.1,10,11 in high-income countries, the incidence of smoking amongst plwh is still two to three times higher than in people without hiv.12 the prevalence of smoking amongst plwh in sub-saharan africa ranges from lower to higher than the hiv-uninfected community.13,14,15,16,17,18,19,20,21 in south africa, the prevalence of smoking in plwh is estimated to be around 20%.13,16 although rates differ between provinces and different social groups, these numbers are concerning, given the background of pre-existing lung damage because of (opportunistic) infections and the possible negative effects of hiv and art on lung function. many studies have investigated the added negative effect of smoking on pulmonary function in plwh.4,8,22,23,24,25 the majority of these cross-sectional studies reported that the negative impact of smoking on lung function in plwh could not be attributed to a history of pulmonary infections, such as tb and pneumonia alone. therefore, this study aimed to investigate the influence of smoking and hiv infection on pulmonary function in johannesburg, south africa. methods data from two existing study databases were combined in this analysis. study population and data collection study group i: the aim of study i was to investigate the interaction between hiv, art, pulmonary function, and cardiovascular traits in an urban south african population. the inclusion criteria for this study were as follows: (1) confirmed hiv-positive status, age ≥ 18 years and enrolled at the hiv clinic at the charlotte maxeke johannesburg academic hospital (cmjah); (2) individuals aged ≥ 18 years with unknown hiv status who participated in the universal test and treat (utt) programme at cmjah and who agreed to share their test result with the researcher. the south african utt initiative was founded in 2016 and aimed to test as many people as possible, and to initiate art regardless of the cd4 count in those testing positive for hiv.26,27 participants who are hiv negative were enrolled through the utt programme. participants unable to undergo study procedures for any reason or unwilling to share hiv test results or with unknown hiv status were excluded from the study. a written informed consent was obtained from all study participants. study group ii: this study aimed to investigate the interaction between hiv, art and cardiopulmonary function in an urban south african population. study ii was also conducted at cmjah and included plwh not yet on art, well-characterised plwh on firstand second-line art, as well as hiv-negative controls as previously described.28 participants were recruited from randomised controlled trials (rcts) comparing art regimens. inclusion and exclusion criteria included those of study i, and additionally excluded pregnant women, people with impaired kidney function and people on active tb treatment. the methods are described in more detail in previous publications.15,29 in both studies, a spirometry test was performed, next to questionnaires on participants’ demographics, characteristics and respiratory profile. the respiratory questionnaire included the st george’s respiratory questionnaire (sgrq).30 spirometry was performed with a handheld device, and included preand post-bronchodilator measurements. acceptability and reproducibly were based on guidelines of the american thoracic society and european respiratory society.31,32 more details on measurements can be found in the supplementary file (table 1-a1). a written informed consent was obtained from all study participants. redcap version 9.7.8 was used for data collection in both studies.39,40 data analysis baseline characteristics of participants were presented as mean with standard deviation (s.d.) or as frequencies and percentages, unless stated otherwise. the characteristics were compared using a t-test for continuous variables and the chi-square test for categorical variables. the primary outcome of this study was post-bronchodilator fev1. the secondary outcome was the post-bronchodilator fev1/forced vital capacity (fvc) ratio. multivariable regression analyses were performed to test the relationship between smoking and pulmonary function in plwh. the following variables were regarded as confounders based on the literature and were included in the models using forced entry of variables: age, sex, body mass index (bmi), time since hiv diagnosis, art duration, history of pneumonia, occupational hazard, indoor smoking in the household and presence of a fireplace during childhood.9,23,41 the first model assessed the effect of smoking on post-bronchodilator fev1, whilst the second model was corrected for the above-mentioned covariates. in a third model, a history of tb was added to account for possible effect modification. all steps were repeated using the fev1/fvc ratio as outcome. in an additional analysis, smoking was treated as a continuous variable using pack-years, with zero pack-years for non-smokers (information on pack-years was only available for study ii). in a second analysis, the influence of hiv on lung function in smokers was assessed using the same steps as described above. hiv status was the main determinant, and the same confounders were taken into account, including smoking status, except for the hiv-related variables, including time since hiv diagnosis and art duration. multicollinearity was checked for all variables in the models.42 a two-sided p-value of < 0.05 was considered to be statistically significant. initially, complete case analysis was performed. subsequently, missing data were imputed using multiple imputation with the r-package mice.43,44 r version 4.0.0 and statistical package for the social sciences (spss) version 26 were used for data analysis.45,46 ethical considerations all participants were required to sign a written informed consent form prior to enrolment. in case the participant was not able to read the english form, an additional consent form had to be signed that verbal explanation of the form was sufficient. the university of the witwatersrand, human research ethics committee (hrec) approved study i (m190628) and study ii (m160130). results in total, 524 plwh were included (66.7% female), of whom 118 individuals were past or current smokers (118/524 (22.5%) (figure 1). four were excluded from analyses because of missing information on the smoking status. the mean age was 40.9 years (s.d.: 9.5), the mean time from hiv diagnosis was 92.3 months (s.d.: 69.6) and the mean art duration was 74.5 months (s.d.: 60.6). one-third of the participants had been previously diagnosed with tb (33.0%), and approximately 10% had been previously diagnosed with pneumonia. figure 1: flow diagram of study composition. past or current smokers were more likely to be men; had a lower bmi; were less likely to be on art; were more likely to consume alcohol; and were more likely to be exposed to chemicals, gases or fumes; working in a dusty job; or working in the farming or mining industry for more than a year (table 1). table 1: baseline characteristics of the study population stratified by smoking. smoking was not significantly related to post-bronchodilator fev1 or the fev1/fvc ratio following regression analysis (table 2). there was no relationship between fev1 and time since hiv diagnosis or time on art. adding tb to the models did not alter the relationship between smoking and fev1 or the fev1/fvc ratio. tuberculosis was associated with a significant decline in both the fev1 and the fev1/fvc ratio. table 2: results of multivariable analysis for post-bronchodilator (bd) forced expiratory volume in 1 second and forced expiratory volume in 1 second/forced vital capacity on hiv-positive participants. similar results were reported when smoking was quantified using pack-years (only available for study ii), that is, smoking not being significantly associated with fev1 nor fev1/fvc (data not shown). however, the spearman correlation coefficient between pack-years and pulmonary function was r = 0.40 (p < 0.01). in the second analysis, 197 smokers were analysed (71.1% part of study ii), of whom 118 were hiv-positive individuals (59.9%) (table 1). the mean age was 38.9 years (s.d.: 12.2), with 70.0% being male participants. the mean smoking time was 15.2 years (s.d.: 0.7). hiv status was not significantly associated with pulmonary function following regression analysis. adding tb to the model did not alter results. a history of tb was significantly associated with a decline in both outcomes (table 3). table 3: results of multivariable analysis for post-bronchodilator (bd) forced expiratory volume in 1 second and forced expiratory volume in 1 second/forced vital capacity on smoking participants. analyses based on data including multiple imputation for missing data showed comparable results (supplementary table 1-a1). discussion in this study of plwh carried out in johannesburg, south africa, no relationship between smoking or hiv positivity and fev1 or the fev1/fvc ratio was observed. however, a history of tb was associated with a decrease in lung function. the finding of this study that smoking was not associated with a decrease in pulmonary function in plwh was unexpected, yet interestingly in line with other cross-sectional studies from high-income countries.4,23,47 in most studies, a decline in pulmonary function was explained by effects of hiv, or by irreversible pulmonary damage because of tb or pneumonia, and not by smoking. however, one study from pittsburgh, united states, observed that smoking was significantly associated with diffusion impairment in plwh.8 cross-sectional studies from sub-saharan africa also found that smoking was not associated with decreased pulmonary function.9,24 in general, the average age of the study populations was around 50 years. we found that age was significantly associated with a decrease in lung function, suggesting that the deleterious effects of smoking on lung function may only become apparent with increasing age. studies that did report any adverse effect of smoking on lung function often limited their inclusion to individuals over 40 years of age.23,24,25 the prevalence of ever smoking was found to be 22% in this study, in line with other studies from south africa and other sub-saharan african countries.12,48 however, studies have reported a higher prevalence of smoking in plwh (34% – 37%13,15,19,49) than in the general population in south africa, despite various cessation strategies implemented by the government.20,50,51 other studies in sub-saharan africa reported a prevalence of smoking in hiv-positive men ranging from 9.7% in ethiopia to 54.8% in the gambia.17,18,19,20,21 in the current study, there was no validation of self-reported smoking, whilst in most studies mentioned above, validation of current smoking was carried out by testing of urine samples for cotinine. inadequate reporting of smoking could be a possible explanation for the lower prevalence of smoking in this study. another explanation might be that in this study, there was a relatively lower prevalence reported from a single centre (cmjah) in johannesburg, gauteng province, than in other provinces.52 another explanation for the low prevalence of smoking might be in the selection of participants. participants in study group i were recruited from the hiv clinic, and participants in study group ii were recruited from rcts. it may be the case that people participating in rcts were more aware of health hazards or had a healthier lifestyle, associated with a lower smoking prevalence. a study, performed in 2011 in the same hospital as the current study, reported a smoking prevalence of 15% amongst plwh, whilst validation by urine samples showed a prevalence of almost 31%.20 subsequent analysis of only smokers, including both hiv-positive and -negative participants, showed no effect of hiv on pulmonary function. although no effect of hiv infection was observed, age was a significant factor in all models and analyses. this result supports our conclusion that the study population was too young to observe a possible additional negative effect of hiv on pulmonary function in smokers. a limitation of this study is that cd4 cell count was not available. cd4 is a marker of immune impairment, and immune dysregulation may affect lung function. in this study, no association between art and pulmonary function was observed, whilst some studies suggest that specific art-regimens may be more strongly associated with decreased pulmonary function than other regimens.5,22,53,54 another limitation is that this is a single-centre study, and, therefore, the results might not be generalisable to different contexts. as all but four participants were black, the study results are only applicable to black south africans. furthermore, no follow-up data are available. to investigate the true effect of smoking on pulmonary function, investigation of longitudinal data is necessary. finally, we only had information on pack-years available for current smokers; this is a powerful measure to reliably reflect the intensity of smoking, especially in lmics, where the number of cigarettes smoked might be correlated with household income so pack-years could possibly be a more suitable and accurate measure than current versus past smoking. the correlation coefficient r = 0.40 (p < 0.01) between age and pack-years shows that participants with higher age also had significantly higher pack-years. this result supports our hypothesis that smoking may very well have influence on pulmonary function; however, our cohort is too young to establish this relationship. strengths of this study include the inclusion of a large urban population, representative of the general hiv-positive population in an urban environment in a low-middle income setting. besides, we present a complementary analysis on the effect of hiv, smoking and lung function by analysing the effect of smoking in hiv-positive people, as well as in people who smoke the effect of hiv on lung function. in summary, in a relatively young population of hiv-positive people, the negative impact of smoking on lung function is not yet measurable, and in smokers, hiv does not seem to be a risk factor for additional pulmonary impairment. a history of tb is, however, a strong risk factor for impaired pulmonary function. more research studies are needed to longitudinally investigate the influence of smoking on decreasing fev1 and fev1/fvc ratio in the aging hiv-positive population in sub-saharan africa. in the meantime, smoking should be discouraged on every occasion, given the high burden of tb, associations with other lung infections and expected persistent lung damage in this population. acknowledgements the authors thank all participants for their cooperation in this study. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions a.e.s., a.g.v. and k.k.g. contributed to the conception or design of the work. a.g.v., k.k.g., s.t. l-e., w.d.f.v., e.s and c.f conceived the original studies. a.e.s. and s.w.l.v.g. contributed to data collection. a.e.s. built the models and carried out the data analysis and interpretation. a.g.v. and k.k.g. supervised the project. a.e.s. and a.g.v. wrote the manuscript with input from all authors. funding information the authors received no financial support for the research, authorship and/or publication of this article. the research study reported in this publication was supported by the national heart, lung, and blood institute of the national institutes of health and the fogarty international center under award no. ug3hl156388. the content is solely the responsibility of the authors and does not necessarily represent the official views of the national institutes of health and the fogarty international center. data availability the de-identified data sets used and/or analysed during the current study are available from the corresponding author upon reasonable request. disclaimer the views and opinions expressed in this article are those 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riha j, et al. association of hiv and art with cardiometabolic traits in sub-saharan africa: a systematic review and meta-analysis. int j epidemiol. 2013;42(6):1754–1771. appendix 1 elaboration on the method section measurements study group i: for spirometry test, the koko® sx 1000 hand-held machine was used. two outcomes were obtained from the spirometry test: the forced expiratory volume in 1 second (fev1) in litres (l) and the forced vital capacity (fvc) in litres.31 each participant was asked to perform a spirometry test twice: once before and once after administering four doses of 100 μg salbutamol for bronchodilation. each spirometry was repeated until three acceptable and reproducible attempts were obtained per participant, with a maximum of eight attempts per test. acceptability and reproducibly were based on guidelines of the american thoracic society and european respiratory society.31,32 participants with an abnormal spirometry test were referred to a pulmonologist for review. definitions of an abnormal test were set up prior to start of the study (table 1-a2). a questionnaire was used to retrieve information on socio-demographics, history of lung and other diseases, and physical activity. the respiratory questionnaire was based on the st george’s respiratory questionnaire (sgrq),30 which was aimed at retrieving information on respiratory complaints, smoking, and pulmonary exposure during work and at home. smoking was limited to tobacco products (cigarettes, cigars and pipes) and was classified into never versus ever (past and current) smokers. race was defined as black or non-black. hiv status was based on test results from utt or art prescription. time since hiv diagnosis was measured in months. education was divided into two groups: less than secondary school completed and secondary school completed or higher. work status was split into four groups: employed, unemployed, retired and student. relationship status was dichotomised into stable relationship yes or no, with stable relationship being defined as married or in a self-defined stable relationship. alcohol use was defined as ever or never. time spent close to an open fire was divided into daily versus less than daily and was defined as fire time. the presence of a smoker in the household during childhood was defined as smoking household. smoking inside the house during childhood was defined as smoking household indoor. fireplace childhood was defined as the presence of an indoor fireplace in childhood home. parental lung disease was defined as either one of the participant’s parents being diagnosed with a chronic pulmonary disease. occupational hazard was dichotomised into ever versus never, and was defined as exposure to gases, chemical fumes or chemicals during work, working in a dusty job, or working in the farming or mining industry for more than a year. breathing problems was classified into presence or absence of breathing or chest troubles or symptoms in the past three months. study group ii: the measurements taken in study ii were identical to those in study i. comparable questionnaires were used to assess demographics, characteristics and respiratory profile of participants of both the study groups. the respiratory questionnaire was based on the sgrq,30 the british medical research council respiratory questionnaire,33,34 the ats-dld-78-a,35 the world health survey36 and questionnaires used in other publications.37,38 physical examination was also performed. for spirometry, a spida 5 handheld machine was used with similar procedures and outcome assessment to the koko® sx 1000 handheld machine. table 1-a1: results of multivariable analysis for post-bronchodilator (bd) forced expiratory volume in 1 second and the forced expiratory volume in 1 second/forced vital capacity ratio, of imputed data sets. table 2-a1: spirometry definitions. abstract introduction material and methods results discussion conclusion acknowledgements references about the author(s) isabel a. michaelis department of health, faculty of paediatrics, walter sisulu university, mthatha, south africa maryke nielsen department of paediatrics and child health, faculty of infectious disease, malawi-liverpool-wellcome clinical research facility, blantyre, malawi institute of infection and global health, faculty of clinical infection, immunology and microbiology, university of liverpool, liverpool, united kingdom department of paediatrics, queen elizabeth central hospital, blantyre, malawi craig carty department of evidence-based social intervention, faculty of sociology, university of oxford, oxford, united kingdom markus wolff department of neuropaediatrics and social paediatrics, faculty of paediatrics, vivantes klinikum neukolln, berlin, germany caroline a. sabin department of medical statistics and epidemiology, faculty of population health sciences, university college london, london, united kingdom john s. lambert department of infectious diseases, faculty of infectious diseases and genitourinary medicine, ucd school of medicine, dublin, ireland citation michaelis ia, nielsen m, carty c, wolff m, sabin ca, lambert js. late diagnosis of human immunodeficiency virus infection is linked to higher rates of epilepsy in children in the eastern cape of south africa. s afr j hiv med. 2020;21(1), a1047. https://doi.org/10.4102/sajhivmed.v21i1.1047 original research late diagnosis of human immunodeficiency virus infection is linked to higher rates of epilepsy in children in the eastern cape of south africa isabel a. michaelis, maryke nielsen, craig carty, markus wolff, caroline a. sabin, john s. lambert received: 23 nov. 2019; accepted: 07 jan. 2020; published: 30 june 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: human immunodeficiency virus (hiv)-positive children may present with a wide range of neurological disorders. among these, epilepsy is of key concern because of its lifelong impact and potential for damage to the central nervous system (cns). few studies in developing regions have investigated the prevalence and aetiology of epilepsy in hiv-infected children as a key population. objectives: we describe the prevalence of epilepsy, associated neurological disabilities, immunological status, clinical stage and history of cns infection at epilepsy diagnosis in a cohort of hiv-infected children receiving antiretroviral therapy (art) in the eastern cape of south africa. methods: we conducted a retrospective study (2004–2014) at two major referral sites for hiv-infected children diagnosed with epilepsy aged 0–16 years. eligible subjects were extracted from the electronic medicine bridging access to care in excellence (embrace) paediatric cohort using the paediatric art data management tool (padmt). fixed data fields were interrogated for exposures to antiepileptic drugs. unstructured ‘comments’ fields were searched for the terms: epilepsy, seizures, fits and szs, as well as abbreviated versions of common antiepileptic drug names. eligible subject folders were then retrieved to validate the digital data. results: from 2139 children enrolled in the two sites, 53 children were diagnosed with epilepsy (2.48%). in these, the median cd4 count was 591 cells/mm3, and the mean viral load was 4.9 log copies/ml, with undetectable viral loads in only seven children (14.0%). world health organization (who) clinical hiv stage was available for 46 patients of the sample, with 3, 6, 26 and 11 children graded at stages 1, 2, 3 and 4, respectively. forty percent children had a history of cns infection prior to the epilepsy diagnosis, and 55% children were reported to have school problems. conclusions: in this descriptive study, the prevalence of epilepsy among children with hiv was 2.48%, mostly diagnosed in advanced hiv-disease stages. our findings support the usefulness of early detection and initiation of art in hiv-infected children in order to reduce the risk of epilepsy. in addition, our study demonstrates that novel techniques are effective in accessing cohort-level data that allow interrogation of both structured and unstructured clinical data. keywords: epilepsy; hiv-infection; children; who staging; paediatric art data management tool. introduction the latest world health organization (who) report on human immunodeficiency virus (hiv) and acquired immunodeficiency syndrome (aids) estimates that 3.2 million children are infected with hiv worldwide, of whom 91% are living in sub-saharan africa.1 south africa is regarded as having the largest hiv and aids burden in the world, with an estimated 17.6% of the population living with the disease; between 370 000 and 450 000 children younger than 14 years in south africa are thought to be infected with the virus.1 human immunodeficiency virus-related neurological manifestations are common in both adults and children.2,3,4,5,6 they include opportunistic central nervous system (cns) infections, behavioural problems and psychiatric disorders, as well as neurodevelopmental delay and epilepsy.4 epilepsyis a potentially disabling disease whose treatment is challenging in sub-saharan africa,7,8,9,10,11,12,13 particularly among children with hiv infection, who are often orphaned and have to face poverty.14 the prevalence of seizures in children with confirmed hiv infection has been reported to range from 2% to 14%,9,15,16,17,18 and the prevalence of epilepsy is estimated between 0.29% and 11.3%.19,20,21 this wide variation is believed to be a result of differences of risk factors in different regions.22 epilepsy in hiv-infected persons may occur as a result of several different processes: direct viral damage to the brain by uncontrolled viral replication; following a cns infection by opportunistic pathogens; as a result of malignancies; following the use of some medications; as a result of metabolic and electrolyte derangements; or as a secondary acquired pathology because of hiv encephalopathy.4 of interest, bearden et al.19 argued that earlier initiation of antiretroviral therapy (art) might prevent the manifestation of epilepsy in children with hiv infection. this study was conducted in botswana, and there is no other study on record so far to confirm or challenge these results in a different population. we describe the prevalence of epilepsy, including associated neurological disabilities, immunological and clinical status and history of cns infection in children with hiv infection on art in a mixed rural/urban area in the eastern cape. the aim is to show that late diagnosis of hiv infection and delayed initiation of art in children are linked to higher rates of epilepsy. material and methods setting we conducted a retrospective study (2004–2014) at two major referral sites for hiv-infected children aged 0–16 years in the eastern cape, south africa. one centre is a paediatric and adolescent hiv referral clinic in a tertiary hospital in east london, and the other is the hiv clinic for children and adolescents in the township of mdantsane, which serves as a major referral centre as well as the local health clinic. the eastern cape belongs to one of the most underprivileged parts of south africa, and its health service is among the most under-resourced. together, the two hospitals serve around 3.5 m people, including more than 890 000 children younger than 15 years (census 2011 municipal report). in south africa, art became available in state health facilities from 2004. at this time, the criteria for art required that children had advanced hiv disease, assessed by who staging.23,24 the eligibility criteria for initiation of art and the type of first-line regimen for infants and children with hiv infection following hiv guidelines changed in 2004, 2010, 2013 and 2015.25 the clinicians in our setting used the appropriate guidelines for the specific year the children were firstly seen in the clinics. since 2014, every child younger than 5 years with confirmed hiv infection was eligible for treatment, regardless of his/her clinical (who staging) and laboratory status (cd4 counts)26; since 2017, all people in south africa with confirmed hiv infection have immediate access to art. in our setting, the routine approach to children presenting with seizures consists of a detailed clinical history and physical examination, including blood pressure, as well as assessment of blood glucose and, if indicated, antiepileptic drug plasma levels. emergency computed tomography (ct) is performed if the child has new-onset focal seizures, encephalopathy or prolonged neurological fallout. in children with suspected meningitis, encephalitis or other inflammations, appropriate serum markers are investigated, and a lumbar puncture is performed unless contraindicated. human immunodeficiency virus testing is offered to all children. in children known to be hiv infected, cd4 count and hiv viral loads (vls) are assessed. cases were identified by screening all available subfiles for ‘epilepsy’ and by interrogating the fixed data fields of an electronic database, the paediatric art data management tool (padmt), for exposure to antiepileptic drugs. unstructured ‘comments’ fields were hand-searched for relevant terms like epilepsy, seizures, fits and szs, paroxysmal events, faints or syncope or electroencephalogram (eeg). eligible subject folders were then retrieved to validate the digital data. children with a single seizure or single seizure episode during acute illness because of metabolic disturbances, hypertension, neurocysticercosis or infection, or those with the diagnosis of febrile seizures were excluded from further analysis. those children with a diagnosis of epilepsy, as defined by fisher et al.,27 were further assessed for aetiology by reviewing clinical information, laboratory results, brain imaging and eeg studies, if available. in epileptic children diagnosed with hiv encephalopathy with no other clinical, laboratory or imaging findings, the neurotoxic effect of hiv was considered as the cause of epilepsy. human immunodeficiency virus encephalopathy is defined as damage or malfunction of the brain because of hiv infection. human immunodeficiency virus encephalopathy in children must include at least one of the following findings present for at least 2 months in the absence of a concurrent illness other than hiv infection: (1) failure to attain or loss of developmental milestones or loss of intellectual ability; (2) impaired brain growth or acquired microcephaly; or (3) acquired symmetric motor deficit.28 the intent of this study was to see how many children in this cohort have epilepsy, even if it was not caused by the hiv infection. absolute cd4 count and cd4%, baseline vl at the start of art, the vl between 6 and 12 months after initiating art, the vl nearest to the diagnosis of epilepsy (for those diagnosed with epilepsy while on art and where the value was available within a window of 5 months before or after diagnosis) and vl at last available follow-up assessment were retrieved. neurological deficits and indicators of developmental delay were also recorded, as well as reports of previous cns infection. prescribed antiepileptic drugs were also recorded. clinical staging of hiv infection as assessed by the attending doctor following the who guidelines were documented. children attending the clinics were followed up at regular 3-monthly intervals (monthly for children with social problems or adherence issues). ethical consideration this article followed all ethical standards for a research without direct contact with human or animal subjects. results of the 2137 children with confirmed hiv infection enrolled in the two clinics, 53 (2.5%) were diagnosed with epilepsy. comprehensive medical records were available in 49 (92%) of the 53 patients. only those children were included in this study. the age of the children ranged from 1 month to 12 years (median 4 years) at the time of diagnosis of epilepsy, and 26 (53%) were boys. all children and infants with hiv infection and epilepsy were initiated on art during the study assessment period. eighty-one per cent of the children were on first-line treatment, which comprised abacavir, lamivudine and lopinavir/ritonavir (n = 18) or efavirenz (n = 22), depending on the age of the child at initiation and the year of treatment initiation. in 16 of the children, stavudine was replaced by abacavir as part of the change in guidelines for first-line treatment. four (8%) of the children were placed on lamivudine-holding regimes, mostly for treatment failure because of non-compliance after extensive counselling of the family. the others (11%) were started on second-line treatment following treatment guidelines. antiretroviral therapy was started either after (20 patients; 40%), at (15 patients; 31%) or before (14 patients; 29%) diagnosis of epilepsy. the who clinical staging at diagnosis of hiv infection was available in the records for 46 children, with 4 (8%), 5 (10%), 26 (53%) and 11 (23%) children graded at stages 1, 2, 3 and 4, respectively. staging data were missing in three (6%) children (table 1). table 1: clinical staging of hiv infected patients according the world health organization guidelines at initiation of treatment. for children who developed epilepsy at the beginning of or after initiating art (n = 29; 59%), the median cd4 count was 591 cells/mm3 (range 15 cells/mm3 – 1980 cells/mm3), and the mean vl was 782 768 copies/ml (range from lower than detectable limit [ldl] to 10 000 000), at the time of diagnosis of epilepsy. in nine of the 14 children (64%) who were diagnosed with epilepsy while already on art, the vl was lower than 800 copies/ml or undetectable at the time of epilepsy diagnosis. in four (29%) children, vl was > 800 copies/ml at the time of diagnosis, with one child having no vl data available in the time period. in six (43%) children, the cd4 percentage was < 25%, even though they had been on art for at least 7 months at the time of diagnosis of epilepsy. five (36%) children had cd4% > 25%, while cd4% data were not available for three (21%) of the children (table 2). table 2: viral loads of patients at diagnosis of epilepsy or at 6–12 months after initiation of antiretroviral therapy if diagnosis of epilepsy was made before antiretroviral therapy initiation. about 74% (26/35) of the children who were diagnosed with epilepsy before or at art initiation had a vl that was below the limit of detection or below 800 copies/ml between 6 and 12 months after art initiation, with only six (17% [6/35]) having vl values > 800 copies/ml. in the group which developed epilepsy at least 7 months after initiation of art, viral suppression was seen only in 57% (8/14). for three children (9% [3/35]), no data were available. nineteen children (39%) were found to have a cns infection, mainly tuberculosis (n = 13), but also other bacterial cns infections. three children were diagnosed with neurocysticercosis. eighteen per cent of the children were diagnosed with hiv encephalopathy by the centers for disease control and prevention (cdc) criteria,25 where neurotoxic effect of hiv was considered as the cause of epilepsy. in one child with spastic quadriplegic cerebral palsy, it was assumed that intra-partum hypoxic ischaemic encephalopathy caused the epilepsy as the child developed seizures right after birth. two children presenting with cerebrovascular accidents, both caused by persistent severe thrombocytopenia, developed epilepsy thereafter. the average duration between cns infection and diagnosis of epilepsy was 11 months (range: 1–24 months). in only one case, the diagnosis of epilepsy was made prior to cns infection. for more than one-third of children (37%), no cause could be found. features of neurodevelopmental delay, as assessed by the medical officer in the antiretroviral therapy (arv) clinic, were present in 17 (34%) of the epileptic children. several children were referred either for assessment in the neurodevelopmental clinic or to the occupational, physioor speech therapist. one of the eight children seen in the neurodevelopmental clinic was diagnosed with hemiplegic cerebral palsy post-stroke, one with quadriplegic cerebral palsy because of hypoxic ischemic encephalopathy, two with speech and cognitive impairment of unknown cause and four with hiv encephalopathy. school failure, school problems, reports from the educational psychologist of intellectual impairment or the notice of attendance of a special school was noted for 27 (55%) of the epileptic children (70% of whom were boys). most children were diagnosed with epilepsy before or at the time of diagnosis of hiv infection (35/49). almost all (48 of 49) children with epilepsy were treated with sodium valproate; 18 received other antiepileptic drugs either before sodium valproate or as a dualor multi-drug regime, including phenobarbitone (n = 16), carbamazepine (n = 2), clonazepam (n = 2), lamotrigine (n = 1) and/or ethosuximide (n = 1). the two children treated with carbamazepine were referred from other health facilities on carbamazepine and were changed to sodium valproate in our clinic. half (24/49) of the children became seizure-free with the use of antiepileptic drugs and eight (16%) had a significant (50% – 75%) reduction in seizure frequency. discussion in this retrospective survey, we were able to show a 2.5% prevalence of epilepsy in children with hiv infection, which is similar to other areas in south africa and sub-saharan africa, as well as in india.19,20,21 this number is about two to three times greater compared to the overall prevalence of epilepsy in africa and south africa, which is estimated between 0.73% and 1.2%.13,28,29 however, this prevalence might still be underestimated as the data were retrospectively collected from case notes, which is a key limitation of this study. most children (76%) with epilepsy were classified as stage 3 or 4 according to the who staging system for hiv/aids at diagnosis of hiv. thus, most of the children with epilepsy were diagnosed at an advanced stage of hiv infection. in contrast, 80% of the children in the group without epilepsy were assessed as stage 1 at diagnosis. (see table 1 and figure 1) figure 1: world health organization stages in percentage of total number of patients (blue) and in percentage of total number of epileptic patients (green). in about half of the patients with epilepsy (48%), treatment for hiv infection was initiated at the time of diagnosis. twenty-eight per cent had treatment initiation months, and sometimes years after hiv diagnosis, probably because of the guidelines for that specific time period. for the rest, the exact date of diagnosis of hiv infection was not available, which is another limitation of this study. none of the children with epilepsy and stage 1 hiv infection had prior cns infection, while 81% of the children with epilepsy and stage 4 hiv infection had prior cns infection. thirty-seven (75%) of the children were diagnosed with epilepsy before or at initiation of art. retrospectively, it was not possible to differentiate in how many children the complaint of seizures was the cause of further investigations, followed by the discovery of hiv infection. these findings might nevertheless indicate not only that many children were only diagnosed as hiv-positive when presenting at the hospital with seizures or cns infection, but also that some of them did not yet qualify for art according to the specific hiv treatment guidelines in place at the time. this led to progression of hiv infection in these children and made them vulnerable to opportunistic infections and increased the risk of developing epilepsy. the above findings also support the findings of a prior study,19 where early initiation of art was assumed to be protective for epilepsy and seizures. the most common specific aetiology for epilepsy was a prior cns infection, with meningitis caused by mycobacterium tuberculosis being the most frequent. again, cns infection was probably because of late diagnosis of hiv infection, and/or late initiation of art, making the children vulnerable to opportunistic infections. human immunodeficiency virus neurotoxicity was the second most common suspected cause. those data correlate well to those of bearden et al. in botswana.19 two children had infection-independent strokes and developed seizures and epilepsy afterwards, and one patient developed seizures as a neonate after suffering from a hypoxic–ischaemic event during birth. as the type of epilepsy was mostly not described in the notes and as most children were unable to receive eeg readings, it is likely that epilepsy syndromes like absence epilepsy or childhood epilepsy with centro-temporal spikes may have been missed. the prevalence of these disorders, however, is low in high resource settings,30 but unknown in south africa. furthermore, besides cd4 counts and vl, limited laboratory investigations were available for most children, which is a further limitation of this study. in more than one-third of children, the aetiology could not be established, which is slightly higher than that in other studies in children and adults.19,31,32,33 in our cohort, almost half of the children with epilepsy became seizure-free and another 16% had a significant reduction (50% – 75%) of seizure frequency. the tight follow-up schedule to assure adherence to art, and thus to antiepileptic treatment, might have contributed to this outcome. one big concern is the high percentage of the epileptic children in our cohort with school problems (55%). it is known that many children with perinatal acquired hiv infection show neurodevelopmental delay.3,15,16,34 human immunodeficiency virus-positive preschool and school children had global deficits in all measures of neurodevelopment, except gross motor skills, in a study from uganda.35,36,37 compared to their non-exposed and non-infected classmates, two to three times more hiv-infected children struggled with language, visual perception and fine motor skills. a study conducted in congo showed that children infected with hiv had a significantly higher incidence, up to 91%, of neurodevelopmental deficits in all domains compared to uninfected children.37 newer studies could show that early start of treatment with art in perinatal infected children correlates with higher neuro-cognitive performance in children and adolescents,38,39,40,41 supporting the recommendation to preferably start art in the first 3 months of life.42,43 conclusion in this retrospective survey, we were able to show a 2.5% prevalence of epilepsy in infants and children with confirmed hiv infection on art in a semi-urban–rural part of south africa. many of the children who developed epilepsy during the course of their hiv infection had prior cns infection, or hiv encephalopathy and advanced disease, as demonstrated by the high who staging at the start of art. in addition, more than half (55%) of the children were found to have educational difficulties including referral to a special school. as shown, hiv-infected infants and children in low-resource settings face an array of additional challenges besides hiv infection, which need to be addressed in a comprehensive manner. it is clear that in a setting with a high prevalence of hiv, early detection of hiv infection and swift initiation of art in children are crucial, and delays will impact on school performance and thus on future socio-economic status, keeping the spiral of poverty going. the new south african hiv guidelines from 2017, which made it possible to start immediate highly active antiretroviral therapy (haart) on every person diagnosed with hiv infection, address this issue. unfortunately, in low-resource areas like the eastern cape, early diagnosis in children and infants is still a challenge and this needs to be addressed. acknowledgements competing interests the authors have declared that no competing interest exists. authors’ contributions all authors contributed equally to this work. funding information this research received no specific grant from any funding agency in the public, commercial or 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vonthanak s, et al. cognitive function and neurodevelopmental outcomes in hiv-infected children older than 1 year of age randomized to early versus deferred antiretroviral therapy: the predict neurodevelopmental study. pediatr infect dis j. 2013 may;32(5):501–508. https://doi.org/10.1097/inf.0b013e31827fb19d laughton b, cornell m, grove d, et al. early antiretroviral therapy improves neurodevelopmental outcomes in infants. aids. 2012 aug 24;26(13):1685–1690. https://doi.org/10.1097/qad.0b013e328355d0ce hiv 991_in.indd o r ig in a l a r t ic l e september 2014, vol. 15, no. 3 sajhivmed 107 original article closing the gaps: steps towards elimination of mother-to-child transmission of hiv m ibeto,1 bsc, mb chb; j giddy,2 mb chb, mfammed; v cox,1 md 1 médecins sans frontières, khayelitsha, cape town, south africa 2 western cape department of health, khayelitsha and eastern substructure, cape town, south africa corresponding author: m ibeto (msfocb-khayelitsha-doc2@brussels.msf.org) background. with significant reductions in the rate of hiv mother-to-child transmission (mtct) in south africa, each case of failed prevention of mtct (pmtct) should be investigated. objective. to establish the cause(s) of mtct at khayelitsha’s community health centre (chc) in order to identify obstacles to mtct elimination. methods. routinely collected data were reviewed for all hiv-infected infants identified at khayelitsha site b chc from january 2012 to april 2013. results. a total of 926/1 158 (80%) of exposed infants had polymerase chain reaction (pcr) results, with 15/926 (1.6%) pcr-positive. median (interquartile range (iqr)) values for the maternal indicators were as follows: maternal age, 27 (23 31) years; parity, 2 (1 3); gestational age at antenatal presentation, 21.5 (17.5 30.5) weeks; cd4+, 377 (219 446) cells/µl. of the 15 pcr-positive infants, five received art, five received azt and five received no prophylaxis. viral loads were not monitored for any of the women receiving antenatal art. nine of the 15 (60%) delivered in hospital, with 6/9 requiring caesarean section. the median (iqr) infant birth weight was 3.0 (2.6 3.5) kg. all received prophylactic nevirapine post exposure. two of the 15 were clinically unwell at birth, and 14 (86.7%) were breastfed, with 10 (66.7%) recorded as exclusively breastfed. median (iqr) time between delivery and pcr results was 6.6 (6.1 7.3) weeks. discussion. pmtct programmes must consider each pcr-positive infant as a sentinel event that can provide valuable insight into correcting ongoing clinical and programmatic reasons for hiv transmission. the main risk factors for mtct identified in this study were late presentation for antenatal care, inadequate antenatal pmtct prophylaxis and a lack of viral load monitoring. s afr j hiv med 2014;15(3):107-109. doi:10.7196/sajhivmed.1047 o r ig in a l a r t ic l e 108 sajhivmed september 2014, vol. 15, no. 3 over the last decade, south africa (sa) has experienced dramatic improvements in its prevention of mother-tochildtransmission (pmtct) programme. the first national-level pmtct programme was introduced in 2002 and included single-dose nevirapine (sd-nvp) during labour for the mother and to the baby postpartum, modified obstetric practices, infant feeding counselling, and the provision of free infant formula to hiv-positive mothers who chose not to breastfeed. [1] in 2005, pregnant women with cd4+ counts ≤200 cells/µl were eligible for triple-drug antiretroviral (arv) therapy (art) for their own health, and in 2008 pregnant women with cd4+ counts >200 cells/µl were offered ‘dual therapy’ (azidothymidine (azt) from 28 weeks, and sd-nvp in labour) and sdnvp with azt postnatal infant prophylaxis. in 2010, there were further improvements to the pmtct programme. these included routine hiv testing and counselling for pregnant women, dual therapy to prevent mtct of hiv, highly active arv therapy for pregnant women with a cd4+ cell count ≤350 cells/µl, postnatal infant prophylaxis with nvp for breastfeeding hiv-positive women and intensified efforts to integrate pmtct services into routine maternal and child health (mch) services.[2] the success of the national pmtct programme was seen in the 2010 sa pmtct evaluation (the first national evaluation of the pmtct programme in sa), which demonstrated a significant reduction in mtct to 3.5% (compared with an estimated transmission risk of 20 30% without any intervention).[3] the sa pmtct evaluation study also showed high uptake of pmtct services nationally, with more than 98% of women getting an hiv test during pregnancy and 92% of hiv-infected mothers receiving arv treatment or prophylaxis.[3] sa’s latest and arguably most controversial pmtct improvements came in april 2013: sa followed the world health organization recommendations by offering art to all hivpositive pregnant or breastfeeding women regardless of cd4+ count.[4] in light of such achievements, what more is needed to ‘close the gaps’ in the pmtct cascade and reach the millennium development goal of elimination of mtct by 2015? the objective of this review was to establish possible cause(s) of transmission for hivinfected infants in order to identify ongoing obstacles to elimination of mtct. antenatal and pmtct history, delivery information and feeding options were obtained from routinely collected data held in antenatal clinic registers and clinical files. methods for this case series, médecins sans frontières (msf) partnered with the western cape department of health (wc doh) to review and document case histories of all pcr-positive infants found in the hiv-exposed infant register at khayelitsha’s site b community health centre in cape town from 1 january 2012 to 30 april 2013. khayelitsha’s site b community health centre is a campus that provides primary healthcare services including casualty, outpatient department for adults and children, an hiv/tuberculosis (tb)/drug-resistant tb (dr-tb) clinic, and a midwifery and obstetrics unit. within its paediatric services, it has a baby clinic that is dedicated to the registration and care of hiv-exposed infants. it is the responsibility of this baby clinic to ensure that all hiv-exposed infants who attend receive a pcr test at around 6 weeks postpartum. results a total of 1 158 hiv-exposed infants were recorded in the exposed infant register at khayelitsha site b community health centre over the 16-month study period (from 1 january 2012 to 30 april 2013). of these, 926 (80%) of exposed infants had hiv dna pcr results available, and 15 (1.6%) were pcr-positive. review of the maternal histories for the 15 positive infants (table 1) found that the median (interquartile range (iqr)) maternal age was 27 (23 31) years, median parity was 2 (1 3), and median gestational age at antenatal presentation was 21.5 (17.5 30.5) weeks. baseline cd4+ count was <350 cells/ µl in 46.7% of women, with a median (iqr) cd4+ count of 377 (219 446) cells/µl. onethird of these mothers received art: two started art after 33 weeks’ gestation and received no more than 5 weeks of art prior to delivery, one started art at 17 weeks’ gestation but then defaulted treatment at month 1 on art, and the remaining two started art at 25 and 21 weeks’ gestation, respectively, but had clinic ally unwell babies at birth, suggesting early in utero transmission. five mothers received azt for a median duration of 20 weeks (based on clinical records only; no record of degree of adherence to azt dual therapy was found) and an additional five received no pmtct prophylaxis (two defaulted on art prior to table 1. clinical and demographic features of mother-infant pairs where transmission of hiv occurred patient characteristics (n=15) maternal age (years), median (iqr) 27 (23 31) parity, median (iqr) 2 (1 3) gestation at 1st anc presentation (weeks), median (iqr) 21.5 (17.5 30.5) maternal cd4+ count (cells/µl), median (iqr) 377 (219 446) cd4+ count (cells/µl), n (%) <200 3 (20.0) 200 349 4 (26.7) ≥350 8 (53.3) pmtct prophylaxis provided, n (%) art 5 (33.3) azt 5 (33.3) no prophylaxis 5 (33.3) mothers requiring hospital care at delivery, n (%) 9 (60) infant birth weight (kg), median (iqr) 3.0 (2.6 3.5) infants clinically unwell at birth, n (%) 2 (13.3) breastfed infants, n (%) documented breastfeeding of any duration 14 (86.7) documented exclusive breastfeeding 10 (66.7) duration between delivery and pcr test (weeks), median (iqr) 6.6 (6.1 7.3) iqr = interquartile range; anc = antenatal clinic; pmtct = prevention of mother-to-child transmission; art = antiretroviral therapy; azt = azidothymidine; pcr = polymerase chain reaction. o r ig in a l a r t ic l e september 2014, vol. 15, no. 3 sajhivmed 109 onset of pregnancy but verbally reported being on art at booking, one presented in labour, one tested negative in pregnancy then positive in labour, and one did not receive prophylaxis despite booking at 6 weeks’ gestation). viral loads were not monitored for women on antenatal art, as the national art/pmtct guidelines at the time required 1st viral load to be drawn at month 4 on art and not prior. out of 15 mothers, 9 (60%) required hospital care at delivery, with 6 requiring caesarean section. review of the early infant histories for the 15 positive infants revealed the following: median (iqr) infant birth weight was 3.0 (2.6 3.5) kg; all received nevirapine as postexposure prophylaxis (the duration and adherence to which was unclear from clinic records); and 14 (87%) were breastfed with 10 (67%) recorded as ‘exclusively breastfed’. median (iqr) time between delivery and pcr results was 6.6 (6.1 7.3) weeks. discussion this case series points to several critical gaps in the pmtct cascade in this setting. it was of great concern to discover that, consistently over the 16-month period, only 80% of exposed infants had documented pcr results. this finding is of particular concern when considered in the context of the sa pmtct evaluation study reported intention to obtain infant pcr testing at 6 weeks; the study found that only 35% of hiv-positive mothers indicated that they planned to obtain early infant diagnosis for their infant during their 6-week immunisation visit. multiple possible causes were identified for the suboptimal pcr testing rate, including poor patient education of the need to return at around 6 weeks for a pcr test, poor staff knowledge (because of staff turnover and shortages) of the need to ensure a pcr is done in infants presenting between 6 weeks and 18 months, the fragmentation of child health services within the facility, and insufficient staff motivation to follow up on missing pcr results or infants not returning for their initial pcr test. further research is required to analyse in more detail all the causes of inadequate infant pcr testing coverage, along with intensified effort to improve the postnatal linkage to care of all hiv-exposed infants and their mothers. analysis of the maternal antenatal histories for infants found to be hiv-infected revealed further gaps in the pmtct cascade. the need to intensify community awareness of the importance of early antenatal booking was highlighted in the following findings: median (iqr) gestational age at antenatal presentation was 21.5 (17.5 30.5) weeks, and one mother presented for the first time in labour (no antenatal care) despite this being her 3rd pregnancy and already knowing her hiv status. to address this gap, msf and wc doh have partnered with the treatment action campaign to launch a community awareness campaign that aims to improve patient literacy particularly on the issue of early antenatal booking. inconsistency in the provision of antenatal prophylaxis and a lack of viral load monitoring for pregnant or breastfeeding women on art were identified as further significant gaps. from clinical records, the median duration of azt dual therapy was 20 weeks, but was complicated by: poor maternal understanding of the importance of adherence to azt twice daily; pregnant women often running out of their azt between appointments; staff not routinely checking azt pill counts during antenatal visits; and no system for monitoring azt provision or adherence. one mother, whose child is now hiv-infected, was not provided antenatal azt prophylaxis despite booking at 6 weeks’ gestation and presenting a further four times in her pregnancy; this woman was told she had booked too early to start prophylaxis on her first visit, and antenatal staff failed to detect that she had not been issued azt on each subsequent visit. the absence of routine viral load monitoring for women on art at antenatal booking and subsequently through pregnancy and breastfeeding resulted in failing to detect women who had defaulted art prior to or during pregnancy; two mothers of hivinfected infants in our review defaulted on art prior to onset of pregnancy but verbally reported being on art at their antenatal booking. vigilance in viral load monitoring for women on art during pregnancy is essential, and infant feeding choice should take into account a woman’s actual or likely viral load at delivery. of the 15 hiv-infected infants, 14 were breastfed, with 10 documented as being exclusively breastfed. in these cases, hiv transmission may have occurred due to breastfeeding in the presence of a high viral load. in a small number of cases, a complicated delivery was also linked with transmission. these data come from a case series, and as such, have fundamental limitations related to absence of a comparator group of hiv-exposed but uninfected infants. nonetheless, several key concerns emerge clearly. the main risk factors for mtct identified in our review of the case histories of pcr-positive infants were late presentation to antenatal care, inadequate provision or duration of antenatal pmtct prophylaxis, and a lack of viral load monitoring to determine whether a pregnant woman is virologically suppressed at delivery and during breastfeeding. women with any of these risk factors should be urgently identified as high risk for transmission and provided additional adherence support, home visits by community care workers, an early infant pcr test, tailored infant feeding advice and dual postnatal infant prophylaxis. recent policy developments calling for provision of art for all hivpositive pregnant or breastfeeding women regardless of cd4+ count is welcomed, and will undoubtedly improve pmtct outcomes in sa. however, the elimination of mtct will require intensified efforts to strengthen each step in the pmtct cascade, from promotion of early antenatal booking to timely identification and appropriate management of high-risk pregnant or breastfeeding women. the introduction of routine birth pcr testing for high-risk infants would allow for early detection of infants infected with hiv; this would reduce the risk that hiv-positive infants are lost to follow-up prior to diagnosis and allow rapid initiation of art. pmtct programmes must consider each pcr-positive infant as a sentinel event that can provide valuable insight into correcting ongoing clinical and programmatic reasons for hiv transmission. references 1. national department of health south africa. policy and guidelines for the implementation of the pmtct programme. pretoria: national department of health south africa, 2001. 2. national department of health south africa/the south african national aids council. clinical guidelines: pmtct (prevention of mother-to-child transmission). pretoria: national department of health south africa and the south african national aids council, 2010. 3. goga ae, dinh th, jackson dj for the south african pmtct evaluation study group. evaluation of the effectiveness of the national prevention of mother-tochild transmission (pmtct) programme measured at six weeks postpartum in south africa, 2010. south african medical research council, national department of health of south africa and president’s emergency plant for aids relief (pepfar/us) centers for disease control and prevention, 2012. 4. national department of health south africa. the south african antiretroviral treatment guideline 2013, pmtct guidelines, revised march 2013. pretoria: national department of health south africa, 2013. abstract introduction objectives methods results discussion conclusion acknowledgements references about the author(s) brian van wyk school of public health, faculty of community and health sciences, university of the western cape, cape town, south africa ebrahim kriel school of public health, faculty of community and health sciences, university of the western cape, cape town, south africa ferdinand mukumbang school of public health, faculty of community and health sciences, university of the western cape, cape town, south africa citation van wyk b, kriel e, mukumbang f. retention in care for adolescents who were newly initiated on antiretroviral therapy in the cape metropole in south africa. s afr j hiv med. 2020;21(1), a1077. https://doi.org/10.4102/hivmed.v21i1.1077 original research retention in care for adolescents who were newly initiated on antiretroviral therapy in the cape metropole in south africa brian van wyk, ebrahim kriel, ferdinand mukumbang received: 12 feb. 2020; accepted: 23 may 2020; published: 22 july 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: long-term retention of adolescents aged 10 -19 years on antiretroviral therapy (art) is crucial to achieve viral load suppression. however, it is reported globally that adolescents have lower retention in care (ric) on art, compared with children and adults. objectives: to determine the prevalence and predictors of ric of adolescents over 2 years following initiation onto art in public health facilities in the metropole district health services of the western cape province in 2013. methods: data of 220 adolescent patients who were newly initiated on art in 2013 were extracted from the provincial electronic database, and subjected to univariate and bivariate analyses using spss. results: the rate of ric post-initiation was low throughout the study period, that is, 68.6%, 50.5% and 36.4% at 4, 12 and 24 months, respectively. the corresponding post-initiation viral load suppression levels on art of those remaining in care and who had viral loads monitored were 84.1%, 77.4% and 68.8% at 4, 12 and 24 months, respectively. retention in care after initiation on art was higher amongst younger adolescents (10-14 years), compared with older adolescents (15-19 years). male adolescents were significantly more likely to be retained, compared with females. pregnant adolescents were significantly less likely to be retained compared with those who were not pregnant. conclusion: key interventions are needed to motivate adolescents to remain in care, and to adhere to their treatment regimen to achieve the target of 90% viral load suppression, with specific emphasis on older and pregnant adolescents. keywords: hiv; aids; adolescents; youth; retention in care. introduction globally, it has been estimated that 190 000 (59 000–380 000) adolescents, between the ages of 10 and 19 years, were newly infected with human immunodeficiency virus (hiv) in 2018, and the total number of adolescents living with hiv (alwh) was 1.6 million (1.1–2.3 million), which accounts for 4% of all people living with hiv (plwh).1 sub-saharan africa has the highest number of hiv-infected adolescents with about 1.5 million of them. in south africa (sa), it is estimated that 280 000 children aged between 0 and 14 years were living with hiv in 2017, and that just under 7 million persons aged ≥ 15 years were plwh.2 the national hiv household survey estimated hiv prevalence in 0–14-year-olds to be 3.0% and 2.4% for females and males, respectively.3 in 15–19-year-olds, it was 5.8% in females and 4.7% in males. the number of adolescents aged 15–19 years receiving antiretroviral therapy (art) in sa increased tenfold between 2005–2008 and 2013–2016.4 this increase is attributed to perinatally infected infants surviving into adolescence and to a rising incidence of hiv in behaviourally infected 15–19-year-olds. despite success in art roll-out in most countries over the last decade, acquired immune deficiency syndrome (aids)-related deaths amongst adolescents have increased whilst declining in other age groups.5 to prevent aids-related deaths, the infected must be diagnosed, receive art and remain in care to maintain viral load (vl) suppression. this would help achieve the 90-90-90 targets of the joint united nations programme on hiv and aids (unaids).6 retention on art is particularly challenging for key populations, such as adolescents, amongst others, and has been noted as a global priority for action.7,8 previous studies confirm that adherence, retention in care (ric) and treatment outcomes for adolescents in southern africa are worse, compared with adults.9,10,11 however, routine monitoring of hiv treatment programmes does not report ric and treatment outcomes for adolescents (10–19 years); they report only for children (0–14 years) and adults (15 years and older).11 in this way, adolescent problems with ric and treatment outcomes remain undetected in the monitoring of hiv programmes. it is argued that because of the general adherence problems faced by adolescents globally, specific analysis is needed to report outcomes for this age group at a health-systems level.8 objectives this article reports on the ric of alwh aged 10–19 years who were newly initiated on art in public health facilities in the western cape metropole, sa, in 2013, and the risk factors associated with remaining in care at 4, 12 and 24 months post-initiation on art. methods design we conducted a retrospective cohort analysis of adolescents aged 10–19 years, who were initiated on art in 2013 in the western cape metropole. study context the western cape’s art programme has been in existence for over 10 years. the 2013 version of the art guidelines was updated in 2016, and had consolidated adult, adolescent, paediatric and prevention of mother-to-child transmission of hiv guidelines.12 in the province of the western cape, most adults and children access art services at primary healthcare facilities, such as clinics, community day centres and community health centres. at the end of june 2017, this province had 237 285 patients on art, of whom 229 171 were aged ≥ 15 years and 8114 were aged < 15 years. the cape town metropole accounts for 74.3% (167 833) of the total number of art patients in the western cape, that is 162 092 aged ≥ 15 years and 5741 aged < 15 years.13 antiretroviral therapy services are rendered at the various western cape facilities, as outlined in table 1.13 table 1: facilities in the western cape rendering antiretroviral therapy services (n = 256).13 however, services rendered at these facilities vary. some provide only adult art services. others offer both adult and paediatric support. some facilities offer art daily, whilst others provide art only on certain days of the week. human resource capacity also varies. not all facilities have resident medical officers or clinical nurse practitioners. hence, the need for outreach support arises. the capacity to care for adults in the western cape has improved with the implementation of the nurse-initiated management of antiretroviral treatment (nimart) programme, whereby nurses are trained and receive structured mentorship and accreditation to initiate first-line art. a challenge in the rural areas is the irregular access to competent and skilled clinicians to manage paediatric patients and complicated adult and adolescent patients. as previously stated, most art services are designated as paediatric or adult. adolescent-specific art services are not yet part of standard care being offered at all art facilities. those that do are limited to services initiated and/or supported by tertiary hospitals or non-profit organisations. data source two data sources were used for this analysis: the three interlinked electronic registers.net (tier.net),14 an electronic art database developed by the university of cape town’s centre for infectious disease epidemiology and research, and patients’ folders accessed at the treating facilities. tier.net is used operationally in the public health facilities of sa to monitor baseline clinical care and client outcomes over time. it is also the platform on which hiv tests are electronically captured in the public sector.15 we first visited the tier.net platform to obtain data on all those who met the inclusion criteria. with the use of our data-capturing form, we searched for the relevant information from the tier.net platform. where information was missing, we accessed the patient’s folder to confirm the availability of the required information. study participants data were found for 332 alwh newly registered on art from 29 facilities across the western cape metropole and extracted from the provincial tier.net register. only 220 participants were included in the final analysis. of the 112 excluded, for 68, folders could not be found in spite of making numerous attempts to trace these documents at the various facilities. furthermore, 28 patients were incorrectly captured as new patients when they had been transferred in from other facilities; 4 patients were not adolescents, and their birth dates had been incorrectly captured; and 12 patients had been incorrectly captured as having initiated art in 2013. main outcome measures and analysis we extracted data on sociodemographic characteristics (age, sex, source of income, type of dwelling, disclosure to significant other and reported alcohol or other drug use) and clinical characteristics (cd4 count, who stage, pregnancy and art regimen). bivariate analysis was conducted to determine the significance and strength of association between ric at 4, 12 and 24 months and various sociodemographic and clinical characteristics. statistical significance was tested by using the chi-square test, with significance set at p < 0.05, and where significant, the strength of association was calculated as risk ratios (rrs) with 95% confidence interval (ci), using spss v23. our use of 4, 12 and 24 months rather than 6, 12 and 24 months is informed by the operational guidelines of the western cape’s art programme, which requires the first vl test to be conducted at 4 months and the patient to return for results in month 5.16 patients would receive 1 month’s medication if they have unsuppressed vl, and 2 months’ supply if their vl is suppressed. the reason for the 4-month ric measurement is to identify how many alwh return for their vl tests. the subsequent ric behaviour of the patients is measured annually. survival analysis was assessed with lost to follow-up (ltfu) as the outcome of interest. we did a comparative survival analysis for the age and sex of the study participants. we reported the hazard ratios and p-values. an alwh was considered ltfu if they had not made contact with a treating healthcare facility within 90 days since their last registered contact for hiv-related treatment and care. the ltfu date was determined from the day when the patient was last seen at the clinic where they were provided with their last medication. therefore, by using the intention-to-treat population in this study, the ric definition was the proportion of hiv-infected adolescents alive and on art at months 4, 12 and 24 in the entire study sample. ethical consideration the protocol was approved by the university of the western cape biomedical research ethics committee (reference number: bm/17/1/15) and the government health impact assessment (reference number: wc_2017rp58_418) committee. results of the 220 adolescents who were newly initiated on art in 2013, the majority were ‘older’ adolescents, 15–19 years (n = 179, 81.4%) and female (n = 182, 82.7%) (table 2). most were financially supported by their families and friends (n = 129, 58.6%) and lived in a formal house (n = 116, 52.7%). as per hiv clinical treatment guidelines, the overwhelming majority (n = 182, 87%) had disclosed their hiv status to a significant other. table 2: sociodemographic and clinical characteristics of adolescents retained in antiretroviral therapy at metropole district health service facilities in the western cape, 2013–2015 (n = 220). the median cd4 count at art initiation was 292.5 cells/mm3 (interquartile range [iqr]: 228.8–391.3). only two participants had no baseline cd4 count recorded. half of the participants (n = 109) were initiated with a cd4 count between 200 cells/mm3 and 349 cells/mm3, and 19% (n = 42) had a baseline cd4 count of < 200 cells/mm3 as per the hiv treatment guidelines of 2013. of the 213 participants who had who staging done at art initiation, 46.5% and 22.5% were who stages i and ii, respectively, and 23.2% and 6.8% were who stages iii and iv, respectively. as with the cd4 counts, clinical staging is taken into consideration in the universal test and treat era. observed ric was low throughout the study period with 68.6%, 50.5% and 36.4% adolescents being retained in care at 4, 12 and 24 months post-initiation on art, respectively. figure 1 illustrates the comparison of ric at 4, 12 and 24 months between younger (10–14 years of age) and older (15–19 years of age) adolescents (90.2% vs. 63.7%, 82.9% vs. 43.0% and 68.3% vs. 29.1%, respectively). however, ric of the younger adolescents at month 4 was just over 90%, but the younger adolescents at months 12 and 24 fell short of 90%. the older adolescents showed poorer rates of ric at months 4, 12 and 24, compared with the younger adolescents at the same time periods. figure 1: a consort diagram illustrating the sampling process. table 3 shows that a significantly higher number of younger adolescents (10–14 years) were retained in care at 4, 12 and 24 months post-initiation on art, compared with older adolescents (15–19 years). at 4 months post-initiation on art, younger adolescents had 37% higher risk (likelihood) of ric (rr = 1.37, 95% ci: 1.17–1.60) compared with older adolescents. at 12 months post-initiation on art, younger adolescents had 85% higher risk of ric (rr = 1.85, 95% ci: 1.48–2.31), compared with older adolescents, and more than two times higher risk (rr = 2.35, 95% ci: 1.73–3.20) at 24 months. table 3: rate of retention in care amongst adolescents initiated on antiretroviral therapy in 2013 in metropole district health service facilities in the western cape (n = 220). male adolescents had higher rates of ric post-initiation of art at 4 months (rr = 1.29, 95% ci: 1.08–1.53), 12 months (rr = 1.39, 95% ci: 1.06–1.83) and 24 months (rr = 1.60, 95% ci: 1.11–2.30), compared with female adolescents. adolescents who were pregnant had significantly lower rates of ric post-initiation of art, compared with all other adolescents at 4 months (rr = 0.73, 95% ci: 0.59–0.90), 12 months (rr = 0.60, 95% ci: 0.44–0.83) and 24 months (rr = 0.47, 95% ci: 0.30–0.74). adolescents who disclosed their hiv status to a significant other were two times more likely to be retained in care at month 12 (rr = 2.06, 95% ci: 1.07–3.95) than adolescents who did not disclose to a significant other. adolescents classified as who stage i at art initiation had significantly lower rates of ric at 4 months post-initiation, compared with adolescents who were classified as who stage iii (rr = 1.29, 95% ci: 1.14–1.42). those classified as who stages ii and iv also had better rates of ric at month 4, compared with adolescents classified as who stage i at baseline, but these did not reach statistical significance. at 12 months post-initiation of art, those who were at who stage ii (rr = 1.35, 95% ci: 1.09–1.53) as well as who stage iii (rr = 1.35, 95% ci: 1.10–1.53) at baseline had a 35% greater risk (likelihood) of ric, compared with those who were who stage i at art initiation. adolescents who were at who stage i at baseline also showed significantly lower ric rates at 24 months post-initiation of art, compared with those who were at who stage ii (rr = 1.52, 95% ci: 1.24–1.69) and who stage iii (rr = 1.46, 95% ci: 1.15–1.66) at baseline. at 24 months post-initiation of art, adolescents who were classified as who stage ii (rr = 1.35, 95% ci: 1.09–1.53) and those who were who stage iii (rr = 1.35, 95% ci: 1.10–1.53) at art initiation had a 35% greater risk of ric, compared with those who were who stage i at art initiation. those adolescents who were classified as who stage iv at art initiation showed better ric rates at months 4, 12 and 24 post-initiation, but none of these reached statistical significance. figures 2, 3 and 4 show the survival curves of the study participants. the overall person-time at risk of being ltfu was 3303 months, with an incidence of 119/3807 (4/100) person-months. the hazard ratio for males compared with females was 0.71 (95% ci: 0.41–1.26). the hazard ratio for those aged 15–19 years compared with those aged 10–14 years was 2.53 (95% ci: 1.30–4.91). figure 2: overall rate of adolescents being lost to follow-up post-initiation of antiretroviral therapy. figure 3: rate of being lost to follow-up of adolescents post-initiation of antiretroviral therapy by sex. figure 4: rate of being lost to follow-up of adolescents’ post-initiation of antiretroviral therapy by age. discussion in 2014, the unaids set a global art target of 90-90-90. this includes the goal that 90% of persons who test hiv-positive should be initiated on art.6 having successfully tested and initiated alwh onto art, their ric and the maintenance of vl suppression of at least 90% are the ongoing challenges. our study reports that the overall ric of alwh was low throughout the 24-month observation period. contrary to our findings, nabukeera-barungi et al. found that 90.4% of ugandan adolescents demonstrated good ric with an ltfu of only 5%.17 a meta-analysis of six south african studies also reported a relatively high alwh retention rate of 83% (95% ci: 68% – 94%) in the first 2 years on art.18 the results of our study are reported with the intention-to-treat population as the denominator at every time point, that is, months 4, 12 and 24, and without the exclusion of transfer-outs, ltfu patients and the numerator being those alive and on art. the above-mentioned studies did not measure ric in the same manner. nabukeera-barungi et al.17 determined ric by dividing those still active in care by the total number that started after subtracting those who died and transferred out from both the numerator and denominator. younger adolescents (10–14 years) demonstrated better ric rates, compared with the older group. this observation could be attributed to the disproportionate attention offered to younger adolescents. in spite of the unique challenges posed by adolescents and art, there is a dearth of comprehensive health services for adolescents, including interventions to improve ric in sub-saharan africa.19 nevertheless, younger adolescents show better ric rates because they depend, to a greater extent, on their caregivers to handle their treatment journey. in this way, the ric of the young adolescent is an extension of the dedication and understanding of the caregiver. another study designed to investigate the ric rates between younger and older adolescents in zimbabwe demonstrated no differences in attrition amongst younger versus older adolescents.20 we found that older adolescents (15–19 years) were significantly less likely to be retained in care over the first 24 months, compared with younger adolescents. this finding is congruent with the trends reported in other studies21,22 and corresponds to the transition of adolescents from paediatric to adult hiv programmes – a known high-risk period for disengagement with care.23,24,25 several authors have argued that patient-level challenges, such as developmental delays, mental health issues, stigma and social support at home and school, must be adequately addressed for a successful transition to take place.26 a supported transition requires a skilful adult treatment team and the provision of facilitated care aimed at overcoming the disruptions of the patient–paediatric provider relationship. the loss of ancillary support is required to foster independence, the exercise of autonomy and the growth of personal responsibility.27,28 although male adolescents constituted a smaller proportion of the study sample, on average, they had greater ric throughout the observation period, compared with females. just under half of the female adolescents (n = 84/182, 46%) were initiated on art whilst pregnant. they exited care at an alarming rate, that is, 44%, 64% and 79% at 4, 12 and 24 months, respectively. these findings correspond to those of nuwagaba-biribonwoha et al. who found a greater rate of ltfu amongst pregnant and non-pregnant female adolescents, compared with male adolescents.29 the current study reports lower ric rates, compared with the 76.4% ric at 12 months noted in a recent systematic review of pregnant and post-partum women in africa.30 this report found younger age and same-day art initiation to be risk factors for poor retention, as was initiating during pregnancy, particularly late pregnancy. our findings indicate that adolescents who were classified as who stage iv at art initiation showed better ric rates at months 4, 12 and 24 post-initiation, although no statistical significance was achieved. individuals at who stages iii and iv are likely to remain in care because they are motivated by their health status and by the association between treatment and health outcomes. clinicians tend to monitor individuals who are at who stages iii and iv more closely because of other comorbidities such as tuberculosis and other opportunistic infections requiring clinical assessments. however, matyanga et al. found that a low cd4 count and advanced hiv infection at initiation were associated with ltfu.20 we also found that adolescents classified as who stage i at art initiation had significantly lower rates of ric at 4 months post-initiation versus those with a who stage iii. contrary to the results in our study, another ugandan study found that the risk of ltfu of adolescents at 12 months was significantly greater amongst those on who clinical stages iii and iv, compared with those on who stages i and ii.31 people living with hiv at who stage i hardly display signs and symptoms associated with aids. the literature has attributed this low ric behaviour amongst adolescents at stage i to not feeling ‘sick’ or feeling ‘well’ as a proxy of nothing being wrong. although the primary focus of our study was not on pregnant, hiv-infected adolescents, many in this sub-group were captured in our sample. this could be explained by the fact that pregnant, hiv-infected adolescents are often horizontally infected and receive their positive hiv test result for the first time when booking for antenatal care. although vertical transmission of hiv is common amongst younger alwh, horizontal transmission is a frequent mode of transmission in older adolescents. adolescent boys tend to not access hiv treatment because they mostly remain asymptomatic at this stage. interventions such as task shifting, community-based adherence support, mhealth platforms and group adherence counselling emerged as strategies in adult populations that could be adapted for adolescents.32,33 these interventions may benefit older adolescents, especially those transitioning to adult programmes that utilise them. however, the effectiveness of, for example, ‘teen clubs’, has had mixed results. mackenzie et al.34 reported that malawian alwh who were not in a teen club were less likely to be retained than those in teen clubs. on the other hand, munyayi and van wyk35 found that group-based adherence interventions such as teen clubs did not improve retention rates for younger adolescents in specialised paediatric art clinics in namibia but did hold potential for improving rates in older adolescents. adolescent-only clinics and monthly meetings have been shown to improve the ric of adolescents.36 to this end, we support the calls of other authors for interventions, especially targeting older adolescents whose needs are increased during the transition period.23 conclusion our study highlights low ric for adolescents over the first 2 years after initiation on art. critical intervention is needed to motivate adolescents to remain in care, adhere to treatment and ultimately to achieve and maintain vl suppression (even when they are not feeling sick). targeted interventions to address transition coordination – preand post-transition from paediatric to adult hiv programmes – are needed to counter older adolescents dropping out of care. female adolescents who initiate art whilst pregnant should receive special attention. this aligns with the increased need to provide and integrate appropriate sexual reproductive health services to alwh. behavioural interventions to improve adherence and ric should ideally be embedded in community health services so that this forms part of an ‘extended’ hiv treatment package. acknowledgements competing interests the authors have declared that no competing interests exist. authors’ contributions e.k. conducted the research under the supervision of b.v.w., and f.m. and b.v.w. drafted the first manuscript. e.k. and f.m. commented on all drafts. all authors approved the final version. funding information this project was supported under a medical research council of south africa self-initiated research grant. data availability statement data are available upon request to the author. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the south african medical research council or university of the western cape. references unicef. turning the tide against aids will require more concentrated focus on adolescents and young people [homepage on the internet]. 2019 [cited 2019 oct 21]. available from: https://data.unicef.org/topic/hivaids/adolescents-young-people/ joint united nations programme on hiv/aids (unaids). data [homepage on the internet]. 2018 [cited 2019 oct 21]. available from: https://www.unaids.org/sites/default/files/media_asset/unaids-data-2018_en.pdf south african national hiv prevalence, incidence, behaviour and communication survey [homepage on the internet]. 2017 [cited 2019 dec 03]. available from: http://www.hsrc.ac.za/uploads/pagecontent/9234/sabssmv_impact_assessment_summary_za_ads_cleared_pdfa4.pdf maskew m, bor j, macleod w, carmona s, sherman gg, fox mp. adolescent hhiv treatment in south africa’s national hiv programme: a retrospective cohort study. lancet hiv. 2019;6(11):e760–e768. https://doi.org/10.1016/s2352-3018(19)30234-6 unicef. children and aids [homepage on the internet]. 2017 [cited 2018 aug 18]. available from: https://data.unicef.org/wp-content/uploads/2017/11/hivaids-statistical-update-2017.pdf unaids. 90-90-90: an ambitious treatment target to help end the aids epidemic [homepage on the internet]. unaids; 2014 [cited 2019 oct 15]. available from: http://www.unaids.org/sites/default/files/media_asset/90-90-90_en.pdf mugglin c, haas ad, van oosterhout jj, et al. long-term retention on antiretroviral therapy among infants, children, adolescents and adults in malawi-term retention on antiretroviral therapy among infants, children, adolescents and adults in malawi: a cohort study. plos one. 2019;14(11):e0224837. https://doi.org/10.1371/journal.pone.0224837 wong vj, murray kr, phelps br, vermund sh, mccarraher dr. adolescents, young people, and the 90-90-90 goals: a call to improve hiv testing and linkage to treatment. aids. 2019;31(suppl. 3):s191–s194. https://doi.org/10.1097/qad.0000000000001539 nglazi md, kranzer k, holele p, et al. treatment outcomes in hiv-infected adolescents attending a community-based antiretroviral therapy clinic in south africa. bmc infect dis. 2012;12:21. https://doi.org/10.1186/1471-2334-12-21 nachega jb, hislop m, nguyen h, dowdy dw, chaisson re, regensberg l. antiretroviral therapy adherence, virologic and immunological outcomes in adolescents compared with adults in southern africa. j acquir immune defic syndr. 2009;51(1):65–71. https://doi.org/10.1097/qai.0b013e318199072e kariminia a, law m, davies m, et al. mortality and losses to follow-up among adolescents living with hiv in the iedea global cohort collaboration. jias. 2018;21:e25215. https://doi.org/10.1002/jia2.25215 western cape government health. 2016. the western cape consolidated guidelines for hiv treatment: prevention of mother-to-child transmission of hiv (pmtct), children, adolescents and adults. western cape: western cape government health. western cape government health: hast. june 2017 art data sign-off document. western cape: western cape government health; 2017. osler m, hilderbrand k, hennessey c, et al. a three-tier framework for monitoring antiretroviral therapy in high hiv burden settings. jias. 2014;17:18908. https://doi.org/10.7448/ias.17.1.18908 lilian rr, rees k, mcintyre ja, struthers he, peters rph. same-day antiretroviral therapy initiation for hiv-infected adults in south africa: analysis of routine data. plos one. 2020;15(1):e0227572. https://doi.org/10.1371/journal.pone.0227572 western cape government health. update to antiretroviral guidelines: circular h116 of 2012 [homepage on the internet]. 2012 [cited 2017 oct 06]. available from: http://www.doh.gov.za. nabukeera-barungi n, elyanu p, asire b, et al. adherence to antiretroviral therapy and retention in care for adolescents living with hiv from 10 districts in uganda. bmc infect dis. 2015;15:520. https://doi.org/10.1186/s12879-015-1265-5 zanoni bc, archary m, buchan s, et al. systematic review and meta-analysis of the adolescent hiv continuum of care in south africa: the cresting wave. bmj global health. 2016;1:e000004. https://doi.org/10.1136/bmjgh-2015-000004 adejumo oa, malee km, ryscavage p, hunter sj, taiwo bo. contemporary issues on the epidemiology and antiretroviral adherence of hiv-infected adolescents in sub-saharan africa: a narrative review. j int aids soc. 2015;18(1):20049. https://doi.org/10.7448/ias.18.1.20049 matyanga cmj, takarinda kc, owiti p, et al. outcomes of antiretroviral therapy among younger versus older adolescents and adults in an urban clinic, zimbabwe. public health action. 2016;6(2):97–104. https://doi.org/10.5588/pha.15.0077 kranzer k, bradley j, musaazi j, et al. loss to follow-up among children and adolescents growing up with hiv infection: age really matters. j int aids soc. 2017;20(1):21737. https://doi.org/10.7448/ias.20.1.21737 okoboi s, ssali l, yansaneh a, et al. factors associated with long-term antiretroviral therapy attrition among adolescents in rural uganda: a retrospective study. j int aids soc. 2016;19(554):20841. https://doi.org/10.7448/ias.19.5.20841 dahourou dl, gautier-lafaye c, teasdale ca, et al. transition from paediatric to adult care of adolescents living with hiv in sub-saharan africa: challenges, youth-friendly models, and outcomes. j int aids soc. 2017;20(suppl. 3):21528. https://doi.org/10.7448/ias.20.4.21528 cervia js. easing the transition of hiv infected adolescents to adult care. aids patient care stds. 2013;27(12):692–696. https://doi.org/10.1089/apc.2013.0253 pinzón-iregui mc, ibanez g, beck-sagué c, halpern m, mendoza rm. ‘… like because you are grownup, you do not need help’: experiences of transition from pediatric to adult care among youth with perinatal hiv infection, their caregivers, and health care providers in the dominican republic. j int assoc provid aids care. 2017;16(6):579–587. https://doi.org/10.1177/2325957417729749 vijayan t, benin al, wagner k, et al. we never thought this would happen: transitioning care of adolescents with perinatally acquired hiv infection from paediatrics to internal medicine. aids care. 2009;21(10):1222–1229. https://doi.org/10.1080/09540120902730054 jones c, ritchwood td, taggart t. barriers and facilitators to the successful transition of adolescents living with hiv from pediatric to adult care in low and middle-income countries: a systematic review and policy analysis. aids behav. 2019;23(9):2498–2513. https://doi.org/10.1007/s10461-019-02621-6 kung th, wallace ml, snyder kl, et al. south african healthcare provider perspectives on transitioning adolescents into adult hiv care. samj. 2016;106(8):804–808. https://doi.org/10.7196/samj.2016.v106i8.10496 nuwagaba-biribonwoha h, kiragga an, yiannoutsos ct, et al. adolescent pregnancy at antiretroviral therapy (art) initiation: a critical barrier to retention on art. j int aids soc. 2018;21:e25178. https://doi.org/10.1002/jia2.25178 knettel ba, cichowitz c, ngocho js, et al. retention in hiv care during pregnancy and the postpartum period in the option b+ era: a systematic review and meta-analysis of studies in africa. j acquir immune defic syndr. 2018;77(5):427–438. https://doi.org/10.1097/qai.000000000001616 ssali l, kalibala s, birungi j, et al. retention of adolescents living with hiv in care, treatment, and support programs in uganda. 2014; washington, dc: united states agency for international development. available from: https://www.popcouncil.org/uploads/pdfs/2014hivcore_ugandaadolhaart.pdf. ridgeway k, dulli ls, murray kr, et al. interventions to improve antiretroviral therapy adherence among adolescents in lowand middle-income countries: a systematic review of the literature. plos one. 2018;13(1):e0189770. https://doi.org/10.1371/journal.pone.0189770 murray kr, dulli ls, ridgeway k, et al. improving retention in hiv care among adolescents and adults in low-and middle-income countries: a systematic review of the literature. plos one. 2017;12(9):e0184879. https://doi.org/10.1371/journal.pone.0184879 mackenzie rk, van lettow m, gondwe c, et al. greater retention in care amongst adolescents on antiretroviral treatment accessing ‘teen club’ an adolescent-centred differentiated care model compared with standard of care: a nested case–control study at a tertiary referral hospital in malawi. j int aids soc. 2017;20(3):e25028. https://doi.org/10.1002/jia2.25028 munyayi f, van wyk b. the effects of teen clubs on retention in hiv care amongst adolescents in windhoek, namibia. s afr j hiv med. 2020;21(1):a1031. https://doi.org/10.4102/sajhivmed.v21i1.1031 izudi j, mugenyi j, mugabekazi m, spector vt, katawera a, kekitiinwa a. retention of hiv-positive adolescents in care: a quality improvement intervention in mid-western uganda. biomed res int. 2018;2018:1524016. https://doi.org/10.1155/2018/1524016 is stavudine.html letters is stavudine worth saving? to the editor: the ultimate goal of hiv therapy in resource-constrained settings must be to keep as many people alive with the best possible quality of life using the resources available. the question debated between andrieux-meyer et al.1 and venter et al.2 , 3 might therefore be: ‘with the resources available, can we keep more people alive with the best possible quality of life using stavudine 20 mg bd or tenofovir 300 mg od as standard first line therapy?’ quality of life is extremely important but unlikely to be the overriding factor if budgetary constraints restrict access to art and therefore increase mortality. both groups seem to agree that tenofovir is superior to stavudine for most patients and that the crux of the argument is about cost. venter et al. describe tenofovir as ‘the gold standard’ and state that ‘these arguments [about the benefits of tenofovir] are likely to be irrelevant when the cost of medication is considered’. andrieux-meyer et al. acknowledge that ‘the rationale for this [proposed] trial is to lower treatment costs’. the question of whether stavudine or tenofovir will ultimately save the most lives within the budget is complex. many of the variables change over time and differ between countries. the ‘resources available’ may even be influenced by the choice of art regimens if, for example, a government tries to save money by using inferior but cheaper drugs. in some settings, the rate-limiting factors for saving lives may not actually be financial resources to buy medications but a lack of human resources or logistic challenges. despite these complexities, it is important that each side provides as clear a picture as possible. in addition to cost-effectiveness estimates, we need absolute cost estimates for competing regimens including the estimated minimum cost of tenofovir once costs are driven primarily by raw materials. we need estimates of the number of patients requiring art over time, and we need to know how much funding is available. in particular, we need to know how the recent cuts to funding from donors such as the global fund will affect the provision of art in different countries. without such figures, any discussion about drugs in phase ii trials that have a high attrition rate and long time delay before affordability is frankly irrelevant. venter et al. have conceded that 2 years may be too short to show differences between the groups, and it will be vital to motivate for lengthening the trial if non-inferiority is shown at 2 years. upon completion of the trial, it would seem sensible to use the cheaper option if non-inferiority is shown. however, even if stavudine is not non-inferior (i.e. is inferior), it still might be preferred in some settings if the alternative is running out of money and restricting access to art. we commonly use inferior treatments owing to cost constraints; just one example is the use of amphoteracin b monotherapy to treat cryptococcal meningitis rather than the superior but more expensive combination of liposomal amphoteracin b and flucytosine. activists will argue that we should continue to lobby for increases in funding and reductions in drug cost. of course we should, but we must also be mindful to look at the problem through the eyes of future patients. they will not thank us if our lobbying efforts fail to prevent art rationing owing to shortfalls in funding. it is clear that both sides of the debate have the best interests of patients in mind. to make an informed decision on the merits of trialling stavudine against tenofovir in the southern african context, we need a clearer description of the costs of each strategy and the likely available resources. in short, we need to know whether choosing tenofovir over stavudine in first-line therapy is likely to lead to restricted access to care in some settings. tom h boyles division of infectious diseases & hiv medicine department of medicine groote schuur hospital and university of cape town references 1. andrieux-meyer i, clayden p, collins s, et al. why it’s time to say goodbye to stavudine... everywhere. southern african journal of hiv medicine 2012;13:17-19. 1. andrieux-meyer i, clayden p, collins s, et al. why it’s time to say goodbye to stavudine... everywhere. southern african journal of hiv medicine 2012;13:17-19. 2. innes s, cotton m, venter f. why should we still care about the stavudine dose? southern african journal of hiv medicine 2011;12:14-15. 2. innes s, cotton m, venter f. why should we still care about the stavudine dose? southern african journal of hiv medicine 2011;12:14-15. 3. venter f, innes s, cotton m. low-dose stavudine trials: a public health priority for developing countries. southern african journal of hiv medicine 2012;13:20-21. 3. venter f, innes s, cotton m. low-dose stavudine trials: a public health priority for developing countries. southern african journal of hiv medicine 2012;13:20-21. http://www.sajhivmed.org.za open access page 1 of 1 reviewer acknowledgementpage 1 of 1 reviewer acknowledgement acknowledgement to reviewers in an effort to facilitate the selection of appropriate peer reviewers for the southern african journal of hiv medicine, we ask that you take a moment to update your electronic portfolio on https://sajhivmed.org. za for our files, allowing us better access to your areas of interest and expertise, in order to match reviewers with submitted manuscripts. if you would like to become a reviewer, please visit the journal website and register as a user. in order to be considered, please email submissions@sajhivmed. org.za indicating your intention to register as a reviewer for the journal. to access your details on the website, you will need to follow these steps: 1. log into the online journal at https:// sajhivmed.org.za 2. in your ‘user home’ [https://sajhivmed.org.za/ index.php/hivmed/user] select ‘edit my profile’ under the heading ‘my account’ and insert all relevant details, bio statement and reviewing interest(s). 3. it is good practice as a reviewer to update your personal details regularly to ensure contact with you throughout your professional term as reviewer to the southern african journal of hiv medicine. please do not hesitate to contact us if you require assistance in performing this task. publisher: publishing@aosis.co.za tel: +27 21 975 2602 the editorial team of the southern african journal of hiv medicine recognises the value and importance of peer reviewers in the overall publication process – not only in shaping individual manuscripts, but also in shaping the credibility and reputation of our journal. we are committed to the timely publication of all original, innovative contributions submitted for publication. as such, the identification and selection of reviewers who have expertise and interest in the topics appropriate to each manuscript are essential elements in ensuring a timely, productive peer review process. we would like to take this opportunity to thank and recognise the following reviewers for their precious time and dedication, regardless of whether the papers they reviewed were finally published. we apologise for any names that have been inadvertently left out. these individuals provided their services to the journal as a reviewer from 01 october 2021 to 30 september 2022. anandan a. moodley anastacia tomson andrew p. scheibe ava avalos bandile e. ndlazi bianca da costa dias brian van wyk carol l. tait carolina e. nel charles c. maponga cleophas chimbetete coceka n. mnyani craig carty denise lawrie emmanuel manu eric decloedt farai k. munyayi geziena e. kruger-swanepoel gonasagrie nair helena rabie igor s. dobe jacqueline pienaar james kangethe jeanette wessels jens hitzeroth jeremy s. nel joana woods johannes p. mouton juan m. jansen van vuuren juliane hiesgen kate braithwaite katherine m. gill kim outhoff krishnee moodley kufre j. okop lauren harris lee fairlie leon levin linda rogers lindi coetzee loredana s.c. manolescu louise j. gilbert marcelle myburgh mareike rabe mark w. sonderup martin kidd michael ekholuenetale michael t. boswell mithra john motlalepula sebilo mpiko ntsekhe nataly woollett nokukhanya mdlalose nondumiso s. makhunga-ramfolo nqoba tsabedze paul l. potsane phumla z. sinxadi prudence ive rannakoe j. lehloenya remco p.h. peters renee de waal roland van rensburg sadiyya sheik samanta t. lalla-edward sarah a. van blydenstein saye khoo senlika naidoo shayne a. loubser sibusiso m. zuma siphamandla b. gumede suzanne mccluskey talitha crowley thabiso mofokeng theresa rossouw theresa c. chikopela tinashe mudzviti tom boyles tonderai mabuto ying zhao http://www.sajhivmed.org.za� https://sajhivmed.org.za� https://sajhivmed.org.za� mailto:submissions@sajhivmed.org.za mailto:submissions@sajhivmed.org.za https://sajhivmed.org.za� https://sajhivmed.org.za� https://sajhivmed.org.za/index.php/hivmed/user https://sajhivmed.org.za/index.php/hivmed/user mailto:publishing@aosis.co.za acknowledgement to reviewers abstract introduction research methods and design results discussion conclusion acknowledgements references about the author(s) timotius i. hariyanto faculty of medicine, pelita harapan university, tangerang, indonesia jane rosalind faculty of medicine, pelita harapan university, tangerang, indonesia kevin christian faculty of medicine, pelita harapan university, tangerang, indonesia andree kurniawan department of internal medicine, faculty of medicine, pelita harapan university, tangerang, indonesia citation hariyanto ti, rosalind j, christian k, kurniawan a. human immunodeficiency virus and mortality from coronavirus disease 2019: a systematic review and meta-analysis. s afr j hiv med. 2021;22(1), a1220. https://doi.org/10.4102/sajhivmed.v22i1.1220 review article human immunodeficiency virus and mortality from coronavirus disease 2019: a systematic review and meta-analysis timotius i. hariyanto, jane rosalind, kevin christian, andree kurniawan received: 26 jan. 2021; accepted: 08 mar. 2021; published: 15 apr. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: persons living with human immunodeficiency virus (plwh) constitute a vulnerable population in view of their impaired immune status. at this time, the full interaction between hiv and severe acute respiratory syndrome coronavirus 2 (sars-cov-2) has been incompletely described. objective: the purpose of this study was to explore the impact of hiv and sars-cov-2 co-infection on mortality. method: we systematically searched pubmed and the europe pmc databases up to 19 january 2021, using specific keywords related to our aims. all published articles on coronavirus disease 2019 (covid-19) and hiv were retrieved. the quality of the studies was evaluated using the newcastle–ottawa scale for observational studies. statistical analysis was performed with review manager version 5.4 and comprehensive meta-analysis version 3 software. results: a total of 28 studies including 18 255 040 covid-19 patients were assessed in this meta-analysis. overall, hiv was associated with a higher mortality from covid-19 on random-effects modelling {odds ratio [or] = 1.19 [95% confidence interval (ci) = 1.01–1.39], p = 0.03; i2 = 72%}. meta-regression confirmed that this association was not influenced by age (p = 0.208), cd4 cell count (p = 0.353) or the presence of antiretroviral therapy (art) (p = 0.647). further subgroup analysis indicated that the association was only statistically significant in studies from africa (or = 1.13, p = 0.004) and the united states (or = 1.30, p = 0.006). conclusion: whilst all persons ought to receive a sars-cov-2 vaccine, plwh should be prioritised to minimise the risk of death because of covid-19. the presence of hiv should be regarded as an important risk factor for future risk stratification of covid-19. keywords: coronavirus disease 2019; covid-19; sars-cov-2; hiv; aids. introduction at the end of december 2019, the first cases of a newly discovered acute respiratory illness named coronavirus disease 2019 (covid-19) were reported in wuhan, china.1 by january 2021, >88.3 million infections and 1.9 million deaths worldwide had been reported.2 the covid-19 disease has various clinical manifestations, ranging from mild symptoms such as fever, cough and anosmia to life-threatening conditions including shock, respiratory failure, arrhythmia, overwhelming sepsis and neurological impairment.3,4 meta-analyses have identified several comorbidities,5,6,7,8,9 medicines10,11 and abnormal laboratory test results12,13 associated with a poor outcome. persons living with human immunodeficiency virus (plwh) are an at-risk population in view of their impaired immunity. this impairment increases susceptibility to tuberculosis, opportunistic infections and cancer.14 in 2019, an estimated 38 million people globally were living with hiv; 1.7 million new (incident) infections and 690 000 deaths were reported that year.15 human immunodeficiency virus–infected individuals with immune suppression (impaired t-cell and humoral responses), unsuppressed hiv rna viral load (untreated or with treatment failure) and comorbid disease (diabetes mellitus, cardiovascular and renal impairment) may be at risk of the life-threatening forms of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection.16 however, this hypothesis requires additional evidence. results from observational studies have been conflicting.17,18,19,20 this meta-analysis aims to explore the impact of hiv and sars-cov-2 co-infection on the mortality outcomes of covid-19 based on available observational studies. research methods and design eligibility criteria this is a systematic review and meta-analysis of published observational studies. articles were selected if they fulfilled the following entry criteria: compliance with the pico framework, namely p = confirmed positive covid-19 patients, i = patients living with hiv, c = hiv-uninfected persons and o = mortality in covid-19-confirmed patients not attributable to unrelated conditions such as trauma. the studies included were randomised clinical trials, cohort, case-cohort and cross-over design, and the full-text paper had to be available and to have been published. excluded studies included non-original research such as review articles, letters or commentaries; case reports; studies in a language other than english; studies of children and youths <18 years of age and pregnant women. search strategy and study selection a systematic search of pubmed and europe pmc provided many papers. additional articles were located by analysing the papers cited by the authors of the identified studies. the search terms included ‘hiv’ or ‘human immunodeficiency virus’ or ‘immunocompromised’ or ‘immune-deficient’ or ‘aids’ or ‘acquired immunodeficiency syndrome’ and ‘sars-cov-2’ or ‘coronavirus disease 2019’ or ‘covid-19’ or ‘novel coronavirus’ or ‘ncov’. the selected time-range included 01 december 2019 to 19 january 2021. only english-language articles were evaluated. details of the search strategy are listed in table 1. studies of hiv and sars-cov-2 co-infection with a valid definition of ‘mortality’ were included. the search strategy is presented in the preferred reporting items for systematic reviews and meta-analyses (prisma) diagram. table 1: literature search strategy. the initial investigation located 10 733 studies. after the removal of duplicates, 8653 records remained. a further 8585 studies were excluded after screening of the titles and abstracts failed to match with the inclusion and exclusion criteria. of the 68 full-text articles evaluated for eligibility, 22 that lacked control or comparator groups were excluded, and 15 more were excluded because they lacked outcomes pertinent to our study. three articles that were not in the english language were rejected. the final meta-analysis included 28 observational studies21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44 that reported on 18 255 040 covid-19-infected persons, of whom 48 703 were co-infected with both hiv and sars-cov-2 (see figure 1). of the included articles, 25 were retrospective and 3 were prospective (see table 2). figure1: prisma diagram of the detailed process of selection of studies for inclusion in the systematic review and meta-analysis. table 2: characteristics of the included studies. data extraction and quality assessment the study’s outcome of interest was mortality from covid-19. this was defined as the number of patients with covid-19 whose death could not be attributed to a cause other than covid-19. two authors performed the data extraction. relevant demographic, laboratory and clinical information was recorded on a dataform: age, gender, ethnicity, the number of plwh, the number of patients with a cd4 cell count of <200 cells/μl, the use of antiretroviral therapy (art) and the mortality outcomes of both hiv-infected and hiv-uninfected participants. two authors independently assessed the quality of each study using the newcastle–ottawa scale.45 the selection, comparability and outcome of each study were assigned a score from zero to nine. studies with scores of ≥7 were considered to be of good quality (see table 3). all included studies were rated ‘good’. in summary, all studies were deemed fit to be included in the meta-analysis. table 3: newcastle–ottawa quality assessment of observational studies. statistical analysis review manager version 5.4 (cochrane collaboration) and the comprehensive meta-analysis version 3 software were used in the meta-analysis, and mantel-haenszel’s formula gave odds ratios (ors) and 95% confidence intervals (cis). the heterogeneity was assessed using the i2 statistic with values of <25%, 26% – 50% and >50% providing low, moderate and high degrees of heterogeneity, respectively. significance was obtained if the two-tailed p-value was ≤0.05. the qualitative risk of publication bias was assessed using begg’s funnel plot analysis. results hiv and mortality our pooled analysis indicated that hiv was associated with mortality from covid-19 [or = 1.19 (95% ci 1.01–1.39), p = 0.03; i2 = 72%, random-effect modelling] (see figure 2). figure 2: forest plot that demonstrates the association of hiv with mortality from covid-19 outcome. meta-regression however, meta-regression showed that the association between hiv and mortality from covid-19 was unaffected by age (p = 0.208), gender (p = 0.608) (see figure 3a), black ethnicity (p = 0.389), cd4 cell count of <200 cells/μl (p = 0.353) (see figure 3b) or art (p = 0.647) (see figure 3c). figure 3: bubble-plot for meta-regression. meta-regression analysis showed that the association between hiv and mortality from covid-19 was not affected by gender (a), cd4 cell count (b) or art (c). subgroup analysis the subgroup analysis revealed that the association between hiv and mortality from covid-19 was only statistically significant for studies from african regions [or = 1.13 (95% ci = 1.04–1.23), p = 0.004; i2 = 0%, random-effect modelling] and the united states of america (usa) [or = 1.30 (95% ci = 1.08–1.59), p = 0.006; i2 = 61%] but not for studies from asia [or = 2.41 (95% ci = 0.16–36.57), p = 0.53; i2 = 76%], or europe [or = 0.90 (95% ci = 0.70–1.15), p = 0.40; i2 = 5%]. publication bias the funnel plot analysis revealed a qualitatively symmetrically inverted funnel plot for the association between hiv and a mortality outcome, suggesting no publication bias. this is demonstrated in figure 4. figure 4: funnel plot for the association of hiv with mortality from covid-19 outcomes. discussion this systematic review and meta-analysis of 28 studies not only analyse the association between hiv and mortality from covid-19 but evaluate the role of confounding factors such as age, gender, ethnicity, cd4 cell count and art in this cohort. an association was found between hiv and mortality from covid-19. however, this did not appear to be influenced by the confounding factors above. instead, the subgroup analysis found that mortality from covid-19 in plwh was more likely to be reported in studies from africa and the usa, rather than asia or europe. factors unique to africa, such as the large background prevalence of hiv, delayed access to healthcare (poor health ‘awareness’, an inadequate healthcare infrastructure and logistical challenges to accessing care) and ready access to alternate, non-western, traditional health practitioners and medicines, are likely to have influenced outcomes.46,47 similarly, the covid-19 epidemic in the usa disproportionately affected the poor, people of colour and the socially marginalised such as drug users and the institutionalised. in both regions, plwh may have been ‘over-represented’ in published studies. our pooled data confirmed an association of higher mortality from covid-19 in plwh. firstly, hiv infection may cause severe depletion of the gut-associated lymphoid tissue, with a predominant loss of memory cd4+ t cells.48 human immunodeficiency virus-induced t-cell lymphopenia, which disrupts the innate and adaptive immune response, may predispose patients to mycobacterium tuberculosis infection and progression to active disease, which increases the risk of latent tuberculosis reactivation by 20-fold.49,50 previously published studies regarding covid-19 have revealed that the presence of tuberculosis was associated with higher severity and mortality from covid-19.51,52 secondly, some proportions of plwh may have incomplete immune reconstitution and evidence of persistent immune activation.53 they may show an abnormal innate and adaptive immune response, characterised by the elevation of macrophages, cytokines [tumour necrosis factor alpha, interleukin (il)-1, il-6, il-8 and il-10], acute phase proteins [serum amyloid a, c-reactive protein (crp)], elements of the coagulation cascade (d-dimer and tissue factor), increased turnover and exhaustion of t cells, increased turnover of b cells and hyperimmunoglobulinaemia.54,55 these conditions may contribute to the development of cytokine storms and severe outcomes in covid-19. furthermore, elevated crp, d-dimer and il-6 have been associated with severe covid-19 based on meta-analysis studies.13,56 thirdly, exhaustion of t-cell lymphocytes, which is observed in hiv progression, may also be exacerbated during covid-19 infection, possibly as a result of the sars-cov-2 infection’s synergistic activity with hiv, which gradually results in t-cell lymphocyte apoptosis.57 this exhaustion of t-cell lymphocytes was associated with the progression and severe manifestation of covid-19.58,59 limitations firstly, only a limited number of our included studies reported on cd4 cell counts, viral loads and art – a fact that is likely to have impacted the precision of the meta-regression analysis of this study. indeed, most studies focussed on the characteristics of covid-19 patients rather than its effects on plwh. secondly, the studies utilised in this review and meta-analysis were primarily observational and thus, may reflect occult confounders or biases unique to the particular study. finally, we included some preprint studies to minimise the risk of publication bias; however, we made exhaustive efforts to ensure that only sound studies were included that we expect will eventually be published. we hope that this study can give further insight into the management of covid-19 patients. conclusion our meta-analysis of observational studies indicates that hiv had an association with a mortality outcome from covid-19; however, larger observational studies or even randomised clinical trials are needed to confirm our results and elucidate additional associations. patients living with hiv must take extra precautions and always adhere to health-promoting protocols. they must be prioritised to receive covid-19 preventive therapy: the sars-cov-2 vaccine. where feasible, practical use must be made of telemedicine and virtual-based practice to provide continuous care to plwh throughout this pandemic. every effort must be made to identify co-infected plwh and to link them with clinicians and treatment centres skilled in covid-19 care. gaps in art-related care, such as medicine stockouts, must be identified by local healthcare providers and authorities. finally, hiv co-infection must be included in future risk stratification models for covid-19 management. acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions t.i.h., j.r., k.c. and a.k. formulated the research questions; t.i.h. and j.r. developed the study protocol, analysed the data and wrote the manuscript. t.i.h., j.r., k.c. and a.k. did the systematic review. a.k. supported and supervised the work. all authors reviewed the manuscript and approved the final version. ethical considerations this article followed all ethical standards for research without direct contact with human or animal subjects. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability the data analysed in this study were a reanalysis of existing data, which are openly available at the locations cited in the reference section. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references cheng zj, shan j. 2019 novel coronavirus: where we are and what we know. infection. 2020;48(2):155–163. https://doi.org/10.1007/s15010-020-01401-y world health organization. coronavirus disease (covid-19): situation report [homepage on the internet]. 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epidemiology and biostatistics, school of public health, isfahan university of medical sciences, isfahan, iran arezu najafi occupational sleep research center, baharloo hospital, tehran university of medical sciences, tehran, iran amin nakhostin-ansari sports medicine research center, neuroscience institute, tehran university of medical sciences, tehran, iran parvin afsar kazerooni center for communicable disease control, ministry of health and medical education, tehran, iran matin bazargani hiv expert of deputy of health, tehran university of medical sciences, tehran, iran fatemeh navaiian hiv expert of deputy of health, shahid beheshti university of medical sciences, tehran, iran samaneh akbarpour occupational sleep research center, baharloo hospital, tehran university of medical sciences, tehran, iran citation mahboobi m, najafi a, nakhostin-ansari a, et al. depression, sleep quality and condom use amongst iranian people living with human immunodeficiency virus. s afr j hiv med. 2020;21(1), a1150. https://doi.org/10.4102/sajhivmed.v21i1.1150 original research depression, sleep quality and condom use amongst iranian people living with human immunodeficiency virus marzieh mahboobi, arezu najafi, amin nakhostin-ansari, parvin afsar kazerooni, matin bazargani, fatemeh navaiian, samaneh akbarpour received: 11 aug. 2020; accepted: 26 sept. 2020; published: 15 dec. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: depression is a common mood disorder in people living with human immunodeficiency virus (plwh) and is associated with risk-taking sexual behaviour. objectives: this study examines depression, sleep quality and condom usage amongst plwh in tehran, iran. method: this cross-sectional study was undertaken between october and november 2019 on 298 plwh referred to voluntary counselling and testing centres (vcts) in tehran. participants provided information as per the following questionnaires: the depression, anxiety, stress scale (dass), the pittsburgh sleep quality index questionnaire and a demographic questionnaire that evaluated condom use. results: a total of 298 plwh, of whom 202 (67.8%) were men with a mean age of 39.81 years, were enrolled in the study. the dass classified 57% with depression. fewer than 20% of these used condoms regularly. the majority of depressed patients were men (68.6%) and 31.4% were women. the depressed patients were more likely not to use condoms than those who were not depressed (adjusted odds ratio [or] = 6.5; 95% confidence interval [ci], 3.70–11.42). the adjusted or for not using a condom amongst the depressed was 7.12 times greater (95% ci, 5.85–10.11) than in those without depression. conclusion: our findings suggest that depression is common amongst plwh in tehran and is associated with risk-taking sexual behaviour. appropriate interventions are needed to address mental disorders in plwh. it is recommended that patients be screened regularly for symptoms of depression and, where indicated, counselled and managed. keywords: depression; condom use; hiv; iran; sleep. introduction the world health organization (who) reports that at the end of 2018, approximately 38 million people were living with human immunodeficiency virus (hiv) globally.1 the general health of these patients has improved, and life expectancy and survival have increased.2 nonetheless, social problems, negative attitudes and stigma remain and affect the mental health of people living with hiv (plwh). mental disorders are common in this group and include depression, mania, psychosis, anxiety, substance abuse and the risk of suicide.3 multiple sexual partners and drug and alcohol abuse are more likely amongst depressed than non-depressed people.4,5,6 these behaviours are also associated with the acquisition of hiv.7 depression has been linked to unreliable adherence to antiretroviral therapy (art) and treatment failure. indeed, risk-taking sexual behaviour, poor adherence to treatment and art failure require the exclusion of depression as a cause.8,9 the correct and consistent use of condoms reduces hiv transmission and other sexually transmitted infections (stis).10,11,12 condom use is influenced by depression. in a study of 278 chinese women at high risk of hiv infection, 62% had high levels of depression. those with more severe depression were more likely not to use a condom or to misuse it.13 although studies of condom use have been conducted in various countries, the generalisability of these to iranian plwh is uncertain in view of significant cultural, social and economic differences. furthermore, iranian studies of condom use in plwh and other at-risk groups with mood disorders are few.14,15,16 given the importance of condoms in preventing stis, this study aimed to identify associations between depression, sleep quality and condom use in this cohort of plwh. materials and methods this study was performed as a cross-sectional study on 298 plwh referred to voluntary counselling and testing centres (vcts) in tehran, the capital of iran, from october to november 2019. we evaluated depression, sleep quality and condom use in plwh and assessed the presence of independent associations between these factors. as tehran is a large city, to ensure the random selection of vcts from all regions of the city, it was divided into four geographical areas – north, south, east and west. after that, a list of these centres was prepared separately for each of the four regions. in each area, two vcts were randomly selected, for a total of eight centres. finally, the existing files in each centre were randomly selected, and people were invited to participate in the study. a demographic questionnaire, the depression anxiety stress scale (dass) and the pittsburgh sleep quality index questionnaire (psqi) were used for data collection. the dass questionnaire is designed to address depression and anxiety overlap. this scale has two different versions. in the main version, which has 42 questions, each of the psychological structures (depression, anxiety and stress) is evaluated by 14 different questions, but in its abbreviated version, there are 21 questions, and each psychological structure is measured by seven questions. each question can be answered by ‘never’, ‘sometimes’, ‘often’ or ‘almost always’. various studies indicate that the dass questionnaire provides valid assessments of the three structures of depression, anxiety and stress and can significantly differentiate between different contexts.17 in this study, the persian translation of the abbreviated version of the questionnaire was used. the validity and reliability of the persian version have been confirmed in several studies.18,19 to assess the quality of sleep in patients in the last month, the psqi was used. this questionnaire has seven components: quality of sleep, sleep delay, sleep duration, sleep efficiency, sleep disorders, sleeping pill use and daily dysfunction. many studies have confirmed the validity and reliability of this questionnaire.20,21 each component can be scored from 0 to 3, and an overall score of 5 and above indicates inappropriate or poor quality of sleep.22 background demographic data also collected included gender, age, education, marital status, body mass index (bmi), employment status, cd4 count, time since hiv diagnosis, route of transmission, concurrent hepatitis b and c and tuberculosis infections and duration of art. participants were asked about condom use during the past year. the response was divided into three parts: people who never used a condom, people who used it sometimes and people who always used a condom. our inclusion criteria were (1) confirmation of hiv infection by rapid and enzyme-linked immunosorbent assay hiv tests, (2) a history of sexual intercourse at least once over the past 12 months, (3) age 18 years or older and (4) informed consent to participate in the study. participants whose condom use status was unclear (n = 8) were excluded from the sample. other participants were included in the study. questions were asked in face-to-face, one-on-one interviews by eight trained interviewers (psychologists). the interviewers provided participants with an explanation of the study and its objectives and invited participants to consider enrolling. participants were assured of confidentiality and an ‘opt-out option’ if they did not wish to continue with the study. informed consent was obtained from participants prior to the study. statistical analysis for quantitative data, mean and standard deviation (sd) were used; frequency and percentage were reported for the qualitative variables. one-way analysis of variance and t-test were used to evaluate the differences between depressed and non-depressed individuals in terms of age, bmi, duration since the hiv diagnosis, cd4 count and duration of art. we used a chi-square test to evaluate differences between depressed and non-depressed individuals in terms of gender, educational level, marital status, condom use status, sleep quality, anxiety, stress, route of hiv transmission and coinfections. the multinomial logistic regression method was used to determine the relationship between depression, age, sex, marital status, duration since the diagnosis of hiv and the use of condoms, and people who always used condoms were defined as a reference. all analyses were performed with stata software, and a p-value of less than 0.05 was considered significant. ethical consideration this study was approved by the ethical committee of tehran university of medical sciences (ethics approval number, ir.tums.vcr.rec.1398.312). results a total of 298 hiv-positive patients, including 96 women (32.2%) and 202 men (67.8%), participated in the study. the average age of participants was 39.81 (sd = 9.67) years. more than half were married. about half of the participants were illiterate or had less than 12 years of formal education, namely, ‘under diploma’ status. the mean bmi of the participants was 24.5 kg/m2. in all, 30% of participants never used condoms, 32% sometimes used condoms and 37.1% always used condoms. the demographics of the participants, their condom use status and their sleep quality are tabulated in table 1. table 1a: demographic characteristics of the depressed and non-depressed participants. table 1b: demographic characteristics of the depressed and non-depressed participants. the overall prevalence of depression was 56.7%. almost 70% of those with depression were men, and more than half of the depressed patients were unemployed and had not completed formal education (p < 0.05). the depressed group had a significantly higher bmi than the non-depressed group. amongst 169 depressed individuals, only 32 (18.9%) always used condoms, whilst 71 (42%) never used condoms. almost 70% of the participants had a psqi of > 5, which means that they had poor sleep quality. eighty-two per cent (n = 139) of plwh with depression suffered from poor sleep quality. similarly, 75% and 91% of depressed people had symptoms of anxiety and stress, respectively. table 2 shows the hiv infection status in depressed and non-depressed participants. the main route of hiv transmission to participants was unsafe drug injection. about 24% of people with depression were co-infected with hiv and hepatitis c. table 2a: clinical status of depressed and non-depressed participants. table 2b: clinical status of depressed and non-depressed participants. table 3 depicts the results of logistic regression, indicating that the odds of not using a condom in people with depression are higher compared to those who do not have depression (odd ration [or], 6.50; 95% confidence interval [ci], 3.70–11.42). table 3: results of the unadjusted and adjusted logistic regression to assess the relation between depression and not using condoms amongst people living with human immunodeficiency virus. according to table 4, in multinomial logistic regression, people with depression tended to be about 7.12 and 5.01 times more likely to not use or occasionally use condoms, respectively, compared to those who were not depressed. table 4: results of unadjusted and adjusted multinomial logistic regression to assess the relation between depression and not continuously using condoms amongst people living with human immunodeficiency virus. discussion whilst many studies have looked at the prevalence of condom use in different populations, including plwh, research on condom use in people with mood disorders, including depression, is very limited. considering the importance of using condoms in plwh in the prevention of the transmission of infection to others, as well as the importance of the infected patients’ health, this study evaluated the relationship between depression and condom use in plwh in tehran. the results of the present study showed that less than 40% of the participants in the study used condoms continuously, and almost 30% did not use condoms at all. a study conducted by lotfi et al. on 121 hiv-positive people in karaj reported that about 60% of participants had not used condoms during sexual intercourse in the preceding 3 months.14 similar studies in london and uganda reported a prevalence of condom use of 73% and 65% in plwh, respectively.23,24 the differences observed between iranian and non-iranian plwh can be a result of cultural differences, lower levels of education and lack of sufficient knowledge about the importance of continuous and correct use of condoms amongst iranian plwh, carelessness25 and lack of continuous access to condoms. depression in plwh is associated with unreliable condom use, with drug and alcohol misuse, poor adherence to treatment, detectable viral load on art, and high-risk sexual behaviour.8,9 considering the high prevalence of depression amongst iranian plwh and the sequelae of depression, there is a need for interventions to address the depression problem amongst iranian plwh. more than half of those living with hiv in the present study had depression. only 19% reported regular condom use. wagner et al. evaluated the effects of art and depression on condom use in ugandan plwh. they found that over time, depression is accompanied in plwh by a reduction in the persistent use of condoms.24 an american study confirmed a relationship between depression and the failure to use condoms in plwh with uninfected partners.26 in our study, depression was more common in men than in women. shadloo et al. evaluated the prevalence of psychological issues amongst iranian plwh: mood disorders, including major depressive disorder, were more prevalent in males than females (34.5% vs. 28.8%, respectively).27 pasdar et al. evaluated the association between dietary intake and depression in plwh in iran and found depression to be more common amongst iranian males living with hiv than females.28 in a systematic review and meta-analysis, rezaei et al. evaluated depression globally amongst plwh and noted a prevalence of 8% amongst males. this was significantly higher compared to females.29 men clearly are at significant risk of depression, and test and treat programs that care for plwh need to address the issue proactively. it also appears that depression is more common in patients with lower educational levels, those who are unemployed and those who are overweight (bmi, > 25). having a job and sufficient income is one of the most important social factors affecting health and has a significant impact on the mental state of individuals. unemployment or low-income work promote the cycle of poverty and limit access to healthcare.30,31 eighty-two per cent of depressed plwh had poor sleep quality. poor sleep quality can lead to daily drowsiness, mood swings, decreased quality of social interaction, exacerbation of depression, anxiety and increased high-risk behaviours.32 it is also a risk factor for mood disorders.33 downing et al. found that good sleep quality is associated with less depression and anxiety and more self-efficient condom use in plwh.34 lack of questions about the reasons for not using condoms in patients is one limitation of our study, as identifying the barriers to protective behaviour could play an essential role in planning strategies to remove these barriers. another limitation is the use of face-to-face interviews for data collecting, which was challenging in some cases, given iran’s cultural, religious and social context. this may have led to various biases (interviewer and reminder bias or bias of social desirability). thirdly, it was a cross-sectional study, and we could not evaluate the transmission of the virus to sexual partners in the depressed and non-depressed patients. fourthly, we did not assess the patients’ viral load, which can also affect the transmission of the virus to patients’ sexual partners. fifthly, we used a questionnaire to see whether the patients were depressed or not, which is another limitation of our study as confirmation of depression by a psychologist could give a more accurate assessment. conclusion in this study, we evaluated the prevalence of depression in plwh and its associations with sleep quality and condom use. the prevalence of depression in iranian plwh is relatively high, and interventions are needed to address this problem. furthermore, depressed plwh have worse sleep quality and use condoms less frequently compared to non-depressed plwh. interventions to improve the sleep quality and mood of plwh may be valuable considering their associations with condom use. acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions all authors contributed to the design and implementation of the research, the analysis of the results and the writing of the manuscript. funding information this study was funded by tehran university of medical sciences. data availability the data that support the findings of this study are available from the corresponding author upon reasonable request. disclaimer the views expressed in the manuscript by the authors are their own and not an official position of the institution. references world health organization. hiv/aids key facts 2019 [homepage on the internet]. 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sexually transmitted infections in hiv clinic attendees in south east london. int j std aids. 2009;20(11):757–760. https://doi.org/10.1258/ijsa.2009.009019 wagner gj, ghosh-dastidar b, slaughter me, akena d, nakasujja n, musisi s. changes in condom use during the first year of hiv treatment in uganda and the relationship to depression. ann behav med. 2014;48(2):175–183. https://doi.org/10.1007/s12160-013-9586-3 taffa n. sexual activity of out-of-school youth, and their knowledge and attitude about stds and hiv/aids in southern ethiopia. ethiop j health dev. 1998;12(1):17–22. brickman c, propert kj, voytek c, metzger d, gross r. association between depression and condom use differs by sexual behavior group in patients with hiv. aids behav. 2017;21(6):1676–1683. https://doi.org/10.1007/s10461-016-1610-8 shadloo b, amin-esmaeili m, motevalian a, et al. psychiatric disorders among people living with hiv/aids in iran: prevalence, severity, service utilization and unmet mental health needs. j psychosom res. 2018;110:24–31. https://doi.org/10.1016/j.jpsychores.2018.04.012 pasdar y, hamzeh b, moludi j, mehaki b, darbandi m, moradi s. dietary intake and risk of depression among male and female with hiv/aids. eat weight disord. 2020;25(4):1029–1038. https://doi.org/10.1007/s40519-019-00726-4 rezaei s, ahmadi s, rahmati j, et al. global prevalence of depression in hiv/aids: a systematic review and meta-analysis. bmj support palliat care. 2019;9(4):404–412. berhe h, bayray a. prevalence of depression and associated factors among people living with hiv/aids in tigray, north ethiopia: a cross sectional hospital based study. int j pharmaceut sci res. 2013;4(2):765. https://doi.org/10.1155/2013/319724 shittu r, issa b, olanrewaju g, et al. prevalence and correlates of depressive disorders among people living with hiv/aids. north central nigeria j aids clin res. 2013;4(11):251. https://doi.org/10.4172/2155-6113.1000251 dabaghzadeh f, khalili h, ghaeli p, alimadadi a. sleep quality and its correlates in hiv positive patients who are candidates for initiation of antiretroviral therapy. iranian j psychiatry. 2013;8(4):160. okun ml, mancuso ra, hobel cj, schetter cd, coussons-read m. poor sleep quality increases symptoms of depression and anxiety in postpartum women. j behav med. 2018;41(5):703–710. https://doi.org/10.1007/s10865-018-9950-7 downing m, millar b, hirshfield s. changes in sleep quality and associated health outcomes among gay and bisexual men living with hiv. behav sleep med. 2020;18(3):406. https://doi.org/10.1080/15402002.2019.1604344 abstract background materials and methods results discussion recommendations limitations and strengths conclusion acknowledgements references about the author(s) samuel mwango centre of excellence for nutrition, faculty of health sciences, north-west university, potchefstroom, south africa janet carboo centre of excellence for nutrition, faculty of health sciences, north-west university, potchefstroom, south africa christa ellis centre of excellence for nutrition, faculty of health sciences, north-west university, potchefstroom, south africa marike cockeran statistics consultation service, faculty of natural sciences, north-west university, potchefstroom, south africa carina m.c. mels department of physiology, faculty of health sciences, north-west university, potchefstroom, south africamedical research council, hypertension and cardiovascular disease research unit, faculty of health sciences, north-west university, potchefstroom, south africa herculina s. kruger centre of excellence for nutrition, faculty of health sciences, north-west university, potchefstroom, south africamedical research council, hypertension and cardiovascular disease research unit, faculty of health sciences, north-west university, potchefstroom, south africa citation mwango s, carboo j, ellis c, cockeran m, mels cmc, kruger hs. the association between serum vitamin d and body composition in south african hiv-infected women. s afr j hiv med. 2021;22(1), a1284. https://doi.org/10.4102/sajhivmed.v22i1.1284 original research the association between serum vitamin d and body composition in south african hiv-infected women samuel mwango, janet carboo, christa ellis, marike cockeran, carina m.c. mels, herculina s. kruger received: 02 july 2021; accepted: 12 aug. 2021; published: 30 sept. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: hiv and antiretroviral therapy (art) alter vitamin d metabolism, and may be associated with bone loss. objectives: the aim of this study was to determine the association between serum 25-hydroxyvitamin d (25(oh)d) and body composition in postmenopausal south african women living with hiv and on art. method: in this 2-year longitudinal study on 120 women conducted in the north west province of south africa, serum 25(oh)d concentration, bone mineral density (bmd) at three sites, lean mass and percentage of body fat (%bf) were measured by dual-energy x-ray absorptiometry (dxa). multivariable linear mixed models were used to assess the association between serum 25(oh)d and body composition over 2 years. linear mixed models were also used to determine the longitudinal association between lean mass, %bf and bmd. results: vitamin d deficiency and insufficiency increased from baseline (10.2% and 19.5%) to 11.5% and 37.5%, respectively, after 2 years. serum 25(oh)d decreased significantly, however, with a small effect size of 0.39 (p = 0.001), whilst total bmd (effect size 0.03, p = 0.02) and left hip femoral neck (fn) bmd (effect size 0.06, p = 0.0001) had significant small increases, whereas total spine bmd did not change over the 2 years. serum 25(oh)d had no association with any bmd outcomes. lean mass had a stronger positive association with total spine and left fn bmd than %bf. conclusion: serum 25(oh)d was not associated with any bmd outcomes. maintenance of lean mass could be important in preventing bone loss in this vulnerable group; however, longer follow-up may be necessary to confirm the association. keywords: vitamin d; postmenopausal; adiposity; bone mineral density; africa; hiv/aids; art. background vitamin d is a pro-hormone primarily known for its role in bone development through calcium and phosphorus homeostasis.1 it is acquired from dietary sources that include fish, egg yolk, liver and vitamin d fortified foods; however, cutaneous synthesis of vitamin d contributes to more than 90% of the requirements.2 epidemiological studies across the world indicate a close association between vitamin d deficiency and chronic diseases, such as bone metabolic disorders, tumours, cardiovascular diseases and diabetes mellitus.3 the prevalence rate of vitamin d deficiency worldwide varies between 30% and 93%, and is a growing public health concern amongst all age categories and ethnic groups.4,5,6 hypovitaminosis d is also a prevalent disorder in lowand middle-income countries.7 durazo-arvizu et al.8 reported a higher prevalence rate of vitamin d deficiency amongst south african men and women aged 25–45 years compared with groups from ghana, jamaica and seychelles. many factors, including skin pigmentation, sun exposure, sex and low dietary intake, are known to be associated with the vitamin d status. in south africa, the country with the largest proportion of people living with hiv, along with the largest antiretroviral therapy (art) programme, the prevalence of vitamin d deficiency may be even worse because of the known relationship between hiv infection and vitamin d status.9,10,11 in south africa, a total of 7.5 million people were reported to be living with hiv in 2019. this makes south africa a country with the highest burden of hiv infection in the world, with a prevalence rate of 19.0%, in the age group 15 to 49 years.12 furthermore, south africa has the largest hiv treatment programme, with 3.9 million people initiated on art in 2016.13 hiv management strategies coupled with the use of art have shifted the trends of hiv from an inevitably fatal disease to a chronic infection.14 chronic hiv infection and exposure to art are associated with altered vitamin d metabolism, decreased bone mineral density (bmd) and increased fracture risk.15,16,17 a longitudinal study in postmenopausal women showed that women living with hiv had greater rates of bone loss at the spine and forearm than hiv-negative postmenopausal women.18 body composition alteration (lipodystrophy) is a common phenomenon in people living with hiv.19 furthermore, body composition is an important factor that influences vitamin d status directly or indirectly through interactions with other factors, such as age, sex, skin pigmentation, menopausal status, chronic diseases and medications.20 an inverse correlation has been established between vitamin d status and adiposity in adults.21,22 lowand middle-income countries including south africa, are experiencing nutrition-related non-communicable diseases resulting from nutrition transition and consequent body composition changes towards increased adiposity.23 the south african national health and nutrition examination survey-1 (sanhanes-1) of 2012 and the south african demographic and health survey of 2016 confirmed the high rates of overweight and obesity in adult women to be 27% and 41%, respectively.24,25 this research study aimed at contributing knowledge on the association between serum 25-hydroxyvitamin d (25(oh)d) and body composition amongst hiv-infected postmenopausal women. to our knowledge, this is the first study to involve the target population in south africa, which has an increased risk of both vitamin d deficiency and poor bone health. the findings from the study can potentially inform treatment and care of hiv-infected postmenopausal women. materials and methods study design, setting and participants this was a longitudinal study that used data measured in 2017 at baseline, 1-year (2018) and 2-year follow-up (2019) from a larger prospective bone study at the centre of excellence for nutrition (cen) at the north-west university in potchefstroom, south africa. study participants were recruited from public outpatient art clinics. participants who met the inclusion criteria were invited individually to participate and receive information about the project. those who accepted were included through consecutive convenience sampling. all measurements were performed at the metabolic unit of the north-west university. signed informed consent was obtained from all participants. the study involved south african postmenopausal women living with hiv and already on art. most participants were on art regimen-1 for the duration of the study (tenofovir [tdf], emtricitabine [ftc] and efavirenz [efv]) as a combined antiretroviral therapy (cart). this sub-study was performed on the available participants from the larger study, which included 120 postmenopausal women. the flowchart of participants shows the number of study participants at each measurement date and reasons for loss to follow-up, as shown in figure 1. figure 1: participant flowchart and reasons for loss to follow-up. a power calculation for the primary analysis of this study (multivariable regression analysis) indicated that a sample size of at least 262 would be necessary at a ß of 0.4 for the primary exposure, a power of 0.95 and an α of 0.05.26 it is therefore possible that the sample size may be too small to show an association even if there was one; however, it was not possible to recruit more women, because most hiv-infected women from these clinics were premenopausal. we therefore analysed and interpreted the available data with caution. the inclusion criteria included hiv-infected postmenopausal women on art. ‘postmenopausal’ was defined as the self-reported absence of menses for at least 6 months prior to the study. the exclusion criteria included use of anti-osteoporotic agents (corticosteroids, thyroid medication initiated during the previous year, anti-vitamin k agents, diuretics, anti-epileptic drugs and β-blockers), calcium and vitamin d supplements, or antacids containing calcium according to their medical records or self-report. chronic liver disease, chronic obstructive pulmonary disease, chronic renal disease, immobility, rheumatoid arthritis, gastrectomy, malabsorption syndromes, diagnosed diabetes mellitus, history of metabolic bone disease, high alcohol consumption (≥ 3 units/day) and history of a fracture within the last 6 months were also part of the exclusion criteria. women with severely low bmd at the hip (t-score < –3) detected at baseline were not enrolled but referred for medical treatment. according to the world health organization (who), a t-score is the distance in the number of standard deviations from the mean bmd for a young reference group based on data from a white reference population. a t-score of –2.5 and below indicates osteoporosis, and –1.0 to –2.5 indicates osteopenia, whereas a t-score of –1.0 and above represents normal bmd.27 measurements socio-demographic and health information information on participants’ socio-demographic and health status was collected using an interviewer-administered structured questionnaire. the following information was captured: age, education level, housing, occupation, smoking, alcohol consumption, chronic medication use (including art), year of first hiv diagnosis and year of art initiation. all women brought their medication along to the study site to be recorded. anthropometric measurements anthropometric measurements included height and weight, and were performed by trained postgraduate nutrition and dietetics students. the measurements were conducted on participants without shoes and with minimal clothing. weight and height were measured using a calibrated digital scale and attached stadiometer (seca 264, hamburg, germany), following standard procedures.28 body mass index (bmi) was calculated by dividing weight in kilograms by height in metres squared. bmi cut-off points were < 18.5 for underweight, 18.5 to < 25 for normal weight, 25.0 to < 30 for overweight and ≥ 30 kg/m2 for obesity. physical activity: physical activity was assessed by a trained fieldworker using the global physical activity questionnaire (gpaq) recommended by the who.29 the questionnaire gathered information on physical activity performed during the previous 7 days in the following occupation: physical activity, transport-related physical activity and physical activity during leisure time. the time spent during the various physical activity domains in terms of frequency (days per week) and duration (minutes per day) was estimated. bone mineral density, lean mass and fat mass: bone mineral density, lean mass and fat mass were measured at all three time points by a registered radiographer using dual-energy x-ray absorptiometry (dxa) with the default hologic settings (hologic discovery w, apex system software version 2.3.1). bmd at total body, lumbar spine and left femoral neck (fn) of the hip was measured in g/cm². participants were asked to remove all jewellery and were provided with cotton gowns without any metal trimmings to wear during the dxa measurement. serum vitamin d and parathyroid hormone concentration: fasting blood samples of 5 ml were collected in serum tubes by a registered nurse, were centrifuged immediately and stored in a bio-freezer at –80 °c until samples of all the study participants were collected. serum 25(oh)d and parathyroid hormone (pth) were measured by electrochemiluminescence (cobas e411, roche, basel, switzerland). samples collected for each time point were analysed together in one batch with the same controls. dietary data: dietary intakes were assessed at baseline and at 1-year follow-up visits in 2018 by trained fieldworkers using a validated quantitative food frequency questionnaire, food models and a validated food picture book to estimate portion sizes.30,31 portion sizes, reported in household measures, were converted to weights. energy and nutrient intakes (i.e. protein, fat, vitamin d and calcium) were calculated using food finder software based on the south african food composition database.32 statistical analysis the distribution of the continuous variables was assessed by histograms, qq plots and the kolmogorov–smirnov test. descriptive statistics of socio-demographic data, physical activity, bmd at different sites, lean and fat mass, as well as serum 25(oh)d and pth are presented as means and standard deviation (s.d.) for variables following a normal distribution or median and interquartile range (iqr) for non-normally distributed data. the percentage of participants with vitamin d deficiency and insufficiency were determined, where vitamin d deficiency was defined as serum 25(oh)d level < 20 ng/ml (50 nmol/l) and insufficiency as 20 ng/ml – 29 ng/ml (50 nmol/l – 74 nmol/l) according to the endocrine society and international osteoporosis foundation cut-offs.33 pearson’s correlation coefficient (for data with a normal distribution) or spearman’s rank order correlation coefficient (for data with a non-normal distribution) was calculated to examine the correlation between serum 25(oh)d and fat mass, lean mass and whole-body bmd, spine bmd and left fn of the hip bmd, as well as possible covariates (age, alcohol intake, calcium intake, physical activity level and number of years since the hiv diagnosis). age correlated significantly with several variables and, therefore, pearson partial correlation with adjustment for age was also performed. variables with a significant correlation were entered in the linear mixed models (lmms). variables with a non-normal distribution were logarithmically transformed before they were entered in the lmm. differences in exposure and outcomes between groups (smokers compared with non-smokers) were assessed using the mann–whitney test, because most variables had a non-normal distribution. linear mixed models were used with fat mass, lean mass and bmd, respectively, as the dependent variables (outcomes) and serum 25(oh)d as the primary exposure, with adjustment for variables identified to correlate with the exposure or outcomes (age, alcohol intake, calcium intake, and physical activity level). these models were also used with bmd as the dependent variable (outcome) and fat mass as well as lean mass as primary exposure, with adjustment for variables identified to correlate with the exposure or outcomes (age, alcohol intake, calcium intake and physical activity level). separate models were used for whole-body bmd, spine bmd and left fn of the hip bmd. time was treated as a fixed effect and participant as a random effect. the restricted maximum likelihood (reml) estimation method was used, and an unstructured covariance structure was specified. an adapted version of cohen’s d is used to indicate the practical significance of the differences between the means. the original formula for cohen’s d for analysis of variance (anova) is as follows: where d denotes effect size, ẋi and ẋj are means of two samples and mse is the mean standard error.34 in this case, however, the estimated marginal means, calculated as part of the lmm analyses, are used and the mse is replaced by the sum of the covariance estimates. the interpretation guidelines indicate a small effect or practical non-significant d at an effect size of 0.2, an effect size of 0.5 indicates a medium effect or practical visible difference and an effect size of 0.8 indicates a large effect or practical significant difference. statistical package for social sciences (spss) software, version 26 (ibm company, armonk, new york, united states) was used for all analyses. ethical considerations the study was approved by the health research ethics committee of the north-west university (project: nwu-00061-17-a1-02). results the study participants’ characteristics are summarised in table 1. their median duration of being diagnosed with hiv was 11 years [iqr 7–13 years], and the median duration of using art was 10 years (iqr 5–13 years). most participants (approximately 85%) remained on art regimen 1 (tdf, ftc, and efv) as a cart during the 2 years of observation. combined vitamin d deficiency and insufficiency was estimated to be 29.7% at baseline, 42.9% at year 1 and 49.0% at year 2 of follow-up. serum pth concentrations showed an increased trend over time. only a small proportion of study participants (10%) were current smokers, with a median of 2 (iqr 1–4) cigarettes per day. only five (4.2%) participants were previous smokers. the median intake of calcium and vitamin d in the study participants was lower than the recommended dietary intake for women, 51–70 years old, of 1200 mg/d and 15 mcg/d, respectively.35 table 1: study participants’ characteristics from baseline to 2-year follow-up. table 2 shows correlations between continuous variables according to the distribution of data. serum 25(oh)d did not correlate with any of the bmd outcomes or total percent fat. total percent body fat reported a moderate positive correlation with total spine bmd (r = 0.319; p < 0.0001) and left hip fn bmd (r = 0.408; p < 0.0001); however, it had a weak positive correlation with total bmd (r = 0.239; p = 0.009). lean mass had a weak negative correlation with age (r = –0.219; p = 0.016) and a strong positive correlation with bmi (r = 0.824; p < 0.0001). table 2: correlation between serum vitamin d, lifestyle, health and body composition variables: pearson’s correlation between serum vitamin d and body composition variables. a comparison between body composition outcomes and vitamin d status of smokers and non-smokers at baseline revealed no difference in total lean mass, total spine bmd, total bmd, total left hip fn bmd, bmi or vitamin d status; the only difference was in total percent body fat (p = 0.032). there was no correlation between serum 25(oh)d and pth at baseline (r = –0.11, p = 0.24), after 1 year (r = –0.16, p = 0.12) or after 2 years of follow-up (r = –0.14, p = 0.17). variables with a non-normal distribution that showed significant correlations from the spearman correlation were log transformed, and similar correlations were found. new significant correlations that were observed included a weak negative correlation between bmi and serum 25(oh)d (r = –0.189; p = 0.04). furthermore, bmi had moderate positive correlations with total bmd, total spine bmd and left hip fn bmd (p < 0.0001). body mass index, however, had a strong correlation with total percent fat (r = 0.841; p < 0.0001). age displayed a weak inverse correlation with total spine bmd (r = –0.242; p = 0.008) and a moderate inverse correlation with total bmd (r = –0.400; p < 0.0001) and left hip bmd (r = –0.346; p < 0.0001). physical activity correlated positively although weakly with total bmd (r = 0.227; p = 0.014) and left hip fn bmd (r = 0.235; p = 0.011). lean mass had a moderate positive correlation with total spine bmd (r = 0.473; p < 0.0001), as well as total bmd (r = 0.429; p < 0.0001), and a strong positive correlation with left hip fn bmd (r = 0.563; p < 0.0001). these results did not change after adjustment for age, except that the correlation between physical activity and total bmd was no longer significant (r = 0.177; p = 0.06). changes of study exposure variable and body composition outcomes over a 2-year period the changes were assessed over the three time points of measurements from baseline to 2-year follow-up. changes of main exposure and body composition outcomes are presented in figures 2, 3 and 4. the serum 25(oh)d concentration declined from baseline through to year 2 follow-up (p < 0.0001) with an effect size of 0.39, indicating a practically visible difference. the bonferroni pairwise comparison showed a significant decline in serum 25(oh)d concentration from baseline to year 1 follow-up and from baseline to year 2 follow-up. total bmd increased from baseline to year 1 follow-up, but with practical non-significant difference (effect size = 0.03). similarly, left hip fn bmd increased over 2 years; however, the difference was practically non-significant (effect size of 0.06). changes in left hip fn bmd over the 2 years were between baseline and year 2 follow-up and year 1 and year 2 follow-up. there were no significant changes in pth from baseline over the two years, although there was an increasing trend over time (table 1). lean mass had a practically non-significant difference between baseline and year 2 follow-up (effect size 0.02), whereas percent body fat mass had a practically visible difference over the two years (effect size 0.66). figure 2: bone mineral density changes over 2 years from baseline. figure 3: serum 25-hydroxyvitamin d changes over 2 years from baseline. figure 4: lean and fat mass changes over 2 years from baseline. association between serum vitamin d concentration and body composition over time linear mixed models were used to describe the association between serum 25(oh)d as the main exposure and body composition outcomes that included percent body fat, lean mass (logarithmically transformed), total bmd, lumbar spine bmd and left hip fn bmd. associations between body composition components (fat mass, lean mass and bmd) were also determined by lmms. estimates of the associations were adjusted for education level, household income, age, physical activity, duration of art and alcohol intake as potential confounders. table 3 presents the associations. all models showed an improvement in goodness of fit after adding covariates to the crude models, as demonstrated by the schwarz bayesian information criterion (bic). table 3: correlation between serum vitamin d, lifestyle, health and body composition variables: spearman’s correlations between lifestyle, demographic variables and body composition. the model with the lowest bic was selected as the best model. serum 25(oh)d was neither associated with any of the three bmd outcomes, nor with percent body fat or lean mass. however, serum 25(oh)d showed a significant association with bmi in the unadjusted model (p = 0.024); however, there was no significant association after adjusting for education level, household income, age, physical activity and alcohol intake. there was a positive association between physical activity and left hip fn bmd. age was consistently inversely associated with all body composition outcomes. both percent fat mass and lean mass were associated with left hip fn bmd and total bmd, but not with total spine bmd (table 4). table 4: association between serum vitamin d and body composition and interdependent associations between body composition variables. discussion this 2-year longitudinal study focused on investigating the association between serum 25(oh)d and body composition (lean mass, fat mass and bmd) in south african postmenopausal women living with hiv and on art. according to the endocrine society and international osteoporosis foundation cut-offs for vitamin d status by valcour et al.,33 serum 25(oh)d insufficiency (deficiency and insufficiency) increased from 29.7% at baseline to 49.0% at year 2 of follow-up. despite a significant decrease in serum 25(oh)d over time, there were practically no changes in bmd over the 2 years. there was no association between serum 25(oh)d concentration and total bmd, spine bmd, left hip fn bmd, lean mass or %bf consistently throughout the study period. from the lmms on the interdependent associations between body composition components, lean mass and fat mass showed positive associations with total bmd and left hip fn bmd but not with total spine bmd. lean mass proved to be stronger predictor of bmd than fat mass. the study findings on vitamin d status (insufficiency and deficiency prevalence) correspond with those from some observational studies amongst postmenopausal women populations.36,37,38 kuchuk et al.39 reported similar serum 25(oh)d deficiency levels in both summer and winter amongst postmenopausal women from 29 countries across the world. serum 25(oh)d concentrations also declined during the 2-year study period in the dallas heart study on a multi-ethnic adult population in dallas, texas, united states.40 vitamin d is primarily known for an association with bmd via the homeostasis of calcium and phosphate.41 there was no association observed between serum 25(oh)d and total bmd, left hip fn bmd and total spine bmd over a follow-up period of two years. the study findings are in agreement with a number of studies, including randomised controlled trials (rcts) with vitamin d supplementation.42,43 a cross-sectional study by kamineni et al.44 in india amongst postmenopausal women revealed findings similar to this study, where no correlation was observed between serum 25(oh)d and bmd. however, a cross-sectional study amongst chinese postmenopausal women found positive correlations between serum 25(oh)d and bmd outcomes at lumbar spine, total hip and fn.45 differences between the findings of these studies and the current study could be partially explained by differences in menopause duration, duration of sunlight exposure amongst the women, genetic factors and ethnicity.44 study observation period is likely another plausible reason for the lack of association between serum 25(oh) and bmd. changes in bmd take a long time to manifest and, hence, the duration could have been inadequate to detect noticeable significant changes in this study. hamill et al.46 observed a cohort of urban black hiv-infected south african premenopausal women over a period of 24 months. a significant finding was the attenuation of bone mass loss beyond 12 months up to 24 months in the hiv-infected group on art. although the participants were premenopausal women, this signifies that bone loss in hiv-infected patients within the first 12 months on art could be transient. our study’s participants showed a small, but significant, bmd increase at left fn bmd and total bmd, but no change at total spine bmd. other authors had suggested a follow-up longer than 24 months to ascertain bmd changes.46 this study’s participants had an average art use duration of 9 years, which might explain bmd stabilisation. information about previous art regimens could not be determined; however, it is likely that most women received first-line art regimens at the public outpatient clinics and could have been switched to the present first-line regimen (tdf, ftc, efv) soon after these fixed dose combinations became available in 2013.47 therefore, most women have been exposed to tdf for three years or longer. despite the lack of association between serum 25(oh)d and bmd, we reported a decline in serum 25(oh)d levels from baseline to two years; however, the effect size was relatively small. this decrease may be related to the hiv status of the women. a high prevalence of vitamin d deficiency has been described amongst hiv-infected patients.10 the inflammatory processes associated with hiv infection and art metabolism both alter vitamin d metabolism and may have been associated with the decline in serum 25(oh)d levels during the observation period.48 very low serum 25(oh)d concentrations trigger pth surge, which leads to bone demineralisation as a compensatory measure to maintain balance in serum calcium.49 the decline in serum 25(oh)d concentrations probably explains the small, although non-significant, progressive increase in pth, which was probably insufficient to lead to a decline in bmd. in agreement with this study’s findings, kota et al.50 reported no direct association between serum 25(oh)d and bmd. however, they found a stronger inverse association with serum 25(oh)d and pth, indicating that low serum 25(oh)d level was indirectly associated with low bmd. contrary findings to ours were reported in a 12-months longitudinal study amongst urban black south african premenopausal women. an increase in serum 25(oh)d regardless of the hiv status was reported over 12 months.51 the obvious difference between the two studies is age of the participants, where the study participants were postmenopausal women (mean age: 50 years), whereas the other study included premenopausal women. aging is a known risk factor for hypovitaminosis d through decreased vitamin d receptors and consequent alteration of vitamin d metabolism.52 we also found a non-significant inverse correlation between serum 25(oh)d concentration and age. a longitudinal study in amsterdam reported a small decline in serum 25(oh)d levels in older participants (65–88 years) over 13 years, which is in agreement with the study findings.53 poopedi et al.54 affirmed progressive fluctuations in serum 25(oh)d levels in a study amongst healthy adolescents over 10 years. these progressive changes in serum 25(oh)d levels observed in longitudinal studies, as well as this study, signify that single measurements are unreliable for determining associations between serum 25(oh)d and diseases. this study reported no association between serum 25(oh)d and percent body fat or lean mass; however, there was a weak negative correlation with bmi. in agreement with this finding, there is a recent cross-sectional study amongst postmenopausal women, which reported an inverse correlation between serum 25(oh)d and anthropometric measurements, including bmi.55 bmi is used as a proxy for adiposity, and the sequestration theory provides a probable explanation for the inverse association displayed between body fat and serum 25(oh)d.56 in a cross-sectional study, however, li et al.45 reported no association between bmi and serum 25(oh)d in chinese postmenopausal women. the authors argued that their result was based on the unique body composition of the chinese women, characterised by a lower prevalence of obesity than in other ethnic groups. this emphasises the role of ethnicity in the interaction between serum 25(oh)d and body composition. the study participants had a relatively high prevalence rate of overweight and obesity, which is in the range of 22.5% – 25.7% and 38.3% – 40.0%, respectively, over two years. previous observational studies have described other known determinants of bmd; however, the relative contribution of lean mass and fat mass to bmd remains a contentious subject. the data of this study showed that both lean mass and percent fat mass were positively associated with left hip fn bmd and total bmd, but not with total spine bmd. however, lean mass was a stronger predictor of bmd than fat mass. this result is a replication of findings from other observational studies amongst postmenopausal women.57,58,59 similarly, a systematic review by ho-pham et al.60 proved lean mass to be a stronger determinant of bmd compared with fat mass. this signifies that the interdependent interactions between body composition components can be influenced by menopause status. the association between fat mass and bmd is probably mediated by the increased load placed on the skeleton, whereas lean mass influences bmd through increased mechanical stress mediated by muscle on the skeleton. both mediators act as stimuli for osteogenesis.61,62 a significant proportion of the women in this study were overweight (22.5% and 25.7% at baseline and 2-year follow-up, respectively) and obese (38.3% at baseline and 40.0% at 2-year follow-up). we reported a quite unusual finding of a small, but significant, fat mass decline and lean mass increase in the women during the 2-year study period, in contrast with normal aging changes.57 the results of this study revealed a significant positive association between physical activity and left hip fn bmd, the site most prone to fracture in postmenopausal women. such findings were reported previously in a canadian retrospective study amongst postmenopausal women.63 apart from serum 25(oh)d concentration, known risk factors for low bmd, such as dark skin, hiv, art and advanced age (postmenopausal status), were present in the study participants. physical activity levels were relatively good, signifying probable adequate exposure to sunlight and adequate stimuli to maintaining bone health. we further reported low exposure to lifestyle risk activities such as smoking and alcohol intake. these factors may further explain the small decrease in serum 25(oh)d levels and the preserved bmd over a follow-up period of two years. diet is another known modifiable risk factor for optimal bone health, with the value of specific nutrients, such as dietary calcium and vitamin d, well established.64 the dietary calcium and vitamin d intake of participants were relatively low compared with dietary recommendations (1200 mg and 15 mcg, respectively, per day).35 these results are in line with those of previous studies amongst south african women.65 foods are poor sources of vitamin d. therefore, most of the daily input of vitamin d comes from cutaneous synthesis rather than from diet.64 in countries where foods are fortified with vitamin d, these foods are the major dietary source of vitamin d64; however, few foods are enriched with vitamin d in south africa.65 recommendations urbanisation of black south african women may increase the risk of low bone mass because of low vitamin d status, low calcium intake and high bone turnover.65 hence, there is a need for advising women on the intake of vitamin d and calcium. as the largest source of vitamin d is through cutaneous synthesis, an increase in outdoor activities and exposure to the sun may help to improve the vitamin d status. limitations and strengths limitations and strengths existed in this study that need to be acknowledged. firstly, this study used an observational design with limited control over other potential covariates, and no hiv-negative reference group was included. secondly, all participants originated from the same locality in the north west province of south africa and, therefore, generalisation of the findings to a wider population across south africa and beyond should be performed cautiously. thirdly, the sample size was relatively small, thereby undermining the power for subgroup analysis, that is, subgroups based on the vitamin d status. it was challenging to recruit more participants, because most hiv-infected women from the outpatient clinics were premenopausal. the findings of no statistically significant associations could, therefore, be because of type ii error, and a larger sample could potentially have yielded a different result. regarding strengths, to the best of our knowledge, this is the first longitudinal study on an association between serum 25(oh)d and body composition in south african postmenopausal women living with hiv and on art in south africa. a longitudinal design provides stronger evidence of probable associations when compared with a cross-sectional study design. future studies should consider all determinants of serum 25(oh)d concentration and body composition, such as duration of sunlight exposure, as well as dietary assessment over a longer duration. conclusion this 2-year longitudinal study indicates no association between serum 25(oh)d concentration and bmd over time. however, bmi was inversely associated with serum 25(oh)d concentration. in terms of the relative contribution of lean mass and fat mass to maintenance of bmd, lean mass is a stronger determinant of bmd than fat mass. south african postmenopausal women living with hiv and on art maintained their bmd at all three sites over a period of two years. the study further suggests that bmd decreased with increasing age, whilst physical activity was protective against a decrease in bmd in this group of women. the results of this study may inform strategies to prevent fractures in postmenopausal women living with hiv. increasing lean mass through physical activity could be important to preventing frailty and morbidity in this vulnerable group. acknowledgements the authors acknowledge the assistance of registered nurses, ms c.m. lessing and ms a. anthony, who acted as study coordinators and assisted with the blood sample collection. ms g. wood performed language editing of the manuscript. postdoctoral associate dr patricia ukegbu and postgraduate students shams bakali, phillip buys and persuade makore assisted with study coordination and data collection. competing interests the authors declare that they have no financial or personal relationships, which may have inappropriately influenced them in writing this article. authors’ contributions s.m., msc student, and c.e., phd student, collected data, drafted the manuscript and analysed the data. j.c. contributed to the manuscript preparation and participated in data collection. m.c. supervised statistical analysis and approved the final version of the manuscript. c.m.c.m. supervised biochemical analyses and approved the final version of the manuscript. h.s.k. conceptualised the study, supervised data collection and quality control, interpreted the data and approved the final version of the article. funding information the authors acknowledge financial support from the support for nutrition research in africa (sunrea), the sugar association of south africa, massey university, new zealand, and the south african national research foundation (nrf twas programme) [uid 1055500]. the funders were not involved in any aspect of the design, implementation, analysis, or interpretation and write-up of the study. any opinion, findings and conclusion or recommendation expressed in this article is that of the authors, and the nrf does not accept any liability in this regard. data availability no data are available from 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mineral density, body composition, and mineral homeostasis over 24 months in urban south african women with hiv exposed to antiretroviral therapy. j bone min res plus. 2020;4(5):e10343. https://doi.org/10.1002/jbm4.10343 davies necg. fixed-dose combination for adults accessing antiretroviral therapy: advice document. s afr j hiv med. 2013;14(1):41–43. https://doi.org/10.7196/sajhivmed.913 childs k, welz t, samarawickrama a, post fa. effects of vitamin d deficiency and combination antiretroviral therapy on bone in hiv-positive patients. aids. 2012;26(3):253–262. https://doi.org/10.1097/qad.0b013e32834f324b. ardawi m-s, sibiany a, bakhsh t, qari m, maimani a. high prevalence of vitamin d deficiency among healthy saudi arabian men: relationship to bone mineral density, parathyroid hormone, bone turnover markers, and lifestyle factors. osteoporos int. 2012;23(2):675–686. https://doi.org/10.1007/s00198-011-1606-1 kota sk, jammula s, kota s, meher l, modi k. correlation of vitamin d, bone mineral density and parathyroid hormone levels in adults with low bone density. indian j orthop. 2013;47(4):402–407. https://doi.org/10.4103/0019-5413.114932 hamill mm, pettifor jm, ward ka, norris sa, prentice a. changes in bone mineral density, body composition, vitamin d status, and mineral metabolism in urban hiv-positive south african women over 12 months. j bone min res. 2017;32(8):1615–1624. https://doi.org/10.1002/jbmr.3147 de jongh rt, van schoor nm, lips p. changes in vitamin d endocrinology during aging in adults. mol cell endocrinol. 2017;453:144–150. https://doi.org/10.1016/j.mce.2017.06.005 van schoor n, knol d, deeg d, peters f, heijboer a, lips p. longitudinal changes and seasonal variations in serum 25-hydroxyvitamin d levels in different age groups: results of the longitudinal aging study amsterdam. osteoporos int. 2014;25(5):1483–1491. https://doi.org/10.1007/s00198-014-2651-3 poopedi ma, norris sa, micklesfield lk, pettifor jm. does vitamin d status track through adolescence? am j clin nutr. 2015;102(5):1025–1029. https://doi.org/10.3945/ajcn.115.112714 vázquez-lorente h, molina-lópez j, herrera-quintana l, gamarra-morales y, lópez-gonzález b, planells e. association between body fatness and vitamin d3 status in a postmenopausal population. nutrients. 2020;12(3):667. https://doi.org/10.3390/nu12030667 rosenstreich sj, rich c, volwiler w. deposition in and release of vitamin d 3 from body fat: evidence for a storage site in the rat. j clin invest. 1971;50(3):679–687. https://doi.org/10.1172/jci106538 chen y, xiang j, wang z, et al. associations of bone mineral density with lean mass, fat mass, and dietary patterns in postmenopausal chinese women: a 2-year prospective study. plos one. 2015;10(9):e0137097. https://doi.org/10.1371/journal.pone.0137097 ilesanmi-oyelere bl, coad j, roy n, kruger mc. lean body mass in the prediction of bone mineral density in postmenopausal women. biores open access. 2018;7(1):150–158. https://doi.org/10.1089/biores.2018.0025 sotunde o, kruger h, wright hh, et al. lean mass appears to be more strongly associated with bone health than fat mass in urban black south african women. j nutr health aging. 2015;19(6):628–636. https://doi.org/10.1007/s12603-015-0492-1 ho-pham lt, nguyen ud, nguyen tv. association between lean mass, fat mass, and bone mineral density: a meta-analysis. j clin endocrinol metab. 2014;99(1):30–38. https://doi.org/10.1210/jc.2013-3190 kelley ga, kelley ks, kohrt wm. exercise and bone mineral density in premenopausal women: a meta-analysis of randomized controlled trials. int j endocrinol. 2013;2013:741639. https://doi.org/10.1155/2013/741639 zhang z, shen x, zhang h, et al. the relationship between body composition and fracture risk using the frax model in central south c hinese postmenopausal women. clin endocrinol (oxf). 2012;77(4):524–530. https://doi.org/10.1111/j.1365-2265.2012.04399.x muir jm, ye c, bhandari m, adachi jd, thabane l. the effect of regular physical activity on bone mineral density in post-menopausal women aged 75 and over: a retrospective analysis from the canadian multicentre osteoporosis study. bmc musculoskelet disord. 2013;14(1):1–9. https://doi.org/10.1186/1471-2474-14-253 bonjour j-p, guéguen l, palacios c, shearer mj, weaver cm. minerals and vitamins in bone health: the potential value of dietary enhancement. br j nutr. 2009;101(11):1581–1596. https://doi.org/10.1017/s0007114509311721. kruger mc, kruger im, wentzel-viljoen e, kruger a. urbanization of black south african women may increase risk of low bone mass due to low vitamin d status, low calcium intake, and high bone turnover. nutr res. 2011;31(10):748–758. https://doi.org/10.1016/j.nutres.2011.09.012. m_sajhiv_n20_a15.pdf the southern african journal of hiv medicine september 2005 49 initiating antiretroviral therapy gary maartens division of clinical pharmacology, university of cape town the current south african department of health guideline on when to initiate highly active antiretroviral therapy (haart) in adults is based on the 2002 who guidelines. it is a very conservative guideline, with haart being initiated with aids, diagnosed either clinically (world health organization (who) stage 4) or immunologically (cd4+ lymphocyte count < 200 cells/µl). the current southern african hiv clinicians society guidelines extend these conservative guidelines to include patients with other evidence of clinical immune suppression (who clinical stage 3) and patients with cd4 counts 200 350 cells/µl. in common with international guidelines, it is recommended that patients in the cd4 stratum 200 350 cells/µl be followed up until their cd4 count is close to 200 cells/µl, unless their viral load is high. i shall centre my argument on the proposal to use the sa hiv clinicians society guidelines to initiate haart in the public sector. the evidence that starting haart at cd4 counts 200 350 cells/µl leads to a better outcome than at counts < 200 cells/µl is persuasive rather than definitive as it comes from observational cohort studies, not randomised controlled trials. these cohort studies show worse short-term (generally 3 years) survival in patients commencing haart at counts < 200 cells/µl. the magnitude of this benefit is less impressive when controlled for lead time,1 which is a source of bias in cohort studies. nevertheless, the survival benefit remains even after correcting for lead time. the key issue though is that the survival benefit is over the short term. as argued by philips et al.,2 haart is a long-term intervention. we do not yet know how long haart will prolong survival, but it is unlikely that the average patient will have normal survival. we know that there is a steady failure rate on haart, and that achieving virological success (an undetectable viral load) is progressively more difficult with successive regimens, largely owing to resistance. although there is clinical benefit in continuing haart despite resistance, ultimately hiv disease progression does occur.3 taking a longer time view of haart, philips et al. concluded that it is ‘likely that those deferring art [until cd4 counts < 200 cells/µl] ... eventually will experience somewhat lower long-term risk of aids and death than if they had started art immediately’, because most patients will eventually fail therapy. therefore i do not believe there is a compelling case to be made for moving the cd4 count criterion for starting haart in the public sector. starting at who stage 3 is attractive for resource-poor countries, particularly for those without access to flow cytometry for cd4+ lymphocyte count monitoring. clinical staging is simple to learn for nurse-driven services. furthermore, it is known that who stage 3 confers a relatively poor survival independently of the cd4 count. however, when facilities to monitor cd4 counts exist, these should be used in conjunction with who staging. tuberculosis occurs across a wide spectrum of immunity in hiv infection. in our study of incident cases of tuberculosis, about a third of cases presented with cd4 counts > 500 cells/µl.4 i do not believe that these patients need haart. a further problem is that oral thrush, a common stage 3 condition, can occur with seroconversion or following a course of antibiotics. the 2003 revision of the who guidelines of when to initiate haart in resource-poor settings has added who 3 together with cd4 count < 350 cells/µl for those countries, like south africa, which can measure cd4 counts. although i do believe we should consider we should not change guidelines for initiation of haart in adults in the south african public sector september 2005 the southern african journal of hiv medicine 50 adding this to our public sector guideline in the future, i do not believe we should add it soon. south africa has a massive burden of hiv infection. adding who stage 3 to the criteria of when to start haart will approximately treble the number of eligible patients. even if we only targeted stage 4 patients (without using cd4 criteria) and only managed to treat 50% of these, we would still need to treat approximately 1 400 000 by 2008 (extrapolated from assa 2002 model by andrew boulle). until it is clear that we can achieve this daunting target we should not talk about easing the criteria for initiation. we have an obligation to first deal with those who are suffering most. references 1. cole s, li r, anastos k, detels r, young m, chmiel js, munoz a. accounting for leadtime in cohort studies: evaluating when to initiate hiv therapies. stat med 2004; 23: 3351-3363. 2. philips an, lepri ac, lampe f, johnson m, sabin ca. when should antiretroviral therapy be started for hiv infection? interpreting the evidence from observational studies. aids 2003; 17: 1863-1869. 3. deeks sg, barbour jd, grant rm, martin nj. uration and predictors of cd4-t cell gains in patients who continue combination therapy despite detectable plasma viremia. aids 2002; 16: 201-207. 4. badri m, ehrlich r, wood r, maartens g. tuberculosis should not be considered an aids-defining illness in areas with a high tuberculosis prevalence. int j tuberc lung dis 2002; 6: 231-237. should we be initiating antiretroviral therapy earlier? robin wood desmond tutu hiv centre, institute of infectious disease and molecular medicine, university of cape town antiretroviral programme rationales antiretroviral therapy (art) programmes are a part of the response to the massive mortality occurring in the countries most affected by the hiv epidemic. unaids estimated that 2.3 million deaths from aids occurred in sub-saharan africa during 2004. south africa faces the prospect of an accumulated 6 7 million aids deaths by 2010, with the majority affecting the age group 20 40 years, a stage of life when adults are productive and caring for the next generation. in september 2003 the world health organization (who) declared the lack of access to hiv treatment a global health emergency. who called for ‘unprecedented action’ to ensure that by the end of 2005 at least 3 million people in need of art will have access to it. to date the national evaluations of the status of art programmes have revolved around reporting on numbers on treatment rather than impact on aids mortality. the primary purpose of the south african and other national arv programmes is to minimise hiv-associated mortality. debate focus the key to the present debate revolves around the thresholds of art initiation as set out in various treatment guidelines and how different programme entry criteria impact on population hiv-related deaths. the who treatment guidelines committee recognises in the 2003 guidelines preface that they will need to be updated on a regular basis in order to reflect ‘best current clinical practice’. the sa national rollout programme currently uses the older who 2000 guidelines, which are not internationally recognised as the ‘best current clinical practice’ and have ceased to be used by many other countries in our region such as botswana, namibia and uganda. the current sa guidelines recommend both clinical and cd4 criteria for allowing access to the art programme. appraisal of present sa guidelines firstly the clinical and cd4 count criteria are very mismatched. patients with aids die at a rate of 6% per month while asymptomatic patients with cd4 counts < 200 µl have approximately a 1% monthly mortality. clinical aids is therefore very specific for identifying patients at high risk of death while a cd4 of < 200 is very sensitive measure. secondly, the majority of patients access health care and antiretroviral (arv) programmes because they have clinical symptoms rather than because they have just passed the cd4 threshold of < 200 cells. the median cd4 cell count of patients accessing arvs in kampala, uganda, is still 65/µl and in gugulethu, cape town, it is less than 100/µl after 3 years of the programme. a cd4 count of < 200 cells/µl will gain utility when a large proportion of people living with aids (pwas) have access to sequential cd4 count monitoring. this cd4 count threshold would then be a very sensitive but not specific measure for identifying patients at high risk of death. however, widespread cd4 count testing is not widely available in south africa or elsewhere in sub-saharan africa. thirdly, the clinical threshold of aids as an entry criterion for art results in high mortality, as there are inevitable delays in accessing treatment. in gugulethu the time between referral and commencing arvs is short at 28 days. however, 66% of programme deaths are recorded during this period, occurring almost exclusively in those patients with aids before they could start arvs. the reported delay in the médecins sans frontières, khayelitsha, arv project was 4 months. waiting time to access arvs in other programmes is frequently much longer. waiting lists in cape town hospitals have been up to 8 months and are in excess of 8 months in malawi, which results in an unrecorded 50% of aids patients dying before access to arv programmes. currently this pre-treatment mortality is not recorded as part of the treatment programme, although reduction of hiv mortality is the primary aim of arv treatment. aids patients not only have a high in-programme death rate, they are also difficult to clinically manage and investigate, thereby consuming a disproportionate amount of programme resources. aids is therefore too late a threshold for entry into an arv programme. if the guidelines do not represent ‘best current clinical practice’ but are being used as a means of rationing access to care, they should identify those who will benefit most from therapy. clinical stage is more predictive of hiv mortality than cd4 count. south african published data have reported that the death rate of patients with who stage 3 disease is 2 2.5 times higher than that of asymptomatic patients with < 200 cd4 cells/µl. until cd4 count testing is more widely available, abstract introduction methods and materials results discussion conclusion acknowledgements references about the author(s) rendani t. mafuyeka department of medical virology, faculty of health sciences, university of pretoria, pretoria, south africa lynne m. webber department of medical virology, faculty of health sciences, university of pretoria, pretoria, south africa department of virology, tshwane academic division, national health laboratory, pretoria, south africa piet becker research office, faculty of health sciences, university of pretoria, pretoria, south africa simnikiwe h. mayaphi department of medical virology, faculty of health sciences, university of pretoria, pretoria, south africa citation mafuyeka rt, webber lm, becker p, mayaphi sh. hiv-1/2 differentiation in a south african public laboratory. s afr j hiv med. 2021;22(1), a1185. https://doi.org/10.4102/sajhivmed.v22i1.1185 original research hiv-1/2 differentiation in a south african public laboratory rendani t. mafuyeka, lynne m. webber, piet becker, simnikiwe h. mayaphi received: 26 oct. 2020; accepted: 30 jan. 2021; published: 12 mar. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the human immunodeficiency virus type-2 (hiv-2) prevalence in south africa (sa) is unknown, however, sporadic cases have been reported. human immunodeficiency virus -1 and 2 differentiation is not part of most south african public laboratories’ testing algorithm. human immunodeficiency virus -2 diagnosis using serology assays may be complicated by hiv-1 and hiv-2 antibody cross-reactivity. objectives: to determine the proportion of hiv-2 infections in specimens that tested hiv-1/2 positive at a public laboratory in tshwane. method: a total of 480 specimens that were previously tested with fourth generation elisa platforms (modular e170 [roche, switzerland] and architect i2000 [abbott, germany]) were randomly selected. human immunodeficiency virus -1 and 2 antibody differentiation testing was carried out using the multispot hiv-1/2 rapid assay (bio-rad laboratories, usa). an in-house nested hiv-2 pcr assay targeting the 5′-long terminal repeats (5′-ltr) region was evaluated and used as a confirmatory test. results: the study tested 480 hiv-1/2 seropositive patients and their mean age was 36.7 years (range 3–82 years). of the 480 patients, 292 (60.8%) were female, 182 (37.9%) were male and 6 (1.3%) were not specified. human immunodeficiency virus differentiation results were as follows: 466 (97.1%) were positive for only hiv-1 antibodies, 11 (2.3%) [95%ci: (0.98%; 3.74%)] were positive for both hiv-1 and hiv-2 antibodies, 3 (0.6%) were negative for both antibodies and none were positive for only hiv-2 antibodies. of the 11 specimens with both hiv-1 and hiv-2 antibodies, seven had sufficient volume for confirmatory testing and were all negative on the in-house hiv-2 pcr assay. conclusion: the multispot hiv-1/2 rapid assay demonstrated cross-reactivity between hiv-1 and hiv-2 antibodies. human immunodeficiency virus -2 infections were not detected. keywords: hiv-1/2 differentiation; hiv-2 testing; hiv1/2 antibody cross reaction; hiv-2 in south africa; hiv-2 pcr. introduction human immunodeficiency virus type 2 (hiv-2) belongs to the retroviridae family, lentivirus genus.1 it is most prevalent in west africa.2 most countries with historical ties with west africa have also detected a significant proportion of hiv-2 infections.3 although the hiv pandemic is mainly caused by hiv-1, hiv-2 is also an important cause of acquired immunodeficiency syndrome (aids).4 both hiv-1 and hiv-2 have similar clinical manifestations, however, hiv-2 progresses much slower to aids.5 south african data on hiv-2 infections is limited. sporadic cases have been reported in the past, which is an indication that hiv-2 may be circulating in south africa (sa).6,7 in addition, sa has a large number of tourists and immigrants from the west african region and other parts of the world where hiv-2 infections have been reported,8,9 which may contribute to the spread of the virus in the country. routine diagnostic serology assays that are widely used in sa national public sector health laboratories do not include hiv-1 and hiv-2 differentiation.10 this may have implications for hiv management,11 as the treatment of hiv-2 differs from that of hiv-1. human immunodeficiency virus-2 is intrinsically resistant to non-nucleoside reverse transcriptase inhibitors (nnrtis) and fusion inhibitors. it is also only weakly suppressed by some protease inhibitors. human immunodeficiency virus-2 has a lower genetic barrier compared with hiv-1 to nucleoside reverse transcriptase inhibitors (nrtis) resistance. dolutegravir is effective against hiv-2, but strains with raltegravir mutations may have low levels of resistance.12 the virology diagnostic laboratory is currently using a fourth generation enzyme-linked immunosorbent assay (4th gen elisa) for hiv-1/2 testing. the fourth generation elisa can detect both hiv-1 and hiv-2 antibodies and p24 antigen, but it does not differentiate between the two types. the world health organization (who) hiv testing guidelines recommend hiv-2 differentiation with serological and/or molecular assays in settings where hiv-2 infections have been detected.13 human immunodeficiency virus -2 molecular testing is an important confirmatory assay, owing to the high hiv-1 and hiv-2 antibody cross-reactivity with serological assays.14 aims this study aimed to determine the proportion of hiv-2 infections in specimens that tested hiv-1/2 positive in a public laboratory in tshwane. objectives human immunodeficiency virus -1 and -2 differentiation using the multispot hiv-1/2 rapid test. evaluation of the in-house hiv-2 nested polymerase chain reaction (pcr) assay. confirmatory testing using the in-house hiv-2 pcr assay. methods and materials study design this was a retrospective, cross-sectional study conducted between february 2013 and july 2016. study setting this study was conducted in the national health laboratory services (nhls), tshwane academic division (tad) virology laboratory at the university of pretoria, faculty of health sciences. the specimens used came from the public sector hospitals and clinics around tshwane metropolitan municipality, submitted for routine hiv screening. specimen selection a total of 480 plasma and serum specimens that had previously tested positive for hiv-1/2 antibody, were randomly selected. the inclusion criteria were age of more than 24 months and hiv-1/2 antibody positive results on two different fourth generation elisa platforms, the modular e170 (roche, switzerland) and the architect i2000 (abbott, germany). statistics the hiv-2 prevalence is unknown in sa. based on the hiv-2 prevalence data from other parts of the world outside the west african region,15,16,17 a prevalence of 1% was assumed for sa. it was determined that a sample size of 459 tests would have a 0.99 probability to detect at least one hiv-2 positive specimen. the sample size calculation was done using software nquery version 7.0.18 hiv-1 and 2 antibody differentiation the multispot hiv-1/2 rapid assay (bio-rad laboratories, usa) was used for hiv-1 and hiv-2 differentiation. the procedure was performed according to the manufacturer’s instructions. four known hiv-2 antibody positive specimens, from a laboratory in portugal, that were previously tested using only the western blot assay, and 52 hiv-1 and hiv-2 antibody negative specimens that were previously tested using hiv-1/2 fourth generation elisa, modular e170 (roche, switzerland) were included to evaluate performance of the multispot hiv-1/2 rapid assay. in-house hiv-2 nested polymerase chain reaction assay two sets of primers, targeting the conserved 5′ long terminal repeat (5′-ltr) region of hiv-2, were designed and numbered according to the hiv-2 rod reference strain, accession number m15390.1 (table 1). the in-house hiv-2 nested pcr assay was evaluated using the four known hiv-2 antibody positive specimens. these specimens were also processed at a private laboratory using a commercial real-time hiv-2 pcr assay (genesig standard kit) that targets the integrase (pol) gene region. the genesig standard kit detects hiv-2 subtypes a and b only. the internal control was also included in the commercial real-time assay. two known hiv-1 specimens with high viral load (132 000 copies/ml and 30 200 copies/ml) were included to determine the specificity of the in-house pcr primers. the in-house hiv-2 nested pcr assay was used to confirm specimens that were positive for both hiv-1 and hiv-2 antibodies on the multispot hiv-1/2 rapid assay. table 1: designed primers used for the in-house nested human immunodeficiency virus-2 polymerase chain reaction and sequencing. nucleic acid extraction except for the initial centrifugation step to get a purified pellet, the extraction of total nucleic acids was performed manually using the qiaamp ultrasens virus kit (qiagen, germany) according to the manufacturer’s instructions. centrifugation was optimised at 800 relative centrifugal force (rcf) for 3 min instead of the recommended 1200 rcf. optimisation to a lower rcf produced an easily dissolvable pellet. sample input volume for extraction was 500 µl, and lower input volume of 250 µl was used for samples with insufficient volume. the final eluate volume was 60 µl. amplification, detection and analysis a nested pcr was carried out using the superscript iii one-step rt-pcr kit with platinum taq deoxyribonucleic acid polymerase (5 u/µl) (life technologies, usa) according to the manufacturer’s instructions. the total reaction volumes for both first and second round pcr were 50 µl. first round pcr contained 25 µl of 2x reaction mix (a buffer containing 0.4 mm of each dntp, 2.4 mm mgso4); 1 µl of each primer (outer forward and reverse) (10 µm); 1 µl of taq enzyme (5 u/µl), 5 µl of template and 17 µl of nuclease-free h2o. the second round pcr reaction contained 25 µl of 2x reaction mix (a buffer containing 0.4 mm of each dntp, 2.4 mm mgso4); 1 µl of each primer (inner forward and reverse)(10 µm); 0.2 µl of taq enzyme (5 u/µl), 0.5 µl of template and 22.3 µl of nuclease-free h2o. the first round pcr conditions were as follows: cdna synthesis for 1 cycle at 50 °c for 30 min; denaturation for 1 cycle at 94 °c for 2 min; amplification 40 cycles (denature at 94 °c for 30 s, annealing at 50 °c for 30 s, extension at 68 °c for 1 min); final extension for 1 cycle at 68 °c for 7 min and hold at 4 °c. the second round pcr conditions were as follows: denaturation for 1 cycle at 94 °c for 2 min; amplification 40 cycles (denature at 94 °c for 30 s, annealing at 50 °c for 30 s, extension at 68 °c for 30 s); final extension for 1 cycle at 68 °c for 7 min and hold at 4 °c. polymerase chain reaction amplicons were visualised on a 1.5% agarose gel by ultraviolet (uv) illumination. hiv-2 sequencing polymerase chain reaction amplicons were sequenced to evaluate the in-house hiv-2 nested pcr, at inqaba biotechnical industries (pty) ltd using the second round pcr primers (mmfw-2 and mmrv-2) (table 1). the original pcr products were sent to inqaba where they performed a clean-up procedure and sanger sequencing. sequence analysis comprised of sequence editing and alignment performed using bioedit sequence alignment editor version 7.2.5 programme.19 molecular evolutionary genetics analysis (mega) version 6 programme,20 was used for constructing the phylogenetic tree using neighbor-joining statistical method (with 1000 bootstrap replicates). ethical consideration this study was approved by the research ethics committee, faculty health sciences, university of pretoria (ethics reference number: 11/2013). permission to use the blood specimens and to retrieve demographics information from the laboratory information system (lis) was obtained from tshwane academic division of the nhls. the information of each specimen was managed with strict confidentiality and each specimen was given a unique study number to ensure patient anonymity. results hiv-1 and 2 antibodies differentiation results the study tested 480 hiv-1 and hiv-2 seropositive patients, and their mean age was 36.7 years (range: 3–82 years). of the 480, 292 (60.8%) were female, 182 (37.9%) were male and 6 (1.3%) were not specified. all four known hiv-2 antibody positive specimens used to evaluate the multispot hiv-1/2 rapid assay were positive for hiv-2 antibodies only. all 52 known hiv-1 and hiv-2 elisa negative specimens were negative. differentiation results of the 480 specimens were as follows: 466 (97.1%) were positive for only hiv-1 antibodies, 11 (2.3%) 95%ci: 0.98%; 3.74% were positive for both hiv-1 and hiv-2 antibodies, 3 (0.6%) were negative for both antibodies and none were positive for only hiv-2 antibodies (figure 1). figure 1: algorithm of the specimens tested with multispot hiv-1/2 rapid assay. in-house hiv-2 nested polymerase chain reaction assay results evaluation results of the in-house nested hiv-2 pcr, on four known hiv-2 antibody positive specimens, were comparable to a commercial real-time pcr, which was carried out in a private laboratory (table 2). two hiv-1 specimens, with high viral load, were also not detected by the in-house hiv-2 pcr (figure 2). of the 11 specimens, which were positive for both hiv-1 and hiv-2 antibodies, only seven had sufficient volume for further testing. all tested hiv-2 pcr negative on the in-house assay. table 2: hiv-2 polymerase chain reaction results of the four known hiv-2 antibody positive specimens. figure 2: gel electrophoresis with a 100 bp dna ladder. specimens 83541, 82176, 77515 and 77538 are known hiv-2 antibody positive. specimen 83541 tested positive for hiv-2 pcr (fragment size = 338 bp). hiv-1 specimens (9820 and 3447) with high viral load were undetectable. hiv-2 sequencing results the pcr products of the confirmed hiv-2 subtype a/b specimen (83541) were sent for sequencing. phylogenetic analysis revealed that this sequence clustered with subtype a of hiv-2 (figure 3). sequencing was not indicated for those specimens that were hiv-2 negative on the in-house pcr assay. figure 3: phylogenetic tree showing the sequence of the known human immunodeficiency virus-2 sample that was positive on in-house polymerase chain reaction (labelled with a black dot). this sequence clustered with subtype a human immunodeficiency virus-2 isolates. discussion this study aimed to determine the proportion of hiv-2 infections in specimens that tested hiv-1/2 antibody positive at a virology diagnostic laboratory using the multispot hiv-1/2 rapid assay for differentiation. the multispot rapid test has been reported as satisfactory with regard to the detection of hiv-1 and hiv-2.21,22,23,24,25,26 differentiation results showed hiv-1 and hiv-2 dual seropositivity in 11 (2.3%) of the specimens. of the 11, seven specimens with sufficient volume for the in-house hiv-2 pcr tested negative. this may indicate hiv-1 and hiv-2 antibody cross-reactivity. these results were not surprising, as hiv-1 and hiv-2 antibody cross-reactivity have been observed in other studies.24,27 a study conducted in sa demonstrated high levels of false hiv-2 seropositivity, at 15%, 71.2% and 10.7%, using the sd bioline hiv1/2 3.0 rapid test, the newlav western blots, and pepti-lav1-2, respectively.27 this south african study demonstrated a high rate of antibody cross reactivity with negative hiv-2 molecular testing. another study carried out in the united states of america, demonstrated antibody cross-reactivity rates of 46.5% and 11.4% using the centres for disease control (cdc) hiv-1 western blot (wb) interpretive criteria and the alternative more stringent hiv-1 wb interpretive criteria, respectively.24 the hiv-1 and hiv-2 antibody cross-reactivity rate was 2.3% in this study. other previous studies that also used the multispot assay demonstrated a cross-reactivity rate of 0.5%26 and 1.3%.24 these previous studies are further demonstrating that hiv-2 testing using serological assays may be complicated owing to high levels of antibody cross-reactivity and should be interpreted with caution. highly sensitive and specific molecular confirmatory testing is always important for those specimens with dual hiv seropositivity14 and for research purposes. the first two reported hiv-2 cases in sa were documented in 19886 and 1993.7 these cases were both diagnosed and confirmed using antibody detection assays. confirmation of the 1988 case was done using an immunofluorescence assay and that of the 1993 case was done using a western blot assay. possibility of hiv-1 and hiv-2 antibody cross reactivity in these two cases cannot be ruled out as no molecular testing was performed. the in-house nested hiv-2 pcr had comparable results, on the four known hiv-2 antibody positive specimens, with the commercial assay (genesig standard kit) processed in a private laboratory (table 2). sequencing of the pcr products of the known hiv-2 positive specimen (83541) indicated hiv-2 subtype a (figure 3). the other three hiv-2 seropositive specimens that failed to amplify using hiv-2-specific pcrs (the in-house and the commercial assays) may have reflected naturally low levels of hiv-2 virus or the effect of antiretroviral therapy exposure. there was no relevant clinical information provided on these known hiv-2 antibody positive specimens from the laboratory in portugal, which could have explained these results. in addition, the in-house nested hiv-2 pcr assay did not detect hiv-1 in two specimens with high viral loads highlighting a lower likelihood of false positive results in individuals with hiv-1 infection. to further evaluate the sensitivity and specificity of the primers used for in-house nested pcr, more hiv-1 and hiv-2 samples need to be tested. the negative hiv-2 pcr on specimens with dual hiv seropositivity may not completely rule out dual hiv infections, as there are many factors that may contribute to false-negative hiv-2 pcr. such factors include naturally low viral load in hiv-2 infections because of the low replication rate.28 in a study by drylewicz j et al., plasma hiv-2 viral load was undetectable in up to 85% of individuals positive for hiv-2 antibodies.29 another possible explanation could be that hiv-1 suppresses hiv-2 replication in individuals with dual infection; hence, the hiv-2 antibodies and viral load remain very low or undetectable. the quality of specimens used in this study may have been compromised as well. specimens were initially stored at 4 °c for more than 7 days prior to testing, which may have led to rna degradation. serum and plasma specimens used in this study may not be the best for hiv-2 detection as evidence suggests that hiv-2 replication is restricted in vivo.30 peripheral blood mononuclear cells (pbmcs) may yield a better outcome with regard to hiv-2 detection.30,31 the limitations of this study include small sample size, quality and type of the specimens used as described here. low specimen volumes (250 µl – 500 µl) were used for extraction because of specimen insufficiency. nucleic acid quantification and quality assessment were also not done. this may have led to false negative results. polymerase chain reaction failure of the in-house pcr could not be excluded because of the lack of internal controls; however, the commercial hiv-2 pcr with comparable results and with internal controls, amplified. the developed in-house nested hiv-2 pcr needs further evaluation with more hiv-2 positive specimens, including other subtypes and addition of more hiv-1 only specimens. the commercial assay can only detect hiv-2 subtypes a and b.32 detection of other hiv-2 subtypes (c–g) could not be evaluated. conclusion the multispot hiv-1/2 rapid assay demonstrated some cross-reactivity between hiv-1 and hiv-2 antibodies. human immunodeficiency virus-2 infections were not detected. dual infections could not be excluded in this study. the in-house hiv-2 pcr assay needs further evaluation to determine its sensitivity and specificity. these results cannot be generalised because the sample size was too small. further studies are needed to explore hiv-2 infections and treatment response in sa. postscript the multispot hiv-1 and hiv-2 rapid assay was later discontinued in 2016 and was replaced by the geenius hiv-1 and hiv-2 supplemental assay.33 acknowledgements (1) tshwane academic division of the nhls and the university of pretoria virology department for support and supply of all patients’ specimens, (2) dr osman for arranging the known hiv-2 specimens from a portugal laboratory and (3) dr allison glass (private laboratory) for testing hiv-2 pcr on the four known hiv-2 specimens. this research was conducted for the fulfilment of the mmed in pathology (clinical virology) and supervised by simnikiwe horatious mayaphi and lynne margaret webber. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions s.h.m. and l.m.w. developed the study concept, design, manuscript editing and they were also supervisors. p.b. contributed in data analysis, statistics and manuscript editing. r.t.m. conducted laboratory tests, data collection, data analysis and writing manuscript. funding information this work was supported by the nhls research trust (grant004 94395), discovery foundation (reference number 034211) and the university of pretoria research grant. data availability the data that support the findings of this study 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comparison of alternative interpretive criteria for the hiv-1 western blot and results of the multispot hiv-1/hiv-2 rapid test for classifying hiv-1 and hiv-2 infections. j clin virol. 2011;52(suppl 1):s23–s27. https://doi.org/10.1016/j.jcv.2011.09.020 o’connell rj, agan bk, anderson sa, malia ja, michael nl. sensitivity of the multispot hiv-1/hiv-2 rapid test using samples from human immunodeficiency virus type-1 positive individuals with various levels of exposure to highly active antiretroviral therapy. j clin microbiol. 2006;44(5):1831–1833. https://doi.org/10.1128/jcm.44.5.1831-1833.2006 ramos em, harb s, dragavon j, coombs rw. clinical performance of the multispot hiv-1/hiv-2 rapid test to correctly differentiate hiv-2 from hiv-1 infection in screening algorithms using third and fourth generation assays and to identify cross reactivity with the hiv-1 western blot. j clin virol. 2013;58(supp 1):s104–s107. https://doi.org/10.1016/j.jcv.2013.08.018 singh l, parboosing r, manasa j, moodley p, de oliveira t. high level of hiv-2 false positivity in kwazulu-natal province: a region of south africa with a very high hiv-1 subtype c prevalence. j med virol. 2013;85(12):2065–2071. https://doi.org/10.1002/jmv.23716 delarue s, didier e, damond f, et al. highly sensitive plasma rna quantification by real-time pcr in hiv-2 group a and group b infection. j clin virol. 2013;58(2):461–467. https://doi.org/10.1016/j.jcv.2013.08.003 drylewicz j, matheron s, lazaro e, et al. comparison of viro-immunological marker changes between hiv-1 and hiv-2-infected patients in france. aids. 2008;22(4):457–468. https://doi.org/10.1097/qad.0b013e3282f4ddfc macneil a, sarr ad, sankalé jl, meloni st, mboup s, kanki p. direct evidence of lower viral replication rates in vivo in human immunodeficiency virus type 2 (hiv-2) infection than in hiv-1 infection. j virol. 2007;81(10):5325–5330. https://doi.org/10.1128/jvi.02625-06 kageyama s, maniar jk, iwasaki m, et al. seronegative hiv-2 carriers in india. int j std aids. 2000;11(1):31–37. https://doi.org/10.1258/0956462001914878 hiv-2 integrase (pol) gene region. genesig standard kit handbook hb10.02.08. us: primerdesign ltd. penner mc, national alliance of state & territorial aids directors (nastad) [homepage on the internet]. 2016 [2020 june 22]. available from: https://www.nastad.org/sites/default/files/resources/docs/february-16discontinuation-multispot-hiv-rapid-test.pdf references about the author(s) gary maartens division of clinical pharmacology, department of medicine, faculty of health sciences, university of cape town, cape town, south africa phumla sinxadi division of clinical pharmacology, department of medicine, faculty of health sciences, university of cape town, cape town, south africa w.d. francois venter ezintsha, faculty of health sciences, university of the witwatersrand, johannesburg, south africa citation maartens g, sinxadi p, venter wdf. weight gain on dolutegravir: association is not the same as causation. s afr j hiv med. 2023;24(1), a1500. https://doi.org/10.4102/sajhivmed.v24i1.1500 editorial weight gain on dolutegravir: association is not the same as causation gary maartens, phumla sinxadi, w.d. francois venter copyright: © 2023. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. dolutegravir and other integrase strand transfer inhibitors are associated with more weight gain in people starting antiretroviral therapy (art) than other antiretroviral drug classes.1,2 antiretroviral therapy-naïve people gain weight after starting art, irrespective of whether the regimen includes dolutegravir – this is a return-to-health phenomenon. weight gain is most marked if art is started with cd4 counts below 200 cells/μl.1 women gain more weight after starting art than men.1 the south african advance study reported more weight gain in participants randomised to dolutegravir than efavirenz, which was more marked among women.3 this observation has caused concern because women in sub-saharan africa have a higher prevalence of both hiv and obesity than men.4 there are two hypotheses for the greater weight gain observed with dolutegravir than efavirenz: dolutegravir may be causing weight gain or efavirenz may be impairing weight gain. there are no credible mechanisms by which dolutegravir could cause weight gain. integrase strand transfer inhibitors inhibit the human melanocortin 4 receptors in vitro, which plays a role in the control of appetite in the brain, but inhibition only occurs at concentrations far exceeding those that are achievable clinically. by contrast, there are biologically plausible reasons why efavirenz could impair weight gain: by impairing appetite from chronic neuropsychiatric effects or by its toxic effects on adipocytes.5,6 recent studies provide very strong evidence for the hypothesis that efavirenz impairs weight gain in genetically susceptible individuals. efavirenz concentrations are highly variable, which is mainly due to loss-of-function mutations in genes encoding for the cytochrome p450 enzymes responsible for metabolising efavirenz, cyp2b6 (major pathway) and cyp2a6 (minor pathway). mutations in these genes are used to categorise people into extensive, intermediate, and slow efavirenz metabolisers – intermediate metabolisers have modestly increased efavirenz concentrations while slow metabolisers (about 20% of south africans) have markedly increased efavirenz concentrations.7 a genetic sub-study in advance participants randomised to the efavirenz arm found that efavirenz metaboliser genotype predicted weight gain to 48 weeks: extensive metabolisers gained the most weight, followed by intermediate metabolisers, then slow metabolisers, who actually experienced a slight decline from baseline in median weight.8 a key point was that weight gain was similar between extensive metabolisers in the efavirenz arm and in the dolutegravir arm with the same nucleoside reverse transcriptase inhibitor backbone (tenofovir disoproxil fumarate and emtricitabine). a cohort study reported that efavirenz slow metabolisers gained the most weight after switching from efavirenz to integrase inhibitors when virologically suppressed, providing further evidence for impaired weight gain on efavirenz-based art in slow metabolisers.9 the belief that dolutegravir causes weight gain is widespread among people with hiv and clinicians, which can result in inappropriate antiretroviral switching, reduced adherence, and failure to manage people who are overweight and obese with appropriate interventions. people with marked weight gain on dolutegravir-based art should be screened for the metabolic syndrome and treated accordingly. the weight gain should be addressed by appropriate lifestyle and other interventions. newer interventions are more effective at maintaining weight loss for people with established obesity than lifestyle measures but access to these interventions is limited in our region, especially in the public sector. switching antiretrovirals in people who experience weight gain on dolutegravir is recommended against in the 2023 guidelines from the southern african hiv clinicians society and the national department of health. switching from dolutegravir to efavirenz could result in weight loss in efavirenz slow metabolisers, but they are at increased risk of severe toxicity, including drug-induced liver-injury and chronic neuropsychiatric conditions.5 references sax pe, erlandson km, lake je, et al. weight gain following initiation of antiretroviral therapy: risk factors in randomized comparative clinical trials. clin infect dis. 2020;71(6):1379–1389. https://doi.org/10.1093/cid/ciz999 bourgi k, jenkins ca, rebeiro pf, et al. weight gain among treatment-naïve persons with hiv starting integrase inhibitors compared to non-nucleoside reverse transcriptase inhibitors or protease inhibitors in a large observational cohort in the united states and canada. j int aids soc. 2020;23(4):e25484. https://doi.org/10.1002/jia2.25484 venter wdf, sokhela s, simmons b, et al. dolutegravir with emtricitabine and tenofovir alafenamide or tenofovir disoproxil fumarate versus efavirenz, emtricitabine, and tenofovir disoproxil fumarate for initial treatment of hiv-1 infection (advance): week 96 results from a randomised, phase 3, non-inferiority trial. lancet hiv. 2020;7:e666–e676. https://doi.org/10.1016/s2352-3018(20)30241-1 jaacks lm, vandevijvere s, pan a, et al. the obesity transition: stages of the global epidemic. lancet diabetes endocrinol. 2019;7:231–240. https://doi.org/10.1016/s2213-8587(19)30026-9 mouton jp, cohen k, maartens g. key toxicity issues with the who-recommended first-line antiretroviral therapy regimen. expert rev clin pharmacol. 2016;9(11):901–915. https://doi.org/10.1080/17512433.2016.1221760 moure r, domingo p, gallego-escuredo jm, et al. impact of elvitegravir on human adipocytes: alterations in differentiation, gene expression and release of adipokines and cytokines. antiviral res. 2016;132:59–65. https://doi.org/10.1016/j.antiviral.2016.05.013 sinxadi pz, leger pd, mcilleron h, et al. pharmacogenetics of plasma efavirenz exposure in hiv-infected adults and children in south africa. br j clin pharmacol. 2015;80(1):146–156. https://doi.org/10.1111/bcp.12590 griesel r, maartens g, chirehwa m, et al. cyp2b6 genotype and weight gain differences between dolutegravir and efavirenz. clin infect dis. 2021;73(11):e3902–e3909. https://doi.org/10.1093/cid/ciaa1073 leonard ma, cindi z, bradford y, et al. efavirenz pharmacogenetics and weight gain following switch to integrase inhibitor-containing regimens. clin infect dis. 2021;73(7):e2153–e2163. https://doi.org/10.1093/cid/ciaa1219 abstract introduction case presentation discussion conclusion acknowledgements references about the author(s) kirstie f. thomson department of internal medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa florence mahlobo department of radiology, faculty of health sciences, university of the witwatersrand, johannesburg, south africa department of medical imaging, faculty of health sciences, university of johannesburg, johannesburg, south africa denasha l. reddy department of internal medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa citation thomson kf, mahlobo f, reddy dl. splenic hydatid disease in pregnancy. s afr j hiv med. 2022;23(1), a1363. https://doi.org/10.4102/sajhivmed.v23i1.1363 case report splenic hydatid disease in pregnancy kirstie f. thomson, florence mahlobo, denasha l. reddy received: 19 dec. 2021; accepted: 09 mar. 2022; published: 26 may 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract introduction: hydatid disease in the south african setting remains an important differential diagnosis in many appropriate clinical presentations, such as splenomegaly. splenic hydatid disease in pregnancy is a rare and complex disease to manage. patient presentation: in this case report we describe a case of isolated splenic hydatid disease in an hiv-positive woman presenting in her third trimester of pregnancy. management and outcome: a multidisciplinary team consisting of specialists from the high-risk maternity unit, hepatobiliary surgery and infectious diseases planned the management of the patient, which included pre-operative albendazole and elective caesarean section with assisted forceps delivery at 36 weeks’ gestation. an elective splenectomy in the post-partum period was planned for definitive management. conclusion: our aim is to highlight the unique treatment challenges of hydatid disease in pregnancy and the need for a multidisciplinary team approach when managing complex cases of hydatid disease. keywords: cystic echinococcosis; hydatid disease; pregnancy; spleen; splenomegaly. introduction hydatid disease is a parasitic infestation by a dog tapeworm of the genus echinococcus.1 cystic echinococcosis is the larval cystic stage of echinococcus granulosus and may cause illness in intermediary hosts such as sheep and occasionally humans.1 in the typical dog-sheep lifecycle, the adult tapeworms inhabit the small intestines of definitive carnivorous hosts such as dogs and the eggs passed in the faeces may be ingested by a grazing sheep.1 humans play the same role as these intermediary hosts and can be infected by ingesting food or drink contaminated with faecal material containing tapeworm eggs.1 the clinical features of cystic echinococcosis are highly variable and the wide spectrum of disease presentation differs according to various factors, such as the involvement of a particular organ, the nature and size of the cysts as well as their effect on surrounding structures.1 complications relating to these cysts are not uncommon and include ruptured cysts, bacteriological infection or immunological reaction to the cysts themselves.1 diagnosis is usually made using a combination of serological tests and imaging.1,2 although isolated splenic hydatid disease is a rare clinical entity with a prevalence of between 2.5% and 5.8% of all patients with hydatid disease, it is the third most commonly affected organ after the liver and lungs.1,2 while the exact pathophysiology for the involvement of the spleen is largely unknown, there are a few mechanisms that could explain the splenic disease process. the parasitic eggs can penetrate the barrier of the liver and the lungs, thus entering the systemic circulation and enter the spleen where they may settle.2 additionally, there is the possibility of retrograde spread via the portal vein, colonic trans-parietal passage of the eggs or intraperitoneal rupture of a hydatid cyst with subsequent ‘seeding’.2 the incidence of hydatid disease in pregnancy is largely unknown, and management in this clinical scenario is determined on a case-by-case basis. according to recent literature, there is no conclusive data to suggest that hiv co-infection is a risk factor for developing hydatidosis. however, a recent prospective study in a south african setting suggested that hiv co-infected patients more often had infected cysts and required emergency surgery more frequently for hepatic hydatid disease than their hiv-negative counterparts.3 comparative studies showed that there seems to be an impaired immune response to e. granulosus in patients with hiv and hydatid disease severity might be offset by viral suppression using antiretroviral therapy in hiv infected patients.4 case presentation a 41-year-old pregnant woman at 35 weeks gestation by early dates presented to our tertiary infectious diseases clinic with a 7-month history of progressively worsening left flank fullness, associated left shoulder pain and clinical findings of a massive splenomegaly. a formal ultrasound confirmed a notably enlarged spleen measuring 21 cm and multiple splenic cystic lesions of varying size, with the largest measuring 4.8 cm × 4 cm (figures 1a and 1c). the cysts involved more than 90% of the normal splenic tissue (figure 1b). the liver was normal and a single intra-uterine pregnancy was confirmed at this time. there was no suspected foetal intra-uterine growth restriction according to the obstetric team during the multidisciplinary team meeting and the gestational age of the foetus was confirmed. figure 1: images taken from the initial ultrasound done on presentation; (a) an image showing the enlarged spleen measuring 21 cm; (b) this image shows the extensive splenic hydatid cysts involving more than 90% of the normal splenic tissue; (c) an indication of the largest splenic cyst measuring 4.8 cm × 4.0 cm. these ultrasound findings were suggestive of splenic hydatid disease. an indirect haemagglutinin assay (iha) for echinococcosis was strongly positive with a titre of 1 in 1024. the patient was diagnosed with hiv eight years ago and was currently virologically suppressed with a cd4 cell count of 500 cells/ul on first-line antiretroviral therapy (tenofovir, emtricitabine and efavirenz).5 she had been successfully treated for tuberculous arthritis eight years ago and, according to the patient, has been adherent to antiretroviral therapy since diagnosis. obstetric history revealed four full-term pregnancies and one first trimester miscarriage. the first two pregnancies were normal vaginal deliveries and the latter two were caesarean sections due to cephalopelvic disproportion. the patient was otherwise well and had no previous hospital admissions, treatment of parasitic infections or anaphylactic reactions and, to her knowledge, this was her first diagnosis of hydatid disease. she grew up in a rural village in the eastern cape, but resided in katlehong, gauteng. a multidisciplinary team, including specialists from the high-risk maternity unit, hepatobiliary surgery and infectious diseases was quickly formed to plan the patient’s further management. on discussion with obstetricians at the high-risk maternal clinic, it was decided that it was safer to deliver the patient at 36 weeks as opposed to later on so as to avoid spontaneous labour (uterine contractions) as far as possible, in order to prevent cyst rupture due to the sheer size of the cysts. the compressive nature of the splenic hydatid disease was already causing subjectively worsening symptoms for the patient as her pregnancy progressed. the delivery at 36 weeks allowed the patient to receive five days of oral albendazole and a planned caesarean section could take place with assisted forceps delivery in order to avoid fundal pressure as much as possible. the foetus was of adequate size according to late ultrasound and showed no signs of intra-uterine growth restriction and thus every possible measure was made to achieve a balance between avoiding cyst rupture and ensuring safety of the foetus. there were no complications peri-operatively and a healthy infant was delivered. following the procedure, the patient continued albendazole 400 mg orally twice daily for six weeks. the discharge plan included routine pre-splenectomy vaccinations and elective splenectomy. the patient was lost to follow-up due to financial reasons, but re-presented and is currently awaiting elective splenectomy. discussion regarding management of splenic hydatid disease, a multimodal approach is required and definitive surgery, by way of splenectomy, is considered the gold standard.6 this intervention however is controversial during pregnancy and the relative timing remains difficult due to the possible precipitation of preterm labour and abortion. the three treatment options available for splenic hydatid disease are: puncture, aspiration, injection of protoscolicidal agent and re-aspiration (pair); oral antiparasitic therapy (using either albendazole alone, or in combination with praziquantel) or surgery (total splenectomy or spleen-conserving treatment).6 a review showed that, of these approaches, pair was used the least although this approach could be most beneficial in patients with cysts of a relatively small diameter (< 50 mm), patients with splenic hydatid cysts of type i or ii gharbi ultrasound classification or patients who refuse surgery or pose a high anaesthetic risk.6 of note, albendazole was used in conjunction with the pair approach in order to reduce cyst size and decrease subsequent risk of an anaphylactic reaction and recurrence.6,7 the use of pharmacological therapy as a primary treatment modality in splenic hydatid disease is discouraged.6 total splenectomy is preferred when more than 75% of the spleen is involved, when multiple cysts occur or when there are centrally located cysts.6 despite the vast number of publications on echinococcosis, there remain only a few cases related to pregnancy and the incidence is thought to be as low as 1 in 20 000–30 000.8 this lack of data has resulted in the lack of consensus on an internationally standardised approach to treatment.9 even more obvious is the lack of publications relating to splenic hydatid disease in pregnancy as most of the cases described involve the liver or lungs. a case report from israel described the management of isolated splenic hydatid disease in pregnancy; however the patient was at five weeks’ gestation and management included termination of the pregnancy on presentation.10 it is important to note that due to the decreased cell-mediated immunity during pregnancy, there may be a rapid increase in parasitic growth and size of the cysts leading to critical complications such as rupture, compression of adjacent structures or communication with the biliary tree when hepatic hydatid disease is present.9,11,12. the enlarging uterus may cause pressure on the cysts, increasing the risk of cyst rupture, inevitable dissemination and possible spillage into the peritoneal cavity and subsequent anaphylaxis.9,12 hydatid disease in pregnancy may result in significant maternal morbidity and possible mortality, as described by robertson et al. in a case of a potentially preventable maternal death in south africa, due to complications of hydatid cysts rupture.13 surgical intervention of the cysts during the latter stages of pregnancy carries a greater chance of cyst rupture and may potentially precipitate early onset labour.9 due to the limited data available in managing splenic hydatid disease in pregnancy, experts suggest a case-by-case assessment.7,9 albendazole should be avoided in the first trimester due to potential teratogenic effects and all invasive therapeutic interventions that are deemed necessary should ideally be performed at 20–24 weeks gestation.10 anti-helminthic drugs are considered safe in the latter stages of pregnancy; however, in the published studies where albendazole had been used in obstetric patients, the reported doses used were far lower than those required in hydatid disease.13 medical management alone may be required in certain instances where the patient refuses surgical intervention, such as the case described by tyagi et al. where albendazole was shown to reduce the size of daughter cysts although it had a limited affect in cyst reduction where the cysts were large.14 despite a number of successful case reports, there is currently no data available to support medical treatment alone for hydatid disease in pregnancy.13 hydatid disease has a post-surgical recurrence rate of about 10%; however, this risk is increased when the surgical procedure is performed in pregnancy.7 this is thought to be due to the decrease in cell-mediated immunity in the gravid state.7 peritoneal recurrence can even present 4–15 years after splenectomy.15 the potential use of exogenous steroids has been explored in hydatid disease. this would be especially relevant if steroids were indicated in possible preterm labour, prior to foetal lung maturity. a case by diem et al. demonstrated the harmful effect of steroids in hydatid disease in a patient where alveolar echinococcus disease was accelerated after the patient was given steroids for autoimmune encephalitis.16 the evidence is, however, limited, as only alveolar involvement was discussed. it was also suggested by romano et al. that the growth, differentiation and performance of certain parasitic species is enhanced by corticosteroids; however, this observation was based on in vitro studies and has not yet been demonstrated clinically in patients with splenic hydatid disease.17 however, observational studies have suggested the benefit of using peri-operative steroids to ameliorate potential anaphylactic reactions from cyst rupture in cases where surgery is the definitive treatment option.18,19 although there is possible benefit from using steroids during the peri-operative phase of treatment, there is still potential for harm and there is currently no conclusive evidence to support their use in hydatid disease during pregnancy. the use of steroids should be considered on a case-by-case basis. the prevention of hydatid disease in endemic areas could be achieved by education regarding the modes of transmission of the disease and simple hygiene techniques when working with sheep viscera and in areas where dogs frequent.1 the stage of the disease was advanced in our patient and highlighted the indolent nature of the disease process. therefore, emphasis needs to be placed on prevention of infection in endemic areas at an early age, rather than targeting prevention in pregnant women. symptoms of pregnancy such as nausea, vomiting and abdominal discomfort may mimic abdominopelvic hydatid disease and therefore a high index of suspicion, especially in an endemic area like south africa, is required. in our case review, due to the impending rupture of the cysts and the isolated splenic involvement, we believed a multi-step approach would be best for adequate management. delivery via elective caesarean section with assisted forceps at 36 weeks’ gestational age, avoided, as far as possible, spontaneous uterine contractions with further pressure-related complications on the cysts. due to > 90% of the spleen being involved, a total splenectomy was deemed safer than other surgical techniques. albendazole was utilised as an adjunctive pharmacologic therapy in order to prevent recurrence of the disease. conclusion hydatid disease in pregnancy may result in significant maternal morbidity and possible mortality due to complications of hydatid cyst rupture.13 there remains no standardised guideline for the management of hydatid disease in pregnancy and therefore the management of each case should be individualised. a multidisciplinary team was formed early due to the immediate concern for complications in both the mother and the foetus. the late presentation to a specialised facility left limited time for decision-making. our aim in describing this patient’s unique presentation and subsequent successful management of her delivery is to contribute to the knowledge base of managing splenic hydatidosis in late pregnancy. clinicians managing cases of hydatid disease in specific patient populations, such as pregnancy, should be encouraged to document them in order to contribute to knowledge in this important and neglected area. acknowledgements for input on the clinical management of the patient, the authors wish to acknowledge dr john devar and dr mary adam. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this case report. authors’ contributions k.f.t. compiled the case report, and d.l.r. and f.m. contributed to its completion. ethical considerations ethical clearance for this case report was obtained from the university of the witwatersrand human research ethics committee (m2011149). funding information this case report received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability data sharing is not applicable to this article, as no new data were created or analysed in this case report. disclaimer the views and opinions expressed in this case report are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references brunetti e, filice c. echinococcosis hydatid cyst [homepage on the internet]. emedicine.medscape.com; 2021 [cited 2020 jan 24]. available from: https://emedicine.medscape.com milosavljevic v, veselinovic m, tadic b, et al. laparoscopic management of initially unrecognized splenic hydatid cysts: a case report and review of the literature. medicina. 2019;55(12):771. https://doi.org/10.3390/medicina55120771 kloppers c, couzens-bohlin k, bernon m, et al. hydatid disease in south-africa – is it a different disease in patients with hiv co-infection?. hpb. 2019;21(suppl 3):s593. https://doi.org/10.1016/j.hpb.2019.10.235 bohlin k, kotze u, lindemann j, et al. impact of hiv co-infection in patients presenting with hepatic hydatid disease. hpb. 2020;22(suppl 2):s256. https://doi.org/10.1016/j.hpb.2020.04.140 national department of health: south africa. 2019 art clinical guidelines for the management of hiv in adults, pregnancy, adolescents, children, infants and neonates [homepage on the internet]. national institute of communicable disease; 2021 [cited 2020 jan 20]. available from: https://www.nicd.ac.za/wp-content/uploads/2019/11/2019-art-clinical-guidelines-25-nov.pdf akbulut s, sogutcu n, eris c. hydatid disease of the spleen: single-center experience and a brief literature review. j gastroenterol. 2013;17(10):1784–1795. https://doi.org/10.1007/s11605-013-2303-5 bhattacharyya s, bhattacharya s, alam h, patua b, chattopadhyay p. dilemmas encountered while dealing a pregnancy complicated by pelvic hydatid disease. arch gynecol obstets. 2013;288(5):965–966. https://doi.org/10.1007/s11605-013-2303-5 can d, oztekin o, oztekin o, tinar s, sanci m. hepatic and splenic hydatid cyst during pregnancy: a case report. arch gynecol obstets. 2003;268(3):239–240. https://doi.org/10.1007/s00404-002-0348-x rodrigues g, seetharam p. management of hydatid disease (echinococcosis) in pregnancy. obstet gynecol surv. 2008;63(2):116–123. https://doi.org/10.1097/ogx.0b013e3181601766 saher sf, sayfan j. echinococcosis of the spleen during pregnancy. imaj. 2006;3:290–291. celik s, okyay o, karaman e, sert oz, clm n, okyay t. analysis of factors affecting outcomes of pregnancy complicated by echinococcus: an algorithm for approach and management. arch gynecol obstets 2018;1:103–110. https://doi.org/10.1007/s00404-018-4792-7 sahin e, nayki u, sadik s. abdominal and pelvic hydatid disease during pregnancy. arch gynecol obstet. 2005; 273:58–59. https://doi.org/10.1007/s00404-004-0679-x robertson m, geerts l, gebhardt g. a case of hydatid cyst associated with postpartum maternal death. ultrasound obstet gynecol. 2006;27(6):693–696. https://doi.org/10.1002/uog.2763 tyagi s, singh c, tripathi r, mala y. pregnancy complicated by abdominopelvic hydatid disease. bmj case rep. 2012;2012:bcr2012007880. https://doi.org/10.1136/bcr-2012-007880 rodrigues-leal ga, moran-villota s, milke-garcia lnm. splenic hydatidosis: a rare differential diagnosis in a cystic lesion of the spleen. rev gastroenterol mex. 2007;72:122–125. diem s, gottstein b, beldi g, semmo n, diem l. accelerated course of alveolar echinococcosis after treatment with steroids in a patient with autoimmune encephalitis. cureus. 2021;13(10):e18831. https://doi.org/10.7759/cureus.18831 romano m, jiménez p, miranda-brito c, valdez r. parasites and steroid hormones: corticosteroid and sex steroid synthesis, their role in the parasite physiology and development. front neurosci. 2015;9:224. https://doi.org/10.3389/fnins.2015.00224 gupta r, sharma s, prabhakar g, mathur p. hydatid disease in children: our experience. formosan j surg. 2014;47(6):211–220. https://doi.org/10.1016/j.fjs.2014.12.001 tercan m, tanriverdi t, kaya a, altay n. our clinical experience and follow-up results in hydatid cyst cases: a review of 393 patients from a single center. braz j anesthesiol. 2020;70(2):104–110. https://doi.org/10.1016/j.bjan.2019.12.013 abstract introduction acknowledgements references about the author(s) david b. meya department of research, infectious diseases institute, makerere university, kampala, ugandadepartment of medicine and international health, university of minnesota, minneapolis, united states of america lillian tugume department of research, infectious diseases institute, makerere university, kampala, uganda vennie nabitaka hiv department, clinton health access initiative, kampala, uganda proscovia namuwenge department of hiv care and treatment, ministry of health, uganda, kampala, uganda sam phiri hiv department, lighthouse trust malawi, lilongwe, malawi rita oladele college of medicine university of lagos, lagos, nigeria bilkisu jibrin department of hiv care, treatment and support, ministry of health, lagos, nigeria mojisola mobolaji-bello department of hiv care, treatment and support, ministry of health, lagos, nigeria cecilia kanyama department of medicine, university of north carolina project-malawi, kamuzu central hospital, lilongwe, malawi werner maokola national aids control program, ministry of health, tanzania, dar-es-saalam, tanzania sayoki mfinanga department of research, muhimbili medical research centre, dar-es-salaam, tanzania cordelia katureebe department of national hiv care and treatment, ministry of health, kampala, uganda ikechukwu amamilo global health access program, clinton health access initiative, abuja, nigeria brian ngwatu hiv program, clinton health access initiative, kampala, uganda joseph n. jarvis department of hiv, london school of hygiene and tropical medicine, london, united kingdom thomas s. harrison centre for global health, institute for infection and immunity, st. george’s university of london, london, united kingdom amir shroufi department of hiv, centres for disease control foundation, atlanta, united states of america radha rajasingham department of medicine and international health, university of minnesota, minneapolis, united states of america david boulware department of medicine and international health, university of minnesota, minneapolis, united states of america nelesh p. govender department of research, national institute for communicable diseases, johannesburg, south africa angela loyse department of research, centre for global health, institute for infection and immunity, st. george’s university of london, london, united kingdom citation meya db, tugume l, nabitaka v, et al. establishing targets for advanced hiv disease: a call to action. s afr j hiv med. 2021;22(1), a1266. https://doi.org/10.4102/sajhivmed.v22i1.1266 opinion paper establishing targets for advanced hiv disease: a call to action david b. meya, lillian tugume, vennie nabitaka, proscovia namuwenge, sam phiri, rita oladele, bilkisu jibrin, mojisola mobolaji-bello, cecilia kanyama, werner maokola, sayoki mfinanga, cordelia katureebe, ikechukwu amamilo, brian ngwatu, joseph n. jarvis, thomas s. harrison, amir shroufi, radha rajasingham, david boulware, nelesh p. govender, angela loyse received: 14 may 2021; accepted: 27 june 2021; published: 10 aug. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract the world health organization (who) has published a guideline for the management of individuals with advanced hiv disease (ahd) to reduce hiv-related deaths. the guideline consists of a package of recommendations including interventions to prevent, diagnose and treat common opportunistic infections, including tuberculosis (tb), cryptococcosis and severe bacterial infections, along with rapid initiation of antiretroviral treatment and enhanced adherence support. currently no clear targets exist for these key interventions. emerging programmatic data from uganda, tanzania and nigeria suggest that an estimated 80% of eligible people continue to miss the recommended cryptococcal or tb testing, highlighting the remaining challenges to the effective implementation of who-recommended ahd packages of care in real-world resource-limited settings. the absence of mortality indicators for the leading causes of hiv-related deaths, because of the lack of mechanisms to ascertain cause of death, has had a negative impact on establishing interventions to reduce mortality. we suggest that setting 95-95-95 targets for cd4 testing, cryptococcal antigen and tb testing, and treatment that are aligned to the who ahd package of care would be a step in the right direction to achieving the greater goal of the who end tb strategy and the proposed new strategy to end cryptococcal meningitis deaths. however, these targets will only be achieved if there is healthcare worker training, expanded access to bedside point-of-care diagnostics for hospitalised patients and those in outpatient care who meet the criteria for ahd, and health systems strengthening to minimise delays in initiating the who-recommended therapies for tb and cryptococcal disease. keywords: advanced hiv disease; cryptococcal antigen; tuberculosis; tb-lam; targets. introduction in 2017, the world health organization (who) published a guideline for the management of individuals with advanced hiv disease (ahd) (defined as having a cd4 count of < 200 cells/µl or hiv stage 3 or 4 disease in adults and adolescents or children younger than 5 years), as part of the strategy to reduce hiv-related deaths.1 this guideline outlines a package of care for persons with ahd and includes interventions to prevent, diagnose and treat common opportunistic infections (ois), including tuberculosis (tb), cryptococcosis and severe bacterial infections, along with rapid initiation of antiretroviral treatment (art) and enhanced adherence support. although the united states (us) centers for disease control and the us president’s emergency plan for aids relief facilitate implementation of the who guideline on the ahd package of care in many sub-saharan african countries, especially in settings with a high number of persons with ahd, no clear targets exist for these key interventions to reduce ois and mortality in persons with ahd. such targets should include the proportion of persons accessing cd4 testing, persons with a cd4 count of < 200 cells/µl who are screened for tb and cryptococcal disease, and co-infected persons subsequently started on therapy (table 1). these targets are akin to the broader 95-95-95 targets of the joint united nations programme on hiv/aids (unaids): to achieve by 2030 95% of persons tested for hiv, 95% of those hiv-positive started on art and 95% of those on art attaining virological suppression. table 1: the basic indicators for advanced hiv disease care. despite the reduction in hiv-related deaths by 39% since 2010, nearly 700 000 hiv-related deaths occurred in 2019,2 with hiv-related illness remaining the leading cause of death in sub-saharan africa. notwithstanding the rapid roll-out of art globally, data from south africa show that about a third of individuals entering or cycling in and out of hiv care have advanced disease, with minimal change over the last decade.3 similarly, in uganda and botswana approximately 20% – 25% of persons entered care with advanced hiv in 2020.4,5 considering that most ahd is diagnosed among art-experienced persons,6 art non-adherence with treatment failure will remain a significant contributor to incident ois despite expanded art initiation.7 based on the who guidance, each person diagnosed with hiv should have a cd4 test performed.1 of those with a cd4 count of < 200 cells/µl, cryptococcal antigen (crag) and tb testing should be offered using a crag lateral flow assay (lfa) and xpert/tb lipoarabinomannan (lam) assay.1 those with evidence of disease (i.e. positive tests) should be started on appropriate treatment; for example, tb preventive therapy should be started for those with latent tb infection. in many countries, some steps in this cascade are not always executed. multiple reasons can exist for this failure to implement, including basic stock-outs of cd4 reagents, diagnostic test kits and the medicines required for oi treatment.8 there is a significant deleterious impact on ahd outcomes when only some of these resources and not all are available. in some cases, the implementation of these interventions is not prioritised by healthcare workers, who may have limited training on ahd management9 and consider these screening tests as less imperative compared to initiating art. in addition, weak health systems may result in greater attrition of persons entering hiv care even after a cd4 test, in the absence of tracking mechanisms to complete this cascade of care when they fail to return. many national programmes lack mortality indicators for the leading causes of hiv-related deaths, which is partly a result of poor data around ascertaining a cause of death. data from the last quarter of 2020 from the aids control programme of the ministry of health in uganda10 showed that only 36% of newly diagnosed hiv-infected patients received a cd4 test. of these, 25% met the definition of ahd with a cd4 count of < 200 cells/µl. subsequently, of those with ahd, 61% received crag testing (8% crag test positive), and 89% of crag-positive persons were then started on pre-emptive fluconazole. for tb screening, only 56% of those with a cd4 count of < 200 cells/µl received urine lam testing (19% positive for urine lam), and 92% of these received tb treatment. overall, this extrapolates to an estimated 80% having missed the recommended cryptococcal or tb screening. similarly, among persons with virological failure, 6% received cd4 testing, with 25% having a cd4 count of < 200 cells/µl. among those with cd4 testing, 73% received crag testing (12% crag test positive; 82% treated), and 74% received urine tb-lam testing (20% urine lam test positive; 80% treated).11 a gap in knowledge remains for the oi prevalence among those persons returning to care after attrition. there are challenges in obtaining data on longer-term disease outcomes among persons who screened for these ois during the cascade of ahd management. however, cryptococcal survival outcomes remain 30% – 40% better when crag-positive persons are pre-emptively treated while asymptomatic, rather than treating symptomatic meningitis.12 data from a retrospective cohort in mwanza, tanzania, of 700 participants showed that 261 (35%) had who stage 3 and 4 hiv disease, and 258 (35%) had baseline cd4 counts of < 200 cells/µl.13 these programmatic data in tanzania show a similar trend to data reported from uganda. among persons who initiated art in 2018, 21% had who clinical stage 3 or 4, and 31% had a cd4 count of < 200 cells/µl.14 in this cohort, the mortality rates decreased with increasing cd4 count at enrolment. persons with a cd4 count of < 200 cells/µl had a high mortality rate of 61.69 per 1000 person/year, compared to the mortality rate of 18.01 per 1000 person/year for those enrolled with cd4 counts of ≥ 350 cells/µl (mortality rate ratio: 3.43). the data also showed a higher mortality rate of 117.03 per 1000 person/year for those enrolled with who clinical stage 4, compared to the mortality rate of 53.25 per 1000 person/year for patients enrolled with who clinical stage 3 (mortality rate ratio 2.20). the nigerian national 2020 data for people living with hiv and on active tb on treatment is 83.5%,15 while there are currently no data from the nigeria repository on crag and urine tb-lam testing. however, preliminary data from a pilot ahd implementation project at a large art centre (lagos university teaching hospital, lagos, nigeria) revealed that from august 2020 to january 2021, 47.9% (69/144) of newly enrolled people living with hiv had a cd4 count of < 200 cells/µl, with all receiving reflex crag screening and 65 (94.2%) receiving tb lateral flow lam testing. sub-saharan africa bears the brunt of hiv-associated ois, with an estimated 162 500 cases of cryptococcal meningitis in 2014 (73% of the global burden) and 135 900 deaths (75% of the estimated global burden).16 in 2019, of the 1.4 million tb-related deaths that occurred, 208 000 were among people living with hiv.17 the who end tb strategy is designed with the aim of achieving a 90% decrease in tb deaths by 2030.18 as a step towards achieving this goal, it is critical that persons with ahd be identified, screened and treated for tb in a timely manner. therefore, we suggest that setting targets for cd4 testing, crag and tb testing, and treatment, that are aligned to the who ahd package of care would be a step in the right direction to achieving the greater goal of the who end tb strategy and the proposed new strategy to end cryptococcal meningitis deaths.19 efforts should be aimed at ensuring that all individuals recently diagnosed with hiv, those returning to care or those who are not virologically suppressed have access to cd4 testing. prompt identification of persons at high risk in the setting of ahd remains important for minimising poor outcomes. the roll-out of the who-approved point-of-care visitect cd4 advanced hiv disease lfa by omega diagnostics (alva, united kingdom) provides an instrument-free, semi-quantitative result for cd4 (greater than or less than 200 cells/µl), which should be rapidly expanded; however, feasibility studies for point-of-care use in routine care settings are needed to inform placement and scale-up. unitaid and the clinton health access initiative have launched an early market access vehicle to provide access to this test at no cost in over 130 countries to determine operational feasibility in routine care settings.20,21 we further recommend that national hiv programmes set 95-95-95 targets for 95% of persons with a new hiv diagnosis, those returning to care or non-suppressed populations to receive cd4 testing, 95% of those with a cd4 count of < 200 cells/µl to be screened with crag and tb lam, and 95% testing crag or lam positive to be treated for those by 2030 (figure 1). these targets would apply to both outpatient and inpatient settings and spur the design and implementation of real-world interventions to reduce the morbidity and mortality complicating ahd. in addition, these targets will drive countries to establish mechanisms for tracking these targets as well as ahd-related mortality within their national reporting systems. we believe that these targets are achievable, given the progress towards the even more challenging unaids 95-95-95 targets set for 2030. figure 1: schematic detailing comparison between ideal ahd targets and current ahd indicator performance. in a crag screening model for uganda, rajasingham and colleagues suggested that crag screening and treatment (assuming a national crag prevalence of 1.4%) would save 7320 lives at a cost of $459.00 per life saved.22 in contrast, the cost of treating a person with ahd who develops cryptococcal meningitis using the current who-recommended regimen of amphotericin b and flucytosine for 1 week is $1861.00,23 making crag screening and fluconazole pre-emptive therapy a more cost-effective approach. menzies and colleagues similarly showed that expanding tb diagnostics and care access produced substantial health gains to achieve the goals set out in the end tb strategy, based on an analysis of nine cost-effectiveness models in china, india and south africa.24 we posit that these gains and cost savings can only be maximised if the ahd package is fully implemented with everyone who should receive cd4, crag and tb-lam testing, with the appropriate therapy for those diagnosed with disease. for instance, cost savings for crag screening would be maximised by screening individuals with a cd4 count of < 200 cells/µl with an expected prevalence of 6% – 7%16 as opposed to 1.4% in the general hiv population. this can be enhanced if point-of-care cd4 testing is implemented adequately as the next step following hiv testing. in order to achieve this, it is imperative that procurement and supply systems for the resources required, are coordinated efficiently while anchored within strong health systems and regular healthcare worker training. furthermore, implementation research is still required to improve clinical outcomes among patients with ahd, for example by evaluating the effectiveness and feasibility of performing lumbar punctures in those with a positive crag test result. the $20 million investment by unitaid through 2022 to avert preventable deaths among persons with ahd in eight african lowand middle-income countries and india is certainly a step in the right direction.25 participating countries should utilise the catalytic procurement of commodities to generate local evidence and leverage the programmatic support during the project period to ensure that ahd interventions are sustainable. furthermore, these interventions need to be expanded to other countries in sub-saharan africa and beyond 2022 through increased and coordinated demand for commodities through entities like institutional donors, along with expanded regular training and health systems strengthening. expanded access to bedside point-of-care diagnostics for hospitalised patients to minimise delays in initiating standard-of-care therapies (for tb and cryptococcal disease) would improve survival. however, waiting for persons with ahd to be hospitalised exposes weaknesses in the health system when ambulatory hiv care neglects essential interventions to prevent ahd complications. by prioritising training, mentorship and health systems strengthening such that outpatient clinicians have excellent clinical skills and are empowered with point-of-care diagnostics (e.g. cd4, crag, tb-lam) and adequate resources for optimal treatment, the proposed targets could be met, resulting in potentially fewer hospitalisations and ahd-related mortality. while ois will continue to occur screening and pre-emptively treating ois at an early stage in an outpatient setting is far less expensive than hospital care and results in better outcomes. we believe that establishing and implementing country-specific interventions to ensure that 95% of persons with a new hiv diagnosis or those without hiv viral suppression receive cd4 testing, 95% of persons with a cd4 count of < 200 cells/µl receive crag and tb-lam testing, and 95% of those with positive crag and lam tests initiate prompt treatment would go a long way in reducing hiv-related mortality. creating targets and ensuring accurate documentation of the metrics including ahd-related mortality would help national programmes focus efforts on addressing interventions to meet targets for optimal ahd care to minimise hiv-related deaths. acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions d.b.m. conceived the idea for this study. d.b.m., l.t and v.n. wrote the manuscript, with support from r.r., d.b., s.p., c. kanyama, i.a., b.n., j.n.j., t.s.h., a.s. and a.l. p.n., r.o, b.j., m.m.-b., s.m., w.m., n.p.g. and c. katureebe provided critical data for the manuscript. all authors provided critical feedback and helped shape the manuscript. ethical considerations this article followed all ethical standards for research without direct contact with human or animal subjects. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. authors d.b.m., r.r., d.r.b. and n.p.g. are supported by the national institute of allergy and infectious diseases (k23ai138851, r01ai118511 and u01ai125003). data availability the data that are reported in this manuscript are available from the ministries of health in uganda, nigeria and tanzania. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the author. references world health organization. guidelines for managing advanced hiv disease and rapid initiation of antiretroviral therapy. who guidelines approved by the guidelines review committee. geneva: who; 2017. unaids. global hiv & aids statistics – 2020 fact sheet. geneva: unaids; 2020. carmona s, bor j, nattey c, et al. persistent high burden of advanced hiv disease among patients seeking care in south africa’s national hiv program: data from a nationwide laboratory cohort. clin infect dis. 2018;66(suppl_2):s111–s117. https://doi.org/10.1093/cid/ciy045 ministry of health. consolidated guidelines for the prevention and treatment of hiv/aids in uganda. kampala: uganda ministry of health, 2020; p. 84–86. leeme tb, mine m, lechiile k, et al. utility of cd4 count measurement in the era of universal antiretroviral therapy: an analysis of routine laboratory data in botswana. hiv med. 2021;22(1):1–10. https://doi.org/10.1111/hiv.12951 osler m, hilderbrand k, goemaere e, et al. the continuing burden of advanced hiv disease over 10 years of increasing antiretroviral therapy coverage in south africa. clin infect dis. 2018;66(suppl_2):s118–s125. https://doi.org/10.1093/cid/cix1140 ellis j, bangdiwala as, cresswell fv, et al. the changing epidemiology of hiv-associated adult meningitis, uganda 2015–2017. open forum infect dis. 2019;6(10):ofz419. https://doi.org/10.1093/ofid/ofz419 lofgren sm, nalintya e, meya db, boulware dr, rajasingham r. a qualitative evaluation of an implementation study for cryptococcal antigen screening and treatment in uganda. medicine (baltimore). 2018;97(31):e11722. https://doi.org/10.1097/md.0000000000011722 vallabhaneni s, longley n, smith m, et al. implementation and operational research: evaluation of a public-sector, provider-initiated cryptococcal antigen screening and treatment program, western cape, south africa. j acquir immune defic syndr. 2016;72(2):e37–e42. https://doi.org/10.1097/qai.0000000000000976 uganda ministry of health. september – december 2020 – advanced hiv disease quarterly report. kampala: uganda ministry of health; 2020. aids control program. programatic data on advanced hiv disease cascade. kampala: ministry of health uganda; 2020. rhein j, huppler hullsiek k, tugume l, et al. adjunctive sertraline for hiv-associated cryptococcal meningitis: a randomised, placebo-controlled, double-blind phase 3 trial. lancet infect dis. 2019;19(8):843–851. gunda dw, nkandala i, kilonzo sb, kilangi bb, mpondo bc. prevalence and risk factors of mortality among adult hiv patients initiating art in rural setting of hiv care and treatment services in north western tanzania: a retrospective cohort study. j sex transm dis. 2017;2017:7075601. https://doi.org/10.1155/2017/7075601 national aids control program. hiv care and treatment report 2019. dar-es salaam: ministry of health, community development, gender, elderly and children; 2020. ministry of health. advanced hiv report, nigeria. lagos: nigeria ministry of health; 2020. rajasingham r, smith rm, park bj, et al. global burden of disease of hiv-associated cryptococcal meningitis: an updated analysis. lancet infect dis. 2017;17(8):873–881. https://doi.org/10.1016/s1473-3099(17)30243-8 fukunaga r, glaziou p, harris jb, date a, floyd k, kasaeva t. epidemiology of tuberculosis and progress toward meeting global targets worldwide, 2019. mmwr morb mortal wkly rep. 2021;70(12):427–430. https://doi.org/10.15585/mmwr.mm7012a4 chakaya j, khan m, ntoumi f, et al. global tuberculosis report 2020 – reflections on the global tb burden, treatment and prevention efforts. int j infect dis. 2021:s1201–9712. https://doi.org/10.1016/j.ijid.2021.02.107 stott ke, loyse a, jarvis jn, et al. cryptococcal meningoencephalitis: time for action. lancet infect dis. 2021. https://doi.org/10.1016/s1473-3099(20)30771-4 clinton health access. clinton health access initiative. unitaid and chai announce agreement with omega diagnostics to increase access to new, instrument-free cd4 test for people living with hiv in over 130 lowand middle-income countries [homepage on the internet]. [cited 2021 apr 2021]. available from: https://wwwclintonhealthaccessorg/unitaid-and-chai-announce-agreement-with-omega-diagnostics-to-increase-access-to-new-portable-cd4-testing-device-for-people-living-with-hiv-in-over-130-low-and-middle-income-countries. clinton health access initiative. early market access vehicle for visitect® cd4 advanced disease test [homepage on the internet]. [cited 2021 apr 21]. available from: https://wwwclintonhealthaccessorg/early-market-access-vehicle-for-visitect-cd4-advanced-disease-test/ rajasingham r, meya db, greene gs, et al. evaluation of a national cryptococcal antigen screening program for hiv-infected patients in uganda: a cost-effectiveness modeling analysis. plos one. 2019;14(1):e0210105. https://doi.org/10.1371/journal.pone.0210105 chen t, mwenge l, lakhi s, et al. healthcare costs and life-years gained from treatments within the advancing cryptococcal meningitis treatment for africa (acta) trial on cryptococcal meningitis: a comparison of antifungal induction strategies in sub-saharan africa. clin infect dis. 2019;69(4):588–595. https://doi.org/10.1093/cid/ciy971 menzies na, gomez gb, bozzani f, et al. cost-effectiveness and resource implications of aggressive action on tuberculosis in china, india, and south africa: a combined analysis of nine models. lancet glob health. 2016;4(11):e816–e826. unitaid invests to cut hiv-related deaths [homepage on the internet]. n.d. [cited 2021 mar 22]. available from: https://unitaid.org/unitaid-invests-to-cut-hiv-related-deaths/#en medecins sans frontieres. advanced hiv disease toolkit [homepage on the internet]. 2020. available from: https://samumsforg/sites/default/files/2019-07/opd%20ahd%20indicators_version%202pdf2020 executive message from the executive by the time you read this, there will be a new board for the society, a new president and a new memorandum of association (legal speak for a constitution) for the society in place. we hope that there will be a new ceo as well, from the beginning of next year. the prior executive and interim board have created a strong, well-run organisation, and the new board will be responsible for making it even better. it has been a pleasure working with this executive, as well as with the office staff and a host of unpaid helpers. we look forward to 2012 being a very good year! francois venter references about the author(s) yunus moosa department of medicine, faculty of internal medicine, university of kwazulu-natal, durban, south africa, south africasouthern african hiv clinicians society, johannesburg, south africa lauren jankelowitz southern african hiv clinicians society, johannesburg, south africa citation moosa y, jankelowitz l. editorial: celebrating 21-year anniversary and introducing the 21st anniversary issue. s afr j hiv med. 2021;22(1), a1317. https://doi.org/10.4102/sajhivmed.v22i1.1317 editorial celebrating 21 years and introducing the 21st anniversary issue yunus moosa, lauren jankelowitz copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. the southern african journal of hiv medicine (sajhivmed) is focused on hiv, in particular disease prevention and treatment, and includes topics relevant to clinical and public health practices. the primary purpose of the sajhivmed is to disseminate original research; however, the journal also includes editorials, case reports and series, clinical reviews, evidence based clinical practice guidelines, national guidelines, and other correspondence relevant to the field of hiv. it has been 21 years since the inaugural publication of the sajhivmed in june 2000. up until 2016, the journal was published quarterly. since then, articles have been published online as they become available, with all the articles compiled into a single printed copy at the end of the year. supplements have been published intermittently to address special themes or mark events, such as the southern african hiv clinicians society’s (sahcs’) biennial conference. since 2020 and the onset of the covid-19 pandemic, annual editions have been published as online e-books only. during the past 21 years, over 660 articles, 50 guidelines and 45 case reports have been published in the journal, covering diverse areas ranging from basic science to clinical practice within the field of hiv, as well as areas closely related to the field. authors and contributors range from local to the southern african region, to global experts, providing the journal with a vast breadth of varied inputs. the sajhivmed, which already boasted scientific electronic library online south africa (scielo sa); scopus; clarivate analytics web of science core collection, science citation index expanded (scie/isi [institute for scientific information]); african index medicus; african journals online; directory of open access journals; ebscohost; embase; gale, cengage learning; google scholar; and proquest indexing, and was added to the norwegian register for scientific journals, series and publishers, level 1, in 2017, was awarded pubmed central accreditation status in 2018. by being an open access journal, all content is freely available at no cost to the reader or institution. in accordance with international best practice and in alignment with the budapest open access initiative (boai; https://www.budapestopenaccessinitiative.org/), users are allowed to read, download, copy, distribute, print, search or link to the full texts of the articles, or use them for any other lawful purpose, without asking prior permission from the publisher or the author. following confirmation of all relevant documentation, such as ethics clearance, the manuscript is then reviewed initially by the editor-in-chief with a view to establishing appropriateness of scope for the journal. following this the blinded manuscript is assigned to at least 2 independent external reviewers. reviewer feedback is then sent to the authors and a process of finalisation begins between the author/s and the editors. at the time of the launch of the journal in 2000, prof. des martin (mbbch, mmed, fcpath, dtm&h, dph), the first president of the sahcs and the first editor-in-chief of the sajhivmed wrote: this first issue of the southern african journal of hiv medicine coincides with the international aids conference in durban, sa, and it is hoped that it will find a place in the reading of medical, scientific and allied professionals dealing with hiv disease in our region. it is also hoped that it will receive broader recognition amongst the international community, which is urged to engage actively in the discourse surrounding the epidemic in our region.1 he went on to say: the journal will provide a home for original scientific articles, review articles and continuing medical education and will also provide a forum for debate and discussion on the topical issues of the day.1 prof. des martin (figure 1), now retired to mpumalanga, was involved in the field of hiv medicine at various levels for over 35 years. martin held a number of prestigious positions, including past president of sahcs from 1998 to 2008; editor-in-chief of the sajhivmed; deputy director of the national institute for virology; convenor of examiners for the colleges of medicine of south africa; chair of the basic sciences track at the 13th international aids conference, durban, sa, in 2000; visiting professor johns hopkins hospital baltimore (1998); and professor in the department of clinical virology, faculty of health sciences, university of pretoria. figure 1: prof. des martin, founding editor of the southern african journal of hiv medicine, may 2021, with his framed copy of the first edition. in may 2021, prof. martin (personal communication) commented that: ‘the southern african journal of hiv medicine was born in july 2000, as it was launched at the ias durban 2000 international aids conference. these were particularly vexed times in the local hiv/aids arena because of the intense activity of the “aids dissidents” who had found favour with a number of prominent persons in south africa and beyond. the “durban declaration” was formulated by a number of the foremost hiv scientists of the day, including many from the society, which effectively countered the misinformation spread by the dissidents. the journal has now “come of age” and continues to provide education, teaching, dissemination of the results of the latest local research and much more to the hiv-community of our region, and indeed, of africa. congratulations to all who contribute to the publication of the journal.’ there have been a further five editors-in-chief, all of whom have contributed immensely to the growth and credibility of the sajhivmed. dr shaun conway, who co-created the journal, spent a brief time as its first managing editor whilst serving as the director of sahcs. he was also the founder of right-to-care, co-founder of re-action! and founded numerous digital innovation start-ups. he worked as an advisor to the world health organization (who), and as the hiv and health systems advisor to the uk department for international development. building on his extensive experience in hiv, global health and international development, dr conway has been building ixo (https://ixo.world), an ambitious project to create a blockchain-based internet of impact, which he describes as a ‘global digital immune system for humanity’. dr conway, expressing surprise at how quickly the years have flown by, sent his heartfelt congratulations to sahcs and the sajhivmed for it’s milestone of 21 years. dr conway’s tenure was followed by prof. linda-gail bekker (mbchb, dtmh, dch, fcp[sa], phd), who is deputy director of the desmond tutu health centre at the institute of infectious disease and molecular medicine at the university of cape town (uct) and chief operating officer of the desmond tutu health foundation. bekker is a physician-scientist and infectious disease specialist focusing on programmatic and action research around antiretroviral rollout, tuberculosis (tb) integration, and hiv prevention in key populations. she is principal investigator of the uct clinical trials unit funded by the us national institutes of health, and is actively involved in the work of its associated clinical research sites and networks. she has chaired protocols for the hiv vaccine trials network and hiv prevention trials network and has been the investigator of record in a number of network-related protocols. prof. bekker has served on numerous national, international and federal scientific and working committees, and is the current chair of the sahcs pre-exposure prophylaxis (prep) and post-exposure prophylaxis (pep) guidelines. bekker leads the desmond tutu centre of adolescent health and wellbeing at uct, which aims to develop evidence-based best practices around adolescent treatment and prevention of hiv, tb and sexually transmitted infections (stis), including the integration of these services within a robust, adolescent-friendly sexual and reproductive service platform. she was president of the international aids society from 2016 to 2018. prof. bekker, as sajhivmed editor-in-chief, wrote at the start of 2005 that: since inception of the journal in july 2000 an impressive list of guidelines has been compiled and peer reviewed by local experts. this year will also see the journal launched online, increasing accessibility of previous guidelines and journal articles.2 prof. bekker was the editor until late 2011 and has remained involved with the direction of the journal by sitting on the editorial board of the sajhivmed since then. prof. bekker reminisced earlier this year that (personal communication, 2021): ‘the wonderful – and persuasive – des martin asked me to take this important role on when i was a relatively green-about-the ears hiv doctor and researcher. i was both thrilled and honoured and i loved the experience. my small role in the development of this important publication and its future wellbeing is something i am really proud to be counted a part of. i recall being particularly obsessed about getting the pubmed accreditation and understanding how that system worked. i’m delighted it has grown in both circulation and significance under the great curatorship of the recent editors.’ prof. landon myer (mbbch, phd), who followed prof. bekker in the role of editor, is director and head of the school of public health and family medicine at the uct. he had undergone training in social anthropology, clinical medicine and epidemiology. his research study focuses on women’s, maternal and child health in the context of hiv, which includes behavioural, clinical and health systems research. he has led multiple clinical and health systems studies investigating the health of hiv-infected women receiving antiretroviral therapy (art) during pregnancy and postpartum, as well as the health and development of hiv-exposed and -infected children and adolescents. within the school, he is professor and head of the division of epidemiology & biostatistics, teaches epidemiological methods and is an academic convenor of the master’s in the public health programme. in prof. myer’s first editorial in 2011, he wrote that he was: [l]ooking forward to continuing the journal’s emphasis on presenting research and clinical experiences from across the region, and keeping readers updated around local and international developments … by seeking to expand several sections, including: feedback reports from local and international conferences; editorial reviews intended to share viewpoints and promote discussion on important topics; and programmatic reports that share local experiences in implementing hiv treatment and prevention services on the ground.3 at the start of 2014, prof. myer whilst introducing a special anniversary edition, to mark 10 years of art in the public sector, commented that: in considering the hiv epidemic and its impact, many of our anniversaries are sad ones … clinicians or scientists may mark the anniversary of the first documented aids case in a country, or the discovery of the virus itself, but these aren’t generally moments for celebration per se. so, it’s not often that we have cause to smile about an anniversary related to the epidemic. however, 1 april 2014 marks one happy anniversary worth remembering – a decade of antiretroviral therapy (art) in the public sector. like many anniversaries, the exact details can depend on where you were, and sometimes dates themselves can be fuzzy. antiretrovirals were available from the 1990s in the private sector, and a trickle was accessible through trials and small donor-funded initiatives in urban centres from the early 2000s. some provinces moved more quickly towards making art available ahead of the national department of health, often with the assistance of partners in local and international non-governmental organisations. after the announcement of a national rollout of art in public sector facilities, some hospitals received supplies of antiretrovirals within weeks. elsewhere, especially in clinics in rural settings, health services took years to have local providers dispensing art. today the number of facilities dispensing art is expanding still, but most communities across the country have reasonable access, and art coverage continues to increase.4 prof. myer, reminiscing about his time as editor and the sajhivmed, said in 2021 (personal communication, sept 9): ‘another happy anniversary, worth pausing a moment to celebrate. the position of the sahcs, and with it the journal, has shifted in the health landscape in south africa – paralleling the shifting position of hiv – from addressing a single, specialised and focused health topic, to a cross-cutting, mainstream institution of sorts that is concerned with the health landscape of the country. it’s an incredible recognition of the central place of hiv in our health system and services – there is no concern that is more integral to our primary healthcare system than hiv and its associated conditions. it’s a credit in great part to the work of sahcs. congratulations to sahcs and sajhivmed for continuing to provide important clinical updates, news and research, and being a leading voice of reason over the past 2 decades.’ dr michelle moorhouse (mbbch, da, frsph) is a senior global medical director at viiv healthcare. prior to this, she worked at ezintsha as head of treatment strategies (2014–2019), where she was the co-principal investigator on the large advance study as well as working on other hiv treatment optimisation studies, policies and guidelines. moorhouse was awarded an honorary clinical fellowship at the royal free hospital in london in 2003. returning to south africa in 2007, she re-established her general and hiv practice and set up a research centre focusing on hiv clinical trials, whilst consulting at an hiv clinic for an eastern cape based non-profit organisation (npo). she served as a sahcs board member between 2012 and 2018 and became a member of the editorial board of hiv nursing matters, shortly before becoming editor of the sajhivmed between 2015 and 2018. her career has been focussed on making a difference in the lives of people affected by hiv (moorhouse m, 2021, personal communication, sept 9): ‘we always think of 21 as a “coming of age” or achieving maturity. i think the sajhivmed is an exception to this, in that right from the start it was clearly a powerful publication that has delivered high quality research, informative guidelines and great educational reads from which i personally have learned so much. a testament to the high calibre of the journal is the fact that it is listed on pubmed, which is a great achievement and one of which to be exceedingly proud. it was my great pleasure and privilege to be at the helm for a short while and i wish the journal continued growth over the next 21 years.’ finally, in his first editorial mid-2019, dr dave spencer (mbchb, mmed, dtm&h), current editor-in-chief, summarised several key articles, so as to encourage journal readership, and stated that: the articles address contemporary and regional issues in hiv medicine. the topics speak to all aspects of the epidemic: epidemiology, public health, prevention, clinical medicine, tuberculosis and opportunistic diseases, management guidelines, opinion pieces, editorials, and case reports. for the teachers, trainers, healthcare managers and administrators among us, there is a wealth of local information in these papers. please acknowledge our talented researchers by reading what they write.5 dr spencer is a specialist physician who started treating hiv patients formally whilst completing a 2-year infectious diseases fellowship at case western reserve university in the united states, 1988–1990. in 1991, he took over as head of the hiv clinic of the johannesburg general hospital. he was in private practice in johannesburg from 1997 until 2011. also trained in oncology and infectious diseases, spencer was thereafter the head of infectious diseases and ran the themba lethu hiv clinic at helen joseph hospital. dr spencer is renowned as a lecturer and teacher in the field of medicine that he loves. he is a sought-after speaker at continuing medical education (cme) meetings and other academic events. his book the clinical practice of hiv medicine (2005) is a primer on hiv care for doctors and a summation of his experience as a practitioner in this field and is to be found on the desks of many practitioners. he has always been committed to imparting his knowledge through lectures, guidelines and one-on-one teaching in his clinic; he has taught hiv medicine throughout africa, and many practitioners have benefitted from these sessions. owing to his background and beliefs, he has been able to instil the need for assessing the patient more broadly than just paying attention to the physical components of the disease. dr spencer has published extensively in the field of hiv and was a local lead investigator for several early studies of art. finally, he was a founding executive member of sahcs. recently retired, dr spencer currently serves as the editor-in-chief of the sajhivmed, and is a key content developer, expert reviewer, teacher and guidelines contributor at sahcs. dr. spencer, who continues to identify key articles and summarise these in ‘newsletters’ to sahcs’ members (2021, personal communication, september), often remarks: ‘the pages of the sajhivmed showcase many of the best of africa’s researchers and clinicians. original articles, opinion pieces, guidelines and reviews that emerge from the global epicentre of the hiv pandemic. what better place to understand the impact of an incurable disease on society and its people? what better place to do good and to influence the continent’s future?’ southern african hiv clinicians society is proud to publish this anniversary special edition. we express our sincerest gratitude to all the editors and peer reviewers who have contributed, and continue to contribute, to the growth of the journal. a special thanks to our authors whose impact on the sajhivmed continues to be felt. thanks are also due to our publishers, aosis, who have walked the last few years of the sajhivmed journey together with sahcs. prof yunus moosa southern african hiv clinicians society president dr lauren jankelowitz southern african hiv clinicians society chief executive officer references martin d. editorial. 2000. s afr j hiv med. 2000;1(1), a489. https://doi.org/10.4102/sajhivmed.v1i1.489 bekker l-g. looking back, looking forward. s afr j hiv med. 2005;6(1), a589. https://doi.org/10.4102/sajhivmed.v6i1.589 myer l. from the editor. s afr j hiv med. 2011;12(3), a175. https://doi.org/10.4102/sajhivmed.v12i3.175 myer l. message from the editor. s afr j hiv med. 2014;15(1), a28. https://doi.org/10.4102/sajhivmed.v15i1.28 spencer dc. editorial. s afr j hiv med. 2019;20(1), a1037. https://doi.org/10.4102/sajhivmed.v20i1.1037 abstract introduction methods measurements results discussion strengths and limitations conclusion and recommendations acknowledgements references about the author(s) motlalepula sebilo school of health systems and public health, faculty of health sciences, university of pretoria, pretoria, south africa elizabeth glaser pediatric aids foundation, maseru, lesotho neo r.t. ledibane school of health systems and public health, faculty of health sciences, university of pretoria, pretoria, south africa simbarashe takuva school of health systems and public health, faculty of health sciences, university of pretoria, pretoria, south africa perinatal hiv research unit, faculty of health sciences, university of the witwatersrand, johannesburg, south africa citation sebilo m, ledibane nrt, takuva s. incidence of cardiometabolic diseases in a lesotho hiv cohort: evidence for policy decision-making. s afr j hiv med. 2021;22(1), a1246. https://doi.org/10.4102/sajhivmed.v22i1.1246 original research incidence of cardiometabolic diseases in a lesotho hiv cohort: evidence for policy decision-making motlalepula sebilo, neo r.t. ledibane, simbarashe takuva received: 16 mar. 2021; accepted: 02 may 2021; published: 28 june 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: antiretroviral treatment (art) has been associated with the development of certain cardiometabolic diseases (cmds). the burden of cmds amongst art-experienced patients in sub-saharan africa was unknown. objective: we quantified the burden of cmds and identified the associated risk factors in a large treatment cohort on art at a high-volume facility in lesotho. methods: in this retrospective cohort study, we extracted data from the daily dispensing electronic system and routine clinical records of 785 adults on art between 2011 and 2015 in maseru, lesotho. cmd was defined as a diagnosis of hypertension, diabetes mellitus or dyslipidaemia (singly or collectively). descriptive statistics were used to describe the disease burden; kaplan–meier curves and cause-specific cox proportional hazards models were fitted to examine the impact of the art regimen and identify the risk factors associated with the occurrence of cmd. results: of the 785 participants, 473 (60%) were women. the median age of the group was 42 years, interquartile range (iqr), 36–51 years. the overall incidence of cmd was 5.6 (95% confidence interval [ci] = 4.4–7.1) per 100 person-months of follow-up. the median time to onset of cmd was 16.6 months (iqr = 7.4–23.4). art was not associated with the occurrence of cmd (cause-specific hazard ratio [chr] = 1.55; 95% ci = 0.14–16.85; p = 0.72). higher body mass index (bmi) was associated with the occurrence of diabetes mellitus (chr = 1.19; 95% ci = 1.14–1.38; p = 0.026). conclusion: the incidence of cmd in this relatively young patient population is low yet noteworthy. we recommend that patients living with hiv and aids should be routinely screened for cmd. higher bmi is generally associated with the occurrence of cmd. keywords: aids; antiretroviral treatment; cardiometabolic disease; hiv; incidence rate; lesotho. introduction sub-saharan africa (ssa) currently has the largest burden of hiv infection in the world and 69.65% of people living with hiv (plwh) were reported to be on antiretroviral treatment (art) in 2019.1 the countries with the highest burden of hiv include swaziland, botswana and lesotho, with approximately 25% of the general population infected.2 the uptake of art has been increasing annually with the scaling up of art services in response to the joint united nations programme on hiv/aids (unaids) 95-95-95 targets, where 95% plwh know their status, 95% of people who know their status are accessing treatment and 95% of people on treatment have suppressed viral loads.3 since the introduction of art, the survival and life expectancy of plwh have been enhanced, with approximately 19.1 million life-years being saved from 1990 to 2013.4,5 prolonged exposure to art, in addition to aging because of improved life expectancy, is associated with a higher risk of cardiometabolic diseases (cmds), which include dyslipidaemia, obesity, hyperglycaemia (diabetes mellitus) and hypertension. antiretroviral treatments, specifically protease inhibitors (pis), are associated with the accelerated progression of metabolic complications in plwh, while some non-nucleoside reverse transcriptase inhibitors (nnrtis) are also reported to have metabolic side-effects.6,7 since the introduction of art, approximately 4 million plwh have survived beyond 50 years of age.8 despite good management and control, elderly patients on art have a higher risk of cmds (which tends to appear approximately 10 years earlier than in hiv-uninfected individuals) compared to their counterparts in the general population, because of interactions between the natural risk factors that develop with aging and the effects of art and hiv. cumulative exposure to art is associated with an increase in the risk of myocardial infarction per year of exposure (relative risk = 1.12; 95% confidence interval [ci] = 1.06–1.18).9 exposure to art for longer than 6 months is also associated with higher serum triglycerides levels, total cholesterol, low-density lipoprotein cholesterol, insulin resistance and cardiovascular disease.10,11,12 the global estimated prevalence of hypertension is 34.7% among art-experienced patients and 12.7% among art-naïve patients.13 there is a dearth of accurate estimates for the global prevalence and incidence of diabetes mellitus and dyslipidaemia among art-experienced patients. in brazil, patients who had been on art for three years had a cumulative incidence of dyslipidaemia of 22.3% and diabetes mellitus of 5.8%.14 the burden of cmd in ssa is increasing parallel to the changing landscape of hiv care. it is projected that deaths attributed to cardiovascular disease will double to 2.4 million in 2030 relative to reports from 2000. these data suggest that cardiovascular disease is becoming a major public health problem in ssa, competing with infectious diseases for limited health resources.15 generally, little is known about art-associated cmds among art-experienced plwh in ssa, despite the region having the greatest burden of hiv infection and increasing access to art.16,17 the understanding of the effect of art on the risk of cmds is crucial to enable an accurate estimation and the assessment of appropriate interventions for the management of cmds in plwh.18,19 understanding the interaction between art and cmd is crucial for managing cmds in plwh.18,19 being part of ssa, lesotho is no exception and needs to be studied. there were approximately 306 000 pwlh in 2016/2017 in lesotho, corresponding to 25.6% of the population.20,21 of these, approximately 70% were enrolled in art care and treatment.20,21 lesotho thus has one of the highest burdens of hiv globally. in this study, we quantified the burden of cmd and identified the associated risk factors among plwh in a large treatment cohort. methods study design and setting this retrospective cohort study used data from the daily dispensing electronic system and routine clinical records at qoaling filter clinic, maseru, south africa, for the period may 2011 to may 2015. qoaling filter clinic is a high-volume public–private partnership primary healthcare facility located in qoaling constituency, which is approximately 8 km from the capital city of lesotho, maseru. in addition to hiv and aids care and tuberculosis (tb) management services, the clinic offers dental services, ophthalmology, antenatal care, pharmacy services, family planning, minor procedures and wound care services and outpatient department services for minor ailments and some chronic conditions. patients access services for a fee subsidised by the government of lesotho except for hiv and aids care services, which are free of charge. in lesotho, art is currently initiated in all people testing positive for hiv as soon as they are ready to commit to treatment, regardless of the availability of baseline laboratory tests. however, prior to 2016, a thorough clinical evaluation coupled with baseline laboratory investigations was mandatory to determine the patients’ eligibility for art. adults and adolescents were eligible for art initiation under certain conditions, that is if they were at world health organization (who) clinical stage 3 or 4 (regardless of cd4 count) or who clinical stage 1 or 2 (cd4 ≤ 500 cells/mm3), hiv serodiscordant couples with tb or hepatitis b co-infection, and hiv-infected women who were pregnant or lactating. prior to art initiation, mandatory baseline laboratory investigations are cd4 count, cryptococcal antigen screening for adolescents and adults with cd4 counts of < 100 cells/mm, hepatitis c serology, haemoglobin (hb) or full blood count, alanine aminotranferase (alt) and creatinine, urine dipstick (glucose, protein), pregnancy test, blood glucose, cholesterol and triglycerides for pi-based regimens.22 the country’s 2014 guidelines on the use of art for hiv prevention and treatment recommended art regimens are shown in table 1.22 table 1: recommended antiretroviral treatment regimens for adolescents and adults in lesotho. because of its lower potency and increased risk of liver toxicity when initiated at cd4 counts of ≥ 250 cells/mm3 in women and ≥ 400 cells/mm3 in men, nevirapine is no longer recommended as part of first-line art regimens. however, hiv-infected patients who are already on a nevirapine-based regimen and stable should continue using the regimen and multidrug-resistant tb (mdr-tb) co-infected patients already on nevirapine because of interactions between mdr-tb medication and efavirenz. study population patient records were included in the study if the patient was older than 18 years old, initiated onto the standard firstor second-line art regimen for one year or longer and had documented viral load measurements. patients who already had diabetes mellitus, hypertension, obesity or dyslipidaemia at art initiation were excluded. sample size and sampling techniques we calculated the required sample size as specified by a prospective cohort study of the incidence of lipodystrophy and metabolic disorders in patients starting on nnrtis in benin.23 using stata version 14 (stata corp., college station, tx, united states [us]), we derived a minimum sample size of 279 participants – 118 men (hazard ratio [hr] = 6.33, standard deviation [s.d.] = 0.14, alpha = 0.05 and power = 0.80) and 161 women (hr = 6.33, s.d. = 0.12, alpha = 0.05 and power = 0.80). given the available database of patients, we increased the detection value to an hr value of 3 or greater to achieve a more optimal minimum sample of 785 patients. after the above calculation, from the facility spreadsheet of approximately 4000 patients currently on art, we filtered the data for eligible patients. we then selected 785 patients through microsoft excel random selection function, and extracted the pertinent data from clinical records and the daily electronic dispensing system. measurements definition of the outcome the primary outcome was the occurrence of cmd which include conditions like hypertension, diabetes mellitus or dyslipidaemia. we assumed that patients had hypertension if they were on antihypertensive medication, similarly had dyslipidaemia if they were on lipid-lowering medication and had diabetes mellitus if they were being treated for diabetes mellitus. independent variables the predictor variables included demographic and clinical characteristics such as age, gender, body mass index (bmi), viral load, cd4 cell count and a history of hypertension, diabetes mellitus or dyslipidaemia. the art regimen was the main exposure variable. other variables included treatment adherence, the date of art initiation, art, duration of art in months, date of diagnosis and initiation dates of hypertension treatment, diabetes mellitus treatment and dyslipidaemia treatment. data management and analysis data were captured using epidata version 3.1 and verified using the double-entry method. data were exported to stata version 14.0 (stata corp.) for analysis. the data were summarised using descriptive statistics. the mean and standard deviation were calculated for normally distributed numerical variables, while the median and interquartile ranges (iqrs) were used to describe the skewed numerical variables. the categorical variables were summarised using frequencies and proportions. the person-time accrued was calculated from six months after treatment initiation, which is the earliest time possible for viral load monitoring and other recommended routine laboratory tests after baseline tests,24 until the earliest of (1) the study outcome (any one of the three cmds); (2) death; (3) loss to follow-up (defined as at least 90 days late for the last scheduled clinic visit); (4) transferring out or (5) the close of the dataset (may 2015). we measured the incidence of cmds as the total number of new cases of cmd at every 6-month follow-up divided by the total number of patients at risk during the same period, expressed per 100 person-months of follow-up. the incidence rates were stratified by first-line and second-line regimens. to estimate the hazards of developing cmd beyond a specified 6-month period, we generated kaplan–meier survival curves. the log-rank test was used to compare the survival curves of participants on nnrti and pi-based regimens.25 all p-values < 0.05 were considered statistically significant. we used a cause-specific cox proportional hazards regression model to investigate the impact of exposure to art, as well as the effect of age, bmi, hb, cd4 cell count and viral load on the development of cmds.26 ethical considerations this study was approved by the ministry of health (lesotho) research ethics committee (reference number 56/2019) and the university of pretoria faculty of health sciences research ethics committee (reference number id36-2019). results demographic and clinical characteristics of the study participants for the period 2011–2015, we randomly selected 785 participants through the microsoft excel random selection (simple random sampling) programme. most of the participants were women (60%, n = 473), with a median age of 42 years (iqr = 36–51) and a median duration on art of 15 months (iqr = 3–49). the participants had a mean bmi of 25.4 kg/m2 (s.d. = 8.42) and a hb level of 13.9 g/dl (s.d. = 1.82). overall, 63.7% (n = 500) of participants had a cd4 count of < 500 copies/mm3. the participants were stratified according to their current art regimen (nnrti-based regimen: 98.1%, n = 770; pi-based regimen: 1.9%, n = 15). all the pi-based regimen participants were initiated onto second-line regimens and the clinical records revealed no history of the conditions under investigation at the beginning of the study. description of the average demographic and clinical characteristics is given in table 2. table 2: description of the demographic and clinical characteristics of the study participants by antiretroviral treatment regimen. incidence of cardiometabolic disease because there were only 15 second-line patients, in the interest of sample homogeneity, the main analysis of the study focused only on first-line patients. additionally, there were only three cases of dyslipidaemia during the period of the study; therefore, they were also left out in the main analysis. twelve (12) participants developed both hypertension and diabetes mellitus and there was only one case in each of the other multimorbidity combinations. the incidence rate was 5.6 (95% ci = 4.4–7.1), 5.7 (95% ci = 4.4–7.3) and 5.5 (95% ci = 3.3–8.9) per 100 person-months of follow-up for cmd, hypertension and diabetes mellitus, respectively (table 3). table 3: incidence rates for hypertension and diabetes mellitus among study participants who had been on antiretroviral treatment for more than 1 year in lesotho (2011–2015). occurrence of cardiometabolic disease figure 1 shows the kaplan–meier survival curves for cmd, hypertension and diabetes mellitus outcomes. patients’ clinical assessments are normally performed at 2 weeks, 1 month, 2 months, 3 months and 6 months after art initiation and at least every 6 months thereafter complemented by laboratory monitoring. the viral load and cd4 count are routinely measured at 6 months and 12 months after art initiation and annually thereafter;22 therefore, we found it relevant to use 6-month segments in our kaplan–meier survival curves. from the date of art initiation, the median time to onset was 16.6 months for cmd (iqr = 7.4–23.4), 15.6 months for hypertension (iqr = 7.4–23.4) and 19.5 months for diabetes mellitus (iqr = 12.1–24.9). figure 1: kaplan–meier time estimates to occurrence of cardiometabolic disease (a), hypertension (b) and diabetes mellitus (c). factors associated with occurrence of either hypertension or diabetes mellitus antiretroviral treatment was not associated with the occurrence of any of the three distinct outcomes, cmd (cause-specific hazard ratio [chr] = 1.55; 95% ci = 0.1–16.85; p = 0.158), hypertension (chr = 2.10; 95% ci = 0.18–24.24; p = 0.552) or diabetes mellitus (chr = 0.60; 95% ci = 0.09–1.83; p = 0.481). a higher bmi was significantly associated with the occurrence of diabetes mellitus (chr = 1.19; 95% ci = 1.14–1.38; p = 0.026) (table 4). table 4: risk factors for cardiometabolic disease, hypertension and diabetes mellitus. discussion we explored the incidence of and identified the risk factors for cmds among plwh in a large treatment cohort in lesotho. in this relatively young cohort of plwh, there was a low incidence of cmds, with the treatment regimen having little effect on the incidence or the time to onset of cmds. a higher bmi was the only predictive factor for diabetes mellitus. our findings provide valuable baseline information about the influence of art on the incidence of cmds in plwh in africa, especially lesotho, which has the second-highest prevalence of hiv after eswatini.2,27,28,29 because we randomly selected 785 patients from a treatment database, we were able to select a sample that was representative of the population available in our patient database. our study comprised 60.3% (473) women and 39.7% (312) men, equivalent to the ratios reported in the 2019 unaids report. the unaids data indicated that the numbers of women and men older than 15 years living with hiv in 2018 were 190 000 and 130 000, a ratio of 59.4% women and 40.6% men, respectively.30 in our study, approximately 90% of patients were virally suppressed, which is similar to 88% reported in 2017.31 most patients had a cd4 count below 500 cells/mm3, which is contrary to the main goals of art. antiretroviral treatment aims to achieve viral suppression in the shortest time possible, sustaining viral suppression and thus allowing patients’ cd4 counts to increase.32 most patients in our study (72.4%) demonstrated good treatment adherence, taking at least 95% of the medication in the correct amount, at the correct time.24 incidence of cardiometabolic diseases in lesotho, plwh had an incidence rate of hypertension of 5.7 (95% ci = 4.4–7.2) per 100 person-months of follow-up or a cumulative incidence of 8.5%, which is much lower than 34.7% reported by xu et al.13 prioreschi et al. reported incidence rates of type 2 diabetes mellitus amongst plwh ranging from 4 to 59 per 1000 person-years in plwh on art.33 in our study, pwlh had a diabetes mellitus incidence rate within the above range: 5.3 (95% ci = 3.3–8.4) per 100 person-months of follow-up or 22.3 per 1000 person-years of follow-up. the proportions and incidence rates reported in our study are lower than those reported in other studies; however, the future projections for non-communicable disease (ncd) burdens are concerning. it is projected that the proportion of people suffering from at least one key ncd in 2035 will increase by 26% among plwh compared to 6% among people not living with hiv. adult plwh will be twice as likely to suffer from at least one key ncd in 2035 compared to uninfected adults.34 occurrence of cardiometabolic diseases in our study, hypertension first occurred at approximately 6 months, which is similar to findings reported by wu et al.10 as portrayed in figure 1, gradual failure was observed for all outcomes although a little bit delayed to start on diabetes mellitus outcome. factors associated with occurrence of either hypertension or diabetes mellitus the main factors associated with metabolic disorders in plwh include a high proportion of central body fat, older age, higher bmi and high calorie, sugar and carbohydrate intake. the hiv-related factors include a high viral load and exposure to certain antiretroviral drugs, such as pis.35 in this study, a higher bmi was significantly associated with the occurrence of diabetes mellitus. higher bmi is a well-known risk factor for both hypertension and diabetes; however, the hiv-associated factors such as the cd4 count and the duration and type of art regimen36 were not associated with either of the two conditions. strengths and limitations strengths our study was conducted in an ssa country, representing the highest hiv burden globally, with most (90.2%)20 of plwh enrolled on art. our study is the first to report on the risk factors associated with cmd among plwh, contributing to the knowledge gap identified in the ssa region. our findings can be used as a baseline for future planning for resource allocation for comprehensive management of hiv and the prediction of the likely economic implications for hiv care. the findings from this study can be used to assess the need for integration of hiv and ncd programmes. other ssa countries of similar demographic characteristics and socio-economic status that still lack data on the burden and risk factors of cmds and the associated risk factors can adapt the findings for baseline planning in their settings. limitations although we took a random sample, there were very few participants enrolled on the pi-based regimen. the findings on the pi-based group cannot be generalised to the general population receiving pi-based regimens for hiv infection management. using secondary data is often associated with misclassification bias because of inappropriate recording of patients’ medical records; some participants shared similar unique numbers and hence, their documents were easily inappropriately filed. finally, this study lacked art-naïve plwh or an uninfected ageand gender-matched group as a comparison to observe whether the incidence rates and risk factors were different between the two groups. conclusion and recommendations conclusion the incidence of cmd in this patient population is low, yet noteworthy. there is a need for routine screening for cmds in plwh. recommendations to enable early detection and early stage treatment, we recommend that routine screening for cmds should be included as part of the standard package among plwh on art in countries with a high burden of hiv, such as lesotho. it has been confirmed that art service delivery models aimed at decongesting local health facilities, encouraging patient retention in care and enhancing adherence to medication are more effective than corresponding facility-based care and superior to individual-based models.37 integrating and harmonising hiv and ncd care services can greatly benefit the care of plwh. acknowledgements the authors would like to thank tsepong (pty) ltd. for granting them an opportunity to access the research data from the medical records. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions m.s., n.r.t.l. and s.t. contributed to designing the study, data analysis, drafting and critically revising the manuscript. funding information this study received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability the data that support the findings of this study are available from the corresponding author, m.s., upon reasonable request. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references wordbank. antiretroviral therapy coverage (% of people living with hiv) – sub-saharan africa [homepage on the internet]. 2019 [cited 2020 sep 28]. available from: https://data.worldbank.org/indicator/sh.hiv.artc.zs?end=2019&locations=zg&start=2001&view=chart coburn bj, okano jt, blower s. current drivers and geographic patterns of hiv in lesotho: 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https://www.avert.org/professionals/hiv-around-world/sub-saharan-africa/lesotho unaids. unaids-data [homepage on the internet]. geneva; 2019 [cited 2020 jan 25]. available from: https://www.unaids.org/sites/default/files/media_asset/2019-unaids-data_en.pdf pepfar. annual report to congress [homepage on the internet]. 2018 [updated april 2018; cited 2018 sep 18]. available from: https://www.pepfar.gov/reports/progress/271472.htm brennan at, maskew m, sanne i, fox mp. the interplay between cd4 cell count, viral load suppression and duration of antiretroviral therapy on mortality in a resource-limited setting. trop med int health. 2013;18(5):619–631. https://doi.org/10.1111/tmi.12079 prioreschi a, munthali rj, soepnel l, et al. incidence and prevalence of type 2 diabetes mellitus with hiv infection in africa: a systematic review and meta-analysis. bmj open. 2017;7(3):e013953. https://doi.org/10.1136/bmjopen-2016-013953 smit m, olney j, ford np, et al. the growing burden of noncommunicable disease among persons living with hiv in zimbabwe. aids. 2018;32(6):773–782. https://doi.org/10.1097/qad.0000000000001754 samad f, harris m, puskas cm, et al. incidence of diabetes mellitus and factors associated with its development in hiv-positive patients over the age of 50. bmj open diabetes res care. 2017;5(1):e000457. https://doi.org/10.1136/bmjdrc-2017-000457 ataro z, ashenafi w, fayera j, abdosh t. magnitude and associated factors of diabetes mellitus and hypertension among adult hiv-positive individuals receiving highly active antiretroviral therapy at jugal hospital, harar, ethiopia. hiv/aids: research and palliative care. 2018:181–192. https://doi.org/10.2147/hiv.s176877 mukumbang fc, van belle s, marchal b, van wyk b. an exploration of group-based hiv/aids treatment and care models in sub-saharan africa using a realist evaluation (intervention-context-actor-mechanism-outcome) heuristic tool: a systematic review. implementation sci. 2017;12(1):107. https://doi.org/10.1186/s13012-017-0638-0 abstract introduction shock and kill limitations of latency-reversing agents interactions of human immunodeficiency virus with apoptosis pro-apoptotic drugs conclusions acknowledgements references about the author(s) alexander m.l. hayes medical sciences division, faculty of clinical medicine, university of oxford, oxford, united kingdom citation hayes aml. future approaches to clearing the latent human immunodeficiency virus reservoir: beyond latency reversal. s afr j hiv med. 2020;21(1), a1089. https://doi.org/10.4102/sajhivmed.v21i1.1089 review article future approaches to clearing the latent human immunodeficiency virus reservoir: beyond latency reversal alexander m.l. hayes received: 25 mar. 2020; accepted: 12 may 2020; published: 12 aug. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: while combined antiretroviral therapy (cart) allows near-normal life expectancy for people living with human immunodeficiency virus (hiv), it is unable to cure the infection and so life long treatment is required. objectives: the main barrier to curing hiv is the latent reservoir of cells, which is stable and resistant to cart. method: current approaches under investigation for clearing this reservoir propose a ‘shock and kill’ mechanism, in which active replication is induced in latent cells by latency reversal agents, theoretically allowing killing of the newly active cells. results: however, previous studies have failed to achieve depletion of the t central memory cell reservoir, are unable to target other latent reservoirs and may be causing neurological damage to participants. conclusion: future approaches to clearing the latent reservoir may bypass latency reversal through the use of drugs that selectively induce apoptosis in infected cells. several classes of these pro-apoptotic drugs have shown promise in in vitro and ex vivo studies, and may represent the basis of a future functional cure for hiv. keywords: hiv; latency reversal; viral reservoir; pro-apoptotic drugs; cart. introduction the global hiv/aids pandemic has caused over 25 million deaths since its origins in the 20th century and remains without a cure. combined antiretroviral therapy (cart) is the current treatment of choice for human immunodeficiency virus (hiv) infection1 and suppresses viral load below detectable levels with correct administration.1,2 however, lifelong treatment is required, at considerable expense to healthcare systems,1 as the cessation of therapy causes a rapid rebound of viraemia within days3 and eventual progression of the disease to aids. furthermore, escape mutations of the virus are common and reduce efficacy,4,5 necessitating expensive combination therapy with multiple drugs. viral rebound occurs due to the presence of latent viral reservoirs, rather than continuing low-level replication during cart, as shown by clonal evolutionary studies.6 on therapy cessation these latently infected cells clonally expand, seeding a population of infected cells containing intact provirus.7 whilst cart has been successful in extending life expectancy of people living with hiv in high-income countries, this remains impaired compared to healthy adults.8 as cart is limited by mutations, is an expensive lifelong treatment and may not be available to those in countries with poorly developed healthcare systems, development of a cure for hiv is desirable. cure research would be of considerable impact in south africa, which has the highest number of people living with hiv in the world, at 7.7 m as of 2018, a prevalence of 20.4% in adults (unaids 2019)9. in that year 77 000 deaths were recorded due to aids-related illnesses (unaids 2019), although this number is coming down and life expectancy is rising as the cart programme continues to grow. reservoirs of latently infected cells are the main barrier to cart curing hiv. the first latently infected cells to be identified were cd4+ central memory t cells (tcm) containing replication-competent, integrated provirus.10 these were found to be present in patients on cart, with no change in reservoir size with continuous therapy11 as the quiescent cells do not contain actively replicating virus, and so are unaffected by cart. the tcmreservoir is present even if cart is initiated within the first week post exposure,12 so is established early in infection. it is also extremely stable, as the latent cells have a half-life of around 44 months,13 so is unlikely to be cleared in a patient’s lifetime. the tcmreservoir contains the majority of latent cells, but other reservoirs are also present and form barriers to cure research. several myeloid cell lines have been shown to harbour latent hiv in chronic infection and contribute to viral rebound on cart cessation.14,15 there is evidence for the presence of latent reservoirs in tissue macrophages16 and microglial cells and astrocytes in the central nervous system (cns).17,18 there is no in vivo evidence of latently infected tissue dendritic cells but infection has been shown in vitro,19 and it has been proposed that this may be transferred to cd4+ cells via a virological synapse.20 follicular dendritic cells have been shown to maintain a stable pool of virus on their surface without being infected, providing a latent reservoir within secondary lymphoid tissue.21 further reservoirs have been suggested, such as within fibrocytes,20 but it is now apparent that the tcm reservoir is not the only source of latently infected cells. potential cures must, therefore, target all identified reservoirs to be successful. several approaches to clearing the latent reservoirs have been investigated, with the ‘shock and kill’ combination receiving particular interest. however, recent findings seem to suggest this is unlikely to ever provide a cure for hiv22,23,24,25,26,27,28,29,30 and may have unresearched deleterious side effects.31,32,33 an emerging class of drugs targeting the apoptosis pathways in latently infected cells may allow reservoir depletion without latency reversal, and therefore merit further research as a potential cure for hiv. shock and kill a potential approach to clearing hiv latent reservoirs is ‘shock and kill’, in which the reservoir would be ‘shocked’ with latency-reversing agents (lras) to induce replication of the provirus. ‘killing’ of the activated cells would then be achieved through viral cytopathic effects, cd8+ t cells, cart or other agent, resulting in clearance of the latent cells and curing the infection. this mechanism is outlined in figure 1. several lras have been developed, many using yang’s in vitro model of latently infected cd4+ tcm34 to identify compounds that selectively induce viral replication in latent cells. these include disulfiram22 and histone deacetylase inhibitors (hdacis) such as vorinostat and panobionstat. early in vivo studies were promising as latency reversal was demonstrated with an increase in viral gene expression in the resting cells observed with disulfiram,23,24 vorinostat25 and panbionstat26 administration. however, the key caveat is that none of these studies decreased reservoir size in vivo as the number of latent cells did not decrease following latency reversal. whilst replication was induced in a proportion of the latent cells, this did not lead to immune or viral-mediated killing of reactivated cells. figure 1: proposed mechanism of ‘shock and kill’. several reasons have been proposed for the failure of lras alone to reduce reservoir size. the initial principle of ‘shock and kill’ was that viral cytopathic effects and lysis, due to hiv replication, aided by cytotoxic t lymphocyte (ctl)-mediated killing of actively infected cells, would be sufficient to kill reactivated, formerly latent, cells. shan et al.27 showed that the viral cytopathic effect alone is insufficient to kill cells, and the vigorous ctl response is lost in chronic hiv infection. however, ctl stimulation increased latent cell clearance, leading to the suggestion that some form of immune stimulation may be required alongside latency reversal to achieve a reduction in reservoir size. the ctl response to reactivated cells may be insufficient to reduce reservoir size on latency reversal, due to 98% of latent t cells carrying escape mutations to ctl killing28 and t cell exhaustion in chronic infection29 reducing the efficacy of the ctl response. furthermore, lras may not affect non-tcmreservoirs30 as macrophages are resistant to the cytopathic effects of hiv, and dendritic cells do not integrate viral dna, meaning that lras would be unable to cause viral replication and subsequent targeting by the immune system. it has also been proposed that continued cart may not completely inhibit infection of further cells by virions produced from reactivated, formerly latent cells.30 thus, lra administration may lead to infection of previously uninfected cells. it is therefore clear that lra administration alone does not reduce reservoir size, due to a lack of viral cytopathic effects and lysis, insufficient ctl response and the potential failure of cart to suppress replication. as such, stages 3 and 4 from figure 1 are unlikely to be successful and an additional killing agent is required to achieve the second goal of ‘shock and kill’. this may involve immune stimulation, with natural killer (nk) cell stimulation showing some promise ex vivo35 or other agents, such as broadly neutralising antibodies (bnabs), which appear to mediate antibody-dependent cellular cytotoxicity of activated latently infected cells in mice36 but human studies are required to assess their efficacy. killing agents that selectively induce apoptosis of hiv-infected cells have also shown promise in vitro (see pro-apoptotic drugs [pads]). limitations of latency-reversing agents whilst it has been repeatedly shown that lras alone are unable to reduce the size of the latent hiv reservoir, administration of a killing agent alongside an lra has been proposed as a method of clearing the reactivated cells.37 however, it seems likely that even with killing agents lras cannot clear enough latent cells to achieve a functional cure and may cause complications due to non-t cell hiv reservoirs. future studies in humans to test the efficacy of killing agents administrated alongside lras could be carried out by administering a previously tested lra, such as disulfiram, alongside a killing agent such as a bnab to participants living with hiv and measuring the change in reservoir size using a technique such as tilda.38 however, the combination of an lra with, for example, a bnab, is unlikely to clear the myeloid reservoir as dendritic cells are likely to be unaffected by lras.30 therefore, even if functional elimination of the tcm reservoir is achieved, viral rebound on cart cessation may still occur due to the presence of the myeloid reservoir, which would likely not be cleared by current ‘shock and kill’ approaches under investigation. human immunodeficiency virus-associated neurological disorders (hands) are well-observed in patients on cart and may lead to widespread neurological impairment,39 suggesting significant damage to the cns even when viraemia elsewhere is suppressed below detectable levels. the cause of this appears to be relatively poor blood-brain barrier (bbb) penetrance by antiretrovirals,31 allowing continued hiv replication alongside the presence of latently infected microglial cells, perivascular macrophages and astrocytes.20 recent research suggests that impaired neurogenesis may underpin hand persistence even with cart.32 a study on the cns penetrance of lras33 showed that disulfiram and vorinostat are able to cross the bbb relatively easily. whilst this could enable targeting of the cns latent reservoir, it may mean that current in vivo studies of lras are damaging to the patients involved, as there is no reduction in latent reservoir size, whilst lras are able to penetrate the cns and increase viral replication with no inhibition from antiretroviral drugs. this may potentially lead to an increase in viral protein, inflammatory cytokine (ck) and neurotoxin release from infected macrophages and microglia, which could increase the probability of hand development (personal communication, grant campbell) as shown in figure 2. therefore, in addition to their inability to affect all hiv reservoirs, even with the accompanying administration of killing agents, lras may cause increased neurological impairment of patients. furthermore, if the killing agent used in a hypothetical cure is unable to penetrate the bbb, there would be no reduction in the size of the cns reservoir. this makes the development of a cure strategy distinct from ‘shock and kill’, involving the direct killing of latent cells without the need for latency reversal, desirable. the pad class mentioned earlier has shown promise in achieving this. figure 2: proposed mechanism for human immunodeficiency virus associated neurological disorder development on latency reversing agent administration. interactions of human immunodeficiency virus with apoptosis the human immunodeficiency virus has complex interactions with apoptosis pathways in infected cells.40 in latently infected cells the increase in longevity observed is partially the result of avoidance of apoptosis.37 a number of specific effects on apoptosis pathways have been suggested as the cause of this. the intrinsic apoptosis pathway is a response to cellular damage and involves pro-apoptotic factors causing mitochondrial outer membrane permeabilisation (momp), triggering the release of soluble proteins from the mitochondrial intermembrane space. these include the cytochrome c and second mitochondria-derived activator of caspase (smac, also known as diablo41). cytochrome c binds cytosolic proteins to form the apoptosome, which activates the ‘initiator’ enzyme caspase-9. this, in turn, cleaves the ‘executioner’ enzymes caspase-3 and caspase-7 which trigger the cleavage cascade of other caspase enzymes resulting in cell death. the second mitochondria-derived activator of caspase activates this process through disinhibition of caspases 3, 7 and 9 via binding and inactivating the x-linked inhibitor of apoptosis (xiap). the x-linked inhibitor of apoptosis binds these caspases in the absence of smac, inhibiting their activity and directing their degradation by the proteasome. the second mitochondria-derived activator of caspase antagonises this activity, allowing the progression of the apoptotic process.41 several other iaps are also inhibited by smac, including the baculoviral iap repeat-containing protein 2 (birc, also known as cellular iap1).41 viral proteins, in particular tat and nef, cause inhibition of this intrinsic apoptosis pathway in latently infected cells. tat upregulates host production of anti-apoptotic proteins including xiap and bcl2.42 the x-linked inhibitor of apoptosis inhibits caspase activity, as detailed earlier, whilst bcl2 inhibits momp,43 thus preventing the release of cytochrome c and smac. tat also inhibits the pro-apoptotic proteins p53 and the bcl2-associated antagonist of cell death (bad).40 nef causes p21-activated kinase activation, leading to phosphorylation of bad, thus inhibiting its pro-apoptotic activity (binding to and inhibition of bcl2),44 and also inhibits caspase-8 and caspase-10.40 conversely, in the cns, it appears that tat and nef may induce autophagy and apoptosis in hand pathogenesis.45,46 expression and activation of anti-apoptotic proteins are therefore increased in latently infected cells, making this an attractive therapeutic target. pro-apoptotic drugs several classes of pro-apoptotic compounds have been developed recently for cancer treatment,47,48 as tumour cells often over-express or activate iaps allowing the evasion of apoptosis, a key hallmark of cancer. some of these have been shown to induce apoptosis of latent hiv infected cells in vitro, leading to speculation that pads may contribute to a future cure. second mitochondria-derived activator of caspase mimetics (sms) are a class of drugs which bind iaps in a similar fashion to the endogenous molecule.48 they cause caspase activation via iap binding49 and appear to reduce iap activity through both degradation and inhibition of the proteins,50 and therefore induce apoptosis. second mitochondrias have recently been developed for cancer treatment, inducing apoptosis48 of tumour cells which over-express or activate iaps. the sms birinapant, embelin and gdc-0152 were investigated for their efficacy to induce apoptosis in latently infected tcm by campbell et al.51 all were found to cause rapid degradation of xiap and birc2, which were upregulated in the infected cells, and importantly showed selective killing of hiv-infected tcm compared to uninfected tcm, with the doses required for 90% clearance of hiv-infected cells causing a small increase of tcm cell death, of 3.5% – 4.6% above basal levels. this occurred in the absence of increased virus production, despite findings in models of latency by pache et al.52 suggesting that sms may act as lras due to the reduction in birc2 leading to increased nfκβ signalling, resulting in an increased viral transcription. however, in latent hiv-tcm from patients undergoing cart, the pache study showed that sms only caused latency reversal when used in combination with an lra such as vorinostat. therefore, it appears that the major effect of sms on latently infected tcm-is to induce apoptosis rather than reactivate transcription. furthermore, campbell et al. demonstrated the mechanism of apoptosis on sm administration is dependent on the induction (but not completion) of autophagy. wortmannin (an inhibitor of early stages of autophagy) led to a reduction in apoptosis despite the degradation of iaps by sms. further findings suggest that, following iap degradation, autophagy proteins form a scaffold for the assembly of a ripoptosome-like death-inducing signaling complex (disc), which can then initiate apoptosis via caspase 8 induction. this is an additional mechanism to the simple removal of iap inhibition due to their degradation and may explain the selectivity of sms for inducing death of hiv-tcm. inhibitors of later stages of autophagy did not reduce apoptosis, suggesting that the process of autophagy itself is not required for this mechanism of cell death. induction of autophagy is sufficient for apoptosis, as autophagy proteins allow disc formation. iaps are degraded by sms in uninfected tcm but this does not lead to the same degree of cell death due to reduced autophagy induction and therefore decreased probability of disc formation. hiv-tcm are more prone to autophagy induction than uninfected cells as a result of the effects of viral proteins. gag and nef interact with autophagy factors to increase autophagy induction, which in turn augments hiv yields in cells containing the actively replicating virus.53 nef and vif inhibit later stages of autophagy to prevent hiv degradation.53,54 therefore, hiv-tcm are more prone to autophagy induction than uninfected cells, providing a potential explanation for the selective apoptosis observed in latently infected cells on sm administration. over-expression or activation of iaps in infected cells may also contribute to the selectivity of sms. these findings present ex vivo evidence of the selective killing of latently infected tcm by sms, along with a convincing mechanism of how uninfected cells are spared. clinical trials in humans may now be justified, but should be performed with caution as the side effects of these drugs in people living with hiv are unknown. a number of sms have been used in phase i trials for various cancers, with a generally tolerable safety profile, although the occasional occurrence of cytokine release syndrome in patients is of some concern.55 in vitro and ex vivo findings suggest sms may be able to deplete the tcm reservoir in vivo, and, whilst if 90% of latently infected cells are killed (as in the campbell study) the patient will not be cured of hiv, this eclipses reservoir clearance demonstrated by current ‘shock and kill’ approaches. however, it is unclear if these drugs would induce apoptosis in non-t cell reservoirs to the same degree, which may prevent the development of a functional cure. future in vitro and ex vivo studies of pads using latently infected myeloid cells from people living with hiv would be advisable to further test their suitability. in vitro and ex vivo studies of other pads have also shown promise. bcl-2 antagonists such as venetoclax caused disinhibition of momp and led to the depletion of latent hiv-tcm from patients on cart in an ex vivo study.56 p13k/akt inhibitors increase the expression of pro-apoptotic genes downregulated by hiv and have shown promise in predisposing latently infected macrophages and microglia to cell death.57,58 rig-1 inducers activate an innate immune response to viral rna, triggering apoptosis. an ex vivo study demonstrated selective depletion of latent hiv-tcm using the rig-1 inducer acitretin.59 these classes of pads also merit further investigation and could be used in combination with sms in a future approach to clearing the latent reservoir to induce apoptosis in a greater portion of latently infected cells. conclusions recent ‘shock and kill’ research has failed to demonstrate significant depletion of the viral reservoir, and it remains unclear if the use of lras may cause hands. pads may represent a promising future approach to curing hiv given their in vitro and ex vivo success in selectively causing apoptosis in latently infected cells, with sms appearing effective against the tcm reservoir and p13k/akt inhibitors against myeloid reservoirs. several of these drugs have been used in clinical trials for other conditions, and further investigation into their potential for people living with hiv is merited. acknowledgements grant campbell provided theoretical assistance via email correspondence for the limitations of the lras section, specifically about the potential neurological side effects lras may have. professor william james, dunn school of pathology, university of oxford, was my supervisor for the review, and so offered me advice and guidance on selecting a subject area and how to go about writing the review. he has not read or edited the review since i began writing it due to university examination regulations. competing interests i declare that no competing interests exists. author’s contributions i am the sole author for this work. ethical consideration this article followed all ethical standards 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https://doi.org/10.1371/journal.pone.0013121 kim y, hollenbaugh ja, kim dh, kim b. novel pi3k/akt inhibitors screened by the cytoprotective function of human immunodeficiency virus type 1 tat. plos one. 2011;6(7):e21781. https://doi.org/10.1371/journal.pone.0021781 li p, kaiser p, lampiris hw, et al. stimulating the rig-i pathway to kill cells in the latent hiv reservoir following viral reactivation. nat med. 2016;22:807–811. https://doi.org/10.1038/nm.4124 southern.html guidelines southern african guidelines for the safe use of pre-exposure prophylaxis in men who have sex with men who are at risk for hiv infection the consensus committee, southern african hiv clinicians society, chaired by linda-gail bekker and kevin rebe. members: ben brown, peter budnik, glenn de swardt, zoe duby, nathan geffen, brian kanyemba, james mcintyre, landon myer, andrew scheibe, laurie schowalter, mark sonderup, wendy spearman, carlos toledo, tim tucker, reon van dyk, gert van zyl corresponding author: a scheibe (andrew.scheibe@gmail.com). background. the use of oral antiretrovirals to prevent hiv infection among hiv-negative men who have sex with men (msm) has been shown to be safe and efficacious. a large, randomised, placebo-controlled trial showed a 44% reduction in the incidence of hiv infection among msm receiving a daily oral fixed-dose combination of tenofovir disoproxil fumarate and emtricitabine (truvada) in combination with an hiv prevention package. improved protection was seen with higher levels of adherence. aim. the purpose of this guideline is to: (i) explain what pre-exposure prophylaxis (prep) is; (ii) outline current indications for its use; (iii) outline steps for appropriate client selection; and (iv) provide guidance for monitoring and maintaining clients on prep. method. prep is indicated for hiv-negative msm who are assessed to be at high risk for hiv acquisition and who are willing and motivated to use prep as part of a package of hiv prevention services (including condoms, lubrication, sexually transmitted infection (sti) management and risk reduction counselling). recommendations. hiv testing, estimation of creatinine clearance and sti and hepatitis b screening are recommended as baseline investigations. daily oral truvada, along with adherence support, can then be prescribed for eligible msm. prep should not be given to msm with abnormal renal function, nor to clients who are unmotivated to use prep as part of an hiv prevention package; nor should it be commenced during an acute viral illness. three-monthly follow-up visits to assess tolerance, renal function, adherence and ongoing eligibility is recommended. six-monthly sti screens and annual creatinine levels to estimate creatinine clearance are recommended. hepatitis b vaccination should be provided to susceptible clients. gastro-intestinal symptoms and weight loss are common side-effects, mostly experienced for the first 4 8 weeks after initiating prep. there is a risk of the development of antiretroviral resistance among those with undiagnosed acute hiv infection during prep initiation and among those with sub-optimal adherence who become hiv infected while on prep. risk compensation (increasing sexual behaviours that can result in exposure to hiv) while on prep may become a concern, and clinicians should continue to support msm clients to continue to use condoms, condom-compatible lubrication and practice safer sex. research is ongoing to assess optimum dosing regimens, potential long-term effects and alternative prep medications. recommendations for the use of prep among other at-risk individuals, and the components of these recommendations, will be informed by future evidence. s afr j hiv med 2012;13(2):40-55. men who have sex with men (msm) is a term that describes men who have sex with men, regardless of social identity (gay, bisexual, heterosexual) or whether they also have sex with women.1 msm have been shown to be at disproportionately high risk of hiv acquisition and transmission.2 , 3 biological susceptibility (efficiency of rectal hiv transmission), behaviours (including unprotected anal intercourse and multiple partners) as well as structural and social factors (including homophobia and discrimination) have been associated with increased vulnerability to hiv.3 unprotected receptive anal intercourse is the main risk factor for sexual transmission of hiv among msm.4 the high concentration of rectal cells vulnerable to hiv-1 infection (macrophages, t-cells and dendritic cells) and the single-cell layer of rectal mucosa, results in a per-act risk for hiv transmission that is 10 20 times greater than unprotected vaginal intercourse.4 msm and hiv in southern africa there is emerging and consistent evidence about the high hiv burden among msm in southern africa.7 hiv prevalence among msm sampled in cross-sectional surveys in south africa has ranged from 10 50%.8 however, owing to the lack of accurate population size estimates, it is hard to assess attributable risk.12 a 2009 modelling study on the modes of hiv transmission in south africa estimated that 8% of all new hiv infections in south africa occur among msm.13 high-risk sexual practices (including unprotected anal intercourse, multiple and concurrent partnerships, and sex work) and limited knowledge about hiv and substance use (alcohol, methamphetamines and heroin) have been associated with increased risk for hiv infection among msm in south africa.2 , 9 , 14 many msm also have female sexual partners. almost half (49%) of the participants in a soweto-based msm study reported recent female sexual partners.10 homophobia, stigma and discrimination (including criminalisation of same-sex behaviours in some southern african countries), health care worker ignorance (about msm vulnerability to hiv and appropriate management of msm clients) and the heterosexual focus of the hiv response have been contributing factors to the failure of southern african public health services to address the health needs of msm.2 , 12 , 17 the purpose of the msm pre-exposure prophylaxis guideline is to: • explain what pre-exposure prophylaxis (prep) is • outline current indications for its use • outline steps for appropriate client selection • provide guidance to monitor and maintain clients using prep. pre-exposure prophylaxis pre-exposure prophylaxis (prep) is the taking of a pharmaceutical agent prior to an exposure to prevent an outcome (e.g. infection by a microbe). prep for hiv utilises antiretroviral medications to prevent hiv infection. research into the use of existing and novel prep agents, topical (microbicide) and oral (tablet) formulations is ongoing. in the global iprex trial, prep was shown to decrease hiv incidence among at-risk msm (see text box).25 the results of this randomised placebo-controlled trial offer a new opportunity for hiv prevention. truvada, the oral antiretroviral agent used in the iprex trial, is available for off-label use for prep in south africa. development of prep truvada (tenofovir disoproxil fumarate (tdf) in combination with emtricitabine (ftc)) was chosen for the evaluation of pre-exposure prophylaxis because of its high level of activity in inhibiting hiv replication; its acceptable safety profile; its high barrier to generating resistant virus; and its low levels of side-effects.26 the protective activity of tdf and ftc has been shown in animal models, with best efficacy when both agents were used together.27 , 28 several trials of daily oral tdf or tdf/ftc among heterosexual men and women have recently been completed. additional trials with heterosexual women and injecting drug users are ongoing (http://www.avac.org/ht/a/getdocumentaction/i/3113). the findings of the prep trials among heterosexual men and women have yielded differing efficacy results, with some showing efficacy among heterosexual sero-discordant couples receiving either tdf or tdf/ftc (partners-prep) and among young men and women (tdf2) receiving tdf/ftc. one prep trial assessing the efficacy of daily oral tdf/ftc among women (fem prep) was stopped for reasons of futility (the inability to determine efficacy), and the oral and topical tenofovir arms in the voice trial with women were stopped for futility while assesment of efficacy of daily oral tdf/ftc in the voice trial is continuing.29 research is under way to assess reasons for these differing results. the global iprex trial the global iprex trial was a double-blinded, randmised placebo-controlled trial to assess the safety and efficacy of daily oral truvada for the prevention of hiv among msm and transgender women. the subjects were 2 499 hiv-seronegative msm or transgender women who have sex with men enrolled from 11 sites in 6 countries. the cape town site was initiated later than other sites, and only 88 msm from south africa were enrolled (3.5% of total cohort) before the study was fully enrolled. all subjects received monthly hiv testing, risk-reduction counselling, condoms and management of stis. the study subjects were followed for 3 324 person-years (median 1.2 years, maximum 2.8 years)(until 1 may 2010). of the subjects, 10 were infected with hiv at enrollment (in their ‘window’ period), and 100 became infected during follow-up (36 in the truvada group and 64 in the placebo group). in the modified intent-to-treat analysis (excluding those who were infected at enrolment and those with no follow-up hiv test results), an overall 44% reduction in the incidence of hiv infection (95% confidence interval 15 63%; p=0.005) among those randomised to truvada use was seen. an as-treated analysis showed that participants who reported taking the study drug at least 50% of the time, experienced 50% fewer infections. participants who reported taking 90% or more of their daily doses, experienced an efficacy of 73%.25 drug levels were assessed in a case-control analysis of a subset of trial participants. each msm who acquired hiv infection during the trial was matched with two msm who remained uninfected. no drug was detected in participants in the placebo arm. among participants in the truvada arm, drug was detected in 22 of 43 participants without hiv infection (51%) and in 3 of 34 hiv-infected participants (9%) (p<0.001).25 nausea and unintentional weight loss were reported more frequently during the first 4 weeks in the group receiving truvada than in the placebo group (p<0.001). the two groups had similar rates of serious adverse events (p=0.57).25 motivation for a msm prep guideline the iprex trial results contributed to the development of interim guidance on the use of prep among msm by the united states centers for disease control and prevention.32 based on the results of the iprex and partners prep trials, a submission to the united states’ food and drug administration is under consideration for expanding the indications for the use of truvada to include the prevention of sexual acquisition of hiv among msm and heterosexual adults. truvada is not currently licensed for use as prep in south africa. southern african guidelines will assist practitioners who may be considering, or are already, prescribing prep to at-risk msm clients. this guideline is based on current evidence, and future data will inform its revision and the potential extension of indications to other population groups. initiation of prep steps for the screening, initiation and maintenance of prep for msm are shown in fig. 1. 1. identification of potential prep users providers should educate and counsel msm clients about prep and conduct an individualised risk-benefit assessment to assess eligibility. eligibility criteria for prep use include: • men who have sex with men (msm) (including those who also have sex with women) who are identified by the provider and client as being at high risk for hiv exposure (see text box on indications for the use of prep) • no contra-indications to truvada (ftc/tdf) • hiv-negative by routine rapid antibody test • absence of symptoms of acute hiv infection (recent acute viral illness) and, if symptoms reported, hiv-negative by 4th-generation hiv test or other hiv antigen test if available (this reduces, but doesn’t eliminate, the window period) • motivated to follow prep prescribing guidelines • willing and able to adhere to daily oral dosing† • willing and able to attend 3-monthly prep maintenance visits, inclusive of hiv counselling and testing, clinical review and safety monitoring procedures • client understanding that the protection provided by prep is not complete, and of the need for prep to be used as part of a package of hiv prevention services (inclusive of condoms, lubrication, risk reduction counselling and sti management) 2. baseline investigations after documenting eligibility and motivation for prep use, mandatory baseline investigations should be completed (table 1). if resources permit, a dexa scan to measure bone mineral density among individuals who report a history of pathologic fracture or a family history of osteoporosis should be considered. unavailability or inability to cover the costs of a dexa scan should not preclude prep use. condoms and condom-compatible lubrication should be provided, and arrangements for follow-up made. indications for the use of prep prep may be suitable for msm who: • engage in anal sex and are hiv uninfected • are at high risk for hiv acquisition • msm with multiple partners • msm engaging in transactional sex, including sex workers • msm who use or abuse drugs • msm who drink alcohol heavily • more than 1 episode of a sti in the last year • couples‡ • hiv-negative partner in a discordant relationship, especially if the positive partner is not on antiretroviral therapy (art) • both partners hiv negative in a non-monogamous concordant relationship • msm who are unable or unwilling to achieve consistent use of male condoms • are motivated, able and willing to adhere to daily oral dosing. contraindications for prep: hiv-1 infected or evidence of possible acute hiv infection • allergy to tenofovir disoproxil fumarate and/or emtricitabine • poor renal function (estimated creatinine clearance <60ml/min) • unwilling or unable to return for 3-monthly hiv testing, counselling and safety monitoring visits. 3. implementing prep at the follow-up visit, repeat the rapid hiv test and do a review for acute viral symptoms. review results from baseline investigations and confirm that estimated creatinine clearance >60 ml/min. commence hepatitis b vaccination if susceptible and provide sti treatment as required (table 2). educate the client about potential prep side-effects and their management, as well as signs and symptoms of acute hiv infection (and need to return for ‘urgent’ hiv testing). initiate a medication adherence plan and provide a 1-month truvada prescription (1 tablet orally, daily) together with a 1-month follow-up date (table 3). risk-reduction counselling risk-reduction counselling is a behavioural intervention that attempts to decrease an individual’s chances of acquiring hiv and other stis,33 and should be implemented together with adherence counselling at follow-up visits for clients using prep. the main objective of risk-reduction counselling is for clients to set a realistic goal for behaviour change that could reduce their risk of contracting hiv. this is most effective when it is non-prejudicial and client-centred. risk reduction counselling can be provided by any trained healthcare provider and should address the following points: 1. explore the context of the user’s specific sexual practices, and assist client to recognise which of their behaviours are associated with higher risks for hiv infection. clinicians should also be aware that clients may not always perceive their own risk, or be in denial about it. 2. identify the sexual health protection needs of the user and reflect on what their main concerns appear to be. 3. strategise with the user on how they can manage these concerns or needs. 4. agree on which strategies the user is willing to explore and guide the user to decide on how to implement the strategy. adherence support adherence to daily prep medication, as shown in the iprex study and other prep trials, is a challenge. adherence counselling should be implemented at each visit where prep prescriptions or distributions are made. in iprex, msm who took prep more consistently and had evidence of drug detection in their blood, had higher levels of protection than those who did not.25 clients will need to be made aware of the fact that drugs only work if present at adequate levels in tissues and, preferably, drug levels should be adequate before and after exposure to hiv has occurred. the use of cell phone reminders, pill boxes, and linking pill taking with a daily routine activity are currently being evaluated for their impact on improving prep adherence. clinicians and clients could use any of these or other strategies to assist in maximising adherence (see text box on tips to support adherence). any trained healthcare worker can implement adherence counselling. a client-centred approach is recommended. drug level testing for tenofovir levels in plasma is available, but is expensive. drug level testing may be useful to assess adherence in the future. tips to support adherence include patient-focused adherence counselling at each contact. provide a clear explanation of the benefits of adherence. in a neutral manner, ask if the client has any challenges that may make adherence difficult. also explore possible facilitators to pill taking. include identified facilitators when developing strategies to improve adherence.34 options to improve daily pill taking: • use reminders (cell phone, alarm clock, diary, partner reminder) • link with daily activity (breakfast, brushing teeth) • use of a pill box. strategies to reduce likelihood of antiretroviral resistance feasibly exclude acute hiv infection before initiating prep by: • conducting antibody hiv testing before commencing or represcribing prep • among persons with a negative antibody hiv test, conduct a clinical screen to detect signs and symptoms of acute hiv infection – history of fever, sore throat, rash, joint pain, cough in the past month and a targeted examination (temperature, ent and skin exam)(see acute hiv infection text box) • if symptoms or signs of acute hiv infection found: • at screening: postpone prep until symptoms subside and rapid antibody test remains negative • at screening: do not initiate prep until confirmatory hiv antigen/antibody testing complete* • at follow-up: may elect to continue prep while awaiting results of confirmatory hiv antigen/antibody testing or may decide to withhold prep until confirmatory tests available • support client to maximise adherence and include adherence counselling at each visit • stop prep should requirements for prep eligibility not be fulfilled. managing abnormal screening results clients with abnormal renal function (estimated creatinine clearance <60 ml/min) should not be placed on prep. an abnormal estimated creatinine clearance result could be rechecked after 2 weeks and, if renal function returns to normal and other prep criteria are met, prep may be initiated. msm who are susceptible to hepatitis b should be immunised.* clients with a history of pathological bone fracture, a family history of osteoporosis, or decreased bone mineral density on dexa scanning, should be educated on ways to improve bone health, such as weight-bearing exercise, maintaining adequate calcium and vitamin d intake, and avoiding alcohol, tobacco and recreational drugs.35 msm who are ineligible for prep require support to assess other prevention options (see hiv prevention for msm text box). treat stis syndromically as per national guidelines (table 2).36 msm who test hiv positive should be clinically staged, have a cd4 count taken and be managed in line with hiv treatment guidelines (http://www.sahivsoc.org/practise-guidelines/national-dept-of-health-guidelines). safety monitoring and maintenance msm using prep require an initial 1-month follow-up to assess ongoing eligibility, tolerance, safety and adherence. hepatitis b vaccination and sti treatment (as appropriate), condoms and condom-compatible lubricant, risk reduction counselling, adherence support, a 3-month prescription for truvada and a follow-up date should be provided. thereafter, 3-monthly visits are recommended (table 3). details on recommended monitoring of bone mineral density is provided under other notes for prep prescribers below. managing abnormal follow-up visit results prep should be stopped if estimated creatinine clearance <60 ml/min. repeat creatinine clearance should be rechecked after 2 weeks; if renal function returns to normal and other prep criteria are met, prep may be restarted. stis should be treated syndromically (table 2). by mutual agreement, prep should be stopped if: hiv test is positive; the client no longer meets eligibility criteria; the client and provider feel that adherence to prep is too onerous; or it is perceived by the clinician that the risks of prep outweigh potential benefits. msm who are ineligible for prep require support to access other prevention options (see hiv prevention for msm text box below). risks and side-effects antiretroviral resistance the only hiv resistance documented to date among prep users has been among clients who started using prep when they were already hiv-infected (during acute hiv infection). predictably, ftc resistance mutations were the first to occur.25 to prevent the risks of arv resistance, clinicians must focus on not providing prep during acute hiv infection. hiv testing should be done 3-monthly, and should be accompanied by a symptom screen and a targeted examination to exclude acute hiv infection (see text box on acute hiv infection). hiv testing should also be repeated whenever symptoms of a viral illness are present. clinicians should advise clients on the need for an hiv test before resuming prep if it was stopped, particularly if they have potentially been exposed to hiv during this period. side-effects most available truvada safety data are derived from studies of hiv positive individuals receiving art.26 safety data of truvada use in hiv-negative individuals are emerging from prep trials and are reassuring.25 gastro-intestinal side-effects the side-effects related to truvada use in prep trials (nausea, weight loss) were mostly self-limiting start-up symptoms (first month), but these may adversely affect prep adherence. supportive counseling and symptomatic treatment (anti-emetics) of these symptoms are often sufficient. rates of other git symptoms (bloating, abdominal tenderness, flatulence) among prep trial participants who took truvada were not significantly different from those who took placebo.25 acute hiv infection severity of the syndrome ranges from mild non-specific ‘viral’ or ‘flu-like’ symptoms to a severe infectious mononucleosis like illness with immune dysregulation and transient profound cd4 depletion.37 , 38 potential predictable side-effects major side-effects: renal toxicity and metabolic complications (decreased bone mineral density) minor side-effects: gastrointestinal symptoms (diarrhoea, nausea, vomiting and flatulence), unintentional weight loss and a small risk of lactic acidosis and hepatic steatosis or steatohepatitis less predictable side-effects: may include hypersensitivity reactions and flares of hepatitis b in clients who are chronic carriers who receive and then stop tenofovir, lamivudine or emtricitabine renal toxicity modest, transient increases in serum creatinine have been noted in completed prep studies, but these did not persist after stopping prep nor recur on rechallenge. proteinuria, decreasing glomerular filtration rate (gfr) and fanconi’s syndrome* have been described in the setting of art, and decreased gfr has been described in the setting of prep but has either been statistically or clinically insignificant.25 renal function needs to be measured prior to commencement and monitored in clients using prep by measuring serum creatinine and calculating the estimated creatinine clearance. these parameters should be measured at baseline, at month 1, month 4 and then annually thereafter. hypertensives, diabetics, and those with existing glomerulonephropathies (if the benefit of prep is still deemed to outweigh clinical risk) should have monthly renal function checks. truvada-based prep should be avoided in patients who require the use of other nephrotoxic drugs such as aminoglycosides for the treatment of drug-resistant tuberculosis (tb). clients with creatinine clearance <60 ml/min should not be placed on prep and, if found during maintenance, prep should be discontinued. decreased bone mineral density decreases in bone mineral density associated with tdf and ftc/tdf have been observed in completed prep trials. decreases were less than those observed in hiv-infected individuals treated with the same drugs, and appeared to stabilise over time.39 , 40 no difference in fracture rates were seen. recreational drugs (amphetamines and inhalant use) were associated with reductions in bone mineral density in hiv-negative msm taking tdf while enrolled in a prep study.39 hepatitis b management tenofovir and emtricitabine both have hepatitis b antiviral activity. the risk exists that exposure to these antivirals may treat unidentified chronic hepatitis b infection with a consequent viral flare (rebound) upon drug withdrawal that can result in a severe liver injury.41 it is recommended that screening for hepatitis b surface antigen and antibodies occurs prior to prep commencement. it is recommended that, if hepatitis b surface antigen (hbsag) is positive, the client be referred for assessment prior to commencement of – in particular – short-term prep (table 4). a possible approach to those with chronic hepatitis b infection may be to prescribe long-term tenofovir/emtricitabine. liver function tests should be checked after stopping prep in those with chronic hepatitis b infection. clients who are negative for both hbsag and hepatitis b surface antibody (hbsab) should commence a hepatitis b vaccine schedule. clients with a history of injecting drug use should be screened for hepatitis c and, if positive, referred for further care. risk compensation this is the theoretical risk that individuals commencing prep will neglect other safer-sex measures, and put themselves at increased risk of hiv exposure. to date, no prep trials have borne out evidence in support of this risk. providers should gauge this during risk reduction and adherence counselling opportunities. hiv prevention package for msm the prevention of hiv acquisition requires a comprehensive approach, inclusive of a combination of biomedical and behavioural/ psychosocial interventions tailored to individual needs. where feasible, condoms and condom-compatible lubrication are key components of all hiv prevention packages, supported by sti detection and treatment, appropriate use of art (post-exposure prophylaxis), and counselling around the identification of high-risk practices and ways to circumvent or reduce risk. stopping prep prep should be stopped: whenever an hiv test is positive; at client request; for safety concerns (particularly if creatinine clearance <60 ml/min); and if the risks of prep outweigh the potential benefits. linkage to appropriate hiv services should be arranged, and use of other hiv prevention strategies used, as needed. the duration of prep use may vary and individuals are likely to start and stop prep depending on their risk assessment at different periods in their lives – including changes in relationship status, behaviours and ability to adhere to a prep maintenance programme. clients should be advised that an hiv test should be done before prep is recommenced. clinicians may want to discuss the options of when to discontinue prep with their clients. other notes for prep prescribers prep will not suit all users. prep should be considered for msm clients who are most likely to benefit from this specific prevention strategy as part of a package of hiv prevention services. prep usage requires commitment. usage will require commitment from both the provider and the user to ensure success. a paradox is that msm clients who are most likely to benefit from prep because they are at the highest risk of exposure to hiv may find adherence to a programme particularly challenging. providers may need to be innovative in providing support to these users. monitoring of bone mineral density. based on current evidence and expert opinion, and where feasible, baseline dexa scans should be done in clients with a family history of osteoporosis and/or a pathological fracture. importantly, the unavailability of dexa should not preclude prep use. annual follow-up dexa scanning is suggested (table 5). ongoing research on the role of dexa scanning will inform future recommendations. hiv prevention for msm • accessibility of condoms and compatible water-based lubricant should be addressed • no single hiv-risk reduction intervention is likely to suit all msm • combinations of prevention options, tailored to address specific risks, should be offered (‘menu of prevention choices’), inclusive of biomedical and psychosocial/behaviour change interventions • prevention options are likely to increase as new evidence becomes available. drug-drug interactions tenofovir should not be co-administered with adefovir. other drugs listed below can be co-administered but may require close monitoring, alteration of dosage or timing of administration. common drugs which may interact with emtricitabine (ftc) or tenofovir (tdf) drug name ftc tdf adefovir x – do not co-administer cimetidine x digoxin x x furosemide x x metformin x x naproxen x x ofloxacin x x streptomycin x x sulfadoxine/pyrimethamine x x source: university of liverpool. interactions with nrtis, october 2011 (http://www.hiv-druginteractions.org/data/printablecharts/nrti_col.pdf). prep: what we don’t yet know • what is the long-term efficacy of prep for msm? • what is the effect of prep on sexual behaviour and hiv risk? • what are the long-term effects of tenofovir/emtricitabine on renal function, bone mineral density, chronic viral hepatitis b and other effects in hiv-negative msm? • will resistance be a common event among those infected while using prep? • what is the ideal prep regimen and dosing interval? • what are the predictors of adherence for msm who use prep? • which msm are most likely to benefit from prep? • what will be the role of prep among sero-discordant msm couples? • what will be the long-term effect on treatment programmes that share art medications with prep programs? the future of prep many questions surrounding the safe and effective use of prep exist; ongoing research aims to address these knowledge gaps (prep: what we don’t yet know text box above). the iprex open-label extension study, and other similar studies, are trying to increase our understanding around long-term prep usage (http://iprexole.com/) specifically for msm. health facilities and health workers may be able to help answer these questions by keeping careful records of side-effects, patient adherence reports and hiv and hepatitis infections in their clients taking prep. adverse events can be reported to the national adverse drug event monitoring centre which is housed in the division of pharmacology at the university of cape town. the reporting guideline is available at: http://www.mccza.com/genericdocuments/2.11_adr_reporting_jun11_v2.doc. external reviewers: stefan baral, chris beyrer, robert grant, al liu, kathy muligan, tim lane, dawn smith. references 1. unaids. unaids terminology guidelines. geneva: world health organization, 2011:1-31. 1. unaids. unaids terminology guidelines. geneva: world health organization, 2011:1-31. 2. baral s, sifakis f, cleghorn f, beyrer c. elevated risk for hiv infection among men who have sex with men in lowand middle-income countries 2000-2006: a systematic review. plos medicine 2007; :e339. 2. baral s, sifakis f, cleghorn f, beyrer c. elevated risk for hiv infection among men who have sex with men in lowand middle-income countries 2000-2006: a systematic review. plos medicine 2007; :e339. 3. beyrer c, wirtz al, walker d, johns b, sifakis f, baral sd. the global hiv epidemics among men who have sex with men. washington, dc: the world bank, 2011. 3. beyrer c, wirtz al, walker d, johns b, sifakis f, baral sd. the global hiv epidemics among men who have sex with men. washington, dc: the world bank, 2011. 4. vittinghoff e, douglas j, judson f, mckirnan d, macqueen k, buchbinder sp. per-contact risk of human immunodeficiency virus transmission between male sexual partners. am j epidemiol 1999;150:306-311. 4. vittinghoff e, douglas j, judson f, mckirnan d, macqueen k, buchbinder sp. per-contact risk of human immunodeficiency virus transmission between male sexual partners. am j epidemiol 1999;150:306-311. 5. baggaley rf, white rg, boily m-c. hiv transmission risk through anal intercourse: systematic review, meta-analysis and implications for hiv prevention. int j epidemiol 2010;39:1048-1063. 5. baggaley rf, white rg, boily m-c. hiv transmission risk through anal intercourse: systematic review, meta-analysis and implications for hiv prevention. int j epidemiol 2010;39:1048-1063. 6. leynaert b, downs am. heterosexual transmission of human immunodeficiency virus. am j epidemiol 1998;148:88-96. 6. leynaert b, downs am. heterosexual transmission of human immunodeficiency virus. am j epidemiol 1998;148:88-96. 7. baral s, trapence g, motimedi f, et al. hiv prevalence, risks for hiv infection, and human rights among men who have sex with men (msm) in malawi, namibia, and 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24. cloete a, simbayi lc, kalichman sc, strebel a, henda n. stigma and discrimination experiences of hiv-positive men who have sex with men in cape town, south africa. aids care 2008;20:1105-1110. 24. cloete a, simbayi lc, kalichman sc, strebel a, henda n. stigma and discrimination experiences of hiv-positive men who have sex with men in cape town, south africa. aids care 2008;20:1105-1110. 25. grant rm, lama jr, anderson pl, et al. preexposure chemoprophylaxis for hiv prevention in men who have sex with men. new engl j med 2010;363:2587-2599. 25. grant rm, lama jr, anderson pl, et al. preexposure chemoprophylaxis for hiv prevention in men who have sex with men. new engl j med 2010;363:2587-2599. 26. grant rm, buchbinder s, clarke e, et al. promote hiv chemoprophylaxis research, don’t prevent it. science 2005;309:2170-2171. 26. grant rm, buchbinder s, clarke e, et al. promote hiv chemoprophylaxis research, don’t prevent it. science 2005;309:2170-2171. 27. cranage m, sharpe s, herrera c, et al. prevention of siv rectal transmission and priming of t cell responses in macaques after local pre-exposure application of tenofovir gel. plos med 2008;5:e157. 27. cranage m, sharpe s, herrera c, et al. prevention of siv rectal transmission and priming of t cell responses in macaques after local pre-exposure application of tenofovir gel. plos med 2008;5:e157. 28. garcia-lerma j, otten r, qari s, et al. prevention of rectoral shiv transmission in macaques by daily or intermittent prophylaxis with emtricitabine and teonofovir. plos med 2008;5:e28. 28. garcia-lerma j, otten r, qari s, et al. prevention of rectoral shiv transmission in macaques by daily or intermittent prophylaxis with emtricitabine and teonofovir. plos med 2008;5:e28. 29. baeten j, celum c. antiretroviral pre-exposure prophylaxis for hiv-1 prevention among heterosexual african men and women: the partners prep study. rome: 6th ias conference on hiv pathogenesis, treatment and prevention, 2011. 29. baeten j, celum c. antiretroviral pre-exposure prophylaxis for hiv-1 prevention among heterosexual african men and women: the partners prep study. rome: 6th ias conference on hiv pathogenesis, treatment and prevention, 2011. 30. thigpen m, kebaabetswe p, smith d, et al. daily oral antiretroviral use for the prevention of hiv infection in heterosexually active young adults in botswana: results from the tdf2 study. rome: 6th ias conference on hiv pathogenesis, treatment and prevention, 2011. 30. thigpen m, kebaabetswe p, smith d, et al. daily oral antiretroviral use for the prevention of hiv infection in heterosexually active young adults in botswana: results from the tdf2 study. rome: 6th ias conference on hiv pathogenesis, treatment and prevention, 2011. 31. liebert ma. early end for fem-prep hiv prevention trial. aids patient care and stds 2011; 25:383. 31. liebert ma. early end for fem-prep hiv prevention trial. aids patient care and stds 2011; 25:383. 32. united states centers for disease control 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prophylaxis randomized clinical trial in san francisco. plos one 2001;6(8):e23688. 39. liu ay, vittinghoff e, sellmeyer de, et al. bone mineral density in hiv-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in san francisco. plos one 2001;6(8):e23688. 40. mulligan k, glidden d, gonzales p, et al. effects of emtricitabine/ tenofovir on bone mineral density in seronegative men from 4 continents: dexa results of the global iprex study. boston: 18th conference on retroviruses and opportunistic infections, march 2011. 40. mulligan k, glidden d, gonzales p, et al. effects of emtricitabine/ tenofovir on bone mineral density in seronegative men from 4 continents: dexa results of the global iprex study. boston: 18th conference on retroviruses and opportunistic infections, march 2011. 41. honkoop p, de man r, niesters h, zondervan p, schalm s. acute exacerbation of chronic hepatits b virus infection after withdrawl of lamivudine therapy. hepatology 2000;32:635-639. 41. honkoop p, de man r, niesters h, zondervan p, schalm s. acute exacerbation of chronic hepatits b virus infection after withdrawl of lamivudine therapy. hepatology 2000;32:635-639. †therapeutic drug monitoring is currently not routine, although methods that require less invasive procedures, such as measuring drug levels in hair, are being validated. ‡couples in this instance refers to men who have had sex with each other more than once. fig. 1. flowchart for the screening, initiation and maintenance of prep among msm. *use 4th-generation hiv rapid (antigen+antibody) tests where available to confirm hiv infection status. table 1. mandatory baseline investigations for prep initiation among msm hiv infection rapid hiv antibody test renal function estimated creatinine clearance (ml/min) (formula for males) (140 age in years) x weight (kg) 0.82 x plasma creatinine (µmol/l) hepatitis b screen surface antigen (hbsag) antibody to surface antigen (hbsab) sti screen symptomatic screen examination if indicated urine dipstix for urethritis serological screening for syphilis (rapid or laboratory) table 2. syndromic treatment of stis among msm urethritis cefixime 400 mg po stat, plus doxycycline 100 mg po 12-hourly for 7 days. if symptoms persist after 7 days and repeat exposure and poor adherence are excluded, give metronidazole 2g po stat. if still symptomatic after a further 7 days, refer. genital ulcers benzathine penicillin 2.4 million units im stat for primary syphilis (repeat benzathine penicillin x 2, at weekly intervals for late syphilis), plus erythromycin 500 mg po 6-hourly for 7 days and acyclovir 400 mg po 8-hourly for 7 days rectal discharge/proctitis cefixime 400 mg po stat (or ceftriaxone 250mg imi stat) plus doxycycline 100 mg 12-hourly for 7 days (also screen for syphilis and consider acyclovir if any suggestion of ulcerative anal disease). table 3. summary of prep visits and procedures visit recommended procedures screening visit educate about the risks and benefits of prep assess eligibility and motivation conduct hiv counselling and testing, serum creatinine level and sti and hepatitis screen arrange follow-up prep initiation visit conduct hiv counselling and testing confirm eligibility (including investigation results and a calculation of creatinine clearance) commence hepatitis b immunisation (if indicated) provide sti treatment (if indicated) educate client about prep side effects and their management educate client about signs and symptoms of acute hiv infection discuss behaviours that promote bone health, such as weight-bearing exercise, maintaining adequate calcium and vitamin d intake, and avoiding alcohol, tobacco and recreational drugs initiate a medication adherence plan provide condoms and lubricant provide 1-month truvada prescription and 1-month follow-up date 1-month follow-up same as prep initiation visit, plus: assess tolerability, side-effects and adherence measure serum creatinine and calculate creatinine clearance provide 3-month truvada prescription and follow-up date 4-month follow-up and maintenance repeat procedures done at 1-month follow-up measure serum creatinine and calculate creatinine clearance at 4-month follow-up, and annually thereafter conduct 6-monthly sti screen for urethritis, genital ulcers and proctitis, including urine dipstix and rapid syphilis test complete hepatitis b immunisation *hepatitis b immunisations could be provided at prep initiation and at 1-month and 7-month follow-up visits. this schedule differs from standard vaccination at months 0, 1 and 6, but would minimise additional visits. *fanconi’s syndrome consists of renal tubular acidosis, hypophosphataemia, hypouricaemia together with urinary losses of glucose, amino acids and protein sometimes coupled with a reduced glomerular filtration rate. symptom sign malaise anorexia myalgias headache sore throat sore glands fever, sweating generalised lymphadenopathy hepatospenomegaly non-exudative pharyngitis aphthous ulceration truncal rash (maculopapular or urticarial) viral meningitis guillian-barre syndrome pneumocystis pneumonia cryptococcal meningitis oesophageal candidiasis table 4. hepatitis b immune status and eligbility for prep hepatits b surface antigen (hbsag) hepatitis b surface antibody (hbsab) action negative (-) negative (-) start prep, vaccinate concurrently negative (-) positive (+) start prep, no vaccine needed positive (+) n/a refer for evaluation biomedical psychosocial male condoms and compatible lubrication regular hiv counselling and screening early access to art reducing number of sex partners post-exposure prophylaxis (pep) reducing alcohol and substance abuse pre-exposure prophylaxis (prep) addressing mental health needs sti screening and treatment couples counselling and programming needle syringe exchange and opioid substitution therapy for msm who inject drugs harm reduction counselling and support for drug using msm table 5. monitoring bone mineral density (dexa scan) among msm using prep hiv acquisition risk osteopaenia risk resources intervention high high high prep + dexa scan (baseline and 12-monthly) moderate high high prep + dexa scan (baseline and 12-monthly) high high low prep + advise and observe moderate low low prep + advise and observe high low high prep + dexa scan (baseline, repeat if indicated) high low low prep + observe abstract introduction materials and methods results discussion conclusion acknowledgements references about the author(s) laston gonah health outcomes research unit, discipline of public health medicine, school of nursing and public health, college of health sciences, university of kwazulu-natal, durban, south africa indres moodley health outcomes research unit, discipline of public health medicine, school of nursing and public health, college of health sciences, university of kwazulu-natal, durban, south africa khumbulani hlongwana health outcomes research unit, discipline of public health medicine, school of nursing and public health, college of health sciences, university of kwazulu-natal, durban, south africa citation gonah l, moodley i, hlongwana k. effects of hiv and non-communicable disease comorbidity on healthcare costs and health experiences in people living with hiv in zimbabwe. s afr j hiv med. 2020;21(1), a1102. https://doi.org/10.4102/sajhivmed.v21i1.1102 original research effects of hiv and non-communicable disease comorbidity on healthcare costs and health experiences in people living with hiv in zimbabwe laston gonah, indres moodley, khumbulani hlongwana received: 04 may 2020; accepted: 23 june 2020; published: 04 sept. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the effects of hiv and non-communicable disease (ncd) comorbidities on healthcare costs and health experiences have been documented in most high-income countries. however, little similar data are available for zimbabwe and most countries in sub-saharan africa. untreated or under-treated ncds can potentially negate the gains achieved from the control of hiv. objectives: the study sought to determine the effects of hiv-ncd comorbidity on healthcare costs, health experiences and treatment options for people living with hiv (plwh) in zimbabwe. methods: a repeated-measures, quantitative study was conducted at six antiretroviral therapy (art) sites in the gweru district of zimbabwe. simple random sampling was used to enrol 100 plwh concurrently diagnosed with hypertension and/or diabetes mellitus (cases). cases were matched by age, sex and viral load to an equal number of plwh without hypertension and/or diabetes mellitus (controls). quantitative data were collected using an interviewer-administered questionnaire at monthly intervals for 6 months. the questionnaire survey sought to compare healthcare costs, health-related experiences and treatment options between cases and controls. data were analysed using stata version 13.1®. a logistic model was used to examine other factors such as demographic, clinical and behavioural data that were assumed to be unchanged over the study period. a random-effects model, including costs and other covariates, was used to compare groups in the final analysis. results: non-communicable disease status was associated with the length of time on art. cases spent significantly more on transport (p = 0.0001) and medication (adjusted odds ratio [aor] = 4.4, 95% confidence interval [ci]: 3.2–7.3); spent more days without doing usual daily activities because of sickness (aor = 4.2, 95% ci: 3.3–7.6) and were more likely to use alternative medication (aor = 3.4, 95% ci: 2.3–4.6) when compared with controls. unemployment, female gender, age of 60 years and above, and living in rural areas were associated with failure to purchase prescribed medication. conclusions: hiv-ncd comorbidity causes an additional burden to plwh because of increased transport costs, ncd prescribed medication expenses and more productive days lost due to illness. the success of hiv programmes does not only rely on improving access to the diagnosis and treatment of hiv. addressing the complications of hiv-related ncds, and the long-term costs of art and its occasional potential for harm will be essential if health outcomes in zimbabweans living with hiv are to be optimised. keywords: human immunodeficiency virus; non-communicable disease; zimbabwe; antiretroviral therapy; unemployment; diagnosis and treatment of hiv; art. introduction unprecedented donor and government funding to address the hiv and aids pandemic resulted in more than 20 million people receiving antiretroviral therapy (art) by mid-2017, against a total of 36.7 million people living with hiv (plwh) worldwide.1 whilst art has markedly increased survival, plwh have been found to be at greater risk of developing non-communicable diseases (ncds).2 people living with hiv have a threefold increased risk of developing ncds because of three main reasons: (1) inflammatory and infectious sequelae of hiv infection, (2) the effects of art treatment itself and (3) finally, the increased risk associated with ageing.3 successful art roll-out has resulted in most plwh living longer, possibly driving the onset of ncds, because of long-term viral infection, accumulation of drug toxins in the body and acceleration of age-related degenerative changes by hiv.4,5,6 according to the world health organization,7 ncds may be present before hiv infection but could be worsened by hiv or the side effects of some of the antiretroviral drugs. hiv-ncd comorbidity could have implications for healthcare costs, health experiences and survival compared with hiv alone. although the effects of hiv-ncd comorbidity on healthcare costs, health experiences and treatment options have previously been documented, especially in high-income countries, this is not true for most sub-saharan african countries, including zimbabwe.2 conducting such studies provides valuable information so that targeted intervention strategies can be developed. studies on hiv-ncd comorbidity are limited to a few cross-sectional surveys that are mainly based on self-reported data without a comparison group.2,8 hiv-ncd comorbidity causes an additional healthcare burden. whilst significant efforts have been made towards hiv control in zimbabwe, untreated or under-treated ncds can potentially negate the gains achieved through the national art roll-out. currently, no integrated care for hiv-ncd comorbidity is available in zimbabwe. despite accessing free services for hiv and aids, plwh have to pay for the treatment of ncds, mostly through out-of-pocket expenditure, which because of the financial burden, may prevent many patients from seeking care for ncds. the study sought to determine the effects of hiv-ncd comorbidity, using hypertension (htn) and diabetes mellitus (dm) as ncd-tracer conditions, on healthcare costs, health experiences and treatment options in plwh in the gweru district of zimbabwe. materials and methods study design a repeated-measures, longitudinal quantitative study design was employed. study setting the study was conducted at six high-volume government art sites that had the highest number of plwh and collectively representing over 80% of all plwh on art in gweru district. the six study sites consisted of four urban and two rural sites. the four urban sites are directly administered by gweru city council health department, whilst the two rural sites are administered by the ministry of health and child care. study population and participant selection procedures in this study, hiv patients of either gender, aged ≥18 years, registered for art programme in the electronic patient monitoring system (epms) and able to respond to the study questionnaire in shona, ndebele or the english language, were considered. in addition to the age and gender inclusion criteria above, the cases had to be plwh and concurrently diagnosed with dm and/or htn. all subjects provided written informed consent to participate in the study. those with a confirmed diagnosis other than the ncd-tracer conditions of htn and dm, as required for the study, were excluded. mentally impaired plwh and those not on art were also excluded from the study. as the epms and the chronic disease register are maintained separately, the identification and linkage of plwh with the tracer ncds were time-consuming and laborious. a total of 2969 plwh and comorbid ncds were identified during a 3-month screening or verification exercise among patients registered for the art programme. the 3-month period (december 2018 to february 2019) was ideal because all patients were expected to have visited the art sites for their monthly art supply. after applying the eligibility criteria, 842 eligible participants from the six sites were identified. proportional representation, as guided by the total number of eligible participants per site, was followed when selecting participants from rural and urban regions, and from among men and women, within all six sites. simple random sampling was then performed to obtain a representative sample per site, coming up with a total of the required sample size. sample size and sampling criteria a sample size of 186 (93 per group) was required to detect a characteristic difference of ± 20% between the two groups with a probability of 95% and power of 80%, assuming 50% in the control group. a 10% assumption was made for missing data and lost to follow-up. as such, a final sample size of 208 (104 per group) was needed to ensure sufficient numbers for analysis. two hundred of those providing informed consent, namely 100 pairs, instead of the initially calculated 208 participants or 104 pairs, were enrolled in the study and followed up for 6 months. (it is anticipated that the use of 100 pairs instead of the initially calculated 104 would not significantly affect the study power because 100 per group is still larger than the originally calculated sample size of 93 pairs needed to achieve the given power at the desired standard error.) the 100 cases were purposively matched by viral load (± 5 copies per milliliter of blood [copies/ml]), age (± 1 years), gender (male, female), distance to art site (± 2 km) and geographical location (rural, urban) in the ratio of 1 case : 1 control to get a total of 200 study participants. data collection methods quantitative data on participants’ demographic profile, disease-related factors, healthcare costs and health experiences were collected using an interviewer-administered questionnaire. health experiences were measured as the number of days spent by participants without carrying out usual daily activities because of ill health. the questionnaire intended for use was pretested among 10 consenting individuals and adjusted according to pretest findings before final use. time to complete a questionnaire survey ranged from 15 minutes to 20 minutes per participant. cases and controls were followed up for 6 months, and data were collected at 1-month intervals. the 6-month follow-up period allowed for repeated measurements, thereby providing sufficient data ‘points’ to determine disease burden, healthcare costs and health experiences. to ensure that participants kept an accurate record of their healthcare costs during the study, participants were requested to keep all receipts of their medical expenses and note down expenditure events within the month. medications for conditions under study required once-off monthly refills, thereby reducing chances of recall bias. data analysis methods data were analysed using stata version 13.1®. descriptive statistics were used to summarise the data for each analysis group. frequencies and percentages were used for categorical data. frequencies of numeric data were examined for normality, and means, standard deviation or medians were used as appropriate. a logistic model was used to examine other factors such as demographics, clinical data and behavioural data of the two groups that had been assumed to be unchanged over the study period. a random-effects mixed model including costs and other covariates was used to compare the groups in the final analysis. ethical consideration ethics approval for the study was obtained from the biomedical research ethics committee (university of kwazulu-natal) ethical clearance number: be086/19, and ministry of health and child care (from both the district office in gweru and the head office in harare). written informed consent was sought from participants and confidentiality was maintained throughout the study by removal of personal identifiers after entry into the electronic database, and the use of non-identifiable coded numbers. furthermore, all data were password protected in the electronic subject-storage database. results demographics of study participants equal numbers of cases and controls (100 participants each) were enrolled into each arm. the age of the participants ranged from 33 to 80 years, with a mean age of 57 (sd ± 10.79) years. the proportion of female participants was greater than that of male participants (table 1). the majority were unemployed at the time of the study, with no significant difference in financial status between cases and controls. mean monthly income per participant was $17.56 (sd ± 28.37), and grants received from relatives had a mean of $6.66 (sd ± 24.26). thirty-eight per cent of participants had viral loads of 0 copies/ml (undetectable viral load), whilst 34% had viral loads of below 20 copies/ml (table 1). average duration on art at baseline for cases was 10.22 years (sd ± 3.165) and was 4.32 years (sd ± 2.12) among controls. table 1: baseline demographic study data. over 98% of study participants were followed for the entire 6 months of the study with n = 3 deaths among the cases, and no loss to follow-up. in the analysis, the mixed-effects model was employed to deal with deaths, and all observations that contributed to the results were measured up to the point of the participant’s death. table 1 shows demographic and other key characteristics of study participants. the non-communicable disease study group, data and outcomes table 2 shows that the proportion of cases with htn alone was greater than that with dm alone, both at baseline and at the end of the study. none of the controls had a diagnosis of any ncd at baseline. the presence of ‘new’ ncds in cases and controls at the 6-month follow-up census is shown in table 2. three (n = 3) deaths (hiv or comorbid disease related) were recorded among cases during the study period. table 2: disease-related information among cases and controls. during the follow-up period, three new diagnoses of dm were recorded in the case group, whereas four new diagnoses of dm were recorded in the control group. again, four new cases of htn were diagnosed in the case group, and four new cases in the control arm. other new diagnostic conditions recorded during the study were peptic (gastrointestinal tract) ulcers (four among cases and two among controls), asthma (two among cases and none among controls), arthritis (three among cases and one among controls) and cataract (one among cases and none among controls). the average monthly number of productive days lost because of sickness was compared between cases and controls. on average, cases spent 11 more days unable to do usual daily activities because of self-reported illness when compared with controls (figure 1). figure 1: average number of days spent without doing usual daily tasks because of sickness. out-of-pocket expenses average monthly amount of money spent on transport by participants for travelling to access healthcare or medication was compared between cases and controls. in general, 52% more cases spent money on transport compared with controls (figure 2). figure 2: average monthly transport expenses. the participants’ ability to purchase dm and antihypertensive medications was assessed. more than 68% reported an inability to purchase prescribed medication for their conditions during the study period (table 3). table 3: summary of participants’ ability to purchase medications. the average monthly amount of money spent on prescription medication for htn and dm was assessed for the study period in both the cases and the controls (table 4). a significant number of cases did not have money to purchase their prescribed medication. only 14.8% reported consistently getting antihypertensive medication for free at their local health centre during the study period. none of the cases and controls reported receiving free diabetic medication from a health facility during the study period. table 4: average monthly amount of money spent on medication ($). concerning the use of traditional medicines, more cases (83.4%) reported using traditional medicines for the treatment and management of ill health compared to the control group (5.3%). similarly, the majority (> 73.0%) reported using traditional medication for the management of dm and/or htn in the case group, than in the control group who developed htn or dm (see table 5). table 5: use of traditional medicines for treatment. usual diet using the 24-hour food recall method participants were asked to name the type of food they had consumed in the previous 24 hours prior to the questionnaire survey, and subsequently for all the six (6-xs) monthly visits. the usual diet for more than 80% of both cases and controls was carbohydrate staples, such as rice and maize meal (sadza), which often included green leafy vegetables. less commonly consumed foods, consumed by less than 30% of the participants, were meat (all types), fruits, cereals, milk and milk products and legumes (figure 3). figure 3: common foods consumed by participants: 24-h food recall. analytical statistics of demographic and personal characteristics according to non-communicable diseases status and type, days spent without usual daily tasks and the ability to purchase non-communicable disease medication our analysis compared healthcare costs and the health-related experiences of cases versus controls. the parameters that were assessed included the ncd diagnosis, the number of days spent without doing usual daily tasks or activities and the ability to purchase prescribed medication. covariates included demographic variables such as age, sex, employment status, marital status, health insurance status, use of alternative medication, transport cost, viral load, duration on art, distance from the art centre, smoking and alcohol consumption. non-communicable disease status in relation to the use of alternative medication, transport costs and hospitalisation compared with the control group, the presence of target ncds in the case group was associated with a longer duration on art, that is, > 5 years, after controlling for other factors (p = 0.0023). as cases were matched to controls by age, sex, employment status, viral load and area of residence, these covariates were not associated with ncd status between the two groups. however, subgroup analysis of the case group indicated that two or more ncds were more common in female cases compared with male cases (p = 0.0021). use of alternative or traditional medicines was compared between cases and controls. cases were significantly more associated with use of alternative or traditional medication compared with controls (adjusted odds ratio [aor] = 3.4, 95% confidence interval [ci]: 2.3–4.6, p = 0.0001). having an ncd was significantly associated with higher monthly transport costs (p = 0.0001). rural cases in particular were associated with higher transport costs compared with urban cases, urban controls and rural controls (p = 0.0041). the average distance to the art centre was 15 km for rural cases as compared with 7 km for urban cases. the usual source of ncd medication (htn and dm) for the majority of cases (over 85%) was private pharmacies, except for only 14.8% of hypertensive patients whose usual source was other public health facilities. cases, whether diagnosed with dm, htn or both, were more likely to be hospitalised compared with controls (aor = 2.4, 95% ci: 1.2–3.3). the average number of hospitalisation days in cases was 5 days compared with 1 day in controls. days spent without usual daily tasks or activities because of illness to assess the effect of ncds on productivity, average monthly number of days spent without doing usual daily activities because of illness was compared between cases and controls. cases were more likely to spend more days without doing usual daily activities compared with controls (aor = 4.2, 95% ci: 3.3–7.6, p = 0.0000). days spent without doing usual daily tasks or activities were associated with female gender, inability to purchase medication and unemployment status. women spent more days without usual daily activities when compared with men in both cases and controls (p = 0.0031). again, the inability to purchase prescribed medication was associated with more days spent without doing usual daily activities because of illness in both cases and controls (p = 0.0023). unemployed participants spent more days without doing ‘usual’ daily activities as compared with formally employed and informally employed participants (p = 0.001). subgroup analysis of cases showed that cases with more than two ncds spent more days without doing usual daily activities (aor = 2.1, 95% ci: 1.3–4.4). ability to purchase non-communicable disease medication not all patients could afford their prescribed medication. therefore, simply estimating costs on the basis of monthly prescriptions would not have represented the actual situation on the ground. participants – cases and controls – were asked to indicate monthly medication expenses and to record for the duration of the study, which medicines had not been purchased each month. this inability to purchase prescribed medication was used in this study as an adjunctive measure of the effect of ncds on healthcare costs in plwh. cases were less likely than controls to be able to purchase medication for ill health. inability to purchase medication was associated with having an ncd (aor = 4.4, 95% ci: 3.2–7.3). among the cases, the inability to purchase ncd medication was associated with the number of ncds per patient, sex, age and employment status. cases with two or more ncds were more unlikely to purchase medication compared with those with one ncd (p = 0.000). female participants were less likely than male cases to afford monthly medication requirements (p = 0.0011). participants living in rural areas and those in the age categories 60–69 years and ≥70 years were similarly less likely to afford medications, than urban participants and those aged <60 years (p = 0.0031, 0.0001 and 0.0000, respectively). formal employment was significantly associated with the ability to purchase medication, after adjusting for potential confounders (p = 0.000). estimated average monthly expense on medication among cases was $12 compared with $1 among controls, considering only those who were able to purchase all the prescribed medication. assessment of usual diet there was no significant difference in usual diet between cases and controls, using the 24-hour food recall method. the usual diet for both cases and controls was carbohydrate staples and green leafy vegetables, with less protein sources of food. employment status was significantly associated with consuming a balanced diet, rich in all the required nutrients, in both cases and controls (p = 0.0003). consumption of a balanced diet was not associated with other demographic characteristics and ncd status. discussion the study compared healthcare costs, health experiences and care-related outcomes in plwh diagnosed with htn and/or dm with a matched control group of plwh without ncds. this study observed numerous important findings of relevance to plwh in africa (zimbabwe) who are on art and virally suppressed: the concurrent presence of comorbid disease is a function of time on art. hiv-ncd comorbidity undermines the goals of hiv treatment, which is to control the virus (hiv) and promote wellness: (1) expenses increase, for example, medication and travel costs; (2) impaired management of comorbid conditions, where over 68% of the case group were unable to afford dm or htn medication, which were not supplied free-of-charge; (3) increasing vulnerability to non-evidence-based health options and (4) hiv-ncd comorbidity results in greater risk of morbidity and mortality. women bear the greater burden of comorbid disease, and experience greater ‘disability’ – unable to do usual daily tasks. rural citizens and the elderly appear to experience a greater negative impact of economic hardship from comorbid conditions. in general, controls, namely, virally suppressed plwh without htn, dm or both, were associated with lower average monthly expenses on prescription medication and spent fewer number of days without carrying out usual daily activities or tasks because of illness, compared with virally suppressed plwh with htn and/or dm. in zimbabwe, most plwh access art free-of-charge in public health facilities.9 however, medication for the ncds is usually not available free-of-charge. these patients have to access medication largely through out-of-pocket expenses. ability to pay for ncd medication, therefore, becomes a major determinant for access to medication, which results in poor management of the ncds and the generally observed higher number of productive days lost because of illness. this has potential to impact negatively on the gains achieved so far in controlling hiv through art. unemployment, gender, age and distance to a healthcare facility are well-known key determinants of health.10 in this study, significant associations were found between these key determinants of health and the ability to purchase prescribed medication, as well as days spent without carrying out usual daily activities because of illness. this finding can be explained in part by the fact that the majority of employed participants in the study were men, below the age of 60 years. given that antihypertensives and diabetic medications were largely accessible through out-of-pocket payment, employment enables those with ncds to purchase the prescribed medications and take control of their health. in patriarchal societies, such as zimbabwe, opportunities for income and control of resources are biased towards the male gender compared with females.11 the female gender and unemployment are inextricably linked together in such societies, predisposing unemployed female participants to negative health outcome, as observed in this study. on the other hand, the lower proportion of male participants and the fewer number of days these male participants spent without undertaking usual daily activities because of illness, compared with female participants, needs further inquiry. observed findings could have been influenced in part by poor health seeking behaviours, which are commonly associated with the male gender.12 because of their masculinity, characteristic of men, participants might deliberately under-report the number of days they spent without carrying out usual daily activities. perhaps, the perception of serious ill health in men might be different from that in women.12,13,14 in general, cases were found to spend more days without undertaking usual daily activities because of illness compared with controls. a study conducted in namibia found similar results, where sickness because of htn and dm was the top cause of absenteeism among workers in the formal sector.15 cases aged 60–69 years and ≥ 70 years were more likely to spend more days without carrying out usual daily activities or tasks because of illness. they were more at risk of not being able to purchase ncd medication, compared with other age categories, and compared with similar age categories in controls, after controlling for potential confounders. productivity days lost because of illness are linked with lower income or loss of employment or limited opportunities for work, which translates to lack of income to purchase the needed medication. a study conducted in usa16 found out-of-pocket medication costs to be a significant challenge faced by older adults with dm, often forcing them to cut back on medication use, forgoing food or other basic necessities or borrowing money. the age group ≥60 years is usually associated with retirement and diminished ability and opportunities for employment.17 when medication for ncds has to be purchased through out-of-pocket payments, this age group is at risk because of inability to afford medication and consequently face a greater risk for the observed poorer health outcomes. having two or more ncds was markedly associated with more days spent without undertaking usual daily activities and more money spent on medication, compared with cases with one ncd. having more than one ncd naturally translates to more money needed to purchase medication, thus increasing the possibility of inability to purchase the required medication, especially given the fact that the majority of the participants were either unemployed or had an unstable source of income. without access to prescribed medication to manage their health, patients would be predisposed to poorer health outcomes as indicated by productive days lost because of illness observed in this study. patients were more likely to opt for alternative medication from informal sources to manage their health in the face of limited or no income to purchase prescribed medication. use of alternative medication was commonly reported among cases as compared with controls. however, use of alternative medication was not associated with positive improvements on days spent without undertaking daily activities because of sickness. use of alternative medication may have been influenced to some extent by the cases’ inability to purchase ncd medication, forcing patients to resort to cheaper alternatives to manage ill health. this could be assumed, given that the controls did not report use of alternative medication for management of hiv other than art. common alternative medication included home remedies and traditional herbs that are readily available at lower costs. toxicity, maximum safe dosage and clinical efficacy for these treatment options are usually not known, thus potentially predisposing the users to other unknown negative health consequences.18 future studies should assess the various types and sources of alternative medications commonly used by this patient population to gain a better understanding about this issue. higher out-of-pocket medication and transport expenses faced by cases can push patients to employ various coping mechanisms, including cutting back on medication use to adopt traditional medication or forgoing other basic necessities including food.16 finally, we need further enquiry to better understand challenges experienced by people with hiv-ncd comorbidity (especially the difficulties faced in accessing medication and care) and the coping mechanisms that they employ in dealing with these challenges. study limitations measurement of the outcome variable, ‘number of days spent by participants without doing usual daily activities or tasks’, was based on self-reported responses by participants and not objectively ascertained. although effort was put in corroborating individual responses with further follow-up questions, there is a possibility that variations in personal characteristics could have affected how participants responded to ill health (to do or not to do usual daily tasks). again, recall bias cannot be ruled out in the measurement of this variable. however, we believe that self-reported episodes of serious sickness within a month are less likely to vary significantly from the actual episodes. adherence to art use in this study was not assessed, but rather assumed, based on satisfactory hiv viral load measurements of participants. there is a possibility that the observed health experiences measured in this study might not have been sorely because of inability to purchase ncd medication alone, but because of interaction with non-compliance to ncd prescribed medication or use of traditional medication for ncds that was common among cases in this study. survival was not assessed in this study to compare survival rates between cases and controls. whilst the 6-month follow-up was adequate to assess trends in health expenses and health experiences, it was not long enough for survival analysis to be performed. survival analysis would have required longer a follow-up period of 5–15 years, which would not have been feasible for this study. representativeness of our research data to other african countries with stable economies might be limited, in part, because of the economic crisis faced by zimbabwe, which makes it unique in sub-saharan africa. conclusion hiv-ncd comorbidity causes an additional burden to plwh because of increased transport costs, ncd prescribed medication expenses and more productive days lost because of illness. access to antihypertensives and diabetic medications is influenced by interplay of the key determinants of health, which include income, gender, age and geographical location. the success of hiv programmes does not only rely on improving access to the diagnosis and treatment of hiv. addressing the complications of hiv-related ncds and the long-term costs of art and its occasional potential for harm will be essential if health outcomes in zimbabweans living with hiv are to be optimised. acknowledgements the authors acknowledge the support received from the university of kwazulu-natal in conducting the study. competing interests the authors have declared that no competing interest exists. authors’ contributions all authors contributed equally to this work. funding information the study was funded by university of kwazulu-natal, under phd research grants. data availability statement due to the private nature of the data, data for the study will be available only upon request and approval of authorising ministry of health. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references joint united nations programme on hiv/aids (unaids). global report: unaids report on the global aids epidemic 2010. geneva: unaids; 2010. harris tg, rabkin m, el-sadr wm. achieving the fourth 90: healthy aging for people living with hiv. aids. 2018;32(12):1563. https://doi.org/10.1097/qad.0000000000001870 narayan kv, miotti pg, anand np, et al. hiv and noncommunicable disease comorbidities in the era of antiretroviral therapy: a vital agenda for research in low-and middle-income country settings. aids. 2014;67:s2–s7. https://doi.org/10.1097/qai.0000000000000267 negin j, mills ej, bärnighausen t. aging with hiv in africa: the challenges of living longer. aids. 2012;26(01):s1. https://doi.org/10.1097/qad.0b013e3283560f54 nugent r, barnabas rv, golovaty i, et al. costs and cost-effectiveness of hiv/ncd integration in africa: from theory to practice. aids. 2018;32(suppl 1):s83. https://doi.org/10.1097/qad.0000000000001884 shade sb, osmand t, luo a, et al. cost of integrating non-communicable disease (ncd) care into ugandan hiv/medical clinics in the search study. 9th international aids society (ias) conference 23–26 july 2017; paris, france: ias. 2017 who. working group on the inclusion of ncds in other programmatic areas: world health organization global coordination mechanism on the prevention and control of noncommunicable diseases. working group 3.1 (2016-2017). geneva: world health organization; 2018. haregu tn, oldenburg b, sestwe g, elliott j, nanayakkara v. epidemiology of comorbidity of hiv/aids and non-communicable diseases in developing countries: a systematic review. j glob health care syst. 2012;2(1):1–2. zimbabwe. the national health strategy for zimbabwe, 2009-2013: equity and quality in health: a people’s right. harare: ministry of health & child welfare; 2009. who. closing the gap in a generation: health equity through action on the social determinants of health: who commission on social determinants of health final report. geneva: world health organization; 2008. türmen t. gender and hiv/aids. int j gynaecol obstet. 2003;82(3):411–418. https://doi.org/10.1016/s0020-7292(03)00202-9 peacock d, stemple l, sawires s, coates tj. men, hiv/aids, and human rights. j acquir immune defic syndr. 2009;51(suppl 3):s119–s125. https://doi.org/10.1097/qai.0b013e3181aafd8a camlin cs, ssemmondo e, chamie g, et al. men ‘missing’ from population-based hiv testing: insights from qualitative research. aids care. 2016;28(suppl 3):67–73. https://doi.org/10.1080/09540121.2016.1164806 dworkin sl. who is epidemiologically fathomable in the hiv/aids epidemic?. gender, sexuality, and intersectionality in public health. cult health sex. 2005;7(6):615–623. https://doi.org/10.1080/13691050500100385 guariguata l, de beer i, hough r, et al. diabetes, hiv and other health determinants associated with absenteeism among formal sector workers in namibia. bmc public health. 2012;12(1):44. https://doi.org/10.1186/1471-2458-12-44 piette jd, heisler m, wagner th. problems paying out-of-pocket medication costs among older adults with diabetes. diabetes care. 2004;27(2):384–391. https://doi.org/10.2337/diacare.27.2.384 maciel ra, klück hm, durand m, sprinz e. comorbidity is more common and occurs earlier in persons living with hiv than in hiv-uninfected matched controls, aged 50 years and older: a cross-sectional study. int j infect dis. 2018;70:30–35. https://doi.org/10.1016/j.ijid.2018.02.009 peltzer k, pengpid s. utilization and practice of traditional/complementary/alternative medicine (t/cam) in southeast asian nations (asean) member states. stud ethno-med. 2015;9(2):209–218. https://doi.org/10.1080/09735070.2015.11905437 pg4-5.html message from the executive the national strategic plan for 2011 2016 is being written as you read this issue of the journal. through its members, the society has contributed a lot to the draft that it is hoped will be out in the next few weeks. the previous plan was constructed in extremely difficult political circumstances (the then minister of health and senior department of health officials were still part of the old mbeki era of hiv denial), and involved long meetings arguing over the most ridiculous points of science. this plan is a completely different beast – broadly consulted in multiple meetings with every corner of society, with the doh leading from the front. the writing team is reviewing a huge number of submissions, and integrating the suggestions into a strategic plan. the plan suggests that there will be more firm targets on everything from monitoring the number of people on art to human rights abuses to drug stock-outs, and some dramatic ‘game changers’. keep your eye on this space – we’ll be profiling the plan through the society. the executive’s term of office is up, as the board has taken over, in terms of the new companies act. they have kindly remained as an advisory board, but elections for a new set of directors for the society will take place in november. i encourage people to consider standing, even though the current exco is a hard act to follow. finally, welcome to landon as the new, energetic editor of the journal – we can’t wait to see how you build on the lgb legacy. francois venter president about the author(s) remco p.h. peters research unit, foundation for professional development, east london, south africa department of medical microbiology, university of pretoria, pretoria, south africa division of medical microbiology, faculty of health sciences, university of cape town, cape town, south africa nigel garrett centre for the aids programme of research in south africa (caprisa), university of kwazulu-natal, durban, south africa department of public health medicine, school of nursing and public health, university of kwazulu-natal, durban, south africa nomathemba chandiwana ezintsha, faculty of health science, university of the witwatersrand, johannesburg, south africa ranmini kularatne department of clinical microbiology and infectious diseases, faculty of health sciences, university of the witwatersrand, johannesburg, south africa adrian j. brink division of medical microbiology, faculty of health sciences, university of cape town, cape town, south africa karen cohen department of medicine, division of clinical pharmacology, university of cape town, cape town, south africa katherine gill desmond tutu hiv centre, university of cape town, cape town, south africa thato chidarikire national department of health, pretoria, south africa camilla wattrus southern african hiv clinicians society (sahcs), johannesburg, south africa jeremy s. nel helen joseph hospital, university of the witwatersrand, johannesburg, south africa mahomed y.s. moosa department of infectious disease, division of internal medicine, nelson r. mandela school of medicine, university of kwazulu-natal, durban, south africa linda-gail bekker desmond tutu hiv centre, university of cape town, cape town, south africa citation peters rph, garrett n, chandiwana n, et al. erratum: southern african hiv clinicians society 2022 guideline for the management of sexually transmitted infections: moving towards best practice. s afr j hiv med. 2022;23(1):a1465. https://doi.org/10.4102/sajhivmed.v23i1.1465 note: doi of original article published: https://doi.org/10.4102/sajhivmed.v23i1.1450 correction erratum: southern african hiv clinicians society 2022 guideline for the management of sexually transmitted infections: moving towards best practice remco p.h. peters, nigel garrett, nomathemba chandiwana, ranmini kularatne, adrian j. brink, karen cohen, katherine gill, thato chidarikire, camilla wattrus, jeremy s. nel, mahomed y.s. moosa, linda-gail bekker published: 24 nov. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. in the published article, peters rph, garrett n, chandiwana n, et al. southern african hiv clinicians society 2022 guideline for the management of sexually transmitted infections: moving towards best practice. s afr j hiv med. 2022;23(1):a1450. https://doi.org/10.4102/sajhivmed.v23i1.1450, a typographical error occurred, where hsv-1 was used instead of hsv-2. the correction has now been made on page 6, in section 3. clinical management of the symptomatic patient, 3.3. genital ulcer disease, paragraph one, and should read: the original paragraph: the manifestation of gud is diverse and the characteristics of the ulcer (e.g. presence or absence of pain, shape of edges, multiplicity) are of poor diagnostic value in determining aetiology, particularly in plhiv.34 attempting to clinically diagnose the aetiology of gud using ulcer characteristics is not recommended and should not be used to inform treatment decisions. hsv-1 and hsv-1 are the most common causes of genital ulcers followed by treponema pallidum, the causative agent of syphilis. lymphogranuloma venereum (lgv) caused by c. trachomatis biovars l1–l3, chancroid (haemophilus ducreyi), and donovanosis (klebsiella granulomatis) have become uncommon in the last decade.14,35,36 the revised and updated paragraph: the manifestation of gud is diverse and the characteristics of the ulcer (e.g. presence or absence of pain, shape of edges, multiplicity) are of poor diagnostic value in determining aetiology, particularly in plhiv.34 attempting to clinically diagnose the aetiology of gud using ulcer characteristics is not recommended and should not be used to inform treatment decisions. hsv-2 and hsv-1 are the most common causes of genital ulcers followed by treponema pallidum, the causative agent of syphilis. lymphogranuloma venereum (lgv) caused by c. trachomatis biovars l1–l3, chancroid (haemophilus ducreyi), and donovanosis (klebsiella granulomatis) have become uncommon in the last decade.14,35,36 the publisher apologises for this error. the correction does not change the study’s findings of significance or overall interpretation of the study’s results or the scientific conclusions of the article in any way. abstract introduction research methods and design results discussion conclusion acknowledgements references about the author(s) kagisho l. thomas department of internal medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa malcolm davies renal department, faculty of health sciences, university of the witwatersrand, johannesburg, south africa citation thomas kl, davies, m. survival outcomes of hiv-positive adults on peritoneal dialysis at helen joseph renal unit. s afr j hiv med. 2023;24(1), a1471. https://doi.org/10.4102/sajhivmed.v24i1.1471 original research survival outcomes of hiv-positive adults on peritoneal dialysis at helen joseph renal unit kagisho l. thomas, malcolm davies received: 16 nov. 2022; accepted: 10 mar. 2023; published: 10 may 2023 copyright: © 2023. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: hiv is a risk factor for the development of chronic kidney disease. people with chronic kidney disease in the state sector are likely to be prescribed continuous ambulatory peritoneal dialysis (capd). previous studies have raised concern about the safety of capd in people living with hiv (plwh) compared to hiv-negative patients. objectives: to compare the risk of peritonitis, and modality and patient survival by hiv status in patients receiving capd at helen joseph hospital. method: a retrospective study of patients receiving capd between 01 january 2007 and 31 december 2017 was undertaken. five-year patient and modality survival were modelled for plwh and hiv-negative subgroups and analysed using the log-rank test; the effect of cd4 count, hiv viral load, and duration of antiretroviral therapy on these parameters in plwh were additionally modelled using the cox proportional hazards technique. results: eighty-four patients, comprising of 21 plwh and 63 hiv-negative patients, were analysed. no difference was observed in the proportion of patients who had at least one episode of peritonitis between plwh (61.2%) and hiv-negative patients (63.5%) (p = 0.547). a trend towards increased risk of peritonitis due to gram-negative organisms in plwh was noted (odds ratio: 3.20, 95% confidence interval: 0.86–11.9, p = 0.083). no difference was observed in 5-year patient or modality survival on capd between plwh (log-rank p = 0.161) and hiv-negative patients (log-rank p = 0.240). conclusion: people living with hiv should not be excluded from capd as a mode of kidney replacement therapy (krt). keywords: hiv; continuous ambulatory peritoneal dialysis; chronic kidney disease; peritonitis; antiretrovirals. what this study adds: patients with hiv should not be excluded from continuous ambulatory peritoneal dialysis kidney replacement therapy. introduction south africa is the epicentre of the global hiv epidemic, with an estimated overall prevalence rate of 13.9%, and approximately 8.45 million people living with the virus as of 2022.1 the advent of the antiretroviral therapy (art) programme in 2004 decreased aids-related deaths from 345 185 in 2006 to 126 755 in 2017, and resulted in an improvement in life expectancy from 52.2 years to 61.2 years in male patients, and 55.3 years to 66.7 years in female patients.1 these victories in survival in people living with hiv (plwh) may, however, come at the cost of increases in the burden of non-communicable disease, including chronic kidney disease (ckd). hiv infection has long been recognised as an aetiological factor in kidney disease.2 in populations of recent african ancestry, genetic polymorphisms in the apolipoprotein-1 protein coding sequence has been associated with a higher prevalence of ckd due to increased risk of the development of hiv-associated nephropathy.3 apolipoprotein-1 mutations are also known to increase the risk of focal segmental glomerulosclerosis and hypertensive nephropathy, and may also play a role in the progression of diabetic kidney disease.2,4 in addition, exposure to nephrotoxic agents including art and prophylactic antibiotics, as well as opportunistic infections and hepatitis b and c co-infections increases the risk of kidney disease in plwh.2,3 improved survival in plwh due to widespread availability of art increases the probability of the development of ageand lifestyle-related disorders such as hypertension and diabetes.5,6 furthermore, relative normalisation of immune system function in patients taking art increases the possibility of the development of immune-mediated kidney disease such as focal segmental glomerulosclerosis.4 these considerations underlie the observation that, despite a decrease in hiv-associated nephropathy incidence since art rollout, there has been an increase in ckd in plwh.3,7 improved life expectancy in the hiv and/or aids population further increases the probability of progression of ckd requiring long-term kidney replacement therapy (krt).1,2 south africa’s historical inequalities mean that plwh who develop ckd are most likely to access krt through the public state sector. chronic resource limitations in state dialysis units limit individual patient choice as to the dialysis modality offered to new initiates. reduced staff and infrastructure costs, and lowered patient transport costs,8,9 result in many state dialysis units preferably initiating onto continuous ambulatory peritoneal dialysis (capd) rather than haemodialysis. as a result, capd is more frequently prescribed in state units than is the case in the private sector.10 patient outcomes on capd in general are similar to those receiving haemodialysis10,11 in high-income countries, with a paucity of data in low-income countries. however, some concern exists as to the safety of capd in plwh, with a previous south african series suggesting an increased risk of peritonitis and modality failure in this group.12 these risks appear to relate to the severity of immunodeficiency in plwh initiating capd, which in turn suggests that art prescription may ameliorate this risk. since institutional policy at the helen joseph dialysis unit requires art initiation before capd prescription, we investigated the effect of hiv-positive status on patient and modality outcomes in a cohort of patients initiating dialysis between 2007 and 2017. research methods and design helen joseph hospital is a tertiary-level facility which provides krt to patients resident in the western areas of johannesburg in the gauteng province. the hospital pursues a ‘capd first’ policy. people living with hiv do not need to demonstrate virological control prior to dialysis but must have been started on art prior to capd initiation. in addition, plwh on dialysis are referred to the on-site hiv clinic for optimal management. all patients above the age of 18 years initiating capd at the helen joseph hospital between 01 january 2007 and 31 december 2017 were considered for inclusion; patients with missing medical records were excluded from the study. consecutive sampling was used to identify patients for inclusion and the final data set comprised all patients on capd during the study period who met inclusion criteria. the patients had to be on dialysis for at least 3 months to be considered eligible for the study. there were no patients on automated peritoneal dialysis enrolled in the study. anonymised data including patient demographics (age, gender and ethnicity), comorbidities (diabetes mellitus, hypertension and known cardiovascular disease), hiv-positive status (including cd4 count, viral load and duration of art prior to dialysis initiation), hiv-associated nephropathy (defined as ckd in plwh with no apparent aetiology persisting for more than 3 months, presenting with sub-nephrotic proteinuria and/or enlarged kidneys on ultrasound), peritonitis episodes and aetiological organism, and patient and capd modality survival data were extracted from clinical records and stored in an excel® database which was subsequently exported for analysis using statistica version 14 (tibco software, palo alto, california, united states). distribution of continuous data was assessed using the shapiro-wilk w test and through visual inspection of the histogram plot. the proportions experiencing at least one episode of peritonitis, and microbiology of peritonitis episodes, were described and compared between plwh and hiv-negative patients using the pearson chi-square test. time to first episode of peritonitis from modality initiation was compared between plwh and hiv-negative patients using the mann-whitney u test. the effect of cd4 count, hiv viral load and duration of art prescription at capd initiation on time to first episode of peritonitis were modelled in plwh using cox proportional hazards modelling. five-year patient and modality survival from time of capd initiation were modelled for plwh and hiv-negative subgroups and analysed using the log-rank test; the effect of cd4 count, hiv viral load and duration of art on these parameters in plwh were additionally modelled using the cox proportional hazards technique. ethical considerations the study was approved by the university of the witwatersrand human research ethics committee (protocol number m190506). results of 115 patients initiated onto capd during the study period, 31 were excluded due to incomplete data, resulting in 84 patients, comprising 21 plwh and 63 patients who were hiv-negative, being included in the final analysis. baseline characteristics of the cohort are shown in table 1. table 1: baseline characteristics of patients receiving continuous ambulatory peritoneal dialysis helen joseph hospital, 2007–2017. all plwh in this study were initiated onto art prior to capd start, although there was considerable variation in the duration of art preceding dialysis (range 1–108 months). among patients not yet achieving virological control on art, the median viral load was 249 copies/ml (range 55 copies/ml – 110 000 copies/ml). a total of 111 episodes of peritonitis were recorded among 53 patients. forty (63.5%) hiv-negative patients experienced at least one episode of peritonitis compared to 13 (61.2%) plwh (p = 0.547). a total of 84 episodes of peritonitis were recorded in hiv-negative patients compared to 27 in plwh; the proportions of peritonitis episodes between hiv-negative patients and plwh was not significantly different (p = 0.943). there was no significant difference in the median time to first episode of peritonitis between plwh (12.7 months) and hiv-negative (10.4 months) patients in this series (p = 0.125). a large proportion of all peritonitis episodes in this cohort were culture negative (46 cases, 41.4%); rates of culture-negative peritonitis were not significantly different between plwh (12 cases, 26.1%) and hiv-negative (34 cases, 73.9%) patients (p = 0.823) (table 2). gram-positive bacteria were the most common isolates (31 cases, 47.7%) among culture-positive peritonitis episodes, followed by gram-negative (28 cases, 43.1%); fungal peritonitis contributed six cases (9.2%) and there were no cases of tuberculous peritonitis in this cohort. gram-positive organisms were more frequent isolates in hiv-negative patients (54% of all cultures organisms in this group), while gram-negatives were more frequently cultured in plwh (60%); a trend towards increased odds of culturing gram-negative organisms in plwh with bacterial peritoneal dialysis-associated peritonitis was observed (odds ratio [or]: 3.20, 95% confidence interval [ci]: 0.86–11.9, p = 0.083). table 2: peritoneal dialysis-associated peritonitis. overall patient survival on capd among plwh was 76.2% compared to 60.3% for hiv-negative patients (p = 0.292); modality survival among plwh was 71.4% compared to 61.9% for the hiv-negative cohort (p = 0.599). five-year patient (figure 1) and modality (figure 2) survival were not significantly different between hiv-positive subgroups (log-rank p = 0.153 and p = 0.233, respectively). figure 1: patient survival at 5 years of follow-up. figure 2: modality survival at 5 years of follow-up. no effect was detected for cd4 count, hiv viral load, or duration of art in plwh on either the time to first episode of peritonitis (p = 0.602, p = 0.723, and p = 0.164, respectively), 5-year patient survival (p = 0.953, p = 0.238, and p = 0.635, respectively) or on 5-year modality survival (p = 0.427, p = 0.783, and p = 0.310, respectively). discussion this study provides evidence for the safety of capd in plwh in the context of universal access to art. in particular, plwh do not appear to be at greater risk of peritonitis, and patient and modality survival on capd appear to be similar to that of hiv-negative patients. the need for improved access to krt among plwh is well illustrated by the observation that 25% of patients included in this cohort were hiv-positive, compared to the estimated population prevalence of hiv infection in south africa of 12.6% during the study period.1 continuous ambulatory peritoneal dialysis offers an attractive means to increase krt availability in the south african context, but concerns exist about the safety of this modality in plwh. in particular, an increased risk of capd-related peritonitis has been reported in plwh who have cd4 counts below 200 cells/mm3 at dialysis initiation.13 in the present study, hiv infection did not increase the number of peritonitis episodes, and no effect was observed for hiv positivity, viral load or cd4 count on time to first episode of peritonitis. reductions in peritonitis risk in the present cohort are likely mediated by use of art, as a result of which two-thirds of plwh included in this series had a cd4 count at dialysis initiation above 200 cells/mm3. while overall risk for peritonitis may be independent of hiv status, seropositivity may affect the microbiological pattern of causative organisms encountered. previous south african reports have suggested an increased risk of staphylococcus species in the nasal carriage, with lower cd4 count in plwh on capd, which has been proposed as a risk factor for peritonitis.14 in contrast, the present study found a trend towards increased odds of gram-negative peritonitis in plwh. a growing body of literature reports intestinal dysbiosis in plhw, which may not revert even with successful virological suppression on art.15 this persistent dysbiosis may result in chronic gut wall inflammation,16 in turn facilitating transmural translocation,15 a known pathogenic pathway for the development of gram-negative capd-related peritonitis.17 peritonitis has been reported to be the most important modifiable risk factor for modality survival.18 similar peritonitis risk between plwh and hiv-negative patients through universal art prescription in the present study is likely to have been a significant contributor to survival outcomes in plwh in this series. however, additional factors related to the selection of patients for capd as practised at this institution are also likely to have played a role. in particular, restriction of capd access to those patients with home circumstances favourable to the creation of a suitably sterile environment to perform dialysate indwell catheterisation is likely to have contributed to reductions in peritonitis rates. peritonitis is also known to be an independent contributor to survival of patients on capd.19 reduction in peritonitis risk in plwh on art may well have contributed to improved survival in the present cohort; in addition, universal access to art has been shown to directly increase survival in plwh prescribed either haemoor peritoneal dialysis.20 there are several limitations to this study. the retrospective nature of this study resulted in the exclusion of a significant number of patients, which may have led to sample bias. furthermore, the retrospective methodology employed limited the ability to include other parameters, such as socio-economic status and education level, which are known to contribute to survival on capd. the small sample size especially limited the generalisation of the results from the patient and modality survival analyses. finally, the single-centre nature of this study may limit generalisability of its findings. it should, however, be noted that restriction of this study to a single centre ensured homogeneity of patient selection for capd as well as hiv infection management, which in turn may have reduced the risk of error. conclusion people living with hiv constitute a significant proportion of patients developing dialysis-requiring kidney failure in south africa. risk of peritonitis was not increased and modality and patient survival were not poorer in plwh on capd. peritoneal dialysis appears to be a safe krt in the era of universal access to arts. acknowledgements i would like to thank the amazing helen joseph renal unit sisters for their assistance with finding records. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions k.l.t. and m.d. conceived and formulated the idea, m.d. supported in the organisation and analysis of the data and all authors contributed to the final manuscript. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability the data collected in the study are available and can be obtained from the corresponding author k.l.t. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references statistics south africa. mid-year population estimates. p0302. stats sa, pretoria, 2022; p. 1–8. swanepoel cr, atta mg, d’agati vd, et al. kidney disease in the setting of hiv infection: conclusions from a kidney disease: improving global outcomes (kdigo) controversies conference. kidney int. 2018 mar;93(3):545–559. https://doi.org/10.1016/j.kint.2017.11.007 kopp jb, nelson gw, sampath k, et al. apol1 genetic variants in focal segmental glomerulosclerosis and hiv-associated nephropathy. j am soc nephrol. 2011 nov;22(11):2129–2137. https://doi.org/10.1681/asn.2011040388 rosenberg az, kopp jb. focal segmental glomerulosclerosis. clin j am soc nephrol. 2017 mar 7;12(3):502–517. https://doi.org/10.2215/cjn.05960616 moosa mr, van der walt i, naicker s, meyers am. important causes of chronic kidney disease in south africa. s afr med j. 2015;105(4):320. stanifer jw, jing b, tolan s, et al. the epidemiology of chronic kidney disease in sub-saharan africa: a systematic review and meta-analysis. lancet glob health. 2014 mar;2(3):e174–e181. https://doi.org/10.1016/s2214-109x(14)70002-6 diana n, davies m, mosiane p, vermeulen a, naicker s. clinicopathological correlation of kidney disease in hiv infection preand post-art rollout. plos one. 2022;17(5):e0269260. https://doi.org/10.1371/journal.pone.0269260 okpechi ig, rayner bl, swanepoel cr. peritoneal dialysis in cape town, south africa. perit dial int. 2012 may–jun;32(3):254–260. https://doi.org/10.3747/pdi.2011.00100 tang ch, chen hh, wu mj, et al. out-of-pocket costs and productivity losses in haemodialysis and peritoneal dialysis from a patient interview survey in taiwan. bmj open. 2019 mar 23;9(3):e023062. https://doi.org/10.1136/bmjopen-2018-023062 wong b, ravani p, oliver mj, et al. comparison of patient survival between hemodialysis and peritoneal dialysis among patients eligible for both modalities. am j kidney dis. 2018 mar;71(3):344–351. https://doi.org/10.1053/j.ajkd.2017.08.028 bello ak, okpechi ig, osman ma, et al. epidemiology of peritoneal dialysis outcomes. nat rev nephrol. 2022;18(12):779–793. 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tnf-alpha promoter polymorphism with viral load and cd4 t-helper cell apoptosis in hiv-1 infected black south africans shivona gounden, mmedsci devapregasan moodley, phd anil a chuturgoon, phd department of medical biochemistry, nelson r mandela school of medicine, university of kwazulu-natal, durban leshern karamchand, mmedsci department of chemistry, university of michigan, ann arbor, michigan, usa halima dawood, mb chb, fcp department of medicine, nelson r mandela school of medicine, university of kwazulu-natal, durban corresponding author: a chuturgoon (chutur@ukzn.ac.za) objective. to determine whether the -308 tnf-α promoter polymorphism is associated with markers of hiv progression in the south african population. methods. polymerase chain reaction-restriction fragment length polymorphism was used to detect the -308 tnf-α polymorphism in 75 patients and 76 healthy controls. serum tnf-α concentrations were measured using elisa in each cohort. cd4+ t cell apoptosis and hiv-1 rna viral load were determined using annexin-v-fitc assay and nuclisens easy q hiv-1 assay respectively. cd4 + t cell counts were measured flow cytometrically. results. the frequency of -308 g allele was similar in the hiv-1 and control cohorts. the -308gg genotype was associated with lower tnf-α concentrations and markers of increased hiv progression indicated by higher th lymphocyte apoptosis, lower th lymphocyte count and higher plasma viral load, irrespective of treatment. conclusion. the presence of the tnf-α -308 g allele in hiv-1 patients may be associated with increased risk of hiv-1 progression. further research is required to investigate the nature of this association. s afr j hiv med 2012;13(2):72-77. patients infected with human immunodeficiency virus (hiv) show a decline in cd4+ t-helper (th) lymphocyte levels and an increase in viral load that ultimately results in compromised immune function and increased susceptibility to various opportunistic infections.1 in early stages of infection, hiv-1 has the ability to manipulate the immune response to ensure its own replication and survival.2 consequently, there has been much controversy as to whether eliciting a robust immune response towards the virus early in infection will be beneficial or detrimental for the patient.2 the differential rate of hiv progression and chronic inflammatory disorders3 may be induced by viral, environmental and host genetic factors. dean et al. observed a 32 base pair deletion in the chemokine receptor 5 (ccr5) that showed better protection against hiv and slower progression to aids.6 another study investigated a chemokine receptor 2 (ccr2) polymorphism with a g→a transition at position 190, that also resulted in slower progression to aids.7 crawley et al. found that a polymorphism associated with il-10 at the -592 position resulted in decreased production of il-10, inhibition of macrophage growth and decreased proliferation of hiv-1 in infected individuals.8 , 9 the molecular mechanisms of most polymorphisms have not been fully elucidated. there is a need to explore more the role of host genetics in understanding hiv disease. in vitro and in vivo studies have shown that hiv-1 infection can induce the secretion of pro-inflammatory cytokines such as tumour necrosis factor alpha (tnf-α).10 tnf-α is the central mediator of the inflammatory response, and high concentrations of tnf-α may influence hiv-1 replication via clonal expansion of infected t lymphocytes.13 in addition, tnf-α is also a potent inducer of apoptosis, which is a function dependent on the death receptor configuration of immune cells.1 , 14 hiv-1 induces immune suppression by rapid apoptosis of bystander th lymphocytes. tnf-α production is tightly controlled but genotypic differences may influence transcriptional regulation.15 , 16 reports have shown that promoter polymorphisms affect tnf-α gene expression.17 a common polymorphism occurs at the -308 locus in the promoter region that results in a guanine (g) to adenine (a) transition.20 the -308 a allele has been associated with higher transcriptional activation and, therefore, increased tnf-α expression in different populations.4 , 17 , 19 this association has also been linked to pathogenesis of various inflammatory disorders and, consequently, poorer disease prognosis.4 , 17 the presence of various allelotypes, especially in promoter regions of cytokines, may severely affect immune responses to infection, given that they exert a large degree of transcriptional control over cytokine production. these effects, however, have not been comprehensively investigated in the context of infection. the precise mechanisms of genotypic influences on transcriptional regulation are currently unknown. however, it is thought that the g to a transition at the -308 locus is associated with conformational changes that increase binding affinity of transcription factors such as nuclear factor-kappa b (nf-κb).15 considering the influence of the -308 tnf-α promoter polymorphism on tnf-α concentration, cd4 th lymphocyte apoptosis and hiv-1 replication, genotype may severely influence clinical outcomes in hiv-1 infected patients. the influence of the -308 tnf-α promoter polymorphism on hiv-1 infected black south africans has not been studied. this is important as south africa has the highest burden of hiv-1 infected individuals, and polymorphic variation may not only affect disease progression, but also response to treatment. the aim of this study was to investigate genotypic frequencies of the -308 tnf-α promoter polymorphism in a cohort of hiv-1 infected black south african patients and determine whether genotype at this locus influenced serum tnf-α concentrations. in addition, the influence of this promoter polymorphism on cd4 th lymphocyte apoptosis and hiv-1 burden was investigated. materials and methods patient recruitment this cross-sectional study was approved by the university of kwazulu-natal, biomedical research ethics administration (h129/04). patients (n=75) were recruited by purposeful sampling from an antiretroviral (arv) rollout clinic at king edward vii hospital, durban, after obtaining informed consent. all patients had confirmed hiv-1 infection. twenty-five patients were on nrti-based haart (nrti: nucleoside reverse transcriptase inhibitor; haart: highly active anti-retroviral therapy); 50 patients were haart-naive. healthy controls (n =76) were sourced from the south african national blood service. there was no follow-up of patients to assess changes in measures or outcomes over time. peripheral lymphocyte preparation buffy coats containing peripheral blood lymphocytes (pl) were extracted as previously described by our laboratory.21 cell density was adjusted to 1×106 cells/ml with the trypan blue exclusion test. dna extraction genomic dna was extracted from pls for each patient. cells were transferred to 500 μl lysis buffer containing 0.5% sds, 150 mm nacl, 10 mm edta, and 10 mm tris-hcl (ph 8.0). to this, rnase a (100 μg/ml, dnase-free) was added, and the solution was incubated at 37°c for 1 hour. following the rnase a step, proteinase k (200 μg/ml) was added to the solution and thereafter incubated for 3 hours at 50°c. protein contaminants were then precipitated by addition of 0.1 volume 5 mm potassium acetate and centrifuging (5 000 ×g, 15 minutes). supernatants containing genomic dna were transferred to fresh tubes and extracted with 100% isopropanol on ice and then washed with 70% ethanol. dna samples were then dissolved in 10 mm tris and 0.1 mm edta (ph 7.4) at 4°c overnight. to verify dna extraction, equal amounts of dna (300 ng) were electrophoresed (150 v, 50 min.) on a 1.8% agarose gel containing 0.5 mg/ml ethidium bromide. dna bands were visualised by uv light and digitally photographed using a gel documentation system (chemi-doc xrs, bio-rad) and quantity one image analysis software (bio-rad). the concentration of each sample was determined spectrophotometrically. genotyping for the -308 tnf-α promoter polymorphism polymerase chain reaction-restriction fragment length polymorphism (pcr-rflp) was used to determine the -308 tnf-α promoter polymorphism. a 107bp pcr product was amplified using 20 pmol of forward and reverse primer in a 25 μl reaction containing 0.2 mm of each dntp, 1.5 mm mgcl2, 1x green gota0071 flexi buffer (promega), 1 u gotaq dna polymerase (promega) and 100 ng genomic dna template. the forward and reverse primers were those according to wilson et al.20 (5’aggcaataggttttgagggccat 3’; 5’ tcctccctgctccgattccg 3’). dna was amplified for 35 cycles with denaturation at 94°c for 3 minutes, annealing at 60°c for 1 minute, extension at 72°c for 1 minute and a final extension at 72°c for 5 minutes. the pcr product was then digested with the restriction enzyme ncoi for 12 hours at 37°c. digestion of the pcr product confirmed 2 alleles viz. -308 g allele which resulted in 2 fragments (87 bp and 20 bp), and –308 a allele which resulted in a single 107 bp fragment (fig. 1).20 tnf-α enzyme-linked immunosorbent assay (elisa) plasma was collected by centrifuging whole blood. plasma tnf-α concentration was measured using the human tnf-α max standard elisa kit (biolegend). a high-affinity microtitre plate was coated with tnf-α capture antibody (100 µl/well, 18 hours at 4oc). plates were washed and treated with 200 µl assay diluent. thereafter, 100 µl standards and samples were added. biotinylated anti-human tnf-α detection antibody and avidin-horseradish peroxidase were then added, followed by the tmb substrate and the stop solution. absorbance was measured at 450 nm (570 nm reference) (bio-tek µquant elisa plate reader). plasma concentrations of tnf-α were calculated by extrapolation from the standard curve. cd4 th cell apoptosis, cd4 th cell counts and viral loads cd4 th lymphocyte apoptosis, cd4 th cell counts and viral loads were determined as described previously.21 statistical analysis genotype and allelic frequencies of the tnf-α -308 polymorphism for the control and hiv-1 cohort were compared by direct counting. hardy-weinberg statistics were used to determine whether our study cohort was representative of the larger population. statistical analyses and correlations were done using graphpad prism software (version 5). results -308 tnf-α promoter polymorphism genotypic distribution did not deviate from those predicted by the hardy-weinberg equilibrium (hiv-1: p=0.331, chi-square statistic=0.946; controls: p=0.194, chi-square statistic=1.688). there were no significant differences in genotypic distribution between the hiv-1 and control cohorts respectively (gg 60% and 65.8%; ga 37.3% and 27.6%; and aa 2.7% and 6.6%). however, when allelic distribution was investigated, we found that the -308 g allele was more frequent in the control population (79.6% v. 78.7%) but this difference did not reach statistical significance (chi square test p=0.888, odds ratio=1.06, 95% ci (confidence interval) 0.607 1.84; see table 1). plasma tnf-α concentration mean plasma tnf-α concentration was determined in patients and controls by elisa. the hiv-1 infected subjects showed significantly higher tnf-α concentration than controls (10.87 pg/ml and 3.57 pg/ml, p<0.0001, 95% ci: hiv-1 infected patients 9.39 12.36 pg/ml, controls 0.74 6.41 pg/ml; see table 2). we then investigated whether genotypic variation at the -308 locus influenced plasma tnf-α concentration in the hiv-1 infected cohort. mean tnf-α concentrations were determined after grouping patients according to genotype. higher plasma tnf-α concentrations were recorded in the -308ga genotype than in the -308gg genotype (15.52 pg/ml v. 15.01 pg/ml). this difference did not reach statistical significance (mann-whitney test, p=0.404, 95% ci: ga 13.35 17.70 pg/ml, gg 12.19 17.83 pg/ml; see table 2). the mean tnf-α concentration in patients with the -308aa genotype was 19.35 pg/ml. genotype and clinical parameters since genotypic differences in tnf-α concentration were noted, we investigated whether genotype influenced viral load and cd4 th cell counts. lower mean plasma viral load and lower mean cd4 th cell counts were observed in the -308gg genotype than in the -308ga genotype (3.69 log copies/ml v. 3.92 log copies/ml and 256.10 cells/μl v. 288.60 cells/μl respectively), with no significant difference (mann-whitney, p=0.970, 95% ci: gg 3.00 4.38 log copies/ml, ga 3.25 4.58 log copies/ml and p=0.242, 95% ci: gg 204.80 307.40 cells/μl, ga 245.30 331.90 cells/μl; table 2). mean plasma viral load and cd4 th cell counts in patients with the -308aa genotype were 3.59 log copies/ml and 197.00 cells/μl respectively. genotype and haart following the observation of genotypic differences in the clinical markers of infection, we investigated whether genotype influenced patient response to treatment. patients were grouped into haart-naive and haart-treated cohorts, and these groups further stratified according to genotype. mean plasma viral load and cd4 th cell counts were analysed according to genotype and treatment. in the haart-naive cohort, higher plasma viral loads and lower cd4 th cell counts were observed in the -308gg genotype than in the -308ga genotype (4.92 log copies/ml v. 4.54 log copies/ml and 244.30 cells/µl v. 283.80 cells/µl) but there were no significant differences (mann-whitney test, p=0.101, 95% ci: gg 4.68 5.16 log copies/ml, ga 4.17 4.90 log copies/ml and p=0.250, 95% ci: gg 179.70 308.80 cells/µl, ga 233.80 333.80 cells/µl; see table 4). higher cd4 th cell counts and statistically significant lower plasma viral loads were recorded in the haart-treated cohort than in the haart-naive cohort (288.64 cells/µl v. 264.80 cells/µl and 1.19 log copies/ml v. 4.72 log copies/ml) (mann-whitney test, p=0.451, 95% ci: haart-naive 226.80 302.80 cells/µl, haart-treated 216.70 360.60 cells/µl and p<0.0001, 95% ci: haart-naive 4.51 4.93 log copies/ml, haart-treated 0.940 1.44 log copies/ml; table 3). this result was expected as haart is associated with lower plasma viral loads and higher cd4 th cell counts. interestingly, we noticed genotypic differences in the haart-treated cohort in the -308gg genotype. the -308gg genotype showed higher plasma viral loads and lower cd4 th cell counts than in the -308ga genotype (1.22 log copies/ml v. 1.13 log copies/ml and 278 cells/µl v. 314.0 cells/µl); however, the differences did not reach statistical significance (mann-whitney, p=0.251, 95% ci: gg 0.855 1.58 log copies/ml, ga 1.02 1.23 log copies/ml and p=0.374, 95% ci: gg 177.70 379.30 cells/µl, ga 185.40 442.60 cells/µl; see table 4). genotype and apoptosis since genotypic differences were observed in tnf-α concentration, we investigated whether genotype influenced cd4 th cell apoptosis. significantly higher mean apoptosis levels were observed in hiv-1 infected patients than in controls (25.98% v. 8.52%; mann-whitney test, p<0.0001, 95% ci: control 6.71 10.32%, hiv-1 infected 22.35 29.61%; see table 2). in the hiv-1 cohort, higher apoptosis levels were observed in the -308gg genotype (28.04%); however, there was no statistical difference between genotypes (mann-whitney, p=0.223, 95% ci: gg 22.87 33.21%, ga 17.56 27.58%; see table 2). we investigated mean apoptosis levels in patients on treatment, and observed higher apoptosis levels in the haart-naive cohort than in the haart-treated hiv-1 infected cohorts; however, the differences did not reach statistical significance (27.13% v. 23.68%, mann-whitney test, p=0.482, 95% ci: haart-naive 22.14 32.13%, haart treated 18.99 28.38%; see table 3). the -308gg genotype showed higher apoptosis levels in both the haart-naive and haart-treated hiv-1 infected cohorts than in the -308ga genotype (32.12% v. 29.58% and 23.77% v. 21.57%); however, differences in both cohorts were not statistically significant (mann-whitney test, p=0.404, 95% ci: gg 25.17 -39.07%, ga 22.79 36.37% and p =0.786, 95% ci: gg 18.19 29.35%, ga 4.82 38.32%; see table 4). the mean apoptosis level in the patients with the -308aa genotype was 27.77%. discussion tnf-α is an immune regulatory cytokine that is released in response to viral antigens to combat infection.10 however, chronically high concentrations of tnf-α may facilitate progression of hiv-1 and apoptosis of bystander t cells.22 tnf-α indirectly induces viral replication by activating nf-κb23 which binds to the long terminal repeat (ltr) of hiv.23 , 24 this may lead to production of viral proteins such as tat and nef which further induce tnf-α production via the inflammatory response.23 , 24 the -308 tnf-α promoter polymorphism has been associated with altered tnf-α concentration.15 , 16 genotypic variation may induce conformational changes in the promoter region that increase binding affinity of transcription factors, such as nf-κb.15 , 16 , 23 ours is the first report on the -308 tnf-α promoter polymorphism in hiv-1 infected black south africans. it is probable that elevated levels of tnf-α may alter clinical outcomes in the patient.4 , 17 a previous study showed lower cd4 th cell apoptosis and plasma viral load in a cohort of hiv-1 infected patients on haart.21 the current study aimed to investigate whether the -308 tnf-α promoter polymorphism influenced tnf-α concentration, cd4 th cell count, cd4 th cell apoptosis and plasma viral load in hiv-1 infected black south africans. it is well established that tnf-α concentration is elevated early in infection.10 , 11 however, during hiv-1 infection, consistently high levels of tnf-α may be attributed to constant antigenic stimulation from viral proteins such as tat and nef.23 , 24 our study shows that the -308 g allele was similar in both the hiv-1 infected and control cohorts. this finding is consistent with other studies that reported similar allelic frequencies in different demographic groups.4 , 25 the -308 g allele in the hiv-1 infected cohort was associated with significantly high levels of tnf-α, which may be due to increased binding affinity of transcription factors. in addition to high tnf-α concentration, this study showed a cross-sectional association between allelic frequency and markers of hiv disease progression, which was indicated by high bystander th cell apoptosis and viral replication. high tnf-α concentration is involved in hiv-1 replication via clonal expansion of infected th cells.13 , 23 it is also involved in rapid apoptosis of bystander th cells, which may account for the high viral titres and high levels of apoptosis observed in this study. during hiv-1 infection, tnf-α may act as a molecular rheostat that switches between clonal expansion and bystander th cell apoptosis, depending on membrane receptor profile.1 , 14 genotypic differences in the tnf-α promoter that influence a cell’s inherent ability to produce the cytokine may exacerbate these functions during hiv-1 infection. in response to rapid apoptosis, the immune system may compensate by increasing bone marrow turnover of mononuclear cells. these may, however, not reach complete maturation and lead to impaired th cell recovery, ultimately contributing to hiv-1 progression.1 , 22 , 28 this study differs from previous studies which have associated the -308 a allele with high tnf-α concentration and disease.4 , 17 , 19 the -308aa genotype has been widely associated with poorer clinical outcomes and disease progression in leishmaniasis, cerebral malaria and insulin-dependent diabetes mellitus.29 interestingly, some reports showed no association between this genotype and disease severity.25 , 32 , 33 in studies that showed the association between the -308aa genotype and disease severity, frequencies of the -308 a allele were low, which may have conferred low statistical power and, as such, these conclusions warrant confirmation in other populations.4 , 34 furthermore, the bulk of these studies were performed in populations of white ancestry. no studies to date have investigated the influence of the -308 tnf-α promoter polymorphism in infectious diseases in a black african population. conclusion in contrast with other studies, our study reports for the first time that the -308 g allele may contribute to mechanisms that lead to poorer response to haart therapy in black south africans infected with hiv-1. similarly, we found the -308aa genotype to be least frequent (n=2), which may preclude disease association studies until adequate sample sizes are collected. comparable clinical outcomes were observed in heterozygote individuals, providing further evidence that the presence of the -308 g allele may be associated with markers of hiv-1 progression in this study. single nucleotide polymorphisms that affect regulation of cytokines may affect host response to hiv-1 infection. this effect may influence disease progression and clinical outcomes. to provide holistic management of patients infected with hiv-1 and develop individual treatment 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replication of human immunodeficiency virus-1 in primary human t cells is dependent on the autocrine secretion of tumor necrosis factor through the control of nuclear factor-kappa b activation. j allergy clin immunol 1997;100(6 pt 1):838-845. 25. azmy ia, balasubramanian sp, wilson ag, et al. role of tumour necrosis factor gene polymorphisms (-308 and -238) in breast cancer susceptibility and severity. breast cancer res 2004;6(4):r395-400. 25. azmy ia, balasubramanian sp, wilson ag, et al. role of tumour necrosis factor gene polymorphisms (-308 and -238) in breast cancer susceptibility and severity. breast cancer res 2004;6(4):r395-400. 26. cuenca j, cuchacovich m, perez c, et al. the -308 polymorphism in the tumour necrosis factor (tnf) gene promoter region and ex vivo lipopolysaccharide-induced tnf expression and cytotoxic activity in chilean patients with rheumatoid arthritis. rheumatology (oxford) 2003;42(2):308-313. 26. cuenca j, cuchacovich m, perez c, et al. the -308 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leishmaniasis. j exp med 1995;182(5):1259-1264. 29. cabrera m, shaw ma, sharples c, et al. polymorphism in tumor necrosis factor genes associated with mucocutaneous leishmaniasis. j exp med 1995;182(5):1259-1264. 30. mcguire w, hill av, allsopp ce, greenwood bm, kwiatkowski d. variation in the tnf-alpha promoter region associated with susceptibility to cerebral malaria. nature 1994;371(6497):508-510. 30. mcguire w, hill av, allsopp ce, greenwood bm, kwiatkowski d. variation in the tnf-alpha promoter region associated with susceptibility to cerebral malaria. nature 1994;371(6497):508-510. 31. pociot f, briant l, jongeneel cv, et al. association of tumor necrosis factor (tnf) and class ii major histocompatibility complex alleles with the secretion of tnf-alpha and tnf-beta by human mononuclear cells: a possible link to insulin-dependent diabetes mellitus. eur j immunol 1993;23(1):224-231. 31. pociot f, briant l, jongeneel cv, et al. association of tumor necrosis factor (tnf) and class ii major histocompatibility complex alleles with the secretion of tnf-alpha and tnf-beta by human mononuclear cells: a possible link to insulin-dependent diabetes mellitus. eur j immunol 1993;23(1):224-231. 32. gander ml, fischer je, maly fe, von kanel r. effect of the g-308a polymorphism of the tumor necrosis factor (tnf)-alpha gene promoter site on plasma levels of tnf-alpha and c-reactive protein in smokers: a cross-sectional study. bmc cardiovasc disord 2004;4:17. 32. gander ml, fischer je, maly fe, von kanel r. effect of the g-308a polymorphism of the tumor necrosis factor (tnf)-alpha gene promoter site on plasma levels of tnf-alpha and c-reactive protein in smokers: a cross-sectional study. bmc cardiovasc disord 2004;4:17. 33. veloso s, olona m, garcia f, et al. effect of tnf-alpha genetic variants and ccr5 delta 32 on the vulnerability to hiv-1 infection and disease progression in caucasian spaniards. bmc med genet 2010;11:63. 33. veloso s, olona m, garcia f, et al. effect of tnf-alpha genetic variants and ccr5 delta 32 on the vulnerability to hiv-1 infection and disease progression in caucasian spaniards. bmc med genet 2010;11:63. 34. corbett el, mozzato-chamay n, butterworth ae, et al. polymorphisms in the tumor necrosis factor-alpha gene promoter may predispose to severe silicosis in black south african miners. am j respir crit care med 2002;165(5):690-693. 34. corbett el, mozzato-chamay n, butterworth ae, et al. polymorphisms in the tumor necrosis factor-alpha gene promoter may predispose to severe silicosis in black south african miners. am j respir crit care med 2002;165(5):690-693. fig. 1. restriction fragment length polymorphism (rflp) showing alleles of the -308 tnf-α promoter polymorphism. the -308 g allele gave rise to a 87 bp and 20 bp fragment, and the -308 a allele to a 107 bp fragment. table 1. genotypic and allelic frequencies of the -308 tnf-α promoter region polymorphism in both hiv-positive and control populations hiv ( n =75) p value controls ( n =76) p value genotype frequency g/g 60% 0.331* 65.8% 0.194* g/a 37.3% 27.6% a/a 2.7% 6.6% allelic frequency a 21.3% 20.4% 0.888 g 78.7% 79.6% *hardy-weinberg equilibrium (hiv-1: chi-square statistic=0.946; controls: chi-square statistic=1.688). table 2. mean tnf-α concentration and markers of hiv-1 progression in the hiv-positive and control cohorts. markers of hiv-1 progression within the -308 gg and -308 ga genotypes of the hiv-positive cohort hiv-positive patients controls p value tnf-α concentration (pg/ml) 10.87±0.73 (14.40) 3.57±1.36 (0.00) p<0.0001 % apoptosis of cd4+ t cells 25.98±1.82 (24.30) 8.52±0.90 (6.94) p<0.0001 hiv-positive patients gg ga tnf-α concentration (pg/ml) 15.01±1.40 (14.04) 15.52±1.05 (15.39) p=0.403 plasma viral load (log copies/ml) 3.69±0.337 (4.66) 3.92±0.321 (4.36) p=0.970 cd4+ t cell count (cells/µl) 256.10±25.04 (243.00) 288.60±20.97 (275.00) p=0.242 % apoptosis of cd4+ t cells 28.04±2.57 (24.52) 22.57±2.45 (23.30) p=0.223 all values reported as mean±sem (median). table 3. markers of hiv progression in haart-naive and haart-treated groups in hiv-positive patients haart-naive haart-treated p value plasma viral load (log copies/ml) 4.72±0.105 (4.85) 1.19±0.115 (1.06) p<0.0001 cd4+ t cell count (cells/µl) 264.80±18.80 (256.00) 288.64±33.31 (293.00) p=0.451 % apoptosis of cd4+ t cells 27.13±2.49 (24.77) 23.68±2.27 (22.86) p=0.482 all values reported as mean±sem (median). table 4. markers of hiv progression in the -308 gg and -308 ga genotypes in the haart-naive and haart-treated groups gg ga p value haart-naive plasma viral load (log copies/ml) 4.92±0.115 (4.91) 4.54±0.173 (4.57) p=0.101 cd4+ t cell count (cells/µl) 244.30±30.72 (188.00) 283.80±23.97 (273.00) p=0.250 % apoptosis of cd4+ t cells 32.12±3.40 (26.49) 29.58±3.34 (24.54) p=0.404 haart-treated plasma viral load (log copies/ml) 1.22±0.16 (1.06) 1.13±0.03 (1.15) p=0.251 cd4+ t cell count (cells/µl) 278.50±44.57 (273.50) 314.00±40.42 (314.00) p=0.374 % apoptosis of cd4+ t cells 23.77±2.67 (22.36) 21.57±5.26 (22.48) p=0.786 all values reported as mean±sem (median). abstract background research methods and design results discussion conclusion acknowledgements references about the author(s) janine scholtz centre of excellence for nutrition, faculty of health sciences, north-west university, potchefstroom, south africa susanna m. ellis department of pure and applied analytics, faculty of natural and agricultural sciences, north-west university, potchefstroom, south africa herculina s. kruger centre of excellence for nutrition, faculty of health sciences, north-west university, potchefstroom, south africa medical research council unit for hypertension and cardiovascular disease, faculty of health sciences, north-west university, potchefstroom, south africa citation scholtz j, ellis sm, kruger hs. weight gain in children from birth to 10 years on antiretroviral treatment. s afr j hiv med. 2022;23(1), a1413. https://doi.org/10.4102/sajhivmed.v23i1.1413 original research weight gain in children from birth to 10 years on antiretroviral treatment janine scholtz, susanna m. ellis, herculina s. kruger received: 13 june 2022; accepted: 16 sept. 2022; published: 28 oct. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: inadequate weight gain could indicate clinical deterioration in infants and children living with hiv (clhiv). the world health organization’s (who) weight-for-age z-score (waz) growth standards and reference charts are currently used in south africa to assess weight gain in clhiv on antiretroviral treatment (art). objectives: to assess weight gain patterns of infants and children initiated on art and to compare weight gain patterns between the who waz growth standards and population-specific curves constructed from data of clhiv on art. method: a quantitative, retrospective and descriptive-comparative design was used. the weight gain patterns of 98 infants and children from birth to 10 years old during the 24-month period following art initiation were recorded and assessed using two different growth charts. results: the children’s rate of weight and length gain improved significantly over 24 months since art initiation, but complete catch-up growth was never achieved. most (69%) of the children had increased weight gain according to the waz growth standard and reference charts versus only 16% according to the hiv-specific weight gain curves. conclusion: antiretroviral treatment improved weight and height gain in clhiv, but the interpretations of weight gain differed significantly between the who chart and hiv-specific weight gain curves. populationand treatment-specific references could improve weight monitoring in clhiv and assist in the timeous identification of malnutrition. keywords: hiv; infants; children; weight; height; art; growth monitoring; nutritional assessment; waz; catch-up growth. background hiv infection remains a global epidemic, with 37.7 million people living with hiv in 2020. an average of 1.7 million children younger than 15 years are living with hiv. an estimated 150 000 children were newly diagnosed in 2020.1 the provision of combination antiretroviral treatment (art) to pregnant and breastfeeding women resulted in a 54% reduction of new infections in children.2 the improved coverage of art among pregnant women in the public sector resulted in 90% of women living with hiv currently on art.3 the increase in art provision has also resulted in an increasing population of hiv-exposed uninfected infants and children.2 it has been established that growth reconstitution occurs following art initiation.4 research indicates that growth in hiv-exposed uninfected infants and children differs and is still lagging behind when compared to that of hiv-unexposed uninfected children.5 this finding could be related to an increased immune activation,6 changes to the gut microbiome, as well as systemic inflammation following prolonged in-utero or postnatal hiv and art exposure, despite a negative hiv status.7,8 children living with hiv (clhiv) on art from resource-limited settings have growth failure.4 most children on art are from resource-limited settings where malnutrition still prevails.9,10 in addition, several studies have shown a high prevalence of undernutrition in clhiv, especially in sub-saharan africa.11,12,13,14,15 malnutrition is multifactorial and impacts negatively on the growth, development and immunity of a child.16 in addition, malnutrition is associated with a high risk of morbidity and mortality.17 furthermore, malnutrition was described as the most important risk factor for the global burden of disease.16 early initiation of art can reduce the risk of malnutrition in clhiv, yet specific interventions are valuable to improve the nutritional care of clhiv, especially because child malnutrition and paediatric hiv infection are two major interacting issues in sub-saharan africa.18 anthropometrical indicators, such as weight and height or length, are common measurements that are obtained in order to assess nutritional status in children. mid-upper arm circumference (muac) measurements are also assessed; however, muac relies on a single absolute cut-off value that is taken, irrespective of age, sex, weight or height to help identify children with existing acute malnutrition.19 mid-upper arm circumference measurements may not be accurate in depicting nutritional status due to genetic variations and should rather be used in conjunction with other variables, such as weight-for-age z-score (waz), in guiding admission for treatment of malnourished children.19 growth is strongly associated with art treatment outcomes20 and it remains crucial to monitor children’s growth in order to establish their risk of malnutrition.21 in 2006, the world health organization (who) released growth standard charts for infants 0–60 months of age22 and growth reference charts for older children in 2007.23 the who standards and references are used to assess the progress of achieving the millennium development goals.24 however, it has been argued that local growth charts might be more suitable for individual growth monitoring.25 it should be considered that the growth environment of clhiv is different to that of a healthy child, due to hiv and art exposure. in 2015, yotebieng et al.20 constructed weight gain percentile curves for clhiv who were initiated on art, in order to investigate the value of these curves in predicting treatment outcomes. in this study, we aim to apply these hiv-specific weight gain curves to investigate how these weight gain patterns compare to the weight gain percentile curves of the who waz growth standards and references. furthermore, this study describes the weight changes of the study participants following their initiation of art at their 6-month, 12-month, 18-month and 24-month follow-up visits at an art clinic in gauteng, south africa. research methods and design study design this study was a quantitative, descriptive-comparative study with a retrospective design. data collection of clinic visits ranged from 2004–2007 to 2010–2015. patient records were accessed and data pertaining to weight and length or height changes of the boys and girls that were treated with art were collected. mid-upper arm circumferences were not recorded in the patient files. other parameters, such as the art regimen, routine blood biochemistry and clinical signs that were recorded in patient files, were also collected. the children’s art regimens at the time of treatment (between 2004 and 2015) included abacavir (abc), lamivudine (3tc), zidovudine (azt), lopinavir/ritonavir (lpv-r), efivarenz (efv), stavudine (d4t) and nevirapine (nvp). unfortunately, viral load data were incomplete in most files and were therefore not recorded; however, cd4 percentages (cd4%) could be obtained from 74% of the participant files. setting the study was conducted in 2017 at dr george mukhari academic and public hospital art clinic in gauteng, south africa. data were collected of patient visits from 2004 up to 2015. all measurements recorded in the patient files were performed using standard operating procedures and definitions based on south african and who guidelines.26,27 study population and sampling boys and girls aged between birth and 10 years old who were initiated on art at any time during the lifespan of this art clinic and who attended follow-up visits for a minimum of six months and a maximum of 24 months after art initiation, were eligible for inclusion in this study. infants and children who received tuberculosis (tb) treatment for more than 6 months (one-quarter of the follow-up time) during the first 24 months after art was initiated were excluded. the art clinic’s physical filing system contained patient records of infants and children (n ~ 2000) who were initiated on art and aged younger than 15 years old. the records included those who are still treated at this clinic, as well as those who have been lost to follow-up. due to random filing, a convenience sampling method was used to locate files of eligible children until the sample size of approximately 100 files was reached. data collection data collected of clinic visits ranged from 2004–2007 (n = 9) to 2008–2010 (n = 52) and 2010–2015 (n = 37). data were captured electronically into microsoft excel. birth dates were captured in order to calculate initiation and follow-up ages, as well as waz and length or height-for-age z-scores (l/haz). demographic information, including sex, age, date of birth and art regimens, was recorded for every follow-up visit. progress notes, clinical or immunological staging, biochemical data, cd4% and haemoglobin (hb) levels were also collected from the patient files. weight gain was the primary outcome variable in this study. in addition, the weight gain patterns of the study participants were interpreted and compared between the who growth standard and reference waz charts22,23 and the hiv-specific weight gain curves.20 length or height measurements were also captured if recorded in the patient files; however, length or height measurements were not performed routinely. baseline weight at art initiation and at least one follow-up visit that fell on a date that was either on the 6th, 12th, 18th or 24th month post art initiation were analysed. weight records that deviated by half a month before or after these follow-up dates were also recorded. the art initiation age was calculated from the date of birth and date of relevant clinic visit. microsoft excel was used to calculate age at follow-up and weight gain for each follow-up. weight gain was plotted onto the hiv-specific weight gain charts.20 these curves are specified for weight gain after art initiation, then at 6-month, 12-month, 18-month and 24-month follow-ups.20 weight gain was manually plotted onto the y-axis against current age (in months) on the x-axis. afterwards, the percentile or percentile range for that specific plotting point was captured. percentiles ranged from the 5th, 10th, 25th, 33rd, 50th, 75th, 90th to the 97th percentile. percentiles and percentile ranges were coded in the following manner: (1) < 3 percentile, (2) 3rd to 9th percentile, (3) 10th to 24th percentile, (4) 25th to 32rd percentile, (5) 33rd to 49th percentile, (6) 50th to 74th percentile, (7) 75th to 89th percentile, (8) 90th to 97th percentile (9) and > 97th percentile. after coding, the growth pattern for each individual child was assessed. the growth patterns were then categorised in the following manner: (1) decreased (consistent decrease from high to lower percentiles), (2) maintained (at least three out of four weight gains were in the same percentile range), (3) increased (consistent increase from low to higher percentiles) and (4) fluctuated (no consistent pattern of increase, decrease or maintenance of weight gain). the scales used at the art clinic were calibrated to confirm validity of the recorded weights. the differences between displayed weight and the calibration weight ranged between 0.0 kg and 0.2 kg, indicating a 98% accuracy of the weight measurements. recorded data were checked for outliers and were routinely corrected during duplicate data collection by confirming values of every fifth file according to the original data in the files. data analysis descriptive statistics were used to describe the baseline and follow-up characteristics of the boys and girls. the distribution of all continuous variables was tested using histograms, q-q plots and the shapiro-wilk test. the variables of the study participants are presented as means and standard deviations (for normally distributed data) or medians and inter-quartile range (for data not normally distributed). categorical data (gender, art regimen, who stage) are presented as frequencies. statistical significance was deemed as a p-value of < 0.05. mixed linear regression was then used to test for significance of increases in weight, waz, hb and cd4% across the follow-up period. mixed methods analysis of longitudinal data was performed using the restricted maximum likelihood (reml) function with an unstructured covariance type. the quality of model fit was estimated by akaike’s information criterion (aic). repeated comparisons were done to test for changes between 6-monthly follow-up visits, with sidak adjustment for multiple comparisons. a kappa test for agreement between the four identified growth pattern categories according to the two growth norms was performed. the kappa test was also repeated in a subgroup analysis, where only children with a low waz at art initiation was included, defined as waz < −1. all statistical analyses were performed using the statistical package for the social sciences (spss), version 23 (ibm company, armonk, new york, united states). ethical considerations ethical approval was obtained by the north-west university research ethics regulatory committee (nwu-irerc) (nwu ethics number: nwu-00080-16-a1). all the data were collected from patient records only. no informed consent was required from the parents of the children. the data were captured anonymously on a password-protected device. permission to conduct research at the arv clinic was approved by the chief executive official of hospital, and ethical clearance from the sefako makgatho health sciences university ethics committee (smurec), prior to hrec approval. this project was conducted under controlled ethical conditions at all times in accordance with the world medical association declaration of helsinki. results the data screening for inclusion eligibility is indicated in table 1. the total number of baseline and follow-up data points included in the statistical analyses was 363, which was derived from 98 infants and children. table 1: data screening, eligible data points and participants. figure 1 illustrates the number of children that had to be excluded. most exclusions were made due to missing information (65%) from participants who were transferred out of this clinic, as well as participants whose follow-up visits fell too far outside of the specified follow-up periods of 6, 12, 18 and 24 months. a total of 94 files were excluded from this study, while 98 files were included for analyses. figure 1: percentage of participants that were excluded. the art regimen of 14% of the infants and children was changed at some point during the 24-month follow-up period. most children were treated with the following art combinations: abc, 3tc and lpv/r (46%), or 3tc, efv and d4t (40%). data collected of clinic visits ranged from 2004–2007 to 2010–2015, therefore the art regimens varied based on the first-line and second-line regimens followed at the time. at baseline 2004–2007 most children ≥ 3 years (and ≥ 10 kg) were on 3tc, d4t and efv, while younger children were on 3tc, d4t and lpv-r. with time children under 3 years (or < 10 kg) were switched to abc + 3tc and lpv-r, while older children were switched to abc, 3tc and efv. small numbers of children were on abc, 3tc and nvp, d4t, 3tc and efv/nvp, azt, 3tc and lpv-r/nvp, or azt, abc and lpv-r. table 2 displays baseline and follow-up characteristics of the boys and girls. the girls were significantly older than the boys at art initiation. weight increased significantly from art initiation to 24 months, and also at each of the 6-month intervals compared to baseline (p < 0.0001; aic = 1484.9). length or height-for-age z-scores did not increase significantly from art initiation to 6-months follow-up (p = 0.058), but increased significantly from baseline to 12-month, 18-month and 24-month visits (p ≤ 0.001; aic = 895.3). the low mean baseline waz (−2.1) falls into the underweight-for-age range. the largest mean improvement was at the 18-month follow-up point with a change from waz of −2.1 to 0.9. weight-for-age z-score increased significantly from art initiation to 24 months, and also at each follow-up visit compared to baseline (p < 0.0001; aic = 970.3). table 2: characteristics of the study participants. both haemoglobin and cd4% increased significantly from art initiation to 24 months, including between each follow-up visit compared to baseline (aic = 723.1 and aic = 1655.3; p < 0.0001). there were no significant differences in prevalence of being underweight (p = 0.43) or stunting (p = 0.68) at initiation of art between the boys and girls. the mean l/haz score at initiation was −2.3, with 55.1% of the participants being stunted when art was started. figure 3 depicts the agreement between weight gain pattern categories according to two different references: hiv-specific weight gain curves20 versus the who waz growth standard and reference charts.22,23 the number of participants (n = 86) includes those who had at least two follow-up visits after art initiation. according to the hiv-specific weight gain curves, most (62.8%) of the participants remained within the same percentile range of weight gain (maintain), compared to only 19.8% according to the who reference. the weight gain of 16.3% of the participants decreased across the percentiles according to the hiv-specific weight gain curves, while only 10.5% of the participants’ weight gain decreased from a higher to a lower percentile according to the who reference. the same proportion of participants showed an increase in their weight gain (16.3%) according to the hiv-specific weight gain curves, while according to the who reference most of the participants (68.9%) showed weight gain. the proportion of participants with fluctuating weight gain patterns was low according to both references (4.6% and 1.2%). figure 2: staging of the infants and children included in the study according to world health organization clinical staging of hiv/aids for infants and children with confirmed hiv infection. figure 3: weight gain patterns according to two references: interpretation according to hiv-specific weight gain curves versus weight-for-age z-scores (who charts). figure 4 depicts a separate subgroup analysis that included only the participants who had a low waz at initiation of art (n = 51, waz < −1). there was an improvement in the agreement between weight gain patterns between the two weight gain charts (hiv-specific weight gain curves versus the who growth charts), but the agreement was still not statistically significant (kappa value = 0.03; p = 0.58). figure 4: subgroup analysis of participants with low baseline weight at art initiation: weight gain patterns according to two references: interpretation according to hiv-specific weight gain curves versus weight-for-age z-scores (who charts). discussion we found that more than half of the children in this study were already stunted and underweight for their age when they started art, according to the who growth standards and references.22,23 these findings are in line with those of the literature, describing the association between growth and hiv infection and the tendency of clhiv to be stunted by as early as three months of age.28 in this study, the children were on average already almost three years old when art was initiated. most of the study participants were clinically at stage 3 and stage 4 of hiv infection (69%), indicating advanced hiv disease progression.27 more recently progress has been made in ensuring that children are initiated on art as soon as possible, due to vigorous testing for hiv during pregnancy.29,30 research suggests that children with more advanced disease progression and associated poor growth at art initiation may show larger improvements in weight gain when compared to children who weigh more at initiation of art.31,32,33 this may have contributed to a threshold effect and also served as the justification behind the subgroup analysis that was performed in this study. the aim was to assess whether the participants who were at a low baseline weight (waz < −1) showed different growth patterns from the total group. results indicated that the growth pattern of the subgroup (n = 51) versus the growth pattern of the entire group (n = 98) was similar, although most participants showed an increase in rate of weight gain. this observation may be explained by the high proportion (53.1%) of the participants who were underweight at baseline (waz < −2). improvements in haemoglobin levels, as well as in cd4% were significant over the 24-month period following art initiation, indicating the positive effect of art on general health and immunity. these results are in agreement with the findings of other studies in africa.34,35 statistically significant improvements in weight gain over the 24-month research period and at each six-month follow-up visit since art was initiated was observed. although the focus was on changes in waz, there was consistent improvement in both waz and l/haz, with more rapid increases in weight as opposed to gradual increases in length or height. this suggests that weight gain improves before height gain. weight gain improved significantly from as early as six months following art initiation, whereas significant improvements in linear growth were observed after 12 or more months of treatment. similar growth reconstitution findings were observed in clhiv on art in other sub-saharan african countries.36 the children in this study did not reach complete catch-up growth after 24 months of art initiation, as the mean waz was still not optimal (waz = −1.1). the proposal that catch-up growth is cohort-specific was suggested, because generally cohorts of children in socio-economically advantaged regions have reached complete catch-up growth after two years on art.37 this study was conducted in a resource-limited setting, where routine monitoring of viral load was not done at the time, although such measurements were done in better-resourced hospitals. growth parameters and time to catch-up growth differ in resource-limited settings, where a high prevalence of malnutrition exists.38 according to the who drug resistance report 2012, zambia was the only country reporting general viral load survey data from children and adolescents receiving art at the time.39 the use of art has a positive impact on the nutritional status of clhiv, although studies have revealed a higher prevalence of wasting, underweight and stunting in this population, when compared to country statistics.38 it is not uncommon that only children with established malnutrition, as evidenced by anthropometrical measurements (weight, height and muac), are referred to dieticians for nutritional support and education, while children with ‘normal’ anthropometry are usually not referred.40 this study aimed to compare the weight gain patterns of the same group of infants and children according to two weight assessment charts: hiv-specific weight gain curves, proposed by yotebieng et al.,20 and the who waz standard and reference charts.22,23 results indicated that there is poor agreement between the assessment findings based on these two reference charts. the who growth standard and reference charts indicated that the largest proportion of the infants and children in this study had an increase in their rate of weight gain, whereas the hiv-specific weight gain curves showed that the largest proportion actually only maintained their rate of weight gain. of special interest was the differences in the number of children that showed improvements in weight gain after art initiation: 69% according to the who standard and reference charts, but only 16% according to the hiv-specific curves. this lack of agreement suggests that children’s weight gain may be over-estimated when applying the who growth charts in the clinical setting. the results support the research conducted by yotebieng et al.20 who suggest the use of population-specific weight gain charts for clhiv and on art, not only for correct referral and support purposes, but also to help understand the effects of different art regimens on weight gain. the who growth standard charts were constructed using growth reference data of exclusively breastfed infants and children from six socio-economically advantaged regions.22 one should consider the significant variability in child growth across different populations, such as in clhiv compared to healthy children. it is unlikely that any single framework can serve as a universal model for healthy growth. in addition, perceptions of caregivers about normal, healthy growth have significant implications for medical treatment and feeding practices.41 the need for diseaseand treatment-specific growth curves should be investigated for the assessment of growth in children on art.20 better awareness of true growth issues in clhiv initiated on art can potentially help to avoid the possibility of clhiv developing more severe malnutrition. improved nutritional care has the capacity to influence disease outcomes, particularly among the vulnerable malnourished population, while malnutrition has long-lasting effects with potential impacts on the health of future generations.42 a limitation of this study was the retrospective design and therefore the reliance on measurements and record-keeping that could not be controlled and which could be susceptible to technical and human error. the impact of different art regimens on the rate of weight gain could not be assessed due to the small sample size. the data were collected in a different era of art and much has been done to improve initiation age and clinical management of clhiv; however, there exists an increasing need for dietary counselling and the provision of nutritional education or supplementation at art initiation in order to improve growth and development as well as health outcomes.43 more research is needed to determine the impact of nutrition interventions, especially at early stages of improper weight gain, in order to assess the effect on art success. improved monitoring of growth in clhiv according to a hiv-specific reference could help to optimise the response to art.18 conclusion in this study, the weight gain improvements were observed among infants and children who were initiated on art before the age of 10 years old. however, the children failed to reach complete catch-up growth after the 24-month study period. in addition, the weight gain patterns of the children varied greatly between the two growth charts that we compared. weight gain of clhiv on art should be monitored according to curves that represent the population, because anthropometrical interpretations are widely used as a scale to evaluate individual and population growth status25 and their interpretations have important implications for child health programmes.44 future research should aim to investigate the feasibility of applying populationor disease-specific growth charts for a larger sample of clhiv who get exposed to art to monitor the impact of art exposure on their growth. strategies to improve the nutritional practices in clhiv may impact long-term growth outcomes in this vulnerable population.45 acknowledgements the researchers would like to acknowledge the hard-working staff at the paediatric out-patient clinic of dr george mukhari academic hospital, especially sister katy thembi mafotsa, who displays a deep love for the children that she treats at the arv clinic. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions j.s. contributed to the conceptualisation, methodology, investigation, writing of the original draft, visualisation, project administration, software, validation and resources, as well as the writing, review and editing of the article. s.m.e. contributed to the methodology, final analysis, writing and supervision of the article. h.s.k. contributed to the conceptualisation, methodology, final analysis, validation, writing, review and editing, as well as the supervision of the project. funding information this research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. data availability no data are available from publicly available data sets; however, data will be made available after approval from the health research ethics committee, north-west university, if requested by reviewers or editors after submission to a scientific journal. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. 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2022 [cited 2022 aug 03]. available from: https://www.who.int/publications/i/item/9789240052390 frigati l, cotton mf, rabie h. antiretroviral therapy for the management of hiv in children. s afr med j. 2014;104(12):898. https://doi.org/10.7196/samj.9091 weigel r, phiri s, chiputula f, et al. growth response to antiretroviral treatment in hiv-infected children: a cohort study from lilongwe, malawi. trop med int health. 2010;15(8):934–944. https://doi.org/10.1111/j.1365-3156.2010.02561.x zanoni bc, phungula t, zanoni hm, france h, cook ef, feeney me. predictors of poor cd4 and weight recovery in hiv-infected children initiating art in south africa. plos one. 2012;7(3):e33611. https://doi.org/10.1371/journal.pone.0033611 jesson j, dahourou dl, folquet ma, et al. (monodanrs 12206 study group). malnutrition, growth response and metabolic changes within the first 24 months after art initiation in hiv-infected children treated before the age of 2 years in west africa. pediatr infect dis j. 2018;37(8):781–787. https://doi.org/10.1097/inf.0000000000001932 payne h, chan mk, watters sa, et al. early art‑initiation and longer art duration reduces hiv‑1 proviral dna levels in children from the cher trial. aids res ther. 2021; 18:63. https://doi.org/10.1186/s12981-021-00389-1 sutcliffe cg, van dijk jh, munsanje b, et al. weight and height z-scores improve after initiating art among hiv-infected children in rural zambia: a cohort study. bmc infect dis j. 2011;11(1):54. https://doi.org/10.1186/1471-2334-11-54 nachman sa, lindsey jc, moye j, et al. pediatric aids clinical trials group 377 study team. growth of human immunodeficiency virus-infected children receiving highly active antiretroviral therapy. pediatr infect dis j. 2005;24(4):352–357. https://doi.org/10.1097/01.inf.0000157095.75081.43 intiful fd, abdulai h, nyarko r, tette e, asante m. malnutrition in hiv infected children on antiretroviral drugs in a cohort of ghanaian children. heliyon. 2021;7(12):e08636. https://doi.org/10.1016/j.heliyon.2021.e08636 world health organization (who). the hiv drug resistance report-2012 [homepage on the internet]. [cited 2017 oct 31]. available from: http://www.who.int/hiv/pub/drugresistance/report2012/en/http://apps.who.int/iris/bitstream/10665/75183/1/9789241503938_eng.pdf ndhlovu l, de maayer t. introducing a nutritional risk screening tool in a south african hospital. s afr j clin nutr. 2022;35(2):44–50. https://doi.org/10.1080/16070658.2021.1940718 thompson al. what is normal, healthy growth? global health, human biology, and parental perspectives. am j human biol. 2021;33(5):e23597. https://doi.org/10.1002/ajhb.23597 cardenas d, correia mi, ochoa jb, et al. clinical nutrition and human rights. an international position paper. clin nutr. 2021;40(6):4029–4036. https://doi.org/10.1016/j.clnu.2021.02.039 musakwa n, feeley a, magwete m, et al. dietary intake among paediatric hiv-positive patients initiating antiretroviral therapy in johannesburg, south africa. vulnerable child youth stud. 2020;15(2):155–170. https://doi.org/10.1080/17450128.2019.1668581 turck d, michaelsen kf, shamir r, et al. world health organization 2006 child growth standards and 2007 growth reference charts: a discussion paper by the committee on nutrition of the european society for pediatric gastroenterology, hepatology, and nutrition. j pediatr gastroenterol nutr. 2013;57(2):258–264. https://doi.org/10.1097/mpg.0b013e318298003f neary j, langat a, singa b, et al. higher prevalence of stunting and poor growth outcomes in hiv-exposed uninfected than hiv-unexposed infants in kenya. aids (london, england). 2022;36(4):605. https://doi.org/10.1097/qad.0000000000003124 november 2005 the southern african journal of hiv medicine46 factors influencing the disclosure of hiv status by parents to their children ■ parents feel responsible for shielding their children from potentially harmful knowledge.6 ■ discrimination against infected persons by peers, at schools, in day-care centres and in the community as a whole.7 ■ parents who are coping with their children’s illness must at the same time cope with their own illness, declining health and imminent death.7 ■ parental feelings of guilt, blame and responsibility for their children’s hiv infection.7 ■ fear that the diagnosis will negatively affect the child’s will to live.8 ■ fear of anger from the child related to perinatal transmission.8 ■ fear of inadvertent disclosure by the child to the broader community.8 advantages of disclosing to a child ■ greater ability to cope and provide support to each other, especially as the disease progresses. ■ increased intimacy between parent and child once disclosure has occurred, which often results in stronger family ties. ■ parents feel relieved of the burden of keeping a secret, and less anxious about medical visits and the possibility of accidental disclosure.1,2 ■ forms an essential part of good health. ■ communicates respect for the child. ■ reflects a child’s individual rights. ■ empowers the child to participate in health care. ■ enables choices and self-protection.5 ■ increases hope.6,9 when to withhold/delay disclosure ■ very young child (usually under the age of 5 years) or a child with developmental delay (as defined by iq < 70).2 ■ children with severe emotional disturbances. these children should have their situations assessed periodically should their circumstances change. factors associated with early disclosure in hiv-infected children lester et al.6 reported their findings in a cross-sectional study of 51 hiv-infected children. they concluded that the following factors play an important role in determining whether disclosure to a child takes place earlier rather than later: d i s c l o s u r e hiv disclosure in children aneesa naeem-sheik, mb bch glenda gray, mb bch, fcp paed (sa) perinatal hiv research unit, university of the witwatersrand, johannesburg with the widespread use of highly active antiretroviral therapy (haart), the epidemic of paediatric hiv has evolved into a chronic disease of childhood. the difference between this disease and most other chronic diseases of childhood, however, is that it is not only a life-threatening diagnosis but also an extremely stigmatising one, resulting in highly emotionally charged responses to disclosure of such a diagnosis to the patient. the disclosure process is made much more difficult when the person being disclosed to is a child. one of the major difficulties is that one is dealing with many layers of disclosure: disclosure of hiv status to the child; the concomitant disclosure of hiv status of the parent/s and other siblings or other family members; and having to anticipate the child’s own disclosure to his/her friends, extended family and community. approaches to disclosing the diagnosis may vary between parents and between health care providers, but one thing that has been established in many studies world-wide1-4 is that the child needs to be informed, many suggesting sooner rather than later during the course of the illness. it has been suggested that disclosure of the diagnosis to the child is an integral part of providing comprehensive medical care to a child infected by hiv 5 and may impact positively on adherence to medication. during adolescence, disclosure of the diagnosis may also aid in preventing high-risk behaviour, thereby curbing spread of the disease. disclosure of hiv to a child should be seen as an ongoing process that may last several years depending on the cognitive development of the child. health care providers who deal with hiv infection in children need to develop a plan that will enable them to support parents in disclosure. the southern african journal of hiv medicine november 2005 47 ■ a child with a higher iq. higher iqs relate to the child’s developmental readiness to understand the complex and changing nature of hiv diagnosis and prognosis. ■ urban family residence. although families from both rural and urban settings expressed fear about negative reactions from the community, it was found that the more negative attitudes were prevalent in communities that lacked hiv/aids education and services. disclosure to children in these communities was therefore found to be delayed. ■ families with higher expressiveness. assessment of family communication style is important in determining whether a child should be disclosed to earlier rather than later. they also found that at the time of study initiation, subjects who had already been disclosed to had: ■ higher mean ages (10.5 years). ■ increased major life events within the family in the preceding year. process of disclosure disclosure is a process that should take place over a period of time. it requires ongoing and effective communication within families. it requires that health professionals respect family needs, wishes and expectations as well as community norms and pressures. disclosure must take into account: ■ the needs of the child and the needs of the parent/family. pushing the process before the family is ready may disrupt the therapeutic alliance and have a negative impact on the ongoing care of the child.9 ■ evolving developmental and psychological status of the child. ■ special adherence challenges for children. ■ the evolving nature of the illness. ■ time for discussion with parents during each visit and time to prepare them for difficult questions that may come later.9 ■ the need to decrease social isolation – this can be achieved by encouraging discussions between parents and other regivers during clinic visits. the child ■ information appropriate to the age and development (including emotional development) of the child in response to questions, especially with regard to clinical visits, drawing of blood, and medication. ■ parents should never knowingly tell untruths, as this will decrease the trust between parent and child. ■ ascertain what the child knows or suspects about his/her diagnosis. ■ determine the child’s state of mind – depressed, worried, anxious?5 ■ determine whether the child is sexually active or not. ■ children who ask direct questions are ready to hear about their diagnosis and will seek that information elsewhere if the parents and health care providers are not forthcoming in providing it.7 the parent factors to consider:5,9 ■ parental hiv status. ■ disease stage. ■ who is the child’s primary caregiver? ■ who is emotionally closest to the child? ■ is the parent living at home? ■ communication style within the family. ■ impact of the disease on other family members. ■ fears, concerns and attitudes with regard to disclosure. the book by mary tasker, how can i tell you?,10 outlines the four common phases of disclosure by a parent, namely: ■ secrecy/privacy phase. this occurs immediately after learning the child’s diagnosis. the diagnosis is kept secret or private from anyone outside the medical centre. ■ exploratory phase. this occurs later, when the parent is willing to disclose the diagnosis to a close friend or family member. the parent will often also offer the child a plausible though not entirely thorough explanation for the numerous medical visits ■ readiness phase. this occurs when the parent begins to disclose to a larger network and starts entertaining the idea of fully disclosing to the child. ■ disclosure phase. this is when full disclosure to the child occurs. lee et al.11 found that disclosure is best done over a period of time at different phases of the child’s life and involving a multidisciplinary approach that includes the parents/caregivers. parents can be helped through these phases taking into account what has been ascertained about the child, the parent, the family and the community as a whole. reactions to disclosure 7 denial children may deny having the disease, or may claim that they are cured of the disease. this becomes a problem when the child starts to refuse medical care, misses appointments or sabotages treatment. these children may need the intervention of a psychologist to help them cope with coming to terms with the diagnosis. support groups with similar children may be helpful. sadness and depression this is a more common response but is usually short-lived. the child requires reassurance and assistance in exploring and coming to terms with his or her feelings, fears and anxieties. should a more chronic period of depression set in, a professional should be consulted to help deal with the depression. november 2005 the southern african journal of hiv medicine48 suicide this is extremely rare, and should there be an expression of suicidal ideation a mental health professional needs to be consulted. good ways to disclose 5 ■ disclosure should occur between the primary caregiver, parent and child with or without health care providers. ■ it should be: • driven by the child’s agenda • planned • private • loving and reassuring • unhurried. ways not to disclose 5 disclosure should not be done: ■ accidentally ■ in the heat of anger ■ after the child has figured it out for him/herself ■ when the child puts a provider ‘on the spot’. what to say ‘you know you have been coming to this clinic for a long time? you come because you have a long-standing illness/infection that requires regular check-ups and medication. the medication you take helps the illness, and helps to keep you well.’ when the parents and health care provider are sure that the child understands these concepts, the disclosure can go a bit further. ‘that illness or infection we spoke about – well, it is caused by a virus/germ. do you know what a virus/germ is? the medication that you take to keep you well works by killing this virus/germ.’ after a period of time, the parents or health care provider may then name the virus. the parent should practise the disclosure with the health care provider. they should also explore answers to some of the difficult questions, like ‘how did i get it?’ or ‘how did you get it?’ conclusions we believe that every health care provider should develop a plan with the hiv-infected child’s parents or guardians that will outline the process of hiv disclosure. disclosure is a process that should occur over a period of time, and should occur before the child discovers his or her own diagnosis. role-playing with the child’s parents or guardians will enable them to prepare answers for difficult questions and facilitate support for adverse outcomes following disclosure. references 1. lipson m. disclosure of diagnosis to children with human immunodeficiency virus or acquired immune deficiency syndrome. j dev behav pediatr 1994; 15(3): 61-65. 2. lipson m. disclosure within families. aids clinical care 1993; 5: 43-44. 3. claflin cj, barbarin oa. does telling less protect more? relationships among age, information disclosure, and what children with cancer see and feel. j ped psych 1991; 16: 169-191. 4. funck-bretano i, costagiola d, seibel n, et al. patterns of disclosure and perceptions of the human immunodeficiency virus in infected elementary school age children. arch pediatr adolesc med 1997; 151: 978-985. 5. mtct+ training (2005) – johannesburg (sa). paediatric disclosure: talking to children about hiv. 6. lester p, chesney m, cooke m, et al. when the time comes to talk about hiv: factors associated with diagnostic disclosure in hiv-infected children. j acquir immune defic syndr 2002; 31(3): 309-317. 7. fxb worldwide – a resource for paediatric hiv/aids clinicians. disclosing the hiv diagnosis to infected children. oct 1997 (4). 8. american academy of pediatrics (committee on paediatric aids). disclosure of illness status to children and adolescents with hiv infection. pediatrics 1999; 103: 164-165. 9. tepper v, bachanas p. pactg training – johannesburg, sa (2004). management of paediatric and perinatal hiv infection in the era of antiretroviral therapy. 10. tasker m. how can i tell you? bethesda, md: association for the care of children’s health, 1992. 11 lee cl, johann-liang r. disclosure of the diagnosis of hiv/aids to children born of hiv-infected mothers. aids patient care stds 1999; 13 (jan): 41-45. recommendations by the american academy of pediatrics with regard to disclosure to children and adolescents parents/guardians of an hiv-infected child need to be counselled by a knowledgeable health care professional about disclosure to the child. this counselling may need to be repeated throughout the course of the child’s illness. ■ disclosure needs to be individualised to include the child’s cognitive ability, developmental stage, clinical status and social circumstances. ■ in general, younger children, if symptomatic with illness, are more interested in learning what will happen to them in the more immediate future. they do not need to be informed of their diagnosis, but the illness should be discussed with them. if children are informed of their diagnosis, effort should be directed towards eliciting and addressing their fears and misconceptions. ■ the american academy of pediatrics strongly encourages disclosure of hiv infection status to school-age children. the process for disclosure should be discussed and planned with the parents and may require a number of visits to assess the child’s knowledge and coping capacity. considerable effort will need to be directed to facilitate coping with the illness. symptomatic children, particularly those requiring hospitalisation, should be informed of their hiv status. the likelihood of children inadvertently learning about their hiv status in a hospital setting is high. disclosure should optimally be conducted in a controlled situation and should include parents and knowledgeable professionals. ■ adolescents should know their hiv status. they should be fully informed to appreciate consequences for many aspects of their health, including sexual behaviour. ■ adolescents also should be informed of their hiv status to make appropriate decisions about treatment and participation in clinical treatment trials. physicians should also encourage adolescents to involve their parents in their care. hiv 864 forum the case for option b and optional b+: ensuring that south africa’s commitment to eliminating mother-to-child transmission of hiv becomes a reality   d besada, g van cutsem, e goemaere, n ford, h bygrave, s lynch   médecins sans frontières, cape town d besada, bsc, mph   centre for infectious disease epidemiology and research, university of cape town, and médecins sans frontières, cape town g van cutsem, md, dtmh, mph e goemaere, md, dtmh, phd   centre for infectious disease epidemiology and research, university of cape town, and médecins sans frontières, geneva, switzerland n ford, mph, phd   médecins sans frontières, london, united kingdom h bygrave, mb chb   médecins sans frontières access campaign, new york, usa s lynch corresponding author: d besada (msfb-capetown-advocacy@msf.org.za) in a previous issue of the southern african journal of hiv medicine, pillay and black summarised the trade-offs of the safety of efavirenz use in pregnancy (pillay p, black v. safety, strength and simplicity of efavirenz in pregnancy. southern african journal of hiv medicine 2012;13(1):28-33.). highlighting the benefits of the world health organization’s proposed options for the prevention of mother-to-child transmission (pmtct) of hiv, the authors argued that the south african government should adopt option b as national pmtct policy and pilot projects implementing option b+ as a means of assessing the individual and population-level effect of the intervention. we echo this call and further propose that the option to remain on lifelong antiretroviral therapy, effectively adopting pmtct option b+, be offered to pregnant women following the cessation of breastfeeding, for their own health, following the provision of counselling on associated benefits and risks. here we highlight the benefits of options b and b+. s afr j hiv med 2012;13(4):178-181. doi:10.7196/sajhivmed.864 in a recent issue of the southern african journal of hiv medicine, pillay and black1 summarised the trade-offs surrounding the safety of efavirenz (efv) use in pregnancy. highlighting the benefits of each option for the prevention of mother-to-child transmission (pmtct) of hiv proposed by the world health organization (who), the authors argued that the south african (sa) government should consider the adoption of option b as national pmtct policy, and pilot projects implementing option b+ as a means of assessing the individual and population-level effect of the intervention. we echo this call and further recommend that ‘optional b+’ (i.e. the option to stay on lifelong antiretroviral therapy (art), effectively adopting pmtct option b+) be offered to pregnant women for their own health after the cessation of breastfeeding, following counselling on the benefits and risks of the intervention. in this article we highlight the benefits of options b and b+. in april 2012, who released a programmatic update to the use of antiretrovirals (arvs) for pmtct and the treatment of hiv-positive pregnant women.2 the key findings indicate that options b and b+ are likely to prove preferable to option a for operational, programmatic and strategic reasons. while all options recommend initiating triple arv therapy in hiv-positive pregnant women with a cd4 count <350 cells/mm3 , their recommendations differ for cd4 counts >350 cells/mm3 . for the latter, option a promotes: the use of zidovudine (azt) from 14 weeks’ gestation, single-dose nevirapine (nvp) at birth, and 7 days of azt/ lamivudine (3tc) postpartum for the mother; and daily nvp for the infant until the cessation of breastfeeding or until 4 6 weeks of age if the mother is receiving antiretroviral therapy (art) or is not breastfeeding. option b recommends art for the mother from 14 weeks’ gestation until birth or the cessation of breastfeeding, and the use of nvp for the infant until 4 6 weeks of age. option b+ advocates lifelong art, and nvp for the infant as for option b. the rationale behind these recommendations stems from increasing evidence at clinical and programme levels highlighting the benefits of a single, standardised regimen to serve pmtct and the treatment of hiv-positive pregnant women. the who update reflects earlier recommendations from major donors such as the united states president’s emergency plan for aids relief (pepfar),3 and has led to the adoption of option b+ by other high-burden african countries including malawi, kenya, uganda, swaziland and rwanda, with pilots underway in several others.4 further support for pmtct options b and b+ are echoed in a newly released report by the united nations children’s fund (unicef), the business leadership council and the clinton health access initiative.5 who further highlights that this suggested approach would strengthen the effectiveness of the pmtct programme through improved linkages with art programmes. options b and b+ are simpler, probably safer, and less resource-intense than option a numerous challenges have been experienced with the implementation of option a. in addition to requiring drug changes across the continuum of care (antenatal, delivery and postpartum care),1 , 6 the option necessitates the use of different arvs depending on cd4 count. option a also involves a long period of azt monotherapy with associated potential for developing thymidine analogue (tam) mutations, and it complicates clinical management and delays treatment initiation, mostly where access to cd4 count measurement is scarce. the provision of effective care in sa is challenged by congested health facilities and a lack of human resources. appropriately, options b and b+ reduce the burden on healthcare workers. option b simplifies the delivery of care by ensuring that the same regimen offered to pregnant women is the first-line regimen for all adults, with the who recommendation of efv for all stages of pregnancy.7 a standardised fixed-dose arv combination throughout antenatal, delivery and postpartum care would not only improve continuity of care, but also simplify drug forecasting, procurement, supply chain management, and stock-out monitoring. the current first-line regimen in sa is tenofovir (tdf)/lamivudine (3tc)/efavirenz (efv); generic single-pill fixed-dose combinations are registered and most likely to be included in sa’s arv tender for 2013. despite reassurance from the 2010 medical research council (mrc) survey showing a reduction of mother-to-child transmission of hiv in sa to 2.7%,8 there are concerns regarding the feasibility and acceptability of the daily administration of nevirapine (nvp) syrup, including multiple reports of associated delivery problems. with the hasty cessation of the provision of free formula in the public sector, there may be a future increase in breastfeeding transmission rates. strangely enough, this seems to have been accepted as a fatality by the national strategic plan (nsp) 2012 2016 target of <2% at birth and <5% at the end of breastfeeding. for even further programmatic simplification, option b+ would altogether send one simple and strong message to patients: ‘art for life’ – promoting good adherence and successful art. stopping art after the cessation of breastfeeding is likely to lead to confusing messages for hiv-infected individuals, their communities and health workers. moreover, there is a risk of developing non-nucleoside reverse transcriptase inhibitor (nnrti) resistance if art is stopped without tail protection (i.e. continuing the 2 remaining arv drugs for 7 days after withdrawal of an nnrti). the possible field implications of this are not yet well understood. while option b remains simpler than option a, it requires that primary healthcare services: determine the hiv status of women at each pregnancy; determine the cd4 count/hiv clinical stage before art initiation at each pregnancy; ensure timeous art initiation at each pregnancy for hiv-positive women; identify intent to breastfeed and the duration thereof after each delivery (taking into consideration that women are known to breastfeed beyond the initially intended period); and ensure that art is ceased safely after each pregnancy, with cd4 count follow-up. each additional step in the treatment cascade increases the risk of patient attrition. a study in sa demonstrated a 33% retention rate from first cd4 count to art initiation.9 option b also recommends art initiation from 14 weeks’ gestation – assuming that women present for care early in pregnancy. programme data, however, show that the majority of women present much later in pregnancy. many of these challenges would be overcome with option b+.   treatment interruptions may be harmful the national fertility rate in sa is 2.5.10 with multiple pregnancies, typical in developing countries, women identified as hiv-positive tend to be exposed to the potentially harmful repeated initiation and discontinuation of arvs. this is particularly pertinent in other sub-saharan countries with much higher fertility rates than sa (e.g. in malawi, with 5 6 births per woman).11 in a recent systematic review,12 unstructured treatment interruptions were associated with a higher risk of death and opportunistic infection, a lower probability of increased cd4 cell counts, a higher prevalence of neurocognitive impairment, a lower health-related quality of life, and an increased risk of virological failure and drug resistance. earlier trials demonstrated that structured treatment interruptions were harmful to patients.13 , 14 consequently, many experts endorse continuous art for pregnant women, rather than stopping and starting therapy with each pregnancy.6   early initiation on art may improve outcomes for mothers following increasing supporting evidence and expert opinion, initiation of art at a cd4 count >350 cells/mm3 to reduce morbidity and mortality (outside the context of pregnancy) is now recommended in us and european guidelines.15 , 16 however, there is ongoing controversy in this regard. while the debate remains open about the individual benefits of art initiation above a cd4 count of 500 cells/ mm3 , a special case could be made for women of childbearing age in an african context. multiple pregnancies and increased infectious risks serve to predispose these women to a rapid decline in cd4 count; hence, there is a relatively short time period within which the women’s cd4 counts are high enough for the benefits of arv initiation to be questionable. in a study from zimbabwe, the peri-partum mortality of women with cd4 counts of 400 600 cells/mm3 was 5.4 times higher than for their hiv-negative counterparts.17 furthermore, continual increases in maternal mortality in sa have been attributed to the aids epidemic.18 option b+ could reduce early in utero hiv transmission option b+ ensures that women are already receiving art for subsequent pregnancies, covering the initial weeks and maintaining a higher cd4 count. several studies have demonstrated that the lowest risk of transmission is among women who have initiated art before conception in comparison with those who initiate art during pregnancy. the reduced risk of transmission is believed to be as a result of reducing the risk of early in utero transmission.19 , 20   horizontal transmission to hiv-negative partners the hiv prevalence among women during their reproductive years is particularly high in sa. a study among couples across eastern and southern africa demonstrated a prevalence of stable hiv-discordant partnerships of 8 31%, with 49% serodiscordance among couples with at least one hiv-infected partner.21 in a meta-analysis in sub-saharan africa, the proportion of hiv-positive women in stable hiv-serodiscordant relationships was 47%, demonstrating that women are just as likely as men to be the index partner.22 as demonstrated in the hptn 052 trial,23 art decreases transmission in hiv-serodiscordant couples by 96%. continuing art in women between pregnancies during their reproductive years would also serve to protect their hiv-negative partners. this is in line with the new who recommendations that hiv-positive individuals in serodiscordant partnerships be given art regardless of cd4 count.24   cost-effectiveness of treatment scale-up the expected reductions in the number of infections, morbidity and mortality, both in children and adults, through the provision of option b+, will contribute to a decline in overall treatment cost after initial funding.25 challenges and arguments against option b+ several arguments against the adoption of option b+ must be discussed when considering the roll-out of this intervention.   adherence adherence among hiv-infected pregnant women is probably the most challenging issue, for short-course (option a/b) and lifelong therapy.26 , 27 , 28 , 29 in a recent meta-analysis of art adherence during and after pregnancy, art adherence was well below what was recommended for adequate virological suppression, especially during the postpartum period.30 this has significant implications for the success of lifelong treatment, as recommended with option b+. loss to follow-up among pregnant women initiating art across sa was found to be the greatest in the first 3 months after art initiation, with differences diminishing over time.31 this highlights where adherence support is most required. new innovative strategies need to be identified and piloted to address this, including: simpler and more tolerable art regimens (tdf – fixed dose and combination); a reduced number of clinic visits and time associated with such visits; and adherence support clubs to optimise peer support. we suggest an ‘opt-out’ option at the end of the breastfeeding period for women with a cd4 count >350 cells/mm3 who do not want to remain on art, allowing structured art cessation with tail protection. cost arv drug cost was a major determinant in the decision of many sub-saharan countries to implement pmtct option a. in 2009, the average drug cost for implementing option b was 3 5 times higher than that of option a. however, by the end of 2011, the cost was only twice as high.2 the annual cost of the tdf/3tc/efv first-line regimen in sa is r1 361.45 (approximately us$162) per patient. a single-pill fixed-dose regimen costs only marginally more: r1 424.88 (approximately us$172) per patient.32 the lowest international price is r828 (us$100) per patient, and further reductions are expected. with the opening of the sa arv tender in october 2012, fixed-dose combination drugs are likely to become available in the public sector. further studies by the united states centre for disease control (cdc) show that option b+ would cost marginally more than option b (incremental cost of $270 at 5 years) in the case of multiple pregnancies.33   risk of renal toxicity from tdf tdf has the potential for renal toxicity. while pregnancy-related conditions such as hypertension, pre-eclampsia and diabetes increase the risk of renal impairment,34 this is offset by the young age of pregnant women. furthermore, option b+ policy ensures that most women start art early in their hiv infection. concerns remain surrounding the effect of tdf exposure on infant growth, with limited available data.35 conclusion recently, sa’s national strategic plan considered the evidence to be insufficient to warrant a change from the current pmtct option a protocol. the who programmatic update concludes that both options b and b+ offer programmatic and operational advantages that would go towards the elimination of mother-to-child hiv transmission. the implementation of option b+ would require increased adherence support mechanisms, funding, and scale-up at the primary healthcare level, including the adoption of task-shifting for art initiation. however, this would result in the best protection for the health of pregnant women and infants, and contribute to reduced hiv transmission among sero-discordant couples according to the latest evidence.23 in the medium term, this strategy is highly likely to be cost-effective. further research is required to address the challenges faced by pmtct programmes while drawing on the latest scientific evidence to ensure that it is translated into policies reflecting the needs and realities of the millions of women living with hiv and their children. sa’s pmtct programme must ensure the delivery of the best care possible and move towards the elimination of paediatric hiv. a more aggressive pmtct option such as b+ should be tested urgently, as it may be a necessary step to reach this goal. references 1. pillay p, black v. safety, strength and simplicity of efavirenz in pregnancy. southern african journal of hiv medicine 2012;13(1):28-33. 1. pillay p, black v. safety, strength and simplicity of efavirenz in pregnancy. southern african journal of hiv medicine 2012;13(1):28-33. 2. world health organization (who). programmatic update: use of antiretroviral drugs for treating pregnant women and preventing hiv infection in infants. geneva: who, 2012. http://www.who.int/hiv/pub/mtct/programmatic_update2012/en/index.html (accessed 18 october 2012). 2. world health organization (who). programmatic update: use of antiretroviral drugs for treating pregnant women and preventing hiv infection in infants. geneva: who, 2012. http://www.who.int/hiv/pub/mtct/programmatic_update2012/en/index.html (accessed 18 october 2012). 3. presidential emergency plan for aids relief (pepfar) scientific advisory board. recommendations for the office of the us global aids coordinator: implications of hptn 052 for pepfar’s treatment programs 2011. washington: pepfar, 2011. http://www.pepfar.gov/documents/organization/177126.pdf (accessed 23 april 2012). 3. presidential emergency plan for aids relief (pepfar) scientific advisory board. recommendations for the office of the us global aids coordinator: implications of hptn 052 for pepfar’s treatment programs 2011. washington: pepfar, 2011. 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[http://dx.doi.org/10.1371/journal.pone.0001411]. 21. lingappa jr, lambdin b, bukusi ea, et al. regional differences in prevalence of hiv-1 discordance in africa and enrolment of hiv-1 discordant couples into an hiv-1 prevention trial. plos one 2008;3(1):e1411. [http://dx.doi.org/10.1371/journal.pone.0001411]. 22. eyawo o, de walque d, ford n, et al. hiv status in discordant couples in sub-saharan africa: a systematic review and meta-analysis. lancet infect dis 2010;10(11):770-777. [http://dx.doi.org/10.1016/s1473-3099(10)70189-4] 22. eyawo o, de walque d, ford n, et al. hiv status in discordant couples in sub-saharan africa: a systematic review and meta-analysis. lancet infect dis 2010;10(11):770-777. [http://dx.doi.org/10.1016/s1473-3099(10)70189-4] 23. donnell d, beaten jm, kiarie j, et al. heterosexual hiv-1 transmission after initiation of antiretroviral therapy: a prospective cohort analysis. lancet 2010;375(9731):2092-2098. 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[http://dx.doi.org/10.1186/1471-2458-11-88] 27. igwegbe ao, ugboaja jo, nwajiaku la. prevalence and determinants of non-adherence to antiretroviral therapy among hiv-positive pregnant women in nnewi, nigeria. international journal of medicine and medical sciences 2010;2(8):238-245. 27. igwegbe ao, ugboaja jo, nwajiaku la. prevalence and determinants of non-adherence to antiretroviral therapy among hiv-positive pregnant women in nnewi, nigeria. international journal of medicine and medical sciences 2010;2(8):238-245. 28. awiti, uo, ekström am, ilako f indalo d, wamalwa d, rubenson b. reasoning and deciding pmtct-adherence during pregnancy among women living with hiv in kenya. cult health sex 2011;13(7):829-840. [http://dx.doi.org/10.1080/13691058.2011.583682] 28. awiti, uo, ekström am, ilako f indalo d, wamalwa d, rubenson b. reasoning and deciding pmtct-adherence during pregnancy among women living with hiv in kenya. cult health sex 2011;13(7):829-840. 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[http://dx.doi.org/10.1080/09540121.2010.516341] 30. nachega jb, uthman oa, anderson j, et al. adherence to antiretroviral therapy during and after pregnancy in low-income, middle-income, and high-income countries: a systematic review and meta-analysis. aids 2012;26(16):2039-2052. 30. nachega jb, uthman oa, anderson j, et al. adherence to antiretroviral therapy during and after pregnancy in low-income, middle-income, and high-income countries: a systematic review and meta-analysis. aids 2012;26(16):2039-2052. 31. myer l, cornell m, fox m. loss to follow up and mortality among pregnant and non-pregnant women initiating art across south africa. http://www.retroconference.org/2012b/abstracts/44356.htm (accessed 18 october 2012). 31. myer l, cornell m, fox m. loss to follow up and mortality among pregnant and non-pregnant women initiating art across south africa. http://www.retroconference.org/2012b/abstracts/44356.htm (accessed 18 october 2012). 32. médecins sans frontières (msf) access campaign. untangling the web of antiretroviral price reductions. 15th edition. geneva: msf access campaign, 2012. http://d2pd3b5abq75bb.cloudfront.net/2012/09/20/11/46/41/289/msf_access_utw_15th_edition_2012_updated18_09_12.pdf (accessed 18 october 2012). 32. médecins sans frontières (msf) access campaign. untangling the web of antiretroviral price reductions. 15th edition. geneva: msf access campaign, 2012. http://d2pd3b5abq75bb.cloudfront.net/2012/09/20/11/46/41/289/msf_access_utw_15th_edition_2012_updated18_09_12.pdf (accessed 18 october 2012). 33. world health organization (who). the strategic use of antiretrovirals for treatment and prevention of hiv infection. geneva: who, 2011. http://www.who.int/hiv/pub/meetingreports/consultation_20111116/en/index.html (accessed 20 october 2012). 33. world health organization (who). the strategic use of antiretrovirals for treatment and prevention of hiv infection. geneva: who, 2011. http://www.who.int/hiv/pub/meetingreports/consultation_20111116/en/index.html (accessed 20 october 2012). 34. struik gm, den exter ra, munthali c, et al. the prevalence of renal impairment among adults with early hiv disease in blantyre, malawi. int j std aids 2011;22(8):457-462. [http://dx.doi.org/10.1258/ijsa.2011.010521] 34. struik gm, den exter ra, munthali c, et al. the prevalence of renal impairment among adults with early hiv disease in blantyre, malawi. int j std aids 2011;22(8):457-462. [http://dx.doi.org/10.1258/ijsa.2011.010521] 35. siberry gk, williams pl, mendez h, et al. safety of tenofovir use during pregnancy: early growth outcomes in hiv-exposed uninfected infants. aids 2012;26(9):1151-1159. 35. siberry gk, williams pl, mendez h, et al. safety of tenofovir use during pregnancy: early growth outcomes in hiv-exposed uninfected infants. aids 2012;26(9):1151-1159. message_from_executive.html message from the executive i hope you are reading this at the durban aids conference! the meeting is a major event on the conference circuit, and is jam-packed with exciting events, talks and seminars, as well as debates about everything from behaviour change to the responsibilities of donors. i'll be particularly interested in the sessions on the revamping of primary care in south africa and on nurse-initiated art (nimart). we’ve made big gains in treatment, but we need to get more people into care and earlier, and for that to happen, we need all our primary care sites to be firing effectively. for the unfortunates who can’t be here, there’s plenty more happening. the annual workshop in advanced clinical care (awaac) will take place in durban later this year (6 and 7 october 2011), co-ordinated by the harvard academics, with local clinical experts yunus moosa and henry sunpath leading from the sa side. it’s a hard-core conference for doctor and nurse clinicians, and thesociety has managed to source some bursaries, so watch your e-mail and transcripts for details. francois venter president inter.html original article interand intra-laboratory variability of cd4 cell counts in swaziland ganizani mlawanda, mb chb, msc clinical epidemiology, dip hiv man, dtm&h school of health systems and public health, faculty of health sciences, university of pretoria, and royal swaziland sugar corporation medical services hospitals, mhlume, swaziland paul rheeder, mb chb, mmed, phd jacqui miot, bpharm, phd school of health systems and public health, faculty of health sciences, university of pretoria corresponding author: g mlawanda (mlawandag@yahoo.co.uk) background. analytical variability in cd4 enumeration is well known, but few studies from southern africa have quantified the interand intra-laboratory variability in cd4 count measurements. in addition, the possible impact of time lapse after sample collection on cd4 reliability is not well understood. methods. a cross-sectional study was conducted at royal swaziland sugar corporation hospital and three laboratories, lab a (comparator), lab b (national reference) and lab c (rural hospital). blood from hiv-infected individuals was collected using routine venepuncture into separate specimens for each of the three laboratories. the samples were further subdivided at each laboratory: one was run at 12 hours and the second at 24 hours after venepuncture. the results of absolute cd4 count and cd4 percentage testing were compared within (intra-laboratory) and between (inter-laboratory) laboratories. results. among 53 participants, the mean cd4 count at 12 hours was 373 cells/µl, 396 cells/µl and 439 cells/µl, and at 24 hours 359 cells/µl, 389 cells/ µl and 431 cells/µl, for laboratories a, b and c, respectively. the coefficient of intra-laboratory variation was 4%, 8% and 20% for cd4 count for laboratories a, b and c, respectively. comparing 12and 24-hour measurements, the mean difference (bias) within the laboratories between the two time points (and limits of agreement, loas) was 14 (-46 to 73), 8 (-161 to 177) and 7 (20 to 33) cells/µl for labs a, b and c, respectively. comparing lab a versus lab b, lab a versus lab c and lab b versus lab c, the inter-laboratory bias for the cd4 count at 12 hours was -32, -64 and -38 cells/µl, respectively. the corresponding loas were -213 to 150, -183 to 55, and -300 to 224, respectively. at 24 hours, the biases and loas were similar to those at 12 hours. conclusions. cd4 counts appeared reliable at all three laboratories. lab b and lab c were clinically interchangeable with the comparator laboratory, lab a, but not between themselves. time to measurement does not affect the inter-laboratory agreement within 12 and 24 hours. s afr j hiv med 2012;13(2):59-63. thirty-five million people are infected by hiv globally, two-thirds of whom live in sub-saharan africa.1 antiretroviral therapy (art) is a critical intervention for reducing hiv-related morbidity and mortality, but delivery of art requires multiple laboratory investigations.2 in particular, determination of eligibility for art initiation relies heavily on cd4 enumeration, and cd4 results are monitored as the major indicator of response to treatment over time. the gold standard technique for cd4 enumeration is flow cytometry.3 , 4 biological and analytical (laboratory) variations are known to affect cd4 enumeration; biological factors can that influence cd4 results include haemodilution in pregnancy, seasonal and diurnal variations (lowest at approximately 12:30 pm, highest at 8:30 pm), surgery, viral infections, tuberculosis, some intercurrent illnesses, corticosteroids, interferon and cancer chemotherapy.3 laboratory variations are known to occur when enumeration techniques different from the gold standard, flow cytometry, are used.3 , 4 in addition, variations are known to be subject to inter-observer differences as well as inter-laboratory differences.5 the time to performing cd4 may also cause variation in final cd4 count; the world health organization (who) therefore recommends that all cd4 counts be done within 72 hours from the time of blood collection.3 , 4 in swaziland and many other parts of southern africa, blood for cd4 testing is collected from various health centres and then sent to central laboratories where analysis is done. the time of arrival of samples differs greatly according to distance from the laboratory, but the impact of time differences on cd4 results is not well understood. clinicians rely on accurate cd4 values, despite this variability, to make decisions regarding art initiation and management. some previous studies of cd4 variability have produced worrying results. sax and boswell analysed the implication of between-laboratory variations and found that 58% of cd4 count results had enough variation to have led to conflicting treatment recommendations.6 pattanapanyasat and chimma found cd4 variation between cd4 cell count results conducted using flow cytometers of different ages in service.7 various new cd4 enumeration techniques, for example the guava easy cd4 and capillary-based cd4, have been compared with gold-standard techniques and found to be comparable.3 , 4 , 8 ensuring accurate cd4 counts has become more important recently, since art is being initiated at higher cd4 counts, when clinical signs tend to be less sensitive in detecting immune suppression.2 in swaziland, there has been widespread suspicion among hiv clinicians regarding discrepancies in cd4 count results within and between laboratories, and concern that these discrepancies may potentially be large enough to affect decisions to start art. in order to address this problem, this study sought to evaluate the intraand inter-laboratory variability in cd4 cell enumeration. methods this study was undertaken at hiv clinics at the royal swaziland sugar corporation hospital in swaziland and three laboratories, lab a, lab b and lab c (identity of the laboratories deliberately not disclosed). lab a was a reputable, internationally accredited south african laboratory commonly used as standard in clinical practice across southern africa. lab b was the swazi national reference laboratory based in the capital city, 250 km away from the study setting, and had a turnover of 4 000 cd4 enumerations per month. lab c was a rural mission hospital laboratory located 80 km from the study site and had a turnover of 1 700 samples per month. all the three laboratories used a flow cytometric cd4 enumeration method, and trained laboratory technicians performed the cd4 tests. to be eligible, patients had to be adults (>18 years), give informed consent to the study, and be visiting the health facility for routine cd4 count. the study included patients regardless of whether they were on art or not. after participants’ consent had been obtained, blood was collected into edta tubes, using routine venepuncture technique, in three aliquots, one each for lab a, lab c and lab b. the samples were further split into two aliquots at each respective laboratory, one of which was run at 12 hours and the second at 24 hours after venepuncture. a reliable transport vehicle ensured that specimens reached all laboratories within stipulated time. a sample size of 53 was used. for this type of study, altman and bland recommend a sample size of 30 as ‘minimum acceptable’ and 50 as ‘good’ as it gives a 95% confidence interval (ci) about ±0.34 s, where s is the standard deviation (sd) of the differences between measurements by the two methods.9 data were analysed using stata version 10. for intra-laboratory variability, the coefficient of variation (cv) and bland-altman (ba) method were used. the ba method was the predominant technique for inter-laboratory variability. bland-altman plots were generated in excel analyze-it. in both cases, for repeatability and agreement, comparison was based on clinically significant reference ranges used previously in most studies: 0 10% for cv, ±250 cells/µl for cd4 count and 19.5% for cd4 percentage.7 , 8 , 10 , 11 clinical impact on antiretroviral therapy (art) initiation was assessed by kappa coefficients with comparison to the standard reference scales.12 results fifty-three participants consented to participate in the study. the mean cd4 count was 373 cells/µl, 396 cells/µl and 439 cells/µl at 12 hours, and 359 cells/µl, 389 cells/µl and 431 cells/µl at 24 hours, for lab a, lab b and lab c, respectively. subsequent wilcoxon sign-rank test revealed some statistically significant differences in cd4 count between the laboratories. table 1 summarises the demographic, clinical and laboratory characteristics of participants. intra-laboratory variability. the cv for cd4 count for lab b was low (3.4%) compared with lab a (8.5%). this was consistent with intra-laboratory repeatability based on clinically significant cv range of 0 10%. for lab c the cv was 20.1%, a finding consistent with poor repeatability. for all three laboratories, the cv of cd4 percentage was even lower: 5.6%, 8.34% and 7.5% for lab a, lab b and lab c, respectively. the results using the ba method showed that both cd4 count and cd4 percentage were repeatable, when compared with clinically significant ranges ±250 cells/µl and ±19.5%, for all the laboratories: for cd4 count, the limits of agreement were -46 cells/ µl to 73 cells/µl for lab a, -20 cells/µl to 33 cells/µl for lab b, and -161 cells/µl to 177 cells/µl for lab c, as per fig. 1 and table 2. the ba plots for lab a, lab b and lab c had no dispersion suggesting evidence of systematic error. inter-laboratory agreement at 12 hours. for cd4 count, at 12 hours, both lab c and lab b could be clinically interchanged with the comparator, lab a, based on the limits of agreement which fell within the clinically significant range (defined as ±250 cells/µl): -184 cells/µl to 55 cells/µl for lab c, and -213 cells/µl to 150 cells/µl for lab b, which was much wider than for lab c. when lab b was compared for agreement with lab c, the limits of agreement were -300 cells/µl to 224 cells/µl, which were out of the clinically significant range, and we therefore concluded that the two laboratories could not be clinically interchanged. for cd4 percentage all the laboratories could be clinically interchanged. compared with the comparator, lab a, the limits of agreement for lab b were -12 cells/µl to 9 cells/µl and -3 cells/µl to 2 cells/µl for lab c; between lab b and lab c the limits were -11 cells/µl to 12 cells/µl. table 3 summarises the results for inter-laboratory variability based on ba results at 12 hours and at 24 hours. inter-laboratory agreement at 24 hours. time to measurement had no significant impact on inter-laboratory agreement based on the limits of agreement and biases at 24 hours were similar to those at 12 hours for both cd4 count and cd4 percentage. when compared with lab a, the limits of agreement at 24 hours were -205 cells/µl to 135 cells/µl for lab b and -195 cells/µl to 66 cells/µl for lab c. for lab b/lab c the limits of agreement were -265 cells/µl to 191 cells/µl. for cd4 percentage, all the laboratories were clinically interchangeable. the limits of agreement were -11% to 9% for lab a/lab b, -5% to 3% for lab a/lab c and -10% to 10% for lab b/lab c, which were within the reference range, ±19.5%. clinical impact on art initiation. compared with lab a, the percentage agreement for art eligibility was 81% (i.e. 19% of patients were misclassified) for lab b and 89% (11% of patients misclassified) for lab c. for lab a/lab b, 23% eligible patients would be misclassified and not initiated on art, as shown in table 4. discussion in this study we looked at intraand inter-laboratory variability, a topic that has been investigated previously but for which there are few data from southern africa.5 , 11 , 13 we also analysed the impact of time to measurement on the eventual cd4 result, both within the same laboratory and across participating laboratories. cd4 count had good repeatability for all the three laboratories, based on preset clinically significant ranges. likewise, cd4 percentage had minimal variation for all the laboratories and even lower cv, a sign of stronger repeatability than for cd4 count. these findings concurred with previous intra-laboratory studies.7 , 8 , 10 , 11 inter-laboratory variability. several studies on inter-laboratory and inter-method variability of cd4 count have been published and most show good agreement and interchangeability.7 , 10 , 11 two studies, however, found significant variations across different laboratories.5 , 13 in this study, inter-laboratory clinical interchangeability results at 12 and 24 hours showed that agreement was independent of time to measurement. the limits of agreement were similar when time to measurement was 12 hours or 24 hours. this finding mirrors the who laboratory recommendation that cd4 remains stable within 72 hours from time of venepuncture.3 , 4 clinicians using the laboratories in this study should therefore trust equally cd4 results done at 12 hours and 24 hours. for cd4 percentage, both lab b and lab c were in agreement with the comparator laboratory, lab a, at 12 and 24 hours with narrower limits of agreement than for cd4 count. once again, stability of cd4 percentage and agreement with the comparator laboratory make it a potentially trustworthy and stable parameter to use in our setting for possible inclusion in guidelines to determine when to start art, as suggested in some previous studies.8 , 10 the degrees of misclassification in this study were similar to findings from a study by thakar and kumar, which found a kappa factor range of 74% for a cd4 count below 350 cells/µl when two laboratories were being compared.11 repeating cd4 count measurement and not relying on single cd4 count results have been known to reduce disease misclassification.6 one shortfall of this use of misclassification as done here is that it does not differentiate between low‐magnitude inaccuracy, for example a count of 349 cells/µl being misclassified as >350 cells/µl, which may be reasonably expected from any test, and high‐magnitude inaccuracy. a study that includes many cd4 values falling close to the defined cut‐off (as measured by the reference test) will show higher rates of misclassification by the new test than a study in which the majority of values lie away from the threshold.4 the clinically significant ranges used in this study were ±250 cells/µl, ±19.5% and cv <10%, because these were the ranges used in similar studies which had pre-defined ranges.7 , 8 , 10 , 11 the results of repeatability and agreement therefore relied on this pre-defined range. however, the choice of clinically significant ranges is debatable, and a narrower range of ±100 cells/µl could have changed the interpretation of these results greatly. however, the magnitude of cd4 count or cd4 percentage variability that can affect clinical decision making remains poorly defined.13 the author felt that based on the new art initiation threshold, 350 cells/µl, a range of ±250 cells is reasonable. in conclusion, cd4 count and cd4 percentage appeared to be repeatable for all the three laboratories. lab b and lab c were clinically interchangeable with the comparator laboratory, lab a, for both cd4 count and cd4 percentage but not between themselves. time to measurement does not affect the inter-laboratory agreement within 12 and 24 hours. the clinical implications of inter-laboratory variation on disease misclassification were comparable to those from previous studies. sources of support and disclosure of funding. a university of pretoria rescom grant partially covered the laboratory costs during the study. competing interests by authors. none. research ethics committee approval. ethics approval was given by the university of pretoria ethics committee 74/2010 on 21 april 2010, and institutional ethical approval was also obtained. author contributions. dr ganizani mlawanda conceived the study, and formulated the study design, data collection, statistical analysis and manuscript design. prof. paul rheeder and dr jacqui miot were active supervisors throughout from conception to final manuscript. all authors read and approved the final manuscript. references 1. unaids. report on the global hiv/aids epidemic 2010: executive summary. geneva: unaids, 2010. http://www.unaids.org/globalreport/ (accessed 2 december 2011). 1. unaids. report on the global hiv/aids epidemic 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[pmid: 1444169] table 1. demographic, clinical and laboratory data of participants demographic characteristics gender (n) male 28 female 25 age (years) (mean (sd)) 37.4 (9.5) weight (kg) (mean (sd)) 64.8 (12.2) clinical characteristics who stage (%) i 32.1 ii 22.6 iii 13.2 iv 32.1 on tb treatment (%) 11.3 on art (%) 47.2 inpatients (%) 9.4 outpatients (%) 90.6 laboratory parameters lab a (52 observations) mean 25th centile 50th centile 75th centile cd4 count at 12 h (cells/µl) 373 181 336 539 cd4 count at 24 h (cells/µl) 359 177 323 518 cd4 % at 12 h 17 10 15 22 cd4 % at 24 h 17 10 15 21 lab b (52 observations) mean 25th centile 50th centile 75th centile cd4 count at 12 h (cells/µl) 396 185 359 568 cd4 count at 24 h (cells/µl) 389 183 346 535 cd4 % at 12 h 18 11 17 24 cd4 % at 24 h 18 10 17 23 lab c (51 observations) mean 25th centile 50th centile 75th centile cd4 count at 12 h (cells/µl) 439 249 397 611 cd4 count at 24 h (cells/µl) 431 233 396 594 cd4 % at 12 h 18 10 16 22 cd4 % at 24 h 18 10 16 22 mean time to running cd4 tests (h) first cd4 second cd4 lab a 12.0 24.0 lab b 12.0 24.0 lab c 12.0 25.1 table 2. intra-laboratory bias and limits of agreement for cd4 count and cd4 percentage at 12 and 24 hours limits of agreement interpretation bias (95% ci) lower (95% ci) upper (95% ci) clinically repeatable? absolute cd4 count lab a 13.5 (5.0 to 21.9) -46.0 (-60.6 to -31.5) 73.0 (58.5 to 87.6) yes lab c 8.2 (-16.0 to 32.4) -160.5 (-202.2 to -118.9) 176.9 (135.3 to 218.6) yes lab b 7.0 (3.2 to 10.7) -19.5 (-25.9 to -13.0) 33.4 (26.9 to 39.9) yes cd4 % lab a 0.1 (-0.2 to 0.3) -1.7 (-2.2 to -1.3) 1.9 (1.5 to 2.4) yes lab c -0.3 (-0.7 to 0.1) -2.9 (-3.5 to -2.2) 2.3 (1.7 to 3.0) yes lab b 0.1 (-0.3 to 0.5) -2.8 (-3.5 to -2.1) 3.0 (2.3 to 3.7) yes *interpretation based on comparison of limits of agreement with clinically significant range of cv <10%, and ranges for clinical significance: ±19.5% for cd4% ±250 cells/µl for cd4 count.7 , 8 , 10 , 11 table 3. inter-laboratory bias and limits of agreement for cd4 count and cd4 percentage at 12 and 24 hours laboratories limits of agreement interpretation* bias (95% ci) lower (95% ci) upper (95% ci) clinically interchangeable? cd4 count at 12 h lab a/lab b -31.5 (-57.6 to -5.5) -213.3 (-258.2 to -168.4) 150.2(105.3 to 195.1) yes lab a/lab c -64.3 (-81.6 to -47.0) -183.8 (-213.6 to -154.0) 55.2 (25.4 to 85.0) yes lab b/lab c -38.2 (-75.6 to -0.6) -300.2 (-364.8 to -235.5) 223.9 (159.2 to 288.5) no cd4 % at 12 h lab a/lab b -1.2 (-2.7 to 0.3) -11.7 (-14.3 to -9.1) 9.3 (6.7 to 11.9) yes lab a/lab c -0.7 (-1.1 to -0.4) -3.1 (-3.7 to -2.5) 1.7 (1.1 to 2.2) yes lab b/lab c 0.5 (-1.1 to 2.1) -10.7 (-13.4 to -7.9) 11.6 (8.9 to 14.4)) yes cd4 count at 24 h lab a/lab b -35.6 (-60.0 to -11.1) -205.7 (-247.6 to -163.7) 134.5 (92.5 to 176.5) yes lab a/lab c 8.2 (-16.0 to 32.4) -195.0 (-227.6 to -162.5) 65.8 (33.3 to 98.3) yes lab b/lab c 7.0 (3.2 to 10.7) -265.0 (-321.3 to -208.7) 191.4 (135.0 to 247.7) no cd4 % at 24 h lab a/lab b -1.2 (-2.5 to 0.2) -10.5 (-12.8 to -8.2) 9.2 (5.7 to 10.5) yes lab a/lab c -1.1 (-1.6 to -0.5) -4.9 (-5.8 to -3.9) 2.7 (1.8 to 3.6) yes lab b/lab c 0.1 (-1.3 to 1.5) -9.7 (-12.1 to -7.3) 9.9 (7.4 to 12.3) yes *interpretation based on comparison of limits of agreement with clinically significant range of cv <10%, and ranges for clinical significance: ±19.5% for cd4 % and ±250 cells/µl for cd4 count.7 , 8 , 10 , 11 table 4. impact of cd4 variations at art initiation threshold on treatment decision laboratories agreement* (%) expected agreement (%) kappa misclassified (%) lab a/lab b 81.1 48.4 0.6 18.9 lab a/lab c 88.7 49.9 0.8 11.3 lab b/lab c 77.4 50.2 0.6 22.6 *strength of agreement according to byrt’s criteria for assessing kappa strength: excellent agreement = 0.93 to 1; very good agreement = 0.81 to 0.92; good agreement = 0.61 to 0.80; fair agreement = 0.41 to 0.60; slight agreement = 0.21 to 0.40; poor agreement = 0.01 to 0.20; no agreement <0.00.12 lab a lab b lab c fig. 1. bland altman plots for intra-laboratory variability of cd4 count for lab a, lab b and lab c. why it's time.html debate why it’s time to say goodbye to stavudine ... everywhere isabelle andrieux-meyer, 1 md polly clayden 2 simon collins 2 nathan geffen 3 eric goemaere,4 md, dtmh, phd mark harrington5 sharonann lynch1 tido von schoen-angerer, 1 md, msc tracy swan5 1 médecins sans frontières access campaign 2 hiv i-base 3 treatment action campaign 4 médecins sans frontières, south africa 5 treatment action group editor’s note: the previous issue of the sajhiv (december 2011) carried an opinion piece by innes, cotton and venter regarding the potential value of low-dose of stavudine (20 mg twice a day). they suggested that reduced dosing of stavudine may lead to levels of viral suppression comparable with those achieved with stavudine 30 mg bd but with a lower risk of toxicity and side-effects, and at a fraction of the cost of tenofovir. the opinion was related to a larger proposal, led by venter, to conduct a head-to-head trial comparing low-dose stavudine with tenofovir (both in a regimen including lamivudine and efavirenz) on viral suppression and other treatment outcomes over 24 months. there has been considerable debate regarding the advantages and disadvantages of low-dose stavudine, and in turn the value of any such trial. here the debate continues with a commentary by isabelle andrieux-meyer et al. and a rebuttal by venter and colleagues. we read with interest an opinion piece by innes et al.1 in the previous issue of the journal, regarding the potential value of low-dose stavudine (20 mg twice daily). the article focused on stavudine use in paediatrics (where there are fewer approved antiretrovirals compared with adults, although there will be greater choice in the near future, as the us food and drug administration (fda) has recently approved tenofovir for 2 12-year-olds, and other regulatory agencies are expected to follow suit). in the article, the authors used the situation with children to argue for a proposal, led by venter, to conduct a head-to-head non-inferiority study in adults comparing low-dose stavudine with tenofovir (both in a regimen including lamivudine and efavirenz) with a 48-week virological endpoint and other treatment outcomes over 96 weeks.* we have serious concerns about this proposed trial, for the following reasons: 1. stavudine is more toxic than tenofovir, and for this reason it is an inferior treatment option. the proposed trial aims to establish virological non-inferiority, which is a moot point, given the severe adverse events associated with stavudine. considerable evidence supports the use of tenofovir over stavudine; regulatory bodies and the world health organization (who) have turned away from the drug. in 2004, stavudine was removed from the list of preferred first-line antiretroviral drugs recommended by the us department of health and human services (dhhs).2 starting in 2006, the who recommended that countries start moving away from stavudine, and in 2009 recommended that the drug be phased out in first-line antiretroviral therapy (art) programmes.3 earlier this year, the european medicines agency (ema) revised the indication for stavudine, noting that ‘… the use of the medicine should be severely restricted in both adults and children ... prescribers are reminded of the severe side effects seen with zerit [stavudine] and should only use the medicine when other appropriate treatments are not available. patients being treated with zerit should be assessed frequently and switched to appropriate alternatives as soon as possible.’4 médecins sans frontières (msf)/doctors without borders have provided further compelling evidence of stavudine’s toxicity in an operational setting. in a lesotho cohort, the authors found that ‘… for patients on stavudine, the risk of a toxicity-driven regimen switch was almost six times higher than tenofovir’.5 the high incidence of adverse events among patients on stavudine-containing first-line regimens has also been documented in a larger prospective study in south africa.6 in that study 30% of patients had to switch from stavudine-based to non-stavudine-based regimens within 3 years. for good reasons, tenofovir has become the gold standard for today’s first-line antiretroviral therapy. its introduction in developing countries is an important step towards bringing treatment in poor countries in line with rich ones. as the who and all countries are phasing out stavudine, this study will send a confusing message, and it may slow down this transition while countries wait for the results. *a randomised, double-blind study to demonstrate non-inferiority of stavudine (20 mg bid) compared with tenofovir (300 mg qd) co-administered with lamivudine and efavirenz in antiretroviral-naive patients over 96 weeks. if funded and approved, the trial is anticipated to start in 2012. there is no prospect that stavudine 20 mg is a better option than tenofovir. the stavudine parallel track programme, in which over 10 000 patients were randomised to receive 40 (30) mg or 20 (15) mg between october 1992 and february 1994, showed a higher incidence of neuropathy in the high-dose arm (21%). nonetheless, the incidence of neuropathy observed in the lower-dose arm was also unacceptably high (15%).7 of particular importance in lowto middle-income countries – where tuberculosis (tb) is prevalent among hiv-positive people, who are also receiving stavudine-containing regimens – a south african study looked at the risk of stavudine substitution for toxicities in 7 066 patients receiving ongoing tb treatment at art initiation; concurrent initiation of tb treatment and art and incident tb treatment after art initiation. the study found people receiving ongoing and concurrent tb treatment to be at increased risk of toxicity leading to stavudine substitution, irrespective of stavudine dose (30 and 40 mg). for ongoing tb treatment, adjusted hazard ratio (ahr) was 3.18 (95% confidence interval (ci) 1.82 5.56) in the first 2 months of art; for concurrent tb treatment, ahr was 6.60 (95% ci 3.03 14.37) in the first 2 months of art. the stavudine 20 mg study is not being proposed in any developed country. instead it is planned to include only middleand lower-income developing countries. patients enrolling in this trial risk being randomised to receive treatment that may be less effective and is more toxic than the current standard of care. there is therefore no good reason why a properly informed patient should want to enrol in this study. 2. the poor tolerability of stavudine limits therapeutic durability. a person has the best chance of successful treatment with their first-line regimen, making it critical that the medicines are as tolerable as possible. a tolerable first-line regimen enhances therapeutic durability by helping people adhere to treatment, and delays their need to switch to more costly second-line regimens, which are complicated for patients, for health workers and from an operational standpoint. 3. stavudine’s side-effects cut into stavudine’s savings on cost. a study published by msf shows that inpatient care and essential drug costs were higher for people on stavudine than for those on tenofovir in a cohort in rural lesotho. according to msf’s cost-effectiveness study of switching from stavudine or zidovudineto tenofovir-based first-line regimens in lesotho, the tenofovir-containing regimen generated higher life years and quality-adjusted life years than zidovudine or stavudine-based treatment.8 as the costs of tenofovir and especially efavirenz drop, the cost benefit to patients and to health systems will become clearer. since the study was completed, the global best price of efavirenz – which partly drives tenofovir costs – has almost halved (us$97 per patient year in 2009 to $52 today). 4. stavudine can compromise second-line options. when someone does fail their first-line regimen, the longer they remain on stavudine – which is likely in a context with limited access to viral load monitoring – the more their second-line options are compromised. unlike stavudine, tenofovir does not confer thymidine analogue mutations (tams); people taking tenofovir can stay on a failing regimen much longer without compromising efficacy of zidovudine and therefore second-line therapy. 5. stavudine’s long-term toxicity question will not be answered by this trial. the proposed 20 mg stavudine dose might be acceptable in a short-term 48or even 96-week virological endpoint study (although bristol-myers squibb studied and rejected 20 mg bd). but, because mitrochondrial toxicity is both dose and time dependent, many of stavudine’s most serious side-effects (such as peripheral neuropathy and lipoatrophy) would not necessarily emerge until after such a study was completed. this study does not include monitoring of surrogate markers for mitochondrial toxicity, so it cannot shed light on the incidence of this serious adverse event. recently published longer-term cambodian data on rates of severe stavudine-associated toxicity show 7% of people to have neuropathy within the first year; by year 3 the cumulative incidence was 16.6%, and it rose to 19.0% at year 6. the cumulative incidence of lipoatrophy was 56% by year 3 and 72% by year 6. stavudine use significantly increased the risk for lactic acidosis among people on concurrent tb treatment; the ahr was 8.6 (95% ci 2.7 27.5).10 the investigators have agreed that this important question about longer-term toxicity will not be answered in the trial, raising the serious issue that the trial will not be able to answer the primary policy question which drives it – whether long-term 20 mg stavudine twice daily is as good as once-daily tenofovir in first-line art regimens for use in public health programmes in resource-limited settings. 6. stavudine must be taken twice a day, compared with tenofovir’s once-daily dosing. a twice-daily dosing regimen (as with stavudine 20 mg) does not have the simplicity of a once-daily fixed-dose combination (as with tenofovir). people are more likely to adhere to simpler regimens and therefore are more likely to have better treatment outcomes, as well as stave off resistance that requires more complex and expensive second-line regimens. 7. a tenofovir-based regimen is recommended for hiv/hepatitis b (hbv) coinfection, because stavudine has no activity against hbv and resistance to lamivudine is inevitable. while hiv/hbv co-infection is an exclusion criterion for this trial, it may encourage persistent use of a suboptimal regimen for hiv/hbv co-infected people. screening for hbv is not routinely performed before initiation of art in most resource-limited settings, yet hbv is endemic. for example, in south africa an estimated 5% of hiv-positive people are hbv co-infected (dr mark sonderup, personal communication). giving a stavudine/lamivudine-based regimen to hiv/hbv co-infected people will create lamivudine-resistant hbv in this population (90% at 4 years).9 continuing lamivudine in the context of hbv drug resistance may lead to hepatitis flares; these flares can cause serious liver damage, and are potentially life-threatening. researchers are also concerned about the transmission of drug-resistant hbv that may not be preventable by currently available hbv vaccines, a potential public health catastrophe. 8. stavudine-related cost savings may become irrelevant by the trial’s end. the rationale for this trial is to lower treatment costs, as stavudine is currently cheaper than its alternatives. however, the price of alternatives, notably tenofovir, has come down dramatically in the last several years, and is expected to decrease further as demand increases. according to msf’s annual arv pricing report, tenofovir is now cheaper than zidovudine, with the price of single-drug tenofovir having decreased by 52% from 2008 to 2011, and the price of the triple fixed-dose combination of tenofovir, lamivudine and efavirenz having decreased by 53% to us$173 per person per year over that same time period.10 the price of the double fdc tdf/3tc co-packed with efv is $143 per person per year. furthermore, the clinton health access initiative (chai) is currently working on the in the reformulation of tenofovir, with the goal of increasing bioavailability, hence reducing the required active pharmaceutical ingredient and in turn the cost. because the stavudine 20 mg 96-week efficacy trial is expected to be completed at the earliest by 2014 2015, and would need to be followed by a larger, longer (perhaps 5-year) field effectiveness trial to determine longer-term tolerability, the drug may not be available for use at the new dose until possibly even 2020. it is therefore likely to take 9 years from now for there to be enough evidence that 20 mg stavudine is safe and non-inferior to tenofovir, and could be used to replace tenofovir in first-line regimens. if current price trends continue, it is likely the anticipated cost savings associated with stavudine could be overtaken by expected further price reductions for tenofovir and other components of the first-line regimen, by the time stavudine 20 mg would be ready for use. it is worth noting that a three-drug one-pill-once-a-day regimen containing efavirenz and tenofovir is now priced at roughly half what stavudine-based triomune cost when it was first introduced a decade ago. further, even greater potential savings could be achieved if the tenofovir prodrug gs 7340, now in phase ii by gilead sciences, is approved at a low milligram dose. results will be available within a similar time frame to those from the 96-week stavudine 20 mg trial. a recent announcement by gilead of an agreement with tibotec to develop a fixed-dose combination of darunavir, emtricitabine, gs 7340 and cobicistat with ‘less than one tenth of the amount of the 300 mg of tenofovir disoproxil fumarate contained in viread and truvada’ suggests that this is feasible.11 chimerix inc. also has a promising tenofovir pro-drug in development, cmx-157. other drugs in late-stage development such as the integrase inhibitor dolutegravir (50 mg once daily) also offer potential savings on manufacturing and could end up being cheaper than stavudine 20 mg by the time it would become available. 9. stavudine has low acceptability in the community. finally, and most importantly, the continued use of stavudine and the proposed trial has raised opposition from people directly affected by its continued use. as an example, the malawi network of people living with hiv/aids (manet+) recently held a press briefing, as the slow pace for phasing out current use of this drug in their country concerns them. despite the funding crisis, the malawi government has a priority for this to be completed by june 2012.12 it is unclear why the bill and melinda gates foundation – who are in discussion with the investigators about funding the proposal – consider this study to be a priority. it seems an aberration in an otherwise carefully considered strategy for supporting research into the optimisation of art for resource-limited settings. this includes the encore 1 study of low-dose efavirenz, the reformulation of tenofovir to increase its bioavailability (working with chai), and the development of innovative potentially long-acting formulations. for the reasons outlined above, research and the resources it requires, as well as activist pressure, should focus on increasing access to safer cost-saving alternatives to stavudine, not on seeking a comeback for a drug virtually abandoned in wealthy countries. please address all correspondence to: sharonann.lynch@msf.org polly.clayden@i-base.org.uk nathangeffen@gmail.com markhar@gmail.com references 1. innes s, cotton m, venter f. why should we still care about the stavudine dose? southern african journal of hiv medicine 201;12(4):14-15. 1. innes s, cotton m, venter f. why should we still care about the stavudine dose? southern african journal of hiv medicine 201;12(4):14-15. 2. panel on clinical practices for treatment of hiv infection. guidelines for the use of antiretroviral agents in hiv-1-infected adults and adolescents. department of health and human services (dhhs), 2004. http://aidsinfo.nih.gov/contentfiles/adultandadolescentgl10292004002.pdf (accessed 20 february 2012). 2. panel on clinical practices for treatment of hiv infection. guidelines for the use of antiretroviral agents in hiv-1-infected adults and adolescents. department of health and human services (dhhs), 2004. http://aidsinfo.nih.gov/contentfiles/adultandadolescentgl10292004002.pdf (accessed 20 february 2012). 3. world health organization. who rapid advice: antiretroviral therapy for hiv infection in adults and adolescents. who, 2009. http://www.who.int/hiv/pub/arv/rapid_advice_art.pdf (accessed 20 february 2012). 3. world health organization. who rapid advice: antiretroviral therapy for hiv infection in adults and adolescents. who, 2009. http://www.who.int/hiv/pub/arv/rapid_advice_art.pdf (accessed 20 february 2012). 4. european medicines agency. questions and answers on the review of zerit (stavudine): outcome of a renewal procedure. european medicines agency, 17 february 2011. http://www.ema.europa.eu/docs/en_gb/document_library/medicine_qa/human/000110/wc500102227.pdf (accessed 20 february 2012). 4. european medicines agency. questions and answers on the review of zerit (stavudine): outcome of a renewal procedure. european medicines agency, 17 february 2011. http://www.ema.europa.eu/docs/en_gb/document_library/medicine_qa/human/000110/wc500102227.pdf (accessed 20 february 2012). 5. bygrave h, ford n, van cutsem g, et al. implementing a tenofovir-based first-line regimen in rural lesotho: clinical outcomes and toxicities after two years. j acquir immune defic syndr 2011;56(3):e75-78 [http://dx.doi.org/10.1097/qai.0b013e3182097505]. 5. bygrave h, ford n, van cutsem g, et al. implementing a tenofovir-based first-line regimen in rural lesotho: clinical outcomes and toxicities after two years. j acquir immune defic syndr 2011;56(3):e75-78 [http://dx.doi.org/10.1097/qai.0b013e3182097505]. 6. menezes c, maskew m, sanne i, crowther n, raal f. a longitudinal study of stavudine-associated toxicities in a large cohort of south african hiv infected subjects. bmc infect dis 2011;11:244 [http://dx.doi.org/10.1186/1471-2334-11-244]. 6. menezes c, maskew m, sanne i, crowther n, raal f. a longitudinal study of stavudine-associated toxicities in a large cohort of south african hiv infected subjects. bmc infect dis 2011;11:244 [http://dx.doi.org/10.1186/1471-2334-11-244]. 7. anderson r, dunkle l, smaldone l, et al. design and implementation of the stavudine parallel track programme. j infect dis 1995;171:118-122. [http://dx.doi.org/10.1093/infdis/171.supplement_2.s118]. 7. anderson r, dunkle l, smaldone l, et al. design and implementation of the stavudine parallel track programme. j infect dis 1995;171:118-122. [http://dx.doi.org/10.1093/infdis/171.supplement_2.s118]. 8. jouquet g, bygrave h, kranzer k, et al. cost and cost-effectiveness of switching from d4t or azt to a tdf-based first-line regimen in a resource limited setting in rural lesotho. j acquir immune defic syndr 2011;58:e68-e74 [http://dx.doi.org/10.1097/qai.0b013e31822a9f8d]. 8. jouquet g, bygrave h, kranzer k, et al. cost and cost-effectiveness of switching from d4t or azt to a tdf-based first-line regimen in a resource limited setting in rural lesotho. j acquir immune defic syndr 2011;58:e68-e74 [http://dx.doi.org/10.1097/qai.0b013e31822a9f8d]. 9. benhamou y, bochet m, thibault v, et al. long-term incidence of hepatitis b virus resistance to lamivudine in human immunodeficiency virus-infected patients. hepatology 1999;30:1302-1306. [http://dx.doi.org/10.1002/hep.510300525]. 9. benhamou y, bochet m, thibault v, et al. long-term incidence of hepatitis b virus resistance to lamivudine in human immunodeficiency virus-infected patients. hepatology 1999;30:1302-1306. [http://dx.doi.org/10.1002/hep.510300525]. 10. médecins sans frontières. untangling the web of antiretroviral price reductions. 14th ed. médecins sans frontières campaign for access to essential medicines, july 2011. http://www.doctorswithoutborders.org/publications/article.cfm?id=5448&cat=special-report (accessed 20 february 2012). 10. médecins sans frontières. untangling the web of antiretroviral price reductions. 14th ed. médecins sans frontières campaign for access to essential medicines, july 2011. http://www.doctorswithoutborders.org/publications/article.cfm?id=5448&cat=special-report (accessed 20 february 2012). 11. gilead. gilead sciences finalizes agreement with tibotec pharmaceuticals to develop and commercialize a single-tablet regimen of prezista(r) with emtriva(r), gs 7340 and cobicistat. gilead press release. http://www.gilead.com/pr_1630785 (accessed 20 february 2012). 11. gilead. gilead sciences finalizes agreement with tibotec pharmaceuticals to develop and commercialize a single-tablet regimen of prezista(r) with emtriva(r), gs 7340 and cobicistat. gilead press release. http://www.gilead.com/pr_1630785 (accessed 20 february 2012). 12. nkhoma p. manet+ wants arv d4t phased out. the daily times, malawi, 30 january 2012. http://www.bnltimes.com/index.php/daily-times/headlines/national/4079-manet-wants-arv-d4t-phased-ou (accessed 20 february 2012). 12. nkhoma p. manet+ wants arv d4t phased out. the daily times, malawi, 30 january 2012. http://www.bnltimes.com/index.php/daily-times/headlines/national/4079-manet-wants-arv-d4t-phased-ou (accessed 20 february 2012). hiv 879 message from the executive 'the times they are a-changing.' the south african national aids council (sanac) reconvened at an impressive inaugural meeting in pietermaritzburg on 4 october 2012, attended by the minister of health, dr aaron motsaeledi, and deputy president kgalema motlanthe. sanac announced that the incidence of mother-to-child transmission of hiv was down and life expectancy was up – all very good news. however, in my opinion, the most important development is that fixed-dose combinations are now going to be part of the national tender. while i think that this will improve adherence, more importantly, we will not be faced with stock-out of a single drug. the impact of patients having received two out of three of their drugs will be felt in the years to come. the southern african hiv clinicians society has been invited to be a plenary member of sanac, so we will continue our role as the voice of reason to the department of health, to ensure that the goals of the national strategic plan are achieved. this is not the time to let up in any way – an aids-free generation is within our grasp. lastly, if you have not yet made travel arrangements to attend the conference of the southern african hiv clinicians society in cape town from 25 to 28 november 2012, you should get onto it as soon as possible. register for the conference as soon as you can. the line-up of speakers is impressive, and we have very interesting debates planned. skills building will be provided in many areas, and conference attendees will have the chance to rub shoulders with the academics. more than that, the conference will present an opportunity to meet a number of brave and hardworking healthcare providers from the region. i encourage you to share your experiences and learn.   f conradie president southern african hiv clinicians society johannesburg fconradie@witshealth.co.za acknowledgements references about the author(s) nils von hentig internal medicine ii, hivcenter, goethe university hospital, frankfurt, germany carlo angioni institute of clinical pharmacology, goethe university hospital, frankfurt, germany christoph königs department of pediatrics and adolescent medicine, goethe university hospital, frankfurt, germany citation von hentig n, angioni c, königs c. determination of lopinavir/ritonavir concentrations in four different oral solutions for the application of antiretroviral therapy in very young, hiv-1-infected children. s afr j hiv med. 2021;22(1), a1222. https://doi.org/10.4102/sajhivmed.v22i1.1222 scientific letter determination of lopinavir/ritonavir concentrations in four different oral solutions for the application of antiretroviral therapy in very young, hiv-1-infected children nils von hentig, carlo angioni, christoph königs received: 04 feb. 2021; accepted: 30 mar. 2021; published: 11 may 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. infants infected with hiv-1 are generally more affected by disease progression and mortality than older children. early initiation of antiretroviral therapy (art) prevents progression to aids and death. however, therapy options for very young children are quite scarce, as many antiretrovirals are not approved for use in children younger than 3 years of age, and experience regarding the dosing, application, side effects and outcome is limited.1,2,3,4,5,6 an antiretroviral regimen containing lopinavir/ritonavir (lpv/r) in addition to two nucleoside reverse transcriptase inhibitors (nrtis) is the main treatment option for hiv-1-infected infants in most african countries.7,8 the lpv/r combination is available as a meltrex tablet, in a fixed-dose combination added to nrtis, or as a liquid formulation that is bodyweight-dose adjusted.2,5,6,9,10,11,12,13 the tablet formulation is not applicable for very young children because of their inability to swallow the tablet. crushing of the lpv/r meltrex formulation is not recommended, and the liquid formulation remains the only alternative for very young patients. however, as the taste of the pure lpv/r liquid formulation is unpalatable, many parents seek alternative ways to give the medicine, including mixing the lpv/r oral solution with formula milk, for example, as part of the child’s nutrition. however, flocculation of the oral solution results, and no bioavailability data are available. following the report of parents administering the solution in formula milk, which was well tolerated by the child, and having observed a good virological response, lopinavir plasma levels were determined at the university of frankfurt, following routine monitoring of the child on art. the parents provided informed consent before the procedure. the standard pharmacokinetic testing protocol for the examination of antiretroviral plasma concentrations in small children allows sampling at the following time points: at 0, 1 and 2 h after the dosing interval. each sample is < 1 ml whole blood in children < 2 years of age. the sample is then processed and analysed by means of liquid chromatography–tandem mass spectrometry (lc-ms/ms). the child was treated with the licensed dose (230 mg/m2) twice daily and surprisingly reached a cmin of 3330 ng/ml and cmax of 5610 ng/ml. we therefore prepared several oral solutions by mixing the lpv/r liquid formulation together with glucose syrup, glucose syrup and ethanol, or formula milk, with and without ultrasound treatment, and tested these oral solutions for their taste and drug stability. three samples each of (1) formula milk (10 ml humana pre containing 0.32 g fat, 0.76 g carbohydrate and 0.12 g protein), (2) ultrasound-treated formula milk (to improve solubility and inhibit flocculation), (3) glucose syrup, and (4) glucose syrup plus ethanol (chemistry-based decision to improve the solubility) were spiked with the same concentration of liquid lpv/r (4000/1000 ng/ml), and the concentrations of lpv/r were measured by means of validated lc-ms/ms.14 the accuracy of controls was 92% – 105% for lopinavir and 95% – 109% for ritonavir. the linearity of the calibration curve ranged from 100 ng/ml to 60 000 ng/ml.15 three samples of each formulation were prepared in order to test the possible variability of sampling. the investigators controlled the taste by taking it orally and inhibiting flocculation by visual inspection; tasting was performed independently and then reported to each other. the three samples of formula milk treated with ultrasound for 25 min and the three samples of untreated formula milk showed lopinavir concentrations ranging from 2450 ng/ml to 2590 ng/ml and from 2450 ng/ml to 2790 ng/ml, respectively. the samples dissolved in ethanol-glucose syrup and glucose syrup alone showed lopinavir concentrations of 3040 ng/ml – 3060 ng/ml and 1520 ng/ml – 4020 ng/ml, respectively (table 1). table 1: plasma concentrations of liquid lopinavir and ritonavir in samples, mixed with formula milk, glucose syrup or glucose syrup plus ethanol. it was found that lpv/r flocculated in formula milk, regardless of whether the formula milk was ultrasound treated, and was intolerably bitter. in contrast, the taste of the lpv/r solution was completely masked when mixed together with glucose syrup. in general, the lpv/r liquid formulation proved to be stable for at least 15 min when dissolved in either formula milk or glucose syrup. the samples from the lpv/r liquid formulation and glucose syrup mixture showed a marked variation in the lopinavir concentrations, but the variable results were not attributable to any instability of the drug in the resulting solution. this variation can be explained by sampling errors, because it was nearly impossible to accurately pipette small quantities of this highly viscous solution. this problem was confirmed through the addition of 1 ml ethanol to the syrup solution, which resulted in improved solubility as well as the most accurate concentration measurements obtained in this case. in general, lpv/r can be dissolved in glucose syrup with a moderate loss of stability. the taste of the solution was greatly improved, so this method of application could very well help young children swallow the medication more easily. dissolving the antiretroviral liquid formulation in formula milk resulted in flocculation of the solution, lower lpv/r concentrations and an incredibly bitter taste. because this report is based on a small sample size, a more comprehensive study should be carried out in order to confirm these findings and assist children living with hiv and their parents with the administration of the liquid lpv/r formulation. acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this letter. authors’ contributions c.a. performed the lab analyses and the previous validation of lab methods regarding liquid chromatography–tandem mass spectrometry. c.k. conceptualised the study, supervised the evaluation and reviewed the publication. n.v.h. conceptualised the study, supervised the evaluation and performed the statistical analysis; he is the corresponding author of this letter. ethical considerations as this study was conducted on material obtained from routine clinical blood assessments being analysed regularly in children with hiv according to treatment guidelines in germany that were then processed ex vivo and in vitro, no ethical clearance was necessary according to the german medical laws, and no informed consent was applicable. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability data are available from the corresponding author, n.v.h., upon reasonable request. disclaimer the views and opinions expressed in this letter are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references siberry gk, abzug mj, nachman s, et al. guidelines for the prevention and treatment of opportunistic infections in hiv-exposed and hiv-infected children: 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https://www.knowledgehub.org.za/elibrary/2019-art-clinical-guidelines-management-hiv-adults-pregnancy-adolescents-children-infants ananworanich j, kosalaraksa p, hill a, et al. pharmacokinetics and 24-week efficacy/safety of dual boosted saquinavir/lopinavir/ritonavir in nucleoside-pretreated children. pediatr infect dis j 2005;24(10):874–879. https://doi.org/10.1097/01.inf.0000180578.38584.da jullien v, urien s, hirt d, et al. population analysis of weight, age, and sex-related differences in the pharmacokinetics of lopinavir in children from birth to 18 years. antimicrob agents chemother 2006;50(11):3548–3555. https://doi.org/10.1128/aac.00943-05 weber v, radeloff d, reimers b, et al. neurocognitive development in hiv-positive children is correlated with plasma viral loads in early childhood. medicine (baltimore) 2017;96(23):e6867. https://doi.org/10.1097/md.0000000000006867 resino s, bellon j, munoz-fernandez m, infection. sgoh. antiretroviral activity and safety of lopinavir/ritonavir in protease inhibitor-experienced hiv-infected children with severe-moderate immunodeficiency. j antimicrob chemother 2006; 57(3):579–582. https://doi.org/10.1093/jac/dki469 rosso r, di biagio a, dentone c, et al. lopinavir/ritonavir exposure in treatment-naive hiv-infected children following twice or once daily administration. j antimicrob chemother 2006;57(6):1168–1171. https://doi.org/10.1093/jac/dkl136 von hentig n, babacan e, staszewski s, sturmer m, doerr hw, lotsch j. predictive factors for response to a boosted dual hiv-protease inhibitor therapy with saquinavir and lopinavir in extensively pre-treated patients. antivir ther 2007;12(8):1237–1246. burger d, teulen m, eerland j, harteveld a, aarnoutse r, touw d. the international interlaboratory quality control program for measurement of antiretroviral drugs in plasma: a global proficiency testing program. ther drug monit 2011;33(2):239–243. https://doi.org/10.1097/ftd.0b013e31820fa528 references about the author(s) gillian sorour department of paediatrics and child health, university of the witwatersrand, johannesburg, south africa nosisa sipambo department of paediatrics and child health, university of the witwatersrand, johannesburg, south africa moherndran archary discipline of paediatrics and child health, college of health sciences, university of kwazulu-natal, durban, south africa department of paediatrics, king edward viii hospital, durban, south africa citation sorour g, sipambo n, archary m. paediatric antiretroviral update. s afr j hiv med. 2023;24(1), a1506. https://doi.org/10.4102/sajhivmed.v24i1.1506 editorial paediatric antiretroviral update gillian sorour, nosisa sipambo, moherndran archary copyright: © 2023. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. south africa has lagged behind other countries in offering daily dosing of palatable, simple, well-tolerated and effective paediatric antiretroviral formulations to children with hiv.1 this is despite the availability of such formulations internationally, including our neighbouring countries in sub-saharan africa. since 2018, dolutegravir (dtg)-based antiretroviral treatment (art) has been the preferred first-line treatment regimen in the world health organization guidelines for adults and children with hiv and has been adopted into south african guidelines for adults since november 2019.2,3 dolutegravir is relatively inexpensive and has improved tolerability, fewer side effects and drug interactions and an increased genetic barrier to drug resistance when compared to other art regimens.4,5,6,7,8 the inclusion of dtg into the guidelines for children and adolescents has been a much slower process. based on a dosing sub-study of the odyssey trial supporting the use of the dtg 50 mg tablet in children over 20 kg,9 south africa’s 2019 art guidelines expanded dtg access to children from 20 kg,3 which greatly improved treatment in these children. further odyssey sub-studies and the p1093 study also showed good data for dtg in children from 3 kg to 20 kg;6,10,11 however, for infants and children weighing less than 20 kg, access to dtg is dependent on availability of a new dispersible child-friendly formulation. first-line art for infants and children < 20 kg has been a backbone of the protease inhibitor lopinavir/ritonavir and the two nucleoside-reverse-transcriptase inhibitors, abacavir and lamivudine. lopinavir/ritonavir syrup needs to be given twice daily, should ideally be refrigerated, and is often poorly tolerated because of its awful taste. abacavir and lamivudine were previously only available as relatively high-volume syrups for children unable to swallow tablets. improvements came in the form of a 60 mg dispersible abacavir tablet and, finally, a fixed-dose combination scored dispersible tablet of abacavir and lamivudine (120/60 mg) which was approved in south africa in 2021. the fixed-dose combination of abacavir and lamivudine can be administered as a once-daily dose and is easily dissolved in liquid for use in infants from 3 kg of weight.12 it is well tolerated and is an improvement on the large volumes of syrups that were previously required. stock-outs and supply chain issues have hampered the roll-out of these formulations to all provinces and clinics. south africa’s recently released 2023 art clinical guidelines for the management of hiv2 come with many welcome improvements for infants and children living with hiv. the good news is that there are two new dtg formulations available: a scored 10 mg dispersible tablet that can be offered to infants from 4 weeks of age if they weigh at least 3 kg, and a single fixed-dose combination tablet of abacavir, lamivudine and dtg that can be given to children who weigh 25 kg or more.12 this aligns treatment with adults and will mean that a child will be able to be on dtg from diagnosis through infancy and childhood to adulthood. all infants and children who are currently on a non-dtg regimen, including second-line regimens, should now be evaluated for a switch to a dtg-based regimen. another change in the guidelines is that tenofovir can now be given to adolescents over 10 years who weigh at least 30 kg (previously 35 kg) and have normal kidney function.2 this means that adolescents over 10 years who weigh more than 30 kg can be transitioned to the fixed-dose combination of tenofovir/lamivudine/dtg in alignment with adult recommendations. countries in sub-saharan africa that have adopted the transition to paediatric dtg have demonstrated rapid uptake with improved viral suppression in children > 20 kg.13 once-daily dosing of a more easily tolerated, effective medication will hopefully improve adherence and outcomes in our vulnerable paediatric population, including those < 20 kg, and support south africa’s goal of achieving the last indicator in the joint united nations programme on hiv/aids 95-95-95 initiative (diagnosis of 95% of all people living with hiv, initiating 95% on art among those diagnosed and achieving 95% virally suppressed among those being treated). current joint united nations programme on hiv/aids treatment cascade figures in south african adults are 94-74-67, with children lagging far behind.14 in the paediatric population, only 83% of children living with hiv are known to be infected. of these, only 48% are on treatment, and a mere 33% of those on treatment are virally suppressed.14 it is likely that the suboptimal regimens used in children in south africa have played a large role in the poor viral suppression in this group. the availability of more child-friendly formulations will undoubtedly be a relief to many parents and clinicians who have struggled with getting infants and children to tolerate existing formulations. the goal of a successful paediatric art programme is to enable all children living with hiv to live a normal life at their full potential with a suppressed hiv viral load throughout their childhood and continued into adulthood and we hopefully will be moving closer to this goal with the switch to optimised regimens. references archary m, van zyl r, sipambo n, sorour g. optimised paediatric antiretroviral treatment to achieve the 95-95-95 goals. s afr j hiv med. 2021;22(1):1–4. https://doi.org/10.4102/sajhivmed.v22i1.1278 national department of health. 2023 art clinical guidelines for the management of hiv in adults, pregnancy and breastfeeding, adolescents, children, infants and neonates. pretoria: national department of health; 2023. national department of health. 2019 art clinical guidelines for the management of hiv in adults, pregnancy, adolescents, children, infants and neonates. pretoria: national department of health; 2019. cevik m, orkin c, sax pe. emergent resistance to dolutegravir among insti-naïve patients on first-line or second-line antiretroviral therapy: a review of published cases. open forum infect dis. 2020 jun 2;7(6):ofaa202. https://doi.org/10.1093/ofid/ofaa202 molina j-m, clotet b, van lunzen j, et al. once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with hiv-1 infection (flamingo): 96 week results from a randomised, open-label, phase 3b study. lancet hiv. 2015;2(4):e127–e136. https://doi.org/10.1016/s2352-3018(15)00027-2 turkova a, white e, mujuru ha, et al. dolutegravir as first-or second-line treatment for hiv-1 infection in children. n engl j med. 2021;385(27):2531–2543. https://doi.org/10.1056/nejmoa2108793 aboud m, kaplan r, lombaard j, et al. dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with hiv-1 infection in whom first-line therapy has failed (dawning): an open-label, non-inferiority, phase 3b trial. lancet infect dis. 2019;19(3):253–264. https://doi.org/10.1016/s1473-3099(19)30036-2 schramm b, temfack e, descamps d, et al. viral suppression and hiv-1 drug resistance 1 year after pragmatic transitioning to dolutegravir first-line therapy in malawi: a prospective cohort study. lancet hiv. 2022;9(8):e544–e553. https://doi.org/10.1016/s2352-3018(22)00136-9 bollen pd, moore cl, mujuru ha, et al. simplified dolutegravir dosing for children with hiv weighing 20 kg or more: pharmacokinetic and safety substudies of the multicentre, randomised odyssey trial. lancet hiv. 2020;7(8):e533–e544. https://doi.org/10.1016/s2352-3018(20)30189-2 ruel td, acosta ep, liu jp, et al. pharmacokinetics, safety, tolerability, and antiviral activity of dolutegravir dispersible tablets in infants and children with hiv-1 (impaact p1093): results of an open-label, phase 1–2 trial. lancet hiv. 2022;9(5):e332–e340. https://doi.org/10.2139/ssrn.3954096 waalewijn h, chan mk, bollen pd, et al. dolutegravir dosing for children with hiv weighing less than 20 kg: pharmacokinetic and safety substudies nested in the open-label, multicentre, randomised, non-inferiority odyssey trial. lancet hiv. 2022;9(5):e341–e352. https://doi.org/10.1016/s2352-3018(21)00292-7 department of health. antiretroviral drug dosing chart for children 2022. pretoria: national department of health; 2022. bacha jm, dlamini s, anabwani f, et al. realizing the promise of dolutegravir in effectively treating children and adolescents living with hiv in real-world settings in 6 countries in eastern and southern africa. the pediatric infectious disease journal 42(7), 576–581. https://doi.org/10.1097/inf.0000000000003878 unaids data 2022. joint united nations programme on hiv/aids (unaids) [homepage on the internet]. c2023 [cited 2023 may 31]. available from: https://www.unaids.org/en/resources/documents/2023/2022_unaids_data m_sajhiv_n20_a15.pdf september 2005 the southern african journal of hiv medicine 50 adding this to our public sector guideline in the future, i do not believe we should add it soon. south africa has a massive burden of hiv infection. adding who stage 3 to the criteria of when to start haart will approximately treble the number of eligible patients. even if we only targeted stage 4 patients (without using cd4 criteria) and only managed to treat 50% of these, we would still need to treat approximately 1 400 000 by 2008 (extrapolated from assa 2002 model by andrew boulle). until it is clear that we can achieve this daunting target we should not talk about easing the criteria for initiation. we have an obligation to first deal with those who are suffering most. references 1. cole s, li r, anastos k, detels r, young m, chmiel js, munoz a. accounting for leadtime in cohort studies: evaluating when to initiate hiv therapies. stat med 2004; 23: 3351-3363. 2. philips an, lepri ac, lampe f, johnson m, sabin ca. when should antiretroviral therapy be started for hiv infection? interpreting the evidence from observational studies. aids 2003; 17: 1863-1869. 3. deeks sg, barbour jd, grant rm, martin nj. uration and predictors of cd4-t cell gains in patients who continue combination therapy despite detectable plasma viremia. aids 2002; 16: 201-207. 4. badri m, ehrlich r, wood r, maartens g. tuberculosis should not be considered an aids-defining illness in areas with a high tuberculosis prevalence. int j tuberc lung dis 2002; 6: 231-237. should we be initiating antiretroviral therapy earlier? robin wood desmond tutu hiv centre, institute of infectious disease and molecular medicine, university of cape town antiretroviral programme rationales antiretroviral therapy (art) programmes are a part of the response to the massive mortality occurring in the countries most affected by the hiv epidemic. unaids estimated that 2.3 million deaths from aids occurred in sub-saharan africa during 2004. south africa faces the prospect of an accumulated 6 7 million aids deaths by 2010, with the majority affecting the age group 20 40 years, a stage of life when adults are productive and caring for the next generation. in september 2003 the world health organization (who) declared the lack of access to hiv treatment a global health emergency. who called for ‘unprecedented action’ to ensure that by the end of 2005 at least 3 million people in need of art will have access to it. to date the national evaluations of the status of art programmes have revolved around reporting on numbers on treatment rather than impact on aids mortality. the primary purpose of the south african and other national arv programmes is to minimise hiv-associated mortality. debate focus the key to the present debate revolves around the thresholds of art initiation as set out in various treatment guidelines and how different programme entry criteria impact on population hiv-related deaths. the who treatment guidelines committee recognises in the 2003 guidelines preface that they will need to be updated on a regular basis in order to reflect ‘best current clinical practice’. the sa national rollout programme currently uses the older who 2000 guidelines, which are not internationally recognised as the ‘best current clinical practice’ and have ceased to be used by many other countries in our region such as botswana, namibia and uganda. the current sa guidelines recommend both clinical and cd4 criteria for allowing access to the art programme. appraisal of present sa guidelines firstly the clinical and cd4 count criteria are very mismatched. patients with aids die at a rate of 6% per month while asymptomatic patients with cd4 counts < 200 µl have approximately a 1% monthly mortality. clinical aids is therefore very specific for identifying patients at high risk of death while a cd4 of < 200 is very sensitive measure. secondly, the majority of patients access health care and antiretroviral (arv) programmes because they have clinical symptoms rather than because they have just passed the cd4 threshold of < 200 cells. the median cd4 cell count of patients accessing arvs in kampala, uganda, is still 65/µl and in gugulethu, cape town, it is less than 100/µl after 3 years of the programme. a cd4 count of < 200 cells/µl will gain utility when a large proportion of people living with aids (pwas) have access to sequential cd4 count monitoring. this cd4 count threshold would then be a very sensitive but not specific measure for identifying patients at high risk of death. however, widespread cd4 count testing is not widely available in south africa or elsewhere in sub-saharan africa. thirdly, the clinical threshold of aids as an entry criterion for art results in high mortality, as there are inevitable delays in accessing treatment. in gugulethu the time between referral and commencing arvs is short at 28 days. however, 66% of programme deaths are recorded during this period, occurring almost exclusively in those patients with aids before they could start arvs. the reported delay in the médecins sans frontières, khayelitsha, arv project was 4 months. waiting time to access arvs in other programmes is frequently much longer. waiting lists in cape town hospitals have been up to 8 months and are in excess of 8 months in malawi, which results in an unrecorded 50% of aids patients dying before access to arv programmes. currently this pre-treatment mortality is not recorded as part of the treatment programme, although reduction of hiv mortality is the primary aim of arv treatment. aids patients not only have a high in-programme death rate, they are also difficult to clinically manage and investigate, thereby consuming a disproportionate amount of programme resources. aids is therefore too late a threshold for entry into an arv programme. if the guidelines do not represent ‘best current clinical practice’ but are being used as a means of rationing access to care, they should identify those who will benefit most from therapy. clinical stage is more predictive of hiv mortality than cd4 count. south african published data have reported that the death rate of patients with who stage 3 disease is 2 2.5 times higher than that of asymptomatic patients with < 200 cd4 cells/µl. until cd4 count testing is more widely available, the southern african journal of hiv medicine september 2005 51 the practical entry into arv programmes will continue to be based on presence of clinical symptoms. the only way to clinically identify patients before aids develops is to encourage programme entry at who clinical stage 3. extension of arv treatment protocols to include the treatment of who stage 3 patients will largely access patients who are already in the health care system and at a time when their mortality is already approximately 2% per month. lastly, expansion of the clinical criteria for programme access to stage 3 disease will decrease the numbers of patients progressing to aids in the population and is therefore a more efficient medium-term strategy. conclusions extension of south african department of health arv treatment guidelines to include the treatment of hivsymptomatic patients (i.e. who stage 3 and 4) will bring us into line with all other major national and regional treatment guidelines. a cd4 count < 200 cells/µl will only become a practical entry threshold to arv programmes when cd4 counts are more widely available; meanwhile clinical criteria will continue to define most programme entry. the cd4 count of < 200 cd4 cells/µl is a very sensitive but not specific threshold for identifying those at high risk of death and therefore greatly increases the potential number of patients qualifying for the arv programme. cd4 counts will become more relevant over time as testing becomes more widespread. the present policy of restricting clinical entry to those with aids, results in unacceptably high pre and in-programme death rates. in order to achieve the primary aim of the arv programme, to minimise deaths of pwa, symptomatic patients (i.e. who stage 3 and 4) should be initially targeted for art. references 1. world health organization. scaling up antiretroviral therapy in resourcelimited settings: treatment guidelines for a public health approach. 2003 revision. geneva: who, 2004. 2. coetzee d, hildebrand k, boulle a, et al. outcomes after two years of providing antiretroviral treatment in khayelitsha, south africa. aids 2004; 18: 887-895. 3. badri m, bekker l-g, orrell c, pitt j, cilliers f, wood r. initiating highly active antiretroviral therapy in sub-saharan africa: an assessment of the who revised scaling up treatment guidelines. aids 2004; 18(8):1159-1168. moderator’s summary guidelines for the initiation of antiretroviral treatment have seen considerable changes over the years. initially, we were persuaded by clinicians in resource-rich settings to ‘hit early, hit hard ’ – in other words, to commence arv treatment at almost any stage of hiv infection. this was clearly not a sound option as prolonged therapy with potentially toxic drugs leads to treatment failure, resistance, cumulative toxicities and patient treatment fatigue. we were then persuaded that deferring therapy until certain end-points were reached was the desirable option. deferred therapy had different meanings in the resource-rich and resource-poor settings. in most guidelines in resource-rich settings treatment was recommended when patients had an aidsdefining condition, cd4 count < 200, stage 3 disease, and in asymptomatic patients whose cd4 count < 350 and viral load count was factored in. in resource-poor settings the 2002 who guidelines were generally adopted, and these were embraced by the south african national programme. these guidelines advised that treatment should commence for who stage 4 disease or a cd4 < 200. as professor wood pointed out, waiting for patients to develop stage 4 disease may lead to an alarming mortality as there are inevitable delays in accessing treatment while patients are being assessed and enrolled on programmes. he also argued that patients should enter programmes at who clinical stage 3. the majority of these patients are already in the health care system and their mortality rate is considerably lower. professor gary maartens' argument is not totally dissimilar and he endorses the southern african hiv clinicians society guidelines which extend the conservative national guidelines to include patients with who clinical stage 3 disease and a cd4 count < 350. in asymptomatic patients close monitoring in the cd4 stratum between 200 and 350 is recommended. this recommendation is similar to that of the 2003 revision of the who guidelines in which who stage 3 disease is added to the initiation criteria together with a cd4 count of < 350 in those countries that can measure cd4 counts. it is sobering to reflect on the scenario that adding who stage 3 to the initiation criteria would approximately treble the number of patients eligible for arv therapy. the arv guidelines of the southern african hiv clinicians society were drawn up taking in mind the constrained resources in our country and do reflect a balance between need and resources. it is interesting to note that they are very similar to the latest version of the who clinical guidelines. both speakers in this debate have endorsed this as a reasonable approach for our country in future. abstract introduction current legal and ethical situation in south africa recommendations/possible ways forward conclusion acknowledgements references about the author(s) marian loveday hiv and other infectious diseases research unit (hidru), south african medical research centre, durban, south africa centre for health systems research and development, university of the free state, bloemfontein, south africa caprisa-mrc hiv-tb pathogenesis and treatment research unit, university of kwazulu-natal, durban, south africa ameena goga hiv and other infectious diseases research unit (hidru), south african medical research centre, durban, south africa department paediatrics, university of pretoria, pretoria, south africa ames dhai school of clinical medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa melodie labuschaigne department of jurisprudence, school of law, university of south africa, pretoria, south africa theresa roussouw department of immunology, university of pretoria, pretoria, south africa up/samrc research centre for maternal, fetal, newborn and child health care strategies, university of pretoria, pretoria, south africa theresa burgess division of physiotherapy, university of cape town, cape town, south africa centre for medical ethics and law, stellenbosch university, stellenbosch, south africa ann strode school of law, college of law and management sciences, university of kwazulu-natal, pietermaritzburg, south africa hiv/aids vaccines ethics group, school of applied human sciences, college of humanities, university of kwazulu-natal, pietermaritzburg, south africa melissa wallace the desmond tutu hiv centre, university of cape town, cape town, south africa marc blockman division of clinical pharmacology, university of cape town, cape town, south africa brodie daniels hiv and other infectious diseases research unit (hidru), south african medical research centre, durban, south africa elizabeth spooner hiv and other infectious diseases research unit (hidru), south african medical research centre, durban, south africa linda-gail bekker the desmond tutu hiv centre, university of cape town, cape town, south africa citation loveday m, goga a, dhai a, et al. ethically acceptable consent approaches to adolescent research in south africa. s afr j hiv med. 2022;23(1), a1385. https://doi.org/10.4102/sajhivmed.v23i1.1385 review article ethically acceptable consent approaches to adolescent research in south africa marian loveday, ameena goga, ames dhai, melodie labuschaigne, theresa roussouw, theresa burgess, ann strode, melissa wallace, marc blockman, brodie daniels, elizabeth spooner, linda-gail bekker received: 08 mar. 2022; accepted: 11 may 2022; published: 05 sept. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: adolescents are a unique population with significant unmet health needs. they are often excluded from research that may benefit them as they are perceived as vulnerable and needing protection from research participation. for research ethics committees, conflicting positions in statutes, regulations and ethical guidelines about who provides informed consent for adolescent involvement in health research can be a significant barrier to approving adolescent research. for researchers, the requirement for parental/guardian proxy consent or prolonged approval processes may potentially result in the exclusion of those adolescents most vulnerable and at risk, particularly if issues such as gender-based violence, gender identity, sexuality and sexual practices are in question. objectives: to describe the challenges to adolescent research and suggest strategies to address these. method: we consider the legal and ethical framework in south africa regarding the consenting age for adolescents in research, outline the challenges and, using examples of best practices, suggest strategies to address the current conundrum. results: we suggest three principles to guide research ethics committees on their approach to reviewing health research involving adolescents. strategies to develop ethically acceptable approaches to adolescent research and consent processes are described, which include community involvement. we elaborate on examples of nuanced approaches to adolescent research. conclusion: the inclusion of adolescents in research is critical in informing appropriate and effective health services for this vulnerable population, whilst providing an opportunity to link them into care and services where relevant. keywords: adolescents; parental waiver of consent; ethics; conflicting legal regulations and statutes; research exclusion. introduction adolescence, defined by the world health organization and statistics south africa as those 10–19 years old, is a transitional stage from childto adulthood.1,2 this life period is one of orientation and discovery as questions of independence, identity and a sense of self emerge. it is a time of heightened vulnerability as choices about future, friendship, sexuality, gender identity, and substance use are negotiated. with an evolving capacity to make sound decisions and participate in promoting their own welfare, the needs and vulnerabilities of preand early (10–13-years-old), middle (14–16-years-old) and late adolescents (17–19-years-old) vary.3 globally 1.2 billion adolescents make up 16% of the world’s population, with 90% living in developing countries, where they make up 23% of the population.4 the vulnerabilities and needs of adolescents and adolescent girls, in particular, often remain unaddressed. large numbers of unsafe abortions and a high risk of pregnancy-related mortality occur, with 11% of the global births in girls occurring before their 18th birthday.5,6,7 health services for adolescents are increasingly recognised as a priority in lowand middle-income countries,8 as it is during adolescence that the foundations for adult health and well-being are laid, underpinning the health and well-being of subsequent generations. the unique health needs of adolescents are seldom addressed, a situation which is further exacerbated by their exclusion from research. exclusions may occur as adolescents require a different and unique approach to that of adults, perceived to be vulnerable, needing protection from possible risks of research involvement, and perceived to be incapable of autonomous consenting with good understanding. ironically, although ethical considerations regarding adolescent involvement should be a balancing act between protection from research harm and inclusion in research that may bring benefit, these ethical issues have themselves become a barrier to adolescent inclusion in research. in south africa, conflicting positions in statutes, regulations, and guidance on who provides informed consent for adolescent involvement in health-related research has become a significant challenge and consequently a barrier. this situation is exacerbated by misunderstandings of adolescents’ cognitive abilities and capacity to provide informed consent, valuing of protection over inclusion, institutional self-protection by research ethics committees (recs) and antiquated attitudes about adolescents not holding equal rights to adults.9,10 this situation is no longer tenable, as recs find themselves increasingly in unenviable positions and researchers are frustrated.10 moreover, the frequent exclusion of adolescents from research is compromising their health and well-being.11,12 in this article, we consider the legal and ethical framework in south africa with regard to the consenting age for adolescents in research. we outline the challenges related to differing requirements of legislation and guidelines and, using examples of best practices, suggest strategies to address the current conundrum. current legal and ethical situation in south africa health research is regulated by legal norms set out in the national health act (nha).13 these norms must be read in conjunction with other pieces of legislation which set standards relating to child and adolescent health. in addition, and overlapping the law, are ethical obligations to health research. national health act 61 of 2003 and regulations relating to research with human participants research involving minors is governed by section 71 of the nha,13 which requires mandatory consent from the parent or guardian. if the minor has the ability to understand, he or she consents (not assents), together with the parents or guardian.13 the significance of a minor’s consent and not assent is borne out by the discussion below which underscores capacity to consent rather than an age-dependent consent framework. there are no permissible exceptions to parental/guardian consent with respect to proxy consent and waiver of consent. the nha is complemented by two provisions from the 2014 regulations that relate to research with human participants14: (1) regulation 4.1 states that research with minors should only take place when adults are not appropriate participants for the research; if the research poses no more than a minimal risk to the minor; if the research poses more than a minimal risk, that it has a direct benefit to the minor; or where the research poses more than minimal risk and has no direct benefit to the minor, it may contribute to generalisable knowledge of the health condition being studied; (2) regulation 2 establishes the 2015 department of health guidelines on ethics in health research as the mandatory minimum benchmark for health research, thereby recognising the legal force of the guidelines. it stipulates that health research be undertaken with ‘appropriate consent processes’, but gives no guidance on how the inconsistency in consent approaches for minors’ participation in research in the nha, regulations and department of health ethical guidelines should be addressed. children’s act 38 of 2005 and the choice on the termination of pregnancy act 92 of 1996 the children’s act, in contrast to the nha, recognises the decision-making autonomy of children as human rights bearers, based on their evolving maturity and mental capacity to participate in decisions that affect them.15,16 in other words: children, as persons and constitutional rights bearers with an evolving capacity for individual autonomy, have the right to make their own decisions regarding matters that affect them, provided they display sufficient maturity. examples of context-specific interventions where children’s consent is recognised in the act include, amongst others, access to contraceptives, medical treatment and hiv testing. similarly, the choice on the termination of pregnancy act provides that children do not need parental consent for termination of an early pregnancy.17 as the children’s act does not regulate research involving minors it does not offer direct guidance in resolving the different consent approaches for minors. however, it is counter-intuitive to allow children to independently access services that impact their sexual, general, and mental health, but deny them the opportunity to participate in research which may benefit their health individually and collectively, on grounds of diminished capacity and autonomy. the 2015 department of health guidelines on ethics in health research18 the department of health ethical guidelines state that minors should participate in research only if the research is relevant to them, cannot be achieved without their involvement, and is in their best interests with minimal or negligible risk of harm. these guidelines are to some extent aligned with the nha on minors’ consent for research, but deviate from the nha’s mandatory parental or legal guardian consent requirement allowing for rec discretion when the participation of minors is considered.11 they provide that, in specific instances: (1) a parental substitute may be appointed to provide consent; and (2) the minor themselves can consent independently to research participation. for example, for studies about sexual activity or substance abuse it may be ethically justifiable and appropriate for mature minors (e.g. 16 years and older) to independently consent to research participation as the involvement of parents/guardians may potentially result in social harm to the minor or may result in the failure of adolescents to participate because of their fear of disclosure. the guidelines recommend prior engagement with community role players to justify minors’ independent consent and that recs may grant a waiver of the requirement of written parental permission. in these cases, the process should be carefully documented. the current conundrum: the 2015 ethical guidelines versus the national health act and regulations as regulation 2 of the 2014 regulations has endorsed the ethical guidelines as the minimum legal standard for research with human participants, section 71 of the nha, the 2014 regulations and the ethical guidelines are all legally binding. however, as the legislation and guidelines provide conflicting stipulations with respect to the consent process for research, we suggest four principles to guide recs on which legal instrument should prevail in reviewing health research involving minors. firstly, where legal provisions on a specific issue may lead to conflicting interpretations, an attempt should be made to harmonise the interpretations in a manner that is aligned with the values enshrined in the constitution or the bill of rights.19,20 the constitution endorses the bill of rights as the cornerstone of democracy in south africa and furthermore directs courts to promote the object, purport and spirit of the bill of rights.20 consequently, an interpretation of the nha, regulations and the children’s act should strive to give effect to and promote the aims and values of the constitution and the bill of rights, which in the case of children’s consent would favour an interpretation that acknowledges the evolving decisional autonomy of children. the children’s act’s recognition of children’s decisional capacity is more attuned to the bill of rights and its interpretation is hence to be preferred above that of the nha. secondly, if there is a conflict in the provisions of two statutes dealing with the same subject (e.g. children’s consent), the general rule in south african law is that the later provision should be followed.21,22 not only was the children’s act promulgated after the nha, but it gives better effect to children’s rights in general, as well as to their autonomy. thirdly, since rules of statutory interpretation provide that any conflict between a prevailing act and any of its regulations be resolved in favour of the prevailing act,23 this would technically favour the nha’s interpretation over the interpretation in its (2014) regulations. however, as pointed out above, since the nha’s interpretation is inconsistent with the constitution and the bill of rights with regard to children’s autonomy, the recommended legal position regarding children’s consent to research should be the position captured in the 2015 guidelines, whose interpretation supports and promotes the autonomy of children. fourthly, the constitution mandates the consideration of international law in the interpretation of the bill of rights, which includes international agreements such as the united nations convention of the rights of the child signed by south africa in 1993, requiring an interpretation of national legislation that is aligned and compliant with international law.20,24 the united nations convention of the rights of the child recognises children as rights holders, draws attention to their protection and provision of rights, the obligation to consider their best interests and their evolving capacities to make sound decisions and participate in promoting their own welfare. although it does not refer specifically to research, its articles are flexible enough to address participation in research. numerous other international documents have also addressed the issue of minors and research and the main themes emerging from these documents are: (1) children are people in their own right and have a right to have a say and be heard, including in the context of well-planned, ethical research; (2) involvement of children in any kind of research should take place in partnership with caring, skilled adults who provide appropriate support and guidance; (3) research should focus on understanding and improving children and adolescents’ lives and circumstances; and (4) a participatory approach in which children are included in the research process should be promoted.25,26,27,28,29,30 the ongoing legal uncertainty as to whether the nha imposes a strict mandatory parental consent approach or whether it can be interpreted in a purposive manner to align it with the norms in the regulations and national ethical guidelines remains contentious. this article does not address this issue as authors have written about it elsewhere.10 instead, it proceeds on the basis that children have a fundamental right to benefit from scientific advances and, to fulfil this right, discussion and debate is needed with recs and researchers on how to do this in an ethical and principled manner. recommendations/possible ways forward getting the framework straight the inclusion of adolescents in research is needed to advance their health. the strategies detailed below to develop ethically acceptable approaches to adolescent research and consent practices are illustrated in figure 1. reform: regulatory, policy and ethical guidance reform are needed to facilitate research involving adolescents. a minimum is closer alignment between the legal and ethical requirements. collaboration between recs: research ethics committees need to collaborate and work together to promote ethical standards, facilitate decision-making around ethical challenges, and through a consensus derived approach standardise approaches to adolescent research within an enabling framework. the generation of a publicly available ‘ethics repository’ of resources to support all stakeholders in adolescent research would develop this capacity in south africa. dialogue and feedback between researchers and recs: to develop a common understanding, opportunities for feedback and dialogue between researchers and recs need to be established. this would provide an opportunity to inform recs of the positive and negative experiences of independent minor consent processes if parental consent is waived. this feedback may be required as part of the approval process to ensure real-time monitoring, accountability, and learning. additionally, reporting back ongoing research findings and adolescent-informed community stakeholder experiences and recommendations would facilitate the amendment of consent approaches to protect the best interests of adolescent participants in an iterative fashion. community engagement: this is addressed in the section below and should be operationalised. adolescent-informed engagement: adolescent-informed engagement strategies are needed to guide research involving adolescents from different sociocultural backgrounds with divergent views of when parental consent is acceptable or necessary. consent procedures may need to be tailored to accommodate the diverse needs and preferences of adolescent participants. figure 1: developing an appropriate framework. how to go about ethically acceptable research with minors before embarking on research with minors, researchers need to ensure they are familiar with the complexities of parental consent and how these are addressed in the nha, subsequent regulations and the ethical guidelines. these will provide guidance in addressing the issues that need to be considered (figure 2). firstly, is the inclusion of minors necessary and justifiable? and, if a waiver of parental consent is being applied for, is this necessary and justifiable? secondly, when designing the research study, the level of risk must be assessed, as the ethical guidelines stipulate that independent minor consent is only appropriate for minimal risk research.18 thirdly, how can both youths and adults be engaged to ensure their input and participation throughout the study process? trained community advisory boards (cabs) that involve youth/minors may achieve this, but in their absence, can community participation be ensured? fourthly, standard operating procedure documents for serious health issues need to be developed, detailing referral procedures to support structures, for instance, for minors diagnosed with sexually transmitted infections including hiv and those who become pregnant, together with mandatory reporting procedures for abuse and neglect of minors, and under-age sexual activity. fifthly, timely and continual dialogue with recs to protect adolescents whilst facilitating their participation in research. figure 2: steps to initiating ethically acceptable research with minors. the importance of community engagement in adolescent studies one of the requirements for independent consent by minors in the ethical guidelines is prior engagement with ‘participating community role players’ with tangible evidence of such engagement.18 based on the principle that individuals are interrelated and decisions are made within a social context, the purpose of community engagement is to assess whether parents and the wider community are supportive of minors’ involvement in the research without explicit individual-level parental consent. community engagement should never be tokenistic or seen as an ancillary component of the research process; it should be authentic, objective and effective. through the exchange of research ideas and community opinions throughout the research process, new and mutually beneficial connections will develop, benefitting the research agenda.31,32 community engagement is challenging, as even a definition of community is contentious. five defining characteristics of communities have been suggested: locus, sharing, joint action, social ties, and diversity; but as communities are increasingly heterogeneous and dispersed, community engagement should involve different strategies and be as inclusive as possible.33,34 for adolescent research, stakeholders could potentially include parents, foster parents, guardians, adolescents of the relevant age range including transgender people and sexual minorities, representatives of child-headed households, teachers, principals and social workers. in addition, key decision-makers (district level government and non-governmental stakeholders and community leaders) may need to be included to facilitate the eventual translation of research findings into policies and practices. researchers need to be aware of the socio-economic context and power relations which result in competing interests, priorities and structural coercion threatening the legitimacy and ethical conduct of the research.35,36 many documents describe how to ensure successful community engagement.27,31 most guidance is based on a cab model, where cabs create a forum through which questions, concerns, and community needs can be raised; the feasibility of protocols determined; bidirectional sharing of information to facilitate understanding of the research and the community channelled; culturally acceptable recruitment strategies identified; and, ultimately, research support generated among the broader community. the tygerberg research ubuntu-inspired community engagement (truce) model (box 1) details eight steps for successful community engagement.34 staff at research sites do well to pay attention to community engagement and establish representative cabs before any research protocols are embarked upon. ensuring cabs are well constituted and continue to function autonomously and effectively requires ongoing time, resources, and expertise. box 1: eight steps for successful community engagement. research protocols should include a description of community engagement activities, the roles, responsibilities and skills of various parties, training needs, how feedback will be given to the communities, together with innovative ways of involving the community during the dissemination of information, including publications and conference presentations. best practice examples of waivers of consent in adolescent research one of the first south african studies involving adolescents in hiv vaccine research highlighted requiring parental/guardian consent as a barrier to the enrolment of high-risk adolescents; careful consideration of the consent approach is advisable.37 the desmond tutu hiv centre has been conducting clinical research with adolescents since 2003 and has developed a nuanced approach to consent, depending on the nature of the study and age of the adolescents participating in the research. a ‘one-size-fits-all’ approach is not possible, and each study requires an individualised, context-specific exercise.38 the design of these approaches is developed in consultation with well-established adult and youth cabs including representative ages, populations and stakeholders’ input, guidance from ethical and legal experts to ensure protective ‘safety nets’ are in place, and open and ongoing communication with recs. depending on the study, adolescents are given the option to involve a trusted adult or parent/guardian, and a parental proxy consent form provided. some examples of these studies, together with the different reasons for waivers of parental consent, are described in table 1. table 1: examples of adolescent studies undertaken at the desmond tutu hiv centre, together with the rationale for a waiver of parental consent. conclusion in early november 2021, statistics south africa released a report on pregnancy in south africa. there were over 1 million babies born in 2020, of which 34 587 were born to girls ≤ 17 years old and 600 to girls aged 9 and 10. eighty per cent of hiv infections occurring in adolescents in sub-saharan africa occur in girls 15–19 years of age, where the prevalence of hiv in adolescent girls and young women is four times higher than in young men, with one-third screening positive for mental health and substance abuse problems.40,41,42,43 in addition, a quarter of sexually active adolescent girls contract a curable sexually transmitted infection annually.44 we as a country are failing to protect our girl children and adolescents and every possible measure must be taken to address this situation as a matter of urgency. our efforts are more likely to be effective if evidence-based interventions are employed. firstly, the nha should be amended to take into consideration the united nations convention of the rights of the child’s provisos on the rights of children and their evolving capacities to make informed decisions. secondly, the national heath research ethics council needs to work together with recs to standardise approaches to adolescent research to ensure adolescents are not excluded from research that will benefit them. thirdly, researchers and recs need to work together so that a more informed position based on the experiences of parental waivers of consent is developed. essentially, what is required is to balance child protection with the facilitation of ethical child and adolescent research. in the meantime, researchers, communities, and ethics committees must find ways to include adolescents safely and ethically in relevant and justifiable research. by investing in adolescent health, we are investing in the health and productivity of future generations. the inclusion of adolescents in research is critical in informing appropriate and effective health services for this vulnerable population whilst providing an opportunity to link them into care and services where relevant. while it is critically important to acknowledge adults in gatekeeping roles for protecting adolescents from potential harm, it is equally important to respect adolescents’ right to privacy and their evolving capacities to take autonomous responsibility for their health and health decisions. acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions m.l., a.g., e.s. and a.s. conceptualised and led the study. m.l., a.d., m.l., t.r., t.b., m.b., m.w., a.s., b.d., e.s. and l.g.b. collected data, analysed, and contributed different sections of the manuscript. m.l. and l.g.b. drafted the initial manuscript. all authors reviewed and contributed to the interpretation and approved the final manuscript. ethical considerations the manuscript we are submitting is a commentary on ethics in adolescent research practice. as the research process did not involve any human subjects, ethics approval and a waiver were not necessary. funding information the publication emanated from research funded by the bill & melinda gates foundation (grant number: inv-004597). the findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the foundation. data availability data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in the submitted article are the authors’ and not an official position of their affiliated institutions or funders. references world health organization. maternal, newborn, child and adolescent health and ageing [homepage on the internet]. geneva: world health organization; 2021 [cited 2021 july 29]. available from: https://www.who.int/data/maternal-newborn-child-adolescent-ageing/adolescent-data statistics south africa. demographic profile of adolescents in south africa [document on the internet]. pretoria: statistics south africa; 2018 [2021 july 29]. available from: www.statssa.gov.za salmela-aro k. stages of adolescence. in: brown bb, prinstein mj, editors. encyclopedia of adolescence. san diego, ca: academic press, 2011; p. 360–368. unicef. adolescent demographics [homepage on the internet]. 2019 [cited 2021 aug 2]. available from: https://data.unicef.org/topic/adolescents/demographics/ ahinkorah bo, 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an evidence-based definition for participatory public health. am j public health. 2001;91(12):1929–1938. https://doi.org/10.2105/ajph.91.12.1929 moodley k, beyer c. tygerberg research ubuntu-inspired community engagement model: integrating community engagement into genomic biobanking. biopreserv biobank. 2019;17(6):613–624. https://doi.org/10.1089/bio.2018.0136 nyirenda d, sariola s, kingori p, et al. structural coercion in the context of community engagement in global health research conducted in a low resource setting in africa. bmc med ethics. 2020;21(1):90. https://doi.org/10.1186/s12910-020-00530-1 fisher ja. expanding the frame of ‘voluntariness’ in informed consent: structural coercion and the power of social and economic context. kennedy inst ethics j. 2013;23(4):355–379. https://doi.org/10.1353/ken.2013.0018 wallace m, middelkoop k, smith p, et al. feasibility and acceptability of conducting hiv vaccine trials in adolescents in south africa: going beyond willingness to participate towards implementation. s afr med j. 2018;108(4):291–298. https://doi.org/10.7196/samj.2017.v108i4.12909 ganya w, kling s, moodley k. autonomy of the child in the south african context: is a 12 year old of sufficient maturity to consent to medical treatment? bmc med ethics. 2016;17(1):66. https://doi.org/10.1186/s12910-016-0150-0 gill k, johnson l, dietrich j, et al. acceptability, safety, and patterns of use of oral tenofovir disoproxil fumarate and emtricitabine for hiv pre-exposure prophylaxis in south african adolescents: an open-label single-arm phase 2 trial. lancet child adolesc health. 2020;4(12):875–883. https://doi.org/10.1016/s2352-4642(20)30248-0 news24. more than 600 girls aged 9 and 10 gave birth in 2020-stats sa [serial online]. 2020 [cited 2021 nov 23] nov 12. available from: https://www.news24.com/news24/southafrica/news/688-girls-as-young-as-9-and-10-gave-birth-in-2020-stats-sa-20211112 south african national aids council (sanac). national stratgeic plan on tb, hiv and stis 2017–2022; 2017 [cited 2021 nov 3]. available from: https://www.gov.za/sites/default/files/gcis_document/201705/nsp-hiv-tb-stia.pdf woollett n, cluver l, bandeira m, brahmbhatt h. identifying risks for mental health problems in hiv positive adolescents accessing hiv treatment in johannesburg. j child adolesc ment health. 2017;29(1):11–26. https://doi.org/10.2989/17280583.2017.1283320 unaids. unaids data 2020. country factsheets south africa 2020 [document on the internet]. [cited 2020 sep 9]. available from: https://www.unaids.org/sites/default/files/media_asset/2020_aids-data-book_en.pdf shannon cl, klausner jd. the growing epidemic of sexually transmitted infections in adolescents: a neglected population. curr opin pediatr. 2018;30(1):137–143. https://doi.org/10.1097/mop.0000000000000578 abstract introduction methods results discussion conclusion acknowledgements references appendix 1 about the author(s) anele dube-pule department of paediatrics and child health, faculty of medicine, university of kwazulu-natal, durban, south africa brian c. zanoni department of pediatrics, division of infectious diseases, emory university school of medicine, atlanta, united states of america cathy connolly school of public health, university of kwazulu-natal, durban, south africa majahonkhe shabangu sawubona health inc., malden, massachusetts, united states of america department of human biology, division of biomedical engineering, university of cape town, cape town, south africa moherndran archary department of paediatrics and child health, college of health sciences, university of kwazulu-natal, durban, south africa department of paediatrics, king edward viii hospital, durban, south africa citation dube-pule a, zanoni bc, connolly c, shabangu m, archary m. evaluation of an sms-based mhealth intervention to enhance early infant diagnosis follow-up testing and assessment of postnatal prophylaxis. s afr j hiv med. 2021;22(1), a1301. https://doi.org/10.4102/sajhivmed.v22i1.1301 original research evaluation of an sms-based mhealth intervention to enhance early infant diagnosis follow-up testing and assessment of postnatal prophylaxis anele dube-pule, brian c. zanoni, cathy connolly, majahonkhe shabangu, moherndran archary received: 18 aug. 2021; accepted: 03 oct. 2021; published: 24 nov. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: adherence to infant antiretroviral (arv) postnatal prophylaxis and early infant diagnosis (eid) uptake is low in africa. promoting eid and adherence are necessary for this age group. objectives: we evaluated an sms-based mobile health (mhealth) intervention to enhance adherence to arv prophylaxis and knowledge of eid and prevention of mother-to-child transmission (pmtct) among high-risk and low-risk mother–infant pairs. method: two hundred and fifty-one mothers were recruited from king edward viii hospital between december 2018 and october 2019. participant information was captured, and sms reminders were sent postnatally to promote immunisation attendance. follow-up hiv polymerase chain reaction (pcr) test results were reviewed, and telephonic interviews were utilised for qualitative data. results: in all, 73.3% of infants had hiv pcr tests performed at 10 weeks. this high rate could be attributed to the mhealth intervention as this is considerably higher than other national studies, though not statistically significant compared to rates reported in the district at the same time. factors that have impacted follow-up eid rates include poor maternal knowledge of eid time points and inadequate implementation of national pmtct protocols. high-risk mothers were younger, commenced antenatal clinic visit later, were less knowledgeable on prophylaxis and have lower-birthweight infants than lower-risk mothers. conclusion: mhealth can play an important role in improving eid by increasing maternal knowledge. further studies should focus on whether maternal education over an mhealth platform can increase knowledge on pmtct and subsequently increase eid. keywords: mhealth; early infant diagnosis; hiv dna pcr; infant prophylaxis; high-risk mothers; low-risk mothers; sms reminders; pmtct. introduction mother-to-child transmission (mtct) rates for hiv declined impressively by 84% between 2008 and 2015 in south africa (sa); however, since then, there has been a slower decline, jeopardising the world health organization (who) targets of preventing 6 million new infections among children by 2030.1 despite high antenatal hiv testing rates and universal maternal antiretroviral treatment (art), sa has yet to eliminate mtct, as the infant hiv transmission rate at 18 months in 2019 was still 3%.2 gaps in the prevention of mother-to-child transmission (pmtct) cascade after delivery contribute to these ongoing hiv transmissions. these include poor monitoring of hiv-negative mothers until the end of breastfeeding, poor viral load (vl) monitoring among hiv-positive mothers, poor adherence to both maternal art and infant antiretroviral (arv) prophylaxis and low rates of repeat testing for early infant diagnosis (eid) at the recommended 10-week, 6-month and 18-month visits.3,4,5 efforts to decrease postnatal mtct rates should be directed at maintaining a suppressed maternal vl through early art initiation and art adherence, together with adherence to infant arv postnatal prophylaxis (pnp). high rates of poor adherence to maternal art and pnp have been reported in africa: infant pnp adherence rates range between 72.0% and 85.0% during the 6 weeks of nevirapine prophylaxis,5,6,7 while in 2019 maternal art adherence was reported at only 63.4%.5 early infant diagnosis is vital in promoting early art initiation for infants diagnosed with hiv. the children with hiv early antiretroviral therapy (cher) trial demonstrated a 76% and 75% reduction in morbidity and mortality, respectively, for infants living with hiv who initiated art before three months of age, making early diagnosis and early art initiation critical.8 the sa eid guidelines changed in line with who recommendations in 2015 to include an hiv polymerase chain reaction (pcr) test at birth and 10 weeks for all hiv-exposed infants. in addition, high-risk infants were also required to have an 18-week hiv pcr. this has subsequently been changed to a 6-month hiv pcr for all exposed infants.9 in addition, all hiv-exposed infants are required to be tested at six weeks post-cessation of breastfeeding and, lastly, to have an hiv antibody test at the age of 18 months, which, if positive, should be followed with an hiv pcr.10 while eid coverage at birth is generally high, 89% in 2018,2 largely as a result of the high percentage of deliveries within healthcare facilities in sa,10 follow-up eid testing at other time points is low.3,11 causes of the low uptake of follow-up eid testing in sub-saharan africa (ssa) include low rates of retention in care in pmtct services,12,13 poor maternal knowledge about the vertical transmission of hiv,14 fear of maternal stigmatisation and lack of privacy at follow-up clinics.15 in addition, only 35% of mothers living with hiv reported intentions to self-request for infant testing at immunisation visits.15 several studies have reported the successful use of mobile devices such as phones to support healthcare practice (mhealth), mostly to improve appointment attendance and adherence to medication.16,17,18,19 following the who recommendation to use sms programmes to support art, several mhealth studies to improve adherence have included people living with hiv as well as eid.16,17,18,19 other positive benefits of mhealth include educating clients, encouraging behaviour change, enhancing decision-making and enabling communication between care providers. mhealth is inexpensive and easy to implement.20 the use of mhealth interventions has been understudied in sa despite a 150% saturation of mobile phones.21 momconnect, a gestation-specific interactive sms national programme for pregnant women, is one of the mhealth services that has been implemented successfully in sa. however, this national programme did not cater to the specific needs of women living with hiv; therefore, not much is known about the acceptability of mhealth among women living with hiv in sa.22 a randomised controlled trial conducted in uganda found that the text messaging of adolescents and young adults was ineffective in improving art adherence, despite a year of study.23 this study highlights the importance of studying new interventions in different communities. we evaluated an sms-based mhealth intervention’s acceptability and explored its impact on follow-up eid uptake in durban, sa. methods this study was a descriptive cohort study that also included telephonic interviews with some (n = 66, 26%) of the participants. two hundred fifty-one mothers living with hiv and their infants were enrolled from king edward viii hospital (keh), an 852-bed hospital serving an urban and peri-urban community in the ethekwini district of kwazulu-natal, sa. the hospital has approximately 7000 deliveries per year, with 40% of infants exposed to hiv. these mother–infant pairs (mips) were recruited from the postnatal and neonatal wards via consecutive sampling (monday through friday) between december 2018 and october 2019. recruitment was integrated with the routine postnatal well-baby examination conducted before discharge. for hiv-exposed infants, this included starting appropriate arv infant prophylaxis and doing a birth hiv pcr test, together with appropriate counselling. the hiv-exposed infants were defined as either low risk (lr) if the mother was on art with an hiv vl of < 1000 copies/ml in the last three months or high risk (hr) if the mother had no hiv vl available or an hiv vl of > 1000 copies/ml. the mother was approached by a research assistant, who provided information about the study and obtained informed consent. a rotation of allocated doctors conducted the postnatal examinations on the neonate. the enrolment form captured the mip’s demographic and maternal hiv information. the study participants were informed that they would receive sms text messages (see figure 1) that would remind them to attend the clinic for the well-baby and immunisation visits, where the hiv pcr on the infant would be performed as part of the national protocol. the mip was assigned a patient identity number, and all the details were entered weekly onto a local password-protected microsoft excel database accessible only to the study investigators. the cell phone numbers were stored on a secure server managed by sawubona health (malden, ma, united states [us]). personalised sms reminders were automatically sent to all recruited participants at weeks 1, 4, 10 and 14 post-delivery via bulksms (celerity systems ltd, sa). the wording of the text messages was piloted and developed by the study team using a focus group of postnatal mothers from keh prior to starting the study. the messages were sent in the participants’ home languages. participants could freely opt out of the sms programme at any point by sending a no-cost response to any one of the smss that they received. figure 1: sample sms message sent to mothers at 1, 4, 10 and 14 weeks post-delivery. a telephonic interview (see appendix 1) was conducted between 14 and 18 weeks of life to verify maternal and infant demographic details; capture information on clinic immunisation attendance, adherence to infant prophylaxis and hiv pcr uptake; and evaluate the intervention’s acceptability. adherence to infant prophylaxis was based on self-reporting by the mothers. all participants were called for a telephonic interview; however, not all were reached, as some numbers were no longer in use, and some participants did not take the calls. the telephonic interviews, conducted in the patients’ preferred language, were recorded and later translated and transcribed into english. for thematic analysis, interview transcripts were uploaded onto dedoose software version 8.0.42, 2018 (sociocultural research consultants, llc, los angeles, california, us; www.dedoose.com). we used an inductive content analysis approach that was derived from reviewing, coding and interpreting the data. a codebook was developed using operational definitions and selected illustrative quotes. the codebook was then refined using an iterative process. following the completion of the codebook, the remainder of the transcripts were coded using dedoose software. categories were developed using coded data to assess the intervention and facilitators’ acceptability, feasibility and barriers to successful preparation and medication administration. the categories were further organised, final definitions created and evidence provided using illustrative quotes from the research participants. all hiv dna pcrs performed at birth (within the first three days of delivery) and follow-up eid (done between 10 and 14 weeks of life) were actively checked through the national health laboratory services online portal, and positive results were communicated to the clinical team at keh for immediate action as per the local protocol. the follow-up eid rates obtained from this study were compared to the follow-up eid rate of 69.3% obtained in 2019 from 53 863 hiv pcr tests that were performed among hiv-exposed infants in the ethekwini district at approximately 10 weeks of life.24 categorical variables were described and summarised by percentages and continuous variables by medians and interquartile ranges (iqr). univariate analyses comparing the uptake of follow-up eid testing and the characteristics associated with hr and lr mothers and their infants were performed using student’s t-test or the mantel–haenszel χ2 test for categorical variables. for each univariate analysis, all available case information was used. p-values of less than 0.05 were considered significant. all two-way interactions were evaluated using stata/ic version 15 (college station, texas, us). ethical considerations the research was approved by the biomedical research ethics committee (brec) of the university of kwazulu-natal (be4/18), king edward viii hospital (ke 2/7/1/[63/2018]) and the kwazulu-natal department of health (kz 201810_013). results two hundred and fifty-one mips were recruited between december 2018 and october 2019. the median age of the mothers was 30 years (iqr: 9), with predominantly black africans (98.8%) and multiparous women (73%). the average age for hr mothers was 28 years (iqr: 23–33) and for lr mothers, 31 years (iqr: 27–35). out of the 251 mips, 178 (70.8%) infants were classified as lr and 73 (29.2%) as hr. among the hr mips, 53 (72.6%) had an undocumented hiv vl and 20 (27.4%) had an hiv vl of > 1000 copies/ml at delivery. mothers of hr infants were significantly younger than those of lr infants (p = 0.003). late booking (first prenatal care visit later than 20 weeks) was more common in mothers of hr infants than in the lr group, although not statistically significant (p = 0.06). the cd4 counts were available for 178 (70.9%) of the mothers. the percentages of those with cd4 counts of < 500 (36.2%) and > 500 (34.6%) were similar among hr and lr mothers. the infant cohort (table 1) comprised mostly term infants (70.1%) that weighed between 2500 g and 3999 g (73%). the infants of hr mothers were significantly more likely to have low birthweight (lbw) (< 2500 g) than those of lr mothers (9.59% vs 7.87%, p = 0.029). the mean birthweight of infants of hr mothers was 3050 g and of lr mothers was 3146 g. infants in this cohort were more likely to be delivered by caesarean section (59.7%) than normal vertex delivery (40.2%), as this is a referral unit that accepts complicated deliveries, although the lr infants were more likely to be born via caesarean section than the hr infants (p = 0.04). table 1: description of maternal and infant characteristics. birth hiv pcrs (table 2) were performed for most of the infants, 238 (94.8%), with only 1 (0.4%) positive and 1 (0.4%) indeterminate. infant prophylaxis was correctly prescribed to most infants (247 of 251, 98.4%). however, 3 (1.1%) hr infants were incorrectly prescribed lr-pnp, and 1 (1.1%) lr infant was incorrectly prescribed hr-pnp. the birth hiv pcrs of 11 infants (7 hr and 4 lr) were not found on the online system and were likely not done. table 2: birth and 10-week polymerase chain reaction. the infant with a positive birth hiv pcr test result was traced as per the hospital tracing protocol and returned to the local clinic on day nine when a confirmatory hiv pcr test was performed. unfortunately, art was not started as per current guidelines. the confirmatory hiv pcr test was positive, but the patient was lost to follow-up and was admitted two months later with severe pneumonia and subsequently died. the delay in art initiation was possibly the result of maternal refusal or of health system failure. linking these patients with local community caregivers, a system already in place in kwazulu-natal, could have been useful to trace this mip. perhaps a two-way sms system could also be useful to trace such patients lost to follow-up, where they could respond with reasons for not coming in for hiv pcr results. the hiv pcr test rate at 10 weeks after the mhealth intervention was found to be 73.3%, 48 (62.7%) hr and 136 (73.9%) lr infants (table 3). this rate is higher than the standard of care of 69.3% in the ethekwini district in 2019; however, we cannot conclude from this data set that the higher rate in this cohort was the result of the mhealth intervention, as there was no comparison group. in addition, the increase in the hiv pcr test rate was not statistically significant, 73.3% versus 69.3% (p = 0.08). table 3: maternal and infant risk factors for not obtaining a 10-week polymerase chain reaction. the maternal and infant risk factors that influence a mother’s likelihood to return for a 10-week hiv dna pcr test are detailed in table 3. low-risk mothers were more likely to return than hr mothers (p = 0.08). maternal age, parity, prenatal care, cd4+ t-cell count and infant birthweight were found not to influence the return for 10-week hiv dna pcr test. mothers of preterm infants were more than twice as likely to return compared to those of term infants. telephonic interviews were conducted in a subset of 66 (26%) participants with no significant differences in age and parity (table 4) compared to the overall cohort. unfortunately, the subset is a small percentage of the study participants because of the difficulty reaching many participants telephonically. table 4: interviewed versus non-interviewed women. out of the 66 interviews, 53 (80%) considered their clinic to be ‘close by’ (took one local taxi or walking distance), and 59 (90%) reported having attended all the clinic dates. only 42 provided complete answers to questions about infant prophylaxis. despite routine postnatal counselling of the mothers regarding infant prophylaxis, only 14 of 42 (33.3%) of the participants knew the infant prophylaxis medication by name, the total duration of administration and when to administer it. the remainder of the participants, 28 of 42 (66.6%), had incomplete knowledge about the infant prophylaxis medication names, duration and administration. of note, the majority (78%) of the lr participants had complete knowledge of infant prophylaxis (i.e. dose, name of the treatment used and duration) compared to 22% of hr participants. this poor maternal knowledge of art translated to poor adherence to infant prophylaxis. adherence was overall poor among all the mothers interviewed. however, it was even worse among the hr versus lr mothers, but the statistical significance was not calculated, as the numbers were too small and the aim of the telephonic interviews was to collect qualitative data. out of 42 mothers (5 hr and 37 lr) who answered questions on adherence, none of the five hr mothers gave art correctly, while 12 of lr mothers gave it correctly. high dependence on clinic staff on when to stop infant prophylaxis we found that the mothers depended heavily on the nursing staff at the busy local clinics to tell them when to stop using infant prophylaxis, and they were mostly unaware of the expected duration for themselves. when asked about the duration of prophylaxis, this is what some moms had to say: ‘they just said i must give him until it is finished.’ (mother 12, kh00419, 29-year-old female) ‘she drank it and got immunised at 6 weeks and carried on with it, and we took the other bloods, and they said she must stop taking it.’ (mother 18, kh01619, 34-year-old female) poor knowledge of antiretroviral treatment names the mothers generally did not know the names of the arv drugs that their infants were using. when asked the names, most mothers would describe the colour of the medication only. when given the names of the commonly used medication for infant prophylaxis, most could still not identify which the child was taking. some of them also confused the hiv prophylaxis with the prophylaxis used for opportunistic infections. this is what some of the moms said when asked about the infant prophylaxis names: ‘she used to take the one in a white bottle, clear in colour, i don’t remember the name.’ (mother 69, kh01519, 23-year-old female) ‘she was taking the white one.’ (mother 34, kl02419, 30-year-old female) ‘she is taking the medication for prevention, the white one.’ (mother 56, kl09419, 34-year-old female) importance of sms reminders the majority, 98% (49/50), of the mothers who responded to mhealth questions found the mhealth intervention helpful as appointment reminders, and 73.9% (34/46) were comfortable receiving the sms messages, as indicated by the following quotes: ‘it’s very important, for instance, if i am on night shift and sleeping during the day when i wake up, i see the sms and remember.’ (mother 2, kl02019, 25-year-old female) ‘they are important because i sometimes wouldn’t check the baby’s card, and the sms will remind me, and then i would quickly check the card.’ (mother 18, kh01619, 34-year-old female) sharing mobile devices and confidentiality sharing of mobile devices was common (30/37); however, most participants expressed that they did not have a problem with a family member reading the sms sent, as expressed in the following quotes: ‘they use it here at home, but they know my status.’ (mother 15, kh01119, 35-year-old female) ‘the only person who can see them is my baby’s dad because he knows our situation.’ (mother 24, kl00519, 29-year-old female) accidental hiv disclosure was a concern to three out of 30 of the participants, even though the sms sent was non-disclosing, and some of the participants emphasised the need to keep the wording of the messages discrete. one of the moms said: ‘it is important, but it must not include full details and what it’s about but just generally remind a person to go to the clinic.’ (mother 22, kl00219, 34-year-old female) discussion in this study evaluating an sms-based mhealth intervention to enhance eid uptake and assess maternal knowledge and adherence to infant arv prophylaxis among the hr and lr mips, the intervention was found to be useful by the interviewed participants, although we could not prove that it promotes adherence. this finding adds to the literature confirming the acceptability of mhealth interventions in various populations.16,25,26 increased uptake in follow-up eid testing was noted compared to the testing rate reported by the department of health in the district during the same period; however, the increase was not statistically significant. the follow-up eid testing rates in the district in 2019 were higher than those reported previously in sa. in a study looking at the impact of national guidelines shifting from 6-week hiv pcr to birth hiv pcr in the whole province of kwazulu-natal in 2015, smith et al.3 reported that only 14.7% of children with an initial negative birth pcr had a follow-up pcr. while the percentage of hiv pcr follow-up testing was estimated to be only 49% in a study done in cape town in 2016, we believe that the sms reminders can play a role in improving adherence to follow-up eid testing of the pmtct cascade.11 the district’s quality improvement initiatives, duplicate testing and testing of infants coming into the district may account for the higher testing rates. the addition of the mhealth intervention and improved service delivery likely had a smaller than expected benefit that this study was not powered to detect. clinic attendance for routine immunisation, which was high among the interviewed participants in this study, does not translate to high follow-up eid uptake. this emphasises the need to integrate pmtct services into routine immunisation services instead of it being run separately. other studies in ssa have identified that poor maternal knowledge about vertical transmission of hiv, fear of stigmatisation and lack of privacy at follow-up clinics contribute to poor eid uptake.12,13 the findings of poor maternal knowledge on pmtct may have contributed to poor adherence, and causality could not be proven. the addition of maternal education on pmtct and eid to mhealth interventions should be further evaluated. several studies have shown that high knowledge levels among women living with hiv on art are associated with higher art adherence.27,28 the participants in this study were not interviewed about their ideas of stigmatisation and lack of privacy, which would be an important area to explore in future studies. although the health professionals followed the pmtct guidelines well, for the most part, we found that there is still room for improvement, such as in prescribing the correct pmtct and in the case of the infant who tested positive but was not initiated onto art on the day the mother and infant reported to the clinic to obtain the results. a strong link with the community caregiver and social workers to trace mips lost to follow-up would also be beneficial. continued quality improvement programmes and support for overwhelmed clinic health workers in national pmtct protocols is still needed. a study by doherty et al. found a lack of ownership of the pmtct programme among nurses, unclear roles and responsibilities, lack of knowledge of the protocol, poor recording systems and poor continuity of care as factors hindering pmtct in a study done at a district in kwazulu-natal. in addition, the study found that after implementing a participatory approach, the staff and managers identified the delivery of effective pmtct programmes in their districts and found solutions, together with regular, data-driven, facility-level support.29 when comparing hr and lr mips, we found younger maternal age, late antenatal booking, poor maternal knowledge of infant prophylaxis and an increased frequency of lbw babies. in the national pmtct protocol, the hr mothers have been described as at hr of transmitting hiv solely based on their vl or absence thereof within 3 months of giving birth. these findings indicate that these mothers are not only at hr of transmitting hiv, but they and their infants are also at increased risk of several other problems. late booking alone is associated with poor maternal health, increased child mortality rates and increased risk of transmitting certain infections such as syphilis and malaria, all factors that the millennium developmental goals aimed to combat.30 literature has also shown that small-for-gestational-age and lbw infants are at significantly increased risk of mortality and morbidity compared with appropriate-for-gestational-age infants.31 these findings mean that our health system should have more stringent criteria for following these high-risk mips to ensure a holistic care approach. strength and limitations limitations noted in this study include self-reporting by the mother to assess adherence to infant prophylaxis. although this often introduces recall bias, several studies have promoted self-reporting to estimate art adherence in developing settings where objective measures are often expensive or impractical.32,33 adherence to maternal art was not assessed. conclusion mhealth via sms reminders is a helpful tool in promoting immunisation clinic visits; however, we could not prove that it is associated with increased eid uptake. maternal knowledge of pmtct and eid is still key, and future mhealth studies should explore the use of these interventions to increase knowledge and empower women living with hiv. a holistic approach to the care of hr mothers should address the factors that may impact maternal and infant health. acknowledgements the authors thank leora sewnarain for assistance with formatting and language review. competing interests m.s. is the volunteer president and co-founder of sawubona health, the non-profit that provided and supported the sms programme. authors’ contributions a.d.-p. contributed to the study design and conducted the data collection, data analysis and drafting of the manuscript. b.c.z. contributed to the study design, data analysis and drafting of the manuscript. c.c. conducted the statistical analysis, interpretation of results and manuscript review. m.s. contributed to the study design and manuscript review, implemented the data collection tools and completed the ethics application documents. m.a. supervised the entire work, study design and manuscript review. funding information the authors received no financial support for the research, authorship or publication of this article. data availability the data sets used and analysed during the current study are available from the corresponding author, m.a., upon reasonable request. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references unaids joint united nations programme on hiv/aids. fast track ending the aids epidemic by 2030 [homepage on the internet]. 2014 [cited 22 june 2021]. available 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biophysical aspects of hiv infection, ottawa, canada. poster, 1999; vol. 18. doherty t, chopra m, nsibande d, mngoma d. improving the coverage of the pmtct programme through a participatory quality improvement intervention in south africa. bmc public health. 2009;9(1):1–9. https://doi.org/10.1186/1471-2458-9-406 sachs jd, mcarthur jw. the millennium project: a plan for meeting the millennium development goals. lancet. 2005;365(9456):347–353. https://doi.org/10.1016/s0140-6736(05)70201-4 madden jv, flatley cj, kumar s. term small-for-gestational-age infants from low-risk women are at significantly greater risk of adverse neonatal outcomes. am j obstet gynecol. 2018;218(5):525.e1–525.e9. https://doi.org/10.1016/j.ajog.2018.02.008 simoni jm, kurth ae, pearson cr, merrill jo, pamela af. self-report measures of antiretroviral therapy adherence: a review with recommendations for hiv research and clinical management. aids behav. 2014;10:227–245. https://doi.org/10.1007/s10461-006-9078-6 nieuwkerk pt, oort fj. self-reported adherence to antiretroviral therapy for hiv-1 infection and virologic treatment response. j acquir immune defic syndr. 2005;38(4):445–448. https://doi.org/10.1097/01.qai.0000147522.34369.12 appendix 1 telephone survey script hello, my name is______________________i am with the sms/prophylaxis research team here at king edward hospital. i am calling because you signed up for our sms reminder programme. does this sound familiar to you? (if no: apologise for having the wrong number and kindly end the call.) (if yes … continue) we are calling up participants of the programme to find out about their attitudes and experiences using the sawubona sms reminder programme and also to find out about the medication you gave to your baby. if you have a few minutes, i’d like to ask you a few questions that will take about 10 min. it is important that you tell me exactly what is in your mind rather than something you think i want to hear. this phone call is not being recorded and what you say here will not be shared with anyone at the hospital or the clinics you attend. the information you provide will be kept confidential. do you have a few minutes to chat? (if no … try to reschedule the call for a later time) (if yes … continue) 1. recruitment/enrolment during the enrolment phase, when you signed up for the programme, did you experience any of the following? reaction response comments yes (1) no (2) 1. trouble understanding purpose of research project and your role in it 2. discomfort giving name to research staff member 3. discomfort giving personal phone number to research staff member 4. unease with phone number confirmation procedure (i.e. replying with ‘yes’ or ‘ yebo’ to initial sms) 5. worry that collected personal information could be lost 6. worry that collected personal information could be shared with third parties, for example telemarketers 7. other concerns 2. acceptability in the course of the study, when you were receiving sms reminders for your appointments, did you experience any of the following? reaction response comments yes (1) no (2) 1. problems (not) receiving sms reminders at the right (wrong) time 2. problems with inaccurate/inappropriate sms content (e.g. names mix up) 3. problems understanding the sms content 4. fear/worry that others might see the sms reminder on your phone 5. feel bothered by the sms (e.g. felt like it was spam) 6. other people asking you about the sms 7. trouble opting out of the programme (for those who have opted out) 8. any other adverse experiences 3. perceived usefulness what effect did the reminders have on your remembering of your appointments? how? effect comment positive neutral/no effect negative what effect did the reminders have on your attendance of your appointments? how? effect comment positive neutral/no effect negative would you recommend that other mothers enrol for the programme? why? response comment yes no overall how much did you like using/being a part of the sawubona sms reminder programme? effect comment liked it neutral did not like it using a 10-point scale, how important was this programme to your health and that of your baby in the time that you were enrolled? (1 = least important; 10 = very important) next, i would like to ask a few questions about the health of your baby and attendance at your local health clinic. please confirm your baby’s sex male female please confirm your baby’s name, surname and date of birth which of the following medications was baby given at the hospital? nvp azt both other how many doses of those medications (azt, nvp, other) did your child receive on most days? select from the following: none once a day other at how many weeks of life did you last attend the clinic? did your baby receive immunisations at six weeks? did your baby receive immunisations at 10 weeks? for how many weeks have you given your baby the medicine? select from following: less than 5 weeks 6 weeks 6–10 weeks 10 weeks conclusion what are your thoughts on this survey? are there ways you think we can use to improve it? do you have any questions for me about the programme or anything we’ve talked about today? thank you very much for your time. your responses have been very helpful. have a nice day. [end] successful treatment.html case report successful treatment of bilateral visual loss caused by idiopathic optic neuritis in an hiv-infected patient claire cullen¹, mb bch, fcophth (sa), mmed (ophth) baile matlala¹, mb chb, fcophth (sa), mmed (ophth) fatima laher² ³, mb bch, dip hiv man (sa) ané pienaar¹, mb chb, mmed (ophth) ¹department of ophthalmology, dr george mukhari hospital, university of limpopo, ga-rankuwa, gauteng ²perinatal hiv research unit, university of the witwatersrand, johannesburg ³wits donald gordon medical centre, johannesburg optic neuritis is not an uncommon diagnosis in hiv-infected patients, but it is rarely idiopathic. we report a case of a young hiv-infected woman who developed optic neuritis as her presenting manifestation of hiv infection. she had initially experienced sudden-onset right-sided painful visual loss; the left eye had become involved within days. bilateral swollen discs were apparent on fundoscopy. investigations were performed for meningitis (including bacterial, cryptococcal, tuberculous and syphilitic types), auto-immune diseases, toxoplasma, rubella, cytomegalovirus, viral hepatitis, htlv-1/2, hiv-1/2 and syphilis. the only positive result was a reactive hiv enzyme-linked immunosorbent assay. the cd4 count was 85 cells/µl. a post-contrast magnetic resonance imaging scan of the brain illustrated enhancement of the optic nerves. treatment was 3 days of intravenous methylprednisolone 1 g daily, followed by 11 days of oral prednisone 60 mg daily. highly active antiretroviral therapy was initiated after 2 weeks. vision improved from day 6 after commencement of steroid therapy, with ongoing recovery at 5 months. the human immunodeficiency virus (hiv) manifests in various ways in the eye. several optic nerve disorders have been described, most commonly resulting from opportunistic infections, neoplasms and inflammatory causes.1 hiv infection as a direct cause of optic neuropathy has been postulated. it is an uncommon presentation and a diagnosis of exclusion, with only a few case reports and case series in the literature. mwanza et al. describe a sub-group of neurologically symptomatic hiv-infected patients from the democratic republic of congo: optic neuropathies occurred in 31%, although only 7% of cases were ascribed solely to hiv.1 we present a case of idiopathic optic neuritis in an hiv-infected person. case presentation a 26-year-old south african woman presented to the ophthalmology clinic of dr george mukhari hospital in ga-rankuwa, gauteng, on 6 january 2009. her main complaint was a 1-week history of sudden-onset, painful visual loss that had originated in the right eye and had progressed over a few days to include the left eye. she described the pain as being ‘deep within the eye’ but unrelated to eye movements. on the second day she had attended her local community clinic, where she had been dispensed chloramphenicol eye ointment, which did not improve the condition. there was no history of trauma. her medical, surgical, ophthalmological and family histories were otherwise unremarkable, and she was not receiving any other medications. general examination revealed a well-looking young woman. her vital signs, including blood pressure, were within normal limits. visual acuity of the right eye was recorded as counting fingers at 1 metre (<6/60), and testing with a snellen visual acuity chart showed that of the left eye to be 6/60. a relative afferent pupil defect was present in the right eye. extra-ocular movements were full and painless. on fundus examination, bilateral swollen optic discs with flame-shaped haemorrhages were apparent (fig. 1). there were no cotton wool spots and no macular star in either eye. the cornea, anterior chamber, vitreous and retina were normal, as were intra-ocular pressure readings. optical coherence tomography objectively documented bilateral swollen optic discs (fig. 2). fluorescein angiography showed hyperfluorescence of the optic discs (fig. 3). the chest radiograph was normal. although there were no unusual findings on computed tomography scanning of the brain, a magnetic resonance imaging scan of the brain illustrated enhancement of the optic nerves post-contrast. there were no periventricular plaques and no other abnormalities were noted. lumbar puncture was performed and the opening pressure was noted as being within normal range. cerebrospinal fluid chemistry and cytology were normal. gram stain and bacterial culture, india ink and latex antigen tests for cryptococcus neoformans, csf adenosine deaminase (ada) for tuberculosis and tpha (treponema pallidum haemagglutinin assay) syphilis tests were all negative. the full blood count showed slight leukocytosis (white cell count 12×109 /1) and neutrocytosis (83%). the erythrocyte sedimentation rate was slightly increased at 33 mm/h, but the c-reactive protein level was normal at 5.8 mg/l. auto-immune studies (antinuclear antibodies, antimitochondrial antibodies, antiparietal cell antibodies and anti-smooth muscle antibodies) were negative. serum angiotensin-converting enzyme for sarcoid was also negative. vitamin b12 levels were normal. tests for mitochondrial mutations associated with leber’s hereditary optic neuropathy were judged unnecessary. infectious studies were all negative, including blood tests for toxoplasma, rubella, cytomegalovirus (cmv) pp65 antigen, viral hepatitis screen, htlv-1 and 2, rpr and tpha for syphilis. the hiv enzyme-linked immunosorbent assay was reactive and the absolute cd4 count was 85 cells/µl. the patient was admitted on the day of her presentation to our clinic. after 3 days she was treated with intravenous methylprednisolone 1 g daily for 3 days, followed by 11 days of oral prednisone 60 mg daily with subsequent gradual tapering to prevent possible steroid withdrawal symptoms. a diagnosis of idiopathic optic neuritis was subsequently made by exclusion of other causes. on the 6th day of treatment, the patient reported improvements in her vision. visual acuity of the right eye was unchanged, but in the left eye it improved to 6/24. two and a half weeks after her initial presentation to us, she started highly active antiretroviral therapy (haart). at a follow-up visit 2 months after presentation, and 5 weeks after haart commencement, vision had improved bilaterally to 6/18 on the right and 6/12 on the left. there was complete resolution of disc swelling bilaterally, but some residual optic nerve pallor (figs 4 and 5). by the 5th month after presentation, the hiv-1 viral load was suppressed at <25 copies/µl and visual acuity remained 6/18 in the right eye but had improved to 6/6 in the left. the cd4 count improved to 265 cells/µl. discussion optic neuritis is an inflammation of the optic nerve and a cause of acute visual loss. it may be categorised as typical or atypical. typical optic neuritis, the most common type, occurs in demyelinating conditions such as multiple sclerosis (ms). the international headache society (ihs) outlines five diagnostic criteria describing dull retrobulbar pain in one or both eyes of maximum 4 weeks’ duration accompanied by impaired central or paracentral vision in the absence of a compressive lesion.4 it has been proposed that the diagnostic criteria be used in conjunction with biomarkers and radiological evidence of multiple sclerosis.4 atypical optic neuritis occurs in non-demyelinating conditions such as viral infections, toxin exposure, meningitis, tumour metastases, syphilis and neuromyelitis optica (devic’s disease), and in some cases it is idiopathic.3 features suggesting atypical optic neuritis include age (<12 years or >50 years), african or asian race, bilateral disease, severe (no light perception) or progressive (>2 weeks) visual loss, unusual description of pain (painless visual loss or severe pain that restricts eye movements or wakes patient from sleep), unusual ocular findings (marked anterior and/or posterior segment inflammation), lack of any visual recovery within 5 weeks or continued deterioration in visual function, symptoms or signs of a systemic disorder other than ms, and corticosteroid-dependent optic neuropathy (deterioration in vision when corticosteroids are withdrawn).5 this patient had features suggesting an atypical optic neuritis, particularly haemorrhages that accompanied optic disc swelling. in addition to tests for auto-immune diseases, sarcoidosis, rubella, viral hepatitis and htlv-1 and 2, investigations for opportunistic infections should also be done in the setting of hiv, and the possibility of false-negative results should be borne in mind. more sensitive tests include serum or csf cryptococcal antigen for the fungus c. neoformans, serology for the protozoan toxoplasma gondii, and pp65 antigen for cmv. tests which should be interpreted with more caution include syphilis serology, which may revert to negative in hiv infection,10 and tuberculosis tests because – despite the availability of multiple methods of investigation including microscopy, culture, csf ada and imaging – tuberculosis is noted to be cryptic in hiv infection. neuro-ophthalmic manifestations of hiv tend to present at an advanced stage of the disease when cd4 cell counts are depleted below 200 cells/µl.6 indeed, in patients with aids there is a 3 8% prevalence of neuro-ophthalmic diseases including eye movement disorders, cranial nerve palsies, neuroretinitis, retrobulbar optic neuropathy, anterior optic neuropathy, papilloedema, visual field defects, cortical blindness, optic atrophy and optic neuritis.1 the latter manifestation was the presenting illness of hiv in our patient, who reported no prior hiv-related diseases even though her cd4 count at presentation was 85 cells/µl. in hiv-infected patients, opportunistic infections such as syphilis, toxoplasmosis, tuberculosis and cytomegalovirus are by far the most common cause of optic nerve disorders.7 , 8 in rare cases, mostly affecting males, mitochondrial toxicity caused by nucleoside reverse transcriptase inhibitor antiretroviral drugs such as stavudine and didanosine may trigger acute painless central visual loss if the 14484 mitochondrial dna mutation of leber’s hereditary optic neuropathy is present.9 we did not test for this mutation because the patient had not been on antiretroviral drugs, was not male, and had no family history of sudden visual loss. to our knowledge at least 10 cases of idiopathic hiv-associated optic neuritis have been reported in the english literature.8 , 10 in the 6 instances where cd4 counts were documented, they were well below 350 cells/µl in all cases except one of acute hiv syndrome. nine of these 10 patients presented with decreased visual acuity in one or both eyes. of the 9 cases where visual outcomes were reported, there was improvement in 16 eyes and 2 eyes remained unchanged. a direct causal link between hiv and optic neuritis has been suggested previously.10 the mechanism by which hiv could cause primary optic neuritis remains unclear despite much research devoted to neurodegeneration in hiv infection.1 , 10 , 11 , 15 , 16 the current widely accepted theory suggests that the pro-inflammatory cytokine tumour necrosis alpha (tnfα) plays a key role.1 , 8 , 11 other proposed mechanisms include damage secondary to activated microglia and macrophages releasing neurotoxic agents.1 consistent with this proposed inflammatory pathogenesis, steroid responsiveness is thought to be a feature of idiopathic optic neuritis in hiv-infected persons.7 , 10 the use of steroids in typical optic neuritis is well established. the prospective randomised and controlled optic neuritis treatment trial reported that oral prednisone alone had no benefit over placebo and may increase the future risk of repeat episodes of optic neuritis, while intravenous methylprednisolone 1 g daily for 3 days followed by 11 days of oral prednisone 1mg/kg/day was associated with slightly faster visual recovery compared with placebo.17 nevertheless, visual recovery within 2 weeks was marked for most participants, regardless of treatment arm.17 treatment for atypical optic neuritis includes treating the underlying cause. the optimal treatment for optic neuritis in hivinfected patients is controversial. on the one hand, spontaneous resolution of optic neuritis in hiv-infected patients after 2 weeks has been reported12 and some (but not all) studies have demonstrated accelerated disease progression with the use of even short courses of immunosuppressive doses of steroids in patients with advanced hiv.18 on the other hand, there are reported cases – ours being one of them – of visual recovery soon after the introduction of systemic steroid therapy.7 , 10 it is also possible that antiretroviral therapy contributed to visual recovery in the medium term.7 , 8 , 11 some authorities advocate the inclusion of penicillin at neurosyphilis treatment doses as part of empiric management for optic neuropathies of cryptic origin in hiv-infected individuals,7 , 10 but we did not employ this strategy. the rationale underlying this approach reflects the attenuating sensitivity of laboratory tests for treponemal infection, which are antibody tests and may be non-reactive in advanced hiv illness.7 conclusions underlying hiv should be considered in cases of atypical optic neuritis in patients at risk. although uncommon, idiopathic optic neuritis in hiv-infected persons is a diagnosis of exclusion when there is a presentation of sudden visual loss and optic disc swelling. management must include assessment for haart, as the condition is linked with advanced disease. it may be reasonable to inform hiv-infected patients with optic neuritis about the possible risks versus benefits of steroid therapy and invite them to consent to the treatment of their choice. competing interests. the authors declare that they have no competing interests. author contributions. cc acquired and interpreted the data and drafted the manuscript. bm and fl critically revised ophthalmological and hiv-related sections of the manuscript, respectively. ap provided final review and approval of the manuscript. ethical considerations. the patient provided voluntary written informed consent to have her anonymous case details published. references 1. mwanza j-c, nyamabo lk, tylleskär t, plant gt. neuro-ophthalmological disorders in hiv infected subjects with neurological manifestations. br j ophthalmol 2004;88:1455-1459. 1. mwanza j-c, nyamabo lk, tylleskär t, plant gt. neuro-ophthalmological disorders in hiv infected subjects with neurological manifestations. br j ophthalmol 2004;88:1455-1459. 2. whiting as, johnson ln. papilledema: clinical clues and differential diagnosis. am fam physician 1992;45:1125-1134. 2. whiting as, johnson ln. papilledema: clinical clues and differential diagnosis. am fam physician 1992;45:1125-1134. 3. hickman sj, dalton cm, miller dh, plant gt. management of acute optic neuritis. lancet 2002;360:1953-1962. 3. hickman sj, dalton cm, miller dh, plant gt. management of acute optic neuritis. lancet 2002;360:1953-1962. 4. ahmed m, gittinger jw jr. optic neuritis. contemporary ophthalmology 2009;17:1-8. 4. ahmed m, gittinger jw jr. optic neuritis. contemporary ophthalmology 2009;17:1-8. 5. shams pn, plant gt. optic neuritis: a review. international ms journal 2009;16:82-89. 5. shams pn, plant gt. optic neuritis: a review. international ms journal 2009;16:82-89. 6. pathai s, deshpande a, gilbert c, lawn s. prevalence of hiv-associated ophthalmic disease among patients enrolling for antiretroviral treatment in india: a cross-sectional study. bmc infect dis 2009;9:158. 6. pathai s, deshpande a, gilbert c, lawn s. prevalence of hiv-associated ophthalmic disease among patients enrolling for antiretroviral treatment in india: a cross-sectional study. bmc infect dis 2009;9:158. 7. newman nj, lessell s. bilateral optic neuropathies with remission in 2 hiv positive men. j clin neuroophthalmol 1992;12:1-5. 7. newman nj, lessell s. bilateral optic neuropathies with remission in 2 hiv positive men. j clin neuroophthalmol 1992;12:1-5. 8. goldsmith p, jones re, ozuzu ge, richardson j, ong el. optic neuropathy as the presenting feature of hiv infection: recovery of vision with highly active antiretroviral therapy. br j ophthalmol 2000;84:551-553. 8. goldsmith p, jones re, ozuzu ge, richardson j, ong el. optic neuropathy as the presenting feature of hiv infection: recovery of vision with highly active antiretroviral therapy. br j ophthalmol 2000;84:551-553. 9. warner j, ries k. optic neuropathy in a patient with aids. j neuroophthalmol 2001;21:92-94. 9. warner j, ries k. optic neuropathy in a patient with aids. j neuroophthalmol 2001;21:92-94. 10. burton bjl, leff ap, plant gt. steroid-responsive hiv optic neuropathy. j neuroophthalmol 1998;18:25-29. 10. burton bjl, leff ap, plant gt. steroid-responsive hiv optic neuropathy. j neuroophthalmol 1998;18:25-29. 11. babu k, murthy k, rajagopalan n, satish b. vision recovery in human immunodeficiency virus-infected patients with optic neuropathy treated with highly active antiretroviral therapy: a case series. indian j ophthalmol 2009;57:515-318. 11. babu k, murthy k, rajagopalan n, satish b. vision recovery in human immunodeficiency virus-infected patients with optic neuropathy treated with highly active antiretroviral therapy: a case series. indian j ophthalmol 2009;57:515-318. 12. sweeney bj, manji h, gilson rjc, harrison mjg. optic neuritis and hiv-1 infection. j neurol neurosurg psychiatry 1993;56:705-707. 12. sweeney bj, manji h, gilson rjc, harrison mjg. optic neuritis and hiv-1 infection. j neurol neurosurg psychiatry 1993;56:705-707. 13. larsen m, toft pb, bernhard p, henning m. bilateral optic neuritis in acute immunodeficiency infection. acta ophthalmol scand 1998;76:737-738. 13. larsen m, toft pb, bernhard p, henning m. bilateral optic neuritis in acute immunodeficiency infection. acta ophthalmol scand 1998;76:737-738. 14. brack mj, cleland pg, owen ri, et al. anterior ischaemic optic neuropathy in acquired immune deficiency syndrome. bmj 1987;295:696-697. 14. brack mj, cleland pg, owen ri, et al. anterior ischaemic optic neuropathy in acquired immune deficiency syndrome. bmj 1987;295:696-697. 15. tenhula wn, xu sz, madigan mc, heller k, freeman wr, sadun aa. morphometric comparisons of optic nerve axon loss in acquired immune deficiency syndrome. am j ophthalmol 1992;113:14-20. 15. tenhula wn, xu sz, madigan mc, heller k, freeman wr, sadun aa. morphometric comparisons of optic nerve axon loss in acquired immune deficiency syndrome. am j ophthalmol 1992;113:14-20. 16. malessa r, agelink m, diene h. dysfunction of visual pathways in hiv-l infection. j neurol sci 1995;130:82-87. 16. malessa r, agelink m, diene h. dysfunction of visual pathways in hiv-l infection. j neurol sci 1995;130:82-87. 17. beck rw, gal rl. treatment of acute optic neuritis: a summary of findings from the optic neuritis treatment trial. arch ophthalmol 2008;126:994-995. 17. beck rw, gal rl. treatment of acute optic neuritis: a summary of findings from the optic neuritis treatment trial. arch ophthalmol 2008;126:994-995. 18. mccomsey ga, whalen cc, mawhorter sd, et al. placebo-controlled trial of prednisone in advanced hiv-1 infection. aids 2001;15:321-327. 18. mccomsey ga, whalen cc, mawhorter sd, et al. placebo-controlled trial of prednisone in advanced hiv-1 infection. aids 2001;15:321-327. fig. 1. fundus photo of the right eye. there is blurring of optic disc margins associated with disc haemorrhages indicative of optic nerve swelling. findings in the left eye were similar. fig. 2. optical coherence tomography of the left disc, objectively demonstrating nerve fibre layer swelling at presentation. fig. 3. fluorescein angiogram of the right eye at presentation. the bright white areas (termed hyperfluorescence) surrounding the optic disc indicate leakage of sodium fluorescein dye and signify disc swelling. fig. 4. optical coherence tomography 2 months after treatment initiation, showing a decrease in disc swelling. fig. 5. fluorescein angiogram of the right eye 2 months after treatment initiation.in comparison with fig. 3 there is less fluorescein leakage, correlating with resolution of optic disc swelling. pg21-22.html case report primary breast lymphoma and hiv/aids pieter barnardt, mb chb, dip oncol medical imaging and clinical oncology, tygerberg hospital, tygerberg, w cape dylan narinesingh, md, fc rad onc trinidad san fernando general hospital, trinidad primary extranodal lymphoma of the breast is rare and accounts for 0.04 0.53% of all malignant tumours, less than 1% of non-hodgkin’s lymphomas (nhls) and 1.7% of extranodal nhls.1 extranodal lymphoma arises from tissue other than lymph nodes and sites that normally contain no lymphoid tissue. this case describes the clinical and treatment dilemma posed by extranodal presentation in an aids-nhl patient. case report a 40-year-old woman presented with a history of a painful left axillary mass that had progressively increased in size. she reported symptoms of night sweats and weight loss. physical examination revealed a 17×13 cm left axillary nodal mass. her left breast had the clinical appearance of mastitis. abnormal laboratory studies revealed elevated serum uric acid (0.50 mmol/l, normal 0.15 0.35 mmol/l) and lactate dehydrogenase (1 009 u/l, normal 100 190 u/l) levels. an enzyme-linked immunosorbent assay was positive and the initial cd4+ count was 435 cells/μml. microscopic examination of the lymph node mass confirmed a diffuse large b-cell lymphoma (dlbcl). bone marrow aspiration and biopsy demonstrated no evidence of infiltration by lymphoma. cerebrospinal fluid (csf) examination was negative for lymphoma infiltration. both the csf cryptococcus indian ink and latex tests were negative, but a positive varicella zoster polymerase chain reaction (pcr) test was reported. a mammogram was not feasible owing to painful ulceration of the breast mass. a computed tomography (ct) scan of the thorax and abdomen revealed a 5 cm lymphoid nodal mass in the left axilla and a 3.4 cm left supraclavicular lymph node. a gallium scan was consistent with uptake in an area overlying the left breast, anterior chest wall and markedly enlarged left axillary lymph nodes. normal gallium biodistribution was seen in the rest of the body (fig. 1). the case was considered to be a stage iibe aids-nhl. chemotherapy the standard chop regimen consisting of cyclophosphamide 750 mg/m2 , doxorubicin 50 mg/m2 and vincristine 1.4 mg/m2 on day 1 and prednisone 60 mg/day on days 1 5 every 3 weeks was started. she completed 3 cycles without significant toxicity but then presented with clinical progression. the left axillary lymph node and breast mass had the appearance of breast cancer with erythema, oedema and nipple retraction. a solid mass was palpable within the breast with associated skin ulceration and multiple cutaneous nodules over the left infra-clavicular region (fig. 2). however, an infection with varicella zoster virus (vzv) was clinically apparent along dermatome t11 and 5 weeks later she reported progressive bilateral lower limb pareses with associated weakening in bladder control. magnetic resonance imaging (mri) of the vertebral column showed degenerative changes with no focal spinal cord lesions. the patient defaulted and returned 8 weeks later reporting that the mass was more painful and larger with newly developed nodular cutaneous lesions of the left breast region. she was given a 4th cycle of chop and started concomitant antiretroviral therapy (lamivudine, stavudine and efavirenz). four weeks later there was no visible change in the axillary and breast mass. the chemotherapeutic regimen was changed to second-line cmv (cyclophosphamide 750 mg/m2 , methotrexate 60 mg/m2 and vincristine 1.2 mg/m2 ). a follow-up review revealed overt clinical progression, as there was an increase in both the size of the breast mass and the number of cutaneous lesions. a clinical oncology consult offered palliative radiotherapy, as she appeared resistant to firstand second-line chemotherapy. the clinical dilemma was as follows: was this (i) a systemic nhl with extranodal involvement of the left breast; (ii) an overlooked primary breast lymphoma (pbl); or (iii) a misdiagnosed primary breast carcinoma? before commencement of radiotherapy histological examination therefore again confirmed positivity for cd45 and cd20 lymphoma cells compatible with a dlbcl. radiotherapy palliative external beam radiotherapy (ebrt) with cobalt-60, consisting of 2 gy × 18 fractions (36 gy), was completed. the clinical target volume was determined by ct scan (fig. 3). this included the left axillary nodal mass, the immediate lymphatic drainage, the left breast, the remaining left anterior chest wall and the left supra-clavicular region. treatment was delivered using 8 mv photons with a 1 cm daily bolus. before initiation of ebrt the patient started allopurinol 600 mg/d to prevent tumour lysis syndrome. her cd4+ count was 312 cells/μl, and trimetroprim-sulfamethoxazole as pneumocystis jiroveci prophylaxis was added mid-course when the cd4+ count decreased to 56 cells/μl. discussion nhl is the second most common aids-associated malignancy and the aids-defining diagnosis in an estimated 1.6 8% of hiv patients.2 pbl is rare, comprising 0.4 0.5% of all breast malignancies reported.3 secondary breast lymphoma represents approximately 0.07%.4 when primary and secondary lymphoma cases are considered the most common sub-type is dlbcl (45 79%).5 systemic aids-nhl treatment should include therapy for opportunistic infections (ois) and the underlying hiv and involves modifications of conventional therapy. there appears to be a survival advantage for patients receiving chop-art therapy, suggesting that a decrease in ois was responsible for reduction in morbidity.6 based on a 15 20% central nervous system involvement at presentation, cns prophylaxis is considered standard practice in aids-nhl. series with chemotherapy reported a 50% complete response and a median survival of 18 months. an improved response rate does not significantly add to survival owing to relapse and death from aids progression.7 neurological manifestations of vzv have been described. encephalitis due to vzv infection results from small-vessel vasculitis, presenting weeks after the original infection. an urgent mri scan or myelography is required to exclude extrinsic cord compression due to bacterial abscess, tuberculous abscess or lymphoma. if these are excluded, csf should be sent for vzv pcr.8 the clinical and radiological features of pbl and carcinoma are similar, as both are diseases of middle age with a median onset in the 6th decade. symptoms include pain, fever, sweating and weight loss. contralateral involvement can be synchronous or metachronous up to 10 years after the primary lesion. pathology remains the only way to differentiate between these malignancies, as treatment differs radically. wiseman and liao devised criteria to categorise breast lymphoma into primary and secondary forms.9 there is no standard treatment for pbl, and for small localised tumours adequate excision followed by radiotherapy may be effective. for widespread tumours with axillary involvement the addition of chemotherapy, surgery and radiotherapy may be required. the literature suggests that the ann arbor stage and histological sub-type are significant factors for survival.10 , 11 reported 5-year survival rates vary from 9% to 85%. pbls have a better outcome than primary breast carcinomas.12 our patient presented with apparent systemic aids-nhl with extranodal involvement of her breast, but review of her clinical presentation and staging allows for reclassification as a pbl. unfortunately she was lost to follow-up and attempts to contact her have failed. close surveillance should be stressed, as contralateral involvement can appear up to 10 years after the primary lesion. the era of aids-related malignancies represents a challenge. there should be a heightened clinical suspicion for extranodal lymphoma in aids-nhl patients. references 1. sokolov t, shimonov m, blickstein d, nobel m, antebi e. primary lymphoma of the breast: unusual presentation of breast cancer. eur j surg 2000;166:390-193. 1. sokolov t, shimonov m, blickstein d, nobel m, antebi e. primary lymphoma of the breast: unusual presentation of breast cancer. eur j surg 2000;166:390-193. 2. pederson c, barton se, chiesi a, et al. hiv-related non-hodgkin’s lymphoma among european aids-patients. eur j haematol 1995;55:245-250. 2. pederson c, barton se, chiesi a, et al. hiv-related non-hodgkin’s lymphoma among european aids-patients. eur j haematol 1995;55:245-250. 3. jeon h, akagi t, hoshida y, et al. primary non-hodgkin’s malignant lymphoma of the breast. cancer 1992;70:2451-2459. 3. jeon h, akagi t, hoshida y, et al. primary non-hodgkin’s malignant lymphoma of the breast. cancer 1992;70:2451-2459. 4. domchek sm, hecht jl, flemming md, et al. lymphomas of the breast. cancer 2002;94:6-13. 4. domchek sm, hecht jl, flemming md, et al. lymphomas of the breast. cancer 2002;94:6-13. 5. duncan ve, reddy vb, jhala nc, et al. non-hodgkin’s lymphoma of the breast: a review of 18 primary and secondary cases. ann diag path 2006;10:144-148. 5. duncan ve, reddy vb, jhala nc, et al. non-hodgkin’s lymphoma of the breast: a review of 18 primary and secondary cases. ann diag path 2006;10:144-148. 6. ratner l, redden d, hamzeh f, et al. chemotherapy for hiv-nhl in combination with haart. j clin oncol 2001;15:2171-2178. 6. ratner l, redden d, hamzeh f, et al. chemotherapy for hiv-nhl in combination with haart. j clin oncol 2001;15:2171-2178. 7. schumann d, grunewald t, weiss r, et al. intensive treatment of aids-related non-hodgkin’s lymphomas with the macop-b protocol. eur j haematol 1995;54:73-77. 7. schumann d, grunewald t, weiss r, et al. intensive treatment of aids-related non-hodgkin’s lymphomas with the macop-b protocol. eur j haematol 1995;54:73-77. 8. wilson d, naidoo s, bekker lg, cotton m, maartens g, eds. in: handbook of hiv medicine. cape town: oxford university press south africa, 2002: chapt 19, 174-185. 8. wilson d, naidoo s, bekker lg, cotton m, maartens g, eds. in: handbook of hiv medicine. cape town: oxford university press south africa, 2002: chapt 19, 174-185. 9. wiseman c, liao kt. primary lymphoma of the breast. cancer 1972;29:1705-1712. 9. wiseman c, liao kt. primary lymphoma of the breast. cancer 1972;29:1705-1712. 10. mpallas g, simatos g, tasidou a, et al. primary breast lymphoma in a male patient. j breast 2003;13:436-438. 10. mpallas g, simatos g, tasidou a, et al. primary breast lymphoma in a male patient. j breast 2003;13:436-438. 11. imai t, shiga t. primary non-hodgkin’s malignant lymphoma of the breast: long-term follow-up. j breast 2004;13:152-154. 11. imai t, shiga t. primary non-hodgkin’s malignant lymphoma of the breast: long-term follow-up. j breast 2004;13:152-154. 12. freeman c, berg jw, cutler sj. occurrence and prognosis of extranodal lymphomas. cancer 1972;29:252-260. 12. freeman c, berg jw, cutler sj. occurrence and prognosis of extranodal lymphomas. cancer 1972;29:252-260. acknowledgement. we acknowledge the assistance of ms s seier in the preparation of this manuscript. prior ethics approval was obtained. part of the data were used for a poster presentation at the stellenbosch university 2010 annual academic year day. no conflict of interest is declared. fig. 1. gallium-67 scans of lymphoma situated in the left breast and axillary lymph nodes and extending into the left anterior chest wall. fig. 2. clinical manifestation of an extranodal diffuse large b-cell lymphoma (dlbcl) of the left breast in an hiv-positive patient. multiple cutaneous nodules, ulcerative skin lesions, erythema and enlarged axillary lymph nodes are present. fig. 3. soma vision – virtual simulator picture for the patient with breast lymphoma. the clinical target volume (ctv) is outlined in red. thf southhln african journal of hiv mfdicinf ------------may 200 i medical education despite these daily reminders hiv/aids remains a condition with which the majority of medical practitioners are unfamiliar. in this country the management of this condition depends on a very small number of experts, far too few to respond adequately to the number of patients requiring treatment and care. daily we are confronted by newspaper headlines documenting the enormity of the hiv/aids pandemic: • 100/0 of south africans are hiv-positive • 5 million south africans are hiv-positive • 100000 civil servants are hiv-positive • 1 600 people are infected per day • 250000 hiv/aids deaths occur every year. the training programme in hiv/aids management being launched to coincide with this article will attempt to: • ensure a critical mass of trained health care professionals within a relatively short period of time • provide health care professionals with comprehensive skills in order to enable them to diagnose and manage hiv/aids and stds and all related clinical conditions, including referral to specialist and support services • provide targeted sectors of the health care profession with appropriate and meaningful information to prevent themselves from becoming infected • establish a support structure that will keep alumni of the programme updated with new developments in the field, and while not neglecting the imperative of prevention of hiv/aids, it has also become a critical challenge for every health care professional to acquire the skills to manage hiv/aids and other sexually transmitted diseases (stds) and all opportunistic infections associated with hiv. by joining forces the foundation and the hiv clinicians society will actively begin to address this challenge. given the number of hiv-positive south africans and the growing feasibility of affordable antiretroviral therapy, it is reasonable to view hiv/aids as a chronic manageable disease. let's do it! the southern african hiv clinicians society and the foundation for professional development, the educational division of the south african medical association, have joined forces to train in the region of 3 000 health care practitioners in hiv/aids management over the next 3 years. may 200 i -------------tiie southern african journal of hiv medicine • create an expanded organised community of health care professionals dedicated to responding to the hiv/aids epidemic. this training programme will utilise a combination of self-study and 3 days of face-ta-face tuition to develop participants' skills in areas such as: • diagnosis of hiv}aids and stds • basic and clinical management and referral • counselling • advocacy • 'living with hiv'. the self-study material has been developed in collaboration with the international aids society (ias) to reflect global best practice customised to south african realities. international sponsorship has also been secured to ensure that cost does not become an obstacle to participation in this training programme. what is the foundation for professional development (fpd)? • the fpd is the educational division of the south african medical association (sama). • the fpd focuses on helping all health care professionals optimise their skills in order to prosper in a rapidly changing environment. • student enrolment. since the launch of our first course in 1998, student enrolment has grown dramatically (fig. 1). ,"",-------------------" "".!------------~ ,""!------------"'''!--------,,"'!-------==,----,~t----""1----fig. 1. student enrolment in the fpd. what makes fpd courses special? • courses are tailor-made to meet the specific needs of health care professionals. • comprehensive study guides eliminate the need for expensive textbooks. • it is acknowledged that time is the most valuable commodity for the health care professional. • courses are developed and taught by --------------acknowledged local and international experts in their field from both the private and the public sector. • participants evaluate every aspect of our courses from faculty to venue, and we act on these evaluations. • an active alumni programme exists which keeps participants informed via e-mail or update seminars of new developments in their area of interest. fpd training programmes focus on the following areas management and leadership development practice staff development clinical skills development corporate training management courses manchester 8usiness school advanced" management programme [part-time 1 year) rnancial health course (3 days) tax planning seminar (1 day) practice management programme [9 months parttime) practice staff development essence of caring course (2 x 'j, days) coding course (2 days) medical terminology and anatomy course (2 days) debt collecting course (2 days) clinical courses rheumatology management course (3 days) obesity management course (2 days) . professional drivers permit course (2 days) mental health course (3 days) practice pathology [2 days) aids et sm programme (in process of development) distance education medical ethics course dental ethics course rheumatology management course for detailed information on any of the courses, please contact the fpd at: foundation for professional development po box 74789, lynnwood ridge 0040 web-site: http://wwwjoundation.co.za e-mail: foundation@samedical.org lel: (on) 481-2032/3/4 fax: (012) 481-2083 hiv immunopaedia.html review immunology for clinicians: a ‘trojan horse’ approach* clive m gray, shayne loubser, carina kriel, monica mercer national institute for communicable diseases, national health laboratory services, johannesburg, south africa heather brookes university of johannesburg, johannesburg a south african website imparts basic immunology information to clinicians and other health care workers. to determine how a program for learning immunology could be most useful for clinicians in south africa, we consulted with the country’s 20 leading hiv specialist pediatricians. they told us that immunology and its underlying concepts were perceived to be complex and arcane and that there was a need for immunology to be better integrated into “real-life” clinical practice. most saw immunology as predominantly a laboratory science with little application to clinical practice; this highlighted a gap between clinical management of patients and theoretical understanding of the etiology and immunopathogenesis of disease. we speculated that one of the possible reasons for this perception and knowledge gap is that immunology is not an independent discipline within the south african medical curriculum. instead, it is diffusely integrated into disciplines such as pathology or internal medicine and is not specifically provided for during post-degree training. we initially developed the project immunopaedia (www.immunopaedia.org) to help bridge the knowledge gap between laboratory research and pediatric hiv clinical science. the rationale for immunopaedia was based on the paradox between the void in knowledge of immunology among hiv infectious disease clinicians and the need to understand and treat the hiv epidemic in south africa. south africa has one of the fastest-growing hiv epidemics with over 5.5 million people living with hiv, many of whom are young children and women (1). the 2008 national population-based surveys estimated hiv prevalence at 16.9% (2). provision of treatment and care for such a large population makes it hard for hiv clinicians to stay informed about the latest developments in infectious disease. immunopaedia was thus created to provide an easy-to-understand summary of the effects of hiv infection on the immune system, which could facilitate improvement in clinical practice. immunopaedia has since progressed to include more general immunology knowledge that is relevant to other disease conditions. we use a clinical case–based perspective to target interns in multiple clinical specialities. immunopaedia is an alternative to more advanced online immunology studies that target the basic-science student (3). information and educational materials are available through open access, and the site can be used as an adjunct to more formal courses or as a stand-alone learning tool. our main method is what we have termed the “trojan horse” approach. derived from the greek iliad, “trojan horse” has come to mean any ploy or scheme used to insinuate a rival into a securely protected stronghold. we use clinical case studies as our trojan horse to tempt clinicians, most of whom consider immunology to have little application to clinical needs, to engage with immunological concepts relevant to diagnosis and treatment (see the figure, above). we explain the key immunological points related to the cases by means of a series of graphics. the web site consists of three key components: clinical cases, immunology learning, and treatment and diagnostics. at present, 34 clinical cases are available on the site. in addition to hiv, clinical cases span topics such as hypersensitivity, tuberculosis (tb) immunopathology, primary and secondary immunodeficiencies, drug responses, gastrointestinal disorders, autoimmunity, and malignancies. each of our cases is used to examine an immunological concept that leads to greater understanding of the human immune system. for example, a case of a 14-year-old boy presenting with severe hip pain allowed us to discuss ankylosing spondylitis and to explore the concept of mimicry and the “arthritogenic peptide” hypothesis. the case of repeated apnea and infections in a premature infant allowed us to highlight “physiological immunodeficiency” caused by impaired humoral and cellular responses in premature infants, a situation that leaves such infants vulnerable to both viral and bacterial pathogens. another presenting case was an 8-month-old boy with recurrent infections. we explored the most likely hypothesis, that the mother had a primary hiv-1 infection during pregnancy in the third trimester and that the child was infected perinatally before maternal seroconversion. these are real-life cases, and in the last-mentioned case, as often in real life, the underlying immunological problem may not be clear. each case discussion provides, in consecutive windows, patient presentation, history, differential diagnosis, examination, investigations, discussion, treatment, and a final outcome. related case studies are cross-referenced. users then evaluate their knowledge and understanding of the concepts in the case study by means of questions accompanied by explanations. to earn the full quota of continuing medical education (cme) points, the user can complete five multiple choice questions for each case study that are freely available but require log-in information. integral to our approach with each case study is the use of clear graphics to explain the immunological basis and mechanisms underlying the condition. the graphics can be downloaded freely as a pdf and used for offline reference or for further teaching tools. the second key component, immunology learning, is divided into three main areas: “immunology” (dealing with the basics), “childhood diseases and vaccinations” (dealing with hypersensitivity reactions and immune reconstitution, for example), and “infections” (dealing with a range of infections from rickettsia to guillain-barré syndrome). the third key component, treatment and diagnostics, covers information related to tb and antiretroviral (arv) drugs, modes of drug action, the hiv life cycle, and specific guidelines for treatment. the “diagnostic tools” section provides laboratory assay information, such as enzyme-linked immunosorbent assays (elisas), polymerase chain reactions (pcrs), and flow cytometry. immunopaedia provides links to other web sites that focus on medical and general aspects of hiv, pediatrics, and treatment guidelines. the design of the web site is such that the user can easily find a source of information in the form of a case study, a graphic, or a scientific article on specific immunological conditions. in addition, breaking scientific news on clinical immunology is posted on the home page and is updated daily. registered users are sent a monthly newsletter that coincides with a monthly clinical case study posting. for the clinical case component, medical practitioners submit case studies from their clinics. our team of clinical and immunology experts reviews and modifies these case studies for presentation on the web site (see the first figure). the rationale behind this approach is that case studies from, or closely related to, real situations are effective learning tools (4). the case-study approach is a form of experiential learning; it integrates practice, knowledge, and skills that further equip clinicians in their professional work (5). as the user reads through the case study on the site, dividing the case study into stages in separate windows, the user is challenged to think about and predict a possible diagnosis based on the clinical evidence he or she has just read. this process is similar to the way a clinician might operate on the job, and the approach fosters lateral and critical thinking, as well as self-guided learning (6). immunopaedia also includes a workshop component as a follow-up to the online material (see the second figure). we use the workshops to evaluate our new case-study material before posting it on the web site, and our teaching team travels to medical schools within south africa to hold 3-hour sessions for medical interns who are specializing in pediatrics, pathology, or internal medicine. the aim of the workshops is to create greater awareness and increased use of immunopaedia as a learning site for clinical immunology. the monthly average number of unique users was 320 in 2007; 1518 in 2008; 2326 in 2009; and 1723 in 2010 (through june). since the site first went live, we have received a total of 87,550 visitors, of which 11,520 have spent more than 5 minutes on the site. each user who completes a case study earns three cme points, and in total, we have awarded 699 cme points over 3 years. we currently have 892 registered users. future directions for immunopaedia involve the expansion of our user base to include point-of-care clinicians for the arv drug roll-out in south africa. we will use clinical case studies to highlight common diagnostic decision points as a mechanism to educate clinicians on laboratory tools and interpretation of results. immunopaedia is an immediate source of information for professionals and represents an effective means for learning and dissemination of immunology information. our aim is to integrate immunology into clinical options for patient management. references and notes 1. s. s. abdool karim, q. abdool karim, hiv/aids in south africa (cambridge univ. press, cambridge, ed. 2, 2010). 1. s. s. abdool karim, q. abdool karim, hiv/aids in south africa (cambridge univ. press, cambridge, ed. 2, 2010). 2. unaids, 2009: aids epidemic update; www.unaids.org. 2. unaids, 2009: aids epidemic update; www.unaids.org. 3. n. debard et al., nat. rev. immunol. 5, 736 (2005). 3. n. debard et al., nat. rev. immunol. 5, 736 (2005). 4. c. davis, e. wilcock, teaching materials using case studies, the uk centre for materials education; www.materials.ac.uk/guides/casestudies.asp. 4. c. davis, e. wilcock, teaching materials using case studies, the uk centre for materials education; www.materials.ac.uk/guides/casestudies.asp. 5. l. maguire, k. lay, j. peters, j. scholarship learn. teach. 9, 93 (2009). 5. l. maguire, k. lay, j. peters, j. scholarship learn. teach. 9, 93 (2009). 6. c. kreber, teach. high. educ. 6, 217 (2001). 6. c. kreber, teach. high. educ. 6, 217 (2001). 7. immunopaedia (www.immunopaedia.org/) initially received funding through the elizabeth glaser pediatric aids foundation international leadership award to c.m.g. in 2004. we have also received funding through south african educational grants, as well as grants for implementing new learning technology, through the national institute of allergy and infectious diseases, nih. immunopaedia is a result of collaborative ventures with many clinicians and scientists. 7. immunopaedia (www.immunopaedia.org/) initially received funding through the elizabeth glaser pediatric aids foundation international leadership award to c.m.g. in 2004. we have also received funding through south african educational grants, as well as grants for implementing new learning technology, through the national institute of allergy and infectious diseases, nih. immunopaedia is a result of collaborative ventures with many clinicians and scientists. *spore science prize for online resources in education) series winner (www.sciencemag.org/special/spore/). corresponding author: c gray (cgray@nicd.ac.za). from science vol. 329, 24 september 2010, pp. 1613-1614. reprinted with permission from the american association for the advancement of science. trojan horse approach. immunopaedia uses a case study to lure clinicians into learning immunology. shown are the steps followed for each case before posting on the web site. the case is used to underpin an immunology concept. about the authors clive gray, founder of immunopaedia, has a phd in immunology and conducts research on hiv/aids in south africa. he received the elizabeth glaser pediatric aids foundation international leadership award, which has allowed the development of immunopaedia. shayne loubser writes the immunology materials and produces the computer-generated graphics for each case study. carina kriel is the curator and coordinator of the web site and oversees all administrative aspects. monica mercer (not pictured) holds an md and is a clinical materials writer and leads the development of educational materials. heather brookes (not pictured) has a phd in language, literacy, and culture and is a consultant for internet learning. from left to right: shayne loubser, clive gray, and carina kriel. workshop participants evaluate case study material. participants of workshops come from tertiary teaching hospitals within south africa and include interns specialising in paediatrics, pathology, and internal medicine. pg25-26.html original article pattern of pericardial diseases in hivpositive patients at university college hospital, ibadan, nigeria u abubakar, mb bs p o adeoye, mb bs, fwacs o a adebo, fwacs, frcs, fmcs v o adegboye, fwacs, fmcs e b kesieme, mrcs, fwacs e k okonta, mb bs division of thoracic and cardiovascular surgery, department of surgery, college of medicine, university of ibadan and university college hospital, ibadan, nigeria rationale.  pericarditis has been reported as the most common cardiac complication of hiv disease, followed by pericardial effusion. methods.  a retrospective review was conducted of all 68 patients treated for pericardial diseases between august 2003 and july 2008 at university college hospital, ibadan, nigeria. hiv-positive patients (n=42) were compared with those who were hiv negative (n=26). results.  more male than female patients presented with pericardial disease, and the hiv-positive patients were younger than those who were hiv negative. pericardial effusion was the commonest mode of presentation, accounting for 20 hivpositive patients (47.7%) and 13 hiv-negative patients (50%). pericardiostomy was the commonest surgical intervention performed in hiv-positive patients (n=15), while the majority of hiv-negative patients had pericardiocentesis. conclusion.  pericardial effusion was the commonest cardiac presentation in hiv-positive patients in our setting. we recommend that patients with pericardial effusion be investigated for hiv infection. previous reports have described cardiac involvement in 28 73% of patients with hiv infection. this includes pericardial effusion, pulmonary hypertension and heart failure, infective endocarditis, tumours, myocarditis and left ventricular dysfunction.1 the association between pericardial diseases and aids has been well documented.2 of interest is the observation that the incidence of aids -related diseases found at autopsy studies is significantly higher than the incidence of abnormalities diagnosed clinically. it is therefore possible that many aids patients have cardiac abnormalities that are not recognised during the course of their illness.3 the number of hiv-positive patients with pericardial diseases has been reported to be increasing in africa.4 pericarditis was reported to be the most common cardiac complication of hiv infection, followed by pericardial effusion.5 methods we reviewed the records of all patients treated for pericardial diseases between august 2003 and july 2008 at university college hospital, ibadan, nigeria. data were obtained from medical, ward and theatre records. demographic data, causes of pericardial diseases, treatment offered and outcome were recorded. pericardial effusion was categorised into mild (<2 cm) and severe (>2 cm), based on echocardiographic evaluation of thickness. comparisons were made between the hiv-positive and hiv-negative groups. the chi-square test was used to compare the two groups. results the total number of patients treated for pericardial diseases during the period under review was 68; 42 were hiv positive and 26 hiv negative. the mean age of the hiv-positive patients was 30 years and that of the hiv-negative patients 53 years (p=0.05). hiv-positive patients were three times more likely to be male and hiv-negative patients twice as likely. diagnoses and the causations of pericardial disease in the two groups are set out in tables i and ii, respectively. large effusions were seen in 80% of hiv-positive patients, but only 15% were categorised as large in the hiv-negative group (table iii). the treatment offered to the patients is shown in table iv. pericardiostomy was performed in 15 of the hiv-positive patients and 4 of the hiv-negative patients. four of the hiv-positive patients and 1 hivnegative patient died. among the hiv-positive patients, 2 died after pericardiectomy, 1 following a complication of tube pericardiostomy, and 1 while being prepared for surgery because he was haemodynamically unstable. discussion the incidence of cardiac manifestations in the course of aids is increasing, although these manifestations are not often diagnosed clinically. myocarditis and pericardial diseases have been reported to be the commonest hiv-related cardiac abnormalities.6 the association of pericardial diseases and aids has been well documented.1 pericardial effusion was the commonest mode of presentation in our patients, which is in keeping with other studies.7 our study showed that hiv-positive patients were younger than hiv-negative patients. this has also been documented by kwan et al.8 the majority of our hiv-positive patients had large effusions, and pericardiostomy was therefore the commonest procedure performed in this group. effusions in hiv-negative patients were small and were mainly drained by pericardiocentesis. this is in keeping with the findings of other studies.9 pleural effusion was associated with pericardial effusion, mainly in hiv-positive patients. this association has also been reported by kaplan et al., and it may be related to the large size of the pericardial effusions. other studies have reported pericarditis as the commonest pericardial condition.11 tuberculosis was the commonest cause of pericardial disease in our patients. the association of tuberculosis and hiv infection has been described,9 although some reports suggest that tuberculosis is less common than opportunistic infections and neoplasms as a cause of pericardial disease.5 of the patients in our study, 7 had malignant pericardial disease (16.7% of hiv-positive patients). most series have reported kaposi’s sarcoma to be the commonest malignancy in hiv patients, mainly as a result of the documented association between this malignancy and hiv infection.15 purulent pericarditis was noted in the majority of hiv-negative patients. this has previously been reported from our centre.16 of the hiv-positive patients in our study, 4 (9.5%) died. mayosi et al. reported a higher mortality rate (26%), and found mortality to be highest in those with clinical aids or who were haemodynamically unstable.10 conclusion although not commonly looked for clinically, cardiac involvement in hiv-positive patients is a reality, with pericardial effusion being the commonest mode of presentation in our environment. we advocate that patients with pericardial effusion be investigated for hiv infection, and likewise that all hiv-infected individuals should undergo periodic cardiac evaluation, including echocardiography, in order to identify sub-clinical pericardial and cardiac diseases. references 1. akhras f, dubrey s, gazzard b, et al. emerging pattern of hiv infected homosexual subjects with and without opportunistic infections; a prospective colour flow doppler echocardiographic study. eur heart j 1994;15:68-75. 1. akhras f, dubrey s, gazzard b, et al. emerging pattern of hiv infected homosexual subjects with and without opportunistic infections; a prospective colour flow doppler echocardiographic study. eur heart j 1994;15:68-75. 2. bosari oa, opadijo og, adeyemi oa. cardiac diseases in hiv and aids. internet journal of cardiology 2008;5(2). 2. bosari oa, opadijo og, adeyemi oa. cardiac diseases in hiv and aids. internet journal of cardiology 2008;5(2). 3. susan rh, marvin b, andrew vt, et al. unsuspected cardiac abnormalities in aids: an echocardiographic study. chest 1999;96:805-808. 3. susan rh, marvin b, andrew vt, et al. unsuspected cardiac abnormalities in aids: an echocardiographic study. chest 1999;96:805-808. 4. longo-mbenza b, tonduangu k, seghers kv, et al. hiv infection and pericardial diseases in africa. arch mal coeur vaiss 1997;90(10):1377-1384. 4. longo-mbenza b, tonduangu k, seghers kv, et al. hiv infection and pericardial diseases in africa. arch mal coeur vaiss 1997;90(10):1377-1384. 5. mastroianni a, coronado o, chiodo f. tuberculous pericarditis and aids: case report and review. eur j epidemiol 1997;13(7):755-759. 5. mastroianni a, coronado o, chiodo f. tuberculous pericarditis and aids: case report and review. eur j epidemiol 1997;13(7):755-759. 6. magula np, mayosi bm. cardiac involvement in hiv infected people living in africa; a review. cardiovasc j s afr 2003;14(15):231-237. 6. magula np, mayosi bm. cardiac involvement in hiv infected people living in africa; a review. cardiovasc j s afr 2003;14(15):231-237. 7. ntsekhe m, hakim j. impact of human immunodeficiency virus infection on the cardiovascular system. circulation 2005;112(23):3602-3607. 7. ntsekhe m, hakim j. impact of human immunodeficiency virus infection on the cardiovascular system. circulation 2005;112(23):3602-3607. 8. kwan t, karve mm, emerole o. cardiac tamponade in patients with hiv infection. a report from an inner-city hospital. chest 1993;104(4):1059-1062. 8. kwan t, karve mm, emerole o. cardiac tamponade in patients with hiv infection. a report from an inner-city hospital. chest 1993;104(4):1059-1062. 9. monica m, reynold sr, hecht m, et al. large pericardial effusion in aids. chest 1992;102:1746-1747. 9. monica m, reynold sr, hecht m, et al. large pericardial effusion in aids. chest 1992;102:1746-1747. 10. kaplan lm, epstein sk, schwartz sl, et al. clinical, echocardiographic, and hemodynamic evidence of cardiac tamponade caused by large pleural effusions. am j respir crit care med 1995;151(3):904-908. 10. kaplan lm, epstein sk, schwartz sl, et al. clinical, echocardiographic, and hemodynamic evidence of cardiac tamponade caused by large pleural effusions. am j respir crit care med 1995;151(3):904-908. 11. strang ji, nunn aj, johnson da, et al. management of tuberculous pericarditis and tuberculous pericardial effusion in transkei: results at 10 year follow-up. qjm 2004;97(8):525-535. 11. strang ji, nunn aj, johnson da, et al. management of tuberculous pericarditis and tuberculous pericardial effusion in transkei: results at 10 year follow-up. qjm 2004;97(8):525-535. 12. mayosi bm, burgess lj, doubell af. tuberculous pericarditis. circulation 2005;112(23):3608 3616. 12. mayosi bm, burgess lj, doubell af. tuberculous pericarditis. circulation 2005;112(23):3608 3616. 13. decker cf, tuazon cu. staphylococcus aureus pericarditis in hiv infected patients. chest 1994;105(2):615-616. 13. decker cf, tuazon cu. staphylococcus aureus pericarditis in hiv infected patients. chest 1994;105(2):615-616. 14. sa i, moco r, cabral s. constrictive pericarditis of tuberculous origin in hiv positive patients: case report and review of literature. rev port cardiol. 2006;25(11):1029-1038. 14. sa i, moco r, cabral s. constrictive pericarditis of tuberculous origin in hiv positive patients: case report and review of literature. rev port cardiol. 2006;25(11):1029-1038. 15. jennifer ls, chester bg, williams rd, et al. pericardial effusion with tamponade due to kaposi’s sarcoma in aids. chest 1989;95:1359-1361. 15. jennifer ls, chester bg, williams rd, et al. pericardial effusion with tamponade due to kaposi’s sarcoma in aids. chest 1989;95:1359-1361. 16. adebo oa, osinowo o, adebonojo sa, et al. purulent pericarditis: a continuing surgical challenge. j nat med assoc 1981;73(5):439-443. 16. adebo oa, osinowo o, adebonojo sa, et al. purulent pericarditis: a continuing surgical challenge. j nat med assoc 1981;73(5):439-443. this analysis has not been presented at scientific conferences or published elsewhere. external funding was not used to support this work. table i. diagnoses in 68 patients with pericardial disease diagnosis hiv positive hiv negative pericardial effusion 20 (47.6%) 13 (50%) constrictive pericarditis 12 (28.6%) 7 (26.9%) effusive constrictive pericarditis 6 (14.3%) 2 (7.7%) pericarditis 4 (9.5%) 4 (15.4%)      total 42 26   table ii. causes of pericardial disease diagnosis hiv positive hiv negative tuberculosis 17 (40.5%) 10 (38.5%) malignant disease 7 (16.7%) 4 (15.4%) chronic inflammation 6 (14.3%) 10 (38.5%) unknown 12 (28.6%) 2 (7.7%)      total 42 26   table iii. pericardial effusion diagnosis hiv positive hiv negative large effusion* 16 (80%) 2 (15.4%) small effusion** 2 (10%) 3 (23.1%) no report*** 2 (10%) 3 (23.1%)      total 20 13 statistical significance was defined as p<0.05. * p<0.01. ** p<0.05. *** p<0.10.   table iv. treatment of pericardial disease treatment hiv positive hiv negative pericardiostomy 15 (37.5%) 6 (23.1%) pericardiocentesis 6 (14.3%) 8 (30.8%) pericardiectomy 14 (33.4%) 8 (30.8%) nil 7 (16.7%) 4 (15.4%)      total 42 26 hiv 863 forum psychotropic prescribing in hiv   e reid, c orrell, k stoloff, j joska   division of neuropsychiatry, department of psychiatry and mental health, faculty of health sciences, university of cape town e reid, mb chb, fc psych (sa) k stoloff, mb chb, fc psych (sa) j joska, mb chb, mmed (psych), phd, fc psych (sa)   desmond tutu hiv centre, institute of infectious diseases and molecular medicine and department of medicine, faculty of health sci ences, university of cape town c orrell, mb chb corresponding author: j joska (john.joska@uct.ac.za)   disclaimer. drug profiles, adverse effects and drug-drug interactions have been shortened to include the most common or serious, and are not intended to be exhaustive. psychiatric disorders frequently co-occur with hiv, as preceding conditions or consequent to hiv infection. this potentially compromises hiv diagnosis and antiretroviral (arv) treatment adherence. we provide a brief guide to the diagnosis and treatment of common mental disorders in people living with hiv/aids, including: prescribing psychotropics in hiv; neuropsychiatric side-effects of arvs and other medications commonly prescribed in hiv; and the diagnosis and treatment of depression, anxiety, psychosis, agitation, sleep disturbance, pain, and mania. psychotropic treatments recommended were drawn primarily from those available in the public sector of south africa. s afr j hiv med 2012;13(4):194-188. doi:10.7196/sajhivmed.863 psychiatric disorders frequently co-occur with hiv infection, as conditions preceding or consequent to infection. a high degree of adherence to highly active antiretroviral therapy (haart) is required to prevent the development of resistant viral strains and to minimise the risk of medication failure. psychiatric co-morbidities potentially compromise adherence to antiretroviral therapy (art) and can complicate hiv diagnosis and treatment. although close collaboration between physicians, psychiatrists and other members of the multidisciplinary team is the ideal, psychiatric support is not readily available in certain settings. this article is intended to guide the diagnosis and psychotropic treatment of common mental disorders in people living with hiv/aids (plwha). many psychotropics are taken for ≥6 months, and both psychotropics and antiretrovirals (arvs) are metabolised by the cytochrome p450 enzyme system, necessitating consideration of pharmacokinetic interactions. there also needs to be awareness of the differences in medication responses and tolerability in this population. here we summarise: prescribing psychotropics in hiv; neuropsychiatric side-effects of arvs and other medications commonly prescribed in hiv; and the diagnosis and treatment of depression, anxiety, psychosis, agitation, sleep disturbance, pain, and mania. the psychotropic treatments recommended here were drawn primarily from those available in the public sector of south africa (sa). psychotropics in hiv: basic principles a few simple points should be kept in mind when considering the management of mental disorders in hiv-infected individuals. firstly, patients with hiv infection are generally very sensitive to medication side-effects as they often metabolise drugs more slowly, have less lean body mass and have compromised blood-brain barrier functioning. although most patients ultimately tolerate standard doses of most medications, it is advisable to start at low doses and escalate dosing slowly over time.1 , 2 furthermore, plwha often receive multiple medications (arvs, antibiotics, tuberculosis (tb) medications, etc.). consequently, healthcare providers need to avoid prescribing complex regimens (e.g. daily dose instead of twice daily, where possible), anticipate drug interactions, and consider possible mood, behavioural and cognitive effects of medications such as arvs. the fact that treating hiv infection and related conditions is essential for optimal psychiatric care is often under-appreciated. close collaboration between psychiatrists, physicians, nursing staff and all members of the multi-disciplinary healthcare team is crucial. it is important to make the distinction between primary and secondary psychiatric symptoms (e.g. those caused by other medications, delirium, central nervous system (cns) infections, etc.), as results of standard psychiatric treatment may be inadequate if these are not addressed.1 arv neuropsychiatric side-effects the introduction of haart has transformed hiv infection from a death sentence to a chronic treatable illness. unfortunately, most arvs have neuropsychiatric side-effects (table 1),2 most commonly insomnia and headache, with efavirenz (efv) being the agent most often implicated. these symptoms usually emerge shortly (within 3 months) after commencing arvs and abate on withdrawal thereof. although efv is not absolutely contra-indicated in patients with a history of severe mental illness, patients should be informed of potential side-effects and closely monitored for any emergence or exacerbation of symptoms. furthermore, where possible, alternative arvs should be considered. the optimal haart regimen for patients with cns disease remains to be established. it is unclear whether arv regimens with better cns penetration are superior to others,3 but there is consensus that optimal peripheral viral suppression is necessary.4 table 1. arv side-effects class agent side-effects* nucleoside reverse transcriptase inhibitors (nrtis) didanosine (ddi) • common: insomnia, mania lamivudine (3tc) • rare: insomnia, mania, restlessness, agitation, delirium, depression, irritability stavudine (d4t) • headache, insomnia, mania, abnormal dreams, anxiety, depression, somnolence, emotional lability tenofovir (tdf) • common: aesthenia, depression, insomnia, anorexia (possibly related to co-use of efv) zidovudine (azt) • common: insomnia, anorexia, dizziness • rare: confusion, mania, convulsions, anxiety, somnolence non-nucleoside reverse transcriptase inhibitors (nnrtis) efavirenz (efv) • common: depression, dizziness, insomnia, somnolence, impaired concentration, vivid dreams, and anxiety • rare: agitation, paranoia, delusions, euphoria, confusion, amnesia, depersonalisation, hallucinations, suicidal ideation, convulsions, false-positive cannabinoid test protease inhibitors (pis) lopinavir/ritonavir (lpv/r) • rare: parasthaesia, insomnia, reduced libido, anxiety, abnormal dreams ritonavir (rtv) • common: aesthenia, circumoral and peripheral paresthaesia, altered taste atazanavir (atv/r) • common: dizziness, insomnia • rare: depression, confusion, amnesia, abnormal dreams, anxiety antibacterials co-trimoxazole • rare: insomnia, depression, anorexia, apathy isoniazid (inh) • common: peripheral neuropathy • rare: agitation, depression, hallucinations, paranoia, impaired memory other metronidazole • rare: cns toxicity, agitation, depression, delirium, seizures amphotericin b • common: headache • rare: delirium, agitation, anorexia, lethargy, diplopia steroids • euphoria, mania, depression, psychosis, confusion cns = central nervous system. *common: <10%; rare: <1%. depression depressive disorder is common in hiv-positive individuals, with a prevalence of 11.1% for major depressive disorder and 29.9% for mild depression in sa clinics.5 it has been suggested that depression is often under-diagnosed2 and insufficiently managed.6 the following screening questions may prove helpful in identifying patients requiring further treatment or referral: • ‘during the past month, have you often been bothered by feeling down, depressed or hopeless?’ • ‘during the past month, have you often been bothered by little interest or pleasure in doing things?’ • ‘is this something with which you would like help?’ it is also important to ask patients about suicidal thoughts, self-esteem, feelings of guilt or worthlessness, and outlook. although the diagnostic and statistical manual of mental disorders (fourth edition) (dsm-iv) includes problems with sleep, energy and appetite as diagnostic criteria for depression, these may be hiv-related. if the patient answers ‘yes’ to one or more of the above questions, it is helpful to differentiate between mild-moderate and severe depression, to inform further management. in mild-moderate depression, patients usually experience transient or mild symptoms occasionally, have low levels of distress, and do not have suicidal thoughts or plans. such symptoms can often be in relation to a recent diagnosis or the commencement of arv treatment. these patients can be referred to a supportive adherence counsellor or can be considered for referral for psychotherapy where psychologists are available. in cases of severe depression, patients often have persistent, severe symptoms, high levels of distress and suicidality. these patients should be referred to psychiatric services and/or treatment with antidepressant medication should be initiated. antidepressants using more than one antidepressant should be avoided, as the risk of serotonin syndrome may be increased in hiv-positive patients.2 the syndrome, which constitues a medical emergency, presents with pyrexia, sweating, diarrhoea, hyperreflexia, myoclonus, loss of consciousness and seizures. in general, the duration of treatment with antidepressant medication depends on whether or not the patient has experienced previous depressive episodes. for a first episode, medication should generally be continued for 6 12 months to prevent relapse. treatment should be continued for 2 3 years in the event of a patient’s second or third episode, and lifelong medication should be considered for >3 prior episodes. st john’s wort, a herbal product with antidepressant effects, may reduce the plasma concentrations and clinical effects of efv, nevirapine (nvp) and lopinavir/ritonavir (lpv/r). patients must therefore be informed that its concurrent use with these arvs is contra-indicated.7 first-line agents include the serotonin selective re-uptake inhibitors (ssris), fluoxetine (for patients on first-line art regimens) or citalopram (for patients on second-line regimens or receiving protease inhibitors (pis)). in most public sector facilities, treatment with citalopram needs to be initiated by a psychiatrist. the side-effects, drug interactions and potential advantages of these ssris are outlined in table 2. table 2. side-effects, drug interactions and advantages of concurrent ssri use with art agent dose side-effects drug interactions 8 , 9 notes fluoxetine   20 60 mg/day nausea, dyspepsia, abdominal pain, anxiety (especially in first 10 days), headache, tremor, sexual dysfunction, hyponatraemia, insomnia and agitation • lpv/r: may increase fluoxetine levels – increased risk of serotonin syndrome • advantages: low cost, available at most centres • agitation can be a big problem in the first few days: adequate explanation and reassurance can reduce impact • safe in overdose citalopram   20 60 mg/day as for fluoxetine   • not a potent inhibitor of most cytochrome-p450 enzymes: few drug interactions • use with caution with nsaids/warfarin • advantage over fluoxetine: starting dose can be halved (10 mg), and fewer drug interactions • safe in overdose lpv/r = lopinavir/ritonavir; ssri = serotonin selective re-uptake inhibitor; nsaids = non-steroidal anti-inflammatory drugs. if the patient has a co-morbid sleep disorder or chronic pain, tricyclic antidepressants (tcas), such as amitriptyline or imipramine, should be considered (table 3). these can be prescribed as monotherapy: 100 150 mg/day, or 25 50 mg/day as augmentation. table 3. side-effects, drugs interactions and advantages of concurrent tca use with art agent dose side-effects drug interactions 8,9 notes amitriptyline 25 150 mg/day (usually taken at night) • dry mouth, blurred vision, constipation, urinary retention, sedation, arrhythmia • contra-indicated if myocardial infarct in preceding 6 months, cardiac conduction abnormalities or prostatism •   rtv: increases levels and thereby the antimuscarinic effects of amitriptyline (reduce the dose)   • lethal in overdose: not suitable for patients at risk of suicide • dry mouth can be a problem with oral candida • usual dose of 25 mg for insomnia or pain is often not sufficient as an antidepressant – may need >3 tablets • useful if sedation/analgesia is required imipramine   75 150 mg/day as for amitriptyline, but less sedating     tca = tricyclic antidepressant; rtv = ritonavir. in patients with co-morbid anxiety and/or patients who have not responded to ssris, the use of venlafaxine (efexor) – a serotonin and noradrenaline re-uptake inhibitor (snri) – could be considered. the drug is not available at all centres and needs to be initiated by a psychiatrist (at a dose of 37.5 mg/day, increased to a maximum of 225 mg/day). treatment with venlafaxine should never be stopped abruptly, as discontinuation symptoms can occur. potential side-effects include nausea, insomnia, dry mouth, somnolence, sweating, headache, nervousness, constipation, sexual dysfunction and elevation of blood pressure at higher doses. the drug should be avoided in patients at risk of arrhythmia.2 anxiety anxiety is a normal human emotion and may be adaptive in many circumstances. however, when it is present for prolonged periods of time, is excessive in relation to the person’s current life stressors, or interferes with daily functioning, an anxiety disorder may be present. anxiety symptoms often mimic common mental conditions and may occur as part of depression, or alone. it is important to exclude and treat physical causes that can resemble the physical symptoms of anxiety, such as thyroid disease, cardiac disease and seizures. the dsm-iv distinguishes between the following anxiety disorders: • generalised anxiety disorder (gad): excessive and pervasive worry and tension about a variety of events and activities in daily life, associated with somatic symptoms • panic disorder: recurrent, unexpected sudden attacks of overwhelming anxiety • phobias: excessive fears of specific objects (e.g. spiders) or situations (e.g. flying or social situations) • post-traumatic stress disorder (ptsd): distressing dreams or flashbacks, nervousness, poor sleep and avoiding reminders following a life-threatening or traumatic event • obsessive-compulsive disorder (ocd): repetitive, uncontrollable thoughts or images that are disturbing; or an inability to cease performing rituals or repetitive actions. if symptoms of the above disorders are present for ≥1 month, where possible, we advise considering pharmacotherapy and referral to a psychologist. ssris are considered first-line treatment. importantly, people with anxiety disorders may be particularly prone to adverse effects and tolerate high initial doses poorly.10 patients with anxiety generally require higher doses of ssris than those with depression; however, medication should be titrated up cautiously to moderate side-effects. antidepressants for anxiety may need to be taken for 12 months after the remission of symptoms, depending on the diagnosis. either fluoxetine (for patients on first-line art regimens) or citalopram (for patients on second-line regimens or receiving pis) could be commenced at half the usual starting dose. citalopram needs to be psychiatrist-initiated, but has the advantage over fluoxetine of being a scored tablet, making it easier to start at half the usual dose (10 mg). venlafaxine (psychiatrist-initiated) should be considered for patients who have not responded to ssris. benzodiazepines (table 4) provide rapid symptomatic relief of anxiety, but because of their potential to cause physical dependence and withdrawal symptoms,11 and the potential for abuse, these drugs should be used at the lowest effective dose for the shortest period of time (<3 weeks). benzodiazepines should be used in conjunction with ssris during treatment initiation. caution should be exercised because of serious interactions with arvs, particularly ritonavir (rtv), and especially with alprazolam, midazolam and triazolam. lorazepam and oxazepam have the least number of interactions with arvs. benzodiazepines also cause or exacerbate cognitive impairment and are sedating; therefore, patients must be advised not to drive, operate machinery or drink alcohol concurrently with their use table 4. benzodiazepine use with art benzodiazepines (short-term prescribing only) long-acting (half-life >20 hours) • diazepam (pax, valium): 2 30 mg (oral or iv; never im) up to 3 times daily • clonazepam (rivotril): 0.5 2 mg twice daily intermediate-acting (12 24 hours) • lorazepam (ativan, tranqipam): 1 12 mg (oral, im or sublingual) up to 3 times daily • alprazolam (alzam, xanor): 0.25 4 mg (see interactions below) twice daily short-acting (6 12 hours) • oxazepam 10 30 mg twice daily ultra-short-acting (<6 hours) • midazolam (dormicum): 7.5 15 mg (see interactions below) usually stat dose, but may be used up to 3 times daily benzodiazepine interactions with arvs 8 , 9 diazepam • use with caution with efv and lpv/r: may need dose adjustment because of increased sedation, confusion and respiratory depression clonazepam • efv: possible increase or decrease in clonazepam levels; avoid combination • nvp: possible decrease in clonazepam concentrations and symptoms of withdrawal • rtv: likely to increase levels of clonazepam – use with caution alprazolam • efv: may increase levels of alprazolam – avoid • rtv: increases alprazolam effect when rtv is started; after 10 days no significant interaction • nvp: may reduce alprazolam effect midazolam • do not co-administer with efv, indinavir or lpv/r • use with caution with nvp lorazepam/oxazepam • no clinically significant interaction expected iv = intravenous; im = intramuscular; efv = efavirenz; rtv = ritonavir; lpv/r = lopinavir/ritonavir; nvp = nevirapine.   psychosis psychosis can occur at any time during the course of hiv disease. a psychotic syndrome includes at least 2 of the following symptoms: • delusions (fixed false beliefs) • hallucinations (auditory and other) • disorganised speech or thought • disorganised behaviour. psychotic disorders include schizophrenia, substance-induced psychosis, and psychosis secondary to a general medical condition such as hiv. reported rates of new-onset psychosis in hiv-positive patients range from 0.5% to 15%.12 it is essential to differentiate psychotic symptoms caused by delirium or encephalopathy, to identify and treat the underlying cause; although short-term symptomatic treatment may include low-dose antipsychotics. in delirium, the psychotic symptoms may occur in the context of fluctuating attention, sleep/wake disturbance and poor orientation. anti-psychotics importantly, with regard to prescribing antipsychotics, hiv-positive patients may be more susceptible to extra-pyramidal side-effects (epses), neuroleptic malignant syndrome and tardive dyskinesia. antipsychotics should always be initiated at the lowest effective dose and for the shortest period of time necessary. atypical or second-generation antipsychotics (sgas), where available, are generally preferred over first-generation antipsychotics, because of the decreased risk of epses. risperidone is the most widely studied atypical antipsychotic (or sga), and generally appears to be safe, although levels have been reported to increase with concurrent rtv use.2 , 13 an overlap in metabolic side-effect profiles, e.g. weight gain, dyslipidaemia and impaired glucose tolerance of the sgas and arvs (pis and nucleoside reverse transcriptase inhibitors (nrtis) in particular), complicates the risk-to-benefit equation.14 , 15 beside the interactions between risperidone and rtv, antipsychotics do not generally significantly inhibit or induce p-450 enzymes and can safely be added to haart regimens without causing toxicity or haart failure. theoretically, rtv may increase the serum levels of haloperidol; therefore, close monitoring of adverse effects is advised. the use of clozapine in hiv-positive patients is not routinely recommended, although it may be helpful in otherwise medically stable patients with higher cd4 cell counts.2 it is not known whether hiv-positive patients receiving clozapine have a greater risk of agranulocytosis; therefore, extremely close monitoring of white cell count is recommended. clozapine should only be initiated by a psychiatrist. the drug should be used with caution with lpv and rtv,8 , 9 as this could increase clozapine plasma concentrations, resulting in an increased risk of arrhythmias, seizures and haematological effects. a guide to initiating appropriate treatment is provided in fig. 1. benzodiazepines can be added in the initial stages for agitation or aggressive or disruptive behaviour. following diagnosis, a depot preparation can be given if adherence is likely to be a problem (or if the patient chooses it). a test dose should be considered. fig. 1. decision tree for initiating appropriate anti-psychotic treatment for psychosis in hiv-infected individuals. epse = extra-pyramidal side-effects; wcc = white cell count; lfts = liver function tests. *risperidone and quetiapine may be initiated only by a psychiatrist. † depot medications are not contra-indicated. consider a zuclopenthixol depot if clinically indicated; use a test dose of 50 100 mg, and repeat in 1 week. thereafter, the depot can be administered monthly. agitation aggressive or disruptive behaviour can occur in the context of psychiatric illness, physical illness, substance abuse or personality disorder. this can put staff and patients at risk. in general, it is important to attempt to examine the patient as thoroughly as possible before sedation to establish the underlying aggravating factors. it is also crucial to gain help from nursing staff, doctors and security staff where possible. the safety of the clinician, other patients and staff must be ensured. non-pharmacological methods should be attempted first, e.g. talking down, distracting, and reassuring the patient. the patient must not be threatened, as this often escalates the situation. oral treatment must be offered first and biperiden must be available if neuroleptics are introduced. drug interactions between benzodiazepines and arvs, and the approach to prescribing psychotropics in the agitated patient are summarised in tables 4 and 5, respectively. table 5. approach to prescribing psychotropics for the agitated patient step agent dose notes oral (first step after non-pharmacological treatment) lorazepam 1 2 mg (maximum 12 mg/day) repeat after 45 min to a maximum of 12 mg/day promethazine 20 25 mg daily im/iv (second step after oral measures have failed/are not possible) lorazepam 1 4 mg im have flumazenil to hand in case of respiratory depression haloperidol 5 mg im should be the last drug considered as incidence of acute dystonia is high diazepam 10 mg over 10 min iv (never im) repeat after 10 min if insufficient effect (up to 3 times)   ivi = intraveous; im = intramuscular. sleep disturbance a patient with insomnia may have difficulty with falling asleep, early-morning wakening and/or frequent waking during the night. before treating insomnia with drugs (table 6), it is important to consider and address underlying reversible causes such as depression, mania, pain, medication side-effects, substance abuse, and poor sleep hygiene. it must be ascertained whether the patient has realistic expectations of sleep and whether other medications are being given at appropriate times, e.g. stimulating drugs in the morning and sedating drugs at night. if medication is prescribed, then the lowest effective dose for short-term use only must be used, and patients must be advised of interactions with alcohol. table 6. available classes of psychotropics for insomnia* agent dose side-effects promethazine 10 25 mg can cause dry mouth and ‘hangover’ effect amitriptyline 10 25 mg useful in patients with peripheral neuropathy oxazepam 15 30 mg risk of dependency; prescribe no more than 14 days’ supply, unless prescribed by a psychiatrist or neurologist *refer to the text for arv drug interactions. pain pain symptoms are common in hiv infection and may be caused by painful neuropathy, headaches, cancers and secondary infections. pain disorders may be acute or chronic, with the latter often accompanied by depression, anxiety, and/or sleep disorders. in addition to analgesia use, psychotropics are frequently used to ameliorate pain symptoms: • tcas (e.g. amitriptyline at doses 25 75 mg at night): refer to the section on ‘depression’ for further information. other antidepressants should be considered if co-morbid depression is present. duloxetine is an antidepressant registered for chronic pain but is not on state code in sa. • anti-convulsants: carbamazepine is not advised because of interactions with arvs.8 , 9 gabapentin (lyrica) is used in chronic pain, but is not freely available. bipolar affective disorder/mania the essential characteristic of a bipolar mood disorder is one or more manic (or hypomanic) episodes with/without depressive episodes. mania is a recognised presentation in hiv-infected individuals. a manic episode, which is severe enough to impair functioning or warrant hospitalisation, is characterised by abnormal and persistently elevated, expansive or irritable mood, with: grandiosity; decreased need for sleep; talkativeness; flight of ideas/accelerated thoughts; distractibility; and/or increased involvement in pleasurable activities with potentially negative consequences, e.g. excessive buying or sexual indiscretions. mood stabilisation management is described in fig. 2. hiv-positive individuals may be more sensitive to the side-effects of mood-stabilisers, especially in the case of neurocognitive dysfunction. agents such as valproate, lamotrigine and lithium may be used cautiously, but carbamazepine (tegretol) should be avoided because of potential interactions with arvs (rtv, nvp and efv), and the risk of neutropenia.2 , 8 , 9 fig. 2. an approach to the hiv-infected patient with mania. haart = highly active antiretroviral therapy. valproate (epilim) is generally considered the first-line treatment, but there is an additive risk of fatty liver with didanosine (ddi), abacavir (abc), lamivudine (3tc), stavudine (d4t) and zidovudine (azt). it is important to monitor the patient’s liver function and adjust the dose accordingly, and it is advisable to test pre-treatment hepatic transaminases (ast/alt) and platelet levels. the potential for teratogenesis in women of child-bearing age remains a concern. some drug interactions do occur with lpv/r and lpv. valproate levels may be decreased with co-administratiokn of rtv. an increase in the dose of valproate may be requried. no significant interaction occurs with tenofovir (tdf), nvp or efv.8 , 9 lithium should be avoided in patients with dehydration and renal function impairment. the agent is not always well tolerated, and it may be advisable to limit its use to individuals with higher cd4 cell counts.2 careful monitoring of lithium levels is needed, usually 5 days after any dose adjustment, then monthly and 3 6-monthly thereafter. lamotrigine (lamictin) can also be considered and is mainly used for depression in bipolar disorder. in most state facilities its use needs to be initiated by a psychiatrist or neurologist and the dose needs to be increased gradually to avoid stevens-johnson syndrome. rtv decreases lamotrigine levels by about 50% due to induction of glucuronidation; therefore, an increased lamotrigine dosage may be required. additional treatments that can be used in manic episodes include antipsychotics (such as risperidone and quetiapine) and benzodiazepines. conclusion many patients with hiv/aids have co-occurring mental health conditions that affect art adherence, quality of life, morbidity and mortality. although close collaboration between physicians, psychiatrists and other members of the multidisciplinary healthcare team is the ideal, many clinicians work in settings where psychiatric support is not readily available. this article is intended to guide prescribing antipsychotics in these settings. additional resources • medicines information centre: http://www.mic.uct.ac.za; tel: +27 (0)21 406 6829 • hiv drug interactions: http://www.hiv-druginteractions.org • psychiatry services and resources in the western cape province: http://www.hivmentalhealth.co.za. references 1. querques j, freudenreich o. hiv and aids. in: stern ta, rosenbaum jf, fava m, et al., eds. massachusetts general hospital comprehensive clinical psychiatry. missouri, usa: mosby, elsevier, 2008. 1. querques j, freudenreich o. hiv and aids. in: stern ta, rosenbaum jf, fava m, et al., eds. massachusetts general hospital comprehensive clinical psychiatry. missouri, usa: mosby, elsevier, 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[http://dx.doi.org/10.1097/qad.0b013e32834171f8] 3. smurzynski m, wu k, letendre s, et al. effects of central nervous system antiretroviral penetration on cognitive functioning in the allrt cohort. aids 2011,25:357-365. [http://dx.doi.org/10.1097/qad.0b013e32834171f8] 4. nath a, sacktor n. influence of haart on persistence of hiv in the central nervous system. curr opin neurol 2006;19:358-361. 4. nath a, sacktor n. influence of haart on persistence of hiv in the central nervous system. curr opin neurol 2006;19:358-361. 5. freeman m, nkomo n, kafaar z, kelly k. mental disorder in people living with hiv/aids in south africa. south african journal of psychology 2007;38(3):489-500. 5. freeman m, nkomo n, kafaar z, kelly k. mental disorder in people living with hiv/aids in south africa. south african journal of psychology 2007;38(3):489-500. 6. kagee a, martin l. symptoms of depression and anxiety among a sample of south african patients living with hiv. aids care 2010;22(2):159-165. 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[http://dx.doi.org/10.1080.09540120903111445] 7. mills e, montori v, perri d, phillips e, koren g. natural health product-hiv drug interactions: a systematic review. int j std aids 2005;16(3):181-186. 7. mills e, montori v, perri d, phillips e, koren g. natural health product-hiv drug interactions: a systematic review. int j std aids 2005;16(3):181-186. 8. swart am, jones j. edl-antiretrovirals interactions table. cape town: medicines information centre, university of cape town, 2009. http://www.mic.uct.ac.za/?page_id=47 (accessed 30 june 2012). 8. swart am, jones j. edl-antiretrovirals interactions table. cape town: medicines information centre, university of cape town, 2009. http://www.mic.uct.ac.za/?page_id=47 (accessed 30 june 2012). 9. university of liverpool. hiv drug interactions. http://www.hiv-druginteractions.org (accessed 30 june 2012). 9. university of liverpool. hiv drug interactions. http://www.hiv-druginteractions.org (accessed 30 june 2012). 10. nash jr, nutt dj. pharmacotherapy of anxiety. handbook exp pharmacol 2005;169:469-501. 10. nash jr, nutt dj. pharmacotherapy of anxiety. handbook exp pharmacol 2005;169:469-501. 11. davidson j. use of benzodiazepines in social anxiety disorder, generalized anxiety disorder, and post traumatic stress disorder. j clin psychiatry 2004;65:29-33. 11. davidson j. use of benzodiazepines in social anxiety disorder, generalized anxiety disorder, and post traumatic stress disorder. j clin psychiatry 2004;65:29-33. 12. work group on hiv/aids, american psychiatric association. practice guideline for the treatment of patients with hiv/aids. am j psychiatry 2006;163:1349-1354. 12. work group on hiv/aids, american psychiatric association. practice guideline for the treatment of patients with hiv/aids. am j psychiatry 2006;163:1349-1354. 13. jover f, cuadrado j, andreu l, merino j. reversible coma caused by risperidone-ritonavir interaction. clin neuropharmacol 2002;25:251-253. 13. jover f, cuadrado j, andreu l, merino j. reversible coma caused by risperidone-ritonavir interaction. clin neuropharmacol 2002;25:251-253. 14. singh d, goodkin k. choice of antipsychotic in hiv infected patients. j clin psychiatry 2007;68(3):479-480. 15. singh d, goodkin k. psychopharmacological treatment response of hiv infected patients to antipsychotic medication. j clin psychiatry 2007;68(4):631-632. 14. singh d, goodkin k. choice of antipsychotic in hiv infected patients. j clin psychiatry 2007;68(3):479-480. 15. singh d, goodkin k. psychopharmacological treatment response of hiv infected patients to antipsychotic medication. j clin psychiatry 2007;68(4):631-632. hivmed_22(1)_2021_contents.indd http://www.sajhivmed.org.za open access table of contents original research estimating qualification and factors associated with third-line antiretroviral therapy referral in the western cape sadiyya sheik, bart willems southern african journal of hiv medicine | vol 22, no 1 | a1184 | 28 january 2021 original research profile of presentation of hiv-positive patients to an emergency department in johannesburg, south africa abdullah e. laher, willem d.f. venter, guy a. richards, fathima paruk southern african journal of hiv medicine | vol 22, no 1 | a1177 | 29 january 2021 original research uptake of the ithaka mobile application in johannesburg, south africa, for human immunodeficiency virus self-testing result reporting alex e. fischer, mothepane phatsoane, mohammed majam, luke shankland, musaed abrahams, naleni rhagnath, samanta t. lalla-edward southern african journal of hiv medicine | vol 22, no 1 | a1197 | 22 february 2021 original research nevirapine-induced stevens-johnson syndrome in children living with hiv in south africa jacques d. du toit, koot kotze, helene-mari van der westhuizen, taryn l. gaunt southern african journal of hiv medicine | vol 22, no 1 | a1182 | 23 february 2021 original research hiv-1/2 differentiation in a south african public laboratory rendani t. mafuyeka, lynne m. webber, piet becker, simnikiwe h. mayaphi southern african journal of hiv medicine | vol 22, no 1 | a1185 | 12 march 2021 original research the clinical and demographic profile of women living with hiv admitted to the acute unit at stikland psychiatric hospital jean-marie le roux, lina groenewald, karis moxley, liezl koen southern african journal of hiv medicine | vol 22, no 1 | a1159 | 16 march 2021 original research access to hiv services and viral load suppression among children during the 90-90-90 strategy implementation in south africa: a time series analysis juliet c.y. nyasulu, innocent maposa, bernard p. sikhakhane, himani pandya southern african journal of hiv medicine | vol 22, no 1 | a1187 | 17 march 2021 original research ocular manifestations of people living with hiv in tunisia dorsaf saadouli, lamia ammari, khaoula ben mansour, yosra yahyaoui, sameh aissa, el afrit mohamed ali, salem yahyaoui, hanene tiouri southern african journal of hiv medicine | vol 22, no 1 | a1193 | 19 march 2021 original research immune activation and arterial stiffness in lean adults with hiv on antiretroviral therapy longa kaluba, fastone goma, chris guure, sody munsaka, wilbroad mutale, douglas c. heimburger, theresa chikopela, john r. koethe southern african journal of hiv medicine | vol 22, no 1 | a1190 | 19 march 2021 81 90 98 105 110 117 125 133 138 scientific letter determination of lopinavir/ritonavir concentrations in four different oral solutions for the application of antiretroviral therapy in very young, hiv-1-infected children nils von hentig, carlo angioni, christoph königs southern african journal of hiv medicine | vol 22, no 1 | a1222 | 11 may 2021 guideline southern african hiv clinicians society gender-affirming healthcare guideline for south africa anastacia tomson, chris/tine mclachlan, camilla wattrus, kevin adams, ronald addinall, rutendo bothma, lauren jankelowitz, elliott kotze, zamasomi luvuno, nkanyiso madlala, savuka matyila, anil padavatan, mershen pillay, mmamontsheng d. rakumakoe, mathilde tomsonmyburgh, willem d.f. venter, elma de vries southern african journal of hiv medicine | vol 22, no 1 | a1299 | 28 september 2021 review article world aids day 2020: reflections on global and south african progress and continuing challenges yogan pillay, leigh johnson southern african journal of hiv medicine | vol 22, no 1 | a1205 | 10 march 2021 review article ten years of nurse-initiated antiretroviral treatment in south africa: a narrative review of enablers and barriers talitha crowley, elizabeth mokoka, nelouise geyer southern african journal of hiv medicine | vol 22, no 1 | a1196 | 11 march 2021 review article human immunodeficiency virus and mortality from coronavirus disease 2019: a systematic review and meta-analysis timotius i. hariyanto, jane rosalind, kevin christian, andree kurniawan southern african journal of hiv medicine | vol 22, no 1 | a1220 | 15 april 2021 review article continuous quality improvement in hiv and tb services at selected healthcare facilities in south africa sisanda gaga, nokuzola mqoqi, raymond chimatira, singilizwe moko, jude o. igumbor southern african journal of hiv medicine | vol 22, no 1 | a1202 | 12 may 2021 opinion paper hiv infection in eastern and southern africa: highest burden, largest challenges, greatest potential erica parker, melinda a. judge, eusebio macete, tacilta nhampossa, jienchi dorward, denise c. langa, caroline de schacht, aleny couto, paula vaz, marco vitoria, lucas molfino, rachel t. idowu, nilesh bhatt, denise naniche, peter n. le souëf southern african journal of hiv medicine | vol 22, no 1 | a1237 | 28 may 2021 original research administering human immunodeficiency virus post-exposure prophylaxis: challenges experienced by mothers in lusaka, zambia mildred lusaka, talitha crowley southern african journal of hiv medicine | vol 22, no 1 | a1183 | 27 january 2021 1 4 31 36 49 56 67 75 page i of iv table of contents vol 22, no 1 (2021) issn: 1608-9693 (print) | issn: 2078-6751 (online)southern african journal of hiv medicine http://www.sajhivmed.org.za open access table of contentspage ii of iv original research symptomatic gallstones and hiv in black south african women: changing trends of gallstone disease? suman mewa kinoo, savania nagiah, anil chuturgoon, bhugwan singh southern african journal of hiv medicine | vol 22, no 1 | a1208 | 25 march 2021 original research undisclosed exposure to antiretrovirals prior to treatment initiation: an exploratory analysis lufuno g. mavhandu-ramarumo, lisa a.m. tambe, nontokozo d. matume, david katerere, pascal o. bessong southern african journal of hiv medicine | vol 22, no 1 | a1200 | 08 april 2021 original research urine lipoarabinomannan for rapid tuberculosis diagnosis in hiv-infected adult outpatients in khayelitsha bianca sossen, amanda ryan, joanna bielawski, riana greyling, gillian matthews, sheetal hurribunce-james, rené goliath, judy caldwell, graeme meintjes southern african journal of hiv medicine | vol 22, no 1 | a1226 | 26 april 2021 original research pharmacogenetics of tenofovir and emtricitabine penetration into cerebrospinal fluid eric h. decloedt, phumla z. sinxadi, lubbe wiesner, john a. joska, david w. haas, gary maartens southern african journal of hiv medicine | vol 22, no 1 | a1206 | 28 april 2021 original research prevalence of incidental premature cardiac calcifications in an hiv-infected south african population using conventional computed tomography chest radiography luize muller, tanusha sewchuran, miranda durand southern african journal of hiv medicine | vol 22, no 1 | a1241 | 13 may 2021 original research indicator-focussed technical assistance in south africa’s hiv programme: a stepped-wedge evaluation geoffrey a. jobson, jean railton, barry mutasa, lucy ranoto, christine maluleke, james mcintyre, helen struthers, remco peters southern african journal of hiv medicine | vol 22, no 1 | a1229 | 15 june 2021 original research incidence of cardiometabolic diseases in a lesotho hiv cohort: evidence for policy decision-making motlalepula sebilo, neo r.t. ledibane, simbarashe takuva southern african journal of hiv medicine | vol 22, no 1 | a1246 | 28 june 2021 original research clinical, radiological, and laboratory predictors of a positive urine lipoarabinomannan test in sputum-scarce and sputum-negative patients with hiv-associated tuberculosis in two johannesburg hospitals lior chernick, ismail s. kalla, michelle venter southern african journal of hiv medicine | vol 22, no 1 | a1234 | 08 july 2021 original research bone outcomes in virally suppressed youth with hiv switching to tenofovir disoproxil fumarate kate braithwaite, tristan d. mcpherson, yanhan shen, stephen arpadi, stephanie shiau, gillian sorour, karl-günter technau, michael t. yin southern african journal of hiv medicine | vol 22, no 1 | a1243 | 05 august 2021 147 154 164 171 195 203 210 217 229 original research predictors of impaired pulmonary function in people living with hiv in an urban african setting sarah e. van riel, kerstin klipstein-grobusch, roos e. barth, diederick e. grobbee, charles feldman, erica shaddock, sarah l. stacey, willem d.f. venter, alinda g. vos southern african journal of hiv medicine | vol 22, no 1 | a1252 | 17 august 2021 original research derangement of protein s and c4b-binding protein levels as acquired thrombophilia in hiv-infected adult nigerians fatai o. bello, alani s. akanmu, titilope a. adeyemo, bukunmi m. idowu, prosper okonkwo, phyllis j. kanki southern african journal of hiv medicine | vol 22, no 1 | a1253 | 23 august 2021 original research a case series of emtricitabine-induced pure red cell aplasia nithendra manickchund, camille du plessis, melanie-anne a. john, thandekile c. manzini, bernadett i. gosnell, mahomed-yunus s. moosa southern african journal of hiv medicine | vol 22, no 1 | a1271 | 30 august 2021 original research impact of a delayed diagnosis of vulvar cancer and its association with hiv infection: a 4-year review at a tertiary hospital in kwazulu-natal, south africa ramakhosana s. hlapane, thandekile l. khumalo, bongumusa s. makhathini, jagidesa moodley southern african journal of hiv medicine | vol 22, no 1 | a1272 | 08 september 2021 original research the association between serum vitamin d and body composition in south african hiv-infected women samuel mwango, janet carboo, christa ellis, marike cockeran, carina m.c. mels, herculina s. kruger southern african journal of hiv medicine | vol 22, no 1 | a1284 | 30 september 2021 original research strength exercise for balance and gait in hiv-associated distal symmetrical polyneuropathy: a randomised controlled trial abdulsalam m. yakasai, sonill maharaj, musa s. danazumi southern african journal of hiv medicine | vol 22, no 1 | a1268 | 05 october 2021 original research earlier antiretroviral initiation is independently associated with better arterial stiffness in children living with perinatally acquired hiv with sustained viral suppression in mozambique igor s. dobe, ana o. mocumbi, noorjean majid, birhanu ayele, sara h. browne, steve innes southern african journal of hiv medicine | vol 22, no 1 | a1282 | 14 october 2021 original research arterial stiffness is associated with oxidative stress and endothelial activation among persons with treated hiv in zambia theresa chikopela, fastone goma, longa kaluba, wilbroad mutale, chris guure, douglas c. heimburger, john r. koethe southern african journal of hiv medicine | vol 22, no 1 | a1298 | 28 october 2021 original research group counselling for adherence support among young people failing first-line antiretroviral therapy in zimbabwe bahati kasimonje, tinei shamu, tinashe mudzviti, ruedi luethy southern african journal of hiv medicine | vol 22, no 1 | a1292 | 29 october 2021 237 245 252 256 262 273 280 286 299 http://www.sajhivmed.org.za open access table of contentspage iii of iv original research the influence of hiv infection and antiretroviral treatment on pulmonary function in individuals in an urban setting in sub-saharan africa oda e. van den berg, erica j. shaddock, sarah l. stacey, charles feldman, roos e. barth, diederick e. grobbee, willem d.f. venter, kerstin klipstein-grobusch, alinda g. vos southern african journal of hiv medicine | vol 22, no 1 | a1312 | 15 november 2021 original research evaluation of an sms-based mhealth intervention to enhance early infant diagnosis follow-up testing and assessment of postnatal prophylaxis anele dube-pule, brian c. zanoni, cathy connolly, majahonkhe shabangu, moherndran archary southern african journal of hiv medicine | vol 22, no 1 | a1301 | 24 november 2021 original research physical development and mental health in south african perinatally hiv-positive adolescents on antiretroviral therapy and their caregivers with and without household food insecurity sarah heany, nicole phillips, landon myer, heather zar, dan stein, jacqueline hoare southern african journal of hiv medicine | vol 22, no 1 | a1316 | 15 december 2021 case report a trio of infectious diseases and pulmonary embolism: a developing world’s reality somasundram pillay, nombulelo magula southern african journal of hiv medicine | vol 22, no 1 | a1192 | 28 january 2021 306 314 322 329 case report false-positive rapid diagnostic tests in paediatric and obstetric patients in south africa josephine keal, ahmad h. mazanderani, nicola van dongen, gillian sorour, karl-gunter technau southern african journal of hiv medicine | vol 22, no 1 | a1186 | 29 january 2021 clinical images skin and mucosal manifestations of an aids-related systemic mycosis michael t. boswell, liam robinson, nelesh govender southern african journal of hiv medicine | vol 22, no 1 | a1198 | 28 january 2021 clinical images giant bacillary angiomatosis jeremy nel, prudence ive, carolina nel southern african journal of hiv medicine | vol 22, no 1 | a1257 | 20 july 2021 clinical images cutaneous lesions in the setting of disseminated cryptococcus neoformans infection mithra john, stacey norsworthy, lauren richards southern african journal of hiv medicine | vol 22, no 1 | a1315 | 29 october 2021 333 337 339 341 editorial celebrating 21 years and introducing the 21st anniversary issue yunus moosa, lauren jankelowitz southern african journal of hiv medicine | vol 22, no 1 | a1317 | 15 october 2021 editorial southern african journal of hiv medicine august 2021 david c. spencer southern african journal of hiv medicine | vol 22, no 1 | a1309 | 15 october 2021 opinion paper establishing targets for advanced hiv disease: a call to action david b. meya, lillian tugume, vennie nabitaka, proscovia namuwenge, sam phiri, rita oladele, bilkisu jibrin, mojisola mobolaji-bello, cecilia kanyama, werner maokola, sayoki mfinanga, cordelia katureebe, ikechukwu amamilo, brian ngwatu, joseph n. jarvis, thomas s. harrison, amir shroufi, radha rajasingham, david boulware, nelesh p. govender, angela loyse southern african journal of hiv medicine | vol 22, no 1 | a1266 | 10 august 2021 opinion paper importance of global communication to combat global pandemics: lessons from the hiv online provider education programme efeose a. airewele, henry sunpath, mahomed-yunus s. moosa, rajesh t. gandhi southern african journal of hiv medicine | vol 22, no 1 | a1281 | 31 august 2021 343 347 353 358 vol 22, no 1 (2021) special collection: the 95-95-95% unaids targets for 2030: are these goals achievable in southern africa? opinion paper optimised paediatric antiretroviral treatment to achieve the 95-95-95 goals moherndran archary, riana van zyl, nosisa sipambo, gillian sorour southern african journal of hiv medicine | vol 22, no 1 | a1278 | 01 september 2021 opinion paper looking back at paediatric hiv treatment in south africa. my, how we have grown! leon j. levin, juliet l. horak, james nuttall southern african journal of hiv medicine | vol 22, no 1 | a1283 | 16 september 2021 original research geographical variation in hiv testing in south africa: evidence from the 2017 national household hiv survey sean jooste, musawenkosi mabaso, myra taylor, alicia north, yolande shean, leickness c. simbayi, tarylee reddy, leonard mwandingi, tenielle schmidt, portia nevhungoni, samuel manda, khangelani zuma southern african journal of hiv medicine | vol 22, no 1 | a1273 | 31 august 2021 original research five years after treat all implementation: botswana’s hiv response and future directions in the era of covid-19 keith jefferis, ava avalos, heston phillips, mpho mmelesi, dinah ramaabya, bornapate nkomo, charles muthoga, joseph n. jarvis, siphiwe ratladi, robert selato, john stover southern african journal of hiv medicine | vol 22, no 1 | a1275 | 15 october 2021 362 366 369 378 http://www.sajhivmed.org.za open access table of contents correction erratum: unexpected low frequency of respiratory symptoms in an hiv-positive urban sub-saharan population compared to an hiv-negative control group maren kummerow, erica j. shaddock, kerstin klipstein-grobusch, roos b. barth, diederick e. grobbee, w.d. francois venter, charles feldman, alinda vos southern african journal of hiv medicine | vol 22, no 1 | a1180 | 19 april 2021 389 correction corrigendum: southern african guidelines on the safe, easy and effective use of pre-exposure prophylaxis: 2020 linda-gail bekker, benjamin brown, dvora joseph-davey, kathrine gill, michelle moorhouse, sinead delany-moretlwe, landon myer, catherine orrell, kevin rebe, w.d. francois venter, carole l. wallis southern african journal of hiv medicine | vol 22, no 1 | a1295 | 08 december 2021 reviewer acknowledgement southern african journal of hiv medicine | vol 22, no 1 | a1357 | 21 december 2021 390 391 page iv of iv abstract introduction research methods and design results discussion conclusion acknowledgements references appendix 1 about the author(s) anisca louwrens hypertension in africa research team (hart), school for physiology, nutrition and consumer science, faculty of health sciences, north-west university, potchefstroom, south africa carla m.t. fourie hypertension in africa research team (hart), school for physiology, nutrition and consumer science, faculty of health sciences, north-west university, potchefstroom, south africa mrc research unit for hypertension and cardiovascular disease, faculty of health sciences, north-west university, potchefstroom, south africa shani botha-le roux hypertension in africa research team (hart), school for physiology, nutrition and consumer science, faculty of health sciences, north-west university, potchefstroom, south africa mrc research unit for hypertension and cardiovascular disease, faculty of health sciences, north-west university, potchefstroom, south africa yolandi breet hypertension in africa research team (hart), school for physiology, nutrition and consumer science, faculty of health sciences, north-west university, potchefstroom, south africa mrc research unit for hypertension and cardiovascular disease, faculty of health sciences, north-west university, potchefstroom, south africa citation louwrens a, fourie cmt, botha-le roux s, breet y. age-related differences in the vascular function and structure of south africans living with hiv. s afr j hiv med. 2022;23(1), a1335. https://doi.org/10.4102/sajhivmed.23i1.1335 review article age-related differences in the vascular function and structure of south africans living with hiv anisca louwrens, carla m.t. fourie, shani botha-le roux, yolandi breet received: 18 oct. 2021; accepted: 26 nov. 2021; published: 24 feb. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: as the life expectancy of people living with the hiv increases because of antiretroviral treatment (art), their risk for vascular co-morbidities and early vascular ageing (eva) also increases. objective: we aimed to investigate whether hiv infection relates to vascular structure and function in black south african adults and whether this relationship is age dependent. method: this cross-sectional study carried out in urban and rural areas of north west province, south africa, included 572 ageand sex-matched people living with hiv (plwh) and without hiv. participants from the endoafrica study and pure study were stratified according to tertiles of age. measures of vascular structure (carotid intima-media thickness) and function (carotid-femoral pulse wave velocity, central systolic blood pressure, central pulse pressure and pulse pressure amplification) were determined. results: blood pressure measures were lower in plwh compared with their controls (all p ≤ 0.001), especially in the younger and middle-aged groups (all p ≤ 0.031), whilst vascular measures did not differ (all p ≥ 0.611). in multivariate linear regression analyses, vascular measures were not associated with a hivpositive status in either the total or any of the age groups. conclusion: black south africans living with hiv have a less adverse blood pressure profile than their counterparts without hiv. the hiv-positive status was not associated with measures of vascular structure or function in any age group. the results suggest that hiv does not contribute to eva in this population; however, further longitudinal investigation is warranted. keywords: arterial stiffness; carotid intima-media thickness; antiretroviral treatment; early vascular ageing; multi-morbidity. introduction the hiv epidemic is a global health problem with south africa contributing a large number of people living with hiv (plwh); of the 38 million plwh worldwide, 7.7 million reside in south africa.1 although communicable diseases, including hiv, were the leading cause of death in 2012,2 the aetiology of mortality in sub-saharan africa (ssa) has shifted to a combination of communicable and non-communicable diseases since then.3 approximately 69.4% of the south african population older than 40 years are battling multimorbidity, which is defined as two or more simultaneously existing chronic diseases.4 multimorbidity adversely affects vascular health, causing acceleration in the vascular ageing process.5,6,7 physiological, vascular ageing occurs with the progression of age and is a gradual and continuous process, characterised by structural and/or mechanical changes within the vessel wall.8,9 these mechanical and structural alterations that occur with vascular ageing may result in arterial stiffness and an increased carotid intima-media thickness (cimt),10 which can affect some individuals prematurely, a term coined early vascular ageing (eva).11 the prevalence of eva causes an accelerated trajectory of prematurely developing hypertension, subclinical cardiovascular damage and cvd.11 an adverse transition from physiological vascular ageing to eva occurs with exposure to risk factors, such as hiv,12,13 and factors commonly related to the disease, namely hypertension,14 dyslipidaemia,15 chronic low-grade inflammation16 and oxidative stress. data on eva in plwh, especially in ssa, are scant as the majority of studies have been carried out on hiv-1 subtype b. however, a previous study carried out by our group found an indication of accelerated vascular ageing in older, never treated hiv-positive south africans (aged > 50 years), as well as probable early atherosclerosis and endothelial dysfunction.17 diabetes mellitus18 and dysglycaemia,19 as well as factors related to an unhealthy lifestyle,20,21,22 also lead to acceleration of the vascular ageing process.23 vascular comorbidities, such as arterial stiffness and atherosclerosis,5,6 as well as cardiometabolic disturbances,24,25 become increasingly evident with the prolonged life expectancy of plwh because of the effectiveness of antiretroviral treatment (art).26 hanna et al. indicated that the effect of hiv on the vasculature may differ through the lifespan of plwh.27 hiv and/or art-related vascular alterations may contribute to eva.8,9,10,28 however, there is a lack of literature regarding the development of eva in plwh from south africa, where the vast majority are infected with hiv type-1 subtype c phenotype.29 therefore, we investigated whether hiv infection relates to vascular structure and function in south african adults on first-line art at different ages. research methods and design setting and study population this study includes data of participants residing in north west province of south africa who participated in both the endoafrica study (vascular endothelial dysfunction: the putative interface of emerging cardiovascular risk factors affecting populations living with and without hiv in ssa) and the prospective urban and rural epidemiology (pure) study. data from the endoafrica study were collected from 2017 to 2018, and data collection for the pure study took place in 2015. both the studies were designed to determine the risk of developing cardiovascular disease amongst south africans living with and without hiv. both studies were previously described in more detail elsewhere.30,31 the endoafrica study recruited participants from seven local clinics in and around potchefstroom; the participants for the pure study were recruited from urban and rural communities, which include potchefstroom (urban), ganyesa and tlakgameng (rural). participants in the endoafrica study were 18–60 years and in the pure study were 42–88 years old. for this study, we included 286 plwh and 286 hiv-free participants (control group). the participants in the group with hiv were matched for age and sex with those who were hiv free (figure 1). the plwh using treatment received first-line fixed dose combination art.26 the exclusion criteria for both studies include plwh using secondand third-line art, individuals who refused hiv testing or to provide a blood sample, women who were pregnant or less than three months post-partum. additional exclusions were made for missing data of the main variables and/or an unknown hiv status. figure 1: study population of the endoafrica and the pure studies. questionnaire and anthropometric measurements a standardised questionnaire provided information regarding the age, sex, lifestyle patterns (which included tobacco use and alcohol consumption) and medication use in both studies. anthropometric measurements were performed according to the standardised methods of the international society for the advancement of kinanthropometry.32 for both studies, height (stadiometer, seca, hamburg, germany [endoafrica]; stadiometer, leicester height measure, seca, birmingham, united kingdom [uk] [pure]), weight (flat scale, seca hamburg, germany [endoafrica]; precision health scale, a & d company, japan [pure]) and waist circumference (wc) (lufkin steel anthropometric tape, w606pm, lufkin, apex, united states [us] [endoafrica]; steel tape, lufkin, cooper tools, apex nc, us [pure]) were measured. body mass index (bmi) was calculated according to international standards. cardiovascular measurements the brachial blood pressure, including systolic blood pressure (sbp), diastolic blood pressure (dbp), and heart rate of each seated participant were taken twice after 10 min of rest (omron m6 automatic digital blood pressure monitor, omron healthcare, kyoto, japan). the final measurement was used in subsequent analyses. we identified participants as hypertensive if sbp ≥ 140 mmhg and/or dbp ≥ 90 mmhg33 and/or if they used anti-hypertensive medication. mean arterial pressure (map) was calculated, map = (sbp(2xdbp))/3. central sbp (csbp), central pulse pressure (cpp) and carotid-femoral pulse wave velocity (cfpwv) were measured by arterial waveform analyses (sphygmocor® xcel system, atcor medical pty. ltd, sydney, australia). the transit-distance method was used to measure cfpwv along the descending carotid-femoral artery. the 80% rule was applied for the calculation of the distance used.34 the cfpwv measurement was performed twice and repeated a third time if the two measurements differed by more than 3 m/s. the average was used for further analyses. pulse pressure amplification (ppa) was defined as the ratio of the amplitude of the pulse pressure between a distal and proximal location. carotid intima-media thickness was measured in the pure (sonosite micromaxx ultrasound system, sonosite, inc., bothel, wa, us) and endoafrica (general electric vivid e9, ge vingmed ultrasound a/s, horten, norway) studies. digitalised images were analysed with carotid vessel analyser automated software (vascular research tools 6, medical imageing applications, coralville, iowa, us) in the endoafrica study and with artery measurements systems software (i version 1.139, chalmers university of technology, gothenburg. sweden) in the pure study. blood sampling and biochemical analyses blood samples were collected, centrifuged and aliquoted according to standardised methods, and were stored in −80 c bio-freezers for future analyses. samples collected from the rural site during the pure study were prepared at the on-site laboratory and immediately stored on dry ice (−18 °c) for a maximum of 5 days. these samples were then transported to the laboratory and stored at −80 °c. in both studies, the cobas integra® 400 roche® clinical system (roche diagnostics, indianapolis, in, us) was used to determine glucose, total cholesterol (tc), high-density lipoprotein (hdl), low-density lipoprotein (ldl) and triglyceride levels using an enzymatic colourimetric method. high-sensitivity c-reactive protein (crp) was analysed with the particle-enhanced turbidimetric assay method and gamma-glutamyl transferase (ggt) with the enzymatic colourimetric assay method. glycated haemoglobin (hba1c) analyses were carried out with ethylenediamine tetraacetic acid whole blood samples in the endoafrica (turbidimetric inhibition immunoassay; cobus integra® 400plus, roche, switzerland) and pure (ion-exchange high-performance liquid chromatography method; d-10 haemoglobin testing system from bio-rad #220-0101) studies. in the endoafrica study, plasma samples were sent to the national health laboratory services (nhls) to determine the cd4+ cell count (beckman coulter® epics® xltm flow cytometer, gmi inc., fullerton, ca, us). the finger-prick blood and a point-of-care device (pimatm cd4, alere, jena, germany) with the fixed volume cytometry analysis were used in the pure study. hiv testing and counselling pre-counselling was given to each participant in both the endoafrica and pure studies before hiv testing was performed with the first-response rapid hiv test (premier medical corporation limited, daman, india). positive hiv results were confirmed by the sd boline hiv 1 / 2 3.0 (standard diagnostics, inc, korea) rapid test in the endoafrica study and the abon (biopharm corporation limited hanyzhou, china) in the pure study. statistical analyses ibm® spss® statistics, version 26.0 (ibm corporation, armonk, ny, usa) software was used for data analyses. in order to assess whether the data were normally distributed, we used graphical inspections (histograms and q-q plots) and numerically inspected the skewness and kurtosis of variables. continuous data with a normal distribution are presented as arithmetic mean ± standard deviation and categorical data as proportions. for non-normally distributed data, we performed non-parametric tests and reported the median and interquartile ranges. the study population was stratified according to tertiles of age. the tertile ranges of the age groups for plwh and without hiv, respectively, were as follows: younger ages were classified as 18–47 years versus 19–48 years, middle as 48–53 years versus 49–53 years, and older as 54–71 years versus 54–71 years. differences between the groups were determined with independent t-tests or mann-whitney u-tests and chi-square tests. correlation analyses included pearson or spearman rank tests. in order to test for independent associations between the main outcome variables (cfpwv, ppa, cpp, csbp and cimt) and hiv infection, we performed multiple regression analyses (with the enter method) in the total group, as well as stratified according to age tertile groups. all the models included hiv status, sex, bmi, tc, ggt, hba1c, crp, tobacco use, art use and anti-hypertensive medication use. mean arterial pressure was additionally included in the models, with cfpwv, cimt and ppa as the dependent variables and heart rate in the model with ppa as the dependent variable. adjustments for each dependent variable were made as follows: cfpwv (sex and map), cimt (sex and map), csbp (sex), cpp (sex) and ppa (sex, map, heart rate and height). ethical considerations this study complies with the requirements of the declaration of helsinki, and the health research ethics committee of the north-west university approved the endoafrica study (nwu-00045-15-a1), the pure study (nwu-00016-10-a1), as well as this study (nwu-00367-20-a1). all procedures were explained to the participants before any measurements were made, and all participants gave written informed consent. results the characteristics of the study population are presented in table 1. the plwh and without hiv were matched for age (p = 0.098) and sex (p = 1.000), and their locality was comparable (p = 0.073). people living with hiv had a lower waist-to-height ratio (wthr) and bmi (both p < 0.001) compared with the hiv-free group. with regard to cardiovascular measurements, all brachial blood pressures were lower in plwh (all p < 0.049); however, no differences were found in either cfpwv, cimt or ppa (all p ≥ 0.204). when comparing biochemical markers, ggt was higher in those with hiv (p < 0.001), whilst levels of glucose, glycated haemoglobin, tc, triglycerides and ldl-cholesterol (p ≤ 0.049) were lower. the cd4+ count was found to be 525.5 cells/µl for plwh. both tobacco use and alcohol consumption (p ≤ 0.014) were more frequent in plwh. table 1: characteristics of the study population (n = 286). in figure 2 and appendix table 1-a1, we compared the adjusted differences in vascular measures (cfpwv, cimt, csbp, cpp and ppa) between the groups with and without hiv in different age tertiles (on the left), as well as across different age groups within the hiv and hiv-free groups, respectively (on the right). plwh in the younger and middle age groups had lower csbp (both p ≤ 0.031) and in all the age groups had lower cpp (all p ≤ 0.027) than those without hiv. carotid-femoral pulse wave velocity, cimt, csbp and cpp increased, whilst ppa decreased across increased tertiles of age in both the hiv and hiv-free groups (all p ≤ 0.028). figure 2: adjusted differences in vascular measures (cfpwv, cimt, csbp, cpp and ppa) between people living with hiv (hiv+) and without hiv (hiv–) according to tertiles of age (on the left), as well as across different age tertile groups within the respective hiv status groups (on the right). confounders included for each dependent variable: cfpwv (sex and mean arterial pressure), cimt (sex and mean arterial pressure), csbp (sex), cpp (sex) and ppa (sex, mean arterial pressure, heart rate and height). we further determined whether vascular measures associated with the hiv status in the total group and in the respective age groups (figure 3 and appendix table 2-a1), whilst taking cardiovascular risk factors and art into account. no associations were observed between any of the vascular measures and hiv infection as the main independent variable (all p ≥ 0.162). figure 3: associations between vascular measures and hiv status in the total group and in different age tertile groups. models that were not significant (carotid imt – middle and older group; central sbp – older group) were not included. confounders included in all the models: hiv status, sex, body mass index, total cholesterol, gamma-glutamyl transferase, glycated haemoglobin, c-reactive protein, tobacco use, antiretroviral treatment use and anti-hypertensive medication use. mean arterial pressure was additionally included in the models, with cfpwv, cimt and ppa as the dependent variables. heart rate was also included in the model, with ppa as the dependent variable. discussion this study found that in a population of plwh in south africa, brachial blood pressure measurements (csbp and cpp) were lower in younger and middle age groups and vascular markers (cfpwv, cimt and ppa) were comparable with the hiv-uninfected population. in addition, we showed a lack of association between hiv infection and any of the vascular markers in any age group. to the best of our knowledge, this was the first study to investigate age-related differences in the vascular structure and function between south africans living with hiv and their age and sex-matched controls without hiv. we also determined whether an association between the hiv-positive status and these vascular measures exists within different age groups. in addressing our first objective, we found that the group with hiv presented with less adverse central and brachial blood pressure profiles compared with their controls. in addition, the age-related deterioration of the vascular profile in the group with hiv was not as pronounced as expected, with csbp being lower in the younger and middle age groups when compared with the group without hiv. moreover, cpp was lower in plwh in all the age groups when compared with their hiv-free counterparts. data on the vascular profile of plwh are controversial, and studies on this topic in a ssa context are scant. previous studies both contradict35,36,37,38 and correspond30,39,40,41 to the study findings. contrary to the study results, an italian study in age-matched plwh and individuals without hiv older than 18 years showed higher csbp in those with hiv, which may have been attributed to renal damage.35 msoka and colleagues concluded in a meta-analysis that cimt, an early marker for atherosclerosis, was higher in plwh compared with their controls in cross-sectional studies.37 the increased cimt in the plwh was associated with elevated levels of crp and an adverse lipid profile.37 high crp levels and an adverse lipid profile commonly occur in immunosuppressive states, such as hiv, where chronic low-grade systemic inflammation is known to prevail.38 similar to our results, a narrative review of studies conducted in ssa concluded that treated plwh had lower sbp and dbp, and hypertension compared with art-naïve or individuals without hiv.39 we recently investigated the cardiovascular profile of plwh and individuals without hiv in the endoafrica study, with a mean age of 42 years.30 the cardiovascular profile of these individuals included vascular markers similar to those in this current study, such as cfpwv, cimt, csbp and cpp.30 neither the cardiovascular profile nor the crp levels of those with hiv and participants without hiv in the endoafrica study differed,30 supporting the current findings that eva was not evident in this study population with hiv. in another cross-sectional study, no increase in arterial stiffness, atherosclerosis or inflammation was found in plwh, despite the presence of endothelial activation, when compared with art-naïve or control groups.41 considering the effect of art on metabolic markers, it was reported that the lipid profile of chinese plwh who used efavirenz-based art was less adverse than those receiving lopinavir or ritonavir-based art.42 the more favourable lipid profile of the group with hiv was also found in this south african study population using efavirenz-based art. although there was no obvious effect on ldl-cholesterol in the chinese study,42 this study found lower levels of ldl-cholesterol, tc and triglycerides in the hiv group (table 1). this study’s less adverse glycaemic profile supports the rising notion that the cardiovascular profile of plwh is less detrimental compared with their uninfected counterparts.43 these results support the findings of shet et al., which showed better treatment outcomes for the hiv subtype c phenotype in south africa, despite a higher baseline viral load, compared with other subtypes of hiv.44 upon investigating whether an association exists between hiv infection and measures of vascular structure and function in different age groups, no significant results were found. in contrast with the study findings, a systematic review of studies conducted in ssa populations showed a positive association between hiv infection and atherosclerosis.45 it is known that atherosclerosis develops as a result of inflammation,46 and it is further suggested that the progression thereof is a plausible link to vasculopathy47 and eva.28,48 however, dillon et al. associated hiv infection with a lower sbp, dbp and bmi in a systematic review and meta-analysis on studies conducted in ssa.40 in our study population living with hiv, we found a lower csbp and bmi compared with their counterparts without hiv in all the three age groups. however, we found no associations between csbp and hiv infection in any of the age groups. the findings from previous studies, which found no association between hiv and arterial stiffness,49 hypertension36 or atherosclerosis,50 are in line with the study findings. monteiro et al.49 reported a higher frequency of hypertension in the uninfected controls, which was also evident in this study. as the carotid-femoral segment of the vasculature is highly sensitive to increases in blood pressure,51 the lower prevalence of hypertension in plwh in this study could explain, at least in part, the absence of association of arterial stiffness with hiv status. furthermore, plwh using art tend to develop cardiometabolic disturbances, resembling those found in the metabolic syndrome, such as lipodystrophy,52 dyslipidaemia53 and hyperglycaemia,54 none of which was encountered in the group with hiv of whom 76% received art in this study. the results on the association of hiv with vascular markers should be interpreted in light of the fact that we did not have art adherence or viral load data. this cross-sectional study design limited us to infer cause and effect, and the study results need to be confirmed in a larger cohort. to the best of our knowledge, this was the first study to investigate the effect of age on the association between vascular structure and function and hiv infection in a south african population. conclusion the results of this study revealed that hiv-positive status did not associate with measures of vascular structure and function in any of the age groups. people living with hiv did not have a worse cardiovascular profile, and eva was not evident in these people compared with those without hiv. the study findings warrant further longitudinal investigation that may observe individual vascular changes over time to determine whether south africans living with hiv have an increased risk of developing cvd. acknowledgements the authors acknowledge all participants of both the endoafrica and pure studies, as well as the students, support staff and researchers at the hypertension research and training clinic in the north-west university, south africa. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions a.l. contributed to data acquisition, drafted the manuscript, performed statistical analyses and interpreted the results. c.m.t.f., s.b.-l.r. and y.b. contributed to conceptualisation and the acquisition, analyses, and interpretation of the data. all authors critically revised the manuscript, gave input and final approval, and agreed to be accountable for all aspects of the work in order to ensure integrity and accuracy. funding information financial support for the endoafrica study conducted in north west province was received from the department of science and technology in south africa (contract number dst/con 0133/2016), and for the pure study from sanpad (south africa – netherlands research programme on alternatives in development, gun number 08/15), phri (population health research institute), the medical research council of south africa, the north-west university, roche diagnostics and the south african national research foundation (nrf, gun numbers fa2006040700010 and 2069139). data availability the data sets used and/or analysed during the current study are available from the corresponding author, y.b., on reasonable request. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references unaids. south africa 2019: 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atherosclerosis risk factor in hiv-infected women and men. aids (london, england). 2008;22(13):1615. https://doi.org/10.1097/qad.0b013e328300581d safar me, levy bi, struijker-boudier h. current perspectives on arterial stiffness and pulse pressure in hypertension and cardiovascular diseases. circulation. 2003;107(22):2864–2869. https://doi.org/10.1161/01.cir.0000069826.36125.b4 alikhani a, morin h, matte s, et al. association between lipodystrophy and length of exposure to arts in adult hiv-1 infected patients in montreal. bmc infect dis. 2019;19(1):820. https://doi.org/10.1186/s12879-019-4446-9 bastard j-p, couffignal c, fellahi s, et al. diabetes and dyslipidaemia are associated with oxidative stress independently of inflammation in long-term antiretroviral-treated hiv-infected patients. diabetes metab. 2019;45(6):573–581. https://doi.org/10.1016/j.diabet.2019.02.008 de wit s, sabin c, weber r, et al. data collection on adverse events of anti-hiv drugs (d: a: d) study. incidence and risk factors for new-onset diabetes in hiv-infected patients: the data collection on adverse events of anti-hiv drugs (d: a: d) study. diabetes care. 2008;31(6):1224–1229. https://doi.org/10.2337/dc07-2013 appendix 1 table 1-a1: characteristics of plwh and without hiv, stratified by age tertile groups. table 1-a1 (continues...): characteristics of plwh and without hiv, stratified by age tertile groups. table 2-a1: multiple regression analyses between vascular measures and hiv status in the total group and in different age tertile groups. table 2-a1 (continues...): multiple regression analyses between vascular measures and hiv status in the total group and in different age tertile groups. abstract introduction case discussion management dilemma conclusion acknowledgements references about the author(s) midhun t. john department of internal medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa michelle venter department of infectious diseases, faculty of health sciences, university of the witwatersrand, johannesburg, south africa jenifer vaughan department of clinical haematology, faculty of health sciences, university of the witwatersrand, johannesburg, south africa marianne black department of microbiology, faculty of health sciences, university of the witwatersrand, johannesburg, south africa daniel prince department of radiology, faculty of health sciences, university of the witwatersrand, johannesburg, south africa aishwarya m. luke department of internal medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa mithra john department of internal medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa citation john mt, venter m, vaughan m, et al. multiple opportunistic infections (pulmonary tuberculosis, mycobacterium avium complex and parvovirus b19) in a single patient. s afr j hiv med. 2022;23(1), a1319. https://doi.org/10.4102/sajhivmed.v23i1.1319 case report multiple opportunistic infections (pulmonary tuberculosis, mycobacterium avium complex and parvovirus b19) in a single patient midhun t. john, michelle venter, jenifer vaughan, marianne black, daniel prince, aishwarya m. luke, mithra john received: 21 sept. 2021; accepted: 17 nov. 2021; published: 25 jan. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract introduction: hiv infection is a common disease in the south african population. the virus can lead to the development of many opportunistic infections. this case study examines co-infection with three opportunistic infections and the need for clinical suspicion of infections in our hiv population. patient presentation: a 36-year-old unemployed female residing in soweto, johannesburg, presented at chris hani baragwanath hospital (chbah). she was hiv positive, defaulting treatment, with no other comorbidities. she presented to chbah with general body weakness, diarrhoea, cough and constitutional symptoms; clinically she appeared pale and chronically ill. a differential diagnosis was made of multiple infections co-inhabiting the patient. management and outcome: the patient had blood, sputum, radiological and invasive bone marrow aspiration, and trephine biopsies completed. the investigations revealed that she was co-infected with mycobacterium tuberculosis (mtb), mycobacterium avium complex (mac) and parvovirus b19. the tb and disseminated mac infection were managed with rifampicin, isoniazid, ethambutol, pyrazinamide and azithromycin, and reinitiation of antiretroviral (arv) treatment was planned on further follow-up of the arv drug resistance test. the parvovirus b19 infection was managed with immunoglobulins (polygam) and steroids (prednisone). she was discharged successfully for further follow-up. conclusion: a thorough history, clinical examination and subsequent targeted investigations are vital to arriving at the correct diagnosis or diagnoses. the case presented above serves to illustrate how three life-threatening opportunistic infections (ois), all with differing treatments, may present in a single patient. clinicians caring for immunosuppressed patients need to remain vigilant for the presence of multiple ois occurring simultaneously. keywords: mac; parvovirus b19; tuberculosis; hiv; multiple organisms. introduction patients with a compromised immune system often present a clinical diagnostic dilemma, because they may be simultaneously infected with multiple opportunistic infections (ois). in this case report, we present the case of a severely immunocompromised patient with advanced hiv infection, who presented with multiple simultaneous ois. case patient j.m. is a 36-year-old female who resides in soweto, johannesburg, with her family. she is unemployed and receives a government social grant. the patient’s first presentation to chris hani baragwanath academic hospital (chbah) was in november 2019. she was referred from the local clinic because of constitutional symptoms, including intermittent diarrhoea, and was reported to have anaemia. she was diagnosed with hiv in january 2019 and defaulted on her antiretroviral treatment (art). her original art regimen could not be ascertained but was restarted at a local facility a week prior to presentation. she was reinitiated onto a regimen of abacavir, lamivudine and efavirenz. her cd4 count on first presentation was 1 cell/µl, and the hiv viral load was 29 300 copies/ml (4.47 log10 copies/ml). there were no retrievable previous trends to compare. no concomitant comorbidities were identified at the time of reinitiation. clinically, she was generally wasted and anaemic. she had unilateral crackles in the right middle lobe of the lung, with no respiratory distress and normal oxygen saturation. the rest of the clinical exam was unremarkable. she was admitted from the medical outpatients’ department (mopd) to the medical wards for further investigation and management. the patient was found to have severe normochromic anaemia with a haemoglobin level of 3.0 g/dl. the differential count revealed that she had severe aplastic pancytopenia, as evidenced by a reticulocyte production index (rpi) of 0.0%. the remaining urea, electrolytes, calcium, magnesium and phosphate were normal (see table 1). table 1: initial blood results. during this admission, her sputum was submitted for genexpert (gxp) mycobacterium/rifampicin (mtb/rif) ultra testing (cepheid) and was positive for mycobacterium tuberculosis complex (rifampicin susceptible). she was initiated onto antituberculosis treatment and infused blood products and was discharged for outpatient follow-up for review of all her investigations, including a bone marrow aspirate and trephine (bmat). the patient presented to the mopd a month later (january 2020), complaining of abdominal pain, diarrhoea and dizziness for two weeks. she was readmitted for investigation and management. again, pancytopenia was noted (table 2). table 2: follow-up blood results. because of her clinical deterioration, despite treatment for microbiologically confirmed tuberculosis (tb), other ois and the possibility of drug-resistant tb were suspected, and a further workup was initiated. the initial chest radiograph could not be retrieved, but a chest radiograph taken after one month of antituberculosis treatment showed features in keeping with bronchopneumonia, with right middle lobe consolidation and/or atelectasis (see figure 1). figure 1: chest radiograph on patient on readmission (1-month post-antituberculosis treatment). patchy consolidation of the right upper lobe, as well as the right and left lower lobes. silhouetting of the right heart border. these are features in keeping with bronchopneumonia with right middle lobe consolidation and/or atelectasis. the mycobacterial culture from the sputum specimen collected on the first admission flagged positive in 11 days. mycobacterium avium, as well as m. tuberculosis complex, was identified using the genotype mycobacterium cm version 2.0 (hain lifescience, centurion, south africa) line probe assay (see figure 2). the line probe assay for susceptibility testing for m. tuberculosis complex, mtbdrplus version 2.0 (hain lifescience) was unsuccessful, because there were mixed mycobacterial species present. figure 2: line probe assay (genotype mycobacterium cm version 2.0) for patient j.m., from sputum culture, collected 18/11/2019. the conjugate control (cc), internal control (ic) and genus control for mycobacteria (gc) is positive (lines numbered 1, 2, 3). mycobacterium avium is identified (line 4), as well as mycobacterium tuberculosis complex (lines 10 and 16). in addition, m. avium complex (mac) was identified on a mycobacterial blood culture (bactec myco/f lytic bottle; becton dickinson), collected on the first admission, confirming the diagnosis of disseminated mac infection (see table 3). table 3: microbiological investigations for mycobacterial infection. the bmat performed during her first admission showed granulomatous inflammation with a ziehl-neelsen stain positive for acid-fast bacilli (afb) (see figure 3). figure 3: bone marrow trephine biopsy showing acid-fast bacilli. (a) an area of granulomatous inflammation (haematoxylin and eosin, 200× magnification). (b) a ziehl-neelson stain was positive for scanty acid-fast bacilli (black arrow, 1000× magnification). on the bmat, a pure red cell aplasia (prca) was noted, attributable to parvovirus b19 infection. on peripheral blood, the patient still had an rpi of 0.0% and antibodies for parvovirus flagged for current infection, supporting the diagnosis of a concomitant prca, most likely due to parvovirus b19 co-infection (see figure 4). figure 4: bone marrow trephine biopsy showing parvovirus b-19 inclusions. (a) occasional parvovirus inclusions were seen (black arrow, haematoxylin and eosin, 500× magnification). (b) parvovirus immunohistochemical stain positive (brown intranuclear staining, 400× magnification). the patient presented with three microbiologically and pathologically confirmed ois: pulmonary mtb, disseminated mac infection and parvovirus b19 infection. the parvovirus b19 infection was managed with intravenous immunoglobulin for three days, blood products and oral steroids. the patient’s blood count improved. the tb and disseminated mac infection were managed with rifampicin, isoniazid, ethambutol, pyrazinamide and azithromycin, and art was placed on hold pending the results of the antiretroviral (arv) drug resistance test. the plan was to reinitiate art after four weeks. the patient was subsequently discharged after three weeks of admission and was clinically stable. she was planned for follow-up at both the haematology and infectious diseases clinics. unfortunately, the patient did not return for her follow-up visits; she relocated to another province and was lost to follow-up. discussion careful history taking, examination and the appropriate use of investigations are crucial in identifying concomitant ois in immunosuppressed patients. according to the world health organization, more than 10 million people were infected with tb in 2018. of those patients infected with tb, 1.5 million people have died.1 the risk of acquiring tb in the setting of hiv is 9–16 times that of an hiv-uninfected individual.2 in the above case, the patient’s constitutional symptoms and the investigation of her sputum and blood cultures confirmed mycobacterial infection, mac infection as well as parvovirus b19. the overall prevalence of parvovirus b19 is likely to be highly underestimated, as it may only become clinically apparent during an episode of reactivation.3 in our setting of hiv, bone marrow aspirate is the method of choice to diagnose co-infection.4 non-tuberculous mycobacteria (ntm) species, such as mac, are seen more commonly in patients with cd4 counts of < 50 cells/ml.5 the risk of developing mac infection is increased with other concurrent infections such as tb.6 along with these clinical features and a positive mycobacterial blood culture, laboratory features supporting a diagnosis of disseminated mac infection include a raised alkaline phosphatase and gamma-glutamyl transferase.7 a diagnosis of mac infection will be missed if only the gxp assay is requested, because this assay detects the m. tuberculosis complex only. blood culture is the preferred initial test; however, there are a few limitations that need to be noted.8 in local mac infection, blood cultures are negative.9 although mac is classified as a fast-growing ntm, the culture may only become positive after 1–2 weeks.9 hussong et al.9 reported that blood cultures, bone marrow aspirate cultures, afb stains and granuloma detection complement the investigations well. acid-fast bacillus staining often has the fastest detection rate of disseminated mac infection, and if positive, it triggers prompt anti-mac treatment.9 management dilemma the management of mac consists of a multidrug regimen of different antimicrobials.10 macrolides (azithromycin and clarithromycin) are the mainstay treatment for mac and need to be used with one or more agents to reduce the potential of drug-resistant mac infections.10 the patient in our study would have been placed on an oral regimen of azithromycin (500 mg tablet daily), ethambutol (15 mg/kg daily) and rifabutin (300 mg daily).10 however, this was not the case because of her co-infection with pulmonary tuberculosis and drug-resistant hiv. the treatment duration for mac infection is 12 months after the first negative sputum culture. conclusion treating the immunocompromised patient is not an easy task. the case presented above serves to illustrate how three life-threatening ois, all with differing treatments, may present in a single patient. clinicians caring for patients with suppressed immune systems are urged to remain vigilant for the presence of multiple ois occurring simultaneously. acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions m.t.j. and m.v. conceived of the presented idea. both developed the theory and performed the computations. the remaining authors were pivotal in the formulation of the article, from the actual writing, to visualisations and interpretation of the investigations. all authors discussed the results and contributed to the final manuscript. ethical considerations ethical clearance to conduct this study was obtained from the university of the witwatersrand human research ethics committee (reference number: m2006101). funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability the data that support the findings of this study are available from the corresponding author, m.t.j., upon reasonable request. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references world health organization. global tuberculosis report 2019 [homepage on the internet]. 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avium complex pulmonary infection in adults [homepage on the internet]. uptodate. 12 november 2020. available from: https://www.uptodate.com/contents/treatment-of-mycobacterium-avium-complex-pulmonary-infection-in-adults#h394560080 hivmed 23-1_2022_contents.indd http://www.sajhivmed.org.za open access table of contents original research predictors of low antiretroviral adherence at an urban south african clinic: a mixed-methods study connor p. bondarchuk, nwabisa mlandu, tasneem adams, elma de vries southern african journal of hiv medicine | vol 23, no 1 | a1343 | 10 february 2022 original research the influence of smoking and hiv infection on pulmonary function annelotte e. sussenbach, sjors w.l. van gijzel, samanta t. lalla-edward, willem d.f. venter, erica shaddock, charles feldman, kerstin klipsteingrobusch, alinda g. vos southern african journal of hiv medicine | vol 23, no 1 | a1329 | 21 february 2022 original research cytomegalovirus retinitis and antiretroviral treatment: a fifteen year experience serisha jay narain, linda visser, wilbert sibanda southern african journal of hiv medicine | vol 23, no 1 | a1322 | 08 march 2022 original research evaluation of the modified wells score in predicting venous thromboembolic disease in patients with tuberculosis or hiv in a south african setting tweedy keokgale, sarah a. van blydenstein, ishmail s. kalla southern african journal of hiv medicine | vol 23, no 1 | a1349 | 23 march 2022 original research association between socio-economic factors and hiv self-testing knowledge amongst south african women michael ekholuenetale, chimezie i. nzoputam, osaretin c. okonji southern african journal of hiv medicine | vol 23, no 1 | a1347 | 24 march 2022 original research utilisation of cervical cancer screening among women living with hiv at kenya’s national referral hospital james m. kangethe, aliza monroe-wise, peter n. muiruri, james g. komu, kenneth k. mutai, mirriam m. nzivo, jillian pintye southern african journal of hiv medicine | vol 23, no 1 | a1353 | 25 april 2022 original research determinants of health-related quality of life in young adults living with perinatally acquired hiv infection in botswana grace karugaba, gloria thupayagale-tshweneagae, mary m. moleki, onkabetse v. mabikwa, mogomotsi matshaba southern african journal of hiv medicine | vol 23, no 1 | a1362 | 29 april 2022 original research tracking adverse drug reactions and medication errors in the central chronic medicine dispensing and distribution (ccmdd) programme in south africa kennedy otwombe, maggie munsamy, mukesh dheda, nishana ramdas, corlee herbst, merlin pillay, tanya van tonder, celicia serenata, samanta lalla-edward southern african journal of hiv medicine | vol 23, no 1 | a1366 | 19 may 2022 48 56 63 71 82 92 101 111 editorial sahcs 2021 conference summary david c. spencer southern african journal of hiv medicine | vol 23, no 1 | a1371 | 14 april 2022 editorial dolutegravir for second-line treatment: programmatic implications of new evidence ying zhao, gary maartens, graeme meintjes southern african journal of hiv medicine | vol 23, no 1 | a1428 | 05 september 2022 editorial cop27 climate change conference: urgent action needed for africa and the world lukoye atwoli, gregory e. erhabor, aiah a. gbakima, abraham haileamlak, jean-marie kayembe ntumba, james kigera, laurie laybourn-langton, robert mash, joy muhia, fhumulani m. mulaudzi, david ofori-adjei, friday okonofua, arash rashidian, maha el-adawy, siaka sidibé, abdelmadjid snouber, james tumwine, sahar yassien mohammad, paul yonga, lilia zakhama, chris zielinski southern african journal of hiv medicine | vol 23, no 1 | a1467 | 04 november 2022 guideline southern african hiv clinicians society 2022 guideline for the management of sexually transmitted infections: moving towards best practice remco p.h. peters, nigel garrett, nomathemba chandiwana, ranmini kularatne, adrian j. brink, karen cohen, katherine gill, thato chidarikire, camilla wattrus, jeremy s. nel, mahomed y.s. moosa, linda-gail bekker southern african journal of hiv medicine | vol 23, no 1 | a1450 | 27 september 2022 review article age-related differences in the vascular function and structure of south africans living with hiv anisca louwrens, carla m.t. fourie, shani botha-le roux, yolandi breet southern african journal of hiv medicine | vol 23, no 1 | a1335 | 24 february 2022 review article ethically acceptable consent approaches to adolescent research in south africa marian loveday, ameena goga, ames dhai, melodie labuschaigne, theresa roussouw, theresa burgess, ann strode, melissa wallace, marc blockman, brodie daniels, elizabeth spooner, linda-gail bekker southern african journal of hiv medicine | vol 23, no 1 | a1385 | 05 september 2022 original research factors influencing the high rejection rates of hiv 1/2 serology samples at charlotte maxeke johannesburg academic hospital and the cost implications bhaveshan reddy, naseem cassim, florette treurnicht, zinhle makatini southern african journal of hiv medicine | vol 23, no 1 | a1326 | 11 january 2022 1 6 8 11 23 35 42 page i of iii table of contents vol 23, no 1 (2022) issn: 1608-9693 (print) | issn: 2078-6751 (online)southern african journal of hiv medicine http://www.sajhivmed.org.za open access table of contentspage ii of iii original research digitally supported hiv self-testing increases facility-based hiv testing capacity in ekurhuleni, south africa nolundi t. mshweshwe-pakela, tonderai mabuto, luke shankland, alex fischer, dikeledi tsukudu, christopher j. hoffmann southern african journal of hiv medicine | vol 23, no 1 | a1352 | 13 june 2022 original research factors associated with viral suppression among adolescents on antiretroviral therapy in free state province, south africa balsam a.y. elashi, brian e. van wyk southern african journal of hiv medicine | vol 23, no 1 | a1356 | 13 june 2022 original research rechallenge after anti-tuberculosis drug-induced liver injury in a high hiv prevalence cohort muhammed shiraz moosa, gary maartens, hannah gunter, shaazia allie, mohamed f. chughlay, mashiko setshedi, sean wasserman, david f. stead, karen cohen southern african journal of hiv medicine | vol 23, no 1 | a1376 | 14 june 2022 original research covid-19 vaccine acceptance and associated factors among people living with hiv in the middle east and north africa region rahma mohamed, trenton m. white, jeffrey v. lazarus, amany salem, reham kaki, wafa marrakchi, sara g. m kheir, ibrahim amer, fida m ahmed, maie a khayat, nabeela al-abdullah, batool ali, roaa sultan, bandar alamri, anouf abdulmajid, ikbal kooli, mohamed chakroun, tariq a. madani, gamal esmat, ahmed cordie southern african journal of hiv medicine | vol 23, no 1 | a1391 | 24 august 2022 original research the sexual and reproductive health needs of young people living with hiv in gauteng, south africa bandile e. ndlazi, thembekile masango southern african journal of hiv medicine | vol 23, no 1 | a1377 | 06 september 2022 original research rifampicin resistance and mortality in patients hospitalised with hiv-associated tuberculosis ruan spies, charlotte schutz, amy ward, avuyonke balfour, muki shey, mark nicol, rosie burton, bianca sossen, robert wilkinson, david barr, graeme meintjes southern african journal of hiv medicine | vol 23, no 1 | a1396 | 27 september 2022 original research delays in third-line antiretroviral therapy and outcomes in north west province babalwa majova, ebrahim variava, neil martinson southern african journal of hiv medicine | vol 23, no 1 | a1394 | 24 october 2022 original research hiv viral load suppression before and after covid-19 in kinshasa and haut katanga, democratic republic of the congo gulzar h. shah, gina etheredge, stacy w. smallwood, lievain maluantesa, kristie waterfield, osaremhen ikhile, john ditekemena, elodie engetele, elizabeth ayangunna, astrid mulenga, bernard bossiky southern african journal of hiv medicine | vol 23, no 1 | a1421 | 28 october 2022 original research weight gain in children from birth to 10 years on antiretroviral treatment janine scholtz, susanna m. ellis, herculina s. kruger southern african journal of hiv medicine | vol 23, no 1 | a1413 | 28 october 2022 119 125 130 135 144 152 160 165 171 original research oral pre-exposure prophylaxis uptake, adherence, and adverse events among south african men who have sex with men and transgender women linda-gail bekker, danielle giovenco, stefan baral, karen dominguez, rachel valencia, travis sanchez, a.d. mcnaghten, ryan zahn, clarence s. yah, zinhle sokhela, richard kaplan, refliwe n. phaswana-mafuya, chris beyrer, patrick s. sullivan southern african journal of hiv medicine | vol 23, no 1 | a1405 | 08 november 2022 original research incidence of hepatitis c virus infection among people living with hiv: an egyptian cohort study fatma elrashdy, suzan haga, rahma mohamed, shereen abdel alem, safa meshaal, ahmed cordie, aisha elsharkawy, gamal esmat southern african journal of hiv medicine | vol 23, no 1 | a1442 | 09 november 2022 original research comparative performance of cardiovascular risk prediction models in people living with hiv irtiza s. tahir, alinda g. vos, johanna a.a. damen, roos e. barth, hugo a. tempelman, diederick e. grobbee, karine scheuermaier, willem d.f. venter, kerstin klipstein-grobusch southern african journal of hiv medicine | vol 23, no 1 | a1395 | 15 november 2022 original research experiences in receiving financial incentives to access hiv care in johannesburg, south africa sara rachel schlehr, leanne singh, athini nyatela, sizwe nqakala, samanta t. lalla-edward southern african journal of hiv medicine | vol 23, no 1 | a1426 | 17 november 2022 original research covid-19 and hiv viral load suppression in children and adolescents in durban, south africa asandile mathamo, kimesh l. naidoo, jienchi dorward, thashir archary, christian bottomly, moherndran archary southern african journal of hiv medicine | vol 23, no 1 | a1424 | 02 december 2022 original research effect of a ward-based outreach team and adherence game on retention and viral load suppression sanele ngcobo, steve olorunju, tshifhiwa nkwenika, theresa rossouw southern african journal of hiv medicine | vol 23, no 1 | a1446 | 07 december 2022 original research effect of obesity on dolutegravir exposure in black southern african adults living with hiv enkosi mondleki, clifford g. banda, nomathemba c. chandiwana, simiso sokhela, lubbe wiesner, francois venter, gary maartens, phumla z. sinxadi southern african journal of hiv medicine | vol 23, no 1 | a1452 | 13 december 2022 scientific letter low-level viraemia despite emergence of dolutegravir-resistant variants johannes c. botha, kim steegen, mariam edoo, jeremy nel, gert u. van zyl southern african journal of hiv medicine | vol 23, no 1 | a1398 | 30 september 2022 179 188 193 203 211 218 227 233 http://www.sajhivmed.org.za open access table of contentspage iii of iii case report multiple opportunistic infections (pulmonary tuberculosis, mycobacterium avium complex and parvovirus b19) in a single patient midhun t. john, michelle venter, jenifer vaughan, marianne black, daniel prince, aishwarya m. luke, mithra john southern african journal of hiv medicine | vol 23, no 1 | a1319 | 25 january 2022 case report alere determine-tuberculosis lipoarabinomannan positivity in disseminated non-tuberculous mycobacteria: an illustrative case series riana greyling, graeme meintjes, bianca sossen southern african journal of hiv medicine | vol 23, no 1 | a1369 | 04 april 2022 case report splenic hydatid disease in pregnancy kirstie f. thomson, florence mahlobo, denasha l. reddy southern african journal of hiv medicine | vol 23, no 1 | a1363 | 26 may 2022 case report cutaneous squamous cell carcinoma in vertically acquired hiv and epidermodysplasia verruciformis linda a. mandikiyana chirimuta, francis j. ndowa, margaret j. pascoe southern african journal of hiv medicine | vol 23, no 1 | a1368 | 27 june 2022 case report emergent dolutegravir resistance in integrase-naïve, treatment experienced patients from zimbabwe linda a. mandikiyana chirimuta, margaret j. pascoe, sara lowe southern african journal of hiv medicine | vol 23, no 1 | a1435 | 26 october 2022 conference abstracts where are the children? case finding in 5–14-year-olds living with hiv in johannesburg jackie l. dunlop, carol l. tait, moyahabo mabitsi, kate rees southern african journal of hiv medicine | vol 23, no 1 | a1378 | 14 april 2022 237 242 245 249 253 256 conference abstracts psychosocial support for adolescents and youth living with hiv during covid-19: a differentiated approach is needed carol l. tait, njabulo mbanda, rudairo tumba, marnie j. vujovic, kate rees southern african journal of hiv medicine | vol 23, no 1 | a1379 | 14 april 2022 conference abstracts understanding patients reinitiating antiretroviral therapy in two south african districts kate rees, melanie bisnauth, cara o’connor, tshifhiwa ramvhulela, nomzamo vali southern african journal of hiv medicine | vol 23, no 1 | a1380 | 14 april 2022 correction corrigendum: the influence of hiv infection and antiretroviral treatment on pulmonary function in individuals in an urban setting in sub-saharan africa oda e. van den berg, erica j. shaddock, sarah l. stacey, charles feldman, roos e. barth, diederick e. grobbee, willem d.f. venter, kerstin klipstein-grobusch, alinda g. vos southern african journal of hiv medicine | vol 23, no 1 | a1351 | 20 may 2022 correction erratum: southern african hiv clinicians society 2022 guideline for the management of sexually transmitted infections: moving towards best practice remco p.h. peters, nigel garrett, nomathemba chandiwana, ranmini kularatne, adrian j. brink, karen cohen, katherine gill, thato chidarikire, camilla wattrus, jeremy s. nel, mahomed y.s. moosa, linda-gail bekker southern african journal of hiv medicine | vol 23, no 1 | a1465 | 24 november 2022 reviewer acknowledgement southern african journal of hiv medicine | vol 23, no 1 | a1464 | 14 december 2022 257 258 259 260 261 a recently released report by united nations secretarygeneral ban ki-moon, titled uniting for universal access: towards zero new hiv infections, zero discrimination and zero aids-related deaths, highlights the facts that the global rate of new hiv infections is declining, treatment access is expanding, and the world has made significant strides in reducing transmission from mother to child. the secretary-general makes five suggestions to strengthen the aids response. we are encouraged to harness the energy of young people for an hiv prevention revolution, revitalise the push towards achieving universal access to hiv prevention, treatment, care and support by 2015, work with countries to make hiv programmes more cost effective, efficient and sustainable, promote the health, human rights and dignity of women and girls, and ensure mutual accountability to translate commitments into action. his goal setting is ambitious: to reduce the sexual transmission of hiv by 50%, and prevent all new hiv infections resulting from injecting drug use; to eliminate transmission from mother to child; to reduce tuberculosis deaths in people living with hiv by 50%; to ensure hiv treatment for 13 million people; to reduce by 50% the number of countries with hiv-related restrictions on entry, stay and residence; and to ensure equal access to education for children orphaned and made vulnerable by aids. with these challenges in mind this journal continues to press forward with the goal of keeping you informed, very much with a philosophy of ‘learning by sharing’. in this edition, campbell makes an eloquent case for an evidence-based approach to palliative care for children. gounden compares outcomes in a private and a public sector cohort on antiretroviral therapy and finds some interesting prescribing differences between the two groups, although outcomes were very similar. the recent national testing campaign has included expansion into schools, and pfaff and de beer describe a youthfriendly testing campaign that has been implemented by an ngo in the manguzi district. the surveillance and causes of infant mortality in south africa was a passion of a very much missed colleague, david bourne, who unexpectedly passed away in february 2009. the paper by boulle and colleagues is dedicated to david and acknowledges his work. polyclonal gammopathy is a common finding in hiv, and tathiah and colleagues present a retrospective study of serum electrophoresis patterns in patients in kzn. readers have expressed great interest in case reports. the benefit in learning from real clinical cases is acknowledged by the review committee, so this edition is full of interesting case reports. continuing our important guidelines series, we present the management of hepatitis b infection as a co-infection with hiv. thanks to the southern african hiv clinicians society for this excellent collaboration. coming soon are guidelines for safer conception, hiv-infected health care worker protection, and pre-exposure prophylaxis. exciting news is that in 2011 the editorial office is undergoing revitalisation and will have increased resources. this will be good news for those of you who have waited so patiently for reviews of your submissions. i sincerely apologise to frustrated authors who have found our current system tardy. this will be improved in 2011. please continue to submit copy! linda-gail bekker editor 5 f r o m t h e e d i tor m e s s a g e f r o m t h e e x e c u t i v e several things are coming to completion in this important year for the society. a new board of interim directors has been elected to construct our new constitution, or ‘memorandum of association’, legalese from the new companies act that is about to come into force. it will be presented to the old executive for discussion, and then circulated for comment, in the next few months. i welcome tim tucker, one of south africa’s unsung heroes from the vaccine enterprise, and eric hefer, who is known by reputation to many of you and is a longtime exco member, to the interim board. they’ll also be advising on our new structure, and how we take the organisation towards new elections in november. the society bids a sad farewell to linda-gail bekker as an editor. it has been a tough tenure – the journal has to compete with many others, and clinicians are not all polite, naturally gifted researchers or writers. despite this, we distribute over 15 000 copies of every issue, and the feedback is that you love it. lgb has all our gratitude. incoming editor will be dr landon myer, another cape town find, who has experience with international journals and an impressive research cv. we have secured a further grant from atlantic philanthropies, which will allow the society’s transition to this new structure as well as support our advocacy and networking work. in addition, we have met with the monument trust, who fund our nurse/nimart work and want this programme expanded even further. on top of all this, all our other activities carry on, and are very successful. francois venter president t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 1 virtrium hiv med journal a 4/14/11 10:11 am page 1 composite c m y cm my cy cmy k hiv cpd_in.indd c p d q u e s t io n n a ir e a maximum of 3 ceus will be awarded per correctly completed test. e�ective in 2014, the cpd programme for sajhivmed will be administered by medical practice consulting: cpd questionnaires must be completed online at www.mpconsulting.co.za. a�er submission, you can check the answers and print your certi�cate. �is programme is available free of charge to members of the southern african hiv clinicians society and sama only. instructions 1. read the journal. all the answers will be found there. 2. go to www.mpconsulting.co.za to answer the questions. accreditation number: mdb001/012/01/2014 (clinical) 112 sajhivmed september 2014, vol. 15, no. 3 cpd questionnaire september 2014 vol. 15 no. 3 true or false: tailoring of adult antiretroviral therapy (art) 1. studies show that hiv-positive people who are receiving treatment and have suppressed viral loads are unlikely to transmit the virus to hiv-negative sexual partners. 2. �e optimal cd4+ threshold to initiate treatment to maximise clinical bene�ts is widely known to be 500 cells/µl. management of mental health disorders and central nervous system (cns) sequelae in hiv-positive children and adolescents 3. hiv-positive children and adolescents are at increased risk of both cns sequelae and mental disorders. 4 . hiv-positive children who begin art in infancy are at increased risk of cns sequelae compared with untreated perinatally hiv-infected children. 5. �e most common primary hiv-related cns complication in children is hiv encephalopathy. expression of dc-sign and dc-signrs in the placentas of hiv-positive women 6. without any form of art or prohylaxis, most vertical transmission of hiv occurs via the virus crossing the placenta. 7. both dc-sign and dc-signr expression were higher in placentas from hiv-positive mothers compared with hivnegative cases. 8. perinatally hiv-infected children present with high rates of mental disorders that exceed population norms and rates observed in other chronically ill children. management of patients presenting with diarrhoea 9. in south africa (sa), diarrhoea is a common presentation to the emergency department only among hiv-infected individuals. 10. hiv infection is not considered in the acute diarrhoea guidelines; only as an opportunistic infection that causes chronic diarrhoea. 11. patients prescribed antibiotics for diarrhoea unrelated to severity of disease or possibility of being admitted are put at risk of both undertreated infection and the development of a resistant organism. management of cryptococcal meningitis (cm) in adults 12. cm is relatively uncommon among hiv-infected individuals in sa. 13. headaches, unexplained fever, nausea, vomiting, neck sti�ness, confusion, seizures, abnormal behaviour, new onset of psychiatric symptoms, altered level of consciousness, focal neurological signs, diplopia, unexplained blindness and sometimes coma are some of the ways in which cm may present in hiv-positive patients. 14. despite the availability of highly active antiretroviral therapy (haart), the mortality from cm has not decreased signi�cantly from the pre-haart era. steps towards elimination of mother-to-child transmission 15. �ere have been only minor improvements to the sa prevention of mother-to-child transmission (pmtct) programme over the last decade. 16. an sa pmtct evaluation study has showed a high uptake of pmtct services nationally. 17. routine birth polymerase chain reaction testing for high-risk infants would allow for early detection of infants infected with hiv and rapid initiation of art. value of lymph node biopsy to detect castleman’s disease 18. a diagnosis of castleman’s disease can be made on clinical �ndings alone. 19. multicentric castleman’s disease (mcd) is a rare, aggressive lymphoproliferative disorder with an increased prevalence in people living with hiv. 20. modality of treatment of mcd is strongly guided by clinical classi�cation, in particular whether a patient has unior multicentric disease. 2014/02/24 12:07 pm 822 estimated use of abacavir among adults and children enrolled in public sector antiretroviral therapy programmes in gauteng province, south africa denise evans, mhairi maskew, cassidy heneger, ian sanne   health economics and epidemiology research office, department of internal medicine, faculty of health sciences, university of the witwatersrand, johannesburg denise evans, phd mhairi maskew, mb bch, msc   department of epidemiology, gillings school of global public health, university of north carolina at chapel hill, usa cassidy heneger, phd   clinical hiv research unit, department of internal medicine, faculty of health sciences, university of the witwatersrand, and right to care, johannesburg ian sanne, mb bch, fcp (sa), frcp (lond) corresponding author: d evans (devans@witshealth.co.za) in south africa, abacavir (abc) is currently recommended as part of firstand second-line antiretroviral therapy (art) for hiv-positive paediatric patients. concerns about overprescribing of the drug, particularly to adults, led to an analysis of abc use in public sector art programmes. we investigated current prescription of the drug to adults and children accessing art in 4 public sector programmes across gauteng province, south africa. abc was almost exclusively prescribed to children initiating art and adults requiring regimen changes due to drug toxicities. patterns of abc use among hiv-positive paediatric patients followed national art treatment guidelines on the application of the drug. although abc is commonly used in the private sector for adults, the current national art treatment guidelines for adults and adolescents should include abc as an alternative to standard firstor second-line art. s afr j hiv med 2012;13(3):134-137. doi:10.719/sajhivmed.822 abacavir (abc), a nucleoside reverse transcriptase inhibitor (nrti), has been shown to be an effective component of combination antiretroviral therapy (art) regimens for both paediatric and adult patients.1 , 2 , 3 south african (sa) national art treatment guidelines recommend abc for firstand second-line regimens in paediatric patients aged ≥3 months.4 despite demonstrating a durable antiretroviral response, abc is not a preferred option for firstor second-line adult regimens in sa, primarily due to its relatively high cost, but also due to concerns about toxicity, particularly hypersensitive reactions, although these are only experienced in 4% of individuals receiving abc.5 , 6 , 7 such reactions commonly present as a rash and fever, but may manifest as fatigue, flu-like symptoms or gastrointestinal upset. common adverse effects include headache, loss of appetite, nausea and diarrhoea.7 of all nucleoside reverse transcriptase inhibitors (nrtis), abc is associated with the lowest rate of mitochondrial dysfunction, including lactic acidosis, peripheral neuropathy and lipo-atrophy.5 substitution of stavudine (d4t) with abc improves mitochondrial indices, reduces adipocyte apoptosis,8 and has been shown to be superior to substitution with zidovudine (zdv) in adults. in older children, once-daily use of abc has also been shown to be effective, facilitating adherence and improving patient satisfaction.9 , 10 abc-containing regimens are used in adult cases where standard firstand second-line treatments have either failed or cannot be tolerated. given current national guidelines for limited inclusion of abc in highly active art (haart) regimens, use of the drug among hiv-positive adults eligible for treatment is generally expected to be low. in 2011, however, a higher than anticipated use of abc was observed across all provinces of sa. actual use outpaced the projected need for the drug, placing strains on supplies and programme budgets. in response to concerns about the unnecessary use of abc (300 mg), we investigated current prescribing of the drug to adults and children accessing art in public sector programmes across gauteng province. methods in 2011 we performed a cross-sectional study of 4 urban public sector antiretroviral clinics in gauteng province supported by right to care – a non-governmental organisation supporting art rollout in sa with funding from the united states agency for international development (usaid)/president’s emergency plan for aids relief (pepfar).12 the clinics operate according to sa national art guidelines and are run by the national department of health, as part of its development of accredited comprehensive care, management and treatment (ccmt) sites with doctor-managed initiation and follow-up.13 , 14 age categories were defined according to the world health organization (who) for paediatrics (<10 years of age), adolescents (aged 10 18 years) and adults (aged >18 years).15 medical records were reviewed for all patients actively receiving haart at the themba lethu clinic (tlc) in central johannesburg (jhb) and at 3 other adjacent sites to the north, east and west of tlc. data on current drug regimens, patient demographics and clinical characteristics were extracted from therapyedge-hivtm (te), an electronic patient management system used at the clinics. use of te data was approved by the human research ethics committee of the university of the witwatersrand (hrec-medical m060626/m110140). results of 23 084 patients, 76% (22 089) were adults and 5% (995) were children and adolescents (aged ≤18 years), reflecting that the hiv clinics were mainly adult-orientated. the majority of patients attending the central-jhb (12 120/12 185; 99.5%), west-jhb (1 875/2 267; 82.7%) and east-jhb (2 705/2 773; 97.5%) clinics were adults aged >18 years. tlc had a small cohort of paediatric (<10 years) and adolescent (10 18 years) patients (65/12 185; 0.5%), compared with north-jhb, where paediatric/adolescent (470/5 859; 8.0%) and adult hiv-positive patients (5 389/5 859; 92%) were seen separately (table 1). table 1. current use of abacavir (300 mg) at 4 right to care-supported sites across johannesburg, gauteng province, south africa total proportion of patients currently receiving abc † themba lethu clinic – central jhb ( n =12 185) 114 (0.9%)   north jhb ( n =5 859) 349 (6.0%)   west jhb ( n =2 267) 131 (6.0%)   east jhb ( n =2 773) 25 (0.9%) >18 years ( n =12 120) 107 (0.9%) ≤18 years ( n =65) 7 (11%)   >18 years ( n =5 389) 95 (1.8%) ≤18 years ( n =470) 254 (54%)   ≤18 years ( n =392) 128 (33%)   ≤18 years ( n =68) 24 (35%) patient demographics and clinical characteristics                   gender male, n (%) female, n (%)   47 (44) 60 (56)   5 (71) 2 (29)     31 (34) 63 (66)   136 (54) 118 (46)     49 (38) 79 (62)     11 (46) 13 (54) age at initiation (years), median (iqr) 42.2 (34.9 51.0) 14.0 (10.9 16.2)   39.5 (33.1 44.8) 6.1 (2.4 9.1)   4.5 (1.8 7.7)   2.8 (1.0 5.7) baseline cd4 (cells/mm3 ), median (iqr) baseline cd4, % 78 (31 171) 7.2 (3.5 13.6) 3.5 (3.0 4.0) 0.9 (0.6 1.2)   117 (37 186) 9.2 (4.5 14.2) 351 (149 665) 14.7 (8.9 21.1)   380 (162 604) 14.5 (9.0 19.3)   440 (232 746) 16.4 (7.3 24.7) baseline bmi (kg/m2 ), median (iqr) 21.0 (18.8 24.8) 17.1 (16.7 17.6)   22.2 (19.2 25.6) 14.5 (12.8 16.1)   14.7 (12.6 16.4)   15.6 (14.7 17.0) baseline haemoglobin (g/dl), median (iqr) time receiving art (months), median (iqr) 10.7 (8.8 12.5) 31.3 (14.3 59.5) 10.7 (2.7 16.9) 90.9 (39.8 94.3)   11.0 (9.9 12.7) 25.7 (16.9 41.3) 10.9 (9.9 11.7) 36.6 (24.3 51.3)   10.4 (9.5 11.3) 6.4 (3.0 26.9)   9.8 (8.4 10.9) 5.7 (1.9 8.0) abc use                   age at start of abc (years), median (iqr) 43.4 (36.5 52.4) 14.3 (11.1 16.2)   39.8 (33.8 46.2) 7.9 (4.5 10.9)   5.7 (2.4 8.9)   3.7 (1.5 5.8) cd4 at start of abc (cells/mm3),* median (iqr) cd4 percentage at start of abc,* median (iqr) 267 (160 392) 14.7 (8.8 22.1) 4.0 (3.0 945) 1.2 (0.6 26.7)   239 (136 425) 16.0 (9.2 21.3) 846 (526 1208) 28.3 (21.3 33.7)   404 (201 743) 15.8 (10.2 23.6)   480 (243 919) 17.5 (7.3 27.9) detectable viral load (>400 copies/ml) at start of abc,* n/n (%) 10/80 (13) 1/7 (14)   20/75 (27) 19/209 (9)   13/32 (41)   12/13 (92) weight at start of abc (kg),* median (iqr) time receiving abc (months), median (iqr) receiving abc for >12 months, n (%) 56 (50 66) 8.5 (4.4 16.3) 37 (35) 30 (15 41) 39.8 (20.0 94.3) 4 (57)   61 (52 69) 16.2 (11.9 19.1) 69 (73) 22 (16 28) 12.5 (6.0 24.2) 129 (51)   18 (11 24) 4.9 (2.3 8.3) 8 (6)   13 (9 18) 4.5 (1.8 6.4) 0/24 (0) initiated on abc, n (%) 19/107(17.8) 5/7 (71.4)   27/95 (28) 53/254 (20.9)   88/128 (68.8)   20/24 (83.3) switched onto abc, n (%) 88/107(82.2) 2/7 (28.6)   68/95 (72) 201/254 (79.1)   40/128 (31.2)   4/24 (16.7) reason for switching, n virological failure clinical progression abnormal fat redistribution peripheral neuropathy toxicity (predominantly kidneys) anaemia hyperlactataemia/lactic acidosis toxicity more effective drug/interaction pregnancy other/not specified   2 1 5 2 10 4 1 12 2 1 48   1 1     1 18 12 3 3 3 1 27   1 39 2 1 6 2 150     1 7 2 30     4 abc = abacavir; jhb = johannesburg. *within 90 days of abc initiation.†abc initiated between april 2004 and august 2011. the total number of patients receiving abc was 619/23 084 (2.7%). an estimated 0.9% (206/22 089) of adults attending the 4 sites were prescribed abc-containing regimens at the time of the study, compared with 42% (413/995) of paediatric/adolescent patients (≤18 years). among patients aged ≤18 years, 11% (7/65), 54% (254/470), 33% (128/392) and 35% (24/68) were receiving abc-containing regimens at the central-, north-, westand east-jhb clinics, respectively. at the westand east-jhb clinics, nearly all patients receiving abc (98%; 128/131 and 96%; 24/25, respectively) were aged ≤18 years. the number of adults receiving abc varied from 2.3% (3/131) in west-jhb, to 4% (1/25) in east-jhb, 27% (95/349) in north-jhb and 94% (107/114) in central-jhb. despite the small size of some cohorts, the results demonstrated a variation in the number of adults prescribed abc at these 4 clinics. among paediatric and adolescent patients (aged ≤18 years), median time receiving art and abc varied by clinic. the tlc paediatric/adolescent population had a median duration on art of 91 months (iqr 40 94 months) compared with 37 months (iqr 24 51) at the north-jhb clinic and 6 months at both the west-jhb (iqr 3 27 months) and east-jhb (iqr 2 8 months) clinics. a longer median duration of art was associated with longer time receiving abc, with paediatric/adolescent patients at tlc prescribed the drug for a median 40 months (iqr 20 94 months). the median time on abc was shorter at the north-jhb (13 months; iqr 6 24 months), west-jhb (5 months; iqr 2 8 months) and east-jhb clinics (5 months; iqr 2 6 months). more than half of the paediatric/adolescent patients at tlc (4/7; 57%) and the north-jhb clinic (129/254; 51%) had been receiving abc for longer than 12 months. among adult patients receiving abc at the clinics at the time of the study, 35% (tlc; 37/107) and 73% (north-jhb; 69/95) had been receiving the drug for longer than 1 year. only 6% (8/128) of patients attending the west-jhb clinic were prescribed abc for longer than 12 months. the majority of adult patients prescribed abc at the time of the study were switched onto the drug from other regimens, with only 18% (19/107) of adult patients at tlc and 28% (27/95) of adult patients at north-jhb clinic initiated on an art regimen containing abc. among adult patients reporting a reason for switching to abc from another regimen (52%; 81/156), the most common reasons were peripheral neuropathy (17%, 14/81), abnormal fat distribution (28%, 23/81) and toxicity (35%, 28/81). few specific reasons for switching to an abc-containing regimen were given for paediatric/adolescent patients (25%, 62/247), but among those cases where a reason was reported, abnormal fat distribution was the leading cause of regimen change (76%, 47/62). discussion when considering sites where both adults and children are routinely treated with art, abc is primarily prescribed to children. at the eastand west-jhb clinics, the drug was almost exclusively provided to patients aged ≤18 years. we demonstrated a high variation in the prescription of abc to adult and paediatric/adolescent patients at the 4 sites across gauteng province. while we did not demonstrate dramatic over-use of the drug, 67% of patients receiving abc were children, consistent with guidelines, while 33% were adults, as a likely result of being switched to abc from another art regimen due to adverse effects or toxicity. however, approximately 23% (46/202) of adults at centraland north-jhb were initiated on an abc-containing regimen. a large proportion of abc users at the north-jhb clinic (73%; 254/349) were paediatric/adolescent patients compared with a smaller proportion (27%; 95/349) of adults, yet still less than 2% (95/5 859) of patients aged ≥18 years were on an abc-containing regimen. a large proportion of these adult patients receiving abc reported long-term use of the drug (73% for 1 year or longer). the large number of adult patients receiving abc at the north-jhb clinic was likely related to being switched onto abc from another art regimen due to an adverse effect (i.e. peripheral neuropathy, lactic acidosis or lipoatrophy/lipodystrophy) – less than 30% of patients aged ≥18 years were initiated on an abc-containing regimen. the majority of paediatric/adolescent patients (<80%) at the north-jhb clinic were switched onto an abc-containing regimen, with 19% (39/201) being due to abnormal fat redistribution. once-daily use of abc has been shown to be effective in older children, thereby facilitating adherence and improving patient satisfaction; and it is therefore possible that specialist paediatricians at north-jhb might have prescribed/switched adolescents to abc for adherence issues.10 , 11 twenty-one per cent of paediatric/adolescent patients were initiated on an abc-containing regimen. a large proportion of these patients reported long-term use of the drug, with 51% (129/254) receiving abc for longer than 1 year. this is likely due to the ageing paediatric population receiving care which has maintained paediatric regimens even after moving into adolescence (age 10 18 years). conversely, <1% (107/12 120) of adults at tlc were receiving abc, only 35% (37/107) of whom had received the drug for longer than 1 year. adults were unlikely (17.8%; 19/107) to be initiated on an abc-containing regimen but rather switched to such a regimen due to toxicity (82.2%; 88/107). the cd4 count (267 cells/mm3 ; iqr 160 392) and proportion with a detectable viral load (13%; 10/80) at the initiation of abc confirmed that adults patients were most likely switched to abc rather than initiated on the drug. tlc treats few patients aged <18 years (0.5% of total patients); however, 71% (5/7) of paediatric/adolescent patients on an abc-containing regimen were initiated on such a regimen. differences in abc use across clinics possibly also partially reflect differences in clinical practice. more than 50% of children from the north-jhb clinic were receiving abc for longer than 1 year, compared with 16% and 0% at westand east-jhb, respectively. this could be a reflection of advice and recommendations concerning treating art side-effects, from specialist paediatric hiv physician services available at north-jhb clinic (not available at the other sites). this advice might have included switching from stavudineto abc-containing regimens before implementation of the new national art treatment guidelines. the switching of many children to abc at north-jhb (79.1%; 201/254) before implementation of the national guideline could explain the perception of high consumption of this drug in jhb. the majority (79%) of children from the north-jhb clinic were switched onto abc from another regimen, while 69% and 83% of children from westand east-jhb, respectively, were initiated onto abc. this likely reflects the implementation of the 2010 sa national art treatment guidelines at these 2 sites, which recommend that infants and children be initiated on a regimen of abc and lamivudine (3tc) plus lopinavir/ritonavir (lpv/r) or efavirenz (efv).16 among paediatric and adolescent patients, the most frequent reason for switching onto an abc-containing regimen was art toxicity and side-effects, most commonly abnormal fat redistribution. this highlights the toxicity of nrtis, particularly d4t, didanosine (ddi) and zidovudine (azt), even in children.7 the majority of adults prescribed abc at the time of the study had been switched onto the drug from other regimens. specified reasons for prescribing abc to these adults were largely related to art toxicity and side-effects, including renal toxicity, anaemia, peripheral neuropathy, abnormal fat distribution, and hyperlactataemia or lactic acidosis. this highlights the need to make abc available to adults and include the drug in the national guidelines for adults as an alternative to standard firstand second-line art.   study strengths and limitations the biggest strengths of this study include the size of the cohort and the depth of the data (using a standardised, electronic data-capturing system, data on art regimens, visit dates, outcomes, laboratory investigations and demographic data is of high quality).12 since these are clinical cohorts, the findings should be considered in light of the study limitations which include missing data (laboratory investigations and reasons for switching) or under-reported conditions or adverse drug effects and the generalisability of the results. this study was done in rtc-supported sites in johannesburg, thus with a higher level of clinical support and progressive prescription than other sites (i.e. rural sites without any supporting ngo). it is likely that abc use, especially in adults, would be lower in rural, unsupported sites. conclusion after reviewing the data, there did not appear to be a dramatic over-use of abc (300 mg) in the 4 gauteng sites. at the time of the study, there were 619 patients on abc-containing regimens, accounting for only 2.7% of all the patients currently receiving art at these clinics. further, patterns of use at the 4 sites appeared in line with national art treatment guidelines; most patients prescribed abc were paediatric patients or adults experiencing drug toxicities on non-abc-containing regimens.   conflict of interest. the authors declare that no competing interests exist. right to care (rtc) funded part of the research and supported the provision of treatment for the study's patients. acknowledgments. we acknowledge the directors and staff of themba lethu clinic (tlc), chru and right to care (rtc) – a pepfar-funded ngo. we wish to acknowledge the gauteng and national departments of health for providing for the care of the patients as part of the national comprehensive care, management and treatment (ccmt) of hiv and aids programme. sincere thanks to the patients attending the rtc-supported clinics for their continued trust in the treatment and care provided at the clinic. funding. funding was provided by united states agency for international development (usaid) under the terms of agreement 674-a-00-08-00007-00 with right to care (rtc). d evans is supported by the claude leon foundation and nih/cfar/ias creative and novel ideas in hiv research (cnihr) programme (sub-award with uab center for aids research: p30ai027767). the opinions expressed herein are those of the authors and do not necessarily reflect the views of the nih, niaid, usaid, the themba lethu clinic or right to care. right to care provided funding for technical and logistical support and for the provision of treatment for patients in this study. references 1. henry k, wallace rj, bellman pc, et al. twice-daily triple nucleoside intensification treatment with lamivudine-zidovudine plus abacavir sustains suppression of human immunodeficiency virus type 1: results of the target study. j infect dis 2001;183:571-578. 1. henry k, wallace rj, bellman pc, et al. twice-daily triple nucleoside intensification treatment with lamivudine-zidovudine plus abacavir sustains suppression of human immunodeficiency virus type 1: results of the target study. j infect dis 2001;183:571-578. 2. green h, gibb dm, walker as, et al. lamivudine/abacavir maintains virological superiority over zidovudine/lamivudine and zidovudine/abacavir beyond 5 years in children. aids 2007;21:947-955. 2. green h, gibb dm, walker as, et al. lamivudine/abacavir maintains virological superiority over zidovudine/lamivudine and zidovudine/abacavir beyond 5 years in children. aids 2007;21:947-955. 3. saez-llorens x, nelson rpj, emmanuel p, et al. a randomized, double-blind study of triple nucleoside therapy of abacavir, lamivudine, and zidovudine versus lamivudine and zidovudine in previously treated human immunodeficiency virus type 1-infected children. paediatrics 2001;107:e4. [http://dx.doi.org/10.1542/peds.107.1.e4] 3. saez-llorens x, nelson rpj, emmanuel p, et al. a randomized, double-blind study of triple nucleoside therapy of abacavir, lamivudine, and zidovudine versus lamivudine and zidovudine in previously treated human immunodeficiency virus type 1-infected children. paediatrics 2001;107:e4. [http://dx.doi.org/10.1542/peds.107.1.e4] 4. serenata c. changes to the art guidelines – an overview. southern african journal of hiv medicine 2010;11:28-30. 4. serenata c. changes to the art guidelines – an overview. southern african journal of hiv medicine 2010;11:28-30. 5. rabie h, henning kl, schoeman p, de villiers n, pretorius ghj, cotton mf. abacavir: its use and hypersensitivity. southern african journal of hiv medicine 2009;10(4):81-84. 5. rabie h, henning kl, schoeman p, de villiers n, pretorius ghj, cotton mf. abacavir: its use and hypersensitivity. southern african journal of hiv medicine 2009;10(4):81-84. 6. hewitt r g. abacavir hypersensitivity reaction. clin infect dis 2002;34(8):1137-1142. [http://dx.doi.org/10.1086/339751] 6. hewitt r g. abacavir hypersensitivity reaction. clin infect dis 2002;34(8):1137-1142. [http://dx.doi.org/10.1086/339751] 7. orrell c. antiretroviral adverse drug reactions and their management. continuing medical education 2011;29:234-237. 7. orrell c. antiretroviral adverse drug reactions and their management. continuing medical education 2011;29:234-237. 8. mccomsey ga, paulsen dm, lonergan jt, et al. improvements in lipoatrophy, mitochondrial dna levels and fat apoptosis after replacing stavudine with abacavir or zidovudine. aids 2005;19:15-23. 8. mccomsey ga, paulsen dm, lonergan jt, et al. improvements in lipoatrophy, mitochondrial dna levels and fat apoptosis after replacing stavudine with abacavir or zidovudine. aids 2005;19:15-23. 9. carr a, workman c, smith de, et al. abacavir substitution for nucleoside analogs in patients with hiv lipoatrophy: a randomized trial. jama 2002;288:207-215. [http://dx.doi.org/10.1001/2012.jama.10158] 9. carr a, workman c, smith de, et al. abacavir substitution for nucleoside analogs in patients with hiv lipoatrophy: a randomized trial. jama 2002;288:207-215. [http://dx.doi.org/10.1001/2012.jama.10158] 10. scherpbier hj, bekker v, pajkrt d, jurriaans s, lange jm, kuijpers tw. once-daily highly active antiretroviral therapy for hiv-infected children: safety and efficacy of an efavirenzcontaining regimen. pediatrics 2007;119:e705-715. [http://dx.doi.org/10.1542/peds.2006-1367] 10. scherpbier hj, bekker v, pajkrt d, jurriaans s, lange jm, kuijpers tw. once-daily highly active antiretroviral therapy for hiv-infected children: safety and efficacy of an efavirenzcontaining regimen. pediatrics 2007;119:e705-715. [http://dx.doi.org/10.1542/peds.2006-1367] 11. leprevost m, green h, flynn j, et al. adherence and acceptability of once daily lamivudine and abacavir in human immunodeficiency virus type-1 infected children. pediatr infect dis j 2006;25:533-537. 11. leprevost m, green h, flynn j, et al. adherence and acceptability of once daily lamivudine and abacavir in human immunodeficiency virus type-1 infected children. pediatr infect dis j 2006;25:533-537. 12. fox mp, maskew m, macphail p, et al. cohort profile: the themba lethu clinical hiv cohort, johannesburg, south africa, 2012. international journal of epidemiology. in press. [http://dx.doi.org/10.1093/ije/dys029] 12. fox mp, maskew m, macphail p, et al. cohort profile: the themba lethu clinical hiv cohort, johannesburg, south africa, 2012. international journal of epidemiology. in press. [http://dx.doi.org/10.1093/ije/dys029] 13. national department of health (doh). the south african antiretroviral treatment guidelines. pretoria: doh, 2010. 13. national department of health (doh). the south african antiretroviral treatment guidelines. pretoria: doh, 2010. 14. world health organization. antiretroviral therapy for hiv infection in adults and adolescents, recommendations for a public health approach: 2010 revision. geneva: who, 2010. http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf (accessed 1 february 2012). 14. world health organization. antiretroviral therapy for hiv infection in adults and adolescents, recommendations for a public health approach: 2010 revision. geneva: who, 2010. http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf (accessed 1 february 2012). 15. world health organization (who). towards universal access: scaling up priority hiv/aids interventions in the health sector. progress report april 2007. geneva, switzerland: who press, 2007. 15. world health organization (who). towards universal access: scaling up priority hiv/aids interventions in the health sector. progress report april 2007. geneva, switzerland: who press, 2007. 16. department of health, south africa. 2010. guidelines for the management of hiv in children, 2nd edition 2010. http://www.hivfshealth.org/sites/default/files/art%20guidelines%20paeds%202010.pdf (accessed 5 june 2012). 16. department of health, south africa. 2010. guidelines for the management of hiv in children, 2nd edition 2010. http://www.hivfshealth.org/sites/default/files/art%20guidelines%20paeds%202010.pdf (accessed 5 june 2012). hiv and infant.html opinion hiv and infant feeding – one step forward, two steps back h saloojee1, mb bch, fcpaed (sa), msc g gray2, mb bch, fcpaed (sa) j a mcintyre3,4, mb bch, frcog 1division of community paediatrics, university of the witwatersrand, johannesburg 2perinatal hiv research unit, university of the witwatersrand 3anova health institute, johannesburg 4centre for infectious diseases epidemiology and research, school of public health and family medicine, university of cape town the recent decision by the south african department of health to withdraw the provision of free replacement (formula) feeds to hiv-exposed infants has hardly evoked any response from clinicians, health professionals or civil society groups. this paper argues that the decision is short-sighted, lacks an adequate evidence base, and is retrogressive and unconstitutional. nine supporting arguments are presented and an alternative policy proposed. the recent ‘tshwane declaration of support for breastfeeding in south africa’ championed by the national department of health seeks to promote breastfeeding and halt practices deterring optimal breastfeeding in south africa (sa).1 the declaration’s intentions are most welcome, including greater support for the baby friendly hospital initiative which facilitates breastfeeding soon after birth, increasing numbers of community health promoters who will visit homes and support mothers with breastfeeding, workplace support for breastfeeding mothers, and stricter monitoring of the milk industry’s compliance with the code of marketing of breastmilk substitutes. however, one decision stands out as short-sighted, poorly evidenced and retrogressive. the plan to remove the provision of free replacement (formula) feeding to infants of hiv-positive women is frankly bewildering. hiv accounts for over 50% of child mortality in sa,2 and is primarily responsible for the loss of hard-earned gains in child health in south africa over the past two decades. postnatal transmission of hiv through breastfeeding is now the commonest form of mother-to-child transmission (mtct), and its contribution is increasing as programmes introduce more effective antenatal and perinatal arv regimens. annually, more than half a million infants globally acquire hiv through breastfeeding, highlighting the failure of previous strategies, including those promoting exclusive breastfeeding. there are currently only two recognised postnatal preventive strategies – antiretroviral prophylaxis provided to mother or infant, and avoiding hiv exposure through replacement feeding. to deliberately discard one of these two strategies is a luxury that the country can ill afford and requires substantial evidence that the strategy is either ineffective or results in major harm. evidence to support either of these contentions in the south african setting is simply lacking. replacement (formula) feeding remains a legitimate hiv prevention strategy multiple strategies are currently available to prevent hiv transmission in adults. despite good evidence about the benefit of condoms, microbicides, circumcision and preand post-exposure prophylaxis, among others, the search continues for different and more effective prevention options such as an hiv vaccine. clearly, a single strategy could never meet the needs of all. if the department of health were to summarily withdraw the provision of any one of the established hiv prevention strategies, the hiv community would be toyi-toying in the streets. yet the government’s decision to remove a well-evidenced child hiv prevention strategy – replacement feeding – has hardly elicited a whisper from hiv activists, clinicians or civil society. is it that they have been cowed into inaction because supporting replacement feeding is somehow automatically viewed as being anti-breast? certainly, this was the fate of the authors of this piece when we recently wrote an opinion piece in the mail & guardian questioning the validity of the department’s decision.3 supporters of the department’s proposal lambasted the newspaper’s irresponsible behaviour in publishing the piece. they went on to describe us as ill-informed and ‘dissidents’.4 such malicious name-calling demonstrates a degree of intolerance unbecoming of fellow scientists on a decision that has great scientific and public health importance and deserves rigorous debate. indeed, at an open public debate hosted by the sa hiv clinicians society in johannesburg in october 2011, over 70% of the more than 120 attendees (who included doctors, nurses, policy makers and nutritionists) voted against the department’s proposed change. a similar percentage of attendees agreed that provinces should be free to determine their own policy rather than being forced to offer a single option. clearly the views of many important stakeholders have not been considered in the department’s decision, and there appear to be many dissidents lurking out there. the most silent voice has been that of hiv-positive women. no evidence that the new proposal will maximise hiv-free child survival in sa supporters of the withdrawal of replacement feeding will quickly point out that it is not just the acquisition of hiv infection but overall child survival (hiv-exposed children staying alive) that matters. that is correct. the pertinent question then is whether replacement feeding inevitably results in increased child mortality in sa. the primary author of the mail & guardian piece attacking our stance readily acknowledged in a paper published in the bulletin of the world health organization in 2011 that ‘… no determination has been made about which feeding practice will maximize hiv-free survival nationally’.5 much of the evidence arguing that hiv-free survival (being alive and hiv uninfected) is similar for formula-fed and exclusively breastfed infants originates from countries such as zambia, malawi and rural botswana. however, the extremely high background mortality in the study children (e.g. 21% in zambia)6 because of the high burden of infectious disease, poor hygiene and sanitation, and limited access to quality health care, easily masks any possible benefits of replacement feeding (since so many children die). these dismal conditions are much less likely in south african settings. in rural kwazulu-natal, for instance, the probability of hiv-free survival at 18 months was marginally higher in hiv-exposed infants who had never been breastfed compared with infants who had ever been exclusively breastfed (80% v. 75%, p=0.05), the difference being mostly attributed to acquisition of infection through breastfeeding.7 a second confounder present in most studies is that since few trials randomised feeding choice, higher-risk women (with lower cd4 counts) were directed to, or selected, replacement feeding. this obviously attenuates possible benefits of replacement feeding. evidence from diverse african cities such as nairobi8 and abidjan9 convincingly indicates that replacement feeding can be safely supported in these settings and can reduce hiv infection rates, without jeopardising child survival. with safe replacement feeding, the vertical hiv transmission rate can be reduced to less than 2%, even in a resource-limited setting such as rural rwanda.10 the high hiv-free survival rate reported in the rwandan cohort of infants whose caregivers were supported with exclusive replacement feeding is remarkable and among the highest reported for a cohort of hiv-exposed infants.10 south africa is not a single homogeneous country using data from poorer southern african countries to argue that replacement (formula) feeding cannot be undertaken safely in sa is inappropriate. over half of south african children are urbanised.11 many have good access to safe water (62%), sanitation (63%) and electricity, and these statistics exceed 87% in gauteng and the western cape, including their townships and informal settlements.12 under-5 mortality rates (u5mr) vary substantially among provinces and districts; for example, in 2008 the u5mr in western cape was 31/1 000 live births, while it was almost fourfold higher in the free state (117/1 000).13 district-level data are unavailable. at least a third to one-half of sa caregivers should therefore be able to safely replacement feed their children. sa data from peri-urban and rural settings such as paarl, umlazi and rietvlei confirm that formula feeding halved hiv transmission or death among children living in households with piped water. among those who had piped water and fuel and who disclosed their hiv status, the protective effect of formula was greater (68% reduction).14 furthermore, the increasing availability of rotavirus and pneumococcal vaccine in sa is rapidly reducing the incidence and severity of diarrhoea and pneumonia, two major morbidities associated with replacement feeding. this does not mean that that choosing to formula feed an infant in some rural parts of the country, or in an under-serviced informal settlement, could ever be considered an appropriate choice. however, denying individual choice and failing to support a legitimate hiv prevention strategy in circumstances where this can be safely done violates caregivers’ and infants’ rights to basic health care and may be unconstitutional. a single infant feeding option is inappropriate for all hiv-positive women in sa a ‘one-size-fits-all policy’ is certainly simpler to promote, and the notion that ‘mixed messages lead to mixed feeding’ makes sense. however, the simplest policy is not necessarily the best. until recently infant feeding policy in sa was made at the provincial level. this makes sense because sa is heterogeneous in so many respects – the rural-urban mix, the availability of water and sanitation, the background infant mortality and the provincial variation in the percentage of mothers with hiv. the newly proposed policy demands that the whole country assume the same position – no free formula provision. this position is contrary even to the 2010 who hiv and infant feeding policy, on which the south african policy is based, which recommended that decisions be made by ‘national or sub-national health authorities’ in recognition of in-country variances.15 the new proposal is retrogressive in terms of supporting women’s choice and anti-poor arguing that parents can pay for formula from their own pockets if they choose this option may seem reasonable, but this denies access to an estimated 25 000 infants in whom formula feeding may be safely undertaken, but is unaffordable. data from rietvlei, paarl and umlazi confirmed that as many as a third of women living in these peri-urban and rural settings met the adequacy for replacement feeding criteria, dubbed afass (affordable, feasible, acceptable, sustainable, safe), despite being poor.14 disallowing middleand upper-class women access to free state-sponsored formula may be justifiable, since access to many health services for this class of citizens require them to bear the costs themselves. however, insisting that a poor woman (who qualifies for a child support grant, for instance) who meets the afass criteria be denied the opportunity to have an hiv-uninfected child, simply because she is poor, is discriminatory. the new proposal is based on extrapolation rather than firm evidence much of the enthusiasm for the proposal to withdraw support for replacement feeding stems from research suggesting that extended nevirapine provision to infants for 6 months, or triple antiretroviral therapy provision to their mothers, can reduce hiv transmission rates to less than 2% at 6 months in exclusively breastfed populations. whether the benefits of antiretroviral prophylaxis continue to 12 months (the suggested duration in sa), and whether the intervention is equally beneficial in mixed-fed infants (the likely situation in sa), is unknown. similarly, the consequences of antiretroviral interruption while breastfeeding are unclear. there are further unanswered questions. how serious are the long-term effects of exposure to multiple antiretroviral drugs in utero and during breastfeeding? can adequate adherence be achieved to avoid emergence of drug resistance? will there be negative effects on discontinuation of antiretroviral therapy (art) after stopping breastfeeding in women who do not require it for their own health? the ability of the health system to support the new proposal is not guaranteed – failure to deliver will have drastic consequences the new proposal is a huge public health experiment and could even be considered a high-stake gamble. while nevirapine toxicity does not seem cumulative, the adherence and programmatic challenges of long-term prophylaxis are untested. extrapolating data from highly controlled experimental settings to real-world situations is risky, particularly in the absence of a single local pilot project demonstrating successful implementation. at present, not one province has any monitoring or evaluation plan to establish effectiveness. perhaps the most pertinent question is whether many south african settings that are still battling to provide single-dose nevirapine or dual therapy are capable of offering this new standard of care. what should not be under-estimated are the demands on the health system of the new proposal. it is anticipated that of the approximately 300 000 hiv-positive pregnant women each year, about half will qualify for art (for life) for their own health. for these mothers ensuring adherence is the major issue, since their infants will not be receiving nevirapine, and if the mother stops taking art her infant will be left with no prophylaxis. mothers not qualifying for art need to be convinced to exclusively breastfeed for 6 months, and to provide their healthy uninfected infants with a daily dose of a drug (nevirapine) for up to one year. the health service will need to monitor these children at least monthly and ensure that drug supplies do not falter. the benefit of extended nevirapine if a mother starts mixed feeding or forgets to provide the drug for any period is unknown. a failure to meet any of these requirements will mean that transmission rates of infant hiv could start escalating again. all the problems of ensuring an adequate formula supply that have plagued the pmtct programme will be replicated with extended nevirapine or art provision, except that the consequences of a failed supply line will be far worse; while mothers still had to feed their infants and make alternative plans when formula was scarce, it is less likely that they will do so when nevirapine or arts runs out at a clinic. little consideration seems to have been taken in the new proposal of the myriad of situations where initiation or continuation of breastfeeding of hiv-exposed infants will not be possible, such as mothers returning to work or school, grannies caring for grandchildren, and abandoned or orphaned children. south african data indicate replacement feeding as an hiv-prevention strategy is cost effective depending on mortality rates during this time of fiscal restraint where healthcare resources are finite, information about both effectiveness and costs is important for policy makers as evidence-based decisions are made. when the issue of costs was raised during the recent breastfeeding consultation, the comment that ‘a back of the envelope calculation shows that breastfeeding is much cheaper and more cost-effective than formula and could save r200 million a year’ was met with wild applause. this type of feeble evidence to support a major policy shift is unfortunate. cost, logistics and cultural preferences should be considered in policy decisions. a new, unpublished modelling exercise using sa data indicates that extended nevirapine is a cost-saving intervention in both typical urban and rural settings and results in improved hiv-free survival. changing feeding practices to promote breastfeeding is cost-saving in typical rural settings, while promoting replacement feeding in typical urban settings is the most cost-effective feeding option (personal communication, mandy maredza, 1 november 2011). an hiv-free generation can never be achieved while breastfeeding continues the current call and challenge posed by the unaids, and taken up in sa national policy, to eliminate mtct by 2015 (i.e. zero new hiv infections) is unlikely to be achieved with a single strategy for infant feeding in sa, since at least 6 000 new infections annually can be expected in breastfeeding infants provided extended nevirapine. in reality there will be many more infected children, since implementation will hardly be perfect because of imperfect behavioural compliance. in the rush to ensure that sa is on a path to decreasing child mortality from all causes it is critical to ensure that recent gains in the number of hiv-exposed children’s lives saved through existing interventions, including replacement feeding, are not erased. what a new policy should say a more appropriate infant feeding policy for the country would offer antiretroviral prophylaxis and breastfeeding as the national default option. however, provinces, and perhaps even districts, should be allowed the freedom to decide whether they wish to continue to support the provision of replacement feeding for poor women who meet the afass criteria, based on their own circumstances. whatever choice women ultimately make, much more emphasis needs to be placed on a more supportive environment including adequate counselling, education and support through community health workers. the availability of antiretroviral prophylaxis is a big step forward for hiv-positive women choosing to breastfeed their infants. it’s a crying shame that in introducing this promising intervention, the department of health has chosen to take the low road (by insisting on a single option) rather than following the high one where the provision of safe water, sanitation and other resources, and employment would also have been prioritised for all citizens, so that any parents wanting to guarantee a hiv-free future for their child could do so knowing that the choice of replacement feeding could be safely supported too. 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but tread cautiously. mail and guardian 9 september 2011. http://mg.co.za/article/2011-09-09-breast-may-be-best-but-tread-cautiously (accessed 13 november 2011). 4. doherty d, sanders d, goga a, et al. stop dithering at death’s door. mail and guardian, 16 september 2011. http://mg.co.za/article/2011-09-16-stop-dithering-at-deaths-door/ (accessed 13 november 2011) 4. doherty d, sanders d, goga a, et al. stop dithering at death’s door. mail and guardian, 16 september 2011. http://mg.co.za/article/2011-09-16-stop-dithering-at-deaths-door/ (accessed 13 november 2011) 5. doherty t, sanders d, goga a, et al. implications of the new who guidelines on hiv and infant feeding for child survival in south africa. bull world health organ 2011;89:62-67. 5. doherty t, sanders d, goga a, et al. implications of the new who guidelines on hiv and infant feeding for child survival in south africa. bull world health organ 2011;89:62-67. 6. kuhn l, aldrvandi gm, sinkala m, et al. effects of early, abrupt weaning on hiv-free survival of children in zambia. n engl j med 2008;359:130-141. 6. kuhn l, aldrvandi gm, sinkala m, et al. effects of early, abrupt weaning on hiv-free survival of children in zambia. n engl j med 2008;359:130-141. 7. rollins nc, becquet r, bland rm, et al. infant feeding, hiv transmission and mortality at 18 months: the need for appropriate choices by mothers and prioritization within programmes. aids 2008;22:2349-2357. 7. rollins nc, becquet r, bland rm, et al. infant feeding, hiv transmission and mortality at 18 months: the need for appropriate choices by mothers and prioritization within programmes. aids 2008;22:2349-2357. 8. nduati r, john g, mbori-ngacha d, et al. effect of breastfeeding and formula feeding on transmission of hiv-1: a randomized clinical trial. jama 2000:283:1167-1174. 8. nduati r, john g, mbori-ngacha d, et al. effect of breastfeeding and formula feeding on transmission of hiv-1: a randomized clinical trial. jama 2000:283:1167-1174. 9. leroy v, ekouevi dk, becquet r, et al. 18-month effectiveness of short-course antiretroviral regimens combined with alternatives to breastfeeding to prevent hiv mother-to-child transmission. plos one 2008;3:e1645. 9. leroy v, ekouevi dk, becquet r, et al. 18-month effectiveness of short-course antiretroviral regimens combined with alternatives to breastfeeding to prevent hiv mother-to-child transmission. plos one 2008;3:e1645. 10. franke mf, stulac sn, rugira ih, et al. high human immunodeficiency virus-free survival of infants born to human immunodeficiency virus-positive mothers in an integrated program to decrease child mortality in rural rwanda. pediatr infect dis j 2011;30:614-616. 10. franke mf, stulac sn, rugira ih, et al. high human immunodeficiency virus-free survival of infants born to human immunodeficiency virus-positive mothers in an integrated program to decrease child mortality in rural rwanda. pediatr infect dis j 2011;30:614-616. 11. hall k. children’s access to housing. in: jamieson l, bray r, viviers a, lake l, pendlebury s, smith c, eds. south african child gauge 2010/2011. cape town: children’s institute, university of cape town, 2011. 11. hall k. children’s access to housing. in: jamieson l, bray r, viviers a, lake l, pendlebury s, smith c, eds. south african child gauge 2010/2011. cape town: children’s institute, university of cape town, 2011. 12. hall k. children’s access to basic services. in: jamieson l, bray r, viviers a, lake l, pendlebury s, smith c, eds. south african child gauge 2010/2011. cape town: children’s institute, university of cape town, 2011. 12. hall k. children’s access to basic services. in: jamieson l, bray r, viviers a, lake l, pendlebury s, smith c, eds. south african child gauge 2010/2011. cape town: children’s institute, university of cape town, 2011. 13. statistics south africa. mortality and causes of death in south africa, 2008: findings from death notification. statistical release p0309.3, 2010. 13. statistics south africa. mortality and causes of death in south africa, 2008: findings from death notification. statistical release p0309.3, 2010. 14. doherty t, chopra m, jackson d, et al. effectiveness of the who/unicef guidelines on infant feeding for hiv-positive women: results from a prospective cohort study in south africa. aids 2007;21:1791-1797. 14. doherty t, chopra m, jackson d, et al. effectiveness of the who/unicef guidelines on infant feeding for hiv-positive women: results from a prospective cohort study in south africa. aids 2007;21:1791-1797. 15. world health organization. guidelines on hiv and infant feeding 2010. principles and recommendations for infant feeding in the context of hiv and a summary of evidence. geneva: who, 2010. 15. world health organization. guidelines on hiv and infant feeding 2010. principles and recommendations for infant feeding in the context of hiv and a summary of evidence. geneva: who, 2010. references about the author(s) david c. spencer division of infectious diseases, faculty of medicine, university of the witwatersrand, johannesburg, south africasouthern african hiv clinicians society, johannesburg, south africa citation spencer dc. sahcs 2021 conference summary. s afr j hiv med. 2022;23(1), a1371. https://doi.org/10.4102/sajhivmed.v23i1.1371 note: summary of presentations and discussions held at the virtual october 2021 hiv conference of the southern african hiv clinicians society. editorial sahcs 2021 conference summary david c. spencer copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. in a letter to the lancet in 2017, brian williams and reuben granich remark (correctly) that ending aids by 2030 does not mean ‘the end of hiv’.1 without a cure and an effective vaccine, an ever-expanding population of those living with the virus will require antiretroviral treatment (art) indefinitely. so far, the world has no cure nor effective vaccine against hiv. however, carrying out something more to dramatically reduce the impact of virus on africa’s current and future generations makes scientific and humanitarian sense. in october 2021, the southern african hiv clinicians society (sahcs) hosted its biannual 4-day conference in johannesburg, south africa (sa), with its opening plenary theme being ‘game-changers for epidemic control’. in 2014, the joint united nations programme on hiv/aids (unaids) launched an initiative to reduce hiv infections by 2020.2 implementation of the 90-90-90% targets by 2020 began the following year. unfortunately, few southern african countries met the 2020 deadline3 (figure 14); botswana,5 a small country with a large hiv burden, met this deadline. nevertheless, it is on track to achieve the revised 2030 targets by 2025: 95% tested or diagnosed, 95% (of these) on art and 95% (of these) virally suppressed. can southern africa end new hiv infections by 2030? perhaps. however, it will require (1) a greater determination and commitment than previously observed, (2) an in-depth reappraisal of local targets, (3) settup of monitoring systems yearly or more frequently, (4) community mobilisation or input – to give momentum to the goal, and (5) a conscious effort to find the missing ‘key groups’ that include: the infected but untreated the uninfected but at-risk the treated but unsuppressed or lost to care. figure 1: the 90-90-90%-hiv treatment cascade in south africa and five of its metropolitan districts in 2018. will the point-of-care tests and the new antiretrovirals – the integrase inhibitors, the long-acting injectables, the new drug classes and the two-drug regimens – detail discussed at the october 2021 conference – achieve the 95-95-95% targets? not on their own. are the important scientific advances also discussed at the conference likely to induce citizens to arrive, get tested, take treatment and stay in care? no. something more is needed. we have learned much from the coronavirus disease 2019 (covid-19) pandemic. what works? clearly reported and accessible science (targeting everyone), truthful and frequent communication in national media by credible scientific leaders, defining a role for everyone, and the engagement of political and community leaders to mobilise constituencies towards an aids-free future. we have made mistakes. in aiming at the 2020 targets, children lagged behind, particularly the very young and adolescents,6 and also young women. the seroprevalence range of antenatal hiv in soweto, south africa, is currently at 27% – 30%. it has been at this level for the past two decades.7 similar levels are reported in other south african districts (figure 2).8 figure 2: the prevalence of hiv among pregnant women by district in south africa, the south african antenatal survey, 2017. jeremy nel (chief of infectious diseases at the helen joseph hospital, the university of the witwatersrand, johannesburg) chaired proceedings. the opening plenaries began with the ‘game-changers’: the long-acting injectables (sinead delaney-moretlwe), pre-exposure prophylaxis (prep) on demand for all (linda-gail bekker), pharmacy-initiated antiretroviral treatment (pimart) (francois venter) and u (undetectable) = u (untransmissible) (mandisa dukashe). each presentation covered new territory or developments in care. pharmacy-initiated antiretroviral treatment is a ‘new’ venture that asks our community pharmacists to get involved. a decade ago, nurses were trained to assist with hiv-patient care – the nurse-initiated management of antiretroviral treatment (nimart). without the support of these nurses, it would have been impossible to roll out care to the near six million south africans currently on treatment. a shortfall of approximately two million remain infected but untreated. pharmacy-initiated management of antiretroviral treatment is an international movement, where community pharmacists assist clients with hiv testing, provide limited but focussed counselling and initiate the client onto hiv prevention medicines (prep or pep) or art as is needed. this opens a portal for the untested and untreated to access ongoing hiv care. pharmacy-initiated antiretroviral treatment is structured around a referral pathway from a pharmacist to clinician and/or hiv clinic. similarly, the ‘game-changer’ concepts of prep, the long-acting injectables and the community u = u initiatives create novel opportunities that link ordinary people to game-changing programmes like pimart. in the opening plenary, i reviewed the history of hiv in africa. a 100 years ago, circa 1884–1920, a simian immunodeficiency virus (sivcpz) crossed from our primate relative, the chimpanzee, into humans in the forests of the congo, central africa. the novelist and sea captain, joseph conrad who at that time worked the waters of the congo river in search of rubber and ivory, describes the appalling living conditions of congolese workers in his novel ‘the heart of darkness’. nuno faria, paul sharp, beatrice hahn, michael worobey and others have explored the origins of hiv in numerous articles over the last 30 years.9,10,11 while specific detail has been lost, bayesian mathematics and phylogenetic mapping of hiv-dna retrieved from the infected human tissue between 1959 and the present lay bare the virus’s evolution in humankind. aids first came to the attention of clinicians and scientists in 1981. reports in the new england journal of medicine (nejm) and morbidity and mortality weekly report (mmwr) described life-threatening opportunistic diseases in young american men and their sexual partners.12,13 but: [s]hortly after the first reports of aids in the united states (us) in 1981, and the isolation of the virus (hiv-1) two years later, the disease was found to be established in the heterosexual populations of central and eastern africa suggesting a much older and at that point, a hidden history of the pandemic in africa.9 [authors own italics]. tulio de oliveira’s description in 2017 of hiv transmission reported in the province of kwazulu-natal (kzn), sa, is a classic (figure 3).14 the authors describe a cycle of sexual networking and viral transmission between adjacent rural and urban districts and between men and women in kzn. women are particularly vulnerable to acquiring infection. the region is easily accessed by road and not far from the province’s commercial hub, ethekwini (durban). of the 8912 people enrolled in this study, 3969 (45%) tested hiv-positive. some were already on treatment. however, a large number had detectable viral loads that permitted phylogenetic analysis and identification. in the under 25-year age group, the prevalence rates of hiv amongst the men and women were 7.6% (n = 1472), and 22.3% (n = 2224), respectively. the prevalence of hiv amongst those aged 25–40 years was high for both women (n = 2835, 59.8%) and men (n = 1548, 40.3%) but greater amongst women. the prevalence of hiv in women in both age groups outstripped that of men. at a time of sexual debut, girls or young women in this community had a three-fold greater risk of testing hiv positive than men of the same age. the researchers were able to fingerprint (‘cluster genotype’) viruses and follow their movement between groups. hiv transmission followed a path from the 25–40-year-old men to the younger, < 25 years women. simultaneously, the virus spread horizontally between the men and women in the 25–40-year-old group. women in the latter group also had a disproportionately higher level of infection. the story is not new:15,16,17 the differential status of men and women in almost every society is perhaps the most pervasive and entrenched inequity. indeed, the feminisation of the aids epidemic in southern africa clearly indicates the lack of power of women to participate as equals in the social freedoms of men.18 figure 3: the hiv prevalence rates in a kwazulu-natal community in south africa by age and gender. if the virus could speak and if we had ears to hear, it would repeat these words and ask why (our) society has performed so little to change this inequity? antiretroviral treatment programmes across southern africa have been very successful. numerically and geographically, sa is the largest of these. aids-related deaths have fallen. however, new infections contribute to the high prevalence rate. in her two talks on prep, linda-gail bekker (cape town, sa) observed that this form of protection is poorly marketed and inadequately utilised in sa. young women of schoolgoing age and students need protection. pharmacy-initiated antiretroviral treatment would be an ideal pathway to do this. there will not be an end of new infections without addressing the gender inequity of hiv. the conference was held virtually and broadcasted live from johannesburg. the first day included the familiar format of workshops – new guidelines and old themes – the resistance workshop, how to write a scientific paper, and sponsored sessions: hiv and viral hepatitis, 5-flucytosine, cryptococcal meningitis (the ambition study), and long-acting antiretroviral therapy. there were many familiar names amongst the speakers, and then the gender-affirming healthcare guidelines. i had read these some months earlier.19 for some, the guideline may appear to be a novelty. however, they do need to be taken seriously: they represent a ‘heads-up’ to us all. what did africa learn from the stonewall riots of the 1960s? or the gay men’s marches in los angeles and new york in the 1980s? or the beautifully (and lovingly) crafted aids remembrance quilts for the thousands of young men who died from aids? it is time to allow individuality to blossom, to let people be who they are. ubuntu is a local term meaning we ‘love one another’. the freedom of the lgbtqia+ community was not gained without cost. the history of the epidemic in africa is not only that of heterosexuals in need. but of gay and bisexual, of transgender men and women imprisoned in uganda, murdered in sa, despised and denigrated by african politicians and africa’s religious leaders … take a look at these guidelines. our world is changing. be part of the new world. learn the vocabulary. congratulations to the conference organisers for placing a sensitive yet timely subject before the delegates. two presentations on the second day, in particular, caught my attention. ‘is it possible to eliminate covid-19: lessons for and from hiv?’: monica gandhi (ca, us) and shabir mahdi (johannesburg, sa) answered the question to the delight of the audience. glenda gray, chief of sas medical research council, chaired the session. the speakers had anticipated the global omicron pandemic. they addressed the ethics of vaccine access in low-income countries, the waning of antiviral immune responses and the need for booster doses. both presentations were a formidable display of speaker skills and the careful marshalling of scientific evidence. definitely worth watching a second time! for those wanting more, i recommend a special report on covid-19 in the 08 july 2021 edition of the nejm. this is down-to-earth, ‘nuts and bolts’, science. extremely helpful.20 the other presentation was nicholas paton’s (united kingdom [uk]/singapore) nadia trial. this is a randomised, two-by-two factorial, open-label, non-inferiority trial of second-line art in n = 464 patients from seven sub-saharan african sites. the study was published in the nejm in 2021. it makes for great reading.21 the design of the study allowed the authors to compare dolutegravir (dtg) with ritonavir boosted-darunavir following first-line nnrti failure. at the same time, the second-line art choice allowed continuation with the failing first-line tenofovir whilst comparing this with the traditional second-line choice of twice daily zidovudine. the results of viral genotyping from the start of second-line art were only revealed at the 48-week assessment. in their nejm paper, the authors conclude: dolutegravir in combination with nrtis was effective in treating patients with hiv-1 infection, including those with extensive nrtiresistance in whom no nrtis were predicted to have activity. tenofovir was non-inferior to zidovudine as second-line therapy.21 (p. 330) it is a remarkable study. and it was a privilege to hear nick paton discuss it and interact with the session’s chair, gary maartens. would this trial have been allowed in europe and the us? what would the ethics committees have said? perhaps not. however, it has taught me a great deal. several years back another of nick paton’s african studies, the earnest trial, provided unexpected and thought-provoking results too.22,23 so do we throw away resistance testing? no. however, earnest and nadia reveal that other factors are at play in arv resistance, and that these fascinating studies are an essential part to understanding the big picture of hiv management. day 3 provided attendees with new data on viral load assessment from annemarie wensing and lucas hermans (the netherlands) and the ‘future of art’ with roy gulick (us). regarding art’s future, there are multiple new options on the horizon, all of which are welcome. however, in africa, cost and availability will be the driver. all three were state-of-the-art talks. in an early evening plenary on day 3, graeme moyle (uk) provided perspective on weight gain in patients on dtg. francois venter’s advance study had pointed to weight problems with dtg and alafenamide (taf). in brief, prof. moyle observed that weight change in patients living with hiv is influenced by their baseline health, and by innate differences in the antiretrovirals and the regimens used. efavirenz appears to have protected against excessive weight gain. alafenamide is associated with an approximately 2 kg initial increase in weight that is not lost by changing back to tenofovir – the tango and dolam studies. women, and particularly women of african ancestry, may be at greater risk. an interesting talk that signals that we are not finished with the metabolic complications of art. many of us recall using stavudine, didanosine and indinavir in the years before contemporary art was born. prof. moyle has an eye for unpacking the detail in the data. his discussion of the relevant studies was flawless. the morning of day 4, 23 october, focussed on the prevention of mother to child transmission, climate change and hiv, the digitisation of the 2020 hiv clinicians society art guidelines, solid organ transplantation guidelines – an african first, the clinicians society’s hiv and harm-reduction guidelines – possibly another (local) first, and a late morning session on ‘advanced hiv disease’. the final session of the conference was in the afternoon. this saw doug richman (us), mark cotton (stellenbosch, sa) and mike cohen (us) discuss ‘cure’ (what i guess all of us had been waiting for since the beginning of the conference). they did not disappoint. seeing and hearing doug richman took me back 20 years to when he and colleagues who are no longer with us, charlie van der horst, dave cooper, mark wainberg and joop lange, would visit african colleagues with advice and support. they were difficult years – a new epidemic, many aids deaths, toxic drugs, a denialist south african government and battles on many fronts. but much that is good has happened since. the southern african hiv clinicians october 2021 conference was memorable. it rekindled the quest for a future without hiv. the organisers thank all participants, particularly, the speakers who freely and readily shared their time, knowledge and insights – many from remote corners of the globe! can southern africa look to a future that is free of hiv and aids? yes, provided that there is commitment from all of us. references williams bg, granich r. ending aids: myth or reality? letter to the editor. lancet. 2017;390(10092):357. https://doi.org/10.1016/s0140-6736(17)31832-9 unaids. 90-90-90; an ambitious treatment target to help end the aids epidemic [homepage on the internet]. geneva: unaids; 2014 [cited 2021 dec 29]. available from: http://www.unaids.org/sites/default/files/,edia_asset/90-90-90_en_0.pdf unaids. global aids update 2019: communities at the centre: defending rights, breaking barriers, reaching people with hiv services 2019 [homepage on the internet]. [cited 2021 dec 29]. available from: http://www.unaids.org/sites/default/files/media_asset/2019-global-aids-update_en.pdf van schalkwyk c, dorrington re, seatlhodi t, et al. modeling of hiv prevention and treatment progress in five south african metropolitan districts. nat sci rep. 2021;11:5652. https://doi.org/10.1038/s41598-021-85154-0 jefferis k, avalos a, phillips h, et al. five years after treat-all implementation: botswana’s hiv response and future directions in the era of covid-19. s afr j hiv med. 2021;22(1):a1275. https://doi.org/10.4102/sajhivmed.v22i1.1275 nyasulu jcy, maposa i, sikakhane bp, pandya h. access to hiv services and viral load suppression among children during the 90-90-90 strategy implementation in south africa: a time-series analysis. s afr j hiv med. 2021;22(1):a1187. https://doi.org/10.4102/sajhivmed.2021.v22i1.1187 mnyani c, tait cl, peters rph, et al. implementation of a pmtct programme in a high hiv prevalence setting in johannesburg, south africa: 2002–2015. s afr j hiv med. 2020;21(1):a1024. https://doi.org/10.4102/sajhivmed.2020.v21i1.1024 woldesenbet sa, kufa t, lombard c, et al. the 2017 national antenatal sentinel hiv survey, south africa. pretoria: national department of health. 2019. faria nr, rambaut a, suchard ma, et al. the early spread and epidemic ignition of hiv-1 in human populations. science. 2014;346(6205):56. https://doi.org/10.1126/science.1256739 sharp pm, hahn bh. the evolution of hiv-1 and the origin of aids. phil trans r soc b. 2010;365(1552):2487–2494. https://doi.org/10.1098/rstb.2010.0031 worobey m, gemmel m, tewwen de, et al. direct evidence of extensive diversity of hiv-1 in kinshasa by 1960. nature. 2008;455(7213):661–664. https://doi.org/10.1038/nature.07390 gottlieb ms, schroff r, schanker hm, et al. pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency. n eng j med. 1981;305:1425–1431. https://doi.org/10.1056/nejm198112103052401 kaposi’s sarcoma and pneumocystis pneumonia among homosexual men in new york city and california. mmwr morb mortal wkly rep. 1981;30:305–308. de oliveira t, kharsany abm, gráf t, et al. transmission networks and risk of hiv infection in kwazulu natal, south africa: a community-wide phylogenetic study. lancet hiv. 2017;4(1):e41–e50. https://doi.10.1016/s2351-3018(16)30186-2 wilkinson e, junqueira dm, lessells r, et al. the effect of interventions on the transmission and spread of hiv in south africa: a phylodynamic analysis. sci rep. 2019;9:2640. https://doi.org/10.1038/s41598-018037749-3 wilkinson e, engelbrecht s, de olviera t. history and origin of the hiv-1 subtype c epidemic in south africa and the greater southern african region. sci rep 2015;5:16897. https://doi.org/10.1038/srep16897 tomita a, vandormael am, barnighausen t, de oliveira t, tanser f. social disequilibrium and the risk of hiv acquisition: a multilevel study in rural kwazulu-natal province, south africa. j acquir immune defic syndr 2017;75(2):164–174. https://doi.org/10.1097/qai.0000000000001349 marmot m, commission on social determinants of health. achieving health equity: from root causes to fair outcomes. lancet. 2007;370(9593):2253–2263. https://doi.org/10.1016/s0140-6736(07)61385-3 tomson a, mclachlan c, wattrus c, et al. the southern african hiv clinicians society gender-affirming public healthcare guidelines for south africa. s afr j hiv med. 2021;22(1):a1299. https://doi.org/10.4102/sajhivmed.v22i1.1299 krause pr, fleming tr, longini im, et al., sars-cov-2 variants and vaccines. n engl j med. 2021;385(2):179–186. https://doi.org/10.1056/nejmsr2105280 paton ni, musaazi j, kityo c, et al. for the nadia trial team. dolutegravir or darunavir in combination with zidovudine or tenofovir to treat hiv. n engl j med. 2021;385:330–341. https://doi.org/10.1056/nejmoa2101609 paton ni, kityo c, hoppe a, et al. assessment of second-line antiretroviral regimens for hiv therapy in africa. n engl j med. 2014;371:234–247. https://doi.org/10.1056/nejmoa1311274 paton ni, kityo c, thompson j, et al. nucleoside reverse transcriptase inhibitor cross-resistance and outcomes from second-line antiretroviral therapy in the public health approach: an observational analysis within the randomized, open-label, earnest trial. lancet hiv. 2017;4(8):e431–e348. message from executive.html message from the executive the first southern african hiv clinicians society meeting that i attended was in or around 2002, at the pharmaceutical society in glenhove road. professor gary maartens spoke on isoniazid preventive therapy, and the room was full (it was the last meeting in that too-small venue). the initial function of the society was to help a group of private doctors to better manage hiv infections. in the dark years, it seemed unlikely that art would ever be affordable and available in either the public or private sectors. i was working in a public service clinic, and all we could do was treatment and prevention of opportunistic infections. art was for a select few with money or taking part in research trials. then, on 1 april 2004, the first patients accessed therapy from the government programme. for months after that, i went and opened the pharmacy cupboards – just to look at the medicines. the atmosphere at the clinic changed; while people arrived very ill, many got better. informal support groups formed. i remember celebrating the first 1 000 patients on treatment at our clinic. today, over 15 000 people receive treatment there. south africa now has the largest art programme in the world, with some 1.5 million on treatment. the doh, under the leadership of dr aaron motsoaledi, commenced the largest-ever hiv testing campaign last year, and over 15 million south african were tested for hiv. there has been a reduction in mother-to-child transmission to 3.5%. so do we have it all sorted out, and is there no need for a southern african hiv clinicians society? what are the present challenges? what role will i play as president? i have always seen the function of the society as pushing the boundaries and leading the way in getting the best possible care to hiv-infected south africans. we must ensure that our guidelines for all aspects of hiv care and prevention are challenged and aligned with international guidelines. research in south africa is of the highest standard. our researchers have been involved in many of the latest breakthroughs in hiv, including early treatment for infants (cher), the use of treatment as prevention (hptn052) and microbiocides (caprisa 004). as soon as any research breakthroughs are made, we in the society need to assist the doh to implement them. and tb must receive more attention. south africa's tb incidence is high – second only to swaziland’s – and we rank fourth-highest in the world in multidrug-resistant tb incidence. this huge increase in tb has been driven largely by hiv infection. it seems a great pity to have made such massive progress in hiv treatment, and then lose our people to tb. francesca conradie president southern african hiv clinicians society johannesburg abstract background methods results discussion limitations conclusion acknowledgements references about the author(s) sabina m. govere college of health sciences, university of kwazulu-natal, durban, south africa moses j. chimbari college of health sciences, university of kwazulu-natal, durban, south africa citation govere sm, chimbari mj. the evolution and adoption of world health organization policy guidelines on antiretroviral therapy initiation in sub-saharan africa: a scoping review. s afr j hiv med. 2020;21(1), a1103. https://doi.org/10.4102/sajhivmed.v21i1.1103 review article the evolution and adoption of world health organization policy guidelines on antiretroviral therapy initiation in sub-saharan africa: a scoping review sabina m. govere, moses j. chimbari received: 06 may 2020; accepted: 26 july 2020; published: 30 sept. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: despite past and present global interventions, the human immunodeficiency virus (hiv) pandemic remains a public health problem in lowand middle-income countries (lmics). the world health organization (who) has assisted these countries by providing antiretroviral therapy (art) policies for adoption and adaptation to local needs. objectives: this article describes the response of countries in sub-saharan africa (ssa), to the who’s changing cd4-threshold art-initiation recommendations of the past two decades. methods: relevant articles published in international peer-reviewed journals were accessed via the following search engines: pubmed, google scholar, cochrane, embase and ebscohost. the study’s inclusion criteria were articles published in the english language between 2000 and 2019 that highlighted changes to the cd4 art-initiation threshold and that focused on the who’s ‘commencement of art’ policy guidelines. sixteen studies (n = 16) from ssa were identified and included in this review: four are cross-sectional, four deal with cost-effectiveness, four are retrospective, one is a randomised trial and three are observational studies. only studies conducted in ssa were assessed. results: four themes emerged: (1) adoption of the who cd4-art-initiation policy by ssa countries, (2) timely implementation of the changing guideline initiation policy in the region, (3) barriers and facilitators encountered in the implementation of the changing guidelines and (4) description of similarities in policy implementation at country level from 2002 to 2019. regional studies – cross-sectional, observational, retrospective, cost-effectiveness and randomised have described greater access to art in ssa. however, barriers remain. the most common barriers to the timely implementation of ‘new’ art-initiation guidelines were economic constraints, drug stock-outs, delays in obtaining baseline blood-test results and staff shortages. conclusion: although countries in ssa have adopted the who-art-cd4 initiation-threshold policy guidelines, implementation has seldom occurred in a timely manner. barriers have been identified. whilst a small number of countries have implemented recommendations promptly, for many, the barriers still require to be overcome. keywords: art initiation; who-art guidelines adoption; implementation of art guidelines in sub-saharan africa; cd4; human immunodeficiency virus. background the first cases of the acquired immunodeficiency syndrome (aids) were reported in 1981. since then, infection with human immunodeficiency virus (hiv) has spread globally and caused an estimated 74.9 million infections and 32 million aids-related illnesses.1 in its first 15 years no treatment could control the infection or halt its spread.2 by 2018, the african region was home to approximately 25.7 million people living with hiv (plwh)1 and in that year alone, africa experienced approximately 1.1 million new infections.1 almost two-thirds of all new global infections occur in sub-saharan africa (ssa).1 the world health organization’s (who’s) antiretroviral therapy (art) initiation-guidelines have changed substantially over the last two decades.2 the guidelines were first published in 2002.3 these (2002/2003) recommended starting art in those with aids-related conditions and/or at a cd4 of ≤ 200 cells/mm. the available treatment at that time was expensive and toxic. delaying art until the cd4 reached levels < 200 c/mm3 was intended to minimise these drawbacks.4 continued deaths from aids and success with art prompted a cd4 increase in 2006 200 to 350 cells/mm3. in addition, all pregnant women and persons with stage 3 and 4 infection were offered art.3 in 2010, the threshold was raised to cd4 < 350 c/mm3 for all irrespective of clinical stage.4,5 by june 2013, the threshold was further increased to cd4 < 500/cells/mm3 for all children > 5 years and adults irrespective of stage/symptoms.6 in 2015, the who and numerous international organisations removed the cd4 threshold and recommended art to all regardless of cd4 cell count and clinical stage.7 data from two highly influential randomised controlled clinical trials, the start and temprano studies, underpinned this decision. both demonstrated survival advantage to those on art irrespective of clinical stage or cd4 count.8,9 this led to the introduction by all international agencies, including the who, of the policy of ‘universal test and treat (utt)’. the who estimates that if these recommendations are adopted globally, 21 million deaths and 28 million new infections could be prevented by 2030.10 the rate at which countries have aligned their national art programmes and implemented who guidelines since 2002 has varied. most ssa countries took ± 2 years to implement the who’s 2010 art guidelines.5 from december 2015 to may 2017, rwanda, kenya, uganda, botswana, malawi, zimbabwe and south africa revised national art eligibility guidelines to align with the who’s 2015 guidelines.11 on average, this integration took 12 months (range, 6–23 months).11 the implementation of the who guidelines in resource-constrained countries is complex. consequently, it has not always been possible to implement the guidelines timeously where art is most needed and where access to health services is limited.2 in this review, we sought to determine how different ssa countries adapted to the who’s art-initiating cd4-threshold changes over time and how who guidelines have impacted art in the region. methods search strategy and selection criteria we carried out a systematic electronic literature search on pubmed, google scholar, cochrane, embase and ebsco host for the period, 2000–2019 (figure 1). the databases were selected based on our inclusion criteria and the availability of free full-text articles and papers. in this review, we used the preferred reporting items for systematic reviews and meta-analysis (prisma) as described by moher et al., to identify an evidence-based dataset and to provide transparency in the selection process of the articles.12 figure 1: preferred reporting items for systematic reviews and meta-analysis flow diagram showing the process of selecting articles included in the review. the search was based on the combination of the following terms and boolean operators: who-art guidelines or art-initiation guidelines and changes in cd4-initiation guidelines and implementation of who guidelines or adoption of who-art guidelines. we also applied a manual country filter to limit our search to ssa. articles published in a language other than english and articles focusing on art regimen-change were excluded. the study included articles that focused on cd4-threshold changes and were published between 2000 and 2019. the following articles were not included: duplicates, articles not centered on the who and art initiation guidelines or their adoption and implementation. exclusion was based on the screening of the title and abstract. the search process is illustrated in figure 1. seventy-nine (79) duplicate articles were removed, which were identical in google scholar and pubmed. fewer articles dealt with the topic in cochrane and embase. the articles in pubmed were more detailed, easier to search and free to access. we also excluded 187 articles because they did not specifically address implementation based on cd4-threshold changes. another 11 were excluded because they focused on only regimen change. only 16 articles remained. these covered quantitative and qualitative synthesis of how ssa countries adopted the who and art initiation guidelines between 2000 and 2019 and its impact on the management of hiv. data extraction and synthesis the following information was extracted from selected studies using a template: publication details, country of study, objective(s) of the study, study design, summary of findings and theme (table 1). two review authors independently assessed the eligibility of the studies identified in the search. articles with different study designs and objectives were selected to reduce the risk of bias. we used different high-impact databases to search for articles and global authors. the study designs were divided into five groups: cross sectional, cost-effectiveness, retrospective, randomised trial and observational studies. we did not subject the reviewed articles to this quality process because this is a scoping review. for synthesis, extracted information was grouped into themes derived from the articles in line with the review objectives and different study designs. the themes identified were: how different ssa countries adopted who and art initiation policy guidelines at country level, timely implementation levels of the policies by different ssa countries, the barriers and facilitators to who and art initiation policy adoption in ssa and the similarities in country characteristics in policy implementation in different ssa countries. table 1: summary of studies. table 1 (continues...): summary of studies. table 1 (continues...): summary of studies. table 1 (continues...): summary of studies. table 1 (continues...): summary of studies. ethical consideration ethical approval was obtained from the university of kwazulu-natal biomedical research ethics committee (ukzn brec, reference number: brec/00000819/2019). results overview of selected studies we reviewed 16 studies from an initial collection of 293 articles in google scholar, pubmed, cochrane, embase and ebscohost (figure 1). we only reviewed studies that examined how different ssa countries adopted changes in who and art initiation guidelines based on cd4 threshold and how the guidelines have impacted art programmes in ssa. the following four themes were identified from the 16 papers: (1) adoption of who and art initiation policy guidelines at country level in ssa, (2) timely implementation of who and art initiation policy guidelines at country level, (3) barriers and facilitators to who policy implementation in ssa and (4) characteristics at country level. of the 16 reviewed articles 4 (articles 4, 13, 14 and 16) addressed all 4 themes, 8 articles addressed 3 themes (articles 1, 2, 7, 9, 10, 11, 12 and 15) and 4 articles (articles 2, 5, 6 and 8) addressed only 2 themes. the theme of the adoption of the who-art initiation guidelines at country level was dominant in all articles. theme 1: adoption of world health organization antiretroviral therapy initiation policy guidelines at country level in sub-saharan africa the results confirm that all the countries in ssa that are part of this review have adopted the who and art initiation guidelines since 2002. hsieh et al. reported that between july 2013 and july 2015, seven national policy documents incorporating the 2013 who guidelines were developed in kenya, malawi, tanzania, uganda, zimbabwe and two in south africa.6 this was further supported by ross et al. who found that ssa countries had some national explicit policies that targeted increasing art access in line with the who 2013 guidelines on art.19 in his study, hsieh et al. indicated that community consultations are crucial if policies are to be effectively implemented.6 labhardt et al. found that health centres in lesotho took longer to adopt the new guidelines because of limited knowledge of who policy changes.21 rwanda implemented the 2006, 2010, 2013 and 2015 who and art initiation guidelines in a timely manner, that is, on an average within 6 months of international release.25 part of rwanda’s success is attributed to the cooperation of government and non-governmental service providers. theme 2: the timely implementation of world health organization antiretroviral therapy initiation policy guidelines at country level teasdale et al. describe high rates of early – within 3 months – art initiation amongst art-eligible rwandan patients. indeed, by 2012, the rwanda national hiv care and treatment programme had managed to initiate 94% of eligible plwh on art in line with the 2006 and 2010 who guidelines. rwanda was also one of the first countries in ssa to implement the higher cd4+ initiation threshold for art eligibility.22 in an observational study in kenya, uganda and zambia, duber et al. indicate that national hiv programmes have implemented who 2013 guidelines at health facility level.17 these findings suggest that several countries have moved quickly to align with the who. however, in a study conducted in 15 ssa countries, facilities were slow to align with the who’s 2006 and 2010 guidelines. they experienced delays in the actual implementation and expanding access to art.20 burrage et al. noted that few tanzanians were initiated on art at cd4 counts of ≤ 500/µl in 2015 despite the country’s earlier adoption of the 2013 who guidelines. as a result, only 64% of eligible plwh were initiated on treatment.14 stanecki et al. recorded that the number of plwh eligible for art in lowand middle-income countries (lmics) under the revised 2010 who guidelines was 14.6 million at a time when only an estimated 10.1 million people actually received art.20 as of 2015, all 20 ssa-supported u.s. president’s emergency plan for aids relief (pepfar) countries had adopted the 2013 who guidelines for art eligibility. nevertheless, alignment and implementation with national guidelines took at least 2 years in all 20 countries.14 this demonstrates the failure of ssa countries to align and implement country guidelines timeously with the who. theme 3: barriers to and facilitators of antiretroviral therapy initiation policy implementation fourteen studies examined the barriers to and facilitators of art-initiation policy implementation in ssa. ambia et al. reported a significant increase in art initiations, from 42% to 87%, in some facilities in the urban centres of kenya, malawi, south africa (sa), tanzania, uganda and zimbabwe.13 healthcare workers’ (hcws) attitudes were found to be both a barrier and a facilitator of implementation at the facility level. teasdale et al. reported that positive learning attitudes from hcws were found to be an enabler for who policy adoption in rwanda. furthermore, the rwandan government’s health department assembled a task team to ensure that the entire country was supported in the implementation of the revised guidelines.22 hsieh et al. found, however, that hcws in malawi and uganda were slow to implement the 2013 who guidelines because their communities ‘had not been consulted and hence lacked understanding’ of the guidelines.6 similarly, labhardt et al., in lesotho found that hcws especially in rural facilities, took longer to adopt and implement the 2006 and 2010 guidelines because of limited training.21 there was little support, mentoring and supervision and overall, less knowledge of health policy. the trainings were conducted in the cities. travel from remote areas proved a challenge as facilities would have been left without clinical staff. the authors make the point that the government did not make sufficient effort to deploy trainers in the remote areas where more people needed the services. the cost-effectiveness articles namely 8, 9, 10 and 11, in table 1, indicate that economic constraints hindered various countries from implementing guidelines timeously. an ethiopian study by konings et al., revealed major financial constraints for the state even before art services could be expanded as per the 2013 who guidelines. the government continued implementing the 2006 art guidelines for more than a year after the 2010 guidelines were released because their financial capacity could not absorb the increased demand.23 hontelez et al., in rural sa, reported that changes to the 2010 who guidelines led to an increase in programme costs requiring the sa government to add at least zar 3 billion to the healthcare budget to allow for an increase in personnel and medication.18 most facilities in ssa failed to fully implement the policy guidelines on time because of limited arv-stock.13 in a study from swaziland, arv-shortages delayed the implementation of the 2015 who guidelines on utt. the available stock was not sufficient for those already on treatment.24 walensky et al. reported that delays in obtaining baseline blood-test results delayed the sa-implementation of art-guidelines in 2010. the 2-week turnaround time resulted in people not returning for results. laboratory services were not readily accessible in rural areas and specimen-transport-delays resulted in the samples clotting and being discarded.5 staff shortages in ethiopia were identified as a barrier to implementation of the 2010 art guidelines. in some facilities, there was neither a doctor nor a qualified nurse trained to initiate art and plwh had to be referred to distant hospitals.23 theme 4: characteristics at country level world health organization guidelines are based on the best available scientific evidence and are directed to the art-needs of lmics. international guidelines unfortunately cannot speak to the individual economic and social realities of individual ssa countries. of the 20 countries addressed in this review, there are nonetheless considerable similarities such as strained healthcare systems, structural and operational barriers and the need of cost-cutting measures to support healthcare systems. with the largest art-programme on the continent, sa also carries the largest art-related financial burden.8 nigeria and uganda have similar challenges.7 funding-cuts from international donors exacerbate these challenges.12 burrage et al. had noted that despite the expanded art eligibility criteria, 20 pepfar-supported ssa countries with a high hiv-burden, had funding cuts before the release of the 2013 guidelines. this created continuing regional gaps in art coverage.14 drug-stock outs have been reported from kenya, malawi, sa, tanzania, uganda and zimbabwe.13 walsh et al. reported a similar challenge in swaziland.24 this review has highlighted delays in aligning and implementing the who-art-initiation guidelines in 20 ssa countries.14 this suggests a need for greater guidance with regard to strategy and implementation in the communities of ssa. discussion this review provides detailed information regarding who and art initiation guidelines on cd4 count threshold changes and adoption of the guidelines in ssa. there were some variations in study designs, however, all the articles focused on cd4 art-initiation changes in the who guidelines. the findings indicate that delays in adoption and implementation were frequent and widespread throughout ssa. we employed a thematic analysis and identified four crucial themes that were in all the articles. several barriers to implementing the guidelines were identified. these include costs related to providing art to eligible individuals, the shortage of staff and drugs in healthcare facilities and limited training of staff when guidelines were changed. our findings are consistent with those of pell et al., who reported that the implementation of the 2015 guidelines took > 12 months to be adopted in all ssa countries after their official release.1 mikkelsen et al. noted that in an effort to contain the demand for art, most african countries were forced to defer treatment-initiation to those eligible plwh who were well.26 whilst policy is well intentioned, it is informed only by epidemiological data. the state of the healthcare system and sociocultural factors are critical for controlling and ending the epidemic. our analysis of the financial, infrastructural, human resources for health and governance landscape in ssa, the feasibility associated with costs of implementing a utt programme indicates health systems and societal perceptions related shortcomings. although with clinical benefits, increasing the cd4 threshold has implications that reverberate across sectors: it affects budgets, infrastructure and human resources. the who-art guidelines are crafted by an international committee of experts drawn from rich and poor nations whose mandate is to provide the world’s lowand middle-income countries (lmics) with affordable high-quality art guidelines. historically, art-guideline development in high-income countries is independent of the who and takes a more local character, for example, the international aids society (ias)-usa division, the southern african hiv clinicians society, the european aids clinical society (eacs), the british hiv association and the asia-pacific hiv society, etc. liaison between the who and these regional societies and associations is constant. who guidelines committee members are also members of their national hiv-agencies. international art guidelines are almost never produced in isolation. local guidelines frequently predate the release of the who’s guidelines as local bodies require less administration/bureaucracy and can respond to new data in real time, for example, utt and the insight-start and the temprano studies, dolutegravir in first-line art and the advance trial, etc.27 mehraj et al. noted that canada implemented the 2002 who and art guidelines 2 months before its general release.28 canada had all the required capacity with regard to resources and regular staff trainings as well as mentoring in implementing the guidelines. within a space of 1 month after the release of the 2015 who and art initiation guidelines, 60% of the facilities in spain were already implementing rapid art initiation.29 this suggests that spain had already started preparing for the changes based on eacs guidelines. larsen et al. revealed that despite significant funding from pepfar, the south african national department of health is still failing to implement rapid art initiation. indeed most ssa countries have experienced fundings cuts in the past few years.30 there is a worrisome trend in ssa countries concerning the national adoption of the who-art initiation guidelines. this may explain why countries in ssa are still struggling to achieve the 90-90-90 target. despite the increase in hiv testing, rapid art initiation based on the 2015 who guidelines are yet to be achieved in ssa. furthermore, there is need for african governments to seriously consider local situations and experiences when embracing global guidelines. limitations one of the limitations of our study is that we reviewed data from ssa and possibly excluded some important articles published in languages other than english. the study included only articles focusing on cd4 threshold changes on art initiation. more articles might have been captured if language and the cd4 threshold had not been a filter. conclusion we conclude that although countries in ssa have generally adopted the who-art guidelines, implementation has frequently been delayed. we noted that the changes in guidelines were fraught with many challenges like switching from treating at a cd4 count of 200 cells/mm3 in 2002 to rapid art initiation in 2015 regardless of the cd4 level. implementation has been variable across the countries of ssa because of differences in the health systems and the availability of resources. because of the financial burden on governments, the reduction in donor funding, the rising incidence and prevalence of hiv and sometimes and the attitudes of healthcare workers, the majority of ssa countries have experienced a delay in the implementation of the guidelines. a comprehensive approach to reduce barriers whilst enhancing facilitators may improve the situation of adopting and implementing timely art initiation guidelines. acknowledgements competing interests the authors declare no conflict of interest. the funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript or in the decision to publish the results. authors’ contributions s.m.g. and m.j.c. conceptualised the study. s.m.g. did literature searches, analysis, writing and compilation of manuscript. m.j.c. supervised the processes, reading all versions. both authors have read and approved the final article. funding information this research was funded by the university of kwazulu-natal through a phd studentship bursary awarded to smg by the college of health sciences. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references 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https://doi.org/10.1097/qad.0000000000000520 mikkelsen e, hontelez jac, nonvignon j, et al. the costs of hiv treatment and care in ghana. aids (london, england). 2017;31(16):2279–2286. https://doi.org/10.1097/qad.0000000000001612 venter wdf, moorhouse m, sokhela s, et al. dolutegravir plus two different prodrugs of tenofovir to treat hiv. n engl j med. 2019;381(9):803–815. https://doi.org/10.1056/nejmoa1902824 mehraj v, cox j, lebouché b, et al. socio-economic status and time trends associated with early art initiation following primary hiv infection in montreal, canada: 1996 to 2015. j int aids soc. 2018;21(2):1-n.pag. https://doi.org/10.1002/jia2.25034 suarez-garcia i, gonzalez j, berenguer j, et al. reasons for noncompliance with the national guidelines for initial antiretroviral therapy of hiv-infected patients in spain, 2010–2015. enfermed infecc microbiol clin. 2019;37(9):580–587. https://doi.org/10.1016/j.eimc.2019.02.007 larsen a, cheyip m, tesfay a, et al. timing and predictors of initiation on antiretroviral therapy amongst newly-diagnosed hiv-infected persons in south africa. aids behav. 2019;23(2):375–385. https://doi.org/10.1007/s10461-018-2222-2 abstract introduction ethical considerations patient presentation management and outcome management and outcome discussion acknowledgements references about the author(s) linda a. mandikiyana chirimuta newlands clinic, ruedi luethy foundation, harare, zimbabwe margaret j. pascoe newlands clinic, ruedi luethy foundation, harare, zimbabwe sara lowe newlands clinic, ruedi luethy foundation, harare, zimbabwe citation mandikiyana chirimuta la, pascoe mj, lowe s. emergent dolutegravir resistance in integrase-naïve, treatment experienced patients from zimbabwe. s afr j hiv med. 2022;23(1), a1435. https://doi.org/10.4102/sajhivmed.v23i1.1435 case report emergent dolutegravir resistance in integrase-naïve, treatment experienced patients from zimbabwe linda a. mandikiyana chirimuta, margaret j. pascoe, sara lowe received: 13 july 2022; accepted: 05 sept. 2022; published: 26 oct. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract we report two cases of dolutegravir (dtg) resistance in highly treatment experienced patients. monitoring for treatment failure and adherence support is important in highly treatment experienced patients taking dtg. what this study adds: dolutegravir is the mainstay of hiv treatment programmes and emergence of drug resistance to dtg is of public health relevance. keywords: hiv drug resistance; dolutegravir; integrase strand inhibitor; antiretroviral treatment; hiv. introduction the world health organization has recommended the inclusion of the integrase strand transferase inhibitor (insti), dolutegravir (dtg), as part of first-, secondand third-line antiretroviral treatment (art) regimens. dolutegravir is co-formulated with other antiretroviral medicines, well tolerated, has a high genetic barrier to resistance and is available in generic formulations. to date, few cases of emergent dtg resistance in integrase-naïve patients have been reported,1 but it is anticipated that with increasing use across treatment regimens, more cases will emerge, particularly in highly treatment experienced patients. we describe two cases of highly treatment experienced, insti-naïve people living with hiv from newlands clinic, harare, zimbabwe, who developed insti drug-resistance mutations (drms) within 14 months of insti initiation. ethical considerations written informed consent was obtained from the patient described in this case report. the patient gave his consent to have his clinical and demographic data to be used as well as his images. ethical approval to conduct a case report on these patients was obtained from the medical research council of zimbabwe. clearance number: e/316. patient presentation case 1 an 18-year-old male patient was commenced on art in september 2010, at seven years of age. his baseline cd4 count was 145 cells/μl. his first-line art regimens were stavudine/lamivudine (3tc)/nevirapine, followed by stavudine/3tc/efavirenz (efv), followed by zidovudine/3tc/efv. viral load (vl) results were not available until 2014, at which time he was noted to have virological treatment failure. an hiv genotypic resistance test done in january 2015 showed significant nucleoside reverse transcriptase inhibitor (nrti) and non-nucleoside reverse transcriptase inhibitor (nnrti) drms with no protease inhibitor resistance (see table 1 for drms and sensitivity results). in january 2015 he was switched to second-line treatment with abacavir (abc)/3tc/lopinavir/ritonavir (lpv/r), which was later simplified to abc/3tc/atazanavir/ritonavir (atz/r). virological suppression was maintained for the duration of protease inhibitor therapy. in august 2019 he was switched to a single tablet regimen of tenofovir (tdf)/3tc/dtg; his vl was suppressed at the time of switch. table 1: historical antiretroviral treatment regimens, treatment switch reasons, viral load results and genotype mutations. virological rebound occurred 11 months after initiation of the insti regimen. the patient reported a history of suboptimal adherence to tdf/3tc/dtg; no other risk factors for virological failure were identified. despite adherence counselling his vl remained high, and an hiv genotypic resistance test taken 14 months after tdf/3tc/dtg initiation showed persistent nrti and nnrti drms, and extensive insti drms (see table 1 for mutations and sensitivity analysis). management and outcome following the genotypic resistance test, the patient was switched to tdf/3tc/boosted darunavir and adherence support was reinforced. eight weeks after the switch, the vl was 400 copies/ml and at 24 weeks, the viral load was undetectable. he continues this regimen with 3-monthly vl monitoring and adherence support. case 2 a 29-year-old female patient was diagnosed with hiv infection in june 2017 and commenced on tdf/3tc/efv. her baseline cd4 count and vl are unknown. three years later, she was switched to abc/3tc/atz/r following virological failure. four weeks after treatment switch, she developed pulmonary tuberculosis and in error was given rifampicin with atz/r for two months. for treatment optimisation reasons, the art regimen was switched to abc/3tc/dtg, but dtg was dosed at 50 mg daily with rifampicin for four months instead of twice daily according to current guidelines. the vl at switch to abc/3tc/dtg is unknown. the clinical response to treatment was poor and she was referred to newlands clinic. a vl taken after seven months on abc/3tc/dtg was 6540 copies/ml, despite adherence counselling. a genotypic resistance test taken 10 months after initiation of dtg showed extensive nrti drms and one major insti drm (see table 1 for mutations and sensitivity analysis). this patient admitted to inconsistent adherence both to tuberculosis treatment and art. management and outcome the patient was retreated for tuberculosis with adherence monitoring and the clinical response was good with weight gain and symptom resolution. on completion of six months of tuberculosis therapy, her integrase resistance data was available, but the initial sequencing of reverse transcriptase and protease had failed and was being repeated. due to the long history of poor adherence, it was assumed that backbone nrti resistance was likely; therefore, a third-line regimen consisting of tdf/3tc, darunavir in addition to twice daily dtg was considered the most robust regimen. after receiving weekly enhanced adherence support her vl at week 12 was 98 copies/ml and at week 24 was 71 copies/ml. discussion we report two cases of treatment experienced, insti-naïve patients who developed insti resistance within 14 months of starting dtg. the first patient had significant nrti resistance prior to switching to tdf/3tc/dtg and suboptimal adherence post treatment switch. the second patient also reported suboptimal adherence and may have had sub-therapeutic drug levels of dtg due to a drug interaction between dtg and rifampicin. known risk factors for incident drug resistance include suboptimal medication adherence, drug interactions, a high baseline vl and active opportunistic infections.1 a similar case from south africa has been described, of a treatment experienced patient who developed resistance to dtg after taking dtg 50 mg once a day with rifampicin, instead of the recommended twice daily dosing. rifampicin is an inducer of the ugt1a1 and cyp3a4 pathways by which dtg is metabolised, resulting in reduced serum dtg concentrations. the current world health organization recommendation is to dose dtg at 50 mg 12-hourly for patients taking both medications concurrently. integrase strand transferase inhibitor resistance in those with previous exposure to first-generation insti has been well described; however, the development of insti resistance in patients taking dtg is rare in art-naïve patients. in a systematic review, cevik et al. report 15 cases of emergent insti resistance in patients on dtg: 5 cases in art-naïve patients and 10 cases in art experienced patients.1 as increasing numbers of cases of dtg resistance are reported, the question arises as to whether patients who are treatment experienced may be at higher risk of insti resistance. the use of dtg in patients with compromised nrti backbones has raised concerns regarding the efficacy and durability of these regimens.2 however, emerging evidence from the nadia, visend and dawning trials appears reassuring that viral suppression despite the presence of nrti mutations is achievable.3,4,5 despite the good virological suppression rates achieved in these trials, it is of concern that a small percentage of participants developed treatment emergent dtg resistance; 4.0% of nadia partcipants at week 96 and 0.6% of dawning participants. although the risk of insti resistance was modest in these clinical trials, it is likely to be increased in real-world settings particularly those with failing health systems. conclusion despite the high barrier to resistance of second-generation instis, emergent drms can occur in treatment experienced insti-naïve patients. evaluation of background resistance, avoidance of drug interactions and adherence support could prevent the development of insti resistance. acknowledgements the authors would like to thank the patient who gave his consent for us to use his case as a learning tool, prof. ruedi luethy for his mentorship and guidance, mr simbarashe chinyowa and dr patience mba for their valuable input in the management of this patient, and, lastly, the ruedi luethy foundation for its support. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions the first author (l.a.m.c) was responsible for writing the original draft report and coming up with the methodology. the second author (m.j.p.) was responsible for reviewing and editing the draft and providing expert opinion on how to manage the patient and recommendations in the report of how to manage to condition discussed. the third author (s.l.) was responsible for reviewing and editing the draft report and conceptualising the idea of writing up this case report. funding information this research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. data availability data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and not an official position of any institution. references cevik m, orkin c, sax pe. emergent resistance to dolutegravir among insti-naïve patients on first-line or second-line antiretroviral therapy: a review of published cases. open forum infect dis. 2020;7(6):ofaa202. https://doi.org/10.1093/ofid/ofaa202 borghetti a, ciccullo a, lombardi f, et al. transmitted drug resistance to nrtis and risk of virological failure in naïve patients treated with integrase inhibitors. hiv med. 2021;22(1):22–27. https://doi.org/10.1111/hiv.12956 paton ni, musaazi j, kityo c, et al. efficacy and safety of dolutegravir or darunavir in combination with lamivudine plus either zidovudine or tenofovir for second-line treatment of hiv infection (nadia): week 96 results from a prospective, multicentre, open-label, factorial, randomised, non-inferiority trial. lancet hiv. 2022;9(6):e381–e393. https://doi.org/10.1016/s2352-3018(22)00092-3 mulenga lb, fwoloshi s, mweemba a, et al. dolutegravir with recycled nrtis is noninferior to pi-based art: visend trial. in: conference on retroviruses and opportunistic infections [homepage on the internet]. 2022 [cited 2022 jul 10]. available from: http://www.croiwebcasts.org/console/player/50578?mediatype=slidevideo& abound m, kaplan r, lombaard j, et al. dolutegravir versus ritonavir-boosted lopinavir both with dual nucleoside reverse transcriptase inhibitor therapy in adults with hiv-1 infection in whom first-line therapy has failed (dawning): an open-label, non-inferiority, phase 3b trial. lancet infect dis. 2019;19(3):253–264. https://doi.org/10.1016/s1473-3099(19)30036-2 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 1 kidney diseases manifesting as proteinuria or elevated creatinine are increasingly prevalent complications of hiv infection. today hiv-associated nephropathy (hivan) is a main cause of end-stage renal disease in hiv-infected african-americans, and it is likely to be a result of a recently identified genetic predisposition based on polymorphisms of the myosin heavy-chain 9 (myh9) gene.1 however, a variety of other histopathological renal diseases affect hiv-infected subjects of all ethnic groups.1 hiv-associated renal disease with overt proteinuria has been associated with poorer outcomes and increased mortality.2 moreover, an increased rate of urinary albumin excretion, even in the micro-albuminuric range, is an indicator of glomerular damage and has been found to be associated with an increased risk of cardiovascular disease (cvd) and mortality in the general population.2 the pathophysiological mechanisms underlying urinary albumin excretion and the increased risk of cvd are not fully understood. both hiv-related and non-hivrelated factors may play a role. there are few studies of albuminuria in hiv-infected patients, and most of these have been undertaken in selected small cohorts limited to the pre-combination antiretroviral therapy (cart) era. the renin-angiotensin system (ras) is a major regulator of blood pressure and vascular response to injury. continual activation of the ras is associated with hypertension and end-organ damage, including renal disease and cvd. inhibitors of the ras have become a cornerstone for the treatment of hypertension. use of these agents in patients with underlying renal disease has revealed that ras inhibition exerts an anti-proteinuric effect independent of blood pressure reduction.3 because ras intervention can be targeted at various points, it has been postulated that combining more than one of these intervention points could lead to more effective inhibition of the ras and a more robust decrement in protein excretion. several studies support the use of combination therapy with angiotensinconverting enzyme inhibitors (ace-is) and angiotensin receptor blockers (arbs) in the general population,4 but there are no data on dual ras blockade effects in hivpositive patients with proteinuria. case report a 45-year-old hiv-infected black african man (cdc a2) came to the infectious disease clinic at ss annunziata hospital, chieti, italy, for follow-up. he had been treated with tenofovir + emtricitabine + efavirenz for one year at another centre in italy. his personal history included multiple sexual partners, use of illegal injected drugs, tobacco smoking and chronic hcv infection. on admission the cd4+ level was 603 cells/µl, the cd4/ cd8 ratio 0.44, the hiv-rna level <40 copies/ml, and the hcv-rna level >5×105 copies/ml. levels of the transaminases and glucose and lipid parameters were within normal limits, the glomerular filtration rate (gfr) assessed by the mdrd logarithmic model (mdrd-gfr) was 114 ml/min/173 m2, and the urinary albumin level was 1.5 g/l. the blood pressure (bp), measured with a mercury sphygmomanometer with an appropriately sized cuff after the patient had rested in a seated position, was elevated at 150/100 mmhg. treatment with 10 mg lercanidipine daily was started, strictly monitoring possible side-effects and interactions with cart. after 1 month of antihypertensive therapy the bp had fallen to effects of dual renin-angiotensin system blockade on proteinuria in a hypertensive black african hivinfected patient c a s e s t u d y – h i v a n d t h e k i d n e y s claudio ucciferri1, md katia falasca1, md paola mancino1, md roberto tommasi2, md alfonso tatasciore2, md jacopo vecchiet1, md 1infectious disease clinic – department of medicine and science of aging, g d’annunzio university, chieti, italy 2institute of cardiology, center of excellence on aging, g d’annunzio university kidney diseases manifesting as proteinuria or elevated creatinine are increasingly prevalent complications of hiv infection. we report the effects of dual renin-angiotensin system blockade on proteinuria in a hypertensive black african hiv-infected patient. 41 www.saaids.com have you or your organisation shown exceptional courage or made an extraordinary contribution in the fight against hiv/aids? tell us all about it in a short essay of 300 words and stand the chance to win r75 000 cash in the dira sengwe leadership in aids award 2011 and attend the 5th sa aids conference in durban from 7 – 10 june 2011 for free, with all your travel and accommodation expenses paid. the winner will be announced at the opening session of the 5th sa aids conference in front of 5000 or more conference delegates. read the rules of the competition on www.saaids.com and submit your entry online, or send it to aids2011@foundation.co.za theme closing date for entries: 13 may 2011 read more about the 5th sa aids conference on register online to attend 5th sa aids conference 7–10 june 2011 icc • durban • south africa tm leadership, delivery & accountablity a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 120/90 mmhg without adverse effects, while the urinary albumin level and mdrd-gfr were 1.21 g/l and 106 ml/ min/173 m2, respectively. a change in cart, withdrawing tenofovir, was proposed, but the patient refused it. as a consequence, in spite of the improved mean bp (130/85 mmhg), the albuminuria progressively worsened over the following months (to 2.52 g/l, with the mdrd-gfr rising to 117 ml/min/173 m2). the patient refused renal biopsy or cart changes. administration of 300 mg irbesartan daily was then started in order to improve the renal dysfunction; after a month, while the bp and mdrd-gfr remained stable, the urinary albumin level had decreased only to 150 mg/dl. we therefore added lisinopril 20 mg/d to achieve dual blockade of the ras. after 5 months the urinary albumin level had fallen to 0.285 g/l without any change in bp, mdrd-gfr or viroimmunological parameters (fig. 1). discussion hiv infection is a strong risk factor for renal disease because of the presence of proteinuria, independent of other risk factors. previously reported risk factors for hiv-related proteinuria include both traditional hiv-specific markers, such as cd4 lymphocyte count and hiv rna levels, and several traditional renal and cardiovascular risk factors, such as higher systolic bp and insulin resistance. african-americans, older people and those with a lower gfr and hepatitis c co-infection are also at increased risk.1 the potential nephrotoxicity induced by cart may considerably increase the risk of renal disease. although previous studies of the longitudinal effects of cart on proteinuria are limited, certain frequently used antiretroviral medications such as tenofovir have been associated with acute renal failure. moreover, there is increasing evidence that hiv-infected patients have hypertension requiring pharmacological treatment, which also represents an important risk factor for kidney disease. the choice of antihypertensive therapy for hiv-infected cart-treated patients must be made carefully. the classes of antihypertensive drugs that block the ras, such as ace-is and arbs, may be ideal. several studies have reported beneficial effects of dual ras blockade on kidney disease progression and proteinuria reduction in the general population. a more recent trial (improve)5 has shown the effectiveness of fixed-dose combination arb/ace-i therapy in reducing albuminuria in non-hivinfected hypertensive subjects. it is therefore advisable to use combination arb/ace-i therapy in more complex cases to obtain a greater nephroprotective effect. data on ace-i and arb use in hiv-infected patients are anecdotal,6 and there have been no well-designed studies on this subject to date. our patient’s race was an additional problem in selecting effective antihypertensive therapy, because antihypertensive regimens that inhibit the ras may be ineffective in black patients. in the african-american non-infected population, responsiveness to monotherapy with ace-is, arbs and beta-blockers may be poorer than responsiveness to diuretics and calcium channel blockers (ccbs).7 in our patient dual ras blockade therapy did not have substantial effects on bp control, while the main antihypertensive effect was achieved with the use of the ccb lercanidipine, in the absence of important interactions with cart. lercanidipine did not improve proteinuria in our patient. this may indicate that hiv-related kidney disease is not only correlated with hypertension levels. the use of combined therapy with 20 mg lisinopril plus 300 mg irbesartan, obtaining a dual ras blockade, produced a marked improvement in kidney function, with a -88% decrease from the baseline urinary albumin level. conclusion this case shows that dual blockade of the ras with combined ace-i and arb therapy reduced albuminuria in an hiv-infected black african patient. furthermore, it indicates that the lowering of protein excretion brought about by dual ras blockade is independent of bp reduction. available data suggest that the beneficial effect achieved with combination therapy derives from more prolonged and complete inhibition of the ras rather than from a physiological interaction between the ace-i and the arb.4 this more extensive ras inhibition may provide incremental end-organ protection through its effects on chronic vascular responses to injury. references 1. szczech la, gupta sk, habash r, et al. the clinical epidemiology and course of the spectrum of renal diseases associated with hiv infection. kidney int 2004;66:1145-1152. 2. hillege hl, fidler v, diercks gf, et al. urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. circulation 2002;106:1777-1782. 3. berl t. renal protection by inhibition of the renin-angiotensin-aldosterone system. j renin angiotensin aldosterone syst 2009;10:1-8. 4. linas sl. are two better than one? angiotensin-converting enzyme inhibitors plus angiotensin receptor blockers for reducing blood pressure and proteinuria in kidney disease. clinical journal of the american society of nephrology 2008;3:s17-s23. 5. bakris gl, ruilope l, locatelli f, et al. treatment of microalbuminuria in hypertensive subjects with elevated cardiovascular risk: results of the improve trial. kidney int 2007;72(7):879-885. 6. ucciferri c, mancino p, vecchiet j, falasca k. beneficial effects of telmisartan in hiv+ diabetic insulin-dependent patient. int j immunopathol pharmacol 2009;22:853-858. 7. ferdinand kc, armani am. the management of hypertension in african americans. critical pathways in cardiology 2007;6:67-71. fig. 1. urinary albumin levels over the treatment period. there are no conflicts of interest. no financial support was given for the study. 42 a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e hiv and serum protein electrophoresis patterns in kwazulunatal: a retrospective study o r i g i n a l a r t i c l e n tathiah, bsc (hons), mb chb, dip hiv med, ms department of public health medicine, university of kwazulu-natal, durban r parboosing, mb chb, fcpath (virol) sa, mmed (virol), ms department of virology, national health laboratory service/university of kwazulu-natal d pudifin, mb chb, fcp (sa), frcp department of medicine, university of kwazulu-natal s mahabeer, mb chb (hons), lrcsi, lrcpi, mmed, frnzcgp lancet laboratories, durban objective. to describe the effect of hiv serostatus on serum proteins, serum protein electrophoresis (spep) patterns and monoclonal bands. setting. inkosi albert luthuli central hospital, durban. design. retrospective, anonymous analysis of routine laboratory results. results. monoclonal bands were not increased in hiv-positive patients, who were younger and had increased polyclonal and oligoclonal bands and total proteins when compared with hiv-negative patients. the hallmark of hiv infection is impairment and dysregulation of the immune system. specific defects in the humoral arm of the immune system, such as polyclonal activation of b cells, have been widely described in hiv infection. an increased incidence of plasma cell disorders, such as benign polyclonal gammopathy, monoclonal gammopathy, oligoclonal gammopathy, b-cell lymphomas and multiple myeloma, has also been reported in hiv-positive individuals. these abnormalities occur at a significantly younger age (mean 33 years) than in hiv-negative patients. hyperactivated b cells secrete hiv-specific and nonspecific antibodies. serum protein plectrophoresis (spep) is a technique that separates proteins on the basis of their electrical charge in order to determine specific patterns in certain diseases. hiv and other infections may have an influence on serum electrophoresis patterns. there may also be ethnic and racial differences in the effects of hiv on immunoglobulin production.1 the prevalence of monoclonal gammopathies, for example, is significantly different between racial groups.2 immunoglobulin levels may also vary depending on differing risk behaviours.1 there is also controversy regarding the association between hiv infection and multiple myeloma. some studies have documented an increased risk (approximately 4.5-fold) of multiple myeloma in hiv/aids patients,3,4 while other studies have not.5 previous studies in south africa have not shown a link between multiple myeloma and hiv infection.3,4,6 however, the diagnosis of myeloma may be difficult or delayed in hiv-positive patients because features such as anaemia and recurrent bacterial infections occur both in multiple myeloma and hiv infection.5 the hallmark laboratory feature of multiple myeloma is the presence of monoclonal bands on spep, although these bands may appear with other conditions. the aims of this study were to determine whether there was a higher prevalence of monoclonal bands in hivpositive patients and to describe differences in serum protein concentrations and electrophoresis patterns in hiv-positive and hiv-negative patients in kwazulu-natal province. methods this retrospective anonymous database study utilised results of routine tests conducted at inkosi albert luthuli central hospital, durban. all patients who had spep performed at this hospital during 2006 were entered into the study. approximately 20% of these patients had clinically suspected haematological malignancies. serum protein levels, electrophoresis patterns, basic demographic data and hiv enzyme-linked immunosorbent assay (elisa) results were downloaded anonymously and compared and described in hiv-positive and negative patients. patients without hiv results were excluded. the chi-square test and fisher’s exact test were used for 24 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 1 the comparison of categorical data, and student’s t-test for the comparison of continuous variables. statistical analysis was performed on stata™10 (statacorp, texas, usa). the study was approved by the biomedical research ethics committee of the nelson r mandela school of medicine, university of kwazulu-natal. results results are set out in table i. discussion hiv-positive patients in whom electrophoretograms were performed were significantly younger than those who were hiv negative. these data are similar to those of other studies, in which indications for spep occur in hiv-positive individuals at a significantly younger age (mean 33 years) than in hiv-negative patients.3 the serum protein abnormalities and spep patterns concur with other studies in hiv-positive individuals.7 the increase in total proteins in hiv-positive individuals may be due to the increase in the igg fraction of the gamma globulins. this is likely to be caused by hyperactivation of b cells due to chronic antigenic stimulation by antigens of hiv, viruses such as hepatitis c, or other opportunistic infections. polyclonal gammopathy and oligoclonal bands were significantly increased in hivpositive patients. the majority of oligoclonal bands were present on a background of polyclonal gammopathy, suggesting simultaneous polyclonal b-cell activation and selective b-cell oligoclonal proliferation. the pathologist interpreting the electrophoretograms in this scenario should repeat the spep, with dilutions, to minimise the interference of the background polyclonal gammopathy. immune paresis, which results from the suppression of normal globulins due to the uncontrolled proliferation of the clone causing the b-cell malignancy, was, as expected, higher in the hiv-negative group. the prevalence of monoclonal bands in hiv-positive patients was 8%, which is higher than previously described (2.5%); estimates of the prevalence of monoclonal bands, however, vary widely. there was no statistical difference in the prevalence of monoclonal gammopathy between the hiv-seronegative and positive groups. however, it is possible that monoclonal bands in hiv-positive patients may be obscured by the background polyclonal gammopathy. the absence of a monoclonal spike therefore does not altogether exclude the possibility of a monoclonal plasma cell disorder in hiv-positive patients. this study is biased because only patients who had indications for both spep and hiv tests were included. however, multiple myeloma and spep abnormalities are likely to be even less prevalent in patients who have no indications for either of these tests. the conclusion of this study, that monoclonal bands are not significantly increased in hiv-positive patients, is therefore valid despite this bias. conclusion hiv-positive patients often succumb to opportunistic infections and other malignancies at a relatively young age. with the roll-out of antiretroviral therapy in south africa, the incidence of multiple myeloma and other hiv seropositive hiv seronegative p-value n 102 229 age (yrs) 37.0 (33.3 40.8) 47.1 (44.7 49.5) <0.00001* albumin (g/l) 32.9 (31.2 34.6) 38.0 (36.8 39.1) 0.00001* total globulin (g/l) 55.7 (52.2 59.2) 40.0 (37.8 42.2) 0.00001* alpha-1 fraction (g/l) 3.5 (3.2 3.7) 3.3 (3.2 3.5) 0.3* alpha-2 fraction (g/l) 9.7 (9.1 10.3) 9.2 (8.9 9.5) 0.1* total proteins (g/l) 89.8 (86.4 93.2) 78.5 (76.4 80.6) 0.00001* beta fraction (g/l) 9.4 (8.8 10.0)) 8.8 (8.3 9.2) 0.1* gamma globulins (g/l) 33.2 (29.8 36.5) 18.8 (16.7 20.9) 0.00001* igg (g/l) 27.2 (21.8 32.6) 14.0 (12.0 16.0) 0.00001* iga (g/l) 3.6 (2.3 4.9) 3.3 (2.5 4.1) 0.7* igm (g/l) 1.9 (1.4 2.5) 1.7 (0.6 2.8) 0.8* beta-2-microglobulin (mg/l) 5.9 (3.8 7.9) 4.3 (2.4 6.2) 0.3* c-reactive protein (mg/l) 88 (-17.4 193) 28 (12.0 44.1) 0.06* spep patterns normal 20/102 (19%) 71/228 (31%) 0.03†‡ polyclonal gammopathy 52/102 (51%) 42/228 (18%) 0.00001†‡ oligoclonal bands 34/102 (33%) 31/227 (14%) 0.00001†‡ monoclonal gammopathy 8/102 (8%) 37/228 (16%) 0.055‡ (2.3 13.15) (11.4 21) immunoparesis 0/102 (0%) 27/228 (12%) 0.00001†‡ p-values in bold are significant at α=0.05. figures in parentheses are percentages where indicated, or otherwise represent the 95% confidence intervals. *t-test. †chi-square test. ‡fisher’s exact test. table i. age, protein levels and spep findings in hiv-positive and negative patients (n=331) 25 a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e malignancies may increase as patients on highly active antiretroviral therapy (haart) survive longer.5 furthermore, the increase in cd4 t-cell numbers following haart may promote b-cell maturation and differentiation to mature plasma cells, with possible emergence of neoplastic clones. although monoclonal bands were not increased in hiv-positive patients in this study, vigilance is nevertheless prudent, since multiple myeloma may occur at a younger age (<40 years) and the interpretation of spep patterns is complex in hivpositive patients. references 1. mcgowan jp, shah ss, small cb, et al. relationship of serum immunoglobulin and igg subclass levels to race, ethnicity and behavioral characteristics in hiv infection. med sci monit 2006;12:cr11-16. 2. rajkumar sv, lacy mq, kyle ra. monoclonal gammopathy of undetermined significance and smoldering multiple myeloma. blood rev 2007;21:255-265. 3. pantanowitz l, dezube bj. editorial comment: multiple myeloma and hiv infection – causal or casual coincidence? aids read 2003;13:386-387. 4. stein l, urban mi, o’connell d, et al. the spectrum of human immunodeficiency virus-associated cancers in a south african black population: results from a casecontrol study, 1995-2004. int j cancer 2008;122:2260-2265. 5. yee tt, murphy k, johnson m, et al. multiple myeloma and human immunodeficiency virus-1 (hiv-1) infection. am j hematol 2001;66:123-125. 6. sitas f, pacella-norman r, carrara h, et al. the spectrum of hiv-1 related cancers in south africa. int j cancer 2000;88:489-492. 7. kapsenberg lc, cronje hs, van jaarsveld h. serum protein electrophoresis in hiv seropositive and seronegative pregnant women. int j gynaecol obstet 2004;84:254-258. 26 e d it o r ia l june 2014, vol. 15, no. 2 sajhivmed 43 message from the editor most editions of sajhivmed are posted to you with a range of different inserts – materials sent in hard copy in addition to the journal itself – related to different aspects of hiv prevention and treatment. several times a year, this includes hiv treatment bulletin (htb) south, an invaluable guide to recent developments in hiv medicine and antiretroviral therapy (art). other materials have included guides on specific aspects of hiv medicine, such as those assisting in the management of hiv-tb co-infection. with this edition of the journal, we are sending a particularly important insert: the national department of health’s new contraception & fer­ tility planning guidelines. experience over the last decade has de mon strated that unintended pregnancies are commonplace in hiv-infected women, and that preventing such preg nancies is a critical but neglected ‘upstream’ intervention to promote the health of hiv-infected women. in turn, these new guidelines place special emphasis on appropriate contraceptive choices for hiv-infected women, and feature integration of family planning services as a key intervention within hiv care and treatment programmes. delivering appropriate counselling and contraception (when indicated) is a basic responsibility of every healthcare provider working in adult hiv services, and we hope that this month’s insert will contribute towards this end. this edition of the journal features several important contributions that demonstrate the interplay of hiv medicine with an array of health systems and social concerns. for patients presenting with meningitis symptoms, lumbar puncture (lp) is a routine investigation in most parts of the coun try.[1] but laboratory access and the ability to examine cerebrospinal fluid is limited in many primary healthcare settings across africa, and evidence-based approaches to help identify patients who require lp (often through referral) are needed. [1] to help address this, loughborough et al.[1] used routine hospital audit data from kwazulu-natal to investigate factors associated with positive lp findings. in addition to providing local insights into the aetiology and predictors of positive lp results, this original article demonstrates the value of thoughtful analysis of routinely collected clinical data. in a similar vein, mnyani et al.[2] use routine antenatal and art clinic data from johannesburg to examine how delays in art ini tiation in hiv-infected pregnant women changed after the inte gration of nurse-initiated management of art (nimart) services into antenatal care. the results are surprising: of the five health facilities surveyed, four experienced increased delays in antenatal art initiation after the start of nimart, suggesting that integrating art into other primary care services is not always straightforward. in addition, in reviewing the implications of new national legislation governing health research, strode et al.[3] explain how hiv prevention and treatment research involving children will be hindered, limiting the ability of research efforts to improve the health of young people across the country. in addition to these examples of hiv-related health programme and policy research, the journal continues to present high-quality clinical research around hiv prevention and treatment. apalata et al.[4] present the results of research on the association between vaginal infections and cervicovaginal shedding of hiv. while they demonstrate no association between vulvovaginal candidiasis and hiv shedding, their data confirm that plasma viraemia is a strong – but by no means complete – predictor of hiv shedding in the female genital tract. also in this issue, three case reports explore the potential for iatrogenic injury in hiv-related healthcare services. first, zingela et al.[5] present an important case of stevens-johnson syndrome in a patient receiving both antipsychotic medications and a nevirapine-based antiretroviral regimen, reminding us of the pharmacological complexities of managing mental disorders in hiv-infected patients. meanwhile, while we usually think of healthcare providers as being at risk of hiv transmission due to needlestick injuries, ngene et al.[6] present a case of a needlestick injury causing hiv exposure between patients. they attributed this particular case to overcrowding within health facilities, another demonstration of how patient safety may be compromised in overburdened health systems. finally, moodley et al.[7] present two cases of a hereditary cause of optic neuropathy, here associated with nucleoside reverse tran scriptase inhibitor use. while the mutations reported here are relatively rare, this report demonstrates the complex differential diagnoses of progressive visual impairment in hivinfected patients. happy reading. landon myer associate professor, school of public health & family medicine, university of cape town, south africa landon.myer@uct.ac.za references 1. loughborough w, abouyannis m, jones l, garach s. which clinical parameters predict a csf diagnosis of meningitis in a population with high hiv prevalence? southern african journal of hiv medicine 2014;15(2):5054. [http://dx.doi.org/10.7196/sajhivmed.1004] 2. mnyani cn, marinda e, struthers h, gulley m, machepa r, mcintyre j. timing of antenatal care and art initiaion in hiv-infected pregnant women before and after introduction of nimart. southern african journal of hiv medicine 2014;15(2):55-56. [http://dx.doi.org/10.7196/sajhivmed.1009] 3. strode a, richter m, wallace m, toohey j, technau k. failing the vulnerable: three new consent norms that will undermine health research with children. southern african journal of hiv medicine 2014;15(2):46-49. [http://dx.doi. org/10.7196/sajhivmed.1014] 4. apalata t, carr wh, longo-mbenza b, sturm wa, moodley p. association between symptomatic vulvovaginal candidiasis and hiv rna levels in plasma and genitcal secretions among women on haart. southern african journal of hiv medicine 2014;15(2):57-64. [http://dx.doi.org/10.7196/ sajhivmed.975] 5. zingela z, bronkhorst a, qwesha wm, magigaba bp. fatal nevirapineinduced stevens-johnson syndrome with hiv-associated mania. southern african journal of hiv medicine 2014;15(2):65-66. [http://dx.doi. org/10.7196/sajhivmed.1011] 6. ngene nc, onyia co, moodley j, titus mj. needlestick injury in a pregnant inpatient in an overcrowded hospital. southern african journal of hiv medicine 2014;15(2):66-68. [http://dx.doi.org/10.7196/sajhivmed.1048] 7. moodley a, bhola s, omar f, mogambery j. antiretroviral therapy-induced leber’s hereditary optic neuropathy. southern african journal of hiv medicine 2014;15(2):69-71. [http://dx.doi.org/10.7196/sajhivmed.1056] e d it o r ia l mailto:landon.myer@uct.ac.za http://dx.doi.org/10.7196/sajhivmed.1004] http://dx.doi.org/10.7196/sajhivmed.1009] http://dx.doi.org/10.7196/sajhivmed.1014] http://dx.doi.org/10.7196/sajhivmed.1014] http://dx.doi.org/10.7196/sajhivmed.975] http://dx.doi.org/10.7196/sajhivmed.975] http://dx.doi.org/10.7196/sajhivmed.1011] http://dx.doi.org/10.7196/sajhivmed.1011] http://dx.doi.org/10.7196/sajhivmed.1048] http://dx.doi.org/10.7196/sajhivmed.1056] the southern african journal of hiv medicine                                                  september  2010 5 the wonderful world cup and a devastating public sector strike are behind us. one generated national pride and reminders that we are the rainbow nation with fabulous potential, and the other national shame that compassion and humanity for the most poor and vulnerable could be sacrificed for material gain. with the enormous responsibility of lifelong antiretroviral treatment for over a million individuals we need a health system that is reliable, responsible and obsessive. the concept that health facilities would not be open, or worse still that patients would be barred from accessing those services, flies in the face of all our hard-won battles for adherence to pills and programmes. you may have seen the economist of 9 august 2008, featuring an article referring to global art programmes, from which i quote: ‘as a result, taxpayers are accumulating an indefinite – and indefinitely growing – responsibility of keeping people alive’. many first-world taxpayers have been generous in helping to expand and sustain our treatment programme – but following international news reports of treatment interruptions as a consequence of the strike, some of them may well be questioning our own commitment to that responsibility. we have a clinically focused edition for you this quarter! cassim and colleagues re-ignite the hope that we can eradicate paediatric hiv in south africa with a report on the outcomes of haart-based pmtct in the private sector in kzn. kwaan and colleagues, also from kzn, report on adherence strategies in a treatment cohort in cato manor. they emphasise simple strategies such as tablet return as a way to encourage dialogue with patients about pill taking. an interesting paper describes traditional healer beliefs and practices around hiv and art, and interactions between biomedical and traditional health care. it seems that we still have a long way to go in terms of the two sectors really understanding each other’s role. ugandan colleagues present data on the immune reconstitution inflammatory syndrome among adolescents – numbers are small, but it is a point well made. this age group typically presents us with adherence challenges above those in adult and paediatric care, and treatment experiences that may be unpleasant need careful handling if we are to keep our adolescents adherent. polly clayden and co-authors summarise what we know (and do not know) about efavirenz in pregnancy. two clinical case studies of gastro-intestinal mycobacterial infection follow, expertly commented on by andrew black from baragwanath hospital. one is from pretoria, the other all the way from taiwan, where hiv is really only just emerging. many will feel a sense of foreboding or déjà vu as authors kao and hung make a plea for thinking of hiv co-infection in patients with extra-pulmonary tb. two clinical cases of well-known opportunistic infections occurring in strange places follow. the first, again from uganda, is a case of toxoplamosis of the hard palate, and the second pneumocystis jirovecii in the external ear canal. finally, mitha and colleagues describe an unusual manifestation of lipodystrophy, namely multiple subcutaneous lipomas, which i hope will stir up interest and invite some comment. finally, we have a letter from the blood transfusion service. this section of the journal could do with much more traffic! the journal office has been offered some additional editorial help, which should enable more efficient management of your copy. thanks to all who have been so patient. i am sure you will see a difference soon. linda-gail bekker editor f r o m t h e e d i tor m e s s a g e f r o m t h e e x e c u t i v e the society is about to embark on some of the most profound changes in its history. an external objective evaluation has pretty much told us what we knew – that we are too big and successful to continue with the current structure. the executive met for 2 days in april, to study the evaluation and suggest changes. many of these are simply improved corporate governance – tightening up our legal, oversight and financial systems, tackling our voting systems (traditionally, only doctors could vote), the structure of the executive, how we administer our branch meetings, providing more support to nurses, creating committees to handle specific projects and areas of works, updating our it and data systems (nonpaid-up members: be afraid) – all sensible stuff any organisation needs to do as it moves out of adolescence. it is an exciting time. but we’ll keep giving you the journal, transcript, the discussion fora, the branch meetings, more guidelines, the new nursing journal, the skills workshops, support for bursaries and an updated website – all the stuff that makes us good and wholesome. francois venter president pg23-25.html case report microscopy ‘aids’ in diagnosing a febrile infant annelize crous, mb chb, da (sa) department of haematology, university of pretoria, and national health laboratory services, tshwane academic division adele visser, mb chb, pg (dip) tm, dtm&h, mmed (clin path), fcpath (sa) (clin path) department of microbiology, division of clinical pathology, university of pretoria, and national health laboratory services, tshwane academic division a 5-month-old south african girl presented to a casualty department with a short history of fever. general examination did not reveal organomegaly or neck stiffness. in keeping with local guidelines, malaria was excluded on antigen testing and microscopy (thick and thin smear with giemsa stain).1 rickettsia typhi, r. conorii and coxiella burnetti were also excluded on the basis of serological testing. the full blood count revealed pancytopenia with a haemoglobin (hb) level of 7.9 g/dl (normal 10 15 g/dl), a white cell count (wcc) of 1.17×109 /l (normal 5.50 18.00×109 /l) with an absolute lymphocyte count of 0.80×109 /l, and a platelet count of 47×109 /l (normal 140 350×109 /l). biochemical values were suggestive of renal dysfunction, with a serum urea level of 9.6 mmol/l (normal 1.4 5.0 mmol/l) and a creatinine level of 180 μmol/l (normal 14 34 μmol/l), as well as a markedly elevated c-reactive protein level of 243.1 mg/l (normal 0.1 7.5 mg/l). on investigation of the patient’s immune status, it was established that she was hiv-1-positive as confirmed by hiv-1 dna amplicor assay version 1.5 (roche diagnostics, mannheim, germany), with an hiv-1 viral load of 2 738 930 rna copies/ml by abbott m2000 real time hiv-1 assay (abbott diagnostics, johannesburg) and a cd4+ lymphocyte percentage of 28%. initial standard paediatric blood cultures did not yield any growth after 7 days of incubation. a follow-up full blood count, performed 2 days after the initial investigations and assayed on the advia 2120 (bayer healthcare, diagnostic division, isando, gauteng), differed markedly from the previous results, showing a wcc of 13.83×109 /l with an absolute lymphocyte count of 10.99×109 /l. on microscopic examination of the peripheral blood smear (fig. 1, a) these counts could not be verified and the leucocytes appeared markedly reduced. in addition, fungal elements could be demonstrated (fig. 1, a and b). subsequent blood cultures, performed in paediatric bacterial blood culture bottles, confirmed the aetiological agent to be candida albicans. fungal morphology clearly showed the presence of oval yeast forms, slightly smaller than a lymphocyte nucleus (fig. 1, a), with blastoconidia and pseudohyphae (fig. 1, b). the fungus was identified by demonstrating formation of a germ tube on 4-hour incubation in horse serum.2 subsequent antifungal susceptibility, performed on the vitek 2 system (biomerieux, randburg, gauteng), demonstrated sensitivity to all antifungal agents tested (amphotericin b, fluconazole and voriconazole). discussion hiv-1 infection has been established as a risk factor for fungaemia in both children3 and adults.4 the routine use of fungal blood cultures remains controversial, being advocated by some authors6 and discouraged by others.7 microscopic examination of the peripheral blood smear revealed a significant leucopenia, despite contradicting automated counts. wccs as well as differential leucocyte counts have been described to be influenced by high fungal loads of candida spp.8 the advia 2120 uses both a lobularity and a peroxidise channel for leucocyte identification and quantification.8 in this case a comparison error had been flagged, indicating the probability of falsely elevated counts. this error, however, does not reflect on the laboratory report issued to the clinician, and is an analytical issue that needs to be addressed by the technologist and pathologist in the laboratory setting. owing to their small size as well as their peroxidise-negative properties, the yeast cells had been identified as lymphocytes by the automated analyser (fig. 1, c). considering the increased prevalence of fungal infections among hiv-1-positive patients,3 full blood count evaluation is best accompanied by morphological evaluation to detect any discrepancies between automated counts and actual observation.8 in most laboratory settings, morphology is evaluated once the clinician requests a differential count. clinicians should further request differential counts once any full blood count parameters show significant abnormalities, or when there is a clinical suspicion of disease affecting the haematological system, including bleeding tendencies, infection, hepatomegaly, splenomegaly, lymphadenopathy, etc.10 in this clinical case, the rapid change in results over a 2-day period should have prompted the clinician to suspect an analytical issue with the samples in question. references 1. zurovac d, rowe a. quality of treatment for febrile illness among children at outpatient facilities in sub-saharan africa. ann trop med parasitol 2006;100(4):283-296. 1. zurovac d, rowe a. quality of treatment for febrile illness among children at outpatient facilities in sub-saharan africa. ann trop med parasitol 2006;100(4):283-296. 2. winn w, allen s, janda w, et al. mycology. 6th ed. philedelphia: lippincott williams & wilkins, 2006. 2. winn w, allen s, janda w, et al. mycology. 6th ed. philedelphia: lippincott williams & wilkins, 2006. 3. walsh t, gonzalez c, roilides e, et al. fungaemia in children infected with the human immunodeficiency virus: new epidemiologic patterns, emerging pathogens, and improved outcome with antifungal therapy. clin infect dis 1995;4:900-906. 3. walsh t, gonzalez c, roilides e, et al. fungaemia in children infected with the human immunodeficiency virus: new epidemiologic patterns, emerging pathogens, and improved outcome with antifungal therapy. clin infect dis 1995;4:900-906. 4. launay o, lortholary o, bouges-michel c, jarrousse b, bentata m, guillevin l. candidemia: a nosocomial complication in adult with late-stage aids. clin infect dis 1998;5:1134-1141. 4. launay o, lortholary o, bouges-michel c, jarrousse b, bentata m, guillevin l. candidemia: a nosocomial complication in adult with late-stage aids. clin infect dis 1998;5:1134-1141. 5. hung c, hsueh p, hsieh s, liu c, chen m, luh k. bacteremia and fungemia in patients with advanced human immunodeficiency virus (hiv) infection in taiwan. j formos med assoc 1998;97(10):690-697. 5. hung c, hsueh p, hsieh s, liu c, chen m, luh k. bacteremia and fungemia in patients with advanced human immunodeficiency virus (hiv) infection in taiwan. j formos med assoc 1998;97(10):690-697. 6. tattevin p, chevrier s, gangneux j. can we describe the epidemiolgy of candidemia without using selective blood culture bottles for fungus detection? clin infect dis 2004;39:598-599. 6. tattevin p, chevrier s, gangneux j. can we describe the epidemiolgy of candidemia without using selective blood culture bottles for fungus detection? clin infect dis 2004;39:598-599. 7. mess t, daar e. utility of fungal blood cultures for patients with aids. clin infect dis 1997;25:1350-1353. 7. mess t, daar e. utility of fungal blood cultures for patients with aids. clin infect dis 1997;25:1350-1353. 8. kim h, park b, lee m. effects of bacteria and yeast on wbc counting in three automated hematology counters. ann hematol 2008;87:557-562. 8. kim h, park b, lee m. effects of bacteria and yeast on wbc counting in three automated hematology counters. ann hematol 2008;87:557-562. 9. branda j, kratz a. effects of yeast on automated cell counting. am j clin pathol 2006;126:248-254. 9. branda j, kratz a. effects of yeast on automated cell counting. am j clin pathol 2006;126:248-254. 10. bain b. diagnosis from the blood smear. n engl j med 2005;353(5):498-507. 10. bain b. diagnosis from the blood smear. n engl j med 2005;353(5):498-507. fig. 1. peripheral blood smear from a 5-year-old hiv-1-positive girl, showing marked fungaemia: a – size of fungal element in relation to lymphocyte (arrow); b – closer view of fungal elements, showing oval yeast forms with blastoconidia and pseudohyphae; c – peroxidase channel on adiva 2120 analyser. the encircled area depicts the region where lymphocytes are typically noted based on both size and peroxidase negativity. in this instance, these events are produced by yeast cells rather than lymphocytes. approaches.html forum approaches to tenofovir and abacavir drug shortages in south africa: a guide for clinicians laurie schowalter, francesca conradie, for the southern african hiv clinicians society corresponding author: f conradie (fconradie@witshealth.co.za) shortages of the nucleoside reverse transcriptase inhibitors (nrti) abacavir and tenofovir have been reported recently at health facilities across south africa.the society issued the following clinical advice to healthcare providers experiencing shortages on 29 march 2012. these recommendations are intended only as a guide to clinical therapy, based on expert consensus and best available evidence. treatment decisions for patients should be made by their responsible clinicians, with due consideration for individual circumstances. s afr j hiv med 2012;13(2):56-57. tenofovir if rationing of tenofovir (tdf) is required at a facility, the following patients should be prioritised to receive remaining tdf stocks: • patients with chronic hepatitis b, as indicated by positive hep b surface antigen. interrupting tdf can cause life-threatening rebound hepatitis in these patients. • patients who have experienced severe side-effects from d4t or azt previously. • if the patient developed symptomatic hyperlactataemia previously, d4t should not be used as this may result in life-threatening lactic acidosis. in the event of tdf shortages, and if a patient on tdf is v ir o lo g i c a ll y c on t r o ll e d: • the patient can in the short term be safely switched to d4t 30 mg bd or azt 300 mg bd. • d4t is well tolerated in the short term, but prolonged use (>6 months) results in high rates of mitochondrial toxicity, causing peripheral neuropathy, lipoatrophy and hyperlactataemia. in any patient on d4t >4 months who complains of nausea, vomiting and/or weight loss, the diagnosis of symptomatic hyperlactataemia should be excluded with a measure of blood lactate. peripheral neuropathy can be caused by d4t, so avoid in patients with pre-existing peripheral neuropathy. • short-term side-effects of azt include nausea, vomiting, headache, dizziness, fatigue, weakness and muscle pain. in addition, azt can cause bone marrow suppression and may result in severe anaemia or neutropaenia. this drug should not be started in patients with haemoglobin <8 g/dl. even if the patient has had azt previously, hb should be monitored after 4, 8 and 12 weeks after switching to azt. • it is very important to explain to the patient that both d4t and azt are given twice daily, not once daily as with tdf. if a patient is currently on tdf, and not virologically controlled: • changing a single drug in these patients may fuel development of resistance. • we recommend continuing tdf for 3 months – with step-up adherence counselling – and repeat the viral load after 3 months. if the patient becomes virally suppressed, and tdf stocks are still limited, switch tdf as described above. however, if the viral load remains detectable, switch to regimen 2. in art-naïve patients, do not delay art initiation. instead of tdf, use d4t 30 mg bd or azt 300 mg bd. counselling as to side-effects should be provided and monitoring performed as per guidelines. when tdf stocks are adequate, patients can transition immediately back to tdf from d4t or azt if they are virologically controlled and have normal creatinine levels. poor adherence during this disrupted period might have resulted in the emergence of drug-resistance. abacavir older children and adults on abacavir (abc) have faced disruption owing to stock-outs of the tablet formulation. the response in this situation is to dispense the paediatric syrup to replace the tablets. however, the syrup is not very palatable, particularly in the large quantities required for older children and adults. many of these patients cannot tolerate the syrup as it causes vomiting owing to its taste. as this threatens adherence, it may be preferable to switch these patients to an alternative nrti for the short term and reserve the syrup for the younger children who require smaller, more manageable volumes. the same principles as described for tdf above should be followed. if rationing of abc is required at a facility, children with previous lactic acidosis or peripheral neuropathy owing to d4t or azt should be prioritised to receive remaining abc stocks. in the event of abc shortages, and if a patient on abc is v ir o lo g i c a ll y c on t r o ll e d: • the patient can in the short term be safely switched to d4t 1 mg/kg twice daily (with counselling on side-effects). • patients with current or previous lipodystrophy owing to d4t may benefit from switching to azt 240 mg/m2 (with counselling on side-effects). if a patient is currently on abc, and n o t v i r olo g i c a ll y c o n tr o ll e d: • changing a single drug in these patients may fuel development of resistance. we recommend continue abc for 3 months – with step-up adherence counselling – and repeat the viral load after 3 months. if the patient becomes virally suppressed, and abc stocks are still limited, switch abc as described above. however, if the viral load remains detectable, switch to regimen 2. • children on an nnrti-based regimen should switch to a second-line pi-based regimen as per guidelines. • children on a pi-based regimen should be discussed with an expert before switching to a second-line regimen. • in adults, be alert as to why the patient is on abc. is it due to previous severe side-effects such that the patient should not be re-challenged with certain other nrtis? in art-naïve patients, do not delay art initiation. instead of abc, use d4t 1 mg/kg twice daily or azt 240 mg/m2 twice daily, with counselling on side-effects. when abc stocks are adequate, patients can transition immediately back to abc from d4t or azt when they are virologically controlled. from the editor.html from the editor sajhivmed has undergone a bit of a facelift since the previous issue. for more than a decade, the layout and formatting had been essentially unchanged, and a revamp was in order to provide a more contemporary profile suitable to a research-driven publication. the new look was shaped by the talented team at the health & medical publishing group (who produce the samj and several other prominent journals, as well as the south african medicines formulary), particularly siobhan tillemans and melissa raemaekers. thanks to both, and the entire hmpg team, for their assistance! along with the new aesthetic, we are pleased to announce a new editorial board to support the journal’s work. the names on the masthead will be known to many readers, as they represent some of south africa’s leading researchers and clinicians working in hiv/aids. in addition, there are some exciting developments planned to increase the international visibility and accessibility of sajhivmed, and i will keep you posted on news as it emerges. this edition of the journal contains several notable items, with a particular focus on laboratory assessments. there is ongoing interest in the new markers that may be used to monitor hiv disease progression and response to antiretroviral therapy; bipath and colleagues suggest that neopterin levels may be more strongly correlated with standard hiv disease markers (e.g. viral load or cd4 cell count) than either c-reactive protein or procalcitonin. in another interesting piece, gounden et al. investigate a case of how host genetics – here, allelic variation in the genes that promote tumour necrosis factor-alpha – may influence hiv disease progression. both these studies present intriguing findings that point to the need for further research with a particular view towards their clinical utility. a more practical laboratory assessment comes from swaziland, where mlawanda and colleagues examined the variability of cd4 enumeration both within and between labs – a real-world concern that is commonly raised by healthcare providers and patients alike. although the sample sizes are small, the results are somewhat reassuring, with reasonable agreement in results between labs. two case series explore common complications of advanced hiv disease, including cmv retinitis (laher), suggesting reasonable outcomes despite the absence of systemic therapy, and pneumocystis pneumonia (shaddock), providing evidence for lung fibrosis in individuals with advanced disease requiring ventilation. this edition also continues sajhivmed’s tradition of publishing important guidelines from the southern african hiv clinicians’ society that help to shape programmes and services across the region. prevention strategies using antiretrovirals have demonstrated efficacy in reducing the sexual transmission of hiv, most notably in the realm of pre-exposure prophylaxis (prep). the evidence for prep’s efficacy is strongest in research among men who have sex with men (msm), yet there are currently no tools to guide service providers. here, bekker and colleagues present comprehensive guidelines on implementing prep among msm, the first such document of its kind internationally. landon myer school of public health & family medicine university of cape town landon.myer@uct.ac.za contents 1. introduction 2. screening for sexually transmitted infections 3. clinical management of the symptomatic patient 4. engaging sex partners in care 5. clinical management of patients with recurrent or persistent symptoms 6. diagnostic testing for sexually transmitted infections 7. pathogen-directed treatment of specific sexually transmitted infections 8. conclusion acknowledgements references about the author(s) remco p.h. peters research unit, foundation for professional development, east london, south africa department of medical microbiology, university of pretoria, pretoria, south africa division of medical microbiology, faculty of health sciences, university of cape town, cape town, south africa nigel garrett centre for the aids programme of research in south africa (caprisa), university of kwazulu-natal, durban, south africa department of public health medicine, school of nursing and public health, university of kwazulu-natal, durban, south africa nomathemba chandiwana ezintsha, faculty of health science, university of the witwatersrand, johannesburg, south africa ranmini kularatne department of clinical microbiology and infectious diseases, faculty of health sciences, university of the witwatersrand, johannesburg, south africa adrian j. brink division of medical microbiology, faculty of health sciences, university of cape town, cape town, south africa karen cohen department of medicine, division of clinical pharmacology, university of cape town, cape town, south africa katherine gill desmond tutu hiv centre, university of cape town, cape town, south africa thato chidarikire national department of health, pretoria, south africa camilla wattrus southern african hiv clinicians society (sahcs), johannesburg, south africa jeremy s. nel helen joseph hospital, university of the witwatersrand, johannesburg, south africa mahomed y.s. moosa department of infectious disease, division of internal medicine, nelson r. mandela school of medicine, university of kwazulu-natal, durban, south africa linda-gail bekker desmond tutu hiv centre, university of cape town, cape town, south africa citation peters rph, garrett n, chandiwana n, et al. southern african hiv clinicians society 2022 guideline for the management of sexually transmitted infections: moving towards best practice. s afr j hiv med. 2022;23(1), a1450. https://doi.org/10.4102/sajhivmed.v23i1.1450 guideline southern african hiv clinicians society 2022 guideline for the management of sexually transmitted infections: moving towards best practice remco p.h. peters, nigel garrett, nomathemba chandiwana, ranmini kularatne, adrian j. brink, karen cohen, katherine gill, thato chidarikire, camilla wattrus, jeremy s. nel, mahomed y.s. moosa, linda-gail bekker received: 12 aug. 2022; accepted: 12 aug. 2022; published: 27 sept. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. contents introduction table 1. microbial aetiology of sexually transmitted infection syndromes screening for stis 2.1. provider-initiated sti-symptom screening 2.2. sti screening using diagnostic tests table 2. recommended diagnostic screening frequency for specific sexually active population groups clinical management of the symptomatic patient 3.1. management of male urethral discharge syndrome (muds) table 3. recommended first-line antimicrobial treatment regimens for sti syndromic management 3.2. management of vaginal discharge syndrome (vds) 3.3. genital ulcer disease (gud) engaging sex partner/s in care clinical management of patients with recurrent or persistent symptoms table 4. reasons for persistent or recurrent sti episodes diagnostic testing for sexually transmitted infections 6.1. chlamydia trachomatis, neisseria gonorrhoeae and trichomonas vaginalis tables 5a and 5b. recommended diagnostic tests for management of sexually transmitted infection-associated symptoms – genital discharge syndromes 6.2. mycoplasma genitalium 6.3. hsv-1 and hsv-2 6.4. treponema pallidum pathogen-directed treatment of specific sexually transmitted infections 7.1. chlamydia trachomatis table 6. recommended antimicrobial drugs for targeted treatment of uncomplicated sexually transmitted infections 7.2. neisseria gonorrhoeae 7.3. trichomonas vaginalis 7.4. mycoplasma genitalium 7.5. hsv-1 and hsv-2 7.6. treponema pallidum conclusion acknowledgments competing interests authors’ contributions ethical considerations funding information data availability disclaimer references 1. introduction sexually transmitted infections (stis) are among the most common acute conditions worldwide with sub-saharan africa ranking among the regions with the highest burdens globally.1 adolescent girls and young women (agyw), people living with hiv (plhiv), pregnant women, and key and vulnerable populations are disproportionally affected by stis. the social determinants of health, gender inequality, and sti-associated stigma and discrimination (at both the community and facility level) are important contributors to the sustained high burden of infection. some stis cause urogenital infections including urethritis, cervicitis, vaginitis and genital ulceration, and may also infect the rectum and pharynx. other stis may cause serious short-term and long-term complications (e.g. pelvic inflammatory disease, arthritis, encephalitis), increase the risk of ectopic pregnancy and tubal-related infertility, and are associated with stillbirth and other adverse pregnancy outcomes.2 furthermore, susceptibility to acquiring hiv as well as hiv infectiousness may be increased depending on which sti is involved.3 lastly, the emergence of antibiotic-resistant gonorrhoea and consequent limited therapeutic options has become a major public health concern, impacting sti management and control activities.4 the world health organization’s (who) global health sector strategy 2022–2030 details the vision, goals and actions to ending the sti epidemic.5 strengthening sti case management is one of the key priorities of this strategy. effective people-centred sti case management is context-dependent and determined by available resources.6 in settings with limited resources, despite its shortcomings, syndromic case management using flow charts is the standard of care. male urethral discharge syndrome (muds), vaginal discharge syndrome (vds) and genital ulcer disease (gud) are the main sti-associated conditions in this approach, and each of these syndromes has a diverse microbial aetiology (table 1).6,7,8,9,10,11,12,13,14 where resources are available, diagnostic tests for specific pathogens, combined with directed treatment, can be used to optimise sti screening and case management. table 1: microbial aetiology of sexually transmitted infection syndromes. this guideline provides basic recommendations to aid appropriate sti case management in the southern african primary care setting. acknowledging that available resources vary between settings, and since this guideline applies to both private and public health sectors, recommendations may on occasion be aspirational in the public sector but feasible within the private sector. further detailed guidance for the management of stis can be found in the 2021 who and 2021 centers for disease control and prevention (cdc) guidelines.6,15 2. screening for sexually transmitted infections screening for stis is essential to reduce the burden of infection, morbidity, and associated health complications within the population. this should be done by asking about sti-associated symptoms followed by a clinical work-up if indicated or, in some instances, by diagnostic screening of asymptomatic individuals. as part of a comprehensive sexual health assessment, in addition to taking history and conducting physical examination, hiv testing, testing for hepatitis b virus (hbv), hepatitis c virus (hcv), syphilis, and cervical cancer screening (oncogenic human papillomavirus [hpv] dna testing or pap smear) should be done in line with local guidelines and resource availability. hiv pre-exposure prophylaxis (prep) may be offered in line with the local guidelines.16,17 2.1. provider-initiated sexually transmitted infection-symptom screening provider-initiated sti-symptom screening should be the standard of care in the primary care context, especially during provision of antenatal care, sexual and reproductive healthcare, hiv testing, hiv prep and antiretroviral therapy (art) services. although there is no documented evidence, provider-initiated symptom screening is likely to result in the identification and treatment of a larger number of symptomatic cases when compared to reliance on patient self-reporting. some patients may be unaware of their symptoms, including women who may not always realise or report a new or changed vaginal discharge.18 in addition, personal perceptions, beliefs and stigma related to sexual health may contribute to creating a barrier to active self-reporting of such symptoms.19,20,21 creating an enabling and supportive environment is vital to overcoming such barriers, including reducing the reluctance of healthcare workers to proactively ask about sti-associated symptoms.22 therefore, regular provider-initiated sti-symptom screening is recommended as a feasible intervention that requires little time, effort and cost. 2.2. sexually transmitted infection screening using diagnostic tests screening for stis using diagnostic tests followed by specific pathogen-directed treatment shortens the duration of infection, reduces ongoing transmission, may reduce complications, and ultimately may result in a lower sti prevalence in populations.15,23,24,25 in addition, diagnostic screening of asymptomatic individuals (with the associated risk of complications and transmission to sexual partners) can identify those patients that would remain untreated using the symptom-based screening approach. in fact, few stis are symptomatic. it is estimated that only 11% – 33% of chlamydia trachomatis infections in men, and 6% – 17% in women, become symptomatic; estimates for symptomatic neisseria gonorrhoeae infection are 45% – 85% in men and 14% – 35% in women.26,27 another benefit of diagnostic sti screening over symptom-based screening is improved antimicrobial stewardship and optimisation of partner management. recommendations for diagnostic testing of asymptomatic individuals should take into account the sti prevalence, sexual behaviour, disease severity and sequelae, health impact and cost.15,21 based on these criteria, recommendations have been made for diagnostic screening in various population groups, and screening frequency detailed based on the individual’s profile (table 2). table 2: recommended diagnostic screening frequency for specific sexually active population groups. in the case of diagnostic testing, detection of c. trachomatis, n. gonorrhoeae and trichomonas vaginalis should be done using a nucleic acid amplification test (naat) using first-void urine in men and, in women, a self-collected or healthcare-worker-collected vulvovaginal or endocervical swab. in some specific situations, collection of first-void urine may provide an alternative option to a vaginal swab; however, a vaginal swab is the preferred specimen as the yield is higher than with urine in women.6 anorectal and pharyngeal specimens for n. gonorrhoeae should also be considered in men who have sex with men (msm), transgender and gender diverse people (tgd), and commercial sex workers (csw) dependent on individual sexual practices.21 serological testing for syphilis should be done using a treponemal test, followed by a nontreponemal test if the treponemal test result was positive. rapid diagnostic tests (rdts) for syphilis (alone or in combination with hiv) have recently become available and provide a good point-of-care screening test option.28 screening of asymptomatic individuals for mycoplasma genitalium is not recommended due to its unclear pathogenicity and concerns of rising antimicrobial resistance (amr) associated with treatment.15,29 serological screening for herpes simplex virus (hsv) is discouraged as a positive screening result has no clinical implication because of a lack of therapeutic options to eradicate latent hsv alongside the high seroprevalence in southern africa.15,30 3. clinical management of the symptomatic patient a comprehensive clinical work-up of a patient with sti-associated symptoms should include a sexual, urological, medical (including medication history, vaccination, and medication allergies) and, for women, gynaecological history (including contraception and pregnancy). physical examination of genital, oral and anal areas should be conducted, and testing for hiv and syphilis carried out. women should be assessed for symptoms and signs suggestive of pelvic inflammatory disease (pid), including an examination for lower abdominal tenderness. cervical cancer screening should be discussed and, if indicated, hpv dna testing (as the preferred option) or a pap smear should be conducted in line with the local available resources, guidelines and policy.31 in the absence of diagnostic tests, syndromic treatment (i.e. empirical antimicrobial treatment that covers the most likely aetiology of the syndrome that the patient presents with) should be provided and patients instructed to return for further management if there is not resolution of symptoms. syndromic management algorithms and treatment regimens differ between countries based on the local epidemiology and access to medications; however, general best practice recommendations are provided. management of stis with systemic presentations (e.g. disseminated gonococcal infection), epididymo-orchitis and pid) are beyond the scope of this guideline. anorectal discharge has a broad aetiology including presence of an sti. clinical assessment and work-up of anorectal discharge and proctitis are not included in this guideline. 3.1. management of male urethral discharge syndrome male urethral discharge syndrome should be confirmed with a physical examination. a urethral discharge may be seen directly but, if not, the penis should be milked. examination of the epididymis and testes is also recommended. most muds cases are caused by c. trachomatis and/or n. gonorrhoeae infection. therefore, the recommended regimen for uncomplicated muds is a combination of azithromycin, to treat c. trachomatis, with ceftriaxone to treat n. gonorrhoeae (table 3). in syndromic management settings, in the absence of diagnostic testing, azithromycin is considered the preferred choice to cover treatment for c. trachomatis infection in the syndromic regimen. although doxycycline has a slightly higher efficacy than azithromycin for urogenital infection in men (lower rate of microbiological failure but not clinical failure) but not women, there are no data that support higher effectiveness of a course of doxycycline for c. trachomatis treatment in syndromic management settings. in the absence of diagnostics, a single dose of azithromycin is considered to outweigh the benefit of the higher efficacy of a course of doxycycline due to its better tolerability and possible adherence issues with a course of treatment. table 3: recommended first-line antimicrobial treatment regimens for sexually transmitted infection syndromic management. ciprofloxacin should be avoided in a syndromic regimen due to the high rates of amr of n. gonorrhoeae globally.4,32 treatment for t. vaginalis is usually not included because the prevalence in men is too low to justify coverage of this pathogen in first-line syndromic treatment regimens. patients with muds should be instructed to return if there is no resolution of symptoms if that is the case and ideally, resources permitting, collection of a urethral discharge smear for light microscopy and/or first-catch urine or urethral swab for sti diagnostic testing undertaken. pathogen-directed same-day treatment and partner management should then be provided (see the pathogen-directed treatment section). 3.2. management of vaginal discharge syndrome the aetiology of vds is more diverse than that of muds. in addition to c. trachomatis, n. gonorrhoeae and t. vaginalis infection, bacterial vaginosis (bv) and vulvo-vaginal candidiasis (vvc) are important conditions to consider. occurrence of bv and vvc is unrelated to sexual activity and may present in combination with an sti or as stand-alone conditions. given the high burden of stis in southern africa, the syndromic treatment regimen of vds should cover c. trachomatis, n. gonorrhoeae and t. vaginalis infection in sexually active women. the recommended empirical regimen is azithromycin, ceftriaxone, and metronidazole (table 3). a 7-day course of metronidazole is preferred over single-dose treatment as it has a higher efficacy for the treatment of t. vaginalis and, if present, the added benefit of treating concurrent bv.15,33 however, single-dose metronidazole may be used in certain populations and settings based on the benefits of same-day and observed therapy, and medication availability. ideally, patients with vds should be reviewed after one week to confirm resolution of their symptoms. most cases of vvc are caused by candida albicans which is generally susceptible to imidazole, polyene and triazole medications. treatment for vvc may be provided to women with vds, either in combination with syndromic treatment or as stand-alone management, based on sexual history and examination findings. typical symptoms of c. albicans include vulvo-vaginal pruritus, a burning sensation of the vulva, and vaginal pain or irritation. in addition, dyspareunia and dysuria may be reported. if a vaginal discharge is present with vvc, it is usually thick, curdy and white or cream in colour. intravaginal pessaries or tablets are recommended first-line treatment (table 3). to support syndromic management, if resources permit, a vaginal discharge smear for light microscopy or a self-collected or healthcare-worker-collected vulvovaginal swab may be taken for diagnostic testing for c. trachomatis, n. gonorrhoeae and t. vaginalis. these tests are useful in providing same-day pathogen-directed treatment, reducing the use of unnecessary antimicrobials and risk of amr, and help inform partner management. 3.3. genital ulcer disease the manifestation of gud is diverse and the characteristics of the ulcer (e.g. presence or absence of pain, shape of edges, multiplicity) are of poor diagnostic value in determining aetiology, particularly in plhiv.34 attempting to clinically diagnose the aetiology of gud using ulcer characteristics is not recommended and should not be used to inform treatment decisions. hsv-1 and hsv-1 are the most common causes of genital ulcers followed by treponema pallidum, the causative agent of syphilis. lymphogranuloma venereum (lgv) caused by c. trachomatis biovars l1–l3, chancroid (haemophilus ducreyi), and donovanosis (klebsiella granulomatis) have become uncommon in the last decade.14,35,36 first-line syndromic regimen for gud should include medications to treat hsv and syphilis (table 3). acyclovir is the medication of choice for hsv while benzathine benzylpenicillin, also called benzathine penicillin g (bpg), is the cornerstone of syphilis treatment. treatment for chancroid should only be considered in a setting where cases are reported or emerging, while lgv treatment should be based on an aetiological diagnosis. limiting empirical treatment of gud to acyclovir (i.e. omitting bpg) may be considered in individuals with a recent history (< 3 months) of adequate syphilis treatment, those who present with recurrent ulcers in the same site, and in individuals reporting no sexual contact in the previous three months. patients with gud should be reassessed for symptoms after one week of treatment. blood for rapid plasma reagin (rpr) titre should be collected at initial presentation. serological monitoring of rpr for response to treatment may be considered 3–6 months after the completion of treatment and, if indicated, every 3–6 months thereafter. a four-fold (two dilution step) decrease in the rpr titre can be expected following 12-months of treatment in hiv-uninfected people, and following 24 months treatment in those that are hiv-infected.15 patients presenting with gud and/or a diagnosis of syphilis should be assessed for neurological symptoms and, if present, referred for treatment. resources permitting, a swab of the genital lesion may be collected for naat testing of hsv and t. pallidum. an hsv naat assay is the most sensitive test for hsv (sensitivity > 90%), and is considered highly specific.15,37 discontinuation of acyclovir may be considered in the case of a negative hsv naat. molecular tests for syphilis have a lower sensitivity (80% – 90%) and specificity. therefore, these tests should not be used to exclude syphilis but can facilitate early diagnosis in the case of a positive result.38,39 herpes simplex virus serology should be avoided as part of any diagnostic work-up as it has a poor sensitivity, specificity, and predictive value. in addition, the result remains positive for life, and immunoglobulin m (igm) antibodies may occur during recurrent infections and are neither sensitive nor specific.40,41 however, blood for treponemal and rpr testing (or another nontreponemal test) should be collected at initial presentation of gud to identify active syphilis and, if positive, the rpr may be used to monitor rpr titres as a marker of response to treatment. if treatment is not initially provided, a repeat rpr should be collected at the time of treatment to serve as the baseline titre. it is important to note that syphilis serological test (both rpr and treponemal tests) and the recently introduced rdts may be negative in early primary syphilis (taking 1–4 weeks after the initial appearance of the chancre to become positive) and therefore a negative result does not exclude syphilis.42 4. engaging sex partners in care treatment of stis should include a discussion about safer sexual practices, emphasis on condom with lubricant use and, if hiv-uninfected, hiv prep should be offered.16,17 efforts should be made to link to care the recent sex partners of patients with an sti. this is important for good sexual healthcare (as many stis are asymptomatic), and for the prevention of re-infection. to avoid sti transmission to the patients’ sex partners, patients diagnosed with an sti should be advised to abstain from sex or to use condoms consistently for at least one week following completion of treatment. patients should be informed about the importance of partner treatment and provided with a notification slip for their sex partners to facilitate linkage to care. the notification slip should specify the syndrome that the index patient was treated for and, ideally, also specific pathogens that have been detected. this aids appropriate partner treatment at any healthcare facility, regardless of the presence of symptoms. sex partners should receive the same antimicrobial treatment regimen as the index case (table 3) but with two exceptions: men should be given a single dose (instead of a seven-day course) of metronidazole, and asymptomatic partners of a patient with gud should be treated with bpg only and not be given acyclovir in addition. expedited partner therapy (ept) for stis is practised in several countries globally but is currently not supported by southern african law, despite promising results in research studies.23,43 in ept, index patients who have had an sti diagnosed are provided with a pill pack based on their laboratory test result that contains a single oral dose of azithromycin (for c. trachomatis) and/or cefixime (for n. gonorrhoeae) to give to their recent sex partners. 5. clinical management of patients with recurrent or persistent symptoms symptom recurrence or persistence may occur for various reasons. causes include reinfection from the same sex partner in the case of unsuccessful partner treatment, a repeat infection from a new sex partner, poor treatment compliance, symptom aetiology that is not covered by the initial empirical regimen, suboptimal treatment efficacy of medications for specific stis, amr and other non-infectious aetiologies (table 4).18,44 table 4: reasons for persistent or recurrent sexually transmitted infection episodes. based on the available surveillance and research data, amr to medications used in most sti first-line syndromic regimens is uncommon in southern africa. nevertheless, amr in n. gonorrhoeae and m. genitalium is on the rise globally and evaluation for amr should be included in any diagnostic work-up.24,45,46 it is essential to take a thorough sexual and clinical history, and to conduct a physical examination of all patients presenting with persistent or recurrent muds or vds. if reinfection, new infection, or poor treatment adherence is likely, then retreatment with the same empirical sti regimen is indicated. in the case of first-line treatment failure for muds, retreatment with ceftriaxone 1 g intramuscularly can be provided to overcome possible elevation in the minimum inhibitory concentration (mic) of some n. gonorrhoeae strains. should resources allow, a culture for amr testing should be obtained. increasing the ceftriaxone dose is not indicated for women as it results in a high level of overtreatment due to the low prevalence of n. gonorrhoeae in vds. women with persistent vds who have received single-dose metronidazole as initial treatment should be given a 7-day oral course of metronidazole. if the scenarios described have been excluded, then referral of patients with persistent or recurrent muds or vds to an expert clinician with access to diagnostic testing is indicated to establish the aetiology of symptoms (including non-infectious causes) and to detect possible amr. similarly, individuals with persistent gud should be referred to a centre with laboratory capacity and clinical expertise to diagnose the various stis, skin and other differential diagnoses. 6. diagnostic testing for sexually transmitted infections diagnostic testing can be used to screen asymptomatic individuals for stis, to guide treatment and partner management of symptomatic individuals, and to inform management of complicated cases with persistent or recurrent symptoms (tables 5a and 5b). table 5a: recommended diagnostic tests for management of sexually transmitted infection-associated symptoms – genital discharge syndromes. table 5b: recommended diagnostic tests for management of sexually transmitted infection-associated symptoms – genitalulcer ulcer disease. 6.1. chlamydia trachomatis, neisseria gonorrhoeae and trichomonas vaginalis currently, there are no point-of-care tests available for c. trachomatis, n. gonorrhoeae and t. vaginalis that meet the who target product profile. however, in-facility naats (such as genexpert®) are used for same-day diagnosis. on-site light microscopy using methylene blueor gram-stained urethral smears may be used by an experienced healthcare worker to establish a rapid presumptive diagnosis of n. gonorrhoeae.47 the amsel criteria or light microscopy (using the hay and ison scoring system or nugent score) of vaginal discharge smears may be used for diagnosis of bv, and vvc can be diagnosed through visualisation of yeasts or pseudohyphae.15 in addition, wet mount microscopy can confirm a diagnosis of t. vaginalis; however, the absence of visible motile protozoa does not rule out a diagnosis of trichomoniasis.6 bacterial culture and drug susceptibility testing is only indicated when there are concerns about drug-resistant n. gonorrhoeae infection. serology is not indicated. molecular detection using a high-quality naat is considered the standard of care for these stis. there is a large variety of available high-quality molecular assays with good diagnostic performance. these can be manual or automated and either single or high throughput. for naat, first-catch urine for men and a self-collected vulvovaginal or healthcare-worker-collected endocervical swab for women is the preferred specimen. the acceptability and feasibility of self-collected vaginal swabs in women is high.48,49,50 dependent on sexual practices, anorectal or pharyngeal swabs may be healthcare-workeror self-collected in msm, tgd and csw. molecular testing for the lgv biovar c. trachomatis is indicated in the case of rectal c. trachomatis infection and may be useful in the differential diagnosis of genital ulcers. a test to confirm cure is not indicated in individuals with a urogenital infection that has been treated using the recommended antimicrobial regimen. an naat may remain positive for several weeks following completion of treatment as a result of the presence of non-viable organisms and uncleared dna in the genital tract.51,52 based on sexual practices, a repeat test at three or six months after the initial episode may be indicated (table 1). 6.2. mycoplasma genitalium m. genitalium can only be detected by naat, and diagnostic testing is only recommended in patients with persistent or recurrent discharge and negative n. gonorrhoeae and c. trachomatis tests. given the rapid global emergence of macrolide resistance over the past decade, it is recommended, if available, to combine testing for m. genitalium with macrolide resistance testing despite the relatively low prevalence of resistance in southern africa. molecular testing for mycoplasma hominis and ureaplasma species is included in some multiplex assays; however, these tests are not recommended as part of routine practice. such testing should only be considered in specific populations as the pathogenicity of these bacteria is uncertain and the relevance of treatment unclear. 6.3. herpes simplex virus-1 and herpes simplex virus-2 the diagnosis of hsv is mainly clinical. an naat of a swab of a genital lesion is the diagnostic standard for hsv-1 and hsv-2 infection. these naat assays have a sensitivity of > 90% and are considered highly specific.15,37 molecular antiviral resistance testing is indicated in chronic ulcers not responding to prolonged acyclovir treatment, especially in plhiv, and histology may also be indicated to aid in a differential diagnosis. herpes simplex virus serology testing should not form part of sti management because of poor test sensitivity, specificity, and predictive values, antibody positivity that may last for life, and igm antibodies that may occur during recurrent infection.40,41 6.4. treponema pallidum there is no single standard test for diagnosis of syphilis. in patients presenting with presumptive syphilis, molecular detection of t. pallidum from an ulcer swab may be used to confirm early diagnosis but, because of a test sensitivity of 80% – 90%, syphilis cannot be excluded by a negative test.38,39 treponemal rdts may be used to diagnose syphilis in asymptomatic individuals; however, these tests are unreliable when it comes to diagnosing primary syphilis due to the delay in antibody response and the limitation of antibody detection as compared to a laboratory assay. if rdts are not available, laboratory testing using the so-called inverse algorithm can be used. this is when an automated specific treponemal antibody test (e.g. t. pallidum enzyme or chemiluminescent immunoassay) is used as the first step in diagnosis and, if positive, is followed by a reflex nontreponemal assay (e.g. rpr). alternatively, in symptomatic individuals, the traditional algorithm could be used (i.e. a nontreponemal test which is quantitated to determine titre is then followed by a specific treponemal antibody test in the case of a positive test). 7. pathogen-directed treatment of specific sexually transmitted infections unlike syndromic treatment that aims to cover the most likely aetiology, pathogen-directed treatment of stis aims to achieve the highest possible cure rate using the most optimal antimicrobial therapy. 7.1. chlamydia trachomatis treatment of c. trachomatis is usually covered with azithromycin in syndromic treatment regimens. however, a recent meta-analysis has shown higher treatment efficacy (lower rate of microbiological failure but not clinical failure) with a 7-day course of doxycycline for urogenital infection in men.53 in addition, recent trials have shown a higher efficacy of doxycycline as compared to azithromycin for the treatment of rectal c. trachomatis infection in msm and women.54,55 concurrent treatment of rectal infection in women is important as auto-inoculation of cervical infection may occur resulting in persistent infection. in addition, rectal infections may remain untreated in msm and women posing an increased risk for hiv transmission.56,57 therefore, doxycycline is recommended as the most effective directed first-line treatment for c. trachomatis (table 6). azithromycin provides a good alternative when managing symptomatic individuals with muds or vds, when there are concerns about tolerability and when adherence may pose a problem in completion of the 7-day course of doxycycline. table 6: recommended antimicrobial drugs for targeted treatment of uncomplicated sexually transmitted infections. 7.2. neisseria gonorrhoeae n. gonorrhoeae has been treated for the past decade using combination therapy with prevention of resistance as an important focus. however, such an effect has not been documented and the decreasing rate of azithromycin susceptibility of n. gonorrhoeae and reported treatment failures of oropharyngeal gonorrhoea are an important concern. some international guidelines, based on local susceptibility data,14,58,59 recommend a single dose of 500 mg or 1 g of ceftriaxone for documented n. gonorrhoeae infection. based on the locally available susceptibility data this guideline recommends a 500 mg intramuscular injection of ceftriaxone without the addition of azithromycin for the treatment of confirmed genital n. gonorrhoeae. the ceftriaxone dose should be increased to 1 g in the case of confirmed oropharyngeal infection due to the lower bioavailability of ceftriaxone in the oropharynx. ceftriaxone as an intramuscular injection, or cefixime 800 mg given as an oral dose, is preferred over intramuscular gentamicin as it has a higher efficacy for both uncomplicated urogenital and extragenital infections.60,61 ceftriaxone-resistance in n. gonorrhoeae is a category 3 notifiable condition in south africa and many other countries. should such resistance be identified, treatment should be based on the full phenotypic and genotypic drug susceptibility profile and guided by expert clinical advice. 7.3. trichomonas vaginalis metronidazole is the mainstay of t. vaginalis treatment. a 7-day oral course of 400 mg or 500 mg twice daily has a substantially higher efficacy than a 2 g single dose, regardless of the patient’s hiv-infection status. however, persistence may still occur in approximately 10% of women.33 tinidazole is a good alternative to a course of metronidazole in women with persistent infection. there are currently no randomised controlled trial data for t. vaginalis treatment in men, but single-dose metronidazole treatment has reportedly high cure rates. 7.4. mycoplasma genitalium a 1 g single oral dose of azithromycin used in syndromic management may treat macrolide susceptible m. genitalium infection but may also facilitate the emergence of macrolide resistance in this pathogen. macrolide resistance has emerged globally; however, limited data for the african region (including south africa and kenya) suggest that local macrolide resistance levels are still low.24,46,56,59,62 in the absence of resistance testing and given the widespread use of moxifloxacin (an alternative treatment) in management of tuberculosis, a course of azithromycin is still recommended as first-line treatment of m. genitalium (table 6). resistance-guided therapy is preferred in settings where macrolide resistance testing is available. this two-stage therapy consists of treatment with doxycycline to reduce organism load and facilitate clearance, followed by treatment with azithromycin or moxifloxacin based on the resistance test result.15 7.5. herpes simplex virus-1 and herpes simplex virus-2 hsv-1 and hsv-2 ulcers should be treatment with acyclovir or valacyclovir. alternative treatment may be given based on the result of acyclovir resistance testing in cases of persistent ulceration unresponsive to standard acyclovir therapy. in general, based on the limited data from surveillance, acyclovir resistance in hsv is uncommon in our region.63 7.6. treponema pallidum benzathine benzylpenicillin, or bpg, is the mainstay of syphilis treatment with high cure rates and no resistance documented. single injections are sufficient for patients with manifestations of primary, secondary, or early latent syphilis infection. however, a series of three injections is recommended for all asymptomatic individuals with a syphilis diagnosis and no documented negative syphilis serology in the past year. asymptomatic individuals with a documented negative syphilis treatment serology in the past two years may be treated with a single bpg injection. in case of suspected or confirmed penicillin allergy, penicillin-desensitisation is recommended and is preferred over an alternative treatment. global shortages of benzathine benzylpenicillin have accelerated the search for alternative treatment regimens. if bpg is unavailable, doxycycline may be given for primary, secondary or latent syphilis in adult men and non-pregnant women. the efficacy of amoxicillin and oral cephalosporins is currently being studied. resistance to macrolides in t. pallidum is common globally and these medications should be avoided in the treatment of syphilis. management of tertiary syphilis (e.g. neurosyphilis) is beyond the scope of this guideline and should be managed in a specialist setting. 8. conclusion symptom screening and syndromic management have been the cornerstone of sti control for the past decades in southern africa; however, the burden of stis remains high.1,45 strengthening sti screening, diagnosis and case management is essential to improve health outcomes and to control the sti epidemic. if resources are available, diagnostic screening and testing, combined with pathogen-directed treatment of stis is essential to improve patient outcomes and make significant progress towards sti control, while mitigating the effects of rising levels of amr. in addition, the development and implementation of rdts for the most common stis is urgently required for the strengthening of sti case management.64 strengthening sti care in southern africa requires the empowerment of patients, capacity building of healthcare workers, and investment in diagnostic and therapeutic resources and infrastructure. this guideline provides an important step towards evidence-based, best-practice and effective sti management in southern africa. acknowledgements the authors would like to thank the southern african hiv clinicians society (sahcs) who supported guideline development and publication. we would also like to acknowledge all contributors involved in the external peer review process. these include, in alphabetical order of surname and with equal contribution: kevin ard, ruanne barnabus, connie celum, henry de vries, rashida ferrand, jeffrey klausner, david lewis, jean-michel molina and francis ndowa. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this research article. authors’ contributions all authors contributed equally to this work. ethical considerations to the fullest extent permitted by law, southern african hiv clinicians society (sahcs) and the authors of this study cannot be held liable for any aspect of healthcare administered using this information or any other use, including any use (or misuse) that is not in accordance with any guidelines. specific recommendations provided here are intended only as a guide to clinical management based on expert consensus and best current evidence at the date of first publication. management decisions for clients should be made by their responsible clinicians, with due consideration for individual circumstances and various contexts. the information provided in this document should not be considered as a substitute for such professional judgement. the most current version of this document should always be consulted. funding information the authors received no financial support for the research, authorship, or publication of this article. data availability data sharing is not applicable to this article, as no new data were created or analysed in this study. disclaimer this research article followed all ethical standards for research without any direct contact with human or animal subjects. references rowley j, hoorn sv, korenromp e, et al. chlamydia, gonorrhoea, trichomoniasis and syphilis: global prevalence and incidence estimates, 2016. bull world health organ. 2019;97(8):548. https://doi.org/10.2471/blt.18.228486 unemo m, bradshaw cs, hocking js, et al. sexually transmitted infections: challenges ahead. lancet infect dis. 2017;17(8):e235–e279. https://doi.org/10.1016/s1473-3099(17)30310-9 cohen ms, council od, chen js. sexually transmitted infections and hiv in the era of antiretroviral treatment and prevention: the biologic basis for epidemiologic synergy. j int aids soc. 2019;22:e25355. https://doi.org/10.1002/jia2.25355 unemo m, lahra mm, escher m, et al. who global antimicrobial resistance surveillance for neisseria gonorrhoeae 2017–18: a retrospective observational study. lancet microbe. 2021;2(11):e627–e636. https://doi.org/10.1016/s2666-5247(21)00171-3 world health organization (who). global health sector strategies on, respectively, hiv, viral hepatitis and sexually transmitted infections for the period 2022–2030. geneva: world health organization; 2022. world health organization (who). guidelines for the management of symptomatic sexually transmitted infections. geneva: world health organization; 2021. mhlongo s, magooa p, müller e, et al. etiology and sti/hiv confections among patients with urethral and vaginal discharge syndromes in south africa. sex transm dis. 2010;37(9):566–570. https://doi.org/10.1097/olq.0b013e3181d877b7 rietmeijer ca, mungati m, machiha a, et al. the etiology of male urethral discharge in zimbabwe: results from the zimbabwe sti etiology study. sex transm dis. 2018;45(1):56–60. https://doi.org/10.1097/olq.0000000000000696 lewis da, marsh k, radebe f, et al. trends and associations of trichomonas vaginalis infection in men and women with genital discharge syndromes in johannesburg, south africa. sex transm infect. 2013;89(6):523–527. https://doi.org/10.1136/sextrans-2013-051049 takuva s, mugurungi o, mutsvangwa j, et al. etiology and antimicrobial susceptibility of pathogens responsible for urethral discharge among men in harare, zimbabwe. sex transm dis. 2014;41(12):713–717. https://doi.org/10.1097/olq.0000000000000204 kufa t, gumede l, maseko dv, radebe f, kularatne r. the demographic and clinical profiles of women presenting with vaginal discharge syndrome at primary care facilities in south africa: associations with age and implications for management. s afr med j. 2018;108(10):876–880. https://doi.org/10.7196/samj.2018.v108i10.13027 mungati m, machiha a, mugurungi o, et al. the etiology of 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very small and embarrassed by the health care provider when i requested to be tested for syphilis’: barriers and facilitators of regular syphilis and hiv testing among female sex workers in uganda. bmc public health. 2021;21(1):1–12. https://doi.org/10.1186/s12889-021-12095-8 world health organization. consolidated guidelines on hiv, viral hepatitis and sti prevention, diagnosis, treatment and care for key populations. geneva: who; 2022. available from: https://apps.who.int/iris/handle/10665/360601 ham dc, hariri s, kamb m, et al. quality of sexually transmitted infection case management services in gauteng province, south africa: an evaluation of health providers’ knowledge, attitudes, and practices. sex transm dis. 2016;43(1):23. https://doi.org/10.1097/olq.0000000000000383 garrett nj, osman f, maharaj b, et al. beyond syndromic management: opportunities for diagnosis-based treatment of sexually transmitted infections in low-and middle-income countries. plos one. 2018;13(4):e0196209. https://doi.org/10.1371/journal.pone.0196209 peters rp, jung hs, muller ee, et al. lack of macrolide resistance in mycoplasma genitalium infections in a cohort of pregnant women in south africa. sex transm infect. 2021;97(8):624–625. https://doi.org/10.1136/sextrans-2020-054583 raifman jr, gebo ka, mathews wc, et al. gonorrhea and chlamydia case detection increased when testing increased in a multisite us hiv cohort, 2004–2014. j acquir immune defic syndr (1999). 2017;76(4):409–416. https://doi.org/10.1097/qai.0000000000001514 korenromp el, sudaryo mk, de vlas sj, et al. what proportion of episodes of gonorrhoea and chlamydia becomes symptomatic? int j std aids. 2002;13(2):91–101. https://doi.org/10.1258/0956462021924712 johnson lf, alkema l, dorrington re. a bayesian approach to uncertainty analysis of sexually transmitted infection models. sex transm infect. 2010;86(3):169–174. angel-müller e, grillo-ardila cf, amaya-guio j, et al. diagnostic accuracy of rapid point-of-care tests for detecting active syphilis: a systematic review and meta-analysis. sex transm dis. 2021;48(12):e202–e208. https://doi.org/10.1097/olq.0000000000001498 soni s, horner p, rayment m, et al. british association for sexual health and hiv national guideline for the management of infection with mycoplasma genitalium (2018). int j std aids. 2019;30(10):938–950. https://doi.org/10.1177/0956462419825948 patel eu, frank ma, hsieh yh, et al. prevalence and factors associated with herpes simplex virus type 2 infection in patients attending a baltimore city emergency department. plos one. 2014;9(7):e102422. https://doi.org/10.1371/journal.pone.0102422 world health organization (who). who guideline for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention. geneva: world health organization; 2021. unemo m, lahra mm, cole m, et al. world health organization global gonococcal antimicrobial surveillance program (who gasp): review of new data and evidence to inform international collaborative actions and research efforts. sex health. 2019;16(5):412–425. https://doi.org/10.1071/sh19023 kissinger p, muzny ca, mena la, et al. single-dose versus 7-day-dose metronidazole for the treatment of trichomoniasis in women: an open-label, randomised controlled trial. lancet infect dis. 2018;18(11):1251–1259. https://doi.org/10.1016/s1473-3099(18)30423-7 loh aj, ting el, wi te, et al. the diagnostic accuracy of syndromic management for genital ulcer disease: a systematic review and meta-analysis. front med. 2021;8:806605. https://doi.org/10.3389/fmed.2021.806605 muller ee, kularatne r. the changing epidemiology of genital ulcer disease in south africa: has donovanosis been eliminated? sex transm infect. 2020;96(8):596–600. https://doi.org/10.1136/sextrans-2019-054316 gonzález-beiras c, marks m, chen cy, et al. epidemiology of haemophilus ducreyi infections. emerg infect dis. 2016;22(1):1. https://doi.org/10.3201/eid2201.150425 scoular a, gillespie g, carman w. 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2016;316(23):2531–2543. https://doi.org/10.1001/jama.2016.17138 unemo m, del rio c, shafer wm. antimicrobial resistance expressed by neisseria gonorrhoeae: a major global public health problem in the 21st century. microbiol spectrum. 2016;4(3):35. https://doi.org/10.1128/microbiolspec.ei10-0009-2015 taleghani s, joseph-davey d, west sb, et al. acceptability and efficacy of partner notification for curable sexually transmitted infections in sub-saharan africa: a systematic review. int j std aids. 2019;30(3):292–303. https://doi.org/10.1177/0956462418803983 van liere ga, kock m, radebe o, et al., high rate of repeat sexually transmitted diseases among men who have sex with men in south africa: a prospective cohort study. sex transm dis. 2019;46(11):e105–e107. https://doi.org/10.1097/olq.0000000000001041 kularatne rs, niit r, rowley j, et al. adult gonorrhea, chlamydia and syphilis prevalence, incidence, treatment and syndromic case reporting in south africa: estimates using the spectrum-sti model, 1990-2017. plos one. 2018;13(10):e0205863. https://doi.org/10.1371/journal.pone.0205863 mahlangu mp, müller ee, da costa dias b, et al. molecular characterisation and detection of macrolide and fluoroquinolone resistance determinants in mycoplasma genitalium in south africa, 2015-2018. sex transm dis. 2022;49(7):511–516. https://doi.org/10.1097/olq.0000000000001631 bartelsman m, straetemans m, vaughan k, et al. comparison of two gram stain point-of-care systems for urogenital gonorrhoea among high-risk patients: diagnostic accuracy and cost-effectiveness before and after changing the screening algorithm at an sti clinic in amsterdam. sex transm infect. 2014;90(5):358–362. https://doi.org/10.1136/sextrans-2013-051500 francis sc, miiro g, nakuya k, et al. self-collection of vaginal swabs among adolescent girls in a school-setting in east africa. sex transm dis. 2019;46(5):335–341. https://doi.org/10.1097/olq.0000000000000990 khan z, bhargava a, mittal p, et al. evaluation of reliability of self-collected vaginal swabs over physician-collected samples for diagnosis of bacterial vaginosis, candidiasis and trichomoniasis, in a resource-limited setting: a cross-sectional study in india. bmj open. 2019;9(8):e025013. https://doi.org/10.1136/bmjopen-2018-025013 verwijs mc, agaba s, umulisa mm, van de wijgert jhhm. feasibility and acceptability of frequent vaginal self-sampling at home by rwandan women at high risk of urogenital tract infections. sexually transmitted infections. 2022;98(1):58–61. https://doi.org/10.1136/sextrans-2020-054816 versteeg b, bruisten sm, heijman t, et al. monitoring therapy success of urogenital chlamydia trachomatis infections in women: a prospective observational cohort study. plos one. 2017;12(9):e0185295. https://doi.org/10.1371/journal.pone.0185295 wind cm, schim van der loeff mf, unemo m, et al. test of cure for anogenital gonorrhoea using modern rna-based and dna-based nucleic acid amplification tests: a prospective cohort study. clin infect dis. 2016;62(11):1348–1355. https://doi.org/10.1093/cid/ciw141 páez-canro c, alzate jp, gonzález lm, et al. antibiotics for treating urogenital chlamydia trachomatis infection in men and non-pregnant women. cochrane database syst rev. 2019;1(1):cd010871. https://doi.org/10.1002/14651858.cd010871.pub2 lau a, kong fys, fairley ck, et al. azithromycin or doxycycline for asymptomatic rectal chlamydia trachomatis. new engl j med. 2021;384(25):2418–2427. https://doi.org/10.1056/nejmoa2031631 peuchant o, lhomme e, martinet p, et al. doxycycline versus azithromycin for the treatment of anorectal chlamydia trachomatis infection in women concurrent with vaginal infection (chlazidoxy study): a multicentre, open-label, randomised, controlled, superiority trial. lancet infect dis. 2022 may;22(8):1221–1230. https://doi.org/10.1016/s1473-3099(22)00148-7 balkus je, manhart le, jensen js, et al. mycoplasma genitalium infection in kenyan and us women. sex transm dis. 2018;45(8):514. https://doi.org/10.1097/olq.0000000000000799 barbee la, khosropour cm, dombrowksi jc, golden mr. new human immunodeficiency virus diagnosis independently associated with rectal gonorrhea and chlamydia in men who have sex with men. sex transm dis. 2017;44(7):385. https://doi.org/10.1097/olq.0000000000000614 kularatne r, maseko v, mahlangu p, muller e, kufa t. etiological surveillance of male urethritis syndrome in south africa: 2019–2020. sex transm dis. 2022;49(8):560–564. https://doi.org/10.1097/olq.0000000000001647 maduna l, peters rph, kingsburgh c, strydom k-a, kock mm. antimicrobial resistance in neisseria gonorrhoeae and mycoplasma genitalium isolates from the private healthcare sector in south africa: a pilot study. s afr med j. 2021;111(10):995–997. https://doi.org/10.7196/samj.2021.v111i10.15714 bai z, bao xj, cheng wd, yang kh, li yp. efficacy and safety of ceftriaxone for uncomplicated gonorrhoea: a meta-analysis of randomized controlled trials. int j std aids. 2012;23(2):126–132. https://doi.org/10.1258/ijsa.2009.009198 ross jd, brittain c, cole m, et al. gentamicin compared with ceftriaxone for the treatment of gonorrhoea (g-tog): a randomised non-inferiority trial. lancet. 2019;393(10190):2511–2520. https://doi.org/10.1016/s0140-6736(18)32817-4 machalek da, tao y, graddip hs, et al. prevalence of macrolide and fluoroquinolone resistance-associated mutations in mycoplasma genitalium: a systematic review and meta-analysis. lancet infect dis. 2020;20:1302–1314. https://doi.org/10.1016/s1473-3099(20)30154-7 muller ee, maseko dv, kularatne rs. phenotypic and genotypic acyclovir resistance surveillance of genital herpes simplex virus 2 in south africa. antivir res. 2022;200:105277. https://doi.org/10.1016/j.antiviral.2022.105277 ferreyra c, osborn j, moussy f, et al. developing target product profiles for neisseria gonorrhoeae diagnostics in the context of antimicrobial resistance: an expert consensus. plos one. 2020;15(9):e0237424. https://doi.org/10.1371/journal.pone.0237424 46 sajhivmed june 2014, vol. 15, no. 2 f o r u m the south african national health act (no. 61 of 2003) provides a legal framework for the regulation of the health system across the country. within the act, section 71 introduces a number of legal norms relating to research or experimentation with human subjects, including research on hiv prevention and treatment. these norms have been criticised for the negative impact they will have on research involving children. this article describes three of the new consent requirements in section 71 of the act. it shows, using a range of case studies, how important hiv-related research will be halted or undermined if the current provisions are implemented. the article argues that the new consent requirements are out of step with other statutory provisions and ethical guidelines, and as a result they will exclude a large population group – children in diverse settings – from much-needed evidence-based healthcare interventions. the article concludes with a clarion call for support of advocacy on this issue with the minister of health and the health portfolio committee. s afr j hiv med 2014;15(2):46-49. doi:10.7196/sajhivmed.1014 failing the vulnerable: three new consent norms that will undermine health research with children a strode,1 ba, llb, llm, phd; m richter,2 ba (hons), ma, llm, phd; m wallace,3 bsoc sci (hons), msc, phd; j toohey,4 llb; k technau,5 mbbch, msc 1 university of kwazulu-natal and hiv/aids vaccines ethics group, durban, south africa 2 international centre for reproductive health, department of obstetrics and gynaecology, ghent university, belgium; school of public health and family medicine, university of cape town, south africa; and african centre for migration and society, university of the witwatersrand, johannesburg, south africa 3 desmond tutu hiv foundation, university of cape town, south africa 4 hiv/aids vaccines ethics group, durban, south africa 5 empilweni services and research unit, department of paediatrics and child health, rahima moosa mother and child hospital, faculty of health sciences, university of the witwatersrand, johannesburg, south africa corresponding author: a strode (strodea@ukzn.ac.za) section 71 of the south african (sa) national health act (nha),[1] which deals with research on or experimentation with human subjects, was put into operation on 1 march 2012.[2] this section fundamentally changes the way in which research with children may be undertaken across the country by introducing highly restrictive and inflexible standards into the current sa ethical-legal framework.[3,4] as a result, it has come under heavy criticism for limiting important research with children and containing impractical and unrealisable provisions.[3-9] the full impact of section 71 has yet to be felt, as very few research ethics committees (recs) require researchers to comply with its standards. however, this grace period may be coming to an end; on 29 may 2013, draft regulations relating to research on human subjects[10] were published for public comment, indicating that the full implementation of section 71 is imminent. this article focuses on three aspects of section 71, which we believe will have far-reaching consequences for research on children. it shows, using a range of case studies, how important research will be halted or undermined if the current provisions are implemented. the article concludes with a call to support advocacy in law reform. the importance of health research with children there is a global trend towards greater inclusivity in research practices and to facilitate research with children, while recognising that they need to be protected.[12] this approach flows from a recognition of the following: • the number and severity of diseases that affect children is growing: for example, 17% of all 15 49-year-olds are hiv-positive.[13] furthermore, mortality among children is unacceptably high, with one out of every ten deaths in the entire population being a child under the age of 14.[14] • some disorders occur only in children or are more common in children; for example, type 1 diabetes[15] and juvenile rheumatoid arthritis.[16,17] a note on terminology: this article uses the term ‘children’ to refer to persons under the age of 18.[11] however, the nha uses the term ‘minors’ in section 71; therefore, when we refer directly to this section we use ‘minors’ rather than children. we also limit our discussion to ‘health research’ on a ‘living person’, as the regulations in section 71 only apply to these types of studies. mailto:strodea@ukzn.ac.za june 2014, vol. 15, no. 2 sajhivmed 47 f o r u m • the dynamics in some diseases are different in children compared with adults. for example, 20% of untreated hiv-infected infants will die within 90 days of birth,[18] 40% within their first year of life, and 52% by the end of their second year.[19] this type of rapid mortality does not occur among newly infected adults. • certain medication has a different impact on children as opposed to adults, as they have differing biokinetics, metabolism, physiology and immunology, and metabolise medicines differently. this results in children needing different dosages, which can only be established through research.[20] without research, limited information is available on the efficacy and safety of many of the medicines commonly used in children.[20] • there is a developing trend against allowing the licensing of drugs, vaccines and other interventions for children before testing their safety and efficacy in this age group. there is also concern about the ‘off label’ use of medicines in children.[20] • using the results from clinical trials on children has resulted in significant health benefits for them.[21] for example, human papilloma virus (hpv) vaccine studies on children have enabled them to receive the vaccine, which can prevent cervical cancer and genital warts.[22] • laws such as the children’s act emphasise that children have the right to participate in decision making.[11] likewise, ‘their participation in research is akin to respecting and promoting their entitlement to have their opinions heard. it assumes that they are persons of value, their experiences are of interest to themselves, and to others, and that they have a valuable contribution to make.’[23] against this backdrop, it is argued that an approach that excludes children from health research, including research related to hiv prevention and treatment, infringes on their constitutional rights to both ‘basic health care’ and access to ‘healthcare services’.[24] for example, their exclusion results in ineffective and even harmful interventions being used owing to the lack of evidence on drug efficacy or dosage.[21] this also has unintended consequences, such as research being delayed or risking lack of funding due to extended enrolment periods that may be required in order to comply with a restrictive legal framework. this may result in research being undertaken in other countries, where the ethical-legal framework is more flexible. new restrictive regulations for all forms of health research with human subjects new standards on health research with children have been introduced, which will limit the circumstances in which they may participate in research. three of the new consent regulations in section 71 are described and critiqued below. requiring written consent section 71 of the nha provides that research participants must give written, informed consent to health research.[1] this will have serious implications for certain types of health research, such as telephonic interviews and postal or electronic studies, in which the voluntary completion of a questionnaire is commonly regarded as consent.[25] it also excludes the use of passive consent (informing parents of a study and assuming they have agreed to their child participating, unless otherwise instructed) – a practice frequently used with adolescent school-based studies.[9] this approach is out of step with the more flexible approach in the national health research ethics council (nhrec) guidelines, which provide that consent may be given verbally or in writing. consent may also, in certain circumstances, be waived, if prior approval of the rec is obtained.[26] prohibiting independent consent from minors the nha[1] provides in section 71 that consent must be obtained from parents or legal guardians, and minors if they have understanding. in other words, children under the age of 18 do not have the capacity to consent independently to any form of health research, but they may in certain circumstances provide dual consent alongside that of their parents or guardians. mandatory parental consent means that it will no longer be possible to undertake health research where it involves the following: • certain socially marginalised groups. for example, adolescent men who have sex with men are highly stigmatised in sa, and may face social harms if they are required to seek parental consent to participate in research focusing on their sexuality or sexual practices. • behaviour that is legal, but which may incur parental disapproval or reprisal. an example is termination of pregnancy in young girls, as it is likely that very few teenage girls would be willing to approach their parents for consent to a study on a decision they had made autonomously to terminate a pregnancy. even though this is a lawful decision, studies have confirmed that teenagers will not use such services if they have to obtain parental consent for fear of disapproval.[27] • illegal behaviours. for example, studies into illegal practices such as child drug use or child prostitution would be complicated by concerns that: (i) children would not be prepared to seek parental consent, or (ii) parents are in fact not available to provide such consent. • minimal or no-risk research with children over the age of 12, using a passive consent approach.[9] for example, this could include completing surveys about drug, alcohol or sexual abuse, eating disorders, attitudes towards oral hygiene, exercise behaviour or even experiences of healthcare provision. • orphaned and vulnerable children (ovcs) who do not have parents or legal guardians who are able to consent. this is discussed further below. it is worth noting that in all of the above examples, the children are likely to be considerably more vulnerable and at risk of ill health than their peers, and research and consequent evidence-based intervention with these groups is particularly pertinent (table 1). prohibiting independent consent from minors is also problematic, in that it conflicts with the consent provisions in the children’s act,[11] which recognises the evolving capacity of children, and allows them to consent to a range of health interventions before the age of 18.[31] furthermore, this regulation in the nha is diametrically opposed to those in the nhrec ethical guidelines, which, for example, allow for independent consent by children in certain circumstances.[26] limiting the authority to provide proxy consent to parents or legal guardians section 71 of the nha limits the authority to provide proxy consent to either parents or legal guardians. generally, parents are the biological 48 sajhivmed june 2014, vol. 15, no. 2 f o r u m or adoptive parents of a child, while a guardian is a ‘person with guardianship of a child’.[11] unmarried, biological mothers over the age of 18 are automatically the guardian of their child, and in certain circumstances an unmarried father will be a co-guardian. if the biological parents are married, they will be joint guardians. a guardian may also be appointed by the high court or nominated by a parent in a will.[11] persons caring for children but not falling into any of the categories above will, in the future, not be able to provide consent for children to participate in health research. this will affect a significant number of children, given that it is estimated that by 2015, ~5 700 000 children would have lost one or both parents to aids.[32] in essence, this means that future studies with children who do not have parents or legal guardians will no longer be possible. furthermore, such children may not volunteer for health research, as they do not have an adult with the legal authority to provide proxy consent. this principle will also apply to mothers under the age of 18 who have lost parental support but who are at particular risk of both hiv acquisition and transmission. there are also far-reaching implications for research on child-headed households, ovcs and undocumented migrant children. ovcs are increasingly recognised as a special population in terms of hiv risk and transmission, yet they will not be able to inform research.[33] ovc and child-headed households present unique and contemporary issues that must be responded to. limiting the authority to provide proxy consent to parents and legal guardians is also out of step with the children’s act, which recognises that caregivers may consent to certain health interventions such as medical treatment and hiv testing on behalf of children.[34] conclusions given the principled nature of many of the concerns set out above, we call on the minister of health and the parliamentary health portfolio committee to address the need for law reform as a matter of urgency. if research institutions are required to comply with these regulations, child research in sa will grind to a halt, and this will ultimately harm the population it purports to protect. ensuring and supporting rigorous and equitable review by recs, and promoting clear communication to children and their caregivers during consent and study processes, should be the emphasis of developments in this field rather than restrictive legislation that reduces access to research participation. the nature and form of consent should be driven by the research itself, its benefits, risks, costs and consequences, rather than a blanket one-size-fits-all approach.[25] acknowledgements. this article is based on a july 2013 submission to the director general of health, on the draft regulation on human subjects by the southern african hiv clinicians society.[35] the society funded a consultative meeting at which many of the points made in the submission were workshopped, and we would like to acknowledge, in particular, the contributions of kelly blanchard, sumaya mall, nataly woollett, naomi lince-deroche, belinda alport, linda-gail bekker, denise evans and andy gray, who all assisted with written input into the final submission. thanks are also due to catherine slack of the hiv/ aids vaccines ethics group, university of kwazulu-natal, for a critical read of the first draft of this article. the article was in part made possible by funding from the national institute of health awarded to the hiv/ aids vaccine ethics group via the desmond tutu hiv foundation (dthf) (1ro1 a1094586) champs (choices for adolescent methods of prevention in south africa). the opinions expressed herein are the views of the authors. they do not represent any position or policy of the nih. references 1. south african government. national health act 61 of 2003. pretoria: government printer, 2003. table 1. examples of completed studies that would in the future be difficult to undertake with the requirement of parental/legal guardian consent name of study ethically approved consent requirements reasons why obtaining parental consent would be difficult or impossible health benefits to children hiv-related knowledge, attitudes and behaviour among sa street youth: reflections on power, sexuality and the autonomous self[28] independent consent the child research participants were street children living away from adult supervision better understanding of the hiv risk of children living on the street a systemic approach to the experiences of adolescents, with regard to terminating their pregnancies[29] participants aged 13 22 years; independent consent obtained the study explored experiences of pregnancy termination. in many cases, participants may not have disclosed their pregnancy or their decision to terminate to their parent/legal guardian. only 5 of 19 participants had disclosed their pregnancy to their mothers better understanding of adolescent experiences could inform policy and practice – particularly regarding school support and processes, as well as health and community services persisting mental-health problems among hiv-orphaned children in sa[30] the mean age of the participants was 13.4 years at the study outset; consent was obtained from participants and caregivers by definition, participants did not have a parent to provide consent, and it was unlikely that all caregivers would have been designated as legal guardians the identification of the impact of psychological distress due to aids orphanhood over time in comparison with other groups, and highlighting the need for a focus on addressing the specific psychosocial needs of children sa = south africa. june 2014, vol. 15, no. 2 sajhivmed 49 f o r u m 2. south african government. government gazette no. 35081, 27 february 2012. pretoria: government printer, 2012. 3. slack cm, strode ae, grant k, et al. implications of the ethical-legal framework for adolescent hiv vaccine trials: report of a consultative forum. s afr med j 2005;95(9):682-685. 4. stobie m, strode ae, slack cm. the dilemma of enrolling children in hiv vaccine research in south africa: what is in ‘the child’s best interests’? in: van niekerk a, kopelman l, eds. ethics and aids in africa. cape town: david philip publishers, 2005:190-207. 5. strode ae, slack cm, wassenaar dr, et al. one step forward, two steps back – requiring ministerial approval for all forms of non-therapeutic health research with minors. s afr med j 2007;97(3):200-202. 6. abdool karim q, khamny abm, frohlich ja, et al. hiv incidence in young girls in kwazulu-natal south africa – public health imperative for the inclusion in hiv biomedical intervention trials. aids behav 2012;16(7):1870-1876. [http://dx.doi. org/10.1007/s10461-012-0209-y] 7. pope a. hiv preventative research with minors. salj 2007;124(1):167-187. 8. singh ja, abdool karim ss, abdool karim q, et al. enrolling adolescents in research on hiv and other sensitive issues: lessons from south africa. plos 2006;2(7):0001-0005. [http://dx.doi.org/10.1371/journal.pmed.0030180] 9. zuch m, mason-jones aj, mathews c, henley l. changes to the law on consent in south africa: implications for school-based adolescent sexual and reproductive health research. biomed central 2012;12(3):1-5. [http://dx.doi.org/10.1186/1472-698x-12-3] 10. south african government. r 378: regulations relating to research on human subjects (published for public comment). in: government gazette no. 36508, 29 may 2013. pretoria: government printer, 2013. 11. south african government. children’s act 38 of 2005. pretoria: government printer, 2005. 12. fraser s, lewis, v, ding s, et al (eds). doing research with children and young people. london: sage, 2004:1-294. 13. rehle tm, hallett tb, shisana o, et al. a decline in new hiv infections in south africa: estimating hiv incidence from three national hiv surveys in 2002, 2005 and 2008. plos one 2010;5(6):e11094. [http://dx.doi.org/10.1371/journal.pone.0011094] 14. statistics south africa. mortality and causes of death in south africa, 2010: findings from death notification. south africa: statistics south africa, 2013. 15. maahs dm, west na, lawrence jm, et al. chapter 1: epidemiology of type 1 diabetes. endocrinol metab clin north am 2010;39(3):481-497. [http://dx.doi. org/10.1016/j.ecl.2010.05.011] 16. gabriel se, michaud k. epidemiological studies in incidence, prevalence, mortality, and comorbidity of the rheumatic diseases. arthritis res ther 2009;11:229. [http:// dx.doi.org/10.1186/ar2669] 17. hahn ys, kim jg. pathogenesis and clinical manifestations of juvenile rheumatoid arthritis. korean j pediatr 2010;53(11):921-930. [http://dx.doi.org/10.3345/ kjp.2010.53.11.921] 18. marston m, becquet r, zaba b, et al. net survival of perinatally and postnatally hiv-infected children: a pooled analysis of individual data from sub-saharan africa. int j epidemiol 2011;40(2):385-396. [http://dx.doi.org/10.1093/ije/dyq255] 19. obimbo em, mbori-ngacha da, ochieng jo, et al. predictors of early mortality in a cohort of human immunodeficiency virus type 1-infected african children. pediatr infect dis j 2004;23(6):536-543. 20. jaspan hb, cunniningham cr, tucker tjb, et al. inclusion of adolescents in preventive hiv vaccine trials: public policy and research design at a crossroads. acquired immune defic syndr 2004;47(1):86-92. [http://dx.doi.org/10.1097/ qai.0b013e31815d2f27] 21. caldwell ph. children in clinical trials. lancet 2004;364(9436):803-811. [http:// dx.doi.org/10.1016/s0140-6736(04)16942-0] 22. reisinger ks, block sl, lazcano-ponce e, et al. safety and persistent immunogenicity of a quadrivalent human papillomavirus type 6, 11, 16, 18 l1 virus-like particle vaccine in preadolescents and adolescents. pediatr infect dis j 2007;26(3):201-209. [http://dx.doi.org/10.1097/01. inf.0000253970.29190.5a] 23. graham a, fitzgerald r. children’s participation in research: some possibilities and constraints in the current australian research environment. j sociol 2012;46(2):133-135. [http://dx.doi.org/10.1177/1440783309355065] 24. south african government. constitution of the republic of south africa, 1996. pretoria: government printer, 1996. 25. jack cl, mars m. informed consent for telemedicine in south africa: a survey of consent practices among healthcare professionals in durban, kwazulu-natal. s afr j bl 2013;6(2):55-59. [http://dx.doi.org/10.7196/sajbl.287] 26. south african national department of health. ethics in health research: principles, structures and processes. south africa: national department of health, 2004. www.doh.gov.za (accessed 8 august 2013). 27. jackson s, hafemeister ti. impact of parental consent and notification policies on the decisions of adolescents to be tested for hiv. j adolesc health 2001;29(2):85. [http://dx.doi.org/10.1016/s1054-139x(00)00178-6] 28. swart-kruger j, richter lm. aids related knowledge, attitudes and behaviour among south african street youth: reflections on power, sexuality and the autonomous self. soc sci med 1997;45(6):957-966. [http://dx.doi.org/10.1016/ s0277-9536(96)00417-0] 29. de lange n, geldenhuys, jl. a systemic approach to adolescents’ experiences of terminating their pregnancies. society in transition 2001;32(2):246-259. [http:// dx.doi.org/10.1080/21528586.2001.10419045] 30. cluver ld, orkin m, gardner f, et al. persisting mental health problems among aids-orphaned children in south africa. j child psychol psychiatry 2012;53(4):363-70. [http://dx.doi.org/10.1111/j.1469-7610.2011.02459.x] 31. strode a, slack c, essack z. norms for child consent in south african law: implications for researchers, service providers and policy-makers. s afr med j 2010;100(4):247-249. 32. holborn l, eddy g. first steps to healing the south african family. sairr. johannesburg: south africa, 2011. 33. cluver l, orkin m, boyes m, gardner f, et al. transactional sex amongst aidsorphaned and aids-affected adolescents predicted by abuse and extreme poverty. j acquir immune defic syndr 2011;58(3):336-343. [http://dx.doi.org/10.1097/ qai.0b013e31822f0d82] 34. strode a, slack c. using the concept of parental responsibilities and rights to identify adults able to provide proxy consent to child research in south africa. s afr j bl 2010;3(2):69-72. 35. southern african hiv clinicians society. draft regulation on human subjects. http://www.sahivsoc.org/upload/documents/submission%20on%20nha%20 regs_final.pdf (accessed 27 september 2013). http://dx.doi.org/10.1007/s10461-012-0209-y] http://dx.doi.org/10.1007/s10461-012-0209-y] http://dx.doi.org/10.1371/journal.pmed.0030180] http://dx.doi.org/10.1186/1472-698x-12-3] http://dx.doi.org/10.1371/journal.pone.0011094] http://dx.doi.org/10.1016/j.ecl.2010.05.011] http://dx.doi.org/10.1016/j.ecl.2010.05.011] http://dx.doi.org/10.1186/ar2669] http://dx.doi.org/10.1186/ar2669] http://dx.doi.org/10.3345/kjp.2010.53.11.921] http://dx.doi.org/10.3345/kjp.2010.53.11.921] http://dx.doi.org/10.1093/ije/dyq255] http://dx.doi.org/10.1097/qai.0b013e31815d2f27] http://dx.doi.org/10.1097/qai.0b013e31815d2f27] http://dx.doi.org/10.1016/s0140-6736 http://dx.doi.org/10.1016/s0140-6736 http://dx.doi.org/10.1097/01.inf.0000253970.29190.5a] http://dx.doi.org/10.1097/01.inf.0000253970.29190.5a] http://dx.doi.org/10.1177/1440783309355065] http://dx.doi.org/10.7196/sajbl.287] http://www.doh.gov.za http://dx.doi.org/10.1016/s1054-139x http://dx.doi.org/10.1016/s0277-9536 http://dx.doi.org/10.1016/s0277-9536 http://dx.doi.org/10.1080/21528586.2001.10419045] http://dx.doi.org/10.1080/21528586.2001.10419045] http://dx.doi.org/10.1111/j.1469-7610.2011.02459.x] http://dx.doi.org/10.1097/qai.0b013e31822f0d82] http://dx.doi.org/10.1097/qai.0b013e31822f0d82] http://www.sahivsoc.org/upload/documents/submission%20on%20nha%20 abstract introduction methods results discussion conclusion acknowledgements references about the author(s) raymond chimatira beyond zero, east london, south africa dumo jebese-mfenqe beyond zero, east london, south africa joram chikwanda beyond zero, east london, south africa edward sibanda beyond zero, east london, south africa qhawekazi thengwa beyond zero, east london, south africa bulumko futshane beyond zero, east london, south africa sisanda gaga beyond zero, east london, south africa citation chimatira r, jebese-mfenqe d, chikwanda j, et al. human rights violations among men who have sex with men and transgender people in south africa. s afr j hiv med. 2023;24(1), a1417. https://doi.org/10.4102/sajhivmed.v24i1.1417 note: additional supporting information may be found in the online version of this article as online appendix 1. original research human rights violations among men who have sex with men and transgender people in south africa raymond chimatira, dumo jebese-mfenqe, joram chikwanda, edward sibanda, qhawekazi thengwa, bulumko futshane, sisanda gaga received: 18 june 2022; accepted: 11 aug. 2022; published: 23 jan. 2023 copyright: © 2023. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: men who have sex with men (msm) and transgender (tg) people face human rights violations (hrvs) which impact their access to critical interventions for hiv prevention, treatment, and related services. objectives: this study describes how beyond zero, a not-for-profit organisation in south africa, built an hrv reporting system and discusses data on the hrvs experienced by msm and tg people who accessed hiv prevention services between 01 january 2021 and 31 december 2021. method: this was a cross-sectional study using secondary analysis of programmatic data routinely collected as part of hiv prevention programmes for msm and tg in 10 rural districts of south africa. results: a total of 249 individuals reported having experienced hrvs. of these, 113 (54.6%) were physical violations, 145 (58.2%) were psychosocial harassment, 15 (18.3%) were experienced within the workplace, and 59 (23.7%) were experienced at a healthcare or social services institution. overall, 77% of the physical violations and 70.4% of the psychosocial violations occurred in the home and local community settings; 76.1% of the perpetrators of physical violence and 79.3% of the perpetrators of psychosocial harassment were known. most incidents of physical violence (80.5%) and psychosocial harassment (92.4%) were not reported due to fear of homophobic or transphobic violence. conclusion: our findings demonstrate the feasibility of documenting hrvs among msm and tg people within hiv prevention programmes. men who have sex with men and tg people should be systematically screened for hrvs and linked to legal or other services. what this study adds: our findings present data on the nature of hrvs in 10 districts outside of the large urban centres where research documenting the lived experiences of msm, tg people and other key populations is traditionally conducted in south africa. this data contribute to addressing the gap in the literature on the needs of msm and tg people in south africa caused by the delayed inclusion of rural msm and tg people in research. keywords: hiv; human rights violations; key populations; men who have sex with men; transgender people; south africa. introduction south africa has one of the highest burdens of hiv globally, with an estimated 7 800 000 people living with hiv in 2020. while south africa has a generalised hiv epidemic, the prevalence rates are highest among key populations.1,2 uptake of hiv-related treatment and prevention services and retention in care also varies, with lower rates reported among sex workers, men who have sex with men (msm) and other vulnerable populations. human rights violations (hrvs) affect this situation by driving the hiv epidemic, contributing to significant vulnerabilities to new infections and presenting barriers to access to hiv prevention and treatment services.3,4,5 consequently, this article focuses on documenting hrvs within the context of comprehensive hiv prevention programmes for msm and transgender (tg) people in 10 districts in south africa. stigma, discrimination, gender inequality and socio-cultural norms that drive physical and sexual violence and psychosocial harassment against key populations create barriers to accessing healthcare and social services, and negatively affect retention in care for the very populations most in need.3,4,6,7,8,9 these violations also negatively affect employment opportunities and relationships in their communities. to address these disparities, public health experts and funding agencies have redefined the right to health to include creating an environment that affirms the dignity of key and vulnerable populations. in addition, funding agencies have increased investment in programmes to remove human rights-related barriers to hiv-related prevention and treatment services.3,7,9,10,11 the national strategic plan (nsp) for hiv, tuberculosis (tb) and sexually transmitted infections (stis): 2017–2022 recognises that: there are still important gaps to close with respect to the full implementation of the human rights agenda, particularly the rights of people living with hiv and tb and key and vulnerable populations.8 (p. 32) goal 5 of the nsp aims to ground the response to hiv, tb and stis in human rights principles and approaches, to reduce stigma and discrimination, ensure equal treatment for all and increase access to justice in the context of hiv, tb and stis for all vulnerable and key populations.2,8 the nsp 2019–2022 sets out key programmes to reduce human rights-related barriers to hiv and tb services and gender inequality in south africa. several interventions are implemented by governmental, non-governmental and private sector stakeholders to ensure the protection and promotion of hiv-related human rights in the country. it is against this background that beyond zero (bz), a not-for-profit organisation in south africa, developed a system for recording and responding to hrvs against msm and tg people to strengthen its human rights programming. this study aimed to describe the nature of hrvs experienced by msm and tg people within the context of comprehensive hiv prevention programmes for msm and tg people in 10 districts in south africa. methods study design we conducted a cross-sectional study using secondary analysis of routinely collected programmatic data under the msm and tg comprehensive hiv prevention programmes implemented by bz through sub-recipients (srs). we used both quantitative and qualitative methods. quantitative data were collected by determining the number of verified violations reported to bz by programme staff from the implementing srs from 01 january 2021 to 31 december 2021. qualitative data were collected by considering the cases of msm and tg people reported to bz by srs in respect of the nature of the violations and factors surrounding the violations, such as the identity of perpetrators, the location where the violations occurred, and the steps taken by srs to address reported violations. study setting beyond zero implemented the msm comprehensive hiv prevention programme in nine districts through five srs and the tg comprehensive hiv prevention programme in four districts through four srs during the grant period 01 april 2019 to 31 march 2022. figure 1 highlights the geographic spread of the msm and tg programmes across south africa. figure 1: districts implementing the beyond zero men who have sex with men and transgender programmes, global fund grant 2019–2022. the comprehensive hiv prevention programmes reached 76 084 msm and 5337 tg people with a defined package of hiv prevention services (reach indicator) from 01 january 2021 to 31 december 2021. the reach indicator is defined as the number of msm who have received the defined minimum package of services, which includes all of the following components: peer education inclusive of comprehensive sexual and reproductive health information. enrolment risk assessment per individual, including hiv risk and sti, tb and gender-based violence screening, risk reduction counselling. offered reasonable access to condoms and lubricants, either directly provided by peer educators or made available through dispensing machines in hotspots or clinics. offered an hiv test if deemed relevant during the risk assessment. assisted hiv self-screening may be offered, in addition to traditional hiv rapid testing. intervention description – screening, documenting, and reporting human rights violations in the absence of a national system to systematically document and report hrvs among key populations, bz used results from a desktop review of nsp, national policies, and the national stigma index to develop the hrv documentation and reporting system between october 2020 and december 2020. during this time, the programme management team and strategic information unit created the hrv documentation forms, developed the system’s electronic data capture forms and determined how the system would integrate with existing bz reporting and data management systems. in addition, the team identified how to address user feedback and trained sr staff on how to screen for and document hrvs among msm and tg people reached by the comprehensive prevention programmes. the hrv monitoring and reporting system is based on a conceptual framework that outlines the following: (1) the necessary activities at the sr level, (2) individual case management strategies, (3) individual-level data collected at the sr level, (4) the use of de-identified data to improve programme implementation, and (5) mechanisms for reporting de-identified data to inform policy and action. figure 2 outlines a high-level summary of the conceptual framework. figure 2: conceptual framework for beyond zero’s human rights monitoring and reporting system. while the system could potentially allow individuals to report the hrvs online, the initial phase focused on the sr staff screening for and documenting hrvs experienced by msm and tg people using an opt-out approach. the approach of in-person screening conducted by trained sr staff allowed the respective service providers to provide or refer individuals who experienced hrvs for psychosocial, legal and other related support services. to improve data security and maintain client confidentiality while documenting hrvs, bz and srs avoid collecting identifying information in paper or electronic forms. at a minimum, the srs collect contact information on a separate de-linked form (e.g. client records) with the client’s unique identification number to track service provision or referral for off-site services. in addition, the srs allow clients to provide information in a private space and only report de-identified data to bz. these data are stored on a secure server with encryption (surveycto®), with user access control. beyond zero has no access to any personally identifiable information that could potentially be used to identify a particular person. in addition, the units of analysis are the districts, which are large enough that it will not be possible to infer information about individuals based on aggregate reports. once a case is documented, each sr provides direct psychosocial support or other appropriate services or linkage to care and support at other organisations or institutions that are better equipped to handle them. for example, srs refer assault cases to the south african police services (saps) and work with legal service organisations to ensure their legal cases are reported to appropriate authorities. beyond zero launched the system in december 2020 and conducted two primary interventions between the launch and january 2021. first, bz trained sr staff to sensitively manage cases of discrimination and hrvs against msm and tg people and use the reporting system. second, bz strengthened the internal relationships between the msm and tg programmes with the community response and systems strengthening programme. the linkage with the community response and systems strengthening module allows for efficient dissemination of the reports and findings among the provincial and district stakeholders, for example provincial councils on aids, district aids councils, local aids councils, and civil society sector representatives. these data are also reported to the aids foundation south africa (afsa), which was coordinating the global fund human rights programme for all the implementing principal recipients in south africa (2020–2022). these data are merged with other hrv data collected by all principal recipients and disseminated to various key national stakeholders during quarterly operational programmatic excellence and coordination meetings. the key stakeholders include the south african national aids council (sanac), the global fund county team, other development partners such as the united states (us) president’s emergency plan for aids relief (pepfar), the us centers for disease control and prevention (cdc), and us agency for international development (usaid) and other non-governmental implementing partners. data collection instrument and case definitions for purposes of monitoring and documenting hrvs, bz developed a detailed screening form through iterative rounds of inputs from programme technical leads and feedback from sr staff, some of whom identify as msm or tg (online appendix 1). recall of the hrvs experienced and characteristics of the perpetrators were elicited during risk assessment. table 1 summarises the key questions and case definitions developed following a literature review. table 1: key variables of the data collection instrument. data collection and analysis the data from srs were captured electronically into an online surveycto® form. the authors used surveycto®’s built-in data explorer to summarise the data submitted for individual fields, summarise the empirical relationships between fields, and drill down to browse individual submissions. the qualitative responses were analysed using thematic content analysis. ethical considerations this study involved secondary analysis of routinely collected hiv prevention programme data that were collected as part of routine programme service delivery. beyond zero obtained ethical clearance for this study from the pharma-access health research ethics committee (ethical clearance reference no. 210223835). results sociodemographic characteristics of individuals experiencing human rights violations between 01 january 2021 and 31 december 2021, srs reported that 249 individuals reported having experienced hrvs. overall, participants were young, with a mean age of 26 years (median 25 years). with regard to sexual orientation, 115 (46.2%) identified as men who have sex with men. with regard to gender identity, 29 (11.7%) identified as tg women, 18 (7.2%) identified as tg men, 42 (16.9%) were gender non-conforming and 45 (18.1%) preferred not to say. the majority, 138 (55.4%), had at least a secondary school education (grades 8 to 12), and 167 (67.1%) were unemployed. mopani, king cetshwayo and capricorn districts accounted for 49.5% of the reported violations. the variation in the number of hrvs reported reflects differences in uptake and rollout of the intervention by the srs. human rights violations reported of the 249 individuals who reported experiencing hrvs during the period 01 january 2021 to 31 december 2021, 145 (58.2%) experienced psychosocial harassment, 113 (45.4%) experienced physical violations, 15 (18.3%) experienced hrvs while at the workplace or applying for work, and 59 (23.7%) experienced hrvs at a healthcare or social services institution (table 2). the most common types of violations reported (table 3) were verbal insults (47.4%), psychosocial humiliation (35.7%), physical assault (26.9%), psychosocial ridicule (16.9%), malicious gossip (16.1%) and sexual assault (14.5%). table 2: selected characteristics of men who sex with men and transgender who experienced human rights violation. table 3: commonly reported violations.† location where human rights violations experienced and the identity of the perpetrators a review of the reported cases revealed that 51.3% of the physical violations occurred in the home, followed by 25.7% occurring on the streets within the local community. in comparison, the psychosocial violations occurred equally in the home (34.5%) and the streets within the local community (35.9%). other incidents of physical attacks occurred in bars or nightclubs (15.9%), educational institutions (8.9%), workplaces (4.4%), parks (0.9%) and public transport (0.9%). other incidents of psychosocial harassment occurred at educational institutions (10.3%), bars or nightclubs (5.5%), workplaces (4.8%), public transport (3.5%) and shopping malls or similar (2.1%). about a quarter (n = 59) of the 249 individuals reported experiencing stigma and discrimination at health or social service institutions in the previous 12 months based on sexual orientation or sexual identity. while 155 (62.2%) did not experience violations when seeking healthcare or other social services, 35 (14.1%) had not utilised any healthcare or social service institutions or concealed their sexual orientation. of 82 (32.9%) beneficiaries who were employed in the previous 12 months, 15 (18.3%) experienced stigma and discrimination in the workplace. in addition, 31 (37.86%) felt the need to conceal their sexual orientation from some of their work colleagues, while 8 (9.8%) concealed their sexual orientation all the time. the data highlight that 77.0% of the physical violations and 70.4% of the psychosocial violations occurred in the home and on the streets within the local communities. as a result, 76.1% of the perpetrators of physical violence and 79.3% of the perpetrators of psychosocial harassment were known by the individuals experiencing hrvs (table 4). table 4: identity of the perpetrators of human rights violations. barriers to reporting physical and psychosocial violations all individuals who reported experiencing hrvs where asked if they had reported these violations to the saps or any relevant authority (e.g. institutional heads). for those who did not report to saps or other relevant authorities, the reasons for not reporting were elicited using predefined categories, with allowance for other reasons to be specified as free text. while 113 individuals (54.6%) experienced physical violence, 91 (80.5%) incidents were not reported to the saps or any relevant authority (e.g. institutional heads). around half, 48 (52.6%), did not report the incident due to fear of homophobic or transphobic violence, 14 (15.4%) felt the incident was not severe enough, and 8 (8.8%) felt that saps were not effective enough or no mechanism would recognise the discriminatory motive of an incident. a further 21 (23.1%) cited other reasons such as fear of being outed and having to come out in public (fear of embarrassing the family and intimate partners), preferring mediation within the family or community, and fear of losing benefits (employment or depended on the abuser for livelihood). while 145 individuals (58.2%) experienced psychosocial violence, 134 (92.4%) incidents were not reported to the authorities. of these, 50 (37.3%) did not report the incident due to fear of homophobic or transphobic violence, 45 (33.6%) felt the incident was not severe enough, and 10 (7.4%) felt that saps were not effective enough or no mechanism would recognise the discriminatory motive of an incident. moreover, 29 (21.6%) cited other reasons such as fear of being outed and having to come out in public (fear of embarrassing the family and intimate partners), preferring mediation within the family or community, and fear of losing benefits (employment or depended on the abuser for livelihood). discussion we analysed routinely collected programmatic data to examine the nature of hrvs among msm and tg people in 10 districts in south africa. the individuals who experienced hrvs in our programmes were mainly young msm and tg people with a mean age of 26 years and a fair level of education (92.8% had secondary education or higher). our findings are similar to observations in several sub-saharan african countries that young msm and tg people are especially vulnerable to hrvs.6,12,13,14,15,16 most perpetrators of physical violence and psychosocial harassment were known by the individuals experiencing hrvs, as these occurred in the home and on the streets within the local communities. similar findings were reported among msm in tanzania, with verbal and moral abuse being the most prevalent from people in the street, neighbours and family members.13 in addition, there is evidence that sexual behaviour stigma at a community level is associated with individual-level risk behaviours among msm and tg people.6,17,18 these high rates of hrvs by known perpetrators in the home and community, as well as the association between homophobic behaviour and individual-level risk behaviours, support the need for evidence-informed community-level interventions addressing stigma and discrimination in a culturally sensitive manner. of particular interest is that most incidents of physical violence (80.5%) and psychosocial harassment (92.4%) were not reported for mediation or action: 52.6% of the incidents of physical violence and 37.3% of the incidents of psychosocial harassment were not reported due to fear of homophobic or transphobic violence. these findings suggest that while south africa has a progressive constitution protecting individual rights, the legal framework is insufficient to safeguard msm, tg people and other key populations who continue to face stigma and discrimination while accessing healthcare and other social services. while not explored in our initial phase of the project, there is evidence that community-level homophobia and concealment of sexual orientation or sexual identity impact mental health, affecting access to, uptake of and retention in hiv prevention services.6,15,18 our findings support the need for legal and social change interventions to change attitudes regarding sexual minorities and address stigma, discrimination and hrvs affecting msm, tg people and other key populations. this requires the rapid scale-up and monitoring of the implementation plan outlined in the nsp to reduce human rights-related barriers to hiv and tb services in south africa 2019–2022. the implementation plan outlines seven critical programme areas to address hiv, tb and sti-related hrvs comprehensively by (1) reducing stigma and discrimination, (2) sensitising and training health and community workers, (3) sensitising lawmakers and law enforcers, (4) launching legal literacy and know your rights campaigns, (5) strengthening legal support services, (6) monitoring, reviewing laws and policies, (7) reducing gender inequality, and (8) addressing gender-based violence. the south african constitutional, legal and policy framework creates a conducive environment for governmental, non-governmental and private sector stakeholders to ensure the protection and promotion of hiv-related human rights in the country. additionally, the prevention and combating of hate crimes and hate speech bill is currently under development. the bill provides grounds for the prosecution of people who commit the offence of hate crime and the offence of hate speech and provides for appropriate sentences that may be imposed on people who commit hate crime and hate speech offences, as well as provides for the prevention of hate crimes and hate speech.19 this study has important limitations. first, the uptake of the intervention differed between implementing sr and across districts. second, there was no routine screening for hrvs among all msm and tg people seeking hiv prevention services. therefore, it is likely that the hrvs are under-reported, and the results from this study may not generalise to msm and tg people in other districts in south africa. third, the cross-sectional study design is limited in inferring causal associations. conclusion our findings demonstrate the utility and feasibility of screening for and documenting hrvs among msm and tg people within the context of hiv prevention programmes. the findings suggest the need to systematically screen msm and tg people of hrvs and link them to legal or other services through a trusted mediator as a standard of care using a rights-based approach that safeguards the dignity and safety of each individual accessing hiv prevention services. most of the incidents of hrvs occurred at home, or within family and local community settings, and most were not reported to the authorities for action or mediation. thus, while the legal basis for redress is necessary, developing the capacity of community-based monitoring systems and structures for mediation is critical for safeguarding and promoting the human rights of msm and tg people in the country. finally, addressing hrvs requires adequate funding to support the operationalisation of the comprehensive nsp to reduce human rights-related barriers to hiv and tb services in south africa 2019–2022 as outlined. acknowledgements the authors would like to acknowledge all those who contributed directly and indirectly to this project, including the global fund to fight aids, tuberculosis and malaria (the global fund), and sub-recipient staff who provided comprehensive hiv prevention services to msm and tg individuals in the coverage districts. we also want to acknowledge msm, tg people and other key and vulnerable populations who continue to fight for their right to health in challenging contexts and circumstances. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions r.c., e.s., d.j.-m., j.c, q.t., b.f and s.g. were involved in the design of the hrv conceptual framework and reporting forms and contributed to developing the routine data use research protocol. r.c., j.c., and d.j-m. supervised the data collection; r.c. undertook data analysis and drafted the initial paper. all authors read, edited, and approved revisions and the final submitted version of the manuscript. funding information this implementation science activity was embedded within the zaf-c-bz global fund grant implemented by beyond zero between 01 april 2019 and 31 march 2022. the views expressed do not necessarily reflect the views of the global fund. data availability the data that support the findings of this study are part of routinely collected data for programme management and improvement collected by beyond zero. the data belong to the organisation and are available upon reasonable request through the corresponding author, r.c. disclaimer views expressed in this report are those of the authors. the data were collected as part of the comprehensive prevention programmes for msm and tg implemented under the global fund grant to south africa (april 2019 to march 2022). the contents of this report are the responsibility of the authors and do not necessarily reflect the views of the global fund. references unaids. country factsheets south africa | 2020 hiv and aids estimates. geneva: united nations; 2020. the south african national aids council. south africa’s national strategic plan for hiv, tb and stis 2017–2022. pretoria: the south african national aids council; 2017. unaids. fast-track and human rights – advancing human rights in efforts to accelerate the response to hiv. geneva: unaids; 2017. the global fund. global fund breaking down barriers initiative summary of key findings of the baseline assessments in 20 countries. geneva: the global fund; 2020. williamson rt, fiscian v, olson ru, poku fn, whittal j. a reporting system to protect the human rights of people living with hiv and key populations. health hum rights. 2017;19(2):211–222. tucker a, liht j, de swardt g, et al. homophobic stigma, depression, self-efficacy and unprotected anal intercourse for peri-urban township men who have sex with men in cape town, south africa: a cross-sectional association model. aids care. 2014 jul 3;26(7):882–889. https://doi.org/10.1080/09540121.2013.859652 the global fund. scaling up programs to reduce human rights related barriers to hiv services. geneva: the global fund; 2018. the south african national aids council. national strategic plan to reduce human rights related barriers to hiv, tb and malaria services: south africa. pretoria: the south african national aids council; 2019. betron m, gonzalez-figueroa e. gender identity, violence, and hiv among msm and tg: a literature review and a call for screening. washington, dc: futures group international, usaid; 2009. frontline aids. implementing and scaling up programmes to remove human rights-related barriers to hiv services: a practical guide. sussex: frontline aids; 2020. p. 1–116. international hiv/aids alliance. reacting to reality: taking action on human rights violations against key populations. east sussex: international hiv/aids alliance; 2018. zahn r, grosso a, scheibe a, et al. human rights violations among men who have sex with men in southern africa: comparisons between legal contexts. plos one. 2016;11(1):1–12. https://doi.org/10.1371/journal.pone.0147156 anderson am, ross mw, nyoni je, mccurdy sq. high prevalence of stigma-related abuse among a sample of men who have sex with men in tanzania: implications for hiv prevention. aids care. 2015;27(1):63–70. https://doi.org/10.1080/09540121.2014.951597 beck j, santos g-m, ayala g. young men who have sex with men: health, access, & hiv. 2012. p. 4. oakland, ca: global forum on msm and hiv (msmgf); 2013. makanjuola o, folayan mo, oginni oa. on being gay in nigeria: discrimination, mental health distress, and coping. j gay lesbian ment health. 2018;22(4):372–384. https://doi.org/10.1080/19359705.2018.1482809 dibble ke, baral sd, beymer mr, et al. stigma and healthcare access among men who have sex with men and transgender women who have sex with men in senegal. sage open med. 2022;10:20503121211069276. https://doi.org/10.1177/20503121211069276 lyons c, stahlman s, holland c, et al. stigma and outness about sexual behaviors among cisgender men who have sex with men and transgender women in eswatini: a latent class analysis. bmc infect dis. 2019;19(1):1–10. https://doi.org/10.1186/s12879-019-3711-2 arnold mp, struthers h, mcintyre j, lane t. contextual correlates of per partner unprotected anal intercourse rates among msm in soweto, south africa. aids behav. 2013 may 29;17(s1):4–11. https://doi.org/10.1007/s10461-012-0324-9 stievenart ca. a critical analysis of the prevention and combating of hate crimes and hate speech bill and section 36 of the constitution of the republic of south africa [doctoral dissertation]. university of johannesburg, south africa; 2019. a recently released report by united nations secretarygeneral ban ki-moon, titled uniting for universal access: towards zero new hiv infections, zero discrimination and zero aids-related deaths, highlights the facts that the global rate of new hiv infections is declining, treatment access is expanding, and the world has made significant strides in reducing transmission from mother to child. the secretary-general makes five suggestions to strengthen the aids response. we are encouraged to harness the energy of young people for an hiv prevention revolution, revitalise the push towards achieving universal access to hiv prevention, treatment, care and support by 2015, work with countries to make hiv programmes more cost effective, efficient and sustainable, promote the health, human rights and dignity of women and girls, and ensure mutual accountability to translate commitments into action. his goal setting is ambitious: to reduce the sexual transmission of hiv by 50%, and prevent all new hiv infections resulting from injecting drug use; to eliminate transmission from mother to child; to reduce tuberculosis deaths in people living with hiv by 50%; to ensure hiv treatment for 13 million people; to reduce by 50% the number of countries with hiv-related restrictions on entry, stay and residence; and to ensure equal access to education for children orphaned and made vulnerable by aids. with these challenges in mind this journal continues to press forward with the goal of keeping you informed, very much with a philosophy of ‘learning by sharing’. in this edition, campbell makes an eloquent case for an evidence-based approach to palliative care for children. gounden compares outcomes in a private and a public sector cohort on antiretroviral therapy and finds some interesting prescribing differences between the two groups, although outcomes were very similar. the recent national testing campaign has included expansion into schools, and pfaff and de beer describe a youthfriendly testing campaign that has been implemented by an ngo in the manguzi district. the surveillance and causes of infant mortality in south africa was a passion of a very much missed colleague, david bourne, who unexpectedly passed away in february 2009. the paper by boulle and colleagues is dedicated to david and acknowledges his work. polyclonal gammopathy is a common finding in hiv, and tathiah and colleagues present a retrospective study of serum electrophoresis patterns in patients in kzn. readers have expressed great interest in case reports. the benefit in learning from real clinical cases is acknowledged by the review committee, so this edition is full of interesting case reports. continuing our important guidelines series, we present the management of hepatitis b infection as a co-infection with hiv. thanks to the southern african hiv clinicians society for this excellent collaboration. coming soon are guidelines for safer conception, hiv-infected health care worker protection, and pre-exposure prophylaxis. exciting news is that in 2011 the editorial office is undergoing revitalisation and will have increased resources. this will be good news for those of you who have waited so patiently for reviews of your submissions. i sincerely apologise to frustrated authors who have found our current system tardy. this will be improved in 2011. please continue to submit copy! linda-gail bekker editor 5 f r o m t h e e d i tor m e s s a g e f r o m t h e e x e c u t i v e several things are coming to completion in this important year for the society. a new board of interim directors has been elected to construct our new constitution, or ‘memorandum of association’, legalese from the new companies act that is about to come into force. it will be presented to the old executive for discussion, and then circulated for comment, in the next few months. i welcome tim tucker, one of south africa’s unsung heroes from the vaccine enterprise, and eric hefer, who is known by reputation to many of you and is a longtime exco member, to the interim board. they’ll also be advising on our new structure, and how we take the organisation towards new elections in november. the society bids a sad farewell to linda-gail bekker as an editor. it has been a tough tenure – the journal has to compete with many others, and clinicians are not all polite, naturally gifted researchers or writers. despite this, we distribute over 15 000 copies of every issue, and the feedback is that you love it. lgb has all our gratitude. incoming editor will be dr landon myer, another cape town find, who has experience with international journals and an impressive research cv. we have secured a further grant from atlantic philanthropies, which will allow the society’s transition to this new structure as well as support our advocacy and networking work. in addition, we have met with the monument trust, who fund our nurse/nimart work and want this programme expanded even further. on top of all this, all our other activities carry on, and are very successful. francois venter president t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 1 virtrium hiv med journal a 4/14/11 10:11 am page 1 composite c m y cm my cy cmy k introduction recommendation 1: cryptococcal antigen screening and pre-emptive treatment recommendation 2: laboratory diagnosis and monitoring recommendation 3: management of a first episode of cryptococcal meningitis recommendation 4: amphotericin b and flucytosine toxicity prevention, monitoring and management recommendation 5: timing of antiretroviral therapy recommendation 6: management of raised intracranial pressure recommendation 7: management of relapse episodes of cryptococcal meningitis acknowledgements references about the author(s) nelesh p. govender national institute for communicable diseases, a division of the national health laboratory service, johannesburg, south africa school of pathology, university of the witwatersrand, johannesburg, south africa division of medical microbiology, university of cape town, cape town, south africa graeme meintjes institute of infectious disease and molecular medicine, university of cape town, cape town, south africa department of medicine, university of cape town, cape town, south africa phetho mangena department of medicine, polokwane hospital, polokwane, south africa jeremy nel helen joseph hospital, university of the witwatersrand, johannesburg, south africa samantha potgieter department of internal medicine, university of the free state, bloemfontein, south africa denasha reddy division of infectious diseases, department of internal medicine, chris hani baragwanath academic hospital, university of the witwatersrand, johannesburg, south africa helena rabie department of paediatrics, tygerberg hospital, stellenbosch university, stellenbosch, south africa douglas wilson department of internal medicine, edendale hospital, pietermaritzburg, south africa school of clinical medicine, university of kwazulu-natal, pietermaritzburg, south africa john black department of infectious diseases, livingstone hospital, port elizabeth, south africa david boulware department of medicine, centre for infectious diseases and microbiology translational research, university of minnesota, minneapolis, united states tom boyles anova health institute, johannesburg, south africa faculty of health sciences, university of the witwatersrand, johannesburg, south africa tom chiller mycotic diseases branch, us centres for disease control and prevention, atlanta, united states halima dawood department of medicine, grey’s hospital, pietermaritzburg, south africa caprisa, university of kwazulu-natal, pietermaritzburg, south africa sipho dlamini division of infectious diseases and hiv medicine, department of medicine, groote schuur hospital, university of cape town, cape town, south africa thomas s. harrison centre for global health, institute of infection and immunity, st george’s university of london, london, united kingdom prudence ive faculty of health sciences, university of the witwatersrand, johannesburg, south africa division of infectious diseases, department of internal medicine, school of clinical medicine, faculty of health sciences, helen joseph hospital, johannesburg, south africa joseph jarvis department of clinical research, faculty of infectious and tropical diseases, london school of hygiene and tropical medicine, london, united kingdom alan karstaedt faculty of health sciences, university of the witwatersrand, johannesburg, south africa division of infectious diseases, department of internal medicine, charlotte maxeke johannesburg hospital, johannesburg, south africa matamela c. madua department of medicine, rob ferreira hospital, mbombela, south africa colin menezes division of infectious diseases, department of internal medicine, chris hani baragwanath academic hospital, university of the witwatersrand, johannesburg, south africa faculty of health sciences, university of the witwatersrand, johannesburg, south africa mahomed-yunus s. moosa department of infectious diseases, nelson r. mandela school of medicine, university of kwazulu-natal, durban, south africa zaaheera motlekar department of medicine, kimberley provincial hospital, kimberley, south africa amir shroufi mycotic diseases branch, us centres for disease control and prevention, atlanta, united states sarah lynn stacey faculty of health sciences, university of the witwatersrand, johannesburg, south africa department of internal medicine, charlotte maxeke johannesburg academic hospital, johannesburg, south africa merika tsitsi division of infectious diseases, department of internal medicine, chris hani baragwanath academic hospital, university of the witwatersrand, johannesburg, south africa faculty of health sciences, university of the witwatersrand, johannesburg, south africa gilles van cutsem southern africa medical unit, médecins sans frontières, cape town, south africa centre for infectious disease epidemiology and research, university of cape town, cape town, south africa ebrahim variava faculty of health sciences, university of the witwatersrand, johannesburg, south africa department of medicine, tshepong hospital, klerksdorp, south africa michelle venter division of infectious diseases, department of internal medicine, chris hani baragwanath academic hospital, university of the witwatersrand, johannesburg, south africa faculty of health sciences, university of the witwatersrand, johannesburg, south africa rachel wake national institute for communicable diseases, a division of the national health laboratory service, johannesburg, south africa centre for global health, institute of infection and immunity, st george’s university of london, london, united kingdom citation govender np, meintjes g, mangena p, et al. southern african hiv clinicians society guideline for the prevention, diagnosis and management of cryptococcal diseases among hiv-infected persons: 2019 update. s afr j hiv med. 2019;20(1), a1030. https://doi.org/10.4102/sajhivmed.v20i1.1030 guideline southern african hiv clinicians society guideline for the prevention, diagnosis and management of cryptococcal disease among hiv-infected persons: 2019 update nelesh p. govender, graeme meintjes, phetho mangena, jeremy nel, samantha potgieter, denasha reddy, helena rabie, douglas wilson, john black, david boulware, tom boyles, tom chiller, halima dawood, sipho dlamini, thomas s. harrison, prudence ive, joseph jarvis, alan karstaedt, matamela c. madua, colin menezes, mahomed-yunus s. moosa, zaaheera motlekar, amir shroufi, sarah lynn stacey, merika tsitsi, gilles van cutsem, ebrahim variava, michelle venter, rachel wake received: 05 sept. 2019; accepted: 12 sept. 2019; published: 08 nov. 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. introduction rationale for guideline update six years after the southern african hiv clinicians society cryptococcal disease guideline was published in 2013, cryptococcal meningitis (cm) remains an important cause of mortality among antiretroviral treatment (art)-naïve and art-experienced hiv-seropositive adults in south africa.1,2 several important practice-changing developments led us to update the guideline to diagnose, prevent and manage this common fungal opportunistic infection. the world health organization (who) published a guideline for advanced hiv disease in 2017 and a guideline relevant to resource-limited settings for hiv-associated cm in 2018.3,4 cryptococcal antigen (crag) screening and pre-emptive treatment reduced all-cause mortality among ambulatory participants in a randomised clinical trial in zambia and uganda.5 following an evaluation of reflex versus provider-initiated screening, national reflex laboratory crag screening was implemented in south africa in 2016.6,7 recently completed clinical trials conducted in resource-limited settings have provided evidence for the best first-line antifungal regimens for cm and the role of corticosteroids in cm.8,9 finally, international and local advocacy efforts have resulted in increasing, yet still limited, access to flucytosine and a reduced cost of liposomal amphotericin b for the treatment of cm.10 summary of major changes to the guideline we now recommend crag screening for all adults or adolescents with a cd4+ t-lymphocyte (cd4) count < 200 cells/µl who are initiating art for the first time, switching after art failure or re-entering into care after prior disengagement. reflex laboratory crag screening is recommended as the preferred approach in south africa, although alternative approaches may be more suitable for other countries in southern africa. to diagnose cm, lumbar puncture (lp) is recommended for all patients with a new positive crag screening test result. the recommended induction regimen for cm is 1 week of amphotericin b deoxycholate (1 mg/kg/day) and flucytosine (100 mg/kg/day in four divided doses), followed by 1 week of fluconazole (1200 mg daily for adults; 12 mg/kg/day for children and adolescents up to a maximum of 800 mg daily). we have recommended alternative induction regimens for cm among patients with renal dysfunction, including liposomal amphotericin b-based options. a higher dose of fluconazole is now recommended during the 8-week consolidation phase for cm (800 mg daily for adults; 12 mg/kg/day for children and adolescents up to a maximum of 800 mg daily). maintenance treatment for cm is recommended to be continued for at least 12 months and until a single cd4 count is > 200 cells/µl and the hiv viral load is suppressed. we have included new recommendations for the prevention, monitoring and management of flucytosine toxicities. although a manometer is the most accurate way to measure raised intracranial pressure, we have suggested alternative options for assessment of elevated pressure when it is unavailable. patients with a positive blood crag test result in whom cm is ruled out by lp (a negative cerebrospinal fluid [csf] crag test is the most rapid method to establish this) should be given oral fluconazole alone as induction therapy (adults: 1200 mg for 2 weeks). antiretroviral treatment may be commenced immediately. we recommend immediate referral for lp in all patients with a new positive blood crag test who initiated art within the 4-week period prior to the crag test. among those with a negative csf crag test (i.e. in whom cm is excluded), art is recommended to be continued and fluconazole pre-emptive therapy should be initiated. among those with a new diagnosis of cm during the first 4 weeks of art, the guideline panel thought that there was clinical equipoise in terms of a decision to continue or interrupt art. antifungal susceptibility testing is now recommended if a patient has a single relapse episode of cm and other causes have been excluded. recommendation 1: cryptococcal antigen screening and pre-emptive treatment background early diagnosis of hiv infection and early initiation of art before immunosuppression is the most important strategy to reduce the incidence of cm and cm-associated mortality. in south africa, patients should initiate art according to the current national guideline.1,11,12 screening for subclinical cryptococcal disease has a proven mortality benefit among hiv-seropositive patients with low cd4 counts. in the reduction of early mortality among hiv-infected subjects starting antiretroviral therapy (remstart) trial, hiv-seropositive outpatients with a cd4 count < 200 cells/µl, who were randomised to receive crag screening and community-based art adherence support, had a 28% reduced all-cause mortality rate compared to those receiving standard of care (intervention: 134/1001 [13%] vs. standard: 180/998 [18%]).5 while the previous southern african guideline recommended crag screening for patients with cd4 < 100 cells/µl, this approach will fail to detect a substantial proportion of cases that occur in patients with cd4 counts between 100 cells/µl and 200 cells/µl. a meta-analysis estimated that the pooled global prevalence of cryptococcal antigenaemia was 6.5% among those with cd4 count < 100 cells/µl and 2% among those with a cd4 count between 101 cells/µl and 200 cells/µl.13 a post hoc analysis of remstart trial data revealed an important mortality benefit of crag screening and pre-emptive treatment in subgroups of patients with a cd4 count < 100 cells/µl and with cd4 count of 101 cells/µl – 200 cells/µl.4 thus, we now recommend that 200 cells/µl should be used as the cd4 threshold below which patients should be screened for cryptococcal disease, where resources permit (table 1). table 1: summary of recommendation 1. detailed recommendations who to screen? hiv-seropositive adults and adolescents (≥ 10 years) with a cd4 count < 200 cells/µl are recommended to be screened for cryptococcal antigenaemia. if screening is initiated by a clinician (medical practitioner or a nurse trained to initiate art) and not performed reflexively in the laboratory, the expert panel recommends that screening must be restricted to adults and adolescents initiating art for the first time, switching after treatment failure or re-initiating art (after an episode of interruption that was > 3 months) with a cd4 count < 200 cells/µl and no prior cm. although adults or adolescents with a cd4 count < 200 cells/µl who are virally suppressed on art may also be at risk of cryptococcal disease,14 there is insufficient current evidence to routinely recommend screening in this group. there are also insufficient data to recommend routine cryptococcal screening of hiv-infected children (< 10 years) in whom the incidence of cm is much lower.15 even though data for adolescents are limited, the who currently recommends screening for adolescents. south african data indicate an increasing incidence of cm from the age of 10 years onwards.15 screening strategies with reflexive laboratory crag screening, remnant blood samples (submitted to the laboratory for cd4 testing) are tested automatically for crag below a specified cd4 threshold. this approach is superior to clinician-initiated screening (where clinicians specifically request a blood crag test) in terms of screening coverage.16 a south african modelling study comparing the two strategies and using a cd4 threshold of < 100 cells/µl demonstrated that reflex screening was more cost-effective and saved more lives.7 although the crag latex agglutination (la) test format has been more extensively evaluated for the diagnosis of cryptococcal disease, a rapid crag lateral flow assay is simpler to perform on blood samples and more accurate.17 the national health laboratory service (nhls) expanded its reflex laboratory crag screening service across south africa in october 2016.6 between october 2016 and march 2019, more than 600 000 persons were screened, with a crag+ prevalence of 5.7% (n.p. govender, pers. comm., 02 september 2019, national institute for communicable diseases). however, the real-world effectiveness of this screen-and-treat strategy in terms of impact on mortality has yet to be determined. the laboratory turnaround time is very short for both cd4 count and reflex crag screening test results; however, initiation of art should not be unnecessarily delayed while awaiting crag test results in patients with advanced hiv disease who have no clinical features of meningitis. management of cryptococcal antigen-positive patients without previous cryptococcal meningitis all patients who screen crag-positive for the first time should have an lp performed. the absence of symptoms of meningitis does not exclude cm: approximately one in three patients with asymptomatic cryptococcal antigenaemia has concurrent cm.18 crag-positive patients who are subsequently identified as having cm should be managed as per recommendation 3. in the latter group, art should be commenced 4–6 weeks after the introduction of antifungal therapy. patients in whom cm is ruled out by lp (a negative csf crag test is the most rapid method to establish this) should be given oral fluconazole alone as induction therapy (adults: 1200 mg for 2 weeks). this is followed by standard consolidation and maintenance treatment regimens as per recommendation 3. in these blood crag-positive/csf crag-negative patients, art may be commenced immediately, with the caveat that there is no published evidence for this recommendation.19 adolescents and children should receive fluconazole 12 mg/kg/day (to a maximum of 800 mg per day) for 2 weeks followed by standard consolidation and maintenance treatment. the timing of art initiation should be the same as adults. patients who decline an lp can be stratified according to the presence or absence of meningitis symptoms (figure 1), although this approach is now recognised to be suboptimal.18 patients with headache, nausea, vomiting or other signs of cm should be treated as such (as per recommendation 3), whereas those without symptoms can be treated with fluconazole alone, as for patients in whom cm has been excluded. however, this approach will result in some cases of asymptomatic or subclinical cm being missed. if a screening blood crag titre is available (this is not routinely performed in south africa’s national crag screening programme), patients with crag titres > 160 may be considered at high risk of cm or cryptococcal disease-related death.20,21 such patients should be carefully monitored for cm signs/symptoms or considered for empirical cm treatment. community adherence support is recommended for all patients who screen crag-positive and are followed up as outpatients, particularly among those who decline an lp.5 figure 1: cryptococcal antigen screening and treatment algorithm. management of a positive blood cryptococcal antigen result obtained after antiretroviral treatment initiation current same-day hiv test-and-treat strategies mean that some patients may start art before a positive reflex blood crag result is received. given the increased risk of mortality associated with early art in cm,22 the panel recommends immediate referral for lp and csf analysis in all patients with a positive blood crag test who initiated art in the 4 weeks prior to the crag test. among patients with a negative csf crag test (i.e. in whom cm is excluded), art can be continued and fluconazole pre-emptive therapy should be initiated. among patients on a new art regimen with a positive csf crag test (i.e. a new diagnosis of cm), data suggest that mortality may be increased if cm is diagnosed in the first 4 weeks of art, possibly mediated through a mechanism of unmasking immune reconstitution inflammatory syndrome (iris).23 not all studies have demonstrated this and we do not know if art interruption would reduce this mortality risk. potential harms of art interruption include hiv resistance (more likely with nnrti-based regimens but less likely with dolutegravir-based regimens) and the risk of hiv disease progression and other opportunistic infections. the panel thought that there was clinical equipoise for the decision whether to continue or stop art in this group, and we therefore do not, at this stage, recommend art interruption. this remains a research question. prior cryptococcal meningitis patients with a history of cm do not need to be routinely screened. cerebrospinal fluid and blood specimens may remain crag-positive for months to years after a cm diagnosis and successful treatment of cryptococcal disease and therefore if these tests are positive in the absence of symptoms and signs, this is not an indication of relapse. however, if a patient with prior cm is screened, found to be crag-positive and has new symptoms or signs of meningitis, a full evaluation should be undertaken for relapse disease (refer to recommendations 2 and 7). if the patient does not have new symptoms or signs of meningitis, the clinician should ensure that the patient receives adequate fluconazole maintenance therapy (refer to recommendation 3). pregnancy or breastfeeding mothers cryptococcal antigen-positive patients who are pregnant should be offered an lp before a decision is made regarding management. if the patient has laboratory evidence of cm, she should be treated for cm with standard treatment.24,25 in a pregnant crag-positive patient without laboratory-confirmed cm or an asymptomatic woman who declines an lp, the patient should be counselled regarding the risks and benefits of fluconazole treatment. fluconazole has rarely been associated with human teratogenicity when administered in the first trimester, particularly at higher doses (≥ 400 mg/day). however, patients with a positive blood crag test treated with art and no fluconazole have a substantial risk of progression to meningitis, which has a high mortality. the panel therefore recommends that pregnant women should be counselled that the benefits of fluconazole outweigh the risks in this situation. an option that could be considered in women who are in the first trimester of pregnancy is to treat with fluconazole 200 mg daily until the second trimester. all women exposed to fluconazole in the first trimester should be referred for a high-resolution ultrasound scan before 20 weeks of gestation to detect congenital abnormalities. for mothers who are breastfeeding, consultation with an experienced medical practitioner is also recommended as fluconazole is present at concentrations similar to maternal plasma concentrations in breast milk and can be transmitted in large amounts through breast milk to the infant.26 clinical liver disease patients with a history of liver disease or with evidence of clinical liver disease deserve careful monitoring of serum liver enzyme and bilirubin levels (with specialist referral if there is a rising trend, or if jaundice develops) because fluconazole may cause liver injury.27 consultation with a medical practitioner experienced in the care of hiv-seropositive patients is recommended. recommendation 2: laboratory diagnosis and monitoring background cryptococcus neoformans is the most commonly detected pathogen causing meningitis in south africa.28 all hiv-seropositive adults and adolescents with clinically suspected meningitis or a positive blood crag test should be investigated for cm. hiv-seropositive children aged < 5 years are considered to have advanced hiv and, if symptomatic, should also be investigated for cm.3 patients with cm usually seek care with symptoms and signs related to inflamed meninges (including neck stiffness), raised intracranial pressure (including headache, confusion, altered level of consciousness, sixth cranial nerve palsies with diplopia and visual impairment and papilloedema) and encephalitis (including memory loss and new-onset psychiatric symptoms).29 cutaneous lesions and pulmonary involvement (including cavitation, nodular infiltrates and consolidation) may also occur. symptomatic relapses are common and are most often because of inadequate or premature cessation of maintenance fluconazole treatment.30 the incidence of cm is much lower among children15; children with cm may present with an acute onset of illness and focal neurological signs may be less common (table 2). table 2: summary of recommendation 2. detailed recommendations diagnosis of a first episode of cryptococcal meningitis an lp is required to confirm the diagnosis and establish the aetiology of suspected meningitis. lumbar puncture may also alleviate symptoms that are a direct result of raised intracranial pressure. for a suspected first episode of cm, csf should be submitted to the laboratory for a crag test and fungal culture. india ink test is not recommended as the only rapid test because of its lower sensitivity (78% compared to csf crag test).31 if a csf india ink test is performed and found negative, the laboratory should either perform a csf crag test or refer the specimen for this test. a crag lfa is the preferred format of testing; there are now several kits on the market although the innovator product (immy, norman, ok) has been most widely studied in pre-clinical and clinical evaluations,5,17,32 and the accuracy of other assays is still unclear. cryptococcus neoformans can be cultured from csf within 72 h among patients with a first episode of cm. cryptococcus gattii is occasionally confirmed on culture (2% of all cases in south africa) and these infections should be managed as for c. neoformans among hiv-seropositive patients.33 there is no need to routinely order a baseline csf crag titre because most patients are diagnosed when the csf fungal burden is already high and the antifungal regimens for a first episode are standardised and not influenced by the crag titre (refer to recommendation 3). a point-of-care crag lfa may be performed on csf at the bedside if laboratory facilities are not immediately available.34 antifungal susceptibility testing should not be routinely requested for a first episode because the vast majority of antifungal minimum inhibitory concentrations (mics) are low at first diagnosis and, even if elevated, the relevance is difficult to interpret in this setting.35 if opening pressure was not measured at the time of diagnostic lp, an lp should be repeated to measure the pressure once a diagnosis of cm is confirmed (refer to recommendation 6). cerebrospinal fluid obtained from therapeutic lps during the course of a hospital admission should not be routinely submitted for laboratory analysis because this is a waste of resources and does not impact on treatment management. diagnosis of cryptococcal meningitis if focal neurological signs are present or if lumbar puncture is not immediately available focal neurological signs are relatively uncommon in cm, except for a sixth cranial nerve palsy. where focal neurological signs are present, a computed tomography (ct) brain scan should be performed before lp to exclude the presence of space-occupying lesions. if a ct brain scan cannot be performed immediately in the case of focal neurological signs or if an lp is not immediately available to make a diagnosis of meningitis, serum/plasma/whole blood may be tested for crag to determine if the patient has disseminated cryptococcal disease. patients with a positive blood crag test and symptoms and signs of meningitis are very likely to have cm and should be started empirically on antifungal treatment (refer to recommendation 3). patients without focal neurological signs should then be referred to a centre where lp can be performed, while patients with focal neurological signs need to have a ct brain scan performed first followed by an lp (if this is not contraindicated by ct brain findings). although the expert panel is aware that it may be difficult to access a ct brain scan in rural settings, the panel recommends that there should be urgent referral for a ct scan before lp in blood crag-positive patients with focal neurologic signs, whenever possible. diagnosis of a subsequent episode of cryptococcal meningitis a careful history should be taken including dates of previous episodes of cm and the patient should be assessed clinically for signs and symptoms of meningitis. an lp is indicated if the patient has signs and symptoms of meningitis. cerebrospinal fluid should be submitted for fungal culture, with plates incubated for at least 14 days to detect slow fungal growth. rapid tests are not useful for the diagnosis of subsequent episodes because both csf india ink and csf/blood crag tests may remain positive for months to years even if treatment has been successful. antifungal susceptibility testing may be considered for a first relapse episode (see below and refer to recommendation 7). monitoring response to treatment resolution of symptoms and signs should be used to monitor the response to treatment. an lp should not be routinely performed after 7 (or 14) days of induction antifungal treatment to document conversion of csf from culture-positive to culture-negative because the expert panel advises routinely changing from induction to consolidation phase treatment at 14 days. given that a fungal culture result may take up to 14 days to become available, the culture result will not affect the timing of this change. if symptoms persist or recur during induction or at day 7 or 14, an lp should be repeated to re-measure the opening pressure, which may increase despite successful csf sterilisation. there is no evidence to support extending the duration of induction treatment. the patient should be investigated for other causes of a poor clinical response, the most common being raised intracranial pressure. patients with raised intracranial pressure should be managed according to recommendation 6. daily therapeutic lumbar puncture, and a ct brain scan if possible, is advised. if the cause of a poor clinical response cannot be found, consider referral to a secondary or tertiary centre for review unless the patient’s prognosis is already deemed to be very poor. cerebrospinal fluid crag tests may remain positive for months to years and crag titres are not recommended to be routinely measured to monitor the response to treatment. blood crag titres are also not useful to monitor the response to treatment for both cm and asymptomatic antigenaemia.36,37 suspected antifungal-resistant isolates antifungal susceptibility testing should be considered if the patient has a relapse episode and the causes listed in table 10 have been excluded. isolates with elevated fluconazole mics have been described from relapse episodes – especially where fluconazole monotherapy is initially given – and are unusual if amphotericin b-based induction treatment was administered during the first episode.35,38 because there are no established clinical breakpoints for c. neoformans and fluconazole, it is useful to test isolates from the initial and subsequent episodes in parallel in an academic or reference laboratory and document a fourfold (double dilution) change in mic that may suggest resistance.25 this requires that the initial isolate is stored, which may not always be possible at a diagnostic laboratory. minimum inhibitory concentrations should be interpreted by an experienced clinical microbiologist in conjunction with the clinical history. in the absence of paired isolates, epidemiologic cut-off values can be applied to distinguish wild-type and mutant strains.39 refer to recommendation 7 for the management of patients with fluconazole-resistant isolates. non-susceptibility to amphotericin b is very unusual and susceptibility testing for this antifungal agent should not be performed. flucytosine resistance develops with monotherapy; hence, combination treatment is always recommended.40 baseline flucytosine mic testing is not routinely recommended at present. recommendation 3: management of a first episode of cryptococcal meningitis detailed recommendations the antifungal treatment of hiv-associated cm is divided into three phases: induction, consolidation and maintenance (table 3). table 3: summary of recommendation 3. induction phase (2 weeks) the who recommends that the first choice for induction phase treatment is amphotericin b 1 mg/kg/day and flucytosine 100 mg/kg/day divided into four doses per day.4 flucytosine is not currently registered in south africa or any other african country.10,41 a flucytosine product manufactured in poland was acquired by mylan in 2016. despite previously lapsed registration in south africa and approval by the who pre-qualification program, the south african health products regulatory authority (sahpra) requires a full dossier to be submitted. the panel and the southern african hiv clinicians society support advocacy efforts to provide greater access to flucytosine through fast-track sahpra registration and development of additional generic products, particularly in light of the findings of the recently published advancing cryptococcal treatment in africa (acta) trial.8,10,41,42 this trial demonstrated a substantial mortality reduction among participants randomised to flucytosine-based combination therapies (table 4). overall, the best-performing treatment arm in the acta trial was the 1-week combination of amphotericin b deoxycholate and flucytosine, followed by high-dose oral fluconazole in the second week. this regimen was also associated with fewer adverse effects, specifically a reduction in amphotericin b deoxycholate-related nephrotoxicity and anaemia, and lower costs. this is the preferred regimen recommended by the panel. both the all-oral fluconazole/flucytosine regimen and 1-week amphotericin b deoxycholate/flucytosine regimen were non-inferior to the previous gold standard (i.e. 2 weeks of amphotericin b and flucytosine) in terms of 2-week mortality. the all-oral regimen is useful in cases where a delay in administration of amphotericin b deoxycholate is expected or its use is contraindicated. the panel now also recommends a higher induction dose of fluconazole (1200 mg daily) based on doses used in the acta trial. there is no evidence from fluconazole monotherapy trials to suggest an increased toxicity at this higher dose.43,44 if flucytosine is unavailable, the preferred treatment option is 2 weeks of amphotericin b and fluconazole (not 1 week of amphotericin b and fluconazole) because the 2-week regimen was associated with lower 2and 10-week mortality rates than 1 week of this drug combination in the acta trial (table 4). in settings with access to liposomal amphotericin b, this antifungal may be used instead of the deoxycholate formulation, especially among patients with renal impairment. although there is no evidence of improved efficacy compared to amphotericin b deoxycholate, liposomal amphotericin b is associated with fewer adverse effects and may be available at a reduced cost for cm in some countries.45,46 in countries where amphotericin b is unavailable, the panel advises clinicians to follow the who guideline with respect to high-dose fluconazole options.4 in south africa, all patients with cm should be treated with an amphotericin b-based induction regimen unless there is a specific contraindication to this. table 4: unadjusted 2and 10-week mortality outcomes for the five combination treatment regimens in the advancing cryptococcal treatment in africa trial. consolidation phase (further 8 weeks) the panel recommends a fluconazole dose of 800 mg daily for 8 weeks. this recommendation is based on expert opinion. maintenance phase (secondary prophylaxis) the panel recommends fluconazole 200 mg daily for at least 10 more months (i.e. to complete a total of 12 months of antifungal treatment). maintenance fluconazole should only be stopped when the cd4 count is documented to be > 200 cells/µl (on one occasion is sufficient) and the most recent hiv viral load is suppressed. adolescents and children during the induction phase, amphotericin b should be prescribed at a daily dose of 1 mg/kg/day and flucytosine as a (divided) daily dose of 100 mg/kg/day (table 5). fluconazole doses should also be calculated by body weight: induction phase: 12 mg/kg/day (up to 800 mg daily); consolidation phase: 6 mg/kg/day – 12 mg/kg/day (up to 800 mg daily); and maintenance phase: 6 mg/kg/day (up to 200 mg daily). table 5: flucytosine dosing in children and adults with normal renal function. renal impairment (creatinine clearance < 50 ml/min) if there is renal impairment at the time of diagnosis of cm with a calculated creatinine clearance of 30 ml/min – 50 ml/min, the recommended induction regimens are the following: if liposomal amphotericin b is available, switch to 1 week of liposomal amphotericin b (3 mg/kg/day – 4 mg/kg/day) and flucytosine, followed by 1 week of fluconazole (both fluconazole and flucytosine dose adjusted according to creatinine clearance) (table 6). one week of amphotericin b deoxycholate (1 mg/kg/day) and flucytosine (dose adjusted according to creatinine clearance), followed by 1 week of fluconazole (dose adjusted according to creatinine clearance) (table 6). table 6: induction therapy doses of flucytosine, fluconazole and amphotericin b adjusted according to estimated glomerular filtration rates for adults. if there is renal impairment at baseline with a creatinine clearance of < 30 ml/min or a deterioration in renal function, the recommended induction regimens are the following: if liposomal amphotericin b is available, 1 week of liposomal amphotericin b (3 mg/kg/day – 4 mg/kg/day) and flucytosine, followed by 1 week of fluconazole (both fluconazole and flucytosine dose adjusted according to creatinine clearance). two weeks of fluconazole (dose adjusted according to creatinine clearance) and flucytosine (dose adjusted according to creatinine clearance). if neither flucytosine nor liposomal amphotericin b is available, administer a single dose of amphotericin b deoxycholate (0.7 mg/kg) and daily fluconazole (dose adjusted according to creatinine clearance) and monitor creatinine clearance daily. administer amphotericin b deoxycholate (0.7 mg/kg) on alternate days if the creatinine clearance remains static and give as many doses as possible over the 2-week induction period. important practice point clinicians should be very clear when prescribing liposomal amphotericin b versus amphotericin b deoxycholate. the daily doses are different. intravenous fluids should be administered to all patients. tenofovir and amphotericin b deoxycholate can be used together provided the patient’s renal function is normal and serum creatinine does not double on treatment. among patients with renal impairment, art regimens containing tenofovir should be adjusted, switching to an alternative antiretroviral agent such as abacavir. if the patient’s initial reason for a reduced creatinine clearance was dehydration and this has been corrected with fluid administration, the patient can be switched back to amphotericin b deoxycholate at normal doses. flucytosine has a short plasma half-life and is cleared unchanged via the kidneys. flucytosine requires dose adjustment if there is renal impairment; where patients are dialysed, it should be given after dialysis (table 6). fluconazole monotherapy is not recommended except as a last resort. when used as monotherapy during induction, the fluconazole dose is 1200 mg daily with normal renal function. with a creatinine clearance of < 50 ml/min, the induction dose of fluconazole should be reduced by 50% to 600 mg daily. management of other forms of disseminated cryptococcosis cryptococcal fungaemia (i.e. a positive blood culture) should be managed as per cm. the treatment of cryptococcomas, pulmonary cryptococcosis and other forms of culture-confirmed disseminated cryptococcal disease is beyond the scope of this guideline. readers are advised to consult the 2010 infectious diseases society of america guideline.25 patients on tuberculosis treatment the panel does not recommend a fluconazole dose increase among patients receiving rifampicin because the induction of fluconazole metabolism by rifampicin causes only moderate reductions in fluconazole exposure and because of the high doses of fluconazole that are now being recommended for induction and consolidation treatment.8,47 adjunctive corticosteroid therapy the expert panel advises against adjunctive corticosteroid therapy in the initial management of cm.9 refer to recommendation 7 for the use of corticosteroids among patients with iris. immunological failure on antiretroviral treatment if patients with priorly treated cm develop immunological failure on art and their cd4 count drops below 200 cells/µl after secondary prophylaxis has been stopped, the panel advises restarting fluconazole at 200 mg daily. this may be considered for patients with priorly treated cryptococcal antigenaemia too. refer to the maintenance phase (secondary prophylaxis) for duration of treatment. non-adherence to maintenance treatment among patients who stop taking fluconazole maintenance prematurely and then return for care but are asymptomatic, the panel advises simply restarting fluconazole 200 mg daily and monitoring closely for recurrence of meningitis. symptomatic patients should be fully investigated for cm. community adherence support for art and fluconazole should be arranged. refer to the maintenance phase (secondary prophylaxis) for duration of treatment. analgesia therapeutic lps are the best form of ‘analgesia’ for headaches associated with raised intracranial pressure. paracetamol can be used but not non-steroidal anti-inflammatory drugs (nsaids) because of the nephrotoxicity concerns with amphotericin b deoxycholate. morphine may also be appropriate and is not contraindicated in the presence of raised intracranial pressure. recommendation 4: amphotericin b and flucytosine toxicity prevention, monitoring and management background amphotericin b deoxycholate-related toxicities major adverse effects of amphotericin b deoxycholate include acute kidney injury (aki) (caused by renal vasoconstriction and acute tubular necrosis) usually in the second week of therapy, hypokalaemia, hypomagnesaemia, anaemia, febrile reactions and chemical phlebitis.48 acute kidney injury and electrolyte abnormalities may be prevented by pre-hydration, by avoiding concurrent use of other nephrotoxins (e.g. nsaids and aminoglycosides) and by routine administration of potassium and magnesium supplements. phlebitis is very common among patients receiving amphotericin b and increases the risk of localised cellulitis as well as sepsis. anaemia commonly occurs among patients receiving amphotericin b and can be clinically significant particularly among those with a low baseline haemoglobin level. decreases in haemoglobin of greater than 2 g/dl occurred in 50% – 71% of patients over 2 weeks’ treatment in an individual-level analysis of data from several trials.49 it is important to also exclude other treatable causes of anaemia and consider transfusion among symptomatic patients. it should be noted that both the nephrotoxic effect of amphotericin b deoxycholate and the decrease in haemoglobin are less commonly observed when using the preferred regimen of 1-week amphotericin b combined with flucytosine compared to regimens using 2 weeks of amphotericin b (table 7).8 table 7: summary of recommendation 4. flucytosine-related toxicities flucytosine is associated with bone marrow toxicity and resultant anaemia, neutropenia and thrombocytopenia. this was observed particularly in early studies when flucytosine was used at high doses for prolonged periods of time.50,51,52 the reported prevalence of toxicity from recent trials, using lower doses for shorter periods, has been much lower. in the acta trial, the preferred regimen of 1-week amphotericin b combined with flucytosine 100 mg/kg/day was not associated with an increase in severe neutropenia compared to flucytosine-free regimens.8 the bioavailability of oral flucytosine was reduced among thai patients with advanced hiv disease compared to the intravenous formulation, minimising toxicity but with no demonstrated difference in early fungicidal activity.53 for these reasons, therapeutic monitoring of serum levels is not recommended in the setting of hiv-related cm. flucytosine plasma clearance is closely related to creatinine clearance and flucytosine thus accumulates with impaired renal function; this may lead to increased risk of toxicity. close monitoring of renal function and appropriate dose adjustment according to estimated creatinine clearance are therefore essential.54 detailed recommendations administration amphotericin b deoxycholate: amphotericin b deoxycholate powder (50 mg vials) should be refrigerated between 2 °c and 8 °c and protected from light.55 the total daily dose of amphotericin b is calculated based on a dose of 1 mg/kg/day; amphotericin b deoxycholate powder from each 50 mg vial should be aseptically reconstituted in 10 ml of sterile water. the calculated volume of the concentrate (i.e. reconstituted drug in sterile water) should be injected into a 1 l bag of 5% dextrose water and shaken to mix well. amphotericin b deoxycholate should never be mixed with normal saline or half-normal saline as it will precipitate. once mixed, the solution, containing ≤ 0.1 mg of amphotericin b per 1 ml of 5% dextrose water for infusion through a peripheral intravenous line, must be infused within 24 h of preparation, or else it should be discarded.55 a test dose is not recommended and protection of the solution from light with a brown bag is unnecessary.55 the line that is used for amphotericin b infusion should not be used to simultaneously administer other medications. the solution should be infused over 4 h or more (infusion < 4 h can result in cardiac complications). once the infusion is complete, the line should be flushed immediately with normal saline. flucytosine: flucytosine (500 mg tablets) should be stored below 25 °c in a cool, dry area. with normal renal function, the total daily dose is 100 mg/kg/day given in four divided doses (i.e. every 6 h) per os (table 5). nausea and vomiting may occur and can be attenuated by administering flucytosine tablets individually during a 15-min window or by pre-medication with anti-emetics. prevention of toxicities amphotericin b deoxycholate patients should be pre-hydrated with 1 l of normal saline containing 1 ampoule of potassium chloride (20 mmol k+ per 10 ml ampoule) infused over 2 h before administration of amphotericin b deoxycholate. this reduces renal toxicity and hypokalaemia. patients should be given 1200 mg potassium chloride orally twice daily (equivalent to 16 mmol of oral potassium, e.g. two slow-k 600 mg tablets twice daily, 8 mmol k+ per tablet) and up to 1500 mg magnesium chloride orally daily (e.g. two slow-mag 535 mg tablets daily, 5.33 mmol mg2+ per tablet, or two ultimag tablets daily, 660 mg mg2+ with zinc oxide 6 mg) for the duration of treatment with amphotericin b deoxycholate.26 routine pre-emptive potassium supplementation should not be given to patients with pre-existing renal impairment or hyperkalaemia. to minimise the risk of phlebitis, lines should be flushed with normal saline immediately after amphotericin b infusion is complete. the empty bag should not be left attached to the intravenous line. the intravenous line should be removed if the patient develops a fever after the infusion or at the first sign of redness or discomfort at the insertion site. febrile reactions may occur; in order to prevent recurrence, the infusion should be administered at a slow rate over the first half hour while observing the patient closely and treatment such as paracetamol may be required. flucytosine renal function should be closely monitored especially when flucytosine is combined with amphotericin b deoxycholate. the dose of flucytosine should be adjusted according to the estimated creatinine clearance in order to prevent accumulation and increased toxicity (table 6). laboratory or clinical monitoring recommendations depend on the induction regimen (table 8). table 8: laboratory monitoring according to induction regimen used. amphotericin b deoxycholate at a minimum, baseline and twice weekly monitoring of serum creatinine/potassium and baseline and weekly monitoring of haemoglobin are recommended for the duration of amphotericin b deoxycholate treatment. renal toxicity is more likely to develop in the second week of treatment in regimens where amphotericin b is used for 2 weeks. fluid input and output should be carefully monitored. chemical phlebitis is often complicated by infection at the intravenous line insertion site, which can result in bacteraemia56; the insertion site should be monitored by regular clinical examination and febrile patients with a suspected insertion site infection should be appropriately investigated and managed. flucytosine baseline grade 1 neutropenia (defined as an absolute neutrophil count ≤ 1000 cells/mm3) was documented among 12% of participants enrolled into the cryptococcal optimal art timing and adjunctive sertraline for the treatment of hiv-associated cryptococcal meningitis clinical trials where they received amphotericin b and fluconazole (plus sertraline in some patients).57 patients with baseline grade 1 neutropenia did not have a higher 30-day mortality compared to those without neutropenia. a baseline full blood/differential count should be done where available and the risk–benefit ratio of flucytosine therapy should be considered in the setting of baseline neutropenia. however, we strongly recommend the use of flucytosine even when there is baseline neutropenia because of the substantial mortality benefit over alternative regimens. both amphotericin b and flucytosine are associated with anaemia and thus serum haemoglobin should be monitored. a full blood count should be done at least weekly. a baseline differential count should be done if available and be repeated with subsequent full blood counts. creatinine clearance needs to be monitored in order to adjust flucytosine dose. this is particularly important where baseline renal function impairment exists or where flucytosine is administered with amphotericin b deoxycholate (table 6). fluconazole the panel recommends checking alanine transaminase (alt) levels if symptoms of hepatitis or jaundice develop while patients are on fluconazole, but routine alt monitoring is not indicated. management of toxicities amphotericin b deoxycholate for significant hypokalaemia (serum k+ <3.3 mmol/l), additional intravenous replacement is required: up to 2 ampoules of potassium chloride (20 mmol k+ per 10 ml ampoule) in 1 l of normal saline 8 hourly. among those who develop hypokalaemia, serum potassium should be monitored daily until it is resolved. if hypokalaemia remains uncorrected, serum magnesium should be checked (if this test is available) and/or oral magnesium supplementation should be doubled. intravenous magnesium sulphate may be considered for persistent hypokalaemia and hypomagnesaemia. if serum creatinine doubles from baseline, one dose of amphotericin b deoxycholate may be omitted and/or pre-hydration may be increased to 1 l of normal saline 8 hourly; serum creatinine should then be monitored daily. if serum creatinine improves, amphotericin b may be restarted at a dose of 0.7 mg/kg/day and/or alternate-day treatment could be considered. if creatinine remains elevated or repeatedly rises, liposomal amphotericin b should be substituted if available or amphotericin b deoxycholate should be stopped and an alternative regimen should be used (refer to recommendation 3). if febrile reactions occur with amphotericin b, paracetamol 1 g may be given 30 min before infusion or, for severe reactions, hydrocortisone 25 mg iv can be administered before subsequent infusions.22 flucytosine bone marrow suppression is uncommon at the recommended induction flucytosine dose for 1 week only, especially if renal function is normal (dose adjustment is important in case of significant renal impairment). other causes of a low neutrophil count should also be considered. however, if grade 4 neutropenia (< 400 cells/mm3) develops, then we recommend to reduce the flucytosine dose and repeat a neutrophil count as soon as possible. if the neutropenia is confirmed, then withhold flucytosine until counts recover. if the patient was on the preferred 1-week amphotericin b and flucytosine regimen, fluconazole may be added to amphotericin b, and extension of amphotericin b treatment to a second week should be considered. recommendation 5: timing of antiretroviral therapy detailed recommendations cryptococcal meningitis the expert panel recommends commencing art 4–6 weeks after the diagnosis of cm. the panel strongly advises that art must not be delayed beyond 6 weeks after diagnosis, and most members of the panel advise that clinicians should aim to start exactly 4 weeks after diagnosis of cm. although most patients with cm have advanced immunosuppression with very low cd4 counts, two randomised clinical trials conducted in sub-saharan africa have shown excess early mortality when art was commenced while patients were still receiving induction phase treatment for cm.22,58 in the later trial conducted in uganda and south africa, patients who started art 1–2 weeks after diagnosis of cm had a 15% higher mortality than those who deferred art until 5–6 weeks.59 another small trial showed possible excess iris in those patients who started art early.60 the in-hospital stay associated with amphotericin b therapy should be used for pre-art counselling, identification of a treatment supporter and early referral to an art clinic. clinicians should aim to set up an art clinic appointment within a week of discharge from hospital to prevent delays in art initiation beyond what is advised in this guideline. patients initiated on art should be counselled regarding the risk of development of iris. if a patient is referred to another facility for art, the need for fluconazole consolidation or maintenance therapy should be communicated. the expert panel recommends standard first-line art regimens among patients with cm.12 if nephrotoxicity occurred on amphotericin b, the renal function should be checked before starting art to ensure that it has improved (to a creatinine clearance of > 60 ml/min) before commencing tenofovir. the panel advises that, among patients who present with relapse of cm or a first cm episode after interrupting art, art should also be restarted after 4–6 weeks. one situation where art may be delayed further is if a patient is still symptomatic with headaches at the visit when art is about to be started. in such a situation, a lp should be repeated to measure pressure and for fungal culture to exclude persistent culture positivity. antiretroviral treatment should be deferred and such patients may require further lps or amphotericin b to ensure control of symptoms before starting art (table 9). table 9: summary of recommendation 5. cryptococcal antigenaemia the panel advises starting art immediately among art-naïve patients who are blood crag-positive on screening and have an lp that excludes cm (with a caveat that there is no evidence for this recommendation). asymptomatic crag-positive patients who decline consent for lp or for whom lp is contraindicated should start art after at least 2 weeks of antifungal treatment (figure 1). recommendation 6: management of raised intracranial pressure background raised intracranial pressure occurs in up to 75% of patients with cm and results from physical obstruction of csf outflow through the arachnoid villi/granulations resulting in build-up of csf pressure.61,62 raised pressure may be present at the diagnosis of cm or develop while the patient is on treatment and may result in severe headaches, vomiting, confusion or depressed level of consciousness, ophthalmoplegia (particularly sixth cranial nerve palsies) and visual disturbance/loss. clinicians need to consider raised intracranial pressure and manage appropriately if a patient exhibits these symptoms or signs at any stage of the management of cm. to alleviate raised pressure, therapeutic lps are indicated. new-onset hypertension may be a sign of increased intracranial pressure (i.e. part of cushing’s triad) and should prompt an lp to measure opening pressure instead of anti-hypertensive medications (box 1). box 1: summary of recommendation 6. detailed recommendations measurement of opening pressure the panel agreed that it is a good practice to measure the csf opening pressure whenever a diagnostic lp is performed. however, in practice, the opening pressure may not have been measured at the initial diagnostic lp. thus, once the diagnosis of cm is made, an lp should be repeated to measure csf opening pressure, particularly if the patient still has a headache (which is usually the case). the pressure should be measured using a manometer with the patient lying down and without excessive spinal flexion. approximately 15% of patients with initially normal intracranial pressure will develop raised intracranial pressure during treatment; thus, all patients should be monitored daily for headache or signs of raised intracranial pressure that should prompt an lp. what to do if a manometer is unavailable? manometers are not readily available in all centres or settings. in the absence of a manometer, the csf pressure can be crudely estimated in various ways: drop counting: obtaining ≥ 40 drops of free-flowing csf in 60 s using a 22-gauge spinal needle suggests a high csf pressure.63 an ‘eyeball test’: a powerful squirt of csf from the lp needle suggests a high csf pressure. makeshift manometers from intravenous line sets can be used to estimate opening pressure in cm h2o although these sets consistently under-estimate the opening pressure.64 the panel cautions that the above methods may be prone to under-estimating the actual csf pressure based on a manometer reading. management of raised pressure if the opening pressure is raised (i.e. a manometer reading > 25 cm h2o), then 10 ml – 30 ml csf should be drained (to normalise pressure to < 20 cm h2o or decrease the pressure by at least 50% – based on repeat measurement of closing pressure). then the need for pressure relief should be dictated by recurrence of symptoms of raised intracranial pressure. patients may require daily lps. where a manometer is not available and there are clinical symptoms or signs of raised intracranial pressure, we advise performing an lp and removing 20 ml – 30 ml of csf. a symptomatic improvement after the therapeutic lp would support the symptoms having been due to raised intracranial pressure (patients with raised intracranial pressure typically experience considerable relief of symptoms following a therapeutic lp). the patient should then be reviewed on subsequent days for ongoing symptoms and signs of raised intracranial pressure, which would indicate the need for further therapeutic lps. in rare cases, twice daily lps are required for controlling raised intracranial pressure in patients with extremely high opening pressures. patients with persistent pressure symptoms and measured high opening pressures who fail to respond to daily lps for more than 1 week may require lumbar drain insertion or shunting procedures. in such cases, neurosurgical consultation should be sought. recommendation 7: management of relapse episodes of cryptococcal meningitis there are several possible reasons for recurrence of symptoms of meningitis among patients treated for cm. in certain cases, recurrence is caused by microbiological relapse (although this is very uncommon with good adherence to maintenance fluconazole). there are situations in which there is a recurrence of symptoms but csf fungal cultures are negative. the causes are summarised in table 10. table 10: possible causes of recurrent symptoms and signs of meningitis in cryptococcal meningitis. initial assessment when a patient seeks care for a recurrent episode of meningitis, it is not always possible to immediately be sure what the aetiology is. the initial assessment should include: an evaluation of the patient’s adherence to fluconazole consolidation and maintenance phase treatment (using self-reported and pharmacy refill data). an enquiry as to whether the patient has recently started art to support a possible iris diagnosis. an lp to measure opening pressure, assess csf inflammation and for a prolonged fungal culture (request 14 days of incubation in the laboratory) on at least 3 ml – 5 ml of csf. there is no role for india ink staining or csf/blood crag assays in establishing the cause of recurrence as these tests may remain positive for months to years even in patients after successful treatment – refer to recommendation 2. if the csf is culture-positive and non-adherence does not appear to be the cause, then fluconazole susceptibility testing should be considered. susceptibility testing should be performed in an academic/reference laboratory. the panel recommends this when there has been at least one documented relapse despite reported good adherence (recommendation 2). if the cause of the recurrence is attributed to non-adherence, then the patient should be treated as for the first episode (recommendation 3). the reasons for non-adherence should be explored and the patient should receive additional adherence counselling, preferably together with a treatment supporter. if the patient also interrupted art, this should be re-initiated 4–6 weeks after induction antifungal treatment is re-started. antiretroviral treatment may need to be adjusted if there is a concern that there has been virological failure. paradoxical cryptococcal iris occurs among patients treated for cryptococcal disease who start art and develop a recurrence or worsening of clinical manifestations of cryptococcal disease. immune reconstitution inflammatory syndrome is thought to be the result of an immunopathological reaction directed at residual fungal antigens at sites of disease.40 iris occurs on average 6 weeks after art is commenced but delayed cases (> 1 year after art initiation) have been described.41 cryptococcal meningitis iris-associated mortality may be substantial.42 the most frequent manifestation is recurrence of symptoms of meningitis often with raised intracranial pressure. typically, the csf fungal culture is negative at the time of iris presentation – iris represents an immunological reaction rather than a microbiological recurrence. however, in cases where induction therapy was recent (< 2 months), the csf fungal culture may still be positive. other cryptococcal iris manifestations include lymphadenitis and cryptococcomas.40 in all patients with suspected paradoxical cm-iris, an lp should be performed to measure pressure and obtain a fungal culture incubated for up to 14 days. it is not possible to make a diagnosis of iris with certainty prior to excluding microbiological relapse on csf fungal culture. suspected cryptococcal meningitis-immune reconstitution inflammatory with mild symptoms if the symptoms are mild, the panel recommends performing therapeutic lps if there is raised intracranial pressure, providing analgesia and increasing the fluconazole dose to 1200 mg daily with regular review and follow-up of the csf fungal culture result. if the csf fungal culture is subsequently confirmed as negative, the dose of fluconazole can be reduced to what it was (800 mg or 200 mg daily depending on the timing of the cm-iris event). suspected cryptococcal meningitis-immune reconstitution inflammatory syndrome with severe symptoms or clinical deterioration if patients have severe symptoms or deteriorate with the approach above, the panel recommends treating with amphotericin b deoxycholate 1 mg/kg/day plus either flucytosine (100 mg/kg/day divided into four doses per day) or fluconazole 1200 mg daily until the csf culture is confirmed as negative. if the csf culture is still negative after 7 days’ incubation, amphotericin b can be stopped. if the fungal culture is positive by 7 days, then amphotericin b should be continued for 14 days if it is given with fluconazole (if it is given with flucytosine, then 7 days is sufficient). daily therapeutic lps may be required if opening pressure is raised. a ct brain scan should be considered as mass lesions and cerebral oedema can occur with iris. analgesia should be provided. among patients with severe iris who do not respond to the above treatment, corticosteroids should be considered: prednisone 1 mg/kg/day or an equivalent dose of dexamethasone for up to 2 weeks or until clinical improvement occurs, tapered over 2–6 weeks. longer treatment may be required depending on the symptom response. the panel recommends that corticosteroids preferably should be used among patients with iris who are documented to be csf fungal culture-negative and when other aetiologies (including tuberculous meningitis [tbm] and neurotropic viral infections) are excluded. however, if there is life-threatening neurological deterioration, corticosteroids should be started immediately. among patients with meningitis caused by fluconazole-resistant cryptococcus, subsequent management should be discussed with a medical practitioner experienced in the treatment of cm. such patients should receive induction therapy with amphotericin b again. consolidation and maintenance options will depend on the fluconazole mic and may include high doses of fluconazole, voriconazole or posaconazole with or without weekly amphotericin b infusions.25 among patients with multiple relapses, it is important to document conversion of csf from culture-positive to culture-negative before stopping amphotericin b and such cases should be discussed with a medical practitioner experienced in cm management and fluconazole susceptibility testing should be performed. distinguishing cm relapse or iris from tbm: immune-suppressed hiv-seropositive adults are at high risk of disseminated tb, including tbm. cerebrospinal fluid cell profiles and protein levels in cm are similar to those seen in tbm.65 however, a positive crag test or fungal culture is diagnostic for cm, and concomitant tbm is then less likely.66 all patients with cm relapse or cryptococcal iris should have diagnostic tests performed for concomitant tb with csf and sputum genexpert ultra assay, urinary lipoarabinomannan assay and chest radiograph (although pulmonary tb and cryptococcosis are difficult to distinguish radiologically). acknowledgements competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions n.p.g. and g.m. chaired the guideline panel. p.m., j.n., s.p., d.r. and d.w. drafted sections of the document. n.p.g. compiled the guideline document and worked on editing and reviewing with g.m. the rest of the authors listed contributed equally. ethical considerations this article followed all ethical standards for a research without direct contact with human or animal subjects. funding information this research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references southern african hiv clinicians society. guideline for the prevention, diagnosis and management of cryptococcal meningitis among hiv-infected persons: 2013 update. s afr j hiv med. 2013;14(2):a82. https://doi.org/10.7196/sajhivmed.930. national institute for communicable diseases. germs-sa annual report johannesburg, south africa [homepage on the internet]. national institute for communicable diseases; 2017 [cited 02 september 2019]. available from: http://www.nicd.ac.za/publications/archives/. world health organization. guidelines for managing advanced hiv 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graybill jr, sobel j, saag m, et al. diagnosis and management of increased intracranial pressure in patients with aids and cryptococcal meningitis. the niaid mycoses study group and aids cooperative treatment groups. clin infect dis. 2000;30(1):47–54. https://doi.org/10.1086/313603 boyles th, gatley e, wasserman s, meintjes g. brief report: flow rate of cerebrospinal fluid through a spinal needle can accurately predict intracranial pressure in cryptococcal meningitis. j acquir immune defic syndr. 2017;74(3):e64–e6. https://doi.org/10.1097/qai.0000000000001183 mogambery ta, moodley a, connolly c. is the intravenous giving set a reliable alternative to the spinal manometer in measuring cerebrospinal fluid opening pressure? s afr med j. 2018;108(10):865–869. https://doi.org/10.7196/samj.2018.v108i10.13176 vidal je, peixoto de miranda ej, gerhardt j, croda m, boulware dr. is it possible to differentiate tuberculous and cryptococcal meningitis in hiv-infected patients using only clinical and basic cerebrospinal fluid characteristics? s afr med j. 2017;107(2):156–159. https://doi.org/10.7196/samj.2017.v107i2.11162 ellis j, cresswell fv, rhein j, ssebambulidde k, boulware dr. cryptococcal meningitis and tuberculous meningitis co-infection in hiv-infected ugandan adults. open forum infect dis. 2018;5(8):ofy193. https://doi.org/10.1093/ofid/ofy193 pg9-11.html opinion when to start antiretroviral therapy in adults: the results of hptn 052 move us closer to a ‘test-and-treat’ policy nathan geffen, msc centre for social science research, university of cape town when is the best time to initiate antiretroviral therapy (art) in adults? this is a vital question in hiv treatment and prevention services. more specifically, is the 350 cells/µl cd4 count threshold recommended by current world health organization (who) guidelines sufficient, or should we move to a ‘test-and-treat’ approach in which anyone who tests hiv-positive is offered art, irrespective of their cd4 count? the recently announced results of the hptn 052 trial take us closer, but not all the way, to a test-and-treat approach. there are several important questions in determining art initiation criteria, including what is best for treating the hiv-positive individual, what is best for hiv and tuberculosis (tb) prevention at the population level, and the costs of the different options for initiating art. while there is not yet enough evidence to confidently change policy to recommend universal art for all hiv-positive individuals, there are certainly enough data to support the implementation and evaluation of ‘test-and-treat’ pilot programmes. what is best for treating the hiv-positive individual? clinical trials have shown definitively that a cd4 threshold of 350 cells/µl for initiating art results in lower morbidity and mortality than 200 cells/µl.1 , 2 however, observational data on whether patients with hiv will benefit from initiating at a higher cd4 count are less clear. researchers from the north american na-accord cohort (including over 17 500 patients) found a nearly two times increased risk of death in patients who deferred art to below 500 cells/µl.3 this study is cited in us treatment guidelines that provide for early treatment. however, the study’s statistical methods have been criticised.4 , 5 other evidence comes from the hiv-causal collaboration, which includes nearly 21 000 patients in europe and america, including the na-accord patients. in this study no mortality benefit was observed for patients who started art with a cd4 count above 500 cells/µl compared with those who started at 350 cells/µl. however, aids-defining illnesses were significantly more likely among patients who started treatment at lower cd4 counts.6 these studies do not offer conclusive evidence that initiating art early (>500 cells/µl) will benefit patients. both na-accord and hiv causal are observational studies and subject to methodological limitations. the long-term side-effects of art and the possible effect of treatment fatigue on adherence might mitigate against early initiation. furthermore, participants in these studies were less likely to use sub-optimal drugs, such as stavudine, that are prevalent in many resource-limited settings. it is hoped that two ongoing clinical trials will answer once and for all whether early treatment is beneficial. the strategic timing of antiretroviral treatment (start) trial is recruiting 4 000 volunteers. patients with cd4 counts >500 cells/µl are randomised to either initiate immediately or defer to 350 cells/µl.7 this international trial currently only has one site in sub-saharan africa, the desmond tutu hiv centre at the university of cape town (uct). start is due to complete in 2015, and clinicians in cape town should encourage their patients with high cd4 counts to consider enrolling at the uct site. in addition, the anrs 12136 trial in côte d’ivoire is due to complete in 2013. the trial objective is to compare the benefits and risks of initiating art according to the who guidelines versus the benefits and risks of initiating art immediately among hiv-positive adults with cd4 counts >350 cells/µl.8 what is best for hiv and tb prevention at the population level? several observational studies show that there is a strong correlation between reduced hiv incidence and either increased art coverage or lower viral loads in the community. in san francisco, new hiv diagnoses decreased along with mean community viral load from 2004 to 2008.9 in taiwan, there was a more than 50% decrease in hiv infections ascertained by community surveillance after the introduction of free art.10 in british columbia from 1996 to 2009, the number of people receiving art increased from 837 to 5 413, while the number of new hiv diagnoses fell over 50% from 702 to 338 per year.11 because of the possibility of confounding factors, these observational studies alone do not prove a causal effect, although they are strongly suggestive. this research was also conducted in populations where a large proportion of hiv-positive individuals are men who have sex with men (msm), and the generalisability of the findings to heterosexual populations may be questioned. however, the recently terminated hptn 052 study indeed demonstrates that art reduces the risk of hiv transmission in serodiscordant predominantly heterosexual couples. hptn 052 was an international study that began enrolling in 2005. a total of 1 763 hiv-positive people in serodiscordant relationships and with cd4 counts from 350 to 550 cells/µl were randomised to either receive art immediately (immediate group) or when their cd4 count fell below 250 cells/µl (delayed group). a total of 39 hiv infections occurred, and genetic analysis demonstrated that most transmission was between partners enrolled in the trial. only one hiv transmission took place from hiv-positive to hiv-negative partner in the immediate group versus 27 in the delayed group (hazard ratio (hr) 0.04; 95% confidence interval (ci) 0.01 0.27; p<0.001).12 the study was due to complete in april 2015, but the data safety monitoring board terminated it in may 2011 because of the highly significant results. an additional important finding from hptn 052 is that patients in the immediate initiation arm had fewer treatment endpoints, defined as first serious hiv-related clinical event or death (hr 0.59; 95% ci 0.40 0.88; p=0.01). the difference was driven by the fact that three participants in the immediate arm versus 17 in the delayed arm developed extrapulmonary tb (p=0.002). however, given the wide ci and the fact that the treatment initiation threshold was 250 cells/µl (not 350 cells/µl), this is not conclusive evidence of the benefit of early treatment to the patient. existing research suggests that a test-and-treat approach is likely to reduce hiv incidence. it is of course not a panacea: test-and-treat will seldom identify patients with primary hiv infection and therefore will not eliminate transmissions during primary hiv infection. infections due to virological failure should also be expected, and there is the inevitable decline in efficacy when moving from trial conditions to programmes serving entire populations. nevertheless, combined with scaled-up male medical circumcisions and condom distribution, we now have a formidable arsenal for reducing sexually transmitted hiv infections. a further public health benefit of test-and-treat is the effect on the tb epidemic. observational data also show a correlation between art scale-up and reduced tb incidence. for example, one study in masiphumelele township in cape town found that pre-art adult tb notifications increased by an average of 212 cases per 100 000 people per year, while post-haart, adult cases decreased by 116 per 100 000 per year.13 , 14 what does this mean for guidelines? while ‘test-and-treat’ policies might still be a few years away, it is perplexing that the south african treatment guidelines still use an art initiation threshold of 200 cells/µl except for pregnant women and people with tb (in which case 350 cells/µl is the initiation threshold). this is not a minor issue. a study by médecins sans frontières of a lesotho cohort found that the 639 patients who initiated above 200 cells/µl were 68% less likely to die and 39% less likely to be lost to follow-up than patients who initiated below 200 cells/µl. only 56 patients were pregnant and 66 had tb, and thus would have been started on treatment according to the south african guidelines.15 by failing to update our guidelines to the who standard, i.e. offering art to all patients at first cd4 count below 350 cells/µl, we are probably losing lives.* what about costs? costing and operational issues are major concerns in implementing a ‘test-and-treat’ strategy on a large scale. one analysis presented at the international aids conference in 2010 estimates the cost of using art for prevention in south africa. this analysis concluded that expanding art to all cd4 levels, beyond the recommended who threshold of 350 cells/µl, would add $700 million to the cost of the programme, but that this would prevent 681 000 new infections over time, and consequently allow the cost of the programme to break even by 2022.16 another analysis by the health economics and epidemiology research office (hero) has examined the cost of art using the who guidelines compared with a cd4 initiation of 200 cells/µl (south africa’s old guidelines). the cost of first-line tenofovir-based regimens is estimated to be r4 320 per patient for the first 6 months of treatment followed by r6 126 per patient per year.17 the assa2008 model estimates that there are 5.6 million people with hiv and 1.2 million on treatment.18 if hypothetically it were possible to initiate 1 million people on art with cd4 counts >350 cells/µl who pass through the hct programme over the next year as part of a test-and-treat programme at an average of r7 000 per patient for the first year, the additional cost of art would be r7 billion – a substantial burden on the state’s finances. however there are also potential cost savings due to reduced hiv infections and possibly reduced opportunistic infections. the potential of reducing the cost of treatment by lowering art prices, task-shifting, and the potential for the private sector to absorb a greater part of the cost of treatment than it currently does should also be considered. the hero study suggests that if task-shifting were implemented and optimal reference prices were paid for art regimens, the who 350 cells/µl initiation threshold including tenofovir-based regimens would cost less to implement than using the old 200 cells/µl threshold with stavudine (without task-shifting and optimal reference prices). analyses like this demonstrate that it is not necessarily guideline improvements that stand in the way of making programmes more affordable, but rather sub-optimal drug prices and programme design and staffing plans. in this light, it is possible that ‘test-and-treat’ approaches could be made highly cost-effective, and analyses of the costs and benefits of such an approach are clearly needed. conclusion while we do not yet have sufficient data to change guidelines to adopt test-and-treat, there are sufficient data to support preliminary programmes to research this approach. the hptn 052 results suggest that ‘test-and-treat’ may present an opportunity to reduce hiv incidence in south africa. nationally, we need to consider piloting in some health facilities the offer of art to hiv-positive people in serodiscordant relationships, heterosexual or homosexual, irrespective of cd4 count. such an operational research cohort would help us estimate the cost of a test-and-treat approach and identify its practical challenges and opportunities. references 1. severe p, juste ma, ambroise a, et al. early versus standard antiretroviral therapy for hiv-infected adults in haiti. n engl j med 2010;363(3):257-265. 1. severe p, juste ma, ambroise a, et al. early versus standard antiretroviral therapy for hiv-infected adults in haiti. n engl j med 2010;363(3):257-265. 2. smart study group, el-sadr wm, lundgren jd, et al. cd4+ count-guided interruption of antiretroviral treatment. n engl j med 2006;355(22):2283-2296. 2. smart study group, el-sadr wm, lundgren jd, et al. cd4+ count-guided interruption of antiretroviral treatment. n engl j med 2006;355(22):2283-2296. 3. kitahata mm, gange sj, abraham ag, et al. effect of early versus deferred antiretroviral therapy for hiv on survival. n engl j med 2009;360(18):1815-1826. 3. kitahata mm, gange sj, abraham ag, et al. effect of early versus deferred antiretroviral therapy for hiv on survival. n engl j med 2009;360(18):1815-1826. 4. buchbinder s, jain v. letter in response to kitahata et al. n engl j med 2009;361:822-824. 4. buchbinder s, jain v. letter in response to kitahata et al. n engl j med 2009;361:822-824. 5. hernán ma, robins j. letter in response to kitahata et al. n engl j med 2009;361: 822-824. 5. hernán ma, robins j. letter in response to kitahata et al. n engl j med 2009;361: 822-824. 6. the hiv-causal collaboration, cain le, logan r, et al. when to initiate combined antiretroviral therapy to reduce mortality and aids-defining illness in hiv-infected persons in developed countries. ann intern med 2011;154(8):509-515. 6. the hiv-causal collaboration, cain le, logan r, et al. when to initiate combined antiretroviral therapy to reduce mortality and aids-defining illness in hiv-infected persons in developed countries. ann intern med 2011;154(8):509-515. 7. insight. strategic timing of antiretroviral treatment (start). 20 march 2009. http://clinicaltrials.gov/ct2/show/nct00867048 (accessed 26 august 2011). 7. insight. strategic timing of antiretroviral treatment (start). 20 march 2009. http://clinicaltrials.gov/ct2/show/nct00867048 (accessed 26 august 2011). 8. anrs. early antiretroviral treatment and/or early isoniazid prophylaxis against tuberculosis in hiv-infected adults (anrs 12136 temprano). 2 july 2007. http://clinicaltrials.gov/ct2/show/nct00495651 (accessed 26 august 2011). 8. anrs. early antiretroviral treatment and/or early isoniazid prophylaxis against tuberculosis in hiv-infected adults (anrs 12136 temprano). 2 july 2007. http://clinicaltrials.gov/ct2/show/nct00495651 (accessed 26 august 2011). 9. das m, chu pl, santos gm, et al. decreases in community viral load are accompanied by reductions in new hiv infections in san francisco. plos one 2010;5(6):e11068. 9. das m, chu pl, santos gm, et al. decreases in community viral load are accompanied by reductions in new hiv infections in san francisco. plos one 2010;5(6):e11068. 10. fang ct, hsu hm, twu sj, et al. decreased hiv transmission after a policy of providing free access to highly active antiretroviral therapy in taiwan. j infect dis 2004;190(5):879-885. 10. fang ct, hsu hm, twu sj, et al. decreased hiv transmission after a policy of providing free access to highly active antiretroviral therapy in taiwan. j infect dis 2004;190(5):879-885. 11. montaner js, lima vd, barrios r, et al. association of highly active antiretroviral therapy coverage, population viral load, and yearly new hiv diagnoses in british columbia, canada: a population-based study. lancet 2010;376:532-539. 11. montaner js, lima vd, barrios r, et al. association of highly active antiretroviral therapy coverage, population viral load, and yearly new hiv diagnoses in british columbia, canada: a population-based study. lancet 2010;376:532-539. 12. cohen m, chen yq, mccauley m, et al. prevention of hiv-1 infection with early antiretroviral therapy. n engl j med 2011 jul 18. [epub ahead of print] 12. cohen m, chen yq, mccauley m, et al. prevention of hiv-1 infection with early antiretroviral therapy. n engl j med 2011 jul 18. [epub ahead of print] 13. middelkoop k, bekker lg, myer l, et al. antiretroviral therapy and tb notification rates in a high hiv prevalence south african community. j acquir immune defic syndr 2011;56(3):263-269. 13. middelkoop k, bekker lg, myer l, et al. antiretroviral therapy and tb notification rates in a high hiv prevalence south african community. j acquir immune defic syndr 2011;56(3):263-269. 14. middelkoop k, bekker lg, myer l, et al. antiretroviral program associated with reduction in untreated prevalent tuberculosis in a south african township. am j respir crit care med 2010;182(8):1080-1085. 14. middelkoop k, bekker lg, myer l, et al. antiretroviral program associated with reduction in untreated prevalent tuberculosis in a south african township. am j respir crit care med 2010;182(8):1080-1085. 15. ford n, kranzer k, hilderbrand k, et al. early initiation of antiretroviral therapy and associated reduction in mortality, morbidity and defaulting in a nurse-managed, community cohort in lesotho. aids 2010;24(17):2645-2650. 15. ford n, kranzer k, hilderbrand k, et al. early initiation of antiretroviral therapy and associated reduction in mortality, morbidity and defaulting in a nurse-managed, community cohort in lesotho. aids 2010;24(17):2645-2650. 16. kahn j. art for prevention of hiv transmission in south africa: estimated cost and cost-effectiveness. xviii international aids conference. moae0405. http://pag.aids2010.org/session.aspx?s=446 (accessed 26 august 2011). 16. kahn j. art for prevention of hiv transmission in south africa: estimated cost and cost-effectiveness. xviii international aids conference. moae0405. http://pag.aids2010.org/session.aspx?s=446 (accessed 26 august 2011). 17. meyer-rath g. the cost of the national art programme under the old and new guidelines: how big can we go, and how much can we save? presentation to 4th budget and expenditure monitoring forum. 12 november 2010. http://www.section27.org.za/wp-content/uploads/2010/11/nacm_presentation.pdf (accessed 26 august 2011). 17. meyer-rath g. the cost of the national art programme under the old and new guidelines: how big can we go, and how much can we save? presentation to 4th budget and expenditure monitoring forum. 12 november 2010. http://www.section27.org.za/wp-content/uploads/2010/11/nacm_presentation.pdf (accessed 26 august 2011). 18. actuarial society of south africa. assa2008 provincial summary outputs. march 2011. http://aids.actuarialsociety.org.za/scripts/buildfile.asp?filename=provoutput_110216.zip (accessed 26 august 2011). 18. actuarial society of south africa. assa2008 provincial summary outputs. march 2011. http://aids.actuarialsociety.org.za/scripts/buildfile.asp?filename=provoutput_110216.zip (accessed 26 august 2011). *this policy was changed after this article was accepted. now all hiv-positive patients with cd4 counts <350 cells/ µl are eligible for art. – editor declaration of conflict of interests: the author is on the community advisory board for the start study. hiv 782 treating depression in hiv-positive patients affects adherence m y h moosa, f y jeenah   division of psychiatry, faculty of health sciences, university of the witwatersrand, johannesburg m y h moosa, fc psych, mmed psych, mfgp, mb chb f y jeenah, fc psych, mmed psych, mb chb corresponding author: m y h moosa (yusuf.moosa@wits.ac.za) aim. to determine changes in adherence to antiretroviral therapy (art) in hiv-positive patients with depression, following treatment with an antidepressant or psychotherapy. methods. the study was prospective, randomised and controlled. consenting volunteers aged ≥18 years and stable on art for ≥6 months were included in the study. sociodemographic data were obtained, and a clinical diagnostic evaluation and the hamilton depression rating scale (hamd) were performed on all subjects at entry to and at the end of the study. participants found to be depressed were randomly assigned antidepressant treatment (20 mg citalopram) or interpersonal psychotherapy (ipt) (5 sessions). medication was dispensed at each visit and patients were asked to return all unused medication to determine art adherence. the study was approved by the university of the witwatersrand. results. sixty-two hiv-positive persons receiving art participated; 30 were not depressed (control group) and 32 were depressed (patient group). no significant differences in demographic characteristics existed between the control and patient groups. mean art adherence at the start of the study was 99.5% (standard error (se) ±0.46) and 92.1% (se ±1.69) in the control and patients groups, respectively. mean art adherence at the end of the study changed marginally in the control group (99.7%; se ±0.46) and increased significantly in the patient group (99.5%; se± 0.13) (p>0.05). the mean art adherence rate of patients who received pharmacotherapy increased from 92.8% to 99.5%, and of those who received psychotherapy increased from 91.1% to 99.6% (p>0.05). there was no significant association between the increased adherence in the patient group and baseline demographic and clinical characteristics, irrespective of antidepressant therapy or ipt (p>0.05). conclusion. successful treatment of depression with an antidepressant or psychotherapy was associated with improved art adherence, independent of the type of treatment and sociodemographic factors. it is necessary to identify hiv-positive patients at risk of depression, to initiate antidepressant treatment which may prevent art non-adherence, and subsequent disease progression and increased morbidity. s afr j hiv med 2012;13(3):144-149. doi:10.7196/sajhivmed.782 the joint united nations programme on hiv and aids recently reported that the number of people newly infected with hiv and the number of aids-related deaths are decreasing globally.1 the programme reported that an estimated 2.6 million people were newly infected with hiv in 2009, representing a 20% drop from the 3.1 million people infected in 1999. in south africa (sa), the estimated hiv prevalence among all age groups was 10.6% (5.2 million people) in 2008.2 although the prevalence in sa has stabilised in recent years, it is still significantly higher than in most countries in sub-saharan africa and the rest of the world. studies have also reported a high prevalence of co-morbid depression among hiv-positive individuals (5 48%).3 , 4 , 5 , 6 , 7 , 8 , 9 these variable rates of depression may be explained by variations in the actual populations studied (age, sex, education and ethnicity), different study designs, and differences in the stages of hiv/aids. adherence refers to the willingness and ability of patients to follow health-related advice, take medication as prescribed, attend scheduled appointments, and complete recommended investigations. actual adherence to treatment in most chronic diseases varies between 33% and 80%;10 , 11 however, the unique characteristics of hiv necessitate near-perfect adherence to antiretroviral therapy (art).12 , 13 , 14 , 15 , 16 , 17 , 18 reportedly, art adherence rates of 90 100% are required to: ensure suppression of viral replication;12 , 19 , 20 , 21 , 22 maintain cd4 cell counts; prevent clinical progression to aids; and prevent the development of art drug resistance and resistant hiv strains,10 , 23 , 24 , 25 , 26 , 27 , 28 which could leave drug-naive patients with few effective treatment options. although debatable, other reports suggest that complete (100%) adherence is required to achieve optimal benefits and to prevent virus mutation to treatment-resistant strains.29 , 30 , 31 depression is reported to be one of the major risk factors affecting art adherence in hiv-positive patients,32 , 33 , 34 , 35 attributed to a passive36 or fatalistic-resigned coping style and hopelessness.37 , 38 art adherence is lower in depressed hiv-positive individuals compared with non-depressed individuals. there are published data indicating that treatment for depression is associated with improved adherence.39 , 40 however, there is not yet sufficient prospective evidence to support this. this study, conducted in 2008 at the perinatal hiv research unit (phru) of the university of the witwatersrand, examined art adherence in a group of hiv-positive patients with depression at chris hani baragwanath academic hospital. the phru receives referrals from antenatal clinics for patients who test hiv-positive, and their partners, for initiation of art. the primary objective was to determine whether any changes in art adherence resulted following treatment with an antidepressant or interpersonal psychotherapy (ipt). methods the study was prospective, randomised and controlled, and sampling was convenience sampling (as it included patients attending the hiv clinic). volunteers aged ≥18 years were included in the study. all patients were stable on art for at least 6 months to reduce any confounding effects of the art on mood and immunity. subjects were excluded if they: met the diagnostic and statistical manual of mental disorders (4th ed.) (dsm-iv) criteria for any other psychotic, mood or substance abuse disorder; were pregnant or nursing; or were medically ill (hiv wasting syndrome, or onset of new opportunistic infections within the preceding 6 weeks). sociodemographic data were obtained at entry to the study. a clinical diagnostic evaluation and the hamilton depression rating scale (hamd) were performed on all subjects at entry to and end of the study. the depressed patients were randomly assigned to receive either an antidepressant (10 20 mg/day citalopram) or ipt. five ipt sessions were administered during the study period according to the comprehensive guide to interpersonal psychotherapy.41 these guidelines are clear, easily digested, highly informative, and illustrate the application of a conceptual model in the treatment of depression. while we were not trained or experienced in conducting ipt, it is our opinion that the therapy was correctly administered according to the aforementioned guidelines; there were, however, no objective measures to ensure this, signalling a limitation of our study. adherence was determined by using the patient self-report (number of doses missed in the preceding 3 days) and the pill count (medication was dispensed at each visit and patients were asked to return all unused medication, which was counted by the investigator). all participants gave written informed consent to participate. the study was approved by the committee for research on human subjects, university of the witwatersrand. in addition to their regular follow-up visits, patients were required to make 2 other visits for which they received financial assistance for travel costs. art and antidepressant drugs were supplied by the district mental-health clinics. descriptive statistics were computed as means and frequencies. the 2-sample t-test was used to compare continuous characteristics (age) between the groups. comparisons of change in adherence as a response to treatment were made between these 2 groups (antidepressant v. psychotherapy). associations with sociodemographic variables were examined with the use of contingency tables (chi-square test with yates correction, fischer’s exact test, and odds ratios). all analyses were performed with statistical package for social sciences (spss) software (version 10.0). a p-value <0.05 was considered significant. results sixty-two hiv-positive persons receiving art participated in the study; 30 were not depressed (control group) and 32 were depressed (patient group). sociodemographic characteristics in the control group, mean age was 37.7 years (standard error (se) ±1.2; range 27 51); 88% were female; 70% were single (not married, divorced or widowed); 70% were unemployed despite being able and willing to work; and 83.3% had achieved a level of education between grade 8 and 12 (table 1). all control patients disclosed their hiv status to a partner or family member. the majority (63.3%) were receiving art from regimen 1a; 23% were receiving triomune. table 1. sociodemographic characteristics of the control v. depressed patient groups characteristics study population (n=62) controls (n=30) patients (n=32)   significance pharmacotherapy ( n =19) psychotherapy ( n =13) gender, n (%)           chi2=2.045; p=0.359 male 9 (14.5) 6 (20) 1 (5.3) 2 (15.4)     female 53 (85.5) 24 (80) 18 (94.7) 11 (84.6) marital status, n (%)           chi2=0.547; p=0.761 single 43 (69.4) 21 (70) 14 (73.7) 8 (61.5)     married 19 (30.6) 9 (30) 5 (26.3) 5 (38.5) employment status, n (%)           chi2=5.707; p=0.058 employed 15 (24.2) 9 (30) 1 (5.3) 5 (38.5)     unemployed 47 (75.8) 21 (70) 17 (94.7) 12 (61.5) level of education, n (%)           chi2=2.391; p=0.664 grade 0 7 5 (8.1) 2 (6.7) 1 (5.2) 2 (15.4)     grade 8 12 48 (77.4) 25 (83.3) 14 (73.7) 9 (69.2) tertiary 9 (14.5) 3 (10) 4 (21.1) 2 (15.4) number of children, n (%)           chi2=5.022; p=0.285 0 1 23 (37.1) 13 (43.3) 7 (36.8) 3 (23.1)     >1 39 (62.9) 17 (56.7) 12 (63.2) 10 (76.9) ph of depression, n (%)           chi2=4.124; p=0.127 yes 4 (6.5) 1 (3.3) 3 (9.4) 0 (0)     no 58 (93.5) 29 (96.7) 16 (84.2) 13 (100)     fh of depression, n (%)           chi2=2.301; p=0.316 yes 1 (1.6) 0 (0) 1 (5.3) 0 (0)     no 61 (98.4) 30 (100) 18 (94.7) 13 (100)     art           chi2=15.68; p=0.047 regimen 1° 35 (56.5) 19 (63.3) 7 (36.8) 9 (69.2)     regimen 1b 8 (12.9) 1 (3.3) 5 (26.3) 2 (15.4)     triomune 12 (17.9) 7 (23.3) 4 (21.1) 1 (7.7)     other regimens 7 (12.7) 3 (10) 3 (15.8) 1 (7.7)     on other medication           chi2=0.779; p=0.677 yes 54 (87.1) 26 (86.7) 17 (89.5) 11 (84.6)     no 8 (12.9) 4 (113.3) 2 (10.5) 2 (15.4)     in the patient group, mean age was 36.8 years (se ±1.38; range 24 53); 90.6% were female; 67.8% were single (not married, divorced or widowed); 81.3% were unemployed despite being able and willing to work; and 71.9% had achieved a level of education between grade 8 and 12 (table 1). all patients disclosed their status to a partner or family member. half of the patients were receiving art from regimen 1a; 15.6% were receiving triomune. there were no significant differences between the control and patient groups (receiving pharmacotherapy or psychotherapy) with respect to demographic characteristics, namely: gender (chi2=2.045; p=0.359); marital status; (chi2=0.547; p=0.761); employment status (chi2=5.707; p=0.058); highest level of education (chi2=2.391; p=0.664); number of children (chi2=5.022; p=0.285); past history of depression (chi2=4.124; p=0.127); family history of depression (chi2=2.301; p=0.316); or other concurrent medication (chi2=0.779; p=0.677) (table 1). art adherence at entry to the study, the mean art adherence was 99.5% (se ±0.46) in the control group, and 92.1% (se ±1.69) (95% confidence interval (ci) 88.65 95.53) in the patient group (fig. 1). at the end of the study, the mean art adherence in the control group changed marginally to 99.7% (se ±0.46) (fig. 1), while in the patient group, the mean adherence increased significantly to 99.5% (se ±0.13; ci 99.25 99.78; p>0.05). the mean art adherence rate of the patients receiving pharmacotherapy increased from 92.8% to 99.5%, and those receiving psychotherapy increased from 91.1% to 99.6% (p>0.05) (fig 2). there was no significant association between this increased adherence rates in the patient group (in those receiving antidepressant medication or ipt) and baseline demographic and clinical characteristics (p>0.05). there was no correlation between the increased adherence rates and changes in hamd scores. fig. 1. changes in art adherence in the control and patient groups. fig. 2. changes in art adherence in the antidepressant v. ipt groups. discussion first-line treatment recommended by the 2010 south african antiretroviral treatment guidelines42 for all new adult and adolescent hiv-positive patients is tenofovir, lamivudine and efavirenz/nevirapine (efavirenz is preferred for tb co-infection, and nevirapine is preferred for women of child-bearing age who are not on reliable contraception). patients who fail on tenofovir-based first-line therapy may be changed to the second-line treatment of zidovudine, lamivudine and ritonavir. the majority of patients in this study were receiving art in accordance with these treatment guidelines. approximately 25% of patients were receiving triomune (a single-tablet fixed-dose combination of stavudine, lamivudine and nevirapine) which enhances compliance. no significant differences existed between the control and test groups with respect to the administering of art or other baseline characteristics. hence, it is unlikely that any of these factors may have influenced the study’s outcomes. all participants in the patient group had hamd scores >15, indicative of depression. depression was confirmed clinically by eliciting cognitive and affective symptoms that solely reflect mood state (i.e. anhedonia, depressed feelings, and feelings of worthlessness). fifty-three per cent of the patients had moderate depression (hamd score 18 24) and 44% had severe depression (hamd scores ≥25).43 all patients responded to treatment – either pharmacotherapy (citalopram) or psychotherapy (ipt) – as evidenced by a significant reduction in the mean hamd scores to <7 in both groups. there was no difference between the type of treatment received and changes in mean hamd scores. these findings are similar to those of other studies utilising pharmacotherapy39 , 40 and psychotherapy,43 , 44 which also report that ipt was more successful than supportive psychotherapy in lessening depression in depressed hiv-positive patients who were not acutely ill. at entry to this study, mean art adherence of the non-depressed control group was 99.5% – much higher than the 50 70% rate reported in other studies in different social and cultural settings.45 , 46 , 47 , 48 , 49 , 50 the higher adherence rate in our study may be attributed to patient attendance at a rollout clinic that enabled regular monitoring and had the staff and resources to support patients as adherence problems emerged. the study also found that the mean adherence rate, at entry to the study, among the depressed patient group was significantly lower (92.1%) than that of non-depressed control group. as previously discussed, studies have reported that depression is a risk factor for non-adherence to highly active art.32 , 33 , 34 , 35 depression is associated with a passive36 or fatalistic-resigned coping style and hopelessness37 with resultant poor treatment adherence. this study adds support to the findings of the above studies. furthermore, following 2 months of treatment, the mean adherence rate of the depressed patients increased significantly to >99%, independent of the type of treatment received (pharmacotherapy or psychotherapy). other published studies have reported similar improved art adherence in depressed hiv-positive patients following treatment with an antidepressant or ipt.5 , 51 when medication is used to treat depression, it is important for clinicians to evaluate tolerability and potential adverse effects which may paradoxically decrease adherence.52 selective serotonin reuptake inhibitors (ssris) have become widely used in hiv-infected depressed patients because of good tolerability and lack of negative effect on adherence. if, however, adherence is negatively impacted by pharmacotherapy, ipt may be the preferred treatment choice, as it results in increased physical and emotional functioning without tolerability issues. finally, a combination of both forms of therapy may result in further improved outcomes. some researchers question the feasibility of the rapid scaling-up and sustainability of art programmes in depressed people,25 , 53 citing concerns about the low and suboptimal adherence in depressed patients leading to the development of resistant hiv strains.54 , 55 , 56 resistant strains may leave subsequently infected patients without effective treatment options24 or require a change to second-line treatment regimens, which are ten times more expensive than first-line regimens.57 on the contrary, the results of our study and others have shown that the onset of depression in hiv-positive patients is negatively associated with art adherence, and can be significantly improved with treatment. screening for depression in all art rollout clinics is essential and hiv-positive patients found to be depressed must be offered art and treatment for their depression. although not considered or evident in our study, many other factors have been reported to negatively affect art adherence. these factors are commonly divided into 5 intersecting categories: patient variables; treatment regimens; disease characteristics; patient-provider relationships; and clinical setting.59 patient variables include sociodemographic factors (age, gender, race, income, education, literacy and housing status) and psychosocial factors (mental health, substance abuse, family support, religious beliefs about illness and medication, and knowledge and attitude about hiv and its treatment).58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 studies investigating the role of patient variables as predictors of adherence have largely produced inconsistent results. the tendency to ascribe low adherence to often-deprived social groups is a well-established trend;68 however, as experience with antibiotics has demonstrated, low adherence is widespread and unpredictable rather than restricted to certain social classes.69 moreover, adherence rates have been shown to vary between individuals and within the same individual over time.59 adherence is therefore best thought of as a variable behaviour rather than a stable characteristic of an individual, and most people will exhibit low adherence some of the time.68 treatment regimen factors include the number of pills prescribed, the complexity of the regimen (dosing frequency and food instruction), the specific type of art and treatment side-effects. the latter two are associated with sub-optimal adherence,58 although experience of symptoms and views about medications may vary according to the type of regimen used.70 , 71 , 72 patient-provider relationship factors include: overall satisfaction and trust in the provider and clinic staff (opinion of the provider’s competency, provider’s willingness to include the patient in the decision-making process, and compatibility of race/ethnicity between patient and provider); affective tone of the relationship (warmth, openness and co-operation); and satisfaction with the health service (adequacy of referral, availability of transport, general environment and flexibility of appointments).73 methods used to asses adherence fall into 3 categories: subjective measures (self-report, others’ report of adherence, and medical chart review); objective measures (pill counts, pharmacy refill records, and use of mechanical or electronic monitors of pill or drug use); and physiological methods or indicators (plasma assay and laboratory reports).15 the hierarchy of adherence measures ranks physician and self-assessment reporting as the least accurate, pill count as intermediate and electronic drug monitoring as the most accurate adherence markers.25 each of these measures is associated with certain inaccuracies and implementation difficulties. pharmacy refill records require that patients always use the same pharmacy. pill counts require patient co-operation to bring their pills to the requested health visits, and not to share pills. the medication event-monitoring system (mems) allows recording of when a drug container is opened via a micro-processor in the cap of the container. however, this requires that patients only remove one dose at a time. moreover, caps only measure bottle opening and not medication ingestion. the pill count method may overestimate adherence compared with mems by about 10%,48 , 74 but still has a higher accuracy compared with structured questionnaires.75 the subjective measure of patient self-report is the most commonly used measure of adherence. in this measure the patient is asked how many doses were missed in the past day, 2 days and 2 weeks or, alternatively, the percentage of prescribed doses taken in the past 4 days.47 the format of the questions varies from study to study. using this measure, inaccuracies may result from use of a longer recall time, in patient forgetfulness and when questioning is imprecise or inconsistent. further, responses may be influenced by patients’ desire to provide a socially acceptable answer, particularly when the interviewer is a health worker whose role has been to exhort the patient to adhere. nevertheless, self-reported adherence questionnaires are simple and inexpensive and the most widely used method in clinical settings.29 , 30 no single measure of adherence is appropriate for all settings or outcomes; therefore, the use of more than one measure is recommended, as performed in this study, to allow the strength of one method to compensate for the weakness of the other and to determine adherence levels more accurately.76 study limitations the relatively small sample size might have hampered statistical comparisons between treatment groups, while the short duration of follow-up might have masked a greater degree of outcomes in both groups. the study was open-labelled, which could have influenced the response to treatment. this was not a population-based study (patients were recruited from the hiv research unit); therefore, the results may be biased by the methods of recruitment and enrolment and are not generalisable. further, an overwhelming majority of the subjects were female; the treatment of hiv-positive men, who face different psychosocial and socio-economic pressures, may have produced different outcomes. strengths of the study include the use of more than one adherence measure to reduce inaccuracies. moreover, comparison of the sociodemographic characteristics did not reveal any substantive differences between the groups. conclusion the onset of depression in hiv-positive patients is negatively associated with art adherence. treatment of this depression with an antidepressant or psychotherapy is associated with significant improvement in art adherence. poor adherence leads to art resistance, which may require a change to a second-line treatment regimen (ten times more expensive than first-line drugs). it is therefore important that healthcare providers identify depression in at-risk patients, to enable closer monitoring and treatment.   note. this report was part of a large study on hiv and depression. the sociodemographic features of the study population described have previously been reported: moosa myh, jeenah fy. antidepressants versus interpersonal psychotherapy in treating depression in hiv-positive patients. south african journal of psychiatry 2012;18(2) 47-52. references 1. unaids. global report: 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[http://dx.doi/org/10.1016/0140-6736(800)902854-3] 73. chesney ma, koblin ba, barresi p, et al. an individually tailored intervention for prevention of hiv infection. am j public health 2003;93:933-938. 73. chesney ma, koblin ba, barresi p, et al. an individually tailored intervention for prevention of hiv infection. am j public health 2003;93:933-938. 74. arnsten j, demas p, gourevitch m, et al. adherence and viral load in hiv-infected drug users: comparison of self-report and medication event monitors (mems). 7th conference on retroviruses and opportunistic infections, san francisco, california, usa, 30 january 2 february 2000. 74. arnsten j, demas p, gourevitch m, et al. adherence and viral load in hiv-infected drug users: comparison of self-report and medication event monitors (mems). 7th conference on retroviruses and opportunistic infections, san francisco, california, usa, 30 january 2 february 2000. 75. haubrich rh, little sj, currier js, et al. the value of patient reported adherence to antiretroviral therapy in predicting virologic and immunologic response. aids 1999;13:1099-1107. 75. haubrich rh, little sj, currier js, et al. the value of patient reported adherence to antiretroviral therapy in predicting virologic and immunologic response. aids 1999;13:1099-1107. 76. vitolins mz, rand cs, rapp sr, et al. measuring adherence to behavioral and medical interventions. control clin trials 2000;21:188s-194s. 76. vitolins mz, rand cs, rapp sr, et al. measuring adherence to behavioral and medical interventions. control clin trials 2000;21:188s-194s. africa has suffered disproportionately although it has done little to cause the crisis the fight against the climate crisis needs all hands on deck acknowledgements references about the author(s) lukoye atwoli department of internal medicine, medical college east africa, the aga khan university, nairobi, kenya brain and mind institute, the aga khan university, nairobi, kenya gregory e. erhabor department of medicine, college of health sciences, obafemi awolowo university, ile-ife, nigeria chest unit, obafemi awolowo university teaching hospital, ile-ife, nigeria aiah a. gbakima department of technical and higher education, government of sierra leone, freetown, sierra leone abraham haileamlak college of public health and medical sciences, jimma university, jimma, ethiopia jean-marie kayembe ntumba department of pneumology, faculty of medicine, university of kinshasa, kinshasa, the democratic republic of the congo james kigera department of human anatomy, college of health sciences, university of nairobi, nairobi, kenya laurie laybourn-langton department of sustainability accelerator, chatham house, london, united kingdom robert mash division of family medicine and primary care, faculty of medicine and health sciences, stellenbosch university, cape town, south africa joy muhia centre for global mental health, london school of hygiene and tropical medicine, london, united kingdom fhumulani m. mulaudzi department of nursing science, faculty of health sciences, university of pretoria, pretoria, south africa david ofori-adjei department of medicine and therapeutics, university of ghana, accra, ghana friday okonofua department of obstetrics and gynecology, university of medical sciences, ondo, nigeria arash rashidian department of science, information and dissemination, eastern mediterranean regional office, world health organization, cairo, egypt maha el-adawy department of health protection and promotion, eastern mediterranean regional office, world health organization, cairo, egypt siaka sidibé faculty of medicine and odonto-stomatology, university of sciences, techniques and technology of bamako, bamako, mali abdelmadjid snouber faculty of medicine, university of oran 1, es sénia, algeria james tumwine department of paediatrics and child health, school of medicine, kabale university, kabale, uganda sahar yassien mohammad faculty of nursing, ain shams university, cairo, egypt paul yonga ca medlynks clinic and laboratory, nairobi, kenya nairobi fountain projects and research office (fopro), fountain health care hospital, eldoret, kenya lilia zakhama faculty of medicine of tunis, university of tunis el manar, tunis, tunisia department of cardiology, security forces hospital, la marsa, tunisia chris zielinski centre for global health, faculty of health and wellbeing, university of winchester, winchester, united kingdom citation atwoli l, erhabor ge, gbakima aa, et al. cop27 climate change conference: urgent action needed for africa and the world. s afr j hiv med. 2022;23(1), a1467. https://doi.org/10.4102/sajhivmed.v23i1.1467 editorial cop27 climate change conference: urgent action needed for africa and the world lukoye atwoli, gregory e. erhabor, aiah a. gbakima, abraham haileamlak, jean-marie kayembe ntumba, james kigera, laurie laybourn-langton, robert mash, joy muhia, fhumulani m. mulaudzi, david ofori-adjei, friday okonofua, arash rashidian, maha el-adawy, siaka sidibé, abdelmadjid snouber, james tumwine, sahar yassien mohammad, paul yonga, lilia zakhama, chris zielinski copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. wealthy nations must step up support for africa and vulnerable countries in addressing past, present and future impacts of climate change the 2022 report of the intergovernmental panel on climate change (ipcc) paints a dark picture of the future of life on earth, characterised by ecosystem collapse, species extinction, and climate hazards such as heatwaves and floods.1 these are all linked to physical and mental health problems, with direct and indirect consequences of increased morbidity and mortality. to avoid these catastrophic health effects across all regions of the globe, there is broad agreement – as 231 health journals argued together in 2021 – that the rise in global temperature must be limited to less than 1.5 °c compared with pre-industrial levels. while the paris agreement of 2015 outlines a global action framework that incorporates providing climate finance to developing countries, this support has yet to materialise.2 cop27 is the fifth conference of the parties (cop) to be organised in africa since its inception in 1995. ahead of this meeting, we – as health journal editors from across the continent – call for urgent action to ensure it is the cop that finally delivers climate justice for africa and vulnerable countries. this is essential not just for the health of those countries, but for the health of the whole world. africa has suffered disproportionately although it has done little to cause the crisis the climate crisis has had an impact on the environmental and social determinants of health across africa, leading to devastating health effects.3 impacts on health can result directly from environmental shocks and indirectly through socially mediated effects.4 climate change-related risks in africa include flooding, drought, heatwaves, reduced food production, and reduced labour productivity.5 droughts in sub-saharan africa have tripled between 1970–1979 and 2010–2019.6 in 2018, devastating cyclones impacted three million people in malawi, mozambique and zimbabwe.6 in west and central africa, severe flooding resulted in mortality and forced migration from loss of shelter, cultivated land, and livestock.7 changes in vector ecology brought about by floods and damage to environmental hygiene has led to increases in diseases across sub-saharan africa, with rises in malaria, dengue fever, lassa fever, rift valley fever, lyme disease, ebola virus, west nile virus and other infections.8,9 rising sea levels reduce water quality, leading to water-borne diseases, including diarrhoeal diseases, a leading cause of mortality in africa.8 extreme weather damages water and food supply, increasing food insecurity and malnutrition, which causes 1.7 million deaths annually in africa.10 according to the food and agriculture organization of the united nations, malnutrition has increased by almost 50% since 2012, owing to the central role agriculture plays in african economies.11 environmental shocks and their knock-on effects also cause severe harm to mental health.12 in all, it is estimated that the climate crisis has destroyed a fifth of the gross domestic product (gdp) of the countries most vulnerable to climate shocks.13 the damage to africa should be of supreme concern to all nations. this is partly for moral reasons. it is highly unjust that the most impacted nations have contributed the least to global cumulative emissions, which are driving the climate crisis and its increasingly severe effects. north america and europe have contributed 62% of carbon dioxide emissions since the industrial revolution, whereas africa has contributed only 3%.14 the fight against the climate crisis needs all hands on deck yet it is not just for moral reasons that all nations should be concerned for africa. the acute and chronic impacts of the climate crisis create problems like poverty, infectious disease, forced migration, and conflict that spread through globalised systems.6,15 these knock-on impacts affect all nations. covid-19 served as a wake-up call to these global dynamics and it is no coincidence that health professionals have been active in identifying and responding to the consequences of growing systemic risks to health. but the lessons of the covid-19 pandemic should not be limited to pandemic risk.16,17 instead, it is imperative that the suffering of frontline nations, including those in africa, be the core consideration at cop27: in an interconnected world, leaving countries to the mercy of environmental shocks creates instability that has severe consequences for all nations. the primary focus of climate summits remains to rapidly reduce emissions so that global temperature rises are kept to below 1.5 °c. this will limit the harm. but, for africa and other vulnerable regions, this harm is already severe. achieving the promised target of providing $100bn of climate finance a year is now globally critical if we are to forestall the systemic risks of leaving societies in crisis. this can be done by ensuring these resources focus on increasing resilience to the existing and inevitable future impacts of the climate crisis, as well as on supporting vulnerable nations to reduce their greenhouse gas emissions: a parity of esteem between adaptation and mitigation. these resources should come through grants not loans, and be urgently scaled up before the current review period of 2025. they must put health system resilience at the forefront, as the compounding crises caused by the climate crisis often manifest in acute health problems. financing adaptation will be more cost-effective than relying on disaster relief. some progress has been made on adaptation in africa and around the world, including early warning systems and infrastructure to defend against extremes. but frontline nations are not compensated for impacts from a crisis they did not cause. this is not only unfair, but also drives the spiral of global destabilisation, as nations pour money into responding to disasters, but can no longer afford to pay for greater resilience or to reduce the root problem through emissions reductions. a financing facility for loss and damage must now be introduced, providing additional resources beyond those given for mitigation and adaptation. this must go beyond the failures of cop26 where the suggestion of such a facility was downgraded to ‘a dialogue’.18 the climate crisis is a product of global inaction, and comes at great cost not only to disproportionately impacted african countries, but to the whole world. africa is united with other frontline regions in urging wealthy nations to finally step up, if for no other reason than that the crises in africa will sooner rather than later spread and engulf all corners of the globe, by which time it may be too late to effectively respond. if so far they have failed to be persuaded by moral arguments, then hopefully their self-interest will now prevail. acknowledgements this editorial is being published simultaneously in multiple journals. for the full list of journals see: https://www.bmj.com/content/full-list-authors-and-signatories-climate-emergency-editorial-october-2022. competing interests we have read and understood the bmj policy on declaration of interests and declare the following roles and relationships: j.k. is the ex-officio, president and secretary of the kenya orthopedic association, and the editor in chief of annals of african surgery. r.m. received a research grant on climate change and primary health care in africa with university ghent, funded by vlir (flemish interuniversity network). p.y. received payment for a cme lecture on antimicrobial use in the intensive care unit (icu) on behalf of novartis, for an educational event on antimicrobial stewardship on behalf of biomerieux, and for a cme lecture on adult vaccination updates on behalf of pfizer. p.y. also serves on the dsmb of the nhlbi-funded strengths trial focusing on hypertension and has served as a chair on a pfizer advisory board on pneumococcal vaccinations in adults. payment is received for both. c.z. received payment from the uk health alliance on climate change as senior advisor on the international journals project. j.m. is an unpaid board member on the international working group for health systems strengthening and employee of london school of hygiene & tropical medicine. doa has involvement with the inovio pharmaceuticals phase 1b vaccine trial and the glico healthcare ltd. the authors declare no further conflicts of interest beyond those inherent in the editorial roles listed above. authors’ contributions l.l-l. developed the idea of the editorial and led drafting along with c.z. j.m. contributed with l.a.’s guidance. all other authors contributed significantly to the editorial content. authors’ affiliated journals lukoye atwoli, editor-in-chief, east african medical journal; gregory e. erhabor, editor-in-chief, west african journal of medicine; aiah a. gbakima, editor-in-chief, sierra leone journal of biomedical research; abraham haileamlak, editor-in-chief, ethiopian journal of health sciences; jean-marie kayembe ntumba, chief editor, annales africaines de medecine; james kigera, editor-in-chief, annals of african surgery; laurie laybourn-langton, university of exeter; bob mash, editor-in-chief, african journal of primary health care & family medicine; joy muhia, london school of medicine and tropical hygiene; fhumulani mavis mulaudzi, editor-in-chief, curationis; david ofori-adjei, editor-in-chief, ghana medical journal; friday okonofua, editor-in-chief, african journal of reproductive health; arash rashidian, executive editor, and maha el-adawy, director of health promotion, eastern mediterranean health journal; siaka sidibé, director of publication, mali médical; abdelmadjid snouber, managing editor, journal de la faculté de médecine d’oran; james tumwine, editor-in-chief, african health sciences; mohammad sahar yassien, editor-in-chief, evidence-based nursing research; paul yonga, managing editor, east african medical journal; lilia zakhama, editor-in-chief, la tunisie médicale; chris zielinski, university of winchester. ethical considerations this article followed all ethical standards for research without direct contact with human or animal subjects. funding information respective authors were paid by their employers. chris zielinski’s time was funded by the uk health alliance on climate change. data availability data sharing is not applicable to this article, as no new data were created or analysed in this study. disclaimer the views and 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centre. climate change and health in africa: issues and options [homepage on the internet]. african climate policy centre; 2013 [cited 2022 sep 12]. available from: https://archive.uneca.org/sites/default/files/publicationfiles/policy_brief_12_climate_change_and_health_in_africa_issues_and_options.pdf un. climate change is an increasing threat to africa [homepage on the internet]. 2020 [cited 2022 sep 12]. available from: https://unfccc.int/news/climate-change-is-an-increasing-threat-to-africa atwoli l, muhia j, merali z. mental health and climate change in africa. bjpsych international. 2022;19(4):86–89. https://doi.org/10.1192/bji.2022.14 vulnerable twenty group. climate vulnerable economies loss report. switzerland: vulnerable twenty group; 2020. ritchie h. who has contributed most to global co2 emissions? our world in data [homepage on the internet]. 2019 [cited 2022 sep 12]. available from: https://ourworldindata.org/contributed-most-global-co2 bilotta n, botti f. paving the way for greener central banks. current trends and future developments around the globe. rome: edizioni nuova cultura for istituto affari internazionali (iai); 2022. who. cop26 special report on climate change and health: the health argument for climate action. geneva: world health organization; 2021. al-mandhari a, al-yousfi a, malkawi m, el-adawy m. ‘our planet, our health’: saving lives, promoting health and attaining well-being by protecting the planet – the eastern mediterranean perspectives. east mediterr health j. 2022;28(4):247–248. https://doi.org/10.26719/2022.28.4.247 evans s, gabbatiss j, mcsweeney r, et al. cop26: key outcomes agreed at the un climate talks in glasgow. carbon brief [homepage on the internet]. 2021 [cited 2022 sep 12]. available from: https://www.carbonbrief.org/cop26-key-outcomes-agreed-at-the-un-climate-talks-in-glasgow/ the southern african journal of hiv medicine                                                  september  2010 case history a 45-year-old man, known to be hypertensive and with a history of smoking (5 cigarettes a day for 18 years), presented to tygerberg hospital with peripheral vascular disease necessitating bilateral amputations at the knee. the patient had no other significant medical disorders and no previous history of tuberculosis (tb), and consumed alcohol socially. he had been well before this admission, with no previous medical or surgical admissions. the findings on general and systemic examination were normal and no lumps were noted on the body. the patient was tested for hiv as part of his surgical work-up and was found to be positive with a cd4 count of 152 cells/µl. he was commenced on arvs: stavudine (d4t) 30 mg 12-hourly, lamivudine (3tc) 150 mg 12-hourly and efavirenz (efv) 600 mg at night. he underwent successful above-knee amputations and was subsequently followed up at the tygerberg hospital infectious disease clinic approximately 1 month later. the patient was doing well and reported no problems or side-effects from the arvs. the stumps were clean and findings on a thorough physical examination were normal. no lumps were detected on the patient’s body at this visit. the patient had no symptoms of tb, but a chest radiograph revealed infiltrates in the right upper zone. at this stage we were still awaiting sputum results from his initial admission. two weeks later (approximately 6 weeks after arv initiation) drugsusceptible tb was diagnosed on sputum culture. tb treatment was immediately commenced. the patient returned for a follow-up visit after a further 2 weeks complaining of multiple lumps on the trunk and abdomen. physical examination revealed multiple soft, mobile, non-tender nodules on the abdomen (fig. 1), measuring approximately 2×2 cm. a fine-needle aspirate and excision biopsy confirmed that these were lipomas. a fasting lipogram revealed a total cholesterol level of 5.7 mmol/l, a triglyceride level of 2.0 mmol/l, a high-density lipoprotein (hdl) cholesterol level of 1.2 mmol/l and a low-density lipoprotein (ldl) cholesterol level of 3.6 mmol/l. the patient was counselled regarding his condition and continued on his anti-tb treatment and arvs. he was started on the appropriate medical management for his dyslipidaemia and given appropriate dietary advice. a rare phenomenon of atypical lipodystrophy in a patient on haart in the absence of a protease inhibitor regimen c a s e s t u dy mohammed mitha, mb chb, dip hiv man (sa) gordon cupido, bsc, mb chb, fcp (sa) jantjie taljaard, mb chb, mmed (intern), dtm&h department of internal medicine, tygerberg hospital and stellenbosch university, w cape 37 lipodystrophy is a complication of patients on antiretroviral (arv) medication; however, it is commonest in patients on long-term treatment and those on protease inhibitor (pi) regimens.1,2 we present a rare case of atypical lipodystrophy, presenting as multiple subcutaneous lipomas, in a patient who had been on a non-pi arv regimen for 6 weeks. fig. 1. multiple lipomas on the patient’s abdomen. september  2010                                                    the southern african journal of hiv medicine                                                   discussion lipodystrophy encompasses both lipo-atrophy and lipohypertrophy. lipo-atrophy presents as subcutaneous fat wasting in the face and peripheries, whereas lipohypertrophy occurs as fat accumulation in the abdomen, breast and dorso-cervical region.2,3 lipodystrophy can be associated with hyperlipidaemia and insulin resistance, which constitute the lipodystrophy syndrome.3 the commonest class of arvs to cause lipodystrophy is the pis.1-3 these agents are commonly used in second-line regimens in arv treatment in south africa. this patient presented with multiple subcutaneous lipomas on the abdomen 6 weeks after commencing arvs and approximately 2 weeks after starting tb treatment. this was an extremely interesting and yet perplexing presentation. diagnosis of a novel immune reconstitution inflammatory syndrome phenomenon or a cutaneous lymphoma was considered, but the patient was clinically well, histological examination confirmed a lipoma with no inflammatory cell infiltrate, and biopsies of the lesions did not culture tb or any other bacterial organism. the reason for the acute onset of the lipomas, and in a patient not on a pi, eludes the authors. the patient’s background medical condition of hypertension and peripheral vascular disease may have contributed to the development of the lipomas. google scholar and pubmed searches in the english language revealed only 1 other case in which subcutaneous lipomas developed on a regimen without pis.4 that patient had been on 3tc, tenofovir and efv. it is unclear whether efv, 3tc or both contributed to the lipomas in our case, as that patient was also on both these agents. most patients who develop lipodystrophy syndrome while on pis are switched to a non-nucleoside reverse transcriptase inhibitor, usually with improvement in their dyslipidaemia.4,5 owing to the unique nature of our case, with no evidence base to guide treatment, it was decided to continue the regimen of 3tc, d4t and efv. it is important that clinicians are aware of this rare and atypical form of lipodystrophy, which can apparently occur in patients taking nucleoside reverse transcriptase inhibitors and non-nucleoside reverse transcriptase inhibitors. if it occurs, the most important issue is to counsel the patient regarding lipomas and their benign nature and that they should remain compliant on treatment. it would be useful if a registry could be created to document such atypical adverse effects of arvs in order for research to be conducted which may prevent such phenomena and guide us on appropriate drug changes if and when required. references 1. miller j, carr a, smith d, et al. lipodystrophy following antiretroviral therapy of primary hiv infection. aids 2000; 15: 2406-2407. 2. southern african hiv clinicians society. guidelines: antiretroviral therapy in adults. southern african journal of hiv medicine 2008; 9(1): 18-31. 3. brown tt. approach to the human immunodeficiency virus-infected patient with lipodystrophy. j clin endocrinol metab 2008; 93(8): 2937-2945. 4. balestreire e, haught jm, english jc. multiple subcutaneous lipomas induced by haart in the absence of protease inhibitors. arch dermatol 2007; 143(12): 15961597. 5. mallewa je, wilkens e, vilar j, et al. hiv-associated lipodystrophy: a review of underlying mechanisms and therapeutic options. j antimicrob chemother 2008; 62(4): 648-660. 38 introduction guideline development process evidence to date transmission risks recommendations for donor and recipient eligibility care of the human immunodeficiency virus-positive recipient after transplantation conclusion acknowledgements references about the author(s) jeremy s. nel helen joseph hospital, department of medicine, university of the witwatersrand, johannesburg, south africa francesca conradie clinical hiv research unit, wits health consortium, johannesburg, south africa department of medicine, university of the witwatersrand, johannesburg, south africa helen joseph hospital, johannesburg, south africa jean botha wits donald gordon medical centre, johannesburg, south africa harriet etheredge wits donald gordon medical centre, johannesburg, south africa june fabian wits donald gordon medical centre, johannesburg, south africa faculty of health sciences, university of witwatersrand, johannesburg, south africa leon levin helen joseph hospital, johannesburg, south africa right to care, ngo, johannesburg, south africa ahmad h. mazanderani centre for hiv and stis, national institute for communicable diseases, national health laboratory service, johannesburg, south africa michelle moorhouse wits rhi, university of the witwatersrand, johannesburg, south africa elmi muller department of medicine, university of cape town, cape town, south africa division of general surgery, groote schuur hospital, cape town, south africa caroline tiemessen faculty of health sciences, university of witwatersrand, johannesburg, south africa centre for hiv and stis, national institute for communicable diseases, national health laboratory service, johannesburg, south africa dst/nrf chair of hiv vaccine translational research, pretoria, south africa david thomson department of medicine, university of cape town, cape town, south africa division of general surgery, groote schuur hospital, cape town, south africa julia turner right to care ngo, centurion, south africa citation nel js, conradie f, botha j, et al. southern african hiv clinicians society guidelines for solid organ transplantation in human immunodeficiency virus: an evidence-based framework for human immunodeficiency virus-positive donors and recipients. s afr j hiv med. 2020;21(1), a1133. https://doi.org/10.4102/sajhivmed.v21i1.1133 note: for the purposes of this guideline, the term ‘hiv positive’ was used in place of the journal’s preferred term, ‘people living with hiv’, in order to avoid confusion with other terms specific to organ transplants, such as ‘living donors’ and ‘deceased donors’. guideline southern african hiv clinicians society guidelines for solid organ transplantation in human immunodeficiency virus: an evidence-based framework for human immunodeficiency virus-positive donors and recipients jeremy s. nel, francesca conradie, jean botha, harriet etheredge, june fabian, leon levin, ahmad h. mazanderani, michelle moorhouse, elmi muller, caroline tiemessen, david thomson, julia turner received: 20 july 2020; accepted: 31 july 2020; published: 15 oct. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. introduction these guidelines, intended for transplantation healthcare practitioners in southern africa, seek to sketch an evidence-based framework for human immunodeficiency virus (hiv)-positive donors and recipients regarding solid organ transplantation. the guidelines include considerations for the transplantation of organs from hiv-positive donors to hiv-negative recipients. donor and recipient eligibility, hiv transmission risks and ethical considerations are discussed. south africa has over 7 million people living with hiv, the largest such population in the world.1 approximately 20% of people aged 15–64 years are living with hiv in south africa.2 compared with hiv-negative controls, people living with hiv are at increased risk of end-stage organ disease. human immunodeficiency virus-positive patients demonstrate a faster decline in renal function than hiv-negative patients, and an approximately threefold increased risk of end-stage renal disease.3,4,5 furthermore, people living with hiv have a higher risk of acute and chronic liver failure, accelerated progression of hepatitis b and c co-infection to cirrhosis, and an increased risk of hepatocellular carcinoma compared with hiv-negative controls.6,7,8 the increased risk posed by hiv is multifactorial, with direct hiv toxicities, opportunistic infections, chronic systemic inflammation, immune dysfunction, antiretroviral therapy (art) side-effects and genetic factors all potentially playing synergistic, contributory roles.9,10 in many cases of end-stage renal or liver disease, organ transplantation may offer definitive cure of the underlying condition, with a resultant reduction in mortality. however, there is a critical shortage of available organs. although thousands of south africans are waitlisted for transplantation, only approximately 500 solid organ and corneal transplantations are performed each year.11 the number of transplantations performed in south africa has declined over the past decade.11,12 a prolonged waiting period prior to organ transplantation adds substantial financial, morbidity and mortality costs to the patients concerned and to the healthcare sector as a whole. one reason for the shortage of available organs is that potential donors may be excluded if they are hiv-positive, particularly for living donors. historically, there has been considerable concern about the transmission of hiv and other opportunistic infections from the donor to the recipient, as well as concerns about graft viability. the high prevalence of hiv within the south african population, particularly in persons aged < 65 years, means that a large pool of potential donors may be unlocked if it is possible to utilise organs from this group safely for transplantation. on the recipient side, it has only recently become understood that hiv-positive patients can make suitable recipients of solid organ transplants because of groundbreaking work both locally and internationally. these guidelines seek to provide best practice recommendations for considering hiv-positive individuals as both potential organ donors and organ recipients and are intended for use by healthcare practitioners in the transplantation field in southern africa in both the state and private sectors. considerations for hiv-negative recipients of organs from hiv-positive donors are also discussed. guideline development process an expert panel was constituted, consisting of hiv experts from the southern african hiv clinicians society, representatives from the south african transplant society, the national institute for communicable diseases, transplant surgeons from the university of cape town and wits donald gordon medical centre, a medical ethics specialist and a transplant infectious diseases specialist. both adult and paediatric domains were represented. the scope and outline of the guidelines were discussed at a meeting in november 2018. a pubmed literature search was conducted on all publications relating to the keywords ‘hiv’, ‘transplantation’ and ‘transplant’ up to january 2020. owing to a paucity of published data, all types of articles were reviewed, including case series and case reports. draft guidelines were compiled and circulated for comment and amendments to the entire committee prior to publication, and decisions were made by consensus. the guidelines will be reviewed as needed in the light of new evidence. evidence to date human immunodeficiency virus-positive recipients of solid organ transplants patients with hiv have received organ transplants since the 1980s, although, owing to inconsistent testing at the time, many of these patients were only diagnosed with hiv months to years subsequently.13,14,15 in the pre-art era, patient survival was frequently poor. in 2010, stock et al. reported the outcomes of 150 prospectively enrolled, hiv-positive recipients of a renal transplant from hiv-negative donors.16 recipient inclusion criteria included a cluster of differentiation 4 t-cell (cd4+) count ≥ 200 cells/µl and a suppressed viral load (vl) on a stable art regimen prior to transplantation. kidneys from both living and deceased donors were used. patient survival rates at 1 and 3 years were approximately 95% and 88%, respectively, and graft survival was 90% and 74%, respectively. these percentages were lower than the national us average at the time, although they were comparable with results for other high-risk renal transplantation groups. importantly, no evidence was seen of any immunosuppression-precipitated hiv viraemia, nor of any hiv-related opportunistic infections. two patients developed limited cutaneous kaposi’s sarcoma that was successfully treated, but no other sign of increased malignancies was observed in comparison with hiv-negative kidney transplant recipients. muller et al. then demonstrated the feasibility of renal transplantation from deceased hiv-positive donors to hiv-positive recipients. initial results were reported in 2010, and long-term follow-up results in 2015.17,18 among 27 patients, survival at 1, 3 and 5 years was 84%, 84% and 74%, respectively, and graft survival was 93%, 84% and 84%, respectively. recipient inclusion criteria included a cd4+ count ≥ 200 cells/µl, a suppressed vl and art duration > 3 months prior to transplantation. patients with acquired immune deficiency syndrome (aids)-defining opportunistic infections and malignancies were excluded. the vl remained suppressed in all patients during the study period. following these data, an advocacy campaign in the usa led to the passage of the hiv organ policy equity (hope) act in 2013, which allowed for research into transplanting organs from hiv-positive donors into hiv-positive recipients.19 when this became federal policy in 2015, several us transplant centres began embarking on such efforts. to date, these have included deceased donor hiv-positive-to-hiv-positive kidney and liver transplantations, and living donor hiv-positive-to-hiv-positive kidney transplantations.20,21,22 successful outcomes in heart, pancreas and lung transplants have also been reported in hiv-positive patients, despite using organs from hiv-negative donors.23,24,25,26 human immunodeficiency virus-negative recipients of solid organs from human immunodeficiency virus-positive donors prior to 2017, hiv-positive-to-hiv-negative transplantations both internationally and locally had been inadvertent (because of diagnosis of the donor’s hiv status subsequent to transplantation). in 2017, botha et al. performed the first intentional liver transplantation from a living hiv-positive donor to an hiv-negative recipient.27 the recipient was a 7-month-old child with biliary atresia and end-stage liver disease who was placed on the waiting list for a liver transplant from an hiv-negative donor. after a prolonged period on the waiting list, the child’s hiv-positive mother requested to be considered as a donor because she was otherwise a suitable candidate and furthermore fulfilled donor criteria outlined in the hope act. she was on stable art, had a cd4+ count > 200 cells/µl and was virally suppressed with no evidence of any opportunistic infections or aids-associated malignancies. following extensive multidisciplinary meetings and counselling, permission for the procedure was obtained from the local institutional review board as part of a research trial, and both of the child’s parents consented to the procedure. the recipient received triple art before the transplantation to minimise the risk of hiv transmission, and this was continued after transplantation. to date, the recipient remains well, with normal-for-age growth and excellent graft function. hiv antibodies were detected at day 43 post-transplantation, although this response gradually attenuated with time. no plasma or cell-associated hiv-1 dna or rna was detected at any stage in the recipient, although early post-transplantation samples were not available for testing. transmission risks blood from donor organs are routinely flushed out prior to insertion in the recipient. however, these organs may still contain replication-competent hiv virions. small amount of donor blood may remain in the organ despite flushing. furthermore, hiv can infect the renal tubular epithelial cells, podocytes and parietal epithelial cells of the kidney.28,29,30 similarly, it is known that the liver’s kupffer cells and sinusoidal endothelial cells may be infected by hiv, as are hepatoma cells.31,32 in addition, hiv could be transmitted by free virus or lymphocytes carried in the interstitium of the organ. recent work suggests that hiv reservoirs probably persist in all deep tissues, although replication-competent viruses likely comprise only a minority of viral strains.27,33,34 human immunodeficiency virus-positive recipients there is concern that, despite being on art for at least several months at the time of transplantation, the hiv-positive recipient may be at risk of acquiring a second strain of hiv via residual virus in the allograft. this strain could either replicate independently or generate a new recombinant viral strain. both are rare phenomena that have previously been documented in non-transplantation settings.35,36,37,38 of critical concern would be the transmission of an hiv strain that is unlikely to be controlled with art in the recipient, either because of extensive resistance or because of recipient contraindications to particular antiretroviral drugs. in theory, despite the flushing of blood, the risk of allograft transmission would be higher with organs from donors with unsuppressed vls at the time of donation (such as might be seen in some deceased hiv-positive donors). selhorst et al. recently reported on the impact of the donor strain on the recipient’s hiv control in muller’s hiv-positive-to-hiv-positive renal transplant cohort.39 plasma and peripheral blood mononuclear cell (pbmc) samples were analysed from donor–recipient pairs. donor virus was detectable in 8/25 recipients (32%) on deep sequencing in plasma samples taken between 1 and 6 weeks post-transplantation. deep sequencing of pbmc samples, targeting reverse transcriptase and the env gene’s v3 region, found drug resistance mutations in a minority of both donors and recipients, but without clear evidence of any transmitted resistance from donor to recipient in 24/25 recipients. possible superinfection was detected in one recipient from a sample taken 12 weeks post-transplantation. however, donor sequences were not found in the recipient’s pbmc samples taken before (6 weeks) or after (26 weeks) that, nor when the 12-week sample was sequenced again. it is unclear whether donor proviral sequences detected in this recipient in a single sample represent true superinfection or shedding of previously infected donor kidney cells into the blood. none of the recipients have to date failed art post-transplantation. although somewhat reassuring, there are several limitations to these data. only one of the donors had drug resistance mutations present at a level > 0.5% (levels thought to be physiologically relevant), and no plasma or pbmc samples from the recipient in that case were available for analysis. furthermore, the recipient’s art regimen in muller’s cohort had substantial activity against the donor strain in each case; this may not be true of a patient cohort with more complicated pre-transplantation art histories. in addition, because none of the donor patients were on protease inhibitors (pis) or integrase strand transfer inhibitors (instis) – only reverse transcriptase was sequenced for drug resistance mutations – the effect of mutations involving protease or integrase remains to be determined. lastly, the ability to detect superinfection was limited by the low proviral loads found in the recipients (who were for the most part virally suppressed post-transplantation) and by anti-thymocyte globulin-induced t-cell depletion. most recently, blasi et al. reported finding a donor’s hiv strain in an hiv-positive recipient’s blood and urine up to 16 days after kidney transplantation, but not thereafter.33 importantly, the donor hiv strain was susceptible to the recipient’s art regimen from the outset, though the recipient’s regimen was additionally fortified with rilpivirine (rpv) from postoperative day 1 as a precaution. in summary, donor hiv viral strains appear to be detected in the blood of recipients in many cases within the first few weeks after transplantation, although whether this represents productive infection of new cells, lysing of donor-derived infected cells or a combination of both is unclear. considering the potential risk of superinfection, we recommend that an infectious diseases and/or hiv expert should review all available donor hiv treatment history and resistance test information prior to transplantation, and that an anticipated inability of the recipient to control the donor hiv strain should be considered a contraindication to transplantation (see ‘recommendations’ section). human immunodeficiency virus-negative recipients the risk of an hiv-negative recipient acquiring hiv from an organ from an hiv-positive donor is currently unknown, and is likely to be influenced by multiple donor and recipient characteristics, and the nature of the solid organ that is transplanted. when the donor’s hiv infection is only diagnosed subsequent to transplantation (because of the donor inadvertently being in the window period of hiv testing), hiv infection of the recipient appears highly likely. however, under the controlled conditions described by botha et al., where the donor has a stably suppressed vl and the recipient is started on art prior to transplantation, the risk of hiv transmission to the recipient is far less certain.27 in the one such published case to date, the results of hiv testing were equivocal, with initial seroconversion at day 43 and then slow waning of the serological response approaching undetectable levels over the course of a year. no plasma or cell-associated hiv has been detected in the recipient even by using ultrasensitive assays, although this testing was only possible on samples obtained from day 111 onwards. the interpretation of these results is not straightforward, particularly in the post-transplantation setting, where antibody responses may be attenuated because of anti-rejection immunosuppression. possible explanations for the hiv antibody pattern observed include the recipients’ systemic infection with hiv, confinement of the hiv infection within the maternally derived donor liver, a purely serological response generated by the donor liver, and a recipient serological response generated to hiv antigens in the absence of replication-competent virus.27,34,40 we recommend that all available donor hiv treatment history and resistance test information should be reviewed prior to transplantation, as for hiv-positive recipients. any anticipated inability of the recipient to control the donor’s hiv strain should similarly be a contraindication to transplant, regardless of the precautions put in place to limit the acquisition of hiv (see ‘recommendations’ section). recommendations for donor and recipient eligibility recipient eligibility human immunodeficiency virus-positive recipient eligibility criteria for hiv-positive transplant recipients: cd4+ count ≥ 200 cells/µl (≥ 100 cells/µl can be considered for liver transplant recipients provided there is no history of opportunistic infections or malignancies). for children aged < 5 years, a cd4+% threshold of 15% should be used. chronic patients: plasma vl < 50 copies/µl (most recent test performed within 3 months prior to transplantation). for organs from hiv-positive donors: the recipient must be able to tolerate an art regimen effective against the donor’s hiv strain. rationale: patients are required to have a cd4+ count ≥ 200 cells/µl (for patients aged < 5 years, a cd4+% threshold of 15% should be used). although any cut-off is somewhat arbitrary, we endorse a cd4+ threshold of 200 cells/µl for two reasons: (1) it is a threshold which provides protection against many opportunistic infections, some of which may be difficult to diagnose and may cause significant post-transplantation morbidity and mortality; and (2) with the exception of liver transplants, the safety of organ transplantation below this recipient cd4+ level has not been established, as trials have generally excluded patients with cd4+ counts below this level. in the case of hiv-positive recipients of liver transplants, there is evidence that using a cd4+ threshold ≥ 100 cells/µl is safe provided there is no history of any opportunistic infection or malignancy (in which case a cd4+ threshold of 200 cells/µl is recommended).41 another exception to the rule would be immune non-responders, who fail to reconstitute an adequate cd4+ count despite prolonged viral suppression, but this requires consultation with an infectious diseases specialist on a case-by-case basis. the patient must also demonstrate virological control of their hiv, as evidenced by a suppressed plasma vl within the 3 months prior to transplantation. achieving this demonstrates that the patient is able to tolerate and adhere to their art regimen and provides sufficient time to unmask any immune reconstitution inflammatory syndrome (iris) reactions. in the setting of acute organ failure, however, patients may not yet have had sufficient time to obtain a suppressed vl, which may take 3 or more months. patients on art for shorter than this time period may still be considered for transplantation provided that their cd4+ count exceeds the thresholds above, but consultation with an infectious diseases specialist is advised. such patients would be regarded as being at higher risk post-transplantation than patients demonstrating stable vl suppression. information about the donor’s art history may not be available in certain time-sensitive transplantation scenarios, such as with deceased donors. although every effort should be undertaken to obtain such information, transplantation should not be delayed unduly in its absence. human immunodeficiency virus-negative recipient the benefit of accepting an organ from an hiv-positive donor must outweigh the potential risks thereof and the risks of remaining on the transplant list while awaiting an organ from an hiv-negative donor. the recipient (and/or caregiver in the case of a minor) must receive appropriate counselling about the potential additional risks of the procedure given the donor’s hiv-positive status. the recipient must be able to tolerate an art regimen effective against the donor’s hiv strain and must agree to take lifelong art. transplantation should be undertaken as part of a human research ethics committee (hrec)-approved research protocol. suggested antiretroviral therapy: the following art is suggested for hiv-negative recipients of organs from hiv-positive donors: the regimen chosen will vary according to the donor’s art history and the recipient’s comorbidities. for most recipients weighing > 20 kg, we suggest using a dolutegravir (dtg)-based regimen where possible. dolutegravir has a very high barrier to resistance, is only rarely hepatotoxic and has no significant drug–drug interactions with commonly used immunosuppressant drugs. dolutegravir is now freely available in both the public and private sectors. regimens for paediatric patients weighing < 20 kg should be discussed with a paediatric hiv expert. we suggest starting art prior to transplantation, so as to achieve therapeutic drug levels at the time of surgery. the exact time period required is not currently well defined, but commencing therapy 2–3 days prior to transplantation should provide adequate time for the drugs to achieve steady state at the time of transplantation (i.e. approximately 4 half-lives of the drug). we currently suggest continuing art indefinitely. any decision to stop art at a later stage should only be made if, despite intensive testing (including with highly sensitive assays), there is still no clear evidence that hiv transmission took place, and this should only be undertaken after informed consent and with the approval of the hrec overseeing the case. donor eligibility living human immunodeficiency virus-positive donor standard living donor work-up duration of art ≥ 3 months cd4+ count ≥ 200 cells/µl (cluster of differentiation 4 t-cell percentage [cd4+%] ≥ 15% for patients aged < 5 years) plasma vl < 50 copies/µl the recipient must be able to receive a safe and effective art regimen, considering the donor’s anticipated hiv viral resistance strains. rationale: the prospective donor must have demonstrated durable and stable control of their hiv, to minimise the risk of unmasking iris reactions occurring subsequent to organ donation, which could jeopardise the health of the donor. a cd4+ threshold ≥ 200 cells/µl is also recommended to minimise the likelihood of occult opportunistic infections either manifesting after organ recovery or being transmitted to the donor during transplantation. we do not consider a -pre-transplantation biopsy of the donor organ to be a routine requirement merely because of hiv infection. deceased human immunodeficiency virus-positive donor standard criteria, as for hiv-negative deceased donors. for deceased donors with a history of hiv resistance or virological failure, the recipient must be able to receive a safe, tolerable and effective art regimen considering the donor’s known or inferred patterns of viral resistance. rationale: although the risk of transmission of the donor virus to the recipient is likely to be higher if the donor has an unsuppressed vl, limiting the deceased donor pool only to virally suppressed individuals would significantly restrict the number of organs available. deceased donors in south africa had vls that ranged from undetectable to > 150 000 copies/µl, and none of the recipients to date have developed virological failure from a transmitted strain of hiv.39,42 for donors with an unsuppressed vl, we recommend that the recipient should be placed on an art regimen that would be expected to treat both their own and the donor’s hiv strains. consultation with an infectious diseases specialist experienced in managing transplant patients is mandatory. care of the human immunodeficiency virus-positive recipient after transplantation for the most part, we recommend routine hiv care post-transplantation, with minor alterations where indicated: in view of the potential for unanticipated treatment interruptions and drug–drug interactions, we recommend performing an hiv vl measurement within 2–3 months after transplantation. a vl > 50 copies/µl should prompt urgent intervention as per the latest southern african hiv clinicians society guidelines. key drug–drug interactions are outlined in table 1. physicians should be aware of these and consider changing therapy accordingly if required. in general, insti-based art offers the fewest drug–drug interactions with commonly used immunosuppressant drugs, as well as a high barrier to resistance. hiv-positive transplant recipients should receive the same vaccines as hiv-negative transplant recipients. hiv-positive transplant recipients should receive the same post-transplantation prophylaxis for opportunistic infections as hiv-negative transplant recipients. table 1: key drug–drug interactions between commonly used immunosuppressant and antiretroviral drugs. ethical consideration in all cases, the decision to receive an organ from an hiv-positive donor should be made freely and without coercion. in addition, potential organ recipients should be made aware of the possibility of receiving an organ from an hiv-negative donor. in the case of children who received hiv-positive donor organs and have not reached the age of consent, every effort must be made to ensure the protection of their best interests. adult recipients of organs from hiv-positive donors and caregivers of child recipients must be made aware of the importance of adherence to antiretroviral medication, and the complexities inherent in this type of transplant. to this end, a social worker should be an integral part of the transplant team involved in donor and recipient assessment, and this person should be in a position to empower potential recipients, and their caregivers, in a manner that will facilitate favourable outcomes. living human immunodeficiency virus-positive donor in addition to standard donor criteria, it is important that the hiv-related clinical criteria outlined below (see also ‘recommendations’ section) are adhered to, so as to minimise harm to the donor. this may be especially important if the donor is a close relative or friend of the recipient, where conflicts of interest may arise. we advise that an independent donor advocate (ida) should be appointed for all cases involving a living hiv-positive donor. an ida is a person with a good understanding of transplants, who is fully independent of the donor, the recipient and the medical team; they need not be a health professional. the role of an independent advocate is to ensure that the donor’s interests and rights are upheld at all times, and to ensure that the donor has adequate understanding of the consent process, surgical procedure and follow-up requirements. independent donor advocates should be a required signature on the surgical consent form, affording them veto status for the procedure. although idas are a legal mandate of most living donor transplant programmes in many countries, this is not currently the case in south africa. however, we regard an ida as essential for any programme using increased-risk living donors, including living hiv-positive donors. human immunodeficiency virus-positive recipients it is a key principle of medical ethics that equal access to treatment should not be denied unreasonably. where outcomes in hiv-positive recipients of organs have been shown to be similar to other patient groups who are offered organ transplantation, as with renal transplants, hiv status alone cannot be used as grounds for exclusion from transplant programmes. where outcomes for hiv-positive organ recipients are not known, it should not be assumed that hiv-positive recipients will necessarily fare more poorly than other transplantable groups. rather, well-monitored clinical trials are encouraged to ascertain outcome data. increasingly, survival data from hiv-positive recipients of solid organs other than kidneys are also proving similar to those of hiv-negative controls in many instances, although often with an increased risk of rejection.23,25,34 as with any disease, medical complications of a condition may legitimately disqualify patients from transplantation. in the case of hiv, these may include active opportunistic infections or aids-associated malignancies. however, patients with hiv should not be disadvantaged solely on the basis of their hiv. human immunodeficiency virus-negative recipients of organs from human immunodeficiency virus-positive donors currently, it is not definitively known whether, and at what frequency, hiv is transmitted from the donor organ to an hiv-negative recipient in a controlled environment when attempts are made to limit transmission. in the absence of definitive data, it is prudent to assume for ethical purposes that this likelihood may be substantial. extreme care should therefore be taken to ascertain that the risk of acquiring hiv is outweighed by the risk of continuing to wait for a transplant from an hiv-negative donor. we anticipate that further data on hiv’s transmissibility in these scenarios may inform these ethical considerations. all potential transplant recipients in this situation should be informed fully of the potential that they might acquire hiv infection, and that the treatment for this will likely require lifelong art. considerations for minors minors who are hiv-negative recipients of organs from hiv-positive donors require special consideration. this scenario may be particularly frequent for living-donor liver recipients, who are most commonly children because of organ size considerations. given that we recommend that transplantations involving hiv-positive patients be performed under the review of a local research ethics committee (see below), the south african national health act requires consent from the minor’s primary caregiver for the procedure regardless of the minor’s age. when the minor is capable of understanding the procedure, the minor’s assent should also be sought. additional ethical considerations for minors include: the capacity of the child’s support network to cater for the additional burden of hiv-related therapies and potential complications: the child will require extensive assistance in the post-transplantation period, and this may include art, additional clinic visits to optimise hiv control and additional admissions in the case of opportunistic infections. the need for age-appropriate disclosure to the child of their hiv status should transmission occur: best practice principles in this regard have been established within the hiv field, and include serial disclosures by qualified counsellors in the presence and with the support of the child’s primary caregivers (usually the parents), at a complexity level appropriate for the child’s understanding at that age. donor disclosure: hiv status disclosure facilitates adherence, and adherence in transplant programmes is essential to promoting good outcomes. it is strongly encouraged that the primary caregiver of the potential recipient child (often the mother, who may also be the donor) has disclosed her or his hiv status to her or his immediate support ‘network’ who will be involved in caring for the recipient child in future. this network may be immediate family members, or it may be a family member at a distant location. research protocols and processes given the rapidly developing nature of the field, and the ethical and medical complexities involved, we advise that organ transplants involving hiv-positive patients should be subject to formal ethics review by a local hrec. rigorous patient protections are particularly vital in the case of hiv-negative recipients, given the ethical considerations involved. we recommend involvement of the local hrec as early as possible in the process, to allow adequate time for discussions and detailed interactions. furthermore, we strongly recommend that all data concerning transplantations with hiv-positive donors or recipients should be peer-reviewed, published and distributed timeously because the experiences shared from other centres may have biomedical and ethical implications. conclusion these guidelines aim to sketch an evidence-based framework for hiv-positive donors and recipients regarding solid organ transplantation. it is expected that specific recommendations will need to be adjusted as further evidence becomes available. furthermore, individual patient circumstances may require deviations from this document, provided that such departures have the backing of the local research ethics committee and contribute to continuing research in the field. these guidelines aim to provide support and a framework for the expansion of programmes incorporating hiv-positive donors and recipients. acknowledgements competing interests the authors have declared that no competing interests exist. authors’ contributions all authors contributed equally to this work. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer specific recommendations provided here are intended only as a guide to clinical management, based on 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https://doi.org/10.1016/j.transproceed.2015.12.049 aguero f, castel ma, cocchi s, et al. an update on heart transplantation in human immunodeficiency virus-infected patients. am j transplant. 2016;16(1):21–28. https://doi.org/10.1111/ajt.13496 kern rm, seethamraju h, blanc pd, et al. the feasibility of lung transplantation in hiv-seropositive patients. ann am thorac soc. 2014;11(6):882–889. https://doi.org/10.1513/annalsats.201402-083oc botha j, conradie f, etheredge h, et al. living donor liver transplant from an hiv-positive mother to her hiv-negative child: opening up new therapeutic options. aids. 2018;32(16):f13–f9. https://doi.org/10.1097/qad.0000000000002000 canaud g, dejucq-rainsford n, avettand-fenoel v, et al. the kidney as a reservoir for hiv-1 after renal transplantation. j am soc nephrol. 2014;25(2):407–419. https://doi.org/10.1681/asn.2013050564 bruggeman la. hiv-1 infection of renal cells in hiv-associated nephropathy. j am soc nephrol. 2017;28(3):719–721. https://doi.org/10.1681/asn.2016111171 ross mj. advances in the pathogenesis of hiv-associated kidney diseases. kidney int. 2014;86(2):266–274. https://doi.org/10.1038/ki.2014.167 crane m, iser d, lewin sr. human immunodeficiency virus infection and the liver. world j hepatol. 2012;4(3):91–98. https:/doi.org/10.4254/wjh.v4.i3.91 cao yz, friedman-kien ae, huang yx, et al. cd4-independent, productive human immunodeficiency virus type 1 infection of hepatoma cell lines in vitro. j virol. 1990;64(6):2553–2559. blasi m, stadtler h, chang j, et al. detection of donor’s hiv strain in hiv-positive kidney-transplant recipient. n engl j med. 2020;382(2):195–197. https://doi.org/10.1056/nejmc1910189 botha j, fabian j, etheredge h, conradie f, tiemessen ct. hiv and solid organ transplantation: where are we now. curr hiv/aids rep. 2019;16(5):404–413. https://doi.org/10.1007/s11904-019-00460-7 redd ad, mullis ce, serwadda d, et al. the rates of hiv superinfection and primary hiv incidence in a 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https://doi.org/10.1097/qad.0000000000002109 harbell j, terrault na, stock p. solid organ transplants in hiv-infected patients. curr hiv/aids rep. 2013;10(3):217–225. muller e, barday z. hiv-positive kidney donor selection for hiv-positive transplant recipients. j am soc nephrol. 2018;29(4):1090–1095. https://doi.org/10.1681/asn.2017080853 special collection: unaids targets for 2030 references summaries of scientific articles published in the 2021 edition of the sajhivmed about the author(s) david c. spencer division of infectious diseases, faculty of medicine, university of the witwatersrand, johannesburg, south africa citation spencer dc. southern african journal of hiv medicine august 2021. s afr j hiv med. 2021;22(1), a1309. https://doi.org/10.4102/sajhivmed.v22i1.1309 editorial southern african journal of hiv medicine august 2021 david c. spencer copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. special collection: unaids targets for 2030 hiv/aids in southern africa. an end to new hiv infections by 2030? the views of our authors. summaries of recent articles in the southern african journal of hiv medicine (sajhivmed). despite the passage of three decades, people living with hiv in south africa are still at risk of serious morbidity and inappropriate mortality from hiv. in order to achieve the target of ending hiv by 2030, a more urgent public health response is required. this must include more innovative strategies to improve hiv awareness, new thought with regard to prevention, upgrading of art services and a renewed dedication to the retention in care of all people living with hiv.1 if significant improvements in differentiated service delivery, increases in human resources and hiv prevention can be realized, botswana could become one of the first countries with a previously high-burdened generalized hiv epidemic to gain epidemic control, despite the demands of the covid-19 [coronavirus disease 2019] pandemic.2 this year marks the 21st anniversary of the existence of the sajhivmed. the journal was first published in 2000. at the time, hiv denialism was rampant, many were confused and large numbers died unable or unwilling to accept or access antiretroviral treatment (art). at the time, the southern african hiv clinicians’ society believed that a journal of hiv medicine was necessary to showcase the work of local researchers and to underpin the southern african hiv epidemic with credible science. though times have changed, the mandate has not. there is much talk of an end to new hiv infections by 2030. my thanks to the guest authors who have submitted articles to the journal addressing this topic. like dorothy,3 ‘we’re not in kansas anymore!’ we are not where we were. antiretrovirals have changed the epidemic. still no protective vaccine exists. and no cure has been found. if there is a rainbow at the end of our story, it is not yet in sight. we are in africa. and the task ahead – an end to new hiv infections by 2030 – is still far off. in the following pages, i summarise several sajhivmed articles that address this story. if you have the opportunity, please read the parent articles. these can be accessed through the links provided at the end of each citation. covid-19 has demonstrated the vulnerability of our world – particularly the lowand middle-income countries. climate change is here. we have an uncertain future on this planet. substantial fault lines have emerged in south african society in recent days. here, too, the winds of change are blowing. as healthcare workers, it is time to do what we can to heal our world and the angry communities around us. we are the so-called experts. all of us seek an end to this hiv epidemic. david c. spencer editor-in-chief sajhivmed references laher ae, venter wdf, richards ga, paruk f. profile of presentation of hv-positive in-patients to an emergency department in johannesburg, south africa. s afr j hiv med. 2021;22(1):a1177. https://doi.org/10.4102/sajhivmed.v22i1.1177 jefferis k, avalos a, phillips h, et al. five years after treat-all implementation: botswana’s hiv response and future directions in the era of covid-19. s afr j hiv med. 2021;22(1):a1275. https://doi.org/10.4102/sajhivmed.v22i1.1275 frank baum, l. the wonderful wizard of oz. chicago, il: geo. m. hill co. publishers; 1900. summaries of scientific articles published in the 2021 edition of the sajhivmed 1. parker e, judge ma, macete e, et al. hiv infection in eastern and southern africa: highest burden, largest challenge, greatest potential. s afr j hiv med. 2021;22(1):a1237. https://doi.org/10.4102/sajhivmed.v22i1.1237 summary: the authors review the hiv epidemic in eastern and southern africa (esa) in the light of the failure of most countries in the region to meet the 2020 unaids 90-90-90 targets and the call to meet the new unaids targets by 2030 (see the full article for the unaids 2020, 90-90-90 targets). the unaids 2025–2030 targets include the following: ≥ 95% of those living with hiv to know their hiv status, ≥ 95% of this group to have started and remain on antiretroviral therapy (art) and ≥ 95% of those on treatment to have persistently undetectable viral loads by 2025–2030. ‘know your epidemic, know your response’ (wilson et al. 2008, further reading). our authors argue that a new commitment and new targets are needed for the current decade. a total of 20.7 million, or 54%, of the globe’s 38 million people living with hiv live in esa. most (87%; range: 15% – 98%) are aware of their diagnosis, 83% (37% – 98%) are on art, and 90% (68% – 97%) of these have suppressed viral loads. interpret the numbers with caution: ranges and confidence intervals are wide, the background data is incomplete, and many clinics and individuals are likely to have been missed. the problems include the following: retention in care. africa’s men are still too easily lost from care. infrastructure. there are too few high-throughput labs and insufficient point-of-care tests and testing. the neglected. how well represented are our key populations and are these being adequately reached? our men who have sex with men, those who inject drugs, female sex workers, the truck drivers, the migrants, mobile miners, the serodiscordant couples, pregnant women and their infants? why are these so often missed? the authors question whether these key groups are on the 2030 roadmap. to this, they add the ‘acutely infected’ – a high-risk transmission group. how well are these groups being recognised and targeted in esa? the authors draw attention to multiple gaps – multiple opportunities – throughout esa. this is an important article. it asks pertinent questions and gives some answers: promote and expand local prevention research (and implementation). improve accessibility to hiv education and testing. ramp up in-country point-of-care clinical trials of affordable and available viral load and cd4 testing diagnostics. read the article. in particular, look at the figures, especially figure 1b (see link: https://doi.org/10.4102/sajhivmed.v22i1.1237) south africa’s hiv numbers dwarf its regional neighbours’. ‘highest burden, largest challenge, greatest potential’. do we want a world without new infections by 2030? yes. yes. yes. however, as a region, we are languishing far behind target. further reading wilson d, halperin dt. ‘know your epidemic, know your response’: a useful approach if we get it right. lancet 2008;372(9637):423–426. https://doi.org/10.1016/s0140-6736(os)60883-1 2. pillay y, johnson l. world aids day 2020: reflections on global and south african progress and continuing challenges. s afr j hiv med. 2021;22(1):a1205. https://doi.org/10.4102/sajhivmed.v22i1.1205 summary: with regard to eliminating new hiv infections by 2030, where are we? three 2020 reports are reviewed: unaids (global), the hiv policy lab (global) and thembisa version 4.3 (local, south african) (further reading: unaids 2020; hiv policy lab 2020; johnson 2020). table 1 in this article outlines south africa’s 2020 90-90-90 goal attainment by province, gender and age (follow the link above to see the article and the table in the sajhivmed). adult females do best (94-74-92). this is followed by adult males (91-67-92) and lastly children (79-70-72). an important detail is recorded in the table’s columns: only 54% of adult males living with hiv in the north west province have been diagnosed. only 58% of children living with hiv in the province of limpopo have been diagnosed and are on art! in gauteng, the economic hub of south africa, only 66% of children living with hiv are on art – and only 63% are virologically suppressed!: five years into the implementation of [south africa] sustainable development goals sdg [sustainable development goals], our children lag behind their adult counterparts. urgent action is called for. (nyasulu et al. 2021, see further reading) the article provides the reader with numbers. between 2010 and 2019, south africa’s total hiv-infected population increased from 5.9 to 7.64 million. in the same period, the overall hiv incidence rate fell by 55%. new infections still occur: 201 000 in 2018/2019. however, the percentage of ‘ever-tested’ south africans has risen, from 47.3% in 2010 to 76.3% currently. has there been improvement? yes. however, we need more … please. prevention? politicians, health administrators and regulatory bodies, industry and healthcare workers must make it easier for all south africans to access antiretrovirals and care. ‘u=u: an undetectable viral load on art = an untransmissible virus’ (further reading: thigpen et al. 2012). in modern practice, art is both treatment and prevention. however, condom use at ‘last sex’ among 15–24-year-old south africans was 23% in 2012 and was still only 29% in 2019. among pregnant sowetan women, hiv prevalence rates have not changed in two decades: 28.9% in 2002, 33.1% in 2009 and 27.4% in 2015 (further reading: mnyani 2020). and in 2019, the national south african antenatal hiv prevalence rate was 30.7% (confidence interval [ci], 30.4% – 31.3%) (further reading: woldesenbet et al. 2019). can the prevention gap be closed? pre-exposure prophylaxis (prep) represents an underutilised opportunity. only 3% of south african female sex workers and 1% of men who have sex with men use prep regularly. rates in the general population are similarly low; prep reliably protects the uninfected. the sajhivmed’s 2020 prep guidelines speak to its efficacy, safety and affordability (further reading: bekker et al. 2020). every clinician in africa must become familiar with these guidelines and ensure that all are protected. the at-risk groups are known, but with a countrywide hiv prevalence of 19.7% among 15–49-year-old south africans, virtually all are at risk. long-acting antiretroviral (arv) injectables represent a new day in hiv prevention. data from the hptn 083 and hptn 084 cabotegravir studies confirm prep’s utility (efficacy) in africa and its value in the poorly adherent (further reading: clement et al. 2020; landovitz et al. 2020; delany-moretlwe et al. 2021). looking to 2030, long-acting prep must be a front-runner. has the covid-19 pandemic taught us lessons that may help us achieve the unaids 2030 goals?: leadership. competent, respected, visible and committed to an hiv-free society. a defined strategy and a defined target population. be strategic and inclusive. acknowledge that the individual is important. provide differentiated care. address stigma. make hiv clinics accessible and welcoming. we need new thoughts on adherence: where should we be placing the long-acting arvs? aim to reduce harm. antiretrovirals reduce harm; we need to involve key groups, providing art for the infected and prep for the uninfected: art is for the entire community. retention in care for the infected. push the 95-95-95 agenda. in-your-face and regularly updated science-based hiv education. promote the 2030 targets. keep all informed, with a regular slot on every television and radio channel. keep the foot on the accelerator. involve the community. we are all in this together. close the gaps. further reading unaids. prevailing against pandemics by putting people at the centre [homepage on the internet]. geneva; 2020 [cited n.d.]. available from: https://www.unaids.org/sites/default/files/media_asset/prevailing-againstpandemics_en.pdf hiv policy lab. 2020 global hiv policy report: policy barriers to hiv progress [homepage on the internet]. 2020 [cited n.d.]. available from: https://www.hivpolicylab.org/documents/reports/2020globalreport/2020%20hiv%20policy%20lab%20executive%20summary%20 johnson lf, dorrington re. thembisa version 4.3: a model for evaluating the impact of hiv/aids in south africa [homepage on the internet]. 2020 [cited n.d.]. available from: https://www.thembisa.org/ nyasulu jcy, maposa i, sikakhane bp, pandya h. access to hiv services and viral load suppression among children during the 90-90-90 strategy implementation in south africa: a time-series analysis. s afr j hiv med. 2021;22(1):a1187. https://doi.org/10.4102/sajhivmedv22i1.1187 thigpen mc, kebaabetswe pm, paxton la, et al. antiretroviral preexposure prophylaxis for heterosexual hiv transmission in botswana. n engl j med. 2012;367(5):423–434. https://doi.org/10.1056/nejmoa1110711 mnyani c, tait cl, peters rph, et al. implementation of a pmtct programme in a high hiv prevalence setting in johannesburg, south africa: 2002–2015. s afr j hiv med. 2020;21(1):a1024. https://doi.org/10.4102/sajhivmed.2020.v21i1.1024 woldesenbet sa, kufa t, lombard c, et al. the 2017 national antenatal sentinel hiv survey key findings, south africa [homepage on the internet]. [cited 2021 sept 22] available from: nicd.ac.za/wp-content/uploads/2019/07/antenatalsurvey-report-24july19.pdf bekker lg, brown b, joseph-davey d, et al. southern african guidelines on the safe, easy and effective use of pre-exposure prophylaxis: 2020. s afr j hiv med. 2020;21(1):a1152. https://doi.org/10.4102/sajhivmed.v21i1.1152 clement me, kofron r, landovitz rj. long-acting injectable cabotegravir for the prevention of hiv infection. curr opin hiv aids. 2020;15(1):19–26. https://doi.org/10.1097/coh.0000000000000597 landovitz r, et al. hptn 083 final results: pre-exposure prophylaxis containing long acting cabotegravir is safe and highly effective for cis-gender man and trans-gender women who have sex with men. international aids conference (iac); july 6–10, 2020 [cited 2021 jan 29]. available from: https://llwww.natap.org/2020/iac/iac_28.htm delany-moretlwe s, hughes jp, et al. long acting cabotegravir is safe and effective in preventing hiv infection in cisgender women: interim results from hptn 084, hiv r4p. hiv research for prevention conference virtual, january 27-28 and february 3-4, 2021. hy01.02. 3. meya db, tugume l, nabitaka v, et al. establishing targets for advanced hiv disease – a call to action. s afr j hiv med. 2021;22(1):a1266. https://doi.org/10.4102/sajhivmed.v22i1.1266 summary: the world health organization (who) defines advanced hiv disease (ahd) as hiv-associated disease in persons living with hiv and presenting to care with a cd4 cell count of < 200 cells/µl or with a who stage 3 or 4 infection. the definition includes all children under the age of 5 years irrespective of their cd4 count (further reading: who 2017). advanced hiv disease carries a high mortality and is more frequent in the hospitalised (further reading: carmona et al. 2018; laher et al. 2021).a third of those who enter or who cycle in and out of hiv care have ahd. many are art experienced. can ahd be harnessed by 2030? the 95% unaids-2030 targets are a strategic opportunity (meya et al. 2021 above): [w]e suggest that these specific targets … cd4 testing, crag [cryptococcal antigen] and tb testing, and treatment … aligned to the who ahd package of care would be a step in the right direction. the authors suggest a focus on: the newly hiv diagnosed those previously in care and (now) returning to care those failing antiretroviral treatment. identify persons with cd4+ counts of < 200 cells/µl, and prioritise checking the serum crag lateral flow assay and urine xpert/tuberculosis (tb) lipoarabinomannan (lam). institute rapid art initiation if patients are art naïve or returning to or failing care. always anticipate tb and tb-associated immune reconstitution – never let it surprise you. the writers urge the strengthening of measures to track and retain patients in care throughout sub-saharan africa. much in this article has been said before. however, this is a timely call to africa’s healthcare community to do something memorable: close the door on hiv by 2030. is it doable? read the article. further reading who. guidelines for managing advanced hiv disease and rapid initiation of antiretroviral therapy. geneva: world health organization; 2017. carmona s, bor j, nattey c, et al. persistnet high-burden of advanced hiv disease among patients seeking care in south africa’s national hiv programme: data from a nationwide laboratory cohort. clin infect dis. 2018;66(suppl_2):s111–s117. htpps://doi.org/10.1193/cid/ciy045 laher ae, venter wdf, richards ga, paruk f. profile of presentation of hiv-positive in-patients to an emergency department in johannesburg, south africa. s afr j hiv med. 2021;22(1):a1177. https://doi.org/10.4102/sajhivmed.v22i1.1177 4. laher ae, venter wdf, richards ga, paruk f. profile of presentation of hiv-positive patients to an emergency department in johannesburg, south africa. s afr j hiv med. 2021;22(1):a1177. https://doi.org/10.4102/sajhivmed.v22i1.1177 summary: this observational study examines the demographics, clinical presentation, diagnosis and outcome of 1224 persons living with hiv (plwh) consecutively admitted to the emergency department of a large public hospital in johannesburg between july 2017 and october 2018. of these, 17.3% were art naïve. of the 75.2% who had started art prior to this admission, 32.2% reported non-adherence. this is a description of south africans who sought medical help when sick – for some, too late. although the group is young (median age, 36 years; interquartile ratio [iqr], 31–44 years), in-hospital mortality was high (n = 166; 13.6%). immunity often severly weakened: the median cd4 count was 112 (iqr, 34–295) cells/µl, and almost half, n = 527 (47.5%), had a baseline cd4 of < 100 cells/µl. active tb was diagnosed in 244 (20%), and 213 (86.3%) had extrapulmonary or disseminated tb infection. the study has limitations: it is observational and its generalisability is limited. a priori, it has an emergency room bias that leans towards severity and poorer outcomes. nevertheless, the authors draw a credible picture of the practice of everyday medicine in south africa’s public sector. their article asks, ‘[w]hy the late presentation? why the break with prior antiretroviral care?’ it is a timely story with which to address the call for an end to new hiv infections by 2030. the authors remind the reader that (laher et al. 2021 above): [t]wo-thirds of the global population of people living with hiv (plwh) are in sub-saharan africa (ssa). south africa (sa) contributes approximately 7.5 million to the global number, more than twice that of any other country worldwide … the burden of hiv-related illness is still substantial, especially among the newly diagnosed, art-naïve and those recently initiated onto treatment. this article speaks to the practice of medicine in south africa. it deserves to be read widely, as a reminder that hiv medicine is also about caring for the sick. i ask myself, what went wrong? why are plwh still dying in emergency room wards? 5. archary m, van zyl r, sipambo n, sorour g. optimised pediatric antiretroviral therapy to achieve the 95-95-95% goals. s afr j hiv med. 2021;22(1):a1278. https://doi.org/10.4102/sajhivmed.v22i1.1278 summary: eighty-four percent of new global hiv infections in children in 2019 were in africa. the first half of this opinion piece reviews south africa’s experience in meeting the 2020 unaids 90-90-90 targets in children. south africa’s children are falling behind. the achieved overall targets in children were 79-47-34! while peripartum and pregnancy-related mother-to-child transmission in south africa is now uncommon, breastfeeding-related transmission (4.3%) continues. and children infected in infancy still slip through the net to reappear, treatment naïve, in late childhood or adolescence. the second half of the article discusses advances in the management of children living with hiv in south africa. medication, adherence and ‘responsible care’ are nonetheless persistent points of worry, as are health systems. the authors cite the 7-year delay between registration of an essential fixed-dose paediatric generic-combination antiretroviral by the food and drug administration in the united states and registration in south africa. the good news in this report is in the new drug formulations for the very young: a dispersible, scored combination of abacavir/lamivudine (120/60 mg) for children weighing from 3 kg to 25 kg and a dispersible, scored 10 mg dolutegravir tablet to treat children from 4 weeks of age or weighing > 3 kg. these await approval by the south african health products agency (sahpra). future innovations? the long-acting injectables (8-weekly cabotegravir/rilpivirine) for children and adolescents aged 12–18 years. will these be the answer to the current unimpressive viral suppression rates? what about the larger context of children’s health on our subcontinent? consider that in the first year of the covid-19 epidemic, 23 000 teenage (10–19 years) pregnancies occurred in south africa’s gauteng province, of which 934 were in girls aged 10–14 years (further reading: bengu 2021). gender-based violence takes many forms. this is one. the subtext of this article is exactly that society’s children, particularly those living with hiv, deserve better. children lag behind. the childhood gap in the diagnosis of hiv, treatment and viral suppression must be closed before 2030. further reading bhengu l. gauteng records more than 23 000 teen pregnancies in one year, some moms as young as 10. news24 , 2021 august 17. 6. jefferis k, avalos a, phillips h, et al. five years after treat-all implementation: botswana’s hiv response and future directions in the era of covid-19. s afr j hiv med. 2021;22(1):a1275. https://doi.org/10.4102/sajhivmed.v22i1.1275 summary: this review of botswana’s current and projected response to the hiv epidemic is clear-headed, thoughtful, data based and, in the main, optimistic. it details the country’s roadmap from 2016 to the anticipated goal of no new or incident hiv infections by 2030. unlike most of africa, botswana achieved the 90-90-90 unaids targets before 2020! the country’s population (2.4 million) is small and mostly urbanised: 375 900 (iqr, 353 500–400 150), or 15.7%, live with hiv. results from the current botswana aids incidence survey are due in 2022. the expectation is that these will validate the country’s positive trajectory towards the 2030 unaids goals and perhaps achieve these before that date! some issues remain. women aged 15–24 years are at great risk of infection. innovative, targeted ideas around prevention are needed. many ‘first-time’ art initiates (25%) do so with a cd4 count of < 200 cells/µl, that is, with advanced immune suppression. and many (76%) with cd4 counts of < 200 cells/µl are actually ‘art experienced’, some poorly adherent and failing treatment and others with a dysfunctional immune response and a suppressed viral load. this represents a group needing more attention. in their economic assessment, the authors anticipate a contraction of gross domestic product as a result of covid-19. botswana’s government has had to increase spending. budget deficits have been unavoidable. however, public spending is still expected to fill the gaps. looking to 2030, the authors define what is still needed: greater investment in sexual reproductive health interventions such as prep, particularly for young women national and international advocacy to reduce the exorbitant costs to africa of laboratory reagents, commodities and supplies strengthening of differentiated care to those living with hiv and the streamlining of the care of those stable on minimal intervention (e.g. fewer laboratory tests) the upskilling (capacitation) of healthcare workers to identify and manage patients with ahd. this article is a hopeful look at botswana’s future. it is recommended reading. 7. lilian rr, davies n, gilbert l, et al. cd4 testing after initiation of antiretroviral therapy: analysis of routine data from the south african hiv programme. s afr j hiv med. 2020;21(1):a1165. https://doi.org/10.4102/sajhivmed.v21i1.1165 comment: i have included this article with our 2021 articles looking at achieving the unaids 2030 guidelines because it speaks to the role of the cd4 cell count in long-term hiv care. this, too, has bearing on achieving the 2030 goals. the authors follow the trajectory of the cd4+ cell count post-art initiation in a large anonymised electronic south african patient database, the three interlinked electronic registers project, or tier.net. records are from 2004–2021 and describe 1 178 190 persons in the south african public sector on art in two urban (gauteng) and two rural (limpopo) settings. overall, baseline cd4+ cell counts were low: 50% had cd4+ counts of < 200 cells/µl. by 2017, this percentage had improved to 37.2%. however, only 46.5% of cd4 counts captured on tier.net were repeated. of these, 14.3% plwh (n = 78 494) remained with cd4 counts of < 200 cells/µl. indeed, 20% (n = 18 566) of those on ≥ 4 years of art and with viral suppression, viz. a viral load (vl) of < 1000 copies/ml, were immune-non-responders or immune-discordant responders (further reading: yang et al. 2020; laprise et al. 2013). the latter were likely to be on second-line art (adjusted odds ratio [aor], 1.79), older, viz. 35–45 years and particularly, > 45 years (aor, 1.15 and 1.50, respectively), male (aor, 2.28) and to have confirmed tuberculosis (aor, 2.49). baseline cd4 cell counts of > 350 cells/µl were protective of long-term immune deficiency (aor: 0.35)! so, when should cd4 tests be repeated in those on art? ‘every 6 months post-baseline if the preceding cd4+ count was < 200 cells/µl’. however (further reading: nel et al. 2020): [i]f the cd4 count is > 200 cells/µl at baseline or it increases above this threshold on art, then cd4 testing can be stopped, as therapeutic monitoring of art is best accomplished with vl, not with cd4 count or clinical criteria. the efficacy of art is measured not with repeated cd4 cell counts, but with regular vl monitoring. beyond the mechanics of treating those with a persistently low cd4+ count, lilian et al.’s article is asking a bigger question: does the immune system ever fully recover from hiv? what does this mean for the future? we are not at the end of the chapter on hiv. nor do we fully understand what lies ahead. this is an article that should be read and its message ruminated on. further reading yang x, su b, zhang x, et al. incomplete immune reconstitution in hiv/aids patients on antiretroviral therapy: challenges of immune non-responders. j leuko biol. 2020;107(4):597–612. https://doi.org/10.1002/jlb.4mr1019-189r laprise c, de pokomandy a, baril j-g, et al. virologic failure following persistent low-level viremia in a cohort of hiv-positive patients: results from 12 years of observation. clin infect dis. 2013;57(10):1489–1496. nel j, dlamini s, meintjes g, et al. south african hiv clinicians’ society guidelines for antiretroviral therapy in adults: 2020 update. s afr j hiv med. 2020;21(1):a1115. https://doi.org/10.4102/sajhivmed.v21i1.1115 about the author(s) oda e. van den berg julius global health, julius center for health sciences and primary care, university medical center utrecht, utrecht, the netherlands erica j. shaddock charlotte maxeke johannesburg academic hospital, division of pulmonology and critical care, school of clinical medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa sarah l. stacey charlotte maxeke johannesburg academic hospital, division of pulmonology and critical care, school of clinical medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa charles feldman charlotte maxeke johannesburg academic hospital, division of pulmonology and critical care, school of clinical medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa roos e. barth department of internal medicine and infectious diseases, university medical center utrecht, utrecht, the netherlands diederick e. grobbee julius global health, julius center for health sciences and primary care, university medical center utrecht, utrecht, the netherlands willem d.f. venter ezintsha, university of the witwatersrand, johannesburg, south africa kerstin klipstein-grobusch julius global health, julius center for health sciences and primary care, university medical center utrecht, utrecht, the netherlands division of epidemiology and biostatistics, school of public health, faculty of health sciences, university of the witwatersrand, johannesburg, south africa alinda g. vos julius global health, julius center for health sciences and primary care, university medical center utrecht, utrecht, the netherlands ezintsha, university of the witwatersrand, johannesburg, south africa citation van den berg oe, shaddock ej, stacey sl, et al. corrigendum: the influence of hiv infection and antiretroviral treatment on pulmonary function in individuals in an urban setting in sub-saharan africa. s afr j hiv med. 2022;23(1), a1351. https://doi.org/10.4102/sajhivmed.v23i1.1351 note: doi of original article published: https://doi.org/10.4102/sajhivmed.v22i1.1312 correction corrigendum: the influence of hiv infection and antiretroviral treatment on pulmonary function in individuals in an urban setting in sub-saharan africa oda e. van den berg, erica j. shaddock, sarah l. stacey, charles feldman, roos e. barth, diederick e. grobbee, willem d.f. venter, kerstin klipstein-grobusch, alinda g. vos published: 20 may 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. in the version of this article initially published, van den berg oe, shaddock ej, stacey sl, et al. the influence of hiv infection and antiretroviral treatment on pulmonary function in individuals in an urban setting in sub-saharan africa. s afr j hiv med. 2021;22(1), a1312. https://doi.org/10.4102/sajhivmed.v22i1.1312, there was an error in affiliation 1. instead of julius center for health sciences and primary care, university medical center utrecht, utrecht, the netherlands, it should be julius global health, julius center for health sciences and primary care, university medical center utrecht, utrecht, the netherlands. in addition, there was an error regarding the affiliation for kerstin klipstein-grobusch. as well as having the affiliation julius global health, julius center for health sciences and primary care, university medical center utrecht, utrecht, the netherlands, he should also have division of epidemiology and biostatistics, school of public health, faculty of health sciences, university of the witwatersrand, johannesburg, south africa. the authors apologise for this error. the correction does not change the study’s findings of significance or overall interpretation of the study’s results or the scientific conclusions of the article in any way. pg27-30.html guideline inh preventive therapy (ipt) in hivinfected south african children mark f cotton, fcpaed (sa), mmed (paed), phd, dtm&h, dch (sa) kidcru, stellenbosch university, tygerberg children’s hospital, w cape hiv-infected children have a high risk of acquiring tuberculosis. the world health organization (who) has released isoniazid preventive therapy (ipt) recommendations for adults and children living with hiv, based on efficacy studies, mainly in adults. data from children appear conflicting. ipt guidelines for children were developed in response to who guidelines at a local meeting, followed by discussions. ipt should be given to all hiv-infected children after exposure to a source case if treatment for active disease is not required. for children whose mothers’ hiv status was known antentally, when tuberculosis has been actively excluded in mothers and at infant follow-up, and when infants have commenced antiretroviral therapy in the first 3 months of life, ipt is not required. otherwise, all infants and children should be given ipt for 6 months once active tuberculosis has been excluded. hiv-infected children are at high risk of contracting tuberculosis (tb). an incidence of 24 cases per 100 hiv-infected children per year was documented in cape town during a period of limited access to antiretroviral therapy (art).1 for hiv-infected adults, ipt is a cornerstone of tb management. ipt for hiv-infected adults refers to giving inh to those without active tb. ipt, together with intensified case finding and infection control, is collectively referred to as the ‘3 is’ strategy of the world health organization (who).2 in a recent meta-analysis of 12 trials and 8 578 randomised hiv-infected subjects >13 years of age, tb preventive therapy (any anti-tb drug) versus placebo resulted in a lower incidence of active tb (relative risk (rr) 0.68, 95% confidence interval (ci) 0.54 0.85). this effect was more pronounced in individuals with a positive tuberculin skin test (tst) (rr 0.38, 95% ci 0.25 0.57). for adults with a negative tst, there was no statistically significant difference between treatment groups as the upper ci was >1 (rr 0.89, 95% ci 0.64 1.24). compared with inh monotherapy, shortcourse multidrug regimens had more adverse effects. a reduction in mortality with inh monotherapy versus placebo was confined to those with a positive tst (rr 0.74, 95% ci 0.55 1.00).3 the meta-analysis did not address the role of art, which also reduces the risk of acquiring tb disease, as no randomised controlled trials have been reported in patients on art. lawn and colleagues have argued that art and ipt have complementary roles, ipt being important in tst-positive individuals with higher cd4 counts and better immunity, and that art (together with active case finding) is the most important component in immunosuppressed individuals.4 a meta-analysis from 2006 showed that ipt is not associated with production of inh resistance,5 although resistance is a concern if patients have active disease before commencing ipt. it is also recognised that ipt is unlikely to prevent tb if a patient is infected with mycobacterium tuberculosis resistant to inh.6 for children there are fewer data. the benefit of ipt after documented tb exposure or infection (tst positive) is undisputed, with the efficacy derived from studies in hiv-uninfected children.7 findings assessing the value of universal ipt before or in the absence of documented exposure to a source case (pre-exposure ipt) seem contradictory. zar and colleagues showed benefit in a double-blind study comparing inh with placebo in children with limited access to art in cape town.1 active tb was excluded at baseline and children already responding to tb treatment were randomised once tb treatment had been completed. mortality was lower in the inh group (11 (8%) v. 21 (16%)) (hazard ratio (hr) 0.46, 95% ci 0.22 0.95, p=0.015). the incidence of tb was also lower in the inh group (5 cases, 3.8%) than in the placebo group (13 cases, 9.9%) (hr 0.28, 95% ci 0.10 0.78, p=0.005).1 a large multicentre trial set in soweto, cape town and durban enrolled infants between 3 and 4 months of age, after excluding all children with known tb contact. it took place during expanding access to art. there was no benefit from pre-exposure ipt compared with placebo, either in preventing tb or in reducing mortality in hiv-infected and hiv-exposed uninfected infants.8 , 9 the apparent contradiction with the study by zar et al. 1 could be explained by differences in the patient populations, excellent surveillance for tb exposure, and rapid institution of open-label inh for any documented exposure to a source case. the benefit of art in reducing tb disease is well documented in children.10 , 11 new long-term data from cape town on children from the original ipt study recently reported additive benefit of art and ipt over 5 years of follow-up. all children on placebo were switched to open-label inh and accessed art through the public programme. inh reduced the risk of tb by 0.22 (95% ci 0.09 0.53) compared with placebo. art alone reduced tb risk by 0.32 (95% ci 0.07 1.55). inh plus art reduced the risk of tb by 0.11 (95% ci 0.04 0.32). restricting the analysis to children receiving art revealed a tb risk reduction of 0.23 (95% ci 0.05 1.00) when comparing inh with no inh.12 this study suggests that ipt and art have additive benefit in hiv-infected children. 1. who recommendations the who has recently published guidance on ipt for both children and adults, mainly based on adult data.13 the recommendations for children are as follows: 1.1 children living with hiv who do not have poor weight gain, fever or current cough are unlikely to have active tb. strong recommendation, low quality of evidence 1.2 children living with hiv and any one of the following symptoms – poor weight gain, fever, current cough or contact history with a tb case – may have tb and should be evaluated for tb and other conditions. once tb is excluded, offer ipt regardless of age. strong recommendation, low quality of evidence comment: all suspected cases must be referred for exclusion of tb according to local guidelines. the timing of this screening is important to avoid excessive referrals. a review after 2 weeks may be useful before referral. in the complete absence of symptoms, no additional work-up is required. 1.3 children living with hiv and >12 months of age and who are unlikely to have active tb on symptombased screening, and have no contact with a tb case, should receive 6 months of ipt (10 mg/kg/d) as part of a comprehensive package of hiv prevention and care services. strong recommendation, low quality of evidence comment: the implication is that all hiv-infected children should receive ipt once active tb has been excluded, regardless of their underlying condition. this recommendation brings ipt guidelines for children in line with those for adults. however, in adults, while a duration of 6 months is regarded as the minimum period, there is support for 36 months or longer. in children, the duration was limited to 6 months, pending longer-term safety data. the risk for tb disease may not be at the time of giving ipt. screening for tb must therefore take place at each clinic visit. 1.4 in children strong recommendation, low quality of evidence comment: the contradiction here is that children at greatest risk (hiv-infected infants) are not offered the same access to ipt as older children. hiv-infected infants have a 20 times higher incidence of tb than hiv-uninfected infants in a setting of expanding but inadequate early identification and access to art.14 1.5 all children living with hiv who have successfully completed treatment for tb disease should receive inh for an additional 6 months.15 conditional recommendation, low quality of evidence 2. the ipt working group the place of ipt for hiv-infected children in southern africa was debated at a small meeting held in cape town on 14 october 2010, sponsored by the hiv clinicians society of south africa. paediatricians from south africa and botswana and adult infectious diseases specialists with expertise in ipt attended. (during a review process, additional colleagues with expertise in childhood hiv and tb gave invaluable input.) the consensus was that ipt should be supported. there is a need to define the extent to which it should be included. there is a role for operational research on ipt. integration of maternal and child health with tb and hiv programmes to accompany ipt (infection control and intensified case finding) is a key component for elimination of tb in children. the following should be addressed: 2.1 who takes responsibility for delivery of ipt? 2.2 how will it be monitored? key indicators include:     • uptake     • adherence     • development of tb in children on or not on ipt. 3. recommendations of the ipt working group at each health care visit, every hiv-infected child must be reviewed for possible tb exposure and/or active disease and managed appropriately. always check the following:     • contact with a tb source case     • failure to thrive (monitor road to health card (rthc))     • present cough (non-remitting cough of >=2 weeks’ duration is suggestive of tb). 4. post-exposure ipt ipt should be provided after each documented tb exposure, unless the child is currently receiving inh or tb treatment (fig. 1). 4.1 first exclude active tb (see below). 4.2 give ipt to all hiv-infected children and all children less than 5 years of age, regardless of hiv status, after exposure to a source case of tb. 4.3 give inh for 6 months (see dosing below). before giving post-exposure ipt, first make sure that the child does not have active tb. • completely asymptomatic children (no current cough, no failure to thrive, no signs of extrathoracic tb, active and playful) require no further investigation prior to ipt initiation. (all children receiving ipt and/or tb treatment should be followed up clinically while on therapy to evaluate for new symptoms or signs of disease.) • any symptomatic child should be carefully assessed (always plot weight and assess rthc for failure to thrive). in the absence of a convincing clinical picture of tb or lethargy, and without easy access to chest radiography, first treat the most likely alternative diagnosis and re-assess the child after 2 weeks. • persistently symptomatic children must be assessed with at least a chest radiograph (antero-posterior or postero-anterior and lateral). respiratory specimens (gastric aspirates and/or induced sputa) for m. tuberculosis culture must be collected in all children with signs suggestive of tb on chest radiograph (prior to initiation of tb treatment). note: evaluate for tb using the best resources available. 5. primary (pre-exposure) ipt primary (pre-exposure) ipt should be given for 6 months (fig. 2). 5.1 give under the following circumstances: • active tb excluded (as for post-exposure ipt). • infant/child diagnosed with hiv or art initiated after 3 months of age (or poor tb exposure screening expected). 5.2. do not give if all of the following criteria are fulfilled: • the mother is identified as hiv infected in antenatal clinic and screened for tb. • no active tb is identified in close contact of the child such as member of the household/plot or a regular visitor. • infants are initiated on art under both of the following circumstances: • art initiated within the 1st 3 months of life when asymptomatic • active tb excluded. • the infant is enrolled in the art programme and seen at least every month for first 3 months and thereafter at least every 3 months (with screening for tb exposure or signs/symptoms of tb at each visit). 6. catch-up phase for children already on art for >6 months at the time of implementation of the ipt guidelines (june 2011), there will be 50 000 children on art. data support ipt in children.12 for children already well established on highly active antiretroviral therapy (haart) (i.e. >3 months) and without active tb, there are two options: 6.1 ipt may be given for 6 months. (apply guidelines for new contact with potential source case.) this is likely to be most beneficial for those who are tst positive (note: in the absence of art, an induration >=5 mm denotes a positive tst (mantoux)). 6.2 defer ipt and continue monitoring for new tb exposure and signs/symptoms of tb. 7. dosage 7.1 inh 10 15 mg/kg/d. 7.2 also give vitamin b6 25 mg/d. 8. additional points 8.1 in the absence of obvious tb disease, initiation of haart takes precedence over ipt. 8.2 ipt must not complicate the haart programme. 8.3 any child assessed for tb after contact with a tb source case must be screened for hiv. references 1. zar hj, cotton mf, strauss s, et al. effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with hiv: randomised controlled trial. bmj 2007;334:136. 1. zar hj, cotton mf, strauss s, et al. effect of isoniazid prophylaxis on mortality and incidence of tuberculosis in children with hiv: randomised controlled trial. bmj 2007;334:136. 2. world health organization. who three i’s meeting (2 4 april 2008). geneva: who, 2008. 2. world health organization. who three i’s meeting (2 4 april 2008). geneva: who, 2008. 3. akolo c, adetifa i, shepperd s, volmink j. treatment of latent tuberculosis infection in hiv infected persons (review). cochrane collection 2010. www.thecochranelibrary. com (accessed 18 january 2011). 3. akolo c, adetifa i, shepperd s, volmink j. treatment of latent tuberculosis infection in hiv infected persons (review). cochrane collection 2010. www.thecochranelibrary. com (accessed 18 january 2011). 4. lawn sd, wood r, de cock km, kranzer k, lewis jj, churchyard gj. antiretrovirals and isoniazid preventive therapy in the prevention of hiv-associated tuberculosis in settings with limited health-care resources. lancet infect dis 2010;10:489-498. 4. lawn sd, wood r, de cock km, kranzer k, lewis jj, churchyard gj. antiretrovirals and isoniazid preventive therapy in the prevention of hiv-associated tuberculosis in settings with limited health-care resources. lancet infect dis 2010;10:489-498. 5. balcells me, thomas sl, godfrey-faussett p, grant ad. isoniazid preventive therapy and risk for resistant tuberculosis. emerg infect dis 2006;12:744-751. 5. balcells me, thomas sl, godfrey-faussett p, grant ad. isoniazid preventive therapy and risk for resistant tuberculosis. emerg infect dis 2006;12:744-751. 6. sneag db, schaaf hs, cotton mf, zar hj. failure of chemoprophylaxis with standard antituberculosis agents in child contacts of multidrug-resistant tuberculosis cases. pediatr infect dis j 2007;26:1142-1146. 6. sneag db, schaaf hs, cotton mf, zar hj. failure of chemoprophylaxis with standard antituberculosis agents in child contacts of multidrug-resistant tuberculosis cases. pediatr infect dis j 2007;26:1142-1146. 7. united states public health service tuberculosis prophylaxis trial collaborators. prophylactic effects of isoniazid on primary tuberculosis in children. am rev tuberc 1957;76:942-963. 7. united states public health service tuberculosis prophylaxis trial collaborators. prophylactic effects of isoniazid on primary tuberculosis in children. am rev tuberc 1957;76:942-963. 8. madhi sa, mcsherry g, violari a, et al. lack of efficacy of primary isoniazid (inh) prophylaxis in reducing tuberculosis (tb) free survival in hiv-infected (hiv+) african children. presented at the interscience conference on antimicrobial agents and chemotherapy, 25 28th october 2008. washington dc: idsa/asm. http:// clinicaloptions.com/hiv/washington2008 (accessed 11 may 2011). 8. madhi sa, mcsherry g, violari a, et al. lack of efficacy of primary isoniazid (inh) prophylaxis in reducing tuberculosis (tb) free survival in hiv-infected (hiv+) african children. presented at the interscience conference on antimicrobial agents and chemotherapy, 25 28th october 2008. washington dc: idsa/asm. http:// clinicaloptions.com/hiv/washington2008 (accessed 11 may 2011). 9. mitchell c, mcsherry g, violari a, et al. primary isoniazid prophylaxis did not protect against tb or latent tb infection in hiv-exposed, uninfected infants in south africa. presented at the 16th conference on retrovirology and opportunistic infections, 8 11 february 2009, montreal, canada. http://www.retroconference.org/ (accessed 11 may 2011). 9. mitchell c, mcsherry g, violari a, et al. primary isoniazid prophylaxis did not protect against tb or latent tb infection in hiv-exposed, uninfected infants in south africa. presented at the 16th conference on retrovirology and opportunistic infections, 8 11 february 2009, montreal, canada. http://www.retroconference.org/ (accessed 11 may 2011). 10. violari a, cotton mf, gibb dm, et al. early antiretroviral therapy and mortality among hiv-infected infants. n engl j med 2008;359:2233-2244. 10. violari a, cotton mf, gibb dm, et al. early antiretroviral therapy and mortality among hiv-infected infants. n engl j med 2008;359:2233-2244. 11. walters e, cotton mf, rabie h, schaaf hs, walters lo, marais bj. clinical presentation and outcome of tuberculosis in human immunodeficiency virus infected children on anti-retroviral therapy. bmc pediatr 2008;8:1. 11. walters e, cotton mf, rabie h, schaaf hs, walters lo, marais bj. clinical presentation and outcome of tuberculosis in human immunodeficiency virus infected children on anti-retroviral therapy. bmc pediatr 2008;8:1. 12. frigati lj, kranzer k, cotton mf, schaaf hs, lombard cj, zar hj. the impact of isoniazid preventive therapy and antiretroviral therapy on tuberculosis in children infected with hiv in a high tuberculosis incidence setting. thorax 2011 (in press, e-pub date 2 april). 12. frigati lj, kranzer k, cotton mf, schaaf hs, lombard cj, zar hj. the impact of isoniazid preventive therapy and antiretroviral therapy on tuberculosis in children infected with hiv in a high tuberculosis incidence setting. thorax 2011 (in press, e-pub date 2 april). 13. world health organization. guidelines for intensified ttuberculosis case-finding and isoniazid preventive therapy for people living with hiv in resource-constrained settings. geneva: who, 2011. 13. world health organization. guidelines for intensified ttuberculosis case-finding and isoniazid preventive therapy for people living with hiv in resource-constrained settings. geneva: who, 2011. 14. hesseling ac, cotton mf, jennings t, et al. high incidence of tuberculosis among hiv-infected infants: evidence from a south african population-based study highlights the need for improved tuberculosis control strategies. clin infect dis 2009;48:108-114. 14. hesseling ac, cotton mf, jennings t, et al. high incidence of tuberculosis among hiv-infected infants: evidence from a south african population-based study highlights the need for improved tuberculosis control strategies. clin infect dis 2009;48:108-114. 15. fitzgerald dw, desvarieux m, severe p, joseph p, johnson wd jr, pape jw. effect of post-treatment isoniazid on prevention of recurrent tuberculosis in hiv-1-infected individuals: a randomised trial. lancet 2000;356:1470-1474. 15. fitzgerald dw, desvarieux m, severe p, joseph p, johnson wd jr, pape jw. effect of post-treatment isoniazid on prevention of recurrent tuberculosis in hiv-1-infected individuals: a randomised trial. lancet 2000;356:1470-1474. 16. world health organization, international union against tuberculosis and lung disease. guidance for national tuberculosis and hiv programmes on the management of tuberculosis in hiv-infected children: recommendations for a public health approach. 2010. www.idoc-africa.org/documents/download/id/206 (accessed15 april 2011). 16. world health organization, international union against tuberculosis and lung disease. guidance for national tuberculosis and hiv programmes on the management of tuberculosis in hiv-infected children: recommendations for a public health approach. 2010. www.idoc-africa.org/documents/download/id/206 (accessed15 april 2011). 17. al-dabbagh m, lapphra k, mcgloin r, et al. drug-resistant tuberculosis. pediatr infect dis j 2011 (in press, e-pub date 3 february). 17. al-dabbagh m, lapphra k, mcgloin r, et al. drug-resistant tuberculosis. pediatr infect dis j 2011 (in press, e-pub date 3 february). contributors to guideline development: mohandran archary (scribe), tonya arscott-mills, theunis avenant, vivienne black, raziya bobat (co-chair), ashraf coovadia (chair), mark cotton (convener), peter donald, angela dramowski, ute feucht, anneke hesseling, prakash jeena, leon levin, anna mandalakas, ben j marais, graeme meintjies, tammy meyers, kimesh naidoo, helena rabie, gary reubenson, paul roux, h simon schaaf, andrew steenhof, helecine zeeman, heather zar. acknowledgements we thank natalie martyn for arranging the meeting and the sa hiv clinicians society for sponsoring it. dosage recommendations for ipt (primary and post-exposure) weight range (kg) 100 mg tablets per dose (total dose 10 mg/kg/d) dose given (mg) <5 0.5 50 5.1 9.9 1 100 10 13.9 1.5 150 14 19.9 2 200 20 24.9 2.5 250 >25 3 300 resources for drug-resistant tb: references 16 and 17.     fig. 1. management of an hiv-infected child with documented tb exposure or suspected to have tb disease. fig. 2. considerations for primary (pre-exposure) ipt. 11-13.html opinion how should we care for patients who are not yet eligible for art? tom h boyles1,2, ma, bm bch, mrcp, dtm&h, md lynne s wilkinson1,3, ba, llb 1madwaleni hospital, e cape 2division of infectious diseases and hiv medicine, department of medicine, groote schuur hospital and university of cape town 3médecins sans frontières, cape town in 2009, there were an estimated 5.6 million people living with hiv in south africa.1 based on a threshold of cd4 <350 cells/µl, it is estimated that around 46% of patients are not yet eligible for antiretroviral therapy (art).2 the department of health guidelines from 20103 have limited recommendations for the care of patients not eligible for art. there is no guidance on how to develop a package of care or how roles should be assigned between different cadres of staff. it is unclear whether pre-art care services are currently being offered to large numbers of patients, and it is our opinion that comprehensive guidelines based on effective models of pre-art care are urgently needed. we believe that this has the potential to reduce morbidity, mortality and transmission and increase long-term retention in care in south africa. currently, rates of retention in pre-art care are disappointing. a recent review of studies from sub-saharan africa found that the median proportion of patients lost to care was 59% between testing and receipt of cd4 counts, 46% between staging and art eligibility, and 68% between art eligibility and initiation.4 based on the information available, only about 18% of patients who are not yet eligible for art when diagnosed with hiv remain continuously in care until art eligibility. although some patients may enter care elsewhere, others may only present again when unwell and some time after becoming eligible for art. the median starting cd4 count of patients in south africa remains well below the level at which patients become eligible for art,5 and loss to care of ineligible patients is likely to be an important contributor to this. low cd4 nadir is associated with poor clinical outcomes7 and increased costs.8 in response, calls have been made for significantly improved adherence to pre-art care and monitoring of patients not yet eligible for art to achieve aids strategy goals and reduce the problem of late presentation and initiation of art.9 one reason for low retention in care in the pre-art period may be lack of availability of comprehensive hiv care services. patients simply asked to return for repeat cd4 testing after 6 months may be less inclined to return than patients offered a comprehensive service package upon diagnosis. another reason may be a perception among patients that art is only necessary as a last resort when becoming sick despite other attempts to remain well while living with hiv. the 2003 world health organization (who) recommendations for art in resource-limited settings were to start art when the cd4 count dropped to ≤200 cells/µl or the patient developed who stage 4 illness.10 this message was interpreted by many as art only being necessary when one becomes sick. many people’s only experience of art was seeing it prescribed to sick and late-presenting patients, which served to reinforce the misunderstanding. the 2010 who recommendations (adopted by south africa in august 2011) that all patients with a cd4 ≤350 cells/µl initiate art11 were widely welcomed by campaigners. however, there was a word of caution from vuyiseka dubula, the general secretary of the treatment action campaign in south africa, who explained: ‘... our communities were made to believe we only needed art when we were sick, now we have a massive task ahead of us to change deeply entrenched community perceptions’ (personal communication). it may take some time for communities to buy into the importance of accessing art early, and engagement of patients not yet eligible for art is an ideal forum to begin. our own service model in the rural eastern cape province of south africa provides an example of how effective comprehensive hiv services including pre-art care can be delivered.12 outcomes analysis of 1 803 patients initiating art found that the 270 who had received >6 months pre-art care started art at higher cd4 counts than the cohort as a whole (192 v. 123). notably, receiving >6 months pre-art care was independently associated with clinically relevant outcomes including a 50% reduction in both mortality and loss to follow-up (ltfu) after starting art. this was an observational study with some selection bias, as the pre-art care group were included as a result of being adherent to the pre-art care programme for at least 6 months. this is more likely to explain the differences in ltfu than those in starting cd4 count and mortality. data from the private sector in south africa also show that patients receiving pre-art care incur lower overall direct costs.13 our service model focuses on engaging patients in peer educator-led community care groups immediately upon testing positive, regardless of eligibility for art. groups are run on a weekly basis and are decentralised to local primary healthcare clinics with patients usually choosing to attend the group nearest their home. meetings begin with group education around a specific topic facilitated by a peer educator; examples include the importance of art adherence and the long-term side-effects of art. each patient has a paper file held at the clinic, and at each attendance the peer educators record weight and replies to specific screening questions about tuberculosis and sexually transmitted infection (sti), and ask whether there are any other symptoms. patients with weight loss or any symptoms are referred to the clinic nurse on the same day. pre-art patients are prescribed multivitamins or co-trimoxazole and counts of returned pills are used to assess readiness for art. peer educators also provide one-on-one counselling for patients preparing for art. groups are fully integrated between those on art and those who are not yet eligible. this approach has allowed groups to grow quickly and may have reduced hiv-related stigma in the community. depression is common following a diagnosis of hiv and may be worse in areas with high levels of stigma.14 depression is associated with both reduced linkage to care and impaired adherence to art,16 but can be effectively treated with interpersonal support group therapy.17 the formation of community support groups of patients who have disclosed their hiv status to the group may prevent depression and improve retention in care in newly diagnosed patients. incentives to remain in long-term pre-art care include the provision of prophylactic medication such as isoniazid preventive therapy (ipt), access to screening services such as pap smears, and inclusion in the social activities associated with joining a community group. until universal art coverage is achieved in south africa it is likely that resources will predominantly be concentrated on art delivery, and it is important that pre-art services are delivered in the most resource-efficient way. in our service model the majority of tasks are performed by lay counsellors. referrals to nurses are only made for specific clinical reasons (fig. 1). while our care groups are run on clinic premises, it would be preferable to move them out of the clinic altogether and into the community. innovative approaches to community-led pre-art care could be adapted from successful community art models, which have been shown to reduce the burden on healthcare facilities and achieve higher rates of retention in care.18 the who recommends at least 6 months of ipt for all hiv-positive adolescents and adults with latent tuberculosis, whether or not on art.19 by the end of 2009, only around 85 000 people with hiv had received ipt, representing <0.3% coverage worldwide.20 art-ineligible patients are a large group who could be targeted to increase ipt coverage. ipt is an ideal component of pre-art care as it provides a tangible treatment option and allows monitoring of adherence issues. distribution of free co-trimoxazole has been shown to decrease loss to follow-up in patients not yet eligible for art,21 and it is likely that ipt would have a similar effect. prescribing ipt in the pre-art period reduces the risk of overlapping drug toxicities and high pill burden once art is commenced. additional benefits are that active tuberculosis must be ruled out before prescribing ipt, which increases active case finding. proven hiv prevention interventions to be included in pre-art care include treatment for sexually transmitted infections after symptom screening by lay counsellors,22 condom promotion and distribution,23 contraception24 and pregnancy planning services.25 initiating art at cd4 counts >350 cells/µl for patients in serodiscordant couples is a highly effective prevention strategy26 that could be implemented more easily if patients were retained in active pre-art care. improved patient preparation has been shown to improve retention in care rates on art.27 patients who are ineligible for art at the time of diagnosis may benefit from extended art preparation, giving them extra time to adjust to the need for lifelong therapy and to attend multiple group education sessions. early preparation and retention of ineligible patients also allows programmes to respond quickly to changes in eligibility criteria. there are many challenges to providing comprehensive hiv services and more data are required to inform us of the cost and benefits. it is unlikely that a single model will be appropriate for all settings, and consultation with patients should guide local programme models. our experience suggests that important features in any setting will be delivering services close to people’s homes or jobs, integrating services with those of patients already on art, and task shifting to appropriate cadres of staff. our opinion is that no time should be wasted in integrating active management of patients not yet eligible for art into programme models. we believe this can have a major public health impact by reducing morbidity, mortality and transmission and by increasing long-term retention in care. furthermore, this can be achieved without overburdening an already stretched healthcare service. the authors declare no conflicts of interest. references 1. unaids. global report: unaids report on the global aids epidemic 2010. 2010. http://www.unaids.org/documents/20101123_globalreport_em.pdf (accessed 6 december 2010). 1. unaids. global report: unaids report on the global aids epidemic 2010. 2010. http://www.unaids.org/documents/20101123_globalreport_em.pdf (accessed 6 december 2010). 2. adam ma, johnson lf. estimation of adult antiretroviral treatment coverage in south africa. s afr med j 2009;99:661-667. 2. adam ma, johnson lf. estimation of adult antiretroviral treatment coverage in south africa. s afr med j 2009;99:661-667. 3. department of health. the south african antiretroviral treatment guidelines, 2010. 2010. http://www.doh.gov.za/docs/factsheets/guidelines/art.pdf (accessed 20 june 2011). 3. department of health. the south african antiretroviral treatment guidelines, 2010. 2010. http://www.doh.gov.za/docs/factsheets/guidelines/art.pdf (accessed 20 june 2011). 4. rosen s, fox mp. retention in hiv care between testing and treatment in sub-saharan africa: a systematic review. plos med 2011;8(7):e1001056. 4. rosen s, fox mp. retention in hiv care between testing and treatment in sub-saharan africa: a systematic review. plos med 2011;8(7):e1001056. 5. boulle a, van cutsem g, hilderbrand k, et al. seven-year experience of a primary care antiretroviral treatment programme in khayelitsha, south africa. aids 2010;24(4):563-752. 5. boulle a, van cutsem g, hilderbrand k, et al. seven-year experience of a primary care antiretroviral treatment programme in khayelitsha, south africa. aids 2010;24(4):563-752. 6. cornell m, grimsrud a, fairall l, et al. temporal changes in programme outcomes among adult patients initiating antiretroviral therapy across south africa, 2002-2007. aids 2010;24(14):2263-2270. 6. cornell m, grimsrud a, fairall l, et al. temporal changes in programme outcomes among adult patients initiating antiretroviral therapy across south africa, 2002-2007. aids 2010;24(14):2263-2270. 7. severe p, juste ma, ambroise a, et al. early versus standard antiretroviral therapy for hiv-infected adults in haiti. n engl j med 2010;363(3):257-265. 7. severe p, juste ma, ambroise a, et al. early versus standard antiretroviral therapy for hiv-infected adults in haiti. n engl j med 2010;363(3):257-265. 8. leisegang r, cleary s, hislop m, et al. early and late direct costs in a southern african antiretroviral treatment programme: a retrospective cohort analysis. plos med 2009;6(12):e1000189. 8. leisegang r, cleary s, hislop m, et al. early and late direct costs in a southern african antiretroviral treatment programme: a retrospective cohort analysis. plos med 2009;6(12):e1000189. 9. larson ba, brennan a, mcnamara l, et al. early loss to follow up after enrolment in pre-art care at a large public clinic in johannesburg, south africa. trop med int health 2010;15(suppl 1):43-47. 9. larson ba, brennan a, mcnamara l, et al. early loss to follow up after enrolment in pre-art care at a large public clinic in johannesburg, south africa. trop med int health 2010;15(suppl 1):43-47. 10. world health organization. scaling up antiretroviral therapy in resource-limited settings: treatment guidelines for a public health approach. geneva: world health organization, 2003. http://whqlibdoc.who.int/publications/2004/9241591552.pdf (accessed 24 november 2010). 10. world health organization. scaling up antiretroviral therapy in resource-limited settings: treatment guidelines for a public health approach. geneva: world health organization, 2003. http://whqlibdoc.who.int/publications/2004/9241591552.pdf (accessed 24 november 2010). 11. world health organization. antiretroviral therapy for hiv infection in adults and adolescents. recommendations for a public health approach. 2010 revision. 2010. http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf (accessed 20 june 2011). 11. world health organization. antiretroviral therapy for hiv infection in adults and adolescents. recommendations for a public health approach. 2010 revision. 2010. http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf (accessed 20 june 2011). 12. boyles th, wilkinson ls, leisegang r, maartens g. factors influencing retention in care after starting antiretroviral therapy in a rural south african programme. plos one 2011;6(5):e19201. 12. boyles th, wilkinson ls, leisegang r, maartens g. factors influencing retention in care after starting antiretroviral therapy in a rural south african programme. plos one 2011;6(5):e19201. 13. leisegang r, maartens g, hislop m, regensberg l, cleary s. improving the evidence base of markov models used to estimate the costs of scaling up antiretroviral programmes in resource-limited settings. bmc health serv res 2010;10(suppl 1):s3. 13. leisegang r, maartens g, hislop m, regensberg l, cleary s. improving the evidence base of markov models used to estimate the costs of scaling up antiretroviral programmes in resource-limited settings. bmc health serv res 2010;10(suppl 1):s3. 14. bhatia r, hartman c, kallen ma, graham j, giordano tp. persons newly diagnosed with hiv infection are at high risk for depression and poor linkage to care: results from the steps study. aids behav 2011;15(6):1161-1170. 14. bhatia r, hartman c, kallen ma, graham j, giordano tp. persons newly diagnosed with hiv infection are at high risk for depression and poor linkage to care: results from the steps study. aids behav 2011;15(6):1161-1170. 15. sorsdahl kr, mall s, stein dj, joska ja. perspectives towards mental illness in people living with hiv/aids in south africa. aids care 2010;22(11):1418-1427. 15. sorsdahl kr, mall s, stein dj, joska ja. perspectives towards mental illness in people living with hiv/aids in south africa. aids care 2010;22(11):1418-1427. 16. starace f, ammassari a, trotta mp, et al. depression is a risk factor for suboptimal adherence to highly active antiretroviral therapy. j acquir immune defic syndr 2002;31(suppl 3):s136-139. 16. starace f, ammassari a, trotta mp, et al. depression is a risk factor for suboptimal adherence to highly active antiretroviral therapy. j acquir immune defic syndr 2002;31(suppl 3):s136-139. 17. heckman tg, sikkema kj, hansen n, kochman a, heh v, neufeld s. a randomized clinical trial of a coping improvement group intervention for hiv-infected older adults. j behav med 2011;34(2):102-111. 17. heckman tg, sikkema kj, hansen n, kochman a, heh v, neufeld s. a randomized clinical trial of a coping improvement group intervention for hiv-infected older adults. j behav med 2011;34(2):102-111. 18. decroo t, telfer b, biot m, et al. distribution of antiretroviral treatment through self-forming groups of patients in tete province, mozambique. j acquir immune defic syndr 2011;56(2):e39-e44. 18. decroo t, telfer b, biot m, et al. distribution of antiretroviral treatment through self-forming groups of patients in tete province, mozambique. j acquir immune defic syndr 2011;56(2):e39-e44. 19. world health organization. guidelines for intensified tuberculosis case finding and isoniazid preventative therapy for people living with hiv in resource constrained settings, 2010. 2010. http://whqlibdoc.who.int/publications/2011/9789241500708_eng.pdf (accessed 6 december 2010). 19. world health organization. guidelines for intensified tuberculosis case finding and isoniazid preventative therapy for people living with hiv in resource constrained settings, 2010. 2010. http://whqlibdoc.who.int/publications/2011/9789241500708_eng.pdf (accessed 6 december 2010). 20. world health organization. global tuberculosis control, 2010. 2010. http://www.who.int/tb/publications/global_report/2010/en/index.html (accessed 6 december 2010). 20. world health organization. global tuberculosis control, 2010. 2010. http://www.who.int/tb/publications/global_report/2010/en/index.html (accessed 6 december 2010). 21. kohler pk, chung mh, mcgrath cj, benki-nugent sf, thiga jw, john-stewart gc. implementation of free cotrimoxazole prophylaxis improves clinic retention among art-ineligible clients in kenya. aids 2011;25(13):1657-1661. 21. kohler pk, chung mh, mcgrath cj, benki-nugent sf, thiga jw, john-stewart gc. implementation of free cotrimoxazole prophylaxis improves clinic retention among art-ineligible clients in kenya. aids 2011;25(13):1657-1661. 22. dallabetta g, neilson g. efforts to control sexually transmitted infections as a means to limit hiv transmission: what is the evidence? curr hiv/aids rep 2004;1(4):166-171. 22. dallabetta g, neilson g. efforts to control sexually transmitted infections as a means to limit hiv transmission: what is the evidence? curr hiv/aids rep 2004;1(4):166-171. 23. padian ns, buve a, balkus j, serwadda d, cates w jr. biomedical interventions to prevent hiv infection: evidence, challenges, and way forward. lancet 2008;372:585-599. 23. padian ns, buve a, balkus j, serwadda d, cates w jr. biomedical interventions to prevent hiv infection: evidence, challenges, and way forward. lancet 2008;372:585-599. 24. wilcher r, petruney t, reynolds hw, cates w. from effectiveness to impact: contraception as an hiv prevention intervention. sex transm infect 2008;84(suppl 2):ii54-60. 24. wilcher r, petruney t, reynolds hw, cates w. from effectiveness to impact: contraception as an hiv prevention intervention. sex transm infect 2008;84(suppl 2):ii54-60. 25. aaron ez, criniti sm. preconception health care for hiv-infected women. top hiv med 2007;15(4):137-141. 25. aaron ez, criniti sm. preconception health care for hiv-infected women. top hiv med 2007;15(4):137-141. 26. cohen ms, chen yq, mccauley m, et al. prevention of hiv-1 infection with early antiretroviral therapy. n engl j med 2011;365(6):493-505. 26. cohen ms, chen yq, mccauley m, et al. prevention of hiv-1 infection with early antiretroviral therapy. n engl j med 2011;365(6):493-505. 27. coetzee d, boulle a, hildebrand k, asselman v, van cutsem g, goemaere e. promoting adherence to antiretroviral therapy: the experience from a primary care setting in khayelitsha, south africa. aids 2004;18(suppl 3):s27-31. 27. coetzee d, boulle a, hildebrand k, asselman v, van cutsem g, goemaere e. promoting adherence to antiretroviral therapy: the experience from a primary care setting in khayelitsha, south africa. aids 2004;18(suppl 3):s27-31. fig. 1. service package delivered in pre-art services by various cadres of staff. overview and summary do hiv-infected south africans need palliative care? figure 1 models of palliative care formal assessment of the need for palliative care the symptomatic management of hiv-infected people receiving palliative care cancer care in the hiv-infected patient: palliative care medical cannabis and palliative care for the hiv-infected people introduction the hiv epidemic in south africa in 2018, palliative care: defining the need models of hiv-palliative care: addressing the need eligibility for home and hospice support: assessing the need managing the hiv-sick: symptom control hiv, cancer and palliative care in southern africa the cannabinoid drugs in the palliative management of hiv-infected patients. final remarks acknowledgements references appendix 1: palliative care model: no care appendix 2: indicators of increased mortality of hiv-infected patients appendix 3: the karnofsky score appendix 4: the support and palliative care indicator tools (spicttm) appendix 5: the established veterans aging cohort study index scoring scheme appendix 6: palliative care management: drugs used for symptom control in hiv palliation about the author(s) david c. spencer division of infectious diseases, department of medicine, helen joseph hospital, university of the witwatersrand, johannesburg, south africa rené krause department of family medicine, university of cape town, cape town, south africa theresa rossouw department of immunology, university of pretoria, pretoria, south africa mahomed-yunus s. moosa department of infectious diseases, nelson mandela school of medicine, university of kwazulu-natal, durban, south africa selma browde community action ngo/npo, johannesburg, south africa esnath maramba clinical unit, council for medical schemes, pretoria, south africa lauren jankelowitz southern african hiv clinicians society, johannesburg, south africa muhangwi b. mulaudzi phomolong medical centre, rustenburg, south africa mpho ratishikana-moloko chris hani baragwanath academic hospital, university of the witwatersrand, johannesburg, south africa oluwarotimi f. modupe council for medical schemes, pretoria, south africa adam mahomed department of internal medicine, charlotte maxake johannesburg academic hospital, johannesburg, south africa citation spencer dc, krause r, rossouw t, et al. palliative care guidelines for the management of hiv-infected people in south africa. s afr j hiv med. 2019;20(1), a1013. https://doi.org/10.4102/sajhivmed.v20i1.1013 guideline palliative care guidelines for the management of hiv-infected people in south africa david c. spencer, rené krause, theresa rossouw, mahomed-yunus s. moosa, selma browde, esnath maramba, lauren jankelowitz, muhangwi b. mulaudzi, mpho ratishikana-moloko, oluwarotimi f. modupe, adam mahomed received: 15 july 2019; accepted: 15 july 2019; published: 13 dec. 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. overview and summary introduction: what is palliative care and what are its essential elements? definition: palliative care is: care that places the relief of suffering at its core, affirms life and does not hasten nor postpone death, but regards dying as a normal process, according to world health organization (who). care that is individualised: the person or patient is its core focus. the recipient is someone who has been diagnosed with a chronic, life-threatening illness that is no longer responsive to curative treatment, for example, cancer, irreversible end-stage end-organ failure, hiv infection and related disorders unresponsive to available treatment, et cetera. ‘end-of-life’ care is an aspect of palliative care that specifically refers to the care of persons estimated to have a life expectancy of ≤ 12 months, according to the national council for palliative care, united kingdom. care that is directed towards the control of distressing symptoms including the relief of pain: ‘total pain’ – this concept refers to pain that cannot be adequately controlled without addressing its contributory factors, namely, physical, emotional, social and spiritual factors. the opioid-use crisis – inappropriate opioid use is a major contributor to the opioid addiction crisis currently reported from highand middle-income countries. under-use of and insufficient access to opioids however characterises opioid use in africa and other low-income countries. palliative care offers appropriate access to opioids without the risk of addiction and within the context of a professionally competent team. (knaul et al.).42 care that is provided by a team. the team is multidisciplinary and comprises nurses, doctors, paramedical persons, for example, physiotherapists, counsellors and accredited members of the religious community. the patient and their personal support network (e.g. family, partner and friends) are advisors to the team and receive support from the team. the team has a leader who takes responsibility for the totality of care, plans specific therapy, prescribes medication, completes medico-legal forms, et cetera. this is usually a medical doctor. team care is intended to integrate the medical, practical, psychological and spiritual aspects of care in a system that promotes as active a lifestyle as possible until death. team care provides support for the patient’s family or partner, et cetera, during the illness and through the time of bereavement. care that is not restricted by the patient’s age and is not restricted to a particular access point, such as a local clinic, district hospital or tertiary level medical centre. the 2017 national draft policy framework and strategy paper on palliative care, department of health, south africa (sa), envisages access to palliative care for all south africans who are in need. (comment: these remarks from the national framework paper are aspirational. few public sector facilities offer access to palliative care at this time.) do hiv-infected south africans need palliative care? figure 1 human immunodeficiency virus infection is incurable. about 770 000 people died of hiv worldwide in 2018. more than two-thirds of these died in africa (unaids global aids update 2019). although statistics south africa has recorded some improvement in the overall survival, hiv-related levels of morbidity and mortality remain high. mortality is greatest among those not on antiretroviral therapy (art), that is, either naïve to art or those who have stopped taking medication and are outside of care. mortality is also high in the first year after the start of art. of south africa’s 7.97 million people living with hiv (plwhiv) in 2019, only 4.94 million are on art. a detectable viral load while on art is usually a sign of treatment failure or poor viral control. these persons are also at increased risk of hiv-related morbidity and mortality. figure 1: the number of deaths by age and hiv-status of men and women admitted to the chris hani baragwanath hospital, soweto, 2006–2009.8 models of palliative care no palliative care: access to formal palliative care within either the public or private health sector in much of africa including sa, is extremely limited. few currently access this care (see figure 3 and appendix 1). the traditional model of palliative care: in this scenario, curative care and palliative care are available to the patient at the time of diagnosis. curative care is initially given priority. but when curative options are exhausted, palliation offers an alternative approach, one that grows in importance as time passes. despite four decades of hiv research, a cure remains out of reach. in these circumstances, health facilities and healthcare workers must be trained to provide palliative care to those in need of it. the long-term model of hiv palliative care: in this scenario, art, prophylactic trimethoprim-sulfamethoxazole, isoniazid (inh) and vaccination against influenza, the pneumococcus, hepatitis b and regular clinic visits form the routine background of care. from time to time, this routine is interrupted by disease. this necessitates a shift in the emphasis of care. palliation becomes an option for those with incurable conditions, such as a central nervous system (cns) lymphoma, disabling stroke, renal and liver failure, et cetera. for plwhiv who live longer, the diseases of old age, for example, chronic lung conditions, diabetes, cardiovascular disease, bone fragility, neurocognitive decline, and the non-aids defining cancers, emerge. indeed, these conditions generally appear a decade or more before identical disease affects uninfected peers (see figures 4, 5 and 6). formal assessment of the need for palliative care limited resources in the face of huge demand necessitate an equitable system of patient triage. with regard to the private funding of costly care options, such as hospice admission and home nursing, these guidelines recommend the spicttm tool (appendix 2) and the vacs score criteria (appendix 3) to be followed as a guide to eligibility. these assessment tools are accredited internationally and with minor adaptation can be used in the south african context. the symptomatic management of hiv-infected people receiving palliative care the core activity of the palliative care team and its clinician(s) is the relief of suffering. pain, particularly chronic pain lasting ≥ 3 months, is experienced by the majority of plwhiv before death. a formal approach to the assessment of both acute and chronic pain underlies its successful management (see table 2). pain control is not always achieved. however, it is more likely if theoretic knowledge is supplemented with bedside experience. in this regard, the 2017 guideline on the management of chronic pain from the hiv division of the infectious diseases society of america (idsa), discusses clinical ‘evidence-based’ support for approaches to hiv-related pain syndromes: this is summarised in the ‘managing the hiv sick’ section. the analgesic drugs are presented in table 3. table 3-a6 (appendix 4) outlines common drug–drug interactions between the antiretrovirals and frequently used analgesics. additional symptoms such as breathlessness (dyspnoea) and fatigue (weakness) are mentioned in the remainder of ‘managing the hiv sick’ section. when the natural course of a disease cannot be reversed, kindness, a safe place, food, a clean bed and good symptom control provide the best environment possible for the end of life. cancer care in the hiv-infected patient: palliative care the ‘hidden cancer epidemic’ refers to the growing number of hiv-infected cancer patients in africa. cancer and the hiv epidemic are interlinked. uncontrolled plasma (hiv) viral load increases the risk of malignancy. aids-defining malignancies were described in the 1980s and 1990s but are still widespread throughout sub-saharan africa today. in the era of art, the risk of non-aids defining cancers is also increasing. universal test and treat (utt) and the 90-90-90 by 2020 initiatives of the who and the unaids, will help to reduce risk in the long term if successful. table 1: causes of death at post-mortem examination of 39 hiv-infected patients of the charlotte maxeke johannesburg academic hospital, january–december 2009.9 table 2: guidelines for the management of acute pain at the end of life.38 however, at this time, oncology and radiotherapy on the african continent face multiple challenges: poor and ageing infrastructure, insufficient numbers of skilled professionals, inconsistent data collection, the huge rural–urban divide, empty drug shelves and constant drug stockouts, et cetera. this section briefly reviews this subject. answers to the palliation of hiv-related cancer include greater access to prevention, for example, vaccination against the human papilloma virus (hpv) and the broader reach of cervical health assessments in women, vaccination against hepatitis b and the improved early diagnosis of cancer and the rapid referral to cancer curative treatment services. closer collaboration between africa’s oncologists, radiotherapists and hiv clinicians is needed if any of this is to be achieved. table 3: hiv+ concurrent disease and commentary. medical cannabis and palliative care for the hiv-infected people the science of cannabinoid use as an adjuvant in hiv-related palliative care is new. although south africa has recently legalised cannabis for medical use, supporting data are largely observational and subjective. table 3 summarises the current knowledge of cannabinoids in the control of common symptoms, for example, nausea, vomiting, pain, anorexia, insomnia, anxiety and depression. however, numerous ‘unknowns’ remain, for example, drug interactions and the dosing of a variety of hiv conditions and contexts. this is still a work in progress that will require updating in subsequent guidelines. introduction what is palliative care? definition 1. according to the national policy framework and strategy policy on palliative care, department of health, south africa, 2017–2022: palliative care is a multidisciplinary approach to the holistic care and support of patients and families facing a life-threatening illness. its aim is to improve quality of life while maintaining dignity from diagnosis to death. for children, the spectrum of illness includes life-limiting conditions that may progress to death or may be severely disabling. palliative care should be available to all patients as needed, from birth until death, and should be accessible at all levels of the health care service. palliative care cuts across all health programmes in the delivery of services.1 the care of the dying is as old as the practice of medicine itself (see box 1). box 1: what is medicine?79 definition 2. according to the world health organization (who): palliative care is an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention, treatment and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial or spiritual. palliative care: affirms life and regards dying as a normal process. neither hastens nor postpones death. provides relief from pain and other distressing symptoms. integrates the psychological and spiritual aspects of patient care. offers a support system to help patients live as actively as possible until death. offers a support system to help the family cope during the patient’s illness and during the experience of bereavement.2 definition 3. end-of-life care: this refers to healthcare, not only of a person in the final hours and days of his or her life, but more broadly care of those with a terminal condition that has become progressive and incurable (wikipedia, accessed 07 october 2018). the national council for palliative care, united kingdom, states that end-of-life care is given to persons ‘likely to die within 12 months’. several commentators make the point that end-of-life care is not identical to palliative care, that is, end-of-life care is a final phase within the broader provision of palliative care. nonetheless, its starting point is sometimes difficult to identify. the principal goal of palliative care is the relief of suffering. this is done through individualising care – addressing symptoms, controlling pain, listening to the patient, responding to fear and anxiety, incorporating families and the patient within a competent, professional and resourceful team, and bereavement support for the patient’s loved ones. a defining characteristic of palliative care is the notion of total pain, the recognition that pain cannot be alleviated completely unless all contributing factors that inform the patient’s life experience are addressed. palliative care is team work. the team comprises a range of medical, nursing, paramedical and psychosocially trained health and community workers. the leader is usually a senior palliative care-trained clinician. the south african national policy framework on palliative care envisages that these teams will be accessed by patients – including those who are human immunodeficiency virus (hiv)-positive – at the community, district and regional levels in free-standing clinics and at all district, secondary and tertiary-level hospitals across the country. these proposals are currently aspirational, however, as significant barriers to implementation still exist: approval and financing, recruitment and staffing, education and training, et cetera. the individual matters. the process of palliative care is just, non-judgmental and given to all irrespective of colour, creed or class. ’the relief of suffering is considered one of the primary ends of medicine by patients and the general public’.3 yet patients and their families do not necessarily agree with health workers on the means to this end. ‘in the care of the dying, patients and their friends and families do not divide suffering into its physical and nonphysical sources the way doctors, who are primarily concerned with the physical, do.’3 palliative care recognises this divide and addresses it by taking all causes of suffering into account when aligning the goals of the patient with that of the caregiver and healthcare system. a consultative, multi-disciplinary approach forms the basis of this model of care. the hiv epidemic in south africa in 2018, palliative care: defining the need hiv morbidity and mortality the joint united nations programme on hiv and aids (unaids) reported in 2016 that 7.1 million south africans were hiv-positive.4 it was estimated that 56% were on antiretroviral therapy (art) yet viral control could only be confirmed in 45%. although 95% of pregnant women had accessed art, mother-to-child transmission of hiv in 2016 still resulted in 12 000 newborn infections. the 2017/2018 sa human sciences research council’s (hsrc) report, released in july 2018, estimated that 7.9 million south africans are now living with hiv, an increase of 1.6 million over the past 5 years; 70.6% are taking art; and 87.5% of plwhiv aged 15–64 years on art have suppressed viral loads. the number of new cases among women aged 15–24 years has remained high since 2012 and is three times that of their male peers, while the overall prevalence of hiv among south africans was 14%. prevalence rates were higher in the provinces of kwazulu-natal (kzn), mpumalanga (mp), the free state (fs) and the eastern cape (ec), with rates of 18.1%, 17.3%, 17.0% and 15.3%, respectively.5 notwithstanding these numbers, new hiv infections have fallen by 44% since 2012 and hiv testing has been on the rise. the evolution of the south african epidemic has meant that many who are infected yet undiagnosed and art naïve, or who have defaulted on art in the past, now present to hospitals and clinics with symptomatic disease, namely, the hiv-sick. it is estimated that as many as 40% – 60% of the beds in the public hospitals in kzn, gauteng, mp and fs are occupied by plwhiv.6,7 few, if any, state hospitals offer a formal palliative care service and despite access to art since 2005, mortality from hiv-related diseases remains high. of the 14 431 patients who died in soweto’s chris hani baragwanath hospital from 2006 to 2009, 64% of the men and 82% of the women were hiv infected. more than 90% of those dying between the ages of 30–40 years were hiv infected.8 causes of death of hospitalised hiv-sick in south africa a small but well-analysed autopsy group from the charlotte maxeke johannesburg academic hospital (cmjah) is reported in table 1.9 the dominant regional pathogen of the hiv-infected patients is mycobacterium tuberculosis. all who died of tb had disseminated infection at the time of their death. the first 90 days following the start of art, namely, ‘early-art’, is a key risk period for death from tb. the recovering immune system has been implicated in these deaths, namely, the immune reconstitution inflammatory syndrome (iris) as the likely cause or complicating event in these deaths.10 figure 2 summarises the admission diagnoses of 741 patients evaluated during a 6-month period on the infectious diseases consultation service of the helen joseph hospital, a public hospital in johannesburg, of which 93% of the consulted patients were hiv-infected. the individual bars demonstrate the wide variety of conditions that affect the acutely sick. although tb is the most frequent diagnosis, it is one of many life-threatening conditions in this group of patients. note that virtually all these conditions are treatable and the majority can be cured.11 figure 2: medical diagnoses of a 6-month review of in-patient infectious disease consultations at the helen joseph hospital, johannesburg, 2015–2016.11 models of hiv-palliative care: addressing the need models of palliative care vary. three models that are frequently encountered by the hiv clinicians in south africa (sa) are briefly discussed in this section. no formal palliative care provided in this model (figure 3), little or no palliative care is accessed prior to death. the hiv infection is not well controlled or is undiagnosed prior to admission, although the patient has been admitted to hospital acutely ill. although the risk of death is often high, palliative care is not offered nor is it integrated with acute care. suffering is not adequately relieved and patients and their families often feel abandoned by the public healthcare system. this model of care is the usual experience of the hiv-sick at this time in sa (for additional comments, see appendix 1). figure 3: the hiv-infected patient, no palliative care.12,13 intermittent palliative care given during periods of need: the hiv-infected patient on antiretroviral therapy with long-term viral control and immune reconstitution in this model, the patient on art initially improves but requires assistance to cope with drug toxicities and possible drug interactions. over time, the need for both acute curative and palliative care is encountered during periods of serious comorbid disease, failure of art, re-introduction of active art and, finally, during special health needs towards the end of life14 (see figure 4). illness increases in importance and frequency with the ageing of hiv survivors as does its complexity and costs. figure 4: palliative care during periods of need. integrated palliative care for people with progressive co-morbid disease chronic lung disease (cld) is a problem for long-term survivors of hiv-infection.15,16 infection from birth, inadequate or intermittent viral control and inter-current respiratory tract infections characterise a group of adolescents with advanced and irreversible small airways disease.17,18 chronic lung disease also affects hiv-infected adults on art, many of whom are smokers, often men and frequently domicile in high-income countries.19 in this model of hiv, people with an active comorbid condition, such as chronic obstructive pulmonary disease (copd), chronic renal failure, heart disease et cetera, experience a slow but progressive downhill trajectory. each new episode of disease or hospital admission compromises organ function further and moves the patient towards the end of life.20 the model in figure 5 also applies to other chronic diseases experienced by the hiv-infected, namely, non-aids-defining cancers, progressive neurocognitive impairment, autoimmune conditions and bone and joint diseases. figure 5: integrated palliative care for people with progressive co-morbid disease, for example, chronic obstructive pulmonary disease (copd).19 the traditional palliative care model: from diagnosis to bereavement palliative care is a continuum of care that starts from the time of diagnosis of a life-threatening illness or condition (e.g. aids) and continues until a time after death when bereavement support is provided to the family members of the deceased.1 during this period, emphasis gradually moves from the curative to the palliative, as dictated by the changing needs of the patient and family (see figure 6). figure 6: current concept of palliative care: from diagnosis to bereavement.1 patients on art who regain normal or near-normal immune activity and whose viral count is ‘undetectable’ (i.e. viral load [vl] < 40–50 copies/ml) have life expectancies similar to that of their uninfected peers.21 while the availability of art has brought great benefits, many still unfortunately die. under normal circumstances, the clinician’s mandate is the restoration of a patient’s health and well-being which begins with obtaining a medical history, the examination of the patient, the formulation of a probable diagnosis, investigation, the start of remedial therapy, the monitoring of the response, a review of laboratory or radiographic data and the confirmation of the diagnosis. patients want and need to feel better and good symptom control is the shared ground of curative and palliative medicine. it addresses the immediate needs of those who suffer. a recent randomised controlled trial (rct) of palliative care in patients with advanced non-small-cell lung cancer found that this intervention reduced depression, improved quality of life and produced a short but significant 3-month survival advantage.22 eligibility for home and hospice support: assessing the need comment for most people, art preserves and restores immune function and extends survival. however, in every hiv clinic, a small group of patients fail to reconstitute cd4 cells despite art and viral control. these ‘immune non-responders’ (inrs) are often older (> 45 years), start art late, begin art at a very low cd4 nadir/baseline (viz. < 100 cells/mm3) and give past medical histories that suggest advanced immune suppression, namely, previous tb, recurrent bacterial and other infections and unexplained weight loss.23 despite adherence to therapy, inrs remain at an increased risk of disease and death notwithstanding years of documented viral suppression.24 no dependable treatment currently reconstitutes the blood compartment with cd4 cells in this group of patients. attempts to address this situation by changing background art in those who are virologically suppressed have not been successful and this is mainly discouraged. where the patient’s usual medication may be incriminated, for example, azt or trimethoprim-sulfamethoxazole, alternative drugs should be tried. prevention, such as commencing art as soon as possible after the start of hiv infection when cd4 cells are likely to be abundant and the thymus is functional, is the therapeutic safeguard against immune non-response to art.25 in addition to this group are those hiv-infected with identifiable causes of immune suppression, for example, steroid use, alcohol abuse, herbs such as the ‘african potato’, chemotherapy, infections such as tb and mycobacterium avium complex (mac), malignancies and rheumatological conditions such as systemic lupus erythematosus (sle), rheumatoid arthritis and drugs that are used to control these conditions. management of the comorbid condition or removal of the offending toxin, for example, alcohol or steroids, may improve the immune response of these patients. the likelihood of cannabinoid use influencing the human immune system either negatively or positively is currently unknown. if these agents are indicated for the palliation of symptoms, it seems reasonable to continue to monitor cd4 response as per the usual intervals recommended in current art guidelines. morbidity and mortality risk from hiv infection: general indicators while all should be able to access the costlier components of a palliative care service, for example, admission to hospice and home nursing, it is acknowledged that the capacity of palliative care services in sa is limited. who are in greatest need? no randomised, controlled palliative care trial addresses this question directly. nevertheless, several observational studies have identified associations that provide some answers (see appendix 2); these indicators change and their significance may diminish or reverse with time on art. the following baseline characteristics in a large south african observational study influenced mortality in the first year after starting art: who stage, body mass index (bmi), haemoglobin level, cd4 cell count, hiv plasma vl and symptoms. yet, once on long-term art, only cd4 cell count, bmi, haemoglobin level and a suppressed vl retained survival significance.26 another observational study that included data from south, central and west africa found that age, gender and baseline cd4 cell count continued to predict death at 6, 12, 24 months and beyond while taking art.27 these factors indicate the need of palliative care but are not to be used to define ‘therapeutic futility’, that is, the discontinuation of active care. in every circumstance, the patient must be treated with dignity and respect and every attempt made to correct the underlying life-threatening process and to offer where possible, life. mortality indicators: assessment tools karnofsky score although scores of ≤ 50% are often used as a qualifier for hospice admission, scores of < 60% are significant and should trigger consultation with the palliative care team.28 however, given the potential for art to reverse underlying disease in the hiv-infected – the lazarus effect – the absolute score must be viewed with caution. the usefulness of the karnofsky score as a measure of impending mortality in this group of patients has not been established (see appendix 3 for more details). the support and palliative care tools the support and palliative care tools (spicttm) are used in the united kingdom and have been applied to patients with hiv and cancer.29 the tool is not specific to hiv and does not consider the role of art and the curative potential of the treatment in several life-threatening infections, for example, sulfonamides in cerebral toxoplasmosis and pneumocystis jiroveci pneumonia (pjp), tb drugs in disseminated tb, antifungals in cryptococcal meningitis (cm), et cetera. general indicators: increasing physical and/or mental regression or dependency a low bmi (viz. < 18 kg/m2 and/or 5% – 10% loss of body weight) ongoing and troublesome symptoms plea for supportive and palliative care or the wish to die. assessment: two or more ‘general’ indicators = unmet supportive and palliative care needs = qualify for palliative care benefits. clinical indicators: worsening frailty and cognitive/neurological, cardiovascular and/or respiratory status worsening of cancer onset of life-threatening end-organ failure. assessment: one or more ‘clinical’ indicators = unmet supportive and palliative care needs = qualify for palliative care benefits (see appendix 5 for more details). the veterans aging cohort study index this scoring system (veterans aging cohort study – vacs index)30 was developed in north america and europe, focuses on the hiv-infected and uses seven clinical or laboratory indices that assist with the long-term (viz. 6 years) prediction of survival (death) following the start of art. although the data reflect the experience of high-income countries and examine the risk of death in patients already on art, the database is large, the index has wide applicability and its predictive value is superior to individual and composite indices currently in use.31,32 most of the indices used in this system, with the exception of baseline hepatitis c virus (hcv) serology, are routinely performed in the public sector in sa. local hcv prevalence is low (viz. 3% – 5%) and the absence of this index in the calculation of the score is unlikely to influence the result (see appendix 6 for more details). choosing an assessment tool for south african patients according to merlin et al.,33 ‘[a]ny attempt at prognostication that does not address whether the patient has had an adequate trial of art would be ill-informed and inaccurate’. in the united states, an estimated life expectancy of ≤ 6 months is a sufficient reason to access hospice support,33 although no similar timeline has been formally adopted in sa. while the vacs index has definite merit, it was not intended to answer the question of eligibility to specialised hospice benefits, namely, home care and hospice admission. the spict tool has wide applicability but fails to take in the reversal of clinical disease on art. this committee recommends the use of the spict tool where art is unlikely to improve outcome, for example, end-stage cancer and irreversible end-organ failure, or where current or future art is judged by the medical and palliative care team to be futile. with regard to patients in sa’s private sector, provision of palliative care and hospice benefits is addressed in and supported by the south african medical schemes act 131 of 1998.34,35 at this time, it is recommended that medical schemes utilise the spict tool when considering the reward of hospice benefits and/or the ≤ 6 month estimated survival time as practised in the united states. however, the patient must be on art or switch to active art if treatment failure has been confirmed and where art remains a therapeutic option. every hiv-infected person should be given the opportunity to access art and enjoy its benefits. where a patient refuses to take art, yet requires hospice admission, addressing the patient’s immediate need is of primary importance and the question of starting art can be postponed. managing the hiv-sick: symptom control pain control (see box 2, table 2 following, and table 3-a6 in appendix 6). of all treatment modalities reviewed, the best evidence for pain reduction averages roughly 30% in about half of treated patients, and these pain reductions do not always occur with concurrent improvement in function. these results suggest that none of the most commonly prescribed treatment regimens are, by themselves, sufficient to eliminate pain and have a major effect on physical and emotional function in most patients with chronic pain. (turck et al.36, p. 2232) box 2: the pain assessment chart: key objectives.36 chronic pain, that is, pain lasting ≥ 3 months, is common in the hiv-infected population and is often the reason for a palliative care consultation.31 pain in hiv-infected south africans is likely to accompany an identifiable clinical cause and the most valuable contribution the hiv and palliative care physician can make to pain management is to identify the cause and treat it. the severity of the pain must be documented: ask the patient to describe the pain and to rate it on a scale of 0 = ‘no pain’ to 10 = ‘the worst pain i have ever experienced’. can the pain be fitted into a recognisable pattern, for example, peripheral neuropathy, post-herpetic neuralgia and meningeal irritation, or is it associated with a specific site or organ, for example, perianal ulcers and bedsores, pulmonary or pleural disease, a tumour such as kaposi’s sarcoma or a collection of enlarged lymph nodes? while the clinical examination will provide some answers, a pain assessment chart will ensure that no aspect of the pain is omitted (see box 3). box 3: thomas browne, the religio medici.75 the control of pain is a priority and must be addressed as soon as the patient arrives at a clinic or the admission ward. tests to confirm the diagnosis are important but must not be allowed to delay the treatment of the pain, which works best when given by an interdisciplinary team.36 ideally, the team should offer, in addition to good medical and nursing care, most or all of the following: physical rehabilitation exercise therapy cognitive restructuring that emphasises self-management, self-efficacy and resourcefulness, that is, activity rather than passivity, reactivity, dependency and hopelessness behavioural treatment, for example, relaxation and/or engagement in activities that enhance functionality vocational rehabilitation if long-term survival is not in doubt drug management – in particular, the avoidance or reduction of opioid dependency. nota bene evidence-based support for opioids as improvers of chronic pain and functionality is weak; therefore, their use must be measured against their risks, for example, addiction, hypogonadism, falls and fractures, depression, overdose and death.36 it is common to treat pain in a stepwise manner, starting with non-opioid medication such as paracetamol (acetaminophen), aspirin and the non-steroidal anti-inflammatory drugs (nsaids) and ending with the opioids or combinations of opioids and non-opioids37,38 (table 2). the 2017 chronic pain guideline of the hiv medicine association of the infectious diseases society of america (idsa) provides an evidence-based evaluation of pain and its management in the hiv-infected people.39 in this assessment, only the following aspects of pain care received unanimous – ‘strong quality, high level’ – support: any ‘new pain’ in a patient with previously controlled pain needs fresh re-assessment. acetaminophen and nsaids are the first-line agents for the treatment of musculoskeletal pain in persons living with hiv. topical capsaicin is indicated for chronic hiv-associated peripheral neuropathy in conjunction with additional analgesics and supportive therapies and adequate viral control. screen all with chronic pain syndromes for depression, that is, direct questioning, via a depression questionnaire and/or through a psychiatric referral. additional remarks that scored well (viz. for their strong quality of evidence) but did not secure unanimous support from reviewers included: the re-evaluation of pain among those with a ‘changing experience of pain’. the ‘immediate or early’commencement of art in those with a sensory polyneuropathy believed to be caused by hiv infection. gabapentin, with dose escalation up to a maximum of 2400 mg daily po in divided doses, is recommended as the first-line oral treatment of chronic hiv-associated neuropathic pain (the authors note that somnolence occurs in 80% and can be problematic). the serotonin-noradrenaline reuptake inhibitors, tricyclic antidepressants and pregabalin received only weak or moderate support. despite the absence of rcts in hiv-related pain syndromes, alpha-lipoic acid (ala) received support for neuropathic pain treatment in view of its confirmed role in diabetic neuropathy, a condition that also targets the peripheral nerves. opioid analgesics are not indicated for first-line control of neuropathic pain or chronic pain syndromes. tramadol, a combination opioid, that is, a serotonin + noradrenaline reuptake inhibitor + a µ-opioid agonist, received support, however, for use in several non-cancer pain syndromes, including osteoarthritis, fibromyalgia and the neuropathic pain syndromes.36 opioid therapy opioid therapy is often the treatment of choice for patients with cancer and those having moderate to severe pain.38,39 although the who analgesic ladder recommends different opioids for different levels of pain, for example, codeine for moderate pain and morphine for severe pain, cautious dose escalation using the initial opioid may avoid an unnecessary switch.38,40 morphine can be given by several routes and subcutaneous, intramuscular and intravenous injection should be considered for those unable to swallow. fentanyl is given by injection and transdermal skin patch but is not widely available to public sector patients in sa. unwelcome respiratory complications can be avoided with careful monitoring of opioid dose increases, which is particularly important where patients and families have expressed a desire for a pain-free yet lucid end to life. drug–drug interactions are important to note. many drugs used in pain control, for example, opioids, benzodiazepines, antidepressants and sedatives, are substrates of the cytochrome p450 (cyp450) family of enzymes. strong inducers or inhibitors of cyp450 will reduce (inducers) or potentiate (inhibitors) serum levels (efficacy and toxicity) of these drugs. several antiretrovirals (arvs) – especially the non-nucleoside reverse transcriptase inhibitors (nnrtis – usually inducers), protease inhibitors (pis – inhibitors) and drugs commonly used in the management of the hiv-sick, for example, rifampicin (inducer) for tb, carbamazepine and phenytoin sodium (inducers) for seizures, will influence the activity of substrates of this enzyme pathway (see appendix 6, table 2-a6 and table 3-a6). the non-medical use of prescription opioids, which has become a major public health issue in the united states and europe,41 should not be withheld from people in need in lowand middle-income countries (lmics), for example, africa and asia. the authors of a recent lancet commission on palliative care and pain relief provide data to show that this happens: the fact that access to such an inexpensive, essential and effective intervention – opioid use for pain relief – is denied to most patients in lmics and in particular to poor people – including many poor or otherwise vulnerable people in high-income countries – is a medical, public health and moral failing and a travesty of justice.42 (p. 1391) the commission notes that the 10 health conditions that result in the largest numbers of patients seeking palliative care in lmics, namely, malignancy, cerebrovascular disease, lung disease, injuries, tb, premature birth, hiv, liver disease, non-ischaemic heart disease and dementia, also account for about 95% of days of serious health-related suffering reported in these countries. fatigue, weakness, anorexia and wasting (see table 3-a4, appendix 4) increased resting energy expenditure (ree) is a persistent accompaniment of hiv infection despite the use of art.43 in situations of inadequate food intake and altered food metabolism, weight loss may become severe. with every 1% increase in unintentional weight loss from the baseline measurement, there is a detectable increase in the risk of death of the hiv-infected patient.44 the lower the bmi, that is, below the normal value (bmi 18 kg/m2 – 20 kg/m2), the greater the risk.45 possible clinical conditions include: disease of the mouth and upper gastrointestinal tract (git), for example, oesophageal candidiasis and cytomegalovirus (cmv) infection and ulceration. anorexia. consider medication, tumour and occult infection, for example, tb (drug-resistant tb) or mac. drugs: chemotherapy, lopinavir/ritonavir. food insecurity. particularly among refugees, migrants and the poor. malabsorption, for example, chronic diarrhoea, git-tb or mac, tumour of the git. send repeated stool samples (× 3) for parasites: cryptosporidia, cystoisospora spp. poorly controlled hiv infection = hiv enteropathy. infection, particularly end-stage hiv, tb, mac and ccm. disseminated tumour. hormonal deficiencies, for example, addison’s disease, hypothyroidism and hypogonadism. (bold indicates conditions that are frequent among the hiv-infected patients.) management: the hiv clinician will look for treatable causes but as the patient approaches death, symptomatic treatment will take priority. start art if the patient is treatment naive or check for resistance if on art and the vl is detectable. glucocorticoids, for example, dexamethasone 2 mg daily po or iv–4 mg daily po or iv, can be considered at the end of life as the risk of additional immunosuppression is unlikely to influence the outcome. steroids are often given to stimulate the appetite and/or to counter the fatigue and weakness of the final illness. vigilance is indicated if steroids are given for a prolonged period of time and patients should be monitored for hypertension, hyperglycaemia, gastrointestinal bleeds, fluid retention, proximal myopathy, confusion and psychosis. testosterone has benefited hypogonadal individuals with fatigue46 and the stimulants, modafinil and armodafinil, have had success in reducing fatigue in small rcts, but caution is advised in view of limited data and the risk of drug abuse.31 invasive procedures, such as nasogastric feeding and percutaneous endoscopic gastrostomy, are discouraged at the end of life but may be considered where a reversible condition has been identified. ensure good nursing, keep the oral mucosa clean, moist and wet and mobilise the indigent patient where possible. avoid bedsores and treat oral thrush with topical nystatin drops 2 ml – 5 ml ‘swish and swallow’ five times a day or oral fluconazole 50 mg – 100 mg daily until the infection clears. if oesophageal candida is diagnosed, give oral fluconazole 100 mg – 200 mg daily for 7–10 days. a short course of iv amphotericin b can be considered if the patient is unable to swallow the fluconazole. treat oral and oesophageal herpes simplex aggressively, prescribe oral acyclovir (public sector) or valaciclovir (private) if the infection is mild and confined to the mouth and iv acyclovir for disease that is extensive, virulent or involves the oesophagus. continue treatment until the infection has cleared, usually for 7–10 days, and control the pain that often requires strong analgesia, for example, codeine or tramadol. food should be liquidised or very soft to minimise oral pain while the infection is acute. dyspnoea and cough (see table 3-a4, appendix 4) the anatomic connections that control the cough reflex link the upper and lower airways to afferent and efferent neural connections within the brain.46 disease at any of these sites may be responsible for cough; however, in hiv-infected patients, cough usually directs attention to the lung. an acute cough lasts from a few days to a few weeks and a chronic cough lasts for ≥ 8 weeks.47 symptoms of dyspnoea and cough include the following: bacterial pneumonia: productive cough, fever, chest pain, sudden onset and acute history. aspiration pneumonia is frequent at the end of life. pulmonary tb (ptb): productive cough, haemoptysis, chest pain, fever, night sweats, weight loss, chronic history or past history of tb, and tb contact history. pjp: a dry incidental chronic cough, worsening dyspnoea with effort, later dyspnoea at rest, severe hypoxia at rest, worsens with exertion, little or no fever, minimal chest pain, profound fatigue and exhaustion, tachycardia and unrelenting tachypnoea. often a bedside diagnosis! pjp: poor prognosis. the persistence of hypoxia or respiratory failure, tachypnoea and tachycardia despite treatment, no decrease in baseline ldh level with treatment, worsening of the chest x-ray (cxr) on treatment, elevated acute physiology and chronic health evaluation (apache) ii score.48,49 pjp: prevention. initiation onto art soon after the initial infection with hiv and prophylactic use of trimethoprim-sulfamethoxazole with all baseline cd4 cell counts < 350 cells/mm3 are recommended.50,51 pjp: ethics. the decision to admit to the intensive care unit (icu) and to ventilate usually rests with the icu clinician or resident pulmonologist; however, this action may be futile, that is, it does not guarantee success or survival. the palliative care team must make itself familiar with this scenario in order to provide wise support (insight and understanding) to patients and colleagues and, where possible the death of a patient in the icu and on a ventilator should be avoided. this is a source of great suffering for patients and their loved ones, although it is best managed through discussion with the patient, family and friends before the urgent need of icu admission and ventilation arises. causes of dyspnoea and cough include the following:47 acute infection: trachea-bronchitis, pneumonia (viral and bacterial). chronic infection: bronchiectasis, chronic lung infection (bacterial, e.g., tb, mac, lung abscess), fungi (pjp, cryptococci, histoplasmosis), protozoa (toxoplasmosis) and rarely helminths. airway diseases: asthma, chronic bronchitis, postnasal drip. diseases of the parenchyma and vessels of the lung: chronic interstitial lung disease, emphysema, sarcoidosis, pulmonary vascular disease, namely, embolic, vasculitis, pulmonary hypertension. tumour: primary and secondary tumours of the lung and chest cavity. cardiovascular disease: left ventricular failure, right-sided endocarditis. anaemia: severe dyspnoea, hb < 8 g/dl. git: acid reflux, aspiration pneumonia (cough often at night). metabolic acidosis: diabetic ketoacidosis, lactic acidosis (nrtis: zidovudine, stavudine), renal tubular acidosis (tenofovir disoproxil fumarate): tachypnoea and dyspnoea but with normal oxygenation (p02), chest auscultation normal, cxr clear. drugs: angiotensin-converting enzyme (ace) inhibitors (cough). (note: bold indicates conditions that are frequent among the hiv-infected patients.) management: many of the conditions that present with cough and dyspnoea in the hiv-infected patient are treatable. however, some conditions, such as non-responsive pjp or end-stage (destroyed) lung disease whether from previous tb or from copd, may not be reversible and will require palliation. blood gas measurements, blood transfusion, intubation and ventilation are likely to be inappropriate when death is imminent. supportive care such as oxygen, bronchodilators, steroids and antimicrobials may be prescribed if indicated and diuretics may be needed to treat pulmonary oedema and fluid overload. opioids are regarded as the treatment of choice for dyspnoea in the context of end-of-life care. these can be given safely, that is, without the risk of respiratory depression, if titrated carefully with attention to dose and response.38 in addition, the careful use of benzodiazepines may relieve anxiety associated with breathlessness and asphyxiation.38 specific end-of-life therapies include the following: morphine: 5 mg po– 10 mg po every 30 min as needed until the patient is comfortable, or iv 2 mg – 4 mg every 30 min to 1 h as needed until the patient is comfortable. oxygen: adjust to achieve satisfactory saturation and subjective relief of dyspnoea. non-pharmacologic measures: support, relaxation and breathing exercises, et cetera. dry mouth causes of dry mouth include: poor oral immunity: often a sign of advanced hiv and aids with or without hiv-associated dementia (had); poorly controlled diabetes mellitus, gingivitis infection: chronic parotitis, salivary duct obstruction (stones, tumour), extensive oral candidiasis autoimmune: sjögrens syndrome drugs: anticholinergics, alphaand beta-blockers, diuretics, calcium channel blockers post-irradiation, for example, cancer of the head and neck. (note: bold indicates conditions that are frequent among the hiv-infected patients.) management: address the cause, clean the mouth regularly, maintain hydration – oral fluids if able to swallow, chewing gum and mildly acidic sweets (lemon drops), stop offending drugs (above), artificial saliva. nausea and vomiting (n&v) nausea is defined as the subjective feeling associated with the action of vomiting. identify and treat the cause, including the common associations mentioned below: abdominal conditions: gastroenteritis, intestinal diseases (inflammatory, obstructive) general causes: middle ear and cns disease, for example, meningitis and raised intracranial pressure (ricp); anxiety and fear; cardiac, for example, acute myocardial infarction; endocrine, for example, pregnancy, diabetic ketoacidosis; pancreatitis; end-organ failure, for example, renal (uraemia), liver disease, adrenal failure (addison’s disease) drugs: arvs (e.g. zidovudine, lopinavir/ritonavir); antimicrobials (e.g. macrolides, beta-lactams, tb drugs); chemotherapy (oncology); digoxin; opioids; alcohol-intoxication, et cetera. (note: bold indicates conditions that are frequent among the hiv-infected patients.) management: address the cause. inner-ear or motion sickness requires antihistamines, for example, dimenhydrinate, cyclizine; if drug-related – antidopaminergic, for example, prochlorperazine; if chemotherapy-related – 5-ht3 antagonist, for example, ondansetron, granisetron; if intestinal and gastro-related – 5-th4 agonist, for example, cisapride, metoclopramide and somatostatin analogues, for example, octreotide. chemotherapy-induced n&v may result in ‘anticipatory’ n&v viz. cns-arousal and anxiety, and may require treatment with a benzodiazepine (e.g. lorazepam), glucocorticoids (e.g. methylprednisone), dexamethasone or with cannabinoids (e.g. tetrahydrocannabinol) (see section 7). suggested end-of-life treatment: bowel obstruction: octreotide 100–200 µg subcutaneous injection 3 times a day or 100–600 µg per day in an iv infusion. should a nasogastric tube (ngt) be placed? where the likelihood is that this will provide little or no improvement and where the expectation is that death is within hours or a few days, it is more humane to withhold ngt and maximise alternative forms of symptomatic relief. dexamethasone 4 mg po/iv–8 mg po/iv daily: maximum 16 mg daily. gastroparesis: metoclopramide 10 mg po/iv–20 mg po/iv every 4–6 h: maximum 100 mg per day. elevated intracranial pressure: dexamethasone 4 mg po/iv–8 mg po/iv daily: maximum 16 mg daily. unspecified cause but including chemotherapy: metoclopramide 10 mg po/iv–20 mg po/iv every 4–6 h: maximum 100 mg per day. haloperidol oral: 1.5 mg–5 mg 2–3x per day iv: 0.5 mg–2 mg every 8 h. ondansetron 8 mg po 8 h as needed. dexamethasone 4 mg po/iv–8 mg po/iv daily: maximum 16 mg daily. usually combined with other anti-emetics.52,53 constipation this is defined as infrequent emptying of bowel or rectum often with a sensation of incomplete evacuation. it is seldom secondary to a significant medical problem. acute or recent onset: local problem (viz. tumour, stricture, trauma or analgesics including opioids, inactivity, not eating). chronic: irritable bowel syndrome; hypothyroidism; hypercalcaemia; pregnancy; chronic cns disorders (e.g. parkinson’s disease, paraplegia et cetera); drugs (e.g. antidepressants, calcium channel blockers, analgesics, including opioids). (note: bold indicates conditions that are frequent among the hiv-infected patients.) management: treat the cause. where feasible, encourage the patient to mobilise and take in more fluids and increase dietary fibre (bran) including vegetables and fruit. the following medicines can be tried: lactulose, psyllium, bisacodyl and fleet enemas. management must be expectant and preventive. suggested end-of-life care: senna 2–4 tabs (8.6 mg sennosides per tab) or 1–2 tabs as a single daily dose or in two divided doses per day. do not exceed 100 mg per day. bisacodyl suppository: 10 mg given rectally per day as needed. fever fever in someone with hiv infection usually suggests an infectious complication. the constellation of fever, cough, weight loss and night sweats in an hiv-infected person in africa indicates a heightened suspicion of tuberculosis. however, tb must be confirmed as it is a treatable, transmissible disease and its presence puts others at risk. even at the end of life, tb must be diagnosed, treated and controlled and it is particularly important to check whether the disease is drug-resistant or not (gene xpert analysis gives information about rifampicin sensitivity or resistance). even in the context of palliative care, patient isolation and infection control measures must be implemented. if fever is part of an end-of-life infection, such as an aspiration pneumonia, the patient and his or her family may resist the idea of prolonging the inevitable with antibiotics and active interventions. the task of the palliative care team is to assist the patient to face the inevitability of death yet at the same time the team must agree to do all that it can to minimise suffering, that is, to support the patient. this is where the palliative care physician and team provide what is frequently missing from the wards of our south african hospitals as death should be about healing even when the latter is not delivered by way of pills, lines and procedures. management: treat the cause when a fever is indicated. paracetamol, aspirin, nsaids and sometimes steroids may assist in controlling it, while tepid sponging, a fan and oral fluids may help to alleviate the patient’s distress. avoid paracetamol in patients with liver disease. antimicrobial therapy that is not directed at a particular pathogen or a likely diagnosis is unlikely to be helpful at the end-of-life. prophylactic trimethoprim sulfamethoxazole is recommended if the baseline cd4 count is < 350 c/mm3 and/or an aids-defining illness (or who stages 3 and 4 disease) is present.50 suggested end-of-life care: paracetamol/acetaminophen650 mg po/pr–100 mg po/pr or iv every 4–6 h as needed: maximum daily dose = 4 g. naproxen 250 mg po bid–500 mg po bid (short course × 2–3 days. can be repeated). confusion and other neurological disease in people living with hiv. human immunodeficiency virus infects the human brain. this occurs during the first few weeks following acquisition of the virus and establishes a chronic but usually low-grade infection which persists for the remainder of the individual’s life. neurological consequences are frequent but generally mild or asymptomatic and usually well controlled with art. if the patient is naïve to art or if the virus in the cns has become resistant to art, the function of the brain will be impaired for example, hiv encephalopathy. the latter is a life-threatening and dementing process characterised by motor-slowing, abnormal movement (basal ganglia involvement) and progressive cognitive decline. human immunodeficiency virus also attacks the peripheral nervous system (pns) and is responsible for a painful symmetric sensory polyneuropathy that leaves the individual wheelchair and bedbound and in constant pain. these conditions will usually respond to viral suppression with arvs tailored to treat the cns infection. treatment with arvs is warranted even in the context of palliation. several of the following conditions need to be considered in the hiv-infected patient with serious neurological disease,54 as detailed in table 4. table 4: the association of certain cancers with hiv-1 infection in south africa, 1995–2004.63 management: treat the cause where identified. is the patient on art (efavirenz)? tb drugs (isoniazid)? is the hiv infection controlled in the serum and in the csf? suggested end-of-life care: lorazepam for anxiety: 0.25 mg po or iv–2 mg po or iv or s/c every 4–6 h as needed. increase the dose to 5 mg if necessary. haloperidol for delirium: 0.5 mg po or iv–1 mg po or iv every hour as needed. when symptoms have settled, give the daily total dose in 3–4 divided doses through the day. hiv, cancer and palliative care in southern africa cancer case fatality rates are higher in low-income regions such as africa (75%) than in high-income regions for example, europe and north america (46%).60 on the back of this, the growing numbers of hiv-infected persons with cancer, a so-called ‘hidden cancer epidemic’ in lmics, is of concern.61,62 more than a decade ago, south african researchers recorded the prevalence of several cancers among hiv-infected south africans63 (see table 5). odds ratios confirmed a substantial increase in risk among the hiv-infected patients, particularly for the traditional aids-defining tumours, and in africa these cancers still predominate: kaposi’s sarcoma, non-hodgkin’s lymphoma, cervical carcinoma and cns lymphoma. the incidence of non-aids-defining cancers, however, in the region (e.g. hodgkin’s disease, solid tumours of the lung, git and breast, et cetera) is rising despite the use of art. the latter is a global trend and affects plwhiv 10–15 years earlier than their peers with similar tumours.64,65 table 5: recommendations for cannabinoid use in symptom management of hiv/palliative care.72 establishing early linkage to care, particularly to palliative and hiv care, is essential if the goal of improved survival and the relief of suffering is to be reached. however, several hurdles must be overcome: late presentation. stigma, misunderstanding and denialism continue as barriers to early detection of hiv and cancer. patients present at an advanced hiv stage, naïve to art, with a low baseline cd4 level and multiple competing diagnoses. delays in receiving cancer treatment. large number of patients, few or inadequately skilled staff, insufficient specialists and unsupportive management cause delay in treatment. in many instances, patients die before test results return and before a link with oncology and radiotherapy is made. thirty african and asian countries have no radiotherapy machines and in many lmics, oncologists, if present, are restricted to the largest cities.66 laboratory support. obtaining reports, for example, biopsy (histology) results, in the public sector in sa is plagued by long delays, while histology reports in the private sector return within a couple of days, and oncology referrals in the public sector cannot be processed without the confirmatory histology. in the absence of histological confirmation, patients die while awaiting their test results or while awaiting their oncology appointment. hiv and cancer therapy. chemotherapy in africa and sa’s public sector is frequently characterised by the ongoing use of drugs that are no longer viewed as optimal in developed regions.67 problems include post-chemotherapy neutropenia, hiv immunosuppression, antimicrobial resistance, frequent drug stock-outs and drug–drug interactions between cytochrome p450 substrates, inducers and inhibitors, and arvs. how can the hiv-infected cancer patient be better served? prevention tobacco use control hepatitis b vaccination hepatitis c serology and access to directly acting antivirals (daas) human papillomavirus (hpv) vaccination cervical and anal pap smears the early introduction of art. uncontrolled plasma (hiv) viral load is associated with the increased risk of malignancy in the hiv-infected cancer patients.68,69 baseline determination of hiv status of every cancer patient. survival of the hiv and cancer patient requires access to art and long-term suppression of hiv.70,71 linkage to care. the ethos of this care is holistic, that is, oncology, hiv-caregivers and the palliative care team work together in the support of the patient. collaboration is needed between oncology and radiotherapy and the disciplines of hiv/infectious diseases and palliative care. cancer care in sa must be sensitive to the needs of the hiv-infected people, and greater collaboration between hiv, palliative care physicians and oncology and radiotherapy specialists must take place if weak links in healthcare delivery are to be strengthened. antiretroviral drugs and regimens are constantly changing, drug–drug interactions and toxicities are common, and secondary infection with opportunistic microbes frequently occurs. a team approach is required to improve the survival outcome in this group of patients. the cannabinoid drugs in the palliative management of hiv-infected patients. south african courts have recently legalised cannabis for medical use. data on hiv-infected people are sparse and restricted to observational reports, and although the use of these compounds is widespread both in africa and globally, the hostility to its use is slowly changing. nonetheless, data are beginning to emerge (see table 5).72 an observational study in > 3000 cancer patients found that cannabis improved sleep, anxiety and depression levels and reduced the fatigue, nausea and vomiting caused by chemotherapy.73 a report of 198 hiv-infected ‘heavy’ cannabis users found reduced activation of inflammatory markers compared with non-cannabis using controls; however, there is clearly a need to better clarify the role of the cannabinoids in evidence-based, well-planned rcts of the hiv-infected and uninfected people.74 the 2016 johns hopkins-lancet commission on drug policy and health makes the additional point: ‘at a time of policy-level concern about dependence on prescription opioids, a few ecological studies suggest that greater access to cannabis could reduce use of opioids for pain relief’.75 cannabinoid side effects are common, usually dose-dependent, that is, higher doses tend to produce more side effects, and are often specific to individual compounds (see table 3). these side effects include cardiac (tachycardia, hypoand hypertension), cns (arousal and depression states, for example cognitive impairment, euphoria, psychosis and paranoia), and gastrointestinal toxicity such as diarrhea, vomiting and abnormal liver enzymes, with higher doses (see table 6).72 with regard to the role of cannabinoids in the palliative care of hiv-infected patients, several ‘unknowns’ remain, for example72: indications for use of cannabinoids require urgent clarification. the pharmacokinetics and pharmacodynamics of cannabinoids in people naïve to and those with prior exposure (to cannabinoids) in the context of palliative care. does this differ? do cannabinoid-exposed people require a higher dosing of cannabis? drug–drug interactions between the cannabinoids, art and tb drugs have minimal or no data. which route of administration should be recommended: oral, inhaled (smoked)? final remarks it was the general belief in the 1980s that a vaccine and cure would have been found by the end of that decade or at the latest, that is, the middle of the 1990s. that did not occur, and the hiv epidemic is now firmly rooted in southern african soil. antiretroviral therapy has transformed the infection into a chronic, manageable disorder yet the condition remains incurable. about 8 million hiv-infected south africans need care and will die from or with the virus. their suffering is the concern of these guidelines as many will require palliative care (see box 3). the ‘total pain’ that accompanies suffering arises from multiple causes. analgesics alone do not effectively control this pain although palliative care teams throughout the country’s health service would go a long way to answer this need. even highly motivated teams require funding, organisation and the support of colleagues and government in a country where its public health is in trouble: underfunded, overcrowded, ageing facilities in need of renewal and a department facing extraordinarily high levels of litigation.77,78 developing a discipline of palliative care and fitting it into this failing system at this time will be a testing experience, but it must happen. somehow.75 the private sector must find a reliable tool that funders can use when providing capital for home nursing and hospice admission. a life expectancy of 6 months or less is a widely used rule of thumb in the united states, although available models are generally insensitive to the gains of art and the treatment of opportunistic disease. no local rcts answer this question; nonetheless, our recommendation has been to follow the us approach and use the 6-month probability of survival or the spicttm tool. the defining treatment ethos of hiv and id clinicians is curative. there is no conflict between curative and symptomatic management provided the goal to treat suffering is central to care. is there a time where curative care is no longer appropriate? is there a time to let go of art? yes. those of us who are hospital-based clinicians encounter these questions daily in our wards and clinics. the answers are not usually found in textbooks but at the patient’s bedside. acknowledgements competing interests the authors have declared that no competing interests exist. authors’ contributions d.c.s. conceived the format and wrote the guidelines. r.k., t.r., m.-y.s.m., s.b., a.m. and e.m. provided specialist material. r.k. and t.r. reviewed individual sections as the guideline developed. all authors participated in the initial guideline committee meeting and comments on the final manuscript prior to submission. ethical consideration this article followed all ethical standards for a research without direct contact with human or animal subjects. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability statement data sharing in not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this guideline are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references south african department of health. national policy framework and strategy on palliative care, 2017–2022. final draft. pretoria, gauteng: south african department of health; 2017. who definition of palliative care. world health organization (who). palliative care factsheet. no date. 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negligence claims [homepage on the internet]. the medical brief. africa’s medical media digest. 2015 [2015 jun 13]. available from: https://www.medicalbrief.co.za/archives/mpumalanga-eastern-cape-face-r10-9bn-medical-negligence-claims. shaner dm. suspending ethical medical practice. n engl j med. 2010;363:1988. appendix 1: palliative care model: no care characteristics of this model include: acute hospitalisation even when seriously ill, palliative care and support are generally not offered in public or private hospitals in south africa. primary attention is directed to acute and curative care. care is seldom a team work; each caregiver works independently and very few have had formal training in palliative care. the public health system’s masterplan is usually focused on early discharge and the emptying of beds in preparation for the next intake of acutely ill patients. patients are seldom, if ever, asked about their end-of-life thoughts or wishes. families rarely participate in the provision of the patient’s care. the day-to-day care provided in many of sa’s public hospitals is given by junior doctors, for example, community service doctors, interns, medical officers, registrars, et cetera, particularly in district and rural hospitals. supervision is not uniform and senior consultants in public hospitals are seldom in the wards every day and less often in the evenings and at night. the hiv patient patient characteristics. many patients are newly diagnosed or previously diagnosed and started on art but had been lost to follow-up. the presentation is diverse: comorbid conditions (e.g. diabetes, renal failure, hepatitis b, et cetera), aids-defining and non-aidsdefining diseases (e.g. community acquired pneumonia [cap], pneumocystis pneumonia [pjp], et cetera), anaemia, low platelets, gastroenteritis, art-associated toxicity and treatment failure (viral resistance), et cetera. occasionally the primary presentation is with a condition not immediately associated with hiv, for example, trauma, malaria, skin rash, et cetera. often patients are very ill and the mortality rate is substantial. tuberculosis (tb) is frequent, needs to be excluded in all and is the major cause of death. care requires attention to symptomatic control (palliation), curative therapy and the prevention of transmission. poverty and limited social resources with adherence problems. non-disclosure to family members is frequent, stigma dictates behaviour and non-disclosure results in non-adherence which leads to treatment failure. neurocognitive dysfunction is common and may contribute to non-adherence (forgetfulness) and unreliable clinic attendance of some. the care of the hiv-infected needs to be broad-based to ensure that social, psychological and practical needs are met. the hiv-sick. many patients present with more than one major diagnosis, for example, tb and bacterial pneumonia, pjp and renal failure, kaposis’s sarcoma (ks) and bacteraemia et cetera, and multiple concurrent diagnoses increase mortality. antiretrovirals are toxic and drug–drug interactions are frequent and occasionally life-threatening, for example, drug-induced liver injury (dili), stevens–johnson syndrome (sjs) and erythema multiforme (em). laboratory indices baseline hiv diagnostic tests (hiv antibody tests) are still not performed on all who are admitted to south african private and public hospitals. hiv-directed care, for example, arvs, cannot be given without this baseline information. only art can control hiv infection. cd4 counts are often low in this group of patients, for example, < 200 cells/mm3, and patients are vulnerable to a variety of opportunistic diseases. viral load. the south african national art guidelines discourage checking a patient’s viral load (vl) at the time of the baseline assessment, but recommend that the vl is checked 6 months after starting art and annually thereafter. elevated vl means adverse survival if on art. persistently high vl indicates increased risk of cancer in the hiv-infected people. markers of mortality: anaemia (hb < 8 g/dl), cd4 < 200 cells/mm3, vl (especially > 100 000 copies/ml), end-organ failure (renal, liver), a low bmi (< 18 kg/m2). delay in laboratory turn-around times. histology results appear particularly resistant to short turn-around times yet the care of the hiv-cancer patient depends on tissue confirmation. patients without timely results do not get chemotherapy, do not start art early enough and do not survive. radiology access to ultrasound, echocardiography, computed tomography (ct) and magnetic resonance imaging (mri) scans, et cetera, in the government sector and especially in rural and secondary level hospitals is poor and delays in obtaining these tests are widespread, even in larger public hospitals. transfer to referral centres is difficult to expedite: transport is not always readily available and permission is needed, as is the willingness of the referral hospital to accept the patient. medical team the care of the hiv-well is explained in guidelines. the care of the hiv-sick requires practical training and the acquisition of bedside skill, as good palliative care will require a good knowledge of the care of the hiv-sick. junior doctors, for example, community service doctors, interns and registrars, carry a major responsibility in the day-to-day provision of patient care in sa’s public hospitals. additional training will be needed to equip junior staff on how to triage between the curative and palliative disciplines of care and the combinations of both. dying in a south african public hospital impending death is often accompanied by feelings of terror, loneliness, pain and abandonment. these feelings are likely to add to the suffering of patients in busy hospitals characterised by shortages of beds, staff and medicines. family often absent at the time of death. the ‘end-of-life’ discussion occurs rarely, if at all, and the family often feels left-out and aggrieved, and regret occurs as seldom the gathering together of loose ends takes place during the contented arrival of life’s end. bereavement counselling usually not given to the patient or family before or after death. questions of the bereaved are often left unaddressed and anger and disappointment are seldom addressed. litigation is an option for the disgruntled family. appendix 2: indicators of increased mortality of hiv-infected patients demographic indicators of an increased risk of death: age ≥ 45–50 years old. risk increases with age and includes risk from comorbid disease. male gender is frequently associated with increased risk but confounded by late entry into care, poor retention in care, lower baseline cd4 cell counts and older age at entry than female gender. clinical indicators of an increased risk of death: unintended weight loss of > 10% of normal body weight, and/or bmi ≤ 18 kg/m2. aids-defining clinical conditions yet the risk is not the same for all events. tuberculosis, cryptococcal meningitis (cm) and malignancy in africa carry a higher risk than other aids-defining conditions. aids and non-aids-defining cancers in the hiv-infected people. comorbid disease and end-organ failure: renal, liver, cardiac and respiratory. confirmed arv-resistance, particularly high-level resistance to all major classes of arv. hospital re-admission rates and grip strength. thirty-day hospital re-admission rates in hiv-positive adults are associated with other markers of poor outcome, namely low cd4 counts, aids-defining illnesses, non-aids-defining infections and unreliable utilisation of medication. laboratory indicators of an increased risk of death: cd4 count: cd4 ≤ 200c/mm3 or lower. the lower the level (e.g. < 50 c/mm2), the greater the risk. anaemia: particularly if severe (viz. hb < 8 g/dl). hiv viral load: high levels (viz. > 100 000 copies/ml) prior to art and detectable levels while on art. the higher the level, the greater the risk, for example, malignancy. combination indicators of an increased risk of death: the veterans aging cohort study (vacs) index. this scoring system developed in the usa incorporates seven clinical or laboratory indices that, taken together, predict death in hiv-infected persons. several observational reports indicate that this index has superior predictive value to both single and composite indices currently in use. the role of hepatitis c virus positivity in the vacs scoring system is numerically small and unlikely to negatively influence its utility in southern africa where the prevalence of hcv is low, that is, 3% – 5%. appendix 3: the karnofsky score the karnofsky score28 was developed in 1948, enabling physicians to evaluate a patient’s ability to survive cancer chemotherapy. it is still in general use; however, its insensitivity and non-specificity with regard to hiv-infected patients limit its use in deciding on access to hospice-related care. 100 – normal; no complaints; no evidence of disease 90 – able to carry on normal activity; minor signs or symptoms of disease 80 – normal activity with effort; some signs or symptoms of disease 70 – cares for self; unable to carry out normal activity or to do active work 60 – requires occasional assistance, but is able to care for most of their personal needs 50 – requires considerable assistance and frequent medical care 40 – disabled; requires special care and assistance 30 – severely disabled; hospital admission is indicated although death not imminent 20 – very sick; hospital admission is necessary; active supportive treatment is necessary 10 – moribund; fatal processes progressing rapidly 0 – dead. source: karnofsky da, abelmann wh, craver lf, burchenal jh. the use of the nitrogen mustards in the palliative treatment of carcinoma – with particular reference to bronchogenic carcinoma. cancer. 1948;1(4):634–656. https://doi.org/10.1002/1097-0142 appendix 4: the support and palliative care indicator tools (spicttm) the spicttm is a guide for identifying people at risk of deteriorating health and imminent death.29 this group of patients must be assessed for unmet supportive and palliative care needs. 1. look for two or more general indicators of deteriorating health: performance status is poor or worsening, that is, the person is in bed or in a chair for ≥ 50% of the day; reversibility is judged as limited dependent on others for most care needs; dependency is because of physical and/or mental health problems two or more unplanned hospital admissions in the past 6 months significant weight loss (5% – 10%) over the past 3–6 months and/or a low bmi < 18 kg/m2 persistent, troublesome symptoms despite optimal treatment of underlying conditions patient asks for supportive and palliative care or for the withdrawal of treatment. 1. look for any clinical indicators of one or more advanced conditions: cancer: functional ability deteriorating because of progressive metastatic cancer too frail for oncology treatment or treatment is for symptom control only. dementia/frailty: unable to dress, walk or eat without help eating and drinking less; swallowing difficulties urinary and faecal incontinence no longer able to communicate using verbal language; minimal social interaction fractured femur; multiple falls recurrent febrile episodes or infections; aspiration pneumonia. neurological disease: progressive deterioration in physical and/or cognitive function despite optimal therapy speech problems with increasing difficulty communicating and/or progressive swallowing difficulties recurrent aspiration pneumonia; breathless or respiratory failure. heart and/or vascular disease: new york heart association (nyha) class iii/iv heart failure or extensive, untreatable coronary artery disease with: breathlessness or chest pain at rest or on minimal exertion severe, inoperable peripheral vascular disease. respiratory disease: severe chronic lung disease with: breathlessness at rest or on minimal exertion between exacerbations needs long-term oxygen therapy has needed ventilation for respiratory failure or in whom ventilation is contraindicated. kidney disease: stage 4 or 5 chronic kidney disease (viz. an egfr < 30 ml/min), with deteriorating health kidney failure complicating other life-limiting conditions or treatments discontinuation of dialysis. liver disease: advanced cirrhosis with one or more complications in the past year: diuretic-resistant ascites hepatic encephalopathy hepatorenal syndrome bacterial peritonitis recurrent variceal bleeds liver transplantation is contraindicated. what to do: review supportive and palliative care planning: review current treatment and medication so that the patient receives optimal care. consider referral for specialist assessment if symptoms or needs are complex and difficult to manage. agree to current and future care goals and a care plan with the patient and his or her family. plan ahead if the patient is at risk of loss of capacity. record, communicate and coordinate the care plan. source: the support and palliative care indicator tools (spicttm) [homepage on the internet]. university of edinburgh, spicttm; 2015.[cited 03 nov 2019] available from: http://www.spict.org.uk appendix 5: the established veterans aging cohort study index scoring scheme the vacs index utilises age, routine laboratory markers such as cd4 count, hiv-1 rna, haemoglobin, platelets, ast and alt, creatinine and markers of liver impairment (viz. fib-4 and hcv status). table 1-a5: a restricted vacs index. the risk of mortality of plwhiv on at least 12 months of art increases with a rising vacs score. (max. vacs score= 164).30 appendix 6: palliative care management: drugs used for symptom control in hiv palliation table 1-a6: palliative care management, drug–drug interactions. table 2-a6: palliative care seizure management, drug–drug interactions. table 3-a6: palliative care pain management, drug–drug interactions. s e p t e m b e r 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e effective prevention of mother-to-child transmission (pmtct) strategies are known to reduce the incidence of paediatric hiv infection.1 a small non-governmental project at mccord hospital in durban, kwazulu-natal, with access to highly active antiretroviral therapy (haart), reported vertical transmission of 2.9%. the authors of that paper also reported results of two studies in the public sector, in 2002 and 2006, respectively, where transmission rates of 8.7% and 20.8% were achieved with a pmtct drug regimen comprising single-dose nevirapine (sdnvp).2 these were in gauteng and kwazulu-natal respectively, while in the western cape in 2003 a rate of 8.8% was recorded for women given dual therapy of zidovudine (zdv) from 34 weeks and sdnvp.3 in the private sector, many patients belong to medical scheme-funded disease management programmes, such as aid for aids (afa). pmtct guidelines for developed countries, where hiv-infected newborns are becoming uncommon, are followed.1,4 the programme comprises prenatal hiv-1 counselling and testing, and haart (irrespective of cd4 count) from the second trimester onwards, unless the mother is already on antiretrovirals or fulfils the criteria for starting haart immediately. elective caesarean section, together with intrapartum intravenous zdv, is offered and zdv is given to the neonate. formula feeding is supplied for 6 months and breastfeeding is avoided. while many private practitioners follow afa guidelines, they may use different regimens, depending on cost considerations. the present study aimed to investigate the outcome of infants born to hiv-positive mothers managed in a group of private paediatric practices in central durban, kwazulu-natal. methods ethical approval for this retrospective chart review was obtained from the biomedical research ethics committee of the nelson r mandela school of medicine (reference number beo47/47). of the 20 paediatricians in the durban central region, 4 (20%) did not respond. all charts of hiv-exposed infants born between january 2004 and june 2005, from the 8 paediatricians who agreed to participate, were included. data were collected by means of previously piloted questionnaires. results one hundred and one charts were available, of which 50 came from a single practice (which is an hiv referral centre). the balance was contributed approximately equally by the remaining practitioners. one hundred and one infants (one set of twins) were delivered to 100 black african women, 93 by caesarean section. fifty infants were boys, 20 were low birth weight, 2 were large for gestational age and 79 were appropriate for gestational age. ninety-seven mothers were medical scheme beneficiaries (86 contracted to afa). the mean age was 30 (range 18 44) years and mean parity was 1 child (range 1 4). presentation and antenatal care initiation were in the first, second prevention of mother-to-child transmission outcomes in the private sector in central durban o r i g i n a l a r t i c l e shakira m cassim, mb chb, dch (sa) fcpaed (sa), mph, dip hiv man (sa) julia h botha, bpharm, phd department of therapeutics and medicines management, nelson r mandela school of medicine, durban the prevention of mother-to-child transmission (pmtct) programme in the central region of ethekweni metro, kwazulu-natal (durban central area), was investigated. data for all hiv-exposed infants from eight private paediatric practices seen between january 2004 and june 2005 were reviewed retrospectively. one hundred and one black african infants were born to 100 hiv-positive women of average age 30 years. median viral loads and cd4 counts were 11 391 copies/ml and 426 cells/μl, respectively. eighty-six women received haart and 5 had no prophylaxis. of the 92 infants tested, 2 were hiv positive, giving a transmission rate of 2.2%. both their mothers had received suboptimal prophylaxis, and if they are excluded, the transmission rate falls to less than 1%, a rate consistent with those in the developed world. 6 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s e p t e m b e r 2 0 1 0 and third trimesters for 40%, 34% and 26% of mothers, respectively. hiv infection had been diagnosed in the current pregnancy in the majority (75%) of cases, and the rest already knew their status. viral load and cd4 count measurements were recorded for 86 and 91 women, respectively. the median cd4 count was 426 (intraquartile range (iqr) 244 613) cells/μl. only 13% of the women had cd4 counts less than 200 cells/μl. the median viral load at first presentation was 3.97 (iqr 1.6 5.8) logs or 11 391 (iqr 2 013 41 502) copies/ml. eighty-six women (86.0%) received haart. this comprised zdv and lamivudine (3tc), either together with lopinavir/ritonavir (if the cd4 count was >250) or together with nvp if the cd4 count was <250. the regimen also included intrapartum intravenous zdv. nine women did not receive haart; 7 received only intrapartum intravenous zdv, 1 had only intrapartum nvp, and 1 had dual therapy with zdv/3tc. treatment was initiated at less than 28 weeks in 32 women and between 28 and 34 weeks in 41 women. five women received no prophylaxis because they presented for antenatal care very late in the third trimester. all infants were formula fed and received zdv for 6 weeks. haemoglobin (hb) measurements in 98 patients revealed 18 (4 preterm) with anaemia. seventy-nine infants received pcp prophylaxis. there were 18 preterm infants, half of whom were born to women with low cd4 counts who received nvp as part of their haart. five and 3 of the premature infants were born to mothers who had received protease inhibitors and no prophylaxis, respectively. one of the latter 3 seroconverted. eight infants defaulted follow-up and 1 died (of unknown cause) at 5 weeks before testing was possible. ninetytwo infants were tested, 61 of them by polymerase chain reaction (pcr) at 6 weeks. fifty-six were tested by enzyme-linked immunosorbent assay (elisa) at 18 months (some of whom had already had a first pcr). two infants were diagnosed positive, and their details are set out in table i. discussion although our transmission rate of 2.2% appears better than the 2.9% from the mccord experience, the proportions of women in that group with low cd4 counts and receiving haart were double and half, respectively. our rate was not as good as the situation that pertains in the usa and europe, where hiv-infected newborns are becoming uncommon, but is close to the 1 2% transmission expected for women from socioeconomically advantaged areas in africa who can safely formula feed.1 the mothers of both positive infants had suboptimal pmtct, and if these women are excluded the transmission rate falls to less than 1%. in fact, in those women who were fully compliant there was no transmission. one of the 2 mothers had been diagnosed 2 years before the pregnancy and presented for antenatal care but was not on medical aid and could not afford haart. it had been planned to initiate haart at 34 weeks, but she went into labour at 33 weeks. the other mother was diagnosed early in the current pregnancy but did not return for results, so haart was initiated only 5 days before delivery. non-adherence is a risk factor in perinatal transmission, but it is a problem with which even a developed country like the uk is grappling.5 our study has confirmed the success of an appropriate pmtct programme and the importance of prophylaxis and adhering to the protocol. references 1. coovadia hm. perspectives on paediatric hiv/aids: prevention of mother to child transmission of hiv. current science 2008; 95(9): 1133-1149. 2. geddes r, knight s, reid s, giddy j, esterhuizen t, roberts c. prevention of mother-to-child transmission of hiv programme: low vertical transmission in kwazulu-natal, south africa. s afr med j 2008; 98: 458-462. 3. draper b, abdullah f. a review of the prevention of mother-to-child transmission program of the western cape provincial government 2003-2004. s afr med j 2008; 98: 431-434. 4. regensberg l, makiwane m. afa clinical guidelines. 7th ed. pinelands: aid for aids; 2009. http://www.aidforaids.co.za/ex_medscheme_vs07/documents/ afa/guidelines_book_final.pdf (accessed 30 may 2009). 5. kingston ma, letham cj, mcquillan o. adherence to antiretroviral therapy in pregnancy. int j std aids 2007; 18(11): 787-789. 7 infant 1 infant 2 birth weight (kg) 2.2 3.0 gestational age 33 38 (wks) health at birth congenital well pneumonia, anaemia treatment zdv for 6 weeks zdv for 6 weeks mother 1 mother 2 age (yrs) 28 37 mode of delivery caesarean section caesarean section diagnosis of hiv 2 3 years earlier during current pregnancy art prophylaxis none haart initiated 5 days before delivery intrapartum iv zdv yes yes viral load at not recorded 50 000 delivery copies/ml cd4 count at delivery not recorded 327 cells/μl table i. details of the 2 hiv-positive infants abstract introduction research methods and design results discussion conclusion acknowledgements references about the author(s) kennedy otwombe perinatal hiv research unit, faculty of health sciences, university of the witwatersrand, johannesburg, south africa school of public health, faculty of health sciences, university of the witwatersrand, johannesburg, south africa maggie munsamy central chronic medicines dispensing and distribution (ccmdd) programme, national department of health, pretoria, south africa mukesh dheda pharmacovigilance programme for public health, national department of health, pretoria, south africa nishana ramdas central chronic medicines dispensing and distribution (ccmdd) programme, national department of health, pretoria, south africa corlee herbst central chronic medicines dispensing and distribution (ccmdd) programme, national department of health, pretoria, south africa merlin pillay central chronic medicines dispensing and distribution (ccmdd) programme, national department of health, pretoria, south africa tanya van tonder opinion solutions, johannesburg, south africa celicia serenata † ezintsha, faculty of health sciences, university of the witwatersrand, johannesburg, south africa samanta lalla-edward ezintsha, faculty of health sciences, university of the witwatersrand, johannesburg, south africa citation otwombe k, munsamy m, dheda m, et al. tracking adverse drug reactions and medication errors in the central chronic medicine dispensing and distribution (ccmdd) programme in south africa. s afr j hiv med. 2022;23(1), a1366. https://doi.org/10.4102/sajhivmed.v23i1.1366 †, 1969–2021 original research tracking adverse drug reactions and medication errors in the central chronic medicine dispensing and distribution (ccmdd) programme in south africa kennedy otwombe, maggie munsamy, mukesh dheda, nishana ramdas, corlee herbst, merlin pillay, tanya van tonder, celicia serenata, samanta lalla-edward received: 20 dec. 2021; accepted: 25 feb. 2022; published: 19 may 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the south african central chronic medicine dispensing and distribution (ccmdd) programme is a national health insurance (nhi) initiative that improves access to medicine for patients. objectives: to describe the frequency of adverse drug reactions (adrs) and medication errors reported in stable patients living with hiv. method: this descriptive cross-sectional survey was conducted from august 2020 to october 2020, targeting tenofovir disoproxil fumarate/lamivudine/dolutegravir (tld) and tenofovir disoproxil fumarate/emtricitabine/efavirenz (tee) patients. the distribution of adrs and medication errors is presented. results: of 9621 patients, 30.8% (n = 2967) were interviewed, 40.2% (n = 1192) on tld and 59.8% (n = 1775) on tee regimens. the majority were women (tld: 55.8%, n = 665; tee: 75.4%, n = 1338); 15% (179/1192) reported adrs on tld. medication errors were low on tld (1.6%, n = 19) and tee (1.2%, n = 22). receipt of incorrect medication (eight each in tld and tee) and associated hospitalisations (one vs two, respectively) were low. common tld-associated adrs were weight gain (47.5%, n = 85), headaches (44.7%, n = 80), insomnia (39.7%, n = 71), restlessness (36.9%, n = 66), dizziness (29.6%, n = 53), brain fog (27.9%, n = 50), nervousness (27.4%, n = 49), rash on the skin (24.6%, n = 44) and poor concentration (21.2%, n = 38). conclusion: about one in seven patients reported adrs under tld. medication errors were low, possibly due to effective quality control measures and stable patients being on the programme. knowing the frequency of adrs and medication errors is critical for enhancing the ccmdd programme. keywords: ccmdd; national health insurance; adrs; medication errors; hiv. introduction the demand for affordable health services prompted the south african government to roll out the national health insurance (nhi) cover. in brief, the nhi seeks to ensure access to a defined package of comprehensive and essential healthcare services for all its citizens, irrespective of their financial status, and to achieve sustainable development goal ‘3’ of ensuring healthy lives and promoting the well-being of all south africans.1,2 the nhi grant funds the central chronic medicine dispensing and distribution (ccmdd) programme with the objective of improving patients’ access to chronic medicines through the public health system and enhancing their healthcare experiences.3 the ccmdd programme delivers pre-dispensed medication to contracted pick-up points offering a larger service footprint for patients which increases convenience and accessibility. this is achieved by harnessing public-private partnerships. stable patients, defined as being adherent to their treatment and clinically well as per specific disease guidelines, are invited to participate in the programme and collect their medicine parcel every 2–3 months at their chosen pick-up point; these include pharmacies, doctors’ rooms, innovative hubs, smart locker systems and community centres. the patients are provided a 6-month repeat prescription and return to a health facility once every six months, or when they experience any health problems. the ccmdd programme has been implemented in south africa since february 2014, when it was first initiated as a pilot programme in 11 nhi pilot districts. subsequently, the programme significantly expanded to eight provinces (excluding the western cape).4 according to the most recent report by the joint united nations programme on hiv/aids, south africa has the largest number of people living with hiv (plwh) and on antiretroviral treatment (art).5 many of these people receive their art through the ccmdd programme.6 there are more than 4 million patients registered on the programme; 75% are plwh (of these, 65% were on art only and 35% on art and medication for co-morbidities), and 25% are hiv-uninfected and on treatment for non-communicable diseases. medication errors in the programme, defined as failure in the treatment process that lead to, or have the potential to cause, harm to the patient,7,8 are isolated. an adverse drug reaction (adr) is any harmful and unwanted reaction to medication that occurs at doses normally prescribed to patients for therapeutic or prophylactic purposes.9,10 few adr cases are reported in the ccmdd programme. patients on the ccmdd programme are counselled to report any adrs or medication errors experienced. the ccmdd team receives reports of adrs and medication errors (classified according to predefined categories of harm) and this is shared with the relevant provinces and districts as well as with the national department of health pharmacovigilance unit. where the fault of the error falls on the service provider, the service provider accepts the responsibility of contacting the patient and, if needed, ensures that the patient receives medical attention. patients can also self-report adrs to the south african health products regulatory authority. while data on adrs from differentiated service delivery models similar to the ccmdd programme for plwh are commonly reported in lowand middle-income countries, reporting of medication errors remains sparse.11,12 this survey describes the frequency of adrs and medication errors reported by stable plwh that receive their art medication through the ccmdd programme. we present the most commonly reported adrs under the tenofovir disoproxil fumarate/lamivudine/dolutegravir (tld) regimen and medication errors reported on tld and tenofovir disoproxil fumarate/emtricitabine/efavirenz (tee) regimens. research methods and design study design this was a descriptive cross-sectional survey conducted between 24 august 2020 and 12 october 2020 to track adrs and medication errors reported by patients in the ccmdd programme. all responses to the occurrence of adrs and medication errors were self-reported by those interviewed. study setting stable patients in the ccmdd programme were identified from the operational database and contacted to participate in the survey. they were recruited from eight provinces, excluding the western cape (which runs an independent programme). study population and sampling strategy clinicians from public healthcare facilities identify stable patients with chronic diseases, including hiv, for possible inclusion in the ccmdd programme. the programme is opt-in, allowing patients to choose to be included or not. once an eligible patient agrees to participate in the ccmdd programme, a 6-month repeat prescription is completed. the patient is given a list of contracted pick-up points from which to choose to collect their medication parcel. the study enrolled patients with chronic diseases, aged ≥ 18 years. two key categories were selected for inclusion in our analysis as they comprised the largest proportion of patients in the ccmdd programme: patients receiving the tld regimen: to collect information on the frequency of adrs and medication errors and to establish whether the correct patients were transitioned as per the ccmdd tld standard operating procedure. patients on the tee regimen: to determine the frequency of adrs and medication errors and to establish why tld was not offered to them, or why patients chose to remain on tee despite the availability of tld. multi-stage sampling was used to select the patients who were interviewed. patients from each province were identified and then proportionately selected for interviews for both tld and tee drug regimens. within the categories, simple random sampling was used to select the patients to be interviewed. sample size the sample size was determined using the method for prevalence: where n = sample size, z = z-statistic for level of confidence, p = expected prevalence and d = precision. approximately 70% of patients in the ccmdd programme are living with hiv and are almost evenly distributed between tld and tee regimens. assuming about 35% of the plwh in the ccmdd programme are on the tld regimen, at least 1115 would be surveyed, with a precision of 2.8%. similarly, at least 1653 would be surveyed, with a 2.3% precision, assuming an equivalent proportion on the tee regimen. data collection prior to data collection, a survey questionnaire was developed based on the aims and objectives of the study. items of interest included: socio-demographic information; episodes of adrs and medication errors; whether the adrs occurred because of medication errors; how adrs and medication errors were handled by the ccmdd programme; whether the medication errors were identified by the patients, health facility staff or service provider; and whether the correct medication was issued thereafter. the initial questionnaire was pre-tested on a small random sample of patients to assess its suitability. responses from pre-testing were used to guide improvements to the final questionnaire. some of the items in the questionnaire, such as weight gain, were open-ended to allow for diversity in responses, whereas others were categorised. the open-ended items were re-categorised following discussions with the study team, for purposes of statistical reporting. data collection was conducted using digital platforms (unstructured supplementary service data, upinion webapp and a mobi-site) and a call centre where staff were trained on the ccmdd programme. a text message was sent to all patients who had made a visit to ccmdd medication sites in the 6 months prior to the survey, excluding known deaths. they were informed that the ccmdd programme was collecting information for a health report. this was followed up with a multimedia messaging service that contained study information and a consent form. only those who agreed to participate were invited to select their preferred mode of survey completion. if no response was received within three days of the last attempt, a trained call centre agent called the patient. an electronic data capturing system was used to capture the survey questionnaire responses in real time via all the digital platforms and the call centre. the call centres operated for extended hours on weekdays, saturdays and public holidays. data were reviewed after each interview and queries were addressed in real time. the database was de-identified and all personal identifiers were redacted prior to conducting statistical analysis. data analysis frequencies and proportions were determined for categorical data that were stratified by province. statistical analysis was conducted using sas enterprise guide 7.15 (2017, sas institute, cary, nc, united states). ethical considerations ethical approval to conduct this study was provided by the university of the witwatersrand human research ethics committee (ethics clearance number m201195). survey respondents did not receive any incentives. results of the initial sample size of 9621, a total of 2967 (30.8%) patients, stable on their hiv treatment, were interviewed. tenofovir disoproxil fumarate/lamivudine/dolutegravir regimen table 1 presents participant characteristics of patients on the tld regimen, stratified by province. a total of 1192 patients on the tld regimen were interviewed. overall, the majority were women (55.8%, n = 665) and the age groups 40–49 (36.3%, n = 433), 30–39 (26%, n = 310) and 50–59 (24.5%, n = 292) years had the highest proportion of responses. the majority had been on the dolutegravir (dtg)-containing regimen, tld (37.3%, n = 445), for at least 6 months. among females of childbearing age (20–49 years), 55.4% (n = 246) reported being counselled regarding the risk of dtg and pregnancy. table 1: participant characteristics of patients on the tenofovir disoproxil fumarate/lamivudine/dolutegravir regimen. table 2 presents overall adrs reported by respondents by province. adverse drug reactions on the tld regimen were reported by 15% (n = 179) of the respondents. limpopo (28.6%, n = 8), kwazulu-natal (23.2%, n = 75) and mpumalanga (21.9%, n = 14) provinces had the highest proportion of adrs. the most commonly reported adrs were weight gain (47.5%, n = 85), headaches (44.7%, n = 80), insomnia (39.7%, n = 71), restlessness (36.9%, n = 66), dizziness (29.6%, n = 53), brain fog (27.9%, n = 50), nervousness (27.4%, n = 49), skin rash (24.6%, n = 44) and poor concentration (21.2%, n = 38). table 2: adverse drug reactions reported by patients on the tenofovir disoproxil fumarate/lamivudine/dolutegravir regimen in the survey. the distribution of medication errors is presented in table 3, disaggregated by province. only 1.6% (n = 19) of respondents reported medication errors. of those who reported medication errors, 42.1% (8/19) reported taking incorrect medication. among those who took incorrect medication, 75% (6/8) reported experiencing problems, whereas one person was hospitalised 12.5% (1/8) and 25% (2/8) were contacted about the error. table 3: medication errors reported by patients on the tenofovir disoproxil fumarate/lamivudine/dolutegravir regimen in the survey. tenofovir disoproxil fumarate/emtricitabine/efavirenz regimen a total of 1775 patients on the tee regimen were interviewed (table 4); the majority were women (75.4%, n = 1338). the highest proportion of the patients was in the age groups 30–39 (34%, n = 603) and 40–49 (31.4%, n = 558) years. only 29.1% (n = 516) of the respondents reported being asked to change to the new antiretroviral regimen, whereas 65.7% (n = 1167) reported going for annual viral loads and 25.5% (n = 452) reported that they knew their viral load results. among those who reported not going for their annual viral loads, the majority were from the gauteng (41.8%, n = 191) and eastern cape (40.3%, n = 58) provinces. table 4: participant characteristics of patients on the tenofovir disoproxil fumarate/emtricitabine/efavirenz regimen. table 5 presents the distribution of medication errors, stratified by province. the proportion of respondents reporting medication errors while on the tee regimen was low (1.2%, n = 22), with gauteng reporting the highest proportion (2.6%, 12/457). of these, 36.4% (n = 8) reported taking incorrect medication, with 87.5% (7/8) of these reporting drug-related side effects. the number of patients reporting hospitalisation or treatment due to medication error (25%, 2/8), receiving the correct medication thereafter (75%, 6/8), and being contacted by the service provider about the medication error (37.5%, 3/8), was low. table 5: medication errors reported by patients on the tenofovir disoproxil fumarate/emtricitabine/efavirenz regimen in the survey. discussion this survey describes adrs, and medication errors reported by hiv-infected patients on art in the ccmdd programme in south africa. though some work exists on medication errors,13,14 quantifiable data on medication errors from large hiv programmes from lowand middle-income countries are sparse. the number of adrs and medication errors reported by patients was low, most probably because the ccmdd programme enrols hiv patients who are stable on their treatment. by design, adrs were largely reported in detail by patients on the tld regimen, as it is a newer regimen and rollout is ongoing. the ccmdd programme provides a mechanism to support health systems with minimal errors and facilitating fewer patients needing to visit healthcare facilities, particularly in this coronavirus disease 2019 (covid-19) pandemic period. at the start of the tld regimen rollout, dtg-containing regimens had been thought to increase the risk of neural tube defects in the offspring of female users and therefore clinicians and prescribers were advised to counsel all women of childbearing potential on these risks.15,16 despite this, only 55.4% of females in this survey who were in the childbearing potential age category reported receiving this risk-associated counselling. the dtg guidelines have since been updated to show no significant difference in neural tube defects between dtg and non-dtg regimens.17 although low in numbers, weight gain, headaches, insomnia, restlessness, dizziness, brain fog, nervousness, skin rash and poor concentration were commonly reported among those on the tld regimen. our findings are in harmony with prior research that shows neuropsychiatric adrs in patients taking dtg-containing regimens.18,19 adverse drug reactions in the ccmdd programme could be low due to the caution observed in enrolling only stable patients on art. additionally, when any adrs are experienced, the patients are immediately transferred to the standard primary health care clinics to be managed by clinicians until they stabilise again. medication errors reported under both the tld and tee regimens in the ccmdd programme were low. though there are limited data on medication errors reported from lowand middle-income countries’ hiv programmes, a study in australia examined medication errors in general in a large public hospital that implemented a system to monitor and reduce their occurrence.13 a previous study from the netherlands observed a high number of medication administration errors in nursing homes.20 in a literature review on the management and care of hospitalised hiv-infected patients receiving art in high-income countries, a large number of medication errors was reported.21 it may be that medication errors reported in the ccmdd programme are low due to close supervision and adherence to the standard operating procedures for dispensed medication. this evaluation of adrs and medication errors from the ccmdd programme has several limitations. due to the covid-19 pandemic, the consenting and interviewing process was telephonic and response bias may have occurred due to fatigue associated with non-face-to-face (telephonic) platforms. while the survey was designed to collect data as objectively as possible, it is likely that social desirability bias (patients responding favourably to questions) occurred. the risk of adrs and medication errors is highest at the start of a new treatment regimen. since only stable chronic disease patients are recruited in the ccmdd programme, high-risk patients who are likely to have poor outcomes are under-represented in this cohort. additionally, those encountering challenges within the system or the medication were more likely to respond. the majority of the participants in this survey had been on the tee regimen for longer than those on tld, which has only been available for a few years. the sampling frame of participants for the survey was generated from the ccmdd database during the covid-19 pandemic. hence, bias due to the pandemic, such as the national lockdown and staff absenteeism, may have been missed. nevertheless, the findings are encouraging and highlight the purpose of the ccmdd programme, to ensure widespread access to art and other chronic medication for patients accessing public healthcare.22 the differentiated service delivery model is commonly used in the management and care of plwh who require art. in brief, the differentiated service delivery model seeks to improve service delivery by offering patient-centred care through optimised drugs and care delivery.23 the ccmdd programme resembles the differentiated service delivery model, but has expanded successfully to include a broader spectrum of chronic diseases beyond hiv. patient-centred care has been shown to significantly improve health outcomes in mozambique, the democratic republic of congo, malawi and south africa.24 in the united kingdom, a study found that patients in nursing homes who received diabetic medication rarely reported medication errors.25 in australia, implementation of multiple patient-centred and system redesign strategies significantly reduced medication errors across the health service.13 this suggests that the implementation of the ccmdd programme in south africa can be expected to become more critical as it expands its service offerings. conclusion findings from this evaluation highlight the relatively low frequency of adrs and medication errors among stable hiv patients on treatment in the ccmdd programme. the ccmdd programme strives to ensure that adrs and medication errors are minimised, as they focus on programme expansion to include other diseases. this will further alleviate in-facility congestion and improve alternate access to treatment and retention in care, through decentralised medication service delivery, especially now during the covid-19 pandemic. knowing the frequency of adrs and medication errors is critical in enhancing the ccmdd programme through continuous evaluation and enhancement of quality control measures for patient safety. although the ccmdd programme has reduced congestion at facilities and freed up time for clinicians to focus on other healthcare services, there is a need to continuously monitor the timeframes for reporting adrs and medication errors. this will allow for prompt responses by clinicians and minimise the impact of adrs and medication errors on patients. acknowledgements central chronic medicine dispensing and distribution (ccmdd), deputy director general anban pillay and affordable medicine directorate. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. author’s contributions k.o. was responsible for methodology, formal analysis, investigation, writing and reviewing the draft, software, validation, and data curation; m.m. was responsible for conceptualisation, methodology, investigation, writing and reviewing the draft, project administration, resources, supervision, and funding acquisition; m.d. was involved in conceptualisation, methodology, investigation, writing and reviewing the draft, and funding acquisition; n.r. was involved in investigation, writing and reviewing the draft, validation, and resources; c.h. was involved in methodology, investigation, and writing and reviewing the draft; m.p. and t.v.t. were involved in methodology, project administration, data curation, and supervision; c.s. was involved in conceptualisation, writing and reviewing the draft, resources, and funding acquisition [c.s. passed away as the manuscript was being finalised]; and s.l.-e. was involved in conceptualisation, methodology, formal analysis, writing and reviewing the draft, project administration, supervision, and funding acquisition. funding information this monitoring activity was embedded within the optimize project. optimize (aid-oaa-a-15-00069) is funded by the united states agency for international development (usaid) under the united states president’s emergency plan for aids relief (pepfar). this assistance is from the american people. the views expressed do not necessarily reflect the views of the us government. data availability the data collected and utilised in this manuscript are available from the ccmdd programme in pretoria with permission from the national department of health. the data request should be made to maggie munsamy through the email address maggie.munsamy@health.gov.za. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or 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strategies on medication errors in an australian health service. int j clin pharm. 2020;42(6):1515–1520. https://doi.org/10.1007/s11096-020-01142-w louw jm, rantloane b, ngcobo s, et al. home delivery of medication as part of reducing congestion in primary healthcare in tshwane district health services. s afr j public health. 2020;4(2):50–55. https://doi.org/10.7196/shs.2020.v4i2.124 who. dolutegravir (dtg) and the fixed dose combination (fdc) of tenofovir/lamivudine/dolutegravir (tld) [homepage on the internet]. 2018 [cited 2020 dec 18]. available from: https://www.who.int/hiv/pub/arv/dtg-tld-arv_briefing_2018.pdf zash r, holmes l, diseko m, et al. neural-tube defects and antiretroviral treatment regimens in botswana. n engl j med. 2019;381(9):827–840. https://doi.org/10.1056/nejmoa1905230 zash r. update on neural tube defects with antiretroviral exposure in the tsepamo study, botswana [homepage on the internet]. 2020 [cited 2021 aug 23]. available from: https://www.natap.org/2020/iac/iac_112.htm correa a, monteiro p, calixto f, batista jdl, de alencar ximenes ra, montarroyos ur. dolutegravir: virologic response and tolerability of initial antiretroviral regimens for adults living with hiv. plos one. 2020;15(8):e0238052. https://doi.org/10.1371/journal.pone.0238052 elzi l, erb s, furrer h, et al. adverse events of raltegravir and dolutegravir. aids. 2017;31(13):1853–1858. https://doi.org/10.1097/qad.0000000000001590 van den bemt pm, idzinga jc, robertz h, kormelink dg, pels n. medication administration errors in nursing homes using an automated medication dispensing system. j am med inform assoc. 2009;16(4):486–492. https://doi.org/10.1197/jamia.m2959 li eh, foisy mm. antiretroviral and medication errors in hospitalized hiv-positive patients. ann pharmacother. 2014;48(8):998–1010. https://doi.org/10.1177/1060028014534195 smith kg, nicol e. process evaluation of the central chronic medicines dispensing and distribution programme in namakwa district, northern cape province protocol: a multimethod approach. bmj open. 2020;10(2):e032530. https://doi.org/10.1136/bmjopen-2019-032530 international aids society. differentiated service delivery [homepage on the internet]. 2020 [cited 2020 dec 18]. available from: http://www.differentiatedcare.org/about2020 bemelmans m, baert s, goemaere e, et al. community-supported models of care for people on hiv treatment in sub-saharan africa. trop med int health. 2014;19(8):968–977. https://doi.org/10.1111/tmi.12332 milligan f, gadsby r, ghaleb m, et al. going beyond blame: reporting nhs medication errors in nursing home residents with diabetes. br j gen pract. 2015;65(636):372–373. https://doi.org/10.3399/bjgp15x685897 abstract introduction methods results discussion conclusion acknowledgements references about the author(s) muhammed shiraz moosa department of medicine, new somerset hospital, cape town, south africa department of medicine, faculty of health sciences, university of cape town, cape town, south africa gary maartens department of medicine, division of clinical pharmacology, faculty of health sciences, university of cape town, cape town, south africa hannah gunter department of medicine, division of clinical pharmacology, faculty of health sciences, university of cape town, cape town, south africa shaazia allie department of medicine, division of clinical pharmacology, faculty of health sciences, university of cape town, cape town, south africa mohamed f. chughlay department of medicine, division of clinical pharmacology, faculty of health sciences, university of cape town, cape town, south africa mashiko setshedi department of medicine, division of gastroenterology, faculty of health sciences, university of cape town, cape town, south africa sean wasserman department of medicine, division of infectious diseases, faculty of health sciences, university of cape town, cape town, south africa david f. stead department of medicine, new somerset hospital, cape town, south africa department of medicine, faculty of health sciences, university of cape town, cape town, south africa karen cohen department of medicine, division of clinical pharmacology, faculty of health sciences, university of cape town, cape town, south africa citation moosa ms, maartens g, gunter h, et al. rechallenge after anti-tuberculosis drug-induced liver injury in a high hiv prevalence cohort. s afr j hiv med. 2022;23(1), a1376. https://doi.org/10.4102/sajhivmed.v23i1.1376 original research rechallenge after anti-tuberculosis drug-induced liver injury in a high hiv prevalence cohort muhammed shiraz moosa, gary maartens, hannah gunter, shaazia allie, mohamed f. chughlay, mashiko setshedi, sean wasserman, david f. stead, karen cohen received: 01 feb. 2022; accepted: 22 mar. 2022; published: 14 june 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: there are limited data on the outcomes of rechallenge with anti-tuberculosis therapy (att) following anti-tuberculosis drug-induced liver injury (at-dili) in a high hiv prevalence setting. objectives: to describe the outcomes of rechallenge with first-line att. method: hospitalised participants with at-dili who were enrolled into a randomised controlled trial of n-acetylcysteine in cape town, south africa, were followed up until completion of att rechallenge. we described rechallenge outcomes, and identified associations with recurrence of liver injury on rechallenge (positive rechallenge). results: seventy-nine participants were rechallenged of whom 41 (52%) were female. mean age was 37 years (standard deviation [s.d.] ±10). sixty-eight (86%) were hiv-positive, of whom 34 (50%) were on antiretroviral therapy (art) at time of at-dili presentation. five participants had serious adverse reactions to an aminoglycoside included in the alternate att regimen given after first-line att interruption: acute kidney injury in three and hearing loss in two. the median time from first-line att interruption to start of first-line att rechallenge was 13 days (interquartile range [iqr]: 8–18 days). antiretroviral therapy was interrupted for a median of 32 days (iqr: 17–58) among hiv-positive participants on art before at-dili. fourteen participants had positive rechallenge (18%). positive rechallenge was associated with pyrazinamide rechallenge (p = 0.005), female sex (p = 0.039) and first episode of tuberculosis (tb) (p = 0.032). conclusion: rechallenge was successful in most of our cohort. pyrazinamide rechallenge should be carefully considered. keywords: tuberculosis; anti-tuberculosis drugs; drug-induced liver injury; positive rechallenge; pyrazinamide; treatment interruption. introduction liver injury is the most frequent complication of first-line anti-tuberculosis therapy (att) with an estimated incidence of 2% – 28%.1 following recovery from anti-tuberculosis drug-induced liver injury (at-dili), rechallenge with hepatotoxic first-line anti-tuberculosis drugs (rifampicin, isoniazid and, in some circumstances, pyrazinamide) is recommended because second-line att regimens are less effective, longer and more toxic.2 while awaiting resolution of liver injury, a background att regimen is given, typically consisting of ethambutol and at least two other second-line anti-tuberculosis drugs. there is limited evidence on rechallenge following at-dili in populations with high prevalence of hiv coinfection. there is limited evidence on optimal background att regimens, optimal att rechallenge protocols, risk factors for positive rechallenge, anti-tuberculosis drugs most frequently implicated in positive rechallenge, and interruption and re-initiation of antiretroviral therapy (art) in people living with hiv (plhiv) who present with at-dili. this study is nested within our randomised placebo-controlled trial of intravenous n-acetylcysteine (nac) in the management of at-dili, which has previously been reported.3 we describe the characteristics, background att regimens (alternate att regimens initiated after first-line att interruption), rechallenge regimens, and outcomes of rechallenge in those participants who were rechallenged with att. among hiv-positive participants, we explore the impact of at-dili and drug rechallenge on initiation or interruption of art. methods study participants participants with at-dili admitted to three hospitals in cape town, south africa, were enrolled in a pragmatic randomised placebo-controlled trial of intravenous nac. anti-tuberculosis drug-induced liver injury was defined as an alanine aminotransferase (alt) ≥ 3 times the upper limit of normal if symptoms of hepatitis were present, or an alt ≥ 5 times the upper limit of normal without symptoms of hepatitis.4 other trial inclusion criteria were age 18 years or older, taking first-line therapy for tuberculosis (tb), and liver injury attributed to att. after completion of the nac or placebo infusion, decisions regarding clinical management were made by clinicians at participating hospitals and outpatient clinics. this included decisions regarding background att initiation and regimen, whether to rechallenge att, choice of rechallenge regimen, and interrupting, rechallenging, or initiating art. participants were followed up until the study primary endpoint (alt reaching < 100 u/l) was reached and att rechallenge was completed. we included all trial participants who were rechallenged with at least one anti-tuberculosis drug in this analysis. identification and assessment of positive rechallenge cases ‘positive rechallenge’ is recurrence of liver injury on drug rechallenge. for this analysis, we defined positive rechallenge as doubling of alt or total bilirubin concentration after rechallenge of an anti-tuberculosis drug.5 a multidisciplinary causality assessment panel including a clinical pharmacologist, a pharmacist, an infectious diseases specialist and a general physician assessed cases with a positive rechallenge, and identified the drug that was most likely to be causative, or any non-drug related cause for the increase in alt or bilirubin. statistical analysis categorical data were described using counts and percentages. numerical data were described using means and standard deviations if normally distributed and medians and ranges if non-normally distributed. we compared parametric data using the student’s t-test, non-parametric data using the wilcoxon rank sum test and categorical data using the fisher’s exact test. when comparing proportion with positive rechallenge between rechallenged drugs, we assumed that the three groups were independent. a p-value of < 0.05 was considered to be statistically significant throughout. data were analysed using stata (version se/15.1 statacorp, college station, texas, united states). we calculated ‘time from first-line att interruption to start of rechallenge’ as the interval from the date of at-dili presentation and first-line att discontinuation to the date that the first rechallenged drug was introduced. in hiv-positive participants on art, we calculated ‘art interruption time’ as the interval from the date of presentation with at-dili and art discontinuation to the date of artre-initiation. in hiv-positive participants not on art, we calculated ‘delay in art initiation time’ as the interval from date of presentation with at-dili to the date of art initiation. ethical considerations the study was conducted in accordance with the principles of the declaration of helsinki and the international conference for harmonisation.6,7 the study protocol was approved by university of cape town human research ethics committee and the western cape department of health (hrec 087/2012). participants provided written informed consent. the trial was registered with the south african national clinical trials registry (sanctr: doh-27-0414-4719). results seventy-nine of 102 participants (77%) with at-dili enrolled into the randomised trial were rechallenged with att (figure 1). reasons for not rechallenging 23 participants were: 12 died before rechallenge was attempted, 8 had insufficient evidence of tb to justify rechallenge, 2 had prolonged hyperbilirubinaemia and were placed on second-line att because the clinical team deemed first-line att rechallenge to be unsafe, and 1 was lost to follow-up before planned rechallenge could be commenced. figure 1: anti-tuberculosis drug rechallenge following drug-induced liver injury in n-acetylcysteine randomised controlled trial participants. baseline characteristics of the 79 rechallenged participants, grouped by positive and negative rechallenge, are described in table 1. sixty-eight of the 79 (86%) participants rechallenged were hiv-positive, 34 of whom were on art at presentation with at-dili, (27 on an efavirenz-based regimen and 7 on a lopinavir plus ritonavir-based regimen) and 18 were on cotrimoxazole prophylaxis. table 1: baseline characteristics of participants with positive and negative rechallenge following anti-tuberculosis drug-induced liver injury. forty-three participants commenced rechallenge during hospital admission, 10 of whom were referred to a community health centre to complete rechallenge. twenty-five participants were rechallenged at a community health centre and 11 at a stepdown inpatient tb care facility. sixty-eight of 79 participants (86%) rechallenged were initiated on background att after first-line att interruption prior to rechallenge (table 2). in the remaining 11 participants, background att was not commenced; reasons for this decision were not documented. all 68 participants initiated on background att received a fluoroquinolone, and 58 received an aminoglycoside (46 kanamycin, 11 amikacin, 1 streptomycin). five of the participants who received an aminoglycoside (9%) had a serious adverse drug reaction: acute kidney injury in 3, and hearing loss in 2. table 2: background anti-tuberculosis drug regimens prescribed following anti-tuberculosis drug-induced liver injury. most participants (96%) were rechallenged with a minimum of two individual drugs re-introduced sequentially and in full dosages (table 3). three participants completed only rifampicin rechallenge after which further rechallenge was discontinued: one was found to have no evidence of tb, one had worsening canalicular enzymes (likely due to tb-immune reconstitution inflammatory syndrome [iris] rather than at-dili recurrence), and one died from sepsis and multi-organ failure before completion of rechallenge. table 3: sequence of anti-tuberculosis drug rechallenge. first-line anti-tuberculosis drugs were rechallenged at full dose. drugs were rechallenged sequentially in 77 of 79 participants, with new drugs introduced at approximately 3-day intervals (table 3). rechallenge regimens differed in the sequence in which individual drugs were re-introduced: rechallenge commenced with rifampicin in 68 participants and with isoniazid in 11 (table 3). the clinical care team elected not to rechallenge with pyrazinamide in 22 of 72 participants who had interrupted att due to liver injury during the intensive phase, because of the severity of the liver injury. the median time from first-line att interruption to start of rechallenge was 13 days (interquartile range [iqr]: 8–18 days). positive rechallenge there were 14 positive rechallenges in the 79 rechallenged participants (18%). positive rechallenge was associated with female sex (fisher’s exact test p = 0.039) and first episode of tb (fisher’s exact test p = 0.032) (table 1). the median time from first-line att interruption to start of rechallenge was similar between those with positive and negative rechallenge: median 12 days (iqr: 8–16 days) and 13 days (iqr: 9–18) respectively, wilcoxon rank sum p = 0.719. rechallenge was positive in 9/46 participants rechallenged with pyrazinamide, 2/78 rechallenged with rifampicin, and 2/74 rechallenged with isoniazid. one participant had a positive rechallenge after sequential introduction of rifampicin and isoniazid. on causality assessment, both drugs were potentially implicated in the positive rechallenge because the participant’s serum alt only settled after both drugs were withdrawn. the proportion with a positive rechallenge was significantly higher among those rechallenged with pyrazinamide than among those rechallenged with rifampicin or isoniazid, fisher’s exact test p = 0.005. one of the participants with positive pyrazinamide rechallenge developed a fatal systemic hypersensitivity reaction with rash, jaundice and acute kidney injury. one participant had markedly increased serum canalicular liver enzymes (alkaline phosphatase and gamma-glutamyl transferase) at at-dili presentation which increased further after rifampicin rechallenge. the hospital clinicians assessed this as a positive rifampicin rechallenge and stopped rifampicin. however, the canalicular enzymes continued to increase after rifampicin cessation. on causality assessment, the increased canalicular enzymes were attributed to tb iris rather than a positive rifampicin rechallenge. antiretroviral therapy was interrupted at presentation with liver injury in 26 of the 34 (79%) hiv-positive participants who were receiving art. at 8 weeks’ follow-up, 24 of these 26 participants had been re-initiated on art: 21 recommenced their previous efavirenz-based regimen and three were switched from efavirenz-based to boosted protease inhibitor-based art. the median art interruption time was 32 days (iqr: 17–58). twenty-one of 34 (62%) hiv-positive participants who were not on art at the time of at-dili were initiated on art after att rechallenge, after a median of 53 days (iqr: 35–91). fifteen of 68 (22%) hiv-positive participants were not yet on art when study follow-up ended. discussion in our cohort of patients with at-dili, the majority of whom had advanced hiv disease, rechallenge was attempted in the majority (77%). a wide variety of background regimens were used during rechallenge; adverse reactions to aminoglycosides in the background regimen were common. rechallenge was positive in 18%, and was associated with female sex and first episode of tb. positive rechallenge was significantly more common with pyrazinamide rechallenge than with isoniazid or rifampicin rechallenge. positive rechallenge resulted in delays in initiating or commencing art. risk of positive rechallenge in a recent network meta-analysis of att rechallenge regimens in participants with at-dili,8 11% of those rechallenged with a sequential full dose regimen had a positive rechallenge. this is lower than the 18% we observed and could be explained by the longer rechallenge regimens used in the studies included in the meta-analysis. the majority of participants in the meta-analysis were rechallenged with rifampicin on day 1, isoniazid on day 8 and pyrazinamide on day 15–18, whereas the majority of our study participants were rechallenged with rifampicin on day 1, isoniazid on day 4 and pyrazinamide on day 7. we found that women and participants with their first episode of tb were more likely to have a positive rechallenge. other studies have also found female sex to be associated with at-dili9,10 as well as with positive att rechallenge.11 we did not find low serum albumin or increased age to be associated with positive rechallenge, in contrast to previous studies.12,13 pyrazinamide rechallenge pyrazinamide was the main cause of positive rechallenge in our study, with positive rechallenge in 20% of those rechallenged. positive pyrazinamide rechallenge contributed to the death of one study participant. in a small randomised trial, 6 of 25 (24%) participants rechallenged with a concomitant full dose regimen including pyrazinamide had a positive rechallenge compared with 0 of 20 in the sequential full dose regimen group excluding pyrazinamide.11 american thoracic society guidelines advise against rechallenging pyrazinamide after severe at-dili.4 with increasing availability of effective second-line anti-tuberculosis drugs including fluroquinolones, linezolid and bedaquiline, avoidance of pyrazinamide rechallenge in all cases of at-dili should be considered. antiretroviral therapy interruption and re-initiation there is little published data on the impact of at-dili on art in plhiv. in our study, 79% of participants on art at the time of at-dili presentation had their art interrupted, with a median interruption of 32 days. antiretroviral therapy interruptions may impact on efficacy of therapy and contribute to the emergence of antiretroviral resistance.14 median delay from at-dili presentation to art initiation in our cohort was 53 days, and 22% of the cohort were not yet on art when study follow-up ended. delays in initiation of art in patients with advanced disease have previously been shown to increase mortality.15 study limitations our study has limitations. although our study was nested within a randomised control trial, it is descriptive, and was not powered to identify risk factors for positive rechallenge. study follow-up ended after rechallenge was complete, and we therefore could not quantify the impact of positive rechallenge on outcomes of att or art. our study cohort had a high prevalence of hiv, and the findings may not be generalisable to lower hiv prevalence settings. conclusion in this cohort of patients with at-dili, the majority of whom were hiv-positive, pyrazinamide was the most common cause of positive rechallenge. positive rechallenge resulted in delays in initiating or recommencing art. use of second-line anti-tuberculosis drugs should be considered as an alternative to pyrazinamide rechallenge. acknowledgements this study was nested within a randomised placebo-controlled trial of intravenous n-acetylcysteine in management of patients hospitalised with liver injury due to anti-tuberculosis drugs (https://doi.org/10.1093/cid/ciaa1255). we thank anri uys for contributing to causality assessment. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions m.s.m., k.c. and g.m. conceived and designed the study. m.s.m. and k.c. performed all the statistical analyses. m.s.m., k.c., g.m., h.g., s.a., m.f.c., m.s., s.w. and d.f.s. discussed the results and contributed to the final manuscript. funding information this study was supported by the south african medical research council (self-initiated grant) and the academy of medical sciences, united kingdom (newton advanced fellowship). data availability the data that support the findings of this study are stored in a controlled access repository and are not openly available due to reasons of sensitivity and patient confidentiality. data are available from the corresponding author, k.c., upon reasonable request. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references tostmann a, boeree mj, aarnoutse re, de lange wc, van der ven aj, dekhuijzen r. antituberculosis drug-induced hepatotoxicity: concise up-to-date review. j gastroenterol hepatol. 2008;23(2):192–202. https://doi.org/10.1111/j.1440-1746.2007.05207.x world health organization. who consolidated guidelines on drug-resistant tuberculosis treatment [homepage on the internet]. [cited 2022 jan 28]. geneva: world health organization; 2019. licence: cc by-nc-sa 3.0 igo. available from: https://www.ncbi.nlm.nih.gov/books/nbk539517/ moosa ms, maartens g, gunter h, et al. a randomized controlled trial of intravenous n-acetylcysteine in the management of anti-tuberculosis drug-induced liver injury. clin infect dis. 2020;73(9):e3377–e83. saukkonen jj, cohn dl, jasmer rm, et al. an official ats statement: hepatotoxicity of antituberculosis therapy. am j respir crit care med. 2006;174(8):935–952. https://doi.org/10.1164/rccm.200510-1666st livertox: clinical and research information on drug-induced liver injury [homepage on the internet]. roussel uclaf causality assessment method (rucam) in drug induced liver injury. bethesda, md: national institute of diabetes and digestive and kidney diseases; 2012 [updated 2019 may 4] [cited 2022 jan 28]. available from: https://www.ncbi.nlm.nih.gov/books/nbk548272/ world medical association. world medical association declaration of helsinki: ethical principles for medical research involving human subjects. jama. 2013;310(20):2191–2194. https://doi.org/10.1001/jama.2013.281053 international council for harmonisation of technical requirements for pharmaceuticals for human use. guideline for good clinical practice. 2016 [cited 2022 jan 28]. available from: https://www.ema.europa.eu/en/ich-e6-r2-good-clinical-practice#document-history---revision-1-section soni h, kumar mp, mishra s, et al. risk of hepatitis with various reintroduction regimens of anti-tubercular therapy: a systematic review and network meta-analysis. expert rev anti infect ther. 2020;18(2):171–179. https://doi.org/10.1080/14787210.2020.1714436 sharma sk, balamurugan a, saha pk, pandey rm, mehra nk. evaluation of clinical and immunogenetic risk factors for the development of hepatotoxicity during antituberculosis treatment. am j respir crit care med. 2002;166(7):916–919. https://doi.org/10.1164/rccm.2108091 gaude gs, chaudhury a, hattiholi j. drug-induced hepatitis and the risk factors for liver injury in pulmonary tuberculosis patients. j fam med prim care. 2015;4(2):238–243. https://doi.org/10.4103/2249-4863.154661 tahaoğlu k, ataç g, sevim t, et al. the management of anti-tuberculosis drug-induced hepatotoxicity. int j tuberc lung dis. 2001;5(1):65–69. sharma sk, singla r, sarda p, et al. safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment-induced hepatotoxicity. clin infect dis. 2010;50(6):833–839. https://doi.org/10.1086/650576 zuberi bf, zuberi ff, bader n, alvi h, salahuddin j. comparison of british thoracic society and american thoracic society reintroduction guidelines for anti-tuberculous therapy induced liver injury. j pak med assoc. 2014;64(8):896–899. luebbert j, tweya h, phiri s, et al. virological failure and drug resistance in patients on antiretroviral therapy after treatment interruption in lilongwe, malawi. clin infect dis. 2012;55(3):441–448. https://doi.org/10.1093/cid/cis438 meintjes g, brust jcm, nuttall j, maartens g. management of active tuberculosis in adults with hiv. lancet hiv. 2019;6(7):e463–e474. https://doi.org/10.1016/s2352-3018(19)30154-7 access.html original article access to antiretroviral treatment in south africa, 2004 2011 leigh f johnson, phd centre for infectious disease epidemiology and research, university of cape town background. south africa’s national strategic plan (nsp) for 2007 2011 aimed to achieve new antiretroviral treatment (art) enrolment numbers equal to 80% of the number of newly eligible individuals in each year, by 2011. objectives. to estimate art coverage in south africa and assess whether nsp targets have been met. methods. art data were collected from public and private providers of art. estimates of hiv incidence rates were obtained from independent demographic projection models. adult art data and incidence estimates were entered into a separate model that estimated rates of progression through cd4 stages, and the model was fitted to south african cd4 data and hiv prevalence data. results. by the middle of 2011, the number of patients receiving art in south africa had increased to 1.79 million (95% ci 1.65 1.93 million). adult art coverage, at the previous art eligibility criterion of cd4 <200/μl, was 79% (95% ci 70 85%), but reduced to 52% (95% ci 46 57%) when assessed according to the new south african art eligibility criteria (cd4<350/μl). the number of adults starting art in 2010/11 was 1.56 times (95% ci 1.08 1.97) the number of adults who became art-eligible in 2010/11, well in excess of the 80% target. however, this ratio was substantially higher in women (1.96, 95% ci 1.33 2.51) than in men (1.23, 95% ci 0.83 1.58) and children (1.13, 95% ci 0.74 1.48). conclusion. south africa has exceeded the art targets in its 2007 2011 nsp, but men and children appear to be accessing art at a lower rate than women. antiretroviral treatment (art) is a powerful tool for reducing both aids mortality1 , 2 and hiv transmission.3 the monitoring of access to art is therefore critical to the evaluation of the impact of hiv treatment and prevention programmes. previous monitoring exercises have shown that, since the announcement of a comprehensive care, management and treatment programme by the south african department of health in late 2003, access to art in south africa has increased dramatically.4 , 5 these assessments suggested that south africa was on track to meet the targets laid out in the 2007 2011 national strategic plan (nsp) for hiv/aids and sexually transmitted infections, which aimed to achieve new art enrolment numbers equal to 80% of the number of newly eligible individuals in each year, by 2011.6 however, there has not as yet been any formal assessment of whether this target has been met. the monitoring of access to art in south africa is challenging for several reasons. the interpretation of public sector statistics is complicated by changes in reporting practices in late 2009, with most provinces switching from reporting numbers of patients cumulatively started on art to numbers of patients currently on art. statistics from disease management programmes and programmes run by non-governmental organizations (ngos) have not been routinely collected and reported. in addition, there is generally a lack of information on the age and sex of patients. this is particularly problematic in view of concerns that art initiation rates may be lower among men than women.7 the estimation of art coverage is also hampered by uncertainty regarding the ‘treatment need’, the denominator in the coverage calculation. mathematical models have been used to estimate numbers of hiv-positive individuals with cd4 counts below different thresholds, but there is substantial uncertainty surrounding the rates of cd4 decline that are assumed in these models, and there is also growing recognition that these rates of cd4 decline may differ between populations.10 there is also concern that cross-sectional measures of art coverage may fail to give a sense of recent programme performance, which is better reflected in the ratio of the number of patients starting art in a year to the number of individuals becoming eligible for art in the same year.11 the latter measure has the advantage of being consistent with the way in which the south african nsp targets are expressed, and is also less sensitive to model assumptions about rates of cd4 decline and art eligibility criteria.11 the objective of this paper is to assess recent changes in access to art in south africa, and to evaluate the extent to which the 2007 2011 nsp treatment targets have been met. this study also aims to improve on previous work4 by including more recent programme statistics, by using locally relevant cd4 data in the estimation of the treatment need, by including 95% confidence intervals (cis) in coverage estimates, and by estimating coverage separately for men, women and children. methods art programme statistics public sector art programme statistics to the end of june 2011 were obtained from the south african department of health, and were adjusted to achieve consistency of definition (cumulative/current), using a previously described formula,4 for each province. unpublished data on the sex ratio of adult patients enrolled in public art programmes in four provinces, collected up to march 2009, were used to estimate the sex ratio of adults starting art in the public sector. private sector data and data from ngos were obtained through surveys conducted every two years, since mid-2006.12 linear interpolation and extrapolation was used to estimate numbers for programmes with missing data and for years in which no survey was conducted. estimates of the proportion of private sector patients who were men, women and children were obtained from submissions by medical schemes to the risk equalization fund up to march 2008, and the geographical distribution of private sector patients was estimated from early private sector statistics.13 detailed data collected from ngo programmes in the 2008 survey were used to determine the profile of ngo patients by age, sex and province. mathematical model to estimate the numbers of adults needing art, a mathematical model was developed to simulate the growth of the south african population over time, the incidence of hiv and the decline in cd4 counts in hiv-positive adults. the model stratifies the population by age and sex, and projects the change in population in one-year intervals, starting in the middle of 1985. assumptions regarding the ageand sex-specific population profile, non-hiv mortality, fertility, migration and hiv incidence are based on the assa2008 aids and demographic model.14 once infected, individuals are assumed to progress through a four-stage model of cd4 decline, in the absence of art (fig. 1). individuals are assumed to experience aids mortality in the cd4 200 349/µl category at a fraction θ of the aids mortality rate in the cd4<200/µl category, if untreated. up to mid-2009, adults of sex g are assumed to start art only once their cd4 count has dropped below 200/µl, at a rate of r g (t) per annum in year t. between mid-2009 and mid-2011, the model also allows individuals to start art in the cd4 200 349 category if they develop tuberculosis or become pregnant, following the change in south african art guidelines in early 2010.15 the r g (t) rates in each year are calculated from the art programme statistics (further detail is provided in the online appendix). adults who start art are assumed to be lost to the art programme with probability κ0 during the first 6 months after starting art, and with probability κ1 for each year after the first 6 months. this does not include individuals who temporarily interrupt art. of those leaving the art programme permanently, a proportion ν are assumed to leave the programme owing to hiv-related mortality, and the remaining proportion (1 – ν) are assumed to stop taking their drugs, after which their mortality risk is assumed to be the same as that of art-naïve adults with cd4 counts below 200/µl. estimates of annual numbers of new paediatric hiv infections were obtained from a separate model of paediatric hiv in south africa.16 since paediatric art guidelines recommend art initiation in all hiv-infected children aged <12 months, regardless of their immunological or clinical status,17 the annual number of new paediatric hiv infections is used to approximate the annual number of children newly eligible for art (the denominator in the art enrolment ratio). calibration and uncertainty analysis the parameters determining the rates of cd4 decline, hiv-related mortality and art discontinuation are estimated by fitting the model to hiv prevalence data from the 2005 and 2008 human sciences research council (hsrc) household surveys,18 , 19 and to cd4 data from hiv-positive adults in three south african surveys,20 using a bayesian melding procedure.23 , 24 a detailed explanation is provided in the online appendix. briefly, prior distributions are specified to represent uncertainty regarding the parameters of interest, including the range of plausible values for the average time to starting art after becoming eligible (1/r g (t)). prior distributions are also specified to represent uncertainty regarding the accuracy of the reported art programme statistics in each year. this uncertainty and the uncertainty regarding art attrition rates affect the model art enrolment inputs. a likelihood function is specified to represent how well the model fits the cd4 data and hiv prevalence data, for a given set of parameter values. the posterior distribution, representing the parameter combinations from the prior distributions that have the highest likelihood values, is then simulated by sampling importance resampling.25 results the posterior estimates of the model parameters are summarised in table 1, and posterior estimates of numbers of patients receiving art are summarised in table 2. over the period mid-2004 to mid-2011, the total number of patients receiving art in south africa increased from 47 500 (95% ci 42 900 – 51 800) to 1.79 million (95% ci 1.65 1.93 million). of the latter, 85% were receiving art through the public health sector, 11% were receiving art through disease management programmes in the private sector, and the remaining 4% were receiving art through community treatment programmes run by ngos. the majority (61%) of patients were women aged 15 or older, men accounted for 31% of patients, and children under the age of 15 comprised the remaining 8% of patients. kwazulu-natal and gauteng were the two provinces with the largest numbers of patients, together accounting for 56% of all patients receiving art. changes over time in numbers of treated and untreated adults in different cd4 stages are shown in fig. 2. as at mid-2011, untreated hiv-positive adults included 58 000 (95% ci 13 000 – 147 000) individuals who had stopped art, 385 000 (95% ci 247 000 – 634 000) art-naive adults with cd4 <200/μl, 1.06 million (95% ci 0.88 1.29 million) with cd4 counts of 200 349/μl, 0.74 million (95% ci 0.61 0.91 million) with cd4 counts of 350 500/μl, and 0.94 million (95% ci 0.77 1.16 million) with cd4 counts >500/μl. the total unmet need in the middle of 2011 (art-naïve adults with cd4 <350/μl plus all adults who had stopped art) was 1.50 million (95% ci 1.24 1.84 million), which is 32% lower than the total unmet need four years previously. estimates of adult art coverage and art enrolment ratios are shown in fig. 3. using previous cd4 thresholds for defining art eligibility (cd4 <200/μl), the fraction of adults eligible to receive art who were actually on art increased from 5.1% (95% ci 4.2 6.1%) in the middle of 2004 to 79% (95% ci 70 85%) by the middle of 2011. however, using the new cd4 thresholds for defining art eligibility (cd4 <350/μl), adult art coverage by the middle of 2011 was 52% (95% ci 46 57%). as noted previously,11 art enrolment ratios are similar when using different cd4 thresholds to define art eligibility. for example, over the period from mid-2010 to mid-2011, the ratio of the number of adults starting art to the number of adults whose cd4 counts fell below the cd4 threshold was 1.64 (95% ci 1.11 2.10) when the cd4 threshold was 200, and 1.56 (95% ci 1.08 1.97) when the cd4 threshold was 350. both ratios are roughly double the target of 80% set in the 2007 2011 nsp, and indicate substantial progress in removing the ‘backlog’ of unmet need that accumulated in previous years. estimates of art access are presented separately for men, women and children in fig. 4. using the cd4 threshold of 350/μl as the criterion for art eligibility, the fraction of art-eligible women who were receiving art by the middle of 2011 (60%, 95% ci 53 65%) was significantly higher than the fraction of art-eligible men who were on treatment (41%, 95% ci 36 46%). a similar difference in magnitude is seen in the art enrolment ratio over the period mid-2010 to mid-2011: using the same art eligibility criterion of cd4 <350/μl, the enrolment ratio was 1.96 (95% ci 1.33 2.51) in women and 1.23 (95% ci 0.83 1.58) in men. over the same period, the ratio of the number of children starting art to the number of new infections in children was 1.13 (95% ci 0.74 1.48). in most previous years, this ratio was below both the male art enrolment ratio and the female art enrolment ratio. discussion south africa has made impressive progress in the rollout of art since the start of the public sector art programme in 2004. the number of patients who started art in 2010/2011 was well in excess of the number of individuals who became eligible to receive art over the same period, exceeding the targets set in the 2007 2011 nsp. the unmet need for art was also reduced by 32% between 2007 and 2011. according to the art initiation criteria that were in place at the time, adult treatment coverage by mid-2011 was close to 80%. however, there appear to be substantial differences between men, women and children in the rate of art initiation. the low rate of art initiation in men relative to women may be a reflection of gender differences in health-seeking behaviour and perceptions that men who seek care are ‘weak’.9 alternatively, the high rate of art initiation in women may be due to higher rates of hiv diagnosis through antenatal screening. the relatively low rates of art initiation in children are probably attributable to the lower rates of hiv testing in children and the greater complexity of paediatric art relative to adult art.26 however, it is difficult to compare adult and paediatric measures of art access meaningfully because the course of hiv infection is so different in children, with many hiv-infected infants dying in the first few months of life before there is an opportunity for testing. this analysis extends previous work4 by including assessment of uncertainty and by incorporating several new data sources. the 95% cis that have been estimated reflect uncertainty regarding rates of cd4 decline, rates of mortality and rates of art retention, and also reflect uncertainty regarding the accuracy of reported art programme statistics. however, the cis do not reflect the uncertainty regarding the hiv incidence rates that have been estimated from the assa2008 model, and this may lead to some exaggeration of precision. cis around the art enrolment ratios are considerably wider in 2009/10 and 2010/11 than in previous years, owing to the change in the way that the department of health has reported public sector art programme statistics. various attempts were made to validate the reported art programme statistics using data from external sources, with limited success. lamivudine sales figures from aspen pharmacare, which until recently supplied 80% of lamivudine in the public sector, were used to obtain crude estimates of numbers of public sector patients on treatment in each quarter. these estimates were not significantly different from the model estimates in table 2 up to the end of 2008, and from october 2009 to march 2010, but were substantially lower than the model estimates from january to september of 2009. numbers of viral load tests performed by the national health laboratory service for public sector clinics were also used to obtain theoretical estimates of numbers of patients receiving art, on the assumption that patients went for viral load testing twice per annum on average. the resulting estimates were slightly higher than the corresponding model estimates up to 2008, but were 18% lower than the model estimates in 2009. finally, the model estimate of the fraction of the 15 49-year-old population on art in the middle of 2008 was compared with the corresponding proportion estimated in the 2008 hsrc national household survey,27 based on testing for the presence of antiretroviral drugs in blood samples: the model estimate of 1.8% (95% ci 1.6 2.0%) was found to be significantly lower than that measured in the survey (3.0%). external data sources therefore do not provide a clear and consistent assessment of the plausibility of the model estimates derived from reported art programme statistics. although attempts were made to produce estimates of art coverage for each province, it was not possible to produce plausible results for two provinces (gauteng and western cape) because the estimated numbers of patients starting art in recent years exceeded the estimated numbers of patients eligible to receive art, in both of these provinces. this could possibly be due to individuals with advanced hiv migrating to urban areas because of the perceived superiority of health services in the major urban centres of gauteng and western cape. the model assumes migration to be independent of hiv status, and may therefore under-estimate the number of hiv-infected art-eligible individuals who migrate into these provinces. alternatively, the problems experienced in producing plausible results for gauteng and western cape may be due to assumed hiv incidence rates in these provinces being too low, or reported numbers of art patients in these provinces being exaggerated. many challenges exist, both in achieving future art rollout targets and in monitoring future progress towards meeting these targets. the new nsp for the 2012 2016 period28 proposes targets that are much more ambitious than those in the previous nsp: the art enrolment target in 2016 is 80% of the new art need in that year plus 80% of the unmet need from previous years. high levels of hiv testing and counselling, as well as expansion of capacity to deliver art, will be required to meet these targets. the new nsp for the 2012 2016 period proposes several measures to strengthen the monitoring and evaluation of south africa’s art programme, including the introduction of a single patient identifier in the health sector and a single registry at the primary care level. it is hoped that these measures will lead to greater precision in the estimation of art coverage in future, as well as a deeper understanding of the factors determining access to care and retention in care. appearing only in the online version of this article is an appendix that provides further detail regarding the method used to model adult art initiation. it also includes a detailed explanation of the bayesian melding procedure: the prior distributions and the data sources on which they are based, the method used to define the likelihood function and the method used to simulate the posterior distribution. acknowledgements i am grateful to the many disease management programmes and ngos that shared data, as well as the national health laboratory service and aspen pharmacare for providing data for validation purposes. references 1. floyd s, molesworth a, dube 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[pmid:17599217]. 13. regensberg ld, hislop ms. a report back on more than four years of hiv/aids disease management in southern africa. south afr j hiv med 2003;4(1):7-10. 13. regensberg ld, hislop ms. a report back on more than four years of hiv/aids disease management in southern africa. south afr j hiv med 2003;4(1):7-10. 14. actuarial society of south africa. assa2008 aids and demographic model. 2011. http://aids.actuarialsociety.org.za (accessed 5 april 2011). 14. actuarial society of south africa. assa2008 aids and demographic model. 2011. http://aids.actuarialsociety.org.za (accessed 5 april 2011). 15. department of health. clinical guidelines for the management of hiv and aids in adults and adolescents. 2010. http://www.doh.gov.za/docs/facts-f.html (accessed 30 july 2010). 15. department of health. clinical guidelines for the management of hiv and aids in adults and adolescents. 2010. http://www.doh.gov.za/docs/facts-f.html (accessed 30 july 2010). 16. johnson lf, stinson k, newell ml, et al. the contribution of maternal hiv seroconversion during late pregnancy and breastfeeding to mother-to-child transmission of hiv. j acquir immun defic syndr 2012 (in press). [http://dx.doi.org/10.1097/qai.0b013e3182432f27] [pmid:22193774]. 16. johnson lf, stinson k, newell ml, et al. the contribution of maternal hiv seroconversion during late pregnancy and breastfeeding to mother-to-child transmission of hiv. j acquir immun defic syndr 2012 (in press). [http://dx.doi.org/10.1097/qai.0b013e3182432f27] [pmid:22193774]. 17. department of health. guidelines for the management of hiv in children. 2010. http://www.doh.gov.za/docs/index.html (accessed 6 march 2011). 17. department of health. guidelines for the management of hiv in children. 2010. http://www.doh.gov.za/docs/index.html (accessed 6 march 2011). 18. shisana o, rehle t, simbayi lc, et al. south african national hiv prevalence, hiv incidence, behaviours and communication survey, 2005. cape town: hsrc press, 2005. http://www.hsrcpress.ac.za (accessed 1 december 2005). 18. shisana o, rehle t, simbayi lc, et al. south african national hiv prevalence, hiv incidence, behaviours and communication survey, 2005. cape town: hsrc press, 2005. http://www.hsrcpress.ac.za (accessed 1 december 2005). 19. shisana o, rehle t, simbayi lc, et al. south african national hiv prevalence, incidence, behaviour and communication survey, 2008: a turning tide among teenagers? cape town: human sciences research council, 2009. http://www.hsrcpress.ac.za (accessed 9 june 2009). 19. shisana o, rehle t, simbayi lc, et al. south african national hiv prevalence, incidence, behaviour and communication survey, 2008: a turning tide among teenagers? cape town: human sciences research council, 2009. http://www.hsrcpress.ac.za (accessed 9 june 2009). 20. auvert b, males s, puren a, taljaard d, carael m, williams b. can highly active antiretroviral therapy reduce the spread of hiv? a study in a township of south africa. j acquir immun defic syndr 2004;36(1):613-21. [http://dx.doi.org/10.1097/00126334-200405010-00010] [pmid:15097305]. 20. auvert b, males s, puren a, taljaard d, carael m, williams b. can highly active antiretroviral therapy reduce the spread of hiv? a study in a township of south africa. j acquir immun defic syndr 2004;36(1):613-21. [http://dx.doi.org/10.1097/00126334-200405010-00010] [pmid:15097305]. 21. rehle tm, shisana o. estimates of eligibility for antiretroviral treatment (art) and projected art impact on aids mortality among south african educators. sahara j 2005;2(3):304-310. [pmid:17600972]. 21. rehle tm, shisana o. estimates of eligibility for antiretroviral treatment (art) and projected art impact on aids mortality among south african educators. sahara j 2005;2(3):304-310. [pmid:17600972]. 22. connelly d, veriava y, roberts s, et al. prevalence of hiv infection and median cd4 counts among health care workers in south africa. s afr med j 2007;97(2):115-120. [pmid:17404672]. 22. connelly d, veriava y, roberts s, et al. prevalence of hiv infection and median cd4 counts among health care workers in south africa. s afr med j 2007;97(2):115-120. [pmid:17404672]. 23. alkema l, raftery ae, clark sj. probabilistic projections of hiv prevalence using bayesian melding. ann appl stat 2007;1(1):229-248. [http://dx.doi.org/10.1214/07-aoas111]. 23. alkema l, raftery ae, clark sj. probabilistic projections of hiv prevalence using bayesian melding. ann appl stat 2007;1(1):229-248. [http://dx.doi.org/10.1214/07-aoas111]. 24. poole d, raftery ae. inference for deterministic simulation models: the bayesian melding approach. j am stat assoc 2000;95(452):1244-1255. [http://dx.doi.org/10.2307/2669764]. 24. poole d, raftery ae. inference for deterministic simulation models: the bayesian melding approach. j am stat assoc 2000;95(452):1244-1255. [http://dx.doi.org/10.2307/2669764]. 25. smith afm, gelfand ae. bayesian statistics without tears a sampling resampling perspective. am stat 1992;46(2):84-88. [http://dx.doi.org/10.2307/2684170]. 25. smith afm, gelfand ae. bayesian statistics without tears a sampling resampling perspective. am stat 1992;46(2):84-88. [http://dx.doi.org/10.2307/2684170]. 26. meyers t, moultrie h, naidoo k, cotton m, eley b, sherman g. challenges to pediatric hiv care and treatment in south africa. j infect dis 2007;196(suppl 3):s474-481. [http://dx.doi.org/10.1086/521116] [pmid:18181697]. 26. meyers t, moultrie h, naidoo k, cotton m, eley b, sherman g. challenges to pediatric hiv care and treatment in south africa. j infect dis 2007;196(suppl 3):s474-481. [http://dx.doi.org/10.1086/521116] [pmid:18181697]. 27. rehle tm, hallett tb, shisana o, et al. a decline in new hiv infections in south africa: estimating hiv incidence from three national hiv surveys in 2002, 2005 and 2008. plos one 2010;5(6):e11094. [http://dx.doi.org/10.1371/journal.pone.0011094] [pmid:20559425]. 27. rehle tm, hallett tb, shisana o, et al. a decline in new hiv infections in south africa: estimating hiv incidence from three national hiv surveys in 2002, 2005 and 2008. plos one 2010;5(6):e11094. [http://dx.doi.org/10.1371/journal.pone.0011094] [pmid:20559425]. 28. south african national aids council. national strategic plan on hiv, stis and tb, 2012-2016. 2011. http://www.doh.gov.za/docs/stratdocs/2011/summary_hiv_nsp.pdf (accessed 6 december 2011). 28. south african national aids council. national strategic plan on hiv, stis and tb, 2012-2016. 2011. http://www.doh.gov.za/docs/stratdocs/2011/summary_hiv_nsp.pdf (accessed 6 december 2011). table 1. posterior estimates of model parameters symbol mean (95% ci) parameters for untreated adults annual rate of progression from cd4 >500 to 350 500 λ1 0.34 (0.28 0.39) annual rate of progression from cd4 350 500 to 200 349 λ2 0.48 (0.40 0.58) annual rate of progression from cd4 200 349 to <200 λ3 0.32 (0.25 0.39) annual rate of hiv mortality if cd4 <200 λ4 0.21 (0.16 0.27) ratio of hiv mortality at cd4 200 349 to hiv mortality at cd4 <200 θ 0.13 (0.05 0.24) parameters for treated adults probability of permanent loss to care in first 6 months after art start κ0 0.078 (0.028 0.141) annual probability of permanent loss to care after first 6 months of art κ1 0.048 (0.018 0.087) proportion of permanent loss to care that is due to death ν 0.74 (0.53 0.92) table 2. numbers of patients receiving art in south africa 2004 2005 2006 2007 2008 2009 2010 2011 currently on art* total 47 500 110 900 235 000 382 000 588 000 912 000 1 287 000 1 793 000 by sex/age men 17 700 37 500 75 000 120 000 183 000 283 000 396 000 551 000 women 25 600 63 600 138 000 228 000 354 000 553 000 777 000 1 090 000 children (<15) 4 200 9 800 22 000 35 000 51 000 76 000 113 000 152 000 by provider public sector 9 600 60 600 163 000 290 000 470 000 748 000 1 073 000 1 525 000 private sector 34 100 43 800 57 000 68 000 86 000 117 000 154 000 190 000 ngo programmes 3 900 6 400 15 000 24 000 32 000 47 000 60 000 78 000 by province eastern cape 5 300 12 600 26 000 43 000 65 000 98 000 137 000 187 000 free state 2 200 4 900 10 000 18 000 29 000 47 000 66 000 91 000 gauteng 13 800 30 800 62 000 95 000 145 000 219 000 280 000 439 000 kwazulu-natal 12 800 30 300 67 000 110 000 174 000 282 000 409 000 558 000 limpopo 2 000 4 800 12 000 21 000 36 000 60 000 101 000 124 000 mpumalanga 3 300 5 800 12 000 24 000 38 000 61 000 96 000 142 000 northern cape 400 1 500 3 000 7 000 9 000 13 000 16 000 19 000 north west 2 700 8 800 21 000 34 000 48 000 70 000 96 000 126 000 western cape 5 000 11 400 21 000 31 000 45 000 64 000 85 000 107 000 started art last year† men 8 400 22 400 43 000 52 000 75 000 118 000 138 000 189 000 women 13 700 42 600 84 000 104 000 149 000 235 000 273 000 380 000 children (<15) 2 700 6 400 13 000 15 000 20 000 29 000 45 000 48 000 total 24 800 71 300 140 000 172 000 243 000 382 000 456 000 617 000 all numbers are rounded to the nearest 1000 (except in the case of 2004 and 2005 totals, which are rounded to the nearest 100). due to rounding, some rows may not sum to the total. all estimates are posterior averages (95% confidence intervals not shown). *totals reflect numbers at the middle of each year. †totals reflect art enrolment over the 12 months up to the middle of the year. fig. 1. multi-state model of decline in cd4 count and art initiation by hiv-infected adults. all states are stratified by age and sex, and all hiv-infected adults are assumed to experience age-specific mortality unrelated to hiv (not shown). fig. 2. numbers of hiv-positive adults, by cd4 count and art status. numbers exclude paediatric hiv infections. bars represent posterior means (95% confidence intervals not shown). fig. 3. adult art access. bars represent posterior means and error bars represent 95% confidence intervals. dashed line in panel (b) represents 2007 2011 national strategic plan target. fig. 4. age and sex differences in art access. bars represent posterior means and error bars represent 95% confidence intervals. dashed line in panel (b) represents 2007 2011 national strategic plan target. abstract introduction methodology results discussion conclusion acknowledgements references about the author(s) ditebogo l. phiri hiv testing services, faculty of public health, johannesburg, south africa anova health institute, johannesburg, south africa kate rees anova health institute, johannesburg, south africa department of community health, school of public health, university of the witwatersrand, johannesburg, south africa natasha davies department of clinical care, faculty of public health, anova health institute, johannesburg, south africa citation phiri dl, rees k, davies n. outcomes of a model for re-testing hiv-negative index contacts in sedibeng, south africa. s afr j hiv med. 2023;24(1), a1482. https://doi.org/10.4102/sajhivmed.v24i1.1482 note: additional supporting information may be found in the online version of this article as online appendix 1. original research outcomes of a model for re-testing hiv-negative index contacts in sedibeng, south africa ditebogo l. phiri, kate rees, natasha davies received: 06 feb. 2023; accepted: 11 apr. 2023; published: 29 may 2023 copyright: © 2023. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: index contact testing is an hiv case-finding approach that elicits sexual or needle-sharing partners, as well as biological children, of people living with hiv (plhiv) and offers them hiv testing services. objectives: we aim to describe the results of an innovative project in sedibeng district that expanded index testing by retesting previously negative contacts and incorporating status-neutral testing. method: we used registers to identify people who previously tested hiv-negative through index testing from march 2019 to september 2021. the individuals were telephonically traced and offered hiv retesting. data were collected on a weekly basis using redcap®. we monitored the number of individuals called, those who came back for retest, and their hiv results. results: fifteen counsellors contacted 968 people over 12 months. forty-eight percent (462 out of 968) of those called returned for testing. of those, 121 (26%) tested positive. overall, 66 out of 276 (24%) men with hiv and 55 out of 186 (30%) women with hiv were identified and linked to antiretroviral treatment (art). fifty-seven percent (194 out of 341) of clients who tested hiv-negative were offered, and 124 out of 194 (64%) initiated, pre-exposure prophylaxis (prep). all individuals who retested hiv-positive had a new diagnosis; none reported having had another positive test result between the original negative and the positive retest. conclusion: revisiting index clients with a previous negative hiv test result is worthwhile, creating an opportunity to identify undiagnosed plhiv and high-risk people for prep. the high positivity rate highlights the importance of providing a sero-neutral approach to hiv testing, including integrating prevention messaging and linkage to prep services. keywords: index contacts testing; routine data; hiv case-finding; seroconversion; sero-different couples; pre-exposure prophylaxis; redcap; u=u. what this study adds: this study has found high positivity rates in people who have recently tested for hiv and provides evidence for the importance of integrating prevention messaging and services into hiv testing. introduction the hiv epidemic remains an important challenge for health systems. index contact testing is an hiv case-finding approach that focuses on eliciting sexual or needle-sharing partners, as well as biological children, of people living with hiv (plhiv) and offering them hiv testing services (hts). it aims to identify people at high-risk of hiv for testing and initiate them on antiretroviral treatment (art) as soon as possible. index testing has been adopted by the south african department of health (doh)1 and is a united states president’s emergency plan for aids relief (pepfar) priority.2 index testing is designed to support achievement of the joint united nations programme on hiv/aids (unaids) 95/95/95 targets, which aims for 95% of the country’s population living with hiv being aware of their hiv-positive status, 95% of those who have been diagnosed being on art and 95% of those on art being virally suppressed.2 the 95/95/95 targets were identified to end the hiv epidemic and minimise hiv-related morbidity and mortality. within this context, index testing is a voluntary service, offered to plhiv by healthcare providers. index testing messaging to encourage uptake by plhiv has been framed to present an opportunity to access disclosure assistance and hts for their partners and children. for hiv programmes, index testing has been identified as an important approach for case-finding, improving positivity rates, and reaching hard-to-find plhiv for testing, especially men.3,4,5 the advantages of such a targeted approach are particularly important in south africa, where the number of plhiv who are unaware of their status has decreased to less than 7% and identifying those who still need to be diagnosed has become more challenging.2 art coverage, however, remains suboptimal6 and index testing can also help to identify partners or children who are living with hiv and are currently disengaged from care or were not linked after diagnosis.2 sero-different couples, where one partner has hiv and the other does not, are common in sub-saharan africa,7,8 contributing to continuing high population transmission rates.9 although it is now known that hiv cannot be transmitted once viral suppression on sustained art has been attained, referred to as u=u (undetectable is equal to untransmittable), the protection of the hiv-uninfected partner is only conferred once the partner living with hiv is consistently adherent to art, and has a viral load below 200 copies/ml.10,11,12,13 index testing is most often offered to people who are newly diagnosed with hiv, those who are not virally suppressed, and those who are re-engaging in care after treatment interruption. thus, contacts of individuals being offered index testing are often not able to benefit from the protection of u=u and remain at higher risk for hiv acquisition, at least until their partner is stable and adherent on art. sero-different couples therefore remain an important target population for hiv prevention initiatives. in addition to its importance in case-finding, index testing provides an opportunity for targeted hiv prevention, by providing a point of entry into health services for the negative partner in sero-different couples, who is at substantial risk of hiv acquisition while their partner is becoming virally suppressed on art.7 the scale up of oral pre-exposure prophylaxis (prep) in south african health services14 provides an opportunity to expand index testing to incorporate the principle of status-neutral testing and offer prep to negative partners in sero-different couples.15,16 sedibeng facilities started rolling out prep in 2020; however, we only started offering prep midway during the project, as we continue to integrate prevention services into hts. anova health institute (anova) is the pepfar district support partner in sedibeng district, south africa. in partnership with sedibeng health district, alongside standard index testing strategies, we implemented an innovative project aiming to ensure that adults known to be in sero-different relationships are offered retesting for hiv and linked to hiv prevention services, including prep. we contacted people who had previously tested negative through index testing services and asked them to return for repeat testing. this article describes the uptake and test results of the index contact retesting approach. methodology setting the study took place in sedibeng health district in gauteng province, south africa. the naomi model estimates that 110 000 plhiv resided in sedibeng in 2021, 40% of whom were men.17 the majority (94%) of plhiv were estimated to know their status, and 89% of those with known status were on art. of the plhiv not on art, 52% were men.17 the naomi model is used by the doh and pepfar for planning and programme monitoring in south africa. it uses programme and survey data to estimate key hiv indicators at district level.18 programme description anova supports the standard doh hiv index testing approach utilised across all facilities in sedibeng district. as part of a quality improvement intervention, the project team developed an innovative element by revisiting individuals who had previously tested hiv-negative as part of routine index testing services. the team undertook a standardised quality improvement project (qip) approach, utilising the plan-do-study-act (pdsa) cycle model to implement this new approach and analyse the outcomes and impact.19 the qip was implemented in 22 primary healthcare facilities across sedibeng district. following development of the qip, 15 hiv testing team counsellors identified individuals who previously tested hiv-negative through index contact testing from march 2019 to september 2021. the implementation of the project started in october 2021, and we report data through september 2022. these individuals were identified by reviewing the index testing registers completed during the time of their last hiv test. we targeted individuals who were in sero-different relationships (index client tested positive and elicited partner tested negative), grouped them according to the date of their last test, telephonically traced them and invited them to facilities for repeat hiv testing through anova’s hiv testing counsellors. the individuals who retested hiv-positive were linked to and initiated on art on the day of their new positive test result while those who tested hiv-negative were offered and linked to prevention services (prep, voluntary medical male circumcision, condom provision). the counsellors offered and performed hiv testing according to the national hts algorithm 2016 revised version, which includes a second confirmatory test should the first result be positive.20 as the project progressed, we developed scripts for common situations encountered by counsellors when telephonically recalling clients (e.g. no longer with the same partner). we also shifted the messaging towards a sero-neutral testing approach wherein individuals were encouraged to test to facilitate access to prep to prevent hiv acquisition, rather than solely testing to become aware of a positive hiv status. for example, the script for initiating the conversation (after introductions) ran: ‘i am just calling to let you know that we now have prep in our facility’ and then provided an explanation about what prep is, and issued the invitation for a hiv test: ‘if you are interested then the first step is to come in to meet with me so you can have another hiv test to confirm that you are still hiv-negative’. the scripts are included as online appendix 1. confidentiality was maintained throughout the implementation of the project, no data were shared beyond the project team and identifying information was removed during analysis. all our testers were trained on how to provide index testing in a safe and ethical manner according to south african guidelines and doh index testing standard operating procedures sop000108/2020. data collection and analysis data were collected on a weekly basis using a redcap database (see figure 1).21,22 anova uses redcap to capture routine programme data. we collected demographic information including age and gender, as well as the date of the repeat test and the repeat test results. three telephonic attempts were made at different times to reach the index contacts before designating ‘unreachable’ as an outcome. figure 1: index contact recall weekly process flow, sedibeng district. we present descriptive statistics for all contacts 15 years and older, including the number of contacts recalled, the rate of return, positivity rate, and prep offer and initiation rates. results are presented as frequencies and proportions. the number of patients who declined repeat hiv testing is reported, including the reasons for declining repeat testing. to investigate associations between age or gender and testing, positivity, prep offer, and prep enrolment rates, we used the chi-squared test for difference between proportions. ethical considerations ethical clearance to conduct this study was obtained from the human sciences research council (no. rec 3/22/08/18). because this qip involved only the use of anonymised aggregated programme data, no informed consent was obtained. results over the 12-month period, 968 people were contacted by the hts counsellors. sixty percent (n = 577) were male, 15% (n = 142) were between 15 and 24 years old, 66% (n = 637) were between 25 and 44 years old and 8% (n = 74) were 50 years or older. just over one-third of people contacted (n = 362) were unreachable on three attempts using the contact details on record. forty-eight percent (n = 462 out of 968) of those called returned to the facility for testing (table 1), and the remaining 144 were reached telephonically but declined the offer to retest. testing rates were the same in women and men at 48% (p = 0.936). since a higher number of the contacts were men, we reached more men for testing (n = 276), compared to women (n = 186). people 50 years and older were more likely to return for testing than those 25–49 years old (61% vs 47%, p = 0.024). positivity was higher in women compared to men, 30% versus 24%, although this was not statistically significant (p = 0.175). positivity was higher in those older than 25 years (15–24 years: 7%, 25–49 years: 48%, 50 years and older: 42%). table 1: index testing recalls in sedibeng district, october 2021 to september 2022. overall, from the 968 individuals identified from the index registers for recall, 12.5% were newly diagnosed with hiv within a maximum interval of 2.5 years (march 2019 – september 2022) between initial negative and subsequent positive test results. all those identified as plhiv were newly diagnosed with hiv at retest, none of them having reported any other positive test in the interim between their original index testing encounter and this retesting intervention. all 121 of these individuals were successfully linked to art following their diagnosis. of the 341 clients who retested hiv-negative, 194 clients were offered prep (57%) and 124 enrolled on prep (64% of those offered). pre-exposure prophylaxis offer rates were similar in age and gender groups, but prep uptake was lower for young people aged 15–24 years compared to people 25–49 years old (48% vs 67%, p = 0.048). for the 144 clients that declined the offer of retesting, the following reasons were given: not ready to test again (17%, n = 24), no longer with the same partner (46%, n = 65), moved to another province (38%, n = 55). discussion we have described an innovative qip designed to strengthen outcomes of hts services through recalling previously hiv-negative index contacts for retesting at least 1 year after their initial contact testing engagement. we found high positivity rates, with just over one-quarter of previously hiv-negative individuals retesting hiv-positive, implying high rates of seroconversion in this population. this project had three important programmatic outcomes: identifying high-risk people to offer prep, identifying hiv quickly in those who had seroconverted since their last hiv test, and reaching a high proportion of men. the project has highlighted high infection rates in sero-different relationships, despite the positive partners having accessed art by the time of initial index testing, and the negative partner accessing hiv testing. it is possible that some of the individuals who retested positive were in the window period during their first test, and either were unaware of the need to retest or did not attend as recommended after 3 months. in both cases, recalling index contacts for retesting provides a way to keep interacting with people at high-risk. it also points to missed opportunities for linkage to hiv prevention services during hts interactions where the clients test hiv-negative. although the project initially started with just offering hiv retesting, the need to integrate prevention services, particularly prep, quickly became clear, to support the client who tested negative to remain so. oral prep has been available in public health facilities in sedibeng since 2020. we only started offering prep midway during the project period but found that more than half of those offered prep took up the offer and initiated prep, including in men, although adolescents and young people had substantially poorer prep uptake. as well as providing prep services, education and awareness are needed for both service providers and users to ensure that prevention messages are structured in ways that are accessible and easily understood. greater effort is needed to strengthen the offer of prep to as many as possible of those testing hiv-negative through index or repeat hiv testing and to understand the reasons clients decline prep despite being identified as belonging to a high-risk group. couple-focussed approaches would enable follow-up of the positive partner to ensure adherence on art and support couples to reach a situation where u=u can be in place. a greater focus on a sero-neutral approach to hiv testing may help to normalise access to, and uptake of, hiv prevention services as well as strengthening the integration of prep offer into index testing and other hts modalities. a similar approach was used in uganda, identifying hiv-negative members of sero-different couples, and offering them prep,23 although they integrated the service into art clinics. the trial was successful in reaching a high proportion of people in sero-different relationships.23 the sedibeng hiv testing team used hts as the entry point to reach a high number of individuals to be enrolled on prep, which we show is another useful approach and could be complementary to offering prep through art sites. in sub-saharan africa, there is generally lower awareness of hiv status in men,24 and men are often diagnosed late.25 previous studies have shown that men who are unaware of their hiv status have often tested in the past, but do not test frequently enough.26 we identified 66 men living with hiv at a 24% positivity rate. close to half (49%) of the men called returned for an hiv test, and more than half (53%) of all plhiv identified were men. although testing rates were similar in men and women, a greater proportion of the original index patients were women, and therefore more men were contacted as partners. because this modality used telephonic outreach, it may have been successful in reaching men because it doesn’t rely on them already being present in the facility and accessing opportunistic offer of testing once already there. this approach shows promise as a way of improving appropriate repeat testing in men, a priority population in south africa. hiv self-testing has been implemented in several settings, including in south africa, and has been shown to increase acceptability of testing,27 including for men.28 the approach has also been used successfully to facilitate partner testing.29,30 the high positivity noted in this project highlights opportunities to use self-testing in hts programmes. for example, distributing a self-test, with advice about when to do it, to any person who tests hiv-negative, could support testing after the window period. the return rate of below 50% also requires attention: hiv self-testing services may support greater testing uptake by increasing convenience. in addition, to improve return rates, there is a need to continuously strengthen the process of recalling, including updating contact details of index contacts. existing stationery should be strengthened to allow for this. a strong emphasis should be placed on communicating the availability and benefits of prep, and other prevention services, when people test negative. it is important for the authors to acknowledge that this project took place during the course of the coronavirus disease 2019 (covid-19) pandemic, including from the time of south africa’s first extensive lockdown in march 2020 up until all restrictions were lifted in june 2022. therefore, it is difficult to assess how much covid-19 restrictions may have impacted both testing and seroconversion rates within the population reached during the project. covid-19 drastically impacted healthcare access in south africa, through myriad mechanisms including health facility closures, limited access to transport, altered health-seeking behaviour and disrupted access to art for people enrolled in the art programme.31,32,33 it is quite possible that some of the original index clients did not attain viral suppression as quickly or successfully because of covid-19 resulting in ongoing, higher risks of transmission to their partners. additionally, their hiv-negative partners may have been less able to access retesting and prevention services in a timely manner. this project is now being rolled out across other anova-supported districts and we continue to analyse outcomes, including seroconversion rates, beyond the covid-19 pandemic era. limitations this project was not designed as a research study, and this analysis uses routine programme data only. there are data quality challenges when using routine data (including missing data and capturing errors), but an added advantage in knowing the approach can be used in a real-world setting. we did not track testing in individuals longitudinally outside of this project, so we are unable to say whether people tested negative during the original window period, whether they had new partners, or whether their partners attended art visits. we are also unable to summarise the time period between individual’s hiv tests, and so were unable to calculate incidence rates. we have adapted our data collection to enable this going forward. conclusion our project indicates that revisiting previously negative index clients is a worthwhile endeavour, both to newly diagnose plhiv and to identify high-risk clients to initiate prep. index testing should continue to be used as an effective modality to identify plhiv not yet aware of their status or not on art, and interaction with contacts should be ongoing, particularly with men, who remain a priority group. the high positivity rate also highlights the critical importance of integrating prevention messaging and linkage to prevention services, including prep, into the offer of index testing. index testing provider training must include a clear emphasis on linking not only those who test positive to art, but also those who test negative to prevention services. in sedibeng, during the period of the qip, rapid art initiation and index testing were offered simultaneously to all newly identified individuals with an hiv-positive test. studies have shown that although same-day initiation may be more effective in supporting linkage to art, achieving high rates of retention and viral suppression remains challenging.17 therefore, some of the seroconversions seen in this population may have arisen from failure to attain u=u with the partners who were rapidly linked to art. prospective research studies are needed to establish how best to provide couples-based services to those identified through index testing to mitigate the risk of ongoing, early transmission while people newly diagnosed are engaged on art before they attain a u=u status. acknowledgements we would like to thank sedibeng health district, hiv testing teams and facility managers for their support in the implementation of this project, as well as prof. james mcintyre and dr helen struthers for providing oversight. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions d.l.p. conceptualised and managed the project. n.d. and k.r. conceptualised the manuscript, and assisted with analysis and write-up. funding information this material is based upon work supported by the united states president’s emergency plan for aids relief (pepfar) through the united states agency for international development (usaid) under cooperative agreement number 72067418ca00023 to the anova health institute. data availability the data that support the findings of this study are not openly available due to the sensitive nature of the data and are available from the corresponding author, d.l.p., upon reasonable request. disclaimer the view and opinions expressed in this manuscript are those of the authors and do not necessarily reflect the official policy or position of any affiliated institution. references south africa national department of health. national consolidated guidelines for the management of hiv in adults, children and infants and prevention of mother to child transmission. pretoria: doh; 2020. pepfar. country operational plan pepfar south africa 2022 strategic direction summary [homepage on the internet]. washington, dc; 2022 [cited 2022 dec 12]. available from: https://www.state.gov/2022-country-operational-plan-guidance/ mwango lk, stafford ka, blanco nc, et al. index and targeted community-based testing to optimize hiv case finding and art linkage among men in zambia [homepage on the internet]. 2020 [cited 2023 mar 28]. available 28 march 2023, from: http://onlinelibrary.wiley.com/doi/10.1002/jia2.25520/full mahachi n, muchedzi a, tafuma ta, et al. sustained high hiv case-finding through index testing 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testing among pregnant women attending antenatal clinics in kenya: a randomized controlled trial. pan afr. med. j. 2019; 13. https://doi.org/10.11604/pamj.2019.33.213.14160 johnson cc, corbett el. hiv self-testing to scale up couples and partner testing. lancet hiv. 2016;3(6):e243–244. https://doi.org/10.1016/s2352-3018(16)00044-8 waterfield kc, shah gh, etheredge gd, ikhile o. consequences of covid-19 crisis for persons with hiv: the impact of social determinants of health. bmc public health. 2021;21(1):299. https://doi.org/10.1186/s12889-021-10296-9 global hiv prevention coalition. maintaining and prioritizing hiv prevention services in the time of covid-19 [homepage on the internet]. 2020 [cited 2023 mar 28]. available from: https://www.unaids.org/sites/default/files/media_asset/maintaining-prioritizing-hiv-prevention-services-covid19_en.pdf dorward j, khubone t, gate k, et al. the impact of the covid-19 lockdown on hiv care in 65 south african primary care clinics: an interrupted time series analysis. lancet hiv. 2021;8(3):e158–e165. https://doi.org/10.1016/s2352-3018(20)30359-3 s e p t e m b e r 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e mixed messages from preclinical data, guidelines and labelling during the development of efavirenz, animal studies were conducted to assess its potential for birth defects. these primate data are likely to have made providers and regulators more aware of the potential risks with efavirenz. malformations were observed in three out of 20 monkey offspring from efavirenz-treated cynomolgus monkeys (versus none among 20 controls) in a developmental toxicity study. the monkeys were dosed throughout pregnancy with a dose resulting in plasma drug concentrations similar to those in humans given 600 mg/day of efavirenz. anencephaly and unilateral anophthalmia were observed in one monkey infant, micro-ophthalmia was observed in another, and cleft palate was seen in a third. as a consequence of this trial, efavirenz was classified as fda category c. in 2005, efavirenz was reclassified as fda category d, indicating an established risk to the human fetus. this classification was based on three reports of myelomeningocele and one of dandy-walker syndrome to the antiretroviral pregnancy register (apr).3 each defect was reported retrospectively and therefore the relative risk cannot be calculated, as the denominator is unknown. two of the reported cases of myelomeningocele (spina bifida) and the case of dandy-walker syndrome were reported in aborted fetuses. the low quality of evidence regarding the safety of efavirenz in pregnancy has led to much uncertainty efavirenz in pregnancy r e v i e w polly clayden1 vivian black2 andrew boulle3 ashraf hassen coovadia4 francois venter2 1hiv i-base, uk 2reproductive health and hiv research unit, university of the witwatersrand, johannesburg 3school of public health and family medicine, university of cape town 4head of hiv services, rahima moosa mother and child hospital and department of paediatrics and child health, university of the witwatersrand, johannesburg 24 clinical guidelines from the national department of health (doh), south africa, for prevention of mother-tochild transmission (pmtct), revised in 2010, recommend that hiv-positive pregnant women with a cd4 count of 350 cells/µl or less commence lifelong antiretroviral therapy (art).1 doh guidance for women initiating art in pregnancy in the public sector – on which the overwhelming majority of hiv-positive south africans rely for their care – recommends they receive nevirapine with tenofovir and lamivudine or emtricitabine at any stage of gestation. in cases where a woman is already receiving art with an efavirenz-based regimen, it is recommended that this should be substituted for nevirapine if she is still in the first trimester of pregnancy. efavirenz is therefore contraindicated in pregnant women at any time during pregnancy; for those already receiving the drug, it is only switched in the first trimester. the concern about the use of efavirenz in pregnancy dates back to preclinical studies. it is the only antiretroviral with preclinical primate data and in turn has the strongest us food and drug administration (fda) category and the most scrutiny during pregnancy.2 the drug also has the most conflicting recommendations, both from guidelines and product labelling. this article is a summary of what we know (and do not know) about using efavirenz in pregnancy. we argue that reconsideration of the risk and benefits of this evidence, which has informed south african guidance, is warranted. t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s e p t e m b e r 2 0 1 0 when making recommendations. this is particularly problematic for guidance in lowand middle-income countries such as south africa, with few antiretroviral options and a public health approach. however, the apr provides some reassurance, as does a meta-analysis performed earlier this year.4 both the registry and the meta-analysis suggest that a twofold increase in overall birth defects can be excluded, but some caution about the potential for increased neural tube defects remains because of the primate data. this, however, needs to be taken in the context of a low incidence of neural tube defects in the general population, which varies from country to country, and is in the range of 0.1% (south africa is 0.36%). with current data it is only possible to exclude a potential tenfold or higher increase in risk, but as the authors of the meta-analysis described below suggest, even a fivefold increase would give an overall increase of less than 1%. it is also important to take into consideration that the neural tube closes by approximately 28 days’ gestation, so the potential risk is for women receiving the drug in the first trimester. since pregnancies are seldom recognised by this stage, if there is a risk it would be in women who conceive while already taking efavirenz. this uncertainty has led to differences in interpretation when making recommendations. the world health organization (who) pregnancy guidelines recommend that efavirenz should not be initiated in the first trimester, but may be initiated in the second and third trimesters.5 the who adult guideline panel was unable to conclude from the evidence available whether there were benefits associated with the use of efavirenz compared with nevirapine in pregnant women after the first trimester and with higher or unknown cd4 cell counts. however, they note that more than half the panel members preferred efavirenz in these situations.6 us guidelines also state that efavirenz use can be considered after the first trimester. other countries such as zambia concur, although most european guidance is similar to south africa.7-9 the british hiv association (bhiva) recommends: ‘until more robust data are available it remains advisable to avoid efavirenz for women who may conceive.’10 these guidelines highlight two issues to consider for women who do conceive on efavirenz: the gestational age at presentation and the plasma half-life of efavirenz. they explain that, after stopping, it can take up to 3 weeks for efavirenz to clear from the plasma. whether there is a key period during the first 6 weeks of fetal development when efavirenz affects central nervous system (cns) development is unknown, as is the minimal teratogenic dose. they suggest ‘discontinuing efavirenz after neural tube closure will not influence the outcome’. furthermore, the prescribing information accompanying the drug is inconsistent. bristol-meyers squibb (bms) markets the originator efavirenz product (sold as sustiva in the usa, canada and some countries in the european union). their package insert states: ‘fetal harm can occur when administered to a pregnant woman during the first trimester.’11 merck sharp and dohme (msd, who market efavirenz as stocrin in south africa and many other parts of the world) provides prescriber information for efavirenz that cautions against conception in patients already on efavirenz as opposed to the prescription of efavirenz in women already known to be pregnant, in line with the who and bhiva recommendations focusing on very early gestational risk. their package insert states that ‘pregnancy should be avoided in women receiving stocrin®’.12 the generic manufacturer aspen states: ‘the use of aspen efavirenz during pregnancy is not recommended, as teratogenicity has been noted.’13 the antiretroviral pregnancy registry the apr is an international registry started in 1989 to prospectively monitor potential birth defects in infants exposed to antiretrovirals in utero. it is one of the largest ongoing pregnancy registries in the world. the objectives of the registry are to provide early warning of major teratogenicity, estimate the risk of birth defects, and collect supplementary data from animal, clinical and epidemiological studies. data collection is through voluntary enrolment by those providing health care to pregnant women exposed to antiretrovirals, and in turn infant follow-up. the registry has summaries of relevant data for all registered antiretrovirals, and reports are updated twice a year. the majority of reports (84.9%) are from the usa, with small numbers from elsewhere (e.g. 1.9% from south africa). one of the current goals of the registry is to increase non-us reporting. as of the last review, through january 2010, the prevalence of birth defects per 100 live births among women with first-trimester exposure to any antiretroviral was 2.8% (95% confidence interval (ci) 2.3 3.3). at this review there were 13 575 pregnancies enrolled in the registry, of which 11 867 (87.4%) reports, of which 5 582 were first-trimester exposures, were used in the analysis. the overall rate reported is not significantly different from the prevalence of defects among women with initial exposure during the second and/or third trimester (2.5 per 100 live births). 25 s e p t e m b e r 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 26 only 14 defects have been recorded in 546 infants born following first-trimester efavirenz exposure (2.6%, 95% ci 1.4 4.3%). these include a single case of myelomeningocele and a single case of anophthalmia with severe oblique facial clefts and amniotic banding. it is worth noting that since the incidence of myelomeningocele in the usa is 4.3 per 10 000 live births it would be expected that the number of cases observed in the prospectively reported register should be greater than this overall. meta-analysis earlier this year, ford et al. performed a systematic review of databases (to 2 february 2010) in order to identify observational cohorts reporting birth outcomes among infants exposed to maternal efavirenz during the first trimester of pregnancy. the findings from this analysis were published in aids in june 2010. slightly modified data (to take in the updated apr report in january) were presented at ias 2010.14 besides birth defects of any kind the investigators looked at spontaneous abortions, termination of pregnancy, stillbirths and preterm delivery. the investigators found that 16 studies met the inclusion criteria for the analysis. these included 11 prospective and 5 retrospective cohorts. nine studies were conducted in low and middle-income countries. six were european and one primarily in the usa. eight were reported in journal articles, and 6 as conference abstracts, one (mtct-plus) was an unpublished cohort and one the apr report. this analysis found a pooled non-significant relative risk for efavirenz versus non-efavirenz of 0.85 (95% ci 0.60 1.21%, p=0.47). the investigators found low heterogeneity between studies (i2 = 0, 95% ci 0 56.3%, p=0.85). the overall prevalence of birth defects was 2.9% (95% ci 2.1 4.0%), range 0 22.6% (95% ci 9.6 41%). this is similar to the ranges observed in the general population: 2.7%, 2.5% and 2.5 8% in the usa, france and south africa, respectively. there was 1 infant out of 1 301 with a neural tube defect (myelomeningocele), giving a prevalence of 0.08% (95% ci 0.02 0.43%). this is also similar to the ranges in the general population, but, as the investigators noted, the upper ci would give a higher prevalence, including than that of south africa. the relative risk between those exposed in the first trimester versus second/third trimester did not differ (rr=0.91, 95% ci 0.46 1.79%, p=0.79). stillbirth, spontaneous abortion and preterm delivery were also within the range of the general population. rates of termination of pregnancy ranged from 5.3% (95% ci 0.64 17.7%) to 33.7% (95% ci 23.7 44.9%). the investigators noted that one study in soweto found a relative risk of termination 5.73 times higher (95% ci 1.45 22.75%, p=0.0017) among women receiving efavirenz compared with other antiretroviral drugs, highlighting a need for careful counselling of women and attitudes among providers. data from frere hospital after the apr, the second largest data set included in the meta-analysis was from a large regional cohort in south africa.15 this is also the largest study to date of efavirenz-based art exposure from the second trimester onwards. in this study bera et al. evaluated data from the efavirenz in pregnancy registry, which is prospective and based at the frere hospital in east london (a referral hospital for a large area of the eastern cape) and set up in january 2006. women who conceived on efavirenz and presented in the first trimester were offered the choice of termination of pregnancy (to 20 weeks’ gestation) or switched to another drug. women who presented at 14 weeks or later and were eligible for art were initiated on an efavirenz-based regimen. between 1 january 2006 and 31 december 2008, 744 women were initiated on efavirenz-based regimens from the second trimester onward. of these, 89 women were still pregnant at the time of evaluation and 32 were lost to follow up. during the same period, 220 women conceived while receiving efavirenz-based art and 42 while receiving nevirapine-based art. of this group, 17 and 7 women were still pregnant and 8 and 2 women were lost to follow-up receiving efavirenz and nevirapine, respectively. women who had received efavirenz-based art throughout the entire first trimester were classified as ‘complete first-trimester exposure’ and those who substituted efavirenz for another drug as ‘partial firsttrimester exposure’. this analysis evaluated data from 851 women with pregnancy outcomes. of 623 women initiated on efavirenz in pregnancy, birth defects occurred in 16 live births, a prevalence of 2.6% (95% ci 1.5 4.2). in 195 women who conceived while receiving efavirenz, birth defects occurred in 5/184 live births and 1/4 stillbirths, a prevalence of 3.3% (95% ci 1.2 7.0). in this group, 93% received efavirenz-based art for longer than 1 month before conception and all pregnancies were unintended. t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s e p t e m b e r 2 0 1 0 27 there were no significant differences in the prevalence of birth defects between the firstand second/thirdtrimester exposure (prevalence ratio 1.27, 95% ci 0.5 3.20, p=0.301). neither were there differences between complete (4/131; 3.1%) and partial (2/53; 3.8%) efavirenz exposure (prevalence ratio 0.81, 95% ci 0.15 4.29, p=0.556). worth noting is that there was also a birth defect in 1 out of 33 live nevirapine-exposed infants, a prevalence of 3.0% (95% ci 0.1 15.8). the prevalence ratio of birth defects following conception on efavirenz compared with nevirapine was 1.08 (95% ci 0.13 8.65, p=0.69). however, the numbers of nevirapine exposures are far too small to draw any conclusions. conflicting findings in retrospective study pactg 219/219c finally, a study of children enrolled in pactg protocols 219 and 219c – a multisite us cohort of children born to hiv-positive women set up to study the long term effects of in utero antiretroviral exposure – recently reported a higher prevalence of birth defects than found in other paediatric cohorts.16 this observation was difficult to interpret as exposed children were enrolled retrospectively up to 1 year of age (only prospective pregnancies are enrolled in the apr), and for reasons discussed below. protocol 219 followed hiv-infected and uninfected children from may 1993 to august 2000. children were eligible if their mothers were enrolled in a pactg trial in pregnancy. in september 2000, protocol 219c was introduced, amending 219 to remove the eligibility criterion mandating enrolment in another pactg trial. birth defect data were recorded at study visits. protocol 219 did not include a direct question about birth defects; 219c included this question. the primary determinant was first-trimester exposure. overall antiretroviral exposure, classes of antiretrovirals and specific antiretrovirals to which at least one child with a birth defect had first-trimester exposure were evaluated. the reference group was children unexposed to the particular antiretroviral (or class of drug) during the first trimester, which included antiretroviralunexposed children, those only exposed in labour, those unexposed to the particular drug but exposed to other antiretrovirals, and children only exposed beyond the first trimester. clinicians were blinded to antiretroviral exposure and the outcome was presence of a birth defect within the first year of life. a total of 117 children with at least one defect were reported out of the study population of 2 202 children. this gave an overall defect prevalence of 5.3% (95% ci 4.4 6.3) and 4.7% (95% ci 3.8 5.6) if just the 103 cases of major defects were included. the prevalence was 4.8% (95% ci 3.7 6.1) in children unexposed in the first trimester and 5.8% (95% ci 4.2 7.8) in exposed children. the majority of defects occurred in the heart and musculoskeletal system. a higher defect rate (5/32, 15.6%) was reported among children exposed to efavirenz in the first trimester compared with unexposed children, adjusted odds ratio 4.31 (95% ci, 1.56 11.86). the defects included 1 laryngomalacia, 1 meningomyelocele, 1 hypospadias, 1 club foot, 1 hypertonicity of extremities and 1 cleft palate. there was also an association in children exposed to lopinavir/ritonavir, but when adjusted for first-trimester folate antagonist exposure, year of birth and perinatal study participation this did not persist (p=0.07), whereas the association with efavirenz continued. it is difficult to know whether this study advances or confuses the field. although based on 2 202 children, only a third (763) were exposed to any antiretroviral during the first trimester, compared with over 5 000 in the apr. consequently, with the exceptions of zidovudine, lamivudine and nelfinavir, few children were exposed to individual drugs, which accounts for the wide range of odds ratios and cis. a similar phenomenon has been observed over the years in the apr with new antiretrovirals, which is followed by a gradual movement towards the mean as the denominator increases, suggesting that initial case notification may drive initial reports to the registry. the findings also generally differ from the apr, in which only didanosine (4.5%, 95% ci 2.6 7.1%) has attracted attention owing to a small but persistent increase in risk of birth defects, while pis in general, and lopinavir/ritonavir (1.7%, 95% ci 0.8 3.1%) in particular, have generally been found to be associated with no increase in risk. as might be anticipated, folate antagonist exposure during the first trimester was associated with an increased prevalence of birth defects, although data were largely incomplete and the observation did not reach statistical significance. the observed confounding of this risk with lopinavir/ritonavir exposure is a reminder not to forget the obvious. discussion there is to date no evidence of an increase in the incidence of birth defects among infants exposed to efavirenz beyond the first trimester, and excluding the retrospective analysis, also no increase among infants s e p t e m b e r 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 28 born to women receiving efavirenz in the first trimester. however, the authors of the meta-analysis note several limitations to the evidence base, including few studies reporting risk of bias or attempting to control for potential confounders, and most importantly the limited sample size. they suggest that although these data should provide reassurance to providers regarding first-trimester exposure, the low incidence of neural tube defects in the general population means a larger sample size is still needed to rule out the increased risk of this specific defect. they write: ‘the balance of risks and benefits of efavirenz in pregnancy merits some recalibration, particularly in resource-limited settings where drug formularies are limited, women of child bearing age represent the majority of those infected with hiv, coinfection with tuberculosis is frequent, and the risk of mortality for those who are eligible for art is high.’ the approach in the new south african guidelines to use of efavirenz is far more cautious than that of the who. whereas the who interpreted the risk as being limited to the first trimester, and allowed for the possibility that some risk may still exist only from first-trimester exposure in spite of the low-quality, conflicting evidence, the south african guidelines do not recommend its inclusion at all in pregnancy. the south african guidelines rely on the 2004 approved package insert for stocrin, which the medicines control council (mcc) believes indicates an absolute bar on the use of efavirenz throughout pregnancy. however the mcc is open to revisiting this package insert should the applicant – in this case msd – apply for an amendment and supply sufficient scientific data to justify the amendment. although it may be prudent to guide prescribers to avoid first-trimester exposure, there seems to be strong rationale to recommend the use of efavirenz in pregnancy in south africa beyond this period, for the following reasons: simplification to maximise adherence. efavirenz must be taken once a day whereas nevirapine is usually dosed twice a day with a 2-week induction phase. the other components of art are dosed daily; use of nevirapine over efavirenz converts a once-daily to a twice-daily regimen. consistency with adult treatment regimens. efavirenz plus tenofovir plus lamivudine or emtricitabine is recommended for almost all non-pregnant adults. simplicity of monitoring. efavirenz does not usually require additional blood tests to the overall regimen. nevirapine requires baseline alanine aminotransferase (alt), and liver function tests (lft) if the baseline alt is abnormal or if patients develop a rash, any significant mucocutaneous reactions, fever, jaundice or abdominal pain. reduction in incidence of toxicity: n efavirenz compared with nevirapine is a safer drug with respect to adverse events, particularly for severe adverse events. n in a representative south african adult population, 7.6% of patients who started art with nevirapine had to stop the drug due to toxicity by 3 years, compared with 1.9% of those starting art with efavirenz having to stop efavirenz due to toxicity. most of the nevirapine substitutions were in the first 3 months of treatment.17 n nevirapine has been associated with an increased risk of toxicity in women with a cd4 count greater than 250 cells/µl in early studies, and a box warning to this effect has been included. the who reviewed the literature and felt reassured to initiate nevirapine in women with high cd4 cell counts. subsequent to this review an article representing over 10 000 patients treated with nevirapine-based art suggested a high cd4 cell count in treatment-naïve patients to be a risk factor for nevirapine toxicity.18,19 co-tuberculosis (tb) treatment: n efavirenz has better blood levels when used with anti-tb treatment, specifically rifampicin, compared with nevirapine, resulting in slightly lower treatment failure.20 n the first-line art choice in the current south african guidelines for a patient with tb would be tenofovir plus lamivudine or emtricitabine plus efavirenz in all patients whether pregnant or not, at odds with the rationale for not recommending efavirenz in pregnant women who do not have tuberculosis. n rash that occurs during co-administration may be due to the tb drugs or nevirapine, and it may occasionally be difficult to determine which to stop. availability of fixed-dose combinations (fdcs): n efavirenz is included in a couple of fdcs that are pending registration in south africa – these are tenofovir plus lamivudine plus efavirenz, and tenofovir plus emtricitabine plus efavirenz. the fda has already tentatively approved such products (tentative only in that patent protection currently prevents them from being marketed in the usa). n fdcs facilitate adherence and simplify the taking of treatment. they take up less space, with transport and storage savings. t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s e p t e m b e r 2 0 1 0 29 it is instructive that in the usa, in 2009, among pregnant women receiving nnrti-based art, over four times as many receive efavirenz compared with nevirapine.21 in a uk cohort, nearly 20% of women receiving an nnrti regimen before conception received efavirenz.22 bera et al. above15 note that all the pregnancies in the women conceiving on efavirenz in their cohort were unintended, and an investigation into the correct application of guidelines in johannesburg revealed that the majority (77 90%) of women were incorrectly assigned to efavirenz with respect to contraception use, and 39% were either trying to conceive or planned to do so in the next year.23 conclusion in short, the recommendation for nevirapine in pregnancy, based on poor data concerning the first trimester and without rationale beyond the first trimester, will result in women being exposed to a more toxic and more complicated regimen, which has significant additional operational challenges and differs from the otherwise very uniform approach to first-line art provision to adults in the national programme. if indeed there is a concern about neural tube defects, the appropriate guideline response should be to focus on the avoidance of conception in women on efavirenz in line with the who recommendations and the prescriber information that accompanies efavirenz when distributed as stocrin. this real risk to maternal health and in turn child health must be weighed up against the theoretical risk of fetal toxicity. we believe that the decision to uniformly use nevirapine in pregnancy is a poor one in the absence of better data, and should be reviewed by the mcc and the department of health. thanks to graham taylor and karen beckerman. references 1. national department of health, south africa: south african national aids council. clinical guidelines: pmtct (prevention of mother-to-child-transmission) 2010. http://www.doh.gov.za/docs/index.html (accessed 23 october 2010). 2. us department of health and human services. food and drug administration. important information about sustiva (efavirenz) and pregnancy. march 2005. http://www.fda.gov/forconsumers/byaudience/forpatientadvocates/ hivandaidsactivities/ucm124885.htm (accessed 23 october 2010). 3. the antiretroviral pregnancy registry. http://www.apregistry.com/ (accessed 23 october 2010). 4. ford n, mofenson l, kranzer k, et al. safety of efavirenz in first trimester of pregnancy: a systematic review and meta-analysis of outcomes from observational cohorts. aids 2010; 24(10): 1461-1470. 5. world health organization. antiretroviral drugs for treating pregnant women and preventing hiv infections in infants. 2010 version. http://whqlibdoc.who.int/ publications/2010/9789241599818_eng.pdf (accessed 23 october 2010). 6. world health organization. antiretroviral therapy for hiv infection in adults and adolescents. 2010 revision. http://whqlibdoc.who.int/ publications/2010/9789241599764_eng.pdf (accessed 23 october 2010). 7. recommendations for use of antiretroviral drugs in pregnant hiv-1 infected women for maternal health and interventions to reduce perinatal hiv transmission in the united states. may 24, 2010. http://www.aidsinfo.nih.gov/ guidelines/guidelinedetail.aspx?guidelineid=9 (accessed 23 october 2010). 8. ministry of health zambia. national protocol guidelines. integrated prevention of mother-to-child-transmission of hiv/aids. september 2009. ministry+of+ health+zambia.+national+protocol+guidelines.+integrated+prevention+of+mo ther-to-child-transmission+of+hiv%2faids.++september+2009 (accessed 23 october 2010). 9. european aids clinical society. clinical management and treatment of hiv infected adults in europe. version 5.2. http://www.europeanaidsclinicalsociety. org/guidelinespdf/1_treatment_of_hiv_infected_adults.pdf (accessed 23 october 2010). 10. british hiv association and children’s hiv association guidelines for the management of hiv infection in pregnant women. hiv medicine (2008). http:// www.bhiva.org/pregnantwomen2008.aspx (accessed 23 october 2010). 11. bristol-meyers squibb. sustiva – package insert. 12. merck sharp dohme. stocrin – package insert. 13. aspen efavirenz. package insert. 14. ford n, mofenson l, kranzer k, et al. safety of efavirenz in first-trimester of pregnancy: a systematic review and meta-analysis of outcomes from observational cohorts. 18th international aids conference. 18-23 july 2010, vienna. oral abstract weax0102. 15. bera e, mccausland k, nonkwelo r, et al. birth defects following exposure to efavirenz-based antiretroviral therapy during pregnancy: a study at a regional south african hospital. aids 2010; 24(2): 283-289. 16. brogly sb, abzug mj, watts dh et al. birth defects among children born to human immunodeficiency virus-infected women. pediatric aids clinical trials protocols 219 and 219c. pediatr infect dis j 2010; 29(8):721-7. 17. boulle a, orrell c, kaplan r, et al. substitution due to art toxicity or contraindication in the first three years of art in large south african cohort. antiviral ther 2007; 12: 753-760. 18. boehringer ingelheim. nevirapine – package insert. 19. kesselring am, wit fw, sabin ca, et al. risk factors for treatment limiting toxicities in patients starting nevirapine-containing antiretroviral therapy. aids 2009; 23(13): 1689-1699. 20. boulle a, van cutsem g, cohen k, et al. outcomes of nevirapine and efavirenzbased antiretroviral therapy when coadministered with rifampicin-based antitubercular therapy. jama 2008; 300: 530-539. 21. griner r, williams p, read j, et al. prenatal exposure to antiretrovirals among hiv-exposed but uninfected children: surveillance monitoring for art toxicities study. 17th conference on retroviruses and opportunistic infections, 16-19 february 2010, san francisco. poster abstract 921. 22. sabin c, huntington s bansi l, et al. use of antiretroviral therapy during and after pregnancy among hiv-infected women already aware of their infection before conceiving. 2nd joint conference of bhiva with bashh, 20-23 april 2010, manchester. poster abstract p154. 23. hanrahan c, schwartz s, rees h, et al. south african antiretroviral treatment guidelines for women: how well are they being followed and for whom? 18th international aids conference, 18-23 july 2010, vienna. poster abstract thpeo120. t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 1 the south african public sector antiretroviral treatment (art) guidelines have recently been changed to include tenofovir in the first-line regimen.1 injectable drugs from the aminoglycoside class are part of the intensive phase of regimen 2 tuberculosis (tb) treatment and the multidrug-resistant (mdr) tb treatment regimen in the south african tb programme. we wish to draw the attention of clinicians managing patients with hivassociated tb to the potential dangers of concurrent administration of these drugs. we present two illustrative cases. case 1 we recently admitted a 47-year-old man with a background of hypertension who had a serum creatinine level of 131 µmol/l prior to art. he was diagnosed with pulmonary tuberculosis (mycobacterium tuberculosis was cultured from his sputum). because he had had a fully treated episode of pulmonary tuberculosis in 2007, he was commenced on regimen 2 tb treatment (including streptomycin during the intensive phase) in march 2010. at this time he tested hiv positive, and because he had a cd4 count of 61 cells/µl he was commenced on tenofovir, lamivudine and efavirenz in may 2010, while still receiving streptomycin. he was referred to our hospital 3 weeks later with a 1-week history of weakness, vomiting and confusion. the creatinine level was now 1 902 µmol/l and the urea level 59 mmol/l. he was admitted, tenofovir was switched to stavudine, streptomycin was stopped, and he received intravenous rehydration and a broad-spectrum antibiotic. his blood culture was negative and urine microscopy showed no evidence of urinary tract infection. his creatinine level steadily decreased and within 3 weeks was 160 µmol/l. case 2 a 28-year-old hiv-infected man was on a tenofovir-based art regimen when he was diagnosed with mdr tb. he was started on mdr tb treatment including kanamycin and remained on tenofovir. his creatinine level rose from 64 µmol/l to 180 µmol/l within 1 month of starting mdr treatment. he was then referred to our hospital. tenofovir was changed to stavudine and the kanamycin was stopped, yet his creatinine remained elevated 3 months later (125 µmol/l), suggesting that chronic renal damage may have resulted. he will continue to be followed up. discussion the aminoglycosides are potent nephrotoxins, in part because of the high concentrations they attain in the proximal tubular cells (ptcs) – up to 10% of the total parenteral dose may be concentrated in these cells.2 here they undergo retrograde transport through the endoplasmic reticulum, where they can interfere with protein sorting and synthesis,3 and are then transported into the nucleus and mitochondria where they can inhibit mitochondrial ribosomes4 (in a way that is analogous to their bactericidal effect on the small ribosomal unit of bacteria). it is thought that one mechanism through which they cause acute tubular necrosis (and fanconi’s syndrome) is tubular mitochondrial toxicity. like the aminoglycosides, tenofovir attains high concentrations in the ptcs as a result of active uptake into these cells. a substantial proportion of patients taking tenofovir may develop certain of the features of fanconi’s syndrome (a proximal tubular wasting syndrome) as a result of ptc dysfunction. one study reported that 22% of patients on tenofovir developed at least 2 out of 6 features of proximal tubular dysfunction such as hyperaminoaciduria, glycosuria in the presence of normoglycaemia, and hyperphosphaturia.5 tenofovir may also cause renal failure. there is evidence to suggest that tenofovir’s nephrotoxicity is related to tubular mitochondrial toxicity with abnormal mitochondria the risks of concurrent treatment with tenofovir and aminoglycosides in patients with hiv-associated tuberculosis chris kenyon1,2, mb chb, fcp (sa), cert id (sa) nicci wearne3, mb chb, fcp (sa) rosie burton1,2, mb chb, fcp (sa), cert id (sa) graeme meintjes1,2,4,5, mb chb, fcp (sa), mrcp, dip hiv man (sa) 1department of medicine, g f jooste hospital, cape town 2division of infectious diseases and hiv medicine, department of medicine, university of cape town 3division of nephrology, department of medicine, university of cape town 4institute of infectious diseases and molecular medicine, university of cape town 5department of medicine, imperial college london 43 c a s e s t u d i e s – h i v a n d t h e k i d n e y s a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e having been observed on electron microscopy of tubular cells in renal biopsies of patients on tenofovir.6 acute tubular necrosis has been observed in patients who have had a renal biopsy after developing tenofovirrelated acute renal failure.7 when tenofovir was developed there were concerns that it would be nephrotoxic because other nucleotide reverse transcriptase inhibitors (adefovir used to treat hepatitis b and cidofovir used to treat herpes virus infections) are nephrotoxic.7 however, early clinical trials failed to demonstrate any excess risk of renal adverse events in participants receiving tenofovir.8,9,10 these clinical trials did, however, exclude patients with impaired renal function and those on other nephrotoxic drugs. subsequent reports from hiv treatment cohorts showed that tenofovir is associated with mild decreases in glomerular filtration rate when compared with patients on other antiretrovirals.11,12 more importantly, a minority of patients on tenofovir develop acute or chronic renal failure. in a review of studies from developed world settings it was estimated that <1% will develop clinically significant renal impairment.7 in 2006, zimmermann et al. published 5 cases of acute renal failure related to tenofovir and reviewed a further 22 cases that had been reported in the literature to that date.13 in 5 of these 27 patients the renal impairment did not fully resolve after stopping tenofovir. in a recent analysis of the eurosida cohort, increasing exposure to tenofovir was associated with a higher incidence of chronic kidney disease.14 a recently published systematic review and meta-analysis found that there was a modest but statistically significant increase in the risk of acute renal failure in patients on tenofovir compared with other antiretrovirals (risk difference 0.7%, 95% confidence interval (ci) 0.2 1.2). importantly, in 11 of the 17 studies in the meta-analysis patients with abnormal renal function at baseline were excluded, and the majority of the studies reviewed were clinical trials from which patients on other nephrotoxic medications were likely to have been excluded.15 these studies may therefore have underestimated the risk of tenofovir nephrotoxicity by excluding patients at higher risk. there is concern that in sub-saharan africa the risks of tenofovir nephrotoxicity may be greater because of the high background prevalence of renal disease, including hiv-associated nephropathy, and lack of capacity to monitor renal function regularly. an analysis of renal outcomes of the dart study, conducted in uganda and zimbabwe, showed no difference in the incidence of severe reductions in estimated glomerular filtration rate in patients started on tenofovir-based regimens compared with other regimens, but all the patients who died of renal failure (n=11) were on tenofovir. contributing co-morbidities were identified in most of these 11 patients. in one of these patients it was thought that the combination of gentamicin and tenofovir was responsible.16 an additional issue to consider in our setting is that if patients do develop severe renal failure, access to dialysis facilities, especially in rural areas, is limited. it is biologically plausible that the toxicities of aminoglycosides and tenofovir may be additive in the mitochondria of ptcs. analysis of data from the tenofovir expanded-access programme revealed that being on concomitant nephrotoxic medications was an independent risk factor for elevations in serum creatinine during follow-up.17 in a case-control study conducted in a us hiv clinic, concurrent nephrotoxic medication (such as high-dose or chronic non-steroidal anti-inflammatory drugs (nsaids), amphotericin b and aminoglycosides) was shown to independently increase the risk of tenofovir-associated nephrotoxicity (odds ratio 6.4, 95% ci 2.2 18.4).18 indeed, the package insert for tenofovir states that it ‘should be avoided with concurrent or recent use of a nephrotoxic agent’.19 a particular concern is that aminoglycosides for treating tb are prescribed for between 2 and 6 months. it is likely that the risk of nephrotoxicity with tenofovir and aminoglycoside will be greater if co-administered for this long duration. one approach that has been suggested is that the combination could be used, but with close monitoring of serum creatinine. however, given that drug-induced nephrotoxicity may result in acute renal failure within 1 2 weeks this would necessitate a frequency of monitoring and follow-up of results that is not practical in busy hiv and tb programmes. while the new national art guidelines do not address the risks of co-administration of tenofovir and aminoglycosides,1 we think that there is sufficient evidence to concur with a recent recommendation to avoid the co-administration of tenofovir and aminoglycosides whenever possible.20 when considering what to do in the light of this co-toxicity, it is important to recall that the aminoglycosides (kanamycin or amikacin) used in the treatment of mdr tb and the cyclic polypeptide, capreomycin, used in the treatment of extensively drugresistant (xdr) tb, are essential components of these treatment regimens. on the other hand, streptomycin is not a critical component of regimen 2 tb treatment, particularly now that rapid drug susceptibility testing is available to appropriately direct therapy in patients being retreated for tb. we therefore recommend the following: n during the intensive phase of mdr tb treatment (while the patient is on amikacin or kanamycin), do not prescribe tenofovir. in place of tenofovir use zidovudine, stavudine or abacavir. after completing the aminoglycoside component of mdr tb treatment, patients could be switched to tenofovir provided the estimated creatinine clearance is >50 ml/min. this switch to tenofovir is particularly important in patients with hepatitis b co-infection. n the same approach should be used in patients on capreomycin during the intensive phase of xdr tb treatment. capreomycin is also nephrotoxic. n in patients on tenofovir who require regimen 2 tb treatment, omit streptomycin from regimen 2. in 44 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 1 patients starting tenofovir-containing art while on regimen 2 tb treatment, omit the streptomycin from regimen 2 from when they start the tenofovir. in all other respects regimen 2 tb treatment should remain unchanged. our first case highlights another important point: that it is critically important to calculate the estimated creatinine clearance in patients before starting tenofovir, and if it is <50 ml/min, tenofovir should not be used.1 this patient had an estimated clearance of 32 ml/min prior to art (this was probably related to hiv-associated nephropathy and/or hypertensive nephropathy). this patient should therefore not have received tenofovir or streptomycin. it is likely that in this case underlying renal impairment and treatment with two nephrotoxins all contributed to the development of severe acute renal failure. references 1. clinical guidelines for the management of hiv & aids in adults and adolescents. pretoria: national department of health, republic of south africa, 2010. 2. galloe am, graudal n, christensen hr, kampmann jp. aminoglycosides: single or multiple daily dosing? a meta-analysis on efficacy and safety. eur j clin pharmacol 1995;48(1):39-43. 3. sandavol rm, molitoris ba. gentamicin traffics through the secretory pathway and is released in the cytosol via the endoplasmic reticulum. am j physiol renal physiol 2004;286(4):617-624. 4. hobbie sn, akshay s, kalapala sk, bruell cm, scherbakov d, bottger ec. genetic analysis of interactions with eukaryotic rrna identify the mitoribosome as target in aminoglycoside ototoxicity. proc natl acad sci usa 2008;105(52):20888-20893. 5. labarga p, barreiro p, martin-carbonero l, et al. kidney tubular abnormalities in the absence of impaired glomerular function in hiv patients treated with tenofovir. aids 2009;23:689-696. 6. côté hc, magil ab, harris m, et al. exploring mitochondrial nephrotoxicity as a potential mechanism of kidney dysfunction among hiv-infected patients on highly active antiretroviral therapy. antivir ther 2006;11(1):79-86. 7. gitman md, hirschwerk d, baskin ch, singhal pc. tenofovir-induced kidney injury. expert opin drug saf 2007;6(2):155-164. 8. schooley rt, ruane p, myers ra, et al.; study 902 team. tenofovir df in antiretroviral-experienced patients: results from a 48-week, randomized, doubleblind study. aids 2002;16(9):1257-1263. 9. gallant je, staszewski s, pozniak al, et al.; 903 study group. efficacy and safety of tenofovir df vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. jama 2004;292(2):191-201. 10. gallant je, dejesus e, arribas jr, et al.; study 934 group. tenofovir df, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for hiv. n engl j med 2006;354(3):251-260. 11. gallant je, parish ma, keruly jc, moore rd. changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reversetranscriptase inhibitor treatment. clin infect dis 2005;40(8):1194-1198. 12. winston a, amin j, mallon p, et al. minor changes in calculated creatinine clearance and anion-gap are associated with tenofovir disoproxil fumarate-containing highly active antiretroviral therapy. hiv med 2006;7(2):105-111. 13. zimmermann ae, pizzoferrato t, bedford j, morris a, hoffman r, braden g. tenofovir-associated acute and chronic kidney disease: a case of multiple drug interactions. clin infect dis 2006;42(2):283-290. 14. mocroft a, kirk o, reiss p, et al. eurosida study group. estimated glomerular filtration rate, chronic kidney disease and antiretroviral drug use in hiv-positive patients. aids 2010;24(11):1667-1678. 15. cooper rd, wiebe n, smith n, keiser p, naiker s, tonelli m. systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in hiv-infected patients. clin infect dis 2010;51(5):496-505. 16. reid a, stohr w, walker s, et al. severe renal dysfunction and risk factors associated with renal impairment in hiv-infected adults in africa initiating antiretroviral therapy. clin infect dis 2008;46:1271-1281. 17. nelson mr, katlama c, montaner js, et al. the safety of tenofovir disoproxil fumarate for the treatment of hiv infection in adults: the first 4 years. aids 2007;21:1273-1281. 18. castellano c, williams w, kepler t, et al. clinical predictors of tenofovir-associated nephrotoxicity in hiv-1 infected patients. presented at the 17th international aids conference, mexico city, 3-8 august 2008. abstract weab0104. 19. viread (tablets) package insert, 23 february 2007. 20. coyne km, pozniak al, lamorde m, boffito m. pharmacology of second-line antituberculosis drugs and potential for interactions with antiretroviral agents. aids 2009; 23:437-446. acknowledgements. graeme meintjes is supported by the wellcome trust and received satbat research training funded by the fogarty international center and the nih (nih/fic 1u2rtw007373 and 5u2rtw007370). how to calculate creatinine clearance (modified cockroft and gault formula) egfr = (140 – age) × weight (kg) serum creatinine (µmol/l) for females multiply the gfr by 0.85. egfr = estimated glomerular filtration rate. 45 abstract introduction objectives methods results discussion conclusion acknowledgements references about the author(s) lyneshree munsami department of neurology, faculty of health science, university of pretoria, pretoria, south africa clara m. schutte department of neurology, faculty of health science, university of pretoria, pretoria, south africa maryke de villiers department of internal medicine, faculty of health science, university of pretoria, pretoria, south africa juliane hiesgen department of neurology, faculty of health science, university of pretoria, pretoria, south africa citation munsami l, schutte cm, de villiers m, hiesgen j. late-onset efavirenz toxicity: a descriptive study from pretoria, south africa. s afr j hiv med. 2023;24(1), a1439. https://doi.org/10.4102/sajhivmed.v24i1.1439 note: additional supporting information may be found in the online version of this article as online appendix 1. original research late-onset efavirenz toxicity: a descriptive study from pretoria, south africa lyneshree munsami, clara m. schutte, maryke de villiers, juliane hiesgen received: 19 july 2022; accepted: 16 sept. 2022; published: 12 jan. 2023 copyright: © 2023. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the neuropsychiatric side effects of efavirenz occur mainly early during treatment and are usually mild. a lesser-known and serious complication is late-onset efavirenz toxicity causing ataxia and encephalopathy. data regarding this condition are limited. objectives: we describe the clinical picture of late-onset efavirenz toxicity, investigate co-morbidities and report outcomes. method: this descriptive study of all patients with late-onset efavirenz toxicity was conducted over three years at kalafong provincial tertiary hospital, pretoria, south africa. results: forty consecutive patients were identified. mean age was 42.1 years, three patients (7.5%) were male and the mean efavirenz level was 49.0 μg/ml (standard deviation [s.d.]: 24.8). cerebellar ataxia (82.5%) and encephalopathy (47.5%) were the most common presenting features (40.0% had both); four patients presented with psychosis. presence of encephalopathy and/or cerebellar ataxia was associated with higher efavirenz levels compared with psychosis (52.1 μg/ml, s.d.: 24.1 vs 25.0 μg/ml, s.d.: 17.1). in most patients, symptoms resolved, but four patients (10.0%) died, and one patient remained ataxic. conclusion: late-onset efavirenz toxicity typically presented with ataxia and encephalopathy, but psychosis can be the presenting feature. the outcome after withdrawal was good, but the mortality of 10.0% is concerning. recent changes in guidelines favour dolutegravir, but many patients remain on efavirenz, and awareness of the condition is vital. what this study adds: this large, single-centre study contributes to the limited data of hiv-positive patients with late-onset efavirenz toxicity and emphasises its ongoing relevance in clinical practice. keywords: hiv; efavirenz toxicity; ataxia; encephalopathy; psychosis. introduction with more than 8.2 million people living with hiv/aids in 2021, south africa contributes approximately 21% to the global burden of the disease.1 about 71% of the hiv-infected population in south africa receive antiretroviral treatment (art).2 over the years, different art regimens have been used because serious side effects of early antiretroviral drugs had caused significant morbidity and mortality and better drugs became available.3 the non-nucleoside reverse transcriptase inhibitor (nnrti) efavirenz was, until recently, the preferred component of first-line art. it is metabolised predominantly by the cytochrome p450 enzyme cyp2b6. loss of function polymorphisms in the cyp2b6 gene increase the plasma concentrations of efavirenz4 and play a role in the interaction of efavirenz with other antiretroviral drugs or anti-tuberculous (tb) medication.5 efavirenz commonly causes early neuropsychiatric toxicity, which is usually not severe enough to warrant discontinuation of the drug and typically resolves despite continuing efavirenz.6,7 however, from around 2016, symptoms of severe efavirenz toxicity with a delayed onset were recognised in adults and children.8,9,10 cerebellar ataxia and encephalopathy constitute the main features of this new clinical syndrome, which was coined ‘late-onset’ toxicity.11 it was soon evident that these findings occurred especially in women and children associated with a low body weight. polymorphisms in the cyp2b6, have also been associated with slower efavirenz metabolism and toxicity.12 if not recognised early, these side effects can lead to significant morbidity and to the death of patients.8 in 2017, the south african guidelines for first-line art were updated.13 efavirenz has been replaced by dolutegravir since 2020. efavirenz is still recommended for patients with tuberculosis and many patients have opted to stay on efavirenz if they are doing well. a recent study reported a slightly higher prevalence of neural-tube defects and major external structural defects in babies born to mothers exposed to dolutegravir compared to other types of art, but this could not be confirmed in other studies.14,15,16 a south african modelling study found an overall benefit of dolutegravir compared to efavirenz, due to fewer deaths among women and less overall hiv transmission, despite a higher risk of neural-tube defects.17 thus, considering benefits, risks and costs, dolutegravir-based regimens are now preferred for art initiation, including in women intending pregnancy, in sub-saharan africa.18,19 nevertheless, some women of childbearing potential might, after adequate counselling about the individual risks and benefits, opt against dolutegravir during pregnancy. efavirenz remains a good first-line art option for individuals who do not tolerate dolutegravir, or where this drug is contraindicated or declined by the patient.19 at kalafong provincial tertiary hospital (kpth), we have seen an increasing number of patients with ataxia and encephalopathy due to late-onset efavirenz toxicity and still encounter them despite the widely implemented new art regimen. with this study, we aim to characterise the clinical spectrum of late-onset efavirenz toxicity. objectives the objectives of this study were to identify patients with late-onset efavirenz toxicity seen at kpth and describe their clinical presentation. in addition, we aimed to collect data about co-morbidities and outcomes and compare these findings with results from other studies on this topic. finally, efavirenz levels were compared between different subgroups in our case series. methods this descriptive cohort study was conducted at kpth, a tertiary academic hospital affiliated to the university of pretoria, south africa. data were collected over a three-year period, with a retrospective (01 january 2018 – 31 december 2019) and a prospective arm (01 january 2020 – 31 december 2020). we included all adult inpatients and outpatients with hiv on an efavirenz-based art regimen with neuropsychiatric symptoms and signs consistent with late-onset efavirenz toxicity and laboratory-confirmed toxic efavirenz levels. for the retrospective period, discharge summaries from patients admitted to the hospital were screened, files were retrieved from the records department and data transferred into a standardised and anonymised data collection sheet. additionally, a list of all patients with toxic efavirenz levels done at our institution was obtained from the national health laboratory service (nhls) and their files were scrutinised, and if the patients had symptoms of efavirenz toxicity, they were included and their data extracted. we considered neuropsychiatric symptoms to be associated with toxic efavirenz levels if no other cause was identified. routine investigations for encephalopathy were undertaken. in the prospective arm, we obtained written consent for study participation before data collection. all participants in the prospective arm and most in the retrospective arm were assessed by a neurologist. we excluded individuals with toxic efavirenz levels due to intentional overdose or without neuropsychiatric symptoms of toxicity. efavirenz levels were quantified at nhls at charlotte maxeke johannesburg academic hospital using ultra-high performance liquid chromatography with tandem mass spectrometry. data collected for this study included demographic data, laboratory and imaging results, data about clinical presentation, course of disease and outcome. data were exported to a microsoft excel sheet and results analysed using statistical software package ibm® statistical package for social sciences (spss) version 28. we used frequencies for descriptive statistics; for efavirenz levels, the normality of the distribution was tested with shapiro-wilks test and q-q plot. for normally distributed data, variables were reported as means and standard deviation. ethical considerations data collection started after ethical clearance was granted from the university of pretoria (research ethics committee of the faculty of health sciences) and from the research committee of kpth (reference number: 224/2020). participation was voluntary and all participants in the prospective arm provided written informed consent. in individuals with encephalopathy or psychosis, the consent was obtained when the person had regained the ability to consent. in addition, a special form for ‘consent by proxy’ was approved by the ethics committee. the data were anonymised to ensure the privacy and confidentiality of the participants’ information. results demographics over the three-year period, we identified 47 participants with efavirenz levels in the toxic range (> 4 μg/ml). seven patients were excluded: one had intentionally overdosed on his hiv medication; four had no neuropsychiatric symptoms, and two only had a polyneuropathy with no central nervous system symptoms. (a flow chart illustrating the exclusion process is available as online appendix 1). twenty-nine participants were recruited retrospectively (2018–2019) and the remaining 11 prospectively in 2020. most of the participants were female (n = 37, 92.5%). the mean age was 42.1 years (standard deviation [s.d.]: 12.6), with three participants younger than 25 (7.5%) and one older than 65 (2.5%). hiv-related data the demographic characteristics and hiv baseline data are summarised in table 1. regarding the duration of art use, 17 individuals were on an efavirenz-based regimen for one year or less, representing 42.5% of the participants with a known duration of hiv treatment. the others were on treatment for more than one year. most of the participants (n = 26, 65.0%) had cd4 counts of greater than 200 cells/μl, with nine (22.5%) showing a normal cd4 count above 500 cells/μl. the hiv viral load was suppressed in 85.0% of participants. table 1: demographic characteristics and hiv-related data of patients with late-onset efavirenz toxicity. clinical presentation the majority of participants (n = 36) presented with cerebellar ataxia and/or encephalopathy. out of 33 participants who presented with cerebellar signs, 17 did not have encephalopathy; they were ataxic but fully alert, without cognitive impairment. most of the 19 participants with encephalopathy also had cerebellar signs, with only three patients being encephalopathic without ataxia. four participants (10%) presented with psychosis without encephalopathy and only one of those had ataxia. only two participants in the retrospective arm had nystagmus as part of the cerebellar presentation. no participant in the prospective arm had nystagmus. four individuals (10%) had additional features of distal symmetrical polyneuropathy at presentation. all of these had identifiable causes (vitamin b12 deficiency, isoniazid [inh] treatment) for a neuropathy in addition to the underlying hiv infection itself. two patients had additional neurological symptoms; one had tetraparesis (with encephalopathy) and one hemiparesis (with ataxia). table 2 illustrates the clinical presentation of the participants. table 2: clinical presentation of patients with late-onset efavirenz toxicity. efavirenz levels the mean efavirenz level for all participants was 49.0 μg/ml (s.d.: 24.8) with a minimum level of 8.0 μg/ml, and a maximum level of 96.0 μg/ml. this level is about 12 times higher than the upper limit of the therapeutic range of efavirenz, defined as 1.0 μg/ml – 4.0 μg/ml. the mean efavirenz levels of different subgroups are shown in table 3. table 3: efavirenz levels in different subgroups. co-infection and co-medication the most common co-infection was tb, which was found in nine participants. one participant had serological evidence of a cryptococcal infection, but the cerebrospinal fluid (csf) was negative for all cryptococcal tests, and two patients had syphilis. table 4 summarises co-infections and co-medications. table 4: co-infections and co-medication at presentation in patients with late-onset efavirenz toxicity. additional investigations thirty-three patients underwent cerebral imaging with computerised tomography (ct) and out of those, 11 later had magnetic resonance imaging (mri) to exclude an alternative diagnosis. twenty-four of the ct scans were normal. nine ct scans showed abnormalities, three in keeping with general cerebral atrophy, three scans had small granulomata or calcifications, and two showed small hypodensities suggestive of old infarcts. one scan revealed a small, supratentorial space-occupying lesion, which we assessed to be most likely a tuberculoma (the patient had tb, including tb meningitis). out of 11 mri scans, only one showed an additional finding, namely that of cerebellar atrophy in the participant with persistent ataxia. thirty-four participants had a lumbar puncture (lp) performed and out of these, the csf was normal in 28. the csf was abnormal in six cases (three showed non-specific abnormalities probably due to the underlying hiv infection: one had mild pleocytosis and two increased protein levels; furthermore, one had a positive treponema pallidum haemagglutination test and two a combination of pleocytosis and elevated protein, of which one had tb meningitis). nine participants had an electroencephalogram (eeg) recorded, all of them were pathological. eight recorded diffuse slowing in keeping with encephalopathy, and one showed an epileptiform dysfunction. blood results showed abnormalities in 16 participants (40%) and mainly consisted of abnormal liver function tests (lft). out of 12 individuals with abnormal lfts, only one had severe liver impairment. other abnormalities included two cases with positive syphilis serology, one with abnormal thyroid stimulating hormone (tsh) levels, and one with a positive serum cryptococcal antigen test. outcome efavirenz was provisionally stopped in all participants with suspected toxicity and later discontinued, once the supratherapeutic levels were confirmed. in participants with suppressed hiv viral loads, a single drug switch was done from efavirenz to either lopinavir/ritonavir (lpv/r) or atazanavir/ritonavir (atv/r), depending on the lipogram. in those instances where the viral load was not suppressed, a regimen change to zidovudine/lamivudine (azt/3tc) and either lpv/r or atv/r was performed. of the 36 individuals discharged from kpth, 32 were asymptomatic at discharge. participants on average improved after two weeks without efavirenz. only one participant recovered in less than one week; three participants needed 3–4 weeks to improve. the remaining four patients had mild residual symptoms at discharge and at 6-month follow up. one participant remained severely ataxic, unable to mobilise independently and requiring a wheelchair and full assistance in her activities of daily living. her mri of the brain was abnormal, showing cerebellar atrophy and we investigated her extensively for alternative causes of cerebellar disease. four patients passed away during the hospital admission. the deaths were most likely related to the efavirenz toxicity because these patients were encephalopathic and ataxic and were bedridden, with complications secondary to these factors leading to their death. discussion with this study, we contribute to the limited data about late-onset efavirenz toxicity in hiv-positive patients. to the knowledge of the authors, this case series is the largest single-centre study describing clinical presentation and outcome of these patients. most side effects of efavirenz manifest soon after initiation of the drug with central nervous symptoms such as dizziness, sleep disturbances, depression and anxiety.7 often, these symptoms are mild and transient, but more severe cases have been reported.20,21 in addition, a study using data from four aids clinical trial group studies in the united states found a twofold increased risk for suicidality with an efavirenz-containing antiretroviral regimen compared to a regimen without efavirenz.22 only recently, an association between efavirenz toxicity and a delayed onset of ataxia and encephalopathy in adults and children has been reported.8,9 in these reports, high levels of efavirenz were detected and an algorithm for the management of late-onset neurotoxicity, including change of the antiretroviral regimen, was proposed.11 although further research regarding the underlying mechanisms involved in neurotoxicity of efavirenz is needed, there is some evidence indicating that disturbances in mitochondrial function and bioenergetics of cells in the central nervous system are important factors.23 the major metabolite of efavirenz, 8-hydroxy-efavirenz, was found to be toxic in neuron cultures and in humans. altered calcium homeostasis, decreased creatine kinase in the brain, mitochondrial damage, as well as increased pro-inflammatory brain cytokines and cannabinoid system involvement may all be potential mechanisms in the development of toxicity.24 other, recent studies assume a more direct effect of efavirenz. in a study using pharmacokinetic simulations, the efavirenz concentrations in brain tissue were found to be higher compared to plasma or csf concentrations and in a recent study of patients with late-onset efavirenz toxicity, the 8-hydroxy-efavirenz levels were even decreased.12,25 in the first case series of patients with late-onset efavirenz toxicity, the authors already observed a female preponderance and a strong association with low body weight.8 these risk factors were confirmed by other authors, and later the concomitant use of inh was found to increase efavirenz levels and result in neuropsychiatric toxicity.11 a recent study of 15 patients with late-onset efavirenz toxicity found that all had polymorphisms of cyp2b6 which result in slower metabolism of efavirenz.12 isoniazid inhibits the cyp2a6 enzyme, which is an accessory pathway to metabolise efavirenz. although usually only a small proportion of efavirenz is metabolised via this enzyme, it becomes more important in slow metabolisers.26,27 inh co-medication has been shown to be an important additional risk factor for the development of efavirenz-associated toxicity.11 the efavirenz levels in our participants varied from just above therapeutic level to almost 100.0 μg/ml, with a mean efavirenz level of 49.0 μg/ml. reports from other centres show similar efavirenz levels as found in our study – variava et al. reported supratherapeutic levels in 19/20 patients (more than twice the upper limit of normal), with 15 showing concentrations that exceeded the upper limit of assay detection which was 20 mg/l in their laboratory.8 in the study by van rensburg et al., the median efavirenz plasma concentrations were 50.5 (47.0–65.4) μg/ml in participants with late-onset efavirenz toxicity, which was almost identical to our results.12 consistent with other studies, cerebellar ataxia was the most common presenting clinical sign, found in 33 participants (82.5%). nineteen (47.5%) had some degree of encephalopathy, which varied from confusion to coma. most of the participants with encephalopathy also had ataxia, with only three patients being encephalopathic without ataxia. variava et al. reported similar findings, where 11 of 20 patients had encephalopathy with ataxia and the remaining patients had isolated ataxia.8 variava et al. found that no patient in their case series of 20 with severe cerebellar ataxia had nystagmus. cross et al. found nystagmus in four out of seven patients, while van rensburg et al. reported nystagmus in two out of 15 participants with late-onset efavirenz toxicity.11,12 in our case series, only two participants out of 33 with cerebellar ataxia were found to have nystagmus. four of our participants had acute psychosis as the presenting feature. these individuals did not show a reduced level of consciousness or confusion but had delusions and hallucinations. one out of these four had cerebellar ataxia. cross et al. described two patients who had a mood disorder and psychotic symptoms prior to their presentation with ataxia and encephalopathy, one requiring admission to a psychiatric ward.11 in 2002, sabato et al. reported a female patient with a previous history of mental illness, who was on antipsychotic therapy and benzodiazepines, developing severe psychosis and catatonia associated with toxic efavirenz levels.20 other isolated case reports with acute psychosis, have been reported.28,29 the possibility of psychosis as a clinical manifestation of late-onset efavirenz toxicity should be further investigated, and we suggest that psychosis occurring in patients on efavirenz-containing art should prompt measuring efavirenz levels. although four patients had polyneuropathy as an additional clinical sign, we do not consider this as a clinical presentation directly related to efavirenz. there was no temporal association of the neuropathy and the efavirenz toxicity and alternative causes for a neuropathy were found in all patients, in addition to the underlying hiv infection. regarding the outcome, we found similar results as previous reports of patients with late-onset efavirenz toxicity. most patients, 80%, had a resolution of symptoms after discontinuation of efavirenz while still in the hospital, usually within two weeks. four patients had residual symptoms at the time of discharge, but only one patient remained severely ataxic, unable to walk unassisted and requiring help in all activities of daily life. unfortunately, four participants (10%) passed away during their hospital stay. this corresponds to data from variava et al.: in their cohort, three out of 20 women died. this study has some limitations. as a combined retrospective and prospective analysis, complete data were not available for all patients. for example, weight was not measured in the retrospective study period. in addition, we did not test for cyp2b6 genotypes and, therefore, do not know what proportion of our patients were slow metabolisers. as in previous studies of patients with late-onset efavirenz toxicity, our number of participants is relatively low. therefore, although we found trends comparing efavirenz levels of different subgroups, further statistical analysis was limited due to the small numbers. conclusion with this single-centre study, we contribute 40 patients with late-onset efavirenz toxicity, adding to the limited data currently available. although female gender was predominant, male patients may also present with efavirenz toxicity. our results validate an association between efavirenz toxicity and inh. in addition to ataxia and encephalopathy, psychosis might be a presenting feature in late-onset toxicity and should prompt efavirenz level testing. acknowledgements for helpful discussions and manuscript revision we thank d. van zyl and a. zimper. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions all authors contributed to the final manuscript. l.m. conducted the literature review, data collection and cleaning as well as assisted in manuscript write-up. j.h. conducted the study design, literature review, data analysis and manuscript write-up. m.d.v. and c.m.s. assisted with analysis and manuscript review. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability the data that support the findings of this study are available from the corresponding author, j.h., upon reasonable request. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy of the affiliated institutions of the authors. references mid-year population estimates [homepage on the 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https://doi.org/10.1093/jac/dkv183 decloedt eh, maartens g. neuronal toxicity of efavirenz: a systematic review. expert opin drug saf. 2013;12(6):841–846. https://doi.org/10.1517/14740338.2013.823396 curley p, rajoli rk, moss dm, et al. efavirenz is predicted to accumulate in brain tissue: an in silico, in vitro, and in vivo investigation. antimicrob agents chemother. 2016;61(1):e01841–16. https://doi.org/10.1128/aac.01841-16 court mh, almutairi fe, greenblatt dj, et al. isoniazid mediates the cyp2b6*6 genotype-dependent interaction between efavirenz and antituberculosis drug therapy through mechanism-based inactivation of cyp2a6. antimicrob agents chemother. 2014;58(7):4145–4152. https://doi.org/10.1128/aac.02532-14 mcilleron hm, schomaker m, ren y, et al. effects of rifampin-based antituberculosis therapy on plasma efavirenz concentrations in children vary by cyp2b6 genotype. aids. 2013;27(12):1933–1940. https://doi.org/10.1097/qad.0b013e328360dbb4 shah md, balderson k. a manic episode associated with efavirenz therapy for hiv infection. aids. 2003;17(11):1713–1714. https://doi.org/10.1097/00002030-200307250-00024 hinsch mc, reichelt d, husstedt iw. akute psychose als nebenwirkung der therapie mit efavirenz bei metabolischer anomalie: eine wichtige differenzialdiagnose hiv-assoziierter psychosen [acute psychosis as a side effect of efavirenz therapy with metabolic anomalies: an important differential diagnosis of hiv-associated psychoses]. nervenarzt. 2014;85(10):1304–1308. https://doi.org/10.1007/s00115-014-4157-9 pg6-11.html overview provider-initiated counselling and testing (pict): an overview nondumiso makhunga-ramfolo1,   mb chb, msc (clin epidemiol) thato chidarikire2,   msc (med) thato farirai3,   bsw, hon soc sci refiloe matji1,   md, mph, dtcd 1university research co., llc (urc), pretoria 2hiv and aids and stis cluster, national department of health, pretoria 3centers for disease control and prevention (cdc-sa), pretoria south africa has the highest number of people living with hiv in the world. despite this, many south africans do not know their hiv status and uptake of voluntary counselling and testing (vct) has been suboptimal. in clinical settings there are many missed opportunities for hiv diagnosis as most patients are not routinely offered hiv counselling and testing (hct). provider-initiated counselling and testing (pict) has been introduced to ensure that hct becomes the standard of care in all consultations with health providers. pict promotes universal access to prevention, care and treatment services for all clients by increasing the utilisation and acceptance of hct services. this article outlines the rationale for pict as well as providing an overview of the implementation protocol that will equip health care providers with the knowledge required to integrate hct into routine medical care. the epidemiology of hiv according to the world health organization (who), in 2007 more than 33 million people were living with hiv/aids with at least 2.7 million new infections being transmitted annually.1 in a mid-term review of the national strategic plan 2007 2011, the human sciences research council reported that while the hiv epidemic in south africa appears to have stabilised, a significant number of south africans do not know their hiv status and testing is still primarily client initiated.2 according to the south african national hiv prevalence, incidence, behaviour and communication survey, 2008, south africa has an estimated national hiv prevalence of 10.6% (5.3 million people). despite the availability of voluntary counselling and testing (vct) services since 2000, many south africans still do not know their hiv status. hiv-infected patients who consult their family practitioners are still being missed as opportunities to test are lost. in 2007, the who made recommendations to introduce provider-initiated counselling and testing (pict) in addition to client-initiated counselling and testing, also known as vct, as an effective public health intervention to increase access to hiv counselling and testing (hct) and reduce missed opportunities for testing.3 with pict the health care provider routinely offers and recommends an hiv test to all clients, irrespective of the medical diagnosis. the main objectives are to integrate hiv testing into routine medical care, thereby facilitating early diagnosis. by implementing pict, family practitioners can not only learn the client’s hiv status, allowing for appropriate clinical decisions to be made, but also enable all clients to know their status. early diagnosis improves health outcomes of those who are hiv positive, while ensuring that they are provided with information to reduce transmission. the recent hct policy guidelines from the national department of health (ndoh)4 emphasised the need to complement vct through the implementation of pict by all health care providers in both the public and private sectors. the overall goal of this strategy is to assist health care providers to expand access to hct for their clients, thereby reducing the burden of disease in communities. pict as a gateway to hiv prevention, care, treatment and support services the availability of hiv rapid tests and same-day results has increased access to accurate, reliable and costeffective diagnosis. hiv rapid tests allow medical practitioners to test their clients and provide results within a short space of time. the relationship between medical practitioners and their patients places them in an ideal situation to offer patient-centred care, allowing for better decisions to be made. for patients visiting medical practitioners, pict is an important and effective model that forms part of the broader prevention strategy and acts as the gateway to accessing care, support and treatment services. beyond vct – differences between pict and vct while there are many similarities between pict and vct, it is important for the medical practitioner to understand the differences between the two models (table i). similarities between pict and vct both vct and pict are voluntary and require consent from the client. in both models testing is always performed in the client’s best interests, in keeping with acceptable principles of medical ethics, and hiv results are always reported back to the client. in both models the client is supported to deal with the hiv test results. counselling always precedes and follows testing. benefits of pict knowing the client’s hiv status can have benefits for the individual concerned, the provider and the community. for hiv-negative people, knowing their status empowers them to protect themselves from becoming infected with hiv. it provides them with information on how to remain negative by assessing their own behaviour and providing solutions for behaviour change. for hiv-positive people, knowing their status ensures that they can be provided with the appropriate treatment, care and support services and assists them in living positively. couples who know their hiv status are empowered to make safer choices with respect to sexual behaviour, e.g. condom use in discordant couples, implementation of positive living strategies, and accessing treatment for the prevention of mother-to-child transmission (pmtct) of hiv. pict enables medical practitioners to treat their clients appropriately by identifying those who need treatment and/or wellness programmes early. this helps health care providers to improve the quality of medical care rendered to their clients and reduce morbidity and mortality. pict assists in reducing stigma in the community by making hiv testing the norm. it leads to the expansion of care and support services to deal with the demand for services. principles of pict pict does not imply that people are coerced to test, nor does it constitute compulsory or mandatory testing. in implementing pict medical practitioners should be guided by three principles, viz. consent, counselling and confidentiality, also known as the three cs. inappropriate use of pict diminishes trust in health care providers and can lead to poor adherence to treatment and inadequate uptake of referrals. informed consent hiv testing by medical practitioners should only occur when the client or his or her legal surrogate, e.g. parent or guardian, has provided informed consent. the client must be provided with information that is understandable according to his or her language, disability and literacy. the client must also understand the nature of the test and its consequences and also understand the purpose of the exchange of information as being in the best interests of his or her own health, that of the partner, and in the case of a pregnant woman, the fetus or the infant being breastfed. the pict protocol implementing pict in the medical practitioner’s rooms has specific steps that need to be followed. the pict protocol is set out in fig. 1. health education education is aimed at providing basic information to clients on hiv and the pict process. education can be provided to an individual verbally and can be supported by other material, e.g. pamphlets and audiovisual tools. the client’s right to refuse to be tested should be discussed. the content of health education should cover the following: • the difference between hiv and aids • how hiv is acquired and transmission • hiv prevention measures and options for prevention, e.g. medical male circumcision, prevention with positives to prevent transmission to hiv negative partners, reduction in the number of concurrent sexual partners, correct regular condom use and pmtct • the advantages of testing and the importance of early diagnosis • assurance that the process is confidential and of the right to privacy, and that only those directly involved in the person’s care will be informed about their hiv status • the different types of rapid tests and the testing process • understanding the results and that they are not an indication of the disease stage. conselling pre-test counselling individual pre-test counselling must precede all hiv testing. for pict a lengthy counselling session is not required, but the medical practitioner should be guided by the client’s knowledge, needs or requests. some of the key points in pretest counselling in adults are: • assessing the client’s understanding of information provided and reinforcing messages and concepts • assisting the client to determine and assess their risk based on the information provided • assessing the client’s readiness for testing and possible results • obtaining informed consent • in the case of refusal, ascertaining reasons and responding to incorrect beliefs. in addition to gauging whether the information that was given was understood, providers need to conduct a risk assessment with the client as part of the history taking. the aim is to assist the client to identify their own risk and the potential adverse events of their behaviour. a good risk assessment allows the family practitioner to devise an individual risk reduction plan with the client. a risk assessment can be incorporated in the history taking and systemic enquiry about:5 • alcohol use • drug use (especially intravenous drug use) • domestic violence • history of prison incarceration • sexual history, including: • number of previous and current partners • history of unprotected high-risk sexual intercourse, anal and vaginal • rape or sexual assault • sexually transmitted infections. post-test counselling all clients who have been tested should receive post-test counselling (table ii), irrespective of hiv results. the content of post-test counselling will be guided by the hiv test results. testing hiv rapid tests are easy to perform with proper training. results can be provided within 10 15 minutes during client consultation and are as reliable and accurate as enzyme immunoassays (eia). all persons performing hiv rapid testing should follow a stipulated quality assurance programme to ensure accurate and reliable results. hiv testing should be conducted using the accepted national hiv testing algorithm using both a screening and a confirmatory test, as indicated in fig. 2. confidentiality and disclosure while hct is a confidential process, clients should be encouraged to disclose their results to their sexual partners. the concept of shared confidentiality, i.e. that health care providers who contribute directly to the care of the person may have access to his or her results, should be discussed with the client. medical practitioners may also offer to help clients to disclose to their partners. medical practitioners should be cautioned against disclosing hiv results to third parties without either the client’s written consent or a court order. where any doubt exists about the appropriate course of action, medical practitioners should consult with senior colleagues for guidance. references 1. world health organization/unaids. guidance on provider-initiated hiv testing and counselling in health facilities. may 2007. http://whqlibdoc.who.int/ publications/2007/9789241595568_eng.pdf (accessed 15 april 2010). 1. world health organization/unaids. guidance on provider-initiated hiv testing and counselling in health facilities. may 2007. http://whqlibdoc.who.int/ publications/2007/9789241595568_eng.pdf (accessed 15 april 2010). 2. shisana o, rehle t, simbayi lc, et al., and the sabssm iii implementation team. south african national hiv prevalence, incidence, behaviour and communication survey 2008: a turning tide among teenagers? cape town: hsrc press, 2009. 2. shisana o, rehle t, simbayi lc, et al., and the sabssm iii implementation team. south african national hiv prevalence, incidence, behaviour and communication survey 2008: a turning tide among teenagers? cape town: hsrc press, 2009. 3. world health organization/unaids. guidance on provider-initiated hiv testing and counselling in health facilities, may 2007. geneva: who, 2007. 3. world health organization/unaids. guidance on provider-initiated hiv testing and counselling in health facilities, may 2007. geneva: who, 2007. 4. national department of health. hct policy guidelines march 2010. pretoria: ndoh, 2010. 4. national department of health. hct policy guidelines march 2010. pretoria: ndoh, 2010. 5. coates t, mayer k, makadon h, schechtel j. hiv risk assessment: physician and patient communication. j gen intern med 1997;12(11):722-723. 5. coates t, mayer k, makadon h, schechtel j. hiv risk assessment: physician and patient communication. j gen intern med 1997;12(11):722-723. acknowledgements this article was supported by cooperative agreement number u62/ps325199-05 from the centers for disease control and prevention (cdc). its contents are solely the responsibility of the authors and do not necessarily represent the official views of cdc. table i. differences between pict and vct pict vct individual is seeking medical care and hct is recommended and performed by medical practitioner as part of the consultation individual chooses to seek hct services provided are confidential and documented in medical record to ensure continuity of care anonymous or confidential services may be offered primary focus is on identifying hiv-infected people and linking them with prevention, care and treatment services primary focus is on preventing hiv acquisition through risk assessment, risk reduction and testing verbal consent is required and should be documented in the patient record written consent or thumb print for illiterate clients is required first user of the test result is the health care worker to make a correct diagnosis and provide appropriate treatment first user of the test result is the client, who uses the information to make personal life decisions   table ii. post-test counselling positive negative  • inform client of positive test result  • inform the client of negative test result  • explore client’s understanding of results and their implications and supports client in adjusting to result, or refers client to on-site lay counsellor  • give client messages about prevention and how to remain negative, e.g. medical male circumcision, condom use, and reduction in the number of concurrent sexual partners  • inform client of need for hiv care, treatment, support and re-infection  • guide client to develop a risk reduction and behaviour change plan  • advise client of need to get partner/s tested as partner/s may be negative  • advise client that partner needs to be tested  • encourage disclosure to an at-risk third party; discuss to whom, when and how this will be done  • offer tuberculosis questionnaire assessment and refer for investigation if necessary  • offer tuberculosis questionnaire assessment and refers for investigation if necessary  • reinforce the need for annual testing  • perform who clinical staging  • make an appointment for retesting at 32 weeks for pregnant women  • collect blood for cd4 count and make follow-up appointment for results  • refer client to nearby community-based resources for: • partner testing • window period retesting for people at risk of recent exposure • additional prevention counselling  • cervical screening (pap smear) and pregnancy test for females    • refer to appropriate support service as required    • nutrition    • psychosocial support    • for pregnant women, discuss: • plans for childbirth • the availability and use of antiretroviral drugs where indicated to prevent mother-to-child transmission • infant feeding options and support for the mother in implementing her infant feeding choice • hiv testing for the infant and the necessary follow-up • partner testing    • record all information required in the client records     fig. 1. the pict protocol (source: hct policy guidelines, 2010, ndoh4). fig. 2. national hiv testing algorithm (source: hct policy guidelines, 2010, ndoh 4 ). a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e there is an urgent need to develop and/or expand palliative care for children in south africa, and this editorial emphasises the scarcity of an evidence base on which to base clinical and operational decisions. children in africa are more likely to face illness and death before the age of 5 years than anywhere else in the world.1 in south africa, hiv infection is the leading cause of death among children aged less than 5 years,2 and there are approximately 300 000 children living with hiv/aids.3 an essential tool in the spectrum of care offered to hivinfected south african children is antiretroviral therapy (art), and south africa’s children’s art programme is the largest in the world.3 unfortunately, according to the national guidelines the programme currently reaches less than half of the children estimated to need art. if the revised world health organization (who) guidelines for art are considered, the proportion of children who need art but are not accessing it is even greater.3 paediatric wards in south african government hospitals are occupied predominantly by children with hiv and aids-related illnesses.4 providing hospital care for hiv-infected children is extremely stressful for both health care providers and caregivers, and sick children may face demoralising cycles of repeated hospital admissions. the needs of very ill young children are many and complex, and may be overlooked in busy, overstretched health care facilities. furthermore, not all sick children reach a health care facility and therefore are cared for in their own homes, placing a heavy burden on families, communities and informal cadres of health care workers, such as homebased care workers. in an attempt to broaden health care coverage the south african government has adopted a home-based care strategy premised on the belief that families are in the best position, with support from homebased care workers, to deliver a continuum of holistic care from infection through illness and death.5 holistic, ongoing care for very ill, dying and bereaved children and their families is situated within the emerging sub-specialty of paediatric palliative care, which focuses on achieving the best quality of life for children with lifethreatening illnesses and their families.6 children’s palliative care is especially important in an african context because it can be delivered by a range of health care providers (professional and nonprofessional) and can be delivered both in health care facilities and in the home. in south africa, a number of health care facilities, hospices, non-governmental organisations, universities and the department of health are already delivering and developing aspects of children’s palliative care. the hospice and palliative care association of south africa is affiliated to a wider african palliative care association and has been active in children’s palliative care, particularly in advocacy and education. some existing home-based interventions cover components of children’s palliative care; however, palliative care in the form of a comprehensive framework that considers the holistic needs of the child and family is currently limited. in particular, current home-based care programmes may lack an element of support and supervision by professionally trained palliative care providers.7 little attention has been paid to the effectiveness and sustainability of home-based care interventions in providing children’s palliative care. research elsewhere in africa shows that when a nurse-led community-based children’s palliative care intervention is available there are increased referrals, increased prescriptions of essential drugs and improved compliance with treatment regimens.8,9 however, the findings from such studies cannot be directly transcribed to the south african context, where care of children is conducted by relatively unskilled homebased care workers, perhaps with little or no support from professionals trained in palliative care. the marginalisation of palliative care research in africa is well documented. reasons given for this marginalisation include lack of skills and knowledge, professional isolation, poor patient accrual, high attrition, lack of agreement on outcome measures, and lack of a common language.10 there are also unique challenges in developing rigour in sampling design and in reporting.11 importantly, there are ethical challenges to be considered when researching very sick children who are hiv infected.12-14 children’s palliative care in south africa: an urgent need for an evidence base f o r u m laura mary campbell human sciences research council, durban 6 given the numbers of children affected and the need for palliative care to reach large numbers, i advocate that providing an evidence base for children’s palliative care must be a priority. any research should consider including perceptions and experiences of both caregivers and children, and researchers must consider cultural, language and ethical issues. references 1. albertyn r, rode h, millar ajw, thomas j. challenges associated with paediatric pain management in sub saharan africa. int j surg 2009;7(2):91-93. 2. bradshaw d, bourne d, nannan n. what are the leading causes of death among south african children? tygerberg: medical research council, 2003. 3. davies m, keiser o, technau k, et al. outcomes of the south african national antiretroviral treatment programme for children: the iedea southern african collaboration. s afr med j 2009;99(10):730-737. 4. richter l, chandan u, rochat t. improving hospital care for young children in the context of hiv/aids and poverty. j child health care 2009;13(3):198-211. 5. mabude za, beksinska me, ramkissoon a, wood s, folsom m. a national survey of home-based care kits for palliative hiv/aids care in south africa. aids care 2008;20(8):931-937. 6. liben s, papadatou d, wolfe j. paediatric palliative care: challenges and emerging ideas. lancet 2008;371:852-864. 7. uys lr. evaluation of the integrated community-based home care model. curationis 2001;24:75-82. 8. amery jm, rose cj, holmes j, nguyen j, byarugaba c. the beginnings of children's palliative care in africa: evaluation of a children's palliative care service in africa. j palliat med 2009;12(11):1015-1021. 9. craig p, dieppe p, macintyre s, michie s, nazareth i, petticrew m. developing and evaluating complex interventions: the new medical research council guidance. bmj 2008;337(a1655). 10. powell ra, downing j, mwangi-powell f, radbruch l, harding r. advancing palliative care research in sub-saharan africa: from venice to nairobi. eur j palliat care 2008;15(5):228-233. 11. bakitas m, lyons k, dixon j, ahles t. palliative care program effectiveness research: developing rigor in sampling design, conduct, and reporting. j pain symptom manage 2006;31(3):270-284. 12. tomlinson d, bartels u, hendershot e, constantin j, wrathall g, sung l. challenges to participation in paediatric palliative care research: a review of the literature. palliat med 2007;21:435-440. 13. currow d, wheeler j, glare p, kaasa s, abernethy a. a framework for generalizability in palliative care. j pain symptom manage 2008;37(3):373-386. 14. allen d, marshall es. children with hiv/aids: a vulnerable population with unique needs for palliative care. j hospice palliat nurs 2008;10(6):359-367. pg26-31.html conference report top2btm symposium on health care for men who have sex with men (msm) k rebe, mb chb, fcp (sa), dtm&h, dip hiv man (sa) g de swardt, ba (mw) h struthers, msc, mba j a mcintyre, mb chb, frcog anova health institute, johannesburg and cape town, south africa men who have sex with men (msm) are at high risk of hiv acquisition and transmission, and country-specific hiv prevalence rates are always higher in msm than among heterosexual men. south african data confirm this, with reported hiv prevalences of 10.4 33.9% across various studies. donors and government health planners have recognised the need for targeted programmes that address the high burden of hiv transmission and disease in stigmatised populations such as msm, as well as other ‘most at risk populations’ (marps) such as commercial sex workers, drug users and displaced refugees. specific programmes targeting msm and other marps have been included in the south african government’s current national strategic plan for health care and will feature in the new plan under development. until recently, african msm have been under-researched and under-resourced, and this has contributed to their stigmatisation. fortunately this deficiency has been recognised locally and a number of innovative programmes have been developed to address this. the top2btm symposium on prevention, treatment and care of msm sought to bring together these programmes to share experiences. the symposium was held in cape town, organised by the anova health institute with support from usaid and pepfar. the conference attracted 188 delegates from across africa as well as europe and north america, including local msm community representatives, a variety of ngos, government leaders and health care workers as well as prominent msm researchers. dr yogan pillay, south africa’s deputy director general of strategic planning in the department of health, opened the conference on behalf of the minister of health. he affirmed government’s commitment to implementing targeted hiv and sexually transmitted infection (sti) prevention and treatment programmes for marps, including msm. he highlighted the importance of msm-targeted hiv testing programmes, considering pre-exposure prophylaxis (prep), promoting post-exposure prophylaxis (pep), encouraging msm-related research and embracing the concept of antiretroviral treatment as prevention. consideration is being given to providing state-funded art to everyone at a cd4 count of 350 cells/µl or less; this would be especially beneficial to msm, since the risk of hiv transmission is much higher during unprotected penile-anal sex than during unprotected penile-vaginal sex, and lowering the viral load of positive msm is likely to provide a large reduction in hiv transmission. the conference incorporated four main themes: 1. understanding the epidemiology of african (and south african) msm 2. prevention interventions to address hiv among msm in africa 3. health care services for hiv-positive msm 4. research to improve understanding of african msm. the epidemiology of msm in africa the conference proceedings were underpinned by several key concepts in thinking about msm and hiv/aids. first, it is important to recognise that ‘msm’ is a medicalised term describing the behaviour of sex between men; it does not describe a particular identity or population group. msm are extremely diverse and probably have many differences from each other and only one main commonality, having sex with other men. msm vary in the way they conduct their lives and in the sex that they have (for example, not all msm engage in anal sex). they may identify as heterosexual, homosexual or bisexual. they may possess a masculine or feminine identity and they may identify with ‘gay’ or mainstream culture. related to this, it is common throughout africa to find msm who identify as heterosexual and are even married, appear masculine but sometimes have sex with men in addition to women. these msm are particularly difficult to reach with traditional health programmes, as they are in many ways invisible in mainstream society. second, msm experience a range of barriers to accessing health care, not least stigma and prejudice from health care providers themselves. msm often receive counselling that is inappropriate to the lives they lead. for example, hiv prevention messages aimed solely at heterosexuals may ignore the risks of hiv transmission associated with anal sex. msm are concerned about the double stigma they may experience in health centres relating to their sexual orientation and their hiv status, and are often reluctant to seek care. with this background, the keynote address entitled ‘time to act: responding to the hiv pandemic among msm’ was delivered by professor chris beyrer of johns hopkins bloomberg school of public health (usa). systematic reviews of hiv in lowand middle-income countries from which data are available consistently show that msm are at higher risk of hiv compared with the local heterosexual population. aggregate hiv prevalences among african msm are reported to range from 8.8% in sudan to 32.9% in zambia. many of these studies were performed using respondent-driven or ‘snowball’ sampling and therefore may not be generalisable; however, they do highlight the concentrated msm hiv epidemic in countries where there is also a heterosexual epidemic. in addition, pooled data from studies in malawi, botswana and namibia demonstrate health provider stigma: 5.1% of msm sampled report being denied health care services because of their sexual orientation, and 22.3% reported ‘any discriminatory event’ based on sexuality. provider stigma is just one of the challenges currently facing msm. for hiv transmission to occur, transfer of an hiv-containing fluid needs to gain entry into a new individual. the anal mucosal lining is thin, does not self-lubricate and is more liable to mucosal tears than vaginal mucosa. biologically, unprotected anal sex, particularly receptive anal sex, carries a high risk of transmitting hiv (estimated to be approximately 1.4% with each episode, which is roughly 18 times higher than for vaginal sex). condoms and other hiv-risk reducing interventions are therefore extremely important for msm. individual-level hiv risks include unprotected anal sex, high numbers of sex partners, and injecting and non-injecting drug use. structural level risks for msm relate to stigma, discrimination and human rights concerns. a study in namibia, malawi and botswana showed self-reporting of human rights abuse to be high; for example, 5.1% of msm studied had been denied health services based on their sexuality and 23% reported any form of discrimination. this and similar studies show the difficulty faced by msm trying to access healthcare in stigmatised and even criminalised environments. hiv prevention interventions for msm a number of presentations addressed hiv prevention for msm. in sub-saharan africa the incidence of hiv is declining among heterosexual people but continues to rise in msm, illustrating the need for innovative prevention programmes. professor linda-gail bekker from uct called for a time of ‘highly active hiv prevention’. in particular, the role of art as prevention is gaining ground, and this was visible during discussion at the conference. evidence cited included the pre-exposure prophylaxis initiative (iprex) and the recently released results of the hptn 052 trial. iprex recruited 2 499 hiv negative high-risk msm and randomised them to receive either truvada or placebo daily in addition to risk reduction counselling, monthly hiv testing, condom and lube provision and treatment of stis. most recruitment occurred in south america, but 90 msm (4%) were recruited at a cape town site. results showed a 44% reduction in hiv infections in the treatment arm and there was a significant dose-response relationship with better adherence associated with increased protection. guideline documents for the use of prep are available and should be included as an option in the ‘prevention package’ for msm. the hptn 052 trial recruited 1 763 discordant couples (only 3% msm) and randomised them to either early (cd4 count 350 550 cells/µl) or late (cd4 <250) art initiation for the positive partner. the trial found that earlier treatment decreased hiv transmission by 96% over the duration of follow-up. the study was stopped early by its monitoring board, and we await full publication. early indications are good that art did provide significant protection in heterosexual discordant couples, but the study was underpowered for msm. other prevention strategies discussed by speakers for inclusion on the prevention ‘menu’ for msm include: biomedical. in addition to prep, biomedical prevention options for msm include post-exposure prophylaxis (pep), innovative marketing and distribution of condoms (including the female condom for anal sex) and sexual lubricants, sti screening and treatment. rectal microbicides are desirable but are not yet fully developed or proven to be effective. medical male circumcision has not been shown to confer protection for msm, except perhaps if they are exclusively the penetrative partner in anal sex or have concurrent sexual relationships with women, where the infective risk is from penile-vaginal sex. programmes targeting msm who use substances, particularly alcohol and crystal methamphetamine, are required, as are needle exchange programmes. behavioural. counselling programmes to modify high-risk behaviour were emphasised. ‘serosorting’ and ‘seropositioning’ (choosing sexual partners on the basis of their hiv status, or deciding on insertive or receptive anal intercourse depending on partner status) were discussed and may be of value but could be construed as ‘sero-guessing’ in areas where msm do not know their status or misinform potential sex partners. structural. advocacy is needed to decrease stigma and discrimination from general society and from health care providers. dr patrick sullivan emphasised the role of using technology, specifically internet-based and mobile phone-based platforms in prevention. related to this, health4men announced a new mobi site where msm in south africa can access hiv information and ask questions from their cellphones (http://h4m.mobi). health care services for hiv-positive msm professor james mcintyre detailed the history of the anova health institute’s health4men project that led to the establishment of holistic sexual health and hiv prevention and treatment services for msm in south africa. two msm-targeted clinics operate in cape town (the ivan toms centre for men’s health) and soweto (the simon nkoli centre for men’s health), with a satellite clinic in pretoria. these clinics are supported by usaid/pepfar and the department of health and are at the forefront of health provision for msm in africa. the ivan toms centre for men’s health in cape town has been operating for more than 2 years. the clinic offers a primary-care level, holistic package of hiv and sti prevention and treatment services, including the provision of government-funded art for hiv-positive msm who qualify for treatment according to national guidelines. the clinic includes an extensive mental health component in collaboration with the department of psychiatry at groote schuur hospital. approximately 3 000 clients have utilised the clinic’s services so far. about half of these clients are hiv-positive and approximately 500 are currently receiving arvs. the clinic addresses a large non-hiv sti burden, with syphilis and human papillomavirus infection being particularly common. for example, approximately 15% of individuals screened at the clinic are positive for syphilis infection. this clinic is unique in not marketing itself as a ‘gay clinic’ or an ‘hiv clinic’. the client cohort includes both negative and positive people, some of whom receive art, and some remain in wellness programmes prior to initiating treatment. this model has advantages in terms of enabling health-seeking behaviour of msm, as individuals are not identifiable as hiv-positive because of the clinic they attend. many attend for other stis, or for counselling or other services. msm treatment challenges were addressed in a number of sessions at the conference. the importance of training of health care workers to decrease homoprejudice in the health sector was stressed. homoprejudice from the health sector acts as a structural barrier to health care access for msm. already organisations in south africa, including the anova health institute and the desmond tutu hiv foundation, are conducting training programmes for health care providers to address this. the conference discussions emphasised that there are some considerations that must be borne in mind when providing art to msm. some groups of msm are very body conscious, and adherence to drugs causing lipo-atrophy may be low. similarly, msm who develop erectile dysfunction may default protease inhibitors if these are perceived as contributing to the problem. mental health and drug use, and how these may influence adherence, also need to be considered when initiating art in hiv-positive msm. mental health the need to incorporate mental health services into the package of care for msm was highlighted by dr kevin stoloff from the department of psychiatry at groote schuur hospital. his presentation, based on literature review and clinical experience at the ivan toms centre for men’s health, stressed that high levels of anxiety, depression, personality disorders, internalised homoprejudice, substance abuse and other mental health challenges make adherence support vital for msm. these same mental health challenges may precipitate or enhance risk taking among msm. drug use drug use is common, and some communities in south africa are experiencing an explosive increase in crystal methamphetamine use. it is recongised that a large percentage of incident hiv infections in the developed world are related to crystal methamphetamine use, and the same may be true of some groups of south african msm. crystal methamphetamine use lowers inhibitions, increases risky sexual behaviours and may increase biological susceptibility to hiv infection. the drug can also be injected, which raises concerns about needle sharing and transmission of other blood-borne viruses such as hepatitis b and c. crystal methamphetamine and other recreational drugs can have unanticipated drug-drug interactions and side-effects for hiv-positive individuals taking antiretroviral medications, making treatment of such people difficult from medication choice and adherence perspectives. anal intra-epithelial neoplasia an under-recognised health care problem for msm is anal intra-epithelial neoplasia (ain) and anal cancer. a presentation on this issue highlighted the complete absence of screening and treatment services in south africa. ain is a precursor to anal cancer and parallels cervical intra-epithelial neoplasia in women. ain is hpv-associated and may lead to cancers that involve peri-anal and anal skin. screening for and early detection and management of ain may prevent anal cancers. many experts now advocate for the inclusion of ain screening in routine care of msm. not doing so represents a missed opportunity to prevent serious malignancies. transgender issues dr anita radix from the callen-lorde clinic in new york provided valuable insights into the health care needs of transgender people (tg). tg face individual and structural barriers to health care access that are sometimes different from those experienced by msm. there is a dearth of services for tg in africa and many health care providers lack the skills to manage complex psychological and medical issues, including management of complex drug-drug interactions between hormones and art. health care worker sensitisation and education programmes are required. 4. research professor carolyn williamson, a medical virologist at the university of cape town, discussed hiv subtypes that circulate in cape town. the predominant hiv subtype in msm in developed nations is subtype b, contrasting with heterosexual epidemics where subtype c predominates, as in south africa. phylogenetic studies performed with 147 hiv samples from mixed urban and rural south african msm showed approximately 80% to be subtype c, 13% to be subtype b and the balance to consist of various other subtypes. this may have consequences for future vaccine research for msm in africa, as a vaccine directed primarily against subtype b virus may be less effective in a subtype c or recombinant subtype epidemic. clinical skills for health service providers two workshops were included in the symposium, both aimed at improving the clinical skills of health providers who service msm. the first workshop addressed discussing sex and taking a sexual history in a clinical setting. participants received guidance in this arena and learned skills were reinforced by role-play activities with concrete examples of sexual histories taken from msm who had recently attended the ivan toms clinic. the second workshop addressed the use of post-exposure prophylaxis. workshop attendees received background information and practical advice about the administration of pep and for including this hiv transmission reducing intervention into the scope of services provided at their clinics. key learning points from each of these workshops are presented in boxes 1 and 2. summary in summary, the top2btm conference offered a full and broad-ranging programmme with topics covering issues in epidemiology, prevention, treatment and research relating to msm in africa. throughout the conference the diversity of msm communities in south africa was stressed, as was the need for innovative and tailored programmes to address the health needs of these often hidden communities. clinics such as the ivan toms centre for men’s health in cape town have developed expertise and a model for disseminating the knowledge and skills required to achieve the aim of targeted health care for marps, including msm, in the country’s national strategic plan for healthcare. box 1. taking a sexual history in a clinical setting • do not assume heterosexuality among men attending hiv clinics. • ensure privacy and confidentiality of information. • ensure staff training to enable them to confidently address a broad range of sexualities and sexual problems. • explain the context of the sexual history in terms of identifying health risks and individualising an hiv risk reduction plan. • build rapport with patients by asking generalised questions. • thereafter, ask all clients if they have sex with women, men or both. • use local colloquial language that is accessible to clients. • do not moralise about clients’ sexual activities. the aim is to normalise all consensual sex while identifying areas where hiv transmission risk can be reduced. box 2. post exposure prophylaxis (pep) • pep is an effective strategy of using arvs to reduce hiv transmission. • evidence for pep efficacy among msm is limited, as conducting randomised placebo controlled trials would be unethical. • pep is indicated for hiv-negative individuals who have been exposed to hi virus-containing body fluids (semen and blood). • pep should be initiated within 72 hours of exposure. • owing to the high hiv transmission risk associated with anal sex, possible hiv exposure during this sex act should be managed with triple-therapy pep. • clients on pep require counselling and support to minimise medication side-effects and psychological stress. • advocacy is required to increase pep in department of health facilities, especially outside normal clinic hours. both prevention and treatment of hiv among msm were addressed at the symposium. antiretroviral medications are finding a new role as prevention and not just treatment. intervention such as pep, prep and earlier treatment initiation should feature in msm-targeted health programmes. successful art for msm requires special consideration of medication choice and appropriate counselling that is not heteronormative. msm-specific diseases such as anal dysplasia and cancer should be included as part of the package of services for msm. despite south africa’s progressive constitution, msm still experience high levels of structural homophobia which negatively affects risk-taking and health-seeking behaviours, and advocacy is required to decrease this. south africa has produced a substantial body of msm research and has contributed significantly to the global body of knowledge regarding african msm. organisations currently active in this field should continue their efforts. symposia such as top2btm provide an opportunity for information sharing, identification of new opportunities to improve the health of msm, and discussion aimed at furthering a research agenda for msm throughout africa. all presentation slides delivered at the top2btm symposium are available on the anova health institute website (www.anovahealth.co.za) by following the link http://www.anovahealth.co.za/resources/entry/top2btm_msm_symposium/. for more information, please contact health4men on (021) 447-2844. about anova health institute & health4men health4men is a special interest programme of the anova health institute, which receives support from usaid / pepfar. this programme targets men who have sex with men (msm) for hiv and sti prevention and treatment. the programme has a strong community focus aimed at improving social support and decreasing stigma experienced by township-based msm. health4men seeks to improve access to health care services and provides education and training for msm as well as for health care providers who deliver care to msm clients. educational programming includes regular training activities and academic symposia. the most recent of these was the top2btm symposium held in cape town in may 2011. abstract introduction methods modelling results discussion conclusion acknowledgements references appendix 1 appendix 2 appendix 3: data sources for spectrum v. 6.06 (2021) appendix 4 about the author(s) keith jefferis e-consult botswana, gaborone, botswana ava avalos careena centre for health, gaborone, botswana heston phillips unaids, lusaka, zambia mpho mmelesi unaids, gaborone, botswana dinah ramaabya botswana ministry of health and wellness, gaborone, botswana bornapate nkomo botswana ministry of health and wellness, gaborone, botswana charles muthoga botswana harvard aids institute partnership, gaborone, botswana joseph n. jarvis botswana harvard aids institute partnership, gaborone, botswana department of clinical research, faculty of infectious and tropical diseases, london school of hygiene and tropical medicine, london, united kingdom siphiwe ratladi national aids and public health agency, gaborone, botswana robert selato national aids and public health agency, gaborone, botswana john stover avenir health, glastonbury, united states of america citation jefferis k, avalos a, phillips h, et al. five years after treat all implementation: botswana’s hiv response and future directions in the era of covid-19. s afr j hiv med. 2021;22(1), a1275. https://doi.org/10.4102/sajhivmed.v22i1.1275 original research five years after treat all implementation: botswana’s hiv response and future directions in the era of covid-19 keith jefferis, ava avalos, heston phillips, mpho mmelesi, dinah ramaabya, bornapate nkomo, charles muthoga, joseph n. jarvis, siphiwe ratladi, robert selato, john stover received: 17 june 2021; accepted: 18 aug. 2021; published: 15 oct. 2021 copyright: © 2021. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: as the relentless coronavirus disease-2019 (covid-19) pandemic continues to spread across africa, botswana could face challenges maintaining the pathway towards control of its hiv epidemic. objective: utilising the spectrum goals module (goals-2021), the 5-year outcomes from the implementation of the treat all strategy were analysed and compared with the original 2016 investment case (2016-ic) projections. future impact of adopting the new joint united nations programme on hiv/aids (unaids) global aids strategy (2021–2026) targets and macroeconomic analysis estimating how the financial constraints from the covid-19 pandemic could impact the available resources for botswana’s national hiv response through 2030 were also considered. method: programmatic costs, population demographics, prevention and treatment outputs were determined. previous 2016-ic data were uploaded for comparison, and inputs for the goals, aim, demproj, resource needs and family planning modules were derived from published reports, strategic plans, programmatic data and expert opinion. the economic projections were recalibrated with consideration of the impact of the covid-19 pandemic. results: decreases in hiv infections, incidence and mortality rates were achieved. increases in laboratory costs were offset by estimated decreases in the population of people living with hiv (plwh). moving forward, young women and others at high risk must be targeted in hiv prevention efforts, as botswana transitions from a generalised to a more concentrated epidemic. conclusion: the treat all strategy contributed positively to decreases in new hiv infections, mortality and costs. if significant improvements in differentiated service delivery, increases in human resources and hiv prevention can be realised, botswana could become one of the first countries with a previously high-burdened generalised hiv epidemic to gain epidemic control, despite the demands of the covid-19 pandemic. keywords: botswana; spectrum; goals; economic modelling; covid-19; treat all. introduction botswana has made substantial gains against the hiv epidemic and is one of the few countries in africa to have reached the joint united nations programme on hiv/aids (unaids) 90-90-90 targets.1 it was also one of the first african countries to successfully implement a treat all strategy, which included antiretroviral (art) treatment optimisation using the integrase inhibitor dolutegravir, following extensive programmatic and economic modelling contained within the 2016 investment case (2016-ic).2 this strategic investment was aimed at reinvigorating the country’s national hiv response and safeguarding the gains already made against the hiv epidemic. for more than 20 years, the government of botswana had financed the largest portion of its national hiv response, contributing more than 65% of its total hiv expenditures.2 together with generous donor and development partner funding as well as a progressive government-led multisectoral approach, the country was able to decrease infections, save lives and approach epidemiologic control of hiv. as the global coronavirus disease-2019 (covid-19) pandemic, however, continues to negatively impact the country’s medical infrastructure and its global economic standing, botswana may face serious challenges to maintain its current level of healthcare capacity and control of its hiv epidemic. it, therefore, remains critical to clearly delineate and prioritise the areas of hiv prevention, treatment and care that will have the greatest impact to ensure economic and programmatic sustainability over the next decade. to this end, in cooperation with the ministry of health and wellness and national aids and health promotion agency, a technical working group composed of programmatic, economic, clinical and modelling experts used the goals module of spectrum (goals-2021) to analyse the 5-year outcomes since the implementation of the treat all strategy in 2016. the outcomes are then compared with the original 2016-ic projections. the work also considers the future programmatic and economic impact of adopting the new unaids global aids strategy targets through 2030 to end hiv as a public health threat. additional macroeconomic analysis estimates how the financial constraints resulting from the covid-19 pandemic might impact the available resources required to maintain the country’s national hiv response. whilst it was projected that the adoption of the treat all strategy and the use of dolutegravir would reduce new hiv infections, hiv mortality and overall costs, this was the first analysis since 2016 that aimed to quantify and test these estimations. methods modelling analysis spectrum is a modelling system used by hiv experts and policymakers as an analytical tool to support the decision-making processes. the model is designed to use the available country-level data within specific modules to produce outputs that are relevant to programme policy and planning, and the software is continuously updated. using spectrum version 6.06 (2021),3 programmatic costs, as well as demographic, prevention and treatment-related outputs, were determined. the original 2016-ic data were also uploaded into version 6.06 for comparison. prevention data and revised inputs were then used to produce the goals-2021 module through 2030. inputs for the resource needs and family planning modules of spectrum were derived from published reports, strategic plans, programmatic data and expert opinion (see appendix 1: inputs and targets by 2030 for the 2016-ic, aim-2020, goals-2021 and the unaids global aids strategy and appendix 3: data sources for spectrum). additional spectrum modules used for this analysis included demproj for demographic characteristics of the population by age and sex, including assumptions on fertility, mortality and migration; aim to estimate the consequences of the hiv epidemic, such as the number of people living with hiv (plwh), new hiv infections, and aids deaths; famplan to determine the family planning requirements to reach national goals; goals to estimate the costs and impact of the hiv interventions; and resource needs to estimate resources needed for the implementation of the hiv programme, including the cost of care and treatment, prevention, and policy and programmes. economic analysis the 2016-ic whilst published in 2016 was prepared in 2015 and was based mainly on economic and fiscal data up to 2014, with projections of the period up to 2030. in 2021, the 6-year period from 2015 to 2020 was evaluated based on actual data. economic projections were recalibrated with consideration of the possible impact of the covid-19 pandemic, as well as the updated goals-2021 cost projections. currency conversions were made at $1.00 to 11.2 botswana pula (bwp), consistent with the conversions used in the 2016-ic. the following assumptions were also made: donor funding is reduced by 5% a year in real usd terms from the 2016 level (bwp 550 million; $51 million), resulting in the contribution being reduced by 50% in real terms to $25m (in 2016 prices) by 2030. private funding (through direct corporate spending and medical aid schemes) will remain constant at 10% of total national treatment costs through to 2030. public spending is sufficient to fill the gap between the donor and private funding and total treatment and programme costs. the covid-19 pandemic is well controlled without catastrophic economic or human resource demands. modelling results total hiv population comparisons of the goals-2021 outputs for the total hiv population were made using the unaids global aids strategy outputs. by adopting the new unaids strategy, botswana could see a decline in the hiv population of approximately 41 500 over the period 2021–2030 because of reductions in hiv infections. however, without implementation, it is unlikely that there would be substantial decreases overall in the hiv population through 2030. goals-2021 estimated the total hiv population for botswana at 375 900 (353 520 – 400 150) in 2020. it is important to note, however, that from routine adjustments of the spectrum model and the addition of actual programmatic data over the last 5 years (2015–2020), the estimates of the overall hiv population are lower by 44 404 cases from the original 2016-ic model estimates. new hiv infections the estimates of annual new hiv infections that were projected in the 2016-ic are closely aligned with the goals-2021 projections, with a predicted decrease in annual newly acquired hiv infections from 9067 in 2016 to approximately 4406 by 2030. by implementation of the unaids global aids strategy, there would be predictably further reduction to 2772 new infections by 2030. there are two important points to note: firstly, although the 2021 national spectrum aim model projects 8568 annual new hiv infections by 2021, which is significantly higher than the goals-2021 estimates at 4640, the aim module does not consider how all prevention and behavioural interventions impact these projections.4 secondly, the botswana aids incidence survey (bais) is a household epidemiological survey that should be completed every 4 years so that all the spectrum projections can be aligned with the results of the actual country incidence survey. the last bais survey was carried out in botswana in 2012. until the updated results are made available, there remains some degree of uncertainty with all botswana hiv modelling projections. it is expected that the results of bais-v, currently underway, will be available in early 2022, at which time incidence projections can be validated. the larger decreases in hiv infections demonstrated using the new targets of the unaids global aids strategy suggests that even further decreases in new hiv infections could be realised by expanding prevention interventions, such as broadly increasing access to pre-exposure prophylaxis (prep) across all high-risk populations including men who have sex with men (msm), female sex workers (fsws) and those who participate in transactional sexual encounters. hiv incidence as concluded in the 2016-ic, young women remain at the highest risk of hiv acquisition (figure 1). at the current prevention levels, young women will continue to have greater than four times the incidence of young men by 2030 and more than double the incidence of adults overall. this indicates that unless even more resources are invested into programmes targeting young women, their hiv infection rates will continue at the current levels without improvement, and they will continue to suffer the burden of hiv disproportionately. figure 1: incidence amongst young people aged 15–24 and adults aged 15+. although the incidence rates of hiv have fallen steadily since 2016 when the treat all strategy was first launched, the continued higher levels of hiv infections reported amongst young women demonstrate that there is a transition of hiv epidemic in botswana from being a generalised epidemic to one that requires a more targeted and differentiated approach towards high-risk populations. this is particularly true for young women who continue to experience higher levels of unemployment, further exacerbating vulnerability to transactional sexual encounters and other high-risk sexual behaviours.5 figure 2 highlights the need for also targeting high-risk women of child-bearing age to prevent mother-to-child transmission of hiv, with the overall transmission rate in botswana for 2020 being less than 2%, one of the lowest estimated globally.4 there were 229 infections estimated in 2020, 9.6% because of mothers who dropped off antiretroviral treatment (art) during pregnancy and 42.4% of all childhood infections occurring during the breastfeeding period.6 the results from goals-2021 reveal that sexual reproductive health (srh) interventions such as the expansion of the contraceptive method mix and training in its delivery, as well as providing prep during pregnancy and breastfeeding to high-risk women, are now critical to reverse these trends and decrease the incidence of hiv during pregnancy. figure 2: source of new child infections. although the spectrum model does not estimate the prevalence of gender-based violence (gbv), its rise in botswana is well documented with estimates as high as double the global average.7 increases in gbv during the lockdown as a result of the covid-19 pandemic, and the lack of contraception and shelter for abused women and children continue to put women at greater risk of hiv infection.8,9 hiv mortality for the past decade, hiv continues to be the number 1 cause of death in botswana.10 figure 3 demonstrates that gains against hiv mortality could be made by expanding prevention interventions, as well as improving the management of advanced hiv cases and comorbidities. both the unaids global aids strategy and the 2016-ic models incorporate higher hiv prevention targets than what is currently being implemented in botswana. reinvigorating botswana’s hiv prevention programmes will not only prevent hiv infections but also save hundreds more lives. figure 3: annual aids deaths: 2016–2030. further decreases in rates of hiv mortality would be achieved through continued efforts to expand hiv testing availability, including home testing and linkage to care. expanding the clinical capacity of healthcare workers to manage advanced hiv disease and comorbidities must also be prioritised. studies conducted in 2020 reported that out of 14 423 newly initiated patients on art in urban botswana, 25% presented for art initiation with cd4 counts < 200 cells/ml.11 as the average age of patients on art continues to rise, managing serious comorbidities and non-communicable diseases will also increase the risks of clinical complications and drug-drug interaction from polypharmacy. a brief report published in the journal of clinical infectious disease in 2020 shared results from a cryptococcal antigen study conducted in 2018–2019, which revealed that 76% of patients identified with cd4 counts < 200 cells/ml were already art experienced, highlighting the importance of tracking patients who default or are lost to follow-up and improving adherence and psychosocial interventions.12 deaths from cancers also continue to rise within the hiv population in botswana. according to the national cancer registry in 2015, 61.6% of all cancer patients were infected with hiv.13 in 2020, tuberculosis became the fifth highest cause of mortality in 2009 and the seventh highest cause of mortality by 2019.10 according to the who, hiv represented 53.8% of all tuberculosis cases in 2018.14 whilst the incidence of tuberculosis is reducing, it remains a serious risk for plwh. epidemic transition until the results of bais v-2021 are complete, it will remain uncertain whether botswana is trending towards or has already achieved epidemiologic transition, defined as when a country is on a trajectory to control the epidemic. remarkably, all the three models predict that epidemic transition may occur as early as the end of 2022 (figure 4). although promising, this should not cause complacency within the national hiv response but rather highlight the urgent need for continuing to initiate more effective prevention interventions to decrease infections and deaths overall, and better safeguard the hiv population in the era of covid-19, and global political and economic uncertainty. figure 4: incidence mortality ratio. economic analysis gdp economic growth has been slightly higher than expected since the completion of the 2016-ic, with total gdp growth of 19.2% between 2015 and 2019, compared with the 17.3% projected in 2015. however, the most dramatic impact has been observed in 2020 as a result of covid-19, leading to a gdp contraction of almost 9%, compared with the expected growth of around 4%. as a result, real gdp in 2020 was 11% lower than anticipated at the time of preparation of the 2016-ic. much of this loss will be permanent, and although there will be some recovery of gdp lost in 2020, it is projected that real gdp in 2030 will now be 6% smaller than what was projected when the 2016-ic was prepared. government budget the government budget also followed a different course to that anticipated in the 2016-ic (figure 5). it was assumed then that there would be consistent efforts to contain spending and reduce budget deficits given the anticipated decline in revenues. in fact, spending has been higher than anticipated and budget deficits larger, compounded by the impact of covid-19. in the medium term, the smaller size of the economy will have implications for the availability of funds to meet the needs of public spending across the board. the long-term need to contain spending in line with the anticipated decline in revenues remains. by 2030, total government spending is projected to be 11% lower than what was estimated in the 2016-ic. figure 5: real government spending (total). fiscal resources for hiv-aids spending fortunately, the lower projected costs for hiv spending under the goals-2021 scenario appears to be manageable even within the reduced overall envelope for public spending. the requirements for public spending on hiv depend on projections of donor funding and private healthcare spending. even with the assumptions outlined in the methodology of decreased donor funding by 50% in real terms and maintaining the private funding at 10% of total national treatment costs by 2030, public spending is sufficient to fill the gap between the donor and private funding and total treatment and programme costs. the outcome is that public spending on hiv will need to increase modestly from p1.15 billion (in constant 2016 bwp prices) in 2020 to p1.38bn in 2030. as a proportion of total public spending, the requirement will increase from an estimated 2.1% in 2020 to 2.4% in 2023 before declining slightly to 2.3% by 2030. this is lower than the estimated p1.66bn (2.8% of total spending) that would have been required to fully fund hiv spending needs in 2016 (figure 6). if, however, public spending on hiv does not increase as indicated and is maintained at the same proportion of overall public spending as in 2020, then a financing gap of up to p235m (2016 prices) is projected, which would have to be filled by donor funding if total hiv spending is to be maintained. figure 6: public spending on hiv. it is important to note that costs of first-line art regimens fell substantially since the implementation of the treat all strategy in 2016.15 the estimated future costs for art regimens contained within the ic-2016 were set before the global generic costs for dolutegravir had been established.16 anticipating a significant cost reduction, the price of art was set at 50% less beginning in 2020. in fact, the cost of generic co-formulated tenofovir-3tc-dolutegravir (tld) fell to levels that were 66% less than the original 2016-ic projections.15 costs of laboratory commodities and reagents that were used in the 2016-ic, however, significantly increased.17 this may be the result of a more comprehensive costing that was completed in 2021.18 whilst it is highly unlikely that global prices for art will decline any further, advocacy for reductions in laboratory reagents and commodities should be taken up on the national and global level with the same ferocity as was seen for the reduction in art treatment costs and current demands for global covid-19 vaccine equity. this advocacy is now taking place by necessity as lowand middle-income countries demand international patent waivers for covid-19 vaccine technologies and other essential medications, including access to affordable contraception. discussion botswana’s progressive national hiv response has continued to optimise the delivery of art treatment and care, as evidenced with the adoption of the treat all strategy and the first use of dolutegravir in 2016. five years later, more than 97% of patients on art have achieved and maintained viral suppression,19 and the incidence of hiv is expected to have dropped to less than 1%.4 with low overall hiv positive testing yields and estimated art coverage of 95% projected in goals-2021 by 2030, it appears that there is a transition of hiv epidemic in the country from a generalised epidemic to one that is concentrated within specific geographical locations and amongst the most vulnerable and high-risk populations.20 the results of the bais v-2021, expected in early 2022, will confirm whether these modelling predictions hold. nonetheless, it is likely that results will fall somewhere between the national model (aim-2020) and goals-2021 model estimates (see appendix 2: selected outputs and results by 2030 for the 2016-ic, aim-2020, goals-2021 and unaids global aids strategy). these projections are encouraging, as all models show significant reductions in key hiv response indicators. economic estimates predict that if the government of botswana can overcome the substantial economic hardships and human resource constraints caused by the covid-19 pandemic, it should be able to continue to finance the greatest share of the financial requirements of its national hiv response through 2030 – even at the current level of treatment costs and before optimisation of laboratory expenses – if the current level of public spending follows the national economic expectations. however, in order to ensure further reductions in hiv infections and cost savings, botswana must focus its efforts on more targeted interventions for maximal impact. priority areas should include at a minimum the following: greater investment in srh programming for young women of child-bearing age. this includes improved implementation of the availability of contraception, prep for high-risk pregnant and breastfeeding women, larger investment in economic opportunities for young women, and substantial investment in the reduction of maternal mortality and gbv that has continued to rise as a result of the covid-19 pandemic. with low levels of hiv transmission and high coverage of art, targeted hiv prevention interventions should continue to be rapidly and broadly expanded for those at highest risk for hiv infection. expanded community interventions should also be prioritised for districts with the highest incidence rates and for geographically hard-to-reach populations, as well as those who may avoid public healthcare facilities, such as msm, fsw, and those who engage in transactional sexual encounters. additionally, detailed costing and efficiency gains studies of targeted art-based prevention programmes should be carried out. action and advocacy at the national and international level for cost reductions in laboratory reagents, commodities and supplies should be made a strategic priority. laboratory expenses are now more than three times the cost of art in botswana.18 therefore, further laboratory costing and cost-efficiency studies are required as a matter of urgency. additional laboratory saving would also be realised if the botswana national art treatment guidelines were revised to decrease laboratory requirements for long-standing virally suppressed and treatment adherent plwh, who might need less frequent monitoring. investment in the establishment of differentiated care for people living with advanced hiv disease and streamlined service delivery for stable patients would substantially decrease opportunity costs for patients and provide much needed relief at all levels for health workers involved in hiv care and treatment. financial investment in medical service delivery innovation within primary care for plwh would likely show solid financial and human resource returns for the government and patients alike. further investment in capacitating healthcare workers to competently manage advanced hiv care patients should also be prioritised. this is particularly important as the complications and comorbidities that will arise from acute and long-term covid-19 infection emerge. additional investments in covid-19 and hiv co-infection surveillance and clinical research will also prove essential as the medical and economic aftermath of the pandemic becomes known. conclusion the implementation of the botswana treat all strategy in 2016 reinvigorated the country’s hiv response and contributed positively to decreases in hiv infections, mortality and costs, based upon modelling results and economic analysis completed 5 years after the strategy was launched. costing estimates made in the ic-2016 also proved to be accurate, despite significant increases in laboratory expenses, which were offset by the lowered estimates of the overall hiv population. with continued widespread access to hiv testing, art treatment and care, botswana is likely to achieve the unaids 95-95-95 before the year 2025, if targeted hiv prevention interventions can be sustained and successfully implemented across all high-risk populations. if the final incidence results of the bais v-2021 survey prove to be aligned with the goals-2021 spectrum estimates and if significant improvements in differentiated service delivery can be realised, botswana could become one of the first countries with a previously high-burden, generalised hiv epidemic to transition to epidemic control. importantly, as a result of the country’s progressive financial investment and the continued optimisation of art treatment, along with the dramatic decline in the costs of art, the hiv epidemic in botswana is no longer the major driver of health costs overall. moving forward, by ring fencing approximately 2.4% of gdp, in addition to continued donor and private funding, the government of botswana should be able to financially maintain its current hiv response. however, if the health demands of the country’s covid-19 pandemic are not controlled successfully and the country’s economic recovery falls short, this could, instead, negatively impact the success of the country’s hiv epidemic control. therefore, the economic impact of covid-19 must continue to be closely monitored, and the commitment towards ending botswana’s hiv epidemic must be further strengthened. acknowledgements special thanks go to ms mia lebanna for administrative assistance, sikhulili moyo, phd, and kago kagiso for critical review, and dr chelsea morronni for contributing srh expertise. competing interests a.a. has received research support from mylan and participated in the advisory boards for viiv, johnson & johnson and mylan. all other authors have declared that no competing interest exists. authors’ contributions the following authors contributed to the report conceptualisation, methodology, formal analysis and writing of the article: a.a., h.p., k.j. and m.m. the following authors contributed their programmatic expertise with data curation, resources, validation and critical review: d.r., b.n., s.r., r.s., j.n.j. and c.m. the following authors contributed their lab costing expertise: j.n.j. and c.m. the following author completed macroeconomic analysis: k.j. the following authors wrote, reviewed and edited the first and final drafts: k.j., a.a. and h.p. project administration was led by a.a. ethical considerations the manuscript consists of excerpts of the public health document and did involve research or human subjects. the report was approved by the ministry of health and wellness and the national aids health promotion agency of botswana. ethical clearance number: hpdme 13/18/1. funding information the research work received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability all data used are within the public domain. spectrum national file is available on the unaids website (http://aidsinfo.unaids.org/). disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references unaids. 2020 global aids update – seizing the moment – tackling entrenched inequalities to end epidemics [homepage on the internet]. 6 july 2020. available from: unaids.org/sites/default/files/media_asset/2020_global-aids-report_en.pfd botswana ministry of health and wellness. the 2016 botswana investment case. gaborone: unaids; 2016. spectrum version 6.06 (2021) [homepage on the internet]. available from: https://www.avenvirhealth.org/software-spectrumphp. 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(crag) screening in human immunodeficiency virus (hiv) – positive patients with cd4 counts of 100–200 cells/ml in botswana. brief report. clin infect dis. 2021;72(9):1635–1638. https://doi.org/10.1093/cid/ciaa899 botswana. princess marina hospital chemotherapy register, 2020–2021. gaborone: princess marina hospital; 2021. world health organization. 2019 global tuberculosis report. geneva: who; 2019. botswana ministry of health and wellness. drug costing and forecasting technical working group in collaboration with central medical stores. gaborone: moh; 2020. botswana ministry of health and wellness. drug costing and forecasting technical working group. direct communications with viiv healthcare on their intention to release the dolutegravir patent protections for generic production of dolutegravir for lower-to-middle-income-countries. gaborone: moh; 2015. menon v., lang e., silva r., mosime w. estimated resource needs for key health interventions offered under botswana’s essential health service package 2013–2018 [homepage on the internet]. washington, dc: futures group, health policy project; 2015. available from: avenirhealth.org/download/ohtcountyapplications/pdf/estimated%20resource%20needs%20four%20key%20health%intervention%20offered%20under%20bots….pdf muthoga c, jarvis jnl. meningitis prevention and treatment in botswana. gaborone: wellcome trust; 2021. botswana ministry of health and wellness. the national hiv data warehouse. the national art data repository. gaborone: moh; 2021. usaid & mohw. botswana 2017 biological and behavioral surveillance survey of hiv/stis among select key populations. gaborone: usaid; 2017. appendix 1 table 1-a1: inputs and targets by 2030 for the 2016-ic, goals 2021 and unaids global aids strategy. appendix 2 table 1-a2: selected outputs and results for the 2016-ic, goals 2021, and unaids global aids strategy for 2016, 2020, 2025, 2030. appendix 3: data sources for spectrum v. 6.06 (2021) demproj: united nation statistics division. 2020, world population prospects: the 2020 revision. united nations, new york, usa. aim file: mohw, 2020. haart patient update summary, december 2020, dhapc mohw, 2020. programme statistics: breastfeeding, dhapc, moh. mohw, 2020. programme statistics: pmtct coverage 2010–2020, dhapc mohw, 2020. programme statistics on knowledge of status & viral load suppression naca bais, (ii-2004, iii-2008, iv-2013) naca (2011) anc sentinel surveillance study goals and resource needs: mohw, 2020. drug costing and forecasting technical working group. mohw, 2019. mapping size estimation and behavioral and biological surveillance survey (bbss) of hiv/stu among select high-risk sub-populations in botswana. technical report, botswana. futures group, 2013 one health tool. futures group. charles muthoga and joseph n. jarvis. botswana laboratory costing. 2021 family planning morronni, c. 2021, sexual reproductive health specialist, mohw. additional hiv & art clinical and programmatic expertise provided by: ramaabya, d. 2021,mohw: head of hiv/aids treatment, care & support nkomo, b. 2021, mohw: head hiv/aids programmes, public health specialist avalos, a. 2021, hiv specialist physician botswana, technical advisor mohw. appendix 4 table 1-a4: numbers and percentage of mtct statistics goals-2021. pg12-13.html opinion how can we reduce the risk of mother-to-child transmission of hiv during invasive obstetric procedures? c n mnyani1, ba, mb chb, fcog e nicolaou2,3, md, fcog, dip fet med e bera4, mb bch, fcog v black5, bsc, mb bch jc hull3, mb bch, mrcog, fcog, dtm&h j a mcintyre1,6, mb chb, frcog 1anova health institute, johannesburg 2maternal fetal medicine centre, morningside mediclinic, university of the witwatersrand, johannesburg 3department of obstetrics and gynaecology, chris hani baragwanath academic hospital, johannesburg 4department of obstetrics and gynaecology, rahima moosa mother and child hospital, university of the witwatersrand, johannesburg 5wits reproductive health and hiv institute, university of the witwatersrand, johannesburg 6centre for infectious diseases epidemiology and research, school of public health and family medicine, university of cape town antenatal invasive obstetric procedures may be diagnostic or therapeutic, and are performed at different stages of pregnancy for various indications. the most common indication for an invasive procedure during pregnancy is for fetal karyotyping when a chromosomal abnormality or a genetic defect is suspected, either from the couple’s history or from ultrasound assessment of the fetus. other less common but equally important indications may be diagnostic (fetoscopy, fetal tissue sampling, estimation of fetal haemoglobin) or therapeutic (aspiration of various fetal cavities, fetal blood transfusion and embryo reductions). in a high hiv prevalence setting like south africa, a significant proportion of pregnant women in need of invasive procedures will be hiv-infected. there are no published data on the number of invasive procedures done in south africa, but unpublished data from national laboratories suggest that the services are under-utilised.1 in 2008, 6 out of 7 national laboratories received 529 amniocentesis specimens done for advanced maternal age – this in a background of 1 049 300 live births.1 , 2 in a high hiv prevalence setting like south africa, where the estimated prevalence in antenatal clinic attendees was 29.4% in 2009, a significant proportion of pregnant women in need of invasive procedures will be hiv-infected.3 hiv clinicians need to be aware of the risk of mother-to-child transmission of hiv (mtct) associated with invasive procedures, and should also be aware of strategies available to minimise the risk. this information needs to be given to clients during the counselling session before the procedure, and hiv clinicians may also be asked to advise obstetric colleagues on optimal management in cases where a hiv-infected woman requires a prenatal invasive procedure. timing of invasive procedures in pregnancy below is a list of commonly performed antenatal invasive obstetric procedures and the gestational age at which each procedure can, or should, be performed. n amniocentesis: from 16 weeks n chorionic villus sampling: from 11 to 14 weeks n cordocentesis: from 20 weeks n fetoscopy: usually in the 2nd and 3rd trimesters n fetal tissue sampling (biopsies of organs, muscle, etc.): usually in the 2nd and 3rd trimesters n aspiration of various fetal cavities, shunt insertion: any gestational age – usually from 16 weeks n embryo reductions: from 11 weeks. several complications may occur with invasive procedures, and as part of pre-procedure counselling the woman/couple should be made aware of the risk of procedure-related complications. these include injury to maternal bowel, fetal injury, failure to obtain a sample, chorio-amnionitis, and most significantly fetal loss.4 the royal college of obstetricians and gynaecologists guideline on amniocentesis and chorionic villus sampling advises that patients should be informed of an additional 1% risk of fetal loss following an amniocentesis, and a slightly higher risk following chorionic villus sampling.5 a 2003 cochrane review advises that, for second-trimester testing, amniocentesis is the safer procedure – safer than early amniocentesis or transcervical chorionic villus sampling.6 for testing before 15 weeks of pregnancy, transabdominal chorionic villus sampling is the safer procedure.6 there is no literature to suggest that the risk of procedure-related complications is higher in hiv-infected women. risk of mtct with antenatal invasive procedures there is limited literature on invasive obstetric procedures in the context of maternal hiv infection. few studies have been published on the topic, most with a small number of patients. important risk factors for mtct such as maternal hiv viral load and cd4+ cell count are not always controlled for, and it may be difficult to infer causality in the reported cases of transmission after an invasive procedure. without any maternal antiretroviral therapy initiated before an invasive procedure the risk of mtct with invasive obstetric procedures is high, with rates of over 30% reported in some studies.7 in one study evaluating the effect of various factors on the risk on mtct, third-trimester amniocentesis without any antiretroviral cover was associated with a fourfold increase in the risk of mtct.8 with the use of combination antiretroviral therapy before antenatal invasive procedures, the risk of mtct is reported to be similar to that of a hiv-infected pregnant woman who has not had an invasive procedure.9 in studies reporting no mtct with combination antiretroviral therapy, a significant number of women were initiated on therapy before conception, and the majority were virally suppressed at the time of the procedure.9 despite the decrease in hiv transmission with antiretroviral cover, procedures that require more technical skills – such as chorionic villus sampling and cordocentesis – should still be avoided in the hiv-infected woman, as the risk of transmission to the fetus may be considerably increased. guidelines on the techniques of performing invasive procedures should be adhered to, and where possible the transplacental route should be avoided owing to the higher risk of transmission.12 recommendations on antiretroviral prophylaxis prior to invasive procedures there is now general consensus that any hiv-infected pregnant woman who needs to undergo an invasive obstetric procedure should have combination antiretroviral therapy initiated before the procedure, regardless of maternal cd4+ cell count.12 , 13 ideally, antiretroviral therapy should be initiated at least 4 6 weeks prior to the procedure to achieve a significant level of maternal hiv viral suppression.14 if the gestational age precludes waiting for the period of 4 6 weeks, the clinician can still go ahead with the procedure as continuation of combination antiretroviral therapy after the procedure should provide post-exposure prophylaxis. there is, however, no evidence on the role of post-procedure combination antiretroviral therapy as post-exposure prophylaxis, but an analogy between needling procedures and needle-stick injuries has been made. there are no data available to suggest a viral load at which hiv transmission is unlikely to occur with an antenatal invasive procedure, and data from general mtct studies cannot be extrapolated to cases with invasive procedures. however, both the royal college of obstetricians and gynaecologists and the british hiv association recommend an undetectable maternal viral load at the time of the invasive procedure.12 , 13 if resources allow and there is sufficient time to wait before the invasive procedure, the maternal viral load should be determined as part of pre-procedure counselling. in a high hiv prevalence setting like south africa, it is advisable that a repeat hiv test be offered immediately before the invasive procedure if a woman has initially tested hiv-negative early in pregnancy. although there are no well-established approaches for managing hiv-infected women undergoing invasive procedures, international guidelines and literature published on the topic do offer guidance for the clinician. local guidelines that are in line with international best practices, but also account for the nature of hiv/aids and obstetric practice in south africa, are required to guide local clinicians. references 1. urban mf, stewart c, ruppelt t, et al. effectiveness of prenatal screening for down syndrome on the basis of maternal age in cape town. s afr med j 2011;101:45-48. 1. urban mf, stewart c, ruppelt t, et al. effectiveness of prenatal screening for down syndrome on the basis of maternal age in cape town. s afr med j 2011;101:45-48. 2. statistics south africa. mid-year population estimates, 2009. pretoria: statistics south africa, 2009. 2. statistics south africa. mid-year population estimates, 2009. pretoria: statistics south africa, 2009. 3. department of health. national antenatal sentinel hiv and syphilis prevalence survey in south africa, 2009. pretoria: department of health, 2010. 3. department of health. national antenatal sentinel hiv and syphilis prevalence survey in south africa, 2009. pretoria: department of health, 2010. 4. rcog consent advice no. 6. amniocentesis, may 2006. royal college of obstetricians and gynaecologists, london. http://www.rcog.org.uk/womens-health/clinical-guidance/amniocentesis-consent-advice (accessed 3 august 2011). 4. rcog consent advice no. 6. amniocentesis, may 2006. royal college of obstetricians and gynaecologists, london. http://www.rcog.org.uk/womens-health/clinical-guidance/amniocentesis-consent-advice (accessed 3 august 2011). 5. rcog green-top guideline no. 8. amniocentesis and chorionic villus sampling, june 2010. royal college of obstetricians and gynaecologists, london. http://www.rcog.org.uk/womens-health/clinical-guidance/amniocentesis-and-chorionic-villus-sampling-green-top-8 (accessed 3 august 2011). 5. rcog green-top guideline no. 8. amniocentesis and chorionic villus sampling, june 2010. royal college of obstetricians and gynaecologists, london. http://www.rcog.org.uk/womens-health/clinical-guidance/amniocentesis-and-chorionic-villus-sampling-green-top-8 (accessed 3 august 2011). 6. alfirevic z, mujezinovic f, sundberg k. amniocentesis and chorionic villus sampling for prenatal diagnosis. cochrane database of systematic reviews 2003, issue 3. art. no.: cd003252. doi: 10.1002/14651858.cd003252. 6. alfirevic z, mujezinovic f, sundberg k. amniocentesis and chorionic villus sampling for prenatal diagnosis. cochrane database of systematic reviews 2003, issue 3. art. no.: cd003252. doi: 10.1002/14651858.cd003252. 7. mandelbrot l, mayaux m, bongain a, et al., for serogest and the french pediatric hiv infection study group. obstetric factors and mother-to-child transmission of human immunodeficiency virus type 1: the french perinatal cohorts. am j obstet gynecol 1996;175(3):661-667. 7. mandelbrot l, mayaux m, bongain a, et al., for serogest and the french pediatric hiv infection study group. obstetric factors and mother-to-child transmission of human immunodeficiency virus type 1: the french perinatal cohorts. am j obstet gynecol 1996;175(3):661-667. 8. tess bh, rodrigues lc, newell ml, et al. breastfeeding, genetic, obstetric and other risk factors associated with mother-to-child transmission of hiv-1 in sao paulo collaborative study for vertical transmission of hiv-1. aids 1999;12(5):513-520. 8. tess bh, rodrigues lc, newell ml, et al. breastfeeding, genetic, obstetric and other risk factors associated with mother-to-child transmission of hiv-1 in sao paulo collaborative study for vertical transmission of hiv-1. aids 1999;12(5):513-520. 9. mandelbrot l, jasseron c, ekoukou d, et al.; for the anrs french perinatal cohort. amniocentesis and mother-to-child human immunodeficiency virus transmission in the agence nationale de recherches sur le sida et les hépatites virales french perinatal cohort. am j obstet gynecol 2009;200:160.e1-160.e9 9. mandelbrot l, jasseron c, ekoukou d, et al.; for the anrs french perinatal cohort. amniocentesis and mother-to-child human immunodeficiency virus transmission in the agence nationale de recherches sur le sida et les hépatites virales french perinatal cohort. am j obstet gynecol 2009;200:160.e1-160.e9 10. somagliana e, bucceri am, tibaldi c, et al. early invasive diagnostic techniques in pregnant women who are infected with hiv: a multicenter case series. am j obstet gynecol 2005;193:437-442. 10. somagliana e, bucceri am, tibaldi c, et al. early invasive diagnostic techniques in pregnant women who are infected with hiv: a multicenter case series. am j obstet gynecol 2005;193:437-442. 11. coll o, suy a, hernandez s, et al. prenatal diagnosis in human immunodeficiency virus-infected women: a new screening program for chromosomal abnormalities. am j obstet gynecol 2006;194:192-198. 11. coll o, suy a, hernandez s, et al. prenatal diagnosis in human immunodeficiency virus-infected women: a new screening program for chromosomal abnormalities. am j obstet gynecol 2006;194:192-198. 12. de ruiter a, mercey d, anderson j, et al. british hiv association and children’s hiv association guidelines for the management of hiv infection in pregnant women, 2008. hiv med 2008;9:452-502. 12. de ruiter a, mercey d, anderson j, et al. british hiv association and children’s hiv association guidelines for the management of hiv infection in pregnant women, 2008. hiv med 2008;9:452-502. 13. rcog green-top guidelines no. 39. management of hiv in pregnancy, june 2010. royal college of obstetricians and gynaecologists, london. http://www.rcog.org.uk/womens-health/clinical-guidance/amniocentesis-consent-advice (accessed 18 july 2011). 13. rcog green-top guidelines no. 39. management of hiv in pregnancy, june 2010. royal college of obstetricians and gynaecologists, london. http://www.rcog.org.uk/womens-health/clinical-guidance/amniocentesis-consent-advice (accessed 18 july 2011). 14. european collaborative study, patel d, cortina-borja m, thorne c, et al. time to undetectable viral load after highly active antiretroviral therapy initiation among hiv-infected pregnant women. clin infect dis 2007;44(12):1647-1656. 14. european collaborative study, patel d, cortina-borja m, thorne c, et al. time to undetectable viral load after highly active antiretroviral therapy initiation among hiv-infected pregnant women. clin infect dis 2007;44(12):1647-1656. a p r i l 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e mosvold hospital is situated in northern kwazulunatal near the borders of swaziland and mozambique. according to estimates by the department of health, the hospital serves a population of about 108 000.1 the population is rural and poor, with adult unemployment at 60%. five per cent of households have piped water and 3.6% of households are supplied with electricity. government health care in the ingwavuma sub-district, in which mosvold hospital is situated, is provided by the hospital, 10 residential clinics and 3 mobile clinic teams. the hospital mortuary is the only government mortuary serving the mosvold sub-district. most deaths occurring in the sub-district, both within and outside the hospital, are certified by medical staff. antiretroviral drugs (arvs) were first prescribed in september 2004 as part of the national antiretroviral rollout programme. table i shows the total number of patients started on arvs from 2004 to 2008. the number of females started in each year was greater than the number of males, and from the beginning of the roll-out at least 11% of the patients enrolled were children. in a previous study,2 an analysis of 4 years’ mortality data from 2003 to 2006 indicated that aids-related illnesses were responsible for 53% of deaths certified at the hospital during the period of the study. there was evidence of an increase in average age at death of women between 2005 and 2006, suggesting a positive impact of the arv roll-out. the present analysis investigated the continuing impact of hiv/aids on mortality and life expectancy and observed trends over the period during which hiv treatment and prevention of mother-to-child transmission therapy (pmtct) were introduced. the use of nevirapine for pmtct was commenced in 2002. dual pmtct, adding zidovudine to nevirapine, was started in april 2008. methods data from counterfoils of form 83/bi-1663, notification/ register of death/stillbirths (republic of south africa, department of home affairs), completed at mosvold hospital from 1 january 2003 to 31 december 2008, were entered into a database (microsoft access). analysis of trends in total and aidsrelated deaths certified at mosvold hospital, ingwavuma, kwazulu-natal, from 2003 to 2008 o r i g i n a l a r t i c l e c h vaughan williams, mb bs, dch, mfammed, doh district family physician, umkhanyakude health district office, jozini, kwazulu-natal 36 objectives. to analyse mortality trends from deaths registered at mosvold hospital, ingwavuma, kwazulu-natal, and possible impact of programmes to treat and prevent hiv infection. design. longitudinal study of death certifications from 2003 to 2008. setting. mosvold hospital mortuary, ingwavuma. subjects. counterfoils of form 83/bi-1663, notification/register of death/stillbirths (republic of south africa, department of home affairs), completed at mosvold hospital from january 2003 to december 2008. outcome measures. age at death, cause of death, patterns of deaths grouped by age, gender and cause of death. results. aids-related deaths were the cause of 53% of deaths, particularly affecting the 20 59-year and under-5 age groups. since 2005 there has been a decline in deaths in the 20 59 age group and an increase in average age at death. conclusions. the decrease in mortality from 2005 may be associated with antiretroviral roll-out reducing mortality from aids-related illnesses. t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 0 ethical considerations the publication of statistics on the causes of death certified at mosvold hospital was approved by the mosvold hospital ethical committee. results figs 1 and 2 show age at death in males and females according to hiv-related and non-hiv-related causes. most deaths between the ages of 20 and 54 years are due to aids-related causes. table ii shows the average age at death by year for males and females (>9 years) between 2003 and 2008 according to aids-related and non-aids-related causes. average age at death for females declined between 2003 and 2005, and appeared to increase again from 2005 and 2007. the pattern for male deaths is less marked. males females total patients cumulative children <15 yrs cumulative number % children year (each year) (each year) started per year total started per year of children <15 yrs <15 yrs 2004 47 78 125 125 14 14 11.2 2005 198 324 522 647 62 76 11.7 2006 367 518 885 1 532 150 226 14.8 2007 397 691 1 088 2 620 170 396 15.1 2008 406 746 1 152 3 772 139 535 14.2 table i. patients started on antiretroviral drugs at mosvold hospital, ingwavuma, kwazulu-natal, from september 2004 fig. 1. total male deaths 2003 2008 certified at mosvold hospital, ingwavuma, northern kwazulu-natal, grouped according to hiv/aids-related and non-hiv/aids-related causes of death. fig. 2. total female deaths 2003 2008 certified at mosvold hospital, ingwavuma, northern kwazulu-natal, grouped according to hiv/aids-related and non-hiv/aids-related causes of death. deaths 37 a p r i l 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e fig. 3 shows the trends in number of deaths certified at mosvold hospital for the 15 59-year age group and deaths attributable to aids-related causes. there is a 39% reduction in all-cause mortality and a 38% reduction in aids-related deaths in women and a 24% reduction in all-cause mortality in men with a 29% reduction in deaths attributable to aids. discussion the national hiv and syphilis survey south africa in 20073 estimated the antenatal hiv prevalence for umkhanyakude district to be 39.8%, an increase on the 2006 estimate of 36.3% and higher than the national estimate of 28%. high mortality from hiv/aids is consistent with these estimates. in a survey of hiv infection prevalence in the southern part of umkhanyakude district, near mtubatuba, tanser et al.4 found that hiv prevalence peaked at 51% in women in the 25 29-year age group and at 44% for men aged 30 34 years, which is consistent with the mortality patterns found in this study of a population in the same district. in a report by statistics south africa entitled ‘mortality and causes of death in south africa, 2006’,5 the proportion of deaths according to age group had a similar pattern to that found in this study, with peaks in the under-5, 30 34 and, for females, 75 79-year age groups. deaths in the 15 59-year age group increased between 2002 and 2006, but with a decreasing annual increase between 2005 and 2006 compared with previous years. the pattern of mortality according to age at death and cause of death in this study shows that hiv/aids is a leading cause of mortality in persons between the ages of 15 and 59, as well as causing substantial mortality in the under-5 age group. however, the decline in deaths in the 15 59 age group after 2005, mostly aids related, combined with increased age at death since the males females year average age at death 95% ci average age at death 95% ci 2003 all causes 47.5 45.8 49.2 48.5 46.6 50.4 hiv/aids 39.4 38.0 40.8 35.1 33.7 36.5 2004 all causes 45.6 43.9 47.3 45.3 43.5 47.1 hiv/aids 38.8 37.5 40.1 36.2 34.9 37.5 2005 all causes 45.9 44.2 47.6 44.1 42.4 45.7 hiv/aids 37.9 36.5 39.3 35.9 34.6 37.2 2006 all causes 45.6 43.8 47.3 47.7 45.8 49.6 hiv/aids 38.7 37.2 40.2 35.4 33.9 36.8 2007 all causes 47.54 45.7 49.4 50.01 48.0 52.0 hiv/aids 39.62 38.1 41.2 37.17 35.5 38.8 2008 all causes 47.31 45.3 49.3 49.06 46.8 51.3 hiv/aids 40.62 38.7 42.6 35.1 33.4 36.8 ci = confidence interval. table ii. average age of death in persons aged >9 years deaths certified at mosvold hospital, ingwavuma, kwazulu-natal, january 2003 december 2008 fig. 3. deaths per year in the age group 15 59 years certified at mosvold hospital, ingwavuma, kwazulu-natal. 38 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 0 start of the arv roll-out, suggests that roll-out may be reducing mortality from aids-related illness in the 15 59-year age group. the greater impact on female mortality compared with male mortality may be explained by the greater number of females compared with males enrolled onto arv treatment. references 1. zondi t, ngomane n. health and health care systems situational analysis. in: umkhanyakude health district situational analysis. braamfontein: health systems trust, 2002: 10. 2. vaughan williams ch. analysis of impact of hiv/aids on deaths certified at mosvold hospital, ingwavuma, northern kwazulu-natal from 2003 2006. south african journal of family practice 2007; 49(5): 16a-16e. http://www.safpj.co.za/ index.php/safpj/article/view/628/756 (accessed 15 june 2009). 3. national department of health, south africa. 2008. the national hiv and syphilis survey south africa 2007. http://www.doh.gov.za/docs/reports/2007/antenatal/ antenatal_report.pdf (accessed 14 june 2009). 4. tanser f, hosegood v, bärnighausen t, et al. cohort profile: africa centre demographic information system (acdis) and population-based hiv survey. int j epidemiol 2008; 37: 956-962. http://www.pubmedcentral.nih.gov/articlerender. fcgi?artid=2557060 (accessed 15 june 2009). 5. statistics south africa. 2008. statistical release p0309.3: mortality and causes of death in south africa, 2006 findings from death notification. http://www.statssa. gov.za/publications/statsdownload.asp?ppn=p0309.3&sch=4254 (accessed 14 june 2009). 39 maternal.html opinion maternal and infant health is protected by antiretroviral drug strategies that preserve breastfeeding by hiv-positive women louise kuhn, phd gertrude h sergievsky center, college of physicians and surgeons; and department of epidemiology, mailman school of public health, columbia university, new york, usa the south african department of health is justified in withdrawing support for free infant formula. by so doing, it recognises that any intervention that might detract from breast feeding poses a serious threat to infant survival. since evidence is now strong that antiretroviral drugs used during lactation prevent transmission of infection from a seropositive mother, strategies that promote breastfeeding can now be recommended for enhancing the health of mothers and infants. the tshwane declaration of support for breastfeeding in south africa was recently championed by the national department of health as a concrete step to improving maternal and child health in the country. saloojee, gray and mcintyre (in the december 2011 edition of this journal) state they are not opposed to this declaration, and welcome the greater support for application of baby-friendly principles in the health services, strengthening community-based programmes to support breastfeeding, and stricter legislation to protect the rights of breastfeeding mothers. they objected to only one item concerning the withdrawal of free formula for hiv-positive women, and lamented that there has been hardly any response from clinicians, health professionals or civil society groups to this decision. aside from their objections, the overwhelming response to the tshwane declaration from clinicians, health professionals and civil society groups has been enthusiastic support. moreover, the tshwane declaration itself was a culmination of more than two years of consultation between the department of health and clinicians, health professionals, civil society groups, including activists and women living with hiv, and saloojee et al. themselves. the latter authors state that the evidence base for withdrawal of formula is inadequate. in this paper, i present the extensive evidence base supporting the new south african government policies. the evidence is strong that provision of free infant formula is dangerous and that antiretroviral drugs (arvs) work. i also discuss whether withdrawal of free formula could be considered unconstitutional – a very important accusation, and one which requires thoughtful consideration. breastfeeding saves lives saloojee et al. assert that to withdraw support for free formula is a luxury that south africa can ill afford unless there is ‘substantial evidence that the strategy is either ineffective or results in major harm’ [emphasis added]. while these are reasonable criteria on which to make any decision about public health, it is extraordinary that they appear to disregard the overwhelming evidence from around the african continent, including countries in southern africa, that formula feeding is associated with significantly higher mortality in young infants. it is precisely the accumulation of substantial evidence that provision of infant formula is either futile or results in major harm that informed the international recommendations released by the world health organization to guide national ministries of health.1 human breast milk is exquisitely regulated, containing not only nutrients but also immunologically active components to protect newborns against disease and support the maturation of their own immune system.2 medical research dating back to the middle ages identified that orphans and abandoned infants would die unless human breast milk were provided.3 an experiment was undertaken in the 1970s by formula manufacturers, confident in their ‘modern’ product, who began marketing it in african countries. provision of infant formula correlated with infant deaths.4 fortunately, these deaths also sparked effective pro-breastfeeding advocacy that has helped to shape global public health initiatives. there are extensive biological, clinical, epidemiological and programmatic data indicating that infant formula results in major harm to infants and their mothers. consequently, it is a falsehood to say that evidence showing the major harm associated with provision of formula is ‘simply lacking’. there is overwhelming evidence of the harmful effects of formula feeding in the general population in southern africa and elsewhere for decades. until recently, there was indeed a lack of evidence of any comparable effect among hiv-infected mothers and their exposed but uninfected infants. yet there is now substantial evidence in betterand less-resourced settings, including the better-resourced settings of south africa and botswana, that formula feeding results in elevated death rates among children who would otherwise be hiv-uninfected and alive. the serious threat to infant survival is the most important justification for the withdrawal of department of health support for infant formula. is hiv in south africa the exception? saloojee et al. do not appear to be aware of this expanse of biological, clinical, epidemiological and programatic research. it seems that their position can only be held if they subscribe to two types of ‘exceptionalism’: (i) hiv exceptionalism and (ii) south african exceptionalism. postnatal transmission of hiv through breastfeeding is indeed a special case that requires cautious and courageous consideration of appropriate infant feeding policy. hiv transmission can occur throughout the period of breastfeeding, therefore complete abstention from breastfeeding will obviously not permit any transmission to occur via this route. abstention from breastfeeding will not, however, prevent intrauterine or intrapartum transmission. in the absence of interventions, most (~70%) infants born to and breastfed by hiv-positive mothers will remain uninfected. when hiv-positive women avoid breastfeeding with the goal of preventing the proportion of vertical transmission attributable to breastfeeding, they place their infants at risk of malnutrition, pneumonia and diarrhoeal morbidity and mortality as well as increasing the child’s risk of developmental and cognitive delays. this is the nub of the dilemma, and provision of free formula is not a solution; instead, it’s part of the dilemma that the hiv epidemic has made us face. in the era prior to the demonstration that arvs used during lactation can provide a constructive solution to the infant-feeding dilemma, two wish-fulfillment strategies were used instead: either deny that hiv is transmitted through breastfeeding or deny that there are substantial risks of death and other serious outcomes from formula feeding. study after study clearly showed that hiv is transmitted to infants through breastfeeding. denial of the dangers of formula became the more popular position. in 2000, the who recommended that hiv-infected women provide formula feeds to their infants as a means of preventing hiv infection. this guidance was based on the premise and intention that public health programmes could be set up that would eliminate the risks associated with handing out formula feeds. this strategy was very powerful because it was able to mobilise resources to buy formula for programmes and for research. but the strategy set aside the large body of breastfeeding research that had been conducted among non-hiv-infected women that had described and quantified the excess risk of death associated with formula feeds; it called for new research and evidence to record the experiences and measure the effects of using formula feeds by hiv-infected mothers. for better or worse, several groups, including my own, bought into this notion and conducted studies to test whether complete avoidance of breastfeeding, or shortening the duration of breastfeeding, would have adverse consequences for infants born to hiv-positive mothers. sadly, they did. these well-conducted, rigorous research studies with results that have been reviewed by peer scientists prior to publication in leading medical journals were conducted in a wide range of settings in africa, including better-resourced settings such as botswana and south africa. for example, in a clinical trial in urban botswana where women were randomised either to formula from birth or breastfeeding for 6 months, a doubled risk of death was observed among uninfected infants born to hiv-infected mothers.5 in this study, participants were carefully screened to ensure all had access to clean water and adequate sanitation, formula was provided free, counselling and support around formula feeding was extensive, and there was a well-functioning health service safety net. in another example in a well-resourced area in rural uganda, with a sophisticated health service, women were counselled about infant feeding options following afass (affordable, feasible, acceptable, sustainable and safe – the acronym summarising the criteria that were proposed at that time as the requirement for formula feeding to be the better choice) and a 6-times greater risk of infant mortality was observed among women who selected formula feeding because they felt it was ‘afass’ for themselves.6 there are several other studies, including numerous studies from south africa.7 the consistency of the findings across diverse settings, across different study designs and with established biological processes makes it highly unlikely that the dangers of formula can be explained away as part of the vagaries of clinical research methodology. the findings of these studies, in conjunction with research findings demonstrating the efficacy of arvs to significantly reduce the risk of hiv infection through breastfeeding, iteratively led the who to revise its recommendations from a position of recommending formula feeds as the default feeding practice for hiv-infected mothers, to recommending breastfeeding with arvs. saloojee et al. dismiss this large body of research with the claim that it comes from settings with much higher rates of infant morbidity and mortality than those observed in south africa (or those parts of south africa with more resources). this is not true i.r.o. botswana and other countries, such as zambia and malawi, that are more economically disadvantaged, and manifests a confusion between an absolute and a relative risk. an absolute risk quantifies the likelihood that an event will occur in a group; e.g. the risk of dying is 40 per 1 000. a relative risk compares two groups: group a has an absolute risk of 40 per 1 000 and group b has an absolute risk of 80 per 1 000, therefore the relative risk of group b v. group a is double. even in countries with very low absolute rates of infant mortality, such as the usa, uk and the netherlands, formula increases mortality; i.e. the relative risk is elevated.15 but in countries with higher absolute infant mortality rates, the same relative risks translate into a larger absolute number of infant deaths. moreover, synergy occurs: in populations with high absolute mortality rates, relative risks of death owing to formula are also higher; for example, water contamination, lack of access to adequate sanitation and poor health service infrastructure exacerbate the dangers of formula. but economic disadvantage does not create the biological disadvantage of formula. there is no threshold below which formula no longer causes harm. breastfeeding saves lives in all countries – south africa is no exception. saloojee et al. misquote three studies18 as evidence that replacement feeding can be safely accomplished. these studies do report equivalent or better outcomes with replacement feeding; however, the outcome reported is hiv-free survival, and at a time when arvs were not available to prevent hiv infection through breastfeeding. hiv-free survival is a composite endpoint defined by the absence of either infant hiv infection or infant death. as a public health indicator, it is useful as it reminds us that there is little point in saving infants from hiv if they are only going to die of other causes. however, consideration of only hiv-free survival does not provide proof of safety of formula feeds. equivalent hiv-free survival means that the number of hiv infections averted has been cancelled by the number of additional uninfected deaths caused. these stark statistics do not resolve the question of whether breastfeeding alone or formula feeding is the better feeding practice for hiv-exposed infants. new data from research studies undertaken in over 6 countries, including south africa, completely transform the context in which the dilemma of infant feeding by hiv-infected mothers should be considered. arv intervention can be used during breastfeeding to reduce the risk of transmission.21 none of the studies referred to above used arvs during breastfeeding; the kenyan study was done before even short-course perinatal interventions became available. these studies are uninformative for the current era when arvs are available to prevent transmission through breastfeeding. saloojee and colleagues remain locked into an evidence base and paradigm that does not recognise the potency of arvs and the opportunity they present to improve the health and survival of hiv-exposed infants. south africa has persisting inequities in health and wealth as an argument in support of free formula, saloojee et al. remind us that south africa is not a single homogenous country. this is absolutely true. south africa is a country is with gross disparities in wealth, health and living conditions. this is not an argument for the government to support formula for the better-off. to the contrary, new government policies can serve to reduce inequities and provide highly effective interventions to everyone and not just a number of favoured groups; the new national policies proactively consider the needs of the poor first – as public health policies should. in saloojee et al.’s view, the government should provide free formula for women in the wealthier provinces, such as gauteng and western cape, where women are sufficiently well-off to meet afass criteria but not so much as to purchase formula themselves. yet this contradicts the first ‘a’ of afass, which is ‘affordable’ – a point which they seem to ignore. but it’s not actually the a which is most relevant – it’s the s for safety. back to the first point: formula feeding is dangerous. study the numbers – they matter it is therefore, reasonable to ask why hiv-positive women in the united states are required to formula feed. it is imperative to pay close attention to the actual absolute and relative risks in the south african context. saloojee et al. in their protest to the mail & guardian claim that, since infant mortality may be as low as 25 per 1 000 in some better-off parts of south africa, this figure is below the ‘accepted’ threshold where formula feeding can be considered ‘safe’. the basis for this claim is mathematical modelling, conducted by several different groups (including myself)29 in the 1990s, calculating the competing risks of hiv transmission associated with breastfeeding v. the increased risk of uninfected child deaths owing to abstention from breastfeeding. a ‘safe’ threshold is the point at which the number of hiv infections averted by formula is exactly equivalent to the number of deaths caused by formula feeding – hardly a basis for a resounding endorsement of formula. nevertheless, the primary limitation of the models used by saloojee et al. is that they ignore the new opportunities provided by arv strategies. arvs, when used throughout lactation, significantly reduce the risk of hiv transmission via lactation.30 if one applies the new rates of hiv transmission observed when arvs are given, the infant mortality rate has to fall to below 10 per 1 000 before the increased number of deaths caused by formula feeding is counterbalanced by the number of hiv infections averted. only when the infant mortality rate is <8 per 1 000 live births, is formula able to save one child per 1 000. if transmission rates are lower than assumed in the model, and are as low as observed in clinical trials, such as the trial in botswana,22 or risks associated with formula feeding are higher than observed in clinical trial settings,5 as is likely to occur in practice, infant mortality rates need to be even lower before formula can be considered a desirable option (fig. 1). the infant mortality rate is nowhere near this level in any of the populations affected by hiv in south africa, even in the wealthier provinces. new government policies take into account the newest up-to-date data, in contrast to the complaints made by salojee et al. that rely on out-of-date data and arguments that exclude the availability of arvs. antiretroviral drugs provide a solution to the infant feeding dilemma many commentators are blithely optimistic about the safety of formula, yet this optimism does not extend to arv strategies. regarding the benefits of arv strategies to prevent mother-to-child hiv transmission, they state these strategies are unproven, based on inference, and with many ‘unanswered questions’. this is surprising, since these authors have been at the forefront of testing arv drug strategies and have published data showing the efficacy and safety of drug interventions and have been highly active in supporting their successful roll-out in gauteng and elsewhere in south africa.31 , 32 south african researchers have a stellar record in implementing arv-based programmes including demonstrating the capacity of the routine health services to provide effective arv strategies for pregnant hiv-positive women.33 this is not to say that arv programmes are easy to implement and that they may fall short. but pessimism, and claiming that failure to implement perfect programmes will have ‘drastic consequences’, damages mobilisation of resources and the will to implement these programmes. arv drug strategies are highly effective in reducing mother-to-child hiv transmission through all routes, including breastfeeding, and save women’s lives. programmes to implement these strategies should be supported, not disparaged. my major concern about this pessimism is that it implies that formula is a better option than arv drugs. this is deeply disturbing because formula does nothing to prevent mother-to-child transmission that can occur during pregnancy and delivery. formula does nothing to improve maternal health. even if formula is provided, arv treatment and prophylactic regimens remain vital. based on current criteria, a large proportion of pregnant hiv-positive women meet criteria for arv treatment. they need this treatment as a matter of urgency for their own survival and well-being, and this treatment needs to be lifelong. to my mind, it is problematic to argue against arv therapy because formula is more cost-effective in preventing hiv transmission in a select group of mothers and children. women who meet criteria for treatment are responsible for a large proportion of the infant infections (>80% of postnatal infections).36 therefore, purely implementing standard adult guidelines for provision of arv therapy for pregnant women who require it based on their own health status would address the majority of postnatal hiv infections and would also reduce maternal deaths. choices of infant nevirapine prophylaxis (option a), or therapeutic regimens that are stopped after the cessation of breastfeeding (option b), are available to address the remaining small proportion, but apply only to those asymptomatic women with high cd4 counts. the focus of public health interventions needs to be on reaching the women who need treatment for their own health and who are also most likely to transmit. hiv is not the only disease from which children need to be protected saloojee et al. argue that ‘[a]n hiv-free generation can never be achieved while breastfeeding continues.’ this is true. but this statement could be more properly rephrased ‘an hiv-free generation can never be achieved while pregnancy continues.’ current arv drug regimens do not result in zero transmission even in formula-fed populations. when arv drug regimens were started early in pregnancy and continued through breastfeeding in a study in botswana, the overall transmission rate, including transmissions that occurred during breastfeeding, was 1.1%. more than 75% of the hiv infections were detected at birth and had occurred before delivery. transmission during 6 months of breastfeeding when arv drugs were given was 0.28%.22 eliminating breastfeeding will not eliminate hiv transmission. eliminating breastfeeding will, however, increase infant mortality. breastfeeding rights and wrongs it was not clear from the arguments presented by saloojee et al. what the basis was for the charge that withdrawal of free formula was unconstitutional. it may be the denial of the ‘opportunity to have an hiv-uninfected child’ that will result if women are denied access to formula despite meeting afass criteria. this rhetoric is seductive but not based on fact. formula will not guarantee that an hiv-positive woman has an uninfected child. without arv drugs, transmission will occur during pregnancy or delivery in about a quarter of women. with adequate arv drugs given during pregnancy and then stopped, transmission rates would be around 2%, assuming complete abstinence from breastfeeding. a woman may have a ‘right’ (in the broadest sense of the word) to purchase harmful commodities if she so chooses – just as she has a ‘right’ to smoke during pregnancy if she so chooses. however, to claim that a woman has a constitutional right to be given harmful products by the health services simply because they prevent hiv transmission, is wrong. moreover, saloojee et al. fail to mention children’s rights, also protected in the south african constitution and detailed in the convention of the rights of children. this is more than just avoidance of hiv infection. health policies should not be decided upon by popularity contest. national health authorities should solicit opinions on policies so that they are sensitive to communities’ needs, but the policies themselves need to be based on biological and public health principles and evidence. involvement of the hiv-infected and -affected community is central. children, who can be both infected and affected by hiv, need special lobby groups to attend to their interests. the majority of hiv-positive women care about hiv transmission to their infants and their overall health, well-being and survival. the answer of the health service to an hiv-positive woman’s question about how best to feed her infant should not be a blunt ‘your choice’. a way forward it is time to put aside polarising debates and conflicts, and come together to address the fundamental public health challenges facing south africa. programmes to support breastfeeding need to be strengthened. this includes addressing the education of healthcare workers so that correct information is conveyed to parents, as well as activism to challenge labour and other policies that deny the rights of breastfeeding women. hiv can be treated with arvs, and those receiving arvs have a very low risk of transmitting hiv to their child or sexual partners. we should synergise to ensure that all people living with hiv have access to effective care and treatment. strengthening these arv programmes can greatly improve maternal and child health in south africa. references 1. world health organization. guidelines on hiv and infant feeding: principles and 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combined with alternatives to breastfeeding to prevent hiv mother-to-child transmission. plos one 2008;3:e1645. 19. leroy v, ekouevi dk, becquet r, et al. 18-month effectiveness of short-course antiretroviral regimens combined with alternatives to breastfeeding to prevent hiv mother-to-child transmission. plos one 2008;3:e1645. 20. franke mf, stulac sn, rugira ih, et al. high human immunodeficiency virus-free survival of infants born to human immunodeficiency virus-positive mothers in an integrated program to decrease child mortality in rural rwanda. pediatr infect dis j 2011;30:614-616. 20. franke mf, stulac sn, rugira ih, et al. high human immunodeficiency virus-free survival of infants born to human immunodeficiency virus-positive mothers in an integrated program to decrease child mortality in rural rwanda. pediatr infect dis j 2011;30:614-616. 21. chasela cs, hudgens mg, jamieson dj, et al. maternal or infant antiretroviral drugs to reduce hiv-1 transmission. n engl j med 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peripartum and postnatal hiv transmission in west africa: evaluation of a two-tiered approach. plos medicine 2007;4:e257. 24. tonwe-gold b, ekouevi dk, viho i, et al. antiretroviral treatment and prevention of peripartum and postnatal hiv transmission in west africa: evaluation of a two-tiered approach. plos medicine 2007;4:e257. 25. palombi l, marazzi mc, voetberg a, magid ma. treatment acceleration program and the experience of the dream program in prevention of mother-to-child transmission of hiv. aids 2007;21(suppl 4):s65-s71. 25. palombi l, marazzi mc, voetberg a, magid ma. treatment acceleration program and the experience of the dream program in prevention of mother-to-child transmission of hiv. aids 2007;21(suppl 4):s65-s71. 26. kilewo c, karlsson k, ngarina m, et al. prevention of mother-to-child transmission of hiv-1 through breastfeeding by treating mothers with triple antiretroviral therapy in dar es salaam, tanzania: the mitra plus study. j acquir immune defic syndr 2009;52:406-416. 26. kilewo c, karlsson k, ngarina m, et al. prevention of mother-to-child transmission of hiv-1 through breastfeeding by treating mothers with triple antiretroviral therapy in dar es salaam, tanzania: the mitra plus study. j acquir immune defic syndr 2009;52:406-416. 27. de vincenzi i. triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of hiv-1 (kesho bora study): a randomised controlled trial. lancet infect dis 2011;11:171-180. 27. de vincenzi i. triple antiretroviral compared with zidovudine and single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of mother-to-child transmission of hiv-1 (kesho bora study): a randomised controlled trial. lancet infect dis 2011;11:171-180. 28. thomas tk, masaba r, borkowf cb, et al. triple-antiretroviral prophylaxis to prevent mother-to-child hiv transmission through breastfeeding--the kisumu breastfeeding study, kenya: a clinical trial. plos med 2011;8:e1001015. 28. thomas tk, masaba r, borkowf cb, et al. triple-antiretroviral prophylaxis to prevent mother-to-child hiv transmission through breastfeeding--the kisumu breastfeeding study, kenya: a clinical trial. plos med 2011;8:e1001015. 29. kuhn l, stein z. infant survival, hiv infection and feeding alternatives in less developed countries. am j public health 1997;87:926-931. 29. kuhn l, stein z. infant survival, hiv infection and feeding alternatives in less developed countries. am j public health 1997;87:926-931. 30. mofenson lm. antiretroviral drugs to prevent breastfeeding hiv transmission. antiviral therapy 2010;15:537-553. 30. mofenson lm. antiretroviral drugs to prevent breastfeeding hiv transmission. antiviral therapy 2010;15:537-553. 31. mcintyre ja, hopley m, moodley d, et al. efficacy of short-course azt plus 3tc to reduce nevirapine resistance in the prevention of mother-to-child hiv transmission: a randomized clinical trial. plos med 2009;6:e1000172. 31. mcintyre ja, hopley m, moodley d, et al. efficacy of short-course azt plus 3tc to reduce nevirapine resistance in the prevention of mother-to-child hiv transmission: a randomized clinical trial. plos med 2009;6:e1000172. 32. gray ge, urban m, chersich mf, et al. a randomized trial of two postexposure prophylaxis regimens to reduce mother-to-child hiv-1 transmission in infants of untreated mothers. aids 2005;19:1289-1297. 32. gray ge, urban m, chersich mf, et al. a randomized trial of two postexposure prophylaxis regimens to reduce mother-to-child hiv-1 transmission in infants of untreated mothers. aids 2005;19:1289-1297. 33. hoffman rm, black v, technau k, et al. effects of highly active antiretroviral therapy duration and regimen on risk for mother-to-child transmission of hiv in johannesburg, south africa. j acquir immune defic syndr 2010;54:35-41. 33. hoffman rm, black v, technau k, et al. effects of highly active antiretroviral therapy duration and regimen on risk for mother-to-child transmission of hiv in johannesburg, south africa. j acquir immune defic syndr 2010;54:35-41. 34. van der merwe k, chersich mf, technau k, umurungi y, conradie f, coovadia a. integration of antiretroviral treatment within antenatal care in gauteng province, south africa. j acquir immune defic syndr 2006;43:577-581. 34. van der merwe k, chersich mf, technau k, umurungi y, conradie f, coovadia a. integration of antiretroviral treatment within antenatal care in gauteng province, south africa. j acquir immune defic syndr 2006;43:577-581. 35. black v, hoffman rm, sugar ca, et al. safety and efficacy of initiating highly active antiretroviral therapy in an integrated antenatal and hiv clinic in johannesburg, south africa. j acquir immune defic syndr 2008;49:276-281. 35. black v, hoffman rm, sugar ca, et al. safety and efficacy of initiating highly active antiretroviral therapy in an integrated antenatal and hiv clinic in johannesburg, south africa. j acquir immune defic syndr 2008;49:276-281. 36. kuhn l, aldrovandi gm, sinkala m, kankasa c, mwiya m, thea dm. potential impact of new world health organization criteria for antiretroviral treatment for prevention of mother-to-child hiv transmission. aids 2010;24:1374-1371. 36. kuhn l, aldrovandi gm, sinkala m, kankasa c, mwiya m, thea dm. potential impact of new world health organization criteria for antiretroviral treatment for prevention of mother-to-child hiv transmission. aids 2010;24:1374-1371. fig. 1. breastfeeding with arvs results in better hiv-free survival when infant mortality rates exceed 10 per 1 000. the graph shows excess adverse outcomes (uninfected infant deaths or hiv infections) per 1 000 as a result of formula-feeding, compared with breastfeeding among hiv-infected women in populations of varying infant mortality rates. the models allow a transmission rate (tr) of 2% assuming arvs are given and a best-case scenario of 1.3%, consistent with the botswana clinical trial22 of which 0.3% were due to breastfeeding acquired infections. the model assumes a relative risk (rr) of 2 which is consistent with best-case scenario of clinical trial-supported formula feeding in a better-off environment 5 and considers rr=3 more likely to represent the programmatic setting. all values >0 indicate that breastfeeding results in better net outcomes; values <0 indicate that formula-feeding results in better net outcomes. abstract introduction research methods and design results discussion conclusion acknowledgements references about the author(s) enkosi mondleki division of clinical pharmacology, department of medicine, faculty of health sciences, university of cape town, cape town, south africa clifford g. banda division of clinical pharmacology, department of medicine, faculty of health sciences, university of cape town, cape town, south africa malawi-liverpool-wellcome trust clinical research programme, blantyre, malawi nomathemba c. chandiwana ezintsha, university of the witwatersrand, johannesburg, south africa simiso sokhela ezintsha, university of the witwatersrand, johannesburg, south africa lubbe wiesner division of clinical pharmacology, department of medicine, faculty of health sciences, university of cape town, cape town, south africa francois venter ezintsha, university of the witwatersrand, johannesburg, south africa gary maartens division of clinical pharmacology, department of medicine, faculty of health sciences, university of cape town, cape town, south africa wellcome centre for infectious diseases research in africa, institute of infectious disease and molecular medicine, university of cape town, cape town, south africa phumla z. sinxadi division of clinical pharmacology, department of medicine, faculty of health sciences, university of cape town, cape town, south africa wellcome centre for infectious diseases research in africa, institute of infectious disease and molecular medicine, university of cape town, cape town, south africa citation mondleki e, banda cg, chandiwana nc, et al. effect of obesity on dolutegravir exposure in black southern african adults living with hiv. s afr j hiv med. 2022;23(1), a1452. https://doi.org/10.4102/sajhivmed.v23i1.1452 original research effect of obesity on dolutegravir exposure in black southern african adults living with hiv enkosi mondleki, clifford g. banda, nomathemba c. chandiwana, simiso sokhela, lubbe wiesner, francois venter, gary maartens, phumla z. sinxadi received: 31 aug. 2022; accepted: 31 oct. 2022; published: 13 dec. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: dolutegravir, a component of the preferred first-line antiretroviral therapy regimen, has been associated with increased weight gain. south africa has a high prevalence of obesity, especially among women. understanding dolutegravir exposure in patients with obesity is important for dose optimisation. objectives: we compared the pharmacokinetic parameters of dolutegravir in southern african adults living with hiv with and without obesity. method: blood samples were collected at various time points over a 24 h-period for dolutegravir assays. non-compartmental analysis was conducted and geometric mean ratios (gmrs), with 90% confidence intervals (cis), were generated to compare dolutegravir pharmacokinetic parameters between the groups. regression analyses to assess predictors of dolutegravir exposure were done. results: forty participants were enrolled, 26 were women and 10 had obesity. dolutegravir area under the concentration-time curve to 24-h and the maximum concentrations were not statistically significantly lower in participants with obesity: gmr 0.91 (90% ci: 0.71–1.16) and gmr 0.86 (90% ci: 0.68–1.07), respectively. in a multivariate linear regression analysis adjusting for age, gender, body mass index, creatinine clearance and randomisation arm (tenofovir alafenamide or tenofovir disoproxil fumarate), a unit increase in body mass index was associated with 1.2% lower dolutegravir area under the concentration-time curve to 24-h (p = 0.035). conclusion: dolutegravir exposure was marginally lower in participants with obesity, but this is not clinically significant. our findings suggest that there is no need to dose adjust dolutegravir in people with obesity. keywords: pharmacokinetics; dolutegravir; obesity; south africa; antiretroviral treatment optimisation; hiv. introduction antiretroviral therapy (art) has reduced morbidity and mortality in patients living with hiv.1 antiretroviral therapy regimens with durable efficacy, better tolerability and long-term safety are now preferred.2 in all current hiv treatment guidelines, second-generation integrase strand transfer inhibitors, such as dolutegravir, are included in first-line art regimens owing to their excellent tolerability and high resistance barrier.3,4 although weight gain can be regarded as an appropriate ‘return-to-health’ phenomenon after initiating art with any class, excessive weight gain can lead to treatment-emergent obesity.5 in pooled analyses of eight randomised clinical trials with more than 5000 participants with more than 10 000 person years of follow-up, more weight gain was associated with the use of integrase strand transfer inhibitors in art-naïve people living with hiv (plwh) than with other classes of antiretrovirals.5,6 over 96 weeks after initiating art, the proportion of participants who were overweight or obese increased from 31.4% to 34.7% and from 16.3% to 21.4%, respectively.6 in sub-saharan africa, two randomised controlled trials conducted in art-naïve plwh compared dolutegravir with efavirenz (standard-dose efavirenz in advance7 and low-dose efavirenz in namsal8) – the advance trial dolutegravir was combined with emtricitabine and tenofovir disoproxil fumarate (tdf) or tenofovir alafenamide (taf). both of these studies reported more weight gain and treatment-emergent obesity in participants treated with dolutegravir compared with efavirenz. in the namsal trial, treatment-emergent obesity at 48 weeks was 12% in the dolutegravir arm and 5% in the low-dose efavirenz arm.8 in the advance trial, treatment-emergent-obesity at 96 weeks was 19% for the dolutegravir-taf arm, 8% for dolutegravir-tdf, and 4% for efavirenz-tdf.7 the weight gain and obesity were more marked in women. the opera cohort of plwh, reported that switching from tdf to taf was associated with weight gain.9,10,11 obesity, is a common outcome of all modern art regimens, especially among black women.6,12,13 in south africa, there are 7.8 million plwh, with 230 000 new hiv infections reported in 2020.14 south africa also has a high level of pre-existing obesity: 68% of women and 31% of men were overweight or obese in a 2016 survey.15 obesity affects several physiological processes relevant to drug exposure (e.g. gut permeability, gastric emptying, cardiac output, liver and renal function).16 it is important to determine if drug exposure is sub-optimal in obese individuals as they are usually excluded in drug development studies that inform dosing.17,18 it has been postulated that dolutegravir could cause weight gain by off-target effects through inhibition of the melanocortin-4 receptor pathway, affecting appetite and energy balance.19,20 however, in vitro studies have shown that the concentrations needed for the direct inhibition of the melanocortin-4 receptor that would explain clinically important weight gain are much higher than those achieved with the currently recommended daily dose of 50 mg.21 in a sub-study of advance, our group has recently shown that weight gain differences between dolutegravir and efavirenz are driven by impaired weight gain in participants who are genetically slow metabolisers of efavirenz22 – this finding suggests that dolutegravir is not causing weight gain but that efavirenz is impairing weight gain in slow metabolisers who have high efavirenz concentrations. the reason for the contributory effect of taf on weight gain is still unclear and may reflect weight loss effects of tdf.12,23 as marked weight gain is increasingly reported in patients treated with dolutegravir, especially when co-administered with taf,5,7 understanding the effects of obesity on dolutegravir exposure is important for dose optimisation to ensure the efficacy and safety dolutegravir in patients with obesity.17,24,25 dolutegravir is a highly protein-bound, non-lipophilic, slightly water soluble drug, with a modest apparent volume of distribution.4,26 pharmacokinetic studies in obesity show that the behaviour of molecules with weak or moderate lipophilicity is generally predictable, as these drugs are distributed mainly in lean tissues.27 however, some of these drugs are partly distributed in adipose tissues, and their dosage should be based on ideal body weight plus a percentage of the patient’s excess bodyweight.27 data comparing dolutegravir exposure in the patients with obesity are lacking. we hypothesised that dolutegravir exposure would be lower in participants with obesity compared to those without, due to the pharmacokinetic changes observed in obesity. we compared the pharmacokinetic parameters of dolutegravir administered in participants with and without obesity in southern african plwh enrolled in the advance randomised clinical trial. we also explored covariates associated with overall dolutegravir exposure. research methods and design study population and study design the advance study (nct03122262) was a phase iii clinical trial conducted in south africa, which randomised 1053 art-naïve participants to one of three treatment arms: (1) dolutegravir, taf and emtricitabine; (2) dolutegravir, tdf and emtricitabine; or (3) efavirenz, tdf and emtricitabine.5 the present pharmacokinetic sub-study included participants from the advance study who were older than 18 years of age, weighed 40 kg or more, were randomised to the dolutegravir arms, and consented to the intensive pharmacokinetic sub-study. all participants included had already completed at least 96 weeks of therapy. we excluded those who missed any art doses within three days before the pharmacokinetic sampling, smokers, and participants who needed concomitant medications with a potential for drug-drug interactions with dolutegravir. we used the world health organization definition to categorise participants into two groups: those with obesity (≥ 30 kg/m2) and those without obesity (< 30 kg/m2).28 pharmacokinetic sampling and analysis enrolled participants had a standardised meal prior to observed oral administration of the study medication. blood sampling was done at 0 (pre-dose), 1, 2, 4, 6, 8 and 24-h post dosing. an intravenous cannula was inserted and remained in situ for serial sampling up to 8 h. at each time point, 4 ml of venous blood was collected in an ethylenediaminetetraacetic acid tube, centrifuged, plasma pipetted, and stored at −80 °c until analysis. dolutegravir was quantified with a validated assay developed at the division of clinical pharmacology, university of cape town. samples were processed with a liquid-liquid extraction method using dolutegravir-d4 as an internal standard, followed by high performance liquid chromatography with tandem mass spectrometry detection using an ab sciex api 4000 triple quadrupole mass spectrometer (ab sciex™, darmstadt, germany). analyte and internal standards were monitored at mass transitions of the protonated precursor ions (mass to charge ratio 420:1 and 424:2) to the product ions (mass to charge ratio 277:2 and 279:1), respectively. the calibration curve fitted a quadratic regression over the range 0.030 µg/ml to 10.0 µg/ml. combined accuracy and precision statistics of quality control samples during validation were between 103.5% and 106.0%, and 4.6% and 6.1%, respectively. the laboratory participated in the clinical pharmacology quality assurance external quality control programme under a contract with the division of aids of the national institute of allergy and infectious diseases, through which this assay was approved. statistical analysis we conducted secondary analyses of 40 study participants enrolled in the intensive pharmacokinetic sampling sub-study (20 in each of the dolutegravir-based arms) and categorised them into participants with or without obesity. baseline characteristics were described using medians (interquartile ranges) for non-parametric continuous variables and proportions (%) for categorical variables. using non-compartmental analysis, employing the trapezoidal rule with cubic splines, the following pharmacokinetic parameters were estimated for dolutegravir: the area under the concentration-time curve to the last measurable time point at 24 h post dosing (auc0–24h), terminal elimination half-life (t1/2), maximum concentration (cmax) and time to cmax (tmax). the apparent clearance of dolutegravir was calculated using the equation dose/auc0–24h, while the trough concentrations were estimated from the sample collected just before the next dose. pharmacokinetic data were log-transformed to calculate the geometric mean ratio (gmr) of the pharmacokinetic parameters of dolutegravir comparing participants with obesity to those without with 90% confidence intervals (ci) evaluated using paired t-tests and back-transformed to absolute ng/ml concentrations. changes in pharmacokinetic parameters between the two arms were considered statistically significant when the 90% ci of the gmr did not cross the value of one. multivariate linear regression was used to explore and determine covariates associated with overall drug exposure (auc0–24). the covariates explored were age, gender, body mass index (bmi), creatinine clearance and the art regimen group (taf vs tdf). a p-value of < 0.05 was considered as significant. there was no correction for multiple testing. all the analyses were conducted in stata® (version 16.0, statacorp llc, college station, texas, united states [us]). ethical considerations this sub-study was approved by the university of the witwatersrand human research ethics committee (wits hrec 160606b) and the university of cape town human research ethics committee (hrec ref: 224/2021). all participants provided additional written informed consent to participate in the pharmacokinetic sub-study. participant samples were labelled with coded identifiers to protect confidentiality and databases were password-protected. all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 helsinki declaration and its later amendments. results forty participants were enrolled into the intensive pharmacokinetic sub-study. the participant flow chart is shown in figure 1. ten participants were classified as participants with obesity, and their baseline characteristics are summarised in table 1. figure 1: participant flow chart. table 1: baseline characteristics of study participants included in analysis (n = 40). pharmacokinetic profile of dolutegravir in participants with versus without obesity pharmacokinetic parameters of dolutegravir when administered in participants with and without obesity are summarised in table 2. numerical reductions in the auc0–24h (9%) and cmax (14%) were observed in the participants with obesity, however, these were not statistically significant. the time to cmax was significantly prolonged (62%) in the participants with obesity. there were no differences in apparent dolutegravir clearance between the two groups. the median (interquartile range) concentration-time profiles of dolutegravir in the participants with and without obesity are shown in figure 2. in both groups, dolutegravir trough concentrations were above the putative minimum effective concentration of 300 ng/ml.29,30 figure 2: median concentration-time of dolutegravir administered in participants with obesity (red line plot, n = 10) and participants without obesity (black line plot, n = 30). the black dashed horizontal line represents the putative minimum effective dolutegravir concentration of 300 ng/ml. table 2: dolutegravir exposure profile in participants with obesity (n = 10) compared with participants without obesity (n = 30). predictors of overall dolutegravir exposure in a multivariate linear regression analysis to investigate covariates associated with dolutegravir auc0–24h in the whole group, a unit increase in bmi was associated with 1.2% lower dolutegravir exposure (beta coefficient = −1838.66, 95% ci: −3540.85 to −136.46, p = 0.035) (table 3). other covariates tested (age, gender, creatinine clearance, and treatment groups [tdf or taf]) were not associated with dolutegravir exposure (table 3). table 3: association between dolutegravir exposure (area under the concentration-time curve to the last measurable time point at 24 h post dosing) and various predictive covariates. discussion we investigated the effects of obesity on dolutegravir pharmacokinetics among participants enrolled into the intensive pharmacokinetic sampling sub-study of the advance study. we investigated predictors of dolutegravir exposure in the whole group using multivariate regression analyses adjusting for age, gender, bmi, creatinine clearance, and tenofovir prodrug: only bmi was independently associated with higher dolutegravir auc0–24h. in the group of participants with obesity, we found that auc0–24h and cmax were marginally lower. however, this was not statistically significant. we also observed that the time to cmax was significantly prolonged in this group. however, these observed minor differences in pharmacokinetic parameters between the groups are not clinically significant. obesity is associated with various physiological changes that can affect drug pharmacokinetics. these include changes in plasma proteins, drug metabolising enzymes, drug transporters and blood flow.16 in our study, we observed a marginal, non-significant, decrease in overall dolutegravir exposure in the group of participants with obesity. the time to cmax was significantly prolonged in this group, which was a surprising finding as drug absorption is not generally affected by obesity.16,25,31 similar observations were made in the swiss hiv cohort study using a physiologically based pharmacokinetic modelling, where obesity was predicted to reduce dolutegravir cmax and auc by 13% and 3%, respectively.32 the observed marginal reduction in dolutegravir exposure in our study is not clinically significant as all participants had concentrations above the putative minimum effective concentration of 300 ng/ml.29,30 we investigated predictors of dolutegravir and found a unit increase in bmi that was associated with a significantly lower dolutegravir auc0–24h. however, this small difference is not clinically significant. our study has limitations. first, this was a post hoc analysis, and we did not do formal sample size calculations. the sample size of 10 participants with, and 30 without, obesity had limited power to detect small differences in overall dolutegravir exposure. the post hoc power estimation showed that a sample size that included 10 participants with obesity and 30 without would provide 80% power if the relative difference in auc between these groups was 30%. second, we classified our participants into those with versus without obesity; however, the group of participants without obesity also included 17 participants who were overweight (bmi: > 25 kg/m2 to < 30 kg/m2). this may have underestimated the impact of obesity on dolutegravir exposure. in a sensitivity analysis comparing the 10 participants with obesity with 13 adults with a healthy weight (bmi: ≤ 25 kg/m2), the dolutegravir pharmacokinetic profile was similar to that seen when overweight participants were included (data not shown). third, all our participants were africans; our findings may, therefore, not be generalisable to other populations. conclusion dolutegravir exposure was marginally lower in participants with obesity, but this is not clinically significant given that trough concentrations were above a putative minimum effective concentration. our findings suggest that there is no need to dose adjust dolutegravir in patients with obesity. however, future research studies with larger sample size are warranted. acknowledgements we thank all the participants in the advance study, who made our study possible. competing interests s.s., n.c.c., f.v. received research funding and drug donations for the advance trial through their institution from viiv healthcare and gilead sciences. f.v. has received personal fees and non-financial support from viiv healthcare and gilead sciences, during the conduct of the study; and personal fees from mylan, merk, adcock-ingram, aspen, abbott, roche, and johnson and johnson, outside the submitted work. all other authors: nothing to declare. authors’ contributions e.m. was responsible for the study design, data analysis including the non-compartmental analysis, data interpretation, drafting and revising the manuscript. p.z.s. was responsible for supervision and study design and critically revising the manuscript. c.g.b. was responsible for data analysis including the non-compartmental analysis in parallel with e.m., drafting and revising the manuscript content. g.m. contributed to the study concept and design, and the critical review of the manuscript content. l.w. supervised the pharmacokinetic assays and critically reviewed the manuscript. n.c.c., s.s. contributed to study design, study conduct, data collection and critically reviewed the manuscript. f.v. is the principal investigator of the advance rct (parent study), and he critically reviewed the manuscript. funding information this work was supported in part by the national research foundation (nrf) (grant numbers uid113983 and uid120647 to p.z.s.), the wellcome trust (grant numbers: 212265/z/18/z and 203135/z/16/z to g.m.), united states agency of infectious diseases (to s.s., n.c.c. and, f.v., unitaid (to s.s., n.c.c. and f.v.), the south african medical research council (to s.s., n.c.c., f.v. and p.z.s.), viiv healthcare (to s.s., n.c.c. and f.v.), and gilead sciences (to s.s., n.c.c. and f.v.). the national institute of allergy and infectious diseases (niaid) (award no's. umi ai068634, umi ai068636 and umi ai106701) (university of cape town’s pharmacology laboratory and to l.w.). data availability the data that support the findings of this study are available from the corresponding author p.z.s. upon reasonable request. disclaimer the views and opinions 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of obesity on pharmacokinetics implications for drug therapy. clin pharmacokinet. 2000;39(3):215–231. https://doi.org/10.2165/00003088-200039030-00004 who. obesity: preventing and managing the global epidemic. report of a who consultation on obesity, 1997 jun 03–05; geneva. who; 1997 [cited 2022 feb 14]. available from: https://apps.who.int/iris/handle/10665/63854 walimbwa si, lamorde m, waitt c, et al. drug interactions between dolutegravir and artemether-lumefantrine or artesunate-amodiaquine. antimicrob agents chemother. 2019;63(2):e01310–e01318. https://doi.org/10.1128/aac.01310-18 dooley ke, savic r, gupte a, et al. once-weekly rifapentine and isoniazid for tuberculosis prevention in patients with hiv taking dolutegravir-based antiretroviral therapy: a phase 1/2 trial. lancet hiv. 2020;7(6):e401–e409. https://doi.org/10.1016/s2352-3018(20)30032-1 smit c, de hoogd s, bruggemann rjm, knibbe caj. obesity and drug pharmacology: a review of the influence of obesity on pharmacokinetic and pharmacodynamic parameters. expert opin drug metab toxicol. 2018;14(3):275–285. https://doi.org/10.1080/17425255.2018.1440287 berton m, bettonte s, decosterd l, et al. pharmacokinetics of dolutegravir and bictegravir in obese people living with hiv. denver, co: conference on retroviruses and opportunistic infections (croi); 2022 feb 12–16. abstract introduction methods results discussion conclusion acknowledgements references about the author(s) linda-gail bekker desmond tutu hiv centre, cape town, south africa faculty of health sciences, university of cape town, cape town, south africa danielle giovenco desmond tutu hiv centre, cape town, south africa international health institute, brown university, providence, united states of america stefan baral bloomberg school of public health, johns hopkins university, baltimore, united states of america karen dominguez desmond tutu hiv centre, cape town, south africa contraceptive research and development (conrad), eastern virginia medical school, norfolk, united states of america rachel valencia department of epidemiology, emory university, atlanta, united states of america travis sanchez department of epidemiology, emory university, atlanta, united states of america a.d. mcnaghten department of epidemiology, emory university, atlanta, united states of america ryan zahn department of epidemiology, emory university, atlanta, united states of america clarence s. yah department of internal medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa faculty of health sciences, school of health system and public health, university of pretoria, pretoria, south africa zinhle sokhela wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, johannesburg, south africa richard kaplan desmond tutu hiv centre, cape town, south africa refliwe n. phaswana-mafuya south african medical research council/university of johannesburg pan african centre for epidemics research, faculty of health sciences, university of johannesburg, johannesburg, south africa chris beyrer faculty of health sciences, university of cape town, cape town, south africa bloomberg school of public health, johns hopkins university, baltimore, united states of america patrick s. sullivan department of epidemiology, emory university, atlanta, united states of america citation bekker l-g, giovenco d, baral s, et al. oral pre-exposure prophylaxis uptake, adherence, and adverse events among south african men who have sex with men and transgender women. s afr j hiv med. 2022;23(1), a1405. https://doi.org/10.4102/sajhivmed.v23i1.1405 note: additional supporting information may be found in the online version of this article as online appendix 1. original research oral pre-exposure prophylaxis uptake, adherence, and adverse events among south african men who have sex with men and transgender women linda-gail bekker, danielle giovenco, stefan baral, karen dominguez, rachel valencia, travis sanchez, a.d. mcnaghten, ryan zahn, clarence s. yah, zinhle sokhela, richard kaplan, refliwe n. phaswana-mafuya, chris beyrer, patrick s. sullivan received: 08 mar. 2022; accepted: 11 may 2022; published: 08 nov. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: hiv prevention programmes that include pre-exposure prophylaxis (prep) for men who have sex with men (msm) and transgender women (tgw) in south africa have not been widely implemented. objectives: the authors examined oral prep uptake, adherence, and adverse events among hiv-uninfected msm and tgw to inform intervention acceptability and feasibility. method: in 2015, msm and tgw in two south african cities were offered a comprehensive package of hiv prevention services, including daily oral prep, and were followed for one year. different models of prep delivery were used at each site. adherence was measured using self-report and pill-count data and tenofovir-diphosphate (tfv-dp) concentrations. results: among 135 participants who were eligible for prep, 82 (61%) initiated prep, of whom 67 (82%) were on prep at study end. participants were on prep for a median of 294 out of 314.5 possible days (93% protected days). the median time from prep initiation to discontinuation or study end was 305 days (interquartile range: 232–325 days). across the follow-up time points, 57% – 72% of participants self-reported taking protective levels of prep and 59% – 74% were adherent to prep as indicated by pill counts. fewer (≤ 18%) achieved protective tfv-dp concentrations of ≥ 700 fmol/punch in dried blood spots. side effects, while typically mild, were the most commonly cited reason by participants for early prep discontinuation. conclusion: many msm and tgw initiated and maintained prep, demonstrating that prep can be successfully delivered to south african msm and tgw in diverse programmatic contexts. biologic adherence measures suggest msm and tgw may experience challenges taking prep regularly. counselling for coping with side effects and motivating daily pill taking is recommended to support south african msm and tgw in achieving protection with prep. keywords: hiv; men who have sex with men; transgender women; sexually transmitted infections; pre-exposure prophylaxis; hiv prevention; south africa. introduction globally, men who have sex with men (msm) are disproportionately affected by hiv.1,2,3 in south africa, the prevalence of hiv among msm in south africa is estimated to be 18.1%.4 this prevalence varies geographically, with estimates as high as 30% in cape town to 51% in port elizabeth.5 south african msm face high levels of societal stigma and discrimination as a result of traditional and conservative attitudes within the general population.6,7 there is also a lack of knowledge and training around managing the particular health needs and vulnerabilities of msm, making it especially difficult for msm to obtain clinically and culturally competent sexual health and hiv prevention services.8 comprehensive hiv prevention programmes for msm are not widely available despite evidence that such programmes may reduce hiv transmission.9 oral antiretroviral pre-exposure prophylaxis (prep) is one of the most efficacious biomedical strategies in our toolkit for hiv prevention. pre-exposure prophylaxis holds enormous potential to substantially reduce hiv acquisition in key populations globally.9,10 among msm, oral prep has been found to be particularly effective given sufficient drug concentrations, with prior research estimating a preventive efficacy of 96% – 100% with adherence to at least four doses of prep per week.11,12 effective biomedical hiv prevention strategies, including prep, should be combined with evidence-based behavioural interventions to reduce hiv incidence on a population level.13,14,15 for prep rollout, however, research is needed to develop delivery programmes tailored to the unique needs of specific populations.16 the purpose of the sibanye health project was to develop and evaluate a combination package of biomedical, behavioural, and community-level hiv prevention interventions, which included oral prep, for msm and transgender women (tgw) in cape town and port elizabeth, south africa.17 we examined prep uptake, adherence, and adverse events among hiv-negative south african msm and tgw enrolled into the sibanye cohort to inform intervention delivery, acceptability, and feasibility. methods screening and enrolment the sibanye health project (nct02043015) was a prospective one-year pilot study evaluating the acceptability and uptake of a comprehensive combination package of hiv prevention services for msm and tgw in south africa. services included condoms with condom-compatible lubricant choices, hiv testing with risk reduction counselling, couples hiv testing and counselling, screening for sexually transmitted infections (stis), daily oral prep for interested and eligible participants, and non-occupational post-exposure prophylaxis. methods for developing components of the prevention package have been described elsewhere.17 the sibanye study recruited msm and tgw living with and without hiv in cape town and port elizabeth from february 2015 to september 2015 using a combination of eventand venue-based, online, and participant referral recruitment methods. the study also recruited walk-in participants at the study clinics. eligibility criteria included: age ≥ 18 years, self-reported anal intercourse with a man in the past year, current resident and planning to remain a resident for at least one year, literacy in english, xhosa, or afrikaans, male gender at birth, willing to provide contact information, and had a phone to facilitate scheduling visits. participants who tested hiv-negative at baseline were offered a combination hiv prevention package that included daily oral prep for those who were behaviourally and clinically eligible. consistent with the 2012 south african hiv clinician society guidelines for safe use of oral prep in msm at risk of hiv infection,18 to be behaviourally eligible for prep, participants had to meet one or more of the following hiv risk criteria as assessed by a provider: multiple partners, transactional sex, illicit drug use or abuse, heavy alcohol intake, at least one sti in the last year (including those diagnosed at screening), hiv-discordant relationship, and inability to use condoms consistently. clinical eligibility criteria for prep included: no contraindications to tenofovir disoproxil fumarate/emtricitabine (tdf/ftc), creatinine clearance of ≥ 60 ml/min, aspartate aminotransferase/alanine aminotransferase (ast/alt) < 2 × upper limit normal, hepatitis b surface antigen (hbsag) negative, proteinuria and glycosuria < 2+, no history of diabetes diagnosis, and no signs of acute hiv infection or liver disease. participants also had to report their willingness to attend visits at least every three months to be eligible for prep. the sibanye study enrolled participants prior to the approval of tdf/ftc for use as prep in south africa. in december 2015, tdf/ftc was approved for use as prep by the south african medicines control council (mcc) in combination with safer sexual practices, and in 2016, updated guidelines recommending prep for hiv-negative msm in south africa were published.19 pre-exposure prophylaxis delivery and monitoring different clinical models for prep delivery were used in the two cities.17 in cape town, prep was delivered through a gay-friendly research clinic located in an academic hospital that was previously providing hiv-related services to msm. in port elizabeth, prep was delivered in three local public clinics; in each clinic, a designated room was used to provide all sibanye services (including prep services) to participants, and all providers and clinic staff were trained in providing culturally competent care for msm. all sibanye participants (regardless of prep uptake) attended a baseline visit and follow-up visits occurring at months 3, 6, and 12. hiv-negative participants who were interested in prep could be screened for prep eligibility at baseline or their month 3 visit. eligible participants returned one month after screening (month 1 or month 4) to initiate prep. in addition to regular study follow-up visits, participants on prep had additional monitoring visits one month after initiating prep (month 2 or month 5) and at month 9. at each visit following prep initiation, participants were monitored for side effects and had lab testing for hiv and to assess their creatinine level, liver enzymes (ast/alt), phosphorus, proteinuria, and glycosuria. adherence based on pill counts was calculated at each visit, and participants were provided with adherence counselling based on this data. medication was dispensed to participants at all visits except the final visit. providers could choose to see prep users more frequently for additional safety or adherence monitoring or to provide medication refills. participants could also ‘drop in’ or schedule non-routine visits as needed during follow-up. in the port elizabeth clinics, providers often had participants come monthly throughout the study follow-up period for medication refills. participants could decide to stop prep at any time, and study providers could temporarily stop or permanently discontinue participants for clinical reasons. if not permanently discontinued, participants could restart prep provided they were still eligible and at the provider’s discretion. participants who tested positive for hiv during the follow-up period were immediately discontinued from tdf/ftc, tested for drug resistance, and enrolled in care services. dates of known prep stops and restarts were recorded on participant case report forms (crfs). at the end of the study, participants on prep in cape town were referred to a non-governmental organisation serving msm for prep continuation. at the time, port elizabeth did not have any local providers prescribing tdf/ftc for prep. outcomes persistence on prep was assessed using dates of stops and restarts from participant crfs. a prep stop was defined as the last date that prep was taken before ≥ 14 days off of prep following initiation, consistent with previous research and when protection with prep is estimated to be low.20,21 permanent stops, or prep discontinuation, was defined as the last date prep was taken without restarting before study end. for participants with an uncertain prep discontinuation date, the halfway point between their last known date on prep and the date they were known to not be on prep was used. self-reported reasons for permanent stops were collected by study staff on a crf at the time of discontinuation. a participant was categorised as persistent to study end if they picked up prep at their month 9 visit or restarted prep following their month 9 visit prior to study end. adherence was measured through the self-reported number of pills missed in the last seven days and by a pill count, measured as pills dispensed minus pills returned, divided by the number of days since the dispense date, and was assessed at all follow-up visits while a participant was taking prep. thresholds for high adherence included ≥ 4 doses of prep self-reported to be taken per week and ≥ 57% of pills taken per week as determined by pill counts. the thresholds were associated with 100% protection against hiv acquisition among msm in the iprex ole study.11,12 for cape town participants only, dried blood spots (dbs) collected at each subsequent visit after prep initiation were used to test intracellular concentrations of tenofovir-diphosphate (tfv-dp). fifty microliters of whole blood was spotted on filter paper, dried at room temperature for 2 hours, sealed in bags with desiccant, and stored at −80 °c until analysis. an indirect method for the quantification of tfv-dp in 50 µl dbs was developed and validated at the division of clinical pharmacology, university of cape town.22 dried blood spots provide a measure of cumulative adherence in the month prior to sample collection.23 thresholds for high (≥ 700 fmol/punch; ≥ 4 pills taken per week), medium (350 fmol/punch – 699 fmol/punch; 2–3 pills taken per week), and low (< 350 fmol/punch; < 2 pills taken per week) adherence24 were used to compare tfv-dp concentrations to self-report and pill-count measures. adverse events were assessed at routine and non-routine visits and were recorded on participant crfs by grade (mild, moderate, severe) and potential relation to prep. adverse events were specified by participant self-report or by a provider based on clinical or lab assessments. lastly, patterns of prep use and discontinuation among participants who seroconverted during the study were described. analysis the authors described the continuum of hiv-negative participants enrolled into the sibanye cohort from diagnosis to prep initiation. a descriptive summary of socio-demographic and behavioural characteristics was conducted for hiv-negative participants, participants who initiated prep, and participants who did not initiate prep at baseline. participants who did and did not initiate prep were compared across characteristics using a fisher’s exact test. to determine the proportion of available days that participants were on and off prep, the median number of days on prep (excluding stops) and median number of available prep days during follow-up were calculated. kaplan-meier estimates were used to describe the time from initiation to first prep stop and prep discontinuation (last stop). participants who did not stop prep early were censored at study end even if they had continued prep as part of their medical care. patterns of prep stops and restarts were described for all participants who initiated prep. adherence to prep was described using multiple measures (self-report, pill-count, tfv-dp) at routine monitoring visits only. assessments during known prep stops and after discontinuation were excluded. kappa statistics were used to assess the agreement between self-report and pill count adherence measures.24 ethical considerations this study was approved by the institutional review board of emory university (protocol irb00054229), the human research ethics committee of the university of cape town, the research ethics committee of the human sciences research council, and the south african mcc. all participants enrolled into the sibanye health project provided written informed consent prior to participation. results among participants screened for the study, 167 participants tested hiv-negative at baseline (80 from cape town and 87 from port elizabeth), of whom 160 (96%) were interested in prep and evaluated for prep eligibility. among these, 135 were behaviourally and clinically eligible (84% eligibility). between month one and month four, 82 participants initiated prep (61% uptake), including 45/60 participants from cape town (75%) and 37/75 participants from port elizabeth (49%). four participants who were interested in prep and who screened as behaviourally and clinically eligible at baseline did not return for their one-month visit. a continuum of participant drop-off from testing to uptake is shown in figure 1. participants who initiated prep were primarily black african, under 30 years of age, and male-identifying. there were no significant socio-demographic and behavioural differences between participants who initiated prep and those who did not (table 1). figure 1: pre-exposure prophylaxis continuum among south african men who have sex with men and transgender women in a combination hiv prevention trial, 2015. table 1: baseline socio-demographic and behavioural characteristics among south african men who have sex with men and transgender women in a combination hiv prevention trial, 2015. most participants (65/82) initiated prep at their month 1 visit. participants who initiated prep were on prep for a median of 294 days (interquartile range [iqr]: 217–319 days) out of a median of 314.5 possible days (iqr: 252–329 days) (figure 2). thus, participants were on prep for a total of approximately 93% of available prep days. the median number of visits for participants in the 11 months after prep initiation (including regular study visits and drop-in visits) was seven (iqr: 6–9). a total of 67 participants (82%) picked up prep at their month 9 visit or, if they were not on prep during their month 9 visit, had restarted prep prior to study end and were thus considered to be persistent to study end, including 34/45 participants from cape town (76%) and 33/37 participants from port elizabeth (89%). early prep discontinuation (n = 15) was most commonly reported by participants to be the result of side effects (n = 9) and was initiated by both participants (n = 6) and clinicians (n = 3). other self-reported reasons for prep discontinuation included family relationships (n = 2), missing medication pick-up (n = 1), no longer interested (n = 1), moving out of the study area (n = 1), and hiv seroconversion (n = 1). figure 2: proportion of available days on and off pre-exposure prophylaxis by study site among south african men who have sex with men and transgender women in a combination hiv prevention trial, 2015. over one-third of participants (37%; 30/82) had at least one known prep stop. the median time from prep initiation to first stop (≥ 14 days) was 265.5 days (iqr: 142–316 days) in the full cohort, 218 days (iqr: 97–305 days) in cape town, and 307 days (iqr: 232–324 days) in port elizabeth (figure 3a). further, the median time from prep initiation to discontinuation (i.e. last stop) was 304.5 days (iqr: 232–325 days) in the full cohort, 304 days (iqr: 230–325 days) in cape town, and 307 days (iqr: 232–324 days) in port elizabeth (figure 3b). twenty-eight participants stopped prep only once before study end, of whom 13 stopped permanently (i.e. discontinued prep) and 15 restarted prep and were persistent to study end. two additional participants stopped prep more than once. these participants permanently discontinued prep at their second and third stop (figure 4). figure 3: (a, b) kaplan-meier survival analysis for time to first pre-exposure prophylaxis stop or study end (for those who did not stop pre-exposure prophylaxis), overall and by site among south african men who have sex with men and transgender women in a combination hiv prevention trial, 2015. (c, d) kaplan-meier survival analysis for time to last pre-exposure prophylaxis stop or study end (for those who did not stop pre-exposure prophylaxis), overall and by site among south african men who have sex with men and transgender women in a combination hiv prevention trial, 2015. figure 4: patterns of pre-exposure prophylaxis stops and restarts for all pre-exposure prophylaxis initiators among south african men who have sex with men and transgender women in a combination hiv prevention trial, 2015. each stop represents ≥ 14-days off pre-exposure prophylaxis. time in days is median time from pre-exposure prophylaxis stop to restart and interquartile range. across the follow-up time points (1–11 months post-prep-initiation), 57% – 72% of participants self-reported taking protective levels of prep, and 59% – 74% were adherent to prep as indicated by pill counts (table 2). results of quantitative tfv-dp concentrations by dbs testing (available for cape town only, online appendix 1, table 1-a1) indicated that no participants had protective concentrations of tfv-dp (≥ 700 fmol/punch) one month after initiating prep, 16% (7/45) had protective levels after two months, 18% (8/45) after 5 months, 9% (4/45) after eight months, and 7% (3/45) after 11 months (figure 5). additionally, 29% (13/45) of participants had tfv-dp levels from 350 fmol/punch to < 700 fmol/punch one month after initiating prep, 24% (11/45) after two months, 13% (6/45) after five and eight months, and 4% (2/45) after 11 months. figure 5: oral hiv pre-exposure prophylaxis adherence measures among 45 men who have sex with men and transgender women from cape town, south africa in a combination hiv prevention trial, 2015. table 2: self-reported and pill-count adherence among south african men who have sex with men and transgender women in a combination hiv prevention trial, 2015. a total of 41 side effects were reported during the study among 28 participants (online appendix 1, table 2-a1). side effects that were most commonly reported included nausea (n = 6), fatigue (n = 6), proteinuria (n = 5), glycosuria (n = 4), heartburn (n = 4), and increased thirst or dry mouth (n = 4). the majority of the side effects were judged to be mild (n = 29) or moderate (n = 9) by study clinicians. two participants had elevated alt/ast levels, which were rated as severe. one side effect (nausea) was missing a severity rating. pre-exposure prophylaxis was held by study clinicians due to side effects, either permanently or temporarily, for 18 participants (22%) during the study. among participants who initiated prep, there were five hiv seroconversions (6%) during study follow-up, all in cape town (online appendix 1, table 3-a1). among these, two participants initiated permanent prep stops ≥ 30 days before their hiv-positive test results due to side effects. the first stopped prep six days following initiation due to a mild hypersensitivity reaction and was diagnosed with hiv 55 days later. the second participant stopped prep the same day they initiated due to gastrointestinal (gi) problems and was diagnosed after approximately one year. one additional participant stopped prep approximately four months following initiation due to gi problems and was diagnosed with hiv 23 days later. lastly, two participants had not stopped prep before their hiv diagnoses and were diagnosed 316 days and 303 days following prep initiation. both participants had low adherence at their diagnosis visit, as indicated by tfv-dp concentrations at their month 12 visit (130 fmol/punch and 0 fmol/punch). discussion the sibanye health project was a prospective one-year pilot study evaluating the acceptability and uptake of a comprehensive hiv prevention package that included daily oral prep for msm and tgw in south africa. approximately half of the participants who tested hiv-negative at baseline initiated prep during the study despite approximately 80% being behaviourally and clinically eligible and interested in prep. uptake was lower than observed among kenyan msm, where over 80% of participants initiated prep.25 in the kenyan study, eligible msm who were willing to start prep could initiate prep right away, while msm in the sibanye health project had to wait one month to initiate prep following confirmation of their lab results. pre-exposure prophylaxis should be available to msm to initiate immediately following an hiv-negative diagnosis to avoid potential fallout between initial screening and prep uptake.26 among those who initiated prep, over 80% were persistent with prep at study end. this estimate was higher than in kenya, where only 46% of msm who initiated prep reported use at study end.25 adherence in the cape town cohort, however, was relatively poor by objective laboratory measures, with 18% of participants or fewer having achieved protective tfv-dp concentrations at any time point. self-report and pill count adherence assessments were higher (57% – 74%) across time points. overestimation of adherence due to recall or social desirability bias has been observed in prior prep studies.27,28,29,30 however, it is possible that there were unknown factors related to dbs collection or storage that negatively impacted the quality of the study samples and, thus, our findings. future research should compare self-report and pill count adherence measures with objective biological measures among south african msm and tgw to provide additional insight into the conflicting estimates observed across measures in this study. given the high level of prep interest and likely challenges with daily adherence, the acceptability of longer-acting prep formulations should be examined. although side effects were typically mild and often resolved for men who remained on prep, for 18 participants (22%), prep was held by study clinicians, either permanently or temporarily, when the side effect was reported. side effects were the most common reason for early prep discontinuation cited by participants at their exit visit. among the five prep initiators who seroconverted during the study, three had previously discontinued prep due to side effects (of whom two were due to gi side effects). thus, adherence counselling for dealing with side effects, and especially gi upset, is likely important for msm taking prep. further, providers prescribing prep should consider if the risks associated with certain side effects outweigh the risks associated with stopping prep, even temporarily. different models of delivery were used in cape town and port elizabeth. while prep uptake was higher in cape town, participants in port elizabeth were on prep for a greater number of days, and fewer participants discontinued prep before study end. the successful experience of implementing a prep programme for msm and tgw in district health clinics in port elizabeth provides evidence that specialised facilities are not required to provide confidential, acceptable, and high-quality prep services, but that provision of prep in public health clinics is likely a feasible approach to reach those at highest risk for hiv infection. the sibanye health project began enrolling msm and tgw in 2015 prior to the approval of tdf/ftc as prep by the south african mcc. despite prep’s novelty in south africa, many msm and tgw were interested in prep; over half of msm and tgw initiated prep, and the majority persisted with prep to study end. notably, these early efforts to provide prep to hiv-negative msm and tgw resulted in higher uptake and persistence than similar programmes reported in the united states21,31 and europe.32 since 2015, prep has gained recognition in south africa as a safe and effective hiv prevention strategy with utility across key populations. south african msm, however, still face high levels of stigma and discrimination that make it difficult to access healthcare services.8 thus, research is still needed to explore methods for reaching south african msm and tgw who may benefit from prep and to develop tailored adherence programmes. our study has limitations. due to this study’s sampling methods, findings from this study may not be generalisable to all south african msm and tgw. although this study describes patterns of prep use behaviour, the main goal of the sibanye health project was not to track prep stops and restarts, and thus this data may have been imprecisely captured. participants who initiated prep were not rescreened for hiv risk during follow-up. risk can be dynamic, particularly in young populations, and it could be that poor adherence or discontinuation of prep was the result of reductions in perceived levels of hiv risk. prep estimates should be interpreted in the context of the other services provided in the sibanye health project; prep uptake and persistence, for example, might be less in the absence of supportive services, including opportunities for drop-in visits, free access to other prevention commodities, risk reduction counselling, and the availability of providers trained in cultural competency and prep provision. finally, data collection began in 2015, before the regulatory approval of prep in south africa. pre-exposure prophylaxis delivery to msm and tgw in africa remains sparse, and research exploring the acceptability and feasibility of oral prep for msm and tgw in south africa is still needed. conclusion our findings suggest that prep can be successfully delivered to msm and tgw in south africa in diverse programmatic contexts. the msm and tgw in the sibanye health project showed a high interest in prep and high persistence on prep over one year. uptake of prep, however, was low, and discrepancies between self-report and biological adherence measures suggest there are adherence challenges for msm and tgw taking prep. counselling for coping with side effects and motivating daily pill taking is recommended to support south african msm and tgw in achieving protection with prep. research is needed on interventions to improve prep uptake and adherence and to examine the acceptability of alternative prep formulations. acknowledgements competing interests l.-g.b. has received honoraria for advisory roles at gilead science, viiv healthcare, and merck pty ltd. no other author has a conflict of interest, a financial interest, or any relationship with an organisation that has a financial interest in the content of this manuscript. authors’ contributions l.-g.b., s.b., and p.s.s. conceived of the research study and obtained funding. l.g.-b, s.b., t.s., a.d.m., and p.s.s. designed the research study. l.-g.b., s.b., k.d., r.v., c.y., z.s., r.n.p.m., and p.s.s. implemented the research. d.g., r.v., and p.s.s. conducted the analysis and l.-g.b., d.g., s.b., and p.s.s. drafted the manuscript. all authors have reviewed and approved the final manuscript. funding information this work was supported by the center for aids research at emory university (p30ai050409) and the national institute for allergy and infectious diseases (r01ai094575). the authors acknowledge the centers for disease control and prevention for support of clinical prevention services for participants. data availability data that support the findings may contain identifying or sensitive patient information. to preserve participant confidentiality, these data cannot be shared publicly. the principal investigator of this study, p.s.s. (pssulli@emory.edu), can be contacted with requests to access these data. disclaimer the views expressed in this article are those of the authors and do not reflect the views of the funders or any affiliated agency of the authors. references baral s, trapence g, motimedi f, et al. hiv prevalence, risks for hiv infection, and human rights among men who have sex with men (msm) in malawi, namibia, and botswana. plos one. 2009;4(3):e4997. https://doi.org/10.1371/journal.pone.0004997 baral sd, grosso a, holland c, papworth e. the epidemiology of hiv among men who have sex with men in countries with generalized hiv epidemics. curr opin hiv aids. 2014;9(2):156–167. https://doi.org/10.1097/coh.0000000000000037 beyrer c, baral sd, van griensven f, et al. global epidemiology of hiv infection in men who have sex with men. lancet. 2012;380(9839):367–377. https://doi.org/10.1016/s0140-6736(12)60821-6 unaids. aidsinfo [homepage on the internet]. 2020 [cited 2020 jan]. available from: 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afr j hiv med. 2018;19(1):a701. https://doi.org/10.4102/sajhivmed.v19i1.701 sullivan ps, carballo-diéguez a, coates t, et al. successes and challenges of hiv prevention in men who have sex with men. lancet. 2012;380(9839):388–399. https://doi.org/10.1016/s0140-6736(12)60955-6 fonner va, dalglish sl, kennedy ce, et al. effectiveness and safety of oral hiv preexposure prophylaxis for all populations. aids. 2016;30(12):1973. https://doi.org/10.1097/qad.0000000000001145 grant rm, anderson pl, mcmahan v, et al. uptake of pre-exposure prophylaxis, sexual practices, and hiv incidence in men and transgender women who have sex with men: a cohort study. lancet infect dis. 2014;14(9):820–829. https://doi.org/10.1016/s1473-3099(14)70847-3 anderson pl, glidden dv, liu a, et al. emtricitabine-tenofovir concentrations and pre-exposure prophylaxis efficacy in men who have sex with men. sci transl med. 2012;4(151):151ra125. https://doi.org/10.1126/scitranslmed.3004006 brookmeyer r, boren d, baral sd, et al. combination hiv prevention among msm in south africa: results from agent-based modeling. plos one. 2014;9(11):e112668. https://doi.org/10.1371/journal.pone.0112668 kurth ae, celum c, baeten jm, vermund sh, wasserheit jn. combination hiv prevention: significance, challenges, and opportunities. curr hiv/aids rep. 2011;8(1):62–72. https://doi.org/10.1007/s11904-010-0063-3 bekker lg, beyrer c, quinn tc. behavioral and biomedical combination strategies for hiv prevention. cold spring harb perspect med. 2012;2(8):a007435. https://doi.org/10.1101/cshperspect.a007435 amico kr, mansoor le, corneli a, torjesen k, van der straten a. adherence support approaches in biomedical hiv prevention trials: experiences, insights and future directions from four multisite prevention trials. aids behav. 2013;17(6):2143–2155. https://doi.org/10.1007/s10461-013-0429-9 mcnaghten ad, kearns r, siegler aj, et al. sibanye methods for prevention packages program project protocol: pilot study of hiv prevention interventions for men who have sex with men in south africa. jmir res protoc. 2014;3(4):e55. https://doi.org/10.2196/resprot.3737 southern african hiv clinicians society consensus committee. southern african guidelines for the safe use of pre-exposure prophylaxis in men who have sex with men who are at risk for hiv infection. s afr j hiv med. 2012;13(2):40–55. https://doi.org/10.4102/sajhivmed.v13i2.136 bekker lg, rebe k, venter f, et al. southern african guidelines on the safe use of pre-exposure prophylaxis in persons at risk of acquiring hiv-1 infection. s afr j hiv med. 2016;17(1):a455. https://doi.org/10.4102/sajhivmed.v17i1.455 seifert sm, glidden dv, meditz al, et al. dose response for starting and stopping hiv preexposure prophylaxis for men who have sex with men. clin infect dis. 2015;60(5):804–810. https://doi.org/10.1093/cid/ciu916 serota dp, rosenberg es, sullivan ps, et al. pre-exposure prophylaxis uptake and discontinuation among young black men who have sex with men in 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https://doi.org/10.1016/j.eclinm.2020.100541 sullivan ps, mena l, elopre l, siegler aj. implementation strategies to increase prep uptake in the south. curr hiv/aids rep. 2019;16(4):259–269. https://doi.org/10.1007/s11904-019-00447-4 amico kr, marcus jl, mcmahan v, et al. study product adherence measurement in the iprex placebo-controlled trial: concordance with drug detection. j acquir immune defic syndr. 2014;66(5):530. https://doi.org/10.1097/qai.0000000000000216 musinguzi n, muganzi cd, boum ii y, et al. comparison of subjective and objective adherence measures for preexposure prophylaxis against hiv infection among serodiscordant couples in east africa. aids. 2016;30(7):1121–1129. https://doi.org/10.1097/qad.0000000000001024 baker z, javanbakht m, mierzwa s, et al. predictors of over-reporting hiv pre-exposure prophylaxis (prep) adherence among young men who have sex with men (ymsm) in self-reported versus biomarker data. aids behav. 2018;22(4):1174–1183. https://doi.org/10.1007/s10461-017-1958-4 van der straten a, brown er, marrazzo jm, et al. divergent adherence estimates with pharmacokinetic and behavioural measures in the mtn-003 (voice) study. j int aids soc. 2016;19(1):20642. https://doi.org/10.7448/ias.19.1.20642 rolle cp, rosenberg es, siegler aj, et al. challenges in translating prep interest into uptake in an observational study of young black msm. j acquir immune defic syndr. 2017;76(3):250. https://doi.org/10.1097/qai.0000000000001497 van dijk m, de wit jb, guadamuz te, martinez je, jonas kj. slow uptake of prep: behavioral predictors and the influence of price on prep uptake among msm with a high interest in prep. aids behav. 2021;25:2382–2390. https://doi.org/10.1007/s10461-021-03200-4 localised.html original article localised treatment and 6-month outcomes in patients with cytomegalo-virus retinitis at a tertiary ophthalmology service in ga-rankuwa fatima laher, mb bch, dip hiv man (sa) perinatal hiv research unit, university of the witwatersrand, johannesburg claire cullen, fcophth, mmed j baile matlala, fcophth, mmed department of ophthalmology, dr george mukhari hospital, ga-rankuwa, gauteng corresponding author: f laher (laherf@phru.co.za). objective. there are few data from before the antiretroviral therapy (art) era for cytomegalovirus retinitis (cmv-r) from settings where cost limits use of systemic treatment. this study examines cmv-r treatment and survival outcomes in a public hospital ophthalmology service in ga-rankuwa, south africa. methods. from october 2009 to october 2010, voluntarily consenting participants over the age of 15 years with incident clinically diagnosed cmv-r seen at the dr george mukhari hospital ophthalmology clinic were prospectively enrolled in an observational study. treatment was per clinic protocols and patients were followed up with structured data collection for up to 6 months. results. eight individuals, all hiv infected and 50% female, were identified and enrolled. at enrolment, median age was 38 years (interquartile range (iqr) 32 39 years), median cd4 count 20 cells/μl (iqr 13 46.5 cells/µl), and 50% were currently receiving art (mean duration of art use 18 days, standard deviation (sd) 2.99 days). no participant received systemic ganciclovir, but 6 reported symptom combinations suggesting systemic cmv: shortness of breath (n=3), diarrhoea (n=3) and/or central nervous system complaints (n=3). ten eyes had visual impairment less than counting fingers at enrolment. treatment combinations were: art plus intravitreal ganciclovir (n=5), intravitreal ganciclovir alone (n=2), and art alone (n=1). six-month outcomes were: death (n=1), survival (n=6), loss to follow-up (n=3), untraceable (n=1), systemic symptom resolution (4/4), visual acuity deterioration (0/5), and persisting uveitis (2/3). conclusion. in the art era, incident cmv-r appears to be uncommon in this setting. cmv-r may occur within the first 3 weeks after art initiation. even in cmv-r patients with suggestive systemic symptoms, 6-month survival is good despite no systemic cmv therapy. s afr j hiv med 2012;13(2):68-71. south africa has both a high burden of hiv disease1 and a large, expanding antiretroviral therapy (art) programme.2 it is noteworthy that many south african hiv patients present for treatment when the cd4 count is less than 50 cells/μl.3 particularly in these individuals with advanced immune compromise, opportunistic infections such as cytomegalovirus (cmv) may present. the most commonly recognised manifestation of cmv is cmv retinitis (cmv-r), but pneumonitis, colitis, oesophagitis, adrenalitis, and neurological involvement are also described.4 in africa, data describing the disease burden of cmv-r in the art era are limited. in the pre-art era, a 20-month longitudinal study in aids patients in togo confirmed a 21.4% incidence.5 also in the pre-art roll-out era in south africa, 90 aids patients were treated for cmv-r at the university of natal, and the incidence was noted to increase with time.6 a cross-sectional study screening all hiv patients with cd4 counts of <50 cells/μl in khayelitsha, south africa, found 2% of these patients to have cmv-r.5 cmv-r treatment strategies include localised and systemic therapies optimally used in combination and in initiation and maintenance phases, and the use of art in the context of hiv diagnosis. cmv has been called the ‘neglected disease of the aids pandemic’, in part because of limited access to treatment, especially in the developing world, where localised intra-ocular ganciclovir implants and systemic oral valganciclovir are unavailable or too costly.5 intravitreal ganciclovir injections, although more cost-effective, require highly skilled administration and may be inconvenient and/or unacceptable to patients.7 art combined with cmv treatment strategies is associated with an improvement in median survival after cmv-r diagnosis from 6 months to over 1 year.8 , 9 there are few art-era data for cmv-r from african countries where cost limits the use of systemic cmv therapy. this study describes the incidence of cmv-r in a public hospital outpatient ophthalmology clinic in ga-rankuwa, south africa, over a 1-year period and examines treatment and survival outcomes of cmv-r cases over a 6-month follow-up period, so as to inform future cmv-r care. methods setting a prospective longitudinal observational study was conducted at the ophthalmology outpatient clinic of the dr george mukhari hospital, a state tertiary academic service situated in ga-rankuwa, gauteng province, south africa. the hospital has a catchment population of 1 800 000 people from the surrounding tshwane and metsweding areas. in 2007, the antenatal hiv seroprevalence in tshwane was 27% and in metsweding it was 33%.10 at the time of the study, the hospital also offered an on-site hiv clinic with free art access for hiv-infected adults with cd4 counts less than 200 cells/µl or world health organization (who) stage 4 disease. arv roll-out began in august 2004. in this setting, ophthalmology referrals are made by healthcare workers in the hospital and hiv clinic or in secondary and primary level facilities. referral is based on presentation with any visual symptoms. in 2011, the hiv clinic saw 7 853 patients of whom 193 initiated art during that year. eligibility patients were eligible for entry into the study if they were aged 15 years or older; able to provide voluntary written informed consent (for those 18 years or older) or assent with parent/guardian consent (for those between 15 and 17 years old); and presented at dr george mukhari hospital ophthalmology clinic with new clinically diagnosed cmv-r during the 1-year enrolment period of the study. case definition the cmv-r case definition was visualisation of at least one of the following on dilated pupil indirect ophthalmoscopy: indolent retinitis characterised by mild granular retinal opacification which may be associated with a few punctuate haemorrhages but absent vasculitis, or fulminating retinitis characterised by mild vitritis, vasculitis with perivascular sheathing and retinal opacification, dense, white, well-demarcated, geographical area of confluent opacification often associated with retinal haemorrhages, and slow relentless brushfire-like extension along retinal vascular arcades that may involve the optic nerve.11 data collection from 6 october 2009 to 6 october 2010, participants identified by clinic staff as having a possible cmv-r diagnosis from routine retinal screening (indirect ophthalmoscopy with fully dilated pupils) were referred to study representatives at the same clinic for assessment of eligibility, voluntary informed consent procedures and enrolment into the study. structured data collection by ophthalmologists was done at enrolment on the day of referral, and at months 3 and 6. this involved two components: (i) a clinical interview to record demographics, hiv status, cd4 count results, use of art and cmv treatments, ocular symptoms, and a brief systemic symptom screen probing shortness of breath, diarrhoea, fever, headache, change in personality and decreased concentration; and (ii) visual acuity measurements using a snellen chart or gross visual tests for vision worse than 6/120, and an ophthalmological examination including indirect ophthalmoscopy with fully dilated pupils to categorise cmv-r zonal location and to assess the presence of cmv-r complications, namely vitreous haemorrhage, cataract, endophthalmitis and uveitis. treatment was neither influenced nor provided by the study, but was managed by the clinic according to local standard of care. patients were referred to the hiv clinic for art per south african guidelines. management of cmv-r in this setting was predetermined by availability of ganciclovir only. current accepted practice in the developing world is intravitreal ganciclovir injection twice a week for the first 2 weeks, and then weekly until the cd4 count recovers to over 150 cells/µl or retinitis becomes quiescent. however, intravitreal ganciclovir is not recommended for patients who will not have recoverable vision, who have less than 3 clock hours of disease in retinal zone 3 and no fundal view, and who cannot come for regular injections.6 telephonic tracing was undertaken for participants who did not attend follow-up appointments. statistical analysis descriptive statistics are reported. there were insufficient cases reported to analyse risk factors for outcomes. ethical considerations ethical approval was received from the medunsa research and ethics committee before initiating the study. results baseline characteristics over the 1-year enrolment period, 8 individuals were eligible and all agreed to participate in the study (table 1). all were hiv infected and 50% were female. the median age at first appearance of cmv symptoms was 38 years (intraquartile rage (iqr) 32 39 years). at enrolment, the median cd4 count was 20 cells/μl (iqr 13 46.5 cells/μl) and 50% were currently receiving art (mean duration of art use prior to cmv presentation 18 days, standard deviation (sd) 3 days). presenting ocular symptoms were either one or a combination of: blind spots (n=3), decreased vision (n=2), dry eyes (n=2), photophobia (n=2), eye redness (n=1), visual distortions (n=1) and ‘floaters’ (n=1). six participants (75%) reported systemic symptoms: shortness of breath (n=3), diarrhoea (n=3) and/or central nervous system complaints of headaches, personality changes and/or decreased concentration (n=3). a summary of visual acuity is presented in table 2. ten eyes were classified as having visual impairment less than counting fingers at enrolment. indirect ophthalmoscopy at enrolment revealed bilateral retinal involvement in 7 participants (88%). the most common retinal zone affected was zone 3 (10 eyes), then zone 2 (8 eyes) and zone 1 (6 eyes). uveitis was found in 7 cases, and vitreous haemorrhage was present in 1 case (figs 1 and 2). treatment none of the participants received systemic therapy, although 6 complained of systemic symptoms. the combination of art and intravitreal ganciclovir injections was given to 5 participants. intravitreal ganciclovir alone was given to 2 male participants who both refused art and defaulted from study follow-up. one patient, who had no light perception bilaterally, received only art because visual benefit with intravitreal ganciclovir was not deemed likely. six-month outcomes by month 6, 1 participant had died, 6 were alive and 1 was untraceable. three participants had defaulted from follow-up. resolution of symptoms and complications at 6 months is described for the 4 participants who remained in follow-up. ocular symptoms resolved for all 3 participants who received both intravitreal ganciclovir and art, but did not resolve in the participant who received art only. all 4 participants reported resolution of their systemic symptoms. visual acuity outcomes are presented in table 2. among the 5 participants who were followed up to month 6, there was no recorded deterioration in visual acuity from enrolment; 6 eyes demonstrated no change and 4 eyes showed slight improvement. uveitis resolved in 2 of 3 cases, and in the third case where it persisted, a cataract developed. there were no cases of endophthalmitis. discussion this study found a low incidence of cmv-r at a resource-constrained public hospital outpatient ophthalmology clinic in ga-rankuwa, south africa: only 8 cases were identified in a 1-year period. the low incidence may be explained by the availability of art in this population. in this setting, cmv-r remains an aids manifestation, and the late presentation to care is highlighted not only by the low median cd4 count of 20 cells/μl but also by the advanced stage of visual loss at enrolment. several studies from the pre-art era describe improved or stable visual outcomes with intravitreal ganciclovir injections for cmv-r lesions.12 , 13 importantly, even though none of the 75% of participants who reported systemic symptoms received systemic ganciclovir, the combination of art and intravitreal ganciclovir did ameliorate visual symptoms in our study. however, possibly owing to severe visual loss, no patient had complete recovery of vision. currently the authors are unable to predict whether the 6-month outcomes reported here would have been better if state-of-the-art treatments such as ganciclovir implants and systemic valganciclovir had been available in our setting. a pressing question in the field of cytomegalovirus medicine is the relative efficacy of localised versus systemic treatment when cmv-r has been diagnosed, and until this is answered, management remains individualised. when comparing localised with systemic treatments, the latter carry an increased risk of systemic side-effects but also a reduced risk of systemic cmv dissemination. there are several limitations to our study. first, the small sample size prevents statistical comparison of outcomes by treatment combination. second, incidence may be underestimated because of missed diagnoses and lack of presentation to hospital. third, when screening for systemic symptoms of cmv infection, no attempt was made to discriminate from co-morbidities. it has been noted, however, that systemic cmv symptoms have been misdiagnosed as pneumocystis jirovecii pneumonia and tuberculosis, among others.14 last, though we attempted in our mortality assessment to control for treatment defaulting by telephonic tracing, loss to follow-up may signify an underestimation of mortality, a phenomenon well described in studies of art programmes.15 in conclusion, cmv-r is an uncommon disease in the art era in ga-rankuwa, south africa. intravitreal ganciclovir, complemented with art, was an effective option to treat cmv-r. acknowledgements. the authors wish to thank the hospital and the participants for their 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[pmid: 17885294] 14. martinson na, karstaedt a, venter wd, et al. causes of death in hospitalized adults with a premortem diagnosis of tuberculosis: an autopsy study. aids 2007;21:2043-2050. [pmid: 17885294] 15. geng eh, bangsberg dr, musinguzi n. understanding reasons for and outcomes of patients lost to follow-up in antiretroviral therapy programs in africa through a sampling-based approach. j acquir immune defic syndr 2009;53:405-411. pmid: 19745753] 15. geng eh, bangsberg dr, musinguzi n. understanding reasons for and outcomes of patients lost to follow-up in antiretroviral therapy programs in africa through a sampling-based approach. j acquir immune defic syndr 2009;53:405-411. pmid: 19745753] table 1. summary of participant characteristics, treatment and symptoms at baseline and 6 months participant baseline characteristics six-month follow-up of symptomatic outcomes gender age (years) presenting ocular symptoms presenting systemic symptoms cmv-r treatment art use 1 f 27 decreased vision shortness of breath, diarrhoea, fever, headache, personality changes, decreased concentration no yes ocular symptoms unresolved but systemic symptoms resolved 2 f 31 ocular dryness diarrhoea intravitreal ganciclovir yes ocular and systemic symptoms resolved 3 m 44 ocular redness and photophobia shortness of breath intravitreal ganciclovir yes defaulted follow-up but confirmed alive 4 f 39 decreased vision nil intravitreal ganciclovir yes death 5 f 31 ocular dryness diarrhoea intravitreal ganciclovir yes ocular and systemic symptoms resolved 6 m 39 blind spots, visual distortions headaches, generalised pain intravitreal ganciclovir yes ocular and systemic symptoms resolved 7 m 44 blind spots, ‘floaters’ nil intravitreal ganciclovir no defaulted follow-up and survival not ascertained 8 m 37 blind sports, photophobia shortness of breath, decreased concentration intravitreal ganciclovir no defaulted follow-up but confirmed alive table 2. visual acuity at enrolment and month 6 right eye (n=8) left eye (n=8) visual acuity category enrolment month 6 enrolment month 6 6/6 6/12 vision 0 0 4 2 6/18 6/60 vision 2 2 0 0 counting fingers to hand motions vision 3 1 2 2 light perception to no light perception 3 2 2 1 defaulted/died not applicable 3 not applicable 3 fig. 1. fundus photograph of the right eye of a 40-year-old woman with cmv-r. vitreous haemorrhage, retinal detachment and retinitis are shown by the retinal opacification with associated retinal haemorrhages indicative of active cmv-r. the picture appears out of focus because the vitreous haemorrhage is anterior to the retina. fig. 2. fundus photograph of the left eye of the same patient as in fig. 1. retinal detachment and retinitis are demonstrated by the retinal opacification and frosted branch angiitis, indicating active cmv-r disease. the southern african journal of hiv medicine                                                  september  2010 case report a 27-year-old man was referred to the ent clinic with a mass in the right external ear canal. he had no past medical history of note. presenting symptoms included bloody otorrhoea, otalgia and decreased hearing in the right ear for 2 months. on examination the presence of a large polyp was confirmed. the tympanic membrane could not be visualised owing to the size of the polyp. the left ear appeared normal. the biopsy showed inflamed, partly necrotic granulation tissue, reported as a pyogenic granuloma. a trial of steroid-antibiotic ointment was commenced. the patient’s symptoms persisted, and he was booked for an examination under anaesthesia. clinically he was pyrexial, with worsening otitis externa and a recurring polypoid mass formation with large, pale granulations. biopsy resulted in profuse bleeding. the differential diagnosis was tuberculosis or glomus tympanicum. laboratory investigations revealed an erythrocyte sedimentation rate of 60 mm/h but a normal peripheral white cell count. he had no clinical evidence of pulmonary disease and a chest radiograph appeared normal. there was no other apparent source of infection. histological examination revealed an acute inflammatory response with no granulomas, and a ziehl-neelsen stain was negative. an hiv test showed the patient to be hiv infected. anti-tuberculosis (tb) medication was commenced empirically and a repeat biopsy was taken. the patient’s pyrexia resolved and he was subsequently discharged. the patient was lost to follow-up and presented again 3 months later. a necrotic polyp occluding the external ear canal was still evident. biopsy taken at the previous presentation suggested a possible cholesteatoma. all specimens sent for tb culture were negative. the cd4 count from the previous admission was 24 cells/ µl. an urgent temporal bone computed tomography (ct) scan revealed opacifications in the middle ear and mastoid cavity with the ossicles and scutum still intact, making the diagnosis of cholesteatoma less likely. the most recent biopsy showed granulation tissue, suppurative inflammation, focal giant cells, fibrin and copious amounts of foamy exudates. special stains were performed to exclude other pathologies. ziehl-neelsen and brown and brenn stains were again non-contributory, but a grocott-gomori methenamine-silver stain (fig. 1) showed the presence of pneumocystis cysts confirming a diagnosis of otic pneumocystosis. the patient was commenced on high doses of oral trimethoprim-sulfamethoxazole and referred to the hiv clinic for initiation of highly active antiretroviral therapy. during a telephonic conversation 2 months later he reported symptomatic improvement. the otorrhoea and pain had subsided but he still had hearing loss. discussion pneumocystis jirovecii infection is an important opportunistic infection. the organism was discovered in 1909 by chagas, but the cystic forms were mistakenly considered to be part of the trypanosome life cycle. it was named p. carinii (greek: pneumon ‘lung’, kystis pneumocystis jirovecii infection of the external auditory canal c a s e s t u dy catherine mary samuel, mb chb division of medical microbiology, university of cape town sairita maistry, bsc, bsc (hons), mb chb, dip forensics (sa) division of forensic pathology, university of cape town estie meyer, mb chb, fcorl (sa) ent department, university of cape town andrew whitelaw, mb bch, msc, fcpath (micro) (sa) division of medical microbiology and national health laboratory service, university of cape town 39 pneumocystis jirovecii is well known to cause interstitial plasma cell pneumonia in immunocompromised patients. it has been implicated as a rare cause of infections in other anatomical sites.1 we report a rare case of p. jirovecii infection of the external auditory canal. this was the first manifestation of a previously unknown hiv infection. september  2010                                                    the southern african journal of hiv medicine                                                   ‘cyst’).2 until 1988 the organism was considered to be a protozoan. the controversy regarding its taxonomy and classification continued for decades and recently, based on ribosomal rna homologous to that found in fungi,2 it was re-classified as a fungus. advances in molecular technology led to pneumocystis organisms infecting humans being re-named p. jirovecii in 1999.3 p. jirovecii infection is an important opportunistic infection, and the incidence of pneumocystis pneumonia is on the increase in sub-saharan africa. extrapulmonary pneumocystosis is, however, a rare complication and represents less than 1% of all cases of infection.4 one or more tissue or organ sites may be involved, with the most common being lymph nodes, bone marrow, spleen and liver. otic pneumocystosis is exceedingly rare. it has only been described in the past 2 decades, and up to 2008 only 14 cases had been reported in the english literature.3 it is postulated that under favourable conditions extrapulmonary dissemination can occur via the lymphatic and haematogenous routes.4 one theory is that these individuals may have more virulent strains. observations in rat models suggest that heavy organism load and destruction of lung tissue may contribute to extrapulmonary dissemination.5 conversely, p. jirovecii infection may be a systemic disease that most commonly affects the lungs. extrapulmonary infection becomes more evident when prophylaxis is focused on the respiratory tract, and this may explain the correlation with the use of aerosolised prophylactic pentamidine.1,4 although the mechanism of primary otic pneumocystosis is as yet unclear, it has been suggested that it may follow airborne invasion by trophozoites of the external auditory canal6 and that the middle ear may become involved after spread from nasopharyngeal carriage via the eustachian tube. individuals with otic pneumocystosis may have nonspecific symptoms of otorrhoea, otalgia, hearing loss, vertigo and tinnitus. clinical findings include a mass in the external auditory canal and occasional otitis media. destruction of the ossicles and sclerosis of the mastoid air cells, extensive bony erosion, and extension into the middle cranial fossa are rare complications documented in the literature.3 diagnosis can be confirmed by biopsy, which is essential to rule out malignancy or other infective pathogens.6 organisms can be demonstrated on microscopic examination of tissue sections and cytological preparations using silver, fluorescent or immunoperoxidase staining methods. the standard method using a grocott-gomori methenamine-silver stain is easy and reliable. cystic forms are round to oval, 4 7 µm in dimension, and appear as collapsed crescentor helmet-shaped forms. the granulomatous reaction is composed of trophozoites and cysts, which appear as basophilic dots on h&e. there is a variable inflammatory infiltrate. as for pulmonary pneumocystis, medical therapy consists of oral or intravenous trimethoprim/sulfamethoxazole. other regimens described include dapsone/trimethoprim, clindamycin/primaquine, atovaquone and pentamidine isethionate.1,3 although there is usually resolution of symptoms after medical therapy, surgical excision of lesions in the external auditory canal may be clinically indicated. disseminated pneumocystosis, like pneumocystis pneumonia, has high mortality rates. the prognosis may be better for those with single extrapulmonary site involvement and no concomitant lung infection.4 it is important for health care professionals to be aware of this infection as the hiv pandemic continues and results in common infections manifesting in extraordinary ways and in unusual sites. references 1. ng vl, yajko dm, hadley wk. extrapulmonary pneumocystosis. clin microbiol rev 1997; 10(3): 401-418. 2. dail dh, tomashefski jf, cagle pt, et al. dail and hammar’s pulmonary pathology. 3rd ed. new york: springer, 2008: 487-508. 3. mahlakwane ms, ramdial pk, sing y, et al. otic pneumocystosis in acquired immune deficiency syndrome. am j surg pathol 2008; 32(7): 1038-1043. 4. raviglione mc. extrapulmonary pneumocystosis: the first 50 cases. rev infect dis 1990; 12(6): 1127-1138. 5. chary-reddy s, graves dc. identification of extrapulmonary pneumocystis carinii in immunocompromised rats by pcr. j clin microbiol 1996; 34: 1660-1665. 6. breda sd, hammerschlag pe, gigliotti f, et al. pneumocystis carinii in the temporal bone as the primary manifestation of the acquired immunodefiency syndrome. ann otol rhinol laryngol 1988; 97: 427-431. 40 fig. 1. grocott-gomori methenamine-silver stain showing pneumocystis cysts of variable shape and size (40 × magnification). khayelitsha 2001.html review khayelitsha 2001 2011: 10 years of primary care hiv and tb programmes daniela belen garone1,2, md, phd katherine hilderbrand1,2, bsc, msc andrew m boulle2, mb chb, msc, fcphm, phd david coetzee2, mb chb, msc, fcphm eric goemaere1,2, md, dsc gilles van cutsem,1,2 md, dtm&h, mph donela besada1,2, bsc, mph 1médecins sans frontières, khayelitsha, cape town, south africa 2centre for infectious disease epidemiology and research, school of public health and family medicine, faculty of health sciences, university of cape town tuberculosis (tb) and hiv care in khayelitsha, and in south africa as a whole, has overcome numerous obstacles in the past three decades. this article highlights what has been achieved in khayelitsha, describes the key clinical programme and policy changes that have supported universal coverage for hiv and tb care over the last 10 years, and outlines the challenges for the next decade. the evolution of tuberculosis (tb) and hiv care in khayelitsha, and in africa as a whole, has overcome numerous obstacles in the past three decades: poor leadership in acknowledging the hiv crisis, inadequate provision of appropriate scientific interventions, and scepticism about the feasibility of treatment programmes in settings challenged with extreme resource constraints. over the past 10 years in khayelitsha, hiv has been transformed from less than 500 people tested for hiv and no one on antiretroviral therapy (art) in 1998 to 50 000 tested and 20 000 on art in 2011.1 stakeholders in the khayelitsha sub-district have reflected in the course of the past year on the previous decade of service developments as part of commemorating 10 years of public sector art provision. this article highlights what has been achieved collectively by several service providers (the city of cape town, médecins sans frontières, the western cape province, academic institutions, the treatment action campaign (tac), non-governmental and community-based organisations), describes the key clinical programme and policy changes that have supported universal coverage for hiv and tb care over the past 10 years, and outlines the challenges for the next decade. hiv prevention and incidence reduction dedicated efforts have been made to scale up a combination of prevention interventions that has resulted in substantial changes in health outcomes over the past decade. prevention of mother-to-child transmission of hiv the implementation of a prevention of mother-to-child transmission (pmtct) programme in 1999, with antenatal and perinatal antiretroviral chemoprophylaxis and free exclusive formula feeding, marked the beginning of public sector antiretroviral-based services in south africa. this programme, with progressive improvements and intensification in line with the evolution of national guidelines, has resulted in a reduction in documented mother-to-child transmission from 12.5% in 2002 to 2.5% in 2010 based on polymerase chain reaction (pcr) testing at 6 weeks (fig. 1). this success is mirrored in many other sites in south africa, and demonstrates that pmtct to very low proportions of infants infected is both feasible and scalable. box 1. key elements of the programme khayelitsha is a large township with approximately 500 000 inhabitants, located on the outskirts of cape town. it has one of the highest burdens of both hiv and toberculosis (tb) in south africa. an estimated 16% of the population is hiv infected; tb incidence is above 1 500/100 000 per year and tb/hiv co-infection is close to 70%. the incidence of drug-resistant tb is estimated at 50/100 000 per year.11 the khayelitsha programme, started in 1999, was the first in south africa to provide antiretroviral therapy (art) at primary care level in the public sector and one of two pilot projects in the country to provide decentralised care for drug-resistant tuberculosis.12 key strategies implemented include: ■prevention of mother to child transmission with art and formula ■large-scale hiv counselling and testing, including out-of-facility testing, youth clinics,and male clinics ■mass community condom distribution ■decentralisation of art to all clinics in the sub-district ■‘one-stop-shop’ integration of art and tb services ■nurse management of hiv and tb care, including nurse-initiated art and tb treatment ■doctor support and mentorship, with a strong secondary care referral system ■district level planning and co-ordination ■three-tier monitoring and evaluation system (paper register, electronic register,and electronic medical record in selected sites) ■ongoing training and mentoring at clinic and district level furthermore, the decentralisation of paediatric art into primary care clinics, which started in 2004, resulted in a steady increase in children being initiated on art each year, from 4 in 2001 to 145 in 2008. the numbers have decreased since then to 115 in 2010. the successful decentralisation of paediatric care has led to positive health outcomes; 87% of children started on art in primary care remained in care, and 98% remained alive after 5 years on art. hiv testing hiv testing has increased steadily since the advent of the programme. the programme started with enzyme-linked immunosorbent assay (elisa) testing of 500 people in january 1999. the introduction of rapid hiv testing kits, pcr testing for infants, employment of lay counsellors to conduct hiv counselling and testing (hct), community-based testing sites, wide-scale hct campaigns, and targeted testing for tb patients/suspects, youth and males saw a dramatic increase in the numbers of people being tested each year. by the end of 2010, 22 centres were providing hct and approximately 57 000 people were being tested annually. in a community survey conducted in 2004, 28% of men and 53% of women of reproductive age in khayelitsha reported having been tested for hiv.2 community condom distribution male condom distribution has been a major priority in the programme. the number of condoms distributed per year increased from 2 million in 2004 to more than 10 million in 2006; currently more than a million condoms are distributed every month. this was made possible through the combined efforts of the public sector, including the city of cape town, and non-governmental organisations, especially tac. tac expanded condom distribution from health care facilities to community distribution points, such as taxi ranks, public libraries, toilets and shebeens.3 during the same period, the number of adults reported to have been treated for sexually transmitted infections (stis) decreased fourfold, from 28 000 in 2004 to less than 5 000 in 2009. opening of a male-friendly clinic recognition of the need for a service dedicated to reaching men and providing hct and sti treatment resulted in the opening of a male walk-in clinic at a taxi rank in 2007. this new service was widely advertised in the community through the use of taxi ranks and the local radio. this clinic has become the largest sti treatment site in the cape metro area, with the number of stis treated increasing from 843 in 2007 to 2 547 in 2010. in the first half of 2011 the clinic counselled and tested as many men as were tested throughout 2010, and the number tested during 2010 in the male clinic represented 27% of all men tested in khayelitsha. the clinic aims to promote and empower men to take ownership of their sexual health and safety and that of their partners. its success demonstrates that men use health services that are adapted to their needs: short waiting times, close to a usual gathering place for men (taxi rank), and separate from public health services attended mostly by women and children. two new male clinics are planned for 2011 to continue to reach out to men, who remain a group with limited access to care. antiretroviral therapy in may 2011 there were 20 000 patients on art, which is estimated to represent 63% coverage of those in need in khayelitsha, according to current world health organization (who) eligibility criteria. retention in care at one year on art has remained consistently above 85% since the beginning of the programme.4 in addition, virological suppression among patients in care also remained above 87% in those tested,4 thereby decreasing the community viral load given the relatively high proportion of infected adults who are on art. it is therefore likely that this is contributing to a reduction in the number of new hiv infections. evolution of hiv prevalence hiv prevalence among women presenting for antenatal care has been routinely measured by the programme since 1999, and since 2003 the testing acceptance rate has been close to 100%. the antenatal hiv prevalence among those who test in routine care has stabilised since 2006 and may now be declining (fig. 2). this decline is not mirrored by the annual anonymous antenatal survey, which might be explained by the fact that in routine care women already on art are often not retested for hiv, whereas during the annual survey all pregnant women are tested, regardless of whether they are on art or not. considering the decreased mortality, the absence of an increase in antenatal prevalence in recent years could be the result of the benefits of art offsetting reduced new infections. emerging data illustrate that treatment serves as a powerful prevention tool,5 and to decrease hiv incidence there is a need to combine wide-scale access to art with available prevention tools, including hct, pmtct and condom distribution. in parallel, there is the need to focus on innovative tools to measure hiv incidence in order to adequately assess hiv prevention efforts. decreasing morbidity increasing access to art, as a result of decentralisation, task shifting and tb/hiv integration, has allowed patients to access and initiate treatment earlier. this in turn has resulted in decreasing hiv-related mortality and morbidity. patients presenting to care earlier are also typically less complex to manage clinically, which facilitates increased nurse management of care. evidence of earlier art access median cd4 counts of people starting art increased from 43 cells/µl in 2001 to 162 cells/µl in 2010. in the same period the proportion of patients presenting with a who stage iv diagnosis decreased from 50% to 20%. better art regimens the programme has also seen a gradual evolution towards improved first-line regimens. documentation of high rates of adverse events with the use of stavudine (d4t) contributed to the growing evidence base that led to the who recommendation to replace d4t with better-tolerated alternatives.6 a tenofovir-based regimen was introduced in 2005 in khayelitsha for patients experiencing d4t toxicity, and was included in the national first-line regimen for all patients in 2010. integration of tb and hiv services the ‘one-stop-shop’ integration of tb and hiv services began in 2004, and allowed co-infected patients to access tb and hiv services in the same clinic and from the same health staff.7 in 2010, 99% of tb patients in tb/hiv integrated clinics were offered hct, and 95% of them were being tested. furthermore, 99% of co-infected patients had a cd4 count result recorded and over 95% were started on co-trimoxazole preventive therapy. the successful integration of the services has led to improvements in the detection rates of smear-negative pulmonary tb and extrapulmonary tb, as nurses’ clinical skills in managing both diseases improved. in addition, integration has resulted in a decrease in the median time from the start of tb treatment to art initiation.7 improved tb diagnostic methods, including smear-negative algorithms, systematic tb culture, line-probe assays, and the piloting of genexpert, as well as the systematic screening of hiv patients for tb, are all expected to contribute to increased tb diagnosis. the integration of hiv/tb care has been accompanied by improved tb cure rates (from 44% in 2005 to 81% in 2010), despite the increased caseload. box 2. community-based model of care for drug-resistant tuberculosis ■drug-resistant tuberculosis (dr-tb) refers to tb that has become resistant to first-line treatment and requires longer and more difficult treatment with second-line anti-tb drugs. ■instead of attempting to hospitalise all dr-tb patients, the khayelitsha model of care uses a patient-centred approach with community-based treatment through existing primary care services. ■using lessons learned from the decentralisation of hiv care, diagnosis and treatment of dr-tb has been integrated into the routine tb and hiv programmes in khayelitsha since early 2008. community-based management of drug-resistant tb before 2007, all patients with drug-resistant tuberculosis (dr-tb) in khayelitsha had to be admitted to a central tb hospital to receive their treatment. khayelitsha has piloted a community-based dr-tb programme in which drugresistant tb is diagnosed and treated in primary care clinics as opposed to a centralised facility. the number of cases of dr-tb diagnosed increased from 14 in 2003 to 200 in 2010. over 80% of patients diagnosed with dr-tb in 2009 and 2010 started treatment. the decentralisation of care was able to ensure that 71% of cases started treatment through the local clinic, while only 14% were admitted to the centralised specialist dr-tb hospital. in addition, the median time to treatment initiation decreased from 71 days in 2007 to 33 days in 2010. decreasing mortality decentralised, tb/hiv integrated, nurse-managed art recorded mortality of adults at 3 months on art decreased from 10% in 2002 to 2.2% in 2010, in part due to patients accessing art earlier. while mortality ascertainment is less complete in recent years, there remains a year-on-year decline in mortality even after linkage to the national death registry to correct for mortality under-ascertainment.4 recorded mortality of adults at one year on art decreased from under 15% to 8% between 2002 and 2007.4 this decline in early mortality and earlier access to art has occurred alongside a dramatic increase from 100 people initiated on art in 2001 to approximately 20 000 by mid-2011 (fig. 3). the sharp rise in treatment enrolment was made possible due to decentralisation of art to every clinic, tb/hiv integration, and nurse-managed art and tb care. decentralised care began in 2006 and new clinics were accredited as art sites each year thereafter. national guidelines allowed for nurse-initiated tb/hiv integrated art in april 2010, and all 11 clinics in khayelitsha were providing art by the end of 2010. in terms of longer-term outcomes, previous data based on death registry linkage have also confirmed that 4 out of 5 patients who started treatment were alive 5 years after starting treatment.4 patients treated for drug-resistant tuberculosis while there has been an increase in the detection of dr-tb, the khayelitsha programme has seen an improvement in the survival of people with dr-tb. of those diagnosed with dr-tb in 2008, 62.4% remained alive after 18 months, reflecting an overall mortality of 38%. while mortality levels remain high, given that 76% of all dr-tb patients are hiv infected, this represents significant improvements in health outcomes among people with dr-tb compared with other settings.8 challenges retention in care while the programme has achieved many successes, several challenges remain in ensuring universal access to art. with the advent of improved drug regimens and models of care, hiv has become a manageable chronic disease. approximately 85% of patients are retained in care after 12 months, while only 65% of patients are still in care at 5 years on treatment; this highlights the need for further innovations to improve long-term retention. with increased enrolment came increased losses to follow-up, probably due to saturation of services, patient mobility and death. this trend in patient losses to follow-up stabilised and even began to decrease in the later years as a result of the adoption of measures to adapt to the high numbers of patients on treatment. innovative models of care included the introduction of adherence clubs and nurse management of patients. men the proportion of men among adults starting art remains lower than expected. although the male walk-in clinic has driven an increase in men testing for hiv and seeking treatment for stis, men still represent only 30% of adults in care after 10 years of art treatment in khayelitsha. there is a need to develop programmes that cater to men’s needs in order to improve their access to health services. furthermore, given that men rarely accompany their partners to antenatal services, innovative mechanisms will be required to identify serodiscordant couples in light of emerging guidelines that will recommend the use of art to reduce the risk of hiv transmission to the negative partner.5 youth pre-art loss to follow up is particularly high among youth. in 2010, up to 70% of eligible young people in the youth clinics were lost to care before starting art; 60% of these losses occurred immediately after hiv testing. youth on art were also more likely than older adults to be lost to follow-up.9 recognition of the need to focus specific interventions targeted at this high-risk group led to the establishment in 2005 of two youth clinics that provide adapted and targeted services. although pre-art loss to follow-up declined in 2010 – from 70% and 60% in the first quarter to 45% and 29% in the last quarter for the two youth clinics, respectively – early loss to care remains high and is indicative of the need to continue to adapt services and interventions that cater appropriately to the needs of youth. treatment failure at 5 years on art, approximately 14% of patients had confirmed virological failure and 12% were on second-line art.4 mortality and treatment failure are found to be high in patients on second-line treatment. out of the 32% of patients who failed second-line art, 60% had poor adherence, and 30% returned to undetectable viral loads after enhanced adherence support; the remainder were switched to a third-line regimen. this highlights the need for early detection of poor adherence in order to provide targeted enhanced adherence support. a recent study in khayelitsha demonstrated that a viral load performed at 3 months resulted in better virological outcomes than one performed at 6 months,10 demonstrating the usefulness of the viral load for early detection of poor adherence and virological failure. third-line drugs are currently not available in the public sector due to their high costs. as access to and time on art increases, the number of patients requiring secondand third-line regimens is rising, and prices for these drugs will need to be driven down. the future the key clinical challenges for the next decade will be to achieve universal coverage of patients in need of art, retain patients in care, and decrease the number of new infections. this will necessitate innovative models of care to decrease the burden of patients on chronic treatment on health facilities – thereby allowing the facilities to increase enrolment on art – and improve long-term adherence and retention, as well as the implementation of combination prevention strategies. box 3. strategies for the future – innovation and wide implementation ■further out-of-facility community-based testing (in schools, taxi ranks, community halls) ■initiation of antiretroviral therapy at higher cd4 thresholds, potentially up to cd4s of 500 cells/µl and/or high viral load thresholds, to further reduce viral circulation and infectiousness at community level (treatment as prevention, tasp) ■community-based delivery of art by community health workers and/or chronic dispensing units ■increased investment in pre-art (e.g. by creating pre-art adherence clubs) ■new pre-exposure prophylaxis strategies targeting young female adolescents combined with development of new long-acting antiretroviral formulations and other biomedical preventive interventions. these strategies will have to be supported by new drug formulations and technologies, including: ■fixed-dose combinations for firstand second-line regimens ■semi-quantitative point of care viral load dipstick to monitor adherence and identify early treatment failures ■poc cd4 devices to reduce pre-art loss to follow-up, mostly among adolescents ■more robust regimens with a better safety profile, including drugs like darunavir, which maintains a low toxicity in the long term once the viral load has become undetectable ■ensure appropriate access to reproductive health services, including pap smears for all women including those living with hiv and medical termination of pregnancy at the primary health level. adherence clubs adherence clubs were established to improve clinic efficiency (decongest clinics and allow clinicians time for initiating patients), sustain high enrolment targets, and improve long-term adherence. the adherence clubs are group clinic visits for stable patients that are run by lay health workers and meet every 2 months. on club days patients receive their medication and are screened for opportunistic infections and adverse events, and are referred to a clinician if necessary. in addition, patients receive an educational talk on the day of their visit. by the end of 2010, a total of 30 clubs were created, 23 of them situated in the community and 7 in the ubuntu clinic in khayelitsha. more than 750 people were enrolled in total. an early evaluation revealed that after 1 year of enrolment in the clubs, 99.2% of the patients were alive; at 2 years this figure stood at 97.5%. after the first year of enrolment, loss to follow-up was 1.1% and mortality 0.7%. this model is currently being expanded to other clinics in order to increase coverage. with the adoption of new national regulations, community health care workers will now be able to manage these clubs effectively. there is still a need to adapt the drug distribution system further in order to allow for regulated and quality-assured chronic drug dispensing units that are able to provide medications more conveniently to patients in the community, thereby ensuring that there is increased access to treatment closer to patient’s homes. reducing hiv and tb incidence despite some early positive signs, the national target of a 50% reduction in hiv incidence is not close to being achieved. an exception to this is in the area of pmtct, where transmission has been reduced by 80% since the beginning of the programme. there is a need to continue to focus on sustained behavioural interventions, including widespread condom distribution, out-of-facility community-based testing, and biomedical interventions to reduce hiv incidence. new targeted pre-exposure prophylaxis strategies (particularly for women wishing to have children), initiation of art at a cd4 count of 500 cells/µl, new drug formulations and technologies including fixed-dose combinations, point-of-care viral load and cd4 testing, and robust low-toxicity regimens must be explored. furthermore, there is a need to continue to focus on the early diagnosis and treatment of tb and dr-tb, both to improve individual patient outcomes and to reduce transmission. despite dramatic improvements in case detection for dr-tb, only half of all estimated dr-tb cases are diagnosed in khayelitsha, and there is a need to increase case detection to curb hiv transmission. access to molecular diagnostics, including genexpert, shows promising results in increasing detection of tb and dr-tb. this could also provide a sensitive screening tool for the provision of inh prophylaxis in tb-negative patients. discussion the success in scaling up hiv/tb service provision in khayelitsha is attributed to the collaborative efforts of service providers, policy makers, academics, civil society and the community at large. the khayelitsha programme was successful in achieving community buy-in because it offered a reliable service within the community, was supported through partnerships, and was complemented by widespread treatment literacy. while the district is best known for its role in demonstrating the feasibility of art in resource-constrained settings, some of the most important lessons have come in more recent years, where the latent capacity of south africa’s public health system has been demonstrated when subjected to energy, innovation and meaningful collaboration. in spite of the numerous partnerships, khayelitsha remains a difficult environment in which to deliver services, but it has nevertheless been possible to achieve coverage and scale for a number of activities beyond the most optimistic outlooks of a decade ago. in the areas of pmtct and art provision this is being demonstrated in south africa as a whole, where expectations have been exceeded in recent years. increased funding for antiretrovirals and the resulting increase in access to care helped to strengthen the overall health system, and the implementation of a large-scale tb/hiv programme resulted in decreased rates of both illness and death among people living with hiv as well as a likely reduction in the number of new hiv infections. this unique clinical programme contributed to national policy changes that have had a tangible impact on the lives of thousands of people living with hiv and tb in south africa, and has demonstrated the possibility of achieving universal coverage of art and positive patient outcomes in resource constrained settings. challenges ahead include the need to reduce hiv transmission in the community. the khayelitsha programme has paved the way for innovative approaches to treatment provision that have allowed an increasing number of people to access quality treatment closer to their communities. the future of hiv and tb treatment and care will require a focus on combination prevention and treatment interventions, in addition to the adoption of new innovations that can have a tangible impact on the spread of the dual epidemics. references 1. médecins sans frontières. khayelitsha 2001-2011 activity report: 10 years of hiv/tb care at primary health care level. june 2011. hyperlink "http://www.msf.org.za/publication/khayelitsha-activity-report-2001-2011-10-years-hivtb-care-primary-health-care-level" http://www.msf.org.za/publication/khayelitsha-activity-report-2001-2011-10-years-hivtb-care-primary-health-care-level (accessed 11 august 2011). 1. médecins sans frontières. khayelitsha 2001-2011 activity report: 10 years of hiv/tb care at primary health care level. june 2011. hyperlink "http://www.msf.org.za/publication/khayelitsha-activity-report-2001-2011-10-years-hivtb-care-primary-health-care-level" http://www.msf.org.za/publication/khayelitsha-activity-report-2001-2011-10-years-hivtb-care-primary-health-care-level (accessed 11 august 2011). 2. boulle a, hilderbrand k, menten j, et al. exploring hiv risk perception and behaviour in the context of antiretroviral treatment: results from a township household survey. aids care 2008;20(7):771-781. 2. boulle a, hilderbrand k, menten j, et al. exploring hiv risk perception and behaviour in the context of antiretroviral treatment: results from a township household survey. aids care 2008;20(7):771-781. 3. south african department of health. a million condoms a month. 2010. hyperlink "http://www.doh.gov.za/docs/hiv/million-condoms.pdf" http://www.doh.gov.za/docs/hiv/million-condoms.pdf (accessed 11 august 2011). 3. south african department of health. a million condoms a month. 2010. hyperlink "http://www.doh.gov.za/docs/hiv/million-condoms.pdf" http://www.doh.gov.za/docs/hiv/million-condoms.pdf (accessed 11 august 2011). 4. boulle a, van cutsem g, hildebrand k, et al. seven-year experience of a primary care antiretroviral treatment programme in khayelitsha, south africa. aids 2010;24(4):563-572. 4. boulle a, van cutsem g, hildebrand k, et al. seven-year experience of a primary care antiretroviral treatment programme in khayelitsha, south africa. aids 2010;24(4):563-572. 5. cohen ms, chen yq, mccauley m, et al. prevention of hiv-1 infection with early antiretroviral therapy. n engl j med 2011;365(6):493-505. 5. cohen ms, chen yq, mccauley m, et al. prevention of hiv-1 infection with early antiretroviral therapy. n engl j med 2011;365(6):493-505. 6. boulle a, orrel c, kaplan r, et al. substitutions due to antiretroviral toxicity or contraindication in the first 3 years of antiretroviral therapy in a large south african cohort. antivir ther 2007;12(5):753-760. 6. boulle a, orrel c, kaplan r, et al. substitutions due to antiretroviral toxicity or contraindication in the first 3 years of antiretroviral therapy in a large south african cohort. antivir ther 2007;12(5):753-760. 7. brown c, kerschberger b, boulle a, et al. tb and hiv service integration within a south african primary health care setting reduces the time to art initiation without negatively impacting tb outcomes. presented at the 18th conference on retroviruses and opportunistic infections (croi 2011), 27 february 2 march 2011, boston, usa. abstract 890. hyperlink "http://www.retroconference.org/2011/abstracts/41110.htm"http://www.retroconference.org/2011/abstracts/41110.htm (accessed 11 august 2011). 7. brown c, kerschberger b, boulle a, et al. tb and hiv service integration within a south african primary health care setting reduces the time to art initiation without negatively impacting tb outcomes. presented at the 18th conference on retroviruses and opportunistic infections (croi 2011), 27 february 2 march 2011, boston, usa. abstract 890. hyperlink "http://www.retroconference.org/2011/abstracts/41110.htm"http://www.retroconference.org/2011/abstracts/41110.htm (accessed 11 august 2011). 8. médecins sans frontières, partners in health, treatment action group. an evaluation of drug-resistant tb treatment scale-up. switzerland, july 2011. hyperlink "http://www.ghdonline.org/uploads/drtb_report_a4_final.pdf"http://www.ghdonline.org/uploads/drtb_report_a4_final.pdf (accessed 11 august 2011). 8. médecins sans frontières, partners in health, treatment action group. an evaluation of drug-resistant tb treatment scale-up. switzerland, july 2011. hyperlink "http://www.ghdonline.org/uploads/drtb_report_a4_final.pdf"http://www.ghdonline.org/uploads/drtb_report_a4_final.pdf (accessed 11 august 2011). 9. van cutsem g, ford n, hildebrand k, et al. correcting for mortality among patients lost to follow up on antiretroviral therapy in south africa: a cohort analysis. plos one 2011;6(2):e14684. 9. van cutsem g, ford n, hildebrand k, et al. correcting for mortality among patients lost to follow up on antiretroviral therapy in south africa: a cohort analysis. plos one 2011;6(2):e14684. 10. kerschberger b, boulle a, hilderbrand k, coetzee d, goemaere e, van cutsem g. viral load at 3 months associated with better virologic outcomes than at 6 months. presented at the 6th ias conference, 17-20 july 2011, rome. mope144. http://pag.ias2011.org/abstracts.aspx?aid=3320 (accessed 11 august 2011). 10. kerschberger b, boulle a, hilderbrand k, coetzee d, goemaere e, van cutsem g. viral load at 3 months associated with better virologic outcomes than at 6 months. presented at the 6th ias conference, 17-20 july 2011, rome. mope144. http://pag.ias2011.org/abstracts.aspx?aid=3320 (accessed 11 august 2011). 11. cox hs, mcdermid c, azevedo v, et al. epidemic levels of drug resistant tuberculosis (mdr and xdr-tb) in a high hiv prevalence setting in khayelitsha, south africa. plos one 2010;5(11):e13901. 11. cox hs, mcdermid c, azevedo v, et al. epidemic levels of drug resistant tuberculosis (mdr and xdr-tb) in a high hiv prevalence setting in khayelitsha, south africa. plos one 2010;5(11):e13901. 12. médecins sans frontières. scaling up diagnosis and treatment of drug-resistant tuberculosis in khayelitsha, south africa. an integrated, community-based approach. march 2011. hyperlink "http://www.msf.org.za/system/files/publication/documents/dr-tb-in-khayelitsha-mar2011.pdf?download=1"http://www.msf.org.za/system/files/publication/documents/dr-tb-in-khayelitsha-mar2011.pdf?download=1 (accessed 11 august 2011). 12. médecins sans frontières. scaling up diagnosis and treatment of drug-resistant tuberculosis in khayelitsha, south africa. an integrated, community-based approach. march 2011. hyperlink "http://www.msf.org.za/system/files/publication/documents/dr-tb-in-khayelitsha-mar2011.pdf?download=1"http://www.msf.org.za/system/files/publication/documents/dr-tb-in-khayelitsha-mar2011.pdf?download=1 (accessed 11 august 2011). fig. 1. rate of mother-to-child hiv transmission, 2002 2010. fig. 2. khayelitsha antenatal prevalence, 1999 2010.chc = community health centre; city clinic = city of cape town clinic. fig. 3. monthly patient art enrollment, 2001 2010. 66 sajhivmed june 2014, vol. 15, no. 2 c a s e r e p o r t needlestick injury (nsi) is commonly reported among healthcare workers, but is not well documented in patients. we report a case of an nsi in an hiv-negative, gestational hypertensive patient admitted to a hospital for induction of labour at term. owing to an insufficient number of hospital beds, patients were seated in an overcrowded corridor of the antenatal ward where a patient stepped on the needle of an inadvertently dis connected intravenous infusion set of another pregnant patient, who was hiv-infected. the injury occurred prior to labour induction. antiretroviral post-exposure prophylaxis to prevent hiv infection was administered to the injured patient and her newborn. this report illustrates how hospital bed shortage may compromise patient safety and discusses measures to prevent nsi among patients and hospital overcrowding. s afr j hiv med 2014;15(2):66-68. doi:10.7196/sajhivmed.1048 needlestick injury in a pregnant inpatient in an overcrowded hospital n c ngene,1,2 mbbs, dip obst (sa), dip hiv man (sa), mmed (fam med), fcog (sa), mmed (o&g); c o onyia,1 mbbs; j moodley,3 mb chb, fcog (sa), frcog, md; m j titus,1,2 mb chb, fcog (sa), llm, pgdip (int res ethics) 1 department of obstetrics and gynaecology, pietermaritzburg metropolitan hospitals complex, kwazulu-natal, south africa 2 department of obstetrics and gynaecology, nelson r mandela school of medicine, university of kwazulu-natal, durban, south africa 3 women’s health and hiv research group, nelson r mandela school of medicine, university of kwazulu-natal, durban, south africa corresponding author: n c ngene (ngenenc@gmail.com) mailto:ngenenc@gmail.com june 2014, vol. 15, no. 2 sajhivmed 67 c a s e r e p o r t despite the availability of medical safety pro grammes,[1] more than 10% of patients suffer harm during hospital care.[2] the occurrence of needlestick injury (nsi) in an inpatient in particular raises serious safety concern. there are reports of nsis sustained by healthcare workers (hcws),[3-5] but there is no publication, to our knowledge, on such injuries occurring among inpatients. we discuss an nsi in a pregnant inpatient and outline appropriate measures to prevent such incidents. case report a 25-year-old primigravida at term, who had gestational hypertension, was referred to hospital for further care. on arrival at the hospital her blood pressure was 143/93 mmhg and she was admitted to the antenatal ward for work-up and labour induction. her ante natal care was uneventful prior to developing hypertension. her risk factors for this condition were primiparity and obesity (body mass index of 30  kg/ m2 at booking). the clinical work-up showed no evidence of proteinuria, target organ damage or intrauterine growth restriction. during the first two days of her hospital admission, all the available beds in the antenatal ward were occupied, as the number of patients was twice the number of beds. as a result, the patient had to wait in the corridor of the antenatal ward until an empty bed became available. in this article she is referred to as the injured patient. another patient, referred to as the source patient, was seated on a chair in the corridor of the antenatal ward and was receiving intravenous fluids through infusion set a (fig. 1). to this was att ached a second intravenous infusion set, set b, through a needle at site x on set a, to administer medication. the needle of set b became disconnected without being discovered by the source patient or the nurses. the source patient had been diagnosed hiv-positive 3 years previously and was on antiretroviral therapy (art) for maternal health. the injured patient, having waited for approximately 48 hours without a bed, took to walking during the day and on her way to join other patients seated on chairs in the corridor of the antenatal ward, stepped on the disconnected needle of set b and sustained an nsi on her right big toe. the patient reported the adverse event to the medical staff on duty and the following immediate measures were taken: blood was squeezed from the injured site; and the site was washed liberally with water and cleaned with an antiseptic solution. the patient was counselled and tested hiv-negative. she was immediately initiated on a 4-week course of prophylactic art as per hospital policy. screening for hepatitis in both patients was negative, and a full blood count and liver and renal function tests of the injured patient were normal. following hospital discharge of other stable pregnant women, the source and the injured patients were provided with beds for their continued medical care. a day after the incident, the injured patient was started on misoprostol to induce labour, but had a caesarean delivery due to fetal compromise and delivered a normal healthy boy (weight 2  870  g) who was started on a 6-week course of nevirapine syrup, 15  mg daily, as recommended by the neonatologist. the injured patient and her baby were discharged in a stable condition on the 3rd day after delivery. they completed the art prophylaxis without any side-effects. six weeks after the incident, they remained healthy, tested hiv-negative and were scheduled for further hiv testing at 3 and 6 months. discussion when the optimal patient care capacity of a healthcare system or provider is exceeded, patient safety is compromised,[6] as was seen in this case. at the time of the nsi, the number of patients in the ward was more than the available beds and the nurses who were on duty during the incident had to perform menial functions that prevented them from monitoring patients closely. the lighting was good where the injury occ urred and the injured patient had no visual or physical impairment, but she may have been tired, given that she had no bed at the time of the injury. the health facility where this incident occurred had a policy on nsi for hcws, but owing to the rarity of nsi in patients, no policy was available for this scenario. the hospital management were aware that the number of patients in the antenatal ward usually exceeds the available beds, and had a long-term plan to construct additional wards to prevent overcrowding. nonetheless, the adverse incident was reported to the hospital management and the interim actions taken included starting the process of converting sections of other less busy wards with extra beds to antenatal ward extensions, and deployment of additional staff to the antenatal ward. to our knowledge, this is the first reported case where: (i) a pregnant inpatient had an nsi; and (ii) nevirapine was administered to a baby due to an nsi sustained by the mother. nevirapine was used as it is recommended for prevention of mother-to-child transmission (pmtct) of hiv in south africa.[7] owing to the urgent need to avert further nsis in patients, particularly in overcrowded health facilities, we outline preventive measures to be taken before the injured patient and her baby complete their follow-up visits (table 1). these consist of components relating to: health facility administration, including developing a pat ient nsi policy; hcws, including safe use of needle-containing devices; and patients and their visitors adhering to the patients’ rights charter and hospital policies. these interventions are based on the authors’ many years of clinical experiences in different countries. nonetheless, different settings may require other interventions and the personnel responsible for implementing a particular task may vary. conclusion nsi in inpatients has not been reported previously. the lesson is that it can occur, although it is preventable using the suggested measures. fig. 1. intravenous infusion set in use, showing an injection site for administration of supplementary medication. (x = injection site where an additional intravenous infusion set was connected.) 68 sajhivmed june 2014, vol. 15, no. 2 c a s e r e p o r t references 1. world health organization. who patient safety – programme areas. http://www. who.int/patientsafety/about/programmes/en/ (accessed 6 march 2014). 2. world health organization. 10 facts on patient safety. http://www.who.int/ features/factfiles/patient_safety/patient_safety_facts/en/index.html (accessed 6 march 2014). 3. gounden yp, moodley j. exposure to human immunodeficiency virus among healthcare workers in south africa. int j gynaecol obstet 2000;69(3):265-270. [http://dx.doi.org/10.1016/s0020-7292(00)00207-1] 4. us public health service working group. updated us public health service guidelines for the management of occupational exposures to hiv and recommendations for postexposure prophylaxis. http://stacks.cdc.gov/view/ cdc/20711 (accessed 6 march 2014). 5. hoffmann c, buchholz l, schnitzler p. reduction of needlestick injuries in healthcare personnel at a university hospital using safety devices. j occup med toxicol 2013;8:1-5. [http://dx.doi.org/10.1186/1745-6673-8-20] 6. jha ak, prasopa-plaizier n, larizgoitia i, bates dw. patient safety research: an overview of the global evidence. qual saf health care 2010;19(1):42-47. [http:// dx.doi.org/10.1136/qshc.2008.029165] 7. south african national department of health. the south african antiretroviral treatment guidelines 2013. http://web.up.ac.za/sitefiles/file/45/1335/877/ pmtct%20guidelines_march%202013_doh.pdf (accessed 6 march 2014). table 1. measures to prevent nsi in patients at different levels of the healthcare system administration develop a policy on nsi sustained by patients provide appropriate staffing organise continuing medical education on nsi for staff and medical trainees provide clerks, porters and phlebotomists in the wards so that nurses/doctors can concentrate on their duties ensure good record keeping so that quality data are available for audit provide social workers, clinical psychologists, infectious disease physicians, occupational health personnel and appropriate medications to aid in managing any patient who sustains an nsi organise quality improvement projects on patient safety and nsi promote the treatment and prevention of hiv infection ensure that patient safety is addressed as part of hcw training promote vaccination against hepatitis ensure that staff are aware of what to do in the event of an nsi provide good leadership and staff motivation improve structural facilities of the health institution as the need arises promote teamwork among staff in the health facility provide good lighting in the hospital environment promote an awareness of patients’ rights charter ensure a regular supply of clean water to the health facility regulate visiting hours in the health facility provide appropriate equipment for patient care provide appropriate laboratory facilities to address patient overcrowding of a health facility: provide additional space where patients can be cared for; support referral of patients to alternative facilities; redeploy additional staff to work in the overcrowded unit; educate patients; support the establishment of a primary healthcare centre within or near the health facility for management of low-risk patients; if possible ensure that patients do not share one bed; inform district/ municipal authority in charge of overcrowding should it persist despite appropriate measures having been taken, etc. establish appropriate referral routes hcws adhere to guidelines on nsis avoid inappropriate prescription of parenteral therapies educate patients on what to do if there is an nsi use needle-free devices where possible, e.g. needle-free syringes and intravenous infusion sets show empathy, support and provide medical care to any patient who sustains an nsi ensure that all intravenous fluid administration sets are properly fastened to prevent inadvertent disconnection report nsis monitor patients with intravenous/intra-arterial lines adhere to treatment protocols and consult senior colleagues for advice if necessary remove intravenous access as soon as there is no indication for their use manage patients at risk of injury (such as children, the mentally ill, the blind and unconscious patients, etc.) appropriately adhere to standard operating procedures regarding the safe use/ sterilisation of equipment and waste disposal counsel patients before any medical procedure avoid unnecessary admission of patients for inhospital care to address patient overcrowding of a health facility: consider discharging stable patients; inform the supervisor; discuss with management, etc. engage in community health promotion so as to prevent illnesses patients and their visitors ask questions when in doubt report concerns to hcws (and to management if not satisfied) adhere to medical advice be aware of patient and visitor rights adhere to health policies such as appropriate referral routes and facility visiting hours nsi = needlestick injury; hcw = healthcare worker. http://www http://www.who.int/ http://dx.doi.org/10.1016/s0020-7292 http://stacks.cdc.gov/view/ http://dx.doi.org/10.1186/1745-6673-8-20] http://dx.doi.org/10.1136/qshc.2008.029165] http://dx.doi.org/10.1136/qshc.2008.029165] http://web.up.ac.za/sitefiles/file/45/1335/877/ why should we.html opinion why should we still care about the stavudine dose? steve innes1, mb bch, mrcpch, mphil mark cotton1, mb chb, mmed, fcpaed, dtm&h, dch (sa), phd françois venter2, mb bch, fcp (sa), dip hiv man (sa), dtm&h (sa), mmed 1children’s infectious diseases clinical research unit (kid-cru), tygerberg children’s hospital and stellenbosch university, w cape 2wits reproductive health and hiv institute (wrhi), department of medicine, university of the witwatersrand and johannesburg academic hospital current recommendations advise that stavudine be phased out of use. the logistics and cost of switching are significant, and the world health organization has forecast that 1.55 million people will still be on stavudine-based antiretroviral therapy by the end of 2012. stavudine is co-formulated in many countries, is very cheap and effective, and is well tolerated in initial therapy. however, the 40 mg bd dose was associated with considerable long-term toxicity. several studies suggest that half the original recommended dose has excellent antiviral efficacy with significantly reduced metabolic side-effects. despite generic tenofovir now being cheaper than zidovudine, tenofovir consumes the majority of adult antiretroviral programme medication budgets in programmes in africa, where it is used in first-line therapy. abacavir is far more expensive than zidovudine or tenofovir, and is a major cost driver in paediatric programmes with access to abacavir-based first-line treatment. low-dose stavudine may offer the only cheaper (and possibly as effective and safe) alternative to programmes grappling with limited financial resources. the unaids 2010 global report estimated that 20 million adults and 2.3 million children in sub-saharan africa are hiv-infected,1 of whom 6.7 million and 518 000, respectively, are currently on antiretroviral therapy (art).2 in the late 1990s stavudine was selected as the first-line antiretroviral of choice for adults and children in the developed world because it is extremely safe in the short term, in contrast to the toxicity and intolerance associated with zidovudine. in fact, stavudine was regarded as so safe that the original recommended dose for adults was 40 mg twice daily (bd), even though a number of randomised clinical trials had shown that it was equally effective at a dose of 20 mg bd.4 forty milligrams bd was chosen fairly arbitrarily over 20 mg bd after the stavudine 019 trial8 chose to test 40 mg twice daily rather than a lower dose, and found that stavudine had minimal short-term toxicity at that dose. the children’s dose was extrapolated from the adult dose using data from paediatric pharmacokinetic studies that showed that an oral dose of 1 mg/kg/dose twice daily in children weighing under 30 kg results in plasma exposure similar to that of an adult over 60 kg taking 40 mg twice daily, and that an oral dose of 0.5 mg/kg/dose twice daily in children results in plasma exposure similar to that of an adult over 60 kg taking 20 mg twice daily.9 no virological outcomes were reported in those paediatric pharmacokinetic studies. art-associated lipoatrophy was first described in 1998,11 4 years after the introduction of stavudine as an antiretroviral agent. by 2002, lipoatrophy was recognised as a frequent delayed adverse effect of stavudine.12 a large number of studies have since shown a causal link with nucleoside reverse transcriptase inhibitor exposure, particularly didanosine, stavudine and zidovudine, of which stavudine shows the strongest link. the effect of stavudine in causing lipoatrophy appears to be strongly dose-related, and in 2007 the world health organization advised that the recommended adult dose be lowered from 40 to 30 mg bd.13 the children’s dose was not lowered, however, because lipoatrophy was believed to be uncommon in children (although this assumption is currently being refuted). the lipoatrophy caused by stavudine typically does not manifest until 18 24 months of therapy, and even then may go unnoticed or may not be taken seriously by the health care provider for months or years as it slowly progresses. the typically long delay between drug initiation and manifestation of toxicity may have contributed to the delay in the global response in reducing the recommended dose from 40 to 30 mg bd. in the meantime, stavudine has gained a bad reputation due to the stigmatising effect of lipoatrophy, which resolves slowly and poorly. however, evidence accumulated over the last 15 years suggests that stavudine given at the equivalent of 20 mg bd leads to a significantly lower rate of lipoatrophy and of other mitochondrial adverse effects.13 , 15 the logistics and cost of switching all antiretroviral-treated individuals to non-stavudine therapy is significant. generic tenofovir costs 6 times more per month than stavudine, while tenofovir co-formulated with emtricitibine costs 4 times more than a month’s supply of stavudine and lamivudine combined.18 in addition, the use of tenofovir, which requires additional renal function monitoring, substantially increases the programme costs of safety monitoring.19 taking the costs of toxicity management into account, the cost-effectiveness ratio (measured in cost per year of life saved) of tenofovir is double that of stavudine (when art is initiated at 350 cd4 cells/μl in a one-line setting) with similar 5-year survival (89% v. 87%) when using the incidence of stavudine toxicity associated with 40 mg bd.20 since the incidence of late adverse events due to stavudine is likely to be substantially reduced by using a more appropriate dose (20 mg bd), the advantages of tenofovir over stavudine may begin to dwindle. given the escalating number of people being initiated on art and the stress this places on existing art programmes, it is unlikely that switching stable patients from stavudine to an alternative will be a high priority. in addition, for those initiated on alternative art regimens, stavudine will probably remain an important second-line agent, especially in patients unable to tolerate or have affordable access to zidovudine or abacavir. using stavudine in first-line therapy further preserves tenofovir for second line. both the world health organization and the clinton health access initiative have forecast that approximately 1.4 million adults (18% of adults on art) and 150 000 children (26% of children on art) will still be on stavudine-based art by the end of 20123 (personal communication, joanna sickler, clinton health access initiative). the authors therefore advocate a head-to-head randomised controlled trial comparing stavudine 20 mg bd with tenofovir 300 mg once daily, powered to show non-inferiority in adults. references 1. unaids. report on the global aids epidemic. 2010. http://www.unaids.org/globalreport/global_report.htm (accessed 8 september 2011). 1. unaids. report on the global aids epidemic. 2010. http://www.unaids.org/globalreport/global_report.htm (accessed 8 september 2011). 2. renaud-thery f, avila-figueroa c, stover j, et al. utilization patterns and projected demand of antiretroviral drugs in lowand middle-income countries. aids research and treatment 2011;2011. doi:10.1155/2011/749041. http://www.hindawi.com/journals/art/2011/749041/cta/ (accessed 15 november 2011). 2. renaud-thery f, avila-figueroa c, stover j, et al. utilization patterns and projected demand of antiretroviral drugs in lowand middle-income countries. aids research and treatment 2011;2011. doi:10.1155/2011/749041. http://www.hindawi.com/journals/art/2011/749041/cta/ (accessed 15 november 2011). 3. world health organization. forecasting antiretroviral demand. 2010. http://www.who.int/hiv/amds/forecasting/en/index4.html (accessed 15 september 2011). 3. world health organization. forecasting antiretroviral demand. 2010. http://www.who.int/hiv/amds/forecasting/en/index4.html (accessed 15 september 2011). 4. anderson re, dunkle lm, smaldone l, et al. design and implementation of the stavudine parallel-track program. j infect dis 1995;171(suppl 2):s118-122. 4. anderson re, dunkle lm, smaldone l, et al. design and implementation of the stavudine parallel-track program. j infect dis 1995;171(suppl 2):s118-122. 5. petersen ea, ramirez-ronda ch, hardy wd, et al. dose-related activity of stavudine in patients infected with human immunodeficiency virus. j infect dis 1995;171(suppl 2):s131-139. 5. petersen ea, ramirez-ronda ch, hardy wd, et al. dose-related activity of stavudine in patients infected with human immunodeficiency virus. j infect dis 1995;171(suppl 2):s131-139. 6. pollard rb, peterson d, hardy d, et al. safety and antiretroviral effects of combined didanosine and stavudine therapy in hiv-infected individuals with cd4 counts of 200 to 500 cells/mm3. j acquir immune defic syndr 1999;22(1):39-48. 6. pollard rb, peterson d, hardy d, et al. safety and antiretroviral effects of combined didanosine and stavudine therapy in hiv-infected individuals with cd4 counts of 200 to 500 cells/mm3. j acquir immune defic syndr 1999;22(1):39-48. 7. ruxrungtham k, kroon ed, ungsedhapand c, et al. a randomized, dose-finding study with didanosine plus stavudine versus didanosine alone in antiviral-naive, hiv-infected thai patients. aids 2000;14(10):1375-1382. 7. ruxrungtham k, kroon ed, ungsedhapand c, et al. a randomized, dose-finding study with didanosine plus stavudine versus didanosine alone in antiviral-naive, hiv-infected thai patients. aids 2000;14(10):1375-1382. 8. spruance sl, pavia at, mellors jw, et al. clinical efficacy of monotherapy with stavudine compared with zidovudine in hiv-infected, zidovudine-experienced patients. a randomized, double-blind, controlled trial. bristol-myers squibb stavudine/019 study group. ann intern med 1997;126(5):355-363. 8. spruance sl, pavia at, mellors jw, et al. clinical efficacy of monotherapy with stavudine compared with zidovudine in hiv-infected, zidovudine-experienced patients. a randomized, double-blind, controlled trial. bristol-myers squibb stavudine/019 study group. ann intern med 1997;126(5):355-363. 9. kaul s, kline mw, church ja, dunkle lm. determination of dosing guidelines for stavudine (2’,3’-didehydro-3’-deoxythymidine) in children with human immunodeficiency virus infection. antimicrob agents chemother 2001;45(3):758-763. 9. kaul s, kline mw, church ja, dunkle lm. determination of dosing guidelines for stavudine (2’,3’-didehydro-3’-deoxythymidine) in children with human immunodeficiency virus infection. antimicrob agents chemother 2001;45(3):758-763. 10. kline mw, dunkle lm, church ja, et al. a phase i/ii evaluation of stavudine (d4t) in children with human immunodeficiency virus infection. pediatrics 1995;96:247-252. 10. kline mw, dunkle lm, church ja, et al. a phase i/ii evaluation of stavudine (d4t) in children with human immunodeficiency virus infection. pediatrics 1995;96:247-252. 11. carr a, samaras k, burton s, et al. a syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving hiv protease inhibitors. aids 1998;12(7):f51-58. 11. carr a, samaras k, burton s, et al. a syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving hiv protease inhibitors. aids 1998;12(7):f51-58. 12. joly v, flandre p, meiffredy v, et al. increased risk of lipoatrophy under stavudine in hiv-1-infected patients: results of a substudy from a comparative trial. aids 2002;16(18):2447-2454. 12. joly v, flandre p, meiffredy v, et al. increased risk of lipoatrophy under stavudine in hiv-1-infected patients: results of a substudy from a comparative trial. aids 2002;16(18):2447-2454. 13. hill a, ruxrungtham k, hanvanich m, et al. systematic review of clinical trials evaluating low doses of stavudine as part of antiretroviral treatment. expert opin pharmacother 2007;8(5):679-688. 13. hill a, ruxrungtham k, hanvanich m, et al. systematic review of clinical trials evaluating low doses of stavudine as part of antiretroviral treatment. expert opin pharmacother 2007;8(5):679-688. 14. world health organization. addendum to 2006 who guidelines on antiretroviral therapy for hiv infection in adults and adolescents. 2007. http://www.who.int/hiv/art/artadultsaddendum.pdf (accessed 26 august 2008). 14. world health organization. addendum to 2006 who guidelines on antiretroviral therapy for hiv infection in adults and adolescents. 2007. http://www.who.int/hiv/art/artadultsaddendum.pdf (accessed 26 august 2008). 15. mccomsey ga, lo re v, 3rd, o’riordan m, et al. effect of reducing the dose of stavudine on body composition, bone density, and markers of mitochondrial toxicity in hiv-infected subjects: a randomized, controlled study. clin infect dis 2008;46(8):1290-1296. 15. mccomsey ga, lo re v, 3rd, o’riordan m, et al. effect of reducing the dose of stavudine on body composition, bone density, and markers of mitochondrial toxicity in hiv-infected subjects: a randomized, controlled study. clin infect dis 2008;46(8):1290-1296. 16. milinkovic a, martinez e, lopez s, et al. the impact of reducing stavudine dose versus switching to tenofovir on plasma lipids, body composition and mitochondrial function in hiv-infected patients. antivir ther 2007;12(3):407-415. 16. milinkovic a, martinez e, lopez s, et al. the impact of reducing stavudine dose versus switching to tenofovir on plasma lipids, body composition and mitochondrial function in hiv-infected patients. antivir ther 2007;12(3):407-415. 17. sanchez-conde m, de mendoza c, jimenez-nacher i, barreiro p, gonzalez-lahoz j, soriano v. reductions in stavudine dose might ameliorate mitochondrial-associated complications without compromising antiviral activity. hiv clin trials 2005;6(4):197-202. 17. sanchez-conde m, de mendoza c, jimenez-nacher i, barreiro p, gonzalez-lahoz j, soriano v. reductions in stavudine dose might ameliorate mitochondrial-associated complications without compromising antiviral activity. hiv clin trials 2005;6(4):197-202. 18. southern african hiv clinicians society. antiretroviral pricelist. 2010. http://www.sahivsoc.org/indexarv.php/arvpricelist (accessed 1 september 2011). 18. southern african hiv clinicians society. antiretroviral pricelist. 2010. http://www.sahivsoc.org/indexarv.php/arvpricelist (accessed 1 september 2011). 19. wood r. the role of stavudine in the south african public sector antiretroviral programme: should the perfect be the enemy of the good? southern african journal of hiv medicine 2006;7(2):5-8. 19. wood r. the role of stavudine in the south african public sector antiretroviral programme: should the perfect be the enemy of the good? southern african journal of hiv medicine 2006;7(2):5-8. 20. walensky rp, wood r, ciaranello al, et al. scaling up the 2010 world health organization hiv treatment guidelines in resource-limited settings: a model-based analysis. plos med 2010;7(12):e1000382. 20. walensky rp, wood r, ciaranello al, et al. scaling up the 2010 world health organization hiv treatment guidelines in resource-limited settings: a model-based analysis. plos med 2010;7(12):e1000382. abstract introduction methods results discussion conclusion acknowledgements references about the author(s) rahma mohamed endemic medicine department, kasr alaini school of medicine, cairo university hospitals, cairo, egypt kasr al-aini hiv and viral hepatitis fighting group, kasr alaini school of medicine, cairo university hospitals, cairo, egypt trenton m. white barcelona institute for global health (isglobal), hospital clinic, university of barcelona, barcelona, spain jeffrey v. lazarus barcelona institute for global health (isglobal), hospital clinic, university of barcelona, barcelona, spain faculty of medicine and health sciences, university of barcelona, barcelona, spain amany salem department of public health, kasr alaini school of medicine, cairo university, cairo, egypt reham kaki department of infectious disease, infection control and environmental health, faculty of medicine, king abdulaziz university, jeddah, saudi arabia wafa marrakchi infectious diseases department, faculty of medicine, university hospital of monastir, monastir, tunisia sara g. m kheir disease control directorate, federal ministry of health, khartoum, sudan ibrahim amer department of hepatology, gastroenterology and infectious diseases, faculty of medicine, kafr el-sheikh university, kafr el-sheikh, egypt fida m ahmed department of infectious disease, infection control and environmental health, faculty of medicine, king abdulaziz university, jeddah, saudi arabia maie a khayat department of infectious disease, infection control and environmental health, faculty of medicine, king abdulaziz university, jeddah, saudi arabia nabeela al-abdullah college of nursing, king abdulaziz university, jeddah, saudi arabia batool ali department of infectious diseases, east jeddah general hospital, jeddah, saudi arabia roaa sultan department of infectious diseases, east jeddah general hospital, jeddah, saudi arabia bandar alamri department of infectious diseases, east jeddah general hospital, jeddah, saudi arabia anouf abdulmajid department of infectious diseases, east jeddah general hospital, jeddah, saudi arabia ikbal kooli infectious diseases department, faculty of medicine, university hospital of monastir, monastir, tunisia mohamed chakroun infectious diseases department, faculty of medicine, university hospital of monastir, monastir, tunisia tariq a. madani department of infectious disease, infection control and environmental health, faculty of medicine, king abdulaziz university, jeddah, saudi arabia gamal esmat endemic medicine department, kasr alaini school of medicine, cairo university hospitals, cairo, egypt ahmed cordie endemic medicine department, kasr alaini school of medicine, cairo university hospitals, cairo, egypt kasr al-aini hiv and viral hepatitis fighting group, kasr alaini school of medicine, cairo university hospitals, cairo, egypt infectious diseases department, armed forces college of medicine, cairo, egypt citation mohamed r, white tm, lazarus jv, et al. covid-19 vaccine acceptance and associated factors among people living with hiv in the middle east and north africa region. s afr j hiv med. 2022;23(1), a1391. https://doi.org/10.4102/sajhivmed.v23i1.1391 note: additional supporting information may be found in the online version of this article as online appendix 1 and 2. original research covid-19 vaccine acceptance and associated factors among people living with hiv in the middle east and north africa region rahma mohamed, trenton m. white, jeffrey v. lazarus, amany salem, reham kaki, wafa marrakchi, sara g. m kheir, ibrahim amer, fida m ahmed, maie a khayat, nabeela al-abdullah, batool ali, roaa sultan, bandar alamri, anouf abdulmajid, ikbal kooli, mohamed chakroun, tariq a. madani, gamal esmat, ahmed cordie received: 18 mar. 2022; accepted: 18 may 2022; published: 24 aug. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: identifying coronavirus disease 2019 (covid-19) vaccine acceptance and associated factors among people living with hiv (plhiv) in the middle east and north africa region is important to meet the need for broad-scale vaccination against covid-19. objectives: to investigate the covid-19 vaccine acceptance rate and factors among plhiv in the middle east and north africa region. method: an online cross-sectional survey was conducted among plhiv currently living in egypt, tunisia and saudi arabia between march 2021 and august 2021. results: of the 540 respondents, 19.3% reported already being vaccinated against covid-19 (n = 104), 32.0% responded ‘definitely yes’ (n = 173), and 13.3% responded ‘probably yes’ (n = 72) for intention to receive a covid-19 vaccine, with an overall covid-19 vaccine acceptance rate of 64.6% among plhiv in the region. the most significant predictors of covid-19 vaccine acceptance included feeling less worried about covid-19 transmission post-vaccination (221.0% higher odds), and believing the disease is vaccine-preventable (160.0% higher odds). reported barriers to covid-19 vaccine acceptance include concerns about vaccine effectiveness and belief that hiv medications protect against covid-19 transmission, living in a rural area and reporting less-frequent engagement with hiv care. nine out of 10 participants reported that the chances of them getting covid-19 vaccine would increase if given adequate information and if their doctor recommended it. conclusion: findings of the study can help researchers, health officials, and other health system actors understand the predictors and barriers to covid-19 vaccine acceptance reported by plhiv. this understanding could inform the future planning of interventions tailored to plhiv. keywords: covid-19; covid-19 vaccine; vaccine acceptance; middle east; hiv introduction for four decades, hiv/aids has been one of the world’s most serious public health challenges, with an estimated 36 million aids-related deaths worldwide since the start of the pandemic, and nearly 38 million people currently living with hiv.1 despite having the lowest estimated hiv prevalence rates in the world (< 0.1%), the middle east and north africa (mena) region is an area of growing concern, with a 47% increase in new infections and a 57% increase in aids-related deaths compared to 2010.2,3 in addition, in this region it is estimated that only 52% of people living with hiv (plhiv) are aware of their status, and only 43% of all plhiv are on antiretroviral treatment.2,4 in the midst of global and regional efforts to control the hiv epidemic, the novel coronavirus disease 2019 (covid-19) pandemic emerged, continuing to threaten hard-won gains made against hiv through service disruption, covid-19 myths among plhiv, and potential unknown implications of long-covid and hiv comorbidity.5,6,7 as of december 2021, more than 17 million cases of covid-19 and some 312 000 deaths have been reported across the region.8 several mena countries adopted strict containment measures to decrease the spread of covid-19, including closing borders, schools, religious sites and public places, and imposing a full lockdown for certain periods of time.9 however, some of these measures intensified existing challenges to hiv care by impeding access to prevention, clinical care and treatment services,5,6 and by generating or exacerbating stress, depression and isolation among plhiv.10 increased risk of covid-19 mortality among plhiv, compared to their hiv-negative counterparts, was demonstrated in south africa and the united kingdom.11,12,13 similarly, a study of over 15 000 cases of covid-19 in plhiv from 24 countries conducted by the world health organization found that plhiv were at higher risk of severe or critical illness at the time of hospital admission and in-hospital mortality after controlling for age, gender and comorbidity burden.14 vaccination is the most effective intervention to prevent severe illness and death from covid-19.15 as of december 2021, over eight billion doses of covid-19 vaccines have been administered globally, and 56% of the world population has received at least one dose.16 despite this global progress, vaccination coverage remains very low in lowand lower-middle income countries, including those in the mena region.17 slow covid-19 vaccine coverage reflects global supply issues as well as decreased demand due to vaccine hesitancy. vaccine hesitancy, defined as ‘a delay in acceptance or refusal of vaccination despite availability of vaccination services’, has been a growing concern worldwide,18 prompting the world health organization to name it one of the top 10 global health threats in 2019. this challenge has grown during the covid-19 pandemic.19 existing studies on public perceptions and acceptance of covid-19 vaccines in the mena region illustrate that the middle east is among the regions with the lowest rates of vaccine acceptance globally.20,21 vaccine hesitancy could jeopardise the success of covid-19 vaccination programmes and undermine efforts to ensure high vaccination coverage rates, especially among vulnerable populations, such as plhiv. the objectives of this study were to evaluate the acceptance of the covid-19 vaccine and influencing factors among plhiv in the mena region. methods study design and sample the study is a cross-sectional web-based anonymous survey, designed and administrated using google forms. people living with hiv aged 18 years or older, whether male, female or transgender, and living in egypt, tunisia or the kingdom of saudi arabia between march 2021 and august 2021 were included. those who disagreed to give consent before submitting their responses were excluded. a sample of plhiv was calculated using purposive quota non-probability methods. the research team then contacted and enrolled plhiv who were on follow-up in their hiv clinics via telephone and email. in addition, there are many community-based organisations providing services to plhiv in each country that facilitated distribution of the survey to their networks through emails and social media platforms (facebook and whatsapp). participants were informed that their participation was voluntary, given a brief introduction to the study and its objective, and requested to provide informed consent prior to accessing the questionnaire. sample size was calculated to determine the minimum proper sample size for the prevalence of acceptance of covid-19 vaccine among plhiv in the mena region. reviewing the literature revealed that no previous studies had been performed on plhiv in the mena region; however, the rate of acceptance of covid-19 vaccine among the general population ranged from 23.6% to 77.6%,19,21 with an average of 50.6%. if we assumed that this was the true population prevalence, we needed to study 164 participants to be able to achieve 80.0% power, setting the alpha error at 0.05 and the prevalence error margin at 5.0% using the generic z test. sample size calculation was done by statcalc, epi info version 7 for ms windows (centers for disease control and prevention, atlanta, georgia, united states [us]). data collection tool the closed-ended questionnaire addressed: (1) sociodemographic characteristics of participants; (2) individual health, including hiv-related health; (3) covid-19 vaccination and intention; and (4) a health belief model (hbm) of covid-19 disease and vaccination (see online appendix 2 file 1). the questionnaire was developed in english and forward translated to arabic by a professional interpreter. the forward translations were then back translated by bilingual members of the research team who, through majority consensus, made decisions about the semantic, idiomatic, experiential and conceptual equivalence of the translated items. before distribution, the questionnaire’s content validity was tested and verified by local hiv experts and through pilot testing among fewer than 10 plhiv, where the questionnaire was estimated to take about 15 min to complete. the data were collected anonymously and assigned a unique identification in the phase of data entry. sociodemographic and health-related variables participants were asked to report their age, gender, marital status, educational attainment, employment status, country and area of residence (rural or urban). participants were also asked if they had other existing chronic diseases (e.g. diabetes, hypertension, lung disease, liver disease, kidney disease, heart disease, and/or malignancy), and to rate their overall health status. participants reported prior receipt of vaccination against seasonal influenza this year and if they were previously covid-19 tested or hospitalised because of covid-19. participants were also asked if they were currently receiving their hiv medications, and for their most recent cd4 count and hiv viral load. covid-19 vaccination and intention participants reported if they had already been vaccinated against covid-19, and, if the answer was ‘no’, they were asked the follow-up question, ‘when a covid-19 vaccine becomes available to you, will you take it?’, to assess their intention to accept a covid-19 vaccine on a five-point scale (‘definitely no’ to ‘definitely yes’). participants were coded by the authors as the vaccine-accepting group if they answered ‘yes’ to already being vaccinated, or ‘definitely yes’ or ‘probably yes’ to the intention question. the vaccine non-accepting group included those who answered, ‘probably no’, ‘not sure’ or ‘definitely no’ to the intention question. all participants were also asked if they ‘would pay a fee to be vaccinated, if needed’, on a five-point scale (‘definitely no’ to ‘definitely yes’). health belief model of covid-19 disease and vaccination the questionnaire items on participants’ beliefs about covid-19 vaccination were partially derived from the hbm. this model is used to describe individuals’ health-related behaviour according to their perception of predisposition, efficacy and outcomes.22 questions included main domains that affect health behaviour: perceived susceptibility to covid-19 infection and severity (three items), perceived benefits of a covid-19 vaccine (two items), perceived vaccination barriers (seven items), and cues to action (two items). each item was based on a five-point likert scale (‘strongly agree’, ‘agree’, ‘neither disagree or agree’, ‘disagree’ or ‘strongly disagree’). chronbach’s alpha tested the internal reliability of the 14-item scale. statistical analysis multivariable ordered logistic regression analyses were used to report the odds ratios across the sample for vaccine acceptance with: (1) a sociodemographic model; (2) an hiv-related and overall individual health model; and (3) an hbm model. a likelihood ratio test was used to test the models’ fit by nesting the sociodemographic model within the other two models. ethical considerations this study was approved by the university of kafr el-sheikh research ethics committee. approval code: mksu 13-3-20. also, the institutional review boards of jeddah (no.h-02-j002/2021) approved this study. results sociodemographic and individual health data descriptive characteristics of the respondents are provided in table 1 and table 2. overall, 540 respondents completed the survey, 72% of whom were male (n = 389), and 54.8% aged 18–39 years (n = 296). forty-two per cent (42%) of respondents (n = 227) were from egypt, 34.4% were from saudi arabia (n = 186), and 23.5% were from tunisia (n = 127), with a higher proportion of participants (85.2%) living in urban areas (n = 460). responses to the hbm are provided in online appendix 1, table 1. table 1: sociodemographic characteristics of the sample (n = 540). table 2: hiv-related and overall health of individual participants (n = 540). overall covid-19 vaccine acceptance figure 1 and figure 2 demonstrate covid-19 vaccine acceptance among plhiv in the studied countries. overall, 64.6% of the sample reported acceptance. of these, 19.3% (n = 104) had already been vaccinated against covid-19, 32.0% responded ‘definitely yes’ (n = 173), and 13.3% responded ‘probably yes’ (n = 72) for intention to receive a covid-19 vaccine, with relative variation in acceptance rate between the three countries. only 6.7% responded ‘definitely no’ (n = 36), 7.0% reported ‘probably no’ (n = 38), and 21.7% ‘not sure’ (n = 117). a higher proportion of participants from saudi arabia (65%) were willing to pay a fee than the average (39.0%) to get the vaccine (figure 3). figure 1: covid-19 vaccine acceptance among middle east and north africa people living with hiv (n = 540). figure 2: covid-19 vaccination intention by country (egypt [n = 227], saudi arabia [n = 186], tunisia [n = 127]). figure 3: willingness to pay for a covid-19 vaccine by country. factors associated with covid-19 vaccine acceptance in the three multivariate models assessing vaccine acceptance, the hbm demonstrated the strongest fit with a pseudo r2 = 0.30 (p = 0.00), compared with the individual health model (pseudo r2 = 0.15; p = 0.00) and sociodemographic model (pseudo r2 = 0.03; p = 0.00). cronbach’s alpha test for the hbm was estimated to be 0.83. in the nested likelihood ratio tests, both models demonstrated a statistically significant improvement in model fit by including the sociodemographic variables (p = 0.00) (table 3). table 3: factors for vaccine acceptance among (a) sociodemographic characteristics, (b) hiv-related and overall health, and (c) covid-19 hbm perceptions. in the sociodemographic model, living in a rural area is associated with 58% lower odds of accepting a covid-19 vaccine compared to living in an urban area, whereas the other variables hold no significant association. in the model assessing individual hiv-related and overall health of participants, those reporting their most recent cd4+ cell check being more than one year ago demonstrated 50% lower odds of covid-19 vaccine acceptance compared to those reporting a recent check within one year, after controlling for sociodemographic characteristics. in the covid-19 hbm after controlling for sociodemographic characteristics, feeling less worried about getting covid-19 post-vaccination (221% higher odds), believing covid-19 is vaccine-preventable (160% higher odds), and a doctor recommendation (142% higher odds) were all associated with higher acceptance. conversely, believing hiv medication protects against covid-19 transmission (35% lower odds) and concerns about vaccine effectiveness (48% lower odds) were associated with lower acceptance. other evaluated items held no significant associations. discussion our study investigated covid-19 vaccine acceptance among plhiv in egypt, tunisia and saudi arabia, including associated factors such as sociodemographic characteristics, individuals’ hiv-related health, vaccine perceptions and health beliefs. the overall covid-19 vaccine acceptance rate among plhiv who participated in this survey is 64.6%, with wide variation between countries (92.0% in saudi arabia, 57.0% in tunisia, and 46.0% in egypt). these regional differences in vaccine acceptance are reflected by vaccination coverage in saudi arabia, where 71.2% of the general population have received at least one dose of a covid-19 vaccine, compared with tunisia (52.9%) and egypt (27.3%), as of 12 december 2021.23 a previous study conducted in january 2021 in france showed that 71.3% of plhiv would accept covid-19 vaccines, while 28.7% demonstrated hesitancy.24 in eight cities in china between january and february 2021, 57.2% of plhiv reported willingness to be vaccinated against covid-19.25 compared to studies conducted in the mena region, the acceptance of a covid-19 vaccine among our study participants was higher than the general population in jordan (28.4%), egypt (43.0%), oman (57.0%), lebanon (58.8%), and qatar (60.0%); similar to that in saudi arabia (64.7%); and lower than in kuwait (67.0%), somalia (76.8%) and iraq (77.6%).20,26,27,28,29,30,31,32,33 our study is consistent with others regarding weaker covid-19 vaccine acceptance among those residing in rural areas34 and regarding age and gender among french plhiv.24 compared to the general population in mena region, there was mixed evidence with respect to the relationship between age and covid-19 vaccine acceptance. some studies demonstrate higher acceptance of covid-19 vaccines among younger age groups,30,32,35 and others report higher acceptance among older age groups.29,31 our results demonstrate comparable vaccine acceptance across gender, marital status and education level, differing from studies that demonstrate higher acceptance among male versus female participants, married versus non-married, and higher versus lower education level.29,30,31,32,35 the low acceptance rate among rural communities may reflect socio-economic disadvantage, lack of knowledge regarding covid-19, and less preventive measures against the covid-19 virus infection, including vaccines. according to the hbm, feeling less worried about getting covid-19 post-vaccination and believing it is vaccine-preventable were the most significant predictors of vaccine acceptance, whereas falsely believing hiv medications protect against covid-19 transmission and having concerns about the vaccines’ effectiveness were stronger predictors for non-acceptance, consistent with similar studies evaluating effectiveness.35,36 more than half of the participants were concerned about the vaccine side effects and 47% were concerned regarding potential interactions between their hiv treatment and covid-19 vaccines. this result is consistent with the findings of huang et al.,25 which showed that about half of plhiv respondents in china had concerns related to side effects, and potential interactions between antiretroviral treatment and covid-19 vaccines. similarly, vallée et al.24 found that concerns about the serious side effects of covid-19 vaccines were independently associated with covid-19 vaccine hesitancy. similar to studies conducted among the general population in the mena region, concerns about covid-19 vaccine safety and fear of side effects were among the most commonly cited reasons for vaccine hesitancy.20,32,35 as relatively small numbers of plhiv have been involved in the phase iii covid-19 vaccine trials, limited data has been available regarding covid-19 vaccines in this specific population.37,38,39 however, the world health organization, as well as several international health authorities, has released recommendations for plhiv to receive covid-19 vaccines and to address their safety and efficacy concerns.40,41,42 these recommendations emphasise no evidence of safety concerns unique to plhiv and, as with the general population, the vaccines are considered safe. moreover, plhiv have been considered as a priority group for the vaccination. despite being widely reported by participants in our study, there is no compelling evidence to support the use of hiv medications for treatment or prevention of covid-19, and no evidence on potential interaction between covid-19 vaccine and hiv drugs.40,41,42 these findings are important for plhiv in this region. authoritative and trustworthy information sources, such as national aids programmes and local health authorities, should engage plhiv with clear, carefully crafted and consistent messages, communicated in plain, non-stigmatising language and in a way that people of all educational levels can understand, to address their specific concerns and perceived barriers regarding covid-19 vaccination. ensuring that plhiv have adequate access to covid-19 vaccines, as well as sufficient information to make evidence-based immunisation decisions, should be priorities of national health authorities. prior studies among the general population have shown that high perceived susceptibility of getting covid-19 or perceptions of the severity of covid-19 were significant predictors for vaccine acceptance.35,43 in addition, low perceived severity of covid-19 infection was highly correlated with covid-19 vaccine refusal among french plhiv.24 however, among plhiv in the mena region, perception of susceptibility and severity of covid-19 infection were not significant predictors. one explanation for decreased risk perception could be that, because of inadequate testing and underreported incidences of covid-19 infections and mortalities in countries across the region,44 people might consider covid-19 to be an ordinary seasonal respiratory illness rather than the highly transmissible disease it is. this highlights a need to address risk perception and severity among plhiv, as high-risk perceptions are important precursors to positive health behaviours, including being a significant predictor of intention to take the covid-19 vaccine.45,46 low perceived risk may be correlated not only with vaccine acceptance, but also to adherence to social distancing measures and other public health countermeasures, in the absence of vaccine access.45,46 our finding on vaccine acceptance associated with a doctor recommendation, consistent with other studies, demonstrates that healthcare workers, on the frontline of hiv care, can play an influential role in building vaccination literacy and in improving trust in covid-19 vaccines among plhiv.47 they should be well trained and equipped with the tools to support plhiv, including listening to their fears and anxieties, answering their questions, and addressing their concerns towards vaccines, as well as correcting misinformation, and being aware of potential stigma concerns. hiv is a highly stigmatised condition in the mena region.48 the stigmatising and discriminatory attitudes plhiv face in healthcare settings could deter populations at high risk from seeking health services.49 many civil society organisations and community-based organisations in the region are led by or involve people most affected by hiv and have become integral to the mena region’s hiv response. civil society organisations are often more effective in reaching plhiv and key populations than health authorities50 and can therefore play an essential role in building trust in covid-19 vaccines among these groups. peer-support for plhiv can also fulfill a useful role in promoting covid-19 vaccination, sharing supportive advice and positive experiences of covid-19 vaccination. those reporting more than one year since their last cd4+ cell count check may be less well engaged with the health system and may, in turn, inadvertently accept higher health risks (e.g., remaining unvaccinated) due to lack of information or access to care than those reporting more engagement. leveraging lessons learned from models of hepatitis c virus/hiv care51 may provide practical solutions to make vaccination more convenient for plhiv without risking disclosure of their hiv status. these include, for example, co-location of vaccination services within hiv clinics, ‘one-stop-shop’ models, and door-to-door administration, and can make vaccines easily accessible in safe, familiar and convenient locations. limitations of this study include potential selection bias using web-based survey methods, and the cross-sectional nature, preventing us from drawing any causal conclusions. although facebook and whatsapp platforms were valuable in helping to achieve the minimum sample, selection bias could have been introduced by using these methods of advertisement. nevertheless, this study is the first to evaluate covid-19 vaccine acceptance and its associated factors among plhiv in the mena region. such findings should help policymakers planning interventions to improve vaccination coverage among this group. conclusion this study reports overall covid-19 vaccine acceptance of 64.6% among plhiv in three countries of the mena region. factors for vaccine acceptance included feeling less worried about covid-19 transmission post-vaccination, believing covid-19 is vaccine-preventable, and having a doctor recommendation. factors against getting vaccinated included living in a rural area, having a most recent cd4+ cell count check more than one year ago, having concerns about vaccine effectiveness and believing hiv medications protect against covid-19 transmission. effective strategies are needed to guarantee plhiv access to covid-19 vaccines as a priority group for vaccination as well as to increase vaccine acceptance among plhiv through clearly tailored messages, addressing their specific concerns and improving their knowledge and awareness about the safety and benefits of covid-19 vaccines. acknowledgements t.m.w. and j.v.l. acknowledge support to isglobal from the spanish ministry of science, innovation and universities through the ‘centro de excelencia severo ochoa 2019–2023’ programme (cex2018-000806-s), and from the government of catalonia through the centres de recerca de catalunya (cerca) programme. competing interests the authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. authors’ contributions the concept for this study was developed by a.c., r.m., a.a.s., g.e. and j.l.; a.c., r.m., r.k., w.m., s.g.m.k., i.a., f.m.a., m.a.k., n.a., b.a., r.s., b.a., a.a., i.k., t.a.m. and m.c. were involved in participant recruitment and data collection; r.m. and a.c. developed the first draft; t.m.w. conducted the data analyses; r.m., a.c., t.m.w. and j.v.l. prepared the final version. all authors revised and approved the final version. funding information this research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. data availability the authors confirm that the data supporting the findings of this study are available within the article and/or its supplementary materials. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references the joint united nations programme on hiv/aids (unaids). global hiv & aids statistics – fact sheet [homepage on the internet]. 2021 [cited 2021 dec 12]. available from: https://www.unaids.org/en/resources/fact-sheet avert. hiv and aids in the middle east & north africa [homepage on the internet]. 2019 [cited 2021 dec 12]. available from: 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https://doi.org/10.1056/nejmoa2035389 voysey m, clemens sa, madhi sa, et al. safety and efficacy of the chadox1 ncov-19 vaccine (azd1222) against sars-cov-2: an interim analysis of four randomised controlled trials in brazil, south africa, and the uk. lancet. 2021;397(10269):99–111. the joint united nations programme on hiv/aids (unaids). covid-19 vaccines and hiv [homepage on the internet]. 2021 [cited 2021 dec 12]. available from: https://www.unaids.org/en/resources/documents/2021/covid19-vaccines-and-hiv world health organization. coronavirus disease (covid-19): covid-19 vaccines and people living with hiv [homepage on the internet]. 2021 [cited 2021 dec 12]. available from: https://www.who.int/news-room/q-a-detail/coronavirus-disease-(covid-19)-covid-19-vaccines-and-people-living-with-hiv british hiv association. sars-cov-2 vaccine advice for adults living with hiv: british hiv association (bhiva) & terrence higgins trust (tht) guidance – plain english version [homepage on the internet]. 2021 [cited 2021 dec 12]. available from: https://www.bhiva.org/sars-cov-2-vaccine-advice-for-adults-living-with-hiv-plain-english-version-update al-metwali bz, al-jumaili aa, al-alag za, sorofman b. exploring the acceptance of covid-19 vaccine among healthcare workers and general population using health belief model. j eval clin pract. 2021;27(5):1112–1122. https://doi.org/10.1111/jep.13581 wehbe s, fahme sa, rizk a, mumtaz gr, dejong j, sibai am. covid-19 in the middle east and north africa region: an urgent call for reliable, disaggregated and openly shared data. bmj global health. 2021;6(2):e005175. https://doi.org/10.1136/bmjgh-2021-005175 dror aa, eisenbach n, taiber s, et al. vaccine hesitancy: the next challenge in the fight against covid-19. eur j epidemiol. 2020;35(8):775–779. https://doi.org/10.1007/s10654-020-00671-y graffigna g, palamenghi l, boccia s, barello s. relationship between citizens’ health engagement and intention to take the covid-19 vaccine in italy: a mediation analysis. vaccines. 2020;8(4):576. https://doi.org/10.3390/vaccines8040576 paterson p, meurice f, stanberry lr, glismann s, rosenthal sl, larson hj. vaccine hesitancy and healthcare providers. vaccine. 2016;34(52):6700–6706. https://doi.org/10.1016/j.vaccine.2016.10.042 maatouk i, assi m, hermez j. partner notification in the eastern mediterranean region: is there a way? east mediterr health j. 2019;25(9):660–661. https://doi.org/10.26719/emhj.19.076 ballouz t, gebara n, rizk n. hiv-related stigma among health-care workers in the mena region. lancet hiv. 2020;7(5):e311–e313. https://doi.org/10.1016/s2352-3018(19)30401-1 gökengin d, doroudi f, tohme j, collins b, madani n. hiv/aids: trends in the middle east and north africa region. int j infect dis. 2016;44:66–73. https://doi.org/10.1016/j.ijid.2015.11.008 lazarus jv, pericàs jm, picchio c, et al. we know daa’s work, so now what? simplifying models of care to enhance the hepatitis c cascade. j intern med. 2019;286(5):503–525. https://doi.org/10.1111/joim.12972 a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e to the editor: we refer to the article by parkhurst and whiteside in the april 2010 issue of the southern african journal of hiv medicine.1 the authors suggest that a limited period of population-wide sexual abstinence might be an effective and low-cost method of interrupting the transmission of hiv, particularly among individuals with acute hiv infection (ahi). evidence is mounting that a large proportion of hiv transmission may be attributed to individuals who are in the acute phase of hiv infection, best described as the time period during which hiv can be detected in blood serum and plasma but before the formation of antibodies, as measured by standard assays.2 the viral burden in blood and genital secretions is particularly high during this brief period, resulting in individuals with ahi being highly infectious.3,4 they are often unaware of their status or believe themselves to be hiv negative. we conducted formative research with individuals with ahi from october 2007 to june 2008 in lilongwe, malawi, and johannesburg, south africa. under the auspices of chavi (the center for hiv/aids vaccine immunology) the research aimed to gain a better understanding of the sexual risk behaviours of individuals with ahi at the time of infection and immediately thereafter to assist with recruitment of such individuals into a formative cohort (chavi 001) and begin investigation into potential interventions for this period of high infectivity. our sample included 37 individuals identified with ahi during this time period. during in-depth interviews participants were asked to comment on topics to include in a potential intervention for individuals with ahi and intervention delivery strategies. we explicitly asked about the feasibility and acceptability of two potential interventions to interrupt hiv transmission during the acute period: 100% condom use or abstinence for 3 months. more detailed information from this study on sexual behaviour at the time of infection and responses to proposed intervention activities is available elsewhere.5 in general, however, there was limited support for a period of enforced abstinence, given partner reluctance, the need to disclose to partners and, in south africa, a strongly expressed desire for children. individuals with ahi in malawi had more positive attitudes to abstinence than those in south africa, but believed that intensive counselling and support would be required. an intervention to reduce risk behaviours during ahi is currently being developed in lilongwe, malawi. the hptn 062 study is evaluating the acceptability and feasibility of an enhanced, individual-level counselling intervention for individuals in the acute and early phase of hiv infection. data collected will provide further understanding of the feasibility of abstaining during the acute period. results are expected in 2012. while a limited period of abstinence might theoretically be effective for limiting hiv transmission, the realities of implementation are likely to be challenging. support for such a strategy was limited in this population of individuals with known hiv infection, despite their ongoing participation and support in an observational study. there is likely to be even less support from individuals who do not know their status or who do not perceive themselves to be at risk of infection. c macphail wits institute for sexual and reproductive health, hiv and related diseases, johannesburg a pettifor gillings school of public health, university of north carolina, usa a corneli family health international niad center for hiv/aids vaccine immunology references 1. parkhurst jo, whiteside a. innovative responses for preventing hiv transmission: the protective value of population-wide interruptions of risk activity. southern african journal of hiv infection 2010;11(1):19-21. 2. pilcher cd, eron jj jr, galvin s, gay c, cohen ms. acute hiv revisited: new opportunities for treatment and prevention. j clin invest 2004;113(7):937-945. 3. pilcher cd, tien hc, eron jj, jr., vernazza pl, leu sy, stewart pw, et al. brief but efficient: acute hiv infection and the sexual transmission of hiv. j infect dis 2004;189(10):1785-1792. 4. pilcher c, shugars d, fiscus s, miller w, menezes p, giner j, et al. hiv in body fluids during primary hiv infection: implications for pathogenesis, treatment and public health. aids annals africa 2001;15(7):837-845. 5. pettifor a, macphail c, corneli a, et al. continued high risk sexual behavior following diagnosis with acute hiv infection in south africa and malawi: implications for prevention. aids behav 2010; oct 27, epub ahead of print. feasibility and acceptability of sexual abstinence for interruption of hiv transmission among individuals with acute hiv infection – formative data from chavi 011 l e t t e r research referred to in this correspondence was supported by the niad center for hiv/aids vaccine immunology grant ai067854. 46 abstract introduction case presentation management and outcome discussion conclusion acknowledgements references about the author(s) linda a. mandikiyana chirimuta newlands clinic, ruedi luethy foundation, harare, zimbabwe department of public health, environments and society, faculty of public health and policy, london school of hygiene and tropical medicine, harare, zimbabwe francis j. ndowa skin and genito-urinary medicine clinic, harare, zimbabwe margaret j. pascoe newlands clinic, ruedi luethy foundation, harare, zimbabwe citation mandikiyana chirimuta la, ndowa fj, pascoe mj. cutaneous squamous cell carcinoma in vertically acquired hiv and epidermodysplasia verruciformis. s afr j hiv med. 2022;23(1), a1368. https://doi.org/10.4102/sajhivmed.v23i1.1368 case report cutaneous squamous cell carcinoma in vertically acquired hiv and epidermodysplasia verruciformis linda a. mandikiyana chirimuta, francis j. ndowa, margaret j. pascoe received: 04 jan. 2022; accepted: 15 feb. 2022; published: 27 june 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract introduction: acquired epidermodysplasia verruciformis (ev) is a skin disorder that has been described in individuals with perinatally acquired hiv. many cases have been identified in sub-saharan africa in keeping with the epidemiology of hiv infection compared to the rest of the world, where cases are rare. epidermodysplasia verruciformis skin lesions may undergo malignant transformation. there are few documented cases of malignant transformation of these skin lesions. we describe a patient with an ev-like skin rash who developed cutaneous squamous cell carcinoma (scc). patient presentation: a 25-year-old man, on antiretroviral treatment for 12 years, presented with a generalised skin rash since the age of 11 years, and a 7-month history of a persistent scalp ulcer. he had no history of trauma, radiation or other chronic conditions. despite an undetectable hiv viral load, he had failed to immune reconstitute (cd4 42 cells/µl). physical examination revealed a generalised hypopigmented, papular skin rash resembling verruca plana and a 3 cm × 3 cm ulcer with rolled edges on the right parietal region of the scalp. there were no palpable lymph nodes in the head and neck areas. biopsy of the ulcer revealed moderately differentiated scc. management and outcome: wide local excision of the lesion was done under local anaesthesia and histological analysis confirmed completely excised moderately differentiated scc. further examination four weeks later revealed two, smaller, histologically similar scalp lesions which were completely excised. conclusion: patients with acquired ev require thorough, frequent examination for skin lesions with possible malignant transformation. early identification of malignant transformation and treatment with surgical intervention is curative. keywords: squamous cell carcinoma; hiv infection; epidermodysplasia verruciformis; verruca plana; human papillomavirus. introduction epidermodysplasia verruciformis (ev) is a rare genetic skin disorder, first described by lewandosky and lutz in 1992,1 and is characterised by disseminated dyschromic, squamous skin macules and flat warts, beginning in childhood and occurring predominantly in sun-exposed areas.1,2 epidermodysplasia verruciformis-like skin lesions have been described in individuals with perinatally acquired hiv and this acquired form of ev is similar, both clinically and histologically, to the autosomal recessive form.3,4 although the prevalence of hiv-associated ev-like skin lesions is unknown, lowe et al. found ev-like skin lesions in approximately one quarter of hospitalised adolescents in zimbabwe with perinatally acquired hiv, suggesting that this skin disease is not uncommon in high hiv prevalence settings.3 epidermodysplasia verruciformis skin lesions develop after specific ev-associated human papillomavirus (hpv) types, referred to as beta-hpv, infect individuals at a young age and persist due to genetic or acquired impairment of cell-mediated immunity.5,6 in hiv-infected individuals, ev-like skin lesions may be a feature of perinatally acquired hiv infection, rather than horizontally acquired infection.4 epidermodysplasia verruciformis is a pre-malignant condition and non-melanoma skin cancers develop in 30% – 50% of patients with ev.5,6 however, only a few cases of malignant change in hiv-associated ev-like skin lesions have been reported.7 we describe a patient with extensive ev-like skin lesions who developed multiple foci of cutaneous squamous cell carcinoma (scc) at 25 years of age. case presentation a 25-year-old man from zimbabwe, with vertically acquired hiv infection diagnosed at the age of 12 years, and commenced on antiretroviral treatment (art). he presented with a scalp ulcer for seven months which had started as a flat wart, became ulcerated and increased in size. there was no history of diabetes mellitus, radiation or trauma to the scalp, and, with the exception of a generalised, non-itchy skin rash for the past 14 years, he had no other chronic conditions. his baseline cd4 cell count and hiv viral load at the time of art commencement are unknown. he received zidovudine/lamivudine/nevirapine for ten years before developing virological treatment failure. he was subsequently switched to abacavir/lamivudine/atazanavir/ritonavir, which he was taking at the time of presentation. on physical examination he had an extensive hypopigmented, flat-topped, papular rash with the lesions varying from 1 mm to 15 mm in diameter, on his scalp, face, neck, trunk and limbs. the lesions resembled verruca plana (figure 1). an ulcerating lesion measuring approximately 3 cm × 3 cm in diameter, with rolled edges and an uneven base, was present on the right parietal region of the scalp (figure 2a). there were no palpable lymph nodes in the head and neck areas, and no oral or genital lesions. blood investigations revealed severe immune suppression (cd4 cells 42/µl) and an undetectable hiv viral load (< 50 copies/ml). figure 1: (a and b) physical examination revealed a generalised hypopigmented macular rash diagnosed as verruca plana. figure 2: (a) right parietal scalp ulcer; (b) left occipital lesion, following a wedge biopsy. management and outcome wide excision of the lesion was performed under local anaethesia, and histology revealed moderately differentiated scc with the margins reported to be free of tumour. repeat examination four weeks later revealed two further hyperpigmented plaque-like scalp lesions, one on the left occipital region, measuring approximately 1.5 cm × 1.5 cm (figure 2b), and a second on the frontal region, measuring 0.7 cm × 0.7 cm in diameter. excisional biopsies of these lesions were done and histology revealed completely excised moderately differented scc with underlying solar keratosis. discussion we present a patient with perinatally acquired hiv, and acquired ev, whose skin disease progressed while taking art, and who later developed multifocal scc. epidermodysplasia verruciformis occurs due to infection by oncogenic beta-hpv (including hpv types 3, 5, 8, 9, 10, 12, 14, 15, 17, 19, 25, 36, 38, 47 and 50) in patients with genetic or acquired impaired cell-mediated immunity.6 in the genetic form of ev, mutations of ever1 and ever2 genes, located on chromosome 17q25, cause down-regulation of cell-mediated immunity, reducing the cell’s ability to present beta-hpv antigens to t-lymphocytes.8 infection with hiv results in destruction of t-helper cells, causing impaired cell-mediated immunity. beta-hpv types found in inherited ev (mostly hpv types 5 and 8) have also been found in hiv-infected patients with acquired ev.3,7 a study in children with hiv infection and acquired ev found that 90% had at least one ev-related hpv type, and over 50% had more than one hpv type detected in skin biopsies.9 in addition to being infected with ev-related hpv types, children who have ev-like skin lesions have been found to be co-infected with other hpv strains, including high risk types.3 this means they may be at concurrent risk of other hpv-related cancers, particularly anogenital scc. the histology of acquired ev lesions is similar to that of inherited ev, with typical blue cells with pallor and mild acanthosis.3,10 the ev-like skin lesions in these patients can be recalcitrant to treatments for warts,9 are disfiguring and stigmatising, and pose a risk of progression to malignancy. studies have shown that art does not have a significant impact on skin disease progression.3,7 malignant transformation has been well documented in patients with inherited ev, but there is a paucity of data regarding malignant transformation in patients who have acquired ev. in 30% – 70% of cases of inherited ev, cutaneous skin cancers develop, and malignant transformation usually develops after 30 years of age.2,5,6,11 a case series of patients with inherited ev who developed skin cancers, found that six of the seven cases had cutaneous scc with multiple foci.2 this picture of multiple foci of carcinoma in our patient is similar to the description in this case report. ultraviolet (uv) radiation acts synergistically with beta-hpv, inducing carcinogenesis by direct damage of dna and immunomodulatory mechanisms. therefore, hpv-related skin cancers usually occur in sun-exposed areas.12 the patient in this case report resided in a rural area and was probably exposed to prolonged periods of uv radiation during the activities of his daily life. conclusion we recommend that hiv-infected patients with ev-like skin lesions should undergo regular, thorough physical examination to enable early detection of new lesions and malignant transformation. because of the risk of other hpv-related malignancies, these patients should undergo regular anogenital examination. complete surgical excision is curative if lesions are detected prior to metastatic spread. other preventive strategies include counselling patients on the avoidance of sun exposure, the use of sunscreens, regular self-examination and early reporting of skin changes or abnormal findings. acknowledgements the authors would like to thank the patient who gave his consent for us to use his case as a learning tool, prof. ruedi luethy for his mentorship and guidance, mr. simbarashe chinyowa and dr patience mba for their valuable input in the management of this patient, and, lastly, the ruedi luethy foundation for its support. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions l.a.m.c. was responsible for writing the original draft report and coming up with the methodology. f.j.n. was responsible for reviewing and editing the draft and providing expert opinion on how to manage the patient and recommendations in the report of how to manage the condition discussed. m.j.p. was responsible for reviewing and editing the draft report and conceptualising the idea of writing up this case report. ethical considerations written informed consent was obtained from the patient described in this case report. the patient gave his consent to have his clinical and demographic data used as well as his images. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and not an official position of any institution. references lewandowsky f, lutz w. ein fall einer bisher nicht beschriebenen hauter-krankung (epidermodysplasia verruciformis). archives of dermatology and syphilology (berlin) 1922;141:193–203. gul u, kilic a, gonul m, cakmak sk, bayis ss. clinical aspects of epidermodysplasia verruciformis and review of the literature. int j dermatol. 2007;46(10): 1069–1072. https://doi.org/10.1111/j.1365-4632.2006.03014.x lowe sm, katsidzira l, meys r, et al. acquired epidermodysplasia verruciformis due to multiple and unusual hpv infection among vertically infected, hiv-positive adolescents in zimbabwe. clin infect dis. 2012;54(10):119–213. https://doi.org/10.1093/cid/cis118 prose ns, mendez h, menikoff h, et al. pediatric human immunodeficiency virus and its cutaneous manifestations. pediatr dermatol. 1987;4:67–74. https://doi.org/10.1111/j.1525-1470.1987.tb00755.x majewski s, jablonska s. do epidermodysplasia verruciformis human papillomaviruses contribute to malignant and benign epidermal proliferations? arch dermatol. 2002;138(5):649–654. https://doi.org/10.1001/archderm.138.5.649 cruz silva ll, pereira de oliverira wp, sotto mn. epidermodysplasia verruciformis: revision of a model of carcinogenic disease. surg exp pathol. 2019;2(20):1–13. jacobelli s, laude h, carlotti a, et al. epidermodysplasia verruciformis in human immunodeficiency virus–infected patients: a marker of human papillomavirus-related disorders not affected by antiretroviral therapy. arch dermatol. 2011;147(5):590–596. https://doi.org/10.1001/archdermatol.2010.399 ramoz n, rueda la, bouadjar b, et al. mutations in two adjacent novel genes are associated with epidermodysplasia verruciformis. nat genet. 2002;32(4): 579–581. https://doi.org/10.1038/ng1044 moore rl, de schaetzen v, joseph m, et al. acquired epidermodysplasia verruciformis syndrome in hiv-infected pediatric patients: prospective treatment trial with topical glycolic acid and human papillomavirus genotype characterization. arch dermatol. 2012;148(1):128–130. https://doi.org/10.1001/archdermatol.2011.268 prose ns, von knebel-doeberitz c, miller s, milburn pb, heilman e. widespread flat warts associated with human papillomavirus type 5: a cutaneous manifestation of human immunodeficiency virus infection. j am acad dermatol. 1990;23(5):978–981. https://doi.org/10.1016/0190-9622(90)70318-c jablonska s, majewski s. epidermodysplasia verrucilormis: immunological and clinical aspects. in: zur hausen h, editor. current topics in microbiology and immunology. berlin: springer, 1994, vol. 186; p. 157–175. de villiers e-m. human papillomavirus infections in skin cancers. biomed pharmacother. 1998;52(1):26–33. https://doi.org/10.1016/s0753-3322(97)86238-5 pg32.html book review written by two dermatologists from the university of kwazulu-natal’s nelson r mandela school of medicine, the much-needed 2nd edition of the atlas of skin conditions in hiv/aids is now available. immunocompromise in hiv cases results in a large variety of skin findings that significantly differ in quality and extent from those in immunocompetent people. acknowledging the fact that dermatological problems are often a challenge to clinicians, this is an important area demanding an easy-to-use atlas to identify the most common diseases. as hiv treatment increasingly becomes a condition to be treated at a general primary health care level, this becomes even more pertinent. to meet the needs of the clinician, the atlas is put together in a way that makes it a pleasure to use quick reference for clinical findings. the book’s chapters are structured by type of skin eruption rather than nosological disease entity, which adds to the ease with which a specific clinical presentation can be found. these groups of skin conditions are ‘blisters’, ‘papulosquamous conditions’, papules and nodules’, ‘ulcers’, ‘nails’, ‘oral lesions’, ‘miscellaneous’ and ‘antiretroviral therapy’. only the chapter on ‘antiretroviral therapy’ attempts a more systemic approach, based on the causation rather than the clinical presentation, when it lists a range of conditions that might erupt under antiretroviral treatment. these conditions are presented in the two sections ‘immune reconstitution inflammatory syndrome’ (iris) and ‘cutaneous manifestations of antiretroviral drugs’. for each condition, on the left page there are high-quality colour pictures displaying the skin condition. this is complemented by a brief description of the condition and its treatment on the opposite page. this includes a hands-on treatment recommendation with standard dosages and durations for the treatment and explicitly including both edl (essential drugs list for primary health care) and non-edl items. with its user-friendly structure, this atlas is a valuable addition to the standard reference in a consultation room in public sector facilities. it is comprehensive enough to include the more common conditions, while at the same time concise enough to serve as a quick reference during or in between consultations. on the wish-list for future editions would be an update of the primary health care edl reference, as the book refers to the 1998 edition of this list. having been published before the new antiretroviral treatment guidelines came into effect in 2010, a future edition should possibly also present clinical examples of the skin presentation of the abacavir hypersensitivity syndrome (which is only mentioned in the text), as this drug is now part of the paediatric first-line regimen and skin eruptions following the initiation of this drug are a major point of concern. similarly, tenofovir, which is now part of the adult first-line regimen, is not mentioned in the book but would probably have shown its dermatological side-effects (if any) by the time the next edition appears. dirk hagemeister paarl a clinical atlas of skin conditions in hiv/aids: an illustrated management guide for health care professionals. by ncoza dlova and anisa mosam. 2nd ed. pretoria: hpmg, 2009. pp. 100. isbn 1-875098-40-2. s e p t e m b e r 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e strategies for improving patient behaviour and enhancing drug adherence exist but are often complex, requiring much one-to-one patient counselling, and they are often implemented too late, once poor habits have already been established. more value may therefore lie in thorough preparation of patients before commencing art, rather than adherence interventions once patients are already on treatment. this is not only because consistent and efficacious drug therapy is life saving, but also because drug-resistant strains of hiv emerge in the presence of sub-therapeutic dosing due to sub-optimal adherence.2,3 the concept of ‘prevention is better than cure’ may therefore be applicable to the problem of non-adherence among patients on art even more than in the management of chronic noninfectious diseases in which drug resistance is not an issue of concern. we therefore undertook an analysis of results from the adherence monitoring in our hiv care and treatment programme to evaluate whether a change in the focus of conventional hiv treatment strategies would be effective in preventing non-adherence. background information on the hiv care and treatment programme our programme, launched in 2003, is situated in cato manor, a ward of the ethekwini (durban) metro in kwazulu-natal, south africa, which encompasses both low-cost housing and informal settlements and is notably an area of low income, with many households and families having no formal income generation. at the end of november 2008 we had 1 238 patients enrolled in hiv care, with 499 of them on art (436 adults and 63 children). the programme provides a patient-centred, rights-based, holistic approach to improving and maintaining the wellbeing of hivpositive mothers, any of their infected family members, and uninfected infants less than 1 year of age. mothers are generally the primary caregivers in a cato manor household, so improvement and maintenance of their health, despite hiv infection, benefits the entire family, as they remain productive and fully functional as caregivers and/or breadwinners. the programme views hiv as a communicable but manageable chronic disease that affects the whole family unit. with a view to keeping family units strong, hiv-positive household members of existing programme participants are eligible for enrolment into hiv care and treatment. while the approach is to maintain good health before art is indicated, once eligibility for art is established patients are prepared, both medically and psychologically, for commencement of treatment according to world health organization (who) guidelines for the treatment of hiv infection. medical preparation involves patient examination, evaluation of patient history, exclusion of current tuberculosis prevention is better than cure – the art of avoiding non-adherence to antiretroviral treatment o r i g i n a l a r t i c l e leith kwaan, msc (pharmacy) gurpreet kindra, mb bs lulama mdutyana anna coutsoudis, bsc (hons), phd department of paediatrics and child health, nelson r mandela school of medicine, university of kwazulu-natal, durban the much-used phrase ‘prevention is better than cure’ is applicable to many circumstances, including human immunodeficiency virus (hiv) infection. in recent years suggestions have been made for a move towards treatment strategies that emphasise prevention of foreseeable adherence problems on a patient-by-patient basis, through focused patient preparation before commencing antiretroviral therapy (art). this is well elucidated in a statement made in 2004 by coetzee et al.:1 ‘as it is difficult to ascertain robust predictors of adherence, there has been a move to concentrate on patient preparation before the initiation of art rather than the use of nonclinical predictors of adherence or selection criteria. a paradigm focused on preparation rather than selection is better suited to the aggressive targets for the scaling up of art in countries with large epidemics (such as in south africa), where the view of art as a very expensive rationed intervention is rapidly changing.’ 8 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s e p t e m b e r 2 0 1 0 (tb) infection, a full blood count, and kidney and liver function tests. psychological readiness is assessed by trained hiv counsellors, who conduct drug readiness training before commencement of treatment. drug readiness training is run over 3 weeks in small-group sessions and includes modules on positive living with hiv infection, preparation for appropriate administration of medicine and adherence to treatment regimens. methods monitoring adherence adherence to treatment in adults receiving art was monitored by pill count at scheduled clinic visits, and expressed as the percentage of the prescribed doses that had actually been taken since the previous visit. data collected over a 1-year period (december 2007 november 2008) were analysed monthly, as well as retrospectively at the end of the observation period. at each visit patients were questioned as to whether they were having problems with adherence. problems with adherence that were identified for specific patients during the course of the year were dealt with at the time by implementing one-to-one adherence counselling, education regarding medication, and the use of any other appropriate aids for helping patients to adhere to treatment. results general patient details at the end of the observation period (end november 2008) there were 499 patients on art (436 adults and 63 children). of the adult group, 77 (17.7%) were male and 359 (82.3%) were female, and the mean age was 31.1 years (range 16 62 years). patients had been on treatment in this programme for a mean of 21.2 months (range 1 69 months). twenty-one of the adults on art were transferred into the programme already on treatment, and had a mean cd4 cell count of 406.3 cells/µl on entry to the programme. the 415 treatment-naïve adults who were initiated on art in our programme had a mean cd4 count of 141.5 cells/µl at initiation (range 0 675 cells/µl). while paediatric adherence monitoring was done at each visit, only results for the adult cohort were included in this analysis, as the number of children in the programme was comparatively small. adherence to treatment analysis of pill count data showed that the mean adherence for every month throughout the year was above 94% and the mean adherence for the patient cohort over the entire observational period was 96.4% (standard deviation (sd) 6.7%), with 90% of patients achieving adherence of 90% or more and 78.5% achieving adherence of 95% or more. treatment failures and mortality during this study (since 2003) 593 patients have been started on art and there have been 6 treatment failures (1%), necessitating switching of patients to second-line regimens. thirty-nine patients on art have died while enrolled in the programme. two deaths were due to injuries unrelated to art and were therefore excluded from the deaths for the purposes of this analysis. thirtyseven deaths were due to opportunistic infections or other hiv-related diseases. none of the patients who died had suffered a known virological treatment failure before death and any changes to the regimen were of single drugs, due to pregnancy, drug toxicity or contraindications. more than half of the deaths occurred within the first 3 months of starting treatment (51%) and 73% within the first year, suggesting that a prominent factor contributing to death was late presentation at the clinic with advanced disease. effects of adherence interventions and monitoring mean adherence values for the patient cohort increased throughout the observation period, with the lowest mean adherence (94.2%) reported in the 2nd month of adherence data collection, and the highest (97.4%) in the 11th month. additionally, the percentage of patients on art who returned their unused medicine at clinic visits increased each month during the observation period, as patients became more aware of the importance of returning medicine at each visit. discussion it is considered that a 95% adherence rate is required for sustained viral suppression in patients taking protease inhibitor (pi)-based regimens.4,5 the mean adherence reported here indicates that medication-taking behaviour for currently used antiretroviral drug regimens was acceptable. our programme compares favourably with other studies that report mean adherence measured by medicine returns. a recent south african study in children reported 79% of patients achieving adherence of 90% or more, measured by pill count,6 and data from a botswana study in adults suggested this figure to be 74.4%,7 compared with 90% for patients in this programme. a 2003 south african study of hiv-positive adults reported that 63% of patients were 90% adherent or better, while the mean adherence for the patient cohort was 87.2%.8 considering the percentage of patients achieving 95% adherence or more, a large public sector antiretroviral treatment programme in zambia reported 62.9% of patients with such adherence,9 more than 15% lower than the 78.5% of patients in our programme cohort. two studies on hiv-positive adults in kenya and uganda reported similar adherence rates to those achieved in our programme, with 86.1% of patients in standard care achieving 95% adherence or more in the kenyan 9 s e p t e m b e r 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e cohort10 and 87 94% (measured at different time points) achieving 95% adherence in the uganda study.11 both these studies used medicine returns as well as selfreport methods of monitoring adherence. the favourable adherence values measured over the observation period are evidenced by the low number of treatment failures of first-line art regimens, and therefore only very few patients being switched to second-line treatment strategies (6 out of 593 patients). adherence has been shown to have a direct impact on virological suppression4,7 and therefore on treatment success, and this is reflected in the positive patient outcomes seen in this programme. we observed an increase in mean adherence values for the patient cohort throughout the observation period. this improvement in mean adherence correlated with patients’ compliance with instructions regarding clinic visits and tablet returns. the mere practice of requesting that unused tablets be returned, and the consistent questioning by pharmacy staff concerning such unused tablets if they are not returned, raised adherence as a point of discussion with patients, resulting in improved patient interaction and better understanding regarding the importance of adherence. the pharmacy staff were given opportunities to discuss specific issues affecting adherence that patients reported when questioned regarding their unused medicine. during the collection of data for adherence measurement, other social and psychological issues surrounding the issue of adherence were identified. our data showed that adherence behaviour of patients who returned unused medicine 50% of the time or more (i.e. 6 out of 12 months or more) was better than for those patients who only returned medication at less than 6 visits. although the difference between the mean adherence for these two groups of patients is not statistically significant, the data may provide a useful tool for highlighting potential adherence problems, as well as a possible area of further research. pharmacy refill adherence (measured as the percentage of expected pharmacy visits filled) has been shown to predict viral load suppression.12 the extended time patients spend in the programme before starting lifelong treatment provides an opportunity for them to observe other patients who are starting treatment, and those who are thriving on art, which reinforces the trust that is built up over several clinic visits and repeated interactions with programme staff. while still physically well, patients have time to work with counsellors towards accepting their hiv status and adapting their lifestyle to accommodate necessary routines, tasks and habits that will enhance their health, including disclosing their hiv status to family and/or household members. it is during this time that they become practically and emotionally prepared for starting treatment over the long term. time to accept their hiv status is important for achieving preparedness for starting art, and for maintaining good adherence over the long term. this approach to treatment would be applicable to large-scale implementation in arv roll-out programmes in resource-poor settings because the staff required to implement the preparative interventions in this programme are at the lay counsellor level. expansion of the lay counsellor quota of a multidisciplinary team will add less of a financial burden on programme resources than would an increase in clinical staff. additionally, the employment and training of such lay people provides employment and empowerment to people who live in the community that the programme serves. employing local residents as lay counsellors enhances knowledge of the community, as well as access into the community and surrounding area, which helps in dealing with difficult patient and family situations through home visits and identification of patients who would otherwise be considered lost to follow-up. on the basis of our results we conclude that preventing non-adherence is a better treatment approach than strategies in which the primary focus is on identifying and rectifying non-adherence once it has been established. we therefore recommend that hiv care and treatment facilities include such preparative approaches for promoting adherence into their treatment programmes. references 1. coetzee d, boulle a, hildebrand k, asselman v, van cutsem g, goemaere e. promoting adherence to antiretroviral therapy: the experience from a primary care setting in khayelitsha, south africa. aids 2004; 18: s27-s31. 2. bangsberg dr, moss ar, deeks sg. paradoxes of adherence and drug resistance to hiv antiretroviral therapy. j antimicrob chemother 2004; 53: 696-699. http:// jac.oxfordjournals.org/cgi/reprint/53/5/696 (accessed 15 june 2010). 3. sethi ak, celentano dd, gange sj, moore rd, gallant je. association between adherence to antiretroviral therapy and human immunodeficiency virus drug resistance. clin infect dis 2003; 37: 1112-1118. 4. maggiolo f, ravasio l, ripamonti d, et al. similar adherence rates favor different virologic outcomes for patients treated with nonnucleoside analogues or protease inhibitors. clin infect dis 2005; 40: 158-163. 5. chen lf, hoy j, lewin sr. ten years of highly active antiretroviral therapy for hiv infection. med j aust 2007; 186: 146-151. http://www.mja.com.au/public/ issues/186_03_050207/che10490_fm.pdf (accessed 15 june 2010). 6. davies ma, boulle a, fakir t, nuttall j, eley b. adherence to antiretroviral therapy in young children in cape town, south africa, measured by medication return and care-giver self report: a prospective cohort study. bmc paediatr 2008; 8: 34. http://www.biomedcentral.com/content/pdf/1471-2431-8-34.pdf (accessed 15 june 2010). 7. bisson gp, rowh a, weinstein r, gaolathe t, frank i, gross r. antiretroviral failure despite high levels of adherence: discordant adherence-response relationship in botswana. j acquir immune defic syndr 2008; 49: 107-110. 8. orrell c, bangsberg dr, badri m, wood r. adherence is not a barrier to successful antiretroviral therapy in south africa. aids 2003; 17: 1369-1375. 9. chi bh, cantrell ra, zulu i, et al. adherence to first-line antiretroviral therapy affects non-virologic outcomes among patients on treatment for more than 12 months in lusaka, zambia. int j epidemiol 2009; 38(3): 746-756. http://ije. oxfordjournals.org/cgi/reprint/38/3/746 (accessed 15 june 2010). 10. sarna a, luchters s, geibel s, et al. shortand long-term efficacy of modified directly observed antiretroviral treatment in mombasa, kenya: a randomized trial. j acquir immune defic syndr 2008; 48: 611-619. 11. muyingo sk, walker as, reid a, et al. patterns of individual and population-level adherence to antiretroviral therapy and risk factors for poor adherence in the first year of the dart trial in uganda and zimbabwe. j acquir immune defic syndr 2008; 48: 468-475. 12. nachega jb, hislop m, dowdy dw, chaisson re, regensberg l, maartens g. adherence to nonnucleoside reverse transcriptase inhibitor-based hiv therapy and virologic outcomes. ann intern med 2007; 146: 564-573. http://www. annals.org/cgi/reprint/146/8/564.pdf (accessed 15 june 2010). 10 5 no, i am not on sabbatical on a tropical island! however, it has been a great pleasure to have the journal guest-edited again for the last edition of 2009 by a superb duo: leon levin and mark cotton. mark cotton is a specialist in paediatric infectious diseases at tygerberg children’s hospital and head of its paediatric infectious diseases unit, affectionately known as kidcru. his main focus is to extend and enhance care through research, with a special interest in children affected by hiv. mark has been involved in some key studies that have shaped paediatric practices and guidelines in southern africa. he also serves as advisor and investigator to a number of international institutions and networks. dr leon j levin graduated mb bch at the university of the witwatersrand in 1987. after training in paediatrics at the wits group of hospitals in johannesburg, he obtained his fcpaed (sa) in 1994. in february 1996 he founded the paediatric hiv clinic at johannesburg hospital, and more recently he has run the paediatric division of right to care. leon has been chairman of the paediatric subcommittee of the sa hiv clinicians society since 1999 and runs the society´s paediatric discussion group, an internet-based forum for paediatricians to discuss and learn about problems in children with hiv. in this edition, besides a fabulous array of paediatric material, we publish the updated paediatric guidelines. with so much positive energy around better hiv support recently, from the highest level, we are confident that we can do better, especially in the important area of paediatric aids. we will kick 2010 off with our usual diverse submitted copy, so please keep sending. review processes will also be improved. we hope it will be a bumper year in many ways, with record numbers of people starting and staying on art, a decreasing incidence of hiv, and millions of south africans testing. we also hope to have four bumper editions of the southern african journal of hiv medicine in 2010, which is set to be a memorable year for south africa. linda-gail bekker editor f r o m  t h e  e di torf r o m t h e e di tor the journal is starting to feel like men’s health, what with posters, guidelines and now a state-of-the art science update, hiv treatment bulletin, falling out of it. exco is pleased to announce an important and strategic partnership with hiv ibase, who publish hiv treatment bulletin. we are distributing the southern african version of their excellent newsletter, which will exclusively focus on the scientific reports and resources that have local relevance – with a strong focus on paediatrics and maternal health. hiv treatment bulletin neatly complements the journal, providing the snobbish clinician and scientist with the most hot-off-the-press analysis of recent clinical trials and basic science research. policy makers can authoritatively pronounce at their guidelines meetings, clinicians can expand their patients’ options, and, most importantly, you can show off at ward rounds. thanks to all the people at i-base, this is a major step forward for quality information sharing. we wish the new health minister, barbara hogan, all the best. she has very small shoes to fill, but a mammoth task ahead of her to repair south africa’s woeful health service. at the time of writing, she and her deputy, dr molefi sefularo, have been very impressive, dealing with a cholera disaster, drug stock-outs, issues of prevention, releasing controversial reports that were stuck on her predecessor’s desk for months, and a dozen other complex health problems. finally, the exco welcomes two new members based in durban, professor yunus moosa and dr henry sunpath, both highly respected clinicians and part of the team responsible for an excellent hiv clinical conference held in october. francois venter president this spring edition brings 2008 to a close. and what a year it has been. not many breakthroughs in hiv or tb, but a lot of activity in terms of understanding early infection better, really getting to grips with early immune responses, and again thinking through our prevention options. in 2008 the concept of antiretrovirals for prevention as well as treatment has come to the fore with second-generation microbicides, pre-exposure prophylaxis and the notion that we may be able to ‘treat our way out of the epidemic’ becoming possibilities. gratifyingly, this year also saw a record number of people being tested and accessing art, and roll-out for both testing and treatment is truly scaling up. as chairperson of the 4th southern african hiv conference i must encourage every one of you to think seriously about coming to durban on 31 march. it promises to be a critical conference where we will really formulate the key steps in getting pmtct, treatment, testing and prevention out there on a scale that will begin to turn the sa statistics around. (i promise that it will also be loads of fun!) please note the early date this year: 31 march to 3 april. this is to ensure brilliant kzn weather! in this edition, we already begin to examine some of these key scale-up questions: jerome singh explores the ethics and legality of traditional healers performing hiv testing (i know many have asked why this has to be the domain of nurses only). francesca esposito and her team examine changes in body composition in women taking antivirals in a kzn clinic. we look at the role of mobile phones in the hiv response with william mapham, and polly clayden gives us pointers to starting infants on art. the role of a liver biopsy in diagnosis of opportunistic infections is described by mark sonderup and colleagues. the vexed question of when it is deemed safe to start haart in patients co-infected with tb is discussed by robin wood, and francois venter and colleagues give a practical view on new antiretrovirals on the horizon for south african practitioners. no guidelines in this issue, but i will whet your appetites – look out for guidelines on prevention of tb occupational exposure for hiv-infected health care workers and on the non-infertile hiv infected couple, hot stuff coming up in the new year! happy reading and every best wish for a restful and peaceful festive season from the whole editorial team. see you next year! linda-gail bekker editor m e s s a g e f r o m t h e e x e c u t i v e msg from the executive.indd 5 12/17/08 3:16:23 pm treating hiv-infected children this edition sees the publication of the fourth sa hiv clinicians society paediatric antiretroviral therapy (art) guidelines. previously it has not been possible to have one guideline for the whole country because of wide discordance between the government and private sectors. this year, for the first time, our guideline is applicable to both the private and public sectors. inevitably some differences remain and are addressed in the document. they include choice of first-line regimen and genotyping recommendations. the national department of health (ndoh) is still updating its guidelines, hopefully for publication in early 2010. we hope you will find the society’s guidelines pragmatic and helpful. we have the potential to save and improve many young lives. we thank all those involved in the writing of the guidelines, especially our fellow member of the writing committee, dr tammy meyers, and our overseas reviewers. as has been done previously when paediatric guidelines have appeared, the entire issue is devoted to paediatrics. we hope it will be useful as a ready reference on paediatric hiv management for all health care workers caring for children. e di tor i a l the southern african journal of hiv medicine                                                      december  2009 m e s s a g e   f r o m    t h e   e x e c u t i v e the global recession has thrown the problem of funding for aids programmes to the fore, with botswana’s president saying his country’s programme is unsustainable, and donors sounding warnings that rationing may need to be implemented. this is very alarming – we have made big strides in terms of antiretroviral access in the last few years, and these are suddenly looking very fragile. it is time to take stock of our programmes and make them as lean and mean as possible, ensuring maximum access to care while ensuring acceptable levels of quality. we need to look critically at the labs we ask for and the drugs we need, while keeping up pressure on the donor community to maintain support. however, we should not let our governments off the hook. health in southern africa has been consistently underfunded as a function of the gross domestic product, in almost every one of our countries. guns, presidential inaugurations and motorcades never seem to be a problem to fund, and we need to do a better job at the southern african journal of hiv medicine                                                      december  20096 we begin with an opinion piece by heather jaspan, rachel li, leigh johnson and linda-gail bekker on the urgent need to develop skills and infrastructure to meet the needs of hiv-infected adolescents, especially given our success in treating children with art. we then address prevention of vertical transmission of hiv, the key to the elimination of hiv infection in children. the paper by laurie schowalter, ashraf coovadia and ameena goga is a plea for action. it is followed by an analysis of vertical transmission data (mark cotton, soyeon kim, helena rabie, joan coetzee and sharon nachman, from the pactg 1041 team), emphasising again the importance of a good antenatal antiretroviral component. infant feeding is integral to child survival and development. there are risks and benefits for breast and replacement feeding. the paper by ameena goga is essential reading for anyone caring for infants and provides the key data to inform rational decision making. the guideline document emphasises the importance of and pitfalls in maintaining adherence. a number of articles provide background information to help in understanding the rationale of recommendations in the guidelines. these include articles on when to start (mark cotton, helena rabie, ute feucht and avy violari), essential pharmacokinetic information (helen mcilleron and hermien gous) and how the weight-based dosage recommendations were derived (james nuttall). what do you do when children starting art deteriorate instead of improve? helena rabie, tammy meyers and mark cotton delve into the paradoxical world of immune reconstitution inflammatory syndrome (iris). we then highlight two adverse events of art, one common and the other rare. the ndoh guidelines do not advocate using abacavir (abc) in the first-line regimen in the absence of adverse effects from other drugs. they still recommend d4t, increasingly implicated in lipodystrophy. lipodystrophy can be reversible if the offending agent (usually d4t) is replaced with abc (or tenofovir in adults) in the early stages. steve innes, leon levin and mark cotton provide background information and useful diagnostic and management advice for lipodystrophy. the sa clinicians society advocates 3tc and abc as the nrti backbone for the first-line regimen. there is much fear of the infamous abc hypersensitivity reaction (hsr). to the best of our knowledge, no one has ever died from the reaction, but people have died from abc rechallenge. fortunately the hsr is rare in black africans. helena rabie, kristin henning, pierre schoeman, nico de villiers, gert h j (oubaas) pretorius and mark cotton provide guidelines for using abc and recount their experience with suspected abc hsr. treatment failure is becoming increasingly complex. fortunately, there are quite a few new antiretrovirals registered overseas and about to be registered in south africa. leon levin takes us through the minefield of paediatric salvage therapy. finally, polly clayden presents us with some cuttingedge reports from the recent international aids society conference in cape town, again informing readers of the type of research needed to continually improve our guidelines. mark cotton leon levin guest editors drawing attention to how health budgets are allocated. in south africa it seems that jacob zuma’s government has declared war on overall wasteful expenditure, and at the same time there has been increasing embarrassing public exposure of ministerial spending on large cars. a new and energetic health minister, aaron motsoaledi, seems intent on reversing the terrible sins of the past under mbeki’s regimen, and to be determined that health resources get used better. please let the society know if you see any indication of rationing! we have active advocacy work, with good partners, and it is to be hoped that we can stop unnecessary restrictions on health care. francois venter president southern african hiv clinicians  society paediatric discussion  group (pdg) the southern african hiv clinicians society paediatric discussion group (pdg) began in december 2001. the concept was born after dr (now adjunct professor) ashraf coovadia of the rahima moosa mother and child hospital, coronationville, johannesburg, sent an e-mail to 5 or 6 local hiv ‘experts’ and professor mark kline of the baylor college of medicine, houston, texas, seeking advice on how to manage a child with severe disfiguring parotomegaly but who had a normal cd4 count, so antiretroviral therapy (art) was not indicated. the answer came back that there was no indication for art for a purely cosmetic condition! i found the concept fascinating and wondered if there was any value in using e-mails as a vehicle for educating health care providers about paediatric hiv. i contacted the south african hiv clinicians society, who were happy with the concept and provided me with a list of their members. the list in those days was very short (unlike today), and i tried to fathom out who was a paediatrician or treated paediatric cases and added them to the mailing list. the first few cases hardly garnered a response. i suspect people were too shy to answer. after a few weeks i would send out an expert opinion. the cases were all real cases (mostly from my own practice), and all had excellent lessons to teach. gradually, as knowledge and familiarity with pdg grew, so the number of responses increased. currently it’s not unusual to have over 100 responses to a case. the cases have spanned the whole range of paediatric hiv issues including opportunistic infections, side-effects of art and ethical issues. at the moment we are concluding pdg no. 51. some notable cases include: n one of the earliest cases in south africa of cushing’s syndrome caused by an interaction between ritonavir and inhaled fluticasone for asthma. n a child from a neighbouring country who was diagnosed as hiv-positive on two different tests and turned out to be hiv negative. n an hiv-positive child with marked failure to thrive and a normal cd4 count who turned out to have an oesophageal stricture and is now thriving after oesophageal dilatation. n cases of lymphoma and kaposi’s sarcoma. n a case where a mother with end-stage hiv had a negative hiv elisa test, having lost the ability to make antibodies due to her poor immunity. n a case of a young infant treated with art very early on who became hiv elisa negative after losing her maternal antibodies. she did, however, remain pcr positive. n interestingly, pdg no. 47 in april 2008 again discussed a patient with disfiguring parotomegaly and a normal cd4 count. this time the opinion was overwhelmingly in favour of starting art. the response to the pdg has been phenomenal. the mailing list currently stands close to 1 500. subscribers are predominantly from south africa but also include namibia, zimbabwe, botswana, zambia, angola, malawi, kenya, rwanda and other countries. subscribers are predominantly doctors but also include nurses, pharmacists, and counsellors. there is no doubt that the pdg has succeeded because of the very active participation of our subscribers and our wonderful panel of local and overseas experts, all of whom deserve my heartfelt thanks. i have merely been the conduit between the two. if you would like to subscribe to the pdg, please send an e-mail to leonlevin@54.co.za. i am also constantly on the lookout for new cases to discuss. they can be sent to the same e-mail address. leon levin head, paediatric programmes right to care m e s s a g e   f r o m   t h e   pa e di at r ic    s u b c o m m i t t e e the southern african journal of hiv medicine                                                      december  20098 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 1 hepatitis b virus infection is a global health problem with an estimated 350 million people chronically infected.1 routes of transmission differ between geographical regions, with acquisition in developed-world settings characteristically occurring in adulthood, predominantly in high-risk groups through parenteral or sexual exposure. in contrast, perinatal or horizontal transmission during childhood is the norm in most sub-saharan african regions that do not routinely vaccinate children in the first year of life. age at hbv infection determines the risk of chronicity of disease, with the highest rates developing in perinatally acquired hbv from mothers who are hbeag positive (90%). in contrast, 25 30% of children infected with hbv develop chronic infection, whereas this figure drops to <5% in adults.25 chronic hbv is endemic in sub-saharan africa, where hbsag prevalence varies between 0.3% and 15%6 and rates of exposure as determined by hbcigg are between 5% and 80% depending on socio-economic groups and geographical location.7 hiv infection adversely affects the course of hbv in co-infected patients (table i). few studies of hiv-hbv co-infection rates have been conducted in southern africa and no community-based data are available. however, two studies from urban clinics in johannesburg documented hbsag positivity rates in hiv patients of 5%8 and 4.8%,9 with a higher rate of 17% reported from an industrial clinic setting.10 this guideline is intended to update and expand on those included in the ‘antiretroviral therapy in adults’ guideline published in the southern african journal of hiv medicine of january 2008 (vol. 9, no. 1 (summer issue), pp. 18-31). the exclusion of hbsag screening at entry into the art treatment programme adopted by the national department of health (ndoh) in 201011 is at odds with the guidelines that we present in this document. it is the belief of the authors that further discussion with the ndoh is needed to reconcile the programmatic approach to hiv-hbv management with the recognition that hbv-related liver disease in hivinfected patients may be prevented by early screening and treatment, thereby positively affecting quality of life, morbidity and mortality. 1. screening for hepatitis b infection in hiv-infected patients the current southern african hiv clinicians society guideline on screening for hbv in hiv-infected patients indicates that all patients should be tested for hbv using blood hbsag as the marker of infection, although no direction is given as to when screening should take place. the consensus from international guidelines is that screening should be undertaken at the time of diagnosis of hiv to allow for early decisions on specific treatments for hbv and hiv, as well as vaccination of hbv-uninfected individuals.12-15 these guidelines were produced to direct management in developed, resourcerich nations with higher rates of hbv acquisition in adulthood. in southern africa, hbv is predominantly acquired between the age of 6 months and 5 years. management of hiv-hepatitis b co-infection southern african hiv clinicians society hiv-hepatitis b virus (hbv) co-infected patients are at risk of increased morbidity and mortality. early recognition of dual infection is a critical factor in directing appropriate therapy, and hbv screening should therefore be undertaken at the time of hiv diagnosis. vaccination against hbv should be considered for all hiv patients who are not yet infected with hbv. antiretroviral therapy containing two antiretrovirals active against hbv should be started if the patient either has symptomatic liver disease or is asymptomatic with a cd4 count of <350 cells/µl. g u i d e l i n e definition of terms chronic hepatitis b: persistence of hepatitis b surface antigen positivity for >6 months. there may be evidence of necro-inflammatory change on histological examination of the liver. alanine transaminase and the hbv dna level in blood may fluctuate over time. occult hepatitis b: hbsag negative but hepatitis b core igg antibody positive, with low-level hbv dna in blood, usually <200 iu/ml. hepatitis b viral flare: an intermittent elevation of aminotransferase activity, often to >10 times the upper limit of normal, or a change of more than twice the baseline value. convenor: marc mendelson expert committee (alphabetical order): michael kew, gary maartens, adam mahomed, james nuttall, regina osih, mark sonderup, wendy spearman, jantjie taljaard, gert van zyl 27 a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e • higher rates of chronicity after acute hbv infection • decreased rates of spontaneous hbsag and hbeag seroconversion • increased rates of hbv dna replication • more severe liver disease, with increased rates of cirrhosis and hepatocellular carcinoma • increased rates of liver-related mortality • increased rates of occult hbv infection • increased rate of reactivation and seroreversion with decreasing cd4 counts • increase risk of hbv flare after starting haart due to hbv-immune reconstitution inflammatory syndrome (hbv-iris) table i. influence of hiv on the course of hepatitis b virus infection key summary points • to reduce the burden of hepatitis b virus (hbv) infection in sub-saharan africa; countries within the region that have not already instigated a programme of hbv vaccination in children should be encouraged to incorporate the vaccine as part of their extended programme of immunisation (epi). • hiv-infected patients should be screened for hbv infection using the hepatitis b surface antigen (hbsag) test at the time of hiv diagnosis. • hiv-hbv co-infected patients should have a cd4 t-cell count performed after diagnosis. if the cd4 count is <350 cells/µl, the patient should be entered into the highly active antiretroviral therapy (haart) programme. haart must include two agents with anti-hbv activity, namely tenofovir plus lamivudine or emtricitabine, in addition to a non-nucleoside reverse transcriptase inhibitor or protease inhibitor (pi). • owing to the propensity of nevirapine to cause hepatitis, its use should be avoided in hiv-hbv coinfected patients whenever possible. • to prevent hbv ‘flares’, co-infected patients taking tenofovir plus lamivudine or emtricitabine who require a change in antiretroviral regimen should continue tenofovir plus lamivudine or emtricitabine in addition to the new antiretrovirals, unless severe adverse effects from these drugs preclude their use. • co-infected patients whose cd4 count is ≥350 cells/ µl should be assessed for symptomatic liver disease and have the secretory protein hepatitis b envelope antigen (hbeag) and alanine transaminase (alt) tested. if hbeag is positive, and/or alt is more than twice the upper limit of normal, the patient should be referred for tenofovir plus lamivudine or emtricitabinebased antiretroviral therapy (art), as above. similarly, any co-infected patient with symptomatic liver disease or chronic liver disease should be referred for art, irrespective of the cd4 count. • co-infected patients whose cd4 count is ≥350 cells/ µl but who test hbeag negative and whose alt level is less than twice the upper limit of normal should have their alt re-checked every 6 months, or before if clinical events dictate. if alt increases to more than twice the upper limit of normal, the patient should be referred for tenofovir plus lamivudine or emtricitabinebased art. • co-infected children should be referred to/ discussed with a specialist paediatrician for further management. • hiv-infected patients who are hbsag negative on screening, but are at high risk of acquiring hbv infection, should be tested for the presence of hepatitis b core igg antibody (hbcigg) and if negative, should be offered vaccination against hbv. • vaccination should not be attempted in patients with cd4 counts <200 cells/µl as protective efficacy is poor. rather, withhold vaccination until immune reconstitution has been achieved on art. • vaccination should include a total of 3 doses administered at 0, 1 and 6 months. double-dose vaccination should be considered in patients with cd4 counts of ≥350 cells/µl. if using the rapid schedule, for example for post-exposure prophylaxis or for babies born to infected mothers, a 4-dose schedule is used, administered at 0, 1, 2 and 12 months. • all hiv-infected pregnant women must be tested for hbsag and may require art. • although not directly related to hiv-hbv co-infection, this guideline strongly supports the testing of all pregnant women for hbsag to identify at-risk babies, irrespective of their hiv status. • babies born to mothers who are hiv-hbv co-infected must receive hepatitis b immunoglobulin (hbig) and the first dose of hbv vaccine at two distinct sites within 12 hours of birth. a 4-dose vaccination course should be completed and the baby tested for presence of hbsag and hepatitis b surface antibodies (hbsab) at 6 months of age. hbig should be repeated at 1 month if the mother is hbeag positive. if the baby is hbsab negative at 6 months of age, a repeat vaccination course is required. • co-infected babies should be referred to a specialist paediatrician for further management. • all co-infected patients should be counselled with regard to lifestyle modifications to reduce hepatotoxicity, including alcohol, substance abuse, and co-prescription of herbal and traditional medicines. • all co-infected patients should be tested for hepatitis c virus (hcv) infection, and those who are co-infected should be discussed with a specialist for advice on management. • all hiv-hbv co-infected patients with evidence of chronic liver disease should be tested for hepatitis a immunity and immunised if non-immune. resource constraints and the high level of hepatitis a infection in the south african population as a whole do not support routine testing for all hiv-hbv co-infected patients. 28 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 1 however, no studies have been conducted on the rate of acquisition of new hbv infection in hiv-infected adults, so the applicability of developed-world guidelines to the southern african setting remains unknown. despite this, screening for hbv at the time of diagnosis of hiv has considerable potential benefits, both for the individual and for public health programmes. • early diagnosis of co-infection allows assessment of the requirement for specific anti-hbv treatment. this applies to co-infected patients who qualify for art because of cd4 count or stage of disease, as well as those who, despite not qualifying for art on those grounds, have signs of active liver disease. this is in line with regional advice such as south african national policy, which advises early art (to include specific anti-hbv drugs) irrespective of cd4 count in these patients. • early instigation of specific anti-hbv therapy to reduce viral replication will decrease infectivity of the patient to others. • early identification of co-infected women and appropriate counselling will alert them to the need for targeted hbv intervention for their babies, should they be chronically infected. • early identification of hiv-hbv co-infection allows intervention in terms of counselling to affect lifestyle modifications that may reduce liver damage: • alcohol • substance abuse • traditional or herbal medicines • screening and intervention for patients who are coinfected with hepatitis c. • hepatitis a vaccination in patients with chronic liver disease, if non-immune. • identification of hbv seronegative hiv-infected individuals will allow for the option of vaccination against hbv. 1.1 occult hepatitis b infection screening for chronic hepatitis b using hbsag will fail to detect a small proportion of patients who have occult hbv, i.e. hbsag negative, hbcigg positive and low level of hbv dna in blood, typically <200 iu/ml. data on the prevalence and significance of occult hbv infection in hiv-infected patients are limited, particularly in the southern african setting. a prospective observational cohort of patients attending an urban art-preparedness clinic in johannesburg found that 10.6% of clinic attendees were positive for anti-hbc alone, 88% of whom had evidence of hbv dna in blood.9 in a second study looking retrospectively at 192 stored sera from hiv-infected patients initiating art, 23% were hbsag positive and a further 23% had occult hbv.16 whether occult hbv infection poses a significant clinical problem to co-infected patients remains undetermined and needs to be the focus of longitudinal studies in the southern african setting. of note, 81% of patients with occult hbv in the prospective cohort study had blood hbv dna levels of <104 copies/ml.9 such low levels of dna replication are less likely to cause significant liver damage, although the long-term natural history remains unknown. both prospective and retrospective studies suggest that the true rate of chronic hbv infection in hiv co-infected patients is higher than our current understanding based on hbsag screening alone. however, with the limited amount of evidence and the major cost implications that additional screening tests would impose (see appendix), we are unable to advocate extension of screening tests to include hbcigg and hbv dna until further studies clarify the significance of occult hbv infection in our setting. 1.2 hepatocellular carcinoma hepatitis b is a recognised risk factor for development of hepatocellular carcinoma (hcc). hcc screening requires measurement of alpha-fetoprotein (afp) and specialist ultrasonography, which are not practical in the southern african setting, where resources should be directed towards preventing infection and treating infected persons with effective antiviral therapy. in summary, these guidelines advocate the continued use of hbsag as the screening test for hiv-hbv coinfection. however, screening should be brought forward from entry into the art programme to the time of hiv diagnosis so as to identify co-infected patients early in the course of their disease, allowing the option of early art to include anti-hbv drugs in those who qualify for treatment. 2. vaccination of hiv-infected patients who screen negative for hbv as indicated previously, it is currently not known how common hbv acquisition is in adulthood in southern africa. however, we do know that acquisition of hbv infection by hiv-infected persons adversely affects morbidity and causes appreciable mortality. hence, there is a rationale for advocating for hbv vaccination in all hiv-infected persons who are not already infected with hbv. hbv vaccination responses depend on cd4 counts; vaccination during the early stages of hiv disease when cd4 counts are preserved will result in improved protection. patients who are eligible for hbv vaccination but who have cd4 counts <200 cells/ml mount poor antibody responses to hbv vaccine. it is therefore generally recommended, that vaccination in these individuals be delayed until immune reconstitution is achieved by art. the exception to this rule is in the event of occupational or non-occupational exposure to blood or potentially infectious material from an hbv-infected source. in that case, if the recipient is hiv-infected and non-immune to hbv, hepatitis b immunoglobulin and vaccination should be offered regardless of cd4 count. in countries such as south africa where a universal childhood hbv vaccination programme has been adopted, vaccination will have a long-term positive impact in reducing hiv-hbv co-infection. however, there has been no catch-up vaccination programme, and until this impact is felt, unvaccinated hiv-infected adolescents and adults remain at risk of a preventable disease. three approaches could be adopted: • do not offer hbv vaccine to hbv-uninfected persons. • target hbv vaccine to high-risk groups – acquisition of 29 a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e hbv infection is increased in intravenous drug users (ivdus), men who have sex with men (msm) and partners of hbsag-positive patients, other high-risk groups that might be targeted include sex workers, patients with chronic liver disease, home-based caregivers of hbv patients, travellers, prisoners, police, traditional healers, and people involved in high-risk contact sports such as boxing. • universal hbv vaccination for all hiv-infected persons who have not yet been infected by hbv. adoption of a particular policy will be countryspecific, depending on current vaccination policy, hbv seroprevalence profile and resources. however, it is the opinion of the authors that all hiv mono-infected persons should be offered hbv vaccination, as the impact of this simple intervention could radically alter the course of hiv disease if the person was to be infected with hbv. the vaccination schedule should comprise 3 doses at 0, 1 and 6 months. results of a randomised controlled trial of singleversus double-dose recombinant hbv vaccine in hiv-infected persons showed an increased seroconversion rate (anti-hbsab titre ≥10 miu/ml) in the double-dose arm in the group whose cd4 count was ≥350 cells/µl (64% for the double dose v. 39% for the single dose).17 at cd4 counts <350 cells/µl, although there was a trend towards increased seroconversion in the double-dose arm, it was not statistically significant. follow-up testing for seroconversion is generally not advocated due to resource limitations. however, certain high-risk groups with anticipated repeat exposure, such as health care workers and ivdus, should have their antibody titres checked as a once-off. if anti-hbs antibody titres are <10 miu/ml, consult an infectious diseases specialist for further advice. guidelines for the management of health care workers exposed to an hbsag-positive or unknown source are detailed in table ii. 3. management of hiv-hbv co-infected patients 3.1 lifestyle modification hiv-hbv co-infected patients will require additional counselling and support over and above that given to patients diagnosed with hiv mono-infection. there is a need to concentrate on lifestyle modifications that will reduce the risk of further liver injury, as well as for explanation of why a more tailored art regimen to include arvs active against both viruses is necessary. all hiv-hbv co-infected patients, irrespective of whether they qualify for art or not, must be counselled on the lifestyle modifications outlined in table iii. 3.2 antiretroviral therapy the cd4 count after diagnosis will dictate the initial management of co-infected patients (fig. 1). south african national guidelines on treatment of hiv infection have recently been updated, with a move to earlier initiation of art in pregnant women and patients with tuberculosis. overwhelming evidence from multiple studies shows that delaying art initiation once the cd4 count has dropped below 350 cells/µl is associated with increased mortality and the number of new aids-defining events.18 accordingly, we advocate the inclusion of hivhbv co-infected patients as a third group to receive art at cd4 counts <350 cells/µl. vaccinated status of exposed worker anti-hbs hbig (0.06 ml/kg) hbv vaccine comment previous vaccination and known responder none none none not vaccinated if anti-hbs >10 mui/ml, no treatment if anti-hbs <10 mui/ml, give stat hbig and repeat at 1 month 1st dose stat and proceed to accelerated schedule 1 2 12 months hbig and hbv vaccine can be administered concomitantly at different sites incomplete vaccination or unsure as above single dose stat complete depending on documentation or restart 0 1 2 12 months as above vaccinated, but unknown response as above as above single booster stat as above non-responder to primary vaccination no 1 dose stat repeated after 1 month 1st dose stat and proceed to accelerated schedule 1 2 12 months as above previously vaccinated with 4 doses or 2 completed vaccine series but non-responder as above consider alternative vaccine adapted from the european recommendations for the management of health care workers occupationally exposed to hepatitis b virus and hepatitis c virus.24 table ii. management of health care worker exposed to hbsag-positive or unknown source 30 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 1 the choice of art in co-infected patients must take into account the need for drugs active against both hiv and hbv, and the need to limit the emergence of drugresistant hbv strains; 14 32% of patients at 1 year of lamivudine monotherapy and 50 90% at 5 years have developed a mutation in the ymdd motif of hbv dna polymerase that confers resistance to the lamivudine.19 emergence of lamivudine resistance in patients on art regimens containing lamivudine as the only drug active against hbv is associated with viral breakthrough and hepatitis flares. hence, to limit the emergence of hbv resistant strains and optimise control of hbv replication, hiv-hbv co-infected patients should be started on an art regimen that includes 2 drugs active against hbv, tenofovir plus either lamivudine or emtricitabine. tenofovir is contraindicated in patients with significant renal impairment (creatinine clearance <50 ml/min), and the choice of art in such patients should be discussed with an hiv specialist. in order to limit the incidence of hepatitis flares, once started, anti-hbv drugs in the art regimen of coinfected patients should not be stopped, even when changes to arvs are required due to hiv virological failure or intolerance to other antiretrovirals. hence, other than severe clinical adverse events or grade 3 or 4 laboratory abnormalities ascribed to tenofovir or lamivudine/emtricitabine, co-infected patients should remain on these drugs lifelong. 3.3 management of co-infected patients with a cd4 count >350 cells/ml although there is increasing evidence of a reduction in disease progression (including non-aids-related events) when hiv-infected patients are started on art at cd4 counts >350 cells/µl, owing to resource constraints throughout southern africa we cannot advocate starting art in all co-infected patients with higher cd4 counts at this time. most international guidelines use the hbv dna level in blood to guide the use of art in co-infected patients with higher cd4 counts. again, resource limitations put this expensive test (see appendix) outside our reach as a decision-making tool. however, for arv-naïve patients with cd4 counts >500 cells/ µl and chronic hepatitis b, where resources allow, the clinician is encouraged to refer/discuss the case with a hepatologist with regard to pegylated interferon. hiv-hbv co-infected patients with alt ≥2 times the upper limit of normal are at increased risk of hbv disease progression. hence, in line with international guidelines, we advocate starting tenofovir + lamivudine or emtricitabine-containing art in patients with cd4 counts > 350 cells/µl if either hbeag is positive or alt is 2 times the upper limit of normal. furthermore, in line with current national policy, art is recommended for any co-infected patient with cd4 counts >350 cells/µl who has symptomatic liver disease. patients with cd4 counts of >350 cells/µl who are asymptomatic, hbeag negative and have an alt <2 times the upper limit of normal should be closely monitored with repeat alt recordings 6-monthly. if there are signs of liver dysfunction without evidence of a cause other than hbv disease progression, the patient should start tenofovir + lamivudine or emtricitabine-based art. 3.4 choice of the third drug in an art regimen for co-infected patients in constructing an art regimen for co-infected patients, apart from needing to choose drugs with dual activity against hiv and hbv, it is also of paramount importance to try to limit further hepatotoxicity. given this, we advise avoiding the use of nevirapine in co-infected patients. we recommend efavirenz for first-line art whenever possible. in women of childbearing age, a boosted pi regimen should be considered if injectable contraception and condom use are not adhered to. alcohol abstinence from alcohol should be encouraged. heavy alcohol intake (>20 g/ day in women and >30 g/day in men) is a risk factor for developing cirrhosis substance abuse intravenous drug use should be discouraged to reduce risk of new infection or re-infection with hbv and/or hcv safe sex although this will already be stressed as part of preventing hiv transmission to others, safe sex practices are to be strongly advocated to reduce transmission of hbv. mucosal traumatic sexual practices associated with high-risk blood contact should be discouraged other measures to reduce risk of transmission attention to prompt clean-up of blood spills with detergent or bleach and avoid sharing razors table iii. lifestyle modification to limit liver injury in hiv-hbv co-infected persons fig. 1. algorithm for management of hiv-hbv co-infected patients. 31 a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 3.5 hepatitis flares in hiv-infected persons who do not know that they are hbv infected there is no current policy in place for ‘catch-up’ hbv testing in hiv-infected patients who started art before the onset of hbv screening. furthermore, if current national policy is adhered to, there will be an increasing number of hiv-hbv co-infected patients who do not know that they are infected with hbv. these patients may be on art regimens that include lamivudine as the sole active drug against hbv. lamivudine resistance will develop in up to 90% at 5 years, at which time a viral breakthrough and hepatitis flare may develop. since there is a wide range of possible causes for sudden deterioration in liver function during art, a clinical approach to the coinfected patient on art who develops liver dysfunction is required. one such approach is depicted in fig. 2. 4. special groups 4.1 pregnant women screening for hbv infection in pregnant women to prevent mother-to-child transmission is a wellestablished, evidence-based standard of care in developed countries. furthermore, a systematic review of randomised controlled trials in 2006 found that prophylaxis (vaccination and/or immunoglobulin) given to newborns of mothers infected with hbv reduced perinatal transmission of the virus.20 this is the critical reason why screening for hbv infection in pregnant women is so important, be it in women who turn out to be co-infected or hbv mono-infected. although there are theoretical concerns about the use of tenofovir in pregnancy in relation to bone mineral density and skeletal development of the newborn, the benefit of dual therapy, which includes tenofovir for pregnant co-infected women, outweighs the risk. similarly, in order to avoid nevirapine, we advocate for the use of efavirenz after 20 weeks’ gestation. boosted lopinavir is an alternative third drug in the co-infected pregnant woman. 4.2 newborns the risk of developing chronic hbv infection is greatest in newborns who are infected perinatally (90%). hence any intervention that prevents transmission will have a major impact on long-term morbidity and mortality as well as reducing transmission of hbv to others during childhood and once the person becomes sexually active. if the mother is known to be hbv infected, post-exposure prophylaxis becomes an option. all newborn babies of mothers infected with hbv, be they mono-infected or co-infected with hiv, should receive hbig plus the first dose of the hepatitis b vaccine within the first 12 hours after delivery. hbig and vaccine should be administered at different sites and the 4-dose vaccination schedule completed. if the mother is known to be hbeag positive, with evidence of high-level viral replication and infectivity, hbig should be repeated at 1 month. babies should be tested for the presence of hbsag at 6 months to determine whether post-exposure prophylaxis was successful. 4.3 children perinatal and horizontal transmission during childhood is the predominant mode of hbv acquisition in southern africa. although the principles underlying treatment of adults and children with hiv-hbv co-infection are similar, there are important differences. only pegylated interferon-alpha, adefovir and lamivudine are licensed for use in children with hbv. although the efficacy of interferon-alpha in children is similar to that in adults if they are in the immune clearance phase of hbv infection, most children, particularly those in the immune tolerant phase, have normal alt with high hbv dna levels, and <10% of these children will clear hbeag with interferonalpha.21 tenofovir is not licensed for use in children <18 years of age, although it has been used off-label as part of salvage therapy. tenofovir is available as an un-scored 300 mg tablet and the suggested childhood dose is 8 mg/ kg/day. this means that it is effectively contraindicated in any child weighing <37 kg. a recent study of the use of tenofovir in children in the uk and ireland as part of art found evidence of considerable underand over-dosing.22 there are also theoretical concerns regarding the use of tenofovir in respect of depletion of bone mineral density. as tenofovir is therefore limited in many infants and children, this effectively leaves lamivudine monotherapy to treat hbv in the face of hiv co-infection. perinatally and childhood-acquired infection is associated with a high hbv viral load, which increases the risk of acquiring lamivudine resistance if the patient is on monotherapy. the options for management include the use of art with lamivudine or withholding lamivudine in the regimen until tenofovir can be used. this will depend on the age of the child and the activity/stage of the liver disease, and should be discussed with a specialist paediatrician and hepatologist. *minimum lfts to include total bilirubin and alt. if bilirubin increased, perform full lfts. fig. 2. clinical approach to management of hiv-hbv co-infected patients who develop liver dysfunction on art. 32 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 1 4.4 alternative treatment options for co-infected patients with high cd4 counts alternative therapy for hbv co-infected patients with high cd4 counts is limited primarily by cost (see appendix). the efficacy of pegylated interferon-alpha depends on viral load, alt level, genotype and the degree of necro-inflammation on liver biopsy. although good trial evidence is lacking for its use in hiv-hbv coinfection, expert opinion suggests that patients who are hbeag positive, have elevated transaminases and high cd4 counts, and are found to have necro-inflammation on liver biopsy are most likely to benefit from pegylated interferon-alpha.23 references 1. lavanchy d. hepatitis b virus epidemiology, disease burden, treatment and current and emerging prevention and control measures. j viral hepat 2004;11:97-107. 2. beasley rp, hwang ly, lin cc, leu ml, et al. incidence of hepatitis b virus infections in preschool children in taiwan. j infect dis 1982;146:198-204. 3. beasley rp, hwang ly, lee gc, et al. prevention of perinatally transmitted hepatitis b virus infections with hepatitis b virus infections with hepatitis b immune globulin and hepatitis b vaccine. lancet 1983;2:1099-1102. 4. coursaget p, yvonnet b, chotard j, et al. ageand sex-related study of hepatitis b virus chronic carrier state in infants from an endemic area (senegal). j med virol 1987;22:1-5. 5. mcmahon bj, alward wl, hall db, heyward wl, bender tr, francis dp, et al. acute hepatitis b virus infection: relation of age to the clinical expression of disease and subsequent development of the carrier state. j infect dis 1985;151:599-603. 6. vardas e, mathai m, blaauw d, mcanerney j, coppin a, sim j. preimmunization epidemiology of hepatitis b virus infection in south african children. j med virol 1999;58(2):111-115.. 7. burnett rj, francois g, kew mc, et al. hepatitis b virus and human immunodeficiency virus coinfection in sub-saharan africa: a call for further investigation. liver int 2005;25:201-213. 8. firnhaber c, reyneke a, schulze d, et al. the prevalence of hepatitis b coinfection in a south african urban government hiv clinic. s afr med j 2008;98(7):541-544. 9. firnhaber c, viana r, reyneke a, et al. occult hepatitis b virus infection in patients with isolated core antibody and hiv coinfection in an urban clinic in johannesburg, south africa. int j infect dis 2009;13(4):488-492. 10. hoffmann cj, charalambous s, thio cl, et al. hepatotoxicity in an african antiretroviral therapy cohort: the effect of tuberculosis and hepatitis b. aids 2007;21(10):1301-1308. 11. national department of health, south africa. clinical guidelines for the management of hiv & aids in adults and adolescents. ndoh, 2010. http://www.doh.gov.za/ docs/factsheets/guidelines/adult_art.pdf (accessed 25 march 2011). 12. bhiva guidelines – hiv and chronic hepatitis: coinfection with hiv and hepatitis b virus infection. updated october 2004. http://www.bhiva.org (accessed 25 march 2011). 13. rockstroh jk, bhagani s, benhamou y, et al. european aids clinical society (eacs) guidelines for the clinical management and treatment of chronic hepatitis b and c coinfection in hiv-infected adults. hiv med 2008;9:82-88. 14. world health organization. antiretroviral therapy for hiv infection in adults and adolescents. recommendations for a public health approach. 2006 revision. http:// www.who.int/hiv/pub/arv/adult/en/ (accessed 25 march 2011). 15. lok asf, mcmahon bj. chronic hepatitis b: update 2009. hepatology 2009;50:661662. 16. lukhwareni a, burnett rj, selabe sg, mzileni mo, mphahlele mj. increased detection of hbv dna in hbsag-positive and hbsag-negative south african hiv/ aids patients enrolling for highly active antiretroviral therapy in a tertiary hospital. j med virol 2009;81(3):406-412. 17. fonseca mo, pang lw, de paula vacalheiro n, barone aa, lopes mh. randomized trial of recombinant hepatitis b vaccine in hiv-infected adult patients comparing a standard dose to a double dose. vaccine 2005;23:2902-2908. 18. sterne ja, may m, costagliola d, et al. timing of initiation of antiretroviral therapy in aids-free hiv-1-infected patients: a collaborative analysis of 18 hiv cohort studies. lancet 2009;373:1352-1363. 19. benhamou y, bochet m, thibault v, et al. long term incidence of hepatitis b virus resistance to lamivudine in human immunodeficiency virus-infected patients. hepatology 1999;30(5):1302-1306. 20. lee c, gong y, brok j, boxall eh, gluud c. effect of hepatitis b immunisation in newborn infants of mothers positive for hepatitis b surface antigen: systematic review and meta-analysis. bmj 2006;332:328-326. 21. lai cl, lok as, lin as, et al. placebo-controlled trial of recombinant alpha 2-interferon in chinese hbsag-carrier children. lancet 1987;2:877-880. 22. riordan a, judd a, boyd k, et al. tenofovir use in human immunodeficiency virus-1-infected children in the united kingdom and ireland. pediatr infect dis j 2009;28:204-209. 23. soriano v, puoti m, bonacini m, et al. care of patients with chronic hepatitis b and hiv coinfection: recommendations from an hiv-hbv international panel. aids 2005;19:221-240. 24. puro v, de carli g, cicalini s, et al. european recommendations for the management of healthcare workers occupationally exposed to hepatitis b virus and hepatitis c virus. eurosurveillance 2005;10(10):260-264. declaration of interests and support within the last 3 years (sponsors, managed care and pharmaceutical organisations) marc mendelson receives support from pepfar/ usaid through anova healthcare, wendy spearman has received travel and conference support from roche, and mark sonderup has received conference support from hoffman-la roche. laboratory tests state sector private sector hbsag r 105.89 r171.30 hbeag r 105.89 r171.30 anti-hbc igg r 105.89 r171.30 anti-hbs antibody r 105.89 r171.30 hbv dna r 1 141.22 r1 772.60 drugs used in the treatment of hbv tenofovir (aspen) r210.90 (1 month, incl. of vat) lamivudine (adcock) lamivudine (sonke) r96.51 (1 month, incl. of vat) r44.40 (1 month, incl. of vat) truvada (tenofovir + emtricitabine) (aspen) r313.50 (1 month, incl. of vat) pegylated interferon-alpha r11 000/month for adults appendix. cost of laboratory tests for hbv in the state and private sectors, 2010/2011 (provided by the national health laboratory service) and drugs used in treatment of hbv infection (prices are subject to change – current prices at the time of going to print) 33 m e s s a g e a5 hiv 2014 advert -lanscape.indd 1 2014/05/13 11:30 am 44 sajhivmed june 2014, vol. 15, no. 2 message from the executive when the minister of health announced that the national department of health was introducing fixed-dose combinations (fdcs) into the antiretroviral programme in december 2012, as hiv clinicians we welcomed the decision. the fdc simplified prescription, dispensing and adherence messages. as of 1 october 2013, the national department of health announced that fdcs should be offered to all hiv-infected adults on first-line therapy in the absence of any contraindications. the previous priority groups no longer apply as the stock levels have now reached the required amounts. as the president of the southern african hiv clinicians society, i encourage all healthcare workers who are responsible for antiretroviral prescriptions to look actively for any remaining patients who are on single drugs and to change them to the fdcs, if clinically appropriate, as soon as possible. • patients who are receiving tdf, 3tc and efv as single drugs can be changed to the fdc at their next dispensing or medical visit. their monitoring visits and blood tests will remain on the same schedule as if they were still on the single drugs. • for patients who were receiving d4t, 3tc and efv prior to the switch, clinicians should please ensure that they have a recent undetectable viral load (vl) (~1 000 copies/ml) and normal creatinine clearance within the previous 3 6 months. • for patients who were receiving d4t, 3tc and efv who have a detectable vl, clinicians should do additional adherence counselling and repeat the vl in 2 3 months. if the repeat vl is undetectable (~1 000 copies/ml), the patient can be changed to the fdc. if the repeat vl is detectable, the patient should be changed to second-line therapy. please remember to reinforce these patient counselling messages: • the dosage is one pill once daily, not three pills once daily. • although the fdc is ‘one pill once a day’, it does contain three different arv medications. • the fdc is easy to take, highly effective and in no way inferior to taking three individual drugs. for any clinical questions or advice on other scenarios, please email us at sahivsoc@sahivsoc.org. also check out our guidelines on fdcs on the society’s website, http://www.sahivsoc.org. let us work together to make sure that all patients who are eligible for an fdc receive it as soon as possible. let us stand behind the minister and the department of health and get this done. francesca conradie president southern african hiv clinicians society fconradie@witshealth.co.za mailto:sahivsoc@sahivsoc.org http://www.sahivsoc.org mailto:fconradie@witshealth.co.za c p d q u e s t i o n s journal 38 two cpd points are awarded for the correct completion and submission of the questions below. cpd questionnaires must be completed online via www.cpdjournals.org.za. after submission you can check the answers and print your certificate. questions may be answered up to 6 months after publication of each issue. this programme is available free of charge to members of the hiv clinicians society and sama only. 1. true (a) or false (b) – click on the correct answer: the immune reconstitution syndrome (iris) typically occurs late in antiretroviral therapy. 2. true (a) or false (b) – click on the correct answer: iris is a typical manifestation of antiretroviral therapy (art) commencement in early hiv infection in pregnant women. 3. true (a) or false (b) – click on the correct answer: cryptococcal meningitis is a serious iris manifestation. 4. true (a) or false (b) – click on the correct answer: in regions where highly active antiretroviral therapy is offered in pregnancy regardless of maternal cd4 count, vertical hiv transmission has almost disappeared. 5. true (a) or false (b) – click on the correct answer: tb colitis may be an extrapulmonary complication of hiv/ tb co-infection. 6. true (a) or false (b) – click on the correct answer: abdominal ultrasound is a useful investigation in hiv patients with abdominal symptoms. 7. true (a) or false (b) – click on the correct answer: non-tuberculous mycobacterial infection is only seen in patients with well-preserved immunity. 8. true (a) or false (b) – click on the correct answer: soluble transferrin receptor levels are low in patients with iron deficiency anaemia. 9. true (a) or false (b) – click on the correct answer: transferrin levels are usually low in anaemia of chronic disorders. 10. true (a) or false (b) – click on the correct answer: mycobacterium avium complex is a non-tuberculous mycobacterial infection that occurs most commonly in the duodenum in gastro-intestinal infections. 11. true (a) or false (b) – click on the correct answer: pneumocystis jirovecii is an important protozoal opportunistic infection in hiv. 12. true (a) or false (b) – click on the correct answer: the grocott-gomori methamine-silver stain is useful for identifying non-tuberculous mycobacteria. 13. true (a) or false (b) – click on the correct answer: treatment for p. jirovecii may involve atovaquone. 14. true (a) or false (b) – click on the correct answer: south africa has a traditional health practitioners act (no. 22 of 2007) that requires registration by traditional healers. 15. true (a) or false (b) – click on the correct answer: in the study discussed in this journal, most traditional healers kept careful records of each of the treatment packages they prepared themselves. 16. true (a) or false (b) – click on the correct answer: a person engaging in potentially high-risk sexual activity as indicated on the south african national blood service questionnaire is deferred from blood donation for 6 months. 17. true (a) or false (b) – click on the correct answer: south africa is a country where men who have sex with men may not donate blood. 18. true (a) or false (b) – click on the correct answer: tablet returns may be a potential way of introducing adherence conversations with patients on art. 19. true (a) or false (b) – click on the correct answer: a haemoglobin level below 8 g/dl in an hiv-infected patient is probably due to anaemia of chronic disorders. 20. true (a) or false (b) – click on the correct answer: the ziehl-neelsen stain will show intracellular acid-fast bacilli in an m. avium complex infection. southern african hiv clinicians society application / renewal form membership fees for 2010 annual membership fees: private sector r300 / public sector r150 / associate member r120 renewal fees are valid for 12 months from date of receipt of payment. payments may be made by cheque or electronic transfer payable to: ‘southern african hiv clinicians society’, nedbank campus square, branch code: 158-105 account no: 1581 048 033. please fax proof of payment to the database manager on 086 682 2880 or post to: suite 233, postnet killarney, private bag x2600, houghton, 2041 tel: + 27 (0) 11 341 0162 e-mail: sahivsoc@sahivsoc.org. website: www.sahivsoc.org nb! please print legibly for accurate entry into the database in order to ensure receipt of services: first name: initials: surname: title: specialty: practice address postal address: city: state/province: country: postal code: hpcsa.no: tel.no fax: cell: e-mail: please tick relevant box: • do you practice in the private sector or in the public sector or both • would you like to be added to the society’s provider network for hiv patient referrals? yes no • would you like your quarterly journal, the southern african journal of hiv medicine, to be posted to you? yes: no (i will read journals on-line, on the society website: http://www.sajhivmed.org.za) • preferred method for receiving your quarterly newsletter transcript: e-mail post • name(s) of hiv training courses successfully completed:………………………………………………………………………………… . ……………………………………………………………………………………………………………………………………………………… method of payment: electronic transfer: direct deposit: post/cheque: cash: amount paid: payment date: society services: quarterly issues of southern african journal of hiv medicine quarterly newsletter transcript cpd points for: branch meetings, journal questionnaires, published submissions hiv/aids cme: courses/alumni programme as training for dip. hiv med.advocacy & day-time telephonic consultancy conference information and discounts regional and international representation specialty sub-groups local and international guidelines the southern african journal of hiv medicine                                                        october  2009 5 i am delighted to introduce you to our guest editors, who have done a sterling job in pulling together this ‘mental health in hiv’ edition. they are two capetonian colleagues who i am also fortunate to consider friends: john joska is a psychiatrist and landon myer is a public health specialist. john joska is a senior specialist and lecturer in the department of psychiatry and mental health at the university of cape town. he is head of the division of neuropsychiatry, western cape provincial programme manager for hiv psychiatry, and director of the gshhiv mental health group. the latter is a newly formed group of mental health professionals who are providing service and investigating the effects of hiv on people living with hiv/aids (plwha) from a mental health point of view. current research projects include investigations into neurocognitive disorders in hiv, screening for mental disorders in hiv, and brief psychological interventions in plwha with depression. landon myer is an associate professor in the school of public health and family medicine at the university of cape town. his research focuses on the roles of hiv/ aids and other infectious diseases in shaping individual and population health in southern africa. he is particularly interested in how the hiv epidemic influences other areas of population health, including mental health and women’s reproductive health. in investigating these topics, his research incorporates biological mechanisms, individual behaviours and exposures, as well as structural socio-economic and health service conditions. i am sure you will agree that with their colleagues they have provided a feast of important reading for you all in this edition. linda-gail bekker editor f r o m  t h e  e di torf r o m t h e e di tor the journal is starting to feel like men’s health, what with posters, guidelines and now a state-of-the art science update, hiv treatment bulletin, falling out of it. exco is pleased to announce an important and strategic partnership with hiv ibase, who publish hiv treatment bulletin. we are distributing the southern african version of their excellent newsletter, which will exclusively focus on the scientific reports and resources that have local relevance – with a strong focus on paediatrics and maternal health. hiv treatment bulletin neatly complements the journal, providing the snobbish clinician and scientist with the most hot-off-the-press analysis of recent clinical trials and basic science research. policy makers can authoritatively pronounce at their guidelines meetings, clinicians can expand their patients’ options, and, most importantly, you can show off at ward rounds. thanks to all the people at i-base, this is a major step forward for quality information sharing. we wish the new health minister, barbara hogan, all the best. she has very small shoes to fill, but a mammoth task ahead of her to repair south africa’s woeful health service. at the time of writing, she and her deputy, dr molefi sefularo, have been very impressive, dealing with a cholera disaster, drug stock-outs, issues of prevention, releasing controversial reports that were stuck on her predecessor’s desk for months, and a dozen other complex health problems. finally, the exco welcomes two new members based in durban, professor yunus moosa and dr henry sunpath, both highly respected clinicians and part of the team responsible for an excellent hiv clinical conference held in october. francois venter president this spring edition brings 2008 to a close. and what a year it has been. not many breakthroughs in hiv or tb, but a lot of activity in terms of understanding early infection better, really getting to grips with early immune responses, and again thinking through our prevention options. in 2008 the concept of antiretrovirals for prevention as well as treatment has come to the fore with second-generation microbicides, pre-exposure prophylaxis and the notion that we may be able to ‘treat our way out of the epidemic’ becoming possibilities. gratifyingly, this year also saw a record number of people being tested and accessing art, and roll-out for both testing and treatment is truly scaling up. as chairperson of the 4th southern african hiv conference i must encourage every one of you to think seriously about coming to durban on 31 march. it promises to be a critical conference where we will really formulate the key steps in getting pmtct, treatment, testing and prevention out there on a scale that will begin to turn the sa statistics around. (i promise that it will also be loads of fun!) please note the early date this year: 31 march to 3 april. this is to ensure brilliant kzn weather! in this edition, we already begin to examine some of these key scale-up questions: jerome singh explores the ethics and legality of traditional healers performing hiv testing (i know many have asked why this has to be the domain of nurses only). francesca esposito and her team examine changes in body composition in women taking antivirals in a kzn clinic. we look at the role of mobile phones in the hiv response with william mapham, and polly clayden gives us pointers to starting infants on art. the role of a liver biopsy in diagnosis of opportunistic infections is described by mark sonderup and colleagues. the vexed question of when it is deemed safe to start haart in patients co-infected with tb is discussed by robin wood, and francois venter and colleagues give a practical view on new antiretrovirals on the horizon for south african practitioners. no guidelines in this issue, but i will whet your appetites – look out for guidelines on prevention of tb occupational exposure for hiv-infected health care workers and on the non-infertile hiv infected couple, hot stuff coming up in the new year! happy reading and every best wish for a restful and peaceful festive season from the whole editorial team. see you next year! linda-gail bekker editor m e s s a g e f r o m t h e e x e c u t i v e msg from the executive.indd 5 12/17/08 3:16:23 pm addressing mental health in routine hiv care and treatment as this journal’s readers are well aware, hiv has complex and wide-ranging impacts on the health of infected individuals. much of this complexity is due to the nature of host-virus interactions and the pathophysiology of the virus and its sequelae in different organ systems over time. other aspects are linked to the profound impact an hiv diagnosis has on the life of an infected individual, both through physical morbidity and the psychological and social consequences of a lifelong illness. the area of mental health is a critical example of the diverse impacts of hiv on patients’ health and well-being. the links between hiv and mental health are multiple: risk taking associated with hiv acquisition is more common among individuals with mental disorders; common mental disorders (such as anxiety, depression and alcohol/substance disorders) are often caused in part by the stress of an hiv diagnosis and related stigma; psychotic states are a relatively common presentation of hiv infected individuals; and neurocognitive manifestations of hiv infection such as hiv-associated dementia emerge later in the course of disease. taken together, mental disorders may be viewed as their own class of ‘opportunistic’ conditions affecting hiv-infected individuals in a unique manner. dealing with the various mental health impacts of hiv infection is a core component of effective hiv care and treatment. anxiety and depression among hiv-infected individuals can negatively impact on medication adherence; in these situations, management of mental disorders can help facilitate the management of hiv disease over the long term. the neurocognitive manifestations of hiv disease are a significant cause of morbidity; increasingly we are recognising that these disorders may e di tor i a l m e s s a g e   f r o m    t h e   e x e c u t i v e the large international aids society meeting has come and gone from cape town. the agenda was dominated by a new big idea, an audacious mathematical model by a group of brave world health organization modellers showing that giving antiretroviral therapy to every one with hiv, immediately, could make the epidemic disappear. we’ve known for a long time that viral load correlates with infectiousness, whether it is sexual contact, pmtct or other forms of exposure. art is so highly effective in reducing viral load that the swiss created an uproar a year ago by claiming that someone on art with an undetectable viral load (and no std) could not transmit hiv sexually. the who researchers essentially argue that if we diagnose hiv quickly and treat everyone who is hiv positive, irrespective of cd4 count, we can arrest sexual transmission early and pretty much eradicate hiv within 10 years. subsequent papers have even postulated that we could reverse the tb epidemic, as hiv drives this like fuel on a fire. finally, early economic work has shown ‘test and treat’ to be cost saving, despite significant initial investment. there is broad acknowledgment that hiv prevention programmes have been very disappointing, and that even effective interventions such as male circumcision and good pmtct are unlikely to eradicate the epidemic alone. it is exciting that researchers are thinking creatively, and that models showing we can reverse things are out there. but to implement this incredibly ambitious model would require a complete restructuring of health systems. we would need to do hiv testing aggressively and provide adequate, easily available art services, as broadly as possible. the health system would have to be transformed from the lumbering unfriendly giant it is at the moment to a responsive and effective service deliverer. the reality is that we need this anyway, even if the modellers are wrong. francois venter president be managed effectively, including by early initiation of antiretroviral therapy, to improve the prognosis of affected individuals. in short, basic mental health care is part of good hiv management. in this context, there is a clear need to make the diagnosis and management of mental disorders more feasible in general hiv care and treatment settings. at the primary and secondary levels of the health care system, medical officers and physicians must be able to identify patients with a possible mental disorder and work up these patients to arrive at a preliminary diagnosis, make management decisions, and follow up patients over time. support from specialist psychiatrists is necessary in some instances, but most cases do not require specialist referral, and the availability of psychiatric services to support hiv care and treatment is limited in most settings across the region. this special issue of the journal aims to address this need through a series of focused contributions from leaders in hiv mental health from across south africa. the first two pieces focus on anxiety and depression in hiv in broad terms (thom) and post-traumatic stress disorder specifically (pingo). following this, the topic of psychotic presentations in hiv is dealt with by an algorithm for the diagnosis and management of psychosis in hiv (jonsson) and then an extended case study (boyles) to help reinforce key concepts. the topic of neurocognitive impairment in hiv/aids is discussed in detail (singh) with a short report on the white matter changes that take place in the brain over the course of hiv disease (hoare) as well as a piece of empirical research investigating the clinical utility of one commonly used tool to identify neurocognitive deficits in hiv (ogunrin). the final piece deals with cross-cutting issues of prescribing psychotropic medications in the context of hiv infection (parker). throughout, these pieces aim to address issues in mental health faced by front-line hiv clinicians on a daily basis, with practical strategies for investigation and management. it is our hope that the contents of this issue may make some contribution towards helping hiv clinicians to better recognise and treat mental disorders in their patients. landon myer john joska guest editors the southern african journal of hiv medicine                                                          october  20096 abstract background methods results discussion conclusion acknowledgements references about the author(s) nolundi t. mshweshwe-pakela department of implementation research, the aurum institute, johannesburg, south africaschool of public health, university of the witwatersrand johannesburg, south africa tonderai mabuto department of implementation research, the aurum institute, johannesburg, south africa luke shankland aviro health, cape town, south africa alex fischer aviro health, cape town, south africa dikeledi tsukudu department of health systems, the aurum institute, johannesburg, south africa christopher j. hoffmann department of implementation research, the aurum institute, johannesburg, south africa department of medicine, johns hopkins university school of medicine, baltimore, united states of america department of health, behavior, and society, johns hopkins bloomberg school of public health, baltimore, united states of america citation mshweshwe-pakela nt, mabuto t, shankland l, fischer a, tsukudu d, hoffmann cj. digitally supported hiv self-testing increases facility-based hiv testing capacity in ekurhuleni, south africa. s afr j hiv med. 2022;23(1), a1352. https://doi.org/10.4102/sajhivmed.v23i1.1352 original research digitally supported hiv self-testing increases facility-based hiv testing capacity in ekurhuleni, south africa nolundi t. mshweshwe-pakela, tonderai mabuto, luke shankland, alex fischer, dikeledi tsukudu, christopher j. hoffmann received: 08 dec. 2021; accepted: 24 feb. 2022; published: 13 june 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: hiv testing is the first step for linkage to hiv prevention or treatment services. facility-based hiv testing is the most utilised method, but faces challenges such as limited work space and human resources. digitally supported hiv self-testing (hivst) provided in clinics shifts testing to the client, potentially empowering the client, and addresses such constraints. objectives: the study primary objective was to determine the feasibility of integrating digitally supported hivst into the clinic. secondary objectives were to describe hiv testing volume, populations reached, and antiretroviral treatment (art) initiation. method: we conducted an analysis of prospectively collected data during implementation of digitally supported hivst in two healthcare facilities based in south africa from june 2019 to september 2019. we described implementation and client characteristics using hivst and compared testing before and during implementation. results: during the 4-month implementation period there were 35 248 client visits. a total of 6997 (19.9%) of these visits involved hiv testing. of those testing, 2278 (32.5%) used hivst. of the 2267 analysed, 264 (11.6%) were positive: 182 (12%) women and 82 (11%) men. of those, 230 (95.4%) were confirmed hiv positive and 150 (65%) initiated art within 14 days. during a four-month pre-implementation period, 14.5% of the clients tested for hiv. compared to the pre-implementation period, we observed a 25% increase in hiv testing. conclusion: digitally supported hivst increased the number of clients completing hiv testing in the health facility, without a need to significantly increase staff or space. facility-based digitally assisted hivst has the potential to increase hiv testing in high hiv prevalence clinic populations. keywords: hiv testing; hiv self-testing; facility-based hiv testing; digital support; linkage to art. background hiv testing is the first step in linkage to hiv care, including prevention or treatment services.1,2 the united nations joint programme on hiv/aids has set interim 95-95-95 targets: that 95% of people living with hiv know their hiv status, 95% of these are to be initiated onto antiretroviral treatment (art), and that 95% of these should be virally suppressed by the end of 2030.3 by the end of 2019, hiv testing services (hts) had reached about 87% of people living with hiv (plhiv)in the eastern and southern african region and up to 92% of the overall population in south africa.4 of all hts strategies, facility-based hts is the mostly widely utilised, with 70% of all testing in south africa occurring in public clinics and hospitals.5 individuals who test hiv positive during facility-based testing have higher subsequent engagement in care, presumably because they are already seeking clinical care and interacting with the medical system.6,7 however, challenges such as limited space and limited human resources are major constraints to the daily test volume.8,9 a second testing challenge is limited acceptability of standard hts for some clinic clients.10,11,12 innovative strategies could increase testing volume and improve outreach to a greater proportion of clinic clients. in 2015, the world health organization recommended the addition of hiv self-test (hivst) as a complementary approach to standard hts.13,14 south africa updated its hiv counselling and testing guidelines and adopted this recommendation.15 hiv self-test is a process whereby a lay-person collects his or her own specimen (usually a buccal mucosa swab), performs the test, and interprets the result.16 it is generally acceptable and is preferred by some clients, especially from hard-to-reach populations.17 hiv self-test shifts testing to the client, potentially empowering the client, while also reducing human resource and space demands on the clinic. if conducted within a clinic, hivst has the potential to substantially increase the overall hiv testing capacity of the facility. considerations for hivst centre around a client’s ability to accurately collect the specimen, conduct the test, and interpret hiv results.18,19 hiv self-test using oraquick test kits has shown high acceptability due to its non-invasive and easy-to-perform nature; however, some clients express the need for assistance, which may not be possible when the test is conducted without a health worker present during testing.20,21 in addition, post-test guidance may support the client’s health journey, and confirmatory testing is needed for positive hivst results as part of the hiv testing algorithm. in prior work, we identified that < 10% of patients visiting the facility received hiv testing.9 a major barrier to increasing testing was lack of space and testing personnel. in response to these challenges, we developed a digitally supported hivst system for facility-based use. the digital platform was designed to shift testing guidance from personnel and to provide standardised guidance and counselling content, thus overcoming the limited supply of hiv counsellors. self-testing by clients in small kiosks maintained privacy while overcoming the challenge of limited space from counsellor-led testing. the digital support is a software application installed on a digital tablet that provides content on conducting hivst, steps after testing, and living with hiv, as well as a countdown timer for the testing process. this software was co-created by aviro and the aurum institute to define and assess a delivery model of digitally supported hivst in a health-facility setting. the primary objective of this study was to determine the feasibility of integrating digitally supported hivst into the clinic; secondary objectives were to describe hiv testing volume, populations reached, and art initiation. methods we collected data from february 2019 to may 2019 prior to implementing hivst (baseline), and from june 2019 to september 2019 during pilot implementation of digitally supported hivst (implementation), for a before-and-after comparison of hiv testing volume and hivst use. setting the study was conducted in the ekurhuleni district located in the gauteng province of south africa, outside the city of johannesburg. in 2019, the city of ekurhuleni had a population of 3 774 638 and a land size of 1975 km². ekurhuleni comprises urban and peri-urban residential areas with a total of 93 public health clinics and 6 public hospitals. all public health facilities provide hts free of charge. this study was conducted in two public community healthcare facilities. both facilities are in urban areas and each had an average daily headcount of 400 clients; each operated for 8 hours per day. both facilities had primary care providers who were professional nurses, with a medical doctor visiting up to three days per week. these facilities provide primary health services, including acute and chronic care, family planning, antenatal care and childhood immunisations. in both facilities, free hts were provided by trained lay counsellors. one facility had five, and the other six, lay counsellors. both facilities allocated two rooms/workspaces for hts inside the facility and two foldable gazebos outside the facility that provided additional private space for hts delivery. these facilities were selected in coordination with the district-level department of health to pilot the digitally supported hivst. hiv testing services posters regarding hiv testing were prominently displayed in the clinics and health talks were conducted in waiting areas during baseline and implementation periods. during the implementation period these talks informed clients about standard testing provided by counsellors and hivst using oraquick. standard hiv testing when a client accepted standard hiv testing, they were sent to a counselling room or a gazebo where a counsellor would provide the service to one client at a time. standard hts takes a median of 26 min, as we have described from prior work in public clinics in this district.9 hiv self-testing oraquick information brochures, translated into several local languages, were distributed to clients in waiting areas to give them more information about self-testing. figure 1 shows the client flow from information to completion of confirmatory testing. figure 1: facility hiv testing flow incorporating digitally supported hiv self-test. three 1 m × 1 m hivst booths were placed inside each health facility. each booth had pictorial instructions to guide the testing process, an oraquick® hiv rapid antibody test (orasure technologies, inc., pennsylvania, united states [us]), a tablet device with the digital application, and headphones for clients to listen to audio content on the digital application. oraquick is a lateral flow test for antibodies using a specimen from an oral mucosal swab. each facility had a dedicated hivst facilitator, trained in hiv testing and the digital platform and allocated to facilitate digitally supported hivst. hiv self-test facilitators requested written consent for hiv testing, and a separate written consent to use the digital application, as it was implemented as a pilot study. hiv self-test facilitators also assisted clients when called upon. hiv self-testing was supported by a digital application delivered through a tablet device in each hivst booth (aviro pocket clinic, aviro health, cape town, south africa) that provided audio-visual content via the screen and attached headphones. the digital support sought to guide a client’s hivst journey from testing to next steps after a negative or positive test. the journey started with the client agreeing to terms of use and data collection and registering demographic information (figure 2). figure 2: digital support journey. clients were then guided through pre-test counselling, testing (including a video demonstrating the use of the oraquick hiv test kit), and post-test counselling. the content features, voice, and examples were tailored to the client’s age and sex as entered at the start of the session. after self-sample collection from the buccal mucosa, the client was prompted to set the on-screen timer. during the 20 min waiting period for the oraquick results, the client was led through audio-visual health-related content regarding hiv and hiv testing. after the 20-min oraquick development time was completed, the client was asked to enter the test result. further audio-visual post-test counselling was provided based on the entered test result. the client also had the option to get assistance from the hivst facilitators. individuals who tested positive were reminded of the need for a confirmatory test as per the south african algorithm. if the client agreed, the facilitator escorted the client to a lay counsellor to conduct a confirmatory test. if they declined testing, the facilitator documented this. if both screening and confirmatory test results were positive, linkage to hiv care was initiated. data collection data were retrospectively abstracted from clinic paper testing registers to identify unique individuals, testing outcome (positive or negative), sex and age grouping. hiv self-test facilitators, funded by the study, recorded sex, age, history of hiv testing, and hiv test results for all clients opting for hivst. for those patients with a positive hiv test result with hivst, we abstracted available art data from the electronic record system and patient paper files (we did not assess linkage to art for patients receiving routine hts). facility headcounts were tabulated daily by clinic staff using a register that listed all clinic clients. abstracted data were queried for missing information. clinic source documents were reviewed to resolve queries and update the study database. analysis we sought to describe operational and technical feasibility based on whether the hivst kiosks could be used within the overall clinic flow and whether their use was sustained during the pilot period (e.g. without equipment breakdown), whether clinic clients would use the hivst system, whether the digital tablet assistance was used by clients, and whether testing was completed with results. this was based primarily on the experience of the hivst facilitators and supported by results of hivst volume. data were analysed using stata© version 16 (2019, statacorp llc, college station, texas, us). we calculated the median age of the patients testing for and diagnosed with hiv before and during the implementation phase. additionally, numbers and proportions were used to report categorical variables. we further calculated percentages of hiv confirmatory test outcomes and linkage to art for the categories listed above. we also calculated percentages for hiv test volume and test outcome for the baseline and implementation periods. we used the chi-square test to compare the proportion of clients receiving hts pre-implementation and while hivst was being implemented. ethical considerations an application for full ethical approval was made to the witwatersrand human research ethics committee and ethics consent was received on 11 february 2021. the ethics approval number is 201111. all procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the 1964 helsinki declaration and its later amendments. additionally, as per hiv testing guidelines, all clinic attendees who participated in the aviro pocket clinic hivst provided consent to hiv testing and counselling. for this analysis, all data variables were de-identified. results during the 4-month pre-implementation baseline period, there were 34 393 client visits, with a total of 4999 (14.5%) involving hts. the majority of clients testing for hiv were women (n = 3474; 69.5%); 541 (10.8%) tested hiv positive. the median age of those testing positive was 34 years (interquartile range [iqr]: 28–40 years). during the 4-month implementation period, there were 35 248 client visits in the two health facilities. a total of 6997 (19.9%) of these visits involved hiv testing. of those testing, 2278 (32.6%) used hivst. we excluded 11 patients from the analysis because they were below 18 years of age. among the 2267 clients who used hivst, 1535 (67.7%) were women (table 1). the median age was 28 (iqr: 24–33 years). the median age of those testing positive was 33 years (iqr: 27–38 years). the majority of clients using hivst were aged 18–35 years (table 1). table 1: characteristics of patients who used the aviro pocket clinic hiv self-test platform in the two pilot health facilities. hiv diagnosis of the 2267 clients that used hivst, 1535 were women and 732 were men (table 1). a total of 264 (11.6%) were positive on oraquick, with a similar proportion of women (182/1535; 12%) and men (82/732; 11%) testing positive. one hundred and thirty-five/264 (51.1%) of those testing hiv positive were aged 25–35 years old; 18/264 (6.1%) were aged ≥ 50 years. of the 264 clients who screened hiv-positive, 241/264 (91.3%), received a documented hiv confirmatory test, of which 230/241 (95.4%) were confirmed to be hiv-positive. of those who were confirmed hiv positive, 150/230 (65%) initiated art at the same clinic within 14 days; overall, 184/230 (80%) initiated art within nine months at the same clinic at which they had the testing. role of digitally supported hiv self-test in overall facility hiv testing services the hivst programme increased overall facility hiv tests of patients aged 15 years and above by 25% (14.5% vs 19.9% of clients testing; chi-square p < 0.001), while maintaining a stable hiv testing yield of 11% (figure 3). the hivst positivity yield was 12% – similar to traditional hts. importantly, the use of this platform almost doubled the number of youth (aged 18–35) diagnosed with hiv, increasing from 240 to 453 (figure 3). figure 3: comparison of facility hiv testing services before and during ithaka (1 february 2019 – 30 september 2019). discussion clinic-based digitally supported hivst increased hiv test volume without decreasing the hiv testing yield in a pilot study in two clinics in south africa. clinic-based hivst was able to increase volume without requiring increased space and with only a modest increase in human resources. hiv self-test has considerable promise that includes demonstrated acceptability22,23 and access to more difficult-to-reach populations.24,25 our study builds on prior work of digitally supported hivst that took place in patients’ homes. using this method, it was found that 70% patients logged into the digital application, and 22% reported their hiv test results. the acceptability of digital hivst support has previously been reported from a qualitative study.26 a meta-analysis of digital support for hiv testing noted that digital support increased hivst when compared with its absence.27 the acceptability and usability of the specific digital support platform used in this study (aviro pocket clinic, previously named ithaka28), as well as other digital platforms used in community or clinic testing, have previously been reported.26,27,28 prior studies of facility hivst have reported an increase in hiv testing compared to standard hiv testing. a study of facility-based hivst that did not use digital assistance required a considerable increase in healthcare worker resources and increased space to complete the testing.29,30 compared to hivst conducted away from health services, health facility-based hivst has the value of being able to rapidly provide confirmatory hiv testing and initiate art among those testing positive. notably, studies of hivst conducted away from health services often have limited data on hiv test outcome, confirmatory testing, and linkage to art.22,31 facility-based hivst has the additional value of being able to directly engage clients in prevention programmes, such as pre-exposure prophylaxis for those at high risk. in south africa and similar settings, space and personnel limitations are a major constraint on the capacity of routine hiv testing.9,32,33 with digitally supported clinic-based hivst, the client manages testing and content can be tailored to the client’s age and gender. this shift from healthcare worker to client testing considerably reduced the human resource requirement, enabling one health worker to provide self-testing support to multiple individuals in private kiosks situated inside a clinic. it is plausible that empowering the client with testing may enhance subsequent care engagement. the digital support element allowed for a uniform content that promoted hiv prevention and the hiv care continuum engagement. we believe that this has the potential to overcome counselling quality and content challenges with current lay-counselor-provided post-test counselling.34 the strength of this study is the integration and assessment of hivst into routine care offered by regular service delivery personnel in public clinics, with minimal intrusion by study staff. a limitation is that only two sites were studied for a relatively short period of 4 months and we relied on a comparison of pre-test data at the same sites over a similarly short period. in addition, we relied on routinely collected data (collected through routine health systems and the aviro pocket clinic). this limited the range of available data and may have affected data quality. for example, we only had age data from the pre-implementation period for individuals who tested hiv positive and not all individuals accessing hts. finally, pre and post comparisons are subject to secular trends unrelated to the study intervention. we conducted the study over a short timeframe which limits the potential of this confounder, but does not eliminate it. conclusion use of technology to support the hiv care continuum from hivst to art initiation to retention in care has the potential to contribute to improved proportions reached along the hiv care continuum. reaching updated 95-95-95 targets will require the use of novel and innovative care engagement approaches. our data support the proposition that digitally supported hivst platforms (and, potentially, other components of the care continuum) enable the shift of the care dynamic toward the client and client-centred care. further studies of hivst implementation and scale-up and digital support platform optimisation are needed to increase hiv testing and diagnosis to reach current targets. acknowledgements competing interests two authors, a.f. and l.s., are employed by the company that developed the digital support platform. all other authors declare that no competing interests exist. authors’ contributions the protocol was developed by c.j.h., t.m. and l.s.; data collection was by n.t.m.-p. and d.t.; data analysis was by n.t.m.-p. and c.j.h.; and the first draft manuscript was written by n.t.m.-p. all authors reviewed and revised the final manuscript. funding information this study was funded by the centers for disease control and prevention (cdc). data availability the data sets used and analysed for this study are available from the corresponding author, n.t.m.-p., on reasonable request. disclaimer the views expressed in this article are those of the authors and not an official position of the institutions or cdc (funder). references ford n, migone c, 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africa, experiences from star demonstration projects in malawi, zambia and zimbabwe. j int aids soc. 2019;22(s1):43–52. https://doi.org/10.1002/jia2.25244 janssen r, engel n, esmail a, et al. alone but supported: a qualitative study of an hiv self-testing app in an observational cohort study in south africa. aids behav. 2020;24(2):467–474. https://doi.org/10.1007/s10461-019-02516-6 mcguire m, de waal a, karellis a, et al. hiv self-testing with digital supports as the new paradigm: a systematic review of global evidence (2010–2021). e clin med. 2021;39:101059. https://doi.org/10.1016/j.eclinm.2021.101059 fischer ae, phatsoane m, majam m, et al. uptake of the ithaka mobile application in johannesburg, south africa, for human immunodeficiency virus self-testing result reporting. s afr j hiv med. 2021;22(1):1–7. https://doi.org/10.4102/sajhivmed.v22i1.1197 dovel k, shaba f, offorjebe oa, et al. effect of facility-based hiv self-testing on uptake of testing among outpatients in malawi: a cluster-randomised trial. lancet glob health. 2020;8(2):e276–e287. https://doi.org/10.1016/s2214-109x(19)30534-0 nichols be, offorjebe oa, cele r, et al. economic evaluation of facility-based hiv self-testing among adult outpatients in malawi. j int aids soc. 2020;23(9):1–8. https://doi.org/10.1002/jia2.25612 masters sh, agot k, obonyo b, napierala mavedzenge s, maman s, thirumurthy h. promoting partner testing and couples testing through secondary distribution of hiv self-tests: a randomized clinical trial. plos med. 2016;13(11):1–15. https://doi.org/10.1371/journal.pmed.1002166 mwisongo a, mehlomakhulu v, mohlabane n, peltzer k, mthembu j, van rooyen h. evaluation of the hiv lay counselling and testing profession in south africa. bmc health serv res. 2015;15(1):1–7. https://doi.org/10.1186/s12913-015-0940-y ahmed s, schwarz m, flick rj, et al. lost opportunities to identify and treat hiv-positive patients: results from a baseline assessment of provider-initiated hiv testing and counselling (pitc) in malawi. trop med int health. 2016;21(4):479–485. https://doi.org/10.1111/tmi.12671 mabuto t, mshweshwe-pakela n, ntombela n, et al. is hiv post-test counselling aligned with universal test and treat goals? a qualitative analysis of counselling session content and delivery in south africa. aids behav. 2021;25(5):1583–1596. https://doi.org/10.1007/s10461-020-03075-x misinterpretation.html letter misinterpretation of the ‘safe sex/no sex’ prevention strategy to the editor: we refer to the letter to the editor by macphail et al. 1 discussing the specifics of whiteside and parkhurst’s article in the april 2010 issue of the journal.2 macphail et al. reported that they theoretically agreed with whiteside and parkhurst that refraining from sex during the acute hiv infection period might reduce the rate of hiv transmission when implemented on a wide scale.1 they summarised the scientific logic of the ‘safe sex/no sex’ prevention strategy, and explained what the acute hiv infection period is and how critical it is in the transmission of hiv. macphail and her colleagues showed interest in the ‘safe sex/no sex’ behavioural intervention and its potential significant contribution to global prevention efforts. however, they misrepresent the core arguments whiteside and parkhurst propose. in their letter they present the ‘safe sex/no sex’ strategy incompletely. for example, they report that ‘the authors suggest that a limited period of population-wide sexual abstinence might be an effective and low-cost method of interrupting the transmission of hiv’ and that ‘a limited period of abstinence might be theoretically infective in limiting hiv transmission’, suggesting that the strategy focuses solely on abstinence. while an important aspect of the strategy, abstinence is not the entire approach, and indeed the benefits of a month-long commitment to ‘safe sex’ behaviour should not be disregarded owing to the perceived infeasibility of a month-long commitment to ‘no sex’. along with considering a limited period of abstinence, whiteside and parkhurst promote ‘safe sex’ or sexual activity engaged in by people who have taken precautions to protect themselves against hiv infection, for instance by adhering to correct and consistent condom use, reducing concurrency, and promoting circumcision and microbicide gel use and other hiv prevention measures. the key arguments for the ‘safe sex/no sex’ prevention strategy are therefore not completely expressed, being reduced to just abstinence. whiteside and parkhurst’s article clearly elucidated that the potential intervention would be an aggressive national campaign to ensure that everyone who is sexually active in a population, whether hiv positive or negative, either commit to 100% condom use or refrain from sexual intercourse over a period of a month or longer.2 macphail et al. reported on research with 37 individuals in lilongwe, malawi, and johannesburg, south africa, to test this theory. their research tested the ‘no sex’ and ‘safe sex’ aspects of the proposed prevention strategy as two distinct and potential interventions to interrupt hiv transmission during the acute infection period. as a result, their findings that there was limited support for the strategy in a population of individuals with known hiv infection, and that there is likely to be even less support from individuals who do not know their status or do not perceive themselves to be at risk of hiv infection, do not adequately indicate the potential challenges the ‘safe sex/no sex’ prevention strategy is likely to encounter, as the study investigated ‘safe sex’ and ‘no sex’ as different interventions, not one as proposed in the ‘safe sex/no sex’ prevention strategy. this does not mean that macphail et al.’s research is not important – it will help to articulate the difficulties with a straight ‘no sex’ approach to the intervention, as well as pointing towards other potential barriers. it does not invalidate the intervention strategy, and perhaps even suggests the need to test out a strategy that is focused on both abstinence and safe sex. we have reason to believe that, while difficult, an intervention that focuses on promoting both ‘safe sex’ and ‘no sex’ has the potential to be successful. in a recent qualitative study of the ‘conceptual impact’ of this strategy, we found that most of the participants (members of non-governmental organisations (ngos), academia, the department of health, the media and hiv/aids researchers) were in favour of the ‘safe sex/no sex’ prevention strategy (unpublished data). the great majority of the positive respondents reported that it should be implemented because it focuses on both infected and uninfected individuals without necessarily requiring people to know their hiv status. the concern of many participants was the personal or individual willingness and commitment of both infected and uninfected individuals to abstain or engage in safe sex, and not the support they would get in the population to abstain or engage in safe sex, as reported by macphail et al.1 in our study, a handful of participants, 2 out of 4, were not in favour of the idea that reported that the ‘safe sex/no sex’ prevention strategy would not work due to lack of interpersonal support in the population.3 in our study, participants in favour of the ‘safe sex/no sex’ prevention strategy believed that it would uphold and promote rights of privacy of individuals and therefore cause less stigma and discrimination based on hiv status. participants explained that this would make it easy to mobilise individuals and communities to abstain from sex or engage in safe sex, as it can be done without distinction of whether one is hiv-positive or negative. however, organisers of the prevention strategy would be aware of the hiv status of the populations as this would help them to monitor the average hiv viral load in the population before, during and after the period of abstinence and safe sex to see how much it impacted on infectiousness, and to get better estimates of effectiveness in practices. the argument by macphail et al. that the ‘safe sex/no sex’ prevention strategy may have less support from individuals because they did not know their status or perceived that they were not at risk of hiv infection1 was not reported as a barrier (in our study) to the feasibility and acceptability of the ‘safe sex/no sex’ prevention strategy.3 this is attributed to the fact that the study investigated the feasibility and acceptability of both ‘safe sex’ and ‘no sex’ as one strategy, implied by the ‘safe sex/no sex’ prevention strategy championed by whiteside and parkhurst. as we have found that in theory there is wide support for this prevention strategy (including support by macphail et al.), it would be of benefit to the entire hiv/aids research community for it to be properly articulated and debated. to reduce the strategy to a period of abstinence, as macphail et al.’s letter to the editor did, obscures the proposed strategy and may prevent us from properly engaging with a very promising prevention effort. g mutinta a whiteside health economics and hiv/aids research division, university of kwazulu-natal, durban references 1. macphail c, pettifor a, corneli a. feasibility and acceptability of sexual abstinence for interruption of hiv transmission among individuals with acute infection – formative data from chavi 011. southern african journal of hiv medicine 2011;12(2):46. 1. macphail c, pettifor a, corneli a. feasibility and acceptability of sexual abstinence for interruption of hiv transmission among individuals with acute infection – formative data from chavi 011. southern african journal of hiv medicine 2011;12(2):46. 2. whiteside a, parkhurst jo. innovative responses for preventing hiv transmission: the protective value of population-wide interruptions of risk activity. southern african journal of hiv infection 2010;11(1):19-21. 2. whiteside a, parkhurst jo. innovative responses for preventing hiv transmission: the protective value of population-wide interruptions of risk activity. southern african journal of hiv infection 2010;11(1):19-21. 3. mutinta g, mcalister h, ga’al k. an explorative study on the ‘conceptual impact’ of the ‘safe sex/no sex’ hiv prevention strategy. african journal for hiv research (in press). 3. mutinta g, mcalister h, ga’al k. an explorative study on the ‘conceptual impact’ of the ‘safe sex/no sex’ hiv prevention strategy. african journal for hiv research (in press). abstract introduction methods results discussion conclusion acknowledgements references about the author(s) jeffrey bolon department of internal medicine, charlotte maxeke johannesburg academic hospital, johannesburg, south africa amy samson department of internal medicine, charlotte maxeke johannesburg academic hospital, johannesburg, south africa natalie irwin division of medical oncology, department of internal medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa division of medical oncology, department of internal medicine, charlotte maxeke johannesburg academic hospital, johannesburg, south africa lyle murray division of infectious diseases, department of internal medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa division of infectious diseases, department of internal medicine, charlotte maxeke johannesburg academic hospital, johannesburg, south africa langanani mbodi division of gynaecological oncology, department of obstetrics and gynaecology, faculty of health sciences, university of the witwatersrand, johannesburg, south africa division of gynaecological oncology, department of obstetrics and gynaecology, charlotte maxeke johannesburg academic hospital, johannesburg, south africa sarah stacey division of infectious diseases, department of internal medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa division of infectious diseases, department of internal medicine, charlotte maxeke johannesburg academic hospital, johannesburg, south africa nicholas aikman department of internal medicine, charlotte maxeke johannesburg academic hospital, johannesburg, south africa louell moonsamy department of internal medicine, charlotte maxeke johannesburg academic hospital, johannesburg, south africa jarrod zamparini department of internal medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa obstetric internal medicine unit, department of internal medicine, charlotte maxeke johannesburg academic hospital, south africa citation bolon j, samson a, irwin n, et al. an audit of adherence to cervical cancer screening guidelines in a tertiary-level hiv clinic. s afr j hiv med. 2023;24(1), a1490. https://doi.org/10.4102/sajhivmed.v24i1.1490 original research an audit of adherence to cervical cancer screening guidelines in a tertiary-level hiv clinic jeffrey bolon, amy samson, natalie irwin, lyle murray, langanani mbodi, sarah stacey, nicholas aikman, louell moonsamy, jarrod zamparini received: 22 feb. 2023; accepted: 11 apr. 2023; published: 26 may 2023 copyright: © 2023. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: cervical cancer is the most common malignancy affecting south african women aged 15–44 years, with a higher prevalence among women living with hiv (wlwh). despite recommendations for a screening target of 70%, the reported rate of cervical cancer screening in south africa is 19.3%. objectives: to investigate the adherence of healthcare workers to cervical cancer screening guidelines in a tertiary-level hiv clinic. method: a retrospective cross-sectional record audit of women attending the charlotte maxeke johannesburg academic hospital hiv clinic over a 1-month period. results: out of 403 wlwh who attended the clinic, 180 (44.7%) were screened for cervical cancer in the 3 years prior to the index consultation. only 115 (51.6%) of those women with no record of prior screening were subsequently referred for screening. women who had undergone screening in the previous 3 years were significantly older (47 years vs 44 years, p = 0.046) and had a longer time since diagnosis of their hiv (12 years vs 10 years, p = 0.001) compared to women who had not undergone screening. there was no significant difference in cd4 count or viral suppression between women who had and had not undergone screening. conclusion: the rate of cervical cancer screening in our institution is below that recommended by the world health organization and the south african national department of health. keywords: hiv; cervical cancer; prevention; women’s health; oncology what this study adds: this study highlights the low rate of cervical cancer screening among women living with hiv. introduction despite being a preventable disease, cervical cancer is the second most common malignancy affecting south african women, second only to breast cancer, and is the most common malignancy in women aged between 15 and 45 years. approximately 11 000 women are diagnosed with and 5900 women die from cervical cancer annually in south africa.1,2 southern africa has the highest incidence of hiv worldwide, with the overall prevalence in south africa being 13.9%. however, this percentage is considerably higher in south africa’s female population with current statistics showing that 24.1% of women of childbearing age are living with hiv.3 women living with hiv (wlwh) are six times more likely to develop cervical cancer compared to hiv-negative women, and the malignancy is classified as an aids-defining illness.4 furthermore, wlwh are more likely to progress to more advanced stages of cervical cancer at a younger age compared to women who are hiv-negative. in a cohort of patients in the early stages of the hiv pandemic, it was shown that wlwh presented with invasive cervical cancer up to 10 years earlier than women without hiv infection.5 data from the charlotte maxeke johannesburg academic hospital (cmjah) postnatal clinic showed that 47% of wlwh who had a papanicolaou (pap) smear done in the postnatal period had an abnormal smear.6 although the increased risk of cervical cancer seen in wlwh is most likely multifactorial, severe immunosuppression and higher rates of coinfection with high-risk strains of human papillomavirus (hpv) are key factors.4,7 therefore, important strategies in preventing cervical malignancies in wlwh include regular cervical cancer screening followed by appropriate management of abnormal results, hpv vaccination and hiv viral suppression using antiretroviral treatment (art) with resultant immune reconstitution.8 the world health organization (who) has estimated that to prevent 62 million deaths from cervical cancer over the next 100 years, and effectively eliminate the disease, a cervical cancer screening target of 70% needs to be met by 2030 (in addition to hpv vaccination and treatment targets of 90%).9,10 south africa has set itself the same target of 70% screening coverage; however, this target was not met for the period 2000–2004, nor for the period 2005–2014 according to the national health laboratory service (nhls) national cytology statistics.11,12 furthermore, it has been shown that coverage of cervical cancer screening in south africa may be as low as 19.3%.2 the south african society of obstetricians and gynaecologists (sasog) currently recommends that in wlwh cervical cancer screening should start at the time of hiv diagnosis and continue three-yearly in low-resource settings, or annually in high-resource settings, and continue throughout the woman’s lifetime. the south african national guidelines recommend three-yearly screening from the time of hiv diagnosis.11,12,13 considering the association between hiv and cervical cancer we aimed to investigate the adherence of healthcare workers to nationally recommended cervical cancer screening guidelines in a tertiary-level hiv clinic. methods study design we conducted a retrospective cross-sectional record audit of all female adult patients attending the cmjah hiv clinic from 01 october 2020 to 31 october 2020. the cmjah hiv clinic is a large tertiary-level hiv clinic that acts as a referral centre for people living with hiv from urban johannesburg and surrounds. approximately 10 000 patients are seen per year, 60% of whom are women. a minimum of 214 files needed to be audited to achieve a 95% confidence level with a 5% of margin error. male patients were excluded from the study as were female patients under the age of 18, and those who had undergone a total hysterectomy. data collection data, including demographic data, date of last cervical screening, result of previous cervical screening, record of referral for cervical screening, time since hiv diagnosis, most recent cd4 count, hiv viral load (vl) within the previous year and record of any previously abnormal cervical screening or previous hysterectomy, were captured directly from patient files using google forms (google llc, mountain view, california, united states) and subsequently exported into microsoft excel 16.67 (microsoft corporation, redmond, washington, united states) for analysis. data were not retrieved from the nhls as the study was an audit of the clinic record. no patient identifying data were collected; however, files were marked once analysed to avoid duplicate data entry. data analysis data were analysed using microsoft excel 16.67 (microsoft corporation, redmond, washington, united states) and prism 8.4 (graphpad software inc., la jolla, california, united states). non-parametric statistical tests were used as data were non-normally distributed using the shapiro-wilk normality test. categorical variables, such as the number of women who had undergone a cervical smear, are presented as percentages and frequencies, and pearson’s chi-square test was used to analyse differences in categorical data between groups. continuous variables such as age, cd4 and hiv vl are presented as medians with interquartile ranges (iqrs), and the mann-whitney test was used to compare continuous variables between two groups. a p-value < 0.05 was considered statistically significant. ethical considerations permission to conduct the study was granted by the research committee and head of internal medicine at cmjah. ethical clearance was obtained from the university of the witwatersrand human research ethics committee (medical) with clearance certificate m2011107. the study was also registered on the national health research database. results during the period under audit, 430 wlwh were seen at the clinic. twenty-six women had undergone a previous total hysterectomy and one was under the age of 18 years, resulting in a final cohort of 403 women. the median age of this cohort was 46 years (iqr: 39–52 years). the median time from diagnosis to the index consultation was 132 months (iqr: 84–176 months). two hundred and thirty women (57%) had a known month and year of hiv diagnosis and the remainder, 173 (43%), only a known year of diagnosis. in the case of woman without a known month of diagnosis the month of diagnosis was assumed to be january for calculation purposes. a cd4 count was available for 389 women. the median cd4 count for those with available data was 523 cells/mm3 (iqr: 345 cells/mm3 – 722 cells/mm3) and 36 women (8.9%) had a cd4 count of less than 200 cells/mm3 at the index consultation. hiv vl data was available for 402 women (99.8%) and most women (n = 343, 85%), were virologically suppressed (vl < 50 copies/ml). twenty-five women (6%) had an unsuppressed vl (> 1000 copies/ml). concerningly, only 180 women (44.7%) were noted to have undergone cervical cancer screening in the 3 years prior to the index consultation and 223 (55.3%) had no record of screening in the same period. among women who had undergone cervical cancer screening in the preceding 3 years, 96 smears (53.3%) were reported as negative for intraepithelial malignancy (nilm), 16 (8.9%) as low-grade squamous intraepithelial lesion (lsil), 6 (3.3%) as high-grade intraepithelial squamous lesion (hsil) and 4 (2.2%) had lesions recorded as ‘other’. fifty-eight (32.2%) women did not have a smear result recorded in their clinic file despite having undergone screening. the differences between screened and unscreened women are described in table 1. women who had undergone cervical cancer screening in the preceding 3 years were significantly older (47 years vs 44 years, p = 0.046) and had a longer time since diagnosis of their hiv (144 months vs 126 months, p = 0.0011) compared to women who had not undergone a cervical smear. there was no significant difference in cd4 count (529 cells/mm3 vs 521 cells/mm3, p = 0.247) nor rate of viral suppression (86.1% vs 84.3%, p = 0.674) between women who had and had not undergone screening. table 1: comparison of women who were and were not screened for cervical cancer in the 3 years prior to the index consultation. in the 223 women who had no record of previous cervical cancer screening only 115 (51.6%) women were noted to have been subsequently referred for screening, as shown in table 2. table 2: comparison of women who had not been screened for cervical cancer in the 3 years prior to the index consultation and who were or were not referred for screening. there was no significant difference in the age of women who had and had not been referred for a cervical smear (45 years vs 44 years, p = 0.496); however, women who were referred for a cervical smear had a median time since hiv diagnosis that was longer than those who were not referred for a smear (132 months vs 118 months, p = 0.021). there was no significant difference in cd4 count (530 cells/mm3 vs 519 cells/mm3, p = 0.900) between the two groups; however, there was a significantly higher rate of viral suppression in women who were referred compared to those who were not (89.6% vs 79.4%, p = 0.041). discussion women living with hiv have a significantly increased risk of cervical cancer. ongoing population-wide efforts to detect non-invasive disease are recommended across national and international guidelines.10,11 in recent years, public health measures to improve accessibility to cervical cancer smear testing for all south african women, and in particular those living with hiv, have been implemented. however, data evaluating adherence and uptake of guideline-recommended screening are lacking.12 in this audit, we report on 403 wlwh attending a large hiv clinic in a tertiary centre with direct access to gynaecology services, in johannesburg. we show that the target of the national programme for cervical cancer screening was not met. fewer than half (44.7%) of the women seen during the study period had undergone screening for cervical cancer within the preceding 3 years. in a similar cross-sectional study among wlwh in uganda, 44% of women had ever been screened for cervical cancer, with 16.1% having been screened in the preceding year.14 while the screening rate in our clinic is well above the national cervical screening rates previously published, it fails to meet both who and national guidelines for cervical cancer screening and raises concerns for the cervical cancer screening programme in smaller clinics at both primary care and district level. women who had undergone screening for cervical cancer were significantly older than those who had not undergone screening. this may reflect adherence to national guidelines for women without hiv (i.e. screening at age 30, 40 and 50 years) and lack of knowledge of the hiv-specific guidelines. while this result is statistically significant it may not be clinically relevant; considering the median age in both groups was greater than 40 years. we observed that women who had undergone screening were more likely to have been living with hiv for longer, suggesting that women in care for longer are more likely to be aware of the need for cervical cancer screening and may request referral or self-refer for screening. this is similar to a finding in an ethiopian study where uptake of cervical cancer screening was significantly higher in women who had been living with hiv for 10 years or longer.15 individuals who are in hiv care for longer also have more opportunity to be referred for cervical cancer screening. linked to this is the correlation between viral suppression and referral for cervical screening: clinicians may assess women who are virally suppressed as needing less hiv-related care, providing more time to discuss health promotional measures. among those with no record of previous cervical cancer screening, just over half were subsequently referred for screening. those who were referred for screening were more likely to be virologically supressed and had been living with hiv for longer, again suggesting that repeat and long-term contact with the healthcare system increases the likelihood of implementation of health promotional measures. it was not possible to assess reasons for lack of referral in this study as a formal assessment through staff interviews has not taken place. however, women requiring cervical screening are referred to their local (primary care) clinic and there is no standard form or referral letter in use for this. this may reflect an extra administrative burden where clinicians are required to write a referral letter for their patients to have cervical screening. sigfrid and colleagues suggest that integrating hiv care and cervical cancer screening is both ‘feasible as well as acceptable to women living with hiv’.7 considering this, a further reflection is the lack of a ‘single-visit’ approach for both hiv care and cervical cancer screening. women are required to attend a primary health clinic for their cervical screening, as noted above, placing an additional time and financial burden on them. further studies are needed to evaluate if the establishment of a dedicated cervical screening service within our hospital for women at high risk would improve screening rates as it has in other studies.16,17,18 considering the prevalence of hiv in south africa and the known links between hiv and cervical cancer, an hiv clinic serves as an ideal site for cervical cancer screening. alternatively, an organised referral system to a dedicated screening facility would greatly improve the number of women referred for screening – this could be initiated through utilisation of currently available gynaecology services in our hospital. finally, we are encouraged by the number of wlwh in our clinic who had a recent vl and by the rate of viral suppression among wlwh in our clinic. limitations our study was limited by its retrospective nature in that incomplete patient notes may have limited the amount of information captured from each file – women may have been referred for or undergone cervical cancer screening but not had this noted in their file. additionally, the nhls system was not checked when results were not recorded in the patient record, thus several patients may have been screened with the result not recorded in the patient record. conclusion our study suggests poor adherence to guideline-recommended cervical cancer screening among wlwh in a single specialised centre. the care of people living with hiv is a complex and multifaceted task involving treatment of existing pathology and screening for co-morbid conditions, including cervical cancer. although this study exhibited promising rates of viral suppression, that is not the only objective of hiv care. our audit has highlighted substantial gaps in cervical cancer screening as part of the overall management of wlwh at a tertiary-level. this raises concerns for the cervical cancer screening programmes at other tertiary hospitals and, perhaps, more so at lower-level facilities. furthermore, it highlights the challenges associated with a compartmentalised approach to hiv care with different tasks allocated to different facilities. this ultimately adds further time and financial burdens onto the patient and increases the risk of poor adherence. the reasons for these gaps in care are unclear; however, this audit may serve as a baseline reference to necessitate an intervention and prompt future investigation and quality improvement audits to improve overall care and patient outcomes. acknowledgements the authors wish to thank the staff of the cmjah hiv clinic for their assistance with data collection. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions j.z. and n.i. conceived the study. j.b., a.s., l. moonsamy and n.a. were responsible for data collection and cleaning. a.s. and j.z. performed statistical analysis. j.z., l. murray, n.i., l. mbodi and s.s. drafted the initial manuscript and all authors contributed to the final manuscript. funding information the authors received no financial support for the research, authorship or publication of this article. data availability the data that support the findings of this study are available from the corresponding author, j.z., upon reasonable request. disclaimer the views expressed in the submitted article are the authors’ own and not an official position of the institution. references denny l, kuhn l. cervical cancer prevention and early detection from a south african perspective. in: padarath a, barron p, editors. south african health review 2017 [homepage on the internet]. durban: health systems trust; 2017 [viewed 2022 nov 01]. available from: 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women at johannesburg hospital [mmed thesis] [homepage on the internet]. university of the witwatersrand; 2010 [viewed 2022 oct 21]. available from: http://hdl.handle.net/10539/9157 sigfrid l, murphy g, haldane v, et al. integrating cervical cancer with hiv healthcare services: a systematic review. plos one. 2017;12(7):e0181156. https://doi.org/10.1371/journal.pone.0181156 stelzle d, tanaka lf, lee kk, et al. estimates of the global burden of cervical cancer associated with hiv. lancet glob health. 2021;9(2):e161–e169. https://doi.org/10.1016/s2214-109x(20)30459-9 tsu vd. cervical cancer elimination: are targets useful? lancet. 2020;395(10224):539–540. https://doi.org/10.1016/s0140-6736(20)30219-1 world health organization. global strategy to accelerate the elimination of cervical cancer as a public health problem [homepage on the internet]. geneva: world health organization; 2020 [viewed 2022 oct 20]. available from: https://www.who.int/publications/i/item/9789240014107 south african society of obstetrics and gynaecology. guideline document cervical cancer screening in south africa 2015 [homepage on the internet]. south african society of obstetrics and gynaecology; 2015 [viewed 2022 oct 20]. available from: https://sasog.co.za/wp-content/uploads/2019/05/sasog_screening_for_cervical_cancer_november_final.pdf jordaan s, michelow p, simoens c, bogers j. challenges and progress of policies on cervical cancer in south africa. health care curr rev. 2017;5:188. https://doi.org/10.4172/2375-4273.1000188 botha m, richter k. guidelines for cervical cancer screening in south africa. s afr j gynaecol oncol. 2017;9(1):8–12. sarah maria n, olwit c, kaggwa mm, nabirye rc, ngabirano td. cervical cancer screening among hiv-positive women in urban uganda: a cross sectional study. bmc womens health. 2022;22(1):148. https://doi.org/10.1186/s12905-022-01743-9 nega ad, woldetsadik ma, gelagay aa. low uptake of cervical cancer screening among hiv positive women in gondar university referral hospital, northwest ethiopia: cross-sectional study design. bmc womens health. 2018;18(1):87. https://doi.org/10.1186/s12905-018-0579-z rao dw, bayer cj, liu g, et al. modelling cervical cancer elimination using single-visit screening and treatment strategies in the context of high hiv prevalence: estimates for kwazulu-natal, south africa. j int aids soc. 2022;25(10):e26021. https://doi.org/10.1002/jia2.26021 shiferaw n, salvador-davila g, et al. the single-visit approach as a cervical cancer prevention strategy among women with hiv in ethiopia: successes and lessons learned. glob health sci pract. 2016;4(1):87–98. https://doi.org/10.9745/ghsp-d-15-00325 mpata pc, nkosi zz. experiences of cervical cancer screening in hiv-positive women in zimbabwe. curationis. 2021;44(1):e1–e7. https://doi.org/10.4102/curationis.v44i1.2184 d e c e m b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e antiretroviral agents have led to dramatic advancements in life expectancy and quality of life for people living with hiv/aids. despite this progress, lower income countries are forced to use older, less expensive antiretrovirals such as stavudine, which are associated with a relatively high frequency of late toxic effects. nevertheless, the older antiretrovirals are likely to remain the backbone of the national first-line highly active antiretroviral therapy (haart) regimen in south africa for the foreseeable future due to cost constraints.1,2 one of the more common late toxic effects of older antiretrovirals is lipodystrophy syndrome (ld). ld is an umbrella term referring to peripheral lipo atrophy (la), central lipohypertrophy (lh), and dyslipidaemia associated with insulin resistance.3,4 these may occur alone or in combination. although ld was initially thought to be a syndrome of fat redistribution resulting in peripheral la combined with central lh, preliminary data from the fram study in adults (study of fat redistribution and metabolic change in hiv infection)5 indicate that lh and la are less closely linked than was previously presumed. other authors have also noted that lh and la often occur independently of one another.6 in addition, dyslipidaemia associated with haart may occur in the absence of la or lh.7 la results in disfigurement, particularly of the face (figs 1 6), which can lead to stigmatisation and even forced disclosure of hiv status. this disfigurement has a major impact on adherence, particularly in adolescents.3,6,7 in addition, the long-term health consequences of ld in hiv-infected children, who require lifetime antiretrovirals, are considerable: the most important consequence arises from dyslipidaemia and insulin resistance, which are known to significantly accelerate lifetime risk for cardiovascular disease in hiv-infected adults with ld.8 it is unclear whether transient drug-induced dyslipidaemia in childhood increases the lifetime risk of cardiovascular disease in children.9,10 nonetheless, these negative health outcomes are of concern given that the prevalence of haart-related ld in resource-limited settings may be as high as 47% after 2 years of therapy.6 the mechanisms of ld have not yet been firmly established. the mechanism of la is related to mitochondrial damage, particularly in adipocytes.11 haart-related apoptosis of adipocytes and suppression of pre-adipocyte differentiation have been described in protease inhibitor (pi)-induced la.12 a similar mechanism may occur in nucleoside reverse transcriptase inhibitor (nrti) induced ld, since it is known that nrtis such as stavudine can damage adipocyte mitochondria11 and cause a reduction in functioning mitochondria in adults.13 other chronic toxic effects such as lactic acidosis and peripheral neuropathy have also been associated with mitochondrial dysfunction.14,15 it has been suggested lipodystrophy syndrome in hivinfected children on haart c l i n i c a l steve innes1, mb bch, mrcpch leon levin2, mb bch, fcpaed (sa), dtm&h mark cotton1,3, mb chb, mmed, phd, fcpaed, dtm&h, dch (sa) 1kid-cru (children’s infectious diseases clinical research unit), tygerberg children’s hospital and stellenbosch university, tygerberg, w cape 2paediatric hiv programmes, right to care, johannesburg 3paediatric infectious diseases unit, department of paediatrics and child health, tygerberg children’s hospital lipodystrophy syndrome (ld) is common in hiv-infected children, particularly those taking didanosine, stavudine or zidovudine. lipo-atrophy in particular causes major stigmatisation and interferes with adherence. in addition, ld may have significant long-term health consequences, particularly cardiovascular. since the stigmatising fat distribution changes of ld are largely permanent, the focus of management remains on early detection and arresting progression. practical guidelines for surveillance and avoidance of ld in routine clinical practice are presented. the diagnosis of ld is described and therapeutic options are reviewed. the most important therapeutic intervention is to switch the most likely offending antiretroviral to a non-ld-inducing agent as soon as ld is recognised. typically, when lipo-atrophy or lipohypertrophy is diagnosed the thymidine nucleoside reverse transcriptase inhibitor (nrti) is switched to a non-thymidine agent such as abacavir (or tenofovir in adults). where dyslipidaemia is predominant, a dietician review is helpful, and the clinician may consider switching to a protease inhibitor-sparing regimen or to atazanavir. 76 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e d e c e m b e r 2 0 0 9 that unknown agents released from damaged mitochondria in adipocytes may directly trigger apoptosis which leads to subcutaneous fat loss. quantification of mitochondrial dna in peripheral leucocytes may be an early warning sign of impending ld in patients exposed to antiretrovirals.16,17 circulating growth hormone (gh) levels are significantly reduced in patients with la/lh, and this is likely to aggravate the abnormal fat distribution.18 haart-related dyslipidaemia is thought to be mediated by a different, though related, mechanism: pi-induced alterations in adipokines and pro-inflammatory cytokines cause an increased production of triglycerides and cholesterol in hepatocytes, while simultaneously inhibiting glucose uptake in peripheral adipocytes.19 the risk of developing ld is strongly related to the dosage and duration of exposure to antiretroviral agents. the thymidine nrtis (zidovudine and stavudine) and didanosine have been linked to la/lh.20,21 in comparison, abacavir, tenofovir, and lamivudine have minimal or no la/lh-causing effect.22 non-nucleoside reverse transcriptase inhibitors (nnrtis) are considered a less potent cause of la.7 although efavirenz has been associated with lipomastia in some children, this usually resolves spontaneously without withdrawal of efavirenz.23,24 pis have been linked to dyslipidaemia,25 and less strongly to la/lh.21,26 stavudine, in particular, has been found to be a potent cause of la in children when taken in the standard paediatric dose of 1 mg/kg/dose twice daily.3,7,27,28 owing to the long-term toxicity of this dose, stavudine is now rarely used in the developed world. a review by hill et al.29 has recently led the world health organization (who) to recommend a reduction in the standardised dose of stavudine for adults weighing over 60 kg from 40 mg to 30 mg twice daily,30 since it has been shown that a reduced dose results in a markedly lower risk of ld, while maintaining excellent antiviral efficacy.31,32 the recommended dose of stavudine for children, however, has not yet been reduced. since the dose of stavudine is a major risk factor for the development of ld,33 it would be reasonable to expect that the incidence of ld will fall when a lower dose is employed. the current standard paediatric dose of stavudine (1 mg/kg/ dose twice daily) was extrapolated from the pharmacokinetic parameters of the adult dose of 40 mg twice daily, using data from a few small but well-controlled paediatric pharmacokinetic studies34-36 which showed that an oral dose of 1 mg/kg/dose twice daily in children under 12 years results in plasma exposure similar to that of adults taking 40 mg twice daily, and that an oral dose of 0.5 mg/kg/dose twice daily in children results in plasma exposure similar to that of adults taking 20 mg twice daily. particular mitochondrial dna sub-groups (haplogroups) have been associated with a vulnerability to developing la after exposure to haart.37 a recent study showed that caucasian american men on haart who have the h mitochondrial haplogroup were at significantly increased risk of la.37 in addition, certain mitochondrial dna mutations may make an individual more vulnerable to developing ld when exposed to antiretroviral agents. this may occur because variations of mitochondrial dna in adipocytes may reduce the efficiency of energy production or lead to increased oxygen free-radical production, resulting in a reduced mitochondrial reserve and an increased vulnerability to apoptosis when exposed to mitochondrial toxins such as antiretrovirals. 77 significance of lipodystrophy syndrome • lipodystrophy syndrome (ld) is common in hivinfected children, particularly in those taking didanosine, stavudine or zidovudine. • lipo-atrophy (la) (a component of ld) causes major stigmatisation and interferes with adherence. • ld may have significant long-term health consequences, particularly cardiovascular. • la is largely permanent, so the focus remains on early detection and arresting progression. what to look out for • look for a lean, muscular appearance of face and limbs with prominent limb veins due to loss of subcutaneous fat tissue. • compare the child’s tricep and bicep skin-fold thickness with your own as a rough guide. • shrinking buttocks with or without an enlarging abdomen may be monitored using a waist-tohip ratio (whr). • children on haart should have their blood lipids measured routinely every year. what to do where subcutaneous la or lipohypertrophy is diagnosed: • the most likely offending nrti should be switched to abacavir (or tenofovir in adults). where dyslipidaemia is predominant: • a dietician review is helpful. • consider switching to a pi-sparing regimen or to atazanavir. • look for insulin resistance. • statins and metformin are only used in extreme cases. risk factors d e c e m b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 78 a complex set of diagnostic criteria for the diagnosis of ld has been developed for adults by carr et al.38 equivalent diagnostic criteria for children have not been formally defined. most clinicians employ a combination of objective anthropometric and biochemical measurements and a subjective assessment in order to diagnose ld in children.6,7,33,39,40 physical signs in children are due to loss of subcutaneous fat in limbs, buttocks and face, with or without accumulation of intra-abdominal visceral fat. loss of limb fat results in prominent limb veins and a well-defined, muscular appearance of limbs in the presence of a normal or enlarged abdomen. reduced skin-fold thickness (sft) may be subjectively assessed by comparing it with one’s own sft as a rough guide. loss of buttock fat, with or without enlargement of the abdomen, results in a greatly increased waist-tohip ratio (whr). breast enlargement and buffalo hump may occur after puberty. other useful anthropometric measurements include mid-upper arm circumference (muac) and waist circumference, from which the waist-to-muac ratio can be calculated. sft measurements may be used to calculate the torso-to-arm ratio (tar) as follows: tar = [subscapular + suprailiac skf]/ [bicep + tricep sft]. a tar z-score of >2.0 has been used as a diagnostic criterion in some studies.39 as haart-related dyslipidaemia may occur independently of la/lh,5-7 children on haart should have their blood lipids measured routinely at least once a year. facial fat loss is often subtle and difficult to detect unless severe. the facial muscles are not normally noticeable because they are covered in fat. loss of facial fat results in a lean, muscular appearance of the face with deep laugh-lines when smiling. an old photograph may be helpful. figs 1 and 2 show a child with mild la of the face. some recovery is seen 4 years after changing from a stavudine-containing regimen (fig. 3). fig. 4 shows a child with moderate facial la. figs 5 and 6 show a child with severe facial la. her la was already advanced when she was changed from a stavudine-containing regimen 4 years previously, and is unlikely to improve. to date there are limited data comparing the sensitivity and specificity of anthropometric and biochemical diagnostic criteria against a gold standard such as dual-energy x-ray absorptiometry or magnetic resonance imaging to diagnose early la/lh in hiv-infected children. studies are underway to define a practical set of diagnostic criteria to detect early ld in children in resource-limited settings. since at least 30% of peripheral fat must be lost before la becomes visibly evident,41 it is hoped that some combination of anthropometric and biochemical measures will have reasonable sensitivity and specificity to detect la/lh in children before it causes noticeable disfigurement (s innes et al. – unpublished data). this will be an important contribution to paediatric hiv care in the developing world. fig. 2. mild la of the face, side view. fig. 1. mild la of the face, front view. diagnosis fig. 3. the same child as in fig. 1. some recovery is seen 4 years after withdrawal of stavudine. t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e d e c e m b e r 2 0 0 9 since the disfiguration caused by ld is largely permanent, the focus of management is on early detection and arrest of progression. once identified, the most likely offending drug is usually withdrawn in an attempt to prevent progression, and is replaced by a less ld-inducing antiretroviral. where dyslipidaemia is identified, diet and lifestyle modification are essential. if severe and persistent (total cholesterol >13 mmol/l or triglycerides >8.5 mmol/l),1 the pi may be switched to a pi-sparing agent or changed to atazanavir/ritonavir (atv/r), which has less effect on blood lipids.21 the effect of statins in lowering triglycerides and cholesterol is well established;42 however, statins are only licensed for use in children over 12 years of age. the potential interaction of statins with pis must be borne in mind. metformin has been shown to be effective for ld-related insulin resistance in adults43 and for obesity-related insulin resistance in hiv-uninfected children.44 however, metformin is rarely used in ld-related insulin resistance in children. when la/lh is diagnosed, significant benefit in halting progression has been shown from switching the thymidine nrti to a non-thymidine agent such as abacavir.21 tenofovir is generally avoided in children because of renal toxicity and osteopenia. however, there may be a place for switching to tenofovir in older children.45 this switch typically arrests progression of la/lh, and may result in a small degree of reversal if la is caught early. various authors have demonstrated that the more advanced the la, the less likely it is to reverse when the offending drug is removed.46,47 intradermal injections of a biodegradable filler such as poly-l-lactic acid (sculptura) can ameliorate the aesthetic effect of facial la in adults,48 but this treatment is not appropriate for children. in addition, the cost is significant and the effect is not permanent and injections may need to be repeated. uridine (nucleomaxx) partially reverses the mitochondrial toxicity caused by thymidine nrtis, and may have a small but beneficial effect on disfiguring la. uridine is not currently available in south africa, and it has no effect on dyslipidaemia.49 growth hormone-releasing hormone analogues (gh-rh) are helpful in the treatment of la/lh.50 the mechanism probably involves reversing the reduced gh levels that are consistently found in patients with la/lh. although the side-effect profile of gh-rh therapy is attractive, the cost is prohibitive. future treatments may involve adipokines such as leptin, but these remain experimental.21 research into reducing the paediatric dose of stavudine is urgently needed in order to minimise the risk of ld without compromising antiviral efficacy, since the number of at-risk hiv-infected children exposed to long-term stavudine therapy in south africa is very large. in addition, non-thymidine nrtis such as abacavir and tenofovir should be more widely available, particularly in the public sector. 79 fig. 4. moderate la of the face, front view. note the loss of the buccal fat pad, resulting in lean, muscular appearance of the face with deep laugh-lines. fig. 6. severe la of the face, side view. fig. 5. severe la of the face, front view. this patient’s la was already advanced when she was changed from a stavudinecontaining regimen 4 years previously. her la is unlikely to improve. management conclusion d e c e m b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e further research is needed to isolate the particular mitochondrial mutations that make a child vulnerable to ld. this may help public sector clinicians to predict which children should avoid thymidine nrtis and rather be started on a more expensive, less ld-inducing antiretroviral regimen. finally, since effective treatment of ld is difficult and remains beyond the reach of resource-limited rural communities, early detection is paramount. it is essential to define a simple set of diagnostic criteria to identify early ld in children that can be easily implemented in resource-limited settings. this will allow the progression of ld to be halted before it causes noticeable disfigurement and stigmatisation. children should be switched from stavudine (or zidovudine) to abacavir (and adults to tenofovir or abacavir) at the slightest sign of ld. references 1. meyers t, eley b, loening w. khomanani guidelines for the management of hivinfected children. johannesburg: national department of health, jacana media, 2005. 2. hogan b (national minister of health – south africa). southern african aids conference, durban, april 2009. plenary address, 3 april. http://www.saaids.com/images/stories/4th_sa_aids_conference_ presentations/minister%20of%20health.pdf (accessed 16 november 2009). 3. mccomsey ga, leonard e. metabolic complications of hiv therapy in children. aids 2004; 18: 1753-1768. 4. aldrovandi gm, lindsey jc, jacobson dl, et al., for the pediatric aids clinical trials group p1045 team. morphologic and metabolic abnormalities in vertically hiv-infected children and youth. aids 2009; 23: 661-672. 5. tien pc, benson c, zolopa ar, sidney s, osmond d, grunfeld c. the study of fat redistribution and metabolic change in hiv infection (fram): methods, design, and sample characteristics. am j epidemiol 2006; 163(9): 860-869. 6. aurpibul l, puthanakit t, lee b, mangklabruks a, sirisanthana t, sirisanthana v. lipodystrophy and metabolic changes in hiv-infected children on nonnucleoside reverse transcriptase inhibitor-based antiretroviral therapy. antivir ther 2007; 12(8): 1247-1254. 7. ene l, goetghebuer t, hainaut m, et al. prevalence of lipodystrophy in hivinfected children: a cross-sectional study. eur j pediatr 2007; 166(1): 13-21. 8. hadigan c, meigs jb, corcoran c, et al. metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. clin infect dis 2001; 32: 130-139. 9. berenson gs, srinivasan sr, bao w, et al. association between multiple cardiovascular risk factors and atherosclerosis in children and young adults. n engl j med 1998; 338: 1650-1656. 10. girardet jp. dyslipidemia in childhood and cardiovascular risk. arch pediatr 2009; 16: 692-693. 11. walker ua, bickel m, lütke volksbeck si, et al. evidence of nucleoside analogue reverse transcriptase inhibitor-associated genetic and structural defects of mitochondria in adipose tissue of hiv-infected patients. j acquir immune defic syndr 2002; 29(2): 117-121. 12. dowell p, flexner c, kwiterovich po, lane md. suppression of preadipocyte differentiation and promotion of adipocyte death by hiv protease inhibitors. j biol chem 2000; 275: 41325-41332. 13. cote hc, brumme zl, craib kj, et al. changes in mitochondrial dna as a marker of nucleoside toxicity in hiv-infected patients. n engl j med 2002; 346: 811820. 14. hurst m, noble s. stavudine: an update of its use in the treatment of hiv infection. drugs 1999; 58(5): 919-949. 15. dragovic g, jevtovic dj. nucleoside reverse transcriptase inhibitor usage and the incidence of peripheral neuropathy in hiv/aids patients. antivir chem chemother 2003; 14(5): 281-284. 16. montaner js, cote hc, harris m, et al. mitochondrial toxicity in the era of haart: evaluating venous lactate and peripheral blood mitochondrial dna in hiv-infected patients taking antiretroviral therapy. j acquir immune defic syndr 2003; 34: suppl 1, s85-s90. 17. petit c, mathez d, barthelemy c, leste-lasserre t, naviaux rk, sonigo p, leibowitch j. quantitation of blood lymphocyte mitochondrial dna for the monitoring of antiretroviral drug-induced mitochondrial dna depletion. j acquir immune defic syndr 2003; 33: 461-469. 18. rietschel p, hadigan c, corcoran c, et al. assessment of growth hormone dynamics in human immunodeficiency virus-related lipodystrophy. j clin endocrinol metab 2001; 86: 504-510. 19. parker ra, flint op, mulvey r, et al. endoplasmic reticulum stress links dyslipidemia to inhibition of proteasome activity and glucose transport by hiv protease inhibitors. mol pharmacol 2005; 67: 1909-1919. 20. jones sp, qazi n, morelese j, et al. assessment of adipokine expression and mitochondrial toxicity in hiv patients with lipoatrophy on stavudineand zidovudine-containing regimens. j acquir immune defic syndr 2005; 40: 565572. 21. mallewa je, wilkins e, vilar j, et al. hiv-associated lipodystrophy: a review of underlying mechanisms and therapeutic options. j antimicrob chemother 2008; 62(4): 648-660. 22. moyle gj, sabin ca, cartledge j, et al. a randomized comparative trial of tenofovir or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. acquir immune defic syndr 2006; 20: 2043-2050. 23. arranz caso j, de miguel prieto j, casas e, sanz j. gynecomastia without ld syndrome in hiv-infected men treated with efavirenz. aids 2001; 15: 14471448. 24. merciéa p, viallarda jp, thiébaut r, et al. efavirenz-associated breast hypertrophy in hiv-infected patients. aids 2001; 15(1): 126-129. 25. behrens g, dejam a, schmidt h, et al. impaired glucose tolerance, beta cell function and lipid metabolism in hiv patients under treatment with protease inhibitors. acquir immune defic syndr 1999; 13: f63-70. 26. mccomsey ga, walker ua. role of mitochondria in hiv lipoatrophy: insight into pathogenesis and potential therapies. mitochondrion 2004; 4: 111-118. 27. murphy ra, sunpath h, kuritzkes dr, venter f, gandhi rt. antiretroviral therapyassociated toxicities in the resource-poor world: the challenge of a limited formulary. j infect dis 2007; 196: s449-s456. 28. ter hofstede hjm, koopmans pp, burger dm. stavudine plasma concentrations and lipoatrophy. j antimicrob chemother 2008; 61(4): 933-938. 29. hill a, ruxrungtham k, hanvanich m, et al. systematic review of clinical trials evaluating low doses of stavudine as part of antiretroviral treatment. expert opin pharmacother 2007; 8(5): 679-688. 30. addendum to 2006 who guidelines on antiretroviral therapy for hiv infection in adults and adolescents. www.who.int/hiv/en/ (accessed 26 august 2008). 31. sánchez-conde m, de mendoza c, jiménez-nacher i, et al. reductions in stavudine dose ameliorate mitochondrial-associated complications without compromising antiviral activity. hiv clin trials 2005; 6(4): 197-202. 32. mccomsey ga, lore v iii, o’riordan m, et al. effect of reducing the dose of stavudine on body composition, bone density and markers of mitochondrial toxicity in hiv-infected subjects – a randomized, controlled study. clin infect dis 2008; 46(8): 1290-1296. 33. amaya ra, kozinetz ca, mcmeans a, schwarzwald h, kline mw. lipodystrophy syndrome in human immunodeficiency virus-infected children. pediatr infect dis j 2002; 21: 405-410. 34. kaul s, kline mw, church ja, dunkle lm. determination of dosing guidelines for stavudine (2’,3’-didehydro-3’-deoxythymidine) in children with human immunodeficiency virus infection. antimicrob agents chemother 2001; 45(3): 758-763. 35. kline mw, dunkle lm, church ja, et al. a phase i/ii evaluation of stavudine (d4t) in children with human immunodeficiency virus infection. pediatrics 1995; 96(2): 247-252. 36. dudley mn, graham kk, kaul s, et al. pharmacokinetics of stavudine in patients with aids or aids-related complex. j infect dis 1992; 166: 480-485. 37. hendrickson sl, kingsley la, ruiz-pesini e, et al. mitochondrial dna haplogroups influence lipoatrophy after highly active antiretroviral therapy. j acquir immune defic syndr 2009; 51(2): 111-116. 38. carr a, emery s, law m, puls r, lundgren jd, powderly wg. an objective case definition of lipodystrophy in hiv-infected adults: a case-control study. lancet 2003; 361: 726-735. 39. hartman k, verweel g, de groot r, hartwig ng. detection of lipoatrophy in human immunodeficiency virus-1-infected children treated with highly active antiretroviral therapy. pediatr infect dis j 2006; 25(5): 427-431. 40. european paediatric lipodystrophy group. antiretroviral therapy, fat redistribution and hyperlipidaemia in hiv-infected children in europe. aids 2004; 18: 14431451. 41. podzamczer d, ferrer e, martınez e, et al., for the abcde study team. how much fat loss is needed for lipoatrophy to become clinically evident? aids res hum retroviruses 2009; 25(6): 563-567. 42. calza l, manfredi r, chiodo f. statins and fibrates for the treatment of hyperlipidaemia in hiv-infected patients receiving haart. aids 2003; 17: 851859. 43. hadigan c, corcoran c, basgoz n, et al. metformin in the treatment of hiv lipodystrophy syndrome: a randomized controlled trial. jama 2000; 284: 472777. 44. park mh, kinra s, ward kj, white b, viner rm. metformin for obesity in children and adolescents: a systematic review. diabetes care 2009; 32(9): 1743-1745. 45. riordan a, judd a, boyd k, cliff d, et al., on behalf of the chips study. tenofovir use in human immunodeficiency virus-1-infected children in the united kingdom and ireland. pediatr infect dis j 2009; 28: 204-209. 46. mccomsey ga, ward dj, hessenthaler sm, et al., for the tarheel study team (trial to assess the regression of hyperlactatemia and to evaluate the regression of established lipodystrophy in hiv-1-positive subjects). improvement in lipoatrophy associated with highly active antiretroviral therapy in human immunodeficiency virus-infected patients switched from stavudine to abacavir or zidovudine: the results of the tarheel study. clin infect dis 2004; 38: 263-270. 47. fisher m, moyle g, shahmanesh m, et al. for the sweet study group. a randomized comparative trial of continued zidovudine/lamivudine or replacement with tenofovir disoproxil fumarate/emtricitabine in efavirenz-treated hiv-1-infected individuals. j acquir immune defic syndr 2009; 51: 562-568. 48. carey dl, baker d, rogers gd, et al., for the facial lipoatrophy study in hiv (flash). a randomized, multicenter, open-label study of poly-l-lactic acid for hiv-1 facial lipoatrophy. j acquir immune defic syndr 2007; 46: 581-589. 49. mccomsey ga, o’riordan m, setzer b, et al. uridine supplementation in hiv lipoatrophy: pilot trial on safety and effect on mitochondrial indices. eur j clin nutr 2008; 62: 1031-1037. 50. falutz j, allas s, blot k, et al. metabolic effects of a growth hormone-releasing factor in patients with hiv. n engl j med 2007; 357: 2359-2370. 80 s e p t e m b e r 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e the number of new cases of human immunodeficiency virus (hiv) infection in taiwan peaked in 2005, and it is still a serious problem.1 tuberculosis (tb), especially extrapulmonary tb, is also common in taiwan1 and is commonly associated with hiv infection.2 when a patient urgently needs surgery, as can occur with perforation of an intestine or appendix, there is no time for definitive testing for hiv and/or tb. we report a case in which a patient required immediate surgery for what appeared to be an abscess with peritonitis from a perforated diverticulum of the ascending colon. the patient was unaware that he had both extrapulmonary tb and hiv. the tb was discovered by the pathologist on examination of the surgical specimen, and the hiv was discovered because the patient’s postoperative condition suggested a systemic disease. the case illustrates that despite co-occurrence of the two diseases surgery can be successful, recovery can be similar to that expected in a patient without the diseases, and patient outcome can be good if anti-tb and antiretroviral therapies are started almost immediately. the case is also consistent with previous reports that patients with hiv undergoing surgery have similar conditions to hiv-negative patients and that the results of treatment are equivalent.3 case report a 38-year-old man who had been well without systemic disease and neither drank alcohol nor smoked had experienced dull, right lower quadrant abdominal pain for 1 week, and fever with chills for 2 days. he had no other associated symptoms such as nausea, vomiting or diarrhoea. he sought help at the emergency department, where physical examination showed rebound tenderness at the right lower quadrant of the abdomen, with muscle guarding and rigidity. the white blood cell count was 8×109 /l, with 11% band-form neutrophils. an elevated c-reactive protein level (5.77 mg/dl) was noted. after he was admitted on 29 april 2006, an abdominal computed tomography scan revealed an ill-defined mass in the right lower quadrant anterior to the right psoas muscle; it was suspected to be an abscess. there were also several small abscesses in the omentum, paracolic gutter and mesentery of the ascending colon (fig. 1). the clinical impression was that he had perforated diverticulitis with intra-abdominal abscess, and he was immediately operated on. at surgery the abscess was found to be at the ascending colon mesentery. a right hemicolectomy was performed because of the high level of suspicion of a perforated diverticulum (fig. 2). postoperatively, the patient had a high fever for 3 days even with intensive treatment with a secondgeneration cephalosporin (cefmetazole 1 g 8-hourly). a systemic disease was suspected because the unusual clinical profile, including the location of the abscess and the pathological findings, did not correspond with the patient’s general condition. hiv infection was considered, and a western blot test was positive for hiv. the patient’s cd4 cell count, measured by flow cytometry, was 306/μl, and his cd8 cell count was 677/ μl. the hiv viral load was measured by indirect enzymetuberculous abdominal abscess in an hiv-infected man: neither infection previously diagnosed c a s e s t u dy kuo-yao kao, md tsung-i hung, md department of general surgery, shin kong wo ho-su memorial hospital, taipei, taiwan a 38-year-old man had a 1-week history of right lower quadrant abdominal pain; the initial impression was that he had diverticulitis of the ascending colon with an intra-abdominal abscess. signs of peritonitis mandated an immediate right hemicolectomy. the unusual location of the abscess and the patient’s unusual postoperative course suggested that he might also have a systemic disease. testing for hiv infection was positive. after 2 weeks in hospital, he was treated as an outpatient for both tuberculosis and hiv with a favourable outcome. in taiwan a pre-operative hiv test is not performed routinely, and the hiv seroprevalence in surgical patient populations is unknown. surgeons should keep the possibility of hiv infection in mind in a patient with an unusual clinical course. 30 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s e p t e m b e r 2 0 1 0 linked immunosorbent assay (elisa) and found to be 6 790 copies/ml. the final diagnosis was hiv infection coincident with the histologically confirmed mycobacterium tuberculosis colitis and abscess formation. anti-tb drugs (rifampin + ethambutol) were started soon after the patient resumed oral intake. he was discharged on 11 may 2006, 14 days after admission, at which time highly active antiretroviral therapy (haart) was started, including abacavir, efavirenz and lamivudine. anti-tb drugs were given continuously in the outpatient department for 18 months; the regimen included isoniazid, rifampin, ethambutol and pyrazinamide. the patient was followed up until august 2009 with a favourable outcome; at that visit he had a viral load of <400 copies/ml, a cd4 count of 332 cells/μl and a cd8 count of 632 cells/μl. discussion our patient was unaware that he had tb and hiv infection, and because he urgently needed surgery we did not have time to perform laboratory tests to diagnose these infections. nevertheless, he quickly recovered from the surgery and was discharged from the hospital 2 weeks after admission. outpatient treatment for the tb and hiv had a favourable outcome. tb has become a major cause of death and disability in many parts of the world, especially in developing countries.4,5 the disease can affect almost any body system, although most cases are pulmonary.6 in the usa, cases of extrapulmonary tb increased from 13.5% of all reported tb cases in 1975 to 21.0% in 2006.7 a study in taiwan found that extrapulmonary tb cases increased from 23% to 27% from 1996 to 2003.8 abdominal tb is a rare manifestation of extrapulmonary tb, with a prevalence of around 3%.6 it may involve the gastrointestinal tract, peritoneum, mesenteric lymph nodes, genito-urinary tract, or other solid organs.4,6,9 abdominal tuberculosis frequently poses a diagnostic challenge because specimens may be difficult to obtain, and the concentration of organisms may be low. sanai and bzeizi compiled data from 39 studies and found that the sensitivities of various diagnostic tests in patients with tb peritonitis were 38% for an abnormal chest radiograph and 53% for a positive purified protein derivative test.10 examination of ascites fluid found that lymphocytes predominated in 68% of cases, and that there was an elevated lactate dehydrogenase level in 77% of cases and an elevated adenosine deaminase level in 84%. mycobacteria were found in 34% of ascites fluids on culture, but only 3% of examinations detected organisms by smear. in contrast, the sensitivity of laparoscopic diagnosis was 92%.10 these diagnostic tests for abdominal tb seem unreliable, partly because not every patient develops ascites. culture of ascites fluid or peritoneal biopsy is the gold standard test. however, even a final diagnosis of pulmonary tb usually takes considerable time; diagnosis of abdominal tb typically takes even longer. one study from the national taiwan university hospital demonstrated that the mean interval between the first day of admission and respiratory isolation for pulmonary tb was 20.5 days.11 on the other hand, bernhard et al. reported that physicians considered abdominal tb in the initial differential diagnosis in only 39% of cases (7/18). time to specific diagnosis ranged from <1 week to >3 months.12 chen et al. reported that the average time to diagnosis of abdominal tb in southeastern taiwan was 48±10 days.13 delay in the diagnosis of abdominal tb is therefore more common than for pulmonary tb. several studies have observed that the proportion of extrapulmonary tb is higher in individuals who also are infected with hiv14,15 and in foreign-born immigrants16 in the usa. in addition, a dramatically increasing tb notification rate was observed in sub-saharan africa between 1990 and 2005, especially in countries with a high prevalence of adult hiv (>5%).17 the international standards for tuberculosis care states that hiv counselling and testing is indicated for all patients with tb in areas with a high hiv prevalence.18 in taiwan, 15 011 cases of hiv infection had been reported to the fig. 2. the largest abscess after excision. this abscess was found adjacent to the ascending colon (arrows). fig. 1. pre-operative computed tomography scan of the abdomen. the largest abscess is located at the ascending colon mesentery, anterior to the right psoas muscle (vertical arrow). there are several smaller abscesses over the omentum, and paracolic gutter (horizontal arrow). 31 s e p t e m b e r 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 32 taiwan centers for disease control as of 31 december 2007.1 the case burden of hiv infection in taiwan is significantly lower than that of tb. more data are required to establish the cost-effectiveness of offering hiv testing to tb patients in a region of high tb and relatively low hiv prevalence, such as taiwan. we describe this rare case to alert physicians to the fact that with the current trend of increasing hiv prevalence among the taiwanese, hiv co-infection should be considered when extrapulmonary tb is suspected. medical treatment is preferable to treat abdominal tb in patients also infected with hiv, surgery being reserved for complications such as intestinal obstruction, fistula, perforation and haemorrhage.19 our patient was operated on because he had abscesses and peritonitis, which were a complication of tb colitis. with the availability of the surgical specimen, we followed our suspicion and diagnosed hiv, enabling prompt initiation of treatment. anti-tb medication was started within 10 days, and the patient was discharged in 14 days. the course of diagnosis and treatment was straightforward. after discharge he received medical treatment as an outpatient with a favourable outcome. conflict of interest: none. references 1. centers for disease control, department of health, roc (taiwan). statistics of communicable diseases and surveillance report. 2007. http://www.cdc.gov.tw/lp. asp?ctnode=2076&ctunit=1144&basedsd=31&mp=5 (accessed 12 september 2009). 2. tuberculosis coalition for technical assistance. international standards for tuberculosis care (istc). the hague: tuberculosis coalition for technical assistance, 2006. http://www.stoptb.org/resource_center/assets/documents/istc_report. pdf (accessed 12 september 2009). 3. saltzman dj, williams ra, gelfand dv, wilson se. the surgeon and aids: twenty years later. arch surg 2005; 140: 961-967. 4. khan r, abid s, jafri w, et al. diagnostic dilemma of abdominal tuberculosis in non-hiv patients: an ongoing challenge for physicians. world j gastroenterol 2006; 12: 6371-6375. 5. uygur-bayramicli o, dabak g, dabak r. a clinical dilemma: abdominal tuberculosis. world j gastroenterol 2003; 9: 1098-1101. 6. sharma sk, mohan a. extrapulmonary tuberculosis. indian j med res 2004; 120: 316-353. 7. kipp am, stout je, hamilton cd, et al. extrapulmonary tuberculosis, human immunodeficiency virus, and foreign birth in north carolina, 1993 2006. bmc public health 2008; 8: 107. 8. hsu yc, yang mh, chen yh, et al. the epidemiology characteristics of extrapulmonary tuberculosis in taiwan, 1996-2003. epidemiol bull 2007; 23: 231-242. 9. golden mp, vikram hr. extrapulmonary tuberculosis: an overview. am fam physician 2005; 72: 1761-1768. 10. sanai fm, bzeizi ki. systematic review: tuberculous peritonitis – presenting features, diagnostic strategies and treatment. aliment pharmacol ther 2005; 22: 685-700. 11. wu yc, hsu gj, chuang ky, et al. intervals before tuberculosis diagnosis and isolation at a regional hospital in taiwan. j formos med assoc 2007; 106: 10071012. 12. bernhard js, bhatia g, knauer cm. gastrointestinal tuberculosis: an eighteenpatient experience and review. j clin gastroenterol 2000; 30: 397-402. 13. chen hl, wu ms, chang wh, et al. abdominal tuberculosis in southeastern taiwan: 20 years of experience. j formos med assoc 2009; 108: 195-201. 14. yang z, kong y, wilson f, et al. identification of risk factors for extrapulmonary tuberculosis. clin infect dis 2004; 38: 199-205. 15. onorato im, mccray e. prevalence of human immunodeficiency virus infection among patients attending tuberculosis clinics in the united states. j infect dis 1992; 165: 87-92. 16. talbot ea, moore m, mccray e, et al. tuberculosis among foreign-born persons in the united states, 1993-1998. jama 2000; 284: 2894-2900. 17. reid a, scano f, getahun h, et al. towards universal access to hiv prevention, treatment, care, and support: the role of tuberculosis/hiv collaboration. lancet infect dis 2006; 6: 483-495. 18. tuberculosis coalition for technical assistance. international standards for tuberculosis care (istc). the hague: tuberculosis coalition for technical assistance, 2006. http://www.stoptb.org/resource_center/assets/documents/istc_report. pdf (accessed 12 september 2009). 19. guex ac, bucher hc, demartines n, et al. inflammatory bowel perforation during immune restoration after one year of antiretroviral and antituberculous therapy in an hiv-1-infected patient: report of a case. dis colon rectum 2002; 45: 977978. anaemia is a relatively common finding in hiv-positive patients, with rates (among females) as high as 37%, compared with their hiv-negative counterparts (17%). anaemia of chronic disease plays a very important role in this population group, and is estimated to occur in 18 95% of cases. for this reason, it is imperative to distinguish this condition from other underlying or concurrent causes of anaemia that may warrant treatment. this clinical case illustrates the value of critically evaluating the parameters of a full blood count and haematinic screen, to so determine which patients warrant further workup. case report a 43-year-old man, known to be hiv-1 positive, presented to the casualty department at kalafong complaining of a 2-week history of fatigue, weight loss, night sweats, dysphagia and general malaise. he further described a 3-day history of vomiting and diarrhoea, with no melaena or haematemesis. at the time of presentation, he had been on firstline highly active antiretroviral (haart) therapy for 2 years. despite this the cd4 count on admission was 3 cells/μl. in the light of this finding, non-compliance was suspected. he had previously been diagnosed with gastro-intestinal mycobacterium avium complex as a cause of anaemia annemarie van de vyver, bsc, mb chb, pgdiptm department of internal medicine, university of pretoria and kalafong hospital, pretoria adele visser, mb chb, dtm&h, pgdiptm department of clinical pathology, university of pretoria, and national health laboratory service, tshwane academic division t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s e p t e m b e r 2 0 1 0 33 disseminated mycobacterium avium-intracellulare by positive blood cultures and had been started on treatment. owing to side-effects, he had not complied with this treatment regimen either. on admission he was pyrexial and tachycardic. he was clinically anaemic with no signs of oral hairy leukoplakia or candida. although abdominal examination was unremarkable (with no hepatomegaly or splenomegaly), he was tender in the epigastric area. cardiovascular and respiratory examinations were essentially normal. the full blood count revealed a significant microcytic hypochromic anaemia (haemoglobin 5.8 g/dl, mean corpuscular volume 68 fl and mean corpuscular haemoglobin 20.4 pg). the white cell count was normal, but he had thrombocytopenia (30×109 /l). creatinine and electrolyte levels were normal. liver function tests revealed an isolated mildly raised gamma-glutamyl transpeptidase (ggt) level (70 u/l) and a low albumin level (16 g/l). c-reactive protein was elevated at 84.9 mg/l. iron studies were also performed and showed low serum iron (1.3 μmol/l) and transferrin (1.4 g/l) levels and transferrin saturation (4%), and a markedly elevated serum ferritin level (1 579 μg/l). as part of the work-up for anaemia, the upper gastrointestinal tract was investigated by endoscopy. this revealed what was clinically judged to be extensive candidiasis throughout the oesophagus. the stomach was normal but the duodenum also had extensively distributed white plaques. a biopsy specimen of these plaques was taken and submitted for histological examination. an h&e stain was performed (fig. 1, a). the periodic acid-schiff (pas) stain revealed multiple clusters of micro-organisms in the histiocytes (fig. 1, b). finally, a ziehl-neelsen (zn) stain was performed, showing large numbers of acid-fast bacilli (fig. 1, c and d). a diagnosis of disseminated m. avium complex (mac) was suggested, as the organisms were found intracellularly. the diagnosis of disseminated mac was confirmed on a urine sample by molecular techniques. discussion patients with advanced hiv-1 disease pose a multitude of challenges in terms of diagnosis and treatment. anaemia is a relatively common finding in hiv-positive patients, with rates (among females) as high as 37%, compared with their hiv-negative counterparts (17%).1 the list of possible causes of anaemia in hiv-positive patients is substantial and differentiation is often difficult. value is certainly added by taking the full blood count results into consideration. a simple distinction between red cell size (reflected in mean corpuscular volume) and red cell haemoglobin content (reflected by mean corpuscular haemoglobin) can significantly contribute to further choices in testing. anaemia of chronic disease plays a very important role in this population group, as inhibition of iron transfer from the reticulo-endothelial cells to the erythroid precursors due to inflammation is estimated to occur in 18 95% of cases.2 for this reason, it is imperative to distinguish this condition from other underlying or concurrent causes of anaemia that may warrant treatment. a haemoglobin level below 8 g/dl should prompt further investigation, as anaemia of chronic disease rarely causes world health organization grade iii or iv anaemia2 (grade iii <7.9 g/dl, grade iv <6.5 g/dl).1 iron studies may facilitate this process. in both iron deficiency anaemia and anaemia of chronic disease, the serum iron level and transferrin saturation will be reduced. the transferrin level, however, may facilitate in making a distinction as it is typically reduced to normal in anaemia of chronic disease and increased in iron deficiency. a further indicator can be found in serum ferritin levels, which are reduced to below 30 ng/l (positive predictive value of 92 98%) in iron deficiency, and normal to elevated in anaemia of chronic disease. the inherent confounder with using ferritin is the fact that it acts as an acute-phase reactant and will be elevated beyond its baseline in any inflammatory condition, irrespective of iron status.2 the soluble transferrin receptor level may be a useful assay to delineate causes of anaemia. levels are typically increased in iron deficiency and essentially normal in anaemia of chronic disease, as inflammatory cytokines negatively influence its expression. this can also be very useful if co-existence of both conditions is suspected. however, the assay is not universally offered. the use of various ratios has also been proposed as possibly helpful in determining the underlying cause of anaemia.2 the finding and confirmation of iron deficiency should prompt further investigation as to the underlying cause. fig. 1. sections from white plaques biopsied in duodenum: a – h&e stain; b – pas stain showing numerous clumps of organisms in histiocytes; c – zn stain showing clumps of acid-fast bacilli; d – closer view of collection of acid-fast bacilli in zn stain. s e p t e m b e r 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 34 imaging of the gastro-intestinal tract may be useful, especially if clinical features are suggestive. of note is the fact that the only feature suggestive of upper gastrointestinal bleeding in our patient was the epigastric tenderness on abdominal examination. it is therefore prudent to have a high index of suspicion. again, the differential diagnosis in this clinical setting is large and relates to the degree of immunosuppression.3 disseminated mac is the most common bacterial opportunistic infection among hiv-1-positive patients in the first world.4 however, it appears to be less common in our local setting.5 it has been postulated that it is caused by the overwhelming presence of m. tuberculosis in the south african context.5 patients with a cd4 count below 50 cells/μl and possibly high hiv-1 viral loads are at increased risk of mac infections, which have been shown to be an independent predictor of mortality. for this reason prophylaxis is advocated by some.4 it is, however, not included in the current south african national antiretroviral treatment guidelines.6 mac can affect any part of the gastro-intestinal tract, with the duodenum being the most common site. macroscopic findings are not diagnostic. biopsy and culture is therefore the mainstay of diagnosis of this condition.3 references 1. moyle g. anaemia in persons with hiv infection: prognostic marker and contributor to morbidity. aids rev 2002; 4: 13-20. 2. weiss g, goodnough l. anemia of chronic disease. n engl j med 2005; 352: 10111023. 3. riedel d, nugent s, gilliam b. upper gastrointestinal bleeding in a patient with hiv infection. clin infect dis 2009; 48: 368-369. 4. karakousis p, moore r, chaisson r. mycobacterium avium complex in patients with hiv infection in the era of highly active antiretroviral therapy. lancet infect dis 2004; 4: 557-565. 5. peter j, sonderup m. diagnosing multiple opportunistic infections: the value of liver biopsy. south african journal of hiv medicine 2008; spring: 51-52. 6. department of health. national antiretroviral treatment guidelines. johannesburg: jacana, 2004. invited comment abdominal mycobacterial infection in hiv the articles in this edition by kao and hung and van de vyver and visser both deal with aspects of abdominal mycobacterial infections. van de vyver’s article highlights the importance of investigating abnormalities that cannot be attributed to hiv infection alone, and demonstrates that abdominal mycobacterial infection may present with a paucity of abdominal symptoms and signs. while tuberculosis (tb) infection is predominant in south africa, non-tuberculous mycobacteria should always be considered in patients with advanced immunosuppression. the article by kao demonstrates a more dramatic presentation in a patient with relatively preserved immunity. notification rates of extrapulmonary tb in south africa are increasing, and it is likely that more patients will present with abdominal tuberculosis.1 tuberculosis can involve the entire gastro-intestinal tract, from the intra-abdominal organs to the peritoneum. the spectrum of symptoms seen in abdominal tb range from insidious nonspecific complaints that may be mistaken for the constitutional symptoms of hiv infection, to an acute abdomen.2 with improved access to antiretrovirals, tb immune reconstitution inflammatory syndrome is being seen more frequently and often involves the abdomen.3 in resource-limited facilities, investigations such as abdominal computed tomography scanning and laparoscopic peritoneal biopsy are seldom available. however, abdominal ultrasound, specifically looking for hepatomegaly, ascites, splenic micro-abscesses and intra-abdominal lymphadenopathy, is a useful investigation for assessing hiv-infected patients with suspected abdominal tuberculosis.4 clinicians need to maintain a high index of suspicion for tb in patients with hiv and abdominal symptoms. in the correct clinical setting empiric anti-tuberculosis therapy is warranted. all patients started on anti-tuberculosis therapy need close follow-up until resolution, and those who fail to respond to tb therapy may require further investigation. nontuberculosis mycobacterial infection should be considered in patients with advanced immune deficiency. while abdominal tuberculosis in hiv-infected patients is best managed with standard tb therapy and anti-retrovirals, complications such as obstruction, perforation and large abscess formation may require surgical intervention.2 depending on clinical presentation, early consultation with the surgeons is essential and if required surgery should not be delayed. a d black department of medicine, chris hani baragwanath hospital and university of the witwatersrand, johannesburg references 1. who global report on tuberculosis 2009. http://apps.who.int/globalatlas/predefinedreports/tb/pdf_files/zaf.pdf (accessed 24 june 2010). 2. lazarus aa, thilagar b. abdominal tuberculosis. dis mon 2007; 53: 32-38. 3. meintjes g, rabie j, wilkinson rj, cotton mf. tuberculosis-associated immune reconstitution inflammatory syndrome and unmasking of tuberculosis by antiretroviral therapy. clin chest med 2009; 30(4): 797-810. 4. sinkala e, gray s, zulu i, et al. clinical and ultrasonographic features of abdominal tuberculosis in hiv positive adults in zambia. bmc infect dis 2009; 9: 44. abstract introduction research method and design results discussion conclusion acknowledgements references appendix 1 appendix 2 about the author(s) bandile e. ndlazi department of health studies, faculty of human sciences, university of south africa, pretoria, south africa thembekile masango department of health studies, faculty of human sciences, university of south africa, pretoria, south africa citation ndlazi be, masango t. the sexual and reproductive health needs of young people living with hiv in gauteng, south africa. s afr j hiv med. 2022;23(1), a1377. https://doi.org/10.4102/sajhivmed.v23i1.1377 original research the sexual and reproductive health needs of young people living with hiv in gauteng, south africa bandile e. ndlazi, thembekile masango received: 04 feb. 2022; accepted: 29 apr. 2022; published: 06 sept. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: hiv has been the focus of health systems strengthening in south africa for the past two decades. despite progress, sexual and reproductive health (srh) challenges such as contraception, condom usage and hiv disclosure of young people living with hiv (yplhiv) remain inadequately addressed. therefore, the purpose of the study was to describe the srh needs of yplhiv and make recommendations to address identified gaps. objectives: to explore and describe the srh needs and potential systemic gaps of yplhiv with an aim to make recommendations for improvement and contribute to the development of an integrated approach to srh care in hiv programming. method: a quantitative cross-sectional research design with purposive sampling was utilised. yplhiv were recruited from five healthcare facilities in gauteng, south africa, for face-to-face interviews. results: one hundred and six yplhiv with a median age of 18 years were enrolled. a large proportion (57/106; 53.8%) of respondents reported being either single or double orphaned. sex-related discussions with parents were reported by only 36/106 (34.0%). history of teenage pregnancy was reported in 39/70 (56.0%) of female respondents. a high prevalence of multiple sexual partnerships 41/97 (42.2%) was noted. consensual partner hiv disclosure was low at 47/97 (48.4%) and the male gender was associated with low 10/35 (28.6%) disclosure of serostatus to sexual partners. conclusion: multiple srh needs were identified. interventions are needed to improve parental guidance on srh issues, increase contraception knowledge and access, and provide better male-centred care. keywords: sexual and reproductive health; hiv; young people; contraception; hiv disclosure. introduction in 2021 it was estimated south africa had 8.2 million people living with hiv.1,2 the hiv programme has made significant progress in south africa, providing strong support for prevention, treatment, and care of those affected and infected. almost 5.2 million people have been enrolled in the antiretroviral therapy (art) programme and were receiving treatment in 2019.3 availability of paediatric and adult art has enabled the reduction of vertical transmission to less than 1% and the survival into adolescence and adulthood of many. a mathematical model study suggests approximately 400 000 children and adolescents are living with hiv in south africa; this is attributed to high maternal hiv prevalence, but attenuated by the impact of art through the prevention of mother-to-child hiv transmission programmes.4 the growth in numbers of children and adolescents living with hiv continues to create a gap in the parental understanding of their sexual and reproductive health (srh) dynamics, which eventually has a negative effect on health-seeking behaviour and accessing of health services. as most young people living with hiv (yplhiv) enter childbearing age, a clear understanding of their srh needs, including dating, sex, contraception, condom usage, consensual partner serostatus disclosure and sexual practices is required, as is further exploration to devise effective interventions and develop focused guidelines.5 social barriers, such as the perception and assumption that yplhiv do not engage in sexual relationships due to their hiv status, serve to exacerbate limited access to relevant srh information as it limits opportunities for sexual education and open discussions on sexual issues.6 yplhiv desire to be accepted and live as their hiv negative peers, which may include engaging in risky sexual behaviours.6 limited early access to sexual information and treatment further exposes yplhiv to additional risks of hiv re-infection, opportunistic infections, and sexually transmitted infections (stis).7 deepened understanding of the srh needs of yplhiv will further inform the design of country-specific, culturally sensitive and multisectoral policies and programmes.7 growing awareness of these challenges is gradually building more demand for healthcare services, especially those focusing on reproductive healthcare services for young people.8,9 as part of a holistic hiv treatment and care package, yplhiv should receive culturally sensitive, accurate, and languageand age-appropriate health information on hiv management, stis, contraception and safe sex. however, this seldom happens.10,11,12 structural and social barriers are also still noted for adolescents to access srh information, contraception, and other related services at an early age. structural barriers refer to various cultural-driven norms that promote dominance of the older generation in making decisions directly affecting adolescents and young people, which further reduces young people’s opportunities for access to srh services and related decisions.13 our study aimed to describe the srh needs of yplhiv in order to contribute to the development of an integrated approach to this group’s srh care in hiv programmes and guidelines. research method and design study design a quantitative cross-sectional research design with the application of non-probability purposive sampling was utilised to study yplhiv from five healthcare facilities in gauteng, south africa. face-to-face interviews were conducted with respondents at the treating facility. the study applied a non-experimental design to explore questions pertaining to the srh needs of yplhiv and describe relationships among variables, rather than supporting inferences of causality. setting the study was conducted in three metropolitan districts in gauteng, namely city of ekurhuleni, city of johannesburg, and city of tswane. non-probability convenience sampling was applied when selecting five healthcare facilities for the study. the selection was made conveniently with the direction of the district programme managers with the consideration of facility size, number of clients and the number of other studies in the facility, avoiding overburdening. the selected healthcare facilities were a mix of two community health centres and three primary health care facilities; all providing general preventative and curative services of minor ailments and chronic diseases including hiv prevention, treatment, care, and support. all professional nurses providing services to yplhiv were trained on nurse initiated and management of antiretroviral treatment (nimart) and, when required, patients are referred to doctors for further diagnosis and management. study population and sampling strategy inclusion criteria were prospective respondents living with either verticallyor horizontally-acquired hiv and receiving hiv treatment, care and support from participating clinics, aged 18–24 years old, and willing to participate. respondents’ hiv treatment adherence was not a prerequisite for this study. mode of hiv acquisition was not used to determine eligibility. the tier.net electronic record system was used to determine the sampling frame from which the sample was drawn – no clinical data were extracted. the sampling procedure was conducted to limit error and determine the sample size to assure reliable results. a sample size was computed from the total population of 374 young people aged 18–24 years receiving hiv treatment and care services in the five facilities drawn from tier.net. a representative sample size of 106 with a 5% margin of acceptance error was concluded for this study. data collection data were collected between june 2018 and february 2019. the interviews were conducted by two trained research assistants using a standardised questionnaire adapted from john cleland’s illustrative questionnaire for interview-surveys with young people (see appendix 2) to capture respondents’ responses to the assisted questionnaire with a maximum duration of 30 min. the list of prospective respondents drawn from tier.net was used to pull out the patients’ records to obtain their contact details. the research assistants approached those who were scheduled for their appointments and telephonically contacted those who were not scheduled for appointments. all respondents were asked to sign written informed consent. for standardisation, questionnaires were not distributed to respondents. the research assistants asked the questions and completed the questionnaires. questions were translated into the respondent’s preferred language during the sessions. as respondents had already reached age 18, srh historic questions were asked based on recall. all completed questionnaires were numbered according to the code assigned for the participating facility, with each respondent allocated an enrolment number for easy tracking of data errors and management of queries arising during data analysis. to maintain anonymity and confidentiality, only respondents’ codes (for identification by the researcher) and demographics were captured on the consent forms. respondents with signs of distress and history of abuse were reported to facility managers for appropriate referrals. data analysis raw data from completed questionnaires were coded, captured into an excel© data sheet, and crosschecked for accuracy and missing values. data were then transferred to statistical software (statistical package for social sciences [spss]© version 24) with the threshold for statistical significance set at p < 0.05 for all statistical analyses. chi-square test was used to compare proportions. the statistical analysis plan included the generation of frequency distribution tables for all variables to enable exploration of data quality. cross-tabulation was done to determine the relationship between the predictor variables and responses. continuous variables were summarised using means with standard deviations or medians with interquartile ranges (iqr) as appropriate. categorical variables were described as the total number and relative percentage of respondents per response category. participation was voluntary and open to all eligible prospective respondents without discrimination or coercion. the study objectives were the determining factor for inclusion and exclusion. adolescents younger than 18 years were not included as the study was aimed at gathering data based on historical experiences. prospective respondents’ culture, race and gender were not used to limit participation eligibility. the researcher treated the collected data and respondents’ personal information with strict confidentiality. ethical considerations the researcher obtained ethical clearance and permission to conduct the study from a northern gauteng university ethical review board (reference number hshdc/630/2017). on receipt of the research proposal approval, approval was obtained from national health research database (nhrd; reference number gp_2017 rp12_180). application was submitted to the districts’ research committees for review and permission to access healthcare facilities, and approvals to proceed were granted on 15 february 2017. results a total of 106 respondents were interviewed in this study. the sample was predominantly female, 70 (66%). respondents’ median age was 18 years (iqr: 17–19). all interviewed respondents were on art – no information was collected on adherence and virologic outcomes. detailed responses to the interview questionnaire are given in appendix 1. data on hiv mode of transmission was self-reported. hiv acquisition was horizontal in 40 (37.7%), vertical in 56 (52.8%) and unknown in 10 (9.4%). twenty-seven of the 56 respondents (48.2%) with vertically acquired hiv were informed of their positive hiv status when they were younger than 14 years. education status was 44 (41.5%) respondents in grade 10–12, 16 (15.1%) at tertiary level, and five (4.7%) in lower grades. most of the study respondents self-reported being sexually active. twenty-five (23.5%) respondents had left school before completing matric, eight due to pregnancy. thirty-nine (55.7%) of the female respondents had a history of teenage pregnancy with eight reporting a miscarriage or stillbirth. general sex discussion at home fifty-seven (53.8%) respondents reported either both (n = 24/106 [22.6%]) or one (n = 33 [31.2%]) of their parents were deceased. thirty of these 57 (52.6%) had been informed their parents’ cause of death was hiv. sex-related discussions with parents were reported by only 36/106 (34%). fifty-seven (53.8%) respondents had someone other than their parents with whom to discuss sex-related issues. gender was associated with discussing sex-related matters with household members: more male respondents 30/36 (83.3%) reported having never discussed sex-related matters with others at home, compared to 40/70 (57.1%) of female respondents (p < 0.01). first consensual relationship partner’s profile and hiv disclosure to sexual partner the first consensual relationship partner profile in the 86 respondents who reported these relationships was with someone 5–10 years older in 33 (38.4%) and was with someone more than 10 years older in four (4.6%). five respondents (5.8%) knowingly had a relationship with a married person. the first consensual partners’ occupational status was 42 (48.8%) employed, 40 (46.5%) full-time students, and four (4.6%) unemployed. slightly above half, 50/97 (51.5%), had not disclosed their hiv-positive status to their sexual partners. gender was associated with hiv status disclosure to sexual partners: 22/32 (68.7%) of the male respondents had never disclosed their hiv status to any of their sexual partners compared to 28/65 (46.1%) of the female respondents (p < 0.01). reasons for hiv status disclosure are shown in figure 1. respondents who reported non-disclosure cited fear of rejection by their partners as the main reason. figure 1: reasons given for hiv serostatus disclosure in the 47 respondents who reported disclosure. sexual practices sexual debut was reported by 97 respondents: 11 (11.3%) at 14 years of age, 27 (27.8%) at 15 years of age, and 57 at 16 years of age or older. the median age of sexual debut was 18 years (iqr: 16–19). nine respondents (8.4%) reported to have never had sex. the first sexual encounter was consensual in 84/97 (86.5%), and non-consensual in 10/97 (10.3%). there was a high prevalence, 41/103 (41.8%), of multiple concurrent sexual partnerships while in a stable relationship. thirty-seven of 70 (52.8%) female respondents reported using pregnancy prevention methods. nineteen of the 36 (52.8%) male respondents reported condoms as their contraceptive method of choice and six (16.7%) used withdrawal as a means of pregnancy prevention. condom usage, practices, and beliefs are shown in table 1. self-reported condom usage at last sexual encounter was 84/95 (88.4%) while only 44/95 (46.3%) reported condom usage on sexual debut. despite the high rate of condom usage among study respondents, findings revealed negative attitudes towards condom usage as 51/106 (48.1%) of respondents believed that condoms reduce sexual pleasure and 47/106 (44.3%) felt it was embarrassing for them to buy or collect condoms. most female respondents 56/70 (80.0%) agreed women could proactively suggest the use of condoms, while more than half 20/36 (55.5%) of male respondents disagreed. table 1: condom (both male and female condoms) usage, practices, and beliefs. past stis were reported by 44/106 (41.5%) with some admitting having had more than one recurrence. most (42/44; 97.7%) respondents who reported sti incidence had sought medical attention, however only 23/44 (52.2%) notified their consensual partners. healthcare-seeking behaviour and communication with healthcare workers sixty-four of 106 (60.4%) respondents indicated they were comfortable with asking clinic staff sex-related questions. fifty-one of 64 (80.0%) respondents indicated they used hiv treatment follow-up consultation sessions as an opportunity to raise srh-related questions, 53 of whom (82.8%) felt that their engagement with healthcare workers was fruitful as questions were responded to satisfactorily and without judgement. gender was associated with whether the respondents felt comfortable with asking clinic staff questions: more male respondents (21/35; 60.0%) were not comfortable with asking clinic staff questions than female respondents (20/70; 28.6%) (p < 0.01). discussion the current study explored the srh needs of yplhiv. the study sample was predominantly female (66%) and included young people who have both vertically and horizontally acquired hiv infection. teenage pregnancy was a common reason for females to drop out of school. these findings concur with chakalisa et al., where 44% of female adolescents reported to have fallen pregnant during their adolescent years.14 high proportions of our respondents were single or double orphaned, which is important as orphaned children, more especially those growing up with vertically acquired hiv, become increasingly susceptible to a variety of hardships negatively impacting their quality of life.15 integration of family planning and mental healthcare within hiv care could reduce unplanned pregnancies and other associated stressors among yplihv.16 the death of parents disrupts adolescents’ and young peoples’ quality of life and creates lifelong instabilities resulting in mental and behavioural challenges.10 our findings that yplhiv were more likely to have experienced the death of one or both parents is similar to those in a study from cambodia where more than 50% of respondents reported at least one deceased parent.9 ntuli et al. cited long-term effects of orphanhood, especially maternal death beyond age 18 years as these children suffer emotional distress from prolonged bereavement, which affects their ability to develop positive coping strategies.17 their common coping strategy becomes silence and withdrawal which then further exacerbates their emotional distress.17 absence of communication by parents and caregivers on sexual topics was found to be common in our respondents. other studies have shown that parent-child sexuality discussions were described as selective, harsh and parent driven while children were just passive information receivers, and parents used threats to promote abstinence.18,19 limited srh support and guidance in the home has been linked to the perception and expectation that yplhiv should not engage in sexual relationships.6 an ethiopian study found only small proportions of young people reporting open communication with parents on topics pertaining to sex – only 28.0% were able to have related discussions with their mothers, and fewer, 18.5%, with their fathers.20 sexual debut findings from the current study align with those of studies in botswana and zambia, where sexual debut was reported at 15 years of age.14 generally, yplhiv delay sexual debut due to their hiv status compared to the general population.21 the current study reported high condom usage at last sexual encounter, but very low condom usage at sexual debut. contrary to these findings, low (38.0%) condom usage among sexually active yplhiv was reported in a ugandan study while 57.9% condom use at last sexual encounter was found in a study conducted among heterosexual sexually active young women in south africa.22,23 the current study found inconsistent condom usage in most relationships, while convenience appeared to play an important role in condom usage with a relatively high proportion finding the purchase or collection of condoms embarrassing. contrary to this finding, wondemagegn et al. reported that only 5.0% referred to condom unavailability as a cause of inconsistent use.24 the current study’s findings, depicted high female autonomy with regard to condom suggestion and negotiation. the finding might not be a true reflection of the real practice: ntshiqa et al. noted that young women reported low (47.0%) condom use with high risky sexual behaviour.23 in the current study, male respondents were more likely to engage in multiple sexual partners, aligning with those of other studies.14,25 young men in the current study displayed reluctance regarding communication with healthcare workers regarding their srh challenges; this was also noted in a study assessing the srh service utilisation by male adolescents in a gauteng district, where healthcare workers were perceived as judgemental.26 these findings indicate the need for male-focused srh interventions. reported contraception use in this study was slightly lower than the national contraceptive use of 60.0% among sexually active women.27 a study conducted among women living with hiv in soweto, south africa, in 2010 found 84.0% were on contraception which is in contrast to our study; however, a study in lao people’s democratic republic found only 34.0%.28,29 different settings where data were collected could be the cause of data variations depending on other barriers. withdrawal as a method to prevent pregnancy was reported by 16.7% of our male respondents which is twice as high as that reported by a study conducted in lao people’s democratic republic.29 the current study found low consensual partner serostatus disclosure among yplhiv. our findings are similar to those of other studies.21,22 male gender was associated with low serostatus disclosure to sexual partners compared to female in our study, which is consistent with other studies.30,31 these findings highlight the need for promotion of consensual partner disclosure of hiv and finding new approaches for partner notification, hiv index testing, and linkage to care and treatment. early disclosure improves both the srh and hiv treatment adherence and viral load suppression of yplhiv.32 limitations of the study our study may be limited in generalisability to other districts and provinces because the sample was exclusively drawn from three metro districts, and because we only studied young people aged 18–24 years. we adopted a cross-sectional design and non-random sampling technique, which might pose a risk of bias. the mode of hiv acquisition relied on self-report. conclusion our findings indicate multiple missed srh needs of yplhiv. interventions are needed to improve parental guidance on srh issues, contraception knowledge and access, especially directed at teenage pregnancies, reduction of hiv-related stigma, and provision of better male-centred care. a high proportion of yplhiv are orphaned, which has profound impacts on health. acknowledgements the authors would like to express their sincere appreciation to the respondents, who took their time to make this study a success, and to the tshwane, ekurhuleni and johannesburg metro research health committees, for granting access and seeing value of the study of this nature. competing interests the authors declare that there are no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions b.e.n. and t.m. conceived of the presented idea. t.m. supported b.e.n. in the investigation of the sexual and reproductive health dynamics of young people living with hiv and supervised the study processes and conclusion of this work. all authors discussed the results and contributed to the final manuscript. funding information the authors disclosed receipt of the following financial support for the research, authorship, or publication of this article: this work was supported by the university of south africa’s m & d bursaries. sead consulting provided support for data analysis. data availability the data that support the findings of this study are openly available on request from the corresponding author, b.e.n. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references joint united nations programme on hiv/aids (unaids). global update aids 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[cited 2022 oct 20]. available from https://doi.org/10.1371/journal.pone.0183180 appendix 1 table 1-a1: responses to the interview questionnaire. appendix 2 figure 1-a2: interview questionnaire. table of contents executive summary scope and purpose of the guidelines audience methods 1. introduction 3. special considerations 4. recommendations 5. acknowledgements references appendix 1: common myths about drugs use appendix 2: assessing patients during first and subsequent encounters appendix 3: guidelines for opioid substitution therapy appendix 4: psychosocial and mental health interventions harm reduction counselling tips about the author(s) andrew scheibe tb hiv care, cape town, south africa department of family medicine, university of pretoria, pretoria, south africa goodman sibeko department of psychiatry and mental health, university of cape town, cape town, south africa shaun shelly tb hiv care, cape town, south africa department of family medicine, university of pretoria, pretoria, south africa theresa rossouw department of immunology, university of pretoria, pretoria, south africa vincent zishiri ezintsha, faculty of health sciences, university of the witwatersrand, johannesburg, south africa willem d.f. venter ezintsha, faculty of health sciences, university of the witwatersrand, johannesburg, south africa citation scheibe a, sibeko g, shelly s, rossouw t, zishiri v, venter wdf. southern african hiv clinicians society guidelines for harm reduction. s afr j hiv med. 2020;21(1), a1161. https://doi.org/10.4102/sajhivmed.v21i1.1161 guideline southern african hiv clinicians society guidelines for harm reduction andrew scheibe, goodman sibeko, shaun shelly, theresa rossouw, vincent zishiri, willem d.f. venter received: 28 aug. 2020; accepted: 28 aug. 2020; published: 17 dec. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. table of contents executive summary introduction 1.1 harm reduction 1.2 drugs and drug use 1.2.1 patterns of use 1.2.2 methods of drug use 1.2.3 drug classifications and common drugs 1.2.4 epidemiology of drug use in southern africa 1.2.5 drug-related harms 1.2.6 reasons for drug use 1.2.7 the relevance of harm reduction 1.3 stigma, discrimination and human rights evidence-based interventions 2.1 a guiding framework 2.2 assessing a person’s needs 2.2.1 screening and brief intervention for common mental disorders and harmful substance use 2.2.1.1 screening 2.2.1.2 brief interventions 2.2.1.3 referral for treatment 2.3 hiv prevention 2.3.1 condoms and lubricant 2.3.2 preand post-exposure prophylaxis 2.3.3 voluntary medical male circumcision 2.4 harm reduction interventions 2.4.1 needle-and-syringe services 2.4.2 opioid substitution therapy 2.4.3 overdose services 2.4.4 emerging and ancillary interventions 2.4.4.1 harm reduction for people who use stimulants 2.4.4.2 drug consumption rooms 2.4.4.3 drug-checking services 2.5 hiv testing, treatment and care 2.5.1 hiv testing and counselling 2.5.2 antiretroviral therapy 2.5.3 prevention of mother-to-child transmission of hiv 2.6 prevention and management of coinfections and comorbidities 2.6.1 tuberculosis services 2.6.2 viral hepatitis services 2.6.3 mental health services 2.6.4 sexual and reproductive health services 2.7 critical enablers 2.7.1 supportive law and policy 2.7.2 countering stigma and discrimination 2.7.3 enabling community empowerment 2.7.4 acting against violence special considerations 3.1 young people who use drugs 3.2 women who use drugs 3.3 substance use in the context of sexual encounters 3.4 prison settings recommendations acknowledgements glossary references appendix 1: common myths about drugs use appendix 2: assessing patients during first and subsequent encounters appendix 3: guidelines for opioid substitution therapy appendix 4: psychosocial and mental health interventions executive summary we support public-health-focused interventions, as opposed to recovery-focused interventions. we support the decriminalisation of drug use as much as we oppose the criminalisation of sex work, mandatory hiv disclosure and policing of sexual preferences. in south africa, despite existing policy that embraces drug harm reduction, populationand individual-level interventions have focused largely on the singular goal of abstinence. this greatly impacts the human rights of people who use drugs and their communities. the failure of countries to implement comprehensive harm reduction measures violates their obligations in international human rights law and public health. these guidelines were developed to provide information for healthcare workers working in the field of hiv and related conditions to address gaps in knowledge around drug use and build capacity around harm reduction and delivery of relevant evidence-based clinical interventions. the guidelines include an emphasis on people who use drugs who are at risk of experiencing harms relative to hiv, viral hepatitis and other related conditions. as with critical areas within hiv, the social context, including social support, stigma and structural drivers such as employment, is important for health workers to understand. harm reduction requires clinicians to understand the broader context in which drugs are used by their patients. the traditional ‘just say no’ approaches to drug use are as ineffective for drug use as they are for sex. clinicians have an ethical obligation to their patients that extends to being advocates for evidence-based harm reduction. drug ‘harm reduction’ takes a pragmatic view that is humane, effective, holistic and fundamentally concerned with the rights of people who use drugs, their socio-economic context and the provision of services that are responsive, preventive and supportive. this approach also enhances the well-being of partners, family members and society at large. harm reduction approaches and related interventions are supported by a large body of evidence. explicit support for needle-and-syringe services is included in the south african national strategic plan for hiv, tb and stis (2017–2022), the national drug master plan (2019–2024) and the national hepatitis action plan. a national department of health policy around opioid substitution therapy and related clinical guideline is under development. by integrating the guidelines in clinical practice, the quality of care provided by clinicians to people who use drugs will be enhanced – benefitting individuals and communities of people who use drugs and broader society. scope and purpose of the guidelines review evidence of the harm reduction approach briefly review the epidemiology of drug use and its consequences present clinical guidance for harm reduction interventions aligned with the framework developed by the world health organization provide guidance around brief screening and interventions related to drug use for each harm reduction intervention, provide: a summary of evidence, main principles and links to related guidelines highlight special considerations for young people who use drugs, women who use drugs, substance use and sexual encounters and drug use within prison settings provide selected recommendations for stakeholders engaged in the delivery of harm reduction services in hiv, tb, viral hepatitis and related services. audience these guidelines are aimed primarily at clinicians (doctors, nurses and clinical associates). other stakeholders who will benefit from this guideline include pharmacists, hiv and health programme officers and policymakers. methods a core writing team developed these guidelines. the process was informed by a review of evidence and guidance from the world health organization. a stakeholder consultation was held in august 2019, followed by international peer review. inputs and recommendations were included. 1. introduction 1.1 harm reduction people have always used drugs to alter health, perceptions, relationships and state of mind1 and this is not likely to change. globally, in 2017, more than 271 million people had used unregulated drugs in the preceding year.2 the criminalisation of people who use certain drugs increases levels of stigma, encourages misinformation and contributes to harms, including high rates of preventable deaths.3 a purely biomedical approach – that presumes that all people who use drugs require treatment, and all drug use and dependence represents a disease requiring specialist medical intervention – carries the risk of stigma and often fails to pay due attention to the social and economic context in which dependent drug use occurs.3 criminalisation and the pathologisation of drug use may intensify social disruption and hinder the provision of effective responses.4 countries that have implemented comprehensive harm reduction programmes have managed to turn around epidemics of hiv and hepatitis c virus (hcv) infection. overdose deaths are lower in contexts where harm reduction services are in place, compared with places where they are not. harm reduction reduces the adverse health, social and economic consequences of drug use without necessarily reducing drug consumption.5 in 2018, 86 countries (11 in africa) had at least one needle-and-syringe service and 86 (nine in africa) had at least one opioid substitution therapy (ost) programme. harm reduction refers to policies, programmes and practices that aim to minimise negative health, social and legal impacts associated with drug use, drug policies and drug laws. harm reduction is grounded in justice and human rights – it focuses on positive change and on working with people without judgement, coercion, discrimination, or requiring that they stop using drugs as a precondition of support. harm reduction encompasses a range of health and social services and practices that apply to illicit and licit drugs. these include, but are not limited to, drug consumption rooms, needle and syringe programmes, non-abstinence-based housing and employment initiatives, drug checking, overdose prevention and reversal, psychosocial support and the provision of information on safer drug use. approaches such as these are cost-effective, evidence-based and have a positive impact on individual and community health. (harm reduction international).6 key points harm reduction is an evidence, rights and public-health-based approach that reduces risks and improves the health and well-being of people who use drugs and the broader community. long-term policies and interventions are needed to address structural factors that contribute to harms related to drug use. box 1: south african policy. harm reduction principles for healthcare settings are listed.7 humanism: care is given without moral judgement and with an understanding that choices are contextual. pragmatism: the priority is the here and now, and the mitigation of immediate risk is what matters most. individualism: people are different and have their own needs and strengths. autonomy: people have a right to make informed choices, even against expert advice. incrementalism: any positive change is viewed as an improvement on current circumstances. accountability without termination: people have the right to make choices, without their access to services being denied in relation to their decisions. the application of these principles can improve patient–clinician relationships. the impact of harm reduction is increased through community engagement and peer-led services as well as removing barriers and increasing support. key points harm reduction is an evidence, rights and public-health-based approach that reduces risks and improves the health and well-being of people who use drugs and the broader community. 1.2 drugs and drug use 1.2.1 patterns of use depending on the drug, 8% – 15% of people who use drugs develop a problem with their use. drug use occurs along a continuum and can shift according to various factors (see table 1). table 1: patterns of drug use. 1.2.2 methods of drug use drugs can be taken by different administration modes, which can lead to different effects and varying degrees of harm. for instance, intravenous (iv) administration is associated with rapid onset and peak of action, with elevated risks: for opioids, this includes overdose and for stimulants, such as cocaine, this includes arrhythmia. common methods of drug use are summarised here. smoking is the most common form of use for cannabis, methaqualone (mandrax), heroin (whoonga, nyaope, sugars) and methamphetamine (tik, crystal meth) in southern africa. onset of action is faster than other forms of use. risks are related to airways and pulmonary disease. nasal inhalation (snort, schnarf, toot, sniff) is often used for cocaine, but also heroin. onset of action is quick and is associated with risk of damage to the nasal mucosa. injecting (slam, spike, smoke) can be done through several routes, most commonly iv. heroin is the most injected drug, followed by methamphetamine and cocaine. onset of action is very rapid. risks are largely related to the use of contaminated injecting equipment and poor hygiene practices, including local and blood-borne infections (notably hiv, hepatitis b virus [hbv] and hcv). the risk of overdose is higher if drugs are injected. a proportion of people who use opioids and/or stimulants for a long period of time will transition to injecting. oral ingesting (pop) is the most common route for gamma-hydroxybutyric acid (ghb), alcohol, methadone and ecstasy, amongst others. onset is slower and risks may vary depending on the food or liquids consumed. rectal suppository or vaginal (booty bumping) administration are less frequent methods of substance intake. 1.2.3 drug classifications and common drugs drugs can be categorised into five broad classes according to their primary effects: stimulants, depressants, hallucinogens, cannabinoids and antipsychotics. an overview of common drugs is given in table 2. table 2: overview of common drug types. 1.2.4 epidemiology of drug use in southern africa as a result of the illegal nature of drug use and associated stigma, obtaining robust data on drug use is difficult and data are limited (see table 3). it is therefore likely that estimates of reported use and risks are under-reported. research reflects increased trafficking of heroin in the region and a review of substance use treatment data in south africa points to a six-fold increase in heroin-related admissions over the last decade, with marked increases seen in methamphetamines and other stimulant-related admissions during the same period.13 box 2: myths about drug use. box 3: heroin has many names. box 4: image and performance-enhancing drugs. box 5: drug, (mind-) set and setting.8 table 3: overview of substance use epidemiology (latest data).14,15,16,17 1.2.5 drug-related harms the harms related to drugs are embedded in social and structural circumstances, including stigma, which is often driven by the illicit nature of drug use. for a variety of reasons, the production, sale and use of certain drugs are restricted or highly regulated through international agreements.18 people who use drugs, especially those who inject drugs, are vulnerable to several health issues including hiv, viral hepatitis, cellulitis and infective endocarditis.19 people who use drugs are also at increased risk of developing tuberculosis (tb).20 long-term smoking of drugs (including cannabis, methaqualone or heroin), particularly amongst people who also smoke tobacco products, can increase risks for the development of chronic obstructive airways disease and emphysema.21,22 globally, the incidence of hiv infection has declined, yet infections amongst people who use drugs continue to increase.23 the quantification of drug-related harms in south africa, including hiv and viral hepatitis infections and overdose, is inadequate. table 4 provides a snapshot of available data. box 6: drug scheduling. box 7: restricting access can render drugs more dangerous. table 4: overview of infectious disease prevalence and morbidity amongst people who inject drugs (latest data). 1.2.6 reasons for drug use the reasons why people are using drugs outside of supervised medical care are poorly understood. the dominant discourses to explain this phenomenon are often based on moral or political foundations rather than science. it is beyond the scope of these guidelines to provide a comprehensive analysis of the use of drugs. people use drugs for a range of reasons (table 5),31 and many myths exist in the context of clinical care around people who use drugs (see appendix 1).32 table 5: insights into reasons for drug use amongst people with unstable housing, south africa (2015).31 chronic problematic drug use is largely caused by personal, social, cultural and political pain and suffering (and at times may also include psychological, physiological and legal issues).33 box 8: overlapping vulnerabilities and intersectionality. box 9: harm reduction case studies. 1.2.7 the relevance of harm reduction it will take a long time to affect a significant reduction in the number of drugs used, and the harms caused because this requires structural reform, which is explored later. the historical focus on abstinence and law enforcement has been ineffective and resulted in significant harm. harm reduction is an effective public health intervention. it keeps people alive and reduces drug-related morbidity. for individuals, harm reduction aligns with the tenets of medical ethics in that it is beneficent and patient centred. it takes a longer-term view and helps people meet their goals in a stepwise manner. specific harm reduction interventions relevant to people who use drugs are covered in the section ‘evidence-based interventions’. key points people use drugs for many reasons, in an array of circumstances and contexts and this cannot be modified rapidly. not all drug use is harmful. addressing drug use in isolation will seldom result in a sustained resolution, unless the underlying motivators are addressed. people use drugs in different ways; drugs are mostly smoked in south africa, but injecting is becoming more prevalent. drug-related risks and effects depend on the drug, (mind-)set and setting. the use of opioids and amphetamine-type stimulants in the region is increasing. in the context of criminalisation, many people who use drugs enter and exit the criminal justice system, placing them at risk for hiv and other infectious diseases. the burden of hiv, viral hepatitis and tb amongst people who use drugs in the region is high. 1.3 stigma, discrimination and human rights stigma is a process of exclusion; it occurs when a person – or group of people – are tainted or disgraced. when people perceive themselves as being stigmatized, they may also come to hold the same negative perceptions about themselves, leading to an internalization of stigma and acceptance of a ‘spoiled identity’.37 stigma, misinformation and the lack of evidence-based harm reduction approaches are major contributing factors to the vulnerabilities people who use drugs face. stigma is often not prioritised by healthcare professionals, yet has a profound effect on the relationships between clinicians and their patients.38 the use of non-stigmatising language can enhance relationships with patients and clinical outcomes. table 6 outlines alternative supportive language to use. table 6: the use of non-stigmatising language to enhance patient outcomes.40† ‘stigma in health facilities undermines diagnosis, treatment, and successful health outcomes. addressing stigma is fundamental to delivering quality healthcare and achieving optimal health.’39 the international network of people who use drugs (inpud) recognises that language cannot be regulated, and that context can transform a term that is used to oppress into one through which emancipation is pursued … ordinarily, however, language that may denigrate, is best avoided.40 discrimination, which is the enactment of stigma, also needs to be addressed and the rights of all people secured. many governments in the region have signed the international covenant on economic, social and cultural rights,40 which outlines the range of rights that are relevant to people who use drugs in health settings. some of the relevant rights are: the right to self-determination (article 1); the right to non-discrimination based on race, colour, sex, language, religion, political or other opinion, national or social origin, property, birth or other status (article 2); and the right to enjoy the highest attainable standard of physical and mental health (article 12). people who use drugs experience frequent violation of these rights, which increases the harms of drug use – including confiscation of sterile injecting equipment and medication that forms part of substance use disorder treatment or other health conditions.41 key points people who use drugs frequently experience stigma, discrimination and human rights violations, which negatively affect their health and well-being. the use of appropriate language is an important component of providing support services. 2. evidence-based interventions 2.1 a guiding framework these guidelines are built upon the framework set out in the who consolidated guidelines on hiv prevention, diagnosis, treatment and care for key populations,19 including health sector interventions (table 7) and critical enablers (table 8). table 7: health sector interventions.19 table 8: critical enablers.19 2.2 assessing a person’s needs the screening for substance use and offer of assistance for potentially harmful substance use can take place in a range of clinical scenarios (see appendix 2). the integration of screening for substance use and mental health conditions, linked to brief interventions and referral for further treatment, is often the first step in supporting people within a harm reduction approach and is outlined here. 2.2.1 screening and brief intervention for common mental disorders and harmful substance use substance use disorders fall into the category of common mental disorders. harmful alcohol and other drug use and other mental health disturbance may result in an increased risk of contracting hiv and in substantial health problems amongst people living with hiv. however, it is important to note that most people who use drugs do so on an occasional basis and will not develop a substance use disorder (dependence). for this group, there may be little need for high-intensity interventions. screening for other common mental disorders including depressive disorders and anxiety disorders should also be performed. these may arise because of psychosocial distress that may be related to the hiv diagnosis or as a consequence of infective processes, which may be primary or secondary in a patient living with hiv. identification of these is essential as they may impact on clinical outcomes and capacity to adhere to art. appropriate treatment is likewise freely available, so there is no need for patients to suffer. suicidal screening should form part of this assessment because of its association with common mental disorders and the particularly high risk within this population.42 screening, brief intervention and referral to treatment (sbirt) for harmful substance use is an evidence-based approach to improve the detection and early intervention of harmful substance use to prevent or address dependence.43 the three core components of sbirt are (1) universal screening, followed by (2) risk triaging, to determine (3) the appropriate level of intervention and/or referral to specialty assessment and care (figure 1). figure 1: pathways following screening for harmful substance use.50 2.2.1.1 screening: screening people at risk for, or living with, hiv for harmful alcohol and/or drug use is crucial and can be performed in a myriad of settings including consulting rooms, emergency units, hospital wards and community settings (see appendix 2). screening tools such as the alcohol, smoking and substance involvement screening test (assist)44 and alcohol use disorders identification test (audit) make use of risk categories determined by screening scores to help determine the ideal intervention strategy (table 9). additional alternative validated tools are listed in appendix 2. table 9: alcohol, smoking and substance involvement screening test risk score and associated risk level and intervention.45 2.2.1.2 brief interventions: a brief intervention is a short (time-limited), often opportunistic, patient-centred strategy, where a healthcare provider provides targeted information and/or advice to individuals during the course of other health activities such as routine outpatient review or hiv testing.45 the aim of the interaction is to increase insight and awareness of harmful substance use to facilitate a patient’s motivation to modify risky behaviour. brief interventions thus seek to reduce drug use and associated behaviours, which increase the risk of contracting or transmitting hiv, for example, risky sexual behaviour and unsafe drug injecting practices. there is little difference in the outcomes between longer, more intensive interventions and brief interventions; and brief interventions are practical, cost-effective and have a growing evidence base.46,47 behavioural interventions, self-regulation coaching and psychosocial counselling can support hiv harm reduction and other hiv prevention objectives for people who use substances, whilst also contributing to longer-term and broader health and wellness goals.48,49 brief interventions should be provided to people with moderate-to-high risk and above substance use. clinical guides or steps for the use of common interventions follow, with details in appendix 2. box 10: key components of brief interventions.50 box 11: motivational interviewing and adherence.51 elements of brief interventions may be aligned to the stages as outlined in table 10. it is important to remain mindful of patient’s social and economic context, an element some reviewers have flagged as not necessarily accounted for by strictly following these stages. table 10: stages of change and recommended brief intervention elements. 2.2.1.3 referral for treatment: people with severe risk/dependency, as identified by a screening tool, require additional and more intensive support. if these are not provided by the person conducting the screening, then the patient should be referred for further assessment and management by a substance use disorder specialist at an appropriate facility. table 11: who should screen, provide brief interventions for substance use and refer for care. 2.3 hiv prevention 2.3.1 condoms and lubricant table 12: hiv prevention – condoms and lubricant.19 2.3.2 preand post-exposure prophylaxis table 13: hiv prevention – preand post-exposure prophylaxis.19 2.3.3 voluntary medical male circumcision table 14: hiv prevention – voluntary medical male circumcision.19 2.4 harm reduction interventions 2.4.1 needle-and-syringe services table 15: harm reduction interventions – needle-and-syringe services. box 12: needle-and-syringe services in southern africa. box 13: behavioural interventions to support risk reduction.19 box 14: low dead-space syringes.73 2.4.2 opioid substitution therapy table 16: harm reduction interventions – opioid substitution therapy.74,81 box 15: testing for the presence of drugs in urine or other fluids. box 16: regulation of opioid substitution therapy medications and diversion. box 17: stimulant drug use by people on opioid substitution therapy.51 box 18: opioid substitution therapy and overdose risk.84 box 19: opioid substitution therapy for special populations.74,81 box 20: management of acute pain in opioid use disorders. 2.4.3 overdose services table 17: harm reduction interventions – overdose services.83,84,85 figure 2: algorithm for managing sedative or stimulant overdose.19,87 box 21: opioid overdose prevention and reversal.83,84,85 box 22: naloxone.83,84,85 box 23: management of withdrawal for other substances.88 2.4.4 emerging and ancillary interventions several additional interventions are important as part of comprehensive harm reduction. some are briefly provided below, including (1) harm reduction for people who use stimulants, (2) drug consumption rooms and (3) drug checking services. 2.4.4.1 harm reduction for people who use stimulants: cocaine, methamphetamine (tik, ice), methcathinone (cat) and mdma (ecstasy) are the most common unregulated stimulants seen in southern africa, and methylphenidate is the most prescribed stimulant. simple harm reduction advice for people who use stimulants is to follow a few steps. avoid the concurrent use of alcohol and cocaine. cocaine use potentially compromises the cardiovascular system and is linked to several cardiovascular diseases; this risk increases with the concurrent use of alcohol. rest: sleep deprivation and stimulant use increase the chance of psychosis. people on stimulants often binge for days. people using stimulants should be encouraged to lie down in a dark space, with eyes close and relax for at least 3–4 h every 24 h. hydrate: people using stimulants may be at risk of dehydration. people should be encouraged to drink 500 ml water per hour, especially if dancing. eat: people using stimulants should be encouraged to eat something at least every 24 h, even if not hungry. dental care: sip water when the mouth is dry and brush teeth twice a day. other relevant harm reduction interventions include psychosocial support, condoms and lubricants (amphetamine-type stimulants can increase sex drive and risky sexual practice) and drug paraphernalia distribution (injecting and/or smoking kits that include mouth pieces for crack pipes), services for sexually transmitted infections, income generation and housing support. substitution therapies for stimulant use disorders are under investigation. 2.4.4.2 drug consumption rooms: drug consumption rooms (also known as safe injecting facilities, medically supervised injecting sites or overdose prevention sites) are protected places for the hygienic consumption of drugs in a non-judgemental environment. they allow people to use drugs under medical supervision or in the presence of trained and equipped peers,89 enabling an immediate response to overdose and decreasing the transmission of blood-borne diseases through access to sterile injecting equipment and education on safe injection practices.90 drug consumption rooms increase uptake of other health services and are an entry into care, for example, facilitating access to hiv, viral hepatitis, tb testing and treatment services and counselling.90 in 2018, 11 countries were operating drug consumption rooms across 117 sites.5 an overview of drug consumption rooms is available at: http://www.drugconsumptionroom-international.org. box 24: resources on harm reduction for stimulant use. 2.4.4.3 drug-checking services: a means to check the quality and purity of drugs should be available to people who use drugs. this includes fixed site testing and on-the-spot testing options, the latter being mostly qualitative tests.91 for example, strips designed to identify fentanyl in drugs may help to prevent overdoses. people who use opioids can use the results of the test kit strip to inform their drug use (i.e. to use slowly, to reduce the volume of drug, to use in the company of others, to have a naloxone rescue kit nearby or not to use the substance). test kits can be used on crushed pills or powders.92 guidance around the use of fentanyl test strips is available at: https://harmreduction.org/issues/fentanyl. key points harm reduction requires engaging with patients to identify immediate risks and develop means to reduce these. screening, brief intervention and referral for treatment is an effective approach to detect and intervene in harmful substance use. needle-and-syringe services are the cornerstone of hiv prevention for people who inject drugs and should be provided at all contacts with health services. people who inject drugs should be supported to return their used injecting equipment and locations for safe disposal of used equipment should be made widely available. opioid substitution therapy is the most effective treatment for opioid use disorder. effectiveness is maximised when patients are supported and provided with an optimal dose of medication. voluntary psychosocial services can improve outcomes. safety risks are greatest early on during treatment, and patients who are stable should be considered for take-home dosing. treatment should be long term. good supply chain and stock management are important to minimise diversion of opioid agonist medications. opioid overdoses cause many deaths and are preventable. people likely to witness an opioid overdose should be trained to identify and respond to this, and access to naloxone should be maximised. 2.5 hiv testing, treatment and care 2.5.1 hiv testing and counselling table 18: hiv testing treatment and care – hiv testing and counselling.19 2.5.2 antiretroviral therapy table 19: hiv testing treatment and care – antiretroviral therapy. 2.5.3 prevention of mother-to-child transmission of hiv table 20: hiv testing treatment and care – prevention of mother-to-child transmission of hiv.19 key points people who use drugs should be informed of their rights to confidentiality and consent and their right to refuse hiv testing if they choose. uptake and retention in care are improved where art is integrated with ost when needed. pregnant women living with hiv who are not on art should be enrolled on an art programme urgently. needle-and-syringe programmes and other evidence-based harm reduction services should be offered to all people who use drugs, irrespective of their hiv status. all people who use drugs and who are found to be hiv-negative should be provided with risk reduction information and commodities tailored to their substance use (considering their patterns and type of substance, etc.) and sexual practices. people who use drugs and who test hiv-negative should test regularly (every 6 weeks to 3 months) depending on their risk profile. an individual with a discrepant hiv test result should be referred for re-testing in 14 days. if a person comes for hts within 72 h after a potential exposure, then pep should be considered52 (see section ‘preand post-exposure prophylaxis’) 2.6 prevention and management of coinfections and comorbidities 2.6.1 tuberculosis services table 21: tuberculosis services.98 2.6.2 viral hepatitis services table 22: viral hepatitis services. 2.6.3 mental health services table 23: mental health services. 2.6.4 sexual and reproductive health services table 24: sexual and reproductive health services. 2.7 critical enablers 2.7.1 supportive law and policy clinicians, programme managers and policymakers should work together to support the decriminalisation of drug use, as well as sex work, to reduce health risks related to arrest, detention and incarceration and ensure the protection of rights. interventions and support to reduce drug dependence should ideally consist of a continuum of care, starting with early development strategies focusing on the delay of drug use and prevention strategies, moving to early-use interventions such as brief interventions and information. more intensive interventions should be reserved for people with dependencies that cause significant impairment.85 a supportive and effective continuum and continuity of care service requires supportive policies. the criminalisation of people who use drugs often disrupts the provision of a continuum of care, by seeing all drug use as a criminal act, thus disrupting the continuity of services through arrest and incarceration and accelerating the development of drug dependence.103,104 considering the additional economic, health, social and psychological harms associated with the criminalisation, arrest and incarceration of people who use drugs, there should be a robust debate on the decriminalisation of the use of drugs and advocacy for the provision of services for incarcerated populations. the southern african hiv clinicians society supports the decriminalisation of drug use: https://sahivsoc.org/files/2019-06-03%20drug%20use%20%20decrim%20statment.pdf clinicians should take on an advocacy role for: better care based on evidence for people who use drugs; human rights for people who use drugs; harm reduction approaches that include the activities described earlier, as well as access a safe supply of opioids (see the text box 26 on safe supply). clinicians should also advocate for the evaluation of current policies regarding illicit drug law and enforcement. 2.7.2 countering stigma and discrimination clinicians and public health leaders should work with civil society organisations and networks of people who use drugs to monitor stigma and discrimination and advocate to change punitive legal and social norms. the development of a stigma index that includes people who use drugs and other people engaged in illegal and/or stigmatised practices could be developed to quantify stigma and measure changes over time. box 25: decriminalisation. box 26: safe supply interventions. clinicians should ensure that the health services they provide are available, accessible and acceptable to people who use drugs. approaches to rendering services friendly to people who use drugs and other key populations: ensuring adequate training of staff and develop supportive attitudes towards people who use drugs integrating health services providing services at times that suit patients locating services strategically where patients congregate or transit involving peers in the planning, promotion, delivery and monitoring of services taking steps to ensure law enforcement does not interfere with access to services 2.7.3 enabling community empowerment clinicians, public health leaders and civil society organisations can support the empowerment of people who use drugs by enabling their active participation in the planning and implementation of services, with a focus on peer education and training on safer drug use, harm reduction and broader issues relating to their rights and health. 2.7.4 acting against violence people who use drugs are at high risk for physical, sexual and psychological violence. this violence increases their risk for hiv and viral hepatitis and negatively affects their mental health. many people who use drugs have been traumatised through their engagement with law enforcement and entry into the criminal justice system. women who use drugs are at particularly high risk of violence and its effects. clinicians, public health leaders and civil society organisations should aim to prevent violence affecting people who use drugs, which can include engagement with law enforcement to sensitise them to the issues and their role to uphold the rights of all people. the occurrence of violence should also be monitored and reported and mechanisms to access redress explored. clinicians should provide clinical care and initial psychological support to survivors of violence, with referral for additional support when needed. processes following instances of rape should follow local guidelines. there is strong evidence linking structural inequities to accessing health services with a higher risk of hiv infection, as well as continuing or everyday intimate partnerand gender-based violence.107,108 structural inequities in access to services hold true particularly for people who use licit drugs in countries where drug use has been criminalised and where no harm reduction services exist. to address the concerns emerging from the many interacting aspects of violence, trauma and substance use, harm-reducing systems of care need to integrate with other primary healthcare services.109 linking harm reduction services to services such as sexual and reproductive health (srh) services, including sexually transmitted infection (sti) prevention services, and supportive primary care would allow for more effective harm reduction programming. 3. special considerations 3.1 young people who use drugs table 25: young people who use drugs. box 27: drug searches and testing in schools.113 3.2 women who use drugs table 26: women who use drugs. box 28: gender-sensitive responses to drug use.114 box 29: transgender people.120 3.3 substance use in the context of sexual encounters table 27: substance use in the context of sexual encounters. 3.4 prison settings table 28: prison settings. 4. recommendations this section summarises the key role of critical stakeholders in the delivery of harm reduction services in hiv, tb, viral hepatitis and related services. table 29: summary of harm reduction recommendations per provider/stakeholder. box 30: recommendations for employees who are hiring people who use drugs.124 5. acknowledgements additional inputs received from lize weich, tanya venter, johannes hugo, urvisha bhoora, magriet spies, rafaela rigoni, cara o’conner, julia samuelson, viriginia macdonald, michelle rodolph, shona dalal, nurain tisaker and shaheema allie. regional harm reduction case studies developed by kunal naik (pils, mauritius) and bernice apondi (vocal, kenya). inputs from the guideline development workshop held in august 2019 are also included. participants of the workshop included: leora casey, andrew gray, harry hausler, signe rotberga, muhangwi mulaudzi, lauren jankelowitz, annette verster, busisiwe msimanga-radebe, nontsikelelo mpulo, zukiswa ngobo, mpho maraisane, rogerio phili, kgalabi ngako, maria sibanyoni, yolanda ndimande, valencia malaza, johannes hugo, urvisha bhoora and cara o’conner. we extend our thanks to the external reviewers, including julie bruneau, annette verster, kunal naik, nkereuwem william ebiti and ali feizzadeh. competing interests the authors confirm that no competing interests exist. authors’ contributions all authors contributed equally to this work. ethical consideration this article followed all ethical standards for research without direct contact with human or animal subjects. funding information no specific grant was received from any funding agency in the public, commercial or non-for-project sectors. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer specific recommendations provided here are intended only as a guide to clinical management, based on expert consensus and best current evidence. treatment decisions for patients should be made by their responsible clinicians, with due consideration for individual circumstances. the most current version of this document should always be consulted. the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official position of any affiliated agency of the authors. glossary references siegel r. intoxication: the universal drive for mind-altering substances. rochester: park street press; 2005. unodc. world drug report 2019. executive 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2019. british columbia centre on substance use, b.c ministry of health, b.c. ministry of mental health and addictions & perinatal services. a guideline for the clinical management of opioid use disorder – pregnancy supplement. vancouver: b.c. ministry of health; 2018. nezu am, nezu cm, d’zurilla tj. problem-solving therapy. a treatment manual. new york, ny: springer publishing company; 2012. appendix 1: common myths about drugs use table 1-a1: common myths about drug use.† appendix 2: assessing patients during first and subsequent encounters table 1-a2: examples of scenarios where drug use screening and management is required. table 2-a2: the first encounter – the five as of intervention (ask, advise, assess, assist, arrange).129 table 3-a2: follow-up or subsequent encounters.129 appendix 3: guidelines for opioid substitution therapy table 1-a3: taking clinical history for opioid substitution therapy.74,83† table 2-a3: opioid withdrawal symptoms.136 table 3-a3: clinical assessment – differs, based on whether or not the patient is acutely ill.81 table 4-a3: comparison between methadone and buprenorphine (± naloxone) and clinical considerations.74,81 dosing optimal dosing is important for full benefits of opioid substitution therapy (ost) to be realised. opioid substitution therapy should be used for as long as a patient requires it (at minimum, 1 year). the risk of other opioid use is decreased with longer duration of ost. supervised dosing it is recommended initially for patients starting on methadone or buprenorphine. continuation of supervised dosing should be assessed once the patient has been on a stable maintenance dose for approximately 3–6 months and should be individualised. daily dosing may need to continue for patients with limited support structures or for those living in areas where safe storage and access are limited. take-home dosing allowing take-home doses is an important component of patient autonomy and ease-of-use, which enhances retention, the strongest determinant of positive outcomes. take-home dosing allows for patients to focus on other areas of their life because they do not have to spend excessive time and resources to access daily dosing. take-home dosing can initially start over weekends, moving to longer periods of time. discussions with patients and their support network should include available options. community pharmacies are an option for dosing outside of health facilities. buprenorphine (± naloxone) take-home dosing is easier (if in tablet form) and is generally safer than methadone as it has a lower overdose risk. opioid substitution therapy projects that have used methadone report few overdose-related deaths and limited diversion.80 facilitate a discussion of processes that will be taken if diversion/selling of ost medications becomes apparent, including taking a restorative justice approach and maximising patient safety. supervised dosing should be reinstituted if the clinician has safety concerns or concerns around diversion (e.g. missed appointments, intoxicated while attending appointments, changes in clinical or social situation). regular monitoring of patients once on a stable dose monthly assessment by a doctor, re-prescribing methadone/buprenorphine75 quarterly assessment of medical and social history repeat assessment of substance use history, using the same tools used at screening (in a non-judgemental manner) – providing counselling and support in relation to outcomes offer hiv and hepatitis c virus (hcv) testing quarterly; assess antiretroviral therapy (art) adherence as needed perform regular tuberculosis (tb) screening (assess weight loss, cough, fever and night sweats) patients who report ongoing injecting, or injecting in the previous year, should have regular hcv testing. retention and support for adherence psychosocial interventions aim to support retention within ost programmes. a broad range of interventions are available and include: social support (which includes addressing basic needs) psychological interventions unstructured supportive therapy (e.g. motivational interviewing [mi]) structured interventions (e.g. contingency management [cm] and cognitive behavioural therapy [cbt]) group therapy managed opioid withdrawal (detoxification).74,81 the most effective treatment for opioid use disorder is opioid substitution therapy as a long-term management approach. (the south african standard treatment guideline and essential medicine list [adult, hospital]136 guidelines for the medical management of opiate withdrawal [detoxification] are available at: http://www.health.gov.za/index.php/component/phocadownload/category/286-hospital-level-adults). short-term detoxification (a process that requires use of medications over several days per weeks, followed by an expectation of abstinence) is ineffective, yet it is still widely used. it has high rates of recurrent opioid use (up to 90% within 1 year), along with a likely sense of failure or shame in abstinence-focused contexts. assisted opioid withdrawal is often done as an in-patient procedure. performing withdrawal management in < 30 days is not recommended.75 withdrawal management should be imbedded within/linked to intensive rehabilitation services to minimise harms should the patient return to use. ideally, the option to switch a patient to ost should be available if the patient is not able to achieve a goal of abstinence. the selection of a substitute opioid is a clinical decision that is made together with the patient after due consideration of: prior response; medical or mental health comorbidities; possible drug interactions; side-effect profile; cost/accessibility; use of other drugs and patient choice. preparation of the patient for withdrawal symptoms is important, and they should be motivated to start a treatment plan, with careful explanations of what they may experience. withdrawal carries little medical risk but can be very unpleasant. nevertheless, most initiation can be safely done on an outpatient basis. principles include gradual decreases in the effects of opiates, either through dose tapering and/or the use of agonists. mild withdrawal reactions can be managed symptomatically, with antidiarrhoeal, antinausea, anxiolytic and analgesic medication. whilst clonidine can be used for its rapid adrenergic agonist effects on symptoms, the evidence supporting this regimen is limited. gradual down-titration of the relevant opioid or use of a less potent opioid, can be attempted in more severe situations. benzodiazepines have been associated with fatal overdoses in people with opioid dependency, and their use in the management of withdrawal is discouraged. risks related to return to the use of opioids after detoxification, particularly amongst people with a history of injecting, include overdose as well as blood-borne infections. management of acute pain in opioid use disorders a careful history, physical examination and relevant diagnostic studies to identify the cause of the acute pain are the essential first steps. table 5-a3: assessment and management of acute pain in opioid use disorders.82,138 appendix 4: psychosocial and mental health interventions table 1-a4: suggested screening tools. table 2-a4: summary of brief intervention methodologies. motivational interviewing (mi) is a psychotherapeutic approach that seeks to move an individual away from a state of ambivalence towards finding motivation to make positive decisions and accomplishing established goals. these goals may include a reduction in harmful behaviour patterns such as harmful substance use or art non-adherence. the approach to mi includes: using the ‘spirit’ of mi to engage with the patient: collaboration, evocation, acceptance and compassion using these principles when interacting with the patient: expressing empathy, developing discrepancy (i.e. identifying conflicts between perceptions, behaviours, personal goals and values), avoid argumentation, roll with resistance, support self-efficacy assessing the patient’s readiness for change: pre-contemplation, contemplation, preparation, action, maintenance and relapse stages of change using the ‘oars’ as a clinical technique: open-ended questions, affirmations, reflections and summaries problem-solving therapy (pst) is a cognitive-behavioural intervention geared at improving an individual’s ability to cope with stressful life experiences. the underlying assumption of this approach is that symptoms of psychopathology can often be understood as the negative consequences of ineffective or maladaptive coping.139 cognitive behavioural therapy (cbt) is a widely used psychotherapy approach. the core theoretical premise is that maladaptive ways of thinking and behaving can generate mental and behavioural problems. the use of cbt ranges from substance use, depressive and anxiety disorders to schizophrenia. it represents a large body of related interventions. these elements include a focus on developing ways of recognising maladaptive thinking and behaviours and then building skills for positive coping to alleviate mental distress and problematic behaviours. it incorporates goal-oriented therapy and some form of talk-based therapy.139 contingency management (cm) is an intervention that provides patients with motivational incentives for meeting pre-determined treatment goals such as abstinence, attendance or medication adherence. the approach is based on principles of behavioural reinforcement. the goal of the treatment is to replace the positive reinforcement obtained from using alcohol and other drugs by providing positive reinforcement for productive behavioural change. behavioural goals should be set over short time periods (typically 1 week or less) and positive reinforcement must be provided consistently and immediately after the goal has been met.87 harm reduction counselling tips the principles of drug set and setting8 are very useful in reducing the harms people experience from drug use. if someone is unable to change one aspect of their drug use, then they may be able to make changes in other domains. table 3-a4: unodc stimulants guidelines counselling tips.51,91 why have.html opinion why have socio-economic explanations been favoured over  cultural ones in explaining the extensive spread of hiv in south africa? chris kenyon, mb chb, ma, mph sizwe zondo, ma robert colebunders, md, phd sipho dlamini, mb chb, fcp (sa) corresponding author: c kenyon (chriskenyon0@gmail.com) the hiv prevalence in south africa’s various racial/ethnic groups differs by more than an order of magnitude. these differences are determined not by the lifetime number of sexual partners, but by how these partnerships are more likely to be arranged concurrently in african communities. the available evidence demonstrates that neither hiv nor concurrency rates are determined by socio-economic factors. rather, high concurrency rates are maintained by a culturally sanctioned tolerance of concurrency. why then do socio-economic explanations trump cultural ones in the south african hiv aetiological literature? in this article, we explore how three factors (a belief in monogamy as a universal norm, hiv’s emergence in a time of the construction of non-racialism, and a simplified understanding of hiv epidemiology) have intersected to produce this bias and therefore continue to hinder the country’s hiv prevention efforts. ‘whereas individual-level parameters may influence which individuals in a given population acquire infection, it is population-level parameters that affect the prevalence of infection.’ aral, lipshutz, blanchard (2007)1 sexually transmitted infections (stis) are transmitted via sexual networks, and differences in the structure of these networks constitute the key population-level parameter that determines differences in hiv prevalence.1 the differences in hiv prevalence between south africa’s racial/ethnic groups (19.9%, 3.2% and 0.5% for 15 49-year-old blacks, coloureds and whites respectively2 are as big as those between the highestand lowest-prevalence countries in the world. these large racial/ethnic differences are not related to individual level risk factors such as lifetime number of sexual partners, but are more likely determined by different sexual network structures.3 in african networks, sexual partnerships are more likely to be arranged concurrently, and this increases the interconnectedness of the sexual network in a non-linear fashion.3 evidence from numerous sources and disciplines shows that these high concurrency rates are a key factor in driving high hiv transmission rates in southern and eastern africa.4 two main categories of factors have been advanced as being important in the promotion of these high concurrency rates: cultural and socio-economic factors. socio-economic factors are unlikely to be the predominant determinants since neither hiv nor concurrency are contoured along the lines of poverty, at the level of countries or individuals. one of the few quantitative studies looking at the determinants of concurrency in south africa found no relationship between income quintile and concurrency, but concurrency was more commonly practiced and accepted in black communities than among whites and coloureds.5 a literature review of the explanations for the striking differences in hiv spread by race in south africa concluded that there was a strong bias favouring socio-economic explanations.6 as an example, one of the premier textbooks on the epidemiology of hiv/aids in south africa argues that the reason why hiv prevalence rates differ between races is that ‘marginalisation and discrimination on the basis of race and/or ethnicity are key factors influencing vulnerability to hiv infection.’7 no evidence however was provided to back up this assertion. what is the explication for this bias? we argue that the playing down of cultural factors in the south african hiv aetiological literature is the result of an intersection of three factors. explaining the under-appreciation of cultural factors hiv’s emergence in a time of the resonance and construction of non-racialism the first factor relates to the post-apartheid context of the emergence of hiv. notions of white racial and cultural superiority were central pillars of the apartheid ideology. an uncritical use of race as an analytical variable and on occasion frankly racist views would characterise much south african medical and public health enquiry during the apartheid period. hiv then emerged into prominence during the difficult period while south africa was attempting to build a new dispensation based on non-racialism. given this backdrop and the fact that hiv was sexually transmitted, deeply stigmatised and then found to disproportionately affect black south africans, it is not difficult to see why many of the investigating experts downplayed the racial differentials in hiv spread and biased their assessments of aetiology towards socioeconomic factors. to have suggested that culturally backed norms were important in hiv spread might well have been construed as racist. an example of the ongoing reluctance to use race or ethnicity as an analytical variable in regard to hiv in south africa, is the 2008 human sciences research council hiv survey. despite it being south africa’s only nationally representative hiv-serolinked survey, it does not mention racial differentials in hiv rates anywhere except in one small table in the appendix.8 monogamy as a universal norm the second factor derives from the unacknowledged post-christian ethical foundation of much of the south african hiv epidemiology. one dimension of this is the subtle way that monogamy (either lifetime or serial) is assumed to be normative for all humans. little consideration is given to the wealth of anthropological and historical evidence as to the normative nature of polygamy in stratified societies across place and time,9 and more pertinently, the fact that polygamy is still far more widely acceptable in sub-saharan africa than elsewhere in the world.10 the spread of christianity in south africa led to the suppression of polygamy. the historical record is clear that this did not lead to a reduction in the total number of concurrent partners, but only to the non-main partners being kept secret.11 having main and more or less secret-extra partners is still widely practised and tolerated in the region. authors who have provided evidence that these high concurrency rates lead to high-risk sexual networks in the region have, however, been portrayed as racist and ‘crypto-racist’.12 if these authors label as racist the argument that monogamy is less prevalent in parts of africa, then it necessarily follows that these authors regard monogamy as more ethical. even if this belief in mononormativity exists at a fairly subliminal level, then the cultural explanation for generalised hiv epidemics in africa may clash with one’s principles of non-racialism – one is stating that africans are more likely to engage in unethical behaviour. given that mononormativism is protected by its unacknowledged status, this clash should lead to the triumph of the commitment to non-racialism. the theory of cognitive dissonance predicts that given this scenario the mind should then actively search for other theories, such as socio-economic and biological ones, to explain the higher hiv prevalences in africa (see fig. 1). poorly developed conceptual framework for hiv spread high-risk networks characterised by high concurrency rates are now recognized to be key to the generation of generalised hiv epidemics. evaluating the strength of these network level effects requires network-level analyses. one of the most dramatic limitations of much of the aetiological literature on hiv epidemiology in south africa, is the absence of network levels of analysis. a recent example is a study that compared individual level sexual behaviours between south african and united states youth surveys.13 based on little difference between these parameters in the two countries the authors conclude that differences in sexual behaviour are unlikely to explain south africa’s generalised hiv epidemic. they ignore network level factors in their analysis and the literature which shows that network level factors are able to explain the magnitude and patterning of south africa’s epidemic.3 the conclusions of the paper and the accompanying editorial14 are that hiv prevention efforts need to shift away from focussing on sexual behaviour and the norms which underpin these, and instead campaign for conditional cash transfers and a range of biological measures of proven efficacy for hiv prevention. technical interventions as the new panacea for hiv prevention in the absence of a national consensus ever having been attained that a culturally sanctioned norm is driving hiv-spread in the country, the majority of contemporary papers on hiv prevention in south africa continue to focus on socio-economic and technical inventions. the currently favoured interventions include vaginal microbicides, test-and-treat, increased condom usage or sti vaccines.13-15 some argue against behaviour change campaigns owing to their futility,14 while others argue that further research on this topic is immoral.16 one prominent paper that does mention dealing with high concurrency rates (albeit as one of a long list of factors) goes on to state that conditions created by apartheid were responsible for the genesis and maintenance of high concurrency rates.15 the authors then claim that south africa’s hiv strategic plan ‘is comprehensive’ and ‘highlights that south africa is not deficient in policy’ (p. 926). unfortunately, this national plan does not mention the urgency of dealing with concurrency. in fact there is still little more than a few small ad hoc programmes in south africa to effect the mass social mobilisation necessary to lead to norm and behaviour change in this regard. conclusion the key to uganda’s success in rapidly bringing down hiv rates was the way uganda fairly rapidly recognised the importance of encouraging ‘zero grazing’ or reducing extra partners.17 unfortunately, hiv is still viewed by too many in south africa as being a disease of poverty and inequality. where concurrency is acknowledged to be important, it is too often regarded as being driven by socio-economic factors. the net effect has been that insufficient focus and research has been directed at the normative cultural factors that sustain the high concurrency rates in south africa. as a result, there has not been the same pressure brought to bear on effecting the necessary changes in tolerance of extra partners in south africa as has been the case in uganda. references 1. aral s, lipshutz j, blanchard j. drivers of std/hiv epidemiology and the timing and targets of std/hiv prevention. sex transm infect 2007;83 (s1):1-4. 1. aral s, lipshutz j, blanchard j. drivers of std/hiv epidemiology and the timing and targets of std/hiv prevention. sex transm infect 2007;83 (s1):1-4. 2. shisana o, rehle t, simbayi l, parker w, zuma k. south african national hiv prevalence, hiv incidence, behaviour and communication survey. pretoria: hsrc press, 2005:90-92. 2. shisana o, rehle t, simbayi l, parker w, zuma k. south african national hiv prevalence, hiv incidence, behaviour and communication survey. pretoria: hsrc press, 2005:90-92. 3. kenyon c, dlamini s, boulle a, white r, badri m. a network-level explanation for the differences in hiv prevalence in south africa’s racial/ethnic groups. african journal of aids research 2009;8:243-254. 3. kenyon c, dlamini s, boulle a, white r, badri m. a network-level explanation for the differences in hiv prevalence in south africa’s racial/ethnic groups. african journal of aids research 2009;8:243-254. 4. mah t, shelton j. concurrency revisited: increasing and compelling epidemiological evidence. journal of the international aids society 2011;14:33-39. 4. mah t, shelton j. concurrency revisited: increasing and compelling epidemiological evidence. journal of the international aids society 2011;14:33-39. 5. kenyon c, boulle a, badri m, asselman v. ‘i don’t use a condom [with my regular partner] because i know that i’m faithful, but with everyone else i do’: the cultural and socioeconomic determinants of sexual partner concurrency in young south africans. journal of social aspects of hiv/aids 2010;7:35-43. 5. kenyon c, boulle a, badri m, asselman v. ‘i don’t use a condom [with my regular partner] because i know that i’m faithful, but with everyone else i do’: the cultural and socioeconomic determinants of sexual partner concurrency in young south africans. journal of social aspects of hiv/aids 2010;7:35-43. 6. kenyon c. “differential poverty rates are responsible for the racial differentials in hiv prevalence in south africa”; an enduring and dangerous epidemiological urban legend? southern african journal of hiv medicine 2010;11:22-27. 6. kenyon c. “differential poverty rates are responsible for the racial differentials in hiv prevalence in south africa”; an enduring and dangerous epidemiological urban legend? southern african journal of hiv medicine 2010;11:22-27. 7. gouws e, abdool karim q. hiv infection in south africa: the evolving epidemic. in: abdool karim ss. hiv/aids in south africa. cambridge: cambridge university press, 2005:63. 7. gouws e, abdool karim q. hiv infection in south africa: the evolving epidemic. in: abdool karim ss. hiv/aids in south africa. cambridge: cambridge university press, 2005:63. 8. shisana o, rehle t, simbayi l, zuma k, jooste s. south african national hiv prevalence, incidence, behaviour and communication survey 2008: a turning tide among teenagers? pretoria: hsrc press, 2009. 8. shisana o, rehle t, simbayi l, zuma k, jooste s. south african national hiv prevalence, incidence, behaviour and communication survey 2008: a turning tide among teenagers? pretoria: hsrc press, 2009. 9. macdonald k. the establishment and maintenance of socially imposed monogamy in western europe. politics and the life sciences 1995;14:3-23. 9. macdonald k. the establishment and maintenance of socially imposed monogamy in western europe. politics and the life sciences 1995;14:3-23. 10. cleland j, scott c, whitelegge d. the world fertility survey: an assessment. oxford: clarendon press, 1987. 10. cleland j, scott c, whitelegge d. the world fertility survey: an assessment. oxford: clarendon press, 1987. 11. delius p, glaser c. the myths of polygamy: a history of extra-marital and multi-partnership sex in south africa. south african historical journal 2004;50:84-114. 11. delius p, glaser c. the myths of polygamy: a history of extra-marital and multi-partnership sex in south africa. south african historical journal 2004;50:84-114. 12. stillwaggon e. racial metaphors: interpreting sex and aids in africa. development and change 2003;35:809-832. 12. stillwaggon e. racial metaphors: interpreting sex and aids in africa. development and change 2003;35:809-832. 13. pettifor a, levandowski b, macphail c, miller w, tabor j. a tale of two countries: rethinking sexual risk for hiv among young people in south africa and the united states. j adolesc health 2011; 49:237-243. 13. pettifor a, levandowski b, macphail c, miller w, tabor j. a tale of two countries: rethinking sexual risk for hiv among young people in south africa and the united states. j adolesc health 2011; 49:237-243. 14. jaspan h. the wrong place at the wrong time: geographic disparities in young people’s hiv risk. j adolesc health 2011;49:227-229. 14. jaspan h. the wrong place at the wrong time: geographic disparities in young people’s hiv risk. j adolesc health 2011;49:227-229. 15. abdool karim s, churchyard g, abdool karim q, lawn s. hiv infection and tuberculosis in south africa: an urgent need to escalate the public health response. lancet 2009;374:921-933. 15. abdool karim s, churchyard g, abdool karim q, lawn s. hiv infection and tuberculosis in south africa: an urgent need to escalate the public health response. lancet 2009;374:921-933. 16. sawers l, stillwaggon e. concurrent sexual partnerships do not explain the hiv epidemics in africa: a systematic review of the evidence. journal of the international aids society 2010;13:34. 16. sawers l, stillwaggon e. concurrent sexual partnerships do not explain the hiv epidemics in africa: a systematic review of the evidence. journal of the international aids society 2010;13:34. 17. kirby d. changes in sexual behaviour leading to the decline in the prevalence of hiv in uganda: confirmation from multiple sources of evidence. sex transm infect 2008;84 (supplement 2):ii35-ii41. 17. kirby d. changes in sexual behaviour leading to the decline in the prevalence of hiv in uganda: confirmation from multiple sources of evidence. sex transm infect 2008;84 (supplement 2):ii35-ii41. fig. 1. the cognitive processes involved in evaluating two competing theories for why hiv has spread so extensively in some racial groups in south africa. as illustrated here, the lack of evidence to support the socio-economic thesis should lead to its dismissal (red arrow), while the validity of the evidence to support the cultural hypothesis should serve to strengthen it as an explanatory cognition (yellow arrow). in the setting of the strong ideologies of class-determinism and monogamy-as-a-universal norm and the anchor cognition of wanting to present oneself as antiracist, however, the cultural thesis generates considerable cognitive dissonance (one is implying that africans are more likely to engage in unethical behaviour), and the theory is therefore rejected (green arrows). likewise, if one is sufficiently committed to class as the explanation for differing hiv rates, then the dissonance produced by the lack of evidence to back one’s ideologically determined theory up can be reduced by the selective interpretation of evidence to back it up (orange arrows). a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e the south african government antiretroviral (arv) programme was designed as a structured, regulated programme utilising standardised treatment guidelines and multidisciplinary concepts. a major reason for these protocols was achieving maximal and durable suppression of viral replication and stemming development of arv resistance.1-3 in contrast, the private sector is not regulated by such controls. unregulation over prescribing practices has resulted in use of various treatment combinations. inevitably, some private patients have entered the government programme. private sector arv provision appears to have been overlooked. no formal study has been conducted in south africa comparing the two sectors with regard to treatment provision to hiv-infected patients. the present study defined a subgroup within the government programme, viz. patients previously treated in the private sector, and compared them with never-treated patients commencing arvs. immunological, virological and clinical parameters were used as a means of comparative assessment. issues raised by this study were lack of policies regulating private sector treatment, treating arv-experienced patients, and development of drug toxicity. methods the retrospective cohort study was performed at hiv clinics at addington and king edward viii hospitals in kwazulu-natal, from 2004 until april 2008. follow-up time ranged from 24 to 41 months. a sample size of 90 subjects was targeted, comprising 30 index subjects and 60 control subjects. the index subjects (private group) were patients previously on art in the private sector who entered the government programme, and the control subjects a clinical assessment of antiretroviral-treated patients referred from the private sector to the south african government antiretroviral (arv) programme: a retrospective analysis o r i g i n a l a r t i c l e rianna gounden, mmedsc (clin pharmacol) pharmacist, department of health objectives. a comparison of the effects of highly active antiretroviral therapy (haart) on the immunological, virological and clinical status of two groups of patients in the south african government antiretroviral (arv) programme in kwazulu-natal, viz. patients previously treated with arvs in the private sector and then entering the government programme (private group), and arv-naïve patients entering the programme directly (government group). methods. a retrospective, cohort study was performed by reviewing records of 58 former private sector patients and 98 patients initiated on arv treatment in the government sector. treatment regimens, cd4 cell counts, viral loads and regimen modifications were analysed. results. the study found that use of various classes of arv drugs varied between the private sector and the government sector. median distribution of cd4 cell count increased from 158.5 to 419 cells/µl for the private group (42 patients (72.4%)) and from 101 to 358 cells/µl for the government group (95 patients (96.9%)), over an average time span ranging from 29 to 30 months. median viral load decreased in the private group (29 patients (50%)) and the government group (66 patients (67.3%)) to approximately 3.22 log copies/ml (25 copies/ml) over an average time span ranging from 27 to 29 months. the rate of change of cd4 cell count (p=0.47) and viral load (p=0.097) between the two groups was not significantly different. conclusion. this study showed that even for patients with prior experience with arvs, virological and immunological success is still achievable with the use of standardised haart regimens in the government programme. 8 a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e (government group) were patients who were initiated on art in the government sector. both index and control subjects met inclusion criteria. inclusion criteria: n adult patients ( over 18 years) n for cd4 count and viral load analysis, at least three sets of measurements were required n all patients regarded as control subjects (government group) had to be arv naïve, i.e. no prior exposure to antiretrovirals. exclusion criterion: n trial patients, i.e. initiated on art as clinical trial participants and then entering the programme. in the study, for every index subject identified, the next 2 subjects (consecutive numbering hospital recordkeeping system) were selected as control subjects. the rationale for this was that the time frame for both indexes and controls would correlate closely. measurements analysed were: n baseline patient characteristics n cd4 cell count n hiv plasma rna levels n comparison of regimen modifications and reasons for these n death. the study was designed with a statistical power of 80%, with a sample size of 30 index subjects and 60 controls deemed sufficient to detect an effect size of 1.5 between the two groups. the α-level of significance was specified at 0.05, with a confidence level of 0.95. following commencement of government arvs, measurements were recorded at baseline and subsequent intervals of 2 13, 14 25 and 26 41 months. in intervals containing more than one measurement, the average was taken. all data were analysed using stata software (windows). the plotting of line graphs comparing cd4 cell counts and viral load changes only included patients with data in all four time intervals. patients presenting with baseline and last recorded readings were included in rate of change and distribution analyses. measurements of rates of change for cd4 counts and viral loads were taken as functions of the difference between the baseline and latest measurements and follow-up time. the two-sample wilcoxon rank-sum (mann-whitney) test was used for analysis of rates of change for cd4 and viral load. distribution of cd4 cell counts and viral loads were calculated using median values and interquartile ranges (iqrs). results patient baseline characteristics are set out in table i. comparing antiretroviral use in the private sector versus the government sector during this study, first-line regimens in the government sector consisted of lamivudine, stavudine and efavirenz/ nevirapine.4 the second-line regimen was zidovudine, didanosine and lopinavir/ritanovir.4 figs 1 3 illustrate percentages of private sector patients on individual arvs before entry into government hospitals, and percentages of all patients studied (both private and government initiates) on individual arvs in the government programme. lamivudine formed the backbone of first-line regimens in the government sector (98%) (n=156), compared with 62% (n=58) in the private sector. zidovudine was characteristics (n=156) private group (n=58) government group (n=98) total females 67 80 75 males 33 20 25 black 75 96 83 coloured 9 1 3 indian 12 1 4 white 4 1 2 who staging (baseline) stage 1 33 18 19 stage 2 12 27 19 stage 3 33 46 34 stage 4 19 10 10 baseline opportunistic infections 32 44 40 oesophageal candiasis 2 9 6 tuberculosis 12 17 16 pneumocystis carinii pneumonia 1 1 toxoplasmosis 3 1 2 aids-related wasting syndrome 7 1 3 table i. patient baseline characteristics (%) 10 a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e the second most frequently used nucleoside reverse transcriptase inhibitor (nrti) (59%) (n=58) among private patients. stavudine was used in regimens of 96% of all government patients compared with 50% of private sector patients. among private patients, 47% had previous experience with didanosine compared with 7% of all government patients. abacavir and tenofovir constituted the private regimens of 2% of patients. efavirenz was commonly used in both the private (55%) and government (74%) sectors. in the private sector, 19% had experience with nevirapine, compared with 37% in the government sector. in the private sector 28% of patients had protease inhibitor (pi)-containing regimens. in many cases, pis constituted part of first-line treatment. the most commonly used pi was lopinavir/ritanovir (used by 12% of patients in the private sector). lopinavir/ritanovir was used in 9% of government sector regimens. ritanovir was used individually in 5% of private sector regimens. indinavir and saquinavir, and nelfinavir and atazanvir, were used in 5% and 2%, respectively, of private sector regimens. in the private sector sample, 69% began treatment privately in 2003 or 2004. twenty-five per cent of these patients were placed on dual therapy at some stage during private treatment. the majority of these regimens included single-class drugs, viz. nrtis. on commencing government arvs, the majority of these patients (82.7%) were placed on first-line regimens. the remainder were either placed on regimen 2 or remained on their private sector regimen. comparing cd4 cell count changes in the private group versus the government group twenty-six private group patients (44.8%) and 63 government group patients (64.3%) presented with baseline median cd4 counts of 156 cells/µl and 106 cells/µl, respectively (fig. 4). commencement of arvs in the government group resulted in an initial higher rate of increase in cd4 count. this subsequently diminished after 12 months, while the private group’s median count increased steadily. the last recorded median cd4 counts were 419 cells/µl for the private group and 360 cells/µl for the government group. cd4 cell count distribution both groups displayed variable cd4 count distribution, so median values and iqrs were calculated. distribution of cd4 counts (cells/µl) at baseline showed: n private group (n=42): median/(iqr) – 158.5 (111 325) n government group (n=95): median/iqr – 101 (33 153) n both groups (n=137): median/iqr – 122( 46 175). distribution of last recorded cd4 counts (cells/µl) showed: n private group (n=42): median/iqr – 419 (231 706) n government group (n=95): median/iqr – 358 (263 506) n both groups (n=137): median/iqr – 368 (254 538). fig. 1. nucleoside reverse transcriptase inhibitor use by patients in the private sector (%) compared with combined use by all patients in the government programme (%). fig. 2. non-nucleoside reverse transcriptase inhibitor use by patients in the private sector (%) compared with combined use by all patients in the government programme (%). fig. 3. protease inhibitor use by patients in the private sector (%) compared with combined use by all patients in the government programme (%). fig. 4. comparison of change in cd4 cell count (cells/µl) in the private group versus the government group. % o f pa ti en ts % o f pa ti en ts 80 70 60 50 40 30 20 10 0 efavirenz nevirapine individual nrtis private government 80 70 60 50 40 30 20 10 0 lopinavir/ritanovir ritanovir indinavir nelfinavir saquinavir atazanavir individual pis private government 12 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 1 the private group’s median cd4 count increased from 158.5 cells/µl to 419 cells/µl over an average of 29 months. in the government group, the baseline median (101 cells/µl) reached 358 cells/µl over an average of 30 months. the majority of observations (75%) in the private group and government group recorded baseline counts of 325 cells/µl and 153 cells/µl, respectively. these values increased substantially after commencement of government arvs. the last recorded readings indicated that 75% of patients in the private and government group had attained median cd4 counts of 706 cells/µl and 506 cells/µl, respectively. average rate of change of cd4 cell count the average rates of change of the cd4 cell count in the government group and the private group were 9.74 cells/ µl and 8.81 cells/µl per month, respectively. the two-sample wilcoxon rank-sum (mann-whitney) test compared rate of change in cd4 count between 42 patients in the private group (72.4%) and 95 patients in the government group (96.9%). average followup time for the private group and government group was 29 months and 30 months, respectively. using a significance level of α=0.05, the test concluded that there was no significant difference in rate of change of cd4 count (p=0.47) between the two groups. comparing viral load change in the private group versus the government group in the government group 43 patients (43.9%) presented with a median baseline viral load of 10.61 log copies/ ml (40 000 copies/ml) (fig. 5), compared with 7.82 log copies/ml (almost 2 500 copies/ml) in 17 patients in the private group (29.3%). commencement of government arvs achieved rapid viral load suppression in the first 8 months in the government group, compared with the private group. however, both groups eventually reached log 3.22 copies/ml (<25 copies/ml – undetectable levels). viral load value distribution distribution of viral load values was variable. distribution of viral load values (log copies/ml) at baseline showed: n private group (n=29): median/iqr – 8.88461 (6.461468 11.39275) n government group (n=66): median/iqr – 10.7425 (9.148465 12.10071) n both groups (n=95): median/iqr – 10.40426 (8.006368 11.98293). distribution of last recorded median viral load values (log copies/ml) showed: n private group (n=29): median/iqr – 3.218876 (3.218876 5.703783) n government group (n=66): median/iqr – 3.218876 (3.218876 3.218876) n both groups (n=95): median/iqr – 3.218876 (3.218876 3.218876). in the private group, median viral load decreased from 8.88461 log copies/ml (7 200 copies/ml) to 3.218876 log copies/ml (<25 copies/ml – undetectable levels), over an average of 27 months. the government group’s median viral load decreased from 10.7425 log copies/ml (>46 000 copies/ml) to undetectable levels, over an average of 29 months. seventy-five per cent of patients in the private group and government group presented with baseline viral load levels of 11.39275 log copies/ml (>88 000 copies/ ml) and 12.10071 log copies/ml (180 000 copies/ml), respectively. viral load decreased after commencement of government arvs. the private group and the government group showed last recorded readings of 5.703783 log copies/ml (300 copies/ml) and undetectable levels, respectively. average rate of change of viral load the average rates of change in viral load for the government group and the private group were 0.345804252 log copies/ml (1.41 copies/ml) per month and 0.328619966 log copies/ml (1.39 copies/ml) per month, respectively. the two-sample wilcoxon rank-sum (mann-whitney) test compared rates of change in viral load between 29 patients in the private group (50%) and 66 patients in the government group (67.3%). average follow-up times for the private group and the government group were 27 months and 29 months, respectively. using a significance level of α=0.05, the test concluded that there was no significant difference in rate of change of viral load (p=0.097) between the two groups. regimen modification and causes in the private group, 46.5% of regimen modifications occurred after commencing government arvs, while the government group recorded 45.9%. major causes for modifications in both groups were lactic acidosis, peripheral neuropathy, tuberculosis, lipodystrophy and virological failure. in the private group and the government group, 12% and 7% of patients, respectively, experienced symptoms of lactic acidosis or hyperlactataemia. in all episodes stavudine was changed to zidovudine. ninety per cent of patients (both groups) who experienced symptoms of fig. 5. comparison of change in viral load (log copies/ml) in the private group versus the government group. 13 a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e hyperlactataemia were female. median ages recorded in the private group and the government group were 34 and 40 years, respectively. nine per cent of private patients and 5% of government patients were diagnosed with lipodystrophy. in all patients stavudine was implicated and replaced with zidovudine. overall, 80% of these patients were female and the median age for both groups was 40 years. the baseline median cd4 counts for patients diagnosed with lipodystrophy in the private group (249.5 cells/µl) and the government group (194 cells/µl) correlated with observations of baseline cd4 counts below 350 cells/ µl being a risk factor for development of lipodystrophy.5 seven per cent of the private group and 19% of the government group experienced peripheral neuropathy. stavudine was implicated in most cases and replaced with zidovudine. in the private group and the government group, 3% and 5% of patients, respectively, were co-infected with tuberculosis while on government arvs, necessitating regimen modification. the second most common factor for regimen changes in the private group was virological failure. approximately 10.3% of private patients developed virological failure. in the government group only 1 patient developed virological failure. approximately 5.2% of private patients were lost to follow-up, probably due to death. this assumption was based on their last recorded cd4 counts (low). however, confirmation of death was incomplete and presumed from loss of follow-up data. no patient deaths were recorded in the government group. discussion and conclusion this study hypothesised that due to prior arv use, and in many instances use of sub-therapeutic regimens and treatment interruption, treatment in the private group would not be as successful in terms of immunological, virological and clinical improvement as in the arv-naïve government group. however, it was observed that with implementation of standardised highly active antiretroviral therapy (haart) regimens for the private group, there was immunological and virological improvement. on commencement of government haart, there was no significant difference in rate of change of cd4 count (p=0.47) or viral load (p=0.097) between the two groups. however, while both groups showed decreased viral loads, an important point in terms of distribution analysis was that over 27 months 75% of patients in the private group recorded a median viral load of 300 copies/ml, while in the government group the same majority recorded undetectable levels (<25 copies/ml). this implies that a better pharmacological response to haart was possibly achieved in the arv-naïve group compared with the previously treated group. this assumption is further enhanced by higher percentages of virological failure (10.3% v. 1%) and death (presumed) (5.2% v. nil) occurring in the private group. usage of various arv classes varied between the two sectors. during this study, drugs reserved as second line in the government sector (didanosine and zidovudine) often formed part of first-line regimens in the private sector. the only pi available in the government sector at the time was lopinavir/ritanovir, which was used by 9% of patients as part of second-line treatment. in the private sector 28% of patients had pi-containing regimens, often as part of first-line treatment. a quarter of private sector patients studied were placed on dual therapy (associated with partial viral suppression2) at some stage during private treatment. this may be attributed to non-standardised prescribing trends in the private sector. studies have found that prescribing practices of physicians may be influenced by interactions with pharmaceutical representatives regarding awareness, preference and rapid prescribing of new drugs.6 in both groups, 90% of patients with hyperlactataemia were female, corresponding with studies showing female gender to be a prognostic factor.7 the higher percentage of lipodystrophy in the private group corresponds with observations of prior arv experience being a risk factor.5 peripheral neuropathy was the most frequently observed toxicity in the government group and was linked to stavudine use. this study has shown that even with previous arv exposure, immunological and virological success is achievable. potent standardised regimens, counselling, regular follow-up and management of side-effects are essential. overall the success achieved in both groups may be attributed to implementation of standardised treatment guidelines and multidisciplinary approach of the government programme. the private sector should seek to be guided by the same approach. references 1. world health organization (who). antiretroviral therapy for hiv infection in adults and adolescents: recommendations for a public health approach – 2006. geneva: who, 2006. http:// www.who.int/hiv/pub/ guidelines/artadultguidelines.pdf (accessed 1 october 2008). 2. dolin r, masur h, saag ms. aids therapy. new york: elsevier science, 2003. 3. shaefer m. abacavir/lamivudine/zidovudine continues to be a valid and useful antiretroviral regimen. ann pharmacother 2004;38:1314-1316. 4. south african department of health. national antiretroviral treatment guidelines. pretoria: government printer, 2004. 5. baril j-g, junod p, leblanc r, et al. hiv-associated lipodystrophy syndrome: a review of clinical aspects. canadian journal of infectious diseases and medical microbiology 2005;16(4):233-243. 6. wazana a. physicians and the pharmaceutical industry: is a gift ever just a gift? jama 2000;283:373-380. 7. fabian j, venter wdf, mkhabela l, levin jb, baker l, naicker s. symptomatic hyperlactataemia in adults on antiretroviral therapy: a single-centre experience. s afr med j 2008;98(10):795-800. the above was submitted as part of the requirements for a masters in medical science (clinical pharmacology), supervisor professor viren rambiritch, phd. the degree was awarded cum laude by the university of kwazulunatal on 24 april 2009. ethics approval was obtained from the university of kzn and the kzn department of health. there was no conflict of interest or competing interests. 14 the southern african journal of hiv medicine                                                              april  2010 the argument there are scientific reasons to believe that population-wide periods of risk reduction could be effective. additionally there is evidence to suggest that sexual behaviours, including periods of abstinence, driven by religious reasons, may have kept the prevalence low in muslim countries. according to unaids only one country in north africa and the middle east region (sudan) had an hiv prevalence over 0.2%. in south and southeast asia, predominantly muslim countries such as pakistan, bangladesh and indonesia show similarly low hiv prevalences, typically below 0.2%.6 there are serious challenges in attributing cause, however. the practice of male circumcision is near universal, and is highly protective against men acquiring hiv.7-9 while islam permits polygamy, it prohibits sex outside marriage and discourages the consumption of alcohol and homosexual sex. all these factors may help explain the lower levels of seroprevalence in countries with large muslim populations.10 norms and patterns of sexual behaviour may also be quite different in observant muslim communities compared with other groups. indonesia, for instance, has a low national prevalence rate, estimated to only be around 0.2%, but papua province has a majority christian population and an hiv prevalence of 2.4%, over 10 times the national rate.11 there are, however, cases where hiv prevalence appears to be unusually low in muslim areas, even given high levels of risk activity. in dhaka, bangladesh, for instance, hiv prevalence apparently remains low despite common risk behaviours of injection drug use and commercial sex.12 so while confounding makes it innovative responses for preventing hiv transmission: the protective value of population-wide interruptions of risk activity f o r u m justin o parkhurst, bse, mphil (oxford), dphil (oxford) health policy unit, london school of hygiene and tropical medicine, keepel street, london, uk alan whiteside, ma, decon director, heard (health economics and hiv/aids research division), university of kwazulu-natal, durban 19 concurrent partnering contributes to high hiv prevalence. this is in part due to the natural history of the virus. after transmission, an individual’s viral load spikes in a period of ‘acute infection’ during which they are highly infectious.1,2 models estimate that around 10 45% of hiv acquisition arises from sex with an individual in the acute infection period.3 if everyone in a population abstained from high-risk sex for a given period of time, in theory the viral loads of all recent seroconverters should pass through the acute infection period. when risk behaviour resumed there would be almost no individuals in the high-viraemic phase, thereby reducing infectivity, and hiv incidence would fall. recurring population-wide shifts in risk behaviour are not unheard of. many, in fact, occur as part of existing religious observances. the month of ramadan in muslim communities is perhaps one of the most obvious cases. ramadan sees significant behaviour changes. in addition to fasting from sunrise to sunset, observant individuals abstain from coitus during daylight hours.4 there is anecdotal evidence that risky sexual behaviours are also significantly reduced over this period. in indonesia, for instance, it was reported that research with sex workers was not possible during ramadan because people ‘abstained from sex from one end of the month to the other … many sex workers returned to home villages during this time.’5 this article argues that a population-wide interruption of risk behaviour for a set period of time could reduce hiv incidence and make a significant contribution to prevention efforts. it calls for mathematical modelling of periodic risk behaviour interruptions, as well as encouragement of policy interventions to develop campaigns of this nature. a policy response, such as a ‘safe sex/no sex’ campaign in a cohesive population, deserves serious consideration as an hiv prevention intervention. in some contexts, periods of abstinence from risk behaviour could also be linked to existing religious practices to provide policy options. april  2010                                                            the southern african journal of hiv medicine                                                   hard to attribute the protection derived from ramadan practices of abstinence, there is scientific plausibility for considering it as an intervention. a potential intervention would be an aggressive national campaign to ensure that everyone who is sexually active in a population either commit to 100% condom use or refrain for sexual intercourse over a period of a month or longer. this would be a national campaign with buy-in from leadership at every level, from the president (or king) through church and business down to local community leaders. it could be trialled best in small homogeneous populations, and indeed the national emergency response council on hiv/aids (nercha) in swaziland has been considering it (personal communication with author aw). there is also evidence from mozambique that a 2-month ‘cooling off’ period during which people would abstain from starting any new sexual relationships would be feasible and acceptable.13 testing and validation avenues can be explored to test or validate the idea that population-wide interruptions in risk behaviour would slow the spread of hiv. on a theoretical level, ideally we feel that this should be further explored through mathematical modelling and estimation exercises. such exercises could predict how a population-wide abstinence campaign might reduce infections, both in the month of abstinence and over the course of a year through reduction in average viral loads when risk activity resumes. however, models may require some additional survey data to inform their parameters. in practice, an experimental trial would be impossible and unethical (abstinence is known to be protective on its own), nor would it be feasible to control some groups when such a wide-scale mobilisation effort might be needed to promote the behaviour change. however, discussions are under way to actually attempt interruptions in risk behaviour in this manner, and these must be observed with sufficient evaluation research to be built in. risk behaviours can be assessed before, during and after the intervention period to assess the impact they may have had. this can be done with surveys as well as in-depth investigation of particular groups to help avoid respondent bias. a campaign for a month of ‘safe sex/no sex’ would also produce easily verifiable data with regard to adherence, evidenced in the number of births occurring nine months after the campaign. finally, in theory, the average hiv viral load in the population could also be monitored before, during and after the period of abstinence to see how much it impacted on infectiousness, and to get better estimates of effectiveness in practice over modelling efficacy calculations. however, this might require very large sample sizes to show significant results. discussion a population-wide ‘month off’ from risk behaviour may help to interrupt the spread of hiv by allowing the acute infection period to pass and the hiv viral load to fall before risk activity is resumed. the month of ramadan may provide one example of this that has unknowingly been protective for muslim societies. we investigated whether there were other opportunities for abstinence from particular practices similar to ramadan through a review of major world religions. we did not find examples of sustained populationwide abstinence from sexual activity outside of islamic societies. small groups might do so, however, such as the marange apostolic sect in zimbabwe’s manicaland, who were found to abstain from sex during passover (and also found to have lower prevalence of hiv than surrounding populations).14,15 however, many religions do incorporate some form of abstinence or asceticism – whether it is the christian lenten restrictions for 40 days,4 the hindu brahmacharya practices (where some young men restrict sexual activity16), or buddhist general notions of self-restraint including life-long dietary restrictions. what is critical about periods such as lent and ramadan, however, is that they provide clear, extended time periods into which a campaign promoting abstinence from sexual risk behaviour might be incorporated. while converting people to a religion is not a reasonable public health strategy, these insights do raise the possibility of campaigns to regularly, if only temporarily, reduce risk behaviour across a population. the world health organization, for instance, has promoted ‘tobacco-free’ days.17 in this vein, key hiv risk behaviours can be targeted in populations. a ‘safe sex/no sex’ campaign for a limited period of time may be a reasonable public health intervention strategy to attempt in some settings. in hyper-epidemic countries in particular, policy makers, populations and politicians are open to new ideas to address the epidemic. prevalence rates and incidence rates are at unacceptably high levels and to be successful interventions take time and require long-term behaviour change. the ‘safe sex/no sex’ campaign has the advantage of requiring a one-off short-term adaption, being relatively cheap, having nation-building qualities, and not carrying stigma. finally, many elements can be easily monitored. while universal permanent abstinence from sex work may be impossible to achieve, a month of ‘no commercial sex’ or ‘no new partners’ might be more possible in some populations in which sex work appears to be a driving influence on spread (mining communities in southern africa, for instance18). permanent monogamy may be a challenging long-term goal for some, but a 20 the southern african journal of hiv medicine                                                              april  2010 ‘month of monogamy’ might be a useful starting point. it has rarely been attempted to put such ideas into practice, but they may reap significant benefits for hiv prevention. references 1. chin j. the aids pandemic: the collision of epidemiology with political correctness. oxford: radcliffe publishing, 2007. 2. halperin dt, epstein h. concurrent sexual partnerships help to explain africa's high hiv prevalence: implications for prevention. lancet 2004; 364: 4-6. 3. wawer mj, gray rh, sewankambo nk, et al. rates of hiv-1 transmission per coital act, by stage of hiv-1 infection, in rakai, uganda. j infect dis 2005; 191: 1403-1409. 4. ryan ft. the sacred art of fasting: preparing to practice. woodstock, vt: skylight paths publishing, 2005. 5. pisani e. the wisdom of whores: bureaucrats, brothels, and the business of aids. london: granta books, 2008. 6. unaids. report on the global hiv/aids epidemic. geneva: unaids, 2008. 7. gray rh, kigozi g, serwadda d, et al. male circumcision for hiv prevention in men in rakai, uganda: a randomised trial. lancet 2007; 369: 657-666. 8. bailey rc, moses s, parker cb, et al. male circumcision for hiv prevention in young men in kisumu, kenya: a randomised controlled trial. lancet 2007; 369: 643-656. 9. auvert b, taljaard d, lagarde e, sobngwi-tambekou j, sitta r, puren a. randomized, controlled intervention trial of male circumcision for reduction of hiv infection risk: the anrs 1265 trial. plos med 2005; 2: 0001-0011. 10. gray p. hiv and islam: is hiv prevalence lower among muslims? soc sci med 2004; 58: 1751-1756. 11. statistics indonesia (bps), orc macro. indonesia demographic and health survey 2007. calverton, md: bps and macro international, 2008. 12. foss am, watts ch, vickerman p, et al. could the care-shakti intervention for injecting drug users be maintaining the low hiv prevalence in dhaka, bangladesh? addiction 2006; 102: 114-125. 13. halperin d, cipriano e, senda r, et al. a two-month national 'cooling-off' period?: acceptability of an intensive behavior change campaign to reduce acute hiv infection in mozambique. presentation at the hiv acute infection meeting, boston, 22 23 september, 2009. 14. gregson s, ndlovu j, mlilo m, dauka e. fluctuations in sexual activity, the validity of sexual behaviour estimates for short time-intervals, and hiv intervention evaluation in rural zimbabwe. j sex res 2001; 2: 180-181. 15. gregson s, zhuwau t, anderson rm, chandiwana sk. apostles and zionists: the influence of religion on demographic change in rural zimbabwe. popul stud 1999; 53: 179-193. 16. alter js. celibacy, sexuality, and the transformation of gender into nationalism in north india. the journal of asian studies 1994; 53: 45-66. 17. world health organization. showing the truth, saving lives: the case for pictoral health warnings. geneva: who, 2009. 18. campbell c. 'letting them die': why hiv/aids prevention programmes fail. oxford: james currey, 2003. 21 pg12-17.html opinion rehabilitation: a crucial component in the future of hiv care and support stephanie nixon, bhsc (physiotherapy), phd department of physical therapy, university of toronto, canada, international centre for disability and rehabilitation, canada, and health economics and hiv/aids research division (heard), university of kwazulu-natal, south africa lisa forman, llb, sjd dalla lana school of public health and munk school of global affairs, university of toronto, canada jill hanass-hancock, drphill heard, university of kwazulu-natal, south africa muriel mac-seing, bscn (nursing), msc handicap international, kenya norbert munyanukato, md unhcr/coopi, chad hellen myezwa, mcsp (physiotherapy), phd department of physiotherapy, university of the witwatersrand, south africa chiara retis, bsc (physiotherapy) handicap international, france provision of antiretroviral therapy (art) is not an end in itself but a means to achieving improved wellness for people living with hiv. rehabilitation, broadly defined, is another key contributor to wellness within this context. understanding the potential for rehabilitation requires that one is able to consider hiv not only within a biomedical model that focuses on body systems, diagnoses and symptoms, but also within a rehabilitation framework that focuses on how these diagnoses and symptoms affect people’s lives more broadly. furthermore, rehabilitation is a human rights imperative, which deserves the energetic attention enjoyed by other aspects of hiv treatment and care. in particular, the united nations convention on the rights of persons with disabilities (uncrpd) is shining a long-overdue spotlight on the human rights imperatives associated with disability. for south africa and other countries, proactively and meaningfully engaging rehabilitation in the hiv response will require major shifts on several fronts, including practice, education, policy and research. we argue that in settings where art delivery is now widespread, hiv should be understood not only as a medical issue, but as a rehabilitation and disability concern. whereas medicine adds years to life, it is rehabilitation that aims to add life to years. the late 1990s: the birth of rehabilitation in the context of hiv in high-income countries until 1995, an hiv diagnosis meant largely the same thing regardless of where one lived globally: people living with hiv typically experienced various hiv-related diseases that progressed steadily until death. in 1996, however, early forms of triple-combination antiretroviral therapy (art) became available and life with hiv changed dramatically for people who could access and tolerate these medications – the vast majority of whom lived in high-income countries. with the advent of art, people with hiv began to live longer, which was a cause for great celebration.1 however, the experience of living with hiv was not without continuing challenges. along with their existing symptoms, many people living with hiv described an unexpected experience of disablement related to primary infection from hiv, hiv-related conditions, and side-effects of art.2 , 3 as their needs changed, so did the way that clinicians and advocates thought about hiv. in canada, a key response came from the rehabilitation community.4 rehabilitation as a field aims to help people address the life-related consequences of medical conditions. as such, an early response to the shift in experience brought about by the advent of art was to reconceptualise hiv out of a biomedical model and into a rehabilitation framework.5 in contrast to an exclusive biomedical focus on diagnoses, symptoms and medications, the world health organization’s rehabilitation framework, the international classification of disability, functioning and health (icf), served to refocus attention on the related ‘impairments’ (problems with body structure or function), ‘activity limitations’ (challenges at the level of the whole body) and ‘participation restrictions’ (challenges related to the person in her/his environment) associated with hiv6 rehabilitation is broadly defined as any services, policies or other actions that respond to these challenges. the reconceptualisation of hiv within a rehabilitation framework enabled people living with hiv and their advocates to articulate their experiences and needs differently.7 this in turn encouraged health care providers to consider the rehabilitation care needs of their clients more comprehensively.8 this reframing offered hiv researchers a strategy for measuring the prevalence of disability among people living with hiv, which was found to be strikingly high.2 , 9 it also led researchers to explore novel dimensions of life with hiv in this new era, such as ‘episodic disability’.10 finally, but not least, this re-orientation prompted policy-makers to meaningfully include rehabilitation and disability in their strategic responses to hiv.14 rehabilitation in the context of hiv is now well entrenched in the hiv response in canada.15 the late 2000s: the rebirth of rehabilitation in the context of hiv in lowand middle-income countries since the mid-2000s, after years of dynamic activism to bridge profound inequities in treatment delivery, access to art has at last begun to improve in many resourcepoor countries with a high hiv prevalence.16 art is a crucially important advance in contributing to the health and well-being of people living with hiv. however, it has been hypothesised that the widespread scale-up of art in sub-saharan africa will prompt experiences of disablement related to hiv, its secondary conditions and side-effects of medication, similar to those in canada in the mid-1990s.17 , 18 indeed, the first studies exploring disablement among people living with hiv in southern africa support this hypothesis: myezwa, van as and colleagues used the who-icf framework to reveal a high level of disablement among 80 people living with hiv who were hospital inpatients,19 as well as 45 clinic outpatients in south africa.20 in addition to formal evidence, rehabilitation providers on the ground are witnessing the disabling effects of hiv and the medications used to treat it. for example, handicap international, an international ngo that supports the development of rehabilitation services in 13 african countries, reports that their rehabilitation programmes in kenya, ethiopia and mozambique are increasingly witnessing the arrival of people living with hiv seeking rehabilitation services. similarly, the south african disability alliance in co-operation with the south african national aids council identified that people living with hiv are at increased risk for developing disability.21 furthermore, a recent research meeting in kwazulu-natal identified the disabling effects of hiv as a priority.22 we argue that this is the beginning of a trend that will see rehabilitation become a key component of hiv care. for south africa and other countries, proactively engaging rehabilitation in the hiv response will require major shifts on several fronts. advancing our practice and education provision of art is not an end in itself, but rather a means to achieve improved wellness for people living with hiv. rehabilitation, broadly defined, is another key contributor to wellness within this context. understanding and engaging rehabilitation requires that one is able to consider hiv not only within a biomedical model that focuses on body systems, diagnoses and symptoms, but also within a rehabilitation framework that refocuses on how physical and mental health diagnoses and symptoms affect people’s lives. the world health organization’s icf contributed importantly to a paradigm shift in canada. the icf is also a leading rehabilitation framework in the global south that has much to offer hiv. reconceptualising hiv through a rehabilitation lens highlights opportunities for enhanced hiv practice and education relevant for at least three broad populations. first, people and organisations who provide hiv health services should come to understand the role of rehabilitation within the continuum of care. this is particularly true for hiv care providers who, as the point of contact with people living with hiv, are uniquely situated to provide referrals to rehabilitation services. hiv providers must be trained to understand the impairments, activity limitations and participation restrictions that can arise from hiv-related conditions, and the options available within the world of rehabilitation to address these concerns. second, we call on the rehabilitation and disability communities to recognise their role in responding to the needs of people living with hiv and their communities, including physiotherapists, occupational therapists, speech-language therapists, audiologists, prosthetics and orthotics specialists and the wide range of other rehabilitation providers for people living with hiv. however, education on the role of rehabilitation for people living with hiv also needs to reach community-based workers, health volunteers and community leaders, as these front-line workers are frequently the information links for people in need of rehabilitation. shortages of all forms of health human resources demand a different approach to rehabilitation delivery to that in the north. however, existing models of community-based rehabilitation have been driving service delivery for decades and have a range of similarities with hiv home-based care. overburdened health systems require that, like all aspects of the hiv response, we must seek synergies for providing rehabilitation within the broader health system, rather than implementing services within a purely vertical response. third, and arguably most importantly, is for people living with hiv and their advocacy partners to recognise the robust role that rehabilitation can play in the future of the hiv response and to include calls for action from stakeholders. historically, it has been people living with hiv who were most effective at prompting change. rehabilitation in the context of hiv needs to be recognised as a new target for advocacy and lobbying, which points to change at the policy level. advancing our policies rehabilitation is a human rights imperative and therefore deserves the kind of energetic attention enjoyed by other aspects of hiv treatment and care. one major advantage for the rehabilitation response in this new era of art scale-up is the recent passing of the united nations convention on the rights of persons with disabilities (uncrpd), which is shining a long-overdue spotlight on issues of disability. the convention requires states to recognise that where people living with hiv have impairments which, in interaction with the environment, result in stigma, discrimination or other barriers to their participation, they fall under the protection of the convention.23 the south african government is an instructive example insofar as it is bound by the human rights imperative to rehabilitate under international and national law. south africa has ratified the uncrpd, which recognises people's right to habilitation and rehabilitation. this requires the state to take steps to allow people with disabilities to achieve maximum independence, full physical, mental, social and vocational ability, and full inclusion and participation in all aspects of life, including through comprehensive habilitation and rehabilitation services and programmes, particularly in the areas of health (article 26). this duty is reinforced in the prohibition of unfair discrimination on the grounds of disability in the south african constitution (section 9.3), and within related protections contained in subsidiary legislation and policy, including the social assistance act of 2004, the employment equity act of 1998, and the integrated national disability strategy of 1997. as such, we need to ensure that recognition of rehabilitation and disability are reflected in national strategic plans for hiv and other health policy instruments.24 importantly, south africa’s 2007 2011 national strategic plan (nsp) introduced a disability sector plan in 2009. 25 under the goal of mitigating the impact of hiv and aids, the nsp describes the need to improve treatment, care and support for people with disabilities. however, little guidance is given for addressing the disabling effects of hiv. furthermore, roles for rehabilitation are not explicitly described, although dimensions of rehabilitation are considered, such as goal 6, which focuses on enabling people living with hiv to lead healthy and productive lives.26 , 27 rehabilitation, therefore, is vital in terms of human rights, health outcomes and quality of life and needs to be integrated into hiv plans. ushering in change will require ‘double mainstreaming’ insofar as national and provincial hiv offices will need to be aware of the rehabilitation needs of people living with hiv, and rehabilitation/disability-related authorities need to be made aware of their role in supporting people living with hiv. advancing our research like all dimensions of the health response to hiv, evidence is required to inform effectiveness, efficiency and acceptability of potential interventions. the same is true of rehabilitation and its role as part of the hiv care continuum. this is an untapped research landscape; several examples can illustrate the potential within this field. first, good research drives not only practice but policy development and the wise distribution of scarce resources. we need to engage in research on the african continent that explores rehabilitative care as a costeffective means of improving autonomy and quality of life for all people living with disability, including people living with hiv. second, it is not known how the concept of episodic disability, which has been a cornerstone of the response in canada, might play out in the context of hyper-epidemics in sub-saharan africa. third, the icf concept of participation squarely engages issues of stigma and discrimination, providing a bridge between rehabilitation researchers and those working in other anti-stigma paradigms. one final illustrative example involves forecasting models of human resource needs in rehabilitation based on increased access to art, given the expected rise in demand. conclusion provision of treatment has necessarily been the central focus of hiv care in recent years. however, many countries including south africa are now at the point of identifying and grappling with new questions related to hiv care, treatment and support in this new era of art – a scenario that is reminiscent of the experience in canada and other resource-rich countries in the late 1990s. while we must pay close attention to the differences between the two scenarios and the contexts in which they are based, we must also seek reciprocal lessons based on similarities. importantly, we must understand hiv not only as a medical issue, but also as a rehabilitation and disability concern in settings where art delivery is now widespread. indeed, whereas medicine adds years to life, it is rehabilitation that aims to add life to years. references 1. palella fj jr, delaney km, moorman ac, et al. declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. hiv outpatient study investigators. n engl j med 1998;338(13):853-860. 1. palella fj jr, delaney km, moorman ac, et al. declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. hiv outpatient study investigators. n engl j med 1998;338(13):853-860. 2. rusch m, nixon s, schilder a, braitstein p, chan k, hogg rs. impairments, activity limitations and participation restrictions: prevalence and associations among persons living with hiv/aids in british columbia. health qual life outcomes 2004;2:46. 2. rusch m, nixon s, schilder a, braitstein p, chan k, hogg rs. impairments, activity limitations and participation restrictions: prevalence and associations among persons living with hiv/aids in british columbia. health qual life outcomes 2004;2:46. 3. o’brien kk, bayoumi am, strike c, young nl, davis am. exploring disability from the perspective of adults living with hiv/aids: development of a conceptual framework. health qual life outcomes 2008;6:76. 3. o’brien kk, bayoumi am, strike c, young nl, davis am. exploring disability from the perspective of adults living with hiv/aids: development of a conceptual framework. health qual life outcomes 2008;6:76. 4. worthington c, myers t, o’brien k, nixon s, cockerill r. rehabilitation in hiv/ aids: development of an expanded conceptual framework. aids patient care stds 2005;19(4):258-271. 4. worthington c, myers t, o’brien k, nixon s, cockerill r. rehabilitation in hiv/ aids: development of an expanded conceptual framework. aids patient care stds 2005;19(4):258-271. 5. nixon s, cott c. shifting perspectives: reconceptualizing hiv disease in a rehabilitation framework. physiother can 2000;52(3):189-207. 5. nixon s, cott c. shifting perspectives: reconceptualizing hiv disease in a rehabilitation framework. physiother can 2000;52(3):189-207. 6. world health organization. icf: international classification of functioning, disability and health. geneva: who, 2001. 6. world health organization. icf: international classification of functioning, disability and health. geneva: who, 2001. 7. canadian working group on hiv and rehabilitation. about us, 2011. http://www. hivandrehab.ca/en/index.php (accessed 9 may 2011). 7. canadian working group on hiv and rehabilitation. about us, 2011. http://www. hivandrehab.ca/en/index.php (accessed 9 may 2011). 8. wellesley central hospital, health canada. a comprehensive guide for people living with hiv disease, module 7: rehabilitation services. toronto: health canada, 1998. 8. wellesley central hospital, health canada. a comprehensive guide for people living with hiv disease, module 7: rehabilitation services. toronto: health canada, 1998. 9. rusch m, nixon s, schilder a, braitstein p, chan k, hogg rs. prevalence of activity limitation among persons living with hiv/aids in british columbia. can j public health 2004;95(6):437-440. 9. rusch m, nixon s, schilder a, braitstein p, chan k, hogg rs. prevalence of activity limitation among persons living with hiv/aids in british columbia. can j public health 2004;95(6):437-440. 10. solomon p, wilkins s. participation among women living with hiv: a rehabilitation perspective. aids care 2008;20(3):292-296. 10. solomon p, wilkins s. participation among women living with hiv: a rehabilitation perspective. aids care 2008;20(3):292-296. 11. nixon s, renwick r. experiences of contemplating returning to work for people living with hiv/aids. qual health res 2003;13(9):1272-1290. 11. nixon s, renwick r. experiences of contemplating returning to work for people living with hiv/aids. qual health res 2003;13(9):1272-1290. 12. o’brien k, wilkins a, zack e, solomon p. scoping the field: identifying key research priorities in hiv and rehabilitation. aids behav 2010;14(2):448-458. 12. o’brien k, wilkins a, zack e, solomon p. scoping the field: identifying key research priorities in hiv and rehabilitation. aids behav 2010;14(2):448-458. 13. o’brien kk, davis am, strike c, young nl, bayoumi am. putting episodic disability into context: a qualitative study exploring factors that influence disability experienced by adults living with hiv/aids. j int aids soc 2009;12(1):5. 13. o’brien kk, davis am, strike c, young nl, bayoumi am. putting episodic disability into context: a qualitative study exploring factors that influence disability experienced by adults living with hiv/aids. j int aids soc 2009;12(1):5. 14. canadian working group on hiv and rehabilitation. episodic disabilities network. 2009. http://www.hivandrehab.ca/en/episodic_disabilities/episodic_disabilities_ network.php (accessed 09 may 2011). 14. canadian working group on hiv and rehabilitation. episodic disabilities network. 2009. http://www.hivandrehab.ca/en/episodic_disabilities/episodic_disabilities_ network.php (accessed 09 may 2011). 15. health canada. leading together: canada takes action on hiv/aids 2005-2010, 2005. http://www.leadingtogether.ca/pdf/leading_together.pdf (accessed 9 may 2011). 15. health canada. leading together: canada takes action on hiv/aids 2005-2010, 2005. http://www.leadingtogether.ca/pdf/leading_together.pdf (accessed 9 may 2011). 16. who, unaids, unicef. universal access: scaling up priority hiv/aids interventions in the health sector. progress report 2010. 2010. http://www.who.int/ hiv/pub/2010progressreport/cover_en.pdf (accessed 9 may 2011). 16. who, unaids, unicef. universal access: scaling up priority hiv/aids interventions in the health sector. progress report 2010. 2010. http://www.who.int/ hiv/pub/2010progressreport/cover_en.pdf (accessed 9 may 2011). 17. hanass-hancock j, nixon sa. the fields of hiv and disability: past, present and future. j int aids soc 2009;2(1):3. 17. hanass-hancock j, nixon sa. the fields of hiv and disability: past, present and future. j int aids soc 2009;2(1):3. 18. unaids. disability and hiv policy brief. 2009. http://data.unaids.org/pub/ manual/2009/jc1632_policy_brief_disability_en.pdf (accessed 9 may 2011). 18. unaids. disability and hiv policy brief. 2009. http://data.unaids.org/pub/ manual/2009/jc1632_policy_brief_disability_en.pdf (accessed 9 may 2011). 19. myezwa h, van as m, musenge e, nesara p. assessment of hiv-positive in-patients using the international classification of functioning, disability and health (icf), at chris hani baragwanath hospital, johannesburg. african journal of aids research 2009;8(1):93-106. 19. myezwa h, van as m, musenge e, nesara p. assessment of hiv-positive in-patients using the international classification of functioning, disability and health (icf), at chris hani baragwanath hospital, johannesburg. african journal of aids research 2009;8(1):93-106. 20. van as m, myezwa h, stewart a, maleka d, musenge e. the international classification of function disability and health (icf) in adults visiting the hiv outpatient clinic at a regional hospital in johannesburg, south africa. aids care 2009;21(1):50-58. 20. van as m, myezwa h, stewart a, maleka d, musenge e. the international classification of function disability and health (icf) in adults visiting the hiv outpatient clinic at a regional hospital in johannesburg, south africa. aids care 2009;21(1):50-58. 21. sanac. hiv, aids and disability in south africa, 2008. http://www.icdr.utoronto.ca/ files/pdf/94a3663acf97d5f.pdf (accessed 9 may 2011). 21. sanac. hiv, aids and disability in south africa, 2008. http://www.icdr.utoronto.ca/ files/pdf/94a3663acf97d5f.pdf (accessed 9 may 2011). 22. health economics and hiv/aids research division (heard), quadpara association of kwazulu-natal. hiv and disability research and advocacy planning meeting, august 15-16, 2010. ashley village, south africa, 2010. 22. health economics and hiv/aids research division (heard), quadpara association of kwazulu-natal. hiv and disability research and advocacy planning meeting, august 15-16, 2010. ashley village, south africa, 2010. 23. united nations. un convention on the rights of persons with disabilities. 2008. http://www.un.org/disabilities/default.asp?id=150 (accessed 09 may 2011). 23. united nations. un convention on the rights of persons with disabilities. 2008. http://www.un.org/disabilities/default.asp?id=150 (accessed 09 may 2011). 24. hanass-hancock j, strode a, grant k. inclusion of disability within national strategic responses to hiv and aids in eastern and southern africa. disability and rehabilitation 2011 [early online], 1-8. http://informahealthcare.com/doi/pdf/10.3109 /09638288.2011.573055 (accessed 9 may 2011). 24. hanass-hancock j, strode a, grant k. inclusion of disability within national strategic responses to hiv and aids in eastern and southern africa. disability and rehabilitation 2011 [early online], 1-8. http://informahealthcare.com/doi/pdf/10.3109 /09638288.2011.573055 (accessed 9 may 2011). 25. sanac. nothing about us without us! hiv, aids and disability in south africa, 2010. http://www.heard.org.za/downloads/nothing-about-us-without-us-hiv-aids-anddisability in-south-africa.pdf (accessed 9 may 2011). 25. sanac. nothing about us without us! hiv, aids and disability in south africa, 2010. http://www.heard.org.za/downloads/nothing-about-us-without-us-hiv-aids-anddisability in-south-africa.pdf (accessed 9 may 2011). 26. grant ka, strode sa, hanass-hancock j. disability in national strategic plans on hiv and aids. a review on the national response to the interrelations of disability and hiv in eastern and southern africa. durban: health economics and hiv/aids research division, 2009. 26. grant ka, strode sa, hanass-hancock j. disability in national strategic plans on hiv and aids. a review on the national response to the interrelations of disability and hiv in eastern and southern africa. durban: health economics and hiv/aids research division, 2009. 27. sanac. hiv and aids and sti strategic plan for south africa, 2007-2011. http://www.tsfsouthernafrica.com/guides/strat_op_plan/folder3/3.6%20south%20 africa%20hiv%20and%20aids%20and%20sti%20plan%202007-11.pdf (accessed 9 may 2011). 27. sanac. hiv and aids and sti strategic plan for south africa, 2007-2011. http://www.tsfsouthernafrica.com/guides/strat_op_plan/folder3/3.6%20south%20 africa%20hiv%20and%20aids%20and%20sti%20plan%202007-11.pdf (accessed 9 may 2011). lung.html original article lung fibrosis in deceased hiv-infected patients with pneumocystis pneumonia e j shaddock, mb bch, fcp (sa) g a richards, mb bch, fcp (sa), phd division of pulmonology and critical care, department of medicine, charlotte maxeke johannesburg academic hospital and university of the witwatersrand, johannesburg j murray, mb bch, ffpath (sa) national institute of occupational health of the national health laboratory services and school of public health, university of the witwatersrand corresponding author: e shaddock (eshaddock@metroweb.co.za) background. pneumocystis pneumonia (pcp) is one of the most common opportunistic infections found in patients with hiv. the prognosis if ventilation is required is poor, with mortality of 36 80%. although more recent studies have shown improved survival, our experience has been that close to 100% of such patients die, and we therefore decided to investigate further. methods. all patients with confirmed or suspected pcp who died owing to respiratory failure were eligible for the study. where consent was obtained, trucut lung biopsies were performed post mortem, stored in formalin and sent for histopathological assessment. results. twelve adequate lung biopsies were obtained from 1 july 2008 to 28 february 2011 – 3 from men and 9 from women. the mean age was 34.7 years (range 24 46), and the mean admission cd4 count was 20.8 (range 1 68) cells/μl and median 18.5 cells/μl. all specimens demonstrated typical pcp histopathology; in addition, 9 showed significant interstitial fibrosis. three had co-infection with cytomegalovirus (cmv), two of which had fibrosis present. there was no evidence of tb or other fungal infections. conclusion. the high mortality seen in this cohort of pcp patients was due to intractable respiratory failure from interstitial lung fibrosis. whereas the differential includes ventilator induced lung injury, drug resistance or co-infections, we suggest that this is part of the disease progression in certain individuals. further studies are required to identify interventions that could modify this process and improve outcomes in patients with pcp who require mechanical ventilation. s afr j hiv med 2012;13(2):64-67. since the introduction of antiretroviral therapy (art) for individuals who are hiv-infected with aids, there has been a dramatic decline in the number of these patients presenting with pneumocystis jerovicii pneumonia (pcp) in the developed world. in south africa, the antiretroviral (arv) rollout was delayed for political reasons until 2004; consequently, significant numbers of patients are still presenting with pcp as a cause of respiratory failure. these patients are either unaware of their diagnosis or have not started arvs for reasons that include poor access to medical facilities and drugs, denial and lack of education. if patients with pcp require mechanical ventilation, the prognosis is poor, with mortality ranging from 36 80%.1 , 2 in fact, prior to the availability of arvs, such patients were not mechanically ventilated in south africa as no definitive therapy was available. once these agents became available to all hiv-positive patients with cd4 counts <200 cells/μl, it became feasible for them to be considered for ventilation. at the charlotte maxeke johannesburg academic hospital, it soon became apparent that few of these patients survived, despite early initiation of both art and effective chemotherapy for pcp. management included use of ardsnet low tidal volume strategies,3 conservative fluid protocols, adjunctive corticosteroids and minimal sedation. despite these, mortality remained extremely high while other units were reporting 50 79% cure rates.1 , 4 it was consequently decided to prospectively investigate the patients who had died in the unit, with the aim of determining the causes of failure of therapy. possibilities that had been considered for this failure were concurrent infections including cytomegalovirus,5 , 6 cryptococcus neoformans, mycobacterial or bacterial infections such as streptococcus pneumonia, drug resistance, as well as pulmonary kaposi’s sarcoma.7 methods this was a prospective study to investigate histological findings of patients who died from confirmed or suspected pcp. all patients in these two categories, with respiratory failure, were considered for the study. pcp was suspected in patients with clinically advanced hiv presenting with hypoxic respiratory failure with typical chest radiograph changes, including bilateral diffuse alveolar infiltrates, granular opacities or, occasionally, unilateral or focal infiltrates.7 pneumocystis was confirmed ante mortem on sputum from 4 of the patients using the giemsa stain; and 9 had organisms seen on histological samples. the remaining 3 had markedly elevated beta-d-glucan (bdg) levels >500 pg/ml.8 pre-mortem biopsies or bronchial washings were not possible owing to the severity of the hypoxia. with family consent, multiple trucut biopsies were taken from different regions of the lungs of each patient after death. the specimens were stored in formalin and subsequently stained with grocott, gordon and sweets, alcian blue, ziehl-neelsen and haematoxylin and eosin. ethics approval was given by the university of the witwatersrand ethics committee. results sixteen lung biopsies were obtained from 1 july 2008 to 28 february 2011. table 1 lists patient demographics and laboratory characteristics. four were inadequate samples and therefore not included. the final 12 were from 3 male and 9 female patients. mean age of patients was 34.7 years (range 24 46 years). mean admission cd4 count 20.8 (range 1 68) cells/μl, and the median cd4 was 18.5 cells/μl. icu details all 12 patients were admitted to the intensive care unit (icu), where 10 were mechanically ventilated; none developed pneumothoraces. all received appropriate high-dose trimethoprim-sulfamethoxazole (tmp-smx) with high-dose corticosteroids as primary management. none were on art at the time of presentation. histopathology all 12 of the final specimens demonstrated the typical histopathological pattern of pcp, including alveoli filled with frothy material, type 2 cell hyperplasia and pneumocystis organisms. in addition, 9 of the 12 showed evidence of interstitial fibrosis with expansion of the interstitium by fibroblasts and collagen of varying degrees of severity. there was significant destruction and distortion of the lung architecture, resulting in a marked decrease in available alveolar-endothelial surface area for diffusion (fig. 1). three had evidence of cmv co-infection with intracellular inclusion bodies, and 2 of these also showed evidence of fibrosis. one of the latter 2 had a super-added bacterial infection that was not evident in any of the other specimens. there was no evidence of tb or other fungal infection in any of the specimens. discussion pneumocystis pneumonia is still one of the most common opportunistic infections found in patients infected with hiv.9 pneumocystis is primarily an alveolar pathogen that does not invade the pneumocyte to which it tightly adheres. the histopathological changes that are seen are explained by the exuberant host inflammatory response to the organism, which promotes pulmonary injury in only some patients during infection. severe pneumocystis pneumonia can result in a significant neutrophilic response that leads to diffuse alveolar damage, impaired gas exchange and respiratory failure.10 p. jirovecii has specific proteases that have the ability to damage the lung interstitium, and endogenous host proteases including matrix metalloproteinases (mmp) are also secreted in response to an influx of pro-inflammatory mediators (interleukin-6 (il-6), interleukin-8 (il-8), monocyte chemotactic protein-1 (mcp-1), and tumour necrosis factor alpha (tnf-α)) from alveolar epithelial cells. 11 , 12 this can explain the extensive capillary leak and frothy hyaline material that fills the alveolus in typical pcp. it is possible that the extensive effacement of normal alveolar architecture with fibrosis demonstrated in these biopsies is part of a reparative process that may occur only in those individuals genetically predisposed to the development of fibrosis, so that not all patients with pcp behave similarly. in our sample, 75% of the patients who died of refractory respiratory failure revealed varying degrees of interstitial fibrosis resulting in obliteration of the alveolar capillary interface and loss of surface area for diffusion with the remainder, demonstrating unresponsive pcp. the pattern of the former is similar to that of the fibrotic stage of acute respiratory distress syndrome (ards); and, whereas it might be argued that this could be consistent with ards following an infection by a more virulent organism such as streptococcus pneumoniae, this organism was not cultured in vivo, and patients all received standard empiric therapy for community-acquired pneumonia. importantly, none presented with the secondary organ dysfunction or systemic inflammatory response syndrome (sirs), more typical of severe infections with this organism. in addition, all the patients received corticosteroids as a component of therapy for pcp that may be effective in the therapy of refractory ards owing to other causes.13 another factor that could be responsible for the fibrotic injury is ventilator-induced lung injury (vili). however, 2 of the 13 patients were not ventilated, and their biopsies showed similar interstitial fibrotic changes to those who were, and the other 11 were ventilated with tidal volumes ≤6ml/kg, and were recruited and maintained on appropriate peep, making this explanation unlikely. in south africa, where medical resources are limited, the majority of patients with pcp and respiratory failure (most of whom have pao2/fio2 ratios <200) are treated with oxygen via a re-breathing mask and appropriate pharmacological therapy in the general wards. only the most severely hypoxic patients or those who fail therapy are considered for ventilation. this observation highlights a weakness in our sample, with a selection bias for those with a worse prognosis. patients who were not considered candidates for icu admission might have developed respiratory failure and died in the general medical wards, or more usually might have made a full recovery despite initial low p/f ratios. the latter, who in more resource-rich environments would have been admitted to icu, could account for the high survival rates in other studies. those admitted to icu in south africa are preselected, with most having already received and failed appropriate pharmacotherapy. it has previously been reported in the pre-art era that patients who required ventilation despite adequate and appropriate therapy, have a poor prognosis.4 the reasons for the failure of therapy and the failure to benefit from mechanical ventilation have not previously been well described. why some patients and not others develop fibrosis has also not been adequately elucidated. it could be argued that these patients might have had 2 disease processes: pcp superimposed on a more chronic condition or that this was an acute exacerbation of a more chronic underlying inflammatory process similar to those that occur in the idiopathic interstitial pneumonias.14 however, this does not explain why these patients had elevated β-d glucan levels in the absence of fungal infection elsewhere, and x-ray features not compatible with the interstitial pneumonias; and in the latter case, why the histological features were typical of pcp. cmv has been postulated to be more than a ‘fellow traveller’ in patients with pcp, and treatment with gancyclovir has been reported to improve outcome.5 , 6 it is conceivable that infection by both organisms could be synergistic regarding the fibro-proliferative effects. however, in only 3 of our cohort was there evidence of cmv co-infection, 2 of whom did have fibrosis. an important consideration for treatment failure is the possibility of resistance to sulfa drugs owing to mutations of pneumocystis dihydropteroate synthase (dhps) gene due to increased drug pressure from the widespread use of tmp-smx prophylaxis. dhps, the enzyme responsible for folate synthesis and the target of tmp-smx, has undergone gene mutations that have been identified in 56% of p. jirovecii strains in south africa.15 however, as human strains of pcp cannot be cultured in vitro, it is difficult to prove that these mutations confer drug resistance. a number of studies have evaluated the effect of these mutations on clinical outcomes with conflicting results. helweg-larsen et al. demonstrated that patients infected by organisms with a dhps mutation had a threefold increased risk of death.16 navin and colleagues, however, found no association with mortality at 6 weeks nor with treatment failure.17 in fact, they found that 85% of patients with dhps mutations treated with tmp-smx responded to treatment. a limitation of our study is the small sample size. in view of our resource-limited setting, these patients are not often viewed as good icu candidates. therefore, even though the pcp burden in south african hospitals is high, the available icu pcp population is restricted. we feel that these are important data and will add to the understanding of the clinical course of these patients, even taking into account the small sample size. interstitial fibrosis has previously been demonstrated in patients who have survived an episode of pcp, as well as on previous necropsy studies.4 , 18 there have also been histological reports of cryptogenic organising pneumonia, granulomatous inflammation and diffuse alveolar damage.19 our cohort, however, was unusual in that the majority of patients with pcp, most of whom were ventilated, had evidence of extensive pulmonary fibrosis – which was associated with an extremely poor prognosis. this phenomenon has been described previously; however, it has not been highlighted as the probable underlying cause for treatment failure and death. we suggest that, if we want to improve the dismal outcome of these patients, we need to consider the state of the underlying lung, and realise that treatment of the organism alone is insufficient. primarily, we need to expand the rollout of arvs and, failing this, try to both recognise and treat the condition sooner, prior to the development of fibrosis. ideally, we should also develop a management protocol that addresses the lung fibrosis once it has occurred. references 1. fernandez p, torres a, miro jm, et al. prognostic factors influencing the outcome in pneumocystis carinii pneumonia in patients with aids. thorax 1995;50:668-671. [http://dx.doi.org/10.1136/thx.50.6.668] [pmid: 7638811]. 1. fernandez p, torres a, miro jm, et al. prognostic factors influencing the outcome in pneumocystis carinii pneumonia in patients with aids. thorax 1995;50:668-671. [http://dx.doi.org/10.1136/thx.50.6.668] [pmid: 7638811]. 2. randell curtis j, yarnold pr, schwartz dn, weinstein ra, bennett cl. improvements in outcomes of acute respiratory failure for patients with hiv related pneumocystis carinii pneumonia. am j respir care med 2000;162:393-398. [pmid:10934059]. 2. randell curtis j, yarnold pr, schwartz dn, weinstein ra, bennett cl. improvements in outcomes of acute respiratory failure for patients with hiv related pneumocystis carinii pneumonia. am j respir care med 2000;162:393-398. [pmid:10934059]. 3. davis jl, morris a, kallet rh, et al. low tidal volume ventilation is associated with reduced mortality in hiv-infected patients with acute lung injury. thorax 2008;63:988-999. 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[http://dx.doi.org/10.1046/j.1365-2362.1998.00299.x] [pmid: 9650017]. 11. pottratz st, reese s, sheldon jl. pneumocystis carinii induces interleukin 6 production by an alveolar epithelial cell line. eur j clin invest 1998; 28:424-429. [http://dx.doi.org/10.1046/j.1365-2362.1998.00299.x] [pmid: 9650017]. 12. benfield tl, lundgren b, shelhamer jh, lundgren jd. pneumocystis carinii major surface glycoprotein induces interleukin-8 and monocyte chemoattractant protein-1 release from a human alveolar epithelial cell line. eur j clin invest 1999:29:717-722. [http://dx.doi.org/10.1046/j.1365-2362.1999.00517.x] [pmid: 10457157]. 12. benfield tl, lundgren b, shelhamer jh, lundgren jd. pneumocystis carinii major surface glycoprotein induces interleukin-8 and monocyte chemoattractant protein-1 release from a human alveolar epithelial cell line. eur j clin invest 1999:29:717-722. [http://dx.doi.org/10.1046/j.1365-2362.1999.00517.x] [pmid: 10457157]. 13. meduri gu, annane d, chrousos gp, marik pe, sinclair se. activation and regulation of systemic inflammation in ards: rationale for prolonged glucocorticoid therapy. chest 2009;136:1631-1643. [pmid: 19801579]. 13. meduri gu, annane d, chrousos gp, marik pe, sinclair se. activation and regulation of systemic inflammation in ards: rationale for prolonged glucocorticoid therapy. chest 2009;136:1631-1643. [pmid: 19801579]. 14. collard hr, moore bb, flaherty kr, et al. acute exacerbations of idiopathic pulmonary fibrosis. am j respir crit care med 2007;176:636-643. [http://dx.doi.org/10.1164/rccm.200703-463pp] [pmid: 17585107]. 14. collard hr, moore bb, flaherty kr, et al. acute exacerbations of idiopathic pulmonary fibrosis. am j respir crit care med 2007;176:636-643. [http://dx.doi.org/10.1164/rccm.200703-463pp] [pmid: 17585107]. 15. dini l, du plessis m, frean j, et al. high prevalence of dihydropteroate synthase mutations in pneumocystis jirovecii isolated from patients with pneumocystis pneumonia in south africa. j clin microbiol 2010; 48:2016-2021 [http://dx.doi.org/10.1128/jcm.02004-09] [pmid: 20351205]. 15. dini l, du plessis m, frean j, et al. high prevalence of dihydropteroate synthase mutations in pneumocystis jirovecii isolated from patients with pneumocystis pneumonia in south africa. j clin microbiol 2010; 48:2016-2021 [http://dx.doi.org/10.1128/jcm.02004-09] [pmid: 20351205]. 16. helweg-larsen j, benfield tl, eugen-olsen j, lungren jd, lundgren b. effects of mutations in pneumocystis carinii dihydropteroate synthase gene on outcome of aids-associated p. carinii pneumonia. lancet 1999;354:1347-1351. [http://dx.doi.org/10.1016/s0140-6736(99)03320-6] [pmid: 10533864]. 16. helweg-larsen j, benfield tl, eugen-olsen j, lungren jd, lundgren b. effects of mutations in pneumocystis carinii dihydropteroate synthase gene on outcome of aids-associated p. carinii pneumonia. lancet 1999;354:1347-1351. [http://dx.doi.org/10.1016/s0140-6736(99)03320-6] [pmid: 10533864]. 17. navin tr, beard cb, huang l, et al. effect of mutations pneumocystis carinii dihydropteroate synthase gene on outcome of p. carinii pneumonia in patients with hiv-1: a prospective study. lancet 2001;358:545-549. [http://dx.doi.org/10.1016/s0140-67369(01)05705-1] [pmid: 11520525]. 17. navin tr, beard cb, huang l, et al. effect of mutations pneumocystis carinii dihydropteroate synthase gene on outcome of p. carinii pneumonia in patients with hiv-1: a prospective study. lancet 2001;358:545-549. [http://dx.doi.org/10.1016/s0140-67369(01)05705-1] [pmid: 11520525]. 18. whitcomb me, schwarz mi, charles ma, larson ph. interstitial fibrosis after pneumocystis carinii pneumonia. ann intern med 1970;73:761-765. [http://dx.doi.org/10.1136/thx.48.10.996] [pmid: 5312204]. 18. whitcomb me, schwarz mi, charles ma, larson ph. interstitial fibrosis after pneumocystis carinii pneumonia. ann intern med 1970;73:761-765. [http://dx.doi.org/10.1136/thx.48.10.996] [pmid: 5312204]. 19. foley nm, griffiths mh, miller rf. histologically atypical pneumocystis carinii pneumonia. thorax 1993;48:996-1001. [pmid: 8256247]. 19. foley nm, griffiths mh, miller rf. histologically atypical pneumocystis carinii pneumonia. thorax 1993;48:996-1001. [pmid: 8256247]. table 1. patient demographics and laboratory characteristics patient sex age (years) cd4 cells/μl pcp on sputum bdg pg/ml pcp on histo cmv on histo fibrosis sm ♂ 27 11 n/a n/a yes no present nm ♀ 46 19 yes n/a yes yes none ms ♂ 40 31 yes 402 yes no present dm ♀ 33 1 yes >500 yes yes present ns* ♀ 44 29 yes >500 no no present xd* ♀ 24 n.a. n/a >500 yes no present nm ♀ 28 68 n/a >500 yes no none tr ♀ 24 22 n/a >500 yes no present nm ♀ 25 7 n/a >500 no no present am ♀ 46 18 n/a n.a. yes no none tm ♀ 41 n.a. n/a >500 no no present jn ♂ 38 2 n/a 51 yes yes present *not ventilated. n/a=not available. fig. 1. low magnification of alveoli showing normal interstitium of (a) alveolar walls and (b) alveolar spaces (gordon and sweet stain). fig. 2. high magnification showing an enlarged pneumocyte with (a) an intranuclear cmv inclusion (haemotoxylin and eosin stain). fig. 3. low magnification showing (a) frothy exudate filling the alveolar spaces (haemotoxylin and eosin stain). fig. 4. low magnification showing (a) marked expansion of the interstitium by fibrous tissue (gordon and sweet stain). fig. 5. higher magnification showing pneumocystis organisms within frothy intra-alveolar exudates (grocott stain). c p d q u e s t i o n s journal 41 two cpd points are awarded for the correct completion and submission of the questions below. cpd questionnaires must be completed online via www.cpdjournals.org.za. after submission you can check the answers and print your certificate. questions may be answered up to 6 months after publication of each issue. this programme is available free of charge to members of the hiv clinicians society and sama only. regarding the use of antiretroviral therapy to prevent the transmission of hiv in serodiscordant partnerships: 1. true (a) or false (b): observational studies have suggested that the lower the average viral load in a community, the lower the incidence of new hiv infections. 2. true (a) or false (b): the hptn 052 trial provides evidence that initiation of art at a threshold of 350 550 cells/μl reduces sexual transmission of hiv to hiv-negative partners. 3. true (a) or false (b): the hptn 052 trial provides clear evidence that initiation of art at a threshold of 350 550 cells/μl reduces mortality and aids-related complications in hiv-infected individuals. 4. evidence for the benefits of art initiation above 500 cells/μl is mixed, and trials investigating these are ongoing within south africa. regarding hiv prevention in the context of mental disorders: 5. true (a) or false (b): individuals diagnosed with mental illness in south africa have a level of knowledge of hiv prevention that is similar to that of the general population. 6. true (a) or false (b): standard hiv prevention messages and interventions may not be adequate for this group, as they have an increased risk of hiv infection compared with the general population. regarding the use of microscopy to diagnose a febrile hivinfected infant: 7. true (a) or false (b): high candida fungal loads may lead to abnormal results of white cell count quantification in peripheral blood. 8. true (a) or false (b): peripheral blood smears may be useful in interpreting unusually rapid changes in full blood count parameters. regarding primary breast lymphoma in the context of hiv/aids: 9. primary extranodal lymphoma is the most common presentation of nonhodgkin’s lymphoma. 10. non-hodgkin’s lymphoma is the most common aids-associated malignancy. 11. which of the following are common presenting symptoms of nonhodgkin’s lymphoma in hiv/aids: a. pain b. fever c. sweating and weight loss d. all of the above. regarding invasive obstetric procedures in hiv-infected women: 12. most current guidelines recommend that pregnant women with higher cd4 cell counts (e.g. >350 cells/μl) do not require any form of prophylaxis or therapy to prevent mother-to-child transmission of hiv before undergoing an invasive obstetric procedure such as amniocentesis. 13. if a woman is established on effective antiretroviral therapy and has an undetectable viral load, invasive obstetric procedures do not appear to significantly increase the risk of mother-to-child transmission of hiv. 14. in contexts where the invasive obstetric procedure is urgent and an hivinfected woman has not received any form of antiretrovirals, initiation of therapy immediately before or after the procedure may still provide some measure of protection against hiv transmission. regarding hiv prevention and treatment interventions for men who have sex with men (msm): 15. in terms of post-exposure prophylaxis, unprotected anal intercourse is a low-risk activity for hiv transmission, and it is appropriate to use 2-drug pep. 16. there is evidence that pre-exposure prophylaxis using antiretroviral medications (prep) can help to protect msm from sexually transmitted hiv infection, but adherence is an important consideration. 17. anal intra-epithelial neoplasia (ain) is recognised as an aids-related malignancy that is associated with the human papillomavirus. 18. existing evidence suggests that the predominant subtype of hiv circulating in msm in south africa is subtype b (also the most common subtype among msm in europe and north america), while subtype c is more common in heterosexual populations in sa. 19. hiv prevention messages aimed solely at heterosexuals invariably include the risks associated with anal sex. 20. recreational drugs can cause drug-drug reactions and side-effects in hivpositive individuals taking antiretroviral medication. table of contents what is new in the 2020 guidelines update? 1. preamble 2. nucleoside or nucleotide reverse transcriptase inhibitor class of antiretroviral drugs 3. integrase strand transfer inhibitor class of antiretroviral drugs 4. non-nucleoside reverse transcriptase inhibitor class of antiretroviral drugs 5. protease inhibitor class of antiretroviral drugs 6. initiation and timing of antiretroviral therapy 7. baseline investigations 8. viral load 9. cd4+ count 10. resistance and genotyping 11. initial antiretroviral therapy regimens for the previously untreated patient 12. management of patients currently receiving first-line therapy 13. management of patients starting or currently receiving second-line therapy 14. third-line antiretroviral therapy 15. laboratory monitoring of the efficacy and safety of antiretroviral therapy 16. patients who return after stopping antiretroviral therapy 17. drug–drug interactions 18. tuberculosis 19. pregnancy and breastfeeding 20. liver disease 21. renal disease 22. psychiatric disease 23. malaria 24. antiretroviral drug-induced liver injury 25. dyslipidaemia 26. immune reconstitution inflammatory syndrome 27. opportunistic infection prophylaxis 28. adherence 29. acknowledgements 31. references about the author(s) jeremy nel helen joseph hospital, department of medicine, university of the witwatersrand, johannesburg, south africa sipho dlamini department of infectious diseases, faculty of medicine, university of cape town, cape town, south africa graeme meintjes department of medicine, division of infectious diseases and hiv medicine, groote schuur hospital, university of cape town, cape town, south africa rosie burton southern african medical unit, médecins sans frontières (msf), cape town, south africa john m. black department of medicine, division of infectious diseases, livingstone tertiary hospital, port elizabeth, south africa natasha e.c.g. davies anova health institute, johannesburg ,south africa eric hefer private practice medical adviser, johannesburg, south africa gary maartens department of medicine, division of clinical pharmacology, university of cape town, cape town, south africa phetho m. mangena department of internal medicine, school of medicine, pietersburg hospital, polokwane, south africa department of medicine, school of medicine, university of limpopo, turfloop, south africa moeketsi t. mathe private practice, vereeniging, south africa mahomed-yunus moosa department of infectious diseases, division of internal medicine, university of kwazulu-natal, durban, south africa muhangwi b. mulaudzi private practice (phomolong medical centre), rustenburg, south africa michelle moorhouse reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, johannesburg, south africa jennifer nash specialist family physician, amathole district clinical specialist team, east london, south africa thandeka c. nkonyane department of infectious diseases, faculty of medicine, sefako makgatho health sciences university, pretoria, south africa department of medicine, dr george mokhari hospital, pretoria, south africa wolfgang preiser department of medical virology, national health laboratory service, tygerberg, south africa department of pathology, faculty of medicine and health, stellenbosch university, cape town, south africa mohammed s. rassool clinical hiv research unit, wits health consortium, johannesburg, south africa david stead department of medicine, faculty of infectious diseases, frere and cecilia makiwane hospitals, east london, south africa department of medicine, faculty of health sciences, walter sisulu university, mthatha, south africa helen van der plas department of infectious diseases, faculty of medicine, university of cape town, cape town, south africa cloete van vuuren department of internal medicine, military hospital, bloemfontein, south africa department of internal medicine, faculty of health sciences, university of the free state, bloemfontein, south africa willem d.f. venter ezintsha, faculty of health sciences, university of the witwatersrand, johannesburg, south africa joana f. woods ezintsha, faculty of health sciences, university of the witwatersrand, johannesburg, south africa citation nel j, dlamini s, meintjes g, et al. southern african hiv clinicians society guidelines for antiretroviral therapy in adults: 2020 update. s afr j hiv med. 2020;21(1), a1115. https://doi.org/10.4102/sajhivmed.v21i1.1115 note: this article was republished as a second edition. the publisher apologises for any inconvenience caused. guideline southern african hiv clinicians society guidelines for antiretroviral therapy in adults: 2020 update jeremy nel, sipho dlamini, graeme meintjes, rosie burton, john m. black, natasha e.c.g. davies, eric hefer, gary maartens, phetho m. mangena, moeketsi t. mathe, mahomed-yunus moosa, muhangwi b. mulaudzi, michelle moorhouse, jennifer nash, thandeka c. nkonyane, wolfgang preiser, mohammed s. rassool, david stead, helen van der plas, cloete van vuuren, willem d.f. venter, joana f. woods received: 18 june 2020; accepted: 21 june 2020; published: 16 sept. 2020; republished: 30 apr. 2021 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. table of contents what is new in the 2020 guidelines update? preamble nucleoside or nucleotide reverse transcriptase inhibitor class of antiretroviral drugs integrase strand transfer inhibitor class of antiretroviral drugs non-nucleoside reverse transcriptase inhibitor class of antiretroviral drugs protease inhibitor class of antiretroviral drugs initiation and timing of antiretroviral therapy baseline investigations viral load cd4+ count resistance and genotyping initial antiretroviral therapy regimens for the previously untreated patient management of patients currently receiving first-line therapy management of patients starting or currently receiving second-line therapy third-line antiretroviral therapy laboratory monitoring of the efficacy and safety of antiretroviral therapy patients who return after stopping antiretroviral therapy drug–drug interactions tuberculosis pregnancy and breastfeeding liver disease renal disease psychiatric disease malaria antiretroviral drug-induced liver injury dyslipidaemia immune reconstitution inflammatory syndrome opportunistic infection prophylaxis adherence acknowledgments abbreviations references what is new in the 2020 guidelines update? key updates ➢ a recommendation for dolutegravir (dtg)-based therapies as the preferred first-line antiretroviral therapy (art) option (section 11). ➢ updated guidelines for secondand third-line art regimens (section 13). ➢ new recommendations on the management of patients on dtg-based therapies who have an elevated viral load (section 12). ➢ a lowering of the threshold for virological failure from 1000 copies/ml to 50 copies/ml (section 8). ➢ a recommendation against routine cluster of differentiation 4 (cd4+) monitoring in patients who are clinically well once the cd4+ count is > 200 cells/µl (section 9). ➢ updated recommendations for isoniazid preventive therapy (ipt) in human immunodeficiency virus (hiv)-positive patients (section 27). ➢ a recommendation for the use of low-dose prednisone as prophylaxis for paradoxical tuberculosis (tb) immune reconstitution inflammatory syndrome (iris) in tb/hiv co-infected patients commencing art within 1 month of tb therapy (section 26). 1. preamble key principles although many antiretroviral therapy (art) guidelines are available internationally, the current guidelines have been written to address issues relevant to southern africa. a major spur for the current guidelines is the introduction of dolutegravir (dtg) into firstand second-line art regimens. dolutegravir-based art regimens hold much promise, although the transition inevitably challenges existing paradigms and generates additional complexities. these guidelines aim to address many of these and to update the text in general to reflect the latest evidence. as with previous iterations, these guidelines take affordability into account, as countries in the region vary according to their lowand middle-income status. hence, only the treatment and diagnostic options that are available in southern africa are included. in addition, these guidelines recognise the need to bridge the gap in treatment recommendations between public and private sector programmes, considering that many patients transition between the two sectors for treatment. the format of this iteration of the guidelines has been modified to highlight each section’s key points and common pitfalls. it will also be released over time as multiple stand-alone modules, designed with an emphasis on readability, ease of access and user-friendliness. goals of antiretroviral therapy the goals of art are to: provide maximal and durable suppression of viral load (vl) restore and/or preserve immune function reduce human immunodeficiency virus (hiv)-related infectious and non-infectious morbidity prolong life expectancy and improve quality of life prevent onward transmission of hiv minimise adverse effects of the treatment these goals are achieved by suppressing viral replication completely for as long as possible, using well-tolerated and sustainable treatment undertaken with good adherence. with prolonged viral suppression, the cd4+ lymphocyte count usually increases, which is accompanied by a restoration of pathogen-specific immune function. for most patients, this results in a dramatic reduction in the risk of hiv-associated morbidity and mortality. in patients who start to receive art with preserved cd4+ counts, art is able to prevent the decline in cd4+ count observed in untreated patients and prevent clinical complications of hiv infection. it is still unclear whether immune function ever returns to full normality, although long-term cohorts have shown that patients who adhere well to art have a near-normal life expectancy.1 patient adherence to the art regimen remains a key focus and challenge. stopping antiretroviral therapy antiretroviral therapy should not be stopped unless there is an extremely compelling reason to do so. in most cases where drug toxicities develop, switching the culprit drug(s) should be attempted instead. if non-nucleoside reverse transcriptase inhibitor (nnrti)-based therapy is stopped, then we generally do not recommend ‘covering the tail’ with an additional 5–7 days of nucleoside reverse transcriptase inhibitors (nrtis). there is little evidence for this in patients on long-term art, and the intracellular half-life of drugs, such as tenofovir disoproxil fumarate (tdf), in any case approximates that of the nnrtis.2 it is important to ensure that the vl is suppressed before substituting a single drug for toxicity; otherwise, resistance may develop to the new drug, consequently compromising future regimens. however, single-drug substitutions can be done in the first few months of art without measuring the vl, as the vl may take up to 6 months to become suppressed. we strongly advise against lamivudine (3tc) monotherapy ‘holding regimens’ in patients who have virological failure. such regimens can be associated with a rapid fall in cd4+ count. when prescribing art, the objective should always be to provide a regimen that could achieve virological suppression. 2. nucleoside or nucleotide reverse transcriptase inhibitor class of antiretroviral drugs key points ➢ the recommended nucleoside or nucleotide reverse transcriptase inhibitor (nrti) drugs for first-line therapy are tenofovir disoproxil fumarate (tdf) and either 3tc or emtricitabine (ftc). ➢ patients with a creatinine clearance rate (crcl) < 50 ml/min should generally be started on abacavir (abc) instead of tdf for first-line therapy. ➢ zidovudine (azt) should only be used in special circumstances as a first-line drug. ➢ tenofovir disoproxil fumarate can cause renal failure or a renal-tubular wasting syndrome. creatinine monitoring at regular intervals is recommended. ➢ abacavir can cause a fatal hypersensitivity reaction in patients with hla-b*5701. if feasible, this allele should be excluded prior to starting abc, although it is very rare in people of african descent. ➢ zidovudine can cause anaemia and neutropenia, and regular monitoring of haemoglobin (hb) and neutrophil counts is recommended for the first 6 months. available nucleoside or nucleotide reverse transcriptase inhibitors nucleoside reverse transcriptase inhibitors and nucleotide reverse transcriptase inhibitors (ntrtis) work by acting as nucleotide base analogues. following incorporation into the deoxyribonucleic acid (dna) chain by hiv’s reverse transcriptase enzyme, they block further chain elongation. a summary of nrtis is provided in table 1, and the appropriate baseline investigations and required monitoring are presented in table 2. nucleoside reverse transcriptase inhibitors may be available as single tablets or in fixed-dose combination (fdc). the latter is recommended where possible to decrease the overall pill burden. many nrtis require dose adjustment in patients with renal failure (see section 21). table 1: dosage and common adverse drug reactions of nucleoside or nucleotide reverse transcriptase inhibitors available in southern africa (adult dosing). table 2: baseline investigations and monitoring required for nucleoside or nucleotide reverse transcriptase inhibitors. lamivudine and emtricitabine lamivudine and ftc are well-tolerated drugs recommended as part of a first-line regimen. although there are minor differences between them, 3tc and ftc are considered functionally interchangeable. their use may be continued in the presence of ‘high-level resistance’ caused by the m184v mutation because this mutation impairs the replication ability of hiv, causing a ~0.5 log decrease in vl. therefore, the drugs are often used in secondand third-line therapies (see the management of patients on second-line art in section 13). lamivudine and ftc are active against hepatitis b, but when used in the absence of a second drug active against hepatitis b, such as tdf, then resistance rates of approximately 50% at 1 year, and 90% at 5 years, are seen3. see section 20. tenofovir disoproxil fumarate tenofovir disoproxil fumarate is the preferred drug in this class for use with 3tc or ftc in first-line therapy because it aligns with public sector programmes, is widely available as an fdc and is generally well tolerated. tenofovir disoproxil fumarate also offers durable therapy against hepatitis b virus (hbv). hepatitis b virus resistance against tdf is extremely rare. in a minority of patients, tdf may cause a tubular wasting syndrome (including wasting of phosphate and potassium).4 if patients receiving tdf develop muscle weakness or other muscle symptoms, then potassium and phosphate levels must be assessed. tenofovir disoproxil fumarate can also cause acute and chronic renal failure, but this is uncommon.5 tenofovir disoproxil fumarate should be switched to abc or an alternative nrti immediately in patients with acute renal failure, as it may exacerbate injury even if it is not the primary cause. consider recommencing tdf with careful monitoring when creatinine level is normal if an alternative cause of renal failure is established. we recommend estimating the crcl before commencing tdf; the drug should not be used if the estimated glomerular filtration rate (egfr) or crcl is < 50 ml/min. for monitoring whilst on tdf, see table 2. where tdf is avoided because crcl is < 50 ml/min at baseline, it may be possible to switch to tdf at a later point if renal function improves. this is often the case where patients had diarrhoea or other opportunistic infections (ois) at the time of art initiation. common pitfall: permanently discontinuing tdf in patients with transiently decreased crcl. most cases of acute kidney injury (aki) are not because of tdf, and if another cause of aki is identified (e.g. severe diarrhoea or pneumonia), then tdf can be re-introduced with monitoring once renal function improves. the long-term use of tdf together with other nephrotoxic agents (e.g. aminoglycosides or non-steroidal anti-inflammatory agents) should be avoided. tenofovir disoproxil fumarate also causes a decrease in bone mineral density; however, this is generally mild and non-progressive, and most studies have not found an increase in fracture risk. abacavir abacavir can be used in patients with a crcl < 50 ml/min at baseline, rather than tdf. abacavir does not require dose adjustment in patients with renal failure and is especially useful in patients with chronic renal failure, where tdf is nephrotoxic and azt could aggravate anaemia in patients with renal failure. a meta-analysis showed that virological suppression is equivalent with abcand tdf-containing first-line regimens regardless of baseline vl.6 common pitfall: avoiding abc at high hiv vls. this is unnecessary as viral suppression rates are equivalent in meta-analyses. abacavir has been associated with an increased risk of myocardial infarction in some but not all cohort studies; however, the association was not confirmed in a meta-analysis of randomised controlled trials (rcts).6,7,8 nevertheless, caution is recommended when considering abc for patients who are at significant risk of or have established ischaemic heart disease. abacavir hypersensitivity is a systemic reaction occurring within the first 8 weeks of therapy in approximately 3% of cases. fatalities may occur on rechallenge. abacavir must be discontinued and never re-introduced if hypersensitivity is suspected. the manifestations of hypersensitivity include fever, rash, fatigue and abdominal or respiratory symptoms. if there is any doubt concerning the diagnosis (e.g. if the patient has a cough with fever), then the patient should be admitted for observation of the next dose; symptoms progress if hypersensitivity is present. the hypersensitivity reaction has been shown to occur on a genetic basis, with a very strong association with the hla-b*5701 allele. this allele is very uncommon in people of african descent; thus, abc hypersensitivity is less frequent. if testing is affordable and available, then the presence of hla-b*5701 should be excluded prior to prescribing abc, especially in patients who are not of african descent. zidovudine we now recommend reserving azt for use only in special circumstances in first-line therapy. if both tdf and abc are unavailable or contraindicated, then azt should be used, provided that the hb is > 8 g/dl. additional syndromes related to nucleoside reverse transcriptase inhibitors haematological toxicity cytopenias occur commonly in patients with hiv infection without exposure to art. patients receiving azt or cotrimoxazole (ctx) may experience full blood count (fbc) abnormalities. zidovudine can cause anaemia and neutropenia; platelet counts generally rise with the use of the drug. monitoring is necessary with azt (see table 2). it is unusual, however, to see haematological toxicity develop after 6 months. macrocytosis is usual with azt therapy and is of little consequence. routine measurement of vitamin b12 and folate concentrations is not needed. common pitfall: discontinuing azt because of macrocytosis. this is of little consequence and does not necessarily portend subsequent anaemia. pure red cell aplasia, which presents with severe anaemia and a low reticulocyte production index, has rarely been associated with 3tc and ftc.9,10 a bone marrow examination should be performed to confirm the condition. a polymerase chain reaction (pcr) test should be conducted to exclude the presence of parvovirus b19 infection. if 3tc and ftc are contraindicated because of pure red cell aplasia, then we suggest contacting an expert for advice about alternative regimens. hyperlactataemia and lactic acidosis lactic acidosis is a rare but serious and potentially fatal side effect of nrtis, most commonly associated with stavudine (d4t), particularly when combined with didanosine (ddi). these drugs are no longer used. it can also occur occasionally with azt. symptomatic hyperlactatemia without acidosis is more common and is associated with the same drugs. neither lactic acidosis nor hyperlactatemia without acidosis is seen with the newer, safer nrtis such as tdf, abc, 3tc or ftc. symptoms are non-specific and include nausea and vomiting, abdominal pain, dyspnoea, fatigue and weight loss. a raised lactate (> 5 mmol/l) together with metabolic acidosis confirms the diagnosis of lactic acidosis. low serum bicarbonate (< 20 mmol/l) is the most sensitive marker of acidosis. patients receiving azt who develop hyperlactatemia should be switched to alternative drugs, and lactate should be monitored serially until resolution. in severe patients, admission may be required. lipoatrophy the thymidine analogue nrtis (azt and especially d4t) are associated with subcutaneous fat loss (most noticeable in the face, limbs and buttocks). lipoatrophy improves when d4t/azt are substituted with tdf or abc, but resolution is very slow and often incomplete; therefore, it is important to recognise lipoatrophy early or, better still, to use nrtis that are not associated with the condition. although d4t is no longer used, patients who received it historically may still have lipoatrophy. 3. integrase strand transfer inhibitor class of antiretroviral drugs key points ➢two integrase strand transfer inhibitors (instis) are available in southern africa, namely, dtg and raltegravir (ral). ➢ dolutegravir is preferred to ral because it has a higher barrier to resistance, is available in fdc formulation and can be taken once daily. ➢ dolutegravir has been shown to have greater efficacy than efavirenz (efv), driven largely by superior tolerability. ➢ dolutegravir causes a small increase in serum creatinine (usually 10 μmol/l – 20 μmol/l) because of interference with tubular creatinine secretion; however, this does not represent a decline in renal function. ➢ although definitive data are still lacking, dtg may be teratogenic in a small proportion of patients; thus, treatment decisions in women of reproductive age should be discussed and evaluated carefully (see section 19). ➢ weight gain is a newly recognised side effect of instis, more so with dtg than with ral, and more so in black women and in patients with lower baseline cd4+ counts and higher vls. overview of integrase strand transfer inhibitors integrase strand transfer inhibitors – often simply termed ‘integrase inhibitors’ – work by preventing the transfer of proviral dna strands into the host chromosomal dna. currently, two instis are available in southern africa: dtg and ral. dolutegravir is preferred to ral because of its higher barrier to resistance, its availability in fdc formulation and the ability to take the drug once daily. the spring-2 trial compared dtgand ral-containing first-line regimens and found no significant differences in virological suppression, and adverse effects were similar between treatment groups11; however, although no patients in the dtg arm were found to have developed resistance, one patient in the ral arm developed insti resistance and four developed nrti resistance. the high barrier to resistance of dtg-containing art regimens has been replicated in other first-line studies and in a study of art-experienced patients in which dtg was compared with ral.12,13,14 in a meta-analysis that included clinical trials and observational studies, the emergence of insti resistance was more common with ral than with dtg (3.9% vs. 0.1%).15 however, the emergence of insti resistance in patients receiving ral can compromise second-generation instis, such as dtg. dolutegravir use has been shown to be superior to efv-based art in the single trial.12 this difference was largely driven by the superior tolerability of the dtg arm: 2% in the dtg arm compared with 10% in the efv arm had an adverse event leading to discontinuation of the study drug. dolutegravir showed superior rates of viral suppression compared with efv (71% vs. 63% at 144 weeks). dolutegravir-based regimens have also been shown to be superior to protease inhibitor (pi)-based regimens. as a first-line therapy, dtg was superior to darunavir/ritonavir (drv/r) in terms of both viral suppression rates and side effect profile.13 the aria trial of art-naive women demonstrated dtg’s non-inferiority to atazanavir (atv)/ritonavir (atv/r), although with a statistically significantly higher rate of viral suppression and fewer side effects overall.16 in the dawning trial considering second-line regimens, dtg was found to be superior to lopinavir/ritonavir (lpv/r).17 importantly, at least one fully active nrti was genotypically confirmed at baseline in this trial. data from the tsepamo surveillance study in botswana demonstrated a statistically higher rate of neural-tube defects (ntds) amongst women who were taking dtg at the time of conception (0.3% vs. 0.1% in women receiving other arts in the periconception period).18 unlike in south africa, folate fortification of staple foods does not occur in botswana. in contrast to the botswana data, no ntds were reported in a brazilian cohort of 1468 women, 382 of whom were dtg-exposed.19 although additional data will undoubtedly be forthcoming, it should be noted that the absolute risk is < 0.5%, which may be outweighed by the additional benefits of dtg over alternative therapies. we recommend that women of childbearing potential (wocp), particularly those who wish to become pregnant or who have no reliable access to effective contraception, should be counselled adequately about the potential risks and benefits of dtgversus efv-based art and should be offered a choice of first-line regimens. common side effects dolutegravir and ral are generally well tolerated, with most side effects being mild and very rarely leading to discontinuation. dolutegravir may cause a mild increase in serum creatinine because of interference with tubular secretion. this does not represent renal damage and is not an indication of switching to another drug. the rise in creatinine occurs within the first few weeks and persists for as long as the patient remains on dtg. common pitfall: assuming that the rise in creatinine seen in patients on dtg necessarily represents renal failure. in reality, the effect of dtg on creatinine secretion is of no consequence and does not represent a decline in renal function. raltegravir and dtg can cause headaches when started, but this usually resolves. these drugs may also cause insomnia and neuropsychiatric side effects. raltegravir and dtg can occasionally cause hypersensitivity rashes, including life-threatening rashes. weight gain is more pronounced in patients taking an insti as part of their art regimen (with the exception of cabotegravir, which is not currently available in south africa). black women, patients with low baseline cd4+ counts and patients with high baseline vls appear to be at greatest risk.20 the risk also appears to be moderated by the companion drugs in the patient’s art regimen. in the advance trial, women on a tenofovir alafenamide (taf) + ftc + dtg regimen were found to gain a median of 10 kg over 96 weeks, with little evidence of a plateau in the increase.21 in women, median weight gain in the same period in the tdf + ftc + dtg arm was 5 kg, and 3 kg in the tdf + ftc + efv arm. in men, weight gain was approximately half as much in each arm. the long-term health implications of these findings are currently unclear; however, clinicians should be aware of the possibility of weight gain and encourage appropriate exercise and dietary measures to limit this. dosage and common adverse drug reactions (adrs) of instis are described in table 3. table 3: dosage and common adverse drug reactions of integrase strand transfer inhibitors available in southern africa. key drug–drug interactions with dolutegravir key drug–drug interactions involving dtg are summarised in table 4. common pitfall: forgetting to dose dtg twice daily when rif-based tuberculosis treatment is commenced. table 4: key drug–drug interactions with dolutegravir. 4. non-nucleoside reverse transcriptase inhibitor class of antiretroviral drugs key points ➢ efavirenz remains a good first-line art option for patients who tolerate dtg poorly, or where dtg is contraindicated or declined. ➢ efavirenz 400 mg is not inferior to efv 600 mg and offers a somewhat improved side-effect profile. however, it is currently not available in fdc and has not been well studied in patients receiving rifampicin (rif)-based tb treatment or in pregnant women. ➢ rilpivirine (rpv) is another good first-line option, but it is not available in fdc, cannot be co-administered with rif-based tb treatment and should not be started in patients with a vl > 100 000 copies/ml. ➢ nevirapine (nvp) is no longer recommended for new patients because of its adverse side effect profile. ➢ etravirine (etr) may be used as part of third-line therapy where appropriate, but is not recommended as a first-line agent. overview of non-nucleoside reverse transcriptase inhibitors non-nucleoside reverse transcriptase inhibitors work by binding irreversibly to hiv’s reverse transcriptase enzyme, which causes a conformational change in the enzyme’s active site and impairs its functioning. the four nnrtis currently available in southern africa are efv, nvp, rpv and etr. individual non-nucleoside reverse transcriptase inhibitors efavirenz efavirenz is available in 600 mg and 400 mg formulations: efavirenz 600 mg is available in public sector programmes in most countries in southern africa. there is extensive clinical experience with the formulation, and it is available in fdc. efavirenz 400 mg showed non-inferior efficacy with moderately improved tolerability in the encore1 study.22 however, there are only limited pharmacokinetics data in pregnant patients, and in patients receiving rif-based tb treatment. efavirenz 400 mg is currently also not available in fdc. for these reasons, we do not recommend the routine use of efv 400 mg in first-line art. it remains an appropriate choice, however, in selected patients. efavirenz frequently causes neuropsychiatric effects in the first few weeks of therapy, typically presenting with insomnia, vivid dreams and dizziness. both dysphoria and euphoria may occur. patients starting on efv should be warned about these symptoms and should be reassured that the symptoms usually resolve within the first few weeks, and if not, then an alternative can be substituted. psychosis may occasionally occur. if the neuropsychiatric effects of efv are not tolerated, then the patient should be switched to rpv, dtg or lower-dose efv. recently, a late-onset encephalopathy syndrome has been linked to efv.23 this is characterised by a subacute encephalopathy and cerebellar dysfunction, frequently presenting months to years after commencing efv, and is associated with supratherapeutic efv levels. patients who are genetically slow metabolisers of efv may be predisposed to this syndrome. two common cyp2b6 polymorphisms linked to slow efv metabolism have been shown to occur with increased frequency in patients of african descent.24 this predisposition to toxic efv levels may be further exacerbated in patients of low body weight and in those taking concomitant isoniazid, which inhibits an accessory efv metabolism pathway via cyp2a6. patients with a compatible clinical syndrome, in the absence of an alternative cause, should have plasma efv levels measured and should be switched to a non-efv-based regimen. clinical improvement is typically seen within 10–21 days after stopping efv. efavirenz may also cause a drug-induced hepatitis. a subset of these cases appears to occur relatively late, several months or even years after the drug has been initiated.25 it is important that this diagnosis is considered in the differential diagnosis of a subacute hepatitis syndrome. gynaecomastia can occur with the use of efv.26 this is not related to lipodystrophy. the onset occurs several months after initiation of art and it may be bilateral or unilateral. the mechanism appears to be related to oestrogen receptor activation in breast tissue by efv.27 it is important to exclude other common causes of gynaecomastia, such as other medications (including spironolactone, calcium channel blockers and metoclopramide). a serum testosterone test is useful in excluding hypogonadism as a possible cause. if serum testosterone is low, then other appropriate investigations should be carried out to identify the cause and manage accordingly; if serum testosterone is normal, then efv should be substituted, bearing in mind the general principles of single-drug substitutions (patients who are virologically suppressed should be switched to dtg or rpv). resolution of gynaecomastia is generally slow, taking months, and may be incomplete in a small percentage of patients.28 it is therefore important to manage the expectations of the patient in this regard. rilpivirine another option in first-line art is rpv, a second-generation nnrti: rilpivirine is inexpensive, but not currently available in fdc in the region. an important drawback is that it should not be started in a patient with a vl > 100 000 copies/ml, as it is inferior to efv in such patients.29 rilpivirine has a lower incidence of neuropsychiatric side effects and rashes than efv.30 there are several important drug–drug interactions with rpv. amongst other considerations, rpv cannot be co-administered with rif or proton pump inhibitors (ppis). histamine-2-receptor antagonists need to be administered 12 h before or 4 h after taking rpv. rilpivirine should be taken with food to increase absorption. common pitfall: prescribing rpv without first checking baseline vl. rilpivirine is less efficacious than comparator drugs when vl is > 100 000 copies/ml. nevirapine we no longer recommend nvp use for new patients starting art because of the severe toxicity that may be associated with its use: in patients currently tolerating nvp, there is no reason to switch treatment because of toxicity concerns, as toxicity characteristically occurs in the first 3 months of nvp treatment and not later. however, switching for the purpose of simplification to a once-daily regimen should be considered, provided that there is virological suppression. etravirine etravirine is a second-generation nnrti that has been studied in treatment-experienced patients rather than in art-naive patients: as seen with rpv, the activity of etr is not affected by the first-generation nnrti’s signature k103n resistance mutation. hypersensitivity with non-nucleoside reverse transcriptase inhibitors rash is common with nnrtis in the first 6 weeks of therapy, notably more severely and frequently with nvp. if the rash is accompanied by systemic features (e.g. fever, elevated alanine transaminase [alt] or hepatitis), mucosal involvement or blistering, then the nnrti should be discontinued immediately and re-challenge must not be performed as these are features of life-threatening reactions. if the rash is mild and occurs without these features, then the nnrti can be continued and the rash can be treated symptomatically with antihistamines and possibly topical steroids. systemic steroids should not be used. if there is a severe reaction to efv or nvp, then we do not recommend switching to rpv or etr – rather use dtg or a pi. dosage and common adrs of nnrtis available in southern africa are described in table 5. common pitfall: immediately discontinuing nnrtis in the case of a mild rash without systemic features. such rashes often resolve if treatment is continued, although close monitoring is required. table 5: dosage and common adverse drug reactions of non-nucleoside reverse transcriptase inhibitors available in southern africa. 5. protease inhibitor class of antiretroviral drugs key points ➢ three pi combinations are recommended in southern africa: lopinavir (lpv), atv or darunavir (drv), each given with low-dose ritonavir (rtv, indicated as /r) for pharmacokinetic boosting. ➢ ritonavir-boosted lopinavir is the only pi combination that can be used with rif-based tb treatment, but the dose of lpv/r must be doubled. ➢ atazanavir and drv offer a better side effect profile than lpv. ➢ darunavir has the highest barrier to resistance of any drug in this class. overview of protease inhibitors protease inhibitors are a class of agents that inhibit hiv’s protease enzyme, which is required to cleave hiv’s polyproteins into the final protein products that permit the production of infectious viral particles. inhibition of this process results in immature, non-infectious virions. three pi combinations are recommended for use in southern africa: lpv, atv and drv, each given with low-dose ritonavir. ritonavir is a pi in its own right, but is used principally as a pharmacokinetic ‘booster’. as a potent inhibitor of cyp3a4, its use results in higher drug levels and prolonged half-lives of its companion pi. this allows for lower or less frequent pi dosing and decreases the chances of developing viral resistance. in rare situations, atv is used without boosting in first-line therapy. however, this inhibition of cyp3a4, together with several other cytochrome p450 (cyp) enzymes and p-glycoprotein, results in numerous drug–drug interactions with other medications (see section 17). common pitfall: not using a drug interaction checker when prescribing pi-based art with other medications. clinically relevant drug–drug interactions are common with this class. all pis may be associated with cardiac conduction abnormalities (especially pr interval prolongation). this seldom results in clinically significant effects, but caution should be taken when co-prescribing other drugs that cause delayed cardiac conduction, such as macrolides or bedaquiline. all pis are, to some extent, associated with metabolic side effects. elevated triglycerides (tgs) and elevated low-density lipoprotein cholesterol (ldl-c) are class effects, although these side effects are more pronounced with lpv/r than with other pi combinations.31,32 dosing and common adrs of pis are presented in table 6. table 6: dosage and common adverse drug reactions of protease inhibitor drugs available in southern africa. individual protease inhibitors lopinavir lopinavir is co-formulated with ritonavir (e.g. aluvia): in general, this twice-daily regimen has greater gastrointestinal (gi) side effects than other pi combinations, and is associated with a worse metabolic profile. lopinavir is the only pi that can be used concurrently with rif-based tb treatment; the lpv/r dose has to be doubled in this instance to 800 mg/200 mg twice daily until 2 weeks after rif has been stopped (see section 18). common pitfall: forgetting to double the dose of lpv/r when starting rif-based tb treatment. atazanavir atazanavir is generally better tolerated than lpv and can be taken once daily: it has important drug interactions with drugs that reduce stomach acidity, such as ppis. atazanavir may cause an unconjugated hyperbilirubinaemia as a result of inhibition of the hepatic enzyme uridine 5'-diphospho-glucuronosyltransferase. although the hyperbilirubinaemia is harmless and does not reflect a drug-induced liver injury (dili), a minority of patients will become visibly jaundiced, and this may require changing art regimens for cosmetic reasons. common pitfall: mistaking the unconjugated hyperbilirubinaemia sometimes seen with atv use with a dili. conversely, it is equally important to note that arvs can also cause a true dili, and therefore a complete liver function test (lft) panel should be performed to distinguish between the two possibilities. darunavir darunavir has the highest barrier to resistance of any pi: mutations selected by atv or lpv can compromise drv efficiency. for patients with mutations that confer any degree of resistance to drv (e.g. i50v, l76v and i84v), the dose should be drv/r 600 mg/100 mg twice daily. for patients without any drv mutations, the drug can be taken at a dose of drv/r 800 mg/100 mg once daily. there is evidence, however, that drv/r 400 mg/100 mg once daily may be sufficient in this scenario, especially for patients with suppressed vls at the time of the switch.33,34 compared with a twice-daily dosing, a once-daily dosing offers the benefits of reduced pill burden and better side effect profile. as with atv, drv cannot be co-prescribed with rif-based tb treatment. common pitfall: prescribing atv or drv in patients receiving rif-based tb treatment. lopinavir/ritonavir is the only pi combination that can be co-prescribed safely with rif, but the dose of lpv/r must be adjusted as above. 6. initiation and timing of antiretroviral therapy key points ➢ all individuals diagnosed with hiv should be initiated on art. ➢ delays to start art should be minimised. several studies have demonstrated that it is safe to initiate. ➢ art on the same day as diagnosis or on receipt of cd4+ count result, with the main benefit being improved retention in care. ➢ screening for tb, cryptococcal meningitis (cm) and other ois prior to art initiation is important, as these conditions may necessitate delaying art initiation. overview all patients who are diagnosed with hiv should be initiated on art as soon as possible. exceptions include patients presenting with cm or tuberculosis meningitis (tbm) – see below. benefits of antiretroviral therapy in reducing morbidity and mortality with art-induced viral suppression, the cd4+ lymphocyte count usually increases, which is accompanied by a restoration of pathogen-specific immune function. for most patients, this results in a dramatic reduction in the risk of hiv-associated morbidity and mortality. for patients who start art with preserved cd4+ counts, art is able to prevent the decline in cd4+ count observed in untreated patients and thereby prevent clinical complications of hiv infection. the benefits in morbidity and mortality extend to patients with relatively preserved cd4+ counts. the start and temprano anrs 12136 trials showed significant individual clinical benefits when starting art immediately in patients with cd4+ counts > 500 cells/µl rather than deferring until a certain lower cd4+ threshold or clinical indication was met.35,36 benefits of antiretroviral therapy in reducing transmission the hptn 052 trial showed that treating the hiv-positive partner in a serodiscordant relationship with art was associated with a 93% reduction in transmission risk to the uninfected partner, with the only linked transmissions occurring from partners without a suppressed vl.37 further evidences in serodiscordant couples from the partner, partner2 and opposites attract trials have confirmed that hiv is essentially not transmittable when the vl is suppressed.38,39,40 community-level evidence has also demonstrated a reduction in hiv incidence as art rollout is scaled up. therefore, early art initiation has significant public health benefits. antiretroviral therapy in primary human immunodeficiency virus infection in patients who are diagnosed with hiv during acute seroconversion, we advise counselling and initiating art as soon as possible. expedited art initiation is preferable as there is evidence that this may limit the size of the hiv reservoir.41 once the patient is established on art, additional counselling may be required for patients who start art in this acute stage because there is limited time for extensive pre-art counselling, and there is often considerable psychological distress around this time. antiretroviral therapy initiation in ‘elite controllers’ a minority of patients (< 1%) have very effective immune control of hiv infection and can control hiv viraemia at undetectable levels even in the absence of art; these patients are termed ‘elite controllers’. although definitive data are lacking for this patient subgroup, we advise initiating art in elite controllers too, as indirect evidence suggests a potential benefit. elite controllers still have evidence of chronic immune activation and inflammation that may drive non-infectious morbidities.42 elite controllers have also been shown to have a higher rate of hospitalisation than patients who are virologically controlled by art.43 furthermore, a prospective study of hiv-positive ‘controllers’, who were able to control viral replication to < 500 copies/ml, showed that hiv therapy led to improvements in markers of immune activation and immune exhaustion, and a slightly improved self-reported quality of life.44 this trial included elite controllers. one important consideration in such patients is that careful attention should be given to confirm the diagnosis of hiv before starting art. these patients typically have a positive hiv enzyme-linked immunosorbent assay (elisa) test, undetectable hiv vl, cd4+ count in the normal range and are clinically well. the possibility of a false-positive hiv elisa test should be excluded either by qualitative hiv dna pcr or western blot assay. if the patient previously had a detectable hiv vl, then this would also serve as confirmation. such patients may need to be discussed with a laboratory virologist to assist with confirmation of hiv status. common pitfall: not confirming the hiv status of an ‘elite controller’. if such patients have been diagnosed with hiv based on an hiv elisa or rapid detection test, then confirmation of their hiv status should be sought by additional testing methods to exclude the possibility of a false-positive result. commencing antiretroviral therapy at the first clinic visit several studies have demonstrated that it is possible to initiate art safely on the same day as hiv diagnosis or reporting of the cd4+ count result.45,46,47 these studies have demonstrated less overall loss to follow-up when art is initiated immediately in selected patients. now that treatment is recommended irrespective of cd4+ count, this same-day strategy should be considered as a means to improve retention in care. when deciding to initiate art on the same day as diagnosis, considerations should include the following: the patient should be motivated to start immediately. same-day initiation is not an adherence support ‘short cut’; ongoing support can occur in the days and weeks immediately after initiation. patients starting tdf (who are the majority) should be contactable in the event of a crcl < 50 ml/min and advised to return to the clinic immediately. a serum/plasma cryptococcal antigen (crag) test should be performed in patients with a cd4+ count < 200 cells/µl; again, the patient should be contactable in the event of a positive result and must be advised to return to the clinic immediately. symptom screen for tb and cm before initiation of treatment remains important, and a positive screening requires further investigation prior to art initiation. medical reasons to delay antiretroviral therapy initiation medical reasons to delay art initiation are outlined in table 7. table 7: medical reasons to delay antiretroviral therapy initiation. tuberculosis: decisions regarding the timing of art in patients with tb should generally be based on the cd4+ count. cd4+ count ≤ 50 cells/μl: antiretroviral therapy should be regarded as urgent, with the aim to start therapy within 2 weeks following the commencement of tb treatment. a meta-analysis of rcts has demonstrated that this approach reduces mortality.48 it is advised to commence art after it is clear that the patient’s tb symptoms are improving and that tb therapy is tolerated. the exception to this is the case of cm or tbm (see below). cd4+ count > 50 cells/µl: antiretroviral therapy can be delayed until 8 weeks after starting tb treatment, but no later. however, if the patient has other world health organization (who) stage 4 conditions, then art should be initiated 2 weeks after tb treatment is started. the exception to this is cm or tbm. the longer delay before commencing art in this group is anticipated to reduce the risk of iris (see section 26). the aforementioned meta-analysis of rcts did not show a higher risk of acquired immune deficiency syndrome (aids) progression/mortality in this group when art initiation was delayed until approximately 8 weeks after starting tb treatment, but a reduced risk of tb-iris.48 tuberculosis meningitis: patients with tbm are an exception to the above: starting art immediately or at 2 months following the diagnosis was shown to have similar high mortality, with more complications in the immediate group.49 we recommend starting art 4–8 weeks after tbm diagnosis. there are important drug interactions and shared side effects when art is co-administered with tb therapy (see section 18). when art is commenced, patients should be warned that tb symptoms or signs may temporarily worsen and new features may occur in the first 3 months as a result of tb-iris (see section 26). cryptococcal disease: for patients with cm, the optimal time to start art is 4–6 weeks from the time of starting cm treatment. the cryptococcal optimal art timing (coat) trial demonstrated significantly higher mortality in patients who started art in hospital 1–2 weeks after cm diagnosis than in those starting 5–6 weeks after diagnosis.50 for patients diagnosed with cryptococcal antigenaemia who have cm excluded by lumbar puncture (lp), art can be commenced immediately. patients commenced on art prior to a positive reflex crag result should be referred immediately for lp to exclude cm. in patients with a negative cerebrospinal fluid (csf) crag result (i.e. cm is excluded), art can be continued and fluconazole pre-emptive therapy should be initiated. it is unclear, however, whether to interrupt art in patients with a positive csf crag result. for further details, refer to the 2019 southern african hiv clinicians society guidelines for the prevention, diagnosis and management of cryptococcal disease amongst hiv-infected persons. starting antiretroviral therapy in patients with other opportunistic infections and acute illnesses: in the case of most ois and acute illnesses (e.g. pneumocystis or bacterial pneumonia), the aim should be to initiate art within 2 weeks of commencing treatment for that infection.51 in patients with severe kaposi’s sarcoma and lymphoma, art counselling should be expedited and art should be initiated as soon as possible. in hiv-infected patients admitted to hospital and unable to take oral medications, for example, patients in intensive care unit (icu): if the patient is receiving art, then this should be continued – through nasogastric tube (ngt) if necessary – and only interrupted if the gi tract is not functional (e.g. ileus). if the patient is not yet received art, then it should not be commenced if the reason for admission is an acute critical illness or injury. there are several potential problems associated with commencing art in this setting: lack of adequate counselling, gi dysfunction, malabsorption and possible development of resistance. there are no intravenous options for art. in patients admitted to the icu for prolonged periods, art initiation in the unit should be considered after multi-organ failure has resolved. certain art preparations should not be administered via ngt. in general, paediatric syrups can be administered via ngt. a pharmacist should always be consulted regarding which art drugs can be administered via ngt and how to do this. 7. baseline investigations confirming the diagnosis of human immunodeficiency virus prior to the initiation of lifelong art, it is recommended that hiv infection is confirmed with two different testing methods, at least one of which should be a laboratory-based test. acceptable combinations include the following: rapid detection test + elisa rapid detection test + vl elisa + vl. note that a vl may be undetectable in < 1% of patients not receiving art, that is, ‘elite controllers’. baseline investigations baseline investigations for art are summarised in table 8. table 8: summary of baseline investigations for antiretroviral therapy. symptom screen we also advise a symptom screen for: tuberculosis: patients should be asked about cough, weight loss, fever, night sweats and a possible tb contact. if any of these symptoms are present, then sputum should be sent for xpert analysis, and if hospitalised or the cd4+ count is < 200 cells/µl, a urine lipoarabinomannan (lam) assay should be performed. cryptococcal meningitis: patients should be asked about new onset of headache; serum cryptococcal antigen (scrag) testing and possibly an lp should be performed if this symptom is present. if the patient’s symptom screen is positive, then art should be deferred until the results of the xpert, lam, scrag test or lp (as indicated) are known. delays in this process should, however, be kept to a minimum. 8. viral load viral load monitoring is key to the success of art. decisions to change art made on the basis of virological failure, rather than on clinical or immunological failure alone, have been shown to result in better patient outcomes.52 if the vl is undetectable, then the virus cannot mutate and develop resistance. a sustained vl < 50 copies/ml is associated with the most durable benefit. a suppressed vl also prevents the transmission of hiv to contacts. timing of viral load monitoring in the patient starting antiretroviral therapy (figure 1) we recommend a baseline vl for the following reasons: the 3-month vl can then be compared with the baseline vl to detect > 2 log10 drop, and if this has not occurred, then it allows for early adherence intervention. it may guide nnrti selection (rpv should not be used if vl > 100 000 copies/ml). it confirms the diagnosis of hiv (antibody tests may very rarely give a false-positive result). figure 1: timing of viral load monitoring of the patient starting antiretroviral therapy. for patients with a viral load > 50 copies/ml on two consecutive occasions, refer to the text. a 3-month vl is desirable to detect adherence problems early before resistance develops. a subset of patients who start art with a very high vl may not be fully suppressed at 3 months despite 100% adherence, but such patients would have had a > 2 log10 drop in vl from baseline if adherence is optimal and there is no resistance. therefore, the 3-month result should be interpreted in relation to the baseline vl. all patients who have a detectable vl at 3 months should receive additional adherence interventions. in general, a patient’s vl declines fastest on insti-based regimens. if the 3-month vl is undetectable, then vl monitoring is recommended at 6 months and every 6 months thereafter. in patients who have an undetectable vl for more than 12 months, and who demonstrate reliable adherence and follow-up, it may be acceptable to reduce the frequency of vl monitoring to 12 monthly. if the vl is > 50 copies/ml at any stage, then this should be an indication for urgent action: the patient should receive counselling and interventions should be implemented to improve adherence. a repeat measurement of vl should then be done in 2–3 months. interpreting viral load results virological criteria for treatment success treatment success is defined as a decline in vl to < 50 copies/ml within 6 months of commencing art, and sustained thereafter. virological criteria for treatment failure treatment failure is defined as a confirmed vl > 50 copies/ml on two consecutive measurements taken 2–3 months apart: the decision to alter art should therefore be based on the results of repeat testing after 2–3 months, following intensive adherence counselling. although previous guidelines used a threshold of 1000 copies/ml to define virological failure, there is now good evidence that a vl > 50 copies/ml is robustly associated with subsequent virological failure, although this has not been established.53,54 sustained viral replication, even at these low levels, can lead to the accumulation of resistance mutations (although this has not yet been definitively established in the case of dtg). viral blips isolated detectable hiv vls < 1000 copies/ml, followed by an undetectable vl, are termed ‘viral blips’ and alone are not a reason to change the art regimen. viral blips can be caused by immune activation (such as from an acute infection), variability in the laboratory testing thresholds or intermittent poor adherence. provided that they are infrequent, and the vl returns to being undetectable at the next measurement, they are not regarded as consequential. reasons for a high viral load a high vl can be attributed to one or more of these three factors: inadequate patient adherence (most commonly) resistance to the prescribed art – including both acquired and transmitted drug resistance inadequate art drug levels as a result of altered pharmacokinetics, such as absorption difficulties, or drug–drug interactions. these explanations are not mutually exclusive. for instance, inadequate patient adherence frequently leads to the development of resistance in patients on a non-dtg-containing regimen. transmitted drug resistance is currently increasing in the region.55 such drug resistance is most frequently associated with the nnrti class, as the signature k103n mutation has little effect on viral fitness and can therefore persist in the population even in the absence of drug pressure. transmitted drug resistance to other drug classes is unusual; therefore, first-line therapy with a dtg-based regimen is unlikely to be affected by this phenomenon. interpreting a high viral load result of a patient receiving dolutegravir dolutegravir has been proved to be a remarkably robust drug in insti-naive patients when paired with at least one active nrti. to date, less than five cases of dtg resistance have been described in this scenario. thus, although a high vl has traditionally been a marker of possible resistance, this paradigm no longer applies for the most part in patients receiving a dtg-based regimen, provided that: the patient has not had previous exposure to instis as part of a failing regimen. the patient is known to have at least one fully active nrti as part of their regimen. (note that patients who contract hiv whilst on pre-exposure prophylaxis [prep] are at risk of not having a fully active nrti backbone). the patient was not recently exposed to a scenario where a drug–drug interaction would have substantially decreased dtg concentrations (e.g. rif-based tb therapy without increasing dtg dosing frequency to 12 hourly). provided that none of the above conditions are met, a detectable vl should not be assumed to reflect possible resistance. rather, it can be assumed that the detectable vl, if not fulfilling criteria for a viral blip, merely represents poor adherence, and efforts to address this should be undertaken. we do not recommend performing resistance testing for patients on a dtg-based regimen within 2 years of commencing the drug, provided that the above conditions are met. 9. cd4+ count key points ➢ all hiv-positive patients should be started on art irrespective of their cd4+ counts. ➢ cd4+ counts should be used only to establish whether ctx prophylaxis and scrag testing are required (cd4+ < 200 cells/µl). ➢ monitoring art efficacy is best established using vl, not cd4+ count. ➢ most patients newly initiating art with an abnormally low cd4+ count will see a rapid initial cd4+ count increase (75 cells/µl – 100 cells/µl), followed by a more gradual rise thereafter (50 cells/µl – 100 cells/µl per year) until a normal cd4+ count > 500 cells/µl is achieved. ➢ if cd4+ count does not rise despite viral suppression, the art regimen does not need to be altered. this phenomenon may reflect an ‘immunological discordant response to art’; however, if the patient is unwell, then other secondary causes should be sought. role of cd4+ count monitoring a cd4+ count < 200 cells/µl indicates the need for ctx prophylaxis, principally to prevent pneumocystis jirovecii pneumonia, although ctx is also active against other opportunistic pathogens, including toxoplasma gondii, cystoisospora belli and nocardia spp. a baseline cd4+ count < 200 cells/µl is also an indication to reflexly perform scrag testing. if the cd4+ count is > 200 cells/µl at baseline or it increases above this threshold on art, then cd4+ testing can be stopped, as therapeutic monitoring on art is best accomplished with vl, not cd4+ count or clinical criteria. however, if virologic or clinical failure occurs, then the cd4+ count should be repeated, as ctx prophylaxis should be commenced if the count drops to < 200 cells/µl on art. common pitfall: routinely checking cd4+ counts if the previous result was > 200 cells/µl. this is unnecessary unless virological or clinical failure subsequently occurs. timing of cd4+ count measurements cd4+ counts should be performed: at baseline (to guide decisions about ctx prophylaxis) every 6 months thereafter if the previous cd4+ count was < 200 cells/µl. cd4+ count response in patients who start art with an abnormally low cd4+ count, the cd4+ count typically increases rapidly in the first month of art, by ~75 cells/µl – 100 cells/µl, with a more gradual rise thereafter (50 cells/µl per year – 100 cells/µl per year).56 most patients achieve a cd4+ count > 500 cells/µl after several years of art, provided that the vl remains suppressed. however, cd4+ count responses are highly variable and may fail to increase despite virological suppression in about 10% – 20% of patients.57,58 such patients have a delayed or absent cd4+ count response to art despite viral suppression, which is termed an ‘immunological discordant response to art’, previously ‘immune non-responders’. some studies have suggested that older patients are at a higher risk of this response. there is no evidence that such patients benefit from a change in art regimen; therefore, the same regimen should be continued. cotrimoxazole prophylaxis should be continued if the cd4+ count remains < 200 cells/µl. there is evidence that the prognosis of such patients is worse than in those who have a cd4+ response, but better than that of patients experiencing both virological and immunological failure.58 if patients with an immunological discordant response to art are clinically unwell, then tb or lymphoma should be considered as the cause of persistent cd4+ lymphopenia. cd4+ counts may remain stable in the presence of incomplete viral suppression in patients receiving art until the vl is high (approximately ≥ 10 000 copies/ml).59 common pitfall: confusing an ‘immunological discordant response to art’ with treatment failure. there is no role for changing art if the vl is suppressed. figure 2 shows the outline of the suggested approach to patients with low cd4+ counts despite a suppressed vl on art. figure 2: suggested approach to patients with low cd4+ counts despite a suppressed viral load on antiretroviral therapy. 10. resistance and genotyping key points ➢ adherence is the key to prevent drug resistance. ➢ resistance testing in patients failing a dtg-based therapy is unnecessary in the majority of cases and should only be undertaken if specific criteria are met. ➢ resistance testing may not detect archived mutations to particular drugs if the patient is not receiving these drugs at the time of resistance testing. overview as a result of transcription errors and recombination, hiv that is replicating can accumulate mutations, leading to drug resistance. durable viral suppression by art is required to limit the chances of developing drug resistance. intermittent drug adherence, as opposed to a total lack of art, provides a greater opportunity for resistance to develop, by exposing replicating virus to sub-therapeutic art drug concentrations. antiretroviral drug resistance mutations are summarised in table 9. table 9: antiretroviral drug resistance mutations. when to perform a resistance test baseline resistance test a baseline resistance test is not generally indicated. we recommend a baseline resistance test to guide first-line regimen choice only in the following situations: pre-exposure prophylaxis received in the previous 6 months history of sexual exposure to a person with known drug-resistant hiv or known to have failed an art regimen. resistance testing at treatment failure resistance testing is generally only possible if the vl is > 500 copies/ml. patients with two or more consecutive vl results of 50 copies/ml – 500 copies/ml are, however, still considered to have a virological failure (see section 8). recommendations for resistance testing are summarised in table 10. table 10: recommendations for resistance testing. first-line therapy non-nucleoside reverse transcriptase inhibitor-based therapy: a resistance test at failure of first-line therapy is not routinely recommended. the earnest and select trials showed that without the use of a resistance test to decide which nrtis to use in second-line therapy, virological outcomes were good and equivalent to a boosted pi + ral regimen.60,61 however, where funds permit, resistance testing will offer some advantages: a resistance test that shows no drug resistance may prevent having to switch unnecessarily to a second-line therapy. a resistance test may permit recycling of some first-line nrtis (e.g. tdf), if they are shown to be susceptible. this is particularly useful if one wants to carry through tdf (or abc) to a second-line dtg-based regimen. a resistance test will identify drug resistance that may be important to identify should the patient require a third-line art in future. dolutegravir-based therapy: because resistance to dtg in first-line therapy is extremely uncommon, we do not recommend resistance testing unless the patient has been on a first-line dtg-based regimen for more than 2 years, provided that they were not exposed to a scenario where a drug–drug interaction would have substantially decreased dtg concentrations (e.g. rif-based tb therapy without increasing dtg dosing frequency to 12 hourly).62 (other rare indications for performing a resistance test before 2 years include patients who were infected with hiv whilst receiving prep – see section 11). because of the extreme rarity of first-line dtg-based resistance mutations, we suggest switching from a dtg-based first-line regimen to a second-line regimen only if resistance testing shows dtg resistance. second-line therapy non-dolutegravir-containing regimens resistance testing is recommended upon failure of a second-line therapy. this enables clinicians to individualise a treatment regimen for a third-line art. for pi-based regimens, sufficient resistance mutations to cause virological failure typically take at least 2 years to develop; therefore, in most cases, we recommend only performing a resistance test after the patient has been on a pi-based regimen for at least this duration. exceptions include exposure to sub-therapeutic pi drug levels as a result of drug–drug interactions (e.g. not doubling the dose of lpv/r when using rif-based tb treatment). patients on pi-based therapy with a vl of 50 copies/ml – 500 copies/ml pose a challenge as resistance testing is generally not possible. such patients should remain on the same regimen with 2–3 monthly vl testing. if the vl rises to > 500 copies/ml, then resistance testing should be performed, whereas if the vl re-suppresses to < 50 copies/ml, then the patient may revert to 6–12 monthly vl testing. dolutegravir-based therapy: we do not recommend performing resistance testing for dtg-based second-line therapies within 2 years where at least one active nrti is present. for instance, if the patient’s first-line nrtis were ftc and tdf, and the patient was changed to 3tc and azt, then the strain of hiv can be assumed to be fully susceptible to azt. scenarios in which to consider resistance testing when failing on a dtg-containing regimen include the following: the patient previously developed resistance to other instis (e.g. ral). the art regimen may not contain any fully active nrtis. accidental exposure to sub-therapeutic levels of dtg (e.g. rif-based therapy was commenced without the dtg being given twice daily). guide for interpreting a resistance test current commercial tests have been licensed for specimens with a vl of at least 1000 ribonucleic acid (rna) copies/ml. nevertheless, many in-house assays can detect vls of 500 rna copies/ml – 1000 rna copies/ml. in general, most commercial hiv resistance tests detect mutations if they are present in > 10% – 20% of the hiv subpopulations in the sample. common pitfall: performing a resistance test in patients with a low or undetectable vl. commercial assays may not be successful in samples where the vl is < 500 copies/ml – 1000 copies/ml. a key concept in interpreting resistance tests is archived resistance. after reverse transcription from its rna template, hiv inserts a dna copy of itself into the host genome. some of the cells that hiv infects are extremely long-lived, and essentially provide an ‘archive’ of hiv variants over time. thus, mutations that are known to have been present at one point in time can be assumed to be present for the lifetime of the patient, even if they are not visible on the patient’s latest resistance test. a second key concept is that of the wild-type virus, which is the naturally occurring hiv strain free of drug resistance mutations. in most cases, this form of the virus replicates more efficiently than viral strains that have acquired resistance. therefore, when drug pressure is removed, the wild-type forms of the virus will predominate, even though the resistant strains have been archived and can become predominant again later if the drug pressure subsequently changes in ways favourable to these strains. a prominent exception to this is the signature mutation of efv and nvp, namely k103n, which imposes no significant fitness cost on the virus. even after these drugs are stopped, the k103n strains may persist at detectable levels for several years. resistance testing should therefore only be performed when the patient is still taking his or her art regimen, or up to a maximum of 4 weeks after discontinuation (see worked examples in box 1). the absence of any identified resistance mutations implies that non-adherence is the cause of a raised vl. this does not exclude the possibility of archived resistance, however, which may only become detectable once the patient is back on art that suppresses the wild-type strain. any significant drug resistance mutations identified by resistance testing can be assumed to be present for the lifetime of the patient, even if subsequent resistance testings fail to show these mutations (as a result of worsened adherence or an art switch, for instance). conversely, it is only possible to identify mutations reliably for drugs that the patient was currently taking when the resistance testing was performed, and for drugs affected by cross-resistance. ‘susceptible’ results to drugs for which there is no drug pressure may be unreliable because of archived resistance. common pitfall: performing a resistance test in the absence of drug pressure. if the patient has defaulted therapy for more than a few weeks, there is little purpose for a resistance test. in this scenario, it is highly likely that the replication of wild-type virus will overtake and obscure any resistant strain, rendering them undetectable by commercial resistance testing. box 1: worked example of resistance testing. 11. initial antiretroviral therapy regimens for the previously untreated patient key points ➢ in art-naive patients, the preferred initial regimen is tdf (300 mg) + 3tc (300 mg) (or ftc 200 mg) + dtg (50 mg) daily – available as a once-daily, one-tablet fdc. ➢ in patients receiving rif, dtg dosing needs to be increased to 50 mg twice-daily until 2 weeks after stopping rif. ➢ dolutegravir has been associated with a small excess risk of ntds in women taking the drug during conception – wocp should be counselled accordingly. preferred initial antiretroviral therapy regimen the preferred initial regimen for previously untreated patients is summarised in table 11. table 11: preferred initial antiretroviral therapy regimen for previously untreated patients. in patients receiving rif, the dtg dose needs to be increased to 50 mg twice daily until 2 weeks after stopping rif. other drug–drug interactions with dtg are discussed in section 3 and section 17. reasons for this preferred regimen are: this combination is available as a once-daily, one-tablet fdc from several suppliers. tenofovir disoproxil fumarate is preferred over abc because of the risk of hypersensitivity reactions with abc (hla-b*5701 testing is not widely available in south africa), certain studies showing lower vl suppression with abc when baseline vl is > 100 000 copies/ml (although not confirmed in a meta-analysis)6 and cost. lamivudine and ftc are regarded as interchangeable in terms of efficacy and safety. dolutegravir is preferred over ral and rpv because of its higher resistance barrier.63 raltegravir also requires a twice-daily dosing and is not co-formulated in fdc. dolutegravir is preferred over efv and pis because superior efficacy and tolerability were demonstrated in clinical trials.12,13 there is an increasing prevalence of pre-treatment resistance to nnrtis in south africa (> 10% in some studies), which may compromise the efficacy of efv-based regimens.64 dolutegravir has been associated with a small but significant risk of ntds in women taking the drug during conception (0.3% vs. 0.1% in women on efv at conception in a large botswana birth outcomes surveillance study).18 this risk is lower than what was originally reported (see section 19). women of childbearing potential should be counselled about the risks and benefits of dtg and allowed to make an informed decision regarding the use of dtg and contraception, in line with who 2019 recommendations. dolutegravir has also been associated with a greater weight gain than efv.21 these issues have been discussed in section 3. alternative initial antiretroviral therapy regimens alternative regimens for previously untreated patients are summarised in table 12. table 12: alternative initial antiretroviral therapy regimens for previously untreated patients. alternative initial antiretroviral therapy regimens in specific clinical situations there are specific clinical situations in which the preferred combination of tdf + 3tc (or ftc) + dtg cannot be used and the alternatives listed in table 13 are advised instead. table 13: recommended alternative initial antiretroviral therapy regimens in specific clinical situations where tdf + 3tc (or ftc) + dtg cannot be used. if both tdf and abc are contraindicated and hb is > 8 g/dl, then azt can be considered as an alternative nrti. considerations for two-drug first-line regimen of dolutegravir + lamivudine this regimen was shown to have an efficacy not inferior to a three-drug regimen in rcts.67 however, these trials did not include patients with a vl > 500 000 copies/ml, and there are no follow-up data beyond 3 years for this regimen. furthermore, virological suppression was lower in patients with a cd4+ count ≤ 200 cells/µl. therefore, we do not routinely recommend this regimen unless neither tdf nor abc can be used. importantly, hepatitis b must be excluded before considering this regimen as patients with hepatitis b must receive tdf + 3tc (or ftc) to prevent rapid emergence of 3tc resistance. the regimen should also not be used in patients receiving rif. 12. management of patients currently receiving first-line therapy key points ➢ clinicians can consider switching patients who are virologically suppressed on nnrti-based first-line therapy from an nnrti to dtg, whilst maintaining the same two-drug nrti backbone. ➢ in patients who are not virologically suppressed on an nnrti-based regimen (vl > 50 copies/ml), we do not recommend an immediate switch to dtg, but rather an enhanced adherence counselling with repeat vl measurement in 2–3 months. if the vl remains > 50 copies/ml, then these patients should be switched to a second-line dtg regimen, which includes switching the nrti back-bone. ➢ the typical criteria of two vl measurements greater than a certain threshold are not appropriate for dtg-based regimens, despite an adherence intervention to define virological failure. rather, in patients started on a first-line dtg regimen, we recommend switching to a second-line therapy only if there is demonstrated insti resistance. patients currently on an efavirenz-, rilpivirineor nevirapine-based first-line regimen patients on these treatment regimens should have vl measurements performed 6–12 monthly (see the sections ‘viral load’ and ‘laboratory monitoring of the efficacy and safety of antiretroviral therapy’). given that dtg is now readily available, clinicians can consider switching patients who are known to have virological suppression (vl < 50 copies/ml within last 6 months) from efv (or nvp or rpv) to dtg whilst maintaining the same two-drug nrti backbone. if the patient is tolerating the efv (or rpv or nvp) regimen with no side effects, then such a switch is optional, as the patient may develop dtg-related side effects which he or she was not experiencing on the nnrti (e.g. insomnia and weight gain). the benefit of such a switch is that a dtg regimen has a more robust resistance profile (dtg boasts a higher barrier to resistance than nnrtis).12 an additional benefit of switching from nvp to dtg is that it is switching from a twice-daily to a once-daily regimen. in patients experiencing efv-related side effects (even mild side effects), we encourage a change to dtg whilst maintaining the same nrtis, provided that the vl is < 50 copies/ml within the last 6 months. another option in patients who are virologically suppressed (vl < 50 copies/ml) whilst receiving a regimen of nnrti + two nrtis, and who have never experienced virological failure, is a switch to the two-drug combination of dtg + rpv. data from two clinical trials (sword i and ii)68 showed that this regimen maintains virological suppression as a switch strategy in patients who have not previously experienced virological failure. this should not be done in patients who have chronic hepatitis b as tdf and 3tc (or ftc) should always form a part of their treatment. the recommended protocol for switching from a first-line nnrti-based regimen to a dtg-based regimen is shown in figure 3. figure 3: switching from a first-line non-nucleoside reverse transcriptase inhibitor-based regimen to a dolutegravir-based regimen. antiretroviral therapy options in patients failing first-line non-nucleoside reverse transcriptase inhibitor-based therapy in patients who are not virologically suppressed on an nnrti-based regimen (vl > 50 copies/ml), we do not suggest an immediate switch to dtg with the same two nrtis. the reason for this is that it is possible that they have developed resistance to the two nrtis and may then be placed on dtg without a fully effective drug to accompany it. in this scenario, we recommend for enhanced adherence counselling and repeating the vl measurement in 2–3 months. if the vl is < 50 copies/ml, then the patient can be switched to dtg + the same two nrtis. if the vl is > 50 copies/ml, then the patient should be switched to a second-line dtg regimen, which includes dtg + two nrtis as follows: if the patient was receiving tdf (or abc) + 3tc (or ftc) first-line therapy, then switch to azt + 3tc in a second-line therapy with dtg. if the patient was receiving azt (or d4t) + 3tc first-line therapy, then the decision regarding a second-line therapy should be based on a resistance test result. if the virus is susceptible to tdf on resistance testing, then the clinician can prescribe tdf + 3tc (or ftc) + dtg (provided that the patient has not potentially previously experienced virological failure on tdf and has not experienced tdf nephrotoxicity previously). if no fully active nrti is available to accompany dtg, then it is best to switch to a pi-based second-line therapy with tdf + 3tc (or ftc). advice is provided in section 13 regarding patients who cannot access a resistance test in this scenario. women of childbearing potential should be counselled about the potential risks and benefits of dtg and allowed to make an informed decision regarding the use of dtg and contraception (see section 3). patients started on a dolutegravir-based first-line regimen these patients should have their vl measured 6–12 monthly (see the sections ‘viral load’ and ‘laboratory monitoring of the efficacy and safety of antiretroviral therapy’). we have previously used the criteria of two vl measurements > 1000 copies/ml despite an adherence intervention to define virological failure and the need to switch from firstto second-line art. this was appropriate for patients on nnrti-based first-line regimens because of the low barrier to resistance of the nnrti class. however, considerations are very different with dtg-based first-line regimens. in several clinical trials of dtg in first-line therapy, no dtg resistance has been described despite some patients having virological failure, and in clinical practice very few cases of dtg resistance (less than five cases worldwide at the time of writing this article) have been described when the drug has been used as part of a three-drug first-line regimen.63 therefore, it would be inappropriate to use the same criteria for switching to second-line art for dtg as it is likely that most patients with two unsuppressed vls will not have resistance and rather require improved adherence on the same first-line regimen to achieve suppression. for that reason, we only recommend switching from a first-line dtg-based art to a second-line regimen if resistance testing demonstrates insti resistance. until further data are available, in patients with an unsuppressed vl on dtg-based first-line art, we recommend for enhanced adherence counselling. the tolerance of the regimen should also be addressed – the regimen may need to be switched because of side effects. integrase strand transfer inhibitor resistance testing should be considered in these situations: dolutegravir monotherapy for a period (dtg resistance has been more frequently described in this situation).63 co-administration of a drug that interacts with dtg without necessary dose adjustment (e.g. dtg given at 50 mg daily with rif or given simultaneously with polyvalent cation-containing agents – see section 3). viral load measurements > 50 copies/ml for > 2 years (despite adherence interventions, 100% pharmacy refills and self-reported adherence) and the current vl is > 500 copies/ml, thereby permitting a resistance test. the patient was infected whilst receiving prep (because of potential nrti resistance at the time of infection). sentinel surveillance projects or research studies, with the purpose of detecting emergence of dtg resistance. if a resistance test is performed, then this should include sequencing of the integrase enzyme. the clinician should only switch from a dtg-based first-line regimen to a second-line therapy if resistance is detected, and the drugs used in the second-line regimen should depend on the resistance test result (see section 13). these recommendations are based on accumulated information on the resistance barrier to dtg to date, suggesting that dtg resistance is extremely rare when the drug is used in a three-drug first-line regimen. these recommendations may be updated when more data become available regarding the incidence and risk factors of dtg resistance with more widespread use in routine clinical practice. figure 4 shows the outline of the virological monitoring of patients on dtg-based first-line art and the recommended response to results. figure 4: virological monitoring of patients receiving dolutegravir-based first-line antiretroviral therapy and response to results. 13. management of patients starting or currently receiving second-line therapy key points ➢ when dtg is used in second-line therapy, there should be at least one fully active accompanying drug until further evidence is available. ➢ if the patient fails an nnrti regimen with 3tc/ftc + either tdf or abc, then azt + 3tc + dtg is the recommended second-line regimen. ➢ if the patient fails other first-line regimens, then resistance testing is advised to decide on the choice of nrtis in a dtg-based second-line regimen. ➢ boosted pi + two nrti second-line regimens are effective even if there is resistance to both nrtis in the regimen. ➢ we advise drv/r 800 mg/100 mg once daily as the first choice pi for use in second-line therapy. recommendations for patients failing a first-line regimen failed first-line regimen of two nucleoside reverse transcriptase inhibitors + non-nucleoside reverse transcriptase inhibitor table 14 shows the summary of the recommended second-line regimen to start in patients who have failed a first-line regimen consisting of two nrtis + nnrti. table 14: recommended second-line regimen in patients who have failed a first-line regimen of two nucleoside reverse transcriptase inhibitors + non-nucleoside reverse transcriptase inhibitor. based on the results of the dawning trial, it is preferable to use a dtg-based regimen rather than a pi/r regimen in second-line therapy.17 in this trial, a second-line regimen of dtg + two nrtis was superior in terms of virological suppression and better tolerated than lpv/r + two nrtis in patients who had failed a first-line regimen of nnrti + two nrtis. an important caveat is that all patients enrolled in this trial had a resistance test performed at entry and had to have at least one fully active nrti to be eligible for inclusion. thus, the current evidence supports a dtg-based regimen in second line only when used with at least one fully active nrti. whether a dtg-based second-line regimen would be equally effective with two nrtis when there is resistance to both those nrtis is currently a knowledge gap that is being addressed by several clinical trials – we do not advise such a strategy until the results of those trials are available. in patients failing a first-line regimen in which the nrtis are tdf + 3tc (or ftc), the mutations selected are typically m184v by 3tc (or ftc) and k65r (or k70e) by tdf. none of these mutations compromise azt; in fact, they render the virus hyper-susceptible to it. therefore, in this scenario, azt remains fully active, and we can infer from the dawning trial results that a second-line regimen of azt + 3tc + dtg will be optimally effective. the same applies for patients failing an abc + 3tc + nnrti regimen: azt retains susceptibility and can be used with 3tc and dtg in a second-line regimen. where patients have failed an azt (or d4t) + 3tc + nnrti regimen, this could have resulted in the accumulation of thymidine analogue mutations (tams) and m184v. certain tams compromise tdf, meaning that it is unpredictable whether there is a fully active nrti if a regimen of tdf + 3tc (or ftc) + dtg is used in second-line therapy. we therefore advise resistance testing in such patients. if the resistance test demonstrates a fully active nrti, then that nrti can be used with 3tc (or ftc) + dtg in the second-line regimen. if there is no fully active nrti or a resistance test is not possible in this situation (e.g. public sector), then we recommend a regimen of tdf + 3tc (or ftc) + drv/r. the reason for this is that boosted pi + two compromised nrtis retain activity as a second-line regimen (see below). women of childbearing potential should be counselled about the risks and benefits of dtg and allowed to make an informed decision regarding the use of dtg and contraception. if they choose not to use dtg in a second-line therapy, then drv/r should be used in its place. failed first-line regimen of two nucleoside reverse transcriptase inhibitors + dolutegravir the second-line regimen to commence in patients who have failed a first-line approach of two nrtis + dtg is provided in table 15. table 15: recommended second-line regimen in patients who have failed a first-line regimen of two nucleoside reverse transcriptase inhibitors + dolutegravir. if patients experience virological failure on a first-line dtg-based regimen, then we do not recommend switching to a second-line therapy unless a resistance test is performed that demonstrates dtg resistance. this is because dtg is a very robust drug and resistance is very rare when used in triple-drug combination first-line therapy. therefore, it is far more likely that a vl > 50 copies/ml is attributed to adherence problems rather than resistance. if dtg resistance is demonstrated, then we advise a regimen of two nrtis + drv/r, with the two nrtis selected based on the resistance test results. patients currently established on protease inhibitor-based second-line therapy viral load < 50 copies/ml clinicians can consider switching of patients currently on a second-line pi/r regimen to a dtg regimen, particularly if patients experience gi side effects of pis. this switch may also simplify the regimen and reduce pill burden. however, before such a switch is made, we advise a careful review of the treatment and resistance (genotype test) history to ensure that there is at least one fully active nrti to accompany dtg in the new regimen. if this cannot be assured, then we advise maintaining the current pi/r regimen – although a switch to an alternative pi/r can be considered to improve tolerance. if continuing a pi is not possible, then a switch to a dtg-based second-line regimen without an assured active nrti could be considered with close vl monitoring. refer to table 16 for our advice when considering switching a patient on a pi/r-based regimen to dtg in a second-line therapy where the vl is < 50 copies/ml. table 16: switching from a boosted protease inhibitor to dolutegravir in second-line antiretroviral therapy when the viral load is < 50 copies/ml.† box 2: choice of boosted protease inhibitor in second-line antiretroviral therapy. box 3: boosted protease inhibitor + two nucleoside reverse transcriptase inhibitors is an option in second-line therapy even if there is resistance to both nucleoside reverse transcriptase inhibitors. viral load > 50 copies/ml in patients on a second-line regimen containing a boosted pi, if the vl is not suppressed, then we do not advise switching to dtg. we advise for enhanced adherence counselling and switching to an alternative boosted pi if there is intolerance. if the vl subsequently re-suppresses to an undetectable vl < 50 copies/ml, then the advice in the section above should be followed. if the vl remains elevated, then the patient may be eligible for a resistance test, with consideration for a third-line therapy if they fulfil the criteria outlined in section 14. 14. third-line antiretroviral therapy key points ➢ for patients with a detectable vl on second-line therapy for < 2 years, intensified adherence counselling and support are required rather than a switch to a third-line therapy. ➢ for a patient on a second-line regimen for > 2 years with two or three vl measurements > 50 copies/ml within a 6-month period despite adherence interventions that have been assessed to be satisfactory (see text), a resistance test should be performed. (note: a resistance test can only be performed if vl > 500 copies/ml.). ➢ the choice of the third-line regimen should be made in consultation with an hiv expert. management of patients with a detectable viral load on second-line therapy and initiation of third-line therapy as outlined in the previous section, there should be documented pi or dtg resistance before switching to a third-line regimen. resistance tests should be interpreted by an expert in conjunction with a full art history. in many patients failing second-line regimens, there are no pi (or dtg) mutations. in these patients, improved adherence is required rather than switching to a third-line regimen. if side effects interfere with adherence, then consideration should be given to switching to a more tolerable regimen, provided that this regimen is predicted to be effective based on the treatment history (see section 13). figure 5 shows the outline of indications for performing resistance testing in second-line art regimens. figure 5: indications for performing resistance (genotype) testing in second-line antiretroviral therapy. in a patient who has been on a second-line regimen for > 2 years, if there are two or three vl measurements > 50 copies/ml in a 6-month period, despite adherence interventions, and adherence is assessed to be satisfactory (e.g. 100% pharmacy claims over 6 months), then a resistance test should be performed (resistance test can only be performed if vl > 500 copies/ml). if a patient who has been on second-line therapy for < 2 years is found to have a detectable vl, then a resistance test should not be performed; rather, the same regimen should be continued and adherence counselling and support should be intensified. the regimen may be switched if there are significant side effects. it is unlikely that significant resistance to the pi or dtg will have developed within 2 years. the exceptions include a patient who in error was not prescribed lpv/r double dosing with concurrent rif use, and subsequently demonstrates a detectable vl, and a patient who has been taking an incorrectly low dose of medication. such patients should be eligible for resistance testing even if they have been on second-line therapy for < 2 years. adherence counselling before third-line therapy specific adherence counselling should be provided for patients preparing to start third-line art, with a clear discussion that this regimen is likely to be their last option for the foreseeable future. third-line regimen choice after failing a protease inhibitor-based second-line regimen a third-line regimen including a combination of drv/r and other drugs decided on the basis of resistance testing results in virological suppression in the majority of patients, provided that adherence is optimal.74,75,76,77 for most patients who require third-line therapy (i.e. patients who experience virological failure on a second-line lpv/r or atv/r regimen with a low-, intermediateor high-level resistance to the pi, i.e. stanford score > 14), we recommend the third-line regimen outlined in table 17. however, the final decision will be based on treatment history and resistance test results for the individual patient. table 17: third-line regimen recommended for the majority of patients failing protease inhibitor-based second-line therapy. exceptions there are exceptions: in patients with renal impairment, replace tdf + ftc with abc + 3tc, or azt + 3tc. the choice between abc and azt will depend on hb (anaemia: do not use azt if hb < 8 g/dl) and resistance testing. if the azt stanford score is lower than the tdf score, then use azt + 3tc rather than tdf + ftc. patients with a drv score of 0 on stanford score (and no drv mutations, see section 5) can take drv/r 800 mg/100 mg once daily. patients with prior virological failure on ral and/or with a dtg score > 0 on integrase resistance testing should receive dtg 50 mg twice daily. in patients with extensive resistance (e.g. drv score > 29 and nrti score > 29), consider adding rpv or etr (provided that the score for these drugs is < 30) or maraviroc (mvc) (provided that the virus is ccr5-tropic on the tropism test). additional points and explanatory notes we generally advise the continuation of nrtis in the third-line regimen, even if there is documented nrti resistance. lamivudine (or ftc) resistance with the m184v mutation impairs viral replication. another nrti (generally tdf, but based on resistance testing) should be added. this is not essential if there are more than two other active drugs in the regimen.78 because most patients are not receiving an nnrti at the time of failing second-line therapy when a genotype resistance test is typically performed, prior nnrti mutations related to first-line nnrti failure may be archived at this time. therefore, it is difficult to be certain from a (this) genotype performed at second-line art failure whether etr/rpv is still active; however, data from south africa suggest that the majority of patients who have failed nvp or efv are still susceptible to etr/rpv.79 in the sailing trial, in treatment-experienced patients, a dtg regimen proved superior to ral and fewer patients in the dtg arm developed treatment-emergent insti resistance. consequently, we no longer recommend the use of ral in third-line therapy unless dtg is not tolerated or otherwise contraindicated or unavailable. we also recommend switching patients currently using ral in third-line therapy to dtg because of its higher barrier to resistance.14 if such patients have a suppressed vl, then they can be switched to standard dose dtg (50 mg daily); however, if they are not virologically suppressed, then we suggest a resistance test with a request for integrase sequencing before switching. if there are insti mutations present that are associated with reduced susceptibility to dtg, then the dtg dose should be 50 mg twice daily. women of childbearing potential should be counselled about the risk and benefits of dtg and allowed to make an informed decision regarding the use of dtg and contraception. maraviroc (a ccr5 blocker) is a consideration in third-line therapy; however, it is currently extremely costly and can only be used after a tropism test demonstrates that the patient’s circulating virus has sole tropism for the ccr5 co-receptor. we advise only considering this when there is intermediateor high-level resistance to all pis, all nnrtis and all nrtis, and dtg is not fully susceptible. if viral suppression is not achieved on third-line therapy, then there is still benefit in continuing failing art because of the residual partial activity and ‘crippling’ effect of such art. ‘crippling’ describes the fact that mutant viruses often have less replicative capacity. provided that the vl can be maintained at < 10 000 copies/ml, the cd4+ count will usually be maintained or even increase.59 third-line regimen choice after failing a dolutegravir-based second-line regimen the choice of a regimen will be guided by resistance test results and should include drv/r with two nrtis (generally 3tc or ftc with the nrti with the lowest stanford score). in patients failing a second-line dtg regimen who have not failed a pi/r previously, it can be assumed that drv/r is fully active and can be used at 800 mg/100 mg daily. based on the results of the earnest, select and second line trials, it can be concluded that a drv/r regimen with two nrtis will be an active regimen even if there is documented resistance to the two nrtis.60,61,72 however, decisions regarding the third-line therapy need to be individualised in consultation with an expert, taking into account the treatment history (which drugs and classes the patient previously failed) and previous and current resistance test results. raltegravir may still be active in patients with dtg resistance – it depends on the specific resistance mutations in the integrase gene – but it is usually not necessary to include it in the regimen. etravirine and rpv are other drugs that can be considered depending on resistance test results and treatment history. 15. laboratory monitoring of the efficacy and safety of antiretroviral therapy key points ➢ antiretroviral therapy efficacy is monitored with vl and cd4+ count – discussed in the sections ‘viral load’ and ‘cd4+ cell count’. ➢ the key efficacy endpoint in art is sustained virological suppression with a vl < 50 copies/ml. ➢ cd4+ count monitoring can be stopped when the cd4+ count is > 200 cells/µl and the vl is suppressed. ➢ creatinine monitoring is advised in patients on tdf, and an fbc is advised in patients on azt. ➢ in most patients taking pis, only one lipid measurement is advised (at 3 months). ➢ in patients on tdf who are admitted to hospital, it is important to check creatinine even if it does not fall within these monitoring guidelines. this is because intercurrent illnesses with dehydration or sepsis may be associated with a deterioration in renal function, in which tdf may act as a co-factor. table 18 shows the list of the laboratory investigations and their frequency advised for monitoring of art safety. common pitfall: monitoring of vl is not done at least annually. this results in a delayed detection of art failure and intervention, with resultant clinical deterioration and increased risk of transmission. table 18: standard laboratory monitoring of patients after commencement of antiretroviral therapy. 16. patients who return after stopping antiretroviral therapy key points ➢ many patients return to care after treatment interruption when they experience clinical deterioration – screening for ois should be performed. ➢ viral load measurement should be performed before re-initiation and repeated 3–6 monthly. ➢ choosing the appropriate regimen in patients who return to therapy depends on their previous regimen, their level of treatment adherence prior to disengaging with care, and their current cd4+ and hospitalisation status. it is common for patients receiving art to interrupt their treatment for a number of reasons (e.g. treatment fatigue, denial, life event, depression, new job, relocation, etc.). many patients return to care after an interruption, often precipitated by clinical deterioration. patients who have clinical symptoms of an oi when returning to care should be investigated and, if appropriate, should be started on treatment for the infection before restarting art. in particular, patients should be screened for headache and for tb symptoms when returning to care. reasons for delaying art re-initiation are the same as for delaying initiation in art-naive patients (see section 6). patients who are asymptomatic when returning to care could be re-initiated on art the same day with appropriate counselling. a counselling plan should be implemented to ensure retention in care going forward and address reasons for disengagement. we recommend performing a vl measurement before re-initiating art, then 3–6 monthly thereafter. the choice of art regimen to restart will depend on prior treatment history. return after stopping a tdf + ftc (or 3tc) + nnrti regimen in patients returning to treatment after disengaging from a tdf + ftc (or 3tc) + nnrti regimen: if the patient had adhered to treatment prior to disengaging, with a suppressed vl, and has only disengaged once or twice, then he or she could either be restarted on the same regimen or restarted on tdf + 3tc (or ftc) + dtg. if a patient restarts an nnrti-based regimen, then switching to a second-line regimen should be considered if the vl is not < 1000 copies/ml at 3 months after restarting. if the patient has a history of poor adherence with multiple episodes of disengaging, then we suggest re-initiating therapy with a second-line regimen of azt + 3tc + dtg, azt + 3tc + pi/r or tdf + ftc + pi/r. we do not recommend tdf + 3tc (or ftc) + dtg in this scenario, as there may be resistance to tdf and 3tc – multiple episodes of treatment interruption, particularly beyond the first year of art, and poor adherence can result in resistance to all drugs in the first-line regimen. hospitalisation with an aids-defining condition and a cd4+ count < 50 cells/µl represents another scenario in which a patient may be restarted immediately on second-line art when returning to care after disengaging. such patients are considered to be at high risk of mortality if restarted on first-line therapy to which their virus may be resistant, and they require an art regimen that is guaranteed to be effective immediately. this decision should typically be taken by the hospital-level clinician. return after stopping a dolutegravir-based regimen in patients returning to treatment after disengaging from a dtg-based regimen: restart the same regimen. assess the vl at 6 months and follow standard guidance in response to the result. return after stopping a tdf + ftc (or 3tc) + pi/r regimen in patients returning to treatment after disengaging from a second-line pi-based regimen: either restart the patient on the same regimen or switch to azt + 3tc + dtg (if the patient had failed a first-line tdf + 3tc (or ftc) + efv regimen). assess the vl at 6 months and follow standard guidance in response to the result. return after stopping a third-line regimen in patients returning to treatment after disengaging from a third-line regimen: restart the same regimen and assess the vl at 6 months. follow standard guidance in response to the result. common pitfall: performing a resistance test after an art treatment interruption of > 4 weeks. such a testing is of limited value. many resistance mutations are overtaken by the wild-type virus when art is stopped and thus the resistance test may not accurately reflect the true resistance pattern. 17. drug–drug interactions key points ➢ whenever patients start or switch antiretroviral drugs or start new concomitant medications, it is important to evaluate potential drug interactions. ➢ many drugs and drug classes have clinically significant drug–drug interactions with arvs. ➢ there are also important drug interactions between several arvs. ➢ it is important to consult a regularly updated database to assess whether drugs can be co-administered and whether dose adjustment is required. ➢ herbal medications may also have interactions with art drugs (e.g. st john’s wort and garlic), but data on herb–drug interactions are very limited. mechanisms of drug interactions there are two main mechanisms of drug–drug interactions: pharmacodynamic interactions: these interactions occur when one drug influences the action of another drug without altering its concentrations. such interactions may be either beneficial, if drug effects are additive or synergistic; or harmful, if drug effects are antagonistic. additive toxicity is also a pharmacodynamic interaction (e.g. azt and linezolid both cause myelosuppression and should not be co-administered). pharmacokinetic interactions: these interactions occur when a perpetrator drug alters the concentrations of a victim drug by affecting its absorption, distribution, metabolism or excretion. inhibition is a direct chemical effect when a drug binds to the active site of drug-metabolising enzyme or drug transporter – typically only one or a few enzymes or transporters are inhibited. inhibition is maximal when the inhibiting drug reaches steady state and wanes rapidly when the inhibiting drug is stopped. strong inhibitors (e.g. ritonavir, clarithromycin and itraconazole) can cause significant increases in the concentrations of victim drugs, resulting in toxicity. induction results in transcriptional activation of many genes involved in drug metabolism and transport, which takes about 2 weeks to be maximal and wanes in a similar time. strong inducers (e.g. rif, carbamazepine and phenytoin) can cause significant decreases in concentrations of victim drugs, resulting in reduced efficacy. pharmacokinetic interactions are occasionally beneficial (e.g. rtv markedly increases the concentrations of other pis). data on herb–drug interactions are very limited – both st john’s wort and garlic are known inducers. clinically significant pharmacokinetic interactions require dose adjustment of the victim drug or, if the interaction is severe, avoiding co-administration with the perpetrator drug. overview of drug–drug interactions by antiretroviral class nrtis. these are generally neither victims nor perpetrators of clinically significant pharmacokinetic interactions. pis. ritonavir is a potent inhibitor of the key cyp enzyme 3a4 and the drug efflux transporter p-glycoprotein; it also induces several other drug-metabolising enzymes and drug transporters. therefore, rtv-boosted pis are frequent perpetrators of pharmacokinetic interactions, but can also be victims of such interactions when co-administered with strong inducers – co-administration with strong inhibitors does not add significantly to the inhibition by rtv. atazanavir/ritonavir requires an acid ph in the stomach for absorption – it should be taken 2 h before or 1 h after antacids, and administration with ppis is not advised. nnrtis. these differ by individual drugs. efavirenz is a moderate inducer. rilpivirine can be the victim when co-administered with strong inducers. although inhibitors increase the exposure to rpv, it is seldom necessary to adjust the dose. etravirine induces cyp3a4 and also inhibits two cyp enzymes; it can also be the victim when co-administered with strong inducers. instis. polyvalent cations (calcium, magnesium, iron and aluminium) bind to instis, reducing their absorption. integrase strand transfer inhibitors can be taken 2 h before or 6 h after polyvalent cations. however, calcium and iron can be co-administered with instis if taken with a meal, but not in the fasted state. integrase strand transfer inhibitors are victim drugs when co-administered with strong inducers. instis are not perpetrator drugs, except dtg that inhibits an efflux transporter important in the elimination of metformin (metformin dose should not exceed 500 mg 12 hourly). there are many important pharmacokinetic drug interactions between arvs and other drugs, as well as between different arvs. some of these drug–drug interactions are discussed in other sections of this article (e.g. interactions with rif in section 18). the full list of all potential drug interactions is very long and beyond the scope of this article. knowledge of drug interactions is constantly evolving. clinicians are advised to seek reliable information on drug–drug interactions when using non-standard art regimens and when drugs are co-administered, using one or more of the resources listed in box 4. common pitfalls: not checking for interactions between concomitant drugs and current or newly initiated arvs. concomitant drugs may need dose adjustment or discontinuation when art is switched, for example, switching from a moderate inducer (efv) to a strong inhibitor (pi/r), or from either of these to an insti. not considering marked increases in statin considerations when used concomitantly with pis. there are major interactions between pis and many statins, which result in marked increases in statin concentrations. low-dose atorvastatin (not exceeding 10 mg, which will give an equivalent exposure to about 60 mg) can be used with pis, but simvastatin cannot be used. box 4: contacts and resources for seeking reliable information on drug–drug interactions. 18. tuberculosis key points ➢ rifampicin is a potent inducer of certain drug-metabolising enzymes and drug transporters and reduces exposure to drugs in the insti, nnrti and pi classes, necessitating dose adjustments of some of these drugs. ➢ lpv/r is the only pi that can be used with rif, but the lpv/r dose needs to be doubled. ➢ rifabutin (rfb) can be used with all pis, but an rfb dose adjustment is required. ➢ several side effects are shared between arvs and tb drugs, including gi intolerance, hepatotoxicity, drug rashes, myelosuppression and neuropsychiatric side effects. considerations for antiretroviral therapy in the context of tuberculosis tuberculosis is the most frequent co-infection affecting hiv-positive people in southern africa. patients may be diagnosed with tb at entry or re-entry into hiv care, or diagnosed with active tb whilst on art. studies in south africa have suggested that tb incidence remains higher in patients who are virally suppressed on long-term art compared with hiv-negative people living in the same community, possibly because of persisting defects in anti-mycobacterial immunity. the co-treatment of hiv and tb is complex because of (1) drug–drug interactions (discussed below), (2) tb-iris (section 26) and (3) shared side effects (discussed below). these issues, which have recently been reviewed,80 affect decisions regarding the timing of art in art-naive patients with tb (section 6). certain art regimens need to be modified for compatibility with rif. rifampicin is a critical component of the drug-sensitive tb regimen that substantially reduces the risk of relapse after completing tb treatment. there are no significant interactions between nrtis and rif; however, instis, nnrtis, pis and mvc all exhibit drug interactions with rif. dolutegravir can be used in patients receiving rif, but a dose adjustment is required (table 19).81 efavirenz is the preferred nnrti for use with rif. nevirapine was previously recommended as an alternative in patients with contraindications to efv (e.g. psychosis), but it carries a higher risk of virological failure when used with rif, and given the availability of the insti class, nvp is no longer recommended. rilpivirine and etr cannot be used with rif. the plasma concentrations of all pi/r are reduced to subtherapeutic ranges with rif. dose adjustment of lpv/r can overcome this induction (table 19), but there is a risk of hepatotoxicity; patients require counselling and alt should be monitored frequently.82,83 table 19: antiretroviral drug interactions with rifampicin and recommendations for co-administration. an alternative approach is to replace rif with rfb in patients taking a pi/r. however, rfb is not co-formulated with other tb drugs, and the evidence base for rfb in the treatment of tb is much less substantial than that for rif.84 there is also uncertainty regarding the optimal dose of rfb with pi/r; these guidelines recommend 150 mg daily (table 20) for efficacy reasons, but careful monitoring for toxicity is required (alt, neutrophil count and visual symptoms at least monthly).85 rfb may be considered in patients who are not able to tolerate co-treatment with double-dose lpv/r and rif-based tb treatment (i.e. patients unable to tolerate the increased lpv/r dose because of hepatotoxicity or gi side effects) or in art-experienced patients on an art regimen that is not compatible with rif (e.g. third-line art with drv/r). if rfb is unavailable and adjusted doses of lpv/r are poorly tolerated in patients receiving second-line art, then dtg (50 mg 12 hourly) may be substituted for the pi. however, it should be noted that good evidence is lacking regarding the robustness of dtg in second-line therapy with both nrtis compromised, as exists for pi/r (section 13). nevertheless, the short-term use of dtg with two compromised nrtis over 6 months is preferable to treating tb without rif, which has a high risk of failure or relapse. table 20: dosage of antiretroviral drugs and rifabutin when prescribed concomitantly. antiretroviral therapy and tb medication share many side effects (table 21). common pitfalls: rifampicin is co-administered with lpv/r, but the dose of lpv/r is not adjusted. this results in sub-therapeutic lpv concentrations and development of pi resistance. rifampicin should not be co-administered with atv/r or drv/r at all. combining linezolid and azt. these drugs should not be combined because both can cause bone marrow suppression (especially anaemia and neutropenia). table 21: shared side effects ofantiretroviral therapy and tuberculosis treatment. 19. pregnancy and breastfeeding note: it is beyond the scope of these guidelines to provide comprehensive guidance for the management of pregnant women. key recommendations relating to the mother are included, but providers are encouraged to refer to national guidelines. all women should be linked to routine antenatal care when pregnancy is confirmed. the prevention of mother-to-child transmission of hiv (pmtct) programme includes periconception, pregnancy, delivery and breastfeeding and encompasses the prevention of unplanned pregnancies. in low-resource settings, breastfeeding commonly continues for up to 24 months. breastfeeding transmission is now the most common mode of mother-to-child transmission of hiv in many parts of sub-saharan africa, rendering post-natal retention-in-care vital to successful pmtct intervention. virological suppression on art is essential for maternal health, and to prevent hiv transmission to the infant. an elevated vl > 50 copies/ml in a pregnant or breastfeeding woman requires urgent action. in well-functioning pmtct programmes, a significant proportion of infections in infants result from undetected seroconversion during pregnancy and breastfeeding. repeated hiv testing throughout these periods is essential for women initially testing hiv-negative. interventions that support hiv risk reduction in women include male partner hiv testing and linkage to art for ‘treatment as prevention’, encouraging consistent condom use throughout pregnancy and breastfeeding, and providing prep to women who are at substantial risk of hiv infection. maternal health is central to healthy infants, and is an essential focus of pmtct services: advanced hiv results in life-threatening ois, leading to miscarriage, stillbirth, premature delivery and maternal death. mother-to-child transmission of human immunodeficiency virus overall, the risk of mother-to-child transmission of hiv is ~ 40% in the absence of any intervention (see box 5 for more information). timing of such transmission is as follows: in utero: 5%; during delivery: 15% – 20%; up to 24 months of breastfeeding: 20%. box 5: south african national guidelines for the prevention of mother-to-child transmission of human immunodeficiency virus. the time of the highest risk coincides with delivery, which spans a matter of hours; the risk during 24 months of breastfeeding is slightly higher, but over a significantly greater timespan. breastfeeding should not be stopped because of a new diagnosis of hiv, or an elevated vl in women already on art. instead, initiation of art and management of raised vl (together with infant prophylaxis) are interventions to ‘make breastfeeding safer’. antiretroviral therapy for women of childbearing potential and during pregnancy and breastfeeding all hiv-positive pregnant and breastfeeding women should be initiated on lifelong art, ideally the same day that pregnancy is confirmed. standard first-, secondand third-line regimens should be used in pregnancy (see the sections ‘initial antiretroviral therapy regimens for the previously untreated patient’, ‘management of patients currently receiving first-line therapy’, ‘management of patients starting or currently receiving second-line therapy’ and ‘third-line antiretroviral therapy’). regarding dtg use in pregnancy, it is important to note that the absolute risk of ntd is low (< 0.5%), and this risk may be outweighed by the additional benefits of dtg over alternative therapies. we currently recommend that wocp who wish to become pregnant or who have no reliable access to effective contraception should be counselled adequately about the potential risks and benefits of dtgversus efv-based art, and should be offered the choice of first-line regimens. other points regarding art in pregnancy include the following: efavirenz 600 mg is a safe and effective regimen for use by wocp including during the time from conception to the end of the first trimester. there are insufficient data to recommend routine use of efv 400 mg in pregnant women. the current guidelines no longer recommend initiating nvp in any patients. maternal deaths in pregnant women have been associated with nvp because of liver and skin hypersensitivity reactions. nrtis: note that commonly used crcl calculations are not validated for pregnant women; therefore, avoid tdf if serum cr ≥ 85 µmol/l. dose adjustment of art during pregnancy is only indicated for women taking both tdf and atv/r during the second/third trimester; the dose should be increased from atv/r 300 mg/100 mg to 400 mg/100 mg. women taking lpv/r 800 mg/200 mg daily should be advised to adjust this to 400 mg/100 mg 12 hourly (twice daily) during pregnancy because of altered pharmacokinetics. these women should also be informed about the association between lpv/r and premature labour and delivery. particular importance should be placed on drug–drug interactions between dtg and divalent cation-containing medication in pregnancy, as pregnant women frequently receive iron supplements and/or magnesium-/aluminium-containing antacids. patients returning to care in pregnancy after defaulting a first-line regimen or those exposed to previous pmtct regimens should generally be put directly on a dtg-based regimen, rather than retrying an nnrti-regimen (section 16). as per current pmtct guidelines, women not already on art at the time of labour or delivery should commence tld immediately and also receive an additional stat dose of nvp 200 mg. women who are newly diagnosed with hiv during the breastfeeding period may continue breastfeeding as per maternal preference, provided that maternal art and infant prophylaxis are initiated and adherence support is given. other key recommendations: all pregnant women should be screened at every visit for sexually transmitted infections and treated as needed. all pregnant and breastfeeding women should be screened for tb at every visit. if the tb screening is negative, then consider tb-preventive therapy during pregnancy only in women with a cd4+ count < 350 cells/µl (section 27). common pitfalls: not performing vl monitoring at appropriate time. see table 22 for the appropriate monitoring intervals. an elevated vl is not acted upon urgently. viral load results should be fast-tracked, and women failing their current regimen must be identified early and, if necessary, a regimen switch should be made without delay. table 22: timing of viral load monitoring during pregnancy, delivery and breastfeeding. 20. liver disease antiretroviral dose adjustment in liver impairment key points ➢ there is no single blood test for accurate quantification of liver impairment. ➢ child–pugh class c may require dose adjustment for some art drugs. ➢ the combination of tdf + 3tc (or ftc) + dtg (or ral) is regarded as least hepatotoxic. antiretroviral dose adjustments table 23 shows the outline of dose adjustments for the relevant art drugs in patients with child–pugh class c liver impairment. table 23: prescribing antiretroviral therapy in liver impairment. hepatitis b and human immunodeficiency virus co-infection key points ➢ all hiv-infected individuals should be screened for active hbv – hepatitis b surface antigen (hbsag) screening is an appropriate test. ➢ the hbv vl correlates with disease progression and is used to monitor anti-hbv therapy. ➢ all children and adults eligible for hbv vaccination should be vaccinated. ➢ antiretroviral therapy drugs with anti-hbv activity are tdf + 3tc (or ftc). ➢ for all hiv-infected hbsag-positive patients, the art regimen should include tdf + 3tc (or ftc). ➢ using 3tc without tdf to treat hbv/hiv co-infection leads to hbv resistance in 80% – 90% of patients after 5 years of treatment. ➢ interruption of tdf and/or 3tc (or ftc) has been associated with flares of life-threatening hepatitis in patients with hepatitis b in case reports. ➢ adjust dosing frequency of tdf in patients with hbv infection and renal dysfunction; if renal function is severe or deteriorates with tdf, then 3tc monotherapy or other drugs with anti-hbv activity should be considered. hepatitis b virus is a common co-infection with hiv in southern africa, with significant implications for progression to cirrhosis, as well as for treatment options. access to vaccination, laboratory resources and treatment options is limited to some extent in southern african countries, and the recommendations below should be considered in the light of the local context. hepatitis b virus and hiv co-infection is associated with: an increased risk of chronic liver disease a higher hbv vl diminished responses to hbv vaccine an increased risk of drug-induced hepatotoxicity a flare of hepatitis within 3 months of commencing art (because of hbv-related iris, which is difficult to differentiate from drug hepatotoxicity). drugs directed against hbv that have no or minimal anti-hiv activity (e.g. entecavir and telbivudine) are largely unavailable or extremely expensive in southern african region. instead, it is usually necessary to use art drugs that also have anti-hbv activity: tdf + 3tc (or ftc). as with hiv, these drugs suppress hbv but do not eradicate it. effective treatment prevents or slows the progression to cirrhosis. for all hiv-infected hbsag-positive patients, the art regimen should include tdf + 3tc (or ftc). using 3tc without including tdf leads to the development of hbv resistance in 80% – 90% of patients after 5 years of treatment. if a patient meets the criteria for switching to a second-line art regimen (to treat hiv), then this combination – tdf + 3tc (or ftc) – should be continued to suppress hbv infection, as interruption of tdf and/or 3tc (or ftc) has been associated with flares of life-threatening hepatitis in case reports. the second-line art regimen should be shaped around these two drugs. in patients with hbv and renal dysfunction, the use of tdf may be considered with dosing frequency adjustment based on crcl (table 24) and more frequent creatinine monitoring. if renal dysfunction is severe or renal function deteriorates with tdf, then 3tc monotherapy or other drugs with anti-hbv activity should be considered. common pitfalls: not continuing with tdf + 3tc (or ftc) combination when switching to second-line art. the second-line art regimen should be shaped around these two drugs. using 3tc without including tdf in the treatment of hiv/hbv co-infected patients. table 24: suggested tenofovir disoproxil fumarate dose adjustment in patients with hepatitis b and renal dysfunction. 21. renal disease antiretroviral drug dose adjustment in renal disease key points ➢ renal function is estimated by the modified cockgraft–gault formula or modification of diet in renal disease (mdrd) formula. ➢ for haemodialysis, the art prescribed should be taken after dialysis. in hiv-positive patients on chronic haemodialysis, there are a number of important art considerations. the nrti class is eliminated through the kidneys; thus, most nrtis require dose adjustment as shown in table 25.86,87,88 for suggested tdf dosing in patients with chronic hepatitis b, see section 20. table 25: antiretroviral drug dose adjustments in renal failure.86,87,88 antiretroviral drug choice and dosing in patients on chronic haemodialysis key points ➢ patients with hiv may develop end-stage renal failure owing to hiv-associated nephropathy or an hiv-unrelated cause, necessitating chronic haemodialysis. ➢ tenofovir disoproxil fumarate can be used in patients on chronic haemodialysis, but with once-weekly dosing which can be difficult for patients to remember. ➢ zidovudine is generally avoided because of anaemia associated with renal failure. ➢ integrase strand transfer inhibitors; and nnrti drugs do not require dose adjustment. ➢ atazanavir concentrations are reduced in patients on haemodialysis to a greater extent than lpv concentrations. ➢ lopinavir/ritonavir requires a twice-daily dosing in patients on haemodialysis. ➢ antiretroviral therapy drugs taken once daily, or the evening doses of drugs taken twice daily, should be given after the haemodialysis session on dialysis days to prevent the drug from being dialysed out. ➢ patients on chronic haemodialysis should be reviewed by a clinician experienced in art management at least 6 monthly to monitor treatment efficacy and side effects and to adjust the regimen when needed. recommendations for antiretroviral therapy for patients on chronic haemodialysis we recommend the following first-line option for patients on chronic haemodialysis: abc (600 mg daily) + 3tc (50 mg first dose and thereafter 25 mg daily) + dtg (50 mg daily). on the days when haemodialysis is performed, the drugs should be given after the haemodialysis session. common pitfall: not giving daily doses or the evening doses of a twice-daily regimen after the haemodialysis session on dialysis days to prevent the drug from being dialysed out. antiretroviral therapy in patients with acute kidney injury key points ➢ in patients with aki, nrti dose adjustments should be implemented based on estimated crcl calculation. ➢ tenofovir disoproxil fumarate should be interrupted even if it is not thought to be the cause of the aki. ➢ re-challenge with tdf may be considered in patients 1-month post-resolution of aki if tdf was not the cause and renal function returns to normal. ➢ in patients with aki who have not yet received art, initiation is preferably deferred until aki has resolved. but avoid significant delays. ➢ once renal function improves (i.e. creatinine is on a downward trend), standard nrti doses should be re-introduced to avoid under-dosing. antiretroviral therapy in acute kidney injury in patients with aki, nrti dose adjustments should be implemented based on estimated crcl calculation (see table 25). tenofovir disoproxil fumarate should be interrupted even if it is not thought to be the cause of aki. care should be taken to identify other drugs that may affect renal function, such as aminoglycoside antibiotics, non-steroidal anti-inflammatory drugs, cotrimoxazole and iodinated radiocontrast; these drugs should be avoided where possible, including temporary discontinuation. once there is clear evidence that renal function is improving (i.e. creatinine is on a downward trend), standard nrti doses should be reintroduced to avoid under-dosing. in patients with aki who have not yet received art, initiation is preferably deferred until aki has resolved. however, art should not be delayed more than 2 weeks for this reason. if renal function does not show any improvement after treating an acute event (e.g. sepsis) and this persists beyond 3 months, then the patient should be assessed for chronic kidney disease and referred to a physician who can evaluate and investigate further. common pitfall: not performing nrti dose adjustment in patients with aki. 22. psychiatric disease key points ➢ dolutegravir may cause insomnia, headache and neuropsychiatric side effects. ➢ zidovudine and ral frequently cause headaches when started, but this usually resolves. ➢ the majority of patients who experience neuropsychiatric features of efv do so within the first 2–6 weeks, and thereafter the drug is better tolerated. late neurological syndromes are described however (see section 4). ➢ most neuropsychiatric effects relating to art occur in the first few weeks of therapy. ➢ depression and other mental illnesses are often undiagnosed or undertreated in hiv-infected individuals and may undermine adherence. ➢ consider avoiding efvand rpv-based regimens in patients with psychiatric illness – these drugs can exacerbate psychiatric symptoms and may be associated with suicidality. mental health, especially mood and behaviour disorder, is associated with non-adherence to art, leading to disability and poorer hiv treatment outcomes. there is a higher prevalence of depression in hiv-positive individuals, with a reported range of 20% – 40% versus 10% in the general population.89 zidovudine and ral frequently cause headaches when started, but this usually resolves after sometime. efavirenz frequently causes neuropsychiatric effects in the first few weeks of therapy, typically presenting with insomnia, vivid dreams and dizziness. both dysphoria and euphoria may occur. fortunately, these features subside in the majority of patients within the first 4–6 weeks. psychosis may occasionally occur. dolutegravir may cause insomnia, headache and neuropsychiatric side effects. raltegravir has been associated with similar central nervous system side effects. common pitfalls: not warning patients starting art about potential neuropsychiatric symptoms. patients must be informed about potential side effects. unnecessary delays in initiating art in patients with psychiatric illness. 23. malaria key points ➢ there are several drug interactions between antimalarial agents and art drugs. ➢ efavirenz has a significant drug interaction with artemether–lumefantrine (coartem) such that artemether (and its active metabolite) and lumefantrine concentrations are lowered, which can lead to failure of antimalarial therapy. consider extending the course of artemether–lumefantrine to 6 days if administered concurrently with efv. ➢ no artemether–lumefantrine dose adjustment is recommended for patients taking pis or instis. ➢ protease inhibitors and nnrtis exhibit several interactions with atovaquone–proguanil (malanil) such that atovaquone concentrations are reduced – atovaquone–proguanil (malanil) is best avoided in patients receiving these drugs. ➢ no significant drug interactions are predicted between instis (dtg) and antimalarial drugs. ➢ quinine is best avoided in patients on pis or nnrtis. there are several drug interactions between antimalarials and art drugs (see table 26). whilst artemether–lumefantrine (coartem) can be administered safely with nvp, efv significantly lowers the concentrations of artemether (and its active metabolite) and lumefantrine, which is likely to increase the risk of failure of antimalarial therapy. there is no clear guideline on how to overcome this interaction, but some experts recommend repeating the 3-day course of artemether–lumefantrine (i.e. treat for 6 days). boosted pis dramatically increase the plasma concentrations of lumefantrine, but a dose reduction is not recommended, as the toxicity threshold of lumefantrine seems to be high. close monitoring for toxicity is recommended when co-administering artemether–lumefantrine with art. table 26: important drug–drug interactions between antimalarial agents and antiretroviral therapy drugs. quinine concentrations are significantly decreased by lpv/r, probably owing to induction of metabolism by rtv. it is likely that quinine concentrations will also be reduced by efv and nvp; therefore, quinine should be avoided in patients receiving pis or nnrtis. patients with severe malaria should receive artesunate, if available, and those with milder malaria should be treated with artemether–lumefantrine. amongst drugs used for chemoprophylaxis, there are no clinically significant pharmacokinetic interactions between arvs and mefloquine or doxycycline. however, mefloquine and efv both cause frequent neuropsychiatric side effects; therefore, doxycycline is the preferred chemoprophylactic agent for patients receiving efv. there are several interactions with atovaquone–proguanil (malanil). atovaquone concentrations are reduced by pis and efv, and also likely by nvp. proguanil concentrations are also reduced by pis and efv. the use of atovaquone–proguanil is therefore best avoided in patients receiving pis or nnrtis. no significant drug interactions are predicted between instis and antimalarial drugs. common pitfalls: not advising patients receiving art on chemoprophylaxis for malaria when travelling to malaria-endemic areas. not providing art recipients with intravenous artesunate or coartem for malaria treatment despite the potential drug interactions. 24. antiretroviral drug-induced liver injury key points ➢ all art classes have been associated with hepatotoxicity and cause injury through an idiosyncratic reaction as the mechanism of injury. ➢ alanine transaminase elevations greater than five times the upper limit of normal (uln) are significant in the absence of symptoms. ➢ in the presence of symptoms of hepatitis, alt elevations greater than 2.5 times the uln are significant. ➢ nevirapine is most frequently associated with dili, with most cases occurring in the first few months after initiation. we no longer recommend nvp initiation. ➢ patients on efv may present with a delayed dili many months after commencing therapy. ➢ re-challenge is best avoided and may be considered in select cases in consultation with a specialist. ➢ if severe hepatitis occurs, or any hepatitis together with a rash, fever or systemic reaction occurs, then re-challenge with nnrtis, abc or ctx should not be attempted. an alt test should be performed in all patients at art initiation. repeat alt testing is indicated in those who develop symptoms or signs suggestive of hepatitis. all arv classes have been associated with hepatotoxicity – most commonly nnrtis. mild alt elevations occur commonly and in general are transient. alanine transaminase elevations greater than five times the uln are significant in the absence of symptoms. in the presence of symptoms of hepatitis, alt elevations greater than 2.5 times the uln are also significant. in such patients, potentially hepatotoxic arvs should be switched to alternative agents. management guidelines are provided in table 27. table 27: guidelines for managing hepatotoxicity. re-challenge may be considered, and in selected cases a specialist should be consulted. if severe hepatitis occurs, or any hepatitis with rash, fever or other systemic manifestation occurs, the opinion of a specialist should be sought. in this situation, re-challenge with nnrtis, abc or ctx should not be attempted. prolonged use of nrtis, especially d4t and ddi (both of which are no longer used), may cause fatty liver. typically, alt concentration is more significantly elevated than aspartate transaminase (ast), and the concentrations of canalicular enzymes gamma-glutamyl transferase (ggt) and alkaline phosphatase (alp) are more elevated than those of the transaminases. non-tender hepatomegaly may be present. ultrasound or computed tomography (ct) imaging may show decreased hepatic density. the condition is not benign, and fibrosis has been reported with long-term ddi use. patients should be advised to avoid alcohol and should be switched to alternative drugs with lower potential for causing fatty liver. in patients with severe hepatitis or jaundice, features of hepatic encephalopathy (i.e. features of hepatic failure) must be clinically assessed, and the international normalised ratio (inr) and serum glucose should be checked. if the concentration of canalicular enzymes is more significantly elevated than that of alt, or if conjugated bilirubin is elevated, then an ultrasound of the liver should be conducted to exclude biliary obstruction. isolated unconjugated hyperbilirubinaemia (drug-induced gilbert’s syndrome) is associated with atv. in this case, all other lfts are normal and the patient has no other symptoms of hepatitis. although this is a benign condition (it does not reflect liver injury, but isolated competitive inhibition of the enzyme in the liver which conjugates bilirubin), it is often cosmetically unacceptable to patients, necessitating a switch from atv to an alternative drug. although efv has been recognised as an infrequent cause of dili since it first became available, a novel pattern of dili associated with the drug has recently been recognised in south africa.25 amongst such patients, many had a particularly severe pattern of liver injury found on liver biopsy (termed ‘submassive necrosis’, and associated with severe jaundice and a raised inr). the overall mortality was 11%. whilst severe efv-related dili is likely to be uncommon, clinicians should be aware of the features observed: the diagnosis of dili was generally made after a longer duration on efv (~ 3–6 months) than what is seen with dili related to nvp or tb medication. the dili was not associated with features of hypersensitivity (e.g. drug rash) and often the first symptom was jaundice rather than abdominal symptoms. once efv was stopped, it typically took several months for lfts to normalise (median resolution > 6 months). we do not advise routine lft monitoring in patients on art, as there is no evidence that this would lead to early detection of this dili or improve outcomes. those managing patients on efv should monitor for symptoms and signs of hepatitis (nausea, vomiting, right-sided abdominal pain or jaundice). if these occur, then alt should be assessed, and the patient should be examined for jaundice. the patient should be managed appropriately for dili if there are hepatitis symptoms with alt > 120 u/l, or if there is jaundice. efavirenz should be switched to an alternative drug (e.g. dtg). many other drugs can cause hepatotoxicity, notably anti-tuberculous agents (including prophylactic isoniazid) and azoles. cotrimoxazole is an uncommon cause of hepatitis, often as part of a systemic hypersensitivity reaction. recommendations for the management of dili in patients receiving tb treatment have been published by the southern african hiv clinicians society in 2013 (see link here).90 common pitfalls: failing to recognise other drugs apart from art as a cause of hepatotoxicity. performing routine lft monitoring in patients on art, in an attempt to detect dili earlier. there is no evidence to support this approach. 25. dyslipidaemia key points ➢ protease inhibitors can cause hypertriglyceridaemia and elevated ldl-c. ➢ atazanavir/ritonavir and drv/r are associated with less significant lipid abnormalities than lpv/r. ➢ efavirenz can cause elevated total cholesterol and mild hypertriglyceridaemia. ➢ dolutegravir does not significantly affect cholesterol. ➢ lipids should be assessed routinely after 3 months on a pi regimen. protease inhibitors can cause hypertriglyceridaemia and elevated ldl-c. atazanavir/ritonavir and once-daily drv/r (800 mg/100 mg drv/r) are associated with less severe dyslipidaemia than other boosted pis; azt can cause mild hypertriglyceridaemia, and efv can cause elevated total cholesterol and mild hypertriglyceridaemia. we suggest that lipids should be assessed routinely after 3 months on a pi regimen. if normal at this stage, then re-assessment should be performed only in those with cardiovascular risk factors. diet and lifestyle modification should always be advised. diet is more effective for controlling hypertriglyceridaemia than hypercholesterolaemia. other cardiovascular risk factors should be addressed. clinicians should consider and investigate secondary causes of hypertriglyceridaemia and hypercholesterolaemia (e.g. diabetes, nephrotic syndrome, alcohol abuse and hypothyroidism). if patients receiving lpv/r develop significant dyslipidaemia, they should be switched to drv/r or atv/r, rather than adding lipid-lowering therapy. however, lipid-lowering therapy is indicated in patients with persistent elevations despite switching to drv/r or atv/r. switching the pi to dtg is another option because dtg has a more favourable lipid profile than pis. however, dtg should only be used in a regimen in which at least one other art drug is known to be fully active. in patients with hyperlipidaemia on efv, the drug should be switched to dtg or rpv. marked hypertriglyceridaemia (> 10 mmol/l) can cause pancreatitis and requires urgent treatment with diet modification (restrict total tg intake to < 30 g/day), fibrates and switching lpv/r to drv/r, atv/r or dtg (fibrates can be stopped after 1 month, followed by reassessment within 4–6 weeks). indications for statin therapy in hiv-positive patients should be the same as in hiv-negative patients, using the framingham heart disease risk score. as a general rule, in young patients with isolated elevated cholesterol but no other cardiovascular risk factors, a threshold of total cholesterol > 7.5 mmol/l (or ldl cholesterol > 5.0 mmol/l) should be used for initiating statin therapy, and the patient should be referred to a lipid clinic for investigation if feasible. in patients with cardiovascular risk factors (e.g. smoking, diabetes and hypertension), decisions should be made using the framingham heart disease risk score. all patients with established atherosclerotic disease (coronary, cerebral or peripheral) or familial hypercholesterolaemia should be started on statin treatment. in addition, type 2 diabetics should also be started on a statin treatment if they have chronic kidney disease, or if they are older than 40 years of age (or have had diabetes for more than 10 years) and have one or more additional cardiovascular risk factors.91 many statins have interactions with pis that can lead to potentially toxic statin concentrations, with the exception of pravastatin and fluvastatin. atorvastatin concentrations are significantly raised by pis, but low doses (maximum 10 mg daily) can be used with monitoring for symptoms of myalgia. lovastatin and simvastatin should not be co-administered with pis, as their concentrations are dramatically increased, and severe rhabdomyolysis has been reported. we also advise against the use of rosuvastatin with pis because of a complex drug–drug interaction; pis increase the plasma concentrations of rosuvastatin whilst reducing their efficacy in the liver. common pitfalls: not routinely assessing lipids whilst the patient is receiving pi-based art. failure to recognise that many statins have interactions with pis that lead to toxic statin concentrations. monitoring of ldl-c in patients on a high-dose statin for secondary prevention. such monitoring is not necessary. 26. immune reconstitution inflammatory syndrome key points ➢ approximately 10% – 20% of patients who start art with advanced immunosuppression experience iris in the first few months of treatment. ➢ two forms of iris have been recognised, namely unmasking and paradoxical iris. ➢ immune reconstitution inflammatory syndrome is most frequently described in association with tb and cm. ➢ integrase strand transfer inhibitors are not associated with an increased risk of tb-iris in clinical trials. ➢ early art initiation (defined as 1–4 weeks after anti-tuberculous therapy) doubles the risk of tb-iris compared with late art initiation (defined as 8–12 weeks after anti-tuberculous therapy), but art should not be delayed for this reason in patients with cd4+ < 50 cells/µl. ➢ there is no confirmatory diagnostic test for iris. ➢ in most instances, art is continued in cases of iris, unless iris is life-threatening (e.g. neurological involvement in tb-iris with depressed level of consciousness). ➢ corticosteroids have been shown to reduce morbidity and improve symptoms in paradoxical tb-iris. approximately 10% – 20% of patients who start art with advanced immunosuppression experience clinical deterioration during the first few months because of iris. most presentations of iris occur within the first 3 months of art. two forms are recognised: unmasking iris occurs in patients who have an unrecognised oi when art is initiated, and who then present with exaggerated inflammatory features of that infection during early art because of it being ‘unmasked’ by recovering immunity. paradoxical iris occurs in patients who are being treated for an oi when they start art, but who develop an immune-mediated worsening or recurrence of features of that infection after starting art. immune reconstitution inflammatory syndrome is most frequently described in association with tb and cm. skin conditions such as molluscum contagiosum and kaposi’s sarcoma may also worsen because of iris. the diagnosis of iris can be difficult, mainly because there is no confirmatory diagnostic test. diagnosis relies on recognition of the characteristic clinical presentation, ensuring that ois are correctly diagnosed, and excluding alternative causes of deterioration, such as drug resistance (e.g. multidrug-resistant tb). case definitions for tb and cryptococcal iris have been published.92,93 it is important to ensure that the underlying oi is treated appropriately. antiretroviral therapy should be continued, unless the iris is life-threatening (e.g. neurological involvement in tb-iris with depressed level of consciousness). corticosteroids have been shown to reduce morbidity and improve symptoms in paradoxical tb-iris,94 and can be used in mycobacterial and fungal forms of iris when other causes of deterioration have been excluded, and particularly when iris features are severe. for paradoxical tb-iris, prednisone can be commenced at a dose of 1.5 mg/kg/day and weaned over 4 weeks, but a longer course may be required if symptoms recur on weaning.95 steroids should not be used in patients with kaposi’s sarcoma. common pitfall: using steroids in patients with kaposi’s sarcoma. prophylactic prednisone key points ➢ patients with active tb and who are improving on tb therapy with a cd4+ count ≤ 100 cells/μl upon starting art can be initiated on prednisone 40 mg daily for 14 days, followed by 20 mg daily for 14 days to prevent paradoxical tb-iris. ➢ the use of prednisone in this context is not associated with high risk of severe infections, cancers or adverse events. the use of prophylactic prednisone for the prevention of paradoxical tb-associated iris in adults with a cd4+ count ≤ 100 cells/μl has been shown in a randomised trial to be associated with a 30% lower relative incidence of tb-iris.96 importantly, this did not come at the expense of any excess risk of severe infections or cancers. the recommended prednisone regimen is 40 mg daily for 14 days, followed by 20 mg daily for 14 days, and prednisone should be started concurrently with art. certain patient groups should be excluded from receiving prednisone; however, including patients with kaposi’s sarcoma and patients with rif-resistant tb, or whose tb has not improved prior to starting art. common pitfall: using prophylactic prednisone in patients who are not improving on tb therapy. 27. opportunistic infection prophylaxis key points ➢ the use of appropriate prophylaxis (primary or secondary) is essential in patients initiating art. ➢ in general, prophylaxis can be discontinued once the cd4+ count has increased to 200 cells/µl, but certain minimal durations of prophylaxis apply for secondary prophylaxis. ➢ local and international guidelines should be consulted. cotrimoxazole primary prophylaxis prophylactic ctx is indicated for hiv-positive patients with a cd4+ count < 200 cells/µl, or with who stage 3 or 4 conditions (including tb). cotrimoxazole offers protection against pneumocystis jirovecii, toxoplasmosis, isosporiasis and certain bacterial infections. the recommended dose is 160 mg/800 mg daily. patients who develop a hypersensitivity reaction to ctx can be given dapsone instead, although this is best avoided if the reaction to ctx is life-threatening. cotrimoxazole can be discontinued once the patient’s cd4+ count is > 200 cells/µl. cotrimoxazole is a common cause of cutaneous and systemic hypersensitivity reactions, indistinguishable from hypersensitivity reactions to art drugs. cotrimoxazole should be interrupted when treating mild suspected nnrti cutaneous hypersensitivity rashes, and permanently discontinued if severe hypersensitivity reactions occur. if ctx is prescribed for secondary prophylaxis or used for primary prophylaxis in those with severe immunosuppression, then an alternative should be substituted. common pitfall: prescribing ctx for newly diagnosed hiv-positive patients with a high cd4+ count (> 200 cells/µl). cryptococcal antigen screening and pre-emptive treatment key points ➢ cryptococcal antigenaemia screening should be performed for all adults or adolescents with a cd4+ count < 200 cells/µl who are initiating or re-initiating art. ➢ reflex laboratory screening is the preferred approach in south africa. ➢ lumbar puncture is recommended for all patients with a new positive crag screening test. screening for subclinical cryptococcal disease has been shown to have a benefit in reducing mortality in hiv-infected patients with a cd4+ count < 200 cells/µl. it is recommended that hiv-seropositive adults or adolescents (≥ 10 years) with a cd4+ count < 200 cells/µl should be screened for crag on serum or plasma by reflex laboratory testing (preferred) or clinician-initiated testing. if the clinician-initiated testing is performed, then it is recommended that screening should be restricted to adults or adolescents without prior cryptococcal disease who are initiating or re-initiating art. for patients with a new positive crag result and an lp that rules out cm, oral fluconazole alone as induction therapy should be given (adults 1200 mg daily for 2 weeks). in these patients with a negative csf crag result, art can be started immediately with fluconazole. patients diagnosed with cm should be managed as per the latest southern african hiv clinicians’ society guideline for the prevention, diagnosis and management of cryptococcal disease among hiv-infected persons: 2019 update. common pitfall: not performing an lp in all patients who are newly diagnosed as crag positive. the absence of any symptoms of meningitis does not exclude cm; approximately one in three patients with asymptomatic antigenaemia has concurrent cm. isoniazid preventive therapy key points ➢ isoniazid preventive therapy should be started at art initiation or added to the treatment regimen of patients already on art who have not yet received ipt, once active tb has been excluded. ➢ there is no need to test for latent tb prior to commencing ipt. ➢ isoniazid preventive therapy should not be started during pregnancy, except in pregnant women where the cd4+ count is < 350 cells/µl and who are at high risk of death from tb. ➢ before commencing ipt, active tb infection should always be excluded. clinical trials conducted in south africa and cote d’ivoire have shown that ipt has an additive effect with art in preventing incident tb in hiv-infected patients.97,98 in the south african trial, there was a 37% reduction in incident tb when patients receiving art were prescribed ipt (vs. placebo) for 12 months. this benefit applied irrespective of tuberculin skin test (tst) status, and the trial included patients established on art. all patients receiving art should be considered for ipt and screened for active tb using a symptom screen99 – ipt should be deferred and investigations should be conducted for active tb if any of the four symptoms (current cough, fever, night sweats or weight loss) is present. in patients receiving ipt, monitoring for neuropathy and hepatitis symptoms should be performed. routine alt monitoring is not indicated, but alt should be tested if hepatitis symptoms occur. a recent trial of ipt in pregnant women receiving art, the tb apprise study, showed that ipt resulted in worse pregnancy outcomes.100 however, this was not confirmed in a larger observational study from the western cape, which showed that ipt use was associated with better pregnancy outcomes, and that incident tb was reduced in women on ipt who had cd4+ counts < 350 cells/µl.101 the duration of ipt is now 12 months irrespective of tst status, as outlined in table 28. table 28: indications for isoniazid preventive therapy (provided that there are no tuberculosis symptoms or contra-indications to isoniazid). 28. adherence patient readiness for antiretroviral therapy key points ➢ each patient commencing art needs to be prepared for treatment before or during early art period. ➢ barriers to adherence (e.g. depression, alcohol use, non-disclosure and food security) and any mis-conceptions about art must be identified in the preparation for art or during the early period of art. preparing patients for lifelong art with good adherence is a critical component of achieving long-term efficacy and preventing treatment resistance. to accommodate counselling, traditionally two or three visits are required, staggered closely together, before art. however, it is now considered acceptable to do some of the counselling during early art rather than delaying initiation (same-day initiation is described in section 6). prolonged delays in commencing art should be avoided. antiretroviral therapy should be delayed only if concerns about adherence are severe enough to outweigh the risk of hiv disease progression. the patient should be provided with details regarding: the benefits of art that art is a life-long therapy the importance of good adherence a list of art side effects relevant to the drugs they will use, including what to do and who to contact if serious side effects occur viral load monitoring on art. the counselling approach should also ensure that the patient has a good understanding of hiv (the virus, the potential clinical complications and transmission) and should cover safer sex practices and address issues related to reproductive health (i.e. family planning, contraception, condom use and pregnancy). clinicians should check family-planning choices at follow-up visits and ensure adequate access to safe and effective contraception. it is important to discuss the concept of ‘undetectable = untransmittable’ with patients and ensure that they have a correct understanding of this concept and that art will only prevent onward transmission if there is optimal adherence with vl suppression. active depression, other mental health issues or substance abuse should be detected actively and treated. a personal treatment plan should be formulated for each patient, specifying drug storage, strategies for missed doses and how to integrate taking medication into their daily routine. the patient must be made aware of scheduling in terms of clinical follow-up. disclosure of hiv status (to a partner and/or other household members) should strongly be encouraged; it is an important determinant of treatment adherence and assists in the provision of patient-directed support. disclosure also identifies exposed contacts for screening and support. this issue needs to be handled carefully in situations where disclosure may have harmful consequences, particularly for women. the patient should be encouraged to join a support group and/or identify a treatment ‘buddy’. however, neither disclosure nor support group participation is a prerequisite for good adherence and should not be a reason for deferring art. clinicians should ensure that they have the contact details of each patient and their treatment buddy. common pitfalls: delaying art because the patient has not completed three clinic visits or not disclosed his or her hiv status. not outlining the goals of art with the patient. these are to: provide maximal and durable suppression of vl restore and preserve immune function reduce hiv-related infectious and non-infectious morbidity prolong life expectancy and improve quality of life prevent onward transmission of hiv minimise adverse effects of the treatment. support and counselling key points ➢ success of art hinges on how well the tablets are taken; at least 90%, preferably more, of treatment doses need to be taken. ➢ support should be provided to ensure high levels of treatment adherence. ➢ none of the commonly used firstand second-line options have meaningful food restrictions. ➢ delayed dosing is rarely a problem; even if out by many hours, most of the drugs have long half-lives, and patients should be encouraged and supported to take their dose once they remember to do so in these instances. ➢ disclosure is not a prerequisite for art. ➢ heavy alcohol use may affect adherence and may potentiate art hepatotoxicity and other hepatic pathology; however, responsible alcohol use is not prohibited in patients established on or starting art. patients should be informed about the benefits of art and that side effects are usually minor and transient, or manageable. they should be given a treatment plan, specifying the drugs to be used (with names and details including the appearance of each drug, when and how they are to be taken, and a brief indication of anticipated side effects and toxicity). the causes of poor adherence are often complex and linked to social issues. common causes are outlined in table 29. common pitfalls: not informing patients about the benefits of art. this includes not only reduced mortality and morbidity, but also prevention of hiv transmission. not informing patients that side effects are usually minor and transient, or manageable. not advising patients on how to deal with delayed dosing. not providing patients with a treatment plan specifying the drugs to be used. table 29: possible reasons for poor adherence. 29. acknowledgements the authors would like to acknowledge the southern african hiv clinicians society for their support. competing interests the authors have declared that no competing interests exist. authors' contribution j.n., s.d. and g.m. constituted the writing committee and were the primary authors of the manuscript. the other authors reviewed the manuscript and offered constructive criticisms. ethical consideration this article followed all ethical standards for carrying out research without direct contact with human or animal subjects. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability statement data sharing is not applicable to this article, as no new data were created or analysed in this study. disclaimer specific recommendations provided here are intended only as a guide to clinical management, based on expert consensus and best current evidence. treatment decisions for patients should be made by their responsible clinicians, with due consideration of individual circumstances. the most current version of this document should always be consulted. 30. abbreviations /r ritonavir-boosted 3tc lamivudine abc abacavir adr adverse drug reaction aki acute kidney injury alp alkaline phosphatase alt alanine transaminase art antiretroviral therapy arv antiretroviral ast aspartate transaminase atv atazanavir atv/r atazanavir/ritonavir azt zidovudine bd twice daily cd4+ cluster of differentiation 4 cm cryptococcal meningitis crag cryptococcal antigen crcl creatinine clearance rate csf cerebrospinal fluid ct computed tomography ctx cotrimoxazole cvs cardiovascular cyp cytochrome p450 d4t stavudine ddi didanosine dili drug-induced liver injury dna deoxyribonucleic acid drv darunavir drv/r darunavir/ritonavir dtg dolutegravir egfr estimated glomerular filtration rate elisa enzyme-linked immunosorbent assay etr etravirine fbc full blood count ftc emtricitabine ggt gamma-glutamyl transferase gi gastrointestinal hb haemoglobin hbsag hepatitis b surface antigen hbv hepatitis b virus hiv human immunodeficiency virus icu intensive care unit inr international normalised ratio insti integrase strand transfer inhibitor ipt isoniazid preventive therapy lam lipoarabinomannan ldl-c low-density lipoprotein cholesterol lp lumbar puncture lpv lopinavir lpv/r lopinavir/ritonavir mdrd modification of diet in renal disease mvc maraviroc ngt nasogastric tube nnrti non-nucleoside reverse transcriptase inhibitor nrti nucleoside reverse transcriptase inhibitor ntds neural-tube defects ntrti nucleotide reverse transcriptase inhibitor nvp nevirapine oi opportunistic infection pcr polymerase chain reaction pi protease inhibitor pi/r ritonavir-boosted ritonavir pmtct prevention of mother-to-child transmission of hiv ppis proton pump inhibitors prep pre-exposure prophylaxis ral raltegravir rcts randomised controlled trials rif rifampicin rfb rifabutin rna ribonucleic acid rpv rilpivirine rtv or /r ritonavir scr serum creatinine scrag serum cryptococcal antigen taf tenofovir alafenamide tam thymidine analogue mutation tb tuberculosis tb-iris tuberculosis immune reconstitution inflammatory syndrome tbm tuberculosis meningitis tc total cholesterol tdf tenofovir disoproxil fumarate tg triglycerides tst tuberculin skin test uln upper limit of normal vl viral load who world health organization wocp women of childbearing potential 31. references johnson lf, mossong j, dorrington re, et al. life expectancies of south african adults starting antiretroviral treatment: collaborative analysis of cohort studies. plos med. 2013;10(4):e1001418. 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safety results of the castle study. j acquir immune defic syndr. 2010;53(3):323–332. https://doi.org/10.1097/qai.0b013e3181c990bf johnson m, grinsztejn b, rodriguez c, et al. 96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. aids. 2006;20(5):711–718. boyd ma, moore cl, molina jm, et al. baseline hiv-1 resistance, virological outcomes, and emergent resistance in the second-line trial: an exploratory analysis. lancet hiv. 2015;2(2):e42–e51. https://doi.org/10.1016/s2352-3018(14)00061-7 hill am, venter f. the unexpected success of nrtis in second-line treatment. lancet infect dis. 2018;18(1):3–5. https://doi.org/10.1016/s1473-3099(17)30631-x yazdanpanah y, fagard c, descamps d, et al. high rate of virologic suppression with raltegravir plus etravirine and darunavir/ritonavir among treatment-experienced patients infected with multidrug-resistant hiv: results of the anrs 139 trio trial. clin infect dis. 2009;49(9):1441–1449. moorhouse m, maartens g, venter wdf, et al. third-line antiretroviral therapy program in the south african public sector: cohort description and virological outcomes. j acquir immune defic syndr. 2019;80(1):73–78. https://doi.org/10.1097/qai.0000000000001883 grinsztejn b, hughes md, ritz j, et al. third-line antiretroviral therapy in low-income and middle-income countries (actg a5288): a prospective strategy study. lancet hiv. 2019;6(9):e588–e600. meintjes g, dunn l, coetsee m, et al. third-line antiretroviral therapy in africa: effectiveness in a southern african retrospective cohort study. aids res ther. 2015;12:39. https://doi.org/10.1186/s12981-015-0081-8 gandhi rt, tashima kt, smeaton lm, et al. long-term outcomes in a large randomized trial of hiv-1 salvage therapy: 96-week results of aids clinical trials group a5241 (options). j infect dis. 2019;221:1407–1415. https://doi.org/10.1093/infdis/jiz281 stevens ws, wallis cl, sanne i, venter f. will etravirine work in patients failing nonnucleoside reverse transcriptase inhibitor-based treatment in southern africa? j acquir immune defic syndr. 2009;52(5):655–656. meintjes g, brust jcm, nuttall j, maartens g. management of active tuberculosis in adults with hiv. lancet hiv. 2019;6(7):e463–e474. https://doi.org/10.1016/s2352-3018(19)30154-7 dooley ke, kaplan r, mwelase n, et al. dolutegravir-based antiretroviral therapy for patients co-infected with tuberculosis and hiv: a multicenter, noncomparative, open-label, randomized trial. clin infect dis. 2019;70:549–556. https://doi.org/10.2139/ssrn.3244943 la porte cj, colbers ep, bertz r, et al. pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers. antimicrob agents chemother. 2004;48(5):1553–1560. decloedt eh, maartens g, smith p, merry c, bango f, mcilleron h. the safety, effectiveness and concentrations of adjusted lopinavir/ritonavir in hiv-infected adults on rifampicin-based antitubercular therapy. plos one. 2012;7(3):e32173. davies g, cerri s, richeldi l. rifabutin for treating pulmonary tuberculosis. cochrane database syst rev. 2007(4):cd005159. https://doi.org/10.1002/14651858.cd005159.pub2 hennig s, svensson em, niebecker r, et al. population pharmacokinetic drug-drug interaction pooled analysis of existing data for rifabutin and hiv pis. j antimicrob chemother. 2016;71(5):1330–1340. https://doi.org/10.1093/jac/dkv470 bartlett jg, gallant je, pham pa (eds). medical management of hiv infection. 15th ed. baltimore, md: john hopkins university press, 2009–2010; 556 pp. gilbert dn, moellering rc, eliopoulos gm, et al. (eds). the sanford guide to antimicrobial therapy. 42nd ed. sperryville, virginia: antimicrobial therapy, inc., 2012; 232 pp. hiv medicine association of the infectious diseases society of america. clinical practice guideline for the management of chronic kidney disease in patients infected with hiv: 2014 update. clin infect dis. 2014;59(9):e96–e138. van coppenhagen b, duvenage hs. prevalence of depression in people living with hiv and aids at the kalafong provincial tertiary hospital antiretroviral clinic. s afr j psychiatr. 2019;25:1175. jong e, conradie f, berhanu r, et al. consensus statement: management of drug-induced liver injury in hiv-positive patients treated for tb. s afr j hiv med. 2013;14(3):7. https://doi.org/10.4102/sajhivmed.v14i3.63 semdsa type 2 diabetes guidelines expert committee. semdsa 2017 guidelines for the management of type 2 diabetes mellitus2017 [homepage on the internet] [cited 2020 june 1]. available from: https://www.semdsa.org.za/images/647-4385-1-pb.pdf haddow lj, colebunders r, meintjes g, et al. cryptococcal immune reconstitution inflammatory syndrome in hiv-1-infected individuals: proposed clinical case definitions. lancet infect dis. 2010;10(11):791–802. meintjes g, lawn sd, scano f, et al. tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. lancet infect dis. 2008;8(8):516–523. https://doi.org/10.1016/s1473-3099(08)70184-1 meintjes g, wilkinson rj, morroni c, et al. randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. aids. 2010;24(15):2381–2390. https://doi.org/10.1097/qad.0b013e32833dfc68 meintjes g, sonderup mw. a practical approach to the diagnosis and management of paradoxical tuberculosis immune reconstitution inflammatory syndrome. contin med educ. 2011;29(10):410–417. meintjes g, stek c, blumenthal l, et al. prednisone for the prevention of paradoxical tuberculosis-associated iris. n engl j med. 2018;379(20):1915–1925. https://doi.org/10.1056/nejmoa1800762 rangaka mx, wilkinson rj, boulle a, et al. isoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trial. lancet. 2014;384(9944):682–690. https://doi.org/10.1016/s0140-6736(14)60162-8 group tas, danel c, moh r, et al. a trial of early antiretrovirals and isoniazid preventive therapy in africa. n engl j med. 2015;373(9):808–822. https://doi.org/10.1056/nejmoa1507198 getahun h, kittikraisak w, heilig cm, et al. development of a standardized screening rule for tuberculosis in people living with hiv in resource-constrained settings: individual participant data meta-analysis of observational studies. plos med. 2011;8(1):e1000391. https://doi.org/10.1371/journal.pmed.1000391 gupta a, montepiedra g, aaron l, et al. isoniazid preventive therapy in hiv-infected pregnant and postpartum women. n engl j med. 2019;381(14):1333–1346. https://doi.org/10.1056/nejmoa1813060 kalk e, heekes a, mehta u, et al. safety and effectiveness of isoniazid preventive therapy in hiv-positive pregnant women on art: an observational study using linked population data. clin infect dis. 2020. https://doi.org/10.1093/cid/ciz1224 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 1 imagine a small gathering. gradually, word spreads and the intimate affair turns into a fulcrum of activity. from a handful of friends, hundreds of people join, bringing strobe lights, powerful loudspeakers and copious amounts of food. the party, one of the most successful ever held, lasts through the night. then the lights are turned on, the cops arrive and the party grinds to a halt. no more parties are allowed, ever again. it is perhaps crude to depict the struggle to get hiv/ aids on the global agenda as a successful party being busted. the hiv/aids ‘community’ – for lack of a better word to describe a disjointed group of people focusing on a common challenge – is, however, a victim of its own success. in the 2000s it managed to rally immense political support and mobilise unprecedented financial and human resources. nowadays, the luxury of that precious capital is no longer there. new priorities are occupying the global community, and hiv/aids is being treated like a scolded child who has squandered both parental trust and pocket money. in this context, a contemplative book like aids: taking a long-term view is particularly necessary. the short, easy-to-read monograph takes a critical look at the field of hiv/aids policy from 1981 until today, 30 years after the virus was first reported. it explains and summarises, in layman’s terms, what the road ahead for hiv looks like. it serves as a useful resource for students of health policy as well as engaged policy makers. ‘it is fair to ask whether the global aids effort has always achieved good value for its money,’ suggests one of the chapters. ‘despite a more than 53-fold increase in aids funding in barely over a decade, the epidemic continues to outpace the rate at which programs are delivering.’ these are indeed sobering estimates. not only are such mind-boggling increases in funding unlikely to recur, but needs for such funds will certainly keep escalating. in light of this, a healthy degree of soul-searching is needed, and the book provides just that. the book succinctly takes stock of what the world of hiv has achieved, what it could have done differently, and what it should do today to ensure that 2031, the anniversary marking 50 years since aids was first reported, will be a party and not a funeral. in so doing, the group of academics and high-level practitioners that authored it – the aids2031 consortium – provides a much-needed vision going forward. the key argument is that the aids community needs to shift from its current short-term thinking to a longer-term action plan. unlike the global campaign against climate change, which has always adopted a long-term view, the reaction to the hiv epidemic was initially framed as an emergency response. from the start, hiv was portrayed as a catastrophe waiting to happen; its complex social and behavioural determinants, which could only be addressed in the long run, were not deemed as crucial as the here-and-now. it is no coincidence, for instance, that the hiv/aids co-ordinating body for swaziland, a country with one of the highest hiv prevalence rates in the world, was named the national emergency response council on hiv and aids (nercha). part of the hiv community’s success in mobilising unprecedented amounts of funds in such a limited time is no doubt due to this approach. nevertheless, this strategy is now back-firing. millions of people have been placed on arvs and thousands of new programmes have sprung up as a result of pepfar and global fund money, but now that the tide has changed and future funding is uncertain, sustainability poses a massive challenge. the book brings together the work of nine working groups focusing on modelling, social drivers, programmes, financing and leadership, among other things. it compiles the current consensus – arrived at following a long and serious consultative process – on all the key aspects of the epidemic into a single document. in so doing, the book does not actually tell us anything new. as the authors suggest, we should focus on prevention, and improve the efficiency of spending on hiv. we must ensure greater donor co-ordination and come up with innovative financing mechanisms and incentive schemes such as advance market commitments, in order to encourage research and investments in the right places. we must devote ourselves to finding and funding more easily administered and longer-lasting first-line treatment. this is particularly important if we are to prevent resistance from developing, particularly in lowresource countries where affordability and availability of second-line drugs are particularly challenging. the authors also suggest that donor funding must focus on low-income/high-prevalence countries, while middleincome countries should be encouraged to finance their hiv/aids services using national resources. given the extent of the hiv problem in sub-saharan africa, the book also highlights a need to institutionalise aids as a political issue. in high-prevalence countries like south africa, an annual parliamentary debate on aids should be mandatory. social activism, which aids: taking a long-term view. the aids2031 consortium. new jersey: ft press science, december 2010. pp. 224. isbn-10: 0-13-217259-3. isbn-13: 978-0-13-217259-2. b o o k r e v i e w 47 a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e was instrumental in obtaining public provision of arvs in the country, needs to play its role in ensuring that hiv remains at the forefront of political debate. the monograph also places the fight against hiv in historical perspective; the past teaches us that hiv must be tackled from all angles at once in order for it to be defeated. ‘virtually every major public health success has been built on a combination of behavioral, biomedical, social and structural approaches,’ point out the authors, citing the campaign against smoking as a key example. in the absence of game-changers – such as the discovery of an effective vaccine, new drugs, or even a cure – our efforts to steer clear of ‘business as usual’ must be strengthened. in sum, none of these recommendations is revolutionary, and that is exactly what is most significant about the book. it tells us what we know we should be doing but aren’t doing. the greatest challenge in 2011 will be to ensure that these recommendations don’t fall on deaf ears. if they do, in 2031 we will find ourselves the victims of a bad hangover at the end of another busted party. ilaria regondi alan whiteside 48 levels.html original article levels of procalcitonin, c-reactive protein and neopterin in patients with advanced hiv-1 infection p bipath, msc m viljoen, phd, phd department of physiology, school of medicine, faculty of health sciences, university of pretoria p f levay, msc, mb chb, mmed (internal) department of internal medicine, kalafong hospital and school of medicine, faculty of health sciences, university of pretoria corresponding author: m viljoen (mviljoen@webafrica.org.za) objectives. to compare the value of procalcitonin, c-reactive protein (crp) and neopterin as indicators of immune deficiency, co-infection, efficacy of treatment, and disease progression, in patients with advanced hiv-1 infection. design. cross-sectional, investigating baseline blood measurements and clinical observations in 82 hiv-positive patients divided into an antiretroviral treatment (art) group and an art-naïve group. setting. secondary general hospital in pretoria. results. procalcitonin and crp levels showed no significant differences between the art and art-naïve groups, and no correlations with cd4 counts or viral loads. crp levels were significantly higher with tb co-infection (p<0.05). neopterin levels were raised above normal in 92% of the art-naïve group and in 75% of the art group. the levels were significantly higher (p<0.05) in the artnaïve group. negative correlations were found between neopterin and cd4 counts for the total patient group (r=-0.482; p<0.001). neopterin was significantly (p<0.05) higher in the hiv/tb co-infection group than in those without tb. higher neopterin levels at baseline were associated with a decline in cd4 counts over the ensuing 6-month period, and patients with higher baseline neopterin levels developed more complications over the 6-month period. conclusions. compared with procalcitonin and crp, neopterin appears to be associated with the degree of immunodeficiency and of co-infection with tb. neopterin levels may be investigated further as a measure of disease progression or treatment response. s afr j hiv med 2012;13(2):78-82. procalcitonin, c-reactive protein (crp) and neopterin are three of the markers most commonly used, with varying degrees of success, as diagnostic or prognostic indicators to monitor disease progression and to estimate the efficacy of therapeutic interventions in infectious diseases and non-infectious inflammatory conditions. all three are, to a lesser or greater extent, used among hiv-positive patients. procalcitonin is the pro-hormone of calcitonin. in normal conditions, transcription of the procalcitonin gene occurs in the c-cells of the thyroid under conditions of hypercalcaemia and neoplastic disease.1 however, in the presence of bacterial infection or endotoxins, virtually all cells produce calcitonin precursors.1 recent indications are that, in infectious or inflammatory conditions, procalcitonin may in fact be considered an acute phase reactant, with the liver being the major source of procalcitonin.2 procalcitonin levels increase in certain pro-inflammatory conditions, especially bacterial infections, but are thought not to show significant increases with viral and non-infectious inflammatory conditions.3 the levels are often used to differentiate between patients with sepsis and those with systemic inflammatory response syndrome (sirs).4 procalcitonin levels have been recommended for distinguishing between bacterial and non-bacterial infections, and therefore as a guideline in the prescription of antibiotics.5 , 6 one disadvantage in the use of procalcitonin is that the levels in healthy individuals are below the reliable detection limit (10 pg/ml) of most clinical assays. c-reactive protein is an acute-phase protein, and its levels are upregulated in viral, bacterial and fungal infections, as well as in non-infectious inflammatory conditions. the cytokine profile found with raised crp levels is predominantly pro-inflammatory, and crp levels are often used as a non-specific indicator of inflammatory activity, irrespective of the cause.7 the levels of crp in bacterial and viral infections differ, and high levels (e.g. >100 mg/l) can be found with bacterial infections, while lower levels (usually <10 mg/l) are more commonly associated with viral infections.8 as an acute-phase reactant, macrophageand perhaps adipocyte-derived il-6 is a major stimulant for the production of crp, and liver failure is the major cause for a decline in crp synthesis.9 , 10 neopterin (6-d-erythro-hydroxy propyl pteridine) is a catabolic product of the purine nucleotide guanosine triphosphate. neopterin is produced in macrophages from guanosine 5’-triphosphate (gtp) which is cleaved by gtp-cyclohydrolase 1 to 7,8-dihydroneopterin triphosphate, followed by conversion of 7,8-dihydroneopterin triphosphate to neopterin and 7,8-dihydroneopterin under the influence of phosphatases.11 gtp-cyclohydrolase 1 is stimulated, predominantly, by t-helper cell type-1 derived interferon-g, but co-stimulation by tumour necrosis factor alpha may contribute.11 neopterin is used as indicator of both macrophage function and cell-mediated immunity. when cell-mediated immunity dominates, circulating neopterin levels are usually high and, when humoral immunity dominates, neopterin levels are low.11 increased neopterin levels are found with viral infections, intracellular bacterial infections, intracellular parasites, a number of auto-immune diseases, malignancies, rheumatoid arthritis, systemic lupus erythromatosus, acute cellular graft rejection or graft-v.-host disease, and in almost every condition where cellular immunity dominates.12 , 13 in hiv-1 infection, serum neopterin has been described as an immune activation marker and predictor of disease progression.14 in hiv/aids, plasma hiv-1 rna concentration reveals the degree of viral replication, and cd4 counts reflect the degree of immune deficiency and, it is speculated, end-organ damage. the outcome is, however, largely influenced by the co-existence of other complications, especially co-infection with tb. although viral load and cd4 counts are considered the diagnostic gold standards for hiv, soluble markers may add valuable information about immune activation status and prognosis. in addition, cost-effective reliable serum markers would be of benefit in resource-limited settings where restrictions are placed on the frequency of laboratory investigations such as viral loads. the aim of this investigation was to compare the associations of procalcitonin, c-reactive protein and neopterin and measures of hiv disease status and co-infection with tb. methods hiv-positive outpatients were randomly recruited from the immunology clinic at the kalafong hospital, pretoria. the study took place during 2010 2011, and patients were followed-up 6 months after baseline, wherever possible. informed consent was obtained from 82 adult patients who were attending the clinic on a friday, who freely gave informed consent to take part, and who were not ruled out by the exclusion criteria. exclusion criteria included patients <18 years of age, patients with cd4 counts >400 cells/µl, patients on antiretroviral treatment (art) for <2 months, treatment defaulters from the art group and, for the art-naïve group, patients previously on any art. ethical approval was obtained from the faculty of health sciences research and ethics committee, university of pretoria. the patients were firstly divided into a group on active art (n=57) and a group not on art (art-naïve; n=25). the art group was further subdivided into groups depending on their time on treatment prior to baseline investigation (2 months 1 year; 1 2 years, and >2 years). at the 6-month follow-up, patients were subdivided into 2 groups according to baseline neopterin levels, and the groups were compared in terms of the cd4 counts and development of complications diagnosed by the attending physician and confirmed by the specialist involved in the study. blood specimens collected at baseline were centrifuged on site; plasma aliquots were stored at -70oc until analysis. procalcitonin (raybiotech inc., usa) and neopterin (immuno-biological laboratories inc., usa) were measured by commercial enzyme-linked immune-absorbent assay (elisa) kits. crp and other routine blood investigations (cd4 count, wbc count, haemoglobin etc.) at baseline were determined according to standard procedures of the national health laboratory service (nhls), and results were extracted from the laboratory reports and patient files. student’s t-test and nonparametric mann-whitney u-test were used to determine group differences. kruskal-wallis one-way anova indicated variance across multiple groups. correlations were determined by regression analysis and spearman rank correlation co-efficient. statistical analysis was performed using ncss/pass (hintze j 2001) software, and all testing was done at a significance level <0.05 unless otherwise specified. results the demographic profiles for the patient groups are presented in table 1. the 2 groups were comparable in age, body mass index (bmi), gender distribution, race and employment status. results of the baseline blood measurements and the comparison between the art and art-naïve groups are presented in table 2. neopterin levels were significantly higher (p=0.0096) in the art-naïve group than in the art group. negative correlations were found between neopterin and cd4 counts for the total group of patients (r=-0.482; p<0.0001; n=82), as well as for the art group (r=-0.451; p=0.0045; n=57). neopterin also correlated negatively with haemoglobin levels for the total patient group (p=-0.597; p<0.0001; n=82). six months after the baseline measurements, 47 of the original 82 patients were still available and could be followed up with regard to cd4 counts and the development of complications. a comparison between patients with complications and those without complications, at baseline and at follow-up, is shown in table 3. additional complications at follow-up consisted of tb (n=6, 2 of whom had extrapulmonary disease); pneumonia (n=5); severe lymphadenopathy (n=4); cardiac/renal disease (n=4) and haematological complications such as anaemia, thrombocytosis or neutrophilia (n=10). the relationship between neopterin and cd4 counts over the 6-month period following the baseline assessments was examined. patients who developed additional complications, stopped taking anti-retroviral drugs or art-naïve patients who started art during this period were excluded. seven patients stopped art over this period; the reasons included non-compliance and drug side-effects. this cessation resulted in a drastic decline in sample sizes, i.e. 11 patients (8 on art) had a decrease, and 9 (all on art) had an increase in cd4 over the period. mean baseline neopterin was significantly higher in the patients whose cd4 counts were decreased at follow-up (35.09 v. 10.82 nmol/l; p=0.035). in the group whose cd4 counts decreased over the 6-month period, baseline neopterin levels correlated negatively with both baseline cd4 count (r=-0.68; p=0.03) and follow-up cd4 count (r=-0.58; p=0.07). as shown in fig. 1, the patients were subdivided into groups according to the period of time they had been on treatment prior to the baseline investigations. analysis of variance showed that neopterin levels were significantly (p<0.01) lower and cd4 counts significantly higher (p<0.001) in the patients who had been on treatment >1 year. discussion this study examined the associations of 3 laboratory markers of disease in hiv-positive patients. the key findings are that neopterin is more strongly associated with the degree of immunodeficiency and of co-infection with tb than crp or procalcitonin. higher neopterin levels at baseline were associated with a decline in cd4 counts and the development of more complications over the ensuing 6-month period. limitations of this study include the fact that not all patients could be traced for the 6-months follow-up, that the groups became progressively smaller as patients who had a change in treatment over this period were excluded from the statistical comparisons, and that disease progression could only be estimated from cd4 counts and not viral loads. the results of this study suggest that crp levels are not specifically associated with immune deficiency, the effects of art, or disease progression. these results are in agreement with those of a study in india in which crp measurement in hiv-positive patients was found neither to be of value as diagnostic aid nor as prognostic marker in hiv/aids.15 however, in view of the fact that crp levels in hiv-positive individuals are generally significantly lower in viral than in bacterial infection, significantly raised levels of crp could be an indication to investigate for a possible co-infection, keeping in mind that other conditions marked by a pronounced pro-inflammatory response can also lead to increases in the levels of crp. this finding is in line with the results of a south african study by wilson et al. who showed that normal crp levels, in combination with clinical evaluation, could be useful to rule out tb in populations with a high prevalence of hiv.16 procalcitonin (pct) is known for its increase in bacterial infections and is used by some to differentiate between viral and bacterial infections.17 one explanation as to why procalcitonin levels remain low in purely viral infections is based on the fact that the production of pct is primarily stimulated by tumour necrosis factor. it is suggested that increases in procalcitonin do not occur with viral infections because alpha interferon, synthesised as a result of viral infections, inhibits synthesis of tumour necrosis factor.1 should this be true, the question remains whether procalcitonin would be of much use for the detection of bacterial co-infection in hiv-positive patients. in developing countries such as south africa, co-infections with tb and other bacterial infections in hiv-positive individuals are common – even major sources of morbidity and mortality – especially at cd4 counts <200 cells/µl. the level of circulating pct in normal healthy individuals is generally below the limit of detection (10 pg/ml) of most clinical assays.18 according to sensitive research assays, the normal level for plasma/serum pct is 33±3 pg/ml.1 the analytical sensitivity for the assay of this study was typically below 30 pg/ml and, from linear extrapolation, individual pct levels were all >10 pg/ml. however, the mean pct levels for the total group of patients were normal, with no significant difference between the art and art-naïve groups, and no significant correlations between pct and cd4 counts or viral loads. although the value of pct as a reliable marker of active tb has on occasion been questioned,19 the overriding assumption is that pct is indeed a valuable marker of mycobacterium tuberculosis in non-immunocompromised patients.20 the procalcitonin findings of this study are in line with studies that showed suppression of the procalcitonin response in hiv-positive individuals.20 , 21 although some diagnostic and prognostic value for the measurement of pct in hiv/tb-co-infection has been described in a south african study, only 58% of their hiv-positive patients with tb had pct levels marginally above 100 pg/ml.22 this is, in view of better performing markers, not adequate for clinical use in individual patients. although procalcitonin induction in hiv-positive individuals is known to occur in sepsis, and reports exist of significant increases in procalcitonin in pneumococcal and a number of other non-viral infections,23 it would appear that secondary infections in hiv-positive patients do not in general trigger overt increases in procalcitonin synthesis,21 , 23 provided that the infections are localised or organ-related without systemic inflammation. neopterin levels were increased above normal (10 nmol/l) in 92% of the art-naïve group and in 75% of the art group. the levels were significantly higher (p<0.01) in the art-naïve group and were inversely associated with cd4 counts. these results confirm the value of neopterin levels as a reflection of the degree of immunodeficiency. fig. 1 shows the increase in cd4 counts that occurred over the same periods on art as the decrease in neopterin. this implication (that neopterin may be an indicator of the efficacy of art) warrants further investigation. among the 18 patients (>26% of the study population; 50% on art) in whom active tb-co-infection was confirmed at the baseline investigations, neopterin levels were significantly higher (p<0.001), and cd4 counts significantly lower (p=0.028), than among the patients without tb co-infection. these results are in agreement with previous indications that neopterin levels are significantly higher in hiv-positive patients with tb-co-infections and that, although neopterin levels may decrease with anti-tb therapy, high levels of neopterin persist with progression of the immune deficiency and a poor prognosis.24 as neopterin levels reflect the degree of immune deficiency in hiv-positive patients, and perhaps the response to art, the question was asked whether neopterin has indeed, as claimed elsewhere, prognostic value concerning disease progression.25 baseline neopterin was significantly higher (p<0.01) in the group of patients in whom other complications were present 6 months after baseline investigations, than patients who progressed well (53.9±39.9 v. 10.8±7.6 nmol/l; p<0.01). when all patients who stopped art over the 6-month period were excluded, the mean neopterin levels were significantly higher in the group with complications than in the group without complications (59.29 v. 30.9 nmol/l; p=0.018). when those patients who did not change antiretroviral status were split into groups, the mean neopterin levels were significantly higher in the group that developed complications than those who did not, both for the art (45.9 v. 24.13 nmol/l; p=0.04) and the art-naïve (75.02 v. 30.99 nmol/l; p=0.001) groups. although these results do not necessarily imply a direct relationship, they warrant further investigation. the possibility that neopterin levels could perhaps be predictive of disease progression was further examined by looking at the changes in cd4 counts. the baseline neopterin values were compared between patients whose cd4 counts decreased and those that increased over the 6-month period following baseline assessments. to minimise the number of confounding factors, any patient who had additional complications or a change in art during the 6 months was excluded. this resulted in a drastic decline in sample sizes, i.e. 11 patients (8 on art) had a decrease, and 9 (all on art) had an increase in cd4 counts over the period. mean baseline neopterin levels were significantly higher in patients whose cd4 counts decreased, and significantly lower in patients whose cd4 counts increased. in the group whose cd4 count decreased over the 6-month period, baseline neopterin levels correlated with both baseline cd4 counts (r=-0.68; p=0.03) and follow-up cd4 counts (r=-0.58; p=0.07). although the group divisions, owing to the exclusion criteria, were small, the association of neopterin levels with cd4 counts is nonetheless seen. these results warrant further investigation into the value of neopterin as a possible predictor of disease progression. in view of the stimulatory role of ifn-γ in neopterin synthesis,11 the link between chronic elevation of ifn-γ and hiv-1 progression, as well as the active role of neopterin in the disease,25 the value of neopterin is not surprising. neopterin has previously been described as one of the better immunological markers in patients with hiv-1 infections.14 , 25 it has even been said that neopterin levels increase before other markers of hiv infections have risen.25 in the present study, 40% of art, and 75% of art-naïve, patients had cd4 counts <200 cells/µl, and all had cd4 counts <400 cells/µl. therefore, with regard to patients in the advanced stages of the disease, the results of this study support the notion of neopterin as an inexpensive indicator of cd4 status and as an indicator of bacterial co-infection. the results warrant further investigation into neopterin as an indicator of disease progression and of the success of art. acknowledgements.financial support was received from the medical research council of south africa (mrc grant a0s541) and the south african sugar association (sasa grant 213). references 1. gilbert dn. use of plasma procalcitonin levels as an adjunct to clinical microbiology. j clin microbiol 2010;48(7):2325-2329. [http://dx.doi.org/10.1128/jcm.00655-10] [pmid:20421436]. 1. gilbert dn. use of plasma procalcitonin levels as an adjunct to clinical microbiology. j clin microbiol 2010;48(7):2325-2329. [http://dx.doi.org/10.1128/jcm.00655-10] [pmid:20421436]. 2. nijsten mw, olinga p, the th, et al. procalcitonin behaves as a fast responding acute phase protein in vivo and in vitro. crit care med 2000;28(2):458-61. [http://dx.doi.org/10.1097/00003246-200002000-00028] [pmid:10708183]. 2. nijsten mw, olinga p, the th, et al. procalcitonin behaves as a fast responding acute phase protein in vivo and in vitro. crit care med 2000;28(2):458-61. [http://dx.doi.org/10.1097/00003246-200002000-00028] [pmid:10708183]. 3. gendrel d, bohuon c. procalcitonin as a marker of bacterial infection: cme review article. pediatr infect dis j 2000;19(8):679-688. 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[http://dx.doi.org/10.1084/jem.160.1.310] [pmid:6429267]. 13. yanchun l, zhidong h. significance of humoral neopterin in clinical diagnosis and prognosis. j med col pla 2011;26:45-51. [http://dx.doi.org/10.1016/s1000-1948(11)60026-9]. 13. yanchun l, zhidong h. significance of humoral neopterin in clinical diagnosis and prognosis. j med col pla 2011;26:45-51. [http://dx.doi.org/10.1016/s1000-1948(11)60026-9]. 14. midvan d, spritzler j, sidney e, et al. serum neopterin, an immune activation marker, independently predicts disease progression in advanced hiv-1 infection. clin infect dis 2005;40:853-858. [pmid:15736019]. 14. midvan d, spritzler j, sidney e, et al. serum neopterin, an immune activation marker, independently predicts disease progression in advanced hiv-1 infection. clin infect dis 2005;40:853-858. [pmid:15736019]. 15. kannangai r, kandathil aj, ebenezer dl, et al. usefulness of alternate prognostic serum and plasma markers for antiretroviral therapy for human immunodeficiency virus type 1 infection. clin vac immunol2008;15(1):154-158. [http://dx.doi.org/10.1128/cvi.00193-07] [pmid:18003813]. 15. kannangai r, kandathil aj, ebenezer dl, et al. usefulness of alternate prognostic serum and plasma markers for antiretroviral therapy for human immunodeficiency virus type 1 infection. clin vac immunol2008;15(1):154-158. [http://dx.doi.org/10.1128/cvi.00193-07] [pmid:18003813]. 16. wilson d, badri m, maartens g. performance of serum c-reactive protein as a screening test for smear-negative tuberculosis in an ambulatory high hiv prevalence population. plos one 6(1):e15248. [http:doi:10.1371/journal.pone.0015248]. 16. wilson d, badri m, maartens g. performance of serum c-reactive protein as a screening test for smear-negative tuberculosis in an ambulatory high hiv prevalence population. plos one 6(1):e15248. [http:doi:10.1371/journal.pone.0015248]. 17. simon l, gauvin f, amre dk, saint-louis p, lacroix j. serum procalcitonin and c-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. clin infect dis 2004;39(2):206-217. [http://dx.doi.org/10.1086/421997] [pmid:15307030]. 17. simon l, gauvin f, amre dk, saint-louis p, lacroix j. serum procalcitonin and c-reactive protein levels as markers of bacterial infection: a systematic review and meta-analysis. clin infect dis 2004;39(2):206-217. [http://dx.doi.org/10.1086/421997] [pmid:15307030]. 18. dandona p, nix d, wilson mf, et al. procalcitonin increase after endotoxin injection in normal subjects. j clin endocrinol metab 1994; 79 (6): 1605-1608. [http://dx.doi.org/10.1210/jc.79.6.1605] [pmid:7989463]. 18. dandona p, nix d, wilson mf, et al. procalcitonin increase after endotoxin injection in normal subjects. j clin endocrinol metab 1994; 79 (6): 1605-1608. [http://dx.doi.org/10.1210/jc.79.6.1605] [pmid:7989463]. 19. baylan o, balkan a, inal a, et al. the predictive value of serum procalcitonin levels in adult patients with active pulmonary tuberculosis. j infect dis 2006;59:164-167. [pmid:16785696]. 19. baylan o, balkan a, inal a, et al. the predictive value of serum procalcitonin levels in adult patients with active pulmonary tuberculosis. j infect dis 2006;59:164-167. [pmid:16785696]. 20. mikula t, lipowski d, stanczak w. the serum concentration of procalcitonin (pct) in various infections in hiv positive patients. hiv & aids review 2008;7(2):5-9. [http://dx.doi.org/10.1016/s1730-1270(10)60002-1]. 20. mikula t, lipowski d, stanczak w. the serum concentration of procalcitonin (pct) in various infections in hiv positive patients. hiv & aids review 2008;7(2):5-9. [http://dx.doi.org/10.1016/s1730-1270(10)60002-1]. 21. michael meisner. procalcitonin (pct). a new innovative infection parameter. biochemical and clinical aspects. 3rd ed. stuttgart: george thieme verlag, 2000:136. 21. michael meisner. procalcitonin (pct). a new innovative infection parameter. biochemical and clinical aspects. 3rd ed. stuttgart: george thieme verlag, 2000:136. 22. schleicher gk, herbert v, brink a, et al. procalcitonin and c-reactive protein levels in hiv-positive subjects with tuberculosis and pneumonia. eur respir j 2005;25(4):688-692. [http://dx.doi.org/10.1183/09031936.05.00067604] [pmid:15802344]. 22. schleicher gk, herbert v, brink a, et al. procalcitonin and c-reactive protein levels in hiv-positive subjects with tuberculosis and pneumonia. eur respir j 2005;25(4):688-692. [http://dx.doi.org/10.1183/09031936.05.00067604] [pmid:15802344]. 23. gerard y, hober d, assicot m, et al. procalcitonin as a marker of bacterial sepsis in patients infected with hiv-1. j infect 1997;35:41-46. [http://dx.doi.org/10.1016/s0163-4453(97)90953-1] [pmid:9279723]. 23. gerard y, hober d, assicot m, et al. procalcitonin as a marker of bacterial sepsis in patients infected with hiv-1. j infect 1997;35:41-46. [http://dx.doi.org/10.1016/s0163-4453(97)90953-1] [pmid:9279723]. 24. immanuel c, victor l, silambu chelvi k, et al. serum neopterin levels in hiv infected patients with and without tuberculosis. indian j med res2005;121:220-225. [pmid:15817939]. 24. immanuel c, victor l, silambu chelvi k, et al. serum neopterin levels in hiv infected patients with and without tuberculosis. indian j med res2005;121:220-225. [pmid:15817939]. 25. wirleitner b, schroecksnadel k, winkler c, fuchs d. neopterin in hiv-1 infection. mol immunol 2005;42:183-194. [http://dx.doi.org/10.1016/j.molimm.2004.06.017] [pmid:15488607]. 25. wirleitner b, schroecksnadel k, winkler c, fuchs d. neopterin in hiv-1 infection. mol immunol 2005;42:183-194. [http://dx.doi.org/10.1016/j.molimm.2004.06.017] [pmid:15488607]. table 1. patient demographic information at baseline art art-naïve n 57 25 females 35 (61.4%) 15 (60%) age (years) 36.6±8.2 36.8±10.8 race 57 black 25 black bmi married employed alcohol (number of patients) smoking (number of patients) average months on treatment tb positive at baseline 22.6±5.0 10 (17.5%) 22 (38.6%) 3 (5.3%) 9 (15.8%) 13.6±16.2 (2 63) 10 (17.5%) 21.2±3.5 7 (28%) 12 (48%) 3 (12%) 5 (20%) 8 (32%) table 2. comparison of baseline blood measurements for the two groups art art-naïve p-value procalcitonin (pg/ml) 13.2±3.3 12.9±1.5 0.767 neopterin (nmol/l) 39.5±38.9 64.4±39.4 0.001* crp (mg/l) 25.3±38.5 34.9±82.9 0.567 cd4 count (cells/µl) 288.2±196.4 157.5±181.9 0.027* viral load (log10 copies/ml) 2.4±0.9 3.6±1.7 0.005* red cell count (x1012 /l) 3.6±0.5 3.9±0.7 0.048* haemoglobin (g/dl) 14.2±15.2 11.1±2.0 0.345 white cell count (x109 /l) 4.9±1.5 5.7±2.8 0.107 neutrophils (x109 /l) 2.7±1.2 3.8±2.7 0.026* lymphocytes (x109 /l) 1.6±0.8 1.4±0.8 0.211 cd4 % of lymphocytes 17.4±7.6 9.2±7.3 0.0006* note: viral load measured within 2 months of baseline (*p<0.05; mean±sd). table 3. comparisons for patients who were followed up after 6 months complications after 6 months no complications after 6 months n 29 (61.7%) 18 (38.3%) art 12 (41.4%) 15 (83.3%) baseline cd4 count (cells/µl) 6 month cd4 count (cells/µl) baseline viral load (log10 copies/ml) baseline crp (mg/l) baseline neopterin (nmol/l) baseline pct (pg/ml) 237.0 232.5 2.34±0.9 43.2±87.4 53.9±33.9 13.7±4.5 327.7 325.1 2.3±1.0 9.5±0.7 10.8±7.6 12.6±0.43 fig. 1. box plots illustrating neopterin and cd4 levels for patients after 0 years (n=25), <1 year (n=30), 1 2 years (n=10) and >2 years (n=10) on art. original article original article abstract background methods results discussion acknowledgements references about the author(s) thabo phologolo department of family medicine and public health, faculty of medicine, university of botswana, gaborone, botswana mogomotsi matshaba botswana-baylor children’s clinical centre of excellence, gaborone, botswana department of pediatrics, section of retrovirology, baylor college of medicine, houston, united states of america bathusi mathuba botswana-baylor children’s clinical centre of excellence, gaborone, botswana keboletse mokete botswana-baylor children’s clinical centre of excellence, gaborone, botswana ontibile tshume botswana-baylor children’s clinical centre of excellence, gaborone, botswana elizabeth lowenthal departments of pediatrics and epidemiology, biostatistics and informatics, perelman school of medicine, university of pennsylvania, philadelphia, united states of america global health center, children’s hospital of philadelphia, philadelphia, united states of america citation phologolo t, matshaba m, mathuba b, mokete k, tshume o, lowenthal e. the prevalence of cervical abnormalities: comparison of youth with perinatally acquired hiv and older women in botswana. s afr j hiv med. 2023;24(1), a1455. https://doi.org/10.4102/sajhivmed.v24i1.1455 original research the prevalence of cervical abnormalities: comparison of youth with perinatally acquired hiv and older women in botswana thabo phologolo, mogomotsi matshaba, bathusi mathuba, keboletse mokete, ontibile tshume, elizabeth lowenthal received: 28 oct. 2022; accepted: 06 feb. 2023; published: 28 mar. 2023 copyright: © 2023. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: cervical cancer burden and prevalence of precursor lesions is unknown among young women living with hiv in high prevalence settings. current cervical cancer screening guidelines in resource-limited settings with high hiv prevalence typically exclude adolescents and young women. after observing two cases of advanced cervical cancer among young women with perinatally acquired hiv, a pilot screening programme was established in botswana. objectives: to compare the prevalence of cervical abnormalities in young women with perinatally acquired hiv with women aged 30–49 years, regardless of hiv status. method: we conducted a cross-sectional study of 30–49-year-old women who had visual inspection with acetic acid screening through the botswana public sector programme, and youth (aged 15–24 years) with perinatally acquired hiv, at a single referral site between 2016 and 2018. we describe the prevalence of cervical abnormalities in each group as well as the crude prevalence ratio. results: the prevalence of cervical abnormalities in women 30–49 years of age was 10.9% (95% confidence interval [ci]: 10.4, 11.4), and 10.1% (95% ci: 4.7, 18.3) for youth. the crude prevalence ratio was 1.07 (95% ci: 0.58, 2.01). conclusion: inclusion of youth living with hiv in cervical cancer screening services should be considered in settings with a high prevalence of hiv and cervical cancer. keywords: perinatal hiv; young women; visual inspection with acetic acid; cervical cancer screening; africa. what this study adds: this study shows that the prevalence of cervical abnormalities amongst youth with perinatally acquired hiv may be comparable to that of older women in high-burden hiv settings. background cervical cancer burden and prevalence of precursor lesions is unknown among young women with perinatally acquired hiv, living in high hiv prevalence settings. young women are generally excluded from cervical cancer screening programmes in current guidelines in high hiv prevalence settings, which prioritise women aged 30–49 years. this approach is contrary to recommendations from other settings for increased frequency of cervical cancer screening and follow-up amongst people living with hiv due to faster progression of disease.1 targeted vaccination with the human papillomavirus (hpv) vaccine is recommended as data suggest that this decreases the risk of developing cervical cancer, although it does not remove the need for screening.2 limited data from other settings3,4,5 and anecdotal evidence suggested that the burden of cervical abnormalities might be substantial in young women with perinatally acquired or early childhood hiv infection. several biological processes have been suggested to explain this phenomenon. hiv increases hpv transmission. cd4+ t-lymphocytes play a central role in the control of established hpv infections. therefore, hiv-related immune suppression facilitates viral persistence,1 and persistent hpv infection is associated with developing cancer.6 faster progression of cervical abnormalities has been found in the context of hiv.7 in youth who were perinatally infected with hiv, the immaturity of the immune system at the time of hiv acquisition, the longevity of immune dysregulation and the frequency of challenges with medication adherence suggests that sexually active youth with perinatally acquired hiv may have similar or higher vulnerability to advanced cervical abnormalities than sexually active older women. however, as an association between antiretroviral therapy initiation at low cd4 counts and faster progression of cervical abnormalities has been shown, women who become infected later in life and start treatment at low cd4 counts may in some instances be at greater progression risk than perinatally infected adolescents who are commenced on antiretroviral therapy early.8 to test our hypothesis that young women with perinatally acquired hiv have similar prevalence of cervical abnormalities to women of 30–49 years, we compare the prevalence of cervical abnormalities between the women evaluated through the national screening programme in botswana and a pilot project for screening adolescents and young women living with hiv at the botswana-baylor children’s clinical centre of excellence (bbcccoe), a centre focused on the care and treatment of children and youth living with hiv. both programmes implemented visual inspection with acetic acid (via) screening, using the same equipment, supplies, trainings and ministry of health (moh)-supported mentorship. methods setting based on stakeholder consensus and international evidence-based recommendations as provided by the world health organization, botswana began implementation of a multipronged cervical cancer prevention and control programme in 2012. the prevention aspect focused on hpv vaccines for girls 9–13 years, while secondary prevention in the form of screening and early treatment targeted women 30–49 years of age. women outside this age range typically are only screened if symptomatic.5,6 data from the government screening programme includes women screened in both primary and tertiary care health facilities offering via countrywide. youth data were obtained from a single tertiary care site, the bbcccoe, a public-private partnership comprehensive free hiv clinic, located in gaborone, botswana. as it is the largest specialised paediatric and adolescent hiv clinic in botswana, individuals come from all parts of the country and represent all socioeconomic strata. the clinic has 2394 registered clients living with hiv, of whom 671 are female between the ages of 15 and 24 years. the site treats children and youth, regardless of mode of hiv acquisition. however, most are enrolled as infants and young children, with documented hiv-positive mothers, which strongly suggests that they may have been infected perinatally. after observing two cases of cervical cancer among perinatally hiv-positive youth, the bbcccoe instituted a pilot cervical abnormalities screening programme in 2017 for sexually active asymptomatic youth in their clinical cohort. the bbcccoe cervical cancer screening clinic is primarily a via site, with pap smears done either as a second-level test for inconclusive via test or as sole screening where it is anatomically or medically impossible or inappropriate to do via screening. participants and definitions data were included for: (1) women 30–49 years of age, regardless of hiv status, who were screened with via for the first time between 2016 and 2018 through the national screening programme; and (2) adolescents and young adults < 24 years of age (‘youth’) with perinatally acquired hiv screened with via at the bbcccoe cervical cancer screening clinic for the first time in 2017 and 2018. we defined perinatal hiv infection as hiv infection that was thought to have resulted from the transmission of hiv from the mother to her child during pregnancy, labour and delivery, or breastfeeding.6 our primary outcome of cervical abnormality was defined as a positive via or positive via-suspected cervical cancer the national guidelines define a positive via as a change in the cervix upon application of the acetic acid, resulting in well-defined, opaque-acetowhite lesions in the transformation zone close to the squamocolumnar junction or to the external orifice, or the entire cervix turning acetowhite.9 a positive via-suspected cervical cancer is reported as a change whereby one or many cervical growths turn acetowhite.10 for youth testing at bbcccoe, we report on an abnormal pap smear test, irrespective of whether via test was done. an abnormal pap smear test was considered a cervical abnormality if the finding was low-grade squamous intraepithelial lesion or high-grade squamous intraepithelial lesion. atypical squamous cells of undetermined significance were not classified as a cervical abnormality. data source we used the national cervical cancer screening database to extract data for women screening for cervical cancer receiving via for the first time. this database is housed in the botswana moh and is disaggregated by age groups, hiv status (positive, negative, unknown), via test results (via positive; via positive – suspected cervical cancer; via negative), and procedures or referrals done in the event of a positive via test (cryotherapy, loop electrosurgical excision procedure, colposcopy). the moh data are reported at the facility-level. individual-level data are not available for the national cohort. the bbcccoe registers and patient electronic data were used to extract and abstract variables for individual youth living with hiv who were included in the screening programme. inclusion/exclusion criteria because the national screening guidelines do not differ based on hiv status, we included data from all women between the ages of 30–49 who were having their first via, regardless of hiv status. for the bbcccoe sample, all data were from hiv-positive youth aged 16–24 years who were having their first via. screening at the bbcccoe was offered to sexually active females patients ≥ 16 years of age. sample size and power we used exhaustive sampling for both groups. we estimated that there would be 120 youth screened at bbcccoe and approximately 6000 30–49-year-old women in the public programme during the sampling period. considering the reported prevalence of positive via among women of mixed hiv status in the region (30.5% among farm workers and sex workers in south africa’s limpopo province,11 28% in general public in zambia, 12.4% in general public in malawi12), we calculated detectable differences across the plausible range of 15% – 25% with positive via in the 30–49-year age group in botswana. with the available sample size, we calculated that we would have 80% power to detect a prevalence ratio for cervical abnormalities less than 0.6 or greater than 1.5 with a two-sided alpha level of 0.05 for the dichotomous comparison of cervical abnormalities/no cervical abnormalities. data collection all data were de-identified and either electronically or manually imported into excel files by trained and authorised staff of the respective organisations. all moh data were downloaded from the national database which is populated at the individual clinic level prior to being compiled centrally. data were manually extracted from the bbcccoe medical records, both electronic and paper-based, by clinic research nurses. we evaluated for missing and out of range data for the two data sets. data from the moh were double-checked by the study principal investigator and an moh data officer against the submitted reports from the respective facilities. all data from the bbcccoe were double-checked for accuracy against the primary source by the study principal investigator, the study nurse, and the nurse in charge of the cervical cancer screening programme. to protect study participants from the youth sample, medical record numbers were replaced with unique study numbers. dates of birth were converted into the age at the time of the via evaluation. data on hiv status (positive/negative/unknown) were reported in the national database. for the perinatally infected cohort, data were collected regarding whether they had ever used hormonal contraception, age of sexual debut, parity, cd4+ t-lymphocyte count (cd4 count) nadir and most recent cd4 count, most recent hiv viral load, and smoking history. hiv viral load was considered to be undetectable for values less than 400 copies/ml, as per botswana guidelines. the most recent viral loads for all youth were within 6 months of index via. statistical analysis data were imported into the stata ic/14.2® (stata corporation, college station, texas, united states) statistical software package for analysis. for our primary analysis, we used the composite endpoint of cervical abnormalities versus no cervical abnormalities. the proportion of cervical abnormalities versus no cervical abnormalities was compared between women 30–49 years of age in the national testing group and bbcccoe youth, using chi-squared test with the criterion for significance set as a p-value < 0.05. mean and standard deviation are reported for parametric data and median (interquartile range [iqr]) for non-parametric data. we calculated the crude cervical abnormalities prevalence ratio and 95% confidence interval (ci) by dividing the cervical abnormalities prevalence of women 30–49 years by that of bbcccoe youth. results a total of 14 819 women aged 30–49 years attended via screening clinics across the country for the first time between january 2016 and december 2018, in 23 of the total 27 health districts. of the 92 youth who attended the bbcccoe cervical cancer screening clinic, 85 of 92 (92.4%) were screened with via alone, three (3.3%) with pap alone and four (4.4%) with both pap and via. for the bbcccoe group, the median age in years for screening was 22 years (range: 17 to 24), and 18 years (range: 8 to 23) for sexual debut. the lowest age of sexual debut was reported in a case of sexual abuse. the median total number was 3 (range: 1 to 16; iqr: 2–5) for sexual partners and 0 (range: 0 to 3; iqr: 0–1) for parity. the median cd4 count was 644 cells/µl (iqr: 370.5–882). the hiv viral load was undetectable in 77 (83.7%) of participants. twenty-six (29.9%) participants reported ever using hormonal contraception and six (6.6%) reported ever smoking. characteristics of screened adults are further described in table 1, and youth in the perinatally infected cohort in table 2. table 1: results of visual inspection with acetic acid in adult women (30–49 years of age) first-time testers (2016–2018). table 2: characteristics of perinatally hiv-positive youth screened with visual inspection with acetic acid. a total of 1617 women and nine youth had cervical abnormalities, giving a prevalence of cervical abnormalities of 10.9% (95% ci: 10.4, 11.4) for women 30–49 years of age and 10.1% (95% ci: 4.7, 18.3) for youth living with hiv. the crude prevalence ratio was 1.07 (95% ci: 0.58, 2.01). of the seven pap smears done amongst the youth, three were atypical squamous cells of undetermined significance, two low-grade squamous intraepithelial lesions, one negative and one not reported. cases of suspected cancer constituted 8.7% (95% ci: 7.3, 10.1) of cervical abnormalities amongst the older women, while no cases of suspected cancer were reported for youth. amongst youth with cervical abnormalities, three (33.3%) had detectable viral loads while viral loads were detectable in 11 (13%) of those without cervical abnormalities. the median cd4 count amongst youth with cervical abnormalities was 342 cells/µl (iqr: 188.5–455.5), and 656 cells/µl (iqr: 450–905) for those without cervical abnormalities. discussion our finding in this cross-sectional study of a group of 30–49-year-old women who received via screening in the public sector and perinatally hiv-positive youth at a single referral site suggests that the risk of cervical abnormalities of these two groups is similar. the overall prevalence of cervical abnormalities was lower in our cohorts (10.1%) compared with previously published samples from the region (15% – 30%).13,14 however, cervical cancer remains the leading cause of cancer in botswana.15 despite the fact that effective screening is available for women in the 30–49-year-old age bracket, relatively few patients presenting with invasive cervical cancer have ever accessed screening services.16 furthermore, mortality rates are highest among women with cervical cancer who are also hiv-positive.17 spontaneous improvement of cervical abnormalities is possible,18 and improvements in immunologic status have been associated with lower prevalence and slower progression of cervical abnormalities in women living with hiv.19 however, our study suggests that national policies that exclude youth from cervical cancer screening programmes likely come with a substantial risk of late cancer presentation for youth who are living with hiv. this may be particularly true for youth who were perinatally hiv-positive due to the longstanding nature of their hiv-related immune aberrations. due to the comparable prevalence of cervical abnormalities among youth with perinatally acquired hiv and 30–49-year-old women who qualify for the national cervical cancer screening programme, expansion of youth-friendly cervical cancer screening and prevention interventions seems prudent. policymakers need to consider their country’s unique disease epidemiology and ethical ideal of universal access and equity in prioritisation of recipients of their cervical cancer screening programmes. advancing the international efforts to improve overall care for adolescents and young adults infected with hiv is a challenge that requires outside the box thinking by providers of health services. this study was limited by the lack of individual-level data for the approximately 15 000 women screened through the national programme. the size of the individual-level data sample for the youth was relatively small since cervical cancer screening for younger women is not currently part of the public treatment programmes. additionally, screening was done with via while the world health organization recommendation is that of using a dna-based hpv assay.19 while we were interested in looking at the relationship between variables such as age at first sexual encounter, number of sexual partners, parity and tobacco use and cervical abnormalities in the perinatally hiv-positive cohort, the relatively small numbers of individuals in this sample precluded meaningful comparisons. our data suggest that cervical cancer screening and prevention services should be expanded to include youth living with hiv as a target population in high cervical cancer and hiv prevalence settings, such as botswana. future studies should evaluate the progression/regression of cervical abnormalities among youth living with hiv, including both those who were perinatally and behaviorally infected. acknowledgements we would like to acknowledge mr kadimo khutsafalo for his librarian editorial support. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions t.p., e.l., m.m. and b.m. conceptualised and developed the protocol. t.p. and e.l. analysed and prepared the draft manuscript. t.p., k.m. and o.t. contributed to the acquisition, cleaning and interpretation of botswana-baylor children’s clinical centre of excellence patient data, these being important aspects of the study. all authors read and approved the final manuscript. ethical considerations ethical approval was sought and received from research ethics committees of the following organisations: botswana health research development committee, university of botswana (reference: hpdme: 13/18/1), university of pennsylvania, botswana-baylor children’s clinical centre of excellence. funding information this work was supported by a national institutes of health d43 hiv research training program for botswana (d43tw009781) grant. this work was made possible, in part, through core services and support from the penn center for aids research (cfar), an nih-funded programme (p30 ai 045008). support was also received from the children’s hospital of philadelphia carole marcus mid-career award to promote career development and mentoring in pediatric research. data availability the data sets used and/or analysed during the current study are available from the corresponding author, t.p., on reasonable request. disclaimer the opinions expressed in this article are those of the authors. they do not purport to reflect the opinions or views of the funder nor that of the institutions to which the authors are affiliated. references stanley ma, sterling jc. host responses to infection with human papillomavirus. curr probl dermatol. 2014;45:58–74. https://doi.org/10.1159/000355964 kamolratanakul s, pitisuttithum p. human papillomavirus vaccine efficacy and effectiveness against cancer. vaccines (basel). 2021;9(12):1413. https://doi.org/10.3390/vaccines9121413 gaym a, mashego m, kharsany abm, walldorf j, frohlich j, abdool karim q. high prevalence of abnormal pap smears among young women co-infected with hiv in rural south africa – implications for cervical cancer screening policies in high hiv prevalence populations. s afr med. j. 2007;97(2):120–123. https://doi.org/10.7196/samj.462 bohlius j, foster c, naidu g, sengayi m, turkova a. cancer in adolescents and young adults living with hiv. curr opin hiv aids. 2018;13(3):196–203. https://doi.org/10.1097/coh.0000000000000460 rohner e, sengayi m, goeieman b, et al. cervical cancer risk and impact of pap-based screening in hiv-positive women on antiretroviral therapy in johannesburg, south africa. int j cancer. 2017;141(3):488–496. https://doi.org/10.1002/ijc.30749 doorbar j, quint w, banks l, et al. the biology and life-cycle of human papillomaviruses. vaccine. 2012;30 suppl 5:f55–f70. https://doi.org/10.1016/j.vaccine.2012.06.083 harris tg, burk rd, yu h, et al. insulin-like growth factor axis and oncogenic human papillomavirus natural history. cancer epidemiol biomarkers prev. 2008;17(1):245–248. https://doi.org/10.1158/1055-9965.epi-07-0686 mthembu n, dorward j, naicker n, et al. low cd4 count and educational status predict abnormal cervical smears amongst hiv-positive women initiating antiretroviral therapy in south africa. s afr j hiv med. 2020;21(1):1045. https://doi.org/10.4102/sajhivmed.v21i1.1045 ministry of health and wellness. botswana national cervical cancer prevention programme strategic plan 2012–2016. gaborone: government of botswana, ministry of health; 2012. world health organization. who guidance note: comprehensive cervical cancer prevention and control: a healthier future for girls and women [homepage on the internet]. n.d. [cited 2018 may 25]. available from: https://apps.who.int/iris/handle/10665/78128 sankaranarayanan r, nessa a, esmy po, dangou jm. visual inspection methods for cervical cancer prevention. best pract res clin obstet gynaecol. 2012;26(2):221–232. https://doi.org/10.1016/j.bpobgyn.2011.08.003 afzal o, lieber m, dottino p, beddoe am. cervical cancer screening in rural south africa among hiv-infected migrant farm workers and sex workers. gynecol oncol rep. 2017;20:18–21. https://doi.org/10.1016/j.gore.2016.12.011 world health organization, international agency for research on cancer, african population and health research center. prevention of cervical cancer through screening using visual inspection with acetic acid (via) and treatment with cryotherapy. a demonstration project in six african countries: malawi, madagascar, nigeria, uganda, the united republic of tanzania, and zambia [homepage on the internet]. 2012 [cited 2018 may 25]. available from: https://apps.who.int/iris/handle/10665/75250 anakwenze c, bhatia r, rate w, et al. factors related to advanced stage of cancer presentation in botswana. j glob oncol. 2018;4:1–9. https://doi.org/10.1200/jgo.18.00129 nassali mn, tadele m, nkuba rm, modimowame j, enyeribe i, katse e. predictors of locally advanced disease at presentation and clinical outcomes among cervical cancer patients admitted at a tertiary hospital in botswana. int j gynecol cancer. 2018;28(6):1218–1225. https://doi.org/10.1097/igc.0000000000001284 dryden-peterson s, bvochora-nsingo m, suneja g, et al. hiv infection and survival among women with cervical cancer. j clin oncol. 2016;34(31):3749–3757. https://doi.org/10.1200/jco.2016.67.9613 tainio k, athanasiou a, tikkinen kao, et al. clinical course of untreated cervical intraepithelial neoplasia grade 2 under active surveillance: systematic review and meta-analysis. bmj. 2018;360:k499. https://doi.org/10.1136/bmj.k499 firnhaber c, westreich d, schulze d, et al. highly active antiretroviral therapy and cervical dysplasia in hiv-positive women in south africa. j int aids soc. 2012;15(2):17382. https://doi.org/10.7448/ias.15.2.17382 world health organization. who guideline for screening and treatment of cervical pre-cancer lesions for cervical cancer prevention. 2nd ed. geneva: world health organization; 2021. licence: cc by-nc-sa 3.0 igo. a p r i l 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e coping is defined as ’the cognitive and behavioral efforts made by an individual to alter or manage the problems caused by stressful situations‘.1 the effectiveness of coping is associated with variables such as extent of social support,2,3 personality factors such as selfesteem and control,4 and rate of occurrence of stressful events.5 individuals with active behavioural coping strategies are likely to have fewer mood disturbances, a better quality of life6 and a reduction in risk-taking behaviour,7 whereas individuals with inadequate and avoidant coping styles are likely to have higher levels of emotional stress and increased feelings of hopelessness or negative expectations.3,8-11 the dynamics of hope are multifaceted and comprise a complex combination of ’hope’, ‘despair’ and ’hopelessness’.12 with hope, the individual fights against inability to cope and has the belief that life is worth living both in the present and the future. despair is a downward process that results in being stuck in a situation, losing grip, sinking into a narrow existence, losing perspective of the future and questioning the possibility of hope.13 hopelessness includes helplessly giving up everything (including hope) and living in emptiness in the face of an assumed non-existent future. hopelessness or negative expectation is among the psychological variables that are predictive of suicide. the patient misconstrues his or her experience in a negative way and anticipates serious outcomes for his or her problems. this sense of hopelessness may lead the person to believe that suicide is the only feasible strategy feelings of hopelessness in stable hiv-positive patients on antiretrovirals o r i g i n a l a r t i c l e m y h moosa, mmed (psych), fcpsych f y jeenah, mmed psych, fcpsych department of psychiatry, university of the witwatersrand, johannesburg 40 aim. the coping skills and styles individuals utilise to deal with the stress of hiv infection greatly influence the psychological impact of this illness and potential consequent feelings of hopelessness. the aim of this study was to describe levels of hopelessness in a group of stable, non-depressed hiv-positive patients receiving antiretroviral therapy, and factors associated with hopelessness. method. thirty randomly selected non-depressed patients (according to diagnostic and statistical manual of mental disorders, 4th edition (dsm-iv) criteria) were included in this study. demographic and other data were obtained from all subjects, who also completed the beck’s hopelessness scale (bhs). the 20 true-false items of the bhs (29) measured three major aspects of hopelessness, which was interpreted on the total scale score as follows: ≤3 minimal, and >3 significant. results. the study population comprised 30 patients with a mean age of 37.9 years (standard error (se) 1.18) (range 28 51 years). the mean bhs score was 4.03 (se 0.55), with a range from 0 to 12. there were no statistically significant correlations between bhs scores of the study population and gender, marital status, employment status, level of education, years since the diagnosis of hiv, or number of children (p>0.05). eighteen subjects (60%) scored 3 or less on the bhs, considered minimal levels of hopelessness. however, 12 (40%) scored more than 3, which is considered significant; of these 23% had scores of 7 or more. there was no statistically significant association between bhs scores and gender, employment status, level of education, number of children or number of years since diagnosis (p>0.05). however, patients who were married or living with partners were statistically more likely to score higher on the hopelessness scale compared with those who were single (p<0.05). conclusion. hopelessness is a psychological distress reaction that is common but largely undetected in stable hiv-positive patients on antiretrovirals. feelings of hopelessness may result in increase in risk-taking behaviour (e.g. unprotected sex, drug use, sharing needles) and attempted suicide. t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 0 for dealing with seemingly insoluble problems.14-17 beck et al.,18 in a 10-year prospective follow-up study of 165 patients hospitalised with suicidal ideation, confirmed that hopelessness was predictive of actual suicide. the prevalence of hiv and aids in south africa has reached pandemic proportions. living with hiv in a country where hiv is hugely stigmatised can be extremely stressful and causes mental suffering. the poorest sectors of society are most vulnerable and the consequences for them are most severe. loss of income, additional care-related expenses and mounting medical fees push affected households deeper into poverty. the burden of coping often rests with women, who are faced with stepping up to a role as income-earners, mothers and caregivers. hiv has resulted in disintegration of family units and households. the effectiveness of the coping abilities and styles individuals utilise to deal with the stresses of hiv greatly influences the psychological impact of this illness. furthermore, the presence of co-morbid personality and adjustment disorders (which have an increased prevalence in the hiv-positive population)19 also impacts on coping abilities. persons with these disorders are more likely to cope in a dysfunctional way.20 there is evidence that hopelessness in individuals with hiv and aids may be associated with depression,21 which may lead to decreased adherence to medication regimes, further suppression of immunity and accelerated disease progression as well as risk of suicide. from a psychobiological perspective, active coping is associated with higher total lymphocyte, cd4 and natural killer cell counts,22,23 while a passive24 or fatalistic– resigned coping style and hopelessness25 are associated with poor hiv treatment adherence and rapid progression of hiv disease,26 particularly if they are associated with depression and occurrence of severe stressful events.27,28 to measure hopelessness, beck et al.29 developed the 20-item beck’s hopelessness scale (bhs), applied exploratory factor analysis and argued that the scale measures three specific components (affective, motivational and cognitive). the kr-20 coefficients (measures of the scale’s internal consistency) range from 0.82 to 0.93. in general practice, the correlation between the bhs and ratings of hopelessness was 0.74 and in suicide attempters it was 0.62. the hopelessness construct is a factor in many mental disorders and is highly correlated with measures of depression and suicidal intent and ideation.30 much of the work on psychiatric morbidity in hiv has been done in the western world. despite the high prevalence of hiv in south africa, very few studies have been published on the ability of individuals to cope with the illness. furthermore, in south africa hiv infected patients may be at greater risk for psycho pathology than patients in the developed world because of their potentially stressful living conditions. the aim of this report was to describe levels of hopelessness and associated factors in a group of stable, non-depressed hiv-positive patients receiving antiretroviral (arv) therapy. methods the study was part of a larger prospective, randomised and controlled study designed to compare response to treatment, effects on immune markers and adherence to arvs in patients with depression compared with those without depression. the sampling was a convenience sampling, as it included only patients attending the perinatal hiv research unit clinic at chris hani baragwanath hospital, johannesburg. volunteers who were 18 years and older and medically stable and had been on antiretroviral therapy for more than 6 months were screened for possible inclusion in the study. thirty randomly selected non-depressed patients (according to diagnostic and statistical manual of mental disorders, 4th edition (dsm-iv) criteria) were included in the study. depressive symptoms were determined using the hamilton depression rating scale (hamd) (the higher cut-off score of 14 or more was regarded as indicative of a diagnosis of depression). additional data (age, gender, marital status, employment status, level of education, number of children, and number of years since diagnosis of hiv) were obtained from all subjects, who also completed the bhs. the 20 true-false items of the bhs29 measured three major aspects of hopelessness, which was interpreted on the total scale score as follows: ≤3 minimal, and >3 significant. the study was approved by the committee for research on human subjects, university of the witwatersrand. for statistical analyses, the subjects were divided into two groups, those with a bhs score of ≤3 and those with a score of >3. descriptive statistics were computed as means and frequencies (count and percentages). comparisons were made between the two groups with regard to gender, marital status, employment status, number of children, level of education and number of years since diagnosis by the use of contingency tables (chi-square test with fischer’s exact test). logistic regression was computed to determine any significant correlations between bhs scores and exposure variables. all analysis was done using the statistical package for social sciences 10.0 for windows (spss inc., chicago, ill.). a value of p<0.05 was considered significant. 41 a p r i l 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e results the study population comprised 30 patients, with a mean age of 37.9 years (standard error (se) 1.18) (range 28 51 years). all had acquired hiv infection through heterosexual contact and had disclosed their status to their partner or a significant member of their family. the majority of patients (63.3%) were on a nevirapine-based first-line regimen. adherence to medication was good, with most patients virally suppressed and with a mean cd4 count of 405.37 cells/µl (se 48.26). clinically all the patients were non-depressed, and the mean hamd score was 2.1 (se 1.63) with a range from 0 to 5. the mean bhs score was 4.03 (se 0.55), with a range from 0 to 12 (fig. 1). eighteen subjects (60%) scored 3 or less on the bhs, considered minimal levels of hopelessness. however, 12 (40%) scored more than 3, which is considered significant; of these 23% had scores of 7 or more. comparisons between these two groups with respect to some variables are listed in table i. there were no statistically significant correlations between bhs scores of the study population and gender (r=-0.19, p=0.313), marital status (r=0.33, p=0.071), employment status (r =-0.26; p=0.162), level of education (r=-0.22; p=0.240), years since the diagnosis of hiv (r=0.24; p=0.203), or number of children (r=0.11; p=0.567). however, there was a trend indicating that subjects who were female, unemployed, married and/ or had more children were more likely to experience higher levels of hopelessness. there was no statistically significant association between bhs scores and gender (p=0.184), employment status (p=0.769), level of education (p=0.933), number of children (p=0.933), or number of years since diagnosis (p=0.755). however, patients were who married or living with partners were statistically more likely to score higher on the hopelessness scale compared with those who were single (p=0.019). discussion although the sample was small, this study found that a significant proportion (40%) of a group of hiv-positive patients had mild to moderate levels of hopelessness as measured by the bhs, despite being medically stable, adherent to their antiretroviral medication and virally suppressed, and having high cd4 counts. similar results of ’mild‘ feelings of hopelessness were reported by remien et al.21 however, nearly all their patients maintained the conviction that good times lay ahead and that their lives were worthwhile. this finding is of relevance because there is published evidence that hopelessness may play a key role in the 42 study population bhs score variables (n=30) ≤3 (n=18) >3 (n=12) gender male 6 (20%) 2 (6.7%) 4 (13.3%) fisher’s exact female 24 (80%) 16 (53.3%) 8 (26.7%) p=0.184 marital status single/divorced/widowed 18 (60%) 14 (46.7%) 4 (13.3%) fisher’s exact married/cohabiting 12 (40%) 4 (13.3%) 8 (26.7%) p=0.01912 employment status employed 9 (30%) 5 (16.7%) 4 (13.3%) fisher’s exact unemployed 21 (70%) 13 (43.3%) 8 (26.7%) p=0.769 level of education grade 0 7 2 (6.7%) 1 (3.3%) 1 (3.3%) χ2 =0.139; df 2; grade 8 12 25 (83.3%) 15 (50%) 10 (33.3%) p=0.933 tertiary 3 (10%) 2 (6.7%) 1 (3.3%) no. of years since diagnosed 0 5 11 (36.7%) 7 (23.3%) 4 (13.3%) fisher’s exact > 5 19 (63.3%) 11 (36.7%) 8 (26.7%) p=0.755 no. of children none 3 (10%) 2 (6.7%) 1 (6.7%) χ2 =0.065; df 2; 1 10 (33.3%) 6 (20%) 4 (20%) p=0.967 >1 17 (56.7%) 10 (33.3%) 7 (33.3%) table i. frequency of beck’s hopelessness scale scores in relation to patient variables   0.0 3.5 7.0 10.5 14.0 0.0 3.0 6.0 9.0 12.0 bhs1 c ou nt fig. 1. histogram of beck’s hopelessness scale scores. t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 0 prediction of suicidal behaviour.30 a high bhs score alerts the therapist to unstated or denied suicidal intentions. remien et al.21 reported that despite ’mild‘ feelings of hopelessness and no current suicidal ideation, several of their patients considered suicide an option for the future should they become more impaired. in interpreting the results of the present study, hopelessness may best be construed as a risk factor. however, unlike certain other predictors of suicide, such as age, sex, or race, hopelessness is a characteristic that can be modified. given the relatively slow natural progression of hiv infection and the increased survival made possible by recent medical therapies, there should be a focus on interventions that promote the expression of negative feelings (i.e. anger) and the development of effective coping strategies that can significantly improve psychological status31 and possibly increase survival time.32 failure to do this may mean that hivpositive subjects repress their feelings of anger and alleviate their discomfort by risk-taking behaviour such as unprotected sex, drug use and sharing needles.33 like the process of learning, which involves the formation of new connections between nerve cells in the brain, psychotherapy works by changing the way the brain functions. certain types of psychotherapy, particularly cognitive-behavioural therapy (cbt) and interpersonal therapy (ipt), can help improve coping skills. the aim of ipt is to solve problems within a brief period rather than devise lifetime solutions, and its emphasis is on restoring the patient to an adequate level of functioning rather than on personality change.34 a study by rush et al.35 showed that depressed patients treated with cognitive therapy showed a more rapid reduction in hopelessness scores than a comparison group of depressed patients treated with an antidepressant drug. although this study did not find any significant correlation between feelings of hopelessness and previously reported stressors such as unemployment, having more children to care for and lack of support, there were suggestions of a trend towards this. the small sample size and the very select sample in this study may have contributed to this finding. contrary to remien et al.’s21 finding that long-term survivors of hiv and aids were more resilient and positive in terms of their mood and outlook, our patients appeared to become more hopeless with time. it is possible that we are not only failing to identify these feelings but do not provide any psychological support for persons expressing such feelings at our arv rollout clinics. a possible objection to the use of the bhs in prediction of suicide is that it yields a large proportion of false positives. the almost inevitable over-inclusiveness of valid predictors of a rare phenomenon such as suicide was first demonstrated by meehl and rosen36 and has since been widely discussed.37-39 however, it should be noted that the connotations of the terms ’false negative‘ and ’false positive‘ may not be completely appropriate. generally these terms are applied when a specific test is able or unable to demonstrate the presence or absence of a known disease, such as diabetes or tuberculosis. the bhs attempts to identify the potential for fatal suicide attempts and not the behaviour itself. many persons with high scores on this scale may continue to be at risk for suicide beyond the observation period, even though they have not yet made a fatal suicide attempt conclusion this small study suggests that hopelessness may be a common psychological distress reaction present in stable hiv-positive patients on arvs that may go undetected. these feelings of hopelessness may result in an increase in risk-taking behaviour (e.g. unprotected sex, drug use, sharing needles) and attempted suicide. we recommend that the staff at arv rollout clinics become aware of this possibility and use the bhs as a screening tool to identify such individuals and refer them for basic psychotherapy to improve coping skills and reduce feelings of hopelessness. references 1. lazarus rs. coping therapy and research: past, present, and future. psychosom med 1993; 55: 234-247. 2. pakenham ki, dadds mr, terry dj. relationships between adjustment to hiv and both social support and coping. j consult clin psychol 1994; 62: 1194-1203. 3. wolf tm, balson pm, morse ev, et al. relationship of coping style to affective state and perceived social support in asymptomatic and symptomatic hivinfected persons: implications for clinical management. j clin psychiatry 1991; 52: 171-173. 4. folkman s, chesney m, pollack l, et al. stress, control, coping, and depressive mood in human immunodeficiency virus-positive and -negative gay men in san francisco. j nerv ment dis 1993; 181: 409-416. 5. vedhara k, nott kh. psychosocial vulnerability to stress: a study of hiv-positive homosexual men. j psychosom res 1996; 41: 255-267. 6. friedland j, renwick r, mccoll m. coping and social support as determinants of quality of life in hiv/aids. aids care 1996; 8: 15-31. 7. martin dj. coping with aids and aids-risk reduction efforts among gay men. aids educ prev 1993; 5: 104-120. 8. krikorian r, kay j, liang wm. emotional distress, coping, and adjustment in human immunodeficiency virus infection and acquired immune deficiency syndrome. j nerv ment dis 1995; 183: 293-298. 9. fleishman ja, fogel b. coping and depressive symptoms among people with aids. health psychol 1994; 13: 156-169. 10. degenova mk, patton dm, jurich ja, et al. ways of coping among hiv-infected individuals. j soc psychol 1994; 134: 655-663. 11. nicholson wd, long bc. self-esteem, social support, internalized homophobia, and coping strategies of hiv gay men. j consult clin psychol 1990; 58: 873876. 12. kylma j, vehvilainen-julkunen k, lahdevirta j. hope, despair and hopelessness in living with hiv/aids: a grounded theory study. j adv nurs 2001; 33: 764775. 13. kylma j. despair and hopelessness in the context of hiv: a meta-synthesis on qualitative research findings. j clin nurs 2005; 14: 813-821. 14. beck at, brown g, berchick rj, et al. relationship between hopelessness and ultimate suicide. am j psychiatry 1990; 147: 190-195. 15. dyer ja, kreitman n. hopelessness, depression, and suicide intent in parasuicide. br j psychiatry 1984; 144: 127-133. 16. nekanda-trepka cjs, bishop s, blackburn m. hopelessness and depression. br j clin psychiatry 1983; 132: 954-956. 17. wetzel kd, margulies t, davis r, et al. hopelessness, depression, and suicide intent. j clin psychiatry 1980; 41: 159-1608. 18. beck at, steer ra, kovacs m, et al. hopelessness and eventual suicide: a 10-year prospective study of patients hospitalized with suicidal ideation. am j psychiatry 1985; 142: 559-563. 19. chuang ht, jason gw, pajurkova em, et al. psychiatric morbidity in hiv infection. int conf aids 1990; 6: 176. 20. perkins do, davidson ej, leserman j, et al. personality disorder in patients infected with hiv: a controlled study with implications for clinical care. am j psychiatry 1993; 150: 309-315. 21. remien rh, rabkin j, katoff l, williams j. suicidality and psychological outlook 43 a p r i l 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e in long term survivors of aids. int conf aids 1991; 7: 50. 22. goodkin k, fuchs i, feaster d, et al. life stressors and coping style are associated with immune measures in hiv-1 infection: a preliminary report. int j psychiatry med 1992; 22: 155-172. 23. goodkin k, blaney nt, feaster d, et al. active coping style is associated with natural killer cell cytotoxicity in asymptomatic hiv-1 seropositive homosexual men. j psychosom res 1992; 36: 635-650. 24. solano l, costa m, salvati s, et al. psychosocial factors and clinical evolution in hiv infection: a longitudinal study. j psychosom res 1993; 37: 39-51. 25. reed gm, kemeny me, taylor se, et al. realistic acceptance as a predictor of decreased survival time in gay men with aids. health psychol 1994; 13: 299307. 26. kalichman sc, rompa d. hiv treatment adherence and unprotected sex practices in people receiving antiretroviral therapy. sexually transmitted infections 2003; 79; 59-61. 27. leserman j, petitto jm, perkins do, et al. severe stress, depressive symptoms, and changes in lymphocyte subsets in human immunodeficiency virus-infected men. arch gen psychiatry 1997; 54: 279-285. 28. evans dl, leserman j, perkins do, et al. severe life stress as a predictor of early disease progression in hiv infection. am j psychiatry 1997; 154: 630-634. 29. beck at, weissman a, lester d, et al. the measurement of pessimism: the hopelessness scale. j consult clin psychol 1974; 42: 861-865. 30. aish a and wasserman d. does beck’s hopelessness scale really measure several components? psychol med 2001; 31(2): 367-372 31. greer s, moorey s, baruch jdr, et al. adjuvant psychological therapy for patients with cancer: a prospective randomised trial. bmj 1992; 304: 675-680. 32. spiegel d, bloom j, kraemer hc, et al. the beneficial effect of psychosocial treatment on survival of metastatic breast cancer patients: a randomized prospective outcome study. lancet 1989; 14: 888-891. 33. kelly ja, murphy da, bahr r, et al. factors associated with severity of depression and high-risk sexual behavior among persons diagnosed with human immunodeficiency virus (hiv) infection. health psychol 1993; 12: 215-219. 34. klerman gl, weissman mm, rounsaville bj, et al. interpersonal psychotherapy of depression. new york: basic books, 1984. 35. rush aj, beck at, kovacs m, et al. comparison of the effects of cognitive therapy and pharmacotherapy on hopelessness and self-concept. am j psychiatry 1982; 139: 862-866. 36. meehl pe, rosen a. antecedent probability and the efficiency of psychometric signs, patterns, or cutting scores. psychol bull 1955; 52: 194-216. 37. galen rs, gambino sr. beyond normality: the predictive value and efficiency of medical diagnoses. new york, john wiley & sons, 1975. 38. reinhardt he. statistical theory and clinical practice in predicting rare phenomena. psychol rep 1979; 45: 468-470. 39. vanderplas jm, vanderplas jh. multipleversus single-index predictors of dangerousness, suicide, and other rare behaviors. psychol rep 1979; 45: 343349. 44 o r ig in a l a r t ic l e june 2014, vol. 15, no. 2 sajhivmed 55 timing of antenatal care and art initiation in hiv-infected pregnant women before and after introduction of nimart c n mnyani,1,2 mb chb, fcog; e marinda,3,4 phd; h struthers,2,5 msc, mba; m gulley;2 r machepa;2 j mcintyre,2,6 mb chb, frcog 1 department of obstetrics and gynaecology and school of public health, faculty of health sciences, university of the witwatersrand, johannesburg, south africa 2 anova health institute, johannesburg, south africa 3 health and development africa, mott macdonald south africa 4 epidemiology and biostatistics unit, school of public health, faculty of health sciences, university of the witwatersrand, johannesburg, south africa 5 department of infectious diseases, faculty of health sciences, university of cape town, south africa 6 school of public health and family medicine, university of cape town, south africa corresponding author: c n mnyani (coceka.mnyani@wits.ac.za) in this review of routinely collected data from five community health centres in the johannesburg health district, we assess timing of antenatal care and antiretroviral therapy (art) initiation in hiv-infected pregnant women before and after the introduction of nurse-initiated management of art in antenatal clinics. there are important lessons to be learnt as we reflect on the south african prevention of mother-to-child transmission of hiv programme. s afr j hiv med 2014;15(2):55-56. doi:10.7196/sajhivmed.1009 it is widely acknowledged that the highest risk of mother-to-child transmission (mtct) of hiv is in hiv-infected women with low cd4+ counts, who are eligible for antiretroviral therapy (art).[1] timely initiation of art in this group is critical to decreasing paediatric hiv infection and hiv-related maternal morbidity and mortality.[2,3] art initiation in pregnancy is also associated with better maternal immunological and virological outcomes compared with starting art after pregnancy.[4] prior to the current prevention of mtct (pmtct) guidelines, criteria for art initiation in pregnant women were based on a cd4+ count of ≤350 cells/µl, or world health organization (who) stage 3 or 4 disease regardless of cd4+ count.[5] reflecting on the history of the pmtct programme in south africa, two of the main early challenges to initiating art in pregnancy were that hiv treatment sites were physically separate from antenatal clinics and art initiation was largely physician led.[6] this led to delays in referral and initiating treatment, and as a result, a significant proportion of arteligible pregnant women would go through pregnancy without starting treatment.[7] nurse-initiated and managed art (nimart) in antenatal clinics was introduced to address these challenges, supported by evidence that integration of art with antenatal care decreases time to initiation and increases the proportion of pregnant women initiated.[8-10] pregnant women need to access antenatal care early for timeous treatment initiation. this retrospective review of routinely collected data assesses timing of antenatal care and art initiation in hiv-infected, eligible pregnant women presenting to five community health centres in the johannesburg health district. method time to initiation in pregnant women who presented prior to the introduction of nimart was compared with those who presented after. between october 2010 and march 2012, a total of 1 436 art-eligible pregnant women were identified. the study was approved by the university of cape town’s human research ethics committee, and by the gauteng province office for policy, planning and research. results characteristics of the women are presented in table 1. the mean gestational age when accessing antenatal care was 19.2 weeks (standard deviation (sd) of 6.6), and the mean gestational age at art initiation was 24.6 weeks (sd 6.2). there was no significant reduction in time to initiation after the introduction of nimart. overall, the median time to initiation prior to the introduction of nimart was 3.4 weeks (interquartile range (iqr) 2.0 5.9) whereas after the introduction of nimart, it was 3.0 weeks (iqr 1.4 5.4). assessing data from individual clinics, there was evi dence of an increase in time to starting art in some facilities. however, overall there was an increase in the proportion of eligible pregnant women who started art after the introduction of nimart, in all the facilities. data on pregnancy outcomes were mailto:coceka.mnyani@wits.ac.za o r ig in a l a r t ic l e 56 sajhivmed june 2014, vol. 15, no. 2 available for 61.8% of the women, namely 881 live births, 1 neonatal death, 4 stillbirths and 2 miscarriages. of the 881 in fants tested at ~6 weeks of age, only two (0.2%) were hiv-infected. discussion the data provided an interesting reflection on the pmtct programme. while pregnant women in the review accessed antenatal care relatively late, in the second trimester, there were no lengthy delays in initiating art in patients who reached the hiv management sites, even prior to the introduction of nimart in antenatal clinics. despite several challenges in the antiretroviral (arv) roll-out in the past few years, the data showed that there were pockets of excellence. in the facilities where the intervention increased time to initiation, there are several possible reasons for this: there could have been a shortage of skilled and properly trained staff to manage art-eligible pregnant women in the antenatal clinics; and during the early stages of the introduction of nimart, antenatal clinics were only able to initiate treatment on select days. conclusion while the updated pmtct guidelines recommend starting all hivinfected pregnant women on art at the first antenatal visit, to reduce delays in initiating therapy, focus needs to shift from quantity to quality. as the number of patients on treatment increases, clinicians need to ensure that they provide high-quality services with appropriate clinical and laboratory monitoring, and long-term retention of patients in care. references 1. mcintyre j. use of antiretrovirals during pregnancy and breastfeeding in low-income and middle-income countries. curr opin hiv aids 2010;5(1):48-53. [http://dx.doi. org/10.101097/coh.0b013e328333b8ab] 2. sturt as, dokubo ek, sint tt. antiretroviral therapy (art) for treating hiv infection in art-eligible pregnant women. cochrane database syst rev 2010;17(3):cd008440. 3. marazzi mc, palombi l, nielsen-saines k, et al. extended antenatal use of triple antiretroviral therapy for prevention of mother-to-child transmission of hiv-1 correlates with favourable pregnancy outcomes. aids 2011;25(13):1611-1618. [http:// dx.doi.org/10.1097/qad.0b013e3283493ed0] 4. melekhin vv, shepherd be, stinnette se, et al. antiretroviral therapy initiation before, during, or after pregnancy in hiv-1-infected women: maternal virologic, immunologic, and clinical response. plos one 2009;4(9):e6961. [http://dx.doi.org/10.1371/journal. pone.0006961] 5. national department of health, south africa; south african national aids council. clinical guidelines: pmtct (prevention of mother-to-child transmission), 2010. pretoria: south african national department of health, 2010. 6. dohrn j, nzama b, murrman m. the impact of hiv scale-up on the role of nurses in south africa: time for a new approach. j acquir immune defic syndr 2009;52:s27-s29. [http://dx.doi.org/10.1097/qai.0b013e3181bbc9e4] 7. myer l. initiating antiretroviral therapy in pregnancy: the importance of timing. j acquir immune defic syndr 2011;58(2):125-126. [http://dx.doi.org/10.1097/ qai.0b013e31822ad573] 8. van der merwe k, chersich mf, technau k, umurungi y, conradie f, coovadia a. integration of antiretroviral treatment within antenatal care in gauteng province, south africa. j acquir immune defic syndr 2006;43(5):577-581. [http://dx.doi. org/10.1097/01.qai.0000243099.72770.d2] 9. killam wp, tambatamba bc, chintu n, et al. antiretroviral therapy in antenatal care to increase treatment initiation in hiv-infected pregnant women: a stepped-wedge evaluation. aids 2010;24(1):85-91. [http://dx.doi.org/10.1097/ qad.0b013e32833298be] 10. stinson k, jennings k, myer l. integration of antiretroviral therapy services into antenatal care increases treatment initiation during pregnancy: a cohort study. plos one 2013;8(5):e63328. [http://dx.doi:10.1371/journal.pone.0063328] table 1. baseline characteristics and timing of art initiation facilities a b c d e baseline cd4+ count (cells/µl) mean (±sd) 211 (±85) 223 (±86) 215 (±87) 240 (±112) 228 (±81) median (iqr) 214 (151 284) 234 (147 299) 225 (152 286) 245 (174 299) 235 (169 296) range 15 344 27 350 23 350 25 650 45 351 gestational age at 1st antenatal visit (weeks) mean (±sd) 20.7 (±6.4) 17.4 (±6.2) 19.9 (±5.9) 18.1 (±6.9) 19.5 (±6.9) median (iqr) 20 (16 24) 18 (12 20) 20 (16 24) 16 (12 24) 20 (15 24) range 8 36 4 30 8 32 4 36 5 36 gestational age at art initiation (weeks) mean (±sd) 25.4 (±6.4) 22.0 (±5.8) 24.3 (±5.5) 24.6 (±6.6) 25.1 (±6.3) median (iqr) 25 (21 30) 21 (18 27) 25 (20 28) 24 (20 30) 25 (21 30) range 12 37 8 34 14 36 11 39 10 38 time to initiation prior to nimart (weeks) mean (±sd) 1.6 (±0.5) 4.0 (±2.7) 5.5 (±2.5) 2.6 (±0.8) 3.3 (±1.8) median (iqr) 1.9 (1.3 2.3) 3.1 (2.0 5.1) 5.6 (1.7 7.0) 2.4 (1.9 3.2) 2.8 (1.9 5.1) range 1.0 2.3 0.9 10.6 1.1 12.6 1.6 4.0 1.3 5.9 time to initiation after nimart (weeks) mean (±sd) 2.0 (±1.9) 4.4 (±3.3) 3.8 (±3.5) 5.7 (±3.8) 6.6 (±3.9) median (iqr) 1.3 (1.0 2.3) 3.7 (2.4 5.1) 2.1 (1.4 4.9) 4.1 (3.0 8.1) 6.0 (4.0 8.8) range 0 9.7 0 18.9 0.7 15.7 0.7 18.4 0.6 18.7 art = antiretroviral therapy; sd = standard deviation; iqr = interquartile range; nimart = nurse-initiated management of antiretroviral therapy. http://dx.doi.org/10.101097/coh.0b013e328333b8ab] http://dx.doi.org/10.101097/coh.0b013e328333b8ab] http://dx.doi.org/10.1097/qad.0b013e3283493ed0] http://dx.doi.org/10.1097/qad.0b013e3283493ed0] http://dx.doi.org/10.1371/journal.pone.0006961] http://dx.doi.org/10.1371/journal.pone.0006961] http://dx.doi.org/10.1097/qai.0b013e3181bbc9e4] http://dx.doi.org/10.1097/qai.0b013e31822ad573] http://dx.doi.org/10.1097/qai.0b013e31822ad573] http://dx.doi.org/10.1097/01.qai.0000243099.72770.d2] http://dx.doi.org/10.1097/01.qai.0000243099.72770.d2] http://dx.doi.org/10.1097/qad.0b013e32833298be] http://dx.doi.org/10.1097/qad.0b013e32833298be] http://dx.doi:10.1371/journal.pone.0063328] abstract introduction methodology results discussion conclusion acknowledgements references about the author(s) asandile mathamo department of paediatrics and child health, faculty of clinical medicine, university of kwazulu-natal, durban, south africa kimesh l. naidoo department of paediatrics and child health, faculty of clinical medicine, university of kwazulu-natal, durban, south africa department of paediatrics, king edward viii hospital, durban, south africa jienchi dorward nuffield department of primary care health sciences, university of oxford, oxford, united kingdom centre for the aids programme of research in south africa (caprisa), university of kwazulu-natal, durban, south africa thashir archary department of engineering, university of the witwatersrand, johannesburg, south africa christian bottomley london school of hygiene and tropical medicine, london, united kingdom moherndran archary nuffield department of primary care health sciences, university of oxford, oxford, united kingdom centre for the aids programme of research in south africa (caprisa), university of kwazulu-natal, durban, south africa citation mathamo a, naidoo kl, dorward j, et al. covid-19 and hiv viral load suppression in children and adolescents in durban, south africa. s afr j hiv med. 2022;23(1), a1424. https://doi.org/10.4102/sajhivmed.v23i1.1424 original research covid-19 and hiv viral load suppression in children and adolescents in durban, south africa asandile mathamo, kimesh l. naidoo, jienchi dorward, thashir archary, christian bottomley, moherndran archary received: 01 july 2022; accepted: 19 aug. 2022; published: 02 dec. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the coronavirus disease 2019 (covid-19) pandemic poses challenges to paediatric and adolescent hiv treatment programme. modelling exercises raised concerns over potential impact of disruptions. objectives: to describe the impact of the covid-19 pandemic on viral load (vl) testing among infants, children and adolescents on antiretroviral treatment (art) in durban, south africa. method: routinely collected, aggregated data of monthly vl counts done on all those less than 19 years old from january 2018 to january 2022 was analysed. an interrupted time series analysis using a prais-winsten linear regression model, including terms for lockdowns and excess mortality determined vl trends. results: the unadjusted mean vl was 2166 (confidence interval [ci]: 252.2) and 2016 (ci: 241.9), p = 0.039, and percentage vl suppression rates (72.9%, ci: 2.4% vs 73.6%, ci: 1.8%) across covid and pre-covid periods, showing no significant difference, p = 0.262. in the interrupted time series analysis, modelled monthly vl counts did not differ significantly by lockdown level (e.g., level 5 lockdown: –210.5 vls, 95% ci: –483.0 to +62.1, p = 0.138) or excess mortality (–0.1, 95% ci: –6.3 to 6.1, p = 0.969). a significant downward trend in vl testing over time, including during the pre-covid-19 period (–6.6 vl per month, 95% ci: –10.4 to –2.7, p = 0.002), was identified. conclusion: viral load suppression for children and adolescents were not negatively affected by covid-19. a trend of decrease in vl testing predated covid-19. what this study adds: evidence presented that hiv vl testing and suppression rates in children and adolescents in a high burden setting were sustained through the covid pandemic. keywords: paediatric hiv, viral load testing, covid-19, children, south africa. introduction antiretroviral treatment (art) coverage for children with hiv has lagged compared to adults in sub-saharan africa.1 the joint united nations programme on hiv/aids (unaids) has set a target, framed within the ‘95-95-95 strategy’, to eliminate new hiv infections by 2030.2 in south africa (sa) in 2017, 84.8% of people living with hiv (plhiv) were aware of their status, 70.7% were on art, and for those on art, 87.4% had suppressed viral loads (vls).3 in children and adolescents, the situation is worse, with only an estimated 54.0% of children under the age of 15 living with hiv receiving art.4 the coronavirus disease 2019 (covid-19) pandemic has disrupted healthcare provision and health-seeking behaviour and poses challenges to hiv treatment programmes.5 kwazulu-natal (kzn) has the largest hiv disease burden of all provinces in sa, and the ethekwini district has the largest child and adolescent antiretroviral programme in the province.2 while these programmes are making significant inroads, concerns remain regarding their efficiency and sustainability, especially with the onset of the covid-19 pandemic.5 the covid-19 pandemic has called for the extra mobilisation of existing health resources, including those allocated to hiv services.3 in addition, lockdown measures have resulted in delayed deliveries of art orders and widening socio-economic inequalities exacerbating poor medical outcomes.5,6,7,8,9 various modelling studies have suggested that an interruption of art would increase mother-to-child transmission of hiv by approximately 1–6 times and potentially increase aids-related deaths overall in sub-saharan africa.5,10 interventions that have been shown to enhance adherence include directly observed treatment therapy, personalised treatment plans, medication diaries, and community-based support. these are affected by covid-19 lockdown regulations and may lead to suboptimal treatment adherence and retention to care.9,10,11 covid-19 lockdowns also increase the risk of infectious diseases like tuberculosis (tb) by encouraging home quarantine and prolonged contact at the household level.12 the redirection of hiv healthcare funding and other resources could result in an inability to adequately support plhiv along the continuum of care. while the most important impact of the pandemic on hiv programmes is art interruption, the effects on hiv prevention, testing services, self-management and treatment adherence are also significant.10,13 the long-term implications of covid-19 on health outcomes in infants, children and adolescents with hiv remain unknown, and there remains a lack of long-term studies on this vulnerable population in lowand middle-income countries (lmic). this study aims to describe the impact of the covid-19 pandemic on vl testing among infants, children and adolescents on art in the ethekwini district, kzn, sa. methodology this was a retrospective cohort study that reviewed the facility-level vl data of infants, children and adolescents on art across all public sector art clinics in the city of durban (ethekwini district), kzn. durban has an estimated 1.7 million plhiv in kzn, with 48 037 children under 15 years documented to be on art and an overall hiv prevalence of 27%.14,15 the study period included 26 months designated as the pre-covid-19 period (01 january 2018 to 28 february 2020) and 23 months of the designated covid-19 period (01 march 2019 to 31 january 2022). south africa implemented a level 5 lockdown (the most severe of the five designated lockdown levels) at midnight on 26 march 2020,16,17 and these restrictions were applied nationwide. level 5 lockdown prohibited non-essential movement and mandated closure of non-essential businesses, schools and services. health workers were exempt from movement restrictions, including clinical staff and data capturers. antiretroviral treatment is provided free of charge at all clinics in ethekwini, which remained open during the entire study period. before and throughout these lockdown periods, there were no reports of art stock-outs in the study clinics. in addition, despite increased demands on laboratory testing for covid-19, hiv vl testing capacity remained high and guidelines on vl testing remained unchanged throughout the study period. data were collected from the national health laboratory service (nhls) electronic registers and tier.net (three interlinked electronic registers for tb and hiv), a database for the facility-based patient management system in ethekwini district. data on the number of vl tests done per month at each clinic are routinely recorded in tier.net and reported by gender and age group. during collation of the data per facility, the data were de-duplicated using a combination of first name, surname, date of birth and gender. we collected data from children and adolescents up to and including 19 years of age for the study period. we used predefined periods related to the national lockdowns and covid-19 waves determined by the national institute for communicable diseases unit (nicd). anonymised facility-level data were aggregated into monthly counts of numbers of vl tests done in specific age groups: 0–12 months, 12–60 months, 60 months – 15 years and 15–19 years. we categorised the vl results into three groups: under 10 000 copies/ml, between 10 000 and 100 000 copies/ml and over 100 000 copies/ml. we used excess mortality data for ethekwini from the south african medical research council report on weekly deaths in south africa.18 data analysis and interpretation we used descriptive statistics to summarise demographic data and numbers of vls taken per month during the study period. we also calculated the mean vl tests per month before and during covid-19. because this does not consider pre-existing trends in vls, we conducted interrupted time series analyses by fitting a prais-winsten linear regression model to account for autocorrelation. the model included a time variable, a continuous variable for excess mortality in ethekwini, a dummy variable for each sa lockdown level 1 to 5, and a dummy variable for december when clinical activities are generally much reduced due to sa national holidays. this approach considers pre-lockdown trends and allows estimation of the effect of covid-19 restrictions through lockdowns and the impact of covid-19 waves on healthcare. because different severe acute respiratory syndrome coronavirus 2 (sars-cov-2) variants caused different levels of morbidity and mortality, we used excess mortality as a proxy for the impact of covid-19 epidemic waves on the healthcare system. we conducted a sensitivity analysis with a negative lag of one month for excess mortality to account for the delays between sars-cov-2 infection, illness, hospitalisation and death. we used a separate dummy variable for each lockdown level to determine whether only a certain lockdown level affected vl numbers. we also built separate models for each age group. we analysed data using r 4.2 (r foundation for statistical computing, vienna, austria). ethical considerations this work was approved by the university of kwazulu-natal biomedical research ethics committee (brec/00003541/2021), the kwazulu-natal department of health’s provincial health research ethics committee (kz_202111_016), the ethekwini municipality health unit, and the ethekwini district health department, with a waiver for informed consent for analysis of anonymised, routinely collected data. results during the study period that extended from 01 january 2018 to 31 january 2022, a total of 102 624 vl tests were done on all patients 19 years and younger across all clinics in the ethekwini district. of these, 2293 (2%) were from infants under one year of age, 8089 (8%) from children between one and five years, 52 704 (51%) from children between five and 15 years and 39 538 (39%) in those aged 15 to 19 years. across all age groups, the mean number of vls done per month was 2095 (standard deviation [s.d.]: 256, range: 1472–2652 samples). table 1 compares the unadjusted mean number of vls done between the pre-covid-19 and covid-19 periods. while the mean was significantly less in the covid-19 period, there was no significant difference in the vl suppression between these periods. table 1: comparison of viral loads done and percentage of patients virologically suppressed over the study period. of all the vls done in the study period, 73% were below 1000 copies/ml, indicating viral suppression. the percentage of patients virologically suppressed by age group was 66%, 63%, 76% and 73% for children below 1 year, 1–5 years, 5–15 years and 15–19 years. there was no significant difference in the percentage of virologically suppressed patients when we compared the pre-covid-19 to the covid-19 periods. interrupted time series analysis in the linear regression model of numbers of monthly vls taken among all patients 19 years old and younger that considers pre-covid-19 trends, there was strong evidence that fewer vls were done in december than in other months (partly due to fewer clinic days available in this annual holiday month compared with other months) (table 2 and figure 1). figure 1: trends in monthly viral loads among under-19-year-olds before and during covid-19, and relationships with lockdown levels and excess mortality in ethekwini, south africa. table 2: linear regression model of trends in monthly viral loads taken among all under-19s in ethekwini from january 2018 to january 2022. although there was some suggestion that the number of vls done reduced during level 5 lockdown and level 4 lockdown, neither of these effects was statistically significant. of note, there was a large increase in vls in the month before the level 5 lockdown, which may have offset the impact of the level 5 lockdown. overall, there was evidence of a gradual decrease in the number of vls taken over time (a decrease of six vls per month). this trend was apparent in both the pre-covid-19 and the covid-19 periods. there was no evidence of an impact of covid-19 variants (using excess mortality as a proxy for covid-19 disruption to healthcare services) during various waves (table 2 and figure 1), including in sensitivity analysis using a 1-month lag for excess mortality that considers the delay between epidemic peaks in sars-cov-2 infections and subsequent deaths. in analyses stratified by age (table 3 and figure 2), there was evidence that vls decreased in december 2020 and december 2021 for all age groups, except those under 1 year old. viral load numbers decreased with time in 1–4-year-olds and 5–15-year-olds. there was also evidence that the level 5 lockdown led to a decrease in vls taken among 5–15-year-olds. figure 2: interrupted time series analysis by age group. table 3: linear regression analyses of monthly viral loads stratified by age. discussion this study reports on a large cohort of children and adolescents in hiv care in kzn spanning four years. we found that while the covid-19 pandemic had no marked impact on vl testing and suppression rates, there were significant decreases in vl testing rates before the covid-19 pandemic, which persisted during covid-19. several modelling studies and early reviews from lmic have raised concerns about the sustainability of art programmes within the fragile healthcare systems in sub-saharan africa following the covid-19 pandemic. studies that reviewed care among children and adolescents during the covid-19 pandemic documented decreases in general paediatric admissions and general outpatient and emergency visits across the world, including sa.1,19,20,21 in this study, while vl testing decreased between the pre-covid-19 and covid-19 periods, this was largely due to continuation of a pre-existing trend of decreased vls before the covid-19 pandemic, as demonstrated in the linear regression comparison models. there was also some evidence that level 5 lockdown impacted significantly on vl numbers among 5–14-year-olds who are mostly schoolgoing children, but the impact of lockdown measures was not significant in other groups or at other lockdown levels. viral load testing can be a proxy marker of both retention in care and the delivery of appropriate monitoring while in care. these findings correlate with other studies that indicated the general preservation of art clinic visits even during the covid-19 pandemic.1,6,12,22 we also found vl suppression rates of more than 70% in this study population over both study periods, similar to other sub-saharan africa studies pre-covid-19.23,24 viral load suppressions rates in this study were maintained throughout almost two years of the covid-19 period and a similar period preceding, indicating infants, children and adolescents have maintained adherence to art regimens. both these findings suggest that the art programmes in the district have the robustness to continue to provide similar care to clients already in the programme and on art despite the pandemic-related disruptions experienced. previous studies from lmics have rarely evaluated art treatment programmes longitudinally over the different covid-19 waves and various national lockdown levels imposed by a national government. in this study, using excess mortality as a proxy, the linear regressions model indicated that art programmes were sustained during all varying levels of disruption experienced during varying covid-19 waves and various lockdown levels. pre-lockdown stocking up, multi-month prescribing and differentiated art delivery platforms have been documented as possible reasons for the sustained care seen specifically in the art programmes.22,25,26 this maintenance of care contrasted sharply with decreases noted over the same time periods with general paediatric hospitalisation rates and outpatient visits. these findings add to the limited data on the impact of the covid-19 pandemic on paediatric art programmes that remained robust for those already on treatment. lessons learned from these programmes can be used to inform other care platforms delivering chronic care to patients.21,27 of significance, this study identified a concerning trend of decreasing vl testing, especially in children between four and 15 years of age. the decrease preceded the covid-19 pandemic and suggests fundamental shifts in art care may be at play. the vl test guidelines remained the same during the study period, recommending annual vl testing for patients in chronic art care. in 2019, the south african national department of health (ndoh) introduced dolutegravir to the programme for children and adolescents over 20 kg with a suppressed vl. we would have expected an increase in vl testing in 2019, which was not seen in this study. apart from guideline changes, service delivery changes may impact the sa art programme, including the large kzn programme catering to children and adolescents. these include active encouragement of down-referral of children from hospital-centric clinics to primary healthcare clinics and amalgamation of hiv care into general outpatient services in larger facilities. many of these down-referrals result in a move away from previous child-friendly clinical, social and peer group support, which is much needed.9,11 in addition, non-governmental support for many of these clinics, including additional staffing, has diminished since 2018, mainly due to funding challenges. the covid-19 pandemic has exacerbated this.26 increasing task shifting to clinics, with existing staff shortages, may also be diluting support and specialised care afforded to families deemed at risk of complying with the strict compliance requirements for the sa art programme. the covid-19 pandemic has exacerbated the socio-economic strife for many such at-risk families, which may limit their ability further. the trend in vl testing rates away from rather than towards achieving the unaids goal of 95% of children on art having a suppressed vl requires a more urgent in-depth understanding. limitations this study focuses on one district in one province of sa and may not reflect specific challenges or strengths in programmes across the country. however, kzn has the largest proportion of patients in hiv care in the country, and the ethekwini district is home to almost 50% of the province. this study did not utilise patient-specific data but rather aggregated facility-level data; therefore, we cannot directly translate the number of vls performed to the number of patients in care. of note, this study did not evaluate hiv testing and art initiation rates which have been found to have decreased with the covid-19 pandemic in other studies. conclusion despite changes in both lockdown restrictions and the burden of disease, the number of both vl tests done and the percentage of unsuppressed vls were not markedly impacted by the covid-19 pandemic. paediatric vl testing across the ethekwini district, kzn, remained largely robust through the covid-19 pandemic negating the predicted negative modelled scenarios. however, a long-term trend of slow reduction in the number of vls done preceding the covid-19 pandemic requires further evaluation. it may be due to changes in service delivery to children on art in the district. acknowledgements leora sewnarain for assistance with formatting and language review. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions a.m., k.l.n., t.a. and m.a. were responsible for the study design, data collection and drafting of the manuscript. j.d. and c.b. were responsible for data analysis and logistic modelling. k.l.n. and m.a. were responsible for supervising the entire work, study design and manuscript review. all authors read and approved the final manuscript. funding information there was no funding for this study. j.d. is supported by grants from the wellcome trust phd programme for primary care clinicians (216421/z/19/z). data availability the data sets used and analysed during the current study are available from the corresponding author, k.l.n., on reasonable request. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references jensen c, mckerrow nh. child health services during a covid-19 outbreak in kwazulu-natal province, south africa. s afr med j. 2020;111(2):13185. https://doi.org/10.7196/samj.2021.v111i2.15243 joint united nations programmes on hiv/aids (unaids). unaids strategy 2016–2021 [homepage on the internet]. [cited 2022 jun 02]. available from: https://www.unaids.org/en/goals/unaidsstrategy marinda e, simbayi l, zuma k, et al. towards achieving the 90-90-90 hiv targets: results from the south african 2017 national hiv survey. bmc public health. 2020;20(1):1375. https://doi.org/10.1186/s12889-020-09457-z united nations children’s fund (unicef). paediatric care and treatment [homepage on the internet]. 2021 [cited 2022 jun 02]. available from: https://data.unicef.org/topic/hivaids/paediatric-treatment-and-care/ jewell bl, mudimu e, stover j, et al. potential effects of disruption to hiv programmes in sub-saharan africa caused by covid-19: results from multiple mathematical models. lancet hiv. 2020;7(9):e629–e640. https://doi.org/10.1016/s2352-3018(20)30211-3 prabhu s, poongulali s, kumarasamy n. impact of covid-19 on people living with hiv: a review. j virus erad. 2020;6(4):100019. https://doi.org/10.1016/j.jve.2020.100019 ponticiello m, mwanga-amumpaire j, tushemereirwe p, nuwagaba g, king r, sundararajan r. ‘everything is a mess’: how covid-19 is impacting engagement with hiv testing services in rural southwestern uganda. aids behav. 2020;24(11):3006–3009. https://doi.org/10.1007/s10461-020-02935-w waterfield kc, shah gh, etheredge gd, ikhile o. consequences of covid-19 crisis for persons with hiv: the impact of social determinants of health. bmc public health. 2021;21(1):299. https://doi.org/10.1186/s12889-021-10296-9 mhango m, chitungo i, dzinamarira t. covid-19 lockdowns: impact on facility-based hiv testing and the case for the scaling up of home-based testing services in sub-saharan africa. aids behav. 2020;24(11):3014–3016. https://doi.org/10.1007/s10461-020-02939-6 nachega jb, grimwood a, mahomed h, et al. from easing lockdowns to scaling up community-based coronavirus disease 2019 screening, testing, and contact tracing in africa-shared approaches, innovations, and challenges to minimise morbidity and mortality. clin infect dis. 2021;72(2):327–331. https://doi.org/10.1093/cid/ciaa695 nyasulu j, pandya h. the effects of coronavirus disease 2019 pandemic on the south african health system: a call to maintain essential health services. afr j prim health care fam med. 2020;12(1):e1–e5. https://doi.org/10.4102/phcfm.v12i1.2480 dorward j, khubone t, gate k, et al. the impact of the covid-19 lockdown on hiv care in 65 south african primary care clinics: an interrupted time series analysis. lancet hiv. 2021 mar 1;8(3):e158–e165. https://doi.org/10.1016/s2352-3018(20)30359-3 plevinsky jm, young ma, carmody jk, et al. the impact of covid-19 on pediatric adherence and self-management. j pediatr psychol. 2020;45(9):977–982. https://doi.org/10.1093/jpepsy/jsaa079 massyn n, barron p, day c, ndlovu n, padarath a, editors. district health barometer 2018/19 [homepage on the internet]. durban: health systems trust; 2020 [cited 2022 jun 02]. available from: https://www.hst.org.za/publications/district%20health%20barometers/district+health+barometer+2018-19+web.pdf human sciences research council. south african national hiv prevalence, incidence, behaviour and communication survey, 2017 [homepage on the internet]. [cited 2022 jun 02]. available from: http://www.hsrc.ac.za/uploads/pagecontent/10779/sabssm%20v.pdf republic of south africa. government gazette. vol. 451. cape town; 15 january 2003. no. 24252. no. 57 of 2002: disaster management act, 2002 [homepage on the internet]. [cited 2022 jun 02]. available from: https://www.gov.za/sites/default/files/gcis_document/201409/a57-020.pdf republic of south africa. covid-19/novel coronavirus – regulations and guidelines – coronavirus covid-19 [homepage on the internet]. [cited 2022 jun 02]. available from: https://www.gov.za/covid-19/resources/regulations-and-guidelines-coronavirus-covid-19 south african medical research council (samrc). report on weekly deaths in south africa [homepage on the internet]. [cited 2022 jun 02]. available from: https://www.samrc.ac.za/reports/report-weekly-deaths-south-africa kruizinga md, peeters d, van veen m, et al. the impact of lockdown on pediatric ed visits and hospital admissions during the covid19 pandemic: a multicenter analysis and review of the literature. eur j pediatr. 2021;180(7):2271–2279. https://doi.org/10.1007/s00431-021-04015-0 williams tc, macrae c, swann ov, et al. indirect effects of the covid-19 pandemic on paediatric healthcare use and severe disease: a retrospective national cohort study. arch dis child. 2021;106(9):911–917. https://doi.org/10.1136/archdischild-2020-321008 chiabi a, forgwei mn, bissong m, niba l, abah jn, nsame d. trends in pediatric hospitalisations and mortality during the covid-19 pandemic in an urban setting in cameroon. j trop pediatr. 2022;68(3):fmac026. https://doi.org/10.1093/tropej/fmac026 jarolimova j, bunda ba, govere sm, et al. experiences of participants in a decentralised hiv medication distribution program in south africa during the covid-19 pandemic. j int aids soc. 2020;23:178. boerma rs, boender ts, bussink ap, et al. suboptimal viral suppression rates among hiv-infected children in lowand middle-income countries: a meta-analysis. clin infect dis. 2016;63(12):1645–1654. https://doi.org/10.1093/cid/ciw645 njuguna i, neary j, mburu c, et al. clinic-level and individual-level factors that influence hiv viral suppression in adolescents and young adults: a national survey in kenya. aids. 2020;34(7):1065–1074. https://doi.org/10.1097/qad.0000000000002538 wilkinson l, grimsrud a. the time is now: expedited hiv differentiated service delivery during the covid-19 pandemic. j int aids soc. 2020;23(5):e25503. https://doi.org/10.1002/jia2.25503 golin r, godfrey c, firth j, et al. pepfar’s response to the convergence of the hiv and covid-19 pandemics in sub-saharan africa. j int aids soc. 2020;23(8):e25587. https://doi.org/10.1002/jia2.25587 mcintosh a, bachmann m, siedner mj, et al. effect of covid-19 lockdown on hospital admissions and mortality in rural kwazulu-natal, south africa: interrupted time series analysis. bmj open. 2021;11(3):e047961. https://doi.org/10.1136/bmjopen-2020-047961 the southern african journal of hiv medicine                                                              april  2010 5 m e s s a g e f r o m t h e e x e c u t i v e weirdness appears to be affecting african hiv prevention efforts recently. governments seem to think that criminalising hiv transmission, on a continent where the vast majority of people do not know their status, is an important way to control hiv. legislation has been enacted, or is being considered in several countries, despite evidence that this simply stigmatises people with hiv. a particularly bizarre and disturbing bill being considered in uganda called for the death penalty against gay men who transmit hiv (implying that it is more ok to transmit if you are straight). it also implies that hiv in uganda, where numbers of cases have been on the rise for the past few years, is driven by gay men, when all data suggest that the epidemic remains heterosexual. human rights and other organisations appear to have stopped the uganda bill; not because it was seen as dangerous, rather because it was a threat to donor funding – obama called the bill ‘odious’. you can read our letter to the ugandan parliament at http:// www.sahivsoc.org/. what is most frustrating, though, is the silence of the medical fraternity in all this. where are the local health care worker and public health organisations, condemning their government’s idiocy? for too long patients have had to rely on treatment activist organisations and international agencies to protect them. health care worker organisations should loudly condemn unscientific approaches to dealing with hiv, especially when these may harm their patients. hiv prevention has proven very complicated. quick-fix, emotional, prejudiced and unscientific solutions are hardly going to help. governments listen to health care workers, as we have status and power. organisations need to stand up to dangerous policy and legislation. francois venter president it is an interesting time in south africa ... with public debate on education, the judicial system, and whether or not politicians should be allowed to say and sing what they like in public, to name just a few issues. the journal also takes on controversy this quarter, and i hope will elicit some debate. i remind you that the opinions expressed in its pages are not necessarily supported by the editorial committee or the clinicians society! the first three papers in this issue are such articles, the first being the ruben sher memorial lecture delivered by judge edwin cameron some weeks ago. he describes his own testing experience and makes a case for why the human rights activism around testing is less relevant in the era of effective hiv treatment, and why hiv testing should be normalised. the sa government will be attempting to do just that through countrywide scale-up of testing. an intriguing article probes the impact of a ‘sexual abstinence month’, and kenyon grapples with some epidemiological ‘holy cows’ and questions the attribution of poverty as a driver for the epidemic in southern africa. the new public sector guidelines are out, and for easy reference we asked celicia serenata from sanac to give a succinct summary of the differences. our review this quarter looks at cytomegalovirus co-infection, but also comments on treatment options for south african practitioners and calls for antiviral price review. we thank visiting opthalmologist sophia pathai for her corroborating comment. the last three articles are original research. the first looks at mortality trends in a hospital district after the introduction of art, the second at mental health, and the third at laboratory abnormalities in hiv-infected pregnant women. remember, we will welcome your letters should any of the above invoke the need to respond! however, i hope this edition will also raise discussions at your place of work and among your colleagues. whichever, i hope you enjoy it, and am happy that we have got to a position in our country where relevant and appropriate issues can be freely debated. linda-gail bekker editor f r o m t h e e d i tor the southern african journal of hiv medicine                                                          winter  2008spring  2008                                                          the southern african journal of hiv medicine                                                   f r o m t h e e d i to r the journal is starting to feel like men’s health, what with posters, guidelines and now a state-of-the art science update, hiv treatment bulletin, falling out of it. exco is pleased to announce an important and strategic partnership with hiv ibase, who publish hiv treatment bulletin. we are distributing the southern african version of their excellent newsletter, which will exclusively focus on the scientific reports and resources that have local relevance – with a strong focus on paediatrics and maternal health. hiv treatment bulletin neatly complements the journal, providing the snobbish clinician and scientist with the most hot-off-the-press analysis of recent clinical trials and basic science research. policy makers can authoritatively pronounce at their guidelines meetings, clinicians can expand their patients’ options, and, most importantly, you can show off at ward rounds. thanks to all the people at i-base, this is a major step forward for quality information sharing. we wish the new health minister, barbara hogan, all the best. she has very small shoes to fill, but a mammoth task ahead of her to repair south africa’s woeful health service. at the time of writing, she and her deputy, dr molefi sefularo, have been very impressive, dealing with a cholera disaster, drug stock-outs, issues of prevention, releasing controversial reports that were stuck on her predecessor’s desk for months, and a dozen other complex health problems. finally, the exco welcomes two new members based in durban, professor yunus moosa and dr henry sunpath, both highly respected clinicians and part of the team responsible for an excellent hiv clinical conference held in october. francois venter president this spring edition brings 2008 to a close. and what a year it has been. not many breakthroughs in hiv or tb, but a lot of activity in terms of understanding early infection better, really getting to grips with early immune responses, and again thinking through our prevention options. in 2008 the concept of antiretrovirals for prevention as well as treatment has come to the fore with second-generation microbicides, pre-exposure prophylaxis and the notion that we may be able to ‘treat our way out of the epidemic’ becoming possibilities. gratifyingly, this year also saw a record number of people being tested and accessing art, and roll-out for both testing and treatment is truly scaling up. as chairperson of the 4th southern african hiv conference i must encourage every one of you to think seriously about coming to durban on 31 march. it promises to be a critical conference where we will really formulate the key steps in getting pmtct, treatment, testing and prevention out there on a scale that will begin to turn the sa statistics around. (i promise that it will also be loads of fun!) please note the early date this year: 31 march to 3 april. this is to ensure brilliant kzn weather! in this edition, we already begin to examine some of these key scale-up questions: jerome singh explores the ethics and legality of traditional healers performing hiv testing (i know many have asked why this has to be the domain of nurses only). francesca esposito and her team examine changes in body composition in women taking antivirals in a kzn clinic. we look at the role of mobile phones in the hiv response with william mapham, and polly clayden gives us pointers to starting infants on art. the role of a liver biopsy in diagnosis of opportunistic infections is described by mark sonderup and colleagues. the vexed question of when it is deemed safe to start haart in patients co-infected with tb is discussed by robin wood, and francois venter and colleagues give a practical view on new antiretrovirals on the horizon for south african practitioners. no guidelines in this issue, but i will whet your appetites – look out for guidelines on prevention of tb occupational exposure for hiv-infected health care workers and on the non-infertile hiv infected couple, hot stuff coming up in the new year! happy reading and every best wish for a restful and peaceful festive season from the whole editorial team. see you next year! linda-gail bekker editor m e s s a g e f r o m t h e e x e c u t i v e � msg from the executive.indd 5 12/17/08 3:16:23 pm safety.html review safety, strength and simplicity of efavirenz in pregnancy prinitha pillay, bsc hons, mb bch, dip infect dis vivian black, bsc, mb bch, dip infect dis wits reproductive health and hiv institute (wrhi), university of the witwatersrand, johannesburg the who recommends starting lifelong art for all pregnant women with a cd4 count at or below 350 cells/mm³, which recognises the important component of ‘when to start’ and the role that timing of initiation plays in reducing mortality and disease progression. the data on ‘what to start’ are conflicting, and options for resource-limited settings are limited. the choice of an art regimen for pregnant women is complicated by the need to take into account the health and safety of both the mother and baby. particularly contentious is whether to use a nevirapine(nvp) or efavirenz(efv) based regimen. this review presents the latest evidence on the safety and efficacy of efv and nvp in pregnancy and offers recommendations for improving maternal and child health outcomes and avoid mother-to-child transmission as south africa moves toward turning back the tide on its hiv epidemic. estimates for south africa for 2010 were that approximately 5.6 million people were hiv-infected,1 accounting for the largest number of cases in a single country.2 according to the latest south african national antenatal survey (2010), 30.2% of pregnant women in south africa were hiv-positive,3 maternal mortality was 6 times higher among hiv-positive women, and more than half of all maternal deaths were attributable to hiv.4 about 40 000 children in south africa are infected with hiv each year, with hiv/aids a major contributor to infant mortality in south africa.5 but amidst the bad news has been some good: more than 1.56 million people in south africa are now receiving art, and the introduction of more robust and better-tolerated antiretrovirals (arvs) such as tenofovir disoproxil fumarate (tdf) for first-line therapy is narrowing the gap between recommended treatment protocols in rich and poor countries. in addition, exciting new knowledge and evidence about the concept of ‘treatment as prevention’ (tasp) has emerged, showing not only the therapeutic but also the potential preventive benefits of art. prevention of mother-to-child transmission (pmtct) as tasp is not new – but it currently lags behind other programme goals and art scale-up efforts.6 earlier initiation of treatment for pregnant women provides extra benefits in pmtct. while efavirenz (efv) has been recommended in the who guidelines for initiation of eligible women after the first trimester; its use in pregnant women has been restricted in the south african clinical pmtct guidelines, where all pregnant women are initiated on a nevirapine (nvp)-based regimen.7 in consequence, as south africa seeks ways in which new knowledge can be integrated into existing programmes that could have measurable effects on mortality and morbidity,8 this review presents the latest evidence of safety and efficacy of efv in pregnancy. is there really an option for women? to date, limited and complicated pmtct and treatment options exist for women infected with hiv. the latest who pmtct guidelines offer lifelong art for those with cd4<350 cells/mm3 and allow resource-limited settings two options for those with cd4 >350 cells/mm³: a or b.9 option b offers all women triple therapy for the duration of pregnancy until the cessation of breast feeding for those with cd4>350 cells/mm3 . the view that option b is superior to option a is emerging, for several reasons:10 its simplicity for women and programmes, as option a is especially complicated and requires many regimen changes6 option b allows more women to have sustained exposure to haart. for those who may fall pregnant during breastfeeding, haart allows women to survive longer,11 which is important for survival of their children. option b may have an added preventative benefit for pregnant women’s partners in discordant relationships12 the unknown risk of non-nucleoside reverse transcriptase inhibitor (nnrti) resistance in the mother or infant, despite prophylaxis13 safety, effectiveness and feasibility of daily infant nvp beyond 6 months of age; and maternal and infant acceptability of daily infant prophylaxis for a long period as well as acceptability in programme settings is largely unknown option b may be better for women, with a growing consensus demonstrating that there are individual benefits for the mother as well as for public health.10 option b, although simpler, has some drawback for women who fall pregnant again or become eligible for lifelong art, as they would need to restart haart. this essentially translates into treatment interruption. some countries, such as malawi, have elaborated on option b. malawi is now implementing what is termed ‘option b+’, which is lifelong art for all pregnant women, irrespective of cd4 cell count, from 14 weeks’ gestation. to achieve this, malawi has included efv as part of a fixed-dose once-daily formulation for treatment of pregnant women. this decision was justified on the basis that the limited potential risk of birth defects owing to efavirenz is far outweighed by the increased public health benefit, coverage, and reduced overall mortality of initiating mothers on haart.14 is efavirenz safe to use in pregnancy? efavirenz’s fda rating was changed from category c to category d in 2005, based on data from animal studies and retrospective case reports of neural tube defects.15 evidence of teratogenicity linked to the use of efv in pregnancy has been limited since then, and current evidence suggests that the risk is lower than previously thought.16 , 17 current who guidelines recommend avoiding efv in the first trimester only, but also note that overall rates of birth defects in infants exposed to efv, nvp and tdf are similar to those in the general population.9 it is evident that the risk of birth defects on exposure to any of the widely used antiretroviral agents shows a similar risk (nvp 2.5%, efv 2.7% and azt 3.3%) (table 2). in addition, the risks are similar for first, second and third trimester exposures (table 3). in review of the data till 31 january 2011, among the prospective antiretroviral pregnancy registry (apr) reports, the prevalence of birth defects per 100 live births among women with a first trimester exposure to any of the antiretroviral therapies included in the apr is 2.9% (95% confidence interval (ci) 2.5 3.4) i.e. 164 outcomes with defects of 5 555 live births.18 the prevalence of defects is not significantly different from the prevalence of defects among women with an initial exposure during the second and/or third trimester of 2.7% (prevalence ratio 1.08, 95% ci 0.88 1.32)/205 birth defects in 7 483 live births.18 the apr result for efv exposure in the first trimester is 2.7% (95% ci 1.6 4.3), and 2.9% (95% ci 0.3 10) for secondand third-trimester exposure to efv. the most recent updated meta-analysis as at july 2011 (which reviews the apr and other prospective cohorts) showed a pooled prevalence of 2% (95% ci 0.82 3.18) and relative risk of birth defects in efv-containing art regimens to non-efv-based art as 0.85 (95% ci 0.61 1.20).17 this confirms no increased risk of overall birth defects among women receiving first-trimester efavirenz. comparatively, the risks in the general population are also quite similar (table 3): in the usa, the prevalence of birth defects in the general population is approximately 3% of live births; and in south africa the prevalence is estimated at 5.3%.19 however, concerns have been raised, owing to retrospective reports of myelo-meningocoeles received after the fda category change. the risk of neural tube abnormalities exists before it closes by 28 days. the prevalence of neural tube defects (ntd) globally is 0.1 0.4%, while in south africa it is estimated at 0.23 0.36%.19 the recent 2011 meta-analysis shows the incidence of neural tube defects (until july 2011) to be low, at 0.07 (95% ci 0.002 0.39).17 given the low baseline prevalence of neural tube defects, many more first-trimester efavirenz exposures would be required to quantify the risk. potentially, it would take a long time for a south african (or another country’s) registry to accumulate sufficient data to allow firmer conclusions to be drawn. in addition, a major problem of retrospective reports is the reporting bias. retrospective reports can be biased toward the reporting of more unusual and severe cases, and are less likely to be representative of the general population experience. therefore, the calculation of prevalence from these reports is often inappropriate and needs to be interpreted with caution. to summarise: current data on efavirenz use in pregnancy shows little and poorly supported evidence of risk to the fetus, with a non-significant relative risk of only 0.85 (95% ci 0.61 1.20) with efv, compared with non-efv-based exposure in the first trimester. there is no significant increase in risk of ntds with efv exposure. importantly, as for any arv drug, it is not possible to conclusively say that efv is safe, and drug companies and regulatory bodies are therefore unlikely to change the efv rating out of fear of litigation. noteworthy is the difference between category x and category d (table 4); and the latter allows policy decision-makers, clinicians and patients alike to weigh up the evidence and allow judgment in their best interests. the fda is currently proposing to update its approach to labeling.20 consequences on comprehensive sexual reproductive health another potentially harmful consequence of the efv category d rating is reported in data on termination of pregnancy (top) for women exposed to efavirenz-containing and non-efavirenz-containing regimens. these reveal a rr of 2.81 (95% ci 0.94 8.36) for efavirenz-exposed women.17 these tops are not informed by prenatal screening and could mean that women on efv are almost 3 times more likely to have a potentially distressing and unnecessary top based on the potential risk of teratogenicity and not the actual presence of a birth defect. this has far-reaching harmful consequences for the woman and for clinicians who could be inadvertently ill-advising patients on the basis of poorly supported evidence of risk. recent studies in johannesburg show that issues around providers and information transferred to patients about efavirenz risk in pregnancy are often misunderstood. in one study, 40.7% of 851 women declared that the healthcare provider had not discussed pregnancy options with them. a small proportion (6.4%) said a provider had told them not to have more children, and 36% were unsure whether their provider had approved of them having children.21 furthermore, women on both efv and nvp had similar pregnancy intentions – either trying to conceive or planning to do so.21 pettifor and rees found in 2005 that roughly 33% of women planned their pregnancies.22 complexity of personal reproductive health issues for women and their relationship with healthcare providers must be acknowledged. what do we know about the alternative – nevirapine? current who guidelines affirm the role of arvs for pregnant women, and recommend the use of arvs in differing combinations, depending on cd4 cell count, in all pregnant hiv-infected women. consequently, according to current south african guidelines, many more women will be initiated on nvp-based regimens. today, nvp is the recommended alternative to efv in women of childbearing age. the 2nn study23 (the largest randomised controlled trial (rct), with more than 1 200 patients) found no difference in efficacy between nvp and efv, and a systematic review of 7 rcts24 also found no difference at 48 weeks. the authors recognise, however, that 48 weeks of follow-up is shorter than other cohort studies, which shows that the difference between efv and nvp grows larger over time.23 when the parkland cohort study data were censored at week 48 (using the endpoint in 2nn), there were no significant differences in time to virological failure (efv = 38.9 weeks v. nvp = 37.2 weeks, p = 0.20); however, when the patient cohort data were not censored at 48 weeks, significant differences were seen between efv and nvp at 192 weeks (p<0.001).25 , 26 efv was specifically found to provide a significantly longer time to treatment failure than nvp (efv = 132 weeks v. nvp = 94.1 weeks, p = 0.027).25 , 26 additionally, in the 2nn study, fewer patients taking efv than those taking nvp experienced treatment failure (37.8% v. 47.3%).23 these results underscore the need to observe patients for longer periods of time to determine the extended durability of antiretroviral regimens. since clinical trials are often difficult and expensive to maintain, observational cohort analyses may be an alternative for examining long-term durability. many observational cohorts show that efv is superior, with an increased risk of virological failure on nvp-based art regimens.27 in june 2011, at the ias conference, a meta-analysis comparing tdf-containing regimens raised concerns that tdf/3tc/nvp might have decreased virological efficacy compared with the efv-containing tdf regimens.31 therefore, we should be concerned about initiating women or switching them to a nvp-based regimen that might not necessarily be superior because of our poorly supported evidence of teratogenicity. to date, there is conflicting evidence of severe adverse events (rash and hepatotoxicity) in pregnant women who have higher cd4 cell counts, initiating haart with a nvp-containing regimen. in 2004, boehringer-ingelheim, manufacturers of nvp (viramune) performed a retrospective analysis of hepatoxicity events and found no consistent cd4 cell-count cut-off that could be identified in women, that was associated with an increased risk of liver enzyme elevations. the analysis also demonstrated no significant differences in the rate of serious hepatic events among arv regimens, including between the non-nucleoside reverse transcriptase inhibitors nvp and efv.32 further scrutiny of this analysis revealed that patients with symptomatic events were not included in the subset analysis. it also revealed the risk of rash-associated hepatic adverse events was 3 times higher in women than in men. a rash-associated hepatic event was also associated with a higher cd4 cell count, with women with pre-treatment cd4 count >250 cells/mm3 having a higher risk of hepatotoxicity than women with cd4 <250 cells/mm³.33 following these results, the company changed the summary of product characteristics to include a caution that women with higher cd4 cell counts are at increased risk of hepatic toxicity.34 previously, it was not recommended to initiate women on nvp if their cd4 cell count was above 250 cells/mm³.35 data are now emerging from both high-income38 , 39 and resource-limited settings,32 suggesting that it is safe for patients who have experienced good increases in their cd4 cell counts on anotherarv regimen to switch to nvp (provided they have an undetectable viral load), even when their cd4 count is above the level recommended for initiating treatment. in 2009, ouyang and colleagues showed that nvp is not uniquely associated with hepatoxicity in pregnancy but rather that pregnancy itself may be an independent risk factor.40 the same study also showed that nvp is not associated with hepatoxicity at higher cd4 cell counts. chu et al.41 found in 2010 no association of cd4 cell count and hepatotoxicity; however, the median cd4 cell count in their cohort was low (112 cells/mm3 ) and, with resource-limited settings still pervaded by patients presenting late and initiated at low cd4 cell counts, this study highlights one of the possible reasons for the lack of observed difference between high-income and resource-limited settings. indeed, a cambodian cohort study in a resource limited setting found (i) that higher cd4 cell counts at the time of nvp substitution from efv increased the risk of subsequent nvp toxicity, and (ii) that art-experienced cambodians appear to have a risk of nvp toxicity comparable with that of art-naive patients, despite higher cd4 counts.42 the analysis from the large randomised clinical trial, the 2nn study, demonstrated that the rate of skin rash and hepatic events was higher in patients with cd4 counts >200 cells/ml, and also that women with cd4 counts >200 cells/mm3 had a significantly greater risk of developing a rash than men.23 , 24 the most recent data from uganda presented at the ias conference in june 2011 have documented 3 cases of stevens-johnson syndrome in stable experienced haart patients when switched to nvp.43 overall, the meta-analysis of 7 randomised controlled trials (rcts) show that efv had a lower incidence of adverse events (aes) and fewer discontinuations than nvp.24 fewer patients taking efv discontinued therapy because of any ae or hiv event than patients taking the other treatment regimens. two deaths were directly associated with nvp use (one from toxic hepatitis and the other from stevens-johnson syndrome); no deaths were associated with efv. overall, efv was associated with a more favorable tolerability profile than nvp, with less grade 3 or 4 clinical aes, fewer discontinuations for aes, and numerically less treatment changes with efv than with nvp.23 there therefore seems to be insufficient evidence to recommend that it is safe to switch nvp for efv, in particular in settings such as south africa with higher co-infection rates of tb i.e. women who are switched to and fro.44 it is possible that the who concluded that using nvp outweighs the risk of not initiating art precisely because of the lack of an alternative for resource-limited settings. this is why efv in pregnancy needs to be carefully rethought in light of the most recent evidence. the more toxic and life-threatening alternative to efv that puts a woman at increased risk needs to be urgently revisited. is efavirenz affordable and cost-effective? the prohibitively high cost of efv had prevented its widespread use in the early part of the decade, and the price evolution is demonstrative (fig. 1). the medicins sans frontieres (msf) report untangling the web reveals that the cost of efv has been driven down from the originator price of $347 in december 2002 to a who-prequalified generic price of $52 in july 2011 (per patient per year).45 despite cost, perhaps more important is a recent study looking to quantify the benefit (life expectancy gains) and risk, that shows that the use of non-efavirenz-based initial art in hiv-infected women of childbearing age may reduce life expectancy gains from art.46 the mean life expectancy for women who would start art at a cd4<250 on nvp-based haart was 25.49, compared with 27.08 for efv-based art, with a resultant 1.6-year life expectancy gain on efv compared with nvp.46 in addition, survival of women who received an efv-based art regimen was 0.89 years greater than all non-efv-based regimens.46 policymakers do indeed need to take into account cost and cost-effectiveness, but the benefit to women and their families favours efv-based art when reduced survival and potential life-threatening severe adverse events on nvp are quite stark. today, the fixed-dose combination of tenofovir, lamivudine and efavirenz in a once-a-day pill is likely to have positive spill-over effects for those women who need to take treatment every day for the rest of their lives, without jeopardising their own health and further resistance through poor adherence. conclusions and recommendations the above describes the most recent evidence available; could we expect more robust evidence? randomised controlled trials (rcts) (gold standard) are not feasible, and it would take a very long time to truly assess and compare outcomes. modeling exercises can help to inform some potential future outlook for those questions not answered by available evidence today or when rcts are not feasible. ouattara et al.’s (2012) latest projections found that starting art with efv, which has a lower rate of switching owing to its toxicity profile, provides a benefit over nvp in survival at 10 years i.e. more women alive; and comparatively the rate of birth defects with efv would need to be 2.3 times the rate of nvp to balance out the number of deaths of women on nvp.47 this seems unlikely if to date the apr birth defect rate for nvp is 2.7%, for efv 2.9%, and the recent meta-analysis by ford et al. (2011) is 2.0%. therefore, the risk-benefit question for women is: does the risk of birth defects (knowing that we have low and poorly supported risk to the fetus and enough data to say we don’t have a tenfold increase in risk of ntds) after the organogenesis period on efv outweigh the risks of life-threatening toxicity, regimen changes and a potential risk of failure when switching women from efv to nvp? particularly as south africa has moved to earlier initiation of haart at cd4<350 cells/mm³, many more women will be picked up early at antenatal clinic with the risk of severe adverse events being potentially higher in women with higher cd4 counts if switched to nvp. it is important to bear in mind that most studies are confounded by hiv disease stage, smoking, co-morbidities and other medication. generally, an hiv-infected population is possibly at increased risk of adverse outcomes of pregnancy unrelated to teratology, and in south africa there is an extra burden of fetal alcohol syndrome. ‘fetal alcohol spectrum disorder is the most common birth defect in south africa, by far more common than down syndrome and neural-tube defects combined,’ according to professor denis viljoen of the foundation for alcohol related research (farr).48 based on the evidence, there are several policy recommendations that the south african government should consider at this critical juncture while heading towards the ‘getting to zero’ goal. firstly, it should allow for already on haart who fall pregnant to continue on efv-based haart instead of switching to nvp. most pregnancies are not detected until at least one month after conception; switching to nvp after this point may not protect against birth defects, and needs to be balanced against the risk of serious adverse events caused by switching to nvp. secondly, it could allow only women who are on art and who want to conceive to switch from efv to nvp before falling pregnant. all women of child-bearing age should be encouraged to plan their pregnancies and be tested before conception. the south african government should consider moving to embrace option b as preferred pmtct, and to initiate all women in need of haart them on the superior combination of tdf/3tc/efv from 14 weeks’ gestation. this has an added benefit of simplification for nurse-initiated art as it is consistent with adult preferred first-line treatment; and has the potential to simplify the supply chain, thereby preventing potential stock-outs. consider pilot projects that could ascertain the benefits and risks for individuals and at the population level, as well as programmatic implications for putting all pregnant women on haart (option b+). regulatory bodies and the government should fast-track the registration of the fixed-dose once-daily formulation of tdf/3tc/efv for all patients. lastly, increased pharmaco-vigilance and a south africa-wide prospective antiretroviral pregnancy registry are needed. with the number of women exposed to efv in the first trimester, however, it would take a very long time for a south african registry to accumulate enough data to allow firmer conclusions to be drawn; therefore, this should not be done at the expense of women in need of treatment now. this paper has argued that, although we could never claim any arv to be completely safe, weak associations in some studies are far outweighed by the benefits of haart in pregnancy. the consideration to use efv in the first trimester of pregnancy in resource-limited settings such as south africa needs to move beyond concerns of poorly supported evidence to recognising new evidence of survival gains, efficacy, toxicity, direct medical and programmatic costs (including costs of simplification and scaling up coverage) – as well as indirect costs e.g. unnecessary and distressing termination of pregnancies. this allows policymakers an opportunity to harness the evidence accumulated to date and focus on pursuing an effective strategy based on evidence and 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http://edocket.access.gpo.gov/2008/pdf/e8-11806.pdf (accessed 23 december 2011). 21. schwartz sr, mehta sh, taha te, rees hv, venter f, black v. high pregnancy intentions and missed opportunities for patient–provider communication about fertility in a south african cohort of hiv-positive women on antiretroviral therapy. aids and behavior. 9 june 2011. http://www.springerlink.com/content/e310h87734262755/ (accessed 23 november 2011). 21. schwartz sr, mehta sh, taha te, rees hv, venter f, black v. high pregnancy intentions and missed opportunities for patient–provider communication about fertility in a south african cohort of hiv-positive women on antiretroviral therapy. aids and behavior. 9 june 2011. http://www.springerlink.com/content/e310h87734262755/ (accessed 23 november 2011). 22. pettifor ae, rees hv. young people’s sexual health in south africa: hiv prevalence and sexual behaviours from a nationally representative household survey. aids 2005;19:1525-1534. 22. pettifor ae, rees hv. young people’s sexual health in south africa: hiv prevalence and sexual behaviours from a nationally representative household survey. aids 2005;19:1525-1534. 23. van leth f, phanuphak p, ruxrungtham k, et al. comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2nn study. lancet 2004;363(9417):1253-1263. 23. van leth f, phanuphak p, ruxrungtham k, et al. comparison of first-line antiretroviral therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and lamivudine: a randomised open-label trial, the 2nn study. lancet 2004;363(9417):1253-1263. 24. mbuagbaw lc, irlam jh, spaulding a, rutherford gw, siegfried n. efavirenz or nevirapine in three‐drug combination therapy with two nucleoside‐reverse transcriptase inhibitors for initial treatment of hiv infection in antiretroviral‐naïve individuals. 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failure and second-line antiretroviral therapy in children in south africa—the iedea southern africa collaboration. j acquir immune defic syndr 2011;56:270-278. 28. davies m-a, moultrie h, eley b, et al. virologic failure and second-line antiretroviral therapy in children in south africa—the iedea southern africa collaboration. j acquir immune defic syndr 2011;56:270-278. 29. nachega jb, hislop m, dowdy dw, et al. efavirenz versus nevirapine-based initial treatment of hiv infection: clinical and virological outcomes in southern african adults. aids 2008;22:2117-2125. 29. nachega jb, hislop m, dowdy dw, et al. efavirenz versus nevirapine-based initial treatment of hiv infection: clinical and virological outcomes in southern african adults. aids 2008;22:2117-2125. 30. datay mi, boulle a, mant d, yudkin p. associations with virologic treatment failure in adults on antiretroviral therapy in south africa. j acquir immune defic syndr 2010;54(5):489-495. 30. datay mi, boulle a, mant d, yudkin p. associations with virologic treatment failure in adults on antiretroviral therapy in south africa. j acquir immune defic syndr 2010;54(5):489-495. 31. tang m, kanki p, shafer r. virological efficacy of the four tenofovir-containing who-recommended regimens for initial antiretroviral therapy. ias 2011 abstract. http://pag.ias2011.org/abstracts.aspx?aid=2206 (accessed 25 november 2011). 31. tang m, kanki p, shafer r. virological efficacy of the four tenofovir-containing who-recommended regimens for initial antiretroviral therapy. ias 2011 abstract. http://pag.ias2011.org/abstracts.aspx?aid=2206 (accessed 25 november 2011). 32. stern jo, robinson pa, love j, lanes s, imperiale ms, mayers dl. a comprehensive hepatic safety analysis of nevirapine in different populations of hiv-infected patients. j acquir immune defic syndr 2003;34:s21-s33. 32. stern jo, robinson pa, love j, lanes s, imperiale ms, mayers dl. a comprehensive hepatic safety analysis of nevirapine in different populations of hiv-infected patients. j acquir immune defic syndr 2003;34:s21-s33. 33. baylor ms, johann-liang r. hepatotoxicity associated with nevirapine use. j acquir immune defic syndr 2004;35(5):538-539. 33. baylor ms, johann-liang r. hepatotoxicity associated with nevirapine use. j acquir immune defic syndr 2004;35(5):538-539. 34. viramune [package insert]. ridgefield, ct: boehringer-ingelheim pharmaceuticals, 2008. 34. viramune [package insert]. ridgefield, ct: boehringer-ingelheim pharmaceuticals, 2008. 35. hitti j, frenkel lm, stek am, et al. maternal toxicity with continuous nevirapine in pregnancy: results from pactg 1022. j acquir immune defic syndr 2004;36(3):772-776. 35. hitti j, frenkel lm, stek am, et al. maternal toxicity with continuous nevirapine in pregnancy: results from pactg 1022. j acquir immune defic syndr 2004;36(3):772-776. 36. lyons f, hopkins s, kelleher b, et al. maternal hepatotoxicity with nevirapine as part of combination antiretroviral therapy in pregnancy. hiv med 2006;7(4):255-260. 36. lyons f, hopkins s, kelleher b, et al. maternal hepatotoxicity with nevirapine as part of combination antiretroviral therapy in pregnancy. hiv med 2006;7(4):255-260. 37. jamisse l, balkus j, hitti j, et al. antiretroviral-associated toxicity among hiv-1-seropositive pregnant women in mozambique receiving nevirapine-based regimens. j acquir immune defic syndr 2007;44:371-376. 37. jamisse l, balkus j, hitti j, et al. antiretroviral-associated toxicity among hiv-1-seropositive pregnant women in mozambique receiving nevirapine-based regimens. j acquir immune defic syndr 2007;44:371-376. 38. de lazzari e, león a, arnaiz ja, et al. hepatotoxicity of nevirapine in virologically suppressed patients according to gender and cd4 cell counts. hiv medicine 2008;9(4):221-226. 38. de lazzari e, león a, arnaiz ja, et al. hepatotoxicity of nevirapine in virologically suppressed patients according to gender and cd4 cell counts. hiv medicine 2008;9(4):221-226. 39. kesselring am, wit fw, sabin ca, et al. risk factors for treatment-limiting toxicities in patients starting nevirapine-containing antiretroviral therapy. aids 2009;23(13):1689-1699. 39. kesselring am, wit fw, sabin ca, et al. risk factors for treatment-limiting toxicities in patients starting nevirapine-containing antiretroviral therapy. aids 2009;23(13):1689-1699. 40. ouyang dw, shapiro de, lu m, et al. increased risk of hepatotoxicity in hiv-infected pregnant women receiving antiretroviral therapy independent of nevirapine exposure. aids 2009;23(18):2425-2430. 40. ouyang dw, shapiro de, lu m, et al. increased risk of hepatotoxicity in hiv-infected pregnant women receiving antiretroviral therapy independent of nevirapine exposure. aids 2009;23(18):2425-2430. 41. chu km, boulle am, ford n, goemaere e, asselman v, van cutsem g. nevirapine-associated early hepatotoxicity: incidence, risk factors, and associated mortality in a primary care art programme in south africa. plos one 2010;5(2):e9183. 41. chu km, boulle am, ford n, goemaere e, asselman v, van cutsem g. nevirapine-associated early hepatotoxicity: incidence, risk factors, and associated mortality in a primary care art programme in south africa. plos one 2010;5(2):e9183. 42. van griensven j, un p, phe t, thai s, lynen l. substituting nevirapine for efavirenz: risk factors for toxicity in nonnaive patients in a resource-constrained setting. aids 2009;23:2374-2376. 42. van griensven j, un p, phe t, thai s, lynen l. substituting nevirapine for efavirenz: risk factors for toxicity in nonnaive patients in a resource-constrained setting. aids 2009;23:2374-2376. 43. kasirye gitta p, bakeera-kitaka s, kekitiinwa a. stevens-johnson syndrome (sjs) following switch to nevirapine based regimen at baylor-uganda´s paediatric infectious diseases clinic, mulago hospital. http://www.iasociety.org/abstracts/a200740712.aspx (accessed 25 november 2011). 43. kasirye gitta p, bakeera-kitaka s, kekitiinwa a. stevens-johnson syndrome (sjs) following switch to nevirapine based regimen at baylor-uganda´s paediatric infectious diseases clinic, mulago hospital. http://www.iasociety.org/abstracts/a200740712.aspx (accessed 25 november 2011). 44. mehta u, maartens g. is it safe to switch between efavirenz and nevirapine in the event of toxicity? lancet infect dis 2007;7(11):733-738. 44. mehta u, maartens g. is it safe to switch between efavirenz and nevirapine in the event of toxicity? lancet infect dis 2007;7(11):733-738. 45. campaign for access to essential medicines. medicins sans frontieres. untangling the web of antiretroviral price reductions. http://utw.msfaccess.org/ (accessed 23 november 2011). 45. campaign for access to essential medicines. medicins sans frontieres. untangling the web of antiretroviral price reductions. http://utw.msfaccess.org/ (accessed 23 november 2011). 46. hsu h, rydzak c, cotich k, et al. quantifying the risks and benefits of efavirenz use in hiv-infected women of childbearing age in the usa. hiv med 2011;12(2):97-108. 46. hsu h, rydzak c, cotich k, et al. quantifying the risks and benefits of efavirenz use in hiv-infected women of childbearing age in the usa. hiv med 2011;12(2):97-108. 47. ouattara en, anglaret x, wong ay, et al. projecting the clinical benefits and risks of using efavirenz-containing art regimens in women of childbearing age in sub-saharan africa. aids 2012;1. [http://dx.doi.org/10.1097/qad.0b013e328350fbfb]. 47. ouattara en, anglaret x, wong ay, et al. projecting the clinical benefits and risks of using efavirenz-containing art regimens in women of childbearing age in sub-saharan africa. aids 2012;1. [http://dx.doi.org/10.1097/qad.0b013e328350fbfb]. 48. fetal alcohol syndrome: dashed hopes, damaged lives. bull world health organ 2011;89:398-399. 48. fetal alcohol syndrome: dashed hopes, damaged lives. bull world health organ 2011;89:398-399. table 1. arv prophylaxis options recommended for hiv-infected pregnant women who do not need treatment for their own health option a: maternal azt option b: maternal triple arv prophylaxis mother mother • antepartum azt (from as early as 14 weeks’ gestation) • sd-nvp at onset of labour* • azt + 3tc during labour and delivery* • azt + 3tc for 7 days postpartum* *sd-nvp and azt+3tc can be omitted if mother receives >4 weeks of azt antepartum triple arv from 14 weeks until one week after all exposure to breast milk has ended • azt + 3tc + lpv/r • azt + 3tc + abc • azt + 3tc + efv • tdf + 3tc (or ftc) + efv infant infant breastfeeding infant sd-nvp at birth plus daily nvp from birth until one week after all exposure to breast milk has ended non-breastfeeding infant sd-nvp at birth plus azt or nvp from birth until 4 6 weeks breastfeeding infant azt or nvp from birth until 4 6 weeks non-breastfeeding infant azt or nvp from birth until 4 6 weeks source: who rapid advice: use of antiretroviral drugs for treating pregnant women and preventing hiv infection in infants, november 2009. revised june 2010. table 2. comparative rates of birth defects for widely used arvs in the first trimester first trimester exposure arv defects/live births prevalence (95% ci) indinavir 6/285 2.1% (0.8% 4.5%) lopinavir 16/738 2.2% (1.2% 3.5%) atazanavir sulfate 12/502 2.4% (1.2% 4.1%) stavudine 19/797 2.4% (1.4% 3.7%) ritonavir 33/1401 2.4% (1.6% 3.3%) tenofovir 26/1092 2.4% (1.6% 3.5%) nevirapine 25/987 2.5% (1.6% 3.7%) emtricitabine 17/641 2.7% (1.5% 4.2%) efavirenz 17/623 2.7% (1.6% 4.3%) abacavir 22/744 3.0% (1.9% 4.5%) lamivudine 118/3864 3.1% (2.5% 3.7%) zidovudine 118/3620 3.3% (2.7% 3.9%) nelfinavir 46/1193 3.9% (2.8% 5.1%) didanosine 19/406 4.7% (2.8% 7.2%) source: antiretroviral pregnancy register (apr) interim report 201118 table 3. prevalence of birth defects general us pop 18 general south african pop 19 1st trimester exposure to any arv 18 2nd/3rd trimester exposure to any arv 18 1st trimester exposure to efv 18 2nd/3rd trimester exposure to efv 18 1st trimester exposure to efv 17 3% 5.3% 2.9% 2.7% 2.7% 2.9% 2.0% 95% ci: (2.5 3.4) (0.88 1.32) (1.6 4.3) (0.3 10.0) (0.82 3.18) numbers: 164/5 555 205/7 483 17/643 2/70 39/1 437 relative risk 1st trimester efv to non-efv art was 0.85 (0.61 1.20)17 table 4. fda categories of risk category description a controlled studies show no risk adequate, well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in any trimester of pregnancy. b no evidence of risk in humans adequate, well-controlled studies in pregnant women have not shown increased risk of fetal abnormalities despite adverse findings in animals or in the absence of adequate human studies, animal studies show no fetal risk. the chance of fetal harm is remote, but remains a possibility. c risk cannot be ruled out adequate, well-controlled human studies are lacking, and animal studies have shown a risk to the fetus, or are lacking as well. there is a chance of foetal harm if the drug is administered during pregnancy, but the potential benefits may outweigh the potential risk. d positive evidence of risk studies in humans, or investigational or post-marketing data, have demonstrated foetal risk. nevertheless, potential benefits from the use of the drug may outweigh the potential risk. for example, the drug may be acceptable if needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective. x contra-indicated in pregnancy studies in animals or humans, or investigational or post-marketing reports, have demonstrated positive evidence of fetal abnormalities or risk which clearly outweighs any possible benefit to the patient. source: fda20 fig. 1. price evolution of nvp and efv. source: www.utw.msfaccess.org sajhiv message from editor message from the editor looking back while looking forward: a decade of art in the public sector in considering the hiv epidemic and its impact, many of our anniversaries are sad ones. personal anniversaries often mark losses – remembrances of the deaths of family, friends or patients. clinicians or scientists may mark the anniversary of the first documented aids case in a country, or the discovery of the virus itself, but these aren’t generally moments for celebration per se. so it’s not often that we have cause to smile about an anniversary related to the epidemic. however, 1 april 2014 marks one happy anniversary worth remembering – a decade of antiretroviral therapy (art) in the public sector. like many anniversaries, the exact details can depend on where you were, and sometimes dates themselves can be fuzzy. antiretrovirals were available from the 1990s in the private sector, and a trickle was accessible through trials and small donor-funded initiatives in urban centres from the early 2000s. some provinces moved more quickly towards making art available ahead of the national department of health, often with the assistance of partners in local and international non-governmental organisations. after the announcement of a national rollout of art in public sector facilities, some hospitals received supplies of antiretrovirals within weeks. elsewhere, especially in clinics in rural settings, health services took years to have local providers dispensing art. today the number of facilities dispensing art is expanding still, but most communities across the country have reasonable access, and art coverage continues to increase. so perhaps this anniversary is not so much a specific date in time, but rather a particular point of inflection in the course of the health service that serves the vast majority of south africans. to mark this anniversary, this edition of the journal is a special issue of sorts. we asked the society’s members, and the public more generally, to submit their thoughts about the art rollout over the last ten years; and the response was remarkable. we received more submissions than we could publish by far, and thank all those who submitted manuscripts for their time and consideration. and so, rather than our usual peer-reviewed scientific articles, case reports, guidelines and opinion pieces, this issue is comprised entirely of short commentaries by way of reflection, drawn from diverse perspectives from authors working across the country. in their opening commentary, gary maartens and eric goemaere1 remind us of the incredible distances traversed during the past decade, and consider what the next ten years may hold. writing from bloemfontein, dirk hagemeister2 asks why the patient-held records, which have become such a routine part of art and tuberculosis (tb) care for many of our patients, are less than routine for many of our doctors (and readers). in cape town, richard kaplan and colleagues3 describe how the earliest days of their art service in gugulethu consisted of working from a cardboard box in a borrowed office, and evolved through partnerships with communities, services and academic medicine. kevin rebe and james mcintyre4 describe working with the public sector to deliver care to men who have sex with men – a population that remains highly marginalised in many parts of the country and continent. many of these contributions are distinctly personal. caroline armstrong5 describes working in a pietermaritzburg hospital before the art rollout, and how her perspective changed in the early days of providing effective therapy to patients. joyce marshall6 discusses how art began to lift the burden of stigma associated with hiv/aids off of her patients, while michelle moorhouse7 describes how her general practitioner practice in the eastern cape changed when art became available. chantél friend8 uses the aids ribbon as a metaphor for the different meanings that hiv has had throughout her career. and writing from the perspective of policy development, celicia serenata9 describes her personal travails in contributing to the national strategic plan during 2003. the challenges of delivering art in rural communities are reflected from zithulele in the eastern cape province (catherine young and ben gaunt10 ) as well as mseleni in northern kwazulu-natal (aurélie nelson11 ). and while art was a doctor-driven service initially, today nurses initiate and manage the vast majority of south africans on art, so it is fitting then that mzi tito12 describes the experience of providing art services in primary care around port elizabeth. one area of dramatic change in the last decade has been in paediatrics, where antiretrovirals have altered the landscape of child health in this country through both prevention and treatment. here, ann moore13 talks about the practical lessons learnt in providing hiv care and treatment to infected children and their families in cape town, while kathryn stinson and colleagues14 describe the changing paradigms of services for the prevention of mother-to-child transmission (pmtct) of hiv in khayelitsha, and the central role that maternal art plays in preventing paediatric hiv infections. and in the final contribution, francois venter15 draws on his experiences of the last ten years to give us lessons for the next decade, with a mix of candour, humour and insight. most of the contributions have a tone of celebration (e.g. ‘how far we have come!’), and many comment on the revelation that art represented in the lives of their patients and their own practice of medicine. however, there are also notes of sadness and frustration here – for preventable deaths and ineptitude that characterised much of the response to the hiv epidemic in an earlier period. if we needed a reminder that health and politics are inseparable, we need not look far into the past. and in some places these notes of frustration seem to echo into the present, as art services become a standard component of primary care in south africa. with this, the revelations of providing art for the first time soon after 2004 appear to be accompanied by the routines of delivering chronic care through the public sector in 2014. whatever this anniversary means to you, i hope you find this special issue filled with new perspectives, perhaps a few knowing smiles, and at least one pause for reflection. happy reading. landon myer associate professor school of public health and family medicine university of cape town landon.myer@uct.ac.za 1. maartens g, goemaere e. building on the first decade of art. southern african journal of hiv medicine 2014;15(1):7-8. [http://dx.doi.org/10.7196/sajhivmed.1031] 1. maartens g, goemaere e. building on the first decade of art. southern african journal of hiv medicine 2014;15(1):7-8. [http://dx.doi.org/10.7196/sajhivmed.1031] 2. hagemeister d. the secrets of the green and white cards. southern african journal of hiv medicine 2014;15(1):33-34. [http://dx.doi.org/10.7196/sajhivmed.1036] 2. hagemeister d. the secrets of the green and white cards. southern african journal of hiv medicine 2014;15(1):33-34. [http://dx.doi.org/10.7196/sajhivmed.1036] 3. kaplan r, orrell c, lawn sd, bekker l-g, wood r. the hannan crusaid treatment centre – early beginnings and lessons learnt. southern african journal of hiv medicine 2014;15(1):35-37. [http://dx.doi.org/10.7196/sajhivmed.1040] 3. kaplan r, orrell c, lawn sd, bekker l-g, wood r. the hannan crusaid treatment centre – early beginnings and lessons learnt. southern african journal of hiv medicine 2014;15(1):35-37. [http://dx.doi.org/10.7196/sajhivmed.1040] 4. rebe kb, mcintyre ja. providing hiv care to men who have sex with men in south african state sector clinics. southern african journal of hiv medicine 2014;15(1):10-11. [http://dx.doi.org/10.7196/sajhivmed.1026] 4. rebe kb, mcintyre ja. providing hiv care to men who have sex with men in south african state sector clinics. southern african journal of hiv medicine 2014;15(1):10-11. [http://dx.doi.org/10.7196/sajhivmed.1026] 5. armstrong c. reflections on hiv care and art – a view from pietermaritzburg. southern african journal of hiv medicine 2014;15(1):16-17. [http://dx.doi.org/10.7196/sajhivmed.1033] 5. armstrong c. reflections on hiv care and art – a view from pietermaritzburg. southern african journal of hiv medicine 2014;15(1):16-17. [http://dx.doi.org/10.7196/sajhivmed.1033] 6. marshall j. ‘they dropped the blanket of their fear’: reflections of hiv medicine in south africa, 2014. southern african journal of hiv medicine 2014;15(1):26. [http://dx.doi.org/10.7196/sajhivmed.1032] 6. marshall j. ‘they dropped the blanket of their fear’: reflections of hiv medicine in south africa, 2014. southern african journal of hiv medicine 2014;15(1):26. [http://dx.doi.org/10.7196/sajhivmed.1032] 7. moorhouse m. closer to zero: reflections on ten years of art rollout. southern african journal of hiv medicine 2014;15(1):9. [http://dx.doi.org/10.7196/sajhivmed.1030] 7. moorhouse m. closer to zero: reflections on ten years of art rollout. southern african journal of hiv medicine 2014;15(1):9. [http://dx.doi.org/10.7196/sajhivmed.1030] 8. friend c. reflections on a decade of hiv in my life. southern african journal of hiv medicine 2014;15(1):27. [http://dx.doi.org/10.7196/sajhivmed.1039] 8. friend c. reflections on a decade of hiv in my life. southern african journal of hiv medicine 2014;15(1):27. [http://dx.doi.org/10.7196/sajhivmed.1039] 9. serenata c. ten years of art in south africa – how far we have come. southern african journal of hiv medicine 2014;15(1):14-15. [http://dx.doi.org/10.7196/sajhivmed.1028] 9. serenata c. ten years of art in south africa – how far we have come. southern african journal of hiv medicine 2014;15(1):14-15. [http://dx.doi.org/10.7196/sajhivmed.1028] 10. young a, gaunt b. providing high-quality care in a deeply rural setting – the zithulele experience. southern african journal of hiv medicine 2014;15(1):28-29. [http://dx.doi.org/10.7196/sajhivmed.1035] 10. young a, gaunt b. providing high-quality care in a deeply rural setting – the zithulele experience. southern african journal of hiv medicine 2014;15(1):28-29. [http://dx.doi.org/10.7196/sajhivmed.1035] 11. nelson ak. within minutes from mseleni to cape town ... southern african journal of hiv medicine 2014;15(1):13. [http://dx.doi.org/10.7196/sajhivmed.1010] 11. nelson ak. within minutes from mseleni to cape town ... southern african journal of hiv medicine 2014;15(1):13. [http://dx.doi.org/10.7196/sajhivmed.1010] 12. tito m. a nurse's perspective on the art rollout. southern african journal of hiv medicine 2014;15(1):19. [http://dx.doi.org/10.7196/sajhivmed.1034] 12. tito m. a nurse's perspective on the art rollout. southern african journal of hiv medicine 2014;15(1):19. [http://dx.doi.org/10.7196/sajhivmed.1034] 13. moore ha. reflections on six years in paediatric art. southern african journal of hiv medicine 2014;15(1):22-23. [http://dx.doi.org/10.7196/sajhivmed.1020] 13. moore ha. reflections on six years in paediatric art. southern african journal of hiv medicine 2014;15(1):22-23. [http://dx.doi.org/10.7196/sajhivmed.1020] 14. stinson k, giddy j, cox v, et al. reflections on a decade of delivering pmtct in khayelitsha, cape town. southern african journal of hiv medicine 2014;15(1):30-32. [http://dx.doi.org/10.7196/sajhivmed.1025] 14. stinson k, giddy j, cox v, et al. reflections on a decade of delivering pmtct in khayelitsha, cape town. southern african journal of hiv medicine 2014;15(1):30-32. [http://dx.doi.org/10.7196/sajhivmed.1025] 15. venter wdf. what have we learnt from the last ten years of art? southern african journal of hiv medicine 2014;15(1):39-40. [http://dx.doi.org/10.7196/sajhivmed.1029] 15. venter wdf. what have we learnt from the last ten years of art? southern african journal of hiv medicine 2014;15(1):39-40. [http://dx.doi.org/10.7196/sajhivmed.1029] the southern african journal of hiv medicine                                                        october  2009 5 i am delighted to introduce you to our guest editors, who have done a sterling job in pulling together this ‘mental health in hiv’ edition. they are two capetonian colleagues who i am also fortunate to consider friends: john joska is a psychiatrist and landon myer is a public health specialist. john joska is a senior specialist and lecturer in the department of psychiatry and mental health at the university of cape town. he is head of the division of neuropsychiatry, western cape provincial programme manager for hiv psychiatry, and director of the gshhiv mental health group. the latter is a newly formed group of mental health professionals who are providing service and investigating the effects of hiv on people living with hiv/aids (plwha) from a mental health point of view. current research projects include investigations into neurocognitive disorders in hiv, screening for mental disorders in hiv, and brief psychological interventions in plwha with depression. landon myer is an associate professor in the school of public health and family medicine at the university of cape town. his research focuses on the roles of hiv/ aids and other infectious diseases in shaping individual and population health in southern africa. he is particularly interested in how the hiv epidemic influences other areas of population health, including mental health and women’s reproductive health. in investigating these topics, his research incorporates biological mechanisms, individual behaviours and exposures, as well as structural socio-economic and health service conditions. i am sure you will agree that with their colleagues they have provided a feast of important reading for you all in this edition. linda-gail bekker editor f r o m  t h e  e di torf r o m t h e e di tor the journal is starting to feel like men’s health, what with posters, guidelines and now a state-of-the art science update, hiv treatment bulletin, falling out of it. exco is pleased to announce an important and strategic partnership with hiv ibase, who publish hiv treatment bulletin. we are distributing the southern african version of their excellent newsletter, which will exclusively focus on the scientific reports and resources that have local relevance – with a strong focus on paediatrics and maternal health. hiv treatment bulletin neatly complements the journal, providing the snobbish clinician and scientist with the most hot-off-the-press analysis of recent clinical trials and basic science research. policy makers can authoritatively pronounce at their guidelines meetings, clinicians can expand their patients’ options, and, most importantly, you can show off at ward rounds. thanks to all the people at i-base, this is a major step forward for quality information sharing. we wish the new health minister, barbara hogan, all the best. she has very small shoes to fill, but a mammoth task ahead of her to repair south africa’s woeful health service. at the time of writing, she and her deputy, dr molefi sefularo, have been very impressive, dealing with a cholera disaster, drug stock-outs, issues of prevention, releasing controversial reports that were stuck on her predecessor’s desk for months, and a dozen other complex health problems. finally, the exco welcomes two new members based in durban, professor yunus moosa and dr henry sunpath, both highly respected clinicians and part of the team responsible for an excellent hiv clinical conference held in october. francois venter president this spring edition brings 2008 to a close. and what a year it has been. not many breakthroughs in hiv or tb, but a lot of activity in terms of understanding early infection better, really getting to grips with early immune responses, and again thinking through our prevention options. in 2008 the concept of antiretrovirals for prevention as well as treatment has come to the fore with second-generation microbicides, pre-exposure prophylaxis and the notion that we may be able to ‘treat our way out of the epidemic’ becoming possibilities. gratifyingly, this year also saw a record number of people being tested and accessing art, and roll-out for both testing and treatment is truly scaling up. as chairperson of the 4th southern african hiv conference i must encourage every one of you to think seriously about coming to durban on 31 march. it promises to be a critical conference where we will really formulate the key steps in getting pmtct, treatment, testing and prevention out there on a scale that will begin to turn the sa statistics around. (i promise that it will also be loads of fun!) please note the early date this year: 31 march to 3 april. this is to ensure brilliant kzn weather! in this edition, we already begin to examine some of these key scale-up questions: jerome singh explores the ethics and legality of traditional healers performing hiv testing (i know many have asked why this has to be the domain of nurses only). francesca esposito and her team examine changes in body composition in women taking antivirals in a kzn clinic. we look at the role of mobile phones in the hiv response with william mapham, and polly clayden gives us pointers to starting infants on art. the role of a liver biopsy in diagnosis of opportunistic infections is described by mark sonderup and colleagues. the vexed question of when it is deemed safe to start haart in patients co-infected with tb is discussed by robin wood, and francois venter and colleagues give a practical view on new antiretrovirals on the horizon for south african practitioners. no guidelines in this issue, but i will whet your appetites – look out for guidelines on prevention of tb occupational exposure for hiv-infected health care workers and on the non-infertile hiv infected couple, hot stuff coming up in the new year! happy reading and every best wish for a restful and peaceful festive season from the whole editorial team. see you next year! linda-gail bekker editor m e s s a g e f r o m t h e e x e c u t i v e msg from the executive.indd 5 12/17/08 3:16:23 pm addressing mental health in routine hiv care and treatment as this journal’s readers are well aware, hiv has complex and wide-ranging impacts on the health of infected individuals. much of this complexity is due to the nature of host-virus interactions and the pathophysiology of the virus and its sequelae in different organ systems over time. other aspects are linked to the profound impact an hiv diagnosis has on the life of an infected individual, both through physical morbidity and the psychological and social consequences of a lifelong illness. the area of mental health is a critical example of the diverse impacts of hiv on patients’ health and well-being. the links between hiv and mental health are multiple: risk taking associated with hiv acquisition is more common among individuals with mental disorders; common mental disorders (such as anxiety, depression and alcohol/substance disorders) are often caused in part by the stress of an hiv diagnosis and related stigma; psychotic states are a relatively common presentation of hiv infected individuals; and neurocognitive manifestations of hiv infection such as hiv-associated dementia emerge later in the course of disease. taken together, mental disorders may be viewed as their own class of ‘opportunistic’ conditions affecting hiv-infected individuals in a unique manner. dealing with the various mental health impacts of hiv infection is a core component of effective hiv care and treatment. anxiety and depression among hiv-infected individuals can negatively impact on medication adherence; in these situations, management of mental disorders can help facilitate the management of hiv disease over the long term. the neurocognitive manifestations of hiv disease are a significant cause of morbidity; increasingly we are recognising that these disorders may e di tor i a l m e s s a g e   f r o m    t h e   e x e c u t i v e the large international aids society meeting has come and gone from cape town. the agenda was dominated by a new big idea, an audacious mathematical model by a group of brave world health organization modellers showing that giving antiretroviral therapy to every one with hiv, immediately, could make the epidemic disappear. we’ve known for a long time that viral load correlates with infectiousness, whether it is sexual contact, pmtct or other forms of exposure. art is so highly effective in reducing viral load that the swiss created an uproar a year ago by claiming that someone on art with an undetectable viral load (and no std) could not transmit hiv sexually. the who researchers essentially argue that if we diagnose hiv quickly and treat everyone who is hiv positive, irrespective of cd4 count, we can arrest sexual transmission early and pretty much eradicate hiv within 10 years. subsequent papers have even postulated that we could reverse the tb epidemic, as hiv drives this like fuel on a fire. finally, early economic work has shown ‘test and treat’ to be cost saving, despite significant initial investment. there is broad acknowledgment that hiv prevention programmes have been very disappointing, and that even effective interventions such as male circumcision and good pmtct are unlikely to eradicate the epidemic alone. it is exciting that researchers are thinking creatively, and that models showing we can reverse things are out there. but to implement this incredibly ambitious model would require a complete restructuring of health systems. we would need to do hiv testing aggressively and provide adequate, easily available art services, as broadly as possible. the health system would have to be transformed from the lumbering unfriendly giant it is at the moment to a responsive and effective service deliverer. the reality is that we need this anyway, even if the modellers are wrong. francois venter president be managed effectively, including by early initiation of antiretroviral therapy, to improve the prognosis of affected individuals. in short, basic mental health care is part of good hiv management. in this context, there is a clear need to make the diagnosis and management of mental disorders more feasible in general hiv care and treatment settings. at the primary and secondary levels of the health care system, medical officers and physicians must be able to identify patients with a possible mental disorder and work up these patients to arrive at a preliminary diagnosis, make management decisions, and follow up patients over time. support from specialist psychiatrists is necessary in some instances, but most cases do not require specialist referral, and the availability of psychiatric services to support hiv care and treatment is limited in most settings across the region. this special issue of the journal aims to address this need through a series of focused contributions from leaders in hiv mental health from across south africa. the first two pieces focus on anxiety and depression in hiv in broad terms (thom) and post-traumatic stress disorder specifically (pingo). following this, the topic of psychotic presentations in hiv is dealt with by an algorithm for the diagnosis and management of psychosis in hiv (jonsson) and then an extended case study (boyles) to help reinforce key concepts. the topic of neurocognitive impairment in hiv/aids is discussed in detail (singh) with a short report on the white matter changes that take place in the brain over the course of hiv disease (hoare) as well as a piece of empirical research investigating the clinical utility of one commonly used tool to identify neurocognitive deficits in hiv (ogunrin). the final piece deals with cross-cutting issues of prescribing psychotropic medications in the context of hiv infection (parker). throughout, these pieces aim to address issues in mental health faced by front-line hiv clinicians on a daily basis, with practical strategies for investigation and management. it is our hope that the contents of this issue may make some contribution towards helping hiv clinicians to better recognise and treat mental disorders in their patients. landon myer john joska guest editors the southern african journal of hiv medicine                                                          october  20096 5 no, i am not on sabbatical on a tropical island! however, it has been a great pleasure to have the journal guest-edited again for the last edition of 2009 by a superb duo: leon levin and mark cotton. mark cotton is a specialist in paediatric infectious diseases at tygerberg children’s hospital and head of its paediatric infectious diseases unit, affectionately known as kidcru. his main focus is to extend and enhance care through research, with a special interest in children affected by hiv. mark has been involved in some key studies that have shaped paediatric practices and guidelines in southern africa. he also serves as advisor and investigator to a number of international institutions and networks. dr leon j levin graduated mb bch at the university of the witwatersrand in 1987. after training in paediatrics at the wits group of hospitals in johannesburg, he obtained his fcpaed (sa) in 1994. in february 1996 he founded the paediatric hiv clinic at johannesburg hospital, and more recently he has run the paediatric division of right to care. leon has been chairman of the paediatric subcommittee of the sa hiv clinicians society since 1999 and runs the society´s paediatric discussion group, an internet-based forum for paediatricians to discuss and learn about problems in children with hiv. in this edition, besides a fabulous array of paediatric material, we publish the updated paediatric guidelines. with so much positive energy around better hiv support recently, from the highest level, we are confident that we can do better, especially in the important area of paediatric aids. we will kick 2010 off with our usual diverse submitted copy, so please keep sending. review processes will also be improved. we hope it will be a bumper year in many ways, with record numbers of people starting and staying on art, a decreasing incidence of hiv, and millions of south africans testing. we also hope to have four bumper editions of the southern african journal of hiv medicine in 2010, which is set to be a memorable year for south africa. linda-gail bekker editor f r o m  t h e  e di torf r o m t h e e di tor the journal is starting to feel like men’s health, what with posters, guidelines and now a state-of-the art science update, hiv treatment bulletin, falling out of it. exco is pleased to announce an important and strategic partnership with hiv ibase, who publish hiv treatment bulletin. we are distributing the southern african version of their excellent newsletter, which will exclusively focus on the scientific reports and resources that have local relevance – with a strong focus on paediatrics and maternal health. hiv treatment bulletin neatly complements the journal, providing the snobbish clinician and scientist with the most hot-off-the-press analysis of recent clinical trials and basic science research. policy makers can authoritatively pronounce at their guidelines meetings, clinicians can expand their patients’ options, and, most importantly, you can show off at ward rounds. thanks to all the people at i-base, this is a major step forward for quality information sharing. we wish the new health minister, barbara hogan, all the best. she has very small shoes to fill, but a mammoth task ahead of her to repair south africa’s woeful health service. at the time of writing, she and her deputy, dr molefi sefularo, have been very impressive, dealing with a cholera disaster, drug stock-outs, issues of prevention, releasing controversial reports that were stuck on her predecessor’s desk for months, and a dozen other complex health problems. finally, the exco welcomes two new members based in durban, professor yunus moosa and dr henry sunpath, both highly respected clinicians and part of the team responsible for an excellent hiv clinical conference held in october. francois venter president this spring edition brings 2008 to a close. and what a year it has been. not many breakthroughs in hiv or tb, but a lot of activity in terms of understanding early infection better, really getting to grips with early immune responses, and again thinking through our prevention options. in 2008 the concept of antiretrovirals for prevention as well as treatment has come to the fore with second-generation microbicides, pre-exposure prophylaxis and the notion that we may be able to ‘treat our way out of the epidemic’ becoming possibilities. gratifyingly, this year also saw a record number of people being tested and accessing art, and roll-out for both testing and treatment is truly scaling up. as chairperson of the 4th southern african hiv conference i must encourage every one of you to think seriously about coming to durban on 31 march. it promises to be a critical conference where we will really formulate the key steps in getting pmtct, treatment, testing and prevention out there on a scale that will begin to turn the sa statistics around. (i promise that it will also be loads of fun!) please note the early date this year: 31 march to 3 april. this is to ensure brilliant kzn weather! in this edition, we already begin to examine some of these key scale-up questions: jerome singh explores the ethics and legality of traditional healers performing hiv testing (i know many have asked why this has to be the domain of nurses only). francesca esposito and her team examine changes in body composition in women taking antivirals in a kzn clinic. we look at the role of mobile phones in the hiv response with william mapham, and polly clayden gives us pointers to starting infants on art. the role of a liver biopsy in diagnosis of opportunistic infections is described by mark sonderup and colleagues. the vexed question of when it is deemed safe to start haart in patients co-infected with tb is discussed by robin wood, and francois venter and colleagues give a practical view on new antiretrovirals on the horizon for south african practitioners. no guidelines in this issue, but i will whet your appetites – look out for guidelines on prevention of tb occupational exposure for hiv-infected health care workers and on the non-infertile hiv infected couple, hot stuff coming up in the new year! happy reading and every best wish for a restful and peaceful festive season from the whole editorial team. see you next year! linda-gail bekker editor m e s s a g e f r o m t h e e x e c u t i v e msg from the executive.indd 5 12/17/08 3:16:23 pm treating hiv-infected children this edition sees the publication of the fourth sa hiv clinicians society paediatric antiretroviral therapy (art) guidelines. previously it has not been possible to have one guideline for the whole country because of wide discordance between the government and private sectors. this year, for the first time, our guideline is applicable to both the private and public sectors. inevitably some differences remain and are addressed in the document. they include choice of first-line regimen and genotyping recommendations. the national department of health (ndoh) is still updating its guidelines, hopefully for publication in early 2010. we hope you will find the society’s guidelines pragmatic and helpful. we have the potential to save and improve many young lives. we thank all those involved in the writing of the guidelines, especially our fellow member of the writing committee, dr tammy meyers, and our overseas reviewers. as has been done previously when paediatric guidelines have appeared, the entire issue is devoted to paediatrics. we hope it will be useful as a ready reference on paediatric hiv management for all health care workers caring for children. e di tor i a l the southern african journal of hiv medicine                                                      december  2009 m e s s a g e   f r o m    t h e   e x e c u t i v e the global recession has thrown the problem of funding for aids programmes to the fore, with botswana’s president saying his country’s programme is unsustainable, and donors sounding warnings that rationing may need to be implemented. this is very alarming – we have made big strides in terms of antiretroviral access in the last few years, and these are suddenly looking very fragile. it is time to take stock of our programmes and make them as lean and mean as possible, ensuring maximum access to care while ensuring acceptable levels of quality. we need to look critically at the labs we ask for and the drugs we need, while keeping up pressure on the donor community to maintain support. however, we should not let our governments off the hook. health in southern africa has been consistently underfunded as a function of the gross domestic product, in almost every one of our countries. guns, presidential inaugurations and motorcades never seem to be a problem to fund, and we need to do a better job at the southern african journal of hiv medicine                                                      december  20096 we begin with an opinion piece by heather jaspan, rachel li, leigh johnson and linda-gail bekker on the urgent need to develop skills and infrastructure to meet the needs of hiv-infected adolescents, especially given our success in treating children with art. we then address prevention of vertical transmission of hiv, the key to the elimination of hiv infection in children. the paper by laurie schowalter, ashraf coovadia and ameena goga is a plea for action. it is followed by an analysis of vertical transmission data (mark cotton, soyeon kim, helena rabie, joan coetzee and sharon nachman, from the pactg 1041 team), emphasising again the importance of a good antenatal antiretroviral component. infant feeding is integral to child survival and development. there are risks and benefits for breast and replacement feeding. the paper by ameena goga is essential reading for anyone caring for infants and provides the key data to inform rational decision making. the guideline document emphasises the importance of and pitfalls in maintaining adherence. a number of articles provide background information to help in understanding the rationale of recommendations in the guidelines. these include articles on when to start (mark cotton, helena rabie, ute feucht and avy violari), essential pharmacokinetic information (helen mcilleron and hermien gous) and how the weight-based dosage recommendations were derived (james nuttall). what do you do when children starting art deteriorate instead of improve? helena rabie, tammy meyers and mark cotton delve into the paradoxical world of immune reconstitution inflammatory syndrome (iris). we then highlight two adverse events of art, one common and the other rare. the ndoh guidelines do not advocate using abacavir (abc) in the first-line regimen in the absence of adverse effects from other drugs. they still recommend d4t, increasingly implicated in lipodystrophy. lipodystrophy can be reversible if the offending agent (usually d4t) is replaced with abc (or tenofovir in adults) in the early stages. steve innes, leon levin and mark cotton provide background information and useful diagnostic and management advice for lipodystrophy. the sa clinicians society advocates 3tc and abc as the nrti backbone for the first-line regimen. there is much fear of the infamous abc hypersensitivity reaction (hsr). to the best of our knowledge, no one has ever died from the reaction, but people have died from abc rechallenge. fortunately the hsr is rare in black africans. helena rabie, kristin henning, pierre schoeman, nico de villiers, gert h j (oubaas) pretorius and mark cotton provide guidelines for using abc and recount their experience with suspected abc hsr. treatment failure is becoming increasingly complex. fortunately, there are quite a few new antiretrovirals registered overseas and about to be registered in south africa. leon levin takes us through the minefield of paediatric salvage therapy. finally, polly clayden presents us with some cuttingedge reports from the recent international aids society conference in cape town, again informing readers of the type of research needed to continually improve our guidelines. mark cotton leon levin guest editors drawing attention to how health budgets are allocated. in south africa it seems that jacob zuma’s government has declared war on overall wasteful expenditure, and at the same time there has been increasing embarrassing public exposure of ministerial spending on large cars. a new and energetic health minister, aaron motsoaledi, seems intent on reversing the terrible sins of the past under mbeki’s regimen, and to be determined that health resources get used better. please let the society know if you see any indication of rationing! we have active advocacy work, with good partners, and it is to be hoped that we can stop unnecessary restrictions on health care. francois venter president southern african hiv clinicians  society paediatric discussion  group (pdg) the southern african hiv clinicians society paediatric discussion group (pdg) began in december 2001. the concept was born after dr (now adjunct professor) ashraf coovadia of the rahima moosa mother and child hospital, coronationville, johannesburg, sent an e-mail to 5 or 6 local hiv ‘experts’ and professor mark kline of the baylor college of medicine, houston, texas, seeking advice on how to manage a child with severe disfiguring parotomegaly but who had a normal cd4 count, so antiretroviral therapy (art) was not indicated. the answer came back that there was no indication for art for a purely cosmetic condition! i found the concept fascinating and wondered if there was any value in using e-mails as a vehicle for educating health care providers about paediatric hiv. i contacted the south african hiv clinicians society, who were happy with the concept and provided me with a list of their members. the list in those days was very short (unlike today), and i tried to fathom out who was a paediatrician or treated paediatric cases and added them to the mailing list. the first few cases hardly garnered a response. i suspect people were too shy to answer. after a few weeks i would send out an expert opinion. the cases were all real cases (mostly from my own practice), and all had excellent lessons to teach. gradually, as knowledge and familiarity with pdg grew, so the number of responses increased. currently it’s not unusual to have over 100 responses to a case. the cases have spanned the whole range of paediatric hiv issues including opportunistic infections, side-effects of art and ethical issues. at the moment we are concluding pdg no. 51. some notable cases include: n one of the earliest cases in south africa of cushing’s syndrome caused by an interaction between ritonavir and inhaled fluticasone for asthma. n a child from a neighbouring country who was diagnosed as hiv-positive on two different tests and turned out to be hiv negative. n an hiv-positive child with marked failure to thrive and a normal cd4 count who turned out to have an oesophageal stricture and is now thriving after oesophageal dilatation. n cases of lymphoma and kaposi’s sarcoma. n a case where a mother with end-stage hiv had a negative hiv elisa test, having lost the ability to make antibodies due to her poor immunity. n a case of a young infant treated with art very early on who became hiv elisa negative after losing her maternal antibodies. she did, however, remain pcr positive. n interestingly, pdg no. 47 in april 2008 again discussed a patient with disfiguring parotomegaly and a normal cd4 count. this time the opinion was overwhelmingly in favour of starting art. the response to the pdg has been phenomenal. the mailing list currently stands close to 1 500. subscribers are predominantly from south africa but also include namibia, zimbabwe, botswana, zambia, angola, malawi, kenya, rwanda and other countries. subscribers are predominantly doctors but also include nurses, pharmacists, and counsellors. there is no doubt that the pdg has succeeded because of the very active participation of our subscribers and our wonderful panel of local and overseas experts, all of whom deserve my heartfelt thanks. i have merely been the conduit between the two. if you would like to subscribe to the pdg, please send an e-mail to leonlevin@54.co.za. i am also constantly on the lookout for new cases to discuss. they can be sent to the same e-mail address. leon levin head, paediatric programmes right to care m e s s a g e   f r o m   t h e   pa e di at r ic    s u b c o m m i t t e e the southern african journal of hiv medicine                                                      december  20098 about the author(s) jackie l. dunlop anova health institute, johannesburg, south africadivision of child health, faculty of health sciences, university of the witwatersrand, johannesburg, south africa carol l. tait anova health institute, johannesburg, south africa moyahabo mabitsi anova health institute, johannesburg, south africa kate rees anova health institute, johannesburg, south africadepartment of public health, faculty of health sciences, university of the witwatersrand, johannesburg, south africa citation dunlop jl, tait cl, mabitsi m, rees k. where are the children? case finding in 5–14-year-olds living with hiv in johannesburg. s afr j hiv med. 2022;23(1), a1378. https://doi.org/10.4102/sajhivmed.v23i1.1378 conference abstracts where are the children? case finding in 5–14-year-olds living with hiv in johannesburg jackie l. dunlop, carol l. tait, moyahabo mabitsi, kate rees received: 09 feb. 2022; accepted: 16 feb. 2022; published: 14 apr. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. south africa has the largest number of children living with hiv (clhiv) globally, with most untreated clhiv being 5 years and older. despite efforts to close this gap, including prioritising paediatric case finding, many clhiv 5–14 years are not in care. we aimed to review programme and research data and compare these with model estimates to better understand this gap in johannesburg, one of the districts with the highest number of clhiv in south africa. we included clhiv 5–14-year-olds in johannesburg. naomi model estimates were compared with case finding data from the district health information system and universal hiv testing data from 10 primary health care clinics. from naomi, the number of clhiv, hiv prevalence, and number on antiretroviral treatment (art) were used. hiv test and test positive data were used from the two sources (september 2020 to july 2021). according to the naomi model, in september 2020, there were an estimated 13 350 clhiv 5 to 14 years, of whom 46.8% were on art (6258). of those not on art, 36.9% had never been tested for hiv (2620). johannesburg had an hiv prevalence of 1.6% in children 5–14 years, with an untreated prevalence of 0.9%. routine data over a period of 12 months indicate that 54 528 were tested finding 523 hiv-positive children, a yield of 1.0%. data representing universal testing elicited a lower yield of 0.3% (3595 children tested with 11 testing positive in 10 weeks). case finding is becoming increasingly difficult with decreasing yields, especially when non-targeted or universal testing is conducted at health facilities. expansion of case finding strategies as well as targeted approaches are needed in this age group. alternative strategies are needed to link clhiv with known status but not on art into care, and retain those already on art, if the untreated gap is going to improve. the authors would like to thank the johannesburg health district management and facility teams and the anova teams for their dedication to caring for children living with hiv. ethical considerations: permission has been granted to conduct this analysis through the human sciences research council ethics committee under the ethics approval number rec 3/22/08/18. funding information: the anova health institute non-profit company is supported by the united states president’s emergency plan (pepfar) programme via the united states agency for international development (usaid) under the cooperative agreement number aid-674-a-12-00015. c p d q u e s t i o n s journal 42 two cpd points are awarded for the correct completion and submission of the questions below. cpd questionnaires must be completed online via www.cpdjournals.co.za. after submission you can check the answers and print your certificate. this programme is available free of charge to members of the hiv clinicians society and sama only. regarding missed opportunities to prevent hiv-related paediatric admissions: 1. true (a) or false (b): gastro-enteritis was the most common reason for admission in the sample of 440 hiv-infected children admitted to baragwanath hospital. 2. true (a) or false (b): in this study, most hiv-infected children admitted to hospital were known to be hiv-infected prior to admission. 3. true (a) or false (b): postnatal uptake of co-trimoxozole was very high in this study and was not commonly related to the reason for admission. 4. true (a) or false (b): failure to receive appropriate pmtct interventions contributes to a large proportion of paediatric admissions related to hiv infection. regarding health services for individuals who do not yet require art: 5. true (a) or false (b): loss to follow-up among hiv-infected individuals who are not yet on art is common, but is unlikely to be related to long-term health outcomes. 6. true (a) or false (b): a simple package of services may help to improve retention in pre-art care and thus facilitate regular cd4 cell count testing. regarding optic neuritis in hiv-infected individuals: 7. true (a) or false (b): the most common cause of optic neuritis in hiv is nrti-related mitochondrial toxicity. 8. true (a) or false (b): there is now consensus that high-dose steroids are part of the definitive management of optic neuritis in hiv-infected individuals. 9. true (a) or false (b): in a patient not on antiretroviral therapy (art), initiation of art may be part of the effective management of optic neuritis. 10. true (a) or false (b): cytomegalovirus, toxoplasmosis and cryptococcus are common opportunistic infections with ophthalmological manifestations. regarding postnatal depression in hiv-infected women: 11. true (a) or false (b): postnatal depression occurs in up to 40% of all hiv-infected women, and typically begins within 6 weeks of birth. 12. true (a) or false (b): postnatal depression does not have hiv-related risk factors (e.g. related to stigmatisation of hiv infection or non-disclosure of hiv status) and does not appear more commonly in hiv-infected compared with uninfected women. 13. true (a) or false (b): key symptoms of postnatal depression are fatigue, irritability and poor functioning, including child care. regarding the development of hiv services in khayelitsha, cape town: 14. true (a) or false (b): decentralised management of drug-resistant tuberculosis (tb) to primary care clinics (rather than hospital-based care for all patients with drugresistant tb) can decrease the average time to treatment initiation. 15. true (a) or false (b): evidence from khayelitsha suggests that an early viral load after 3 months on art is a better predictor of subsequent virological failure than viral load testing at 6 months. 16. true (a) or false (b): development of ‘male-friendly’ clinics located away from traditional public sector clinics (e.g. around taxi ranks) can help to increase the uptake of services as well as detection and effective treatment of men with sexually transmitted infections. regarding the use of stavudine: 17. true (a) or false (b): stavudine is appreciably more expensive than tenofovir or abacavir, and cost is the principal reason why tenofovir replaced stavudine in first-line art regimens in south africa. 18. true (a) or false (b): randomised controlled trials have shown that stavudine 20 mg given twice daily is as effective as 40 mg given twice daily. 19. true (a) or false (b): lipoatrophy related to stavudine use typically manifests within the first year on treatment. 20. true (a) or false (b): lipoatrophy related to stavudine use is usually dose-related, and occurs less frequently at lower doses. o cto b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e post-traumatic stress disorder (ptsd) is a complex psychological and physiological response to serious, lifethreatening trauma. the prevalence of ptsd in hivinfected individuals varies across studies, ranging from 30% to 64%4-6 depending on the various methods of assessment, sample characteristics and diagnostic criteria used. in one south african study of recently diagnosed hiv/aids patients (n=149), 14.8% met current criteria for ptsd at baseline, and 26.2% met criteria at 6-month follow-up.7,8 rates of ptsd appear to be significantly higher among hiv-infected individuals than in the general population. many studies show that a history of trauma, particularly physical and sexual abuse, is common among hiv-positive individuals and exceeds that in the general population.9 in one study in the usa, 95% of the women in primary care had experienced some form of sexual abuse in their lifetime, and 83% had experienced significant physical abuse.10 another study found that 72.5% of the participants had experienced at least two types of traumatic events during their lifetime, and 53.5% had some sexual and/or physical abuse history in their lifetime.11 the association between hiv infection and trauma exposure may be causal (for example, childhood sexual abuse has been linked to higher rates of sexual and drug use risk behaviours that increase the risk of hiv) or may reflect of the concentration of hiv infection in socio-economically deprived populations who are at high risk of trauma exposures.12 traumatic life events, especially multiple traumatic events, are strongly associated with poorer treatment adherence, hiv risk behaviours, a history of alcohol abuse and depression, more hospitalisations, and faster hiv disease progression.9,11-14 furthermore, there is a dose-response relationship with the odds of non-adherence to antiretroviral therapy (art) increasing with each additional lifetime traumatic exposure.14 prior trauma may affect adherence through a variety of pathways, including: (i) ptsd or other mental health problems (as well as substance misuse); (ii) subjective experiences of and trust in the health care system; (iii) individual coping styles and self-efficacy mechanisms; and (iv) the availability of social support.14,15 there are essentially three core aspects to consider in the assessment for ptsd in people living with hiv/aids (plwha): (i) identification of patients who are predisposed to the disorder (i.e. at risk); (ii) careful assessment of all traumatic events that a patient has experienced; and (iii) understanding of the diagnostic criteria for ptsd. hiv-infected patients with ptsd can present a special challenge to the primary care physician as they comthe management of trauma and posttraumatic stress disorder in hivinfected individuals c l i n i c a l : p t s d janine pingo, mb chb lentegeur hospital, mitchell’s plain, cape town soraya seedat, mb chb, fc psych, mmed psych (us), phd department of psychiatry, stellenbosch university, tygerberg, w cape women are disproportionately affected by the hiv epidemic and also carry a higher burden of early childhood trauma, other life traumas (e.g. rape and partner violence) and post-traumatic stress disorder (ptsd).1,2 yet ptsd and other common psychiatric disorders (e.g. depression, alcohol abuse) are commonly under-detected in hiv care settings. for many hiv-infected individuals in south africa, hiv clinical care is the primary point at which mental illness can be identified and an intervention can be administered.3 when one considers the high prevalence of trauma and ptsd in infected patients, and its potential effects on antiretroviral therapy (art) adherence, disease progression and quality of life, it is clear that correctly identifying and treating these conditions can significantly contribute to optimal patient care. hiv, trauma and ptsd interface assessment of trauma and ptsd 14 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e o cto b e r 2 0 0 9 monly complain of vague somatic symptoms that may be the somatic expression of their disorder, be exacerbated by their ptsd, or be unrelated.16 patients with ptsd also suffer from psychiatric co-morbidities such as depression, other anxiety disorders and substance abuse. many patients use alcohol or drugs in an attempt to self-medicate their ptsd symptoms. in addition, patients with ptsd are at an increased risk of gastro-intestinal, cardiac, respiratory and neurological problems.17 risk factors in both infected and uninfected individuals associated with the development of ptsd are listed in table i. in plwha, additional factors such as stigma may be contributory. for example, a study of 102 hiv-infected women that examined risk factors for ptsd symptomatology found that ptsd was associated with a higher degree of perceived stigma, more hiv-related physical symptoms, less perceived social support, more pre-hiv trauma, and more negative life events.19 stigma was the strongest individual predictor of ptsd, which highlights its importance in assessing for ptsd co-morbidity in infected individuals. plwha who have ptsd are typically unaware of the connection between a past traumatic experience and their current symptoms. at the same time, primary care physicians are often reluctant to ask about trauma for fear of upsetting or offending patients or because of their own discomfort around hearing patients’ trauma narratives. asking hiv-positive patients about trauma with a simple question such as ‘have you ever been physically, sexually or emotionally harmed?’ may be useful in helping patients understand the relationship between trauma and its effects (i.e. in providing psycho-education), eliciting any underlying disorder/s, and then managing patients appropriately.16 there are six criteria (a f) for the diagnosis of ptsd according to the diagnostic and statistical manual of mental disorders, 4th edition, text revision (dsm-ivtr).20 criterion a defines the ptsd-qualifying event/ stressor as one that involves actual or threatened death or injury and evokes a response of intense fear, horror or helplessness. traumatic events that give rise to ptsd include childhood abuse, rape, domestic violence, violent physical assault, motor vehicle accidents, military combat, and natural and man-made disasters.20 although being given a diagnosis of a life-threatening disease such as hiv may be considered as ‘traumatic’, there is some controversy about whether it classifies as an event that is capable of giving rise to ptsd.21,22 it is crucial to ask patients whether a traumatic experience is ongoing or in the past (e.g. ‘is this dangerous/life-threatening experience continuing in your life now?’).16 this should be followed up with questions including ‘some people who have had extremely traumatic experiences develop symptoms (e.g. nightmares, sleep disturbances, flashbacks) like the one you describe’, or ‘some people who have had traumatic experiences like you also have symptoms of ... [e.g. chronic pain]. have you ever thought that there might be a connection between your traumatic experience and your symptoms?’16 criteria b d refer to the three symptom clusters of ptsd: intrusive recollections, avoidance/numbing, and hyper-arousal. intrusive recollections include recurrent distressing memories and nightmares of the event, acting or feeling as if the traumatic event were recurring, pre-traumatic factors • previous psychiatric disorder • female gender • personality (external locus of control greater than internal locus of control) • lower socio-economic status • lack of education • minority status/race* • previous trauma • family history of psychiatric disorders peri-traumatic factors • severity of trauma • perceived threat to life • peri-traumatic emotions • peri-traumatic dissociation post-traumatic factors • perceived lack of social support • subsequent life stress *the effect of race/minority status has been documented primarily in us samples. table i. factors associated with the development of ptsd18 risk factors for ptsd traumatic life events the dsm-iv criteria for ptsd 15 o cto b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e and intense psychological and physiological distress on exposure to internal or external cues that remind one of a certain aspect of the event. avoidance/numbing symptoms refer to avoiding thoughts, feelings, conversations, activities, people or places that arouse recollections of the trauma, inability to recall important aspects of the trauma, lack of interest or participation in significant activities, feelings of detachment from others, restricted range of affect, and a sense of a foreshortened future. hyper-arousal symptoms include difficulty falling or staying asleep, irritability or outbursts of anger, difficulty concentrating, hyper-vigilance, and an exaggerated startle response. criterion e refers to the duration of the symptoms (lasting more than 1 month), and criterion f refers to the functional significance of symptoms (whether there is clinically significant distress or impairment in social, occupational or other important areas of functioning). lastly, one needs to specify whether the symptoms are acute (less than 3 months) or chronic, and whether symptom onset is delayed (onset of symptoms at least 6 months after the trauma). while a detailed diagnostic interview such as the clinician administered ptsd checklist (caps) is the ‘gold standard’, such an interview is lengthy and may be impractical for use in primary care settings. brief and simple-to-complete screening tools may be more feasible. the four-item primary care post-traumatic stress disorder screen (pc-ptsd) is one such measure that assesses symptoms specific to the core domains of ptsd.23 the pc-ptsd asks the patient ‘in your life have you ever had any experience that was so frightening, horrible or upsetting that, in the past month, you ...’ n have had nightmares about it or thought about it when you did not want to n tried hard not to think about it or went out of your way to avoid situations that reminded you of it n were constantly on guard, watchful, or easily startled n felt numb or detached from others, activities or your surroundings. three or more ‘yes’ responses to these questions is highly suggestive of ptsd, requiring further evaluation of symptoms and other trauma-related problems by a mental health care practitioner if need be. a cut-off of 3 on the pc-ptsd yields a sensitivity of 78% and specificity of 87% compared with the gold-standard caps.23 the pc-ptsd is simple to administer and may be easily used in a busy clinical setting alongside the sa-miss (see related article in this issue on common mental disorders in hiv). plwha who have ptsd are often fearful and highly sensitive to physical sensations (e.g. a physical examination can remind some patients of their traumatic experience), and in turn may be ambivalent about medical treatment. being supportive, enhancing a sense of personal safety, and recommending self-care strategies (e.g. an activity that is enjoyable and self-fulfilling) can help patients manage their anxiety and reduce risktaking and self-destructive behaviours. in clinical practice, the majority of adults with ptsd derive most benefit from a combination of treatment approaches encompassing psychopharmacology and psychotherapy.17 the management principles discussed below are illustrated in the form of a case study (see box). pharmacological treatment medication has been shown to be significantly more effective than placebo across all three symptom clusters in ptsd, and has also been shown to be effective in reducing co-morbid symptoms and improving quality of life.24-30 medication should be considered from the beginning if the patient prefers it, if the symptoms are severe and persistent, if there is co-morbid depression and anxiety, and if functioning is severely disrupted. plwha who have ptsd may be highly sensitive to physical symptoms and to medication side-effects. adherence may be enhanced by starting medication at low doses with gradual increases based on tolerability. n selective serotonin reuptake inhibitors (ssris) are the most studied medications for ptsd and are widely considered as first-line agents for this condition. in south africa fluoxetine is easily available and can be used as a first-line agent. ssri treatment is most helpful in the long term if it is continued for at least 12 months after remission of symptoms. more on the use of ssris can be found in the article on psychotropic prescribing in hiv infection. n if there is no response in 8 weeks, the primary care physician should refer the patient for psychiatric care. further indications for referral to specialised psychiatric care are shown in table ii.31 n benzodiazepines should be avoided or used with caution. while they reduce anxiety and promote sleep, controlled trials have not shown them to be superior in efficacy to placebo; with the risk of drug dependence, benzodiazepines are not recommended. screening management of ptsd 16 o cto b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e psychological treatments psychological treatments are widely used to treat ptsd as they have been shown to significantly reduce symptoms.32 all patients willing to attend should be referred for psychological treatment, depending on the available services. trauma-focused cognitive-behavioural therapy (cbt) is recommended as it has been extensively studied in ptsd.33 cbt consists of anxiety management (teaching patients skills to cope with stress, such as relaxation training, breathing training, assertiveness training, etc), cognitive therapy (modifying unrealistic assumptions, beliefs and automatic thoughts), and prolonged exposure therapy (learning to confront situations associated with the trauma).25 supportive interventions when a patient has recently experienced an extremely traumatic event, time should be taken to educate the patient and his or her family about acute stress reactions and ptsd, and to reassure the patient that it is normal to be upset and distressed shortly after a trauma. the family should be encouraged to talk about the traumatic event with the patient and provide the necessary support, where possible.33 in instances of domestic violence, for example, the physician will need to assess whether reporting is required and should inform the patient of the limits of confidentiality. involvement of social workers should be considered to ensure that ongoing abuse does not occur. references 1. wyatt ge, myers hf, loeb tb. women, trauma, and hiv: an overview. aids behav 2004; 8(4): 401-403. 2. seedat s, stein dj, carey pd. post-traumatic stress disorder in women: epidemiological and treatment issues. cns drugs 2005; 19(5): 411-427. 3. pence bw. the impact of mental health and traumatic life experiences on antiretroviral treatment outcomes for people living with hiv/aids. j antimicrob chemother 2009; 63(4): 636-640. 4. kelly b, raphael b, judd f, et al. posttraumatic stress disorder in response to hiv infection. gen hosp psychiatry 1998; 20: 345-352. 5. martinez a, israelski d, walker c, koopman c. posttraumatic stress disorder in women attending human immunodeficiency virus outpatient clinics. aids patient care stds 2002; 16(6): 283-291. 6. safren sa, gershuny bs, hendriksen e. symptoms of posttraumatic stress and death anxiety in persons with hiv and medication adherence difficulties. aids patient care stds 2003; 17(12): 657-664. 7. olley bo, zeier md, seedat s, stein dj. post-traumatic stress disorder among recently diagnosed patients with hiv/aids in south africa. aids care 2005; 17(5): 550-557. 8. olley bo, seedat s, stein dj. persistence of psychiatric disorders in a cohort of hiv/aids patients in south africa. j psychosom res 2006; 61: 479-484. 9. whetten k, reif s, whetten r, murphy-mcmillan lk. trauma, mental health, distrust, and stigma among hiv-positive persons: implications for effective care. psychosom med 2008; 70(5): 531-538. 10. brady s, gallagher d, berger j, vega m. physical and sexual abuse in the lives of hiv-positive women enrolled in a primary medicine health maintenance organization. aids patient care stds 2002; 16(3): 121-125. 11. leserman j, whetten k, lowe k, stangl d, swartz m, thielman n. how trauma, recent stressful events, and ptsd affect functional health status and health utilization in hiv-infected patients in the south. psychosom med 2005; 67(3): 500-507. 12. brief dj, bollinger ar, vielhauer mj, et al. hiv/aids treatment adherence, health outcomes and cost study group. understanding the interface of hiv, trauma, post-traumatic stress disorder, and substance use and its implications for health outcomes. aids care 2004; 16: suppl 1, s97-120. 13. leserman j, ironson g, o’cleirigh c, fordiani j, balbin e. stressful life events and adherence in hiv. aids patient care stds 2008; 22(5): 403-411. 14. mugavero m, ostermann j, whetten k, et al. barriers to antiretroviral adherence: the importance of depression, abuse, and other traumatic events. aids patient care stds 2006; 20(6): 418-428. 15. olley bo, bolajoko aj. psychosocial determinants of hiv-related quality of life among hiv-positive military in nigeria. int j std aids 2008; 19: 94-98. case study a 26-year-old hiv-positive woman with a cd4 count of 180 cells/µl is referred to her local arv clinic to initiate antiretroviral therapy. in the initial interview the hiv clinician notices that she appears to be a little anxious and withdrawn, and seems tired. the patient says that she was diagnosed with hiv 3 years ago after she was sexually and physically abused by her boyfriend at the time. a year ago she left her family and friends in the eastern cape to find work in cape town. she has grade 10 education, and is currently a casual employee at a fast-food restaurant and living with a friend. the hiv clinician becomes concerned, as this patient has a history of previous trauma, comes from an impoverished background and has little social support, and enquires further about her symptoms of anxiety and tiredness. the patient says that about 2 months ago she was mugged on the way home from work, physically assaulted and threatened with a knife. since then she’s had difficulty sleeping, occasionally experiences nightmares of the event, can’t recall certain aspects, feels constantly on guard, and feels as if her emotions are numbed. she has taken a number of days off work recently as she’s afraid she will be mugged again, and her supervisor has already warned her that she may lose her job. the hiv clinician makes the diagnosis of posttraumatic stress disorder, and explains the treatment options available. at the patient’s request, fluoxetine 20 mg daily is prescribed and a referral is made to the clinic psychologist to initiate cognitive-behavioural therapy. the patient is also started on arvs and warned of possible side effects, and regular follow-up is arranged to monitor her progress. • if the patient has other serious psychiatric problems which are not improving on treatment • if the patient has suicidal thoughts/behaviour • if there are persistent problems with medication side-effects • if ptsd symptoms are not responsive to an adequate trial ((8 weeks at an average therapeutic dose) of at least one medication • if there are co-existing substance abuse problems • if the patient is experiencing other life stressors and/or poor social support table ii. when to refer for specialised psychiatric care 18 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e o cto b e r 2 0 0 9 16. nakell l. adult post-traumatic stress disorder: screening and treating in primary care. primary care 2007; 34(3): 593-610. 17. lecrubier y. posttraumatic stress disorder in primary care: a hidden diagnosis. j clin psychiatry 2004; 65: suppl 1, 49-54. 18. bisson j. post-traumatic stress disorder. bmj 2007; 334: 789-793. 19. katz s, nevid js. risk factors associated with posttraumatic stress disorder symptomatology in hiv-infected women. aids patient care stds 2005; 19(2): 110-120. 20. american psychiatric association. diagnostic and statistical manual of mental disorders (dsm-iv-tr).4th ed., text revision. washington, dc: american psychiatric press, 2000. 21. shemesh e, stuber ml. posttraumatic stress disorder in medically ill patients: what is known, what needs to be determined, and why is it important? cns spectrums 2006; 11(2): 106-117. 22. kagee a. application of the dsm-iv criteria to the experience of living with aids: some concerns. j health psychol 2008; 13(8): 1008-1011. 23. prins a, ouimette p, kimerling r, et al. the primary care ptsd screen (pc-ptsd): development and operating characteristics. primary care psychiatry 2004; 9: 9-14 24. ipser j, seedat s, stein dj. pharmacotherapy for post-traumatic stress disorder – a systematic review and meta-analysis. s afr med j 2006; 96: 1088-1096. 25. seedat s. post-traumatic stress disorder in the primary care setting. south african family practice 2004; 46(6): 35-36. 26. colibazzi t, hsu tt, gilmer ws. human immunodeficiency virus and depression in primary care: a clinical review. prim care companion j clin psychiatry 2006; 8(4): 201-211. 27. asnis gm, kohn sr, henderson m, brown n. ssris versus non-ssris in posttraumatic stress disorder. drugs 2004; 64(4): 383-404. 28. cruess dg, evans dl, repetto mj, gettes d, douglas sd, petitto jm. prevalence, diagnosis, and pharmacological treatment of mood disorders in hiv disease. biol psychiatry 2003; 54: 307-316. 29. desilva ke, le flore db, marston bj, rimland d. serotonin syndrome in hivinfected individuals receiving antiretroviral therapy and fluoxetine. aids 2001; 15(10): 1281-1285. 30. repetto mj, petitto jm. psychopharmacology in hiv-infected patients. psychosom med 2008; 70: 585-592. 31. foa eb, davidson jrt, frances a. the expert consensus guidelines series: treatment of post-traumatic stress disorder. j clin psychiatry 1999; 60(16): 1-76. 32. bisson j, andrew m. psychological treatment of post-traumatic stress disorder (ptsd). cochrane database of systematic reviews 2007, issue 3. art. no.: cd003388. doi: 10.1002/14651858. cd003388.pub3. 33. bisson ji, ehlers a, matthews r, pilling s, richards d, turner s. psychological treatments for chronic post-traumatic stress disorder. systematic review and meta-analysis. br j psychiatry 2007; 190: 97-104. 19 c p d q u e s t i o n s journal 39 two cpd points are awarded for the correct completion and submission of the questions below. cpd questionnaires must be completed online via www.cpdjournals.org.za. after submission you can check the answers and print your certificate. questions may be answered up to 6 months after publication of each issue. this programme is available free of charge to members of the hiv clinicians society and sama only. concerning paediatric palliative care and infant mortality: 1. true (a) or false (b) – click on the correct answer: in south africa most deaths of children under 5 are due to trauma. 2. true (a) or false (b) – click on the correct answer: most aids-related palliative care in south africa is rendered by unskilled home-based carers. 3. true (a) or false (b) – click on the correct answer: antenatal zidovudine may reduce intra-uterine vertical transmission. 4. true (a) or false (b) – click on the correct answer: postpartum transmission contributes relatively more to infant mortality than intra-uterine transmission. concerning art and hiv testing programmes: 5. true (a) or false (b) – click on the correct answer: less stavudine and more protease inhibitors are prescribed as first-line therapy in private sector patients. 6. true (a) or false (b) – click on the correct answer: stavudine is a cause of peripheral neuropathy. 7. true (a) or false (b) – click on the correct answer: providing vct in the workplace is stigmatising and leads to boycott of testing. concerning hiv and the lungs, nerves and kidneys: 8. true (a) or false (b) – click on the correct answer: cytomegalovirus (cmv) infection usually occurs in patients with well-preserved immunity. 9. true (a) or false (b) – click on the correct answer: in transbronchial biopsy specimens, cmv is identified by viewing ring forms. 10. true (a) or false (b) – click on the correct answer: hiv plus smoking predisposes to emphysematous lung disease in an additive way. 11. true (a) or false (b) – click on the correct answer: bilateral facial palsy is reported and may be a result of an inflammatory radiculopathy similar to guillainbarré syndrome. 12. true (a) or false (b) – click on the correct answer: hiv-related renal disease manifests as proteinuria or elevated creatinine clearance. concerning hepatitis b infection in hiv: 13. true (a) or false (b) – click on the correct answer: ninety per cent of children with perinatally acquired hbv from mothers who are hbeag positive will go on to have chronic disease. 14. true (a) or false (b) – click on the correct answer: hiv decreases the rate of spontaneous hbsag seroconversion. 15. true (a) or false (b) – click on the correct answer: patients who are eligible for hbv vaccination but have cd4 counts <200 cells/µl mount poor antibody responses to hbv vaccine. 16. true (a) or false (b) – click on the correct answer: vaccinate patients with hepatitis b vaccine regardless of cd4 count. concerning management of hepatitis b/hiv coinfection: 17. true (a) or false (b) – click on the correct answer: hiv-hbv co-infected patients with alt ≥2 times the upper limit of normal are at an increased risk of hbv disease progression. 18. true (a) or false (b) – click on the correct answer: art is contraindicated for any co-infected patient with cd4 counts >350 cells/µl who has symptomatic liver disease. 19. true (a) or false (b) – click on the correct answer: a hepatitis flare may occur in a patient who has been on a lamivudine-containing regimen and develops hepatitis b resistance to lamivudine. 20. true (a) or false (b) – click on the correct answer: only newborn babies of mothers infected with hbv who are co-infected with hiv should receive hepatitis b immunoglobulin (hbig) plus the first dose of the hepatitis b vaccine within the first 12 hours after delivery. cpd insert.indd 1 4/18/11 1:14:31 pm message_from_editor.html from the editor you may well be at the 5th south african aids conference in durban as you read this! the conference promises to build on the resounding success of the previous four. in keeping with the mission of such conferences, the journal continues to help you ensure not only fewer infections and longer lives but also better quality of life for your patients, both before and after commencement of antiretroviral therapy. this issue brings guidance on isoniazid prevention therapy in children and safer conception counselling and strategies for concordant and discordant couples. guidance documents supported by the hiv clinicians society and published in this journal are the result of consensus among south african experts. subjects are chosen that are considered areas of controversy or complexity or where clear evidencebased direction is lacking. other topics covered include an overview of provider-initiated hiv testing and counselling. hiv testing has evolved since the onset of the era of successful treatment, and hiv testing is now less of a privacy issue and more of a health issue. nixon and colleagues remind us that rehabilitation and the rehabilitation sciences are important in hiv care. the co-epidemic of hpv in our population is resulting in a growing burden of cervical carcinoma in hiv-positive women, and menon explores and discusses various cervical screening strategies in hiv-prevalent settings. kirkcaldy and colleagues describe their original data from mozambique on other sexually transmitted infections in hiv-infected women, and abubakar and colleagues from nigeria present a retrospective review of pericardial disease cases. khan and colleagues remind us that tb can present in a range of tissues and organs in hiv, and describe a case of mammary tb. de zoysa and colleagues from sri lanka present a patient with oesophageal carcinoma in whom oesophagectomy was performed. this is the last issue of which i will be journal editor. i wish to thank all at hpmg for their extraordinary professionalism, the clinicians society staff, and tammy, my pa who has held the fort through many a deadline. i wish you all well as you continue to provide excellent hiv care, prevention, testing and management. may we in our lifetimes realise a southern african region in which not only aids but hiv is a receding threat. linda-gail bekker editor abstract introduction methods results discussion conclusion acknowledgements references about the author(s) ruan spies department of medicine, new somerset hospital, cape town, south africa charlotte schutz department of medicine, faculty of health sciences, university of cape town, cape town, south africa wellcome centre for infectious diseases research in africa (cidri-africa) and institute of infectious disease and molecular medicine, faculty of health sciences, university of cape town, cape town, south africa amy ward department of medicine, faculty of health sciences, university of cape town, cape town, south africa wellcome centre for infectious diseases research in africa (cidri-africa) and institute of infectious disease and molecular medicine, faculty of health sciences, university of cape town, cape town, south africa avuyonke balfour wellcome centre for infectious diseases research in africa (cidri-africa) and institute of infectious disease and molecular medicine, faculty of health sciences, university of cape town, cape town, south africa muki shey department of medicine, faculty of health sciences, university of cape town, cape town, south africa wellcome centre for infectious diseases research in africa (cidri-africa) and institute of infectious disease and molecular medicine, faculty of health sciences, university of cape town, cape town, south africa mark nicol division of infection and immunity, school of biomedical sciences, university of western australia, perth, australia rosie burton médecins sans frontières, cape town, south africa bianca sossen department of medicine, faculty of health sciences, university of cape town, cape town, south africa wellcome centre for infectious diseases research in africa (cidri-africa) and institute of infectious disease and molecular medicine, faculty of health sciences, university of cape town, cape town, south africa robert wilkinson wellcome centre for infectious diseases research in africa (cidri-africa) and institute of infectious disease and molecular medicine, faculty of health sciences, university of cape town, cape town, south africa the francis crick institute, london, united kingdom department of infectious disease, university college london, london, united kingdom david barr wellcome centre for infectious diseases research in africa (cidri-africa) and institute of infectious disease and molecular medicine, faculty of health sciences, university of cape town, cape town, south africa institute of infection and global health, university of liverpool, liverpool, united kingdom graeme meintjes department of medicine, faculty of health sciences, university of cape town, cape town, south africa wellcome centre for infectious diseases research in africa (cidri-africa) and institute of infectious disease and molecular medicine, faculty of health sciences, university of cape town, cape town, south africa citation spies r, schutz c, ward a, et al. rifampicin resistance and mortality in patients hospitalised with hiv-associated tuberculosis. s afr j hiv med. 2022;23(1), a1396. https://doi.org/10.4102/sajhivmed.v23i1.1396. original research rifampicin resistance and mortality in patients hospitalised with hiv-associated tuberculosis ruan spies, charlotte schutz, amy ward, avuyonke balfour, muki shey, mark nicol, rosie burton, bianca sossen, robert wilkinson, david barr, graeme meintjes received: 25 apr. 2022; accepted: 30 june 2022; published: 27 sept. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: patients with hiv and drug-resistant tuberculosis (tb) are at high risk of death. objectives: we investigated the association between rifampicin-resistant tb (rr-tb) and mortality in a cohort of patients who were admitted to hospital at the time of tb diagnosis. method: adults hospitalised at khayelitsha hospital and diagnosed with hiv-associated tb during admission, were enrolled between 2013 and 2016. clinical, biochemical and microbiological data were prospectively collected and participants were followed up for 12 weeks. results: participants with microbiologically confirmed tb (n = 482) were enrolled a median of two days (interquartile range [iqr]: 1–3 days) following admission. fifty-three participants (11.0%) had rr-tb. participants with rifampicin-susceptible tb (rs-tb) received appropriate treatment a median of one day (iqr: 1–2 days) following enrolment compared to three days (iqr: 1–9 days) in participants with rr-tb. eight participants with rs-tb (1.9%) and six participants with rr-tb (11.3%) died prior to the initiation of appropriate treatment. mortality at 12 weeks was 87/429 (20.3%) in the rs-tb group and 21/53 (39.6%) in the rr-tb group. rr-tb was a significant predictor of 12-week mortality (hazard ratio: 1.88; 95% confidence interval: 1.07–3.29; p = 0.03). conclusion: mortality at 12 weeks in participants with rr-tb was high compared to participants with rs-tb. delays in the initiation of appropriate treatment and poorer regimen efficacy are proposed as contributors to higher mortality in hospitalised patients with hiv and rr-tb. keywords: hiv-associated tuberculosis; rifampicin-resistant tuberculosis; drug-resistant tuberculosis; multi-drug resistant tb; tb; khayelitsha hospital. introduction drug-resistant tuberculosis (dr-tb) is a global health concern.1 in south africa (sa), 13 005 cases of rifampicin-resistant tb (rr-tb) were identified in 2019.2,3 people living with hiv are at higher risk of acquiring dr-tb, which is associated with poorer treatment outcomes in this patient population.2,4,5,6 the treatment of dr-tb has low success rates and high mortality due to lengthy, poorly tolerated and poorly efficacious regimens.7,8 in 2018, only 58% of patients with dr-tb globally were successfully treated.1 mortality estimates from studies conducted primarily in outpatients or in tb hospitals in high-burden settings, prior to the introduction of bedaquiline-based regimens, range from 11% to 39%.9,10,11,12,13,14 the introduction of bedaquiline-based treatment has been associated with a reduction in mortality in patients with dr-tb; however, treatment failure and mortality remain high in high-prevalence settings, with mortality still ranging from 6% to 17%.15,16,17,18,19,20,21 as most dr-tb is managed in outpatient clinics or in tb hospitals, most research on dr-tb outcomes occurs in these settings. patients who are hospitalised with hiv-associated tb are often severely ill and inpatient case fatality rates range from 11% to 32%.22,23,24,25,26,27 in autopsy series, inpatient deaths occur with a median of 4–5 days following admission.28,29,30 there are scarce data on outcomes of patients diagnosed with hiv-associated dr-tb admitted to general hospitals. the outcomes of a cohort of patients admitted to hospital in khayelitsha, sa, newly diagnosed with hiv-associated tb, were previously described.31 in this cohort, rr-tb was present in 16.9% of participants who died and in 7.2% of survivors.31 in this secondary analysis, we aimed to describe the association between rr-tb and mortality in patients diagnosed with hiv-associated tb while hospitalised and to identify factors associated with mortality in patients with rr-tb. methods study design and setting patients admitted to khayelitsha hospital were enrolled to a prospective cohort study between january 2013 and october 2016. the hospital is in khayelitsha – a large township in cape town, sa, with high rates of hiv, tb and dr-tb.32 most cases of tb are managed in primary healthcare clinics; however, patients may be referred to hospital if they require inpatient care. participants all patients in the emergency unit and medical wards were screened on weekdays. adults with hiv infection, a cd4 count of < 350 cells/µl and a high clinical suspicion of tb were eligible to enrol into the study. pregnant patients, patients who received anti-tb therapy within the past month, or patients who were recently initiated and received three or more doses of anti-tb therapy, were not eligible for enrolment. clinical details, chest x-ray, sputum, urine and blood samples were obtained at enrolment. additional samples, including extra-pulmonary samples such as pleural fluid, cerebrospinal fluid and lymph node aspirates, were obtained as indicated by clinical staff. participants remained under routine clinical care and treatment decisions were made by clinical staff and not by study staff. results of validated sputum, urine and blood tb tests that were collected by the study were communicated to the routine clinical team. participants were assessed daily in the ward and, after discharge, were managed in primary care according to local guidelines. participants had a telephonic follow-up at week 4 and returned for a clinical assessment at week 12. laboratory assays tuberculosis microbiology was performed by the national health laboratory services (nhls). sputum and urine were sent for tb culture and xpert mtb/rif assay (cepheid, sunnyvale, california, united states). the study preceded the introduction of xpert mtb/rif ultra, which has a higher sensitivity than xpert mtb/rif ultra for pulmonary tb.33 mycobacterial blood culture was performed by culturing 5 ml of whole blood in myco/f lytic (becton dickinson biosciences, franklin lakes, new jersey, united states) bottles for 42 days. the genotype mtbrplus assay (hain lifesciences, nehren, germany) was used to identify mycobacterium tuberculosis complex from the positive sputum and blood cultures and provided rifampicin and isoniazid resistance testing. rr isolates underwent susceptibility testing to second-line drugs at a referral laboratory. between 2014 and 2016, phenotypic resistance testing was performed for amikacin and ofloxacin. from 2016 the genotype mtbdrsl (hain lifesciences, nehren, germany) line probe assay was used to assess susceptibility to aminoglycosides and fluoroquinolones. cd4 count, hiv viral load, haemoglobin, creatinine and electrolytes, liver function and c-reactive protein (crp) tests were performed on all participants. data collection and definitions clinical data were captured on standardised case record forms from patient interviews, hospital folders and clinical review at enrolment. the primary outcome was survival at 12 weeks. if patients could not be contacted at 12 weeks, searches of electronic records were conducted. participants with an electronic entry indicating a clinic visit, collection of medicine or a laboratory test performed beyond 12 weeks were assumed to be alive at week 12. participants without electronic entries at or beyond 12 weeks were classified as lost to follow-up. in this study we describe and analyse the subset of patients with microbiologically confirmed tb, defined as participants with m. tuberculosis identified by culture or xpert mtb/rif from any clinical sample. rr-tb was defined as rifampicin resistance on any sample using either of the genotypic tests performed at the nhls while rifampicin-susceptible tb (rs-tb) was defined as rifampicin susceptibility on all samples. statistical analyses data were analysed using r version 4.02 (r core team, vienna, austria). median values with interquartile ranges were used as measures of central tendency and dispersion. categorical variables were described using counts and proportions and were compared using the fisher’s exact test. continuous variables were compared between study groups using the mann-whitney u test. to investigate the association of rr-tb with 12-week mortality, we hypothesised that rr-tb could cause mortality through two mechanisms: (1) delayed initiation of effective therapy and (2) lower efficacy of dr-tb therapy in preventing early mortality. we therefore treated receipt of appropriate anti-tb therapy (i.e. rifampicin-based therapy for rs-tb, any dr-tb therapy for rr-tb and an individualised regimen for extremely drug-resistant [xdr] tb) as a time-dependent variable in a cox proportional hazards model, where hazard of mortality after start of appropriate therapy was compared to hazard of mortality prior to initiation of appropriate therapy, capturing effect of delay to appropriate treatment initiation. this allowed assessment of the association between rr-tb and mortality after adjusting for an effect of rr-tb on delay to appropriate treatment initiation. we further hypothesised that measures of disease severity at baseline (hypoxia defined as peripheral oxygen saturation < 94% on room air, serum creatinine, sodium, protein gap [pg] [defined as the difference between total protein and albumin], haemoglobin, cd4 count, hiv viral load, glasgow coma scale [gcs] < 15 and weight) could confound tb treatment status and mortality (with patients presenting more unwell being initiated on anti-tb therapy more urgently). finally, we considered that patient factors associated with both rr-tb and mortality, including age and sex, and the above markers of baseline disease severity could confound the relationship between rr-tb and mortality. both these sets of variables were therefore included as covariates in the model. continuous predictor variables were log-transformed to resolve highly skewed distributions, and because proportional or multiplicative changes in the values of these variables were thought to be more biologically meaningful. peripheral oxygen saturation was dichotomised to reflect a non-linear relationship between oxygen saturation and partial pressure of oxygen as parsimoniously as possible. the hypothesised causal structure is summarised in a directed acyclic graph (figure 1). figure 1: hypothesised causal structure for the relationship between rifampicin-resistant tuberculosis and 12-week mortality. observations on variables included in cox regression were all > 95% complete except for weight which was missing in 8% of participants. all missing values were considered missing completely at random or missing at random after adjusting for other observed covariates and single-imputed for model fitting using classification and regression trees implemented with the mice package in r. participants lost to follow-up were censored on their last day of contact with health services. kaplan-meier plots were used to estimate survival over the study period, stratified by rifampicin-sensitivity status. ethical considerations this study was approved by the university of cape town human research ethics committee (reference number 057/2013). participants provided written informed consent where possible. the process involved in enrolling patients who did not have the capacity to provide informed consent has been described previously. results participant characteristics a total of 482 participants with hiv-associated, microbiologically confirmed tb were included in this analysis, enrolled a median of two days (interquartile range [iqr]: 1–3 days) after admission to hospital. fifty-three participants (11.0%) had rr-tb. of these, 16 (30.0%) had tb resistant to rifampicin only and 32 (60.0%) had multi-drug resistant tb, three (6.0%) of whom had tb resistant to a second-line drug (one participant had xdr-tb and two participants had pre-xdr-tb). five (9.0%) participants provided samples that were identified as rr by genexpert mtb/rif but the results of further drug susceptibility testing were unavailable. in the rs-tb group, 194 (45.2%) tested positive for m. tuberculosis by xpert mtb/rif compared to 22 (41.5%) participants in the rr-tb group. thirteen (2.7%) participants were lost to follow-up over the 12-week study period. demographic and clinical characteristics, stratified by rifampicin susceptibility, are displayed in table 1. characteristics for the rr-tb group, stratified by vital status, are shown in table 2. table 1: demographic and clinical characteristics and outcomes, stratified by rifampicin susceptibility status. table 2: demographic and clinical characteristics of patients with rifampicin-resistant tuberculosis, stratified by vital status at 12 weeks. time to treatment initiation and treatment status participants in the rs-tb group initiated appropriate treatment (rifampicin-based therapy for rs-tb, any dr-tb therapy for rr-tb and an individualised regimen for xdr-tb) a median of 1 day following enrolment (iqr: 1–2 days) compared to three days in the rr-tb group (iqr: 1–9 days), p < 0.001. eight (1.9%) participants in the rs-tb group were not initiated on appropriate treatment during their admission, six of whom died. six (11.3%) participants in the rr-tb group died prior to the initiation of appropriate treatment (figure 2). four of the six participants died within three days of enrolment. in the two remaining participants, rr-tb was confirmed on blood culture – the results of which were only available after their deaths. figure 2: histogram of time to appropriate treatment initiation stratified by rifampicin susceptibility status. (a) rifampicin-susceptible tb, (b) rifampicin-resistent tb. mortality mortality at 12 weeks was 87/429 (20.3%) in the rs-tb group and 21/53 (39.6%) in the rr-tb group (p = 0.008). the kaplan-meier curve in figure 3 demonstrates the relationship between rifampicin susceptibility and time-to-death. table 3 depicts the results of the cox proportional hazards model which modelled the relationship between rr-tb and 12-week mortality. rr-tb was significantly associated with 12-week mortality (hazard ratio 1.88; 95% confidence interval 1.07–3.29; p = 0.03) when adjusting for crp, cd4 count, hiv viral load, creatinine, sodium, pg, haemoglobin, weight, gcs, hypoxia, age, sex, and tb treatment status as a time-dependent variable to adjust for treatment delay. figure 3: kaplan-meier estimate of survival function, stratified by rifampicin susceptibility status. table 3: cox proportional hazards model of association between rifampicin-resistant tuberculosis and 12-week mortality, adjusted for markers of illness severity, tuberculosis treatment status and anticipated confounders. discussion in this study we describe 482 patients with hiv-associated, microbiologically confirmed tb, diagnosed while admitted to a general hospital. we found a high prevalence of rr-tb in the study cohort and a high 12-week mortality in participants with rr-tb. rifampicin-resistant tb was significantly associated with mortality, even when controlling for markers of disease severity and delay to treatment initiation. the mortality rate we describe is significantly higher than described in other studies of patients with hiv-associated rr-tb. unlike our study, these studies included participants both with and without hiv, longer follow-up periods and participants in predominantly outpatient or tb hospital settings. prospective cohorts of outpatients with rr-tb, with follow-up periods ranging 6–24 months, describe mortality rates of 9% – 31%, with hiv prevalence 38% – 85%.34,35,36,37 retrospective cohorts of patients with rr-tb in tb hospitals describe mortality rates of 18% – 29%, with hiv prevalence 52% – 100%.38,39,40 retrospective studies of outpatients describe mortality rates of 13% – 21%, with hiv prevalence 70% – 100%.10,12,13 in our cohort, 29% of participants with rr-tb who died did so prior to the initiation of a dr-tb regimen. this suggests that a substantial proportion of acutely ill patients with dr-tb die as inpatients, before a diagnosis of dr-tb can be confirmed, before dr-tb treatment regimens can be initiated and before they are registered on the national tb programme. these patients would contribute to the recognised gap between numbers of dr-tb diagnoses and numbers registered in the dr-tb programme.3 the authors hypothesised that the high mortality rates they observed could be driven by two, not necessarily mutually exclusive, mechanisms: delays to initiation of appropriate treatment for rr-tb and less effective therapies for rr-tb compared to rs-tb. in this study, time to initiation of appropriate treatment was shorter than described in previous studies,9,41 likely reflecting access to rapid diagnostics, multiple different samples taken for tb testing, and regular monitoring available in hospital. although the difference in time to treatment initiation between the rs-tb and rr-tb groups was statistically significant, the difference is of unknown clinical significance. several factors may have contributed to delays in appropriate treatment initiation in the rr-tb group including delays in specimen collection (patients in the rr-tb group may have been sicker at baseline and thus sputum sample acquisition for microbiological testing may have been more difficult), in awaiting the results of tb culture and drug susceptibility testing and in initiating appropriate treatment once these became available. previous studies have failed to demonstrate a reduction in mortality in rr-tb with a reduction in time to treatment initiation.9,42 in this study analysis, the effect of being on appropriate tb therapy on mortality during the follow-up period was unclear. this implies that the association between rr-tb and 12-week mortality observed in this cohort was not mediated by diagnostic delay. despite the marginal difference in time to treatment initiation, the 12-week mortality in the rr-tb group was much higher. when adjusting for tb treatment status as a time-dependent variable, rr-tb remained significantly associated with 12-week mortality, suggesting that additional factors related to rr-tb, other than time to treatment initiation, were important. these additional factors could include residual confounding, but the finding is also consistent with lower efficacy of dr-tb regimens during the study period. interestingly, the kaplan-meier survival curves for participants with rr-tb versus rs-tb (figure 3) diverge at day 21 of follow-up, suggesting early factors, including delays to treatment initiation, are less important contributors to differences in mortality than later factors, such as poorer efficacy of dr-tb treatment regimens. this study preceded the introduction of bedaquiline-based regimens for patients with rr-tb and participants in our study received rr-tb regimens containing injectable second-line drugs which are poorly tolerated and which have poor efficacy.8 the introduction of bedaquiline-based regimens has resulted in promising improvements in survival in dr-tb;17 however, prospective data in hospitalised patients at high risk of early mortality are lacking. this study suggests that efficacy of evolving dr-tb regimens in seriously ill patients with hiv-associated tb is an important topic for future research. this study has several limitations. although our cohort was relatively large, the population of participants with rr-tb was small. the authors did not objectively measure adherence to tb treatment once participants had been discharged, potentially introducing uncertainty into their measurement of the association between treatment status and mortality. due to the observational design of this study, the authors were unable to eliminate residual confounding when measuring the association between rr-tb and mortality and they cannot therefore make conclusions as to the causal nature of this relationship. the strengths of this study include its extensive tb testing and prospective follow-up, with vital status at 12 weeks identified for 98% of participants. this study also describes a unique, under-studied population of hospitalised patients with hiv-associated rr-tb and cd4 count < 350 cell/µl. conclusion this study describes a high 12-week mortality in patients admitted to hospital at the time of tb diagnosis with hiv-associated rr-tb. we suggest that delays in treatment initiation and poorly efficacious treatment regimens, prior to the introduction of bedaquiline as standard of care, are possible contributors to mortality in this population. hospitalised patients with dr-tb represent an under-studied group with a high risk of early mortality. research into the contributors to mortality in this population and improved diagnostic and therapeutic strategies are required. acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions g.m. and d.b. conceived the study; c.s., m.s., r.s., r.j.w. and m.n. contributed to study design. g.m. and c.s. conceived the parent study; c.s., a.w. and d.b. contributed to clinical data acquisition; g.m. and r.b. provided clinical oversight. a.b. and c.s. contributed to laboratory data acquisition. m.s. and m.n. provided laboratory oversight. r.j.w. provided laboratory facilities for storage and processing of samples. r.s. and d.b. performed data analysis with input from all co-authors and oversight from g.m. and c.s. r.s. wrote the manuscript and all co-authors reviewed and contributed to the manuscript. all authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. d.a.b. and r.s. both verified underlying data of the study. c.s. verified all the clinical and immune data and khayelithsa hospital tb study (kdhtb) data. funding information c.s. was funded by the south african medical research council under the national health scholars programme. d.a.b. was supported by wellcome (105165/z/14/a) and an national institute for health and care research (uk) clinical lectureship. g.m. and m.s. were supported by wellcome (098316, 203135, 214321/z/18/z and 211360/z/18/z), g.m. was supported by the south african research chairs initiative of the department of science and technology and national research foundation (nrf) of south africa (grant no. 64787), nrf incentive funding (uid: 85858) and the south african medical research council through its tb and hiv collaborating centres programme with funds received from the national department of health (rfa# samrc-rfa-cc: tb/hiv/aids-01-2014). r.j.w. is supported by the francis crick institute, which receives funding from wellcome (fc00110218), cancer research uk (fc00110218), the uk medical research council (fc00110218). r.j.w. also received support from wellcome (104803, 203135) and the national institutes of health (u01ai115940) and european and developing countries clinical trials (sria 2015-1065). for the purpose of open access, the authors have applied a cc-by public copyright licence to any author-accepted manuscript version arising from this submission. the funders had no role in the study design, data collection, data analysis, data interpretation, or writing of this report. data availability the data sets generated and analysed during the current study are available from the corresponding author, r.s., on reasonable request. disclaimer the views and opinions expressed in this article are those of the authors and not an 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https://doi.org/10.5588/ijtld.17.0202 evans d, sineke t, schnippel k, et al. impact of xpert mtb/rif and decentralized care on linkage to care and drug-resistant tuberculosis treatment outcomes in johannesburg, south africa. bmc health serv res. 2018;18(1):1–12. https://doi.org/10.1186/s12913-018-3762-x cox h, hughes j, daniels j, et al. community-based treatment of drug-resistant tuberculosis in khayelitsha, south africa. int j tuberc lung dis. 2014;18(4):441–448. https://doi.org/10.5588/ijtld.13.0742 chingonzoh r, manesen mr, madlavu mj, et al. risk factors for mortality among adults registered on the routine drug resistant tuberculosis reporting database in the eastern cape province, south africa, 2011 to 2013. plos one. 2018;13(8):e0202469. https://doi.org/10.1371/journal.pone.0202469 mohr e, cox v, wilkinson l, et al. programmatic treatment outcomes in hiv-infected and uninfected drug-resistant tb patients in khayelitsha, south africa. trans r soc trop med hyg. 2015;109(7):425–432. https://doi.org/10.1093/trstmh/trv037 daniels jf, khogali m, mohr e, et al. time to art initiation among patients treated for rifampicin-resistant tuberculosis in khayelitsha, south africa: impact on mortality and treatment success. plos one. 2015;10(11):e0142873. https://doi.org/10.1371/journal.pone.0142873 schnippel k, shearer k, evans d, berhanu r, dlamini s, ndjeka n. predictors of mortality and treatment success during treatment for rifampicin-resistant tuberculosis within the south african national tb programme, 2009 to 2011: a cohort analysis of the national case register. int j infect dis. 2015;39:89–94. https://doi.org/10.1016/j.ijid.2015.09.002 wang m-g, wu s-q, he j-q. efficacy of bedaquiline in the treatment of drug-resistant tuberculosis: a systematic review and meta-analysis. bmc infect dis. 2021;21(1):1–10. https://doi.org/10.1186/s12879-021-06666-8 conradie f, diacon ah, ngubane n, et al. treatment of highly drug-resistant pulmonary tuberculosis. n engl j med. 2020;382:893–902. https://doi.org/10.1056/nejmoa1901814 schnippel k, ndjeka n, maartens g, et al. effect of bedaquiline on mortality in south african patients with drug-resistant tuberculosis: a retrospective cohort study. lancet respir med. 2018;6(9):699–706. https://doi.org/10.1016/s2213-2600(18)30235-2 mbuagbaw l, guglielmetti l, hewison c, et al. outcomes of bedaquiline treatment in patients with multidrug-resistant tuberculosis. emerg infect dis. 2019;25(5):936. https://doi.org/10.3201/eid2505.181823 pym as, diacon ah, tang s-j, et al. bedaquiline in the treatment of multidrugand extensively drug-resistant tuberculosis. eur respir j. 2016;47(2):564–574. https://doi.org/10.1183/13993003.00724-2015 olayanju o, limberis j, esmail a, et al. long-term bedaquiline-related treatment outcomes in patients with extensively drug-resistant tuberculosis from south africa. eur respir j. 2018;51(5):1800544. padayatchi n, bionghi n, osman f, et al. treatment outcomes in patients with drug-resistant tb-hiv co-infection treated with bedaquiline and linezolid. int j tuberc lung dis. 2020;24(10):1024. https://doi.org/10.5588/ijtld.20.0048 kyeyune r, den boon s, cattamanchi a, et al. causes of early mortality in hiv-infected tb suspects in an east african referral hospital. j acquir immune defic syndr. 2010;55(4):446–450. https://doi.org/10.1097/qai.0b013e3181eb611a bigna jjr, noubiap jjn, agbor aa, et al. early mortality during initial treatment of tuberculosis in patients co-infected with hiv at the yaoundé central hospital, cameroon: an 8-year retrospective cohort study (2006–2013). plos one. 2015;10(7):e0132394. https://doi.org/10.1371/journal.pone.0132394 subbarao s, wilkinson ka, van halsema cl, et al. raised venous lactate and markers of intestinal translocation are associated with mortality among in-patients with hiv-associated tb in rural south africa. j acquir immune defic syndr. 2015;70(4):406–413. https://doi.org/10.1097/qai.0000000000000763 meintjes g, kerkhoff ad, burton r, et al. hiv-related medical admissions to a south african district hospital remain frequent despite effective antiretroviral therapy scale-up. med. 2015;94(50):e2269. griesel r, stewart a, van der plas h, sikhondze w, mendelson m, maartens g. prognostic indicators in the world health organization’s algorithm for seriously ill hiv-infected inpatients with suspected tuberculosis. aids res ther. 2018;15(1):1–9. https://doi.org/10.1186/s12981-018-0192-0 saavedra a, campinha-bacote n, hajjar m, et al. causes of death and factors associated with early mortality of hiv-infected adults admitted to korle-bu teaching hospital. pan afr med j. 2017;27:48. https://doi.org/10.11604/pamj.2017.27.48.8917 ansari na, kombe ah, kenyon ta, et al. pathology and causes of death in a group of 128 predominantly hiv-positive patients in botswana, 1997–1998. int j tuberc lung dis. 2002;6(1):55–63. cohen t, murray m, wallengren k, alvarez gg, samuel ey, wilson d. the prevalence and drug sensitivity of tuberculosis among patients dying in hospital in kwazulu-natal, south africa: a postmortem study. plos med. 2010;7(6):e1000296. https://doi.org/10.1371/journal.pmed.1000296 wong eb, omar t, setlhako gj, et al. causes of death on antiretroviral therapy: a post-mortem study from south africa. plos one. 2012;7(10):e47542. https://doi.org/10.1371/journal.pone.0047542 schutz c, barr d, andrade bb, et al. clinical, microbiologic, and immunologic determinants of mortality in hospitalized patients with hiv-associated tuberculosis: a prospective cohort study. plos med. 2019;16(7):e1002840. https://doi.org/10.1371/journal.pmed.1002840 medecins sans frontieres. khayelitsha 2001–2011: activity report. 10 years of hiv/tb care at primary health care level [homepage on the internet]. 2011 [cited 2021 oct 6]; p. 1–36. available from: https://www.msf.org/khayelitsha-activity-report-2001-2011-10-years-hivtb-care-primary-health-care-level zifodya j, kreniske j, schiller i, et al. xpert ultra versus xpert mtb/rif for pulmonary tuberculosis and rifampicin resistance in adults with presumptive pulmonary tuberculosis. cochrane database syst rev. 2021;2:cd009593. https://doi.org/10.1002/14651858.cd009593.pub5 berhanu r, schnippel k, mohr e, et al. early outcomes of decentralized care for rifampicin-resistant tuberculosis in johannesburg, south africa: an observational cohort study. plos one. 2016;11(11):e0164974. https://doi.org/10.1371/journal.pone.0164974 loveday m, wallengren k, brust j, et al. community-based care vs. centralised hospitalisation for mdrtb patients, kwazulu-natal, south africa. int j tuberc lung dis. 2015;19(2):163–171. https://doi.org/10.5588/ijtld.14.0369 farley je, ram m, pan w, et al. outcomes of multi-drug resistant tuberculosis (mdr-tb) among a cohort of south african patients with high hiv prevalence. plos one. 2011;6(7):e20436. https://doi.org/10.1371/journal.pone.0020436 hirasen k, berhanu r, evans d, rosen s, sanne i, long l. high rates of death and loss to follow-up by 12 months of rifampicin resistant tb treatment in south africa. plos one. 2018;13(10):e0205463. https://doi.org/10.1371/journal.pone.0205463 umanah ta, ncayiyana jr, nyasulu ps. predictors of cure among hiv co-infected multidrug-resistant tb patients at sizwe tropical disease hospital johannesburg, south africa. trans r soc trop med hyg. 2015;109(5):340–348. https://doi.org/10.1093/trstmh/trv025 marais e, mlambo ck, lewis jj, et al. treatment outcomes of multidrug-resistant tuberculosis patients in gauteng, south africa. infect. 2013;42(2):405–413. https://doi.org/10.1007/s15010-013-0572-2 brust jcm, gandhi nr, carrara h, osburn g, padayatchi n. high treatment failure and default rates for patients with multidrug-resistant tuberculosis in kwazulu-natal, south africa. int j tuberc lung dis. 2010;14(4):413–419. boyd r, ford n, padgen p, cox h. time to treatment for rifampicin-resistant tuberculosis: systematic review and meta-analysis. int j tuberc lung dis. 2017;21(11):1173–1180. https://doi.org/10.5588/ijtld.17.0230 mahwire tc, zunza m, marukutira tc, naidoo p. impact of xpert mtb/rif assay on multidrug-resistant tuberculosis treatment outcomes in a health district in south africa. s afr med j. 2019;109(4):259–263. https://doi.org/10.7196/samj.2019.v109i4.13180 the southern african journal of hiv medicine                                                    december  2009 abacavir (abc), a nucleoside reverse transcriptase inhibitor (nrti), combined with lamivudine (3tc), has a better shortand long-term outcome than 3tc combined with zidovudine (zdv) as first-line hiv therapy.1,2 in addition, children failing abc/3tc-based first-line therapy do not select thymidine nrti-related mutations, allowing for better choice in second-line therapy.2 with current first-line options, both first-line (stavudine (d4t)) and second-line therapy (zdv) include a thymidine-based nrti, thus compromising second-line regimens.3-5 in well-selected children, abc is also an important drug in second-line and salvage therapy.6 of all the nrtis, abc is associated with the lowest rate of mitochondrial dysfunction. types of dysfunction include lactic acidosis, peripheral neuropathy and lipo-atrophy. substitution of d4t for abc improves mitochondrial indices and reduces adipocyte apoptosis.7 in adults, switching from d4t to abc was superior to switching from d4t to zdv.8 in older children, once-daily use of abc has also been shown to be effective, thereby facilitating adherence and improving patient satisfaction, particularly when all drugs are given once daily.9,10 despite these advantages, abc is rarely used as part of first-line therapy in south africa owing to cost. tenofovir, commonly used in adults experiencing nrti adverse events, is not licensed for children. with large cohorts of children now on antiretroviral therapy for long periods of time, increased use of abc is likely as nrti adverse events become apparent. currently, the national department of health permits using abc when there have been adverse events related to other nrtis. of concern is the severe and life-threatening hypersensitivity reaction (hsr) that occasionally occurs, necessitating permanent discontinuation of abc. abc hsr has been reported in adults and children. the prevalence in clinical trials varies.11 in a european trial of first-line therapy, where 92 children were initiated on abc, 4 (4.3%) terminated abc for adverse reactions, 1 case (1%) being considered an hsr. there is clear heterogeneity in risk according to ethnic groups, with caucasians at higher risk and a 40% reduction in risk for african americans. in the arrow study of >1 200 hiv-infected children in uganda and zimbabwe, hsr was reported in 0.2% of the children.12 other factors that may be protective are male sex and more advanced disease. however, this assessment was performed before identification of the genetic link to hsr.13 hla-b*5701 and hsr an association with abc hsr was described with hlab*5701, hla-dr7 and hla-dq3. if all three markers are present, the positive predictive value for hsr is 100% with a negative predictive value of 97%. hla-b*5701 alone is highly predictive.14 it is clear that the varied distribution of the hla-b*5701 genotype is responsible for variability of the risk of abc hsr between races and studies.15 studies from the usa indicated that this mutation is more prevalent among white and hispanic persons than african americans.16 in korea the hla-b*5701 genotype and abc hsr are rare.17 in the predict-1 study, where patients with hlab*5701 did not receive abc, 3.4% of patients given abc were diagnosed with hsr but no cases could be confirmed with patch testing (a research tool only).18 prospective screening for hla-b*5701 in patients and abacavir: its use and hypersensitivity c l i n i c a l helena rabie1, fcp (paed) kristin lorenc henning1, mb chb, dch pierre schoeman2, mb chb, mmed (clin path) nico de villiers2, phd (hum gen) g h j (oubaas) pretorius2, phd (biochem) mark f cotton1, phd 1department of paediatrics and child health, tygerberg children’s hospital and stellenbosch university, tygerberg, w cape 2pathcare laboratories, n1 city, goodwood, w cape abacavir, a nucleoside reverse transcriptase inhibitor, is useful in firstand second-line hiv therapy and as a substitute for stavudine and zidovudine when toxicity is a problem. although it is safe and well tolerated, a lifethreatening hypersensitivity reaction can occur. the risk for developing this reaction relates to the presence of specific genotypes, especially hla-b*5701. epidemiology and estimation of risk for hsr 81 december  2009                                                      the southern african journal of hiv medicine                                                   avoidance of abc in positive patients is effective in reducing hsr, and this is now the standard of care in the first world. over-diagnosis of hsr is well documented in the absence of testing.19 a reduction in confirmed cases occurs when routine testing is performed.18 despite the availability of testing and the recommendation to test, there is a debate as to the cost effectiveness and cost benefit of testing in ethnic groups where hla-b*5701 is not prevalent.17 there are no data on the prevalence of hla-b*5701 in the various south african ethnic groups. full genetic screening for hla-b*5701 is very costly. cheaper methods involving pcr for small sequences of the gene are currently under review. although full testing is available in south africa, patients in the public sector do not have access. we recommend that testing be offered to all patients where affordable, regardless of ethnic group, until more information is available. however, it is reasonable to use abc without prior screening if there is no alternative. it is important to remember that hsr has been reported in patients negative for hla-b*5701.20 in patients in whom hsr reaction was diagnosed and who subsequently tested negative for hla-b*5701, abc remains contraindicated. diagnosis of abc hsr is complicated by its subtle initial features. also, other drugs such as trimethoprim-sulfamethoxazole, nevirapine and efavirenz are known to cause hypersensitivity and should be recognised. distinguishing the abc hsr from other drug-related adverse events, intercurrent infections and even immune reconstitution inflammatory syndrome may be particularly difficult when abc is used as first-line therapy, as all drugs are initiated simultaneously. in addition, abc initiation may lead to symptoms that are similar but not related to hsr, including nausea and vomiting, fever and rash. these reactions are usually mild. ninety-four per cent of patients who experience hsr do so within 6 weeks after initiation of therapy. the median time to onset is 11 days, but symptoms can start on the first day and have been reported up to 318 days later. abc hsr has occurred in patients who interrupted therapy without having had hypersensitivity and subsequently restart, but this is believed to be rare.11,21 a single case of abc hsr after switching from twice daily to once daily administration has also been reported.22 vigilance for the duration of abc exposure is required. the abc hsr is a multi-organ process manifesting signs or symptoms from at least two of the following groups: n fever is the most common manifestation of abc hsr, occurring in 80% of cases. chills have been reported to accompany fever. n rash is experienced by 70% of cases, and pruritus can also occur. in contrast to the rash caused by non-nrtis and sulphonamides, it is often mild and may go unnoticed by patients. when rash occurs in the absence of other features of hsr, abc should not be discontinued. n gastro-intestinal symptoms such as nausea, vomiting, diarrhoea and abdominal pain are all features of hsr but may also occur in the absence of hsr, particularly when abc is used with zdv. therefore, as with rash, patients with isolated gastro-intestinal symptoms should not discontinue abc but should be followed up closely. n constitutional symptoms include fatigue, myalgias and generalised malaise. n respiratory symptoms occur in 18% of cases and include dyspnoea, cough and pharyngitis. symptoms may be difficult to distinguish from those caused by influenza and other respiratory viruses. respiratory symptoms together with abdominal symptoms suggest hsr rather than influenza or other respiratory illness.23 clusters and combinations of symptoms are important in the diagnosis of abc hsr. table i illustrates the frequency of some combinations.11,24 with abc hsr, there is an accentuation of symptoms in the hours immediately after the dose and worsening of symptoms with each subsequent dose. a number of case reports illustrate the varied clinical presentation, with kawasaki-like illness, prominent exanthema and even disseminated intravascular coagulation being seen.25-29 if abc is not terminated, or if it is re-initiated after temporary cessation, the hsr will progress to hypotension, renal dysfunction, bronchospasm and ultimately death.11 abnormal laboratory findings may include leucopenia, anaemia and thrombocytopenia, as well as elevations systems and combinations % 3 or 4 organ systems 49 fever and rash 20 fever and git 8 skin and git 3 skin and constitutional 3 other combinations 17 git = gastro-intestinal. table i. frequency of symptom combinations in abacavir hypersensitivity (adapted from clay24) clinical features and diagnosis of abc hsr 82 the southern african journal of hiv medicine                                                    december  2009 in transaminases, urea, creatinine and lactate dehydrogenase (ldh). eosinophilia is usually absent.11 patch testing is currently only a research tool. termination of therapy is followed by rapid improvement in the symptoms. rechallenging with abc leads to anaphylaxis and should be avoided even in cases where there was diagnostic uncertainty. in table ii we set out the features of the first 3 cases of suspected hsr seen at the tygerberg children’s hospital family clinic for hiv. of note is that hsr was documented in children across the racial spectrum. in all patients there was progression of symptoms over time and in 1 case there was a clear increase in severity associated with dosing. all children had abdominal symptoms and nonspecific rash. in these cases, children were stable on other art drugs as they had all switched to abc because of d4t toxicity. on commencement of abc, patients should be counselled in detail about the possible signs of hsr and be advised to contact their care provider should any occur. to avoid confusion, therapy should not be initiated in patients with intercurrent symptoms. it is advisable for patients to discuss symptoms early with the clinician rather than terminating therapy without consultation. where termination without consultation occurs, abc cannot be reinitiated. patients should also be made aware of the special ‘patient alert card’ that comes in the packaging. this card should be presented to any health care provider who sees the child, especially when care is not given by the usual provider. providers at emergency facilities may be less familiar with this condition, and where possible contact information for the usual care provider should be supplied as well. deciding whether to terminate therapy in a patient with suggestive symptoms can be difficult given the very nonspecific nature of the presentation. a detailed medical history should be obtained. the following should be considered: n when was abc initiated? in the case of abc hsr, usually within the past 6 weeks. n are two or more systems involved? n do the symptoms increase with each dose? n are the symptoms exacerbated just after the dose? n do the symptoms fit into the well-recognised clusters? n what other medications/medication is the patient taking, and what was the timing of their initiation related to the abc? if patients present with mild symptoms and it is not clear whether symptoms are due to hsr, the clinician may consider allowing an additional dose. the patient should be able to report back, or hospitalisation may be required for observation. if symptoms worsen, abc should be terminated immediately and permanently. if symptoms do not worsen, abc can be carefully con case 1 case 2 case 3 race white coloured black age (years) 9 5 10 gender female male male time to onset of symptoms <1 day 9 days 2 months accentuation with dose yes uncertain uncertain increasing severity yes yes yes time after onset to presentation to tch (days) 1 5 3 fever no yes no rash blotchy, erythematous on extensive maculopapular fine papular rash on neck and hands on trunk, arms and legs the chest papules on the trunk and exanthema in mouth left arm non-purulent conjunctivitis gastrointestinal loss of appetite nausea abdominal pain and epigastric and right upper loose stools tenderness quadrant tenderness vomiting loss of appetite constitutional myalgias lethargy weight loss (1 kg) malaise respiratory no no cough red throat number of systems affected 3 4 4 time to resolution 48 hours 5 days 2 3 days hla-b*5701 negative – tested after positive – tested after negative – tested after the hsr the hsr the hsr table ii. clinical features in 3 children diagnosed with abc hsr at tygerberg children’s hospital after a single drug substitution of stavudine for lipo-atrophy management of patients initiating abc 83 december  2009                                                      the southern african journal of hiv medicine                                                   tinued while other possible reasons for the patient’s symptoms are investigated. when the diagnosis is thought to be clear or there is sufficient concern, abc should be terminated immediately and permanently. hospitalisation and special investigations will depend on the severity of symptoms. corticosteroids do not prevent or alter the natural history of abc hsr.30 the reaction usually improves within 48 hours. clinicians treating children need to be very aware of the usefulness of abc. although there is no information on the prevalence of either abc hypersensitivity or hla-b*5701 in south african children, available data suggest that black children are at lower risk than caucasian children, with no data on children of mixed race. although screening for hla-b*5701 is recommended and will prevent cases, research is needed to assess its cost effectiveness in the south african public health setting. references 1. comparison of dual nucleoside-analogue reverse-transcriptase inhibitor regimens with and without nelfinavir in children with hiv-1 who have not previously been treated: the penta 5 randomised trial. lancet 2002; 359: 733-740. 2. green h, gibb dm, walker as, et al. lamivudine/abacavir maintains virological superiority over zidovudine/lamivudine and zidovudine/abacavir 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[prospective validation of a pharmacogenetic test: the predict-1 study.] enferm infecc microbiol clin 2008; 26: suppl 6, 40-44. 19. rauch a, nolan d, thurnheer c, et al. refining abacavir hypersensitivity diagnoses using a structured clinical assessment and genetic testing in the swiss hiv cohort study. antivir ther 2008; 13: 1019-1028. 20. calza l, rosseti n, biagetti c, pocaterra d, colangeli v, manfredi r. abacavirinduced reaction with fever and severe skin rash in a patient tested human leukocyte antigen-b*5701 negative. int j std aids 2009; 20: 276-277. 21. frissen ph, de vries j, weigel hm, brinkman k. severe anaphylactic shock after rechallenge with abacavir without preceding hypersensitivity. aids 2001; 15: 289. 22. gervasoni c, vigano o, grinelli e, ortu m, galli m, rusconi s. abacavir hypersensitivity reaction after switching from the twice-daily to the once-daily formulation. aids patient care stds 2007; 21: 1-3. 23. keiser p, nassar n, skiest d, et al. comparison of symptoms of influenza a with abacavir-associated hypersensitivity reaction. int j std aids 2003; 14: 478-481. 24. clay pg. the abacavir hypersensitivity reaction: a review. clin ther 2002; 24: 1502-1514. 25. abacavir warning: certain respiratory symptoms can indicate hypersensitivity reaction. aids treat news 2000; no. 337. 26. aquilina c, mularczyk m, lucas f, viraben r. unusual clinical presentation of hypersensitivity reaction to abacavir. aids 2003; 17: 2403-2404. 27. dargere s, verdon r, bouhier k, bazin c. disseminated intravascular coagulation as a manifestation of abacavir hypersensitivity reaction. aids 2002; 16: 16961697. 28. lanzafame m, trevenzoli m, lattuada e, faggian f, vento s, concia e. enanthema as the first clinical manifestation of abacavir hypersensitivity reaction: a case report. infez med 2003; 11: 40-41. 29. toerner jg, cvetkovich t. kawasaki-like syndrome: abacavir hypersensitivity? clin infect dis 2002; 34: 131-133. 30. wit fw, wood r, horban a, et al. prednisolone does not prevent hypersensitivity reactions in antiretroviral drug regimens containing abacavir with or without nevirapine. aids 2001; 15: 2423-2429. conclusion acknowledgement we thank the staff from pathcare for their assistance and drs b leibbrandt and clair edson for providing patient details. we also thank dr leon levin and dr tammy meyers for their editorial contribution. 84 low-dose.html debate low-dose stavudine trials: a public health priority for developing countries w d francois venter, mb bch, fcp (sa), dip hiv man (sa), dtm&h (sa), mmed wits reproductive health and hiv institute (wrhi), department of medicine, university of the witwatersrand and charlotte maxeke johannesburg academic hospital, johannesburg steve innes, mb bch, mrcpch, mphil mark cotton, mb chb, mmed, fcpaed, dtm&h, dch (sa), phd children’s infectious diseases clinical research unit (kid-cru), tygerberg children’s hospital and stellenbosch university, w cape the debate around relooking at stavudine dosing, both in terms of the adult low-dose stavudine study and more broadly, is welcome. the study being proposed to evaluate low-dose stavudine v. tenofovir is a fairly standard placebo-controlled non-inferiority study. the study design is not controversial; however, the choice of study drug has attracted critical attention. we have previously discussed the issue of stavudine use, cost and access, and the significant implications of stavudine in developing countries, in detail in a recent article.1 we continue to believe that low-dose stavudine clinical trials, in both adults and children, are a priority for developing countries. these studies are being proposed simply because tenofovir is very expensive, and the only available cheaper alternative is stavudine. with recession, unertainty about donor commitments, the compromise of several treatment projects by lack of money, and the plain fact that many developing countries are unable to take ownership of the antiretroviral programme within their budgets, this and similar studies are urgent and necessary for our region to continue to expand access to antiretroviral therapy. stavudine was chosen because it is very cheap, easily co-formulated, very well tolerated initially, and requires no laboratory toxicity monitoring in routine clinical practice. tenofovir was chosen as the comparator for the trial as it is currently the ‘gold standard’ in many guidelines, and the alternatives (zidovudine (azt) and abacavir) are now more expensive than tenofovir. abacavir would be regarded as the equivalent gold standard for paediatric care. as clinicians involved with antiretroviral (arv) programmes for the last few years, and having used stavudine in large numbers of both adults and children in the past decade, we identify with the instinctive discomfort of many critics. however, we feel that there is a very strong case for studying stavudine further, and many of the arguments against further trials are not consistent with how we study other antiretrovirals, or indeed medication efficacy in general. tenofovir certainly has benefits over stavudine: it is dosed daily, and has anti-hepatitis b activity; counter-arguments could be that hepatitis b is easily screened for, and that renal toxicity increasingly recognised with tenofovir has potentially serious consequences in developing countries, where monitoring and access to renal care, dialysis and transplantation are almost non-existent.2 these arguments, however, are likely to be irrelevant when the cost of medication is considered. broadly, other more substantial arguments fall into the following categories. stavudine toxicity this is the most serious disagreement. critics maintain that stavudine is too toxic to be used, that it is not possible to monitor toxicity safely, and that the trial duration is only 2 years, hence limiting the usefulness of the data. toxicity concerns are exclusively based on data around high dosages of stavudine, largely the (now historic) adult 40 mg twice a day (bd) dosage, for which there are extensive toxicity data, including from our own centres. more limited data suggest that 30 mg bd is significantly safer, at least in the medium term, but still carries significant toxicity. we do not contest this – stavudine causes often irreversible and stigmatising lipo-atrophy, as well as peripheral neuropathy and other mitochondrial toxicity in adults. however, all drugs are toxic in sufficient dosages. azt was originally dosed at far higher levels than currently; toxicity forced the testing of lower doses that were far better tolerated with equal virological suppression levels, and azt became the standard of first-line care for almost a decade. however, azt still has some toxicity at this lower dose, and even lower doses are being tried.3 the original dose-finding studies of stavudine (d4t) were a complex affair, and the originator company did not complete what we consider to have been the natural next phase of study, largely as it was clear that the significant investment on another large clinical trial was unlikely to be recouped, as well as a probable internal assessment that the drug had a significant public relations problem related to lipo-atrophy in developed countries, where profits are made. there is some evidence that dosing at 20 mg bd is safer and gives equivalent virological efficacy, but these data have not been tested in a rigorous manner.5 this study plans to repeat those done for drugs such as azt and many others – optimising the dosage of stavudine so as to minimise toxicity, while maintaining virological efficacy. it also responds to observer calls for more research on stavudine using high-quality trials.3 , 5 , 10 critics have maintained that stavudine toxicity is impossible to monitor safely. safety and toxicity monitoring in the proposed study has been extensively examined by many experts, and we are confident that we can pursue the study safely. ethics committees are currently examining the proposed toxicity monitoring schedules. the doctors involved in the study have plenty of experience in the early recognition of stavudine toxicity. we agree with critics that the study will not give us evidence on long-term toxicity. our study is currently funded to run for 2 years, like most registration arv studies. for many countries, providing 2 years of safe therapy at reduced cost is of significant importance. however, we have extensive lipo-atrophy pre-clinical toxicity monitoring built into the study; if no additional toxicity in the stavudine arm using dexa scans is demonstrated, it is plausible that the drug could be used for longer, and we therefore intend motivating to extend the study. finally, it is contended that this study would never be run in a developed country. we see absolutely no scientific and ethical reasons why not. however, the urgency remains in our region. rationing has already begun in many programmes, and universal access, with the attendant benefits of hiv prevention suggested by the hptn 052 trial, is unlikely to be more than a public health dream unless we lower the cost of safe treatment. even developed countries have had to make rationing decisions, cf. the recent decision to restrict access to first-line tenofovir in the uk; rationing was made easier by having good data to base these decisions on. tenofovir cost it is asserted that the price of tenofovir is still dropping and will approach that of stavudine. we have consulted extensively over this with the clinton health access initiative (chai) as well as generic companies, and it seems that price equivalence will not be possible, simply because the daily milligram dosage (a daily 300 mg v. the proposed 40 mg) is so different, as raw chemicals drive the generic manufacturing costs. furthermore, the incremental drops in the price of tenofovir (the latest announced by the chai in january 2012) are unlikely to be as significant as previous ones, as manufacturing efficiencies have largely been realised. new drug availability the next assertion is that new drugs are in the offing and will be available by the time this study has results, making the results irrelevant. we believe that confidence in a new drug that will cost-effectively and timeously replace tenofovir is a huge act of faith. many new medications are indeed being tested, and a small number may show efficacy when this study is completed. however, most drugs fail, even in phase 3 studies, so even this is uncertain. also, the drugs may not be tested with backbones conventionally used in our context (e.g. raltegravir may be used instead of efavirenz), which may limit agreement on whether we can use the drug safely with available backbone drugs. furthermore, the registration process, local regulatory approval, negotiations with generic manufacturers and acceptance into national guidelines mean that it takes many years to go from clinical trial success to broad availability. tenofovir took over 5 years for registration in south africa. prolonged registration is the rule rather than the exception in many developing countries. we may need several more years for adequate costing, price reductions and agreement on priorities for access to this treatment. we believe that it is responsible to study alternatives to tenofovir and other expensive first-line medications. other issues in paediatric care, abacavir is the current preferred first-line drug owing to concerns about tenofovir toxicity and also to to preserve azt for a second-line nrti backbone. abacavir is very expensive. stavudine remains the most widely used arv for hiv-infected children in sub-saharan africa. apart from cost, abacavir has other real problems. although the incidence of abacavir hypersensitivity reactions is probably low, there is no confirmatory test widely available in the public sector. the hla-b5701 gene test is simply not available outside large tertiary centres, and the gene appears to be a largely caucasian one anyway. nonspecific fever and rash are common in childhood, especially during immune reconstitution, and many children are likely to receive the label ‘possible previous abacavir hypersensitivity reaction’, which eliminates the option of ever re-introducing abacavir in their regimen. once abacavir is eliminated, the remaining options in sub-saharan africa are zidovudine or stavudine. the danger of zidovudine-related bone marrow suppression (a common problem with varying degrees of severity) is significant and requires some laboratory monitoring. stavudine offers almost toxicity-free short-term efficacy. for unknown reasons, thymidine-related peripheral neuropathy has not been documented in pre-pubertal children, and symptomatic lactic acidosis appears remarkably less common than in adults. the incidence of lipo-atrophy is concerning but is strongly dose-related. we think that its frequency and severity will be significantly reduced with the use of low-dose stavudine. in addition, stigmatising lipo-atrophy is avoidable if reasonable awareness is maintained and appropriate drug switches made before lipo-atrophy becomes obvious.9 , 11 , 12 an unrecognised benefit of using children’s regimens similar to adults’ is that it makes children less susceptible to supply-line problems, a huge problem in developing countries. getting the dose of stavudine right in children is as compelling as it is in adults, and these studies should be prioritised by funders. in the end, we desperately need alternatives to tenofovir for adults and to abacavir in children in poorer countries. the only current alternative is conventionally dosed stavudine, as azt and abacavir are more expensive than tenofovir. a minister of health or donor faced with the decision to treat two people with a moderately toxic drug or one with a relatively safe regimen, with the other person definitely dying of aids, faces very little choice. making stavudine safer is an urgent public health issue. we think that doing it safely, efficiently and ethically is possible and should be everyone’s priority. references 1. innes s, cotton m, venter f. why should we still care about the stavudine dose? southern african journal of hiv medicine 2011;12(4):14-15. 1. innes s, cotton m, venter f. why should we still care about the stavudine dose? southern african journal of hiv medicine 2011;12(4):14-15. 2. scherzer r, estrella m, li y, deeks sg, grunfeld c, shlipak mg. association of tenofovir exposure with kidney disease risk in hiv infection. aids 2012 [epub ahead of print, 4 feb]. 2. scherzer r, estrella m, li y, deeks sg, grunfeld c, shlipak mg. association of tenofovir exposure with kidney disease risk in hiv infection. aids 2012 [epub ahead of print, 4 feb]. 3. makinson a, moing vl, kouanfack c, laurent c, delaporte e. safety of stavudine in the treatment of hiv infection with a special focus on resource-limited settings. expert opin drug saf 2008;7(3):283-293. 3. makinson a, moing vl, kouanfack c, laurent c, delaporte e. safety of stavudine in the treatment of hiv infection with a special focus on resource-limited settings. expert opin drug saf 2008;7(3):283-293. 4. pujades-rodríguez m, dantony e, pinoges l, et al. aids working group of médecins sans frontières. toxicity associated with stavudine dose reduction from 40 to 30 mg in first-line antiretroviral therapy. plos one 2011;6(11):e28112 [epub 21 nov 2011]. 4. pujades-rodríguez m, dantony e, pinoges l, et al. aids working group of médecins sans frontières. toxicity associated with stavudine dose reduction from 40 to 30 mg in first-line antiretroviral therapy. plos one 2011;6(11):e28112 [epub 21 nov 2011]. 5. hill a. d4t: keep it or abandon it? asian biomedicine 2010;4(4):541-546. 5. hill a. d4t: keep it or abandon it? asian biomedicine 2010;4(4):541-546. 6. boulle a, orrell c, kaplan r, et al. substitution due to antiretroviral toxicity or contraindication in the first 3 years of antiretroviral therapy in a large south african cohort. antivir ther 2007;12:753-760. 6. boulle a, orrell c, kaplan r, et al. substitution due to antiretroviral toxicity or contraindication in the first 3 years of antiretroviral therapy in a large south african cohort. antivir ther 2007;12:753-760. 7. george ja, venter wd, van deventer he, crowther nj. a longitudinal study of the changes in body fat and metabolic parameters in a south african population of hiv-positive patients receiving an antiretroviral therapeutic regimen containing stavudine. aids res hum retroviruses 2009;25(8):771-781. 7. george ja, venter wd, van deventer he, crowther nj. a longitudinal study of the changes in body fat and metabolic parameters in a south african population of hiv-positive patients receiving an antiretroviral therapeutic regimen containing stavudine. aids res hum retroviruses 2009;25(8):771-781. 8. innes s, levin l, cotton m. lipodystrophy syndrome in hiv-infected children on haart. south african journal of hiv medicine 2009;10(4):76-80. 8. innes s, levin l, cotton m. lipodystrophy syndrome in hiv-infected children on haart. south african journal of hiv medicine 2009;10(4):76-80. 9. bobat r, kindra g, kiepiela p, et al. use of abacavir in 30 hiv-infected children from durban, south africa: report from a pilot study. pediatr infect dis j 2010;29(9):890. 9. bobat r, kindra g, kiepiela p, et al. use of abacavir in 30 hiv-infected children from durban, south africa: report from a pilot study. pediatr infect dis j 2010;29(9):890. 10. spaulding a, rutherford gw, siegfried n. stavudine or zidovudine in three-drug combination therapy for initial treatment of hiv infection in antiretroviral-naïve individuals. cochrane database syst rev 2010 aug 4;(8):cd008651. 10. spaulding a, rutherford gw, siegfried n. stavudine or zidovudine in three-drug combination therapy for initial treatment of hiv infection in antiretroviral-naïve individuals. cochrane database syst rev 2010 aug 4;(8):cd008651. 11. eley b. metabolic complications of antiretroviral therapy in hiv-infected children. expert opin drug metab toxicol 2008;4(1):37-49. 11. eley b. metabolic complications of antiretroviral therapy in hiv-infected children. expert opin drug metab toxicol 2008;4(1):37-49. 12. rabie h, henning kl, schoeman p, de villiers n, pretorius ghj, cotton m. abacavir: its use and hypersensitivity. southern african journal of hiv medicine 2009;10(4):81-84. 12. rabie h, henning kl, schoeman p, de villiers n, pretorius ghj, cotton m. abacavir: its use and hypersensitivity. southern african journal of hiv medicine 2009;10(4):81-84. acknowledgements references about the author(s) ahmed cordie endemic medicine department, cairo university hospitals, cairo, egypt menna-t-allah el-kotamy egyptian patent office, academy of scientific research and technology, cairo, egypt gamal esmat endemic medicine department, cairo university hospitals, cairo, egypt citation cordie a, el-kotamy m, esmat g. antiretroviral therapy optimisation in the time of covid-19: is it really different in north and south africa? s afr j hiv med. 2020;21(1), a1118. https://doi.org/10.4102/sajhivmed.v21i1.1118 editorial antiretroviral therapy optimisation in the time of covid-19: is it really different in north and south africa? ahmed cordie, menna-t-allah el-kotamy, gamal esmat copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. dear editors, we are attentively pursuing calls for an urgent need to have global and national actions to adopt differentiated service delivery (dsd) to ensure continuity of human immunodeficiency virus (hiv) services, especially uninterrupted antiretroviral therapy (art) supply, during the covid-19 (coronavirus disease 2019) pandemic.1 location modification, longer refill times and tailored packages of clinical services, including art optimisation, are the main pillars of the transition toward dsd.2 however, these interventions alone are not sufficient in lowto middle-income countries (lmics), where the lockdown and restrictions applied to international movement may affect art supply, especially for imported medications. medicine stock-outs are an unfortunate possibility for treatment discontinuation and the emergence of drug resistance.3 following the world health organization (who) recommendations, the egyptian guidelines set the combination of tenofovir disoproxil fumarate (tdf) and emtricitabine (ftc) plus dolutegravir (dtg) as the preferred first-line treatment regimen for adults and tdf/ftc/efavirenz (efv) as an alternative first-line regimen.4,5 egypt is reported to have very low hiv prevalence; however, it has the fastest increasing epidemic in the middle east and north african regions.6,7 the medicines policy and standards (psm) system can guarantee uninterrupted art supply when the framework cycle is properly functioning at all levels of the healthcare system. unfortunately, lmics usually have underdeveloped psms, and hence face the risk of stock-outs.3 during the covid-19 crisis, the situation is expected to be more complicated; therefore, resilience is needed to enable the health system to follow the who treatment recommendation guidelines and keep treatment for all as a first priority,4 at the same time as the context is rapidly evolving. therefore, art included in national treatment regimens may need to be locally manufactured for the time being. our search revealed that ftc and efv are not patented in egypt, and the only patent on lamivudine (3tc) has expired. tenofovir disoproxil fumarate, 3tc and efv are all locally manufactured and available at an affordable price. dolutegravir (a viiv product), provided under voluntary license in south africa, is part of a patent filed in egypt that was technically rejected and is still under appeal; however, it is also provided under voluntary license. gilead sciences have patents on tdf/ftc in a number of countries, but not in egypt or south africa.8 neither dtg nor the tdf/ftc 2-in-1 combination is locally manufactured in egypt. in these critical times, local pharmaceutical companies should be encouraged to produce these medicines to avoid dependence on the originators, who do not even have patent rights in egypt. currently, egypt and many lmics are in an extraordinary situation. these desperate times demand extraordinary measures. with respect to the who first-line art recommendation for adults during the covid-19 crisis, to ensure stable art supply, we recommend the following: antiretroviral therapy–naïve patients should start locally produced tdf + 3tc + efv, as this stock may be less threatened than the tdf/ftc 2-in-1 combination and dtg-based regimens. in contradiction to what is recommended in south africa and many sub-saharan countries, we recommend slowing down the transition from efv to dtg to save it for those already using it. in the case of stock-outs, virally suppressed patients on the tdf/ftc 2-in-1 combination-based regimen can be switched safely to locally produced tdf + 3tc, as the available evidence confirms the interchangeability between ftc and 3tc.9 healthcare workers can follow art-switching guidelines that can be applied by means of telemedicine.10 we should highlight that increased pill burden (four instead of two pills) is the main limitation of this recommended locally manufactured regimen. however, the priority under the current circumstances is to ensure uninterrupted art supply. acknowledgements competing interests the authors have declared that no competing interests exist. authors’ contributions all authors contributed equally to this work. ethical consideration this article followed all ethical standards for a research without direct contact with human or animal subjects. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability statement data sharing is not applicable to this article as no new data were created. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references wilkinson l, grimard a. the time is now: expedited hiv differentiated service delivery during the covid-19 pandemic. j int aids soc. 2020;23(5):e25503. https://doi.org/10.1002/jia2.25503 world health organization. consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection. recommendations for a public health approach [homepage on the internet]. geneva: who; 2016 [cited 15 june 2020]. available from: https://www.who.int/hiv/pub/arv/arv-2016/en/ world health organization. access to antiretroviral drugs in lowand middle-income countries: technical report [homepage on the internet]. geneva: who; 2014 [cited 15 june 2020]. available from: https://www.who.int/hiv/pub/amds/access-arv-2014/en/ world health organization. update of recommendations on firstand second-line antiretroviral regimens. policy brief [homepage on the internet]. geneva: who; 2019 [cited 15 june 2020]. available from: https://apps.who.int/iris/bitstream/handle/10665/325892/who-cds-hiv-19.15-eng.pdf national aids program in egypt. antiretroviral guidelines for adults with hiv: update. cairo: egyptian ministry of health, 2017; p. 91–94. a map showing the distribution of the number of plhiv [homepage on the internet] [cited 15 june 2020]. available from: http://aidsinfo.unaids.org/ unaids. miles to go — closing gaps, breaking barriers, righting injustices: global aids update 2018 [homepage on the internet]. geneva: unaids, 2018; p. 233. available from: https://www.unaids.org/en/resources/documents/2018/global-aids-update checking the validity of license status and information regarding the patent of dtg and tdf/ftc combination [homepage on the internet] [cited 15 june 2020]. available from: https://www.medspal.org/?country_name%5b%5d=egypt&product_standardized_name%5b%5d=dolutegravir+50+mg&product_standardized_name%5b%5d=tenofovir%2femtricitabine+300%2f200+mg&page=1 world health organization. appropriate medicines: options for pre-exposure prophylaxis [homepage on the internet]. geneva: world health organization; 2018. licence: cc by-nc-sa 3.0 igo [cited 15 june 2020]. available from: https://www.who.int/hiv/pub/journal_articles/3tc-ftc-interchangeable/en/ us dhhs. guidelines for the use of antiretroviral agents in hiv-1-infected adults and adolescents [homepage on the internet]. 2019 [cited 15 june 2020]. available from: http://aidsinfo.nih.gov/guidelines identifying missed.html original article identifying missed opportunities for early intervention among hiv-infected paediatric admissions at chris hani baragwanath hospital, soweto, south africa angela dramowski1, mb chb, fcpaed, mmed (paed), cert paed id, dch ashraf coovadia2, mb chb, fcpaed, dip hiv man, dch tammy meyers3, mb chb, fcpaed, mmed (paed), dtm&h ameena goga4, mb chb, fcpaed, dtm&h, msc (mch), msc (epid) 1department of paediatrics and child health, tygerberg children’s hospital and stellenbosch university, tygerberg, w cape 2department of paediatrics and child health, rahima moosa mother and child hospital, faculty of health sciences, university of the witwatersrand, johannesburg 3department of paediatrics and child health, chris hani baragwanath hospital, faculty of health sciences, university of the witwatersrand 4south african medical research council, pretoria background and design. hiv is a major contributor to childhood morbidity and mortality in south africa. we describe hiv prevalence, disease profile, outcome and missed opportunities for early intervention in a cohort of hiv-infected children admitted to chris hani baragwanath hospital’s general paediatric wards between 1 october 2007 and 31 december 2007. results. of 1 510 admissions, 446 (29.5%) were hiv infected. many children (238, 54.1%) were newly diagnosed in hospital and most had advanced hiv disease (405, 92%). the principal admission diagnoses were pneumonia (165, 37.5%), gastro-enteritis (97, 22%), sepsis (86, 19.5%) and tuberculosis (92, 21%). of children identified as hiv infected before admission, 128/202 (63.4%) were not accessing antiretroviral treatment (art), although 121/128 (94.5%) met art eligibility criteria. of 364 art-naïve eligible children, only 15 (4.1%) were commenced on art as inpatients. problems with pmtct implementation in infants under 6 months (n=166) included lack of maternal antenatal hiv testing (51, 30.7%); poor uptake of maternal/infant nevirapine prophylaxis (60, 36.2%); limited use of co-trimoxazole (ctx) prophylaxis (44/147, 29.9%); and delayed infant hiv polymerase chain reaction testing (98/147, 87.5%). of infants known to be hiv infected prior to hospitalisation, 37/51 (73%) had not initiated art. the in-hospital case fatality rate (cfr) among hiv-infected children was triple that of the combined hiv-uninfected, exposed and unknown group (12% v. 3.6%). infants <12 months of age accounted for 73.6% of all hiv-related deaths (cfr 17.1%). conclusions. hiv remains highly prevalent and contributes to significant in-hospital mortality. missed opportunities for pmtct, hiv diagnosis and art initiation are frequent. interventions to optimise paediatric hiv outcomes should target maternal hiv diagnosis, early infant diagnosis, uptake of ctx prophylaxis and prompt initiation of art, especially among infants. hospitalised art-eligible children should be prioritised for inpatient initiation of art. south africa has 5.6 million people living with hiv, including approximately 280 000 children1 who suffer disproportionate morbidity and double the mortality of their hiv-uninfected counterparts.2 , 3 past progress in reducing national child mortality has been reversed by paediatric hiv, with under-5 mortality rates (u5mr) increasing from 56 to 67 deaths per 1 000 live births between 1990 and 2008.4 much of the increase in the u5mr can be accounted for by deaths in young hiv-infected infants, many of whom progress rapidly to aids and death from opportunistic infections, without early initiation of antiretroviral therapy (art).5 , 6 south africa introduced the prevention of mother-to-child transmission (pmtct) and art programmes nationwide in 2001 and 2004, respectively. the national pmtct guidelines at the time of this study (2007) recommended haart for pregnant women with a cd4 count <200 cells/µl or zidovudine (azt) from 28 weeks’ gestation plus intrapartum single-dose nevirapine (sdnvp) at cd4 counts >200 cells/µl. all infants were scheduled to receive sdnvp at delivery. the policy for early infant diagnosis (eid) at the time recommended hiv polymerase chain reaction (pcr) testing at 6 weeks of life, and for breastfed babies a repeat hiv pcr test 6 weeks after complete cessation of breastfeeding. art initiation was recommended for any child with clinically advanced disease (who hiv stage 3 or 4) or immunological compromise (cd4 <20% in children less than 18 months of age and cd4 <15% in children over 18 months).7 despite national implementation of these programmes, coverage and uptake of pmtct, eid and paediatric art programmes were highly variable between provinces.8 more recently, improved coverage of these interventions has been achieved; however, many infants miss entry points for the pmtct programme and routine hiv testing. others may be identified but are lost from the system or become ill before art is initiated.9 these children typically present to hospital with advanced hiv disease and consequently have high mortality rates.10 , 11 chris hani baragwanath hospital (chbh) is south africa’s largest public sector hospital, delivering care to the burgeoning urban and low-income population of soweto, johannesburg. paediatric hiv prevalence at chbh (described in two previous studies prior to the implementation of pmtct programmes) rose from 3% to 19%12 to 29%13 between 1992 and 1996. over the same period the proportion of paediatric in-hospital mortality accounted for by hiv increased dramatically from 6.7% to 46.1%.12 similar trends in hiv prevalence and hiv-related mortality in other south african hospitals have been reported from a national data collection programme, child pip.10 , 11 we report on paediatric hiv period prevalence, disease profile and outcome of children admitted to chbh in the last quarter of 2007, several years after introduction of national pmtct and paediatric hiv management programmes. in addition we describe missed opportunities for hiv prevention, diagnosis and medical intervention among this cohort of hiv-infected children. methods ethics. the study was approved by university of the witwatersrand human research ethics committee (reference no. m080202). study site. the study was undertaken at chbh, soweto, johannesburg, in the gauteng province of south africa. this 2 964-bed referral hospital is the only public hospital serving approximately 3.5 million sowetans and accepts referrals from local primary health care clinics, regional hospitals in gauteng and neighbouring provinces of south africa. in 2010, the estimated hiv prevalence in gauteng province was 10.5%.14 the province’s health sector, although challenged by high tb and hiv prevalence, is relatively well resourced and staffed when compared with other areas of south africa. the hospital and all referring institutions follow national pmtct and hiv management guidelines. a dedicated paediatric hiv clinic on the hospital premises (harriet shezi clinic) provides outpatient services to more than 3 500 hiv-infected children and the perinatal hiv research unit (phru) provides pmtct support in the soweto area. study design and sampling. a cross-sectional retrospective review of all children (from birth to 14 years of age) hospitalised in the general paediatric wards between 1 october 2007 and 31 december 2007 was performed. newborns with reactive hiv pcr test results during their stay in the neonatal unit were not included in this study, unless they were subsequently admitted to the general paediatric wards during the 3-month study period. patient admission numbers and profile over this 3-month period did not differ significantly from the preceding three-quarters of 2007. two populations were of interest (fig. 1). firstly, admission register lists of all hospitalised children were used to determine hiv status (collected from laboratory and/or hospital records) and calculate hiv period prevalence. secondly, individual patient records for children identified as hiv infected were reviewed. monthly paediatric mortality reports were used to calculate in-hospital mortality. self-reported data on pmtct coverage were analysed only for hiv-infected infants less than 6 months of age, to minimise information recall bias. for analysis of missed opportunities in provision of co-trimoxazole (ctx) prophylaxis and uptake of eid, infants <6 weeks were excluded. determination of hiv status. all hiv tests were performed by the accredited national health laboratory service (nhls). a reactive hiv-dna pcr test confirmed hiv-infected status in children under 18 months. a reactive hiv enzyme-linked immunosorbent assay (elisa) confirmed hiv-infected status in children older than 18 months of age. mothers’ self-reported hiv status (as documented in hospital records) was used. four definitions were used: hiv uninfected refers to the infant or child being confirmed hiv uninfected; hiv infected refers to the infant or child being confirmed hiv infected; if the mother’s status was reportedly hiv infected and her infant had no hiv pcr result, the infant’s status was classified as hiv exposed. if maternal hiv status was unknown or uninfected and the child had no hiv test result in laboratory or folder records, the status was classified as hiv unknown. case definitions and reference classifications. in cases where laboratory confirmation was not obtained, a working diagnosis was based on clinical suspicion and the world health organization (who) published case definitions15 for the following conditions: pneumocystis jiroveci pneumonia (pcp),16 , 17 pulmonary tuberculosis (ptb), cytomegalovirus (cmv) pneumonitis or disseminated disease, septicaemia, meningitis and urinary tract infection. hiv disease severity was assessed using the who clinical staging system for children15 and nutritional status using the who 2006 growth standards18 for calculation of z-scores in children under 60 months of age. calculation of art eligibility was based on the south african national guidelines (2005)7 at the time of the study, using immunological (cd4% <20% under 18 months of age; cd4% <15% above 18 months of age) and clinical criteria (who stage 3 and 4 disease) only. the who and the south african department of health published extensively revised guidelines for child art initiation in 2010. statistical analysis. data were analysed in sas version 9.1 (sas institute inc., cary, nc, usa). crude hiv period prevalence was calculated from ward records as total hiv-infected admissions/total admissions. case fatality rates in the hiv-infected and combined hiv-uninfected, hiv-unknown and hiv-exposed groups were calculated from total number of deaths/total number of admissions for each group. for the pmtct sub-analysis, frequency calculations were performed for maternal hiv status, sdnvp exposure, ctx prophylaxis and place of birth. the uptake of pmtct interventions was then compared by maternal hiv status grouping using the chi-square test. a p-value of <0.05 was considered to be statistically significant. results hiv prevalence of 1 510 children admitted during the 3-month study period, 446 (29.5%) were hiv infected, 780 (51.7%) were hiv uninfected, 57 (3.8%) were hiv exposed and 227 (15%) were of unknown hiv status (fig. 1). for the 446 children identified as hiv infected, 440 (98.7%) individual patient records were located. hiv-infected children: profile of study population table i outlines the demographic and disease profile of the 440 hiv-infected children. almost 93% had advanced hiv disease (who stage 3 or 4) and 55.3% of children <5 years of age had severe malnutrition. across all age groups, 225/320 children (70.3%) had severe immune suppression. reason for hospitalisation infectious disease was the principal reason for hospitalisation (table i). lower respiratory tract infections (including presumed pcp and presumed cytomegalovirus pneumonitis) accounted for the majority of admissions, with the highest prevalence among infants. one hundred and ten children (25%) had a confirmed bacterial, viral or fungal infection during their hospital admission. streptococcus pneumoniae and cmv were the most common bacterial and viral pathogens isolated. missed opportunities prevention of mother-to-child transmission of hiv self-reported maternal hiv status and sdnvp exposure were analysed in hiv-infected infants under the age of 6 months (n=166). uptake of ctx prophylaxis and eid were analysed only for infants >6 weeks of age (n=147) so as to be consistent with programme guidelines. fig. 2 highlights the multiple levels of missed opportunities for pmtct implementation in infants (<6 months of age) whose mothers reported their status as hiv infected versus hiv uninfected versus hiv unknown. lack of maternal antenatal hiv testing was documented among 51/166 (30.7%) mothers. there was poor uptake of maternal/infant nvp prophylaxis (60/166, 36.2%). usage of ctx prophylaxis was limited (44/147, 29.9%) and in most cases infant hiv pcr testing was delayed or lacking (98/147, 87.5%). there was no association between place of birth (chbh versus clinic/other hospital/home) and access to nvp or ctx (p=0.1288 and p=0.5818, respectively). of the 147 hiv-infected infants 6 weeks <6 months of age, 51 (34.7%) were known to be hiv infected while the remainder, 96 (65.3%), were newly diagnosed (i.e. had not previously had hiv pcr testing) at the time of hospital admission. sixty-seven (45.6%) of the 147 infants received no pmtct interventions at all. only 20/147 (13.6%) infants received all recommended interventions, i.e. nvp and ctx and eid. table i reflects additional missed opportunities for the provision of ctx prophylaxis among other categories of the study population. hiv diagnosis and antiretroviral therapy (art) eligibility and uptake most children, 238/440 (54.1%), were newly diagnosed at the time of hospitalisation at chbh. newly diagnosed children were younger than those already known to be hiv infected (median 6 v. 12 months of age) (p=0.001). children known to be infected and already on art had a median treatment duration of 2 months and were significantly older than art-naïve children (median age 38 v. 7 months) (p<0.0001). of children known to be infected but not on art (128/202, 63.4%), nearly all (121/128, 94.5%) were eligible for art based on advanced disease stage. of 364 art-naïve eligible children, only 15 (4.1%) were commenced on art as inpatients (fig. 1). table ii compares eligibility for art with actual art uptake among children who died. outcome of hospitalisation median duration of hospital stay was 7 days (interquartile range (iqr) 4 10.) fifty-three children died (table i) with a median duration of stay before death of 4 days (iqr 2 7.8). only 13 children (3.0%) were admitted to an icu or underwent mechanical ventilation in the high-care area of the acute admissions ward. ten of these 13 children (76.9%) survived to hospital discharge. fifty-eight per cent of all paediatric deaths (53/91) occurred among the hiv-infected group. the overall case fatality rate in the hiv-infected children was 53/440 (12.0% (95% confidence interval (ci) 9.2 15.5%)). in contrast, the case fatality rate in the hiv-uninfected, hiv-exposed and hiv-unknown group over the study period was 38/1 064 (3.6% (95% ci 2.5 4.9%)). the highest case fatality rate by age group was in infants aged less than 12 months (table i). the most prevalent causes of death included pneumonia/suspected pcp (18/53, 34%), tb (14/53, 26.3%) and gastro-enteritis (5/53, 9.4%). the inpatient mortality rate did not differ significantly between children receiving art at the time of hospitalisation (7.9%, 6/76) versus art-naïve children (13.6%, 47/345) (p=0.17, odds ratio 0.54). discussion hiv prevalence this paper reports the first published data on paediatric hiv prevalence, disease profile and outcome at chbh subsequent to widespread implementation of pmtct and paediatric hiv management programmes. the hiv period prevalence of 29.5% was almost identical to that found in 1996. however, the true hiv prevalence remains unquantified, since both cohorts had large numbers of untested children. several years after national roll-out of pmtct and art programmes, there is therefore little evidence of a decreasing impact of paediatric hiv at chbh. possible explanations for this could include increasing antenatal hiv prevalence in gauteng province (15.5 29.8% between 1996 and 2009)19 with more vertical infections; failure of sdnvp pmtct regimens; the possibility of an even higher (undocumented) peak paediatric hiv prevalence reached between 1996 and 2007; poor pmtct coverage; improved survival rates (particularly in older hiv-infected children on art); and the establishment of a dedicated paediatric hiv clinic at chbh (pooling children with complicated hiv disease). missed opportunities prevention of mother-to-child transmission of hiv a major limitation of the chosen study design is possible maternal recall bias regarding pmtct interventions. in addition, reported maternal hiv status could not be verified in all cases. healthcare workers’ documentation of pmtct interventions was poor. in order to decrease missed opportunities among hiv-exposed infants, all pmtct interventions should be clearly explained to caregivers and documented in all patient records, especially the infants’ road to health card (rthc). this is the most important linkage and communication tool for paediatric healthcare providers, especially when children access care at multiple facilities. uptake of pmtct interventions was poor, with almost half of infants under 6 months of age receiving no pmtct interventions at all. of particular concern was the large proportion of mothers who reported their status as hiv uninfected (15.1%) or hiv unknown/untested (30.7%). there are several possible explanations for the 15.1% of mothers who reported their status as hiv uninfected: a negative test in early pregnancy with subsequent seroconversion before delivery (3% reported seroconversion of pregnant women);20 postnatal hiv infection with breastfeeding transmission; or fear of stigmatisation after disclosure of hiv status. antenatal identification of hiv-infected pregnant women is the gateway to a successful pmtct programme, since all other interventions rely on this key step. opt-out antenatal hiv testing, and repeat hiv testing late in pregnancy, during labour and at immunisation services, would maximise identification of hiv-infected mothers. in addition, clear recording of maternal hiv status on the infant’s rthc would increase awareness of hiv exposure and hopefully prompt prescription of ctx and uptake of infant hiv pcr testing. this would allow for earlier infant diagnosis and rapid art initiation, resulting in improved infant outcomes. the poor uptake rates reported for sdnvp and ctx prophylaxis in this study are alarming. possible factors contributing to this problem include mothers who test at a clinic and then deliver in hospital; ‘cryptic’ written communication between health facilities about patients’ hiv status in an attempt to maintain confidentiality; women’s reluctance to disclose hiv status due to stigma; and health care workers’ reluctance to offer hiv testing or to enquire about hiv status. failure to provide ctx prophylaxis represents a major missed opportunity to prevent early mortality from pcp, as demonstrated in this cohort with 15% of deaths ascribed to pcp. since 2007 there has been considerable improvement (but increased complexity) in pmtct regimens. however, these changes will be not be effective unless universal uptake of pmtct, ctx prophylaxis and early infant diagnosis is achieved. high loss to follow-up of hiv-exposed infants remains a major problem in the pmtct programme, both at chbh and at a national level as reported by previous studies.21 , 22 hiv diagnosis and antiretroviral therapy eligibility and uptake despite calls for universal testing, 15% of children admitted to chbh had no documentation of hiv exposure status or hiv testing. in a subgroup (3.8%) noted to be hiv exposed and symptomatic (requiring hospitalisation), hiv pcr testing was not performed. although usually recommended at 4 6 weeks of age, immediate hiv pcr testing should be performed in symptomatic hiv-exposed infants regardless of age so as to expedite art initiation.23 maternal hiv status, pmtct interventions and results of hiv pcr testing should be routinely enquired about at every infant’s health care visit. similarly, any child who presents with malnutrition must be screened for hiv, as reflected in this cohort, where 54.1% of children were newly diagnosed in hospital despite a background of malnutrition (in 72%) and previous hospitalisations. however, rapid hiv tests (used for screening or to establish hiv exposure status in infants) have high false-negative rates, especially among young infants.24 despite growing awareness of the benefits of paediatric art at the time, art coverage of these hospitalised children was low (83% of eligible children were not accessing art). the short treatment duration and older age of children on art at chbh highlights the fact that few children and even fewer infants had the benefit of early art initiation. to ensure timeous and equitable access for children, art must be initiated and monitored at entry levels of the health care system (primary health care clinics). furthermore, hospitalised, symptomatic hiv-infected children should be fast-tracked for inpatient art initiation. this measure should be strongly considered for every art-eligible hospitalised child, and especially for infants ≤12 months of age, who are at highest risk of disease progression and death.23 in our study setting (a hospital with an established paediatric art service), only 4.1% of art-naïve, art-eligible children had treatment commenced as an inpatient, despite weekly ward visits by clinicians from the onsite hiv clinic. in addition, none of those commenced on art as inpatients were infants, despite this being the age category with the highest case fatality rate. we postulate that multiple hurdles to inpatient art initiation exist, such as parental illness or death, complex social circumstances, advanced hiv disease and clinician inexperience with or reluctance to commence haart. despite these obstacles, clinicians need to be more aggressive in identifying and treating art-eligible infants and children during ward admission. outcome of hospitalisation infectious diseases such as diarrhoea, tb and pcp – which are preventable by immunisation, prophylaxis or early art initiation – accounted for all of the deaths. dual or multiple concurrent infections are well recognised among hiv-infected children with pneumonia. there were no documented cases in this cohort, but this may simply reflect the lack of aggressive screening for multiple respiratory pathogens. cmv was demonstrated on postmortem specimens from several patients. it was difficult to distinguish cmv infection from disease, additional laboratory testing was limited and ganciclovir treatment was not readily accessible at chbh at the time of the study. the contribution of cmv disease to the burden of pneumonia and deaths in this cohort is therefore uncertain. during the study, only 3% of hiv-infected children were admitted to icu/high care; however, they demonstrated a 76.9% survival rate. data on icu candidate selection policies, duration of stay, incidence of complications and long-term morbidity and mortality compared with that of hiv-negative children admitted to icu were not available. with expanding art access and improved hiv outcomes, institutional policies for the admission of hiv-infected children to paediatric icu facilities in south africa should be reviewed. at chbh from 1992 to 1996 the proportion of paediatric in-hospital mortality accounted for by hiv increased from 6.7% to 46.1% and in 2007 (this study) to 58%. this figure shows striking concordance with the 2008 south african statistics from the countdown to 2015 report, which attributed 57% of under-5 mortality to hiv/aids (current hiv-attributable mortality is 46%).25 despite implementation of pmtct and paediatric art programmes, hiv prevalence and in-hospital case fatality rates (among hiv-infected children under 5 years of age) have remained static between 1996 and 2007. over the same period, however, mortality among uninfected children has declined. hiv-infected children at chbh are at a 3-fold increased risk of death compared with hiv-uninfected, hiv-exposed and hiv-unknown children. hospitalised hiv-infected infants under 12 months of age at chbh are a particularly vulnerable group with a high case fatality rate (17.1%), and should be prioritised for early art initiation. art status at the time of hospitalisation did not significantly impact on inpatient mortality; however, the median duration of art in the treatment group was only 2 months, reducing the likelihood of treatment survival benefit. early hospitalisations after initiation of art are a well-documented phenomenon,26 but no immune reconstitution inflammatory syndrome (iris) or art adverse event-related admissions were documented in this cohort. it is possible that these conditions were unrecognised and thus under-reported owing to lack of experience of hospital staff at that time. this study has several limitations that may impair its generalisability: a retrospective study design; small sample size; a short study period; and lack of an hiv-uninfected comparison group. the large percentage of children (15%) with unknown hiv status also limits the accuracy of the hiv prevalence data. missed opportunities among hiv-exposed, status unknown infants were also not captured. however, the data provide a ‘snap-shot’ of hiv impact at a large referral hospital and may reflect commonly encountered challenges to paediatric hiv care provision. experiences after introduction of pmtct and art at chbh may provide insights for other institutions struggling to implement best practice guidelines for paediatric hiv care. conclusion hiv remains highly prevalent and contributes to significant in-hospital mortality at chbh. multiple missed opportunities for pmtct, hiv diagnosis and art initiation were identified, demonstrating the need to monitor and assist with hiv guideline implementation at service delivery level. interventions to optimise paediatric hiv outcomes should target maternal hiv diagnosis, early infant diagnosis, uptake of ctx prophylaxis and prompt initiation of art, especially among infants. hospitalised art-eligible children should be prioritised for inpatient initiation of art. ongoing surveillance of hiv prevalence, disease profile and mortality at chbh and other hospitals may be used to identify programmatic problems, plan service improvement interventions and measure progress towards the millennium goal of a two-thirds reduction in u5mr by 2015.27 declaration of competing interests. the authors declare that they have no competing interests. authors’ contributions. all authors contributed to study design, data interpretation and critical revision of the manuscript. ad performed the data collection, data analysis (supervised by ag) and drafted the manuscript. acknowledgements. this research was supported by a medical faculty research endowment fund grant from the university of the witwatersrand. tammy meyers is a fogarty fellow sponsored by grant no. 5u2rtw007370 and 5u2rtw007373. references 1. unaids. world health organisation. global report: unaids report on the global aids epidemic 2010. http://www.unaids.org/documents/20101123_globalreport_em.pdf (accessed 1 december 2010). 1. unaids. world health organisation. global report: unaids report on the global aids epidemic 2010. http://www.unaids.org/documents/20101123_globalreport_em.pdf (accessed 1 december 2010). 2. rogerson sr, gladstone m, callaghan m, et al. hiv infection among paediatric in-patients in blantyre, malawi. trans r soc trop med hyg 2004;98(9):544-552. 2. rogerson 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27. chopra m, daviaud e, pattinson r, fonn s, lawn je. saving the lives of south africa’s mothers, babies, and children: can the health system deliver? lancet 2009;374(9692):835-846. 27. chopra m, daviaud e, pattinson r, fonn s, lawn je. saving the lives of south africa’s mothers, babies, and children: can the health system deliver? lancet 2009;374(9692):835-846. fig. 1. determination of hiv prevalence and study population and art uptake among 440 hiv-infected children. table i. disease profile of hiv-infected children (n=440) gender male 234 (53.2%) female 206 (46.8%) age category ≤11 months 228 (51.8%) 12 35 months 85 (19.3%) 36 59 months 29 (6.6%) ≥5 years 98 (22.3%) timing of hiv diagnosis newly diagnosed 238 (54.1%) known hiv-infected 202 (45.9%) who hiv stage i 3 (0.7%) ii 29 (6.6%) iii 188 (42.7%) iv 220 (50%) median (iqr) weight-for-age z-score (waz)* (n=342) ≤11 months (n=228) -3.53 (-4.59 -2.44) 12 35 months (n=85) -2.69 (-3.60 -1.43) 36 59 months (n=29) -1.89 (-3.03 -1.41) no. 0 59 months with waz -3 -2 (%) 56 (16.4) no. 0 59 months with waz <-3 (%) 189 (55.3) median (iqr) cd4 percentage by age group† (n=320) ≤11 months (n=155) 18.6 (12.8 28) 12 35 months (n=57) 16.2 (9.6 23) 36 59 months (n=23) 9.1 (6.3 15.3) ≥5 years (n=85) 8.0 (4.5 14.7) median (iqr) cd4 absolute count (cells/µl) by age group† (n=320) ≤11 months (n=155) 700 (361 1294) 12 35 months (n=57) 565 (422 909) 36 59 months (n=23) 414 (197 863) ≥5 years (n=85) 171 (45 379) severe immunosuppression (all ages)‡ 225/320, 70.3.% no. (%) of children receiving ctx prophylaxis all hiv-infected infants <12 months of age 73/228 (32%) known to be hiv-infected and not yet on art 86/127 (67.7%) known to be hiv-infected and on art <12 months 53/55 (96.4%) reason for hospitalisation pneumonia 165 (37.5%) gastro-enteritis 97 (22%) tuberculosis (including ptb + extrapulmonary tb) 92 (21%) sepsis 86 (19.5%) (including septicaemia (n=48), meningitis (n=23), and urinary tract infection (n=15) outcome of hospitalisation discharged alive 319 (72.5%) died 53 (12%) transferred to a step-down hospital facility 68 (15.5%) deaths by age group (case fatality rate§, 95% ci) by age group (n=53) ≤11 months 39 (17.1%, 12.5 22.6) 12 -35 months 4 (4.7%, 1.3 11.6) 36 59 months 2 (6.9%, 0.8 22.8) ≥5 years 8 (8.2%, 3.6 15.5) * calculation of waz scores was only done for children 0 59 months of age (n=342). †cd4-positive t-cell counts and percentages were analysed in a subgroup of the study population who had had cd4 testing at any point 1 month before, during or after hospitalisation (n=320/440). ‡proportion of children with severe immunosuppression was defined using who (2007) criteria11 as follows: <11 months of age, cd4 <25%; 12 35 months, cd4 <20%; 36 59 months, cd4 <15%; >5 years, cd4 <200 or <15%. §case fatality rate was calculated as total number of deaths per age group/total number of admissions per age group. table ii. eligibility for art versus art access in 53 hiv-infected children who died age categories no. (%) with immunological criteria qualifying for art* no. (%) with clinically advanced disease (stage 3 or 4) qualifying for art no. (%) of eligible children actually receiving art at time of death all deaths (n=53) 18/27† (66.7) 50/53 (94.3) 6/50 (12) deaths <18 months (n=40) 10/17† (58.8) 38/40 (95) 6/38 (15.8) deaths >18 months (n=13) 8/10† (80) 12/13 (92.3) 0/12 (0) *cd4 percentage <20% for children <18 months old, cd4 <15% for children >18 months old. †the denominators differ from the overall group denominators because only a proportion of the 53 hiv-infected children who died had recent cd4 percentage results available. fig. 2. missed opportunities for pmtct implementation, ctx prophylaxis, eid and art initiation in infants (<6 months). the southern african journal of hiv medicine                                                  september  2010 arguments in favour of the incorporation of traditional health practitioners (thps) into the overall health system are highly persuasive,1,2 especially in the context of south africa’s hiv epidemic and the inability of the public health sector to cover the health care needs of all hiv-positive patients.3 however, even those who support a more significant role for thps have articulated a set of minimum standards that must be met as a pre-condition to this step, including:2,4,5 n the systematic evaluation of african traditional medicines (atms) n the standardisation, processing and packaging of traditional medicines n training on hiv to ensure a high level of prevention (of hiv) and care (of patients) n the development of mechanisms to regulate the practice of traditional healing. over the past 3 years, arvir technologies, a publicfunded company that was established to validate and register a herbal medicine for the treatment of hiv based on atms, have been working on the first of these standards, namely the evaluation of atms, and more specifically on three plant extracts the use of which for the treatment of hiv/aids by thps has been reported previously.6,7 this project has raised a number the role of south african traditional health practitioners in the treatment of hiv/aids: a study of their practices and use of herbal medicines o r i g i n a l a r t i c l e david walwyn, bsc (chem eng), phd ithemba pharmaceuticals, po box 21, modderfontein, 1645, and graduate school of technology management, university of pretoria boitumelo maitshotlo, nat dip food service management ithemba pharmaceuticals 11 background. a large proportion of hiv-positive south africans regularly consult traditional health practitioners (thps) for their health care needs, despite evidence of negative interactions with antiretrovirals (arvs) and no published peer-reviewed clinical evidence for the efficacy of traditional medicines in the treatment of hiv. we investigated the dominant practices of thps towards hiv-positive patients and whether these practices have changed following widespread public awareness campaigns covering hiv and its treatment. method. the study used a semi-structured interviewer-administered questionnaire in the home language of the interviewee. a total of 52 thps from four provinces (gauteng, limpopo, kwazulu-natal and eastern cape) were interviewed. of the respondents 38% were based in the rural areas, and 69% classified themselves as inyangas, the remainder being sangomas. findings. all the thps in the survey offered treatment for hiv, although only 20% claimed to be able to cure the disease; 88% prepared their own medication, mostly from plant material, and sold their products as aqueous extracts in labelled bottles. none of these products had been systematically evaluated, and there was generally no record keeping, either of the patient or of the medicine itself. quality control practices such as expiry dates, controlled storage conditions and batch records were totally unknown in our sample. only 38% of the thps had received training on hiv/aids, although 75% believed that they were well informed about the disease. our own assessment was that only 50% had a working knowledge of hiv; more disturbingly, 37% believed that only traditional medicines should be used for its treatment and a further 50% believed that traditional medicines and arvs can be taken simultaneously. interpretation. despite ongoing public educational campaigns on hiv, some of which have specifically targeted thps, the care of hiv-positive patients continues to be compromised by the traditional sector. although some progress is evident, thp approaches to hiv treatment fail to conform to minimum standards proposed by the world health organization and other organisations, and represent a considerable challenge to the integration of thps with the biomedical sector and the antiretroviral treatment programme in south africa. september  2010                                                    the southern african journal of hiv medicine                                                   of important questions about the curative approaches and practices of thps, and the supply channels for the plant-based ingredients of their medicines, as follows: n several studies8-11 have reported widespread consultation of thps by people living with hiv/ aids, reflecting a high level of trust in both traditional methods and atms; what is the basis of this support, and is there any evidence for the efficacy claims of thps in their treatment of hiv (anecdotal or clinical)? n the traditional health sector is known to be highly divergent; what are the dominant treatment approaches, and what are the trends in this regard? n regulation of the sector has recently been implemented through the promulgation of the traditional health practitioners act (no. 22 of 2007); to what extent has the act changed the profile and conduct of the sector, and could this facilitate the introduction of a fully validated herbal medicine? n similarly, there have been several educational programmes to assist thps to improve their understanding of the disease and their alignment with the goals of the antiretroviral (arv) treatment (art) programme in south africa; have the programmes been successful in this regard? n allopathic and traditional medicines are typically seen as highly divergent; what is the level of interaction between the two sectors (biomedical and traditional health care), and are inter-sectoral referrals increasing? in our research, we have attempted to answer these questions. the underlying intention was to develop an understanding of whether and how we could engage with the traditional health sector, and to define better approaches for improving the biomedical/traditional health interface. methods the study was undertaken using a semi-structured interview-administered questionnaire. it was conducted in four provinces of south africa, and a total of 52 thps were interviewed (table i). the interviewees were identified by asking members of the community for information on the prominent thps; once identified, the researcher explained the purpose of the study to the practitioner and requested permission for the interview. the questionnaire covered a range of areas including membership of a professional association (as prescribed by the traditional health practitioners act), the extent of training on hiv/aids already completed (including treatment with arvs), the level of knowledge about the prevention, incidence, diagnosis and biomedical treatment of hiv/aids, the number of hiv-positive patients being treated, interaction with the biomedical sector (referrals and diagnosis), and the nature of the thp’s treatment for hiv (including quality control of prescribed medicines). results an overview of thp practice and hiv/aids the majority of thps (69%) in our study classified themselves as inyangas (herbalists); in other words, the source of their healing is considered to derive from their use of medicinal plants, as opposed to the approach of the sangomas (diviners), who rely more on divination for their healing approach. diviners have different names in different regions of south africa, depending on the dominant regional culture, including izangoma in zulu, amagqira in xhosa, ngaka in northern sotho and mungome in venda, although the majority of south africans refer collectively to this group of thps as ‘sangomas’.12,13 except in the eastern cape and gauteng (where the figure was only 50%), most of the thps in this study (79%) were registered with a local thp association, although no practitioners were as yet registered in terms of the traditional health practitioners act (no. 22 of 2007). this and other observations lead to the inevitable conclusion that implementation of the act since its promulgation has been almost non-existent in all regions of the country. not surprisingly, all the thps in our study regularly see hiv-positive patients (between 3 and 10 patients per week). the thps stated that most of their patients were women, but believed that males are the dominant transmitters of hiv/aids. in their view, the gender differences make it difficult to treat couples (either discordant or both hiv positive) because men do not talk openly about their hiv status and are therefore less likely to seek treatment. training and knowledge of hiv/aids only 38% of the thps had received hiv/aids training of one or more days; as a result, their knowledge of the disease was limited and influenced by a high level of suspicion of non-traditional interventions and biomedical strategies. for instance, some thps still believe that there is no such thing as hiv/aids and continue to associate the symptoms of the disease with cultural notions of sickness, e.g. makgome in pedi and isifusenhlu in zulu, which require the performance of 12 province no. of thps participating eastern cape 13 gauteng 11 kwazulu-natal 15 limpopo 13 table i. distribution of interviewees by province the southern african journal of hiv medicine                                                  september  2010 a cleansing ceremony for healing. in our assessment, which was based on answers to a standard set of questions about hiv, its treatment and its prevention, only 50% of respondents have a working knowledge of hiv, although 75% feel that they were well informed about the disease and its symptoms (fig. 1). although limited in the sample, thps’ ignorance and mistrust of condom use as a prevention strategy is of great concern. some opinions expressed in this regard were: ‘in the past there were no such things as condoms or hiv in our society; ever since condoms were brought to us there is a high rate of hiv/aids because they are infested with diseases. proof is in that oil lubricant.’ ‘condoms are contributing to the spread of hiv/ aids, for an example if you put condom in a sunny condition or pour hot water on it, you will notice worms coming out of that experiment. that is the very same worm they are referring to as aids.’ diagnosis and treatment for the diagnosis of hiv, at least 69% of the thps stated that they refer their patients to the biomedical sector for testing and require a positive hiv test result before the patient can start treatment (fig. 2). the remaining practitioners use various approaches including thp observation, patient self-diagnosis and ‘dreams and guidance from the ancestors’. the modality of the treatment, even within the two separate groups of inyangas and sangomas, varied considerably. the latter often require patients to undergo a rigorous in-house cleansing and treatment routine. for instance, a thp in rural eastern cape, who sees hiv-positive clients from all over the country, has built a hospice in his yard for his patients. inyangas, on the other hand, follow an approach of an initial consultation with fortnightly or monthly followup visits, depending on how quickly the prescribed treatments are completed. of thps in our sample 73% prescribe a herb-based solution called imbiza (zulu) which is sold in a 2 litre or 750 ml bottle and is claimed to cleanse or purify the blood. it was apparent from the research that a wide range of plants collected from different geographical regions and ecological systems are used in the preparation of the imbiza. it is claimed that the practitioners’ understanding of plant medicinal properties is based on an extensive knowledge of their traditional use, obtained from the ancestors and passed down through oral tradition. almost all the thps (88%) prepare their own medicine using the natural plant ingredients and a hot water infusion process. the questionnaire specifically avoided detailed questions about the exact identity of the ingredients in order to protect any potential intellectual property. in some cases, however, this information was provided without any prompting and included a number of plants, the antiviral and immunomodulatory properties of which have already been reported.7,14-17 the plants were sourced from the local area (collected personally by the thp) and also from markets trading in medicinal plants (mostly in the major urban areas). the recommended dosage varies according to a number of factors, as follows: n stage of the disease (chronic stage 125 ml 3 times a day; bed-ridden patients 250 ml 3 times a day) fig. 2. thps referring patients to clinics for hiv testing. fig. 1. extent of knowledge (thps and interviewer assessment). are you well informed about hiv? (self-assessment by thp) extent of knowledge (assessment of interviewer) 13 september  2010                                                    the southern african journal of hiv medicine                                                  14 n affordability to the patient (unemployed patients 3 times a day; employed patients 4 times a day) n distance from which the patient comes (patients from far places are given a 5 litre bottle and take 60 ml of the medicine 3 times a day). the cost of medicine also varies from a minimum of r200 to a maximum of r2 800 (fig. 3). the treatment cost is determined by the following: n the local reputation of the thp and hence patient belief in the efficacy of atms (the better the reputation, the more expensive the treatment) n the variety of herbs used (the more herbs, the higher the price) n the location of the practice (prices in the rural areas are generally lower). all the thps in our survey were confident about the efficacy of their treatment for both hiv (20% claim to be able to cure hiv; the remainder to treat the infection) and hiv/aids-related opportunistic infections, although we were shown no recorded evidence for these claims. when asked to show evidence to support their statement, a number of claims were made including verbal reports of increases in cd4 count and patient well-being. as noted later, only 17% of thps keep any patient records and track hiv status. based on our own research and the work of other drug discovery organisations, the basis for claims relating to most of the plants is highly questionable. this statement is supported by two main arguments derived from an extensive evaluation of the antiretroviral properties of plant extracts, as follows:6 n most of the plant-based traditional medicines are prepared through hot water infusion of dried plant material (leaves, roots, bark, etc.); the resultant solutions contain at most 0.5% of extracted solids, so that a 250 ml dose in turn contains the equivalent of 1.25 g solid material. the concentration of the active ingredient(s) varies considerably depending on the plant itself and in many cases these ingredients have not been properly identified. however, our work with three local products indicates that the active ingredient(s) are at most 5% by mass of the total extract. in other words, a patient taking a 250 ml dose of a herbal infusion (the highest dose recorded in our study) will be consuming not more than 63 mg of active ingredient(s) per dose, or 188 mg per day. n a wide range of specific antiretroviral activities for plant-based natural products (and other compounds) has been reported in the literature,14-17 but even the most active natural compounds have activities no better than between 1 and 5 μm based on a range of in vitro cell-based assays. these values are between 100 and 1 000 times less active than the equivalent allopathic medicines such as zidovudine, efavirenz and tenofovir (tables ii and iii). in other words, a patient taking a traditional medicine for the treatment of hiv will be receiving on average less than 0.5% of a therapeutic dose. this calculation does make some assumptions about the bio-availability of the natural product(s) but is a reasonable estimate of effective dose and its comparison with the registered antiretroviral products. in summary, although many plant extracts have a measurable level of antiretroviral activity (as determined in cell-based assays), this activity is many times lower than that of the synthetic products. considering that hiv patients on traditional medicines are taking on average less than 150 mg of the active compound(s), the net dose is only a fraction of the required therapeutic dose, and the possibility that a level of viral control is achieved is remote. quality control, efficacy and patient records most of the thps (69%) claimed that their medication is of good quality and that there is no need for batch records, expiry dates or quality assessment of the ingredients/final product, which are standard concepts in the preparation of allopathic medicines. when asked to explain the reason for the difference, the thps noted that ‘unlike western medicine our medicine doesn’t have any preservatives; therefore there is no need to include expiry dates because natural plants don’t expire’. in addition, very few thps label their products. in terms of patient records, as has been stated previously, only 17% of thps keep any form of records, with the actual proportion varying from 26% in gauteng to 8% in the eastern cape. as a result, no conclusive results can be derived from analysis of the treatment outcomes since these cannot be supported by documented evidence including health assessments, viral loads and other indicators of disease progression in hiv-positive patients. it is clear that this is one important area in which training can play a major role in upgrading the quality of care being provided by thps in south africa. fig. 3. cost of traditional medicines for the treatment of hiv. the southern african journal of hiv medicine                                                  september  2010 15 interaction with the biomedical health care sector when asked about the possibility of interaction with other health practitioners, thps believed that nurses undermine their work and do not accept the efficacy of their treatment. as a result, thps are reluctant to refer their patients to the biomedical sector for art. a similar observation has been reported in other studies.19 the thps indicated that unlike nurses and doctors they do not take the patients off art but encourage their patients to take both atms and arvs, since they believe that arvs are also made from muti (fig. 4). at least 50% of the thps participating in our study showed little interest in learning or working with the biomedical sector and several openly criticised the allopathic approach, making statements such as ‘doctors kill patients with their arvs’. discussion the results of this study have shown that many thps offer treatment for hiv/aids despite a somewhat limited understanding of the virus, the symptoms of infection and its treatment. furthermore, the medicines are expensive relative to both patient incomes and the biomedical equivalents, have no recorded evidence of efficacy, and are not quality controlled in most respects. despite these factors, many patients continue to consult thps for hiv-related illness and to use traditional medicines. the persistence of this support is due to many factors, including: n an ongoing belief in the efficacy of traditional medicines, which is considered to have been passed down through generations from the ancestors drug name class ic50 (μm) tc50 (μm) therapeutic index dosage (mg/d) efavirenz nnrti 0.0015 80 53 333 600 maraviroc ei 0.001 25 20 161 600 lamivudine nrti 0.07 360 5 143 300 nevirapine nnrti 0.029 320 11 034 400 stavudine nrti 0.03 100 3 333 60 zidovudine nrti 0.002 32 16 000 600 emtricitabine nrti 0.04 150 3 750 200 tenofovir nrti 0.005 29 5 800 300 indinavir pi 0.014 32 2 286 1 600 *data for all the synthetic and natural products have been obtained directly from the national institute of health’s database,18 which lists the anti-hiv activity of over 170 000 compounds based on information in the literature. where possible the values for the pbmc assay have been used. nnrti = non-nucleoside reverse transcriptase inhibitor; ei = entry inhibitor; nrti = nucleoside reverse transcriptase inhibitor; pi = protease inhibitor. table ii. antiretroviral activity and actual dosage of several synthetic products* estimated plant active ingredient ic50 (μm) tc50 (μm) therapeutic index dosage (mg/d) syzygium claviflorum betulinic acid 1.4 13 9 60 000 lobostemon trigonus6 unknown (data shown for crude extract) ~2.5 2 000 800 150 000 curcuma longa curcumin 5.0 10.0 2 100 000 inula britannica 3,5-di-o-caffeoylquinic acid 2.0 486 243 40 000 calophyllum lanigerum calanolide a 0.1 10 100 8 000 *data for all the synthetic and natural products have been obtained directly from the national institute of health’s database,18 which lists the anti-hiv activity of over 170 000 compounds based on information in the literature. where possible the values for the pbmc assay have been used. table iii. antiretroviral activity and estimated dosage of several natural products* fig. 4. thps’ attitudes to arv treatment. can arvs and atms be taken together? attitude to arvs september  2010                                                    the southern african journal of hiv medicine                                                  16 n considerable competition between the two treatment methodologies, especially by the thps, who openly discredit the conventional sector in various ways (referral of a patient to the tertiary sector by a thp is in many respects a direct conflict of interest) n the confidentiality of consulting a traditional healer (there is a belief that information such as the patient’s hiv status is not secure in the biomedical sector) n the perceived uncaring, unsympathetic and impersonal approach of the biomedical sector to patients, which is humiliating and hurtful to the patient; doctors are considered to give inadequate time to patient consultation n the side-effects of arvs and the fact that these medications are not a cure, but have to be taken forever n lack of regulation in the sector, which encourages illegal and opportunistic practices including wild claims about treatment efficacy; in some cases the more bizarre the treatment, the greater the number of patients. these problems are well known in the sector, and other authors have identified a set of minimum standards that require urgent implementation.9 our study has shown that little progress has been made with implementation of these standards. for instance: n although all of the thps claim to treat hiv (and 20% to cure the disease), none of the treatments have been systematically evaluated. n the majority (88%) of the thps interviewed prepare their own medication but fail to keep patient records or batch data for each preparation. most of the products are sold in labelled bottles as liquids, and none have any expiry dates on the labels. the opinion of the thps is that plants do not expire; there is therefore no need for proper packaging or controlled storage conditions. n of the thps in our sample, 38% have received training on hiv/aids and 75% believe that they are well informed about the disease; however, based on their replies to a few rudimentary questions about the disease, our assessment was that only 50% have a working knowledge of hiv. n perhaps more disturbingly, 37% believe that only atms should be used for the treatment of hiv and a further 50% believe that both atms and arvs can be taken simultaneously. it is apparent that many thps play a role in hiv prevention and care by referring patients for hiv testing (69% of thps), counselling patients with hiv and opportunistic infections, and distributing condoms to their patients (62% of the total). our study makes it clear that this role is sub-optimal and could be improved through further training and regulation. despite the fact that such regulation has recently been implemented by promulgation of the traditional health practitioners act, and that 79% of our sample of thps were registered with a thp association, the interim traditional health practitioners council of south africa is not yet operational and there is no quality control in the sector or enforcement of the legislation. with respect to capacity development of thps, it is recommended that training in the following areas should be urgently addressed: n an understanding of the hiv and the pathology of the disease n the adoption of safe sexual practices and use of biomedical prevention methods n quality control of traditional medicines, including concepts such as expiry and variability of raw materials n the dangers of taking atms and arvs together n identification of symptoms of hiv infection to assist with counselling and treatment, including referral to the biomedical sector. conclusion in conclusion, it will be a major challenge to use the thp network for distribution of a registered herbal medicine owing to ongoing ignorance regarding hiv, a high rate of illiteracy among thps especially in rural areas, and local cultural beliefs that may prevent adoption of biomedical approaches. nevertheless, the extensive network of thps and ongoing confidence in their abilities within local communities suggest that efforts to address these challenges will be worthwhile. authors’ contributions. this article was written by dr david walwyn. the field work was undertaken by ms biotumelo maitshotlo, who also contributed to the preparation of the manuscript with written material in certain sections, graphics and checking of the contents. conflict of interest. there is no conflict of interest for either author. the work was undertaken to understand the dynamics of the traditional health care sector in south africa with respect to the treatment of hiv/aids, and to consider the suitability of this sector for the distribution of a herbal medicine. these objectives are clearly stated in the text of the article. acknowledgements. payment of the salary of ms maitshotlo and overall funding of arvir technologies by lifelab are gratefully acknowledged. the southern african journal of hiv medicine                                                  september  2010 17 references 1. wreford, j. missing each other: problems and potential for collaborative efforts between biomedical and traditional healers in the time of aids. social dynamics 2005; 31(2): 55-89. 2. world health assembly. resolution of the 62nd world health assembly on traditional medicine. document number eb124.r9. geneva: world health assembly, 2009. 3. cleary s. scaling-up access to art: confronting affordability and sustainability. presented at the 4th south african aids conference, durban, 31 march 3 april 2009. 4. dickinson d. traditional healers and company hiv/aids programmes. african journal of aids research 2008; 7(3): 281-291. 5. southern african development community. article 20 of the sadc protocol on health. adopted in august 1999, maputo. http://www.doh.gov.za/department/ sadc/docs/protocol99.html (accessed 25 june 2009). 6. walwyn d. herbal medicines for the treatment of hiv: fanciful notion or real possibility? poster presented at the 4th south african aids conference, durban, 31 march 3 april 2009. 7. bessong po, obi cl. ethnopharmacology of human immunodeficiency virus in south africa – a minireview. african journal of biotechnology 2006; 5(19): 16931699. 8. peltzer k, friend-du preez n, ramlagan s, fomundam h. use of traditional complementary and alternative medicine for hiv patients in kwazulu-natal, south africa. bmc public health 2008; 8: 255-269. 9. homsy j, king r, tenywa j, kyeyune p, opio a, balaba d. defining the minimum standards of practice for incorporating african traditional medicine into hiv/aids prevention, care and support: a regional initiative in eastern and southern africa. african journal of traditional, complementary and alternative medicines 2004; 10(5): 905-910. 10. mngqundaniso n, peltzer k. patients consulting traditional health practitioners in the context of hiv/aids in urban areas in kwazulu natal, south africa. african journal of traditional, complementary and alternative medicine 2008; 5(4): 370379. 11. babb da, pemba l, seatlanyane p, charalambous s, churchyard gj, grant ad. use of traditional medicine by hiv-infected individuals in south africa in the era of antiretroviral therapy. psychol health med 2007; 12(3): 314-320. 12. wreford j. sincedisa – we can help: a literature review of current practice involving traditional african healers in biomedical hiv/aids interventions in south africa. social dynamics 2005; 31(2): 90-117. 13. pretorius e. traditional healers. in: south african health review. 5th ed. durban: health systems trust, 1999: 249-256. 14. singh ip, bharate sb, bhutani kk. anti-hiv natural products. current science 2005; 89(2): 269-290. 15. de clercq e. current lead natural products for the chemotherapy of human immunodeficiency virus (hiv) infection. med res rev 2000; 20: 323-349. 16. cos p, maes l, van den berghe d, hermans n, pieters l, vlietinck a. plant substances as anti-hiv agents selected according to their putative mechanism of action. j nat prod 2004; 67: 284-293. 17. yu d, morris-natschke sl, lee k-h. new developments in natural products-based anti-aids research. med res rev 2007; 27(1): 108-132. 18. national institute of health. http://chemdb.niaid.nih.gov/struct_search/ivt/ivt_ search.asp (accessed 26 june 2009). 19. mngqundaniso n, peltzer k. traditional healers and nurses: a qualitative study on their role on sexual transmitted infections including hiv and aids in kwazulu natal, south africa. african journal of traditional, complementary and alternative medicine 2008; 5(4): 380-386. j u n e 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e18 hiv and hpv co-infection hiv is believed to increase the risk of hpv infection and cervical neoplasia, in part due to hiv-induced immunodeficiency and the resulting inability to control hpv infection.1,2 hiv status, herpes zoster, oral candidiasis and tuberculosis have all been found to be associated with carcinogenic human papillomavirus (hpv), consistent with other studies that found hiv and hiv-associated immunosuppression to be independently associated with hpv positivity.3 although it has been recognised that hiv plays a significant role in increasing the risk of persistent/latent hpv infection and/or rates of progression of precancerous lesions to high-grade cervical neoplasia and cancer, several key variables remain to be elucidated. these include a better understanding of the role of hpv viral load in the genesis of cervical neoplasia in hiv-infected women, and the relationship between early initiation of haart and the possible inadvertent result of an increased risk of the acquisition of molecular changes characteristic of carcinoma in situ. in contrast to a very small subset of the many immunocompetent women infected with oncogenic types of hpv who develop cervical cancer, women infected with hiv are thought to be 3 5 times more likely to develop cervical lesions that can become cancerous.4 both pre-invasive disease and invasive cervical cancer have been reported to have a much poorer outcome in hiv-infected women than in the general population.5 similar to cervical disease progression, recurrent disease after treatment is correlated with low cd4 cell counts.6 although at least seven studies have examined the effects of highly active antiretroviral therapy (haart) on the course of cervical lesions, it is still not clear whether haart substantially affects the natural history of cervical squamous intra-epithelial lesions (sil). the impact of haart has led to some improved resolution of abnormal pap smears, but has not made a significant impact on the risk of cervical cancer in hiv-infected women.7 this may be because administration of haart is most often offered to women with more advanced hiv disease status and higher hpv viral loads. haart also prolongs survival in women with cervical pre-invasive lesions.8 in this article, it will be argued that while a ‘one-visitin-a-lifetime’ strategy with immediate cryotherapy or the loop electrosurgical excision procedure (leep) as part of the minimum package for the high-risk age group of women between 35 and 50 years may have an impact in resource-poor settings, this protocol in areas of high hiv prevalence may not take into account the high rates of recurrence and cervical disease progression associated with low cd4 cell counts. secondly, it will be explored how a hpv dna-based screening programme in high hiv prevalence areas may result in overtreatment because of its low specificity. finally, it will be argued why a vaccinebased cervical cancer prevention programme may not be sufficient to reduce cervical cancer in southern africa. discussion screen-and-treat protocol in settings with high prevalences of hiv and genital ulceration in developing countries, inadequate screening programmes have contributed to high incidences of cervical cancer. while in developed countries the introduction of large-scale cytological testing has resulted in a major decline in cervical cancer mortality, in low-resource settings the high specificity of cytological testing is offset by its lack of sensitivity for detection of precursors of invasive cervical cancer (ranging from 30% to 90%) and highly dependent on adequacy of sample collection, slide preparation and slide interpretation. as part of an efficient cervical prevention programme, alternatives to cervical cytology have been sought but have not met a high level of specificity. several recent cervical cancer prevention in settings of high hiv prevalence sonia menon, mph, ma, pgd in infectious diseases london school of hygiene and tropical medicine alumni, london, uk o p i n i o n despite being a preventable disease, cervical cancer is still the second most common cancer in women worldwide. hiv infection is associated with a higher incidence, more rapid progression, and increased recurrence rates of human papillomavirus (hpv)-associated cervical intra-epithelial neoplasia and invasive cancer. the disease burden in developing countries is the result of inadequate national health care infrastructures that cannot establish or sustain comprehensive screening programmes, together with a high prevalence of hiv infection, particularly in southern africa. in this article, clinically relevant issues for primary prevention of cervical lesions by a quadrivalent hpv vaccine and the ‘screen-and-treat’ protocol in settings of high hiv prevalence will be explored. t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u n e 2 0 1 1 19 studies have demonstrated that direct visual inspection of the cervix with acetic acid (via) is a reasonably sensitive and a cost-effective alternative to cytological screening.9 with a sensitivity of 76% in hiv-positive women, via is also a useful screening test for pre-invasive lesions of the cervix in low-resource settings.10 however, the high prevalence of sexually transmitted infection (sti)-related genital ulcers in the african countries worst affected with hiv may lead to a relatively low specificity of via.11 hpv dna testing has emerged as a convincing option for cervical cancer screening. a large study in india in 1999 on healthy women aged between 30 and 59 years found that a programme strategy based on a single round of hpv testing was associated with a 50% reduction in cervical cancer incidence and mortality, whereas strategies based on a single round of via or pap screening had little, if any, effect on these outcomes.12 it was recommended that since most hpv infections in young women regress rapidly without causing clinically significant disease, a single hpv testing round would be associated with a significant reduction in the numbers of advanced cervical cancers and death from cervical cancer if targeted at women aged over 30 years.12 a randomised controlled trial in south africa in 2000 2002 led to recommendations that both via and hpvbased screening and immediate cryotherapy treatment were safe and decreased the prevalence of high-grade cervical cancer precursor lesions.13 several studies have been undertaken in low-resource settings to assess the optimal age group for cervical cancer screening to achieve the greatest public health impact. a costeffectiveness modelling exercise comparing screening strategies in five developing countries predicted that for 35-year-old women screened only once in their lives, a 1 2-visit approach with the via method could reduce the lifetime risk of cervical cancer by 25%, and hpv dna testing could reduce it by 36%.14 although these recommendations may be effective in hiv-negative women, in whom there is the possibility of spontaneous regression of pre-invasive lesions because of their normally functioning immune systems, certain issues would need to be explored in resource-poor settings with a high prevalence of hiv. hiv-positive women have high rates of sil and concurrent hpv infections with a variety of genotypes in which the oncogenic risk is poorly documented. a high diversity of hpv genotypes was observed in hiv-infected women in brazil. many of these women infected with hpv were found to carry oncogenic genotypes, even when cytological evaluation showed normal results.15 although hpv testing of cervical smears is more sensitive than cytological assessment, the specificity of hpv dna testing may be unacceptably low in areas of high hiv prevalence. in one study, the specificity of hpv dna testing for detection of high-grade squamous intraepithelial lesions (hsil) was 75% in hiv-seronegative women and 41% in hiv-seropositive women.16 in hiv-positive women, rapid progression of hpv may reduce the age at which women are ‘at high risk’. in a study to determine the effect of the hiv epidemic on invasive cervical cancer in kenya, hiv-positive women who presented with cervical cancer were found to be significantly younger than hiv-negative women.17 these findings imply that screening of 35-year-old women only once in their lives may not reduce the lifetime risk of cervical cancer in a high hiv prevalence setting. in zambia, where the prevalence of hiv infection is one of the highest in the world and the incidence of cervical cancer the highest in sub-saharan africa,18 it was found that in a resource-constrained environment it would be feasible to implement a system of referral of cryotherapy-ineligible patients for leep in a ‘screenand-treat’ cervical cancer prevention programme targeting hiv-infected women.19 a study conducted in thailand between 2004 and 2008 demonstrated that hiv infection was not significantly associated with leep complications.20 prophylaxis-based secondary cervical cancer prevention programme settings of high hiv prevalence such as rakia, uganda, where almost 50% of hiv-positive women are infected with strains of hpv that are associated with a risk of cervical cancer,21 would stand to benefit most from a prophylaxis-based (vaccine) cervical cancer prevention programme aimed at hpv-naïve women. a robust surveillance system capable of monitoring long-term safety, sustained immune responses, vaccine efficacy, and the epidemiological distribution of hpv oncogenic strains also encountered in hiv-positive women would be needed. although the quadrivalent hpv vaccine against hpv 6, 11, 16 and 18 constitutes an important breakthrough in cervical cancer control in hiv-negative women in the developed world, the limited epidemiological data available suggest that a much wider variety of hpv types are involved in the pathogenesis of cervical neoplasia in developing countries.22 also, hivinfected women in various geographical regions, such as zambia, brazil and rochester, ny, appear to be infected with less prevalent types of hpv compared with the general population.23 evidence suggests that different hpv types behave as independent infections, with no cross-reactive cellmediated immunity that might potentially be able to keep the oncogenic non-vaccine types under control. in 2009 a double-blind randomised study in young women indicated that the immune response stimulated by hpv 16 and 18 may also confer individual cross-protection against genetically related hpv oncogenic types, such as hpv 31, 33 and 45.24 monitoring would be necessary to see whether individual cross-protection could extend some protection to hiv-infected women in sub-saharan africa, and whether the af variants of hpv 16 and 18 common in women of african descent25 impact on the effectiveness of the hpv 16 and 18 vaccine and on individual cross-protection. j u n e 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e20 conclusion this paper has explored issues regarding screening for cervical cancer in settings with a high prevalence of hiv and genital ulceration. while the new hpv test has proved to be a successful cancer screening tool in detecting 14 high-risk types of carcinogenic hpv with 90% accuracy when tested on a group of local women in eastern china,26 its effectiveness will also need to be assessed in a high hiv prevalence setting to ascertain its specificity and sensitivity in hiv-positive women. although in zambia piggybacking on established hiv infrastructure has optimised resources and increased the efficiency of both hiv and cervical cancer programmes,27 the once-in-a-lifetime screen-and-treat protocol focusing on women between 30 and 45 years of age recommended for sub-saharan africa may not adequately take into account what is already known about the epidemiology of hiv-hpv co-infection. longer follow-up will be needed to assess the efficacy, cost-effectiveness and safety of via with same-visit treatment with leep in hiv-positive women. it is important to keep in mind that the prophylaxis prevention programme would be implemented in a setting where malnutrition and decreased immunity due to hiv/aids result in far less spontaneous regression of cervical lesions than would be seen in industrialised countries. this fact underscores the need for prevailing strains to be fully characterised and linkage to be established between vaccination history, screening history and hpv exposure. references 1. robinson wr, freeman d. improved outcome of cervical neoplasia in hiv-infected women in the era of highly active antiretroviral therapy. aids patient care stds 2002;16(2):61-65. http://www.ncbi.nlm.nih.gov/pubmed/11874637 (accessed 14 december 2009). 2. mckenzie nd, kobetz en. women with hiv are more commonly infected with non-16 and -18 high-risk hpv types. gynecol oncol 2010;116:572-577. 3. carter m. high prevalence of cervical cancer associated hpv strains in hiv-positive women. 2008. http://www.womensnet.org.za/high-prevalence-cervical-cancer-associatedhpv-strains-hivpositive-women (accessed 10 march 2010). 4. plusnews. global hiv/aids news and analysis. south africa: cervical cancer vaccine offers distant hope. 19 june 2007. http://www.plusnews.org/report.aspx?reportid=72809 (accessed 10 march 2010). 5. robinson wr, freeman d. improved outcome of cervical neoplasia in hiv-infected women in the era of highly active antiretroviral therapy. aids patient care stds 2002;16(2):61-65. http://www.ncbi.nlm.nih.gov/pubmed/11874637 (accessed 14 december 2009). 6. sweet rl, gibbs rs. infectious diseases of the female genital tract. 5th ed. philadelphia: lippincott williams & willkins, 2009. 7. cameron je, hagensee me. human papillomavirus infection and disease in the hiv+ individual. cancer treat res 2007;133:185-213. http://www.springerlink.com/content/ g12t34x256681832/ (accessed 10 february 2010). 8. xi lf, kiviat nb. cervical neoplasia and highly active antiretroviral therapy. j natl cancer inst 2004;96(14):1051-1053. http://jnci.oxfordjournals.org/cgi/reprint/96/14/1051 (accessed 7 january 2010). 9. goldie sj, kuhn l, denny l, pollack a, wright tc. policy analysis of cervical cancer screening strategies in low-resource settings. jama 2001;285:3107-3115. http://jama.amaassn.org/cgi/content/full/285/24/3107 (accessed 10 november 2009). 10. denny l, kuhn l, pollack a, wainwright h, wright tc jr. evaluation of alternative methods of cervical cancer screening for resource-poor settings. cancer 2000;89:826-833. http:// www.ncbi.nlm.nih.gov/sites/entrez?cmd=search&db=pubmed&term=10951346 (accessed 20 november 2009). 11. walraven g. prevention of cervical cancer in resource-poor settings. lancet 2009;361:21602161. 12. sankaranarayanan r, nene bm, shastri ss, et al. hpv screening for cervical cancer in rural india. n engl j med 2009;360:1385-1394. http://content.nejm.org/cgi/content/full/360/ 14/1385?ijkey=468a8b491975664292c6caae48a7a3e86b057962 (accessed 24 november 2009). 13. kuhn l, wang c, tsai w-y, wright tc, denny l. efficacy of human papillomavirusbased screen-and-treat for cervical cancer prevention among hiv-infected women. aids 2010;24:2553-2561. http://www.ph.ucla.edu/epi/faculty/detels/epi293/cervcancer_ aids_2010.pdf (accessed 1 january 2010). 14. goldie sj, gaffikin l, goldhaber-fiebert jd, et al cost-effectiveness of cervical-cancer screening in five developing countries. n engl j med 2005;353(20):2158-2168. http:// content.nejm.org/cgi/content/full/353/20/2158 (accessed 29 november 2009). 15. cerqueira dm, moraes ds, camara gn, et al. high hpv genetic diversity in women infected with hiv-1 in brazil. arch virol 2007;152:75-83. http://www.springerlink.com/content/ h47682624327j607/ (accessed 10 march 2010). 16. belinson j, qiao y, pretorius r, et al. prevalence of cervical cancer and feasibility of screening in rural china: a pilot study for the shanxi province cervical cancer screening study. int j gynecol cancer 1999;9:411-417. 17. gichangi p, de vuyst h, estambale b, et al. hiv and cervical cancer in kenya. int j gynecol obstet 2002;76(1):55-63. 18. plusnews. global hiv/aids news and analysis: zambia (2009). treating cervical cancer and hiv simultaneously. http://www.plusnews.org/report.aspx?reportid=85961(accessed 27 april 2011). 19. pfaendler ks, mwanahamuntu mh, sahasrabuddhe vv, mudenda v, stringer jsa, parham gb. management of cryotherapy-ineligible women in a ‘screen-and-treat’ cervical cancer prevention program targeting hiv-infected women in zambia: lessons from the field. gynecol oncol 2008;110:402-407. http://web.cs.swarthmore.edu/~turnbull/cs91/f09/paper/ pfaendler08.pdf (accessed 31 jaunary 2010). 20. kietpeerakool c, suprasert p, srisomboon j. outcome of loop electrosurgical excision for hiv-positive women in a low-resource outpatient setting. int j gynecol obstet 2009;105(1):10-13. 21. safaeian m, kiddugavu m, gravitt pe, et al. prevalence and risk factors for carcinogenic human papillomavirus infection in rural rakai, uganda. sex transm infect 2008;84:306-311. http://sti.bmj.com/content/84/4/306 (accessed 14 january 2010). 22. bosch fx, manos mm, munoz n, et al. prevalence of human papillomavirus in cervical cancer: a worldwide perspective. j natl cancer inst 1995;87:796-802. http://www.ncbi.nlm. nih.gov/pubmed/7791229 (accessed 14 january 2010). 23. mckenzie nd, kobetz en, hnatyszyn j, twiggs lb, lucci ja. women with hiv are more commonly infected with non-16 and -18 high-risk hpv types. gynecol oncol 2010;116(3):572. 24. paavonen j, naud p, salmerón j, et al. efficacy of human papillomavirus (hpv)-16/18 as04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic hpv types (patricia): final analysis of a double-blind, randomised study in young women. lancet 2009;374:301-314. http://www.thelancet.com/journals/lancet/article/piis01406736(09)61248-4/fulltext (accessed 20 november 2009). 25. schelcht nf, bick rd, palefsky jm, et al. variants of human papillomavirus 16 and 18 and their natural history in human immunodeficiency virus-positive women. j gen virol 2005;86:2709-2720. http://vir.sgmjournals.org/cgi/reprint/86/10/2709.pdf (accessed 20 november 2009).. 26. qiao y-l, sellors jw, eder ps, et al. a new hpv-dna test for cervical-cancer screening in developing regions: a cross-sectional study of clinical accuracy in rural china. lancet oncol 2008;9(10):929-936. http://www.thelancet.com/journals/lanonc/article/ piis1470204508702109/abstract# (accessed 15 january 2010). 27. mwanahamuntu mh, sahasrabuddhe vv. implementation of ‘see-and-treat’ cervical cancer prevention services linked to hiv care in zambia. aids 2009;23(6):n1-n5. http://www. medscape.com/viewarticle/705167 (accessed 1 july 2010). abstract introduction case discussion conclusion acknowledgements references about the author(s) sibongiseni malinga department of paediatrics, king edward viii hospital, durban, south africa aabida khan department of virology, inkosi albert luthuli central hospital, national health laboratory service (nhls), durban, south africa school of laboratory medicine and medical sciences, university of kwazulu-natal, durban, south africa moherndran archary department of paediatrics, king edward viii hospital, durban, south africa department of paediatrics and child health, faculty of health sciences, university of kwazulu-natal, durban, south africa citation malinga s, khan, a, archary, m. breaking the unbreakable: a paediatric case of dolutegravir resistance from kwazulu-natal. s afr j hiv med. 2023;24(1), a1458. https://doi.org/10.4102/sajhivmed.v24i1.1458 case report breaking the unbreakable: a paediatric case of dolutegravir resistance from kwazulu-natal sibongiseni malinga, aabida khan, moherndran archary received: 22 sept. 2022; accepted: 16 nov. 2022; published: 23 may 2023 copyright: © 2023. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract we report a case of dolutegravir resistance in kwazulu-natal in a 13-year-old male two years after starting dolutegravir. resistance most likely developed due to poor adherence as a result of psychosocial issues. this case highlights the importance of the role of the family unit in impacting adherence and close monitoring of treatment-experienced patients with virologic failure following switching to dolutegravir-based regimens. keywords: paediatrics; dolutegravir; dtg; resistance; hiv; adolescence. what this study adds: numerous challenges affect hiv-infected children and adolescents, impacting adherence, as highlighted in this case. the benefit of hiv drug resistance genotyping to guide the selection of a suitable regimen was shown – there is a need for evidence-based guidelines of indications for resistance testing on dolutegravir. introduction south africa transitioned to dolutegravir (dtg)-based antiretroviral therapy (art) from 2019.1 various studies have demonstrated that dtg-based art is highly effective at achieving viral suppression in both art-naïve and -experienced individuals. dolutegravir has better tolerability, higher genetic barrier to resistance and is available in a fixed-dose combination of tenofovir (tdf), lamivudine (3tc), and dtg for adults and adolescents ≥ 35 kg.1 in south africa, dtg is currently available as a 50 mg tablet for children ≥ 20 kg.1 we present the first paediatric case of dtg resistance identified in a treatment-experienced integrase strand inhibitor (insti)-naïve adolescent in kwazulu-natal. case our index case is a 13-year-old male from a rural area in who acquired hiv through vertical transmission. the mother tested negative during antenatal care, but she was not tested at delivery. he was diagnosed with hiv and pulmonary tuberculosis in 2010, started tuberculosis treatment and later on art. as per the national guidelines, abacavir, 3tc and ritonavir-boosted lopinavir (lpv/r) syrups were initiated1 but it is unclear if he received ritonavir super-boosting during his tuberculosis treatment to overcome the inducing effect of rifampicin. he was diagnosed with tuberculosis again in 2013, again without documentation that lpv/r was super-boosted with ritonavir during treatment. since art initiation, he has never been virally suppressed, despite ongoing enhanced adherence support. figure 1 shows the hiv viral load (vl) and cd4 count timeline after art initiation with no evidence of viral suppression defined as < 50 copies/ml.1 hiv vl is in log10 copies/ml (right vertical axis) and cd4 count is in cells/µl (left vertical axis). hiv vl ≥ 1000 copies/ml (≥ 3 log10 copies/ml) is defined as virological failure.1 figure 1: hiv viral load and cd4 count history. in 2018 hiv drug resistance (dr) genotyping was performed, showing only m184v mutation with no protease resistance mutations, which suggested suboptimal adherence. he was switched to zidovudine (azt) and 3tc, and was started on lpv/r paediatric tablets. the patient received continuous enhanced adherence counselling by the attending doctor and via the social worker. in january 2020, lpv/r was switched to dtg in an attempt to simplify the regimen and decrease the pill burden; however, he remained on azt/3tc as he weighed 28 kg. the vl at the time of the switch was 529 copies/ml and hence a hiv dr test was not performed. however, he remained unsuppressed and admitted to often forgetting his medication as he lacked a treatment supporter. there were major social issues impacting adherence; he is the product of rape by his mother’s older cousin. being a teen mom, and not having disclosed the rape issue to her mother proved to have affected the patient’s mother, as well as her ability to provide optimum care for her child. she was the primary caregiver living with the maternal grandmother and was responsible for bringing him for his hospital appointments, but would sometimes not be available to bring him, and occasionally the patient’s biological father would accompany the patient to hospital but identified himself as the patient’s uncle. in 2017, the father became ill, and the grandmother (not knowing the issues around the rape) took him into their home, resulting in family conflict and missed hospital appointments. in 2019, both the patient’s biological parents died due to aids-related complications. upon discovering for the first time at her daughter’s funeral that her nephew had raped her daughter and infected her with hiv, the patient’s grandmother struggled to accept the situation. as a result, the grandmother avoided involving herself in the healthcare of her grandson including supervising him when taking treatment, or accompanying him to hospital, making addressing the adherence issues and disclosure difficult, requiring a home visit by the social workers. due to poor adherence and patient not suppressing for two years on the dtg-based regimen, despite enhanced adherence counselling, hiv dr was done in april 2022 which showed m184v again and the development of insti mutations (major t66ti, g118r, e138k, minor m50i), conferring high-level resistance to dtg (refer to table 1). table 1: hiv drug resistance genotyping results april 2022. the third-line regimen commenced in may 2022 was tdf, emtricitabine and ritonavir-boosted darunavir once daily. the viral load done after one month was 473 copies/ml with a 2 log10 drop. discussion this case report highlights the complexities and psycho-social factors impacting the management of hiv in children and adolescents. the paediatric population has unique challenges such as disclosure, caregiver issues, challenges with understanding and acceptance of the disease, limited drug options and child-friendly formulations. in this case, family issues with a lack of supervision resulted in suboptimal adherence, which resulted in the emergence of dtg resistance. due to his weight of 28 kg in 2020, he was not eligible for a simple once-daily fixed-dose combination of tdf, 3tc and dtg, which may have improved adherence and potentially prevented dtg resistance. most clinical trials have evaluated dtg in adults. the odyssey (once-daily dtg based art in young people vs. standard therapy) trial done in children and adolescents found that dtg was superior to standard care with lower rates of treatment failure.2 none of the participants on first-line dtg-based art with treatment failure had dtg resistance mutations, while 4/22 (18%) participants with virologic failure on second-line dtg-based art had dtg resistance.2 similarly, in the impaact p1093 study that assessed dtg in treatment-experienced children and adolescents, 8/36 (22%) participants with virologic failure had resistance to dtg.3 the most common mutations selected by dtg in insti-naïve patients are reported to be r263k and g118r.4 r263k reduces dtg susceptibility two-fold, conferring intermediate resistance, while g118r reduces dtg susceptibility by > 5-fold, also conferring intermediate resistance.4 other resistance mutations selected by dtg in insti-naïve patients include e138k/t, n155h, q148k, s230r, t66i and h51y.4 accumulation of mutations further reduces dtg susceptibility. these reported mutations are similar to those found in our case. in sub-saharan africa, real-world cohorts have shown high viral suppression rates in countries that have transitioned to dtg. although dtg is hailed as the silver bullet, it must still be recognised that treatment failure and resistance, especially in treatment-experienced patients with suboptimal adherence, can occur. the potential factors contributing to dtg resistance include poor adherence, dtg monotherapy, advanced hiv and opportunistic infections.5 an evaluation of the advance (dolutegravir plus two different prodrugs of tenofovir to treat hiv) and namsal (new antiretroviral and monitoring strategies in hiv-infected adults in low-income countries) studies highlighted the impact of social and demographic factors on adherence even on dtg-based art with younger age associated with reduced adherence.6 the family unit plays an important role in supporting children and adolescents. decentralisation of care and other avenues of support such as community based family or youth clubs can also help to improve adherence. the value of vl monitoring and dr genotyping is crucial in detecting cases of resistance. with increasing transitioning to dtg, population surveillance for dtg resistance must be implemented. there is also a need for the availability of a wide repertoire of drug options that are effective, tolerable and cost-effective with child-friendly formulations. conclusion this report describes the first case of dtg resistance identified in the paediatric population in kwazulu-natal in a treatment-experienced adolescent. it highlights the impact of family and psychosocial issues on adherence, issues affecting adherence in children and paediatric population (including availability of a caregiver to supervise drinking of medications, coming for hospital appointments, poorly tolerated regimens and the lack of availability of simplified treatment options [fixed-dose combination] for paediatric populations), and the need to closely monitor treatment-experienced patients with virologic failure, even on dtg-based regimens. the availability of the abacavir/3tc fixed-dose combination and dtg dispersible tablet will help address some of these issues and improve adherence. acknowledgements the authors would like to thank the patient and family and mrs leora sewnarain for assistance with formatting and language review. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions a.k., s.m. and m.a. were responsible for the study design, data collection, drafting and finalising of the manuscript. all authors read and approved the final manuscript. ethical considerations the biomedical research ethics committee (brec) of the university of kwazulu-natal approved the research (bca 143/09). funding information the authors received no financial support for the research, authorship, and publication of this article. data availability the data sets used and analysed during the current study are available from the corresponding author, m.a., on reasonable request. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references south african national department of health. national consolidated guidelines for the management of hiv in adults, adolescents, children and infants and prevention of mother-to-child transmission 2019 [homepage on the internet]. february 2020. available from: https://www.knowledgehub.org.za/e-library turkova a, white e, mujuru ha, et al. dolutegravir as first or second-line treatment for hiv-1 infection in children. n engl j med. 2021 dec 30;385(27):2531–2543. https://doi.org/10.1056/nejmoa2108793 vavro c, ruel t, wiznia a, et al. emergence of resistance in hiv-1 integrase with dolutegravir treatment in a pediatric population from the impaact p1093 study. antimicrob agents chemother. 2021 oct 25;66(1):e0164521. https://doi.org/10.1128/aac.01645-21 rhee sy, grant pm, tzou pl, et al. a systematic review of the genetic mechanisms of dolutegravir resistance. j antimicrob chemother. 2019 nov 1;74(11):3135–3149. https://doi.org/10.1093/jac/dkz256 cevik m, orkin c, sax pe. emergent resistance to dolutegravir among insti-naive patients on first-line or second-line antiretroviral therapy: a review of published cases. open forum infect dis. 2020;7(6):ofaa202. https://doi.org/10.1093/ofid/ofaa202 mccluskey sm, pepperrell t, hill a, venter wd, gupta rk, siedner mj. adherence, resistance, and viral suppression on dolutegravir in sub-saharan africa: implications for the tld era. aids. 2021 dec 15;35(supplement 2):s127–s135. https://doi.org/10.1097/qad.0000000000003082 december 2009                                                          the southern african journal of hiv medicine                                                  32 1. goals of therapy n durable suppression of viral load (vl) (undetectable vl using an ultrasensitive assay) n restoration or preservation of immunological function (cd4+ count) n sustained improvement in clinical symptoms and quality of life n reduction in morbidity and mortality. 1.1 family treatment since hiv is usually a disease occurring within families, the following are important: n always enquire about the health and hiv status of the caregivers and other family members. n encourage and assist caregivers to start art if required; ideally families should receive treatment simultaneously in the same facility to avoid inconvenience and unnecessary expense for patients. n hiv testing should be offered and recommended for other family members if their status is unknown. n ascertain and encourage hiv disclosure status of caregivers themselves, the child and other family members. 2. adherence high levels of adherence to antiretroviral therapy (art) are vital for treatment success. the goal is for the patient to receive 100% of scheduled doses. factors that impact on adherence include: n parental/caregiver education: they must understand that poor adherence is the single most important factor for drug failure and resistance, leading to loss of future therapeutic options. n a good health care provider-patient relationship underpins adherence. n motivation and commitment of caregiver/parent to the child’s lifelong therapy. n address any social issues as appropriate. n although unpredictable events can acutely impact on adherence (e.g. severe illness or death of a parent), frequent visits and good communication may help to anticipate and pro-actively plan for such events guidelines for antiretroviral therapy in children – november 2009 version guidelines conveners: prof. mark cotton and dr leon levin writing committee: prof. mark cotton, dr leon levin and dr tammy meyers expert panel members: profs ashraf coovadia, mark cotton, brian eley, glenda gray, prakash jeena, simon schaaf; drs moherndran archary, lee fairlie, ute feucht, leon levin, pippa macdonald, tammy meyers, harry moultrie, kimesh naidoo, james nuttall, helena rabie, paul roux , lizzy tabane, avy violari, marnie vujovic; ms liezel pienaar international reviewers: drs stephane blanche, ann melvin, gareth tudor williams, andrew wiznia with thanks to dr claire von mollendorf for her assistance in the section on drug interactions. these guidelines are intended to provide paediatric hiv antiretroviral treatment (art) recommendations for both the public and private sectors. art in children follows the same principles as in adults, and treaters should not be daunted by some of the differences, which include more frequent dose adjustments, liquid formulations occasionally being poorly palatable, and the dependence of children on adult caregivers for receiving medication. these should not be viewed as obstacles, and everything should be done to assist the process of treating children. since the last publication of these guidelines there have been pivotal paediatric studies that have necessitated the updating of paediatric guidelines in south africa. the southern african journal of hiv medicine                                                        december 2009   33 talking about adherence working with the client a short checklist of points should include: n checking caregiver’s capacity to understand treatment plan/adherence (intellectual/developmental level, literacy) n checking the basic facts about art n explaining adherence and why it is important n explaining common art side-effects and likely course n explaining that symptoms associated with other illnesses (i.e. vomiting, diarrhoea, cough, fever, rash) overlap with drug toxicity and are not a reason to stop therapy. however, if an acute illness (acute gastro-enteritis) occurs and the child is unable to tolerate medications, it is permissible to stop all meds for a short period of time n exploring the caregiver’s readiness to start the child on antiretroviral therapy n assessing the level of commitment to art adherence n assessing the caregiver’s perception of the advantages and disadvantages of being on art. discussion should include an assessment of the caregiver’s psychosocial situation. this covers: n exploration of the caregiver’s lifestyle (e.g. work, daily routine, sleep, other responsibilities) n exploration of the caregiver’s personality traits (e.g. sense of organisation, self-discipline and responsibility) n assessment of the caregiver’s own hiv status and health and lifestyle choices (use of alcohol and drugs) (remember – hiv infection in adults not yet on art can cause cognitive impairment) n possible use of alternative/complementary medicine n exploration of the caregiver’s financial and material resources. it is also necessary to explore possible barriers to adherence as well as sources of support, including: n discussion around disclosure (e.g. how much the child knows about own status/how much other household members know about child’s status/reasons for not wanting to disclose to child/others if applicable). disclosure is an evolving process requiring an active plan and involvement of the parent/caregiver n exploration of the current and potential sources of support n problem solving with regard to barriers n anticipation of events that might present an obstacle to adherence, e.g. school trips, visits to grandparents. finally, a specific adherence plan is developed in collaboration with the client (and child where appropriate). the plan should specify: n the treatment regimen (specifics of medication, doses and the intervals at which the medication should be given). remember that the same drug may have many names (formula, generic, trade, fixed-dose combinations), which may be confusing to patients and families n possible side-effects, what to do and who to contact in the case of serious side-effects n ways of integrating treatment into the daily routine of the caregiver/child, especially the specific times the medication will be given. the plan should be individualised and the health care professional is encouraged to provide practical aids and supportive information sheets. demonstration of dosage and method of administration by the counsellor as well as by the caregiver is important. social disruption or catastrophic events can happen at any time and could affect adherence. events such as loss of a caregiver or severe illness in a caregiver should be mentioned, with possible solutions. tips in the case of school-age children and adolescents, it is important that adult caregivers are available to supervise. routine is reassuring: caregivers should try to give medication in the same way, at the same time and in the same place every day. caregivers should be encouraged to: december 2009                                                          the southern african journal of hiv medicine                                                  34 additional factors enhancing adherence include: n children should be taught to swallow pills/capsules as early as possible (from about 4 years). this can be done using appropriately sized sweets. liquid formulations may have an unpleasant taste or involve administering large volumes of liquids. n ideally the caregiver should identify and disclose to one other person in the home who can help with treatment (treatment buddy) as a back-up and enhance treatment support. n dosages of liquid formulations should be rounded up to a convenient volume. n syringes for liquid formulations should be marked at the correct dosage with a blade or permanent marker. show the caregiver how to draw up the correct volume and expel excess air. make sure that the syringes are appropriately cleaned. n each liquid medicine and its syringe should be colourcoded to prevent confusing medicines and dosages. n ensure that the caregiver’s eyesight is adequate to administer medication accurately. n teach caregivers to open childproof containers. n medications should fit into the patient’s lifestyle. for example, twice-daily medication does not have to be given strictly 12-hourly, rather at a convenient time. it is far better to give a dose later than usual than not to give the medication at all. n too many caregivers involved in administering medicines can be an obstacle to good adherence. a different caregiver accompanying the child to n remind the child that medicines are important and will help to keep him or her from getting sick. n be positive and consistent when it comes to giving the child medicine. n always say something positive when the child has taken his/her medication. n reward the child with a sticker or a star on a record chart or calendar or other age-appropriate token. n allow the child to earn a special treat for sticking to his/her schedule (e.g. a small weekly treat and a bigger monthly treat. avoid monetary rewards; a story or a favourite meal is more than adequate). n get other people who care about the child to encourage and reward him/her for taking medication. n anticipate and talk about possible problems before they arise. n be flexible with the treatment plan. accommodate change (e.g. in the scheduled time of doses) if this would result in better adherence. n think of possible simplification of the regimen. n ask about any side-effects. suggest ways to manage less serious side-effects and indicate the likelihood of relatively short duration. n ask about other medication that the child may be taking in order to avoid possible drug interactions and better co-ordinate dosing of all medications. n anticipate possible adherence fall-off during times of increased stress. make time to discuss and deal with problems and feelings. n vomiting after taking medication: make sure that the caregiver knows that if a child vomits within 30 minutes of taking a medication the dose should be repeated. some tools and strategies n setting an alarm on an alarm clock n setting a cell phone alarm or reminder n using a pillbox n using a diary card n using a wall calendar n keeping a treatment diary n sending sms reminders to the caregiver n using daily tv or radio programmes as cues n using mealtime (breakfast and supper) as a cue n having a treatment supporter n having a treatment buddy (another child, also on treatment) n keeping medication in a familiar place and not hidden or locked up n using directly observed treatment support (dots) as for tb if needed. the southern african journal of hiv medicine                                                        december 2009   35 each appointment is a warning sign, requiring exploration. n emphasise good adherence at each visit. it is useful to compare art with therapy for diabetes and hypertension, both conditions requiring lifelong therapy and in which poor adherence is associated with disease progression. hiv is a chronic, manageable condition, with minimal morbidity, if the correct approach is taken. n it is useful to monitor whether treatment is being collected. 3. indications for starting art in children first assess the child clinically and stage the child according to the world health organization (who) staging system (table i) to determine whether the child needs art or not (note: all infants diagnosed <12 months of age should be started on art regardless of clinical or immunological staging). if the child is clinically well, cd4 testing will further ascertain whether the child needs art. clinical stage 1 asymptomatic persistent generalised lymphadenopathy clinical stage 2 unexplained persistent hepatosplenomegaly papular pruritic eruptions extensive wart virus infection extensive molluscum contagiosum fungal nail infections recurrent oral ulcerations unexplained persistent parotid enlargement lineal gingival erythema herpes zoster recurrent or chronic upper respiratory tract infections (otitis media, otorrhoea, sinusitis or tonsillitis) clinical stage 3 unexplained moderate malnutrition not adequately responding to standard therapy unexplained persistent diarrhoea (14 days or more) unexplained persistent fever (above 37.5°c intermittent or constant for longer than one month) persistent oral candidiasis (after first 6 8 weeks of life) oral hairy leukoplakia acute necrotising ulcerative gingivitis or periodontitis lymph node tuberculosis pulmonary tuberculosis severe recurrent bacterial pneumonia symptomatic lymphoid interstitial pneumonitis chronic hiv-associated lung disease including bronchiectasis unexplained anaemia (<8 g/dl), neutropenia (<0.5×109/l) and/or chronic thrombocytopenia (<50×109/l) clinical stage 4i unexplained severe wasting, stunting or severe malnutrition not responding to standard therapy pneumocystis pneumonia recurrent severe bacterial infections (such as empyema, pyomyositis, bone or joint infection or meningitis but excluding pneumonia) chronic herpes simplex infection (orolabial or cutaneous of more than 1 month’s duration or visceral at any site) extrapulmonary tuberculosis kaposi’s sarcoma oesophageal candidiasis (or candidiasis of trachea, bronchi or lungs) central nervous system toxoplasmosis (after 1 month of life) hiv encephalopathy cytomegalovirus infection: retinitis or cytomegalovirus infection affecting another organ, with onset at age older than 1 month extrapulmonary cryptococcosis (including meningitis) disseminated endemic mycosis (extrapulmonary histoplasmosis, coccidiomycosis) chronic cryptosporidiosis chronic isosporiasis disseminated non-tuberculous mycobacterial infection cerebral or b-cell non-hodgkin’s lymphoma progressive multifocal leuco-encephalopathy symptomatic hiv-associated nephropathy or hiv-associated cardiomyopathy hiv-associated rectovaginal fistula table i. who clinical staging of hiv/aids for children with confirmed hiv infection december 2009                                                          the southern african journal of hiv medicine                                                  36 the cher study 1 demonstrated that: n by 6 weeks of age 20% of infants already had severe immunosuppression. n in relatively asymptomatic infants, starting art before 3 months of age reduced the mortality rate by 76%. as a result of this research, all international art guidelines now recommend immediate art for all hivpositive infants <12 months of age, irrespective of the clinical or immunological status (table ii). in the infant, art should be started as soon as possible after diagnosis, preferably within 2 weeks. 4. initiation of therapy note: for young infants initiation of treatment should be rapid, with ongoing counselling while on arvs. 4.1 first 1 2 visits full clinical examination, including accurate baseline weight, height, and for children <2 years, head circumference measurement. bloods should be taken for hiv vl and cd4+ count. counselling and information – topics to be covered include: n hiv prognosis n treatment options n adherence n drug formulations n taste issues (including taste test where appropriate) n initiate prophylaxis as indicated n ensure family/caregivers have contact details for staff in case of any questions/adverse events. 4.2 next visit if therapy is indicated and if the family is adequately counselled and able to continue to maintain adherence, dispense drugs. graphically illustrate the drugs and how and when to take them, preferably with actual drugs or samples. consider observing initial administration of the drugs. 4.3 day 2 of treatment if possible, a quick phone call to make sure that everything is in order is a good idea. 4.4 1 2 weeks later a phone call to the caregiver/parent is recommended to discuss tolerance and adherence issues. the government roll-out programme recommends a 2-week visit where adherence is discussed and medication technique is checked. 4.5 one month after starting treatment the clinician should conduct a general examination and draw blood to monitor drug toxicity (in national department of health (ndoh) guidelines, only if on tuberculosis (tb) treatment or on zidovudine (azt)). tolerance and adherence issues should be discussed. it may be useful to ask how many doses have been missed in the last 3 days, and how many in the last month. in young children weight gain can be surprisingly rapid. check whether doses need to be increased. 4.6 three months after starting treatment the clinician should conduct a general examination and draw blood to monitor drug toxicity. check weight and alter doses accordingly. bloods should also be taken for hiv vl and cd4+ count. in the ndoh guidelines, bloods would only be drawn if clinically indicated for suspected toxicity, if on azt or if co-treated for tb. adverse effects, tolerance and adherence issues should be discussed with the caregiver. 4.7 three-monthly thereafter the clinician should conduct a general examination and draw blood for drug toxicity, hiv vl and cd4+ count. ndoh guidelines recommend 6-monthly bloods with 3monthly clinical checks. check weight and alter doses accordingly. if the patient’s results remain stable, clinical examinations and blood tests can be carried out 6monthly, but children aged less than 2 years need to be seen at least 3-monthly to adjust drug doses according to growth. discuss adverse effects, tolerance and adherence issues with the caregiver at every visit. age clinical stage cd4 criteria <1year all infants any cd4 1 5 years who stage iii, iv cd4 ≤25% absolute cd4 <750 cells/µl >5 years who stage iii, iv cd4 <350 cells/µl table ii. criteria for art initiation the southern african journal of hiv medicine                                                        december 2009   37 5. monitoring: special considerations for children (table iii) 5.1 viral load recent reports on outcomes on art of children from resource-poor centres demonstrate that undetectable vls are initially achieved in over 80% of treatment-naïve children. 2 vls should be measured at baseline and then 3 6-monthly. in the ndoh guidelines vl testing is recommended at 6-monthly intervals unless there is a clinical indication to do it earlier. a recent metaanalysis suggests that vl monitoring at intervals of ≥3 months was associated with a significantly lower risk of resistance mutations at the time of failure. 3 therapeutic options for children are currently limited. the decision to switch therapy because of suboptimal response should therefore be carefully considered and balanced against the risk of accumulating additional resistance in a non-suppressive regimen. although there is no consensus, a growing number of international experts advise aggressively achieving and maintaining viral suppression. note: n a repeat test is recommended whenever a routine measurement yields an unexpected result. it is usually not worth doing routine plasma hiv rna levels during an intercurrent infection. additional non-routine testing may be indicated if the clinical condition changes. n two measurements should be performed 1 month apart before instituting changes. n vls can be temporarily raised for up to a month after intercurrent infection or vaccination. n patients should be sequentially tested using the same method and the same laboratory. n the ndoh has decided to omit the baseline vl in order to save costs. since the baseline vl doubles as a confirmatory test for infants diagnosed by pcr, it is strongly recommended that the baseline vl still be done in infants diagnosed by pcr. 5.2 cd4+ lymphocyte counts and percentages the cd4+ count should be measured with the vl, except when the vl is repeated for an unexpected result. absolute cd4+ lymphocyte counts are much higher in infancy than adulthood, but the cd4+ percentage is more constant, although also higher in children <2 years. cd4+ percentages may be easier to work with, but cd4+ counts should also be used. over the age of 5 years, adult cut-offs using cd4 counts can be used for therapeutic decision making. lymphopenia and lymphocytosis may overor understate cd4 percentages or counts. cd4+ counts/percentages are useful for monitoring response to arvs. vl changes will typically precede changes in cd4 counts. cd4+ counts can be temporarily lowered by intercurrent infections or vaccinations, taking up to a month to recover. although there is a strong association between cd4+ depletion and opportunistic diseases, pneumocystis jirovecii pneumonia (pcp) may occur in the first year of life despite ‘normal’ counts for age. 5.3 height and weight the ‘road to health’ chart is a valuable tool for monitoring the well-being of children. failure to maintain growth is suggestive of progressive hiv disease or superimposed infection such as tb. test baseline 2 weeks (nvp) 1 month* 3 months* 6 months 3 6monthly thereafter* additional annual tests viral load x† x x x cd4 x x x x fbc with differential x x x x x alt x x x x x x cholesterol x triglycerides x glucose x urine dipstix x x *ndoh guidelines recommend 6-monthly monitoring. †ndoh guidelines recommend not to do a baseline vl as a cost-saving practice. it is imperative that a baseline vl be done in all infants diagnosed on pcr as this doubles as a confirmatory test. do not delay initiation of haart while awaiting the confirmatory test result. fbc = full blood count; alt = alanine transaminase. table iii. routine monitoring december 2009                                                          the southern african journal of hiv medicine                                                  38 6. recommended arv regimens art drugs are listed in table iv, and dosages in table v. simplified weight-based dosing is set out in fig. 1. 6.1 preferred regimens first line <3 years: 3tc + abacavir + lopinavir/ritonavir. >3 years and >10 kg: 3tc + abacavir + efavirenz. alternate first line <3 years: 3tc + stavudine + lopinavir/ritonavir. >3 years and >10 kg: 3tc + stavudine + efavirenz. this is the regimen currently recommended by the ndoh. there are major concerns about d4t toxicity, especially lipodystrophy. stavudine should be changed to abc at the first sign of lipodystrophy. in addition, zidovudine as part of second-line therapy will be compromised by resistance to stavudine. consider a boosted pi as the third drug in a child over 3 years exposed to sd-nvp or where there are concerns about adherence. rationale for choice of regimen 3tc and abc backbone: n very good long-term data from penta 5. 4 n spares thymidine analogue for next regimen. n both drugs select for the same resistance pathway (m184v). n abc should only be used for first line (without genotyping) since >3 tams + m184v confers high level cross-resistance to abc. n hypersensitivity is linked to hla b*5701, which is extremely uncommon in the black population. the arrow study of >1 200 hiv-infected children in uganda and zimbabwe had a hypersensitivity reaction rate of 0.2%. n tenofovir should not be used in children because of potential toxicity issues. lopinavir/ritonavir in children <3 years data show that young children have far better viral suppression on a boosted pi regimen than on an nnrti regimen 5 (irrespective of single-dose nvp). in addition the impaact p1060 study indicates that in sd-nvpexposed infants, those starting nvp-based regimens have poorer virological outcomes than those starting a boosted pi regimen. 6 7. drug interactions there are multiple opportunities for serious drug interactions. treaters are advised to scrutinise package information and seek advice if uncertain. n rifampicin reduces levels of lopinavir, indinavir, saquinavir, atazanavir, fosamprenavir (pis) and nevirapine and should not be used with any of these drugs. n efavirenz causes reduced levels of clarithromycin, but not azithromycin. n ritonavir should not be given with numerous drugs. n of the anti-epileptic drugs, sodium valproate is the safest to use with antiretrovirals. n ritonavir inhibits cytochrome p450 3a4, preventing metabolism of inhaled steroids, thereby facilitating systemic absorption and cushing’s syndrome. rather use an nnrti if the patient is on inhaled or nasal steroids, or consult the hiv clinicians society if this is not feasible. n oral contraceptives. there are limited data available on potential drug interactions between many arvs (particularly some nnrtis and rtv-boosted pis) and hormonal contraceptives, which may modify their safety and effectiveness. rtv-boosted pis are not recommended with combined or category i nrti – thymidine base stavudine (d4t)* zidovudine (zdv)* category ii nrti – other didanosine (ddi)*† lamivudine (3tc)* emtricitabine (ftc) abacavir (abc)* ntrti tenofovir (tdf)‡ category iii nnrti nevirapine (nvp)* efavirenz (efv)¶ etravirine (etr)§ category iv pi ritonavir (rtv)* lopinavir/ritonavir (lpv/rtv)* saquinavir (sqv) indinavir (idv)‡ darunavir (drv)§ atazanavir (atv)‡ fosamprenavir (fpv) category v integrase inhibitors raltegravir§ category vi ccr5 inhibitors maraviroc§ *available in paediatric formulations. †enteric-coated formulation for adults can be used (especially when given once instead of twice daily). ‡not available in paediatric formulation. ¶efv is only available in capsule form and tablet form. there are no data for children under 3 years of age or <10 kg. §paediatric dosage still uncertain. requires section 21 authorisation from the medicines control council. nrti = nucleoside reverse transcriptase inhibitor; ntrti = nucleotide reverse transcriptase inhibitor; nnrti = non-nucleoside reverse transcriptase inhibitor; pi = protease inhibitor. table iv. art drugs the southern african journal of hiv medicine                                                        december 2009   39 drug formulations dosage (per dose) frequency storage comments nucleoside reverse transcriptase inhibitors (nrtis) zidovudine (azt, zdv) retrovir® generics susp: 10 mg/ml caps: 100 mg, 250 mg, tabs 300 mg neonates 4 mg/kg/dose until 29 d, then 240 mg/m2 2 2 room temperature may be taken with or without food didanosine (ddi) videx® generics susp: 10 mg/ml tabs: 25 mg, 50 mg, 100 mg, 150 mg enteric-coated didanosine (ec) 250 mg, 400 mg 2 wks 3 mo. of age: 50 100 mg/m2/dose >3 mo. of age: 90 120 mg/m2/dose 2 2 can give total daily dosage × 1 refrigerate suspension half hour before or 1 hour after meal use single daily dose if necessary for adherence. give at least 2 tabs of buffered formulation. needs to be separated from pi by 1 2 hours. ec ddi still needs to be taken on empty stomach but can be given together with pi ec ddi capsules can be opened and sprinkled on food stavudine (d4t) zerit® generics susp: 1 mg/ml caps: 15 mg, 20 mg, 30 mg, 40 mg neonates <2 wks of age: 0.5 mg/kg/dose thereafter 1 mg/kg/dose (max 30 mg/dose) 2 2 refrigerate suspension may be taken with or without food. capsules stable in water suspension for 24 hours at room temperature abacavir (abc) ziagen® generics susp: 20 mg/ml tabs: 300 mg kivexa® tabs = 600 mg abc & 300 mg 3tc all ages: 8 mg/kg/ dose ≥25 kg: 1 tab or 2 tabs kivexa® if ≥25 kg – 1 tab 2 2 1 1 room temperature may be taken with or without food watch for hypersensitivity reaction (hsr). do not rechallenge if hsr occurs if being given as suspension with 3tc, the two volumes should always be equal lamivudine 3tc (3tc®) generics susp: 10 mg/ml tabs: 150 mg, 300 mg kivexa® tabs = 600 mg abc & 300 mg 3tc neonates: 2 mg/kg paediatric (>1 month): 5 6 mg/kg ≥25 kg: 1 × 150 mg tab or 2 × 150 mg tab or 1 × 300 mg tab 2 2 2 1 1 room temperature may be taken with or without can food use tablets from 25 kg nucleotide reverse transcriptase inhibitors (ntrtis) tenofovir (tdf) viread® tablets 300 mg truvada® = 300 mg tdf + 200 mg ftc atripla®* = 300 mg tdf + 200 mg ftc + 600 mg efv* 8 mg/kg/dose 8 mg/kg/dose of tdf component 1 1 room temperature should not be routinely used in children <18 years – concerns about osteopenia and renal toxicity. may have a place in salvage in older children. consult with a paediatric hiv expert. viread tablets irregular shape – difficult to halve. may be taken with or without food. dose adjustment required with renal impairment non-nucleoside reverse transcriptase inhibitors (nnrtis) nevirapine (nvp) viramune® generics susp: 10 mg/ml tabs: 200 mg infants (>14 days) and children: 150 200 mg/m2/dose give dose once daily for first 14 days and increase to bd if no rash or severe sideeffects occur 2 room temperature may be taken with or without food skin rash usually occurs in 1st 6 weeks; do not increase dosage until rash resolves watch for liver toxicity try to maintain dosage >150 mg/m2/dose bd table v. dosage and frequency of arvs in children december 2009                                                          the southern african journal of hiv medicine                                                  40 progesterone-only oral contraceptives, while nnrtis can be used. a combined oral contraceptive containing at least 30 µg of ethinyl oestradiol should be used. progesterone-only injectables can be used with all arvs. concomitant consistent condom use is recommended for preventing hiv transmission drug formulations dosage (per dose) frequency storage comments non-nucleoside reverse transcriptase inhibitors (nnrtis) efavirenz (efv) stocrin® generics tabs: 50 mg, 200 mg, 600 mg caps: 50 mg, 200 mg 10 <15 kg: 200 mg 15 < 20 kg: 250 mg 20 <25 kg: 300 mg 25 <32.5 kg: 350 mg 32.5 <40 kg: 400 mg >40 kg: 600 mg 1 room temperature no data <3 yrs and <10 kg tablets cannot be crushed. use generic capsules in children unable to swallow tablets. capsules can be opened & given with food give at night to avoid cns side-effects anticipate mild transient rash and cns side-effects protease inhibitors (pis) atazanavir (atv) reyataz® capsules:150 mg, 200 mg from 6 years of age: 205 mg/m2 6 18 years: 15 <25 kg: atv 150 mg + rtv 80 mg 25 <32 kg: atv 200 mg + rtv 100 mg 32 <35 kg: atv 300 mg + rtv 100 mg >35 kg: atv 300 mg + rtv 100 mg, both given once daily with food 1 ideally should always be used with rtv boosting (unboosted atv requires a higher dose and gives unpredictable plasma levels) give with food unconjugated hyperbilirubinaemia may occur and as long as the patient is comfortable with it, is not a reason to discontinue the drug fosamprenavir (fapv) telzir® tablets 700 mg oral suspension, 50 mg/ml 2 5 years: 20 mg/kg/dose (max. dose 700 mg) + rtv 3 mg/kg/dose (max. dose 100 mg) 6-18 years: 18 mg/kg/dose (max. dose 700 mg) + rtv 3 mg/kg/dose (max. dose 100 mg) 2 2 2 2 room temperature ideally should always be used with rtv boosting (unboosted fapv requires a higher dose) give suspension with food and tablets with or without food lopinavir/ ritonavir (lpv/r) kaletra® aluvia® oral solution (kaletra®) 80 mg lopinavir (lpv) & 20 mg ritonavir (rtv) per ml kaletra® capsules 133 mg lpv/33 mg rtv aluvia® tablets 200 mg lpv/50 mg rtv aluvia® half-dose (hd) tablets* 100 mg lpv/25 mg rtv 300 mg/m2/dose lpv component (max. 400 mg lpv = adolescent dose) 2 capsules should be refrigerated oral solution should be refrigerated until dispensed can be kept at room temperature up to 25ºc if used within 6 weeks aluvia tabs can be stored at room temperature aluvia® tabs can be given with or without food. aluvia tabs must be swallowed whole crushing the tabs reduces the absorption of the drugs kaletra solution and capsules: administer with food. high fat meal increases absorption, especially of the liquid preparation if co-administered with buffered ddi, ddi should be given 1 hour before or 2 hours after lopinavir/ritonavir aluvia® can be taken with ec didanosine on an empty stomach dose adjustments required if lpv/r used in combination with nnrtis kaletra® capsules are being discontinued table v. dosage and frequency of arvs in children (continued) the southern african journal of hiv medicine                                                        december 2009   41 and to compensate for any possible reduction in the effectiveness of the hormonal contraceptive. n lpv/r co-administration can increase tenofovir levels by 30%, and may result in increased renal and bone toxicity. the following website may be of assistance in assessing potential interactions: http://www.hiv-druginteractions.org/frames.asp?drug/ drg_main.asp 8. additional practical points 8.1 practical dosing although paediatric dosages are calculated using the child’s weight or surface area, one must consider the practicalities of the dose. for example, 1.75 ml is very difficult to measure accurately, so a more practical dose is 2 ml (generally round upwards). certain arv solutions, e.g. lpv/rtv (kaletra) or rtv (norvir) are highly concentrated, so dosages do need to be calculated to the nearest 1/10th of a ml (but it is not necessary to calculate to the nearest 1/100th of a ml). others, e.g azt, 3tc, nvp (viramune) or abc (ziagen) solutions, can quite safely be rounded up to the nearest ml. the volume of 3tc and abc should always be the same, which makes dosing easier for caregivers. when using d4t capsules dissolved in water, dosages can be rounded up to the nearest 5 mg. every effort should be made to switch to tablets or capsules as soon as possible. certain drugs should still rather be dosed according to surface area, but where this is difficult the weight-based chart (fig. 1) can be used. kivexa kivexa is a fixed-dose combination tablet containing 300 mg 3tc and 600 mg abc. it is dosed as 1 tablet once a day and can be given to children >25 kg who can swallow this large tablet. it is particularly useful in older children to facilitate adherence. atazanavir (reyataz) atv is a useful pi. it has the advantage of minimal lipid disturbances (although rtv boosting will cause some elevations of cholesterol and triglycerides). it should generally always be given with rtv boosting. its advantages include once-daily dosing, a low pill burden and a good safety and tolerability profile. for this reason atv may be a preferable alternative to aluvia in pi-naïve older children in the private sector with adherence issues. it is best not to use atv in pi-experienced patients unless one knows that no or limited pi mutations are present. drug formulations dosage (per dose) frequency storage comments protease inhibitors (pis) ritonavir (rtv) norvir® susp: 80 mg/ml capsules: 100 mg no longer recommended for use as full-dose single pi >1 mo.: 350 450 mg/m2/dose for pharmacological boosting of other pis: see individual pi concerned boosting dose of rtv when used with rifampicin and lpv/r: same dose in mg as lpv. alternatively ¾ (volume) of kaletra dose 2 2 2 take with food bitter: coat mouth with peanut butter or give with chocolate milk. take 2 hours apart from didanosine can be taken together with ec didanosine saquinavir (sqv) invirase® – hard gel capsule hard gel capsules (hgc) 200 mg (only use together with rtv) sqv 50 mg/kg rtv 100 mg/m2 adolescent /adult sqv 1 000 mg rtv 100 mg 2 2 2 2 should always be used with rtv boosting administer within 2 hours of a full meal to increase absorption sun exposure can cause photosensitivity reactions; sunscreen or protective clothing recommended *awaiting mcc approval. available with section 21 authorisation. body surface area (m2) = √ (height (cm) × weight (kg) ÷ 3 600). table v. dosage and frequency of arvs in children (continued) december 2009                                                          the southern african journal of hiv medicine                                                  42 8.2 timing of dosing there is a common misconception that arvs need to be given exactly 12 hours or 24 hours apart. this is because older drugs with very short half-lives needed to be dosed exactly on time. however, there is much more flexibility with the drugs in current use. drugs with twice-daily doses can generally be given between 10 and 14 hours apart. for drugs that are dosed with meals, the best approach is to give them strictly twice daily with breakfast and supper. it is clearly much more important to fit the drugs into our patients’ lifestyles than vice versa. fig. 1. weight-based dosing chart. the southern african journal of hiv medicine                                                        december 2009   43 8.3 haart after failed mtct prophylaxis n where nevirapine was used as a single dose in prevention of mother-to-child (pmtct) prophylaxis. in the hivnet 012 study, up to 45% of hiv-infected infants had nnrti-associated resistance mutations after 1 dose of nvp to the mother and the infant. there are good data in adults and infants suggesting reduced efficacy of future nnrti-containing highly active antiretroviral therapy (haart) regimens. results from p1060 also indicate that in children who have been exposed to nnrtis for pmtct, there is an increased risk of virological failure when nvp is used subsequently for treatment. 6 it is therefore advisable to avoid nevirapine and efavirenz as part of first-line therapy in this situation. n if azt monotherapy was used in mtct prophylaxis. data support its use in combination therapy for infected infants. resistance has, however, been described. n if the mother was on triple combination therapy. in this situation, do genotyping on the baby and design a regimen accordingly. if unable to do genotyping, avoid the drugs the mother was taking, especially if she had a detectable vl. if the mother had an undetectable vl, it is probably acceptable to use the same agents in her hiv-infected baby. 8.4 tuberculosis treatment and haart in coinfected children rifampicin increases the breakdown of pis and nnrtis. also, there are overlapping toxicities between tb drugs and arvs. the immune reconstitution inflammatory syndrome (iris) causes morbidity and higher risk of mortality. iris can be misinterpreted as progression of tb or medication side-effects. in addition, the increased pill burden can impact on adherence. options when to start arvs: n since tb is a clinical stage 3 disease, most children will need to be started on art. art should be initiated 2 4 weeks after starting tb treatment. this may reduce the likelihood of immune reconstitution disease and will allow time to identify early adverse events from anti-tb drugs. n if the cd4 count is normal and the child is >12 months old, initiation of art may be delayed until completion of tb treatment. (allow 2 weeks for the effects of rifampicin on the liver to ‘wash out’.) n if the child is already on art when tb is diagnosed, continue art with tb treatment. monitor for iris and adapt arvs as required. what regimen to use: n try to make a bacteriological diagnosis. submit all sputa and gastric washings for mycobacterial culture. all isolates require speciation into mycobacterium tuberculosis and m. bovis-bcg and drug susceptibility testing. make every effort to exclude multidrugresistant (mdr) tb in the patient and in the source case. n use standard tb treatment (i.e. a rifampicin-based regimen). n arv regimens: >3 years: 2 nrtis + efavirenz (standard dose) <3 years: 2 nrtis + superboosted lpv/rtv 300 mg/ m 2 /dose bd + extra ritonavir (dosed at 0.75 × volume of lpv/r) bd to achieve per mg equivalence for lpv and rtv). if rtv is not available, one can consider giving lpv/r 600 mg/m 2 /dose bd. however, one should revert to superboosted lpv/rtv when rtv becomes available. the efficacy and toxic side-effects of this approach are unknown. recent pharmacokinetic data show that super-boosted lpv/r yields good levels of lpv whereas simply doubling the dose yields suboptimal levels. 7 8.5 specific issues for adolescents these issues apply to both vertically and sexually transmitted hiv. n non-adherence is often a problem, and strategies should be introduced to promote adherence, including more frequent visits and intensive counselling. n adult supervision of treatment should continue throughout adolescence and includes verification that the medicine has been swallowed. n disclosure of hiv status must have occurred before onset of sexual activity. n adolescent-friendly services include: n a specific convenient day set aside for adolescent clinics n adolescent groups and peer support groups n access to family planning, sexually transmitted infection (sti) treatment, cervical cancer prevention and screening and gynaecological services n human papillomavirus vaccination. 8.6 changing therapy for toxicity or intolerance, a simple substitution can be made, being mindful of previous therapies that may have failed. do not reduce dosage unless the reduced dose is still in the therapeutic range. for failure of a regimen, proceed as outlined below. december 2009                                                          the southern african journal of hiv medicine                                                  44 failure of first-line therapy if viraemia occurs, even at a low level, check and encourage adherence. also check dosages or other ‘technical problems’. these include vomiting or spitting out medications and not receiving meds on time. if the vl is persistently >5 000 copies/ml on two or three occasions despite good adherence and technical problems having been resolved, consider changing regimens. be sure to resolve the adherence problems before changing therapy, otherwise the second regimen will fail. on the other hand, continuing with a failing regimen results in ongoing viral replication with the development of new mutations and cross-resistance, thus limiting future options. resolving adherence issues is paramount for any child failing art. in children on a pi-based first-line regimen, adherence interventions may be sufficient. on the other hand, failing an nnrti-based regimen invariably requires a regimen change after resolving adherence issues. see below for choice of second-line regimen. since virological failure usually precedes immunological and clinical failure, by changing on virological criteria, one can hopefully prevent clinical and immunological deterioration. when failure is due to viral resistance, at least two new active drugs should be used. previous drug history and genotyping (see below) are helpful in deciding on a new regimen. in the case of nnrti resistance n there is no place for maintaining patients failing an nnrti regimen on the same regimen; the longer it is maintained, the more resistance mutations are likely to occur. n the regimen should be changed to a boosted pi with 2 active nrtis (based on genotyping if possible). in the case of pi resistance n patients on a boosted pi regimen not suppressing may have no pi and minimal nrti mutations, in which case the original regimen may be resumed after addressing the adherence issues. n in nnrti-naïve patients with no nnrti and at least 2 fully active nrtis on genotyping, a simple switch to 2 nrtis + nnrti may be appropriate. n patients with multiple pi mutations may achieve viral control when some of the newer agents not yet registered in south africa are used. consult an expert. failure of second-line or subsequent regimens in this situation, consult an expert. 8.7 resistance nucleoside analogues resistance is slow to develop, except for 3tc. resistance to 3tc occurs within weeks on a non-suppressive regimen. useful benefits of 3tc resistance are the partial reversal of azt, d4t and tdf resistance and rendering hiv less pathogenic (m184v mutation). non-nucleoside reverse transcriptase inhibitors there is complete cross-resistance between the currently available nnrtis. a patient resistant to nvp will also have resistance to efavirenz (despite what the genotyping indicates). this does not apply to the new second-generation nnrti (not yet available in south africa) etravirine, which needs a few nnrti mutations for high-level resistance. for this reason, a patient failing an nnrti should change regimens soon to prevent compromising this future option. protease inhibitors the boosted pis are very slow to develop resistance and need several mutations before high-level resistance occurs. in a pi-naïve patient who fails a boosted pi, it is generally accepted that resistance mutations do not occur over a short period of time. however, if a patient has pi mutations from previous pi failure, new mutations can occur even with a boosted pi. resistance testing at present only genotypic resistance testing is available in south africa. genotyping is still expensive (±r4 400). genotyping will only provide information about resistance to the current regimen, and not necessarily about previous art the child may have been exposed to. for this reason genotyping needs to be interpreted in conjunction with a detailed art history. the interpretation is complicated and should be done in conjunction with an expert. ideally genotyping should be done in any child whose vl is persistently above 5 000 copies/ml despite good adherence. genotyping is also indicated for infants infected despite maternal haart, before starting art. contact the south african hiv clinicians society for further information on when to perform and interpreting genotyping. 8.8 choice of second-line regimen patient failing abc/3tc/efv or d4t/3tc/efv second-line choice: azt + ddi + lpv/r. genotyping, if available, may suggest an easier alternative regimen. discuss with an expert. the southern african journal of hiv medicine                                                        december 2009   45 patient failing abc/3tc/lpv/r or d4t/3tc/lpv/r current ndoh guidelines recommend azt + ddi + nvp (<3 years) or efv (>3 years). some experts feel that this regimen is prone to failure. it is advisable to do resistance testing and /or discuss with an expert to devise a suitable second-line regimen. after changing regimens, there should be frequent adherence and toxicity checks. 8.9 switching from a pito an nnrticontaining regimen numerous adult studies and one paediatric study have demonstrated the feasibility of switching from a pi to an nnrti once vls are <50 copies/ml. this approach will avoid some long-term adverse effects of the pis. only consider if vls are consistently <50 copies/ml and adherence is excellent. where the mother and/or baby were given a single dose of nvp for pmtct, switching should be avoided until further data are available. 8.10 interrupting therapy generally art should not be stopped except on the advice of an expert. when it is necessary to stop or interrupt a regimen containing an nnrti, be aware that the long half-life of the nnrti will cause sub-therapeutic levels to persist for up to several weeks. either continue the nrtis for a week after stopping the nnrti if feasible (for example if nnrti-associated rash is suspected) or use a boosted pi for a week to avoid developing resistance to the nnrti. 8.11 immune reconstitution inflammatory syndrome iris is characterised by a paradoxical clinical deterioration after starting haart. this results from rapid restoration of pathogen-specific immunity to opportunistic infections (ois) and causes deterioration of an existing infection (paradoxical iris) or new clinical manifestations of a previously unrecognised subclinical infection (unmasking iris) during the early stages of art. iris is usually associated with improvements in surrogate markers of hiv infection (virological, immunological, clinical). it may have distinct clinical presentations with pronounced inflammatory response. iris usually occurs within 6 months of starting haart and in patients with a low starting cd4 count. the most common presentations in south african children include bcg adenitis, tb and herpes zoster. causes include m. tuberculosis, bcg, m. avium complex (mac), m. leprae, cryptococcus neoformans, aspergillus, candida albicans, p. jirovecii, cytomegalovirus (cmv), jc virus, human herpesviruses, herpes simplex virus, varicella zoster virus, human papillomavirus and hepatitis b and c viruses (hbv, hcv). 9. selected adverse effects of antiretroviral drugs in children (table vi) arvs are generally well tolerated in children. a few more serious adverse effects are mentioned here. 9.1 lactic acidosis lactic acidosis is a rare but serious, life-threatening complication of nrti therapy, especially when ddi and d4t are used together. symptoms include nausea and vomiting, abdominal pain, tachypnoea and dyspnoea, weight loss and fatigue. it may also cause neurological symptoms including a guillain-barré-like picture. there is no value in screening for lactic acidosis in asymptomatic children. clinicians should be aware of the symptoms and diagnose the condition timeously. diagnosis is confirmed with a serum lactate level >5 mmol/l, metabolic acidosis and a raised anion gap. liver enzymes may be increased. in patients with a lactate level >10 mmol/l or >5 mmol/l with metabolic acidosis, art should be discontinued and supportive therapy instituted. treatment (usually in an icu) consists of intravenous fluids and ensuring oxygenation. some reports suggest that alkalinising the blood with bicarbonate might improve prognosis, but this remains controversial. other controversial treatments include thiamine (vitamin b1), riboflavin (vitamin b2) and l-carnitine (no data to show efficacy). following an episode of lactic acidosis, it may take several months for lactate levels and liver enzymes to normalise. contact the hiv clinicians society for assistance in designing a new regimen after lactic acidosis. 9.2 haematological toxicity the two major agents are azt and co-trimoxazole (usually only high-dose co-trimoxazole for treating pcp, but occasionally with prophylactic doses, and this is reversible with folinic acid – not folic acid). patients on azt should have full blood counts (fbcs) monitored monthly for the first 3 months and 3-monthly thereafter. the main bone marrow toxicities from azt are anaemia and neutropenia. anaemia may be due to hiv infection itself, or to aidsrelated conditions such as disseminated mac, cmv or lymphoma. it may also be nutritional (e.g. iron or folate deficiency) or drug-related. management depends on the underlying cause of anaemia, available options and the extent of the problem. it is reasonable to switch to a drug that causes fewer haematological side-effects, december 2009                                                          the southern african journal of hiv medicine                                                  46 e.g. switch from zdv to d4t or abc. a haemoglobin level below 7 – 8 g/dl warrants investigation and treatment. nutritional deficiencies, especially iron, should be addressed. neutropenia is quite common before or on haart. unless severe, <0.25×10 9 /l, neutropenia often resolves spontaneously (providing there are no associated signs such as persistent fever or localised infection) and a repeat fbc should be done a week later. if neutropenia is severe, <0.25×10 9 /l, the offending agent should be replaced if feasible. 9.3 rashes most rashes following arvs are mild to moderate and resolve spontaneously with drug continuation. most rashes are either maculopapular or urticarial. the most severe rashes include stevens-johnson syndrome, toxic epidermal necrolysis, abc hypersensitivity, and the drug rash with eosinophilia and systemic symptoms (dress) reported with nnrtis. the highest prevalence of drug rashes occurs with the nnrtis (more severe and more frequent with nvp). rash usually occurs in the first 2 4 weeks of treatment. the rash is usually maculopapular and erythematous. nvp is given daily for the first 2 weeks and only increased to twice daily once the rash has resolved. mild to moderate rashes will often resolve spontaneously but must be closely monitored. oral antihistamines can be used in mild to moderate cases. in children who develop severe rash, cutaneous bullae or target lesions, mucosal lesions or systemic symptoms, nvp class drug adverse effects nrtis azt (retrovir®) anaemia, granulocytopenia, myopathy, lactic acidosis ddi (videx®) common: abdominal pain, nausea and vomiting uncommon: diarrhoea, pancreatitis, peripheral neuropathy, lactic acidosis stavudine (zerit®) common: headache, rash, gastro-intestinal, lipo-atrophy uncommon: pancreatitis, peripheral neuropathy (adults), lactic acidosis abacavir (ziagen®) hypersensitivity reaction (with or without rash) – fever, rash, fatigue, nausea, vomiting, diarrhoea, pharyngitis, dyspnoea, cough elevated alt, creatinine or ck. lymphopenia lactic acidosis lamivudine (3tc®) well tolerated. common: headache, fatigue and abdominal pain uncommon: lactic acidosis ntrtis tenofovir (viread®) more common: nausea, diarrhoea, vomiting, flatulence less common: osteomalacia, renal toxicity, lactic acidosis nnrtis nevirapine (viramune®) skin rash, sedative effect and diarrhoea. liver toxicity efavirenz (stocrin®) skin rash. cns – sleep disturbance, confusion, abnormal thinking teratogenic in primates, but prospective data in humans are reassuring (no higher than background fetal malformation rate). may be implicated in breast enlargement (lipomastia) pis ritonavir (norvir®) nausea, vomiting, diarrhoea. hypercholesterolaemia and hypertriglyceridaemia, lipodystrophy atazanavir (reyataz®) common: unconjugated hyperbilirubinaemia – usually mild and does not warrant discontinuing drug. has less effect on lipids than other pis but rtv boosting may affect lipids lopinavir/ritonavir (kaletra®)(aluvia®) nausea, vomiting, diarrhoea. hypercholesterolaemia and hypertriglyceridaemia, lipodystrophy fosamprenavir (telzir®) nausea, vomiting, diarrhoea. hypercholesterolaemia and hypertriglyceridaemia, lipodystrophy. less common (more severe): life-threatening rash, including stevens-johnson syndrome, in <1% of patients, neutropenia, elevated serum creatinine kinase levels saquinavir (invirase®) nausea, vomiting, diarrhoea. hypercholesterolaemia and hypertriglyceridaemia, lipodystrophy alt = alanine transaminase; ck = creatine kinase. *see section 9. table vi. adverse effects of arvs in children* the southern african journal of hiv medicine                                                        december 2009   47 should be permanently discontinued and hospitalisation is required. if nvp is discontinued for mild or moderate rash, restarting nvp after the rash has resolved may be considered with close monitoring. cross-reactivity among nnrtis may occur. therefore avoid efv after a severe rash. however, in children with mild or moderate rash without mucosal involvement or systemic symptoms, efv may be substituted with caution. rashes may occur in children receiving efv. these rashes are usually less severe than those with nvp, and resolution during treatment continuation is common. however, if efv-associated rash is severe, or is accompanied by mucosal or systemic symptoms, efv should be permanently discontinued. 9.4 hypersensitivity syndrome abc and nvp are most commonly implicated. abc hypersensitivity reaction occurs in 4 8% of patients but is less common in black africans. there is a 100% correlation between skin patch test-positive reactions and hla b*5701. hla b*5701 is rare in black africans. hypersensitivity reaction usually occurs in the first 6 weeks of abc. abc hypersensitivity is multisystemic. fever and rash occur commonly and may be associated with nausea, vomiting, diarrhoea, fatigue, myalgia and arthralgia. respiratory symptoms, such as pharyngitis, cough or dyspnoea, may also be present. the skin rash, usually maculopapular or urticarial, occurs in about 70% of cases. symptoms worsen with each dose. abc hypersensitivity reaction is fully reversible on discontinuing abc, and fatalities have not been reported on first exposure to the drug. patients must however never be rechallenged with abc after a hypersensitivity reaction, as deaths have occurred due to hypotension. parents need specific counselling to recognise the hypersensitivity reaction; they also require a letter to alert any health care worker who may be consulted and need the contact number of the prescribing doctor. a hypersensitivity reaction has been described for nvp. systemic symptoms such as fever, myalgia, arthralgia, hepatitis, and eosinophilia may occur. it usually occurs in the first 8 weeks of treatment. nvp should then be permanently discontinued and efv should be avoided as well. 9.5 hepatotoxicity all three classes of arv drugs currently in use in south africa have been implicated. liver dysfunction in hiv infection may be caused by hiv, co-infection with hepatitis b or c viruses, ois, malignancies, drug interactions or drug-induced hepatotoxicity. nrti-associated hepatotoxicity is primarily caused by mitochondrial toxicity. nnrtis are associated with asymptomatic elevations in liver enzymes and hypersensitivity with hepatitis. nvp is associated with more hepatotoxicity than efv. pi-associated elevations in liver enzymes can occur at any time during therapy. patients with chronic hepatitis b or c may experience an increase in liver enzymes after starting haart as part of iris. there may also be an increase in liver enzymes after discontinuing drugs such as 3tc or tdf (which are used to treat hepatitis b). children do seem to get less hepatic dysfunction on haart than adults. patients on nvp should have liver function tests (lfts) done 2-weekly for the first 2 months, then 3-monthly thereafter. lfts should be monitored routinely 3 4monthly in patients on other haart regimens. if transaminases are elevated <10 times the upper limit of normal (uln) there is no need to interrupt haart. patients with clinical hepatitis or severe hepatotoxicity (>10 × uln) should have a work-up for other causes of hepatitis, e.g. hepatitis a, b or c, and interruption of haart. patients on nvp with clinical hepatitis should discontinue nvp and have their haart regimen changed. rechallenge with nvp or abc after acute hepatitis is not recommended. patients with hepatitis b co-infection may need to continue with 3tc if their haart regimen is changed to prevent a flare-up in hepatitis b. 9.6 lipodystrophy (lipo-hypertrophy/lipoatrophy) lipodystrophy typically involves accumulation of visceral fat in the abdomen (central obesity), dorsocervical area (buffalo hump) and breasts (visceral fat accumulation) and/or loss of subcutaneous fat in the face, extremities and buttocks (lipo-atrophy (la)). pis have been implicated in fat accumulation, whereas the nrtis, especially stavudine, have been implicated in la. efv may be implicated in breast enlargement. there are no data in children, but adult data suggest that switching from d4t or zdv to abc will at least arrest and may partially reverse la but not the visceral fat accumulation. switching early, when the la is mild, is advisable as la may be irreversible. there are also limited data indicating that switching to a regimen containing a pi and an nnrti only will also reverse la. 9.7 hyperlipidaemia pis (especially rtv and lpv/r) are implicated in hyperlipidaemia. however, both d4t and efv have also been implicated. while pi therapy in adults is associated with an increased risk of cardiovascular disease, there is currently no evidence of an association between elevated cholesterol levels in children and an increased risk of premature death. as a result, there is no consensus december 2009                                                          the southern african journal of hiv medicine                                                  48 or experience in lipid-lowering agents in children. cholesterol and triglycerides should be measured 12monthly in children on pis. a random cholesterol and triglyceride is probably adequate, but if these are raised, a fasting level should be done. referral to a dietician and encouraging exercise are the first interventions. if these are unsuccessful, consult the hiv clinicians society. options available include observation, arv agent switching (e.g. from a pi to an nnrti or to atv), or lipidlowering agents. statins are metabolised by cytochrome p450 resulting in either toxicity or diminished effect with rtv, so use with caution and only on the advice of an expert. 10. prophylaxis 10.1 pneumocystis jirovecii pneumonia indications for co-trimoxazole prophylaxis and when to start and stop it are set out in table vii. re-institute co-trimoxazole prophylaxis if the cd4 count or percentage subsequently drops and the criteria in table vii for starting prophylaxis are reached. 10.2 inh prophylaxis the following children should receive inh prophylaxis: n hiv-infected infants and children with a positive ppd test (>5 mm) n hiv-infected infants and children exposed to a person who has contagious tb. active tb disease first needs to be excluded. the dosage of inh is 10 15 mg/kg/day and it should be continued for 6 months. where the source case has inh-resistant tb, give rifampicin 15 mg/kg/d for 4 6 months. for mdr and extensively drug-resistant (xdr) contacts an expert should be consulted. indications for co-trimoxazole when to start when to stop all hiv-exposed newborns start from 4 6 weeks after birth stop when pcr negative ≥6 weeks after full weaning and infant is clinically hiv negative all hiv-exposed exclusive formulafeeding children (eff) start from 4 6 weeks after birth stop when pcr negative and infant is clinically hiv negative and eff is expected to continue all hiv-exposed breastfeeding children start from 4 6 weeks after birth stop when pcr negative ≥6 weeks after full weaning and infant is clinically hiv negative hiv-infected infants <12 months old start from 4 6 weeks after birth or as soon as possible after hiv diagnosis even if on haart note: all hiv-positive infants <1 year should be started on haart regardless of clinical stage or cd4 count or percentage all infants <12 months should remain on prophylaxis hiv-infected children 1 5 years with or without art all symptomatic children (who clinical stage 2, 3 or 4) or cd4 <15% or <500 cells/µl* stop once art-associated immune reconstitution has occurred for ≥6 months, i.e. cd4+ percentage ≥15% or cd4 count ≥500 cells/µl on ≥2 occasions, 3 6 months apart hiv-infected children ≥6 years of age with or without haart start if cd4 count <200 cells/µl or <15% or who clinical stage 3 or 4 disease (including tb) stop once art-associated immune reconstitution has occurred for ≥6 months: cd4 ≥15% or ≥200 cells/µl on ≥2 occasions, 3 6 months apart any hiv-infected child with high risk for bacterial infections, e.g. severe malnutrition, on oncological drugs or corticosteroids or at risk of malaria start co-trimoxazole prophylaxis even with art immune reconstitution do not stop until risk has been eliminated and all cd4 cell percentage or cd4 cell count criteria listed above have been met hiv-infected child with previous pcp infection start as soon as first pcp episode has been treated stop once art-associated immune reconstitution has occurred for ≥6 months in children over 1 year of age: cd4 ≥15% or ≥500 cells/µl (1 5 years) or ≥200 cells/µl (>6 years) on ≥2 occasions, 3 6 months apart *note: any one of the criteria could be used for starting therapy. table vii. co-trimoxazole prophylaxis the southern african journal of hiv medicine                                                        december 2009   49 10.3 mycobacterium avium complex mac is a true oi. disseminated mac only occurs in patients with extremely low cd4 counts, although it is unusual in very young children. the best prophylaxis against mac is art and immune recovery. where resources allow, there is a role for azithromycin prophylaxis against disseminated mac in patients with extremely low cd4 counts. before prophylaxis is instituted a mycobacterial blood culture should be done to exclude disseminated mac. children aged 2 5 years with a cd4 count <75 cells/µl and >6 years with a cd4 count <50 should be offered azithromycin prophylaxis. the dosage of azithromycin is 20 mg/kg body weight (max. 1 200 mg) orally once weekly. discontinue once the cd4 count has been >200 cells/µl for children aged 2 5 years and >100 cells/µl for children aged ≥6 years for >6 months in children on stable art. recommended reading working group on antiretroviral therapy and medical management of hiv-infected children. guidelines for the use of antiretroviral agents in pediatric hiv infection. february 23, 2009; pp 1-139. http://aidsinfo.nih.gov/ contentfiles/pediatricguidelines.pdf sharland m, castelli g, ramos jt, blanche s. gibb dm. on behalf of the penta steering committee penta guidelines for the use of antiretroviral therapy in paediatric hiv infection. www.ctu.mrc.ac.uk/penta/ who guidelines: www.who.int ndoh guidelines: www.doh.gov.za/ centers for disease control and prevention. guidelines for the prevention and treatment of opportunistic infections among hiv-exposed and hiv-infected. mmwr morb mortal wkly rep 2009; 58 (no. rr-11): 1-166. moore dp, schaaf hs, nuttall j, marais bj. childhood tuberculosis guidelines of the southern african society for paediatric infectious diseases. south african journal of epidemiology and infection 2009; 24(3): 57-68. selected references 1. violari a, cotton mf, gibb dm, et al. early antiretroviral therapy and mortality among hiv-infected infants. n engl j med 2008; 359(21): 2233-2244. 2. davies m-a, keiser o, technau k, et al. outcomes of the south african national antiretroviral treatment programme for children: the iedea southern africa collaboration. s afr med j 2009; 99: 730-737. 3. gupta rk, hill a, sawyer as, et al. virological monitoring and resistance to firstline highly active antiretroviral therapy in adults infected with hiv-1 treated under who guidelines: a systematic review and meta-analysis. lancet infect dis 2009; 9: 409-417. 4. green h, gibb dm, walker as, et al.; paediatric european network for the treatment of aids (penta). lamivudine/abacavir maintains virological superiority over zidovudine/lamivudine and zidovudine/abacavir beyond 5 years in children. aids 2007; 21(8): 947-255. 5. jaspan hb, berrisford ae, boulle am. two-year outcome of children on nonnucleoside reverse transcriptase inhibitor and protease inhibitor regimens in a south african pediatric antiretroviral program. pediatr infect dis j 2008; 27: 993998. 6. palumbo p, violari a, lindsey j, et al. impaact p1060 team. nevirapine (nvp) vs lopinavir-ritonavir (lpv/r)-based antiretroviral therapy (art) in single dose nevirapine (sdnvp)-exposed hiv-infected infants: preliminary results from the impaact p1060 trial. presented at the 5th ias conference on hiv pathogenesis, treatment and prevention, 19-22 july 2009, cape town. abstract lbpeb12. 7. mcilleron h, ren y, nuttall j, et al. double-dose lopinavir/ritonavir provides insufficient lopinavir exposure in children receiving rifampicin-based anti-tb treatment. presented at the 16th conference on retrovirology and opportunistic infections, 8 11 february 2009, montreal. disclaimer: specific recommendations provided in this document are intended only as a guide to clinical therapy, based on expert consensus and best current evidence. recommended drugs and dosages are based on current available data and may differ from dosages recommended by manufacturers. treatment decisions for patients should be made by their responsible clinicians with due consideration for individual circumstances. the most current version of this document should always be consulted. pg4-5.html from the editor new directions at the journal as some readers of the south african journal of hiv medicine will know, professor linda-gail bekker has elected to step down as editor, and i am moving into this position beginning with the september issue. under linda-gail’s leadership the journal has grown considerably, and we are indebted to her for her contribution over the past years. on a personal note linda-gail has been immensely helpful during the handover of the editorship, and i am happy to report that she will continue to provide guidance while serving on the journal’s editorial board. we are looking forward to continuing the journal’s emphasis on presenting research and clinical experiences from across the region, and keeping readers updated around local and international developments. to this end we will seek to expand several sections over the coming issues, including: • feedback reports from local and international conferences • editorial reviews intended to share viewpoints and promote discussion on important topics, and • programmatic reports that share local experiences in implementing hiv treatment and prevention services on the ground. these new sections will be in addition to the ongoing emphasis on research articles and case reports that are established strengths of the journal. we are also aiming to increase the number of articles published in each edition, so please keep your submissions coming. in addition i want to continue linda-gail’s ‘open door’ policy regarding suggestions for future content. if you have ideas, thoughts or feedback, please e-mail me directly (landon.myer@uct.ac.za). this issue of the journal features a number of important contributions. an opinion piece from nathan geffen discusses the implications of the recently announced findings of hptn 052, demonstrating that antiretroviral therapy is an effective form of hiv prevention in serodiscordant partnerships. there was a time when hiv prevention and treatment were distinct spheres (in both service delivery and our thinking about the epidemic), and these boundaries are rapidly falling away. next, coceka mnyani and colleagues discuss the risks associated with invasive obstetric procedures in hiv-infected women, a valuable follow-up to the previous issue’s emphasis on pmtct. in an original scientific article, greg jonsson and colleagues report on a survey of hiv-related knowledge among psychiatric patients in soweto. a case report on hiv and primary lymphoma of the breast (barnardt) reminds us of the unusual complications that can accompany advanced hiv disease, while another case report demonstrates the value of simple microscopy in diagnosing a deep fungal infection in an hiv-infected child (crous). finally, in a report back from a local meeting kevin rebe discusses the findings of a recent conference on the health of men who have sex with men. this issue also features a special article on the teaching (and understanding) of clinical immunology in the context of hiv/aids. clive gray and colleagues developed an innovative approach to ‘lure clinicians into learning immunology’ – no easy task. this work has won several awards, and is well worth checking out: www.immunopaedia.org. i hope that this breadth and depth is a flavour of things to come! happy reading. landon myer editor associate professor, school of public health and family medicine, university of cape town the southern african journal of hiv medicine                                                              april  2010 5 m e s s a g e f r o m t h e e x e c u t i v e weirdness appears to be affecting african hiv prevention efforts recently. governments seem to think that criminalising hiv transmission, on a continent where the vast majority of people do not know their status, is an important way to control hiv. legislation has been enacted, or is being considered in several countries, despite evidence that this simply stigmatises people with hiv. a particularly bizarre and disturbing bill being considered in uganda called for the death penalty against gay men who transmit hiv (implying that it is more ok to transmit if you are straight). it also implies that hiv in uganda, where numbers of cases have been on the rise for the past few years, is driven by gay men, when all data suggest that the epidemic remains heterosexual. human rights and other organisations appear to have stopped the uganda bill; not because it was seen as dangerous, rather because it was a threat to donor funding – obama called the bill ‘odious’. you can read our letter to the ugandan parliament at http:// www.sahivsoc.org/. what is most frustrating, though, is the silence of the medical fraternity in all this. where are the local health care worker and public health organisations, condemning their government’s idiocy? for too long patients have had to rely on treatment activist organisations and international agencies to protect them. health care worker organisations should loudly condemn unscientific approaches to dealing with hiv, especially when these may harm their patients. hiv prevention has proven very complicated. quick-fix, emotional, prejudiced and unscientific solutions are hardly going to help. governments listen to health care workers, as we have status and power. organisations need to stand up to dangerous policy and legislation. francois venter president it is an interesting time in south africa ... with public debate on education, the judicial system, and whether or not politicians should be allowed to say and sing what they like in public, to name just a few issues. the journal also takes on controversy this quarter, and i hope will elicit some debate. i remind you that the opinions expressed in its pages are not necessarily supported by the editorial committee or the clinicians society! the first three papers in this issue are such articles, the first being the ruben sher memorial lecture delivered by judge edwin cameron some weeks ago. he describes his own testing experience and makes a case for why the human rights activism around testing is less relevant in the era of effective hiv treatment, and why hiv testing should be normalised. the sa government will be attempting to do just that through countrywide scale-up of testing. an intriguing article probes the impact of a ‘sexual abstinence month’, and kenyon grapples with some epidemiological ‘holy cows’ and questions the attribution of poverty as a driver for the epidemic in southern africa. the new public sector guidelines are out, and for easy reference we asked celicia serenata from sanac to give a succinct summary of the differences. our review this quarter looks at cytomegalovirus co-infection, but also comments on treatment options for south african practitioners and calls for antiviral price review. we thank visiting opthalmologist sophia pathai for her corroborating comment. the last three articles are original research. the first looks at mortality trends in a hospital district after the introduction of art, the second at mental health, and the third at laboratory abnormalities in hiv-infected pregnant women. remember, we will welcome your letters should any of the above invoke the need to respond! however, i hope this edition will also raise discussions at your place of work and among your colleagues. whichever, i hope you enjoy it, and am happy that we have got to a position in our country where relevant and appropriate issues can be freely debated. linda-gail bekker editor f r o m t h e e d i tor the southern african journal of hiv medicine                                                          winter  2008spring  2008                                                          the southern african journal of hiv medicine                                                   f r o m t h e e d i to r the journal is starting to feel like men’s health, what with posters, guidelines and now a state-of-the art science update, hiv treatment bulletin, falling out of it. exco is pleased to announce an important and strategic partnership with hiv ibase, who publish hiv treatment bulletin. we are distributing the southern african version of their excellent newsletter, which will exclusively focus on the scientific reports and resources that have local relevance – with a strong focus on paediatrics and maternal health. hiv treatment bulletin neatly complements the journal, providing the snobbish clinician and scientist with the most hot-off-the-press analysis of recent clinical trials and basic science research. policy makers can authoritatively pronounce at their guidelines meetings, clinicians can expand their patients’ options, and, most importantly, you can show off at ward rounds. thanks to all the people at i-base, this is a major step forward for quality information sharing. we wish the new health minister, barbara hogan, all the best. she has very small shoes to fill, but a mammoth task ahead of her to repair south africa’s woeful health service. at the time of writing, she and her deputy, dr molefi sefularo, have been very impressive, dealing with a cholera disaster, drug stock-outs, issues of prevention, releasing controversial reports that were stuck on her predecessor’s desk for months, and a dozen other complex health problems. finally, the exco welcomes two new members based in durban, professor yunus moosa and dr henry sunpath, both highly respected clinicians and part of the team responsible for an excellent hiv clinical conference held in october. francois venter president this spring edition brings 2008 to a close. and what a year it has been. not many breakthroughs in hiv or tb, but a lot of activity in terms of understanding early infection better, really getting to grips with early immune responses, and again thinking through our prevention options. in 2008 the concept of antiretrovirals for prevention as well as treatment has come to the fore with second-generation microbicides, pre-exposure prophylaxis and the notion that we may be able to ‘treat our way out of the epidemic’ becoming possibilities. gratifyingly, this year also saw a record number of people being tested and accessing art, and roll-out for both testing and treatment is truly scaling up. as chairperson of the 4th southern african hiv conference i must encourage every one of you to think seriously about coming to durban on 31 march. it promises to be a critical conference where we will really formulate the key steps in getting pmtct, treatment, testing and prevention out there on a scale that will begin to turn the sa statistics around. (i promise that it will also be loads of fun!) please note the early date this year: 31 march to 3 april. this is to ensure brilliant kzn weather! in this edition, we already begin to examine some of these key scale-up questions: jerome singh explores the ethics and legality of traditional healers performing hiv testing (i know many have asked why this has to be the domain of nurses only). francesca esposito and her team examine changes in body composition in women taking antivirals in a kzn clinic. we look at the role of mobile phones in the hiv response with william mapham, and polly clayden gives us pointers to starting infants on art. the role of a liver biopsy in diagnosis of opportunistic infections is described by mark sonderup and colleagues. the vexed question of when it is deemed safe to start haart in patients co-infected with tb is discussed by robin wood, and francois venter and colleagues give a practical view on new antiretrovirals on the horizon for south african practitioners. no guidelines in this issue, but i will whet your appetites – look out for guidelines on prevention of tb occupational exposure for hiv-infected health care workers and on the non-infertile hiv infected couple, hot stuff coming up in the new year! happy reading and every best wish for a restful and peaceful festive season from the whole editorial team. see you next year! linda-gail bekker editor m e s s a g e f r o m t h e e x e c u t i v e � msg from the executive.indd 5 12/17/08 3:16:23 pm a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e case 1 a 45-year-old man with a history of previous tuberculosis (tb) infection presented with a cough and chest pain. sputum results and blood cultures were negative. the chest radiograph (cxr) demonstrated bilateral multifocal areas of patchy airspace disease, as well as a dominant focal area of density in the right upper lobe (fig. 1). no effusions were noted. a presumed diagnosis of pjp was made, but the patient did not respond to treatment. bronchoscopic biopsy confirmed cmv infection. case 2 a 43-year-old woman with no history of tb or tb contacts presented with a cough and haemoptysis, loss of weight, low fever and rigors. the white cell count (wcc) was 6.4×109/l, and sputum results and blood cultures were negative. the cxr revealed bilateral reticular-nodular and ground-glass opacities without any effusions (fig. 2, a). the differential diagnosis included tb and pjp. bronchoscopic biopsy confirmed the diagnosis of both cmv and pjp infections. case 3 a 30-year-old woman presented with shortness of breath, a dry cough, loss of weight and fever. the wcc was 13×109/l and the cd4 count 481 cells/µl. the cxr demonstrated bilateral reticular and ground-glass opacities (fig. 2, b). treatment for tb and pjp was started, but the patient showed no clinical improvement. bronchoscopic biopsy confirmed both cmv and pneumocystis pneumonia (pcp). case 4 a 29-year-old woman presented with a cough, chest pain, loss of weight and shortness of breath. the wcc was 9.1×109/l and the cd4 count 14 cells/µl. on the cxr there were bilateral, diffuse, reticular and airspace shadows with no effusions (fig. 2, c). both tb and pjp were considered in the differential diagnosis. transbronchial biopsy revealed cmv and pjp infections. transbronchial biopsy in all patients demonstrated alveolar tissue containing cmv with nuclear and cytoplasmic inclusions (fig. 3). this was accompanied by alveolitis and an associated inflammatory cell infiltrate nonspecific radiographic manifestations of cytomegalovirus infection in 4 hiv-positive adults – diagnosis through trans bronchial biopsy matthew goodier, mb chb grace rubin, mb bch, da (sa), fcrad (diag) (sa) department of radiology, university of the witwatersrand, johannesburg we report on 4 hiv-positive adult patients who presented (over a 2-year period) with clinically significant cytomegalovirus (cmv) pneumonia requiring transbronchial biopsy for diagnosis. the patients were not on antiretroviral therapy. clinical findings were nonspecific, sputum samples were negative, blood test results were non-contributory, and empirical treatment had failed. radiological findings were extensive but nonspecific. three of the 4 patients were co-infected with pneumocystis jirovecii (pjp) pneumonia, further confounding the radiological diagnosis. fig. 1. the chest radiograph in patient 1 demonstrates bilateral multifocal areas of patchy airspace disease, as well as a dominant focal area of density in the right upper lobe. c a s e s t u d i e s – h i v a n d l u n g d i s e a s e 2334 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 1 of the alveolar walls. ziehl-neelsen staining and culture for tb were negative in all patients. discussion cmv is a relatively commonly identified pathogen in immunocompromised patients. this was first recognised in patients on immunosuppressive therapy for haematological malignancies or bone marrow and other organ transplants. in the south african setting, most cmv infections occur in patients with hiv/aids. cmv disease usually occurs in patients with low cd4 counts (<100 cells/µl).1 disseminated infection is relatively common and may manifest clinically as retinitis, encephalitis, hepatitis, oesophagitis or colitis. clinically significant pulmonary infection is uncommon. however, cmv may be isolated in more than half of broncho-alveolar lavage (bal) specimens in aids patients with pulmonary symptoms.2 in most patients, cmv infection co-exists with other opportunistic infections, particularly pcp. in this setting, there is doubt regarding to what extent cmv is acting as a pathogen.3 the diagnosis of cmv pneumonitis is therefore often based on typical symptoms of fever, shortness of breath, hypoxaemia and diffuse infiltrates on the cxr in combination with detection of the virus in bal fluid and the absence of other pathogens.4 however, because of the high rates of co-infection, a definitive diagnosis of cmv requires identification of cmv intranuclear or cytoplasmic inclusion bodies in transbronchial biopsy specimens (used in our patients) or open lung biopsy specimens.5 routinely securing a tissue diagnosis in the local setting is impractical and may be dangerous in patients with certain conditions, e.g. thrombocytopenia.4 in one study examining aids patients undergoing diagnostic bronchoscopy for pulmonary symptoms, 72% had cmv cultured from bal fluid but only 2 had pathological fig. 2, a c. in the chest radiographs of patients 2, 3 and 4, nonspecific bilateral reticular-nodular and ground-glass opacities were present with no features of an effusion. a b c fig. 3. haematoxylin and eosin, high power. a = enlarged alveolar pneumocyte with brick-red intranuclear cmv inclusion body; b = alveolar space; c = alveolar wall showing a nonspecific inflammatory cell infiltrate. (acknowledgement: jill murray, school of public health, university of the witwatersrand and national health laboratory service.) 35 a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e evidence of cmv pneumonitis. only 1 of these patients had autopsy confirmation that the cause of death was cmv pneumonitis.6 in practice, treatment is therefore usually aimed at all other organisms, and only if the patient does not improve is anti-cmv therapy initiated. in patients with pathologically proven cmv pneumonia, cxrs usually show bilateral, reticular, interstitial disease that classically begins in the periphery of the lower lobes and spreads centrally and superiorly, as seen in 3 of our patients. focal infiltrates, nodules and diffuse alveolar infiltrates are less common findings and were noted in 2 of our patients.7 because of the nonspecific clinical presentation, clinicians tend to rely on imaging to distinguish between cmv and pjp. however, it is usually impossible to differentiate between these two conditions on the basis of radiographic findings. in this context some consider thin-section computed tomography (ct) to be the investigation of choice.1 ct scans may reveal bilateral or focal ground-glass or consolidative changes, as well as (less commonly) well-defined solitary or multiple nodules measuring up to 3 cm in diameter,8 which makes ct also poor at differentiating between pcp and cmv infection. in a study comparing ct findings in these two infections in 58 immunocompromised hivnegative patients, small and centrilobular nodules, unsharp demarcation of the ground-glass infiltrates and consolidation favoured cmv pneumonia, while an apical distribution and the occurrence of a mosaic pattern suggested pcp.1 although cmv usually mimics pcp, the radiological differential diagnosis of diffuse interstitial pulmonary infiltrates in aids also includes infections with other organisms. conclusion even though cmv is a relatively commonly identified organism in bal specimens from immunocompromised hiv patients, cmv pneumonia is uncommon. as demonstrated in our patients, cmv pneumonitis typically has a nonspecific plain radiographic presentation which overlaps with that of pcp, a common co-infection. the diagnosis then relies on transbronchial biopsy. in subsaharan africa, where a large proportion of patients are not yet on antiretroviral therapy and have low cd4 counts, cmv remains an important differential diagnosis in pneumonia in hiv/aids. where there are resource limitations for performing bronchoscopic biopsy, failure of a trial of therapy and diffuse interstitial or patchy airspace disease on cxr should prompt the clinician to initiate treatment for cmv. references 1. vogel m, brodoefel h, hierl t, beck r, bethge a, claussen d, horger m. differences and similarities of cytomegalovirus and pneumocystis pneumonia in hiv-negative immunocompromised patients – thin section ct morphology in the early phase of the disease. br j radiol 2007;80:516-523. 2. miles pr, baughman rp, linnemann cc jr. cytomegalovirus in the bronchoalveolar lavage fluid of patients with aids. chest 1990;97:1072-1076. 3. millar ab, patou g, miller rf, et al. cytomegalovirus in the lungs of patients with aids. respiratory pathogen or passenger? am rev respir dis 1990;141:14741477. 4. tamm m, traenkle p, grilli b, et al. pulmonary cytomegalovirus infection in immunocompromised patients. chest 2001;119:838-843. 5. waxman ab, goldie sj, brett-smith h, matthay ra. cytomegalovirus as a primary pulmonary pathogen in aids. chest 1997;111:128-134. 6. mann m, shelhamer jh, masur h, et al. lack of clinical utility of bronchoalveolar lavage cultures for cytomegalovirus in hiv infection. am j respir crit care med 1997;155:1723-1728. 7. hirsch m. cytomegalovirus and human herpesvirus types 6, 7 and 8. in: braunwald e, anthony f, kasper d, hauser s, longo d, jameson j, eds. harrison’s principles of internal medicine. 15th ed. new york: mcgraw-hill, 2001: 1111-1115. 8. mcguinness g, scholes jv, garay sm, leitman bs, mccauley di, naidich dp. cytomegalovirus pneumonitis: spectrum of parenchymal ct findings with pathologic correlation in 21 aids patients. radiology 1994;192:451-459. 36 s e p t e m b e r 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e the number of new cases of human immunodeficiency virus (hiv) infection in taiwan peaked in 2005, and it is still a serious problem.1 tuberculosis (tb), especially extrapulmonary tb, is also common in taiwan1 and is commonly associated with hiv infection.2 when a patient urgently needs surgery, as can occur with perforation of an intestine or appendix, there is no time for definitive testing for hiv and/or tb. we report a case in which a patient required immediate surgery for what appeared to be an abscess with peritonitis from a perforated diverticulum of the ascending colon. the patient was unaware that he had both extrapulmonary tb and hiv. the tb was discovered by the pathologist on examination of the surgical specimen, and the hiv was discovered because the patient’s postoperative condition suggested a systemic disease. the case illustrates that despite co-occurrence of the two diseases surgery can be successful, recovery can be similar to that expected in a patient without the diseases, and patient outcome can be good if anti-tb and antiretroviral therapies are started almost immediately. the case is also consistent with previous reports that patients with hiv undergoing surgery have similar conditions to hiv-negative patients and that the results of treatment are equivalent.3 case report a 38-year-old man who had been well without systemic disease and neither drank alcohol nor smoked had experienced dull, right lower quadrant abdominal pain for 1 week, and fever with chills for 2 days. he had no other associated symptoms such as nausea, vomiting or diarrhoea. he sought help at the emergency department, where physical examination showed rebound tenderness at the right lower quadrant of the abdomen, with muscle guarding and rigidity. the white blood cell count was 8×109 /l, with 11% band-form neutrophils. an elevated c-reactive protein level (5.77 mg/dl) was noted. after he was admitted on 29 april 2006, an abdominal computed tomography scan revealed an ill-defined mass in the right lower quadrant anterior to the right psoas muscle; it was suspected to be an abscess. there were also several small abscesses in the omentum, paracolic gutter and mesentery of the ascending colon (fig. 1). the clinical impression was that he had perforated diverticulitis with intra-abdominal abscess, and he was immediately operated on. at surgery the abscess was found to be at the ascending colon mesentery. a right hemicolectomy was performed because of the high level of suspicion of a perforated diverticulum (fig. 2). postoperatively, the patient had a high fever for 3 days even with intensive treatment with a secondgeneration cephalosporin (cefmetazole 1 g 8-hourly). a systemic disease was suspected because the unusual clinical profile, including the location of the abscess and the pathological findings, did not correspond with the patient’s general condition. hiv infection was considered, and a western blot test was positive for hiv. the patient’s cd4 cell count, measured by flow cytometry, was 306/μl, and his cd8 cell count was 677/ μl. the hiv viral load was measured by indirect enzymetuberculous abdominal abscess in an hiv-infected man: neither infection previously diagnosed c a s e s t u dy kuo-yao kao, md tsung-i hung, md department of general surgery, shin kong wo ho-su memorial hospital, taipei, taiwan a 38-year-old man had a 1-week history of right lower quadrant abdominal pain; the initial impression was that he had diverticulitis of the ascending colon with an intra-abdominal abscess. signs of peritonitis mandated an immediate right hemicolectomy. the unusual location of the abscess and the patient’s unusual postoperative course suggested that he might also have a systemic disease. testing for hiv infection was positive. after 2 weeks in hospital, he was treated as an outpatient for both tuberculosis and hiv with a favourable outcome. in taiwan a pre-operative hiv test is not performed routinely, and the hiv seroprevalence in surgical patient populations is unknown. surgeons should keep the possibility of hiv infection in mind in a patient with an unusual clinical course. 30 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s e p t e m b e r 2 0 1 0 linked immunosorbent assay (elisa) and found to be 6 790 copies/ml. the final diagnosis was hiv infection coincident with the histologically confirmed mycobacterium tuberculosis colitis and abscess formation. anti-tb drugs (rifampin + ethambutol) were started soon after the patient resumed oral intake. he was discharged on 11 may 2006, 14 days after admission, at which time highly active antiretroviral therapy (haart) was started, including abacavir, efavirenz and lamivudine. anti-tb drugs were given continuously in the outpatient department for 18 months; the regimen included isoniazid, rifampin, ethambutol and pyrazinamide. the patient was followed up until august 2009 with a favourable outcome; at that visit he had a viral load of <400 copies/ml, a cd4 count of 332 cells/μl and a cd8 count of 632 cells/μl. discussion our patient was unaware that he had tb and hiv infection, and because he urgently needed surgery we did not have time to perform laboratory tests to diagnose these infections. nevertheless, he quickly recovered from the surgery and was discharged from the hospital 2 weeks after admission. outpatient treatment for the tb and hiv had a favourable outcome. tb has become a major cause of death and disability in many parts of the world, especially in developing countries.4,5 the disease can affect almost any body system, although most cases are pulmonary.6 in the usa, cases of extrapulmonary tb increased from 13.5% of all reported tb cases in 1975 to 21.0% in 2006.7 a study in taiwan found that extrapulmonary tb cases increased from 23% to 27% from 1996 to 2003.8 abdominal tb is a rare manifestation of extrapulmonary tb, with a prevalence of around 3%.6 it may involve the gastrointestinal tract, peritoneum, mesenteric lymph nodes, genito-urinary tract, or other solid organs.4,6,9 abdominal tuberculosis frequently poses a diagnostic challenge because specimens may be difficult to obtain, and the concentration of organisms may be low. sanai and bzeizi compiled data from 39 studies and found that the sensitivities of various diagnostic tests in patients with tb peritonitis were 38% for an abnormal chest radiograph and 53% for a positive purified protein derivative test.10 examination of ascites fluid found that lymphocytes predominated in 68% of cases, and that there was an elevated lactate dehydrogenase level in 77% of cases and an elevated adenosine deaminase level in 84%. mycobacteria were found in 34% of ascites fluids on culture, but only 3% of examinations detected organisms by smear. in contrast, the sensitivity of laparoscopic diagnosis was 92%.10 these diagnostic tests for abdominal tb seem unreliable, partly because not every patient develops ascites. culture of ascites fluid or peritoneal biopsy is the gold standard test. however, even a final diagnosis of pulmonary tb usually takes considerable time; diagnosis of abdominal tb typically takes even longer. one study from the national taiwan university hospital demonstrated that the mean interval between the first day of admission and respiratory isolation for pulmonary tb was 20.5 days.11 on the other hand, bernhard et al. reported that physicians considered abdominal tb in the initial differential diagnosis in only 39% of cases (7/18). time to specific diagnosis ranged from <1 week to >3 months.12 chen et al. reported that the average time to diagnosis of abdominal tb in southeastern taiwan was 48±10 days.13 delay in the diagnosis of abdominal tb is therefore more common than for pulmonary tb. several studies have observed that the proportion of extrapulmonary tb is higher in individuals who also are infected with hiv14,15 and in foreign-born immigrants16 in the usa. in addition, a dramatically increasing tb notification rate was observed in sub-saharan africa between 1990 and 2005, especially in countries with a high prevalence of adult hiv (>5%).17 the international standards for tuberculosis care states that hiv counselling and testing is indicated for all patients with tb in areas with a high hiv prevalence.18 in taiwan, 15 011 cases of hiv infection had been reported to the fig. 2. the largest abscess after excision. this abscess was found adjacent to the ascending colon (arrows). fig. 1. pre-operative computed tomography scan of the abdomen. the largest abscess is located at the ascending colon mesentery, anterior to the right psoas muscle (vertical arrow). there are several smaller abscesses over the omentum, and paracolic gutter (horizontal arrow). 31 s e p t e m b e r 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 32 taiwan centers for disease control as of 31 december 2007.1 the case burden of hiv infection in taiwan is significantly lower than that of tb. more data are required to establish the cost-effectiveness of offering hiv testing to tb patients in a region of high tb and relatively low hiv prevalence, such as taiwan. we describe this rare case to alert physicians to the fact that with the current trend of increasing hiv prevalence among the taiwanese, hiv co-infection should be considered when extrapulmonary tb is suspected. medical treatment is preferable to treat abdominal tb in patients also infected with hiv, surgery being reserved for complications such as intestinal obstruction, fistula, perforation and haemorrhage.19 our patient was operated on because he had abscesses and peritonitis, which were a complication of tb colitis. with the availability of the surgical specimen, we followed our suspicion and diagnosed hiv, enabling prompt initiation of treatment. anti-tb medication was started within 10 days, and the patient was discharged in 14 days. the course of diagnosis and treatment was straightforward. after discharge he received medical treatment as an outpatient with a favourable outcome. conflict of interest: none. references 1. centers for disease control, department of health, roc (taiwan). statistics of communicable diseases and surveillance report. 2007. http://www.cdc.gov.tw/lp. asp?ctnode=2076&ctunit=1144&basedsd=31&mp=5 (accessed 12 september 2009). 2. tuberculosis coalition for technical assistance. international standards for tuberculosis care (istc). the hague: tuberculosis coalition for technical assistance, 2006. http://www.stoptb.org/resource_center/assets/documents/istc_report. pdf (accessed 12 september 2009). 3. saltzman dj, williams ra, gelfand dv, wilson se. the surgeon and aids: twenty years later. arch surg 2005; 140: 961-967. 4. khan r, abid s, jafri w, et al. diagnostic dilemma of abdominal tuberculosis in non-hiv patients: an ongoing challenge for physicians. world j gastroenterol 2006; 12: 6371-6375. 5. uygur-bayramicli o, dabak g, dabak r. a clinical dilemma: abdominal tuberculosis. world j gastroenterol 2003; 9: 1098-1101. 6. sharma sk, mohan a. extrapulmonary tuberculosis. indian j med res 2004; 120: 316-353. 7. kipp am, stout je, hamilton cd, et al. extrapulmonary tuberculosis, human immunodeficiency virus, and foreign birth in north carolina, 1993 2006. bmc public health 2008; 8: 107. 8. hsu yc, yang mh, chen yh, et al. the epidemiology characteristics of extrapulmonary tuberculosis in taiwan, 1996-2003. epidemiol bull 2007; 23: 231-242. 9. golden mp, vikram hr. extrapulmonary tuberculosis: an overview. am fam physician 2005; 72: 1761-1768. 10. sanai fm, bzeizi ki. systematic review: tuberculous peritonitis – presenting features, diagnostic strategies and treatment. aliment pharmacol ther 2005; 22: 685-700. 11. wu yc, hsu gj, chuang ky, et al. intervals before tuberculosis diagnosis and isolation at a regional hospital in taiwan. j formos med assoc 2007; 106: 10071012. 12. bernhard js, bhatia g, knauer cm. gastrointestinal tuberculosis: an eighteenpatient experience and review. j clin gastroenterol 2000; 30: 397-402. 13. chen hl, wu ms, chang wh, et al. abdominal tuberculosis in southeastern taiwan: 20 years of experience. j formos med assoc 2009; 108: 195-201. 14. yang z, kong y, wilson f, et al. identification of risk factors for extrapulmonary tuberculosis. clin infect dis 2004; 38: 199-205. 15. onorato im, mccray e. prevalence of human immunodeficiency virus infection among patients attending tuberculosis clinics in the united states. j infect dis 1992; 165: 87-92. 16. talbot ea, moore m, mccray e, et al. tuberculosis among foreign-born persons in the united states, 1993-1998. jama 2000; 284: 2894-2900. 17. reid a, scano f, getahun h, et al. towards universal access to hiv prevention, treatment, care, and support: the role of tuberculosis/hiv collaboration. lancet infect dis 2006; 6: 483-495. 18. tuberculosis coalition for technical assistance. international standards for tuberculosis care (istc). the hague: tuberculosis coalition for technical assistance, 2006. http://www.stoptb.org/resource_center/assets/documents/istc_report. pdf (accessed 12 september 2009). 19. guex ac, bucher hc, demartines n, et al. inflammatory bowel perforation during immune restoration after one year of antiretroviral and antituberculous therapy in an hiv-1-infected patient: report of a case. dis colon rectum 2002; 45: 977978. anaemia is a relatively common finding in hiv-positive patients, with rates (among females) as high as 37%, compared with their hiv-negative counterparts (17%). anaemia of chronic disease plays a very important role in this population group, and is estimated to occur in 18 95% of cases. for this reason, it is imperative to distinguish this condition from other underlying or concurrent causes of anaemia that may warrant treatment. this clinical case illustrates the value of critically evaluating the parameters of a full blood count and haematinic screen, to so determine which patients warrant further workup. case report a 43-year-old man, known to be hiv-1 positive, presented to the casualty department at kalafong complaining of a 2-week history of fatigue, weight loss, night sweats, dysphagia and general malaise. he further described a 3-day history of vomiting and diarrhoea, with no melaena or haematemesis. at the time of presentation, he had been on firstline highly active antiretroviral (haart) therapy for 2 years. despite this the cd4 count on admission was 3 cells/μl. in the light of this finding, non-compliance was suspected. he had previously been diagnosed with gastro-intestinal mycobacterium avium complex as a cause of anaemia annemarie van de vyver, bsc, mb chb, pgdiptm department of internal medicine, university of pretoria and kalafong hospital, pretoria adele visser, mb chb, dtm&h, pgdiptm department of clinical pathology, university of pretoria, and national health laboratory service, tshwane academic division t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s e p t e m b e r 2 0 1 0 33 disseminated mycobacterium avium-intracellulare by positive blood cultures and had been started on treatment. owing to side-effects, he had not complied with this treatment regimen either. on admission he was pyrexial and tachycardic. he was clinically anaemic with no signs of oral hairy leukoplakia or candida. although abdominal examination was unremarkable (with no hepatomegaly or splenomegaly), he was tender in the epigastric area. cardiovascular and respiratory examinations were essentially normal. the full blood count revealed a significant microcytic hypochromic anaemia (haemoglobin 5.8 g/dl, mean corpuscular volume 68 fl and mean corpuscular haemoglobin 20.4 pg). the white cell count was normal, but he had thrombocytopenia (30×109 /l). creatinine and electrolyte levels were normal. liver function tests revealed an isolated mildly raised gamma-glutamyl transpeptidase (ggt) level (70 u/l) and a low albumin level (16 g/l). c-reactive protein was elevated at 84.9 mg/l. iron studies were also performed and showed low serum iron (1.3 μmol/l) and transferrin (1.4 g/l) levels and transferrin saturation (4%), and a markedly elevated serum ferritin level (1 579 μg/l). as part of the work-up for anaemia, the upper gastrointestinal tract was investigated by endoscopy. this revealed what was clinically judged to be extensive candidiasis throughout the oesophagus. the stomach was normal but the duodenum also had extensively distributed white plaques. a biopsy specimen of these plaques was taken and submitted for histological examination. an h&e stain was performed (fig. 1, a). the periodic acid-schiff (pas) stain revealed multiple clusters of micro-organisms in the histiocytes (fig. 1, b). finally, a ziehl-neelsen (zn) stain was performed, showing large numbers of acid-fast bacilli (fig. 1, c and d). a diagnosis of disseminated m. avium complex (mac) was suggested, as the organisms were found intracellularly. the diagnosis of disseminated mac was confirmed on a urine sample by molecular techniques. discussion patients with advanced hiv-1 disease pose a multitude of challenges in terms of diagnosis and treatment. anaemia is a relatively common finding in hiv-positive patients, with rates (among females) as high as 37%, compared with their hiv-negative counterparts (17%).1 the list of possible causes of anaemia in hiv-positive patients is substantial and differentiation is often difficult. value is certainly added by taking the full blood count results into consideration. a simple distinction between red cell size (reflected in mean corpuscular volume) and red cell haemoglobin content (reflected by mean corpuscular haemoglobin) can significantly contribute to further choices in testing. anaemia of chronic disease plays a very important role in this population group, as inhibition of iron transfer from the reticulo-endothelial cells to the erythroid precursors due to inflammation is estimated to occur in 18 95% of cases.2 for this reason, it is imperative to distinguish this condition from other underlying or concurrent causes of anaemia that may warrant treatment. a haemoglobin level below 8 g/dl should prompt further investigation, as anaemia of chronic disease rarely causes world health organization grade iii or iv anaemia2 (grade iii <7.9 g/dl, grade iv <6.5 g/dl).1 iron studies may facilitate this process. in both iron deficiency anaemia and anaemia of chronic disease, the serum iron level and transferrin saturation will be reduced. the transferrin level, however, may facilitate in making a distinction as it is typically reduced to normal in anaemia of chronic disease and increased in iron deficiency. a further indicator can be found in serum ferritin levels, which are reduced to below 30 ng/l (positive predictive value of 92 98%) in iron deficiency, and normal to elevated in anaemia of chronic disease. the inherent confounder with using ferritin is the fact that it acts as an acute-phase reactant and will be elevated beyond its baseline in any inflammatory condition, irrespective of iron status.2 the soluble transferrin receptor level may be a useful assay to delineate causes of anaemia. levels are typically increased in iron deficiency and essentially normal in anaemia of chronic disease, as inflammatory cytokines negatively influence its expression. this can also be very useful if co-existence of both conditions is suspected. however, the assay is not universally offered. the use of various ratios has also been proposed as possibly helpful in determining the underlying cause of anaemia.2 the finding and confirmation of iron deficiency should prompt further investigation as to the underlying cause. fig. 1. sections from white plaques biopsied in duodenum: a – h&e stain; b – pas stain showing numerous clumps of organisms in histiocytes; c – zn stain showing clumps of acid-fast bacilli; d – closer view of collection of acid-fast bacilli in zn stain. s e p t e m b e r 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 34 imaging of the gastro-intestinal tract may be useful, especially if clinical features are suggestive. of note is the fact that the only feature suggestive of upper gastrointestinal bleeding in our patient was the epigastric tenderness on abdominal examination. it is therefore prudent to have a high index of suspicion. again, the differential diagnosis in this clinical setting is large and relates to the degree of immunosuppression.3 disseminated mac is the most common bacterial opportunistic infection among hiv-1-positive patients in the first world.4 however, it appears to be less common in our local setting.5 it has been postulated that it is caused by the overwhelming presence of m. tuberculosis in the south african context.5 patients with a cd4 count below 50 cells/μl and possibly high hiv-1 viral loads are at increased risk of mac infections, which have been shown to be an independent predictor of mortality. for this reason prophylaxis is advocated by some.4 it is, however, not included in the current south african national antiretroviral treatment guidelines.6 mac can affect any part of the gastro-intestinal tract, with the duodenum being the most common site. macroscopic findings are not diagnostic. biopsy and culture is therefore the mainstay of diagnosis of this condition.3 references 1. moyle g. anaemia in persons with hiv infection: prognostic marker and contributor to morbidity. aids rev 2002; 4: 13-20. 2. weiss g, goodnough l. anemia of chronic disease. n engl j med 2005; 352: 10111023. 3. riedel d, nugent s, gilliam b. upper gastrointestinal bleeding in a patient with hiv infection. clin infect dis 2009; 48: 368-369. 4. karakousis p, moore r, chaisson r. mycobacterium avium complex in patients with hiv infection in the era of highly active antiretroviral therapy. lancet infect dis 2004; 4: 557-565. 5. peter j, sonderup m. diagnosing multiple opportunistic infections: the value of liver biopsy. south african journal of hiv medicine 2008; spring: 51-52. 6. department of health. national antiretroviral treatment guidelines. johannesburg: jacana, 2004. invited comment abdominal mycobacterial infection in hiv the articles in this edition by kao and hung and van de vyver and visser both deal with aspects of abdominal mycobacterial infections. van de vyver’s article highlights the importance of investigating abnormalities that cannot be attributed to hiv infection alone, and demonstrates that abdominal mycobacterial infection may present with a paucity of abdominal symptoms and signs. while tuberculosis (tb) infection is predominant in south africa, non-tuberculous mycobacteria should always be considered in patients with advanced immunosuppression. the article by kao demonstrates a more dramatic presentation in a patient with relatively preserved immunity. notification rates of extrapulmonary tb in south africa are increasing, and it is likely that more patients will present with abdominal tuberculosis.1 tuberculosis can involve the entire gastro-intestinal tract, from the intra-abdominal organs to the peritoneum. the spectrum of symptoms seen in abdominal tb range from insidious nonspecific complaints that may be mistaken for the constitutional symptoms of hiv infection, to an acute abdomen.2 with improved access to antiretrovirals, tb immune reconstitution inflammatory syndrome is being seen more frequently and often involves the abdomen.3 in resource-limited facilities, investigations such as abdominal computed tomography scanning and laparoscopic peritoneal biopsy are seldom available. however, abdominal ultrasound, specifically looking for hepatomegaly, ascites, splenic micro-abscesses and intra-abdominal lymphadenopathy, is a useful investigation for assessing hiv-infected patients with suspected abdominal tuberculosis.4 clinicians need to maintain a high index of suspicion for tb in patients with hiv and abdominal symptoms. in the correct clinical setting empiric anti-tuberculosis therapy is warranted. all patients started on anti-tuberculosis therapy need close follow-up until resolution, and those who fail to respond to tb therapy may require further investigation. nontuberculosis mycobacterial infection should be considered in patients with advanced immune deficiency. while abdominal tuberculosis in hiv-infected patients is best managed with standard tb therapy and anti-retrovirals, complications such as obstruction, perforation and large abscess formation may require surgical intervention.2 depending on clinical presentation, early consultation with the surgeons is essential and if required surgery should not be delayed. a d black department of medicine, chris hani baragwanath hospital and university of the witwatersrand, johannesburg references 1. who global report on tuberculosis 2009. http://apps.who.int/globalatlas/predefinedreports/tb/pdf_files/zaf.pdf (accessed 24 june 2010). 2. lazarus aa, thilagar b. abdominal tuberculosis. dis mon 2007; 53: 32-38. 3. meintjes g, rabie j, wilkinson rj, cotton mf. tuberculosis-associated immune reconstitution inflammatory syndrome and unmasking of tuberculosis by antiretroviral therapy. clin chest med 2009; 30(4): 797-810. 4. sinkala e, gray s, zulu i, et al. clinical and ultrasonographic features of abdominal tuberculosis in hiv positive adults in zambia. bmc infect dis 2009; 9: 44. abstract introduction methods results discussion conclusion acknowledgements references about the author(s) fatma elrashdy department of endemic medicine and hepatology, faculty of medicine, cairo university, cairo, egypt suzan hagag department of public health and community medicine, faculty of medicine, cairo university, cairo, egypt rahma mohamed department of endemic medicine and hepatology, faculty of medicine, cairo university, cairo, egypt kasr al-aini hiv and viral hepatitis fighting group, cairo university hospitals, cairo university, cairo, egypt shereen abdel alem department of endemic medicine and hepatology, faculty of medicine, cairo university, cairo, egypt safa meshaal department of clinical pathology, faculty of medicine, cairo university, cairo, egypt ahmed cordie department of endemic medicine and hepatology, faculty of medicine, cairo university, cairo, egypt kasr al-aini hiv and viral hepatitis fighting group, cairo university hospitals, cairo university, cairo, egypt aisha elsharkawy department of endemic medicine and hepatology, faculty of medicine, cairo university, cairo, egypt gamal esmat department of endemic medicine and hepatology, faculty of medicine, cairo university, cairo, egypt citation elrashdy f, hagag s, mohamed r, et al. incidence of hepatitis c virus infection among people living with hiv: an egyptian cohort study. s afr j hiv med. 2022;23(1), a1442. https://doi.org/10.4102/sajhivmed.v23i1.1442 original research incidence of hepatitis c virus infection among people living with hiv: an egyptian cohort study fatma elrashdy, suzan hagag, rahma mohamed, shereen abdel alem, safa meshaal, ahmed cordie, aisha elsharkawy, gamal esmat received: 03 aug. 2022; accepted: 16 sept. 2022; published: 09 nov. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: egypt used to have one of the highest hepatitis c virus (hcv) infection prevalence rates worldwide, with an estimated hcv prevalence of around 4.5% to 6.7%. objectives: to determine the hcv infection incidence rate amid egyptian patients living with hiv. method: a total of 460 hiv-positive patients were recruited in a retrospective cohort study from imbaba fever hospital, cairo, between january 2016 and march 2019. the patients had a negative baseline and at least one other hcv antibody test. hepatitis c virus antibody testing was done by antibody sandwich third-generation enzyme-linked immunosorbent assay. the hepatitis c virus infection incidence rate among hiv-infected patients was calculated using the person-time incidence rate. results: two hundred and eighteen patients were finally included: 146 (31.7%) patients were excluded for having a positive baseline hcv ab result and 96 patients were excluded for not having a follow-up hcv ab test. eighteen patients had hcv seroconversion (8.3%), achieving an incidence rate of 4.06 cases per 100 person-years (95% confidence interval: 3.87–4.24). injection drug use (idu) was the commonest risk factor among seroconverters, with an hcv incidence rate of 7.08 cases per 100 person-years. injection drug use history was reported in 83.3% of the seroconverters and in only 47.2% of non-seroconverters; p = 0.005. conclusion: egyptian hiv-infected patients show a high incidence rate of hcv infection especially among those who have a history of idu. accordingly, attention should be paid for prevention, screening and timely treatment of hcv in patients infected with hiv. what this study adds: the demonstration of a high hcv infection incidence rate among hiv-infected patients and shows the need for screening and prevention in this population. keywords: incidence rate of hcv; hcv screening; people living with hiv; egypt; idu; hcv seroconversion. introduction the hepatitis c virus (hcv) and hiv infections, which share some of the same modes of transmission and affected populations,1 represent major public health problems worldwide. globally, there are 58 million people with chronic hcv infection, 37.7 million people infected with hiv and 2.3 million with hiv/hcv co-infection.1,2,3 egypt used to have one of the highest hcv infection prevalence rates worldwide, with an estimated hcv prevalence of 4.5% to 6.7%.4 upon introduction of tolerable oral direct acting antiretrovirals (daas) in 2014 and the start of an unprecedented nationwide hcv screening and treatment campaign in egypt in 2018 to achieve the world health organization (who) 2030 hcv disease elimination target, the prevalence of hcv declined dramatically; it is expected to reach less than 0.5% during 2020.5,6,7 however, special high-risk groups of hcv-infected patients like people who inject drugs (pwid) and people living with hiv (plhiv) need more attention and micro-elimination strategies to achieve the who elimination goal.8 hiv/hcv co-infection changes the course and outcomes of both infections significantly.9 chronic hcv infection increases morbidity and mortality among plhiv.10 hepatitis c virus causes chronic inflammation with impaired immune system reconstitution after anti-retroviral therapy (art).9,11 in addition, hcv increases the risk of renal, cardiovascular diseases and hepatocellular carcinoma (hcc).9 people living with hiv have a higher hcv viral load with less possibility of spontaneous clearance of hcv infection.12 moreover, hiv makes hcv a more aggressive infection with accelerated progression to liver cirrhosis, liver cell failure and hcc.13 in 2020, the joint united nations programme on hiv/aids (unaids) stated that out of the middle east and north africa region (mena), egypt has the fastest growing hiv epidemic despite low (< 0.1% by the end of 2020) hiv prevalence in the general population.14 over the past 10 years, incidence of hiv increased by 25% – 35% every year with men who have sex with men (msm) and pwid being the most affected groups.14 there are scarce data about the burden of and risk factors for hcv infection among plhiv in egypt. therefore, the aim of this study is to fill the existing knowledge gap on hcv epidemiology among patients infected with hiv attending one of the large reference centres of hiv in cairo, egypt. methods study participants and settings we performed a retrospective cohort study in which we recruited plhiv aged 18 years or older attending imbaba fever hospital, cairo, between january 2016 and march 2019, excluding patients who refused to participate. the inclusion criteria for this study was a negative baseline anti-hcv test and at least one subsequent hcv antibody test during the study time. study methods demographic data were reported including age, gender and marital status. data about self-reported risk factors for hiv infection were collected as history of injection drug use (idu), risky sexual behaviour, previous operations and dental procedures. the status of hiv was assessed regarding the current cd4 t-cell count, plasma hiv viral load and art treatment status. hepatitis c virus antibody testing was done by using the murex anti-hcv third-generation enzyme-linked immunosorbent assay (elisa) (version 4) sandwich technique (abbott laboratories, abbott park, illinois, united states). the first positive anti-hcv test during follow-up was considered as the hcv seroconversion. the midpoint between the first positive and last negative anti-hcv tests was estimated as the date of this seroconversion (incident hcv infection). the person-time incidence rate is defined as the number of new cases of a disease occurring in a population during a specified period of time per total person-time (sum of the time period of observation of each person who has been observed). the equation we used to calculate hcv incidence rate was: observation durations were calculated until hcv seroconversion, death, loss to follow-up or the end of the study, whichever occurred first. data management data were analysed by mean and standard deviation in the case of quantitative data, and by frequencies (number of cases) and percentages in the case of categorical data. a chi-square test was used to compare categorical data. p-values less than 0.05 were considered statistically significant. a mann–whitney u test was used to compare quantitative variables between the studied groups. when the expected frequency was less than 5, we used an exact test instead. all data were processed using ibm® spss® version 22 (ibm corp., armonk, new york, united states). ethical considerations the study was designed to respect all ethical guidelines of the 1975 declaration of helsinki and was approved by the institutional review board of the faculty of medicine, cairo university (approval code n-149-2018). results incidence rate of hepatitis c virus infection four hundred and sixty patients were screened. after exclusion of patients with a positive baseline hcv test and who didn’t have any follow-up anti-hcv test, 218 patients were finally included (figure 1). the 218 patients at risk of incident hcv infection at baseline contributed 5312 person-months or 443 person-years of observation. eighteen patients had hcv seroconversion representing an incidence rate of 4.06 per 100 person-years (95% confidence interval [ci]: 3.87–4.24). figure 1: a flowchart illustrating the study population selection. grey boxes denote the patients excluded from the study. characteristics of patients with and without hepatitis c virus seroconversion at the time of seroconversion the mean age was 42.3 years, and 83.3% of seroconverters were male. no significant difference was found between hcv ab negative patients and hcv seroconverters (table 1). table 1: sociodemographic characteristics and hiv status of study participants. injection drug use (p-value 0.005), history of dental procedures (p-value < 0.001) and previous operations (p-value 0.019) were significantly higher in hcv seroconverters compared to hcv ab negative patients (table 2). table 2: self-reported risk factors for hiv and hepatitis c virus among study participants. there were 108 pwid at risk of hcv infection at baseline contributing 2541 person-months or 212 person-years of observation. fifteen of the 108 pwid had hcv seroconversion representing an hcv incidence rate of 7.08 per 100 person-years (95% ci: 6.72–7.44). discussion in this cohort of egyptian plhiv, the hcv infection incidence rate is 4.06 per 100 person-years. this high hcv incidence rate among egyptian plhiv is likely due to several factors. first, there is a lack of effective prevention programmes for hiv and hcv transmission in egypt like opioid substitution therapy (ost) and needle and syringe programmes (nsp).15 second, there is limited hcv screening in some high-risk groups like msm, despite the well-established screening programme dedicated to pwid as a part of the process to meet who targets of hcv elimination.16 third, there are barriers of access to treatment of hcv in plhiv, like fear of community stigma.17 the incidence rate we observed is higher than that of the incidence of hcv infection in the general egyptian population, which was estimated as 0.08–1.02 per 100 person-years by a systematic review conducted in 2018.18 moreover, in 2020, prevalence of hcv infection in the general egyptian population is expected to decrease to less than 0.5%, thanks to the nationwide screening and treatment programme ‘100 million health’ started in 2018.5 however, the hcv infection incidence rate among egyptian plhiv remains high, raising the need for more effective application of prevention programmes, regular screening and micro-elimination strategies of hcv in plhiv in egypt. the available egyptian and african studies in literature usually reported the epidemiology of hiv/hcv co-infection in terms of prevalence. however, the incidence rate estimation is also needed to assess the rate of new hcv infections among plhiv so we can better judge the prevention programmes and hcv treatment strategies among this population. the incidence rates of hiv/hcv co-infection in some asian and european countries were lower than that reported in this study with a rate of 0.88 per 100 person-years in singapore,19 and 0.72 and 0.44 per 100 person-years among msm in france20 and italy21. a systematic review conducted between 2000 and 2016 reported an incidence rate of 0.78 per 100 person-years among msm.22 in our study, the risk factors found to be associated with getting hcv infection in plhiv are idu, history of dental procedures and operations. injection drug use was associated with the highest incidence rate of hcv infection of 7.08 per 100 person-years. globally, the two most vulnerable groups for hiv infection and hiv/hcv co-infection are msm and pwid.3 however, pwid is the commonest group to get these infections in mena countries because of the religious and social backgrounds that prohibit and limit msm actions.1 in a global systematic review conducted between 01 january 2002 and 28 january 2015, 1.4 million out of 2.3 million hiv/hcv co-infected patients were estimated to be pwid worldwide. the prevalence of hiv/hcv co-infection was estimated as 2.4% in the general population, 6.4% in msm (highest in north american region) and 82.4% in pwid (highest in mena region).1 in the eurosida cohort study, 23 309 plhiv were enrolled from the who european region and argentina, showing that 57.4% of patients with hiv/hcv co-infection were pwid.23 the effect of hcv infection on cd4 cell count is controversial. some studies found a decrease in cd4 cell count with hiv/hcv co-infection, hypothesised to be due to the apoptosis of cd4 cells caused by hcv.24 other studies found no effect, like we reported.25,26 our study has some limitations. first, we did not confirm hcv infection by doing hcv polymerase chain reaction, which could have resulted in an over-estimation of incidence. however, a positive hcv antibody test can indicate current infection. second, most of included patients performed follow-up hcv antibody tests only once. this occurred because of the retrospective nature of the study. conclusion despite the great success of hcv infection control in the general egyptian population thanks to the enormous nationwide screening programme ‘100 million health’, the incidence rate of hcv infection in egyptian plhiv is high, especially among pwid. accordingly, more effort is needed in preventive measures of risk factors, regular screening of plhiv for hcv, and the start of daa treatment once diagnosed. acknowledgements we acknowledge cairo university for sponsoring and support of the project entitled ‘hepatitis c virus prevalence among patients infected with human immunodeficiency virus registered for antiretroviral therapy in fever hospitals of cairo’ (project id 51) which represented part of this article’s data. competing interests g.e. is a speaker, advisory board member and investigator for gilead science. all other authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions f.e., s.h., r.m., s.a.a., s.m., a.c., a.e. and g.e. substantially contributed to the conception and design, acquisition of data and data analysis and interpretation. all authors have read and approved the manuscript. f.e. and s.h. were responsible for data analysis and interpretation and manuscript writing. s.a.a. and a.e. were responsible for data analysis and interpretation. r.m. and a.c. designed the study protocol and were responsible for data collection and acquisition. s.m. carried out the laboratory tests. g.e. was responsible for the study design, conception and manuscript revision. funding information this work was supported by cairo university (project id 51), cairo, egypt. data availability the data supporting the results are available from the corresponding author, f.e., on reasonable request. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references platt l, easterbrook p, gower e, et al. prevalence and burden of hcv co-infection in people living with hiv: a global systematic review and meta-analysis. lancet infect dis. 2016;16(7):797–808. https://doi.org/10.1016/s1473-3099(15)00485-5 world health organization. hepatitis c: fact sheet [homepage on the internet]. 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[cited 2022 mar 18]. available from: www.unaids.org/sites/default/files/media_asset/unaids_factsheet_en.pdf el-zanaty and associates. egypt health issues survey 2015. rockville, md: ministry of health and population, icf international; 2015. waked i, esmat g, elsharkawy a, et al. screening and treatment program to eliminate hepatitis c in egypt. n engl j med. 2020;382(12):1166–1174. https://doi.org/10.1056/nejmsr1912628 world health organization. global health sector strategy on viral hepatitis 2016–2021 [homepage on the internet]. 2016 [cited 2022 mar 18]. available from: https://www.who.int/publications/i/item/who-hiv-2016.06 falade-nwulia o, suarez-cuervo c, nelson dr, et al. oral direct-acting agent therapy for hepatitis c virus infection: a systematic review. ann intern med. 2017;166(9):637–648. https://doi.org/10.7326/m16-2575 hollande c, parlati l, pol s. micro-elimination of hepatitis c virus. liver int. 2020;40(suppl. 1):67–71. https://doi.org/10.1111/liv.14363 soriano v, vispo e, fernandez-montero jv, et al. update on hiv/hcv coinfection. curr hiv/aids rep. 2013;10(3):226–234. https://doi.org/10.1007/s11904-013-0169-5 collins s, mertenskoetter t, loeliger e, et al. liver-related deaths in persons infected with the human immunodeficiency virus: the d:a:d study. archiv intern med. 2006;166(15):1632–1641. https://doi.org/10.1001/archinte.166.15.1632 kim ay, onofrey s, church dr. an epidemiologic update on hepatitis c infection in persons living with or at risk of hiv infection. j infect dis. 2013;207(suppl_1):s1–s6. https://doi.org/10.1093/infdis/jis927 sulkowski ms. viral hepatitis and hiv coinfection. j hepatol. 2008;48(2):353–367. https://doi.org/10.1016/j.jhep.2007.11.009 holmberg s, ly k, xing j, et al. the growing burden of mortality associated with viral hepatitis in the united states, 1999–2007. hepatology. 2011;54(4):243. unaids. country factsheets: egypt 2020 [homepage on the internet]. [cited 2022 mar 18]. available from: https://www.unaids.org/en/regionscountries/countries/egypt oraby d. harm reduction approach in egypt: the insight of injecting drug users. harm reduct j. 2013;10:17. https://doi.org/10.1186/1477-7517-10-17 world health organization. implementation tool for pre-exposure prophylaxis (prep) of hiv infection. module 10: testing providers [homepage on the internet]. 2017 [cited 2022 apr 11]. available from: https://apps.who.int/iris/handle/10665/258516 eletreby r, esmat g, elsharkawy a, et al. hcv/hiv coinfected egyptian patients: a cross-sectional study of their main characteristics and barriers to hcv treatment initiation. trans r soc trop med hyg. 2022;116(3):227–232. https://doi.org/10.1093/trstmh/trab106 kouyoumjian sp, chemaitelly h, abu-raddad lj. characterizing hepatitis c virus epidemiology in egypt: systematic reviews, meta-analyses, and meta-regressions. sci rep. 2018;8(1):1661. https://doi.org/10.1038/s41598-017-17936-4 ang lw, choy cy, ng ot, et al. hepatitis c virus infection in hiv-infected men in singapore, 2006–2018: incidence and associated factors. sex health. 2021;18(3):221–231. https://doi.org/10.1071/sh20197 castry m, cousien a, bellet j, et al. hepatitis c virus (hcv) incidence among men who have sex with men (msm) living with hiv: results from the french hospital database on hiv (anrs co4-fhdh) cohort study, 2014 to 2017. euro surveill. 2021;26(38):2001321. https://doi.org/10.2807/1560-7917.es.2021.26.38.2001321 cuomo g, digaetano m, menozzi m, et al. incidence of hcv infection amongst hiv positive men who had sex with men and prevalence data from patients followed at the infectious diseases clinic of modena, italy. dig liver dis. 2018;50(12):1334–1338. https://doi.org/10.1016/j.dld.2018.05.021 ghisla v, scherrer au, nicca d, et al. incidence of hepatitis c in hiv positive and negative men who have sex with men 2000–2016: a systematic review and meta-analysis. infection. 2017;45(3):309–321. https://doi.org/10.1007/s15010-016-0975-y fursa o, mocroft a, lazarus jv, et al. the hepatitis c cascade of care in hiv/hepatitis c virus coinfected individuals in europe: regional and intra-regional differences. aids. 2022;36(3):423–435. https://doi.org/10.1097/qad.0000000000003112 potter m, odueyungbo a, yang h, et al. impact of hepatitis c viral replication on cd4+ t-lymphocyte progression in hiv-hcv coinfection before and after antiretroviral therapy. aids. 2010;24(12):1857–1865. https://doi.org/10.1097/qad.0b013e32833adbb5 shmagel kv, saidakova ev, korolevskaya lb, et al. influence of hepatitis c virus coinfection on cd4+ t cells of hiv-infected patients receiving haart. aids. 2014;28(16):2381–2388. https://doi.org/10.1097/qad.0000000000000418 korner c, kramer b, schulte d, et al. effects of hcv co-infection on apoptosis of cd4 t-cells in hiv positive patients. clin sci. 2009;116(12):861–870. https://doi.org/10.1042/cs20080532 abstract the promise and pitfalls of oral pre-exposure prophylaxis the promises and pitfalls of injectable pre-exposure prophylaxis fulfilling the promises through choice acknowledgements references about the author(s) carey pike desmond tutu hiv centre, faculty of health sciences, university of cape town, cape town, south africa elzette rousseau desmond tutu hiv centre, faculty of health sciences, university of cape town, cape town, south africa linda-gail bekker desmond tutu hiv centre, faculty of health sciences, university of cape town, cape town, south africa citation pike c, rousseau e, bekker l-g. promises and potential pitfalls of long-acting injectable pre-exposure prophylaxis. s afr j hiv med. 2023;24(1), a1497. https://doi.org/10.4102/sajhivmed.v24i1.1497 review article promises and potential pitfalls of long-acting injectable pre-exposure prophylaxis carey pike, elzette rousseau, linda-gail bekker received: 29 mar. 2023; accepted: 19 apr. 2023; published: 27 july 2023 copyright: © 2023. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract the number of products that can provide pre-exposure prophylaxis (prep) for hiv prevention is expanding, with three now approved in south africa (oral tenofovir-based prep, injectable cabotegravir, and a dapivirine-based vaginal ring) and more in the development pipeline. although highly effective and safe, oral prep products have not reduced hiv incidence in south africa to the extent seen in other countries, primarily due to adherence challenges, rapidly diminishing persistence over time, and insufficient scale-up of prep service delivery. the dapivirine vaginal ring, which provides 1-month-long protection, provides women with a new and discreet choice for prep; however, it is cabotegravir long-acting (cab la) that is anticipated to land the largest impact. administered as an intramuscular injection given every 2 months, cab la is safe, highly efficacious, and expected to become available in south africa in late 2023. yet, clinical and implementation questions remain, including the need to understand and characterise breakthrough hiv infections amongst cab la users, knowledge of how to package each prep product in a new context of prep choice, and how to avoid the remedicalisation of prep access following extensive efforts to make oral prep delivery differentiated and community based. keywords: hiv prevention; pre-exposure prophylaxis; long-acting prep; cabotegravir long-acting; injectable prep. what this study adds: a new hiv prevention product, injectable cabotegravir long-acting (cab la) for pre-exposure prophylaxis (prep), has been approved for use in south africa. this article explores cab la’s promise to boost hiv prevention product uptake and persistence and outlines the current implementation questions and concerns. more than 40 years after the discovery of hiv and aids, one of the last remaining hiv vaccine candidates in late-stage clinical trials (mosaic trial) failed to show efficacy in preventing hiv infection compared to a placebo.1 in the continued absence of an effective hiv vaccine, alternative hiv prevention approaches remain critical to stemming the ongoing high annual incidence of new hiv infections.2 although the annual hiv incidence has decreased by 54% since its peak in 1996, in 2021 an estimated 1.5 million people were infected. in sub-saharan africa (ssa), women and girls account for the majority (63%) of all new infections, while elsewhere key populations face significantly higher risk (28 times greater risk amongst men who have sex with men [msm]; 35 times higher among people who inject drugs).3 fortunately, there has been a flurry of new prevention products and interventions in the last 15 years, particularly the onset of antiretroviral-based prevention options. the promise and pitfalls of oral pre-exposure prophylaxis when hiv emerged, hiv prevention strategies were restricted to the abc strategy: abstinence, being faithful to your partner, and condoms. while an effective approach, this was viewed as unpalatable by most and unfeasible by many, and failed to stem the tide of hiv infections that was to come. over time, a range of new methods have been developed that are people-centred, respectful of choice and differences in lifestyle, and allow for combined behavioural and biomedical approaches. a key biomedical approach available on the market since 2012 has been oral pre-exposure prophylaxis (prep). oral prep regimens, which provide prophylactic antiretroviral cover with either tenofovir/emtricitabine (tdf/ftc) or tenofovir alafenamide/emtricitabine have a strong safety profile and were found to be highly effective in diverse populations, including adolescents, msm and serodiscordant couples.4,5,6,7 oral prep appeared poised to deliver the promised land: tumbling hiv infections, a user-controlled method, and a simple regimen – albeit tedious in its daily repetition. the promised land has been slow to materialise – at least here in ssa. while as of february 2023, prep watch reported 792 434 prep initiations in south africa, which is more than three times the national target, high uptake of oral prep alone does not necessarily equate to effective hiv prevention and transmission reductions, as good adherence and long-term persistence are required to ensure optimal coverage of hiv exposure events.8 a global systematic review and meta-analysis that included 43 917 participants showed that 41.0% (95% confidence interval [ci]: 18.8–63.5) of participants discontinued prep within 6 months, with higher discontinuation rates (47%, 95% ci: 29.4–66.4) in the ssa region.9 the rate of return within the first month of prep initiation in south africa, a checkpoint visit for side effects and adherence challenges, was found to be less than 30% (personal communication from the western cape department of health, august 2022). although clinical efficacy trials showed high prep adherence among msm, adherence challenges were forewarned during efficacy trials amongst african women (voice and fem-prep), where efficacy was limited or completely absent.10,11 drug level testing in these trials later showed that adherence to a daily prep regimen was achieved in less than 25% of participants, although effectiveness did improve in follow-up open-label trials.10 pre-exposure prophylaxis use does need to be understood within the context of dynamic individual risk, however, where not all prep discontinuation is necessarily inappropriate. a recent study on prep discontinuation within a large, national programme in kenya found that three-quarters of prep discontinuations occurred because participant risk profiles had changed (e.g. partner separation, partner viral suppression achieved) or they were using another appropriate hiv prevention method. reaching people at times of high risk and allowing them to appropriately cycle on and off prep as needed may be critical, and realistic, for real-world success. in addition, for prep users who may not be exposed to hiv via the vaginal mucosa, such as msm, the option of event-driven prep is now also feasible and effective.12 this is particularly useful for people in whom sex is reliably predictable, since it requires two pills 2 h – 24 h before sex and then a pill 24 h and 48 h later.13 since the introduction of oral prep into the market, young people (< 30 years) have shown lower reported levels of adherence to oral prep agents.14 reasons reported include clinical challenges such as side effects, logistical challenges such as pill storage and the risk of stock-outs, and social challenges such as fear and experiences of stigma, judgement, and violence.14,15 preference and acceptability studies have indicated that a pill product may not be the preferred formulation in young south african populations. the ‘uchoose’ study employed a crossover design, where young women were randomised to receive contraceptive oral pills, rings, and injectable products analogous to potential new prep formulations, in order to determine user preference. the predominant reason provided by this cohort against daily oral contraception, and hence daily oral prep, was that three-quarters of participants feared they would forget to regularly take the tablets.16 the development of new longer-acting (less-frequently dosed) prep formulations, such as vaginal rings (the dapivirine vaginal ring, which provides hiv protection for 28 days, was licensed for use in south africa in march 2022), injectable products, and implants, have been proposed as a means to overcome these barriers and to maximise the potential of prep to prevent hiv among adolescents and young people (figure 1). figure 1: the primary prevention train: hiv prevention options, of which pre-exposure prophylaxis options are expanding to provide a choice of products that can be used preferentially by different populations. the promises and pitfalls of injectable pre-exposure prophylaxis an injectable prep option, cabotegravir long-acting (cab la) was approved by the south african health products regulatory authorities (sahpra) in december 2022 for use by individuals (weighing at least 35 kg) at risk of sexually acquired hiv-1 infection.17 cabotegravir long-acting comprises cabotegravir, a strand-transfer integrase inhibitor. when delivered as a suspension via a gluteal 600 mg intramuscular injection, it provides protection against hiv infection for at least 8 weeks. this necessitates injections every 8 weeks, with an initial two injections 4 weeks apart.17 two double-blind, double-placebo studies (hptn 083 and hptn 084) showed that cab la is superior to daily, oral tdf/ftc, as evidenced by a lower hiv incidence in the cab la arms compared to oral prep arms, in both male and female populations.14,18 this superior effectiveness likely resulted, at least partially, from improved adherence to injectable versus oral prep, as oral prep’s efficacy is up to 100% (95% ci: 83.7–100) when adherence is high (> 80%).19 hptn 083 was conducted amongst cisgender men and transgender women who have sex with men in the united states, latin america, asia and africa, and those in the cab la arm had a 66% lower risk of hiv infection compared to the tdf/ftc cohort.18 the hptn 084 study was conducted amongst cisgender women across seven ssa countries and those in the cab la arm had an 88% lower risk of hiv infection compared to the tdf/ftc cohort.14 a systematic review and meta-analysis of all cab la safety and efficacy studies gave a pooled relative risk ratio of 0.21 (95% ci: 0.07–0.61), which indicates a 79% reduction in hiv risk with cab la compared to oral prep.20 cabotegravir long-acting was subsequently approved for use as hiv prep in the united states, australia, zimbabwe and south africa, and is recommended by the world health organization as an ‘additional prevention choice for people at substantial risk of hiv infection, as part of combination prevention approaches (conditional recommendation, moderate certainty of evidence)’.21 the predicted promise of cab la, according to a modelling study focused on cab la impact in ssa, is a reduction in hiv incidence by 29% over a 20-year period, with a knock-on reduction in aids deaths of 4540 annually, assuming an adult population of 10 million.22 this impact is at least partially attributed to an expected significant rise in prep use following cab la introduction, with 46% of those eligible for prep using compared to 28% in a no cab la scenario.22 this preference has also played out in the open-label choice component of the efficacy trials where the majority of participants are choosing the cab la option over oral prep. part of the power of long-acting injectable prep modalities is thus to mitigate daily adherence challenges, while likely allowing for earlier detection of non-adherence due to the need for a healthcare professional to administer the drug directly.15 however, injectable prep also has the disadvantage of needing trained healthcare professionals to administer the product (a large volume, intramuscular injection), which requires prep users to return to health facilities every 2 months – a high clinic visit frequency compared to oral prep, which can be given as a 3-month supply.23 alternative injectable formulations currently in clinical trials may offer a future solution. lenacapavir for prep, currently in phase three trials known as ‘purpose 1 and 2’, is administered subcutaneously every 6 months and so will also have the added advantage for possible self-administration, especially by at-risk populations familiar with injecting techniques (such as people who inject drugs and transgender populations already self-administrating gender-affirming hormone therapy).23 lastly, while oral tdf/ftc prep is associated with a decline in bone mineral density, cab la has been found to be associated with a slight increase (0.82% with cab la use compared to −0.82% with tdf/ftc use, p < 0.01) over the short (57 weeks) and long term (105 weeks).25 this may make cab la a suitable alternative for people with low bone mineral density at prep initiation. while cab la efficacy and safety have been broadly established, there remain a number of outstanding clinical and implementation questions.21 first, for women in ssa at high risk for hiv acquisition during pregnancy and breastfeeding (up to three times higher risk compared to non-pregnant women),26 prep provides a powerful means of protection, but safety for cab la injectable prep has not yet been established during pregnancy. no congenital birth anomalies were reported in hptn 084, which reported a pregnancy incidence of 1.3 per 100 person years (0.9–1.7) and is currently in an open-label extension phase allowing for the inclusion of pregnant participants.14 based on large numbers of pregnancies in hiv-treated women, oral tdf-based prep is now recommended in women at high risk of hiv acquisition before and during pregnancy and lactation. so far, data from animal and clinical trials have been reassuring, and injectable prep is not contra-indicated during pregnancy and lactation on the patient information leaflet. however, given the paucity of safety data, healthcare providers are encouraged to counsel pregnant women on the risks and benefits of its use, and pregnancy registries are also being established.17,27,28 the dapivirine vaginal ring has also recently been shown in early results from two studies from the microbicides trials network to be safe for use in pregnant and lactating women, with one study showing very low concentrations of dapivirine in infant plasma samples with good ring adherence, while the second study showed no safety concerns in the third trimester of pregnancy.29,30 the latter trial is ongoing to provide data regarding safety in early pregnancy (12–20 weeks). overall, the results are showing promise that pregnant and lactating women will be able to safely access a range of prep options; however, close monitoring is ongoing and pregnancy registries remain good practice. second, cabotegravir persists in the plasma for months following a single injection, only decreasing below the lower limit of quantification at a median time of 44 weeks for men and 67 weeks for women (primarily due to slower absorption in women, resulting in a longer half-life).31,32 furthermore, there appear to be a number of factors that influence cabotegravir half-life, including body mass index, indicating that it will likely be variable across populations.32 it remains unknown whether such residual drug concentrations (the pharmacological ‘tail’) following cessation of prep injections could contribute to selection of hiv variants resistant to integrase inhibitors. the development of integrase inhibitor resistance is concerning because it will render the individual unable to use dolutegravir and other integrase inhibitors during treatment.33 drug-resistant variants have been found in people who have been initiated onto cab la with an undiagnosed hiv infection and in the rare instances (< 0.3% in hptn 083; 0.06% in hptn 084) breakthrough infections have occurred while the individuals had high (protective) systemic concentrations of cabotegravir.34,35 this may be due to false-negative hiv screening during acute hiv infection prior to seroconversion. in order to reduce this risk, the food and drug administration has approved cab la injectable prep in the united states, with the proviso that initiation must include the use of a nucleic acid test. this requirement, if implemented in lowto middle-income countries, may be an additional cost and logistical barrier to injectable prep use. there was one recent case of a 28-year-old gender-diverse patient in the united states who seroconverted after 91 days on cab la, despite correct on-time dosing and laboratory monitoring for hiv infection.36 such breakthrough infections have been rare in the case of oral prep (< 10 cases out of 2 million users, attributable primarily to viral resistance to tdf or ftc).37 these breakthrough infections have recently been coined ‘long-acting early viral inhibition (levi)’ syndrome in which the presentation of acute infection is atypical – people do not feel unwell, the viral load is reduced, and the infections are generally more difficult to detect with standard tests, resulting in very delayed diagnosis.38 the majority of these rare infections have shown resistance to integrase inhibitors and further studies, such as the picasso trial, are planned to guide what the optimal first-line treatment could then be for cab la users that develop resistance. a modelling study contextualised in ssa predicts integrase inhibitor resistance to rise to 12.1% (4.1% – 30.9%) following cab la introduction, compared to 1.7% (0% – 6.4%) in its absence.22 while no new infections occurring after cessation of cab la have shown resistance, there remains concern that it is theoretically plausible due to the prolonged ‘tail’ and dwindling plasma concentrations. while further studies are needed to understand the level of risk, this also needs to be viewed in context with the development of resistance in treatment of people living with hiv due to inadequate adherence and the overall benefit of cab la in preventing this by preventing new infections.21 third, although cab la has been approved for adolescent populations in south africa and elsewhere, the original cab la trials did not include participants under the age of 18. there are two ongoing sub-studies of hptn 083-01 and 084-01 that are evaluating the safety, tolerability, and acceptability of cab la among adolescent female and male patients (< 18 years).39,40 early findings from hptn 084-01 have shown cab la to be safe, tolerable, and acceptable to adolescent (< 18 years) female patients in south africa, uganda and zimbabwe.41 in ssa, adolescents and youth are at high risk of hiv acquisition, with adolescent girls and young women (15–24 years) accounting for 25% of all new infections, despite representing just 10% of the population.3 hiv incidence starts to rise from age 15–19 years and peaks between 20 and 24 years for adolescent girls and young women and other key populations in the region.42,43 this makes their inclusion in injectable prep roll-outs a significant priority, especially considering the strong evidence that this population, in particular, has struggled with adherence and persistence with oral formulations and has voiced a preference for injectable options.14,15,16 the lenacapavir, purpose 1 trial currently underway in african women includes both pregnant and adolescent women.24 finally, the cost of cab la, which is currently pegged substantially higher than that of oral prep, has already been called out by providers, patients, and advocates as far too high to be sustainable for public sector roll-out in the south african and lowerto middle-income country context. given the predicted advantageous impact of cab la on prep use, hiv incidence, and aids deaths in ssa, cab la would be cost effective in a scenario where long-acting prep is delivered at the same or no more than double the cost of generic oral prep. this modelling study also recommended the use of antibody-based rapid hiv testing in order to be cost effective.22 the cost of cab la currently lies > 185 times higher than the cost-effectiveness threshold (estimated to be $60.00 – $199.00)44 for middle-income countries. viiv healthcare has provided generic version access to 90 countries in the medicines patent pool, which includes south africa alongside all other african nations, but notably excludes other middle-income countries with similar gross domestic products.45 beyond the cost of cab la product, the need for and cost of close monitoring and follow-up with cab la users, at least initially, in order to monitor for breakthrough hiv infections and resistance development, should be considered. fulfilling the promises through choice expanding prep choice needs to include more than a selection of prep options. there needs to be choice across all hiv prevention products, including condoms, voluntary male medical circumcision, education on treatment as prevention and u=u (undetectable viral load means there is no chance of sexual hiv transmission – it is untransmissible). individuals’ preferences may cycle between options or include multiple approaches. there should be choice around where and how to receive prep, including health facility versus community-based delivery services. while there have been extensive efforts to diversify service delivery for oral prep, there are a number of anticipated challenges for delivering injectable products outside of a clinical environment (figure 2).46 this may turn out to be a major affecter of choice, depending on whether someone would be happier accessing oral prep via courier or from a community depot versus accessing injectable from a formal clinic facility. innovation to overcome the remedicalisation of prep with injectables is possible, especially off the back of coronavirus disease 2019 vaccine campaigns that included highly accessible pop-up vaccine centres and ‘vaxi taxis’.47 alternatively, prep choice could further be couched into a menu of other sexual reproductive health services, such as contraception and testing, for sexually transmitted infections. ultimately, choice should look like a fast-food menu: would you like a side of condoms with your oral prep bottle? upsize from oral to injectable prep! spend 20 minutes extra and also receive contraceptive choice counselling from the same friendly healthcare provider. figure 2: will new pre-exposure prophylaxis (prep) options lead to remedicalisation? comparison of implementation considerations across prep products (available and in clinical trials) and passive vaccination options. there are a number of injectable prep and prep choice trials poised to commence in south africa in 2023, some of which are poised to investigate uptake of cab la, the impact of cab la on prep persistence, patient and provider perspectives on prep products and delivery settings, and what a feasible and acceptable delivery package would look like for various populations.48 these efforts are necessary if we are to realise the full potential of cab la and prep choice, as well as set the ground for other longer-acting modalities. acknowledgements competing interests l.-g.b. sits on advisory panels for gilead sciences and viiv healthcare (unrelated to this review). c.p. and e.r. have no competing interests. authors’ contributions c.p., e.r., and l.-g.b. conceptualised the manuscript. c.p. wrote the original draft and all authors were involved in its review and editing. ethical considerations this article followed all ethical standards for research without direct contact with human or animal subjects. funding information the review received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability data sharing is not applicable to this article, as no new data were created or analysed in this study. disclaimer the views and opinions in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references buchbinder s. overview of the mosaico hiv vaccine trial. in: conference on retroviruses and opportunistic infections, seattle, special session, 2023 (unpublished). rosenberg ne, shook-sa be, liu m, et al. adult hiv-1 incidence across 15 high-burden countries in sub-saharan africa from 2015 to 2019: a pooled analysis of nationally representative data. lancet hiv. 2023;10(3):e175–e185. https://doi.org/10.1016/s2352-3018(22)00328-9 unaids. in danger: unaids global aids update 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[cited 2023 mar 22]. available from: https://www.croiconference.org/abstract/bone-density-changes-with-cab-la-or-tdf-ftc-prep-in-msm-and-tgw-in-hptn-083/ drake al, wagner a, richardson b, john-stewart g. incident hiv during pregnancy and postpartum and risk of mother-to-child hiv transmission: a systematic review and meta-analysis. plos med. 2014;11(2):e1001608. https://doi.org/10.1371/journal.pmed.1001608 joseph davey dl, pintye j, baeten jm, et al. emerging evidence from a systematic review of safety of pre-exposure prophylaxis for pregnant and postpartum women: where are we now and where are we heading? j int aids soc. 2020;23(1):e25426. https://doi.org/10.1002/jia2.25426 south african national department of health. 2021 update guidelines for the provision of oral pre-exposure prophylaxis (prep) to persons at substantial risk of hiv infection [homepage on the internet]. 2021 [cited 2023 mar 01]. available from: https://www.knowledgehub.org.za/system/files/elibdownloads/2022-08/prep%20guidelines%20update%2012%20%20nov%20%202021%20final.pdf bunge k, balkus j, mhlanga f, et al. a safety study of a dapivirine vaginal ring and oral prep for the prevention of hiv during pregnancy. in: conference on retroviruses and opportunistic infections, seattle. abstract 127. 2023. available: https://www.croiconference.org/abstract/deliver-a-safety-study-of-a-dapivirine-vaginal-ring-and-oral-prep-during-pregnancy/ owor m, ngouchi l, horne e, et al. dapivirine ring safety and drug detection in breastfeeding mother-infant pairs. in: conference on retroviruses and opportunistic infections, seattle, abstract 785. 2023. available: https://www.croiconference.org/abstract/dapivirine-ring-safety-and-drug-detection-in-breastfeeding-mother-infant-pairs/ landovitz rj, li s, eron jj, et al. tail-phase safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in hiv-uninfected adults: a secondary analysis of the hptn 077 trial. lancet hiv. 2020;7(7):e472–e481. https://doi.org/10.1016/s2352-3018(20)30106-5 han k, baker m, lovern m, et al. population pharmacokinetics of cabotegravir following administration of oral tablet and long-acting intramuscular injection in adult hiv-1-infected and uninfected subjects. br j clin pharmacol. 2022;88(10):4607–4622. https://doi.org/10.1111/bcp.15439 parikh um, mellors jw. how could hiv-1 drug resistance impact preexposure prophylaxis for hiv prevention? curr opin hiv aids. 2022;17(4):213–221. https://doi.org/10.1097/coh.0000000000000746 eshleman sh, fogel jm, piwowar-manning e, et al. characterization of human immunodeficiency virus (hiv) infections in women who received injectable cabotegravir or tenofovir disoproxil fumarate/emtricitabine for hiv prevention: hptn 084. j infect dis. 2022;225(10):1741–1749. https://doi.org/10.1093/infdis/jiab576 marzinke ma, grinsztejn b, fogel jm, et al. characterization of human immunodeficiency virus (hiv) infection in cisgender men and transgender women who have sex with men receiving injectable cabotegravir for hiv prevention: hptn 083. j infect dis. 2021;224(9):1581–1592. https://doi.org/10.1093/infdis/jiab152 hazra a, quinby c, creticos c. breakthrough hiv-1 infection in setting of long-acting cabotegravir for prep [homepage on the internet]. in: croi, february 19–22, 2023. seattle, wa. abstract: 981. [cited 2023 mar 22]. available from: https://www.croiconference.org/abstract/breakthrough-hiv-1-infection-in-setting-of-long-acting-cabotegravir-for-prep/ gibas km, van den berg p, powell ve, krakower ds. drug resistance during hiv pre-exposure prophylaxis. drugs. 2019;79(6):609–619. https://doi.org/10.1007/s40265-019-01108-x eshleman sh, fogel jm, piwowar-manning e, et al. the levi syndrome: characteristics of early hiv infection with cabotegravir for prep. in: conference on retroviruses and opportunistic infections, seattle. abstract 160. 2023. [cited 2023 mar 22]. available: https://www.croiconference.org/abstract/the-levi-syndrome-characteristics-of-early-hiv-infection-with-cabotegravir-for-prep/ clinicaltrials.gov. bethesda (md): national library of medicine (us). 2020, december 31. identifier nct04692077. safety, tolerability and acceptability of long-acting cabotegravir (cab la) for the prevention of hiv among adolescent males – a sub-study of hptn 083. available: https://clinicaltrials.gov/ct2/show/nct04692077 clinicaltrials.gov. bethesda (md): national library of medicine (us). 2020, december 31. identifier nct04824131. safety, tolerability and acceptability of long-acting cabotegravir (cab la) for the prevention of hiv among adolescent females – a sub-study of hptn 084. available: https://clinicaltrials.gov/ct2/show/nct04824131 hosek s, hamilton el, ngo j, et al. cab la for hiv prevention in african cisgender female adolescents (hptn 084-01) [homepage on the internet]. croi, february 19–22, 2023. seattle, wa. abstract 162. available from: https://www.croiconference.org/abstract/cab-la-for-hiv-prevention-in-african-cisgender-female-adolescents-hptn-084-01/ karim ssa, baxter c. hiv incidence rates in adolescent girls and young women in sub-saharan africa. the lancet global health. 2019;7(11):e1470–e1471. https://doi.org/10.1016/s2214-109x(19)30404-8 birdthistle i, tanton c, tomita a, et al. recent levels and trends in hiv incidence rates among adolescent girls and young women in ten high-prevalence african countries: a systematic review and meta-analysis. lancet global health. 2019;7(11):e1521–e1540. https://doi.org/10.1016/s2214-109x(19)30410-3 jamieson l, johnson lf, nichols be, et al. the relative cost-effectiveness of long-acting injectable cabotegravir versus oral pre-exposure prophylaxis a modelled economic evaluation and threshold analysis in south africa based on the hptn 083 and 084 trials he ro 2 [homepage on the internet]. 2022 [cited 2023 mar 03]. available from: https://thembisa.org pepperrell t, cross s, hill a. cabotegravir-global access to long-acting pre-exposure prophylaxis for hiv. open forum infect dis. 2022;10(1):ofac673. https://doi.org/10.1093/ofid/ofac673 phanuphak n. accessing long-acting hiv prevention and treatment innovations: landscape, service delivery, and pathways to affordability. aids, july 29–aug 02, 2022. session sa028, satellite session. available from: https://programme.aids2022.org/programme/session/55 casas mg. how vaxi taxi is repurposing public spaces and partnering with western cape communities to bridge the vaccination gap. daily maverick [serial online]. 2021 dec 21 [cited 2023 mar 22]. available from: https://www.dailymaverick.co.za/article/2021-12-21-how-vaxi-taxi-is-repurposing-public-spaces-and-partnering-with-western-cape-communities-to-bridge-the-vaccination-gap/ aids vaccine advocacy coalition. prep implementation study tracker [homepage on the internet]. [cited 2023 mar 02]. available from: https://www.prepwatch.org/resources/implementation-study-tracker/ about the author(s) carol l. tait anova health institute, johannesburg, south africa njabulo mbanda anova health institute, johannesburg, south africa rudairo tumba anova health institute, johannesburg, south africa marnie j. vujovic anova health institute, johannesburg, south africa kate rees anova health institute, johannesburg, south africaschool of public health, faculty of medicine, university of the witwatersrand, johannesburg, south africa citation tait cl, mbanda n, tumba r, vujovic mj, rees k. psychosocial support for adolescents and youth living with hiv during covid-19: a differentiated approach is needed. s afr j hiv med. 2022;23(1), a1379. https://doi.org/10.4102/sajhivmed.v23i1.1379 conference abstracts psychosocial support for adolescents and youth living with hiv during covid-19: a differentiated approach is needed carol l. tait, njabulo mbanda, rudairo tumba, marnie j. vujovic, kate rees received: 09 feb. 2022; accepted: 23 feb. 2022; published: 14 apr. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. south africa has a high number of adolescents and youth accessing hiv treatment. psychosocial support is needed to support retention and suppression in this group, who are navigating this life stage while living with hiv. in johannesburg, this was traditionally delivered through facility-based youth care clubs (ycc), which were adapted to virtual delivery due to coronavirus disease 2019 (covid-19). despite the benefits, several challenges were identified during implementation. we aimed to improve the virtual support offering through utilising an alternative reverse-billed platform. existing and alternative platforms were reviewed with collaborating partners. challenges of whatsapp-based ycc included data costs, access to devices, lack of interaction and inability to see or hear group members. a reverse-billed platform was identified as a possible solution, requiring no data or applications. staff were trained and existing virtual groups selected based on age and current activity. data are presented for june 2021 to august 2021. of the 91 existing virtual groups, 31 were selected for the new platform. four days/month were selected to minimise running costs, based on participant preferences. several trainings were needed to cover all facilitators. a step-by-step guide was introduced to mitigate technical challenges. ten tablets were procured to assist participants without devices. on average 255 participants planned to join groups each month. of these, 110 joined (43%). benefits included live discussion, video sharing, and feeling more connected due to voice and video sharing. groups also continued discussion on whatsapp platforms. challenges included network coverage (mainly due to electricity cuts), difficulty navigating the platform, lack of flexibility over group times, and participants not joining as planned. the new platform offered additional benefits; however, despite data-free access, network connectivity and other challenges affected participation. a differentiated approach continues to be needed, with more flexibility, to enable access to retention support for adolescents and youth. the authors would like to thank the implementing psychosocial team from anova health institute for embracing new ways to care for adolescents and youth despite the challenges, and also to the department of health teams for managing these clients at health facilities with dedication. this work would not be possible without the generous support and donation of our funders. ethical considerations: approval to conduct the study was received from the human sciences research council ethics committee (rec3/22/08/18). funding information: a covid-relief grant was received through an existing funder to implement virtual support for adolescents. the anova health institute non-profit company is supported by the united states president’s emergency plan (pepfar) programme via the united states agency for international development (usaid) under the cooperative agreement number aid-674-a-12-00015. a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e study setting tholulwazi uzivikele (tu)4 is a non-profit organisation serving the communities surrounding manguzi hospital in northern kwazulu-natal. the area borders mozambique and is extremely rural with poor access on sandy roads. unemployment is estimated at 70%5 and the antenatal hiv prevalence is 28%. tu was founded in 2002 by concerned staff members at manguzi hospital wanting to mitigate the effect of the hiv epidemic on the surrounding community. the organisation started with an emphasis on orphans and vulnerable children and home-based care, but has subsequently expanded to include programmes for poverty relief, hiv prevention, and access to medical care and social services. antiretroviral treatment (art) is available at manguzi hospital and all 10 local clinics. cd4 tests can be done and art initiated at any of these sites. patients can usually commence treatment within 2 weeks of a diagnosis, and most of the population lives within a 10 km radius of such a clinic. description of activities the vct programme was started by tu in august 2007. the aim of the programme was to increase hiv awareness and offer vct in schools, using drama to sensitise, educate and encourage participation among the learners. this programme was made possible by close co-operation with the department of education and local school principals and teachers and financial and technical support from oxfam ohap. tu has built credibility over the years with these role-players, initially through the orphan programme. principals realise the difficulties that learners face in accessing vct and recognise that the programme meets an unmet learner need to access a non-judgemental, youth-friendly information service. before this programme started, learners wanting to access vct could only do so by going to the clinic, which often required the whole day away from school as most government vct activities were not available on weekends. in order to increase levels of participation by learners during the education process, it was decided to use ‘forum drama’. while drama has been used for many years in the hiv/aids field, forum drama specifically encourages the audience to intervene and make decisions for the actors at various stages of the drama. the audience thus determines the eventual outcome of the story by the choices they have made, simulating real life. an organisation skilled in using forum drama for hiv awareness, dramatic change,6 provided training for all the actors. at the same time, all the actors were also trained as vct counsellors by the foundation for professional development, supported by funding from usaid. expanding access to hiv counselling and testing at schools – the manguzi experience o r i g i n a l a r t i c l e colin pfaff, mb bch, mmed (fam), dch, dip hiv man, da centre for rural health, university of the witwatersrand johriaan de beer, blc, mba programme manager, tholulwazi uzivikele south africa’s hiv epidemic disproportionately affects the youth.1 the importance of knowing one’s status via voluntary counselling and testing (vct) is recognised as a key strategy in fighting the epidemic and is reflected in the national strategic plan (nsp),2 which has set targets of 70% of all adults knowing their status by 2011 and 25% of all adults having been tested in the past 12 months. the human sciences research council survey in 20081 showed that 50.8% of all south africans 15 years and older have had an hiv test, pointing to wider acceptance of vct. as a further response to reaching the nsp target, the national hiv counselling and testing campaign3 was launched in april 2010 with a focus on mobilising all south africans to be tested for hiv and ensuring that every south african knows their hiv status. both the nsp and the national hiv testing campaign recognise the importance of community mobilisation and community-based models of vct to achieve these targets. the nsp in particular has a goal to expand successful strategies of testing outside health care facilities to cover 70% of all districts by 2011. young people are reluctant to use health care facilities, and several ‘youth friendly’ strategies have been tried to target adolescents. this case study serves to document the successes of one such community-based vct strategy, aimed at young people in northern kwazulu-natal, south africa. 16 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 1 of the 64 high schools in the manguzi sub-district, 19 were initially targeted, being secondary level schools. the team visited each school on a 5-day programme. most programme activities, such as sensitisation and drama, occurred during school hours. these activities were integrated into the school syllabus in subjects such as life orientation and sport with the participation of teachers. the team consisted of four actors, who also functioned as educators and had all been trained as vct counsellors. several of the actors were hiv positive. during the first two days, the actors were invited as guest teachers and taught classes during the life orientation lessons at the schools. topics covered included life skills, goal setting, vision and romantic relationships, moving on to the origin of hiv/aids, hiv as an infectious disease, stigma, transmission, prevention and vct. on the third day the forum drama was performed for the entire school. the story line consisted of friends discussing relationships, social situations touching on peer pressure, abuse, and choices made with an emphasis on knowing one’s status and avoiding risky situations. it was interrupted at regular intervals by a narrator who gave the audience the chance to make decisions for the actors or even to come on stage and play their role. the sessions were very interactive, as learners were given the opportunity to dramatise events from their own experience. on the fourth day confidential counselling was offered to all students who might decide to test for hiv. the counselling and testing was conducted in temporary tent structures that allowed for discretion in terms of location. learners could access testing at any time during the school day. the actors conducted the counselling and testing, with support from a nurse. the service was promoted as a health and life skills counselling service – not all learners who accessed the service were necessarily tested. the emphasis was placed on gaining more information and was rooted in psychosocial support and risk management strategies flowing from the drama of the previous day. learners were provided with information, and only given the option of testing once they were comfortable. learners who were diagnosed and confirmed as being hiv positive were referred to a local clinic, where cd4 testing and art were available. the vct team also provided ongoing psychosocial support for diagnosed individuals by phoning them within a week of the test being conducted and linking individuals in need of support to a local support group. on the fifth day a talent search was conducted as a closure event, strengthening the relations with the programme and encouraging ongoing dialogue between learners. often learners presented different drama plays around hiv awareness, from which the vct team in turn learnt more about the context. through interaction with concerned school principals and teachers the vct team also facilitated the establishment of ‘hiv champions’ at schools. hiv champions were teachers or student leaders who augmented the knowledge of students and teachers in a specific school and were selected on the basis of their willingness to lead and their interest in the future of youth. support groups were also organised in the schools and structured as social clubs or sports clubs, without discriminating on the basis of hiv status. outcomes during 2008 and 2009 all 19 secondary schools were visited once and 13 were visited twice; 12 996 beneficiaries were reached with the awareness drama, and 2 394 students were tested. hiv prevalence in the tested population was 2.8% in october 2009 the last three secondary schools on the schedule were visited again in order to evaluate the programme. the counsellors went to each school, surveying clients who had been tested previously. in each of the three schools, questionnaires were handed out to the first 79 clients who were found of the total of 217 who had been tested. all 79 forms were returned. of the respondents, 91% felt that the counsellor was sympathetic throughout the counselling session, 94% felt that the service was done with confidentiality and privacy, and 100% said they would recommend the service to someone else. when asked how the service could be improved, most made comments such as ‘well done’ and ‘keep it up’. nine respondents gave minor suggestions as to how the service could be improved, e.g. by handing out t-shirts or refreshments after testing, and one respondent suggested that testing be done in a building rather than in a tent. evaluation of how many accessed art or underwent any behaviour change will need to be more detailed and has not yet been done. discussion vct services have been identified as an essential component of comprehensive hiv care. vct is both an entry point to antiretroviral care and may promote behaviour change, particularly for those who test positive.7 however, vct services are often underutilised. in south africa, although rates of testing in adults aged 15 years and above increased from 21.4% in 2002 to 30.5% in 20058 and 50.8% in 2008,1 still almost half of south africans have never had an hiv test. the 2005 study8 showed that those in informal rural areas were less likely to know their status than those living in formal urban areas (19.3% v. 40.4%). there are several reasons for low uptake of vct services, including confidentiality, concern about reaction from male partners, lack of access to free testing, transport costs,9 trust, stigma of being seen at a health care facility,10 and lack of perceived personal risk.11 community-based strategies of vct have been proposed as one way to address these barriers. community-based strategies move the services closer to the people, but may also overcome stigma and confidentiality issues that are concerns in visiting a health care facility. communitybased vct has been shown to increase acceptability and rates of testing in several studies. moving vct to 17 a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e the workplace in zimbabwe was associated with a 51.1% uptake of testing compared with offering vouchers for testing in the community, which resulted in a 19.2% uptake.12 similarly, in zimbabwe community-based vct provided in a mobile van increased vct uptake by 98% for 1 000 rural women.13 in a feasibility study in uganda many clients were found to prefer a mobile van to facilitybased testing.14 another community-based strategy has been to offer vct in the home. after collecting blood as part of a doorto-door health census, delivery of results to the home as opposed to collecting them at a facility increased the number of adults aged 25 54 who accessed their results from 10% to 46%.15 travel distance, facility waiting time and issues of confidentiality, including emotional composure during the walk home, were all cited by participants as factors favouring home-based vct. youth, however, were reluctant to receive results in the home, stating that the visit would invite questions and speculation by other family members. a recent cochrane review of home-based vct found that homebased testing or delivering results to the home rather than collecting them at the clinic leads to a higher uptake in testing, but cautioned that the literature was too limited to recommend large-scale implementation.16 young people in particular are reluctant to use health services, and several strategies to target adolescents have been tried. the department of health has piloted a programme of ‘youth friendly’ clinics under the national adolescent friendly clinic initiative to try to address this situation. several community-based vct strategies have also been specifically aimed at making vct more accessible to young people and increasing uptake. a review of these initiatives has highlighted their diversity and emphasised that there is no one ideal model for vct in young people and that programmes must be innovative and tailored to meet the specific context and reach a specific target of young people. the review did note several key principles that these diverse youth-centred vct programmes had in common.17 these included involving learners in the planning and delivery process, mobilising community-based peer educators, ensuring suitable accommodation to enable privacy, training providers in youth-friendly approaches, integrating posttesting services, and supplying educational material and condoms. many of these principles feature in the tu vct programme. drama has been recognised as a key medium to reach young people and has been used successfully to motivate adolescents to undertake hiv testing, both in south africa18 and in malawi.19 in khayelitsha hiv testing increased by 172% in sites that had received a drama presentation compared with sites that had not.18 however, none of these drama programmes were combined with offering hiv testing as part of the same programme. similarly, very little has been written about the process of taking vct into the schools. in uganda the kitovu mission hospital has successfully provided a mobile vct service in school settings whereby, at one outpost, a van is parked at the school and offers same-day testing.17 mpilonhle, a non-governmental organisation working 200 km further south in the same district as tu,20 has developed a similar strategy, offering hiv testing as part of a general health check using mobile caravans on site at schools. this is combined with offering computer training at the same venue. the hiv prevalence in students who were tested in manguzi was 2.8%. this is similar to the experience of mpilonhle, where an hiv prevalence of 2.7% was found among high-school students who underwent voluntary testing (personal communication). both programmes indicate that offering vct in schools is both feasible and acceptable as part of a package of increasing provision of hiv care to young people. conclusion south africa has an ambitious nsp, but more needs to be done if the targets are to be met with the time remaining. the tu vct programme is an example of a successful community-based vct strategy that has been effective in reaching young people. references 1. shisana o, rehle t, simbayi lc, et al. south african national hiv prevalence, incidence, behaviour and communication survey 2008. a turning tide among teenagers? cape town: hsrc press, 2008. 2. department of health. hiv and aids and sti national strategic plan for south africa 2007-2011. 2007. http://www.doh.gov.za/docs/misc/stratplan/2007-2011/ part2.pdf (accessed 6 february 2011). 3. sanac secretariat. national hiv counselling and testing campaign strategy. 2010. http://www.capegateway.gov.za/other/2010/6/hct_campaign_strategy_2_3_10_final. pdf (accessed 6 february 2011). 4. tholulwazi uzivikele. empower yourself through knowledge. http://www.tuproject. org (accessed 11 april 2010). 5. umhlabuyalingana municipality idp review 2007/2008. http://devplan.kzntl.gov.za/ idp_reviewed_2007_8/idps/kz271/.../11.pdf, url (accessed 23 november 2009). 6. dramatic change: zisize drama project. //www.adcid.org/zisize.html (accessed 11 april 2010). 7. solomon v, van rooyen h, griesel r, gray d, stein j, nott v. critical review and analysis of voluntary counselling and testing – literature in africa. durban: health systems trust, 2004. 8. shisana o, rehle t, simbayi lc, et al. south african national hiv prevalence, hiv incidence, behaviour and communication survey 2005. cape town: hsrc press, 2005. 9. urassa p, gosling r, pool r, reyburn h. attitudes to voluntary counselling and testing prior to the offer of nevirapine to prevent vertical transmission of hiv in northern tanzania. aids care 2005;17:842-852. 10. kalichman sc, simbayi lc. hiv testing attitudes, aids stigma, and voluntary hiv counselling and testing in a black township in cape town, south africa. sex transm infect 2003;79:442-447. 11. nakanjako d, kamya m, kyabayinze d, et al. acceptance of routine testing for hiv among adult patients at the medical emergency unit at a national referral hospital in kampala, uganda. aids behav 2006;11:753-758. 12. corbett el, dauya e, matambo r, et al. uptake of workplace hiv counselling and testing: a cluster-randomised trial in zimbabwe. plos med 2006;3:e238. 13. morin sf, khumalo-sakutukwa g, charlebois ed, et al. removing barriers to knowing hiv status: same-day mobile testing in zimbabwe. j acquir immune defic syndr 2006;24:218-224. 14. asingwire n. feasibility study of the mobile van for voluntary counselling and testing for hiv ⁄ aids. final report submitted to the uganda program for human and holistic development (uphold), kampala, uganda. 2004. http://www.uphold.jsi.com/docs/ mobile_van_vct.pdf (accessed 31 december 2009). 15. wolff b, nyanzi b, katongole g, ssensanga d, ruberantwari a, whitworth j. evaluation of home based voluntary counselling and testing intervention in rural uganda. health policy plan 2005;20(2):109-116. 16. bateganya mh, abdulwadud oa, kiene sm. home based hiv voluntary counseling and testing in developing countries. cochrane database syst rev 2007;4. 17. boswell d, baggely r. voluntary counseling and testing young people: a summary overview. arlington, va: family health international, 2002: 6. 18. middelkoop k, myer l, smit j, wood r, bekker lg. design and evaluation of a drama-based intervention to promote voluntary counseling and hiv testing in a south african community. sex transm dis 2006;33:524-526. 19. rumsey ds, brabin l, mfutso-bengo j-m, cuevas le, hogg a, brabin bj. effectiveness of drama in promoting voluntary hiv counseling and testing in rural villages in southern malawi. int j std aids 2004;15:494-495. 20. mpilonhle – programmes: health screening. http://www.mplionhle.org/programmes_ health_screening.php (accessed 11 april 2010). 18 chronic.html case study chronic genital ulcer disease with subsequent development of methicillin-resistant staphylococcus aureus (mrsa) urethritis and bacteraemia in an hiv-seropositive person – a case observation christine katusiime, mb chb, pgdppm, miph andrew kambugu, mb chb, mmed infectious diseases institute, college of health sciences, makerere university, kampala, uganda hiv-seropositive persons are at increased risk of methicillin-resistant staphylococcus aureus (mrsa). genital ulcerative disease and sexually transmitted infection with subsequent mrsa infection in hiv-seropositive persons have been documented only once. we report a case of a 44-year-old man who presented to the infectious diseases institute, kampala, uganda, with chronic genital ulcer disease and who subsequently developed mrsa urethritis and bacteraemia. this case also demonstrates that persistent genital ulcer disease in hiv-seropositive persons may be as a result of concurrent mrsa infection. hiv-seronegative persons are less likely to become infected with staphylococcus aureus and associated s. aureus septicaemia than their hiv-seropositive counterparts.1 , 2 studies have demonstrated an increased risk of mrsa infection among hiv-seropositive persons of up to 18 times.3 mrsa infection therefore presents a public health concern. mrsa infection has also been found to be associated with sexually transmitted infections (stis) and genital ulcer disease (gud) in hiv-seropositive persons.6 gud with associated mrsa infection has only been documented once.6 the case we present in this report is of chronic genital ulceration complicated by mrsa urethritis and bacteraemia. this case of chronic gud with subsequent mrsa infection in an hiv-seropositive host also highlights the importance of ruling out concurrent mrsa infection in chronic gud in hiv-seropositive persons. case presentation a 44-year-old hiv-seropositive man with world health organization (who) stage iv disease, who had been on highly active anti-retroviral therapy (haart) of tenofovir, lamivudine and efavirenz, and co-trimoxazole prophylaxis since march 2008, presented with an 8-month history of genital ulceration and a 4-month history of urethral pus discharge. he initially noticed a small papule on the glans of his penis which increased in size and ulcerated. he subsequently developed a yellow non-odorous urethral discharge. on review of symptoms, he denied associated fevers and chills, or trauma to the site. he had no significant previous medical history and denied cigarette smoking, alcohol consumption and intravenous drug usage. he was heterosexual, denied unsafe sexual practices, and had no history of previous stis, antibiotic use, and recurrent stis or gud. physical examination revealed a body temperature of 36.1oc, pulse rate 86 beats per minute, blood pressure 120/70 mmhg, and respiratory rate 12 breaths per minute. genital examination revealed an ulcer involving the glans of the penis with a yellow urethral discharge. precordial, ophthalmic, gastrointestinal and respiratory examinations were unremarkable. neurologically, there were no cranial nerve deficits, reflexes were symmetrical and normal, and distal sensation was intact. laboratory data revealed a white blood cell (wbc) count of 5 000/mm3 and an elevated erythrocyte sedimentation rate (esr) of 80 mm/hr. his urine revealed 500 leukocytes/ul, trace protein, 66 white blood cells/high-power field (hpf) and 1 cast/hpf. the rest of the routine laboratory tests including renal function tests, liver function tests, random blood sugar (rbs), treponemal pallidum haemagglutination assay (tpha), serum cryptococcal antigen (crag) titres, hepatitis b surface antigen (hbsag) and brucella agglutination assay were unremarkable. cd4+ cell counts were 944 cells/mm3 (30%), and plasma hiv rna levels were undetectable. herpes simplex virus-2 (hsv-2) serology could not be done because of the high costs involved. a penile wedge biopsy taken for histopathological examination showed features suggestive of a chronic penile ulcer. the urethral pus swabs and blood cultures grew mrsa sensitive to gentamicin, ciprofloxacin and vancomycin but resistant to oxacillin, tetracycline, penicillin and erythromycin. urine cultures depicted no growth. a clinical diagnosis of chronic ulcerative genital herpes was made, following consultation with an std specialist. the patient was then admitted and commenced on a course of oral acyclovir 400 mg twice daily for 6 months and intravenous vancomycin for 2 weeks for chronic ulcerative genital herpes and mrsa urethritis and bacteraemia respectively. intravenous ceftriaxone was also administered to treat the urinary tract infection (uti). continual adherence to co-trimoxazole, acyclovir and haart was continually emphasised. the course of treatment was successful; examination at 1 month and 2 months follow-up revealed no urethral discharge and completely healed penile ulcerations. discussion hiv-infected persons have a higher risk of mrsa infection than the general population. 3 the reason why our patient was predisposed to mrsa infection could have been a result of the chronic genital ulceration. prior studies have implicated lack of co-trimoxazole prophylaxis, intravenous drug usage, low cd4 t-cell count, high hiv viral load and hospitalisation as risk factors for mrsa colonisation in hiv-seropositive patients.10 these factors, however, were not noted in our patient. ramsetty and colleagues demonstrated that hiv-seropositive patients with cd4 t-cell counts <200 cells/mm3 were at significant risk of mrsa infections.13 our patient was the exception to this finding, as his cd4 t-cell count was 944 cells/mm3 . a ramification of this case is the importance of considering concurrent mrsa infection in hiv-seropositive patients with chronic gud. other factors that make this case unique are the development of mrsa urethritis and bacteraemia despite the patient’s high cd4 t-cell counts and good virological control. conclusion our patient developed mrsa infection following chronic gud that was not effectively managed. clinicians need to maintain vigilance in the management of chronic gud in hiv-seropositive persons, as mrsa co-infection may become an increasing complication in the future. references 1. enthilkumar a, kumar s, sheagren j. increased incidence of staphylococcus aureus bacteremia in hospitalized patients with acquired immunodeficiency syndrome. clin infect dis 2001;33:1412-1416. 1. enthilkumar a, kumar s, sheagren j. increased incidence of staphylococcus aureus bacteremia in hospitalized patients with acquired immunodeficiency syndrome. clin infect dis 2001;33:1412-1416. 2. weinke t, schiller r, fehrenbach fj, pohle hd. association between staphylococcus aureus nasopharyngeal colonization and septicemia in patients infected with the human immunodeficiency virus. eur j clin microbiol infect dis 1992;11:985-989. 2. weinke t, schiller r, fehrenbach fj, pohle hd. association between staphylococcus aureus nasopharyngeal colonization and septicemia in patients infected with the human immunodeficiency virus. eur j clin microbiol infect dis 1992;11:985-989. 3. matthews wc, caperna jc, barbaer re, et al. incidence of and risk factors for clinically significant methicillin-resistant staphylococcus aureus infection in a cohort of hiv infected adults. j acquir immune defic syndr 2005;40:155-160. 3. matthews wc, caperna jc, barbaer re, et al. incidence of and risk factors for clinically significant methicillin-resistant staphylococcus aureus infection in a cohort of hiv infected adults. j acquir immune defic syndr 2005;40:155-160. 4. crum-cianflone nf, burgi aa, hale br. increasing rates of community-acquired methicillin-resistant staphylococcus aureus infections among hiv-infected persons. int j std aids 2007;18:521-526. 4. crum-cianflone nf, burgi aa, hale br. increasing rates of community-acquired methicillin-resistant staphylococcus aureus infections among hiv-infected persons. int j std aids 2007;18:521-526. 5. popovich kj, weinstein ra, aroutcheva a, rice t, hota b. community-associated methicillin-resistant staphylococcus aureus and hiv: intersecting epidemics. clin infect dis 2010;50:979-987. 5. popovich kj, weinstein ra, aroutcheva a, rice t, hota b. community-associated methicillin-resistant staphylococcus aureus and hiv: intersecting epidemics. clin infect dis 2010;50:979-987. 6. crum-cianflone nf, shadyab ah, weintrob a, et al. association of methicillin-resistant staphylococcus aureus (mrsa) colonization with high-risk sexual behaviors in persons infected with human immunodeficiency virus (hiv). med 2011;90:379-389. 6. crum-cianflone nf, shadyab ah, weintrob a, et al. association of methicillin-resistant staphylococcus aureus (mrsa) colonization with high-risk sexual behaviors in persons infected with human immunodeficiency virus (hiv). med 2011;90:379-389. 7. burkey md, wilson le, moore rd, lucas gm, francis j, gebo ka. the incidence of and risk factors for mrsa bacteraemia in an hiv-infected cohort in the haart era. hiv med 2008;9:858-862. 7. burkey md, wilson le, moore rd, lucas gm, francis j, gebo ka. the incidence of and risk factors for mrsa bacteraemia in an hiv-infected cohort in the haart era. hiv med 2008;9:858-862. 8. cenizal mj, hardy rd, anderson m, katz k, skiest dj. prevalence of and risk factors for methicillin-resistant staphylococcus aureus (mrsa) nasal colonization in hiv-infected ambulatory patients. j acquir immune syndr 2008;48:567-571. 8. cenizal mj, hardy rd, anderson m, katz k, skiest dj. prevalence of and risk factors for methicillin-resistant staphylococcus aureus (mrsa) nasal colonization in hiv-infected ambulatory patients. j acquir immune syndr 2008;48:567-571. 9. diep ba, chambers hf, graber cj, et al. emergence of multidrug-resistant community-associated methicillin-resistant staphylococcus aureus clone usa300 in men who have sex with men. ann intern med 2008;148:249-257. 9. diep ba, chambers hf, graber cj, et al. emergence of multidrug-resistant community-associated methicillin-resistant staphylococcus aureus clone usa300 in men who have sex with men. ann intern med 2008;148:249-257. 10. sissolak d, geusau a, heinze g, witte w, rotter ml. risk factors for nasal carriage of staphylococcus aureus in infectious disease patients, including patients infected with hiv, and molecular typing of colonizing strains. eur j clin microbiol infect dis 2002;21:88-96. 10. sissolak d, geusau a, heinze g, witte w, rotter ml. risk factors for nasal carriage of staphylococcus aureus in infectious disease patients, including patients infected with hiv, and molecular typing of colonizing strains. eur j clin microbiol infect dis 2002;21:88-96. 11. szumowski jd, wener km, gold hs, et al. methicillin-resistant staphylococcus aureus colonization, behavioral risk factors, and skin and soft-tissue infection at an ambulatory clinic serving a large population of hiv-infected men who have sex with men. clin infect dis 2009;49:118-121. 11. szumowski jd, wener km, gold hs, et al. methicillin-resistant staphylococcus aureus colonization, behavioral risk factors, and skin and soft-tissue infection at an ambulatory clinic serving a large population of hiv-infected men who have sex with men. clin infect dis 2009;49:118-121. 12. villacian js, barkham t, earnest a, paton ni. prevalence of and risk factors for nasal colonization with staphylococcus aureus among human immunodeficiency virus-positive outpatients in singapore. infect control hosp epidemiol 2004;25:438-440. 12. villacian js, barkham t, earnest a, paton ni. prevalence of and risk factors for nasal colonization with staphylococcus aureus among human immunodeficiency virus-positive outpatients in singapore. infect control hosp epidemiol 2004;25:438-440. 13. shet a, mathema b, mediavilla jr, et al. colonization and subsequent skin and soft tissue infection due to methicillin-resistant staphylococcus aureus in a cohort of otherwise healthy adults infected with hiv type 1. j infect dis 2009;200:88-93. 13. shet a, mathema b, mediavilla jr, et al. colonization and subsequent skin and soft tissue infection due to methicillin-resistant staphylococcus aureus in a cohort of otherwise healthy adults infected with hiv type 1. j infect dis 2009;200:88-93. 14. ramsetty sk, stuart ll, blake rt, parsons ch, salgado cd. risks for methicillin-resistant staphylococcus aureus colonization or infection among patients with hiv infection. hiv med 2010;11:389-394. 14. ramsetty sk, stuart ll, blake rt, parsons ch, salgado cd. risks for methicillin-resistant staphylococcus aureus colonization or infection among patients with hiv infection. hiv med 2010;11:389-394. fig. 1. ulceration and yellow penile urethral discharge. fig. 2. ulceration involving entire glans. the southern african journal of hiv medicine                                                              april  2010 the rate of hiv infection in pregnancy is high.1-7 there is evidence that hiv infection in pregnant women is associated with adverse maternal and fetal outcomes.2,5,6 the effects of hiv infection include severe anaemia, infectious morbidities and vertical transmission.2,5,8-14 in a malawian study, aids and anaemia were the leading causes of maternal mortality,15 and in zaire maternal mortality rates in hiv-infected women were 10 times those of hiv-negative women.16 a personal communication revealed that in a recent unpublished report from a nigerian teaching hospital, hiv/aids accounted for 20.2% of maternal deaths. however, the effect of pregnancy on hiv disease progression remains contentious. evidence from developed countries suggests that pregnancy does not accelerate the progression of hiv disease,17-21 while reports from low-resource settings imply otherwise, indicating that pregnancy may influence the rate of disease progression.2 it has been suggested that other factors, including genetics, nutritional status and intercurrent infections, may be responsible for the rate of hiv disease progression in low-resource settings.2,22,23 john and colleagues report an association between ccr5 promotor polymorphism and increased maternal mortality in a kenyan cohort.23 the objectives of the present study were to determine the association between pregnancy and biochemical and haematological changes in hiv-infected nigerian women as a possible indicator of disease severity. is pregnancy associated with biochemical and haematological changes in hiv-infected nigerian women? o r i g i n a l a r t i c l e l o omo-aghoja1, mb bs, fwacs, fmcog, fics e abe2, mb bs, fwacs v w omo-aghoja3, bds, fmcds a onowhakpor1, mb bs, fwacs p feyi-waboso4, mb bs, fwacs 1department of obstetrics and gynaecology, college of health sciences, delta state university, abraka, nigeria 2department of obstetrics and gynaecology, central hospital, benin city, nigeria 3department of oral and maxillofacial surgery, central hospital, sapele, nigeria 4department of obstetrics and gynaecology, abia state university teaching hospital, aba, nigeria 8 45 background. while there is evidence that hiv affects the course and outcome of pregnancy, reports on the effects of pregnancy on hiv infection remain conflicting, especially in low-resource settings. methodology. a prospective study of two demographically similar cohorts of hiv-seropositive women, 154 pregnant and 151 non-pregnant, was conducted in a hospital setting in nigeria. results. cases and controls were matched for age, but parity in controls was significantly higher than in cases (p<0.0001). the time between diagnosis and treatment commencement was greater in controls compared with cases (p<0.0001). electrolyte, urea and creatinine levels were within normal limits, with mean serum urea and potassium higher in controls compared with cases (p=0.002 and p=0.023). aspartate aminotransferase (aat)/ serum glutamic oxaloacetic acid transaminase (sgot), alanine aminotransferase (alt)/serum glutamic-pyruvic transaminase (sgpt) and amylase levels were higher in controls compared with cases (p=0.001, p=0.0001 and p=0.05), but the mean cd4 count was higher in cases compared with controls (p=0.001). the haematological parameters were within normal limits and comparable in cases and controls. a comparison of cd4 count, total white blood cell count and packed cell volume across the three trimesters in the cases did not reveal any statistically significant differences in these parameters. conclusion. pregnancy did not affect biochemical and haematological parameters in hiv-infected nigerian women. april  2010                                                                the southern african journal of hiv medicine                                                   methodology this study was conducted in central hospital, benin city, nigeria, which provides tertiary care to patients in benin city and its environs. it was a prospective study of two demographically similar cohorts of hiv-seropositive women, 154 pregnant and 151 non-pregnant. the cases were pregnant women attending the antenatal clinics of the hospital from october 2005 to october 2007. once a pregnant case was identified, the next non-pregnant hiv-seropositive patient presenting to the hiv treatment, control and prevention programme unit of the hospital and matched for social class (patient’s educational status and husband’s occupation,24 location of residence, size of apartment, average weekly income, number and types of cars if any, types of electronic and electrical gadgets at home) was selected as a control. any patient who experienced repeated attacks of malaria or other intercurrent infections was excluded from the study. upon recruitment, both pregnant and non-pregnant women had a data sheet completed that elicited information on socio-demographic variables, time since diagnosis of seropositive status, duration of antiretroviral therapy, and biochemical and haematological parameters. specifically, the following biochemical measurements were done: serum electrolyte, urea and creatinine levels, serum fasting blood sugar (fbs), serum aspartate aminotransferase (aat)/ glutamic oxaloacetic acid transaminase (sgot), alanine aminotransferase (alt)/ serum glutamic-pyruvic transaminase (sgpt), total bilirubin, serum amylase, serum cholesterol, very low-density lipoprotein (vldl) and lactate dehydrogenase (lh). in addition, a full blood count (fbc packed cell volume (pcv), white blood cell (wbc) count, platelet count and differentials) and cd4 cell count were performed. the study was approved by the hospital’s human ethics committee and was carefully explained to the patients, and only those who gave informed written consent were recruited into the study. the statistical package for social sciences (spss) version 13 was used for the data management and statistical analysis, with fisher’s exact test, the chi-square test or student’s t-test (as appropriate) being used for comparison of the mean absolute values and standard deviations (sds). the level of significance was 0.05. results the socio-demographic profile and time since diagnosis and commencement of treatment are set out in table i. the pregnant women had had their hiv diagnosis for periods ranging from 1 to 30 months (median 10 months) and had been on treatment for periods ranging from 1 to 30 months (median 8 months), while the non-pregnant women had had their hiv diagnosis for periods ranging from 14 to 29 months (median 17 months) and had been on treatment for periods ranging from 2 to 29 months (median 16 months). the median age of the pregnant women was 29.4 years, with a range of 18 36 years (mean 28.6, sd 4.6) and the median age of the non-pregnant women 30.2 years, with a range of 16 42 years (mean 29.2, sd 3.9). the median parity in the pregnant women was 1.00, with a range of 0 7 (mean 1.25, sd 1.59), and that for the non-pregnant women 2.00, with a range of 0 13 (mean 2.10, sd 2.29). this difference was statistically significant (p<0.0001). the median estimated gestational age at booking was 26 weeks, with a range of 2 42 weeks (mean 25.8, sd 8.13). in the pregnant 46 parameters n mean (sd) median p-value age (yrs) cases 154 28.6 (4.2) 29.4 controls 151 28.9 (4.1) 30.2 0.239 parity cases 154 1.25 (1.59) 1.00 controls 151 2.10 (2.29) 2.00 <0.0001 ega at booking (wks) cases 154 25.8 (8.13) 26.00 controls 151 n/a n/a time since diagnosis (mo.) cases 154 10.27 (6.12) 10.00 controls 151 16.86 (1.69) 17.00 <0.0001 duration of treatment (mo.) cases 154 8.86 (5.99) 8.00 controls 151 15.02 (3.82) 16.00 <0.0001 sd = standard deviation; ega = estimated gestational age. table i. comparison of the summary statistics of the socio-demographic profile, duration of diagnosis and treatment of cases v. controls the southern african journal of hiv medicine                                                              april  2010 47 parameter n mean (sd) p-value sodium (mmol/l) cases 154 139.36 (17.21) 0.260 controls 151 142.00 (19.99) potassium (mmol/l) cases 154 4.15 (0.65) 0.023 controls 151 4.48 (0.96) urea (mmol/l) cases 154 6.67 (9.81) 0.002 controls 151 11.70 (14.70) creatinine (mmol/l) cases 154 1.16 (1.44) 0.629 controls 151 1.24 (1.26) table ii. comparison of means of serum electrolyte, urea and creatinine levels of cases v. cohorts parameters n mean (sd) p-value fbs (mg/dl) cases 154 79.67 (8.41) 0.808 controls 151 91.00 (13.92) aat/sgot (u/l) cases 154 35.66 (35.28) 0.001 controls 151 57.91 (68.17) alt/sgpt (u/l) cases 154 17.29 (16.27) <0.0001 controls 151 27.68 (24.89) amylase (u/l) cases 154 69.3 (37.86) 0.05 controls 151 83.17 (45.36) vldl (mg/dl) cases 154 67.79 (162.75) 0.045 controls 151 31.58 (53.28) table iii. comparison of means of other biochemical parameters of cases v. controls parameter n mean (sd) p-value cd4 count (cells/µl) cases 154 378.16 (272.57) 0.001 controls 151 279.74 (230.74) total wbc (×109 /l) cases 154 5.64 (1.77) 0.304 controls 151 5.35 (2.81) lymphocytes (×109 /l) cases 154 2.15 (2.04 ) 0.920 controls 151 2.17 (1.96) table iv. comparison of means of haematological parameters of cases v. controls group a median of 10 months had elapsed since the diagnosis of hiv, with a range of 1 30 months (mean 10.27, sd 6.12), and in the non-pregnant group a median of 17 months had elapsed, with a range of 14 29 months (mean 16.86, sd 1.69). this difference was statistically significant (p<0.0001). serum electrolyte, urea and creatinine levels in cases versus controls are set out in table ii. the mean serum urea and potassium levels, though within normal limits, were higher in non-pregnant than pregnant women, as were the mean serum aspartate amino transferase (aat)/ serum glutamic oxaloacetic acid transaminase (sgot), alanine aminotransferase (alt)/ serum glutamic-pyruvic transaminase (sgpt) and serum amylase (table iii). however, the cd4 cell count was higher in the pregnant women than in the controls (p=0.001), while the haematological parameters were within normal limits and comparable between cases and controls (table iv). comparison of the mean cd4 april  2010                                                                the southern african journal of hiv medicine                                                   count, total wbc count and pcv in the three trimesters of pregnancy did not reveal any statistically significant differences in the respective values. discussion a systematic review and meta-analysis of seven cohort studies from 1983 to 1996 suggested that there is an association between adverse maternal outcomes and pregnancy in hiv-infected women. the summary odds ratios for the risk of an adverse maternal outcome related to hiv infection and pregnancy were 1.8 (85% confidence interval (ci) 0.99 3.3) for death, 1.41 (95% ci 0.85 2.33) for hiv disease progression, and 1.63 (95% ci 1.00 2.67) for progression to an aids-defining illness. this association appeared to be stronger in the one study in this group conducted in a resourcepoor setting.2 the objective of the present study was to describe any biochemical and haematological differences in the plasma of pregnant and non-pregnant hiv-infected nigerian women. in all women, the parameters assessed were within normal limits. the cd4 count was significantly higher in the pregnant compared with the non-pregnant controls, despite the fact that the non-pregnant women had been on antiretroviral drugs for longer. nutritional factors and intercurrent infections have been shown to play a role in disease progression in lowresource settings. these factors were controlled for in this study, as the two groups were matched for social class and women with intercurrent infections were excluded from the study. the prognosis for hiv disease in pregnancy is worse for patients with intercurrent infections such as malaria, urinary tract infections, sexually transmitted infections and parasitic infestation.2,24 malnutrition, infections and infestations are generally widespread in low resource-settings. in conclusion, this study failed to show any independent association between pregnancy and abnormal blood parameters that may suggest disease severity in hiv-infected nigerian women. it is reasonable to suppose that any increased morbidity and mortality of pregnancy may be modulated through the combined effects of nutritional factors, intercurrent infections and genetic factors. efforts to address these are likely to contribute to reducing the burden of hiv morbidity in infected pregnant nigerian women. conflict of interest. we confirm that this study was selffunded by the authors and that the outcome is a true reflection and interpretation of the scientific findings and was in no way influenced by the authors. the work is original and it is not being considered for publication by any other journal. references 1. mcintyre j. maternal health and hiv. reprod health matters 2005; 13(35): 129135. 2. mcintyre j. mothers infected with hiv. br med bull 2003; 67: 127-135. 3. offiong ra, bunza fm, uya ao. prevalence of hiv infection among prenatal patients in abuja. tropical journal of obstetrics and gynaecology 2001; 18: suppl. 1, 12. . 4. urassa e, massawe s, mgaya h, lindmark g, nystrom l. female mortality in reproductive ages in dar es salaam, tanzania. east afr med j 1994; 71: 226231. 5. mertz kj, parker al, halpin gj. pregnancy-related mortality in new jersey, 1975 to 1989. am j public health 1992; 82: 1082-1088. 6. huss m, bongain a, bertrandy m, hofman p, grimaud d, gillet jy. maternal mortality in nice. results of a reproductive age mortality survey using death registries in the nice university hospital, 1986-1993. j gynecol obstet biol reprod (paris) 1996; 25: 636-644. 7. rosenfield a, mwaba p, chintu c, grange jm, ustianowski a, zumla a. a study of maternal mortality in resource-poor countries. journal of the american medical women’s association 2002; 57: 167-168. 8. public health service task force. recommendations for use of antiretroviral drugs in pregnant hiv-1-infected women for maternal health and interventions to reduce perinatal hiv-1 transmission in the united states. june 16, 2003. http:// www.aidsinfo.nih.gov/guidelines (accessed 30 march 2004). 9. ahmed y, mwaba p, chintu c, grange jm, ustianowski a, zumla a. a study of maternal mortality at the university teaching hospital, lusaka, zambia: the emergence of tuberculosis as a major non-obstetric cause of maternal death. int j tuberc lung dis 1999; 3: 675-680. 10. bicego g, boerma jt, ronsmans c. the effect of aids on maternal mortality in malawi and zimbabwe. aids 2002; 16: 1078-1081. 11. iloki lh, g’bala sapoulou mv, kpekpede f, ekoundzola jr. maternal mortality in brazzaville (1993-1994). j gynecol obstet biol reprod (paris) 1997; 26: 163168. 12. macloed j, rhode r. retrospective follow-up of maternal deaths and their associated risk factors in a rural district tanzania. trop med int health 1998; 3: 130-137. 13. kumar rm, uduman sa, khurrana ak. impact of pregnancy on maternal deaths aids. j reprod med 1997; 42: 429-434. 14. national committee on confidential enquiries into maternal deaths. a review of maternal deaths in south africa during 1998. s afr med j 2000; 90: 367-373. 15. mcdermott jm, slutsker l, steketee rw, wirima jj, breman jg, heymann dl. prospective assessment of mortality among a cohort of pregnant women in rural malawi. am j trop med hyg 1996; 55: 66-70. 16. ryder rw, nsuami m, nsa w, et al. mortality in hiv-1-seropositive women, their spouses and their newly born children during 36 months of follow-up in kinshasa, zaire. aids 1994; 8: 667-672. 17. bledsoe k, olopoenia l, barnes s, delapenha r, saxinger c, frederick w. effect of pregnancy on progression of hiv infection. int conf aids 1990; 6: 288. 18. bessinger r, clark r, kissinger p, rice j, coughlin s. pregnancy is not associated with the progression of hiv disease in women attending an hiv outpatient program. am j epidemiol 1998; 147: 434-440. 19. mcintyre ja. hiv in pregnancy: a review. occasional paper no. 2. geneva: world health organization, 1999. 20. weisser m, rudin c, battegay m, pfluger d, kully c, egger m. does pregnancy influence the course of hiv infection? evidence from two large swiss cohort studies. j acquir immune defic syndr hum retrovirol 1998; 17: 404-410. 21. ahdieh l. pregnancy and infection with human immunodeficiency virus. clin obstet gynecol 2001; 44: 154-166. 22. villamor e, msamanga g, spiegelman d, peterson ke, antelman g, fawzi w. pattern and predictors of weight gain during pregnancy among hiv-1 women from tanzania. j acquir immune deficiency syndr 2003; 32 (5): 560-569. 23. john gc, bird t, overbaugh j, et al. ccr5 promoter polymorphism in kenyan perinatal human immunodeficiency virus type 1 cohort: association with increased 2-year maternal mortality. j infect dis 2001; 184: 89-92. 24. olusanya o, okpere e, ezimokhai m. the importance of social class in voluntary fertility control in developing country. west afr j med 1985; 4(4): 205212. 25. ayisi jg, van eijk am, ter kuile fo, et al. the effect of dual infection with hiv and malaria on pregnancy outcome in western kenya. aids 2003; 17: 585-594. 48 pg14-20.html original article knowledge, attitudes and personal beliefs about hiv and aids among mentally ill patients in soweto, johannesburg g jonsson, mb chb, dmh (sa), fcpsych (sa), mmed (psych) m y h moosa, mb chb, fcpsych (sa) mmed (psych) f y jeenah, mb chb, mmed (psych), fcpsych (sa) luthando psychiatric hiv clinic, chris hani baragwanath hospital, division of psychiatry, university of witwatersrand, johannesburg aim. the aim of the study was to determine knowledge, attitudes and personal beliefs regarding hiv and aids in a group of mentally ill patients attending outpatient clinics in soweto, johannesburg. method. all patients attending four randomly chosen clinics in soweto were invited to complete a self-administered questionnaire after obtaining informed written consent. the 63-item questionnaire, developed from others specifically for this study, included questions on socio-demographic and clinical characteristics; knowledge on how hiv is acquired and spread; attitudes and beliefs regarding hiv and aids; and condom usage. the statements in the knowledge sections were used to calculate a composite score, which if greater than or equal to 75% was defined as ‘adequate knowledge’. results. a total of 1 151 patients with mental illness participated in the study. the mean age was 41.9 years (standard deviation 11.6) and the majority were males (50%); single (55%), and had achieved only a secondary level of education (53.3%). overall, most of the study population did not believe in the myths surrounding the spread and acquisition of hiv and aids. there were however, significant associations between a low level of education and the belief that hiv is acquired from mosquito bites (odds ratio (or) 1.61; 95% ci 1.19 2.18; p=0.002) and through masturbation or body rubbing (or 1.76; 95% ci 1.34 2.33; p=0.000). although more than 90% of the patients were aware of the facts regarding the spread of hiv, approximately 40% did not believe that one could acquire hiv through a single sexual encounter. the composite scoring for knowledge showed that less than half the patients had adequate knowledge of hiv/aids. this was significantly associated with gender and level of education: females were 1.6 times (p<0.0004) and patients with grade 8 or higher education 1.5 times more knowledgeable (p=0.002). conclusion. among mentally ill patients there is both a lack of knowledge about most aspects of hiv and aids and a belief in some of the myths associated with the acquisition and spread of the disease, especially among older, less educated patients. it is imperative that a targeted strategy be developed for this vulnerable group, taking into cognisance their inherent lower level of education and the cognitive impairment associated with mental illness, to educate them on all aspects of hiv and aids and to improve access to services. the prevalence of hiv in developed countries is higher among patients with mental illness than among those without.1 in the usa it is estimated to be 13 76 times that of the general population.2 in southern africa the prevalence ranges from 0% to 59% (0 22.9% before 1996 and 2.6 59% after 1996, suggesting an upward trend).3 the prevalence also varies according to where the study was performed, the highest being in zimbabwe.4 collins et al. more recently reported that in south africa, despite the supposition that people with mental illness may engage in high-risk sexual behaviours more than the general population, the prevalence largely matches that of the general population.5 they suggest that as there is little injection drug use, the high prevalence of hiv in the general population is probably due to acquisition of the virus shortly after sexual initiation.5 nonetheless, there is sufficient evidence that mental illness increases the individual’s vulnerability to hiv infection.6 , 7 hiv risk among people with mental illness has been associated with lack of condom use, multiple sexual partners and injection drug use.8 , 9 the social exclusion that often accompanies life with mental illness may also increase vulnerability to infection. it may lead to exchange of sex for money or goods and an increase in coercive sexual encounters. in addition, cognitive deficits associated with certain mental disorders may impair judgement and the ability to negotiate safe sexual encounters.10 in the general population, education and providing information about hiv and aids is one of the important ways of reducing risky sexual behaviour and the spread of the disease.11 yet studies have shown that levels of knowledge about hiv and aids are sub-optimal among patients with mental illness, and that levels differ among inpatients and outpatients and are influenced by psychiatric diagnosis.12 patients with mental illness tend to engage in risky sexual behaviour because of these lower levels of knowledge, which places them at risk of contracting or transmitting hiv.1 , 3 , 14 melo et al. found in their study that high hiv and aids knowledge scores were associated with a past history of sexually transmitted infections, previous hiv testing and consistent condom use and that low knowledge scores were associated with mental illness.11 similarly, a study in a psychiatric hospital in rio de janeiro also showed knowledge to be lower in patients with mental illness compared with the general population.15 the authors used a 17-item aids knowledge test and found the average correct score to be only 61.2%. chandra et al., who assessed hiv knowledge among a group of indian patients with mental illness at baseline and 5 days later after an hiv risk reduction programme, showed that brief hiv-focused educational intervention can improve knowledge.16 however, different methodologies employed in the various studies make it difficult to ascertain accurate knowledge among psychiatric patients. in spite of evidence showing poor knowledge of hiv and aids among mentally ill patients and the risks thereof, very few mental health services routinely assess knowledge of hiv transmission and risk behaviour,1 , 13 let alone attempt to educate this vulnerable group of individuals. hiv risk reduction interventions targeting south africans with psychiatric illness remain few and far between. collins examined the attitudes of 46 mental health care providers in four provinces of south africa and reported that ‘personal, contextual and political factors in the clinic and the hospital create barriers to integrating prevention activities. in particular, providers face at least three challenges to intervening in the epidemic among their patients: their own views of psychiatric illness, the transitions occurring in the mental health care system, and shifting social attitudes toward sexuality.’17 although barriers exist in implementing such education programmes, the mental health care act no. 17 of 2002 requires the integration of all prevention and promotion programmes into psychiatric services.18 this is supported by research that shows it to be implementable.1 , 19 hodgson stated that: ‘hiv for many south africans defies precise classification: it does not fit the profile of a ‘normal’ disease. it affects the developed and the developing world in different ways and has a long period of apparent inactivity, and any of a large number of symptoms can present as the immune system weakens. this is further complicated by the association of hiv with sex, death, taboo and youth. it is therefore not surprising that people depend upon cultural models of illness, constructed from existing mythical frameworks and illness narratives, to provide meaning and to guide behaviour.’20 some prevalent cultural norms and beliefs include negative attitudes towards condoms (‘flesh-to-flesh’ sex is equated with masculinity and is necessary for male health); engaging in dry sex (the vagina is expected to be small and dry); the importance of fertility (which may hinder the practice of safer sex); polygamy (males are biologically programmed to need sex with more than one woman); misconceptions regarding the virus (that it can be contracted by sharing food, or mosquito bites; that sex with a virgin can cure the disease); that circumcised men cannot contract hiv; that alcohol kills hiv in the blood; and that you cannot contract hiv if you have one unprotected sexual encounter.21 the assessment of knowledge deficits will help in determining which patients need knowledge interventions as opposed to which need skills development or motivational behaviour change,11 hence the need for this study, the aim of which was to determine baseline knowledge about prevention and acquisition of hiv among mentally ill patients in soweto. it was hoped that the information obtained from this study would assist in developing protocols, guidelines and focused interventions to improve the level of knowledge and reduce the risk of spread of hiv among people with mental illness. method the study design was cross-sectional in nature and undertaken to determine the knowledge, attitudes and personal beliefs among patients attending specialist psychiatric clinics in soweto, gauteng, from april 2009 to june 2009. there are 8 specialist psychiatry clinics in soweto, of which 4 were randomly selected from a hat containing the names of all the clinics. patients (18 years and older) from these four randomly chosen psychiatric clinics were approached to participate in the study in the waiting room while they were waiting to see the psychiatrist. informed consent was obtained after the contents of the form had been explained to the patients. although the questionnaire was self-administered, a trained facilitator assisted patients where translation or explanation of the questions was necessary. the study was approved by the human research ethics committee of the university of the witwatersrand. there is no specific questionnaire that is validated to assess knowledge, attitude and personal beliefs in mentally ill patients in south africa. for the purpose of this study, questions from other validated questionnaires for the general population were used to construct our 63-item questionnaire.22 we included questions on knowledge, attitudes and beliefs that were commonly recurring. although not performed on mentally ill patients, the questions were general and appeared appropriate to be used in our study on mentally ill patients. the final questionnaire comprised of nine sub-sections; however the sub-sections analysed in this report were those on socio-demographic and clinical characteristics; knowledge on the acquisition and spread of hiv and aids; attitudes and beliefs regarding hiv and aids; and condom usage. the questions were rephrased where they might have been confusing, were not positively or negatively worded so as to prevent a set response bias, and attempted to take into consideration the cultural beliefs and norms of the participants so as not to appear offensive. the questions were in english and not translated into any of the official african languages. reliability was ensured by having one facilitator and one interviewer, who was a nurse mental health practitioner with 30 years’ experience. knowledge scores for the various categories were coded as 1 for a correct response and 0 for an incorrect or unknown response. a composite score was derived for each of the categories. a patient who achieved a composite score greater than or equal to 75% was defined as having ‘adequate knowledge’. nachega et al. used a similar technique in their study to determine average knowledge scores.23 kuder richardson (kr20) reliability coefficients were calculated for the questions pertaining to knowledge of hiv and aids (0.6591), prevention of acquiring hiv (0.0464), mental illness and hiv association (0.5832), and all questions (0.7428).24 descriptive statistics, frequency distribution tables and chi-square tests for categorical data were produced using stata (stata statistical software, release 10).25 results a total of 1 151 patients (50% males, 43.1% females, 6.9% unknown) with mental illness completed the self-administered questionnaire. typical diagnoses seen at the community clinics comprise mood disorders (both unipolar and bipolar disorders), psychotic disorders, anxiety disorders, personality disorders and disorders due to general medical conditions. the numbers of patients approached and those refusing to participate in the study were unfortunately not recorded. approximately 79% of patients were in the age group 25 54 years. patients between the ages of 15 and 24 years and those over 55 years accounted for 6.1% and 15.4%, respectively. the mean age of the entire study population was 41.9 years (standard deviation 11.6), while that for males was 39.5 years and that for females 44.1 years. female patients were significantly older (p<0.001, two-sample wilcoxon rank-sum test). marital status was as follows: single (55.2%), married or living together (21.6%), divorced or separated (13.1%), and widowed (8.1%). most of the patients had some formal education: grades 1 7 in 38.8%, grades 8 12 in 55.3%, and tertiary education in 3.2%. only 80 patients (7%) were employed and 918 (79.7%) were receiving a grant (disability or pension); 499 patients (43.4%) had a positive family history of mental illness. more than half the patients (54.6%) were unaware of the details of their own current psychiatric illness. common psychiatric diagnoses included depression (8.2%), bipolar disorder (17.3) and schizophrenia (18.9%). ninety-three per cent of the study population was aware that aids is caused by the human immunodeficiency virus (hiv). although only 2.26% responded that hiv and aids was a result of being bewitched, the majority (87%) were unsure, as they did not complete this question. overall, most of the study population did not believe in the myths surrounding the spread and acquisition of hiv and aids. however, a significantly large number believed that sharing utensils (86.7%), masturbation or body rubbing (65.4%), and a bite from a mosquito that has bitten someone with hiv (72.3%) leads to the spread of hiv (table i). although more than 90% of the patients were aware of facts relating to the spread of hiv, approximately 40% did not believe that one could acquire hiv through a single sexual encounter. there were significant associations between having a grade 8 or higher level of education and the belief that hiv is acquired from mosquito bites (odds ratio (or) 1.61; 95% confidence interval (ci) 1.19 2.18; p=0.002) or through masturbation or body rubbing (or 1.76; 95% ci 1.34 2.33; p=0.000), and that there is no hope for people with hiv and mental illness (or 4.133; 95% ci 2.00 8.50; p=0.000). similarly, there were significant associations between advancing age and the belief that hiv is acquired through masturbation or body rubbing (or 1.12; 95% ci 0.85 1.46; p=0.001) and that there is no hope for people with hiv and mental illness (or 0.961; 95% ci=0.93 0.98; p=0.002). with regard to attitudes towards condom use, only half of the patients believed that the condom completely protects one from contracting hiv. despite more than 90% of the patients reporting that they did not experience difficulty in obtaining condoms at clinics and believed that condoms did not decrease the full enjoyment of sex, only 70% of the patients reported that they used condoms with every partner they had sexual intercourse with (table ii). the majority of the patients reported that they engaged in safe sex practices. ten per cent (n=197) of the patients reported risky sexual behaviour, the reasons cited being lack of information about safe sex (n=112), lack of skills in dealing with provocative situations (n=77), because they were in hospital (n=1), no social support (n=2), actively using drugs and alcohol (n=3), and exchange sex, i.e. for cigarettes, a place to live or drugs (n=2). using the composite scoring for knowledge described in the methodology, the results showed that 49% of the patients had adequate knowledge of hiv/aids and that 42% had adequate knowledge pertaining to the prevention of acquiring hiv (table iii). the patients’ limited knowledge of hiv and aids was largely obtained from radio and television (12.7%), friends and relatives (6.2%), health care workers (5.5%), public speeches (0.4%), newspapers or magazines (0.5%), church (0.9%) and school (1.7%). however, a large majority of patients did not respond to this question. adequate knowledge about hiv and aids was significantly associated with gender, females being 1.6 times more knowledgeable than males (p<0.0004), and a higher level of education, patients with grade 8 or higher of education being 1.5 times more knowledgeable than those with less education (p=0.002). after controlling for age, gender and educational level, the results from multivariate logistic regression analysis showed similar associations to the unadjusted ors. discussion various studies have shown that a large proportion of patients with mental illness engage in behaviours that place them at high risk of contracting hiv, e.g. promiscuity, intravenous drug use with shared needles, and unprotected sex.2 , 14 , 26 although clinical factors such as poor reality perception, affective instability and impulsiveness play a major role in such behaviours, lack of knowledge and/or inaccurate information about hiv infection is also a significant variable.26 published studies in developed countries conclude that knowledge about hiv and aids is poorer in mentally ill patients than the general population.27 yet other studies, in a variety of psychiatric patient groups, reported higher proportions of correct responses to aids knowledge questionnaires, ranging from 63% to 80% 30 (comparable to that of the general us population).33 chuang and atkinson at the calgary community mental health clinic utilised a 10-item instrument to assess knowledge about hiv and aids.30 chandra et al. in india reported a low 34% accuracy in responses to questions on hiv and aids.16 we utilised a 63-item questionnaire and found that approximately 50% of the mentally ill patients surveyed had adequate knowledge of hiv and aids. while this level of knowledge is not the lowest reported among mentally ill patients, it is significantly lower than that of the general population, and specifically the soweto population. nachega et al. in their cross-sectional study of 105 hiv-infected adults attending an hiv clinic in soweto reported that 89% had good knowledge about the cause of hiv infection and 83% knew about modes of transmission.23 similarly, the 2003 south african demographic and health survey (sadhs), conducted on the general population, showed that 93 95% had heard of aids, 71 85% agreed that condoms reduce the risk of hiv infection, and 78% agreed with the statement that a healthy-looking person could be carrying hiv.34 these studies support a better level of knowledge than that of mentally ill patients. the most likely reason for low levels of knowledge is the very few education programmes specifically designed for patients with mental illness and conducted in mental health clinics, where the targeted group would be most accessible. kloos et al. found that only a little more than half of their enrolled patients reported receiving hiv-related education, which was limited to brief one-time group overviews of hiv/aids.35 further, they report that education in groups is difficult because needs and levels of functioning vary widely within the different sub-groups of mental illness.35 other factors that influence levels of knowledge include age, gender and level of education. these individual factors are more significantly associated with improved knowledge rather than treatment setting factors and condom distribution.11 our study found that female patients and patients with higher level of education (grade 8 and higher) were relatively more knowledgeable about hiv and aids. this is in contrast to chandra et al.’s finding16 that men demonstrated better knowledge, and the katz study,36 which reported no gender difference in knowledge, either for total knowledge scores or for scores on individual items. it is likely that the bias towards females in this study may be because in general females tend to be better utilisers of health facilities (including antenatal clinics), where they access education and improve knowledge, while men are notoriously known to shy away from and avoid health facilities.37 , 38 with regard to education, several studies have also reported that higher levels of education lower the risk of being hiv-positive and that educated individuals are more responsive to the hiv/aids information campaigns and condom use.11 , 39 , 40 koen et al. reported that negative symptoms associated with mental illness also impact on acquisition of knowledge.41 the participants in our study obtained their limited knowledge of hiv and aids mainly from radio and television, friends and relatives, and to a much lesser extent from health care workers. this is similar to nigerian studies, which also found that the main source of information on hiv was electronic media (radio and television).22 , 42 health care providers/institutions are significantly lacking as a source of information despite having the opportunity and having most contact with mentally ill patients. education of the mentally ill must utilise all available modalities. the vision project, although not directed at patients with mental illness, showed that individuals with high programme exposure were one and a half times more likely than those with no exposure to have discussed aids with their partner and over twice as likely to know that condom use can reduce the risk of hiv infection.43 similar outcomes were reported in india by chandra et al., whose patients received an hiv educational programme and were then re-assessed for their knowledge 1 and 5 days later. the results indicated a poor level of baseline knowledge, which improved after education; knowledge gains were sustained at 5 days.16 there is strong evidence to support the recommendation that mental health practitioners should develop specific training programmes aimed at increasing knowledge among the mentally ill. these programmes must take into cognisance the lower level of education and cognitive impairment among mentally ill patients and should be incorporated not only in health facilities but also in the print media and the radio. while education is important, misinformation, myths and urban legends have been found to be associated with higher rates of hiv risk behaviours (impulsivity, increased sexual activity, poor skills at negotiating safe sex and drug abuse) among mentally ill patients.19 approximately 1 in 10 patients in our study engaged in risky sexual behaviour, largely because of lack of information or misinformation. one in 5 of our participants believed that a shower after sex prevented one from contracting hiv. this was similar to figures in studies by koen et al. 41 and chandra et al. 16 katz et al. reported that 42% of their subjects were unaware that they could be infected by injection drug use.36 otto-salaj et al. reported that 48% of their subjects believed that careful cleansing after sex would provide protection from the virus,32 and kalichman et al. that 37% of their patients believed that showering after sex would prevent hiv infection.19 in the study by chuang and atkinson, a significant number of subjects believed that one could acquire aids by donating blood and 25% did not think that having only one unsafe sexual contact would make them vulnerable to hiv infection.30 in our study, a much higher proportion (40%) of respondents believed that one could not acquire hiv after just one sexual contact. the majority also believed that sharing utensils (86.7%) and masturbation or body rubbing (65.4%) leads to the acquisition of hiv. more than two-thirds of the respondents held the belief that that hiv can be acquired from the bite of a mosquito. in a nigerian study, only 23.5% of patients held this belief,42 while only 57% in the sadhs rejected the statement that hiv cannot be transmitted by mosquito bites.34 our study also found significant associations between the frequency of some of these beliefs and a grade 8 or lower level of education and advancing age. only half of our patients believed that condoms completely protect one from contracting hiv, and 90% believed that condoms do not decrease the full enjoyment of sex. despite this, 14.6% of the participants did not use condoms with every partner they had sexual intercourse with and would not insist that either they or their partners wear condoms. this compares favourably with the sadhs study, in which 76% of men knew that using condoms and having sex with one uninfected partner prevents hiv, while only 68% of women knew this.34 bonhert et al. reported that while misinformation and myths may be associated with negative attitudes towards condoms and a greater number of sex partners, holding these beliefs was not an impediment to hiv testing or increased risk behaviour.44 while the majority of our patients were aware that aids was caused by hiv, 1 out of 10 patients believed that it was caused by bewitchment. in comparison, in the sadhs 76% of women surveyed agreed that hiv could not be transmitted by witchcraft.34 witchcraft or invisible forces have long been thought of in africa as causing untimely death or illness. in the south african context this is often seen as malicious individuals using spiritual entities or ‘muti’ to effect harm on another person. jealousy is thought to be the main reason why a malicious lover, neighbour or relative would want to harm a particular individual. of equal concern is the fact that 24% of our patients responded that they used additional protective measures from traditional healers to guard themselves against the acquisition of hiv. in a study among inmates (not reported as having mental illness) of quthiing prison in lesotho, 2.1% of respondents interviewed thought that hiv was caused by bewitchment and 23% believed that traditional protective measures against witchcraft may prevent the transmission of hiv/aids.22 efforts to combat hiv/aids in prevention campaigns need to include tackling cultural beliefs and not just provide information on cause and transmission. understanding these cultural beliefs is important, as they influence decision making concerning choice of therapy. in these cases, hospitals or clinics are only approached for help as a last resort when traditional therapies have failed. it is then often too late for biomedical treatments to be effective. we also need to extend this information to what symptoms suggest infection and how to respond to those symptoms.45 it is these gaps in our prevention programmes that continue to facilitate infection, as misinformation about aids leads to high-risk behaviours.36 a few limitations to this study are worth noting. although diagnosis was not correlated with clinical records and no measure of level of severity of psychiatric illness at the time of the interview was made, reliability was ensured by having one facilitator and one interviewer who was a nurse mental health practitioner with 30 years’ experience. our sample was also predominantly urban and hence may not be generalisable to other study populations. the self-report nature, although facilitated, might have caused bias that might have led to overor under-estimation of certain variables. similarly, a minimum level of literacy was required that may have biased the sample towards higher functioning and more literate respondents. our questionnaire has not been validated in mentally ill patients or in a developing country and may have been too lengthy. further work is required to explore and improve the psychometric properties of this questionnaire, and to develop preventive programmes and means to assess whether such programmes work in terms of retained knowledge and behavioural change. sexual risk behaviour was not analysed in this research study, but is the basis of a future report. conclusion given the relatively high prevalence of both mental illness and hiv/aids in our general population, there is a proportion of patients with mental illness who lack knowledge about hiv and aids. comprehensive basic information and medical facts concerning the acquisition, prevention and further transmission of hiv are needed. promotion of hiv testing and counselling of psychiatric patients and their families is needed and should further enable this group to receive appropriate psychological support. the uninfected segment of the mentally ill population should have adequate knowledge about how to protect themselves against this devastating disease. knowledge of hiv status, with appropriate counselling, may mean that these individuals can change risk behaviour to protect their quality of life and that of their families. prevention activities should include peer programmes, leadership seminars, and development and distribution of adaptable programmes that target high-risk groups such as patients with severe mental illness. innovative ways of targeting messages and delivering focused prevention education packages to patients with psychiatric illness are needed in developing countries. we need to dispel myths about condoms and improve distribution of condoms (especially female condoms) in our clinics and psychiatric institutions. although most mental health clinics in our area do not provide any sexual health orientation, it is vital that this situation is improved upon and that policies are developed towards implementing prevention packages among mentally ill patients, as prevention programmes based on research on group-specific needs are most likely to be successful.36 clinicians need to address basic hiv knowledge and risk reduction interventions with all patients they see on a daily basis. acknowledgments. we thank rauf sayed of the department of public health, university of cape town, for his valuable input and computation of statistics for this manuscript. we also thank mrs beryl mohr and ms phangisile mtshali of bristol myers squibb, secure the future foundation, who provided the necessary support and funding for this study to take place. references 1. collins py, mestry k, wainberg ml, et al. training south african mental health care providers to talk about sex in the era of aids. psychiatr serv 2006;57(11):1644-1647. 1. collins py, mestry k, wainberg ml, et al. training south african mental health 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j, meeker d, adewuyi a. assessing effects of a media campaign on hiv/aids awareness and prevention in nigeria: results form the vision project. bmc public health 2006;6:123-135. 43. keating j, meeker d, adewuyi a. assessing effects of a media campaign on hiv/aids awareness and prevention in nigeria: results form the vision project. bmc public health 2006;6:123-135. 44. bohnert asb, latkin ca. hiv testing and conspiracy beliefs regarding the origins of hiv among african americans. aids patient care stds 2009;23(9):759-763. 44. bohnert asb, latkin ca. hiv testing and conspiracy beliefs regarding the origins of hiv among african americans. aids patient care stds 2009;23(9):759-763. 45. golooba-mutebi f, tollman sm. confronting hiv/aids in a south african village: the impact of health seeking behavior. scand j public health suppl 2007;69:175-180 45. golooba-mutebi f, tollman sm. confronting hiv/aids in a south african village: the impact of health seeking behavior. scand j public health suppl 2007;69:175-180 table i. myths and facts relating to spread of hiv and protection against acquiring hiv (% of questions answered as ‘yes’, ‘no’ or ‘unknown’) yes no unknown myths relating to spread of hiv living in the same house as someone who has hiv 8.6 88.6 2.8 sharing utensils 86.7 10.9 2.3 sharing cigarettes, food or drinks 7.7 89.0 2.6 hugging someone who has hiv 7.3 89.4 2.4 kissing 25.1 72.8 1.9 masturbation or body rubbing 65.4 31.5 2.5 coughing 17.9 78.9 2.9 mosquito that has bitten someone with hiv 72.3 24.5 2.6 myths relating to protection against acquiring hiv a shower after sex reduces the risk of getting hiv 17.7 80.2 2 oral sex is safe when partners don’t swallow 80.5 16.1 2.9 additional protective measures from traditional healers 24.2 71.8 3.9 facts relating to spread of hiv in one sexual contact 57.0 40.2 2.8 having sex with multiple partners 92.2 5.7 1.7 during anal sex 92.3 5.2 2.4 having sex without a condom 82.3 5.1 1.9 through broken skin, e.g. cuts or grazes 94.6 3.4 1.9 through injection drug use 89.9 6.6 2.5 an hiv-infected pregnant woman infecting her baby 92.7 5.1 2 table ii. frequency distribution of attitude towards condoms and safe sex practices (% of questions answered as ‘yes’, ‘no’ or ‘unknown’) yes no unknown attitude toward condoms do you use condoms with every partner you have sex with intercourse with? 70.2 14.6 14.9 condoms decrease my full enjoyment of sex so it is not necessary to use it 5.8 91.2 2.9 have you ever had problems obtaining male/female condoms? 5.9 91.7 2.4 safe sex practices i should have as many sexual partners as possible as it will prove that i am a real man 1.5 95.7 2.9 are you faithful to a single partner? 76.7 8.3 14.9 have you had more than one partner with whom you have had unprotected sex? 6.4 78.9 14.6 table iii. knowledge of hiv/aids and prevention of acquiring hiv n % adequate knowledge of hiv/aids no 592 51.4 yes 559 48.6 adequate knowledge pertaining to prevention of acquiring hiv no 665 57.8 yes 486 42.2 or = 1.55 (95% ci 1.21 1.99); chi-square test: p<0.0004. the southern african journal of hiv medicine                                                                july  2009 on 16 december 2007 parts of the new sexual offences act came into operation. among other things the act aims to address the vulnerability of children (persons under 18) to sexual abuse or exploitation by enacting a number of new, expanded or amended provisions. it provides among others that: n a male or female under the age of 12 years is incapable of consenting to a sexual act (section 57(1)). n the age of consent to sexual penetration and other related sexual activities is 16 (s 15 and 16). n if anyone engages in consensual sexual activity (which includes penetration) with a child between the ages of 12 and 16, they are both committing the crime of statutory rape. n if anyone engages in consensual sexual activity (which includes non-penetrative direct or indirect contact with the genital organs or mouth) with a child between the ages of 12 and 16, they have both committed the crime of statutory sexual assault (s 16). n sexual exploitation of children, with or without their consent, is an offence. this can occur when a person unlawfully uses a child as a sex worker (s 17(1)). it is also an offence to facilitate the involvement of a child in sex work and to live off the earnings of a child involved in sex work (s 17(2) and (5)). n children may not be involved in or exposed to child pornography (s 19). n it is an offence to compel children to witness various sexual acts or offences (s 21). n it is an offence to ‘flash’ or expose certain body parts to children (s 22). this act also creates a broad obligation to report any sexual offence involving a child. section 54(1) places this duty on ‘any person’ to report this information ‘immediately’ to a police officer. the duty comes into operation once the person is ‘aware’ of a sexual offence involving a child. the oxford dictionary defines awareness as ‘having knowledge’, so any person with information that any of the child sexual offences described in the act have been committed is obliged to report this to the police. any person failing to comply with this obligation commits an offence and may be sentenced to a fine or a maximum of 5 years in prison or both (s 54(1)(b)). sex, lies and disclosures: researchers and the reporting of under-age sex o p i n i o n ann strode, ba llb, llm faculty of law, university of kwazulu-natal, pietermaritzburg catherine slack, ba, ma clin psych hiv/aids vaccines ethics group, school of psychology, university of kwazulu-natal, pietermaritzburg children (persons under 18) are a vulnerable group and require legal protection because of their youth and inexperience.1 as a result, various provisions in the law ensure the care and protection of children through mechanisms such as mandatory reporting obligations, which generally require persons in positions of authority, in special relationships with children or even strangers to report to the authorities when a child is in need of care and protection.2 within this context, a recent change in the law has placed an obligation on any person who is aware of a sexual offence having been committed against a child to report this to the police in terms of the criminal law (sexual offences and related matters) amendment act, hereafter referred to as the ‘sexual offences act’.3 given that it is an offence in terms of this act to have sex below the age of 16, researchers involved in research with teenage participants in the course of which they may become aware that participants are engaging in sex or sexual activity but are under the age of 16 will be obliged to inform the police of this fact. this article describes the changes introduced by the sexual offences act and the implications it poses for the research relationship. it proposes non-compliance with certain provisions in this act when specific conditions are met, and concludes with recommendations for advocacy against inappropriate and senseless reporting of consensual under-age sex or sexual activity. overview of the sexual offences act 8 the southern african journal of hiv medicine                                                                july  2009 in many instances researchers may become aware through biomedical or social science research that an adolescent is involved in a sexual offence because they will have knowledge of a child’s sexual activity – this may be because they ask adolescents questions about their sexual activity, identify sexually transmitted diseases or provide hiv testing services or access to contraceptives. many of these adolescents will be between the ages of 12 and 16. through these interactions researchers may well gain knowledge of a sexual offence that has been committed against or by a child. the issue of reporting under-age sex is very complex, as in our view there are various categories of under-age sex. the first is under-age sex that is non-consensual, for example an adolescent of any age who has been raped. the second is under-age sex that is ‘consensual’ but could be regarded as abusive or exploitative, for example, a 15-year-old having sex with an 35-yearold for air time. the third is under-age sex and sexual activity that is ‘consensual’ and non-exploitative, for example, two 15-year-olds in a peer relationship. accordingly, we argue that under-age sex and sexual activity that is ‘consensual’ and non-exploitative should be treated differently from the first two categories. we submit that researchers should not report consensual, non-exploitative under-age sex or activities to the police. this approach requires researchers and research ethics committees to agree to not apply one portion of the sexual offences act, and opens researchers to the possibility of being charged with violating the act. however, we argue that reporting consensual non-exploitative underage sex is in direct conflict with the principles articulated in the children’s act,4 which expressly allows children under the age of 16 to access services such as contraceptive advice and methods, hiv testing, and medical treatment — the underlying principle being that they ought to be drawn into the service system and not excluded from it by the paternalistic approach of the criminal law. our approach is in line with the rights provided for in the children’s act, which recognises the emerging autonomy of children by giving them the right to access to information on health promotion and the prevention and treatment of ill-health/diseases (s 13), to confidentiality regarding their health status provided this is in their best interests (s 13), to consent independently to hiv testing from the age of 12 (s 130) and to access contraceptives independently, and to confidentiality in this regard from the age of 12 (s 134). this approach can also be defended on the ethical grounds that harmful activities (non-consensual or exploitative) are reported, but that non-harmful activities (consensual and non-exploitative) are not reported because this is unlikely to protect children, may erode trust in adult or authority figures, and may decrease the veracity of disclosures children make to research staff — impeding the ability to steer them to appropriate services. furthermore, the sexual offences act itself seems to imply that where under-age sex is not exploitative prosecutions are only to be instituted in exceptional circumstances. section 15(2)(a) states that where both children were under the age of 16 at the time of the alleged offence prosecutions are only to be instituted if authorisation has been obtained from the national director of public prosecutions. if this approach is considered to be unworkable because, for instance, researchers are vulnerable to being charged with being in contravention of the sexual offences act, then researchers could consider reporting all sexual offences, including instances of consensual non-exploitative sexual activity. in this case, there could be either formalistic of full compliance with the law. if researchers opt for formalistic compliance they could do this through submitting a monthly sheet of names of adolescents having committed the sexual offences of consensual sex or sexual activity under the age of 16 with a member of their peer group, using a brief form. this could be sent to their closest police station. this form could contain the names of the adolescents but not other details, thus to some extent protecting the relationship between participant and researcher. alternatively, there could be full compliance with the law by providing the police with all details of the under-age sex including the names and addresses of the participants. we think both approaches have disadvantages because they may: (i) baffle community groups being mobilised for the research; (ii) impact on the scientific validity of the data the research is collecting, as adolescents may be less truthful; (iii) impact on enrolment practices, perhaps skewing enrolment towards a certain category of adolescent, affecting the generalisability of the data; (iv) increase risks of social harms for adolescents (like stigma); (v) be difficult to explain to adolescents and parents in the consent process; (vi) represent a threat to confidentiality as, in small communities, adolescents may be known to the police, and the protection of the list once in the hands of the police cannot be guaranteed; and (vii) erode beneficial aspects of the research such as steering adolescents in need to the appropriate services. we argue that researchers should not comply with the mandatory reporting obligations for under-age consensual, non-exploitative sexual activity on the carefully considered grounds described above. implications and recommendations conclusions 9 the southern african journal of hiv medicine                                                                july  2009 in all other cases there should be reporting, even of sex or sexual activity that is described as consensual by the adolescent, but appears exploitative in nature. this approach may actually require researchers to work harder than if they merely followed the letter of the law, by requiring them to assess the consensual, nonexploitative nature of the sexual activity, intervene in various ways to assist children, and design consent forms and processes with enough detail to enable parents and children to fully understand when reporting of sexual activity will occur. we argue that because mandatory reporting of underage sex/sexual activity (even consensual and non-exploitative activity) may alienate children from services and ‘punish’ them by reporting their conduct to the police, advocacy is needed for a change to the sexual offences act to ensure consistency with the approach taken in the children’s act. references 1. kruger jm, robinson ja. the legal status of children and young persons. in: robinson ja, ed. the law of children and young persons. durban: butterworths, 1997: 1-48. . 2. south african law reform commission. report on the review of the child care act (2002). http://www.doj.gov.za/salrc/reports/r_prj110_childcare/r_pr110_ cont_2002dec.pdf (accessed 20 may 2009). 3. act no. 32 of 2007. 4. act no. 38 of 2005. 10 erratum in the article entitled ‘the ghost of aids denialism: manguzi hospital and dual loyalty’, which appeared in the third issue of this journal last year, there was an error in order of authorship. the first author should have been donna knapp van bogaert, and the correct citation is as follows: donna knapp van bogaert, marlise richter. the ghost of aids denialism: manguzi hospital and dual loyalty. southern african journal of hiv medicine 2008; 9(3): 8-12, 14. the southern african journal of hiv medicine                                                    december  2009 before the widespread introduction of antiretroviral therapy (art), most perinatally infected children did not survive beyond the first 2 years of life.1 with treatment, hiv-positive children are living longer. in the developed world, where haart has been widely available since 1996, survival of perinatally infected children into adolescence is now the norm. of a french cohort of perinatally infected children born before 1993, 58% were still alive and receiving hiv care 13 years later.2 in the uk the proportion of hiv-infected children in care aged 10 19 years increased from 11% to 44% between 1996 and 2005.3 as haart becomes increasingly available in south africa, we can expect similar trends. in addition to a growing population of vertically infected adolescents in south africa, youth are among those at greatest risk of hiv acquisition.4 uptake of voluntary counselling and testing is low in adolescents, with only 20% of youth ever having had an hiv test5 and even fewer engaging with the health care system for cd4 monitoring and health maintenance. at youth centres in the cape metropole, catering to 15 25year-olds only, testing uptake is 85% and two-thirds go on to receive cd4 counts (karen jennings, personal communication). although most horizontally infected adolescents are not in immediate need of treatment, they could benefit from care and certainly from knowledge of their hiv status. mathematical models can be used to project the growth in the numbers of adolescents needing antiretroviral treatment in south africa. the assa2003 aids and demographic model,6,7 updated to reflect recent data on prevention of mother-to-child transmission8 and paediatric survival on antiretroviral treatment,9 estimates that by the middle of 2008, approximately 6 000 youth aged 10 19 were receiving highly active antiretroviral therapy (haart) and a further 6 000 met entry criteria for haart. if it is assumed that south africa meets the national strategic plan target of providing antiretroviral treatment to 80% of all individuals progressing to aids,10 the number of adolescents receiving antiretroviral treatment can be expected to increase to 153 000 by 2020. while youth aged 10 19 accounted for only 1% of the total number of patients receiving haart in 2008, this proportion is expected to grow to approximately 5% by 2020, mainly as a result of vertically infected children surviving into adolescence. treatment and care for hiv-positive adolescents will therefore become increasingly important over the next decade. this contrasts with other chronic childhood illnesses such as rheumatic heart disease, where the prevalence is declining. for example an estimated 46 cases of acute rheumatic fever were reported in 2002 in adolescents aged 10 19 years, only some of whom went on to develop rheumatic heart disease.11 adolescent health care is distinct from both paediatric and adult heath care because of the physiological and psychosocial transitions that occur during this period. hiv interferes with these normal developmental processes by delaying physical and intellectual development. in addition, hiv-positive adolescents confront many extra challenges, including concerns about medication regimens, doctors’ appointments, life expectancy, social upheaval, disclosure, stigmatisation, transmission of virus to others and the fear of being ‘abnormal’. the combination of hiv-related issues that are common to any age group and the extensive and rapid changes of adolescence create an exceptional and formidable challenge for both young people themselves and the adults who care for them. providing quality care and treatment for hiv-positive adolescents requires distinct needs to be addressed: n young people living with hiv require knowledge and understanding of their hiv status. disclosure of status at this age is paramount, although often not easy to accomplish. once aware of their serostatus, adolescents require frank ongoing communication and education to ensure understanding of the implications and acceptance of living with their illness. while often deferred in childhood, disclosure is the emerging need for adolescentfocused hiv care in south africa o p i n i o n h b jaspan1, md, phd, faap r li2, mphil l johnson3, phd, aia l-g bekker1, mb chb, phd, fcp 1desmond tutu hiv centre, institute of infectious diseases and molecular medicine, university of cape town 2centre for social science research, university of cape town 3centre for actuarial research, university of cape town 8 9 december  2009                                                      the southern african journal of hiv medicine                                                   crucial during adolescence as individuals approach cognitive maturity.12 significant adults may need to be guided and supported in this process. n hiv places multiple stressors on the life of the adolescent, including side-effects from medication, chronic illness, real or perceived stigma, and frequently the death of family members. young people living with hiv may struggle to achieve mental health. north american research has described high rates of mental disorders among hiv-infected adolescents, although it remains unclear whether these problems are associated with the virus itself or other environmental factors.13 whatever the cause, evidence suggests that young people living with hiv need appropriate psychological services for adjustment and survival of the youth into adulthood. this is particularly important given that mental health status affects haart adherence and engagement in risky sexual behaviour.14,15 n adolescents need social, emotional, spiritual, and often material support.16 often hiv-infected adolescents are alienated from their peers.17 support groups can provide this support where peers do not. however, such groups cannot replace support for daily living, where additional assistance is often required. n because adherence to treatment and treatment programmes is integral for sustaining positive health outcomes, hiv-positive young people need support in managing their treatment. during childhood, caregivers are often heavily involved in their children’s daily routines, and provide instrumental help in taking tablets. however, as children grow up, expectations for them to take increasing responsibility for their medication and clinic appointments emerge. among adolescents adherence is a major problem, and studies suggest that compliance during this period is lower than in other stages of life.18-20 this is probably due to disease denial,21 peer pressure and social norms, rebelliousness and risk-taking behaviour, among other reasons. in a local large, private sector, sub-saharan african programme, where adolescents were treated similarly to adults, the adolescent patients were 1.5 times less likely to be virologically suppressed at one year, due to poorer adherence.20 adolescents therefore need targeted interventions that enhance adherence and promote responsible treatment management. n finally, young people living with hiv need to learn how to make healthy decisions about reproductive and sexual health. like their hiv-negative peers, hiv-positive adolescents will be maturing sexually and will have questions about their ability to date and engage in sexual activity.23,24 with sexual behaviour comes the potential for unwanted pregnancy, acquisition of other sexually transmitted infections, re-infection with more pathogenic virus, and transmission of the virus to others. the potential costs of unsafe sex are therefore exceptionally high for infected young people and their partners. young people need age-specific sexual and reproductive health services, and information and counselling to minimise risky sexual behaviour and encourage positive sexual identities.24 we are currently in a critical moment of transition, during which the first generation of perinatally infected south african children are navigating their way through adolescence. as numbers increase, we need to plan for their distinct needs. multidisciplinary adolescent specific programmes, addressing both the biomedical and the psychosocial aspects of living with hiv, would help prevent young people from falling through the cracks of paediatric or adult-orientated health care services. a few such interventions, such as the national adolescent friendly clinic initiative, have already been implemented in a number of clinics and hospitals around the country25 and should be monitored, evaluated, and expanded. adolescent-targeted care is a glaring gap in our health care system, where we have neither specialists nor wards to cater for teenagers with chronic illness. endocrinologists, cardiologists, oncologists, and other specialities that care for adolescents in south africa have been struggling with this challenge for years.26,27 the hiv epidemic, with its unprecedented numbers and characteristic disease burden in youth, may provide the impetus for the south african medical system to address the specific needs of our adolescent population. failing to do so may jeopardise the longevity of more than 150 000 adolescents requiring haart in the next decade. references 1. brahmbhatt h, kigozi g, wabwire-mangen f, et al. mortality in hiv-infected and uninfected children of hiv-infected and uninfected mothers in rural uganda. j acquir immune defic syndr 2006; 41(4): 504-508. 2. dollfus c, tabone md, trocmé n, vaudré g, leverger g. devenir à l’adolescence des enfants séropositifs au vih après transmission mère-enfant [long term outcomes in hiv infected adolescents followed from birth]. med mal infect 2006; 36(9): 479-480. 3. judd a, doerholt k, tookey pa, et al. morbidity, mortality and response to treatment by children in the united kingdom and ireland with perinatally acquired hiv infection during 1996-2006: planning for teenage and adult care. clin infect dis 2007; 45(7): 918-924. 4. department of health. national hiv and syphilis antenatal seroprevalence survey in south africa 2007. pretoria, 2008. 5. shisana o, rehle t, simbayi lc, et al. south african national hiv prevalence, hiv incidence, behavior and communication survey. cape town: hsrc press, 2005. 6. dorrington re, johnson lf, bradshaw d, daniel t. the demographic impact of hiv/aids in south africa. national and provincial indicators for 2006. cape town: centre for actuarial research, south african medical research council and actuarial society of south africa, 2006. http://www.commerce.uct.ac.za/care 7. johnson lf, dorrington re. modelling the demographic impact of hiv/aids in south africa and the likely impact of interventions. demographic research 2006; 14: 541-574. 8. barron p, day c, monticelli f. the disrict health barometer – year 2006/07. health systems trust, 2008. http://www.hst.org.za/publications/717 (accessed 22 february 2008). 9. boulle a, bock p, osler m, et al. antiretroviral therapy and early mortality in south africa. bull world health organ 2008; 86(9): 678-687. 10. department of health. hiv and aids and sti strategic plan for south africa, 2007-2011. 2007. http://www.doh.gov.za/docs/misc/stratplan-f.html (accessed 23 march 2007). 11. department of health, statistical notes, feb 2002. www.doh.gov.za/facts/statsnotes/2002/rheumatic.pdf (accessed 19 november 2009). 12. abadia barrero ce, larusso md. the disclosure model versus a developmental illness experience model for children and adolescents living with hiv/aids in são paulo, brazil. aids patient care stds 2006; 20(1): 36-43. 910 the southern african journal of hiv medicine                                                    december  200910 13. scharko am. dsm psychiatric disorders in the context of pediatric hiv/aids. aids care 18(5): 441-445. 14. murphy da, durako sj, mockicki ab, et al. no change in risk behaviours over time among hiv infected adolescents in care: role of distress. j adolesc health 2001; 29(3 suppl 1): 57-63. 15. murphy da, belzer m, durako sj, sarr m, wilson cm, muenz lr. longitudinal antiretroviral adherence among adolescents infected with human immunodeficiency virus. arch pediatr adolesc med 2005; 159(8): 767-770. 16. lam pk, naar-king s, wright k. social support and disclosure as predictors of mental health in hiv-positive youth. aids patient care stds 2007; 21(1): 20-29. 17. li r, jaspan hb, o’brien v, rabie h, cotton mf, nattrass n. positive futures: a qualitative study on the needs of adolescents on antiretroviral therapy in south africa. aids care (in press). 18. williams pl, storm d, montepiedra g, et al. predictors of adherence to antiretroviral medications in children and adolescents with hiv infection. pediatrics 2006; 118(6): e1745-e1757. 19. becker sl, dezii cm, burtcel b, kawabata h, hodder s, et al. young hiv-infected adults are at greater risk for medication nonadherence. medgenmed 2002; 4(3): 21. 20. nachega j, hislop m, nguyen h, et al. antiretroviral therapy adherence, virologic and immunologic outcomes in adolescents compared with adults in southern africa. j acquir immune defic syndr 2009; 51: 65-71. 21. simmons rj, corey m, cowen l, keenan n, robertson j, levison h. emotional adjustment of early adolescents with cystic fibrosis. psychosom med 1985; 47(2): 111-122. 22. bernstein k, trexler c, d’angelo lj. ‘i’m just like anyone else’: risk behaviours and health consequences in perinatally infected hiv-positive adolescents. j adolesc health 2006; 38 (abstracts): 114-115. 23. wiener ls, battles hb, wood lv. a longitudinal study of adolescents with perinatally or transfusion acquired hiv infection: sexual knowledge, risk reduction self-efficacy and sexual behavior. aids behav 2007; 11(3): 471-478. 24. birungi h. hiv/aids programming and sexuality of young people perinatally infected with hiv. proceedings of the international conference on actions to strengthen linkages between sexual and reproductive health and hiv/aids, 4 8 february 2007, mumbai, india, pp. 141-151. 25. pettifor ae, kleinschmidt i, levin j, et al. a community-based study to examine the effect of a youth hiv prevention intervention on young people aged 15 24 in south africa: results of the baseline survey. trop med int health 2005; 10(10): 971-980. 26. richter ms, mfolo v. the perception of south african adolescents regarding primary health care services. scientificworldjournal 2006; 6: 737-744. 27. stefan dc. adolescents with cancer in developing countries: who offers the best care? pediatr blood cancer 2008; 51(5): 716. 11 a p r i l 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e with the aim of presenting an overview of the key literature that analyses the relationship between class, race, culture and hiv in south africa, a literature review was conducted using pubmed and google scholar to search for the following key words: ‘south africa’, ‘socioeconomic status’, ‘socioeconomic’, ‘poverty’, ‘wealth’, ‘education’, ‘hiv prevalence’, ‘hiv risk’ and ‘sexual behaviour’. the argument that class determines racial differences in hiv prevalence a salient feature of the literature on this topic is how commonly it is assumed (with little or no substantiating evidence) that racial differences in hiv rates in south africa can all be explained by socio-economic differentials. according to one of the premier textbooks on hiv/aids in south africa, the reason hiv prevalence rates differ between races is that ‘marginalisation and discrimination on the basis of race and/or ethnicity are key factors influencing vulnerability to hiv infection’ (p. 63).1 similarly, mitton’s paper entitled ‘the sociological spread of hiv/aids in south africa’ argues that aids is ‘primarily an illness of marginalised persons’ and hence has spread faster among black africans due to their marginalised position in apartheid society.2 no evidence is provided in either of these two pieces to back up these claims. a more convincing argument is that hiv is a disease of poverty and inequality, and black africans’ ongoing state of economic deprivation (both relative and absolute) is the underlying determinant of the racial divergences in hiv rates. in many of the articles that make this argument no empirical evidence is provided. as an example, mccoy et al. claim without any supporting evidence that ‘critically the profound link between aids and poverty must be recognised and broken [in dealing with south africa’s hiv epidemic]’.3 a further example is gilbert and walker’s ‘treading the path of least resistance: hiv/aids and social inequalities – a south african case study’. here an unreferenced assertion is simply made that ‘there is a strong link between low income, high unemployment and poor education … and rates of hiv infection’ (p. 1106).4 other papers which assume that socio-economic factors determine racial differential hiv rates include those by tladi,5 phatlane,6 cunha7 and marks.8 an urban legend can be defined as ‘a story or anecdote that is based on hearsay and widely circulated as true’.9 characteristically, when the storyteller is questioned as to the evidence backing up the story they claim that there were eye-witnesses, but when pressed it emerges that these were friends of friends. in a similar vein, one of the striking features of the above-quoted papers is how they either present no evidence or references ‘differential poverty rates are responsible for the racial differentials in hiv prevalence in south africa’: an enduring and dangerous epidemiological urban legend? o p i n i o n chris kenyon, mb chb, ba (hons), mph, fcp division of infectious diseases and hiv medicine unit, department of medicine, university of cape town 22 it is widely held to be axiomatic in south african epidemiological and social science circles that it is not worth comparing the risk factors underpinning the dramatic differences in hiv spread in south africa’s racial groups, as these are all explained by corresponding differences in socio-economic status. the available evidence, however, suggests that hiv is not simply contoured along lines of socio-economic deprivation; rather, other – largely culturally determined – factors such as the practice and acceptance of multiple concurrent sexual partnerships play a key role. comparison of sexual behaviours between south africa’s different races supports the likelihood that cultural and not socio-economic factors are the mediators of differential racial hiv spread. finally, it is argued that the failure of many south african experts in the study of hiv to consider race as a valid variable for analysis, and allied to this their continued exaggeration of the importance of socio-economic rather than cultural factors, has contributed to the relative failure of our national aids strategy. t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 0 to back up their claims or else refer to other papers that have no empirical data to substantiate their assertions. an exception to this is a paper by fassin and schneider,10 which argues that ‘social inequalities in income and employment status’ are, together with sexual violence and enhanced mobility, the three social factors responsible for the magnitude of south africa’s epidemic. they provide evidence to back up the assertion that ‘social inequalities in income and employment status are powerful predictors of hiv infection’ in the form of a study in a mining company that stratified hiv status by race and occupational status (fig. 1). the authors claim that the higher hiv rates in blacks than whites, and in the unskilled versus the skilled job categories, are ‘the legacy of centuries of colonial exploitation and racial segregation, culminating in the institution of apartheid in the second half of the 20th century’. their argument is that ‘epidemiologically this segregation translates as differential hiv seroprevalence between black and white groups and between social classes’. they do not, however, comment on why the hiv rate within each occupational stratum is so much higher in the black than the white workers. as an example, within the lowest job category, the hiv rate is five times higher in blacks than whites. the original authors of the study note that this patterning does not support the hypothesis that socio-economic differentials determine racial differences in hiv.11 one of the most compelling proponents of the povertyinequality thesis is the anthropologist mark hunter. he too is unable to provide much empirical evidence to back up his engaging ethnographic material. one of the few pieces of quantitative evidence he does advance is that hiv incidence and prevalence rates are higher in informal than formal settlements in south africa.12 this is based on the 2005 human sciences research council (hsrc) hiv survey.13 there is, however, not much one can conclude from the fact that hiv prevalences in formal and informal urban settlements are 9% and 17% respectively, when no attempt is made to control for the fact that race (which was itself strongly correlated with hiv status) co-varies with type of urban settlement. how is hiv contoured along the lines of race and class in south africa? johnson, budlender and kirk have undertaken much more thorough analyses of the relationship between income, race and hiv. kirk14 analysed south africa’s national antenatal clinic hiv survey data to try to tease out the relationship between income, race and hiv. unfortunately the antenatal survey does not collect information about income, but kirk was able to use other data sources to show that the level of poverty in a magisterial district is negatively associated with the hiv prevalence among women attending antenatal services in that district. this finding was backed up by his analysis, which found that women with no education are at a lower risk of hiv infection than women who received high-school education (women with university education had the lowest hiv rates). johnson and budlender’s review of this topic demonstrates some of the complex ways in which race, class and culture interact to produce south africa’s hiv epidemic.11 one of these pieces of evidence is their presentation of a multivariate logistic regression analysis of the antenatal clinic data to reveal that racial differences persist despite controlling for socio-economic status (which was done here by using education level) (table i). three more recent studies from south africa have confirmed the finding that hiv is not simply a disease of poverty. using a cohort study of 3 881 individuals in eight villages in rural south africa between 2001 and 2004, hargreaves et al. were able to show that there was no association between hiv incidence and household wealth for the men and women.15 less educated women did, however, have a higher rate of infection. in the second study, barnighausen et al. used data from a longitudinal hiv surveillance and linked demographic surveillance in rural kwazulu-natal to test the relationship between socio-economic status, education and hiv incidence.16 hiv incidence was found to be related to household wealth – with the incidence lowest in the lowand high-wealth brackets and highest in the middle-income bracket. education level in this study was found to be associated with a lower risk of acquiring hiv. likewise, the carltonville project found no difference in hiv prevalence between the employed and the unemployed.17 finally, a cluster randomised odds ratio p-value african 1 asian 0.23 0.05 coloured 0.17 <0.001 white 0.13 <0.001 table i. odds ratios for hiv infection in different race groups based on a multivariate analysis of the 1998 and 1999 hiv antenatal survey data11 fig. 1. odds ratios for hiv prevalence among employees in south africa.10 23 a p r i l 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e trial designed to evaluate the impact of a microfinance lending scheme on hiv incidence found it had no impact despite improving the economic wellbeing of the participants.18 there is conflicting evidence regarding the extent to which hiv knowledge or risky behaviour varies by socio economic status. a multivariate study using data from the 1998 south african demographic and health survey found ‘little evidence that poverty is associated with risky sexual behaviour’. poorer women were, however, slightly less likely to have the necessary knowledge about hiv.19 in contrast, hallman, using household survey data from 14 24-year-olds in kwazulu-natal, showed that among females but not males low wealth is associated with earlier sexual debut, having had multiple sexual partners in the year before the survey, and lower chances of condom use at last sex.20 one of the reasons why south africans are still debating whether hiv is or is not a disease of poverty may relate to the poor quality of our national surveys. this is illustrated by the way that good-quality evidence from elsewhere in africa has established that ‘hiv infection does not disproportionately affect the poorer in sub-saharan africa’.21 this was the title of a paper that published the results of eight national hiv-serolinked demographic surveys. the most salient finding was that in all eight countries, adults in the wealthiest quintiles had a higher prevalence of hiv than those in the poorer quintiles. there was a step-wise increase in hiv with wealth quintiles in most cases. three other hivserolinked demographic studies, from kenya,22 tanzania23 and burkino faso,24 have produced similar results (fig. 2). a review article from the ‘poverty, wealth and hiv’ supplement in the journal aids concluded that poor individuals are not necessarily more likely to be exposed to hiv and therefore ‘aids cannot accurately be termed a disease of poverty’ (p. s15).25 so what do the equivalent south african sero-surveys tell us about the relationship between hiv, wealth, race and sexual behaviours in south africa? remarkably little. the hsrc is the only body that has received funding to conduct nationally representative serolinked surveys of all south africans. it has conducted three such surveys, in 2002, 2005 and 2008. by tracking knowledge, sexual behaviours and hiv prevalence, the hsrc surveys are supposed to be south africa’s flagship surveys to track progress in dealing with our epidemic. unfortunately, the surveys fail to a considerable extent on all three accounts. knowledge about hiv and its prevention, we are told, has declined from 2002. it is, however, hard to interpret what this means, given the ambiguities associated with one of the two questions assessing hiv knowledge: ‘to prevent hiv infection, a condom must be used for every round of sex?’ if a mutually monogamous couple with no recent other relationships has undergone couple hiv testing and both are negative, they would be quite correct to answer ‘no’ to this question. according to the hsrc they would score zero for this answer. sexual behaviours are tracked, but nowhere in any of the hsrc surveys is sexual partner concurrency (arguably the key risk factor in our setting) evaluated in any way. in the last survey we are informed that the percentage of persons who had more than one sexual partner in the past year is ‘a factor contributing to concurrent sexual partnerships’ (p. 41). this factor is then used as a surrogate for concurrency. no evidence is provided to back up this assumption. arguably the most marked inadequacy in the three hsrc surveys is how poorly the epidemic is mapped. sexual behaviour surveys in the usa, such as the national health and social life survey (nhsls), have found that ‘the vast majority of sexual partnerships originate within tightly circumscribed social settings, resulting in partnerships involving persons with similar characteristics’ (p. 255).26 most sexual partnerships and marriages therefore occur within the same racial/ ethnic, class, age and religion categories. this effect is strongest for race/ethnic group. the nhsls found that 91% of short-term relationships and 93% of marriages were between persons of the same racial/ethnic group. it would be very useful to know if this is the case, as seems likely, in south africa, but this kind of basic information was not assessed in the hsrc surveys. for similar reasons, the hsrc surveys are unable to break the epidemic down by socio-economic status or education levels – except to show that hiv rates are higher in informal than formal settlements. in their current format our surveys are simply not able to answer the most basic questions such as the relationship between hiv, income and race. in fact, race seems an almost taboo variable in the surveys. at no stage, for example, are sexual behaviours compared between racial groups. in the 2008 survey, there is only one place in the 120page report where hiv rates are broken down by race – in a small table in appendix a, where overall hiv rates in each racial group are presented. fig. 2. hiv prevalences for males and females by wealth quintiles in tanzania.45 24 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 0 if we cannot explain south africa’s racial differences in hiv by economic differentials, then how can we? an obvious, if rather simplistic, way to examine this question is to compare sexual behaviours between the races premised on the fact that hiv is spread by sex and more specifically via sex networks. comparing sex networks is especially important, since differences in network structure are more likely to explain large differences in hiv rates than individual level differences. network level differences, for example, have been shown to explain a third of the difference in sexually transmitted infections between races in the usa.27 we were unable to find a single published study that makes a comprehensive comparison of sexual behaviours in different racial groups in south africa. we therefore conducted an analysis of a representative sample of 3 531 14 25-year-old cape town inhabitants in the cape area panel survey (caps). individual level behavioural risk factors did not vary much by race (in fact, the lifetime number of sexual partners was highest in the white group). however, this was not the case for network factors. blacks were much more likely to have engaged in concurrency themselves or to have a partner who engaged in concurrency (table ii).28 various lines of evidence have supported the importance of concurrency in hiv spread in this area. numerous epidemiological studies have shown a strong link between partner concurrency and the incidence of sexually transmitted infections.29-31 the most compelling difference in sexual behaviours between highand low-prevalence hiv countries globally is that sexual partner concurrency is far more prevalent in the highincidence countries of southern and eastern africa.32,33 modelling exercises have shown that the key way concurrency increases hiv transmission is at a network level, where it increases the network interconnections in a manner that creates ‘superhighways’ for hiv spread.34 in this way concurrency increases hiv transmission exponentially – even if the number of sex partners does not increase. what then are the underlying reasons for the racial differences in sexual behaviour in south africa – in this case, the elevated concurrency rates in blacks? two main categories of factors have been advanced as being important in the promotion of high concurrency rates – cultural and socio-economic factors. in a separate study looking at the determinants of concurrency in the caps dataset, we found that the relationship between income quintile and concurrency found on univariate analysis disappeared on multivariate analysis.35 in addition, when we broke concurrency rates down by income quintile for each race and gender, there was no relationship between concurrency and income in any of these groups. this supports the view that, as in uganda, it is cultural factors which are responsible for the high concurrency rates.36 indeed, the ‘10 countries’ study found that a crucial factor underpinning high concurrency rates in the 10 countries in southern and eastern africa was that it was regarded as normative for men to have multiple concurrent partners.37 it is important to acknowledge three important caveats to the findings presented here. firstly, the analyses presented have attempted to ascertain the relationship between poverty and hiv. no studies in south africa that we are aware of have examined the role of socioeconomic inequalities in hiv spread. secondly, we cannot exclude the possibility that high poverty rates over generations may have had an effect on producing a set of enduring norms pertaining to sexual behaviour in blacks which, due to its population level effect, applies as much to wealthier blacks. this would mean that analyses such as our caps data, which controlled for wealth using contemporary levels of wealth, are unable to discern this legacy-of-poverty effect. thirdly, there is good evidence that the hiv epidemic is following the pattern of many other behaviour-related diseases (such as smoking-related ones) which were more prevalent among the wealthy in the early stages, but became more prevalent among the poor as knowledge of the ill effects gathers.38 should we downplay what is psychologically painful? the hsrc survey of 2005 revealed hiv prevalences of 19.9%, 3.2% and 0.5% for 15 49-year-old blacks, coloureds and whites, respectively.13 the racial differ blacks (%) coloureds (%) whites (%) partner engaged in concurrency 33 13.2 11.9 any partner definitely or possibly had concurrent partner 68.2 34.9 25.9 interviewee has had two sexual relationships simultaneously at some stage 30.1 10.8 4.9 respondents who have had 1, 2 or ≥3 concurrent relationships: 1 19.1 5.9 4.5 2 7.2 1.3 0.6 ≥3 2.0 0.5 0.6 concurrently concurrent 15.3 2.7 1.3 more than one partner had a concurrent relationship 10.8 3.1 2.4 table ii. concurrency rates by race among 14 25-year-old capetonians26 25 a p r i l 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e ences in hiv within south africa are therefore similar in magnitude to those between the highest and lowest prevalence countries in the world. finding the underlying determinants for these differences should therefore provide us with important clues as to the nature of the ‘holy grail’ in south african hiv research – what we need to do to stop the scandalously high current incidence rates. according to recently published data from a surveillance site in rural kwazulu-natal, 3.4% of adults acquired hiv during 2008, and this incidence rate has not declined at all over the past 5 years.39 our investigations along these lines provided strong support for the view that a (largely) culturally driven practice of concurrency was the likely key factor responsible for the elevated hiv rates seen in blacks. although at the 4th sa aids conference there was considerable interest in dealing with multiple concurrent partnerships, there still remains an embarrassing paucity of evidence that has been generated in south africa on the link between concurrency and hiv transmission, and on the cultural and other factors responsible for our high concurrency rates. as described above, part of the reason for this has been a peculiar reluctance to use race as an analytical variable as regards to hiv. the origins of this racial blind spot are not hard to fathom. concepts of white racial and cultural superiority were central to the ideology of apartheid. thabo mbeki would later characterise this ideology as one where black people were made to feel ‘their inferiority by being reminded of their role as germ carriers … [and attend] schools where they learn a history that pictures black people as human beings of a lower order, unable to subject passion to reason’.40 given this background, when, in the early days of the new non-racial dispensation, a new and lethal disease that was sexually transmitted was found to disproportionately affect black south africans, it should not be too surprising that the investigating experts biased their assessments of aetiology towards socio-economic factors. to suggest that cultural practices were responsible might have sounded at best insensitive and at worst racist. an example of these dynamics is a book published earlier this year by a respected south african professor of anthropology on the topic of how differences in sex networks explain the different hiv trajectories in uganda and south africa.41 in the preface, the author explains that he ‘largely ignores race’; as he explains, ‘it appears to me that with respect to sex and choice of sexual partners, race does not predict or determine significant social differences’ (p. xviii). the only argument he produces to justify ignoring race is his rejection of apartheid, which sought to ‘convince south africans that they were more different from one another than they in fact are’. this belief, he explains, ‘was empirically, not just morally, wrong. i treat south africa as an african country and do not distinguish south africans by race.’ despite sexual behaviour being one of the most culturally varied of all human behaviours42 and despite the abundant evidence of the striking differences in racial hiv rates, thornton simply assumes there are no differences in the makeup of sexual networks by race in south africa. because we reject apartheid, his argument seems to be, we must ignore all the evidence to the contrary and simply assume away all racial differences in sexual behaviour and sex network makeup. ironically, if this reluctance to venture into uncomfortable psychological spaces explains part of the origins of this denial of cultural/behavioural explanations for hiv’s rapid spread in south africa (termed third-generation denialism here), its origins have much in common with south africa’s more famous forms of hiv denialism. both mbeki’s biological hiv denialism (a virus can’t cause a syndrome) and his second generation treatment denialism (which sought to encourage vegetables and vitamins over antiretrovirals) had their origins in a similar psychological process, which sought to downplay cognitions dissonant with his belief in the dawn of an african renaissance.43 more important than the similarity in their origins, however, is the similar effects that firstto third-generation denialism are having in undermining hiv prevention efforts. it is not just that the average south african does not have a good idea of which sexual behavioural factors are responsible for the high hiv rates, but an unacceptably high proportion of leaders and experts in the field do not either. it is interesting to note how a country without this legacy of race-based conflict, such as uganda, was able in a short space of time to undergo a process of painful introspection which correctly identified and successfully targeted the practices of multiple concurrent partnerships that were fuelling the epidemic.44 it is surely time for south africa to rectify this blind spot and venture into the psychologically painful but productive places that uganda did decades ago. one of the reasons why urban legends are believed and spread is because they construct and reinforce the conceptual framework of the group within which they are told. if we contrast the unquestioning acceptance of thepoverty-explains-racial-hiv-differences thesis with the amount of evidence underpinning it, then it follows that not only did its spread share certain features in common with urban legends, but as with urban legends, its spread reveals more about the psychologies of its followers than about the differential hiv spread it purported to explain. references 1. gouws e, abdool karim q. hiv infection in south africa: the evolving epidemic. in: abdool karim ss, abdool karim q, eds. hiv/aids in south africa. cambridge: cambridge university press, 2005. 2. mitton j. the sociological spread of hiv/aids in south africa. journal of the association of nurses in aids care 2000; 11 (4):17-26. 3. mccoy d, wood r, dudley l, barron p. south africa: the hiv pandemic. in: beck ej, mays n, whiteside a, zuniga jm, eds. the hiv pandemic. oxford: oxford university press, 2006. 4. gilbert l, walker l. treading the path of least resistance: hiv/aids and social inequalities – a south african case study. soc sci med 2002; 54(7): 1093-1110. 26 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 0 5. tladi ls. poverty and hiv/aids in south africa: an empirical contribution. journal of social aspects of hiv/aids 2006; 3(1): 369-381. 6. phatlane sn. poverty and hiv/aids in apartheid south africa. social identities 2003; 9(1): 73-91. 7. cunha m. south african politics, inequalities, and hiv/aids: applications for public health education. journal of developing studies 2007; 23(1-2): 207-219. 8. marks s. 2002. an epidemic waiting to happen? the spread of hiv/aids in south africa in social and historical perspective. african studies 2002; 61(13): 13-26. 9. mirriam-websters collegiate dictionary. 11th ed. springfield, ill.: miriam-webster, 2003. 10. fassin d, schneider h.the politics of aids in south africa: beyond the controversies. bmj 2003; 326: 495-497. 11. johnson l, budlender d. hiv risk factors: a review of the demographic, socioeconomic, biomedical and behavioural determinants of hiv prevalence in south africa. cape town: centre for actuarial research, university of cape town, 2002. 12. hunter m. the changing political economy of sex in south africa: the significance of unemployment and inequalities to the scale of the aids pandemic. soc sci med 2007; 64: 689-700. 13. shisana o, rehle t, simbayi lc, et al. south african national hiv prevalence, hiv incidence, behaviour and communication survey, 2005. cape town: hsrc press, 2005. 14. kirk d. risk factors associated with hiv prevalence. honours research project, department of actuarial science, university of cape town, 2001. 15. hargreaves jr, bonell cp, morison la, et al. explaining continued high hiv prevalence in south africa: socioeconomic factors, hiv incidence and sexual behaviour change among a rural cohort, 2001 2004. aids 2007; 21 (suppl. 7): s39-s48. 16. barnighausen t, hosegood v, timaeus im, newell m. the socioeconomic determinants of hiv incidence: evidence from a longitudinal, population-based study in rural south africa. aids 2007; 21 (suppl. 7): s29-s38. 17. williams bg, gilgen d, campbell cm, taljaard d, macphail c. the natural history of hiv/aids in south africa: a biomedical and social survey. johannesburg: csir, 2000. 18. pronyk, pm, hargreaves jr, kim jc, et al. effect of a structural intervention for the prevention of intimate-partner violence and hiv in rural south africa: a cluster randomised trial. lancet 2006; 368: 1973-1983. 19. le booysen f, sumerton j. poverty, risky sexual behaviour, and vulnerability to hiv infection: evidence from south africa. j health popul nutr 2002; 20(4): 285-288. 20. hallman k. gendered socioeconomic conditions and hiv risk behaviours among young people in south africa. african journal of aids research 2005; 4(1): 37-50. 21. mishra v, assche sb-v, greener r, et al. hiv infection does not disproportionately affect the poorer in sub-saharan africa. aids 2007; 21 (suppl. 7): s17-s28. 22. johnson k, way a. risk factors for hiv infection in a national adult population: evidence from 2003 kenya demographic and health survey. j acquir immune defic syndr 2006; 42: 627-636. 23. tanzania commission for aids (tacaids), national bureau of statistics (nbs), and orc macro. tanzania hiv/aids indicator survey 2003-04. calverton, md: tacaids, nbs, and orc macro, 2005. 24. lachaud jp. hiv prevalence and poverty in africa: microand macro-econometric evidences applied to burkina faso. j health econ 2007; 26: 483-504. 25. gillespie s, kadiyala s, greener r. is poverty or wealth driving hiv transmission? aids 2007; 21 (suppl. 7): s5-s16. 26. laumann eo, mahay j, paik m. network data collection and its relevance for the analysis of stds: the chsls and the nhsls. in: morris m, ed. network epidemiology. oxford: oxford university press, 2004. 27. laumann eo, youm y. racial/ethnic/ethnic group differences in the prevalence of sexually transmitted diseases in the united states: a network explanation. sex transm dis 1999; 26(5): 250-261. 28. kenyon c, dlamini s, boulle a, white r, badri m. 2009. a network level explanation for the differences in hiv prevalence in south africa’s racial/ethnic groups. african journal of aids research 2009; 8(3): 243-254. 29. ghani ac, swinton sj, garnett gp. the role of sexual partnership networks in the epidemiology of gonorrhea. sex transm dis 1997; 24(1): 45-56. 30. potterat jj, zimmerman-rogers hz, muth sq, et al. chlamydia transmission: concurrency, reproduction number, and the epidemic trajectory. am j epidemiol 1999; 150(12): 1331-1339. 31. kenyon c, badri m. the role of concurrent sexual relationships in the spread of sexually transmitted infections in young south africans. southern african journal of hiv medicine 2009; summer, 29-36 32. wellings k, collumbien m, slaymaker e, et al. sexual behaviour in context: a global perspective. lancet 2006; 368: 1706-1728. 33. halperin dt, epstein h. why is hiv prevalence so severe in southern africa? the role of multiple concurrent partnerships and lack of male circumcision: implications for aids prevention. southern african journal of hiv medicine 2007; 26: 19-23. 34. morris m, kretzschmar m. concurrent partnerships and the spread of hiv. aids 1997; 11(5): 641-648. 35. kenyon c, boulle a , badri m, asselman v. ‘i don’t use a condom (with my regular partner) because i know that i’m faithful, but with everyone else i do’: the cultural and socioeconomic determinants of sexual partner concurrency in young south africans. presented at the ias conference, 19 22 july 2009, cape town. abstract no. mopec022 36. epstein h. the invisible cure: africa, the west and the fight against aids. london: penguin, 2007. 37. jana m, nkambule m, tumbo d, goldstein s, weiner r, for the soul city institute regional programme (2007). one love: multiple and concurrent sexual partnerships in southern africa. a ten country research report. http://www.soulcity.org.za/ programmes/research/research-reports (accessed 20 june 2009). 38. lopman b, lewis j, nyamukapa c. hiv incidence and poverty in manicaland, zimbabwe: is hiv becoming a disease of the poor? aids 2007; 21 (suppl 7): s57s66. 39. bärnighausen t, tanser f, newell ml. lack of a decline in hiv incidence in a rural community with high hiv prevalence in south africa, 2003 2007. aids res hum retroviruses. 2009; 25(4): 405-409. 40. mbeki t. zk matthews memorial lecture, university of fort hare, alice, south africa, 12 october 2001. 41. thornton rj. unimagined community: sex, networks and aids in uganda and south africa. london: university of california press, 2008. 42. youm y, paik a. the sex market and its implications for family formation. in: laumann eo, ellingson s, eds. the sexual organization of the city. chicago: university of chicago press, 2004. 43. kenyon c. cognitive dissonance as an explanation of the genesis, evolution and persistence of thabo mbeki’s hiv denialism. african journal of aids research 2008; 7(1): 29-35. 44. kirby d. changes in sexual behaviour leading to the decline in the prevalence of hiv in uganda: confirmation from multiple sources of evidence. sex transm infect 2008; 84 (suppl. 2): ii35-41. 45. shelton jd, cassel mm, adetunji j. is poverty or wealth at the root of hiv? lancet 2005; 366: 1057-1058. 27 abstract introduction methods results discussion acknowledgements references about the author(s) michael t. boswell department of internal medicine, steve biko academic hospital, university of pretoria, pretoria, south africa tshegofatso maimela clinical public health unit, department of public health medicine, steve biko academic hospital, pretoria, south africa dan hameiri-bowen nuffield department of medicine, oxford university, oxford, united kingdom george riley department of internal medicine, steve biko academic hospital, university of pretoria, pretoria, south africa albertus malan tshwane district hospital, pretoria, south africa nickietta steyn department of internal medicine, steve biko academic hospital, university of pretoria, pretoria, south africa nomonde nolutshungu department of medical immunology, university of pretoria, pretoria, south africa talita r. de villiers tshwane district hospital, pretoria, south africa zelda de beer tshwane district hospital, pretoria, south africa john mathabathe clinical public health unit, department of public health medicine, steve biko academic hospital, pretoria, south africa khanyisile tshabalala clinical public health unit, department of public health medicine, steve biko academic hospital, pretoria, south africa fareed abdullah south african medical research council, pretoria, south africa rajiev ramlall tshwane district hospital, pretoria, south africa marthinus heystek tshwane district hospital, pretoria, south africa debashis basu clinical public health unit, department of public health medicine, steve biko academic hospital, pretoria, south africa paul rheeder department of internal medicine, steve biko academic hospital, university of pretoria, pretoria, south africa veronica ueckermann department of internal medicine, steve biko academic hospital, university of pretoria, pretoria, south africa wesley van hougenhouck-tulleken department of internal medicine, steve biko academic hospital, university of pretoria, pretoria, south africa citation boswell mt, maimela t, hameiri-bowen d, et al. covid-19 severity and in-hospital mortality in an area with high hiv prevalence. s afr j hiv med. 2023;24(1), a1412. https://doi.org/10.4102/sajhivmed.v24i1.1412 note: additional supporting information may be found in the online version of this article as online appendix 1. original research covid-19 severity and in-hospital mortality in an area with high hiv prevalence michael t. boswell, tshegofatso maimela, dan hameiri-bowen, george riley, albertus malan, nickietta steyn, nomonde nolutshungu, talita r. de villiers, zelda de beer, john mathabathe, khanyisile tshabalala, fareed abdullah, rajiev ramlall, marthinus heystek, debashis basu, paul rheeder, veronica ueckermann, wesley van hougenhouck-tulleken received: 24 july 2022; accepted: 10 oct. 2022; published: 27 jan. 2023 copyright: © 2023. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: hiv infection causes immune dysregulation affecting t-cell and monocyte function, which may alter coronavirus disease 2019 (covid-19) pathophysiology. objectives: we investigated the associations among clinical phenotypes, laboratory biomarkers, and hospitalisation outcomes in a cohort of people hospitalised with covid-19 in a high hiv prevalence area. method: we conducted a prospective observational cohort study in tshwane, south africa. respiratory disease severity was quantified using the respiratory oxygenation score. analysed biomarkers included inflammatory and coagulation biomarkers, cd4 t-cell counts, and hiv-1 viral loads (hivvl). results: the analysis included 558 patients, of whom 21.7% died during admission. the mean age was 54 years. a total of 82 participants were hiv-positive. people living with hiv (plwh) were younger (mean age 46 years) than hiv-negative people; most were on antiretroviral treatment with a suppressed hivvl (72%) and the median cd4 count was 159 (interquartile range: 66–397) cells/µl. after adjusting for age, hiv was not associated with increased risk of mortality during hospitalisation (age-adjusted hazard ratio = 1.1, 95% confidence interval: 0.6–2.0). inflammatory biomarker levels were similar in plwh and hiv-negative patients. detectable hivvl was associated with less severe respiratory disease. in plwh, mortality was associated with higher levels of inflammatory biomarkers. opportunistic infections, and other risk factors for severe covid-19, were common in plwh who died. conclusion: plwh were not at increased risk of mortality and those with detectable hivvl had less severe respiratory disease than those with suppressed hivvl. what this study adds: this study advances our understanding of severe covid-19 in plwh. keywords: hiv; covid-19; sars-cov-2; mortality; biomarker. introduction people living with hiv (plwh) have an increased risk of mortality from infection with respiratory viruses, including influenza and human metapneumovirus.1,2 many studies have reported that plwh, especially those not on antiretroviral treatment (art) and with a detectable hiv-1 viral load (hivvl), have a higher risk of coronavirus disease 2019 (covid-19)-related in-hospital mortality.3,4,5 however, observational cohort studies of hospitalised patients with covid-19 have reported that plwh had lower oxygen requirements during their admission. in these studies, patients with detectable hivvl had lower relative risk of intubation than plwh with suppressed hivvl.6,7 in an observational study, plwh had similar outcomes after initiation of high-flow nasal oxygen or ventilatory support.8 there is still some uncertainty as to whether covid-19 immunopathology and clinical phenotypes are altered by hiv coinfection. current evidence suggests that severe covid-19 is associated with dysregulation of the monocyte-macrophage response, defective t-cell responses, elevated inflammatory cytokines, and hyperactivated neutrophils which culminate in ongoing, inappropriate systemic inflammation which damages pulmonary and other tissues.9,10,11,12 people hospitalised with covid-19, particularly with the more severe spectrum of disease, can develop acute respiratory distress syndrome (ards), which is associated with systemic inflammation.13 established markers of respiratory disease severity in covid-19 include respiratory oxygenation (rox) scores and partial pressure of oxygen (pao2)/fraction of inspired oxygen (fio2) ratios.8,13,14 antiviral therapy in early covid-19 leads to lower risk of hospitalisation and mortality.15,16,17 in addition, anti-inflammatories with either broad and non-specific targets, like high-dose corticosteroids, or targeted, like the interleukin 6 inhibitor tocilizumab, also lead to reduced risk of in-hospital mortality.18 hiv infection has strong effects on cellular immune phenotypes and function, affecting t and b lymphocytes, and monocytes – all of which are implicated in covid-19 pathophysiology.19,20,21 recently, more evidence has emerged to assess the effect of hiv on cellular immune responses on covid-19. hiv coinfection does not appear to alter severe acute respiratory syndrome coronavirus type 2 (sars-cov-2) cd4+ function or phenotypes, but is associated with reduced cxcr3 expression on cd8+ t-cells.22,23 higher hivvls are also associated with increased expression of activation markers on cd8+ t-cells in covid-19, which may alter disease phenotypes. people living with hiv mount similar sars-cov-2-specific antibody responses in acute covid-19 to hiv-negative people.24 hiv viraemia alters monocyte subpopulation phenotypes, reducing ccr2 and cx3cr1 expression, which may affect their ability to move from blood into tissue. in covid-19 this may reduce pulmonary inflammation.21 the majority of plwh analysed in larger cohorts or systematic reviews were on art, with suppressed hivvl and high cd4 t-cell counts.3,4,25 consequently, the effect of hiv viraemia and associated immunological changes on the clinical manifestations of covid-19 remain poorly described. uncertainty also exists as to the extent to which comorbidities in plwh, such as hypertension, diabetes, or opportunistic infections, contribute to the increased risk of morbidity and mortality. we investigated whether hiv infection is associated with covid-19 severity, differences in routinely collected laboratory biomarkers, and in-hospital mortality in a well-characterised clinical cohort of patients admitted with covid-19, in a setting with a high hiv prevalence. methods cohort description we conducted a prospective, single centre, observational cohort study of patients admitted to the tshwane district hospital complex (tdh) from april 2020 to november 2020. all patients were admitted with covid-19 as determined by a positive sars-cov-2 pcr test. this period encompasses the first covid-19 wave in pretoria and predates the widespread prevalence of the sars-cov-2 beta/b.1.351 variant which occurred during the second wave from december 2020 to february 2021. this hospital complex was the primary referral centre for covid-19 cases in the greater tshwane area, encompassing a population of approximately 3 000 000 people, with a hiv prevalence of 10.5% (95% confidence interval [ci]: 7.7% – 14.1%) in 2017.26,27 the hospital could admit 66 adults to general ward care levels, a dedicated covid-19 high care (hc) unit (22 adult beds) and an intensive care unit (icu) (10 adult beds). the hc unit admitted patients in need of dialysis, close monitoring on oxygen, high-flow nasal oxygen and non-invasive ventilation. the icu was used for patients who were intubated and ventilated. data including demographic information, comorbidities, presence of central obesity (classified as ‘overweight’), date of admission, symptom onset, date of sars-cov-2 pcr test, vital signs, level of care, and admission outcome were captured on standardised case report forms (crf). the crfs were completed by treating clinicians during patients’ admission. data from the crfs were entered by research assistants into a redcap database hosted by the university of pretoria and reviewed for accuracy by clinicians involved in the study.28 hospital admission outcome was coded as survived or died. ‘survived’ included patients transferred to other hospitals for further medical care after discharge from the covid-19 units. ‘died’ included patients with confirmed deaths during hospitalisation for covid-19. we analysed age as a continuous variable and additionally stratified the cohort into age groups with 20 year-increments. admission vital sign data were taken as the worst score within a 48 h window around the date of admission (admission ± 24 h). the rox score was calculated for participants with admission vital data (online appendix 1 figure 1-a1).14 the rox score is a continuous variable which estimates respiratory disease severity by creating a composite score considering the supplemental oxygen concentration, peripheral oxygen saturation, and respiratory rate. laboratory biomarker data were extracted from the south african national health laboratory services (nhls) online data warehouse. we analysed haematology panels (full blood count; differential white cell counts including absolute neutrophil count [anc], lymphocyte count [alc] and neutrophil-to-lymphocyte ratio [nlr]); organ function biomarkers (creatinine, alanine aminotransferase [alt]); inflammatory biomarkers (c-reactive protein [crp], ferritin, procalcitonin [pct]); and d-dimer (ddim). laboratory biomarkers were aggregated as median values for admission ± 24 h. we analysed cd4+ t-cell counts taken during admission. cd4+ t-cell counts were stratified into higher (equal to, or above, 200 cells/µl) and lower (below 200 cells/µl) cd4 counts. plasma hivvl was assessed from the previous 12 months and during admission, with the most recent value being used for this analysis. hiv-1 viral loads were stratified at 1000 copies/ml into detectable (equal to, or above, 1000 copies/ml) and suppressed (below 1000 copies/ml). statistical analysis data were analysed in r studio.29,30,31,32,33 baseline characteristics of participants were summarised as means and standard deviations, medians and interquartile ranges (iqr), and counts with percentages as appropriate. pairwise comparisons of continuous variables were done using mann-whitney (mw) u tests or t tests, dependent on the variables’ distribution. comparison of proportions was performed using chi-squared tests, or fisher’s exact test (fet). correlations were analysed by spearman rank or pearson correlation coefficients – depending on the variable’s distribution. the sensitivity and specificity of variables’ ability to predict higher levels of supportive care were calculated using area under the receiver operating characteristic curve (auroc). an auroc cut-off of 0.7 was used to decide if a variable had good predictive ability for a specified outcome. the association between age and comorbidities was analysed by logistic regression models, with age treated as a continuous variable, and results reported as odds ratios (or). univariate survival analysis was analysed by kaplan-meier survival curves with hypothesis testing via log rank tests. multivariable survival analysis was done using cox regression models, with results reported as hazard ratios (hr). schoenfield residuals were used to test for violation of the proportional hazard’s assumption. markers of disease severity, including rox scores, and laboratory biomarkers were used to stratify the cohort into mutually exclusive tertiles of comparable size. ethical considerations ethics approval was granted by the university of pretoria’s faculty of health sciences research ethics committee, and permission obtained from the institutional authorities to collect clinical data from patients admitted to the tshwane district hospital complex. protocol ethics reference number: 637/2020. results cohort description a total of 558 patient records were analysed (table 1). the mean age of this cohort was 54 (standard deviation [s.d.] ± 16) years with equivalent numbers of male (50.5%) and female (49.5%) patients. hypertension and diabetes were the most common comorbidities, at 55% and 41%. younger patients were more likely to be hiv positive at admission (age and hiv: odds ration [or] = 0.96, 95% confidence interval [ci]: 0.94–0.97, p < 0.001), and older patients were more likely to have non-communicable comorbidities including hypertension (or = 1.07, 95% ci: 1.06–1.09, p < 0.001), diabetes (or = 1.03, 95% ci: 1.02–1.04, p < 0.001), cardiovascular disease (or = 1.04, 95% ci: 1.03–1.06, p < 0.001) and chronic kidney disease (or = 1.02, 95% ci: 1.0–1.04, p = 0.03) (figure 1). figure 1: (a) the prevalence of comorbidities by age categories is shown. hiv and diabetes were the most common comorbidities in patients younger than 40 years. prevalence of non-communicable comorbidities increased with age, and hiv prevalence decreased. (b) no significant differences in symptoms at admission by hiv status (chi-squared p > 0.05 for all pairwise comparisons). cough and dyspnoea were the most common symptoms at admission. table 1: cohort demographics, admission vital signs and biomarker levels. a total of 82 plwh were admitted during this period (15% of cohort). people living with hiv were younger than hiv-negative patients and were less likely to have hypertension or cardiovascular disease (cvd) (table 2). people living with hiv were more likely to have a previous, or current, diagnosis of tuberculosis (tb), but the number of patients with active tb was small (n = 14). cd4 counts were available for 56 (68.3%) patients, and the median cd4 count was 159 (iqr: 66–397) cells/µl. a total of 32/56 (61.5%) plwh had cd4 counts below 200 cells/µl. hiv-1 viral loads were available for 52 (63.4%), and the median hivvl was 59 789 (iqr: 9417–194 534) copies/ml. hiv-1 viral loads were suppressed in 37/52 (71.2%). the median duration of symptoms before admission was slightly longer in plwh (8.4 days vs 7.1 days, p = 0.04). there was no difference in the proportion of symptoms reported at admission, with cough and dyspnoea the most common (figure 2) (chi-squared p > 0.05 for all comparisons). figure 2: (a) age and respiratory oxygenation (rox) scores at admission correlated negatively (rho = –0.2, p < 0.001). (b) correlation matrix of biomarkers with age and rox score, non-significant correlations are shown as blank cells. the size and colour of the circles show the strength and direction of the spearman correlation coefficients. (c) forest plot of the hazard ratio (hr) and their confidence intervals for variables association with in-hospital mortality. age was associated with a strong effect on mortality; therefore, all other hrs are age-adjusted. table 2: summary and comparison of admission variables by hiv status. respiratory oxygenation scores and laboratory biomarkers are associated with covid-19 severity and mortality the median rox score at admission was 8.2 (iqr: 4.8–16.7). increasing age was associated with lower rox scores at admission (correlation of age and rox score: rho = –0.2, p < 0.001), and higher ddim and inflammatory biomarker levels (figure 2a and figure 2b). rox scores, inflammatory biomarkers and ddim levels showed significant collinearity with each other (figure 2b). a total of 85 patients required hc as their highest level of supportive care and 48 patients were admitted to icu. length of hospitalisation was longer for those admitted to icu than the general wards (median 16 days vs 5 days, p < 0.001). in addition, patients admitted to icu had more severe disease – rox scores were lower, anc, pct, ddim and alt levels were significantly higher when compared to patients admitted to hc or general wards (online appendix 1 table 1-a1). consequently, higher rox scores, anc, nlr and pct levels predicted admission to icu with auroc > 0.7. rox scores below 4.5 had the highest specificity at 82% (sensitivity 62%), and pct above 0.13 the highest sensitivity at 94% (specificity 57%). the mortality rate was 57% for patients admitted to icu, 24% for hc, and 17% for general ward admissions (fet p < 0.001 for icu vs hc or general wards). a total of 121 (21.7%) patients died during admission. increasing age was associated with increased mortality during admission (figure 2c). a rox score below six at admission was associated with a twofold increase in mortality compared to higher rox scores (age-adjusted hazard ratio [ahr] = 2.1, 95% ci: 1.2–3.6, p = 0.01). the tertiles grouping the highest levels of creatinine, crp, ferritin, nlr and ddim were also associated with increased mortality (figure 3c). gender and diabetes were not associated with increased mortality during hospitalisation, but chronic kidney disease was (ahr = 2.4, 95% ci: 1.5–3.9, p < 0.001). hiv was not associated with significantly increased mortality (ahr = 1.1, 95% ci: 0.6–2.0, p = 0.14) (figure 2c). figure 3: (a) pairwise comparisons for respiratory oxygenation (rox) scores, c-reactive protein (crp), neutrophil-to-lymphocyte ratio (nlr) and d-dimer (ddim) levels are shown for higher and lower cd4 counts. lower cd4 counts were associated with higher nlr and ddim levels at admission. (b) kaplan-meier survival curves are shown for plwh stratified by cd4 count. there was no significant difference in time to death in hospital, logrank p-value shown. (c) pairwise comparisons for rox scores, crp, nlr and d-dimer levels are shown for plwh by hivvl. an hivvl above 1000 copies/ml was associated with significantly higher rox scores at admission. (d) kaplan-meier survival curves overlapped for these patients indicating no significant difference in survival, logrank p-value shown. covid-19 severity in people living with hiv respiratory rates were similar between plwh and hiv-negative patients; however, plwh needed less oxygen at admission, and had higher peripheral oxygen saturation readings. respiratory oxygen scores were higher in plwh, but the difference was not statistically significant (table 2). there was also no significant difference in nlr, crp, ferritin, pct, ddim, alt, or haemoglobin a1c (hba1c) between plwh and hiv-negative patients. creatinine levels were slightly lower in plwh, when compared to hiv-negative patients. these associations were unchanged in linear regression models which adjusted for age differences in hiv-negative patients and plwh. people living with hiv were as likely as hiv-negative patients to be admitted to icu – 3.7% of plwh versus 9.5% hiv-negative patients (fet p = 0.2). markers of disease severity in people living with hiv, stratified by cd4 count and hiv-1 viral load in plwh, a cd4 count below 200 cells/µl was associated with lower odds of having hypertension, diabetes or being on art (online appendix 1 table 2-a1). people living with hiv with cd4 counts below 200 cells/µl had higher hivvls, nlrs and ddim levels (figure 3a) and were more likely to have tb (25% vs 4%, p = 0.06) when compared to plwh with higher cd4 counts. respiratory oxygen scores were equivalent between those with higher and lower cd4 counts (figure 3a). admission rates to hc or icu were equivalent between plwh with cd4 counts above or below 200 cells/µl. people living with hiv with detectable hivvls were less likely to be on art (or = 0.11, 95% ci: 0.01–0.59, p = 0.003), and had lower median cd4 counts when compared to those with suppressed hivvls (34 [iqr: 16–47] vs 256 [iqr: 134–429], mw p < 0.0001) (table 3). people living with hiv with detectable hivvls were younger than those with suppressed hivvls (mean age 40 years vs 48 years, t test p = 0.02) and were less likely to have diabetes (or = 0.12, 95% ci: 0.003–0.97, p = 0.04). people living with hiv with detectable hivvls had significantly higher rox scores than those with a suppressed hivvl (17.8 [iqr: 10.9–20.5] vs 6.7 [iqr: 4.3–10.1], mw p = 0.005). laboratory biomarker levels were not associated with hivvl (figure 3c). none of the plwh with detectable hivvls was admitted to hc or icu. table 3: comparison of people with hiv by viral load. variables associated with mortality by hiv status in total, 109/476 (23.1%) hiv-negative patients died during admission. among hiv-negative patients, those who died were older (mean age 62 vs 52 years, t test p < 0.001), and more likely to have hypertension (p < 0.001), diabetes (p = 0.06), cvd (p < 0.001), or ckd (p < 0.001). respiratory disease severity was significantly worse at admission in hiv-negative patients who died versus those who survived (rox score: 4.8 vs 9.5, mw p < 0.001). mortality in the hiv-negative patients was also associated with higher levels of laboratory biomarkers, higher anc, lower alc and higher creatinine levels (mw p < 0.001). a total of 12/82 (14.8%) plwh died during admission. people living with hiv who died all had significant hiv-related comorbidities, or other risk factors for covid-19-related mortality (table 4). their hospital stay was shorter than those who survived (median of 3 days vs 7 days), and hivvl and cd4 counts were not associated with in-hospital mortality in univariate analyses (logrank p > 0.05) (figure 3b & figure 3d). creatinine, crp, pct and ddim levels were higher at admission in plwh who died compared to those who survived (p < 0.05 for all comparisons). when compared to hiv-negative patients who died, plwh who died had higher ddim levels at admission (2.3 [iqr: 1.6–5.9] vs 1.5 [iqr: 0.9–3.4], mw p = 0.05), were younger (mean age 49 vs 64, t test p = 0.001), less likely to be hypertensive (or = 0.23, p = 0.02) and more likely to have tb (16.7% vs 0.9%, or = 20.3, p = 0.03). table 4: clinical description of people with hiv who died during admission. discussion we report a detailed analysis of clinical phenotypes of covid-19 in hospitalised patients, with and without hiv, and their association with laboratory biomarkers. people living with hiv had similar levels of covid-19 severity, whether estimated by levels of supportive care during hospitalisation, rox scores or laboratory biomarkers when compared to hiv-negative patients. people living with hiv were younger, less likely to be hypertensive, and had lower creatinine levels at admission. people living with hiv with detectable hivvls had less severe respiratory disease, with equivalent levels of systemic inflammation as those with suppressed hivvls. similar results have been reported in hospital cohorts from higher-income settings.7,34 people living with hiv with suppressed hivvls were older, more likely to be on art, and more likely to have other comorbidities when compared to those with detectable hivvls. the prevalence of comorbidities increased with age in this cohort, as has been reported in other studies.3 therefore, it is possible that the association between respiratory disease severity and hivvl was confounded by baseline differences in age and comorbidities in plwh, and not necessarily because of hiv viraemia. effective art suppresses viral replication and reverses much of the immunopathology of hiv, but t-cell and monocyte phenotypes, as well as levels of systemic immune activation, remain altered for years afterwards.21,35 monocytes and cytokines involved in monocyte trafficking are central to the pathophysiology of covid-19.11 monocytes are recruited to tissue by the interaction of their ccr2 receptor and its ligand ccl2, which is dysregulated in severe covid-19.9 hiv infection decreases ccr2 expression on monocytes, and this is reversed with suppressive art.21 reduced monocyte trafficking to lungs after sars-cov-2 infection may reduce later monocyte-derived inflammation in covid-19, and this may be a mechanism to explain the less severe respiratory disease in plwh with detectable hivvls in this study. currently reported covid-19 studies have included few plwh with detectable hiv vls, and more research is needed to determine the effect of hiv infection on covid-19 immune responses. people living with hiv who died often had significant coexisting comorbidities including active tb infection, lymphoma, disseminated cytomegalovirus, autoimmune disease, or other comorbidities, such as hypertension, diabetes, or ckd. this complicates any discussion of covid-19 clinical phenotypes in plwh, who are at risk of opportunistic infections which can cause concomitant respiratory disease and raised inflammatory markers (pulmonary tb or pneumocystis jirovecii pneumonia [pjp]). furthermore, without systematic investigation it is difficult to know how much underlying hiv-related disease contributed to in-hospital mortality in this cohort. people living with hiv who died with suppressed viral loads were older, had higher cd4 counts and had additional comorbidities like hypertension, obesity, and diabetes, while those with detectable hiv vls had significant coinfections or hiv-associated malignancies. the sample size of plwh who died was small, and it is therefore difficult to draw statistically supported conclusions on these observations. many of the larger studies which reported that hiv infection is associated with increased risk of severe covid-19 and related mortality included a higher proportion of men in their analysis than our study.3,36,37,38 it is possible that sex and hiv interact with covid-19 to alter disease phenotypes. neutrophils play an important role in covid-19 related immunothrombosis, and neutrophils isolated from women have greater inflammatory responses to interferon, which may allow for better innate immune antiviral response.39 men with severe covid-19 have altered kynurenic acid metabolism which is associated weaker t-cell responses.40 further research should be undertaken to investigate the interaction of sex, age, and hiv infection on immune responses. this analysis has several limitations: we analysed records for patients admitted to a single tertiary academic medical centre in an urban area; many patients are sent there by referral which may bias admission towards those with more severe disease. this cohort’s prevalence of hiv infection was within the range for other reported estimates and is likely to be broadly representative of similar hospital cohorts in south africa.6,41,42 approximately one-third of plwh in this study did not have hivvls measured which may have biased the comparison between detectable versus undetectable hivvl participants. strengths of our study include prospective data collection, a validated method for quantifying respiratory disease severity on a continuum, many patients with laboratory biomarkers during admission, and plwh well characterised in terms of other comorbidities. we have generated several hypotheses related to hiv and covid-19 for future exploration. this study shows that plwh who were hospitalised with covid-19 did not have significantly different in-hospital mortality rates, levels of inflammatory biomarkers or respiratory disease severity. people living with hiv who died often had other risk factors for covid-19-associated mortality, or aids-defining illness. acknowledgements the authors would like to thank all the staff at the steve biko academic hospital and tshwane district hospitals who made it possible to collect these data. we specifically thank tshilidzi maselesele, universe masoma, mantwa tolo, katlego boshielo, bongani mashaba and simon spoor for assistance with data collection. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. 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[cited 2021 oct 20]. available from: https://www.medrxiv.org/content/10.1101/2021.07.26.21261028v1 tesoriero jm, swain cae, pierce jl, et al. covid-19 outcomes among persons living with or without diagnosed hiv infection in new york state. jama netw open. 2021;4(2):e2037069. https://doi.org/10.1001/jamanetworkopen.2020.37069 nomah dk, reyes-urueña j, díaz y, et al. sociodemographic, clinical, and immunological factors associated with sars-cov-2 diagnosis and severe covid-19 outcomes in people living with hiv: a retrospective cohort study. lancet hiv. 2021;8(11):e701–e710. https://doi.org/10.1016/s2352-3018(21)00240-x gupta s, nakabo s, blanco lp, et al. sex differences in neutrophil biology modulate response to type i interferons and immunometabolism. proc natl acad sci u s a. 2020;117(28):16481–16491. https://doi.org/10.1073/pnas.2003603117 cai y, kim dj, takahashi t, et al. kynurenic acid may underlie sex-specific immune responses to covid-19. sci signal. 2021;14(690):eabf8483. https://doi.org/10.1126/scisignal.abf8483 mash rj, presence-vollenhoven m, adeniji a, et al. evaluation of patient characteristics, management and outcomes for covid-19 at district hospitals in the western cape, south africa: descriptive observational study. bmj open. 2021;11(1):e047016. https://doi.org/10.1136/bmjopen-2020-047016 parker a, boloko l, moolla ms, et al. clinical features and outcomes of covid-19 admissions in a population with a high prevalence of hiv and tuberculosis: a multicentre cohort study. bmc infect dis. 2022;22(1):559. https://doi.org/10.1186/s12879-022-07519-8 pg31-44.html guideline guideline on safer conception in fertile hiv-infected individuals and couples l-g bekker, v black, l myer, h rees, d cooper, s mall, c mnyami, f conradie, i mahabeer, l gilbert, s schwartz ninety years ago the isolation of insulin transformed the lives of people with type 1 diabetes. now, models based on empirical data estimate that a 25-year-old person with hiv, when appropriately treated with antiretroviral therapy, can expect to enjoy a median survival of 35 years, remarkably similar to that for someone of the same age with type 1 diabetes. it is high time we normalised the lives of people living positively with hiv. this includes the basic human right to conceive and raise children. hiv-positive individuals may be in serodiscordant relationships or in seroconcordant relationships. as health care providers, it is our responsibility to ensure we understand the opportunities and risks of natural conception in these scenarios, so that we can help our patients to make informed decisions about their own lives. most of all, it is our duty to make family planning in the setting of positive prevention as safe as we can. this includes informed decisions on contraception, adoption, fostering, conception and prevention of mother-to-child transmission. some months ago a dedicated group of individuals, invited and sponsored by the southern african hiv clinicians society, came together in cape town to devise guidance in this area, recognising that there are ideal strategies that may be outside the realm of the resource constraints of the public sector or health programmes in southern africa. this guideline therefore attempts to provide a range of strategies for various resource settings. it is up to us, the providers, to familiarise ourselves with the merits/benefits and risks of each, and to then engage patients in meaningful discussions. all the above, however, is based on the premise and prerequisite that the subject of family planning is actively raised and frequently discussed in our patient encounters. 1. introduction across south and sub-saharan africa, the vast majority of hiv-positive individuals are adults of reproductive age. before universal access to effective antiretroviral therapy (art), traditional medical wisdom generally discouraged childbearing because of the risk of hiv transmission (both to uninfected partners and from mother to child) and the reduced survival of infected parents and children. in the era of art, hiv/aids has come to be viewed as a manageable chronic illness. in addition to leading to dramatic reductions in morbidity and mortality of hiv-infected parents, use of highly active antiretroviral therapy (haart) in europe and north america has driven the virtual elimination of paediatric hiv infection, and in southern africa pmtct programmes have greatly reduced paediatric infections.1 although many patients feel uncomfortable discussing it with their health care providers, many hiv-infected adults are sexually active. in advanced hiv infection fertility is reduced, but the incidence of pregnancy increases with art initiation,2 through increased sexual activity and attitudinal changes in hopes and desires for the future. south africa has an estimated 1 million births annually, and an estimated 29% of these occur in women living with hiv. other southern african countries have similar antenatal hiv prevalence rates. a substantial proportion of these pregnancies are unplanned, despite effective contraception being a critical component of the prevention of mother-to-child transmission (pmtct) of hiv/aids programme. however, many hiv-infected women and men want to have children, either immediately or at some time in the future. reproduction is a basic human right,3 and for many women having a child is part of their life plan. indeed, in many parts of southern africa being without a child attracts significant stigma.4 in this context, dealing with issues of fertility and childbearing should be seen as part of routine hiv care. clinicians are responsible for identifying and supporting the fertility desires of their hiv-infected patients – both in the interests of ‘normalising’ the lives of people living with this chronic infection, and to help ensure that conception, pregnancy and delivery take place with the least possible risk to the mother, her partner, and the resulting child. this consensus guideline for the southern african hiv clinicians society has been formulated through a process of consultation with the south african health services in mind. it is designed to assist clinicians to identify patients’ fertility desires, and to give safe and effective conception guidance to a presumed fertile couple where one or more partners are hiv infected. we have considered ‘resource-intensive’ clinical settings, such as the private sector, where technologically advanced assisted reproduction technologies may be available, as well as ‘resource-limited’ settings such as most public sector health facilities across the region. it is understood that these two levels are often not clearly demarcated, and it is recommended that providers should become familiar with which services documented here are available to patients in their setting. while we present the optimal management for safest conception, there is recognition that state-run and resource-limited clinical settings may not yet facilitate or fund these interventions. in these cases we have attempted to quantify the increased risk that not meeting these standards would incur for your patient. while specialist referral is not contraindicated for those couples in whom one or both partners are suspected of having compromised fertility, these advanced fertility interventions will not be covered in these guidelines. the guideline is divided into three sections. the first section discusses how the clinician can raise the issue of childbearing and help identify the fertility desires of hiv-infected women and men, with a brief discussion on contraceptive strategies for women who do not wish to become pregnant. the second part focuses on the management of individuals and couples who do desire a pregnancy, with emphasis on the management of hiv disease and co-morbidities before attempting conception. this includes specific conception strategies for hivseroconcordant positive couples and serodiscordant couples. finally, several key issues are discussed, and a series of illustrative scenarios have been appended to the guideline to assist with their understanding and implementation. the guideline has been devised with an eye on international norms but also with a keen view to local resource issues. the change in the natural history of hiv infection and reduction in mtct as a result of art has led to a re-evaluation of the ethical and moral arguments previously used to deny assisted reproduction to hivinfected patients. increasingly, parenting is regarded as a realistic option for couples where one or both partners are infected, and the demand for reproductive management is rising. it is also imperative to provide some measure of protection to both the uninfected partner and the uninfected fetus. this guideline attempts to provide some pointers to how this can be done more safely in the southern african context. 2. discussing fertility and childbearing with hiv-infected women and men the first step towards addressing the issues of fertility and childbearing is to regularly and repeatedly raise these with hiv-infected patients, to understand their desires and related health care needs (fig. 1). issues about fertility choices should be discussed with both men and women, and men should be encouraged to bring their partners in for further consultation should this be appropriate. local research demonstrates that the majority of individuals attending hiv care and treatment services have never had an open discussion about fertility and childbearing with their health care providers.5 when these discussions do take place, patients report that the tone is strongly judgemental – often discouraging individuals from childbearing regardless of their desires – with an exclusive focus on the need for contraception and condom use.6 iensuring that patients have a basic understanding of hiv transmission and conception is fundamental to safer conception in hiv. basic information for this can be obtained online in ‘pregnancy in our lives’ at http// www.tac.org.za/community/files/file/treatmentlit/2010/pregnancyinourlivesenglish2010.pdf to introduce this topic, the health care provider may find the following discussion points useful and informative: • the number of living children, the age of the patient's youngest child, and/or the number of other children the patient may help to care for, and how easy or difficult they find their child care responsibilities • the health of their existing children, including whether any child is hiv infected • the partnership status of the patient, the number of children the patient has with their current partner, and perceptions of a partner’s desires. because of the stigma around sexual activity and pregnancy for hiv-infected individuals, raising issues of fertility and childbearing can be sensitive for many patients. in these discussions, the use of ‘normalising’ statements – for instance, pointing out that many other patients are grappling with these issues – may help patients to feel comfortable expressing their own thoughts and opinions. typically discussions will focus on female patients, but it is critical to note that male partners can have a strong influence on women’s fertility-related desires and decisions. these issues are often highly relevant for male patients, and local studies have shown that hiv-infected men are at least as likely as women (often more so) to want another child.7 male or female patients may wish to return with their partners to discuss fertility and related issues with the health care provider, and we strongly recommend a couples-based approach to these issues (see below). throughout this discussion, the objective of the provider should be to assist patients in arriving at their own informed choice about their fertility desires. key aspects of information that providers may share which can help the patient arrive at an informed decision include: the patient's current health status and their prognosis; their age; the possibility of hiv transmission if the partner is hiv negative; and the probabilities of having an hivnegative child given appropriate interventions. other topics the provider may raise with a patient include: current versus desired family size; partner, family and community influences on fertility desires; whether any existing children are hiv infected; and the current and future resources required in caring for a child. these discussions may include an evaluation of some of the alternatives to childbearing, including adoption (box 1). ultimately these discussions should help to identify the patient’s current fertility intentions, which in turn indicate various possible health care interventions. specifically, providers should encourage patients to decide between: (a) wanting to become pregnant immediately (i.e.actively trying to conceive), versus (b) not wanting a child now, but considering a possible pregnancy in the future, versus (c) the desire to not become pregnant at all. for patients who remain unsure of their choice, option (b) above (not wanting a child in the present, but reserving the possibility of a child in the future) may be a useful default position, as it holds options open and seeks to emphasise that individuals' fertility intentions may change over time. for example, an hiv-infected woman who does not want a child at present may decide to have a child in the future. or, a couple who wants a child at present, and has one, may decide afterwards that they do not want more children. as a result, it is important to raise issues of fertility and childbearing at regular intervals during the course of chronic hiv care, even if these are brief discussions to confirm previous decisions. briefly documenting the discussions between patient and provider can be useful as a reference for future consultations and as a cross-reference in a busy public sector clinic. 3. contraception for the hiv-infected individual or couple who does not want a child while this guideline focuses on the needs of individuals and couples who wish to conceive, local research suggests that the majority of hiv-infected individuals are not actively trying to conceive and do not at present want a child.5 , 6 hiv care and treatment services are ideally suited to address family planning needs.8 a range of detailed resources are available on appropriate contraception among hiv-infected women and men (see references). however, a few key points emerge from the literature on this subject. first, there are a number of effective contraception options that may be used safely by patients living with hiv.9 choices may be somewhat restricted in the public sector to barrier methods (such as male and female condoms), injectable progestins and combined oral contraceptive pills. although availability in the public sector may be limited, intra-uterine contraceptive devices (both copper iucds and progesterone iucds) are very effective long-acting methods that can be used safely in hiv-infected women, and their use deserves further attention. male or female sterilisation should be considered for individuals or couples who are certain that they do not wish to become pregnant in the future. in making recommendations about which method to recommend, the efficacy of the different methods should be considered. if a woman is unwell and a pregnancy could impact on her health, a highly effective method should be recommended. if she does not want to use these methods and an unplanned pregnancy would not be a problem, the condom should be considered. table i shows the relative effectiveness of the common contraceptive methods, the safety of using each method in hiv-infected women, and whether there is any increased risk of transmission to partners. hiv-infected women will have the same general contraindications to use as the general population of women.10 for women who can negotiate condom use, we strongly recommend that all patients who require effective contraception be advised to practise dual method use – the concurrent use of a highly effective contraceptive method and a male or female condom. because of the relatively high failure rates of condoms, this approach should be recommended even to women who report consistent condom use. women who do not currently want a pregnancy but are reluctant to use contraception should be offered contraceptive counselling at every subsequent opportunity.10 , 11 4. the hiv-infected individual or couple who wants a child a significant proportion of hiv-infected individuals will desire a child, and may be actively trying to conceive at the time of a clinical consultation. in consulting these individuals, there are several important considerations that the hiv clinician should keep in mind. natural conception – unprotected intercourse. the risks of hiv transmission depend on hiv plasma viral load, the presence of sexually transmitted infections, and the length and frequency of exposure. the impact of hiv viral load. plasma hiv-1 ribonucleic acid (rna) levels can be correlated with the sexual transmission of hiv. viral load is the single greatest risk factor for all transmission modes. art reduces the plasma and genital hiv viral load in the infected individual to undetectable levels.12 in a study of 415 hiv serodiscordant couples in uganda, 21.7% of initially uninfected partners became infected over 30 months of follow-up, translating to a transmission rate of approximately 12 infections per 100 person-years.13 no transmission events occurred in couples in which the infected partner had a plasma hiv-1 rna level of less than 1 500 copies/ml, and the transmission risk increased as plasma hiv-1 rna levels increased. for every 10-fold increase in viral load, there was a >2-fold risk of transmission. plasma hiv-1 rna levels generally correlate positively with the concentration of hiv in genital secretions, rectal mucosa and saliva, although inflammation can stimulate local replication. other studies have shown that transmission events may be observed at a very low plasma hiv-1 rna level, suggesting that plasma hiv-1 rna level is not the only determinant of transmission.15 , 16 these data suggest that transmission probability drops markedly in people with naturally controlled viral loads or with art controlled viral loads.15 , 16 clinical research in discordant couples. findings from a large multinational clinical study conducted by the hiv prevention trials network (hptn) recently showed that men and women infected with hiv reduced the risk of transmitting the virus to their sexual partners through initiation of oral art. the study, known as hptn 052, was designed to evaluate whether immediate versus delayed use of art by hiv-infected individuals would reduce transmission of hiv to their hiv-uninfected partners and potentially benefit the hiv-infected individual as well. findings from the study were reviewed by an independent data and safety monitoring board (dsmb). the dsmb concluded that initiation of art by hiv-infected individuals substantially protected their hiv-uninfected sexual partners from acquiring hiv infection, with a 96% reduction in risk of hiv transmission.17 so what are the risks for natural conception and unprotected intercourse? one of the difficulties in counselling serodiscordant couples on natural conception methods involving unprotected intercourse is that the risk to the uninfected partner is difficult to quantify, but can certainly not be quoted as zero. mathematical models cite a risk of 1 in 100 000 per act of intercourse. in practice, viral shedding in semen has been reported to occur even in men fully suppressed on art.18 a recent retrospective study of 551 semen samples analysed in hiv-1-infected men undergoing sperm washing identified 15 cases of detectable hiv-1 in ejaculated semen in men with a long-term undetectable plasma viral load through use of art, highlighting a need for caution when couples consider a natural conception approach.19 in the case of serodiscordant couples where the woman is hiv-positive, the evidence is equally concerning: detectable hiv has been identified in follicular fluid and endometrial samples from a series of hiv-positive women undergoing in vitro fertilisation (ivf), even when plasma viral load was suppressed fully through the use of art.20 three studies have analysed infection risk in serodiscordant couples attempting to conceive naturally. the first was a prospective study conducted before the widespread use of art and examining the risk of unprotected intercourse timed to the fertile window in 96 discordant couples where the male was infected. four seroconversions were noted in the female partners, 2 during pregnancy and 2 post partum.21 the seroconversions were identified in couples in whom condom use after conception and outside the fertile window was inconsistent. a more recent, retrospective study attempted to quantify the risks of unprotected intercourse in discordant couples where the man had an undetectable viral load through use of art for at least 6 months. there were no seroconversions in 62 discordant couples who conceived.22 apart from the small sample size, the study is further weakened by the fact that seroconversions were not analysed in couples who failed to conceive, where the risk might be enhanced by repeated exposures. the only study to prospectively assess viral transmission risk in serodiscordant couples attempting to conceive naturally, where the man was fully suppressed on art and additional pre-exposure prophylaxis (prep) was used in the female partner, involved only 22 couples.23 4.1 engaging couples while we typically see patients in individual consultations, ideally hiv care and treatment services should discuss fertility and childbearing jointly with female and male partners. there are several distinct advantages to a couples-based approach. first, because partnerships have an important influence on fertility decisions, consulting with couples can be useful in helping individuals and their partners arrive at appropriate informed decisions about fertility. second, the health of both partners is important towards safe conception and pregnancy, and delivering care to both partners may therefore be necessary. third, if a couple is struggling to conceive, there are specific investigations and interventions for both women and men, and investigating and treating one partner only may lead to suboptimal outcomes. however, this entails disclosure of hiv status between partners, which can be a major challenge. at the minimum, the hiv status of both partners must be known and disclosed in order to manage this process safely and effectively. despite the importance of a couples-based approach, there are circumstances where an individual desires a child but does not know the serostatus of their partner, or desires a child in the absence of a regular partner or a partner who is willing or able to attend the clinic. these situations present particular challenges (see ‘special issues’, below). 4.2 optimising hiv therapy and addressing other health concerns as with any chronic condition, optimising the health status of an hiv-infected couple prior to conception is an important step both to facilitate conception and help ensure a safe pregnancy. in the case of hiv, this means: 4.2.1 documenting the hiv status of both partners. the recommended strategies to conceive vary depending on the serostatus of both partners, with key differences in optimal strategies for hiv-seroconcordant positive couples, and for hiv-serodiscordant partners (where either the male or female partner is hiv infected). hiv counselling and testing is a prerequisite if the hiv status of both partners is not known. 4.2.2 identifying and managing co-morbidities. this includes hiv-related co-morbidities, most notably opportunistic infections such as tuberculosis (tb), as well as other medical conditions that may influence the pregnancy, such as epilepsy or diabetes. for conditions with short-term management (e.g. tb or acute infections), we recommend delaying attempts at conception until treatment is completed. for chronic conditions that will require treatment throughout pregnancy, it is necessary to avoid potentially teratogenic medications and ensure optimal management before proceeding. 4.2.3 determination of health status for hiv-infected partners. all hiv-infected patients should undergo thorough clinical assessment and have a cd4 count to determine eligibility for art before conception. in settings where viral loads are available, these should be included as part of this work-up. however, it should be noted that an undetectable plasma viral load does not necessarily mean that there is an undetectable viral load in the genital tract. 4.2.4 art initiation as appropriate. given the benefits of art in reducing viraemia and reducing the risk of hiv transmission (in addition to its benefits for adult health), art initiation in eligible individuals and optimisation of appropriate therapy is necessary before proceeding. ideally, given the data above, any hiv-infected patient wishing to conceive and therefore contemplating unprotected sex should have an undetectable viral load before doing so. this would imply art for at least 3 4 months prior to sexual intercourse. world health organization (who) guidelines and a number of southern african countries have adopted short-course haart for pmtct regardless of cd4, stopping after delivery in women whose baseline count was >350 cells/µl and in whom formula feeding will be implemented, and after cessation of breastfeeding in those women who choose to do so. while current south african national guidelines call for art initiation in pregnant women with cd4 cell counts <350 cells/µl, clinicians should consider the initiation of art in a non-pregnant woman with a cd4 count of <350 (ideally this should be <550) cells/µl who is attempting to conceive. it is hoped south african pmtct guidelines will adopt the strategy of haart for all pregnant women, continuing haart for maternal health in women with cd4 <350 cells/µl, and cessation of haart after pregnancy or breastfeeding in women in whom cd4 counts are >350 cells/µl depending on the infant feeding method of choice. care is needed in the selection of regimens preconception and in pregnancy, and the risks and advantages of using any antiretroviral with potential teratogenicity (such as efavirenz (efv)) should be considered in the first trimester. in discordant couples where the man is infected, similar consideration should be given to initiating art with cd4 counts of >350 (ideally 200 550) cells/µl if he and his negative partner are trying to conceive. it is hoped that with the hptn 052 results17 (hiv acquisition was reduced by 96% in discordant heterosexual couples where the hiv-infected partner commenced art at cd4 levels between 350 and 550 cells/µl compared with those in whom it was commenced at 250 cells/µl or with onset of aids), the recommendations above can be modified to that described as ‘ideal’. for an art-eligible hiv-infected woman who conceives while not on art (and may be diagnosed in pregnancy), therapy should be initiated as soon as possible using pregnancy-friendly regimens (at least by the end of the first trimester), as the duration of art received during gestation is an important determinant of mtct risk.24 for women who are not art eligible (do not need art for their own health), pmtct interventions, focusing on short-course antiretroviral prophylaxis regimens according to national pmtct guidelines, should be initiated when appropriate (see box 2). suggested pregnancy-friendly regimens would include a boosted protease inhibitor (pi) in the first trimester (if the cd4 count is >250 cells/µl) or an efv-based regimen after the first trimester. a nevirapine-based regimen can be used throughout pregnancy if the starting cd4 count is <250 cells/µl.25 4.2.5. optimisation of art. for male or female partners who are either initiating or already established on art, evidence that therapy is optimised is required before attempting to conceive. this should include evidence of high levels of adherence and immune recovery, and preferably documented virological suppression for at least 4 6 months. 4.3 preconception work-up table ii shows recommended basic investigations that may be undertaken in primary care facilities in the preconception work-up of an hiv-infected couple who desires a child, with adaptations for resource-limited and resource-intensive settings. at a minimum, all women should receive hiv-related investigations as well as syphilis screening, haemoglobin measurement, and physical examination with visual inspection of the cervix for abnormalities and for signs of sexually transmitted infections. consider a papanicolau smear (pap smear) in resource-intensive settings; this may be extended to include a full screen for torch infections (congenital infections: toxoplasmosis, rubella, cmv and herpes simplex and other congenital infections) and viral hepatitis, a pap smear, and a full blood count. in resource-intensive settings, patients who are struggling to conceive may be referred to specialist fertility services for further work-up, including assessment of luteinising hormone levels in women and sperm assessment in men. couples found to be non-fertile may be candidates for assisted reproductive technologies. 4.4 safer conception strategies the tools at our disposal to make conception safer in seroconcordant and serodiscordant couples now include (some are proven, some experimental, and they are not listed in any particular order): • haart and viral load suppression in the positive partner(s) • timed, limited, peri-ovulatory, unprotected sex • intra-uterine insemination • intravaginal insemination • male circumcision • sperm washing • surrogate sperm donation • post-exposure prophylaxis (pep) in the negative partner • prep in the negative partner. it is important to note that in deciding which strategies to use for safer conception while in an hiv-positive seroconcordant or discordant relationship, resources, risk and preference may play a role for both the patient and the provider. table iii shows the recommended conception strategies for serodiscordant and hiv-infected seroconcordant couples, stratified for resource-intensive and resource-limited settings. in all cases where unprotected sex with a positive partner or vaginal insemination with potentially infected semen is considered, both partners should be counselled about the risk of transmission and measures such as art or prophylaxis, male circumcision, sperm washing and donor insemination. which of these options are utilised will be determined by available resources and will determine the level of risk of transmission. where unprotected exposure is embarked upon this should be in the presence of reasonable expectations for fertility, e.g. no evidence of reduced ovarian reserve or tubal damage, and no more than 6 12 cycles of peri-ovulatory sex should be performed unsuccessfully without considering referral for infertility investigation. 4.4.1 seroconcordant positive couples. in resource-limited settings, sperm conception with self-insemination may be considered. limited peri-ovulatory unprotected sex is a feasible approach to insemination, although both partners must acknowledge the potential risks associated with superinfection, and have a good understanding of how to time intercourse to the periovulatory window (see box 3). superinfection occurs when an already infected individual becomes ‘reinfected’ with another strain of hiv that may or may not be drug sensitive. this is thought to be more common than first thought, although there are few case series. a study in kenyan sex workers quantified the incidence at 4% per annum.26 the implications may include increased viral load in someone not on therapy, or infection with a drug-resistant virus in someone who is. ideally, even in resource-limited settings this risk can be further reduced in seroconcordant couples by ensuring viral load suppression during conception in both partners and selfvaginal inception. in resource-intensive settings, optimal conception may take place under the supervision of a specialist in reproductive medicine. in such contexts, sperm collection and intra-uterine insemination may be optimal. as discussed above, in all settings art-eligible individuals should be stabilised on optimal therapy prior to conception. 4.4.2 serodiscordant couples where the male partner is infected. when the male partner is positive in a serodiscordant relationship he requires optimal medical therapy, including art when indicated, to minimise the risk of transmission. in resource-limited settings, both partners should be counselled on the risks of transmission, and limited, timed, unprotected intercourse or sperm collection and self-vaginal insemination (box 4) may be advised. in this scenario, the hiv-negative female partner requires regular hiv antibody testing throughout pregnancy to detect and manage possible seroconversion as soon as possible. in resource-intensive settings, a serodiscordant couple with a positive male partner is an indication for ‘sperm washing’ and intrauterine insemination, which affords the possibility of conception with minimal risk of male-to-female hiv transmission. pep/prep may also be considered in this setting as protection for the hiv uninfected female partner although this is unproven (see later). 4.4.3 serodiscordant couples where the female partner is infected. when the female partner is positive in a serodiscordant relationship, there are a wider range of options. it is beneficial for the uninfected male to have been circumcised. if he undergoes a male circumcision procedure, this should be at least 2 months before considering unprotected sex. with the woman's hiv management optimised (viral load undetectable on art), couples in resource-limited settings may attempt timed peri-ovulatory unprotected sex with appropriate counselling on the risks of transmission. in this case, the male partner may benefit from prep or pep and at the very least will require ongoing hiv testing to identify possible seroconversion. however, it is preferable and feasible to collect the semen of the uninfected male partner and perform vaginal self-insemination around the time of ovulation, thus avoiding the risk of female-to-male transmission. this procedure can easily be taught to the female partner and can be performed with ease in her own home. in addition, if a freshly collected seminal fluid specimen is brought to a clinic, vaginal insemination can easily be performed as a service. in resource-intensive settings, sperm collection and intra-uterine insemination in a female patient with undetectable viral load, would be a preferable option. see appendix, ‘vaginal artificial self-insemination instructions’. 5. special issues this guideline provides a general approach to safer conception and pregnancy in different situations involving hiv infection. however, there are several potentially common circumstances that are not directly addressed by the strategies described above. 5.1 is it ever appropriate to discourage pregnancy in an hiv-infected individual or couple? ultimately the decision to have a child rests with the patient. however, there are several instances when a clinician may reasonably decide to discourage attempting to have a child. these may include: • either of the couple has a viral load that cannot be suppressed • non-disclosure of hiv status to a partner • documented infertility in either partner • conditions affecting fertility (although specialist fertility clinics may be able to intervene here) • medical contraindications, such as active opportunistic/intercurrent infections. 5.2 what if an hiv-infected woman desires a child, but does not have a partner? this raises the question of insemination from alternative sperm sources such as sperm banks, surrogacy and adoption. should this possibility arise, it is worth knowing what the resources in your area are, what the stipulated eligibilities are and what resources are required for these services. in addition, this situation might be addressed by a sperm donation from a friend, in which case the hiv status of that friend should first be established. 5.3 can we use prep and/or pep to facilitate conception without hiv transmission in serodiscordant partners? pep for sexual assault survivors has been used for some time, and there is growing interest in prep to prevent transmission in serodiscordant partnerships. however, it is important to note that prep and/or pep for discordant couples, initiated before or after sexual intercourse in situations where sperm washing/insemination is not available, have not been validated and could have significant implications for the health of the man, woman or a subsequent child. while pep efficacy has not yet been established in a randomised clinical trial, significant data have been collected from cohort studies that suggest that it is an effective intervention. pep has been recommended for accidental exposure to hiv, either occupational or non-occupational, where the benefits of the medication clearly outweigh the risks. in the case of a serodiscordant couple wanting to conceive, the exposure would be planned. the use of pep has been reported from a study in men who have sex with men (msm) in brazil, who were randomised to take pep after a risky sexual exposure. the study, conducted by schecter et al., 27 demonstrated that people have difficulty recognising risk after the fact. this may be due to denial, substance abuse and other factors. animal models have explored a number of different drug exposures both preand/or post-exposure.28 current pep protocols generally state that antiretrovirals have to be given for 28 days after exposure. some studies have reported that side-effects related to pep occur in as many as 77% of users. currently, then, for every episode of unprotected intercourse, the hiv non-infected partner would take 28 days of antiretrovirals with possible artrelated side-effects.29 the evidence for prep is also still not well established. the most promising candidate drugs are tenofovir or emtricitabine/tenofovir disoproxil fumarate (ftc/tdf, truvada). in november 2010, results from a phase iii large-scale study, iprex, showed that prep provided an additional 44% protection from hiv acquisition in men exposed to hiv rectally.30 the study enrolled 2 499 men and transgender women who have sex with men (who were all at high risk of hiv infection) from peru, ecuador, south africa, brazil, thailand and the usa. half the study subjects were given once-daily oral ftc/tdf and the other half was given a placebo. all subjects received monthly hiv testing and risk-reduction counselling. among those taking ftc-tdf, 36 became infected with hiv during the trial, compared with 64 in the placebo group. the fem-prep clinical trial31 – implemented by fhi in partnership with research centers in africa – was designed to study whether hiv-negative women who are at higher risk of being exposed to hiv can safely use a daily dose of ftc/tdf to prevent infection. following a scheduled interim review of the fem-prep study data in march 2011, the independent data monitoring committee (idmc) advised that the fem-prep study would be highly unlikely to be able to demonstrate the effectiveness of ftc/tdf in preventing hiv infection in the study population, even if it continued to its originally planned conclusion. the fhi subsequently concurred and has therefore decided to initiate an orderly closure of the study over the next few months. there are a number of possible reasons for the study findings, including low adherence to the study regimen, a true lack of effect of the product among women (v. msm), or other factors still to be determined. there is more prep research being conducted (table iv), with the studies on heterosexual transmission being undertaken in africa in a variety of population groups. there is still much to be learned about effectiveness and real-life implementation, as well as cost-effectiveness.32 so what advice can be given to the serodiscordant couple with regard to prep? while the results among msm are promising, and it is likely that prep may offer some protection (although whether this will be the case in heterosexual hiv transmission is unknown today), unprotected intercourse with an hiv infected person is never ‘no-risk’, even if prep is partially effective. 6. case studies cast study 1 lm is a 33-year-old woman initiated on efv, stavudine and lamivudine in may 2005. she responded well to treatment and is currently receiving treatment and care at a down-referral primary health clinic. her most recent viral load, may 2009, was lower than the detectable limit and her cd4 cell count in january 2010 was 797 cells/ µl. she has two children, both over 12 years old, but has no children with her current partner of several years, to whom she has disclosed her status. he is hiv negative. initially the patient said that she had no desire to have more children. however, over time she indicated that she and her partner wanted to have a child together. aside from her art regimen, she was a good candidate for a safe conception. upon indicating her intention to conceive, she was referred by study staff for a regimen change. she was told by clinic nurses that a referral was useless as she would need to be up-referred to her initiation site for a regimen change and that up-referrals for regimen changes were not being accepted for planned pregnancies; she should request a regimen change only after conceiving. at a subsequent visit on 3 june 2010, the patient had a positive pregnancy test and the same day was up-referred by the primary health centre to her art initiation site for a regimen change. upon presenting at the up-referral site with her referral letter, the clinic chose not to accept her back, saying that her current living address was outside their jurisdiction, and referred her elsewhere. the second clinic was willing to receive her, but would not change her regimen or provide an explanation for refusing a regimen change. after 10 weeks of going between clinics the patient was clearly distressed about potential harm that might have been caused to the baby by her current regimen, and after one more failed attempt to receive a regimen change she booked to terminate her planned pregnancy. she had a termination of pregnancy on 25 august, without seeking counselling and discussing her concerns with health care providers or study staff, who might have been able to assuage her fears about the efv-related risks posed to the baby. this situation would have been avoided if the patient had: (i) received a regimen change when she initially indicated that she was trying to conceive; or (ii) failing this, been received by the clinic she was referred to and given an immediate regimen change, as was the expected protocol. furthermore, had any counselling been provided to her about the actual level of risk associated with efv-based conceptions, the outcome would probably have been different.25 it is important to note that efv poses a risk to fetal neural tube development. neural tube formation occurs at approximately 4 weeks' gestation. the practical point is that unless planned prior to conception, most women on efv will present after this sensitive time period, making regimen changes both unnecessary and unhelpful. the alternative regimens may be more problematic, e.g. in the case of nevirapine in women with higher cd4 counts (>250 cells/µl), and much more difficult to adhere to in the case of lopinavir/ritonovir (kaletra). a rule of thumb is not to change unless a pregnant woman on efv presents at <12 weeks' gestation (first trimester), although one could argue that change is necessary in the case of presentation at >6 weeks. cast study 2 a nulliparous, 33-year-old hiv-positive woman seeks counselling around safe conception. she had first tested positive for hiv 3 years previously and had been participating in wellness care as her cd4 cell count was still >200 cells/μl. her partner is hiv positive and on art. in 2009, the patient’s cd4 count was 420 cells/µl. her most recent cd4 count (june 2010) was 318 cells/µl; a viral load had not been done. the patient desperately wants to conceive, but is worried about mtct as she is not on art. this woman's case is challenging, as she is not indicated to start art under the national treatment guidelines until her cd4 count drops to 200 cells/µl. however, she is relatively healthy and it may be another year or more before she becomes eligible for art. the patient understands that as her cd4 count decreases her viral load is rising, and she is worried about a large spike in her viral load around the time of pregnancy if she were to conceive now. on the other hand, if she were to conceive, under the new guidelines she would immediately be eligible to start art as a pregnant woman, since her cd4 count is <350 cells/µl. what is the best plan of action for this woman if she cannot get started on art? she can wait for a year or so for her cd4 count to drop and her viral load to spike, start art and then wait again for another 6 months to achieve virological suppression. at this point she will be 35 and potentially have lowered fertility due to the disease progression and increasing age. alternatively, she can conceive before art initiation, with a sub-optimal cd4 cell count and a rising viral load. in this situation she would hope to diagnose the pregnancy as soon as possible, and be initiated onto art sooner rather than later. the second option allows her to maximise her fertility, particularly now while she is still relatively healthy, but may increase the risk of mtct and infant mortality, the primary concerns for many hiv-positive women planning to conceive.14 , 15 in a resource-intensive setting, the patient would be offered antiretrovirals immediately. there is a potential risk for hypersensitivity and/or hepatotoxicity with nevirapine at a cd4 count of 318 cells/µl. however, efv is also contraindicated in the first trimester. in south africa, it would be an option to commence treatment with a boosted pi such as lopinavir or atazanavir. it must be confirmed that both partners are virally suppressed before conception. cast study 3 a 24-year-old woman who had been on nevirapine, stavudine and lamivudine since january 2009 indicated that she did not currently want to have any more children. she had a cd4 count of 265 cells/µl and a history of irregular menstrual cycles since hiv diagnosis; she had not menstruated since giving birth 9 months previously. she had a positive pregnancy test during a routine clinic visit in november 2009. she was not prepared for another child and chose to terminate the pregnancy. during her subsequent visit she was encouraged to start family planning, as she indicated that she has difficulty negotiating condom use with her partner. in may 2010, she was diagnosed with a second pregnancy. at this point she went for a second termination of pregnancy in 6 months and was strongly counselled by medical staff to begin using family planning. at her next clinic visit she was still amenorrhoeic. she had a pregnancy test and was given the negative result to present to the clinic nurses in order to initiate an injectable method of family planning. however, she was refused family planning because she was not menstruating. she had a third pregnancy in september 2010. amenorrhoea is not uncommon in women, and prolonged amenorrhoea may be more prevalent among hiv-positive women, particularly those with lower cd4 cell counts.16 research also suggests that hiv-positive women may be more likely to be ovulating while amenorrhoeic than their hiv-negative counterparts. 17 policies, whether formally written or just informally followed, to initiate family planning only on the first day of a woman’s menstrual cycle are inconvenient for women and result in lower contraceptive uptake and increased rates of unplanned pregnancies. these policies also do not take into consideration hiv-related health concerns, such as an increased risk of amenorrhoea, specific to hiv-positive women. clear guidelines must be in place to address fertility concerns related to family planning for hiv-positive women. references 1. mofenson lm. protecting the next generation – eliminating perinatal hiv-1 infection. n engl j med 2010;362(24):2316-2318. 1. mofenson lm. protecting the next generation – eliminating perinatal hiv-1 infection. n engl j med 2010;362(24):2316-2318. 2. myer l, carter rj, katyal m, toro p, el-sadr wm, abrams ej. impact of antiretroviral therapy on incidence of pregnancy among hiv-infected women in sub-saharan africa: a cohort study. plos med 2010;7(2):e1000229. 2. myer l, carter rj, katyal m, toro p, el-sadr wm, abrams ej. impact of antiretroviral therapy on incidence of pregnancy among hiv-infected women in sub-saharan africa: a cohort study. plos med 2010;7(2):e1000229. 3. gruskin s, ferguson l, o’malley j. ensuring sexual and reproductive health for people living with hiv: an overview of key human rights, policy and health systems issues. reprod health matters 2007;15(29 suppl):4-26. 3. gruskin s, ferguson l, o’malley j. ensuring sexual and reproductive health for people living with hiv: an overview of key human rights, policy and health systems issues. reprod health matters 2007;15(29 suppl):4-26. 4. dyer sj. the value of children in african countries: insights from studies on infertility. j psychosom obstet gynaecol 2007;28(2):69-77. 4. dyer sj. the value of children in african countries: insights from studies on infertility. j psychosom obstet gynaecol 2007;28(2):69-77. 5. cooper d, moodley j, zweigenthal v, bekker lg, shah i, myer l. fertility intentions and reproductive health care needs of people living with hiv in cape town, south africa: implications for integrating reproductive health and hiv care services. aids behav 2009;13 suppl 1:38-46. 5. cooper d, moodley j, zweigenthal v, bekker lg, shah i, myer l. fertility intentions and reproductive health care needs of people living with hiv in cape town, south africa: implications for integrating reproductive health and hiv care services. aids behav 2009;13 suppl 1:38-46. 6. cooper d, harries j, myer l, orner p, bracken h, zweigenthal v. ‘life is still going on’: reproductive intentions among hiv-positive women and men in south africa. soc sci med 2007;65(2):274-283. 6. cooper d, harries j, myer l, orner p, bracken h, zweigenthal v. ‘life is still going on’: reproductive intentions among hiv-positive women and men in south africa. soc sci med 2007;65(2):274-283. 7. myer l, morroni c, rebe k. prevalence and determinants of fertility intentions of hiv-infected women and men receiving antiretroviral therapy in south africa. aids patient care stds 2007;21(4):278-285. 7. myer l, morroni c, rebe k. prevalence and determinants of fertility intentions of hiv-infected women and men receiving antiretroviral therapy in south africa. aids patient care stds 2007;21(4):278-285. 8. kaida a, laher f, strathdee sa, money d, janssen pa, hogg rs, gray g. contraceptive use and method preference among women in soweto, south africa: the influence of expanding access to hiv care and treatment services. plos one 2010;5(11):e13868. 8. kaida a, laher f, strathdee sa, money d, janssen pa, hogg rs, gray g. contraceptive use and method preference among women in soweto, south africa: the influence of expanding access to hiv care and treatment services. plos one 2010;5(11):e13868. 9. heikinheimo o, lähteenmäki p. contraception and hiv infection in women. hum reprod update 2009;15(2):165-176. 9. heikinheimo o, lähteenmäki p. contraception and hiv infection in women. hum reprod update 2009;15(2):165-176. 10. world health organization. medical eligibility for criteria for contraceptive use, 2008 update. who/rhr/08.19. geneva: who, 2008. 10. world health organization. medical eligibility for criteria for contraceptive use, 2008 update. who/rhr/08.19. geneva: who, 2008. 11. trussell j. contraceptive efficacy. in hatcher ra, trussell j, nelson al, cates w, stewart fh, kowal d, eds. contraceptive technology. 19th rev ed. new york: ardent media, 2007. 11. trussell j. contraceptive efficacy. in hatcher ra, trussell j, nelson al, cates w, stewart fh, kowal d, eds. contraceptive technology. 19th rev ed. new york: ardent media, 2007. 12. granich r, crowley s, vitoria m, smyth c, kahn jg, bennett r, lo yr, souteyrand y, williams b. highly active antiretroviral treatment as prevention of hiv transmission: review of scientific evidence and update. curr opin hiv aids 2010;5(4):298-304. 12. granich r, crowley s, vitoria m, smyth c, kahn jg, bennett r, lo yr, souteyrand y, williams b. highly active antiretroviral treatment as prevention of hiv transmission: review of scientific evidence and update. curr opin hiv aids 2010;5(4):298-304. 13. quinn tc, wawer mj, sewankambo n, et al. viral load and heterosexual transmission of human immunodeficiency virus type 1. rakai project study group. n engl j med 2000;342:921-927. 13. quinn tc, wawer mj, sewankambo n, et al. viral load and heterosexual transmission of human immunodeficiency virus type 1. rakai project study group. n engl j med 2000;342:921-927. 14. liuzzi g, chirianni a, clementi m, et al. analysis of hiv-1 load in blood, semen and saliva: evidence for different viral compartments in a cross-sectional and longitudinal study. aids 1996;10:51-56. 14. liuzzi g, chirianni a, clementi m, et al. analysis of hiv-1 load in blood, semen and saliva: evidence for different viral compartments in a cross-sectional and longitudinal study. aids 1996;10:51-56. 15. cu-uvin s, caliendo am, reinert s, et al. effect of highly active antiretroviral therapy on cervicovaginal hiv-1 rna. aids 2000;14(4):415-421. 15. cu-uvin s, caliendo am, reinert s, et al. effect of highly active antiretroviral therapy on cervicovaginal hiv-1 rna. aids 2000;14(4):415-421. 16. vernazza pl, troiani l, flepp mj, et al. potent antiretroviral treatment of hivinfection results in suppression of the seminal shedding of hiv. the swiss hiv cohort study. aids 2000;14(2):117-121. 16. vernazza pl, troiani l, flepp mj, et al. potent antiretroviral treatment of hivinfection results in suppression of the seminal shedding of hiv. the swiss hiv cohort study. aids 2000;14(2):117-121. 17. initiation of antiretroviral treatment protects uninfected sexual partners from hiv infection (hptn study 052). http://www.hptn.org/web%20documents/pressreleases/ hptn052pressreleasefinal5_12_118am.pdf 17. initiation of antiretroviral treatment protects uninfected sexual partners from hiv infection (hptn study 052). http://www.hptn.org/web%20documents/pressreleases/ hptn052pressreleasefinal5_12_118am.pdf 18. coombs rw, speck ce, hughes jp, et al. association between culturable human immunodeficiency virus type 1 (hiv-1) in semen and hiv-1 rna levels in semen and blood: evidence for compartmentalization of hiv-1 between semen and blood. j infect dis 1998;177:320-330. 18. coombs rw, speck ce, hughes jp, et al. association between culturable human immunodeficiency virus type 1 (hiv-1) in semen and hiv-1 rna levels in semen and blood: evidence for compartmentalization of hiv-1 between semen and blood. j infect dis 1998;177:320-330. 19. gilling-smith c, nicopoullos jdm, cox a, almeida p, wood r, vourliotis m. detectable hiv in semen from hiv-positive men on haart with undetectable serum viral load. human reproduction. presented at the european society for human reproduction and embryology (eshre) 24th annual meeting, barcelona, 6 9 july 2008. 19. gilling-smith c, nicopoullos jdm, cox a, almeida p, wood r, vourliotis m. detectable hiv in semen from hiv-positive men on haart with undetectable serum viral load. human reproduction. presented at the european society for human reproduction and embryology (eshre) 24th annual meeting, barcelona, 6 9 july 2008. 20 frodsham lcg, cox ad, almeida a, rozis g, gilling-smith c. in vitro fertilisation in hiv-positive women: potential mother-to-embryo viral transmission risk. hum reprod 2004;9:138. 21. minkoff h, santoro n. ethical considerations in the treatment of infertility in women with human immunodeficiency virus infection. n engl j med 2000;342:1748-1750. 21. minkoff h, santoro n. ethical considerations in the treatment of infertility in women with human immunodeficiency virus infection. n engl j med 2000;342:1748-1750. 22. barreiro p, del romero j, leal m, et al. natural pregnancies in hiv-serodiscordant couples receiving successful antiretroviral therapy. j acquir immune defic syndr 2006;43:324-326. 22. barreiro p, del romero j, leal m, et al. natural pregnancies in hiv-serodiscordant couples receiving successful antiretroviral therapy. j acquir immune defic syndr 2006;43:324-326. 23. vernazza p. haart improves quality of life: should we care about the quality of spermatozoa? aids 2008;22:647-648. 23. vernazza p. haart improves quality of life: should we care about the quality of spermatozoa? aids 2008;22:647-648. 24. fitzgerald fc, bekker lg, kaplan r, myer l, lawn sd, wood r. mother-to-child transmission of hiv in a community-based antiretroviral clinic in south africa. s afr med j 2010;100(12):827-831. 24. fitzgerald fc, bekker lg, kaplan r, myer l, lawn sd, wood r. mother-to-child transmission of hiv in a community-based antiretroviral clinic in south africa. s afr med j 2010;100(12):827-831. 25. efavirenz-based regimens among women of reproductive age receiving art in johannesburg. http://i-base.info/htb/13998 25. efavirenz-based regimens among women of reproductive age receiving art in johannesburg. http://i-base.info/htb/13998 26. piantadosi a, chohan b, chohan v, mcclelland rs, overbaugh j. chronic hiv-1 infection. frequently fails to protect against superinfection. plos pathog 2007;3(11):e177. doi:10.1371/journal.ppat.0030177. 26. piantadosi a, chohan b, chohan v, mcclelland rs, overbaugh j. chronic hiv-1 infection. frequently fails to protect against superinfection. plos pathog 2007;3(11):e177. doi:10.1371/journal.ppat.0030177. 27. schechter m, do lago rf, mendelsohn ab, moreira ri, moulton lh, harrison lh; praca onze study team. behavioral impact, acceptability, and hiv incidence among homosexual men with access to postexposure chemoprophylaxis for hiv j acquir immune defic syndr 2004;35(5):519-525. 27. schechter m, do lago rf, mendelsohn ab, moreira ri, moulton lh, harrison lh; praca onze study team. behavioral impact, acceptability, and hiv incidence among homosexual men with access to postexposure chemoprophylaxis for hiv j acquir immune defic syndr 2004;35(5):519-525. 28. garcía-lerma jg, cong me, mitchell j, et al. intermittent prophylaxis with oral truvada protects macaques from rectal shiv infection. sci transl med 2010;2(14):14ra4. 28. garcía-lerma jg, cong me, mitchell j, et al. intermittent prophylaxis with oral truvada protects macaques from rectal shiv infection. sci transl med 2010;2(14):14ra4. 29. lunding s, katzenstein tl, kronborg g, lindberg ja, jensen j, nielsen hi, pedersen c, jørgensen lb. the danish pep registry: experience with the use of postexposure prophylaxis (pep) following sexual exposure to hiv from 1998 to 2006. sex transm dis 2010;37(1):49-52. 29. lunding s, katzenstein tl, kronborg g, lindberg ja, jensen j, nielsen hi, pedersen c, jørgensen lb. the danish pep registry: experience with the use of postexposure prophylaxis (pep) following sexual exposure to hiv from 1998 to 2006. sex transm dis 2010;37(1):49-52. 30. grant rm, lama jr, anderson pl; iprex study team. preexposure chemoprophylaxis for hiv prevention in men who have sex with men. n engl j med 2010;363(27):2587 2599. epub 2010 nov 23. 30. grant rm, lama jr, anderson pl; iprex study team. preexposure chemoprophylaxis for hiv prevention in men who have sex with men. n engl j med 2010;363(27):2587 2599. epub 2010 nov 23. 31. fhi to initiate orderly closure of fem-prep. http://www.fhi.org/en/aboutfhi/media/ releases/fem-prep_statement041811.htm 31. fhi to initiate orderly closure of fem-prep. http://www.fhi.org/en/aboutfhi/media/ releases/fem-prep_statement041811.htm 32. avac: ongoing prep trials as of feb 2011. http://www.avac.org/ht/a/ getdocumentaction/i/3113 32. avac: ongoing prep trials as of feb 2011. http://www.avac.org/ht/a/ getdocumentaction/i/3113 consensus committee (for the southern african hiv clinicians society) chaired by linda-gail bekker and vivien black members: helen rees, silke dyer, di cooper, karin richter, sumaya mall, coceka mnyami, francesca conradie, natalie martyn, charmaine macdonald, glenda gray, ishania mahabeer, karen cohen, karen jennings, fatima shaik reviewed by: karin richter, polly clayden we are indebted to karin richter and polly clayden for their insightful and helpful comments on this guidance document. box 1. other options to consider in making a decision around fertility and childbearing in discussing the desire to have a child with hiv-infected women and men, there are several potentially useful options that patients may not be aware of. these include: • an hiv-infected male partner may consider hiv-negative sperm donations from an hpcsaaccredited facility in south africa (appropriate accreditation bodies should be sought in other southern african countries), or in low-resource settings from an hiv-negative man. • adoption may be possible through an approved facility, or through a social worker. note that chronic illnesses (including hiv) are not a contraindication, provided the illness is well controlled and the adopting parents are relatively healthy. • surrogacy may be an option (i.e. another woman carries the pregnancy for the couple), but this would only be acceptable if the male partner is hiv negative. surrogacy is not widely practised in south africa. • not to have or formally adopt a child, but to focus on becoming more involved in the care of children in the family or community. what should be covered in preconception counselling? preconception counselling should ensure an informed choice about reproductive options, including the inherent risks and costs of each treatment and the likely chances of success. it must include: • a summary of the available data on safety for each method together with advice on additional methods of reducing risk, such as limiting intercourse to the fertile window, or early initiation of art • regular screening for sexually transmitted infections • the need to identify evidence of reduced fertility or sterility at an early stage in either or both partners • the possible use of pre-exposure prophylaxis. the discussion should balance the risk of natural conception with that of more established risk-reduction methods such as sperm washing or risk-free options such as donor insemination. although timed unprotected intercourse may be the only option for discordant couples in resource-limited settings, this has risk. preconceptual counselling should also address: • the possibility of treatment failure and how the couple would cope if they successfully had a child but the infected parent became more seriously ill or died. • those electing to have assisted conception with sperm washing have to understand that this is a risk-reduction method and not a risk-free method. • when the female partner is hiv-positive they need to understand the risks of mtct and the methods used. • they should plan and agree to attend an antenatal clinic once pregnant to ensure that they receive the best possible advice to minimise mtct risk. box 2. principles of reducing mother-to-child hiv transmission this is not intended to be a comprehensive guide to pmtct. please see the reference below for details. • ideally all hiv-infected women should already be on art as part of preconception management; this should be continued throughout pregnancy and breastfeeding. • if a woman is not on art, initiate art as soon as possible irrespective of cd4 cell count, using the appropriate antiretrovirals to avoid teratogenicity, and reduce side-effects and pill burden. • women with a baseline cd4 cell count <=350 cells/µl should continue art indefinitely for their own health. • women with a cd4 cell >350 cells/µl who elect to breastfeed should continue art until the baby is weaned. • women with a baseline cd4 count >350 cells/µl may discontinue art after delivery. • in situations where the above cannot be applied, local pmtct guidelines should be followed. additional reading national department of health. the south african antiretroviral treatment guidelines 2010 (2010). http://www.doh.gov.za/aids/index.html box 3. how to determine a woman’s fertile period when a couple is living with hiv and attempting conception, determining a woman’s fertile period is necessary to time peri-ovulatory intercourse. there are various ways in which a woman’s fertile period can be determined. the methods described here presume normal fertility and require minimal resources. in situations where a woman’s fertility may be impaired, more resource-intensive methods (such as day 21 progesterone measurements or serial ultrasound monitoring, with or without ovulation stimulation – clomiphene administration is usually performed in consultation with specialist services) may be used by a reproductive specialist. these more intensive methods may also be used in women living with hiv (who has presumed normal fertility) in order to increase her chance of fertility prediction. fertile dates the average normal duration of a menstrual cycle is 28 days. the first day of a woman’s menstrual period is considered to be day 1 of her menstrual cycle. ovulation is assumed to occur half way through her cycle. her fertile period would be from 5 days before predicted ovulation up until 1 2 days after ovulation. for example, in a woman whose cycle is 28 days long, this would mean that ovulation would be assumed on day 14. the woman’s fertile period would therefore occur between days 9 and 16 of her menstrual cycle. however, menstrual cycle length may differ considerably between women and may even differ from month to month for an individual woman. it is therefore essential that a woman keeps record of her menstrual cycle (typically taking into account the first day of her menstrual period) for at least 4 months in order to determine an average menstrual cycle length. it is important to explain to patients that regular menstrual cycles may not necessarily indicate that ovulation has occurred. ovulation prediction kits (for urine and saliva) a number of over-the-counter products are available that enable ovulation prediction. these methods may utilise sampling and analysis of either urine or saliva, and detect the surge of luteinising hormone that occurs immediately before ovulation. basal body temperature (bbt) charting a woman’s body temperature increases by 0.25 0.5 °c during ovulation. charting a woman’s bbt daily will therefore result in a pattern that may assist her in predicting ovulation. for this method of ovulation prediction to be accurate, it is essential that the woman plots her bbt at the same time every day (preferably between 6 and 8 a.m.), before getting out of bed or drinking or eating anything. attempt conception after the first rise in bbt has been detected. the chances of conceiving after the 3rd day of raised bbt are greatly reduced. cervical mucus monitoring in addition to bbt, a number of other physiological changes occur around the time of ovulation that may be used to help time intercourse. cervical mucous changes are used most commonly. during nonfertile days, the cervical mucus is thick and acidic. in contrast, during fertile days, the mucus undergoes a change to become thin, profuse, transparent and ‘stretchy’ (spinnbarkeit). a woman's awareness of these changes in her cervical mucus may help her to predict her fertile period. box 4. low-technology sperm collection and selfinsemination techniques artificial insemination is the process whereby semen is introduced into the female reproductive tract other than by sexual intercourse. it may be intra-uterine or vaginal, the former being a specialist procedure. the latter is a low-risk procedure that can be carried out by a health care provider or by the patient herself. it is advisable that vaginal insemination be attempted at the most fertile time in the menstrual cycle, which is approximately 2 weeks prior to menses. in a woman with a regular cycle this can be worked out per calendar, but other methodologies include using an ovulation predictor kit, which is commercially available and measures the lh surge. other indicators include the quality of the cervical mucus and body temperature. semen needs to be provided in a clean receptacle, either by male ejaculation into a condom during intercourse or by male ejaculation into a clean specimen jar provided for the purpose. the semen (most men ejaculate 3 5 ml) should be inseminated as soon as possible. other equipment to carry out the vaginal insemination would include a ‘turkey baster’ (!), 5 ml plastic syringe or plastic discardable pipette. these items should be supplied to prospective female patients along with the instructions in the appendix. what art is appropriate to use in this setting? any woman with reproductive intent who has a cd4 count <250 cells/µl should commence with nevirapine and tenofovir plus lamivudine or ftc. if she is already pregnant and on efv and presenting in the first trimester, consider changing efv. if the cd4 count is <250, opt for nevirapine; if >250, opt for a pi, e.g. atazanavir or lopinavir. note, however, the greater pill burden and possibly greater nausea and vomiting with the latter, especially in the first trimester. if necessary and for simplicity the pi can be changed to efv in the second or third trimester. further reading contraception in hiv-infected women •  heikinheimo o, lähteenmäki p. contraception and hiv infection in women. hum reprod update 2009;15(2):165-176. •  world health organization. medical eligibility for criteria for contraceptive use, 2008 update. who/rhr/08.19. geneva: who, 2008. reproductive strategies in hiv-infected individuals •  semprini ae, hollander lh, vucetich a, gilling-smith c. infertility treatment for hiv-positive women. womens health 2008;4(4):369-382. •  waters l, gilling-smith c, boag f. hiv infection and subfertility. int j std aids 2007;18(1):1-6. •  barreiro p, castilla ja, labarga p, soriano v. is natural conception a valid option for hiv-serodiscordant couples? hum reprod 2007;22(9):2353-2358. other guidelines •  fakoya a, lamba h, mackie n, et al. british hiv association, bashh and fsrh guidelines for the management of the sexual and reproductive health of people living with hiv infection 2008. hiv med 2008;9:681-720. •  new york state department of health. preconception care for hiv-infected women. guideline summary ngc-8022. new york: new york state department of health, 2010. appendix. vaginal artificial selfinsemination instructions vaginal artificial self-insemination is the process of placing sperm into your vagina without your partner’s penis going inside you. this gives you the chance to get pregnant without the risk of passing hiv on to your partner. two important things will give you the best opportunity to get pregnant. firstly, do the artificial insemination at the time of the month when you are the most fertile, and secondly do not wait too long to place his sperm inside you. how do you know when it is your most fertile time? the most fertile time in your menstruation cycle is 2 weeks before you get your period, or around day 14 of your cycle. other signs to look out for are an increase in your body temperature (if you have a thermometer) or changes in your vaginal discharge. the mucus will become more clear and sticky – you can pull it into strings if you rub it between your fingers. what you need to do when the time is right. the first thing to do is to get a sample of sperm from your partner. you can do this in two ways. you can have sex with a condom (don't use one with spermicide) and use the semen that is captured in the end of the condom. the other way is to get your partner to ejaculate into a clean container you can get from the clinic for this purpose. he can do this with your help or on his own. once you have the semen sample, don't wait too long. as soon as possible you need to draw the semen into a 5 millilitre (ml) clean plastic syringe without a needle or a bulb pipette (your local clinic can provide you with one). the next thing to do is to get yourself in the right position. lie on your back with your knees bent. place a cushion under your hips to get your back flat and your pelvis tipped up. make sure you have got all the extra air out of the pipette or syringe and place it into your vagina, a bit like you would a tampon. don’t push it up too far. (this should not be painful. if it is, stop what you are doing and report to your clinic.) then slowly push the semen out of the syringe or pipette backwards into your vagina. if possible try to stay in this position for an hour. the chance that you will get pregnant might be a bit better if you masturbate and bring yourself to orgasm while you are lying there, although this is not required if you are not used to it. realistically, the possibility that you will get pregnant is around 5 10%. you can try this technique 2 4 times during your fertile time. the more often you try, the greater your chance of success. if you have any questions ask your counsellor or health care provider. table i. effectiveness of the common contraceptive methods, and their safety in hiv infection method failure rate/100 woman-years impact on disease progression increased hiv transmission to partner impact on haart or tuberculosis treatment oral combined oral contraceptive 0.2 3 no conclusive evidence of harm: can use no conclusive evidence of harm: can use drug interaction with some nnrtis: do not use drug interaction with rifampicin and related tb drugs: do not use dmpa and net-en (injectable progestins) 0 2 no conclusive evidence of harm: can use no conclusive evidence of harm: can use haart: can use, no need to increase dose or injection frequency tb drugs: can use, no need to increase dose or injection frequency male condom careful use: 0.4 8 typical use: around 10 none: may prevent re-infection barrier method protects partner n/a female condom careful use: 5 typical use: 21 none: may prevent re-infection barrier method protects partner n/a copper iucd 0.1 0.3 evidence on safety reassuring: can use limited evidence but reassuring: can use no interactions levonorgestrel iucd 20 0.1 0.3 limited evidence of safety reassuring: can use little evidence but extrapolating from cu iucd can use no interactions male and female sterilisation female 0 0.5 male 0 0.2 no evidence but unlikely: can recommend no evidence but unlikely: can recommend n/a nnrti = non-nucleoside reverse transcriptase inhibitor.   table ii. preconception work-up for hiv-infected individuals desiring a child in resourceintensive and resource-limited settings   female partner male partner resource-intensive strategy cd4, hiv viral load, hepatitis serology (a); investigations for syphilis, cmv, rubella, hsv, toxoplasmosis; full blood count; pap smear if on haart preconception, adaptation of regimen as needed; ensure undetectable hiv viral load in blood if difficulty conceiving lutenising hormone, referral for fertility assessment cd4, hiv viral load, syphilis serology; laboratory investigations for other sexually transmitted infections if on haart preconception, ensure undetectable hiv viral load in blood if difficulty conceiving referral for sperm assessment; fertility assessment resource-limited strategy cd4, syphilis serology, clinical assessment for other sexually transmitted infections; haemoglobin; visual inspection of the cervix art and undetectable viral load also strongly advised cd4, syphilis serology; clinical assessment for other sexually transmitted infections art and undetectable viral load also strongly advised cmv = cytomegalovirus; hsv = herpes simplex virus. table iii. optimal conception support strategies for resource-intensive and resourcelimited settings, according to the hiv status of the couple   seroconcordant (male and female hiv infected) serodiscordant (male hiv infected) serodiscordant (female hiv infected) resource-intensive strategy female partner if on haart preconception, adaptation of regimen as needed; ensure undetectable hiv viral load in blood; no use of efavirenz in the first trimester among hiv-infected women trying to conceive repeated hiv pcr testing before pregnancy conception: undectable viral load preferable; sperm washing and intra-uterine insemination if on haart preconception, adaptation of regimen as needed; ensure undetectable hiv viral load in blood conception: sperm collection with intra-uterine insemination   conception: consider sperm collection with intra-uterine insemination; selfinsemination possible; peri-ovulatory unprotected sexual intercourse only in the face of demonstrated undetectable viral loads repeated hiv pcr during pregnancy with appropriate management if female partner becomes infected if not on haart preconception, maternal haart initiation early in the second trimester   if not on haart preconception, maternal haart initiation as soon as possible with appropriate regimen     male partner preconception haart until un-detectable hiv viral load in blood and semen preconception haart until undetectable hiv viral load in blood, semen conception: sperm assessment; sperm washing with hiv pcr ongoing hiv testing; male medical circumcision where appropriate, especially if couple choose peri-ovulatory unprotected sexual intercourse for conception resource-limited strategy female partner if on haart preconception, adaptation of regimen as needed; ensure high levels of adherence and cd4 monitoring; no use of efavirenz in women trying to conceive repeated hiv antibody testing before pregnancy conception: unprotected sex during the fertile period (preferably while on art with viral load control) if on haart preconception, adaptation of regimen as needed; ensure high levels of adherence and cd4 monitoring; consider art for conception and pregnancy regardless   conception: consider sperm collection with self-insemination; peri-ovulatory unprotected sex possible under safe conditions. this would include undetectable viral loads if possible, timed sexual intercourse and limited exposures (see text) repeated hiv antibody testing during pregnancy with appropriate management if female partner becomes infected consider use of monoor dual-therapy prep conception: sperm collection with self-insemination at the time of ovulation (avoiding spermicide-containing condoms)   if not on haart prconception, maternal pmtct initiation asap with appropriate antivirals   if not on haart preconception, maternal pmtct initiation as soon as possible with appropriate regimen male partner if required, preconception haart for at least 6 months with intensive adherence support and cd4 monitoring and viral loads monitoring if required, preconception haart for at least 6 months with intensive adherence support and cd4 and viral load monitoring ongoing hiv testing; male medical circumcision where appropriate, especially if couple choose peri-ovulatory unprotected sexual intercourse for conception pcr = polymerase chain reaction. table iv. prep research in progress 32 location population expected completion date thailand (cdc) 2 400 injecting drug users 2012 south africa, uganda, zimbabwe (voice) 5 000 heterosexual men 2013 kenya, uganda (partners for prevention) 4 700 serodiscordant heterosexual couples 2013   fig. 1. flow diagram to approach pregnancy-related issues in hiv-infected women and men. the southern african journal of hiv medicine                                                  september  2010 5 the wonderful world cup and a devastating public sector strike are behind us. one generated national pride and reminders that we are the rainbow nation with fabulous potential, and the other national shame that compassion and humanity for the most poor and vulnerable could be sacrificed for material gain. with the enormous responsibility of lifelong antiretroviral treatment for over a million individuals we need a health system that is reliable, responsible and obsessive. the concept that health facilities would not be open, or worse still that patients would be barred from accessing those services, flies in the face of all our hard-won battles for adherence to pills and programmes. you may have seen the economist of 9 august 2008, featuring an article referring to global art programmes, from which i quote: ‘as a result, taxpayers are accumulating an indefinite – and indefinitely growing – responsibility of keeping people alive’. many first-world taxpayers have been generous in helping to expand and sustain our treatment programme – but following international news reports of treatment interruptions as a consequence of the strike, some of them may well be questioning our own commitment to that responsibility. we have a clinically focused edition for you this quarter! cassim and colleagues re-ignite the hope that we can eradicate paediatric hiv in south africa with a report on the outcomes of haart-based pmtct in the private sector in kzn. kwaan and colleagues, also from kzn, report on adherence strategies in a treatment cohort in cato manor. they emphasise simple strategies such as tablet return as a way to encourage dialogue with patients about pill taking. an interesting paper describes traditional healer beliefs and practices around hiv and art, and interactions between biomedical and traditional health care. it seems that we still have a long way to go in terms of the two sectors really understanding each other’s role. ugandan colleagues present data on the immune reconstitution inflammatory syndrome among adolescents – numbers are small, but it is a point well made. this age group typically presents us with adherence challenges above those in adult and paediatric care, and treatment experiences that may be unpleasant need careful handling if we are to keep our adolescents adherent. polly clayden and co-authors summarise what we know (and do not know) about efavirenz in pregnancy. two clinical case studies of gastro-intestinal mycobacterial infection follow, expertly commented on by andrew black from baragwanath hospital. one is from pretoria, the other all the way from taiwan, where hiv is really only just emerging. many will feel a sense of foreboding or déjà vu as authors kao and hung make a plea for thinking of hiv co-infection in patients with extra-pulmonary tb. two clinical cases of well-known opportunistic infections occurring in strange places follow. the first, again from uganda, is a case of toxoplamosis of the hard palate, and the second pneumocystis jirovecii in the external ear canal. finally, mitha and colleagues describe an unusual manifestation of lipodystrophy, namely multiple subcutaneous lipomas, which i hope will stir up interest and invite some comment. finally, we have a letter from the blood transfusion service. this section of the journal could do with much more traffic! the journal office has been offered some additional editorial help, which should enable more efficient management of your copy. thanks to all who have been so patient. i am sure you will see a difference soon. linda-gail bekker editor f r o m t h e e d i tor m e s s a g e f r o m t h e e x e c u t i v e the society is about to embark on some of the most profound changes in its history. an external objective evaluation has pretty much told us what we knew – that we are too big and successful to continue with the current structure. the executive met for 2 days in april, to study the evaluation and suggest changes. many of these are simply improved corporate governance – tightening up our legal, oversight and financial systems, tackling our voting systems (traditionally, only doctors could vote), the structure of the executive, how we administer our branch meetings, providing more support to nurses, creating committees to handle specific projects and areas of works, updating our it and data systems (nonpaid-up members: be afraid) – all sensible stuff any organisation needs to do as it moves out of adolescence. it is an exciting time. but we’ll keep giving you the journal, transcript, the discussion fora, the branch meetings, more guidelines, the new nursing journal, the skills workshops, support for bursaries and an updated website – all the stuff that makes us good and wholesome. francois venter president june 2006 make up 3the southern african journal of hiv medicine march 2006 the article by professor robin wood in this issue highlights the dilemma surrounding antiretroviral first-line regimens. we do have an effective, cheap, first-line therapy: however it contains d4t, which has toxicities. these have been noted and vary in prevalence in south africa. the efficacy and cost of the current first-line therapy has to be balanced against the decreased toxicity and increased expense of a first-line therapy containing tenofovir (expected to be registered in south africa in about 12 months). the increased costs of a tenofovircontaining regimen will include the higher cost of monitoring, this time for renal toxicities. on the one hand the public health viewpoint would support increasing access to antiretroviral therapy, but increased numbers of treated people would mean having to deal with an increase in disabling side-effects, which include neuropathies, hepatotoxicities, lipoadenopathies, and sometimes serious and even fatal toxicities such as lactic acidosis. it will be interesting to see how the debate regarding proposed new firstand second-line regimens recommended by the world health organization unfolds. it is indeed heartening to see increased access to antiretroviral therapy in a number of under-resourced rural communities as a result of the energy and dedication of informed hiv clinicians. this issue of the journal highlights two examples, the kosh branch of the hiv clinicians society (klerksdorp, orkney, stilfontein and hartebeesfontein, also known as the matlosana district of the southern region of north west province (nwp)) and madwaleni hospital, which is over 100 km away from its referral centre, the nelson mandela hospital complex in mthatha. in the nwp the southern and bojonala regions have the highest hiv prevalence rates (31.1% and 30.4% respectively). the kosh branch was recently launched by a dedicated and energetic team led by ms tanya nielson and dr bramie variava. three branch meetings have been held so far at which experts have given talks and difficult cases have been discussed. these cme meetings facilitate local networking and offer additional support to health care professionals involved in the rollout of private, corporate and public sector art programmes. madwaleni hospital, a 220-bed district hospital serving a population of approximately 256 000, was initially built as a missionary hospital in the early fifties. at the end of 2005 it had only a rudimentary hiv service, but with the enthusiasm and hard work of dr richard cooke and ms lynne wilkinson it now has well over 200 patients on arv treatment and only one patient has been lost to follow-up! the focus on hiv/aids is often on treatment, but prevention strategies should not be minimised as they are so important in the fight against the spread of hiv. methods include microbicides, condom use, circumcision, delaying of sexual activity, monogamous relationships and so on, discussed eloquently by dr linda-gail bekker et al. the society wishes the southern african delegates attending the toronto conference in august a safe journey and a stimulating and informative conference. des martin editor, southern african journal of hiv medicine the society executive is very excited to report that we have secured funding to significantly expand our support to hiv care programmes in southern africa. we will be looking at improving existing treatment and other guidelines. we will also be looking at new guidelines in areas that have been raised by clinicians on the ground, as well as establish several 'think tanks' to give people space to start throwing around new ideas in the field of hiv prevention and treatment. we will be expanding access to the journal and transcript wherever possible, and providing more support to our advocacy arm to organisations involved with access to hiv care. the society has recently been instrumental in several high-profile court cases promoting the scientific and rational approach to hiv chronic treatment. i hope that by the time you read this our new website will be functioning, as this will allow access to back issues of the journal, a resource on which our members seem to place huge value. i hope that you will continue to support us in all these initiatives. the central office will grow to accommodate these expanded programmes, and we hope we will be able to continually improve the service to our members. giving quality hiv care to huge numbers of people is an unbelievably massive challenge. we need creative and brave thinking. our respective governments and our patients are relying on us to step up and give calm, professional advice on the best way forward. the society needs to take this responsibility very seriously, and we will be asking for your help at every turn. francois venter president, southern african hiv clinicians society the southern african journal of hiv medicine june 2006 from the editor message from the executive the southern african journal of hiv medicine                                                                july  2009   23 cervical cancer and its precursor lesions are caused by infection with the human papillomavirus (hpv). the human papillomaviruses are part of the papovaviridae family of viruses and consist of tightly coiled, circular, double-stranded dna with about 8 000 base pairs in their genome. the papillomavirus is an obligatory intranuclear virus that must infect mitotically active cells to institute infection. within the cervix hpv most commonly infects the mitotically active transformation zone at the squamo-columnar junction, which explains in part why hpv is associated with both squamous and glandular neoplasia. over 100 different hpv types have been identified, of which approximately 30 40 infect the anogenital tract. hpv viruses of the anogenital tract are divided into ‘low-risk’ and ‘high-risk’ types depending on their ability to produce neoplasia.7,8 there are a variety of opinions on how the human papillomavirus types should be classified. one commonly used classification (munoz) published in 2003 divided them into 15 oncogenic (high-risk) types (hpv 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82) and 12 nononcogenic (low-risk) types (hpv 6, 11, 40, 42, 43, 44, 54, 61, 70 and 72, 81 and cp6108).9 the vast majority of hpv viral infections are cleared within 14 months in women with competent immune systems. however, through a complicated cascade of events some infections evade the immune system, becoming a persistent infection. persistent hpv infection is the first step towards cervical dysplasia and cancer. the e6 and e7 proteins of oncogenic hpv types are known to facilitate the degradation of tumour suppression proteins.² with the loss of suppression of these oncogenes, the cell cycle is disturbed. factors that may increase the risk of persistent infection and cell dysregulation include immune suppression, cigarette smoke, multiple sexual partners, age of first intercourse, hormonal birth control and possibly other sexually transmitted infections such as chlamydia.7,8 according to denny et al.,10 a strong relationship exists between two significant sexually transmitted viruses, hiv and hpv. cervical cancer was made an aids-defining diagnosis by the centers for disease control (cdc) in 1993. the natural history of cervical neoplasia is one of progression and regression, partially mediated by local cervical immunity. this process is not well understood.11 in hiv-positive women with cervical neoplasia, both pro-inflammatory and anti-inflammatory pathways in the cervical mucosa were found to be suppressed in comparison with the local mucosal encervical cancer and the human immunodeficiency virus: a review c l i n i c a l cynthia s firnhaber, md, ms, dtm&h clinical hiv research unit, university of the witwatersrand and helen joseph hospital, johannesburg pam michelow, mb bch, msc, miac cytology unit, department of anatomical pathology, national health laboratory service and university of the witwatersrand globally cervical cancer is one of the commonest cancers in women. it comprises approximately 12% of all cancers and is the commonest cancer in women in developing countries. the most recent compilation of global data indicates that an estimated 490 000 new cases of cervical cancer occur annually worldwide and nearly 80% of these are in developing countries, where screening programmes are not well established and are poorly organised. cervical cancer is the leading cause of cancer death among women. it is estimated that 270 000 women die annually from cervical cancer, 85% of them in low-resource nations.1-3 in africa, cervical cancer comprises 23.3% of all cancers in women.4 according to the south african national cancer registry (ncr) data, the lifetime risk for the development of cervical cancer in 1998 was 1 in 26 for south african women and 1 in 21 for black south african women.5 these are believed to be minimal rates, as the registry publishes only data collected from the pathology laboratories and is not a population-based cancer registry. hiv/ aids poses a severe threat to global health. in addition, the hiv epidemic has hit hardest in regions of high prevalence of cervical dysplasia and cancer. the hiv epidemic in south africa is one of the worst in the world. the prevalence of hiv among south african women attending antenatal clinics in 2006 was 29.1%.6 with improved access to antiretroviral therapy, women are expected to live longer as the risk of death from opportunistic infections decreases. it is assumed that the incidence of cervical cancer and the prevalence of precursor lesions will increase, especially in countries that lack well-organised cervical screening. however, this remains to be seen. human papillomavirus relationship between hiv and hpv viruses july 2009                                                                  the southern african journal of hiv medicine                                                   vironment of hiv-negative women.12 hiv may increase the risk of hpv replication or transcription by a direct viral-viral interaction.13,14 hpv oncogenic types 16 and 18 account for 90% of high-grade intraepithelial precursor lesions in hiv-negative women.15 however, data from a variety of studies in southern africa show a diversity of hpv types. in zambia professor parham in a 150-women study found that 98% of hiv-infected women harboured at least one type of hpv (85% had a high-risk hpv type), with a median of four types per participant. hpv 52 was the most common.16 a study in south africa of 148 hiv-infected women showed similar results, with 95% of the women harbouring hpv, a median of three hpv types per participant, and 85% of women having one or more oncogenic hpv types (hpv 16 accounted for 30%, followed by 35 and 53).17 data from other developing countries in south america and asia also show a large diversity of oncogenic hpv types (including 16 and 18) in addition to other types, such as 33, 35, 52 and 81.18,19 which oncogenic types are causing cervical cancer in hiv-seropositive women in africa still needs to be determined. recent results from a study in kenya indicate that the prevalence of hpv 16 was similar in hiv-seropositive and hiv-seronegative women with invasive cervical cancer.20 several studies have shown that invasive cervical cancer in hiv-positive women tends to present 10 15 years earlier than in their hiv-negative counterparts. in addition, hiv-positive women with invasive cervical cancer have a much greater degree of immunosuppression than hiv-positive women without cervical cancer. women with cd4 counts below 200 cells/µl are significantly more likely than hiv-negative women to have advanced-stage disease at presentation.21,22 hiv-positive women have higher rates of hpv and cervical abnormalities than hiv-negative women. a study by denny et al.10 of 400 untreated hiv-infected women who underwent hpv dna testing, cytology, colposcopy, histology and a cd4 count every 6 months for 36 months showed that 68% of women were positive for high-risk hpv dna, 35% had low-grade squamous intraepithelial lesions (lsil) on pap smear, and 13% had high-grade squamous intraepithelial lesions (hsil) on pap smear. abnormal cytology and the presence of high-risk hpv dna were strongly correlated with low cd4 counts and high viral loads. a study by yamada and co-workers in kenya23 demonstrated cervical hpv infection in 17% of hiv-negative and 49% of hiv-positive women. lsil was found in 6.9% hiv-negative and 21% of hiv-positive women, and hsil in 0.6% of negative and 5.8% of positive women. hsil was strongly associated with high-risk hpv types and low cd4 counts. a study by cardillo et al.24 showed hiv viral load to be significantly higher in women with cytological abnormalities. this study concluded that the degree of immunosuppression may contribute to the development of a squamous intraepithelial lesion, but once the lesion is established, disease progression may not be affected by cd4 counts. a finnish study25 of 153 hiv-positive women followed up for a mean of 5.6 years showed 33% to have cervical neoplasia. the risk of cervical neoplasia was not associated with decreased cd4 counts, duration of hiv infection or use of antiretrovirals.25 the vast majority of lsil regress spontaneously in immunocompetent women. hiv-positive women with lsil have a lower rate of regression and more tendency to progression. in a study by massad et al.,26 progression of cervical dysplasia was observed in 14% of hiv-positive women compared with 7% of hiv-negative women. regression to normal was noted in 43% of hivpositive women and 66% of hiv-negative women. in a study by ahdieh et al.,27 cervical dysplasia regressed in only 45% of hiv-positive women after a median of 2.7 years, which was significantly lower than the regression rate in hiv-negative women. in summary, hiv-positive women tend to have a higher prevalence of hpv, more hpv types with multiple oncogenic-type infection, more hpv persistence and a higher prevalence of cytological abnormalities than their hiv-negative counterparts, and tend to present at an earlier age with cervical cancer. prevention of cervical cancer can be primary or secondary. primary prevention modalities include adopting safe sex practices and hpv vaccination. secondary preventive (screening) techniques include cytology, visual inspection of the cervix and hpv testing. primary prevention sexual abstinence is the only way to completely prevent transmission of hpv. transmission of hpv appears to be fairly easy. correlated hpv types have been found on the external genitalia and cervix of women without any history of sexual intercourse and in reportedly monogamous couples.28-30 the rate of hpv transmission may be lower in circumcised males.31 the efficacy of condoms in preventing transmission of hpv is uncertain. one small study32 showed a decrease in the rate of genital hpv infection from 89.3/100 patient-years to 37.8/100 patient-years in women reporting 100% cervical lesions in hiv-positive women prevention of cervical cancer hpv in hiv-seropositive women 24 the southern african journal of hiv medicine                                                                july  2009   condom use. consistent use of condoms may increase hpv clearance and increase the rate of regression in hiv-negative women.32 the impact of condom use on hpv transmission in hiv-positive women is unknown. two vaccines that protect against certain types of hpv have recently become available. cervarix (glaxosmithkline) produces antibodies to hpv types 16 and 18 while gardasil (merck) produces antibodies to hpv types 16, 18, 6 and 11 (the latter two cause genital warts).33,34 overseas trials have suggested that these two vaccines reduce the incidence of cervical cancer significantly, as it has been estimated that approximately 70% of cervical cancer is caused by hpv types 16 and 18. however, cervical screening will still be necessary as 30% of cervical cancers are caused by hpv types other than 16 and 18. also, it will be required for women who have not received the vaccine. the prevalence of hpv types in southern africa as discussed above may differ from those overseas, so data from hpv vaccination studies elsewhere may not be as helpful in southern africa. the safety and efficacy of the preventive hpv vaccines in hiv-positive women also remains to be determined, as it is not known whether a sufficient antibody response to the vaccine will be obtained. ideally girls should be vaccinated before risk of exposure to either hiv or hpv. in addition, hiv-positive women have a higher rate of infection with multiple hpv types, which may impact negatively on the efficacy of current vaccines against hpv types 16 and 18. another type of hpv vaccine that is still in the early phases of testing is the therapeutic vaccine, to be given to women already infected with hpv to block the e6 and e7 oncogenic proteins and thus prevent progression.35 screening for cervical cancer cervical screening programmes are traditionally based on cervical smears. in countries with well-organised cytologically based cervical screening programmes (such as mexico, columbia and many developed nations), the reduction in the incidence of and mortality from cervical cancer has been dramatic.36,37 a cervical smear-based screening programme is a three-step (visits) approach, viz. women have a smear taken at a clinic, women with abnormal smears then have to be referred to a colposcopy centre for colposcopic biopsy to confirm the cervical results, and then, once confirmed, women have to be referred for treatment of the lesion. cytology is associated with a significant false-negative rate. the estimated sensitivity is only 50 60% for detection of cervical intra-epithelial neoplasia hsil or greater in routine screening settings. the range of sensitivities and specificities of conventional cytology for the detection of hsil in screening studies are 40 86% and 88 99%, respectively.38-41 despite these limitations, cervical cytology remains the only proven method for reducing the incidence and mortality of cervical cancer in large-scale population screening. south africa’s cervical screening programme includes three smears in a lifetime at 10-year intervals starting at age 30. if this could be undertaken effectively, it is estimated that 66% of invasive cervical cancer would be eliminated.42 although south africa’s screening programme was launched in 2000, it has yet to be implemented on any large scale. a cytologically based cervical screening programme requires a reasonably well-functioning health care system. unless good follow-up and referral mechanisms are in place, women may be lost to follow-up at any one of these steps. accessibility of colposcopy and treatment of cervical dysplasia is currently very limited in the south african public sector. visual inspection of the cervix with acetic acid (via) has been investigated as an alternative to cytology in low-resource nations. via is a simple procedure involving swabbing the cervix with 5% acetic acid and after a few minutes observing any change of colour of a normal pink cervix to white. the white areas may represent cervical dysplasia. the normal columnar epithelium is dark pink to red. if in the area of the mitotically active transition zone, the white areas may be indicative of cervical dysplasia and can be treated with cryotherapy at the same visit.43 the convenience and relative simplicity of via makes it preferable to the pap smear in many resource-limited settings, because it does not require the client to return to the clinic for her results. assessment of via accuracy in large cross-sectional, randomised controlled trials in developing countries in hiv-negative women indicates that its sensitivity in detecting high-grade precancerous lesions ranges from 66% to 96% (median 84%), its specificity from 64% to 98% (median 82%), its positive predictive value from 10% to 20% and its negative predictive value from 92% to 97%.44,45 the major strengths of via include its simplicity: there is no need to prepare the patient; it can be taught to nurses, nurse-midwives and other health workers in a short space of time; it costs less than other approaches in routine use; there is real-time availability of results (results are available immediately, eliminating the need for multiple visits in most cases, and reducing loss to follow-up); there is potential for immediate linkage with investigation/treatment; and no specimen transport, expensive laboratory equipment or highly trained personnel are needed. the major limitations of via include low specificity (generally less than 85%) – a considerable number of women who test positive do not have disease, resulting in excessive diagnosis and treatment, and unnecessary anxiety; 25 july 2009                                                                  the southern african journal of hiv medicine                                                   lack of standardised methods of quality control (there is no permanent record of the test that can be reviewed later); training and competency of screeners are difficult to evaluate; its ability to detect endocervical lesions is limited as a result of difficulties in sampling and visualising the endocervical canal, as well as less experience among readers in recognising glandular cell lesions; and tests to follow up women who have been treated are lacking. finally, the efficacy and cost-effectiveness of via-based population screening programmes in reducing the incidence of, and mortality from, cervical cancer are not known and remain to be established, as do the long-term complications of over-treatment.43-45 via has mostly been evaluated as an once-in-a-lifetime screening test, and its performance in periodic screening has not been assessed. validation in hiv-positive women is required. the vast majority of hpv infections will clear spontaneously, especially in women below the age of 30 years, so hpv dna testing has good negative predictive value but less good positive predictive value. other disadvantages of hpv dna testing are the cost, dependence on reagents currently produced by very few commercial manufacturers, and low specificity in younger women. hpv testing usually requires sophisticated laboratories with highly trained personnel, often not available in low-resource nations. in addition, samples for hpv tests need to be transported to the laboratory and patients need to return to the clinic for results, so there is potential loss to follow-up.46-48 a rapid hpv test for use in low-resource countries, the hpv digene fast test, has recently been developed. it obviates the need for sophisticated laboratories, and one study has shown good results.49 further investigations in this regard are required, especially in hiv-seropositive women. various combinations of cytology, via and hpv testing have been described, but the best method of screening in both hiv-positive and hiv-negative women has yet to be determined.50,51 if colposcopy has confirmed the pap smear cytology result of a high-grade lesion with histological results of cin 2 or cin 3, treatment of the lesion is required. treatment can be done via a variety of methods. a very efficient outpatient procedure requiring only local anaesthesia is called either leetz (loop electrosurgical excision of the transition zone) or leep (loop electrosurgical excision procedure) biopsy. the procedure uses a thin electrified wire to remove the lesion up to 7 mm in depth from the transitional zone. leep or leetz is a very effective procedure in non-hiv-seropositive women, with a success rate of 80 85%.44,52 however, a study in soweto indicated that in hiv-seropositive women in south africa the failure rate may be as high as 50% (defined as incomplete margins on pathological specimens).53 close follow-up is required in hiv seropositive women and additional procedures may be needed. more definitive treatment includes the cone biopsy. this is an effective mode of treatment, but requires referral to a centre with a skilled gynaecologist, inpatient admission, and operating room availability.52 cryotherapy can be done after the via procedure, during the same visit as discussed above, eliminating the anxiety and loss to follow-up that lengthy delays in follow-up visits cause and reducing the inconvenience of work, child-care and transportation issues. the procedure needs a consistent supply of nitrous oxide with a cryotherapy gun and probe. freezing the lesion requires application of the gas for about 2 minutes and the patient should come for follow-up visits at 6 weeks, 6 months and 12 months (gosbeck parham, personal communication). recurrent lesions found after via are referred for leep. cryotherapy means that there are no pathology results, so it is not known what lesion was treated. large lesions and lesions spreading into the cervical canal cannot be treated with cryotherapy and need to be referred for leep.43 hysterectomy is reserved for refractory cases of carcinoma in situ that cannot be treated appropriately with the above methods. other treatment modalities micronutrients, vitamins (vitamins a, e and c) and antiretroviral agents (gancyclovir and cidofovir) have not shown any positive effect in the treatment of cervical dysplasia and should not be recommended.52 as hpv infection is an immunomodulated disease, there is some hope that hiv antiretroviral therapy (art) would improve regression rates and prevent the progression of cervical dysplasia as art has improved the outcomes of patients suffering from kaposi’s sarcoma.54 however, findings of reversal of cervical dysplasia in hiv-positive women receiving art have been quite controversial, with disparate results.55,56 reports indicate that antiretroviral drugs may improve outcomes in cervical dysplasia in hiv-infected women. however, other cohort studies show that art has no effect on cervical dysplasia.57 as hpv is already integrated into the host genome and oncogenic gene changes are already occurring, art given after the lesions have been developed may be too late to change the course of the hpv disease progression. larger prospective cohort studies are needed to assess the effectiveness of art in preventing cervical cancer in women with hpv-hiv coinfection. with the effective art roll-out in south africa many women will survive opportunistic diseases, and cervical cancer screening needs to be on the agenda of hiv/art treatment of cervical dysplasia 26 the southern african journal of hiv medicine                                                                july  2009   clinics. with the overwhelmed public sector obstetrics and gynaecology services in south africa, limited accessibility, long waiting periods between pap smears, colposcopy and leep, disjointed care and loss to follow-up between departments, cervical cancer screening and treatment need to be available and offered in hiv clinics as an integrated service. references 1. ferlay j, bray f, pisani p, parkin dm. international agency for research on cancer (iarc). globocan 2002: cancer incidence, mortality and prevalence worldwide. lyon, france: iarcpress; 2004; cancer base no. 5, version 2.0. 2. parkin d, whelan s, ferlay j, et al., eds. cancer incidence in five continents. vol. viii. lyon: iarc press, 2002 ( iarc scientific publications no. 155). 3. steward bw, kleihues p. world cancer report. lyon: iarc press, 2003. 4. parkin d, sitas f, chirenje m, stein l, abratt r, wabinga h. cancer in indigenous africans – burden, distribution and trends. lancet oncol 2008; 9: 683-692. 5. mqoqi n, kellet p, sitas f, jula m. incidence of histologically diagnosed cancer in south africa, 1998-1999. national cancer registry report. johannesburg: national health laboratory service, 2004: 116. 6. summary of biennial report on the state of the south african hiv/aids epidemic. south african department of health study, 2006. www.doh.gov.za/docs/reports (accessed 28 december 2008). 7. shew m, fortenberry d, wanzhu t, et al. association of condom use, sexual behaviours, and sexually transmitted infections with the duration of genital human papillomavirus infection among adolescent women. arch pediatr adolesc med 2006; 160: 151-156. 8. iac task force. human papillomavirus. acta cytol 1998; 42: 50-58. 9. muñoz n, bosch fx, de sanjosé s, et al. epidemiologic classification of human papillomavirus types associated with cervical cancer. n engl j med 2003; 348: 518527. 10. denny l, boa r, williamson a, et al. human papillomavirus infection and cervical disease in human immunodeficiency virus-1 infected women. obstet gynecol 2008; 111: 1380-1387. 11. stanley m. immune responses to human papillomavirus. vaccine 2006; 24: suppl 1, s16-s22. 12. kobayashi a, greenblatt r, anastos k, et al. functional attributes of mucosal immunity in cervical neoplasia and effects of hiv infection. cancer res 2004; 64: 6766-6774. 13. dolei a, curreli s, marongui p, et al. human immunodeficiency virus infection in vitro activates naturally integrated human papillomavirus type 18 and induces synthesis of l1 capsid protein. j gen virol 1999; 80: 2937-2944. 14. vernon s, hart c, reeves w, icenogle j. the hiv-1 tat protein enhances e2dependant human papillomavirus 16 transcription. virus res 1993; 27: 133-145. 15. smith js, lindsay l, hoots b, et al. human papillomavirus type distribution in invasive cervical cancer and high grade cervical lesions: a meta-analysis update. int j cancer 2007; 121: 621-632. 16. parham gp, sahasrabuddhe vv, mwanahamuntu mh, shepherd be, hicks ml, stringer em. prevalence and predictors of squamous intraepithelial lesions of the cervix in hiv-infected women in lusaka, zambia. gynecol oncol 2006; 103(3): 10171022. 17. firnhaber c, zungu k, williamson a, et al. diverse and high prevalence of human papillomavirus associated with a significant high rate of cervical dysplasia in hivinfected women in johannesburg. acta cytol 2009; 53: 10-18. 18. cerqueira dm, moraes dd, camara gn, et al. high hpv genetic diversity in women infected with hiv-1 in brazil. arch virol 2007; 152(1): 75-83. 19. bollen lj, chuachoowong r, kilmarx ph, et al. human papillomavirus (hpv) detection among human immunodeficiency virus-infected pregnant thai women: implications for future hpv immunization. sex transm dis 2006; 33(4): 259-264. 20. de vuyst h, gichangi p, estambale b, njuguna e, franceschi s, temmerman m. human papillomavirus types in women with invasive cervical carcinoma by hiv status in kenya. int j cancer 2008; 122: 244-246. 21. lomalisa p, smith t, guidozzi f. human immunodeficiency virus infection and invasive cervical cancer in south africa. gynecol oncol 2000; 77: 460-463. 22. moodley m, moodley j, kleinschmidt i. invasive cervical cancer and human immunodeficiency virus infection: a south african perspective. int j gynecol cancer 2001; 11(3): 194-197. 23. yamada r, sasagawa t, kirumbi l, kingoro a, karanja d, kiptoo m. human papillomavirus infection and cervival abnormalities in nairobi, kenya, an area with a high prevalence of human immunodeficiency virus infection. j med virol 2008; 80: 847-855. 24. cardillo m, hagan r, abadi j, abadi m. cd4 t-cell count, viral load and squamous intraepithelial lesions in women infected with the human immunodeficiency virus. cancer (cancer cytopathol) 2001; 93: 111-114. 25. lehtovirta p, paavonen j, heikinheimo o. risk factors, diagnosis and prognosis of cervical intraepithelial neoplasia among hiv-infected women. int j std aids 2008; 19: 37-41. 26. massad s, ahdieh l, benning l, et al. evolution of cervical abnormalities among women with hiv-1: evidence from surveillance cytology in the wh study. j infect dis 2001; 27: 432-442. 27. ahdieh l, li r, levine a, massad l, et al. highly active antiretroviral therapy and cervical squamous intraepithelial lesions in human immunodeficiency virus-positive women. j natl cancer inst 2004; 96: 1070-1076. 28. winer r, lee s, hughes j, et al. genital human papillomavirus infection: incidence and risk factors in a cohort of female university students. am j epidemiol 2003; 157: 218-226. 29. moscicki a. impact of hpv infection in adolescent populations. j adolesc health 2005; 37: 6 suppl, s3-s9. 30. castellsague x, bosch f, munoz n, et al. male circumcision, penile human papillomavirus infection and cervical cancer in female partners. n engl j med 2002; 346: 1105-1112. 31. winer r, hughes j, feng q, et al. condom use and the risk of genital human papillomavirus infection in young women. n engl j med 2006; 354: 2642-2654. 32. holmes k, levine r, weaver m. effectiveness of condoms in preventing sexually transmitted infections. bull world health organ 2004; 82: 454-461. 33. harper d, franco el, wheeler c, et al. efficacy of a bivalent l1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. lancet 2004; 364: 1757-1765. 34. villa ll, costa rl, petta ca, et al. prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) l1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase ii efficacy trial. lancet oncol 2005; 6(5): 271-278. 35. de jong a, o’neil t, khan a, et al. enhancement of human papillomavirus (hpv) type 16 e6 and e7 specific t cell immunity in healthy volunteers through vaccination with ta-cin, an hpv 16 l2e7e6 fusion protein vaccine. vaccine 2002; 20: 34563464. 36. aristizabal n, cuello c, correa p. the impact of vaginal cytology on cervical cancer risks in cali, columbia. int j cancer 1984; 34: 5-9. 37. lazcano-ponce e, palacio-meijia l, allen-leigh b, et al. decreasing cervical cancer mortality in mexico: effect of papanicoloau coverage, birth rate and the importance of diagnostic validity of cytology. cancer epidemiol biomarkers prev 2008; 17: 28082817. 38. nanda k, mccrory dc, myers er, et al. accuracy of the papanicolaou test in screening for and follow-up of cervical cytological abnormalities: a systematic review. ann intern med 2000; 132: 819. 39. bastian l, datta s, hasselbald v, hickey j, myers e, nanda k. evaluation of cervical cytology, 5. rockville, md: agency for health care policy and research (ahcpr), 1999. evidence report/technology assessment prepared by duke university under contract 290-97-0014. ahcpr puplication 99-e010. hstat nlm nih gov/hq/hquest/ db/local epc er cyt/screen/doctitle/s48139 (accessed 25 february 2003). 40. fahey mt, irwig l, macaskill p. meta-analyses of pap test accuracy. am j epidemiol 1995; 141: 680-689. 41. mannino jr. natural history of false-negative papanicolaou smears: a prospective study using screening colposcopy in addition to cytology. j am osteopath assoc 1998; 98: 546. 42. sankaranarayanan r, budukh a, rajkumar r. effective screening programmes for cervical cancer in low and middle income developing countries. bull world health organ 2001; 79: 954-962. 43. carr k, sellors j. cervical cancer screening in low resource settings: using visual inspection with acetic acid. j midwifery womens health 2004; 49(4): 329-337. 44. sankaranarayanan r, gaffikin l, jacob m, sellors j, robles s. a critical assessment of screening methods for cervical neoplasia. int j gynecol obstet 2005; 89: 504-512. 45. miller ba, nazeer s, fonn s, et al. report on consensus conference on cervical cancer screening and management. int j cancer 2000; 86: 440-447. 46. wright tc, schiffman m, solomon d, et al. interim guidance for the use of human papilloma virus dna testing as an adjunct to cervical cytology for screening. obstet gynecol 2004; 103: 304-309. 47. howard m, sellors j, kaczorowski j. optimizing the hybrid capture ii human papillomavirus test to detect cervical intraepithelial neoplasia. obstet gynecol 2002; 100: 980-982. 48. sellors j. hpv in screening and triage: towards an affordable test. hpv today 2005; 8: 4-5. 49. qiao y, sellors j, eder p, et al. a new hpv-dna test for cervical cancer screening in developing regions: a cross-sectional study of clinical accuracy in china. lancet oncol (in press). 50. goldie s, gaffikin l, goldhaber-fiebert j, et al. cost-effectiveness of cervical cancer screening in five developing countries. n engl j med 2005; 353: 2158-2168. 51. mandelblatt j, lawrence w, gaffikin l, et al. costs and benefits of different strategies to screen for cervical cancer in less-developed countries. j natl cancer inst 2002; 94: 1469-1483. 52. cox md. management of precursor lesions of cervical carcinoma: history, host defense, and a survey of modalities. obstet gynecol clin north am 2002; 29: 751758. 53. adam y, van gelderen c, de bruyn g, et al. predictors of persistent cytologic abnormalities after treatment of cervical intraepithelial neoplasia in soweto, south africa: a cohort study in a hiv high prevalence population. bmc cancer 2008; 8: 211. 54. nasti g, marellotta f, berretta m, et al. impact of highly antiretroviral therapy on the presenting features and outcome of patients with acquired immunodeficiency syndrome-related kaposi sarcoma. cancer 2003; 98(11): 2440-2446. 55. heard i, tassie jm, kazatchikine m, et al. highly active antiretroviral therapy enhances regression of cervical intraepithelial neoplasia in hiv-seropositive women. aids 2002; 16: 1799-1802. 56. minkoff h, ahdieh l, massad ls, et al. the effect of highly active antiretroviral therapy on cervical cytologic changes associated with oncogenic hpv among hivinfected women. aids 2001; 15: 2157-2164. 57. lillo f, ferrari d, veglia f, et al. human papillomavirus infection and associated cervical disease in human immunodeficiency virus-infected women: effect of highly active antiretroviral therapy. j infect dis 2001; 184: 547-551. 27 untitled the southern african journal of hiv medicine december 2006 15 o p i n i o n the origins, evolution and outsourcing of hiv denialism chris kenyon, mb chb, ba hons, mph medical registrar, groote schuur hospital, cape town the hiv denialism propagated in statements such as mbeki’s often repeated ‘a virus cannot cause a syndrome’ led to the situation where in 2001 only 0.5% of south africans believed they had a member of their family infected with hiv.1 in such conditions of ignorance and denial few were taking adequate precautions, and the virus was able to spread like wildfire. both the origins and subsequent evolution of hiv denialism are rooted in ideology. hiv emerged at a time of great global and local polarisation. the cold war was raging and the anc, siding predominantly with the eastern block, was engaged in a bitter revolutionary struggle to overthrow the apartheid regime. to counter the brutal ‘total onslaught’ of the regime, the anc developed a revolutionary fanaticism of its own. much of this battle was ideological: to fight against the regime’s racist and anti-communist propaganda machine, the anc aggressively promoted a counter-paradigm in which all issues were seen predominantly in terms of their bearing on the anti-apartheid (and to a lesser extent, anti-capitalist) struggle. it should come as no surprise, then, that hiv/aids was interpreted in this light. there were only two articles in sechaba (the magazine which was the voice of the anc in exile) in the 1980s that deal with a specific disease. both are about aids and both are written by cde. ‘mzala’. in the first article, entitled ‘aids – misinformation and racism’, we are treated in advance to carbon copies of many of mbeki’s favourite gaffes on the subject.2 the ‘vast majority’ of hiv tests done by the elisa method in africa are ‘false positives’ due to africans’ ‘sticky blood’. in the second article, entitled ’aids and the imperialist connection’, we hear that ’the aids virus was a product of united states military conspiracy (sic).’ the source of this assertion is an ‘80-page paper’ produced by three east german scientists.3 mzala ends with a line that mbeki will go on to echo: ‘aids has fallen victim to the same process that has bedeviled health under capitalism, where medical facts are often over-dramatized for the sake of making huge profits for the drugs industry.’ as mbeki’s brazen a-virus-can’t-cause-a-syndrome brand of denialism attracted increasing ridicule, and with elections approaching in 2003, he was left with two options – back down or adapt. the closest mbeki came to an admission of error was in his official press release announcing his intention to withdraw from the debate on the link between hiv and aids; here he conceded that ‘a virus may be one of the causes of aids’. more recently we were informed that minister tshabalala-msimang will no longer be the government’s spokesperson on hiv. the events of the last few years reveal more of an evolution than a renunciation of hiv denialism. december 2006 the southern african journal of hiv medicine 16 the new form of denialism does not overtly deny the existence of the hiv virus, but rather asserts that aids can be treated by proper diet and various nutritional supplements. furthermore, it claims that antiretrovirals (arvs) are not only ineffective but actually toxic. mbeki was one of the first to elaborate this new direction of denialism in his ‘castro hlongwane’ article.4 in this document, written on his computer,5 he described an unholy alliance or ‘omnipotent apparatus’ of doctors and pharmaceutical companies who were trying to make a fortune out of poisoning poor africans with toxic arvs. more recently this work has been continued by the rath foundation, who have inundated poor communities with leaflets advising them of the lethal toxicity of arvs, how aids can be reversed with rath’s multivitamins, and how these multivitamins herald ‘the end of the aids epidemic’. the most disturbing aspect of their activities is the active support they have received from officials in the anc, sanco and government. sanco has publicly endorsed many of rath’s claims, anc branches have been disseminating rath’s material and the national director general of health has intervened personally to overturn medicines control council decisions prohibiting the import of unscheduled rath products into the country.6 the national minister of health has defended rath and shared platforms with him on multiple occasions.7 why then is the government supporting the work of an organisation that is seeking to undermine the government’s own arv programme? once again, part of the answer is ideological – this time in the new neoliberal ideology which has gripped our government.8 the first hint of this influence was mbeki’s letter to the cabinet on 6 august 2001 where he implores cabinet members to ensure that spending on aids is kept within 2.2% of total spending so that ‘the allocation of resources reflect(s) the incidence of death (from hiv/aids).’9 the extent to which this cost-saving neoliberal ideology has motivated hiv policy was perhaps most chillingly demonstrated by ex-presidential spokesperson parks mahlanyana who, while himself in the late stages of a wasting disease, announced that the state would not implement a programme to reduce hiv transmission from mothers to their children as this would leave the state with too high a bill of child care maintenance.10 the new form of denialism dovetails perfectly with this neoliberal ethos. the neoliberalism justifies the pitiful spending on this social catastrophe, while the new denialism spread by msimang, rath and company reduces the demand for and hence the cost of the arv programme. mbeki and msimang may have withdrawn from the public face of the national hiv response, but like good neoliberals they have merely outsourced their denialism to bodies such as the rath foundation. that mbeki continues to be a denialist is clear from the fact that he still refuses to have an hiv test as ‘that would reinforce a particular paradigm’. until such time as mbeki and msimang offer a meaningful apology to all south africans for how they have misled us, and lead us in going for public confidential hiv testing, their views will continue to warp the thinking and practice of millions of south africans. we should demand nothing less than an unconditional apology from our leaders. primo levi, looking back at the social response to the nazi genocide, noted: ‘and there is another, vaster shame, the shame of the world … every bell tolls for everybody. and yet there are those who faced by the crime of others or their own, turn their backs so as not to see it and feel touched by it.’11 when cde. mzala (jabulani nxumalo) and parks mahlanyana tragically died in their thirties and forties from ‘long illnesses’, the bells were ordered to toll for them alone. in a democracy as hard fought for as our own, the fact that we allow our rulers to continue to get away with such actions casts a vast shame on us all. references 1. national youth survey. national adolescent friendly clinic initiative. love life, 2001. 2. nxumalo j. aids – misinformation and racism. sechaba aug. 1988. 3. nxumalo j. aids and the imperialist connection. sechaba sept.1988. 4. anon. castro hlongwane: cats, geese and foot and mouth disease. http://www.virusmyth.net/aids/data/ancdoc.htm (accessed 10 sept. 2006). 5. barrel h. would the real aids dissident please stand up. mail and guardian 2002; 22 april. 6. joubert p. health department dg frees seized rath drugs. mail and guardian 2006; 7 july. 7. joubert p. deadly silence. fair lady 2005; nov. 8. bond p. elite transition: from apartheid to neoliberalism in south africa. london: pluto press, 1996. 9. mbeki questions spending on aids. business day 2001; 10 sept. http:// www.bday.co.za/bday/content/direct/1.3523.924850-6078-0.00.html (accessed 10 sept. 2006). 10. cohen j. south africa’s new enemy. science 2000; 288: 2168-2170. 11. levi p. survival in auschwitz. new york: touchstone, 1995. o cto b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a comprehensive history from the patient and/or caregiver is needed. there should be special focus on the history of the current complaint, past psychiatric history, past and present substance abuse history, full medical history and sexual risk history and the patient’s adherence to previous treatment regimens. of equal importance is identification of social support systems. a mental status examination will need to be conducted. in the psychotic patient one needs to focus specifically on the behaviour and appearance of the patient. his or her speech and speed of thoughts should be assessed, and mood symptoms, affect, suicidality and neuro-vegetative symptoms evaluated. perceptual disturbances, thought form, thought content and finally insight and judgement also need to be assessed. a comprehensive and meticulous physical and neurological examination should be performed to exclude any organic causes for the presenting psychiatric symptoms. a useful hierarchical approach has been suggested by ambrosino et al.2 one should first examine for signs of delirium and rule out hiv-associated cognitive disorders. medical diagnoses should first be considered and only after that should a psychiatric diagnosis be entertained. the differential diagnosis needs to consider the course of the hiv infection, the presence of a pre-existing psychiatric illness, use of illicit substances and the presence of cognitive impairment.3 a useful delineation may be to divide psychosis in the plwha into: (i) psychiatric disorders predating hiv infection; (ii) new-onset psychotic disorders; and (iii) disorders associated with medical conditions (delirium) or substance intoxication or withdrawal, and those that are likely to be complications of treatment (i.e. antiretrovirals or antituberculosis drugs).4 psychotic disorders predating hiv infection major psychiatric disorders presenting with psychosis and predating hiv infection include schizophrenia, bipolar mood disorder and major depressive disorder with psychotic features. these disorders present with significant impairment of functioning and follow a chronic course.5 substance abuse may predispose and/ or precipitate a substance-induced psychotic disorder. there are a multitude of substances that may cause psychotic symptoms or psychotic disorders, and a clear collateral history is vital. new-onset psychotic disorders new-onset psychosis in the hiv-infected patient is the development of psychotic symptoms (delusions, hallucinations, disorganised behaviour, negative symptoms or altered form of thought), either acutely or subacutely, in the absence of concurrent substance abuse, opportunistic infections, space-occupying lesions, cognitive impairment or various medications. it is hypo thesised that this is caused by subcortical neurodegeneration and the direct neurotropic effects of hiv on the central nervous system (cns), or is a manifestation of assessment and treatment of psychosis in people living with hiv/aids c l i n i c a l : a s s e s s m e n t g jonsson, fcpsych (sa), mmed (psych) division of psychiatry, university of the witwatersrand, johannesburg john a joska, mmed (psych), fcpsych (sa) department of psychiatry and mental health, university of cape town and groote schuur hospital, cape town for: south african society of psychiatrists hiv special interest group the pathophysiology of psychosis and other forms of severe mental illness in hiv infection is complex, and multifactorial causation is likely in most instances. severe mental illness has been identified as a risk factor for the acquisition of hiv infection and occurs as both a manifestation of opportunistic infections and a result of the neurotropic effects of the virus.1 a full psychiatric assessment in people living with hiv/aids (plwha) presenting with psychosis is important but may prove difficult in many parts of south africa. this paper presents a variety of algorithms to simplify the assessment and management of an hiv-infected patient with psychosis. approach to plwha and psychosis (fig. 1) psychotic disorders in plwha (fig. 1) 20 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e o cto b e r 2 0 0 9 hiv-associated encephalopathy in the absence of severe hiv-associated dementia. some suggest that it is due to an increase in intracellular free calcium.6 rates of new-onset psychosis in hiv-positive patients have been reported to range from 0.5% to 15%.7 psychotic symptoms may also occur in the presence of major hiv-related mood disorders. in a ugandan study in which hiv-negative patients with primary mania and patients with hiv-related secondary mania were compared, the patients with secondary mania were more irritable, aggressive and disruptive and had a higher rate of psychotic symptoms than those with primary mania.8 finally, new-onset psychotic symptoms may also occur in the presence of hiv related-cognitive disorders.9 psychosis associated with medical conditions, substance intoxication, substance withdrawal or as a complication of medication delirium delirium often has multifactorial causation and manifests with an acute presentation of disturbance in consciousness, change in cognition and development fig. 1. approach to the assessment of psychosis in plwha. 17                      psychosis in plwha obtain comprehensive history and perform physical and neurological examination mental status examination is performed investigations and collateral information are obtained psychiatric disorders presenting with psychosis, predating hiv diagnosis new-onset psychosis psychosis associated with medical conditions, substance intoxication and withdrawal or resulting from medication-related side-effects go to fig. 2 go to fig. 3 go to fig. 4 21 o cto b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e of perceptual disturbances, with a fluctuating course.10 it may be due to the presence of cns opportunistic infections, metabolic disorders, neuropsychiatric sideeffects of various drugs, or substance intoxication or withdrawal. studies from before the era of highly active antiretroviral therapy (haart) reported a prevalence of delirium of 12 29% among individuals with aids.11 the diagnosis of delirium depends on accurate diagnosis of the underlying cause. a comprehensive physical examination, diagnostic work-up (biochemical and microbiological parameters, cerebrospinal fluid examination) and brain imaging (computed tomography) are needed to help make the diagnosis. hospitalised patients with hiv should be assessed early and frequently for delirium, and treatment for the underlying cause should be initiated as soon as possible. substance intoxication or withdrawal substance intoxication and withdrawal are reversible substance-specific syndromes and may present with a delirium-type picture. hiv-infected individuals have a high prevalence of substance abuse, with lifetime rates as high as 50%.12 hiv-positive drug abusers are reported to have higher rates of both hiv-associated dementia and hiv encephalopathy than hiv-infected people who do not abuse drugs.13 drug abuse may increase the risk of developing delirium. furthermore, it may not only affect disease progression but also be associated with reduced adherence to antiretroviral therapy (art) and is therefore a very important co-morbidity to consider in the patient with ‘triple diagnosis’ disorders, i.e. psychiatric disorders, hiv infection and substance abuse disorders.14 psychosis as a complication of medical treatment some medications used to treat hiv or the medical complications of hiv/aids may cause psychiatric disorders presenting with psychotic symptoms. efavirenz has been associated with a wide range of neuropsychiatric sideeffects. psychotic symptoms associated with the commencement of efavirenz therapy are reported to occur early on and may necessitate its discontinuation.15 other medications commonly used in hiv medicine that can be associated with mental state changes and psychotic symptoms include corticosteroids; other antiviral agents, e.g. ganciclovir; antifungal agents, e.g. amphotericin b; and some antibacterials, e.g. anti tuberculosis drugs, dapsone and sulphadiazines.4,16 these ‘psychotoxic’ reactions, which may manifest as psychosis, mania or delirium, have been associated with the commencement of treatment with isoniazid, ethionamide, ethambutol and some of the fluoroquinolones. a study in peru found that severe psychiatric syndromes associated with isoniazid occurred in approximately 1% of patients with tuberculosis between 1991 and 1999.17 a careful history is therefore necessary to determine the temporal relationship between the development of psychotic symptoms and commencement of the drug, as this has very important implications in terms of management. when a patient presents with psychotic symptoms in the presence of hiv infection it is essential to exclude life-threatening medical causes of the psychotic symptoms. this may be extremely difficult in the agitated, fig. 2. psychotic disorders predating hiv infection. treatment of hiv-associated psychosis 18                       psychiatric disorders presenting with psychosis, predating hiv diagnosis treat underlying psychiatric condition optimally – it may be necessary to refer to a psychiatrist for optimal control investigate home circumstances and support refer to government art clinic for work-up and commencement of art reinforce adherence to medication. refer to specialist centre for psychiatric follow-up 22 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e o cto b e r 2 0 0 9 disorganised or violent patient, and antipsychotic medications may need to be instituted before a thorough work-up is completed. antipsychotic medications are safe and effective in the presence of hiv disease, but treatment modifications may be necessary and conservative dosing strategies may need to be implemented. antipsychotic medication should always be used at the lowest possible dose for the shortest possible duration. the choice of antipsychotic drugs depends largely on the patient, presenting symptoms, past response, potential side-effect profile, possible drug interactions, cost, and pill burden of the chronically ill patient. many patients with new-onset psychosis or psychosis associated with various medical conditions may only require short-term treatment with antipsychotic medication. however, some patients may require long-term maintenance treatment with antipsychotic agents, and here special attention must be paid to the followfig. 3. new-onset psychosis. 19                       new-onset psychosis treat psychotic symptoms with typical agents, i.e haloperidol 0.5 mg 2.5 mg p.o. nocte and/or lorazepam 1 2 mg p.o. q 8 h. observe for side-effects if extrapyramidal side-effects occur, change to atypical agent, i.e. risperidone 1 2 mg p.o. nocte or in divided doses, i.e. 1 mg p.o. b.d. if no extrapyramidal side-effects occur, continue with haloperidol once stable, investigate social support and identify treatment supporter work up for art and commence art in line with doh guidelines, paying attention to neuropsychiatric side-effects of art and drug-drug interactions reinforce adherence to medication. refer to specialist centre for psychiatric follow-up 23 o cto b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e ing factors. the typical antipsychotics are commonly used in resource-constrained settings. here low doses of haloperidol (0.5 2.5 mg) and chlorpromazine (25 50 mg) have proven effective and safe. vigilance is required with regard to extrapyramidal side-effects with haloperidol and anticholinergic side-effects with chlorpromazine. among the atypical antipsychotics, risperidone (1 4 mg/d) is commonly used, if available. this may be used in patients who present with or pose a risk of developing extra-pyramidal side-effects. the atypical antipsychotics are generally better tolerated than the typical antipsychotics, but they are associated with longer-term metabolic side-effects and the potential development of drug-drug interactions. development of the metabolic syndrome, weight gain, abnormal lipid profiles and diabetes mellitus are well described with some of the atypical antipsychotics (olanzapine and clozapine). the lipodystrophy syndrome described in hiv-positive patients on art predisposes these patients to the development of diabetes mellitus and coronary artery disease. the atypical antipsychotics with a propensity to develop metabolic syndrome and certain art regimens (protease inhibitors (pis) and the nucleoside reverse transcriptase inhibitors (nrtis) in particular), taken together, may have serious long-term adverse effects.18,19 many psychotropic medications and art (especially the pis and nnrtis) share the same cytochrome p450 (cyp) iso-enzymes for metabolism, and competition between the two is prominent.18,19 interactions resulting in a decreased plasma concentration-time curve fig. 4. psychosis associated with medical conditions or substance intoxication/withdrawal, or resulting from medicationrelated side-effects. 20                              psychosis associated with medical conditions or substance intoxication and withdrawal, or resulting from medication side-effects investigate underlying cause thoroughly substance intoxication or withdrawal delirium medication-related side-effects treat appropriately and refer to substance rehabilitation unit or ‘dual diagnosis’ unit treat underlying cause of delirium. psychotic symptoms may be treated with haloperidol 0.5 2.5 mg p.o. nocte and/or lorazepam 1 2 mg p.o. q 8 h investigate temporal relationship refer to specialist infectious diseases expert and/or specialist psychiatrist work up for art and commence art in line with doh guidelines, paying attention to neuropsychiatric side-effects of art and drug-drug interactions reinforce adherence to medication. refer to specialist centre for psychiatric follow-up 24 o cto b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e for olanzapine may be clinically important.20 for other important interactions, see the article in this issue on psychotropic prescribing. it may be necessary to make use of benzodiazepines in the agitated, aggressive patient when antipsychotics alone do not provide sufficient containment. the use of benzodiazepines with few or no active metabolites is crucial. lorazepam in small divided doses may be necessary, i.e. 1 2 mg orally every 8 hours. caution is needed when using lorazepam in the patient with delirium, as one study found it to be ineffective and associated with significant adverse effects.21 however, this agent may be the only drug available in certain resource-limited settings, and benefit versus risk will need to be ascertained for each individual patient. psycho-education is imperative throughout all stages of treatment. psychosocial interventions and regular follow-up with the multidisciplinary team (psychiatrist, psychiatric nurse, social worker, occupational therapist and psychologist) are important. adherence should consistently be reinforced and improved. referral to an occupational therapist who uses various activity groups, support groups and food garden/nutrition security groups to help improve adherence may be considered. supportive therapy is vitally important as the patient recovers. temporary placement in an appropriate facility may be necessary for patients who are difficult to treat and those who require longer inpatient care. ongoing viral replication in the brain is a risk factor for neuropsychiatric disorders, and in combination with degree of immunodeficiency and other factors that lower the threshold for developing psychosis (family history, substance abuse) these constitute a stress-within-astress diathesis model. it is often not realistic to start art in a psychotic patient without antipsychotics as adherence is likely to be poor, but once the patient has reached a state of relative stability art should be started as soon as possible to decrease the contribution of hiv replication in the brain. in patients with psychosis related to immunosuppression and brain dysfunction, treatment with antipsychotics and art simultaneously may be necessary from the time of initial presentation. it is vitally important that the patient be monitored closely, either as an inpatient if difficult to contain, or very closely by caregivers to ensure intensive adherence. adherence counselling at all stages of recovery is imperative to ensure understanding of the need for art and adherence to prevent possible resistance. it is difficult to recommend a time frame with regard to duration of antipsychotic medication, as there is a relative paucity of literature. a possible option is to wean the patient slowly off antipsychotics after psychotic symptoms have remitted for 6 months, then take a watch-and-wait approach. this must only be done if good follow-up is possible so that antipsychotic medication can be reintroduced the moment symptoms recur. in order to simplify the management of psychosis in the hiv-positive patient, three algorithms are presented. fig. 2 describes the management of psychotic disorders predating hiv infection, fig. 3 details the treatment and referral procedure for new-onset psychosis, and fig. 4 describes the process for the assessment, management and referral of psychosis associated with medical conditions, substance intoxication/withdrawal and symptoms resulting from medication-related side-effects. commencement of art may be initiated in accordance with the department of health guidelines.22 department of health first-line regimens are used, but special attention needs to be paid to co-existing antituberculosis treatment, liver toxicity, drug-drug interactions and possible neuropsychiatric side-effects of various arts. ideally commencement of art in the patient with psychosis should be instituted in a multidisciplinary setting. adherence is an important concern in preparing patients for lifelong art, but it is also crucial not to exclude patients with serious mental illness from receiving art because they may ‘possibly’ be non-adherent. involvement of a treatment supporter is essential to assist with adherence, with the patient’s consent or assent. intensive pretreatment education and adherence counselling of the patient and treatment partner are vital in order to assess treatment appropriateness and commitment to long-term neuropsychiatric follow-up. it is imperative to exclude an underlying medical cause for psychotic symptoms in the hiv-infected patient, and a careful differential diagnosis needs to be established based on the criteria set out above. psychotic symptoms respond well to antipsychotic medication, but medication side-effects and drug-drug interactions must be vigilantly watched out for. it is important to remember that patients with mental illness are at an increased risk of being infected with hiv and of transmitting the virus. prevention strategies, testing and referral of patients with mental illness and hiv/aids is vital. the algorithmic approach offered here serves to simplify and unite the assessment and treatment of psychosis in the hiv-positive patient at all levels of health care. conclusion commencement and choice of arv drugs following comprehensive work-up and remission of psychotic symptoms 26 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e o cto b e r 2 0 0 9 references 1. mcdaniel sj, purcell dw, farber ew. severe mental illness and hiv related medical and neuropsychiatric sequelae. clin psychol rev 1997; 17(3): 311-325. 2. ambrosino wa, bruno b, ying p, et al. the hiv infected patient. in: ambrosino wa, wyszynski b, eds. manual of psychiatric care for the medically ill. washington, dc: american psychiatric press, 2005. 3. gomez mf, o’dowd ma. psychiatric assessment. in: fernandez f, ruiz p, eds. psychiatric aspects of hiv/aids. philadelphia: lippincott williams & wilkins, 2006: 39-47. 4. horwath e, cournos f. psychotic disorders. in: fernandez f, ruiz p, eds. psychiatric aspects of hiv/aids. philadelphia: lippincott williams & wilkins, 2006: 119-126. 5. walkup j, satriano j, barry d, sadler p, cournos f. hiv testing policy and serious mental illness. am j public health 2002; 92(12): 1931-1939. 6. dolder cr, patterson tl, jeste dv. hiv, psychosis and aging: past present and future. aids 2004; 18: suppl 1, s35-s42. 7. work group on hiv/aids, american psychiatric association. practice guideline for the treatment of patients with hiv/aids. am j psychiatry 2000; 157: 1-62. 8. nakimuli-mpungu e, musisi s, mpungu sk, katabira e. primary mania versus hiv related secondary mania in uganda. am j psychiatry 2006; 163: 1349-1354. 9. dube b, benton t, cruess dg, evans dl. neuropsychiatric manifestations of hiv infection and aids. j psychiatry neurosci 2005; 30(4): 237-246. 10. american psychiatric association. diagnostic and statistical manual of mental disorders. 4th ed., text revision. washington, dc: american psychiatric association, 2000. 11. bailer p, wallack j, prenzlauer s, bogdonoff l, wilets i. psychiatric comorbidity among hospitalized aids patients vs non aids patients referred for psychiatric consultation. psychosomatics 1996; 37: 469-475. 12. chander g, himeloch s, moore rd. substance abuse and psychiatric disorders in hiv positive patients: epidemiology and impact on antiretroviral therapy. drugs 2006; 66(6): 769-789. 13. anthony ic, bell je. the neuropathology of hiv/aids. int rev psychiatry 2008; 20(1): 15-24. 14. arnsten jh, demas pa, grant rw, et al. impact of active drug use on antiretroviral therapy adherence and viral suppression in hiv infected drug users. j gen intern med 2002; 17: 377-381. 15. arendt g, de nocker d, von giesen hj, nolting t. neuropsychiatric side effects of efavirenz therapy. expert opin drug saf 2007; 6(2): 147-154. 16. perantie dc, brown es. corticosteroids, immune suppression and psychosis. curr psychiatry rep 2002; 4(3): 171-176. 17. vega p, sweetland a, acha j, et al. psychiatric issues in the management of patients with multidrug-resistant tuberculosis. int j tuberc lung dis 2004; 8(6): 749-759. 18. singh d, goodkin k. choice of antipsychotic in hiv infected patients. j clin psychiatry 2007; 68(3): 479-480. 19. singh d, goodkin k. psychopharmacologic treatment response of hiv infected patients to antipsychotic medications. j clin psychiatry 2007; 68(4): 631-632. 20. penzak sr, hon yy, lawhorn wd, shirley kl, spratlin v, jann mw. influence of ritonavir on olanzapine pharmacokinetics in healthy volunteers. j clin psychopharmacol 2002; 22(4): 366-370. 21. ferrando sj, wapenyi k. psychopharmacological treatment of patients with hiv and aids. psychiatr q 2002; 73(1): 33-49. 22. national department of health. national antiretroviral treatment guidelines. 2004. http://www.st.org.za/uploads/files/sa_art_guidelines1.pdf (accessed 23 february 2009). 27 from the editor.html from the editor this issue of the journal continues discussions started in the december 2011 issue. professor kuhn responds to the concerns raised by salojee about the national policy promoting breastfeeding in hiv-exposed infants; she discusses the scientific rationale for the policy revisions, and presents a population perspective rooted in overall child morbidity and mortality. for better or worse, infant feeding is likely to remain an important topic for years to come. both viewpoints need careful consideration, and subsequent discussions in these pages hopefully can be informed by experiences from implementing the new infant feeding policies in different settings around the country. another matter is low-dose stavudine in hiv management. in the last journal, innes et al. presented a rationale for a trial investigating low-dose stavudine’s impact on therapeutic and toxicity endpoints. given increasingly scarce resources for art in much of sub-saharan africa, this proposal has intuitive appeal. we now publish a strong response by andrieux-meyer et al., who argue that further research into stavudine's use is untenable – with a clear rebuttal from venter et al. there are important nuances – the use of stavudine in adults v. children; follow-up duration of a trial investigating long-term outcomes; and the changing costs of tenofovir and other more expensive medications – that evade oversimplified judgments. more generally, these two ongoing debates raise important questions about what we know and how well we know it. although we aim to practice ‘evidence-based medicine’, the evidence base for many policies and decisions may be surprisingly thin and malleable. the same body of evidence can lead to opposing interpretations, as seen in the debates on infant feeding and low-dose stavudine. the challenge and talent of skilled clinicians and good policymakers is to make sensible decisions in the face of flawed evidence. fundamental to this is perceiving the likelihood of misjudging – and in turn the ability to acknowledge opposing viewpoints and the importance of continually trying to improve the evidence base on which our decisions are based. these challenges re-emerge constantly, and again in this issue of the journal. they have been entwined in the theory and practice of medicine for millennia, as recorded in one of hippocrates’ aphorisms on the art of medicine, from around 400 bc: ‘life is short; the art is long; opportunity fleeting; experiment fallible; judgment difficult.’ the journal presents other exciting pieces, including an important critique on the role of efavirenz in pregnancy from pillay and black, where clinical judgment has greatly outpaced policymaking. johnson presents a model-based analysis of art initiation across the country, and suggests that the scope of the art roll-out approaches the targets set by the nsp for 2007 2011. this is a major accomplishment that underscores the ability of the public health system to achieve ambitious goals, given adequate capacity and resources. in addition, an opinion piece by kenyon and colleagues calls into question the widely held belief that poverty alone drives the sexual transmission of hiv across south africa (a contentious assertion that may give rise to more debate), and katusiime presents an interesting case study on chronic genital ulcer disease in the context of hiv infection. good reading! landon myer school of public health & family medicine university of cape town landon.myer@uct.ac.za the southern african journal of hiv medicine                                                        summer 2009   27 it has become apparent that hiv mortality immediately before initiation of art accounts for the majority of the deaths that occur in the peri-art initiation period. the rate of hospitalisation during this period is also high. while the reasons for this situation are complex, at least some of the morbidity and mortality relates to delayed initiation owing to a lack of urgency in staging, referral, counselling and the clinical process of art initiation. anecdotal reports of sites with waiting lists of several months for art appointments, sites insisting on in-person appointments, delays in staging cd4 counts and difficulty in contacting art sites, along with unnecessarily protracted counselling, have all been reported to the south african national aids council (sanac) treatment care and support technical task team. there have even been reports that at several sites (largely hospital sites) the switchboard does not know whether an hiv or art site exists there, despite the site being fully functional. adequate allocated resources are available through the department of health for the hiv programme, including the provision of timely art. no deserving patient should have to experience unreasonable delays for appointments or art initiation. the consequence of these delays is delayed initiation of art with unnecessary mortality and morbidity, and patient frustration at difficult referral procedures, with subsequent loss to follow-up. the delays are often due to a lack of insight into the urgency of initiation of art. the resulting increased hospitalisation is unnecessary and a massive drain on hospital resources. criteria for expedited antiretroviral initiation and emergency triage guidelines few medical interventions for any illness arrest morbidity and mortality as effectively as antiretroviral therapy (art) does for hiv. delays result in rapid progression to illness and death. the guidelines below list the patients who qualify for urgent art, with timeline expectations. in addition, those who do not qualify for ‘urgent’ art must receive as rapid an assessment as is possible. letter to health care colleagues subject: urgent – expedited arv initiation guidelines for south african state hiv clinics this is the latest version of the expedited antiretroviral initiation guidelines. these have been extensively discussed by the treatment task team of the programme implementation committee of the south african national aids council (sanac). this task team has endorsed the content of the guidelines. the guidelines are now national department of health policy. we recommend that the guidelines are urgently adopted, since we have multiple reports of delays in art initiation throughout the country, as well as the recent suspension of the arv initiation programme in the free state. recent local research from the universities of cape town and and kwazulu-natal has emphasised the urgency of initiation of art in patients with low cd4 counts, those who are very ill and those with tuberculosis. sanac is aware of the serious problems recently experienced with the maintenance of arv supplies in the free state and the provincial and national departments of health are urgently trying to rectify this situation in partnership with sanac’s civil society members. should you experience problems with drug supplies please refer these to line managers or to the hiv directorates in the provincial or national doh. the establishment of a hotline for these reports is currently under discussion and we will inform you once a decision on this has been taken. we encourage private practitioners who experience problems with referrals, or any other health care worker who feels that hiv services are not being adequately provided, to contact the provincial or national doh with these reports, which will be urgently investigated. thank you for your ongoing efforts to provide these critically important services for our hiv-infected patients. kind regards, dr ashraf coovadia and dr françois venter, sanac treatment task team professor helen rees, sanac pic co-chairperson guidelines.indd 27 3/16/09 2:13:00 pm summer 2009                                                          the southern african journal of hiv medicine                                                  28 cd4 staging n no patient should wait longer than a month for a cd4 count result, from the time blood is taken to the time of clinical assessment and staging and appropriate referral. n hospitalised patients and those with tuberculosis (tb) should have this assessment within 1 week of blood being taken. art referral and initiation the following patients should not experience a delay in referral to an art site of more than a week, and must receive their first adherence counselling session immediately upon their first arrival at the clinic. in general, art should be started within a week of entry to the art site, unless there are compelling concerns regarding adherence, or an immediate opportunistic infection requires treatment first. in general, any delay should be an exception. in other words, the interval between referral and art initiation should never be longer than 2 weeks, unless adherence is considered to be a serious problem. all patients who fulfil the criteria below, who present on site for the first time, should be seen immediately, even without an appointment. while the patient is in the clinic, take the opportunity to do the first adherence counselling session and to take blood for necessary laboratory tests. adults: n all adults with a cd4 count <100 cells/µl n all adults with unexplained (after investigation) ongoing loss of weight n all pregnant women qualifying for art n all adults recently hospitalised with an hiv-linked condition (including tb). children: n all children under 2 years of age n any child over 2 years with a cd4 percentage <15% or a cd4 count <100 cells/µl n all children with unexplained (after investigation) ongoing loss of weight n all children recently hospitalised with an hiv-linked condition (including tb). adherence assessment must be rapid and geared towards addressing any specific issues the individual patient may have. in certain situations, art initiation can be done in an inpatient setting. this is especially appropriate where the art site is hospital based, and hospitalisation is protracted (e.g. a patient started on 2 weeks of amphotericin b for cryptococcal meningitis can be counselled on adherence during hospitalisation, initiated on art on discharge, and brought back to the clinic directly). process if the above conditions are not being met the local clinic manager has responsibility for ensuring expedited staging, referral and initiation in sites, including that the switchboard is aware of the clinic’s referral processes. all clinic personnel should be trained on which patients require expedited care. if the clinic is not able to function as above, the district manager must investigate and develop an emergency plan to address the situation. patients should be empowered to know what they can expect from the site, and to make the managers aware if they are experiencing obstruction from clinic personnel. for both adults and children who do not fulfil these criteria but qualify for art, the waiting time should not be longer than a month. guidelines.indd 28 3/16/09 2:13:03 pm c p d q u e s t io n n a ir e a maximum of 3 ceus will be awarded per correctly completed test. cpd questionnaires must be completed online at www.mpconsulting.co.za. after submission, you can check the answers and print your certificate. this programme is available free of charge to members of the sa hiv clinicians society and sama only. instructions 1. read the journal. all the answers will be found there. 2. go to www.mpconsulting.co.za to answer the questions. accreditation number: mdb001/012/01/2014 (clinical) cpd questionnaire december 2014 vol. 15, no. 4 160 december 2014, vol. 15, no. 4 sajhivmed 1. currently, there are six classes of antiretroviral agents available in south africa. 2. integrase inhibitors prevent the assembly and maturation of infectious viral progeny. 3. there is definitive evidence that patients with cd4+ >500 cells/ul should initiate antiretroviral therapy (art) for their own health. 4. in patients with tuberculosis, art initiation may be delayed by up to 8 weeks to reduce the risk of immune reconstitution inflammatory syndrome (iris). 5. in patients with cryptococcal meningitis, art initiation should not be delayed by more than 2 weeks after initiation of antifungal therapy, to reduce the risk of mortality. 6. in an otherwise stable patient on efavirenz 600 mg once a day who has significant non-reversing central nervous system side-effects, dose reduction to 400 mg once a day may be a viable strategy to maintain viral suppression while reducing side-effects. 7. any detectable viral load (e.g. above 50 copies/ml) is significant and requires interventions to improve adherence. 8. in stable patients with suppressed viral loads and cd4+ >200 cells/ul, it may be possible to stop cd4+ monitoring as it adds little to clinical management. 9. in patients who are seroconverting (newly infected with hiv), immediate art initiation may be associated with improved viral control and long-term health outcomes. 10. if hiv diagnosis is made using rapid tests outside of the laboratory, confirmation of hiv infection using a laboratory-based test (viral load or enzyme-linked immunosorbent assay (elisa)) is advised before art initiation to rule out false positive rapid-test results. 11. atazanavir may be preferred to lopinavir as the protease inhibitor of choice because it has a lower gastrointestinal and blood lipid side-effect profile, and does not require boosting with ritonavir. 12. in a patient who reinitiates art after stopping therapy, the first viral load testing should ideally take place 6 12 months after reinitiation. 13. for patients with liver impairment, a regimen of tenofovir, lamivudine (or emtracitibine) and raltegravir is considered the least hepatotoxic. 14. there are few drug-drug interactions between antiretrovirals and antimalarial drugs. 15. surgeons’ use of two surgical gloves (‘double-gloving’) is unlikely to be useful in preventing exposure to blood-borne pathogens. 16. surgeons may be least likely to experience intraoperative glove puncture when the patient is known to be hivpositive. 17. talaromyces marneffei is a common aids-defining opportunistic infection in south-east asia and central africa, which may resemble disseminated tuberculosis, and which is sensitive to fluconazole. 18. deep fungal infections in hiv-infected patients commonly present with fever, weight loss, skin papules with central necrosis, respiratory involvement, lymphadenopathy and hepatosplenomegaly. 19. while possible to down-refer hiv-infected children on art from tertiary or secondary hospitals to primary healthcare facilities, their outcomes are generally not as good as those of children kept in hospital-based, specialist paediatrician care. 20. for children initiating art, mortality is lower in infants compared with older children. true or false: 84 sajhivmed june 2012, vol. 13, no. 2 c p d q u es t io n n a ir e two cpd points are awarded for the correct completion and submission of the questions below. cpd questionnaires must be completed online via www.cpdjournals.co.za. after submission, you can check the answers and print your certificate. this programme is available free of charge to members of the hiv clinicians society and sama only. true (a) or false (b) – click on the correct answer: regarding levels of soluble inflammatory markers in hiv infection 1. the kidneys are the major source of increased levels of procalcitonin during acute infection. 2. levels of c-reactive protein may be used to distinguish bacterial from viral infections. 3. neopterin is produced by macrophages and is a marker of cell-mediated immunity. 4. levels of neopterin may be lower in individuals with untreated hiv infection, compared with individuals on antiretroviral therapy. regarding reliability of cd4 cell count enumeration 5. cd4 cell counts vary naturally according to the time of day (diurnal variation) and by the site of phlebotomy. 6. the time delay between phlebotomy and laboratory testing can influence cd4 cell count results, and the world health organization recommends conducting tests within 72 hours of specimen collection. 7. data from swaziland show that there is variability in cd4 count results within and between laboratories; this variability may lead to incorrect decisions to initiate antiretroviral therapy in up to 20% of patients. regarding tumour necrosis factor-alpha 8. high levels of tnf-alpha may help to reduce hiv viral replication. 9. tnf-alpha levels may be increased in individuals with particular genetic variations, such as -308 tnf-alpha polymorphisms. 10. there is clear evidence that -308 tnf-alpha polymorphisms occur more commonly in hiv-infected individuals than uninfected individuals. regarding cytomegalovirus (cmv) retinitis 11. intravitrial gancyclovir injections are the gold-standard for managing cmv retinitis. 12. with management through gancyclovir injections and antiretroviral therapy, the vast majority of patients with visual loss due to cmv-retinitis will regain normal visual function. 13. cmv disease in the retina occurs early in the course of hiv disease, and the incidence of cmv-retinitis is not affected by use of antiretroviral therapy. regarding pneumocystis pneumonia 14. patients with pneumocystis pneumonia who require mechanical ventilation have a high risk of mortality. 15. lung fibrosis may help to explain the poor prognosis of patients with pneumocystis pneumonia who require ventilation. 16. pneumocystic jirovecii is universally sensitive to trimethoprim-sulfamethoxazole, and antibiotic resistance is unknown. regarding anaemia in the context of hiv infection 17. bone marrow infiltration from aids-related conditions is common in advanced, untreated hiv; this may be evidenced by a pancytopaenia, or an anaemia with minimal reticulocyte production. regarding pre-exposure prophylaxis to prevent hiv infection 18. use of tenofovir or truvada for prep requires monitoring of renal function and annual bone mineral density scanning in all individuals (e.g. dexa). 19. real-world adherence to prep regimens is a critical determinant of their effectiveness in preventing hiv infection, and ongoing adherence counseling is required. 20. careful consideration needs to be given to drug-drug interactions in prep, as tenofovir may interact with cimetidine, metformin and some aminoglycosides. cpd questionnaire vol. 13, no. 2 c p d q u e s t io n n a ir e instructions 1. read the journal. all the answers will be found there. 2. go to www.mpconsulting.co.za to answer the questions. accreditation number: mdb001/012/01/2014 (clinical) cpd questionnaire vol. 15, no. 2 a maximum of 3 ceus will be awarded per correctly completed test. effective in 2014, the cpd programme for sajhivmed will be administered by medical practice consulting: cpd questionnaires must be completed online at www.mpconsulting.co.za. after submission, you can check the answers and print your certificate. this programme is available free of charge to members of the sa hiv clinicians society and sama only. true or false: regarding consent of minors to health research: 1. usually, health research involving children only requires parental consent for children <12 years of age. 2. new national health legislation calls for written parental consent for all minors before participating in hiv-related health research, thus making research into marginalised groups or illegal behaviours unusually difficult. regarding cerebrospinal fluid (csf) findings in patients with meningitis: 3. cryptococcal meningitis accounts for more than half of premature mortality in hiv-infected individuals. 4. confusion on initial presentation may be a significant predictor of an abnormal csf analysis result. 5. coagulopathies are uncommon in hiv-infected individuals, thus checking platelets and international normalised ratio before lumbar puncture is not usually recommended. regarding antiretroviral therapy (art) use in pregnancy: 6. the integration of art services into antenatal care will always decrease the time to art initiation during pregnancy, and increase the proportion of pregnant women initiated on art. 7. the greatest risk of mother-to-child transmission is in hiv-infected women with low cd4+ counts, who are eligible for lifelong art. 8. the updated prevention of mother-to-child transmission (pmtct) guidelines recommend starting all hiv-infected pregnant women on a triple-drug antiretroviral regimen at their first antenatal visit. regarding shedding of hiv in the female genital tract: 9. ability to detect hiv in genital secretions is associated with higher plasma hiv viral loads. 10. women on art for extended periods of time are likely to have lower plasma viral loads but higher viral loads in genital tract secretions. regarding stevens-johnson syndrome: 11. stevens-johnson syndrome (sjs) is different from toxic epidermal necrolysis (ten) mainly in that sjs covers more body surface area than ten. 12. an immunological response involving cd8+ t lymphocytes is the most likely explanation for the pathogenesis of sjs/ten. 13. sulphonamides and nevirapine are the drugs most commonly implicated in the comorbidity of sjs/ten and hiv in sub-saharan africa. regarding needlestick injuries among hospitalised patients: 14. more than 10% of patients suffer some form of harm during hospital care. 15. needlestick injury between patients is a well-documented form of iatrogenic injury. 16. health systems factors, such as overcrowding, are important preventable risk factors for needlestick injuries. regarding optic neuropathy in hiv: 17. among antituberculous agents, rifampicin is most widely known to cause optic neuropathies. 18. optic neuropathy in hiv-infected patients usually results from hereditary conditions that are exacerbated by antiretroviral drugs. 19. leber’s hereditary optic neuropathy (lhon) can be triggered by nucleoside reverse transcriptase inhibitors in hiv-infected patients who harbour the lhon mutations. 20. individuals with the mutation for lhon display a number of preceding symptoms that culminate in visual loss. 19064 mylan hiv a4ad rf.indd 1 2013/04/29 3:21 pm 72 sajhivmed june 2014, vol. 15, no. 2 http://www.mpconsulting.co.za http://www.mpconsulting.co.za c p d q u e s t i o n s journal 37 two cpd points are awarded for the correct completion and submission of the questions below. cpd questionnaires must be completed online via www.cpdjournals.org.za. after submission you can check the answers and print your certificate. questions may be answered up to 6 months after publication of each issue. this programme is available free of charge to members of the hiv clinicians society and sama only. 1. true (a) or false (b) – click on the correct answer: art will be offered to adult patients with a cd4 count <200 cells/µl and an aids-defining illness. 2. true (a) or false (b) – click on the correct answer: art will be offered only to adult patients with tuberculosis and cd4 <350 cells/µl. 3. true (a) or false (b) – click on the correct answer: adult patients with multidrug-resistant tuberculosis are excluded from art due to drug-drug interactions. 4. true (a) or false (b) – click on the correct answer: children diagnosed with cryptococcal meningitis between the ages of 5 and 15 will be considered for art when the cd4 count is below 350 cells/µl. 5. true (a) or false (b) – click on the correct answer: children diagnosed with tb between the ages of 5 and 15 will be considered for art when the cd4 count is below 350 cells/µl. 6. true (a) or false (b) – click on the correct answer: art should be deferred in infants <12 months who have a cd4 percentage above 25. 7. true (a) or false (b) – click on the correct answer: d4t toxicity occurs most frequently in patients who have a high body mass index and are younger, male and/or on tb treatment. 8. true (a) or false (b) – click on the correct answer: older men with lipodystrophy, reduced creatinine clearance and low bmi should preferentially receive tenofovir. 9. true (a) or false (b) – click on the correct answer: pregnant women who do not need art for their own health should commence azt from the first month of pregnancy. 10. true (a) or false (b) – click on the correct answer: pregnant women who are commencing art for their own health may do so with efv or nvp from the time of booking. 11. true (a) or false (b) – click on the correct answer: ganciclovir can be given intra-ocularly instead of intravenous and oral therapy to treat cytomegalovirus retinitis. 12. true (a) or false (b) – click on the correct answer: ganciclovir should be used cautiously with azt since it has similar bone marrow toxicities. 13. true (a) or false (b) – click on the correct answer: intravenous ganciclovir in pregnancy can reduce congenital abnormalities in hiv co-infected women. 14. true (a) or false (b) – click on the correct answer: cmv is a cause of transverse myelitis in hiv-infected patients. 15. true (a) or false (b) – click on the correct answer: in order to perform hiv testing, the provider must have signed written consent or he or she will be liable. 16. true (a) or false (b) – click on the correct answer: feelings of hopelessness falsely predict suicide. 17. true (a) or false (b) – click on the correct answer: depression in individuals with hiv/aids has not been found to affect adherence to medication regimens. 18. true (a) or false (b) – click on the correct answer: valganciclovir can be used in the oral form to initiate and maintain cmv treatment in hiv cmv retinitis. 19. true (a) or false (b) – click on the correct answer: hiv has been shown unequivocally to be a disease of poverty. 20. true (a) or false (b) – click on the correct answer: there is no evidence that multiple concurrent partners are linked to higher rates of sexually transmitted infections. c p d q u e s t i o n s journal 43 two cpd points are awarded for the correct completion and submission of the questions below. cpd questionnaires must be completed online via www.cpdjournals.co.za. after submission you can check the answers and print your certificate. questions may be answered up to 6 months after publication of each issue. this programme is available free of charge to members of the hiv clinicians society and sama only. regarding chronic genital ulcer disease in hiv-infected individuals 1. true (a) or false (b) – click on the correct answer: chronic genital ulcer disease in hiv-infected individuals is only observed at low cd4 cell counts and resolves after aetiological treatment with the use of antiretroviral therapy. 2. true (a) or false (b) – click on the correct answer: mrsa superinfection is a common complication of chronic genital ulcer disease in hiv-infected men. regarding the use of efavirenz during pregnancy 3. click on the correct answer: the current labelling of efavirenz in pregnancy is: a: controlled studies show no risk b: no evidence of risk in humans c: risk in pregnancy can not be ruled out d: evidence of risk in pregnancy x: contra-indicated in pregnancy 4. true (a) or false (b) – click on the correct answer: there is substantial evidence from clinical research that efv is associated with birth defects in humans. 5. true (a) or false (b) – click on the correct answer: data from the antiretroviral pregnancy register demonstrate that efavirenz is associated with a higher rate of birth defects than both azt and 3tc. 6. true (a) or false (b) – click on the correct answer: data show that among nnrtis, efavirenz is associated with equal or greater levels of long-term viral suppression than nevirapine. 7. true (a) or false (b) – click on the correct answer: women with high cd4 cell counts using nevirapine are at an increased risk of hepatotoxicities, and therefore nevirapine may not be an ideal choice of nnrti for a strategy for universal art use in pregnancy (e.g. ‘test and treat’). 8. true (a) or false (b) – click on the correct answer: nevirapine is more expensive than efavirenz. regarding the coverage of antiretroviral therapy across south africa 9. true (a) or false (b) – click on the correct answer: calculating the number of patients on art in south africa is a simple addition because of consistently high quality health statistics reported uniformly by all art services. 10. true (a) or false (b) – click on the correct answer: by the middle of 2011, more than 1.5 million south africans had been started on art. 11. true (a) or false (b) – click on the correct answer: the proportion of art-eligible men who are receiving art is higher than the proportion of eligible women receiving art. 12. true (a) or false (b) – click on the correct answer: the numbers of individuals starting art nationwide fell far short of the targets set by the 2007-2011 national strategic plan. regarding socioeconomic v. cultural explanations for the spread of hiv in south africa 13. true (a) or false (b) – click on the correct answer: concurrent partnerships are likely to play a role in understanding the spread of hiv infection at a population level. regarding the impact of breastfeeding by hiv-infected mothers on the health of exposed infants 14. true (a) or false (b) – click on the correct answer: antiretroviral drug interventions such as nevirapine prophylaxis for infants, and/or maternal use of multi-drug arv regimens, can be used during breastfeeding to reduce the risk of transmission. 15. at a population level, the benefits of formula feeding (related to prevention of hiv infection) are likely to outweigh the risks (in other sources of morbidity and mortality) only in countries where the infant mortality rate is less than 10 per 1 000. regarding the use of stavudine 16. true (a) or false (b) – click on the correct answer: both stavudine and tenofovir can lead to thymidine analogue mutations (tams). 17. although lipo-atrophy occurs with stavudine, it is highly reversible after stopping stavudine use. 18. neuropathy is a complication of stavudine use that may be more likely in patients receiving tb co-treatment. 19. most toxicities associated with stavudine use take place in the first year on therapy. 20. most toxicities associated with stavudine use appear to be dose-dependent. o cto b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e there has been considerable interest in the neuropsychological complications of hiv/aids in the last two decades.1,2 a range of hiv-related cognitive complications has been reported to include poor performance on tests of attention and concentration, movement and coordination, reaction time and mental flexibility.1,3,4 these hiv-associated neurocognitive deficits (hand) manifest in their mild form as minor cognitive motor disorder (mcmd) and grossly as hiv-associated dementia (had). the annual incidence of had is 7% after development of aids5 and it occurs in 20% of all hiv-infected persons,6 although prevalence rates in sub-saharan africa are higher, ranging between 16% and 54%.7-9 with an hiv prevalence of 5.8% among adults there are more than 3 million people living with hiv/aids (plwha) in nigeria, more than in any other country in the world with the exception of south africa and india.10-12 hiv-associated cognitive impairment may be a factor contributing to poor medication adherence in sub-saharan africa. with the increasing burden of disease there is clearly a need for a simple tool for rapid screening of cognitive functioning in hiv-infected persons. efforts to develop appropriate screening techniques include the hiv dementia scale (hds),13 a brief measure that has shown promise but lacks extensive independent evaluation. the hds (especially the modified and international versions, which exclude a difficult-to-administer antisaccadic task) has been shown to be simpler to administer than most cognitive tests used in hiv patients and may be useful for screening of cognitive dysfunction in clinics with no neurologist or neuropsychologist on the staff, as it does not require special training.13,14 this attribute makes it appealing in the african setting, where it is likely to be applied by primary care providers because of the dearth of neuropsychologists in health care facilities. the present study examines the usefulness of the modified hds in screening for cognitive deficits in a sample of hiv-positive adults in nigeria. dementia was diagnosed according to the universally accepted criteria in the diagnostic and statistical manual for mental diseases, 4th edition (dsm-iv-tr).15 usefulness of the hiv dementia scale in nigerian patients with hiv/aids o r i g i n a l a r t i c l e olubunmi a ogunrin, bsc, mb chb, fwacp emeka u eze, mb bs, fwacp francis alika, mb bs department of medicine, university of benin teaching hospital, benin city, nigeria objective. information on the cognitive complications of hiv/aids from sub-saharan africa, where statistics on hiv are alarming, is sparse because of lack of validated cognitive tools. this study assessed the usefulness and predictive validity of the hiv dementia scale (hds) as a screening tool in hiv-positive nigerians. design. hiv-positive patients were randomly selected over a period of 2 months. setting. the hiv/aids outpatient clinic at the university of benin teaching hospital, benin city, nigeria. subjects. asymptomatic and symptomatic hiv-positive patients were compared with controls matched with regard to age, gender and level of education. outcome measures. cognitive performances on the modified hds. results. performances on the hds of 160 hiv-positive subjects (80 asymptomatic and 80 symptomatic) were compared with those of 80 hiv-negative controls. the mean hds scores (maximum 12) were 10.78 (significant deviation (sd) 1.18) (hiv-negative subjects), 8.85 (sd 1.38) (hiv, asymptomatic) and 5.2 (sd 1.13) (hiv, symptomatic); p<0.01. the hds was found to have sensitivity of 97.3%, specificity of 80.4%, accuracy of 91.9% and a positive predictive value of 91.4% and a negative predictive value of 93.2%. conclusion. the hds was shown to be a sensitive screening tool for patients with hiv/aids in sub-saharan africa, but it was insensitive to memory impairment in asymptomatic hiv-positive patients. 38 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e o cto b e r 2 0 0 9 a total of 160 antiretroviral therapy-naïve subjects with positive enzyme-linked immunosorbent assays for hiv were randomly selected (using a table of random numbers) from the hiv/aids clinic at the university of benin teaching hospital, benin city, nigeria, between may and june 2006. demographic data were obtained and the hds was used to assess the patients’ cognitive status after a detailed physical examination, including a comprehensive neuropsychiatric evaluation. the hiv-positive subjects were compared with 80 healthy seronegative subjects selected randomly from hospital staff and undergraduate students. informed consent was obtained from the patients and the controls. the patients and the controls were matched with regard to age, gender and level of education. the hiv-positive patients were categorised into two groups, asymptomatic and symptomatic, on the basis of their cd4+ t-lymphocyte counts (< 200 cells/μl for symptomatic) and the presence of hiv/aids-defining symptoms (unexplained fever – core body temperature >37.2oc – for more than 4 weeks, diarrhoea for more than 4 weeks, unexplained weight loss of >10% of previous body weight, and a generalised papular rash). we did not determine hiv clades (i.e. genetic subtypes of hiv groups) owing to lack of facilities, but some earlier studies have shown that the pattern of cognitive impairments may be affected by different clades in sub-saharan africa.16,17 clinical neuropsychological evaluation including the identification of diagnostic features of dementia based on the dsm-iv-tr was conducted on all patients by a single neurologist (oao) who was blind to the hds rating. deterioration in daily functioning was determined from information provided by family members living with the patients. they were questioned on the presence of the following cognitive symptoms: (i) memory disturbances (forgetfulness of new events, difficulty finding words or not knowing common facts) affecting daily activities; (ii) inability to cope with employment, academic demands and social activities that the patient could cope with before the onset of the illness; and (iii) deterioration in day-to-day functioning (i.e. difficulty in driving, shopping, handling money and self-care). patients without functional deterioration, i.e. cognitive disturbances sufficient to interfere with day-to-day functioning, were not considered to have dementia. exclusion criteria included age under 18 years, already being on antiretroviral therapy, co-morbidity (diabetes mellitus, hypertension, epilepsy, hepatitis, intracranial disorders such as brain tumour, and other metabolic diseases), an inconclusive diagnosis, a major axis i psychiatric illness, a history of substance abuse, presence of clinical signs of cardiac failure, alcohol intake above 120 g per week or 13 units per week, a history of previous head injury with loss of consciousness, and anticholinergic medications. measures the hds was developed as a rapid screening test to assess for had.13 it is a paper-and-pencil neuropsychological instrument with objective subtests measuring psychomotor processing speed, verbal memory, constructional ability and executive function (response inhibition, set shifting) (fig. 1). the score is based on performance for each subtest. this scale also exists in a modified form (eliminating the anti-saccadic subtest, which is often difficult to administer), and both the earlier and the modified versions have been validated for determining the presence and severity of had.12 the modified version was used in this study. the modified scale has a maximum score of 12, i.e. psychomotor speed score of 6, verbal memory recall score of 4, and construction task score of 2. details are outlined in fig. 1. for the psychomotor speed and construction task, the subject is timed using a stopwatch and the appropriate score given as indicated in fig. 1. the modified hds was administered by one of the authors (ee), who had no prior knowledge of the functional status categorisation using the dsm-iv-tr. statistical analyses statistical analysis was done using epi info 2000 software (centers for diseases control and prevention, atlanta, ga). the age, gender and level of education of the three groups were analysed for significant differences using the chi-square test. the means of the performances of the hiv-positive patients were compared with those of the controls using the two-way analysis of variance. an f-test was used to determine the trend of linearity between cognitive performances and cd4+ levels. the level of significance was p<0.05. a receiver operating curve (roc) was used to determine the cutoff score for hds. the strength of association between cognitive disturbance and hiv seropositivity was determined with mantel-haenszel matched analysis and expressed as a likelihood ratio with 95% confidence interval (ci). the predictive value model using the 2×2 contingency table yielded the sensitivity, specificity and predictive values. the demographic data for the subjects are set out in table i. the majority were in the 21 40-year age range. clinical characteristics of the hiv-positive symptomatic subjects are set out in table ii. mean (sd) cd4+ tlymphocyte counts for the controls, the asymptomatic hiv-positive patients and the symptomatic hiv-positive patients were 668 (sd 8.6), 286 (sd 7.4) and 102 (sd 10.8) cells/μl, respectively (p<0.01). mean (sd) total patients and methods results 39 o cto b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e hds scores (maximum 12) for the controls, asymptomatic hiv-positive patients and symptomatic hiv-seropositive patients were 10.78 (sd 1.18), 8.85 (sd 1.38) and 5.2 (sd 1.13), respectively (f=522.28, p<0.001). details of the performances for the three categories are set out in table iii. there was a significant difference between the total scores for the normal subjects and the hiv-positive patients, irrespective of whether the patients were symptomatic or not. the asymptomatic hiv-positive patients performed better than the symptomatic patients (t=20.13, p<0.001). comparison of the memory scores did not reveal a significant difference between the performances of the controls and the asymptomatic hiv-positive patients, but the performance of the symptomatic hiv-positive patients was significantly poorer (p<0.05). the psychomotor speed of the hiv-positive subjects was significantly prolonged compared with the controls (p<0.001) but the time taken to perform the construction task did not differ significantly between the controls and the asymptomatic seropositive patients (p>0.05), although the construction task was performed poorly by the asymptomatic hiv-positive group (table iii). deterioration in the performance of the hivseropositive subjects as cd4+ t-lymphocyte counts decreased was observed. the f-test for linear trend showed this observation to be significant (p<0.05), as outlined in table iv. a cut-off score of 9, obtained by roc analysis, was used to determine the sensitivity, specificity and predictive values of the hds. the hds total scores were below the cut-off score of 9 in 109 hiv-seropositive patients (68.1%), but 41 (25.6%) of the patients had no features of functional deterioration and their hds total scores were above 9. the total hds scores were normal (i.e. above the cut-off score of 9) in 10 patients with functional deterioration, while 4 patients had no functional deterioration but had abnormal total hds scores (table v). this implies false-positive and false-negative rates of 8.6% and 6.8%, respectively. the likelihood ratio for cognitive disturbance in hiv-positive patients based on modified hds scores in the presence of functional deterioration was 41 (95% ci 13 138). this implies that patients with clinical evidence of dementia based on cognitive symptoms sufficient to interfere with functional abilities are approximately 40 times more likely to have a score of <9 on the modified hds. the sensitivity of the modified hds was 97%, the specificity was 80%, the positive predictive value was 91% and the negative predictive value was 93% (overall accuracy, 92%). 0 fig. 1. modified hiv dementia scale maximum score subject’s score test memory – registration give 4 words to recall and 1 second to say each. then ask the patient all 4 after you have said them. 6 psychomotor speed ask patient to write the alphabet in uppercase letters horizontally across the page (use back of questionnaire) and record time …… seconds. ≤21sec = 6; 21.1 – 24 sec = 5; 24.1 – 27 sec = 4; 27.1 – 30 sec = 3; 30.1 – 33 sec = 2; 33.1 36 = 1; >36 sec = 0 4 memory – recall ask for the 4 words from memory – registration test above. give 1 point for each correct word. for words not recalled, prompt with a semantic clue. give half a point for each correct word after prompting. 2 construction copy the cube below; record time …… seconds <25 sec = 2; 25 – 35 sec = 1; >35 sec = 0 fig. 1. modified hiv dementia scale. 40 28 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e o cto b e r 2 0 0 9 the epidemiology of hiv-associated cognitive impairment in africa is poorly understood. vaguely defined criteria for cognitive impairment and assessment tools that are inadequate and lack validation, coupled with absence of normative population data, have limited proper study of cognitive impairment in hiv-positive populations in these settings. although the clinical presentation of dementia may vary, depending on the causation, the diagnostic features are constant as set out in the dsm-iv-tr. the performance of an individual in the cognitive subtests may therefore reflect the degree of interference with performing similar tasks in daily life, although this is not invariable, as a poor cognitive score does not always infer functional incapacity. by comparing the performances of hiv-positive patients with controls, we assessed the differences in their abilities in these cognitive domains. this study showed the usefulness and predictive validity of the modified hds as a screening cognitive tool in nigerian patients. the findings applied to subjects who met the dsm-iv diagnostic criteria for dementia and were also reported by family members to display functional deterioration in performance of daily activities. the modified hds revealed deficits in all the tested cognitive domains in the symptomatic hiv-positive patients. although the modified hds showed impairment in cognitive abilities of the asymptomatic hiv-positive patients compared with the controls, the memory performances were similar. the predictive values, sensitivity and specificity values obtained from this study are comparable to those obtained by earlier authors, who used cut-off scores of 9 and 7.5.18,19 the memory scores and the time taken to perform the construction task did not differ significantly between controls and asymptomatic hiv-positive patients. a similar observation was reported by smith et al.20 these findings corroborate earlier reports of a low prevalence of memory impairment among asymptomatic hiv-positive patients.4,21,22 the total scores showed the ability of the modified hds to demonstrate the presence of cognitive impairments in hiv/aids, and it is therefore likely to be especially useful for population-based studies. it clearly demonstrated the presence of psychomotor retardation in the hiv-positive subjects, as has been reported by others.1,5,14 the 68.1% prevalence of had observed in this study using the modified hds is high. this figure discussion controls (n=80) asymptomatic hiv positive (n=80) symptomatic hiv positive (n=80) gender male 32 32 34 female 48 48 46 χ2 0.104 p 0.95 age groups (yrs) <20 6 4 6 21 30 25 26 26 31 40 27 28 26 41 50 14 14 15 >50 8 8 7 χ2 0.734 p 0.99 age range (yrs) 8 58 20 64 18 56 level of education primary 18 19 18 secondary 37 38 38 tertiary 25 23 24 χ2 0.137 p 0.99 primary education = maximum of 6 years of schooling; secondary education = more than 6 years of schooling without post-secondary education; tertiary education = more than 11 years of schooling with post-secondary education. table i. demographic data of the study subjects symptom frequency (n) % unexplained fever (>37.2oc for >4 wks) 72 90 unexplained weight loss (>10% of previous body weight) 76 95 persistent diarrhoea (>4 wks) 62 78 generalised papular rash 48 60 generalised herpes zoster 18 23 clinical/radiological signs of pulmonary tuberculosis 54 68 unexplained anaemia (haematocrit <30% or haemoglobin<9 g/dl) 68 85 table ii. clinical characteristics of the symptomatic hiv-positive subjects 28 41 o cto b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e is higher than rates of 16 54% reported by other authors in africa7-9 but similar to the 64.3% prevalence of cognitive impairment in a nigerian population with asymptomatic mild hiv infection.23 this may be due to hiv clade diversity and the differences in the sensitivity of neurocognitive assessment tools utilised in these studies. more recently studies have demonstrated the presence and pattern of cognitive impairments in black africans with hiv/aids, but most of these studies used either complex psychometric21,24 or computerised cognitive tests,22,25 which are difficult to administer in most rural clinical settings and cumbersome for community-based research in sub-saharan africa. the prevalence data available for hiv-associated cognitive impairment in africa represent rates in people presenting to tertiary care centres and are unlikely to reflect rates in the general population. the level of education of research subjects affects performance on the hds (a higher level of education improving cognitive performance), but the effects of age and gender remain inconclusive.3,19 the hds has been validated in subcortical cognitive impairment, the pattern of impairment observed in hiv-associated neurocognitive deficits.19 the modified hds requires no computer. it is a pen-and-paper cognitive instrument that can easily be administered in rural clinic settings. it can be controls asymptomatic hiv positive symptomatic hiv positive memory (mean sd)) 3.68 (0.15) 3.56 (0.64) 1.82 (1.84) (p>0.05)* (p<0.001)† construction (mean (sd)) 1.96 (0.20) 1.23 (0.62) 0.84 (0.71) (p<0.05) (p<0.001 time taken for task 9.84 (5.84) 10.12 (3.46) 24.21 (6.43) (s) (mean (sd)) (range) (2 28) (4 32) (16 56) (p>0.05) (p<0.001) psychomotor speed (mean (sd)) 5.14 (0.77) 4.06 (1.72) 2.54 (1.46) (p<0.01) (p<0.001) time taken for task 15.9 (4.59) 19.32 (6.72) 39.2 (2.44) (s) (mean (sd)) (range) (10 36) (11 48) (26 54) (p<0.001) (p<0.001) total score 10.78 (1.18) 8.85 (1.38) 5.2 (1.13) (p<0.001) (p<0.001) *levels of significance for comparison between mean performances of the controls and asymptomatic hiv-positive subjects. † levels of significance for comparison between mean performances of the controls and symptomatic hiv-positive subjects. table iii. hiv dementia scale scores for the subjects cognitive domains slope (r2) f-values p-values memory -0.98 (0.33) 120.75 p<0.0001 construction -0.41 (0.26) 86.90 p<0.0001 time taken 7.19 (0.47) 283.45 p <0.001 psychomotor speed -1.15 (0.31) 111.70 p<0.001 time taken 9.15 (0.64) 556.76 p<0.001 total -3.62 (0.65) 579.11 p<0.001 table iv. the comparison of cognitive performance with cd4+ levels using the f-test for linear trend symptomatic hiv+ asymptomatic hiv+ hiv+ subjects controls hiv (n=80) (n=160) (n=80) (n=80) functional status* (n (%)) deterioration 80 (100.0) 39 (48.75) 119 (74.38) na still coping 0 (0) 41 (51.25) 41 (25.62) na hds total score (mean (sd)) 5.2 (1.13) 8.85 (1.38) 7.03 (1.64) 10.78 (1.18) (maximum 12) normal (n (%)) 4 (5.0) 47 (58.75) 51 (31.87) 78 (97.5) abnormal† (n (%)) 76 (95.0) 33 (41.25) 109 (68.13) 2 (2.5) χ2 84.94 p<0.001‡ *based on deterioration of functional abilities of patients (as expressed by family members living with patients). † hds cut-off score obtained by receiver operating characteristics analysis (cut-off score of 9; abnormal score <9). ‡ mantel-haenszel matched analysis. na = not applicable. table v. functional and cognitive status of subjects and hds scores 42 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e o cto b e r 2 0 0 9 administered by health care providers who are nonprofessionals but have received instruction in its application. it is therefore suitable for community-based research in low-income developing countries. it has acceptable false-negative and false-positive rates. on the basis of our findings we believe it to be a useful screening tool for determining the baseline cognitive abilities of patients with hiv/aids and recommend its use for monitoring the response of patients with hivassociated cognitive impairment who are on highly active antiretroviral therapy (haart), as an earlier study has demonstrated improvement in neurocognitive and functional performance in hiv-positive individuals on haart in sub-saharan africa.26 in conclusion, this study suggests the usefulness of the hds as a screening tool for the assessment of cognitive abilities of patients with hiv/aids in sub-saharan africa. the sensitivity, specificity and predictive values compared favourably with those obtained among patients in developed countries. it is, however, limited by its inability to detect significant memory impairment in asymptomatic hiv-seropositive patients. references 1. heaton rk, grant i, butters n, et al. neuropsychology of hiv infection at different disease stages – hiv neurobehavioural research center. j int neuropsychol soc 1995; 1: 231-251. 2. mcarthur jc, sacktor n, selnes o. human immunodeficiency virus-associated dementia. semin neurol 1999; 19: 129-150. 3. richardson ma, morgan ee, vielhauer mj, et al. utility of the hiv dementia scale in assessing risk for significant hiv-related cognitive-motor deficits in a high-risk urban adult sample. aids care 2005; 17(8): 1013-1021. 4. selnes oa. memory loss in persons with hiv/aids: assessment and strategies for coping. aids reader 2005; 15: 289-294. 5. almeida sm de, letendre s, ellis r. human immunodeficiency virus and the central nervous system. braz j infect dis 2006; 10(1): 41-50. 6. mcarthur jc, hoover dr, bacellar h. dementia in aids patients: incidence and risk factors. neurology 1993; 43: 2245-2252. 7. howlett, wp, nkya wm, mmuni ka, et al. neurological disorders in aids and hiv disease in the northern zone of tanzania. aids 1989; 3(5): 289-296. 8. sacktor nc, wong m, nakasujja n, et al. the international hiv dementia scale: a new rapid screening test for hiv dementia. aids 2005; 19: 1367-1374. 9. wong mh, robertson k, nakasujja n, et al. frequency of and risk factors for hiv dementia in an hiv clinic in sub-saharan africa. neurology 2007; 68(5): 350355. 10. unaids report on the global hiv/aids epidemic. joint united nations program on hiv/aids, geneva. http://www.unaids.org/en/regions_countries/regions/ subsaharanafrica.asp (accessed 5 july 2004). 11. sani mu, mohammed az, adamu b, et al. aids mortality in a tertiary institution: a four-year review. j natl med assoc 2006; 98: 862-866. 12. federal ministry of health nigeria/national action committee on hiv/aids. 2006 national hiv sero-prevalence sentinel survey: technical report. abuja: federal ministry of health, 2007. 13. power c, selnes oa, grim ja, et al. hiv dementia scale: a rapid screening test. j acquir immune defic syndr hum retrovirol 1995; 8(3): 273-278. 14. von giesen hj, haslinger ba, rohe s, et al. hiv dementia scale and psychomotor slowing – the best methods in screening for neuro-aids. j neuropsychiatry clin neurosci 2005; 17(2): 185-191. 15. american psychiatric association. diagnostic and statistical manual of mental disorders. 4th ed., text revised. washington, dc: american psychiatric association, 2000. 16. clifford db, mitike mt, mekonnen y, et al. neurological evaluation of untreated human immunodeficiency virus infected adults in ethiopia. j neurovirol 2007; 13(1): 67-72. 17. rolfe m. hiv-2 and its neurological manifestations. s afr med j 1994; 84: 503505. 18. davis hf, skolasky rl jr., selnes oa, et al. assessing hiv-associated dementia: modified hiv dementia scale versus the grooved pegboard. aids reader 2002; 12(1): 32-33. 19. van harten b, courant mn, scheltens p, et al. validation of the hiv dementia scale in an elderly cohort of patients with subcortical cognitive impairment caused by subcortical ischemic vascular disease or a normal pressure hydrocephalus. dement geriatr cogn disord 2004; 18(1): 109-114. 20. smith ca, van gorp wg, ryan er, et al. screening subtle hiv-related cognitive dysfunction: the clinical utility of the hiv dementia scale. j acquir immune defic syndr hum retrovirol 2003; 33: 116-118. 21. odiase f, ogunrin o, ogunniyi a. effect of progression of disease on cognitive performance in hiv/aids. j natl med assoc 2006; 98: 1260-1262. 22. ogunrin o, odiase f. motor speed and reaction time in hiv/aids patients: a casecontrol study. african journal of aids research 2006; 5(3): 217-220. 23. salawu fk, bwala sa, wakil ma, et al. cognitive function in hiv-seropositive nigerians without aids. j neurol sci 2008; 267: 142-146. 24. birbeck gl. human immunodeficiency virus dementia patients in africa. how many? who cares? and where to from here? j neurovirol 2005; 11 (suppl. 36): 30-33. 25. miller en, satz p, visscher bv. computerized and conventional neuropsychological assessment of hiv-infected homosexual men. neurology 1991; 41: 1608-1616. 26. sacktor n, nakasujja n, skolasky r, et al. antiretroviral therapy improves cognitive impairment in hiv+ individuals in sub-saharan africa. neurology 2006; 67(2): 311-314. 43 abstract introduction methods results discussion conclusion acknowledgements references about the author(s) sara rachel schlehr department of interdisciplinary social sciences, faculty of social and behavioral sciences, utrecht university, utrecht, the netherlands department of research development, ezintsha research centre, johannesburg, south africa leanne singh department of research development, ezintsha research centre, johannesburg, south africa athini nyatela department of research development, ezintsha research centre, johannesburg, south africa sizwe nqakala department of research development, ezintsha research centre, johannesburg, south africa samanta t. lalla-edward department of research development, ezintsha research centre, johannesburg, south africa citation schlehr sr, singh l, nyatela a, nqakala s, lalla-edward st. experiences in receiving financial incentives to access hiv care in johannesburg, south africa. s afr j hiv med. 2022;23(1), a1426. https://doi.org/10.4102/sajhivmed.v23i1.1426 original research experiences in receiving financial incentives to access hiv care in johannesburg, south africa sara rachel schlehr, leanne singh, athini nyatela, sizwe nqakala, samanta t. lalla-edward received: 01 july 2022; accepted: 07 sept. 2022; published: 17 nov. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: financial incentivisation has been used to improve all steps of the hiv cascade with varying results. most studies conducted on the matter are of a quantitative nature, not giving enough space for in-depth understanding as to why financial incentives work or do not work. objectives: to describe experiences with, and opinions on, the use of financial incentives to promote linkage to and retention in care from the perspective of people living with hiv. method: we performed a qualitative cross-sectional study. in-depth interviews were conducted with adult men and women with hiv accessing health services or research study visits. after codebook development, nvivo 12 software was used to code and analyse the data. results: through the provision of financial incentives, participants were able to cover basic needs. however, some deemed financial incentives as a form of income rather than a nudge to spark interest in changing their health behaviour. participants communicated that a need for some type of incentive exists and recommended food vouchers as the best possible solution. conclusion: financial incentivisation can facilitate engagement in the hiv care continuum through providing support to people living with hiv. what this study adds: this study complements the body of research that explores the feasibility of using incentives and which of them may be most beneficial in encouraging patients with hiv to enter into and sustain hiv care. keywords: hiv care continuum; financial incentivisation; qualitative cross-sectional study; people living with hiv; behavioural nudge. introduction there are 37.7 million hiv-positive individuals globally, 7.8 million of whom are from south africa.1,2 prompt linkage to care (ltc) and initiation on antiretroviral treatment (art) are necessary to facilitate viral suppression, which is a key strategy to control the hiv epidemic.3,4,5,6 since the joint united nations programme on hiv/aids (unaids) and who introduced their 90-90-90 targets (90% of all hiv-positive people know their status, 90% of those who know are on art, 90% of those who are on art are virally suppressed), there has been significant improvement in achieving these targets in eastern and southern africa but viral suppression showed the least improvement.7,8 to boost the uptake of the hiv cascade, different strategies have been employed.9,10,11 one systematic review identified financial incentivisation as a promising tool.12 iguna et al. highlight that most research into the effects of financial incentives is quantitative, without considering the recipients’ experience.13 the lack of sufficient qualitative evidence that considers experiences of patients receiving financial incentives should be addressed to understand why financial incentivisation works in some environments. in south africa 85% of people living with hiv (plhiv) know their status, 71% of whom are on art.14 this suggests there is a gap between testing and ltc, which needs to be closed to rapidly initiate plhiv on art, as advised by the universal ‘test and treat’ policy.15,16 plhiv who are lost to follow-up have poor outcomes.17,18 plhiv need to be linked to care promptly to initiate art, as those who are lost in these stages tend to present late.19 failing to swiftly enter into art poses a threat to the successful end of the hiv epidemic.20 incentivisation has been used to encourage patients to adopt a more accountable attitude towards their health. pettifor et al. mention two main types of incentive programmes: (1) incentives targeting upstream factors (social, economic and macrolevel factors that affect health), like poverty, and (2) incentive programmes exchanging cash for desired behaviour.21 interventions targeting upstream factors, which are part of the social determinants of health,22 have been shown to be more successful.21,23 given south africa’s high unemployment rate of almost 35.0%24 and food insecurity rate of 38.5%,25,26 targeting these upstream factors may be a feasible way to boost engagement in the hiv cascade. financial incentivisation has become a popular strategy in different fields of hiv care and in other diseases with varied results.27 yotebieng et al. conducted a study on prevention of mother-to-child hiv transmission (pmtct) and concluded that small financial incentives improved the uptake of available services and boosted retention in the pmtct cascade.28 el-sadr et al. found a link between financial incentivisation and viral suppression in plhiv.29 however, a ugandan study found no effect of financial incentives on viral suppression,30 as did a study on improved linkage and retention of newly diagnosed plhiv in cape town, south africa.31 such conflicting results cannot be fully understood solely by an analysis of quantitative data. understanding why, in some environments, financial incentivisation improved the engagement in the hiv care continuum, and why it failed in others, may be hidden in patients’ own opinions, feelings and experiences. to comprehensively understand plhiv’s views on financial incentivisation, we conducted a cross-sectional qualitative study of individuals who participated in a quantitative study on the effects of financial incentives and sustained linkage to hiv care (linkme2care study, hstar013).32 our aim is to present their motivations to link to and remain in care, as well as their opinions on and experiences with financial incentives. methods this study set out to learn about participants’ perspectives, opinions, and recommendations on the use of financial incentivisation to achieve linkage to and retention in care. design the study was a qualitative cross-sectional study of adult male and female plhiv accessing health services and attending research study visits. setting this study was conducted at sites selected by the ezintsha research centre for the linkme2care study in the inner city of johannesburg, south africa, and adjoining areas in alexandra, soweto and yeoville. the inner city of johannesburg is a unique environment with high prevalence of tuberculosis and hiv. with its dense population of refugees and economic migrants, the inner city of johannesburg is synonymous with sex work, drugs, and crime. however, the area has many healthcare facilities and is marked with extraordinary progress towards rehabilitating disadvantaged districts.33 linkme2care study overview figure 134 shows the linkme2care study flow. figure 1: study design workflow. recruitment and study population participants from linkme2care were recruited from existing research studies and they were grouped according to the study channel from which they originated: self testing africa hiv self screening (star hivss), anova, the hepatitis c and sedia usability and performance studies. recruitment for linkme2care was meant to only be from star hivss however, since the study was being conducted during the coronavirus disease 2019 (covid-19) lockdown, there were recruitment challenges posed by the restrictions that were placed on the movement and gathering of people. therefore, recruitment was extended to include eligible participants from other studies also being conducted in the research setting at that time. from those participating in linkme2care, convenience instead of systematic sampling was used to identify potential interview participants for this qualitative study. as people completed the linkme2care study they were invited to participate in our qualitative interviews. all suitable individuals were telephoned by the research team and invited to participate in the interviews. younger men and women were prioritised in line with the hivss priority groups. data collection data were collected by two trained interviewers who were fluent in several of the south african official languages. semi-structured interview guides were used. the interview guides were piloted for six interviews which were all included in the analysis. the exit interviews were conducted between july and august 2021 and each interview lasted 18–35 min. given the circumstances of the covid-19 lockdown, all interviews were conducted via mobile phone. recording devices were used to record the audio from the phone calls. the recordings were then transcribed by an independent transcriber and, where needed, translated into english. the research team was responsible for the quality of all transcripts. demographic information was extracted from the linkme2care database and where data were not available, participants were contacted to collect the missing information. in cases where participants could not be reached, a ‘no response’ was recorded. data analysis as data were collected, transcribed, and reviewed, five researchers independently coded four transcripts to develop the initial codebook. the initial codebook was then used by a researcher to guide the coding of the interviews and was expanded upon by including new codes where needed. once the final codebook was created, coding was completed by two independent coders and the thematic analysis from braun and clarke35,36 was employed to search for commonly communicated feelings, opinions or experiences on different topics covered in the interviews. thereafter, these were reported on as the key themes. nvivo 12 software was used. ethical considerations ethical approval was received from the human research ethics committee of the university of the witwatersrand (ethics reference: 191121) and the research committee of johannesburg health district (district research committee [drc] reference: 2020-09-007). all participants provided consent for interview participation and audio recording. all of the participants signed consent forms. participants received r150.00 as reimbursement for their time. the interviews were conducted telephonically, and therefore all of the data are stored solely electronically on a password-restricted server in password-protected folders. results participant characteristics altogether, 26 interviews (6 pilot and 20 study) in the participants’ language of choice were conducted. participant characteristics are shown in table 1. an equal number (n = 13) of participants from the intervention and control arms of linkme2care participated in the exit interviews. the majority of participants entered from the sedia study. most of the participants were in the 25 to 44 years age range. there were fairly equal numbers of male and female participants. most of the participants were unemployed. table 1: characteristics of the 26 enrolled participants. key themes the majority of the participants in the control arm of linkme2care misinterpreted their study reimbursement as incentives whereas participants who received the intervention understood this to be amounts additional to the study participation reimbursement. based on this interpretation, in the majority of instances we did not see differences between the two groups in their perceptions of incentives. four key themes emerged: (1) perception of financial incentivisation, (2) financial incentivisation as a facilitator of the hiv care continuum, (3) financial incentivisation as a supplement to income and (4) recommendations on how to improve incentivisation-based programmes. all these themes are presented and discussed. perception of financial incentivisation this theme demonstrates participants’ opinions on financial incentives being used as a tool to improve the individual’s engagement in the hiv care continuum. three main perceptions arose from the analysis. first, many participants deemed financial incentivisation as a necessity to motivate them to join or continue with the study. participants noted that the financial incentives allowed them to pay transport and food costs that they would incur once they entered the study. participants explained that financial reimbursements would allow them to afford better nutrition: ‘it is necessary for instances like you had called someone to come and you find that person you called wants to come but they do not have money for transport you see mara? … this is where it helps okay it is not that much but at least when i pass town, i am able to get something to eat like meat you see?’ (male, 33 years old, control) ‘yes, the way i see it, it is important that people must be given that money because a person is able to get transport and be able to be motivated to attend the study when they are needed there’. (male, 55 years old, control) ‘yes, it is to other people because some people are staying far away from places like sebokeng in the vaal area. they need it to be able to come to you guys, they also need the money to eat’. (male, 30 years old, control) second, at least half of the participants across both groups disclosed that they perceive financial incentivisation as a reward on their journey to better health. although the financial incentives were appreciated by those that received them, this was not seen as a primary incentive. these participants were more motivated by their desire for improved health outcomes. one person went so far as to suggest that incentives should be used to attract people into care and then removed once they understand that they are responsible for their own care: ‘like, i think it would depend on an individual because we all think the same. on my side, i would continue because this is for my health, i am not doing it for money. yes, when the money is there, that is a bonus, i take it as a bonus’. (female, 40 years old, intervention) ‘no, it didn’t have anything to do with joining the study, it was just a bonus’. (female, 31 years old, intervention) ‘in most cases, it’s to encourage. i think it is. it makes a person eager to start. along the process, you wean them off and make them aware that they don’t need to do this for the money, this is my life, i am being accountable for my responsibilities’. (female, 31 years old, control) third, a little more than a third of the participants considered financial incentives as being ineffective in linking patients to and retaining them in care. for these participants, financial incentives were seen as a negative motivator. in their opinion, people should be determined to join a study such as this with the intent of regaining their health, and taking responsibility for themselves: ‘yeah people should not go to studies chasing money, they must join based on their health, because they want to take care of their health. what i am trying to say is that money mustn’t motivate them to join studies’. (male, 49 years old, intervention) ‘what is important sisi is that each individual must take care of themselves. sometimes, these incentives [programmes] do not work, what remains important is people taking an individual initiative to take care of themselves. … so, that is why i am saying money doesn’t always work because people pay attention to the money, whereas they need to pay attention to their health’. (male, 39 years old, intervention) financial incentivisation as a facilitator of the hiv care continuum people living with hiv in south africa experience a range of different barriers to healthcare31 which can result in both intentional and unintentional neglect of their health. the main barriers to hiv healthcare are the costs of transportation to and from the clinic, healthcare costs and low income.32,33 this theme uncovers the perceived benefits of financial incentivising captured in the interviews. participants often mentioned that without the financial incentives they would not be able to join the study due to the lack of financial means necessary to remain in the study. by receiving monetary reimbursements, it was no longer difficult to secure basic needs for food or transport to and from the healthcare facility, all of which are vital to successfully adhere to art. this theme illustrates how financial incentivisation facilitated opportunities which participants did not have before financial incentivisation: ‘like i said in the beginning, when you do not work, it does help a lot because you can buy food so you can take your medication well’. (female, 40 years old, intervention) ‘it is helpful for transport like me. i am from thokoza. i take three taxis to come here, so it is necessary’. (male, 34 years old, control) ‘it is a good thing for those who are not employed so that this money can help them buy some things so that they can be able to boost their immune systems like buying food and for transport things like that. yes, it should be done’. (female, 40 years old, control) one participant noted the value in remaining adherent to being able to getting a better incentive: ‘the time i came back for my six months i came with my sister she got r150 and got again r300 for checking her blood for viral load then they saw that her viral load is okay then she got r300 on top of the r150 she received and that thing also motivate and i think for me it was because my viral load was not okay because i was not taking my treatment correctly so i saw that next time as i am trying to push and do the right thing so that next time when they call me they must find my viral load low so that i get something’. (female, 28 years old, control) financial incentivisation as a supplement to income financial incentivisation, apart from its potential to mitigate some barriers to engaging in hiv care, became a source of income to some participants. at times participants were quite honest in acknowledging that the opportunity to earn money was their sole motivation for joining the study. moreover, participants elaborated that without financial incentives earned from study participation, they would not be able to afford their everyday needs: ‘the fact that i knew that when i am done, i will get money. because i am unemployed, i know i will be able to get myself some vegetables and food with the money, that’s why i was motivated. i know that i will ask someone to lend me some money for transport because i catch two taxis. i live in soweto, but i know that i will get money and i will have leftover for vegetables’. (female, 55 years old, intervention) ‘you continue collecting your treatment because you know that there is a study that is going to give you money for that should you go’. (female, 42 years old, intervention) ‘yes, it is necessary because it is a motivation and frankly speaking people would not come if it were not for the money including me. i would have not joined the study if there was no money. i am not going to lie’. (male, 34 years old, control) recommendations on how to improve incentivisation-based programmes many participants suggested food parcels and vouchers as improvements to the incentivisation scheme. food parcels were recommended as a means to providing basic foods that could be made available to participants without them having to make a further trip to the store to purchase them: ‘perhaps food parcels. i am thinking about food parcels because that is something everyone can get. just small things like vegetables, sugar, maize meal, rice, just basic things’. (female, 40 years old, intervention) ‘what i think you can improve on is that you can give us food vouchers so that if i find out that i am positive i can get a voucher to have food that will last me the whole month’. (male, 33 years old, control) furthermore, food parcels and vouchers increased the likelihood that these incentives would positively influence engagement in the hiv cascade. the need to eat before taking the medication was the predominant concern, because taking art before meals can cause discomfort. ‘people could get food parcels, any kind. this will enable them to eat before taking the medication, unlike sometimes when there is nothing to eat and you have to take your treatment. you ran out of food. and one must take their medication’. (female, 55 years old, intervention) ‘it would be better to provide food because you can’t take your treatment while hungry. that is what i think would be motivational’. (male, 43 years old, intervention) ‘you come back with positive results, you need to take medication, you can’t take medication on an empty stomach. you need a little bit of something to sustain the medication in your stomach. so, vouchers that someone can go buy something where there won’t be change back; if you get a r150 voucher, you need to take things that are limited to that r150’. (female, 31 years old, intervention) however, a minority of participants did not recommend any other solutions as they thought that financial incentives are appropriate. some reasons offered for these opinions were that money would reduce dishonest practices like selling food that was given to them for a profit, and ensure study participation. others cited simply having faith in the success of the existing behavioural nudge programme and felt that there was no need to change it: ‘no. money [laughs]. i’ll give you my honest opinion, you said there’s no right or wrong answer, so keeping it honest. since i was going through this period, i call it surviving by the grace of god, you go for help somewhere, some organisations give out clothes, some will give food parcels. what happened is that people would take those food parcels and then they would sell them, so that contradicts. i mean they tell us that they can’t give us money on hand, but they’re going to sell that food that you gave them to someone who has money. i still think that money is a better solution because if you don’t pay then they won’t show up’. (female, 34 years old, intervention) ‘no, i don’t think i can recommend anything else. i think you guys are doing a great job. i think i told the other guy that i don’t think i have any recommendations because i believe that you are doing a good job’. (male, 44 years old, intervention) discussion this study aimed at understanding and evaluating participants’ experiences of opinions about and feelings towards financial incentivisation to improve linkage to and retention in care. to obtain this, we conducted exit interviews with adult plhiv after they completed the linkme2care study. participants shared their motivations, opinions, and experiences with financial incentives. besides perceptions and opinions directly related to the value of financial incentives in healthcare, and in particular hiv care, other themes also emerged. we discovered that while financial incentives were mostly well received by the participants, it was not the only reason they chose to enrol in the linkme2care study. it was evident that participants viewed financial incentives as a means to fulfil the needs required for them to link to care and maintain their art routines. participants in our study were clear about the fact that receiving financial incentives helped them to pay for their transport to and from the clinics, as well as the food required to meet their nutritional needs. ghose et al. found a similar trend, and explain how patients repeatedly expressed being in favour of financial incentives as it helped them to pay for their food over and above maintaining them in hiv care.37 participants expressed an awareness of how financial incentives could assist them to fulfil their unmet needs. by contrast another south african study showed that both patients and providers generally did not link financial incentivisation with structural barriers to the hiv cascade like transport costs or food insecurity, but rather with individual factors like intrinsic motivation.38 even though most participants thought financial incentives were a positive influence on linkage and retention, a few participants expressed that financial incentivisation should not be used in the hiv care continuum because being responsible for one’s health behaviour is the most important factor. this finding is supported by clouse et al.’s findings from a study on acceptability and feasibility of financial incentives among pregnant south african women, where it was found that participants deemed health education and counselling to be more important than financial incentives.39 health accountability is an important factor in the hiv care continuum as was similarly shown in a ukrainian study on patients and provider perspectives on improving ltc.40 robbins and dunn emphasise that responsibility drives and sustains change.41 a study from kenya reported that participants who were intrinsically motivated to engage in care were less prompted by financial incentives.13 an important area for future research would be to consider interventions that target replacing patients’ dependence on financial incentives with non-incentivised self-management of their health. for instance, the benefits of combining education and self-management were demonstrated in the systematic review of the teach-back method applied on people with chronic diseases. this study showed improvement in adherence, self-care, and disease-specific knowledge.42 given that over a third of participants place their health above financial incentives and view financial incentives as no more than ‘a bonus’, it would be beneficial to investigate how a similar attitude can be instilled in plhiv who neglect their health. some plhiv see financial incentives as a gateway to an improved lifestyle not necessarily linked to the desire for health improvement or to the study. for these participants, financial incentives are a way to earn an income or supplement an existing one. based on the high unemployment rate in south africa,24 we think the main driver of this behaviour lies within this particular upstream factor combined with a relatively low standard of living compared to other country members of the organisation for economic co-operation and development.21,43 therefore, we suggest new interventions focusing on upstream structural factors like unemployment or low education standards to improve engagement in the hiv care continuum. drawing on the participants’ motivations, this study showed that a demand for some type of incentive or support is still in place. participants expressed a need for an improvement or adjustment in the incentivisation programmes. for them this can be achieved by promoting non-financial incentives, like food vouchers. according to them, this may alleviate the possible physical stress to the body that is caused by not eating properly before taking hiv treatment. however, mccoy et al., in their tanzanian study, point out that distributing food baskets as a form of incentive may be harder than distributing cash, and therefore less effective.44 this is a reminder that while other forms of support beyond money and food can be effective, they may not necessarily be able to be applied in all contexts. kennedy et al.’s systematic review on the uptake of medical male circumcision for hiv prevention, particularly as it pertains to awarding food or transport vouchers, exemplifies this.44 to avoid distribution problems, we suggest that vouchers for specific foods or amounts that limit spend to particular items, within an accessible south african grocery store, should be distributed instead of direct cash transfers. strengths and limitations despite completing the study during covid-19 lockdown, we were still able to conduct the research with a sufficient number of participants to reach data saturation. the semi-structured interviews allowed the researchers to ask additional questions uncovering more in-depth information regarding financial incentives. covid-19 restrictions (particularly around movement and social distancing) hindered the ability to access and conduct in-field recruitment. this together with the failure to achieve high self-reporting among star hivss participants negatively impacted the implementation of the linkme2care study, which prompted the team to include more recruitment channels as reported. due to the necessitated deviation from the original protocol of the linkme2care study, participants were also recruited from different study channels (sedia and hepatitis c usability and performance studies, anova) and had varying knowledge about financial incentivisation. the star hivss recruits had a generally better understanding of the study compared to others. however, only six star hivss recruits participated in the exit interviews compared to 17 sedia recruits which was not desirable due to the differences in knowledge about financial incentivisation. to add to that, some participants were part of multiple studies, confusing which study they were being contacted about, and ultimately resulting in mixed messages. however, when this was noticed early on in the recruitment for the exit interviews and data collection processes, as mitigation, the research team developed a second interview guide for particpants who did not enter linkme2care through star hivss so that the questions asked would still yield some of the information we were seeking to find. recommendations to boost the engagement in the hiv care continuum, we recommend that public health professionals and policymakers consider interventions that target upstream factors in addition to offering financial incentives to catalyse responsible health-related behaviour adjustments. we also suggest that researchers conduct studies into the effects of other types of incentives, namely food or travel vouchers, based on the findings of this study. conclusion three specific opinion sub-groups emerged: (1) participants who deemed financial incentives as unimportant and regarded them as just ‘a bonus’ in their journey to better health, anticipating they did not need the nudge to enter into the hiv cascade, (2) participants who considered financial incentives as imperative as they provided for their unmet needs and created an opportunity to start caring about their health, and (3) participants who joined the study solely on the premise of cash incentives without taking into consideration their health. based on the distribution of the opinions we conclude that financial incentives can facilitate engagement in the hiv care continuum through providing support to plhiv. this support facilitates participants meeting basic needs like food and transport costs which are necessary to link patients to care and sustain them in art. acknowledgements the authors would like to acknowledge taylor johnson, mothepane phatsoane and theodore wonderlik for their contribution towards the data collection process. they also thank the participants for sharing their experiences, views, and recommendations. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions s.t.l.-e. conceptualised and designed the qualitative study, s.n. and a.n. collected the data, and s.r.s. and s.t.l.-e analysed the data. s.r.s. and l.s. wrote the first and final draft of the manuscript. all authors reviewed the final manuscript and gave permission for submission. funding information the funding for this project was made possible through the academic support from ezintsha. data availability the data that support the findings of this study are available upon reasonable request from the senior author, s.t.l.-e. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. some of the information will be reported in a master’s thesis. references joint united nations. fact sheet – world aids day 2021 [homepage on the internet]. 2021 [cited 2022 jun 12]. available from: https://www.unaids.org/sites/default/files/media_asset/unaids_factsheet_en.pdf joint united nations. hiv and aids 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test users who obtain a reactive result. forthcoming 2022. braun v, clarke v. using thematic analysis in psychology. qual res psychol. 2006;3(2):77–101. https://doi.org/10.1191/1478088706qp063oa braun v, clarke v. thematic analysis. in: cooper h, camic pm, long dl, panter at, rindskopf d, sher kj, editors. apa handbook of research methods in psychology, vol 2: research designs: quantitative, qualitative, neuropsychological, and biological [homepage on the internet]. washington, dc: american psychological association, 2012 [cited 2022 jan 31]; p. 57–71. available from: http://content.apa.org/books/13620-004 ghose t, shubert v, chaudhuri s, poitevien v, updyke a. are financial incentives appropriate means of encouraging medication adherence among people living with hiv? ama j ethics. 2021;23(5):e394–e401. https://doi.org/10.1001/amajethics.2021.394 swartz a, maughan-brown b, perera s, et al. ‘the money, it’s ok but it’s not ok’: patients’ and providers’ perceptions of the acceptability of cash incentives for hiv treatment initiation in cape town, south africa. aids behav. 2022;26(1):116–122. https://doi.org/10.1007/s10461-021-03355-0 clouse k, mongwenyana c, musina m, et al. acceptability and feasibility of a financial incentive intervention to improve retention in hiv care among pregnant women in johannesburg, south africa. aids care. 2018;30(4):453–460. https://doi.org/10.1080/09540121.2017.1394436 kiriazova t, postnov o, bingham t, et al. patient and provider perspectives inform an intervention to improve linkage to care for hiv patients in ukraine. bmc health serv res. 2018;18(1):58. https://doi.org/10.1186/s12913-018-2885-4 robbins d, dunn p. digital health literacy in a person-centric world. int j cardiol. 2019;290:154–155. https://doi.org/10.1016/j.ijcard.2019.05.033 ha dinh tt, bonner a, clark r, ramsbotham j, hines s. the effectiveness of the teach-back method on adherence and self-management in health education for people with chronic disease: a systematic review. jbi database syst rev implement rep. 2016;14(1):210–247. https://doi.org/10.11124/jbisrir-2016-2296 oecd. how’s life? 2020: measuring well-being [homepage on the internet]. how’s life? oecd; 2020 [cited 2022 jun 21]. available from: https://www.oecd-ilibrary.org/economics/how-s-life/volume-/issue-_9870c393-en kennedy ce, yeh pt, atkins k, et al. economic compensation interventions to increase uptake of voluntary medical male circumcision for hiv prevention: a systematic review and meta-analysis. plos one. 2020;15(1):e0227623. https://doi.org/10.1371/journal.pone.0227623 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 1 hiv and bullous lung disease liat malek, mb chb grace rubin, mb chb, da (sa), fcrad (d) sa susan lucas, mb chb department of radiology, university of the witwatersrand, and helen joseph hospital, johannesburg the mechanisms behind accelerated emphysema in adults with hiv infection and the hiv-infected smoking population are both multifactorial and unclear. however, the association of hiv and emphysematous lung disease is recognised. we describe a patient with hiv infection and accelerated emphysema, highlighting the facts that no other background disease predisposed him to these lung changes, and that smoking in conjunction with hiv infection acted synergistically to produce the changes. case report a 38-year-old man with a 3-day history of shortness of breath, productive cough and pleuritic chest pain presented to the medical department at helen joseph hospital, johannesburg. there was no history of tuberculosis or other lung disease, but the patient had been a smoker for 10 years. he was on no medication. on examination he presented with a respiratory rate of 20/min, tachycardia (164 beats/min), and a blood pressure of 98/66 mmhg. he had decreased air entry on auscultation of the left chest. an initial chest radiograph revealed a differential transradiancy of the hemithoraces, and a diagnosis of spontaneous left pneumothorax was made. the patient was placed on oxygen and an intercostal drain (icd) inserted. blood tests revealed that he was hiv infected, with a cd4 count of 469 cells/µl and a white cell count of 469 x 109/l. he was not on antiretroviral therapy. once his condition had stabilised, a high-resolution computed tomography scan of the chest was done (figs 1 and 2). this revealed large bilateral, diffuse, predominantly apical, medial and lateral bullous lung disease associated with a small residual left pneumothorax. the underlying lung parenchyma deep to the paraseptal bullae was not affected. no radiological features of pre-existing consolidation, cavities or cysts were present, and there were no nodules, reticules or bronchiectasis. there was no lymphadenopathy or effusions. the diagnosis of spontaneous pneumothorax secondary to bullous lung disease in an hiv-positive male smoker was made. near-total re-expansion of the left lung occurred. the icd was removed and the patient was discharged to an outpatient clinic. discussion emphysematous lung disease has become a known pulmonary complication of hiv and aids. hiv-related bullous lung disease was first reported in the late 1980s. subsequently numerous studies have indicated that the hi virus itself is a predisposing factor in the pathogenesis of bullous lung disease.1-3 in 1989 a publication by kuhlman et al. compared the incidence of bullous lung damage in a group of hiv-positive patients with that in a similar group of immunocompromised patients with acute leukaemia.4 bullous lung damage was found in 42% of the hivpositive group, as opposed to 16% of the acute leukaemia group. the average age of the hiv-positive group was also significantly lower than that of the leukaemia group. the study documented the distribution of bullous fig. 1. coronal reconstruction of the lung parenchyma on lung windows. large bilateral apical and medial paraseptal bullae are present. note the absence of any parenchymal pathology deep to the paraseptal bullae. an intercostal drain tip is seen in the left lateral pleural space. fig. 2. axial computed tomography scan on lung windows. large bilateral paraseptal bullae are demonstrated with residual antero-medial pneumothorax. 37 c a s e s t u d y – h i v a n d l u n g d i s e a s e a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e changes to be predominantly apical and peripheral. of the patients 70% had a history of previous documented pulmonary infections (in particular pneumocystis jirovecii pneumonia) and 13% did not, emphasising the direct effect of hiv itself on the lung parenchyma. spontaneous pneumothoraces were a common complication in patients with bullous lung disease. other studies also emphasise the role of hiv in premature emphysema and bullous lung disease. hiv-infected subjects have significantly more emphysematous lung damage than hiv-negative smokers.1,5 hiv-associated emphysema also occurs over a much shorter period of time than smoking-related emphysema in hiv-negative patients. this is thought to reflect an increase in and a susceptibility to damage caused by cigarette smoking in hiv-positive patients.1 in 2000 diaz and co-workers compared the incidence of emphysema in an hiv-positive group and an hivnegative group matched for age and smoking history.5 the incidence of emphysema was 15% for the hivpositive and 2% for the hiv-negative group. smoking was the single most important risk factor in the hivpositive group, contributing to 37% of the patients with emphysema in this group, compared with 0% in the hivnegative group. the differential diagnosis of bullous lung disease includes tobacco smoking, intravenous drug use (methyphenidate, heroin, cocaine), marijuana and cocaine smoking, and a long list of diseases including α1-antitrypsin deficiency, hiv infection, auto-immune and connective tissue disorders, bullous sarcoidosis, idiopathic giant bullous emphysema and neurofibromatosis.2 a higher percentage of cytotoxic lymphocytes has been demonstrated in broncho-alveolar lavage specimens of hiv-infected patients than in uninfected subjects.1,5 in the 1990s reports of accumulation of cd8 cytotoxic t lymphocytes in the lungs of patients with severe chronic obstructive pulmonary disease (copd) appeared. this may explain the accelerated emphysema in hiv-infected patients, whose lung response to the hiv infection is characterised by the accumulation of cd8 lymphocytes in alveolar spaces. lymphocytic alveolitis, defined as more than 15% lymphocytes in broncho-alveolar lavage, is a common finding in hiv-infected subjects.1 more recently, highly active retroviral therapy (haart) has been associated with a significant decrease in the number of cd8 cells in broncho-alveolar lavage. this raises the interesting possibility that the incidence of copd in hiv-infected subjects may decrease significantly in the haart era.1 conclusion the spectrum of hiv-associated accelerated emphysematous lung changes carries significant morbidity. it is therefore important to recognise early lung changes as well as understand the predisposing factors associated with accelerated bullous lung disease in the hope that prevention, early detection and treatment will decrease morbidity and mortality in these patients. references 1. petrache i, diab k, knox ks, et al. hiv associated pulmonary emphysema: a review of literature and inquiry into its mechanism. thorax 2008;63:463-469. 2. mireles-cabodevila e, sahi h, farver c, mohammed tl, culver da. a young patient with a minimal smoking history presents with bullous emphysema and recurrent pneumothorax. chest 2000;132:338-343. 3. crothers k. chronic obstructive pulmonary disease in patients who have hiv infection. clin chest med 2007;28(3):575-587. 4. kuhlman je, knowels mc, fishman ek, siegelman ss. premature bullous pulmonary damage in aids: ct diagnosis. radiology 1989;173:23-26. 5. diaz pt, king ma, pacht er, et al. increased susceptibility to pulmonary emphysema among hiv-seropositive smokers. intern med 2000;32:369-372. 38 june 2014, vol. 15, no. 2 sajhivmed 65 mania with psychotic features is one of the common presenting clusters of psychiatric symptoms in hiv-infected patients. commonly, patients with hiv-associated mania receive antiretroviral treatment, mood stabilisers and antipsychotics. this case of stevens-johnson syndrome highlights the dilemmas and complications that may arise when prescribing multiple medications in hiv-associated psychiatric disorders. s afr j hiv med 2014;15(2):65-66. doi:10.7196/sajhivmed.1011 fatal nevirapine-induced stevensjohnson syndrome with hiv-associated mania z zingela,1 mb chb, mmed (psych), fc psych (sa); a bronkhorst,1 mb chb, dmh (sa); w m qwesha,2 mb chb; b p magigaba,2 mb chb, fc derm (sa) 1 department of psychiatry, port elizabeth hospital complex, walter sisulu university, south africa 2 department of dermatology, port elizabeth hospital complex, walter sisulu university, south africa corresponding author: z zingela (zingelaz@telkomsa.net) hiv enters the central nervous system early in the course of hiv infection and causes a range of neuropsychiatric complications, including hiv encephalopathy, depression, mania, cognitive disorders and frank demen tia. [1] mania is one of the most common psychiatric presentations in hiv-infected patients and requires antiretroviral therapy (art), mood stabilisers and antipsychotics to increase patient quality of life and decrease mortality.[1-3] art may also protect from further cognitive deterioration and preserve functionality.[1] the link between systemic hypersensitivity reactions and nevirapine has been well documented.[4] case reports have also demonstrated adverse cutaneous reactions associated with the use of sodium valproate and risperidone.[5,6] this report describes the case of an hiv-seropositive patient who presented with mania for the first time and was treated with nevirapine, sodium valproate and risperidone. he developed stevens-johnson syndrome (sjs), which progressed to toxic epidermal necrolysis (ten) and death over a period of 26 days. background sjs/ten comprises cutaneous adverse reactions ranging from mild erythematous macules to extensive epidermal detachment and mucous membrane erosion. the international classification of sjs/ten is based on the body surface area (bsa) involved: sjs involves <10% of bsa; ten involves >30%; and there is an overlap in definitions with involvement of 10 30%.[7] mortality associated with sjs, sjs/ten and ten is 10%, 30% and >50%, respectively.[7] common causes of death include septic shock, hypovolaemic shock, acute renal failure and fulminant hepatitis.[8] the most common drugs implicated are sulphonamide antibiotics (38%) and nevirapine (20%). [9] an immunological response involving cd8+ t lymphocytes is the most likely explanation for the pathogenesis of sjs/ten.[10] other potential factors are the causative drug’s inherent properties or chemical structure, patient factors such as hiv status and cd4+ count, ethnic background, age and gender. affected individuals with sjs/ten are genetically predisposed to developing severe cutaneous reactions based on the major histocompatibility complex molecules on their leukocyte cell surface.[10] a study in taiwan showed that 100% of han chinese patients who developed sjs in response to carbamazepine had an hla b*1502 allele.[11] comorbidity of sjs/ten and hiv is posing a challenge in sub-saharan africa due to the high prevalence of hiv. in this setting, sulphonamides and nevirapine are the most commonly implicated drugs. case report a 28-year-old man was referred to the mental health unit (mhu) with a 3-week history of manic symptoms, presenting for the first time. he was irritable, displayed pressure of speech, and had decreased need for sleep, increased drive, hyper-religiosity, impulsivity (reckless spending of money) and auditory hallucinations. he tested positive for hiv and syphilis (rapid plasma reagin (rpr) titre of 1:8). his cd4+ count was 334 cells/µl and he was not on art. cerebrospinal fluid analysis was negative for neurosyphilis. chest x-ray and genexpert on sputum excluded tuberculosis. treatment initiated on admission was 3 mg risperidone daily, 500 mg sodium valproate twice daily and penicillin. on day 3 after admission, he was prescribed 300 mg zidovudine twice daily, 150 mg lamivudine twice daily and 200 mg nevirapine daily. the nevirapine dose was to be doubled to 200  mg twice daily after 14 days. his psychiatric symptoms responded well to treatment and he was discharged on day 8 post admission. on day 7 he had complained of a mild rash on his hands and nevirapine was suspected as the cause. art was continued, and 4 mg chlorphenamine three times daily and hydrocortisone 1% cream were prescribed. review at follow-up on day 3 and day 6 post discharge revealed that the rash had settled and he remained physically and mentally well. the nevirapine dose was increased, as per treatment plan, on day 10 post discharge. he presented at his next review appointment on day 13 post discharge with c a s e r e p o r t mailto:zingelaz@telkomsa.net 66 sajhivmed june 2014, vol. 15, no. 2 c a s e r e p o r t a severe sjs/ten reaction (fig. 1), which had developed on day 10 post discharge, coinciding with the increase in nevirapine. he had continued his treatment and had waited for his next follow-up appointment before reporting the rash. he was re-admitted to the intensive care unit where his condition deteriorated, with death occurring on day 6 of his second admission. death was thought to be related to infection and renal failure. the patient was initiated on art while admitted to the mhu, which is common in our setting and other parts of south africa (sa) as art initiation may help to ameliorate hiv-associated neuropsychiatric symptoms and potentially improve cognitive function in particular. in this case, the choice of art regimen was influenced by a number of factors, including the safety profile of both efavirenz and nevirapine, the risk of art-induced neuropsychiatric side-effects (more commonly seen with efavirenz), the patient’s wishes, informed consent given for further management of his condition, the applicable world health organization staging and the latest sa national department of health art guidelines.[12] the fatal outcome raises questions regarding the initiation of art in patients with similar presentations and the role played by the following factors in the development and clinical outcome of sjs/ten: hiv infection, cd4+ count, causative drug, age, gender and use of steroids during the acute stages. this case emphasises the need for further research into these factors to aid clinicians in decisionmaking when it comes to safe options for hiv-associated mania. references 1. nakimuli-mpungu e, musisi s, mpungu sk, katabira e. early-onset versus-onset hiv-related secondary mania in uganda. psychosomatics 2008;49(6):530-534. [http://dx.doi.org/10.1176/appi.psy.49.6.530] 2. hutchinson g. hiv mania as a marker for clinical deterioration in aids. west indian med j 2005;54(2):149-151. [http://dx.doi.org/10.1590/s0043-31442005000200013] 3. adler cohen ma, jacobson jm. maximising life’s potential in aids: a psychopharmacological update. gen hosp psychiatry 2000; 22(6):542. http://www.ncbi. nlm.nih.gov/pubmed/11020544 (accessed 19 june 2013). 4. singh h, kachhap vk, kumar bn, nayak k. nevirapine induced stevens-johnson syndrome in an hiv-infected patient. indian j pharmacol 2011;43(1):84-86. http:// www.ncbi.nlm.nih.gov/pubmed/21455432 (accessed 19 june 2013). 5. kumar pn, kumar sk. stevens-johnson syndrome induced by sodium valproate. indian j psychiatry 2004;46(3):269-270. 6. desarkar p, nizamie h. risperidone-induced erythema multiforme minor. br j clin pharmacol 2006;62(4):504-505. [http://dx.doi.org/10.1111/j.13652125.2006.02708.x] 7. mockenhaupt m. the current understanding of stevens-johnson syndrome and toxic epidermal necrolysis. expert rev clin immunol 2011;7(6):803-815. [http:// dx.doi.org/10.1586/eci.11.66] 8. bera e, mia r. safety of nevirapine in hiv-infected pregnant women initiating antiretroviral therapy at higher cd4+ counts: a systematic review and metaanalysis. s afr med j 2012;102(11):855-859. [http://dx.doi.org/10.7196/ samj.5700] 9. saka b, barro-traoré f, atadokpédé fa, et al. stevens-johnson syndrome and toxic epidermal necrolysis in sub-saharan africa: a multicentric study in four countries. int j dermatol 2013;52(5):575-579. [http://dx.doi.org/10.1111/j.13654632.2012.05743.x] 10. namayanja gk, nankya jm, byamugisha jk, et al. stevens-johnson syndrome due to nevirapine. afr health sci 2005;5(4):338-340. 11. chung wh, hung si, hong hs, et al. medical genetics: a marker for stevens-johnson syndrome. nature 2004;428(6982):486. [http://dx.doi. org/10.1038/428486a] 12. national department of health. the south african antiretroviral treatment guidelines 2013. pretoria: national department of health, 2013:6-8. fig. 1. severe sjs/ten affecting trunk and upper limbs. (sjs = stevensjohnson syndrome; ten = toxic epidermal necrolysis.) http://dx.doi.org/10.1176/appi.psy.49.6.530] http://dx.doi.org/10.1590/s0043-31442005000200013] http://www.ncbi http://www.ncbi.nlm.nih.gov/pubmed/21455432 http://www.ncbi.nlm.nih.gov/pubmed/21455432 http://dx.doi.org/10.1111/j.1365-2125.2006.02708.x] http://dx.doi.org/10.1111/j.1365-2125.2006.02708.x] http://dx.doi.org/10.1586/eci.11.66] http://dx.doi.org/10.1586/eci.11.66] http://dx.doi.org/10.7196/samj.5700] http://dx.doi.org/10.7196/samj.5700] http://dx.doi.org/10.1111/j.1365-4632.2012.05743.x] http://dx.doi.org/10.1111/j.1365-4632.2012.05743.x] http://dx.doi.org/10.1038/428486a] http://dx.doi.org/10.1038/428486a] pg22-24.html original article bacterial vaginosis, alterations in vaginal flora and hiv genital shedding among hiv-1-infected women in mozambique robert d kirkcaldy1,   md, mph jennifer mika1,   mph lori m newman1,   md judite langa1,   md linhui tian1,   md, ms ilesh jani2,   md, phd ron ballard1,   phd lisa nelson1,   md, mph, msc elena folgosa3,   md, phd 1centers for disease control and prevention, atlanta, ga, usa 2national institute of health, ministry of health, mozambique 3eduardo mondlane university, mozambique objectives.  we investigated whether abnormal vaginal flora, including bacterial vaginosis (bv), are associated with detection of cervical hiv-1 rna among hiv-infected women in mozambique. methods.  we obtained clinical data and vaginal specimens from hiv-infected women registering for their first visit at one of two hiv care clinics in mozambique. we compared women with detectable cervical hiv viral load (<=40 copies/ml) with women with undetectable cervical hiv. results.  we enrolled 106 women. women with abnormal vaginal flora (intermediate nugent scores, 4 6) were more likely to have detectable cervical hiv rna than women with normal vaginal flora (adjusted odds ratio 7.2 (95% confidence interval 1.8 29.1), adjusted for cd4 count). women with bv had a non-significantly higher likelihood of detectable cervical hiv than women with normal flora. conclusions.  abnormal vaginal flora were significantly associated with cervical hiv expression. further research is needed to confirm this relationship. hiv genital shedding enhances hiv transmission to sexual partners.1 we investigated whether abnormal vaginal flora, including bacterial vaginosis (bv), are associated with cervical hiv-1 rna expression among hiv-infected women in mozambique. methods women were enrolled from october 2007 to march 2008 as part of an evaluation of reproductive tract infections among hiv-infected individuals registering for a first visit at one of two hiv care clinics in mozambique: xai xai provincial hospital and mavalane general hospital.2 we collected demographic and clinical data, and plasma and vaginal specimens. cervical lavage specimens were obtained by application of 10 ml of sterile saline to the cervix and collection from the posterior fornix after 3 minutes. diagnosis of bv was based on nugent’s criteria. diagnoses of trichomonas vaginalis, chlamydia trachomatis, neisseria gonorrhoeae and mycoplasma genitalium were done by real-time multiplex polymerase chain reaction testing. hiv rna levels were determined by nucleic acid sequence-based amplification assay, with a lower limit of detection of 40 copies/ml. patients were treated according to the 2006 mozambique ministry of health treatment guidelines and offered partner notification cards. the evaluation protocol, consent form and questionnaires were approved by mozambique’s national health bioethics committee and the cdc institutional review board. data were analysed using sas version 9.2 (sas institute, cary, nc). nugent scores were categorised as normal (0 3), intermediate vaginal flora (4 6) and bv (7 10). cervical hiv rna was dichotomised as detectable (>=40 copies/ml) or undetectable. women with detectable cervical hiv were compared with women without detectable cervical hiv by the chi-square or fisher’s exact test for categorical variables, and the t-test for continuous variables. we used multivariable logistic regression models to test whether abnormal vaginal flora (intermediate vaginal flora or bv) were associated with detectable cervical hiv rna. plasma viral load, cd4 count, trichomoniasis and age were considered for inclusion; variables were excluded if they were not significant (p>=0.05) or disrupted the model’s goodness of fit (e.g. cd4 count was included in the final model and plasma viral load was not). missing data were excluded from the analyses. results of 258 women enrolled in the larger study, 106 agreed to have cervical lavage specimens collected; there were no significant differences between women who agreed and did not agree to cervical lavage. the mean age of the 106 participating women was 33 years and most of them were from xai xai (table i). none of the women was receiving antiretroviral therapy. lower cd4 counts (p=0.01) and abnormal vaginal flora (p=0.04) were associated with cervical hiv rna detection (table i). in multivariable logistic regression modelling, women with intermediate vaginal flora had higher odds of detectable cervical hiv rna than women with normal vaginal flora (adjusted odds ratio (aor) 7.2 (95% confidence interval (ci) 1.8 29.1), adjusted for cd4 count). women with bv had non-significantly higher odds of detectable cervical hiv rna compared with women with normal vaginal flora (aor 2.7 (95% ci 0.8 8.7), adjusted for cd4 count). mean nugent scores of women with detectable cervical hiv were comparable to those of women without detectable cervical hiv (5.7 v. 5.3, p=0.64). compared with women with plasma viral loads of >=100 000 copies/ml, women with plasma viral loads of <10 000 copies/ml more often had abnormal vaginal flora (58% v. 21%, p=0.049). on stratified analysis, there was a non-significant trend towards higher plasma viral load and cervical hiv rna detection among women with normal nugent’s scores or bv, yet there was no association between plasma viral load and cervical hiv among women with intermediate vaginal flora. conclusions we found positive associations between intermediate vaginal flora and bv and detection of cervical hiv rna among hiv-infected women in mozambique, suggesting that abnormal vaginal flora might enhance hiv genital viral shedding. previously published work demonstrated associations between the presence of bv and detection of cervical hiv rna,3 , 4 possibly because of immune activation.5 it was surprising that although intermediate vaginal flora were significantly associated with genital hiv expression, bv was not. it is possible that intermediate vaginal flora are more conducive to hiv viral shedding than bv, yet the explanatory mechanism is unclear. it is also possible that our study lacked adequate power to detect a significant association between bv and detectable cervical hiv due to a small sample size: this may be reflected in the wide confidence intervals. limitations include that we did not control for menstrual cycle timing, contraceptive use, possible semen contamination of cervical specimens and herpes simplex viral infection, and cold-chain interruptions may have occurred. we did not find a clear overall association between plasma hiv viral load and cervical hiv expression, although the association may have been confounded by the presence of abnormal vaginal flora. despite these limitations, these data suggest that abnormal vaginal flora might enhance hiv genital shedding and thus potentially enhance hiv transmission to sexual partners. further research is needed to confirm this association. references 1. chakraborty h, sen pk, helms rw, et al. viral burden in genital secretions determines male-to-female sexual transmission of hiv-1: a probabilistic empiric model. aids 2001;15:621-627. 1. chakraborty h, sen pk, helms rw, et al. viral burden in genital secretions determines male-to-female sexual transmission of hiv-1: a probabilistic empiric model. aids 2001;15:621-627. 2. langa j, gaspar f, folgosa e, et al. integration of sexually transmitted infection (sti) management into hiv outpatient clinics in mozambique, 2008 [o8.5.5]. presented at the 11th world congress of the international union against sexually transmitted infections, 11 november 2009, cape town. 2. langa j, gaspar f, folgosa e, et al. integration of sexually transmitted infection (sti) management into hiv outpatient clinics in mozambique, 2008 [o8.5.5]. presented at the 11th world congress of the international union against sexually transmitted infections, 11 november 2009, cape town. 3. cu-uvin s, hogan jw, caliendo am, et al. association between bacterial vaginosis and expression of human immunodeficiency virus type 1 rna in the female genital tract. clin infect dis 2001;33:894-896. 3. cu-uvin s, hogan jw, caliendo am, et al. association between bacterial vaginosis and expression of human immunodeficiency virus type 1 rna in the female genital tract. clin infect dis 2001;33:894-896. 4. sha be, zariffard mr, want qj, et al. female genital-tract hiv load correlates inversely with lactobacillus species but positively with bacterial vaginosis and mycoplasma hominis. j infect dis 2005;191:25-32. 4. sha be, zariffard mr, want qj, et al. female genital-tract hiv load correlates inversely with lactobacillus species but positively with bacterial vaginosis and mycoplasma hominis. j infect dis 2005;191:25-32. 5. rebbapragada a, howe k, wachihi c, et al. bacterial vaginosis in hiv-infected women induces reversible alterations in the cervical immune environment. j aids 2008;49:520-522. 5. rebbapragada a, howe k, wachihi c, et al. bacterial vaginosis in hiv-infected women induces reversible alterations in the cervical immune environment. j aids 2008;49:520-522. this analysis has not been presented at scientific conferences or published elsewhere. external funding was not used to support this work. table i. characteristics of enrolled women and association with detection of cervical hiv rna   detection of cervical hiv rna     n yes (n(%)) no (n(%)) p total 106 75 (71) 31 (29) - study site (n=106) xai xai 70 48 (69) 22 (31) 0.49 maputo 36 27 (75) 9 (25)   education (n=84) no education 2 1 (50) 1 (50) 0.51 primary 66 45 (68) 21 (32)   secondary or mid-level 16 10 (63) 6 (37)   marital status(n=81) single 38 24 (63) 14 (67) 0.93 unmarried, in relationship 32 22 (69) 10 (31)   married 2 1 (50) 1 (50)   widowed 9 6 (67) 3 (33)   prior antiretroviral therapy(n=84) yes 1 0 (0) 1 (100) 0.15 no 83 56 (67) 27 (33)   cd4 count (cells/µl)(n=106) <50 14 12 (86) 2 (14) 0.01 50 199 31 25 (81) 6 (19)   200 349 26 21 (81) 5 (19)   >= 350 35 17 (49) 18 (51)   hiv-1 plasma viral load (copies/ml)(n=76) <10 000 12 5 (42) 7 (58) 0.006 10 000 99 999 31 24 (77) 7 (23)   >=100 000 33 24 (73) 9 (27)   abnormal vaginal flora categories* (n=106) bacterial vaginosis 47 32 (68) 15 (32) 0.04 intermediate vagina flora 34 29 (85) 5 (15)   normal vaginal flora 25 14 (56) 11 (44)   mycoplasma genitalium† (n=103) positive 14 9 (64) 5 (36) 0.62 negative 89 63 (71) 26 (29)   trichomonas vaginalis† (n=103) positive 54 41 (76) 13 (24) 0.16 negative 49 31 (63) 18 (37)   chlamydia trachomatis† (n=103) positive 1 1 (100) 0 (0) 0.51 negative 102 71 (70) 31 (30)   neisseria gonorrhoeae† (n=103) positive 1 1 (100) 0 (0) 0.51 negative 102 71 (70) 31 (30)   * diagnosed by nugent’s criteria (normal 0 3, intermediate 4 6, bacterial vaginosis 7 10). † diagnosed by polymerase chain reaction of vaginal specimens.   s e p t e m b e r 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e the immune reconstitution inflammatory syndrome (iris) is a frequent early complication of antiretroviral therapy (art), particularly in patients who commence art with low cd4 counts and established opportunistic infections. iris in hiv-infected patients results from a pathological inflammatory response to pre-existing infective, host or other antigens, alive or dead, causing clinical deterioration after initiating art.1 the most common forms of iris occur in association with mycobacterial and herpesvirus infections.2 adolescents and young adults comprise an increasing proportion of new hiv infections both in developing and developed countries, and little is known regarding hiv iris in this group. as the art roll-out has gathered pace since 2004 in resource-limited settings, adolescent iris has emerged as a clinical challenge. we describe adolescent/young adult patients who presented to our clinic with iris events. methods the study was performed at the adult infectious diseases institute (idi) at mulago hospital, kampala, uganda. the aidc is part of the makerere university infectious diseases institute and provides hiv care, including free art, to hiv-infected patients with a cd4+ count <200 cells/µl or with world health organization stage iv disease. the study was approved by the ethics panel and the institutional review board since this was a case series. among our adolescent/ young adult cohort aged 16 24 years of about 480, we have seen 6 cases of iris, including cryptococcal meningitis iris, kaposi’s sarcoma iris, herpes zoster iris, pulmonary tuberculosis iris and 2 cases of oral candidiasis iris within the past 12 months. the incidence of iris after initiation of haart was 1.25%. the median age of presentation was 22 years and the median cd4+ count before commencing art 65 cells/ µl. iris presented a median of 6 weeks from the start of haart (range 3 16 weeks). mycobacteria are by far the most common pathogens associated with iris in hiv-infected patients.3-7 other infections that have been associated with iris events include varicella zoster, herpes simplex, meningeal cryptococcosis, hepatitis, cytomegalovirus retinitis, progressive multifocal leuco-encephalopathy and intestinal parasites. while the majority of iris events are infectious in nature, auto-immune iris reactions have also been described in adults.8 discussion iris is a condition seen in some cases of aids or immunosuppression, in which the immune system begins to recover but then responds to a previously acquired opportunistic infection with an overwhelming inflammatory response that paradoxically makes the symptoms of infection worse.9 it is thought that the immunopathological response initiated by haart restores the immune response against pathogenic antigens.10 there is paradoxical worsening of preexisting infectious processes following initiation of haart in hiv-infected individuals.9 these cases highlight the risks faced during immune reconstitution in adolescent and young adult patients who commence art with advanced immunosuppression. immune reconsitution inflammatory syndrome among adolescents: a report of cases in a resource-limited setting (uganda) o r i g i n a l a r t i c l e christine katusiime1, mb chb, pgdppm ponsiano ocama2, mb chb, mmed andrew kambugu1, mb chb, mmed 1makerere university, college of health sciences, infectious diseases institute, kampala, uganda 2makerere university, college of health sciences, department of medicine, kampala, uganda we report immune reconstitution inflammatory syndromes in a cohort of adolescents/young adults over a period of 1 year at the infectious diseases institute, kampala, uganda. 18 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s e p t e m b e r 2 0 1 0 conclusion iris occurs in adolescents and young adults, but little is known about iris in general and minimal research has been conducted in the adolescent/young adult age group. references 1. lehloenya r, meintjes g. dermatologic manifestations of the immune reconstitution inflammatory syndrome. dermatol clin 2006; 24: 549-570. 2. french ma. disorders of immune reconstitution in patients with hiv infection responding to antiretroviral therapy. curr hiv/aids rep 2007; 4: 16-21. 3. fishman je, saraf-lavi e, narita m, hollender es, ramsinghani r, ashkin d. pulmonary tuberculosis in aids patients: transient chest radiographic worsening after initiation of antiretroviral therapy. ajr am j roentgenol 2000; 174: 43-49. 4. french ma. ‘tuberculosis’ after commencing antiretroviral therapy in hiv patients from countries where mycobacterium tuberculosis infection is common. aids 2006; 20: 473-474. 5. john m, french ma. exacerbation of the inflammatory response to mycobacterium tuberculosis after antiretroviral therapy. med j aust 1998; 169: 473-474. 6. narita m, ashkin d, hollender es, pitchenik ae. paradoxical worsening of tuberculosis following antiretroviral therapy in patients with aids. am j respir crit care med 1998; 158: 157-161. 7. phillips p, kwiatkowski mb, copland m, craib k, montaner j. mycobacterial lymphadenitis associated with the initiation of combination antiretroviral therapy. j acquir immune defic syndr hum retrovirol 1999; 20: 122-128. 8. viani rm. sarcoidosis and interstitial nephritis in a child with acquired immunodeficiency syndrome: implications of immune reconstitution syndrome with an indinavir-based regimen. pediatr infect dis j 2002; 21: 435-438. 9. desimone ja, pomerantz rj, babinchak tj. inflammatory reactions in hiv infected persons after initiation of highly active antiretroviral therapy. ann intern med 2000; 133: 447-454. 10. french ma, price p, stone sf. immune restoration disease after antiretroviral therapy. aids 2004; 18: 1615-1627. age (yrs) cd4 counts at initiation of haart (cells/µl) iris condition time from start of haart to onset of iris (wks) 19 45 pulmonary tuberculosis 4 20 77 oral candidiasis 6 21 56 kaposi’s sarcoma 3 23 65 herpes zoster 9 24 65 cryptococcal meningitis 16 24 73 oral candidiasis 6 table i. table displaying ages, absolute cd4 counts and presentation time of iris among adolescents/young adults over 1 year at the infectious diseases institute, kampala 19 to the editor: we at the south african national blood service (sanbs) are acutely aware of the issues surrounding the exclusion of men who have sex with men (msm) from donating blood and the negative emotions that surround this policy. i would like to assure readers that sanbs does not make such decisions lightly, and we constantly review policies based on the latest scientific findings. it is perhaps time to review the basis of the current policy and engage in debate on its scientific merit. it is, however, important to clarify a few misconceptions regarding our policies on the sexual activities of our donors. in an editorial comment on 6 january 2010, the editor of the herald newspaper in port elizabeth stated: ‘a pattern of multiple partners or of unprotected sex … is clearly also high-risk and yet heterosexual donors who may be sexually reckless are spared prying questions and the possible refusal of their offer of blood.’1 this statement is factually incorrect. when donating blood, all donors, whatever their sexual orientation, have to answer very personal questions regarding their sexual activities during the preceding 6 months.2 any person who has had any form of potentially high-risk sexual activity will be deferred for a period of 6 months following the high-risk activity. a donor who has multiple sex partners will be regarded as being at potentially high risk regardless of sexual orientation. at no point does sanbs suggest that high-risk sexual practices are exclusive to the gay community, hence the self-exclusion questionnaire’s comprehensive set of questions regarding various sexual activities and practices. there are over 450 rules guiding donor selection with sanbs’s policy on blood donations from men who have sex with men l e t t e r • l e t t e r • l e t t e r • l e t t e r s e p t e m b e r 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e regard to medical conditions and lifestyle, and there are many groups of people whom we defer from donating, either temporarily or permanently.3 some individuals in these groups may have a very low risk of blood-borne infections and their blood would probably be safe to give to patients, but since it is impossible to identify specific individuals at low risk it is safest to ask everyone in the higher risk groups not to donate blood. the request not to donate blood can be disappointing and frustrating to some people who wish to do so. our decisions are based on information and research about the effects our policies on blood supply safety, not out of a desire to discriminate against any particular group. the aims of donor selection are to: n select donors whose blood is most unlikely to transmit any infection n collect enough blood to meet patients’ needs n make sure that donors themselves come to no harm through the blood donation process. we have to balance these three aims while keeping the selection process clear and simple, bearing in mind that almost a million units of blood are collected each year – a mammoth task complicated by stringent quality control and logistics. the preliminary findings of recent studies among msm, such as the jems study conducted in johannesburg and durban and the soweto men’s study, have found their hiv prevalence to be more than double the actuarial scientists of south africa (assa)’s estimate of a 15.5% national hiv prevalence and the unaids estimate of 18.1%.4-8 south africa was one of the first countries in the world to lift the total ban on men who have sex with men donating blood. other countries such as sweden are only now starting to follow our example. we still have among the most progressive policies regarding msm in the world, and while this may not be much consolation to gay men in stable relationships, it is testimony to sanbs’s commitment to be as inclusive as possible with regard to the community we serve. internationally this is a very topical discussion. it is interesting to note that in the usa some politicians have called for the lifting of the ban against msm donating blood and that this was countered by the haemophiliac society, a group whose members were severely affected by infected blood during the 1980s. it is easy to get lost in all the numbers and emotions, but at sanbs we have the very tough responsibility of weighing up the right of an individual to donate blood against that of a patient to receive blood that is as safe as it is humanly possible to make it. the decision on which groups of the population will be or should be allowed to donate must be taken on the basis of scientific merit and the blood service’s ability to implement policies that are clear and concise. karin van den berg zone medical officer, eastern cape south african national blood service references 1. the editor. the herald, port elizabeth, 6 january 2010. 2. south african national blood service. comprehensive donor questionnaire. frmdcd-016e rev 1 (02-03-09). 3. south african national blood service. guidelines for medical assessment of blood donors. 3rd ed. pm-med-001 rev 2 (01/10/2006). 4. rispel l, metcalf c. hiv prevalence and risk behaviour among men who have sex with men (msm) in the johannesburg/ethekwini men’s study (jems). 4th south african aids conference, 31 march 3 april 2009, durban. abstract 586. 5. metcalf c, rispel l. to what extent does the hiv epidemic among men who have sex with men (msm) overlap with the generalised hiv epidemic in south africa. preliminary findings from the johannesburg / ethekwini mens study (jems). 4th south african aids conference, 31 march 3 april 2009, durban. abstract 597. 6. lane t, raymond h, dladla s, et al. high hiv prevalence among msm in soweto: results from the soweto men’s study. 4th south african aids conference, 31 march 3 april 2009, durban. abstract 597. 7. actuarial society of south africa. assa2003 aids and demographics model. 2005. http://aids.actuarialsociety.org.za/assa2003-model-3165.htm (accessed 13 may 2009). 8. unaids. http://www.unaids.org/en/countryresponses/countries/south_africa. asp (accessed 13 may 2009). 22 erratum in ‘changes to the art guidelines – an overview’, which appeared on pp. 28 30 of the april 2010 issue of the journal, the first sentence under the heading ‘national regimens’ and the heading to table i should have read ‘national regimens for adults and adolescents’ and not ‘national regimens for children and adolescents’. we apologise for these errors and have corrected them on the web version of the article, in which there are also other adjustments. abstract introduction methodology results discussion conclusion acknowledgements references about the author(s) jeanmari king division of family medicine and primary care, stellenbosch university, south africa district health services, western cape department of health, south africa dirk t. hagemeister department of family medicine, university of the free state, south africa universitas academic hospital, bloemfontein, south africa citation king j, hagemeister dt. hepatitis b co-infection in hiv-infected patients receiving antiretroviral therapy at the tc newman anti retroviral treatment clinic in paarl, western cape. s afr j hiv med. 2016;17(1), a336. http://dx.doi.org/10.4102/sajhivmed.v17i1.336 review hepatitis b co-infection in hiv-infected patients receiving antiretroviral therapy at the tc newman anti retroviral treatment clinic in paarl, western cape jeanmari king, dirk t. hagemeister received: 07 jan. 2015; accepted: 13 nov. 2015; published: 20 may 2016 copyright: © 2016. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: hepatitis b virus (hbv) and human immunodeficiency virus (hiv) co-infection in south africa is estimated to be between 5% and 23%; however, only limited evidence is available. co-infection increases the risk of chronification of hbv, liver cirrhosis and death. objective: to assess the hbv and/or hiv co-infection rate amongst the adult antiretroviral treatment cohort at the tc newman art clinic in paarl, western cape. methods: in a retrospective, cross-sectional study, the routine hepatitis b surface antigen screening results for all adult hiv patients who were started on antiretroviral treatment over a period of 19 months were collected and analysed for gender, cd4 count and age. results: amongst the 498 participants (60% female participants), the hepatitis b surface antigen positivity rate was 7.6%. male gender, age between 50 and 59 years and a low cd4 count were correlated with higher rates. conclusion: useful insight could be obtained by analysing routine data. the prevalence of almost 8% confirms the need for testing of hiv-positive patients for hepatitis b. introduction hepatitis b-hiv co-infection in global perspective hepatitis b virus (hbv), the most serious type of viral hepatitis, remains a public health problem worldwide, with an estimated 400 million cases of chronic infections and possibly as many as 6 million people co-infected with the human immunodeficiency virus (hiv) and hbv.1 hbv-hiv co-infections commonly occur because of their endemicity in the same world regions and shared routes of transmission.2,3 the rates for hbv co-infection in hiv-positive people are given as 5% – 30%, depending on geographic regions, and the co-infection is associated with an increased risk of liver cirrhosis, end-stage liver disease, and death, with low cd4 counts or concomitant alcohol use being additional risk factors.4 for two large european and north american hiv treatment cohorts, the prevalence of hbv co-infection has been given as 8.7%4 and 7.6%,5 respectively. studies in south africa have reported a hbsag positivity rate of 19.8% in a mining/industrial antiretroviral treatment (art) cohort,6 4.8% and 6.5% in two urban,7,8 22.9% in a peri-urban,9 and 7.1% in a rural10 art clinic population, respectively. chronic hbv may complicate the administration of art for hiv, because of the three-fold increase in the incidence of antiretroviral (arv) hepatotoxicity with hiv-hbv co-infection as well as the more complex selection of drugs to avoid resistances.4,6,11 lamivudine, emtricitabine and tenofovir have been shown to possess both anti-hiv and anti-hbv properties.3 as lamivudine has a comparatively low genetic barrier to viral resistance, monotherapy with this drug should be avoided.12 management of hepatitis b virus-hiv co-infection in south africa based on evidence on the efficacy of tenofovir against hbv,11 the potential problem of hbv monotherapy with the existing first-line art regimen and an estimated 5% hiv-hbv co-infection rate, the provincial government of the western cape province in south africa introduced a policy on hepatitis b screening of hiv patients and the substitution of tenofovir for stavudine in july 2008.13 subsequently, all patients attending the art clinics to initiate treatment were to be screened using the serum hbsag test. this testing policy was terminated in 2010, when new national south african antiretroviral treatment guidelines introduced tenofovir as recommended first-line treatment in place of stavudine. with two hbv-active substances now part of the first-line hiv treatment, hepatitis b screening was no longer recommended during baseline workup. however, the period of hbsag screening provided a window of opportunity for retrospective ‘data mining’ to establish an estimate for the local positivity rate amongst the hiv-infected population. an active hepatitis b vaccination has been part of the south african childhood vaccination programme since 1995, giving hope that the rate of co-infection in the younger population will decrease significantly. with regards to screening recommendations, the most recent (2014) hiv treatment guidelines by the southern african hiv clinicians society recommend hbsag screening for all newly diagnosed hiv patients.14 those with chronic hbv (positive hbsag) qualify for art initiation, and ‘eligible’ (negative) adults should be considered for vaccination. the national hiv treatment guidelines by the south african department of health (2014) include hbsag screening and art initiation of co-infected patients, but do not mention the option of vaccination.15 methodology a retrospective, observational and cross-sectional study was performed. approval was obtained from the health research ethics committee of stellenbosch university (n10/11/360) and the department of health of the provincial government of the western cape. the study population consisted of all adult (aged 18 years and older) hiv patients presenting to the tc newman art centre for art initiation from 01 october 2008 until end of april 2010, when a new art protocol was introduced and the routine hbsag screening was omitted. serum was routinely tested for hbsag as part of baseline screening tests as per provincial protocol, and the results were available retrospectively. no additional expenditure for laboratory testing was incurred. information regarding all patients started on art at the tc newman art centre was available from an existing database. tc newman is a community health centre with a dedicated arv clinic, located in the cape winelands town of paarl, about 40 km from cape town. from 2004 to 2010, approximately 2700 patients had been started on art. the relevant data (gender, age, cd4 counts and hbsag) for the study population were retrieved and the anonymised data were entered into a ms excel spreadsheet and analysed by a statistician using statistica version 8 (statsoft inc. 2008). as the hbsag results were not routinely captured on the database, the results had to be retrieved from the national health laboratory services’ database (wwdisa). for those patients (185) where no results could be found on this system, patients’ folders had to be retrieved and reviewed manually. summary statistics were used to describe the variables. distributions of variables were presented with histograms and frequency tables. relations between input and response variables were analysed using appropriate statistical tools (analysis of variance and likelihood ratio chi-square tests), as applicable. a p-value of < 0.05 was considered to represent statistical significance in hypothesis testing, and 95% confidence intervals were used to describe the estimates of unknown parameters. results demographics of research sample out of a total of 569 patients examined for initiation of highly active antiretroviral therapy at tc newman (i.e. approximately 30 per month), 498 had hepatitis b results available and were included in the study population. of the 71 patients (12.4%) who had no hepatitis b result available, folders for 7 patients could not be located, whilst 64 had not been tested, most of them during the phasing-in and -out of the protocol in the first and last months. a breakdown of the basic demographics of the study sample is given in table 1. table 1: demographics and baseline values of the sample. hepatitis b surface antigen positivity rates the overall prevalence for hbsag positivity was 7.6%, with a prevalence amongst male patients of 9% (18/199) and amongst female patients of 6.6% (20/299); however, the difference was not statistically significant (p = 0.33). the highest prevalence of hepatitis b was found in the age group 50–59 years of 17.2% (5/29), followed by 12% (12/100) in the age group 40–49, 5.9% (13/220) in the age group 30–39, 5.8% (8/137) in the age group 18–29 and 0% (0/10) in the age group 60–69 (figure 1). this tendency of correlation with age was not significant (p = 0.076). figure 1: hepatitis b surface antigen positivity for different cd4 counts and age groups in the study population. in the group with the lowest cd4 count, the highest prevalence of 12% was found, with the next highest of 8.3% in those with a cd4 count of 51–200. no significant correlation between hbsag positivity and cd4 count occurred (p = 0.1). discussion the prevalence of hbsag positivity in hiv-positive patients of 7.6% is comparable to those rates found in studies in the northern hemisphere as well as to those in a number of south african treatment cohorts, with most of the studies showing rates between 5% and 9%, with only two ‘outliers’ around 20%.4,5,6,7,8,9,10 also in keeping with the generally documented trends are our findings of higher co-infection rates amongst males and in individuals with lower cd4 counts. the rate of 7.6% of active chronic infections found in this study might reflect a higher rate of chronification of hbv infections after acute infections in the hiv-positive population, as suggested in the literature, but might also be due to increased risk behaviour or exposure that led to the hiv infection. hiv-hbv co-infections constitute a significant problem in our local population, with 1 in 12 patients who start art being co-infected. against the background of the current treatment guidelines,14,15 these cases will be picked up if the guidelines are adhered to. as the two first-line hiv drugs tenofovir and lamivudine (or its ‘equivalent’, emtricitabine) are both active against hbv, the clinical relevance of these co-infections arises once the decision to discontinue tenofovir would be on the cards. this might either be the case in hiv treatment failure with the first-line regimen or if tenofovir needs to be discontinued because of its nephrotoxicity, e.g. in renal failure or the concurrent use of other nephrotoxic drugs such as second-line tb drugs. whilst it is appropriate in the former scenario to continue tenofovir together with the new (second-line) arv regimen, the latter scenario is more complicated and would need expert advice to balance harm and benefit. the finding that the majority of our study population had a cd4 count below 200 can be explained by the fact that the major trigger for treatment initiation in the 2008 national arv protocol was a cd4 count below this threshold. strengths and limitations of our study the fairly complete cohort is a strength of this study, with only 12% of the study population not having hbsag results available. limitations are the selection of the study population. as all patients required arv treatment, they represent a sample of advanced hiv infection. the (opportunistic) use of existing laboratory data is a further limitation, as the screening with hbsag is unable to detect so-called ‘occult’ infections and no further serological tests could be performed on the samples. conclusion in this study, we found the overall prevalence of hepatitis b antigen positivity amongst hiv-positive adult patients starting art in paarl to be 7.6%. there was a trend towards a higher prevalence amongst men, the age group 50–59 as well as those with a cd4 count below 50 µl; however these findings were not statistically significant. ‘opportunistic’ research, using existing data collected as part of routine screening policies, can successfully be used to acquire relevant epidemiological information. a reasonably good compliance with the testing policy was found, with only 11.2% of the study population not having had a hbsag performed, whilst 1.2% of the folders could not be located. acknowledgements we gratefully acknowledge professor daan nel’s assistance with the statistical analysis of the data. competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions both authors conceptualised the research together, j.k. collected the data and drafted the initial report. d.t.h. supervised the research and redrafted the manuscript for publication. references kourtis ap, bulterys m, hu dj, jamieson dj. hiv–hbv coinfection — a global challenge. n engl j med. 2012;366(19):1749–1752. soriano v, puoti m, peters m, et al. care of hiv patients with chronic hepatitis b: updated recommendations from the hiv-hepatitis b virus international panel. aids. 2008;22(12):1399–1410. dienstag jl. hepatitis b virus infection. n engl j med. 2008;359(14):1486–1500. konopnicki d, mocroft a, de wit s, et al. hepatitis b and hiv: prevalence, aids progression, response to highly active antiretroviral therapy and increased mortality in the eurosida cohort. aids lond engl. 2005;9(6):593–601. kellerman se, hanson dl, mcnaghten ad, fleming pl. prevalence of chronic hepatitis b and incidence of acute hepatitis b infection in human immunodeficiency virus–infected subjects. j infect dis. 2003;88(4):571–577. hoffmann cj, charalambous s, martin dj, et al. hepatitis b virus infection and response to antiretroviral therapy (art) in a south african art program. clin infect dis. 2008;47(11):1479–1485. firnhaber c, reyneke a, schulze d, et al. the prevalence of hepatitis b co-infection in a south african urban government hiv clinic. s afr med j. 2008;98(7):541–544. mayaphi sh, rossouw tm, masemola dp, olorunju sa, mphahlele mj, martin dj. hbv/hiv co-infection: the dynamics of hbv in south african patients with aids. s afr med j. 2012;102(3):157–162. lukhwareni a, burnett rj, selabe sg, mzileni mo, mphahlele mj. increased detection of hbv dna in hbsag-positive and hbsag-negative south african hiv/aids patients enrolling for highly active antiretroviral therapy at a tertiary hospital. j med virol. 2009;81(3):406–412. boyles th, cohen k. the prevalence of hepatitis b infection in a rural south african hiv clinic. s afr med j. 2011;101(7):470–471. dore gj, cooper da, pozniak al, et al. efficacy of tenofovir disoproxil fumarate in antiretroviral therapy-naive and-experienced patients coinfected with hiv-1 and hepatitis b virus. j infect dis. 2004;189(7):1185–1192. spearman cwn, sonderup mw, botha jf, et al. south african guideline for the management of chronic hepatitis b: 2013. s afr med j [serial online]. 2013 [cited 2015 sep 19]; 103(5). available from: http://hmpg.co.za/index.php/samj/article/view/3333 department of health of the western cape. arv treatment: substitution of tenofovir in place of stavudine and/or zidovudine: baseline screening for hepatitis b chronic infection in patients starting antiretroviral treatment. circular no h81/08. cape town: department of health; 2008. meintjes g, black j, conradie f. guideline – adult antiretroviral therapy guidelines 2014 – by the southern african hiv clinicians society. s afr j hiv med. 2014;15(4):121–143. republic of south africa. department of health. national consolidated guidelines for the prevention of mother-to-child transmission of hiv (pmtct) and the management of hiv in children, adolescents and adults – 24 december 2014 [homepage on the internet]. 2014 [cited 2015 sep 19]. available from: www.health.gov.za/index.php/2014-03-17-09-09-38/policies-and-guidelines/category/230-2015p?download=937:national-art-guidelines-2015final make up sept 2006 the southern african journal of hiv medicine september 2006 55 of late we have witnessed a number of important initiatives that aim to promote expanded screening for hiv infection. there have been calls by public health authorities, including the world health organization, for a move away from the traditional voluntary counselling and testing (vct) model. one initiative currently underway in many countries, including botswana, is the ‘opt out’ model where patients would be subjected to routine hiv testing unless they expressly state that they do not wish to be tested. the centers for disease control has developed a document entitled ‘revised recommendations for hiv testing of adults, adolescents, and pregnant women in health care settings’. this document recommends that hiv testing become a routine part of medical care for all teenagers and adults in the usa. this will have the effect of enhancing hiv case finding and represents a major shift to hiv testing in clinical practice in the usa. the rationale for this expanded screening meets many of the criteria for an effective preventive practice intervention, in that hiv serological tests are reliable and inexpensive, untreated infection has serious health consequences, and highly effective treatment is now becoming increasingly accessible. recent cost-effectiveness analyses have demonstrated that hiv screening is as cost-effective as screening interventions for other chronic diseases. two articles in this issue of the journal look at various aspects related to testing, vct and the stigmatisation around hiv. we have published an article by a person living with hiv who describes his personal experiences at the time of testing: how he faced the stigmatisation, how it changed his life, and how he used this life-changing event to become an advocate of promoting vct in order to know your status. as he says, ‘take action now and know your status.’ in common with other scientific journals we have included a personal essay to emphasise the issues at stake. des martin editor, southern african journal of hiv medicine f r o m t h e e d i t o r this issue of the journal is being put to bed as the first botswana hiv conference closes. the conference, put together by a committed group of local members of the botswana hiv clinicians society, has been an overwhelming success – an audience of over 700, international and local experts giving excellent talks, within a professionally run operation. feedback on proceedings has been very positive, and i would like to congratulate the conference committee and the botswana branch on an inspired and brave programme. i sincerely hope you repeat it in the future – the flavour was distinctly african, the debate robust and honest, and the clinical exposure impressive. there are rumours of the conference being repeated, and word of mouth on the quality of this one will ensure that the next is even bigger. congratulations again to botswana, who seem to know how to lead from the front in all areas of hiv. francois venter president m e s s a g e f r o m t h e e x e c u t i v e professor sheila tlou, botswana minister of health, dr francois venter, southern african hiv clinicians society, his excellency festus mogae, president of the republic of botswana, and dr kgosi mompati, president of the botswana branch of the sahivcs and chairman of the conference committee. sajhiv message from exec message from the executive at the outset, i ask that you forgive my odd poetic licence and mixed metaphors. this describes my journey as an hiv clinician in the decade that has seen us develop the biggest hiv treatment programme in the world. i clearly remember the first day that our clinic started administering antiretrovirals (arvs). it was the day that i wrote and passed the exam for the hiv management diploma, and i was unable to be at the clinic. it was only on 2 april 2004 that i went to the clinic. i looked in the drug cupboard and realised that we would finally be able to provide south africans access to life-saving medication. for the next couple of months, as soon as i was finished at the research site where i worked, i went to the clinic at helen joseph hospital to start patients on arvs. in august of that year we celebrated with cake and tea after we had started our 1 000th patient on treatment. then it dawned on me that despite having initiated 1 000 patients in our clinic through all that work, time and effort, on that day the same number of people in south africa had become infected with the virus. that was when i adopted the so-called ‘starfish’ approach. the story goes that a man was walking along a deserted beach at sunset and saw a young boy on the beach, picking something up and throwing it into the water. when asked what he was doing, the boy replied: ‘i am throwing these washed up starfish back into the ocean, or else they will die.’ ‘you can’t possibly save them all, there are thousands on this beach, and this must be happening on hundreds of beaches along the coast. you can’t possibly make a difference,’ said the bystander. the boy looked down, frowned for a moment; bent down to pick up another starfish, and smiled as he threw it back into the sea. he replied: ‘i made a huge difference to that one!’ i loved telling my hiv stories or tales of starfishes: patients arriving looking like skeletons and getting better; my marathon-running hiv-infected patient; and babies so sick they were sent home to die, but having been started on treatment, are now at school. i even coined a term for this in our clinic: ‘the lazarus experience’. and my activist side was fuelled by the ongoing battles with the mbeki-era denialist and our erstwhile minister of health, manto tshabalala-msimang. however, two things bothered me. the first was that south africa became the laughing stock at international conferences, despite a growing arv programme and good research emanating from the country. quips about beetroot and garlic may have been taken in good humour, but i felt hard done by. we had a good grassroots programme staffed by dedicated healthcare workers who hated to see patients who could have been saved, die. the other was that tossing starfishes back into the sea was no longer enough for me. i wanted a more effective approach to prevent the starfish from getting stranded on the beach and more effective ways of getting those who were stranded on the beach back into the sea. in retrospect, this was when i changed from being a clinician to more of a public health person. fortunately, this also coincided with the end of the ‘manto era’, and within a short while, the appointment of dr aaron motsaeledi as the national minister of health. what the latter has done for the programme is immense. i have highlighted some of the aspects that i have seen in my work as really pushing forward access. dr motsaeledi decreased the amount of red tape that clinics had to go through to become arv sites, considerably decentralising the service. we now have over 3 500 clinics in south africa providing arvs. his ambitious aim to test 15 million for hiv was achieved. the mean cd4+ count on presentation is increasing and we are seeing fewer and fewer patients presenting in extremi s. at the academic ward rounds that i attend every six weeks, we are now seeing older patients presenting with malignancies or long-term complications of antiretroviral therapy (art). with the review of the guidelines in 2010, stavudine (d4t), a drug we all knew had severe side-effects, was removed from the first line and replaced with the gentler tenofovir (tdf). finally, the fixed-dose combination means that most patient have to swallow just one pill once a day. so ten years down the line, what is my role in the arv pro­gramme? as an activist, i am perplexed. the national depart­ment of health is making all the right noises, but we still need to be vigilant in ensuring that they keep their promises. this includes keeping an eye on stock-outs and making sure that no one is turned away from clinics on the basis of their nationality. i need to keep up with the latest research and do what i can to ensure that when a significant development takes place, it is included in policy. most of all, i must just do what i can to support the programme with clinical advice, training and advocacy. while much has been made in the media of getting to zero and the end of aids – we are getting closer than ever before – if we let up now, we will see an increase in hiv-related morbidity and mortality. we need to buckle down and do the work of testing and treating all who come to our doors, and of ensuring that they adhere to lifelong art. francesca conradie president southern african hiv clinicians society fconradie@witshealth.co.za a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e the response to hiv in sub-saharan africa (ssa) in the past decade has resulted in one of the largest and most dramatic health interventions in recent history,1 with the provision of antiretroviral therapy (art) both as treatment to infected adults and children and to prevent vertical transmission of hiv from mother to child. where monitoring systems have been able to track outcomes of large-scale art programmes in ssa, they appear to be effective.2,3 however, outside of small demographic surveillance sites4 6 weak vital registration systems limit our ability to demonstrate the populationlevel impact of these interventions. south africa is unique in having a high burden of hiv disease together with one of the most complete vital registration systems on the continent, in which 80% of deaths are currently estimated to be registered.7 we have previously demonstrated in south africa at a national level that infant deaths (at ages 1 11 months) increased over the period 1997 2002,8 with the greatest increase at 2 3 months of age. this peak in early provincial differences in infant deaths in south africa – an effect of antiretroviral interventions? o r i g i n a l a r t i c l e a boulle,1 mb chb, phd m l thompson,1,2 phd r laubscher,3 bcom l f johnson,1 phd, aia r sayed,1 msc l l brody,1 mph b draper,4 mb chb, mmed m f cotton,5 mmed, phd f abdullah,6 mb chb, bsc (hons), fcpmh (sa) j e myers,1 bsc, mb chb, dtm&h, md d e bourne,1 bsc, bphil 1school of public health and family medicine, faculty of health sciences, university of cape town 2department of biostatistics, university of washington, seattle, usa 3biostatistics unit, south african medical research council, cape town 4knowledge translation unit, lung institute, university of cape town 5department of paediatrics and child health, stellenbosch university, tygerberg, w cape 6the global fund to fight aids, tuberculosis and malaria, geneva, switzerland objective. it has previously been demonstrated that a peak in registered infant deaths, at 2 3 months of age at death, developed between 1997 and 2002 in south africa, alongside the evolving hiv epidemic. the objective of this analysis was to explore the age distribution of post-neonatal infant deaths in south africa by province, and relate the observed distributions to hiv and intervention characteristics. design. ecological study based on registered infant deaths and published hiv and intervention characteristics. methods. numbers of registered infant deaths beyond 1 month of age at death were plotted by year of death, province of south africa and age at death in months, for the years 1997 2007. results. the total number of registered deaths in infants aged 1 11 months increased from 15 404 in 1997 to 34 479 in 2006. eight of the 9 provinces experienced an annual peak in registered infant deaths at 2 3 months of age between 1997 and 2007. this peak in mortality was not observed in the western cape. in 7 of 9 provinces registered post-neonatal infant deaths did not rise markedly in 2007 compared with 2005. conclusions. we identified a single province out of 9 south african provinces in which a peak in early infant deaths at age 2 3 months did not occur during the period 1997 2007. this was the province with the earliest and highest coverage of antiretroviral interventions from 1999 onwards. it is possible that these interventions have averted the greater increase in early infant deaths seen in the rest of south africa over this period. 20 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 1 infant deaths could not be ascribed solely to improving registration of deaths over time, and was consistent with cohort studies of hiv-infected infants.9 -10 in this present analysis we describe post-neonatal infant mortality by age in months across the 9 provinces in south africa from 1997 to 2007, and reflect on the relationship between the early peak in infant deaths and province-specific hiv epidemic and intervention characteristics. setting antenatal hiv-1 seroprovalence had reached 17.0% in pregnant women in south africa by 1996, rose steadily to 30.2% by 2005, and has subsequently remained around this level.11 in 2005, the hiv seroprevalence varied between provinces from 15.7% in the western cape to 39.1% in kwazulu-natal (table i). there have also been large inter-provincial variations in both timing and coverage of antiretroviral interventions in south africa.12 methods we obtained south african infant mortality counts by age at death for the period 1997 2007 from statistics south africa. infant deaths under 1 month were excluded from analysis because of the potential misclassification of live and stillbirths. absolute counts of infant deaths were considered by province, year and age at death in months, starting at 1 month of age. for graphical presentation purposes, counts were averaged across the periods 1997 1999, 2000 2001, 2002 2003, 2004 2005 and 2006 2007. all analyses were conducted using stata statistical software v11.0 (stata-corp inc, college station, texas). the study was approved by the university of cape town research ethics committee. results the total number of registered deaths in infants aged 1 11 months increased from 15 404 in 1997 to 34 479 in 2006 (32 828 in 2007). eight of the 9 provinces experienced an annual peak in registered infant deaths at 2 3 months of age between 1997 and 2007 (fig. 1). this peak in mortality was not observed in the western cape. in 7 of 9 provinces registered post-neonatal infant deaths did not rise markedly in 2007 compared with 2005 (table i). expressed as a ratio to deaths at 11 months of age (which compensates for increasing registration over time), this peak was still present in 2006 2007 in the 8 provinces where it was observed, but had declined in 5 compared with the ratios seen in previous calendar periods. discussion our previous study demonstrated, at a national level for the period 1997 2002, a year-on-year increase in infant mortality at each age of death (1 11 months), with the greatest increase at 2 3 months.8 this current analysis by province for the period 1997 2007 demonstrates the continued presence of a peak in infant deaths at 2 3 months of age in the context of the evolving hiv epidemic in south africa, with reported mortality stabilising in most fig. 1. registered post-neonatal deaths in south african infants by age in months, province and year of death registration (note that the scale differs between provinces). 21 a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e provinces in 2006 2007. the analysis further identifies the absence of a peak in mortality at 2 3 months in the western cape. the rapid rise in registered deaths over the period 1997 2005 is largely attributable to improvements in the registration of infant deaths,13 but could also in part be due to increasing levels of maternal hiv prevalence (table i), which have led to increasing levels of vertical hiv transmission and aids mortality. the absence of a further increase after 2005 in registered early infant deaths in 7 of the 9 provinces could potentially be ascribed to the slowing of the year-on-year increases in the completeness of infant death registration,13 the stable proportion of pregnant women with hiv since 2005, and the accelerated scale-up of prevention of mother-to-child transmission (pmtct) and art interventions after 2005 (table i). the absence of this peak in the western cape corresponds with a delayed provincial hiv epidemic, and exceptionally high coverage of pregnant women with pmtct interventions of increasing effectiveness. pmtct was first introduced in the western cape in 1999 in khayelitsha,14 following the protocols that had been effective in thailand.15 at the time this was the sub-district in the province with the highest antenatal hiv seroprevalence (22% in 2001).16 between 2000 and 2003, pmtct interventions were extended to the rest of the province based on the hivnet-012 protocols,17 reaching universal availability and over 80% coverage in early 2003.18 by early 2004 the intervention had been intensified, combining antenatal zidovudine with peripartum nevirapine, and both nevirapine and zidovudine prophylaxis to neonates.19,20 in contrast, in other provinces pmtct was only officially sanctioned in 18 pilot sites in 2001. in 2003 less than a quarter of pregnant women in south africa received hiv testing, and less than half in 2005 (table i),12 with more than a third of those testing hiv positive in these provinces in 2005 not receiving even the moderately effective single-dose nevirapine-based interventions that were available at the time.21 a plausible explanation for the absence of the peak in infant deaths at 2 3 months of age in the western cape is that by the time the proportion of pregnant women who were hiv-infected reached high levels, the majority were able to access pmtct interventions, which increased in effectiveness over time. in addition to the high coverage of pmtct in the province, the inclusion of antenatal zidovudine in provincial pmtct protocols probably resulted in less intra-uterine vertical transmission, which is believed to contribute relatively more to early infant mortality than intrapartum and postpartum transmission.9,22 ec fs gt kzn lp mp nc nw wc sa births (100 000s)* 2001 1.66 0.64 2.08 2.48 1.53 0.85 0.18 0.85 1.00 11.27 2003 1.61 0.63 2.10 2.45 1.52 0.84 0.18 0.84 1.01 11.15 2005 1.59 0.62 2.04 2.41 1.53 0.82 0.18 0.83 1.00 11.00 2007 1.61 0.61 1.94 2.38 1.55 0.82 0.18 0.82 0.99 10.84 registered infant deaths, 1 11 months (1 000s) 2001 1.97 2.43 5.06 5.09 1.08 1.60 0.55 2.59 1.36 21.72 2003 2.77 3.06 6.35 5.87 1.62 2.43 0.53 3.25 1.43 27.31 2005 3.47 3.88 7.09 7.07 2.50 3.13 0.51 4.13 1.55 33.33 2007 3.24 3.45 7.21 6.75 3.25 2.91 0.80 3.56 1.67 32.83 antenatal hiv seroprevalence (%)† 2001 21.7 30.1 29.8 33.5 14.5 29.2 15.9 25.2 8.6 24.8 2003 27.1 30.1 29.6 37.5 17.5 32.6 16.7 29.9 13.1 27.9 2005 29.5 30.3 32.4 39.1 21.5 34.8 18.5 31.8 15.7 30.2 2007 26.0 33.5 30.3 37.4 18.5 32.0 16.1 29.0 16.1 28 hiv testing of pregnant women (%)‡ 2001 1.7 4.6 7.2 1.0 0.6 5.0 2.2 6.9 2003 31.1 17.6 26.0 10.9 18.2 86.0 25.3 2005 40.4 47.4 43.8 46.5 31.4 59.1 47.9 49.1 2007 75.3 80.1 73.3 70.7 90.1 74.6 88.5 85.6 95.7 81.0 adult art coverage (%)§ 2001 3.0 2.5 3.9 3.4 2.2 2.9 3.3 2.4 5.1 3.3 2003 5.2 2.9 10.0 4.6 3.0 4.2 5.8 3.4 33.9 6.7 2005 26.6 16.6 37.0 32.4 24.2 20.5 42.5 35.8 66.5 32.8 2007 40.9 36.8 58.4 56.5 47.7 44.0 81.3 40.7 89.2 54.0 paediatric art coverage (%)§ 2001 1.1 1.2 1.8 1.4 0.7 1.2 1.5 1.1 2.5 1.4 2003 2.3 1.7 6.9 2.2 1.2 1.8 3.9 1.6 36.8 3.9 2005 13.1 11.7 31.1 20.8 9.0 12.2 51.8 18.9 58.5 20.6 2007 26.8 22.1 46.0 30.6 35.9 29.4 96.1 50.7 96.9 36.9 table i. births, infant deaths, and hiv and antiretroviral intervention characteristics in south africa by province *source: actuarial society of south africa aids and demographic model.24 †source: antenatal surveys from the national department of health.25 -27 ‡source: child gauge 2009.12 value in italics is from an alternative source.18 §coverage reflects the ratio of new enrolments to the number of individuals anticipated to be newly aids symptomatic in each year, based on (*) above.28 22 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 1 a decline in under-2 mortality has recently been described in a rural kwazulu-natal setting after 2004,4 ascribed in part to the pmtct programme that was rapidly scaled up in the surveillance area before the observed decline. the kwazulu-natal study found that the major part of this decline was in post-neonatal infant deaths, in keeping with the currently presented data. the current study has a number of limitations. the ecological design cautions us to consider alternative explanations for our observations. as discussed, the lack of clarity on the completeness of infant death registration complicates the interpretation of these data. further, we did not attempt to analyse mortality trends by cause of death, owing to the low proportion of hivrelated deaths recorded as being due to hiv.23 we have, however, demonstrated previously that the peak at 2 3 months of age was absent in the small proportion of infant deaths where hiv was unlikely to be related to the underlying cause.8 we have identified a single province out of 9 south african provinces in which a peak in early infant deaths at 2 3 months of age did not occur during the period 1997 2007. this was the province with the earliest and highest coverage of arv interventions from 1999 onwards. it is possible that these interventions have averted the greater increase in early infant deaths seen in the rest of south africa over this period. prospective monitoring of the age pattern of infant deaths by province could in future prove an important tool for assessing the impact of arv and pmtct interventions on child survival in south africa as the completeness of infant death registration stabilises, and the coverage and effectiveness of interventions are further intensified. references 1. world health organization. towards universal access: scaling up priority hiv/ aids in the health sector. progress report. geneva: who, 2008. 2. stringer js, zulu i, levy j, et al. rapid scale-up of antiretroviral therapy at primary care sites in zambia: feasibility and early outcomes. jama 2006;296(7):782-793. 3. boulle a, bock p, osler m, et al. antiretroviral therapy and early mortality in south africa. bull world health organ 2008;86(9):678-687. 4. ndirangu j, newell ml, tanser f, herbst aj, bland r. decline in early life mortality in a high hiv prevalence rural area of south africa: evidence of hiv prevention or treatment impact? aids 2010;24(4):593-602. 5. herbst aj, cooke gs, barnighausen t, kanykany a, tanser f, newell ml. adult mortality and antiretroviral treatment roll-out in rural kwazulu-natal, south africa. bull world health organ 2009;87(10):754-762. 6. jahn a, floyd s, crampin ac, et al. population-level effect of hiv on adult mortality and early evidence of reversal after introduction of antiretroviral therapy in malawi. lancet 2008;371:1603-1611. 7. statistics south africa. mortality and causes of death in south africa, 2006: findings from death notification. pretoria: statistics south africa, 2008. 8. bourne de, thompson m, brody ll, et al. emergence of a peak in early infant mortality due to hiv/aids in south africa. aids 2009;23(1):101-106. 9. marinda e, humphrey jh, iliff pj, et al. child mortality according to maternal and infant hiv status in zimbabwe. pediatr infect dis j 2007;26(6):519-526. 10. newell ml, coovadia h, cortina-borja m, rollins n, gaillard p, dabis f. mortality of infected and uninfected infants born to hiv-infected mothers in africa: a pooled analysis. lancet 2004;364:1236-1243. 11. national department of health. 2008 national antenatal sentinel hiv & syphilis prevalence survey. pretoria: department of health, 2009. 12. johnson l. child health: hiv/aids. in: pendlebury s, lake l, smith c, eds. south african child gauge 2008/2009. cape town: children's institute, university of cape town, 2009. 13. darikwa tb. estimating the level and trends of child mortality in south africa, 19962006. mphil (demography) thesis, university of cape town, 2009. 14. abdullah mf, young t, bitalo l, coetzee n, myers je. public health lessons from a pilot programme to reduce mother-to-child transmission of hiv-1 in khayelitsha. s afr med j 2001;91(7):579-583. 15. shaffer n, chuachoowong r, mock pa, et al. short-course zidovudine for perinatal hiv-1 transmission in bangkok, thailand: a randomised controlled trial. bangkok collaborative perinatal hiv transmission study group. lancet 1999;353:773-780. 16. western cape department of health. antenatal hiv and syphilis prevalence survey 2001. cape town: western cape department of health, 2002. 17. guay la, musoke p, fleming t, et al. intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of hiv-1 in kampala, uganda: hivnet 012 randomised trial. lancet 1999;354:795802. 18. draper b, abdullah f. a review of the prevention of mother-to-child transmission programme of the western cape provincial government, 2003 2004. s afr med j 2008;98(6):431-434. 19. lallemant m, jourdain g, le coeur s, et al. single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of hiv-1 in thailand. n engl j med 2004;351(3):217-228. 20. coetzee d, hilderbrand k, boulle a, draper b, abdullah f, goemaere e. effectiveness of the first district-wide programme for the prevention of mother-tochild transmission of hiv in south africa. bull world health organ 2005;83(7):489494. 21. health systems trust. district health barometer 2007/08. durban: health systems trust, 2009. 22. mayaux mj, burgard m, teglas jp, et al. neonatal characteristics in rapidly progressive perinatally acquired hiv-1 disease. the french pediatric hiv infection study group. jama 1996;275(8):606-610. 23. yudkin pl, burger eh, bradshaw d, groenewald p, ward am, volmink j. deaths caused by hiv disease under-reported in south africa. aids 2009;23(12):16001602. 24. assa2003lite aids and demographic model of the acturial society of south africa. http://www.assa.org.za (accessed 7 may 2009). 25. national department of health. the national hiv and syphilis prevalence survey south africa 2003. pretoria: department of health, 2004. 26. national department of health. the national hiv and syphilis prevalence survey south africa 2005. pretoria: department of health, 2006. 27. national department of health. the national hiv and syphilis prevalence survey south africa 2007. pretoria: department of health, 2008. 28. johnson l. hiv and health – access to pmtct: hiv testing. children count: statistics on children in south africa. cape town: children's institute, university of cape town, 2009. http://www.childrencount.ci.org.za (accessed 24 may 2010). we dedicate this report to the memory of our friend and colleague, david bourne, who died unexpectedly in february 2009. david worked as a statistician and demographer in the school of public health and family medicine at the university of cape town for over 30 years, and was a passionate voice in describing the impact of hiv in south africa. in recent years he became increasingly interested in the use of routine surveillance to track the evolving hiv epidemic, and in particular the age distribution of infant deaths, initiating among others this analysis, which was in process at the time of his death. 23 a p r i l 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e the purpose of the changes to the guidelines is not just to meet the presidential mandates, but also to bring the guidelines in line with international recommendations and ensure the use of more efficacious drugs, including the phasing out of stavudine from the national art programme. electronic versions of the treatment guidelines are available on the sanac website (www.sanac.org.za). the following is a brief summary of the key changes. priority groups owing to the high cost associated with art, and the high burden of people in need of art in south africa, eligibility criteria have been adapted only for priority groups. these are: n hiv-infected pregnant women n hiv-infected infants n people with both tuberculosis (tb) and hiv infection n people with multidrug-resistant (mdr) or extensively drug-resistant (xdr) tb. eligibility to start art n cd4 count <200 cells/µl, irrespective of clinical stage, or n cd4 count <350 cells/µl in patients with tb/hiv co-infection, or pregnant women, or n who stage 4 disease, irrespective of cd4 count, or n mdr/xdr tb, irrespective of cd4 count. in addition, certain patients are fast-tracked to be initiated on art, which means they should be started within 2 weeks of receiving their cd4 result and choosing to start lifelong art: n pregnant women n patients with a cd4 count below 100 cells/µl n any patient with who stage 4 disease n any patient with mdr or xdr tb. national regimens national regimens for children and adolescents are set out in table i. national regimens for mothers and infants are set out in tables ii and iii. national regimen for infants children for children, eligibility criteria to start art are: n all children under 1 year of age, irrespective of cd4 level n children between 1 and 5 years with clinical stage 3 or 4, or a cd4 percentage of 25 or below, or an absolute cd4 count under 750 n children over 5 and up to 15 with clinical stage 3 or 4, or cd4 350 and below. the first-line regimens for children are: n infants and children under 3: abacavir + lamivudine + lopinavir/ritonavir n children 3 and older: abacavir + lamivudine + efavirenz. changes to the art guidelines – an overview g u i d e l i n e s celicia serenata south african national aids council secretariat 28 in 2009 the south african national aids council (sanac) treatment technical task team (ttt) finalised recommendations for changes to the national standard treatment guidelines for adult and paediatric management and treatment, as well as changes in the prevention of mother-to-child transmission of hiv (pmtct) guidelines, moving away from monotherapy to dual therapy. president zuma announced changes in the national antiretroviral therapy (art) programme on world aids day 2009. subsequently additional changes were made to the treatment guidelines to be in line with these new presidential mandates, which came into effect on 1 april 2010. t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 0 29 if a child is currently on a stavudine-based regimen, and is not experiencing any side-effects, the regimen should be maintained. substitutions are only made once lipodystrophy is suspected. the second-line regimens for children are: n children 3 and older: zidovudine + didanosine + lopinavir/ritonavir n children failing on the first-line regimen: zidovudine + didanosine + lopinavir/ritonavir woman regimen comment eligible for lifelong art (i.e. cd4 ≤350/µl tdf + 3tc/ftc + nvp start lifelong art within 2 weeks or who clinical stage 3 or 4) currently on lifelong art continue art substitute efv with nvp if in first 12 weeks of pregnancy contraindication to tdf (renal disease) azt + 3tc + nvp not eligible for art, i.e. cd4 >350/µl and azt from 14 weeks who stage 1 or 2 sdnvp + azt 3-hrly in labour tdf + ftc single dose (stat) post-delivery unbooked and presents in labour sdnvp + azt 3-hrly in labour assess maternal art eligibility tdf + ftc single dose post-delivery before discharge table ii. national regimen for mothers infant regimen comment mother on lifelong art nvp at birth and then daily for 6 weeks irrespective of infant feeding choice mother on pmtct nvp at birth and then daily for 6 weeks continued if formula fed, baby can stop nvp at as long as any breastfeeding 6 weeks mother did not get any arv nvp as soon as possible and daily for at least assess art eligibility for the motherbefore or during delivery 6 weeks continued as long as any breastfeeding within 2 weeks unknown maternal status give nvp immediately because orphaned or abandoned test infant with rapid hiv test. if positive, continue follow-up 6-week hiv dna pcr nvp for 6 weeks. if negative, discontinue nvp table iii. national regimen for infants first line all new patients needing treatment tdf + 3tc/ftc + efv/nvp for tb co-infection efv is preferred for pregnant women or women of child-bearing age, not on reliable contraception, nvp is preferred currently on d4t-based regimen d4t + 3tc + efv/nvp remain on d4t if well tolerated with no side-effects early switch with any toxicity substitute tdf if at high risk of toxicity (high body mass index, older, female, tb treatment) contraindication to tdf: renal disease azt+ 3tc + efv/nvp second line failing on a d4t or azt-based first-line regimen tdf + 3tc/ftc + lpv/r virological failure must be followed by intensive adherence management if repeat viral load remains >1 000 in 3 months despite adherence intervention, switch failing on a tdf-based first-line regimen azt + 3tc + lpv/r virological failure must be followed by intensive adherence management, as re-suppression is often possible if repeat vl remains >1 000 in 3 months despite adherence intervention, switch. salvage therapy failing any second-line regimen specialist referral intensively explore and address issues relating to causes of non-adherence if vl remains high, refer where possible, but maintain on failing regimen table i. national regimens for children and adolescents a p r i l 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e n children failing on the zidovudine or didanosine-based regimen: abacavir + lamivudine + lopinavir/ritonavir hiv-infected pregnant women with cd4 above 350 these women follow the new national pmtct guidelines, namely: n zidovudine from 14 weeks n single-dose nevirapine and zidovudine 3-hourly during labour n tenofovir and emtricitabine single-dose after delivery. if a women presents in labour without having started either art or the pmtct regimen at 14 weeks, she should still receive the single-dose nevirapine and zidovudine 3-hourly and tenofovir and emtricitabine as per above. final comments even though these guidelines are focused on the public sector, it is hoped that they will also be adopted in the private and ngo sectors. implementing these new guidelines would not just be of immediate benefit to the patient needing treatment. as has been shown in recent studies, patients on art have a decreased viral load, and this impacts on hiv transmission. this meets the major objective of what president zuma announced on 1 december 2009 – decrease mortality, and increase hiv prevention. 30 c p d  q u e s t i o n s journal 33 two cpd points are awarded for the correct completion and submission of the questions below. cpd questionnaires must be completed online via www.cpdjournals.org.za. after submission you can check the answers and print your certificate. questions may be answered up to 6 months after publication of each issue. this programme is available free of charge to members of the hiv clinicians society and sama only. 1. true (a) or false (b) – click on the correct answer: clinical deterioration due to tb-iris generally occurs within 9 months of starting haart. 2. true (a) or false (b) – click on the correct answer: iris is thought to be due to the recovery of the th1 immune response following successful suppression of viral replication by haart. 3. true (a) or false (b) – click on the correct answer: the demonstration of intranuclear inclusions or cowdry type a bodies in lung biopsies is highly suggestive of pjp infection in the lungs. 4. true (a) or false (b) – click on the correct answer: hepatitis b is an rna virus that replicates in the liver. 5. true (a) or false (b) – click on the correct answer: in south africa, the most common hbv genotypes are a1 and e. 6. true (a) or false (b) – click on the correct answer: genotype c of hbv is associated more often than others with liver failure and hepatocellular carcinoma. 7. true (a) or false (b) – click on the correct answer: hepatitis b surface antigen (infectious agent) is the first serological marker to appear after infection, and persistence for >6 months indicates chronic hbv infection. 8. true (a) or false (b) – click on the correct answer: hiv increases the risk of acute hbv infection progressing to a chronic active infection (positive hbsag for >6 months) by at least 3-fold. 9. true (a) or false (b) – click on the correct answer: interferon and nelfinavir are anti-hiv drugs that also have an anti-hbv effect. 10. true (a) or false (b) – click on the correct answer: other agents active against hepatitis b mono-infection include entecavir, adefovir and telbivudine. 11. true (a) or false (b) – click on the correct answer: monotherapy with 3tc for hepatitis b in co-infected patients will result in resistance in 60 80% of patients in 12 months. 12. true (a) or false (b) – click on the correct answer: hbv vaccination is not recommended in hiv infection. 13. true (a) or false (b) – click on the correct answer: the use of ddi and d4t in pregnancy as part of triple combination therapy regimens is not recommended due to increased risk of lipodystrophy. 14. true (a) or false (b) – click on the correct answer: women with cd4 t-cell counts >250 cells/µl are more likely to experience hepatic toxicity when commencing nevirapine than if cd4 t-cell counts are lower. 15. true (a) or false (b) – click on the correct answer: efavirenz is listed as category d in the us fda pregnancy categories. 16. true (a) or false (b) – click on the correct answer: reasons for expedited art initiation in adults include low cd4 count and pregnancy. 17. true (a) or false (b) – click on the correct answer: expedited art initiation in children is indicated when children reach 5 years of age. 18. true (a) or false (b) – click on the correct answer: expedited art initiation in children is indicated when cd4 is <15% or the cd4 count is <100 cells/µl. 19. true (a) or false (b) – click on the correct answer: no one should wait more than 1 month for art, and in expedited cases the wait should be no more than 2 weeks. 20. true (a) or false (b) – click on the correct answer: concurrency is defined as sexual partnerships overlapping in time. cpd march 2009.indd 1 3/16/09 2:20:24 pm article information author: brian eley1,2 affiliations: 1paediatric infectious diseases unit, red cross war memorial children's hospital, south africa 2department of paediatrics and child health, university of cape town, south africa correspondence to:    brian eley email: brian.eley@uct.ac.za postal address: department of paediatrics and child health, red cross war memorial children's hospital, rondebosch 7700, south africa how to cite this article: eley b. care of hiv-exposed and hiv-infected neonates. s afr j hiv med. 2015;16(1), art. #360, 3 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.360 copyright notice: © 2015. the authors. licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. care of hiv-exposed and hiv-infected neonates in this editorial... open access • references • appendix 1 south africa has implemented a successful prevention-of-mother-to-child-transmission (pmtct) intervention programme. important milestones achieved in 2012 include: (1) an estimated 83% of all pregnant women living with hiv in south africa received antiretrovirals (arvs) for pmtct, (2) early vertical transmission of hiv in infants ≤ 2 months of age declined to 2.4% and (3) early infant hiv diagnosis coverage (i.e. coverage in infants < 2 months of age) reached 72.6%.1,2 complete elimination of mother-to-child transmission (mtct) will be hard to accomplish. however, further reduction in mtct may be possible if newborns at high risk of acquiring hiv infection (high-risk infants) after intrapartum exposure are routinely identified and administered an intensified post-exposure prophylaxis (pep) regimen comprising 2 or 3 arvs.3 the recently updated hospital-level standard treatment guidelines and essential medicines list, and the 2014 national consolidated hiv guidelines, include risk stratification for newborns.4,5 the latter document recommends one of several neonatal pep regimens depending on the risk of mtct: (1) for low-risk infants whose mothers were on lifelong antiretroviral therapy (art) during pregnancy, daily nevirapine (nvp) for 6 weeks is recommended, (2) for high-risk infants because their mothers were on art for < 4 weeks prior to delivery, or because their mothers were diagnosed with hiv infection within 72 h of delivery, or because their mothers tested hiv positive > 72 h post-delivery, daily nvp for 12 weeks is recommended if breastfed, (3) for infants of breastfeeding mothers with newly diagnosed hiv infection, dual nvp/zidovudine (azt) prophylaxis is recommended with revision based on the infant's immediate hiv dna polymerase chain reaction (pcr) result and (4) for high-risk infants born to mothers whose latest viral load results were > 1000 copies/ml, dual nvp/azt prophylaxis is recommended.5 these recommendations may be difficult for the average clinician to digest and remember. consequently, the extent to which they are correctly administered in routine clinical practice requires evaluation. if implementation proves difficult, a simplified intervention for high-risk infants should be devised. identifying high-risk infants and initiating art when needed is critical to reduce the associated hiv-related morbidity and mortality. a south african study that analysed post-neonatal deaths under 12 months of age identified a peak in mortality between 1 and 3 months owing to hiv infection.6 early survival was estimated in an analysis of pooled individual data from antiretroviral-naïve infants who had been enrolled in 12 sub-saharan african studies. according to this analysis, net survival of perinatally infected infants declined from 99% at 28 days to 83% by 90 days of life, confirming that a significant mortality risk exists between 1 and 3 months of life.7 the children with hiv early antiretroviral therapy (cher) trial drew further attention to the vulnerability of hiv-infected infants, convincingly demonstrating that early art significantly lowered the mortality and disease progression risks of hiv-infected infants. the cher trial randomly assigned hiv-infected infants aged between 6 and 12 weeks with mild hiv disease (cd4 percentage ≥ 25% and cdc stage n or a disease) to receive art either immediately (early art cohort) or when the cd4% had declined to less than 20% (deferred art cohort). the median age at which art was initiated was 7.4 weeks in the early art cohort, and 20 weeks in the deferred art cohort.8,9 of 532 infants who were screened for eligibility for the cher trial, 122 (22.9%) were excluded from the trial because they had a cd4 percentage < 25%, were symptomatic or had cdc stage c disease, implying that a sizeable proportion of young hiv-infected infants have advanced hiv disease.8 a more recent analysis of 403 infants commenced on art before the age of 12 weeks in public sector clinics in cape town and soweto showed that, at art initiation, 250 (62%) had advanced hiv disease.10 in june 2008, the world health organization (who) acknowledged the public health importance of the cher trial's findings by recommending that, upon diagnosis, all hiv-infected infants (< 12 months of age) should commence art as soon as possible, irrespective of their clinical stage or cd4 count.11 south africa was slow to embrace this recommendation; on 01 december 2009, 18 months after the who report, president zuma announced in his world aids day speech that the country would implement this intervention.12 although the benefits of early treatment of hiv-infected infants are now well established, identifying these infants remains a challenge. south africa's practice of routine hiv dna pcr testing at 6 weeks of life for hiv-exposed infants fails to recognise hiv infection during the first 6 weeks of life, which may be too late to initiate art at 7.4 weeks of age as per the cher trial and has reduced sensitivity for detecting hiv infection in infants who receive a minimum of 6 weeks of arvs for pmtct.3 birth hiv dna pcr testing of hiv-exposed neonates coupled with early art initiation in hiv-infected neonates should be liberalised so as to reduce the observed increase in mortality between 1 and 3 months of age in untreated infants. in 2013, south africa recommended birth hiv dna pcr testing for hiv-exposed low birth weight infants, and the 2014 national consolidated hiv guidelines recently extended birth testing to 6 categories of newborns deemed to be at high risk of antenatal or intrapartum hiv infection.4,5 it will be important to assess how well this recommendation is implemented, and whether it results in increased art initiation during the neonatal period and reduced hiv-related infant morbidity and mortality. finally, recent studies suggesting additional benefits of early art provide further motivation to identify and treat during the early neonatal period. when art is initiated in infants less than 6 months of age, the period of viraemia is shortened and the size of the resting cd4+ t-cell latent hiv-1 reservoir is limited.13 continuous decay of this reservoir occurs, provided that virological control is sustained, suggesting that lifelong art may not be necessary for all patients.14 the clinical course experienced by the mississippi baby suggested that art initiation within 30 h of life may prolong the control of viral replication in the absence of art.15 however, this supposition was recently challenged by yet another case study. in that report, an hiv-infected neonate was initiated on art within 30 min of birth, seroreverted and remained clinically well and virologically suppressed while on art. at the age of 4 years, both hiv-1 rna and dna were undetectable. a few weeks later, art was discontinued, on the assumption that functional cure had been achieved. however, evidence of viral rebound was detected within 7 days of art discontinuation, raising concerns about the durability of virological control following early neonatal art.16 the challenge for clinicians is the lack of pharmacokinetic and dosing information in neonates for some commonly used arvs such as abacavir; safety concerns about lopinavir/ritonavir co-formulation in neonates < 14 days of age or infants less than a corrected gestational age of 42 weeks; and uncertainty about the optimal approach of transitioning a neonate from antiretroviral prophylaxis to art.17,18 because of these limitations, a nvp-containing art regimen should be administered during the neonatal period until it is safe to prescribe lopinavir/ritonavir co-formulation.15,16,18 south african clinicians are grappling with the prevention, diagnosis and management of hiv infection in neonates and a limited body of evidence to guide them. in february 2014, the southern african hiv clinicians society convened a colloquium to review the state of knowledge regarding post-exposure prophylaxis for neonates who experienced high-risk hiv exposures during the intrapartum period, and hiv diagnosis and art during the neonatal period. the meeting was attended by a group of south african paediatric hiv and aids experts (appendix 1). arising from this meeting are papers by max kroon, gayle sherman and james nuttall addressing these very issues, published in this edition of the southern african journal of hiv medicine. these papers provide comprehensive guidance for practising clinicians. the colloquium identified potential research questions, discussed in a separate paper by mary-ann davies. references top ↑ united nations children's fund. towards an aids-free generation – children and aids: sixth stocktaking report. c2013 [cited 03 december 2013]. available from: http://www.childrenandaids.org/files/str6_full_report_29-11-2013.pdf sherman gg, lilian rr, bhardwaj s, candy s, barron p. laboratory information system data demonstrate successful implementation of the prevention of mother-to-child transmission programme in south africa. s afr med j. 2014;104(3 suppl 1):235–238. http://dx.doi.org/10.7196/samj.7598 nielsen-saines k, watts dh, veloso vg, et al. three postpartum antiretroviral regimens to prevent intrapartum hiv infection. new engl j med. 2012;366:2368–2379. http://dx.doi.org/10.1056/nejmoa1108275 national department of health. standard treatment guidelines and essential medicines list for south africa: hospital level paediatrics. 2013 ed. pretoria: national department of health; 2013. department of health. national consolidated guidelines for the prevention of mother-to-child transmission of hiv (pmtct) and the management of hiv in children, adolescents and adults. 24 december 2014. c2014 [cited 10 january 2015]. available from: http://www.health.gov.za/docs/policies/2014/hiv_guidelines_jan2015-final_edits-yp.pdf bourne de, thompson m, brody ll, et al. emergence of a peak in early infant mortality due to hiv/aids in south africa. aids. 2009;23:101–106. http://dx.doi.org/10.1097/qad.0b013e32831c54bd marston m, becquet r, zaba b, et al. net survival of perinatally and postnatally hiv-infected children: a pooled analysis of individual data from sub-saharan africa. int j epidemiol. 2011;40:385–396. http://dx.doi.org/10.1093/ije/dyq255 violari a, cotton mf, gibb dm, et al. early antiretroviral therapy and mortality among hiv-infected infants. n engl j med. 2008;359:2233–2244. http://dx.doi.org/10.1056/nejmoa0800971 cotton mf, violari a, otwombe k, et al. early time-limited antiretroviral therapy versus deferred therapy in south african infants infected with hiv: results from the children with hiv early antiretroviral (cher) randomised trial. lancet. 2013;382:1555–1563. http://dx.doi.org/10.1016/s0140-6736(13)61409-9 innes s, lazarus e, otwombe k, et al. early severe hiv disease precedes early antiretroviral therapy in infants: are we too late? j int aids soc. 2014;17:18914. http://dx.doi.org/10.7448/ias.17.1.18914 world health organization. report of the who technical reference group, paediatric hiv/art care guideline group meeting. 10–11 april 2008. c2008 [cited 01 july 2008]. available from: http://www.who.int/hiv/pub/paediatric/who_paediatric_art_guideline_rev_mreport_2008.pdf?ua=1 unaids. president zuma and unaids executive director, call for mass prevention movement at world aids day commemoration in pretoria. c2014 [cited 03 november 2014]. available from: http://www.unaids.org/en/resources/presscentre/featurestories/2009/december/20091201wadms/ persaud d, palumbo pe, ziemniak c, et al. dynamics of the resting cd4(+) t-cell latent hiv reservoir in infants initiating haart less than 6 months of age. aids. 2012;26:1483–1490. http://dx.doi.org/10.1097/qad.0b013e3283553638 luzuriaga k, tabak b, garber m, et al. hiv type 1 (hiv-1) proviral reservoirs decay continuously under sustained virologic control in hiv-1-infected children who received early treatment. j infect dis. 2014;210:1529–1538. http://dx.doi.org/10.1093/infdis/jiu297 persaud d, gay h, ziemniak c, et al. absence of detectable hiv-1 viremia after treatment cessation in an infant. n engl j med. 2013;369:1828–1835. http://dx.doi.org/10.1056/nejmoa1302976 butler km, gavin p, coughlan s, et al. rapid viral rebound after 4 years of suppressive therapy in a seronegative hiv-1 infected infant treated from birth. pediatr infect dis j. 2014 sep 23. [epub ahead of print]. panel on antiretroviral therapy and medical management of hiv-infected children. guidelines for the use of antiretroviral agents in pediatric hiv infection. c2015 [cited 08 january 2015]. available from: http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf food and drug administration. fda drug safety communication: serious health problems seen in premature babies given kaletra (lopinavir/ritonavir) oral solution. 08 march 2011. c2015 [cited 08 january 2015]. available from: http://www.fda.gov/drugs/drugsafety/ucm246002.htm appendix 1 top ↑ the following individuals, listed in alphabetical order, participated in the colloquium entitled ‘diagnosis and treatment of hiv infection in neonates’ which took place on 21 february 2014 and/or commented on the series of neonatal papers published in this edition of the southern african journal of hiv medicine: theunis avenant mo archary ashraf coovadia mark cotton vivian cox mary-ann davies nonhlanhla dlamini nicolette du plessis brian eley lee fairlee ute feucht lisa frigati ute hallbauer sandy holgate max kroon louise kuhn leon levin aurelie nelson james nuttall helena rabie gary reubenson gayle sherman gillian sorour karl technau lloyd tooke kerry uebel pg45-46.html case study unusual presentation of extrapulmonary tuberculosis: a case report on mammary tuberculosis munira khan, mb chb, mmedsci kogieleum naidoo, mb chb, dip hiv man centre for the aids programme of research in south africa (caprisa), university of kwazulu-natal, durban this case study highlights an unusual manifestation of extrapulmonary tuberculosis (tb) in a person living with hiv, namely mammary tb. clinicians practising in settings where hiv and tb are endemic need to be aware of the clinical presentation, diagnosis and management of mammary tb. the incidence of extrapulmonary (ep) tuberculosis (tb) is increased in patients with advanced hiv infection.1 , 2 mammary tb is a rare manifestation of eptb, and this report describes a case of tb mastitis and tb-associated immune reconstitution syndrome (iris) with advanced hiv infection. case report a 34-year-old woman presented with a 2-month history of loss of weight, non-productive cough and painful swelling of the right breast. there was no past history of tb, and the patient did not know her hiv status. clinical examination revealed a unilateral 10x8 cm mass in the upper outer quadrant of the breast, with no lymph node involvement. a fine-needle aspirate (fna) was performed and the mass was then incised, drained and dressed. acid-fast bacilli (afb) were isolated from the fna using an auramine stain, and the mycobacterial growth indicator tube culture was positive at 3 weeks. the mycobacterium tuberculosis (mtb) strain isolated was sensitive to all anti-tb drugs. in addition, concurrent pulmonary tuberculosis (ptb) was diagnosed through a positive sputum afb smear and compatible changes on the chest radiograph (cxr). the cxr also showed no communication between the lung and chest wall. the intensive phase (ip) of tb treatment, consisting of rifampicin, isoniazid, pyrazinamide and ethambutol, was commenced. an uneventful clinical course followed on tb treatment, and the breast mass resolved completely. the patient accepted counselling and testing for hiv on diagnosis of ptb and was found to be hiv infected. sputum smear reversion occurred 2 months after tb diagnosis. the patient was commenced on antiretroviral therapy (art) after 3 months of tb treatment. a oncedaily regimen of didanosine, efavirenz and lamivudine was chosen because of its substantial potency and tolerability with tb treatment. the patient presented 2 weeks after initiation of art with a 4-day history of a painful sternal mass. clinical findings included newonset generalised lymphadenopathy, a 3 cm tender erythematous sternal mass with overlying desquamation, a 5 cm firm non-tender right breast mass recurring in the previous site, and two 10 cm soft, non-tender mobile masses, one over the left scapula and the other centrally over the spinal column. a full blood count demonstrated bicytopenia, neutropenia and normochromic anaemia with abnormally low folate levels. the patient's cd4 count was 163 cells/µl and her viral load 932 553 copies/ml (log 5.97). staphylococcus aureus was isolated from a pus swab of the sternal lesion and treated with a course of flucloxacillin. a ziehl-neelsen stain of an fna of the breast mass isolated afb but was culture negative. cytology demonstrated thick inflammatory/necrotic debris with numerous epithelial granulomas, and no ductal cells. the patient completed 7 months of tb treatment and uninterrupted art. eighteen months after art initiation, her cd4 count was 480 cells/µl with an undetectable viral load. the sternal and breast masses had resolved completely. however, the patient refused excision biopsy for histologically confirmed lipomas on the posterior chest wall. discussion in the pre-aids era, incidence rates of tb mastitis were 0.1% and 3% of all breast lesions in developed and developing countries, respectively.3 however, reports of tb of the breast are becoming more common with the advancing hiv epidemic, especially over the past decade (table i). in immunocompromised patients in particular, haematogenous spread of mtb from a primary focus can result in mammary tb. the primary site of tb in this report was the lung parenchyma. tb of the breast most commonly presents as a lump in the central or upper outer quadrant of the breast,18 as in this case. diagnosis is based on multiple factors including clinical history, examination, histological features, and in some cases response to empiric tb treatment. fna of the breast lesion remains the single most important diagnostic method.14 histopathological examination reveals suppuration and a degree of necrotising inflammation that is uncommon in profoundly immunocompromised patients.19 the development of the breast mass after initiation of art may be related to the unmasking of tb-associated iris. it is unusual for mtb-associated iris to present as a breast mass; commonly fever, lymphadenopathy or worsening pulmonary symptoms characterise mtb iris. this case highlights the need for a high index of suspicion of eptb presenting in unusual sites particularly against a background of high tb and hiv prevalence. it also demonstrates the clinical diagnostic and management dilemmas faced by clinicians in this setting. references 1. jones be, young sm, antoniskis d, davidson pt, kramer f, barnes pf. relationship of the manifestations of tuberculosis to cd4 cell counts in patients with human immunodeficiency virus infection. am rev respir dis 1993;148:1292-1297. 1. jones be, young sm, antoniskis d, davidson pt, kramer f, barnes pf. relationship of the manifestations of tuberculosis to cd4 cell counts in patients with human immunodeficiency virus infection. am rev respir dis 1993;148:1292-1297. 2. barnes pf, bloch ab, davidson pt, snider de jr. tuberculosis in patients with human immunodeficiency virus infection. n engl j med 1991;324:16441650. 2. barnes pf, bloch ab, davidson pt, snider de jr. tuberculosis in patients with human immunodeficiency virus infection. n engl j med 1991;324:16441650. 3. hamit hf, ragsdale th. mammary tuberculosis. j r soc med 1982;75:764. 3. hamit hf, ragsdale th. mammary tuberculosis. j r soc med 1982;75:764. 4. kalaç n, ozkan b, bayiz h, dursun ab, demirağ f. breast tuberculosis. breast 2002;11:346-349. 4. kalaç n, ozkan b, bayiz h, dursun ab, demirağ f. breast tuberculosis. breast 2002;11:346-349. 5. tewari m, shukla hs. breast tuberculosis: diagnosis, clinical features and management. indian j med res 2005;122:103-110. 5. tewari m, shukla hs. breast tuberculosis: diagnosis, clinical features and management. indian j med res 2005;122:103-110. 6. khanna r, prasanna gv, gupta p, kumar m, khanna s, khanna ak. mammary tuberculosis: report on 52 cases. postgrad med j 2002;78:422-424. 6. khanna r, prasanna gv, gupta p, kumar m, khanna s, khanna ak. mammary tuberculosis: report on 52 cases. postgrad med j 2002;78:422-424. 7. green rm, ormerod l. mammary tuberculosis: rare but still present in the united kingdom. int j tuberc lung dis 2000;4:788-790. 7. green rm, ormerod l. mammary tuberculosis: rare but still present in the united kingdom. int j tuberc lung dis 2000;4:788-790. 8. morino gf, rizzardi g, gobbi f, baldan m. breast tuberculosis mimicking other diseases. trop doct 2007;37:177-178. 8. morino gf, rizzardi g, gobbi f, baldan m. breast tuberculosis mimicking other diseases. trop doct 2007;37:177-178. 9. sakr aa, fawzy rk, fadaly g, baky ma. mammographic and sonographic features of tuberculous mastitis. eur j radiol 2004;51:54-60. 9. sakr aa, fawzy rk, fadaly g, baky ma. mammographic and sonographic features of tuberculous mastitis. eur j radiol 2004;51:54-60. 10. ahmed r, sultan f. granulomatous mastitis: a review of 14 cases. j ayub med coll abbottabad 2006;18:52-54. 10. ahmed r, sultan f. granulomatous mastitis: a review of 14 cases. j ayub med coll abbottabad 2006;18:52-54. 11. sriram k, moffatt d, stapledon r. tuberculosis infection of the breast mistaken for granulomatous mastitis: a case report. cases j 2008;1:273. 11. sriram k, moffatt d, stapledon r. tuberculosis infection of the breast mistaken for granulomatous mastitis: a case report. cases j 2008;1:273. 12. fadaei-araghi m, geranpayeh l, irani s, matloob r, kuraki s. breast tuberculosis: report of eight cases. arch iran med 2008;11:463-465. 12. fadaei-araghi m, geranpayeh l, irani s, matloob r, kuraki s. breast tuberculosis: report of eight cases. arch iran med 2008;11:463-465. 13. kumar p, sharma n. primary mdr-tb of the breast. indian j chest dis allied sci 2003 jan-mar;45(1):63-65. 13. kumar p, sharma n. primary mdr-tb of the breast. indian j chest dis allied sci 2003 jan-mar;45(1):63-65. 14. kakkar s, kapila k, singh mk, verma k. tuberculosis of the breast. a cytomorphologic study. acta cytol 2000;44:292296. 14. kakkar s, kapila k, singh mk, verma k. tuberculosis of the breast. a cytomorphologic study. acta cytol 2000;44:292296. 15. o'reilly m, patel kr, cummins r. tuberculosis of the breast presenting as carcinoma. mil med 2000;165:800-802. 15. o'reilly m, patel kr, cummins r. tuberculosis of the breast presenting as carcinoma. mil med 2000;165:800-802. 16. al-marri mr, almosleh a, almoslmani y. primary tuberculosis of the breast in qatar: ten year experience and review of the literature. eur j surg 2000;166:687-690. 16. al-marri mr, almosleh a, almoslmani y. primary tuberculosis of the breast in qatar: ten year experience and review of the literature. eur j surg 2000;166:687-690. 17. harris sh, khan ma, khan r, haque f, syed a, ansari mm. mammary tuberculosis: analysis of thirty-eight patients. aust n z j surg 2006;76:234-237. 17. harris sh, khan ma, khan r, haque f, syed a, ansari mm. mammary tuberculosis: analysis of thirty-eight patients. aust n z j surg 2006;76:234-237. 18. gupta r, gupta as, duggal n. tubercular mastitis. int surg 1982;67:422-424. 18. gupta r, gupta as, duggal n. tubercular mastitis. int surg 1982;67:422-424. 19. cabie a, abel s, brebion a, desbois n, sobesky g. mycobacterium lymphadenitis after initiation of highly active antiretroviral therapy. eur j clin microbiol infect dis 1998;17:812813. 19. cabie a, abel s, brebion a, desbois n, sobesky g. mycobacterium lymphadenitis after initiation of highly active antiretroviral therapy. eur j clin microbiol infect dis 1998;17:812813. the us president's emergency plan for aids relief (pepfar) funded the care of patients in the cat programme. the global fund to fight aids, tuberculosis and malaria funded the drugs used in the cat programme. the sponsors of the study had no role in study design, writing or the decision to submit the material for publication. posts held and contribution to article: munira khan, research clinician: concept, drafting and writing of paper; kogieleum naidoo, head of treatment programme: assisted with writing and editing of paper. ethics approval: the university of kwazulu-natal biomedical research ethics committee (reference number e 248/05) approved the retrospective chart review. conflict of interest: the authors declare that there are no conflicts of interest. conference presentation: part of this case report was accepted for presentation at the 40th union world conference on lung health, 3 7 december 2009, cancun, mexico. table i. summary of literature review of tb mastitis cases   isolation of mtb author, year no. of cases breast only co-morbid ptb pattern of drug-resistant tb, site kalaç et al. 4 5 4 1 ri resistance, lung tewari and shukla 5 30 30 khanna et al. 6 52 52 green and ormerod 7 30 30 ie resistance, breast morina et al. 8 2 1 1 sakr et al. 9 10 10 ahmed and sultan 10 10 2 8 sriram et al. 11 1 1 fadaei-araghi et al. 12 8 1 kumar and sharma 13 1 1 ris resistance, breast kakkar et al. 14 164 164 o'reilly et al. 15 1 1 al-marri et al. 16 13 13 harris et al. 17 38 33 5 *this was the only report that documented hiv status; the patient was hiv uninfected. r = rifampicin; i = isoniazid; e = ethambutol; s = streptomycin. sajhiv 1039 reflections reflections on a decade of hiv in my life c friend, mb chb, diphivman corresponding author: c friend (chantelfriend@gmail.com) chantél friend is affiliated with the qhakaza mbokodo research centre, ladysmith, kwazulu-natal, south africa the red hiv ribbon is an almost universal icon for the hiv/aids cause. i see the hiv ribbon in four different ways as i reflect on the different periods of work in my medical career thus far. firstly, i see the red ribbon upside down, just like my head was firmly ostriched in the ground soon after qualifying in the western cape. there was one ward right at the top, out of the way of a medical intern’s rounds, where all those patients went to die and at least i didn’t need to worry about a ‘resus’ in that ward. but, towards the end of 2003, my interest was piqued when a few of the respected medical officers were heading towards hiv care. that was forgotten though when i started private general practitioner work with not a single hiv-positive patient, until one routine insurance test came back positive – one devastated patient! but then the ribbon turned on its side as i moved to the eastern cape and worked for a non-governmental organisation. the number of devastated patients there could not be counted. i quickly had to learn to swim in the deep sea of hiv treatment. there were days when i almost drowned, like the day i was summoned into a small room full of people and was called a racist for limiting (extraordinarily long) tea times in order to get through the patients first. as a team we thrashed it out in that dark room, and going forward we became a centre of excellence in our area, not only for our work, but also for our love for each other. we saw an entire town rally around us by providing soup, toys for the children, beautiful paintings and more. but most importantly, i saw life after hiv: a man on death’s door walking back to work in a few months; a skeleton of a child smiling with her new toy after a few weeks of antiretrovirals; and venus, who encouraged me at every consultation, despite being left blind and in a wheelchair after cryptococcal meningitis, and deserted by her family, but just managing to force the words out of her facial-palsied mouth, ‘thank you’. thirdly, on moving to kwazulu-natal and working for the department of health, i turned the ribbon upright. a handful of doctors slaving away at the heart of the epidemic, seeing upwards of 80 patients a day. clearly this was not sustainable, so we embraced nurse-initiated management of art (nimart). we worked within our crippled system, taking the literal ‘iskoro skoro ’ (old broken car) on the road to the rural areas in our district to present our hopeful plan to all the clinics. and, lo and behold, it worked! this gave us the opportunity to look into quality: checking viral load trends intensively, training nurses, evaluating resistance patterns and fighting with (but more accurately for) non-adherent patients. and then all too soon i left behind the teenager who kept me busy on mxit but lied to my face about adherence, and the many others who influenced my thoughts on hiv in one way or another. unfortunately, i still bump into them every now and then in pick ‘n pay or at the local nursery, where i get an update on cd4+ counts from mom and the grades of her healthy little boy. and lastly, after seeing one too many a sick child not cared for by mom, another unplanned pregnancy, the dreaded positive polymerase chain reaction test in a 6-week-old baby, there came a point when i started asking, ‘what now?’, ‘where to from here?’, ‘how do we stop this?’ and that is when the red ribbon started to look more like an arrow pointing firmly towards hiv-prevention research. i am now privileged to be involved in two promising phase-three trials looking at conquering the transmission of hiv in females. there are, however, days when i feel like pointing the red-tipped arrow firmly at the participants (figuratively speaking, of course) who indulge in risky behaviour after the team’s best counselling efforts. fortunately though, i mostly see the big picture of south africa leading the world into ‘getting to zero’, with the red arrow firmly pointed towards the ‘icilwane’ (‘gogga’, virus). s afr j hiv med 2014;15(1):27. doi:10.7196/sajhivmed.1039 o r ig in a l a r t ic l emessage from the editor december 2014, vol. 15, no. 4 sajhivmed 115 december is a useful time to pause and reflect on another year’s passage, with milestones reached, hurdles overcome and lessons learned. this year has witnessed several notable editions of the southern african journal of hiv medicine (sajhivmed). the march edition focused on the 10-year anniversary of public sector antiretroviral therapy (art) provision in south africa – an anniversary worth celebrating. the june and september editions continued the journal’s tradition of publishing some of the best research from across the region, including some particularly insightful pieces from local clinicians on the ground, and discussing the shortcomings of existing management strategies or the challenges of providing care under difficult circumstances. the contributions from local clinicians – particularly those working outside tertiary academic medicine – are often the most widely read contributions to the journal, and we look forward to seeing more submissions in this category. september’s issue accompanied the second national conference of the southern african hiv clinicians society in cape town. the meeting was an all-round success, with local and international speakers of the highest quality, debates and discussion aplenty, and some of the best local scientific research presented. the top peer-reviewed abstracts from the conference are published in this edition of the journal, and we look forward to seeing more indepth presentations of many of these data in the coming months. also in this month’s journal are articles exploring aspects of hiv medicine that may, at least at first glance, appear off the beaten track. an unusual case report from govender et al.1 reports on a disseminated fungal infection in an hiv-infected international traveller. arowolo et al.2 present a unique study on the practice of ‘double-gloving’ by surgeons to reduce hiv transmission risk – a widespread technique that is a source of discussion but for which there has been, until now, few data. finally, morsheimer et al.3 present an analysis of the decentralisation of paediatric hiv services in cape town; there are surpisingly few studies of patients’ outcomes across different service platforms, and the integration of clinical and health systems perspectives provides useful insights. lastly, this edition of the journal contains a holiday present of sorts. sajhivmed is valued by its readership in part for its publication of the society’s clinical guidelines, which are frequently invaluable tools for supporting the local practice of hiv medicine. here, meintjies et al.4 present the latest revision to the adult art guidelines, synthesising a diverse and complex body of evidence with grace and without losing critical nuance. in outlining the current state of knowledge for specific issues, the authors distinguish points supported by strong evidence from issues where there is room for debate and disagreement. in addition to its value in informing the clinical management of individual patients, these guidelines will be important reading for policymakers, public health programmers and researchers alike. happy reading. landon myer school of public health & family medicine university of cape town landon.myer@uct.ac.za references 1. govender np, maobo re, zulu tg, du plooy m, corcoran c. disseminated fatal talaromyces (penicillium) marneffei infection in a returning hiv-infected traveller. southern african journal of hiv medicine 2014;15(4):154-155. [doi:10.7196/sajhivmed.1087] 2. arowolo oa, agbakwuru ea, g c obonna gc, onyia cu, akinkuolie aa, olaogun jg. safety of the surgeon: ‘double-gloving’ during surgical procedures. southern african journal of hiv medicine 2014; 15(4): 144147. [doi:10.7196/sajhivmed.1050] 3. morsheimer mm, dramowski a, rabie h, cotton mf. paediatric art outcomes in a decentralised model of care in cape town, south africa. southern african journal of hiv medicine 2014; 15(4):144-147. [doi:10.7196/sajhivmed.1050] 4. meintjes g, black j, conradie f, et al. adult antiretroviral therapy guidelines 2014. southern african journal of hiv medicine 2014; 15(4): 121-143. [doi:10.7196/sajhivmed.1130] e d it o r ia l article information authors: anand moodley1,2 william rae3 ahmed bhigjee2 affiliations: 1department of neurology, greys hospital, south africa 2department of neurology, university of kwazulu-natal, south africa 3department of medical physics, university of the free state, south africa correspondence to: anand moodley email: anand.moodley1@gmail.com postal address: po box 13833, cascades 3202, south africa dates: received: 17 dec. 2014 accepted: 21 aug. 2015 published: 16 oct. 2015 how to cite this article: moodley a, rae w, bhigjee a. visual loss in hiv-associated cryptococcal meningitis: a case series and review of the mechanisms involved. s afr j hiv med. 2015;16(1), art. #305, 9 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.305 copyright notice: © 2015. the authors. licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. visual loss in hiv-associated cryptococcal meningitis: a case series and review of the mechanisms involved in this original research... open access • abstract • introduction • method    • statistics • results and discussion    • clinical findings    • electrophysiological findings • mechanisms implicated    • the papilloedema mechanism    • the optic nerve infiltration/inflammation mechanism    • the optic nerve sheath compartment mechanism • management of visual loss • conclusion • acknowledgements    • competing interests    • authors’ contributions • references abstract top ↑ permanent visual loss is a devastating yet preventable complication of cryptococcal meningitis. early and aggressive management of cerebrospinal fluid pressure in conjunction with antifungal therapy is required. historically, the mechanisms of visual loss in cryptococcal meningitis have included optic neuritis and papilloedema. hence, the basis of visual loss therapy has been steroid therapy and intracranial pressure lowering without clear guidelines. with the use of high-resolution magnetic resonance imaging of the optic nerve, an additional mechanism has emerged, namely an optic nerve sheath compartment syndrome (onscs) caused by severely elevated intracranial pressure and fungal loading in the peri-optic space. an improved understanding of these mechanisms and recognition of the important role played by raised intracranial pressure allows for more targeted treatment measures and better outcomes. in the present case series of 90 hiv co-infected patients with cryptococcal meningitis, we present the clinical and electrophysiological manifestations of cryptococcus-induced visual loss and review the mechanisms involved. introduction top ↑ meningitis owing to cryptococcus neoformans remains a frequent human immunodeficiency virus (hiv)associated opportunistic infection even in developing countries with effective antiretroviral therapy (art) rollout programs.1 this is largely a result of failure of hiv testing by individuals with risky sexual behaviour, and late presentation for and poor compliance with art. therefore, it is not uncommon to still encounter severely immunocompromised patients presenting for the first time with opportunistic infections and cd4+ t-lymphocyte counts < 100 cells/µl. headache, high fever, nuchal pain and stiffness, photophobia, confusion, nausea, vomiting and diplopia are the common presenting symptoms of cryptococcal meningitis (cm). symptoms arise from raised intracranial pressure and meningeal inflammation, usually within 1–2 weeks of the onset of the illness. high cerebrospinal fluid (csf) pressure, depressed level of consciousness and an acellular csf are poor prognostic features. effective antifungal therapy (amphotericin b, flucytosine and fluconazole) is not readily available in most developing countries.2 mortality remains high and contributes up to 20% of hiv-related deaths.1 complications in survivors are severe, with visual loss being the most disabling, yet are potentially preventable and reversible. recognition of visual impairment in encephalopathic patients is difficult and therefore often neglected and underreported. in the following case series, we evaluated 90 patients with culture-confirmed cm. their results and a discussion of the mechanisms implicated in cryptococcus-induced visual loss are discussed. an illustrative case of the optic nerve sheath compartment syndrome (onscs) as a putative mechanism is also presented in the discussion. method top ↑ in a prospective study approved by the greys hospital and university of kwazulu-natal ethics committees, we consecutively recruited 90 patients with culture-confirmed cm between february 2008 and december 2011 (table 1). patients with reduced levels of consciousness were excluded (gcs < 14). all were hiv co-infected, provided informed consent, had full neuro-ophthalmological assessments and had magnetic resonance imaging (mri) using standard imaging protocols. patients were recruited within 4 weeks of the disease onset, during the induction and consolidation phases of cm treatment. drug treatment and management of raised intracranial pressure were based on the 2007 south african hiv clinician society guidelines.3 table 1: demographic data, cerebrospinal fluid pressure and cd4 count of 90 cryptococcal meningitis patients. eighty-six patients underwent electrophysiological testing that involved visual evoked potentials (vep) and humphreys visual fields (hvf). vep involved testing of each optic nerve's functioning by requesting the patient to look at a screen one metre away that displayed an alternating full-field checkerboard pattern. the cortical responses thus obtained were detected by silver-surface electrodes placed over the occipital scalp. averaging of the cortical responses provided a reliable and reproducible triphasic wave from which the p100 latency (the large positive wave that occurs at approximately 100 ms from the stimulus) and amplitude (the vertical height in µv between the largest positive p100 and negative n80 waves) were obtained in accordance with international society for clinical electrophysiology of vision (iscev) guidelines.4 hvf was performed using the sita 30-2 standard protocol. pattern deviation fields that fulfilled acceptable reliability indices were included for analysis. flash vep using led goggles were used in patients who were delirious; however, hvf was not possible in such patients. statistics visual acuity, vep latency and amplitude were dichotomised into abnormal and normal groups using standard normal references. one-sample t tests were used to compare mean latency and amplitude with laboratory references that have been previously described.5 tests for association between groups were analysed using a chi-square test or fisher's exact test, as appropriate. statistical analysis was done by stata, version 12. results and discussion top ↑ clinical findings visual loss occurred at any stage of the illness and occurred frequently before starting drug therapy. subgroup analysis not reflected in table 2 showed that the majority of cases occurred within 2–4 weeks of cm onset, regardless of drug therapy. rex's landmark article in 1993 of cryptococcus-induced visual loss suggested two main mechanisms: an early and sudden visual loss owing to optic neuritis, and a late and gradual visual loss owing to papilloedema. such distinct mechanisms, however, do not exist in isolation and an explanation for visual loss where neither mechanism is in operation needs clarification.6 gradual, symmetrical and bilateral visual blurring associated with headache was the most common presentation in our series (table 2). sudden and catastrophic visual loss was rare, occurring in only one patient. forty-six percent of patients had appreciable loss of vision (< 6/9 on snellen) and profound visual loss of < 6/60 in 13%. colour desaturation, pupillary reflex changes and pain on eye movement were relatively uncommon. sixth nerve palsies owing to elevated intracranial pressure or meningitis occurred in 16% of patients. bilateral and symmetrical cerebellar ataxia was common in this group and probably accounted for the impaired smooth pursuit and nystagmus – findings also commonly encountered in hiv-associated neurocognitive disorder. table 2: neuro-ophthalmological manifestations of cryptococcal meningitis in 90 patients. electrophysiological findings vep testing and hvf defects were common in the series we reported, both in visually impaired and visually normal patients with cm (table 3).5 in the cross-section of 86/90 patients who underwent electrophysiological tests, vep abnormalities were detected in visually impaired patients (68.9% of right eyes and 67.6% of left eyes), and in visually normal patients (56.5% of all eyes). in subgroup analysis, prolongation of the p100 latency was the predominant abnormality (42.3% of all eyes).5 in the absence of demyelination, these findings were interpreted as resulting from conduction block caused by optic nerve compression. optic nerve compression with secondary conduction block and optic nerve infiltration were both deemed likely from these findings. vep amplitude changes suggesting axonal loss were less frequent (14.6%) in eyes tested. as shown in table 3, hvf abnormalities were also very frequent in patients who could be tested (76.6% of right eyes and 71.1% of left eyes). the predominant field defects were peripheral constriction with large blind spots – field defects consistent with papilloedema-related optic nerve dysfunction (figure 1).5 consequently, the interpretation of these findings was that the hvf defects supported raised intracranial pressure as an important cause of optic nerve dysfunction in cryptococcus-induced visual loss. table 3: frequencies of abnormal visual acuity, visual evoked potentials and humphreys visual fields in 86 patients tested. figure 1: frequencies of visual field defects. mechanisms implicated top ↑ rex's classification of visual loss was time based.6 he suggested that early visual loss was a result of optic nerve infiltration/inflammation and occurred within 6 days of the onset of meningitic symptoms, whereas late visual loss occurred a few weeks into the infection and was the result of optic disc oedema from raised intracranial pressure (papilloedema). remarkably, the rapid visual loss group in rex's series had elevated csf pressure (90%), thickened optic nerves on computed tomography (ct) scan (22%) and symmetrical visual loss (93%). the visual loss occurred before or soon after initiation of antifungal therapy and was severe and permanent. the slow visual loss group did not differ much, having elevated csf pressure (83%), thickened optic nerves (22%) and symmetrical visual loss (93%). as to whether there was dilatation of the peri-optic csf space or thickening of the optic nerve itself was not defined on ct scan for both groups in rex's series. so, apart from the tempo of presentation, a clear distinction between these groups does seem artificial. we too have previously shown that raised intracranial pressure is common in cm-induced visual loss (69%), and that papilloedema was present in only 25%; but, in addition, we have shown that on mri there is no difference between the optic nerve sheath diameter in patients with cm and that of a normal control group, regardless of csf pressure.7 none of the optic nerves demonstrated post-contrast enhancement either, reflecting a poor inflammatory response. evidence for a third mechanism of optic nerve dysfunction was compelling. subsequent reports, as discussed below, have supported or refuted the findings of rex with evidence for and against the optic neuritis and papilloedema models. however, his work certainly laid down the foundation for investigation into cryptococcus-induced visual loss; and in fact much of our current understanding has resulted from his original observations. recovery of vision has always been documented as poor. drug treatment alone is insufficient as demonstrated by graybill et al. where steroids alone were ineffective but serial lumbar punctures and reduction of csf pressure were more successful.8 in torres's meta-analysis of rapid and slow visual loss cases, the outcome was generally poor when only the underlying cm was treated and not the raised intracranial pressure.9 the papilloedema mechanism raised intracranial pressure in cm is well documented.10,11 csf outflow obstruction caused by plugging of the arachnoid granulations by the organism and/or polysaccharide capsule is postulated to result in the elevated intracranial pressure (figure 2c).10,12 good support for obstruction at the arachnoid villi has come from loyse et al. who demonstrated histopathologically that fungal loading (high fungal burden) occurs within the arachnoid villi and is positively correlated with elevated intracranial pressure.12 bicanic et al. have shown that higher fungal burden and higher cryptococcal antigen titres are associated with higher intracranial pressure and have therefore recommended early and aggressive fungicidal treatment with lowering of intracranial pressure by either serial lumbar punctures or lumbar drainage to lower morbidity and mortality in patients with cm.13 in 1993, garrity et al. performed optic nerve sheath fenestrations in two patients with visual loss and papilloedema.14 following the procedure, both patients had improved vision from lowering of intracranial pressure. cryptococcal organisms were present in the dural sheaths of both patients. at autopsy of one of the patients, patency of the sheath fenestration was still present. figure 2: proposed mechanisms involved in cryptococcus-induced visual loss. (a) normal, (b) inflammation/infiltration, (c) papilloedema and (d) compartment syndrome. the evidence for visual loss resulting from raised intracranial pressure and papilloedema, and the benefit from csf pressure lowering either by serial lumbar punctures,8,10,15,16,17 acetazolamide,17,18 lumbo-peritoneal (lp) shunt, lumbar drain,18,19,20 ventriculo-peritoneal (vp) shunt10,21 and optic nerve sheath fenestration14,22 are well documented, but unfortunately mostly anecdotal. comparative studies between surgical lowering of intracranial pressure and drug-only therapy to prevent or reverse visual loss in cm have not been done. lowering of the raised intracranial pressure is shown to improve the overall prognosis of cm and therefore cannot be ethically withheld in a randomised controlled trial. pharmaceutical approaches alone to control raised intracranial pressure in cm have not been shown to be effective. surgically invasive methods to decrease intracranial pressure in cm also carry their own risks such as over drainage, shunt infection, distal catheter migration and need for shunt revision.23 vp shunts are associated with lower risk of shunt obstruction and revision than lp shunts and are therefore recommended when serial lumbar punctures are ineffective or not an option. ct and mri scans show normal ventricular size in most cases of cm despite profoundly elevated csf pressure. presumably the equivalent pressures between the intraventricular fluid and the csf surrounding the brain and the paucity of intraventricular fungal elements prevent ventricular dilatation, unlike tuberculous meningitis where hydrocephalus is often encountered from blockage at the sylvian aqueduct or foramina of lushka and magendie.10 raised intracranial pressure and fungal loading are common and well described in cm patients, but inflammation is minimal if at all, regardless of hiv coinfection. the frequent finding of an acellular csf in cm despite markedly elevated csf pressure is a case in point. the significance of raised intracranial pressure cannot be underestimated in visual loss, and perhaps optic disc swelling and optic nerve infiltration/inflammation are secondary or co-occurrences. reports of raised intracranial pressure-related visual loss are many in the literature, and the benefit of early lowering of intracranial pressure in reversing blindness in cryptococcus-induced visual loss is well documented.15,19,21,24 the optic nerve infiltration/inflammation mechanism evidence for optic nerve infiltration by c. neoformans has come from case reports only. lipson et al. first described two cases of aids-associated cryptococcal arachnoiditis resulting in bilateral visual loss secondary to an optic neuropathy (figure 2b).25 ofner's claim of optic nerve infiltration in a patient with visual loss and elevated intracranial pressure was not robust.26 histology obtained from the optic nerve sheath showed fungal infiltration with inflammation, but optic nerve infiltration was only presumed. histological evidence of cryptococcal infiltration of the intracanalicular segment of the optic nerve with associated necrosis was provided by cohen et al. in 199327 and further supported by a histopathological case reported by corti et al. in 2010.28 corti's case also showed a perineuritis, but in addition showed optic nerve infiltration by the fungus. by inference, hoepelman29 and seaton30 suggested that corticosteroids could only play a beneficial role in cryptococcus-induced visual loss by reducing the optic nerve inflammation so induced by the organism. further support for an optic neuritis model has come from de schacht's report of a 26-year-old cm patient who developed an immune reconstitution illness with bilateral blindness after starting antiretroviral therapy.31 supposedly, the exaggerated optic nerve inflammation secondary to fungal infiltration caused the bilateral blindness. unfortunately, such case reports in the literature are scanty and the evidence for optic nerve infiltration is mostly speculative.32 in our cohort of patients, optic nerve infiltration was uncommon, as evidenced by the lack of nerve signal changes and enhancement on mri, and the dissimilar magnetic resonance diffusion parameters to that of optic neuritis.7 optic nerve infiltration possibly results from direct cryptococcal invasion from the peri-optic csf, or perhaps develops from retrograde extension of the meningo-encephalitis from the thalamus and other diencephalic structures that seem particularly susceptible to cryptococcal infiltration. the common finding of pseudocysts and dilated virchow-robin spaces in these regions supports this assertion. the optic nerve sheath compartment mechanism we have reported a case that demonstrates the strong likelihood of onscs which we propose as a probable third mechanism of optic nerve dysfunction (figure 2d). during elevated csf pressure, there was loss of the peri-optic csf signal on t2 mri and return of the csf signal following lowering of csf pressure.33 the stasis of contrast-filled csf at the mid-orbital segment of the optic nerve sheath suggests complete plugging of the peri-optic space by cryptococcal fungal elements. we further postulate that a large pressure gradient resulted from blockage between the significantly elevated intracranial pressure within the intracranial subarachnoid space (sas) and the pressure of the proximal peri-optic csf space. an onscs thus followed, causing optic nerve compression, axoplasmic stasis and ischaemia. optic nerve dysfunction ensued with visual blurring and visual loss. a subsequent case of a 33-year-old hiv-infected patient with bilateral blindness from cm and elevated csf pressure (> 50 cm csf) also demonstrates this phenomenon. in addition to the blockage within the optic canals bilaterally, dilatation of the peri-optic csf space ahead of the obstruction is visible on the left side (figure 3). notably, this case showed obstruction within the optic canal, unlike the previous case that showed mid-orbital obstruction. after lowering of the csf pressure, there is return of the csf to the orbital peri-optic space. we postulate that, following the blockage at the optic canal level, csf from the orbital peri-optic space is drained by the peri-optic lymphatics and hence there is loss of the csf signal on the t2 high-resolution scan. this is more plausible than loss of the csf signal prior to csf pressure lowering being the result of fungal loading alone, as the interval between the two scans was only 11 days and much too soon for all the fungal elements to clear from that space. figure 3: (a–h), illustrative case of optic nerve sheath compartment syndrome. cohen's histological description of intracanalicular necrosis of the optic nerve and obliteration of the intracanalicular peri-optic space by fungal loading provides the only credible histopathological evidence of a clear compartment syndrome in cm-induced visual loss.27 killer et al. have shown by electron microscopy that the peri-optic sas is not occupied by csf alone but also by a network of trabeculae, septae and pillars comprising fibroblasts and blood vessels.34 they provide histological evidence that the peri-optic sas narrows in the mid-orbital segment where the delicate trabeculae change into broader septae and stout pillars that subdivide the sas into compartments. the sas within the intracanalicular segment is extremely narrow and consists of pillars and trabeculae only. hence the potential sites of blockage to csf flow are the mid-orbital and the intracanalicular segments of the peri-optic sas. killer et al. also suggest that the varying anatomy of these subarachnoid trabeculae, septae and pillars between the two optic nerves account for the asymmetrical papilloedema in idiopathic intracranial hypertension (iih).35 asymmetrical pressure is transmitted to the laminar cribrosa of the two optic nerves. on the side with more trabeculae, septae and pillars, a lower pressure is transmitted to the optic nerve head and hence little or no papilloedema ensues. we have expanded on this theory in cm, where, in addition to raised intracranial pressure, there is loading of the peri-optic sas with fungal elements (the organism and fragments of the polysaccharide capsule). cm is a pauci-inflammatory disorder, and hence fungal loading rather than inflammatory cell accumulation occurs. fungal loading in the peri-optic csf space has been shown by histology of the optic nerve sheath during optic nerve sheath fenestration.22 sequestration of csf in the immediate retrobulbar space is not evident, and the contribution made by the fungal clumping needs exploration. we have not been able to demonstrate optic nerve sheath dilatation nor optic nerve thickening in the setting of cm with or without papilloedema and regardless of csf pressure measured at the lumbar level.7 it is conceivable that the retrobulbar segment of the nerve is subjected to toxic byproducts from the fungi, venous stasis, ischaemia from vascular compromise and axoplasmic stasis from mechanical compression. we propose therefore that these findings suggest axoplasmic stasis, mitochondrial dysfunction and ischaemia of the axons which develop from compression at the site of blockage. the end result is optic disc swelling that occurs in only 25% of cm patients, despite raised intracranial pressure occurring in 69% – 90% of cm patients. the blockage at the mid-orbital or intracanalicular segments from raised pressure and fungal elements creates compartmentalisation between the peri-optic sas and the intracranial sas. we propose that the raised pressure and fungal loading cause apposition of the trabeculae, septae and pillars against each other, creating a block by a valve-like mechanism. when intracranial pressure is then lowered, reopening of the channels between the trabeculae and septae occurs, and re-establishment of csf flow to the peri-optic space. furthermore, the lack of optic nerve sheath dilatation and optic nerve signal changes on mri make papilloedema and optic nerve infiltration less likely to be the only pathogenic mechanisms in cm-induced visual loss. magnetic resonance diffusion studies do not support optic neuritis as an early cause of visual loss in cm.7 the co-occurrence of elevated csf pressure, swollen optic disc and visual loss was in 15.4% of our cohort, visual loss and swollen discs in 17.3%, and visual loss and elevated pressure in 26.9%. whilst visual loss was documented in 34.6% and elevated pressure was recorded in 69%, clearly disc swelling alone either from optic nerve infiltration or papilloedema was insufficient to account for all cases of visual loss. elevated csf pressure with an additional compromise of optic nerve function seems likely – not from axoplasma stasis at the lamina cribrosa but compression upstream. we postulate that this compression results from onscs. the steep pressure gradients at the optic canal or mid-orbital level and fungal elements trapped by subarachnoid trabeculae cause a functional block that reverses with pressure lowering. we prefer the term onscs to explain the above pathogenesis, which is in line with killer's explanation of asymmetrical papilloedema in iih,35 but different to the optic nerve compartmentation he described in optic neuritis where csf was trapped in the bulbar peri-optic space, causing disc swelling.36 our use of the term is also different from orgul's description of optic nerve compartment syndrome.37 orgul uses the term to describe compartmentalisation in glaucoma where the slit-like pores in the lamina cribrosa cause venous congestion and constriction of the nerve fibre bundles. management of visual loss top ↑ early screening of vision in patients with cm is imperative. screening should involve proper snellen chart assessments with pinhole correction if required. baseline documentation of visual acuity with weekly documentation during the first 4 weeks and bimonthly thereafter until the maintenance phase is complete is essential and should become standard practice. when there is doubt, vep can be done to detect subtle and even preclinical optic nerve disease. hvf is useful and should be done at initiation of treatment and repeated 4 weeks later when cognition improves with treatment. field defects are possible, even with intact visual acuity. with raised intracranial pressure being the predominant mechanism by which visual loss occurs, it is prudent to address this complication in cm. antifungal therapy alone is insufficient. early and aggressive lowering of intracranial pressure not only improves the overall prognosis of cm but also definitely prevents, alleviates and reverses visual loss.13 the benefit of intracranial pressure lowering is well documented by using serial lumbar punctures, lumbar drains, vp shunts and optic nerve sheath fenestration.8,10,11,15,16,20,21,22 reports of reversal of visual loss from csf pressure lowering are encouraging. medical management alone of raised intracranial pressure in lowering csf pressure and thereby improving vision has been less satisfactory.38 the latest recommendations by the southern african hiv clinicians society (2013) are to remove 10 ml – 30 ml of csf if opening pressure is > 25 cm csf and daily lp's until symptoms of raised intracranial pressure settle.39 evidence for the benefit of corticosteroids and nonsteroidal anti-inflammatory drugs (nsaids) to decrease optic nerve inflammation and thus improve vision has been anecdotal at best and is counter-intuitive, considering the pauci-inflammatory state of cm.30 conclusion top ↑ the major limitations of our case series have been the lack of long-term follow-up and the exclusion of patients with depressed levels of consciousness. however, we feel that the data from this cohort is compelling and certainly contributes to the improved understanding of cryptococcus-induced visual loss. visual loss in cm is common and varies from mild loss to no light perception. bilateral involvement is usual and occurs at any time during the illness, regardless of drug therapy. electrophysiology shows early and subclinical optic nerve dysfunction in cm. three mechanisms seem to operate in the pathogenesis of cm-induced visual loss: (1) papilloedema, (2) optic nerve infiltration/inflammation and (3) onscs (figures 2 and 4). optic nerve infiltration/inflammation does occur but infrequently and is either a manifestation of the meningo-encephalitis that extends to the optic nerve by continuous spread from the diencephalon or a result of direct infiltration of fungi from the peri-optic csf space. raised intracranial pressure plays an important role in visual loss with or without papilloedema. when papilloedema and optic nerve infiltration are not demonstrable, raised intracranial pressure causes optic nerve dysfunction and visual loss, presumably by onscs. fungal loading and obstruction of the peri-optic csf space compartmentalising the intra-orbital peri-optic sas from the intracranial sas is probably the key mechanism but needs further investigation. our understanding of cryptococcus-induced visual loss has improved since rex's initial contribution to the field. however, further studies are eagerly awaited – and preferably those that focus on csf flow, the peri-optic and intracranial sas compartments and the impact of pressure lowering measures on visual acuity. figure 4: the pathogenesis of cryptococcus-induced visual loss. acknowledgements top ↑ competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions a.m. (greys hospital) was responsible for drafting of the manuscript, project design, collection and analysis of data. w.r. (university of the free state) made conceptual contributions and reviewed the manuscript. a.b. 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twinoweitu o, mukasa b, tomberland m, mbidde ek. feasibility study of serial lumbar puncture and acetazolamide combination in the management of elevated cerebrospinal fluid pressure in aids patients with cryptococcal meningitis in uganda. trop doct. 2005;35:19–21. pmid: 15712536, http://dx.doi.org/10.1258/0049475053001967 ng cw, lam ms, paton ni. cryptococcal meningitis resulting in irreversible visual impairment in aids patients--a report of two cases. singapore med j. 2000;41:80–82. pmid: 11063209. claus jj, portegies p. reversible blindness in aids-related cryptococcal meningitis. clin neurol neurosurg. 1998;100:51–52. pmid: 9637206, http://dx.doi.org/10.1016/s0303-8467(97)00119-4 macsween kf, bicanic t, brouwer ae, marsh h, macallan dc, harrison ts. lumbar drainage for control of raised cerebrospinal fluid pressure in cryptococcal meningitis: case report and review. j infect. 2005;51:e221–e224. pmid: 16291274, http://dx.doi.org/10.1016/j.jinf.2005.02.010 petrou p, moscovici s, leker rr, itshayek e, gomori jm, cohen je. ventriculoperitoneal shunt for intracranial hypertension in cryptococcal meningitis without hydrocephalus. j clin neurosci. 2012;19:1175–1176. pmid: 22658489, http://dx.doi.org/10.1016/j.jocn.2012.01.008 milman t, mirani n, turbin re. optic nerve sheath fenestration in cryptococcal meningitis. clin ophthalmol. 2008;2:637–639. pmid: 19668765, http://dx.doi.org/10.2147/opth.s2096 york j, bodi i, reeves i, riordan-eva p, easterbrook pj. raised intracranial pressure complicating cryptococcal meningitis: immune reconstitution inflammatory syndrome or recurrent cryptococcal disease? j infect. 2005;51:165–171. pmid: 15961162, http://dx.doi.org/10.1016/j.jinf.2005.04.022 chan kh, mak w, ho sl. cryptococcal meningitis with raised intracranial pressure masquerading as malignant hypertension. int j infect dis. 2007;11:366–367. pmid: 17331778, http://dx.doi.org/10.1016/j.ijid.2006.07.005 lipson bk, freeman wr, beniz j, et al. optic neuropathy associated with cryptococcal arachnoiditis in aids patients. am j ophthalmol. 1989;107:523–527. pmid: 2540660, http://dx.doi.org/10.1016/0002-9394(89)90498-4 ofner s, baker rs. visual loss in cryptococcal meningitis. j clin neuro-ophthalmol. 1987;7:45–48. pmid: 2952681. cohen db, glasgow bj. bilateral optic nerve cryptococcosis in sudden blindness in patients with acquired immune deficiency syndrome. ophthalmology. 1993;100:1689–1694. pmid: 8233396, http://dx.doi.org/10.1016/s0161-6420(93)31416-8 corti m, solari r, cangelosi d, et al. sudden blindness due to bilateral optic neuropathy associated with cryptococcal meningitis in an aids patient. rev iberoam micol. 2010;27:207–209. pmid: 20965271, http://dx.doi.org/10.1016/j.riam.2010.09.002 hoepelman ai, van der flier m, coenjaerts fe. dexamethasone downregulates cryptococcus neoformans–induced vascular endothelial growth factor production: a role for corticosteroids in cryptococcal meningitis? j acquir immune defic syndr. 2004;37:1431–1432. pmid: 15483473 seaton ra, verma n, naraqi s, wembri jp, warrell da. the effect of corticosteroids on visual loss in cryptococcus neoformans var. gattii meningitis. trans r soc trop med hyg. 1997;91:50–52. pmid: 9093628, http://dx.doi.org/10.1016/s0035-9203(97)90393-x de schacht c, smets rm, callens s, colebunders r. bilateral blindness after starting highly active antiretroviral treatment in a patient with hiv infection and cryptococcal meningitis. acta clin belg. 2005;60:10–12. pmid: 15981698, http://dx.doi.org/10.1179/acb.2005.003 kestelyn p, taelman h. visual loss and cryptococcal meningitis. trans r soc trop med hyg. 1997;91:727–728. http://dx.doi.org/10.1016/s0035-9203(97)90542-3 moodley a, naidoo n, reitz d, chetty n, rae w. the optic nerve compartment syndrome in cryptococcus-induced visual loss. neuro-ophthalmology. 2013;37:124–128. http://dx.doi.org/10.3109/01658107.2013.792359 killer he, laeng hr, flammer j, groscurth p. architecture of arachnoid trabeculae, pillars, and septa in the subarachnoid space of the human optic nerve: anatomy and clinical considerations. br j ophthalmol. 2003;87:777–781. pmid: 12770980, http://dx.doi.org/10.1136/bjo.87.6.777 killer he, jaggi gp, miller nr, et al. cerebrospinal fluid dynamics between the basal cisterns and the subarachnoid space of the optic nerve in patients with papilloedema. br j ophthalmol. 2011;95:822–827. pmid: 20956279, http://dx.doi.org/10.1136/bjo.2010.189324 killer he, mironov a, flammer j. optic neuritis with marked distension of the optic nerve sheath due to local fluid congestion. br j ophthalmol. 2003;87:249. pmid: 12543769, http://dx.doi.org/10.1136/bjo.87.2.249 orgul s. compartment syndrome in the optic nerve: a new hypothesis in the pathogenesis of glaucoma. acta ophthalmol. 2012;90:686–689. pmid: 21294853, http://dx.doi.org/10.1111/j.1755-3768.2010.02071.x megson gm, stevens da, hamilton jr, denning dw. d-mannitol in cerebrospinal fluid of patients with aids and cryptococcal meningitis. j clin microbiol. 1996;34:218–221. pmid: 8748311. govender np, meintjes g, bicanic t, et al. guideline for the prevention, diagnosis and management of cryptococcal meningitis among hiv-infected persons: 2013 update. s afr j hiv med. 2013;14:76–86. the southern african journal of hiv medicine                                                        december 2009  85 an important maxim in treating patients with hiv is that the first regimen is your best chance for success. get it right the first time. recent data show that the response of children to antiretroviral therapy (art) both overseas and locally has been phenomenal.1-4 nevertheless, inevitably, increasing numbers of children will require a second-line regimen. it is therefore important that we have an approach to changing therapy. there are two main reasons for changing art – toxicity or intolerance, and failure of the current regimen. other reasons include poor adherence (often improved with alternative antiretrovirals (arvs)) and emergence of more effective or safer regimens. toxicity or intolerance see the guidelines for antiretroviral therapy in children, p. 32 of this issue. when a patient exhibits intolerance to or toxicity from a single drug, the offending drug can often be replaced, e.g. replacing zidovudine (azt) with abacavir (abc) for bone marrow toxicity caused by azt. rarely, a reduction in dosage may be considered as long as the reduced dose is still in the therapeutic range. for severe toxicity such as lactic acidosis or abc hypersensitivity reaction, all art should be stopped until the patient recovers. only then can one cautiously restart art. the offending agent should be switched for one that does not cause the same reaction. failure of current regimen ideally one should not change therapy on the basis of a single viral load (vl) or cd4 count. before changing art, a thorough assessment of adherence issues should be made. adherence is the most important factor determining the success of an art regimen.5-7 adherence issues must be resolved before changing therapy. the us public health service guidelines8 lists three types of failure of an antiretroviral regimen – virological, immunological and clinical failure (fig. 1). unfortunately there are few paediatric data on when to change art. penpact1, a study in europe and the usa, is comparing changing art at a vl of 1 000 versus 30 000 copies/ml. their results will be presented at the world aids congress in 2010. the south african guidelines recommend changing regimens when the vl is repeatedly above 1 000 copies/ml. some paediatric experts would not change the therapy until the vl was repeatedly >5 000 10 000 copies/ml. intervention does not necessarily mean a change of regimen. it may involve resolving adherence issues or changing to a holding strategy. with a persistently elevated vl, resistance mutations will accumulate9 and cross-resistance to drugs that the patient has not been exposed to will occur. isolated vl ‘blips’, e.g. single levels of 50 1 000 copies/ml, are not usually associated with subsequent virological failure.10,11 it is important to follow up a blip changing antiretroviral therapy in children clinical leon j levin, mb bch, fcpaed (sa), dtm&h head, paediatric programmes, right to care please note: the recommendations given in this article are only a guide. there is no substitute for expert advice when changing art. please consult the sa hiv clinicians society or the author for a list of local and overseas experts willing to assist you. this article is an update of a similar article published in the november 2005 edition of this journal. the rapid pace of changes in this field necessitates this update. alarming numbers of children are failing both firstand secondline antiretroviral therapy regimens in a very short space of time, underscoring the importance of adhering to the basic guiding principles of changing therapy outlined below. december 2009                                                          the southern african journal of hiv medicine                                                  86 with another vl after 3 months to exclude virological failure. in children with low cd4 counts, an opportunistic infection can occur before the immune system has recovered and is not an indication to change art. similarly, with bronchiectasis recurrent lower respiratory tract infections are to be expected. immune reconstitution inflammatory syndrome (iris) is also not an indication to change art. changing therapy different scenarios when changing art there are three main scenarios when changing art for drug failure. n early failure of a first regimen – there is unlikely to be much cross-resistance. a simple choice of a different regimen is usually adequate. n intermediate failure of a first regimen – some crossresistance may be present. genotyping may be helpful in ascertaining the degree of cross-resistance. n extensive prior treatment – extensive drug resistance is likely. initial assessment this is important in determining the cause of failure, as frequently the same issues will be a barrier to the success of a subsequent regimen. assessing adherence adherence is the most important factor in determining the success of an art regimen.5-7 virological failure often follows poor adherence. do not change therapy until the adherence issues have been resolved. since the first regimen is often the best tolerated, subsequent regimens are often not as well tolerated and are likely to exacerbate adherence issues. changing art is never an emergency and is futile without addressing adherence. if adherence issues cannot be resolved quickly and you are worried about accumulating new resistance mutations, there may be a role for a ‘holding strategy’ until the family is ready to start the new regimen (see ‘holding strategies’ below). virological considerations: incomplete response to therapy: n <10 × (1 log10) decrease from baseline vl at 8 12 weeks n hiv rna >400 copies/ml after 6 months or above the level of detection using an ultrasensitive assay after 12 months of therapy (some would accept a vl <5 000 copies/ml in a stable patient) viral rebound: repeated detection of plasma hiv rna on ultrasensitive pcr assays where viral load was previously undetectable. infrequent episodes of low level viraemia (<1 000 copies/ml) are common and not generally reflective of virological failure, whereas repeated or persistent viraemia (>1 000 copies/ml) more probably represents viral rebound (some would accept a vl <5 000 copies/ml in a stable patient) immunological considerations: incomplete immunological response to therapy: n <5 years of age: failure to improve cd4% values by ≥5% where cd4% was previously <15% n ≥5 years of age: failure to improve cd4 values by ≥50 cells/µl above baseline where cd4 was previously <200 cells/µl within the first year of therapy immunological decline: sustained decline of 5% in cd4% below pre-therapy baseline at any age, or decline to below pre-therapy baseline in absolute cd4 cell count in children who are age 5 years and older clinical considerations: progressive neuro-developmental deterioration growth failure: persistent decline in weight-growth velocity despite adequate nutritional support and without other explanation severe or recurrent infection or illness: recurrence or persistence of aids-defining conditions or other serious infections fig. 1. considerations for changing therapy in paediatric patients on antiretroviral therapy.8 the southern african journal of hiv medicine                                                        december 2009  87 exclude inadequate drug exposure possible causes include: n drug not being ingested, e.g. poor adherence, vomiting, or spitting up of an unpalatable drug such as ritonavir. n poor absorption, often in children with chronic diarrhoea or malabsorptive states. n increased drug metabolism – children beyond the neonatal age have markedly increased drug metabolism compared with adults. post-marketing research often reveals package insert dosages to be inadequate. consult an up-to-date paediatric art guideline for correct dosages. n drug interactions – investigate all medications the patient is taking (including over-the-counter drugs and ‘herbal’ products) for possible drug interactions with arv agents. commonly implicated drugs include rifampicin, anti-epileptics, antimalarials and st john’s wort. exclude other causes of a raised vl and/or a lower cd4 count intercurrent infections, opportunistic infections and immunisations may temporarily drop the cd4 count or raise the vl. ideally one should repeat the cd4 and vl 1 month later to ensure a return to baseline. factors to consider when changing antiretroviral therapy expert advice there is no substitute for expert advice when changing art. the field is fraught with pitfalls for the unwary. many patients’ futures have been compromised by poor choices when changing therapy. there is always enough time to consult with an expert before changing therapy. resistance testing only genotypic assays are available in south africa. adult data reveal a short-term benefit of resistance testing in terms of virological response.12,13 paediatric data are conflicting,14-17 but most experts believe that these assays have a role in changing art in the face of resistance. overseas guidelines recommend using resistance testing with every change of art regimen caused by treatment failure.8,18 this is also the recommendation of the sa hiv clinicians society, but prohibitive cost (over r4 000) will probably mean that in the south african state sector genotyping will only be done (if at all) after failure of a second regimen. apart from the cost, genotyping has other limitations, including the following: n genotyping will only give information about the current regimen. if a patient has failed a drug in a previous regimen, genotyping may therefore falsely report susceptibility to that drug. n genotyping should be done while the patient is still taking their ‘failing’ regimen or within 4 weeks of stopping it.18 n genotyping needs expert interpretation. it requires in-depth analysis by someone highly experienced in the field who also has all the details of the patient’s treatment history. knowledge of paediatric data and formulations are essential for correct advice. at least 2 new drugs always try to include at least 2 (preferably 3) new or active agents.18 one needs to be aware of cross-resistance (see below), since what may look like a ‘new agent’ may be ineffective as the virus is already resistant to it. genotyping may help to select which drugs in the present regimen could be re-used. this does not apply to drugs in a previous regimen, as resistance mutations may be below the level of detection. preferably a new drug class studies have shown that the success of a subsequent regimen is increased if it contains an antiretroviral class to which the patient has not previously been exposed.19,20 two new drug classes, integrase and ccr5 inhibitors, should be available locally soon. they will be useful in highly experienced patients. do not add one drug to a failing regimen adding one drug to a failing regimen will predispose to the rapid development of resistance. this is the equivalent of monotherapy, which should generally be avoided at all costs. a variant of this is combining an active drug with a low genetic threshold for resistance, such as a non-nucleoside reverse transcriptase inhibitor (nnrti) or raltegravir (integrase inhibitor), with 2 partially active drugs – in this situation the active drug will fail quickly. consider cross-resistance cross-resistance can be defined as phenotypic resistance to one drug resulting from mutations (genotypic) selected by another drug.21 there is no cross-resistance between the different arv classes. in the nucleoside reverse transcriptase inhibitor (nrti) class, azt and stavudine (d4t) are both thymidine analogues that select for the same resistance mutations, and there is crossresistance between them. generally, however, there is unlikely to be much nrti cross-resistance after failing a first regimen.21 with the currently available nnrtis, on the other hand, there is a high level of cross-resistance. if a patient fails nevirapine (nvp), there will be high-level resistance to efavirenz (efv). the new second-generation nnrti etravirine (etr), which will soon be available in south africa, needs a few nnrti mutations before there is high-level resistance against it. unfortunately, december 2009                                                          the southern african journal of hiv medicine                                                  88 genotyping is necessary to ascertain whether etr will be active after failing an nnrti. cross-resistance in the protease inhibitors (pis) depends on the pi concerned. some pis, e.g. atazanavir, amprenavir and nelfinavir, develop specific primary mutations first without conferring cross-resistance to other pis. secondary mutations conferring cross-resistance to other pis will only occur after prolonged non-suppressive therapy. genotyping may help to clarify whether cross-resistance is present. expert advice can be invaluable in this situation. consider drugs used for prevention of mother-tochild transmission (pmtct) numerous studies have demonstrated resistance to nvp where mothers and their babies each receive one dose of nvp. there are emerging data in adults and infants suggesting reduced efficacy of future first-generation nnrti-containing regimens.22-24 it is therefore advisable to avoid nvp and efv as part of first-line therapy in this situation. consult the guidelines for antiretroviral therapy in children (p. 32 of this issue) when other arvs have been used for prophylaxis. consider adding 3tc where m184v mutation present to maintain m184v mutation resistant hiv-1 with the hallmark 3tc resistance mutation, m184v, has reduced viral fitness, i.e. it replicates at a reduced rate and may reverse resistance to azt, d4t and tenofovir (tdf). therefore there may be value in adding in 3tc for salvage despite documented resistance. however, the data are conflicting.25,26 abc will also maintain the m184v mutation without adding in 3tc (personal communication, professor mark wainberg). pharmacokinetic enhancement where a single pi has been used previously, there may be a place for using a ‘boosted pi’, i.e. adding a small dose of ritonavir to the pi to inhibit the enzyme cytochrome p450 3a4, thus resulting in much higher levels of the pi. this may overcome minor degrees of pi resistance. generally, however, it is advisable to only use boosted pi regimens. therapeutic drug monitoring (tdm) tdm is still largely experimental in art. however, there may be a place for tdm in salvage therapy with multiple drugs and multiple possible interactions. contact the sa hiv clinicians society. dual pis this used to be quite ‘fashionable’ as a salvage therapy a few years ago. invariably these children will have extremely high cholesterol and triglyceride levels. with the advent of newer agents and with data suggesting that dual pis are no more efficacious than one boosted pi, this approach has become less popular.27,28 megaor giga-haart there are some adult data on empiric multidrug regimens,29,30 but these are complex and poorly tolerated, and often with unfavourable drug interactions. with the advent of newer arvs these regimens are no longer used much. a feeding gastrostomy tube may be used to simplify the administration of multiple medications.31 new arvs several new agents are already available overseas with activity against resistant virus. tdf is available in south africa, but it is not used routinely in children because of osteopenia and nephrotoxicity. however, if properly monitored tdf has some merit as a salvage drug in older patients. new pis such as darunavir32 and tipranavir33 have revolutionised the management of highly resistant patients overseas. raltegravir will be the first integrase inhibitor to be launched in south africa. this potent and well-tolerated agent has shown phenomenal results in both naïve and art-experienced adults.34,35 paediatric studies are ongoing.36 etravirine, the second-generation nnrti, may still be active in the face of resistance to first-line nnrtis.37,38 the ccr5 inhibitor maraviroc will probably have limited use in south africa since it is only effective in patients who are ccr5-tropic and requires an expensive tropism assay prior to initiation.39 these new agents have achieved undetectable vls in heavily arv-experienced adults in contrast to earlier salvage regimens. paediatric dosages and formulations are in development. nevertheless, one can obtain section 21 authorisation from the medicines control council. consult an expert. holding strategies not uncommonly one encounters a situation where a child needs to change art but for various reasons is unable to. common situations are unresolved adherence issues, inability to swallow tablets, or needing a new arv that lacks paediatric dosing data or formulations. if the cd4 count is not too low, there may be place for a ‘holding strategy’. these are only temporary solutions and do not replace a suppressive regimen. holding strategies include structured treatment interruptions, 3tc monotherapy and holding regimens. these approaches should only be used on the advice of an expert. n structured treatment interruptions (stis) there are three scenarios where one might consider stopping therapy: the southern african journal of hiv medicine                                                        december 2009  89 infants. since paediatric hiv infection occurs with an immature immune system, treating with arvs may allow the immune system to mature. thus, a baby who has had several months of art and is now over 1 year of age may cope without art for several years because the immune system is now mature enough to cope with the baby’s own hiv virus. the cher study is currently looking at this phenomenon. until the results of this study are published, this is not recommended as a routine practice. infants and children with immune reconstitution. this is a situation where the patient’s cd4 count has recovered but the child is now virologically failing the current regimen. in this situation, there may be a place for taking the child off all therapy and watching the cd4 count carefully. once the cd4 count drops below the criteria for starting art, a new regimen can be started. the smart study, in adults, showed a worse outcome in patients who stopped their art compared with those who remained on art,40 but there are few paediatric data. penta11, a pilot interruption study in children, showed no deaths or serious clinical events on interruption for up to 48 weeks.41 multidrug-experienced children with low cd4 counts. adult data reveal that there is no place for stis in a salvage situation.42-44 the cd4 count drops rapidly and the patients are at risk for opportunistic infection. n 3tc monotherapy although there are comparatively few adult data on this approach, 3tc monotherapy has gained popularity. there are data to suggest that giving 3tc monotherapy in patients failing multiple drugs results in slower disease progression than no therapy at all45 because of reduced viral fitness in virus with the m184v mutation. this can be attempted. the approach may have merit in patients failing 3tc but with good cd4 counts and unable to start a definitive suppressive regimen. 3tc monotherapy should be avoided in patients who have ever had a very low cd4 count (low cd4 nadir). when the cd4 drops or symptoms develop, the child should be placed on a fully suppressive regimen. n holding or bridging regimens these are simplified regimens, usually consisting of 3 or 4 nrtis with the purpose of maintaining resistance mutations so that the virus has a reduced replicative ability. the aim once again is to ‘buy time’ for the child who is unable to start a definitive suppressive regimen. a suitable child would be one with extensive nrti resistance but in whom you would not want to develop more pi or nnrti resistance. therefore future options are preserved. since there is already extensive nrti resistance, there is no worry that the child will develop more resistance to the nrtis. in adults, azt/3tc/abc/tdf has been used.46 in younger children, tdf can be omitted. once again this approach is inappropriate for patients with a very low cd4 count. once the cd4 count drops or symptoms develop the child should be placed on a fully suppressive regimen. quality of life in end-stage disease in patients without further arv options and who are failing or not tolerating mega-haart, there may be a place for reducing the number of drugs to make life more tolerable. the disease will still progress more slowly than if off arvs. consult an expert to reduce the number of agents to a more tolerable regimen. 3tc should always be included in such a regimen. as more new drugs become available, this scenario is becoming less common. conclusion changing art is a highly complex field, which can have major impact on a child’s future if done incorrectly. it is therefore strongly recommended that an expert be consulted before changing any child’s art. this would apply equally to a child failing their first regimen. however, the future is rosy with wonderful new antiretroviral options and certainly something worth looking forward to. references 1. starr se, fletcher cv, spector sa, et al., for the pediatric aids clinical trials group 382 team. combination therapy with efavirenz, nelfinavir, and nucleoside reversetranscriptase inhibitors in children infected with human immunodeficiency virus type 1. n engl j med 1999; 341: 1874-1881. 2. saez-llorens x, violari a, deetz co, et al. forty-eight-week evaluation of lopinavir/ ritonavir, a new protease inhibitor, in human immunodeficiency virus-infected children. pediatr infect dis j 2003; 22: 216-223. 3. puthanakit t, oberdorfer a, akarathum n, et al. efficacy of highly active antiretroviral therapy in hiv-infected children participating in thailand’s national access to antiretroviral program. clin infect dis 2005; 41: 100-107. 4. davies md, keiser o, technau k, et al. outcomes of the south african national antiretroviral treatment programme for children: the iedea southern africa collaboration. s afr med j 2009; 99: 730-737. 5. paterson dl, swindells s, mohr j, et al. adherence to protease inhibitor therapy and outcomes in patients with hiv infection. ann intern med 2000; 133(1): 21-30. 6. van dyke rb, lee s, johnson gm, et al. reported adherence as a determinant of response to highly active antiretroviral therapy in children who have human immunodeficiency virus infection. pediatrics 2002; 109(4): e61. 7. watson dc, farley jj. efficacy of and adherence to highly active antiretroviral therapy in children infected with human immunodeficiency virus type 1. pediatr infect dis j 1999; 18(8): 682-689. 8. working group on antiretroviral therapy and medical management of hivinfected children. guidelines for the use of antiretroviral agents in pediatric hiv infection. 23 february 2009; pp. 1-139. http://aidsinfo.nih.gov/contentfiles/ pediatricguidelines.pdf 9. barbour jd, wrin t, grant rm, et al. evolution of phenotypic drug susceptibility and viral replication capacity during long-term virologic failure of protease inhibitor therapy in human immunodeficiency virus-infected adults. j virol 2002; 76(21): 11104-11112. 10. greub g, cozzi-lepri a, ledergerber b, et al. clinical intermittent and sustained low-level hiv viral rebound in patients receiving potent antiretroviral therapy. aids 2002; 16(14): 1967-1969. 11. havlir dv, bassett r, levitan d, et al. prevalence and predictive value of intermittent viremia with combination hiv therapy. jama 2001; 286(2): 171-179. 12. durant j, clevenbergh p, halfon p, et al. drug resistance genotyping in hiv-1 therapy: the viradapt randomized controlled trial. lancet 1999; 353: 2195-2199. 13. baxter jd, mayers dl, wentworth dn, et al. a randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy. cpcra 046 study team for the terry beirn community programs for clinical research on aids. aids 2000; 14(9): f83-93. 14. cohen nj, oram r, elsen c, englund ja. response to changes in antiretroviral therapy after genotyping in human immunodeficiency virus-infected children. pediatr infect dis j 2002; 21: 647-653. 15. servais j, hainaut m, schmitz v, et al. resistance testing in hiv-1 infected children changing protease inhibitor based therapy. pediatr infect dis j 2002; 21: 214-220. 16. badolato r, schumacher rf, rodella e, et al. genotyping for guiding drug choice in human immunodeficiency virus-infected children failing multiple antiretroviral treatment regimens. pediatr infect dis j 2005; 24(8): 747-749. 17. green h, gibb dm, compagnucci a, et al. a randomized controlled trial of genotypic hiv drug resistance testing in hiv-1-infected children: the pera (penta 8) trial. antivir ther 2006; 11(7): 857-867. december 2009                                                          the southern african journal of hiv medicine                                                  90 18. panel on antiretroviral guidelines for adults and adolescents. guidelines for the use of antiretroviral agents in hiv-1-infected adults and adolescents. department of health and human services. 3 november 2008; 1-139. http://www.aidsinfo.nih. gov/contentfiles/adultandadolescentgl.pdf 19. gulick m, hu xj, fiscus sa, et al. randomized study of saquinavir with ritonavir or nelfinavir together with delavirdine, adefovir, or both in human immunodeficiency virus-infected adults with virologic failure on indinavir: aids clinical trials group study 359. j infect dis 2000; 182(5): 1375-1384. 20. hammer sm, vaida f, bennett kk, et al. dual vs single protease inhibitor therapy following antiretroviral treatment failure: a randomized trial. jama 2002; 288(2): 169-180. 21. richman d, staszewski s. a practical guide to hiv drug resistance and its implications for antiretroviral treatment strategies. 2nd ed. international medical press, 2000. 22. jourdain g, ngo-giang-huong n, le coeur s, et al., for the perinatal hiv prevention trial group. intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. n engl j med 2004; 351: 229240. 23. lockman s, shapiro rl, smeaton lm, et al. response to antiretroviral therapy after a single, peripartum dose of nevirapine. n engl j med 2007; 356 (2): 135-147. 24. palumbo p, violari a, lindsey j, et al. nevirapine (nvp) vs. lopinavir-ritonavir (lpv/ r)-based antiretroviral therapy (art) in single dose nevirapine (sdnvp)-exposed hiv-infected infants: preliminary results from the impaact p1060 trial. presented at the 5th ias conference on hiv pathogenesis treatment and prevention 19 22 july 2009, cape town. abstract lbpeb12. 25. campbell tb, shulman ns, johnson sc, et al. antiviral activity of lamivudine in salvage therapy for multidrug-resistant hiv-1 infection. clin infect dis 2005; 41(2): 236-242. 26. dragsted u, fox z, mathiesen l, et al., for the colate trial group. final week 48 analysis of a phase 4, randomised, open-label, multi-center trial to evaluate safety and efficacy of continued lamivudine twice daily versus discontinuation of lamivudine in hiv-1-infected adults with virological failure on ongoing combination treatments containing lamivudine: the colate trial. presented at the 11th conference on retroviruses and opportunistic infections, 8 11 february 2004, san francisco. abstract no. 549. 27. loutfy m, raboud j, thompson c, et al. clinical impact of double protease inhibitor boosting with lopinavir/ritonavir and amprenavir as part of salvage antiretroviral therapy. hiv clin trials 2003; 4: 301-310. 28. petersen ml, wang y, van der laan, mj, rhee, sy, shafer, rw, fessel, wj. virologic efficacy of boosted double versus boosted single protease inhibitor therapy. aids 2007; 21(12): 1547-1554. 29. montaner js, harrigan pr, jahnke n, et al. multiple drug rescue therapy for hivinfected individuals with prior virologic failure to multiple regimens. aids 2001; 15(1): 61-69. 30. youle m, tyrer m, fisher m, et al. brief report: two-year outcome of a multidrug regimen in patients who did not respond to a protease inhibitor regimen. j acquir immune defic syndr 2002; 29(1): 58-61. 31. shingadia d, viani rm, yogev r, et al. gastrostomy tube insertion for improvement of adherence to highly active antiretroviral therapy in pediatric patients with human immunodeficiency virus. pediatrics 2000; 105(6): e80. 32. blanche s, bologna r, cahn p, et al. pharmacokinetics, safety and efficacy of darunavir/ritonavir in treatment-experienced children and adolescents. aids 2009; 23(15): 2005-2013. 33. courter j, girotto j, salazar j. tipranavir: a new protease inhibitor for the pediatric population. expert rev anti infect ther 2008; 6(6): 797-803. 34. steigbigel rt, cooper da, kumar pn, et al. (benchmrk study teams). raltegravir with optimized background therapy for resistant hiv-1 infection. n engl j med 2008; 359(4): 339-354. 35. cooper da, steigbigel rt, gatell jm, et al. (benchmrk study teams). subgroup and resistance analyses of raltegravir for resistant hiv-1 infection. n engl j med 2008; 359(4): 355-365. 36. wiznia a, samson p, acosta e, et al. safety and efficacy of raltegravir in pediatric hiv infection. preliminary analysis from the international maternal pediatric adolescent aids clinical trials group, p1066. presented at the 16th conference on retroviruses and opportunistic infections (croi 2009), 8 11 february 2009, montreal, canada. abstract 874. 37. valdez madruga j, cahn p, grinsztejn b, et al. efficacy and safety of tmc125 (etravirine) in treatment-experienced hiv-1-infected patients in duet-1: 24-week results from a randomised, double-blind, placebo-controlled trial. lancet 2007; 370: 29-38. 38. lazzarin a, campbell t, clotet b, et al. efficacy and safety of tmc125 (etravirine) in treatment-experienced hiv-1-infected patients in duet-2: 24-week results from a randomised, double-blind, placebo-controlled trial. lancet 2007; 370: 39-48. 39. gulick rm, lalezari j, goodrich j, et al. maraviroc for previously treated patients with r5 hiv-1 infection. n engl j med 2008; 359: 1429-1441. 40. strategies for management of antiretroviral therapy (smart) study group, el-sadr wm, lundgren jd, neaton jd, et al. cd4+ count-guided interruption of antiretroviral treatment. n engl j med 2006; 355(22): 2283-2296. 41. gibb dm, compagnucci a, green h, et al. treatment interruption in children with chronic hiv-infection: the results of the paediatric european network for treatment of aids (penta) 11 trial. j int aids soc 2008; 11: (suppl 1):21 doi:10.1186/17582652-11-s1-o21. 42. lawrence j, mayers dl, hullsiek kh, et al. structured treatment interruption in patients with multidrug-resistant human immunodeficiency virus. n engl j med 2003; 349: 837-846. 43. katlama c, dominguez s, gourlain k, et al. benefit of treatment interruption in hiv-infected patients with multiple therapeutic failures: a randomized controlled trial (anrs 097). aids 2004; 18: 217-226. 44. ruiz l, ribera e, bonjoch a, et al. role of structured treatment interruption before a 5-drug salvage regimen: the retrogene study. j infect dis 2003; 188: 977-985. 45. castagna a, danise a, menzo s, et al. lamivudine monotherapy in hiv-1-infected patients harbouring a lamivudine-resistant virus: a randomized pilot study (e-184v study). aids 2006, 20: 795-803. 46. llibre jm, bonjoch a, iribarren j, et al. targeting only reverse transcriptase with zidovudine/lamivudine/abacavir plus tenofovir in hiv-1-infected patients with multidrug-resistant virus: a multicentre pilot study. hiv med 2008; 9: 508-513. j u ly 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e criticisms of the abc (abstain, be faithful, condomise) and abstinence/faithfulness approaches are well established,1 and yet these remain the core of hiv education. in august 2008, the global live hiv prevention working group (glhwg), representing the thoughts of over 50 prominent hiv activists from around the world, agreed that while behaviour change was a vital part of hiv prevention, current behaviour change strategies of the abstain/be faithful style were not living up to expectations. a key recommendation made by the glhwg was that prevention strategies should be more culturally and contextually sensitive.2 however, culture has also been suggested as a key driver of the hiv pandemic in southern africa,3,4 and as a result in the hiv arena in southern africa today people are talking about ‘culture’. for example, unesco’s main health and culture project is called ‘culture, hiv and aids’.5 a key aspect of the cultural approaches to hiv education involves education around gender issues; it is assumed that women’s lack of empowerment, which is largely culturally defined, is linked to women’s inability to negotiate safer sex. another key aspect of cultural approaches to hiv education involves advocacy against people having multiple partners; it is assumed that the traditional culture of much of southern africa sanctions multiple partnerships and that this is linked to increased vulnerability to hiv infection. these two trends in hiv education, of respecting culture but also making culture partially responsible for the hiv pandemic, have created an uncomfortable tension. in this commentary i try to resolve this tension, specifically as it pertains to educational interventions. to carry out this examination of hiv education i use a form of critical discourse analysis (cda), based on the work of norman fairclough.6-8 fairclough’s discourse analysis work is distinctive in that he explicitly admits a connection to the critical realism (cr) of conserving (not preserving) culture: avoiding the damage to culture of veiled moralism in hiv education o p i n i o n leigh price, phd shanduko centre for agrarian and environmental research, harare, zimbabwe language mechanisms in much hiv discourse insist that a western-based moralism dominates. these mechanisms include the use of strategic absences of information about the moral grounding of texts, and slippages of meaning where one word is used to refer to many meanings. a common slippage of meaning is use of the word ‘polygamy’ to refer to a range of behaviours, thus hiding low-hiv-risk sexual practices (polyfidelity) under the same umbrella as high-risk practices (promiscuity) and advocating their general removal. another dubious method of achieving a moral position is to take a true premise and use it to advance a false conclusion. for example, the true premise that wife inheritance in its historical form is an hiv risk factor does not automatically lead to the conclusion that wife inheritance ‘must’ be eradicated. this is only one possible conclusion. another more culturally sensitive conclusion could be that wife inheritance should be embarked upon, as should all sexual relationships, in a context of hiv tests and safer sexual practice. i argue that moralism (such as ‘wife inheritance is morally wrong’) cloaked as science (the claim that science ‘proves’ the moral position that wife inheritance is wrong) is a threat to traditional culture and discriminates against upholders of traditional lifestyles. drawing primarily from my experience of hiv education in a development setting in southern africa, i offer a weak (realist) moral relativism as an alternative to on the one hand the positivist-based, absolutist morality that threatens to destroy traditional cultures in the name of hiv education, and on the other hand extreme cultural relativism in which ‘anything goes’. possibly hiv educators have not done enough to include some traditional safer sex practices in their professional inventory of acceptable behaviours, such as hlobonga (thigh sex) and polygamy interpreted as polyfidelity. my hope is that by being more respectful of traditional culture, while encouraging cultural change where necessary, hiv education will register greater success in achieving safer sexual practice. this article will be particularly useful for writers and researchers tasked with achieving behavioural change and/or writing educational materials on hiv in the southern african context. methodology 12 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u ly 2 0 0 9 roy bhaskar.9 a significant characteristic of cr is that validity is not only judged by empirical measurement but also by explanation. the validity of the claims that i make in this commentary must therefore be judged inter alia by their ability to explain the current status quo of hiv education and culture. furthermore, cr accounts allow judgemental rationalism, allowing us to decide between, in this case, better or worse sexual behaviours. however, the associated epistemic relativism of cr allows a variety of interpretations of facts. in this case, a variety of behaviours may arguably achieve a similar goal of safer sex. in much of the hiv educational literature available in southern africa there is a tangle of science, morality and culture, and in the battle for clarity it seems that traditional culture loses, while only a certain type of morality wins. for example, the science of the sexual transmission of hiv apparently gives support to the idea that polygamy is an hiv liability. the two issues, hiv transmission and polygamy, are so closely linked in much hiv information, education and communication (iec) material that it is common to come across the misconception that polygamy actually causes hiv infection. assuming that something is the case, when in fact it is not true, or is at least arguable, is a language strategy that can avoid dissent.10 for example, the statement ‘zimbabweans agreed that polygamy spreads hiv’ can be found on the website of world links for development.11 additionally, in much hiv educational material the following terms are incorrectly used synonymously: ‘polygamy’, ‘promiscuity', ‘small-house phenomenon’ (where a man is secretly polygamous), and ‘multiple concurrent partners’ (as it suggests, similar to the ‘small-house phenomenon’ but including situations where the partners do not set up house together).12 ‘slippage of meaning’ or vagueness can be manipulative, such as using one word to mean several things or not being clear as to the meaning in context. in this case, using ‘polygamy’ to mean many different kinds of non-monogamy could be seen as strategic.13 while there is evidence that promiscuity, the small-house phenomenon and multiple concurrent partnerships provide preconditions for higher hiv risk,4,14,15 this relationship has not been conclusively demonstrated for traditional polygamy.15 on the contrary, there is evidence that lower rates of transmission are present in traditional polygamous communities. for example, in the north of ghana, where 44% of families are polygamous, the lowest prevalence rates in the country have been recorded.15 additionally, where polygamy is the norm but promiscuity is socially unacceptable (such as in senegal, where islam strictly forbids promiscuity), people may be at less risk than in societies that frown on polygamy but accept a long series of monogamous relationships.15 it appears that polygamy can create closed sexual communities that may protect against hiv transmission.15 i therefore suggest that the popularity of hiv arguments against the traditional, polygamous lifestyle is not based on scientific evidence but rather on a particular moral position. by conflating all non-monogamous behaviours together, educators can use hiv issues strategically to achieve cultural change towards their version of a moral society. the result is potentially a powerful neo-colonial force that will perhaps succeed where the colonial missionaries failed; namely, it may achieve a large-scale conversion of people away from traditional lifestyles. because a majority of hiv texts do not accept or include traditional polygamist lifestyles, traditional polygamists are not receiving education that addresses their specific circumstances. this discrimination is facilitated by the common avoidance of direct mention of moral positions by educators. absences of information or presuppositions can be manipulative.17 for example, in much mainstream hiv literature, especially of the abc kind, western christian-based ideals of the nuclear family are presupposed, while rarely being identified as such. here it is necessary to qualify that only the dominant christian position in southern africa supports monogamy; some christian sects find no evidence against polygamy. the effect of the omission of the moral base of much hiv education is that the nuclear, monogamous family approach is portrayed as ‘what any right-minded person would think’ rather than, to a significant extent, a personal, moral, religious choice, which might be different in a different culture. while the abc message will seem natural to a monogamous western-influenced urban african, it is likely to seem foreign to a polygamous, traditional african, such as a shangaan. one problem with the abc construction is that it apparently leaves no way for a polygamous family to have children, since condoms are presented as their only safe option. while the abcs are readerfriendly, the positioning of the condom option at the end of the list also implies that it is a last resort and that people really ought to be faithful to their (only) partner or abstain.1,18 for a shangaan, the abcs will seem to be ‘against our culture’ and to choose safer sexual behaviour, since it is dressed in western morality, will be to choose western morality. for many advocates of safer sex, their task is to convert the shangaan from polygamy to monogamy. i disagree. i think their task is to encourage safer sex, and it is possible to have safer sex within a polygamous context.15,16 a tangle of science, morality and culture polygamists in southern africa not receiving adequate hiv education 13 j u ly 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e therefore, while i have some problems with cries of ‘it’s against our culture’, which i will mention later, i also have some sympathy for them. when a person enters an hiv counselling centre, she or he should be offered a variety of information, education and communication (iec) and counselling options, based on her or his religious and cultural preferences. this is just as important as offering packages in vernacular languages. to offer an hiv package steeped in western morality, but merely translated into, for example, the shangaan language, is effectively (if not purposively) to use a trojan horse approach to changing culture; the recipients of safer sex interventions become initiated into western sexual morality as a by-product of their safer sex education. the questionable assumption here is that the same message is appropriate in all contexts and this message merely needs to be translated into different languages. however, it would be remiss to assume that all cultural practices are appropriate after the hiv pandemic, simply because of their historical existence. this is where unthought-through cries of ‘it’s against our culture’ need to be questioned. how do we conserve cultural heritage, while nevertheless ensuring safer sexual practice? we can do this by looking at a cultural practice and asking ‘if it is unsafe according to our medical understanding of the modes of transmission of the virus, how can we change it in a way that is culturally sensitive?’ many cultural practices are clearly unsafe as they are, such as the use of unsterilised blades for circumcision ceremonies. however, the essential aspect of the practice can be conserved by making relatively minor changes. circumcision can be carried out safely if sterile conditions are maintained. similarly, some sexual practices may be unsafe as they are, but can lose their high risk through relatively small changes. for example, the practice of a man marrying his brother’s widow is risky in its historical form. however, it would be significantly less risky if the wife and future husband were properly tested for hiv, then received safer sex counselling depending on the outcome of the tests. attempting to stamp out the practice, instead of exploring ways to adapt it, could be a sign that inappropriate moralism is present. in this example of wife inheritance, educators should avoid making strategic use of the presence of the (surmountable) hiv hazards of the practice to achieve an unrelated, moral, culturechanging goal of stopping the practice. this is an example of the questionable use of science to justify a moral position. because, like sayer,19 i am a weak moral relativist, i agree that there are arguments against wife inheritance, such as those influenced by religion or feminism. personally, i am convinced by many feminist arguments. i also believe it is important to allow religious commentators to air their views. however, people with values they would like to argue for (moralists) should be up-front about their moral position. because of hiv education, traditional people are changing their culture, sometimes when they do not need to do so from a medical point of view. moralists are not drawing clear lines between values derived from medical facts and values derived from other arenas and are exploiting the confusion. to try to change culture because of religious or social equality reasons, but to do so indirectly by using the hiv pandemic, is to be condescending towards the recipients of hiv education. to preach a message of morality but to cloak it as something else is to mistrust the power, even the truth, of that message. from the perspective of reducing hiv infection, trying to ‘amend’ people’s ‘immorality’ at the same time as their safer sex behaviour might be counter-productive; some people turn away from safer sex education altogether if it seems too foreign to their moral norms.20 perhaps further evidence of the conflation of western morality and hiv education is that traditional practices that may limit the spread of hiv, such as the traditional pre-marriage practice of thigh sex (hlobonga in zulu), have not been adequately explored. in the past hlobonga allowed for safer sexual experimentation.21,22 hlobonga does not involve the sharing of bodily fluids and therefore poses a low risk of sexual transmission of infections. furthermore, because hlobonga is not abstinence, given a broad definition of sex, it might satisfy those who suggest that abstinence ‘is not part of our culture’. there is evidence that hlobonga was used successfully in the past inter alia to prevent sexually transmitted diseases. in the early 1900s many migrant african mineworkers (such as the zulu and shangaan) preferred hlobonga to conventional sex in the absence of their wives, whereas the basotho workers disdained the activity as a mere boyish activity. the basotho preferred conventional heterosexual intercourse. by the 1930s the basotho had a much higher rate of syphilis, nearly 10 times higher than certain other tribal groupings of workers.22 incidentally, hlobonga was traditionally the preferred method used by men who had sex with men (msm); many of the mineworkers took male ‘wives’ during their time away from home, and hlocries of ‘it’s against our culture’: both valid and not valid practical advice on conserving cultural heritage in the context of hiv hlobonga (thigh sex) as a safer sex alternative 14 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u ly 2 0 0 9 bonga was frequently used for sexual experimentation between young herdboys.22 perhaps, in order to be sensitive to the traditionalists and to begin the process of finding a properly southern african approach to hiv education, the abcs (if we decide to keep them at all) should become the abcts (abstain, be faithful, condomise, try traditional thigh sex). ‘be faithful’ might also be re-interpreted to include both the fidelity of monogamous couples and the polyfidelity of traditional polygamous unions. polyfidelity describes the situation where the spouses of the polygamous household carry out intercourse only among themselves. advice might also be given on the importance of having hiv tests when choosing multiple spouses. perhaps the traditional practice whereby a man must marry his brother’s widow could also be reinterpreted in the context of hiv with the insistence on hiv testing and/or symbolic marriage that brings the widow into the household and gives her children security but does not involve conjugal rights. thigh sex would be appropriate safer sex for both heterosexual and homosexual activities. the historical existence of thigh sex among african msm provides an antidote to so-called traditionalists who claim that homosexuality is un-african. note how these suggestions do not detract from the original abc message but add to it. the suggestions allow the abcs to become more inclusive of a variety of lifestyle options. in their current form, the abcs discriminate against african people who practise their traditional culture. the abcts approach encourages a return to some of the traditional practices, such as hlobonga, and the traditional polyfidelity of polygamous unions. koktvedgaard zeitzen23 addresses some of the difficult and controversial issues facing modern polygamists such as prejudice and women’s emancipation. a recent new scientist article24 has found that men in polygamous marriages tend to live longer than men in monogamous relationships, further indicating that blanket positions against polygamy may need to be reassessed. a hope for the educational approach advocated here, which accepts many kinds of sexual union, is that it will reduce hiv transmission by making hiv education palatable to a wider variety of people. to conserve culture is to ensure that it keeps its distinct characteristics but continues to serve the interests of its practitioners. nevertheless, in a changing world, culture must also necessarily change if it is to remain useful. to preserve culture is to keep it pure from modern influences, and is perilous in the current hiv context. in this article, i have argued that we can achieve safer sexual practice while conserving, but not preserving, culture if we avoid the conflation of western morality with safer sexual practice and accept the validity of a broader range of moral positions. hiv behavioural interventions based on feminist or religious premises are particularly vulnerable to inadvertent, veiled moralistic positions, especially, but not uniquely, concerning the issue of polygamy. however, we should not stop addressing moral issues; rather, we should make our moral positions transparent and meticulously avoid clouding morals informed by medical values with morals informed by values drawn from other sources. references 1. barnett t, pankhurst j. hiv/aids: sex, abstinence, and behaviour change. lancet infect dis 2005; 5(9): 590-593. 2. global hiv prevention working group (ghpwg). behavior change and hiv prevention: (re)considerations for the 21st century. 2008. http://www. globalhivprevention.org/august2008_release.html (accessed 20 january 2009). 3. ntseane pg. cultural dimensions of sexuality: empowerment challenge for hiv/aids prevention in botswana. paper presented at the international seminar/ workshop on learning and empowerment: key issues in strategies for hiv/aids prevention, 1-5 march 2004, chiangmai, thailand. http://www.unesco.org/ education/uie/pdf/ntseane.pdf (accessed 5 september 2005). 4. halperin d, epstein h. why is hiv prevalence so severe in southern africa? the role of multiple concurrent partnerships and lack of male circumcision: implications for aids prevention. southern african journal of hiv medicine 2007; march: 19-25. 5. unesco (united nations educational, scientific and cultural organization) culture, hiv and aids. 2008. www.unesco.org/culture/aids (accessed 4 january 2009). 6. fairclough n. language and power. new york: longman, 1989: 152-154. 7. fairclough n. new labour, new language? london: routledge, 2000: 157-163. 8. fairclough n. analysing discourse: textual analysis for social research. london: routledge, 2003. 9. bhaskar r. reclaiming reality: a critical introduction to contemporary philosophy. london: verso, 1989. 10. fairclough n. new labour, new language? london: routledge, 2000: 163. 11. world (world links for development). challenges to hiv prevention. 2000. http:// www.world-links.org/aidsweb/goal3.html (accessed 22 december 2008). 12. brady e. healing logics: culture and medicine in modern health belief systems. logan: utah state university press, 2001: 137. 13. fairclough n. new labour, new language? london: routledge, 2000: 157. 14. chingandu l. multiple concurrent partnerships: the story of zimbabwe – are small houses a key driver? harare: southern african information dissemination service, 2007. http://www.kubatana.net/html/archive/hivaid/070612lc.asp?sector=hivaid (accessed 5 january 2008). 15. chga (commission on hiv/aids and governance in africa). securing our future: report of the commission on hiv/aids and governance in africa. an initiative of the secretary-general of the united nations. addis ababa: united nations economic commission for africa, 2008. http://www.uneca.org/chga/report/ (accessed 4 january 2009). 16. kalipeni e, craddock s, oppong j, ghosh j. hiv and aids in africa: beyond epidemiology. oxford: blackwell publishing, 2004: 74. 17. fairclough n. language and power. new york: longman, 1989: 152-154. 18. wetherell m, yates s, taylor s. discourse as data: a guide for analysis. london: sage, 2001: 259. 19. sayer a. realism and social science. london: sage publications, 1999: 172-189. 20. underhill k, montgomery p, operario d. sexual abstinence only programmes to prevent hiv infection in high income countries: systematic review. bmj 2007; 335: 248. 21. epprecht m. ‘unnatural vice’ in south africa: the 1907 commission of enquiry. the international journal of african historical studies 2001; 34(1): 121-140. http://www.jstor.org/pss/3097289 (accessed 22 december 2008). 22. galz (gays and lesbians of zimbabwe). unspoken facts: a history of homosexualities in africa. harare: galz, 2008: 162. 23. koktvedgaard zeitzen m. polygamy: a cross-cultural analysis. oxford: berg publishers, 2008. 24. callaway e. polygamy is the key to a long life. new scientist 2008; 19 august. http://www.newscientist.com/article/dn14564-polygamy-is-the-key-to-a-longlife.html (accessed 20 december 2008). abcts instead of the abcs conserving, not preserving, culture conflict of interest. there was no conflict of interest in the writing of this article. 15 feeding hiv-exposed.html from the editor feeding hiv-exposed infants the most appropriate strategies for feeding hiv-exposed infants have been a source of great debate in south africa for years. during this time policy makers, healthcare providers and (most importantly) mothers living with hiv infection have been concerned and sometimes confused about what is best for the hiv-exposed but uninfected infant. over the past few months, the announcement of a new national policy promoting breastfeeding with daily nevirapine prophylaxis for infants has presented a single, unified policy for services across the country. this is leading to the rapid cessation of replacement feeding provided through the public sector to hiv-infected mothers and their infants. but far from ending the debate on infant feeding, these new policies have refreshed the discussion. there have been a number of newspaper editorials and media releases presenting strong voices in support of, and cautioning against, the wholesale withdrawal of replacement feeding. a recent debate in johannesburg held by the sa hiv clinicians society provided a valuable summary of the key issues and a sense of the complexity in any attempt to develop a nationwide infant feeding strategy (for those who missed it, the presentations from the debate are available on the society’s website, http://sahivsoc.org). in this issue of the journal, haroon saloojee and colleagues present one viewpoint on the new national policies. dr saloojee was one of the participants in the johannesburg debate, and i hope that this opinion piece will help generate productive discussions on a topic that clearly remains unresolved. (note that opinion pieces that include other perspectives on the new infant feeding policies were solicited, but unavailable at the time of going to press – we hope these will be available for the next issue.) looking forward, the hiv clinicians society has been a leader, nationally and internationally, in developing evidence-based guidelines to address various issues in hiv treatment and prevention. given the ongoing debate, there is certainly scope for rational guidelines to address the safest infant feeding choices across a range of scenarios. we hope the society will take up the challenge of developing guidelines on infant feeding in the coming months, as this is an important time to present a balanced voice on a topic that remains contentious. also in this issue, dramowski and colleagues describe the ‘missed opportunities’ for reducing hiv-related paediatric admissions at baragwanath hospital in soweto. among the missed opportunities they document are the failure to deliver effective prevention of mother-to-child transmission (pmtct) services, including antenatal counselling and testing and antiretroviral interventions, leading to preventable paediatric infections. this research took place in a period when use of replacement feeding was common in soweto, but presumably this will change radically during 2012 under the new feeding policies. reading the articles by dramowski and saloojee together, the future seems unusually opaque. will we look back 10 years from now to view the removal of replacement feeding for hiv-exposed infants as a critical opportunity rightly taken to promote child health, or yet another opportunity missed in our efforts to eliminate paediatric hiv? this edition has many other exciting contributions. innes and colleagues ask important questions about stavudine dosing, and provide an intriguing proposal for future research into a neglected issue with major implications given the number of patients on stavudine. boyles discusses the ideal package of care for individuals who do not yet require antiretroviral therapy (art), an aspect of services that may be sorely neglected in many parts of the country. an original article from peltzer suggests a very high prevalence of depression among new hiv-infected mothers in kwazulu-natal, raising an important issue in thinking about pmtct interventions in the postpartum period. cullen presents a case report on an unusual case of optic neuritis in an hiv-infected patient, and in a review article garone and colleagues discuss the progress to date and lessons learned from 10 years of programmes delivered through médecins sans frontières in khayelitsha, cape town. msf’s projects in khayelitsha have been a vanguard for the development of models to deliver art as well as integrated hiv/tb care, and as we approach the 10-year anniversary of public sector art services in south africa, this review provides an important reminder of how far things have come. happy reading. landon myer editor associate professor, school of public health and family medicine, university of cape town prevalence of postnatal.html original article prevalence of postnatal depression and associated factors among hiv-positive women in primary care in nkangala district, south africa k peltzer1,2, phd, dr habil m e shikwane1, ma (psych) 1 hiv/aids/sti and tb (hast), human sciences research council, pretoria 2 department of psychology, university of limpopo, turfloop background. the prevalence of postpartum depression in south africa is high, but there is lack of prevalence data on postnatal depression among hiv-infected women. aim. the aim of this study was to determine the prevalence of depressed mood and associated factors in postnatal hiv-positive women in primary care facilities in nkangala district, mpumalanga, south africa. methods. this cross-sectional study was carried out on 607 hiv-positive postnatal women in 48 primary health care clinics and community health centres in nkangala district. postnatal women were recruited by systematic sampling (every consecutive patient over a period of 2 months). demographic and other data were obtained from all the women who responded to a questionnaire in the local language on male involvement, hiv test disclosure, delivery and infant profile, infant hiv diagnosis, stigma, discrimination, postnatal depression, attendance of support groups and social support. results. overall, 45.1% of women reported a depressed mood in the postnatal period. depressed mood in a multivariable analysis was significantly associated with internalised stigma (odds ratio (or) 1.12, 95% confidence interval (ci) 1.05 1.19; p=0.000), discrimination experiences (or 1.22, ci 1.03 1.46; p=0.023), lack of social support (or 0.86, ci 0.74 0.99; p=0.037) and having had an sti in the past 12 months (or 2.22, ci 1.21 4.04; p=0.010). there were no statistically significant correlations between the edinburgh postnatal depression scale (epds) scores of the women and age, marital status, level of education, employment status and number of own children. conclusion. depressed mood is common among hiv-positive postpartum women. this is significantly associated with lack of social support, stigma and discrimination. routine screening to identify those currently depressed or at risk of depression should be integrated into postnatal care settings to target those most needing intervention. postnatal depression is the most frequently recognised mental disorder after delivery and generally begins within 4 6 weeks after childbirth.1 the symptoms include low mood, tiredness, insomnia, lack of energy, forgetfulness, irritability and poor functioning. the occurrence of depressive illness after childbirth can be detrimental to the mother, her marital relationship and her children and can have adverse long-term effects if not treated.2 in addition, maternal postpartum depression poses significant risks for mother-child interaction and long-term infant outcomes.2 although the prevalence of postpartum depression in south africa is high (34.7%), there are few studies on the prevalence of postnatal depression among hiv-infected women.3 the postpartum period is a time in which women are more vulnerable to depressive symptoms,4 but most studies have only focused on depressive symptoms in hiv-positive individuals in general. in a study conducted in an urban setting in south africa, maternal postpartum depression was measured using the edinburgh postnatal depression scale (epds) among 83 hiv-infected mother infant dyads and 42.2% of the women scored above the cut-off point for depression.5 hiv-infected mothers are at high risk for a range of emotional and psychiatric problems that may impact on immunity and hiv disease progression.4 , 6 preterm delivery9 and difficulties with partners10 have been found to be associated with postpartum depression. in addition, low levels of social support, particularly partner support and availability of people to depend on during the pregnancy and early postpartum, and a woman’s relationship with her own parents were found to be significant factors for both antenatal and postnatal depression.11 society expects women to be mothers, and yet at the same time it negatively judges hiv-positive women who choose to become pregnant.12 emotional support plays a role in depressive symptoms; with limited support, hiv-positive individuals are more likely to exhibit depressive symptoms.13 , 14 the present study aimed to determine the prevalence of depressed mood and associated factors in postnatal hiv-positive women in primary care facilities in nkangala district, mpumalanga, south africa. method study setting the study was conducted in nkangala district, mpumalanga, which is ranked the third most rural province in south africa, with 60.9% of its population living in rural areas.15 nkangala district had a population of 1 121 839 people in 2008/9. at 28.4%, the unemployment rate is higher than the national unemployment rate (25.3%). more than a quarter (28.6%) of households in nkangala earned less than r30 000 per year (r2 500 per month) in 2009.15 it was estimated that 90% of the population was dependent on the state for the provision of all their health services.16 the primary health care utilisation rate of 2.2 visits per person per year has been constant from 2008 to 2009.17 the antenatal hiv prevalence rate in nkangala district was 32.5% in 2009.18 sample and procedure the sample included 607 postnatal hiv-positive women with an infant aged 1 10 weeks (30.8%), 11 weeks 6 months (36.7%) or 7 12 months (32.5%). almost all (98%) were from a black african population group, mainly zulu, swati and tswana. the inclusion criteria for the postnatal study were that the participant attended the clinic, was hiv positive, was 18 years of age and older, and had an infant less than 12 months old. postnatal women were recruited by systematic sampling (every consecutive patient over a period of 2 months) from 48 primary care clinics and community health centres (of in total 74 clinics) in all 6 sub-districts of nkangala district in mpumalanga province. in all the 48 prevention of mother-to-child transmission (pmtct) service points in the study area, every consecutive hiv-positive mother was invited to participate in the study through referrals by health care providers. these individuals were asked to inform hiv-positive mothers about the study when the mothers came to clinic visits, and to encourage them to volunteer. trained interviewers conducted interviews with postnatal women at health care facilities, using structured questionnaires. the questionnaire was translated into the local language, isizulu. informed consent was obtained from each participant before she was interviewed. study approval was obtained from the human sciences research council ethics committee and health authorities (provincial, district, sub-district and clinic level). measures the questionnaire included socio-demographic items, male involvement, hiv test disclosure, delivery and infant profile, infant hiv diagnosis, stigma, discrimination, postnatal depression, attendance of support groups, and social support. male involvement was assessed with one item, ‘did the father of the baby accompany you to the clinic when you received antenatal care?’ response options were ‘yes’ or ‘no’. postnatal depression. the 10-question edinburgh postnatal depression scale (epds) is a valuable and efficient way of identifying patients at risk for ‘perinatal’ depression.19 the epds is easy to administer and has proved to be an effective screening tool. mothers who score above 13 are likely to be suffering from a depressive illness of varying severity.20 , 21 the epds score should not override clinical judgment. a careful clinical assessment should be carried out to confirm the diagnosis. the scale indicates how the mother has felt during the previous week. it has specificity and sensitivity greater than 76%,22 has been validated antenatally and postnatally,20 and has been validated in a black south african population.23 the epds consists of 10-self-reported items, each response rated 0 3 based on severity, and summed to yield the total score (0 30). the scale has items related to anxiety and depressive symptoms such as anhedonia, anxiety, tearfulness, helplessness and motivation. the epds scale does not rely on somatic symptoms, which is common in postpartum women irrespective of depression. research has supported the construct validity of an interviewer-administered isixhosa version of the epds for use in south africa.24 in south africa there have been two validation studies of the epds in community samples. the first found an optimal threshold of 11/12, or 12 and above, for women in the postnatal period.25 the second found that a threshold of 13/14, or 14 and above, was optimal for classifying ‘probable’ cases of depression.25 the present study uses the threshold of 14 as a basis for interpretation.5 cronbach’s alpha for epds in this sample was 0.84. hiv/aids discrimination experiences. to assess aids-related discrimination, we asked participants if they had experienced seven discrimination-related events. all items referred to discrimination experiences related to their hiv-positive status, e.g. ‘have you experienced discrimination because of hiv?’ each item was responded to dichotomously, yes or no; scale scores represent the sum total of endorsed items, range 0 7.26 the cronbach’s alpha of this 7-item scale was 0.75. in addition, three items on discrimination experiences with health care providers were included. to assess exposure to discrimination experiences with the health care provider, interviewees were prompted with the following: ‘people with hiv often sense discrimination from health care providers in subtle ways. has anyone in the health care system ever done any of the following to you?’ e.g. ‘has anyone in the health care system ever exhibited hostility or a lack of respect toward you?’ each item was responded to dichotomously, yes or no; scale scores represent the sum total of endorsed items, range 0 3. the cronbach’s alpha of this 3-item sub-scale was 0.83. internalised aids stigma. we used the 7-item internalised aids-related stigma scale for people infected with hiv.27 items reflected self-defacing beliefs and negative perceptions of people living with hiv/aids, e.g. ‘it is difficult to tell other people about my hiv infection.’ response options ranged from 1 = strongly agree to 4 = strongly disagree. the cronbach’s alpha of this 7-item scale was 0.88. social support. three items were drawn from the social support questionnaire to assess perceived social support.26 the items were selected to reflect perceived tangible and emotional support. the four response options ranged from ‘completely true’ to ‘completely false’; scale scores represent the sum total of endorsed items, range 3 12. the cronbach’s alpha of this 3-item scale was 0.61. in addition, three individual items were used to assess social support. two items referred to support during pregnancy (‘saw a traditional birth attendent during pregnancy’ and ‘father of baby accompanied to antenatal care’), and one item assessed the attendance of a support group. response options were ‘yes’ or ‘no’. alcohol use was assessed with one item, ‘did you ever drink alcohol (beer, wine, home-brewed beer or spirits) in the past month?’ response options were ‘yes’ or ‘no’. data analysis the statistical package for social sciences (spss version 18.0 for windows; spss inc., chicago, il, usa) was used for data analyses. descriptive data on the total sample were first examined. postnatal women were then classified as having depressed mood or not, based on a score greater than or equal to 14 on the epds. significantly skewed variables such as discrimination experiences were transformed using the formula log10 (x+1). bivariate analysis and multivariable logistic regressions were used to investigate associations between the socio-demographic, stressor, risk behaviour and social support variables and depressed mood. unconditional logistic regression was then performed including the variables that had a significant (p<0.05) bivariate relationship with epds. associations were considered significant at p<0.05. results socio-demographic characteristics of the 615 women invited to participate in the study, 8 declined, resulting in a total sample of 607 participants (response rate 98.7%). the mean age of the women was 28.5 (standard deviation (sd) 5.8) years, with a range of 18 51 years. one hundred and eighty-seven (30.8%) of the participants had an infant aged 1 10 weeks, 223 (36.7%) an infant aged 11 weeks 6 months and 197 (32.5%) an infant aged 7 12 months. thirty-five per cent had grade 12 or higher formal education, 53.6% grade 8 11 education, and 11.4% grade 7 or less education. most postnatal women (69.6%) had never been married, 28.4% were married or cohabitating and 2% were separated, divorced or widowed. almost all came from a black african population group (98.3%), with the main ethnic groups being ndebele (27.8%), northern sotho (26.8%) and zulu (26.0%). economically, few mothers were employed (11.4%) or receiving money from their partner (23.2%) or family (9.6%), while most received a child care support grant (66.4%) and/or disability grant (3%). prevalence and correlates of depressed mood overall, 45.1% of women reported depressed mood in the postnatal period. bivariate comparisons are presented in table i. having an hiv-positive sexual partner, no alcohol use in the past month, having been diagnosed with a sexually transmitted infection (sti) (other than hiv) in the past 12 months, inconsistent condom use with the primary partner, internalised stigma, discrimination experiences, lack of social support, and the baby’s father not accompanying the woman to antenatal care were all found to be associated with depressed mood. results from multivariable logistic regression are presented in table ii. in multivariable analysis, having been diagnosed with an sti (other than hiv) in the past 12 months, internalised stigma, discrimination experiences and lack of social support were associated with depressed mood. discussion overall, 45.1% of women reported depressed mood in the postnatal period in the present study compared with 42.2% found in the study conducted by hartley et al.5 in cape town and 54% meeting dsm-iv criteria for depression among urban primary clinic attendees in zimbabwe.28 the study found that the strongest predictors of depressed mood among postnatal women were having had an sti in the past 12 months, internalised stigma, discrimination experiences and lack of social support. in a large canadian community study stis among women also increased the risk of depression.29 diagnosis with an sti may contribute to the development of depression.29 further, in previous studies it was also found that discrimination experiences were common and internalised aids stigma was prevalent among people living with hiv/aids.26 the results of the current study show a significant relationship between internalised stigma and depressed mood, and these results concurs with the study conducted by ross et al.,4 which found self-esteem to be the most powerful predictor of depressive symptoms among hiv-positive postpartum women and wight’s30 finding that internalised stigma is related to the development of depressive symptoms. social support was found to be a factor buffering against postnatal depression. in the multivariate analysis, lack of social support remained significantly associated with depressed mood, and this finding concurs with other studies.5 , 14 , 31 , 32 having an unintended unplanned pregnancy, the infant being hiv positive and preterm delivery were not associated with a depressed mood in the current study. tomlinson et al.33 also found that having an unintended pregnancy was associated with a depressed mood. alcohol use in the current study was not associated with depressed mood in multivariate analysis, although it reached significance in the bivariate analysis. this concurs with the results of hartley et al.5 other factors that were significantly associated with a depressed mood in the current study in bivariate analysis included having an hiv-positive partner and inconsistent condom use with the primary partner. this seems to indicate that partner dynamics may influence the wellbeing of hiv-infected mothers. conclusion the study found a high prevalence of postnatal depression symptoms among hiv-positive women, and that several factors were associated with depression. the development of interventions can specifically address such factors, i.e. encouraging partner involvement campaigns, and training health workers to address their own and mothers’ stigma towards hiv. it is feasible to screen for postnatal depression in primary care clinics using peer counsellors. we recommend that screening for postnatal depression and access to mental health interventions should be part of routine antenatal care for all women. acknowledgement. this publication was supported by cooperative agreement number u2g/ps000570 from the centers for disease control and prevention (cdc). its contents are solely the responsibility of the authors and do not necessarily represent the official views of the cdc. references 1. sawyer a, ayers s, smith, h. preand postnatal psychological wellbeing in africa: a systematic review. j affect disord 2010;123:17-29. 1. sawyer a, ayers s, smith, h. preand postnatal psychological wellbeing in africa: a systematic review. j affect disord 2010;123:17-29. 2. robertson e, grace s, wallington md, et al. antenatal risk factors for postpartum depression: a synthesis of recent literature. gen hosp psychiatry 2004;26:289-295. 2. robertson e, grace s, wallington md, et al. antenatal risk factors for postpartum 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al. the factor structure of the edinburgh postnatal depression scale in south african peri-urban settlement. s afr j psychol 2004;34:113-121. 24. lawrie ta, hofmeyr gj, de jager m, et al. validation of the edinburgh postnatal depression scale on a cohort of south african women. s afr med j 1998;88:1340-1344. 24. lawrie ta, hofmeyr gj, de jager m, et al. validation of the edinburgh postnatal depression scale on a cohort of south african women. s afr med j 1998;88:1340-1344. 25. rochat t, tomlinson m, newell m, et al., depression among pregnant women testing for hiv in rural south africa: implications for vct. 9th international aids impact conference; botswana, 2009. 25. rochat t, tomlinson m, newell m, et al., depression among pregnant women testing for hiv in rural south africa: implications for vct. 9th international aids impact conference; botswana, 2009. 26. simbayi lc, kalichman s, strebel a, et al. internalized stigma, discrimination, and depression among men and women living with hiv/aids in cape town, south africa. soc sci med 2007;64:1823-1831. 26. simbayi lc, kalichman s, strebel a, et al. internalized stigma, discrimination, and depression among men and women living with hiv/aids in cape town, south africa. soc sci med 2007;64:1823-1831. 27. kalichman sc, simbayi lc, cloete a, mthembuc pp, mkhontac rn, ginindza t. measuring aids stigmas in people living with hiv/aids: the internalized aids-related stigma scale. aids care 2009;21(1):87-93. 27. kalichman sc, simbayi lc, cloete a, mthembuc pp, mkhontac rn, ginindza t. measuring aids stigmas in people living with hiv/aids: the internalized aids-related stigma scale. aids care 2009;21(1):87-93. 28. chibanda d, mangezi w, tshimanga m, et al. postnatal depression by hiv status among women in zimbabwe. j womens health 2010;19(11):2071-2077. 28. chibanda d, mangezi w, tshimanga m, et al. postnatal depression by hiv status among women in zimbabwe. j womens health 2010;19(11):2071-2077. 29. chen y, wu j, yi q, huang g, wong t. depression associated with sexually transmitted infection in canada. sex transm infect 2008;84(7):535-540. 29. chen y, wu j, yi q, huang g, wong t. depression associated with sexually transmitted infection in canada. sex transm infect 2008;84(7):535-540. 30. wight rg. precursive depression among hiv infected aids caregivers over time. soc sci med 2000;51:759-770. 30. wight rg. precursive depression among hiv infected aids caregivers over time. soc sci med 2000;51:759-770. 31. howell ea, mora pa, dibonaventura md. modifiable factors associated with changes in postpartum depressive symptoms. arch womens ment health 2009;12:113-120. 31. howell ea, mora pa, dibonaventura md. modifiable factors associated with changes in postpartum depressive symptoms. arch womens ment health 2009;12:113-120. 32. gao y, macdonald d, collins kd, alaghehbandan r, chen y. role of social support in the relationship between sexually transmitted infection and depression among young women in canada. j epidemiol 2010;20(4):313-318. 32. gao y, macdonald d, collins kd, alaghehbandan r, chen y. role of social support in the relationship between sexually transmitted infection and depression among young women in canada. j epidemiol 2010;20(4):313-318. 33. tomlinson m, swartz l, cooper p, et al. social factors and postpartum depression in khayelitsha, cape town. s afr j psychol 2004;34:409-420. 33. tomlinson m, swartz l, cooper p, et al. social factors and postpartum depression in khayelitsha, cape town. s afr j psychol 2004;34:409-420. table i. sample characteristics and epds (n=607) epds <14 ( n =333) epds ≥14 ( n =274) unadjusted or (95% ci) p -value socio-economic variables n or mean % or sd n or mean % or sd age 28.7 5.9 28.3 5.7 0.99 (0.96 1.02) 0.440 age of infant 1 10 weeks 11 weeks 6 months 7 12 months 85 110 102 51.2 53.1 56.0 81 97 80 48.8 46.9 44.0 1.00 0.97 (0.66 1.43) 0.87 (0.58 1.31) 0.874 0.506 education grade 0 7 grade 8 11 grade 12+ 32 183 116 46.4 56.5 54.7 37 141 91 53.6 43.5 45.3 1.00 0.67 (0.40 1.12) 0.72 (0.42 1.23) 0.127 0.229 single married/cohabitating separated/divorced/widowed 232 89 10 55.4 52.0 83.3 187 82 2 44.6 48.0 16.7 1.00 1.14 (0.80 1.63) 0.25 (0.05 1.15) 0.462 0.074 number of (own) children 2.2 1.2 2.2 1.6 0.98 (0.85 1.13) 0.784 mother employed mother receives child care grant mother receives money from partner mother receives money from family 44 224 84 25 63.8 55.6 59.6 43.1 25 179 57 33 36.2 44.4 40.4 56.9 1.00 0.95 (0.64 1.39) 0.80 (0.53 1.21) 1.57 (0.86 2.85) 0.785 0.288 0.140 health status and reproductive health cd4 cell count <200 cells/µl 68 56.7 52 43.3 0.77 (0.51-1.18) 0.235 had sti (other than hiv) in the past 12 months 49 34.8 92 25.6 2.66 (1.80 3.91) 0.000 alcohol use in past month 29 74.4 10 25.6 0.40 (0.19 0.84) 0.016 current baby unintended 186 51.5 175 48.5 1.33 (0.95 1.88) 0.102 preterm (v. term) delivery) 31 63.3 18 36.7 0.68 (0.37 1.24) 0.209 baby had hospital admission 75 56.0 59 44.0 0.80 (0.55 1.16) 0.234 infant hiv positive 9 56.3 7 43.8 0.94 (0.35 2.57) 0.910 sexual behaviour and partner characteristics main sexual partner hiv positive 105 45.1 128 54.9 1.48 (1.04 2.11) 0.029 intimate partner violence in past 12 months 16 44.4 20 55.6 1.49 (0.75 2.93) 0.253 more than one sexual partner in past 12 months 34 53.1 30 46.9 0.98 (0.58 1.65) 0.932 casual partner in past 3 months 23 48.9 24 51.1 1.19 (0.66 2.17) 0.562 inconsistent condom use with primary partner 166 49.1 172 50.9 1.47 (1.04 2.07) 0.030 discrimination and stigma internalised stigma score (range 7 28) 16.0 4.2 18.6 5.2 1.13 (1.08 1.17) 0.000 discrimination experiences score (range 0 7) 0.9 1.3 1.4 1.7 1.28 (1.13 1.44) 0.000 social support social support score (range 3 12) 8.2 1.7 7.3 2.0 0.77 (0.70 0.84) 0.000 saw a traditional birth attendant during pregnancy 68 45.6 81 54.4 1.35 (0.94 1.93) 0.105 father of baby accompanied to antenatal care 77 67.0 38 33.0 0.51 (0.34 0.78) 0.002 attended support group 62 51.2 59 48.8 1.20 (0.81 1.80) 0.368 or = odds ratio; ci = confidence interval; sd = standard deviation. table ii. logistic regression analysis: predictors of depressed mood (n=607) adjusted or (95% ci)* † p -value health status, sexual behaviour and partner characteristics had sti (other than hiv) in the past 12 months 2.22 (1.21 4.04) 0.010 alcohol use in past month 0.43 (0.16 1.17) 0.099 main sexual partner hiv positive 1.63 (0.97 2.71) 0.063 inconsistent condom use with primary partner 1.51 (0.88 2.59) 0.140 discrimination and stigma discrimination experiences score (range 0 7) 1.22 (1.03 1.46) 0.023 internalised stigma score (range 7 28) 1.12 (1.05 1.19) 0.000 social support social support score (range 3 12) 0.86 (0.74 0.99) 0.037 father accompanied to antenatal care 0.55 (0.28-1.08) 0.084 *using ‘enter’ logistic regression selection of variables. †hosmer and lemeshow chi-square 14.55, df 8, 0.536; cox and snell r2 0.20; nagelkerke r2 0.27. or = odds ratio; ci = confidence interval. june 2006 make up the southern african journal of hiv medicine june 2006 5 p u b l i c h e a l t h the role of stavudine in the south african public sector antiretroviral programme: should the perfect be the enemy of the good? robin wood, bsc, bm, mmed, fcp (sa) desmund tutu hiv centre, institute of infectious disease and molecular medicine, university of cape town stavudine (d4t) was one of the first nucleoside analogues developed as an hiv antiretroviral (arv). an early monotherapy trial demonstrated similar antiviral activity to zidovudine (azt),1 and a comparative study of d4t and azt in combination with lamivudine (3tc) and a protease inhibitor(pi) reported similar therapeutic outcome in each randomised treatment arm.2 since registration in 1993 by the us federal drug agency, d4t has been used extensively in combination therapy and was one of the first arvs to become available in south africa as a generic formulation. there is recently published evidence that its use is associated with higher cd4 cell count responses than other nucleoside analogues.3 the generic formulation with 3tc and nevirapine (nvp) is currently the cheapest arv combination therapy available worldwide. with the development of a necessary public health approach to expanded access to arvs in resource-poor settings the world health organization (who) included d4t in its recommended first-line arv regimens.4 following widespread use of d4t, adverse events including lipodystrophy, neuropathy and lactic acidosis associated with long-term therapy have been increasingly recognised. despite the proven utility of d4t in more than a decade of use and its very low cost there has been an increasing swing of medical opinion against use of d4t and a search for alternatives. mechanism of action stavudine is a nucleoside analogue of thymidine, which is a pro-drug requiring phosphorylation by cellular kinases to the active metabolite stavudine triphosphate. the triphosphorylated molecule inhibits hiv reverse transcriptase by competing with the natural substrate deoxythymidine triphosphate and by incorporation into the viral cdna causing chain termination.5 resistance genotypes generated during d4t use show much overlap with those generated by azt, another thymidine analogue. d4t also inhibits human cellular dna polymerases beta and gamma resulting in a marked reduction in the synthesis of mitochondrial dna. this crossinhibition of human dna polymerases may constitute the causative mechanism of the more serious toxicities associated with d4t use. toxicity the toxicity of d4t is exacerbated when the drug is used in combination with other dideoxy nucleoside analogues and the combination with didanosine (ddi) is now discouraged in most treatment guidelines. impairment of mitochondrial function is postulated to be the cause of increased lactate production and/or decreased clearance. the clinical sequelae vary from asymptomatic hyperlactataemia to fatal lactic acidosis, and from hepatomegaly with steatosis to hepatic failure. recognised risk factors for lactic acidosis include female gender, increased body mass index, and prolonged use of d4t. monitoring for elevated lactate is indicated in patients on d4t when hepatic transaminases rise, or there is unexplained weight loss or gastrointestinal symptoms. peripheral neuropathy is also considered to result from mitochondrial dysfunction and symptoms are related to the dose of d4t. neuropathy is more frequently reported in patients with advanced hiv disease and those with a prior history of neuropathy and when other neurotoxic drugs such as isoniazid and ddi are coadministered. experience with d4t in south african public sector programmes the cape town gugulethu treatment programme6 was the first public sector arv programme to initiate therapy in september 2002 with d4t/3tc and a non-nucleoside reverse transcriptase inhibitor (nnrti) using a treatment protocol based on the who 2002 expanded access recommendations.4 a second regimen of azt, ddi and ritonavir-boosted lopinavir (kaletra) is available to those who fail first-line therapy. mortality early in this programme showed that 66% of deaths the southern african journal of hiv medicine june 2006 7 occurred in patients awaiting art and the majority of deaths on art occurred in the first 6 months of treatment due to causes associated with the advanced stage of hiv infection of those accessing treatment.7 of the 68 programme deaths only 2 were arv drug-related, a nevirapine rash with septicaemia and a d4t-associated lactic acidosis.7 by april 2006 over 2 000 patients had received arvs in this clinic. d4t substitution has been required in 206 individuals in the treatment programme, in 158 cases as a direct result of drug toxicity. the median time on d4t before switching was 403 days (iqr 280 569). causes of drug-related switches were, in descending frequency, lipodystrophy (76 cases, 48%), peripheral neuropathy (57, 36%), hyperlactataemia (16, with 8 cases of acidosis – 10% and 5% respectively), elevated hepatic transaminases (5, 3%), unspecified causes (3, 2%) and pancreatitis (1, 1%). another large hiv treatment programme in khayelitsha, cape town, which began using d4t as a first-line regimen in 2003, has reported approximately 10% of patients switching from both azt and d4t by 12 months.8 nucleoside reverse transcriptase inhibitor (nrti) switches due to azt toxicity were mainly the result of anaemia (82%), which occurred early, while d4t switches were reported later in therapy and appeared to be increasing with longer use of d4t in the programme. these cohort data indicate a higher rate of switching due to d4t toxicity than is reflected in published randomised trial data. a multinational comparative 3-year study of 602 drug-naïve individuals (26% female and 20% black) randomised to d4t or tenofovir in combination with 3tc and efavirenz had identical discontinuation rates (6%) due to adverse events in each drug allocation arm, and a sub-analysis of women in the study also showed similar regimen discontinuation rates in both arms.9 lactic acidaemia was reported in 1 patient who had been randomised to the d4t arm. if similar dosages and formulations of d4t are used in gugulethu and khayelitsha, there are two possible explanations for this apparent increased switching due to toxicity: firstly that the south african population is more susceptible to adverse effects of d4t than the randomised study population, or that there is significant ascertainment bias in the cohort data due to over-diagnosis of possible d4t-related clinical events. it is particularly important to establish if there is an increased population susceptibility to adverse effects of d4t, which may in turn be due to genetic or exposure to environmental cofactors. role of (d4t) in treatment programmes d4t has been used successfully in the public health arv programmes because it is cheap and initially very well tolerated. toxicities accumulate after prolonged therapy and pose significant challenges to programme staff, who must maintain a high vigilance for potentially serious metabolic complications. the inability to monitor serum lactate easily together with the serious consequences that can result makes management of lactate metabolic derangements particularly problematic. however, the major challenge facing the south african arv programme is to reduce hiv-related deaths by increasing coverage of the existing programme to the 800 000 individuals currently in immediate need of therapy. the public health approach is epitomised by national tuberculosis control programmes, where treatment regimens are cheap, simple and effective and co-formulations are used where possible. treatment options are limited, so that medical officers and nurses can be well acquainted with a small number of agents. first-line arv therapy should be well tolerated and sideeffects should be predictable and require minimal toxicity monitoring. within such a public health framework it is important to establish whether any changes to existing regimens or use of alternative therapies will help or impede the necessary wider access to arv therapy. possible alternative regimens standard arv therapy is based on a nucleoside backbone of two nrtis together with either an nnrti or a pi. there are 6 nrtis registered in south africa, stavudine (d4t), zidovudine (azt), lamivudine (3tc), didanosine (ddi), zalcitabine (ddc) and abacavir (abc). of these only ddc and abc are not already included in standard firstand second-line regimens. currently the cost of abc and the neurotoxicity of ddc would exclude them as substitutes for d4t in a first-line regimen. with the present choice of registered nrtis, substitution of azt for d4t in the initial first-line regimen would necessitate the subsequent use of d4t with ddi in the second-line regimen, a combination that is discouraged due to co-toxicity.4 the present use of azt in second-line following initial d4t failure in first-line therapy is not ideal, as both drugs have shared hiv resistance mutation profiles. the choice of available nrtis will be increased if tenofovir (tnf), a nucleotide analogue of adenosine 5’-monophosphate, is registered for use in south africa. the drug has been licensed since 2001 in the usa and is under review for registration by the south african medicines control council. its us labelled use was initially for patients failing previous therapies and more recently extended to use in first-line therapy. it is generally well tolerated with some gastrointestinal adverse events and increased bioavailability when administered with food (40%). the prolonged elimination half-life allows oncedaily administration, with the major route of elimination being both renal glomerular filtration and active tubular secretion. it has adverse pharmacokinetic interactions with ddi and has activity against hepatitis b virus which may precipitate severe acute exacerbations of hepatitis b in patients who have discontinued the drug.10 the use of tnf, which will require additional renal function monitoring, will increase the programme costs of safety monitoring. tnf is also coformulated with emitricitabine (ftc) into a single daily tablet (truvada), which offers a reduced pill burden. if tnf became available for use in the national arv programme in south africa, how could it be utilised? substitution of d4t with tnf would increase the cost of the first-line regimen and increase monitoring requirements and therefore impede increased access to therapy. the cost june 2006 the southern african journal of hiv medicine8 effectiveness of an arv programme is very sensitive to the costs of the first-line therapy.11 a direct substitution of the azt in the second-line regimen would not be possible as coadministration with ddi is discouraged. replacement of both azt and ddi with tnf and 3tc or ftc would not increase costs and would provide a more rational second-line nrti backbone. this strategy, although it would require the recycling of 3tc/ftc, would release azt to be used as a switch alternative for d4t within the first-line regimen. the toxicity profiles of azt and d4t differ in both spectrum and timing (table i). anaemia related to azt occurs early after initiation of treatment in approximately 6 10% of african patients, while d4t is initially well tolerated. d4t and azt could be used in a similar fashion to efavirenz and nevirapine, which have different toxicity profiles but are susceptible to similar genetic mutations of hiv. the use of low-cost d4t/3tc/nvp could be maintained in the initial first-line regimen if either those identified at high risk or those with early d4t toxicity could be switched to azt. summary the major challenge facing the arv programme in south africa is to expand access rapidly to very large numbers of individuals at high immediate risk of death. in order to achieve this, a public health approach to arv therapy requires the use of cheap effective drugs in simply administered regimens. currently the generic combination of d4t/3tc/nvp constitutes the cheapest available arv regimen. serious toxicities associated with long-term use of d4t have raised concerns about the continued use of this drug in the first-line regimen. the rate of drug switching due to d4t toxicity in south african cohorts appears higher than that reported in controlled randomised studies, and this may either be due to a real higher toxicity event rate in the south african population or be an apparent increase caused by ascertainment biases. mortality in existing arv programmes is overwhelmingly dominated by late access to programmes rather than deaths due to drug toxicity. changes to present arv regimens must therefore be judged within a public health framework, which should enable wider access to therapy for those in immediate need of treatment. references 1. spruance sl, pavia at, mellors jw, et al. clinical efficacy of monotherapy with stavudine compared with zidovudine in hiv-infected, zidovudine-experienced patients. a randomized, double-blind controlled trial. bristol-myers squibb/019 study group. ann intern med 1997; 126(5): 355-363. 2. squires ke, gulick r, tebas p, et al. a comparison of stavudine plus lamivudine versus zidovudine plus lamivudine in combination with indinavir in antiretroviral naïve individuals with hiv infection: selection of thymidine analog regimen therapy (start 1). aids 2000; 14(11): 1591-1600. 3. mocroft a, phillps an, lederberber b, et al. relationship between antiretrovirals used as part of a cart regimen and cd4 cell count increases in patients with suppressed viremia. aids 2006; 20(8): 1141-1150. 4. world health organization. scaling up antiretroviral therapy in resourcelimited settings: guidelines for a public health approach. world health organization, executive summary april 2002, geneva, switzerland. http://www.who.int/hiv/topics/arv/en/scaling_exe_summary.pdf (accessed 14 june 2006). 5. zerit (stavudine) patient information leaflet. bristol-myers squibb. princeton, nj 08543, usa. http://bms.com (accessed 16 june 2006). 6. bekker l-g, myer l, orrell c, wood r. a south african community-based antiretroviral programme: outcomes during 3 years of scale-up. s afr med j 2006; 96(4): 315-320. 7. lawn sd, myer l, orrel c, bekker l-g, wood r. early mortality among patients accessing a community-based antiretroviral service in south africa: implications for program design. aids 2005; 19: 2141-2148. 8. boule a, hildebrand k, coetzee d, et al. regimen durability and reasons for regimen changes in the first 1 000 treatment naïve adults accessing art in kayelitsha. 9th international workshop on hiv databases, budapest, hungary, 21-22 april 2005. 9. gallant je, staszewski s, pozniac al, et al. efficacy and safety of tenofovir vs stavudine in combination therapy in antiretroviral-naïve patients: a 3-year randomized trial. jama 2004; 292(2): 266-268. 10. truvada patient information leaflet. http://www.gilead.com/pdf/truvada_ pi/pdf (accessed 16 june 2006). 11. badri m, cleary s, maartens g, et al. when to initiate haart in sub-saharan africa: a cost-effectiveness study. antivir ther 2006: 11(1): 63-72. stavudine zidovudine abacavir tenofovir (d4t) (azt) (abc) (tnf) cost/ r42.59 r 126.79 r527.92 r123.05 month (22.66) (143.64) (na) (na) (generic) toxicity late early early early timing main neuropathy anaemia hypersensitivity renal toxicities lactic acidosis tubular lipodystrophy available d4t/3tc/nvp azt/3tc; azt/3tc/abc tnf/ftc combinaazt/3tc/abc tions pill burden/ 2 tabs 2 tabs 2 tabs 1 tab day table i. comparison of rand costs per month (public sector tender prices may 2006), toxicities, available co-formulations and pill burden of stavudine, zidovudine, abacavir and tenofovir article information authors: nishana ramdas1,2 johanna c. meyer1 david cameron2,3 affiliations: 1department of pharmacy, sefako makgatho health sciences university, south africa 2foundation for professional development, pretoria, south africa 3department of family medicine, university of pretoria, south africa correspondence to: hannelie meyer email: hannelie.meyer@smu.ac.za postal address: po box 218, medunsa 0204, south africa dates: received: 09 jan. 2015 accepted: 13 may 2015 published: 01 july 2015 how to cite this article: ramdas n, meyer jc, cameron d. factors associated with retention in hiv care at sediba hope medical centre. s afr j hiv med. 2015;16(1), art. #347, 6 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.347 copyright notice: © 2015. the author(s). licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. factors associated with retention in hiv care at sediba hope medical centre in this original research... open access • abstract • introduction • methods    • patient population and data collection    • data analysis • ethical approval • results    • patient flow process and tracking of lost to follow-up patients       • extent of lost to follow-up       • disclosure of hiv status       • travelling distance to the clinic       • clinical profile of lost to follow-up patients: cd4+ cell count and viral load       • antiretroviral treatment and adherence       • reasons for lost to follow-up • discussion    • limitations • conclusion • acknowledgements    • competing interests    • authors’ contributions • references abstract top ↑ background: lost to follow-up (ltfu) is a major challenge that hinders the success of antiretroviral treatment (art). objective: to identify factors conducted to a low ltfu rate. methods: we conducted a two-part descriptive and quantitative study. part 1 comprised interviews with clinic staff to determine their perspectives on ltfu and to establish the clinic’s follow-up procedures for patients on art. part 2 of the study was a retrospective review of clinic and patient records. ltfu patients were identified and those with contact details were contacted for telephonic interview to determine if they were still on art and/or their reasons for becoming ltfu. results: a low ltfu rate (7.9%; n = 683) was identified. work-related stress, and lack of transport and funds were reported reasons for ltfu. monthly visits, non-adherent defaulters and ltfu patients were tracked by an electronic system (sozo). factors contributing to high rates of retention in care were: location of the clinic in the inner city, thus in close proximity to patients’ homes or work; clinic operating on saturdays, which was convenient for patients who could not attend during the week; an appointment/booking system that was in place and strictly adhered to; a reminder sms being sent out the day before an appointment; individual counselling sessions at each visit and referrals where necessary; and a stable staff complement and support group at the clinic. conclusion: achieving a low ltfu rate is possible by having a patient-centred approach and monitoring systems in place. introduction top ↑ adhering to antiretroviral treatment (art) is a lifelong commitment that requires patients to diligently adhere to daily medication dosing schedules and make regular clinic visits for care.1 art has improved the lives of many people living with the human immunodeficiency virus (hiv), but many challenges still exist before art programmes might achieve total success in terms of patient outcomes.1 two of the major challenges and concerns for art programmes are retention in care and patients who are lost to follow-up (ltfu).1 several studies have been conducted on these problems, investigating various ways to improve retention in hiv care and patient outcomes.1,2,3,4 ‘lost to follow-up’ refers to the disappearance of a patient from the programme, for no reported reason.5 definitions of when a patient is classified as ltfu vary widely across studies and countries.6 in a pooled analysis of 111 facilities, a threshold of 180 days since the last clinic visit was recommended as a standard definition for ltfu.7 in sub-saharan african countries, rates of ltfu vary extensively. according to a systematic review of patient retention following art initiation, it was evident that 1 year after initiation approximately 25% of patients were no longer in care, with ltfu figures escalating to 40% after 2 years.8 lower ltfu figures (3.3%; n = 2548) were reported from a retrospective cross-sectional study of a community-based art cohort in cape town, south africa, which used a computerised tracking tool to manage patients in care.9 sediba hope medical centre (shmc) is a nongovernmental organisation (ngo) clinic, situated in the city centre of tshwane in south africa. it caters for patients working and living in and around the city of tshwane. the centre was previously known as fountain of hope (foh), which was a foundation for professional development (fpd) clinic funded by the president's emergency plan for aids relief (pepfar) and the united states agency for international development (usaid). the clinic's budget allowance provided for a patient database of only 500 patients. the main purpose of the foh clinic was to provide art for hiv-positive patients living and working in the inner city. in 2011, fpd joined in a project with participate empower and navigate (pen), a non-profit, non-denominational, faith-based organisation, and subsequently the foh clinic became the shmc. since the name change, it has operated as an arv site for the pepfarand usaid-funded patients on art and as a primary healthcare (phc) private practice for patients using medical aid or paying privately. the move from the foh clinic to the shmc had some implications for patients as they had to adapt to a new site, new processes, new staff and additional travelling distances for some patients. patients living near the foh clinic had to walk an average of 1.4 km further to the shmc, which represents approximately 17 minutes. ltfu had not been evaluated at this site previously. in the present study, we aimed to quantify ltfu at the shmc, investigate the factors that contributed to patients on art becoming ltfu, and identify factors that could contribute to low ltfu rates and be implemented to improve retention in care. methods top ↑ patient population and data collection we conducted a two-part descriptive and quantitative study at shmc between august and november 2013. the first part of the study included an individual interview based on a structured questionnaire with each of the nine staff members. we aimed to determine staff members’ perspectives on the reasons for ltfu and to establish the procedures used at the clinic to monitor patients on art and to identify and trace those who were ltfu. the second part of the study was a retrospective review of clinic and patient records for the previous 4 years (2010–2013). the review included ‘hard copy’ patient files and an electronic patient management system, known as sozo, which was developed by fpd in partnership with infocare and john snow international (jsi) in 2007. all patients on art, who had become ltfu with no obvious reason for default, were identified. a patient record sheet was used to record ltfu patients’ details from their files and the sozo system. patients identified as ltfu, with contact details in their records, were contacted telephonically for a structured telephonic interview to investigate reasons for ltfu. data analysis data were analysed with spss v21.0 statistical software. the percentage of ltfu patients was calculated with a 95% confidence interval. patient demographics and clinical, treatment and social data were summarised descriptively. associations between variables and differences in means were identified with fisher's exact test and independent samples t-test as appropriate. statistical significance was set at p ≤ 0.05. ethical approval top ↑ ethical clearance for the study was granted by the medunsa research ethics committee of the university of limpopo. permission to conduct the study at the shmc was provided by fpd and the manager of shmc. written consent was obtained from staff members of shmc and verbal consent from responding patients, prior to their participation in the interviews. results top ↑ shmc is conveniently situated in the city centre; that is, close to home or work for most patients. the clinic operates on weekdays as well as saturdays to accommodate patients who work or are unable to attend the clinic during the week. the previous foh clinic also hosted a support group with regular meetings every second saturday, which were available to all patients from the time they started treatment. patient flow process and tracking of lost to follow-up patients interviews with staff members revealed that the clinic followed a structured patient flow process, according to which patients were seen by appointment only and according to bookings done on the sozo system. according to the staff interviewed, patient waiting time was kept to a minimum, as appointments were made according to a time schedule. the patient flow process and the tracking of ltfu patients at shmc are illustrated in figure 1. figure 1: flow process of monitoring and tracking patients on antiretroviral treatment at sediba hope medical centre. patients at shmc are sent a reminder short message service (sms) the day prior to their scheduled appointment. a booking list is printed daily to track patients as they attend. the service received is personalised and, should patients not attend their appointment, follow-up phone calls are made. when a patient on art is identified as ltfu, the social worker phones the patient weekly or at least bi-monthly for a period of 3 months, in an attempt to reschedule an appointment and get the patient back into care. all phone numbers on patient records are contacted in an attempt to trace them. after 3 months of no success in tracing a patient, no further action is taken. the staff complement at the previous foh clinic was stable for a period of 4 years and, consequently, patients interacted with the same healthcare worker at each visit. for this reason, patients felt comfortable and built good relationships with the staff. extent of lost to follow-up of the total number of 683 patient records reviewed, 54 (7.9%; 95% confidence interval [ci], 6.1%–10.2%) patients were identified as ltfu (figure 2). only 17 of the 54 patients had contact details in their records and were contacted for a telephonic interview. sociodemographic characteristics of the 54 patients who were ltfu are summarised in table 1. figure 2: overall proportion of patients lost to follow-up at sediba hope medical centre. table 1: sociodemographic characteristics of lost to follow-up patients. disclosure of hiv status according to the patient records, most patients (90.7%; n = 54) had disclosed their hiv status. women preferred to disclose to a relative (82.1%; n = 28) rather than a partner (28.6%; n = 28) whilst men disclosed mainly to relatives (46.1%; n = 26) and their partners (42.3%; n = 26). three male patients did not disclose their status to anybody. travelling distance to the clinic travelling distance to the clinic was known for 16 of the 17 ltfu patients who were contacted for an interview. nine of them (56.3%) lived less than 1 km away from the clinic, and so required minimal travelling; 3 (18.8%) lived between 1 km and 5 km from the clinic; and 4 (25.0%) lived more than 10 km from the clinic. clinical profile of lost to follow-up patients: cd4+ cell count and viral load table 2 shows the gender distribution of ltfu patients, for whom cd4+ cell count test results were available within 6 months of their final clinic visit, prior to becoming ltfu. table 2: distribution of patients according to cd4+ cell count results, based on testing done within 6 months of the patient's final clinic visit prior to becoming lost to follow-up. the median cd4+ count for patients (n = 35) who had a test done within 6 months of their last clinic visit prior to becoming ltfu was 289.0 cells/μl (interquartile range [iqr] 186–438), with a cd4+ count below 350 cells/μl for the majority (68.6%) of them. categorisation of cd4+ count results available within 6 months of the final clinic visit prior to becoming ltfu showed a statistically significant association with gender (p = 0.001; fisher's exact test). being female was associated with the probability of a cd4+ count > 350 cells/μl, and being male was associated with a probability of a lower cd4+ count (100 cells/μl – 350 cells/μl) at the time of being ltfu. a detectable viral load (vl) within 6 months of their final visit to the clinic was evident in 44.1% (n = 35) of patients, with more of the men (58.8%; n = 17) than the women (29.4%; n = 17) having a detectable vl. the association between gender and detectable vl was, however, not significant (p = 0.472; fisher's exact test). antiretroviral treatment and adherence at the time of their final visit, just more than half of ltfu patients (57.4%; n = 54) were on the current first-line regimen, comprising tenofovir (tdf), lamivudine (3tc) and efavirenz (efv). thirteen per cent of the ltfu patients were still on the previous regimen 1a (stavudine [d4t], 3tc, efv) and 11.1% on the previous regimen 1b (d4t, 3tc, nevirapine [nvp]). only 13% of ltfu patients were on the second-line regimen (tdf, 3tc or emtricitabine [ftc] and lopinavir/ritonavir [lpv/r]). adherence to art at the shmc was monitored at each visit by means of pill counts, conducted by the social worker or counsellor and recorded as descriptive notes in the patient files and on the sozo system. table 3 shows the adherence patterns for patient visits over the period of 3 months prior to becoming ltfu. table 3: adherence patterns over the period of 3 months prior to becoming lost to follow-up. reasons for lost to follow-up staff members’ perceptions of the reasons for ltfu are summarised in table 4. table 4: reported reasons for lost to follow-up, according to staff perceptions. based on the contact details available in the files of patients identified as ltfu, only 17 patients could be contacted successfully for a telephonic interview. one patient was identified to have demised while on art. another patient had relocated to europe, and it could not be determined whether he was still on art or not. nine patients were confirmed to be still active on art at other sites, of whom one patient was actually ltfu at shmc before initiation on art. this patient subsequently commenced art at another site, as he moved from one city to another. three patients indicated that they were using delivery services to obtain their arvs. explanations from the remaining five patients who continued treatment at a different art facility were related to proximity and travelling time. two of these patients reported that the alternative facility was closer to home, and three reported it as being closer to their workplace. only six of the patients interviewed reported that they had discontinued art altogether. all six patients provided transport costs as a reason for discontinuing treatment; 2 of these patients also mentioned the side-effects of arvs, whilst one patient was using traditional or herbal medication instead of arvs. discussion top ↑ the ltfu rate at the shmc (7.9%; n = 683) was evidently much lower in comparison to most sub-saharan countries.1,9 this reasonably low ltfu rate could be attributed to various processes at the centre, one being the follow-up of patients from an early stage after a missed appointment at the clinic. a previous study confirmed that early active follow-up of patients can improve retention on treatment and programme outcomes.9 the use of an electronic patient management system (sozo) facilitated patient follow-up and engagement, thus improving the efficiency of the system immensely. appointments were booked electronically according to a time schedule which, according to the staff, minimised patient waiting time. a large art programme in malawi also considered time-specific appointments for each patient as an option to reduce waiting times.2 in addition, the sozo system identified patients due for appointment, and a reminder sms was sent to them the day beforehand. similarly, low ltfu rates (3.3%) were identified elsewhere in south africa where a computerised pharmacy tracking system (idart) was used to trace patients who failed to collect their medication.9 most (90.7%) of the ltfu patients disclosed their hiv status, which was a positive finding and attributed to the fact that disclosure is encouraged during counselling. disclosure of hiv status to one's spouse is known to be associated with good adherence.10 women in our study had a higher cd4+ count at the time of being ltfu. this could be expected as previous studies from sub-saharan africa have shown that women usually have a higher cd4+ count at art initiation and a better median cd4+ count increase from baseline across all time periods after art initiation, than men.11 it is evident that an elevated vl may be a factor to consider for ltfu, which is supported by the findings from other studies which demonstrated that unsuppressed viral loads at any time point in treatment are predictive of loss.12 good adherence rates were supported by consistent pill counts and counselling sessions, which happened at each clinic visit. having a stable staff complement at the clinic meant that patients saw the same counsellor or social worker at every visit, which facilitated good relationships between staff and patients. the staff perceived the regular support group meetings as a contributing factor to adherence. support groups are known to encourage adherence and improve retention in care.13 from our findings, it was apparent that work-related stress, lack of transportation, and lack of funds for travel and food were reported as contributing factors to ltfu at shmc. travelling distance was the main reported reason why patients changed facilities and opted for a clinic closer to home or to work, or preferred the convenience of art delivery services to their home or work. high transport costs and patients having to travel long distances to get to arv clinics were identified as problems in a study conducted at themba lethu clinic, helen joseph hospital, in johannesburg, south africa.3 lack of transport and employment obstacles as reasons for ltfu are supported by a number of other studies conducted in south africa and mozambique.3,14,15 lack of availability of contact details for all patients at shmc made follow-up and tracing of ltfu patients difficult in our study. the majority of ltfu patients had incorrect information or no contact information at all. it is apparent that art programmes should invest in obtaining accurate, complete and up-to-date contact details for patients to aid tracing. availability of more updated contact information for all patients at shmc may have resulted in an even lower number of ltfus altogether. limitations our study was conducted at only one facility and the results can therefore not be generalised to other art facilities in south africa. incomplete and incorrect patient records (manual and sozo system) made it difficult to trace all ltfu patients and therefore negatively affected the number of ltfu patients interviewed. a limitation of the study itself was that the review did not include patients who remained in care. consequently, comparisons between ltfu patients and those who remained in care were not possible. furthermore, as a result of incomplete clinic records, information about the proportion of patients who did not become ltfu as a result of successful contact by social workers could not be determined. conclusion top ↑ from our study, it is evident that low ltfu rates and measures to prevent ltfu are possible. the flow through the clinic was efficient and patients in general were pleased with the services rendered at shmc. most patients had built good relationships with the staff, which made them feel comfortable and cared for. the complete functioning of shmc took the form of a patient-centred approach and was much more than only having a computer system in place. shmc can be an example to similar art sites with high ltfu rates. the sms reminder service and tracking system may benefit other art sites. seeing patients on an appointment only basis proved to be beneficial. however, it might be difficult in facilities with larger numbers of patients. acknowledgements top ↑ the authors thank the staff members and patients at shmc for their willingness to participate in the study. the fpd is also thanked, and the management of shmc for making their facility available as a study site. we gratefully acknowledge professor herman schoeman's assistance with the statistical analysis of the data and ms barbara english for editing the manuscript. competing interests two of the authors (n.r. and d.c.) are employees of the fpd, which provides facility-based technical assistance to shmc, within its model for strengthening district health systems. authors’ contributions n.r. (sefako makgatho health sciences university) was a master's student at the former university of limpopo, medunsa campus, now sefako makgatho health sciences university. n.r. developed the methodology and collected the data. j.c.m. (sefako makgatho health sciences university) and d.c. (foundation for professional development) supervised the master's project. n.r. wrote the first draft of the manuscript. all authors discussed the results and implications and commented on the manuscript at all its stages. references top ↑ miller cm, ketlhapile m, rybasack-smith h, et al. why are antiretroviral treatment patients lost to follow up? a qualitative study from south africa. trop med int health. 2010;15:48–54. http://dx.doi.org/10.1111/j.1365-3156.2010.02514.x tweya h, feldacker c, estill j, et al. are they really lost? ’true’ status and reasons for treatment discontinuation among hiv infected patients on antiretroviral therapy considered lost to follow up in urban malawi. plos one. 2013:8:e75761. http://dx.doi.org/10.1371/journal.pone.0075761 maskew m, macphail p, menezes c, et al. lost to follow up – contributing factors and challenges in south african patients on antiretroviral therapy. s afr med j. 2007;97:853–857. tweya h, gareta d, chagwera f, et al. early active follow-up of patients on antiretroviral therapy (art) who are lost to follow-up: the ‘back-to-care’ project in lilongwe, malawi. trop med int health. 2010;15:82–89. http://dx.doi.org/10.1111/j.1365-3156.2010.02509.x rosen s, ketlhapile m. cost of using a patient tracer to reduce loss to follow-up and ascertain patient status in a large antiretroviral therapy program in johannesburg, south africa. trop med int health. 2010;15:98–104. http://dx.doi.org/10.1111/j.1365-3156.2010.02512.x chalker jc, andualem t, gitau ln, et al. measuring adherence to antiretroviral treatment in resource-poor settings: the feasibility of collecting routine data for key indicators. bmc health serv res. 2010;10:1–11. http://dx.doi.org/10.1186/1472-6963-10-43 chi bh, yiannoutsos ct, westfall ao, et al. universal definition of loss to follow-up in hiv treatment programs: a statistical analysis of 111 facilities in africa, asia and latin america. plos one. 2011;8:1–12. http://dx.doi.org/10.1371/journal.pmed.1001111 rosen s, fox mp, gill cj. patient retention in antiretroviral therapy programs in sub-saharan africa: a systematic review. plos med. 2007;4(10):e298. http://dx.doi.org/10.1371/journal.pmed.0040298 nglazi md, kaplan r, wood r, et al. identification of losses to follow-up in a community-based antiretroviral therapy clinic in south africa using a computerized pharmacy tracking system. biomed central. 2010;10:1–7. http://dx.doi.org/10.1186/1471-2334-10-329 maskew m, brennan at, westreich d, et al. gender differences in mortality and cd4 count response among virally suppressed hiv-positive patients. j women’s health. 2013:22. http://dx.doi.org/10.1089/jwh.2012.3585 meloni st, chang c, chaplin b, et al. time-dependent predictors of loss to follow-up in a large hiv treatment cohort in nigeria. open forum infect dis. 2014;1:ofu055. http://dx.doi.org/10.1093/ofid/ofu055 birbeck gl, chomba e, kvalsund m, et al. antiretroviral adherence in rural zambia: the first year of treatment availability. am j trop med hyg. 2009;80:669–674. geng eh, nash d, kambugu a, et al. retention in care among hiv-infected patients in resource-limited settings: emerging insights and new directions. curr hiv/aids rep. 2010;7:234–244. http://dx.doi.org/10.1007/s11904-010-0061-5 groh k, audet cm, baptista a, et al. barriers to antiretroviral therapy adherence in rural mozambique. biomed central. 2011;11:1–8. http://dx.doi.org/10.1186/1471-2458-11-650 charurat m, oyegunle m, benjamin r, et al. patient retention and adherence to antiretrovirals in a large antiretroviral therapy program in nigeria: a longitudinal analysis for risk factors. plos one. 2010;5:1–9. http://dx.doi.org/10.1371/journal.pone.0010584 sajhiv 1020 reflections reflections on six years in paediatric art h a moore corresponding author: h a moore (hazel.ann.moore@gmail.com) dr hazel ann moore is a general practitioner based in khayelitsha, cape town, south africa as part of my work at a primary care clinic in khayelitsha, i started the paediatric arm of the antiretroviral therapy (art) service in our clinic six years ago. when i first started, many children were being cared for by family members or foster carers because their mothers had died. this is now the exception, as most mothers receiving art survive. today, the numbers of patients are still relatively small compared with those in many other programmes, although there are now over 210 children, with a further 10 15 adolescents having graduated to the adult art section. over time, this had the advantage of allowing me to get to know the families and essentially to function as their general practitioner. in terms of the model of care, a doctor (myself) starts all the small children on art and then passes their care on to the nursing sisters when they are stable and about 3 years of age; i continue to see the children with clinical problems until they are stabilised. this approach is obviously not possible in many parts of our country, but has had many advantages. some of my reflections on spending time in primary care services for paediatric hiv include: adherence and support i have cared for a lot of children from a local children’s home who have made a brilliant control group, as they are all suppressed as a result of getting their medication on time every day. this demonstrates the importance of adherence to treatment regimens. i have even used the home temporarily for children who were failing their regimens – once suppressed, they were returned to their families, who had in the meanwhile been educated to ensure better adherence. one child, placed there voluntarily by her mother because of concerns about carer adherence, continued to show a detectable viral load. having proven that it was not due to a lack of adherence, we could confidently place her on treatment with second-line drugs; she subsequently suppressed, indicating that she had developed resistance. disclosure disclosure is often a problem, by the mother to her family as well as disclosure to the child. i believe that we need age-appropriate support groups to assist in this. small children grow up into big children and adolescents, and they need progressive disclosure so that they are fully informed about their status well before puberty. disclosure is often a particular problem with the very young mother (who may be scared to tell her own mother her status), or the working mother (who may not want her employer to know and does not want to take time off work to come to the clinic; the family may be dependent on her work income and so she does not want them to worry about her health status). pmtct in contrast to previous years, the prevention of mother-to-child transmission (pmtct) of hiv programme is now so effective that few babies become hiv-positive; but those who do frequently pose real problems. they are often born to young mothers who have not disclosed their status and/or have poor home circumstances. these mothers need intense counselling and support, especially for the first few months, as there is a high drop-out rate, especially if they have not yet disclosed their status to their family. mothers often have difficulty accepting the positive status of their child, as they no longer expect it. mobile populations we serve a very mobile population who constantly transfer in and out of the clinic, with or without informing the clinic. often clients are called away unexpectedly (e.g. to a funeral in another province) and they do not think about, or do not have time to come to the clinic for medication before departure. the national health laboratory service (nhls) is sometimes a good resource when trying to ascertain a client’s previous history, as we can track where blood samples have been taken! i have found this helpful when trying to find out more about an abandoned child. this, however, illustrates the need for a national database or a medicalert-type card where clients could voluntarily access their medication anywhere. they would also then be recorded as compliant by collecting their medication. defaulters the computer programme that we utilise (tier.net) has a system for following up defaulters, but in practice this is not well implemented for various reasons. one reason is the delay in data capturing. it would be helpful if each clinician had a desktop computer, to allow data to be updated during the consultation. i have kept my own computer records on my laptop, as well as an appointment book for consultations, which has helped me to keep track of my patients. i have found that i received a good response from those mothers/carers whom i texted personally quite soon after they defaulted (one week later) and i think this was partly because they felt a sense of personal interest from ‘their doctor’. once they have defaulted for a long time, they are often too embarrassed to return, but a text message, even at this late stage, may give them a reason to return to the clinic without losing face. it certainly does not help to get angry with defaulters as there is usually a very valid reason for defaulting, such as problems in the family, and these need to be dealt with as part of the greater model of care. seeing the same clinician seeing the same clinician at each visit has many advantages. if possible, this is a much better system as it leads to good clinician/patient/family interaction and usually results in better adherence. it can be organised to an extent by making appointments on certain days for specific clinicians. neurological side-effects the neurological side-effects of hiv are considerable. children with major impairment are appropriately referred to special schools, but those with minor impairment (and this is a large proportion of children receiving art) remain in mainstream education with little, if any, assistance. there seems to be very little in place to help the children with minor impairment and this will need to be addressed urgently by educational authorities. clubs for children receiving art this would be of considerable value for stable children. maybe, one for pre-schoolers, one for primary school and one for high school/teenagers. occasionally, it would be helpful to have carers and children together, and sometimes to have them separate. in this way, issues such as progressive disclosure could be dealt with in an age-appropriate manner, together with other issues that affect the specific age groups. teenagers are a particular challenge. they need lots of support and interaction to prevent them from defaulting, as well as lots of input about sexuality and their responsibilities in this regard. teens at school find it difficult to miss school to come to the clinic. a possible solution would be to evaluate the stable ones clinically only four times a year (in the school holidays) with their carer collecting their medication in between. treating the entire family i have found it very helpful to treat both mother and child in the same consultation, essentially offering a one-stop-shop. this way, the mother’s time in the clinic is minimised and the clinician gets to know the family circumstances. this is an essential part of treating patients as their social circumstances have a considerable impact on how they perform on treatment. in one particular case, i treat both parents and their child. it has been interesting and stimulating to be in the field of hiv medication, particularly with regard to treatment in children. the management has come a long way, but it is an evolving field and there is a long way to go yet. s afr j hiv med 2014;15(1):22-23. doi:10.7196/sajhivmed.1020 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 1 case report a 34-year-old woman presented with a 1-week history of occipital headache and acute-onset bilateral facial weakness that resulted in her being unable to close her mouth and eyes. no visual deficits were noted, but her sense of taste was markedly reduced. she had no past medical history of note and was on no medications. on examination she was apyrexial, with a blood pressure of 140/123 mmhg and a pulse rate of 113 beats/min. there was complete bilateral lower motor neuron 7th cranial nerve palsy in keeping with bilateral bell’s palsy. she was unable to close her eyes or mouth on request and could not speak without the support of her hand. no other focal neurology was present. there was a small aphthous ulcer on her upper palate. a lumbar puncture, which was unfortunately traumatic, resulted in a cerebrospinal fluid reading with elevated erythrocytes (10 000×109/l) and protein 4.16 g/l. however, after corrections were made using blood sample cell levels the csf showed evidence of aseptic meningitis with elevated polymorphs (5×109/l) and lymphocytes (299×109/l) as well as a glucose level towards the lower end of normal at 2.3 mmol/l. consent to conduct hiv testing was obtained, and while the rapid test was negative, the cd4 count was reduced at 352 cells/µl and the viral load was elevated at 5 300 counts/ ml (log = 3.72), a result in keeping with an acute hiv infection and seroconversion illness. the patient was informed of the likelihood of seroconversion, and booked for an enzyme-linked immunosorbent assay (elisa) hiv test in 6 weeks. she was discharged on oral acyclovir in order to cover any underlying herpes simplex infection, nystatin to cover fungal infections, and an artificial tear solution to prevent drying out of the eyes. simple analgesia was provided and a follow-up magnetic resonance imaging scan and ent consultation were organised. discussion bilateral facial nerve palsy is a rare but recognised complication of seroconversion, the process by which the hiv virus becomes widespread throughout the body.1 the presence of acute hiv infection in this case is supported by the low cd4 count and high viral load. in 40 90% of patients with a new hiv infection an acute seroconversion illness occurs between 2 and 6 weeks after exposure. typical symptoms include fever, fatigue, pharyngitis, weight loss, night sweats, lymphadenopathy, myalgias, headache, nausea and diarrhoea.1 while this patient did not suffer from the majority of these symptoms, she did have a severe headache (resulting in vomiting) and aseptic meningitis, both of which have previously been described in seroconversion.1 the first case of bilateral 7th cranial nerve palsy as part of an acute seroconversion reaction was reported in 1989 in a 45-year-old homosexual postgraduate student in california.2 since then only 14 other cases have been reported in the literature worldwide, including our own (which to our knowledge is the first case in south africa).3 in the 14 cases described, ages ranged from 21 to 73 years, and 71.4% were men.3 sexual transmission was the means of acquiring hiv in 64.3% of cases, and the median interval between the onset of symptoms of hiv infection and the development of 7th cranial nerve palsy was 15 days (range 2 180 days). aseptic meningitis and a maculopaular rash were present in the majority of bilateral lower motor neuron facial nerve palsy due to hiv seroconversion c a s e s t u d y – h i v a n d t h e n e u r o n s r dolan, mb chb, ma, ba university of dundee medical school, uk d maritz, mb chb l wallis, mb chb, fcem, md division of emergency medicine, university of cape town and stellenbosch university, w cape m parak, mb bs g f jooste hospital, cape town a 34-year-old-woman presented with acute onset of headache and bilateral facial nerve paralysis. on examination bilateral lower motor neuron 7th cranial nerve palsy in keeping with bilateral bell’s palsy was apparent. investigations showed aseptic meningitis, with a low cd4 count of 352 cells/µl and an elevated viral load (5 300 counts/ml, log = 3.72), in keeping with acute hiv infection. bell’s palsy is a known complication of seroconversion – 13 cases have been reported worldwide. to our knowledge this is the first reported case in south africa. 39 a p r i l 2 0 1 1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e cases. all patients who had a recorded cd4 cell count had counts over 300 cells/µl (range 323 825 cells/µl). three patients had additional neurological symptoms at diagnosis, while just one patient received antiretroviral therapy. all but one patient made a complete recovery in terms of their nerve paralysis. the pathogenic mechanism of bilateral bell’s palsy in patients with acute hiv infection is not completely understood. there are several schools of thought as to how this rare sign appears, including a proposed direct insult to the ne rve by the hiv virus. another possibility would be immunologically mediated inflammatory polyradiculopathy, similar to a regional guillain-barré syndrome, which would make more sense immunologically and therefore has slightly more scientific merit; however, neither theory has yet been fully tested.3 facial nerve paralysis has a high predictive value for hiv infection in populations with high rates of seroconversion, including those who engage in highrisk activities such as intravenous drug users and men who have sex with men, and patients from hivendemic areas such as sub-saharan africa.4 this case and the supportive evidence from the literature would indicate the necessity of including acute seroconversion syndrome in a list of differential diagnoses for bilateral facial nerve palsy, especially in sexually active patients who have had a prior acute febrile illness with rash or headache. a full hiv work-up should form part of the investigation of bilateral bell’s palsy. references 1. kassutto s, rosenberg es. primary hiv type 1 infection. clin infect dis 2004;38:1447-1453. 2. wechsler af, ho dd. bilateral bell's palsy at the time of hiv seroconversion. neurology 1989; 39:747-748. 3. serrano p, hernandez n, arroyo ja, et al. bilateral bell palsy and acute hiv type 1 infection: report of 2 cases and review. clin infect dis 2007;44:57-61. 4. youle m. aids and the british healthcare system. j int assoc physicians aids care 1997;3:34-38. this case report was approved by the health research ethics committee, stellenbosch university. 40 acknowledgements references about the author(s) ying zhao department of medicine, faculty of health science, university of cape town, cape town, south africawellcome centre for infectious diseases research in africa, institute of infectious disease and molecular medicine, university of cape town, cape town, south africa gary maartens wellcome centre for infectious diseases research in africa, institute of infectious disease and molecular medicine, university of cape town, cape town, south africadivision of clinical pharmacology, department of medicine, university of cape town, cape town, south africa graeme meintjes department of medicine, faculty of health science, university of cape town, cape town, south africa wellcome centre for infectious diseases research in africa, institute of infectious disease and molecular medicine, university of cape town, cape town, south africa citation zhao y, maartens g, meintjes g. dolutegravir for second-line treatment: programmatic implications of new evidence. s afr j hiv med. 2022;23(1), a1428. https://doi.org/10.4102/sajhivmed.v23i1.1428 editorial dolutegravir for second-line treatment: programmatic implications of new evidence ying zhao, gary maartens, graeme meintjes copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. dolutegravir, an integrase strand transfer inhibitor, with an optimised nucleoside reverse transcriptase inhibitor (nrti) backbone is the world health organization (who)-recommended second-line antiretroviral therapy (art) regimen for adults after failing a first-line regimen based on a non-nucleoside reverse transcriptase inhibitor (nnrti), either nevirapine or efavirenz.1 this who recommendation is based on the dawning study, which showed that dolutegravir was superior in both safety and efficacy compared to lopinavir-ritonavir, when administered with two nrtis, at least one of which had to be fully active on resistance testing.2 the world health organization recommends substituting tenofovir with zidovudine when switching to second-line art to ensure that there will be at least one fully active nrti because the signature tenofovir resistance mutation k65r does not compromise zidovudine’s effectiveness and there is limited access to resistance testing in high-burden, resource-limited settings to select an optimised nrti backbone.3 the question has been raised whether recycling tenofovir and lamivudine (or emtricitabine) with dolutegravir in second-line art could be an effective and easily implementable regimen. tenofovir is less toxic than zidovudine4 and is dosed once rather than twice daily, which improves adherence. recent evidence has shown that recycling tenofovir in second-line art is efficacious. the nadia study randomly assigned participants in a 2 × 2 factorial design to daily dolutegravir or darunavir-ritonavir combined with either tenofovir or zidovudine (both with lamivudine).5 at week 96, recycling tenofovir was superior to switching to zidovudine (percentage point difference 7.0%, 95% confidence interval [ci]: 1.2% – 12.8%).5 artist, a prospective cohort study of recycled tenofovir and lamivudine with dolutegravir in second-line art, reported that 85% of 60 participants achieved hiv-1 rna < 50 copies/ml at week 24, despite 65% having resistance to both tenofovir and lamivudine at baseline.6 in the visend randomised trial, 83% achieved hiv-1 rna < 1000 copies/ml in the tenofovir-lamivudine-dolutegravir group at week 48, compared with 82% in the atazanavir-ritonavir-zidovudine-lamivudine group and 69% in the lopinavir-ritonavir-zidovudine-lamivudine group.7 it is well established that the modest effect of nrtis on reducing viral fitness in the presence of nrti resistance is both necessary and sufficient to achieve virologic suppression in combination with a protease inhibitor8 – this is likely also true for dolutegravir as over 90% of those taking either dolutegravir or darunavir-ritonavir and two nrtis with resistance to both nrtis achieved virologic suppression in the nadia study.5 in our view, these findings from recent studies strengthen the evidence base for recycling tenofovir and lamivudine (or emtricitabine) with dolutegravir in second-line art in resource-limited settings. there is an important caveat for clinicians to be aware of: resistance to dolutegravir has been documented more frequently in second-line when compared with first-line art. emergent dolutegravir resistance was reported in a small proportion of integrase inhibitor-naïve participants switching to second-line dolutegravir-based art in randomised trials (9 [4%] of 235 participants by week 96 in nadia and 6 [2%] of 314 participants by week 159 in dawning).2,5,9 notably, emergence of protease inhibitor resistance did not occur in either nadia or dawning, indicating that dolutegravir has a lower genetic barrier to resistance than protease inhibitors when dolutegravir is administered with nrtis potentially compromised by resistance mutations. risk factors associated with emergent dolutegravir resistance include intermittent adherence, drug-drug interactions, high baseline hiv-1 rna and active opportunistic infections.9 further research is needed to better understand the risks associated with the development of dolutegravir resistance and particularly when combined with pre-existing resistance to nrtis, as well as strategies to mitigate dolutegravir resistance selection and second-line failure. darunavir-ritonavir was non-inferior to dolutegravir for the outcome of virologic suppression at week 96 in the nadia study5 and is, therefore, a robust alternative to dolutegravir in second-line art. the cost and availability of a fixed-dose combination with nrtis currently favour the use of dolutegravir over darunavir-ritonavir. darunavir-ritonavir with two nrtis, even if there is resistance to both these nrtis, should be an effective treatment option if virologic failure with dolutegravir resistance develops on dolutegravir-based second-line art. the nadia study investigators argue that patients switching to dolutegravir after virologic failure on a nnrti-based first-line regimen are a high-risk group for developing resistance and hiv-1 rna rebound on dolutegravir-based second-line regimens should trigger intensive adherence counselling and an earlier repeat hiv-1 rna test following adherence interventions, based on the observation that most participants who developed dolutegravir resistance self-reported suboptimum adherence at multiple study visits.5 a cohort study in east and central africa reported that patients who switched from a first-line nnrti regimen to dolutegravir with hiv-1 rna ≥ 1000 copies/ml or unknown hiv-1 rna levels had worse hiv treatment outcomes compared with those who switched with hiv-1 rna < 200 copies/ml.10 therefore, these patients may benefit from additional clinical monitoring and adherence support. in summary, dolutegravir in second-line art with recycled tenofovir is more effective than switching to zidovudine. however, emergent dolutegravir resistance in a small minority of participants raises a public health concern as dolutegravir is recommended in most patients requiring first-line art. there is, therefore, a need for appropriate surveillance programmes to monitor the emergence of dolutegravir resistance in second-line art. acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions y.z. wrote and revised the manuscript. g. maartens and g. meintjes assisted with the development and revision of the manuscript. ethical considerations this article followed all ethical standards for research without direct contact with human or animal subjects. funding information this research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. data availability data sharing is not applicable to this article as no new data were created or analysed. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references world health organization. consolidated guidelines on hiv prevention, testing, treatment, service delivery and monitoring: recommendations for a public health approach [homepage on the internet]. 2021 [cited 2022 june 21] july. available from: https://www.who.int/publications/i/item/9789240031593 underwood m, horton j, nangle k, et al. integrase inhibitor resistance mechanisms and structural characteristics in antiretroviral therapy-experienced, integrase inhibitor-naive adults with hiv-1 infection treated with dolutegravir plus two nucleoside reverse transcriptase inhibitors in the dawning study. antimicrob agents chemother. 2021;66(1):e01643-21. https://doi.org/10.1128/aac.01643-21 chammartin f, ostinelli chd, anastos k, et al. international epidemiology databases to evaluate aids (iedea) in sub-saharan africa, 2012–2019. bmj open. 2020;10(5):e035246. https://doi.org/10.1136/bmjopen-2019-035246 gallant je, dejesus e, arribas jr, et al. tenofovir df, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for hiv. n engl j med. 2006;354(3):251–260. https://doi.org/10.1056/nejmoa051871 paton ni, musaazi j, kityo c, et al. efficacy and safety of dolutegravir or darunavir in combination with lamivudine plus either zidovudine or tenofovir for second-line treatment of hiv infection (nadia): week 96 results from a prospective, multicentre, open-label, factorial, randomised, non-inferiority trial. lancet hiv. 2022;9(6):e381–e393. keene cm, griesel r, zhao y, et al. virologic efficacy of tenofovir, lamivudine and dolutegravir as second-line antiretroviral therapy in adults failing a tenofovir-based first-line regimen: a prospective cohort study. aids. 2021;35(9):1423. https://doi.org/10.1097/qad.0000000000002936 mulenga l, fwoloshi s, mweemba a. dolutegravir with recycled nrtis is noninferior to pi-based art: visend trial. presented at 2022 croi; online, 12–16 and 22–24 feb. hakim jg, thompson j, kityo c, et al. lopinavir plus nucleoside reverse-transcriptase inhibitors, lopinavir plus raltegravir, or lopinavir monotherapy for second-line treatment of hiv (earnest): 144-week follow-up results from a randomised controlled trial. lancet infect dis. 2018;18(1):47–57. https://doi.org/10.1016/s1473-3099(17)30630-8 cevik m, orkin c, sax pe. emergent resistance to dolutegravir among insti-naive patients on first-line or second-line antiretroviral therapy: a review of published cases. open forum infect dis. 2020;7(6):ofaa202. https://doi.org/10.1093/ofid/ofaa202 romo ml, edwards jk, semeere as, et al. viral load status before switching to dolutegravir-containing antiretroviral therapy and associations with hiv treatment outcomes in sub-saharan africa. clin infect dis. 2021;ciab1006. https://doi.org/10.1093/cid/ciab1006 a 30-year-old woman presented to a rural district hospital in the eastern cape. she was unable to give any history. her family said she had recently returned from cape town. she had seemed normal on the day she arrived home but since then had become increasingly confused but with no specific complaints. her patient records confirmed that she had recently completed 6 months of tb treatment and had started antiretrovirals (arvs), comprising stavudine (d4t), lamivudine (3tc) and efavirenz, 2 months previously. her cd4 nadir was 180 cells/µl. on examination she was apyrexial, with a pulse rate of 120/min and a blood glucose level of 8.0 mmol/l. there was no meningism or clear focal neurological deficit, so lumbar puncture was not performed. on mental state examination she was found to be agitated and aggressive, with loud and incoherent speech; it was not possible to elicit delusions, but she appeared to be hallucinating. she gave appropriate answers to some simple questions and was orientated to month and year but not to day or date. a working diagnosis of psychosis secondary to hiv was made. the patient was sedated with haloperidol and diazepam and admitted for further investigation. the following day she remained aggressive and confused. efavirenz was stopped but d4t and 3tc were continued. over the next week there was gradual improvement in her mental state. she became oriented to day and place, but complained of seeing people who were coming to steal her medication. collateral history from her mother was that she had no known previous psychiatric history and that the hallucinations had started during her father’s funeral a week before admission. the results of basic blood tests were normal other than c-reactive protein (crp) 63.4 mg/l and platelets 67 x 109 /l. after 1 week, the diagnosis of psychosis secondary to hiv was confirmed by a doctor at a tertiary level psychiatric unit. the recommendation was to wean the patient off haloperidol and replace it with risperidone. risperidone is not available at level 1 district hospitals, so haloperidol 2.5 mg 3 times daily was continued. nevirapine was introduced after 10 days. she was discharged a week later. two weeks later, having defaulted her follow-up appointment, she presented with what the admitting doctor described as ‘aggressive and psychotic behaviour’. he increased the haloperidol dose to 5 mg twice the behaviourally disturbed patient with hiv/aids c a s e s t u dy tom h boyles, ma, bm bch, mrcp, dtm&h, md madwaleni hospital, eastern cape, and division of clinical pharmacology, university of cape town john a joska, mmed (psych), fcpsych (sa) department of psychiatry and mental health, university of cape town and groote schuur hospital, cape town while hiv invades the brain early in the course of hiv infection,1 severe mental illness probably only occurs later in the disease.2 in many instances this may be the first presentation of a psychiatric illness in a younger person. in addition, the clinical syndrome may include manic and/or psychotic features, together with neurocognitive disturbance. these patients are at risk of secondary opportunistic infections or other features of systemic immunocompromise which may cause or confound the clinical picture. a clinical case 28 clinical presentation n where history from the patient is limited, a collateral history is essential. n there are potentially multiple contributing causes, such as hiv itself, drugs including arvs, opportunistic infections including tuberculosis or a primary psychotic disorder. n it is critical to exclude delirium through careful clinical evaluation and targeted special investigations. investigation n in a case where severe behavioural disturbance is present in a setting of severe immunocompromise, investigations should include basic blood work-up, as well as lumbar puncture and a computed tomography scan of the brain. n if confusion is prominent and/or the patient has a headache and/or fever, it is prudent to request polymerase chain reaction (pcr) testing of the cerebrospinal fluid for cytomegalovirus, herpes simplex virus, epstein-barr virus and jc virus. o cto b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e o cto b e r 2 0 0 9 a day plus diazepam 5 mg at night. she claimed that her family were trying to kill her. she was prescribed fluphenazine 12.5 mg as an intramuscular injection and over the next week she settled and regained orientation to time, person and place. five days later, after much discussion with her family, she was discharged with a review date in 1 month. one month later, the clinical presentation recurred. she was sedated with haloperidol and lorazepam and after consultation with an hiv psychiatrist valproate 200 mg bd was added. it had emerged that prominent mood symptoms were present, namely irritability and expansiveness. the persecutory delusions were paired with grandiosity. over the next week she gradually improved and regained her orientation to time and place. valproate was increased to 400 mg bd and nevirapine was changed back to efavirenz on the basis that stopping the efavirenz had had no impact on her mental state and there is a potential drug-drug interaction between valproate and nevirapine. a week later, the patient was feeling well with no psychotic symptoms and was fully orientated. she was discharged with a prescription for valproate 400 mg bd. she has now been followed up regularly for 4 months. she remains completely well and is adherent to both her valproate and arvs. neuropsychiatric presentations in late-stage hiv require clinicians to carefully exclude a range of possible contributory causes. one case series reported a 2% incidence of new-onset psychosis in patients presenting with an aids-defining diagnosis. of these, 50% had an underlying infective or metabolic cause while 50% were thought to have an hiv-related psychosis.3 infectious causes may be due to bacteria, mycobacteria, viruses, fungi or spirochaetes and may form part of an immune reconstitution inflammatory syndrome (iris) if occurring after the onset of arv medication. in the above case, the absence of fever and headache weighed against this possibility. medication-related causes of psychosis also occur. these include arvs,4 antituberculosis drugs and prednisone. efavirenz is often implicated. a stepwise approach to removing potential drug causes is advised – treat the psychosis or mania appropriately, and if no response is seen, remove the most likely offending agent. once the effect (or not) of this move has been appraised, an informed decision to make additional changes or switches can be made. primary psychiatric disorders are frequently seen in the setting of hiv infection. while bipolar disorder, mania and major depressive disorder with psychosis must all be considered, so too must the effects of psychosocial stressors such as bereavement, loss, unemployment and disability. psychotropic treatments need to be used alongside psychosocial measures, which include educating families, addressing needs for disability grants and counselling. the management of behaviourally disturbed patients with hiv in a remote rural hospital presents many challenges. one such problem is that once the diagnosis of hiv infection is made there is a tendency to attribute multiple symptoms to the hiv itself without a full consideration of other possibilities. while the initial probability of hiv-related psychosis may be fairly high in the presence of suggestive features, a definitive diagnosis requires the exclusion of a number of other possibilities. a similar problem is related to the treatment of all patients with psychiatric illness in this setting, namely that they are labelled a ‘psych patient’ without consideration of which of many underlying conditions may be responsible for their symptoms. this situation is exacerbated by lack of resources. under these conditions the standard of care for patients with features of psychosis is monthly injectable antipsychotics with reliance on the patient and relatives to ensure adherence. patients with features of depression are similarly prescribed low-dose amitriptyline, often without a full explanation of time course or dose of treatment required. with more complex interventions being beyond the scope of the service, it is perhaps understandable that little attention is paid to the exact diagnosis. however, despite these drawbacks it is important that all patients are seen by a doctor at the district hospital and that complex cases be referred to the tertiary centre for an opinion and a follow-up plan before being referred back to peripheral clinics. references 1. mcarthur jc, brew bj, nath a. neurological complications of hiv infection. lancet neurol 2005; 4(9): 543-555. 2. dube b, benton t, cruess dg, evans dl. neuropsychiatric manifestations of hiv infection and aids. j psychiatry neurosci 2005; 30(4): 237-246. 3. alciati a, fusi a, d’arminio ma, coen m, ferri a, mellado c. new-onset delusions and hallucinations in patients infected with hiv. j psychiatry neurosci 2001; 26(3): 229-234. 4. foster r, olajide d, everall ip. antiretroviral therapy-induced psychosis: case report and brief review of the literature. hiv med 2003; 4(2): 139-144. 29 discussion psychotropics n haloperidol is safe to use in this setting with the drawback of a high potential for extrapyramidal side-effects; atypical antipsychotics, such as risperidone 0.5 2 mg 2 × daily or quetiapine 50 200 mg 2 × daily, if available, may be better. n in the short term, lorazepam 2 4 mg 8-hourly (or oxazepam if liver impairment is present) may be used for sedation. n if manic symptoms are a prominent feature, consider using valproate 300 mg 2 × daily, increasing to 600 mg 2 × daily; use lower doses and monitor liver function tests if liver impairment is present. article information authors: george du toit1 martin kidd2 affiliations: 1department of obsterics and gynaecology, stellenbosch university, south africa 2centre for statistical consultation, stellenbosch university, south africa correspondence to: george du toit email: dutoitg@worldonline.co.za postal address: private bag x1, matieland 7602, south africa dates: received: 05 mar. 2015 accepted: 06 aug. 2015 published: 18 sept. 2015 how to cite this article: du toit g, kidd m. a prospective study of demographic features and quality of life in hiv-positive women with cervical cancer treated at tygerberg hospital. s afr j hiv med. 2015;16(1), art. #368, 5 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.368 copyright notice: © 2015. the authors. licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. a prospective study of demographic features and quality of life in hiv-positive women with cervical cancer treated at tygerberg hospital in this original research... open access • abstract • introduction • methods and materials    • inclusion criteria    • questionnaires    • statistical analysis • results    • demographic characteristics    • hiv status and change in quality of life over the study period • discussion • acknowledgements    • competing interests    • authors’ contributions • references abstract top ↑ background: cervical cancer and human immunodeficiency virus (hiv) infection/acquired immune deficiency syndrome (aids) both have a high incidence in south africa. cervical cancer treatment of hiv-positive women poses challenges. treatment-related changes in quality of life (qol) of such women are important to future treatment protocols. aim: to examine demographic data of hiv-negative and hiv-positive women at diagnosis of cervical cancer and describe their changes in qol as a result of treatment. methods and materials: all newly diagnosed patients with cervical cancer at tygerberg hospital were approached to participate in the study. the european organisation for research and treatment of cancer quality of life core questionnaire (eortc qlq-c30) and the cervix cancer module (qlq-cx24) were used. general qol was measured with the eortc qlq-c30 and cervical-specific qol with the qlq-cx24 questionnaire. the patients completed the questionnaire at diagnosis, on completion of treatment and at 3 months’ follow-up. results: the study included a total of 221 women of whom 22% were hiv-positive; the latter were younger and of higher educational level than the rest. mean monthly income and stage distribution was similar between the two groups. hiv-positive patients underwent radiation therapy more commonly than chemoradiation. hiv-positive women showed statistically significantly higher loss to follow-up during the study. hiv-positive women experienced no improvement in insomnia, appetite loss, nausea, vomiting, diarrhoea, social role or any of the sexual domains. in contrast, hiv-negative women experienced statistically significant improvement in all sexual domains other than sexual/vaginal functioning. the qol improvement of hiv-negative women was statistically significantly greater than their hiv-positive counterparts in the majority of qol domains. global health improved in both groups, with hiv-negative women experiencing greater improvement. hiv-positive women experienced an initial decline of peripheral neuropathy (pn) symptoms post treatment with a return to pretreatment values at 3 months’ follow-up. the change in pn was statistically significant between the hiv-negative and hiv-positive women. conclusion: demographic differences exist between the hiv-negative and hiv-positive groups. the differential outcome in the qol of hiv-positive and hiv-negative women treated for cervical cancer might be related to persistence of aids-related symptoms on completion of cervical cancer treatment. introduction top ↑ the quality of life (qol) of human immunodeficiency virus (hiv)-positive women with cervical cancer is the result of both diseases and the impact of their respective treatments. invasive cervical cancer is an acquired immune deficiency syndrome (aids)-defining condition (world health organization stage 4).1 aids is endemic in sub-saharan africa. the south african population has a 12% – 18% incidence of hiv-positivity.2 south africa has a cervical cancer incidence rate of 26.8/100 000.3 most south african women present at an advanced stage of the disease. cervical cancer and hiv infection are epidemiologically related owing to the sexual transmission of both conditions. peripheral neuropathy (pn) in hiv-infected persons occurs in 50% – 60% of cases. at autopsy, pn can be shown in all hiv-positive persons despite their having no signs or symptoms during their lifetime. antiretroviral medication (particularly didanosine, zalcitabine and stavudine) is directly neurotoxic and results in pn identical to aids-associated neuropathy. the disease and its treatment synergistically increase pn. cisplatin is the drug of choice in chemoradiation (cr) treatment of cervical cancer. cisplatin results, in a dose-dependent fashion, in sensory pn in the stocking-glove distribution.4 poor tolerance of chemotherapy for cervical cancer by hiv-positive women results in substantially less completion of cr than their hiv-negative counterparts. the use of cr in advanced stage (iii to iva) cervical cancer in hiv-positive women has been questioned owing to the limited survival benefit.5 a cochrane review shows a statistically non-significant 3% benefit in 5-year survival of cr over radiation therapy (rt) in stage iii to iva.6 simonds et al.5 suggest that the omission of chemotherapy in these hiv-positive women with cervical cancer would result in timely completion of the full dose of radiation therapy. a limitation of the study by simonds et al.5 was the 15.4% (59 out of a cohort of 383) incidence of hiv-positive women.5 data on the impact of rt on qol of hiv-positive women with cervical cancer are lacking. the aim of the present study was to examine demographic data for hiv-negative and hiv-positive women at diagnosis of cervical cancer and to describe qol changes in these women after treatment for cervical cancer. methods and materials top ↑ inclusion criteria patients referred to the unit of gynaecologic oncology at tygerberg hospital who had newly diagnosed cervical cancer were approached to participate in the study. the unit is one of two tertiary referral units for public-sector patients in western cape province. the province has a population of 5.8 million. most (85%) of the population do not have private medical insurance and are dependent on public facilities provided by two tertiary hospitals (tygerberg hospital and groote schuur hospital) for treatment of cervical cancer.7 patients were eligible for the study if they had histologically proven cervical cancer. exclusion criteria included concurrent, or previous history of, cancers and medical disorders that might affect qol, such as diabetes. patients unable to provide informed consent owing to psychiatric disorders were excluded. cervical cancer was staged according to international guidelines.8 clinical management included hiv testing and initiation of antiretroviral treatment. hiv-positive women did not receive chemotherapy if their cd4 count was < 200 cells/µl, or active tuberculosis was present. questionnaires patients completed the questionnaire in the language of their choice (isixhosa, english or afrikaans) after informed consent was obtained.9 a research assistant helped illiterate patients. to exclude bias, the research assistant had no medical background and was not involved in clinical management of the patients. questionnaires were completed prior to treatment, after initial treatment, and after a 3-month post-treatment period. the follow-up visits coincided with clinical follow-up of patients. patients failing to attend visits were contacted telephonically where possible. patient records were used to extract relevant clinical data. ethical approval was obtained from the local committee (s12/06/174). clinical management followed protocols as previously described.5 the european organisation for research and treatment of cancer (eortc) quality of life core questionnaire (eortc qlq-c30) and the cervix cancer module (qlq-cx24) were both used. the eortc qlq-c30 consists of 30 items comprising 5 functional scales (physical, role, emotional, social and cognitive), 3 symptom scales (fatigue, nausea/vomiting and pain), an overall qol scale, and 6 individual items (dyspnoea, insomnia, appetite loss, constipation, diarrhoea, and financial difficulties). the eortc qlq-c30 was analysed according to the procedures recommended by the eortc qol group. higher scores on the qlq-c30 functioning scales and the overall qol scale indicate a better qol. higher scores on the symptom and individual item scales represent a decrease in qol.10 the eortc qlq-cx24 includes 3 multi-item scales (symptom experience, body image, and sexual functioning) and 5 single-item scales (lymphoedema, lower back pain, menopausal symptoms, tingling and numbness, and sexual enjoyment). higher scores indicate a decrease in qol except for items 49 and 54 (where higher scores indicate better qol).11 the questionnaires used were translated and validated for use in south africa.9 statistical analysis descriptive statistics were used to characterise the study sample in terms of the contextual factors of socio-demographic and medical variables. data presented as medians were analysed using kruskal–wallis tests. post hoc analyses were done with fisher's least significant difference (lsd) test. chi-square tests were used for categorical data. a p value < 0.05 was considered to be significant. statistical analysis was performed with the use of statistica version 12 software. results top ↑ demographic characteristics the study included a total of 221 women (table 1). hiv-positivity of the study group was 22%. the mean age of the hiv-positive women was statistically significantly 7 years less than that of the hiv-negative women. age had a normal distribution without any outliers. hiv-positive women had a higher educational grade. racial distribution shows a statistically significant difference between black (40%), mixed race (12%) and white (0%) participants’ hiv-positivity rates. mean monthly income as well as the percentage of patients under the poverty line were not statistically significantly different between the hiv-positive and -negative groups. single women had a statistically significantly higher rate of hiv-positivity than their married, widowed and divorced counterparts. the stage distribution of hiv-negative and hiv-positive cases was not statistically significantly different. hiv-positive patients underwent rt more commonly than cr. table 1: comparative demographic data of hiv-negative and hiv-positive women (poverty line as defined by the western cape provincial government). unemployed women had a statistically significantly higher hiv-positivity rate (26%) than the employed women (23%). the loss to follow-up of hiv-positive women v. hiv-negative women during the post-treatment (56% v. 34%) and 3-month (38% v. 30%) follow-up visits was statistically significantly higher for the hiv-positive women (figure 1). cause and confirmation of death could be accurately determined in 20 women in the total study population. figure 1: follow-up of hiv-negative versus hiv-positive women over the study period. hiv status and change in quality of life over the study period the domains of dyspnoea, financial difficulties, lymphoedema and menopausal symptoms remained unchanged during the study period. hiv-positive women experienced no improvement in insomnia, appetite loss, nausea and vomiting, diarrhoea, social role or any of the sexual domains over the study period. in contrast, hiv-negative women experienced statistically significant improvement in all sexual domains other than sexual/vaginal function. the improvement in qol of hiv-negative women was statistically significantly more than their hiv-positive counterparts in all domains, with the exception of role function, insomnia, constipation, sexual worry and sexual activity (table 2). global health improved in both groups, with hiv-negative women experiencing a greater improvement. pn did not change in hiv-negative women but hiv-positive women experienced an initial decline in this symptom at post treatment with a return to pretreatment values at the 3-month follow-up visit. the change in pn was statistically significantly different between hiv-negative and hiv-positive women. table 2: change in quality of life during study period. discussion top ↑ the results of the study show significant demographic differences between hiv-positive and hiv-negative women with a diagnosis of cervical cancer. the former group is statistically younger, and has a higher educational level and higher unemployment rate than the latter. black women have a statistically higher hiv-positivity rate than mixed race and white women. single women had the highest hiv-positivity rate. monthly income is similar in both groups. rt was more frequently used than cr in hiv-positive patients. the 22% hiv-positive rate in the current study is higher than previously reported rates. this change is the result of a general change in hiv-positive rates in the total population over time.2 black women had a higher hiv-positive rate than mixed race or white women. a previous study documented a higher incidence (30%) of positive syphilis serology amongst black women with cervical cancer than in their white and mixed race counterparts.12 the younger age of hiv-positive cervical cancer patients confirms previous studies of hiv in cervical cancer cases. in previous studies, the difference in mean age between hiv-negative and hiv-positive patients was reported as 10 years, whilst the current study shows a 7-year age difference.5,13,14 the stage distribution in the current study was similar in hiv-negative and hiv-positive women. despite the similar stage distribution, significantly more hiv-negative than hiv-positive women received cr. the selection by the presiding clinician of the inability of hiv-positive women to tolerate the chemotherapy because of low cd4 counts, gave rise to this difference. the majority of qol domains in hiv-negative women improved with treatment with prolonged effect up to 3 months’ follow-up. improvement of qol domains in hiv-positive women was statistically less than in hiv-negative women. pn domain did not change in hiv-negative women. in hiv-positive women, initial improvement occurred in pn with relapse to pretreatment level at 3 months. appetite loss in hiv-positive women initially improved after treatment and returned to pretreatment levels at 3 months’ follow-up. hiv-negative women showed an improvement in appetite loss up to 3 months’ follow-up. the qol of hiv-negative women significantly improved in the majority of domains. hiv-positive women had fewer domains improved by treatment, and the magnitude of improvement was less than that amongst hiv-negative women. temporary improvement of pain, fatigue and appetite loss after treatment in hiv-positive women reverted to pretreatment levels at 3 months’ follow-up. pain and fatigue are aids-related conditions that are prevalent in aids patients, despite adequate treatment. depression is associated with these symptoms, and the difference in emotional functioning in the current study underlines the element of depression in the hiv-positive women.15 the aids-related impact on qol accounts for these relapses in qol domains. diarrhoea was significantly more in hiv-positive women than in hiv-negative women, and treatment did not change the incidence in either group. diarrhoea is commonly associated with aids and can have numerous causes, both infectious and non-infectious, for example aids medication-related gastro-intestinal side-effects.16 constipation improved in both hiv-negative and hiv-positive women. radiation is associated with increased stool frequency owing to radiation-induced mucosal rectal damage. pn paradoxically improved in both groups after treatment and reverted to pretreatment levels in hiv-positive women. contrary to expected cisplatin-related toxicity, treatment did not result in an increase of pn. the dose of cisplatin, which did not reach the cumulative threshold dose > 250 mg – 350 mg/m², may explain the absence of pn. cisplatin-associated pn may occur up to 8 months after exposure, and therefore longer follow-up may reveal pn.17 in the present study, higher rates of loss to follow-up occurred in hiv-positive women. a meta-analysis of sub-saharan lowand middle-income countries’ antiretroviral treatment programmes reports on causes of loss to follow-up. self-transferring care to other facilities (18.6%), unreported death (38.8%) and stopping treatment were identified as the major reasons for loss to follow-up.18 who aids stage 3 and 4 cases have a mortality rate of 72.12 per 100 person-years in the first 6 months after initiation of treatment. the mortality rate decreases to 7.9 per 100 person-years after 12 months.19 the mortality rate is compounded by cervical cancer-related death. in a south african study, the mortality rate after treatment of stage iii cervical cancer was the highest in the first 6 months after treatment.12 in kenya, a 41% loss to follow-up occurred in women receiving treatment for cervical cancer.20 tracking of women after missed appointments is not done routinely owing to resource constraints.18 verifying hiv-related deaths by checking death certificates is subject to 90% misclassification of hiv deaths in south africa.21 limitations of the present study include a short follow-up subsequent to completion of therapy. the short follow-up limits the conclusion to long-term effects of treatment. prolonged follow-up may reveal an increased incidence of pn. the higher loss to follow-up rate of hiv-positive women during the study period precludes sub-analysis of smaller groups, for example treatment-related pn in those women undergoing cr. in conclusion, the study documents the demographic difference in hiv-negative and hiv-positive women with cervical cancer with regard to a younger age in the latter group. the 5-year survival benefit of cr in comparison with rt in hiv-negative women with stage iii to iva is a statistically non-significant 3%.6 the poor response of hiv-positive women to cr raises the question of whether cr is appropriate in these circumstances.5 a significant difference exists in the short term in certain qol domains of hiv-positive women with cervical cancer receiving rt or cr. in these circumstances, the different impact on long-term qol of hiv-positive women with cervical cancer receiving rt or cr warrants further study. acknowledgements top ↑ the research forms part of a phd thesis (gcdt) with promotor prof. t.f. kruger, department of obstetrics and gynaecology, stellenbosch university. the members of the unit of gynaecological oncology, tygerberg hospital and the head of the unit, prof. m.h. botha, are acknowledged for their assistance. competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions g.d.t. (stellenbosch university) was the project leader and designed the study, wrote the protocol, collected the data and wrote the paper. m.k. (stellenbosch university) performed the statistical analysis and contributed to discussions. both authors read and approved the manuscript. references top ↑ black j, conradie f, cox v, et al. adult antiretroviral therapy guidelines 2014 by the southern african hiv clinicians society. s afr j hiv med. 2014;15:121–143. shisana o, rehle t, simbayi lc, et al. south african national hiv prevalence, incidence and behaviour survey, 2012. cape town: hsrc press; 2014. arbyn m, castellsague x, de sanjose s, et al. worldwide burden of cervical cancer in 2008. ann oncol. 2011;22:2675–2686. pmid: 21471563, http://dx.doi.org/10.1093/annonc/mdr015 wadley al, cherry cl, price p, kamerman pr. hiv neuropathy risk factors and symptom characterization in stavudine-exposed south africans. j pain symptom manage. 2011;41:700–706. http://dx.doi.org/10.1016/j.jpainsymman.2010.07.006 simonds hm, wright jd, du toit n, neugut ai, jacobson js. completion of and early response to chemoradiation among human immunodeficiency virus (hiv)-positive and hiv-negative patients with locally advanced cervical carcinoma in south africa. cancer. 2012;118:2971–2979. pmid: 22072021, http://dx.doi.org/10.1002/cncr.26639 chemoradiotherapy for cervical cancer meta-analysis collaboration (cccmac). reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: individual patient data meta-analysis. cochrane database syst rev. 2010;issue 1. art. no.: cd008285. pmid: 20091664, http://dx.doi.org/10.1002/14651858.cd008285 western cape provincial treasury. regional development profile city of cape town. 2012 [cited 2014 jul 23]. available from: http://www.westerncape.gov.za/assets/departments/treasury/dc0_city_of_cape_town_sep-lg_profile_02_2013.pdf pecorelli s. revised figo staging for carcinoma of the vulva, cervix, and endometrium. int j gynaecol obstet. 2009;105:103–104. pmid: 19367689, http://dx.doi.org/10.1016/j.ijgo.2009.02.012 du toit gc, nel d. translation and validation of european organisation for research and treatment of cancer qlq-cx24 questionnaire into the indigenous african languages of isixhosa and afrikaans. s afr j gynecol oncol. 2012;4:59–62. aaronson nk, ahmedzai s, bergman b, et al. the european organization for research and treatment of cancer qlq-c30: a quality-of-life instrument for use in international clinical trials in oncology. j natl cancer inst. 1993;85:365–376. pmid: 8433390. greimel er, kuljanic vlasic k, waldenstrom ac, et al. the european organization for research and treatment of cancer (eortc) quality-of-life questionnaire cervical cancer module: eortc qlq-cx24. cancer. 2006;107:1812–1822. pmid: 16977652. du toit gc, smit bj. clinical prognostic parameters in stage iii cervical carcinoma: an analysis of 732 patients. s afr med j. 1997;87:l434–i440. lomalisa p, smith t, guidozzi f. human immunodeficiency virus infection and invasive cervical cancer in south africa. gynecol oncol. 2000;77:460–463. pmid: 10831360, http://dx.doi.org/10.1006/gyno.2000.5775 moodley m, mould s. invasive cervical cancer and human immunodeficiency virus (hiv) infection in kwazulu-natal, south africa. j obstet gynaecol. 2005;25:706–710.pmid: 16263548, http://dx.doi.org/10.1080/01443610500294599 matilda b, streinu-cercel a, mariana m, et al. fatigue in hiv/aids patients. ther pharmacol clin toxicol. 2012;16:111–115. feasey na, healey p, gordon ma. review article: the aetiology, investigation and management of diarrhoea in the hiv-positive patient. aliment pharmacol ther. 2011;34:587–603. pmid: 21777262, http://dx.doi.org/10.1111/j.1365-2036.2011.04781.x grisold w, cavaletti g, windebank aj. peripheral neuropathies from chemotherapeutics and targeted agents: diagnosis, treatment, and prevention. neuro oncol. 2012;14(suppl 4):iv45–54. pmid: 23095830, http://dx.doi.org/10.1093/neuonc/nos203 wilkinson ls, skordis-worrall j, ajose o, ford n. self-transfer and mortality amongst adults lost to follow-up in art programmes in lowand middle-income countries: systematic review and meta-analysis. trop med int health. 2015;20:365–379. pmid: 25418366, http://dx.doi.org/10.1111/tmi.12434 wubshet m, berhane y, worku a, kebede y. death and seeking alternative therapy largely accounted for lost to follow-up of patients on art in northwest ethiopia: a community tracking survey. plos one. 2013;8:e59197. pmid: 23527132, http://dx.doi.org/10.1371/journal.pone.0059197 maranga io, hampson l, oliver aw, et al. analysis of factors contributing to the low survival of cervical cancer patients undergoing radiotherapy in kenya. plos one. 2013;8:e78411. pmid: 24205226, http://dx.doi.org/10.1371/journal.pone.0078411 birnbaum jk, murray cjl, lozanoa r. exposing misclassified hiv/aids deaths in south africa. bull world health organ. 2011;89:278–285. pmid: 21479092, http://dx.doi.org/10.2471/blt.11.086280 abstract introduction methods results discussion conclusion acknowledgements references about the author(s) sanele ngcobo department of family medicine, faculty of health sciences, university of pretoria, pretoria, south africa steve olorunju biostatistics unit, south african medical research council, pretoria, south africa tshifhiwa nkwenika biostatistics unit, south african medical research council, pretoria, south africa theresa rossouw department of immunology, faculty of health sciences, university of pretoria, pretoria, south africa citation ngcobo s, olorunju s, nkwenika t, rossouw t. effect of a ward-based outreach team and adherence game on retention and viral load suppression. s afr j hiv med. 2022;23(1), a1446. https://doi.org/10.4102/sajhivmed.v23i1.1446 original research effect of a ward-based outreach team and adherence game on retention and viral load suppression sanele ngcobo, steve olorunju, tshifhiwa nkwenika, theresa rossouw received: 26 july 2022; accepted: 30 sept. 2022; published: 07 dec. 2022 copyright: © 2022. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: only 66% of south african people living with hiv (plwh) are virologically suppressed. therefore, it is important to develop strategies to improve outcomes. objectives: assess the effect of interventions on 12-month retention in care and virological suppression in participants newly initiated on antiretroviral therapy. method: fifty-seven clinics were randomised into four arms: ward-based primary health care outreach teams (wbphcots); game; wbphcot–game in combination; and control (standard of care). sixteen clinics were excluded and four re-allocated because lay counsellors and operational team leaders failed to attend the required training. seventeen clinics were excluded due to non-enrolment. results: a total of 558 participants from tshwane district were enrolled. after excluding ineligible participants, 467 participants were included in the analysis: wbphcots (n = 72); games (n = 126); wbphcot–games (n = 85); and control (n = 184). retention in care at 12 months was evaluable in 340 participants (86.2%) were retained in care and 13.8% were lost to follow-up. the intervention groups had higher retention in care than the control group, but this only reached statistical significance in the games group (96.8% vs 77.8%; relative risk [rr] 1.25; 95% confidence interval [ci]: 1.13–1.38; p = 0.01). the 12 month virologic suppression rate was 75.3% and was similar across the four arms. conclusion: this study demonstrated that an adherence game intervention could help keep plwh in care. what this study adds: evidence that interventions, especially games, could improve retention in care. keywords: hiv; community health workers; hiv; games; retention in care; viral load suppression; aids. introduction in 2020, an estimated 7 800 000 adults and children were living with hiv in south africa.1 this equates to 20% of the global population of people living with hiv (plwh). south africa’s progress towards the unaids 2020 90-90-90 goals were: 90% of plwh knew their status, 62% of plwh were on antiretroviral treatment (art) and 66% of plwh were virally suppressed in 2020.1 an undetectable viral load (vl) predicts normal survival amongst plwh and virtually eliminates sexual transmission of hiv among hiv-discordant couples. unaids updated their targets to 95-95-95 by 2025, which aim to get more than 95% of plwh on treatment.2,3 poor adherence to art is the major cause of therapeutic failure and increases the risk of opportunistic infections and death.4 many factors impede adherence, such as stigma, non-disclosure, unemployment, lack of transport, insufficient access to food, alternative forms of therapy, inadequate follow-up, and lack of patient confidentiality.5 in the face of these challenges, there is an urgent need to develop and implement strategies to increase adherence and, subsequently, the proportion of plwh who attain and maintain an undetectable vl. one such strategy is assigning community health workers (chws) to care for plwh at a household level as ward-based primary health care outreach teams (wbphcots). the role of chws in hiv care in sub-saharan africa include educating families, caregivers, and communities about hiv/aids and its symptoms, as well as preparing plwh for art and the possible side effects they may experience.6 since low health literacy has been associated with poor health outcomes,7 there is growing interest in ways to improve patients’ health literacy in order to improve retention in care and treatment adherence.8,9 traditional ways of patient education have met with limited success10,11 and many health disciplines have started experimenting with gamification, where gaming techniques are used to engage audiences and make everyday tasks more fun and engaging. in the hiv field, bridges of hope training developed experiential learning games and activities to enhance treatment adherence (figure 112). the art adherence games were designed based on educationally validated theories, such as using experimental metaphor, multisensory learning, social cognitive theory, logical and neurological behavioural frameworks;13 and skilled task performance: association, dissociation, and mental models.14 the adherence games are specifically designed for use with groups of people who have recently tested hiv-positive, to help them address a range of issues they may face around living positively, such as: stigma, support, disclosure, and treatment adherence. the programme includes 12 sessions, each requiring about 1 hour. each of the first nine sessions includes two experiential learning activities. figure 1: antiretroviral treatment and adherence game (a description of the antiretroviral treatment adherence game, extracted from the bridges of hope’s training guide). although both wbphcots and various gaming strategies have shown promise in the health space,6,15,16 they have not been tested as a combined strategy in south africa. to fill this gap, this study assessed the independent and combined effect of a wbphcot and games intervention on retention in care and virological suppression of plwh newly initiated on art in tshwane district, south africa. methods overview this quasi-experimental interventional study consisted of four arms: wbphcots; bridges of hope training’s adherence game (henceforth referred to as ‘games’); wbphcots and games combined; and a control group that received standard care. recruitment started in february 2019 and ended in december 2019, and follow-up was done between february 2019 and december 2020. all participants were recruited from primary health care clinics that provide art. in line with the national programme, newly diagnosed patients were assessed for same-day art initiation as part of the universal test and treat strategy and visited the clinic monthly (increased to two-monthly once deemed to be stable) to collect treatment.17 the sample size was calculated on the assumption that the intervention groups would achieve a 12% improvement in the primary outcome (retention in care), analysed as a binary outcome. accordingly, a sample size of 460 participants with complete follow-up would give the study an estimated power of 82%. clinic and participant selection using district health management information systems data, facilities in tshwane were selected based on the expected number of newly infected persons in their catchment area as calculated from the population size and the national hiv incidence of 1.2%.18 clinics with fewer than 60 potential participants in six months were excluded. fifty-seven clinics that met the inclusion criteria were randomised in microsoft excel into the four study arms. sixteen clinics were excluded from the study after they were not represented in the required study training. four clinics were subsequently reassigned to a different intervention since the lay counsellor and operational team leaders failed to attend the required training before patient recruitment began. in addition, 17 clinics that did not recruit participants within the first six months of the study were excluded (figure 2). figure 2: flow diagram showing number of participants randomised, allocated, followed up and analysed. participant inclusion and exclusion criteria patients were invited to participate in the study if they were 18 years or older, newly diagnosed with hiv, and initiated on art within the last month. patients who were too ill to provide informed consent were excluded. only participants who were initiated on treatment between january 2019 and december 2019 were included in the study. interventions staff that were part of the usual clinic team conducted all interventions in this study. the principal investigator trained staff in preparation for this study. while the integrated access to care and treatment strategy aimed at empowering newly diagnosed plwh with the skills to manage their condition was introduced in tshwane at the time, none of the staff members participating in this study was directly involved in it. staff cadres were similar between the clinics, although case load and responsibilities differed depending on the size of the clinic. all interventions were planned to last 12 months and no tracing strategies were employed for those who missed appointments. ward-based primary health care outreach teams intervention participants from clinics with the wbphcot intervention were visited at home by a chw within a week of treatment initiation. the purpose of the first home visit was to continue with hiv post-test counselling, making use of a patient-centred approach. this session was conducted in a private setting, unless the participant requested members of their family to be present. counselling was performed by a trained chw with relevant counselling experience. this session focused on: medical implications of the diagnosis, including prognosis and treatment; disclosure; psychological issues (coping, support, relationships); and social implications (stigma, employment, discrimination). at the end of the first visit, the chw scheduled a follow-up visit. the second visit focused on treatment adherence support and addressed any arising medical and psychosocial issues. community health workers also performed a pill count; screened for opportunistic infections, such as tuberculosis, and adverse effects of the medication; and assisted participants with disclosure. after the first two visits, depending on the response of the participant, a chw did follow-up visits at least once a month, mostly before the date of the participant’s appointment at the clinic. these visits focused on treatment adherence support; checking for, educating about, and managing adverse effects; screening for opportunistic infections, including tuberculosis; providing nutritional advice, mental health care and other services. games intervention at least one lay counsellor was trained per facility to offer the games intervention. the training was conducted over three days by bridges of hope training in collaboration with the department of family medicine of the university of pretoria. participants enrolled into this intervention arm had their clinic visits scheduled to coincide with the return dates of at least five other participants in the study. a minimum of six participants played the game at any given time and the game lasted approximately 1 hour. the first game (focusing on treatment adherence) was played approximately one month after initiation of art and subsequent sessions were scheduled for at least once every month. each participant was required to play at least the first game to be part of the study. figure 112 provides a brief description of the game. ward-based primary health care outreach teams and games intervention this arm consisted of a combination of the two interventions: wbphcot and games. scheduling occurred in the same way as described previously. control group lay counsellors from clinics allocated to the control group were trained on the recruitment of participants. participants in this group received the usual hiv care offered by primary health care clinics. based on the qualitative evaluation of perceived barriers to offering home-based hiv care by wbphcot members in tshwane,19 which reported that chws’ role was mainly to trace patients who have been lost to follow-up, it was not expected that the control group would be exposed to any of the wbphcot interventions employed in this study. data collection all clinics that were part of this study used tier.net, an electronic version of a paper-based register, with individual patient folders with standardised clinical records captured by data captures. tier.net consists of individual patient folders with standardised clinical records. it is divided into four parts: the first part contains the patient details, such as folder number, name and surname, date of birth and gender. the second section includes data on art, including art start date and tuberculosis treatment started (yes/no). the next section gives details about the outcome: died, transferred, lost to follow-up (ltfu), and retained in care. the last section gives information about the treatment visits, such as pregnancy status, tuberculosis status, vl, and cd4 count; this section is updated every time patients come to collect their medication. tier.net data for all the clinics were received from the district information officer at quarterly intervals. individual patient folders were used to capture monthly visit data to avoid data being overwritten in the outcome section. outcomes the primary outcome of the study was retention in care at 12 months. retention was measured monthly and possible outcomes included: retained in care; ltfu (missed three consecutive clinic visits or confirmed to be untraceable after missing a clinic visit); died; missed a visit; or transferred to another health facility. outcomes in this study are reported exactly as they were on tier.net. participants with retention in care results at 6 months but without a retention outcome at 12 months were recorded under ‘no data’ at 12 months. the retention outcome captured at 12 months was reported as both a binary (retained/ltfu) and categorical (retained/ltfu/died/missed a visit/transferred) variable. we defined retention in care as participants who were retained in facilities where they were initiated. the secondary outcome was virological suppression at 12 months, coded as a binary variable: detectable vl (≥ 50 copies/ml) and undetectable vl (< 50 copies/ml). clinics taking part in this study monitored vl load 6 and 12 months after treatment initiation, in line with the national hiv guidelines.20 our time window for the 12-month vl was between 9 and 15 months. data analysis monthly retention in care data and vl at 12 months were extracted from tier.net and exported to microsoft excel. data cleaning included identifying and removing duplicates and removing irrelevant observations. participant characteristics and retention outcome status were analysed using ibm® spss® statistics for windows, version 26.0 (ibm corp., armonk, new york, united states, 2019).21 results were described according to the mean and standard deviation, frequencies and proportions, as appropriate. age was analysed as both a continuous, binary (dichotomised according to the mean), and categorical (18–24, 25–34, 35–44, 45+) variable. an intention-to-treat analysis was followed. for the outcomes of interest (retention in care and virological suppression), participants who transferred to other facilities, died, or had no outcome at 12 months were excluded from the analysis. the relative risk (rr) was calculated for retention in care and virological suppression at 12 months, and an odds ratio (or) was calculated by means of multivariable regression analysis. participants without vl results at 12 months were excluded from the 12-month vl suppression analysis. all main outcome analyses and planned comparisons defined statistical significance as p < 0.05. ethical considerations the research ethics committee of the faculty of health sciences of the university of pretoria granted ethics approval for the study (reference number: 580/2018). permission to collect data was obtained from tshwane health district and all facilities involved. each participant gave informed consent before participating in the study. patients meeting the eligibility criteria were informed about the study by lay counsellors and gave written informed consent before being enrolled in the study. participation was completely voluntary, no treatment was delayed, and confidentiality was always respected. the tshwane research committee granted the clearance certificate for the study (71/2018) before the study began. results of the 558 participants enrolled in the study, 73 were excluded from the analysis as they started treatment before january 2019 and therefore did not meet the inclusion criteria. an additional 18 participants who did not have retention in care data for at least six months at the end of the study were excluded from the data analysis (figure 2). characteristics of participants four hundred and sixty-seven participants from 26 clinics across tshwane met the inclusion criteria for this study and were included in the analysis: 72 in the wbphcot group, 126 in games, 85 in wbphcot and games, and 184 in the control group (figure 2). of these, 320/467 (68.5%) were female, of whom 64 (20.0%) were pregnant. the wbphcot and games group had the highest proportion of women 62/85 (72.9%) and the games group had the highest proportion of pregnant women 25/85 (29.4%). the wbphcot group had the highest proportion of participants ≥ 35 years old (56.9%), while the games group had the highest proportion of participants < 35 years old (57.1%) (table 1). no pre-initiation vl was available since this test is not conducted in the national hiv treatment programme. table 1: characteristics of participants. outcome at 12 months overall outcome at 12 months, 293 out of the 467 participants (62.7%) remained on treatment in the facility where they were initiated, 18 (3.9%) had no retention data, seven (1.5%) died, 23 (4.9%) had missed a clinic visit, 47 (10.1%) were confirmed ltfu, and 79 (16.9%) had been transferred to another facility (table 2). there were no statistically significant differences between the intervention and control groups in terms of the number of deaths or missed clinic visits. only three participants (2.4%) were confirmed to be ltfu at 12 months in the games group, compared to 28 (15.2%) in the control group (p < 0.001). a higher proportion of participants remained in care in both the games (72.2%, p < 0.001) and the wbphcot and games group (68.2%, p = 0.02), compared to the control group (53.3%). there was, however, no significant difference in retention of participants in the wbphcot group (63.9%, p = 0.12) when compared to the control group. a higher proportion of participants were transferred to other facilities in the control group (21.2%) compared to the wbphcot and games group (10.6%, p = 0.03). table 2: participant outcomes at 12 months. there were no significant differences between men and women in any of the outcomes. however, the proportion of pregnant women who remained in care at 12 months was significantly lower than non-pregnant women: 46.9% versus 68.0% (p < 0.0001). in addition, a higher proportion of pregnant women were transferred to other facilities when compared to non-pregnant women (25.0% vs 14.2%, p = 0.04). the age group 25–35 years had the largest proportion of ltfu (16.4%). in contrast, the age group 45 years and above had the highest proportion of participants who remained in care (81.0%) and were the least likely to be transferred (8.0%). retention in care retention in care outcomes were restricted to binary outcomes, with participants either retained in care or ltfu. at 12 months, 340 participants were either retained in care (86.2%) or ltfu (13.8%) (table 3). the games group had the highest retention in care rate of 96.8% and rr 1.25 (95% ci: 1.13–1.38; p = 0.01) when compared to the control group (77.8%). although proportionally more participants were retained in the other intervention groups, there was not a significant difference in retention rates between the wbphcot and the control group, or the wbphcot and games and the control group. younger participants (< 35 years) were significantly less likely to be retained in care when compared to older (≥ 35 years) participants (81.0% vs 91.3%, rr: 0.88, 95% ci: 0.81–0.97, p = 0.006). table 3: factors associated with retention in care, considered as a binary outcome. monthly ltfu data (figure 3) show that 6.3% in the control group, 2.7% in the wbphcot and games group, and none in the wbphcot group or the games group were ltfu a month after participants were initiated on treatment. at three months, 10.1% of participants in the control group were ltfu, compared to 4.3% in the wbphcot and games group and 3.6% in the wbphcot group. no participants were ltfu in the games group at this point. by 12 months, 22.2% in the control group were ltfu compared with 14.7% in the wbphcot and games group and 11.5% in wbphcot group, and 3.2% in the games group. figure 3: monthly lost to follow-up rate (according to the binary outcome). virological suppression at 12 months, 332 out of the 467 participants (71.1%) had their vl results recorded on tier.net. a similar proportion of participants achieved virological suppression in the three intervention arms when compared to the control arm (table 4). pregnant women had a lower rate of virological suppression than non-pregnant women. table 4: virological suppression. in multivariable logistic regression, only the association between pregnancy and virological failure remained statistically significant, with an or of 2.37 (95% ci: 1.15–4.9; p = 0.019) (table 5). table 5: multivariable analysis of factors associated with virologic failure. discussion in this study, we found that an adherence game intervention significantly improved retention of participants who had been newly initiated on art than while previous studies have evaluated digital games for hiv prevention and care,8,9,22,23 there is little information on the effectiveness of physical games that aim to improve patients’ adherence to treatment. physical games could be of special importance in settings where access and knowledge of digital technology are limited. the overall ltfu rate was 10.1% after 12 months of treatment. when excluding participants who had died, missed visits, were transferred to other facilities, and those without an outcome at 12 months, the ltfu rate was 13.8%. a meta-analysis (2008–2013), published in 2016, reported a 23% ltfu rate at 12 months in 22 studies from south africa.24 this is comparable to the rate in the control group (22.2%), but almost double that of the wbphcot intervention groups and almost seven times more than the games group in our study. in a study of 1041 patients who were receiving home-based hiv care from chws in rwanda, 92.3% were retained in care, compared to 88.5% from our study.25 even though the groups exposed to the wbphcot intervention outperformed the control group, the difference in retention in care was not significantly different. this was contrary to our expectation. the researchers therefore conducted a qualitative evaluation of perceived barriers to offering home-based hiv care among wbphcot members and plwh in a different study population.19 these included: patients giving incorrect addresses; fear of stigma through association with wbphcots, especially those in uniform; little or no preparation of patients for home-based care; and lack of confidentiality and trust. future interventions should take these perceived barriers into account in order to optimise the benefit that might be obtained from utilising wbphcots. we expected the combination of the wbphcot and games intervention to have the best results in terms of retention in care and viral suppression. while this group did indeed have better retention compared to the control group, it was worse than in the games group. furthermore this group had the highest proportion of participants transferred to other facilities. this could have contributed to the lower proportion of participants retained in care in the overall analysis (table 2). it appears that logistical challenges had made it difficult for chws to work with lay counsellors who were offering the games intervention; this could have negatively affected the outcome in this intervention. some participants would have preferred one intervention, instead of both. for example, some participants preferred the games intervention, but refused chw visits to their households. some of these challenges were previously noted in community-based hiv prevention trials in kwazulu-natal, with some participants refusing to take part in some components of the intervention because of perceived stigma.26 this is an important consideration for future intervention studies. at the time of our study, most participants were on tenofovir, emtricitabine, and efavirenz which has higher pretreatment resistance when compared to the current first-line option (tenofovir, lamivudine, and dolutegravir). results of patients on tenofovir, lamivudine and dolutegravir may be different from those of this study.27,28 the overall rate of vl suppression in our study was 75.3% and was similar among the groups. pretreatment drug resistance in south africa is currently at 23.0%, mostly driven by resistance to the non-nucleoside reverse transcriptase inhibitor class.29 since participants in this study would have been initiated on an art regimen including the non-nucleoside reverse transcriptase inhibitor, efavirenz, it can be expected that a large proportion would fail to achieve virological suppression, despite adequate adherence.30 it is interesting that the proportion of participants with virological suppression recorded in our study is lower than the 12-month suppression rates of 90.6% (national) and 92.3% (tshwane district), reported in adult south africans in 2018.31 it is however important to note that this national and district suppression rate is based on the national indicator data set, which defines suppressed vl as < 400 copies/ml, while in our study we used a definition of < 50 copies/ml.31 pregnant women were significantly less likely to achieve a suppressed vl. although not directly comparable, a study of 10 052 pregnant women living with hiv reported a 56.2% vl suppression rate, mostly due to late antenatal care booking.32 the games intervention had the highest proportion of pregnant participants; this could have contributed to the high proportion of participants with an unsuppressed vl in this group. limitations the study is limited by the absence of a randomised design. the quasi-experimental design was necessitated by the inability to ensure training and participant recruitment in all the allocated facilities. the associations identified in this study do, however, meet some requirements of causality, because the intervention preceded the measurement of the outcome. the coronavirus disease 2019 pandemic limited the availability of vl results since the number of clinic visits decreased as per national restrictions. furthermore, it impacted negatively on the implementation of the interventions, as most chws were asked to assist facilities with screening for coronavirus disease 2019 in the community and in health facilities. there were restrictions around gatherings; this affected the arms of the study, especially the games intervention. however, it is important to note that more than 70% of participants were recruited in the first two months of the study and had therefore not been affected by the pandemic. barriers to offering home-based hiv care by chws negatively affected intervention arms with wbphcot members; these barriers were clearly documented in our qualitative study.19 out of 57 randomised clinics, only 26 reached the final stage of data analysis since some clinics failed to attend the required training and some had not recruited any participants by six months. no data were collected on existing adherence support offered in clinics that were part of this study. only the list of participants who participated in the first game (focusing on treatment adherence) was sent to the principal investigator. unfortunately, no additional data are available on the number of games played by each participant. conclusion this quasi-experimental interventional study demonstrated that a physical adherence game improves the retention of plwh newly initiated on art and hence has the potential to improve treatment outcomes. despite the challenges encountered with the wbphcot-containing interventions, they still outperformed the control arm, and the observed improvement might become significant once the potential barriers identified in the study have been addressed. more studies should be performed to assess the optimal way of including wbphcots in home-based hiv care as well as how to combine different interventions in a meaningful way. acknowledgements we would like to thank all participants who were part of the study. we would also like to thank clive nkgadima, lethabo phefadu and ofentse mathibe for helping with logistical arrangements. we also acknowledge the support we received from tshwane health district management, including hast (hiv and aids/sti/tb) and wbphcot leaders. we acknowledge the contribution of wbphcot members including operational team leaders and chws. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions s.n., t.r., and s.o. conceptualised and designed the study. the study procedures and data collection were implemented by s.n. study analyses were completed by s.o., s.n. and t.n., with input from t.r., and s.n. wrote the first manuscript draft. t.r. led review (with inputs from s.o. and t.n.) and substantive contributions to manuscript revisions, which all authors supported. all authors have read and approved the final manuscript. funding information s.n. is supported by the south african medical research council through the bongani mayosi national health scholars programme. data availability supporting data will be made available upon request from the corresponding author, s.n. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references joint un programme on hiv/aids. unaids data 2020. geneva: joint united nations programme on hiv/aids; 2020. lemessurier j, traversy g, varsaneux o, et al. risk of sexual transmission of human immunodeficiency virus with antiretroviral therapy, suppressed viral load and condom use: a systematic review. cmaj. 2018;190(46):e1350–e1360. https://doi.org/10.1503/cmaj.180311 eisinger rw, dieffenbach cw, fauci as. hiv viral load and transmissibility of hiv infection: undetectable equals untransmittable. jama. 2019;321(5):451–452. https://doi.org/10.1001/jama.2018.21167 kaufmann gr, elzi l, weber r, et al. interruptions of cart limits cd4 t-cell recovery and increases the risk for opportunistic complications and death. aids. 2011;25(4):441–451. https://doi.org/10.1097/qad.0b013e3283430013 azia in, mukumbang fc, van wyk b. barriers to adherence to antiretroviral treatment in a regional hospital in vredenburg, western cape, south africa. south afr j hiv med. 2016;17(1):1–8. https://doi.org/10.4102/sajhivmed.v17i1.476 mwai gw, mburu g, torpey k, frost p, ford n, seeley j. role and outcomes of community health workers in hiv care in sub-saharan africa: a systematic review. j int aids soc. 2013;16(1):18586. https://doi.org/10.7448/ias.16.1.18586 berkman nd, sheridan sl, donahue ke, halpern dj, crotty k. low health literacy and health outcomes: an updated systematic review. ann intern med. 2011;155(2):97–107. https://doi.org/10.7326/0003-4819-155-2-201107190-00005 castel ad, qasmieh s, greenberg d, et al. digital gaming to improve adherence among adolescents and young adults living with hiv: mixed-methods study to test feasibility and acceptability. jmir serious games. 2018;6(4):e10213. https://doi.org/10.2196/10213 whiteley l, mena l, craker lk, healy mg, brown lk. creating a theoretically grounded gaming app to increase adherence to pre-exposure prophylaxis: lessons from the development of the viral combat mobile phone game. jmir serious games. 2019;7(1):e11861. https://doi.org/10.2196/11861 howell k. games for health conference 2004: issues, trends, and needs unique to games for health. cyberpsychol behav. 2005;8(2):103–109. https://doi.org/10.1089/cpb.2005.8.103 zhonggen y. a meta-analysis of use of serious games in education over a decade. int j comput games technol. 2019;2019(1):4797032. https://doi.org/10.1155/2019/4797032 labouchere p. experiential learning games and activities to enhance treatment adherence [serial online]. 2019 [cited 2019 feb 1]. viewed from https://boht.org/wp-content/uploads/2019/07/bridges-of-hope-training-products-and-services-summary.pdf dilts r. from coach to awakener. capitola, ca: meta publications; 2003. sanderson pm. verbalizable knowledge and skilled task performance: association, dissociation, and mental models. j exp psychol learn mem cogn. 1989;15(4):729. https://doi.org/10.1037/0278-7393.15.4.729 naidoo n, railton j, jobson g, et al. making ward-based outreach teams an effective component of human immunodeficiency virus programmes in south africa. south afr j hiv med. 2018;19(1):778. https://doi.org/10.4102/sajhivmed.v19i1.778 kharrazi h, lu as, gharghabi f, coleman w. a scoping review of health game research: past, present, and future. games health j. 2012;1(2):153–164. https://doi.org/10.1089/g4h.2012.0011 hayes rj, donnell d, floyd s, et al. effect of universal testing and treatment on hiv incidence – hptn 071 (popart). n engl j med. 2019;381(3):207–218. https://doi.org/10.1056/nejmoa1814556 statistics south africa. mid-year population estimates, 2021. pretoria: statistics south africa; 2021. ngcobo s, rossouw t. ‘they come and knock at the gate until the neighbours see’. perceived barriers and benefits of implementing hiv care at the community level in tshwane district: a qualitative study. plos one. 2020;15(10):e0240740. https://doi.org/10.1371/journal.pone.0240740 national department of health. national consolidated guidelines for the prevention of mother-to-child transmission of hiv (pmtct) and the management of hiv in children, adolescents and adults [homepage on the internet]. c2015 [cited 2022 jan 05]. available from: https://www.knowledgehub.org.za/system/files/elibdownloads/2019-07/national%2520consolidated%2520guidelines%25202015.pdf pallant j. spss survival manual: a step by step guide to data analysis using ibm spss. london: routledge; 2020. hightow-weidman lb, muessig ke, bauermeister ja, legrand s, fiellin le. the future of digital games for hiv prevention and care. curr opin hiv aids. 2017;12(5):501–507. https://doi.org/10.1097/coh.0000000000000399 legrand s, muessig ke, mcnulty t, et al. epic allies: development of a gaming app to improve antiretroviral therapy adherence among young hiv-positive men who have sex with men. jmir serious games. 2016;4(1):e6. https://doi.org/10.2196/games.5687 fox mp, bor j, brennan at, et al. estimating retention in hiv care accounting for patient transfers: a national laboratory cohort study in south africa. plos med. 2018;15(6):e1002589. https://doi.org/10.1371/journal.pmed.1002589 rich ml, miller ac, niyigena p, et al. excellent clinical outcomes and high retention in care among adults in a community-based hiv treatment program in rural rwanda. j acquir immune defic syndr. 2012;59(3):e35–e42. https://doi.org/10.1097/qai.0b013e31824476c4 ramjee g, coumi n, dladla-qwabe n, et al. experiences in conducting multiple community-based hiv prevention trials among women in kwazulu-natal, south africa. aids res ther. 2010;7(1):10. https://doi.org/10.1186/1742-6405-7-10 kanters s, vitoria m, doherty m, et al. comparative efficacy and safety of first-line antiretroviral therapy for the treatment of hiv infection: a systematic review and network meta-analysis. lancet hiv. 2016;3(11):e510–e520. https://doi.org/10.1016/s2352-3018(16)30091-1 world health organization. updated recommendations on first-line and second-line antiretroviral regimens and post-exposure prophylaxis and recommendations on early infant diagnosis of hiv: interim guidelines: supplement to the 2016 consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection. geneva: world health organization; 2018. world health organization. hiv drug resistance report 2019. geneva: world health organization; 2019. bisson gp, rowh a, weinstein r, gaolathe t, frank i, gross r. antiretroviral failure despite high levels of adherence: discordant adherence–response relationship in botswana. j acquir immune defic syndr. 2008;49(1):107. https://doi.org/10.1097/qai.0b013e3181820141 massyn n, barron p, day c, ndlovu n, padarath a. district health barometer, 2018/19. durban: health systems trust; 2020. woldesenbet sa, kufa t, barron p, et al. viral suppression and factors associated with failure to achieve viral suppression among pregnant women in south africa. aids. 2020;34(4):589–597. https://doi.org/10.1097/qad.0000000000002457 d e c e m b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e prevention of mother-to-child transmission of hiv (pmtct) is the single most effective medical intervention to significantly reduce the burden of hiv in communities, and its optimal implementation is essential to meet both the hiv reduction targets in the national strategic plan (nsp)1 and to achieve millennium development goals (mdgs) 4 (reducing infant and child mortality) and 5 (reducing maternal mortality).2 in 1994 the landmark paediatric aids clinical trial group (pactg) 076 study found a 67% reduction in hiv transmission when pregnant women were given zidovudine (azt) from the second trimester onwards and when infants received azt for the first 6 weeks of life.3 by demonstrating that vertical transmission was preventable, these data represented the most dramatic results in hiv research at the time. global inequities were also highlighted, as the pact 076 pmtct interventions were not feasible in resource-limited settings. pactg 076 was quickly followed by studies from thailand4 and africa (petra)5 demonstrating that shorter courses of therapy were also highly effective, but these were still not feasible for large-scale implementation in most resource-limited settings. however, thailand did implement the short-course therapy in 1999 as part of its national pmtct policy. in 1999 the ugandan hivnet 012 study, conducted in a breastfeeding population, found that just a single dose of nevirapine (nvp) to the mother and a single dose to the child could reduce hiv transmission to 13%,6 making pmtct now accessible in resource-limited settings. countries all over the world quickly implemented the pactg and hivnet 012 pmtct regimens; in the usa, for example, transmission rates dropped sharply once guidelines for the use of azt were adopted. over a period of 6 years transmission rates in the usa dropped sharply and remain below 2% today largely as a result of haart (highly active antiretroviral therapy) to mothers.7 over the decade after pactg 076, evidence of the superiority of haart or multidrug therapy to prevent motherto-child transmission (mtct) accumulated. in 2004, the thailand phpt-2 study found that the use of azt combined with nvp (‘dual therapy’) could reduce hiv transmission to 1.9%,8 forming the basis of the current south african pmtct policy. since 1999 and the initial drug trials much work has been done to minimise, and possibly eliminate, vertical transmission of hiv. the world health organization (who) developed a comprehensive strategic fourpronged approach, based on providing a continuum of appropriate care for mothers and their infants, to prevent hiv infection in infants and young children and optimise maternal and child health. the four-prong strategy includes: (i) primary prevention of hiv infection; (ii) prevention of unintended pregnancies among hiv-infected women; (iii) prevention of hiv transmiscall to action: prevention of mother-to-child transmission of hiv o p i n i o n ashraf hassen coovadia, fcppaed (sa), dch (sa), dip hiv man (sa) department of paediatrics and child health, rahima moosa mother and child hospital and university of the witwatersrand, johannesburg ameena ebrahim goga, fcppaed (sa), msc, mch, msc (epidemiol) health systems research unit, medical research council, and department of paediatrics and child health, university of limpopo, medunsa campus, ga-rankuwa, pretoria laurie schowalter, mph policy and implementation, south african hiv clinicians society the prevention of mother-to-child transmission of hiv (pmtct) programme is a critical intervention to reduce the incidence of paediatric hiv infections. it is also a key intervention to decrease infant, child and maternal mortality. the optimal implementation of a sound, evidence-based pmtct programme is essential to meet both the hiv reduction targets in the national strategic plan and to achieve millennium development goals (mdgs) 4 (reducing infant and child mortality) and 5 (reducing maternal mortality). since 2001, south africa has been implementing a programme to prevent mother-to-child transmission (mtct) of hiv. since 2007, national pmtct policy has evolved into a strong, enabling framework that should reduce vertical transmission significantly. this paper reviews the milestone studies that have contributed to our knowledge about drug regimens to reduce mtct, and reviews the latest south african pmtct guidelines and the possible future changes. strengthened/revised drug regimens for pmtct are essential but insufficient for measureable decreases in hiv transmission and improvements in maternal and child health. the main challenge is implementation. until the enhanced pmtct policy is effectively operationalised, measurable achievements will remain elusive. 12 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e d e c e m b e r 2 0 0 9 sion from mother to child; and (iv) provision of care and support for hiv-infected mothers and their infants, partners and families.9 this comprehensive strategy states that because primary hiv infection during pregnancy and breastfeeding poses an increased threat of mtct, hiv prevention efforts should address the needs of pregnant and lactating women, especially in highprevalence areas. the third prong (pmtct) comprises five interventions, namely: (i) increasing access to hiv testing and counselling; (ii) provision of antiretroviral (arv) therapy, the choice depending on local feasibility, efficacy and cost; (iii) implementation of safe delivery practices, including avoiding invasive obstetric procedures such as artificial rupture of membranes, fetal scalp monitoring and episiotomy; and (iv) providing optimal counselling and support on infant-feeding methods and provision of care and support, through all health programmes, for hiv-infected mothers, their infants, partners and families. this paper focuses mainly on the third prong, but acknowledges the importance of the other strategies. in south africa, the use of a single dose of nvp (at the onset of labour for mother, and within 72 hours for the baby) to prevent mtct of hiv was implemented in 2001. although the policy was in place, significant implementation obstacles remained. at the inception of the programme there was insufficient guidance on how to implement pmtct, resulting in inconsistent programme implementation across the country, and in pmtct being mainly a vertical programme that was implemented independently of maternal, neonatal and child health services. the science also continued to advance. as the evidence continued to mount on the superiority of multidrug therapy, academics, clinicians and civil society in south africa mobilised and advocated for the urgent adoption of an updated pmtct policy incorporating dual therapy, particularly in the wake of updated who pmtct guidelines in 2006.9 in early 2008 the national department of health (ndoh) updated the pmtct guidelines.10 changes included: (i) a slight change in the testing strategy, calling this a routine offer of voluntary counselling and testing; (ii) the addition of azt from 28 weeks of gestation and a renewed emphasis on getting cd4 counts on all pregnant women to determine the need for initiation of highly active antiretroviral therapy (haart) in pregnancy (cd4 cell count <200 cells/µl or who clinical stage 4); and (iii) improved guidance on infant feeding options and a greater emphasis on ensuring infant diagnosis at 6 weeks of life. these guidelines are undergoing further review at the time of writing, with recommendations from the pmtct guidelines committee to lower the threshold for the initiation of haart in pregnancy, starting with a cd4 count of 350 cells/ µl or less. this significant change, coupled with the new proposed paediatric guidelines (ndoh 2009) calling for the early treatment of all hiv-infected infants regardless of cd4 count, creates the necessary policy framework to set south africa on a path to achieving both mdgs 4 and 5 and the hiv reduction targets set in the nsp 2007 2011. while a sound pmtct policy is a significant step in the right direction, in itself this is insufficient for programme success. data show that implementation of the national pmtct programme has been fraught with challenges since its inception:11 among other issues, these relate to lack of health system capacity to absorb the programme into routine care, lack of health worker knowledge about pmtct, confusing messages about pmtct and infant feeding, and pmtct messages that do not fit into current socio-cultural frames of reference. consequently all of the available evidence on hiv seroprevalence and maternal and child mortality indicate that south africa is well behind in meeting its nsp and mdg targets, and is therefore unlikely to achieve these without a major improvement in the performance of its hiv programmes. data from several pmtct-related studies show that early vertical transmission rates vary from 7% to 19%,12-14 that 9-month hiv-free survival might range between 64% and 80%,15 and that guidelines on infant feeding and especially breastfeeding cessation were not feasible and not adhered to,16 despite the implementation of pmtct interventions. national data on the effectiveness and impact of the pmtct programme are still unavailable. in the first half of 2009, approximately 40% of hiv-exposed infants accessed an hiv polymerase chain reaction (pcr) test before 3 months of age nationally compared with approximately 32% over the same time period in 2008 (unpublished data). while it is encouraging that the average prevalence of positivity among those tested declined from 10% in 2008 to 7% in 2009, there is no measure of the rate of paediatric hiv infection in the more than half of hivexposed infants in the country whose mothers are less likely to be accessing pmtct services. furthermore, data from the just-released 2008 national antenatal sentinel hiv and syphilis prevalence survey found that hiv infection among antenatal clinic attendees is at an unacceptably high level of 29.3%.17 this figure is a national aggregate, with a range of seroprevalences across provinces and even more vari13 the development of south african policy on pmtct, and experiences thereof current state of the national pmtct programme d e c e m b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 14 ation across the 52 districts. the distribution of hiv prevalence by district in 2008 ranged from 2.2% in the district of namakwa (northern cape) to 45.7% in umgungundlovu (kwazulu-natal), the highest recorded in the country. an investigation into these differences as well as the coverage and quality of pmtct services across all districts would be instructive in designing implementation strategies. the district health barometer (dhb), an annual assessment of performance on key health indicators in the public health sector conducted by the health systems trust, corroborated evidence of suboptimal pmtct programme implementation based on the district health information system (dhis).18 the dhb has published data since 2005, so improvements over time can be measured. the 2007/2008 report found that the national antenatal hiv testing average increased from 69% in 2006 to 80% in 2007/2008. while this indicates an improvement in testing rates, the numbers are well short of the nsp 2009 target of 90%. the report also found huge variations in the uptake of nvp by pregnant women, ranging from 12% to 108%, with a national average of 76% – an increase on the 61% from the year before. while there are significant weaknesses with this data set, the trend and overall data set across all districts provide useful insights into the level of coverage and quality of the programme nationally. a review of three south african mortality audit reports (saving mothers – 2004, saving babies and saving children) called the ‘every death counts’ report found south africa in the unenviable position of being a country where maternal and child mortality has increased since the baseline for the mdgs in 1990.19 in that report, citing the saving mothers report of 2004, the largest cause of maternal mortality was reported to be non-pregnancy related, with infections such as hiv, tuberculosis and pneumonia accounting for the deaths of approximately 38% of the women.19 similarly, hiv/ aids accounted for 35% of premature deaths among neonates and children.19 the latest saving mothers report (2005 2007) sadly shows the same trend as earlier, with about 44% of maternal deaths caused by non-pregnancy-related infections (mostly aids).20 the time to consider a paradigm shift from narrowly thinking of pmtct as simply an intervention of reducing vertical transmission of hiv to seeing this programme as key for the survival of women, children and indeed families is long overdue. the available data indicate that a sound pmtct policy is insufficient to assure hiv transmission rates of less than 5%. south africa now faces a more mundane struggle in the battle against hiv: the battle of implementation. there are numerous and varied implementation challenges faced by the programme at several levels. the interruption of essential drugs, scarce human resources at sites, hiv stigma and discrimination, and lack of clear operational guidelines at provincial and local levels remain serious hurdles to achieving smooth implementation of the programme and optimisation of maternal and child health outcomes. a culture of accountability for optimisation of the programme and attainment of targets is required at all levels of health care providers as well as by health care managers from facility level up to the ndoh. under the current system, there are few incentives for health care personnel to ensure that the pmtct programme is performing optimally. for instance, no health manager’s annual performance appraisal takes pmtct performance targets into account, and health care facilities are not routinely audited on pmtct outcomes with a view to assigning responsibility for improved performance. in order to strengthen the focus of health care facilities and ensure management support and rigorous stewardship, the ndoh should not only request accurate reports on pmtct indicators (e.g. percentage of mothers tested for hiv) on a regular basis, but also include the site’s pmtct programme performance in every relevant manager’s portfolio of performance assessment. programme data collected at a site are rarely used for ongoing feedback to staff on their own performance, or as a tool for quality improvement. health care facilities and provincial and district departments of health must make use of data to monitor pmtct performance and assist all sites in meeting national goals. health care facilities must also re-invigorate their hiv counselling and testing programme to ensure that all women entering antenatal clinics are offered an hiv test and all infants attending well-baby/immunisation clinics are assessed for hiv exposure. there is a move within the ndoh towards provider-initiated counselling and testing, placing a greater emphasis on health care providers to ensure they discharge their duty to present hiv testing as a routine procedure with lifesaving benefits. given that approximately 3% of women who initially test negative will seroconvert during pregnancy,22 systems must also be in place to retest hiv-negative women at around 34 weeks of gestation and in the immediate postnatal period before mother and baby are discharged. health care workers bear a responsibility to both mothers and children to ensure that no woman leaves a health care facility unaware of her hiv status. failure to do so would be tantamount to negligence, given the availability of life-saving and challenges and opportunities t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e d e c e m b e r 2 0 0 9 life-prolonging therapy, not to mention the option of preventing a paediatric hiv infection. retesting should also be strongly encouraged at later points in the postnatal period when the mother is seen as part of her follow-up care. pmtct targets can only be achieved by deliberately addressing the challenges and weaknesses in the system. all health care personnel in the facility must be educated on the importance of pmtct and of the integral role the programme plays in infant, child and maternal survival. a designated team with an identified leader must take responsibility for pmtct programme performance. until there is a renewed emphasis on responsibility for the pmtct programme within each health care facility, a lack of programme ownership will continue to prevail. while the challenges may seem vast, there are a number of outstanding solutions that have been applied to overcome key bottlenecks and challenges in pmtct implementation in south africa from which much can be learned. the ndoh, medical research council, university of the western cape and unicef jointly developed a ‘possible solutions’ document that highlighted these.21 the document highlights districts or facilities that have applied a comprehensive or selective approach to overcoming key bottlenecks in pmtct. of note is the success that facilities have experienced when they integrate pmtct care into routine care, e.g. when the birth register was adapted to include pmtct information, when community-based activities to increase the demand for pmtct services were implemented, or when data were used at a local level to monitor and improve pmtct-related care. this ‘possible solutions’ document highlights that progress can be achieved when health care facilities apply ingenuity, creativity and commitment to improving pmtct programmes. pmtct has been implemented in south africa since 2001, first in 18 pilot sites and now nationally in more than 3 000 facilities. despite the limited documented impact of the programme (and there is a dearth of data in this regard), pmtct has now received support for renewed action at the highest political level. the current minister of health (hon. aaron motsoaledi) has been frank in his admission that ‘south africa is losing the battle against hiv and that maternal deaths are at unacceptably high levels’. his administration has renewed its commitment to the programme and has announced an accelerated pmtct programme aimed at improving its coverage and quality. the ndoh is currently revising the pmtct policy, which it is hoped will initiate haart in all pregnant women with a cd4 count <350 cells/µl and in all hiv-infected infants less than 12 months old. these policy changes will help set south africa on a path towards achieving hiv reduction targets and improved child and maternal health. the government is demonstrating leadership and political will. as health care workers we must recommit to the pmtct programme, bring a shared sense of responsibility and accountability for improving maternal, newborn and infant health, and move beyond policies so that they become sustained action at all levels of the health care system. it is only when this occurs that we will meet the targets set in the nsp and meet the 4th and 5th mdgs. references 1. national department of health. hiv and aids and sti strategic plan for south africa 2007-2011. pretoria: national department of health, 2007. 2. united nations. the millennium development goals report 2008. new york: united nations department of economic and social affairs (desa), 2008. 3. connor em, sperling rs, gelber r, et al. reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. paediatric aids clinical trials group protocol 076 study group. n engl j med 1994; 331: 1173-1180. 4. lallemant m, jourdain g, le coeur s, et al. a trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. n engl 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transmission of hiv-1 in thailand. n engl j med 2004; 351(3): 217-228. 9. world health organization. antiretroviral drugs for treating pregnant women and preventing hiv infection in infants in resource-limited settings: towards universal access. recommendations for a public health approach. geneva: who, 2006. 10. national department of health. policy and guidelines for the implementation of the pmtct programme. pretoria: national department of health, 2008. 11. doherty t, besser m, donohue s, et al. an evaluation of the prevention of mother to child transmission (pmtct) of hiv initiative in south africa: outcomes and key recommendations. durban: health systems trust, 2003. 12. colvin m, chopra m, doherty t, et al., for the good start study team. operational effectiveness of single dose nevirapine in the south african programme to prevent mother-to-child transmission of hiv. bull world health organ 2007; 85: 466-473. 13. coetzee d, hilderbrand k, boulle a, et al. effectiveness of the first district-wide programme for the prevention of mother-to-child transmission of hiv in south africa. bull world health organ 2006; 83: 489-494. 14. rollins n, little k, mzoloa s, horwood c, newell ml. surveillance of mother-tochild transmission prevention programmes at immunization clinics: the case for universal screening. aids 2007; 21: 1341-1347. 15. jackson d, chopra m, doherty t, et al., for the good start study team. operational effectiveness and 36 week hiv-free survival in the south african programme to prevent mother-to-child transmission of hiv-1. aids 2007; 21: 509-516. 16. goga a, van wyk eb, doherty t, et al., for the good start study team. operational effectiveness of guidelines on complete breast-feeding cessation to reduce mother-to-child transmission of hiv: results from a prospective observational cohort study at routine prevention of mother-to-child transmission sites, south africa. j acquir immune defic syndr 2009; 50: 521-528. 17. national department of health. 2008 national antenatal sentinel hiv and syphilis report, south africa. pretoria: national department of health, 2009. 18. day c, barron p, monticelli f, sello e, eds. the district health barometer 2007/2008. durban: health systems trust, 2009. 19. south africa every death counts writing group. every death counts: use of mortality audit data for decision making to save the lives of mothers, babies, and children in south africa. lancet 2008; 371: 1294-1304. 20. national committee on confidential enquiries into maternal deaths in the office of the minister of health. saving mothers 2005-2007: fourth report on confidential enquiries into maternal deaths in south africa, expanded executive summary. pretoria: department of health, 2009. 21. goga ae, woldesenbet s, solomon w, rohde s (medical research council), jackson d (university of the western cape), national department of health, unicef. solutions to operational challenges in pmtct implementation in south africa: selected experiences and case studies. pretoria: national department of health, october 2009. 22. moodley d, esterhuizen tm, pather t, chetty v, ngaleka l. high hiv incidence during pregnancy: compelling reason for repeat hiv testing. aids 2009; 23(10): 1255-1259. 15 conclusion guideline cover final cover.indd june 2012, vol. 13, no. 2 sajhivmed 87 r ev iew ‘blood transfusion is like marriage: it should not be entered upon lightly, unadvisedly or wantonly, or more often than is absolutely necessary.’1 blood services have been at the forefront of raising awareness of the hiv pandemic. the emergence and recognition of hiv as a transfusion transmissible infection (tti) in the early 1980s had a profound impact on blood services worldwide. there has been concerted international effort, expending considerable resources, to prevent transmission of ttis through blood products and to provide safe blood products for transfusion. one means of reducing the risk of ttis and properly managing haematological symptoms, especially in immunocompromised individuals, is appropriate clinical use of blood. this is contingent upon an appreciation of the risks of unnecessary transfusion. clinicians should consider nontransfusion options such as haematinics in the management of anaemia. the decision to transfuse should be based on an individual patient’s co-morbid and clinical status, rather than on laboratory indices only. specific and careful consideration of each patient is therefore required when hiv-related anaemia or associated conditions raise the possibility of transfusion. there have been numerous requests from members of the southern african hiv clinicians society for guidance and direction on blood transfusion in hiv-infected patients. while the role of blood transfusion in the management of haematological conditions such as anaemia and thrombocytopaenia does not differ substantially between hivnegative and hiv-positive patients, it is the authors’ experience that there is a general need to promote rational transfusion practice. the objective of this review is not to provide a novel approach to the management of haematological conditions; rather, it is intended to provide a practical and succinct review on the rational use of blood transfusion in the management of haematological abnormalities, focusing on conditions either unique to, or more frequently encountered in, hiv-infected patients. this review should be read in conjunction with published national and international clinical guidelines. (for a review of the ethical and legal considerations of transfusion and hiv, with a specific focus on south africa, please refer to appendix 1.) cytopaenias in hiv clinically significant cytopaenias (anaemia, thrombocytopaenia, neutropaenia) are common in persons with hiv.2 many factors may contribute to the development of cytopaenias in hiv, including the virus itself that can infect progenitor cells directly, cytokine effects, reticulin fibrosis, altered immune function with auto-antibody production, micro-nutrient deficiency (folate, vitamin b 12 , iron), co-infection with other agents both opportunistic (e.g. tb, mycobacterium avium complex (mac), cytomegalovirus (cmv), ebstein-barr virus) and conventional (e.g. bacteria, parvovirus), bone marrow infiltration by malignancy, and anaemia of chronic disease. numerous drugs used in the management of hiv – including anti-retroviral therapy (art) (e.g. azt) and prophylactic therapies (e.g. co-trimoxazole) both may cause and exacerbate cytopaenias in hiv. in addition, bone marrow suppression in hiv occurs due to the effect of cytokines as well as reduced erythropoietin production and function.3-5 the decision to transfuse a patient is a clinical decision that needs to be individualised, informed by the patient’s clinical status, the laboratory findings where available, and available resources. this decision may incorporate the patient’s socio-economic circumstances: a patient with borderline despite numerous publications on the appropriate use of blood and blood products, few specifically consider the role of transfusion in the management of hiv. this review is a synthesis of conditions encountered in the management of hiv-infected patients where the transfusion of blood or blood products may be indicated. a consistent message emerging from the review is that the principles of transfusion medicine do not differ between hiv-negative and -positive patients. the aim of the review is to provide clinicians with a practical and succinct overview of the haematological abnormalities and clinical circumstances most commonly encountered in the hiv setting, while focusing on the rational and appropriate use of blood and blood products for hiv patients. important ethical considerations in dealing with both the collection and transfusion blood and blood products in the hiv era have also been addressed. s afr j hiv med 2012;13(2):87-103. review a review of the use of blood and blood products in hiv-infected patients karin van den berg (chairperson), james van hasselt, evan bloch, robert crookes, james kelley, jonathan berger, charlotte ingram, anel dippenaar, rajendra thejpal, neil littleton, tersia elliz, gary reubenson, mark cotton, jennifer c hull, pamela moodley, yasmin goga, william eldridge, moosa patel, eric hefer, arthur bird dr vis poovalingam, who had a critical role in motivating for this review, is acknowledged for her valuable contribution. corresponding author: k van den berg (karin.vandenberg@sanbs.org.za) r ev iew 88 sajhivmed june 2012, vol. 13, no. 2 r ev ie w decompensated anaemia, living in a remote area with poor access to follow-up care, might warrant transfusion; whilst the same patient might otherwise be managed conservatively in an urban setting with access to care.6 in general, indications for transfusion in hiv-positive patients are the same as for hiv-negative patients. hiv-positive patients may, however, have compromised bone marrow function and require additional haematological support until such time that art results in improved bone marrow function. bone marrow involvement bone marrow infiltration can result in anaemia through destruction of the haematopoietic environment. infiltration is reflected by pancytopaenia and a reticulocyte production index (rpi) <1% and sometimes by a leucoerythroblastic reaction where immature red and white blood cells are visible on the peripheral blood smear. ideally, evidence of a leucoerythroblastic reaction requires consideration of a bone marrow biopsy and specialist input. common infiltrative processes in the setting of hiv include granulomatous infection (e.g. mycobacterial and fungal), lymphoproliferative disorders and fibrosis. management will be determined by the underlying cause, with transfusion limited to patients who are symptomatic. dysplastic changes in the bone marrow are common, and may occur at any stage of hiv infection. where available, bone marrow biopsy may be informative in investigating various diagnoses e.g. neoplasia (lymphoproliferative or myeloproliferative disorder) and opportunistic infections such as tb. special stains and cultures for fungi, viruses and mycobacteria may help to resolve the cause of unexplained fever or source of infection.7 although the same indications for bone marrow biopsy apply independently of hiv status, certain indications (e.g. pancytopaenia, pyrexia of unknown origin (puo), and lymphadenopathy) feature more prominently in patients with hiv. similarly, certain diagnoses are more prevalent in the hiv population (e.g. immune thrombocytopaenia, disseminated mycobacterial infection, disseminated fungal infection). a bone marrow biopsy is an invasive procedure; it may be painful and is not without risk. the latter includes infection, bleeding and haematoma. it should not be a first step in investigation and, regarding haematological disorders, should ideally be accompanied, where available, by additional testing i.e. bone marrow aspiration, cytogenetics and immunophenotyping (e.g. flow cytometry) to provide maximal diagnostic yield. availability of this testing is often confined to tertiary academic and private referral laboratories. bone marrow investigations may be helpful in the following situations: • bone marrow failure (pancytopaenia and reticulocyte production index (rpi) <1%) • cytopaenias unresponsive to treatment • investigation of opportunistic infection • pyrexia of unknown origin (puo) after initial investigations fail to identify the cause • exclusion/staging of malignancy • diagnosis of specific pathology, such as pure red cell aplasia • atypical and/or abnormal blood cells noted in the peripheral blood smear. specimen adequacy is important for identifying a focal process (e.g. granuloma, metastatic carcinoma or lymphoid infiltrate). both the focal nature of the pathology and increased marrow fibrosis (a component of granuloma formation) increases the risk of a non-diagnostic specimen. anaemia anaemia is not a diagnosis, and management should focus on investigation and treatment of the underlying cause, independent of hiv status. anaemia refers to a reduced red cell mass as reflected by a decreased haematocrit or haemoglobin level. it is a clinical sign that reflects an underlying disease process that requires appropriate investigation and management that is specific to the underlying process. anaemia is common to a diverse array of pathologies with similarly broad therapeutic options. consequently, generic treatment (e.g. blood transfusion or haematinics) without knowledge of the specific cause is considered bad practice. as an example, iron-deficiency anaemia can be due to dietary deficiency (a simple problem of insufficient intake). however, it can also be due to chronic blood loss (e.g. menorrhagia, helminth infestation, visceral malignancy). simply treating with iron supplements without a root-cause analysis ignores the differential diagnosis and may delay time-sensitive treatment of the actual cause (e.g. colonic carcinoma). table 1. anaemia and hiv-infection decreased production increased loss and/or destruction deficiencies erythropoietin iron folate vitamin b 12 drugs zidovudine co-trimoxazole anti-mycobacterial therapy amphotericin b ganciclovir dapsone chemotherapy infections hiv cytomegalovirus (cmv) epstein-barr virus (ebv) parvovirus b19 mycobacterium tuberculosis (mtb) mycobacterium avium complex (mac) histoplasma capsulatum neoplasia hodgkin’s disease non-hodgkin’s lymphoma kaposi’s sarcoma miscellaneous anaemia of chronic disease pure red cell aplasia (prca) hypoplastic/aplastic anaemia haemophagocytic syndrome secondary myelodysplastic syndrome haemolysis autoimmune haemolytic anaemia thrombotic thrombocytopaenic purpura (ttp) disseminated intravascular coagulation (dic) infections: malaria pre-existing conditions glucose-6-phosphate dehydrogenase deficiency sickle cell disease thalassaemia gastrointestinal bleeding infections (cmv, candida, parasites) kaposi’s sarcoma git lymphoma hypersplenism infection haemophagocytosis lymphoma idiopathic june 2012, vol. 13, no. 2 sajhivmed 89 r ev iew anaemia may occur at any stage of hiv infection, and 63 95% of infected persons will develop anaemia during the course of their illness; furthermore, the incidence of anaemia increases with disease progression.2 the presence of anaemia is an independent, yet reversible, predictor of mortality.6,8,9 table 1 lists some of the causes of anaemia in hiv; it is by no means complete. the main aetiologies for hiv-related anaemia are dyserythropoiesis (anaemia of chronic disease), infections and drugs.2-5 in addition, anaemia may be compounded by co-morbid haematinic deficiency (iron, folate and vitamin b 12 ), suggesting a need for early replacement in the management of anaemia in hiv. zidovudine (azt), especially when used as a single agent, is the drug historically most frequently implicated in hiv-related anaemia; a dose-dependent macrocytic anaemia is characteristic.10 with lower doses, and in combination therapy, the haematological adverse events occur less frequently. anaemia at baseline should not preclude the use of zidovudine in patients initiating art in resource-limited settings.11 the following revised haemoglobin (hb) and haematocrit (hct) levels are based on recommendations published by lawrie et al.12 in 2009, in which the normal ranges for hb were found to be: 13.4 17.5 g/dl in males and 11.6 16.4 g/dl in females. lower values may be accepted as normal in selected settings (e.g. evaluation during pregnancy or at sea level). there is significant variability in the definition of anaemia in relation to hb level. although anaemia may be strictly defined as a hb level <13.4 g/dl for males and <11.6 g/dl in females, investigating all patients with hb levels that approximate these values are both impractical and of questionable value in resource limited settings. a baseline full blood count (fbc) with a differential count should be performed on all newly diagnosed hiv-positive patients. clinicians are advised to monitor the patient’s hb level regularly in accordance with local guidelines. all patients with anaemia should be investigated for the underlying cause(s) and treated appropriately. while reduced red blood cell (rbc) production frequently underlies hiv-related anaemia, it is important to exclude other causes e.g. haemolysis or blood loss. the reticulocyte count and corrected reticulocyte production index (rpi) will guide one with regard to the underlying aetiology (e.g. decreased production or increased destruction). this discrimination is important as management differs accordingly. the reticulocyte count is a useful index of bone marrow function, and should increase in response to any blood loss (e.g. haemorrhage or haemolysis). failure to increase appropriately may reflect a primary production problem that can affect multiple cell lines (e.g. aplastic anaemia) or be specific to one cell line (e.g. parvovirus b19-related pure red cell aplasia (prca)). the reticulocyte count is normally 0.6 1.83%,13 but different textbooks and laboratories use different reference ranges. with anaemia, the corrected reticulocyte count (cc) is adjusted for the lower hct. a reticulocyte production index of 1 2% indicates an appropriate marrow production; 3% or more indicates haemolysis; and levels <1% suggest reduced production. mean corpuscular volume (mcv) changes with age. from age 1 to 8 years, the lower limit of the mcv can be roughly calculated using the formula: age in years + 70 fl. in adults, mcv is typically 80 100 fl. an mcv less than this range suggests microcytosis, while greater levels suggest macrocytosis. fig. 1 provides a practical investigative approach to the causes of anaemia in the hiv positive patient. iron deficiency is the most common cause of microcytic anaemia. iron deficiency is not a definitive diagnosis; rather, it reflects an underlying pathology that must be identified and treated appropriately and specifically. the mechanisms for iron deficiency include reduced intake (e.g. nutritional deficiency and inflammatory bowel disease) as well as increased loss (either acute haemorrhage or chronic, e.g. menorrhagia, helminthic infestation, gastrointestinal bleeding). iron deficiency requires iron supplementation administered orally or parenterally. the latter may incur risk of, among others, anaphylaxis, and should only be reserved for severe cases of iron deficiency where oral supplementation is not tolerated (e.g. inflammatory bowel disorders, malabsorption). patients should respond to iron replacement therapy within 2 months if the underlying cause has been addressed. failure to respond within this period should prompt review of initial diagnosis with attention to patient adherence. adherence is a recognised problem of iron supplementation, given gastrointestinal side effects. excessive iron therapy can be deleterious and should not be given as a routine supplement in the absence of a clinical indication.14 in proven iron deficiency, one should – especially in children – consider administration of an anti-helminthic agent, in conjunction with iron therapy, in view of the high prevalence of co-morbid helminthic infestation in low-resource settings. helminthic infestation (e.g. hookworm) is known both to cause and exacerbate underlying iron deficiency. transfusion should not be a first line of intervention in iron deficiency; oral iron is generally effective in managing stable patients. transfusion is reserved for patients with decompensated anaemia (e.g. patients with signs of hypoxia, angina, cerebrovascular compromise, heart failure). transfusion with red cell concentrate (‘packed cells’) can ameliorate symptoms in these patients. each unit of packed red cells contains (replaces) approximately 250 mg of iron. macrocytic anaemia is often attributed to deficiencies in vitamin b 12 (cobalamin) and/or folate. in stable patients with proven vitamin b 12 deficiency (pernicious anaemia), the patient should be treated with injectable vitamin b 12 for at least 3 days before starting folate therapy. this is essential to avoid permanent neurological complications. in all other cases, start supplementation with folate and vitamin b 12 . the response to vitamin b 12 occurs within 48 to 72 hours. serum potassium levels can fall during initial therapy for severe vitamin b 12 or folate deficiencies owing to increased utilisation of potassium by new haematopoietic cells; potassium levels should be monitored during therapy, with potassium supplementation where indicated.15,16 blood transfusion should be avoided as patients with macrocytic anaemia generally tolerate extremely low haemoglobin levels very well. transfusion can lead to circulatory overload especially in critically ill patients who require stringent maintenance of fluid volume status. in severely symptomatic anaemic patients, a maximum of 1 2 units of red cell concentrate may be administering slowly (over 4 hours per unit), followed by intravenous furosemide (20 40 mg), or be given in an isovolemic manner (i.e. removing 250 ml of the patient’s whole blood, which has a low haematocrit, and replacing with 250 ml of packed rbcs, which has a high haematocrit). anaemia of chronic disease (acd) is common in hiv; the mechanism is complex and is caused, in part, by the release of cytokines, resulting in iron blockade and dyserythropoiesis. in acd, haemoglobin 90 sajhivmed june 2012, vol. 13, no. 2 r ev ie w levels seldom drop below 7 g/dl. additional causes should be considered if haemoglobin levels fall below 7 g/dl. acd does not respond to haematinics and requires treatment of the underlying condition (e.g. art in the setting of hiv). where treatment is not possible and the patient remains symptomatic, judicious use of erythropoietin can be considered.17,18 autoimmune haemolytic anaemia is more common in hiv-infected patients than in hivnegative patients. the direct anti-globulin test (dat) (coombs test) is positive in up to 20 40% of hiv-positive patients;19 few patients, however, demonstrate signs of haemolysis.20 the presence of a high reticulocyte count, unconjugated hyperbilirubinaemia, elevated ldh, spherocytes on the peripheral smear, and falling haemoglobin, suggests haemolysis and should prompt further investigation. primary management of aiha is similar to that of the hiv-negative patient (i.e. treatment of the underlying cause (e.g. art), corticosteroids, ivig, and immunosuppressive therapy).21 these therapies generally require specialist reticulocyte production indexreticulocyte production index < 1< 1 >1>1 mcv lowmcv low acute blood loss autoimmune haemolytic anaemia § haemolysis with functional bone marrow e.g. malaria, g6pd deficiency disseminated intravascular coagulopathy thrombotic thrombocytopenic purpura post-treatment response to iron, folate, or b12 replacement hypersplenismhypersplenism acute blood loss autoimmune haemolytic anaemia § haemolysis with functional bone marrow e.g. malaria, g6pd deficiency disseminated intravascular coagulopathy thrombotic thrombocytopenic purpura post-treatment response to iron, folate, or b12 replacement hypersplenism iron deficiency † anaemia of chronic disease ‡ chronic blood loss thalassaemia iron deficiency † anaemia of chronic disease ‡ chronic blood loss thalassaemia mcv highmcv highmcv normalmcv normal hiv dyserythropoeisis vit b12 and/or folate deficiency, e.g. chemotherapy, pcp prophylaxis (co-trimoxazole) hypothyroidism alcohol abuse liver disease myelodysplasia thalassaemia hiv dyserythropoeisis vit b12 and/or folate deficiency, e.g. chemotherapy, pcp prophylaxis (co-trimoxazole) hypothyroidism alcohol abuse liver disease myelodysplasia thalassaemia anaemia of chronic disease ‡ antiretroviral drugs bone marrow failure e.g. bone marrow tumours and infections prca hypo/aplastic anaemia anaemia of chronic disease ‡ antiretroviral drugs bone marrow failure e.g. bone marrow tumours and infections prca hypo/aplastic anaemia hb < 12.4 (males)* hb < 10.6 (females)* hb < 12.4 (males)* hb < 10.6 (females)* check check b12 folate, ferritin check check b12 folate, ferritin * investigating all hiv+ patients with hb levels below the normal range is not possible in resource limited settings. † always suspect iron deficiency when the mcv is low. steps: exclude blood loss; treat for parasites, start therapeutic trial (elemental iron 2mg/ kg/day x 3 weeks); if response inadequate (<2g/dl increase in hb) refer for investigation. ‡ anaemia of chronic disease may be hypochromic microcytic of normochronic normocytic § with ldh↑ and/or indirect bilirubin↑ suspect haemolysis * investigating all hiv+ patients with hb levels below the normal range is not possible in resource limited settings. § with ldh↑ and/or indirect bilirubin↑ suspect haemolysis * investigating all hiv+ patients with hb levels below the normal range is not possible in resource limited settings. † always suspect iron deficiency when the mcv is low. steps: exclude blood loss; treat for parasites, start therapeutic trial (elemental iron 2mg/ kg/day x 3 weeks); if response inadequate (<2g/dl increase in hb) refer for investigation. ‡ anaemia of chronic disease may be hypochromic microcytic of normochronic normocytic § with ldh↑ and/or indirect bilirubin↑ suspect haemolysis fig.1. diagnostic algorithm for anaemia in hiv infection. june 2012, vol. 13, no. 2 sajhivmed 91 r ev iew input and/or support. aiha can complicate compatibility testing and the rapid access to blood for transfusion. red cell autoantibodies can mask clinically significant allo-antibodies that have developed owing to prior antigen exposure (e.g. pregnancy and/ or previous blood transfusion). in non-urgent cases, a full serological investigation should be done to resolve the specificity of the autoantibody as well as to exclude any co-existing allo-antibodies. once an allo-antibody has been excluded, it is generally acceptable to administer red cell transfusions to patients whose dat is positive and where the indirect anti-globulin test (iat) phase of the crossmatch is also positive; a haemolytic transfusion reaction in these patients is unlikely.21 these patients do, however, warrant slow transfusion and careful monitoring. importantly, the reticulocyte count and peripheral smear must be requested before a transfusion, since the value of the count as well as the appearance of the peripheral blood morphology and the mcv may change after a transfusion and not truly reflect the patient’s haematological status. thrombocytopaenia thrombocytopaenia occurs commonly (often as one of the presenting symptoms), increases with disease progression, and is associated with shortened survival in hiv-positive patients.22-25 the most common cause of primary hiv-associated thrombocytopaenia is immune-mediated destruction.25 this is frequently attributed to high levels of autoantibodies directed against platelet-associated antigens. hiv can also infect megakaryocytes directly, given megakaryocyte expression of cd4 and cxcr4 receptors which are known docking points for hiv.25 consequently, platelet production and lifespan are reduced in the hiv-positive patient. additional causes of reduced platelet survival and decreased production are listed in table 2. as with anaemia, thrombocytopaenia is associated with a poor prognosis, while the treatment of the cause of the thrombocytopaenia confers improved survival.26-28 most patients with a platelet count >30 x109/l do not require treatment but do warrant investigation to elucidate the underlying cause. patients do not generally bleed spontaneously at platelet counts >10 20x109/l. prophylactic platelet transfusion is seldom indicated. some exceptions include: prematurity or neonatal thrombocytopaenia; intracranial pathology or risk of intra-cranial haemorrhage; functional platelet disorders independent of platelet count. therefore, platelet counts <100x109/l may warrant investigation as to the underlying cause with appropriate management, but do not necessarily require platelet transfusions in the absence of bleeding. a unit of platelet concentrate containing >3x1011 platelets usually results in an increment in the platelet count, in an adult, of ~ 30x109/l. in the absence of factors that shorten the lifespan of transfused platelets (such as fever, splenomegaly and/ or anti-platelet antibodies), the lifespan of transfused platelets is ~3 4 days. immune mediated thrombocytopaenias immune thrombocytopaenia (itp) can occur at any stage of hiv but most commonly in early disease. auto-antibodies directed against platelet antigens are readily found in most people with hiv, but they are not necessarily clinically significant. laboratory confirmation of itp is complex; consequently, itp is a diagnosis of exclusion. first line therapy is oral prednisone (1 mg/ kg each day). prednisone at this dosage does not appear to significantly affect viral replication; it may, however, promote kaposi sarcoma growth.29 if there is no response to steroids after one week, prednisone dosage can be increased to 2 mg/kg per day. patients should not receive high-dose steroids for more than 2 weeks without referring the patient to a specialist unit. patients on steroids require proton pump inhibitor (ppi) or h2-receptor antagonist prophylaxis for the prevention of peptic ulcer disease related to steroid therapy. if the platelet count drops below 30x109/l, ivig therapy, with or without steroids, should be considered (exception: patients with haemophilia or patients on anticoagulation therapy, where the lowest accepted platelet count is usually 50x109/l). response to therapy should be monitored, and art needs to be initiated or continued. a high index of suspicion of concomitant tb should be maintained. tranexamic acid and progesterone should be considered in female itp patients presenting with a platelet count <50x109/l and genito-urinary bleeding – remembering, though, that tranexamic acid in patients with haematuria may result in blood clots and urinary colic. it is prudent to give patients prophylactic pneumococcal vaccination in anticipation of potential need for splenectomy. it is recommended that refractory patients be referred to a tertiary unit for further management. table 2. thrombocytopaenia and hiv infection decreased production increased loss/destruction/sequestration drugs azt co-trimoxazole fluconazole ganciclovir acyclovir rifabutin clarithromycin didanosine chemotherapy deficiencies vitamin b 12 folate infections hiv cmv mtb mac histoplasma capsulatum neoplasia hodgkin’s disease non-hodgkin’s lymphoma miscellaneous hypoplastic/aplastic anaemia haemophagocytic syndrome secondary myelodysplastic syndrome immune thrombocytopaenia (secondary – hiv associated) thrombotic thrombocytopenic purpura (ttp) disseminated intravascular coagulation (dic) haemolytic uraemic syndrome (hus) hypersplenism infection haemophagocytosis drugs interferon saquinavir secondary anti-phospholipid syndrome 92 sajhivmed june 2012, vol. 13, no. 2 r ev ie w thrombotic thrombocytopaenic purpura (ttp) is a medical emergency with a high mortality rate. despite being frequently encountered in hiv, the diagnosis is often missed. with timely and appropriate management, the prognosis is significantly improved. ttp should be considered in all patients presenting with signs of micro-angiopathic haemolytic anaemia, thrombocytopaenia, fever, renal and liver dysfunction, and fluctuating neurological signs. where possible, patients should be referred urgently to a tertiary facility for further aggressive management. therapeutic plasma exchange (tpe) is ideal as it allows large volume plasma transfusions. if tpe is not available, fresh frozen plasma (ffp) or cryo-poor plasma at ~30 ml/kg per day should be infused in divided doses. ttp associated with hiv has been shown to respond well to ffp infusion alone and is appropriate in resource-limited settings without tpe.5,30 prednisone therapy at 1 mg/kg per day is also recommended. tranexamic acid should be avoided. platelet transfusions are not routinely given to patients with ttp as they may potentiate thrombotic events and complicate monitoring therapeutic response. neutropaenia the incidence of neutropaenia similarly increases with hiv disease progression.31,32 the aetiology of neutropaenia is often multifactorial and attributable to conditions considered under the pathogenesis discussed above. transfusion medicine best practice • transfusion is only one element of the patient’s management. • the decision to prescribe blood products should be based on individual patient needs, informed by best practice as well as the transfusing institution or national guidelines (e.g. clinical guidelines for the use of blood products in south africa).33 blood should only be transfused when clinically indicated and where the benefits outweigh the recognised risks. • appropriate management of chronic anaemia through investigation and treatment of the underlying cause may help to reduce the need for blood transfusion. • blood loss should be minimised to reduce the need for transfusion. • a patient with acute blood loss should receive effective resuscitation with intravenous replacement fluids, oxygen and immediate measures to stop further blood loss, while the need for transfusion is being assessed. • an appropriately trained healthcare worker must monitor the transfused patient and respond immediately and appropriately if any adverse event occurs. • to avoid wastage and unnecessary risk, the clinician should prescribe the minimum effective volume of blood and blood products necessary to stabilise the patient. routine transfusion to predefined haemoglobin (hb) levels should be avoided. blood should be transfused or discarded within 6 hours of breaking the seal on the blood bag to prevent risks associated with bacterial contamination. special considerations rate of transfusion. the rate of transfusion depends on the indication for the transfusion, patient’s co-morbidities and prior response to transfusion, if known. for example, those with acute haemorrhagic shock require rapid rates of transfusion as part of urgent resuscitation management. in contrast, patients with longstanding chronic anaemia should not be transfused rapidly (rate should not exceed 2 ml per minute), given adaptation to their longstanding anaemia where rapid transfusion can precipitate cardio-respiratory failure. particular caution needs to be taken for patients at age extremes (e.g. neonates, children, and age ≥60) and those with co-morbid disease (e.g. renal and cardio-pulmonary disease). these patient groups are at particular risk of volume overload, also referred to as transfusion associated circulatory overload (taco). precautions to minimise the risk of volume overload include spacing of transfusions where possible, small volume infusion, and/ or low dose furosemide following transfusion (where not contraindicated). filters. red blood cells, whole blood, ffp and cryoprecipitate must be administered through a standard blood administration set. these sets have 170 240 µm mesh filters to prevent the transfusion of clots or coagulation debris. the filter should be covered (‘primed’) with blood to ensure that the full filtering area is used. platelets should be transfused with a platelet giving set (a standard filter may be used in an emergency). standard filters incur significantly greater platelet loss owing to adhesion to the comparatively larger surface area, larger chamber and longer tubing. administration sets should be changed: • following reported transfusion reactions; this prevents further introduction of potentially harmful blood entering the patient. this is particularly important in the setting of suspected septic transfusion reactions where bacteria from the implicated unit can similarly contaminate the original administration set. • between red cells and other blood products • between red cell units of different abo groups (e.g. group o and group a red cells administered consecutively) • prior to infusing other fluids (e.g. dextran, ringers lactate) • every 12 24 hours (or according to the package insert/instruction) in patients requiring on-going transfusion. temperature of the blood. blood warmers are not indicated for routine blood transfusion; cold blood transfused at a slow rate is unlikely to adversely affect the patient. selected indications for blood warming include: • massive transfusion >50 ml/kg/hr • infants transfused at >15 ml/kg/hr • neonates receiving exchange transfusion or large volume transfusion • patients with high titre cold haemagglutinins reactive in vitro at temperatures >30oc. in these select settings, large volume or rapid infusion of cold blood can precipitate cardiac arrhythmias and impair haemostasis. blood warmers should be designated only for transfusion use, and require a temperaturemonitoring device that has been properly maintained in line with the manufacturer’s instructions. improper or excessive warming can induce haemolysis of the red cells, with consequent renal failure and even death. blood must never be placed in a microwave or oven. rapid warming in a water bath is ineffective as only the outer cells are warmed and, at temperatures >37°c, may cause damage to these cells. moreover, this practice risks bacterial contamination of the transfusion ports. patient identification. near-miss or actual misdirected transfusions remains the greatest risk of a haemolytic reaction to any patient receiving a blood transfusion. it is the responsibility of each person involved in the transfusion of the patient to avoid identification errors. this begins with the prescribing doctor and extends to all staff involved in administering the transfusion. patient identification should be repeated at every step of the transfusion process to ensure june 2012, vol. 13, no. 2 sajhivmed 93 r ev iew that errors do not occur. where possible, the patient should be positively identified in the presence of 2 staff members. the patient needs to state his or her name, which should be an identical match with that on the chart and with the name on the blood packs for transfusion. where the patient is unable to state his or her name, confirm the identity by using at least 2 or, if possible, 3 identification points, e.g. full name, hospital number, date of birth and/or identification number. scrupulous attention to detail can help to prevent serious harm. clerical error (i.e. through patient or blood product misidentification) is the foremost reason for severe haemolytic transfusion reactions. paediatric patients. anaemia in paediatric patients is very common in africa.34 in ghana and malawi, for example, more than 50% of children <5 years have a haemoglobin level <11 g/dl, and 20 47% of those admitted to hospital, reportedly receive blood transfusions.35-37 furthermore, 6 13% of patients admitted with severe anaemia (hb<5 g/dl) die – many before transfusion is possible. anaemia in southern africa disproportionately affects the young, given pervasive malnutrition, and helminthic and infectious diseases (specifically hiv and malaria, both endemic to southern africa). this has a major adverse effect on childhood morbidity and mortality, particularly where resource constraints and the relatively high cost of blood transfusion limit availability of safe blood. both anaemia and thrombocytopaenia are common among south african hiv-positive children. of those referred with cytopaenias, ~35% are anaemic (hb <11 g/dl), ~12.5% have thrombocytopaenia, ~35% have combined anaemia and thrombocytopaenia, and ~10% are pancytopenic.38 the need for blood transfusion places a significant burden on transfusion inventories and hospital budgets. critically ill paediatric patients and neonates have special transfusion requirements. neonates specifically, require small-volume transfusions that are relatively fresh (collected within the previous 14 days) and, when feasible, leucodepleted and/or cmv-negative. neonates are particularly susceptible to volume overload, and measures should be adopted to counteract the risk e.g. smallvolume and slow rates of transfusion. given the risks of transfusion, both the decision to transfuse and the required volume should be carefully considered and individualised.39 in stable hiv-infected anaemic children, it is reasonable to consider a hb <6 g/dl as the transfusion trigger.40,41 a threshold hb of 7 8 g/dl is recommended in haemodynamically stable, critically ill patients (e.g. trauma, intensive supportive care, or surgery).42-44 higher thresholds are required in premature infants and children who are actively bleeding.45 the recommended volume of transfusion is 10 ml/kg for red cell concentrate and, in severe malnutrition or heart failure, 5 ml/kg. for each 1 g/dl rise in hb desired, 3 5 ml/kg are needed. a paediatric unit of red cell concentrate contains 60 80 ml of red cells, compared with an adult unit of approximately 265 ml red blood cells. the calculated transfusion volume needed should be rounded off to the nearest volume of bag available, to not waste this scarce resource. appropriate clinical use of plasma products.33 plasma products produced by component processing laboratories at the blood service centres through physical separation techniques are referred to as plasma components. products derived from large pools of plasma by chemico-physical processing techniques (fractionation) are referred to as plasma derivatives. fresh frozen plasma (ffp) refers to plasma that is separated from anticoagulated whole blood and frozen within 18 hours of donation. ffp contains all coagulation factors at normal physiological levels. the indications for transfusion of ffp are outlined in table 3 and are identical to those for hiv-negative patients. ffp should be transfused judiciously. in addition to infectious risk, it is associated with transfusion-related acute lung injury (trali), which has significant morbidity and mortality. inappropriate uses of ffp include volume expansion and nutritional supplementation. cryoprecipitate is the cold insoluble fraction of ffp and contains factor viii and von willebrand factor (100 iu per unit), fibrinogen (150 250 mg per unit), fibronectin, and factor xiii. it is indicated primarily for the treatment of hypofibrinogenaemia (acquired or congenital) as found mainly in dic states. owing to the relative low levels of factor viii and von willebrand factor, it is not indicated in von willebrand ’s disease or in haemophillia a. freeze dried plasma (fdp) is produced from pooled fresh human plasma that has been subjected to a pathogen inactivation procedure that inactivates lipid-enveloped viruses. fdp has the same indications and dosage as ffp. intravenous immunoglobulin (ivig) is prepared by a fractionation process which inactivates lipid-enveloped viruses. the two principal indications for ivig are antibody replacement therapy and immunomodulation. in the setting of hiv, ivig is primarily used in the management of itp and prca. intramuscular hyperimmune immunoglobulin is produced by a method of fractionation similar to that of intravenous preparations. most preparations have a high titre of antibodies for passive immune prophylaxis against selected infections (e.g. chicken pox, hepatitis b, rabies etc). oncology patients. independent of hiv status, the oncology population is a major user of blood and blood products. certain malignancies are aids-defining conditions (e.g. high-grade b-cell non-hodgkin’s lymphoma, kaposi’s sarcoma and carcinoma of the cervix). however, hiv-positive patients are susceptible to the full range of malignancies encountered in hiv-negative patients, such as breast cancer, colorectal cancer etc. with the advent of haart, as hiv-positive patients live table 3. clinical indications for ffp indications multiple coagulation factor deficiencies e.g. dic massive blood transfusion liver disease active or ongoing bleeding with abnormal coagulation tests replacement of inherited single factor deficiencies, where single factor concentrate is not available thrombotic thrombocytopaenic purpura reversal of warfarin with active bleeding where prothrombin complex concentrate (pcc) is not available vitamin k deficiency associated with active bleeding scoline apnoea 94 sajhivmed june 2012, vol. 13, no. 2 r ev ie w longer, they will be at risk of the same spectrum of malignancies as seen in negative individuals. general transfusion principles apply to the hiv-positive oncology patient. the decision to transfuse should be individualised to the patient’s needs; this can be challenging in patients with uncertain outcomes. for example, transfusion in patients with poor expected short-term outcomes may be inappropriate if it is unlikely to change the outcome. however, transfusion has a role in palliative care where it can be used to maintain or improve quality of life in terminally ill patients. adjunctive therapy with haematinics, erythropoietin and other alternatives to transfusion should be considered in patients who require active management of their anaemia. transfusion thresholds can differ to accommodate planned therapies. for example, radiotherapy requires a higher tissue oxygenation to be effective; therefore these patients require a higher haemoglobin level, and a target of 10 g/dl should be used. similarly, maintenance of higher haemoglobin levels has been shown to improve radiotherapy outcomes in head and neck cancer.46 surgical patients. perioperative indications for blood transfusion are the same for both hiv-positive and -negative patients. however, hiv-positive patients are more likely to be anaemic and consequently more likely to require transfusion pre-operatively. all reasonable measures must be taken to treat and correct anaemia and its causes before surgery. estimating transfusion needs and communicating with the hospital blood bank is especially important. algorithms to help predict need for transfusion may be useful47 but, in practice, if the patient presents at surgery with a haemoglobin level <7 8 g/dl, and the predicted blood loss is >500 ml, then perioperative transfusion should be anticipated and planned according to the patient’s condition.48 a study of jehovah’s witness patients undergoing surgery who refused transfusion noted that mortality in elective surgery depended on estimated blood loss rather than on preoperative haemoglobin levels. furthermore, the study found that elective surgery could be performed safely in patients with a preoperative haemoglobin level as low as 6 g/dl if estimated blood loss was maintained below 500 ml.49 other studies in jehovah’s witness patients have demonstrated a significant increase in mortality and morbidity in patients with a postoperative haemoglobin level <7 g/dl and 8 g/dl respectively.50 it has been shown that the risks of surgery and anaesthesia in hiv-positive patients is similar to that of surgery in immunocompromised or malnourished patients, with increased risk with disease progression.51 as for any patient, the preoperative physiological status (including an assessment of nutritional reserve) is considered the best predictor of surgical morbidity and mortality.52 hivassociated thrombocytopaenia can potentially increase the risk of bleeding, but regional anaesthesia is not contraindicated.52,53 haemophiliac patients. in the late 1970s and early 1980s, patients with haemophilia (pwh) were infected with hiv through the use of contaminated blood products, specifically clotting factor concentrates, ffp and cryoprecipitate. this tragedy has since lead to a complete revision of transfusion practice, policy and procedures. with robust donor selection, sensitive laboratory testing and good manufacturing practice for the production of fractionated factor concentrates, the current risk of transfusion-transmitted hiv is very low. however, development of thrombocytopaenia, lymphadenopathy or splenomegaly in pwh still warrants testing for hiv infection. pwh who are found to be hiv-positive can develop thrombocytopaenia consequent to their hiv disease. therefore, the development of purpura or increased mucosal bleeding in an hiv-positive pwh may be due to thrombocytopaenia rather than factor deficiency. investigation and identification of the cause is important: factor administration alone may not be sufficient, and therapy may need to be directed toward the hiv thrombocytopaenia (as a primary cause). management is similar to that of patients without haemophilia, and includes steroids, platelet transfusions and, in the hiv-positive patients, the initiation of haart. obstetric patients. regarding blood transfusion, the management of hivpositive obstetric patients should not differ from that of hiv-negative obstetric patients. transfusion should be used sparingly in obstetrics. pregnancy may, however, be associated with sudden massive blood loss – obstetric haemorrhage remains the third most common cause of maternal mortality in south africa.54 hospital maternity sections frequently rank among the highest in terms of demand for blood and blood products, along with trauma and icu.55 there is a high prevalence of underlying anaemia in pregnancy owing to various causes. this anaemia must be anticipated, recognised and treated to lessen the risk associated with blood loss at delivery and to lessen the requirements for transfusion. specific physiological changes in the haematological system occur in pregnancy, including haemodilution (there is an increase in plasma volume by 45 50% that reaches a maximum at about 34 weeks’ gestation and exceeds the 18 30% increase in the red cell mass).56 in the anaemic patient on oral haematinics, a static hb may represent a response to the anaemia masked by haemodilution. plasma volume increases more in multiple pregnancies. the fetus must also be considered in terms of the potential effects of the anaemia. folic acid deficiency (a cause of pregnancyrelated anaemia) has been associated with neural tube defects. periconceptual folic acid supplementation is recommended.57 pregnancy is also associated with specific disorders that affect the haematological system, increasing the need for transfusion. these include hellp syndrome (haemolysis, elevated liver enzymes and low platelets) associated with pre-eclampsia/eclampsia and pregnancy-associated thrombocytopaenia. although these guidelines contain recommendations for complex investigations and discuss current blood product use, it is also recognised that a large proportion of pregnant patients in south africa and elsewhere in africa are cared for at primary care centres where only basic haematological investigation may be available. in parts of southern africa, the available blood supply does not meet the clinical demand, and clinicians face a chronic shortage of blood. in all circumstances, much can be achieved by the prompt use of standard obstetric protocols to minimise blood loss. where possible, the more complex patient who requires specialised antenatal or intrapartum care should be transferred to betterresourced settings. the prevalence and cause of anaemia in pregnancy varies throughout africa. in malawi and zimbabwe (and in the limpopo and northern kwazulu-natal provinces of south africa), for example, malaria and/or gastrointestinal parasite infection may be a cause of anaemia in addition to underlying nutritional deficiencies. should a patient in such areas become infected with hiv, these underlying causes of anaemia will persist and require treatment in accordance with the principles mentioned before.58 anaemia should be identified, appropriately investigated, and treated early in pregnancy. june 2012, vol. 13, no. 2 sajhivmed 95 r ev iew other haematological complications such as bleeding tendencies and cardiac failure warrant urgent admission or referral to a secondary/tertiary centre. routine obstetric assessment includes the gestational age, which indicates the time available to treat a low hb. risk factors for obstetric haemorrhage may indicate referral to a secondary/tertiary centre for delivery, where transfusion, if required, will be available. according to the south african national prevention of mother to child transmission of hiv (pmtct) clinical guidelines (2010),59 all hiv-positive pregnant women should receive iron and folate supplementation. in south africa, folate should be available at the treatment dose of 5 mg and not the prophylactic dose. in countries where folate fortification of food takes place, folate deficiency is rare. the recommended daily dosage for iron is 60/65 mg elemental iron in the 2nd trimester and 120 mg elemental iron, in divided doses, in the 3rd trimester. if there is intolerance, replacement can be deferred since, in the 1st trimester, oral iron may cause increased nausea and vomiting. if calcium is given antenatally, it must not be given at the same time as the iron, as it blocks absorption.60,61 there is an exception: patients with a known haemolytic anaemia – e.g. thalassaemia or sickle cell anaemia (particularly from malaria-endemic areas) – should not be given iron routinely. anaemia must be recognised and managed promptly before the time of likely delivery. the time intervals for assessment of response are therefore shorter than in the non-pregnant patient. a review after only 3 months is not appropriate. 1. for treatment, dosage: 200 250 mg elemental iron daily in divided doses, i.e. one tablet of iron sulphate or iron fumarate 3 times daily. if vitamin c is available, it should be given with iron, also in divided doses.61 iron taken with food increases tolerance. 2. there is an increased absorption of iron in pregnancy. if the anaemia is a result of iron deficiency, an hb increase of up to 0.7 g/dl per week may result. the lower the starting hb, the more rapid the anticipated response. 2.1 with an inadequate (<0.5 mg/dl per week) or absent response, a full blood count (fbc) and reticulocyte production index (rpi) should be performed. the rpi is frequently >2 in the early response to iron deficiency anaemia in pregnancy. 2.2 the fbc may direct further investigation of the anaemia as mentioned above. 2.3 in iron deficiency anaemia responding to iron but with a delayed hb response, the red cell distribution width (rdw) may also increase, usually to >20%. the increase in rdw is not valuable if a recent transfusion or drugs have been given that cause macrocytosis e.g. azt62 causing an artificial increase in rdw. 2.4 if the mcv is high (>110 fl), vitamin b 12 deficiency, though rare, should be considered, especially if there is oral ulceration or neurological symptoms. intravenous iron is only indicated, remote from term, if iron deficiency anaemia, proven on fbc and iron studies, is associated with intolerance of oral iron or there is no improvement of the anaemia despite apparent compliance.63 intravenous iron should only be given where there is no other reason for immediate transfusion. according to the national pmtct guidelines (2010), the newly diagnosed hivpositive pregnant patient who has a cd4 count >350 cells/mm3 or who staging 1 or 2 should, after 14 weeks’ gestation, commence zidovudine (azt), if consenting. if cd4 count <350 cells/mm3, or who stage 3 or 4, full art should be offered.59 azt is associated with macrocytosis,62 but rarely associated with severe anaemia as a result of a pure red cell aplasia.64 if there is adequate time remaining in the pregnancy, patients who are treatmentnaïve, do not qualify for full art, and have an hb <10g/dl, should receive a full course of haematinics and their response observed. their response should be re-assessed after 2 weeks and, if there is a response, azt be commenced. if the patient’s hb is <8g/ dl, the south african pmtct guidelines suggest withholding azt.59 if, however, there is a rapid response of the anaemia to iron and folate, azt can be given. if the hb is <8g/ dl and there is no response to haematinics, further investigation is warranted. in certain patients, there may be a case for considering full art. these include cases where delivery is approaching and where the hb remains low or is falling. patients with a falling hb on azt (or azt-containing regimen) should be investigated for other causes of anaemia, usually nutritional or infective, but autoimmune haemolytic anaemia should also be considered. haematinics should be commenced if not yet initiated and the patient examined and investigated further for additional underlying pathology. if a pure red cell aplasia is confirmed, azt should be stopped. in such cases, patients usually respond within a week. blood transfusion may be required if the patient is symptomatic or if the hb falls below 6g/dl with no response to treatment. many patients tolerate very low levels of hb (5 6 g/dl). if there are no medical or obstetric complications, and it is early in pregnancy (<34 weeks), oral replacement with haematinics should be used and the patient reassessed after 1 2 weeks. where patients are in cardiac failure, have worsening anaemia with no response to haematinics, or where delivery is imminent, transfusion should be considered. transfuse one unit of red cell concentrate and reassess. there is no need to transfuse if the hb >7 g/dl and there are no obstetric complications. a higher hb (>8 g/dl) should be targeted in patients at increased risk of obstetric haemorrhage, e.g. previous pph, multiple pregnancy and placenta previa (where a hb >9g/dl should be targeted). routine obstetric intervention may prevent transfusion. appropriate observation is critical. timely caesarean section for antepartum haemorrhage, controlled delivery of the placenta in vaginal delivery, and the recognition and treatment of uterine atony may prevent the need for transfusion. if a transfusion is not to be given to a patient in whom the peripartum loss has been considerable (>500 ml in normal delivery, >1000 ml in caesarean section), the cause of bleeding must be controlled and the condition of the patient considered. close observation is essential; any further blood loss must be accurately recorded and action taken if necessary. blood loss is frequently underestimated.63 in patients with physiological compromise (both hiv-negative or -positive), transfusion should be considered earlier than in otherwise healthy counterparts. if blood products are required and not available at the point of care, the patient should be transferred to a unit with access to a blood bank as soon as possible. the patient should be oxygenated, kept warm, with adequate intravenous (iv) support and with adequate measures to control further haemorrhage. there is no need to give blood to reach a particular hb level. transfusion practice depends on the availability and proximity of blood products in the case of an emergency; the american and british anaesthetic task forces in obstetrics recommend neither 96 sajhivmed june 2012, vol. 13, no. 2 r ev ie w routine type and screen, nor crossmatch of patients who undergo a routine normal delivery or routine caesarean section if these services are readily available.63,65 despite these recommendations, patients at risk for greater than average blood loss (e.g. caesarean section for placenta previa) should have blood crossmatched and should, wherever possible, give birth in a place where further blood products are readily available.54 malaria. the risk of severe malaria appears to be greater in hiv-positive (non-immune) patients than in hiv-negative patients.66 in addition, hiv-positive patients are at a significantly higher risk of developing severe anaemia. pregnant women co-infected with hiv and malaria are at greater risk of complicated disease than women with either malaria or hiv infection alone. peripartum complications include severe anaemia,67 thereby increasing the need for blood transfusion. severely anaemic patients may benefit from transfusion early in the course of acute malaria but, once stable and in process of recovery, the benefit of transfusion68 is limited. however, persistent worsening anaemia is a recognised complication in the weeks following clearance of parasitemia.69 clinicians should therefore monitor hiv-positive patients for at least 3 months following malaria treatment. paediatric patients are at greatest risk. one study of hiv-1 and plasmodium falciparum co-infected children aged 3 36 months demonstrated significantly worse anaemia (hb <6.0 g/dl) and a nearly 10 times greater mortality within 3 months post treatment, compared with an hiv-negative cohort.70 hiv-malaria co-infected patients are particularly prone to invasive bacterial infection (ibi); this underscores the need for good transfusion practice and vigilance against bacterial contamination.71 improper handling of blood and blood products further increases the risk of gram-positive bacteraemia. broad-spectrum antibiotics (such as a third generation cephalosporin) should be routinely administered to hivmalaria co-infected patients with severe malaria, to provide cover against both gram-positive and gram-negative bacteria; this should be instituted from the time of admission.72 aggressive initial management of malaria is essential. blood transfusion has a role in management, but should not delay initiation of anti-malarial therapy. haemoglobinopathies. there is no evidence to suggest that patients with haemoglobinopathies who are hiv-positive should be managed differently to those who are hiv-negative. massive transfusions. the principles of management of patients requiring massive blood transfusion are the same for hivpositive and hiv-negative patients. leukodepleted blood. the routine use of leukodepleted blood in hiv-positive patients is not recommended. even though hiv/ aids patients are immunosuppressed, there is no substantive data supporting improved outcomes in patients who routinely receive leukodepleted blood components. currently, the indications for the transfusion of leukodepleted blood products are the same for hiv-positive and hiv-negative patients. while the use of leukodepleted blood products may reduce the risk of transmission of leucocyteassociated pathogens such as cmv and htlv, the viral activation transfusion study (vats) demonstrated no clinical benefit for hivpositive persons, who received white-bloodcell-reduced transfusions.73-75 the indications for use of leukodepleted products include: • prevention of alloimmunisation: • patients on chronic transfusion regimens, such as aplastic anaemia or sickle cell anaemia • organ and stem cell transplant patients • haem-oncology patients • patients at risk for cmv infection such as: • transplant patients receiving immunosuppressant drugs • infants <1 year old • prevention of febrile non-haemolytic transfusion reactions • other • patients undergoing cardiac surgery. note: where indicated and if available, prestorage leukodepleted products obtained from blood services are preferable to bedside leukodepletion; prestorage leukodepletion removes leucocytes prior to release of cytokines, which are responsible for adverse effects such as febrile non-haemolytic reactions. random-donor platelet concentrates are prepared from buffy coats and are not usually leukodepleted. single donor (apheresis) platelet concentrates are routinely leukodepleted; the indications for this product are similar to those mentioned above for leukodepleted products. irradiated blood products. hiv-positive patients do not routinely require blood products to be irradiated. blood products are irradiated to prevent transfusion-associated graft v. host disease (ta-gvhd). it has been postulated that, in patients with hiv infection, depletion of cd4 cells increases the number of donor cells needed to induce ta-gvhd. in hiv and aids, there has to date only been one reported case of ta-gvhd despite widespread use of blood transfusions in patients with profound hiv-associated immune suppression. the indications for irradiated blood products are the same for hiv-positive as for hiv-negative patients. specific indications for irradiation include: • blood donations from blood relatives • hla-matched platelet concentrates • recipients of allogeneic bone marrow transplant • hodgkin’s disease • intrauterine transfusions • p at i e nt s ( h a e m at o l o g i c a l / n o n haematological disorders) receiving fludarabine therapy. note: please refer to the clinical guidelines for the use of blood products in south africa or your national guidelines for additional information. blood conservation strategies blood conservation (restrictive transfusion practice) is clinically effective in most patient subsets. in particular, the tricc study76 showed that restrictive transfusion practice applied to critically ill adult patients was at least as effective and potentially superior to that of liberal transfusion practice in terms of lower morbidity and mortality.76 this was also shown in a major randomised control trial (picu study) of stable, critically ill children.43 low-cost and relatively simple preventative measures can be employed to minimise blood use. one example is that of judicious screening for anaemia with early intervention. all cases of clinically significant anaemia should be investigated, and the underlying cause addressed and appropriately managed. early intervention is particularly important for surgical candidates where timely management of anaemia can help to minimise periopertaive transfusion. clinicians should employ alternatives to blood transfusion wherever appropriate e.g. haematinic therapy in chronic anaemia or the use of crystalloids/colloids to restore blood volume in resuscitation. where indicated and where available, erythropoietin is another measure to be considered in patients refractory to standard therapy.6,9,77 erythropoietin has been shown to benefit hiv-positive patients. in the critical care setting, excessive phlebotomy june 2012, vol. 13, no. 2 sajhivmed 97 r ev iew can exacerbate underlying anaemia; this can be avoided through considered testing, confined to that which directly influences patient management. good surgical and anaesthetic techniques, with particular attention to haemostasis and keeping patients warm, are essential transfusion conservation principles. suitable alternatives or adjuncts to transfusion should be considered, e.g. anti-fibrinolytics and fibrin sealants. bleeding, when it occurs, should be managed aggressively, avoiding a passive watch-and-wait approach. the use of medication that can impede haemostasis (e.g. anticoagulants, anti-platelet agents and non-steroidal anti-inflammatories) should be prescribed cautiously in the chronic patient at risk for bleeding, and stopped in the bleeding patient. the latter may require specific reversal of anticoagulation if bleeding does not stop with conservative management. pre-surgical autologous blood donation obtained from hiv-positive donors is not routinely available and should not be accepted. hiv-infected blood products pose significant risk, both to blood service staff as well as to other patients. risk to other patients can occur through administrative or clerical error resulting in mis-transfusion (unintentional transfusion to the incorrect recipient). finally: acute normovolemic haemodilution and cell salvage are two intraoperative blood conservation techniques that can be used in hiv-positive surgical patients. these techniques should be considered particularly where significant blood loss is anticipated. lookback programmes the blood service’s transfusion transmissible infection (tti) lookback programme aims to trace all patients who are identified as recipients of blood from donors who test positive for a transfusion-transmissible infection on a subsequent blood donation, where the initial (index) donation might possibly have been donated in a window period. in such a ‘donor-triggered’ lookback investigation, the recipient/s of the previous tti negative units is/are identified and their treating doctor notified. as far as possible, the patient must be recalled, counselled and tested for the relevant viral marker, and the result reported to the blood service. despite diligent donor selection and laboratory screening, suspicion may arise that a patient might have been infected with hiv, hbv or hcv through blood transfusion. in such instances, the attending clinician should contact the blood service promptly to initiate a ‘recipient-triggered’ lookback investigation, a formal procedure designed to trace and confirm the status of the implicated blood donor(s). haemovigilance programme haemovigilance is the process through which information related to the transfusion of blood and blood products is monitored and centrally reported. it is a system to detect, gather and analyse information on untoward and unexpected effects of the transfusion of blood and blood products. such programmes aim to improve blood systems and blood safety through the early detection and comprehensive reporting of untoward effects of blood transfusion e.g. transfusion reactions, transfusion-transmitted infections, etc. ideally, a haemovigilance programme is integrated into blood transfusion practice to maximise the safety of not only the blood supply, but also all aspects of laboratory and clinical blood transfusion practice. in some countries such as namibia and south africa, data reported to the national haemovigilance programme are analysed and the results published in an annual haemovigilance report. it is important that medical practitioners who transfuse blood and blood products report all adverse transfusion events to the blood service. laboratory testing of donated blood serological tests are performed on every blood donation to determine the donor’s abo group and rh type and to detect irregular blood group antibodies. every blood donation is tested for hiv, hepatitis b, hepatitis c and syphilis, using serological techniques. nucleic acid testing (nat) is used in combination with serological testing in a few well-resourced african countries. clinicians should consider the following options when ordering blood for their patients: • type and screen. the clinician should select this option if their patient has a low probability of needing a transfusion or in, for example, certain elective surgical procedures where the extent of blood loss is unpredictable. the blood specimen submitted to the blood bank will be tested to determine the patient’s abo group and rh type and will be tested to ensure that the patient does not have irregular blood group antibodies (a ‘rare blood type’) that could delay finding compatible blood. the specimen will be held for approximately 96 hours, depending on blood bank policy. blood will only be crossmatched when requested by the attending doctor. the ‘type and screen’ expedites crossmatching and dispatch of blood from the blood bank should transfusion be required. if irregular antibodies are detected, the requesting doctor will be notified. the presence of irregular antibodies can delay procurement of compatible blood, and patient management needs to be changed accordingly. this could, for instance, necessitate delaying surgery. • a full crossmatch refers to full compatibility testing between a patient’s blood sample (intended recipient) and a given donor (unit of blood). this includes the type and screen as described above as well as confirmatory blood grouping on the intended donor unit. in addition, the patient’s serum is ‘crossmatched’ with the red blood cells of the donor to ensure serological compatibility. incompatibility between patient and donor is reflected by in vitro agglutination. • in contrast, an emergency crossmatch refers to partial compatibility testing, given the urgent need to transfuse. blood is issued after performing the abo group, rh type and antibody screen only. further testing is completed after the unit has been issued. providing sufficient clinical detail, including the hiv status of the recipient, to the hospital blood bank staff, will expedite the crossmatching process and the timely availability of compatible blood. the direct antiglobulin test (dat) is, for example, positive in up to 40% of hiv-positive patients. this will manifest as a positive crossmatch. knowing the patient’s hiv status will therefore assist the blood bank’s medical and technical staff in interpreting the compatibility test results and, as indicated, expedite the release of compatible blood. adverse events associated with blood transfusion33 evaluation of benefits and risks of transfusions should precede the decision to transfuse. all blood products carry risk of adverse effects. these include transfusion reactions, transfusion transmissible infections, alloimmunisation and immune modulation. the attending doctor must be familiar with best practice recommendations regarding transfusion practice, and is also responsible for obtaining and documenting informed consent. transfusion reactions are the most common hazard of blood transfusion, occurring with 98 sajhivmed june 2012, vol. 13, no. 2 r ev ie w ta b le 4 . p ro d u ct s, s er vi ce s an d g lo ss ar y r ed c el l p r o d u c t s: s t o r e a t 1 °c 6° c . d ef in iti on s, p ro du ct s an d se rv ic es d es cr ib ed b el ow r ef er to th os e av ai la bl e in s ou th a fr ic a an d m ay n ot b e av ai la bl e in o th er c ou nt ri es a nd r eg io ns . p ro du ct a ve ra ge v ol . a ve ra ge u ni t p ri ce in cl . v a t ( 20 12 ) c ha ra ct er is ti cs m aj or in di ca ti on s w ho le b lo od le uc od ep le te d (< 5 da ys o ld ) 48 5 m l r 2 49 9. 00 w b c : < 5x 10 6 /u ni t le uc oc yt e de pl et ed a t t he ti m e of p ro ce ss in g. in di ca te d fo r ne on at al e xc ha ng e tr an sf us io n. r ed c el l c on ce nt ra te in a dd iti ve so lu tio n 30 0 m l r 1 36 9. 00 bu ff y co at r em ov ed w b c : < 2. 4x 10 9 /u ni t to in cr ea se ti ss ue o xy ge na tio n ow in g to r ed uc ed ha em og lo bi n co nc en tr at io n. r ed c el l c on ce nt ra te ( le uc od ep le te d) 26 0 m l r 2 23 7. 00 w b c : < 5x 10 6 /u ni t le uc oc yt e de pl et ed a t t he ti m e of p ro ce ss in g. se e in di ca tio ns fo r le uc od ep le te d pr od uc ts . r ed c el l c on ce nt ra te in a dd iti ve so lu tio n (< 5 da ys o ld ) 30 0 m l r 1 4 84 .0 0 bu ff y co at r em ov ed w b c : < 2. 4x 10 9 /u ni t r ed c el l c on ce nt ra te ( le uc od ep le te d) (< 5 da ys o ld ) 26 0 m l r 2 23 7. 00 w b c : < 5x 10 6 /u ni t le uc oc yt e de pl et ed a t t he ti m e of p ro ce ss in g. su ita bl e fo r ne on at al e xc ha ng e tr an sf us io n. se e in di ca tio ns fo r le uc od ep le te d pr od uc ts . r ed c el l c on ce nt ra te p ae di at ri c le uc od ep le te d 75 m l r 1 26 5. 00 w b c : < 5x 10 6 /u ni t le uc oc yt e de pl et ed a t t he ti m e of p ro ce ss in g. fo r pa ed ia tr ic u se . p la t el et p r o d u c t s: u se i m m ed ia t el y a ft er i ss u e; d o n o t r ef r ig er a t e. p ro du ct a ve ra ge v ol . a ve ra ge u ni t p ri ce in cl . v a t ( 20 12 ) c ha ra ct er is ti cs m aj or in di ca ti on s pl at el et c on ce nt ra te p oo le d no nle uc od ep le te d 25 0 m l r 5 76 9. 00 pl at el et s: ≥ 2. 4x 10 11 /u ni t w b c : < 5x 10 8 /u ni t pr ep ar ed fr om b uf fy c oa t o f 5 w ho le b lo od do na tio ns . n ot le uc od ep le te d. c lin ic al ly s ig ni fic an t t hr om bo cy to pa en ia o r pl at el et fu nc tio n ab no rm al iti es . pl at el et c on ce nt ra te le uc od ep le te d (a ph er es is ) 20 0 m l r 7 93 6. 00 pl at el et s: ≥ 2. 4x 10 11 /u ni t w b c : < 5x 10 6 /u ni t pr ep ar ed fr om a s in gl e do no r by a ph er es is . i f un av ai la bl e, le uc od ep le te d po ol ed p la te le ts w ill b e su pp lie d. se e in di ca tio ns fo r le uc od ep le te d pr od uc ts . pl at el et c on ce nt ra te p ae di at ri c le uc od ep le te d r 1 74 1. 18 pl at el et s: ≥ 5 .5 x1 01 0 /u ni t w b c : < 5x 10 6 / un it pr ep ar ed fr om a s in gl e do no r by a ph er es is . fo r pa ed ia tr ic u se . p la sm a p r o d u c t s – m u st b e t r a n sf u se d i m m ed ia t el y a ft er i ss u e. p ro du ct a ve ra ge v ol . a ve ra ge u ni t p ri ce c ha ra ct er is ti cs m aj or i nd ic at io ns c ry op re ci pi ta te 30 m l r 77 4. 00 fi br in og en c on te nt – > 30 0 m g/ un it 1. h yp of ib ri no ge na em ia 2. f ac to r x ii i de fic ie nc y fr es h fr oz en p la sm a – pa ed ia tr ic 13 0 m l r 63 7. 00 c on ta in s ph ys io lo gi ca l l ev el s of m os t c lo tt in g fa ct or s. n b : f re ez edr ie d pl as m a is u se d as a n al te rn at iv e. ff p – cr yo -p oo r 25 0 m l r 88 3. 79 ff p fr om w hi ch th e cr yo pr ec ip ita te h as b ee n re m ov ed . l im ite d av ai la bi lit y. m ay b e in di ca te d fo r t t p. june 2012, vol. 13, no. 2 sajhivmed 99 r ev iew ta b le 4 . p ro d u ct s, s er vi ce s an d g lo ss ar y (c o n ti n u ed 2 ) sp ec ia l r eq u es t s: c o n ta c t t h e b lo o d b a n k – a d va n c e n o t ic e is r eq u ir ed . se rv ic e/ pr oc ed ur e a ve ra ge u ni t co st c ha ra ct er is ti cs m aj or in di ca ti on s ir ra di at ed p ro du ct s r 29 3. 00 fo r th e pr ev en tio n of tr an sf us io nas so ci at ed g ra ft ve rs us -h os t d is ea se . 1. in tr au te ri ne tr an sf us io n 2. b on e m ar ro w tr an sp la nt r ec ip ie nt s 3. d ir ec te d do na tio ns fr om b lo od r el at iv es h la -m at ch ed p la te le t c on ce nt ra te r 1 07 3. 00 h la -m at ch ed s in gl edo no r ap he re si s pl at el et co nc en tr at e. pr ev en tio n an d m an ag em en t o f p la te le t r ef ra ct or in es s. a ut ol og ou s pr og ra m m es r 15 0. 00 t he c ol le ct io n, n or m al te st in g an d pr oc es si ng o f a pa tie nt ’s ow n bl oo d fo r hi m or h er se lf. fo r us e in c er ta in li m ite d el ec tiv e su rg ic al c as es in s ui ta bl e pa tie nt s d ir ec te d pr og ra m m es r 18 1. 00 pr og ra m m e w he re fa m ily m em be rs o r fr ie nd s do na te fo r a sp ec ifi c pa tie nt . c ho se n do no rs h av e to m ee t th e sa m e cr ite ri a as n or m al d on or s an d m us t h av e a co m pa tib le b lo od g ro up . bl oo d do na te d by fi rs tlin e bl oo d re la tiv es r eq ui re s ir ra di at io n to p re ve nt tr an sf us io n as so ci at ed g ra ft v . ho st d is ea se . fo r us e in c er ta in li m ite d ca se s. t he b lo od m us t b e te st ed a nd pr oc es se d as u su al , r eq ui ri ng 3 5 d ay s be fo re th e un it is a va ila bl e fo r tr an sf us io n. w as he d pr od uc ts r 1 05 1. 00 t he p ro du ct is s us pe nd ed in is ot on ic s al in e an d ce nt ri fu ge d; th e sa lin e fr om th e fir st s al in e ‘w as h’ is re m ov ed , a nd th e re d ce lls r esu sp en de d in is ot on ic sa lin e. a s w as he d ce lls a re m an ip ul at ed in a n op en s ys te m , w ith a p os si bi lit y of b ac te ri al c on ta m in at io n, th ey m us t b e tr an sf us ed w ith in 2 4 ho ur s of pr ep ar at io n. c ry opr es er ve d ce lls ~r 7 40 0. 00 t he s to ra ge o f f ro ze n ra re d on at io ns fo r us e lo ca lly an d in te rn at io na lly . a s w as he d ce lls a re m an ip ul at ed in a n op en s ys te m , w ith a p os si bi lit y of b ac te ri al c on ta m in at io n, th ey m us t b e tr an sf us ed w ith in 2 4 ho ur s of pr ep ar at io n. le uc oc yt e de pl et ed ( le uc od ep le te d) pr od uc ts in cl ud ed in c os t of p ro du ct fi lte re d un de r la bo ra to ry c on di tio ns . t hi s en su re s op tim al r em ov al o f l eu co cy te s to m in im is e cy to ki ne re le as e. l eu co cy te d ep le tio n w ill r es ul t i n a le uc oc yt e co un t < 5x 10 6 p er u ni t a nd u su al ly < 1x 10 6 p er u ni t. 1. p re ve nt io n of tr an sf us io n tr an sm itt ed c m v. 2. p ot en tia l h ae m op oi et ic tr an sp la nt r ec ip ie nt s. 3. in tr au te ri ne tr an sf us io ns a nd c hi ld re n <1 y ea r ol d. 4. p re ve nt io n of fe br ile n on -h ae m ol yt ic tr an sf us io n re ac tio ns . t y p es o f c r o ss m a t c h te st t im efr am e a ve ra ge c os t c om m en ts ty pe a nd s cr ee n n /a r 27 2. 00 t he s pe ci m en w ill b e gr ou pe d an d te st ed to e ns ur e th at it d oe s no t co nt ai n an tib od ie s th at c ou ld d el ay fi nd in g co m pa tib le b lo od . t he sp ec im en w ill b e he ld fo r 96 h ou rs . b lo od w ill o nl y be c ro ss m at ch ed w he n re qu es te d by th e at te nd in g do ct or . st an da rd c ro ss m at ch w ith in 2 h ou rs r 60 9. 00 c ro ss m at ch ed p ro du ct s w ill b e he ld in r es er ve fo r 24 h ou rs u nl es s ot he rw is e in di ca te d by th e at te nd in g do ct or . c ro ss m at ch ed p ro du ct s no t c ol le ct ed , w ill in cu r th e fe e. 100 sajhivmed june 2012, vol. 13, no. 2 r ev ie w variable frequency depending on the type of reaction. transfusion reactions fall broadly into the following categories: • haemolytic – acute • haemolytic – delayed (dhtr) • febrile non-haemolytic • allergic • anaphylactic • reactions due to bacterial contamination • reactions due to ‘citrate toxicity’ • reactions due to circulatory overload (taco) • transfusion-associated acute lung injury (trali) • transfusion-associated graft versus host disease (ta-gvhd). signs and symptoms suggestive of a transfusion reaction include: • chills/rigors • fever/sweating • tachycardia/bradycardia • dyspnoea/bronchospasm • hypertension/hypotension • urticaria/pruritus • chest/flank pain • nausea/vomiting • haemoglobinuria • oliguria/anuria • restlessness • jaundice. if a transfusion reaction is suspected, the transfusion must be stopped immediately pending further evaluation. the administration set must be changed and venous access should be maintained with normal saline unless it is a simple urticarial reaction. if the latter is the case, the transfusion can continue with symptoms or after use of an antihistamine (such as diphenhydramine 12.5 25mg for an adult patient). the following additional steps should be taken: • both a member of the medical staff as well as the blood bank must be contacted immediately. • the medical management of the transfusion reaction will depend on the type and severity of the reaction. • the patient’s temperature, pulse, respirations and blood pressure must be recorded. • all clerical and identity checks must be repeated to ensure that the correct blood product was transfused to the intended patient. clerical error is the foremost reason for major acute haemolytic transfusion reaction, i.e. blood given to the wrong patient. • if a case of misdirected transfusion is noted, immediate steps must be taken to locate the units originally intended for the patient, as they may be in the process of being transfused to another incorrect patient. • send a fresh blood specimen for compatibility testing to the blood bank. • all empty and non-transfused blood units should be returned to the blood bank. ta b le 4 . p ro d u ct s, s er vi ce s an d g lo ss ar y (c o n ti n u ed 3 ) em er ge nc y cr os sm at ch 20 3 0 m in ut es r 11 4. 00 bl oo d is su ed o n em er ge nc y or w ith ou t a c om pa tib ili ty te st is tr an sf us ed a t t he a tt en di ng d oc to r’s o w n re sp on si bi lit y. t he re a re r is ks in vo lv ed in e m er ge nc y pr oc ed ur es – u se th em o nl y fo r em er ge nc ie s. u nc ro ss m at ch ed b lo od 5 10 m in ut es r 13 6. 00 bl oo d is su ed o n em er ge nc y or w ith ou t a c om pa tib ili ty te st is tr an sf us ed a t t he a tt en di ng d oc to r’s o w n re sp on si bi lit y. t he re a re r is ks in vo lv ed in e m er ge nc y pr oc ed ur es – u se th em o nl y fo r em er ge nc ie s. g en er a l bl oo d on r et ur na bl e ba si s (b r b ) in fo rm ed c on se nt bl oo d ad m in is tr at io n se t pl at el et a dm in is tr at io n se t bl oo d pa ck w ith ou t a nt ic oa gu la nt bl oo d pa ck w ith a nt ic oa gu la nt v ol un ta ry d on or r ec ip ie nt bl oo d is tr an sp or te d in a te m pe ra tu re -c on tr ol le d ha m pe r. pr ov id ed th e bl oo d is r et ur ne d w ith in 1 0 ho ur s of is su e, r em ai ns s ea le d in th e ha m pe r, an d th e te m pe ra tu re o f t he h am pe r do es n ot e xc ee d 10 °c , t he fe e fo r th e bl oo d w ill fa ll aw ay . h ow ev er , t he s er vi ce a nd la bo ra to ry te st c ha rg e w ill b e le vi ed . a s w ith a ny tr ea tm en t, th e pa tie nt h as th e ri gh t t o de ci de w he th er o r no t t o ac ce pt th e tr ea tm en t. a s fa r as p os si bl e, th e pa tie nt s ho ul d un de rs ta nd th e be ne fit s, ri sk s an d al te rn at iv es to tr an sf us io n as e xp la in ed b y th e pr es cr ib in g do ct or . i t i s re co m m en de d th at tr an sf us io n tr an sm is si bl e in fe ct io ns a nd r ec ei vi ng o f in co rr ec t p ro du ct s be m en tio ne d sp ec ifi ca lly . i nf or m ed c on se nt is a p ro ce ss w hi ch m us t b e ac kn ow le dg ed a nd d oc um en te d. fo r th e in fu si on o f w ho le b lo od a nd r ed c el l c on ce nt ra te . fo r th e in fu si on o f p la te le ts . fo r th er ap eu tic v en es ec tio ns . fo r bl oo d sa lv ag e an d su bs eq ue nt a ut ol og ou s re in fu si on . a p er so n w ho d on at ed b lo od o r a bl oo d co m po ne nt s w ith ou t c om pe ns at io n. a p er so n w ho r ec ei ve s bl oo d or b lo od p ro du ct s. lo ok -b ac k pr og ra m m e a fo rm al p ro ce ss fo r th e id en tif ic at io n of d on or s an d re ci pi en ts w ho te st p os iti ve fo r vi ra l m ar ke rs a ft er h av in g do na te d or r ec ei vi ng , r es pe ct iv el y, a u ni t w hi ch at th e tim e of is su e te st ed n eg at iv e. in c as es w he re th e re ci pi en t t es ts p os iti ve , t he d on or /s o f t he o ri gi na l u ni t/ s a re tr ac ed a nd te st ed to c on fir m w he th er th e in fe ct io n w as tr an sm itt ed v ia th e tr an sf us io n. in c as es w he re th e do no r te st s po si tiv e on a s ub se qu en t u ni t, th e re ci pi en ts o f t he p re vi ou s un it ar e tr ac ed a nd te st ed to c on fir m w he th er o r no t t he in fe ct io n w as tr an sm itt ed th ro ug h tr an sf us io n of b lo od o r bl oo d pr od uc ts h ae m ov ig ila nc e a s ys te m to d et ec t, ga th er a nd a na ly se in fo rm at io n on u nt ow ar d an d un ex pe ct ed e ff ec ts o f t he tr an sf us io n of b lo od a nd b lo od p ro du ct s june 2012, vol. 13, no. 2 sajhivmed 101 r ev iew popular misconceptions an hiv-infected patient doesn’t warrant transfusion as the prognosis is poor anyway anecdotal reports of patients dying following transfusion led to the unjustifiable practice of withholding blood transfusion from hiv-positive patients. at the start of the hiv pandemic, patients presented with advanced disease and generally had little prospect of effective management. today, with highly effective art and prophylaxis, hiv is a chronic manageable disease with an excellent outcome. transfusion best practice and a rational approach to the management of anaemia apply, independent of hiv status. moribund hiv+ patients require rapid correction of their anaemia again, best transfusion practice applies to the hiv-positive patient. rapid correction of chronic anaemia increases the risk of transfusion-associated circulatory overload (taco) and cardiac decompensation as would be encountered in any patient with severe chronic anaemia (see section on transfusion rates). hiv-positive patients with acute haemorrhage may require resuscitation and rapid transfusion, similarly to hivnegative patients. if a patient needs only one unit of blood, he/ she does not need blood at all the indication for transfusion is based on clinical symptoms and signs, and not on laboratory indices. patients should be evaluated after each unit transfused. a single unit transfusion, in the right circumstances, may be sufficient to stabilise the patient. ‘topping up’ the patient with additional blood after the indication for transfusion has been addressed, may confer additional unnecessary risk. disclaimer specific recommendations provided in this document are intended only as a guide to clinical therapy, based on expert consensus and best current evidence. treatment decisions for patients should be made by their responsible clinicians, with due consideration for individual circumstances. the most current peer-reviewed literature, reference text books and local guidelines should always be consulted. references and recommended reading 1. beal rw. the rational use of blood. australian and new zealand journal of surgery 1976;46:309-313. 2. evans rh, scadden dt. haematological aspects of hiv infection. baillière’s best practice & research clinical haematology 2000;13:215-230. 3. volberding pa, baker kr, levine am. human immunodeficiency virus hematology. hematology/ the education program of the american society of hematology american society of hematology education program 2003:294-313. 4. claster s. biology of anemia, differential diagnosis, and treatment options in human immunodeficiency virus infection. j infect dis 2002;185 suppl 2:s105-s109. 5. sloand e. hematologic complications of hiv 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neonates and older children. br j haematol 2004;124:433-453. 46. hu k, harrison lb. impact of anemia in patients 102 sajhivmed june 2012, vol. 13, no. 2 r ev ie w appendix 1: legal and human rights considerations with head and neck cancer treated with radiation therapy. curr treat options oncol 2005;6:31-45. 47. fenton pm. managing situations of acute blood loss with limited resources. transfusion alternatives in transfusion medicine 2008;10:82-89. 48. safe transfusion practice in sub-saharan africa a manual for field workers. 2010. http://www. safetransfusionmanual.org/2010/03/indicationssurgical-patient.html. 49. spence rk, carson ja, poses r, et al. elective surgery without transfusion: influence of preoperative hemoglobin level and blood loss on mortality. am j surg 1990;159:320-324. 50. carson jl, noveck h, berlin ja, gould sa. mortality and morbidity in patients with very low postoperative hb levels who decline blood transfusion. transfusion 2002;42:812-818. 51. nelson l, fried m, stewart k. the risks of surgery in hiv-infected patients. j perioper pract 2007;17:470. 52. avidan ms, jones n, pozniak al. the implications of hiv for the anaesthetist and the intensivist. anaesthesia 2000;55:344-354. 53. prout j, agarwal b. anaesthesia and critical care for patients with hiv infection. continuing education in anaesthesia, critical care & pain 2005;5:153-156. 54. committee for confidential enquiry into maternal mortality in south africa. saving mothers report, 2002-2004. confidential enquiry into maternal mortality in south africa. pretoria: department of health, 2006. 55. blood transfusion committee statistics. johannesburg: chris hani baragwanath hospital blood transfusion committee, 2010. 56. hytten f. blood volume changes in normal pregnancy. clinics in haematology 1985;14:601-612. 57. rose nc, mennuti mt. periconceptional folate supplementation and neural tube defects. clin obstet gynecol 1994;37:605-620. 58. van den broek nr, letsky ea. etiology of anemia in pregnancy in south malawi. am j clin nutr 2000;72:247s-256s. 59. prevention of mother to child transmission. pretoria: south african national aids council, 2010. 60. bendich a. calcium supplementation and iron status of females. nutrition 2001;17:46-51. 61. hallberg l, brune m, rossander l. iron absorption in man: ascorbic acid and dose-dependent inhibition by phytate. am j clin nutr 1989;49:140-144. 62. snower d, weil s. changing aetiology of macrocytosis: zidovudine as a frequent causative factor. am j clin pathol 1993;99:57-60. 63. blood transfusion in obstetrics. london: royal college of obstetricians and gynaecologists, 2007. 64. balakrishnan a, valsalan r, sheshadri s, pandit vr, medep v, agrawal rk. zidovudine-induced reversible pure red cell aplasia. indian journal of pharmacology 2010;42:189-191. 65. practice guidelines for obstetric anesthesia: an updated report by the american society of anesthesiologists task force on obstetric anesthesia. anesthesiology 2007;106:843-863. 66. cohen c, karstaedt a, frean j, et al. increased prevalence of severe malaria in hiv-infected adults in south africa. clin infect dis 2005;41:1631-1637. 67. malaria and hiv/aids interactions and implications: conclusions of a technical consultation convened by who. geneva: world health organization, 2004. 68. meremikwu m, smith hj. blood transfusion for treating malarial anaemia. cochrane database of systematic reviews (online) 2000:cd001475. 69. tolentino k, friedman jf. an update on anemia in less developed countries. am j trop med hyg 2007;77:44-51. 70. davenport gc, ouma c, hittner jb, et al. hematological predictors of increased severe anemia in kenyan children coinfected with plasmodium falciparum and hiv-1. am j hematol 2010;85:227233. 71. gwer s, newton crjc, berkley ja. over-diagnosis and co-morbidity of severe malaria in african children: a guide for clinicians. am j trop med hyg 2007;77:6-13. 72. guidelines for the treatment of malaria 2009, pretoria: department of health, 2009. 73. collier ac, kalish la, busch mp, et al. leukocytereduced red blood cell transfusions in patients with anemia and human immunodeficiency virus infection: the viral activation transfusion study: a randomized controlled trial. jama 2001;285:15921601. 74. drew wl, chou s, mohr ba, et al. absence of activation of cmv by blood transfusion to hivinfected, cmv-seropositive patients. transfusion 2003;43:1351-1357. 75. buskin se, sullivan ps. anemia and its treatment and outcomes in persons infected with human immunodeficiency virus. transfusion 2004;44:826832. 76. hébert pc, wells g, blajchman ma, et al. a multicenter, randomized, controlled clinical trial of transfusion requirements in critical care transfusion requirements in critical care investigators, canadian critical care trials group. new engl j med 1999;340:409-417. 77. moore rd. anemia and human immunodeficiency virus disease in the era of highly active antiretroviral therapy. semin hematol 2000;37:18-23. the use of blood and blood products raises two broad categories of legal and human rights considerations: the rights of donors and the rights of recipients. much of the debate regarding blood, blood products and hiv has historically focused on the rights of people to be protected from infection; very little focus has been placed on the rights of people living with hiv insofar as access to blood and blood products is concerned. this appendix expands on both categories of rights bearers – including the legal requirements of informed consent – as well as the issue of confidentiality as it relates to the communication of information on a patient’s hiv status. informed consent south african law has recognised the concept of informed consent for many years.1,2, the right to informed consent has been fleshed out by way of case law,3 regulatory council guidelines,4 the patients’ rights charter, and legislation.5 in particular, the national health act 61 of 2003 (nha) has codified the law on informed consent and defines it as consent for the provision of a specific health service; the act further stipulates that informed consent may only be provided by a person with legal capacity to do so, and that the person providing consent has been adequately informed.6 the law on informed consent is based on the notion that a patient – referred to in the nha as a user – has the right to participate in any decision affecting his or her personal health and treatment.7 if, however, the circumstances prevent the user from making the decision himself or herself, the nha provides guidance on how to proceed.8 confidentiality the communication of any information pertaining to a patient’s hiv status, whether positive or negative, is subject to the confidentiality provisions in the nha.9 section 14 of that statute makes it clear that ‘[a]ll information concerning a user, including information relating to his or her health status … is confidential.’ this guarantee is subject to the provisions of section 15, which deals with access to health records. simply put, section 15(1) ensures that the guarantee of confidentiality should not stand in the way of running an efficient and effective blood service, including the appropriate handling of blood and blood products. the rights of donors in considering the rights of donors, two key questions arise: (i) is there a right to donate blood?; and (ii) can blood services be used as a testing facility to determine an individual’s hiv status? is there a right to donate blood? there is no right to donate blood. on the contrary, blood services are constitutionally obliged to take all reasonable steps to ensure a safe supply of blood and blood products. by necessity, this implies refusal to accept as donors those at high risk of carrying a transfusion-transmissible pathogen (such as hiv). however, the manner in which donors are treated may not result in the violation of fundamental constitutional rights and values. the need to protect public health cannot be done in a manner that unreasonably and unjustifiably limits rights. if it did, potential donors would have legal recourse to vindicate their rights. june 2012, vol. 13, no. 2 sajhivmed 103 r ev iew can blood services be used as a testing site to test for hiv? while potential donors should be discouraged from using blood donation services for the purpose of establishing their hiv status, there is nothing in the law that can be used to prevent this from happening. both donor education and evidencebased self-exclusion questionnaires serve as appropriate means to discourage and defer those at risk of hiv infection from donating blood. provision of alternative hiv counselling and testing services also help to prevent the blood collection centre from being used as a default testing site. this relies on the premise that alternative testing services, of high quality, rendered in a nondiscriminatory way, are available outside of hiv-specific service points and are either free or affordable at point of delivery. the rights of recipients in considering the rights of recipients, two key issues arise: (i) the right to have access to safe blood and blood products; and (ii) the rights of terminally ill patients. right to have access to blood and blood products. the right to have access to health services, which includes access to blood and blood products, is guaranteed in section 27 of the constitution. the central issue is whether access to blood and blood products can be denied solely on the basis of hiv status. this raises concerns of health rights as outlined in section 27; it also breeches the constitutional guarantee of equality and protection against unfair discrimination. in this regard, two constitutional court decisions are relevant.10,11, read together, the cases are clear: given that hiv infection is a chronic manageable condition for those with access to appropriate treatment and care, it would not be reasonable to limit access on the basis of hiv status alone.12 the right of access to safe and adequate blood and blood products obligates blood services to take all reasonable measures to ensure that such products are indeed available and safe for use; such measures do not require a blood service that is 100% safe, as the technology to ensure this does not exist. where people have been exposed to unsafe blood and/or blood products despite blood services having acted reasonably, the latter cannot be held liable for any resultant harm. on the other hand, donors who have acted unreasonably – such as by misrepresenting their actual risk of infection in self-exclusion questionnaires – may indeed be sued for damages.13 in addition to civil liability, such a donor may also be criminally liable. rights of terminally ill patients. the right to have access to health care services does not impose an obligation on the state – and those who provide public services – to ensure that everyone receives every health service they need. instead, it is an obligation to ‘take reasonable legislative and other measures, within … available resources, to achieve the progressive realisation of [the right]’.14 this was made clear in soobramoney v minister of health, kwazulu-natal.15 in its judgment on mr soobramoney’s appeal, the constitutional court adjudicated the claim on the basis of the state’s positive obligations under section 26(2), holding that the guidelines according to which access was limited were reasonable and had been applied ‘fairly and rationally’.16 in the result, the state had complied with its section 27(2) obligations. the primary responsibilities of the physician are to assist the patient in maintaining an optimal quality of life by controlling symptoms and addressing psychosocial needs, as well as enabling the patient to die with dignity and in comfort.17 it is considered ethically justifiable to discontinue life-sustaining treatment if the patient has the ability to make that decision, fully understands its consequences, and states that they no longer wish to continue treatment. a decision to withhold or withdraw life-prolonging treatment should be only be made by the senior clinician in charge of a patient’s care, informed by the patient’s views or those closest to him or her.18 there may be circumstances when withholding treatment, even if it is not requested by the patient, may be permissible. this may apply, for example, in cases akin to that of soobramoney. ordinarily, it would not be justifiable to discontinue life-sustaining treatment for cost reasons alone. that said, there may be cases in which the costs expended on one terminally ill patient could be better used on another patient with an improved outlook.19 in such circumstances, a health care facility may have the right to limit access to life-sustaining interventions, provided that such a limitation is based on reasonable national admission criteria developed by expert professional bodies, such as the hpcsa.20 appendix 1 citations 1. 1923 cpd 128. 2. anneke meerkotter, ‘the rights and duties of users of the health care system’, in adila hassim et al, health & democracy: a guide to human rights, health law and policy in post-apartheid south africa (cape town: siber ink, 2007:249. 3. see, for example, castell v de greef 1994 (4) sa 320 (c); c v minister of correctional services 1996 (4) sa 292 (t). 4. such as the health professions council guideline for good practice in medicine, dentistry and medical sciences 5. in particular, consider the children’s act 38 of 2005 and the national health act 61 of 2003. 6. above note 2 at page 252. 7. this is codified in section 8 of the nha. 8. see generally sections 7 to 9 of the nha (in chapter 2 entitled rights and duties of users and health care personnel). see also sections 129 and 130 of the children’s act. 9. as is the case with the provisions of the nha dealing with informed consent, the nha also codifies the common law – decisions of the courts – on confidentiality. this is underpinned by the constitutional guarantee of privacy. 10. 2001 (1) sa 1 cc. 11. 2004 (6) sa 505 (cc). 12. this position is supported by the isbt code of ethics for blood donation and transfusion which states that ‘blood is a public resource and access should not be restricted’ (see above note 10 at paragraph 10). 13. in canadian blood services/société canadienne du sang v freeman [2010] onsc 4885), a gay man who knowingly provided false information on a self-exclusion questionnaire was successfully sued by the blood services for negligent misrepresentation. his blood sample, which was tested and resulted in a false negative for syphilis, subsequently tainted an entire unit of blood. it is likely that the case, if decided under our constitution, would have been decided differently. however, the principle of negligent (material) misrepresentation would stand. 14. section 27(2) of the constitution. 15. 1998 (1) sa 765 (cc). 16. at paragraph 25. 17. at principle 5. 18. at section 3. 19. see section 9.1. 20. at section 9.2. see also paragraph 3 of the preamble to the world medical association (wma) declaration on terminal illness, first adopted by the 35th world assembly (october 1983) and revised by the wma general assembly in october 2006. that preamble recognises that many palliative and life-sustaining measures require technologies and/or financial resources that are simply not available globally. the declaration is available at http://www.wma. net/en/30publications/10policies/i2/. 104 sajhivmed june 2012, vol. 13, no. 2 n o t es 5 no, i am not on sabbatical on a tropical island! however, it has been a great pleasure to have the journal guest-edited again for the last edition of 2009 by a superb duo: leon levin and mark cotton. mark cotton is a specialist in paediatric infectious diseases at tygerberg children’s hospital and head of its paediatric infectious diseases unit, affectionately known as kidcru. his main focus is to extend and enhance care through research, with a special interest in children affected by hiv. mark has been involved in some key studies that have shaped paediatric practices and guidelines in southern africa. he also serves as advisor and investigator to a number of international institutions and networks. dr leon j levin graduated mb bch at the university of the witwatersrand in 1987. after training in paediatrics at the wits group of hospitals in johannesburg, he obtained his fcpaed (sa) in 1994. in february 1996 he founded the paediatric hiv clinic at johannesburg hospital, and more recently he has run the paediatric division of right to care. leon has been chairman of the paediatric subcommittee of the sa hiv clinicians society since 1999 and runs the society´s paediatric discussion group, an internet-based forum for paediatricians to discuss and learn about problems in children with hiv. in this edition, besides a fabulous array of paediatric material, we publish the updated paediatric guidelines. with so much positive energy around better hiv support recently, from the highest level, we are confident that we can do better, especially in the important area of paediatric aids. we will kick 2010 off with our usual diverse submitted copy, so please keep sending. review processes will also be improved. we hope it will be a bumper year in many ways, with record numbers of people starting and staying on art, a decreasing incidence of hiv, and millions of south africans testing. we also hope to have four bumper editions of the southern african journal of hiv medicine in 2010, which is set to be a memorable year for south africa. linda-gail bekker editor f r o m  t h e  e di torf r o m t h e e di tor the journal is starting to feel like men’s health, what with posters, guidelines and now a state-of-the art science update, hiv treatment bulletin, falling out of it. exco is pleased to announce an important and strategic partnership with hiv ibase, who publish hiv treatment bulletin. we are distributing the southern african version of their excellent newsletter, which will exclusively focus on the scientific reports and resources that have local relevance – with a strong focus on paediatrics and maternal health. hiv treatment bulletin neatly complements the journal, providing the snobbish clinician and scientist with the most hot-off-the-press analysis of recent clinical trials and basic science research. policy makers can authoritatively pronounce at their guidelines meetings, clinicians can expand their patients’ options, and, most importantly, you can show off at ward rounds. thanks to all the people at i-base, this is a major step forward for quality information sharing. we wish the new health minister, barbara hogan, all the best. she has very small shoes to fill, but a mammoth task ahead of her to repair south africa’s woeful health service. at the time of writing, she and her deputy, dr molefi sefularo, have been very impressive, dealing with a cholera disaster, drug stock-outs, issues of prevention, releasing controversial reports that were stuck on her predecessor’s desk for months, and a dozen other complex health problems. finally, the exco welcomes two new members based in durban, professor yunus moosa and dr henry sunpath, both highly respected clinicians and part of the team responsible for an excellent hiv clinical conference held in october. francois venter president this spring edition brings 2008 to a close. and what a year it has been. not many breakthroughs in hiv or tb, but a lot of activity in terms of understanding early infection better, really getting to grips with early immune responses, and again thinking through our prevention options. in 2008 the concept of antiretrovirals for prevention as well as treatment has come to the fore with second-generation microbicides, pre-exposure prophylaxis and the notion that we may be able to ‘treat our way out of the epidemic’ becoming possibilities. gratifyingly, this year also saw a record number of people being tested and accessing art, and roll-out for both testing and treatment is truly scaling up. as chairperson of the 4th southern african hiv conference i must encourage every one of you to think seriously about coming to durban on 31 march. it promises to be a critical conference where we will really formulate the key steps in getting pmtct, treatment, testing and prevention out there on a scale that will begin to turn the sa statistics around. (i promise that it will also be loads of fun!) please note the early date this year: 31 march to 3 april. this is to ensure brilliant kzn weather! in this edition, we already begin to examine some of these key scale-up questions: jerome singh explores the ethics and legality of traditional healers performing hiv testing (i know many have asked why this has to be the domain of nurses only). francesca esposito and her team examine changes in body composition in women taking antivirals in a kzn clinic. we look at the role of mobile phones in the hiv response with william mapham, and polly clayden gives us pointers to starting infants on art. the role of a liver biopsy in diagnosis of opportunistic infections is described by mark sonderup and colleagues. the vexed question of when it is deemed safe to start haart in patients co-infected with tb is discussed by robin wood, and francois venter and colleagues give a practical view on new antiretrovirals on the horizon for south african practitioners. no guidelines in this issue, but i will whet your appetites – look out for guidelines on prevention of tb occupational exposure for hiv-infected health care workers and on the non-infertile hiv infected couple, hot stuff coming up in the new year! happy reading and every best wish for a restful and peaceful festive season from the whole editorial team. see you next year! linda-gail bekker editor m e s s a g e f r o m t h e e x e c u t i v e msg from the executive.indd 5 12/17/08 3:16:23 pm treating hiv-infected children this edition sees the publication of the fourth sa hiv clinicians society paediatric antiretroviral therapy (art) guidelines. previously it has not been possible to have one guideline for the whole country because of wide discordance between the government and private sectors. this year, for the first time, our guideline is applicable to both the private and public sectors. inevitably some differences remain and are addressed in the document. they include choice of first-line regimen and genotyping recommendations. the national department of health (ndoh) is still updating its guidelines, hopefully for publication in early 2010. we hope you will find the society’s guidelines pragmatic and helpful. we have the potential to save and improve many young lives. we thank all those involved in the writing of the guidelines, especially our fellow member of the writing committee, dr tammy meyers, and our overseas reviewers. as has been done previously when paediatric guidelines have appeared, the entire issue is devoted to paediatrics. we hope it will be useful as a ready reference on paediatric hiv management for all health care workers caring for children. e di tor i a l the southern african journal of hiv medicine                                                      december  2009 m e s s a g e   f r o m    t h e   e x e c u t i v e the global recession has thrown the problem of funding for aids programmes to the fore, with botswana’s president saying his country’s programme is unsustainable, and donors sounding warnings that rationing may need to be implemented. this is very alarming – we have made big strides in terms of antiretroviral access in the last few years, and these are suddenly looking very fragile. it is time to take stock of our programmes and make them as lean and mean as possible, ensuring maximum access to care while ensuring acceptable levels of quality. we need to look critically at the labs we ask for and the drugs we need, while keeping up pressure on the donor community to maintain support. however, we should not let our governments off the hook. health in southern africa has been consistently underfunded as a function of the gross domestic product, in almost every one of our countries. guns, presidential inaugurations and motorcades never seem to be a problem to fund, and we need to do a better job at the southern african journal of hiv medicine                                                      december  20096 we begin with an opinion piece by heather jaspan, rachel li, leigh johnson and linda-gail bekker on the urgent need to develop skills and infrastructure to meet the needs of hiv-infected adolescents, especially given our success in treating children with art. we then address prevention of vertical transmission of hiv, the key to the elimination of hiv infection in children. the paper by laurie schowalter, ashraf coovadia and ameena goga is a plea for action. it is followed by an analysis of vertical transmission data (mark cotton, soyeon kim, helena rabie, joan coetzee and sharon nachman, from the pactg 1041 team), emphasising again the importance of a good antenatal antiretroviral component. infant feeding is integral to child survival and development. there are risks and benefits for breast and replacement feeding. the paper by ameena goga is essential reading for anyone caring for infants and provides the key data to inform rational decision making. the guideline document emphasises the importance of and pitfalls in maintaining adherence. a number of articles provide background information to help in understanding the rationale of recommendations in the guidelines. these include articles on when to start (mark cotton, helena rabie, ute feucht and avy violari), essential pharmacokinetic information (helen mcilleron and hermien gous) and how the weight-based dosage recommendations were derived (james nuttall). what do you do when children starting art deteriorate instead of improve? helena rabie, tammy meyers and mark cotton delve into the paradoxical world of immune reconstitution inflammatory syndrome (iris). we then highlight two adverse events of art, one common and the other rare. the ndoh guidelines do not advocate using abacavir (abc) in the first-line regimen in the absence of adverse effects from other drugs. they still recommend d4t, increasingly implicated in lipodystrophy. lipodystrophy can be reversible if the offending agent (usually d4t) is replaced with abc (or tenofovir in adults) in the early stages. steve innes, leon levin and mark cotton provide background information and useful diagnostic and management advice for lipodystrophy. the sa clinicians society advocates 3tc and abc as the nrti backbone for the first-line regimen. there is much fear of the infamous abc hypersensitivity reaction (hsr). to the best of our knowledge, no one has ever died from the reaction, but people have died from abc rechallenge. fortunately the hsr is rare in black africans. helena rabie, kristin henning, pierre schoeman, nico de villiers, gert h j (oubaas) pretorius and mark cotton provide guidelines for using abc and recount their experience with suspected abc hsr. treatment failure is becoming increasingly complex. fortunately, there are quite a few new antiretrovirals registered overseas and about to be registered in south africa. leon levin takes us through the minefield of paediatric salvage therapy. finally, polly clayden presents us with some cuttingedge reports from the recent international aids society conference in cape town, again informing readers of the type of research needed to continually improve our guidelines. mark cotton leon levin guest editors drawing attention to how health budgets are allocated. in south africa it seems that jacob zuma’s government has declared war on overall wasteful expenditure, and at the same time there has been increasing embarrassing public exposure of ministerial spending on large cars. a new and energetic health minister, aaron motsoaledi, seems intent on reversing the terrible sins of the past under mbeki’s regimen, and to be determined that health resources get used better. please let the society know if you see any indication of rationing! we have active advocacy work, with good partners, and it is to be hoped that we can stop unnecessary restrictions on health care. francois venter president southern african hiv clinicians  society paediatric discussion  group (pdg) the southern african hiv clinicians society paediatric discussion group (pdg) began in december 2001. the concept was born after dr (now adjunct professor) ashraf coovadia of the rahima moosa mother and child hospital, coronationville, johannesburg, sent an e-mail to 5 or 6 local hiv ‘experts’ and professor mark kline of the baylor college of medicine, houston, texas, seeking advice on how to manage a child with severe disfiguring parotomegaly but who had a normal cd4 count, so antiretroviral therapy (art) was not indicated. the answer came back that there was no indication for art for a purely cosmetic condition! i found the concept fascinating and wondered if there was any value in using e-mails as a vehicle for educating health care providers about paediatric hiv. i contacted the south african hiv clinicians society, who were happy with the concept and provided me with a list of their members. the list in those days was very short (unlike today), and i tried to fathom out who was a paediatrician or treated paediatric cases and added them to the mailing list. the first few cases hardly garnered a response. i suspect people were too shy to answer. after a few weeks i would send out an expert opinion. the cases were all real cases (mostly from my own practice), and all had excellent lessons to teach. gradually, as knowledge and familiarity with pdg grew, so the number of responses increased. currently it’s not unusual to have over 100 responses to a case. the cases have spanned the whole range of paediatric hiv issues including opportunistic infections, side-effects of art and ethical issues. at the moment we are concluding pdg no. 51. some notable cases include: n one of the earliest cases in south africa of cushing’s syndrome caused by an interaction between ritonavir and inhaled fluticasone for asthma. n a child from a neighbouring country who was diagnosed as hiv-positive on two different tests and turned out to be hiv negative. n an hiv-positive child with marked failure to thrive and a normal cd4 count who turned out to have an oesophageal stricture and is now thriving after oesophageal dilatation. n cases of lymphoma and kaposi’s sarcoma. n a case where a mother with end-stage hiv had a negative hiv elisa test, having lost the ability to make antibodies due to her poor immunity. n a case of a young infant treated with art very early on who became hiv elisa negative after losing her maternal antibodies. she did, however, remain pcr positive. n interestingly, pdg no. 47 in april 2008 again discussed a patient with disfiguring parotomegaly and a normal cd4 count. this time the opinion was overwhelmingly in favour of starting art. the response to the pdg has been phenomenal. the mailing list currently stands close to 1 500. subscribers are predominantly from south africa but also include namibia, zimbabwe, botswana, zambia, angola, malawi, kenya, rwanda and other countries. subscribers are predominantly doctors but also include nurses, pharmacists, and counsellors. there is no doubt that the pdg has succeeded because of the very active participation of our subscribers and our wonderful panel of local and overseas experts, all of whom deserve my heartfelt thanks. i have merely been the conduit between the two. if you would like to subscribe to the pdg, please send an e-mail to leonlevin@54.co.za. i am also constantly on the lookout for new cases to discuss. they can be sent to the same e-mail address. leon levin head, paediatric programmes right to care m e s s a g e   f r o m   t h e   pa e di at r ic    s u b c o m m i t t e e the southern african journal of hiv medicine                                                      december  20098 s e p t e m b e r 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e the immune reconstitution inflammatory syndrome (iris) is a frequent early complication of antiretroviral therapy (art), particularly in patients who commence art with low cd4 counts and established opportunistic infections. iris in hiv-infected patients results from a pathological inflammatory response to pre-existing infective, host or other antigens, alive or dead, causing clinical deterioration after initiating art.1 the most common forms of iris occur in association with mycobacterial and herpesvirus infections.2 adolescents and young adults comprise an increasing proportion of new hiv infections both in developing and developed countries, and little is known regarding hiv iris in this group. as the art roll-out has gathered pace since 2004 in resource-limited settings, adolescent iris has emerged as a clinical challenge. we describe adolescent/young adult patients who presented to our clinic with iris events. methods the study was performed at the adult infectious diseases institute (idi) at mulago hospital, kampala, uganda. the aidc is part of the makerere university infectious diseases institute and provides hiv care, including free art, to hiv-infected patients with a cd4+ count <200 cells/µl or with world health organization stage iv disease. the study was approved by the ethics panel and the institutional review board since this was a case series. among our adolescent/ young adult cohort aged 16 24 years of about 480, we have seen 6 cases of iris, including cryptococcal meningitis iris, kaposi’s sarcoma iris, herpes zoster iris, pulmonary tuberculosis iris and 2 cases of oral candidiasis iris within the past 12 months. the incidence of iris after initiation of haart was 1.25%. the median age of presentation was 22 years and the median cd4+ count before commencing art 65 cells/ µl. iris presented a median of 6 weeks from the start of haart (range 3 16 weeks). mycobacteria are by far the most common pathogens associated with iris in hiv-infected patients.3-7 other infections that have been associated with iris events include varicella zoster, herpes simplex, meningeal cryptococcosis, hepatitis, cytomegalovirus retinitis, progressive multifocal leuco-encephalopathy and intestinal parasites. while the majority of iris events are infectious in nature, auto-immune iris reactions have also been described in adults.8 discussion iris is a condition seen in some cases of aids or immunosuppression, in which the immune system begins to recover but then responds to a previously acquired opportunistic infection with an overwhelming inflammatory response that paradoxically makes the symptoms of infection worse.9 it is thought that the immunopathological response initiated by haart restores the immune response against pathogenic antigens.10 there is paradoxical worsening of preexisting infectious processes following initiation of haart in hiv-infected individuals.9 these cases highlight the risks faced during immune reconstitution in adolescent and young adult patients who commence art with advanced immunosuppression. immune reconsitution inflammatory syndrome among adolescents: a report of cases in a resource-limited setting (uganda) o r i g i n a l a r t i c l e christine katusiime1, mb chb, pgdppm ponsiano ocama2, mb chb, mmed andrew kambugu1, mb chb, mmed 1makerere university, college of health sciences, infectious diseases institute, kampala, uganda 2makerere university, college of health sciences, department of medicine, kampala, uganda we report immune reconstitution inflammatory syndromes in a cohort of adolescents/young adults over a period of 1 year at the infectious diseases institute, kampala, uganda. 18 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s e p t e m b e r 2 0 1 0 conclusion iris occurs in adolescents and young adults, but little is known about iris in general and minimal research has been conducted in the adolescent/young adult age group. references 1. lehloenya r, meintjes g. dermatologic manifestations of the immune reconstitution inflammatory syndrome. dermatol clin 2006; 24: 549-570. 2. french ma. disorders of immune reconstitution in patients with hiv infection responding to antiretroviral therapy. curr hiv/aids rep 2007; 4: 16-21. 3. fishman je, saraf-lavi e, narita m, hollender es, ramsinghani r, ashkin d. pulmonary tuberculosis in aids patients: transient chest radiographic worsening after initiation of antiretroviral therapy. ajr am j roentgenol 2000; 174: 43-49. 4. french ma. ‘tuberculosis’ after commencing antiretroviral therapy in hiv patients from countries where mycobacterium tuberculosis infection is common. aids 2006; 20: 473-474. 5. john m, french ma. exacerbation of the inflammatory response to mycobacterium tuberculosis after antiretroviral therapy. med j aust 1998; 169: 473-474. 6. narita m, ashkin d, hollender es, pitchenik ae. paradoxical worsening of tuberculosis following antiretroviral therapy in patients with aids. am j respir crit care med 1998; 158: 157-161. 7. phillips p, kwiatkowski mb, copland m, craib k, montaner j. mycobacterial lymphadenitis associated with the initiation of combination antiretroviral therapy. j acquir immune defic syndr hum retrovirol 1999; 20: 122-128. 8. viani rm. sarcoidosis and interstitial nephritis in a child with acquired immunodeficiency syndrome: implications of immune reconstitution syndrome with an indinavir-based regimen. pediatr infect dis j 2002; 21: 435-438. 9. desimone ja, pomerantz rj, babinchak tj. inflammatory reactions in hiv infected persons after initiation of highly active antiretroviral therapy. ann intern med 2000; 133: 447-454. 10. french ma, price p, stone sf. immune restoration disease after antiretroviral therapy. aids 2004; 18: 1615-1627. age (yrs) cd4 counts at initiation of haart (cells/µl) iris condition time from start of haart to onset of iris (wks) 19 45 pulmonary tuberculosis 4 20 77 oral candidiasis 6 21 56 kaposi’s sarcoma 3 23 65 herpes zoster 9 24 65 cryptococcal meningitis 16 24 73 oral candidiasis 6 table i. table displaying ages, absolute cd4 counts and presentation time of iris among adolescents/young adults over 1 year at the infectious diseases institute, kampala 19 to the editor: we at the south african national blood service (sanbs) are acutely aware of the issues surrounding the exclusion of men who have sex with men (msm) from donating blood and the negative emotions that surround this policy. i would like to assure readers that sanbs does not make such decisions lightly, and we constantly review policies based on the latest scientific findings. it is perhaps time to review the basis of the current policy and engage in debate on its scientific merit. it is, however, important to clarify a few misconceptions regarding our policies on the sexual activities of our donors. in an editorial comment on 6 january 2010, the editor of the herald newspaper in port elizabeth stated: ‘a pattern of multiple partners or of unprotected sex … is clearly also high-risk and yet heterosexual donors who may be sexually reckless are spared prying questions and the possible refusal of their offer of blood.’1 this statement is factually incorrect. when donating blood, all donors, whatever their sexual orientation, have to answer very personal questions regarding their sexual activities during the preceding 6 months.2 any person who has had any form of potentially high-risk sexual activity will be deferred for a period of 6 months following the high-risk activity. a donor who has multiple sex partners will be regarded as being at potentially high risk regardless of sexual orientation. at no point does sanbs suggest that high-risk sexual practices are exclusive to the gay community, hence the self-exclusion questionnaire’s comprehensive set of questions regarding various sexual activities and practices. there are over 450 rules guiding donor selection with sanbs’s policy on blood donations from men who have sex with men l e t t e r • l e t t e r • l e t t e r • l e t t e r s e p t e m b e r 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e regard to medical conditions and lifestyle, and there are many groups of people whom we defer from donating, either temporarily or permanently.3 some individuals in these groups may have a very low risk of blood-borne infections and their blood would probably be safe to give to patients, but since it is impossible to identify specific individuals at low risk it is safest to ask everyone in the higher risk groups not to donate blood. the request not to donate blood can be disappointing and frustrating to some people who wish to do so. our decisions are based on information and research about the effects our policies on blood supply safety, not out of a desire to discriminate against any particular group. the aims of donor selection are to: n select donors whose blood is most unlikely to transmit any infection n collect enough blood to meet patients’ needs n make sure that donors themselves come to no harm through the blood donation process. we have to balance these three aims while keeping the selection process clear and simple, bearing in mind that almost a million units of blood are collected each year – a mammoth task complicated by stringent quality control and logistics. the preliminary findings of recent studies among msm, such as the jems study conducted in johannesburg and durban and the soweto men’s study, have found their hiv prevalence to be more than double the actuarial scientists of south africa (assa)’s estimate of a 15.5% national hiv prevalence and the unaids estimate of 18.1%.4-8 south africa was one of the first countries in the world to lift the total ban on men who have sex with men donating blood. other countries such as sweden are only now starting to follow our example. we still have among the most progressive policies regarding msm in the world, and while this may not be much consolation to gay men in stable relationships, it is testimony to sanbs’s commitment to be as inclusive as possible with regard to the community we serve. internationally this is a very topical discussion. it is interesting to note that in the usa some politicians have called for the lifting of the ban against msm donating blood and that this was countered by the haemophiliac society, a group whose members were severely affected by infected blood during the 1980s. it is easy to get lost in all the numbers and emotions, but at sanbs we have the very tough responsibility of weighing up the right of an individual to donate blood against that of a patient to receive blood that is as safe as it is humanly possible to make it. the decision on which groups of the population will be or should be allowed to donate must be taken on the basis of scientific merit and the blood service’s ability to implement policies that are clear and concise. karin van den berg zone medical officer, eastern cape south african national blood service references 1. the editor. the herald, port elizabeth, 6 january 2010. 2. south african national blood service. comprehensive donor questionnaire. frmdcd-016e rev 1 (02-03-09). 3. south african national blood service. guidelines for medical assessment of blood donors. 3rd ed. pm-med-001 rev 2 (01/10/2006). 4. rispel l, metcalf c. hiv prevalence and risk behaviour among men who have sex with men (msm) in the johannesburg/ethekwini men’s study (jems). 4th south african aids conference, 31 march 3 april 2009, durban. abstract 586. 5. metcalf c, rispel l. to what extent does the hiv epidemic among men who have sex with men (msm) overlap with the generalised hiv epidemic in south africa. preliminary findings from the johannesburg / ethekwini mens study (jems). 4th south african aids conference, 31 march 3 april 2009, durban. abstract 597. 6. lane t, raymond h, dladla s, et al. high hiv prevalence among msm in soweto: results from the soweto men’s study. 4th south african aids conference, 31 march 3 april 2009, durban. abstract 597. 7. actuarial society of south africa. assa2003 aids and demographics model. 2005. http://aids.actuarialsociety.org.za/assa2003-model-3165.htm (accessed 13 may 2009). 8. unaids. http://www.unaids.org/en/countryresponses/countries/south_africa. asp (accessed 13 may 2009). 22 erratum in ‘changes to the art guidelines – an overview’, which appeared on pp. 28 30 of the april 2010 issue of the journal, the first sentence under the heading ‘national regimens’ and the heading to table i should have read ‘national regimens for adults and adolescents’ and not ‘national regimens for children and adolescents’. we apologise for these errors and have corrected them on the web version of the article, in which there are also other adjustments. october 2009                                                           the southern african journal of hiv medicine                                                   hiv infection of the central nervous system occurs almost simultaneously with systemic infection. primary neurological disorders can affect the brain (e.g. hiv-associated dementia), spinal cord (e.g. hivassociated vacuolar myelopathy) and meninges.1 hiv-associated dementia (had) has also been referred to as hiv encephalopathy or aids dementia complex. these terms have been used interchangeably and describe a syndrome that includes the symptom triad of psychomotor slowing, memory impairment and behavioural problems. we now understand that neurocognitive impairment (nci) in hiv is a spectrum of disorders.2 in addition to had, lesser forms of nci have also been described, namely hiv-associated minor cognitivemotor deficit (now called mild neurocognitive disorder) and asymptomatic neurocognitive impairment (ani).3 these disorders now fall under the new term hiv-associated neurocognitive disorder (hand) (table i). the diagnosis of hand requires a history, clinical examination, appropriate investigations and neuropsychological testing. this review presents the clinical features, diagnostic criteria and tools to help diagnose hand. hiv neuropathogenesis is not fully understood. it is unclear whether the cognitive decline seen in hiv-infected people is partly or wholly due to the direct effects of hiv, to secondary effects from the chronic hyperimmune activation, to other immunological factors (e.g. cytokines, chemokines and tumour necrosis factor) in the cns, or to other factors such as hepatitis co-infection and clade diversity. however, it is understood that:4 n hiv does not infect the neurons and oligodenrocytes but the monocytes, microglia, astrocytes and endothelial cells. n once in the cns the virus persists and evolves into different strains independent of the systemic reservoir. n hiv is not evenly distributed in the cns, and has a predilection for the basal ganglia. n hiv rna levels in the cerebrospinal fluid do not correlate with those in the peripheral circulation, especially in advanced hiv disease. involvement of the basal ganglia accounts for the clinical distinction between ‘subcortical dementia’ seen in had and the ‘cortical dementia’ typically seen in alzheimer’s disease. had occurs in approximately 10 15% of all individuals with hiv/aids and is more common in late stages neurocognitive impairment in plwha: clinical features and assessment c l i n i c a l : d e m e n t i a dinesh singh, mb chb, mmed (psych), fcpsych (sa), ms (epi)(columbia, usa) department of psychiatry, nelson r mandela school of medicine, university of kwa-zulu natal, durban neurocognitive impairment (nci) occurs in 10 60% of people living with hiv/aids (plwha), depending on the severity of the nci and the stage of the disease. the clinical features and definitions have evolved over the past two decades. hiv-associated neurocognitive disorder (hand) is a new term used to describe the spectrum of neuro cognitive impairment seen in hiv/aids. the earliest to most advanced stages are asymptomatic neurocognitive impairment (ani), minor neurocognitive disorder (mnd) and hiv dementia (had), respectively. people with hand have impairment on multiple cognitive domains, including attention, concentration, memory, executive function, motor functioning and speed of information processing, and sensory perceptual/motor skills deficits. the milder forms of hand are easily missed. diagnosis can be made on clinical grounds in the most severe cases; however, milder forms and confirmation of the diagnosis require neuropsychological testing. screening tests have limited utility, especially in the milder forms of hand. individual subtests derived from longer neuropsychological batteries may be complementary in the diagnosis of hand. highly active antiretroviral therapy (haart) has led to a 40% decline in the incidence of had. in the post-haart era, had runs a more chronic course, is milder and is reversed in about a third of cases. however, haart is not universally successful because incident cases occur in people on haart. overall haart has been shown to be of benefit, and screening for hand should be the standard of care for plwha. had is an aids-defining illness and patients qualify for haart irrespective of their cd4 count. however, the benefit of starting arvs for people with ani and mnd is currently inconclusive. pathogenesis epidemiology 30 the southern african journal of hiv medicine                                                        october  2009   of infection.1 less severe forms of hand occur in 30 60% of people infected with hiv, depending on the stage of the disease.1 approximately 17% of the people attending a highly active antiretroviral therapy (haart) primary health clinic in cape town had some level of nci, including hand.5 the epidemiology of nci has changed distinctly with the introduction of haart. in the pre-haart era had was common and more severe, with death likely within 6 months of diagnosis.6 the introduction of haart led to a major decline in the incidence of had.1,6,7 however, data from cohorts on long-term haart in the usa show that incident cases of had occur despite haart, that progression of had is variable, and that nci seems to be milder.1 the overall prevalence of hand continues to rise, presumably owing to incomplete reversal or prevention of cognitive impairment, longer survival on haart and an increasing hiv prevalence. at present there are no guidelines that recommend specific haart regimens for the treatment or prevention of hand. however, epidemiological data suggest at least partial benefit in giving haart to prevent and reverse hand.7-9 had is an aids-defining illness and people with had qualify for haart irrespective of cd4 counts. there is therefore an urgent need to raise awareness and develop rapid screening tools to detect and monitor hand. most clinicians can recognise frank had, but the more subtle hands are easily missed. hand is: (i) a cognitive disorder, accompanied by (ii) motor dysfunction and/or (iii) behaviour problems. cognitive changes are problems with memory, decreased attention and concentration. these patients have decreased ability to learn new information and the speed at which they process information and mental tasks is slower than normal. executive functioning, which includes planning, impulse control, organisation, abstract thinking and judgement, is also affected. motor changes are more subtle and are often missed. patients complain of changes in their handwriting, tremor, and ‘clumsiness’. they have gait abnormalities in the late stages. behaviour problems vary and range from aggression or marked isolation to the vegetative state seen in the late stages when patients are mute, immobile and incontinent. the presentation is similar to that of severe depression, because patients appear very apathetic and amotivated, with lack of initiative and psychomotor slowing. the new classification requires systematic assessment of the following six domains:3 (i) attention-information processing; (ii) language; (iii) abstraction/executive; (iv) complex perceptual motor; (v) memory; and (vi) sensory perceptual/motor. assessment of these domains requires neuropsychological tests that are often not intuitive to the clinician. most clinicians can test memory with ‘bedside’ tests; however, assessment of executive functioning and psychomotor speed is more difficult. the challenge is to translate these research criteria and recommend specific tests that can be widely used by non-neuropsychologists. we can recommend a few tests that can assess these various domains (table ii). the distinction between ani, mnd and had depends on: (i) the severity of impairment (when compared with population ageand education-appropriate norms for the above domains); and (ii) level of functional impairment in everyday activities at work, home or socially. asymptomatic neurocognitive minor neurocognitive hiv-associated deficit (ani) disorder (mnd) dementia (had) level of impairment none mild everyday activities: reduced marked impairment in mental acuity, inefficiency in work, day-to-day activities homemaking or social activities at work, home or affected social functioning number sd below 1 2 population norm on neuropsychological test number of domains 2 impaired attention/working memory; verbal/language; abstraction/executive; complex perceptual motor; memory (learning and recall); speed of information processing; sensory perceptual/motor skills exclusion criteria absence of criteria for delirium or other causes for dementia. the condition cannot be explained by another co-morbid condition, e.g. substance abuse, infections, pre-existing neurological condition *summarised from antinori et al. 3 table i. criteria for hiv-associated neurocognitve impairment* clinical features 31 october 2009                                                           the southern african journal of hiv medicine                                                   asymptomatic neurocognitive impairment this is the mildest form of hand. the person has no impairment in everyday activities. they may complain of mild slowing in mental acuity and loss of concentration. abnormalities can only be detected by testing the six domains and comparing against population norms. patients must have 1 standard deviation (sd) abnormality on two of the six domains. ani can progress to the next stage in the spectrum of hand. minor neurocognitive disorder mnd was previously called hivassociated minor motor-cognitive disorder. mnd has the same criteria as ani, i.e. the patient has 1 sd abnormality on two of the six domains. unlike patients with ani, they have impairment in their daily activities, at work or in social functioning or homemaking. this can be by self-report or by observation by someone who knows the patient. hiv-associated dementia had is the most severe form of hand. by definition patients have at least 2 sd abnormality on two domains, and these deficits cause significant impairment in everyday activities.3 however, the clinical presentation can vary widely. in early had, the patient may appear depressed with apathy, lethargy and social withdrawal. personality changes are not uncommon, and are often reported more by others than by the patient. in late had, psychotic symptoms may be prominent along with severe language dysfunction, verbal memory loss, seizures and mutism. the patient may be incontinent of urine and stool. neurological examination may show interruption of smooth ocular pursuit, slowing or inaccuracy of saccades, hyper-reflexia, ‘frontal release’ signs, slowing of rapid alternating movement of fingers, wrist or feet, and ataxia. in the post-haart era the progression of had has changed. based on clinical observation of long-term treatment cohorts, three sub-types of had have been defined:7 1. sub-acute progressive dementia occurs in arvnaïve people and has a course similar to that observed in the pre-haart era. 2. chronic active dementia. these patients are on treatment but have poor adherence leading to viral resistance. they are at risk of developing other neurological complications. 3. chronic inactive dementia occurs in people who are adherent to haart and have undetectable viral loads. they have some recovery from neuronal injury and are neurologically stable. hand is a diagnosis of exclusion. other diseases that affect cns functioning, i.e. opportunistic infections, neoplasms, metabolic disturbances and iatrogenic complications, have to be systematically ruled out. delirium and substance use are common in hiv-infected patients. appropriate first-line investigations, e.g. a full blood count, assessment of kidney, liver and thyroid function, measurement of the vitamin b12 level and serological testing for syphilis, are necessary. lumbar puncture is also useful to exclude other opportunistic infections. the csf viral load is not useful in the diagnosis of hand and does not correlate with the severity of the impairment. neuro-radiological investigations, e.g. computed tomography and magnetic resonance imaging, are necessary to exclude conditions such as progressive multifocal leuco-encephalopathy and primary cns lymphomas that can mimic hand. however, in resource-constrained settings these investigations are not readily available and they are not vital in the absence of focal localising signs. with delirium and medical causes excluded, the diagnosis of hand requires testing of the six domains using neuropsychological tests. however, these are often impractical or not available in busy clinical settings. two-stage clinical work-up for hand neuropsychological test description domains assessed rey auditory verbal learning test recall as many words as possible from a list of 15 words memory grooved peg-board motor digit span forward patient is given an increasing number of random digits. attention and concentration they must repeat digits in the same order digit span backward patient is given an increasing number of random digits. attention, concentration they must repeat the digits in reverse order and working memory trail making test a join 25 circles with numbers in the correct sequence as motor and speed of quickly as possible. the numbers are distributed across the information processing page and are not in order trail making test b join 25 circles with numbers and letters in alternating motor and speed of sequence, i.e. join 1, a, 2, b, 3, c as quickly as possible information processing and executive function table ii. selected neuropsychological tests and the domains assessed 32 the southern african journal of hiv medicine                                                        october  2009   testing is commonly used in psychiatry. in the first stage a brief, bedside cognitive screening test is administered and people who screen positive can then be subjected to more detailed testing in the form of a neuropsychological battery. see fig. 1 for algorithm for assessing and managing newly diagnosed patients with hiv. cognitive screening work-up the mini-mental state examination (mmse) was validated for distinguishing alzheimer’s dementia from other dementing disorders.10 it is loaded with items that are representative of ‘cortical’ functions. since hand is primarily affects sub-cortical processes, the mmse is not ideal. it is not useful in detecting the milder forms of hand, and it is affected by age, education and cultural background.11 the hiv dementia scale comprises four items – an anti-saccadic eye movement error task, timed alphabet, verbal memory and copying a cube.12 two of these items are timed and therefore more sensitive to subcortical functions. this scale has been used in the usa13 and validated in south africa.5 however, observing the anti-saccadic eye movement requires training and is difficult for non-neurologists to administer.14 mental alternation test. patients are asked to count to 20, say the alphabet, and then alternate between the numbers and letters in the following fashion: ‘1-a, 2-b, 3-c ...’. progressing from the most recent number or letter to the next letter or number in the sequence is one alternation. the number of correct alternations in 30 seconds, discounting any errors, determines the fig. 1. summary assessment and management of neurocognitive function in newly diagnosed plwha. fig. 1. summary assessment and management of neurocognitive function in newly diagnosed plwha. classify as normal, ani, mnd or had assess all newly diagnosed hiv positive patients with neuropsychological subtests (tmt-a, tmt-b, dsf, dsb) ani and mnd had start arvs, monitor and reinforce adherence monitor, repeat in 6 months. if progress to had start arv treat depression and other medical conditions cd4 <200 cd4 >200 cd4 >200 baseline investigation e.g. fbc, u& e, lft – ct and lp (if indicated) 33 october 2009                                                           the southern african journal of hiv medicine                                                   score. the maximum score is 52 points, and a score of ≤15 indicates the need for more extensive cognitive testing. this tests a limited number of cognitive domains and is dependent on level of education.15 international hiv dementia scale (ihds). the ihds was tested in the usa and uganda and developed specifically for resource-constrained settings.14 it has three subtests: timed alternating hand sequence, timed finger tapping, and recall of four items after two minutes. this test has many advantages over its predecessors: it is brief, it can be completed in 2 3 minutes, and the patient does not need knowledge of english. it can be performed by non-neurologists and does not require any special equipment other than a stop-watch. the recommended cut-off score of 10 had 80% sensitivity and 55% specificity in the ugandan study.14 the specificity declines rapidly with small increment changes in the score, and this may limit its utility. while it has many advantages, validation studies are needed for our local population. neuropsychological battery. various neuropsychological test batteries have been proposed. longer batteries may take as long as 9 hours and brief batteries as little as 1 2 hours. further, the absence of local population norms may limit their utility.16 work to develop brief, normed bedside tests is underway (singh et al. – unpublished data) focusing on the separate domains of memory and recall, attention and working memory, speed of information processing, executive functioning, and motor abnormalities. we have collected population norms for the following bedside tests: digit span forward, digit span backwards, trail making test a and trail making test b. while these tests require training to conduct and are likely to be beyond the reach of a busy primary care hiv clinical service, they have an important role to play as part of specialist referral to diagnose hand. antiretroviral therapy haart has lowered the incidence of hand and improved patient outcomes, but haart is not universally successful in reversing or preventing hand.1 while haart can effectively suppress viral replication in the systemic circulation, its pharmacodynamics and effects on the virus in the cns are less clear. arvs, especially protease inhibitors, do not cross the blood-brain barrier easily and do not achieve significant levels in the csf. there is some evidence that cns-penetrating haart (e.g. abacavir and zidovudine) may be effective in improving neuropsychological functioning.8,17 growing evidence suggests that for milder neurocognitive disorders the use of antiretrovirals may slow progression or at least prevent severe forms of hand. however, owing to the lack of conclusive evidence that haart can prevent or reverse neurological damage caused by hiv, the role of initiating haart in asymptomatic individuals is undefined. references 1. grant i. neurocognitive disturbances in hiv 1. int rev psychiatry 2008; 20(1): 33-47. 2. janssen rs, saykin aj, cannon l, et al. neurological and neuropsychological manifestations of hiv-1 infection: association with aids-related complex but not asymptomatic hiv-1 infection. ann neurol 1989; 26(5): 592-600. 3. antinori a, arendt g, becker jt, et al. updated research nosology for hivassociated neurocognitive disorders. neurology 2007; 69(18): 1789-1799. 4. phair jp, simpson dm, cikurel k. pathogenenesis of the neurological complications of hiv. available: http://www.clinicaloptions.com/hiv/management%20series/ neuroaids.aspx [accessed 10 september 2009]. 5. ganasen ka, fincham d, smit j, seedat s, stein d. utility of the hiv dementia scale (hds) in identifying hiv dementia in a south african sample. j neurol sci 2008; 269(1-2): 62-64. 6. brodt hr, kamps bs, gute p, knupp b, staszewski s, helm eb. changing incidence of aids-defining illnesses in the era of antiretroviral combination therapy. aids 1997; 11(14): 1731-1738. 7. nath a, schiess n, venkatesan a, rumbaugh j, sacktor n, mcarthur j. evolution of hiv dementia with hiv infection. int rev psychiatry 2008; 20(1): 25-31. 8. letendre s, marquie-beck j, capparelli e, et al. validation of the cns penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. arch neurol 2008; 65(1): 65-70. 9. sacktor n, nakasujja n, skolasky r, et al. antiretroviral therapy improves cognitive impairment in hiv+ individuals in sub-saharan africa. neurology 2006; 67(2): 311-314. 10. folstein mf, folstein se, mchugh pr. ‘mini-mental state’. a practical method for grading the cognitive state of patients for the clinician. j psychiatr res 1975; 12(3): 189-198. 11. tombaugh tn, mcintyre nj. the mini-mental state examination. a comprehensive review. j am geriatr soc 1992; 40: 922-935. 12. power c, selnes oa, grim ja, mcarthur jc. hiv dementia scale: a rapid screening test. j acquir immune defic syndr hum retrovirol 1995; 8(3): 273-278. 13. von giesen hj, haslinger ba, rohe s, koller h, arendt g. hiv dementia scale and psychomotor slowing – the best methods in screening for neuro-aids. j neuropsychiatry clin neurosci 2005; 17(2): 185-191. 14. sacktor nc, wong m, nakasujja n, et al. the international hiv dementia scale: a new rapid screening test for hiv dementia. aids 2005; 19(13): 1367-1374. 15. jones bn, teng el, folstein mf, harrison ks. a new bedside test of cognition for patients with hiv infection. ann intern med 1993; 119(10): 1001-1004. 16. fernandez al, marcopulos ba. a comparison of normative data for the trail making test from several countries: equivalence of norms and considerations for interpretation. scand j psychol 2008; 49(3): 239-246. 17. brew bj, halman m, catalan j, et al. factors in aids dementia complex trial design: results and lessons from the abacavir trial. plos clintrials 2007; 2(3): e13. treatment acknowledgments i would like to thank j joska for all his assistance in preparing this manuscript. dinesh singh was supported by the fogarty international centre, nih, grant 5-d43-tw00231 (aids international training and research program, quarraisha abdool karim, phd, principal investigator). 34 december 2014, vol. 15, no. 4 sajhivmed 117 o r ig in a l a r t ic l emessage from the executive this is our final issue before the end of the year, and what a year it has been. there is no doubt that the high point for the society was our second biennial conference in september. we had an even better turn-out than our first conference in 2012, with over 900 delegates from across south africa and the world. of course i am biased, but i thought that a really good time was had by all. the conference opened on a public holiday (heritage day) and i thought no one would turn up – to my surprise over 600 people attended the opening session. the plenaries were of an international standard and featured national and global experts. the opening plenary on the elimination of tb by dick chaisson reminded me that while we may be turning the tide on the hiv epidemic, we have lots still to do regarding tb. there were thought-provoking debates that at times i thought may end in fisticuffs (academic of course). while the programme focused on clinical aspects of hiv, i received many positive comments about the ethics sessions, and as usual, the skillsbuilding sessions were oversubscribed. i was also particularly impressed with the quality of abstracts we received. the nine submissions judged ‘the best’ by a panel of researchers have been included in this issue. i hope you will read them. on a private note, there were some other highlights. one exhibit featured an ice-cream guru who, after asking you some questions, would provide you a personalised dessert. not sure if it fits in with healthy living, but there was much laughter and fun. occasional  sightings of the springbok rugby team, who were staying in a hotel opposite the conference centre, also added to my experience. but most of all, i was affected by the realisation that i have the privilege to head up a fantastic membership organisation of hiv clinicians. i met old friends and made many new ones. we are all bound by a common purpose. the team who organised this conference, led by lauren jankelowitz, did a superb job. so brace yourselves, there will be another one in 2016. save up your pennies and get your research done so that you, too, can be part of this experience. francesca conradie president: southern african hiv clinicians society fconradie@witshealth.co.za m e s s a g e eftenem advert 5 4/25/14 12:37 pm page 2 composite c m y cm my cy cmy k 13-16 april 2016 sandton convention centre 3rd southern african hiv clinicians society conference save the date sajhiv 1030 reflections closer to zero: reflections on ten years of art rollout m moorhouse, mb bch, da (sa) corresponding author: m moorhouse (michelle@iydsa.co.za) dr michelle moorhouse is the research and training technical lead for beyond zero and serves on the board of directors of the southern african hiv clinicians society to reflect upon ten years of antiretroviral therapy (art) rollout, one really should set the clock back a little further to see the massive impact of art on our lives – for clinicians and patients alike. my own journey with hiv began in 1999 when, as a young doctor, i decided to venture into private practice with a local general practitioner (gp) while assessing my career prospects. a week into my new job, the gp went on a trip overseas, leaving me with the following pearls: ‘look after the hiv patients and don’t let any die before i get back’. i was terrified, as hiv had not formed an extensive part of the medical school curriculum when i trained, and while our exposure to such patients was considerable, we were taught that the only management options were palliative. so i had a baptism of fire, as the bulk of the practice patient load was hiv, and patients came from many corners of the eastern cape to our practice. many gps in the region at that time did not have the time or interest to manage these patients and were afraid of attracting stigma to their practices and driving away other patients. mostly i think that they felt helpless and were not aware of what was happening in hiv medicine outside south africa. they didn’t know that effective treatments were available, and that in the usa and europe, hospital wards previously dedicated to caring for dying aids patients were closing down, because patients were living. hiv was becoming a chronic, manageable disease, and although compared to current treatments, they were more toxic and less tolerable, people were living with hiv. and so, when my partner returned from his trip, all his hiv patients were still alive, and i was filled with passion to learn more about hiv and treatment options. but they were the lucky ones, and not too long after that i lost my first patient to aids; unfortunately, the first of many. despite the availability of effective treatment, accessibility was still very limited at that time, as was expertise in art. antiretrovirals (arvs) were expensive (triple art regimens often costing up to several thousands of rands each month). monitoring tests were expensive. few medical aids covered hiv treatment, despite the evidence that even with the high cost of art at the time, treating hiv was more cost-effective than the costs associated with managing opportunistic infections in very sick patients requiring hospital admission. art was not available in the public sector, so was only an option for those few who could afford to buy medications and pay for the laboratory monitoring tests themselves, or those who had access to clinical trials. despite the medications that existed, i still had patients being carried in on mattresses, stretchers, home-made wheelchairs made of garden chairs on tricycle wheels, and i still had to send many patients home with what was palliative care at best. one way of accessing treatment was through my involvement in clinical trials, to bypass the inadequacies of the prevailing system. i wanted to help as many patients as we could in this way. consequently, we were seeing two ends of the spectrum: the patients enrolled in clinical trials were flourishing – they were gaining weight, feeling well and returning to work – while others continued to die. this dichotomy was very difficult to reconcile in my mind as a clinician wanting to help all my patients. more lives were lost due to the pervasiveness of aids denialism at that time. the strong stance taken by thabo mbeki not only prevented access to treatment, but also resulted in many of those accessing art through clinical trials or other means stopping their treatment. the treatment action campaign (tac) was fighting battles on many fronts: demanding access to treatment; campaigning for pharmaceutical companies to make arvs affordable; and debunking the myths of aids denialism – and their fortitude and perseverance prevailed. finally, in 2004, art was made available in the public sector. fast-forward ten years to 2014. art is available; treatment guidelines make provision for earlier initiation of treatment; the incidence of hiv is slowly declining; life expectancy has increased; and fewer babies are infected with hiv. south africa has the biggest arv programme in the world, with more than 2 million people receiving treatment. now we have shifted from simply providing some treatment, to providing treatment that is easier to take in terms of toxicity as well as convenience. no longer are we merely trying to save lives – now we aim for quality of life as well as longevity, and our patients are growing old with us. we are watching them start families, and helping them to have children who are free of hiv. now we are aiming for zero new infections, zero deaths and zero stigma related to hiv. we are making significant strides towards achieving what ten years ago seemed impossible. yes we now have some great new drugs, with yet more in the pipeline. and yes, we have managed to build what is, without any doubt, the largest, most successful arv treatment programme in the world. and yes, we will eventually resolve the logistical issues that result in stock-outs. and yet there are still patients who are presenting just as sick as those i was seeing when i first started treating hiv. they delay testing, or once tested, delay accessing treatment because they fear they will face discrimination and stigma. while we have made such great inroads towards zero new infections and zero deaths, we are not doing as well when it comes to zero stigma. until we are able to temper and eliminate stigma, zero new infections and zero deaths will remain just beyond our grasp. s afr j hiv med 2014;15(1):9. doi:10.7196/sajhivmed.1030 pg47-48.html case study trans-hiatal oesophagectomy in an aids patient m i m de zoysa, mb bs, ms, frcs, frcs (edin) s sivaganesh, mb bs, ms, mrcs, phd a u abayadeera, mb bs, md, frca university of colombo, sri lanka k buddhakorale, mb bs, md university of colombo, sri lanka a 49-year-old man was diagnosed as hiv infected, with a cd4 count of 60 cells/µl. he was started on an antiretroviral treatment regimen comprising zidovudine, lamivudine and efavirenz. following treatment, his cd4 count improved and the viral load was undetectable. he was subsequently found to have a moderately differentiated adenocarcinoma of the lower oesophagus. case study a 49-year-old male security supervisor was admitted to hospital with recurrent chest infections. he was found to be hiv positive with a cd4 count of 60 cells/µl, and was started on an antiretroviral treatment regimen comprising zidovudine, lamivudine and efavirenz. six months later the absolute cd4 count had increased to 249 cells/µl and the viral load was undetectable. nine months after initial hiv diagnosis the patient complained of progressive dysphagia for solids for 2 months and a weight loss of 5 kg during the same period. he denied loss of appetite, haematemesis or symptoms of gastro-oesophageal reflux disease. he weighed 76 kg with a body mass index of 25.9. clinical examination was unremarkable, with no evidence of an abdominal mass, hepatomegaly or left supraclavicular lymph nodes. upper gastro-intestinal endoscopy showed a polypoidal growth of the abdominal oesophagus. there was no evidence of candidal oesophagitis. histological examination revealed a moderately differentiated adenocarcinoma. a computed tomography (ct) scan showed a t2 tumour with no evidence of regional lymph node enlargement or hepatic metastases. the patient underwent trans-hiatal oesophagectomy with a cervical oesophago-gastric anastomosis. a jejunostomy feeding tube was placed at the time of surgery in view of his dysphagia and poor oral intake. three days after surgery, he developed a lower respiratory tract infection which was treated with intravenous co-amoxyclavulanic acid. he responded to treatment and was discharged on the 11th postoperative day. histological examination showed a moderately differentiated adenocarcinoma with involvement of the para-oesophageal and left gastric lymph nodes. the feeding jejunostomy was removed. the patient received an adjuvant regimen of two cycles of chemotherapy (5-fluorouracil 1 g/m2 and cisplatin 100 mg/m2 ) and concurrent local radiotherapy (45 gy). twelve weeks after the conclusion of his treatment course, a repeat ct scan of the chest and abdomen showed significant tumour regression and no evidence of metastatic disease. he was able to return to his occupation, and his quality of life was not affected. at 2 months' follow-up the patient’s absolute cd4 count had decreased to 117 cells/µl. at 6 months it had risen to 211/µl. he continued on antiretroviral therapy, but died of metastatic disease and opportunistic infections 16 months after surgery. discussion the commonest cause of dysphagia in patients with aids is candidal oesophagitis. cytomegalovirus oesophagitis is less frequently seen.1 because oesophagitis is a common complaint in this group of patients, heightened awareness of the risk of malignancy and a low threshold for upper gastro-intestinal endoscopy are necessary to avoid a delay in diagnosis. our patient was free of oesophagitis, and his symptoms were suggestive of mechanical oesophageal obstruction. oesophageal adenocarcinoma in hiv/aids has been reported, but very few of these patients have undergone a potentially curative resection.2 , 4 demographic analysis of hiv/aids patients with oesophageal carcinoma is not possible owing to the paucity of reported cases. it is likely that improved survival in these patients has permitted the development of other disease processes. it is also possible that the immunosuppression associated with hiv/aids puts them at a higher risk of developing oesophageal cancer. the impact of oesophageal cancer surgery, in terms of postoperative survival as well as quality of life, is still largely unknown. clinical experience and the scarce existing literature both suggest that these patients find it difficult to return to their previous lifestyles and social activities, not just owing to the problems common to all malignant tumours but because of the specific dietary and digestive disturbances resulting from oesophageal cancer therapy.5 our patient was able to eat a normal diet and return to work and to his original lifestyle within 1 month after surgery. the impact of oesophageal cancer and its treatment on survival in aids patients can only be ascertained with long-term follow-up. however, the recent improvement in life expectancy in aids patients means that oesophageal malignancies should be treated aggressively to ensure maximal survival in this challenging subgroup. the treatment of hiv infection has undergone considerable change. when used as part of combination drug regimens, protease inhibitors and non-nucleoside reverse transcriptase inhibitors can profoundly suppress viral replication, with consequent repletion of cd4 cell counts.6 our patient responded well to antiretroviral therapy, both before diagnosis and after treatment of his oesophageal cancer. pre-operative status and co-morbidity are strong predictors of outcome. the prognosis for oesophageal carcinoma varies depending on the stage at presentation. a 2005 study showed 5-year survival rates of around 67% for resectable stage 0 1 oesophageal cancer, 33% for stage 2, and 8% for stage 3.7 references 1. ilcox cm. esophageal disease in the acquired immunodeficiency syndrome: etiology, diagnosis, and management. am j med 1992;92(4):412-421. 1. ilcox cm. esophageal disease in the acquired immunodeficiency syndrome: etiology, diagnosis, and management. am j med 1992;92(4):412-421. 2. chalasani n, parker k, wilcox cm. barrett’s adenocarcinoma in a patient with acquired immune deficiency syndrome. j clin gastroenterol 1997;24(3):184-191. 2. chalasani n, parker k, wilcox cm. barrett’s adenocarcinoma in a patient with acquired immune deficiency syndrome. j clin gastroenterol 1997;24(3):184-191. 3. botha a, kochhar s. laparoscopic-assisted oesophagectomy for adenocarcinoma in an aids patient. br j hosp med (lond) 2006;67(6):324-325. 3. botha a, kochhar s. laparoscopic-assisted oesophagectomy for adenocarcinoma in an aids patient. br j hosp med (lond) 2006;67(6):324-325. 4. issa ra, podbielski fj, fontaine jp, connolly ae, walsh wv, fraire ae. esophagectomy in a patient with aids. dis esophagus 2004;17(3):270-272. 4. issa ra, podbielski fj, fontaine jp, connolly ae, walsh wv, fraire ae. esophagectomy in a patient with aids. dis esophagus 2004;17(3):270-272. 5. magrone g, bozzone a, romanelli a, et al. rehabilitation and quality of life in patients undergoing surgery for esophageal cancer. rays 2006;31(1):13-16. 5. magrone g, bozzone a, romanelli a, et al. rehabilitation and quality of life in patients undergoing surgery for esophageal cancer. rays 2006;31(1):13-16. 6. hogg rs, heath kv, yip b, et al. improved survival among hiv infected individuals following initiation of antiretroviral therapy. jama 1998;279(6):450-454. 6. hogg rs, heath kv, yip b, et al. improved survival among hiv infected individuals following initiation of antiretroviral therapy. jama 1998;279(6):450-454. 7. rouvelas i, zeng w, lindblad m, et al. survival after surgery for oesophageal cancer: a population-based study. lancet oncol 2005;6(11):864-870. 7. rouvelas i, zeng w, lindblad m, et al. survival after surgery for oesophageal cancer: a population-based study. lancet oncol 2005;6(11):864-870. sajhiv 1035 reflections providing high-quality hiv care in a deeply rural setting – the zithulele experience c young, ba, bcom (hons), mcom; b gaunt, mb chb, msc (phc), da, dipobst, diphivman corresponding author: b gaunt (ben@zithulele.org) catherine young is affiliated with the donald woods foundation, east london, south africa. benjamin gaunt hails from zithulele hospital, mqanduli, eastern cape province, and is affiliated with the eastern cape provincial department of health, south africa. in the deeply rural zithulele community, based in one of the poorest districts in south africa, the clinical and hiv programme staff believe that despite our resource-poor, rural setting, our patients deserve the same quality of medical care as their compatriots elsewhere. as a result, the hiv service that we have developed over the past seven years has had a strategic emphasis on providing accessible, quality care delivered in an innovative way that addresses local challenges and builds a robust foundation for future growth and sustainability. while our challenges are not unique, rural health facilities are often fragile entities. they have low staff numbers, yet carry a relatively heavy responsibility. in these parts, there is no plan b unless you devise it yourself! various aspects of the programme have evolved over time and have been modified, as we have learnt from our experiences, as the programme has expanded, and as the hiv climate has changed over the eight years since we started our first patient on highly active antiretroviral therapy (haart) with the assistance of our neighbouring hospital. specific aspects of our rural reality that have informed the innovations we have brought to the model of care include: • fragile clinics: there is high staff turnover, significant problems with procurement, an isolated work environment and lack of on-site clinical and systematic support. while staff receive training in clinical and policy implementation, this is often rote learning and ongoing mentorship is essential to bring depth of understanding. zithulele staff provide strong links between the clinics and hospital, improving access to expertise and morale among clinic nurses. • mobile patients: our large, still-growing number of patients are extremely mobile, with a lot of patient movement both between facilities within the programme borders, but also in and out of the geographical area due to migrant labour. a uniform system that works effectively across all sites and that is easy for patients to access from any programme facility has been critical to avoid confusion and to ensure continuity of care. • drug supply: in common with many other areas, our primary healthcare facilities have struggled to maintain continuous access to medication and other stock items. (everything from paracetamol to antibiotics to art for the prevention of mother-to-child transmission (pmtct), as well as needles, hiv test kits and more, has been out of stock at some point over the years.) not only is our district hospital committed to supporting primary healthcare, it is a resource-efficient and economically viable approach to link hospital and clinic care in order to prevent more complicated, expensive care at hospital level due to stock-outs at clinic level. preventing resistance in a context where drug regimens are limited and advanced treatment regimens may be difficult or impossible to access is critically important, both from a programmatic and individual patient perspective. more information on how we do this is included in the model presented below. in light of these issues, we realised early on that while our programme requires an element of flexibility to meet the needs of a rural community, it also needs: to ensure that high quality, comprehensive care is accessible to all; to be stringent enough to promote adherence to lifelong treatment; and to provide an effective method of monitoring patients. we are privileged to have had access to resources that made it possible to avoid compromise on any of these aspects. operating within a public sector context has also meant that any model that we implemented needed to meet national priorities and be flexible enough to adapt as these priorities change over time. the hiv care model implemented across the zithulele catchment area is outlined in fig. 1. programmes are always about more than just the numbers, but these indicators demonstrate how the model illustrated successfully provides high quality, accessible care: • large number of patients receiving treatment: as of end october 2013, 3 785 patients were receiving treatment, inclu­ding 269 children; and over 5 000 patients have been initiated on antiretrovirals (arvs) since 2005 (large numbers transfer out, often back to the mines) • ninety-one per cent of patients in the programme collect from their facility of choice: those patients who remain receiving care at the hospital are either those who require hospital-level intervention or those who choose, for reasons of their own, not to receive treatment at a clinic • there is no waiting list to start arvs at any facility, whether hospital or clinic, and patients can be initiated on treatment by doctors or nurses on any day of the week • excellent viral load (vl) protocol compliance: the results of a recent vl audit (a randomised review of half of the programme facilities) showed that in the past year, 92% of patients had a vl measurement performed on time – this is a significant achievement, especially considering the recently introduced changes in protocol • a recent audit showed that 91% of our adult patients are still receiving first-line treatment and 94.5% of these have a suppressed vl (and 91% of all our active adult patients currently have a suppressed vl) • no patient in the programme has ever been turned away without their full regimen of treatment – a momentous achievement in a district and province where arv stock-outs have made regular headline news. fig. 1. service delivery model of hiv care at zithulele hospital. (haart = highly active antiretroviral therapy; ngo = non-governmental organisation; tb = tuberculosis.) the government has focused on expanding programmes across the country, with energy and resources being directed towards ensuring access for all who need treatment. however, given the challenges outlined above and in line with our philosophy that rural care should not be second rate, we have emphasised the need for accessibility to quality care. the way we have designed and structured our programme, particularly our adoption of pre-packing medication from as soon as we started to provide decentralised, clinic-based care, has not always been well understood or received by middle managers who occasionally misinterpreted national policy as a one-size-fits-all directive. neverthe­less, the outcomes that have been achieved demonstrate that the long hours spent negotiating have been worthwhile. as far as possible, we work within the existing structure and resources of the eastern cape department of health (ecdoh), but implementing the above programme does require some additional funding. non-governmental organisation (ngo) support has made this possible, and in the current budgetary climate, continued ngo support remains essential to maintain this model. however, with the attention we are giving to strengthening and supporting the ecdoh systems and structures, and with an imminent expansion of government-funded prepacking, it is hoped that over time we will be able to maintain this standard of care without outside support. acknowledgements. our thanks to the many staff who have worked with us over the years to design and implement this programme, including drs karl and sally le roux, dr taryn gaunt, dr liz gatley, ms monique lines, staff of the donald woods foundation and the jabulani rural health foundation. we also thank cell-life who developed the idart programme and the vodacom foundation who donated hardware and training. s afr j hiv med 2014;15(1):28-29. doi:10.7196/sajhivmed.1035 article information authors: graeme meintjes1 john black2 francesca conradie3 sipho dlamini4 gary maartens5 thandekile c. manzini6 moeketsi mathe7 michelle moorhouse8 yunus moosa9 jennifer nash10 catherine orrell11 francois venter8 douglas wilson12 affiliations: 1department of medicine and institute of infectious disease and molecular medicine, university of cape town, south africa 2department of medicine, livingstone hospital, south africa 3right to care and clinical hiv research unit, university of the witwatersrand, south africa 4division of infectious diseases & hiv medicine, department of medicine, university of cape town, south africa 5division of clinical pharmacology, university of cape town, south africa 6department of infectious diseases, king edward viii hospital, university of kwazulu-natal, south africa 7private practice, vereeniging, south africa 8wits reproductive health and hiv institute, johannesburg, south africa 9department of infectious diseases, university of kwazulu-natal, south africa 10amathole district clinical specialist team, eastern cape, south africa 11desmond tutu hiv foundation, university of cape town, south africa 12department of internal medicine, edendale hospital, university of kwazulu-natal, south africa correspondence to: graeme meintjes email: graemein@mweb.co.za postal address: private bag x3, rondebosch 7701, south africa how to cite this article: meintjes g, black j, conradie f, et al. southern african hiv clinicians society adult antiretroviral therapy guidelines: update on when to initiate antiretroviral therapy. s afr j hiv med. 2015;16(1), art. #428, 4 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.428 note: this guideline was compiled by the southern african hiv clinicians society. disclaimer: specific recommendations provided here are intended only as a guide to clinical management, based on expert consensus and best current evidence. treatment decisions for patients should be made by their responsible clinicians, with due consideration for individual circumstances. the most current version of this document should always be consulted. update of: meintjes g, black j, conradie f, et al. adult antiretroviral therapy guidelines 2014. s afr j hiv med. 2014;15(4), art. #330, 22 pages. http://dx.doi.org/10.4102/hivmed.v15i4.330 copyright notice: © 2015. the authors. licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. southern african hiv clinicians society adult antiretroviral therapy guidelines: update on when to initiate antiretroviral therapy in this guidelines... open access • abstract • the 2014 guidelines • the strategic timing of antiretroviral therapy and temprano trials • isoniazid preventive therapy in patients on antiretroviral therapy • updated recommendations of sa hiv clinicians society regarding antiretroviral therapy initiation • specific patient groups • acknowledgements    • competing interests    • authors’ contributions • references abstract top ↑ the most recent version of the southern african hiv clinicians society’s adult antiretroviral therapy (art) guidelines was published in december 2014. in the 27 august 2015 edition of the new england journal of medicine, two seminal randomised controlled trials that addressed the optimal timing of art in hiv-infected patients with high cd4 counts were published: strategic timing of antiretroviral therapy (start) and temprano anrs 12136 (early antiretroviral treatment and/or early isoniazid prophylaxis against tuberculosis in hiv-infected adults). the findings of these two trials were consistent: there was significant individual clinical benefit from starting art immediately in patients with cd4 counts higher than 500 cells/μl rather than deferring until a certain lower cd4 threshold or clinical indication was met. the findings add to prior evidence showing that art reduces the risk of onward hiv transmission. therefore, early art initiation has the public health benefits of potentially reducing both hiv incidence and morbidity. given this new and important evidence, the society took the decision to provide a specific update on the section of the adult art guidelines relating to when art should be initiated. the 2014 guidelines top ↑ in the 2014 version of the southern african hiv clinicians society’s adult antiretroviral therapy guidelines, antiretroviral therapy (art) was recommended for certain clinical indications (including who stage 3 and 4 disease, and other significant morbidities), for hiv-infected partners in serodiscordant relationships, and in all patients with a cd4 < 350 cells/μl. further, these guidelines advised that if patients had two cd4 counts between 350 and 500 cells/μl, art should be started if the patient was ready and motivated to start art. however, in these guidelines it was advised that if a patient’s cd4 count was > 500 cells/μl and the patient did not qualify on clinical grounds, then art should be deferred. the rationale was that insufficient evidence existed to advise a ‘test-and-treat’ approach to hiv at that time, and it was stated that we awaited the results of the temprano and strategic timing of antiretroviral therapy (start) trials.1 for patients diagnosed during acute hiv seroconversion, initiation of standard first-line art was advised, provided that adherence requirements were met. for such patients, it was advised that art should be continued for at least 3 years, but consideration should be given to continuing lifelong art. the strategic timing of antiretroviral therapy and temprano trials top ↑ both the start and temprano trials enrolled patients with high cd4 counts (in start all participants had a study entry cd4 count > 500 cells/μl; in temprano, 41% had an entry cd4 count > 500 cells/μl). a summary of the trials is presented in table 1. both trials involved randomisation to one of two strategies: immediate art initiation, or to defer art until the participant was eligible on the basis of cd4 count or clinical criteria. patients were followed for about 3 years in each trial, and the primary endpoint was a composite endpoint that included aids events, serious non-aids events and death, with minor differences in specific aspects of the endpoint definition between the two trials. table 1: summary of design, conduct and findings of the strategic timing of antiretroviral therapy and temprano anrs 12136 (early antiretroviral treatment and/or early isoniazid prophylaxis against tuberculosis in hiv-infected adults) randomised controlled trials. both trials demonstrated a statistically significant, approximate halving of events contributing to the primary endpoint when art was started immediately. in temprano, this benefit was largely attributable to reductions in incident tb and invasive bacterial diseases (particularly pneumonia). in start, the benefit was related to a decrease in aids-related events (including tb) and serious non-aids events (including cancer). the relative reduction in the rate of primary endpoint events was greater in start (57% reduction compared with 44%). however, the absolute benefit of immediate art was greater in the temprano trial (conducted in cote d’ivoire) than in the start trial (which was conducted in countries across the world), because the event rate in the control arms (mainly from tb and invasive bacterial infections) was higher in the temprano trial, reflecting the high co-infection risks that exist for individuals living with hiv infection in africa, even with higher cd4 counts. no significant difference in mortality was observed between the study arms in either trial.2,3 there are two main concerns about art initiation with cd4 counts > 500 cells/μl. firstly, the risk of adverse events could outweigh clinical benefits. secondly, adherence could be lower in asymptomatic patients. in both trials, immediate art did not increase the risk of adverse events overall, nor did patients who started immediately have a higher risk of adherence problems, at least in the short term, as evidenced by the high proportion of patients achieving hiv viral suppression seen in the immediate arms in both trials (table 1). the hptn052 trial4 previously demonstrated that art prevented onward transmission of hiv within serodiscordant couples, which suggested that art at hiv diagnosis for all may be an important strategy to help prevent the growth of the hiv epidemic at a public health level. however, such an approach would be difficult to justify if there were no individual benefit and potential individual harm. what these two trials have demonstrated is that there is indeed individual clinical benefit with no signal of harm during ~3 years of follow-up, providing significant additional support for the ‘test-and-treat’ strategy. these were well-conducted randomised controlled trials with good participant retention and assured drug supply, and the vast majority of participants were on tenofovir/emtricitabine/efavirenz regimens in both trials. in less motivated patients, or in the context of inconsistent drug supply or different first-line art regimens, these results should be treated with caution, as the modest benefits seen with early treatment may not be realised. in particular, if tenofovir (or abacavir) is unavailable and zidovudine or stavudine needs to be used in place, then the substantial side-effect profile of these drugs and effect on patients’ quality of life may outweigh the benefit of early art. isoniazid preventive therapy in patients on antiretroviral therapy top ↑ the temprano trial involved a separate randomisation of participants to 6 months of isoniazid preventive therapy (ipt) started one month after study entry, versus no ipt. the addition of ipt to art provided added protection against active tb disease, even in these patients with relatively high cd4 counts. this finding was similar to those of a placebo-controlled trial conducted in khayelitsha, south africa, where 12 months of ipt prescribed to patients on art reduced tb incidence by 37%.5 our december 2014 guidelines1 recommended ipt for all patients on art provided that there was no contra-indication to isoniazid, and active tb was not suspected based on symptom screen. guidelines on duration of ipt based on tuberculin skin test results were provided. given that southern africa has the highest incidence rates of hiv-associated tb in the world, ipt as a tb-preventive strategy implemented within art clinics should be prioritised. updated recommendations of sa hiv clinicians society regarding antiretroviral therapy initiation top ↑ our updated recommendations are shown in box 1. it is important to note that these are the guidelines of the sa hiv clinicians society, and clinicians working within national public sector art programmes should continue to follow the guidelines that pertain to their programme. whilst national departments of health are very likely to consider a change in art initiation policy in the near future based on these study findings, such a change will need to factor the financial cost, adequate planning of drug supply and health service capacity. sustaining funding for art programmes in resource-limited countries is a huge challenge currently.6 box 1: indications for antiretroviral therapy in adults with hiv infection. specific patient groups top ↑ for patients who are diagnosed with hiv during acute seroconversion, we continue to advise that those patients be counselled and initiated on art. this should preferably be expedited art initiation as there is evidence that this may limit the size of the hiv reservoir.7 however, we no longer recommend that these patients should have art interrupted after 3 years. rather, once art is started in this situation, this should be lifelong art, and this should be discussed with the patient. additional counselling once the patient is established on art may be required for patients who start art in this acute situation because there is limited time for extensive counselling pre-art and there is often considerable psychological distress around this time. a minority of patients (< 1%) have very effective immune control of hiv infection and are able to control hiv viraemia at undetectable levels in the absence of art – termed ‘elite controllers’. an argument could be made that such individuals do not require art if their cd4 count is > 500 cells/μl. the start and temprano trials did not specifically address the question of whether early art was beneficial in such patients, and it is highly unlikely that any sufficiently powered randomised controlled trial could ever be conducted focused on these individuals. in the absence of such data, we rely on indirect evidence. firstly, elite controllers still have evidence of chronic immune activation and inflammation that may drive non-infectious morbidities.8 secondly, elite controllers have been shown to have a higher rate of hospitalisation than patients who are virologically controlled by art.9 for these reasons, we do advise starting art in elite controllers too, with the same caveats regarding the patient being prepared. one important consideration in such patients is that careful attention should be paid to confirming the diagnosis of hiv before starting art. they are typically patients who have a positive hiv elisa test, undetectable hiv viral load, cd4 count in the normal range and are clinically well. the possibility of a false positive hiv elisa test should be excluded either by performing a qualitative hiv dna pcr assay or a western blot assay. if the patient at some point previously had a detectable hiv viral load, this would also serve as confirmation. such patients should be discussed with a laboratory virologist to assist with confirmation of hiv infection status. in patients with active tb or opportunistic infections, the 2014 guidelines included guidance as to when to initiate art in relation to treatment of the tb or opportunistic infection. this guidance remains unchanged. we recommend art initiation without delay in all hiv-infected women who are pregnant or breastfeeding, irrespective of cd4 cell count, to prevent mother-to-child transmission of hiv infection. we advise that such art should be continued lifelong and not stopped after the pregnancy or weaning. in children and adolescents, advice from the society’s child and adolescent guidelines committee is that the ‘test-and-treat’ approach is supported in principle for all ages. however, there is an absence of data for the 5–15-year-old age group. adherence issues for adolescents in particular and the lack of a simplified first-line regimen make ‘test-and-treat’ for 5–15– year-olds complicated. please refer to national department of health guidelines for further advice regarding children and adolescents. acknowledgements top ↑ competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. g.m. is a consultant for aid for aids and received speaker fees from sanofi aventis. f.c. have received support from janssen pharmaceutica, abbvie, gsk, merck, aspen, sanofi aventis and mylan to attend conference, and received honoraria for speaking and attendance at advisory board. authors’ contributions g.m. (university of cape town) is the first author, and undertook preparation of the first draft of the manuscript. the remaining authors were involved in the discussions that guided the development of the manuscript and also reviewed the first draft. all authors contributed to the review of the data informing the new recommendations, and to the development of the recommendations. references top ↑ meintjes g, black j, conradie f, et al. adult antiretroviral therapy guidelines 2014. s afr j hiv med. 2014;15:121–143. http://dx.doi.org/10.7196/sajhivmed.1130 insight start study group, lundgren jd, babiker ag, et al. initiation of antiretroviral therapy in early asymptomatic hiv infection. n engl j med. 2015;373:795–807. pmid: 26192873, http://dx.doi.org/10.1056/nejmoa1506816 temprano anrs 12136 study group, danel c, moh r, et al. a trial of early antiretrovirals and isoniazid preventive therapy in africa. n engl j med. 2015;373:808–822. pmid: 26193126, http://dx.doi.org/10.1056/nejmoa1507198 cohen ms, chen yq, mccauley m, et al. prevention of hiv-1 infection with early antiretroviral therapy. n engl j med. 2011;365:493–505. pmid: 21767103, http://dx.doi.org/10.1056/nejmoa1105243 rangaka mx, wilkinson rj, boulle a, et al. isoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trial. lancet. 2014;384:682–690. pmid: 24835842, http://dx.doi.org/10.1016/s0140-6736(14)60162-8 abdool karim ss. overcoming impediments to global implementation of early antiretroviral therapy. n engl j med. 2015;373:875–876. pmid: 26193047, http://dx.doi.org/10.1056/nejme1508527 o’brien m, markowitz m. should we treat acute hiv infection? curr hiv/aids rep. 2012;9:101–110. pmid: 22415472, http://dx.doi.org/10.1007/s11904-012-0113-0 krishnan s, wilson em, sheikh v, et al. evidence for innate immune system activation in hiv type 1-infected elite controllers. j infect dis. 2014;209:931–939. pmid: 24185941, http://dx.doi.org/10.1093/infdis/jit581 crowell ta, gebo ka, blankson jn, et al. hospitalisation rates and reasons among hiv elite controllers and persons with medically controlled hiv infection. j infect dis. 2015;211:1692–1702. pmid: 25512624, http://dx.doi.org/10.1093/infdis/jiu809 severe p, juste ma, ambroise a, et al. early versus standard antiretroviral therapy for hiv-infected adults in haiti. n engl j med. 2010;363:257–265. pmid: 20647201, http://dx.doi.org/10.1056/nejmoa0910370 sajhiv 1029 reflections what have we learnt from the last ten years of art? w d f venter, fcp (sa), mmed, dtm&h, diphivman corresponding author: w d f venter (fventer@wrhi.ac.za) professor francois venter hails from the wits reproductive health and hiv institute and department of internal medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa the state programme giving free antiretrovirals (arvs) started on 1 april 2004 in several large centres across south africa. for many of us, it seemed unimaginable, after years of running hiv battles with president thabo mbeki and his odious minister of health, ‘manto’ tshabalala-msimang, on everything from the cause of hiv to the efficacy of arvs. a decade later, the state programme is the biggest in the world, with millions of lives saved and families returned back to normal life. i was involved in the initial design of the programme, and have since been heavily involved in the implementation in rural and urban environments. i like to think about what i’ve learnt about hiv, and all the things i got wrong. interestingly, seeing where we are in 2014, much of what has happened in the last decade was as unimaginable as the heady days of starting all those sick, desperate people on arvs in 2004. be ambitious i remember mark heywood, the human rights crusader for section 27, insisting that we put ‘80% antiretroviral coverage’ when we wrote the 2nd national strategic plan, released at the end of 2006. the fractious paediatricians also insisted on ambitious prevention of mother-to-child transmission (pmtct) targets. at the time, there were few places with >30% arv coverage, and reports of poor antenatal pmtct coverage were everywhere. i thought that they were being silly. by 2010, arv coverage was close to 80%, and pmtct transmission rates had fallen below 2%. even when we designed the programme, in 2002 in dark rooms in the birchwood hotel, we continually asked whether drugs were affordable. before we knew it, we had a pretty good first and second line, which were refined in 2010. now we sit with a world-class fixed-dose combination and third-line drugs not even available in many developed countries, thanks to the decrease in cost. the minister’s crazy rush of blood to the head, where he wanted to test 20 million south africans for hiv in one year in 2010, maybe took a few months longer than he had anticipated, but it got there – even though i thought it was impossible – and we’re probably now the most tested nation on earth. we’ve taught chronic diseases a thing or two about adherence i come from the typical physician world of diabetes, hypertension and asthma, where we hug patients who get >70% adherence. the 90%-plus adherence demanded by arvs seemed fanciful, until we tried it. thanks to médecins sans frontières (msf) and the treatment action campaign (tac) and their adherence programmes, i’ve realised that meaningfully involving people in their care and making them understand their disease and how their drugs work, magically transforms them into prize adherence patients. i heard prof. steve reid, a rural advocate, once say that he was amazed at how hiv patients could describe the lifecycle of the virus and evolution of resistance, while diabetic and hypertension patients, when asked what was wrong, would shrug and say: ‘i have the high-high’. we may have saved the world from tb if it wasn’t for the hiv world seizing the tuberculosis (tb) research and policy agenda, we’d still be stuck with the gross lack of ambition that has left us with third-rate tb drugs and tenth-rate tb diagnostics for decades, couched in one of the most offensive and patronising public health programmes of all – ‘dots’ – while staring down the barrel of a growing multidrug resistance (mdr) nightmare. it staggered me that my patients in hillbrow could permanently take arvs 90% of the time, but the same patients had a <50% completion rate of six months of tb therapy at the tb clinic across the road. the story of how they came to the recommended dose of rifampicin (essentially ‘what dose can we afford’), and my realisation that, far from what i was taught at med school, mdr was the fault of the programme (bad doses, poor support, poor understanding of the epidemiology), speaks volumes about the kind of history that tb has. it’s become better. i still think the programme lacks some creativity and certainly resources, but at least we have a fighting chance, thanks to the increasing focus by clinicians and activists and their demand for integrated therapy and better drugs and diagnostics. we may have saved the world from old-fashioned public health specialists speaking of a lack of ambition, some of the most dispiriting conver­sations i have had have been with conventional public health specialists, saying that we were diverting resources from their sanitation/food/whatever programmes, with our ‘non-sustainable’ hiv programmes. initially, i was defensive, until i realised how they had failed our continent on so many levels for decades – whether health promotion or disease prevention. hiv is common, serious, preventable and treatable, yet many did not seem to think it mattered. arvs alone have increased life expectancy in south africa by a decade, in just a few years, making it one of the most powerful public health interventions ever, right up there with good sanitation and vaccines. hiv care has driven energy and creativity into health delivery, and the focus on an evidence base has, at least somewhat, allowed us to question some of the holy cows of public health – from the design of healthcare delivery, the evidence for cancer screening, to obesity definitions and food recommendations – and this has meant a new and critical generation of people who can claim to have public health expertise. now we routinely demand attention to evidence bases, human rights and patient demands from public health programmes, not always successfully it must be said, but a far cry from the kind of largely irrelevant public health i grew up studying. health system inertia may be our biggest challenge we sit with a health delivery system largely designed by european colonisers. they’ve moved on, but we have clung to a clinic-hospital, nurse-doctor model that was out of date 50 years ago. it is especially poor in dealing with an enlightened, google-empowered population asking hard questions of ill-prepared clinical services. drug-delivery systems and training of health professionals seem constantly to be hamstrung by laws and rules generated by opaque bureaucracies within structures like the health professions council of south africa (hpcsa) and the nursing council – where it is very difficult to see which interest these structures serve. it seems we need massive re-engineering of the health system that goes well beyond what even the idealised national health insurance (nhi) looks like. attend many meetings and be patient one of my epiphanies of the last 15 years of working with the department of health (doh) (it’s true also in academia) is s/he who goes to the most meetings, wins. this is frustrating, but attention to process and keeping a beady eye on policy and choices, in an excitable field like hiv where there are many strident and powerful voices, is imperative. you can’t rely on minutes and proxies; you’ve just got to make sure that you get on that gautrain to civicus building with a fully charged ipad and lots of coffee. we need a strong civil society more than ever for a while, we were all big buddies in the zuma era. government em­braced activists and clinician groups. post manto, it was a breath of fresh air to be told how important we were. but we need to be careful – the defensiveness from prominent doh members that followed the release of the drug stock-outs reported in december, including death threats and thuggish behaviour by security forces focused on tac members in the free state where the stock-outs were the worst, remind us of how prickly and unaccountable politicians and civil servants can be. we still do not have adequate explanation or closure on the bizarre tara clamp issue, where a harmful device was used in the circumcision programmes in kwazulu-natal (kzn). neliswa ‘peggy’ nkonyeni, ex-health minister for kzn, instrumental in several superb kzn healthcare workers losing their jobs when she was manto’s quack foot soldier, is making a political comeback, and there are many people from mbeki’s cabinet who still seem to be successful, despite sitting quietly in his aids-denialist circle (c’mon trevor, what really happened?). at a provincial level, patient advocates and concerned clinicians are routinely treated as optional extras or have their jobs threatened if they rock the boat in local aids councils. ‘protection’ agencies such as the hpcsa continue to let wouter basson earn a handsome living while his victims’ families live in poverty, while slapping down non-governmental organisations (ngos) who support whistle-blowing with spurious appeals to privacy; the hpcsa and nursing council seem to think that it’s better to let rural people die for want of healthcare, than license foreigners willing to work in places desperate for their skills. civil society needs your money and your support, for all our future, to take on powerful vested interests. the private sector, unions, churches and educational institutions have had a largely easy ride the excesses of the mbeki era have allowed for many of these sectors to coast quietly on world aids day platitudes and occasional hiv testing campaigns. i’m struck at dr jan pienaar’s aggressive no-nonsense hiv programme tackling new infections, stigma and fear at anglo-american’s thermal coal, and at the empty public statements from banks, shopping chains, universities, unions, major churches (in fairness, i’ve seen some amazing courage, especially from some catholic groups), large ngos, and opposition political parties. we need tangible commitments to testing and treating people, not the candle-lighting hand-wringing we all dread every 1 december. i visited a very rural hospital in the eastern cape in late december – simply tarring the disastrous dirt road, now promised for years, would make ambulances accessible, health staff happier and prepared to stay, and allow for better support. the staff accommodation is appalling, and the hospital perennially grapples with understaffing. not a single south african doctor works there. i was angry at how a middle-income country could let its citizens be neglected in this way. but the senior doctor working there spoke approvingly of the new district manager and how he was trying to get things going, about how she had got cooperation from the nurses by improving their living conditions, how the doctors were happier, and how successful the arv programme was. we picked up a rural woman looking for a lift en route to the hospital, who spoke loudly and confidently about how she loved ‘our hospital’ (it was embarrassing that the doctor, who is from europe, had to translate for me). a week later, back in civilisation, i bumped into a newly appointed senior member of the doh who i’ve known and respected for years, who knew all the details of the hospital and the district manager, and rattled off ambitious plans for the next six months, expressing deep dismay at the previous maladministration. there is cause for hope. we all have a stake in our doh being as strong as it can be. there is a lot to be angry and concerned about, but it can’t stop there. we have to continue to work constructively and critically, even if we are told we are not welcome at times. we need the protective institutions to be challenged, and we need to continue to strengthen civil society, even if it is just giving them much-needed cash. we need to keep re-imagining a better healthcare system. and we need to attend those long meetings. s afr j hiv med 2014;15(1):39-40. doi:10.7196/sajhivmed.1029 sajhiv 1028 reflections ten years of art in south africa – how far we have come c serenata, ba (hons), mba corresponding author: c serenata (cserenata@clintonhealthaccess.org) celicia serenata is director, hiv and tb, strategic advisor for the clinton health access initiative based in boston, usa i became involved in the hiv response in 1999, when i joined the hiv, aids, sti and tb (hast) unit within the national department of health. little did i know in 1999 that hiv would become my life. i had already been working in public health since 1993, and had been on the fringes of hiv, through the interdepartmental hiv and aids committee. at that point, the focus was on hiv awareness for public sector workers, and success was measured by the availability of condoms. the first task we had after i joined the hast unit was to participate in the writing of the new national strategic plan (nsp) covering the period 2000 2005. this was my first exposure to the small world of hiv in south africa – filled with many interest and stakeholder groups, all with honourable intentions, but not always on the same page. fifteen years later, i am happy to say that i think this has definitely changed, for the better. this is where i was introduced to the process of stakeholder consultation, and through trial and error, we ended up with a document upon which we could all agree. when we wrote that plan, the antenatal seroprevalence rate among pregnant hiv-positive women was 22.4%, with around 4.2 million people living with hiv; and of course, this would climb over the next few years to around 30%, and around 5.6 million people living with hiv. at this point there were no public sector treatment programmes, though there were some patients receiving antiretroviral therapy (art) in research programmes. however, the nsp 2000 2005 put into words the intention to change this, and had as one of its four strategies: ‘improve the care and treatment of hiv-positive persons and persons living with aids to promote a better quality of life and limit the need for hospital care’. honestly, we did not really know what this would involve, but the nsp opened the door to allow us to start thinking about it. unfortunately, it would take another three years for that thinking to be put into action. following a meeting between then president thabo mbeki and former us president bill clinton, the then minister of health, manto tshabalala-msimang, put together a task team to develop an operational plan for implementing comprehensive care, management and treatment of hiv in the public sector. bringing together technical expertise from the clinton foundation, local clinical practitioners, academics and government officials, we started working for many months to put together what was then a revolutionary plan to introduce art. i will not dwell on the politics of hiv at the time, but suffice it to say that there were equal amounts of enthusiasm and resistance being experienced at the time of writing the plan. my life became consumed by writing this plan. the task team pretty much lived out of the sixth floor of a pretoria hotel. we would work from morning to midnight, catch a few hours of sleep, and then start all over again. writing, consulting, rewriting, reviewing, submitting for review, incorporating comments, visiting provinces and facilities. and repeat. and repeat. and again. draft after draft was critiqued and rejected, but still we kept on going. we did so because we knew that the pay-off was something to which we were all so committed. that period of working with 20 or so hardworking, visionary individuals was the most rewarding professional experience. ten years after joining the public health sector, i was participating in something that would be revolutionary. through the blood, sweat and tears (it was a 258-page docu­ment!), we would come out victorious. on my birthday, 19 november 2003, i received a call from my boss, dr nono simelela, with the best five words i could have wished for: ‘cabinet just approved the plan!’ this was before 10 am in the morning. i went to the nearest bar, and had a large cocktail to celebrate. once the plan was approved, we seemed to move at warp speed. putting in place the budget, people and systems to introduce art in the public sector required a monumental effort from government, clinicians, advocacy groups and civil society in general. participating in facility visits to ensure that everything was in place to initiate patients, the massive training effort that had to be rolled out, job aides, guidelines – it was intoxicating. when thursday 1 april 2004 rolled around, it felt like the culmination of something that started in mid-1999 when we started working on the nsp. i was also there when another minister of health, aaron motsoaledi, inspired us to think bigger, collectively, by pushing for the decentrali­sation of treatment from mainly hospitals to primary healthcare services. by april 2010, treatment was offered in fewer than 500 facilities – by the end of 2013 that number had risen to over 3 500, and the number of people receiving art, from under 1 million to over 2 million. i look forward to the next challenge – with more than 5.6 million people living with hiv, there are many more millions that need to be initiated on art in the next decade – and this within the existing public sector constraints. however, knowing where we were ten years ago, i have faith in our ability, collectively, to make this happen successfully. as a society we have shown that with vision, collective response and commitment, we can overcome obstacles for the improvement of the health of all who live within the borders of south africa, and i hope to be a part of this for the next decade, and beyond. conflict of interest. this work is written in ms serenata’s personal capacity and does not necessarily represent the views of the clinton health access initiative. s afr j hiv med 2014;15(1):14-15. doi:10.7196/sajhivmed.1028 march hiv issue 1-16 march 2005 the southern african journal of hiv medicine 1 0 fda public advisory for nevirapine (viramune) p u b l i c h e a l t h recently the us federal drug administration has issued a public advisory for nevirapine (nvp) (vira-mune) informing health care providers of a safety-related change to the nevirapine package insert. this advisory, issued on 19 january 2005, notified a change in nevirapine prescribing information with a warning against starting nevirapine in women with cd4 counts > 250 cells/µl and in men with counts > 400/µl. the risk of developing a hepatic hypersensitivity reaction in the first 6 weeks of nevirapine therapy had been shown to be increased 12-fold in women with counts > 250/µl and 5-fold in men with counts > 400/µl, compared with women with counts < 250/µl and men with counts < 400/µl. nevirapine was the first non-nucleoside drug (nnrti) to be approved by the federal drug administration (fda) for use in highly active antiretroviral therapy (haart) of hiv infection in 1996. since then it has been extensively used throughout the world, and it is manufactured in a very inexpensive generic form and in fixed-dose combinations. it is also licensed for use in prevention of mother-to-child transmission. that this warning should come to light at this stage is probably due to a number of factors which will be reviewed by a senior hiv specialist in the next edition of this journal. in this review, recommendations for the use of nevirapine in the public and private sectors are made. the toxicity strongly associated with nvp is hypersensitivity hepatitis characterised by rash, raised transaminases (> 5 × normal) or systemic illness and occurs within 42 days of commencement. the risk for this reaction is modified by gender and cd4 count. these warnings will have implications for commencement of haart in patients with higher cd4 counts. this is most likely to be pregnant women. the warning will also apply to patients switching later in their course of haart when cd4 counts have improved, again most likely due to pregnancy or in those women wishing to conceive. in the private sector there are more choices, since other options such as nelfinavir exist. in the national roll-out plan it may be necessary to anticipate fertility issues and initiate treatment with nvp in these women when cd4 counts are still low; if a change is needed later in treatment when cd4 counts are higher, utilisation of the second-line drug. kaletra may be required. we print the fda warning below, but look out for a south african expert’s perspective on the public advisory and the other publicity surrounding this drug in the next edition of this journal. the editors http://www.fda.gov/cder/drug/advisory/ nevirapine.htm this public health advisory informs health care providers and patients about recent safety-related changes to the nevirapine (viramune) label (package insert) and about appropriate use of hiv triple combination therapy containing nevirapine, which is one treatment option in the united states and which is increasingly being used globally. the nevirapine label has been revised several times over the last two years to include more information on liver toxicity associated with long term nevirapine use. the indications and usage section of the viramune label now recommends against starting nevirapine treatment in women with cd4+ cell counts greater than 250 cells/mm 3 unless benefits clearly outweigh risks. this recommendation is based on a higher observed risk of serious liver toxicity in patients with higher cd4 cell counts prior to initiation of therapy. in addition, the revised label now includes a medication guide to inform patients about risks associated with nevirapine when used for the treatmentofhiv. both clinically symptomatic and asymptomatic liver toxicity are observed with long-term use of nevirapine in combination with other hiv drugs. asymptomatic liver toxicity is defined as increases in liver enzymes without any associated clinical signs or symptoms and is similar to that seen with other antiretroviral drugs. symptomatic liver toxicity is more common with nevirapine compared to other antiretroviral drugs. important information regarding symptomatic nevirapine liver toxicity is summarised as follows: fda public health advisory for nevirapine (viramune) march hiv issue 1-16 4/16/05 9:36 am page 10 the southern african journal of hiv medicine march 2005 1 1 symptomatic nevirapine liver toxicity consists of elevated liver enzymes plus at least one symptom, which is typically rash but may include flu-like symptoms or fever. the severity of symptomatic liver toxicity ranges from mild symptoms with liver enzyme abnormalities to rapidly occurring liver failure and death. symptomatic nevirapine liver toxicity typically occurs after only a few weeks of dosing and may progress to liver failure despite monitoring of laboratory tests, which is not characteristic of other antiretrovirals. females and patients with higher cd4+ cell counts are at increased risk of liver toxicity. females have a threefold higher risk of symptomatic nevirapine liver toxicity than males, and females with cd4+ cell counts > 250 cells/mm3 have a 12-fold higher risk of symptomatic liver toxicity than females with cd4+ cell counts < 250 (11% v. 0.9%). males with cd4+ cell counts > 400 cells/mm3 have a five-fold higher risk of symptomatic liver toxicity than males with cd4+ cell counts < 400 (6.3% v.1.2%). nevirapine-related deaths due to symptomatic liver toxicity, including some in hiv-infected pregnant women, have been reported to fda’s medwatch program. serious and fatal liver toxicity has not been reported after single doses of nevirapine. in spite of the potential for serious and lifethreatening liver toxicity and skin rashes with nevirapine, there are multiple reasons why nevirapine remains an important part of an hiv treatment regimen for many hiv-infected individuals worldwide. these reasons include: triple antiretroviral regimens have been shown to have a large impact on the reduction of aids morbidity and mortality. triple antiretroviral drug regimens containing a protease inhibitor (pi) or a non-nucleoside reverse transcriptase inhibitor (nnrti), such as nevirapine, are standard of care for hiv treatment and are needed to adequately and durably suppress virus. many options are needed for hiv-infected patients since resistance to antiretroviral drugs or to an entire antiretroviral class can develop. symptomatic liver toxicity has not been reported with the use of single doses of nevirapine to the mother and to the child for prevention of perinatal hiv infection. alternatives to nevirapine are limited by other toxicities, potential drug interactions, and by the risk of drug-related birth defects if given to a female in the first trimester of pregnancy. nevirapine liver toxicity is less frequent (< 2% for both males and females with cd4+ cell counts <250 cells/mm3) when started in patients with lower cd4 counts. therefore, symptomatic liver toxicity in resource poor countries is likely to be much lower if world health organization standards are used for starting treatment. the who recommends the initiation of art treatment in patients with advanced disease or with cd4 counts < 200 cells/mm3. nevirapine is chemically stable in environmental conditions where other antiretrovirals are not. symptomatic liver toxicity has not been reported in hiv-infected children, and nevirapine is available in a liquid formulation while many other antiretrovirals are not. in conclusion, the seriousness of the underlying disease must be considered as part of the risk benefit analysis when treating hiv-infected patients. hiv infection will progress to aids and death if untreated. treatment with combination antiretroviral drugs, including nevirapine, can slow clinical progression and may delay the development of aids or death for years. health care providers should weigh the benefits and risks associated with nevirapine use before prescribing nevirapine for the treatment of their hiv-infected patients. date created: 19 january 2005 march hiv issue 1-16 4/16/05 9:36 am page 11 make up sept 2006 september 2006 the southern african journal of hiv medicine 3 4 judge cameron, himself a well-known advocate for the human rights of people with hiv, suggests that the time has arrived to re-assess hiv testing procedures, in particular whether the current protocol, which includes access to both preand posttest counselling, informed consent and guaranteed confidentiality, is acting as a barrier to the scaling up of hiv testing, and contributing to further self-stigmatisation of people with hiv. while acknowledging the continued prevalence of external stigma, he expresses a profound and moving concern that the safeguards around testing are now reinforcing ‘the inner fears and dread – the inner sense of selfcontamination – of those who suspect that they may have hiv’. he controversially suggests that the exceptionalisation of hiv, including the strict requirements regarding testing, now constitutes a source of risk and harm to people with hiv. judge cameron advocates routine testing. he suggests that where antiretroviral treatment is available and can be offered to the patient, where the patient is assured that he or she will not be discriminated against if they have hiv and where adequate safeguards exist to ensure confidentiality of the test and its outcome, hiv testing must take place unless the patient expressly refuses the test. he acknowledges that counselling is useful, but that it should only be provided if ‘a health care facility is able to offer it without sacrificing the time and energy of its health care personnel’. that time, says judge cameron, ‘is urgently required for diagnosis and treatment of hiv’. judge cameron’s lecture coincides with increasingly loud calls by public health authorities, including the world health organization (who), for a move away from the traditional voluntary counselling and testing (vct) model. options being debated range from routine offers of testing to all patients at all points of contact with the health system, to routine testing where patients must expressly state that they do not wish to be tested, the so-called ‘opt-out model’. some countries, e.g. botswana, have already introduced a policy of routine testing. public health officials arguing for this approach reiterate many of the arguments articulated by judge cameron and specifically point to the high costs of providing vct in resource-poor settings. they argue that in high-prevalence countries there is great urgency to scale up hiv testing to facilitate access to antiretroviral treatment. human rights activists, however, continue to advocate for vct, arguing that other models, where consent and counselling are not central to the process of testing, will violate basic human rights norms and expose unprepared and vulnerable individuals to stigma, discrimination and prejudice.1 an international symposium on hiv testing and human rights in september 2005 concluded that ‘informed consent, counseling before and after a test, and confidentiality of test results are all grounded in human rights norms. forms of hiv testing that significantly curtail these elements are not acceptable.’ there is currently a lack of empirical data confirming the effectiveness of any of these approaches, and there is clearly a need for research that will develop a detailed understanding of the benefits and disadvantages of different models of testing. data regarding the experiences of people who are tested, and their responses to the process and the test result, must be gathered and are crucial to building an understanding of what the best model is to encourage testing and knowledge of hiv status. attention should be paid to the specific needs of vulnerable groups, including women, gay men and sex workers, and their experiences of testing. in the absence of such research, however, there is little to suggest that vct does not work, and in my view it has much to recommend it, especially for women. i do not mean to suggest that vct is not equally important for men, merely that v o l u n t a r y c o u n s e l l i n g a n d t e s t i n g commentary on judge cameron’s speech liesl gerntholtz, ba, llb executive director, tshwaranang legal advocacy centre, braamfontein, johannesburg in may 2006, judge edwin cameron, probably the most high-profile south african living openly with hiv, delivered a lecture at the university of kwazulu-natal in honour of professor ronald louw. professor louw, a lecturer in the faculty of law at the university, a member of the treatment action campaign and a human rights activist, had died a few weeks earlier of an aids-related illness. despite his access to information about hiv, and to adequate resources to manage his illness, professor louw had not tested for hiv, and by the time his hiv status was discovered he was too ill to benefit from treatment. the tshwaranang legal advocacy centre to end violence against women is an ngo that aims to make the legal system a vehicle of social change for women by influencing policy and legislation through advocacy, training and education, research and information dissemination. the southern african journal of hiv medicine september 2006 3 5 there is a specific context for women that must be carefully considered when assessing which models of hiv testing will be most effective. despite a plethora of laws and policies that provide for equality and non-discrimination, south african society continues to be characterised by high levels of inequality between men and women, and disturbingly high levels of violence against women. this context suggests that programmes intended to facilitate greater access to hiv testing and treatment for women, especially poor women who rely on the public health system, will not be successful unless they take these realities into account. in the context of sexual violence, research internationally and locally has affirmed the importance of access to adequate psycho-social care for survivors of gender-based violence, and activists and service providers continue to emphasise the importance of this access as part of the healing process for women. the lack of resources committed to providing this care has been a source of ongoing advocacy and lobbying. the value of counselling is starkly illustrated by research2 conducted into adherence to postexposure prophylaxis (pep) after sexual assault, in gauteng hospitals and clinics. this research reveals that pep services are significantly undermined and weakened if they are not supported by access to counselling and properly integrated into other services for women. the research also shows that women themselves see counselling as necessary and important to their health and well-being. the provision of counselling should be therefore be seen as an essential part of a package of care for poor women who may suspect that they have hiv. for many women, this fear is exacerbated and reinforced by additional fears of violence, abandonment and loss. although there is also little empirical research regarding the true extent of hiv-related stigma and discrimination, there is sufficient anecdotal evidence to show that it continues to be a major problem that must be addressed. pre-test counselling represents one of the very few opportunities for poor women to access any form of psychosocial care where they can discuss their fears and concerns regarding their health status and the consequences of a positive test result for themselves and their families, and where they are able to develop strategies to cope with hiv and its potential impact on their lives. post-test counselling plays an equally important role – for those women who are negative, it is a chance to receive and discuss information that could save their lives; for those who are not, it is a safe space to begin the process of coming to terms with having a lifethreatening illness. for many poor women, vct may also have an important symbolic value. living in deeply sexist societies, for many it is the first opportunity where their rights to autonomy and agency are respected and encouraged. so, rather than eliminating vct, it should adequately resourced so that it is more widely accessible and effective – some research has suggested that the quality of counselling is weak. it should also be integrated more holistically into health services so that it can support and strengthen health services generally. references 1. briefing paper, ‘outcomes of the symposium on hiv testing and human rights, 24-25 october 2005’, canadian hiv/aids legal network. 2. vetten l. ‘factors affecting adherence to post-exposure prophylaxis in the aftermath of sexual assault: key findings from seven sites in gauteng province’, 2004. p e r s o n a l s t o r y living positively with hiv/aids geddes m nala in 1985 my employer, scaw metals, appointed me as a candidate to attend a course as a non-departmental advisor. the course was run by the department of health and population development at their training centre in west fort, pretoria. the objective of the 2-week course was to train both departmental and non-departmental advisors in hygiene, high blood pressure, diabetes, family planning, obesity, stds, communicable diseases and hiv/aids. after completing the course successfully, i would then impart the knowledge to my co-workers. together with the nursing sister who was in charge of our medical centre, we gathered as many teaching aids as we could lay our hands on. we borrowed a range of videotapes from chris hani baragwanath hospital and acquired audiovisual materials, booklets and posters from various health centres. we then played the self-explanatory videotapes on the medical centre tv for employees who had come to see the doctor, while they were waiting. we also conducted health sessions at the company’s hostel after work. never did it dawn on me that i would be the carrier of the virus one day. today i am living with hiv. the reason why i disclose my status is that i know what i am talking about. in 1999 i became very sick. i was losing weight drastically and always felt tired. i also had night sweats and was short of breath. i had sajhiv 1034 reflections a nurse’s perspective on the art rollout m tito, rn, dip nursing science, ahmp corresponding author: m tito (mzi@iydsa.co.za) mzi tito is the technical advisor for beyond zero, in the nelson mandela bay metropolitan, cacadu and harry gwala districts of the eastern cape province, south africa the introduction of antiretroviral therapy (art) brought about an exciting, yet some­how scary period in terms of treatment and care in our health facilities. in 2004, when the rollout of art started, i was fortunate to have been working in one of the first facilities to be accredited as an art site in the nelson mandela bay metropolitan district. only one registered nurse was trained in the art programme; she became the ‘queen’ of the programme and the envy of the rest of the colleagues, as suddenly she was elevated to a specialised position. there was new terminology that we had to get used to, and the names of the new drugs were so many and complex that i thought i would never be able to pronounce them, let alone remember them. drug names like ‘stavudine’ and ‘lamivudine’ sounded like some eastern european names! early on, there were rumours making the rounds from some media and within communities that these drugs were actually very potent, toxic and dangerous to the patients – and this did little to attract some nurses to the art programme. in fact the envy towards our trained colleagues turned to pity, because in our view, they were treading on dangerous ground (sometimes nurses can be reluctant to take professional risks for fear of medico-legal implications). coupled with our lack of training in those early days, this ignorance instilled fear and doubt in many of us. yet throughout this, the number of clients receiving art began to grow significantly. this impacted on space, as waiting areas were overflowing with art patients. facility managers faced several health systems challenges that had not been faced before, and planning for facilities became more difficult. this also posed a serious challenge to the facilities as nurses saw the increased patient health needs as an added burden and workload on the already overburdened staff; and this was compounded by a gross shortage of staff in general. in facilities where there was only a single nurse trained in initiation and management of art, that person would burn out sooner or later due to increased workload. and when a lone nurse trained in nurse-initiated management of art (nimart) was off sick or on leave, there was often no one trained to take over from her. in this context, i volunteered to become part of the art programme. for me it was a great opportunity to become involved and i was mentored by a trained nimart nurse while working alongside her. working with patients receiving art became a rewarding and fulfilling experience in my professional life. soon i was able to breeze through the names of the drugs like an old expert! it was rewarding to see clients who were brought to the clinic unable to walk, some even in wheelbarrows, starting art, and a few weeks later walking into the clinic unassisted and smiling. i was fortunate to work alongside a team of very capable and intelligent community health workers who had been trained in various aspects of the programme, and of course, fellow nimart nurses who were pioneers in the programme. today a large number of people living with hiv are receiving art and the number is growing each day. it has been incredible to witness the process unfolding right in front of my eyes, with all the excitement of seeing people’s lives transformed in front of you: patients who would have died, coming back after receiving art to live normal and healthy lives. ten years of art has changed a lot of lives for the better and has impacted positively on many communities. s afr j hiv med 2014;15(1):19. doi:10.7196/sajhivmed.1034 political power and bad science is never a good combination. the virus, vitamins & vegetables is a collection of essays that takes a look at the baffling government response to the hiv/aids epidemic in post-apartheid south africa and ‘the failure of those in powerful positions to acknowledge that a crisis was unfolding ...’. at first glance the book could be slightly deceptive (candy-coloured pulp-fiction cover, snappy alliterative title, and strap line, ‘the south african hiv/aids mystery’). so you might be forgiven for expecting to settle down with something a bit satirical, perhaps with a few swipes at the former health minister’s promotion of the antiretroviral properties of beetroot. the introduction, however, delivers a better clue to its content. here the editors – ‘long-time slow progressors’ of hiv journalism from health-e – describe how impossible it is to walk away or ‘unsee’ ‘... the matchstick-bodies; the listless babies; the rasping whispers of those whose throats are raw from thrush ...’, i.e. the ravages delivered by untreated hiv/aids. the authors, some of south africa’s key writers, activists and doctors, take us down the bewildering pathway of aids denialism (normally relegated to the rantings of a lunatic fringe) placed firmly at the centre of government policy in the face of a massive epidemic. ‘in the beginning there was virodene’ – the book kicks off with james myburg’s description of mbeki and the anc’s involvement in the controversial research agenda of the industrial solvent dimethylformamide, ‘viorodene’, promoted as an aids cure, though rejected by the scientific community. michael cherry’s chapter reveals how the giants of aids denialism were gathered together by government to make up the majority of a panel of experts, to ‘explore all aspects of ... developing prevention and treatment strategies that are appropriate to the african reality’ – meanwhile denying the provision of proven antiretroviral prophylaxis strategies to reduce perinatal transmission in hiv-positive women. ‘accidental activist’, also known as paediatrician ashraf coovadia, explains how ‘becoming a doctor always felt right ... i wanted to use my medical skills to relieve pain, heal and, hopefully, make the world a better place. never in my wildest dreams did i think that being a doctor in south africa’s state sector would turn me into an activist, mediator, negotiator and protester.’ he describes the hoops he had to go through, including an application to the constitutional court with a group of activists and medical professionals, just in order to be able to get on with his job of doctoring. kerry cullinan examines the ‘strange bedfellows’ that government chose as experts above internationally renowned south african researchers, clinicians and virologists, in particular the vitriolic, dissident lawyer anthony brink. anso thom and liz mcgregor tell tales of charlatan vitamin peddler mattias rath and ‘lazaras programme’ (liquidised vegetables, lemon juice, olive oil, pronutro, and a mysterious magic ingredient named african solution) chief, tine van der maas. these chapters reveal the tacit endorsement of quacks and their cures by the minister of health and the inevitable consequences. former leaders of the treatment action campaign (tac) provide the closing chapters. zackie achmat remembers the decade as a time of great losses and great triumphs in a personal reflection of the years struggling for health, life and dignity for people with aids. sipho mthathi looks to a post-mbeki and manto era, with some trepidation about zuma’s chauvinism, calling for social and economic programmes to properly address inequality and poverty. all this and more left me with an overwhelming sense of exhaustion. in addition to stating the obvious, that too many people died unnecessarily while government questioned the link between hiv and aids and delayed their effective treatment, too many clever and inspiring people were distracted during this time from what would still have been a monumental task without denialism in the mix. the editors and authors are to be applauded in that little space is wasted trying to rationalise the irrational. in the introduction the editors explain that in many ways mbeki’s official biographer, ronald suresh roberts, spurred them on to put the book together, with his revisionism of a ‘poor misunderstood president’, who had ‘never been an aids dissident’. more importantly the book documents an era in an attempt to try, as justice edwin cameron writes, ‘to understand the extent of the calamity that befell us through the mismanagement of aids, and how it happened, so as to forewarn us against a repetition’. polly clayden the virus, vitamins & vegetables: the south african hiv/aids mystery. edited by kerry cullinan and anso thorn. johannesburg: jacana, 2009. pp. 232. price r169.95. isbn 978-1-77009-691-2. b o o k r e v i e w 48 o cto b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e ----------------------------------------------_. -----from the the issue editor advocating access antiretroviral (arv) therapies are again featured in this issue of the journal. the guidelines for the use of arv therapy in paediatric practice, formulated by the paediatric subcommittee under the leadership of or lean levin, are highlighted. these guidelines are different from those that have appeared elsewhere and are unique to our setting. the guidelines were circulated to a panel of international reviewers and their views were incorporated into the document. these guidelines are a companion to the adult guidelines that appeared in the july launch issue of the journal. it may be argued that in both instances there has been a focus on options that are not available to the vast majority of the hivinfected people in our country. this may be so, but we would argue that it is important for our clinicians to be well informed with regard to the difficulties and complexities inherent in the use of these drugs. we are witnessing an increasing use of these therapies in the private sector as more health care funders are providing benefits to hiv-infected individuals, so it behoves all of us to keep abreast of developments in this dynamic field of medicine. of equal importance is the article by mark heywood of the aids law project who urges clinicians to be more vocal in their efforts to expand access to arv therapies among their patients or among the communities they serve. the hiv clinicians society would endorse this stance and urge its members to be more outspoken on these issues and become advocates of expanded access to quality care. it is realised that combination therapies do come with a significant price tag, but the cost-effectiveness of these therapies must not be underestimated. we need only refiect that in the recent past combination therapies to treat tuberculosis were deemed unaffordable, but are now freely available at no cost to the patient. the society congratulates the aids law project on its achievements in protecting the rights of hiv-infected persons, including the positive outcome in two recent court cases, that have led to significant changes in corporate policies for hiv-positive employees or prospective employees. the controversy surrounding hiv as the causative agent of aids has once again surfaced in south africa, gaining political support at the highest level, including the support of the state president. this dehate has had widespread repercussions among scientists, clinicians, hiv-infected individuals and more importantly, the general population at large. a response to this situation was the 'durban declaration', which was distributed at the 13th international aids conference in july 2000 and is published in full in this issue of the journal. the declaration was formulated by a committee consisting of a number of prominent international scientists and this document was subsequently circulated to thousands of scientists and clinicians throughout the world, who in turn became signatories to the document. this document will be useful for clinicians in answering the many questions currently being asked of them by their patients. des martin editor, southern africon journal of hiv medicine president, southern africon hiv clinicians society while neighbouring botswana and other sadc countries and states have been solicited with offers of free or highly reduced-price antiretroviral treatments that will bring the cost of haart to around us$l 000 for a year of therapy per patient, south africa continues to face tough marketeering by the same drug manufacturers, who see the country as a lucrative market with virtually unlimited need for their products. lack of political support, or infrastructural inadequacies are cited for the continued refusal of these companies to consider south africa as a priority for broadening treatment access through preferential pricing strategies, while they continue to milk the private sector of resources in exchange for suboptimal regimens or barely affordable combinations of therapy. by discounting drug prices only through guaranteed volumes of sales, these companies ensure that the higher demand they create among those who somehow manage to pay for these combination packages, leads to volume-linked profitability. the pharmaceutical industry continues to extract unreasonable profits in the developing world for their formulations through 'patent protection', when the costs of developing these patents are already being recovered in their primary markets and the costs of producing the drugs are a fraction of the prices charged. there is no doubt that poverty both facilitates hiv infection and exacerbates the progression to aids, yet the current solutions being offered by the industry will only worsen poverty through their net effect over time. offers from these sources are not benevolent and the countries contemplating their responses to the offers that have been presented face difficult decisions that will leave them responsible for the uncertain long-term consequences and implications. this could be one of the reasons for south africa's strong position within the sadc on defining the framework and conditions for negotiating these deals and for the principled guidelines for countries participating in the process to have been put forward within the sadc. pharmaceutical manufacturers have not been the only businesses to profit from the epidemic, as managed care companies and other service industries are deriving income for delivering hiv-linked products and services that are of highly variable value. the same business models that have been proven over time to make money have been applied to this 'new market: this has to change, as the region faces an unprecedented crisis that cannot be addressed through 'business as usual' approaches. the west and the wealthy can no longer be allowed to profit once more from the misfortunes of africa. antiretroviral therapy is life giving, yet it must be sustainable and effective, as well as being affordable to the households, communities and countries of the individuals who benefit from treatment. a starting point is to ensure that a proper, transparent framework of assistance is created that not only enables treatments to be made available, but also the means to pay for, distribute, administer and monitor them. it is time for the professions and civil society to take issue with the current status of hiv care access in our region and to become better-informed participants in negotiations and stronger advocates for our patients' survival. shaun conway managing editor, southern african journal of hiv medicine executive director, iapac southern africa thf sou ihfrn african journal of hiv mtdlcinf ----------novfmhfr 2000 11 -------------l_f----------interesting times the old chinese proverb 'may you live in interesting times' has surely never been more apt than in the current hivlaids arena in south africa. last month the pharmaceutical manufacturers association, on behalf of 39 drug companies, unconditionally withdrew its challenge to legislation passed in 1997 but not yet implemented that allows the government to make or buy cheaper drugs. the drug companies, which include giants merck, bristol-myers squibb, glaxosmithkline and boehringer ingelheim, had claimed that a section of the 1997 law that allows south africa to import or make cheaper drugs overrode their patent rights. the patents are necessary, they said, to encourage drug research. the health minister, manto tshabalalamsiman9, is however quoted as saying that the victory allowed south africa to pursue policies that she believes are critical to securing medicines at affordable rates and exercising 'wise control' over them. south africa must still reconcile the 1997 law with its commitment to honour international trade agreements and patent rules. the health minister said that the government has invited members of the pharmaceuticai industry and the public to help draft the regulations goveming the law. mirryena deeb, chief executive of the pharmaceutical manufacturers association, termed it 'a partnership, a settlement based on trust'. mark heywood of treatment action campaign believes that the court case will embolden people in developing countries around the world to stand up for medicines that are affordable. glaxosmithkline's south african head, john kearney, has said that the ball is now in south africa's court to deliver aids drugs to its people. this is an awesome challenge, and not a moment too late. with 4.7 million south africans (approximately 10% of the population) living with hiv infection, development of an infrastructure that will allow those afficted access to life-saving drugs is a matter of extreme urgency. even when the drugs are affordable we will need to sort out the operational issues that will enable them to be delivered to people in need. this will require concerted efforts from government as well as non-government and private structures to work together to really tackle our country's aids crisis. jean-pierre garnier, glaxosmithkline chief executive, summed things up well in a statement following the court case, saying 'this settlement meets the objectives of both the south african government and the pharmaceutical industry, but it is my fervent hope that the real winners will be patients'. we couldn't agree more. as pressure for drug access shifts slightly from those who manufacture and price the drugs to those who deliver, such as government and medical aids, the country's wealthiest medical aid scheme, discovery, came under some flack recently. it would appear that the brochures and information used to lure clients to join offer anti-h iv drugs in a misleading way. people have discovered to their horror after joining that the promised 'antiretroviral cover' amounts to little more than supportive counselling. while discovery is aggressively marketing itself to young professionals, and emphasising and rewarding healthy lifestyle, it has not taken into consideration that young people are the group most at risk of hiviaids, and appears to have chosen not to reimburse for treatment for this disease. other medical aids in this country, such as medscheme, which have had an antiretroviral treatment policy for at least 2 years, already have compelling data to show that the intervention is coshonstraining and will be even more so as drug prices continue to fall. in a recent press article discovery health's general manager claimed that the misleading brochure was currently under revision and that independent brokers misinforming the pubiic would be dealt with. we hope so. there is no doubt that all the changes in the hivlaids arena in recent months have made for interesting and exciting times. the onus is now very much on us to grasp the opportunities, to bring ourselves up to speed on treatment issues, and as quickly, safely and effectively as possible to translate this into benefits to our hivinfected population. l1nda-gail bekker managing editor the southern african journal o~ hiv medicine -----------ma 200 i 11 article information authors: rofiah o. sarumi1 ann e. strode2 affiliations: 1college of law and management studies, university of kwazulu-natal, south africa 2school of law, university of kwazulu-natal, south africa correspondence to: ann strode email: strodea@ukzn.ac.za postal address: private bag x01, scottsville 3209, south africa dates: received: 07 jan. 2015 accepted: 16 july 2015 published: 11 sept. 2015 how to cite this article: sarumi ro, strode ae. new law on hiv testing in botswana: the implications for healthcare professionals. s afr j hiv med. 2015;16(1), art. #337, 4 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.337 copyright notice: © 2015. the authors. licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. new law on hiv testing in botswana: the implications for healthcare professionals in this overview... open access • abstract • introduction • hiv testing: the human rights framework • the new legal framework regulating hiv testing in botswana    • access to efficient hiv testing services    • consent must be provided for the testing    • mandatory hiv testing    • pretest information    • confidentiality of hiv test results    • nonconsensual disclosure of a person’s hiv status    • hiv testing may only be undertaken at designated hiv testing centres • review of the new legal framework for hiv testing in botswana • implications of the new hiv testing provisions for healthcare workers in botswana • conclusion    • recommendations • acknowledgements    • competing interests    • authors’ contributions • references abstract top ↑ background: botswana is one of the countries with the highest hiv prevalence rates in the world. innovative hiv testing strategies are required to ensure that those infected or at risk of infection become aware of their hiv status and are able to access treatment, care and support. despite this public health imperative, hiv testing strategies in botswana will in future be based around the principles in the new public health act (2013). the present article describes the hiv testing norms in the act, and sets out the strengths and weaknesses of this approach and its implications for healthcare professionals in botswana. objectives: to compare international norms on hiv testing with the provisions governing such testing in the new botswana public health act and to assess the extent to which the new act meets international human rights norms on hiv testing. method: a ‘desktop’ review of international human rights norms and those in the botswana public health act. conclusion: hiv testing norms in the new public health act in botswana violate individual rights and will place healthcare workers in a position where they will have to elect between acting lawfully or ethically. law reform is required in order to ensure that hiv testing achieves the joint goals of public health and human rights. introduction top ↑ botswana continues to have one of the highest hiv prevalence rates in the world.1 although the rate of new hiv infections has dropped, the prevalence rate remains high amongst certain populations, such as young persons with an estimated 23% of 15–49 year-olds being hiv infected.1 in this context, increasing access to hiv testing as the gateway to hiv prevention and treatment is important, and international best practice requires innovative hiv testing strategies to reach those at risk.2 it is against this background that the recently introduced public health act (2013) which deals directly with hiv testing services in botswana should be reviewed.3 the present article maintains that the approach adopted by the public health act does not follow a rights-based approach to accessing hiv testing as set out in international norms. the article describes some of the implications this approach has for healthcare workers (hcws), and it concludes with recommendations for law reform. hiv testing: the human rights framework top ↑ a rights-based approach has been defined as ‘a conceptual framework for the process of protecting human rights, based on international human rights standards and operationally directed towards promoting and protecting human rights’.4 this human rights approach is reflected in the well-established hiv testing norms at an international level. although these standards have evolved over time, reflecting changing public health approaches, they have continued to be based on the fundamental human rights to exercise one’s autonomy, to privacy and to access the highest attainable standard of healthcare.5,6 early guidance was established in the hiv and human rights guidelines, a set of international norms describing the way in which governments ought to respond to the epidemic.7 issued jointly by the united nations programme on hiv/aids (unaids) and the united nations office of the high commissioner for human rights in 1996, the guidelines provide that governments should review and reform their public health laws to ensure that they protect the right to consent, privacy and confidentiality during hiv testing.7 in 2004, further guidance from unaids and the world health organization (who) established the principle of a rights-based approach to hiv testing3 by stating that the only form of acceptable mandatory screening is that done on donated blood.8 it provided further that the ‘3 cs’ (consent, counselling and confidentiality) should form the bedrock of hiv testing services.3 in this approach, the focus is on patients voluntarily electing to test for their hiv status.8 in 2007, there was a shift in the international guidance when unaids and the who issued guidelines on provider initiated counselling and testing (pict).9 these proposed an approach in which hiv testing was to be recommended to all patients who present themselves at a healthcare facility with certain conditions.9 if the offer of hiv testing was accepted, consent would be obtained for the test with the overriding principle being the best interests of the individual patient.10 this approach requires the giving to individuals of sufficient information to make an informed and voluntary decision to be tested, maintaining patient confidentiality, performing post-test counselling and making referrals to appropriate services.10 this shift was prompted by the new human rights goals of universal access to prevention, treatment, care and support services.10 the new legal framework regulating hiv testing in botswana top ↑ the public health act (no. 23 of 2013)3 attempts to comprehensively address key public health concerns in botswana by creating regulatory structures and setting normative standards on certain issues such as which diseases should be notifiable.3 part xii of the act identifies hiv as a significant public health issue facing botswana, and it sets a number of norms relating to hiv prevention and control.3 these include seven norms for hiv testing, as follows. access to efficient hiv testing services the public health act provides that there is an obligation on the minister of health to ensure that confidential hiv testing facilities are available to all persons over the age of 16 (section 1043). furthermore, the services ought to be efficient as every person has a right to receive their hiv test results as soon as they are approved (section 1113). consent must be provided for the testing hiv testing may only be undertaken with the consent of the person or their parent (if they are under 16) (s 105) unless the test falls into one of the mandatory testing categories described below.3 mandatory hiv testing nonconsensual testing may be done in six situations: (1) if a mentally disabled person is incapable of providing consent, they may be tested without consent (section 105[c]),3 (2) if the hiv test is required under this or any other act, for example the compulsory hiv testing of any person convicted of rape or defilement under the penal code (section 108),3 (3) if the person is unconscious and unable to give consent,5 (4) where the medical practitioner believes that such a test is clinically necessary or desirable in the interests of that person (section 105[2]),3 (5) all donated blood and tissue, (s 106–107) and (6) before any dental or surgical procedure (section 109). if a patient refuses to consent, the hcw may carry out the test without consent or refer the person to another hcw to do the procedure (section 109).3 a hcw who conducts an hiv test without consent is indemnified against any civil or criminal liability that may arise out of the nonconsensual hiv testing (section 105[3]).3 pretest information pretest information should be provided to any person who is to undergo an hiv test (section 110).3 confidentiality of hiv test results users of test services are entitled to confidentiality regarding both their test results and information on their sexual behaviour or the use of drugs.3 furthermore, the public health act provides that all positive results must be confidentially recorded by hcws in terms of the notifiable disease obligations (section 114).3 such information may only be disclosed with consent (section 115) or in terms of the circumstances described below.3 nonconsensual disclosure of a person’s hiv status hcws may disclose a person’s hiv status without consent in three circumstances: (1) to a sexual contact or caregiver if after a reasonable period they have not made such a disclosure themselves (section 116[7]).3 (2) after the death of the person (section 115)3 and (3) where there may be disclosure to other hcws directly involved in the care of the patient.3 hiv testing may only be undertaken at designated hiv testing centres section 119 provides that hiv testing may only be undertaken at a designated hiv testing centre.3 review of the new legal framework for hiv testing in botswana top ↑ the provisions in the new public health act strengthen patient rights by providing, firstly, that there is a positive obligation on the state to provide confidential hiv testing facilities to all persons over the age of 16.3 given that hiv testing is the gateway to both hiv prevention and treatment, the act makes access to these services a fundamental human right. if the state fails to make such services available, it could be held accountable for its inaction. secondly, the testing services must be provided in a manner that respects rights, in that consent must be obtained from patients and their rights to privacy protected.3 furthermore, patients must be given information before the test and this promotes their rights to autonomy in the decision-making process. thirdly, the service must also be efficiently provided as the test results should be made available to patients as soon as the result is obtained and approved, which promotes their right to the highest attainable standard of healthcare. fourthly, in line with international norms, all donated blood and tissue must be tested for hiv. fifthly, the act lowers the age of consent to hiv testing to 16, so enabling young persons at risk of hiv infection to become aware of their hiv status independently.5 previously this was not a legal right as the children’s act is silent on the issue11 but it was allowed in terms of the national guidelines for hiv testing and counselling of 2009.12 based on the above provisions, those in the new public health act appear on the face of it to be in line with the ‘3cs’ as required in terms of international guidance issued by the who and unaids. the act also promotes a number of fundamental human rights as it protects the rights to autonomy and privacy. however, all of these rights are undermined by claw-back clauses in the act. firstly, the right to voluntarily consent to all forms of hiv testing is severely limited by the seven forms of mandatory or compulsory hiv testing that may take place in terms of the act. as stated above, only one form of mandatory testing is allowed in terms of international hiv testing norms – the testing of donated blood. however, the drafters of the act have created a further six circumstances in which testing may be undertaken without consent. it is particularly concerning that all persons undergoing surgical and dental procedures must be tested for hiv.3 this means that all persons visiting healthcare services for routine dental check-ups or minor procedures such as the removal of an ingrown toenail will be subjected to mandatory hiv testing. the public health value of testing all persons before surgical or dental procedures is unclear, given the use of universal precautions. the personal benefit to the patient is also unclear as there is no direct obligation to provide post-test counselling or refer them for treatment. in addition to mandatory testing, the act also allows hcws to undertake hiv testing where they believe that the testing is clinically necessary or even simply ‘desirable’ in the interests of that person.3 this creates a very low threshold at which hcw paternalism could override patient autonomy, which undermines the right to autonomy as it places the decision to test in the hands of the hcw. this opens the door to inter alia hiv testing practices being driven by, for example, stigmatising or discriminatory attitudes towards certain populations such as men who have sex with men, or sex workers. secondly, the right to privacy established in the act is undermined by the sweeping powers of hcws to disclose the hiv status of a patient to any sexual contact or caregiver of the patient if they become aware that the patient has not made such a disclosure themselves.3 this power is out of step with international norms that would generally only require disclosure if the sexual partner or caregiver is at risk of hiv infection.13 mandatory disclosure not only violates the right to privacy, but it also places persons living with hiv at increased risk of stigma and discrimination. furthermore, the kenyan high court recently found that the term ‘sexual contact’ in the kenyan hiv/aids prevention and control act (no. 14 of 2006) violated the principle of legality in that it was ‘vague and overbroad and lacks certainty’.14 the court was of the opinion that hcws would not be able to comply with the provision as it was not clear who would be considered a sexual contact. thirdly, although the act allows children of 16 and above to consent independently to hiv testing, this is an acontextual approach as there is nothing in the laws of botswana which allow children of this age to independently consent to hiv treatment. this means that children will still require parental assistance, which may act as a barrier to some of them accessing antiretrovirals. fourthly, the approach taken in the act to mandatory testing and disclosure places hcws in an ethical dilemma. the medical council (professional conduct) (amendment) regulations provide that doctors have an ethical obligation to maintain confidentiality and may only violate this rule in limited circumstances, such as when ordered to do so by a court.15 this means that doctors complying with the act will be violating professional ethical obligations. finally, the narrow approach taken in the act to limiting hiv testing services to designated facilities means that innovations such as home or self hiv testing cannot be rolled out in botswana as they are expressly prohibited by law; this undermines the right to the highest attainable standard of healthcare. implications of the new hiv testing provisions for healthcare workers in botswana top ↑ there are several implications of this new law for healthcare professionals working in botswana, including that they: need to be aware that they may be asked to act unethically but legally in carrying out mandatory hiv testing, particularly before all surgical and dental procedures. in this regard, it is recommended that practitioners consult with their professional structures to obtain advice on what to do in such instances will be under a legal obligation to disclose the hiv status of, for example, pregnant hiv-positive women if they are not convinced that the patient has made the disclosure herself to her partner. this may place women at risk of domestic violence or other negative consequences12 may lawfully disclose a patient’s hiv status to other hcws directly involved in the care of the patient will need to advise children over the age of 16 that, even if they consent on their own to an hiv test, they will need parental assistance to access hiv treatment will be unable to offer hiv testing to children under the age of 16 who do not have a parent or guardian to advise them as there is no provision in the act for any alternative proxy consenter ought to provide pretest information but no legal obligation to provide post-test counselling cannot offer new innovations such as home hiv testing for these will be illegal as testing is limited to being done at authorised centres. conclusion top ↑ sadly, the new 2013 public health act3 in botswana goes against international best practices as laid out in instruments such as the unaids/who policy statement on hiv,8 the hiv and human rights guidelines,7 and the pict guidelines.9 although the act provides a veneer of human rights, hiv testing will generally now be undertaken in a coercive manner, which undermines efforts to increase awareness of one’s hiv status. the drafters of the act have also misunderstood the shift in international norms as, although there is a focus on increasing access to hiv testing, it still requires such testing to be done in a way that is consistent with human rights norms. the botswana legislature has elected to ignore this approach. it is unlikely that the current coercive approach to hiv testing as set out in the public health act will result in greater individual awareness of hiv status, as most of the testing will be directed at hiv testing in the interests of the healthcare provider. recommendations we submit that there is a need to reform the public health act to ensure that hiv testing services are provided in a way that does not infringe people’s rights. as a minimum, the power to test patients without their informed consent should be removed and the mandatory disclosure provisions limited to situations where a third party is at significant risk of hiv infection. acknowledgements top ↑ competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions r.o.s. (university of kwazulu-natal) is the first author, undertaking the initial research and preparing a first draft of the manuscript. a.e.s. (university of kwazulu-natal) is second author; she reviewed the first draft and wrote the analysis of the public health act. both authors developed the conclusion and recommendations. references top ↑ unaids hiv and aids estimates. c2012 [cited 2014 july 02]. available from: http://www.unaids.org/en/regionscountries/countries/botswana kalichman sc, simbayi lc. hiv testing attitudes, aids stigma, and voluntary hiv counselling and testing in a black township in cape town, south africa. sex transm infect. 2003;79:442–447 pmid: 14663117, http://dx.doi.org/10.1136/sti.79.6.442 government of botswana public health act. 2013 [cited 2014 april 23]. available from: https://dl.dropboxusercontent.com/u/1576514/botswana%20public%20health%20bill%202012.pdf office of the united nations high commissioner for human rights. frequently asked questions on a human rights-based approach to development cooperation. c2006 [cited 2015 may 13]. available from: http://www.ohchr.org/documents/publications/faqen.pdf uno. international covenant on civil and political rights. geneva: united nations organization; 1966. uno. international covenant on economic, social and cultural rights. geneva: united nations organization; 1966. unaids. unaids international guidelines on hiv/aids and human rights. consolidated version. c2006 [cited 2014 july 04]. available from: http://data.unaids.org/publications/irc-pub07/jc1252-internguidelines_en.pdf unaids. unaids/who policy statement on hiv testing. c2004 [cited 2014 july 10]. available from: http://www.who.int/hiv/pub/vct/en/hivtestingpolicy04.pdf?ua=1 who. guidance on provider-initiated hiv testing and counselling. c2007 [cited 2014 july 03]. available from: http://www.unicef.org/aids/files/pitcguidance2007_eng.pdf heywood mj. the routine offer of hiv counselling and testing: a human right. hiv aids policy law rev. 2006;11:71–72. pmid: 17375428. government of botswana. children’s act, 2009. c2009 [cited 2014 may 19]. available from: http://www.aclr.info/images/stories/uploader/publication_files/acts/botswana_children_act_08_of_2009.pdf government of botswana. national guidelines for hiv testing and counselling centres, 2009. c2009 [cited 2014 aug 28]. available from: http://www.gov.bw/global/moh/pc_moh_01.pdf r v cuerrier [1998]. can. sup. ct. lexis 4312. aids law project v attorney general of kenya and others, case no. 97 of 2010. kenya law. 2015. government of botswana. medical council (professional council) (amendment) regulations 77 of 1999. gaborone: government of botswana; 1999. the southern african journal of hiv medicine                                                              april  2010 almost all humans are latently igg-seropositive for the double-stranded dna human herpesvirus 5 named cytomegalovirus (cmv). cmv is an aidsdefining world health organization (who) stage 4 opportunistic infection for both adults and children, seen when the cd4 t-cell count falls below 100 cells/µl and as an immune reconstitution syndrome after starting highly active antiretroviral therapy (haart).1 clinical manifestations active cmv disease may present multi-systemically, with significant morbidity and mortality. organ system manifestations include: cmv retinitis (cmv-r). this is a visual emergency usually presenting with blurred vision, floaters, black spots, flashing lights, distortions, redness and photophobia, but sometimes asymptomatic. who clinical diagnosis guidelines for cmv-r include dilated pupil indirect fundoscopic identification of ‘discrete patches of retinal whitening with distinct borders, spreading centrifugally, often following blood vessels, associated with retinal vasculitis, haemorrhage and necrosis’.2 figs 1 and 2 show cmv-r before and after local treatment, respectively. this fundoscopic picture is known as the ‘pizza pie’ appearance. cmvr may result in blindness.3 cmv of the gastro-intestinal tract. colitis is symptomatic as chronic watery diarrhoea that may become bloody, and oesophagitis symptomatic as dysphagia, anorexia and weight loss. hepatitis may occur, and there are reports of acalculous cholecystitis. cmv adrenalitis. adrenal insufficiency may manifest as postural hypotension, fatigue, hyponatraemia, hyperkalaemia and acidosis. it has a high mortality rate.4 cmv pneumonitis. manifestations are tachypnoea, hypoxia and dry cough, which are commonly misdiagnosed as pneumocystis jirovecii pneumonia.5 held to ransom cmv treatment in south africa r e v i e w fatima laher1, mb bch, dip hiv man (sa) gail ashford 2, fcfp, dip hiv man (sa), dmh (sa) angela cescon3, bsc/bphe claire cullen4, mb bch erica lazarus1, mb bch, dip hiv man (sa) adrian puren5, mb bch phd linda visser6, fcophth 1perinatal hiv research unit, soweto, johannesburg 2donald gordon medical centre, parktown, johannesburg 3faculty of health sciences, simon fraser university, canada 4department of ophthalmology, university of limpopo and dr george mukhari hospital, limpopo province 5national institute for communicable diseases, sandringham, johannesburg 6department of ophthalmology, university of kwazulu-natal, durban 31 cytomegalovirus is a multi-systemic infection reactivated in the immunocompromised. diagnosis and treatment are prohibitively costly in sub-saharan africa, and efforts need to be made for their price reduction to support the expanding highly active antiretroviral treatment programme in the region. fig. 1. cmv retinitis at baseline. full-thickness retinal necrosis along the inferotemporal arcade with some haemorrhage. there is minimal vitritis and mild macular oedema (courtesy dr linda visser, university of kwazulunatal). april  2010                                                                the southern african journal of hiv medicine                                                   cmv of the neurological system.6 encephalitis presents with headache, subacute personality changes, decreased concentration, and progressive dementia. transverse myelitis may occur. cmv is a recognised cause of acute inflammatory demyelinating polyradiculopathy (guillain-barré syndrome), the hallmarks of which are rapidly progressive ascending and often asymmetrical paraesthesiae, sensory loss and areflexia, as well as urinary retention, constipation and incontinence. the cerebrospinal fluid may demonstrate polymorphonucleocytosis and raised protein, and the diagnostic method of choice is polymerase chain reaction (pcr) testing of the cerebrospinal fluid for cmv dna. south african spectrum of disease most data for cmv in the developed world were established in the 1990s, before the haart era. cmv-r was found in a third of aids patients, with a large resulting burden of blindness.7 in one prehaart swiss study of 48 patients, median survival after cmv retinitis was 6 months.8 haart improved survival markedly in aids cmv-r patients.9 there is a paucity of cmv data in the developing world. cmv has been called the ‘neglected disease of the aids pandemic’ because of poor diagnostic and treatment capability.1 in south africa’s pre-haart era, 90 aids patients were treated for cmv-r at the university of natal over 7 years, and the incidence was noted to increase with time.10 a cross-sectional study screening all hiv-infected patients with cd4 counts <50 cells/µl in khayelitsha, south africa, diagnosed cmv-r in 2% of these patients using dilated pupil indirect ophthalmoscopy.1 in a south african autopsy study of 47 hiv-infected cadavers where the clinician-attributed cause of death had been tuberculosis, cmv pneumonitis was proven in 15% and 66% tested positive for cmv-dna.11 south africa has both a high burden of hiv disease12 and a large, expanding haart programme.13 many south african hiv-infected patients present for initiation of haart when the cd4 count is less than 100 cells/µl,14 and often the median is less than 50 cells/µl,15 which makes them susceptible to cmv disease. the return to health and longevity that haart confers16 shapes a powerful argument to treat cmv efficiently and prevent its debilitating effects. diagnostic options a variety of testing options exist to identify active systemic cmv infection (table i). viral culture is traditionally accepted as the ‘gold standard’ method of detection.17 simpler and more rapid options are now proving as or more effective.18 the pp65 antigen assay can provide very sensitive results in less than 6 hours, the main drawback being the need for immediate sample processing after retrieval in order to ensure test validity. serological tests for the presence of igm and igg antibodies may have little diagnostic value in the immunocompromised patient. cmv dna-pcr tests provide sensitive results that can reproducibly quantify cmv viral loads.19 in hivinfected patients, both dna-pcr and pp65 antigen assay have proven to be more predictive in detecting cmv than serology or viral culture.20 the cmv pp67 mrna test is a promising new method used in research settings. treatment: the urgent need for valganciclovir price reduction in sa for cmv treatment in hiv patients cmv treatment strategies (table ii) include systemic as well as local products, the latter for opthalmological indications. after completion of an induction phase, patients remain on maintenance therapy until immune recovery (cd4 >100 cells/µl). because southern african health facilities are poorly resourced, widespread use of intra-ocular ganciclovir (gcv) is not feasible.1 specialist ophthalmological services are scarce in the state sector, and sometimes non-existent in rural areas. intra-ocular gcv may not always be acceptable to patients, and is not without procedure-related adverse effects such as end ophthalmitis.10 most importantly, intra-ocular gcv does not prevent spread of cmv to the other eye, and completely fails to treat disseminated cmv.1,10 unfortunately, the exorbitant cost of systemic cmv treatments is prohibitive in the state sector. systemic gcv necessitates a 3-week stay in hospital for intravenous induction, followed by oral maintenance gcv.21 lengthy intravenous induction is not always realistic in resource-poor settings and may place 32 fig. 2. cmv retinitis after six intra-ocular ganciclovir injections. note scarring in the area of previous necrosis. there is less vitritis, and the macular oedema has resolved. haemorrhages may take months to resolve, and intraretinal gliosis can usually be seen late (courtesy dr linda visser, university of kwazulu-natal). 32 the southern african journal of hiv medicine                                                              april  2010 test tube/transport samples volume required turnaround time price estimate (2009) pvt = estimated prices courtesy toga laboratories; state = estimated prices courtesy nhls/nicd. table i. cmv diagnostic tests cmv viral culture (shell vial) cmv pp65 antigen (ifa) cmv igg and igm qualitative cmv dna-pcr quantitative cmv dna-pcr (i.e. cmv viral load) no preservative send on ice to arrive at lab and be processed within 24 hours edta, room temperature, must be received at nicd before 14h00 same day as collection yellow-top edta edta urine, csf aspirate, breastmilk blood not an ideal sample whole blood result may be impossible if patient neutropenic blood (serum) any sample including blood, csf, etc. whole blood 1 ml 5 ml 2 7 d (state), 3 28 d (pvt) 1 3 d 1 d 1 d 1 d r82 (state), r97.11 (pvt) r171 (state), r182.97 (pvt) igg r104.85 (pvt), igm r113.76 (pvt) r607.14 (pvt) r1 214.18 (pvt) drug dose price estimates across sectors safety private state ngo valganciclovir (valcyte; roche) 450 mg per tablet, 60 tablets per bottle no generics currently available in south africa ganciclovir (cymevene; roche) inj.: 500 mg in 10 ml vials ×5 caps: 250 mg (84), 500 mg (90) no generics currently available in south africa initiation phase maintenance phase induction phase: intravenous maintenance phase: oral local treatment for cmv retinitis 900 mg bd po with meals × 21 days 900 mg/d po with meals until haart restores cd4 count >100 cells/µl 5 mg/kg iv bd × 21 days 1 g tds po r24 719.87 for 21 days r17 657.05 per month r2 558.24 for 5 vials r19 479.32 for 21 days r13 913.85 per month r1 789.65 for 5 vials specially imprinted price-reduced boxes can be ordered by ngos from roche switzerland* n/a doubles ddi levels monitor fbc 2 3 × week discontinue if neutrophils <0.5 ×109/l or platelets <25×109/l. adjust doses in renal failure beware pancytopenia monitor fbc every 2 days reduce dose by 30 50% if neutrophils 0.5 0.8×109/l. discontinue if neutrophils <0.5 ×109/l. cautious use with azt or ddi: similar toxicities oral ganciclovir is not available in south africa suggest maintenance with valganciclovir in a recumbent patient, 2 mg of a 25 mg/ml ganciclovir solution in normal saline is injected with a 1 ml syringe and 30g needle, 4 mm behind the limbus of the eye superiorly with the patient looking down. patients are given intravitreal ganciclovir injections twice a week for the first 2 weeks, then weekly until immune recovery or retinitis quiescence9 *minimum order of chf 10 000. each 60-tab box of 450 mg tablets costs chf 500, plus freight and insurance changes apply (estimated chf 177.40 + 40.20 respectively for a 26-box order) (chf = swiss franc, 1 chf = 7.47309 zar, exchange rate at 1 june 2009). ngo orders can be placed only at roche basle (sandra.torriani_ cazzato@roche.com). the lead time is 3 months after receipt of firm order. prices quoted are per roche, may/june 2009. fbi = full blood count; azt = zidovudine. table ii. cmv treatment in adults 33 april  2010                                                                the southern african journal of hiv medicine                                                   immune-compromised patients at risk of contracting nosocomial illnesses. the benefits of valganciclovir are evident: it is taken orally, easy to administer in resource-poor settings, well tolerated, and efficacious in both induction and maintenance phases of treatment.21 its cost currently prevents its use in south african cmv aids patients. second-line intravenous treatment options such as foscarnet and cidofovir are avoided because of nephro-toxicity. paediatric cmv treatment and prevention in pregnancy congenital cmv causes a broad range of neurodevelopmental deficits in both symptomatic and initially asymptomatic neonates, including microcephaly, chorioretinits and sensorineural hearing loss. a 6-week course of intravenous ganciclovir has been shown to be effective in preventing hearing loss, improving weight gain and head circumference, and resolving hepatic dysfunction, hepatomegaly and retinitis. ganciclovir toxicity, especially neutropenia, can however be life-threatening.22 results of a small pharmacokinetic study show that oral valganciclovir at a dose of 16 mg/kg provided similar plasma levels of drug compared with 6 mg/kg intravenous ganciclovir, so it appears that valganciclovir is a promising option for treating neonatal and paediatric patients.23 vertical cmv transmission is trans-placental, and the rate is observed to be higher in hiv-1-infected mothers. infants who are co-infected with hiv-1 and cmv are more likely to have rapid hiv disease progression.24 valganciclovir and ganciclovir are both considered potentially teratogenic from animal data, but there are no controlled studies in pregnant women. a recent development in march 2009 is a cmv vaccine that may offer future public health benefits for pregnant women by eliminating congenital cmv.25 how can valganciclovir price reduction be achieved in south africa? currently, the cost of cmv treatment makes it unaffordable to most. letters of concern on behalf of the south african hiv clinicians society have been sent to roche urging price reduction of cmv treatments in the sub-saharan african region. various organisations internationally are lobbying for price reduction, including médecins sans frontières, universities allied for essential medicines and the clinton hiv/aids foundation. valganciclovir for cmv treatment in aids patients must be placed on our state tender request list. currently it is available through state discretionary funds to transplant patients only. government should consider compulsory licensing for price-slashed generic production of valganciclovir for the state sector. references 1. heiden d, ford n, wilson d, et al. cytomegalovirus retinitis: the neglected disease of the aids pandemic. plos med 2007; 4(12): 1845-1851. 2. world health organization. revised who clinical staging and immunological classification of hiv/aids and case definitions of hiv and related conditions. geneva: who, 2006. 3. jacobson ma, stanley h, holtzer c, et al. natural history and outcome of new aids-related cytomegalovirus retinitis diagnosed in the era of highly active antiretroviral therapy. clin infect dis 2000; 30: 231-233. 4. eddleston m, peacock m, juniper m, et al. severe cytomegalovirus infection in immunocompetent patients. clin infect dis 1997; 24: 52-56. 5. baughman rp. cytomegalovirus: the monster in the closet? am j respir crit care med 1997; 156(1): 1-2. 6. mccutchan ja. cytomegalovirus infections of the nervous system in patients with aids. clin infect dis 1995; 20: 747-754. 7. holbrook jt, jabs da, weinberg dv, lewis ra, et al. visual loss in patients with cytomegalovirus retinitis and acquired immunodeficiency syndrome before widespread availability of highly active antiretroviral therapy. arch ophthalmol 2003; 121: 99-107. 8. olmari m, gabriel v, sansonetti a, et al. long-term visual outcome in cmv retinitis. presented at the xth international conference on aids, yokohama, japan, 7-12 august 1994 (abstract no. pb0517). 9. gross jg, bozzette sa, mathews wc, et al. longitudinal study of cytomegalovirus retinitis in acquired immune deficiency syndrome. ophthalmology 1990; 97(5): 681-686. 10. visser l. managing cmv retinitis in the developing world. comm eye health 2003; 16(47): 38-39. 11. martinson na, karstaedt a, venter wd, et al. causes of death in hospitalized adults with a premortem diagnosis of tuberculosis: an autopsy study. aids 2007; 21(15): 2043-2050. 12. national department of health, south africa. report: the national hiv and syphilis prevalence survey south africa 2007. http://data.unaids.org/ pub/report/2008/20080904_southafrica_anc_2008_en.pdf (accessed 7 may 2009). 13. national department of health, south africa. hiv and aids and sti strategic plan for south africa for 2007-2011, 2007. www.doh.gov.za/docs/misc/ stratplan/2007-2011/part1.pdf (accessed 7 august 2009). 14. keiser o, orrell c, egger m, et al. public-health and individual approaches to antiretroviral therapy: township south africa and switzerland compared. plos med 2008; 5(7): e148. doi:10.1371/journal.pmed.0050148. 15. coetzee d, hildebrand k, boulle a, et al. outcomes after two years of providing antiretroviral treatment in khayelitsha, south africa. aids 2004; 18(6): 887895. 16. lima vd, hogg rs, harrigan pr, et al. continued improvement in survival among hiv-infected individuals with newer forms of highly active antiretroviral therapy. aids 2007; 21(6): 685-692. 17. müller lv, hampl w, hinz j, et al. high variability between results of different in-house tests for cytomegalovirus (cmv) monitoring and a standardized quantitative plasma cmv pcr assay. j clin microbiol 2002; 40(6): 2285-2287. 18. mocarski es, shenk t, pass rf. cytomegaloviruses. in: knipe dm, howley pm, griffin de, eds. fields virology. 5th ed, philadelphia: lippincott williams & wilkins, 2007: 2701-2772. 19. boeckh m, boivin g. quantitation of cytomegalovirus: methodologic aspects and clinical applications. clin microbiol rev 1998; 11(3): 533-554. 20. dodt kk, jacobsen ph, hofmann b, et al. development of cytomegalovirus (cmv) disease may be predicted in hiv-infected patients by cmv polymerase chain reaction and the antigenemia test. aids 1997; 11: f21-f28. 21. martin df, sierra-madero j, walmsley s, et al., for the valganciclovir study group. a controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis. n engl j med 2002; 346: 1119-1126. 22. nasetta l, kimberlin d, whitley r. treatment of congenital cytomegalovirus infection: implications for future therapeutic strategies. j antimicrob chemother 2009; 63: 862-867. 23. kimberlin d, acosta e, sanchez p, et al. pharmakokinetic and pharmacodynamic assessment of oral valganciclovir in the treatment of symptomatic congenital cytomegalovirus disease. j infect dis 2008; 197: 836-845. 24. kovacs a, schluchter m, easley k, et al. cytomegalovirus infection and hiv-1 disease progression in infants born to hiv-1-infected women. n engl j med 1999; 341: 77-84. 25. pass rf, zhang c, evans a, et al. vaccine prevention of maternal cytomegalovirus infection. n engl j med 2009; 360: 1191-1199. 34 s e p t e m b e r 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e the number of new cases of human immunodeficiency virus (hiv) infection in taiwan peaked in 2005, and it is still a serious problem.1 tuberculosis (tb), especially extrapulmonary tb, is also common in taiwan1 and is commonly associated with hiv infection.2 when a patient urgently needs surgery, as can occur with perforation of an intestine or appendix, there is no time for definitive testing for hiv and/or tb. we report a case in which a patient required immediate surgery for what appeared to be an abscess with peritonitis from a perforated diverticulum of the ascending colon. the patient was unaware that he had both extrapulmonary tb and hiv. the tb was discovered by the pathologist on examination of the surgical specimen, and the hiv was discovered because the patient’s postoperative condition suggested a systemic disease. the case illustrates that despite co-occurrence of the two diseases surgery can be successful, recovery can be similar to that expected in a patient without the diseases, and patient outcome can be good if anti-tb and antiretroviral therapies are started almost immediately. the case is also consistent with previous reports that patients with hiv undergoing surgery have similar conditions to hiv-negative patients and that the results of treatment are equivalent.3 case report a 38-year-old man who had been well without systemic disease and neither drank alcohol nor smoked had experienced dull, right lower quadrant abdominal pain for 1 week, and fever with chills for 2 days. he had no other associated symptoms such as nausea, vomiting or diarrhoea. he sought help at the emergency department, where physical examination showed rebound tenderness at the right lower quadrant of the abdomen, with muscle guarding and rigidity. the white blood cell count was 8×109 /l, with 11% band-form neutrophils. an elevated c-reactive protein level (5.77 mg/dl) was noted. after he was admitted on 29 april 2006, an abdominal computed tomography scan revealed an ill-defined mass in the right lower quadrant anterior to the right psoas muscle; it was suspected to be an abscess. there were also several small abscesses in the omentum, paracolic gutter and mesentery of the ascending colon (fig. 1). the clinical impression was that he had perforated diverticulitis with intra-abdominal abscess, and he was immediately operated on. at surgery the abscess was found to be at the ascending colon mesentery. a right hemicolectomy was performed because of the high level of suspicion of a perforated diverticulum (fig. 2). postoperatively, the patient had a high fever for 3 days even with intensive treatment with a secondgeneration cephalosporin (cefmetazole 1 g 8-hourly). a systemic disease was suspected because the unusual clinical profile, including the location of the abscess and the pathological findings, did not correspond with the patient’s general condition. hiv infection was considered, and a western blot test was positive for hiv. the patient’s cd4 cell count, measured by flow cytometry, was 306/μl, and his cd8 cell count was 677/ μl. the hiv viral load was measured by indirect enzymetuberculous abdominal abscess in an hiv-infected man: neither infection previously diagnosed c a s e s t u dy kuo-yao kao, md tsung-i hung, md department of general surgery, shin kong wo ho-su memorial hospital, taipei, taiwan a 38-year-old man had a 1-week history of right lower quadrant abdominal pain; the initial impression was that he had diverticulitis of the ascending colon with an intra-abdominal abscess. signs of peritonitis mandated an immediate right hemicolectomy. the unusual location of the abscess and the patient’s unusual postoperative course suggested that he might also have a systemic disease. testing for hiv infection was positive. after 2 weeks in hospital, he was treated as an outpatient for both tuberculosis and hiv with a favourable outcome. in taiwan a pre-operative hiv test is not performed routinely, and the hiv seroprevalence in surgical patient populations is unknown. surgeons should keep the possibility of hiv infection in mind in a patient with an unusual clinical course. 30 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s e p t e m b e r 2 0 1 0 linked immunosorbent assay (elisa) and found to be 6 790 copies/ml. the final diagnosis was hiv infection coincident with the histologically confirmed mycobacterium tuberculosis colitis and abscess formation. anti-tb drugs (rifampin + ethambutol) were started soon after the patient resumed oral intake. he was discharged on 11 may 2006, 14 days after admission, at which time highly active antiretroviral therapy (haart) was started, including abacavir, efavirenz and lamivudine. anti-tb drugs were given continuously in the outpatient department for 18 months; the regimen included isoniazid, rifampin, ethambutol and pyrazinamide. the patient was followed up until august 2009 with a favourable outcome; at that visit he had a viral load of <400 copies/ml, a cd4 count of 332 cells/μl and a cd8 count of 632 cells/μl. discussion our patient was unaware that he had tb and hiv infection, and because he urgently needed surgery we did not have time to perform laboratory tests to diagnose these infections. nevertheless, he quickly recovered from the surgery and was discharged from the hospital 2 weeks after admission. outpatient treatment for the tb and hiv had a favourable outcome. tb has become a major cause of death and disability in many parts of the world, especially in developing countries.4,5 the disease can affect almost any body system, although most cases are pulmonary.6 in the usa, cases of extrapulmonary tb increased from 13.5% of all reported tb cases in 1975 to 21.0% in 2006.7 a study in taiwan found that extrapulmonary tb cases increased from 23% to 27% from 1996 to 2003.8 abdominal tb is a rare manifestation of extrapulmonary tb, with a prevalence of around 3%.6 it may involve the gastrointestinal tract, peritoneum, mesenteric lymph nodes, genito-urinary tract, or other solid organs.4,6,9 abdominal tuberculosis frequently poses a diagnostic challenge because specimens may be difficult to obtain, and the concentration of organisms may be low. sanai and bzeizi compiled data from 39 studies and found that the sensitivities of various diagnostic tests in patients with tb peritonitis were 38% for an abnormal chest radiograph and 53% for a positive purified protein derivative test.10 examination of ascites fluid found that lymphocytes predominated in 68% of cases, and that there was an elevated lactate dehydrogenase level in 77% of cases and an elevated adenosine deaminase level in 84%. mycobacteria were found in 34% of ascites fluids on culture, but only 3% of examinations detected organisms by smear. in contrast, the sensitivity of laparoscopic diagnosis was 92%.10 these diagnostic tests for abdominal tb seem unreliable, partly because not every patient develops ascites. culture of ascites fluid or peritoneal biopsy is the gold standard test. however, even a final diagnosis of pulmonary tb usually takes considerable time; diagnosis of abdominal tb typically takes even longer. one study from the national taiwan university hospital demonstrated that the mean interval between the first day of admission and respiratory isolation for pulmonary tb was 20.5 days.11 on the other hand, bernhard et al. reported that physicians considered abdominal tb in the initial differential diagnosis in only 39% of cases (7/18). time to specific diagnosis ranged from <1 week to >3 months.12 chen et al. reported that the average time to diagnosis of abdominal tb in southeastern taiwan was 48±10 days.13 delay in the diagnosis of abdominal tb is therefore more common than for pulmonary tb. several studies have observed that the proportion of extrapulmonary tb is higher in individuals who also are infected with hiv14,15 and in foreign-born immigrants16 in the usa. in addition, a dramatically increasing tb notification rate was observed in sub-saharan africa between 1990 and 2005, especially in countries with a high prevalence of adult hiv (>5%).17 the international standards for tuberculosis care states that hiv counselling and testing is indicated for all patients with tb in areas with a high hiv prevalence.18 in taiwan, 15 011 cases of hiv infection had been reported to the fig. 2. the largest abscess after excision. this abscess was found adjacent to the ascending colon (arrows). fig. 1. pre-operative computed tomography scan of the abdomen. the largest abscess is located at the ascending colon mesentery, anterior to the right psoas muscle (vertical arrow). there are several smaller abscesses over the omentum, and paracolic gutter (horizontal arrow). 31 s e p t e m b e r 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 32 taiwan centers for disease control as of 31 december 2007.1 the case burden of hiv infection in taiwan is significantly lower than that of tb. more data are required to establish the cost-effectiveness of offering hiv testing to tb patients in a region of high tb and relatively low hiv prevalence, such as taiwan. we describe this rare case to alert physicians to the fact that with the current trend of increasing hiv prevalence among the taiwanese, hiv co-infection should be considered when extrapulmonary tb is suspected. medical treatment is preferable to treat abdominal tb in patients also infected with hiv, surgery being reserved for complications such as intestinal obstruction, fistula, perforation and haemorrhage.19 our patient was operated on because he had abscesses and peritonitis, which were a complication of tb colitis. with the availability of the surgical specimen, we followed our suspicion and diagnosed hiv, enabling prompt initiation of treatment. anti-tb medication was started within 10 days, and the patient was discharged in 14 days. the course of diagnosis and treatment was straightforward. after discharge he received medical treatment as an outpatient with a favourable outcome. conflict of interest: none. references 1. centers for disease control, department of health, roc (taiwan). statistics of communicable diseases and surveillance report. 2007. http://www.cdc.gov.tw/lp. asp?ctnode=2076&ctunit=1144&basedsd=31&mp=5 (accessed 12 september 2009). 2. tuberculosis coalition for technical assistance. international standards for tuberculosis care (istc). the hague: tuberculosis coalition for technical assistance, 2006. http://www.stoptb.org/resource_center/assets/documents/istc_report. pdf (accessed 12 september 2009). 3. saltzman dj, williams ra, gelfand dv, wilson se. the surgeon and aids: twenty years later. arch surg 2005; 140: 961-967. 4. khan r, abid s, jafri w, et al. diagnostic dilemma of abdominal tuberculosis in non-hiv patients: an ongoing challenge for physicians. world j gastroenterol 2006; 12: 6371-6375. 5. uygur-bayramicli o, dabak g, dabak r. a clinical dilemma: abdominal tuberculosis. world j gastroenterol 2003; 9: 1098-1101. 6. sharma sk, mohan a. extrapulmonary tuberculosis. indian j med res 2004; 120: 316-353. 7. kipp am, stout je, hamilton cd, et al. extrapulmonary tuberculosis, human immunodeficiency virus, and foreign birth in north carolina, 1993 2006. bmc public health 2008; 8: 107. 8. hsu yc, yang mh, chen yh, et al. the epidemiology characteristics of extrapulmonary tuberculosis in taiwan, 1996-2003. epidemiol bull 2007; 23: 231-242. 9. golden mp, vikram hr. extrapulmonary tuberculosis: an overview. am fam physician 2005; 72: 1761-1768. 10. sanai fm, bzeizi ki. systematic review: tuberculous peritonitis – presenting features, diagnostic strategies and treatment. aliment pharmacol ther 2005; 22: 685-700. 11. wu yc, hsu gj, chuang ky, et al. intervals before tuberculosis diagnosis and isolation at a regional hospital in taiwan. j formos med assoc 2007; 106: 10071012. 12. bernhard js, bhatia g, knauer cm. gastrointestinal tuberculosis: an eighteenpatient experience and review. j clin gastroenterol 2000; 30: 397-402. 13. chen hl, wu ms, chang wh, et al. abdominal tuberculosis in southeastern taiwan: 20 years of experience. j formos med assoc 2009; 108: 195-201. 14. yang z, kong y, wilson f, et al. identification of risk factors for extrapulmonary tuberculosis. clin infect dis 2004; 38: 199-205. 15. onorato im, mccray e. prevalence of human immunodeficiency virus infection among patients attending tuberculosis clinics in the united states. j infect dis 1992; 165: 87-92. 16. talbot ea, moore m, mccray e, et al. tuberculosis among foreign-born persons in the united states, 1993-1998. jama 2000; 284: 2894-2900. 17. reid a, scano f, getahun h, et al. towards universal access to hiv prevention, treatment, care, and support: the role of tuberculosis/hiv collaboration. lancet infect dis 2006; 6: 483-495. 18. tuberculosis coalition for technical assistance. international standards for tuberculosis care (istc). the hague: tuberculosis coalition for technical assistance, 2006. http://www.stoptb.org/resource_center/assets/documents/istc_report. pdf (accessed 12 september 2009). 19. guex ac, bucher hc, demartines n, et al. inflammatory bowel perforation during immune restoration after one year of antiretroviral and antituberculous therapy in an hiv-1-infected patient: report of a case. dis colon rectum 2002; 45: 977978. anaemia is a relatively common finding in hiv-positive patients, with rates (among females) as high as 37%, compared with their hiv-negative counterparts (17%). anaemia of chronic disease plays a very important role in this population group, and is estimated to occur in 18 95% of cases. for this reason, it is imperative to distinguish this condition from other underlying or concurrent causes of anaemia that may warrant treatment. this clinical case illustrates the value of critically evaluating the parameters of a full blood count and haematinic screen, to so determine which patients warrant further workup. case report a 43-year-old man, known to be hiv-1 positive, presented to the casualty department at kalafong complaining of a 2-week history of fatigue, weight loss, night sweats, dysphagia and general malaise. he further described a 3-day history of vomiting and diarrhoea, with no melaena or haematemesis. at the time of presentation, he had been on firstline highly active antiretroviral (haart) therapy for 2 years. despite this the cd4 count on admission was 3 cells/μl. in the light of this finding, non-compliance was suspected. he had previously been diagnosed with gastro-intestinal mycobacterium avium complex as a cause of anaemia annemarie van de vyver, bsc, mb chb, pgdiptm department of internal medicine, university of pretoria and kalafong hospital, pretoria adele visser, mb chb, dtm&h, pgdiptm department of clinical pathology, university of pretoria, and national health laboratory service, tshwane academic division t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s e p t e m b e r 2 0 1 0 33 disseminated mycobacterium avium-intracellulare by positive blood cultures and had been started on treatment. owing to side-effects, he had not complied with this treatment regimen either. on admission he was pyrexial and tachycardic. he was clinically anaemic with no signs of oral hairy leukoplakia or candida. although abdominal examination was unremarkable (with no hepatomegaly or splenomegaly), he was tender in the epigastric area. cardiovascular and respiratory examinations were essentially normal. the full blood count revealed a significant microcytic hypochromic anaemia (haemoglobin 5.8 g/dl, mean corpuscular volume 68 fl and mean corpuscular haemoglobin 20.4 pg). the white cell count was normal, but he had thrombocytopenia (30×109 /l). creatinine and electrolyte levels were normal. liver function tests revealed an isolated mildly raised gamma-glutamyl transpeptidase (ggt) level (70 u/l) and a low albumin level (16 g/l). c-reactive protein was elevated at 84.9 mg/l. iron studies were also performed and showed low serum iron (1.3 μmol/l) and transferrin (1.4 g/l) levels and transferrin saturation (4%), and a markedly elevated serum ferritin level (1 579 μg/l). as part of the work-up for anaemia, the upper gastrointestinal tract was investigated by endoscopy. this revealed what was clinically judged to be extensive candidiasis throughout the oesophagus. the stomach was normal but the duodenum also had extensively distributed white plaques. a biopsy specimen of these plaques was taken and submitted for histological examination. an h&e stain was performed (fig. 1, a). the periodic acid-schiff (pas) stain revealed multiple clusters of micro-organisms in the histiocytes (fig. 1, b). finally, a ziehl-neelsen (zn) stain was performed, showing large numbers of acid-fast bacilli (fig. 1, c and d). a diagnosis of disseminated m. avium complex (mac) was suggested, as the organisms were found intracellularly. the diagnosis of disseminated mac was confirmed on a urine sample by molecular techniques. discussion patients with advanced hiv-1 disease pose a multitude of challenges in terms of diagnosis and treatment. anaemia is a relatively common finding in hiv-positive patients, with rates (among females) as high as 37%, compared with their hiv-negative counterparts (17%).1 the list of possible causes of anaemia in hiv-positive patients is substantial and differentiation is often difficult. value is certainly added by taking the full blood count results into consideration. a simple distinction between red cell size (reflected in mean corpuscular volume) and red cell haemoglobin content (reflected by mean corpuscular haemoglobin) can significantly contribute to further choices in testing. anaemia of chronic disease plays a very important role in this population group, as inhibition of iron transfer from the reticulo-endothelial cells to the erythroid precursors due to inflammation is estimated to occur in 18 95% of cases.2 for this reason, it is imperative to distinguish this condition from other underlying or concurrent causes of anaemia that may warrant treatment. a haemoglobin level below 8 g/dl should prompt further investigation, as anaemia of chronic disease rarely causes world health organization grade iii or iv anaemia2 (grade iii <7.9 g/dl, grade iv <6.5 g/dl).1 iron studies may facilitate this process. in both iron deficiency anaemia and anaemia of chronic disease, the serum iron level and transferrin saturation will be reduced. the transferrin level, however, may facilitate in making a distinction as it is typically reduced to normal in anaemia of chronic disease and increased in iron deficiency. a further indicator can be found in serum ferritin levels, which are reduced to below 30 ng/l (positive predictive value of 92 98%) in iron deficiency, and normal to elevated in anaemia of chronic disease. the inherent confounder with using ferritin is the fact that it acts as an acute-phase reactant and will be elevated beyond its baseline in any inflammatory condition, irrespective of iron status.2 the soluble transferrin receptor level may be a useful assay to delineate causes of anaemia. levels are typically increased in iron deficiency and essentially normal in anaemia of chronic disease, as inflammatory cytokines negatively influence its expression. this can also be very useful if co-existence of both conditions is suspected. however, the assay is not universally offered. the use of various ratios has also been proposed as possibly helpful in determining the underlying cause of anaemia.2 the finding and confirmation of iron deficiency should prompt further investigation as to the underlying cause. fig. 1. sections from white plaques biopsied in duodenum: a – h&e stain; b – pas stain showing numerous clumps of organisms in histiocytes; c – zn stain showing clumps of acid-fast bacilli; d – closer view of collection of acid-fast bacilli in zn stain. s e p t e m b e r 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 34 imaging of the gastro-intestinal tract may be useful, especially if clinical features are suggestive. of note is the fact that the only feature suggestive of upper gastrointestinal bleeding in our patient was the epigastric tenderness on abdominal examination. it is therefore prudent to have a high index of suspicion. again, the differential diagnosis in this clinical setting is large and relates to the degree of immunosuppression.3 disseminated mac is the most common bacterial opportunistic infection among hiv-1-positive patients in the first world.4 however, it appears to be less common in our local setting.5 it has been postulated that it is caused by the overwhelming presence of m. tuberculosis in the south african context.5 patients with a cd4 count below 50 cells/μl and possibly high hiv-1 viral loads are at increased risk of mac infections, which have been shown to be an independent predictor of mortality. for this reason prophylaxis is advocated by some.4 it is, however, not included in the current south african national antiretroviral treatment guidelines.6 mac can affect any part of the gastro-intestinal tract, with the duodenum being the most common site. macroscopic findings are not diagnostic. biopsy and culture is therefore the mainstay of diagnosis of this condition.3 references 1. moyle g. anaemia in persons with hiv infection: prognostic marker and contributor to morbidity. aids rev 2002; 4: 13-20. 2. weiss g, goodnough l. anemia of chronic disease. n engl j med 2005; 352: 10111023. 3. riedel d, nugent s, gilliam b. upper gastrointestinal bleeding in a patient with hiv infection. clin infect dis 2009; 48: 368-369. 4. karakousis p, moore r, chaisson r. mycobacterium avium complex in patients with hiv infection in the era of highly active antiretroviral therapy. lancet infect dis 2004; 4: 557-565. 5. peter j, sonderup m. diagnosing multiple opportunistic infections: the value of liver biopsy. south african journal of hiv medicine 2008; spring: 51-52. 6. department of health. national antiretroviral treatment guidelines. johannesburg: jacana, 2004. invited comment abdominal mycobacterial infection in hiv the articles in this edition by kao and hung and van de vyver and visser both deal with aspects of abdominal mycobacterial infections. van de vyver’s article highlights the importance of investigating abnormalities that cannot be attributed to hiv infection alone, and demonstrates that abdominal mycobacterial infection may present with a paucity of abdominal symptoms and signs. while tuberculosis (tb) infection is predominant in south africa, non-tuberculous mycobacteria should always be considered in patients with advanced immunosuppression. the article by kao demonstrates a more dramatic presentation in a patient with relatively preserved immunity. notification rates of extrapulmonary tb in south africa are increasing, and it is likely that more patients will present with abdominal tuberculosis.1 tuberculosis can involve the entire gastro-intestinal tract, from the intra-abdominal organs to the peritoneum. the spectrum of symptoms seen in abdominal tb range from insidious nonspecific complaints that may be mistaken for the constitutional symptoms of hiv infection, to an acute abdomen.2 with improved access to antiretrovirals, tb immune reconstitution inflammatory syndrome is being seen more frequently and often involves the abdomen.3 in resource-limited facilities, investigations such as abdominal computed tomography scanning and laparoscopic peritoneal biopsy are seldom available. however, abdominal ultrasound, specifically looking for hepatomegaly, ascites, splenic micro-abscesses and intra-abdominal lymphadenopathy, is a useful investigation for assessing hiv-infected patients with suspected abdominal tuberculosis.4 clinicians need to maintain a high index of suspicion for tb in patients with hiv and abdominal symptoms. in the correct clinical setting empiric anti-tuberculosis therapy is warranted. all patients started on anti-tuberculosis therapy need close follow-up until resolution, and those who fail to respond to tb therapy may require further investigation. nontuberculosis mycobacterial infection should be considered in patients with advanced immune deficiency. while abdominal tuberculosis in hiv-infected patients is best managed with standard tb therapy and anti-retrovirals, complications such as obstruction, perforation and large abscess formation may require surgical intervention.2 depending on clinical presentation, early consultation with the surgeons is essential and if required surgery should not be delayed. a d black department of medicine, chris hani baragwanath hospital and university of the witwatersrand, johannesburg references 1. who global report on tuberculosis 2009. http://apps.who.int/globalatlas/predefinedreports/tb/pdf_files/zaf.pdf (accessed 24 june 2010). 2. lazarus aa, thilagar b. abdominal tuberculosis. dis mon 2007; 53: 32-38. 3. meintjes g, rabie j, wilkinson rj, cotton mf. tuberculosis-associated immune reconstitution inflammatory syndrome and unmasking of tuberculosis by antiretroviral therapy. clin chest med 2009; 30(4): 797-810. 4. sinkala e, gray s, zulu i, et al. clinical and ultrasonographic features of abdominal tuberculosis in hiv positive adults in zambia. bmc infect dis 2009; 9: 44. thf southf nmrican jou nal of hi mtolcinf -----------july 2000 from the editor daniel j ncayiyana welcome, the new hiv journal editor, south african medical journal it is my great pleasure to salute the launch of the southern african journal of hiv medicine, and to congratulate the southern african hiv clinicians society on their foresight in planning this venture, and their tenacity in seeing it through to fruition. the pestilence of hivlaids threatens to wreak havoc on the social and economic fabric of our country, and to disrupt the lives of all south africans in almost unimaginable ways. yet the available information on hiv/aids has oiten tended to be fragmentary, distorted and confusing. this journal will serve as one of the very few homegrown, dependable sources of information for the practising physician, backed as it is by the authority of the southern african hiv clinicians society. president mbeki has been much criticised for his perceived stand on hivlaids, but one of his pronouncements is indisputable, namely that african solutions must be sought and found for aids in africa. this new publication will help do just that. i trust that the south african medical community will give this venture its wholehearted support, and that those in a position to do so will contribute regularly to the contents. it will serve as a forum for the news and views of the society and updates on its own activities, regional news and the activities of its international affiliates. although the next issue of the journal is scheduled for november of this year, it is hoped that a monthly edition will soon become a reality. this will of course depend on the future support that the journal receives, and in this regard it would be appropriate for me to thank those who have contributed to making this launch edition possible. des martin editor, southern african journal of hiv medicine president elect, southern african hiv clinicians society anew journal fora rapidly emerging disease the 13th international aids conference takes place in durban, south africa, from 9 to 14 july 2000. this is noteworthy for a number of reasons: in the first instance, it is the first time that the conference is being held on the african continent, and notably, it is also the first time it is being held in a developing country. the host country is witnessing the fastest growing hiv epidemic in the world it is estimated that 1 in 10 south africans is infected with the virus. the scientific community, and indeed the population at large, has recently witnessed the re-emergence of the debate surrounding the link between hiv and ai ds. the sensationalism surrounding this has only served to deviate and diffuse the focus away from the prevention and management of the problem. the southern african hiv clinicians society has played an active part during recent times in reassuring both the public and clinicians about the way forward in dealing with the epidemic. continuing medical education plays an important role in achieving this and is one of the key programmes of the society. this first issue of the southern african journal of hiv medicine coincides with the conference in durban and it is hoped that it will find a place in the reading of medical, scientific and allied professionals dealing with hiv disease in our region. it is also hoped that it will receive broader recognition amongst the international community, which is urged to engage actively in the discourse surrounding the epidemic in our region. hiv-related research continues to flourish in south africa and the scientific community is placed to answer important questions, particularly in the fields of vaccine research, mother-ta-child transmission of hiv and coinfection with hiv and tuberculosis. in addition, increasing access to antiretroviral therapies is becoming a reality so that appropriate therapies now fall within the grasp of a wider treater base of practitioners. the journal will provide a home for original scientific articles, review articles and continuing medical education and will also provide a forum for debate and discussion on the topical issues of the day. article information authors: palesa nkomo1 natasha davies2 gayle sherman3,4 sanjana bhardwaj5 vundli ramokolo1 nobubelo k. ngandu1 nobuntu noveve1 trisha ramraj1 vuyolwethu magasana1 yages singh1 duduzile nsibande1 ameena e. goga1,6 affiliations: 1health systems research unit, south african medical research council, south africa 2wits reproductive health and hiv institute, university of the witwatersrand, south africa 3national institute for communicable diseases, johannesburg, south africa 4department of paediatrics and child health, university of the witwatersrand, south africa 5the united nations children's fund, pretoria, south africa 6department of paediatrics, university of pretoria, south africa correspondence to: palesa nkomo email: palesa.nkomo@mrc.ac.za postal address: private bag x385, pretoria 0002, south africa dates: received: 15 apr. 2015 accepted: 06 aug. 2015 published: 07 oct. 2015 how to cite this article: nkomo p, davies n, sherman g, et al. how ready are our health systems to implement prevention of mother to child transmission option b+? s afr j hiv med. 2015;16(1), art. #386, 5 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.386 copyright notice: © 2015. the authors. licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. how ready are our health systems to implement prevention of mother to child transmission option b+? in this forum... open access • abstract • introduction    • context and summary of 2015 prevention of mother to child transmission guidelines • health systems’ readiness to implement the new guidelines    • system gaps that may hinder successful implementation of the 2015 south african prevention of mother to child transmission guidelines    • late antenatal booking    • late hiv testing and poor quality hiv testing    • late referral into care and poor retention in care    • limited laboratory capacity    • interrupted drug supplies • recommendations • conclusion • acknowledgements    • competing interests    • authors’ contributions • references abstract top ↑ in january 2015, the south african national department of health released new consolidated guidelines for the prevention of mother to child transmission (pmtct) of hiv, in line with the world health organization's (who) pmtct option b+. implementing these guidelines should make it possible to eliminate mother to child transmission (mtct) of hiv and improve long-term maternal and infant outcomes. the present article summarises the key recommendations of the 2015 guidelines and highlights current gaps that hinder optimal implementation; these include late antenatal booking (as a result of poor staff attitudes towards ‘early bookers’ and foreigners, unsuitable clinic hours, lack of transport to facilities, quota systems being applied to antenatal clients and clinic staff shortages); poor compliance with rapid hiv testing protocols; weak referral systems with inadequate follow-up; inadequate numbers of laboratory staff to handle hiv-related monitoring procedures and return of results to the correct facility; and inadequate supply chain management, leading to interrupted supplies of antiretroviral drugs. additionally, recommendations are proposed on how to address these gaps. there is a need to evaluate the implementation of the 2015 guidelines and proactively communicate with ground-level implementers to identify operational bottlenecks, test solutions to these bottlenecks, and develop realistic implementation plans. introduction top ↑ context and summary of 2015 prevention of mother to child transmission guidelines south africa has the highest hiv incidence rates globally, and is the largest provider of antiretroviral therapy in the world.1,2 in january 2015, the south african national department of health (ndoh) released new national consolidated guidelines, including an approach akin to world health organization (who) option b+ for the prevention of mother to child transmission (pmtct) of hiv.3 these guidelines harmonise triple antiretroviral treatment (art) regimens for infants and young children, adolescents, pregnant and breastfeeding women, and adults to facilitate continuity of care. the guidelines stipulate lifelong art for all pregnant and breastfeeding women and hiv-positive infants regardless of their cd4 cell count.3 box 1 summarises the main differences between the 20153 and 20134 pmtct guidelines. specific algorithms have been developed for women with comorbidities (e.g. active psychiatric illness, renal dysfunction and/or anaemia) and these remain unchanged compared with the 2013 south african guidelines.3,4 the 2015 guidelines highlight the need to improve access to testing and treatment in general, to achieve the 90/90/90 target (90% coverage for hiv testing, 90% coverage for art uptake amongst hiv-positive patients, and viral suppression of 90% of patients on art) and to prioritise hiv prevention and treatment amongst adolescents.3 despite the complexity of the new policy, its ‘treatment as prevention’ approach amongst pregnant and breastfeeding women could move south africa closer to achieving the fourth and fifth millennium development goals and the post-2015 sustainable development goals. box 1: key changes between the 2013 and january 2015 south africa prevention of mother to child transmission guidelines. health systems’ readiness to implement the new guidelines top ↑ system gaps that may hinder successful implementation of the 2015 south african prevention of mother to child transmission guidelines in our opinion, there are five main requirements for successful implementation of the 2015 pmtct guidelines: (1) early presentation at the health facility to access care (i.e. early antenatal booking), (2) universal antenatal hiv testing based on high-quality standardised operating procedures, with repeat testing of hiv-negative women, (3) immediate referral into appropriate care and retention in care, (4) adequate coverage of appropriate laboratory systems and (5) uninterrupted drug supplies. these require appropriate actions within the health system and amongst sufficiently informed and empowered individual mother-infant pairs. box 2 presents a summary of the main health system and community gaps in optimal implementation of the 2015 pmtct guidelines; these are explained in more detail below. box 2: summary of impediments to optimal prevention of mother to child transmission guideline implementation. late antenatal booking since 2001, south africa has improved access to antenatal care, hiv testing and art provision for pregnant women. currently, antenatal care uptake is over 95%; hiv testing is offered by over 95% of health facilities, and more than 87% of hiv-positive pregnant women receive some form of art.3,5 however, the district health information system shows that in 2011/2012 only 40.2% (range 33.6% in eastern cape to 56.2% in western cape) of pregnant women had their first antenatal booking visit before 20 weeks’ gestation, highlighting the first key bottleneck to successful guideline implementation.6 a study in north-west province identified a variety of reasons for late booking, including late pregnancy disclosure amongst teenagers, fear of hiv testing, non-caring nurse attitudes, cultural beliefs that dissuade early revealing of pregnancy, lack of transport and unsuitable clinic opening hours.6 these findings were corroborated by research in johannesburg which showed that 54% of pregnant women sought antenatal care later than 5 months’ gestation.7 solarin and black found that almost half of new mothers interviewed reported that their first antenatal booking was not accepted by health facilities for various reasons including (1) they needed ‘to make a booking appointment’, (2) they did not have a south african identity document and (3) clinics had reached their quota for the day.7 these obstacles delay first antenatal booking and thus hiv screening, art initiation and detection of treatment failure amongst pregnant women on art as recommended by the 2015 south african pmtct guidelines.3 late hiv testing and poor quality hiv testing there are grave concerns about quality control of hiv counselling and testing (hct) at facilities, as shown by a study conducted in 455 sites (primary health care clinics, community healthcare centres and hospital gateway clinics) in limpopo province (adrian puren, personal communication, 11 march 2015). poor quality control increases the risk of false-positive and -negative hiv results within the pmtct programme. concerns identified included inadequate training, frequent rotation of staff, lack of supervision and on-site quality control, incorrect storage of control samples, poor adherence to standard operating procedures (sop) and improper stock control (adrian puren, personal communication, 11 march 2015). anecdotal information gathered during healthcare provider (hcp) pmtct guideline training found that hcps are not waiting the required time before reading the hiv result, increasing the risk of false-negatives. late referral into care and poor retention in care appropriate, timely referrals and linkages to care are needed antenatally and post delivery to facilitate uptake of and retention in care. over 90% of facilities assessed during a national south african medical research council (samrc) review conducted in 2010 had a referral system for infant and adult art clients.5 similarly, an eastern cape study found that 100% of facilities reported appropriate referral mechanisms for hiv-positive women.8 however, in the mrc review, 38% of facilities did not make appointments for their patients at referral centres, and only 50% of clinics followed up whether clients engaged with care at the referral site.5 from our research and clinical experience, postnatal loss to follow-up is particularly high in south africa. poor information systems and documentation contribute to difficulties with tracing such patients. in malawi, loss to follow-up was five times higher for women who started art during pregnancy and two times higher for women who started art whilst breastfeeding than for women who started art with who stage 3/4 disease or cd4 cell count ≤ 350 cells/µl.9 these data highlight the risk of poor retention in care postnatally and emphasise the need for robust referral systems, integrated services and effective tracking mechanisms to retain, or re-engage, women in art care post delivery. limited laboratory capacity laboratory capacity is needed for (1) viral load monitoring to identify poor adherence and treatment failure – a vitally important step in pmtct programme success, (2) cd4 cell count to identify women who need cryptococcal antigen screening or cotrimoxazole prophylaxis, (3) routine antenatal bloods for art toxicity monitoring and (4) repeated polymerase chain reaction (pcr) testing of hiv-exposed infants from birth (for symptomatic infants) to 18 months;3 laboratory capacity is accordingly a critical component of the pmtct programme, and is key to timely referral into appropriate care. previous challenges to implementing laboratory-based hiv tests in south africa included difficulties processing large numbers of hiv-related specimens, high staff turn-over, and insufficient training in pcr techniques and cd4 measurements.10 consequently, experienced staff carry the burden of training new staff10 and processing high quantities of specimens. interrupted drug supplies by mid-2014, an estimated 2.6 million people were on art in south africa.3 this number will further increase following the 2015 guideline implementation, creating additional demand for art stock. sustaining such art programme expansion will necessitate more efficient, effective supply chain management and increased human resources. yet the healthcare system remains plagued by frequent hiv medicines stock-outs and clinic staff shortages. inadequate supply chain management and ‘corruption’ contribute to avoidable stock-out-related treatment interruptions,11 resulting in regimen modification at best or, at worst, drug discontinuation.12 considering the complexity of the new guidelines in part reflects south africa's mature hiv epidemic, including increasing rates of highly experienced art patients with treatment failure and drug resistance. the effects of recurrent stock-outs on adherence, viral loads and drug resistance should not be underestimated. recommendations top ↑ in light of the gaps identified above, we make several recommendations for optimal 2015 guideline implementation (box 3). box 3: recommendations for optimal 2015 guideline implementation. conclusion top ↑ the january 2015 pmtct guideline recommendations are of a very high standard and based on the best intentions to improve the management of both hiv-positive and hiv-negative women. by implementing these guidelines, it should be possible to eliminate mtct, improve maternal and infant outcomes, and ensure that women remain virologically suppressed and engaged in lifelong art care. however, the implementation challenges might have been underestimated. evaluation of the implementation process is needed to identify key bottlenecks and develop realistic implementation plans. a proactive process of communicating with ground-level implementers is needed to understand their challenges and to address these through well recognised, quality improvement processes. acknowledgements top ↑ our sincere thanks to professor adrian puren from the national institute of communicable diseases for help with data on the internal quality control (iqc) implementation report in limpopo (april 2014). this work was supported by funds from the south african medical research council. competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions p.n. (south african medical research council) conceptualised and designed, drafted, wrote and finalised the article. n.d. (wits reproductive health and hiv institute) designed, contributed to and assisted with finalisation of the article. g.s. (national institute for communicable diseases); s.b. (the united nations children's fund) and v.r. (south african medical research council), n.k.n. (south african medical research council), t.r. (south african medical research council), n.n. (south african medical research council), v.m. (south african medical research council), y.s. (south african medical research council) and d.n. (south african medical research council) reviewed, commented on and approved the final version of the article. a.e.g. (south african medical research council) conceptualised and designed, contributed to and assisted with finalisation of the article. references top ↑ human sciences research council. launch of the 2012 south african national hiv prevalence, incidence and behaviour survey report. april 2014 [cited 2015 mar 02]. available from http://www.hsrc.ac.za/en/media-briefs/hiv-aids-stis-and-tb/sabssm4-launch. full report available from http://www.hsrc.ac.za/uploads/pagecontent/4565/sabssm%20iv%20leo%20final.pdf unaids. report of the global aids epidemic 2013 [cited 2015 mar 02]. available from http://www.unaids.org/sites/default/files/en/media/unaids/contentassets/documents/epidemiology/2013/gr2013/unaids_global_report_2013_en.pdf south african national department of health. 2014 [cited 2015 mar 02]. national consolidated guidelines for the prevention of mother-to-child transmission of hiv (pmtct) and the management of hiv in children, adolescents and adults. available from http://www.sahivsoc.org/upload/documents/hiv%20guidelines%20_jan%202015.pdf south african antiretroviral treatment guidelines 2013. pmtct guidelines: revised march 2013 [cited 2015 aug 27]. available from http://www.sahivsoc.org/upload/documents/2013%20art%20guidelines-short%20combined%20final%20draft%20guidelines%2014%20march%202013.pdf goga ae, dinh th, jackson dj for the sapmtcte study group. early (4–8 weeks post-delivery) population-level effectiveness of who pmtct option a, south africa, 2011. south african medical research council, national department of health of south africa and pepfar/us centers for disease control and prevention. 2013 [cited 2015 mar 12]. available from http://www.mrc.ac.za/healthsystems/sapmtcte2011.pdf district health barometer 2011/2012. durban: health systems trust; 2013 [cited 2015 apr 02]. available from http://www.health-e.org.za/wp-content/uploads/2013/04/dhb2011_12lowres.pdf solarin i, black v. ‘they told me to come back’: women's antenatal care booking experience in inner-city johannesburg. matern child health j. 2013;17:359–367. pmid: 22527767, http://dx.doi.org/10.1007/s10995-012-1019-6 rispel lc, peltzer k, phaswana-mafuya n, metcalf ca, treger l. assessing missed opportunities for the prevention of mother-to-child hiv transmission in an eastern cape local service area. s afr med j. 2009;99:174–179. pmid: 19563095 tenthani l, haas ad, tweya h, et al. retention in care under universal antiretroviral therapy for hiv-infected pregnant and breastfeeding women (‘option b+’) in malawi. aids. 2014;28:589–598. pmid: 24468999, http://dx.doi.org/10.1097/qad.0000000000000143 stevens ws, marshall tm. challenges in implementing hiv load testing in south africa. j infect dis. 2010;201(suppl. 1):s78–s84. pmid: 20225952, http://dx.doi.org/10.1086/650383 bateman c. drug stock-outs: inept supply-chain management and corruption. s afr med j. 2013;103:600–602. pmid: 24344422, http://dx.doi.org/10.7196/samj.7332 pasquet a, messou e, gabillard d, et al. impact of drug stock-outs on death and retention to care among hiv-infected patients on combination antiretroviral therapy in abidjan, côte d’ivoire. plos one. 2010;5:e13414. pmid: 20976211, http://dx.doi.org/10.1371/journal.pone.0013414 j u ly 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e fogarty et al.6 reviewed 18 descriptive studies in published articles and 57 conference proceedings and found over 200 variables regarding patient adherence to antiretroviral therapy (art), falling into four broad areas: n factors related to treatment regimen n social and psychological factors n institutional resources n personal attributes. they found that more complex regimens were associated with decreased adherence. social and psychological factors reflecting emotional adjustment to hiv/aids and provider support were associated with improved adherence, as was access to institutional resources. personal attributes showed a mixed relationship; gender was not consistently related to adherence, but younger age, minority status, and a history of substance abuse were often associated with non-adherence. an intervention search yielded 16 interventions employing a wide range of behavioural, cognitive and affective strategies. however, evidence of effectiveness of the interventions appeared to be poor. according to nischal et al.,7 studies have indicated that at least 95% adherence to art regimens is optimal. it has been demonstrated that a 10% higher level of adherence results in a 21% reduction in disease progression. the various factors affecting success of art are social aspects such as motivation to begin therapy, ability to adhere to therapy, lifestyle pattern, financial support, family support, pros and cons of starting therapy, and pharmacological aspects such as tolerability of the regimen and availability of the drugs. furthermore, the regimen’s pill burden, dosing frequency, food requirements, convenience, toxicity and drug interaction profile compared with other regimens need to be considered before starting art. lack of trust between clinician and patient, active drug and alcohol use, active mental illness (e.g. depression), lack of patient education, inability of patients to identify their medications, and lack of reliable access to primary medical care or medication may all contribute to inadequate adherence. mehta et al.4 found the following factors in an extensive study on adherence: adherence increases with age, except in the most elderly (those aged over 75 years).8 it is known that the very elderly often have comorbidities such as vision, hearing or memory impairment as well as multiple chronic illnesses. in several studies of patients with hiv infection, chronic illness, mental illness, older age and male gender were associated with decreased adherence. lower socio-economic status (ses) has been shown to be another contributor to decreased adherence.9 socio-economic factors specifically related to decreased adherence are unstable or poor housing, low income and low level of education. the presence of psychiatric illness is commonly associated with decreased adherence.10 other psychological factors affecting adherence among the mentally ill are hostility, guilt, anxiety, paranoia and grandiosity.11 in contrast, in a prospective study of hiv-infected individuals, adherent patients (defined as >80% adherence) had significantly less depression than non-compliant patients.12 negative attitudes about medications or illness may also interfere with patient adherence. among the mentally ill, reasons cited for not taking medications were fear of addiction and the belief that medication use was a sign of weakness.13 among hivinfected patients, attitudes and beliefs related to decreased adherence included the patient’s acceptance/ perception of disease, and perceived lack of benefit.13 the role of the multidisciplinary team meeting in an antiretroviral treatment programme o r i g i n a l a r t i c l e c van deventer, md chb, fcfp (sa), mfammed (med) principal family physician, southern district, north west province, and senior lecturer, rural health and family medicine, university of the witwatersrand m radebe, mb potchefstroom hospital, north west the importance of adherence in the management of patients on combination antiretroviral therapy has been well documented.1-6 however, for sustainability of the overall programme adequate patient ‘tracking’ is required in order to understand where the programme may be failing. 50 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u ly 2 0 0 9 the art clinic at potchefstroom hospital, known as the wellness clinic, was accredited in november 2005 and currently manages >3 000 adults and children. there is a dedicated team with good continuity of nursing, counselling and administration personnel but a high turnover of doctors and allied health workers. early in the clinic’s history it was decided to hold multidisciplinary meetings monthly, in order to understand and deal with difficulties arising from the management of patients on art. the meetings started in january 2006 and are ongoing. patients with perceived problems affecting their optimal management were identified by personnel at the wellness clinic during routine consultations, and booked for the bi-weekly multidisciplinary team (mdt) discussion. this team consisted of the physician and family physician involved in the clinic, the unit manager, one nurse, the pharmacist, the social worker and the dietician, one counsellor and a data collector. an audit of the minutes of the 2006 mdt meetings was done. all the minutes of the 2006 mdt meetings were examined and patients identified together with the decisions made regarding them. the files of these patients were drawn and the following variables were investigated: n the original and most recent cd4 cell count and viral load (vl) n reason for being on the mdt’s agenda n if there was an adherence issue, the reason for the poor adherence n whether support was available or not n interventions decided upon n the outcomes, where possible, of any interventions. according to the minutes, 76 people were discussed. all were adults, 39% were female, and their mean age was 38 years. of the files 13 could not be found for the audit, but reasons for inclusion in the mdt meetings included the following: 6 patients (8%) had virological failure with no apparent cause, as they had good pill counts at each visit and were physically well. there was documented poor adherence in 5 patients (7%), reflected in ongoing poor pill counts. forty-eight patients (63%) had defaulted treatment for varying lengths of time. in 2 patients (3%) the reasons for inclusion were not clear from the minutes or the files. eight (11%) were included because of alcohol abuse concerns and 7 (9%) for a variety of other reasons. since the group of defaulters was the largest group, it was investigated in more detail. some of the patients had more than one reason for defaulting, while 13 patients had no real documented reason. work was cited as being a problem by 7 patients, especially with contract workers being moved to different areas to work. six patients said that they had had financial problems. however, most of these were already on disability grants. alcohol played a role in 4 patients and a variety of other reasons were given by the remaining 25. these included parasuicide, mental retardation, hospital admission, felt sick from pills/not feeling better, incarceration, lost in down-referral process, transfer out, recent birth, painful legs, ashamed to come, domestic upheavals and disputes, traditional medication, amputated leg, staff confidentiality issues, cryptococcal meningitis, and tuberculosis treatment (streptomycin). in each case, a course of action was discussed and decided upon by the multidisciplinary team. interventions the following were the most common interventions decided upon by the mdt: n 3 months’ adherence counselling and prophylaxis and re-initiate if appropriate n buddy system, e.g. someone to accompany the patient to the clinic visits n social worker intervention n individual interviews n home visits n link appropriate patients to alcoholics anonymous. outcomes the results of these interventions were then analysed from the available files. thirteen files could not be found. four patients were confirmed as lost to follow-up. viral loads had decreased in 23 patients after the interventions discussed above, while 17 patients’ viral loads had remained in the same range or increased. viral loads had not been properly done or recorded in 4 patients. five patients had died, and 10 had other outcomes, e.g. art stopped. following the mdt discussion and intervention, 23 of the available 63 files (36%) of patients who had been referred to the meeting because of staff and performance concerns indicated that they were doing well at the time of the audit, with virological and clinical stability. this audit revealed that non-adherence or difficulty coping with the art programme was often caused by the potchefstroom wellness clinic the role of the mdt meeting results discussion 51 j u ly 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e social and psychological problems. this tends to be a difficult area for health workers to intervene in, and the programmes have to rely on social welfare as well as community-based groups as active partners. alcohol appears to have a small but significant influence, as was found in larger studies on adherence.4,6,9 more males than females in the mdt group were encountering problems as a result of their alcohol histories, but women were also affected. work-related absenteeism often applied to contract workers, especially where artisans were moved for certain periods to other provinces or countries. it remains a crucial part of general and individual counselling that work be taken into consideration and that medication amounts be negotiated, or referral letters written for patients who plan to be away for a period of time. deaths are not always reported to the hospital, and a number of the patients recorded as lost to follow-up may in fact have died. other ways to minimise loss to follow-up include optimised ‘tracking’ systems including ‘defaulter tracing’, down-referrals to satellite clinics closer to home, and involvement of other community-based organisations in tracing patients and doing home visits. the multidisciplinary team meeting at the potchefstroom wellness clinic did play a role in identifying and solving problems relating to patients on art. since the team represents a core of interested people, there is the potential to expand its role to discuss new policies, novel interventions and issues in the clinic and the programme as they arise. the challenge with providing an optimal service for patients is that each person has their own story and many need individualised attention. without this understanding, and good relationships between personnel and patients, the battle for optimal care within the art programmes cannot be won. references 1. sherr l. understanding adherence. j hiv ther 2000; 5: 30-35. 2. crespo-fierro m. compliance/adherence and care management in hiv disease. j assoc nurses aids care 1997; 8: 43-54. 3. chesney ma, morin m, sherr l. adherence to hiv combination therapy. soc sci med 2000; 50(11): 1599-1605. 4. mehta s, moore rd, graham nmh. potential factors affecting adherence with hiv therapy. aids 1997; 11(14): 1665-1670. 5. day m. patient adherence to haart regimens: challenges for physician assistants and health care providers. the internet journal of academic physician assistants 2003; 3(1). http://www.ispub.com/journal/the_internet_journal_ of_academic_physician_assistants/volume_3_number_1_7/article/patient_ adherence_to_haart_regimens_challenges_for_physician_assistants_and_ health_care_providers.html (accessed 18 june 2009). 6. fogarty l, roter d, larson s, burke j, gillespie j, levy r. patient adherence to hiv medication regimens: a review of published and abstract reports. patient educ couns 2002; 46(2): 91-92. 7. nischal kc, khopkar u, saple dg. improving adherence to antiretroviral therapy. indian j dermatol venereol leprol 2005; 71: 316-320. 8. fedder do. drug use in the elderly: issues of noncompliance. drug intell clin pharmacol 1984, 18: 158-162. 9. kissinger p, cohen d, brandon w, rice j, morse a, clark r. compliance with public sector hiv medical care. j natl med assoc 1995; 87: 19-24. 10. young j, howard z, shepler l. medication noncompliance in schizophrenia: codification and update. bull am acad psychiatry law 1986; 14: 105-122. 11. pugh r. an association between hostility and poor adherence to treatment in patients suffering from depression. br j med psychol 1983; 56: 205-208. 12. singh n, squier c, hayes p. determinants of compliance in patients with hiv: prospective assessment with implications for enhancing compliance. paper presented at the 34th interscience conference on antimicrobial agents and chemotherapy, orlando, fla, 4 7 october 1994. 13. youssef f. adherence to therapy in psychiatric patients: an empirical investigation. int j nurs stud 1984; 21: 51-57. a few patient stories a young woman who had started art had had a boyfriend for 10 years. he suddenly left her for another woman. she had repeated counselling but became profoundly depressed, which influenced her adherence. an older married couple were both patients at the wellness clinic and on art, but the husband was apparently being abused by his wife and eventually died in hospital from an hiv-related infection. the wife never came back in spite of intensive counselling and support from the clinic personnel. two mothers insisted on their daughters taking traditional medicines and stopping haart. both young women eventually returned to the clinic in spite of this pressure. a very problematic patient, who is still receiving haart, returns to the clinic with repeated stis. she has been caught lying about her pills and pill counts, comes and goes as she wishes, and is constantly abusive towards clinic staff. 52 ----------1_------south afrlca in my fantasy world 'from bushveld through deserts and forests, up winter snow clad peaks down to wide, unspoiled beaches and coastal wetlands, lies the sprawling land called south africa. this land of unequalled splendour and diversity beckons you ....: these words, from the satour website description of south africa, entice multitudes of tourists to our exquisite beaches and sites all year round. there is no doubt that with so much exceptional natural beauty south africa is a popular tourist destination. on just one such perfect day recently, under cornfiower blue cape town skies, with the soothing sound of rolling waves in the background and the fragrant smell of fresh spring flowers, i dreamed of a perfect south africa. in this fantasy south africa, cricket was played well, like cricket should be played, and bribing and betting were kept to the blackjack tables. every child had equal schooling opportunity, and all experienced the joy of learning from enthusiastic educators equipped with more than minimal learning aids. in this perfect south africa minibus taxis indicated when stopping and gave way politely to pedestrians. tax payers' money went to social upliftment and provision of clean water and housing for all rather than on submarines and warheads. the gravy train was traded in for an ai ds awareness 'lovelife' train. personal safety and private belongings were not violated by sundry thieves and criminals. there was more job security for our rugby coaches and the rand rallied and even superseded the dollar! court cases were used to bring criminals to book, and were not needed to bring rationality to government policy. presidential campaigns from neighbouring states to the north were based on sound legal and humanitarian principles despots were not tolerated and were quickly and effectively deposed. in this wonderful, vivid dream, our own president directed state funding to well-organised targetdriven primary prevention programmes that resulted in a falling hiv incidence rate among our young population. this same leader was frequently seen visiting the sick and orphaned, listening to their plight and doing all that he could to alleviate the suffering that hiv infiicts. he had issued a loud call to arms to all governmental ministers, departments and organisations to mobilise all resources in all areas so as to tackle this challenge head-on. every expectant mother throughout the country had access to non-discriminatory hiv testing and the choice of maternal transmission prophylaxis and formula feeding. in this dream our president had called in african and local experts to advise on the best methods for providing equal and costeffective universal access to antiretrovirals. south africa was blazing a trail and was foremost in showing the way to other african countries with regard to providing comprehensive care for the hn-infected. this provided an inspiring example of how to utilise cheaper agents and truly african-friendly methods of drug provision and monitoring. but then poof! the dream ended and reality swept in. while the world observed world aids day, and many in this country attended remembrance services, art exhibition openings and other sundry activities to commemorate and heighten hn awareness, our president attended a meeting of the anc national executive committee. his spokesperson hastened to assure us all that he was involved via 'institutions' and that his deputy was dealing with the problem of hiv/aids while presumably he dealt with more pressing problems. one such institution which jacob zuma does chair is the south african national aids council (sanac). even if you are involved in hiv care you would be forgiven for not knowing about the existence of this council, despite the recent publicity it received for the dubious highlight of sanae's year being the launch of the government's hiv/aids programme in braille. the deputy 11 ofctmbtr 200 i ----------thf southfrn mrican journal of hiv mfoicinf chief executive, yacoob abba-omar, feels that sanae's work has 'been penetrating deeper and deeper and whilst its profile [isn't] great, the effect has been felt: in the words of another council member, 'the last 2 years have been putting the building blocks in place and the council [is] still in the developmental phase: a classic case of 'while rome burns: i am inclined to prefer the words of lucky mazibuko. he too is a council member but acknowledges that the mood among members is one of dissa isfaction, that little difference has been made and that sanac should rather be an independent body since the government tends to dominate. government domination seems to be another recurring theme recently. i was very dismayed to see that the human rights commission (hrc) had pulled out from the treatment action campaign's (tac) mother-ta-child court case because of government pressure. anne routier, the former chairperson of policy and planning of the same hrc recently asked if the hrc is too effete to stand up for those who cannot yet stand, namely those pregnant women throughout the country who face the possibility of transmitting the virus to their unborn children and who currently have no opportunity to do something about it. she ends her comments with an even more powerful question: how long will the hrc, which has the strongest powers of any human rights commission in the world, continue to roll over and lie down? even more disturbing in this pattern of government influence was the apparent retraction of statements by our former president on world aids day. i was thrilled to read on front page news that nelson mandela had visited beautiful gate in crossroads and had sent a clear message to the government: 'heads of state and their first ladies must be in the forefront of the campaign to ght aids. we must combine various strategies with giving people the necessary drugs to prevent the disease getting the upper hand: but then just a few short hours later at the opening of the nelson mandela gateway to robben island, the former president said that journalists had misinterpreted the comments he had made earlier in the day at crossroads and rejected that he had in any way attacked mbe i's stance on aids. this retraction seemingly followed a phone call from mbeki's office after his visit to the aids care centre. one wonders how we will ever get out of this impasse if constructive criticism is not tolerated and institutions are hamstrung by the need to conform to government policy regardless of how wrong or harmful it is. a highlight of my own world aids day activities was attending the opening of the higgin's trust pho agraphic exhibition entitled 'positive lives: zackie achmat opened the exhibition and in his quiet but forthright way questioned why a court case such as the mtct case against the government was even being waged this week. the futile waste of energy, time and resources required to bring our government thinking into line with the rest of the continent, and indeed the world, is saddening. the exhibition currently running at the south african national gallery of art until march is wonderful. poignant pictures and stories from artists worldwide are captured and those of you familiar with gideon mendel's work will see an abundance of it on display. in the words of zackie, those of us who are continually in the business of caring for, fighting for, supporting and treating those who have been infected and affected by hiv and aids will have the opportunity, when standing in front of these pictures and portraits, to mourn and grieve, and this is a good thing to do. i highly recommend the pilgrimage. linda-gall bekker monaging editor thf southfrn africa journal o~ hiv mfoicinf ----------ofcfmbfil 200 i 11 a p r i l 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e ruben sher came into my life at perhaps its darkest moment. i was diagnosed with hiv on a rainstormfilled friday afternoon in the second half of december 1986. my well-meaning doctor, who had not obtained my consent, phoned me with the bad news and left me in anguish, not only for the weekend but for the ensuing years. his one act of solicitude in telling me that i was infected with hiv was to suggest that i contact professor ruben sher at the south african institute of medical research (saimr). uncounselled, unadvised and unsupported, i saw a grim future ahead. and indeed the ensuing years years of fear, silence and inner shame were hard. my hiv diagnosis was shocking for two reasons. i was 33 at the time. i was building a growing practice as a human rights lawyer at a time of challenge and excitement. my diagnosis meant death. there was no cure for aids. indeed, there was no treatment for it. palliation was the best that medical science could offer. the mortality figures from north america and western europe, where the epidemic still seemed predominant, were horrific. by late 1986 perhaps half a million people had died of aids in north america alone most of them, like myself, gay men in the prime of their lives. i had no doubt that death would overtake me soon. the further reason why my diagnosis shocked me so was in many ways worse. it was the sense of shame, embarrassment, defilement and pollution i felt at being infected with hiv possibly the most stigmatised disease in human history. i thought my shame stemmed from the fact that, only just out of the closet as an openly gay man, i had become infected with hiv. but, as i was soon to discover, my shame and the stigma of aids had little to do with homosexuality. i became involved in aids work not because of my own bodily engagement with the epidemic, but through my human rights work. and through it i met people who, seemingly very different from myself in that they were black and mostly women and mostly poor, nevertheless shared with me a sense of fear and horror at being known to have hiv. in this bleakest time, i did follow my doctor’s advice. i contacted ruben sher at the saimr. i well knew who he was. an avuncular spike milligan-like presence on tv, he had already assumed the role of a foremost public health commentator on aids. and he did not merely seem avuncular. he was in truth a voice of compassion and reason in the midst of an epidemic of stigma and fear. while many of his clinical and academic colleagues including surgeons at baragwanath and some academics at wits called for isolation and compulsory screening, ruben stood out as a voice of rationality and justice. he made the obvious points that hiv is difficult to transmit; that testing could be imprecise; and that there was no cure for those who sought to be diagnosed. but in times of panic the obvious is rarely stated. ruben’s courage and clarity and persistence in voicing the call for justice in dealing with the epidemic justify our honouring his memory this evening. at one of the lowest points in my life, on a warm march day in 1987, i went to see him. he offered me kindness and reassurance and, importantly, utter confidentiality. he suggested that i be tested again. and when (inevitably) the test returned positive, he imparted the news, as such news should always be imparted, with gentle matter-of-fact kindness. as the epidemic grew, ruben and i started working together. he asked me onto platforms with him. we started being invited to speak together. we even travstigma, human rights, testing and treatment time for action ruben sher memorial lecture, 26 november 2009 f o r u m edwin cameron constitutional court of south africa 6 this is an outline of a lecture delivered to the sa hiv clinicians society on 26 november 2009. the author is indebted to nicholas ferreira and ting ting cheng for considerable help. a p r i l 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e elled together. i remember one eccentric expedition to tzaneen, where he and i were billeted in a luxury country lodge for the purpose of speaking to hundreds of farm workers and local officials about aids. working with ruben could be trying. in fact, he could drive you nuts. he had a joke he invariably told. it was that you could get hiv whether you are heterosexual, homosexual, bisexual or trisexual. what is trisexual, ruben would ask his audiences? he would confide triumphantly it was someone who will try anything. he had another joke. this one i like better. it was about a rich suburban lady who phoned him suspecting that her malawian gardener had hiv. she confided to ruben her fears about her proximity to him. might he have infected me, she asked? his reply according to him was ‘madam, when last did you have sex with your gardener?’ i greatly cared for ruben and honoured his roles as an academic, as a crusader for right, as a caring clinician and as an astute physician. he gave me a gavel when i became a judge but the symbol of dispensing to all alike without fear or favour was as appropriate for him as it was for my new job. for tonight’s lecture i hope to meld the themes that entwined my own life with that of ruben sher namely hiv infection, testing, stigma and shame. four social facts mass scale, medical manageability, continuing deaths, and stigma four features of the aids epidemic stand out in any attempt to grapple with its social meaning. n first, its scale. even on recently adjusted lower estimates, aids is human society’s largest microbially borne pandemic for seven centuries since onethird of europe’s people died in the great plague of the mid-14th century. estimates reckon that globally there are around 33 million people living with hiv or aids.1 of these the great majority (67% or 22 million in 2007) are in sub-saharan africa.2 more than 13 million are black women, and roughly 2 million black children.3 the total number of people who have died of aids is probably close to 30 million (in south africa, according to the actuarial society of south africa, 2.5 million).4 many more deaths are likely to come. n against this numbing volume of human fragility, suffering and death stands counterpoised a second fact that infection with hiv is now fully medically manageable. the revolution that the arrival of treatment implied was not universally or immediately recognised.5 but it was momentous. if diagnosed early enough, with properly administered combinations of antiretroviral (arv) medications, the bodily progression of hiv can be stopped, and those sick with aids can be restored fully to life and health. my presence here tonight more than 12 years after i fell severely ill with aids is evidence of the longterm success and sustainability of treatment. perhaps the most important political fact about treatment is it works for poor and wealthy patients, in rural and urban settings, and in economically developed as well as undeveloped areas.6 given the shroud of horror that surrounded the disease in western europe and north america in its first 15 years, and still surrounds it almost everywhere else, this is still a radiant fact. but, as i will show, it continues to be insufficiently appreciated. n third, despite the medical manageability of the disease, and the fact that treatment for it certainly compared with other long-term chronic conditions such as insulin-dependent diabetes is relatively simple, and that it is increasingly available, millions of people are still dying of aids. especially in africa: in 2007, 1.5 million people died (75% of all aids deaths), 350 000 of them in south africa. in any terms, this is monstrous: avoidable human suffering, unnecessary deaths, wasted lives. but why are people still dying of aids in africa and elsewhere when the disease can be easily managed?7 much death and illness can be ascribed to the developmental deficits of the locations worst affected: poor health care infrastructure, missing or poorly trained personnel, africa’s burdens of disease (including other easily preventable and treatable diseases),8 and poverty. n but much is due to the fourth and most signal fact about aids namely the stigma that surrounds it. it is this i want to talk about tonight: the fact that dying and suffering that is attributable to stigma persists in an epidemic of otherwise manageable disease. stigma and public health/political responses to aids stigma is the mark of blame, rejection, disapproval and shame that society places on conduct and conditions that repel it or elicit its moral censure. from the first day, society’s reaction to aids has been defined by stigma. more than any other disease more than leprosy, tuberculosis, and the black death, for all of which people 8 a p r i l 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e felt understandable fear of contagion hiv has been intensely stigmatised, even though its transmission occurs in known and narrow circumstances.9 it was stigma arising from its initial manifestation among gay men that led president ronald reagan to maintain what randy shilts called a ‘ritualistic’10 (and blameful) silence about aids, for six long years, from 1981 to 1987, implicitly conniving in the deaths of hundreds of thousands of men in the prime of their lives. it was stigma, less than the rational pursuit of public health goals, that led countries as different as sweden11 and cuba12 to isolate and detain those with hiv. and, perhaps most catastrophically, it was stigma that caused our own country’s president thabo mbeki to question the viral aetiology of aids. he did so because he took umbrage at the notion of an epidemic of sexually transmitted disease manifesting in mass form among black africans.13 for 28 years, stigma has pervaded and defined this epidemic. this triggered debate between those who advocated applying ordinary public health measures to the disease, and those who contended that this was inapposite and unjust. many argued that the disease should be treated by applying well-known public health principles primarily in identifying, reporting and isolating those infected with hiv. yet hiv was different. n first, for 15 long years doctors could do very little about it. they could offer only palliation. so diagnosis had strictly limited value. n second, a different approach was warranted because of the years of relative wellness that most enjoy before aids sets in, and because of difficulties (both technical and patient-related) in diagnosing infection. n but the overriding and most persuasive argument for exceptional treatment of hiv was that society’s reaction to it was exceptional.14 it was not the infectiousness of hiv, or its viral properties, or its morbid or mortal effects (for in this it was not intrinsically different from many other conditions) that made this disease different: it was stigma.15 it was stigma that necessitated anti-discrimination protections for those with hiv or suspected to have it, in medical care, housing, jobs, public facilities and anti-violence legislation.16 the paradigm of aids exceptionalism the ensuing debate resulted in a decisive victory for those who urged human rights protections for people with hiv/aids. the preponderant, if not quite universal, consensus among public health experts was that aids required special treatment. the only dissentients seemed to be policy deviants making ill-judged populist appeals and even these proved mostly ineffectual. in our own country, the african national congress government came to power just as the epidemic seeped remorselessly southwards. in august 1994 it adopted a national aids plan that expressly espoused the international human rights consensus, and enacted a very sizeable body of legislation that protects the rights of those with hiv and prohibits unfair discrimination against them.17 the courts have followed suit.18 the most eloquent voices justifying this approach were dr jonathan mann19 and later justice michael kirby.20 their powerful advocacy of the ‘aids paradox’ the notion that human rights protections for those with and at risk of hiv is an integral component of sound public health practice, and not its enemy achieved not only moral, but intellectual predominance in virtually all places where international and national aids policy was made. and rightly so. the wellspring of the aids paradox is stigma. because of discrimination and ostracism people are reluctant to be tested, and hence cannot be reached for counselling, treatment and behaviour change interventions.21 traditional public health measures (mandatory testing,22 partner notification, quarantine) merely fuel their fears, driving the disease underground, thus proliferating its spread. the rational way out is therefore more, not fewer, human rights safeguards for those with hiv: to allay their fears, and to alleviate the horrific impact on them of abuses and malpractices. only with its main bearers thus protected can the epidemic be rationally managed.23 stigma, the source of the problem, was in this approach confronted obliquely by protecting those with hiv from its effects; first, by shielding them from the terrifying invasion traditional public health approaches entailed; and second by enacting anti-discrimination protections to diminish the injustice of ostracism. aids exceptionalism and broadening access to testing but the key practical product of the aids paradox, and perhaps its most telling achievement, lay not in warding off invasive public health measures, nor in the enactment of anti-discrimination laws. it took effect in 10 a p r i l 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e the medical diagnosis of hiv. it was to hedge testing for hiv with significant prerequisites. to test for hiv a health care practitioner could not assume consent: nor could it be implicitly, or even generally, given. it had to be explicit, and it had to be specific. in many jurisdictions,24 it had to be given in writing. in some, even written consent was not valid unless the test was preceded by statutorily prescribed counselling. in the pre-test counselling session, the counsellor had to warn the patient not merely of the medical implications of a positive diagnosis, but of its social repercussions the discrimination and ostracism the patient would almost certainly face in consequence. what is more, because of the risk that those choosing to test might be inferentially associated with hiv, testing had to be done in near-secret at separate locations, on separate days, in unmarked (or code-marked) rooms. and special measures had to be taken to ensure that the resultant patient information was handled confidentially. the unquestionable consequence of all this was massive disinducement to testing. and not without reason. for as long as the major outcome of a positive diagnosis was ostracism, and for as long as doctors were powerless to offer more than palliation, there was little justification for exhorting those at risk to be tested. its only point was to help them make better lifestyle and safer sex choices. the disinducement was therefore warranted and the aids paradox served us well for the epidemic’s first 15 years. in some parts of the world, it still serves us well. in the countries of south and east asia, and in comparably affected regions, human rights activists continue to report that an hiv diagnosis too often provides an excuse for mistreatment, exclusion and denial of medical and other facilities. it remains primarily a badge of shame and a basis for ostracism (including the enactment of harsh criminal laws that target those with hiv).25 i can attest to these harsh realities, for they were vividly reported to me in colombo in september 2007, and in beijing in october 2008. in these countries reluctance to testing for hiv remains understandable. yet the causes may lie in a distinctive epidemiological pattern. in countries such as india, china and malaysia the epidemic remains overwhelmingly associated with groups that are still socially and politically marginalised mainly men who have sex with men, commercial sex workers and intravenous drug users. public health interventions and policy in these countries necessarily have to recognise this also in relation to testing. yet, since the mid-1980s, the most striking demographic feature of the epidemic has been its racial and continental overload. most people with hiv are africans. and most of those dying of aids are africans more specifically, africans in the bantu-speaking regions of central and southern africa. in these regions, aids is a mass epidemic of heterosexually transmitted disease. what is distinctive about this epidemic is not merely that the vectors of transmission are different it is that its consequences are omnipresent. it is impossible to ask any audience in central or southern africa who among them have lost family members to aids, without a massed sea of hands rising in result. aids is everywhere, and its deathly impact presses on every household, every family, every workplace and every street. and the worst is this. despite the availability of treatment, despite the good news of its increasingly known efficacy, despite the knowledge of family support and despite legislative and social protections against discrimination, many people in africa continue to contemplate testing for hiv with dread reluctance.26 more than dread: deathly reluctance. disincentives to testing the fact is that many africans experience stigma so intensely that they ‘prefer’ (if in such constrained circumstances one can speak of preferences) to die, rather than to be diagnosed with hiv.27 part of this deathly dread stems from the external manifestations of stigma the enacted discrimination, exclusion, dispossession and violence that are the social product of stigma; since undoubtedly well-warranted fear of discrimination by others inhibits many from choosing to be tested. but a greater part, in my view, and perhaps the more crucial part, results from internal stigma. this is because too often the external stigma of aids finds an ally within in internalised feelings of contamination, shame, self-revulsion, abasement, defilement and dread that those with hiv and at risk of it experience about themselves even when they know they will receive acceptance and support from others. 12 a p r i l 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e much of this, i suggest, derives from the fact that, overwhelmingly, hiv is a sexually transmitted disease: and we still poorly understand the intensity, intimacy, embarrassment and shame that our need for sexual connection which seems to be inescapably human occasions.28 a great deal has been written about external stigma; but surprisingly little perhaps astonishingly little about internal stigma. (in a review article in the issue of the journal aids published to coincide with the international aids conference in mexico in august 2008, there was extensive discussion of stigma and its external manifestations, but no apparent recognition at all of its internal dimension.29) internal stigma consists not of fear of discrimination or hostile treatment at the hands of peers or colleagues, or dread of others’ reactions. it is something more opaque, and therefore difficult to confront. it is often stronger than a cognitive appreciation that friends, family and colleagues will offer love; it is stronger even than the knowledge that treatment is now readily accessible (even in many poor african countries). it ultimately proves stronger than the capacity to make lifeaffirming choices, because it paralyses them in favour of postponement, avoidance and death. it is the most intractable part of stigma because it comes not from others, but springs from within. and it is more insidious, and more destructive, than external stigma, since it eludes the direct politically determined confrontation with which we fight discrimination. the result of internal stigma is death, needless death, and its gross attendant human and social costs of suffering, bereavement and loss. internal stigma and obstacles to testing the role of human rights protections recognising stigma’s internal dimension raises a new set of questions. these have been particularly hard for aids activists and human rights protagonists to confront. if stigma stems not only from the hostile ‘other’, but partly from within those who themselves have hiv, we need new methods of understanding its origins and its effects. we need to understand with greater insight what we are combating. here i have made an inflammatory suggestion. it is that the very differentness attributed to aids, especially in the health care setting, is one of the principal causes of internal stigma, or at least powerfully underscores it. the suggestion involves a provocative corollary: that the human rights protections, carefully and necessarily erected during the early stages of the epidemic to protect against discrimination, have themselves become a potent source of harm.30 particularly in hiv testing, human rights safeguards have become harmful because they emphasise the differentness of aids. this reinforces internally those who are scared to test the exceptional, untoward, and distinctive features of aids. instead of people being diagnosed with mundane medical regularity, and steered towards treatment, diagnosis is hedged around with a fuss and palaver and hullabaloo that accentuates the feelings of self disabling ignominy those at risk of hiv experience. in the age of treatment where aids can be medically managed, if only those suffering its effects can be reached timeously this is a hideous cost. we cannot without untruth deny or ignore the part that the protections erected against testing play in exacting this cost. exceptionalism was a necessary response to the public ignorance, disdain, moralism and ostracism those with and at risk of hiv experienced; but it was also its logical counterpart. exceptionalism, born in reaction to stigma, has itself helped spawn stigma. a new and grim equation must be inscribed on the wall of aids remembrance, a footnote to the activists’ famously plangent equation in the 1980s that silence = death: the new equation is that differentness = death. these considerations have given rise to acrid debate between those urging radical expansion of testing in mass-prevalence areas where treatment is available, and those who resist it. the debate echoes that about aids exceptionalism in the 1980s. and its logical and formal premises have hardly changed: its essence still concerns the extent to which ordinary medical precepts and procedures should be applied to the management of hiv. the contesting protagonists have changed. no longer, as in the 1980s, are the protagonists of de-exceptionalising the disease aids-ignorant policy wonks insensitive to its science and politics. they are experts who are themselves deeply versed in the clinical and human skills of aids treatment and prevention. but, more significantly even, the factual setting of the debate has changed. the increasing availability of treatment is now the most important social fact about aids. 14 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 0 the test for aids policy is whether we can ensure that treatment effectively eclipses stigma, yet without sacrificing any single patient’s right to choice, or to confidentiality. and in this difficult quest, rigid policy positions are unefficacious and unhelpful. on one side, those who support testing expansion point out that: n ‘unlike other infectious diseases (e.g. syphilis, hepatitis b), for which consent for testing is implicitly assumed by virtue of medical consultation, and diagnosis is encouraged, the diagnosis of hiv infection has often been actively avoided. in many ways the approach to diagnosis of hiv infection has been more similar to that of an incurable genetic disorder than to an infectious disease’.31 n as a matter of fact, this analysis is incontestably accurate. yet it provoked intensely ireful reaction. n this was because of the same authors’ assertion that ‘the emphasis on human rights in hiv/aids prevention has reduced the importance of public health and social justice, which offer a framework for prevention efforts in africa that might be more relevant to people’s daily lives, and more likely to be effective’.32 on the other side, human rights advocates have resisted the medical ‘normalisation’ of hiv diagnosis, principally on the premise that expanded hiv testing infringes patient autonomy, and that it exposes those subjected to it to violation of their rights.33 instead of radically and immediately increasing access to testing to diminish the deficit between treatment and death in africa, we have been told that we must focus on the anxieties of ‘the disempowered and still fearful ... by demanding investment in dignified health systems and protection from harmful social and legal effects of their health status being known’.34 the argument of those favouring expansion, that death is the ultimate rights violation, and that testing inhibitions collude with it, has not been acknowledged to have force against the motive forces of a ‘real world’ ‘influenced by poverty-determined life choices, gender based violence, [and] fears of discrimination and stigma’.35 in this setting, human rights advocates have treated with suspicion or resisted: n rapid and more easily accessible forms of testing for hiv (including home-test kits) currently, hiv tests are not available at the largest retail pharmacy chain in south africa, clicks pharmacy, as well as dis-chem pharmacies, another large pharmacy chain. yet home test kits are available for pregnancy, ovulation, prostate cancer, cannabis, and alcohol (breathalyser): some of the arguments against rapid access to testing are feeble, but some should justly be denounced as bizarre.36 n legislation that compels mothers who might risk passing hiv to their babies to test for hiv so as to be able to receive prophylaxis that would reduce the risk.37 n the implementation of opt-out testing in botswana (a mass-prevalence country where patients presenting for treatment at any public health facility have since 2002 been tested for hiv unless expressly refusing)38 even though evidence indicates that ‘opt-in’ requirements (where the patient must expressly choose to be hiv tested) cause deaths.39 n more recently, an article suggesting that universal arv provision to everyone testing positive for hiv (using a mathematical model of hiv reduction in which everyone seroconverting to hiv is tested within a year) could be an important possible means of preventing and even eliminating endemic hiv dissemination,40 triggered vigorous criticism from those concerned at its overly medicalist approach. a group of respected human rights experts issued a statement complaining that the analysis did not address ‘the issues of acceptability and safe applicability of universal testing and treatment in the face of widespread stigma and discrimination’, and that it ‘threatens to serve as justification for imposing mandatory hiv testing’. this response seemed to me not only to miss the point of the mathematical model; it attributed an unconcern about rights protections to the authors which seems to me troublingly misplaced.41 it also failed to appreciate that the authors’ argument finally unseamed one of the great canards of the epidemic, namely the supposed disjunct between treatment and prevention, by successfully telescoping the two into one overriding public health strategy. in my view, we should immediately urge the health professions council to adopt testing guidelines that permit for radically expanded testing. in this regard, i commend the suggested minimum reasonable approach to testing that nathan geffen propounds for a busy, resource-stretched, but functional public health facility. he suggests that the counsellor follows the following standard procedure with all patients who s/he judges have some risk for hiv: 15 a p r i l 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e ‘ms x, i would like to proceed to give you an hiv test. if you have hiv, we can help you to live a healthy life because there are safe and effective medicines to treat you.’ at this point ms x either says no (which is unlikely) or permits the blood to be drawn.42 to propound radically expanded testing in this or other forms, including opt-out testing that does not even mention hiv specifically when a patient presents for general medical treatment is not to ignore stigma (or to sacrifice confidentiality). it is to seek to mitigate it by more directly effective interventions than have hitherto been applied including the beneficent effect of more widespread testing and diagnosis as well as bringing home the fact that testing is a necessary first step to life-restoring treatment.43 it is here where recognising the role of internal stigma is critical. to see that stigma is not exclusively external, and that anxiety about testing is not solely about discrimination, is to open a vista of new, more flexible and supple policy positions, and more fruitful debate.44 crucial to that is recognising the cost that human rights may now be exacting in fuelling stigma and in impeding access to testing and treatment. this is not to decry the vital role of human rights activists in the past or in the present: it is to question the focus of their engagement. the current trend toward enacting harsh criminal statutes in africa, that specifically target people with hiv, seems to me a much more pressing and important issue than resisting expansion of treatment. what is more, there has been a heavy shift of the weight of the argument in favour of expansion of treatment.45 president zuma, in a remarkable address to the national council of provinces on 29 october 2009, urged ‘a massive mobilisation campaign’ for testing. the president stated: ‘let me emphasise that although we have a comprehensive strategy to tackle hiv and aids that has been acknowledged internationally, and though we have the largest anti-retroviral programme in the world, we are not yet winning this battle. we must come to terms with this reality as south africans. we must accept that we need to work harder, and with renewed focus, to implement the strategy that we have developed together. we need to do more, and we need to do better, together. we need to move with urgency and purpose to confront this enormous challenge. if we are to stop the progress of this disease through our society, we will need to pursue extraordinary measures. we will need to mobilise all south africans to take responsibility for their health and well-being and that of their partners, their families and their communities. all south africans must know that they are at risk and must take informed decisions to reduce their vulnerability to infection, or, if infected, to slow the advance of the disease. ‘most importantly, all south africans need to know their hiv status, and be informed of the treatment options available to them. though it poses a grave threat to the well-being of our nation, hiv and aids should be treated like any other disease. ‘there should be no shame, no discrimination, no recriminations. we must break the stigma surrounding aids.’46 common ground between testing expansionists and human rights proponents exists. it lies in their joint commitment to lessening aids deaths and human suffering. but harnessing the joint energy in service of those worst affected by the epidemic will require greater flexibility than has until now been evident. instead, until now, responses from human rights protagonists have seemed to suggest an overly defensive posture, reacting with alarm to creative new models and suggestions, rather than engaging constructively with them, in the light of the central and luminous fact that testing is the indispensable prerequisite to treatment and care, and thus that it embodies the difference between life and death.47 the aids epidemic has made the world sadder and older and perhaps wiser. some of what we have learnt from the epidemic is that due commitment to medical beneficence cannot always be assumed. we have also learned that technology and science alone will not provide answers if they ignore complex human reactions that spring from the material conditions of people’s lives. but suspicion about medical beneficence and reserve about technology’s role does not justify rigid, inflexible and unresponsive defence of human rights protections that may have become outdated and inapposite. ruben sher would have regretted the inaccurate characterisations and unproductive dichotomies that have resulted. aids has been a heavy consciousness, burdening our beings and exacting, at least in africa, a continuing daily price in grief and bereavement and mourning. but in the end aids exacts its toll on human bodies. if all could see that more clearly those at risk of hiv no less than human rights activists and the medical 16 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e a p r i l 2 0 1 0 specialists eager to expand testing and thus save lives we may begin to assert the primacy of the material and the rational over the shadow of stigma and misconception. 1. see unaids report on the global aids epidemic (hereinafter ‘unaids report’, at p. 33, available at http://data.unaids.org/pub/globalreport/2008/ jc1510_2008globalreport_en.zip (accessed 21 october 2009). 2. idem at p. 30. 3. idem at p. 33 (globally, there are 2 million children (under 15) living with hiv, of whom almost 90% live in africa). 4. http://www.actuarialsociety.org.za/portals/1/documents/ab739d74-e6fe-483fb205-718f20195c12.xls; see also on the website of the treatment action campaign http://www.tac.org.za/community/keystatistics. there are an estimated 5.7 million people in south africa living with hiv in 2007, making this the largest hiv epidemic in the world. unaids report above at p. 40. 5. see the sceptical, even pessimistic, approach of catherine campbell, letting them die: why hiv/aids prevention programmes fail (indiana university press, 2003), p. 5 (‘there is little hope of pharmaceutical solutions being available in ways that can be affordably and effectively implemented in the short-term future by many of the poorest countries where hiv flourishes’), and p.19 (while art has a role in ‘reducing the immensity of the suffering of those who have already been infected, and of their loved ones and careers’, ‘on their own they neglect the needs of the majority who are not yet infected’); and more recent but comparable scepticism in helen epstein’s the invisible cure: why we are losing the fight against aids in africa (picador, 2008). 6. since 1986 partners in health and zanmi lasante have provided hiv care in squatter settlements in rural haiti: see ‘scaling-up hiv treatment programmes in resource-limited settings: the rural haiti experience’, koenig, leandre and farmer, available at http://www.pih.org/inforesources/articles/aids_2004_koenig-et-al_ scaling_up_hiv_treatment.pdf; farmer et al., ‘an information system and medical record to support hiv treatment in rural haiti’, available at http://groups.csail. mit.edu/medg/people/hamish/hiv-emr-bmj.pdf; also joint partnerships between médecins sans frontières (msf) and the department of health in south africa such as the hiv/aids programme in lusikisiki, eastern cape, available at http:// www.msf.org.za/docs/lusikisiki_final_report_2006.pdf; the 2000 joint programme in khayelitsha, western cape, ‘comprehensive hiv service development at primary care clinics’, available at http://www.msf.org.za/docs/khayelitsha_report_ july_2005.pdf. experience in countries including botswana, tanzania, thailand, brazil and zambia indicates that policy on health care funding can be adjusted to eliminate user charges for hiv treatment, helping to overcome socio-economic barriers and increasing rates of long-term adherence to medication, see ‘progress on global access on antiretroviral therapy, a report on ‘3 by 5’ and beyond’, march 2006, available at http://www.who.int/hiv/fullreport_en_highres.pdf. 7. according to a 2008 world health organization report, ‘towards universal access: scaling up priority hiv/aids interventions in the health sector’, 2.9 million people are receiving arv therapy in sub-saharan africa, while 6.7 people need it. worldwide, 4 million people have access to arv therapy, while 9.5 million lack access. available at http://www.who.int/hiv/pub/tuapr_2009_en.pdf (accessed 22 october 2009). the number of new hiv infections continues to outstrip the increase each year in the number of people on arv therapy by 2.5 to 1 (unaids report). for south africa, then health minister barbara hogan told sabc radio news on wednesday 28 january 2009 that 700 000 were on arv treatment: http://www.iol.co.za/index. php?set_id=1&click_id=125&art_id=nw20090128183422743c506795 (accessed 31 january 2009) but unaids estimates that 1.3 2.1 million south africans need treatment now. 8. such as tuberculosis, measles and syphilis see appendix to helen epstein’s the invisible cure: africa, the west, and the fight against aids (farrar, straus and giroux, may 2007). 9. stigma (a process model): ‘disease stigmatisation can be defined as a social process by which people use shared social representations to distance themselves and their ingroup from the risk of contracting a disease by (a) constructing it as preventable or controllable; (b) identifying ‘immoral’ behaviours in contracting the disease; (c) associating these behaviours with ‘carriers’ of the disease in other groups; and (d) thus blaming certain people for their own infection and justifying punitive action against them’ (deacon, understanding hiv/aids stigma. cape town: hsrc press, 2005, p. 23). 10. randy shilts, and the band played on: politics, people, and the aids epidemic (stonewall inn editions, 1987), p. 588. 11. see danziger r, ‘hiv testing and hiv prevention in sweden’ (british medical journal 24 january 1998), available at http://findarticles.com/p/articles/mi_m0999/is_ n7127_v316/ai_20303083/pg_2 (accessed 31 january 2009). 12. hansen h, groce n, ‘human immunodeficiency virus and quarantine in cuba’ (jama 2003; 290: 2875), available at http://jama.ama-assn.org/cgi/content/ full/290/21/2875 (accessed 31 january 2009). 13. see nicoli nattrass, the moral economy of aids in south africa (cambridge university press, march 2004), mortal combat: aids denialism and the struggle for antiretrovirals in south africa (university of natal press, july 2007), and denying aids: conspiracy theories, pseudoscience, and human tragedy (springer verlag, february 2009) co-written with seth c kalichman. 14. ronald bayer, ‘public health policy and the aids epidemic. an end to hiv exceptionalism?’ (n engl j med 1991; 324: 1500-1504); see also ronald bayer and claire edington, ‘hiv testing, human rights, and global aids policy: exceptionalism and its discontents’ (journal of health politics, policy and law 2009; 34(3)). 15. wynia mk, ‘routine screening: informed consent, stigma, and the waning of hiv exceptionalism’ (am j bioethics 2006; 6(4): 5) explains aids exceptionalism as ‘the notion that being diagnosed with hiv is so different from any other diagnosis that it must be handled very differently. there should be exceptional confidentiality protections, because the information involved is so sensitive; exceptional informed consent, because the test is so personally invasive; and exceptional caution prior to testing, since a positive result can be so disruptive’. it has rightly been pointed out that this view of hiv testing in particular derives from the genetic counselling model of testing for untreatable conditions, which no longer applies: frieden tr, et al., ‘applying public health principles to the hiv epidemic’ (n engl med j 2005; 335: 22: 2397). 16. titles i and ii of the americans with disabilities act (ada) protects individuals with disabilities from discrimination in employment and in the enjoyment of all public entities such as schools, doctors’ rooms and shopping malls. the express intent of the ada was to define ‘disabilities’ broadly (see board of nassau county v. arline, 480 u.s. 273 (1987); and in the ada amendments act of 2008). similarly to title i of the ada, the us rehabilitation act of 1973 prohibits discrimination on the basis of disability in programmes conducted by federal agencies, in programmes receiving federal financial assistance, in federal employment, and in the employment practices of federal contractors. 17. the labour relations act 66 of 1995 prohibits unfair labour practices (including against job applicants) on grounds of ‘disability’; the employment equity act 55 of 1998 specifically mentions hiv status as a prohibited ground of unfair discrimination and prohibits testing of employees and job applicants for hiv status unless the labour court determines it justifiable; the code of good practice on hiv/aids and employment was approved by the southern african development community (sadc) in september 1997 and a ministerial code of good practice on hiv/aids and employment was promulgated in terms of the employment equity act 55 of 1998 on 1 december 2000; the promotion of equality and prevention of unfair discrimination act 4 of 2000 prohibits unfair discrimination on the grounds of ‘disability’ (which was anticipated to include hiv/aids, but is not expressly so defined), contains directive principles on hiv/aids, establishes an ‘equality review committee’ and requires the minister of justice and constitutional development to give special consideration to the inclusion of, among others, hiv/aids as an expressly prohibited ground of discrimination (the erc in 2006 apparently recommended to the minister of justice that ‘hiv/aids status’ be formally included under the listed grounds of discrimination in the equality act); the medical schemes act 101 of 1998 includes hiv-related diseases as a category benefiting from ‘prescribed minimum benefits’, provides for the compulsory cover of medical and surgical management of opportunistic infections, and prohibits denial of membership on the basis of ‘disability or state of health’; the national health act 61 of 2003 provides for the introduction of a ‘national policy on testing for hiv’ (the policy was published in august 2000), describes the circumstances under which hiv testing may be conducted and sets out requirements for preand post-test counselling and informed consent; the national education policy act 27 of 1996 provides for the drafting of national policies on educators and learners the minister of education in august 1999 issued a ‘national policy on hiv/aids for learners and educators’ which prohibits unfair discrimination against learners, students and educators with hiv/aids. 18. see hoffmann v south african airways 2001 (1) sa 1 (cc). 19. justice kirby correctly credits jonathan mann with initiating the human rights approach in the epidemic see ‘the never-ending paradoxes of hiv/aids and human rights’ (african human rights law journal 2004; 163, 165f). 20. justice kirby explains his engagement with the epidemic, and the first paradox, in ‘the never-ending paradoxes of hiv/aids and human rights’ (african human rights law journal 2004; 163). 21. as justice kirby puts it, the first paradox was necessary ‘because only behaviour change could curb the spread of hiv, and a human rights-based approach was regarded as the most feasible way to ensure the knowledge of an means to effect the behaviour change’: ‘the never-ending paradoxes of hiv/aids and human rights’ (african human rights law journal 2004; 163). 22. ‘who and unaids have asserted that there is no public health justification for mandatory hiv screening as it does not prevent the introduction or spread of hiv’ (unhcr ‘10 key points on hiv/aids and the protection of refugees, idps and other persons of concern’, 12 april 2006), available at http://www.unhcr.org/444e20f32. html (accessed 20 november 2009). 23. see anand grover (un special rapporteur), ‘[r]ight of everyone to the enjoyment of the highest attainable standard of physical and mental health’, paras 26 27, submitted to the un general assembly 64th session, 10 august 2009: ‘importantly, a rights-based approach addresses structural barriers to achieving informed consent within the appropriate health-care continuum. such an approach is especially cognizant of the power imbalances resulting from inequalities in knowledge, experience and trust between the health-care provider and the individual, particularly those from vulnerable groups. importantly, stigma and discrimination serve as disincentives for such patients to seek out services ad providers to treat patients equally. ‘compulsory, and, at times, routine testing is disempowering and frequently compromises human rights. such testing is coercive and generally results in inadequate provision of information and counselling, compromising informed consent and deterring individuals from accessing test results and appropriate services.’ 24. in the united states, for example, eight states currently require written consent for hiv testing new york, massachusetts, wisconsin, nebraska, rhode island, pennsylvania, michigan, and alabama. however, bills are currently pending in the new york and massachussetts state legislatures eliminating written consent for hiv testing. california and illinois eliminated their written consent requirement in 2008. 25. see burris s and cameron e, ‘the case against criminalization of hiv transmission’ (jama 2008; 300(5): 578-581); see also my address, criminal statutes and criminal prosecutions in the epidemic: help or hindrance? at the 17th international aids conference, august 2008, mexico city; lawrence k altman, ‘seeking better laws on hiv’, new york times, 8 august 2008, available at http://www.nytimes. com/2008/08/09/health/09aids.html?_r=3&oref=slogin&ref=world&pagewanted (accessed 21 october 2009); rebecca wexler, ‘criminalization of hiv’, international relations and security network, 27 august 2008, available at http://www.isn. ethz.ch/isn/current-affairs/security-watch/detail/?id=90570&lng=en (accessed 21 october 2009). 26. i explore some of this in my ronald louw memorial lecture (may 2006), ‘normalising testing, normalising aids’ (theoria, april 2007, pp. 99-108). 27. see jonny steinberg, the three-letter plague (us title sizwe’s test) (simon & schuster, february 2007). 28. this i try to grapple with in chapter 2 of witness to aids (tafelberg, 2005). 17 a p r i l 2 0 1 0 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 29. anish p, et al., ‘stigma in the hiv/aids epidemic: a review of the literature and recommendations for the way forward’ (aids 2008, 22 (suppl 2): s67-s79). it is notable that the foundational work of erving goffman (1922-1982), which the authors cite (from stigma: notes on the management of spoiled identity (1963)) does recognise that ‘the social label of deviance compels stigmatized individuals to view themselves ... as discredited or undesirable’ yet there is no explication in the context of aids of this vital ‘self-viewing’ aspect. see also robert crawford, ‘the boundaries of the self and the unhealthy other: reflections on health, culture and aids’ (soc sci med 1994; 38(10): 1347-1365). 30. compare, recognising this point, de cock km, et al. (2002) ‘shadow in the continent: public health and hiv/aids in africa in the 21st century’ (lancet 2002; 360: 67) at p. 69 (‘paradoxically, treating hiv/aids as being different from other infectious diseases probably enhances stigma rather than reduces it. the emphasis that has been placed on anonymity for hiv-infected people, which is different from confidentiality and analogous to secrecy, might also have been counter-productive. anonymity is impossible to maintain as immune deficiency progresses’); and frieden tr, et al. ‘applying public health principles to the hiv epidemic’ (n engl j med, 2005; 335: 22: 2397) at p. 2398 (suggesting that targeting hiv testing at those perceived to be at risk may perpetuate stigma). 31. de cock km, et al., ‘shadow in the continent: public health and hiv/aids in africa in the 21st century’ (lancet 2002; 360: 67-72), at p. 68. 32. idem. 33. a recent statement, ‘civil society statement on art as prevention: scaling down hiv requires scaling up human rights, testing and treatment’, submitted to the participants at the who consultation on art as hiv prevention (available at http://www.icaso.org/resources/2009/art_statementen.pdf, accessed 20 november 2009), states: ‘we urge un bodies, donors and researchers involved in this exploration to be mindful that people living with hiv and many who are highly vulnerable to it remain unable to gain access to hiv testing and to initiate treatment earlier, in a timely fashion, as a result of many human rights violations, as well as clinical and systemic barriers. research models that do not adequately consider and address these barriers do a disservice to the important goal of making art available to all as both prevention and treatment. ‘it is neither desirable nor possible to scale up voluntary hiv testing and treatment sustainably to implement art as prevention without addressing these human rights, clinical and health-systems challenges. supporting and strengthening civil society organizations in affected communities in the work of creating enabling environments are crucial to achieve this goal. ‘any feasibility study or pilot study of art as prevention must include an assessment of the social, policy and legal framework to address impediments to human rights protections and barriers to testing and treatment uptake before the study proceeds.’ 34. mark harrington (executive director of treatment action group) blog post on the critical path aids project, 4 december 2008, in response to web discussions regarding the granich article (‘universal voluntary hiv testing and immediate antiretroviral therapy’, lancet march 2009). the blog post is available at http://critpath.org/pipermail/healthgap_critpath.org/2008-december/000513.html (accessed 21 october 2009). 35. idem. 36. some aids activist organisations oppose rapid home-test kits on the basis that counselling would be absent, and that those testing positive might react unpredictably; already suggested presciently a 1997 lancet article by merson mh, et al., ‘rapid self-testing for hiv’ (lancet 1996; 348: 352-353); yet see ‘sa hiv home test kits withdrawn’ (24 may 2005), available at http://news.bbc.co.uk/2/ hi/africa/4576179.stm (accessed 21 october 2009); natasha joseph, ‘student devastated by home hiv test result’, 30 october 2007, available at http://www.iol. co.za/index.php?set_id=1&click_id=125&art_id=vn20071030055441964c325889 (accessed 21 october 2009); http://www.avert.org/testing.htm (‘avert opposes the legalisation of the sale of home testing kits in the uk because of the lack of post-test counselling’); ‘risks associated with home-use medical tests’, health canada, available at http://www.hc-sc.gc.ca/hl-vs/iyh-vsv/med/medtest-eng.php#ri (accessed 21 october 2009) (‘there is also a significant chance that people may interpret test results incorrectly and/or decide to change their treatment or lifestyle unnecessarily, if they don’t consult a qualified health care provider. interpretation of test results should always be part of a comprehensive health assessment’). 37. see the debate between chersich and richter and scorgie et al. in m. chersich m and richter m, ‘hiv testing and arv prophylaxis for newborns without their mothers’ consent’, southern african journal of hiv medicine, autumn 2008, pp. 6-8; and rebuttal by scorgie f, filiano ba and shapiro k, ‘coercive policies do not make for better health outcomes’, southern african journal of hiv medicine, autumn 2008, pp. 8-9. 38. because about one-quarter of those with hiv in the usa are still undiagnosed, the centers for disease control (cdc) has now published guidelines recommending routine hiv testing in all heath care settings in patients between 13 and 64 years, the patient being told that testing is done unless patients opt out separate signed consent and prevention counselling are no longer required. (lifson ar et al., ‘routine opt-out hiv testing’, lancet 2007; 369: 539-540.) 39. see ‘reduction in hiv testing due to opt-in consent linked to significant loss of life’ (31 october 2009), referring to research findings by michael april et al., available at http://www.infectiousdiseasenews.com/article/50172.aspx (accessed 20 november 2009). 40. granich rm, et al., ‘universal voluntary hiv testing with immediate antiretroviral therapy as a strategy for elimination of hiv transmission: a mathematical model’ (lancet 2009; 373: 48-57). 41. see ‘testing millions’, a message from aids healthcare foundation president michael weinstein (available at http://www.testingmillions.org/): ‘we at aids healthcare foundation (ahf) believe that the best way to reach the estimated 33 million people living with hiv/aids is to identify those who do not know they are infected and link them to treatment. this is also the best route to combating the spread of the disease, as it is believed that the source of the majority of new infections are people who are hiv positive, but do not know it. ‘clearly, testing in much greater numbers is urgently needed. ahf’s testing millions campaign is designed to not only increase testing, but also to establish a new, more streamlined testing model that if widely adopted could result in a dramatic drop in new infections and deaths.’ 42. nathan geffen’s proposal continues: the counsellor then does the test. if it comes back negative, s/he tells ms x that she’s hiv-negative. if and only if s/he has time, the counsellor also gives her some condoms and informs her that using condoms during sex is a good way to reduce the risk of contracting hiv. if the test comes back positive, the counsellor explains in a few minutes the following: • that ms x needs to have a cd4 and viral load test every x months and what these measure. • when ms x’s cd4 drops below 350, ms x must start arv treatment which involves taking one pill (maybe two) once daily for the rest of her life. • ms x can continue to have sex using condoms. • ms x can have a child if she chooses, but she will need to take measures to reduce the risk of the child contracting hiv. (the same goes for a mr x.) • counsellor refers ms x to a treatment literacy class/support group/structure of some kind. • counsellor informs ms x that if she is distressed or confused, she can contact him/her for further counselling. 43. see ‘reduction in hiv testing due to opt-in consent linked to significant loss of life’, infectious diseases news 31 october 2009, available at http://www. infectiousdiseasenews.com/article/50172.aspx. 44. i am indebted to gregg gonsalves (private communication, 4 february 2009) for the following perceptive comments: ‘the fear of death and the fear of lack of access to treatment constitute an important aspect of the internal stigma and present a substantial barrier to consent to testing. the fear of testing stems from a deep psychological desire to avoid the knowledge that one has been infected with the disease and is therefore dying, compounded by the lack of knowledge of treatment and whether treatment will be available. in addition, the nature of the calculation that one makes relating to one’s relationship with death or behavior feeds into fear and internal stigma.’ 45. federal health officials in the united states will conduct a study implementing the strategy ‘test and treat’ in two locations with some of the country’s highest hiv infection rates, washington, dc and the bronx. the goal is to stop the spread of hiv by routinely testing virtually every adult in the community and providing prompt treatment to those who test positive. this is a first step not to measure whether the programme actually works to slow the epidemic, but to find out whether such a strategy can even be carried out given the many obstacles to testing and treatment. susan okie, ‘fighting hiv a community at a time’, new york times 27 october 2009, available at http://www.nytimes.com/2009/10/27/health/27hiv.html (accessed 20 november 2009). 46. available at http://www.tac.org.za/community/files/pres%20zuma%20 address%20to%20ncop%20291009.pdf (accessed 20 november 2009). 47. granich et al. do not, as has been claimed, give ‘unexamined endorsement [to] annual universal testing’: rather, they pose a hypothetical question if there were such testing, and immediate antiretroviral therapy, would endemic hiv transmission cease; and their suggestive hopeful answer is yes. see the discussion on aidsmap of the granich et al. article, available at http://www. aidsmap.com/cms1282664.aspx (accessed 20 november 2009): ‘[u]niversal testing and treatment is only likely to be cost-effective in settings where hiv is hyperendemic and where aids seriously threatens long-term stability and growth. further cost-effectiveness analysis will be needed. the who analysis looks at the relative costs of pursuing the universal approach or treating people when their cd4 count falls below 350 cells/mm3. the universal approach demands substantially greater expenditure during the first two decades, but begins to become cheaper than the default treatment approach by 2030. this balance and time-scale may differ in other countries in the southern africa region.’ for criticism of the granich hypothesis, see dr geoffrey garnett, from imperial college london, in a commentary piece published in the lancet: ‘at its best, the strategy would prevent morbidity and mortality for the population, both through better treatment of the individual and reduced spread of hiv. at its worst, the strategy will involve overtesting, over-treatment, side effects, resistance, and potentially reduced autonomy of the individual in their choices of care.’ imogen foulkes, ‘universal test “would slash aids”’, bbc news 26 november 2008, available at http://news.bbc.co.uk/2/hi/7749437.stm (accessed 20 november 2009). 18 hiv message from editor message from the editor call for submissions: a decade of antiretroviral therapy in the public sector for the last 13 years, the southern african journal of hiv medicine (sajhivmed) has provided state-of-the art updates and indepth local insights into both the population-level impact of the hiv epidemic and the management of hiv-infected and at-risk individuals across southern africa. the history of the journal is intertwined with the expansion of access to antiretroviral therapy (art) across south africa and the region. as 2014 marks the 10-year anniversary of the public sector roll-out of art services in south africa, sajhivmed is planning a special edition to reflect on the lessons and celebrate the achievements during this time. as part of this, sajhivmed is calling for submissions from healthcare workers, policy makers and researchers for this special edition. contributions of all shapes and sizes are welcome. we are particularly interested in ‘reflections’ from clinicians on the ground – providing insight into the realities of delivering art to increasing numbers of patients under difficult circumstances. these submissions can take the form of short editorials of 500 1 000 words commenting on individual experiences of providing hiv care and treatment services at all levels of care. if you are interested, please submit these pieces by 1 december 2013 via the journal website (http://www.sajhivmed.org.za), or feel free to email me directly at the address below. landon myer school of public health & family medicine university of cape town landon.myer@uct.ac.za ------_1------learning from mistakes and trlumphs news out of africa is often bad, and certainly he hiv pandemic at present ravaging this continent must rate as one of the worst disasters of all time. however, even in the face of this disaster there have been glimmers of hope emanating out of this continent and other developing countries. perhaps most exciting of all are the lessons we learn from uganda, where an intensive programme of primary school education on lifestyle choices and encouragement to delay sexual debut have resulted in a largely aids-free generation coming up' and now contemplating marriage proud of their hiv-negative status. indeed numbers reflect this, with under19-year-old females having less than 1'1'0 hiv prevalence in a recent unaids report similarly, programmes launched in zambia have had good effect and sentinel surveys in lusaka show that the percentage of pregnant girls aged 15 19 infected with hiv has on average dropped by almost half in the last 6 years. senegal is another african country that can teach some lessons. president abdoulaye wade attributes his country's successful campaign against aids to his governmenfs early response to the disease; its mobilisation of the community in the fight against it, and its investment in research. senegal began tackling hiv/aids in 1986 when the first 6 cases were detected and became one of the first countries to develop a national aids council. by 1987, it had a national blood screening programme to ensure safe blood transfusions. in a recent interview, wade states that all population groups were mobilised the youth, women, and especially religions. these played a very important role; 95'1'0 of the population is muslim and 5'1'0 are christian, and both were involved in the struggle. he goes on to say that although the christians may not have accepted the use of condoms, they are working well for protection against hiv. the 11 august 200 i country's muslims, many of whom practise polygamy, also do not condone the use of condoms: they have therefore decided that the most important factor is prevention through abstinence. at the end of 1999, the estimated hiv prevalence in senegal was 1.8'1'0 among the adult population. mocambique, on the other hand, has in recent years put much effort into its sexually transmitted disease prevention and treatment programmes, with good effect. this· has paid dividends in the hiv epidemic, since we know that genital ulcer disease is a very important factor in efficient hiv transmission. among other developing countries, thailand stands out as having curbed a rampant heterosexual epidemic by ensuring 100'1'0 condom use by commercial sex workers and general education of the male population. other routes of transmission have unfortunately assumed greater importance, such as sharing of intravenous drug injecting equipment and unprotected sex between men. in brazil, where over half a million adults are living with hiv, the government has taken an active lead in hiv prevention, care and protection of the rights of people affected by the epidemic. perhaps the most visible commitment is the governmenfs undertaking to provide free antiretroviral therapy to all those who need it. actively engaging non-governmental organisations, the brazilian government has sought to reach the general as well as the marginalised public in information campaigns and prevention services. a recent survey conducted in brazil showed that while less than 5'1'0 of young men in 1989 reported using a condom the first time they had sex, the figure in 1999 was close to 50'1'0 a tenfold increase, borne out by the massive rise in sales of commercial condoms from 70 million a year in 1993 to 320 million a year in 19991 in our own country i am hugely excited by the loveufe the southern african journal of hiv meoicine campaign. which i see spilling into the media and making its presence felt on billboards and in townships. i have as yet not seen any evaluation of efficacy, but i imagine that this is just the kind of upfront and contemporary message that much of our south african youth could relate to. what remains unfathomable to me is how easily we south africans miss opportunities to engage and move forward constructively. recently the catholic bishops came under a great deal of criticism for negating the use of condoms by the catholic community as a valid method of protection against hiv. as i see it, both the critics and the bishops are partially right and partially wrong. the tragedy in the whole debacle is that neither group seems to have realised that the epidemic is occurring in a heterogeneous and vastly diverse population, which cannot be regarded as one population when finding preventive strategies. it is clear that there are high-risk groups, namely sex workers, where the condom message is not only important but probably life-saving. in this group i would advocate 100'\'0 condom use and sound information about consequences for not doing so. conversely, in the as yet sexually uninitiated i would think that a message of abstinence (couched in as funky and hip-hop terms as are necessary to be age-acceptable) is both wise and reasonable, but again sound information should be provided about consequences and alternatives. everyone else falls into the spectrum between, depending on their risk stratification. in brazil, for example, it was shown in 1999 that men were more likely to use condoms in their more risky partnerships than with wives or long-term partners. there is no doubt that we must learn from the mistakes of others, but we can also learn from their triumphs. uganda and zambia have somehow found ways to safeguard the aids-free generation in their countries by empowering them with opportunities for lifestyle choices and we should put most of our energy into doing the same. our aids-free generation is precious. yet there are those who, by choice of profession or recreation, place themselves at risk, and they need the condom message. finally, a vast number of south africans are beyond prevention strategy and are in need of antiretroviral therapy. in this regard brazil has shown what can be done in a developing country, but south africa still has the opportunity to show what an african country can do. unda-gall bekker managing editor conference notice the biennial joint conference of southern african sexually transmitted diseases. infectious diseases and hiv clinicians societies is to be held from 2 to 6 december 2001 at the music conservatoire, stellenbosch, western cape. collectively the conference will cover a comprehensive array of medical challenges facing subsaharan africa tuberculosis, malaria, sexually transmitted diseases, pertussis, small pox, typhoid, cholera, yellow fever, diarrhoeal disease, infection control and most matters related to hiv/a10s. hiv will feature throughout the meeting with the last day focusing on practical, clinical, community and ethical issues in hiv management for doctors and primary care professional practitioners. an update with final details of the planned programme will be available shortly. for further information contact the congress secretariat: sune van rooyen or uezel horn at the faculty of medicine, po box 19063, tygerberg, 7505. sune van rooyen lel: 021 9389245 fax: +27 021 933 2649 e-mail: sunevr@matiessun.ac.za liezel horn lel: +27 021 9389238 fax: +27 021 933 2649 e-mail: lh@matiessun.ac:.za tllf soutilfa. african journal of iii mfoici f ----------august 200 i 11 the southern african journal of hiv medicine                                                        october  2009 many individuals infected with hiv eventually present with evidence of neurological involvement, including cognitive deterioration. autopsy studies of patients with hiv-associated dementia (had) demonstrate damage to the deep white matter areas involved in sub-cortical dementia (including the caudate nucleus and basal ganglia).8 this finding is complemented by results of both computed tomography (ct) and structural magnetic resonance imaging (smri), with association between had and both diffuse atrophy with ventricular dilatation9 and deep white matter lesions. furthermore, a correlation between declining cognitive function and the loss of volume in certain brain structures, including the basal ganglia and caudate nucleus, has also been reported.10 dynamic contrast-enhanced mri has identified subcortical grey and frontal white matter as the principal sites of early metabolic abnormalities in hiv disease.11 both increased regional cerebral blood volume and post-contrast enhancement have been reported in the basal ganglia in moderate and advanced had, reflecting increased vascularity and blood-brain barrier (bbb) permeability. these findings are consistent with the characteristics of the early neurological deficits, and the known predilection of hiv for the basal ganglia.12 the degree of neurocognitive impairment in hiv is correlated both with the degree of bbb breakdown in the basal ganglia and with viral load.13 diffusion tensor imaging (dti), a recent advance in mri methods, is uniquely suited to the study of subtle white matter abnormalities that are not detected by traditional mri. dti can be used to quantify the magnitude and directionality of tissue water mobility (i.e. self-diffusion). barriers such as myelin sheaths, membranes, or white matter tracts result in greater self-diffusion along the axis of the barrier and reduced diffusion out of the tract. this type of restricted self-diffusion is termed ‘anisotropic’. fractional anisotropy (fa) is a measure derived from the diffusion tensor imaging that assesses the degree of anisotropic self-diffusion, i.e. the integrity of the white matter tract.14 the higher the fa the healthier the tract; lower fa indicates damage to its integrity. dti provides us with information about the large-scale networks that are made up of long tracts connecting distant relay stations in the brain (fig. 1).15 these networks are important for the development of higher brain functions such as language, praxis, social behaviour and emotion. lesions affecting white matter connections lead to dysfunction, and cognitive disorders are sometimes better explained by a disconnection mechanism between distant cerebral regions than by primary damage of those regions themselves.16 dti studies have revealed central nervous system abnormalities in asymptomatic hiv-positive patients with no cognitive impairment and normal structural the imaging of hiv-related brain disease c l i n i c a l : i m a g i n g jackie hoare, mb chb, mrcpsych, fcpsych (sa) division of neuropsychiatry, department of psychiatry and mental health, university of cape town advanced hiv disease is strongly associated with an increased occurrence of various neuropsychiatric disorders,1 and highly active antiretroviral therapy (haart) is an important aspect of managing these conditions effectively.2 in addition, there is growing recognition that many hiv-infected individuals will develop neuropsychiatric disorders relatively early in the course of hiv disease, in many cases before cd4 cell counts drop below 500 cells/µl.3 however, it is not known who in the earlier phases of the disease will go on to develop neurocognitive disorders, or who will respond to treatment.4,5 new approaches in neuro-imaging have the potential to detect early hiv-associated damage in the brain. preliminary evidence suggests that the neurotoxic effects of hiv result in damage to white matter tracts in the brain.6 once damage is established and related cognitive disorders ensue, the ability of haart to reverse existing dysfunction is probably limited.7 earlier treatment with haart in at-risk or minimally symptomatic patients may prevent further decline in cognition and delay the course of hiv disease. findings from autopsy, ct and mri studies dti in hiv diffusion tensor imaging 35 the southern african journal of hiv medicine                                                          october  2009 mr studies. diffuse damage to cerebral white matter, as evidenced by pallor on dti, is one of the most frequent neuropathological features of hiv-1 infection and has been found to be particularly prominent in the advanced stages of the disease.17 the white matter pallor has been found to be more prevalent and severe in patients with had.17 dti abnormalities have been reported in the frontal white matter of cognitively asymptomatic patients infected with hiv,18 and mr spectroscopy studies indicate that this region may be subject to early injury in patients infected with hiv.19 studies utilising dti have identified sub-cortical white matter and corpus callosum abnormalities in patients with hiv, despite normal-appearing white matter on mr and non-focal neurological examinations20 (fig. 2). patients with the largest anisotropy decreases had the most advanced hiv disease. interestingly, patients with the lowest viral loads and normal anisotropy were receiving haart. this has led some to suggest that dti fig. 1. dti tractography showing axial, sagittal and coronal views in an individual patient. areas shaded green represent white matter tracts from anterior to posterior, those in blue inferior to superior, those in red, from left to right. it is possible to isolate regions of interest, or to detect areas where significant abnormalities in integrity of white matter occur. fig. 2. dti images showing changes in fa in three groups of patients by clinical severity. these changes reflect significant differences between the groups compared with hiv-negative controls, and indicate (i) that fa is impaired across the spectrum of hiv-associated neurocognitive disorder, including asymptomatic neuropsychological impairment, and (ii) that different regions may be affected across different severities, with some affected areas being responsible for a greater degree of clinical impairment. the amount of fa does not correspond to the location or severity of fa. 36 the southern african journal of hiv medicine                                                        october  2009 could be used as a potential biomarker of brain injury in patients infected with hiv.21 dti and other emerging neuro-imaging technologies may provide markers for early cns disease in hiv-positive patients, allowing for the earliest possible detection of cognitive impairment. this in turn may facilitate early preventive antiretroviral treatment to reduce long-term damage. novel imaging techniques such as dti applied in individuals with mild forms of neurocognitive disorder may be a good place to start. studies examining response to haart in patients infected with hiv will be important to determine whether dti abnormalities reflect reversible or more advanced, irreversible injury. correlates of white matter damage and neurocognitive decline need to be sought, including whether measures of white matter damage in the central nervous system correlate with viral load, illness duration, age, treatment exposure and treatment adherence. these factors are almost certainly critical in determining the overall impact of hiv on brain function, and in particular on white matter integrity. references 1. grant i, sacktor n, mcarthur j. hiv and neurocognitive disorders. in: gendelman h, grant i, everall i, lipton s, swindells s, eds. the neurology of aids. oxford: oxford university press, 2005. 2. chang l, ernst t, leonido-yee m, et al. highly active antiretroviral therapy reverses brain metabolite abnormalities in mild hiv dementia. neurology 1999; 53: 782-789. 3. ernst t, chang l, jovicich j, ames n, arnold s, abnormal brain activation on functional mri in cognitively asymptomatic hiv patients. neurology 2002, 59: 1343-1349. 4. tozzi v, balestra p, galgani s, et al. positive and sustained effects of highly active antiretroviral therapy on hiv-1-associated neurocognitive impairment. aids 1999; 13(14): 1889-1897. 5. ferrando s, van gw, mcelhiney m, goggin k, sewell m, rabkin j. highly active antiretroviral treatment in hiv infection: benefits for neuropsychological function. aids 1998; 12(8): f65-f70. 6. langford td, letendre sl, larrea gj, masliah e. changing patterns in the neuropathogenesis of hiv during the haart era. brain pathol 2003; 13: 195210. 7. nath a, schiess n, venkatesan a, rumbaugh j, sacktor n, mcarthur j. evolution of hiv dementia with hiv infection. baltimore, md: department of neurology, johns hopkins university, 2007. 8. bell je. an update on the neuropathology of hiv in the haart era. histopathology 2004; 45: 549-559. 9. stout jc, ellis rj, jernigan tl, et al. progressive cerebral volume loss in human immunodeficiency virus infection: a longitudinal volumetric magnetic resonance imaging study. hiv neurobehavioral research center group. arch neurol 1998; 55: 161-168. 10. tucker ka, robertson kr, lin w, et al. neuroimaging in human immunodeficiency virus infection. j neuroimmunol 2004; 157: 153-162. 11. berger jr, nath a, greenberg rn, et al. cerebrovascular changes in the basal ganglia with hiv dementia. neurology 2000; 54: 921-926. 12. brew bj, rosenblum m, cronin k, price rw. aids dementia complex and hiv-1 brain infection: clinical-virological correlations. ann neurol 1995; 38: 563-570. 13. avison mj, nath a, greene-avison r, schmitt fa, greenberg rn, berger jr. neuroimaging correlates of hiv-associated bbb compromise. j immunol 2004; 157: 140-146. 14. basser pj. inferring microstructural features and the physiological state of tissues from diffusion-weighted images. nmr in biomedicine 1995; 8(7/8): 333344. 15. musulam m-m. imaging connectivity in the human cerebral cortex: the next frontier? ann neurol 2005; 57: 5-8. 16. catani m. diffusion tensor magnetic resonance imaging tractography in cognitive disorders. curr opin neurol 2006; 9(6): 599-606. 17. gray f, scaravilli f, everall i, et al. neuropathology of early hiv-1 infection. brain pathol 1996; 6(1): 1-15. 18. pomara n, crandall dt, choi sj, johnson g, lim ko. white matter abnormalities in hiv-1 infection: a diffusion tensor imaging study, psychiatry res neuroimaging 2001; 106: 15-24. 19. chang l, lee pl, yiannoutsos ct, et al. a multicenter in vivo proton-mrs study of hiv-associated dementia and its relationship to age. neuroimage 2004; 23: 1336-1347. 20. filippi cg, ulug am, ryan e, ferrando sj, van gorp w. diffusion tensor imaging of patients with hiv and normal-appearing white matter on mr images of the brain. ajnr am j neuroradiol 2001; 22: 277-283. 21. wu y, storey p, cohen ba, epstein lg, edelman rr, ragin ab. diffusion alterations in corpus callosum of patients with hiv. am j neuroradiol 2006; 27: 656-660. conclusion 37 sajhiv 1036 reflections the secrets of the green and white cards d hagemeister, ba, da (sa), diphivman, pgdipire, mph, emmb, fafallgmed, md corresponding author: d hagemeister (hagemeisterdt@ufs.ac.za) dr dirk hagemeister is a senior lecturer in the department of family medicine, faculty of health sciences , university of the free state, bloemfontein, south africa it has been more than ten years now that we have been rolling out antiretrovirals (arvs) to the general population. and we have achieved a lot. we have successfully initiated the world’s largest arv treatment programme in south africa, and we are starting to see the positive impact of these efforts in indicators such as life expectancy and maternal deaths. however, there is still much room for improvement. and i am not going to talk about the sometimes erratic drug supply in our system, nor about the fact that far too many patients still arrive at the hospitals’ casualty departments with advanced disease, nor about the chronic deficits with regards to resources, including human resources. however, the missing improvement that many people do not consider is the lack of adjustment in our own practice of medicine. have we, ourselves, as clinicians in 21st century south africa, arrived at a point where we can sufficiently meet our patients’ health needs? have we, as senior clinicians and academic teachers, internalised the need for ‘clinical literacy in hiv medicine’ as a basic skill that we need to teach our young colleagues at medical schools and internship sites? yes, maybe sometimes we have. but far too often we are not meeting these needs. in my experience teaching clinical medicine, i routinely attempt to use the learning opportunity of ward rounds to sensitise junior colleagues to the value of the simple patient-held progress cards which are routinely used in public sector antiretroviral therapy (art) and tuberculosis (tb) services across the country. with a number of such tools being utilised in our country by now, it is striking to see the differences in familiarity with such tools between our healthcare programmes. clinicians are fairly comfortable with extracting the relevant information from antenatal booklets and from children’s ‘road-to-health-cards’, but the same is not true for the ‘green’ and ‘white’ cards that we are using in art and tb services. just in case you are not terribly familiar with the two patient-held treatment cards used in the public sector for tb and hiv patients, the ‘white card’ is the art progress card, usually folded into one-third of an a4 size (and often further by the patient), while the ‘green card’ is the a5-sized two-paged tb treatment card. rather saddening, the same procedure repeats itself over and over again. during ward rounds, no matter whether in casualty, adult or maternity wards, a young eager colleague presents a patient as ‘known hiv and tb patient, on treatment, now admitted because of shortness of breath, diarrhoea, abdominal pains, etc.’ . the standard conversation then continues as such: me: ‘when was the patient started on treatment?’ colleague: ‘i don’t know.’ me: ‘did you look at the treatment cards?’ colleague: ‘the patient didn’t bring them.’ me, turning to the patient: ‘can you please give me the clinic card’, when the patient usually grabs a plastic bag that is lying somewhere on his or her bed, containing some food supplies, money, possibly a handkerchief and the green/white cards. what upsets me most about this exchange is not the ‘taking chances’ of our young colleagues – as a father of three i am used to such approaches, and after a busy night in the emergency department with multiple admissions, one probably has every reason to try to cut some corners. what really makes me sad is that we do not recognise the intrinsic value of these patient-held tools for our assessment and further management of the patient in front of us. more often than not, the tb and art cards reveal scarring gaps in the clinical practice of these basic programmes. patients are started on tb medication ‘on clinical grounds’, no sputum smear result is documented, or the intensive (four-drug) phase is ended and the continuation (two-drug) phase of pulmonary tb treatment is commenced without having confirmed sputum conversion in smear-positive cases. similarly, hiv patients have been on ‘failing regimens’ for years, high viral loads were documented one to two years ago, but never followed up; worse even, single-drug substitutions have been performed in the presence of large, detectable viral loads. please do not get me wrong, i am not blaming the staff in our primary healthcare clinics for this – it is enough that they are often left alone in challenging supply chain settings, have no clinical support or supervision, and have overwhelming expectations placed on them. as far as i am concerned, we need to pull up our socks as senior clinicians and academics. yes, hiv treatment is today where tb treatment was a couple of years ago: it is largely governed by national protocols, has been handed over to primary healthcare clinics and is done by dedicated nursing staff in those facilities. but as with tb, the ‘handing-over’ of hiv treatment to primary healthcare services bears a real risk in clinical practice: we as medical doctors may not bother anymore to understand the basics of these programmatic treatments, as they may be perceived to be below our scope of practice. however, this attitude is going to cost us dearly as we sit on a national time-bomb of ever-increasing drug resistance in tb, and possibly soon in hiv, too. nurse-initiation and management of art is an essential, and incredibly valuable step in the broad rollout of arvs. however, it must not result in us as medical professionals ‘disempowering’ ourselves in terms of clinical skills in treating these conditions. in an attempt to address this growing trend, we recently reverted to the ultimate means an academic teacher has available to emphasise the importance of a topic we teach: including the interpretation of patient-held treatment progress cards into both the postgraduate and undergraduate examinations in family medicine. inevitably, the results of the examinations were rather sobering this year. but now that it is no secret anymore that green cards and white cards may be in next year’s examination ... s afr j hiv med 2014;15(1):33-34. doi:10.7196/sajhivmed.1036 the southern african journal of hiv medicine                                                    december  2009 several guidelines now recommend universal treatment for hiv-infected infants. however, in resource-limited settings early infant diagnosis (eid) is frequently an obstacle to early initiation of antiretrovirals. a survey by world health organization (who) asked, ‘what is available for early infant diagnosis?’ and found the number of laboratories in several countries mismatched to the estimated number of hiv-exposed infants and necessary tests. this assessment of national capacity was conducted to inform revisions to their guidelines for infant diagnosis and treatment.1 for this survey, a questionnaire on clinical and laboratory capacity was sent to hiv experts in 34 high-burden countries and data were collected between february and april 2008. replies were received from 18 of the 34 selected countries: 12 african, two south american, two asian and one middle eastern. this revealed huge variation in the number of children assessed per laboratory (range 7 190 000 during the study period). when virological tests were offered, the entry points were usually inpatient/outpatient services, prevention of mother-to-child transmission (pmtct) or antiretroviral therapy (art) sites, and laboratories were centralised and usually located in capital cities. six countries surveyed implement hiv dna polymerase chain reaction (pcr), 5 rna pcr and 7 both. ten countries used filter paper with dried blood spots (dbs) to transport samples. all the countries that responded had capacity to measure cd4% and absolute cd4 cell counts. although the survey confirmed that several high-burden countries are building capacity for eid, it showed that at present in many countries capacity does not reflect estimated need. in many resource-limited countries it is only possible to use a single diagnostic test. the optimal time to perpaediatric overview, ias2009 c o n f e r e n c e r e p o r t polly clayden hiv i-base, uk a wealth of paediatric data was presented at ias 2009. also preceding the conference was the 1st international workshop on hiv pediatrics, which looks as if it will become an annual fixture on the conference calendar and gave an additional opportunity to present and discuss the state of the art in the field. overall, far too much was presented to review here. abstracts, some slides and, for ias2009, webcasts can be viewed on the respective conference websites. we have also covered some paediatric cohorts and a few studies in more detail in our review of programme data in htb south, distributed with the journal. several themes occurred over and over again at both meetings. national capacity for early infant diagnosis, which not only enables early initiation of treatment but also gives a clearer picture of how well prevention of mother-to-child transmission (pmtct) programmes are performing, with the goal of vastly reducing cases of paediatric hiv, is not yet nearly sufficient in most places. where infants are diagnosed in time, early initiation of treatment is not without its difficulties. it can, however, be extremely beneficial in young children. treatment of children who are hiv-infected despite exposure to single-dose nevirapine through pmtct is another challenge, as is what to do in the longer term with exposed children initiated on a protease inhibitor-containing haart to overcome the risks of nnrti resistance. strategies to simplify regimens, including paediatric fixed-dose combinations and once-a-day dosing, are essential for successful management of children with hiv, as are strategies to enable co-treatment of tuberculosis in this population. the research summarised below addresses these issues. early infant diagnosis 91 december  2009                                                      the southern african journal of hiv medicine                                                   form this is unclear, however, particularly when children are breastfed. the who researchers used a model to calculate the number of children becoming infected and being diagnosed at different time points from birth in order to estimate the optimal time to diagnose the maximum number of children but at the same time minimise mortality.2 this modelling showed a decreasing trend of infant survival at 6 months, depending on the time the test was performed. the investigators suggested that 4 6 weeks of age is the optimal time for infant testing in a breastfeeding population. with greater laboratory capacity and newer technology, testing earlier than 6 weeks could mean earlier initiation of treatment. but the sensitivity of viral detection tests before 6 weeks of age is unknown, particularly when performed on infants with antiretroviral exposure for pmtct. a south african study looked at the sensitivity of assays at earlier time points in infants born to hiv-positive women at rahima moosa hospital, johannesburg.3 blood was sampled at birth and at 2, 4, 6 and 10 weeks, and stored. hiv-exposed infants were routinely tested at 6 weeks with hiv dna pcr using a liquid blood sample. stored dbs samples from each time point were tested with hiv dna pcr (amplicor v1.5), taqman hiv-1 (cap/ctm) and aptima hiv-1 (gen-probe) assays. the investigators used samples from two age-matched, pcr-negative infants as controls. mothers received a range of pmtct interventions: no antiretrovirals, single-dose nevirapine (nvp), singledose nvp plus zidovudine (azt) or haart. at 9 months of the study, 253/373 (68%) infants had 6-week pcr results; the remaining 120 (32%) did not return for testing. eighteen (7.1%) were hiv infected at 6 weeks despite the majority receiving formula milk exclusively and all receiving nvp and azt pmtct prophylaxis. of the 17 infected infants with complete results, both cap/ctm and aptima assays were positive in 11/17, 13/13 and 14/14 birth, 4and 6-week samples, respectively. the quantitative cap/ctm assay showed lower viral load results at 2 weeks of age (the only time point when false negatives occurred). the investigators noted that this was probably due to pmtct prophylaxis increasing the proportional number of infants infected in utero who can therefore be diagnosed at birth. both assays were more sensitive for earlier hiv detection than hiv dna pcr, which detected 9/17 birth samples. cap/ctm had the highest specificity (100%) and hiv dna pcr the lowest (95%). although this is a small sample, newer technologies appear to be more sensitive than standard pcr. these initial results suggest that the majority of in utero and perinatal infections can be detected by using either cap/ctm or aptima assays if they are available. there were also reports from programmes using dbs. a sub-study of the pmtct keso bora trial conducted in burkina faso used a quantitative hiv rna assay (biocentric) and assessed dbs samples compared with paired plasma samples obtained from hiv-exposed infants aged up to 6 weeks, 3 6 months and 9 18 months.4 all measurements were performed locally. the study investigators reported 100% sensitivity (102/102) and specificity (105/105) (95% confidence interval (ci) 97.2 100%, correlation 0.906) using dbs. (of note: biocentric is the homebrew anrs assay, so they would have to develop their own probes, reagents, etc.) a cambodian study assessed the feasibility of very early diagnosis (0 3 days of age) using heel-prick samples on dbs and a real time dna assay (bicentric).5 a second dbs was performed at week 6. infants with positive results at 0 3 days or 6 weeks were followed up with hiv rna quantification as soon as possible. at 0 3 days, 3/370 (0.8%) infants had positive results (1 infant died before week 6). 327/333 were confirmed negative at 6 weeks and 6 were dna positive (1.8%) and subsequently confirmed rna positive. the investigators suggested that these preliminary results demonstrate the feasibility of a minimally invasive very early diagnosis using dbs. a study from swaziland, conducted by the national art programme and the clinton foundation, highlighted the difficulties of treatment initiation in infants following early diagnosis.6 since march 2007 the eid programme using dna pcr was expanded in response to high infant mortality in hiv-infected children. by november 2008, however, this had led to neither an increase in infants receiving treatment nor a decrease in mortality. the study was a retrospective record review of all infants testing positive at 15 health facilities in the manzini region from january to august 2008. the investigators reported that 78% of results were available at the facility, and 44% of results were documented as having been received by the caregiver. only 58/176 (33%) of children were enrolled at an art centre and 34 initiated on treatment. of those with data available difficulties with implementation 92 the southern african journal of hiv medicine                                                    december  2009 81% were eligible for art, and among eligible children, 82% initiated treatment. overall 19% of infants testing positive were initiated on treatment at the time of the evaluation. this study found that the greatest points of loss are return of the result to caregivers and infant enrolment at the art centre for treatment. there are limited data describing outcomes for infants initiating treatment at less than 1 year. the mtct plus initiative showed data from sites in eight african countries and thailand comparing infants with older children initiated between february 2003 and september 2008.7 the investigators looked at change in cd4 percentage from baseline using linear modelling adjusted for duration of highly active antiretroviral therapy (haart), country, baseline cd4 percentage, nvp exposure for pmtct, and age at initiation. of 542 children initiating treatment and followed up for a median of 30 months (intraquartile range (iqr) 12 39), 190 (35%) were aged <12 months at initiation and the remainder >12 months (median 36 months, iqr 19.5 67), 51% were male, and18% had centers for disease control (cdc) stage c disease. the infants had a higher mortality rate than the older children, 7.5 v. 3.2/100 person-years. of 31 (54%) infant deaths, 81% occurred within 3 months of treatment initiation. among the children for whom data were available there was no difference between infants and older children in change of cd4 percentage from baseline. baseline cd4 percentage (p<0.01) and time on haart (p<0.001) were significantly associated with an increase in cd4 percentage in multivariate analysis. in this analysis, although infants initiating haart had a higher mortality at the start of treatment, the infants who survived had good immunological response over >3 years of follow-up, similar to that of older children. a south african review of infants initiated on haart at the family clinic for hiv at tygerberg hospital and ikwezi community clinic from june 2007 to august 2008 showed high levels of virological suppression to 24 weeks.8 infants received lopinavir/ritonavir (lpv/r) with stavudine (d4t) and lamivudine (3tc) in accordance with south african guidelines. of 98 initiated, 47 had 24 weeks of follow-up. of the remainder, 6 (6%) were lost to follow-up, 6 (6%) died and 33 (33.7%) were transferred. the median age at initiation was 4.5 months and 33 (70%) infants were <6 months old (median age 3.68 months). all had immunological or clinical criteria for treatment. the majority, 42/47 (89.4%) of all infants and 30/33 (91%) <6 months of age, had who stage 3 or 4 disease. tuberculosis (tb) is a common co-morbidity in this population, and 11/47 infants required co-therapy with rifampicin (given with additional ritonavir). at 24 weeks 37/47 children (78.7%) in the >6 months age group and 26/33 (81.8%) aged <6 months had viral loads <50 copies/ml. the investigators noted that the low age of initiation of treatment in this cohort reflected young infants with severe hiv disease rather than early initiation of treatment to prevent mortality and morbidity. the developing brain is a major target for hiv. it is not yet known whether timing of initiation of antiretroviral therapy will affect neurodevelopmental outcomes in infants. a substudy of cher compared neurodevelopmental outcomes of 115 infants in this study from tygerberg children’s hospital with 84 control infants enrolled in a linked vaccine study, cipra-sa project4.9 in this prospective study, the investigators looked at the neurodevelopmental profile, according to the griffiths mental developmental scales (gmds), at 10 15 months of age in four groups of infants: n hiv-unexposed, uninfected n hiv-exposed, uninfected n hiv-infected, haart initiated before 12 weeks of age n hiv infected, haart deferred until eligibility criteria met. the investigators were blinded to the infants’ groups and a translator was used for xhosa-speaking participants. of 115 infants from cher enrolled, 13 withdrew from the study and/or were not co-enrolled (10 early, 3 deferred), 8 died (all deferred) and 4 were excluded (3 early, 1 deferred). the investigators found that infants initiated on early art have significantly better locomotor and general scores on the gmds at a median age of 11 months compared with infants on deferred haart. although mean quotients were lower on the other subscales in the deferred group, the differences were not significant. the mean scores on all subscales in the unexposed, uninfected group and the early haart group were similar. they noted these results were ‘despite careful monitoring and ready access to art in the latter’ (table i). infant outcomes improved neurodevelopmental outcomes 93 december  2009                                                      the southern african journal of hiv medicine                                                   two studies looked at treatment of hiv-infected children with prior exposure to nvp to prevent mtct. preliminary findings from impaact 1060 confirmed concerns that nvp-exposed children could do less well receiving nvp containing haart than protease inhibitor (pi)-containing haart.10,11 this was a randomised trial of treatment-eligible children aged 6 months 3 years conducted in seven african countries. nvp-exposed (cohort 1, n=288) and unexposed (cohort 2, n=288) children received either lpv/r or nvp plus 3tc and azt. children were stratified by age <12 months v. >12 months with an equal number to be enrolled in each age group. a similar study of exposed and unexposed mothers had also been conducted (a5208). in this trial, the arm in which exposed mothers received nvp-containing haart was stopped early by the data safety monitoring board (dsmb) owing to superior performance of the lpv/r-containing haart arm.12,13 following a scheduled dsmb review of impaact 1060 on 20 april 2009, enrolment to cohort 1 also closed prematurely owing to a trend towards consistency with the a5208 results. at 24 weeks, virological failure (<400 copies/ml) was observed in 40% of the 60 infants <12 months v. 23% >12 months receiving nvp and lpv/r, respectively. among the older children, 29% out of 22 and 17% of 19 receiving nvp and lpv/r experienced failure. several guidelines already recommend using lpv/rbased treatment for single-dose nvp-exposed infants. the neverest study investigated whether nvp-exposed children, initially suppressed on lpv/r-based haart, can safely switch to a nvp-based regimen.14,15 in this study children aged 6 weeks 2 years and eligible for treatment (n=323) were initiated on lpv/r plus 3tc and d4t. children achieving a viral load <400 copies/ml and stable for >3 months were randomised (n=195) to either remain on lpv/r (control, n=99) or switch to nvp (switch, n=96), and then followed up to 52 weeks. when the investigators looked at viral load <50 copies/ ml to 52 weeks they found that 42.4% of children in the control group and 56.2% in the switch group sustained viral suppression (p=0.01). however, allowing for one elevated result (blip) the two groups were similar, 72.8% v. 73.4% in the control and switch groups, respectively. they suggested that poorer adherence in the control group, due to the unpleasantness in taste of lpv/r syrup, may have led to more blipping and, in turn, unsustained viral suppression to 50 copies/ml during follow-up. in contrast, when they looked at sustained suppression to <1 000 copies/ml, 98% v. 80% of children in the control and switch groups achieved this (p=0.001). the investigators suggest that this study provides proof of concept that re-use of nvp is possible under some circumstances for hiv-infected children exposed to nvp prophylaxis and should be further investigated. they note that the clinical significance of low-level viraemia in the control group needs further study. this group also showed data from an evaluation of lipid profiles in children in the control and switch groups.16 they found no difference between the two groups at randomisation. but at 9 months after the change in regimen non-fasting total cholesterol (tc) and highdensity lipoprotein (hdl) were significantly higher among the switch group (mean tc 4.13, hdl 1.36 mmol/l) compared with the control group (mean tc 3.73, hdl 1.07 mmol/l). significantly lower triglyceride (tg) levels were found in the switch group (mean tg 1.36 mmol/l) compared with the control group (mean tg 1.53 mmol/l). they noted that the clinical significance of these non-fasting lipid changes requires further investigation. switching may provide a promising option for children originally initiated on pi-based haart to preserve second-line options. at this stage, switching requires close virological monitoring after the switch in order to be done safely. 11 hiv-exposed p-value deferred art early art uninfected hiv-unexposed early v. deferred no. assessed 26 66 28 34 median age in months (range) 11.0 (10.1 14.4) 11.0 (10.0 15.5) 11.4 (10.1 15.5) 11.5 (9.9 13.6) mean locomotor quotient ± 1 sd 88.9±16.3 97.6±12.5 105.3±14.3 101.6±3.7 0.01 mean general quotient ± 1 sd 100.1±13.8 106.3±10.6 106.0±10.1 106.9±11.7 0.02 table i. mean quotients of infants for deferred v. early haart and hiv-exposed uninfected and unexposed infants treating children exposed to single-dose nevirapine for pmtct 94 the southern african journal of hiv medicine                                                    december  2009 another neverest trial of efavirenz (efv) v. lpv/r is planned in nvp-exposed children >3 years old. these studies all underscore the limited treatment options available for children, particularly in resourcelimited settings. paediatric fixed-dose combination (fdc) tablets provide simpler alternatives to liquids for children. cipla have produced scored, dispersible tablets of d4t/ 3tc/nvp (baby and junior triomune) with the correct dose ratios for children. a sub-study of the chapas trial (children with hiv in africa pharmacokinetics and adherence of simple antiretroviral regimens), in zambia, evaluated the need for dose escalation of nvp.17 this strategy is currently recommended but requires dosing with separate tablets, making initial treatment more complex. children were randomised to start antiretroviral therapy with full-dose nevirapine (triomune a.m./p.m.) v. dose escalation, using an initial 14 days of half-dose nvp (triomune a.m.; lamivir-s (combined d4t/3tc) p.m.) followed by full dose. children were dosed in accordance with who weight band tables. the primary endpoint was clinical/laboratory grade 3/4 adverse events (aes) related to nvp. in this comparison, 211 children aged 2 9 years with a median cd4 percentage of 13% were followed for a median of 92 weeks. severe stunting, wasting and immunosuppression were common in the children. seventeen children were lost to follow-up. the investigators reported 31 (18 per 100 person-years) v. 29 (16.5 per 100 person-years) grade 3/4 aes definitely/probably or uncertainly nvp-related in children receiving full-dose v. dose-escalation (incidence rate ratio (irr) 1.09 (95% ci 0.63 1.87), p=0.74). twelve (11%) full-dose v. 2 (2%) dose escalation children had grade 2 disseminated skin rash and 1 receiving full dose had grade 1 rash. two children (one from each arm) substituted with efv; 3 continued full-dose nvp; 9 (8 full dose and 1 dose escalation) stopped nvp and restarted with successful dose escalation; and 1 full dose stopped, started a lower nvp dose, had another rash and substituted efv. overall 90% of children who started with full-dose nvp continued uninterrupted in this study. as dose escalation requires provision of separate drug formulations, the evaluation of policy implications for dose escalation of nvp in fixed-dose combination haart is ongoing. the chapas trial also investigated the pharmacokinetics of nvp in children treated with triomune baby/junior and rifampicin-based tb treatment.18 efv-based regimens are currently recommended for concomitant use with rifampicin, but efv is not currently indicated for children below 3 years of age. earlier chapas data suggest that the higher dose ratio of nvp to nrti in triomune baby/junior may compensate for the dose reduction induced by rifampicin. pharmacokinetic sampling was performed in 22 children after 4 weeks of concurrent nvp and rifampicincontaining regimens. rifampicin was dosed at 10 20 mg/kg per day. samples were pre-dose (c0) and 1, 2 and 6 hours post-dose, and nvp plasma concentrations were determined using lc-ms/ms. nvp pharmacokinetics in children without tb treatment (n=16) were compared in multivariate linear regression analysis. the median age of the 21 children analysed was 1.55 (range 0.66 3.18) years, and 10 were girls. the investigators found that only 11 (52%) of the children receiving tb treatment reached sufficient nvp trough levels (c0 <3.0 mg/l). multivariate analysis revealed a 41% (95% ci 24 55%) reduction in nvp auc with concomitant rifampicin. they noted a 3.4% increase in auc for each 10 mg/m2 increase in nvp dose/m2. they recommend caution with this approach in young children until more efficacy and safety data are available. they suggest that an increased nvp dose is likely to be necessary and requires further evaluation. simplification of haart regimens provides benefit for children, caregivers and health workers. to date there are no data on once-daily use of 3tc and abacavir (abc) in resource-limited settings. a substudy from the arrow trial (a randomised trial of monitoring and first-line induction-maintenance strategies) compared the pk of oncev. twice-daily 3tc and abacavir (abc) (kivexa).19 this was a cross-over study performed in 41 ugandan children aged 3 12 years receiving haart, dosed according to weight bands. the arrow trial uses scored tablets of abc/3tc to ensure better accuracy of division and more flexible dosing. total daily doses were 150+300 mg, 225+450 mg and 300+600 mg for children weighing 12 20 kg, 20 25 kg and >25 kg, respectively. using a nevirapine-containing fixed-dose combination in the chapas trial once-a-day lamivudine and abacavir, and abacavir hypersensitivity in the arrow trial 95 december  2009                                                      the southern african journal of hiv medicine                                                   pk sampling was performed for twice-daily dosing at steady state (36 weeks) pre-dose, and 1, 2, 4, 6, 8 and 12 hours post dose. children were then switched to the once-daily dose and further sampling was performed at 4 weeks with an additional sampling at 24 hours. daily area under the curve (auc0-24) and peak level (cmax) were compared by geometric mean ratios (gmr). gmr with 90% ci within 0.80 1.25 was considered to be bioequivalent. pk parameters were available for 35 and 36 children for 3tc and abc, respectively. approximately half were in the younger age group. the investigators reported that in children 3 12 years, auc0-24 of both 3tc and abc were bioequivalent with once and twice-daily regimens but cmax was 76% and 64% higher for 3tc and abc respectively. no grade 3/4 adverse events were reported and no child discontinued after the switch to once-daily dosing. in this analysis, in contrast to data from european children in penta 13, 3tc auc levels in 3 6and 7 12-year-old children were similar for both once and twice-daily dosing and similar to levels in older children. the investigators noted that many younger children in penta 13, whose 3tc levels were lower, received syrups, but arrow children received tablets. they concluded that these results suggest that oncedaily dosing of 3tc and abc is feasible in resourcelimited settings. the arrow investigators also showed data describing successful management of hypersensitivity reactions among children in this trial in uganda and zimbabwe.20 the who recommends abc for paediatric first-line treatment. hypersensitivity reactions (hsr) occur in 2 5% of people receiving abc in clinical trials and are strongly associated with the presence of the hlab*5701 allele. prospective screening for hla-b*5701 is sometimes recommended, but this pharmacogenetic test is rarely available in resource-limited settings. clinical diagnosis and management may be complicated in this setting due to widespread use of nvp and co-trimoxazole and febrile infections. health workers and caregivers were trained in recognition and management of abc-hsr and all suspected hsr underwent independent clinical review. abc was only discontinued in 7 cases. the investigators reported that suspected abc-hsr was rare (3/1 207, 0.2% (95% ci, 0.05 0.7%)) in this trial, consistent with reports of a lower prevalence of hla-b*5701 in black populations. clinical symptoms (fever, rash) occurred 9 13 days after initiation of haart; 2/3 cases had additional gastro-intestinal and respiratory symptoms and required hospitalisation. abc-hsr was successfully managed despite co-administration of co-trimoxazole and nvp, and the investigators recommend that abc can be used safely in resource-limited settings. all references from 5th ias conference on hiv pathogenesis, treatment and prevention, 19 22 july 2009, cape town, unless otherwise stated. references 1. penazzato m, crowley s. what is available for early infant diagnosis?: results from who survey 2008. abstract wepeb269. 2. penazzato m, crowley s. early infant diagnosis in resource limited settings: determining the optimum timing in a breastfeeding population. abstract wepeb270. 3. sherman g, technau k, kalk e, et al. earlier diagnosis of hiv infection in infants in low resource settings. abstract wepeb267. 4. gampini se, kania d, valea d, et al. early diagnosis of paediatric hiv-1 infection among west-african breast-fed children using dried blood spots and a quantitative hiv-1 rna assay. abstract wepeb264. 5. ngin s, kruy ls, kong c, et al. very early diagnosis of hiv infection in newborn at day 0-3 on dbs in cambodia. abstract mopeb009. 6. sundaram m, lukele b. identification patient loss points from testing to treatment initiation among infants tested in swaziland. abstract mopdd103. 7. carter rj, katyal m, p. toro p, et al. immunologic response and survival of infants initiating antiretroviral treatment (art) at less than one year of age compared to older children enrolled at mtct-plus initiative sites in 8 african countries and thailand. abstract mopeb048. 8. rabie h, edson c, paling a, et al. 24 week outcome of infants started on lopinavir/ ritonavir based haart in a resource limited setting. abstract mopeb076. 9. laughton b, grove d, kidd m, et al. early antiretroviral therapy is associated with improved neurodevelopmental outcome in hiv infected infants: evidence from the cher (children with hiv early antiretroviral therapy) trial. abstract mopeb080. 10. violari a, palumbo p, lindsey j, et al. nevirapine vs. lopinavir-ritonavirbased antiretroviral therapy (art) in single dose nevirapine (sdnvp)-exposed hiv infected infants: preliminary results from the impaact p1060 trial. hiv pediatrics, 17 18 july 2009, cape town. abstract o_08. 11. palumbo p, violari a, lindsey j, et al. nevirapine (nvp) vs. lopinavir-ritonavir (lpv/ r)based antiretroviral therapy (art) in single dose nevirapine (sdnvp)-exposed hiv-infected infants: preliminary results from the impaact p1060 trial. abstract lbpeb12. 12. http:/www.i-base.info/htb/v9/htb9-11-12/octane.html 13. http://www.i-base.info/htb/v10/htb10-3-4/lopinavir.html 14. coovadia a, abrams e, stehlau r, et al.. randomized clinical trial of switching to nvp-based therapy for infected children exposed to nevirapine prophylaxis. hiv pediatrics, 17 18 july 2009, cape town. abstract o_09. 15. coovadia a, abrams e, stehlau r, et al. randomized clinical trial of switching to nevirapine-based therapy for infected children exposed to nevirapine prophylaxis. abstract moab103. 16. strehlau r, coovadia a, martens l, et al. changes in lipid profiles after switching young children from a suppressive lopinavir/ritonavir-based regimen to a nevirapine-based regimen. abstract tupeb166. 17. kabamba d, mulenga v, chijoka c, et al. strategies for nevirapine initiation in hiv-infected children taking paediatric fixed-dose combination ‘baby pills’ in zambia: a randomised controlled trial. abstract mopeb090. 18. oudijk jm, mcilleron h, mulenga v, et al. pharmacokinetics of nevirapine in young children during combined art and rifampicin-containing antituberculosis treatment. abstract lbpeb10. 19. musiime v, ferrier a, bakeera-kitaka s, et al. pharmacokinetics of once versus twice daily lamivudine and abacavir in hiv-1 infected ugandan children in the arrow trial. abstract wepeb271. 20. nahirya-ntege p, naidoo b, nathoo kj, et al. successful management of suspected abacavir hypersensitivity reactions among african children in the arrow (antiretroviral research for watoto) trial. abstract tupeb183. websites http://www.ias2009.org 1st international workshop on hiv pediatrics, 17 18 july 2009, cape town http://www.hivpresentation.com hiv i-base http://www.i-base.info 96 c p d q u e s t i o n s journal 40 two cpd points are awarded for the correct completion and submission of the questions below. cpd questionnaires must be completed online via www.cpdjournals.org.za. after submission you can check the answers and print your certificate. questions may be answered up to 6 months after publication of each issue. this programme is available free of charge to members of the hiv clinicians society and sama only. concerning inh preventive therapy (ipt) in children: true (a) or false (b):1. tuberculosis (tb) must be excluded before commencing ipt in hiv-positive children. true (a) or false (b):2. hiv-infected infants have a twofold greater incidence of tb than their hiv-uninfected counterparts. true (a) or false (b):3. failure to thrive is a strong consideration in deciding whether an infant is possibly infected with tb. true (a) or false (b):4. infant exposure to a tb case requires 3 months of ipt. true (a) or false (b):5. ipt should only be given to children >5 years after a tb exposure. true (a) or false (b):6. children of mothers who did not receive screening for tb during antenatal care may require ipt. true (a) or false (b):7. ipt may be given to children already on art, especially if they are mantoux positive and have no tb symptoms. true (a) or false (b):8. in a child, a mantoux induration of >2 mm is considered positive in the absence of art. true (a) or false (b):9. in the absence of tb disease, ipt must always be commenced before art. concerning safer conception in hiv infected couples: true (a) or false (b):10. pre-exposure prophylaxis involves giving antiretroviral therapy to hiv-uninfected individuals to reduce the risk of hiv acquisition. true (a) or false (b):11. hiv transmission is independent of hiv viral load in the blood. true (a) or false (b):12. in discordant couples considering conception, it is important to know the hiv status of both individuals. true (a) or false (b):13. in the case of an hiv-infected male partner, sperm can be washed to reduce the hiv viral load before insemination into a negative partner. true (a) or false (b):14. in the case of a positive female partner, vaginal insemination can reduce the risk of hiv transmission to a negative male partner. true (a) or false (b):15. vaginal insemination is a technical procedure that requires a sterile environment and specialist input. true (a) or false (b):16. in discordant couples, ensuring that the positive partner is well established on art with an undetectable viral load is an effective way to reduce hiv transmission. true (a) or false (b):17. art is only safe in the third trimester of pregnancy. true (a) or false (b):18. efavirenz should be avoided throughout pregnancy. concerning human papillomavirus (hpv): true (a) or false (b):19. infection with hpv may result in cancerous transformation in the cervical mucosa. true (a) or false (b):20. all strains of hpv are oncogenic. cpd insert.indd 1 5/24/11 4:06:56 pm j u ly 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e there are an estimated 6 million south africans living with hiv today. the hiv and aids and sti strategic plan for south africa, ambitious though it is, provides an excellent framework to implement nationally to begin to make a dent in the epidemic by 2011. but plans without implementation and scale are of little value. the 4th south african hiv conference held at the international convention centre, durban, on 31 march 3 april 2009 attempted to address some of the operational gaps and prioritise our efforts to get the ‘best bang for our bucks’ before 2011. with the theme ‘scaling up for success’, overwhelming attendance, participation and feedback indicated that many of the goals set by the scientific and organising committee were met. perhaps most significant to many of us was the tangible and positive spirit of determination and cooperation between researchers, practitioners, activists, civil society and government at the conference, which bodes well for the busy time ahead. a large portion of the scientific programme was abstract driven (almost 2 000 abstracts were received) with 6 tracks, listed below with chairs and co-chairs. each track had 4 oral sessions covering a series of themes derived from the abstract submissions. perhaps one of the best innovations this year was the addition of the community engagement programme that ran as a theme throughout the whole conference, culminating in a full post-conference workshop on 3 april at the same venue. this year, two south africans and an african representative chaired each track. we warmly thank them for taking the time to engage and appreciate the contribution they have already made. track 1: basic sciences chairs: thumbi n’dungu, jo-ann passmore, rosemary musonda rapporteur: victoria kasprowicz and team track 2: clinical sciences chairs: doug wilson, vivian black, moses sinkala rapporteur: claire von mollendorf and team track 3: epidemiology, prevention and public health systems chairs: virginia zweigenthal, guy de bruyn rapporteur: lilian dudley and team track 4: social and economic sciences, human rights and ethics chairs: catherine slack, vasu reddy, michaela clayton rapporteur: catherine slack and team track 5: best practices and programs chairs: astrid dearham, nigel rollins rapporteur: astrid dearham and team track 6: community exchange encounters chairs: victor lakay, peter mathebula, pauline sambo rapporteur: victor lakay and team two major themes were highlighted from the studies in this track. firstly, renewed emphasis was placed on the identification of correlates of hiv control and protection. secondly, the research community has begun to focus research efforts on two special subsets of infected individuals: elite controllers and individuals in the acute phase of infection. elite controllers bruce walker (ragon institute of mgh, mit and harvard) presented a talk in the plenary session entitled ‘elite control of hiv: implications for treatment and vaccines’. dr walker suggested that elite controllers might be able to act as a successful model for t-cell vaccination. he reported that the cd8 t-cell response is responsible for inducing the less fit virus found in elite controllers. walker emphasised that it is the interplay between adaptive immunity (cytotoxic t lymphocyte neutralisation), host genetics (hla) and viral genetics (fitness) that is responsible for determining infection outcome. data were presented showing that ctls are shaping hiv evolution, and that strongly targeted epitopes are being lost at the population level. more information on his efforts and those of his fellow researchers can be found at www.elitecontrollers.org. ‘scaling up for success’: the 4th southern african aids conference 31 march 3 april 2009, durban c o n f e r e n c e r e p o r t track rapporteurs and members of the scientific committee track 1: basic sciences 30 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u ly 2 0 0 9 early infection andile nofemela (uct) presented an excellent talk entitled ‘characterisation of transmitted hiv-1 env variants from mbeya, tanzania’) in which he highlighted the observation that 73% of new infections are caused by infection of a single virus. this ‘bottle-neck’ effect supports the findings of others that also show that the viral populations in the majority of newly infected individuals are largely homogenous. gama bandawe (uct) reported that shorter and less glycosylated v1 loops were associated with enhanced entry efficiency of certain isolates. many groups reported on work carried out investigating the immune response in the acute phase and reported on a common theme that early immunological events are complex, and that some may predict viral set-point and disease progression. for example, wendy burgers (uct) showed data indicating that hivspecific immune activation occurs early and predicts poor disease outcome. pholo maenetje (nicd) shared data that showed that hiv-specific t cells may be more prone to viral infection. clive gray (nicd) presented data showing that hiv-1-specific t-cell immune responses at 3 months do not predict viral load set point and that the early immune responses are characterised by waves of ‘waxing and waning’ whereby responses frequently appear and then disappear. the reasons for this remain unclear. various other talks focused on the quality and quantity of t-cell immune responses in adult and paediatric hiv-1 infection. interestingly, koleka mlisana (ukzn) reported that 33% of individuals in the caprisa acute infection cohort progressed to cd4 counts <350 within 3 years of infection, 40% of whom were started on antiretroviral therapy (art). moving away from characterising immune responses in the periphery, lindi roberts (uct) presented some interesting data looking at the genital tract. essentially, inflammatory cytokine responses, e.g. il-6 and tnf-alpha, were found to be associated with hiv disease progression. it is important to remember that a number of factors may play a role in the control of hiv, including cd4 t-cell immunity, cd8 t-cell immunity, innate immunity, neutralising antibodies, viral genetics and host genetics. antibodies and innate immunity even though lynn morris (nicd) presented a great talk on ‘limited neutralising antibody specificities drive neutralisation escape in early hiv-1 subtype c infection’, which demonstrated that the immune system can make antibodies that have an effect on viral load, and dr william carr presented a talk on the role of nk cells, there was a paucity of presentations and scientific discussion on role of antibodies and the innate arm of the immune response. in summary the key points from this track of the conference are: elite controllers may hold the key to understanding hiv immune control; in acute infection immune system damage occurs early and predicts the course of disease; further research on the role of antibodies and innate immunity in immune control is required. antiretroviral treatment a number of presentations looked at successes of art programmes, including alison riddick’s study from rural hlabisa. this study showed a reduction in adult medical admissions from 2002 to 2007 following the introduction of art, with no deaths recorded secondary to art toxicity. the international epidemiologic databases to evaluate aids (iedea) cohort, which included 6 078 children from seven hospitals in johannesburg, cape town and durban, showed good survival and clinical, immunological and virological outcomes among children initiated on art. of concern was inequity of access, with 20% of south african children being treated at these seven urban sites. reassuring data from khayelitsha showed that women who switched from efavirenz to nevirapine at a cd4 cell count >250 cells/µl did not have more adverse events than those who initiated nevirapine at a cd4 cell count <250 cells/µl. however, the numbers in the high cd4 cell count group were too small to show statistical significance. systems a study done in kwazulu-natal and limpopo evaluating the integrated management of childhood illness (imci) showed that while hiv is common in children presenting at primary care facilities and the hiv algorithm performs well in identifying hiv-infected children, imci-trained health care workers do not routinely use the algorithm and do not test for hiv regularly among sick children. a presentation from the africa centre suggests that hiv-exposed infants are less likely to be vaccinated than hiv-unexposed infants. it was suggested that maternal hiv is responsible for this. a number of presenters showed the devastating effects of hiv, particularly for younger infants (<6 months of age), through retardation of early growth, increased susceptibility to infections and a higher case fatality rate. it is vital to reduce vertical transmission and identify and treat hiv-infected infants early for opportunistic infectrack 2: clinical sciences 31 j u ly 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e tions and with art. data from chris hani baragwanath hospital highlighted shortcomings in the prevention of mother-to-child transmission (pmtct) programme, with 15.1% of women with positive infants reporting that they tested hiv negative in pregnancy (probably due to late seroconversion or confusion secondary to the complex coding system) and only 36% of mother-infant pairs receiving single-dose nevirapine. tuberculosis a file review from the hlabisa district showed that mortality in patients on art doubled in the presence of prevalent or incident tuberculosis. this mortality rate is higher than that reported in other studies but may reflect the extent of hiv advancement and also time in the programme, since higher mortality in the first 100 days is well described in art programmes. after improvement of infection control, including basic administrative, environmental and personnel measures, in tugela ferry, admissions of patients with extensively drug-resistant (xdr) and multi-drug resistant (mdr) tuberculosis decreased significantly (p=0.02) from 2006 to 2008. community infection control remained an unaddressed challenge. a case series of four children from tugela ferry showed that a diagnosis of xdr tb took many months. the average duration of treatment was 18 months and all children were successfully treated. opportunistic infections preliminary data from ngwelezane hospital showed no differences in wound infections between hiv-positive and negative patients who had open fractures treated with internal or external fixation. potential modifiers were albumin (lower in hiv-positive group) and age (younger in hiv-positive group). a study from the africa centre reporting on hiv and hbv co-infection in kzn showed rates as high as 10%. of concern was that less than 50% of patients started on nevirapine had follow-up alanine transaminase monitoring. a review of 23 years of records from hospitals in kzn showed a dramatic increase in incidence of kaposi’s sarcoma (20 times in males) and an age shift towards a younger population. new developments lesley scott presented a paper on the use of dried blood spots compared with plasma for viral load analysis. results were equivalent, suggesting that dried blood spots be utilised to monitor response to art among patients. with a proposed shift towards decentralising art services, this is an important finding. in summary antiretroviral therapy continues to have a significant impact on morbidity and mortality in both the adult and paediatric hiv epidemic in south africa – there are operational issues around scale up which need ongoing monitoring and evaluation. the tb epidemic continues unabated and exerts a major impact on art scale-up and now added surveillance and inflectional control to limit multidrug resistance. new point-of-care diagnostics for diagnosis and monitoring remain areas requiring ongoing research. measurement several papers discussed the need for rigorous methods for measuring incidence. these include laboratory assays to estimate incidence (mcwalter), assays from cohort studies (hargrove), and modelling incidence from antenatal survey data (dorrington). johnson presented a mathematical model measuring the effects of different types of sexual risk behaviour on the spread of hiv. he demonstrated that the highest transmission rates were in multiple concurrent heterosexual partnerships (mcps). he estimated that reducing unprotected sex in non-spousal relationships could reduce the hiv incidence in south africa by a third over the next 10 years. epidemic drivers a regional study by soul city confirmed that mcps are common practice, and hiv risk and mcp messages from communication strategies are not internalised. zembe found that transactional sex among young south african women is seen as normative behaviour, and is associated with alcohol use and intimate partner violence (ipv). high levels of ipv were associated with males older than 35 years, multiple sexual partners, high alcohol intake, and failure to use condoms (townsend). prevention interventions the session focused on male circumcision in different settings, including orange farm (taljaard), kenya (loolpapit) and the eastern cape (peltzer). male circumcision is feasible and acceptable in these settings, and had a high uptake. the importance of linking medical intervention with the cultural context of initiation practices was emphasised. in south africa, service is doctor dependent, although the orange farm team approach reduced dependence on doctors. in kenya other categories of trained health workers performed the surgery. scaling up in south africa may require such alternative models of delivery. track 3: epidemiology, prevention and public health 32 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u ly 2 0 0 9 no studies described interventions to reduce mcps, transactional sex and ipv, which highlights a major gap in prevention research, and a need for closer collaboration between social and medical scientists. pmtct the session described the operational effectiveness of a dual-therapy pmtct regimen, and long-term art as an intervention for pmtct. studies demonstrated improved outcomes in cohorts of pregnant women on long-term art, with reductions of mtct to 2.7% at frere hospital (bera) and 5.1% in a community-based clinic cohort (fitzgerald). good-quality local trials of the effectiveness and timing of art in pregnancy to prevent mtct will provide additional evidence. although few studies were presented on postnatal transmission, important data on the low rate of adherence of hiv-positive women to early breastfeeding cessation (24 weeks) were presented. cessation of breastfeeding after 24 weeks may be more feasible, and further research is needed into prophylactic regimens to protect infants from infection during the breastfeeding period (goga). health systems and programme evaluation a review of 3 years of art at multiple ngo sites identified factors associated with increased mortality, poor adherence and loss to follow-up. the first 6 months of treatment had the highest loss to follow-up, and adolescents initiating haart were identified as needing additional support (fatti). good patient adherence to art was associated with reduced health care costs and investment in interventions to improve adherence and monitoring of adherence is recommended (nachega). the international epidemiologic database to evaluate aids (iedea), a large cohort study collecting individual patient data in the region, identified a trend for men and children to access treatment late. sentinel surveillance of patient-based data could provide important clinical information in the monitoring of the national arv programme (cornell). integration of services, including hiv services, with family planning, sexually transmitted infection (sti) clinics, cervical screening, and tb services, was found to be acceptable to clients and providers, and resulted in increase in uptake of hiv testing and other services (menziwa, chabikulu, leon, bomela). contributors: catherine slack, ann strode, nicola barsdorf, jenny koen, zaynab essack, michaela clayton and vasu reddy track 4 examined how social-behavioural, economic and legal/human rights factors shape both our epidemic and responses to it. in the track there were a number of key interventions that were continually raised due to the social-cultural and human rights implications. there were also a number of vulnerable and marginalised groups that were focused on. key interventions hiv testing. three sessions focused on testing, where it was noted that uptake of testing is still low and resources are limited. in the main, there was greater acceptance that more than one model is needed. client-initiated testing needs to be re-tooled and taken to people in innovative ways. it needs to be compressed in a way that does not short-change on consent or confidentiality. the merits of self-testing were noted provided there was adequate support through, for example, telephone counsellors. it was also observed that the health system may not be ready to manage a routine offer of testing and will have to be strengthened to do so. male circumcision (mc). two sessions focused on mc. it was noted that this priority for scale-up will require attention to consent, counselling and confidentiality (the 3 cs); that monitoring behavioural disinhibition and the ability of men to abstain until the wound heals is a key part of roll-out; and that providing this service to adolescents will require understanding of the legal framework and parental involvement in many instances. partner reduction. the need to reduce mcps came up repeatedly in satellites, plenarys and oral sessions. key issues included the need to proceed to implement and monitor mcp programmes in the absence of perfect tools; the need to acknowledge that culture is a highly contested construct and that cultural practices can be challenged; that mcp programmes will compete with messages from the commercial media; and that involving celebrities in de-norming mcp will be important. key groups children. a special session on children demonstrated innovative research into the lives of children in the sadc region. it was noted that the full range of children made vulnerable by hiv must be recognised; that a significant number of children remain invisible because they are not registered at birth and remain marginalised from education and support systems; that children living on the streets need far more tailored services and protection; and that children are best assisted by strengthening their families, and a key way to do this is through social protection policies. track 4: social and economic sciences, human rights and ethics 33 j u ly 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e migrant populations. a dedicated oral session and satellite highlighted the needs and rights of migrant populations. their relative poverty, lack of services, separation from regular partners and stigma increase both hiv risk and impact for this group. the need for better information and services was underscored. in terms of treatment access, it was noted that in the main it is not the legal and policy environment that may be problematic for migrants, but implementation of these rights that is lacking. people living with hiv (plwhiv). it was noted that far better integration of hiv and sexual/reproductive services is needed for plwhiv and that policies and programmes need a far better focus on discordant couples. food price rises are directly affecting hiv prevention as people move in search of food and work, and this situation is affecting aids care, because people on treatment cannot get the nutrition they need in many instances. it was noted that welfare grants are a critical safety net. men who have sex with men a dedicated satellite looked at the needs and rights of men who have sex with men (msm). it was noted that stigma and in some cases criminalisation of samesex relationships drive msm from services, and better surveillance is needed, as well as programmes for this group. in terms of prison populations, a dedicated satellite session focused on their increased risk. it was argued that hiv care, management and prevention in prisons must be better integrated into policy instruments, and funding is needed for service delivery to this vulnerable group. in terms of sex workers, one presentation highlighted how criminalisation of sex work limits their uptake of services, and argued that such work should be decriminalised and a customised package rolled out. several sessions addressed the needs and rights of research participants in large-scale hiv trials, and the communities from which they are drawn. because the current array of methods (such as abstinence, fidelity, condoms and circumcision) may not address the particular needs of young women and older women in stable relationships, new tools such as microbicides are needed. research literacy was advanced as a tool to offset power imbalances between investigators and participants and involve communities more authentically in research. it was stressed that these efforts must avoid tokenism and that sound partnerships with communities can buffer disappointing trial results – which are an inevitable part of product development. a special session was devoted to sadc countries’ implementation of key human rights norms. it was noted that major gains have been made – for example, all 14 countries have a law or national policy that prohibits unfair discrimination against plwhiv. a key concern was that in 4 out of 14 countries there are specific laws making the intentional transmission of hiv a crime, and in 9 out of 14 countries there are laws criminalising samesex relationships, heightening stigma and undermining services. it was noted that such laws contribute to the structural conditions that fuel hiv. other contributors: ann strode, nicola barsdorf, jenny koen, zaynab essack the following themes emanated from this track, which covered evidence-based policy and practice, and models of prevention, treatment, care and support activities in communities, the workplace and the media. education, the youth and hiv grierson et al. found that peer networks are not consistent across the population but cluster according to key socio-demographic characteristics. more targeted interventions that recognise gender differences and the role of partner violence are needed in peer education programmes (rogan et al.). in an evaluation of adolescent programmes, nkala et al. found that although adolescents are aware of the risks of hiv transmission, they were not personalising it and the repeated pregnancy testing at the clinic was indicative of unprotected sex. once the adolescents tested hiv positive, they were lost to follow-up. there is a substantial gap in tracing adolescents who become infected but have never tested (chagan et al.). in high-risk hospital catchment areas, testing strategies for children needed to be conducted in both health facility (outpatient department, ward) and mobile community settings (chabikuli et al.). reporting on the establishment of a male clinic, mgwele et al. found this to be the first port of entry for men into the public health system. critical success factors included the location, operating hours, staff and the services that were offered. in terms of intergenerational sex, pretorius et al. found that a variation in age difference results in persistence of the hiv epidemic. the establishment of more gay-friendly services was also advocated in the ‘men and hiv’ theme. decentralisation and nurse-based services there was support for the down-referral of patients to primary care level as well as integrated health care. however, standardised guidelines were still considered to be lacking (mabaso et al., carolus et al., vintges et al.). track 5: best practices and programmes 34 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u ly 2 0 0 9 the issues of nurse prescription and pharmacy support were still a concern. the re-defining of roles of health care workers was one way of addressing the increasing workload and waiting lists (draper). the generally poor or non-existent state of health services in prisons was highlighted (united nations). the transient nature of the offender population may be fuelling hiv and tb in the community, as the prevalence of hiv in prisons is estimated to be 6 50 times greater than that of the general adult population. prison systems are rarely included in country plans, and there is a need to be proactive and take responsibility for putting hiv response plans in prisons into the national aids response. best practices and health systems innovative strategies reported were the use of cell phones for mass messaging (benjamin) and targeting the youth with online, interactive mtv-like programmes using celebrities as role models with hiv messages about prevention and testing (pahl et al.). men were the focus of the ‘one man can’ and ‘you can count on me’ initiatives to facilitate and encourage awareness about hiv/aids (colvin et al., becker et al.). the need for dedicated health care worker programmes that offer psychosocial support, encourage hiv testing and tb screening and provide hiv treatment and support if a worker tests positive was raised (vazi et al.). mobile clinics aimed at the asymptomatic, males, defaulters, the elderly and under-serviced areas, and offering not only voluntary counselling and testing but also screening for chronic disease, were promoted (van schaik et al.). overall there was a call for health systems to document best practices (eghtessadi et al.), and the importance of partnerships for sustainable, measurable and quality programmes was highlighted. other contributors: meg osler, maria sibanyoni unprecedented numbers of plwhiv and hiv activist delegates attended the 4th south african aids conference. instead of just covering the community exchange encounters track, rapporteurs for track 6 attended almost every session on the programme, as well as evaluating all six tracks from a community, plwhiv perspective. it was felt that this unprecedented turnout was in keeping with the sentiment that activists must scale up participation in aids conferences to ensure that the experiences and needs of hiv-positive communities remain at the epicentre of tb/hiv research projects and programmes. financing: ‘hiv is not in recession’ in the past months we have seen trillions of dollars spent on so-called financial ‘bailouts’ that are supposed to stimulate economic recovery. a tiny part of this sum could buy quality, sustainable health care for millions of poor people. there is a multi-billion dollar deficit currently facing the global fund and a continued increase in demand with decreasing of resources. drugs are notably most abundant where infections are least prevalent. the current global economic recession has meant a strong backlash due to possible budgeting cutbacks for hiv programmes. the lessons learned from hiv interventions continue to transform organisation and delivery of all health services. hiv treatment must become part of primary health care. the department of health budget allocation for arvs through the current hiv/aids conditional grant to provinces is at least r1 billion short of the amount initially budgeted to treat 220 000 people this year. a great need therefore exists to work collectively to achieve these ambitious targets and ensure that sufficient resources are mobilised and properly managed. in november 2008 the national department of health instituted an arv moratorium in the free state province. there are already similar shortages manifesting in other provinces across south africa, including gauteng, south africa’s richest province. task-shifting médecins sans frontières (msf) and the reproductive health research unit (rhru) presented compelling data showing that task-shifting is essential due to the overburdened state of clinics and the chronic nature of art management. the ways that have been presented for task shifting to be implemented are unfair to community health care workers, nurses and doctors. current laws and regulations that separate the roles of community health care workers, nurses and doctors must change. government must implement policy on task-shifting based on extensive consultation with health care workers, health systems experts and community activists to address the lasting inequalities which continue to see health resources and responsibilities concentrated in hospitals, in urban areas, and in the hands of doctors. arv treatment we need more ‘bang for our bucks’. nachega’s ‘excellent adherence to art predicts lower direct health care costs for hiv-infected adults’ showed that poor art track 6: community exchange encounters 35 j u ly 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e adherence is a major predictor of virological failure, resistance, disease progression and death. there is a need for communities to access arvs that do not cause drug toxicity but that are more expensive. dr francois venter presented an interesting plenary, ‘key drugs for the next five years’, and made the point that toxicity drives arv regimen switches, particularly resulting from d4t. tenofovir is good replacement for d4t but is unaffordable to the majority at current prices. communities must embark on a larger campaign for access to essential medicines, including other exciting new arvs such as etravirine, raltigravir and tipranavir. opportunistic infections: tb a plenary presented by robin wood on hiv/tb control indicated that despite reasonably functioning tb programmes, tb rates are continuing to rise to unprecedented numbers in hiv hyperendemic areas. there is still not enough progress in health systems or scientific developments to combat hiv-associated tb. the treatment action campaign (tac), tb/hiv care and other organisations are mobilising for better, more integrated tb/hiv programmes and improved treatments; but government must join in this struggle beyond mere rhetoric. there is a need for vastly increased resources – biomedical, financial and human – in order to integrate tb and hiv treatment. opportunistic infections: cervical cancer in ‘development in progress: a policy analysis of the national cervical cancer screening policy factoring in hiv/aids’ bomela described strong community support for the integration of cervical cancer programmes into hiv care and highlighted that financial resources are lacking, women are not educated about how and where to access cervical screening services, and nurses are not adequately trained to implement guidelines. this advocacy seeks to mobilise women in communities to increase screening and public access to hpv vaccines. youth hiv awareness programmes in schools are poorly funded. there is a strong need for peer-to-peer programmes in hiv education and a greater emphasis on skills development. a satellite session on ‘progress towards achieving nsp targets for children’ exposed shortcomings of the department of health and department of education. there are no specific policies on teenage pregnancy or circumcision. the department of education has recommitted itself to the abc strategy (abstain, be faithful, condomise), yet condoms are not made available in schools, thus failing learners. communities must mobilise to ensure that condoms and accurate information on their use are readily available to sexually active youth. there may be a mistaken perception that the battle for health care in south africa has been won, but this perception is incorrect. we must improve access to and quality of services where they are needed most if we are to achieve the nsp goals. but … growing financial constraints, the necessity for task-shifting, and rising rates of tb prove that the struggle continues! now is the time for communities to refocus and mobilise around these critical issues! • • conclusion 36 d e c e m b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e hiv infection has a high prevalence in antenatal attendees in south africa. in the annual seroprevalence survey conducted through the national department of health from 2005, the prevalence in the western cape province was 15.7%.1 here, a pilot zidovudine (zdv)based prevention of mother-to-child transmission (pmtct) programme began in 1999,2 and has gradually been expanded since january 2001. since april 2003 the pmtct interventions have been available at all public sector antenatal service facilities in the province (300 antenatal clinics and 53 delivery centres and hospitals) and 350 primary health care clinics where infant follow-up occurs. attendees are offered voluntary, confidential counselling and testing (vct) and if hiv positive, antiretrovirals (arvs) for the mother and infant. uptake was reported as 97% in 2006 (status report – prevention of mother-to-child transmission programme, 14 july 2006, hiv/aids/sti directorate, a window into a public programme for prevention of mother-to-child transmission of hiv: evidence from a prospective clinical trial o r i g i n a l a r t i c l e m cotton1, fcpaed (sa), phd s kim2, scd (biostats) h rabie1, fcpaed (sa) j coetzee1, cpn, pn s nachman3, md for the pactg 1041 team 1centre for infectious diseases, department of paediatrics and child health and kid-cru, tygerberg children’s hospital and faculty of health sciences, stellenbosch university, tygerberg, w cape 2department of biostatistics, harvard school of public health, boston, mass, usa 3division of infectious diseases, state university of new york, ny, usa objectives. to evaluate efficacy of the antenatal, intrapartum and postnatal antiretroviral components of a public service prevention of mother-to-child (pmtct) programme in infants. design. analysis of prospectively collected screening data of demographic and mtct-related interventions and hiv infection status of infants identified through hiv-specific dna polymerase chain reaction. setting. tygerberg children’s hospital, western cape, south africa. subjects. hiv-infected women and their infants identified through participation in a public service pmtct programme were referred for possible participation in a prospective study of isoniazid prophylaxis. interventions. key components of the programme include voluntary counselling and testing, administration of zidovudine to the mother from between 28 and 34 weeks’ gestation and to the newborn infant for the first week, single-dose nevirapine to the mother in labour and to the newborn shortly after birth, and free formula for 6 months. main outcome measures. number and percentage of hiv-infected infants and extent of exposure to antenatal, intrapartum and postnatal antiretrovirals. results. of 656 infants with a median age of 12.6 weeks, screened between 1 april 2005 through may 2006, 39 were hiv-infected, giving a transmission rate of 5.9% (95% confidence interval (ci) 4.4 8.0%). antenatal prophylaxis was significantly associated with reduced transmission (odds ratio (or) 0.43 (95% ci 0.21 0.94)) as opposed to intrapartum and postpartum components (p=0.85 and p=0.84, respectively). in multivariable analysis the antenatal component remained significant (or=0.40 (95% ci 0.19 0.90)). conclusions. the antenatal phase is the most important antiretroviral component of the pmtct programme, allowing most opportunity for intervention. 16 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e d e c e m b e r 2 0 0 9 western cape). follow-up of mother and infant, cotrimoxazole from 6 weeks of age and modified infant feeding practices are also important components. the majority of women (95%) choose formula feeding, which is provided free for the first 6 months. the initial arv intervention was single-dose nevirapine (sd-nvp) to mother and infant, introduced after the success of the hivnet 012 study.3 since mid-2003, zdv was added from 34 weeks’ gestation for the mother and for a week for the neonate.4 in early 2006, antenatal zdv from 28 weeks was gradually introduced. with the advent of the national antiretroviral rollout in 2004, all pregnant women with a cd4 count below 200 cells/µl were offered highly active antiretroviral therapy (haart). pactg 1041 is a prospective phase iii clinical trial evaluating the efficacy of isoniazid (inh) primary prophylaxis in hiv-exposed infected and uninfected infants. through screening for this trial at tygerberg children’s hospital (tch), we had the opportunity to evaluate the pmtct programme in referred infants. hiv-exposed infants between 3 and 4 months of age were referred for study participation from health care facilities in the urban and semi-rural areas close to tch. referring clinics were requested not to refer infants exposed to tb. infants were pre-screened by lay counsellors and nurses for eligibility to enrol in pactg 1041. exclusion criteria included exposure to tuberculosis and not receiving bacille calmette-guérin (bcg) immunisation within the first week of life. eligible subjects were entered onto a screening log, comprising the dataset for the present report. a medical doctor undertook formal screening. note was taken of the extent of participation in the pmtct programme and whether the mother received haart in pregnancy. those receiving either antenatal haart or zdv were categorised as having received antenatal prophylaxis. intrapartum prophylaxis was either zdv or nvp or both. postnatal intervention to the neonate was either zdv or nvp or both. hiv dna polymerase chain reaction (pcr) was performed on all exposed infants eligible for the trial. all samples were tested in duplicate. for discordant results, the test was repeated in duplicate. simple percentages were used to estimate rates of transmission and 95% confidence intervals (cis) were based on the score method. medians and interquartile ranges (iqr) were used to summarise continuous data. logistic regression was used to evaluate the effectiveness of pmtct components. odds ratios (ors) were calculated through the logistic regression model and 95% cis are based on the profile likelihood. for antenatal haart, fisher's exact test was used because of the small cell size. in multivariable logistic regression analysis, we evaluated all two-way and three-way interactions between the three pmtct programme components and found no statistically significant interactions, and therefore present a multivariable model that includes main effects for the three components. all tests are two-sided at the 5% significance level and are not adjusted for multiple comparisons. analyses were done using sas 9.1 (cary, nc, usa). permission to conduct p1041 and to report on antenatal interventions was obtained from the committee for pharmaceutical trials, stellenbosch university, and the medicines control council of south africa. the trial was approved by the national institute of allergy and infectious diseases (niaid) according to the office of human rights protection, national institutes of health guidelines. between 1 april 2005 and 31 may 2006, 773 infants were referred for pre-screening. seven infants were excluded because their mothers were hiv-negative and had been referred in error. one hundred and ten hiv-exposed infants were excluded at pre-screening, of whom 52 (47.3%) had known exposure to tuberculosis.5 other common reasons included the infant being too old for participation in the inh trial (15), bcg given after 7 days of life (15) and family relocating (7). six hundred and fifty-six infants were entered onto the screening log and are reported on here. the median age (iqr) of infants was 12.6 (11.0 13.6) weeks and that of mothers 26 (23 30) years. thirty-nine of 656 infants had a positive hiv dna pcr, giving a transmission rate of 5.9% (95% ci 4.4 8.0%). two hundred and seventy-eight (85.8%) of 324 mothers who were asked decided on exclusive formula feeding. data on transmission and extent of participation in the pmtct programme are shown in table i. we evaluated the antenatal, intrapartum and postnatal components of the programme separately, using logistic regression (table ii). we found that antenatal prophylaxis was significantly associated with a reduction in rate of transmission (or 0.43 (95% ci 0.21 0.94), p=0.035) as opposed to intrapartum and postnatal components (p=0.85 and p=0.84, respectively). the results of fitting a multivariable logistic regression model to the data, which included the three components of the pmtct programme, are shown in table iii. 17 methods results d e c e m b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 18 the antenatal component of the pmtct regimen remained significant in the multivariable model, indicating that it is an independent predictor of decreased transmission (or 0.40 (95% ci 0.19 0.90), p=0.027). of 57 mothers with cd4 cell counts below 200/µl receiving haart, only 1 (1.8% (95% ci 0.3 9.3%)) transmitted hiv to her infant versus 26 of 453 with cd4 counts >200/µl not receiving haart (5.7% (95% ci 3.9 8.3%), p=0.34). fifty-one (7.8%) mother/infant pairs with missing pmtct information were excluded from the above analyses. of these, only 1 woman (2.0% (95% ci 3.5 10.3%)) transmitted hiv to her infant. there is little information on vertical transmission in the absence of intervention in south africa. transmission rates vary between 15% and 34%.6,7 in the zdv-based pilot programme in khayelitsha, western cape, the transmission rate was 11%.2 in a study evaluating sdnvp in different south african settings, the transmission rate in paarl, a recruitment site for p1041, was 8.3% at 3 weeks of age.8 the combination of antenatal zdv from 28 weeks and sd-nvp under optimal circumstances is associated with a transmission rate as low as 1.1%.4 our data confirm a relatively effective pmtct programme despite only 53% actually participating in all components of the programme. importantly, an additional 25% received antenatal arvs. a multi-faceted intervention programme means that there are many opportunities for intervention, as opposed to one relying on only a single intervention such as sd-nvp, which, if missed, severely compromises efficacy. the world health organization has endorsed the programme as practised in the western cape.9 our data confirm the relative importance of antenatal as opposed to perinatal or postnatal intervention. the transmission rate of 5.9% was achieved due to concerted efforts to facilitate success of the programme despite widespread perceived obstacles to initial implementation.10 although we did not record duration of antenatal arvs in each case, 75% of mothers were reported to have received ≥2 weeks of therapy, defined as adequate by the programme (personal communication – pauline pieters, pmtct co-ordinator, 20 september 2006). an important preliminary finding in our study is that among women with cd4 cell counts <200/µl, only 1 of 57 mothers on haart (1.8%) transmitted hiv, as opposed to 26 (5.7%) of 453 mothers receiving zdv. although this was not statistically significant, we expectpmtct component adjusted or (95% ci) p-value* antenatal 0.40 (0.19 0.90) 0.027 intrapartum 1.26 (0.57 2.89) 0.57 postnatal 1.05 (0.46 2.60) 0.91 *likelihood ratio test. table iii. multivariable analysis received component/total (%) infant not infant or programme component hiv infected hiv infected (95% ci) p-value† antenatal pmtct 483/568 (85.0) 27/38 (71.1) 0.43 (0.21 0.94) 0.035 intrapartum pmtct 380/568 (66.9) 26/38 (68.4) 1.07 (0.54 2.25) 0.85 postnatal pmtct 425/568 (74.8) 29/38 (76.3) 1.08 (0.52 2.48) 0.84 antenatal haart* 56/564 (9.9) 1/38 (2.6) 0.25 (0.01 1.52) 0.24 *exact ci and fisher’s exact test p-value provided for antenatal haart due to the small number of infections among those who received antenatal haart. † likelihood ratio test from logistic regression model, except for antenatal haart which is a fisher’s exact test. table ii. univariate analyses discussion infants hiv-infected screened (n (%))* (n (% of screened)) pmtct 656 39 (5.9) full participation 348 (53.0) 21 (6.0) antenatal only 105 (16.0) 4 (3.8) antenatal + postnatal (no intrapartum) 42 (6.4) 1 (2.4) antenatal + intrapartum 15 (2.3) 1 (6.7) postnatal only 39 (5.9) 4 (10.3) intrapartum only 18 (2.7) 1 (5.6) intrapartum + postnatal 25 (3.8) 3 (12.0) none 13 (2.0) 3 (23.1) no data 51 (7.8) 1 (2.0) *percentages do not add to 100.0 due to rounding. antenatal = either zdv or haart; intrapartum and postnatal = sd-nvp, zdv. table i. extent of participation of mothers and their infants in the pmtct programme and hiv transmission rates t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e d e c e m b e r 2 0 0 9 ed more transmission among these mothers because of their low cd4 counts before initiation of haart. there are a number of limitations to our study. we did not record the mothers’ cd4 counts; rather, we assumed that they were appropriately managed according to the pmtct guidelines. also, we only screened infants whose mothers expressed interest in their infants participating in the inh study. nevertheless, our data are similar to those of the department of health, western cape, which reports a transmission rate of 6.2% (personal communication – pauline pieters, pmtct coordinator, 20 september 2006). there were missing pmtct data on 7.8% of screened mother/infant pairs, and the transmission rate was low in this group (2.0%). if we assume that none of these women received any component of pmtct or that these women received all components of pmtct, the conclusions drawn here remain unchanged. the antenatal arv component is extremely important for reduction of mtct and reduces intra-uterine infection, for example, lallemant et al. showed that initiating zdv at 28 weeks was far more effective than at 35 weeks and was not compensated for by extending postnatal zdv for 6 weeks.11 nevertheless, the intrapartum and postnatal components also have an important role. for example, wade et al. showed that in the absence of zdv, perinatal transmission of hiv was 26.6% (95% ci 21.1 32.7%).12 when zdv was begun antenatally, the transmission rate was 6.1% (95% ci 4.1 8.9%). administration of postnatal zdv alone within 48 hours of life had a transmission rate of 9.3% (95% ci 4.1 17.5%), indicating the importance of the postnatal component.12 gray et al. found postnatal sdnvp to be slightly more effective than zdv for 6 weeks when neither antenatal nor intrapartum arvs could be given.13 the public service pmtct programme in the western cape has successfully reduced the vertical transmission of hiv. the antenatal arv component is critical for success. references 1. national department of health. national hiv and syphilis seroprevalence survey south africa 2005. pretoria: national department of health, 2005. 2. abdullah mf, young t, bitalo l, coetzee n, myers je. public health lessons from a pilot programme to reduce mother-to-child transmission of hiv-1 in khayalitsha. s afr med j 2001; 81: 579-583. 3. guay la, musoke p, fleming t, et al. intrapartum and neonatal singledose nevirapine compared with zidovudine for prevention of mother-to-child transmission of hiv-1 in kampala, uganda: hivnet 012 randomised trial. lancet 1999; 354: 795-802. 4. lallemant m, jourdain g, le coeur s, et al. single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of hiv-1 in thailand. n engl j med 2004; 351(3): 217-228. 5. cotton mf, schaaf hs, lottering g, weber hl, coetzee j, nachman s. tuberculosis exposure in hiv-exposed infants in a high-prevalence setting. int j tuberc lung dis 2008; 12(2): 225-227. 6. bobat r, coovadia h, coutsoudis a, moodley d. determinants of mother-to-child transmission of human immunodeficiency virus type 1 infection in a cohort from durban, south africa. pediatr infect dis j 1996; 15(7): 604-610. 7. the petra study team. efficacy of three short-course regimens of zidovudine and lamivudine in preventing early and late transmission of hiv-1 from mother to child in tanzania, south africa, and uganda (petra study): a randomised, doubleblind, placebo-controlled trial. lancet 2002; 359: 1178-1186. 8. good start study team. the good start study: early perinatal transmission, infant feeding and hiv-free survival. paper presented at the 25th conference on priorities in perinatal care, 7 10 march 2006, drakensberg, kwazulu-natal. 9. world health organization. antiretroviral drugs for treating pregnant women and preventing hiv infection in infants in resource-limited settings: towards universal access. recommendations for a public health approach. geneva: who, 2006. 10. delva w, draper b, temmerman m. implementation of single-dose nevirapine for prevention of mtct of hiv – lessons from cape town. s afr med j 2006; 96: 706-709. 11. lallemant m, jourdain g, le coeur s, et al. a trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. perinatal hiv prevention trial (thailand) investigators. n engl j med 2000; 343(14): 982-991. 12. wade na, birkhead gs, warren bl, et al. abbreviated regimens of zidovudine prophylaxis and perinatal transmission of the human immunodeficiency virus. n engl j med 1998; 339(20): 1409-1414. 13. gray ge, urban m, chersich mf, et al. a randomized trial of two postexposure prophylaxis regimens to reduce mother-to-child hiv-1 transmission in infants of untreated mothers. aids 2005; 19(12): 1289-1297. 19 acknowledgements we thank the kid-cru pactg team: g lottering, h s schaaf, h c weber, j karpakis, h l weber, m louw, v ntlokondala, e thompson, c janse van rensburg, p ketelo, g boswell, m tizora, k smith, n dlaku, l hoorn, n mpotololo and l kwane. we also thank najmaar shaikh, senior public health specialist and infectious disease epidemiologist, provincial government of the western cape, for helpful advice. support for this study was provided by the niaid of the us national institutes of health (nih), grant number uo1 a1 41809. the content of this publication does not necessarily reflect the views or policies of niaid, nor does mention of trade names, commercial projects, or organisations imply endorsement by the us government. the authors declare no conflicts of interest. conclusions article information authors: juliane hiesgen1 ebrahim variava2 affiliations: 1department of neurology, kalafong hospital, university of pretoria, south africa 2department of internal medicine, tshepong hospital, university of the witwatersrand, south africa correspondence to: juliane hiesgen email: juliane.hiesgen@up.ac.za postal address: private bag x323, arcadia 0007, south africa dates: received: 27 oct. 2014 accepted: 13 may 2015 published: 26 june 2015 how to cite this article: hiesgen j, variava e. neuroendocrine tumour in a patient with neurofibromatosis type 1 and hiv. s afr j hiv med. 2015;16(1), art. #323, 4 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.323 copyright notice: © 2015. the author(s). licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. neuroendocrine tumour in a patient with neurofibromatosis type 1 and hiv in this case report... open access • abstract • introduction • case presentation • discussion • conclusion • acknowledgements    • competing interests    • authors’ contributions • references abstract top ↑ we report the case of an hiv-positive female patient with neurofibromatosis type 1 who was treated for recurrent peptic ulcer disease and later developed diabetes mellitus and chronic diarrhoea. a metastasising somatostatinoma was histologically proven and evidence of a concomitant gastrin-producing neuroendocrine tumour was found. neuroendocrine tumours (nets) are very rare neoplasms originating from a wide variety of endocrine and nervous system tissue with the ability to produce different hormones. a somatostatinand gastrin-secreting net in a patient with hiv has not been reported in the literature, to the best of our knowledge. we discuss oncogenic pathomechanisms related to the underlying conditions and propose stringent monitoring for tumours in hiv-positive patients with phakomatoses as well as initiation of antiretroviral therapy. introduction top ↑ neuroendocrine tumours (nets) are neoplasms originating from a wide variety of endocrine and nervous system tissues with the ability to produce different hormones. pancreatic hormone-producing nets are often associated with specific clinical manifestations, resulting from the excessive production and action of the respective hormone. we report on a 30-year-old hiv-positive female patient with neurofibromatosis type 1 (nf1) who presented with zollinger-ellison syndrome and later developed diabetes mellitus and chronic diarrhoea. a somatostatinoma was proven histologically and we found laboratory evidence for the concomitant production of gastrin by the tumour. somatostatinomas are very rare tumours, and a somatostatinand gastrin-secreting net in a patient with hiv has not been reported. we discuss oncogenic pathomechanisms related to the underlying conditions and propose stringent monitoring for tumours in hiv-positive patients with phakomatoses. case presentation top ↑ a 30-year-old woman had been seen at the surgical department over the past five years for recurrent upper gastro-intestinal bleeds. peptic ulcer disease was proven gastroscopically on four occasions. she was repeatedly treated with proton-pump inhibitors and on one occasion received empiric triple therapy for helicobacter pylori eradication. her past medical history included visits to the plastic surgery department for removal of a plexiform neurofibroma with enucleation of her right eye. clinically, with numerous neurofibromata, one big plexiform neurofibroma on the right side of her face, several café-au-lait spots and axillary freckling, she fulfilled the criteria for nf1.1 she had tested hiv-positive a few months earlier, with a baseline cd4 count of 290 cells/µl. one week prior to admission, diabetes mellitus was diagnosed by the local primary healthcare clinic and she was started on metformin 850 mg bd. she then presented to the medical department with a four-day history of diarrhoea without melaena or epigastric pain. on admission, she was moderately dehydrated with features of nf1 (figures 1a and 1b). the rest of the clinical examination was normal. a chest x-ray was unremarkable, and blood results were essentially normal except for a thrombocytosis of 614 x 109 cells/l. the patient received intravenous fluids and antibiotics. insulin was commenced and antiretroviral therapy (art) with tdf, 3tc and efv was started. figure 1: clinical features of nf 1, with numerous neurofibromata (a), big plexiform neurofibroma over the right side of the face (b) and (c) ct image showing several hypodense lesions in the liver parenchyma, suggestive of metastases. source: photographs of patient and ct abdomen taken by juliane hiesgen with the patient's consent abdominal ultrasound demonstrated several solid, round lesions in the liver that were confirmed on computed tomography (figure 1c). liver biopsy showed polygonal tumour cells with granular eosinophilic cytoplasm and monomorphic nuclei, coarse dispersed chromatin and focal glandular formations. synaptophysin and chromogranin stains were positive, compatible with a metastatic neuroendocrine carcinoma. special somatostatin staining was positive, proving the somatostatinoma (figure 2a and 2b). the excessively increased fasting gastrin level of 19 577 ng/l (13 ng/l – 115 ng/l) strongly suggested the additional hypersecretion of gastrin by the tumour. figure 2: histological slides from liver lesions: (a) he staining showing polyglandular tumour cells with granular eosinophilic cytoplasm and glandular formation and (b) strongly positive immuno-histochemical synaptophysin stain (specific for neuroendocrine tumours). a malignant, metastatic neuroendocrine tumour secreting somatostatin and gastrin was diagnosed. unfortunately, the patient died soon after diagnosis. discussion top ↑ somatostatinomas are extremely rare neuroendocrine tumours with an estimated annual incidence of 1 in 40 million per year, arising from the delta cells in the pancreas or, in about 40% of cases, from the duodenum.2 gender distribution is equal and mean age at presentation is between 51 and 53 years. occasionally, additional hormones such as glucagon, calcitonin, insulin, gastrin or others are produced. somatostatinomas often metastasise early and present late, resulting in a poorer prognosis.2 whilst non-metastatic somatostatinomas with full tumour resection can be cured, metastatic forms often have a fatal course as they are diagnosed late. appropriate surgery combined with chemotherapy results in an average 5-year survival of about 59.9%.2 the association between nf1 and somatostatinomas is well documented. fendrich et al. reported a case of nf1 and a duodenal somatostatinoma, and found 36 other cases in the literature until 2004, of which only 14 involved metastasis.3 somatostatinomas in nf1 occur with a higher frequency and are located more often in the duodenum than in patients without nf1, in whom pancreatic tumours dominate. nets located in the duodenum tend to present less often with a somatostatinoma syndrome but rather with local or non-specific symptoms.3 most somatostatinomas are symptomatic. the full clinical picture of the somatostatinoma syndrome, characterised as an inhibitory syndrome, was initially reported by krejs et al. in 1979.4 it comprises diabetes mellitus (suppression of insulin), steatorrhoea and cholelithiasis (inhibition of cholecystokinin and biliary motility). additionally, patients often have general symptoms such as nausea and vomiting, abdominal pain and weight loss. duodenal somatostatinomas might present with abdominal pain, duodenal obstruction, gastro-intestinal bleeding or jaundice, owing to local growth of the tumour.2 the differential diagnosis is wide, depending on the patient's presentation. it includes, amongst others, refractory diabetes mellitus and other endocrine conditions, carcinoids and gastro-intestinal malignancies, pancreatitis, inflammatory bowel disease, coeliac disease, irritable bowel syndrome or even depression. nf1, originally described by friedrich von recklinghausen in 1882, is a fairly common hereditary disease that is autosomal-dominantly inherited and occurs in 1:3500 births. it forms part of the neuro-cutaneous syndromes or phakomatoses, a group of genetic conditions predominantly involving tissues of ectodermal origin, mainly the nervous system, skin and eye. nf1 is characterised by the slow evolution of tumour lesions in childhood and adolescence, as well as by a tendency to form hamartomas and a disposition to fatal malignant transformation. the mutated gene, encoding the protein neurofibromin (17q11.2), is a tumour-suppressor gene. involved mechanisms are rat sarcoma viral oncogene homologue (ras)-mitogen activated protein kinase (mapk), mammalian target of rapamycin (mtor) and p21 protein (cdc42/rac)-activated kinase (pak1).5 patients with this disorder are predisposed to both benign and malignant tumours of neurogenic and non-neurogenic origin. nf1 reduces average life expectancy by 10–15 years, with malignant tumours being the most common cause of death. in addition to nf1, our patient was hiv-positive with a low cd4 count. hiv infection is strongly associated with specific malignancies. kaposi's sarcoma (ks), non-hodgkin lymphomas (nhls) and invasive cervical cancer are aids-defining illnesses.6 several non-aids-defining malignancies appear more common amongst hiv-positive patients, and their incidence is increasing; these include invasive anal carcinoma, hodgkin lymphomas, skin cancers, leukaemia, lung cancer, multiple myeloma, prostate cancer and others.7,8,9,10,11 different pathomechanisms, direct and indirect, are involved in the oncogenesis in hiv. opportunistic co-infections with oncogenic viruses can result in hiv-associated malignancies. here the role of viral encoded micro-rna is under investigation.12 in particular, the associations of kaposi's sarcoma and primary effusion nhl with human herpes virus type 8 (hhv 8), of primary cns lymphoma and nhl with epstein-barr virus (ebv) and of invasive cervical cancer with human papillomavirus (hpv) are well documented.13,14,15 immune deficiency itself seems to play a role in hiv malignancies.16 impaired t-cell surveillance in particular may lead to insufficient elimination of transformed cells, resulting in oncogenesis. furthermore, the hiv tat protein, a nonstructural protein secreted by infected cells and taken up by uninfected cells, seems to be involved in the pathomechanism of hiv-related malignancies. it has been found to deregulate cellular genes (as prb2/p130) that work as onco-suppressor proteins.17,18 recently, hyperactivation of mtor has been found to play a role in different aspects of hiv pathology including hiv-associated nephropathy (hivan), hiv encephalopathy, and hiv-associated and non-hiv-associated malignancies.19,20 as mentioned above, the mtor pathway disinhibition is also one of the pathomechanisms involved in the oncogenesis in nf1. additional mtor activation in the setting of hiv infection as a compounding contributor may confer a 'second hit’, leading to the question of the potential use of mtor inhibitors in the treatment of these patients. this point also raises the interesting question of whether hiv patients with an increased risk for malignancies develop these at earlier ages and whether these tumours are more aggressive. conclusion top ↑ people living with hiv and/or aids have a significantly increased risk of developing malignancies, as have patients with neurofibromatosis (and other phakomatoses). different mechanisms are involved in these two independent pro-oncogenic diseases, and there are no data on incidence or prevalence rates for patients affected by both conditions. we assume that these rates might be higher than for hiv or nf1 alone. therefore, in a setting of high hiv prevalence – such as south africa – we suggest regular hiv testing in patients with nf1 and other phakomatoses. frequent follow-up (e.g. 6-monthly) with close monitoring for malignancies and further diagnostic work-up, where a tumour is suspected, is encouraged. because the risk resulting from the genetic condition is not modifiable, the aim can only be to reduce the tumour risk from hiv infection and immunosuppression. we therefore recommend starting arvs irrespective of cd4 counts in such patients. acknowledgements top ↑ we thank dr a. mochan for the critical review of the manuscript and dr tanvier omar for help with the somatostatin staining and for providing the histological images. competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions both authors were the treating specialists of the patient. j.h. (university of pretoria) collected the results and wrote the manuscript. e.v. (university of the witwatersrand) edited the article and contributed, especially regarding the literature about oncogenesis in hiv. references top ↑ national institutes of health consensus development conference statement: neurofibromatosis. arch neurol. 1988;45:575–578. http://dx.doi.org/10.1001/archneur.1988.00520290115023 economopoulos p, christopoulos c. somatostatinoma syndrome. ann gastroenterol. 2001;14:252–260. fendrich v, ramaswamy a, slater ep, bartsch dk. duodenal somatostatinoma associated with von recklinghausen's disease. j hepatobiliary pancreat surg. 2004;11:417–421. http://dx.doi.org/10.1007/s00534-004-0918-3 krejs gj, orci l, conion jm, et al. somatostatinoma syndrome. biochemical, morphologic and clinical features. n engl j med. 1979;301:285–292. http://dx.doi.org/10.1056/nejm197908093010601 brems h, beert e, de ravel t, legius e. mechanisms in the pathogenesis of malignant tumours in neurofibromatosis type 1. lancet oncol. 2009;10:508–515. http://dx.doi.org/10.1016/s1470-2045(09)70033-6 national center for infectious diseases division of hiv/aids. 1993 revised revised classification system for hiv infection and expanded surveillance case definition for aids among adolescents and adults. mmwr. 1992;41:1–19. spano jp, costagliola d, katlama c, et al. aids-related malignancies: state of the art and therapeutic challenges. j clin oncol. 2008;26:4834–4842. http://dx.doi.org/10.1200/jco.2008.16.8252 engels ea, pfeiffer rm, goedert jj, et al. trends in cancer risk among people with aids in the united states 1980-2002. aids. 2006;20:1645–1654. http://dx.doi.org/10.1097/01.aids.0000238411.75324.59 cooley tp. non-aids-defining cancer in hiv-infected people. hematol oncol clin north am. 2003;17:889–899. http://dx.doi.org/10.1016/s0889-8588(03)00038-8 burgi a, brodine s, wegner s, et al. incidence and risk factors for the occurrence of non-aids-defining cancers among human immunodeficiency virus-infected individuals. cancer. 2005;104:1505–1511. http://dx.doi.org/10.1002/cncr.21334 stein l, urban mi, o’connell d, et al. the spectrum of human immunodeficiency virus-associated cancers in a south african black population: results from a case-control study, 1995-2004. int j cancer. 2008;122:2260–2265. http://dx.doi.org/10.1002/ijc.23391 vinod s, vaibhav j. micrornas in viral oncogenesis. retrovirology. 2007;4:82. http://dx.doi.org/10.1186/1742-4690-4-82 chang y, cesarman e, pessin ms, et al. identification of herpesvirus-like dna sequences in aids associated kaposi's sarcoma. science. 1994;266:1865–1869. http://dx.doi.org/10.1126/science.7997879 cesarman e, chang y, moore ps, et al. kaposi's sarcoma-associated herpes virus-like dna sequences in aids-related body-cavity-based lymphomas. n engl j med. 1995;332:1186–1191. http://dx.doi.org/10.1056/nejm199505043321802 frisch m, biggar rj, goedert jj. human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. j natl cancer inst. 2000;92:1500–1510. http://dx.doi.org/10.1093/jnci/92.18.1500 grulich ae, van leeuwen mt, falster mo, vajdic cm. incidence of cancers in people with hiv/aids compared with immunosuppressed transplant recipients: a meta-analysis. lancet. 2007;70:59–67. http://dx.doi.org/10.1016/s0140-6736(07)61050-2 albini a, barillari g, benelli r, gallo rc, ensolo b. angiogenic properties of human immunodeficiency virus type 1 tat protein. proc natl acad sci usa. 1995;92:4838–4842. http://dx.doi.org/10.1073/pnas.92.11.4838 prakash o, tang zy, he ye, et al. human kaposi's sarcoma cell-mediated tumorigenesis in human immunodeficiency type 1 tat-expressing transgenic mice. j natl cancer inst. 2000;92:721–728. http://dx.doi.org/10.1093/jnci/92.9.721 kumar d, konkimalla s, yadav a, et al. hiv-associated nephropathy: role of mammalian target of rapamycin pathway. am j pathol. 2010;177:813–821. http://dx.doi.org/10.2353/ajpath.2010.100131 nicoletti f, fagone p, meroni p, mccubrey j, bendtzen k. mtor as a multifunctional therapeutic target in hiv infection. drug discov today. 2011;16:715–721. http://dx.doi.org/10.1016/j.drudis.2011.05.008 the southern african journal of hiv medicine                                                              april  2010 35 invited comment cytomegalovirus can cause a wide spectrum of multi-systemic disorders including pulmonary disease, gastrointestinal disorders and disabling central or peripheral neurological dysfunction, as well as other manifestations that are well described by laher et al. in their article. however, retinal disease is by far the most common clinical manifestation of cmv for patients with hiv, and this devastating condition has rightly been termed ‘the neglected disease of the aids pandemic’.1 cytomegalovirus retinitis (cmvr) is the most frequent cause of visual loss in individuals with aids, and before availability of haart in the usa approximately 30% of patients with aids developed cmvr.2 direct involvement of the optic disc and macula, retinal detachment and immune recovery-related phenomena can all complicate the condition, and may lead to visual impairment or blindness. a recent survey in botswana suggests that up to 16.5% of individuals accessing haart in a hospital setting have cmvr, in alignment with the findings of visser, based in durban.3,4 the high burden of hiv disease and the increasing scale-up of haart provision in south africa (with patients often initiating treatment at low cd4 counts) suggest that cytomegalovirus disease, whether ocular or systemic, will have a huge impact on hiv-related morbidity and mortality. detection of systemic cmv disease may need to be augmented by diagnostic laboratory tests, as outlined by the authors. however, retinal cmv disease is considered to have a characteristic appearance on ophthalmoscopy. clinical examination of the fundus by indirect ophthalmoscopy is the gold standard for detection of cmvr, yet in many resource-limited settings the geographical and numerical maldistribution of ophthalmologists to hivaffected individuals renders this an untenable situation. furthermore, the cost of treatment is prohibitive, and intra-ocular injections for cmvr also require ophthalmic expertise. as hiv clinicians and eye care professionals, we are in a position to curtail the ‘neglect’ of cmv – diagnosis and management of cmv infection, whether systemic or ocular, should be part of routine care. the development of novel strategies to train non-ophthalmologists to screen for cmvr means that ocular case detection may be possible even with decentralisation of hiv services to primary care levels. however, detection of cmv infection is just the first of many steps. a major obstacle faced in south africa is the challenge of making treatment available, effective and affordable. we need to rise to the challenge and lobby for availability of economically priced treatment, otherwise we risk leaving our patients vulnerable to the scourge of cmv disease – and potentially a life filled with darkness. sophia pathai clinical research fellow international centre for eye health london school of hygiene and tropical medicine references 1. heiden d, ford n, wilson d, rodriguez wr, et al. cytomegalovirus retinitis: the neglected disease of the aids pandemic. plos med 2007; 4(12): e334. 2. hoover dr, peng y, saah a, et al. occurrence of cytomegalovirus retinitis after human immunodeficiency virus immunosuppression. arch ophthalmol 1996; 114(7): 821827. 3. nkomazana o, tshitswana d. ocular complications of hiv infection in sub-saharan africa. current hiv/aids reports 2008, 5: 120-125. 4. visser l. managing cmv retinitis in the developing world. comm eye health 2003; 16(47): 38-39. sajhiv 1026 reflections providing hiv care to men who have sex with men in south african state sector clinics k b rebe, mb chb, fcp (sa), dtm&h, diphivman; j a mcintyre, mb chb, frcog corresponding author: k b rebe (rebe@anovahealth.co.za) drs kevin rebe and james mcintyre represent the anova health institute, johannesburg and cape town, south africa. dr rebe is affiliated with the department of medicine, faculty of health sciences, university of cape town, south africa, while dr mcintyre hails from the school of public health and family medicine in the same institution. south africa’s mass rollout of antiretroviral therapy (art) a decade ago changed the face of the aids epidemic in the country. various populations have, however, not benefited equally. treatment programmes have been success­­ful in reaching women, who make up two-thirds of those receiving treatment in state sector clinics, but less so in reaching men.1 this is even more apparent for south african men who have sex with men (msm), who have historically been ignored for directed service provision, despite being a key population at high risk of hiv acquisition and transmission. hiv prevalence among local msm has been estimated at 10 43% in various studies.2-5 until fairly recently, local and regional data were unavailable to inform targeted and appropriate health programming for this population group. south africa’s enabling constitution and government’s (sag’s) commitment to providing appropriate care to key populations, including msm, has provided an opportunity to gather data and develop and implement evidence-based health services. anova health institute, in partnership with the provincial departments of health (dohs) and with support and funding from the president's emergency plan for aids relief (pepfar)/ united states agency for international development (usaid) launched health4men, the first state sector programme aimed at addressing msm sexual health and wellness.6 the programme includes limited ‘centres of excellence’ in cape town and johannesburg where large cohorts of msm can receive direct health services. data collected from these cohorts are used to develop, test and refine locally responsive and appropriate management guidelines. operational research is also conducted at these sites, aimed at improving the quality of service and providing the sag with data to assist in future health planning. although important, such centres of excellence are expensive and not scalable. therefore, the core activity advocated by the anova model is widespread sensitivity and skills training for healthcare workers already active in state sector hiv, sexually transmitted infection (sti), tuberculosis (tb) and primary health clinics. the aim is to enable them to provide appropriate care for their msm patients, based on local guidance developed by centres of excellence.7 this competency training has occurred in four provinces thus far, with plans to roll out nationally in the near future. currently, six msm-competent clinics are supported by this project, and many lessons have been learnt from the experience in the field. services for msm can only exist with buy-in from multiple stake­holders. the sag and provincial dohs have been responsive to the health needs of msm at a high level, and have included targeted health services in the country’s national and provincial strategic plans. local hiv, aids sti and tb (hast) managers have mostly been supportive of integrating msm healthcare skills into their current facilities. training has been well received by state clinics and msm training has been approved and integrated into provincial regional training centres. international donors such as pepfar/usaid and the global fund have developed normative guidance on developing and implementing msm-targeted services and have been willing to fund such initiatives. civil society has been able to influence local policy through representation via the lesbian, gay, bisexual, trans­gender and intersex (lgbti) sector in the south african national aids council (sanac). strong community engagement with groupings of gay/other msm has created a demand for targeted hiv and sexual health initiatives. anova’s experience has identified certain factors that facilitate attracting msm to healthcare services, retaining them for chronic care and reducing hiv and sti transmission risks: • hiv services: screening for hiv (hiv counselling and testing) should include msm-sensitive counselling. coun­sellors who adopt a judgmental, heteronormative attitude risk alienating clients, thus negating the benefits of counselling. many counsellors do not ask men if they have same-sex partners and assume only female partners. this results in inappropriate service delivery, resource and time wastage (e.g. no risk reduction occurs if msm receive counselling on safe penile-vaginal sex but they do not engage in that activity). msm attending services are particularly concerned about the confidentiality of their information, specifically their sexual orientation and hiv status, and need to be convinced that their private information is adequately protected. • hiv treatment services: msm should be treated according to the national doh’s art guidelines, as for any other adult, with a few additional considerations. due to the efficiency of hiv transmission during unprotected anal sex (approximately 18 times that of unprotected penile-vaginal sex8 ), early treatment should be considered even at high cd4+ counts to prevent onward transmission of infection, i.e. treatment as prevention. some subsets of msm are extremely body-conscious and will not adhere to medications that cause visible side-effects, such as lipodystrophy. one also needs to consider drug interactions with anabolic steroids and other supplements in this body-conscious group. art agents that cause diarrhoea as a side-effect may cause sexual dysfunction in msm who engage in receptive anal sex. adherence support is often complex due to a lack of family support. substance and alcohol abuse and mental health problems such as anxiety and depression are more prevalent among msm than heterosexual men. of importance is that msm status does not cause mental illness; rather, that depression and anxiety result from the constant stress of being marginalised and stigmatised.9 • stis: a significant proportion of visits to many msm clinics are for stis other than hiv. sti symptoms are a common reason for seeking healthcare in this key population. this should be leveraged in healthcare messaging to attract men into care. once they attend a clinic, an opportunity for risk-reduction counselling and hiv screening arises. stis are treated locally according to governmental guidance, which advocates for empirical treatment of various syndromes such as genital discharge or genital ulcer syndromes.10 attempts to identify the aetiology of the infection and determine antibiotic sensitivity are not advocated. these guidelines are not responsive to the needs of msm and will likely be ineffective. this is because most cases of gonorrhoea and chlamydia are asymptomatic in msm and the rate of cephalosporin-resistant gonococcus is higher than in heterosexual men and women.11 the guidelines do not encourage healthcare workers to consider oro-pharyngeal and anal stis in men. • hiv-prevention services: msm attending many clinics have reported difficulty in accessing post-exposure prophylaxis (pep) from mainstream state health services, and many barriers have been identified. these include: most pep is required after hours when experienced hiv clinics are closed; the need to be screened for hiv (often performed by msm-insensitive staff who are unable to provide appropriate counselling); and the myth that pep is only available in state clinics for the prevention of nosocomial hiv or following sexual assault. we firmly advocate for pep following sexual assault and it is not the onus of a health provider to determine whether or not sexual exposure was consensual. • pre-exposure prophylaxis (prep): prep with tenofovir plus emtri­citabine is potentially extremely effective at preventing hiv trans­mission.12 high hiv-risk populations such as msm, commercial sex workers, drug users and negative partners in discordant relationships should be offered prep. prep is being offered in the private sector, but no services exist in the state sector; this is an omission that should be addressed. • medical male circumcision (mmc): this is an effective intervention for preventing hiv in heterosexual men and has been taken to scale by the sag. unfortunately, this intervention is less effective in msm as their main route of hiv infection is receptive anal sex, where circumcision status plays no role. however, there is robust evidence that approximately half of south african msm also have sex with women and they would derive risk-reduction benefits during such encounters. mmc should therefore be offered to all men, irrespective of sexual orientation, but education and information needs to be nuanced correctly so that men understand the benefits and deficiencies of the procedure.13   underlying all of this, community engagement is essential to the success of msm-targeted health provision. many local msm are fearful of health-provider stigma and avoid health services, even if their perception is unfounded. peer educators and health ambassadors should be deployed to inform msm of their human and healthcare rights, and to promote access to clinics that have received msm sensitivity and skills competency training. community upliftment programmes aimed at raising the social capital of the most marginalised msm are important. the anova health4men experience has lead to the production of a variety of tools that could be adopted by mainstream state sector hiv/art clinics. these include, among others: appropriately branded condoms and sexual lubricants, information and educational communication materials and instructive manuals for health providers. anova has made use of a number of technology-lead health initiatives such as its website (http://www.health4men.co.za), smartphone site (http://h4m.mobi) and a variety of online health and health satisfaction surveys. we applaud the sag’s current willingness to engage with msm healthcare and the inclusion of targeted services in our country’s health plans. this is especially relevant on the african continent where the attitude of the sag stands in stark contrast to countries such as nigeria, uganda and zimbabwe, where persecution of gay and other msm is legally and politically sanctioned and where targeted services providing art to msm are almost impossible. we anticipate that the fruitful partnership between the sag and anova, as well as other non-governmental organisations active in this field, will continue to allow south africa to take the lead in providing hiv and art services to all citizens as a basic human right, in the absence of stigma and judgement. references 1. cornell m. gender inequality: bad for men's health. southern african journal of hiv medicine 2013;14(1):12-14. [http://dx.doi.org/10.7196/sajhivmed.894] 1. cornell m. gender inequality: bad for men's health. southern african journal of hiv medicine 2013;14(1):12-14. [http://dx.doi.org/10.7196/sajhivmed.894] 2. burrell e, mark d, grant r, wood r, bekker l-g. sexual risk behaviours and hiv-1 prevalence among urban men who have sex with men in cape town, south africa. sex health 2010;7(2):149-153. 2. burrell e, mark d, grant r, wood r, bekker l-g. sexual risk behaviours and hiv-1 prevalence among urban men who have sex with men in cape town, south africa. sex health 2010;7(2):149-153. 3. baral sd. elevated risk for hiv infection among men who have sex with men in lowand middle-income countries 2000-2006. plos med 2007;4(12):1901-1911. [http://dx.doi.org/10.1371/journal.pmed.0040339] 3. baral sd. elevated risk for hiv infection among men who have sex with men in lowand middle-income countries 2000-2006. plos med 2007;4(12):1901-1911. [http://dx.doi.org/10.1371/journal.pmed.0040339] 4. lane t, raymond f, dladla s, et al. high hiv prevalence among men who have sex with men in soweto, south africa: results from the soweto men's study. aids behav 2009;15(3):626-634. 4. lane t, raymond f, dladla s, et al. high hiv prevalence among men who have sex with men in soweto, south africa: results from the soweto men's study. aids behav 2009;15(3):626-634. 5. rispel lc, metcalf ca, cloete a, reddy v, lombaard j. hiv prevalence and risk practices among men who have sex with men in two south african cities. j acquir immune defic syndr 2011;57(1):69-76. [http://dx.doi.org/10.1097/qai.0b013e318211b40a] 5. rispel lc, metcalf ca, cloete a, reddy v, lombaard j. hiv prevalence and risk practices among men who have sex with men in two south african cities. j acquir immune defic syndr 2011;57(1):69-76. [http://dx.doi.org/10.1097/qai.0b013e318211b40a] 6. rebe kb, de swardt g, struthers h, mcintyre ja. towards 'men who have sex with men-appropriate' health services in south africa. southern african journal of hiv medicine 2013;14(2):52-57. [http://dx.doi.org/10.7196/sajhivmed.841] 6. rebe kb, de swardt g, struthers h, mcintyre ja. towards 'men who have sex with men-appropriate' health services in south africa. southern african journal of hiv medicine 2013;14(2):52-57. [http://dx.doi.org/10.7196/sajhivmed.841] 7. rebe kb, struthers h, de swardt g, mcintyre ja. hiv prevention and treatment for south african men who have sex with men. s afr med j 2011;101(10):708-710. 7. rebe kb, struthers h, de swardt g, mcintyre ja. hiv prevention and treatment for south african men who have sex with men. s afr med j 2011;101(10):708-710. 8. baggaley r, white r, boily m. hiv transmission risk through anal intercourse, systematic review, meta-analysis and implications for hiv prevention. int j epidemiol 2010;39(4):1048-1063. [http://dx.doi.org/10.1093/ije/dyq057] 8. baggaley r, white r, boily m. hiv transmission risk through anal intercourse, systematic review, meta-analysis and implications for hiv prevention. int j epidemiol 2010;39(4):1048-1063. [http://dx.doi.org/10.1093/ije/dyq057] 9. tucker a, liht j, de swardt g, et al. homophobic stigma, depression, self-efficacy and unprotected anal intercourse for peri-urban township men who have sex with men in cape town, south africa: a cross-sectional association model. aids care 2013 (in press). 9. tucker a, liht j, de swardt g, et al. homophobic stigma, depression, self-efficacy and unprotected anal intercourse for peri-urban township men who have sex with men in cape town, south africa: a cross-sectional association model. aids care 2013 (in press). 10. national department of health. first line comprehensive management and control of sexually transmitted infections (stis). protocol for the management of a person with a sexually transmitted infection according to the essential drug list. pretoria: ndoh, 2003:1-20. 10. national department of health. first line comprehensive management and control of sexually transmitted infections (stis). protocol for the management of a person with a sexually transmitted infection according to the essential drug list. pretoria: ndoh, 2003:1-20. 11. lewis da, sriruttan c, muller e, et al. phenotypic and genetic characterization of the first two cases of extended-spectrum-cephalosporin-resistant neisseria gonorrhoeae infection in south africa and association with cefixime treatment failure. j antimicrob chemother 2013;68(6):1267-1270. [http://dx.doi.org/10.1093/jac/dkt034] 11. lewis da, sriruttan c, muller e, et al. phenotypic and genetic characterization of the first two cases of extended-spectrum-cephalosporin-resistant neisseria gonorrhoeae infection in south africa and association with cefixime treatment failure. j antimicrob chemother 2013;68(6):1267-1270. [http://dx.doi.org/10.1093/jac/dkt034] 12. grant r, lama jr, anderson pl, et al. pre-exposure chemoprophylaxis for hiv prevention in men who have sex with men. n engl j med 2010;363(27):2587-2599. [http://dx.doi.org/10.1056/nejmoa1011205] 12. grant r, lama jr, anderson pl, et al. pre-exposure chemoprophylaxis for hiv prevention in men who have sex with men. n engl j med 2010;363(27):2587-2599. [http://dx.doi.org/10.1056/nejmoa1011205] 13. lane t, raymond hf, dladla s, et al. lower risk of hiv infection among circumcised msm: results from the soweto men's study. 5th international aids society conference on hiv pathogenesis, treatment and prevention, cape town, 2009. 13. lane t, raymond hf, dladla s, et al. lower risk of hiv infection among circumcised msm: results from the soweto men's study. 5th international aids society conference on hiv pathogenesis, treatment and prevention, cape town, 2009. s afr j hiv med 2014;15(1):10-11. doi:10.7196/sajhivmed.1026 ----------------------------------------------_. -----from the the issue editor advocating access antiretroviral (arv) therapies are again featured in this issue of the journal. the guidelines for the use of arv therapy in paediatric practice, formulated by the paediatric subcommittee under the leadership of or lean levin, are highlighted. these guidelines are different from those that have appeared elsewhere and are unique to our setting. the guidelines were circulated to a panel of international reviewers and their views were incorporated into the document. these guidelines are a companion to the adult guidelines that appeared in the july launch issue of the journal. it may be argued that in both instances there has been a focus on options that are not available to the vast majority of the hivinfected people in our country. this may be so, but we would argue that it is important for our clinicians to be well informed with regard to the difficulties and complexities inherent in the use of these drugs. we are witnessing an increasing use of these therapies in the private sector as more health care funders are providing benefits to hiv-infected individuals, so it behoves all of us to keep abreast of developments in this dynamic field of medicine. of equal importance is the article by mark heywood of the aids law project who urges clinicians to be more vocal in their efforts to expand access to arv therapies among their patients or among the communities they serve. the hiv clinicians society would endorse this stance and urge its members to be more outspoken on these issues and become advocates of expanded access to quality care. it is realised that combination therapies do come with a significant price tag, but the cost-effectiveness of these therapies must not be underestimated. we need only refiect that in the recent past combination therapies to treat tuberculosis were deemed unaffordable, but are now freely available at no cost to the patient. the society congratulates the aids law project on its achievements in protecting the rights of hiv-infected persons, including the positive outcome in two recent court cases, that have led to significant changes in corporate policies for hiv-positive employees or prospective employees. the controversy surrounding hiv as the causative agent of aids has once again surfaced in south africa, gaining political support at the highest level, including the support of the state president. this dehate has had widespread repercussions among scientists, clinicians, hiv-infected individuals and more importantly, the general population at large. a response to this situation was the 'durban declaration', which was distributed at the 13th international aids conference in july 2000 and is published in full in this issue of the journal. the declaration was formulated by a committee consisting of a number of prominent international scientists and this document was subsequently circulated to thousands of scientists and clinicians throughout the world, who in turn became signatories to the document. this document will be useful for clinicians in answering the many questions currently being asked of them by their patients. des martin editor, southern africon journal of hiv medicine president, southern africon hiv clinicians society while neighbouring botswana and other sadc countries and states have been solicited with offers of free or highly reduced-price antiretroviral treatments that will bring the cost of haart to around us$l 000 for a year of therapy per patient, south africa continues to face tough marketeering by the same drug manufacturers, who see the country as a lucrative market with virtually unlimited need for their products. lack of political support, or infrastructural inadequacies are cited for the continued refusal of these companies to consider south africa as a priority for broadening treatment access through preferential pricing strategies, while they continue to milk the private sector of resources in exchange for suboptimal regimens or barely affordable combinations of therapy. by discounting drug prices only through guaranteed volumes of sales, these companies ensure that the higher demand they create among those who somehow manage to pay for these combination packages, leads to volume-linked profitability. the pharmaceutical industry continues to extract unreasonable profits in the developing world for their formulations through 'patent protection', when the costs of developing these patents are already being recovered in their primary markets and the costs of producing the drugs are a fraction of the prices charged. there is no doubt that poverty both facilitates hiv infection and exacerbates the progression to aids, yet the current solutions being offered by the industry will only worsen poverty through their net effect over time. offers from these sources are not benevolent and the countries contemplating their responses to the offers that have been presented face difficult decisions that will leave them responsible for the uncertain long-term consequences and implications. this could be one of the reasons for south africa's strong position within the sadc on defining the framework and conditions for negotiating these deals and for the principled guidelines for countries participating in the process to have been put forward within the sadc. pharmaceutical manufacturers have not been the only businesses to profit from the epidemic, as managed care companies and other service industries are deriving income for delivering hiv-linked products and services that are of highly variable value. the same business models that have been proven over time to make money have been applied to this 'new market: this has to change, as the region faces an unprecedented crisis that cannot be addressed through 'business as usual' approaches. the west and the wealthy can no longer be allowed to profit once more from the misfortunes of africa. antiretroviral therapy is life giving, yet it must be sustainable and effective, as well as being affordable to the households, communities and countries of the individuals who benefit from treatment. a starting point is to ensure that a proper, transparent framework of assistance is created that not only enables treatments to be made available, but also the means to pay for, distribute, administer and monitor them. it is time for the professions and civil society to take issue with the current status of hiv care access in our region and to become better-informed participants in negotiations and stronger advocates for our patients' survival. shaun conway managing editor, southern african journal of hiv medicine executive director, iapac southern africa thf sou ihfrn african journal of hiv mtdlcinf ----------novfmhfr 2000 11 there is nothing we con do for you! why did you come now!' may 2001-------------th£ southfrn african journal of hiv m£oicin£ home-based care this is the situation i, as a rural doctor in mpumalanga, find myself facing on a daily basis. the challenge that faces me, like many other rural doctors, is how to improve the plight of the thousands of pwas in our rural areas of south africa. talking to department of health [doh) professionals and managers, the problem is a lack of finances to provide basic medication, transport and staff at the clinics. talking to the patients and their families, their biggest need is food and painkillers. digging a little deeper, there is a need to be treated with respect and dignity, and to be accepted by the health system. funeral costs have added to the huge debt of the family and/or orphans. in my search to see how other african countries have coped with the aids epidemic, i visited uganda, where i stayed at the mildmay aids hospice in kampula. i also visited hospice uganda, and several community homebased care projects. i observed the patients, rich and poor, streaming into mildmay hospice. i was surprised that there were no inpatient beds either there or at hospice uganda. the patients were greeted with a big smile and, 'you are welcome. we are so glad you came today. i can see you are suffering. how can we help you?' i asked if i could sit in at the paediatric hiv clinic, and the doctor stood up and shook my hand and welcomed me to his clinic. he introduced his patient, aged 8 years, and asked permission for the doctor from south africa to be present during the consultation. the little patient replied, 'you are very welcome: i could hardly hold back my tears as i saw again the very there ore no medicines to give you! go home! come bock tomorrow. there is no doctor todoy! why don't you look ofter your child!' many go to the 'special doctor', the general practitioner, who is also overwhelmed by patients to whom a cure can no longer be offered. because patients want to get their money's worth, gps are often pressured into prescribing inappropriate medication or resorting to alternative medicine, reassuring patients that they will get better with this 'special' treatment. dr margie hardman, mb chb, dch, mcfp director, aids care training and support (ags) initiative, white river, mpumalanga plight of aids patients in rural south africa a challenge to health professionals finally, having spent all their money, and in debt to neighbours and friends, the family attempts to care for the dying relative at home. news may get around that there is aids in the house, neighbours and friends cease to visit, the children are ostracised at school and drop out, and there is no income, apart from possibly the granny's pension, and little or no food in the house. in desperation they attempt to go to the clinic to ask for a disability grant, often sitting in queues for many hours, and are usually told they don't qualify. if they are successful, many months will pass before the grant is processed, by which stage the extra all of the above are a sad reflection of many of our rural health facilities. nurses who are already demotivated, inadequately trained for the huge responsibilities they have to carry, and frustrated by the lack of resources, now have to carry the extra burden of seeing people dying daily of aids in their communities, often friends and family members. frequently, out of a sense of inadequacy and hopelessness, they respond in anger and frustration. the patients in turn, lose hope in the formal government health system, and turn instead to any other source where they can grasp for hope for a cure. many others turn back to their traditional healers, where they attempt to get some spiritual explanation for their sickness, perform some rituals, and receive some traditional medicine, which they are assured will cure them. the southern african journal of hiv meoicine ------------may 200 i basics of medical care treating patients with unconditional love, warmth, and respect. treating them as precious human beings in the sight of god and their fellow human beings. most of the terminally ill patients in uganda are cared for in their homes, by community home-based care volunteers. these volunteers receive excellent training at places like mildmay and hospice uganda as well as other centres. a multidisciplinary team from mildmay goes out into the communities every wednesday to run workshops for the family members caring for terminally ill patients at home. at the workshop i attended, which was held at a church hall, the physiotherapist demonstrated how to lift and turn patients. the nutritionist spoke on how to prepare nutritious meals for the patients. the nurse spoke on how to manage persistent diarrhoea at home, and the counsellor spoke on how to manage a difficult patient. there was a lot of participation from the group. finally, the pastor encouraged and prayed for the family members, and then cooldrinks and cakes were provided. mildmay provides an hiv outpatient clinic, which operates on a monday, tuesday, thursday and friday. patients are assessed firstly by a professional nurse, and then by a doctor. they are then referred as necessary, to the appropriate member or members of the multidisciplinary team. the team consists of an occupational therapist, a counsellor, a nutritionist, and a pastor or spiritual counsellor. basic laboratory tests were done while the patient was visiting various members of the team. finally, patients would collect their medication from the pharmacist, and pay according to their means. a good supply of medication was available, including morphine suspension, oral antifungals and antivirals, as well as prophylactic treatment. those who could afford it, and had had extensive counselling, were offered antiretrovirals. they also had more extensive laboratory tests including cd4 counts and viral loads. there was an excellent follow-up and monitoring system. i came home with hope in my heart again, and a vision of what we could do in south africa. from small beginnings we have a home-based care programme operating in the northern nzikazi area of mpumalanga. sixty wonderful community volunteers visit the chronically and terminally ill patients in their homes, and provide holistic care, including basic counselling, nursing care, directly observed therapy, practical help and social and spiritual care. in the year 2000, '7000 visits were recorded and at present 500 patients and 600 orphans are being cared for in their homes. modelled on mildmay, we are building a clinic and training centre to provide support to the home-based care projects. we also endeavour to provide palliative care training to the nurses and doctors at the government clinics and district hospital. i believe that this is a model that can be replicated in other rural areas. i also believe that there are many health professionals who are willing and wanting to provide compassionate quality care for aids patients, whether rich or poor. i believe this is what we as south africans need to strive for, and not settle for anything less. sajhiv 1032 reflections ‘they dropped the blanket of their fear’: reflections on hiv medicine in south africa, 2014 j marshall, mb bch, da (sa), doh (wits) corresponding author: j marshall (gavinjoyce@telkomsa.net) dr joyce marshall is an occupational health practitioner based in gauteng province, south africa coming from a community health background in kwazulu-natal and the informal settlements around the grasmere toll plaza, i was working in occupational health in the late 1990s and seeing a number of truck drivers with all the clinical features of hiv/aids, and feeling frustrated at how little we could do for these patients. then i sustained a needle-stick injury with hiv-positive blood in 1997. spending a nauseous month on combivir, i became aware that hiv had come to visit me and my family. what was this experience saying to me? it was calling me to engage. as i reflect on the past two decades, we have lived through seismic shifts in our medical understanding and management of the infection. i recall watching a polymerase chain reaction viral load being reduced to nearly undetectable levels in eight days in one clinical trial that required weekly testing in the first six weeks. from an inevitable death sentence, we have moved to being able to offer our patients chronic disease management and wellness. the costs of antiretrovirals and monitoring have dropped significantly. in the occupational health world, we have integrated hiv testing into our periodic medicals along with blood pressure and fasting glucose. each company with whom we work, has a policy on hiv/aids – including non-discrimination. there are peer educators and ongoing education on the factory floors. but perhaps the most profound observation has been to watch people ‘drop the blanket of their fear’. this happened slowly in support groups and with one-on-one encounters with patients in the early part of the millennium. but the rate of change has accelerated. recently, for world aids day, i spoke at a company with one of my patients who shared her ‘lazarus’ story. three people came up to her and disclosed their status and requested to join the support group. s afr j hiv med 2014;15(1):26. doi:10.7196/sajhivmed.1032 hiv message from executive message from the executive i have spoken before about where we are in the hiv epidemic in south africa (sa) today. the heady days when there were scientific breakthroughs every few months are over. the excitement surrounding increased treatment access, improved antiretroviral therapy (art) regimens and nurse-initiated management of antiretroviral therapy (nimart) have settled; hiv no longer makes the news every other day. what we have achieved is truly remarkable: sa has the largest antiretroviral (arv) programme in the world, with estimates of as many as 2.4 million people receiving art. hiv healthcare workers can be proud of the contributions they have made – and continue to make – to lessen the burden of this disease. now that the excitement has passed, it is time to get on with the slog of rolling out and sustaining a massive treatment programme. what we are finding is that this may actually be our greatest challenge yet. in this issue of sajhivmed you will find an insert highlighting key points from a national survey conducted by the stop stock outs project assessing arv and tuberculosis drug stockouts at the facility level. as you will see, the report found that the problem is far beyond previous estimates, and affects most provinces. the telephone survey, which took place during september and october 2013, obtained information from over 2 000 health facilities. around one in every five facilities in sa reported a stockout or shortage during the 90-day period covered in the survey. free state, limpopo and mpumalanga provinces were the worst affected, with 54%, 41% and 26% of facilities affected, respectively. in 20% of facilities facing stockouts, patients were sent away with no medicine. to some of you these results won’t be surprising at all, as you are negotiating medicine shortages and stockouts on a daily basis. what the report makes clear is that stockouts are so common, that they represent a credible threat to the success of the national arv programme. the report is also a reminder that although the fight may be over, the battle is far from won. as we begin 2014 and prepare to mark ten years of art in the public sector, we must celebrate what we have achieved, but not become complacent about where we need to be. as healthcare workers we must redouble our efforts and contribute our part to strengthening the health system, whether it’s reporting medicine stockouts, corruption or inefficiencies with­in the system. what we have accomplished in ten years is no less than remarkable; what is possible for us to achieve in the next ten is truly inspiring. francesca conradie president southern african hiv clinicians society fconradie@witshealth.co.za article information author: james j.c. nuttall1,2 affiliations: 1red cross war memorial children's hospital, cape town, south africa 2department of paediatrics and child health, university of cape town, south africa correspondence to: james nuttall email: james.nuttall@uct.ac.za postal address: red cross war memorial children's hospital, rondebosch 7700, cape town, south africa dates: received: 01 dec. 2014 accepted: 10 feb. 2015 published: 04 may 2015 how to cite this article: nuttall jjc. antiretroviral therapy during the neonatal period. s afr j hiv med. 2015;16(1), art. #361, 8 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.361 copyright notice: © 2015. the authors. licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. antiretroviral therapy during the neonatal period in this guidelines... open access • rationale for initiating combination antiretroviral therapy during the neonatal period • outline of pharmacokinetics, dosing and safety of antiretrovirals during the neonatal period    • nucleoside reverse transcriptase inhibitors       • abacavir       • lamivudine       • stavudine       • zidovudine    • non-nucleoside reverse transcriptase inhibitors       • nevirapine    • protease inhibitors       • lopinavir/ritonavir    • integrase inhibitors       • raltegravir • choice of combination antiretroviral therapy regimen in neonates • transition from antiretroviral prophylaxis to treatment • acknowledgements    • competing interests • references rationale for initiating combination antiretroviral therapy during the neonatal period top ↑ initiation of combination antiretroviral therapy (cart) at 6–9 weeks of age has been shown to reduce early infant mortality by 76% and hiv progression by 75% compared with cart deferred until clinical or cd4 criteria were met.1 in the landmark children with hiv early antiretroviral therapy (cher) trial, although the median age of starting cart in the early treatment arm was 7.4 weeks, one-third (10/30) of the overall mortality in the trial occurred in the early treatment arm.1 in another study, 62% of 403 infants who initiated cart at median 8.4 weeks of age already had advanced hiv disease (cd4 < 25% or < 1500 cells/mm3 or world health organization [who] stage 3 or 4) at initiation.2 the above, with other findings describing the benefits of early cart, raise the question of whether even earlier cart initiation – immediately after birth or during the neonatal period – could further reduce morbidity and mortality rates, and confer greater benefits, particularly for infants who acquired hiv infection during the pregnancy and are consequently at highest risk of rapid disease progression.3,4,5,6,7 the potential of early neonatal cart initiation in modifying the longer-term trajectory of hiv infection in an individual patient and need for lifelong cart is an area of intensive research. the recent shift to targeted hiv polymerase chain reaction (pcr) testing at birth rather than only at 6 weeks of age allows for the earliest detection of neonates in whom intrauterine transmission of hiv infection has occurred and has opened the door to neonatal cart initiation. availability of validated point-of-care hiv pcr testing will further increase the drive to initiate cart during the early neonatal period. safety and efficacy data on neonatal cart is currently very limited. there is even less experience with treating premature and low birth weight neonates with cart. uncertainties relate to pharmacokinetics (pk), dosing, safety and choice of cart regimen. in addition, timing of the transition from prophylactic antiretroviral (arv) regimens aimed at prevention of transmission to cart regimens aimed at long-term treatment requires further investigation. outline of pharmacokinetics, dosing and safety of antiretrovirals during the neonatal period top ↑ nucleoside reverse transcriptase inhibitors abacavir despite the south african (sa) arv treatment guidelines recommendation that abacavir (abc) should be used in all first-line cart regimens for children, there are insufficient safety data to recommend the use of abc in infants < 3 months old.8 there is also a lack of pk studies to guide dosing in this age group.9 lamivudine the sa arv drug dosing chart (2013) recommends a lamivudine (3tc) dose of 2 ml (20 mg) twice daily from 3 kg – 4.9 kg but advises expert consultation for neonates and infants weighing < 3 kg.10 although 3tc is not food and drug administration (fda) approved for use in infants < 3 months of age, it has been used and studied in neonates. the recommended dose for neonates (< 4 weeks of age) for either prevention of transmission or treatment is 2 mg/kg/dose twice daily. the recommended paediatric dose (age ≥ 4 weeks) is 4 mg/kg/dose twice daily to a maximum dose of 150 mg twice daily.11 these recommendations are based on population pk analyses in infants < 6 weeks of age.12,13 the higher who dosage recommendations (3 ml [30 mg] twice daily from 3 kg – 4.9 kg) result in increased plasma concentrations compared with the 2 mg/kg/dose recommendations and should be avoided in neonates.14,15 there are no published data to guide dosing in premature neonates. lamivudine has generally been associated with minimal toxicity in older children and adults but studies suggest that haematological toxicity (anaemia, neutropaenia, thrombocytopaenia) increases when combined zidovudine (azt)/3tc neonatal prophylaxis is used when compared with azt alone, with increasing numbers of patients requiring treatment discontinuation or blood transfusions.16 lamivudine may be given without regard to food, and the oral solution may be stored at room temperature. excretion is via the renal route, and dose adjustment is required in renal insufficiency.11 stavudine the recommended dose for neonates from birth to 13 days of age is 0.5 mg/kg/dose twice daily and, from 14 days onwards, 1 mg/kg/dose twice daily to a maximum of 30 mg twice daily.11,17 dose reduction is recommended if there is renal dysfunction. there are no published data to guide stavudine (d4t) dosing in premature neonates. the oral liquid formulation requires the addition of water to powder, has a concentration of 1 mg/ml, requires refrigeration and is stable for 30 days.11 an alternative dosing method using opened capsules (available as 15 mg, 20 mg or 30 mg) with the contents dispersed in a small amount of water and the appropriate dose administered via oral syringe, has been investigated and plasma exposure shown to be equivalent to ingested whole capsules.18 stavudine is no longer included in sa treatment guidelines, and the oral liquid formulation is not readily available in the public sector.8 although there is limited experience in the context of neonatal cart, d4t in older infants and children generally has minimal short-term toxicity and good efficacy.11 it may therefore be a consideration for short-term use in neonatal cart when azt is contraindicated or haematological toxicity has occurred. alternative options for substitution of azt are limited owing to lack of abc safety and dosing information in infants < 3 months of age. zidovudine there is considerable experience with the use of azt in the neonatal period, although mostly for prevention of transmission. although the landmark pactg 076 study of prevention of mother-to-child transmission of hiv (pmtct) used dosing of 2 mg/kg/dose 6 hourly, more recent data support twice-daily dosing.19 current usa guidelines recommend a dose of 4 mg/kg/dose twice daily for either prevention of transmission (4–6 weeks) or treatment (4 weeks) for neonates with gestational age ≥ 35 weeks.11 western cape (south africa) pmtct guidelines (2014) incorporate combination azt/ nevirapine (nvp) prophylaxis to prevent transmission in high-risk infants and recommend a standardised azt dose according to birth weight (> 2 kg: 12 mg 12-hourly; < 2 kg: 4 mg/kg 12-hourly) or gestational age (< 35 weeks: 2 mg/kg 12-hourly) administered as post-exposure prophylaxis for 4 weeks.20 the sa arv drug dosing chart (2013) and who weight band dosing (2010) recommend a dose of 6 ml (60 mg) twice daily from 3 kg – 5.9 kg which is equivalent to 10 mg – 20 mg/kg/dose or 172 mg – 300 mg/m2/dose but advises expert consultation for neonates and infants weighing < 3 kg.10,15 it is recognised that the standard paediatric azt dose (240 mg/m2/dose twice daily) may lead to haematological toxicity (anaemia, neutropaenia, thrombocytopaenia), particularly in premature neonates with anaemia of prematurity and where other agents that may cause bone marrow suppression (e.g. ganciclovir, co-trimoxazole) are administered concurrently. specific dosing based on pk studies in premature neonates is available and close monitoring of haematological parameters is recommended (at least every 2–4 weeks) during the neonatal and early infant period.11,21 switching from azt to an alternative medication should be considered if signs of haematological or other toxicity are severe or persistent. dosing adjustment is required in the setting of renal insufficiency or hepatic impairment.11 an intravenous (iv) azt formulation is available. it is generally used in the setting of prevention of transmission when the neonate is unable to tolerate oral medication.11 as no other iv arv formulations are available, a fully iv treatment regimen is not feasible. monotherapy with iv azt as treatment in hiv-infected neonates is not recommended. after 6 weeks of age, azt dosing according to the sa arv drug dosing chart (2013) is recommended.10 alternatively, body surface area-based dosing (240 mg/m2/dose twice daily) may be used.11 non-nucleoside reverse transcriptase inhibitors nevirapine although the use of nvp is well established for prevention of transmission, the optimal treatment dose for neonates < 14 days of age has not been established. the dose of oral suspension approved for treatment in neonates > 15 days of age and children is 200 mg/m2/dose twice daily with a maximum dose of 200 mg (immediate-release formulation) twice daily.11 the standard practice of using a 14-day lead-in dose when initiating treatment with nvp in order to allow induction of cytochrome p450 metabolising enzymes and reduce occurrence of rash, can lead to subtherapeutic plasma nvp levels. this effect increases the risk of developing drug resistance and associated worse virological and clinical outcomes. initiating cart with full-dose twice-daily nvp in black african children < 2 years of age without previous nvp exposure resulted in fewer subtherapeutic nvp levels than the 14-day dose escalation approach, and none of the children less than 2 years of age who received full-dose nvp developed rash.22 in hiv-infected neonates who are transitioning from once-daily nvp prophylaxis for prevention of transmission to cart containing nvp, it would seem appropriate to use full-dose nvp with careful clinical and laboratory monitoring from the start of cart because some degree of induction of cytochrome p450 metabolising enzymes is likely to have already occurred. further studies that include both neonates exposed to nvp prophylaxis for prevention of transmission and those without previous nvp exposure are required to validate the safety, efficacy and feasibility of full-dose nvp initiation. based on pk modelling, the international maternal pediatric adolescent aids clinical trials (impaact) p1115 study will investigate a nvp treatment dose of 6 mg/kg/dose twice daily with full-dose initiation in full-term neonates < 48 hours of age.23 nevirapine toxicities include rash, hypersensitivity reactions, and hepatotoxicity. close monitoring for rash and liver function test abnormalities is required. nvp should not be administered to patients with moderate or severe hepatic impairment. in addition, drug-drug interactions are common and concomitant medications should be carefully reviewed prior to initiating nvp.11 efavirenz, etravirine and rilpivirine are not approved for use in neonates and are not recommended.11 protease inhibitors lopinavir/ritonavir lopinavir/ritonavir (lpv/r) co-formulated oral solution (kaletra) was first approved by the usa's fda in 2000 for the treatment of hiv-infected children ≥ 6 months old. in 2008, kaletra oral solution was approved for use in children ≥ 14 days old.24 the recommended dose of oral solution is 300 mg/m2/dose twice daily.11 in january 2011, the fda released a statement on kaletra toxicity in neonates.24 post-marketing cases of toxicity were reported to the fda's adverse event reporting system (aers) in september 2010 and were attributable to lpv and/or the inactive ingredients propylene glycol and ethanol. kaletra oral solution contains 152.7 mg/ml of propylene glycol (15.3% w/v) and has a high ethanol content (356 mg/ml or 42.4% v/v). a search of the aers database revealed 10 reported cases with adverse events that might have been related to lpv, propylene glycol or ethanol. all 10 patients were neonates, and 8 of the 10 were premature neonates. cardiac toxicity occurred in 7 of the patients and included bradycardia, sinoatrial block, complete atrioventricular block, congestive cardiomyopathy, cardiac failure and cardiogenic shock. an elevated lactate level was documented in 2 cases. neuromuscular toxicity in 3 neonates included hypotonia, abnormal electroencephalogram (eeg), altered state of consciousness, somnolence and asthenia. acute renal failure was seen in 5 neonates and an increased serum creatinine was documented in 1. four neonates developed hyperkalaemia. respiratory complications occurred in 3 neonates and included respiratory failure, pulmonary haemorrhage, respiratory arrest, dyspnoea and wheezing. gastrointestinal events in 5 neonates included vomiting, failure to thrive, abdominal distension and ulcerative colitis. one of the 10 neonates died.24,25 eight of the 10 neonates received their first dose of kaletra within the first 2 days of life. the onset of toxicity occurred within 1–6 days in 8 of the neonates. a full-term infant showed the first signs of toxicity 20 days after birth. after kaletra was discontinued, 6 neonates recovered within 5 days.24,25 transient asymptomatic elevation in 17-hydroxyprogesterone levels has been reported in term neonates treated at birth with lpv/r.26 as an appropriate dose in premature infants and neonates < 14 days of age is not known and the consequences of kaletra toxicity in premature infants can be severe or possibly fatal, the fda strongly recommends that kaletra should be avoided in this age group:11,24 if in the judgment of the health care professional, the benefit of using kaletra oral solution in babies to treat hiv infection immediately after birth outweighs the potential risks, then the neonate should be monitored closely for increases in serum osmolality and serum creatinine and for toxicity related to kaletra oral solution. these toxicities include hyperosmolality with or without lactic acidosis, renal toxicity, cns depression (including stupor, coma, and apnea), seizures, hypotonia, cardiac arrhythmias, ecg changes and hemolysis.24 the impaact p1030 study evaluated pk, safety and efficacy of lpv/r 300 mg/m2/dose twice daily in combination with 2 nucleoside analogues in 10 hiv-infected infants with an age range of 3.6–5.9 weeks. amongst 9 infants completing intensive pk evaluation on a median dose of 267 mg/m2/dose (range 246–305) twice daily, the lpv area-under-the curve (auc) was significantly lower than that in the 6-weeks to 6-months of age cohort. the lpv trough level (cmin) ranged from 0.99 µg/ml – 4.87 µg/ml which did not differ from the older children. a plasma lpv trough concentration of ≥ 1 µg/ml has been used as a correlate of efficacy in treatment-naïve adults. after 24 weeks’ follow-up, adverse events were limited to transient neutropaenia in 3 infants, and only 2 of 10 infants met criteria for protocol-defined virological failure. noting the low lpv exposure (auc), the authors advised careful dose calculation and frequent dose adjustment for weight gain, and proposed studying a higher dose for very young infants.27,28 taking into account the increasing usage of lpv/r administration to neonates at risk of perinatal or postnatal hiv transmission, urien et al.29 aimed to determine optimal dosing for lpv/r in the first weeks of life based on a population pk approach incorporating body weight, gestational age and postnatal age in 96 infants from france and the uk. amongst the 96 neonates, 7 were on treatment for neonatal hiv infection. the median postnatal age was 2 weeks (range 1 day – 102 weeks), median gestational age was 38 weeks (range 27.3–41 weeks), median body weight was 3.3 kg (range 1.16 kg – 10.4 kg). a total of 163 lpv concentrations were available for analysis. the mean lpv dosage was 590 mg/m2/day (range 106–1454) or 39 mg/kg/day (range 11–110) dosed between 1 and 3 times per day. a one-compartment model described the data with body weight and age being the main influential covariates. the following dosage regimen was derived from the predicted lpv trough concentrations using a therapeutic range of 1 µg/ml – 8 µg/ml: 40 mg 12-hourly, 80 mg 12-hourly and 120 mg 12-hourly for 1 kg – 2 kg, 2 kg – 6 kg and 6 kg – 10 kg groups respectively.29 holgate et al.30 described the use of kaletra-based cart in 8 hiv-infected premature neonates treated between 2006 and 2011 in cape town. the median gestational age at birth was 31 weeks (range 27–33), median age at initiation of lpv/r-based cart was 26.5 days (range 5–96), median corrected gestational age at cart initiation was 34.1 (range 31.6–44.7) and median dose of lpv/r at time of measuring lpv levels was 287 mg/m2/dose or 23.1 mg/kg (range 235–325; 21.1–28.6, respectively). lpv trough levels were sampled a median 7 days after lpv/r initiation, 3 infants had subtherapeutic plasma levels (< 1 µg/ml), and in 1 infant the plasma level was above the recommended target range (> 4 µg/ml). the dose of lpv/r was adjusted in the 3 infants with low levels and a median dose of 533 mg/m2 (range 400–540) resulted in plasma levels within the recommended therapeutic range. overall, 5/8 infants required doses > 300 mg/m2 to achieve plasma lpv trough levels within the recommended range. no adverse effects attributable to lpv/r solution were observed. the study highlighted the role of therapeutic drug monitoring in order to achieve target trough lpv levels. although no toxicity was observed, the authors emphasised the need for extreme caution and careful monitoring of premature neonates treated with kaletra.30 although nelfinavir (nfv) has been used in art regimens for prevention of transmission and treatment, it is not currently recommended for treatment in children < 2 years of age as there is significant inter-individual variation in plasma levels and insufficient pk data to support a standardised dosing regimen.11 atazanavir, darunavir, fosamprenavir, indinavir, full-dose ritonavir (rtv), saquinavir and tipranavir are not approved for use in neonates and are not recommended.11 integrase inhibitors raltegravir there are currently no published data on safety and dosing of raltegravir (ral) in neonates. however, phase 1 and 2 studies are underway. the impaact p1097 study investigated washout pk in neonates born to hiv-infected mothers and showed that the neonatal half-life of ral varied between 9 and 184 hours, most likely owing to reduced capacity for metabolism and elimination in newborns.31 the phase 1 impaact p1110 trial is investigating the safety and pk of ral suspension (granules for suspension) in hiv-exposed neonates at high risk of acquiring hiv infection. different dosing strategies between birth and 6 weeks of age will be investigated with the option of continuing ral beyond 6 weeks of age in infants found to be hiv-infected.32 the impaact p1066 study investigated the use of ral oral suspension in combination with an optimised background arv regimen in 26 hiv-infected infants and young children aged 4 weeks to 2 years who had previously received arv medication for prevention of perinatal transmission. clinical outcomes were acceptable, there were no treatment discontinuations owing to adverse events, and pk parameters were similar to those achieved amongst cohorts of older children in the same study.33 raltegravir oral suspension is currently approved by the fda for use in infants > 4 weeks of age and > 3 kg body weight.11 in sa, ral suspension is not currently registered by the medicines control council. in the sa public sector, ral has been restricted for use in third-line art regimens. dolutegravir and elvitegravir are not approved for use in neonates and are not recommended.11 choice of combination antiretroviral therapy regimen in neonates top ↑ current sa hiv treatment guidelines recommend abc+3tc+lpv/r as first-line cart for all hiv-infected children < 3 years of age; there are no separate recommendations for full-term or premature neonates.8 there are currently no published clinical trial data comparing different cart regimens initiated during the neonatal period. clinical trials in older infants and young children have informed treatment recommendations in these age groups and are important to consider in relation to cart initiation during the neonatal period. the impaact p1060 trial showed that lpv/r-based cart was virologically superior to nvp-based cart both in infants with previous exposure to nvp (6–36 months of age) and in infants without previous exposure to nvp (3–36 months of age).34,35 one of the reasons proposed to explain the difference in virological efficacy between nvp and lpv/r is the dose escalation strategy used when initiating nvp, as this has been associated with subtherapeutic plasma nvp levels which could increase the risk of developing drug resistance and treatment failure.22 initiation of cart with full-dose nvp has been investigated and further studies are underway.22,23 an additional possible explanation for the difference in outcomes relates to the presence of drug resistance mutations prior to cart initiation. in settings of high nucleoside reverse transcriptase inhibitor (nrti) exposure owing to the use of nvp for prevention of transmission and use of nrti/ non-nucleoside reverse transcriptase inhibitor (nnrti) regimens during pregnancy, the presence of resistance mutations may compromise the efficacy of nvp-based regimens in the neonate. hiv drug resistance mutations in plasma virus were determined using population sequencing in 230 newly-diagnosed hiv-infected children < 2 years of age in johannesburg in 2011. two-thirds of the hiv-infected children had been exposed to maternal and/or infant pmtct, 56.8% had nnrti, 14.8% nrti and 1.3% pi mutations. in children with no reported pmtct exposure, resistance to nnrti was detected in 24%, to nrti in 10.7% and to pi in 1.3%. in the children who were tested at ≤ 8 weeks of age, 85% had nnrti drug resistant mutations present.36 the above data support the use of pi-based first-line cart in hiv-infected infants and young children regardless of pmtct history. however, owing to potentially severe and life-threatening short-term toxicity concerns, kaletra is currently not recommended in neonates < 14 days old and < 42 weeks corrected gestational age. long-term toxicities of pis, including effects on growth and lipid metabolism, have also been reported.37,38 other studies have investigated whether 4 rather than 3 arv drugs could improve outcomes based on the observation that young infants commonly have very high hiv viral loads and the hypothesis that increased regimen potency might achieve more rapid virological suppression, immunological recovery and better long-term treatment efficacy. however, the available studies are heterogeneous in nature and therefore difficult to compare directly, and 3 drug regimens have remained the standard-of-care in most guidelines. the pactg 356 study showed superior virological suppression rates of a 4-drug regimen comprising d4t/3tc/nvp/nfv compared with either azt/3tc/abc/nvp or azt/3tc/nvp.39 prendergast et al.40 showed that infants randomised to receive immediate or deferred (until cd4 count reached < 20%) 4-drug cart comprising azt/3tc/nfv/nvp were able to achieve excellent adherence and virological suppression after one year by intention-to-treat analysis of 80%. the european pregnancy and pediatric hiv cohort collaboration (eppicc) observational study of 437 infants initiating cart during the first year of life showed better virological and immunological responses among those starting 4-drug nnrti-based regimens than 3-drug nnrti-based and lpv/r-based regimens after median 5.9 years of follow-up.41 the antiretroviral research for watoto (arrow) trial conducted among 3-month – 17-year-old children in uganda and zimbabwe showed no long-term (72 weeks) immunological benefit to starting 4-drug cart (nnrti +3 nrtis) then simplifying to 3-drug cart (either nnrti + 2 nrtis, or 3 nrtis) compared with starting 3-drug cart (nnrti + 2 nrtis), and there was increased toxicity with 4-drug cart.42 further clinical trials comparing safety, tolerability and efficacy of different cart regimens, including consideration of 4-drug and triple class regimens, initiated during the neonatal period in high burden settings are warranted in order to better guide treatment recommendations. transition from antiretroviral prophylaxis to treatment top ↑ neonatal arv prophylaxis regimens vary between guidelines. in sa, prophylaxis regimens include nvp alone, azt alone, nvp + azt, and nvp + azt + 3tc, and recommended duration ranges from 6 weeks to 3 months or more.8,43 as a result, most neonates will be receiving arv prophylaxis at the time that a positive birth hiv pcr test result is obtained. transition from neonatal arv prophylaxis to neonatal cart requires adjustment to the number and choice of arvs, dosage and dose frequency in most cases. clinical assessment of the neonate, baseline investigations and careful counselling of the mother and family are pre-requisites to cart initiation. although optimal strategies for transition from prophylaxis to cart have not been widely studied, it is recommended that a standardised approach applicable to the majority of hiv-infected neonates is adopted (figure 1). expert opinion and individualised guidance will still be required for certain categories of neonates; for example, low birth weight, premature or unwell neonates. figure 1: recommended process for initiation of combination antiretroviral therapy in neonates. after obtaining a positive hiv pcr test result in a neonate, the following actions are required prior to consideration of cart initiation: a blood sample for confirmatory viral detection assay (second hiv dna pcr test as per current national department of health [ndoh] sa guidelines or hiv rna/viral load) must be submitted to the laboratory.8,43 initiation of cart should not be delayed on the basis that the result of the confirmatory pcr test has not yet been obtained. rapid and systematic follow-up of birth hiv pcr tests that might have been submitted to the laboratory by the birthing facility or a referring clinic or hospital, and recall of hiv-positive neonates, is essential. the clinical condition of the neonate must be assessed. this includes determining the corrected gestational age (in weeks), postnatal age, birth weight and current weight, presence of any vital organ dysfunction including neonatal jaundice, hepatitis or renal dysfunction, and presence of other congenital or acquired infections including syphilis, tuberculosis (tb) and cytomegalovirus as indicated by the maternal history and clinical state of the neonate. co-morbidities and their treatment may alter the timing of cart initiation and the treatment regimen required in the neonate. in neonates who are clinically unstable at the time that hiv infection is diagnosed, arv prophylaxis should be discontinued and the neonate stabilised and treated as necessary prior to initiation of cart. in addition, neonates who are not fully established on enteral feeding are not eligible to initiate cart. hiv-infected neonates who are also exposed to and/or infected with tb require evaluation as to the infectiousness and drug sensitivity profile of the contact, and assessment (clinical, radiological, bacteriological) of tb infection/disease followed by anti-tb chemoprophylaxis or treatment. hiv-infected neonates initiated on rifampicin and receiving lpv/r-based cart will require additional rtv (0.75 x lpv dose) to be added to the cart regimen although pk, safety and efficacy data for the super-boosting strategy in the neonatal age group is lacking. the pk, safety and efficacy of rifampicin in combination with nvp-based cart in the neonatal age group is also not known. expert advice should be obtained. baseline blood investigations should be performed including full blood count and differential white cell count, urea and creatinine, and alanine aminotransferase (alt). careful and detailed counselling of the mother and if possible other family members who will be involved in the care of the neonate is required. the mother of the child might not have disclosed her own hiv status to other family members, and disclosure of the neonate's hiv status to the family should be discussed. in addition to providing support, counselling should include information about the hiv diagnosis in the neonate as well as details about cart. information and guidance on infant feeding should be provided. mothers who had chosen to breastfeed should be encouraged to continue breastfeeding whilst mothers who had chosen formula feeding should consider switching to breastfeeding if feasible. ideally, a blood sample should be submitted for arv drug resistance testing (genotyping) prior to initiation of cart in the neonate. this is particularly relevant when the neonate has been exposed to maternal cart or arv prophylaxis prior to the diagnosis of hiv infection, and may assist in determining optimal arv drug choices in future cart regimens for the child. expert advice should be obtained to assist in the management of hiv-infected neonates born to mothers on 2ndor 3rd-line cart regimens. in neonates ≥ 15 days of age and ≥ 42 weeks corrected gestational age and with normal renal and hepatic function, an initial regimen of azt+3tc+lpv/r is recommended. refer to table 1 and figure 1 for guidance on dosing and monitoring. table 1: antiretroviral drugs, formulations and dose recommendations for treatment of full-term neonates. in full-term neonates ≤ 14 days of age, approved dosing recommendations are only available for azt and 3tc. treatment with only 2 drugs is not recommended. based on a detailed review of available pk data, an nvp dose of 6 mg/kg/dose twice daily in full-term neonates initiating cart < 48 hours of age is under investigation in the impaact p1115 study. pending the results of this and other studies, a provisional recommendation to use an initial regimen of azt+3tc+nvp dosed twice daily in neonates ≥ 35 weeks gestational age at birth, regardless of postnatal age, with normal hepatic function and appropriate monitoring for toxicity seems reasonable. refer to table 1 and figure 1 for guidance on dosing and monitoring. as there are data for older infants and young children showing superior efficacy of lpv/r-based, compared with nnrti-based, cart, these neonates should be considered for elective switch to azt+3tc+lpv/r when they are ≥ 15 days of age and ≥ 42 weeks corrected gestational age. the decision to initiate cart in premature neonates < 35 weeks gestational age involves assessing the relative risks and benefits of using unapproved dosing and the inherent concerns regarding drug toxicity. dosing recommendations for premature neonates are currently only available for azt. treatment with azt alone is not recommended and, based on currently available data, it is recommended that kaletra should be avoided in this age group (refer to table 2). if cart is initiated in premature neonates, expert guidance on dosing and toxicity monitoring should be obtained. table 2: antiretroviral drugs, formulations and dose recommendations for treatment of premature neonates. acknowledgements top ↑ competing interests the author declares that he has no financial or personal relationship(s) which may have inappropriately influenced him in writing this article. references top ↑ violari a, cotton m, gibb d, et al. early antiretroviral therapy and mortality among hiv-infected infants. n engl j med. 2008;359:2233–2244. http://dx.doi.org/10.1056/nejmoa0800971 innes s, lazarus e, otwombe k, et al. early severe hiv disease precedes early antiretroviral therapy in infants: are we too late? j int aids soc. 2014;17:18914. http://dx.doi.org/10.7448/ias.17.1.18914 laughton b, cornell m, grove d, et al. early antiretroviral therapy improves neurodevelopmental outcomes in infants. aids. 2012;26:1685–1690. http://dx.doi.org/10.1097/qad.0b013e328355d0ce rabie h, violari a, duong t, et al. early antiretroviral treatment reduces risk of bacille calmette-guerin immune reconstitution adenitis. int j tuberc lung dis. 2011;15:1194–11200. http://dx.doi.org/10.5588/ijtld.10.0721 hainline c, taliep r, sorour g, et al. early antiretroviral therapy reduces the incidence of otorrhea in a randomised study of early and deferred antiretroviral therapy: evidence from the children with hiv early antiretroviral therapy (cher) study. bmc res notes. 2011;4:48. http://dx.doi.org/10.1186/1756-0500-4-448 penisieroso s, cagigi a, palma p, et al. timing of haart defines the integrity of memory b cells and the longevity of humoral responses in hiv-1 vertically-infected children. proc natl acad sci usa. 2009;106:7939–7944. http://dx.doi.org/10.1073/pnas.0901702106 persaud d, palumbo p, ziemniak c, et al. dynamics of the resting cd4(+) t-cell latent hiv reservoir in infants initiating haart less than 6 months of age. aids. 2012;26:1483–1490. http://dx.doi.org/10.1097/qad.0b013e3283553638 national department of health, south africa. national consolidated guidelines for the prevention of mother-to-child transmission of hiv (pmtct) and the management of hiv in children, adolescents and adults. 24 december 2014. available from: http://www.health.gov.za/docs/hivaids/hivguidelinesjan2015final.pdf intekom. abacavir package insert. c2014 [cited 06 october 2014]. available from: http://home.intekom.com/pharm/aspen-p/a-abac-s.html child and adolescent committee of the sa hiv clinicians society in collaboration with the department of health. antiretroviral drug dosing chart for children 2013. c2013 [cited 09 october 2014]. available from: http://www.sahivsoc.org/upload/documents/arv%20dosing%20chart%20for%20children%202013.pdf panel on antiretroviral therapy and medical management of hiv-infected children. guidelines for the use of antiretroviral agents in pediatric hiv infection. c2015 [cited 08 april 2015]. available from: http://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf mirochnick m, stek a, acevedo m, et al. safety and pharmacokinetics of nelfinavir coadministered with zidovudine and lamivudine in infants during the first 6 weeks of life. j acquir immune defic syndr. 2005;39:189–194. tremoulet ah, capparelli ev, patel p, et al. population pharmacokinetics of lamivudine in human immunodeficiency virus-exposed and -infected infants. antimicrob agents chemother. 2007;51:4297–4302. http://dx.doi.org/10.1128/aac.00332-07 tremoulet ah, nikanjam m, cressey tr, et al. developmental pharmacokinetic changes of lamivudine in infants and children. j clin pharmacol. 2012;52: 1824–1832. http://dx.doi.org/10.1177/0091270011426563 world health organization. antiretroviral therapy for hiv infection in infants and children: towards universal access. recommendations for a public health approach. 2010. c2010 [cited 06 october 2014]. available from: http://who.int/hiv/pub/paediatric_arv_dosing.pdf?ua=1 mandelbrot l, landreau-mascaro a, rekacewicz c, et al. lamivudine-zidovudine combination for prevention of maternal-infant transmission of hiv-1. jama. 2001;285:2083–2093. http://dx.doi.org/10.1001/jama.285.16.2083 kaul s, kline mw, church ja, dunkle lm. determination of dosing guidelines for stavudine (2’, 3’-didehydro-3’-deoxythymidine) in children with human immunodeficiency virus infection. antimicrob agents chemother. 2001;45: 758–763. http://dx.doi.org/10.1128/aac.45.3.758-763.2001 innes s, norman j, smith p, et al. bioequivalence of dispersed stavudine: opened versus closed capsule dosing. antivir ther. 2011;16:1131–1134. http://dx.doi.org/10.3851/imp1876 connor em, sperling rs, gelber r, et al. reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. pediatric aids clinical trials group protocol 076 study group. n engl j med. 1994;331: 1173–1180. http://dx.doi.org/10.1056/nejm199411033311801 pmtct clinical guidelines. june 2014. cape town: western cape government department of health. capparelli ev, mirochnick m, dankner wm, et al. pharmacokinetics and tolerance of zidovudine in preterm infants. j pediatr. 2003;142:47–52. http://dx.doi.org/10.1067/mpd.2003.mpd0335 fillekes q, mulenga v, kabamba d, et al. is nevirapine dose escalation appropriate in young, african, hiv-infected children? aids. 2013;27:2111–2115. http://dx.doi.org/10.1097/qad.0b013e3283620811 international maternal pediatric adolescent aids clinical trials (impaact) network. very early intensive treatment of hiv-infected infants to achieve hiv remission: a proof of concept study (p1115). c2014 [cited 10 october 2014]. available from: http://www.impaactnetwork.org/studies/ us food and drug administration. fda drug safety communication. serious health problems seen in premature babies given kaletra (lopinavir/ritonavir) oral solution. silver springs, fda; 2011. available from: www.fda.gov/drugs/drugsafety/ucm246002.htm mcarthur m, kalu s, foulks a, et al. twin preterm neonates with cardiac toxicity related to lopinavir/ritonavir therapy. pediatr infect dis j. 2009;28:1127–1129. http://dx.doi.org/10.1097/inf.0b013e3181acd17e simon a, warszawaski j, kariyawasam d, et al. association of prenatal and postnatal exposure to lopinavir/ritonavir and adrenal dysfunction among uninfected infants of hiv-infected mothers. jama. 2011;306:70–78. http://dx.doi.org/10.1001/jama.2011.915 chadwick e, pinto j, yogev r, et al. early initiation of lopinavir/ritonavir in infants less than 6 weeks of age: pharmacokinetics and 24-week safety and efficacy. pediatr infect dis j. 2009;28:215–219. http://dx.doi.org/10.1097/inf.0b013e31818cc053 chadwick eg, yogev r, alvero cg, et al. long-term outcomes for hiv-infected infants less than 6 months of age at initiation of lopinavir/ritonavir combination antiretroviral therapy. aids. 2011;25:643–649. http://dx.doi.org/10.1097/qad.0b013e32834403f6 urien s, firtion g, anderson st, et al. lopinavir/ritonavir population pharmacokinetics in neonates and infants. br j clin pharmacol. 2011;71:956–960. http://dx.doi.org/10.1111/j.1365-2125.2011.03926.x holgate s, rabie h, smith p, cotton m. trough lopinavir concentrations in preterm hiv-infected infants. pediatr infect dis j. 2012;31:602–604. http://dx.doi.org/10.1097/inf.0b013e31825046ae clarke df, acosta ep, rizk m, et al. raltegravir pharmacokinetics and safety in neonates: impaact p1097. paper presented at conference on retroviruses and opportunistic infections (croi); atlanta, ga; 2013. international maternal pediatric adolescent aids clinical trials (impaact) network. a phase 1 trial to evaluate the safety and pharmacokinetics of raltegravir in hiv exposed infants at high risk (p1110). c2014 [cited 10 october 2014]. available from: http://www.impaactnetwork.org/studies/ nachman s, zheng n, acosta ep, et al. pharmacokinetics, safety, and 48-week efficacy of oral raltegravir in hiv-1-infected children aged 2 through 18 years. clin infect dis. 2014;58:413–422. http://dx.doi.org/10.1093/cid/cit696 palumbo p, lindsey j, hughes m, et al. antiretroviral treatment for children with peripartum nevirapine exposure. n engl j med. 2010;363:1510–1520. http://dx.doi.org/10.1056/nejmoa1000931 violari a, lindsey j, hughes m, et al. nevirapine versus ritonavir-boosted lopinavir for hiv-infected children. n engl j med. 2012;366:2380–2389. http://dx.doi.org/10.1056/nejmoa1113249 kuhn l, hunt g, technau k, et al. drug resistance among newly diagnosed hiv-infected children in the era of more efficacious antiretroviral prophylaxis. aids. 2014;28:1673–1678. http://dx.doi.org/10.1097/qad.0000000000000261 strehlau r, coovadia a, abrams e, et al. lipid profiles in young hiv-infected children initiating and changing antiretroviral therapy. j acquir immune defic syndr. 2012;60:369–376. http://dx.doi.org/10.1097/qai.0b013e318243760b nachman, s, lindsey j, pelton s, et al. growth in human immunodeficiency virus-infected children receiving ritonavir-containing antiretroviral therapy. arch pediatr adolesc med. 2002;156:497–503. http://dx.doi.org/10.1001/archpedi.156.5.497 luzuriaga k, mcmanus m, mofenson l, et al. for the pactg 356 investigators. a trial of three antiretroviral regimens in hiv-1-infected children. n engl j med. 2004;350:2471–2480. http://dx.doi.org/10.1056/nejmoa032706 prendergast a, mphatswe w, tudor-williams g, et al. early virological suppression with three-class antiretroviral therapy in hiv-infected african infants. aids. 2008;22:1333–1343. http://dx.doi.org/10.1097/qad.0b013e32830437df the european pregnancy and paediatric hiv cohort collaboration (eppicc) study group in eurocoord. early antiretroviral therapy in hiv-1-infected infants, 1996-2008: treatment response and duration of first-line regimens. aids. 2011;25:2279–2287. kekitiinwa a, cook a, nathoo k, et al. routine versus clinically driven laboratory monitoring and first-line antiretroviral therapy strategies in african children with hiv (arrow): a 5-year open-label randomised factorial trial. lancet. 2013;381:1391–1403. http://dx.doi.org/10.1016/s0140-6736(12)62198-9 aid for aids. clinical guidelines. 10th ed. c2015 [cited 08 february 2015]. available from: http://www.aidforaids.co.za/downloads/afa_clinical_guidelines_v10.pdf the southern african journal of hiv medicine                                                  september  2010 hiv infection has several oral manifestations, including oral candidiasis and oral hairy leucoplakia. occasionally unusual presentations requiring rigorous investigations are seen, and in these cases the diagnosis sometimes remains a dilemma owing to limited investigation facilities.1-3 we present the case of a patient who presented with a puzzling oral lesion. case history a 35-year-old hiv-positive man first presented to the infectious diseases institute, kampala, in 2006. he had world health organization (who) stage iv disease with a history of oesophageal candidiasis, a baseline weight of 58 kg and a cd4+ count of 56 cells/µl. he was initiated on highly active antiretroviral therapy (haart) using a combination of stavudine, lamivudine and nevirapine (triomune-30) together with cotrimoxazole prophylaxis. six months after initiating art, a follow-up cd4+ count had risen to 226 cells/µl. subsequently the count rose to 298 cells/µl. in september 2008, the patient presented with a 4-month history of drenching night sweats and high-grade fevers, his temperature being recorded as 39.3oc and 39.7oc on two occasions. there was no history of cough, weight loss or loss of appetite. the results of investigations at this time were as follows: full blood count – leucocytopenia, 1.1×103/l ; esr – 25 mm/h; blood slide for malaria parasites – none seen; urinalysis – normal; chest radiograph – normal; abdominal ultrasound scan – hepatosplenomegaly with a suggestion of a haemangioma in the liver; serum cryptococcal antigen – negative; blood cultures – no bacterial growth after 7 days of incubation; tpha – non-reactive. on the basis of the unrelenting fever the patient was started on tuberculosis (tb) treatment consisting of rifampicin, isoniazid, ethambutol and pyrazinamide. during this time his antiretroviral therapy was switched to zidovudine, lamivudine and efavirenz. two weeks after the start of tb treatment, the patient developed drug-induced hepatotoxicity and the tb treatment was stopped. a week later difficulty in swallowing and marked weight loss were noted. he was treated with fluconazole and acyclovir for a month with no improvement, at which time he was admitted. two months after stopping tb medication the liver enzymes stabilised and he was restarted on anti-tb medication. in january 2009, the patient presented with a 3-week history of high-grade fever, loss of appetite, cervical lymphadenopathy and a 2-week history of pus discharge from a palatal perforation, which was treated with ceftriaxone and fluconazole (fig. 1). a case of palatal perforation caused by toxoplasmosis c a s e s t u dy christine katusiime1, mb chb, pgdppm ponsiano ocama2, mb chb, mmed andrew kambugu1, mb chb, mmed 1makerere university, college of health sciences, infectious diseases institute, kampala, uganda 2makerere university, college of health sciences, department of medicine, kampala, uganda 35 we describe the case of a 35-year-old hiv-positive man seen at the infectious diseases institute, kampala, uganda, with a 2-week history of palatal perforation. fig. 1. perforation of hard palate. september  2010                                                    the southern african journal of hiv medicine                                                   an ent consultation gave a presumptive diagnosis of histoplasmosis and the patient was initiated on amphotericin b. the results of investigations at this stage were as follows: oral fistula swab – 2+ yeast cells, 2+ gram-positive cocci and 3+ gram-negative rods; no inflammatory cells seen. a complete blood count showed macrocytosis and mean corpuscular volume of 103 fl; cd4+ count (13 january) – 71 cells/µl (this was less than half the peak cd4+ count, prompting measurement of viral load to exclude immunological failure); viral load (13 january) – not detected, with a lower limit of detection of 400 copies; lymph node aspirate – polymorphonuclear leucocytes 3+, gramnegative rods 2+, gram-positive cocci 1+, no acid and alcohol-fast bacilli seen, escherichia coli isolated; lymph node biopsy – fibrosis and chronic granulomatous inflammation with central necrosis and epitheloid cells, small organisms with halo extracellular and withinmacrophage cytoplasm. morphological features were consistent with toxoplasma lymphadenitis (fig. 2). the patient did not return to the institute. the first follow-up phone call (within a week) revealed that he was deteriorating and was too weak to come to the clinic, and when we called the next week we were told that he had died. unfortunately, the histopathology results were only obtained after his death. discussion this case is an example of the rare oral lesions seen in hiv-infected patients in our clinic. we comprehensively reviewed the literature on bone and joint disease in association with hiv infection but did not find a case of toxoplasma-related bone disease. toxoplasma infection of the oral cavity is uncommon.4 a case of intra-oral lymphadenitis secondary to toxoplasmosis has however been reported.4 in our case defective cell-mediated immunity as a result of immunosuppression may have facilitated the rapid dissemination of toxoplasma,5 resulting in bone invasion causing bone disintegration and destruction.5 acknowledgement: dr robert lukande, histo-pathologist, college of health sciences, makerere university. references 1. ficarra g, shillitoe e. hiv-related infections of the oral cavity. crit rev oral biol med 1992; 3(3): 207-231. 2. ficarra g. oral lesions of iatrogenic and undefined etiology and neurologic disorders associated with hiv infection. oral surg oral med oral pathol 1992; 73(2): 201-211. 3. penneys n, hicks b. unusual cutaneous lesions associated with acquired immunodeficiency syndrome. j am acad dermatol 1985; 13: 845-852. 4. appel b, mendelow h, pasqual h. acquired toxoplasma lymphadenitis. oral surg oral med oral pathol 1979; 47(6): 529-532. 5. balachandran c, sabita l, kanthraj g. perforation of hard palate in lues maligna associated with hiv infection. genitourin med 1997; 73(3): 225. 36 fig. 2. intracellular organisms with prominent outlines indicated by arrows. abstract introduction methods ethical consideration results discussion conclusion acknowledgements references about the author(s) michélle pienaar department of nutrition and dietetics, university of the free state, south africa francois c. van rooyen department of biostatistics, university of the free state, south africa corinna m. walsh department of nutrition and dietetics, university of the free state, south africa citation pienaar m, van rooyen fc, walsh cm. reported health, lifestyle and clinical manifestations associated with hiv status in people from rural and urban communities in the free state province, south africa. s afr j hiv med. 2017;18(1), a465. https://doi.org/10.4102/sajhivmed.v18i1.465 original research reported health, lifestyle and clinical manifestations associated with hiv status in people from rural and urban communities in the free state province, south africa michélle pienaar, francois c. van rooyen, corinna m. walsh received: 19 feb. 2016; accepted: 01 june 2017; published: 28 aug. 2017 copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: hiv infection impacts heavily on the infected individual’s overall health status. aim: to determine significant health, lifestyle (smoking and alcohol use) and independent clinical manifestations associated with hiv status in rural and urban communities. methods: adults aged between 25 and 64 years completed a questionnaire in a structured interview with each participant. blood specimens were analysed in an accredited laboratory using standard techniques and controls. anthropometric measurements were determined using standardised methods. results: of the 567 rural participants, 97 (17.1%) were hiv-infected, and 172 (40.6%) of the 424 urban participants. more than half of hiv-infected rural participants used alcohol and more than 40% smoked. median body mass index (bmi) of hiv-infected participants was lower than that of uninfected participants. significantly more hiv-infected participants reported experiencing cough (rural), skin rash (urban), diarrhoea (rural and urban), vomiting (rural), loss of appetite (urban) and involuntary weight loss (rural). significantly more hiv-uninfected participants reported diabetes mellitus (urban) and high blood pressure (rural and urban). in rural areas, hiv infection was positively associated with losing weight involuntarily (odds ratio 1.86), ever being diagnosed with tuberculosis (tb) (odds ratio 2.50) and being on tb treatment (odds ratio 3.29). in the urban sample, hiv infection was positively associated with having diarrhoea (odds ratio 2.04) and ever being diagnosed with tb (odds ratio 2.49). conclusion: involuntary weight loss and diarrhoea were most likely to predict the presence of hiv. in addition, present or past diagnosis of tb increased the odds of being hiv-infected. information related to diarrhoea, weight loss and tb is easy to obtain from patients and should prompt healthcare workers to screen for hiv. introduction lifestyle factors such as tobacco smoking, use of snuff and alcohol intake impact on quality of life. cigarette smoking accounts for a large burden of preventable disease in south africa.1 it presents unique health risks in the context of the human immunodeficiency virus (hiv), by increasing receptiveness to hiv or other infections, changing the course of hiv infection itself or altering the risk of smoking-related chronic diseases.2 alcohol consumption is another important risk factor for burden of disease and social destruction worldwide3,4 and is discouraged in hiv-infected patients, especially in those on antiretroviral therapy (art).5 in resource-limited countries both infectious and lifestyle diseases contribute to disease burden. infection with hiv initiates a series of events that ultimately leads to profound immunosuppression caused by functional abnormalities in the immune system, mainly because of severe depletion of cd4+ t cells.6 nutritional alterations are common in hiv infection.7 opportunistic infections affecting the gastrointestinal tract may result in various types of malabsorption,8 while advanced immunosuppression from hiv infection can lead to gastrointestinal symptoms such as diarrhoea, nausea, vomiting, dysphagia, weight loss and abdominal pain.9 diarrhoea is a common complaint in patients with hiv infection,10 and the severity of symptoms ranges from mild, self-limiting diarrhoea to debilitating disease that can result in malnutrition. body mass is likely to contribute to the functional impairments seen in patients who are hiv-infected.11 wasting implies unintentional weight loss and loss of lean body mass, and has been strongly associated with an increased risk of disease progression and mortality.12 wasting is associated with chronic diarrhoea, fever or asthenia.13 concurrent hiv and tuberculosis (tb) infection remains a serious challenge. in 2010, 8.8 million people acquired active tb worldwide, of which 1.1 million were living with hiv.14 the global burden of tb is increasing, largely because of the spread of hiv,8 but these statistics can also be ascribed to other contributing factors such as crowding, poverty, unemployment, malnutrition and poor treatment intervention.8 lifestyle diseases are the leading cause of death globally, killing more people each year than all other causes combined.14 in the general population, chronic lifestyle diseases share similar risk factors, including tobacco smoking, diabetes mellitus, hypertension (often associated with increasing age15), obesity, hyperlipidaemia and physical inactivity.16 the presence of comorbidities such as heart disease, diabetes mellitus, hepatitis and opportunistic infections may also complicate the profile of the hiv-infected patient on art.17 this study formed part of the assuring health for all in the free state (aha-fs) study, which aimed to determine how living in rural and urban communities can influence lifestyle and health. despite the large body of evidence related to clinical and anthropometric manifestations of hiv, epidemiological data on these manifestations in the free state province are limited. the clinical relevance of identifying variables that are likely to predict hiv lies in improved screening, diagnosis and care of the large numbers of patients that visit primary healthcare facilities. the aim of this sub-study was thus to investigate health (history of disease, medication, anthropometric symptoms experienced) and lifestyle (smoking and alcohol use) of hiv-infected and hiv-uninfected, rural and urban respondents and to determine significant independent clinical manifestations associated with hiv status. methods the rural study was performed in three free state towns, namely, trompsburg, philippolis and springfontein, and the urban study in mangaung. study design, target population and sampling a cross-sectional study was undertaken. in rural areas, all households were eligible to participate. before data were collected, induction meetings for community members and other role-players were arranged in each community. the role-players included clinic staff, church leaders, community leaders and any members of the community who were interested in learning more about the project or had questions that they wanted to ask. these role-players informed community members that were not present at induction meetings that all adults that met the inclusion criteria were welcome to participate. on days of data collection, adults that arrived at the research venue were included in the rural sample. in urban mangaung, the number of plots in the mangaung university community partnerships programme (mucpp) service area was counted on a municipal map and included buffer, freedom square, kagisanong, chris hani, namibia and turflaagte. an estimate was made of additional squatter households in open areas. a stratified proportional cluster sample was selected, stratified by area and formal plot or squatter households in open areas. using randomly selected x and y coordinates, 100 starting points were selected in this way. from each point, five adjacent starting households were approached to participate in the study. every adult member of households in these black and mixed-ethnic communities, who gave informed consent and was between 25 and 64 years of age, was eligible to participate. pilot study prior to the main survey, a pilot study was undertaken with five individuals in each area, similar to the target group, in order to determine whether questions included in the questionnaire could be easily understood and to estimate the amount of time needed to complete the questionnaires. the questionnaire and all anthropometric measurements were piloted. minor changes (mostly technical editing) were made to questionnaire after the pilot study. variables and operational definitions for the purpose of this study, health referred to medical history, medication used, hospitalisation, anthropometry and symptoms experienced. lifestyle referred to tobacco and alcohol consumption patterns. among others, laboratory investigations included hiv status. anthropometric variables included height, weight and waist circumference (wc). adults were categorised as underweight (body mass index [bmi] less than 18.5 kg/m2); normal weight (bmi 18.5 kg/m2 or over, but less than 25 kg/m2); overweight (bmi 25 kg/m2 or over, but less than 30 kg/m2); or obese (bmi 30 kg/m2 or over).18 a wc equal to or larger than 94 cm for men and 80 cm for women was considered as a high risk for lifestyle-related diseases.18 methods and techniques a health questionnaire, adapted from the one developed for the prospective urban rural epidemiology (pure) study,19 was completed for all adults in each household. information was collected in an interview with each adult by trained final-year dietetics students, using a structured questionnaire. to assure validity, all questions in the health questionnaire were related to the objectives of the study and were based on health-related issues associated with hiv in relevant literature. random samples of 10% of the rural and urban participants were interviewed a second time by the researchers to determine reliability of questions asked in the health questionnaire within a month of the initial survey. where the percentage of answers to questions differed with more than 20%, the question was considered unreliable. no questions were found to be unreliable in the health questionnaire. all blood specimens were analysed in an accredited laboratory using standard techniques and controls. anthropometric measurements were taken with respondents wearing an examination gown, without shoes. anthropometric measurements were performed by trained dietetics students, using standardised methods.20 data collection data collection took place at different research venues, including the community hall in the rural area or at the mucpp nutrition centre in the urban area. on days of data collection, identity documents were screened in order to make sure that participants met the inclusion criteria with regard to age. the research venues included stations for the collection of blood samples; a food station; medical examination; anthropometric measurements (participants arrived in a fasting state for the collection of blood samples). thereafter, questionnaires related to the following were completed: sociodemography; household food security; dietary intake; physical activity; and self-reported health. statistical analysis all analyses were performed by the department of biostatistics, ufs. descriptive statistics, including frequencies and percentages for categorical data, and means and standard deviations (sds) for symmetrical numerical variables, or medians and percentiles for skew numerical variables, were calculated. differences between hiv-infected and hiv-uninfected groups were assessed by p-values (t-tests [for symmetrical numerical variables], mann–whitney tests [for skew numerical variables], chi-squared tests [for categorical variables] or fischer’s extract test [for categorical variables with sparse data]) or 95% confidence intervals (cis) for median, mean or percentage differences. in addition to descriptive comparisons between hiv-infected and hiv-uninfected participants, logistic regression was applied to identify significant clinical manifestations associated with hiv. for each of the variables, a univariate analysis was applied to identify variables that could be included in the rural and urban model (p < 0.15). in the rural sample, the following health variables were included in the model: history of alcohol use, loose stools or diarrhoea for at least three days in last six months, involuntary weight loss > 3 kg in last six months, ever diagnosed with tb, family member diagnosed with tb and tb treatment. in the urban sample, the health variables that were included in the model were: loose stools or diarrhoea for at least three days in last six months, loss of appetite in last six months, involuntary weight loss > 3 kg in last six months, ever diagnosed with tb and tb treatment. following this, logistic regression with forward selection (p < 0.05) was applied to select significant independent factors associated with hiv status in the rural and urban samples. ethical consideration the study was approved by the ethics committee of the faculty of health sciences at the ufs (etovs 21/07), the free state department of health (doh) and local municipalities. the researchers obtained written consent from all participants in their language of choice. results of the 570 rural participants, 567 had hiv results. of these, 97 (17.1%) were hiv-infected. of the 426 urban participants, 424 had hiv results, of which 172 (40.6%) were hiv-infected. twenty-five per cent (n = 43) of the total number of hiv-infected urban respondents reported using art, compared to only four (4.1%) hiv-infected respondents in rural areas. smoking and snuffing results related to smoking and use of snuff are shown in table 1. in both areas, more or less the same percentage of hiv-infected participants smoked or used snuff compared to hiv-uninfected participants. a fairly large percentage of rural participants smoked (40.9% hiv-infected and 39.6% hiv-uninfected participants), while one in four urban participants used snuff (25% of both hiv-infected and hiv-uninfected participants). table 1: history of smoking and use of snuff. alcohol consumption table 2 shows categories of alcohol consumption of hiv-infected and hiv-uninfected rural and urban respondents. more hiv-infected participants used alcohol than their uninfected counterparts (54.6% vs. 47.6% [rural] and 42.3% vs. 36.5% [urban]), although the difference was not significant. beer was the most frequently consumed alcoholic beverage in all groups, but more rural respondents consumed homemade beer, ranging from 47.8% of hiv-infected participants to 57.9% of hiv-uninfected participants. more hiv-infected rural respondents (84.2%) felt tired on mondays after heavy drinking than uninfected rural participants (61.8%), but the difference was not statistically significant (p = 0.07). table 2: alcohol consumption. reported symptoms, diagnoses and medication use reported symptoms and medication use of hiv-infected and hiv-uninfected rural and urban participants are described in table 3. hiv-infected participants in both areas reported that they had experienced significantly more loose stools and diarrhoea compared to hiv-uninfected participants (rural = 38.2% vs. 27.7%, p = 0.04; urban = 32.9% vs. 19.8%, p = 0.002). rural hiv-infected respondents experienced significantly more vomiting than hiv-uninfected counterparts (32.6% vs. 21.8%, p = 0.02) and involuntary weight loss of more than 3 kg (64.0% vs. 50.3%, p = 0.01). significantly more rural hiv-infected respondents had experienced chest pain or tightness (60.7% vs. 46.8%, p = 0.02) and cough for at least two weeks (53.9% vs. 40.8%, p = 0.02) compared to hiv-uninfected rural participants. on the other hand, significantly more hiv-uninfected rural participants reported joint pain (70.1% vs. 55.7%, p = 0.008), as well as high blood pressure (66.1% vs. 44.9%, p = 0.002) compared to their hiv-infected counterparts. table 3: reported symptoms, diagnoses and medication use. in urban areas, significantly more hiv-infected urban participants reported loose stools or diarrhoea for at least three days (32.9% vs. 19.8%, p = 0.002), loss of appetite (57.9% vs. 45.5%, p = 0.01), skin rash (37.8% vs. 24.6%, p = 0.004), as well as liver diseases, hepatitis or jaundice (7.3% vs. 2.9%, p = 0.03), compared to hiv-uninfected respondents. in contrast, more hiv-uninfected participants reported swelling of feet (50.8% vs. 40.9%, p = 0.04), diabetes mellitus (10.3% vs. 4.3%, p = 0.02) and hypertension (57.0% vs. 35.4%, p = 0.0001) than their hiv-infected counterparts. hiv-infected participants in both groups were significantly more likely to have been diagnosed with tb (27.3% vs. 10.2% in rural areas [p = 0.0001] and 24.4% vs. 10.7% in urban areas [p = 0.0002]). in both areas, significantly more hiv-uninfected participants compared to hiv-infected participants were on medication to treat diabetes (12.1% vs. 3.2%, p = 0.02) and hypertension: 72.6% vs. 45.2% in rural areas (p = 0.0001) and 68.2% vs. 24.4% in urban areas (p = 0.0001). on the other hand, significantly more hiv-infected participants took tb medication than their uninfected counterparts: 16.1% vs. 2.3% in rural areas (p = 0.0001) and 11.1% vs. 3.0% in urban areas (p = 0.01). anthropometric information in rural areas, the median bmi of hiv-uninfected men fell into the normal weight category at 21.0 kg/m2 compared to 18.7 kg/m2 of the hiv-infected men, indicating a median difference of 2.3 kg/m2, which was statistically significant (p = 0.02) (table 4). the median bmi of hiv-infected rural women fell within the normal range at 23.1 kg/m2, while the median bmi of hiv-uninfected rural women fell in the overweight category at 27.7 kg/m2, with a significant median difference of 4.6 kg/m2 (p = 0.009). table 4: body mass index of hiv-infected and hiv-uninfected participants in rural and urban communities. the median bmi of hiv-infected and uninfected urban men fell within the normal weight category at 19.4 kg/m2 and 20.9 kg/m², respectively, a difference which was not statistically significant (p = 0.07). the median bmi of hiv-infected and hiv-uninfected urban women fell within the overweight and obese category at 25.0 kg/m2 and 31.8 kg/m2, respectively, with a significant median difference of 6.8 kg/m2 (p = 0.001). a larger percentage of hiv-infected women had a wc below 80 cm compared to hiv-uninfected women, a difference that was statistically significant (p = 0.0003 in rural and p = 0.0001 in urban areas). significantly more hiv-uninfected women tended to have a wc in the ‘high risk’ category (wc of more than 88 cm) compared to hiv-infected women (p = 0.0003 in rural areas and p = 0.0001 in urban areas). reported clinical manifestations associated with hiv status in rural participants logistic regression was applied to identify significant clinical manifestations associated with hiv in the rural (table 5) and urban (table 6) samples. table 5: reported clinical manifestations associated with hiv status (rural). table 6: reported clinical manifestations associated with hiv status (urban). in the rural sample, for every year that age increased, the odds of having hiv decreased by 8%. hiv infection was positively associated with losing weight involuntarily (> 3 kg in the past six months; odds ratio 1.86), ever being diagnosed with tb (odds ratio 2.50) and being on tb treatment (odds ratio 3.29). in the urban sample, for every year that age increased, the odds of having hiv decreased by 7%. hiv infection was positively associated with having diarrhoea for at least three days in the past six months (odds ratio 2.04) and ever being diagnosed with tb (odds ratio 2.49). discussion the high prevalence of hiv in urban mangaung has been reported previously.21 in sub-saharan africa, the hiv epidemic was traditionally concentrated in urban areas, where significantly higher hiv prevalence rates have been recorded than in rural areas.22 possible reasons may include a correlation between hiv and the level of urbanisation in south africa, a higher percentage of younger people living in urban areas, poor living conditions (including a lack of food security) and gender relations.22 in addition to hiv-related burden of disease, the high prevalence of obesity and overweight has reached epidemic proportions in south african communities.23 a fairly large percentage of participants in the current study smoked and used snuff. lifestyle factors such as tobacco smoking, use of snuff and alcohol intake impact on quality of life of both the general population, as well as those with hiv. more hiv-infected participants tended to use alcohol than their uninfected counterparts, with beer being the most frequently consumed alcoholic beverage in all groups. alcohol may be a mediating factor in risky sexual behaviour and therefore impacts on the transmission of hiv.24 in addition, heavy drinking may lead to people on treatment not taking their medication properly.25 in the early period, infectious diseases such as hiv and lifestyle diseases were perceived to be largely different.26 however, more and more hiv-infected persons are using art, resulting in them living longer and developing chronic conditions similar to the rest of the population. significantly more hiv-infected participants reported experiencing loose stools and diarrhoea, as well as involuntary weight loss, compared to hiv-uninfected participants, and were therefore at higher risk of developing malnutrition. diarrhoea affects 40–80% of hiv-infected adults who do not receive art.27 this was confirmed in this study where the majority of hiv-infected participants were not using art (only 25% of all hiv-infected urban participants and 4.1% of rural hiv-infected participants reported using art). at the time that the study was undertaken, art was only available at one clinic in the rural southern free state, namely jagersfontein, possibly explaining why such a low percentage of hiv-infected participants in the rural areas were accessing art. some common nutritional challenges in hiv-infected individuals include inadequate oral food intake; increased nutrient needs; swallowing difficulty; altered gastrointestinal function; food–medication interactions; involuntary weight loss and impaired ability to prepare foods and meals.12 food insecurity (also observed in this study) is also an important aspect of hiv-associated weight loss and wasting. it is generally complicated further by the fact that individuals who are ill are not able to go to work to earn enough money to buy food.8 in the current study, logistic regression indicated that hiv infection was positively associated with losing weight involuntarily (more than 3 kg in the past six months) (rural) and having diarrhoea for at least three days in the past six months (urban). previous research has shown significant weight loss and a high prevalence of underweight among hiv-infected adults.28 up to 40% of patients with hiv infection report at least one episode of diarrhoea in a given month, and approximately one quarter of patients experience chronic diarrhoea at some point.10 south africa has a high tb–hiv co-infection rate of 73%, yet only 46% of tb patients are tested for hiv.29 results from the logistic regression in this study confirmed that hiv infection was positively associated with a history of tb diagnosis (rural and urban) as well as tb treatment (rural). this finding is similar to a retrospective analysis carried out in cape town by osman et al.,30 reporting that hiv-infected and hiv-unknown patients with tb have an increased risk of death during tb treatment. in the current study a larger percentage of hiv-uninfected participants reported having diabetes mellitus and hypertension. this could probably be ascribed to the lower median bmi and wc of hiv-infected participants. a similar trend has also been reported among hiv-infected black women in mangaung.31 overnutrition is prevalent among the general population of adult south africans, particularly women.32 although the prevalence of overweight and obesity was lower in hiv-infected participants in the current study, a large proportion of both hiv-infected and hiv-uninfected women were still overweight and obese, while men were more likely to have a normal or low bmi. epidemiological studies have shown gender differences in the prevalence of obesity in african nations, with levels of overweight considerably higher in females than males.32,33,34 the younger mean age of hiv-infected participants should also be kept in mind, because weight gain is often the result of ageing. the results of the current study confirm that the clinical and anthropometric manifestations of hiv infection reported in the literature are also evident in hiv-infected persons from the free state. the high prevalence of overweight (among women) associated with symptoms such as weight loss and diarrhoea that were identified in the participants in the current study, can complicate the management of hiv-infected patients in the primary healthcare setting. information about unintentional weight loss, diarrhoea and a history of tb can prompt healthcare professionals to screen for hiv, even in women who are not underweight. we acknowledge that there could have been a certain degree of bias because older and unemployed individuals were more likely to participate. it is also possible that because of limited health services, ill persons might have been more likely to participate in the study where medical examinations were conducted, especially in rural areas. furthermore, the younger age and lower bmi of hiv-infected participants complicate a comparison of clinical manifestations of hiv-infected participants to those of hiv-uninfected participants. because of these reasons, the authors are aware that the study group is probably not representative of the general population. conclusion involuntary weight loss (rural) and diarrhoea (urban) were most likely to predict hiv infection. in both samples, a history of tb (rural and urban) or tb treatment (rural) was positively associated with hiv infection. in addition, median bmi and wc of hiv-infected respondents were significantly lower than in hiv-uninfected respondents (although many hiv-infected women were still in the overweight category). the hiv-uninfected group consequently had a higher occurrence of lifestyle diseases, such as diabetes mellitus and hypertension. the results of the current study confirm the higher prevalence of opportunistic infections and the associated symptoms (such as diarrhoea and weight loss) in hiv-infected persons in this sample. information related to diarrhoea, weight loss and past or present tb is easy to obtain from patients and should prompt healthcare workers to screen patients for hiv and to implement relevant interventions. acknowledgements we acknowledge the national research foundation (nrf) for funding this study; the participants; the local community members and the research team; and dr daleen struwig, medical writer/editor, faculty of health sciences. university of the free state, for technical and editorial preparation of the manuscript. competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions m.p. was a phd student and primary author of the manuscript. c.m.w. was the principal investigator and promotor. f.c.v.r. was responsible for statistical analysis of the data. references groenewald p, vos t, norman r, et al. estimating the burden of disease attributable to smoking in south africa in 2000. s afr med j. 2007;97:674–681. webb ms, vanable pa, carey mp, blair dc. cigarette smoking among hiv+ men and women: 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https://doi.org/10.1038/oby.2002.141 abubakari ar, lauder w, agyemang c, jones m, kirk a, bhopal rs. prevalence and time trends in obesity among adult west african populations: a meta-analysis. obes rev. 2008;9:297–311. https://doi.org/10.1111/j.1467-789x.2007.00462.x kruger hs, venter cs, vorster hh. obesity in african women in the north west province, south africa is associated with an increased risk of noncommunicable diseases: the thusa study. br j nutr. 2001;86:733–740. https://doi.org/10.1079/bjn2001469 article information authors: harsha lochan1,2 preneshni naicker3,4 tsidiso maphanga5 anthea ryan3,4 komala pillay6,7 nelesh p. govender5 brian eley1,2 affiliations: 1paediatric infectious diseases unit, red cross war memorial children's hospital, south africa 2department of paediatrics and child health, university of cape town, south africa 3national health laboratory service, groote schuur hospital, south africa 4division of clinical microbiology, university of cape town, south africa 5national institute for communicable diseases: centre for opportunistic, tropical and hospital infections, national health laboratory service, south africa 6department of anatomical pathology, red cross war memorial children's hospital, south africa 7division of anatomical pathology, university of cape town, south africa correspondence to: brian eley email: brian.eley@uct.ac.za postal address: private bag x5, rondebosch 7700, south africa dates: received: 18 nov. 2014 accepted: 10 apr. 2015 published: 11 june 2015 how to cite this article: lochan h, naicker p, maphanga t. et al. a case of emmonsiosis in an hiv-infected child. s afr j hiv med. 2015;16(1), art. #352, 4 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.352 copyright notice: © 2015. the author(s). licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. a case of emmonsiosis in an hiv-infected child in this case report... open access • abstract • introduction • case report • discussion • conclusion • acknowledgements    • competing interests    • authors’ contributions • references abstract top ↑ opportunistic fungal infections can cause significant morbidity and mortality in immunocompromised patients. we describe a paediatric case of an unusual disseminated fungal infection. a three-year-old hiv-infected child with severe immunosuppression (cd4+ t-cell count 12 × 106/l) was admitted to hospital with pneumonia, gastroenteritis and herpes gingivostomatitis. despite antibacterial and antiviral therapy, he experienced high fevers and developed an erythematous maculopapular rash and abdominal tenderness. the child's condition progressively worsened during the admission. a thermally dimorphic fungus was cultured from bone marrow and identified as an emmonsia species on dna sequencing. the patient made a good recovery on amphotericin b deoxycholate and antiretroviral therapy. itraconazole was continued for a minimum of 12 months, allowing for immune reconstitution to occur. this case is the first documented description of disseminated disease caused by a novel emmonsia species in an hiv-infected child in south africa. introduction top ↑ opportunistic fungal infections can cause significant morbidity and mortality in immunocompromised patients. the diagnosis and treatment of these infections may be challenging.1,2 the manifestation of invasive fungal infection (ifi) is determined by numerous factors including the virulence of the fungal species, the adequacy of host immune responses, the size of the inoculum inhaled or disruption of mucosal barriers. individuals at risk for ifis include those who have received transplants, immunosuppressive therapy or chemotherapy for neoplastic diseases; hiv-infected patients; premature infants; and individuals with defects in neutrophil, monocyte, t-lymphocyte or b-lymphocyte function.3 in the present report, we describe an unusual disseminated fungal infection caused by a novel emmonsia species in an hiv-infected child. case report top ↑ a 3-year-old boy was admitted to red cross war memorial children's hospital, cape town, south africa, with acute gastroenteritis, pneumonia and herpes gingivostomatitis. six months earlier, hiv infection was diagnosed at a primary health care clinic. antiretroviral therapy (art) was not initiated despite it being indicated for such patients by the south african art guidelines. he was stunted (height 85 cm, height–age z-score – 3) but not wasted (weight 12.6 kg, weight-for-height z-score +1 [2006 who child growth standards]). blood results on admission showed a normocytic anaemia (haemoglobin 6.8 g/dl, reference range 10.7–13.1) and leucopaenia (white cell count [wcc] 2.71 × 109/l, reference range 6–18). the differential wcc showed that neutropaenia (1.22 × 109/l, reference range 2–5.5) and lymphopaenia (1.49 × 109/l, reference range 3.6–12) were present. a chest radiograph showed features of a bilateral pneumonia (figure 1), for which he was commenced on ampicillin and gentamicin, and acyclovir, for the pneumonia and herpes gingivostomatitis, respectively. no supplemental oxygen therapy was required at admission and empiric treatment for pneumocystis jirovecii pneumonia was not initiated. however, cotrimoxazole prophylaxis was commenced on admission. figure 1: chest radiograph on admission, with features of bilateral pneumonia. he experienced high fevers, peaking at 40 °c. on day 6 of admission, he developed diffuse abdominal tenderness and a generalised erythematous maculopapular exanthem. liver function tests (lfts) showed normal total bilirubin (2 µmol/l, ref. range 0–21) and alkaline phosphatase (alp 268 u/l, ref. range 104–345) concentrations, and elevated γ-glutamyl transferase (ggt 120 u/l, ref. range 3–22), alanine transaminase (alt 223 u/l, ref. range 5–30) and aspartate transaminase (ast 1304 u/l, ref. range 0–56) concentrations. the c-reactive protein (crp) was 58.2 mg/l (reference range 0.1–7.5). owing to the persistent fever, antimicrobial therapy was changed to ertapenem and fluconazole for presumed hospital-acquired infection. there was no growth on blood culture after 5 days of incubation, and a urine culture yielded mixed bacterial growth. tuberculin skin testing (mantoux method) and xpert mtb/rif (cepheid, inc., sunnyvale, ca, usa) on induced sputum specimens were negative. two days later, he had generalised tonic clonic seizures for which he received an intravenous loading dose of phenobarbitone. the antibiotic was empirically changed to meropenem for possible hospital-acquired meningitis. a cerebrospinal fluid specimen was bloodstained but there was no bacterial growth, and polymerase chain reaction (pcr) assays for enteroand herpesviruses were negative. the fever and maculopapular rash persisted. repeat crp (88.4 mg/l), procalcitonin (5.3 µg/l, reference range 0.0–0.5), ferritin (91 705 µg/l, reference range 20–200) and triglyceride concentrations (4.7 mmol/l, reference range 0.3–1.1) were elevated. the differential diagnosis included haemophagocytic lymphohistiocytosis (hlh), disseminated tuberculosis and invasive fungal infection. the patient subsequently developed respiratory distress requiring supplemental nasal prong oxygen therapy. repeat chest radiography was unchanged from admission with features not suggestive of tuberculosis or fungal infection. he was given packed red blood cell, platelet and cryoprecipitate transfusions for severe anaemia (hb 5.6 g/dl), thrombocytopaenia (platelet count 52 × 109/l) and hypofibrinogenaemia (fibrinogen concentration 1.0 g/l, reference range 1.7 g/l – 4.0 g/l), respectively. skin and bone marrow biopsies were performed on day 10 in hospital. skin histology showed extensive karyorrhexis and numerous dermal histiocytes containing cytoplasmic small fungal organisms. grocott and periodic acid–schiff stains were positive and suggestive of dermal histoplasmosis (figure 2). skin culture did not grow fungi or myco­bacteria. bone marrow histology revealed histiocytosis and haemophagocytosis consistent with a diagnosis of hlh. fungal stains showed scanty structures 1.5 µm × 2.5 µm in diameter and morphologically compatible with histoplasma capsulatum. a diagnosis of disseminated fungal infection with secondary hlh was made and intravenous amphotericin b deoxycholate 1 mg/kg/day commenced 14 days later. figure 2: skin histology biopsy demonstrating fungal elements measuring 1.5 μm × 2.5 μm using (a) periodic acid-schiff and (b) grocott methenamine silver stains. culture of the bone marrow aspirate in a bactec mycof/lytic bottle (becton dickinson, new jersey) flagged positive after 17.6 days of incubation, and small yeasts were seen on gram stain. the isolate was submitted to the national institute for communicable diseases for further identification. the fungus was converted from the mycelial to yeast phase on brain heart infusion agar with 5% sheep blood (diagnostic media products, sandringham) at 35 °c and morphologically characterised based on dna sequencing of the internal transcribed spacer region of the isolate's ribosomal gene. the isolate was identified as the thermally dimorphic fungus emmonsia species. the dna sequence was the same as those of previously described isolates of a novel emmonsia species. an investigational urine histoplasma antigen test (immunomycologics, norman, ok) was negative. art, comprising abacavir, lamivudine and efavirenz, was commenced 3 days before amphotericin b was started. the lft concentrations had marginally improved at this stage with an alt of 156 u/l, ast 560 u/l and ggt 102 u/l. the baseline cd4+ t-cell count (percentage) was 12 × 106/l (0.45%) and hiv-1 viral load 2 149 305 rna copies/ml. after art and amphotericin b were commenced, he made a remarkable recovery. within 3 days, supplemental oxygen was discontinued and, after 5 days, the skin lesions and fever had resolved. the abdominal tenderness and abnormal lfts resolved on day 11 and 12 of amphotericin b, respectively. daily amphotericin b was continued for 6 weeks via a central venous catheter. adverse effects were minimised through pre-emptive hydration before amphotericin b infusions, close monitoring of renal function, potassium and magnesium concentrations and, where necessary, electrolyte replacement. itraconazole 100 mg daily orally was commenced once amphotericin b had been discontinued. because of its potential for reducing the bioavailability of itraconazole, efavirenz was replaced with a lopinavir/ritonavir co-formulation. six months after commencing art, the patient was well, virologically suppressed (hiv-1 viral load < 40 rna copies/ml), had a cd4+ t-cell (percentage) of 884 × 106 cells/l (17.9%) and normal lfts. at last evaluation, there was no clinical evidence of active fungal infection. the intention is to maintain him on itraconazole for a minimum of 12 months and until his cd4 count reaches 25%, before considering discontinuation of antifungal therapy. discussion top ↑ emmonsia species, a group of dimorphic fungi, are found in soil, and some species can cause pulmonary infection in rodents.4 the genus currently contains three species, namely emmonsia crescens, emmonsia parva and emmonsia pasteuriana. infection caused by emmonsia species has been described in hiv-uninfected adults and one child. the infections were caused by e. crescens and e. parva, resulting in predominantly pulmonary adiaspiromycosis and occasional cutaneous manifestations.4,5,6,7 more recently, invasive infection caused by a new species of emmonsia closely related to e. pasteuriana was documented in 13 hiv-infected adults with advanced hiv disease in south africa.8 our case is the first description of disseminated disease caused by this new emmonsia species in an hiv-infected child. all 13 adult patients presented with very low cd4+ t-cell counts, anaemia and widespread skin lesions. the skin manifestations ranged from erythematous papules to plaques and ulcers. twelve had a documented fever and 8 of 9 who underwent lfts had deranged liver enzymes, suggesting hepatic involvement. our patient similarly developed severe immune suppression, anaemia, an erythematous papular eruption and deranged lfts, and in addition had neutropaenia and lymphopaenia. in that series, the original histological diagnosis on skin biopsy samples morphologically resembled h. capsulatum. on gene sequencing, the fungus was identified as belonging to the genus emmonsia.8 not all fungi require molecular diagnosis. however, emmonsia species is difficult to diagnose by morphological appearance alone, necessitating molecular confirmation. the role of the beta d glucan assay in the diagnosis of emmonsiosis is currently not known. the assay is likely to be elevated but, as it detects most common fungi, is unlikely to be specific for emmonsia species. our patient was empirically commenced on fluconazole during the course of his clinical deterioration. fluconazole is less active than itraconazole against dimorphic fungi especially histoplasmosis, probably explaining the lack of clinical response until amphotericin b deoxycholate was commenced.9,10 currently there are no treatment guidelines for hiv-associated disseminated emmonsia infection. our regimen of amphotericin b deoxycholate followed by maintenance itraconazole therapy was extrapolated from treatment guidelines for other dimorphic fungal infections.11 duration of therapy depends on the extent of the disease. as our patient had disseminated fungal infection with severe immunosuppression, we elected to follow recommendations for treating disseminated histoplasmosis in hiv-infected patients. lifelong antifungal prophylaxis may not be required in our patient because he has already had a good immunological response.12 itraconazole is metabolised by the cytochrome p450 c3a4 enzyme. this pathway is also responsible for the metabolism of the non-nucleoside reverse transcriptase (nnrti) class of antiretroviral drugs. theoretically, levels of either the itraconazole or nnrti could be affected. there is a paucity of literature describing the drug–drug interactions between itraconazole and the nnrtis. a case report of an hiv-infected male patient with disseminated histoplasma infection demonstrated reduced levels of itraconazole and an increase in the urine histoplasma antigen level while he was receiving efavirenz. after switching to a protease inhibitor, the serum drug levels of itraconazole increased and the urine histoplasma antigen levels declined.13 drug levels of itraconazole were not monitored in the case described because the test is not available in south africa. conclusion top ↑ the recently published case series and the present case report confirm that emmonsiosis occurs among both hiv-infected adults and children in south africa.8 prolonged incubation (up to 6 weeks) of the fungal culture may be necessary for the diagnosis. this infection should be considered in immunocompromised patients presenting with persistent fever and other clinical features suggestive of ifi. acknowledgements top ↑ competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions h.l. (red cross war memorial children's hospital), b.e. (red cross war memorial children's hospital), n.p.g. (national health laboratory service) and p.n. (groote schuur hospital) reviewed, contributed to and approved the final submitted manuscript. k.p. (red cross war memorial children's hospital) was involved in assessing the skin histology and preparation of the slides featured in the report. p.n. and a.r. (groote schuur hospital) were responsible for the microbiological diagnosis. n.p.g. and t.m. (national health laboratory service) carried out the molecular analysis for the final diagnosis. references top ↑ mofenson lm, brady mt, danner sp, et al. guideline for the prevention and treatment of opportunistic infections among hiv-exposed and hiv-infected children. centre for diseases control mortality and morbidity weekly report. 2009;58. armstrong-james d, meintjies g, brown gd. a neglected epidemic: fungal infections in hiv/aids. trends in microbiol. 2014;22:120–127. http://dx.doi.org/10.1016/j.tim.2014.01.001 guarner j, brandt me. histopathological diagnosis of fungal infections in the 21st century. clin microbiol rev. 2011;24:247–280. http://dx.doi.org/10.1128/cmr.00053-10 anstead gm, sutton da, graybill gr. adiaspiromycosis causing respiratory failure and a review of human infections due to emmonsia and chrysosporium spp. j clin microb. 2012;50:1346–1354. http://dx.doi.org/10.1128/jcm.00226-11 dot j-m, debourgogne a, champigneulle j, et al. molecular diagnosis of disseminated adiaspiromycosis due to emmonsia crescens. j clin microbiol. 2009;47:1269–1273. http://dx.doi.org/10.1128/jcm.01885-08 nuorva k, pitkänen r, issakainen j, huttunen n-p, juhola m. pulmonary adiaspiromycosis in a two year old. j clin pathol. 1997;50:82–85. http://dx.doi.org/10.1136/jcp.50.1.82 pelegrìn i, ayats j, xiol x, et al. disseminated adiaspiromycosis: case report of a liver transplant patient with human immunodeficiency infection, and literature review. transpl infect dis. 2011;13:507–514. http://dx.doi.org/10.1111/j.1399-3062.2011.00611 kenyon c, bonorchis k, corcoran c, et al. a dimorphic fungus causing disseminated infection in south africa. n engl j med. 2013;369:1416–1424. http://dx.doi.org/10.1056/nejmoa1215460 wheat, lj, mawhinney s, hafner r, et al. treatment of histoplasmosis with fluconazole in patients with acquired immunodeficiency syndrome. am j med. 1997;103:223–232. http://dx.doi.org/10.1016/s0002-9343(97)00151-4 wheat lj, connolly p, smedema m, et al. emergence of resistance to fluconazole as a cause of failure during treatment of histoplasmosis in patients with acquired immunodeficiency disease syndrome. clin infec dis. 2001;33:1910–1913. http://dx.doi.org/10.1086/323781 wheat lj, freifeld ag, kleiman mb, et al. clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the infectious diseases society of america. clin infect dis. 2007;45:807–825. http://dx.doi.org/10.1086/521259 goldman m, zackin r, fichtenbaum cj, et al. safety of discontinuation of maintenance therapy for disseminated histoplasmosis after immunological response to antiretroviral therapy. clin infect dis. 2004;38:1485–1459. http://dx.doi.org/10.1086/420749 hoonmo lk, hamill rj, andrade ra. drug–drug interaction between itraconazole and efavirenz in a patient with aids and disseminated histoplasmosis. clin infect dis. 2007;45:e77–79. http://dx.doi.org/10.1086/520978 june 2006 make up 1 3 lessons from hiv epidemiology in africa our understanding of prevention interventions can be framed by two general principles from infectious diseases epidemiology. first, the transmission dynamics of hiv can be described in terms of the basic reproductive number (ro), which represents the number of secondary infections emanating from a singe infectious individual (i.e. a primary case) introduced into a population of susceptible individuals. the equation: ro = ßcd shows how the basic reproduction number ro is influenced by the probability of hiv transmission between individuals (ß, a function of both the infectiousness of the primary case and the susceptibility of uninfected individuals), as well as the number of sexual partners (c) and the duration of infectiousness (d) of the primary case.2 evidence from different parts of africa suggests that variability in both the transmission probability and sexual partner changes are important in explaining the variable course of hiv epidemics in different regions. the second key hiv prevention principle suggested by infectious diseases epidemiology is that reductions in transmission risk among the most sexually active members of the population can have a disproportionately large impact on the hiv epidemic. in other words, the most efficient and effective prevention strategies should be targeted at specific population groups where hiv acquisition risk is high. recent epidemiological research demonstrates how these principles may operate in sub-saharan africa. at a national level, zimbabwe is one of the few countries that has seen a marked decrease in hiv prevalence that can be linked to changes in sexual behaviours (other notable examples include uganda and thailand). one recent analysis from zimbabwe,3 based on repeated studies of a rural zimbabwean population between 1998 and 2003, shows a 23% reduction in hiv prevalence among men aged 17 29 years and 49% reduction among young women aged 15 24 years. these reductions have been attributed to proportional decline in sexual risk behaviours, namely delayed sexual debut, reduction in numbers of casual sexual partners and more condom use among females. further insights into the population spread of hiv in africa come from the four cities study,4 a cross-sectional study of hiv, other sexually transmitted infections, and sexual behaviours from kisumu (kenya), ndola (zambia), cotonou (benin) and yaounde (cameroon). this study suggested that high male circumcision rates in west africa may have reduced the rate of hiv and other stis, while genital ulcer disease, especially herpes simplex virus type 2 (hsv-2), may have contributed to higher rates in east and southern africa. male circumcision the role of male circumcision in the prevention of hiv and sti acquisition became a hotly debated topic when a number of cross-sectional studies from different parts of africa suggested that this intervention might have a protective effect,5,6 and this finding has been supported by more recent data suggesting reductions in hiv transmission among hiv serodiscordant couples where the man is circumcised.7 in addition to these epidemiological data, there are biologically plausible mechanisms for the observed reduction in hiv-1 acquisiton among circumcised males. the inner mucosa of the foreskin is rich in hiv-1 target cells, e.g. dendritic cells, cd4+ t cells, and macrophages that express relevant hiv-1 binding receptors such as chemokine receptors (ccr5) and dc-sign.8 by contrast the external foreskin is keratinised and much less vulnerable to hiv infection. after circumcision, the only exposed mucosa is in the urethral meatus. removal of the foreskin's target cells and receptors can represent a direct biological mechanism of protection. the southern african journal of hiv medicine june 2006 p r e v e n t i o n aids prevention in south africa sinead delany-moretlwe1*, glenda gray2*, ashraf kagee3*, landon myer4*, adrian puren6*, gita ramjee7*, helen rees1*, leslie swartz3*, linda-gail bekker5 more individuals were newly infected with hiv in 2005 than any other year. sub-saharan africa and especially southern africa bears the brunt of this pandemic. although the picture in sub-saharan africa is largely one of a 'stable' epidemic where aidsrelated mortality is matched by the incidence of new infections, some countries in the southern regions have continued to see increasing hiv prevalence.1 in this light, there is an urgent need for new approaches to hiv prevention. here we review the current state of hiv prevention technologies, with particular emphasis on new approaches to hiv prevention that have particular promise in southern africa. the focus here is on interventions that address sexually transmitted hiv, since the vast majority of new hiv infections in africa are through heterosexual contact, and other important hiv prevention interventions (such as blood safety interventions and the prevention of mother-to-child transmission) are not included. reproductive health & hiv research unit1 and perinatal hiv research unit2, university of the witwatersrand; department of psychology, stellenbosch university3; infectious diseases epidemiology unit, school of public health & family medicine4, and desmond tutu hiv centre, institute of infectious diseases & molecular medicine5, university of cape town; national institute of communicable diseases6; and hiv prevention research unit, medical research council7. *authors are listed alphabetically. june 2006 the southern african journal of hiv medicine1 4 three randomised controlled trials (rcts) have recently been initiated in sub-saharan africa to explore the efficacy of male circumcision. the results of the rct conducted in orange farm, south africa, demonstrated a 60% reduction in the risk of acquiring hiv infection over 21 months of follow-up in newly circumcised, 18 24-year-old males. the incidence rate in the intervention group was 0.7 per 100 person years while in the control group it was 2.2 per 100 person years, a crude incidence rate ratio of 0.35 (95% ci: 0.20, 0.60). the other two rcts (in uganda and kenya) are still to be completed. should these randomised controlled trials also show the efficacy of male circumcision in reducing hiv acquisition risk, the implementation of this modality in the general population will still require further investigation of a range of issues including acceptability, rates and types of adverse events of the procedure, cost and logistics of introduction, and importantly the long-term effect of circumcision on behaviours such as partner reduction and condom use.9 vaccines an effective preventive hiv vaccine would provide the best method for controlling the hiv pandemic, especially in underresourced countries, and so any successful vaccine will need to be applicable to all regions regardless of virus subtype and be licensed for use in all age groups including older children and adolescents. after almost 20 years of hiv vaccine clinical trials, and numerous phase 1 and 2 studies, there are a variety of vaccine products in the pipeline that look hopeful enough to be subjected to efficacy trials.10 vaccine strategies for a number of years the vaccine pipeline was limited to simple gp 120 or gp 160 proteins based on lab strains of the virus, synthetic peptides and simple poxvirus hiv-recombinant vectors. the constructs currently in the pipeline include gp 120 constructs based on clinical hiv isolates, bird virus vectors and other vectors such as modified vaccinia ankara and venezuelan equine encephalitis virus replicon expressing multiple hiv genes, and different constructs of naked dna. the most promising candidates in the last few years have included live attenuated vectors containing a variety of hiv genes. these attenuated vectors include adenovirus, associated adenovirus and sindbis.11,12 challenges to vaccine design the lack of an immune correlate of protection (clear type of immune response needed to provide protection against hiv) and the lack of an adequate animal model that can mimic human disease infection poses significant scientific challenges to developing a successful vaccine. in addition hiv-1 genetic diversity may complicate the development of a globally relevant hiv vaccine. diversity may be addressed by the development of vaccine candidates comprised of cocktails of proteins of regional variants with the assumption that the immune responses elicited by a multiclade, multi-gene vaccine will be of sufficient cross-reactivity to protect against a range of wild-type strains.13 protection required current hiv vaccine candidates elicit reasonably potent cellular immune responses, but very low levels of neutralising antibodies. cytotoxic t-lymphocytes are part of the cellular immune response that controls viral replication. vaccines that produce strong ctl responses are more likely to control viral replication and thus reduce viral load. used as preventive vaccines they may then modify disease in an individual who has breakthrough infection, leading to less morbidity, longer time to aids and possibly less hiv transmission. antibodies provide the first line to the immune system defence and neutralising antibodies inactivate or prevent the virus making contact with target cells, providing the best possibility to abort or prevent infection. neutralising antibody stimulation would thus be a highly sought after characteristic in a preventive vaccine, but has to date been very difficult to achieve. the gp 160 protein on the outside of the virus is important for stimulating neutralising antibodies but is oligomeric and susceptible to glycosylation. most hiv infections occur via the mucosal route and so it may be important to stimulate mucosal immunity in rectal and genital tracts as well as cellular and humoral responses in the blood to achieve protection.10,14 prime-boosting is a new combination strategy that seeks to enhance vaccine responses by invoking various types of immunity. a typical strategy would involve priming with a naked dna vaccine which would be expected to do little more than stimulate production of memory t cells, followed by boosting with a live vector/protein, which would then stimulate a strong cellular response as well as neutralising antibodies. so far early studies in humans have shown this to be safe.12 promising candidates that are further on in human testing a number of world-wide networks, e.g. the hiv vaccine trials network (hvtn), the international aids vaccine initiative and the south african aids vaccine initiative, as well as pharmaceutical companies, are involved in the global effort to develop and test preventive vaccines. after 20 years of ongoing research and only one completed, albeit ineffective, phase 3 trial in aidsvax, a bivalent recombinant gp120 vaccine, the hiv vaccine development pipeline is full with a number of promising candidates that look good enough to move beyond phase 1 and 2 clinical trials into efficacy testing. the niaid in collaboration with merck and the hvtn have initiated a test of concept study (phase iib) in north america and south america, the carribean and australia. this randomised placebo-controlled trial will test merck's hiv vaccine, the mrk ad5 hiv-1 gag/pol/nef vaccin, in a study that will enroll 3 000 participants. the trial is set to answer two questions: whether (i ) pre-existing immunity to the adenovirus subtype 5 (ad5), which is the vector used in this vaccine design, dampens the immune response to this vaccine; and (ii ) the cellular immune response elicited by this vaccine is robust enough to protect against infection. this trial will also assess disease progression in those who become infected despite receiving the vaccine. a sister trial, the hvtn 503, is scheduled to take place in south africa later in 2006. since south africa is a subtype c region 1 5 where there is a high prevalence of pre-existing immunity to ad5, this trial will answer the question regarding the importance of sub-type in vaccine design as well as the role of pre-existing immunity to ad5. three thousand adults, the majority of whom are likely to be women, will participate in this trial. shortly thereafter, a second large efficacy trial is planned to evaluate the vrc multiclade dna vaccine and the vrc multiclade ad5-based vaccine sequentially also in a primeboost strategy. saavi vaccine development programme the south african aids vaccine initiative (saavi) is also contributing significantly to the global effort. not only are there several community clinical trial sites being prepared around the country to ensure that there are large numbers of well-educated and carefully prepared healthy volunteers to participate in these imminent large-scale trials, but in collaboration with the university of cape town there are also two products that are about to enter into human testing. the saavi dna-c2 is a multigene subtype-c dna vaccine and the saavi mva-c is a multigene hiv-1 subtype-c recombinant mva vaccine. these two south african vaccine candidates will be tested in a ‘prime-boost’ phase i trial design in collaboration with the hvtn both in south africa and the usa in 2007. adolescent involvement in vaccine trials one of the most effective ways to curb the epidemic in the developing world would be to vaccinate older children and adolescents prior to their sexual debut. the use of an hiv vaccine in this population will require clinical trials in adolescents to determine the vaccine’s safety and immunogenicity. a precise strategy for the involvement of adolescents in clinical trials is urgently required, and again saavi and south african researchers are leaders in the international dialogue on this topic.15,16 vaccine manufacture, procurement and distribution previous vaccine history has shown that once an efficacious vaccine is developed the usual pattern of deployment is in the developed world first and the developing world later. a plan for the urgent procurement and distribution of a successful hiv vaccine when available needs to exist to make the vaccine available it is where needed most – namely in resource-poor settings – as quickly as possible. this includes mechanisms for pricing, global financing, demand estimates and preparedness for production capacity, appropriate delivery systems and strategies for high-risk populations. harmonisation of african regulatory systems and guidelines for approval are urgent, not only for this later phase of vaccine deployment, but also during this current important phase of vaccine testing. the newly established hiv vaccine enterprise aims to co-ordinate global efforts around these issues.17 microbicides in view of the problems associated with male condoms, developing hiv prevention technologies that are under the control of women is an important avenue for hiv prevention. one of the most promising technologies currently in largescale human trials is vaginal microbicides. a microbicide is a substance formulated to significantly reduce transmission of hiv and other sexually transmitted infections (stis) when applied topically to the vagina or rectum.18,19 they can be formulated as gels, creams, films, suppositories, sponges or vaginal rings, or used in conjunction with other barrier methods such as the diaphragm or cervical cap. the mode of action of microbicides includes antiviral activities, barrier action between the pathogens and vaginal and rectal tissue, or modification of vaginal or rectal milieu which makes hiv infection less likely.20 compared with male or female condoms, microbicides are expected to interfere less with intimacy and sexual pleasure and be more discreet.21 although microbicides are primarily being developed for use by women, it is possible that they may have a bidirectional protective effect for men as well. as women's reproductive intentions alter throughout their lives, both contraceptive and noncontraceptive microbicides are being developed. another research agenda is to develop a microbicide that is protective for partners practising anal sex, as such a product could be used for both heterosexual and msm sex. importantly, a microbicide shown to be safe and effective should be easily available over the counter. mathematical modelling of a microbicide assumed to be 60% efficacious and to have 20% uptake by women at risk of hiv suggests that 2.5 million new hiv infections could be averted in developing countries. there are currently 16 candidate microbicides in clinical development including five products in advanced stages of clinical testing (phase iib/iii trials). all of these products are being tested in africa, and most are being tested in south africa specifically. more than 20 000 women will take part in the current trials over the next 5 years. results of the first products are expected to be available in late 2008.12,22 barrier methods currently the most widely available tool for prevention of hiv infection during sexual intercourse is the male condom. male condoms afford a high degree of protection: consistent and correct male condom use reduces hiv transmission by between 80% and 97%. however, in many parts of africa condoms are not acceptable as they act as a contraceptive and may also interfere with sexual pleasure and reduce intimacy. men predominantly control use of male condoms during sexual intercourse, and many women do not have the power to negotiate condom use in their relationships. as a result, there have been significant recent developments in other types of barrier methods to prevent the sexual transmission of hiv.23 the female condom numerous studies have shown that the female condom is an acceptable method for many women and men, and is a valuable alternative for women whose partners refuse to use male condoms. unlike the male condom, the female condom can be inserted some time before sex, and does not depend on the same degree of male co-operation for its successful use. the female condom is a soft, loose-fitting polyurethane the southern african journal of hiv medicine june 2006 june 2006 the southern african journal of hiv medicine1 6 sheath that covers the vagina, cervix and external genitalia. laboratory studies have shown that the female condom is effective at preventing the transmission of viruses and bacteria. while there are less clinical data available than for the male condom, the who has agreed that the female condom is effective in preventing hiv and other sexually transmitted infections (stis). however, despite the effectiveness and acceptability of the female condom, they are not widely distributed or available in south africa. this is partly due to costs (more than 10 times that of a male condom) but also to a lack of commitment to this femaleinitiated technology by donors and governments. nonetheless, the female condom represents an important hiv prevention option where it is available.24,25 cervical barrier methods in the last few years, interest has grown in cervical barrier methods as potential technologies for hiv prevention. the cervix is covered by a single cell layer of columnar epithelium, in contrast to the stratified squamous epithelium of the vagina. as a result cervical columnar epithelium is more friable than the stratified squamous epithelium of the vaginal walls, making it more susceptible to mechanical disruption. this anatomical vulnerability is compounded by the increased presence around the cervix of surface receptors targeted by hiv as well as inflammatory cytokines, both which may also facilitate hiv infection. additional evidence from primate experiments has shown that cervical epithelium is the first site of infection after vaginal exposure to simian immunodeficiency virus (siv). on the basis of this evidence, barrier methods that protect the cervix specifically (such as the diaphragm, the sponge and the cervical cap) may be useful tools for hiv prevention, and there are currently a number of trials of this topic underway in southern africa. there is ample evidence that the different cervical barrier methods are safe, easy to use, inexpensive and highly acceptable to both women and men. new cervical barriers are in development, and the efficacy of these methods against pregnancy, stis and hiv is being investigated. in addition, should an effective microbicide be identified, the combination of a cervical barrier and a microbicide may offer even greater potential for prevention of hiv transmission.26 herpetic genital ulcer disease control the role of bacterial stis (including syphilis, chlamydia infections and gonorrhoea) in increasing the risk of hiv infection is well established. more recently, hsv-2 has received attention as an important risk factor for heterosexually-transmitted hiv. hsv-2 is the most common sexually transmitted infection worldwide, typically causing recurrent episodes of genital ulcers, although a large proportion of infected individuals are asymptomatic.27-29 recently, there have been growing concerns about the role of hsv-2 in hiv transmission given the fact that it is the most common cause of recurrent genital ulcer disease in a significant proportion of the adult population, which is also at risk for hiv. genital ulcers act as a portal of entry or exit for hiv and activated lymphocytes, including cd4 cells, are frequently recruited to these sites of inflammation and are primed to receive or present hiv at the site of ulceration. a recent meta-analysis of 19 epidemiological studies showed that prevalent hsv-2 may increase the risk of hiv acquisition in men and in women by as much as 3-fold even after adjustment for sexual behaviour, and that hsv-2 may account for as many as 38 60% of new hiv infections in women, and 8 49% in men in the general populations.30 controlling hsv-2 may have an important impact on hiv incidence, particularly in settings where hsv-2 prevalence is high. currently the options for herpes control are limited to a few strategies: primary prevention through condom use and behavioural modification will be useful in uninfected populations, e.g. young people. treatment of hsv-2, primarily with acyclovir, may also have an effect on hiv and randomised control trials are currently underway to investigate this. there is strong evidence that suppressive treatment for genital herpes reduces the levels of hiv in the genital secretions of infected women (a potential marker of infectiousness and therefore transmission). the results of trials to evaluate the effect of suppressive therapy on hiv acquisition and hiv transmission are likely to be available within 2 years.31 sociobehavioural interventions in addition to the biomedically focused interventions discussed above, behavioural interventions remain a valuable strategy for reducing new infections. we know what specific behaviours contribute to the spread of hiv in south africa (large numbers of new sexual partners and unprotected sexual contacts), and yet the virus continues to spread. two theories have been used to explain and predict the spread of hiv and attempts to curb this spread.32 the first theory focuses on individual behaviour and behaviour change, and discusses the ways in which intentions, attitudes and beliefs affect health behaviour. the second theory involves understanding broader social issues which affect the epidemic. for example, it seems clear that an important part of what drives the epidemic is not individual intentions and behaviours but broader social, economic and cultural conditions. women, for example, may find themselves in a situation in which they have little power or decision-making in their lives, and for reasons of immediate survival may be forced into transactional sexual relationships with men that will involve unprotected sex. a key challenge for those wishing to reduce the spread of hiv through behaviour change is to design interventions that bridge the divide between individual models of behaviour change and focus on broader social issues. health practitioners, by virtue of their training, are often better at thinking about individual level issues and interventions than in intervening and assessing interventions at a broad social level. the need for both levels does, however, remain. successes in hiv prevention in african countries such as uganda, furthermore, have similarly been attributed both to individuallevel interventions and to the commitment of government as a whole to creating social conditions and relationships in which safe sex is not a taboo topic but an issue which is seen to concern everyone. campbell33 has discussed the importance of what she terms 'political will' in curbing and containing the epidemic. 1 7 at a practical level, voluntary counselling and testing (vct) represents an important strategy for changing sexual behaviours. there is substantial evidence that appropriate risk reduction messages provided during vct can have a significant impact in reducing high risk behaviours among individuals who wish to be tested for hiv. in one multicountry trial, including sites in kenya and tanzania, there was a more than 30% reduction in unprotected intercourse among individuals receiving vct compared with individuals who received health promotion messages only. this study and related research has contributed to what some policy makers have called a ‘serostatus approach’ to addressing the hiv epidemic, in which hiv testing is a critical first step that can be used to target services for hiv prevention (for hiv-negative individuals) or care and treatment (for hiv-positive individuals).34 within south africa, a number of large, multifaceted behaviour change campaigns have been developed to reduce sexual risk behaviours, particularly among young people. two of the best known of these are soul city (a multimedia intervention including television, radio and magazines) and lovelife (a media campaign linked to adolescent-focused health care services). it is difficult to examine the precise impacts of campaigns of this type, but preliminary evaluations have suggested that these interventions have played a valuable role in both increasing awareness and knowledge of hiv/aids among individuals, and in shifting popular perceptions of the disease in communities heavily affected by hiv. however the role that these interventions may play in altering the incidence of hiv infection remains unknown.12 conclusion while prevention efforts need to be redoubled in sub-saharan africa, where prevalence rates are so high, there is at least some hope for success.1 the most recent unaids report on the global aids epidemic states: ‘among the notable new trends are the recent declines in national hiv prevalence in two subsaharan african countries (kenya and zimbabwe), urban areas of burkina faso, and similarly in haiti, in the caribbean, alongside indications of significant behavioural change – including increased condom use, fewer partners and delayed sexual debut.’ however, perhaps even more spine-chilling are indications that in regions where hiv rates had declined, a resurgence in new infections particularly among specific risk groups such as young msm populations, is occurring. a subject we have not covered here is the ultimate impact of antiretroviral treatment (art) and the impact that the new drive to increase world access to art will have on transmission and subsequently prevalence in many parts of the world. at the very least, in this new era of antiretroviral access, limiting numbers requiring antiretrovirals in the long term is good medicine and cost saving. this demands more research into efficacious prevention strategies and monitoring vigilance. it has been said that an ounce of prevention is worth a pound of cure ... but it takes a ton of work! references 1. asamoah-odei e, garcia calleja jm, boerma jt. hiv prevalence and trends in subsaharan africa: no decline and large subregional differences. lancet 2004; 364: 35. 2. anderson rm, may rm. infectious diseases of humans: dynamics and control. oxford: oxford university press, 1991. 3. gregson s, garnett gp, nyamukapa ca, et al. hiv decline associated with behaviour change in eastern zimbabwe. science 2006; 311: 664-666. 4. buve a, weiss ha, laga m, et al. the epidemiology of trichomoniasis in women in four african cities. aids 2001; 15: suppl 4, s89-s96. 5. auvert b, taljaard d, lagarde e, sobngwi-tambekou j, sitta r, puren a. randomized, controlled intervention trial of male circumcision for reduction of hiv infection risk: the anrs 1265 trial. plos med 2005; 2(11): e298. 6. scott be, weiss ha, viljoen ji. (2005) the acceptability of male circumcision as an hiv intervention among a rural zulu population, kwazulu-natal, south africa. aids care 2005; 17: 304-313. 7. gray rh, kiwanuka n, quinn tc, et al. male circumcision and hiv acquisition and transmission: cohort studies in rakai, uganda. rakai project team. aids 14: 2371-2381. 8. patterson bk, landay a, siegel jn, et al. susceptibility to human immunodeficiency virus-1 infection of human foreskin and cervical tissue grown in explant culture. am j pathol 2002; 161: 867-873. 9. gray r, azire j, serwadda d, et al. male circumcision and the risk of sexually transmitted infections and hiv in rakai, uganda. aids 2004; 18: 2428-2430. 10. mcmichael aj. hiv vaccines. annu rev immunol 2006; 24: 227-255. 11. joseph j, etcheverry f, alcami j, maria gj. a safe, effective and affordable hiv vaccine – an urgent global need. aids rev 2005; 7(3):131-138. 12. abdool-karim ss, abdool-karim q. hiv/aids in south africa. cambridge: cambridge university press, 2005. 13. slobod ks, coleclough c, bonsignori m, et al. hiv vaccine rationale, design and testing. curr hiv res 2005; 3(2): 107-112. 14. belyakov im, ahlers jd, berzofsky ja. mucosal aids vaccines: current status and future directions. expert rev vaccines 2004; 3(4 suppl):s65-s73. 15. jaspan hb, lawn sd, safrit jt, bekker l-g. the maturing immune system: implications for development and testing hiv-1 vaccines for children and adolescents. aids 2006; 20(4): 483-494. 16. bekker l-g, jaspan h, mcintyre j, wood r, gray g. adolescents and hiv vaccine trials: what are the clinical trial site issues? j int assoc physicians aids care 2005; 4(4): 93-97. 17. barth-jones dc, cheng h, kang ly, et al. cost effectiveness and delivery study for future hiv vaccines. aids 2005; 19(13): w1-w6. 18. scholand sj, desimone ja, pomerantz rj. anti-hiv-1 microbicides – ‘chemical condoms’ designed to limit the scourge of the hiv-1 pandemic. curr pharm des 2005; 11(29): 3747-3756. 19. stone a. microbicides: a new approach to preventing hiv and other sexually transmitted infections. nature review 2002; 1: 977-985. 20. d’cruz oj, uckun fm. dawn of non-nucleoside inhibitor-based anti-hiv microbicides. j antimicrob chemother 2006; 57(3): 411-423. epub 23 jan 2006. 21. orner p, harries j, cooper d, challenges to microbicide introduction in south africa. soc sci med 2006; 63(4): 968-978. 22. van damme l, ramjee g, alary m, et al. effectiveness of col-1492, a nonoxynol -9 vaginal gel, on hiv transmission in female sex workers: a randomized controlled trial. lancet 2002; 360: 971-977. 23. davis kr, weller sc. the effectiveness of condoms in reducing heterosexual transmission of hiv. family planning perspectives 1999; 31: 272-279. 24. smit j, beksinska m, vijayakumar g, mabude z. short-term acceptability of the reality polyurethane female condom and a synthetic latex prototype: a randomized crossover trial among south african women. contraception 2006; 73(4): 394-398. epub 3 feb 2006. 25. beksinska me, rees hv, dickson-tetteh ke, et al. structural integrity of the female condom after multiple uses, washing, drying, and re-lubrication. contraception 2001; 63: 33-36. 26. warren m, philpott a. expanding safer sex options: introducing the female condom into national programmes. reprod health matters 2003; 11(21): 130139. 27. sacks sl, griffiths pd, corey l, et al. hsv-2 transmission. antiviral res 2004; 63: suppl 1: s27-s35. 28. ramjee g, williams b, gouws e. the impact of incident and prevalent herpes simplex virus-2 infection on the incidence of hiv-1 infection among commercial sex workers in south africa. j acquir immune defic syndr 2005; 39(3): 333-339. 29. wasserheit j. epidemiologic synergy: interrelationships between human immunodeficiency virus infection and other sexually transmiited diseases. sex transm dis 1992; 19: 61-77. 30. freeman ee, weiss ha, glynn jr. herpes simplex virus 2 infection increases hiv acquisition in men and women: systematic review and meta-analysis of longitudinal studies. aids 2006; 20(1): 73-83. 31. celum c, levine r, weaver m, wald a. genital herpes and human immunodeficiency virus: double trouble. bull world health organ 2004; 82(6): 447-453. 32. aaro le, flisher aj, kaaya s, et al. promoting sexual and reproductive health in early adolescence in south africa and tanzania: development of a theoryand evidence-based intervention programme. scand j public health 2006; 34(2):150-158. 33. campbell c. letting them die: why hiv/aids prevention programmes fail. oxford: james currey, bloomington & indianapolis: indiana university press, and cape town: double story/juta, 2003. 34. urassa w, kaaya s, mwakagile d, et al. evidence of a substantial decline in prevalence of hiv-1 infection among pregnant women: data from 1995 to 2003 in dar es salaam, tanzania. scand j public health 2006; 34(3): 272-278. the southern african journal of hiv medicine june 2006 ofumhtr 2001-----------the southhln african jour.nal of hiv medicine ethical issues elsabe klinck legal advisor, south african medical assoaac£on known to the employer. if the employee provides informed consent that his or her status may be disclosed to the employer, the employer must keep that information confidential unless the employee consents to that information being made known to co-employees. these disclosures should take place with the necessary counselling and training exercises. do the same principles apply to doctors who are hivpositive 7 the guidelines of the medical and dental professions board of the health professions council of south africa (hpcsa) on the management of patients with hiv infection or aids (july 2001) state that no doctor is obliged to disclose his or her hiv status to an employer or co-employee. infected doctors may continue to practise, but have to seek counselling and advice so as to adjust their professional activities to protect their patients. in general, only scientifically justifiable restrictions will be permissible. some aspects of medical training may be sensitive for hiv-positive medical students and doctors. medical schools and facilities are currently attempting to address this issue so as to balance the rights of people to choose a profession with the rights of patients. the hpcsa has suggested that medical academic institutions should designate an appropriate and professional counselling service. all employers should have hiv policies for the workplace and should conduct educational and training activities. medical practitioners can play a constructive role in imparting scientific and clinical knowledge on this matter. the code of good practice on hiv and aids in employment, issued by the department of labour in 2001 (http:/www.labour.gov.za/docs/legislation/eea/index.asp), provides more details. employers who are not covered by the employment equity act will be bound by the promotion of equality and prevention of unfair discrimination act of 2000. this act also binds employers towards 'any person', i.e. not only employees, and claims may be lodged at any magistrates' court. south african national defence force members are not covered by most of the employment legislation. however, the constitutional court ruled in 1998 that they section 7 of the employment equity act prohibits the medical testing of employees and job applicants. this may only be done if the consent of the labour court has been obtained in this regard. the only case that has, up to now, dealt with this issue, reaffirmed the fact that testing at the request of an employer may only be conducted with the informed consent of each individual employee. this means that no employer may force an employee or job applicant to undergo an hiv test. the employment equity act of 1998 prohibits unfair discrimination against employees based on their hiv status. in the recent case of hoffman v. south african airways (2000 (11) bclr 1235 (cc)) the south african constitutional court found the discrimination against an hiv-positive prospective employee to be unfair. the court took notice of the employee's cd4 count, his actual ability to do the work and whether he would be able to take necessary medication for fiights to african countries. the court rejected arguments that passengers would feel uncomfortable with an hiv-positive flight attendant. it also rejected arguments that many other airlines have similar discriminatory policies, stating that discrimination elsewhere in the world cannot be used as a justification for unconstitutional behaviour in south africa. furthermore, this case means that refusal to retain an hiv-positive employee will be unlawful. dismissal based on a person's hiv status constitutes a prima facie unfair dismissal in terms of the labour relations act of 1995. employment-related hiv testing some considerations medical practitioners can be either employers (when for example in private practice) or employees (when working for the state or another employer). they are also expected to deal with employers requesting hiv tests for prospective or existing employees. for these reasons they have to be familiar with the relevant provisions of labour law in this regard. the much-publicised cases of testing of domestic workers have emphasised instances where employers place doctors in difficult ethical and legal situations. confidentiality in relation to an hiv test and the results thereof applies even where the employer pays for the test. it is unlawful for a medical practitioner to test an employee solely at the request of the employer and to make the result membership benefits ikiilw clinicians society .postal code .......•.•. quarterly newsletter transcript portion membership to support web site advocacy and professional support education and training incentives . country ..... .hpcsa number employees should also have access to medical aid schemes that must provide a minimum benefit to people living with hiv/aids. although an employee does not have to disclose his or her hiv status to the medical aid. extra medical cover may be provided for in terms of special hiv programmes and it would benefit the patient to disclose that information to the fund. the patient/employee should disclose this fact rather than the medical practitioner to prevent legal action or complaints of breach of confidentiality. ..................... date membership member fees for 2002 • .........•.••••••••.......... fax no . emall application form sa hn clinicians society: private sector r250 per annum and public sector r125 per annum. these fees ore now due. • quarterly issues southem african journal of hiv medicine • • accredited cpo points • • discounted attendance at sponsored conferences • • regional and international representation • postal address . city state/province . telephone no . cell no . signature ikiilw clinicians society nb please print legibly and return to: the sauth african hiv clinicians socielj. suite 233. poslne! killarney. private bag x2600, houghlon, johannesburg, 2041 first name second name last name . title degree(sj .. . . . . . ..............•.........••..••.••..•. institution/organisation/agency speciality physical address ...................•••••••..•. . . do you practice in southem africa? 0 yes 0 no 0 other . .iruraucityi place of practice? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . for how many years have you been treating hiv patients? . . is your area of hiv practice in: 0 private sector 0 public sector 0 both proportion: private: public:-:do you have any formal training in hiv medicine? 0 yes 0 no if 'yes' please specify, . approximately how many of your patients are currently receiving antiretroviral therapy? .....•.••... would you like to become a member of the hiv clinicians provider network? 0 yes 0 no please enrol! me as a member of the south african clinicians society please tick preferred method of payment 0 cheque 0 direct oebit 0 electronic transfer in favour of the south african hiv clinicians society should you wish to deposit the membership fee, please ring (011) 453 5066 in terms of the occupational health and safety act of 1993 all employers have to adopt measures to reduce the risk of hiv transmission at work. these measures have to be rational and therefore based on the relevant scientific and legal facts. the basic conditions of employment act of 1997 stipulates the rights of employees to sick leave. hivpositive employees may require reasonable accommodation in this regard and in the allocation of duties. etc. as prescribed by the employment equity act. have a constitutional right to fair labour practices. which would include those in relation to hiv. ofcemher 2001----------the southern african journal of hiv medicine march hiv issue 1-16 march 2005 the southern african journal of hiv medicine 4 4 michelle rotchford galloway, mphil (journ) media and communications manager, south african aids vaccine initiative (saavi) v a c c i n e r e s e a r c h building bridges of understanding and empowerment between society and researchers masikhulisane, meaning ‘let us grow together’, is the new name of the revamped and refocused community involvement programme of the south african aids vaccine initiative (saavi). the programme aims to create an equal, meaningful partnership between community and scientists to facilitate aids vaccine research and promote overall understanding of medical research. as the programme manager elise levendal says: ‘it’s for us to bring aids vaccine researchers and communities closer to each other.’ community preparatory work and educating communities about aids vaccines and clinical trials has been an important component of the initiative since it started in 1999. since then, this work has received funding from the european commission. ‘it started off as a community preparation programme,’ says elise. ‘we have changed it into a community involvement programme because we think that people can be involved in many different ways.’ it’s a challenging arena, and one that has required adaptation and refocusing over the years. ‘i don’t think this work is unique,’ says elise. ‘in the 1980s in this country there was a big move towards community-based research. but what is particular to this programme is that it is a dedicated community programme for aids vaccine research and development.’ among the questions that have arisen are which communities to focus on, how to work at a national level with limited resources, how to educate about vaccines when people don’t have a basic understanding of hiv/aids, how to integrate your efforts with other educational initiatives, and, importantly, how to do all of this within an ethos that respects human rights. vaccine educator petronella goliath highlights the complexities. ‘when you talk about community involvement, communities want to know what you mean – what level of community do you want to involve?’ ‘you also need to be really knowledgeable about hiv because sometimes when the group doesn’t have the basic information you can spend the whole session on that and not even cover vaccines,’ she continues. ‘then you have to go back and do a follow-up session on vaccines.’ ‘most of our strategies are based around education, communication and training,’ says elise, ‘but we also work within a human rights approach.’ among the strategies employed are direct awareness raising and educational initiatives via workshops, information provision at local, national and international events, and the development of high-quality learning materials. masikhulisane hopes to have its learning programme accredited and is working with the standards generating body for ancillary health care. the aim is to have standards generated for hiv/aids vaccine education and approved by the south african qualifications authority. elise explains that the programme works on a sectoral basis. ‘the vaccine educators in each of the three provinces we are working in — cape town, gauteng and kwazulu-natal, where there are already trial sites — have prioritised sectors. these could be traditional healers, the youth sector, community radio, for example.’ ‘in terms of when to start with community education, what we have learnt is that there is never a right or wrong time. some countries started with generic education and later wondered if they shouldn’t have started with site specific. other countries firmly believe that they should have started with generic education before going on to site specific. we are doing a bit of both. we started off with generic and moved into site specific — now we are doing both.’ ‘we believe that people retain the memory of the generic education,’ she continues. ‘it’s not lost. when the trials start you do your site-specific education.’ the philosophy is not to influence people to be in favour of or against aids vaccine research but rather to share ideas and provide accurate information. ‘we believe that when people have the education they will decide which role they want to have within vaccine research and development,’ says elise. ‘there are different roles — it could be as a community advisory group member, it could be as a trial participant, it could be educating other people about vaccines, it could be advocacy for vaccines. but communities and individuals must decide for themselves based on adequate information.’ all about timing march hiv issue 17-48 4/17/05 11:42 am page 44 the southern african journal of hiv medicine march 2005 4 5 interestingly, research done in kenya has shown that the more information people have the less likely they are to participate in vaccine trials. ‘that is worrying, of course,’ says elise, ‘but it is only research from one country. we believe — but this is just an assumption — that the more education people get, the more informed people will become to take decisions about involvement in the vaccine development process.’ ‘it’s all about getting accurate information and ideas out to people. and the education works both ways. ‘it’s a two-way process — we are not only taking scientific knowledge to communities but also taking community knowledge back to scientists,’ says petronella. ‘we want to ensure that both society and researchers learn together about human rights in medical research,’ explains the programme’s human rights advisor, thomas smit. ‘human rights in medical and related research would be concerned with both the development of a safe, affordable and effective vaccine, and with the human rights challenges posed by the development of such a vaccine. human participation in clinical trials needs particular attention from a human rights perspective.’ ‘we want to build bridges of understanding and empowerment between society and researchers,’ he continues. ‘when saavi initially engaged with human rights activists and ethicists there was a huge gap. that gap has narrowed — researchers no longer react as defensively as many did initially and society generally is starting to see more value in research. we need to ensure that those bridges are further developed and maintained as we undertake more and more relevant research especially in diseases that affect the developing world and our population.’ ‘the fact that we come to people and educate them about this new process — it’s a human right, education is a basic right,’ says petronella. ‘although our work is conceptualised within aids vaccine work we see it as beneficial to all research, all clinical trials within the country,’ says elise. a firm principle of the programme is that meaningful community involvement enhances and can even guide research processes, and there is definitely more of a culture of asking questions about research. some of the human rights issues that are important in vaccine development and will be further investigated include ensuring proper informed consent for participation; issues around the appropriateness of research populations, which also includes the involvement of children and adolescents in research; ensuring broad-based gender and population issues around how to conduct trials appropriately in conditions of underdevelopment; and ensuring that society can engage in a meaningful way with medical research. ‘communities need to be learning about and addressing the human rights impact of medical research,’ says thomas. ‘we need to develop capacity together to ensure that research is developed and used for the benefit of all humanity and does not result in exploitation.’ ‘the more people become aware about hiv, the more they will ask questions — are scientists ready to answer the questions?’ asks petronella. ‘you have to be honest with people,’ she continues. ‘this is research and you don’t always know what the outcome will be.’ masikhulisane is facilitating three national processes – the development of a national cab, the development of a national vaccine educator’s forum, with a focus on capacity development and information sharing, and the formation of a saavi community working group. they are also working with the world health organization and unaids to pull together the african aids vaccine programme community working group and a meeting of community representatives from seven african countries. ‘the relationship with who fits in so well with our own plans because we were planning on working much more closely with other african countries,’ says elise. ‘we can learn from other countries but they can learn from us as well.’ a big challenge is to extend the programme’s presence beyond the three provinces. ‘obviously we would like to work throughout the country,’ says elise, ‘but that would require major resources. i’m not that sure that that is necessarily one of the country’s immediate priorities.’ the programme recently undertook a visit to all the trial sites and received support from the people working within the trial site communities and from the community representatives as well. ‘now we know we have support from the rest of the people doing this work,’ says elise. ‘it’s an exciting programme,’ she continues. ‘it’s combining community development and community education experience with science and research, and that is challenging. to convince people that something like this can work could be a major challenge.’ national and international presence march hiv issue 17-48 4/16/05 10:47 am page 45 5 no, i am not on sabbatical on a tropical island! however, it has been a great pleasure to have the journal guest-edited again for the last edition of 2009 by a superb duo: leon levin and mark cotton. mark cotton is a specialist in paediatric infectious diseases at tygerberg children’s hospital and head of its paediatric infectious diseases unit, affectionately known as kidcru. his main focus is to extend and enhance care through research, with a special interest in children affected by hiv. mark has been involved in some key studies that have shaped paediatric practices and guidelines in southern africa. he also serves as advisor and investigator to a number of international institutions and networks. dr leon j levin graduated mb bch at the university of the witwatersrand in 1987. after training in paediatrics at the wits group of hospitals in johannesburg, he obtained his fcpaed (sa) in 1994. in february 1996 he founded the paediatric hiv clinic at johannesburg hospital, and more recently he has run the paediatric division of right to care. leon has been chairman of the paediatric subcommittee of the sa hiv clinicians society since 1999 and runs the society´s paediatric discussion group, an internet-based forum for paediatricians to discuss and learn about problems in children with hiv. in this edition, besides a fabulous array of paediatric material, we publish the updated paediatric guidelines. with so much positive energy around better hiv support recently, from the highest level, we are confident that we can do better, especially in the important area of paediatric aids. we will kick 2010 off with our usual diverse submitted copy, so please keep sending. review processes will also be improved. we hope it will be a bumper year in many ways, with record numbers of people starting and staying on art, a decreasing incidence of hiv, and millions of south africans testing. we also hope to have four bumper editions of the southern african journal of hiv medicine in 2010, which is set to be a memorable year for south africa. linda-gail bekker editor f r o m  t h e  e di torf r o m t h e e di tor the journal is starting to feel like men’s health, what with posters, guidelines and now a state-of-the art science update, hiv treatment bulletin, falling out of it. exco is pleased to announce an important and strategic partnership with hiv ibase, who publish hiv treatment bulletin. we are distributing the southern african version of their excellent newsletter, which will exclusively focus on the scientific reports and resources that have local relevance – with a strong focus on paediatrics and maternal health. hiv treatment bulletin neatly complements the journal, providing the snobbish clinician and scientist with the most hot-off-the-press analysis of recent clinical trials and basic science research. policy makers can authoritatively pronounce at their guidelines meetings, clinicians can expand their patients’ options, and, most importantly, you can show off at ward rounds. thanks to all the people at i-base, this is a major step forward for quality information sharing. we wish the new health minister, barbara hogan, all the best. she has very small shoes to fill, but a mammoth task ahead of her to repair south africa’s woeful health service. at the time of writing, she and her deputy, dr molefi sefularo, have been very impressive, dealing with a cholera disaster, drug stock-outs, issues of prevention, releasing controversial reports that were stuck on her predecessor’s desk for months, and a dozen other complex health problems. finally, the exco welcomes two new members based in durban, professor yunus moosa and dr henry sunpath, both highly respected clinicians and part of the team responsible for an excellent hiv clinical conference held in october. francois venter president this spring edition brings 2008 to a close. and what a year it has been. not many breakthroughs in hiv or tb, but a lot of activity in terms of understanding early infection better, really getting to grips with early immune responses, and again thinking through our prevention options. in 2008 the concept of antiretrovirals for prevention as well as treatment has come to the fore with second-generation microbicides, pre-exposure prophylaxis and the notion that we may be able to ‘treat our way out of the epidemic’ becoming possibilities. gratifyingly, this year also saw a record number of people being tested and accessing art, and roll-out for both testing and treatment is truly scaling up. as chairperson of the 4th southern african hiv conference i must encourage every one of you to think seriously about coming to durban on 31 march. it promises to be a critical conference where we will really formulate the key steps in getting pmtct, treatment, testing and prevention out there on a scale that will begin to turn the sa statistics around. (i promise that it will also be loads of fun!) please note the early date this year: 31 march to 3 april. this is to ensure brilliant kzn weather! in this edition, we already begin to examine some of these key scale-up questions: jerome singh explores the ethics and legality of traditional healers performing hiv testing (i know many have asked why this has to be the domain of nurses only). francesca esposito and her team examine changes in body composition in women taking antivirals in a kzn clinic. we look at the role of mobile phones in the hiv response with william mapham, and polly clayden gives us pointers to starting infants on art. the role of a liver biopsy in diagnosis of opportunistic infections is described by mark sonderup and colleagues. the vexed question of when it is deemed safe to start haart in patients co-infected with tb is discussed by robin wood, and francois venter and colleagues give a practical view on new antiretrovirals on the horizon for south african practitioners. no guidelines in this issue, but i will whet your appetites – look out for guidelines on prevention of tb occupational exposure for hiv-infected health care workers and on the non-infertile hiv infected couple, hot stuff coming up in the new year! happy reading and every best wish for a restful and peaceful festive season from the whole editorial team. see you next year! linda-gail bekker editor m e s s a g e f r o m t h e e x e c u t i v e msg from the executive.indd 5 12/17/08 3:16:23 pm treating hiv-infected children this edition sees the publication of the fourth sa hiv clinicians society paediatric antiretroviral therapy (art) guidelines. previously it has not been possible to have one guideline for the whole country because of wide discordance between the government and private sectors. this year, for the first time, our guideline is applicable to both the private and public sectors. inevitably some differences remain and are addressed in the document. they include choice of first-line regimen and genotyping recommendations. the national department of health (ndoh) is still updating its guidelines, hopefully for publication in early 2010. we hope you will find the society’s guidelines pragmatic and helpful. we have the potential to save and improve many young lives. we thank all those involved in the writing of the guidelines, especially our fellow member of the writing committee, dr tammy meyers, and our overseas reviewers. as has been done previously when paediatric guidelines have appeared, the entire issue is devoted to paediatrics. we hope it will be useful as a ready reference on paediatric hiv management for all health care workers caring for children. e di tor i a l the southern african journal of hiv medicine                                                      december  2009 m e s s a g e   f r o m    t h e   e x e c u t i v e the global recession has thrown the problem of funding for aids programmes to the fore, with botswana’s president saying his country’s programme is unsustainable, and donors sounding warnings that rationing may need to be implemented. this is very alarming – we have made big strides in terms of antiretroviral access in the last few years, and these are suddenly looking very fragile. it is time to take stock of our programmes and make them as lean and mean as possible, ensuring maximum access to care while ensuring acceptable levels of quality. we need to look critically at the labs we ask for and the drugs we need, while keeping up pressure on the donor community to maintain support. however, we should not let our governments off the hook. health in southern africa has been consistently underfunded as a function of the gross domestic product, in almost every one of our countries. guns, presidential inaugurations and motorcades never seem to be a problem to fund, and we need to do a better job at the southern african journal of hiv medicine                                                      december  20096 we begin with an opinion piece by heather jaspan, rachel li, leigh johnson and linda-gail bekker on the urgent need to develop skills and infrastructure to meet the needs of hiv-infected adolescents, especially given our success in treating children with art. we then address prevention of vertical transmission of hiv, the key to the elimination of hiv infection in children. the paper by laurie schowalter, ashraf coovadia and ameena goga is a plea for action. it is followed by an analysis of vertical transmission data (mark cotton, soyeon kim, helena rabie, joan coetzee and sharon nachman, from the pactg 1041 team), emphasising again the importance of a good antenatal antiretroviral component. infant feeding is integral to child survival and development. there are risks and benefits for breast and replacement feeding. the paper by ameena goga is essential reading for anyone caring for infants and provides the key data to inform rational decision making. the guideline document emphasises the importance of and pitfalls in maintaining adherence. a number of articles provide background information to help in understanding the rationale of recommendations in the guidelines. these include articles on when to start (mark cotton, helena rabie, ute feucht and avy violari), essential pharmacokinetic information (helen mcilleron and hermien gous) and how the weight-based dosage recommendations were derived (james nuttall). what do you do when children starting art deteriorate instead of improve? helena rabie, tammy meyers and mark cotton delve into the paradoxical world of immune reconstitution inflammatory syndrome (iris). we then highlight two adverse events of art, one common and the other rare. the ndoh guidelines do not advocate using abacavir (abc) in the first-line regimen in the absence of adverse effects from other drugs. they still recommend d4t, increasingly implicated in lipodystrophy. lipodystrophy can be reversible if the offending agent (usually d4t) is replaced with abc (or tenofovir in adults) in the early stages. steve innes, leon levin and mark cotton provide background information and useful diagnostic and management advice for lipodystrophy. the sa clinicians society advocates 3tc and abc as the nrti backbone for the first-line regimen. there is much fear of the infamous abc hypersensitivity reaction (hsr). to the best of our knowledge, no one has ever died from the reaction, but people have died from abc rechallenge. fortunately the hsr is rare in black africans. helena rabie, kristin henning, pierre schoeman, nico de villiers, gert h j (oubaas) pretorius and mark cotton provide guidelines for using abc and recount their experience with suspected abc hsr. treatment failure is becoming increasingly complex. fortunately, there are quite a few new antiretrovirals registered overseas and about to be registered in south africa. leon levin takes us through the minefield of paediatric salvage therapy. finally, polly clayden presents us with some cuttingedge reports from the recent international aids society conference in cape town, again informing readers of the type of research needed to continually improve our guidelines. mark cotton leon levin guest editors drawing attention to how health budgets are allocated. in south africa it seems that jacob zuma’s government has declared war on overall wasteful expenditure, and at the same time there has been increasing embarrassing public exposure of ministerial spending on large cars. a new and energetic health minister, aaron motsoaledi, seems intent on reversing the terrible sins of the past under mbeki’s regimen, and to be determined that health resources get used better. please let the society know if you see any indication of rationing! we have active advocacy work, with good partners, and it is to be hoped that we can stop unnecessary restrictions on health care. francois venter president southern african hiv clinicians  society paediatric discussion  group (pdg) the southern african hiv clinicians society paediatric discussion group (pdg) began in december 2001. the concept was born after dr (now adjunct professor) ashraf coovadia of the rahima moosa mother and child hospital, coronationville, johannesburg, sent an e-mail to 5 or 6 local hiv ‘experts’ and professor mark kline of the baylor college of medicine, houston, texas, seeking advice on how to manage a child with severe disfiguring parotomegaly but who had a normal cd4 count, so antiretroviral therapy (art) was not indicated. the answer came back that there was no indication for art for a purely cosmetic condition! i found the concept fascinating and wondered if there was any value in using e-mails as a vehicle for educating health care providers about paediatric hiv. i contacted the south african hiv clinicians society, who were happy with the concept and provided me with a list of their members. the list in those days was very short (unlike today), and i tried to fathom out who was a paediatrician or treated paediatric cases and added them to the mailing list. the first few cases hardly garnered a response. i suspect people were too shy to answer. after a few weeks i would send out an expert opinion. the cases were all real cases (mostly from my own practice), and all had excellent lessons to teach. gradually, as knowledge and familiarity with pdg grew, so the number of responses increased. currently it’s not unusual to have over 100 responses to a case. the cases have spanned the whole range of paediatric hiv issues including opportunistic infections, side-effects of art and ethical issues. at the moment we are concluding pdg no. 51. some notable cases include: n one of the earliest cases in south africa of cushing’s syndrome caused by an interaction between ritonavir and inhaled fluticasone for asthma. n a child from a neighbouring country who was diagnosed as hiv-positive on two different tests and turned out to be hiv negative. n an hiv-positive child with marked failure to thrive and a normal cd4 count who turned out to have an oesophageal stricture and is now thriving after oesophageal dilatation. n cases of lymphoma and kaposi’s sarcoma. n a case where a mother with end-stage hiv had a negative hiv elisa test, having lost the ability to make antibodies due to her poor immunity. n a case of a young infant treated with art very early on who became hiv elisa negative after losing her maternal antibodies. she did, however, remain pcr positive. n interestingly, pdg no. 47 in april 2008 again discussed a patient with disfiguring parotomegaly and a normal cd4 count. this time the opinion was overwhelmingly in favour of starting art. the response to the pdg has been phenomenal. the mailing list currently stands close to 1 500. subscribers are predominantly from south africa but also include namibia, zimbabwe, botswana, zambia, angola, malawi, kenya, rwanda and other countries. subscribers are predominantly doctors but also include nurses, pharmacists, and counsellors. there is no doubt that the pdg has succeeded because of the very active participation of our subscribers and our wonderful panel of local and overseas experts, all of whom deserve my heartfelt thanks. i have merely been the conduit between the two. if you would like to subscribe to the pdg, please send an e-mail to leonlevin@54.co.za. i am also constantly on the lookout for new cases to discuss. they can be sent to the same e-mail address. leon levin head, paediatric programmes right to care m e s s a g e   f r o m   t h e   pa e di at r ic    s u b c o m m i t t e e the southern african journal of hiv medicine                                                      december  20098 d e c e m b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e infancy (from birth until 1 year of age) is a time of rapid changes in the body of a child. these changes affect pharmacokinetics in many ways. the cher study1 showed that early antiretroviral (arv) treatment reduces mortality and disease progression among infants acquiring hiv infection before 12 weeks of age. as a result the world health organization has recently revised treatment initiation recommendations in children less than 1 year of age: all infants under 12 months of age with confirmed hiv infection should be started on arv therapy, irrespective of clinical or immunological stage.2 dosing in infants is challenging because drug concentrations are highly variable, there is frequently scant pharmacokinetic information on young children, and few suitable drug formulations are available. furthermore, adherence to treatment is reliant on the caregiver rather than the patient. periand postnatal hiv transmission are reduced by maternal highly active arv treatment (haart). however, the benefits and risks to breast-fed infants of exposure to maternal arv drugs during lactation are poorly understood. in this article we review the pharmacokinetics of arv drugs relevant to south african infants, and highlight some of the challenges to delivering arv treatment in safe and effective doses. growth and development are accompanied by changes that influence drug concentrations. as these developmental changes begin in utero, post-conceptional age is a better descriptor of maturation than postnatal age. size and age explain a considerable part of the pharmacokinetic variability. however, there is a non-linear relationship between clearance and size. consequently, simple proportional adjustment of the adult dose based on weight leads to underestimation of the maintenance dose required in children. dose calculation methods based on scaling of clearance do not account for changes during early infancy in multiple processes affecting drug absorption, distribution, metabolism and elimination. in recent years there has been a trend to provide simplified dosing guidelines using weight bands, which provide many practical advantages. ideally dosing would also account for differences in lean body size and maturity within the weight bands. drug absorption is highly variable and difficult to predict. it is determined by multiple interacting factors including enteric ph, gastric motility, intestinal transit time, the physico-chemical properties of the drug, intestinal metabolic capacity and activity of drug transporters. gastric ph rapidly declines and then rises again during the first few days of life. acidity then increases over several months, reaching adult levels (ph 2 3) between 2 and 7 years. frequent feeding with milk or formula may influence gastric ph. the absorption of atazanavir is reduced at a higher ph and it should be taken with food to enhance bio-availability. although by 36 weeks’ gestational age an infant has developed intestinal motility patterns similar to those in adults, motility is irregular and variable, and the frequency of movement is reduced until 6 8 months of age. dietary factors affect the rate of gastric emptying: increased caloric density feeds with increased concentrations of complex fat and sugars delay gastric emptying, so formula-fed infants may have shorter intestinal transit times than breast-fed infants.3 body composition changes affect drug distribution. total body water (tbw) comprises approximately 90% and 75% of body weight in preterm and term infants, respectively. by 1 year of age tbw approaches adult proportions of 60%. extracellular fluid ranges from 65% in premature to 40% in term infants, while adult pharmacokinetics of antiretroviral drugs in infancy c l i n i c a l helen mcilleron, mb chb, phd division of clinical pharmacology, department of medicine, university of cape town hermien gous, pharmd harriet shezi children’s clinic, enhancing children’s hiv outcomes (echo), chris hani baragwanath hospital, johannesburg dosing in infancy is complicated by inadequate characterisation of pharmacokinetics, unpredictable drug concentrations and a lack of suitable dosage forms. additional challenges are presented by the concomitant administration of interacting drugs (e.g. rifampicin in antituberculosis treatment) and disease conditions that may alter drug disposition. the extent and implications of breastmilk transfer of drugs to the infant are poorly understood. new technologies facilitate pharmacokinetic studies in infants and will improve access to therapeutic drug monitoring. 54 pharmacokinetic principles t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e d e c e m b e r 2 0 0 9 values of 20% are reached after a year. preterm infants have very little body fat (1 5%). term infants typically have 12 15% body fat. by 12 months body fat increases to approximately 30% before declining to adult levels of 18%. tissue binding of drugs also affects their distribution. bound drugs are inactive. free drug concentration (unbound drug) gives a better indication of how much drug is available for distribution to the site of action. in adults, lopinavir is highly bound to plasma proteins (98 99%), mainly α1-acid glycoprotein (aag), for which it has the higher affinity, and albumin. several other protease inhibitors (pis) are highly bound to plasma proteins. marked changes in plasma protein concentrations and their binding characteristics occur during the first 2 weeks after birth. albumin, which binds acidic and neutral drugs, increases by almost 30% in the first week. basic drugs bind to aag, globulins and lipoproteins. neonates have aag concentrations one-third those of children aged 1 year and older. the lower ph of neonatal blood (7.25 7.3) results in an increased free fraction of some drugs. moreover, drugs may compete with free fatty acids and unconjugated bilirubin for binding sites. the increased permeability of the bloodbrain barrier during infancy may have implications for those with hiv-related encephalopathy. pis and non-nucleoside reverse transcriptase inhibitors (nnrtis) undergo extensive pre-systemic (in the intestine and liver) and systemic (largely hepatic) metabolism. the cytochrome p450 (cyp) enzymes cyp 3a4 (pis and nevirapine) and cyp2b6 (nnrtis) are important isoforms for arv biotransformation. unlike most nucleoside reverse transcriptase inhibitors (nrtis), zidovudine and abacavir are extensively metabolised in the liver: both drugs by glucuronidation, and abacavir by the enzyme alcohol dehydrogenase. maturation of drug metabolising enzymes accounts for age-associated differences in metabolism. differential rates of maturation are associated with the specific metabolic enzymes. activity of cyp 3a4 in the fetus is 30 70% of that in adults. cyp activity increases during infancy. by 1 year of age the activity of most cyp isoforms exceeds adult values. the capacity for glucuronidation is limited at birth and highly variable. adult levels of activity are achieved between 2 months and 3 years of age. the activity and expression of drug transporters such as p-glycoprotein are important determinants of drug absorption, distribution and clearance. very little is known about the developmental pattern of these transporters which, like those of the drug metabolising enzymes, may be influenced by exogenous factors such as diet in addition to genetic and maturational determinants. nrtis other than zidovudine and abacavir are eliminated primarily unchanged by the kidneys. both glomerular filtration and tubular secretion are immature at birth. before 34 weeks’ gestation the glomerular filtration rate (gfr) is reduced and highly variable. thereafter, there is a strong correlation between gfr and age. term infants have a gfr of 2 4 ml/min, which increases to 8 20 ml/min during the first few days of life. in contrast, premature infants may be born with a gfr of 0.6 0.8 ml/min, which may increase to 2 4 ml/min during the first few days after birth. by 3 6 months of age adult maturity in gfr is attained.3 there are frequently inadequate pharmacokinetic data on infants. moreover, studies in infants are often limited by small sample size and sparse sampling. table i sets out pharmacokinetic data for arv drugs used in south african infants. dosing of infants is challenging. they cannot swallow solid dosing forms. liquid formulations often have decreased stability and require refrigeration. stavudine, for example, comes in a powder that needs reconstitution before dispensing as an oral solution. it is stable for only 30 days in a refrigerator. lopinavir/ritonavir solution may be stored at room temperature (up to 25°c) if it is used within 42 days. in many high-burden settings access to refrigeration is limited. stability issues therefore complicate drug supply, storage and dispensing. most tablets and capsules should not be crushed, as stability and absorption may be altered and accurate dosing is impossible. dispensing and dosing errors are common, as the dose has to be translated into the volume dispensed or administered. accurate measurement of the dose is challenging for many carers, and liquid formulations need to be shaken well before administration to ensure that the correct dose is administered. relatively large-volume liquid doses can be problematic: infants do not always swallow the entire dose and often spit some of it out. paediatric formulations such as dispersible fixed-dose combination tablets in doses suitable for infants and young children may provide considerable advantages. the routine use of therapeutic drug monitoring (tdm) has not been proven to alter treatment outcomes in adults. however, it is recommended that tdm be considered in paediatric patients (particularly infants and severely ill children) owing to unpredictable drug exposure and, in many instances, a paucity of evidence to support the dosing guidelines. additional indications include potentially significant drug-drug (see ‘impact of antituberculosis treatment’, below) or drug-food interactions; gastro-intestinal disease, or hepatic or renal 55 dosage forms therapeutic drug monitoring d e c e m b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 56 re co m m en de d do se re co m m en de d ta rg et a ve ra ge p k pk d at a in in fa nt s/ d ru g (a ct iv e in gr ed ie nt /s ) in in fa nt s1 1 co nc en tr at io n* in a du lt yo un g ch ild re n co m m en ts re fe re nc es pr ot ea se in hi bi to rs ta bl e i. ta rg et c o n ce n tr a ti o n s, a v er a g e co n ce n tr a ti o n s in a d u lt s o n s ta n d a rd a n ti re tr o v ir a l d o se s a n d p h a rm a co k in et ic d a ta f o r a n ti re tr o v ir a l d ru g s u se d i n s o u th a fr ic a n i n fa n ts lo pi na vi r (l pv )/ ri to na vi r (c ofo rm ul at ed in a 4 :1 r at io ; ka le tr a or al s ol ut io n) 14 d ay s 6 m on th s: 3 00 m g lp v/ m 2 b sa 1 2ho ur ly , o r 16 m g lp v/ kg 12 -h ou rl y > 6 m on th s: 2 30 m g lp v/ m 2 , 1 2 m g lp v/ kg if < 15 k g, o r 10 m g lp v/ kg if > 15 k g. d os es g iv en 1 2ho ur ly lo pi na vi r c m in > 1. 0 m g/ l c m in 5 8 m g/ l < 8 w ee ks : m ed ia n lp v c m in 2. 22 m g/ l ( 9 in fa nt s ag ed 5 .6 7. 9 w ee ks ; m ed ia n do se 2 76 m g/ m 2 ) 6 w ee ks 6 m on th s: c m in 2. 37 m g/ l ( 18 in fa nt s 1. 6 5. 9 m on th s ol d; a ve ra ge d os e 26 7 m g/ m 2 ). in b ot h st ud ie s pk s am pl in g w as 2 w ee ks af te r st ar ti ng t re at m en t. a s c m in in cr ea se d at la te r ti m es , di ffi cu lt ie s w it h do se a dm in is tr at io n m ay in p ar t ac co un t fo r lo w c on ce nt ra ti on s > 6 m on th s: m ed ia n c m in 4 .6 4 m g/ l ( 15 s ou th a fr ic an c hi ld re n 9 47 m on th s; m ed ia n lp v do se 2 69 m g/ m 2 ) o nc eda ily d os in g is n o t re co m m en de d. n o da ta in co m bi na ti on w it h an ti -t b tr ea tm en t, n n r ti s or o th er pi s in < 6m on th -o ld s. a u c in c hi ld re n > 6 m on th s do se d w it h 23 0 m g lp v/ m 2 ap pr ox im at es t ha t in a du lt s, al th ou gh c m in is lo w er 4 6 r it on av ir ( r tv ) > 1 m on th : 35 0 45 0 m g/ m 2 b sa 12 -h ou rl y c m in > 2. 1 m g/ l c m in 4 m g/ l 4 w ee ks 2 4 m on th s: c m in w as lo w a nd h ig hl y va ri ab le a m on g 35 in fa nt s: r tv 3 50 m g/ m 2 tw ic e da ily a nd 4 50 m g/ m 2 tw ic e da ily r es ul te d in m ed ia n c m in o f 0. 99 m g/ l a nd 0 .7 4 m g/ l, re sp ec ti ve ly n ot r ec om m en de d in in fa nt s < 1 m on th o ld ; d os es o f 45 0 m g/ m 2 12 -h ou rl y re su lt ed in lo w p la sm a co nc en tr at io ns . lo w r tv c on ce nt ra ti on s ar e lin ke d to in fe ri or v ir al re sp on se s in c hi ld re n 7, 8 in di na vi r (i d v) n ot a pp ro ve d fo r us e in c hi ld re n c m in > 0. 1 m g/ l c m ax < 10 .0 m g/ l id v al on e: c m in 0. 1 0. 4 m g/ l; id v/ r: c m in 0 .2 0. 5 m g/ l 3 m on th to 1 6ye ar -o ld s gi ve n id v 50 m g/ kg ( ± 60 0 m g/ m 2 ) 8ho ur ly a ch ie ve d c m in m ed ia n (r an ge ) 0. 07 m g/ l ( 0. 02 0 .2 1) . c l/ f w as h ig he r in < 6ye ar ol ds ( 2. 5 v. 1 .0 l/ h/ kg ) an d m or e va ri ab le . i d v 40 0 m g/ m 2 pl us 10 0 12 5 m g/ m 2 ri to na vi r 12 ho ur ly a ch ie ve s sa ti sf ac to ry id v co nc en tr at io ns in o ld er c hi ld re n sh ou ld n ot b e us ed in ne on at es o w in g to t he r is k of k er ni ct er us . a s af e an d ef fe ct iv e do se h as n ot b ee n es ta bl is he d in c hi ld re n. d os ere la te d ne ph ro lit hi as is is a c on ce rn 9 11 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e d e c e m b e r 2 0 0 9 57 recom m ended dose recom m ended target a verage pk pk data in infants/ d rug (active ingredient/s) in infants 11 concentration* in adult young children com m ents references protease inhibitors ta ble i. co n tin u ed n elfi navir (n fv) n ot approved for use in < 2-year-olds c m in > 0.8 m g/l c m in 1.5 m g/l n fv 45 m g/kg tw ice daily from birth: m edian c m in 3.2 m g/l on day 7, but by day 14 and 28 only 0.7 m g/l. sim ilarly, < 6w eek-olds on 40 m g/kg tw ice daily achieved m edian c m in 1.35 m g/l w ith 3 of 11 infants failing to reach a u c targets. o lder infants m ay require even higher doses: 50% of 2.3 8.5m onth-olds on an average 136 m g n fv/kg/d failed to reach the a u c target d oses of n fv 25 35 m g/kg 3 tim es a day, or 45 55 m g/kg tw ice daily, are used in children 2 13 years, but younger children require higher doses 12 14 a tazanavir (a tv) n ot approved for use in children < 6 years of age c m in > 0.15 m g/l a tz 400 m g/d: c m in 0.27 m g/l; a tz/r tv 300/100 m g/d: c m in 0.86 m g/l the recently reported results of n ih pa c tg study p1020a dem onstrated adequate a tv concentrations (c m in 0.43 m g/l; a u c 0-24 48.54 m g/h/l) in 3 24-m onth-olds using r tv boosted a tv 339 m g/m 2. c l/f w as high in infants (12.4 l/h/m 2 w ith m edian age 0.8 years v. 2.9 l/h/m 2 w ith m edian age 10.5 years) a void in < 3-m onth-olds: risk of kernicterus. r tvboosting achieves higher c m in w ith low er c m ax , and inter-individual variability is reduced. h igher m g/m 2 doses are required in children com pared w ith adults: the recom m ended daily dose in infants > 3 m onths old is a tv/r tv 310/100 m g/m 2 15,16 n on-nucleoside reverse transcriptase inhibitors perinatal: 200 m g single m aternal dose during labour + single dose of 2 m g/kg to infant up to 72 h after birth c m in > 0.1 m g/l (10 × in vitro ic 50 ) transplacental transfer after a single m aternal 200 m g dose during labour m aintains infant n vp > 0.1 m g/l for several days. a 2 m g/kg n vp dose at 48 72 h keeps n vp > 0.1 m g/l for a w eek in m ost infants (0.11 0.28 m g/l in 7-day-old infants). a study evaluating chronic n vp (4 m g/kg from birth to 14 days, then 8 m g/ kg until 24 w eeks) for breastfeeding infants found n vp > 0.1 m g/l in 95% and 100% of those receiving tw ice w eekly or daily doses; once-w eekly dosing w as insufficient in > 60% of infants evaluation of chronic n vp adm inistration (4 m g/kg/d) for prevention of breastm ilk transm ission is ongoing. long-term m aternal n vp before delivery accelerates n vp elim ination in new borns, presum ably due to in utero autoinduction of n vp elim ination 17 19 n evirapine (n vp) for pm tc t d e c e m b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e re co m m en de d do se re co m m en de d ta rg et a ve ra ge p k pk d at a in in fa nt s/ d ru g (a ct iv e in gr ed ie nt /s ) in in fa nt s1 1 co nc en tr at io n* in a du lt yo un g ch ild re n co m m en ts re fe re nc es n on -n uc le os id e re ve rs e tr an sc ri pt as e in hi bi to rs ta bl e i. co n ti n u ed zi do vu di ne ( zd v) f or p m tc t an d pr em at ur e in fa nt s < 2 w ee ks : 2 m g/ kg /1 2 h (i v: 1 .5 m g/ kg ) 2 6 w ee ks : i nc re as e to 8 -h ou rl y c l/ f is lo w in p re m at ur e ne on at es ( 0. 15 l/ h/ kg ). in t er m ne w bo rn s c l/ f is 0 .3 4 l/ h/ kg be fo re in cr ea si ng r ap id ly t o 0. 65 l/ h/ kg b y 7 da ys a nd 1 .1 4 l/ h/ kg in in fa nt s > 14 d ay s ol d 22 zi do vu di ne < 6 w ee ks : 2 m g/ kg /6 h ( iv : 1 .5 m g/ kg ) > 6 w ee ks : 4 < 9 kg : 1 2 m g/ kg /1 2 h; > 9 kg : 9 m g/ kg /1 2 h c l/ f 1. 5 l/ h/ kg ; t1 /2 1 .1 h 1s tpa ss m et ab ol is m r ed uc es b io av ai la bi lit y by 3 5% . u nd er go es h ep at ic g lu cu ro ni da ti on ; a s m al l a m ou nt is ex cr et ed u nc ha ng ed in u ri ne 0 13 d ay s: 0 .5 m g/ kg 1 2ho ur ly > 13 d ay s: 1 m g/ kg 1 2ho ur ly c l/ f 35 .6 l/ h; t 1/ 2 1 h; ic t1 /2 3 .5 7 .0 h c l/ f 5. 6 m l/ m in /k g at 1 w ee k, 6. 8 m l/ m in /k g at 6 w ee ks . o n 1 m g/ kg /1 2 h, 1 4 a nd 2 8da yol ds h ad s im ila r a u c ( 1. 9 m g/ h/ l) an d t1 /2 ( 1. 1 1. 2 h) a bs or pt io n is d el ay ed in ne on at es 23 st av ud in e > 14 d ay s: 1 50 2 00 m g/ m 2 b sa on ce d ai ly f or 1 4 da ys t he n tw ic e da ily c m in > 3. 0 m g/ l c m in 4 6 m g/ l za m bi an in fa nt s (m ea n ag e 5. 3 m on th s) h ad m ea n n vp a u c 012 h, c m ax a nd c m in o f 78 .7 h/ m g/ l, 8. 1 m g/ l, an d 4. 9 m g/ l, re sp ec ti ve ly . t hr ee o f 6 in fa nt s < 5 m on th s ol d (r ec ei vi ng n vp 32 4 40 6 m g/ m 2 /d ay , i n 2 do se s) , h ad s ub th er ap eu ti c c m in n vp a bs or pt io n is v ar ia bl e an d de la ye d. e lim in at io n is pr ol on ge d in n ew bo rn s, b ut ac ce le ra te s du ri ng t he fi rs t da ys o f lif e; in fa nt s re qu ir e hi gh er m g/ m 2 do se s th an ol de r ch ild re n 20 n ev ir ap in e < 30 d ay s: 2 m g/ kg t w ic e a da y > 30 d ay s: 4 m g/ kg t w ic e da ily c l/ f 0. 3 l/ h/ kg ; t1 /2 6 h ; i c t1 /2 ( of a ct iv e tr ip ho sp ha te ) 15 h in fa nt s 3 28 d ay s ol d: m ea n c l/ f 0. 37 l/ h/ kg ; a u c 012 6 .0 m g/ h/ l o n 2 m g/ kg t w ic e da ily . in c on tr as t, in fa nt s > 1 m on th ha d m ea n c l/ f 0. 66 l/ h/ kg ; 4 m g/ kg t w ic e da ily a ch ie ve d m ea n a u c 6 .8 m g/ h/ l ex cr et ed u nc ha ng ed in t he ur in e. c l/ f do ub le s du ri ng th e fi rs t m on th , a ft er w hi ch it s ta bi lis es f or t he d ur at io n of in fa nc y 21 la m iv ud in e n uc le os id e re ve rs e tr an sc ri pt as e in hi bi to rs 2 w ee ks 8 m on th s: 1 00 m g/ m 2 12 -h ou rl y > 8 m on th s: 1 20 m g/ m 2 12 -h ou rl y c l/ f 1 l/ h/ kg ; t1 /2 1 .5 h ; i c t 1/ 2 12 4 0 h a lt ho ug h va ri ab le , o ne s tu dy fo un d lit tl e ch an ge in c l/ f be tw ee n th e 1s t da y of li fe an d 6 w ee ks ( c l/ f 4. 5 an d 5. 0 l/ m in /m 2 re sp ec ti ve ly ). o th er so ur ce s re po rt c l/ f to b e 4fo ld hi gh er in 6 -w ee kol ds t ha n in ne w bo rn s 50 m g/ m 2 12 -h ou rl y is re co m m en de d in n ew bo rn s. u ns ta bl e at lo w p h ( he nc e gi ve n w it h an ta ci d) 23 d id an os in e 58 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e d e c e m b e r 2 0 0 9 re co m m en de d do se re co m m en de d ta rg et a ve ra ge p k pk d at a in in fa nt s/ d ru g (a ct iv e in gr ed ie nt /s ) in in fa nt s1 1 co nc en tr at io n* in a du lt yo un g ch ild re n co m m en ts re fe re nc es n on -n uc le os id e re ve rs e tr an sc ri pt as e in hi bi to rs ta bl e i. co n ti n u ed *c on ce nt ra ti on -b as ed c ut -o ff v al ue s fo r pe rf or m in g td m o f an ti re tr ov ir al a ge nt s in n aï ve p at ie nt s. 25 pk = p ha rm ac ok in et ic ; p m tc t = p re ve nt io n of m ot he rto -c hi ld t ra ns m is si on ; b sa = b od y su rf ac e ar ea ; i v = in tr av en ou s; ic = in tr ac el lu la r; a u c = a re a un de r th e co nc en tr at io nti m e cu rv e; c l/ f = a pp ar en t cl ea ra nc e; c m ax = p ea k co nc en tr at io n; c m in = t ro ug h/ m in im um c on ce nt ra ti on ; i c 50 = 5 0% in hi bi to ry c on ce nt ra ti on ; t 1/ 2 = h al f lif e. fo sa m pr en av ir is n ot a pp ro ve d fo r us e in in fa nt s bu t is c ur re nt ly b ei ng e va lu at ed in s ou th a fr ic an c hi ld re n 1 6 m on th s ol d. > 3 m on th s: 8 m g/ kg t w ic e da ily 30 0 m g2 × d ay an d 60 0 m g da ily : a u c 024 8 m g/ h/ l si ng le 8 m g/ kg d os e in 3 23 -m on th -o ld s: m ea n a u c 8. 67 m g/ h/ l. th er e ar e fe w d at a in in fa nt s re ce iv in g re pe at ed do se s, b ut t he d ru g’ s ph ar m aco ki ne ti c pr op er ti es a re s im ila r ac ro ss a ge g ro up s n ot a pp ro ve d fo r us e in < 3m on th -o ld s. c le ar an ce is in cr ea se d in c hi ld re n; t he re co m m en de d 8 m g/ kg d os e is d ou bl e th e ad ul t m g/ kg do se 24 a ba ca vi r impairment; treatment-experienced patients who may have viral isolates with reduced susceptibility to highly active arv therapy (haart); use of alternative dosing regimens the safety and efficacy of which have not been established in clinical trials; concentration-dependent toxicity; unexpectedly poor virological response in a treatment-naïve person; and monitoring of adherence.25 the minimum (predose trough) drug concentration is used to monitor virological efficacy. peak concentrations relate more closely to toxicity for some drugs, and the area under the drug concentrationtime curve is a measure of overall systemic exposure. therapeutic ranges have not been defined for nrtis, which are metabolised intracellularly to the active triphosphate, as plasma concentrations are not closely related to efficacy. target concentrations for nnrtis and pis (table i) are based largely on studies in adults. while it is likely that good responses to treatment will be achieved in children, provided that they are given drug formulations and doses that achieve drug exposure similar to those that have demonstrated safety and efficacy among adults, important differences may apply. routinely, total plasma arv concentrations are measured in the laboratory. the recommended drug concentration ranges are therefore based on the sum of the free active component and protein-bound drug. altered protein binding during early infancy may alter the proportion of active drug in the measured concentration. furthermore, day-to-day variability complicates interpretation of a single drug concentration result. drug concentration results should be interpreted on an individual basis, and safety and efficacy should also be carefully monitored. clearly, poor adherence to treatment needs to be ruled out as a cause of low drug concentrations before dose adjustments are made. modern technologies such as liquid chromatography mass spectrometry allow drug concentration measurement in low-volume samples, thus facilitating tdm in infants. the development of methods using blood spots dried onto filter paper is likely to make tdm increasingly accessible and affordable. however, although it is frequently indicated in infants as part of an integrated approach, tdm of arvs is currently not available to the vast majority patients in high-burden settings. although the use of arv therapy complicates the management of tuberculosis, patients with tuberculosis who meet the criteria for arv therapy should be started on an effective arv regimen once they are established on rifampicin-based antituberculosis treatment. through activation of the pregnane x receptor, which results in increased expression of multiple drug metabolising enzymes and transporters, rifampicin increases the oral clearance of many medications. rifampicin lowers the concentrations of pis to subtherapeutic levels; nevirapine trough concentrations are reduced by about 30% in south african adults;26 and zidovudine concentrations are reported to decline by 50%. there are concerns associated with all the currently available co-treatment options for infants, and there are very few data on which to base optimal co-treatment approaches. careful monitoring is indicated. impact of antituberculosis treatment 59 d e c e m b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e in hiv-infected infants exposed to single-dose nevirapine, or maternal nnrti-containing arv treatment or prevention regimens, pi-based haart should be started. super-boosted lopinavir (extra ritonavir is added to lopinavir/ritonavir; a total 12-hourly lopinavir/ritonavir dose of 230/230 mg/m2) achieves adequate lopinavir exposure in most children older than 6 months during rifampicin-containing antituberculosis treatment.27 however, lopinavir concentrations are highly variable, there are no data to support this approach in younger infants, and it is poorly tolerated and complex to prescribe, dispense and administer. double-dose lopinavir/ritonavir has been shown to result in sub-therapeutic concentrations in children during antituberculosis treatment. when adjusted doses of pis are used with rifampicin, tdm should be implemented if it is available, and it is essential to regularly monitor liver function. rifabutin (in reduced doses) is preferred to rifampicin in adults requiring pis, but it is expensive and suitable formulations are not available for infants and young children. in many settings nevirapine plus 2 nrtis is the only effective treatment option available to young children. standard doses of nevirapine twice daily provide acceptable outcomes in adults with tuberculosis (although it is inferior to efavirenz). recent evidence suggests, however, that the majority of young children on tuberculosis treatment fail to achieve trough concentrations >3 mg/l (the lower limit of the recommended range),28 and data for infants younger than 6 months are lacking. the approach should be used with caution until more safety and efficacy information is available, and patients should be carefully monitored. arv regimens comprising 3 or 4 nucleos(t)ides have inferior efficacy compared with piand nnrti-based regimens, and are not adequately evaluated in children. however, they may have a role in arv-naïve patients with hiv-associated tuberculosis, as the substantial interactions of rifampicin with the pis and nnrtis are avoided. the use of arv drugs by mothers is increasing as access to treatment programmes improves, thresholds for starting treatment become less stringent and arvs are implemented to prevent hiv transmission during childbirth and breastfeeding. however, the benefits and risks to breastfed infants of exposure to maternal arv drugs during lactation are poorly understood. the different physicochemical properties of drugs lead to differential transfer from maternal plasma to breastmilk (table ii) and to the breastfed infant. incomplete exposure of infants to components of a maternal regimen may favour the selection of drug-resistant virus should transmission occur. little is known about the safety of arvs in breastmilk. the small doses of nrtis and pis ingested through breastmilk may invoke subtle or idiosyncratic side-effects, while the more substantial exposure to nevirapine and efavirenz are of more importance. a study of arv concentrations in exclusively breastfed kenyan infants younger than 6 months, whose mothers were receiving haart, found biologically significant concentrations of lamivudine and nevirapine, but not zidovudine.29 lamivudine concentrations were just greater than the 50% inhibitory concentration (ic50) for wild-type hiv. median nevirapine concentrations (0.90 mg/l) were well above the median hiv ic50 (0.017 mg/ l).29 rwandan infants of mothers receiving efavirenzbased haart achieved median efavirenz concentrations of 0.87 mg/l through breastmilk ingestion, just below the recommended target trough concentration of >1 mg/l.30 transfer of nnrtis from mothers receiving haart may therefore result in substantial exposure in their breastfed infants along with potential benefit for prevention of hiv transmission, the risk of side-effects and the risk of developing viral resistance to nnrtis median breastmilk/maternal estimated median daily median infant drug plasma ratio (iqr) infant dose from breastmilk concentration reference zidovudine 0.44 (0.23, 0.65) 1.35 µg/kg/d (<1 000 × lower undetectable* 29 than standard infant dose for pmtct) lamivudine 2.56 (1.79, 3.89) 182 µg/kg (2% daily treatment dose for 0.02 0.03 mg/l* 29 >3-month-olds) nevirapine 0.75 (0.64, 0.89) 600 µg/kg/d 0.73 1.03 mg/l* 29 (15% of the 4 mg/kg/d infant dose being evaluated in pmtct studies) efavirenz 0.52 (0.43, 0.62) 0.87 mg/l† 30 lopinavir 0.11 (0.06, 0.15) undetectable† 31 ritonavir 0.11 (0.08, 0.18) undetectable† 31 *whole blood concentrations from 2 to 14 weeks after birth. † plasma concentrations 6 weeks to 6 months after birth. iqr = intraquartile range; pmtct = prevention of mother-to-child transmission. table ii. antiretroviral distribution to breastmilk and infant exposure resulting from maternal haart arvs in breastmilk 60 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e d e c e m b e r 2 0 0 9 should hiv transmission occur. conversely, breastmilk concentrations of pis are low and there is little if any transfer to the infant via breastmilk.31 the pharmacokinetics of infancy are unique and evolve rapidly during this period of life. drug doses used during infancy are often based on extrapolation from other age groups. for many of the arv drugs, evidence to support the dosing approaches is rudimentary and suitable dosage forms are lacking. it is important to ensure that adequate concentrations of arv drugs are obtained, to ensure efficacy and prevent toxicity. the infant is further exposed to maternal arv drugs before and during birth, and during lactation. there is an urgent need for pharmacokinetic studies in the relevant infant populations to support optimal dosing approaches which should then undergo more extensive evaluation of efficacy and safety. as drug concentrations in infants are highly unpredictable, particularly in neonates and premature infants, severely ill children or those treated concomitantly with interacting medications, tdm has a role in optimising individual dosing. references 1. violari a, cotton mf, gibb dm, et al. early antiretroviral therapy and mortality among hiv-infected infants. n engl j med 2008; 359: 2233-2244. 2. world health organization. report of the who technical reference group, paediatric hiv/art care guideline group meeting, who headquarters, geneva, switzerland, 10-11 april 2008. www.who.int/hiv/pub/paediatric/who_paediatric_ art_guideline_rev_mreport_2008.pdf (accessed 6 june 2009). 3. maples hd, james lp, stowe cd. special pharmacokinetic and pharmacodynamic considerations in children. in: burton me, shaw lm, schentag jj, evans we, eds. applied pharmacokinetics & pharmacodynamics. 4th ed. baltimore: lippincott williams & wilkins, 2006: 213-230. 4. chadwick eg, pinto j, yogev r, et al. early initiation of lopinavir/ritonavir in infants less than 6 weeks of age: pharmacokinetics and 24-week safety and efficacy. pediatr infect dis j 2009; 28: 215-219. 5. chadwick eg, capparelli ev, yogev r, et al. pharmacokinetics, safety and efficacy of lopinavir/ritonavir in infants less than 6 months of age: 24 week results. aids 2008; 22: 249-255. 6. ren y, nuttall jj, egbers c, et al. effect of rifampicin on lopinavir pharmacokinetics in hiv-infected children with tuberculosis. j acquir immune defic syndr 2008; 47: 566-569. 7. chadwick eg, rodman jh, britto p, et al. ritonavir-based highly active antiretroviral therapy in human immunodeficiency virus type 1-infected infants younger than 24 months of age. pediatr infect dis j. 2005; 24: 793-800. 8. dumon c, solas c, thuret i, et al. relationship between efficacy, tolerance, and plasma drug concentration of ritonavir in children with advanced hiv infection. ther drug monit 2000; 22: 402-408. 9. burger dm, van rossum am, hugen pw, et al. pharmacokinetics of the protease inhibitor indinavir in human immunodeficiency virus type 1-infected children. antimicrob agents chemother 2001; 45: 701-705. 10. bergshoeff as, fraaij pl, van rossum am, et al. pharmacokinetics of indinavir combined with low-dose ritonavir in human immunodeficiency virus type 1infected children. antimicrob agents chemother 2004; 48: 1904-1907. 11. curras v, hocht c, mangano a, et al. pharmacokinetic study of the variability of indinavir drug levels when boosted with ritonavir in hiv-infected children. pharmacology 2009; 83: 59-66. 12. rongkavilit c, van heeswijk rp, limpongsanurak s, et al. dose-escalating study of the safety and pharmacokinetics of nelfinavir in hiv-exposed neonates. j acquir immune defic syndr 2002; 29: 455-463. 13. mirochnick m, stek a, acevedo m, et al. safety and pharmacokinetics of nelfinavir coadministered with zidovudine and lamivudine in infants during the first 6 weeks of life. j acquir immune defic syndr 2005; 39: 189-194. 14. litalien c, faye a, compagnucci a, giaquinto c, et al. pharmacokinetics of nelfinavir and its active metabolite, hydroxy-tert-butylamide, in infants perinatally infected with human immunodeficiency virus type 1. pediatr infect dis j 2003; 22:48-55. 15. rutstein r, samson p, kiser j, et al. the pactg 1020a protocol: atazanavir with or without ritonavir in hiv-infected infants, children, and adolescents. presented at the 14th conference on retroviruses and opportunistic infections, 25 28 february 2007, los angeles (abstract 715). 16. kiser j, rutstein r, aldrovandi g, et al. pharmacokinetics of atazanavir/ritonavir in hiv-infected infants, children, and adolescents: pactg 1020a. presented at the 12th conference on retroviruses and opportunistic infections, 22 25 february 2005, boston (abstract 767). 17. mirochnick m, fenton t, gagnier p, et al. pharmacokinetics of nevirapine in human immunodeficiency virus type 1-infected pregnant women and their neonates. pediatric aids clinical trials group protocol 250 team. j infect dis 1998; 178: 368-374. 18. shetty ak, coovadia hm, mirochnick mm, et al. safety and trough concentrations of nevirapine prophylaxis given daily, twice weekly, or weekly in breast-feeding infants from birth to 6 months. j acquir immune defic syndr 2003; 34: 482490. 19. six week extended-dose nevirapine (swen) study team, bedri a, gudetta b, et al. extended-dose nevirapine to 6 weeks of age for infants to prevent hiv transmission via breastfeeding in ethiopia, india, and uganda: an analysis of three randomised controlled trials. lancet 2008; 372: 300-313. 20. mulenga v, fillekes q, kabamba d, et al. pharmacokinetics of nevirapine in 3 to 6-kg, hiv-infected infants taking pediatric fixed-dose combination tablets. presented at the 16th conference on retroviruses and opportunistic infections, 8 11 february 2007, montreal (abstract 881). 21. tremoulet ah, capparelli ev, patel p, et al. population pharmacokinetics of lamivudine in human immunodeficiency virus-exposed and -infected infants. antimicrob agents chemother 2007; 51: 4297-4302. 22. pacifici gm. pharmacokinetics of antivirals in neonate. early hum dev 2005; 81:773-780. 23. capparelli e, rakhmanina n, mirochnick m. pharmacotherapy of perinatal hiv. semin fetal neonatal med 2005; 10: 161-175. 24. yuen gj, weller s, pakes ge. a review of the pharmacokinetics of abacavir. clin pharmacokinet 2008; 47: 351-371. 25. la porte cjl, back dj, blaschke t, et al. updated guideline to perform therapeutic drug monitoring for antiretroviral agents. reviews in antiviral therapy 2006; 3: 4-14. 26. cohen k, van cutsem g, boulle a, et al. effect of rifampicin-based antitubercular therapy on nevirapine plasma concentrations in south african adults with hivassociated tuberculosis. j antimicrob chemother 2008; 61(2): 389-393. 27. ren y, nuttall jj, egbers c, et al. effect of rifampicin on lopinavir pharmacokinetics in hiv-infected children with tuberculosis. j acquir immune defic syndr 2008; 47(5): 566-569. 28. oudijk m, mcilleron h, mulenga h, et al. pharmacokinetics of nevirapine in young children during combined art and rifampicin-containing antituberculosis treatment. presented at the ias conference, 19 22 july 2009, cape town. (abstract lbpeb10). 29. mirochnick m, thomas t, capparelli e, et al. antiretroviral concentrations in breast-feeding infants of mothers receiving highly active antiretroviral therapy. antimicrob agents chemother 2009; 53: 1170-1176. 30. schneider s, peltier a, gras a, et al. efavirenz in human breast milk, mothers’, and newborns’ plasma. j acquir immune defic syndr 2008; 48: 450-454. 31. corbett a, martinson f, rezk n. lopinavir/ritonavir concentrations in breast milk and breast-feeding infants. presented at the 16th conference on retroviruses and opportunistic infections, 8-11 february 2009, montreal (abstract 947). 32. working group on antiretroviral therapy and medical management of hivinfected children. guidelines for the use of antiretroviral agents in pediatric hiv infection. 23 february 2009, pp. 1-139. http://aidsinfo.nih.gov/contentfiles/ pediatricguidelines.pdf (accessed 30 june 2009). conclusion acknowledgement hm received research support from the european and developing countries clinical trials partnership. hg received support from echo, impaact and pepfar. 61 abstract introduction research methods and design results discussion conclusion acknowledgements references about the author(s) linneth n. mabila department of pharmacy, faculty of health sciences, university of limpopo, polokwane, south africa patrick h. demana school of pharmacy, faculty of health sciences, sefako makgatho health sciences university, pretoria, south africa tebogo m. mothiba faculty of health sciences, university of limpopo, polokwane, south africa citation mabila ln, demana, ph, mothiba, tm. rural nurses’ antiretroviral prescribing practices in children, limpopo province, south africa. s afr j hiv med. 2023;24(1), a1470. https://doi.org/10.4102/sajhivmed.v24i1.1470 original research rural nurses’ antiretroviral prescribing practices in children, limpopo province, south africa linneth n. mabila, patrick h. demana, tebogo m. mothiba received: 12 nov. 2022; accepted: 17 jan. 2023; published: 07 july 2023 copyright: © 2023. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: errors in antiretroviral therapy (art) use are common in children living with hiv (clhiv), but there is limited evidence from rural primary healthcare (phc) facilities where trained professional nurses initiate and manage most clhiv. objectives: to assess antiretroviral prescribing practices of trained professional nurses in mopani district’s rural facilities and compare them to the 2015 national consolidated guidelines to evaluate the appropriateness of art use. method: a four-year (2015–2018) retrospective cross-sectional medical record review was conducted of clhiv in 94 rural phc facilities of mopani district. inclusion criteria were: age under 15 years, initiated on art by nurses in 2015 and virally unsuppressed (viral load ≥ 400 copies/ml) by the end of december 2018. results: a total of 16 669 antiretrovirals were prescribed from 7035 clinic visits. a correct art regimen and dosage form was prescribed in 7045 (96%) and 15 502 (93%) of the cases. however, errors were common: 2928 (23%) incorrect doses, 15 502 (93%) incorrect dosing frequencies, and 4122 (61%) incorrectly dispensed antiretrovirals, and 3636 (28%) incorrect dosing frequencies. conclusion: antiretroviral prescribing errors in the form of drug omissions in art regimens, incorrect dosing and dosing frequencies, lack of formulation considerations, and inadequate monthly supplies of antiretrovirals were commonly observed in this review. antiretroviral stewardship programmes should be considered to develop and establish a fundamental strategy for improving quality in managing clhiv. keywords: antiretroviral therapy; art; children; nurse prescriber; prescribing practices; prescribing errors; antiretroviral stewardship. what this study adds: a high prevalence of prescribing and dispensing errors in managing children on art by trained nurses in rural phc facilities was observed. introduction in south africa (sa), since 2010, nurses have taken on various hiv care tasks, such as hiv diagnosis and prescribing antiretroviral treatment (art), adopting the task-shifting approach developed by the world health organization (who).1,2 this decision led to the decentralisation of art services to rural primary healthcare (phc) facilities, where professional nurses were trained and capacitated in the nurse-initiated management of art (nimart) programme.3,4,5,6,7,8,9 challenges have been identified with nimart training and implementation in phc facilities.6 there are many other challenges in achieving and maintaining virological suppression in children on art. despite these challenges, the scale-up of art programmes has considerably improved survival in children living with hiv (clhiv) in sa.10,11 antiretroviral treatment failure in children has received insufficient attention in managing clhiv,12,13 which results in the development of resistance to antiretrovirals.13,14 antiretroviral therapy failure rates among children in poor, resource-limited settings have recently been shown to have escalated from 19.3% to over 32%.15,16 excellent adherence to art is required in order to achieve and maintain virological suppression, but this is challenging in clhiv, especially in adolescents.17,18,19,20,21,22,23,24 prescribing and dispensing errors are the most significant cause of medication errors. they occur in general clinical practice as well as in hospitals and clinics.25,26,27,28 they can affect patient safety and healthcare quality.26 to our knowledge, there is currently limited published research and evaluations of antiretroviral prescribing practices in children under 15 years initiated and managed on art by nimart-trained professional nurses in resource-limited rural phc facilities. this study aimed to evaluate the appropriateness of antiretroviral use and describe the compliance of nimart-trained nurses with hiv and/or aids treatment guidelines. research methods and design this was a four-year (01 january 2015 to 31 december 2018) descriptive, cross-sectional medical record study to determine nimart-trained professional nurses’ art prescribing practices in rural phc facilities of the mopani district in limpopo province, south africa. study setting the study was conducted in 94 rural phc facilities, comprised of eight community health centres and 86 clinics in the mopani district. these facilities were selected because they were accredited to roll out antiretrovirals in 2015 and had children on art in their programme. mopani municipality comprises 354 rural villages and 16 urban areas. of the total district population, 81% live in rural villages, 14% in urban areas and 5% in agricultural areas. the district is divided into five local municipalities: ba-phalaborwa, greater giyani, greater letaba, greater tzaneen and maruleng.29 study population and sampling strategy the study population comprised children under the age of 15, initiated and managed on art at phc facilities of mopani district in 2015 and virally unsuppressed (viral load [vl] ≥ 400 copies/ml) by 31 december 2018. a census data collection technique (total population purposive sampling) was used to obtain a complete picture of the problem in these phc facilities.30 first, the district tier.net system was used to generate a list of all children under 15 years initiated on art in 2015 (n = 516) and those virally unsuppressed by 31 december 2018 (n = 255). second, a physical census of all 255 medical records was conducted in the facilities. data collection the principal investigator physically went to all the phc facilities for data collection. a data collection checklist designed for this study was used to extract demographic and baseline clinical data from the medical records including age at art initiation, gender, who clinical staging at art initiation, concomitant diseases at art initiation, and the art regimen at initiation. the data collection checklist also captured the longitudinal art treatment history, the prescribed dose (strength) for each drug in the regimen, the prescribed dosage form for each drug in the regimen, the prescribed dosing frequency for each drug in the regimen, and the quantity or amount dispensed for each prescribed drug in the regimen. data analysis the data collected were entered into a microsoft exceltm spreadsheet and cleaned and imported into the statistical package for social sciences (spss). the mean, median, mode, and standard deviation descriptively summarise the patient’s demographic and clinical characteristics. categorical variables, such as gender, were selected through frequency counts and percentage calculations. for continuous variables, such as age, minimum and maximum values were determined. similar to studies conducted by grossberg et al.31 and fairley et al.,32 adherence to art was assessed by the timeliness of clinic attendance. actual dates for clinic visits were compared with scheduled appointments for every patient. to this end, the researcher cumulatively determined the days each patient was late for art treatment over the four years. this variable was standardised by determining its quotient from the months each patient received art. guided by the consolidated hiv and/or aids treatment guidelines, prescriptions were then analysed, evaluating the appropriateness of the prescribed art regimen, the dose, dosage form, dosing frequency, and the quantity of monthly treatment supplied. ethical considerations ethical approval was obtained from the university of limpopo’s turfloop research ethics committee (trec), certificate number trec/81/2019: pg. permission to conduct the study was granted by the limpopo department of health, approval number lp_20190, and the department of health mopani district municipality (reference: s4/2/2). results from the census of the 255 medical records of the children under study, 7351 analysable visits were obtained. the baseline characteristics of the 255 clhiv are shown in table 1 at art initiation. the majority were of school-going age. most children (58%) were initiated on art while in who clinical stages 1 and 2, with 28% (n = 72) of children without who clinical stage information. of the 255 children, only 40 had notable concomitant diseases at initiation, such as pulmonary tuberculosis, fungal skin infections, and gastrointestinal problems. table 1: baseline characteristics of virally unsuppressed children initiated on antiretroviral treatment in 2015. table 2 gives an overview of the art regimens the children were initiated on per sub-district. most children (78%) were initiated on an abacavir-containing regimen, as recommended by the 2015 south african hiv/aids guidelines, but 7% of children were initiated on stavudine-containing regimens. table 2: antiretroviral treatment initiation by sub-district and antiretroviral treatment regimens. in 96% of the prescriptions, children were prescribed a triple regimen of art by the nurses, as recommended by the south african hiv/aids treatment guidelines. in three cases the nurses prescribed four antiretrovirals instead of the three recommended by the treatment guidelines by prescribing lamivudine in addition to the abacavir/lamivudine fixed-dose combination. the nurses’ art prescribing practices and medication dispensed are shown in table 3. the majority (93%) of the antiretrovirals were prescribed in a correct dosage form suitable for the children’s weight and age. the reasons for the 1192 incorrect prescriptions included: incomplete prescription (n = 928), incorrect doses (n = 106), and illegible (n = 102). dosing frequency was not indicated in 22% of prescriptions. table 3: summary of nurse-initiated-management of antiretroviral treatment-trained nurses’ antiretroviral treatment prescribing practices for children living with hiv and antiretroviral treatment supplied. a common reason for incorrectly prescribed dosage forms was related to efavirenz (efv) 50 mg stockouts – nurses prescribed efv 600 mg enteric-coated tablets for children in the 300 mg weight band, and caregivers were instructed to administer half of the tablet even though the guidelines advise against chewing or crushing this form of a tablet. medication dosage errors were more commonly an overdose than an underdose of their art regimen (defined by dakshina et al.33 as antiretroviral drugs prescribed at a dose higher or lower than the dose recommended in the 2015 south african consolidated treatment guideline for the child’s weight band). the amount of art dispensed could be assessed in 15 502 cases (missing values due to missing data on weight, dose, dose frequency, or drug prescribed). nurses only indicated the amount of art dispensed in 48% of prescribed antiretrovirals (table 3). from the 7449 antiretrovirals with an indication of the quantity dispensed, only 39% (n = 2883) of the children were dispensed an adequate amount of art to last them until their next appointment date and 16% (n = 1195) of the antiretrovirals were over-supplied. table 4 gives details of the correctness of the dosing frequencies from the 12 647 prescriptions with a dosing frequency indicated. table 4: correctness of prescribed dosing frequencies. discussion in this medicine utilisation review, the following forms of medication errors and prescribing irrationalities were documented: (1) antiretroviral omissions in 4% of the prescriptions, (2) 7% incorrectly prescribed dosage forms, (3) 23% incorrectly prescribed doses, (4) 28% incorrectly prescribed dosing frequencies, and (5) 61% of inadequately supplied monthly treatments. these findings are similar to those in other studies. mulema et al.34 in uganda reported the prevalence of irrational prescribing was high among children under 15 years. sterling35 reported that dosing errors, such as inappropriate dosages or frequency of administration like underdosing or overdosing, are the most common medication errors in the management of children. other noted medication errors include the incorrect selection of the indication, incorrect route of administration, and failure to screen drug interactions or monitor side effects.36,37 simonsen et al.38 highlight that nurses experience an insufficient pharmacological knowledge of medication, mainly in dosage calculations and medicine management. in this study we see the high prevalence of irrational prescriptions in this review of children as an indication that there is a need to make nimart-trained nurses aware of the importance of rational prescribing in children on art since their failure to prescribe art according to treatment guidelines is an irrational use of antiretrovirals.27,39 irrational prescribing often results from wrong medical decisions associated with the lack of knowledge, skill or inadequate training.27,36,40,41,42 also, strenuous working conditions, complex or unclear guidelines and insufficient communication between health professionals such as nurses and doctors have been identified as contributing to prescribing errors.27,43,44,45 since clinical nursing knowledge is the key to quality patient care,46 it is, therefore, crucial for nimart-trained nurses to have an adequate understanding of the relevant aspects of antiretroviral (arv) use to address issues of irrational antiretroviral use. nurse-initiated-management of art-trained nurses should follow the proposed rational art prescribing cycle and always prescribe for children initiated and managed on art (1) a correct triple regimen as recommended in recent hiv and aids treatment guidelines, (2) the correct dosage form mindful of their age and drug administration properties, (3) the correct strength suitable for their body weight that avoids cases of underdosing or overdosing, and (4) correct dosing frequency that takes into consideration the pharmacokintetics (pks) and pharmacodynamics (pds) aspects of the antiretrovirals prescribed (see figure 147 for visual emphasis). figure 1: visual illustration of the rational antiretroviral therapy prescribing cycle. our findings indicate that education, training, mentorship, and support should be targeted at all nurses who have art prescribing responsibility for children, which aims at empowering them with the knowledge of (1) which antiretroviral tablets should be swallowed whole, (2) which ones cannot be crushed, divided, or chewed, (3) which ones are 12 hourly or 24 hourly formulations, and (4) the correct quantity of all prescribed antiretrovirals to last them until their next scheduled appointment to ensure that they do not run out of treatment as this could predispose the children to the development of drug resistance and ultimately treatment failure. this study has limitations. first, this study was conducted in 94 of 108 rural phc clinics of one district municipality out of five districts in the limpopo province. therefore, the results of this study may not be generalisable to urban areas or settings. second, the study was cross-sectional and thus could not evaluate the relationship between incorrect antiretroviral dosing and virological outcomes or whether treatment discontinuations or adverse effects were associated with overdosing. third, the study only reviewed the prescribing practices of virologically unsuppressed children (vl ≥ 400 copies/ml) initiated on art and we did not review prescribing practices of virally suppressed children. therefore, we cannot comment on whether these findings are comparable with prescribing practices in virally suppressed children. conclusion from the findings of this antiretroviral utilisation review, there is evidence of the prevalence of art prescribing errors in the form of drug omissions in antiretroviral regimens. in addition, there were incorrect dosing and dosing frequencies, a lack of formulation considerations, and inadequate monthly supplies of antiretrovirals. the observed irrationality of the nimart-trained nurse’s prescribing practices in this review depicts a lack of compliance with hiv and aids treatment guideline recommendations. we consider the high prevalence of prescribing errors in this review as an indication that there is a need to train nimart-trained nurses on the importance of rational prescribing in children on art since the failure to prescribe art according to treatment guidelines results in art medication errors.48 therefore, tackling the prescribing and medication errors in children should be prioritised to improve healthcare delivery towards ensuring patient safety and allowing for optimal utilisation of antiretrovirals. it is standard practice during nursing education to receive instructions on a guide to clinical medication administration and the protection of patient safety known as the ‘five rights’ or ‘five rs’ of medication administration.49,50 in phc settings, nurses have a role to play in the promotion of the rational medicine use.51 hence, for successful treatment outcomes in children, professional nurses need to perform their art dosing and dispensing roles as guided by the hiv and aids guidelines to ensure the rational use of antiretrovirals in managing children. the rational use of antiretrovirals should be an adopted strategy for improving treatment outcomes.52 a pharmacist-led art stewardship programme, as well as dosing and dispensing continuous professional development training programmes promoting the appropriate use of antiretrovirals in children on art in resource-limited rural phc clinics, should be a considered intervention to give special attention to the rational use of antiretrovirals in children especially now that antiretroviral resistance is currently becoming a significant rural health problem in clhiv. acknowledgements the authors would like to thank the limpopo department of health for permitting them to conduct the study in the 94 selected rural primary healthcare clinics. the operational managers and all data capturers and administration clerks who assisted with access to the tier.net information system as well as the retrieval of medical records for the study. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions l.n.m. wrote the proposal and conducted the study as part of her doctor of pharmacy degree. p.h.d. supervised the study and t.m.m. co-supervised the study. the article was reviewed by all the authors. funding information this project received funding from the university of limpopo’s staff capacity development programme (ucdp), as well as funding from the national research foundation black academics advancement programme (baap) (previously known as the national research foundation [nrf]) – first rand foundation (frf) sabbatical grant (reference number nfsg180605340566, grant number: 116803). data availability the data supporting the results are available from the corresponding author, l.n.m., upon reasonable request. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references zuber a, mccarthy cf, verani ar, msidi e, johnson c. a survey of nurse-initiated and-managed antiretroviral therapy (nimart) in practice, education, policy, and regulation in east, central, and southern africa. j assoc nurses aids care. 2014;25(6):520–531. https://doi.org/10.1016/j.jana.2014.02.003 long l, brennan a, fox mp, et al. treatment outcomes and cost-effectiveness of shifting management of stable art patients to nurses in south africa: an observational cohort. plos med. 2011;8(7):e1001055. 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dis child. 2019;104(6):588–595. https://doi.org/10.1136/archdischild-2018-315981 bengtsson m, ekedahl abi, sjöström k. errors linked to medication management in nursing homes: an interview study. bmc nurs. 2021;20(1):69. https://doi.org/10.1186/s12912-021-00587-2 mchugh md, lake et. understanding clinical expertise: nurse education, experience, and the hospital context. res nurs health. 2010;33(4):276–287. https://doi.org/10.1002/nur.20388 world health organization. promoting rational use of medicines: core components. geneva: world health organization; 2002. holloway k, van dijk l. the world medicines situation 2011. rational use of medicines. geneva: world health organization; 2011. macdonald m. patient safety: examining the adequacy of the 5 rights of medication administration. clin nurse spec. 2010;24(4):196–201. https://doi.org/10.1097/nur.0b013e3181e3605f hanson a, haddad lm. nursing rights of medication administration. st. petersburg, florida: statpearls publishing; 2021. elliott m, liu y. the nine rights of medication administration: an overview. br j nurs. 2010;19(5):300–305. https://doi.org/10.12968/bjon.2010.19.5.47064 world health organization (who). the pursuit of responsible use of medicines: sharing and learning from country experiences [homepage on the internet]. 2012 [cited 2022 dec 19]. available from: https://apps.who.int/iris/handle/10665/75828 hiv editorial_in.indd september 2014, vol. 15, no. 3 sajhivmed 75 e d it o r ia l m e s s a g e s message from the executive while i was attending the melbourne international aids society (ias) conference in july, i must admit that i was surprised at the announcement by the minister of health on the change in our eligibility criteria for antiretrovirals (arvs). he announced that, to be in line with the world health organization, all hiv-infected individuals with a cd4+ count <500 cells/µl should be started on antiretroviral therapy (art), and that all hiv-infected pregnant women should initiate lifelong therapy, namely option b+. �e society congratulates the national department of health on their willingness to amend south african arv policy in order to treat as many individuals as possible. in terms of raising the  cd4+ entry level to 500 cells/µl, it must be noted that while randomised, clinical trial data on the clinical benefit of art in patients with cd4+ counts >350 cells/µl are not yet available, we do recognise that there are advantages to having more people on medication. there is a clear transmission-prevention benefit in discordant couples and there are accumulating data in the community setting. so, as clinicians, we need to up our counselling game. the task of taking lifelong medication is an onerous one. our current first line is not forgiving of missed doses. we, as healthcare workers, should have a thorough discussion with patients about the potential benefits, uncertainties and side-effects of medication. if patients are motivated to stick to their treatment, they should be prescribed art; if they do not yet feel ready, they should be given time to work through the issues needed to adhere to therapy. obviously, this would be done with close monitoring of their cd4+ counts. on another note, september 2014 brings our next confe rence. it promises to be packed with interesting debates, excellent plenaries and top-notch speakers. for those of you who are attending, enjoy the opportunity to network and connect with other hiv clinicians. for those of you who cannot make it, follow our facebook page (http:// www.facebook.com/sahivsoc), twitter account (@sahivsoc) and the media. francesca conradie president: southern african hiv clinicians society fconradie@witshealth.co.za n o n e s h a l l b e d e n i e d s4 reg. no. 44/20.2.8/0779 odimune tenofovir df 300 mg emtricitabine 200 mg efavirenz 600 mg “simplify, simplify.” henry david thoreau fdc philosopher cipla medpro (pty) ltd. reg. no. 1995/004182/07, building 9, parc du cap, mispel street, bellville, 7530, rsa. tel (021) 943 4200, fax (021) 914 4699. e-mail: medicalpa@ciplamedpro.co.za website: www.cipla.co.za customer care: 080 222 6662 who pre-qualified 3-in-1 once daily fixed dose combination r390.001 fda approved recommended as preferred 1st line regimen by national and international guidelines 2,3 reference: 1. sep excl. vat as per pcd february 2014. 2. the use of antiretroviral drugs for treating and preventing hiv infection (who guidelines-june 2013). 3. the south african antiretroviral treatment guidelines 2013. abstract introduction early infant diagnostic testing within the south african public sector indeterminate hiv pcr results extent of indeterminate results clinical and laboratory management of indeterminate results laboratory management clinical management counselling of caregivers summary acknowledgements references about the author(s) ahmad haeri mazanderani centre for hiv & stis, national institute for communicable diseases, south africa department of medical virology, university of pretoria, south africa karl-günter technau empilweni services and research unit, johannesburg, south africa department of paediatrics and child health, university of the witwatersrand, south africa nei-yuan hsiao division of medical virology, university of cape town, south africa national health laboratory service, south africa jean maritz national health laboratory service, south africa division of medical virology, department of pathology, stellenbosch university, south africa sergio carmona national health laboratory service, south africa department of molecular medicine and haematology, university of the witwatersrand, south africa gayle g. sherman centre for hiv & stis, national institute for communicable diseases, south africa department of paediatrics and child health, university of the witwatersrand, south africa citation haeri mazanderani a, technau k-g, hsiao n-y, maritz j, carmona s, sherman gg. recommendations for the management of indeterminate hiv pcr results within south africa’s early infant diagnosis programme. s afr j hiv med. 2016;17(1), a451. http://dx.doi.org/10.4102/sajhivmed.v17i1.451 review recommendations for the management of indeterminate hiv pcr results within south africa’s early infant diagnosis programme ahmad haeri mazanderani, karl-günter technau, nei-yuan hsiao, jean maritz, sergio carmona, gayle g. sherman received: 17 nov. 2015; accepted: 21 jan. 2016; published: 13 may 2016 copyright: © 2016. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract indeterminate hiv pcr results represent missed diagnostic opportunities within south africa’s early infant diagnosis programme. these results not only delay diagnosis and appropriate management but are also a source of confusion and apprehension amongst clinicians and caregivers. we describe the extent of indeterminate hiv pcr results within south africa’s early infant diagnosis programme and provide recommendations for the management of these cases, both in terms of laboratory practice and the clinical care of the infants. introduction early infant diagnosis (eid) of hiv using highly sensitive polymerase chain reaction (pcr) methods and rapid linkage for the treatment of those who test positive is considered the gold standard of paediatric hiv care. failure to initiate prompt combination antiretroviral therapy (cart) in an hiv-infected infant has been associated with considerable morbidity and mortality.1,2 the peak mortality rate for hiv-infected infants has been found to occur before 3 months of age in south africa, emphasising the importance of rapid access to treatment.3 hence, an early definitive test result indicating either a positive or negative hiv status is imperative. indeterminate hiv pcr results, which can occur at all ages of testing (i.e. between birth and 18 months), represent missed diagnostic opportunities where the result is neither clearly positive nor negative. this not only delays diagnosis and appropriate management but is also a source of confusion and apprehension amongst clinicians and caregivers. we describe the extent of indeterminate hiv pcr results within south africa’s eid programme and provide recommendations for the management of these cases, both in terms of laboratory practice and the clinical care of the infants. the purpose of these recommendations is to provide guidance for laboratory staff and the relevant clinical care providers on managing indeterminate hiv pcr results and to standardise practice within the national health laboratory service (nhls) eid laboratories. early infant diagnostic testing within the south african public sector whereas previously the south african national department of health recommended routine hiv pcr testing at 6 weeks of age for hiv-exposed infants, new guidelines published on 01 june 2015 state that all hiv-exposed infants should have an hiv pcr test at birth, 10 weeks of age and 6 weeks after stopping breastfeeding if still under 18 months of age at that time.4 in children receiving prolonged nevirapine prophylaxis up to 12 weeks of age, an additional hiv pcr test is required at 18 weeks of age. the current guidelines recommend confirming the hiv status of all infants with a positive hiv pcr result by repeating the hiv pcr test on a second specimen.4 two types of specimens can be used for hiv pcr testing. the most common specimen used is capillary blood from a heel prick spotted onto a cotton-based paper card, which is dried at the site of collection. this is known as a dried blood spot (dbs) and requires three full spots per card. anti-coagulated ethylenediaminetetraacetic acid (edta) whole blood (purple top tube) with the minimum volume of 250 µl (0.25 ml) is also a suitable specimen. since 2010, all eid laboratories within the nhls have used the same hiv pcr assay. the cobas® ampliprep/cobas® taqman (cap/ctm) hiv-1 qualitative test (roche molecular systems, inc., branchburg, nj) is a total nucleic acid real-time reverse transcriptase pcr assay that detects hiv-1 proviral dna and hiv-1 rna on edta whole blood or dbs specimens.5 a new version of the assay, cap/ctm v2.0, was introduced during the course of 2014. this version replaces the cap/ctm test, is approved for in vitro diagnostic use and has improved analytical sensitivity.6 whereas the previous version of the assay was found to have a limit of detection of 1090 rna copies/ml using 60 µl dbs specimens, the cap/ctm v2.0 has a reported limit of detection of 300 rna copies/ml.6,7 indeterminate hiv pcr results an indeterminate result means that the hiv pcr test yielded a valid but inconclusive result that is interpreted as being neither clearly positive nor negative. the term ‘equivocal’ was used in the past to qualify hiv pcr results of uncertain significance but is no longer used in nhls eid laboratories. indeterminate results have a detectable target, as determined by the instrument, but the amplified viral signal is of such a low level that it could potentially be a false-positive result. standard operating procedures (sops) within the nhls define results as ‘indeterminate’ according to specific real-time pcr parameters. the cut-off criteria are based on laboratory findings of poor positive predictive value and irreproducible positive results associated with higher cycle threshold (ct) and lower relative fluorescence intensity (rfi) values.8,9 currently, the nhls’ national eid sop defines an indeterminate hiv pcr result as a result with a detected target that has a ct value > 33 and/or rfi < 5. these cut-off criteria will be continuously reviewed and, as they can potentially be influenced by a number of clinical, pre-analytic and analytic considerations, are likely to change with time. these variables include the type of specimen tested (i.e. dbs versus edta whole blood), reduction in mother-to-child transmission rate (i.e. reduced background prevalence) and the potential for antiretroviral prophylaxis to impact on diagnostic sensitivity. extent of indeterminate results there are approximately 270 000 hiv-exposed infants born each year in south africa.10,11 whereas this number is thought to be fairly constant, the volume of testing has increased year on year throughout the country. in 2014, 375 469 hiv pcr tests were performed, equating to an estimated testing coverage of 85% with approximately 1.8% of infants testing positive at 6 weeks of age (personal communication prof gayle sherman).12 indeterminate results are relatively rare and represent less than 1% of all registered specimens within the south african eid programme, on average amounting to less than 300 specimens per month. however, since 2012 indeterminate results have consistently comprised greater than 16% of all detected specimens (i.e. all positive and indeterminate specimens combined). hence, indeterminate results represent a significant proportion of infants requiring urgent follow-up within the eid programme. clinical and laboratory management of indeterminate results the management of infants with indeterminate results is distinct from those with a positive result and requires a multidisciplinary approach from laboratories, pathologists, clinicians and programme managers. depending on the referral structures in each district, the primary clinician should urgently seek advice for each case from more specialised clinicians, such as district clinical specialist team paediatricians and paediatric infectious disease specialists. furthermore, pathologists based at the nhls eid laboratories should be consulted, and prevention of mother to child transmission (pmtct) and hiv and/or aids, stis and tb (hast) programme managers should be contacted. laboratory management indeterminate results, as defined by the nhls’ eid sop, should be treated as urgent and reviewed by an appropriately trained and experienced laboratory staff member, preferably a registrar or pathologist. the ct and rfi values should be entered on the laboratory information system and the laboratory information system should be searched for previous hiv pcr and hiv viral load (vl) test results. furthermore, the contact clinician who requested the hiv pcr test and/or a designated centralised responsible person for the district or province (e.g. district clinical specialist team paediatrician or paediatric infectious disease specialist or pmtct coordinator or hast programme manager) should be contacted to discuss the case and requested to submit repeat samples where appropriate. clinical management every primary clinician should have contact details of specialist clinicians, programme managers and their nhls eid laboratory from the outset. accurate completion of the nhls requisition form, with patient and clinician contact details, facilitates this multidisciplinary approach and should include the data set listed in box 1. special care should be taken to ensure that the details on the request form reflect those on the specimen (i.e. ensure that the name, surname and barcode on the form and on the specimen are the same). box 1: hiv pcr request form details. the actions required following an indeterminate result are described in two broad scenarios. scenario a outlines the management where an initial hiv pcr test, at any age between birth and 18 months, has an indeterminate result. scenario b outlines the management where an initial hiv pcr test is positive, but the confirmatory hiv pcr is indeterminate (figures 1 and 2, respectively). figure 1: scenario a. figure 2: scenario b. scenario a the first hiv pcr test has an indeterminate result a specimen for repeat hiv pcr testing and an additional specimen for hiv vl testing should be submitted immediately and the patient referred.4 referral can mean seeking advice from clinicians and/or pathologists or sending the patient to a specialist referral centre urgently. importantly, appropriate referral should not be delayed whilst awaiting the laboratory results of the repeat hiv pcr and hiv vl tests. where the repeat hiv pcr test is positive and/or hiv vl is detectable (i.e. any value above the detection limit of the assay), the child is likely hiv-infected (figure 1: a1). infant cart initiation should not be delayed by further testing. although these cases require a confirmatory hiv pcr and/or hiv vl to definitively establish a positive hiv infection status, the clinical team must consider each case individually. in some cases, an indeterminate hiv pcr result, depending on ct/rfi values, followed by a positive hiv pcr and/or detectable hiv vl result may be sufficient to establish a diagnosis of hiv infection. if not, another specimen for confirmatory hiv pcr and hiv vl tests is required at the time of cart initiation. where the repeat hiv pcr is negative or indeterminate again and the hiv vl is undetectable, it is important to consider that hiv infection cannot be excluded in the presence of antiretroviral prophylaxis (e.g. daily nevirapine [nvp]) or within 4 weeks of discontinuing prophylaxis (figure 1: a2). as antiretroviral therapy (art) may suppress the target to less than detectable levels, it is important to complete the infant art prophylaxis course and repeat hiv pcr and hiv vl 4 weeks later. the infant should be monitored clinically every 2 weeks prior to this, and if the child becomes symptomatic for hiv infection, testing should be repeated immediately. healthcare workers should have a low threshold for repeat hiv pcr testing at any opportunity before 10–18 weeks of age. scenario b the first hiv pcr is positive but the second, confirmatory hiv pcr is indeterminate a specimen for repeat hiv pcr testing and an additional specimen for hiv vl testing should be submitted immediately and the patient referred. where the patient has already been initiated on cart, as per guidelines, this should not be interrupted. appropriate referral should not be delayed whilst awaiting the laboratory results of the repeat hiv pcr and hiv vl tests. where the repeat hiv pcr is positive and/or hiv vl is detectable (i.e. any value above the detection limit of the assay), the child is confirmed hiv-infected on account of hiv having been detected twice on separate samples (figure 2: b1). it is imperative that such patients continue receiving cart. where the repeat hiv pcr is indeterminate and hiv vl is undetectable, the ct and rfi should be reviewed in consultation with a pathologist (e.g. clinical virologist) to decide whether the infant can be considered hiv-infected or whether hiv pcr and hiv vl require repeat testing (figure 2: b2). where the repeat hiv pcr is negative and the hiv vl is undetectable, it is important to consider that hiv infection cannot be excluded in the presence of antiretroviral prophylaxis (daily nvp) or cart if already initiated (figure 2: b3). the best approach for these infants should be determined within the multidisciplinary team. it is vital to keep the patient’s caregiver informed and supported (see ‘counselling suggestions’ below) and the patient kept in close clinical follow-up. the same approach should be followed for infants with repeatedly indeterminate hiv pcr results. in all cases, a clear plan should be documented, communicated and adhered to. if the diagnosis remains unclear despite all attempts at resolution, the last resort is a monitored treatment interruption under the guidance of an experienced paediatric hiv clinician, if treatment has been started. it is recommended that follow-up testing be performed at 1 month, 3 months, and 3 monthly thereafter for a minimum of 18 months off art. counselling of caregivers the mother or primary caregiver should be consulted regarding the further management and follow-up of an infant who has received an hiv pcr indeterminate result. the decision to initiate cart, when indicated, must consider the practical implications of where and how treatment will be continued. infant feeding should be carefully discussed considering that breastfeeding improves outcome in hiv-infected infants, and maternal adherence to art during breastfeeding should be stressed. all cases should urgently be brought to the attention of the relevant hiv clinic. engagement of the family should be encouraged but the mother or primary caregiver should guide the level of family involvement. the mother’s well-being should be monitored by providing adequate art care, tb screening and adequate psychosocial support. it is important to document discussions with the mother in the infant’s bed letter and road to health booklet. the mother should have the clinic contact numbers and clinical course and decisions should be documented in the infant’s road to health booklet to facilitate communication between different healthcare providers. where possible, to improve compliance, continuity of care should occur at a single facility, preferably with a single healthcare worker. the guiding principles of counselling in these cases should include: the mother or primary caregiver must be involved with honest and frank information at every stage. the message must be communicated that there is a team involved with the infant’s care, that guidelines and resources exist to determine the final outcome. however, the length of this process is uncertain. follow-up care and clear communication, both verbal and written, is critical especially for mobile mothers. the team may not know the answer to the diagnostic dilemma at present but is aware how stressful this is and will undertake to find the solution in consultation with the mother and the necessary experts. at this stage, it is critical that the follow-up care is monitored and tracked to reassure the mother or family that somebody is pursuing the problem. in the absence of a clear answer, this should provide some level of relief. a clear plan should be documented, communicated and adhered to. in the event of an unclear diagnosis despite all attempts to come to a clear solution, the last resort will be a monitored treatment interruption, if the infant is on cart. it is recommended that follow-up testing be performed at 1 month, 3 months and 3 monthly thereafter for a minimum of 18 months off art. note that these families need increased adherence support as they may be confused by the indeterminate results and the lack of a final confirmed diagnosis may contribute to poor adherence to art. summary the laboratory diagnosis of hiv in infants less than 18 months of age requires two hiv pcr-positive results, each on a separate specimen, as per south africa’s national consolidated guidelines of 01 june 2015. alternatively, one hiv pcr-positive result in association with an hiv vl that is detectable on a separate specimen is also diagnostic of hiv. an indeterminate hiv pcr result means that the test is inconclusive (i.e. it is not clearly positive or negative). patients with indeterminate results require immediate further testing, to determine whether the infant is hiv-infected, and referral. repeat hiv pcr and hiv vl testing needs to be performed as a matter of urgency and the patient managed according to the algorithm outlined in this recommendation (figures 1 and 2). infants in whom the diagnosis of hiv remains inconclusive or where discordant results have been obtained (i.e. a positive hiv pcr followed by a negative hiv pcr and undetectable hiv vl) need to be managed by a multidisciplinary team and should be discussed as a matter of urgency with a specialist clinician and pathologist. repeat hiv testing and clinical monitoring is required until an hiv status is established. it is important to remember that infants cannot be considered hiv-uninfected unless repeat testing occurs at least 4 weeks after cessation of infant prophylaxis and 6 weeks after cessation of breastfeeding. counselling the mother or primary caregiver regarding the indeterminate result is of paramount importance to ensure successful follow-up and arrival at a definitive diagnosis. acknowledgements the authors thank members of the nhls virology expert committee and the paediatric committee of the sa hiv clinicians society for their contribution. they also thank the united nations children’s emergency fund (unicef) for partial funding of this work. a.h.m. acknowledges the discovery foundation for financial support. a sop, on which this article is based, can be found at http://www.sahivsoc.org/upload/documents/clinical%20and%20lab%20sop%20for%20hiv%20pcr%20indeterminates.pdf. competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions a.h.m. was involved with design, drafting, coordinating the revision process and final approval of the article. k-g.t. provided content, critical revision and final approval. n-y.h. provided critical revision and final approval. j.m. provided critical revision and final approval. s.c. provided critical revision and final approval. g.g.s. was the project leader and was involved with the article conception, design, drafting, critical revision and final approval. references newell ml, coovadia h, cortina-borja m, et al. mortality of infected and uninfected infants born to hiv infected mothers in africa: a pooled analysis. lancet. 2004;364:1236–1243. http://dx.doi.org/10.1016/s0140-6736(04)17140-7 violari a, cotton mf, gibb dm, et al. early antiretroviral therapy and mortality among hiv-infected infants. n engl j med. 2008;359:2233–2244. http://dx.doi.org/10.1056/nejmoa0800971 bourne de, thompson m, brody ll, et al. emergence of a peak in early infant mortality due to hiv/aids in south africa. aids. 2009;23:101–106. http://dx.doi.org/10.1097/qad.0b013e32831c54bd national department of health. national consolidated guidelines for the prevention of mother-to-child transmission of hiv (pmtct) and the management of hiv in children, adolescents and adults. pretoria: department of health; 2014. roche® cobas® ampliprep/cobas® taqman hiv-1 qual test [package insert]. branchburg, nj: roche; 2007. roche® cobas® ampliprep/cobas® taqman hiv-1 qualitative test, version 2.0 [package insert]. branchburg, nj: roche; 2013. stevens w, erasmus l, moloi m, taleng t, sarang s. performance of a novel human immunodeficiency virus (hiv) type 1 total nucleic acid-based real-time pcr assay using whole blood and dried blood spots for diagnosis of hiv in infants. j clin microbiol. 2008;46(12):3941–3945. http://dx.doi.org/10.1128/jcm.00727-09 maritz j, preiser w, van zyl gu. establishing diagnostic cut-off criteria for the cobas ampliprep/cobas taqman hiv-1 qualitative test through validation against the amplicor dna test v1.5 for infant diagnosis using dried blood spots. j clin virol. 2012;53:106–109. http://dx.doi.org/10.1016/j.jcv.2011.12.002 maritz j, van zyl gu, preiser w. irreproducible positive results on the cobasampliprep/cobastaqman hiv-1 qual test are different qualitatively from confirmed positive results. j med virol. 2014;86:82–87. http://dx.doi.org/10.1002/jmv.23811 national department of health. the 2011 national antenatal sentinel hiv & syphilis prevalence survey in south africa. pretoria: department of health; 2012. statistics south africa. recorded live births 2011. pretoria: stats sa; 2012. sherman gg, lilian rr, bhardwaj s, candy s, barron p. laboratory information system data demonstrate successful implementation of the prevention of mother-to-child transmission programme in south africa. s afr med j. 2014;104(3 suppl 1):235–238. http://dx.doi.org/10.7196/samj.7598 j u ly 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e the united nations aids report (2005, cited by ibrahim1) showed that hiv is continuing to spread to an alarming extent all over the world, particularly africa. by the end of 2006 it was estimated that there were 2.99 million nigerians living with hiv/aids, and heterosexual transmission accounted for nearly 80% of cases of hiv infection.2 long-distance truck drivers (ldtds) are known to engage in high-risk sexual behaviour. long periods away from home and family results in high levels of engagement with commercial sex workers, so drivers are exposed to hiv and other sexually transmitted infections (stis). the correct and consistent use of condoms is an important component in the prevention of stis, including hiv infection, and is reported to be the most reliable method of prevention other than abstinence.3 although knowledge about condoms is relatively high and increasing in many african countries, including nigeria, there has as yet been no commensurate increase in their use.3 the aim of this study was to determine hiv/aids-related knowledge, sexual practices and predictors of condom use among ldtds in nigeria. the findings may inform policy makers on how to design effective programmes to promote condom use in this high-risk group. a cross-sectional survey of 130 male ldtds was carried out at three major truck depots in enugu, south-eastern nigeria. the minimum sample size was calculated using the formula p×q/(se)2, where p = prevalence, q = 100–p and se = sampling error tolerated.4 using a hiv/aids-related knowledge, sexual practices and predictors of condom use among long-distance truck drivers in nigeria o r i g i n a l a r t i c l e p n aniebue, mb bs, fwacp department of community medicine, university of nigeria teaching hospital, enugu, nigeria u u aniebue, mb bs, fwacs department of obstetrics and gynaecology, university of nigeria teaching hospital background. long-distance truck drivers (ldtds) are exposed to high-risk sexual behaviour because of the nature of their work and are at high risk for hiv acquisition. assessing their sexual practices and condom use is an important step in hiv/aids prevention in this target group. objective. to determine hiv/aids-related knowledge, sexual practices and predictors of condom use among nigerian ldtds. design, setting, subjects. a cross-sectional survey of 116 ldtds in enugu, nigeria, was carried out using pretested structured questionnaires. results. the 116 respondents ranged in age from 21 to 69 years with a mean of 40.5 years; 95.7% were aware of hiv/aids, 88.8% identified unprotected sexual intercourse as a mode of transmission, and 78.4% knew that use of a condom during sexual intercourse protects against hiv/aids transmission. ninety-eight drivers (84.5%) engaged in extramarital sexual relationships and 42.9% had multiple sexual partners. of the drivers 43.1% had used condoms at some stage and 28.6% used them consistently. reasons for non-use were mainly unavailability, sexual dissatisfaction and religious convictions. age, marital status and educational status were significant predictors of condom use among sexually active ldtds. conclusion. condom use among ldtds is low despite their high-risk sexual behaviour. promotion campaigns to improve the general acceptability of condoms are recommended. improved distribution of condoms at the stations where the drivers stop would improve accessibility and use. materials and methods 54 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u ly 2 0 0 9 prevalence of 65.6% from a previous study5 and a sampling error of 5% the minimum sample size required was calculated as 93, but a total of 130 drivers were studied to accommodate attrition. the drivers were consecutively recruited into the study over a 3-month period. the objectives of the study were explained to them and confidentiality was assured by non-inclusion of identifying characteristics in the questionnaire that was used for data collection. verbal consent was then received from each driver before recruitment into the study. the pre-tested structured questionnaire was administered to the drivers by medical students specially trained for the survey. information obtained from the questionnaires were the socio-demographic characteristics of the drivers, their knowledge of hiv/aids, sexual practices and condom use, and factors influencing condom use. data analysis was carried out with epi info version 2002 computer software. the chi-square test was used for testing statistical significance. a pvalue <0.05 was considered to indicate statistical significance. of a total of 130 questionnaires distributed 116 were correctly filled in, giving a response rate of 89.2%. the drivers ranged in age from 21 to 69 years. twenty-seven (23.3%) were single, 88 (75.9%) married and 1 (0.9%) widowed. they were predominantly christians and the majority had secondary or primary education (table i). of the drivers 95.7% were aware of hiv/aids, and the major source of information on this was the media (41.9%). other sources included health talks (25.2%), friends (21.3%) and church (11.6%). knowledge of modes of transmission and prevention of hiv/aids is shown in table ii. one hundred and three drivers (88.8%) knew that hiv could be transmitted through unprotected sexual intercourse, and 91 (78.4%) identified condom use as one of the modes of prevention of transmission. ninety-eight drivers (84.5%) engaged in extramarital sexual relationships. forty-two of these (42.9%) had multiple sexual partners, while one (0.01%) was bisexual. during the 6 months prior to the study 92 drivers (79.3%) had engaged in extramarital sex. fifty drivers (43.1%) had ever used condoms during extramarital sex, 38 (38.8%) had used condoms in their last extramarital sexual relationship, and 28.6% consistently used condoms when engaged in extramarital sexual relationships. the majority of those who used condoms (71.2%) got them from a pharmacy shop, other sources being sexual partners (2 cases) and a health facility (1). the main reasons for not using a condom were unavailability (16 cases, 30.8%), perception of reduced sexual satisfaction (15, 28.8%), religion (8, 15.4%), embarrassment about buying condoms (5, 9.4%), itching (5, 9.4%) and fear that the condom would burst or tear (3, 5.8%). use of condoms during extramarital sex had been suggested by 82.0% of the drivers and by 18.0% of their partners. table iii shows the relationship between condom use in the last extramarital sexual relationship and socio-demographic characteristics of the drivers. condom use was significantly higher among drivers with higher levels of education, unmarried drivers and drivers in the younger age group. condoms are a key preventive strategy as rates of hiv and other sexually transmitted infections continue to increase. when used correctly and consistently male age (yrs) n 21 30 29 31 40 37 41 50 31 51 60 12 >60 7 marital status single 27 married 88 widowed 1 religion christianity 87 islam 27 others 1 educational level no formal education 8 primary education 49 secondary 48 tertiary 11 table i. socio-demographic characteristics of 116 ldtds studied mode of transmission* unprotected sexual intercourse 88.8 blood transfusion 86.2 needles/syringes/sharps 77.6 breastfeeding 66.4 mother-to-child transmission 59.5 hand shaking 18.1 preventive measures* marital faithfulness 90.5 screening of blood 88.8 abstinence 86.2 condom use 78.4 prayers 39.7 preventive drug 17.2 * there were multiple responses. table ii. knowledge of modes of transmission and prevention of hiv/aids (%) among 116 ldtds studied results discussion 55 j u ly 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e condoms can provide as much as 94% reduction in the risk of hiv transmission.6 many drivers in this study were aware of hiv/aids, the media being their major source of information. this finding is consistent with a previous report on hiv/aids knowledge among ldtds.7 the majority of the drivers correctly identified unprotected sex as a mode of transmission of hiv/aids and the consistent use of condoms as a preventive measure. despite this high level of knowledge about hiv/aids many of the drivers (84.5%) still engaged in risk-taking behaviour, including extramarital sex. however, only 43.1% had ever used condoms and only 28.6% used condoms consistently during sex with casual partners. ekanem et al.5 reported that of intra-city bus drivers in lagos, western nigeria, 65.6% had ever used condoms and 11.6% consistently used them. in contrast, podhista et al.8 reported a high level (58.5%) of consistent condom use in a study of ldtds in thailand. the high rate of condom use in societies such as thailand could be explained by low resistance to their use.9 our finding of lower rates of consistent condom use may reflect the fact that in nigeria there is an aversion to condom use, which is generally believed to be a licence to sexual promiscuity. use of condoms in the last episode of extramarital sex was significantly higher among drivers with secondary education or above, those who were single, and the younger age group. other studies have corroborated this finding.3,10 it may suggest that health promotion and condom use is beginning to be effective in younger, better educated people. this should be encouraged, and appropriate media promotions of condom use utilised in order to bridge the educational divide. the reasons given by the drivers for not using condoms included unavailability of condoms, reduced sexual satisfaction, religious beliefs, and embarrassment when buying condoms. this underscores the need for educational campaigns to improve the general acceptability of condoms.11 enhanced distribution of condoms at the truck terminals might help improve their accessibility, reduce the embarrassment associated with purchase, and so increase use. condom use is still low among ldtds despite their high levels of hiv-related knowledge and ongoing high-risk sexual behaviour. enhanced distribution of condoms at truck terminals could improve access to and use of condoms in this group. there is a need for increased and sustained campaigns to educate people about condoms, using appropriate messages in the local language. references 1. ibrahim mto, opara wek, tanimono t. knowledge of hiv/aids, infection prevention practices and accidental skin cuts in barbing saloons in sokoto, nigeria. nigeria medical practitioner 2007; 51(6): 123-127. 2. federal ministry of health, abuja, nigeria. national guidelines on prevention of mother to child transmission of hiv (pmtct). abuja: federal ministry of health, 2007: 1. 3. sabitu k, illiyasu z, baba se. sexual behaviour and predictors of condom use among students of a nigerian tertiary institution. niger j med 2007; 16(4): 338342. 4. akpala o. epidemiologic research. a practical approach for the medical and nursing sciences. enugu: university of nigeria, 1994: 64-65. 5. ekanem ee, afolabi bm, nuga ao, adebayo sb. sexual behaviour hiv-related knowledge and condom use by intra-city commercial bus drivers and motor park attendants in lagos, nigeria. afr j reprod health 2005; 9(1): 78-87. 6. holmes kk, levine r, weaver m. effectiveness of condoms in preventing sexually transmitted infections. bull world health organ 2004; 82(45): 454-461. 7. onwasigwe cn, aniebue pn, ndu ac. awareness and sexual behaviour of nigerian long distance drivers. journal of college of medicine 2001, 6(1): 44-46. 8. podhista c, wawer mj, pramuairatama a, kaungsukkasem u, mcnamara r. multiple sexual partners and condom use among long distance truck drivers in thailand. aids educ prev 1996; 8(6): 490-498. 9. marck j. long-distance truck driver sexual cultures and attempts to reduce hiv risk behaviours amongst them: a review of the african and asian literature. in: caldwell jc, caldwell p, anarfi j, et al., eds. resistances to behavioural change to reduce hiv/aids infection in predominantly heterosexual epidemics in third world countries. canberra: health transition centre, national centre for epidemiology and population health, australian national university. 10. sunmola am. sexual practices, barriers to condom use and its consistent use among long distance truck drivers in nigeria. aids care 2005; 17(2): 208-221. 11. chigbu b, onwere s, kamanu c, aluka c, feyi-waboso pa. awareness, acceptability and use of male condoms for contraception and prevention of sexually transmitted infection among female students in a tertiary institution in south eastern nigeria. niger j clin pract 2007; 10(3): 267-268. used condom did not use condom p-value age (yrs) 21 30 9 (39.1%) 14 (60.9%) χ2=12.82, 31 40 20 (60.6%) 13 (39.4%) df 3, 41 50 7 (26.9%) 19 (73.1%) p<0.001 >50 2 (12.5%) 14 (87.5%) marital status single/widowed 15 (60.0%) 10 (40.0%) χ2=6.37, married 23 (31.5%) 50 (68.5%) df 1, p=0.01 educational status no formal/primary 14 (26.9%) 38 (73.1%) χ2=6.57, secondary 20 (52.6%) 18 (47.4%) df 2, tertiary 4 (50.0%) 4 (50.0%) p=0.037 table iii. relationship between socio-demographic variables and use of condom in last extra-marital sex (73 subjects) we acknowledge the help of c okoye, s mgbekwere and e agbeyeke in distributing the questionnaires used for the survey. 56 c p d  q u e s t i o n s journal 36 two cpd points are awarded for the correct completion and submission of the questions below. cpd questionnaires must be completed online via www.cpdjournals.org.za. after submission you can check the answers and print your certificate. questions may be answered up to 6 months after publication of each issue. this programme is available free of charge to members of the hiv clinicians society and sama only. 1. true (a) or false (b) – click on the correct answer: the new sa hiv clinicians society guidelines state that all infants under 2 years of age should start antiretroviral therapy (art) irrespective of their cd4 count or clinical stage. 2. true (a) or false (b) – click on the correct answer: the guidelines state that all infants under 1 year of age should start art irrespective of their cd4 count or clinical stage. 3. true (a) or false (b) – click on the correct answer: the guidelines state that tenofovir + ftc or 3tc is the ideal nrti backbone for children. 4. true (a) or false (b) – click on the correct answer: the guidelines state that abacavir + 3tc is the ideal nrti backbone for children. 5. true (a) or false (b) – click on the correct answer: with regard to lipodystrophy, efavirenz has been implicated in lipomastia (fat deposited in the breasts). 6. true (a) or false (b) – click on the correct answer: breast enlargement typically resolves without changing the regimen. 7. true (a) or false (b) – click on the correct answer: lipo-atrophy of the face typically resolves without changing the regimen. 8. true (a) or false (b) – click on the correct answer: it is only necessary to substitute another agent for the offending agent when the lipo-atrophy is severe. 9. true (a) or false (b) – click on the correct answer: the commonest agent implicated in lipo-atrophy is stavudine (d4t). 10. true (a) or false (b) – click on the correct answer: with regard to changing art in children, the regimen should be changed when the viral load returns to baseline. 11. true (a) or false (b) – click on the correct answer: an isolated viral load of 600 is called a blip and is a sign that the regimen must be changed. 12. true (a) or false (b) – click on the correct answer: do not change therapy until adherence issues have been resolved. 13. true (a) or false (b) – click on the correct answer: 3tc monotherapy should only be used as a temporary measure in a patient with a good cd4 level who has failed 3tc previously. 14. true (a) or false (b) – click on the correct answer: the m185e mutation is the classic 3tc resistance mutation. 15. true (a) or false (b) – click on the correct answer: with regard to the abacavir hypersensitivity reaction (hsr), hla-b*5701 is common in black africans. 16. true (a) or false (b) – click on the correct answer: trimethoprim-sulfamethoxazole, nevirapine and efavirenz may cause a very similar hsr. 17. true (a) or false (b) – click on the correct answer: only 50% of patients experience the hsr within 6 weeks after starting abacavir. 18. true (a) or false (b) – click on the correct answer: fever is the most common manifestation of abc hsr, occurring in 80% of cases. 19. true (a) or false (b) – click on the correct answer: isolated gastro-intestinal symptoms such as nausea, vomiting, diarrhoea and abdominal pain may be a feature of abc hsr, and abc should be discontinued promptly if they occur. 20. with regard to immune reconstitution inflammatory syndrome (iris) in children, state which one of the following is true: a) the most common cause of iris in infants in south africa is tuberculosis. b) one of the differentials for paradoxical tb iris is resistant tb. c) bcg is never resistant to pyrazinamide (pza). d) kaposi’s sarcoma does not present as an iris in children because it is a malignancy and not an infection. e) steroids should be used in all cases of iris. article information authors: tine t. hansen1,2 marietjie herselman1 lisanne du plessis1 luzette daniels1 tirsa bezuidenhout1 cora van niekerk1 laura truter1 per o. iversen1,2 affiliations: 1division of human nutrition, stellenbosch university, tygerberg campus, south africa 2department of nutrition, institute of basic medical sciences, university of oslo, norway correspondence to: per iversen email: p.o.iversen@medisin.uio.no postal address: po box 1046, blindern 0317, oslo, norway dates: received: 25 mar. 2014 accepted: 12 dec. 2014 published: 28 apr. 2015 how to cite this article: hansen tt, herselman m, du plessis l, et al. evaluation of selected aspects of the nutrition therapeutic programme offered to hiv-positive women of childbearing age in western cape province, south africa. s afr j hiv med. 2015;16(1), art. #338, 5 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.338 copyright notice: © 2015. the authors. licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. evaluation of selected aspects of the nutrition therapeutic programme offered to hiv-positive women of child-bearing age in western cape province, south africa in this original research... open access • abstract • introduction • methods    • study sites and participants    • data collection methods • results    • characteristics of the clients    • food insecurity    • clients’ experiences of the nutrition therapeutic programme    • staff members’ characteristics    • knowledge, training and responsibilities of staff members regarding the nutrition therapeutic programme • discussion    • limitations • conclusion • acknowledgements    • competing interests    • authors’ contributions • references abstract top ↑ background: the nutrition therapeutic programme (ntp) involves the provision of food supplements at primary health clinics (phcs) to correct nutritional deficiencies in vulnerable groups. although previous studies have identified problems with implementing the programme at phcs, assessments of its efficiency have been scarce. objective: to evaluate implementation of the ntp at phcs that provide antiretroviral therapy. methods: a cross-sectional, descriptive study was conducted at 17 phcs located within 3 districts of western cape province. two target groups were chosen: 32 staff members working at the sites and 21 women of child-bearing age enrolled in the ntp. questionnaires were used to obtain data. results: only 2 women (10%) lived in food-secure households; the rest were either at risk of hunger (29%) or classified as hungry (61%). most of the women knew they had to take the supplements to improve their nutritional status, but the majority only recalled receiving basic nutritional advice, and the information was mainly given verbally. ten of the women had shared their supplements with others, mostly with their children. the study identified lack of clearly defined ntp responsibilities at the phcs, causing confusion amongst the staff. although many staff members expressed problems with the ntp, only 38% of them reported having routine evaluations regarding the programme. conclusion: several aspects compromised the effectiveness of the ntp, including socio-economic factors leading to clients’ non-compliance. the strategic organisation and implementation of the ntp varied between different phcs offering antiretroviral therapy, and staff experienced difficulties with the logistics of the programme. introduction top ↑ in 1995, the south african government implemented the integrated nutrition programme (inp) as a response to the poor nutritional status of the country’s population. a targeted supplementary feeding programme termed the nutrition therapeutic programme (ntp), as one component of the inp, involves the provision of food supplements at primary health clinics (phcs) to correct nutritional deficiencies in vulnerable groups.1 these groups include babies and children (0–18 years), pregnant and lactating women, and patients diagnosed with hiv/tuberculosis (tb) and other chronic diseases (table 1). eligible adult patients are referred and admitted to the ntp based on the following criteria: body mass index (bmi) < 18.5 kg/m2; unintentional weight loss > 10% over 6 months and unintentional weight loss > 5% in one month. after 6 months, patients are re-evaluated and, if they suit the exit criteria, they are taken off the programme.2 however, studies have identified problems with implementing the ntp at phcs, including insufficient financing, unclear responsibilities amongst staff, and knowledge gaps amongst the clients.3,4,5 table 1: current target groups, entry criteria and product options available for patients on the nutrition therapeutic programme in western cape province. south africa is severely affected by hiv. even though antiretroviral therapy (art) coverage increases, the government still faces challenges in combating the spread of the disease. good nutrition is crucial when infected with hiv, as both the disease itself and the treatment have metabolic consequences.6,7 also, a lowered bmi, which is associated with malnutrition, might increase mortality in hiv patients.8 the present study evaluated the ntp at phcs offering art, with particular focus on women, as this group had previously not been addressed.3,4,5 as the ntp relies largely on compliance of the individuals receiving the supplements, it is important to understand how well the programme is implemented at clinic level and adhered to at household level, to ensure that the maximum number of patients reap the full ntp benefits. therefore the main aim of the study was to establish the opinions, perceptions and current practices of hiv-positive female beneficiaries of the ntp. it was further necessary to investigate whether patients received adequate information and education regarding the ntp to utilise it effectively. lastly, we also examined the opinions, perceptions and practices of staff members concerning the ntp and the resources at their disposal for effectively implementing and managing the programme. methods top ↑ a cross-sectional descriptive study was conducted in the city of cape town, overberg and cape winelands districts from december 2009 to april 2010, and from march 2011 to february 2012. ethical approval was obtained from the health research ethics committee at stellenbosch university (ref no: n07/10/232), the provincial government of the western cape, the municipality of the city of cape town, and the norwegian regional committee for medical and health research ethics (ref. no. 2009/1364b). study sites and participants of the 52 registered phcs that provide art, 17 were randomly included. twelve were within the city of cape town, and 5 in rural areas of the cape winelands and overberg districts. data obtained from urban and rural sites were pooled for analyses. we targeted two groups: (1) various staff members (managers, nurses, dieticians) at the phcs working with the ntp and (2) female clients (15–49 years old) enrolled in the ntp. thirty-two staff members were included, with all phcs represented. clients were selected by convenience sampling as randomisation was not feasible. clients eligible for inclusion were either approached on the day of a clinic visit, or identified by means of the ntp register. twenty-one women were included from 10 of the sites, whilst no women were eligible at the remaining 7 sites. data collection methods questionnaires adapted from a previous study regarding the ntp conducted at phcs were used.4 the questionnaires for both clients and staff members were available in afrikaans, english and isixhosa. clients’ experience with and knowledge about the ntp were collected through an interviewer-administered questionnaire containing both option-based as well as open questions. a validated hunger questionnaire was used as a proxy for food insecurity experienced in clients’ households and was based on 8 questions addressing the availability of food and their ability to secure an adequate food intake.9 staff members were questioned about their training, knowledge, opinions, perceptions, practices and resources regarding the ntp, also through both open and option-based questions. in addition, sociodemographic data were obtained. results top ↑ characteristics of the clients the median age of the 21 clients included was 30 (range 16–46) years. seventeen of them received art, 5 had aids and 17 had tb. most of the women were unemployed (86%), and only 33% had grade 11–12 education or higher. table 2 shows the income and money spent on food per household. twelve (57%) of the women stated that they and/or their family received social grants, including child support (58%), old age pension (25%), disability grant (8%), or financial support from other family members (17%). table 2: income and food expenses per household. food insecurity scores from the hunger questionnaire was used to identify household food insecurity. thirteen out of the 21 women were classified within the hungry category. four of these 13 women answered yes to all 8 questions, indicating severe household food insecurity. six women were at risk of hunger, and only 2 had scores that put them in the food secure category. clients’ experiences of the nutrition therapeutic programme when clients were asked if they knew why they were receiving supplements, 19/21 (90%) answered yes. only 2 women said that they did not follow instructions given by staff members for use of the supplements. fourteen reported receiving nutritional advice before receiving supplements. sixteen received verbal instructions on how to take the supplements and/or information as to why they had to take them. only 4 had received any written information about the ntp and supplements, whilst 5 said that they had not received any information. two women had experienced problems with the supplements owing to a lack of ingredients to mix them with. regarding side-effects, 5 women reported nausea, but 3 of them specified that this occurred only when starting to use the supplements. none of the responders reported that they had ever sold their supplements, but 10 had shared the supplements with others, mainly their children. staff members’ characteristics the positions of the 32 staff members (30 female and 2 male) were as follows: 8 facility managers, 10 professional nurses, 5 dieticians, 3 nursing staff, 2 medical doctors and 4 defined as other (2 health promoters, 1 nutrition adviser and 1 nutritionist). the median age of the staff members was 40 (range 26–56) years. knowledge, training and responsibilities of staff members regarding the nutrition therapeutic programme twenty of the staff members had received training and/or education in implementing the ntp after their formal training, including oral lecture (65%), written material (45%) and practical demonstration (45%). thirteen had received training once, whilst only 7 had regular training. when asked what role staff had in the ntp, the categories most frequently answered were handing out supplements (66%) and recording statistics (66%), followed by storage (44%) and ordering (34%). regarding storage, 71% of the staff with this responsibility had written guidelines on how to store the supplements, but 43% reported that their facility was inadequate because of space constraints. for handing out supplements, 90% with this responsibility had written instructions. all staff members indicated that they explained to clients the purpose of the supplements, but only 29% reported giving clients written information. staff found that clients receiving supplements were generally grateful. one of the stated reasons for poor compliance was clients failing to come back for follow-up appointments. three staff members said this was because of ignorance; the rest thought that social factors (e.g. no funds for transport to the clinic, or important activities such as work) prohibited clients from attending scheduled appointments. when asked to specify who were in charge of the different components of the ntp, staff members gave inconsistent answers (table 3). there was a discrepancy between sites regarding which staff categories were assigned ntp responsibilities, but answers also differed between staff members working at the same site. table 3: distribution of nutrition therapeutic programme responsibilities amongst primary health clinics site staff categories. nineteen staff members stated that there was a lack of supplements within the last year. reasons for this were mainly lack of stock in the clinic (32%) or lack of stock at the suppliers (63%). five staff members said that the clinic’s budget had been exceeded. eight staff members said that they had tried to improve the nutrition budget with their superiors; 5 had succeeded. twelve of the 32 staff members stated that their clinic had undergone evaluations of their ntp implementation routines. when asked to specify what problems they experienced with the ntp, 2 commented that a staff shortage was an issue, and said that staff had inadequate time to implement the programme properly. five staff members said that inadequate clinic routines prohibited efficient utilisation of the ntp, and another 5 staff members attributed lack of success with the programme to clients’ failing to come back for follow-up appointments. six of the 8 facility managers said that their staff had received training in implementing the ntp. only 2 managers reported that the training took place regularly; this corresponded well with what staff members had responded about training. seven facility managers had a separate budget for the ntp, and 2 stated that their budget was never adequate to cover expenses related to the ntp. discussion top ↑ our results indicated that there were several aspects that potentially compromised the effectiveness of the ntp, including socio-economic factors leading to clients’ non-compliance. the strategic organisation and implementation of the ntp varied between clinics, and staff experienced some difficulties with the programme logistics at phcs. many of the women studied experienced food insecurity; this jeopardised their nutritional status and increased the need for supplementation, which could result in clients becoming dependent on supplements. in theory, these women should benefit from the supplements, but it was evident that many shared their supplements with others, indicating a shortfall in taking the advised dosage. this conclusion was further supported by findings from the hunger questionnaire that established that more patients reported reducing the size of their own meals rather than those of their children. the long-term effectiveness of the programme depends largely on the ability of former clients to sustain nutritional status after they have been exited from the ntp. this is difficult for them as they have increased nutritional needs owing to hiv and aids and tb, and the task is made even more challenging when their socio-economic status is low. malnutrition also hastens disease progression amongst such people and puts added pressure on healthcare services. educational levels affected the understanding and effective utilisation of supplementation amongst clients. even though the women understood that they had to take the supplements to gain weight, more in-depth counselling, or use of illustrated instructions and/or written information in their own language, could have contributed to a better understanding of the programme and possibly promoted better adherence. both the clients and staff experienced difficulties in implementing the programme. one of the main problems identified by staff members was poor compliance of the women in attending clinic. if client attendance reflects reality, it can be assumed that clients failing to attend follow-up appointments have increased the defaulter rate of the programme. it must be noted that client compliance was largely influenced by their socio-economic difficulties, which manifest as poor clinic attendance, despite the fact that most of the attending clients were perceived to be grateful for the supplements and support they received. the lack of strategic organisation, and no clear responsibility distribution at clinic level, must be suspected of causing obstacles to efficiency and programme coverage. the scarcity of evaluation routines would indicate that any problems experienced with the programme would continue without being properly addressed; an example is the lack of supplements owing to poor ordering routines, which could easily be corrected. considering south africa’s burdens of malnutrition, the lack of food and nutrition security and the need for multisectoral interventions, the low health sector budgetary allocation by government to nutrition (less than 0.3% of the health budget) is a further problem. in current expenditure, most funds are spent on targeted supplementary feeding, including to hiv-infected individuals as a target group. appropriate monitoring and evaluation of this programme is therefore of cardinal importance. there is a concern that the returns on nutrition expenditure are not as high as could be, owing to inappropriate interventions and poor implementation.10 the national nutrition directorate (nnd) acknowledges the challenges that the programme faces, including: poor institutional co-ordination amongst various departments that are giving assistance to people facing food and nutritional insecurity; lack of proper mechanisms to facilitate referral of individuals across programmes; under-developed information management; different entry and exit criteria for nutritional support for people living with hiv and aids and tb; and little or no community involvement in nutrition support interventions for such people.10 however, very little strategic guidance from the nnd is provided to overcome these challenges. limitations the main limitation of this study was the small number of eligible clients identified at the phcs. the reason for the specific inclusion criteria was because these individuals form part of the vulnerable group in society of whom very little is known. although most clinics had specific days on which the ntp supplements were handed out, and researchers made a concerted effort to remind them of their appointments, this did not ensure that clients would visit the clinic on those days. despite the small number of participants, the data obtained were extensive. through open questions, clients could freely express opinions and experiences, and thus provided us with a good understanding of whether they felt the programme worked optimally, both for staff members issuing supplements, and also for the clients receiving them. notably, the study was performed in the western cape – one of the most affluent provinces in the country, and this fact might limit the generalisability of our findings. conclusion top ↑ our results support the findings from previous studies that there are problems with the implementation of the ntp and that these problems are also evident at phcs.1,3,4 it is clear that the challenges experienced by staff members and clients are obstructing the effective implementation of the programme. it is therefore necessary to take note of the relevant challenges mentioned in this study and strive to solve the problems that, if left unattended, could ultimately result in clients not reaping the benefits of the programme, which in turn will lead to increased government expenditure and depletion of clinic funds in support of a programme that is ineffective, as patients are not reaching the goals set out in the programme. therefore, to successfully implement nutrition interventions, sufficient capacity and resources, strategic management, evaluation routines and monitoring of results must be in place.11,12,13 the findings from our study advocate for an increased effort in these matters when implementing the ntp at phcs that provide art in western cape province and possibly also elsewhere in south africa. acknowledgements top ↑ the authors thank the clients and staff who participated in the study, and nora jantjies for help with translating during interviews. the study was supported in part by the university of oslo, norway. competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions t.t.h. (stellenbosch university), l.d. (stellenbosch university), t.b. (stellenbosch university), c.v.n. (stellenbosch university) and l.t. (stellenbosch university) collected and analysed the data. m.h. (stellenbosch university), l.d.p. (stellenbosch university) and p.o.i. (stellenbosch university) designed the study and analysed the data. all authors co-wrote the article and accepted the final version and the decision to submit. references top ↑ implementation policy guidelines for nutrition therapeutic programme. guidelines for care at district and community level including clinics, chc, district hospitals and community facilities in the western cape. pretoria: department of health; 2011. western cape province. nutrition supplementation programme circular. pretoria: department of health; 2007. grundlingh h, herselman m, iversen po. an assessment of the implementation of the national therapeutic programme for pregnant women within the city of cape town district. s afr j med. 2013;103:549–551. http://dx.doi.org/10.7196/samj.6670 iversen po, høisæther ea, morseth m, herselman m. diverging opinions of supplementation programmes between mothers of small children and staff at primary health clinics in the western cape province of south africa. publ health nutr. 2011;14:923–930. http://dx.doi.org/10.1017/s1368980010003319 iversen po, andresen ec, wandel m, eide wb, herselman m. delivery of the nutrition supplementation programme in the cape town metropolitan area from the perspective of mothers of under-fives: a qualitative study. s afr j child health. 2009;3:90–95. de pee s, semba rd. role of nutrition in hiv infection: review of evidence for more effective programming in resource-limited settings. food nutr bull. 2010;31:s313–344. greenaway k. gain working paper series. no. 2: food by prescription: a landscape paper. geneva: global alliance for improved nutrition (gain); 2009. masiira b, baisley k, mayanja bn, kazooba p, maher d, kaleebu p. mortality and its predictors among antiretroviral therapy naive hiv-infected individuals with cd4 cell count ≥350 cells/mm3 compared to the general population: data from a population-based prospective hiv cohort in uganda. glob health action. 2014;7. http://dx.doi.org/10.3402/gha.v7.21843 labadarios d, steyn np, maunder e, et al. the national food consumption survey (nfcs): south africa, 1999. publ health nutr. 2005;8:533–543. http://dx.doi.org/10.1079/phn2005816 department of health. nutrition roadmap 2012–2016. roadmap for nutrition in south africa for 2012–2016. pretoria: department of health; 2012. bhutta za, ahmed t, black re, et al. what works? interventions for maternal and child undernutrition and survival. lancet. 2008;371:417–440. http://dx.doi.org/10.1016/s0140-6736(07)61693-6 gillespie s, haddad l, mannar v, menon p, nisbett n. the politics of reducing malnutrition: building commitment and accelerating progress. lancet. 2013;382:552–569. http://dx.doi.org/10.1016/s0140-6736(13)60842-9 world health organization. global nutrition policy review: what does it take to scale up nutrition action? 2013. [cited 16 march 2014]. available from: http://www.who.int/nutrition/publications/policies/global_nut_policyreview/en/index.html o cto b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e in south africa, depressive and anxiety disorders are common in the general population. according to the world health organization-led south african stress and health (sash) study, the 12-month prevalence of depressive and anxiety disorders (combined) was 12.6%,4 while the lifetime prevalence of these disorders was 25.6%.5 similarly, the sash study found a 12month prevalence of 5.8% and a lifetime prevalence of 13.4% for substance use disorders.4-5 there is good evidence from international research that the prevalence of depression and anxiety in people living with hiv or aids is higher than the prevalence of these disorders in hiv-negative controls.6 one meta-analysis suggests that the prevalence is at least double that in the general community.7 there is growing evidence that this is true in south africa and other african countries.8-13 the main factors contributing to the increased prevalence of depression and anxiety in individuals living with hiv are: biological, resulting from both direct and indirect forms of neurotoxicity due to hiv invasion of the central nervous system and the sequelae of immunocompromise. the areas predominantly affected are the sub-cortical areas of the brain, including those within the temporal lobes, which are the seat of emotional/ mental disorders.14 depressive and anxiety disorders that occur as a result of hiv cns infection often coexist with cognitive impairment that is also the result of this infection (see box 1). opportunistic conditions such as herpes simplex infection and various malignancies, as well as certain medications used to treat these conditions and antiretroviral medications, can also cause depression or anxiety.15-16 psychological. the prevalence of depression and anxiety in people living with hiv or aids is similar to that in people suffering from other serious, chronic and life-threatening medical illnesses.17 a major factor is the psychological reaction to having such an illness. the individual is faced with the reality of serious illness and possible death at an early age. in many cases there are additional stressors related to the stigma associated with hiv/aids and lack of social support for the infected individual (see box 2). primary psychiatric disorder. some individuals may be particularly vulnerable to depression and anxiety as a result of genetic loading or early childhood adversity.18 some hiv-infected individuals may already have a history of such mental disorder, or the stress of the illness (and the psychosocial consequences) may precipitate a depressive illness and/or an anxiety disorder. in addition, the time of first onset and presentation with primary psychiatric disorders is generally in young adulthood, and this is also the time when most people infected with hiv present for treatment or are diagnosed with the infection. depressive or anxiety disorders may be completely unrelated to hiv status, or the underlying mental disorder may have contributed to the events associated with acquiring hiv infection (e.g. alcohol abuse and sexual risk taking). common mental disorders in people living with hiv/aids c l i n i c a l : o v e r v i e w rita thom, mb chb, dch, fcpsych, phd division of psychiatry, faculty of health sciences, university of the witwatersrand, johannesburg the term ‘common mental disorders’ is an overarching term for conditions that affect a significant number of people in the community. these conditions include depression, anxiety and substance use disorders. in contrast, so-called ‘severe mental illnesses’ (such as schizophrenia or bipolar mood disorder) are conditions that usually require admission for inpatient treatment and tend both to recur and to be chronically debilitating. nonetheless, common mental disorders result in a considerable burden to the individual, their families, the community and the economy. many people with these conditions do not present for treatment, or if they do they usually present to primary care facilities, where these diagnoses are often missed. this is unfortunate, since there is good evidence that these disorders can be effectively treated1-2 and that much of this treatment can be provided by primary care clinicians.3 common mental disorders in hiv-infected individuals 8 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e o cto b e r 2 0 0 9 several of the most frequently observed presentations of common mental disorders are listed in table i. identifying depression in a medically ill individual can be difficult owing to the overlap in somatic symptoms (e.g. loss of appetite or weight, sleep disturbance, pain, fatigue, poor concentration). it is important to consider mood and affect, particularly if alterations in these are constant, unvarying and more severe than is warranted by the individual’s circumstances, as well as anhedonia (loss of pleasure in usually enjoyable activities) and functional impairment caused by the symptoms that are present. it is also suggested that an inclusive approach should be used when considering the criteria for making a diagnosis of depression in a medically ill individual.17 the relationship between substance abuse, mood and anxiety disorders and hiv infection is complex, and all these disorders may play a role in increasing the risk of being infected with hiv, as well as contributing to the burden of disease, poor adherence and disease progression. because the presentation of depression and anxiety can be unclear and because many people do not volunteer information about substance use disorder, it is critical that people who are infected with hiv should be screened for these disorders. a range of screening instruments have been validated in south africa and are recommended for use.19-21 some of these are self-report instruments, while others are administered by the health worker. once an individual is identified through screening, they should receive a more thorough assessment by a trained clinician. the substance abuse and mental illness symptoms screener (samiss) is a 13-item screening questionnaire developed for use in hiv-positive individuals that can easily be applied in a busy primary care setting (box 4). the samiss was found to have a sensitivity of 86% and specificity of 95% in diagnosing dsm-iv-defined substance use and depressive/anxiety disorders,22 and validation of this tool in south africa is underway. the advantages of using this instrument are that it is reasonably quick to administer and that it covers all the common mental disorders including substance use disorders. 9 screening for common mental disorders in hiv primary care services box 1 mrs k is a 50-year-old woman living in a rural area. her husband died of aids a year ago. she presents at the clinic with severe oral thrush. she is hiv positive and has severe weight loss. she looks depressed and is very tearful, complaining of fatigue and poor sleep and appetite. she has psychomotor retardation and her memory is poor. she is not on antiretroviral therapy. her cd4 count is 150 cells/µl. what possible diagnoses should you consider? how would you approach her treatment? box 2 mr m is a 29-year-old man who was recently diagnosed hiv positive when he presented to health services with a severe upper respiratory tract infection. his cd4 count is 250 cells/µl. he comes for a follow-up appointment in a dishevelled state, smelling of alcohol. he recently lost his job as a clerk in an office, his wife is unemployed and they have a young child. he starts crying in your office and voices suicidal ideation. what would your immediate management be? and in the longer term? box 3 ms b is a 24-year-old woman who was diagnosed hiv positive during antenatal screening. she had pmtct and her baby was delivered safely 2 weeks ago. she is living with the father of the child, who is aware of her status and has also tested hiv positive. they are both currently asymptomatic. he is very supportive and it is their first child. she is extremely anxious about the well-being and hiv status of her baby. she complains that she is not sleeping and that she gets very irritable with the baby at times. sometimes she finds herself just bursting into tears for no reason. what could be going on here? what are the risks in this situation? how would you manage her? presentation features somatic headache, backache, abdominal pain may be atypical, or show limited response to somatic treatments insomnia common presentation; an important depressive symptom other neuro-vegetative symptoms fatigue, weight loss, loss of energy and libido low mood or depression may be expressed differently, such as ‘stress’ or tension substance abuse this commonly coexists with depression, and may be a presenting feature table i. clinical presentations of common mental disorders in primary hiv/aids care settings o cto b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 10 substance use items: 1. how often do you have a drink containing alcohol? (alcoholic drinks include one beer, one glass of wine, a mixed drink of hard liquor, or one wine cooler. each of these counts as one drink, unless they have double shots, which would equal two drinks.) (if you do not drink, go to question 4.) 0 never 1 monthly or less 2 2 4 times a month 3 2 3 times a week 4 4 or more times a week 2. how many drinks do you have on a typical day when you are drinking? 0 1 or 2 1 3 or 4 2 5 or 6 3 7 to 9 4 10 or more 3. how often do you have four or more drinks on one occasion? 0 never 1 monthly or less 2 2 4 times a month 3 2 3 times a week 4 4 or more times a week 4. in the past year, how often did you use non-prescription drugs to get high or change the way you feel? 0 never 1 monthly or less 2 2 4 times a month 3 2 3 times a week 4 4 or more times a week 5. in the past year, how often did you use drugs prescribed to you or to someone else to get high or change the way you feel? 0 never 1 monthly or less 2 2 4 times a month 3 2 3 times a week 4 4 or more times a week 6. in the last year, how often did you drink or use drugs more than you meant to? 0 never 1 monthly or less 2 2 4 times a month 3 2 3 times a week 4 4 or more times a week 7. how often did you feel you wanted or needed to cut down on your drinking or drug use in the last year, and not been able to? 0 never 1 monthly or less 2 2 4 times a month 3 2 3 times a week 4 4 or more times a week patient considered positive for substance use symptoms if any of the following criteria are met: a) the sum of responses for questions 1 3 is >5 b) the sum of responses for questions 4 5 is >3 c) the sum of responses for questions 6 7 is >1 mental health items: medications/antidepressants 8. during the past 12 months, were you ever on medication/antidepressants for depression or nerve problems? 1 yes 2 no major depression 9. during the past 12 months, was there ever a time when you felt sad, blue or depressed for 2 weeks or more in a row? 1 yes 2 no 10. during the past 12 months, was there ever a time lasting 2 weeks or more when you lost interest in most things like hobbies, work, or activities that usually give you pleasure? 1 yes 2 no generalised anxiety disorders 11. during the past 12 months, did you ever have a period lasting 1 month or longer when most of the time you felt worried and anxious? 1 yes 2 no panic disorder 12. during the past 12 months, did you have a spell or an attack when all of a sudden you felt frightened, anxious or very uneasy when most people would not be afraid or anxious? 1 yes 2 no 13. during the past 12 months, did you ever have a spell or an attack when for no reason your heart suddenly started to race, you felt faint, or you couldn’t catch your breath? [if respondent volunteers ‘only when having a heart attack or due to physical causes’, mark ‘no’.] 1 yes 2 no patient considered positive for symptoms of mental illness if he/she responded yes to any mental health question. box 4. the substance abuse and mental illness screener t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e o cto b e r 2 0 0 9 given the increased risk of common mental disorders in hiv-infected individuals, it makes sense to put basic preventive services into place in hiv treatment services. these include support groups, counselling, psycho-education, social work and occupational therapy interventions, as available. it is important to note that services of this kind are commonly available as part of hiv primary care services (particularly in the context of antiretroviral therapy), but are usually focused on treatment initiation and adherence; however, such types of psychosocial support have important additional benefits in promoting mental health. individuals who provide this kind of psychosocial support should be trained to identify patients who may have a common mental disorder (e.g. using the samiss), and to refer them for appropriate assessment and intervention. ideally, psychiatric and mental health care services should be offered on site in hiv treatment services, but this may not always be possible and specialist services are not required to effectively diagnose and manage many common mental disorders. alternatively, it would be important to identify referral resources and establish good links and communication channels between the hiv treatment service and the psychiatric/mental health services. treating common mental disorders has direct benefits on the quality of life and well-being of affected individuals. in addition, there is evidence from international research that untreated depressive and anxiety disorders lead to poor antiretroviral adherence23 and may speed hiv disease progression.24-26 the management of mental disorders requires a holistic approach with attention to biological as well as psychosocial factors. biological management identify and treat any underlying or associated general medical condition hiv infection itself is associated with features of depression and apathy. other chronic conditions such as peripheral neuropathy, or intra-cranial secondary infections or tumours, may produce depression. these include progressive multifocal leuco-encephalopathy or vasculopathy. usually a careful history, physical examination and routine investigations (e.g. serological testing for syphilis) are adequate to rule these out as causes of psychiatric symptoms, and special investigations (such as lumbar puncture or computed tomography of the brain) are not necessary in many primary care settings. assess cognitive impairment cognitive impairment often co-exists with depressive disorders, and may be a confounding variable. it is sometimes difficult to assess whether there is depression in the presence of dementia, and depressive illness may also present with cognitive features consistent with dementia. if there are other features and markers of late-stage hiv infection, the need for antiretroviral medication should be considered, as this is an important treatment for hiv-associated dementia (see related article by singh in this edition). assess for suicidality suicidal ideation is common in hiv-infected individuals. in a study in south africa,27 22.5% of a sample of hiv-infected individuals attending hiv treatment sites had experienced suicidal ideation in the past, and 8.6% had current suicidal ideation; 69% of the participants with past suicidal ideation had experienced this as a result of their diagnosis. the period after diagnosis is therefore a period of high risk. in the same study, suicidal ideation was strongly associated with the presence of a depressive disorder. it is important to ask patients who are at high risk about thoughts of suicide, as these may not be volunteered. a thorough risk assessment should be conducted, and the need for inpatient admission should always be considered. treat depressive or anxiety disorders with medication when necessary antidepressant medication is effective in treating both depressive and anxiety disorders in hiv-infected people, even in the presence of cognitive impairment (for more detail on specific medications and their use, see the article in this edition on psychotropic prescribing in hiv-infected individuals). antidepressant medication can be used safely in combination with anti retroviral medication, as long as one is aware of several specific drug interactions and monitors the patient, adjusting medication when necessary. generally antidepressant medication should be used for 6 months to 1 year to treat a single episode of a depressive illness. people with recurrent episodes should remain on longterm treatment. anxiety disorders are best managed with a combination of psychosocial interventions and judicious use of medication. benzodiazepines should be avoided, only being used in acute crisis situations for short periods of time (less than 2 weeks). should medication be needed to manage anxiety, the selective serotonin reuptake inhibitors (ssris) should be used. manage substance withdrawal and provide rehabilitation for substance use disorders the initial intervention in terms of substance use disorders is safe medical detoxification, followed by assessprevention of common mental disorders in hiv primary care services management of common mental disorders 11 o cto b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e ment of the need for and possibilities of rehabilitation. motivational interviewing is a useful tool for engaging people with substance use disorders in treatment of their addictive behaviour. rehabilitation usually consists of group and individual psychotherapy, and can usually be managed on an outpatient basis. support groups, where available, are useful in keeping people sober and drug-free. interpersonal, cognitive-behavioural psychotherapy there is evidence of benefit from interpersonal psychotherapy for the treatment of depressive disorders in hiv-infected individuals.28 cognitive-behavioural therapy (cbt) has been shown to have benefit in depressive illnesses in general primary health care.28 supportive therapy and support groups are not sufficient where individuals are depressed, but support group facilitators should be trained to identify people who may be depressed. an adaptation of cbt for people living with hiv, called cognitive-behavioural stress management (cbsm), has been found to be effective when conducted in group settings in hiv clinics in the usa.28 this intervention includes didactics on physiological effects of stress, stress management strategies, cbt interpretation of stress and emotions (addressing cognitive distortions, automatic thoughts), coping skills training, assertiveness training, anger management, identification of social supports, and group support. this is a structured intervention that could be implemented in hiv clinics or primary care settings where group treatment can be used to treat a number of depressed individuals at the same time, and it deserves attention in south africa. most common mental disorders can be managed effectively in primary care, but there are several specific indications for referring a patient to specialist psychiatric and mental health services (box 5). references 1. patel v, chisholm d, rabe-hesketh s, dias-saxena f, andrew g, mann a. efficacy and cost-effectiveness of drug and psychological treatments for common mental disorders in general health care in goa, india: a randomized controlled trial. lancet 2003; 361: 33-39. 2. sumathipala a, hewege s, hanwella r, mann h. randomized controlled trial of cognitive behaviour therapy for repeated consultations for medically unexplained complaints: a feasibility study in sri lanka. psychol med 2000; 30: 747-757. 3. world health organization and world organization of family doctors (wonca). integrating mental health into primary care: a global perspective. geneva: who press, 2008. 4. stein dj, seedat s, herman aa, et al. findings from the first south african stress and health study. policy brief, october 2007. tygerberg: south african medical research council, 2007. 5. stein dj, seedat s, herman aa, et al. lifetime prevalence of psychiatric disorders in south africa. br j psychiatry 2008; 192: 112-117. 6. morrison mf, pettito jm, ten have t, et al. depressive and anxiety disorders in women with hiv infection. am j psychiatry 2002; 159: 789-796. 7. ciesla gr, roberts je. meta-analysis of the relationship between hiv infection and risk for depressive disorders. am j psychiatry 2001; 158: 725-730. box 5 indications for referring a patient to specialist psychiatric and mental health services: 1. any patient who requires inpatient treatment should be referred for a psychiatric assessment. 2. any patient who presents with suicidal ideation should be referred for a psychiatric assessment. 3. failure to respond to primary care interventions as outlined above. 4. patients who fail to respond to an equivalent dose of fluoxetine or citalopram of 20 mg per day for a depressive or anxiety disorder should be referred for a psychiatric assessment or opinion. mrs k (box 1) has stage 3 or 4 hiv disease. she may have neurocognitive impairment and she may also have a depressive disorder. assessment should include physical examination, and assessment of her cognitive status. she is clearly a candidate for antiretroviral therapy, which should be started as soon as possible. one would re-assess her mental state regularly, and if her mood did not lift once she has recovered physically, one would consider starting her on an ssri. a suicide risk assessment should be carried out on mr m (box 2). because he is intoxicated, he would need to be supervised until he became sober. his wife could be called into the clinic to discuss the situation with her. it would be important to educate him about alcohol abuse and its consequences in terms of his hiv status as well as his mood. another important consideration would be when to start antiretroviral treatment. a social work referral should be made for assistance or advice regarding the couple’s financial situation, as well as referral to a support group or a psychologist depending on his condition. his mood should be monitored over time and if it remains low one would consider starting him on an antidepressant. ms b (box 3) could be suffering from postpartum depression. it is important to assess her mental state and do a risk assessment with regard to selfharm as well as possible harm to her baby. one could call her husband in and discuss the situation with them both. if she has features of a depressive disorder, she should be started on an ssri. it is also important to make sure that there is adequate support and supervision for her and her baby. if the safety of either is a concern, she should be admitted to hospital. discussion of case scenarios 12 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e o cto b e r 2 0 0 9 8. olley bo, gxamza f, seedat s, et al. psychopathology and coping in recently diagnosed hiv/aids patients the role of gender. s afr med j 2003; 93: 928931. 9. olley bo, seedat s, nei dg, et al. predictors of major depression in recently diagnosed patients with hiv/aids in south africa. aids patient care stds 2004; 18: 481-487. 10. olley bo, seedat s, stein dj. persistence of psychiatric disorders in a cohort of hiv/aids patients in south africa: a 6-month follow-up study. j psychosom res 2006; 61: 479-484. 11. olley bo, zeier md, seedat s, et al. post-traumatic stress disorder among recently diagnosed patients with hiv/aids in south africa. aids care 2005; 17: 550557. 12. els c, boshoff w, scott c, et al. psychiatric co-morbidity in south african hiv/ aids patients. s afr med j 1999; 89: 992-995. 13. freeman m, nkomo n, kafaar z, kelly k. factors associated with prevalence of mental disorder in people living with hiv/aids in south africa. aids care 2007; 19: 1201-1209. 14. martin l, tummala r, fernandez f. psychiatric management of hiv-1 infection and aids. psychiatr ann 2002; 32: 133-140. 15. stolar a, catalano g, hakala sm, et al. mood disorders and psychosis in hiv. in: citron k, brouillette m-j, beckett a, eds. hiv and psychiatry: a training and resource manual. 2nd ed. cambridge: cambridge university press, 2005: 30-55. 16. blalock ac, sharma sm, mcdaniel js. anxiety disorders and hiv disease. in: citron k, brouillette m-j, beckett a, eds. hiv and psychiatry: a training and resource manual. 2nd ed. cambridge: cambridge university press, 2005: 120127. 17. koenig hg, george lk, peterson bl, et al. depression in medically ill hospitalized older adults: prevalence, characteristics, and course of symptoms according to six diagnostic schemes. am j psychiatry 1997; 154: 1376-1383. 18. pollak sd. early adversity and mechanisms of plasticity: integrating affective neuroscience with developmental approaches to psychopathology. dev psychopathol 2005; 17: 735-752. http://journals.cambridge.org/download (accessed 13 june 2007). 19. kroenke k, spitzer rl, williams jbw. the pgq-9 validity of a brief depression severity measure. j intern med 2001; 16: 606-613. 20. cherian vi, peltzer k, cherian l. the factor structure of the self report questionnaire (srq20) in south africa. east afr med j 1998; 75(11): 654-656. 21. babor tf, higgins-biddle jc, saunders jb, monteiro mg. audit: the alcohol use disorders identification test. guidelines for use in primary care. world health organization. department of mental health and substance dependence. 2nd ed. geneva: who press, 2001. 22. pence bw, gaynes bn, whetton k, et al. validation of a brief screening instrument for substance abuse and mental illness in hiv-positive patients. j acquir immune defic syndr 2005; 40: 434-444. 23. ickovics jr, meade cs. adherence to antiretroviral therapy among patients with hiv: a critical link between behavioral and biomedical sciences. j acquir immune defic syndr 2002; 31: 98-102. 24. evans dl, ten have tr, douglas sd, et al. association of depression with viral load, cd8 lymphocytes, and natural killer cells in women with hiv infection. am j psychiatry 2002; 159(10): 1752-1758. 25. ickovics jr, hamburger me, vlahov d, et al. mortality, cd4 cell count decline, and depressive symptoms among hiv-seropositive women: longitudinal analysis from the hiv epidemiology research study. jama 2001; 285: 1466-1474. http://0-gateway.ut.ovid.com.innopac.wits.ac.za/gw2/ovidweb.cgi (accessed 25 may 2006). 26. leserman j. hiv disease progression: depression, stress and possible mechanisms. biol psychiatry 2003; 54: 295-306. http:/www.sobp.org/journal/ (accessed 24 april 2007). 27. thom rgm. depressive and anxiety disorders in hiv-infected individuals attending hiv-treatment facilities at various sites in south africa. phd thesis, university of the witwatersrand, december 2008. 28. ferrando sj, freyburg z. treatment of depression in hiv positive individuals: a critical review. int rev psychiatry 2008; 20(1): 61-71. 13 may 2001-------------the southern african jour al d~ hiv medicine finance tax implications of hiv-care costs to obtain a fixed percentage tax directive an irp 3 should be obtained, completed, and submitted to sars. fixed percentage tax d1rectne while the above method is one way to receive tax relief retrospectively, there is another method of tax relief that could enhance patients' cash fiow on a monthly basis. for further information contact: ra parkes and associates po box 1533, morningside, 2057 tel: (011) 706-9138 fax: (011) 463-8284 people on chronic medication usually take fixed doses of regular medication, and therefore the cost of treatment can be calculated for a full financial year. in this case, people on chronic medication (including treatment for hiv/aids) may apply for a fixed percentage tax directive. important information a patient reminder the following documentation should be submitted simultaneously with the completed irp 3 form: • a copy of the patient's identification document • a completed application form for a tax reference number • a completed irp 3 form • a doctor's letter confirming that the patient suffers from a chronic disease • a projection of all medical expenses for the full financial year including medication, consultations and investigations. patients need to obtain this document at the beginning of the tax year, although sars is lenient with applications lodged after the first 3 months of the fiscal year. it is essential that patients retain all health care expense vouchers/receipts as all claims have to be substantiated at the financial year-end by submitting an income tax return. retrospective tax reuef to lodge a claim the patient needs to submit the following information: • a copy of his/her identification document • the employer's irp 5 form • all medical expense claims • a fully completed itll form. while the 2001 budget speech did not address the hiv/aids crisis in south africa, some south africans are really doing their homework. for example, r a parkes and associates have established how hiv-positive patients can obtain tax relief from the south african revenue services (sars). this tax relief could make hiv-care costs more affordable. many hiv-positive patients and other individuals with chronic illnesses are unaware thal they have a right to claim medical expenses against their net remuneration. patients earning less than r60 000 per annum are not registered as taxpayers and are therefore not required to submit annual income tax returns. what they may not know is that despite not being registered as taxpayers, a claim can still be lodged with the sars by completing and lodging what is referred to as an itll form. patients who have not claimed these expenses for a period of 5 years may still lodge a claim as long as they are in possession of their original relevant irp 5 form and all medical expense vouchers. medical expense claims should include the following: • details of medical scheme contributions (subscriptions) • excess health care costs not covered by the medical aid • all incidentals, i.e. pharmacy bills not submitted to the medical scheme • travelling costs related to obtaining treatment • other medical professionals' costs, e.g. nursing and dietician. where a patient's net remuneration exceeds r60 000 per year, he/she should register as a taxpayer with sars and lodge an 1t12 form. the same documentation is required to lodge the it12 form (as outlined for the itll form). june 2006 make up june 2006 the southern african journal of hiv medicine3 2 in june this year, world leaders met in new york at the united nations general assembly special session (ungass) on hiv/aids to review whether member states have met certain obligations agreed in the 2001 declaration of commitment on hiv and aids. while the meeting is politically important, it is bound to offer very little hope to millions of people living with hiv in africa, south america and asia who continue to wait for access to treatment. this is because even though there seems to be an international commitment to expand aids treatment access, the global rate of access is short of the internationally endorsed universal access goal for 2010, leaving millions without lifesaving care and hundreds of thousands of people with hiv/aids facing the prospect of imminent death. according to the world health organization (who), about 600 000 more people gained treatment access in 2005. at that rate, fewer than half of those who need aids treatment will have access in 2010.1 this is why an international alliance of civil society advocates has called for setting a new global aids treatment target of ‘10 by 10’ – 10 million people accessing treatment by 2010. but the international community seems to have gone out of its way to avoid setting explicit global treatment targets that would focus attention on specific outcomes, acknowledge the responsibilities of global institutions as well as countries, and drive accountability. current negotiations on the 2006 ungass political declaration suggest that the treatment section is weak, particularly on setting explicit treatment targets. in sa, the national department of health submitted its final progress report on the declaration of commitment on hiv and aids (progress report) to the un for the purposes of this meeting.2 but it did so unilaterally and without any significant consultation with stakeholders. the department excluded the views of civil society, private bodies and health academics, and it has been accused of failing to confer adequately with many partners that have assisted it with implementing the operational plan. for example, at a public meeting of the joint civil society monitoring forum (jcsmf) held in march 2006, participants and members of the jcsmf were informed of one consultative meeting hastily convened by the national department of health on 2 march 2006 to discuss sa’s report to ungass on progress with the implementation of the ungass declaration of commitment (2001). at that meeting, civil society and other stakeholders were told to submit comments on the draft progress report within a week. but even though some organisations managed to submit short recommendations within a week, those recommendations were subsequently ignored in the final report. the progress report has been criticised by many organisations in sa for glaring inaccuracies as well as its attempt to gloss over key shortcomings of sa’s aids policies.3,4 significantly, the progress report fails to include information, data and statistics relating to hiv mortality, prevalence, tb and hiv incidence, arv patient numbers and arv treatment targets. globally and locally, targets are important. for example, the who committed to treating 3 million people in the developing world by the end of 2005. even though these targets were not met by then, it created the momentum to scale up treatment access in many parts of the world – including in sa and countries that until then did not have domestic capacity to start art. the world’s leaders have now committed themselves to achieving universal access by 2010. will they fail? a lot depends on whether this commitment is vigorously pursued by member states at a local level. so far the picture does not look promising. in november last year the international treatment preparedness coalition (itpc)* issued missing the target: a report on hiv/aids treatment access from the frontlines. the report detailed specific barriers and potential solutions to aids l e g a l i s s u e s taking stock of the national arv programme: what exactly have we done? fatima hassan, ba llb, llm attorney, aids law project on 8 august 2003, the government of south africa (sa) made a commitment to provide antiretroviral (arv) treatment in the public health sector. on 19 november 2003, it published the operational plan on comprehensive hiv and aids care, management and treatment for south africa (the operational plan). some 2� 1 2 � years later, let us take stock of what is happening. * the international treatment preparedness coalition (itpc) was born at the international treatment preparedness summit that took place in cape town, south africa, in march 2003. that meeting brought together for the first time community-based treatment activists and educators from over 60 countries. since the summit, itpc has grown to include over 700 activists from around the world and has emerged as a leading civil society coalition on treatment preparedness and access issues. 3 3 treatment delivery in six countries heavily affected by the epidemic (including south africa) and made recommendations for national governments and multilateral institutions. six months after the publication of missing the target, the itpc has found progress on several of the barriers to scale-up identified in november. however, deficient national leadership, and slow implementation of reforms remain critical roadblocks to treatment delivery and are costing lives every day in each of the six countries reviewed.1 with regard to sa, the itpc identified the lack of proper leadership coupled with aids denialism as the main obstacles to increasing the number of patients on treatment. other barriers include an acute shortage of health workers, mainly nurses and pharmacists, lack of proper infrastructure, and insufficient access to and promotion of vct. the report noted that too few children were on treatment. on a global level, the itpc called for a new and more effective global fund for aids tb and malaria (gfatm) country coordinating mechanism (ccm) as well as sustainable funding for the gfatm, fewer restrictions and more collaboration from the pepfar programme including using generics registered by individual states and providing reproductive health services including condom distribution, increased visibility and leadership from unaids and who, and greater involvement from civil society in treatment expansion. what has happened? so let us look at what has happened since. in sa, by january 2006, the total number of people on arv treatment in both the public and private sector was estimated to be about 200 000 220 000. about 110 000 120 000 people were purportedly accessing arvs in the public sector, with an additional 90 000 100 000 receiving it in the private and not-for-profit sectors. (f hassan and d bosch – unpublished data, 2006, and f hassan – unpublished data, 2006. see also social cluster briefing, parliamentary media 10 february 2006,5 where the minister stated that there were 229 sites treating 117 897 patients on arvs at the end of december 2005. for a more detailed analysis of the operational plan see hassan f, forthcoming publication by equinet, ‘the provision of arv treatment in sa’, www.equinetafrica.org). the majority of the approximately 110 000 120 000 patients (both adults and children) receiving public sector care are concentrated in three provinces (gauteng, western cape, and kwazulu-natal). most of the patients in the public sector are women, averaging at about 60% of all patients. without the significant contribution of donors such as ark, msf and pepfar the public sector numbers would be even lower. at the end of 2005, about 245 000 300 000 children were estimated to be living with hiv. some experts suggest that on the basis of these figures, about 50 60% need immediate access to arvs. at present we estimate that only about 10 000 15 000 children are receiving arv treatment, that is about 10% of the total patients on treatment, while others argue that this figure is substantially lower. in particular, in many smaller and less resourced provinces the number of children on treatment is far below 10%.6 children therefore continue to be neglected during the planning for the provision of arvs and hiv care. and the same trend is merging in other developing countries. in addition, very few men are accessing treatment in the public sector in sa. but in the private sector, men outnumber women on treatment. this is because workplace treatment programmes are generally more available to male workers. most patients on arv treatment in the public sector are still receiving care at academic hospitals and so-called hospital ‘main sites’, with very few patients accessing arv treatment at non-hospital, rural and remote sites. what all of this tells us is that accurate numbers are hard to come by. this is because there is no proper monitoring and evaluation system (m&e) in sa. (clinicians have warned that accurate data are absent on the number of patients on arvs. for example, there are two separate systems (pharmacy and clinical) for capturing key data, and they rarely agree.) the national department of health has confirmed this.7 it has admitted that the total number of people receiving arv treatment is ‘not yet known, as the patient monitoring system is not yet able to collect information to this level of detail in a reliable manner’7 (p. 26) – this some 2� 1 2 � years after the operational plan was adopted. public health experts advise that the failure to have a proper m&e system has resulted in provinces being entrenched in a range of different data collection solutions and approaches. according to them even though revised indicators for the hiv programme are available, many of these are not feasible without a facility-based system through which data can be aggregated. the indicators themselves are often confusing and do not follow principles of collecting limited but necessary information (see hassan f, forthcoming publication by equinet, ‘the provision of arv treatment in sa’). barriers to implementation as in most other developing countries, human resources are a major barrier to the speedy implementation of prevention and treatment programmes in sa. even though the national department of health has finally released its country plan for human resources in health (hrh plan) it remains to be seen how the plan will address real shortages in the short, medium and long term.8,9 notwithstanding an initial forecast made to parliament by the national department of health in february 2004 that the process of drug procurement would be completed by june 2004, the award of the drug tender was only announced on 2 march 2005, some 13 months after the drug procurement process commenced and more than 16 months after the operational plan was adopted.10 the tender is worth over r3.7 billion and expires in 2007. but serious problems may arise with drug supplies. this is because, unlike the brazilian government, the sa government is not planning ahead. for the southern african journal of hiv medicine june 2006 june 2006 the southern african journal of hiv medicine3 4 example, it is not taking steps to ensure a sustainable supply of a range of key drugs. there appears to be very little government concern that there is only one supplier of kaletra. the same is true of efavirenz (marketed by msd as stocrin) – even though a licence has been issued to aspen pharmacare to manufacture a generic version, it is still not yet registered for commercial use. if more competition truly existed, we would also witness a downward pressure on prices. this is important given that in terms of value, two pharmaceutical companies, abbott pharmaceuticals and msd, have secured a substantial percentage of the tender (more than 50% jointly). therefore, if the prices of key drugs are not brought down through generic competition, government will continue to waste valuable resources. in addition, without multiple suppliers sustainable supplies of key drugs will be jeopardised. for example, since the inception of the operational plan there have been several reports regarding problems with drug availability in various parts of the country (gauteng, kwazulunatal and mpumalanga in particular). the supply of efavirenz has been beset with problems of repeated stock-outs. on treatment regimens, while there is consensus among hiv clinicians in the private sector that d4t should be removed from the first-line treatment regimen and replaced with tenofovir (which has fewer side-effects), this has not happened because tenofovir is not yet registered by the medicines control council (mcc). it is unclear when it is likely to be registered or why the fast-track process that it has been subject to has not materialised. clinicians have warned that this delay is undermining the possibility of using optimal treatment regimens in the public sector. in order to achieve universal access by 2010, sa and other developing countries will therefore have to step up their efforts. if ineffective national leadership and aids denialism continue, these targets will be undermined locally and globally. and it is worrying that there are no signs of these problems abating. for example, in legal papers filed by the national department of health this year in the cape high court in a case brought by the treatment action campaign (tac) against inter alia matthias rath, his associates and the government of sa for making widespread false and exaggerated claims about the medical utility of high dosages of multivitamins (claiming that multivitamins are substitutes for arvs), the director general of health has reported finding no wrongdoing by rath or his associates, and has therefore defended not taking any steps to end the widespread distribution of false information by rath suggesting that vitamins are a substitute for arvs.11 therefore, despite having some of the best hiv/aids policies on paper and a strong legal framework for protection against unfair discrimination, confusion and ambiguity has characterised our government’s response to aids. while members of parliament (mps) and senior anc officials have privately berated such a response, none, save for two prominent anc members, kader asmal (former minister of education and anc mp) and ben turok (anc mp), have publicly drawn themselves (albeit unwittingly) into the debate. international donors and institutions such as the who, gfatm, and unaids have also shied away from publicly doing so. the one exception has been stephen lewis in his capacity as special un envoy for hiv/aids in africa. lewis has repeatedly declared that the lack of leadership and political commitment in sa is undermining the regional and international struggle against hiv/aids. for this the ministry of health has unfairly attacked and attempted to marginalise him. regionally and internationally, sa’s response is not only embarrassing but dangerous as well. this is because many developing countries look to sa for solutions and leadership. therefore, in my view, the arv programme has become a comfortable hiding zone for government and in particular the denialist views of certain senior officials. because government is paying for arvs, no one dare criticise the pace of implementation. but we must. you see, our government may be paying for arvs but it is doing so slowly, reluctantly and without any great vigour or creativity. in fact, it is deliberately stalling on its own programme. reference 1. missing the target: off target for 2010: how to avoid breaking the promise of universal access. update to itpc’s aids treatment report from the frontlines. http://www.aidstreatmentaccess.org/itpcupdatefinal.pdf (last accessed 28 june 2006). 2. progress report on the declaration of commitment on hiv and aids. http://www.doh.gov.za/docs/index.html (last accessed 28 june 2006). 3. south africa joint civil society monitoring forum: resolutions and minutes. http://www.alp.org.za/modules.php?op=modload&name=news&file=articl e&sid=8 (last accessed 28 june 2006). 4. letter from jcsmf dated 6 april 2006 to kofi annan regarding sa's progress report. http://dedi20a.your-server.co.za/alp/images/upload/jcsmf.ungass. pdf (last accessed 28 june 2006). 5. social cluster briefing: parliamentary media 10 february 2006. http://www.doh.gov.za/mediaroom/index.html (last accessed 28 june 2006). 6. hassan f, bosch d. monitoring the provision of arvs in south africa – a critical assessment. alp briefing for tac nec. 17 and 18 january 2006, cape town. available from author. 7. republic of south africa: progress report on the declaration of commitment on hiv and aids. prepared for: united nations general assembly special session on hiv and aids, february 2006. http://www.doh.gov.za/ docs/index.html (last accessed 28 june 2006). 8. a national human resources plan for health, april 2006. http://www.doh.gov.za/docs/discuss-f.html (last accessed 28 june 2006). 9. alp and tac. joint submission on a strategic framework for the human resources for health plan: draft for discussion. http://www.alp.org.za/ modules.php?op=modload&name=news&file=article&sid=261 (last accessed 28 june 2006). 10. hassan f. let them eat cake – a short assessment of provision of treatment and care 18 months after the adoption of the operational plan, june 2005. updated second joint report on the implementation of the operational plan for comprehensive hiv and aids care, management and treatment for south africa. aids law project and treatment action campaign. http://dedi20a.your-server.co.za/alp/images/upload/2nd%20report.pdf (last accessed 28 june 2006). 11. affidavit of t mseleku (dg of health). in tac v matthias rath and 11 others. cape of good hope provincial division case number 12156/05. sajhiv 1040 reflections the hannan crusaid treatment centre – early beginnings and lessons learnt r kaplan, md; c orrell, mb chb, msc, mmed; s d lawn, frcp, md, dtm&h, diphivmed; l-g bekker, mb chb, dtm&h, dch, fcp (sa), phd; r wood, dsc (med), fcp (sa) corresponding authors: l-g bekker (linda-gail.bekker@hiv-research.org.za) and r wood (robin.wood@hiv-research.org.za) richard kaplan, catherine orrell, stephen lawn, linda-gail bekker and robin wood hail from the desmond tutu hiv centre, institute of infectious disease and molecular medicine, department of medicine, university of cape town, south africa after 12 years, the hannan crusaid treatment centre (hctc) in gugulethu, cape town has screened more than 10 000 women, men, adolescents and children for life-saving antiretro­viral therapy (art). while we have seen a slow but steady increase in the starting cd4+ count of new patients, the monthly inflow of new clients goes on unabated. a successful example of public-private partnership, this provincial clinic, supported by a local non-governmental organisation and initially funded by a uk-based charity, may provide a model for similar programmes within the national health insurance plan. here we discuss the history and development of this programme, with a focus on lessons learnt about rolling out art in south africa more generally. early beginnings the first community-based treatment at the gugulethu day hospital was provided in 2002 by a team from the desmond tutu hiv centre, literally working out of a biscuit box! dr catherine orrell, sr felicity cope and six counsellors opened a clinic on three days a week, bringing in their daily supplies each time in a cardboard box and having to wait for the availability of a consultation room. the first patients were extremely ill and many did not survive the first few months of art. shortages of medication meant that rationing decisions had to be made on a daily basis. despite this, the team continued with enthusiasm, as every patient was known by name, many received regular home visits, and some were at times escorted to hospitals by our doctors or had art hand-delivered to them while in hospice care. by march 2003, the art service was able to open full-time with the addition of dr kwezi matoti (and his room in the clinic, giving a dedicated space for the service), with sr lulu mtwisha heading sizophila, a team of therapeutic counsellors who provided support for patients starting treatment. the first 150 carefully rationed treatment places were expanded to just 350, but we endeavoured to have an open-door policy – allowing people to attend whenever they felt they needed, and never turning anyone away. while the initial focus of the treatment programme was predominantly on the provision of art in a primary healthcare setting, over time we also established a strong research programme that enabled us to better understand the hiv epidemic and the impact of our interventions. much of this work has gone on to inform local, national and international policies and, as elsewhere in south africa, this demonstrates the potential synergies that academic medicine can bring to strengthening healthcare delivery. this has included insights into art adherence, nurse-driven services to step-down art management, earlier treatment of hiv/tuberculosis (tb) co-infection and rapid initiation of art in pregnancy. of note, the hctc team helped to shape the first western province art guidelines using the lessons learnt from this clinic, and these subsequently went on to inform the first national art guidelines. in 2001, the size of the problem made it very clear that art would need to be delivered at primary healthcare level and money was sought to provide such a programme in the nyanga district of cape town. so began a three-way partnership between the western cape provincial department of health, led by dr fareed abdullah, the desmond tutu hiv foundation and crusaid, the uk-based aids charity with a large endowment from ms katy hannan. lessons learnt adherence, loss to follow-up and virological failure a strong interest in adherence led us to design our programme to include three treatment-preparedness sessions and to include pill counts at each visit. early adherence data were excellent and virological suppression (viral load (vl) <50 copies/ml) was noted in >90% of those receiving treatment at every time point in the first 3 years.1 a system, initially called the ‘red alert’ system, was designed to identify and support those whose vl was unsuppressed (>1 000 copies/ ml) at any point after starting art. this ‘red alert’ system included an extra adherence-focused education session, an increased frequency of counsellor home visits, the provision of pill boxes and monthly visits to the clinic. we showed that 75% of those who experienced virological breakthrough could re-suppress their vl after this intervention.2 based on counting tablet returns, adherence appears to remain high in the cohort. adher­ence continues to be an important focus of the programme and, with the introduction of tb treatment in the clinic in 2011, the adherence support system was expanded to provide integrated community support for hiv/tb co-infected patients. sizophila (‘we are well’) therapeutic counsellors in 1999, a small band of enthusiastic women who had survived hiv as participants in our early art clinical trials stepped forward requesting to help others do the same. we taught them all we knew about art, called them ‘therapeutic counsellors’ and initially asked them to work in our programmes at somerset and groote schuur hospitals in cape town. these counsellors were the earliest accompanateurs or patient advocates and the forerunners of the community care workers we have in our primary health programme today. elaine dube, one of the earliest and as passionate today, went on to become involved in the very successful antenatal care mothers2mothers programme. initially we started with a ratio of one therapeutic counsellor to every ten patients. community-based, they worked in the areas where they lived, knew their ‘assigned’ patients personally, and were highly effective for many reasons: two important ones being their deep understanding of their condition and the impact of art in their own lives, and the intense empathy that they offered, living openly with their own infection at a time when hiv was highly stigmatised. today they remain the cornerstone of the success of the clinic and it is well accepted that any community-based art programme requires community-based support. the sizophila choir. hiv/tb co-infection early on in the introduction of art at hctc, tb was recognised as the leading serious opportunistic disease, with more than half of patients receiving treatment for tb at the time that they started art. this not only caused much suffering for affected patients, but patients with tb also had a doubled mortality risk compared with those without tb.3 however, the problem was compounded by the difficulty in diagnosing tb in patients with hiv. we found that only 25% of patients with sputum culture-positive pulmonary tb reported having a chronic cough for longer than 2 weeks. moreover, we described how sputum smear microscopy and chest x-rays are able to diagnose only a small fraction of the disease present; in turn, one-fifth of unselected patients not receiving tb treatment at the time of first enrolment in the clinic actually have sputum culture-positive tb, and this has led to much greater use of culture-based diagnosis. our studies have shown that patients who have hiv and tb face great challenges in receiving optimum and timely care when art and tb treatment services are not integrated. in particular, art is often unacceptably delayed. it has therefore been a huge step forward that, from 2011 onwards, patients have been able to receive tb treatment at the hctc, and from 2012, multidrug-resistant (mdr)-tb patients have also been treated on site. we have further been able to show that increases in cd4+ counts during art are associated with major reductions in long-term tb risk. pregnancy programmes for the prevention of mother-to-child transmission (pmtct) of hiv were introduced at the midwife obstetric unit (mou) at the gugulethu community health clinic in 2001. with an antenatal care hiv prevalence rate of 29% in gugulethu, pregnant women constituted a significant proportion of the patients who were eligible for art. work at the hctc intensified to develop a ‘fast track’ system that would ensure a quicker route to art commencement for pregnant and sick patients. in 2010, the desmond tutu hiv foundation ran a pilot programme in partnership with the western cape depart­ment of health, demonstrating that it was safe, feasible and acceptable to initiate women whose cd4+ counts were <350 cells/ μl on the same day as their diagnosis during the first antenatal care visit, and that by doing so transmission rates could drop to as low as <1%. 4 this approach is now standard in the mou as part of growing emphasis on providing rapid art, and ongoing care and support to hiv-positive women during pregnancy and post partum. adolescents a review of the programme’s outcomes confirmed what many first-world hiv pro­grammes and other chronic disease clinical services were showing: that adolescents often experience a turbulent transitional developmental phase and may experience significant challenges in traditional art programmes. despite growing up in the clinic as model patients, older children often lose their vl control and find it difficult to adhere and attend services as they move into the teen years. in 2005, the hctc recognised the need to be sensitive to adolescent needs, and organised patients aged 10 22 years into four age bands to attend clinic appointments in their specific age strata. these age-specific clinics were held in the afternoons with dedicated youth-oriented counsellors and a fun ‘chill room’ within the clinic. it is recognised that many of the adolescents are now growing into adulthood and from 2012 the clinic developed a health care transition model to facilitate the shift from adolescent to adult services. the future the hctc was one of the pioneers of community-based art in south africa. the early provincial and national treatment protocols, as well as a score of subsequent policies and models, have emanated from this centre. the lessons learnt have been captured in peer-reviewed publications, which have in turn influenced the treatment programmes and policies, not only in south africa, but in many treatment programmes throughout africa and further afield. the centre has become an example of what can be achieved through a public-private-academic partnership whereby, via careful application of a variety of resources – financial, logistical, expertise and innovation – in a climate of shared partnership and collaboration, much can be ‘learnt by doing’. in a nationwide, public sector health intervention such as the south african art programme, it is critical that specific facilities and services are maintained, where critical thinking, rigorous evaluation and innovation can be applied to ensure that, in an evolving and dynamic epidemic, the best health models and programmes are being utilised. the hctc has, over the last 12 years, not only screened over 10 000 women, men and children for the need for life-saving art, it has in many ways reached much further to advocate for, instruct, change and improve the way in which antiretrovirals are administered on this continent and beyond. importantly, this clinic – with its strong emphasis on patient education, patient support and mutual respect – epitomised the paradigm of the patient-centred approach that became the hallmark of hiv management. our hope is that these lessons will continue to be learnt and written about as we enter the next decade in which we hope the flames of the hiv epidemic will be doused and we will see our patients growing older in good health. references 1. bekker l-g, myer l, orrell c, lawn s, wood r. rapid scale-up of a community-based hiv treatment service: programme performance over 3 consecutive years in guguletu, south africa. s afr med j 2006;96(4):315-320. 1. bekker l-g, myer l, orrell c, lawn s, wood r. rapid scale-up of a community-based hiv treatment service: programme performance over 3 consecutive years in guguletu, south africa. s afr med j 2006;96(4):315-320. 2. orrell c, harling g, lawn sd, et al. conservation of first-line antiretroviral treatment regimen where therapeutic options are limited. antivir ther 2007;12(1):83-88. 2. orrell c, harling g, lawn sd, et al. conservation of first-line antiretroviral treatment regimen where therapeutic options are limited. antivir ther 2007;12(1):83-88. 3. lawn sd, myer l, bekker l-g, wood r. burden of tuberculosis in an antiretroviral treatment programme in sub-saharan africa: impact on treatment outcomes and implications for tuberculosis control. aids 2006;20(12):1605-1612. [http://dx.doi.org/10.1097/01.aids.0000238406.93249.cd] 3. lawn sd, myer l, bekker l-g, wood r. burden of tuberculosis in an antiretroviral treatment programme in sub-saharan africa: impact on treatment outcomes and implications for tuberculosis control. aids 2006;20(12):1605-1612. [http://dx.doi.org/10.1097/01.aids.0000238406.93249.cd] 4. black s, zulliger r, myer l, et al. safety, feasibility and efficacy of a rapid art initiation in pregnancy pilot programme in cape town, south africa. s afr med j 2013;103(8):557-562. [http://dx.doi.org/10.7196/samj.6565] 4. black s, zulliger r, myer l, et al. safety, feasibility and efficacy of a rapid art initiation in pregnancy pilot programme in cape town, south africa. s afr med j 2013;103(8):557-562. [http://dx.doi.org/10.7196/samj.6565] s afr j hiv med 2014;15(1):35-37. doi:10.7196/sajhivmed.1040 ----------_1----------iapac: battling complacency, advancing commitment in southern africa iapac will bring to the region the support of its more than 10 000 members across the globe, together with educational resources (publications, training and conferences), public policy initiatives (working with government and non-government agencies to advance advocacy and human rights issues), and model programme development that is designed to demonstrate more effective ways in which to meet these objectives in a way that will strengthen hiv/aids care in the region. iapac hopes to build strong partnerships through its physician members in the region, with the southern african hiv clinicians society and other key stakeholders in southern africa, so as to achieve the highest possible degree of co-ordinated impact. far further information about iapac, or to apply far membership, visit wlnwjapac.org iapac's objectives are to assist in developing and implementing effective strategies that lead to: • increased access to drugs and related technologies for all people living with hiv/alos and life-threatening ca-infectious diseases • reduced transmission and acquisition of hiv and iifethreatening co~infectious diseases • enhanced capacity amongst healthcare workers to provide treatment, care and support to hiv-infected adults, adolescents and children based on the most current and appropriate guidelines, which are made more accessible • protection of the human rights of all people at risk for and living with hivlaids and other life-threatening co-infectious diseases. in a move that is seen as a significant commitment to battling the hiv/aids epidemic in southern africa, the international association of physicians in aids care (iapac) has announced that it will be strengthening its representation and involvement in the region by appointing or shaun conway as executive director to head its operations in southern africa and by establishing a regional office in johannesburg. this is part of the organisation's global comshaun conway mitment to changing the course of the hiv executive director pandemic through mobilising physicians and other agencies that are involved in hivlaids care towards greater levels of activity and more effective prevention, treatment and care strategies. it is hoped that by enabling effective actions and strategies, this will impact on many more of the millions of people living with hiv infection globally, many of whom lack access to essential healthcare services, life-sustaining drugsj diagnostic technologies and humane care. southern africa presents a particularly urgent and highpriority area where mare co-ordinatedj innovativej sustained and stronger efforts are needed to deal with its exploding epidemic that is the fastest growing in the world. iapac will work closely with the southern african hiv clinicians society and other local and international agencies to fulfill its mission, which is to prevent hiv infection and to maximize the survival and quality of life of all people affected by hivlaids and its resultant life-threatening co-infectious diseases. hn clinicians sociely southern african imperatnes the southern african hiv clinicians society has an imperative to enable greater access to quality hiv care. it represents medical professionals who are involved in hiv/aids care within the region and serves as the specialist interest group for hiv/aids to the south african medical association. as a relatively new organisation, established in 1998, the society has grown in membership, influence and reputation to become active in a number of forums, representing the care needs of hiv-infected individuals, as well as advancing scientific and professional programmes for its members. the society's mission is to respond to the profession's needs, undertaking supportive, facilitating and advocacy activities that will enable clinicians to better manage the clinical, public health and research demands of hiv and aids, and increasing the capacity of the profession to respond more effectively to the hiv/aids epidemic. a number of important services and initiatives have been planned and implemented over recent months, including the production of this journal, as well as the consensus guidelines for antiretroviral therapy that appear in this edition. tuberculosis prevention guidelines were recently published and appeared in the aids forum section of the south african medical journal, to which the society has had an ongoing commitment. recommendations for the management of opportunistic and other hiv-associated conditions were also compiled by the society for the south african department of health and these are expected to be published in due course. the details of a programme to support hiv antiretroviral treatment by less experienced clinicians, based on the clinical guidelines of the society, will aiso be announced soon. the society is a partner in developing an internet portal, .www.hiv.co.za. that will become southern africa's main resource and point of entry to hiv/aids services on the web, serving as an increasingly useful platform for the society's educational, networking and clinical support services. continuing medical education meetings are currently held each month in johannesburg, cape town and durban and are planned for other regions in the near future. training opportunities are being developed that will lead to formal accreditation in hiv medicine, and a credential ling mechanism that will enable an accredited preferred provider network to be established is being planned, in partnership with iapac. the network of accredited hiv clinicians is being put in place and an innovative logistical model for this has been developed, with the vision that this will enable the profession in the region to demonstrate that is has the logistical and infrastructural capacity through which to deliver high-quality care at lower cost, in order to bring down the costs of hiv drugs, laboratory and ancillary services. this is seen as a fundamental process in achieving greater levels of access for individuals who are hiv-infected. strategic partnerships are seen as important to the society's future growth and success and the society looks forward to working closely with the international association of physicians in aids care (iapac) and other stakeholders in the region to improve hiv prevention, treatment, care and support extended to the rapidly increasing numbers of hiv-infected and aiosaffected individuals. this is the society's imperative and a challenge that cannot be ignored. the southern mrican journal of hiv medicine ------------july 2000 11 unaids describes its progress in implementing drug access initiatives horizons to participate in the right-ta-care initiative, or for more information, please contact: peter black, iapac southern africa regional office tel: +27(011) 482 2630 e-mail: pblack@iapac.org.za health care funders and employers increasingly appear to be seeking appropriate care solutions for their members and employees in order to keep these populations healthy, realising the benefits of their investment, which includes the opportunities for secondary prevention. notwithstanding the reluctance of pharmaceutical manufacturers to lose their potentially lucrative hiv market, opportunities do exist to negotiate drug discounts based on higher volumes of patients treated or, more ideally, to obtain preferentially priced drugs through international advocacy and other alternative supply mechanisms (although the latter do require political support that must continue to be demanded though strong advocacy by the profession and by civil society especially those people living with hiv/aids). the right-to-care programme will provide innovative ways to enhance clinical decision-support, through guidelinebased computerised tools, accessible specialist advice and incentivised training programmes, 50 that patients receive the most optimal treatment interventions. once implemented, right-ta-care will facilitate significant growth in the numbers of hiv-infected individuals who will be able to access enhanced, high-quality hiv care across a continuum, which includes making the widespread use of antiretroviral therapy both affordable and effective, while better managing proven preventive interventions and coinfectious diseases. 'enhanced hiv care' access will be achieved in the shortest time possible by building and supporting the skills and capacity of health care providers co-ordinated within a strong hiv clinicians' network, and by leveraging available resources within the south african private health care sector, using these more efficiently, and advocating for international support to make hiv treatments more affordable. through this proposed initiative and its affiliated programmes within iapac, many more hiv-infected individuals will lead productive lives, remaining healthy for longer, and the spread of hiv infection will be reduced. during a panel discussion at the october iapac cairo conference, moderator badera samb from unaids and panelists reviewed the status of the unaids' drug access initiative, which was initiated in 1997. as examples, samb presented projects carried out in four pilot countries: chile, cote d'lvoire, uganda and vietnam. these countries had been carefully chosen, based on their relative political and social stability and the level of support of their respective governments. right to care it is strikingly obvious that today's problems cannot be solved with yesterday's solutions and that the hiv epidemic cannot be managed by 'business-as-usual' approaches. the magnitude of the hiv crisis in southern africa and its seemingly unattainable treatment solutions, for which 'access' has almost become an anathema, desperately needs new, innovative and realistic solutions. the international aids conference in july and recent iapac resource allocation for hiv/aids and other ufe-threatening illnesses conference in cairo (16 18 october 2000) only served to highlight the plight of our region and presented few solutions. fascinating insights into the global economics surrounding the disease were also presented in a keynote address by jeffrey sachs, director of the harvard institute for international development, who believes that the required lo-fold increase in annual global aids funding (from the current estimate of approximately 500 million us dollars to 5 billion dollars), is very feasible, given the multi-trillion dollar economies of the usa and other industrialised world countries. sachs recommended a comprehensive global approach, which would have four major elements: adequate financial support, global strategy, global co-ordination and mobilisation of government support; and emphasised that much more careful co-ordination of funding and resources is critical. in our region of the world, we remain overwhelmed by the costs of caring for hiv patients, as well as the complexities and increasingly high demands of hiv treatments. or shaun con way of iapac proposed a bold solution in cairo for a programme of expanded access to enhanced hiv care for hiv-infected individuals in south africa. the 'right-tocare initiative', which is being launched by iapac as an hiv clinician-led care management programme, is based on the principle of risk sharing through capitation contracts within a well-supported and credentialled preferred provider network. it-enabled clinical decision-support, specialist back-up and co-ordinated individual care management would allow for optimal resource utilisation and enable patient outcomes to be monitored closely and care to be co-ordinated properly. the programme will use highly innovative approaches to data collection, guarantee payment for clinical services and implement an intelligent drug supply logistic to ensure that treatments reach and benefit the end-user. the most unusual aspect of this initiative is that it will be 'not-for-profit' all surplus revenues would be ploughed back into building the capacity to expand care even further and into subsidising treatment or conway proposed that there are enormous unmet opportunities to strengthen and expand hiv care through developing, and vastly improving the co-ordination of, clinical expertise in genera list hiv medicine. available resources must be better utilised and this can be achieved through an integrated care management model that leverages care provider and ancillary services networks: he went on to say that 'this makes antiretroviral treatment access and the provision of hiv care across the continuum within an "enhanced care package" an attainable possibility, if widely supported and part of a dedicated care delivery effort: november 2000 -----------the southern mrican journal of i1iv medicine what is the drug access initiative? the initiative focuses on widening access to hiv treatment interventions in developing countries. the latest phase of this initiative, which has been named 'accelerating access', has involved unaidsbrokered negotiations with the 5 large pharmaceutical companies that supply the majority of hiv-related drugs. the challenge of drug access initiatives is not only to lower the cost of hiv-related drugs, but also to ensure rational prescription and use of the drugs, to implement an adequate and responsive distribution service, and to work with governments to implement and strengthen existing health care systems. full range of support country-level support for the drug access initiative has ranged from entirely private sector to entirely state-sponsored. in uganda, treatment activities have been privately supported, while in other countries, such as cote d'lvoire, there has been both private and government support. chile and vietnam, have received total government support for costs of therapy. the drug access initiative has encouraged competition that has pushed down the prices of certain drugs. one confounding factor, however, has been local currency fluctuations, an effect that can also hamper a patient's ability to afford regular treatment. the achievements so far have shown that the rational use of art is feasible in developing countries. other countries such as senegal, morocco and malawi have been encouraged to move forward with access to art. in the process, countries have learned how to negotiate better prices, but the overall costs of providing hiv care remain daunting to the economies of the developing world. put in context, switzerland could fund the care of all hiv cases with only 0.06% of its gnp, while zimbabwe would have to spend 265% of its gnp. this shows the enormous gap between rich and poor countries that still needs to be overcome in some concerted way. dorothy ochola, from the ministry of health in uganda, pointed out that uganda has the capacity to handle up to eight times more patients than proposed by the drug access initiative. once again, the main barrier is the cost of drugs. new programmes and further negotiations for improving access to treatment for more patients will strengthen this infrastructure and enable greater numbers to be treated, although at much higher cost to the country. update on unaids' current accelerating access initiative jos perriens of unaids presented details on the essential, intermediate and high complexity care packages recently proposed by the who, and he stated the principles for how hiv/aids can be tackled. the unaids secretariat recently published a call for 'expressions of interest' to pharmaceutical companies that manufacture opportunistic disease drugs and antiretroviral drugs, as well as to manufactures of hiv-related diagnostic commodities, for them to supply developing countries with their goods at preferential prices. unaids is currently working with an increasing number of countries, mainly in sub-saharan africa, to support them in achieving government commitment and well-planned policies for managing their responses to the epidemic, including how they can improve access to hiv-related treatments. after these sessions many questions remained, ranging from the effects of poverty and family issues, to controversial policies in some countries requiring patients to pay for their treatment out of their own pockets. ihe southern african journal of hiv mhicinf -----------novfmber 2000 b untitled t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u n e 2 0 0 7 1 5 apart from overwhelming mortality figures, economic arguments exist for keeping up, if not accelerating, the pace of antiretroviral therapy (art) provision in south africa and elsewhere. in june 2006, the copenhagen consensus reemphasised the importance of hiv and infectious disease control. the authors called for its prioritisation ahead of a multitude of other worthy causes – based not on the need of people, but on the cost-effectiveness of interventions to remedy this plight. the copenhagen consensus, set up in 2004 by the danish environmentalist bjorn lomborg, works to answer a single question: what are the most cost-effective ways for a government to improve or save its citizens' lives? the novelty of this approach is to draw on experts, findings and methods from a large variety of scientific areas, while forcing a consolidation of results to a single common denominator for better comparison: the quality-adjusted life-year, or qaly.1 for the first time interventions as diverse as combating climate change and combating malaria could be compared in respect of their outcome in a meaningful way. the process lists 40 interventions tackling 10 areas of global concern (including communicable diseases, sanitation and water, education, malnutrition and hunger, subsidies and trade barriers, education, corruption, conflicts, and financial instability), which are being ranked in order of priority. in the first round in 2004, a group of academically acclaimed economists reviewed the papers summarising the evidence on each of these interventions and ranked them accordingly. back then, hiv prevention and treatment was awarded the highest priority among the 40 interventions, being judged to be able to save the most lives at the lowest cost (fig. 1). in june last year, the process was repeated as a ranking exercise among un diplomats from china, india, pakistan, tanzania, thailand, the usa, vietnam and zambia. in a slightly different take on the original task, the ambassadors listened to presentations from experts on each problem and were then confronted with the question: how would you spend p u b l i c h e a l t h p r i o r i t i e s the cost-effectiveness of hiv control: getting the priorities right gesine meyer-rath, md health policy unit, london school of hygiene and tropical medicine, and hiv management cluster, reproductive health and hiv research unit, university of the witwatersrand, johannesburg a growing body of international and local evidence shows that infectious disease control and hiv prevention and treatment are the most efficient ways for governments to spend their money to improve the lot of their citizens, in both developed and developing countries. fig. 1. outcome of ranking exercise during the copenhagen consensus 2004 (for more information see www.copenhagenconsensus.com). project rating challenge opportunity very good 1 diseases control of hiv/aids 2 malnutrition providing micronutrients 3 subsidies and trade trade liberalisation 4 diseases control of malaria good 5 malnutrition development of new agricultural technologies 6 sanitation and small-scale water water technology for livelihoods 7 sanitation and community-managed water water supply and sanitation 8 sanitation and research on water water productivity in food production 9 government lowering the cost of starting a new business fair 10 migration lowering barriers to migration for skilled workers 11 malnutrition improving infant and child nutrition 12 malnutrition reducing the prevalence of low birth weight 13 diseases scaled-up basic health services bad 14 migration guest worker programmes for the unskilled 15 climate optimal carbon tax 16 climate the kyoto protocol 17 climate value-at-risk carbon tax j u n e 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e1 6 us$50 billion to make the world a better place? this time, scaling up basic health services was awarded top priority, with hiv control coming sixth (fig. 2). the results of the copenhagen consensus process mirror the conclusion of the commission for macroeconomics and health, set up by the world health organization in 2001, that ‘as with the economic well-being of individual households, good population health is a critical input into poverty reduction, economic growth, and long-term economic development at the scale of whole societies’.2 as with every other science, many of the results of economic analyses, and the advice to policy-makers based on them, depend on having asked the right question, and pursuing answers with the right tools. the copenhagen consensus process, particularly in its second version, depends extensively on the quality of the evidence presented. in 2004 assessment of interventions against hiv and aids was based, in the absence of large-scale public sector art programmes in lowincome countries, on the hundredfold higher costs of programmes in industrialised countries at that time. despite these much higher costs, art was still highly recommended on the basis of cost-effectiveness alone. from a large body of research in industrialised countries, and increasingly from non-industrialised ones, we know the reasons for the striking cost-effectiveness of art: in delaying the onset of opportunistic infections and the costly hospitalisations they necessitate, art defers resource use and costs for the health system and adds not only length but also quality to a patient's life.3-5 in a cost-effectiveness analysis that takes all three factors into account (costs, life expectancy and quality of life), these benefits are large enough to offset the additional costs of the drugs, and of the systems that have to be put in place to reliably provide them. a number of local economic analyses and modelling exercises has shown that this cost-effectiveness can be achieved in south africa as well. one of these used data on costs and outcomes of art provision at the msf-led hiv clinics in khayelitsha, showing that in this setting providing art was more cost-effective than hiv care without art.6 msf (médecins sans frontières) is a non-governmental organisation dedicated to improving health care and access to essential medicines in emergency and low-income settings. providing art in this setting cost r13.754 per qaly versus r14.189 per qaly for patients who did not receive art, in 2002 south african rands. an analysis of art provision in a standard public-sector clinic would probably yield even more favourable results, as the staffing levels at khayelitsha are higher than in a public sector clinic, and arv drug costs were significantly higher at the time of the study. overall, there is a scarcity of economic analyses of art provision in low-income settings that use data from real-world settings to analyse cost factors and advise on the efficiency of public sector roll-out programmes. in south africa, despite the significant political progress of the last few months and the latest figures for patients initiated on art showing that south africa has the largest art programme in the world in terms of absolute numbers, there remains a need for massive upscaling of art provision this will continue for quite some time – a time in which the deadly toll from aids is set to continue to rise. it is high time for governments to invest accordingly. governments in southern africa need to support the enormous task of providing hiv care financially and politically. the hierarchy of cost-effective interventions noted by the copenhagen consensus can guide governments towards effective spending across all sectors, not just health. for south africa this means maintaining the collaborative spirit shown in setting up the inter-ministerial working committee on hiv and aids and revamping the south african aids council, while continuing to support the efforts of health-care professionals and volunteers who refuse to be intimidated by the enormous scale of the task. after all, a cost-effective medical intervention offers the best of two worlds, saving lives as well as money. references 1. lomborg b. need for economists to set global priorities. nature 2004; 431: 17. 2. commission on macroeconomics and health. macroeconomics and health: investing in health for economic development. geneva: world health organization, 2001 (http://www.who.int/macrohealth/en/). 3. beck e, miners ah, tolley k. the cost of hiv treatment and care. pharmacoecon 2001; 19(1): 13-39, 4. youle m, trueman p, simpson k, et al. health economics in hiv disease: a review of the european literature. pharmacoeconomics 1999; 15(suppl. 1): 1-12. 5. rosen s, long l. how much does it cost to provide antiretroviral therapy for hiv/aids in africa? health and development discussion paper no. 9, center for international health and development, boston university, october 2006. 6. cleary s, boulle a, mcintyre d, coetzee d. cost-effectiveness of antiretroviral treatment for hiv-positive adults in a south african township. cape town: health systems trust, 2004. fig. 2. outcome of ranking exercise during the copenhagen consensus 2006: a united nations perspective (for more information see www.copenhagenconsensus.com). challenge opportunity 1 communicable diseases scaled-up basic health services 2 sanitation and water community-managed water supply and sanitation 3 education physical expansion 4 malnutrition and hunger improving infant and child nutrition 5 malnutrition and hunger investment in technology in developing country agriculture 6 communicable diseases control of hiv/aids 7 communicable diseases control of malaria 8 malnutrition and hunger reducing micronutrient deficiencies 9 subsidies and trade barriers optimistic doha: 50% liberalisation 10 education improve quality/systemic reforms i am grateful to dr catherine mcphail for comments on an earlier draft of this article. abstract introduction south african context as backdrop to the study methods data analysis results of the study discussion conclusion acknowledgements references about the author(s) simon taukeni hiv and aids unit, university of fort hare, south africa ronel ferreira department of educational psychology, university of pretoria, south africa citation taukeni s, ferreira r. hiv and/or aids awareness among adolescents in a south african at-risk rural community. s afr j hiv med. 2016;17(1), a418. http://dx.doi.org/10.4102/sajhivmed.v17i1.418 original research hiv and/or aids awareness among adolescents in a south african at-risk rural community simon taukeni, ronel ferreira received: 16 sept. 2015; accepted: 22 mar. 2016; published: 09 june 2016 copyright: © 2016. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the devastating effects of hiv and/or aids are widely documented. despite ongoing efforts to address the challenges associated with the pandemic, the impact on children orphaned because of the disease, as well as on adolescents, remains problematic. more specifically, orphaned adolescents living in poverty are particularly vulnerable and are often exposed to, for example, emotional and physical abuse and transactional sexual exploitation. against this background, the importance of informed awareness among adolescents is continually emphasised, yet the outcomes of awareness campaigns require ongoing research. objectives: the main objective of this study was to explore hiv and/or aids awareness among adolescents living in a rural community in south africa, in the chris hani district of the eastern cape province. sixteen adolescents (aged 12–24) who had lost one or both of their parents because of hiv and/or aids-related reasons were purposefully selected to participate in the study. method: for this qualitative investigation, we implemented a descriptive case study design. semi-structured individual interviews, observation and field notes were used to collect and document data, and inductive thematic analysis was completed using the software programme atlas.ti 7. results: the three themes that were identified relate to hiv and/or aids awareness, disclosure of parents’ hiv and/or aids status and experiences of adolescents surrounding the death of their parents. adolescents of the community viewed hiv and/or aids as an infectious disease that can lead to death; however, this can be prevented by avoiding at-risk sexual behaviour. schools and family members were the main sources of information regarding hiv and/or aids to the participants. even though parents tended not to disclose their hiv and/or aids status, adolescents became aware of their parents’ status when reading about this on their parents’ medical report cards or when being told about the status by others following the death of their parents. for adolescents, their parents’ deaths were associated with the parents being chronically ill or showing visible signs of deterioration such as weight loss. conclusion: the study concludes that even though current campaigns and informative interventions have seemingly succeeded in ensuring hiv and/or aids awareness among adolescents – also those in remote areas – continued educational campaigns are important. such initiatives may prove to be beneficial by focusing on ways that parents can discuss hiv and/or aids-related issues with their children and disclose an hiv-positive status. introduction unaids1 estimates that about 35 million people were living with hiv and/or aids in 2013, of which 70.6% were situated in sub-saharan africa. in south africa alone, 2.3 million children had been orphaned by aids at the time and around 6.3 million people were living with hiv and/or aids.2 worldwide, many of those affected are women and children. when narrowing the focus to adolescent children and young adults, worldwide figures indicated 10.3 million hiv-positive youth within the age range 15–24.3 in many parts of the globe, young people, particularly adolescents, are at great risk of contracting the virus through sexual activity as well as sexual exploitation and abuse.4 durojaiye5 as well as unaids6 indicate that, worldwide, 45% of people contracting hiv and/or aids are youth aged 15–24 years. this is supported by ebeniro7 and other scholars who found that adolescents aged 15–24 years constitute the largest population of hiv-infected subjects. similarly, avert2 indicates a high hiv prevalence in the age group 15–29. adolescents find themselves in a developmental phase where they search for an identity and are often negatively influenced by their peers. adding poverty and parental sickness, or orphanhood, to the challenges already experienced during adolescence will result in high levels of vulnerability. more specifically, orphaned adolescents living in poverty are particularly at risk of emotional and physical abuse and transactional sexual exploitation.8 south african context as backdrop to the study according to statistics south africa,9 this country accounts for the highest number of people living with hiv and/or aids in the world, currently estimated at 10.2% of the total population. sinelela et al.10 confirm this by very recently stating that: south africa is home to the largest concentration of people living with hiv anywhere in the world; of all the hiv-positive people in the world, nearly one fifth live in south africa. (n.p.) in terms of the rise in numbers, it is rather concerning to note the increase from 4.09 million people living with hiv and/or aids in south africa in 2002 to 5.51 million in 2014.9 the hiv and/or aids pandemic has caused unprecedented suffering and social disruption for children and communities throughout sub-saharan africa.11 even though all children are vulnerable and at risk of contracting hiv, it was, for example, reported in a study by mpanju-shumbusho12 that, in sub-saharan africa, teenage girls’ hiv infection rate is five times higher than the rate of infection among teenage boys. against the background of the challenge of hiv and/or aids encountered by adolescents, it seems vitally important that their awareness of the risks associated with sexual behaviour, and the importance of applying this knowledge to real-life experience, is made clear.13 adolescents (ages 10–19) find themselves in a phase of physical growth and development accompanied by sexual maturation, which often lead to intimate relationships.4 additionally, adolescents orphaned by hiv and/or aids or living with sick parents as a result of the disease, in poor conditions, are specifically vulnerable to transactional sexual exploitation.8 even though the 1998 south african demographic and health survey indicated that awareness and knowledge about hiv and/or aids are high among adolescents in south africa, this has seemingly not translated into substantial behaviour change among adolescents.14 however, south africa has a range of relevant policies and interventions geared towards fighting the hiv and/or aids scourge15 in place. examples of these include the national strategic plan on hiv and/or aids and std 2000–2005, the national strategic plan on hiv and aids and sti 2007–2011, and the current policy of national strategic plan on hiv, stis and tb 2012–2016. these policies are an indication that the south african government and its partners have the intention to address the hiv and/or aids pandemic, despite attempted actions not yet showing results in terms of changed behaviour and a reduction in hiv and/or aids prevalence among this age group. social challenges and the current state of affairs in south africa add to the vulnerability of adolescent children. currently, 53.8% of all south african citizens are considered to live in poverty,16 and the unemployment level is estimated to be 25.5%.17 poverty and high levels of unemployment have resulted in people at the ground level pursuing all possible avenues to survive, even if this may place the well-being of the family and children at risk. it is a common phenomenon that parents seek employment away from home, resulting in a situation where many children reside with relatives or even friends. such living arrangements and the lack of parental involvement intensify the vulnerability of children, more so during the developmental phase of adolescents, when children are in need of the involvement and support of caring adults. in addition to the developmental phase and prominent effect of peer pressure adding to the vulnerability of adolescents not cared for by their parents, social challenges such as abuse, violence and promiscuity in poor communities in south africa add to the challenges these children face. furthermore, the high prevalence of hiv and/or aids and related deaths in south africa have resulted in high numbers of orphaned children – 1.5 million in 2009 and estimated to increase to almost 1.8 million children in 2015.18 these children need to be cared for, or in some cases where parents live with hiv and/or aids, children are expected to take over the role of provision from their parents, in order to support sick parents and siblings to survive.19 the death of parents and migration to other regions in pursuing careers, have also resulted in the phenomenon of child-headed households in south africa. this further intensifies the population of vulnerable and at-risk children (often adolescents) in south africa. against this background, the present study explored the awareness of hiv and/or aids among adolescents whose parents had died of hiv and/or aids, in an at-risk rural community in the chris hani district in the eastern cape of south africa. the rationale for undertaking the study rested on scientific evidence indicating that knowledge about hiv and/or aids is essential for adolescents to be able to make rational decisions regarding sexual behaviour and protecting themselves against hiv infection.20 because there is no cure for aids, prevention remains the only sure way for combating the disease.21 adolescents are often victims of the pandemic, because of reasons such as limited awareness of hiv and/or aids or inadequate access to hiv prevention and treatment services.22 the study could thus add new insights in terms of the effect of such community-based initiatives and preventative campaigns among adolescents in at-risk rural settings. methods study population and sample a qualitative approach was followed and a descriptive case study design employed to conduct the study. the target population comprised all adolescents whose parents had died of hiv and/or aids-related illnesses, who reside in a rural community in the eastern cape province of south africa. this village represents at-risk rural communities in south africa and is characterised by high levels of poverty, hiv and/or aids prevalence and vulnerable children – some because of being orphaned and some as a result of parents not residing with their children. a sample of 16 children (10 boys and 6 girls), aged 11–24 years, were included in the study. selection of participants purposive sampling was used to select the participants. community members played a crucial role in the initial identification of adolescents who could potentially provide rich information on the hiv and/or aids awareness among youth in the specific community. as community members knew the children of the community, they were viewed as important access point and key role-players in the sampling process. the selection criteria that applied stipulated that participants (1) had to be adolescents from a rural community in the eastern cape, (2) had to be between the age of 11 and 24 years, (3) had lost one or both parents because of hiv and/or aids, (4) who were available for participation in the project, and (5) whose caregivers provided informed consent for their participation. adolescents whose parents had died of any disease or event other than hiv and/or aids and children who fell outside the stipulated age range were thus excluded from the study. the participants’ demographics are summarised in table 1. table 1: participants’ demographics in the study. ethical considerations approval to conduct the study was first sought from the university of fort hare, who approved the research proposal and proposed instruments for data collection and documentation. informal meetings with leading people in the study community were held to discuss the research project, proposed time frames, ways of sampling and participation. introduction of both the researcher and assistant researchers was done during these meetings in order to identify and select suitable participants and obtain permission to conduct the research in the seven subdivisions of the village. the headman subsequently provided written permission to the research team. after obtaining permission from the relevant authority figures, written consent was obtained from the caregivers and parents of the adolescent participants. only children with signed consent forms participated in the study. the necessary measures were taken to ensure confidentiality, anonymity, autonomy and respect for privacy.23 in obtaining individual informed consent, participants were informed that the study would include sensitive questions and they were reminded that their participation was voluntary and that they had the right to withdraw from the study at any time without penalty. as the study progressed, caution was taken to identify any child experiencing discomfort or potential emotional harm, yet no such incidences occurred. the research team was, however, prepared to refer any such cases for professional support if these were to occur. data collection and documentation semi-structured individual interviews were conducted with the 16 participants, focusing on their experiences and awareness of the hiv and/or aids pandemic and related issues. interviews lasted an average of 45 minutes each, with no interview being longer than an hour. all interviews were guided by a pre-formulated interview guide. interviews were conducted in isixhosa – the home language of the participants. all interviews were voice recorded and transcribed verbatim following the data collection sessions. two xhosa-speaking ma psychology students from the psychology department of the university of fort hare conducted the interviews and translated the transcripts into english. an independent researcher who served as project supervisor, whose origin is also xhosa, confirmed the back translation as a true reflection of what was said by the participants. observations and interviews were furthermore captured by means of field notes. data analysis inductive thematic analysis was used, which resulted in the identification of three main themes. atlas.ti7 was employed as software programme assisting in the identification of codes and related quotations and memo purposes. atlas.ti7 made the data analysis process easier and more effective. for interpretation of the data, an interpretivist paradigm was adopted.24 as stated, all interviews were transcribed in preparation of the analysis. after completing the transcriptions, data were organised according to a set of questions and responses. the thematic analysis was further used to uncover themes and trends that are similar to ideas and concepts which formed the main themes of the study. results of the study following inductive thematic analysis, three main themes were identified. the first theme relates to participants’ awareness of hiv and/or aids, and the second theme relates to the disclosure of their parents’ status and the third theme relates to their own experiences when their parents passed on. hiv and/or aids awareness results revealed that the majority of the participants were aware of hiv and/or aids and aspects related to the pandemic. awareness centred around three topics, namely that hiv and/or aids can but do not necessarily have to result in death, that it is an infectious disease and that several sources of information could be accessed in the community. firstly, participants indicated an awareness that hiv and/or aids can ‘kill’ and has resulted in the death of many people. this idea is captured in the following contribution: ‘hiv kills, it killed my mother.’ (p06, female, 14 years old) participants, however, also seemed aware that hiv and/or aids does not necessarily have to result in death and that living a positive life is a possibility if one accepts one’s status, as captured in the following extract from the data: ‘when one accepts his or her hiv status, one can live with it.’ (p10, male, 21 years old) secondly, several participants articulated that aids is an infectious disease and can be transmitted. they stated: ‘i heard people saying you must not touch the other person’s blood or you will be infected.’ (p02, male, 13 years old) ‘it is a disease that is sexually transmitted and through body fluids for example blood and semen.’ (p07, female, 20 years old) ‘i know about hiv. one gets it through infected blood and sex.’ (p08, male, 20 years old) in this regard, participants also referred to protection and using contraceptives. they shared the following views: ‘one gets hiv and/or aids by sleeping with someone without a condom and he or she will die.’ (p01, male, 18 years old) ‘i know what hiv and/or aids is, one gets it when the boyfriend has it and has sex without protection.’ (p11, female, 19 years old) next, participants identified the sources where they had learnt about hiv and/or aids, indicating their schools and the local clinic. they commented: ‘i learnt about hiv from my teacher at school.’ (p02, male, 13 years old) ‘i learnt about hiv from school through class discussion and my friends.’ (p08, male, 20 years old) ‘at school in the life orientation subject and nurses visited our school and taught us about hiv.’ (p11, female, 19 years old) ‘i learnt it from school and clinic when i tested for it.’ (p03 [hiv-positive], female, 23 years old) some participants also shared how experience with their own family members served as a source of knowledge to them: ‘i saw it from my father.’ (p05, female, 17 years old) ‘i learned about hiv from my grandmother.’ (p06, female, 14 years old) despite the majority of the participants indicating awareness of hiv and/or aids, a few participants revealed not knowing enough: ‘i do not know much, all i know i used to have it but not anymore. i was given a treatment that healed me.’ (p04, female, 12 years old) quite surprisingly, two participants apparently had no knowledge on the pandemic, saying: ‘nothing, i have never heard about it.’ (p12, male, 12 years old) ‘i don’t know anything. i have not paid attention to it as far as information is concerned.’ (p15, male, 16 years old) disclosure of parents’ hiv and/or aids status as part of the study, it was investigated whether participants had knowledge on the hiv status of their parents and how they came to learn about it. participants expressed different views on this, with some of them merely becoming aware that their parents were sick: ‘my mother got sick but i did not know with what, her feet were swollen.’ (p02, male, 13 years old) ‘no, i did not know, he just said to me he was having chest pains.’ (p04, female, 12 years old) unsurprisingly, some of the parents reportedly did not want their children to know about their hiv status, with the participants only realising this after their parents had passed away. the following examples apply: ‘she was hiding her status from me but her boyfriend told me after the funeral.’ (p03, female, 23 years old) ‘no, i only knew after my father died.’ (p08, male, 20 years old) some of the participating adolescents indicated that they read their parents’ medical cards and then realised their hiv and/or aids status. one participant reported: ‘i knew because i saw my father’s clinic card and he developed a rash and sores. i had a picture of him sick in hospital.’ (p05, female, 17 years old) in some other cases, grandparents informed the participants, for example: ‘yes my grandmother told me about my mother’s status.’ (p06, female, 14 years old) ‘i knew that she was hiv-positive. my grandmother told me when she was seriously ill.’ (p07, female, 20 years old) in some cases, however, participants reported that they did not have any knowledge of their parents’ hiv and/or aids status. the following excerpts provide examples: ‘i did not have any idea whether they had hiv and/or aids or not. both my parents were sick but i did not know what was wrong with them.’(p15, male, 16 years old) ‘i did not know i was only two years when they died.’ (p16, male, 12 years old) experiences of parents’ deaths the majority of the participants associated their own recollections of their parents’ deaths with a distinct awareness of their parents constantly being sick and in pain. they shared the following experiences: ‘my mother was always sickly until she died. i was not staying with her so i could not know how she looked like.’ (p03, female, 23 years old) ‘he was in pain all the time. very weak. i was consistently worried about him.’ (p04, female, 12 years old) ‘i remember him being sick until he died.’ (p05, female, 17 years old) when sharing their observations of their parents being chronically ill, participants also indicated concern on their side both prior to and following the death of their parents, as captured in the following contribution: ‘my father was always sick and going to the clinic and taking pills. i was really worried before he died. when he died, life was hard, we could not get everything we wanted by the time we wanted it.’ (p08, male, 20 years old) in addition to their parents being sick, participants reportedly noticed physical signs and symptoms associated with aids and aids-related deaths. the namely mentioned weight loss and noticeable pimples on their parents’ bodies, reporting as follows: ‘my mother was epileptic. she became sick with unknown sickness and she lost her weight.’ (p06, female, 14 years old) ‘she lost so much weight she had pimples all over her body and she was coughing severely.’ (p07, female, 20 years old) ‘my father had shingils and was unable to do anything for himself. my mother looked fine because she was doing everything for us. there were no visible symptoms.’ (p15, male, 16 years old) a few participants could, however, not recall anything about their parents’ deaths primarily because they were still young at the time of death. one participant for example said: ‘i did not remember well because they died while i was very young.’ (p01, male, 18 years old) discussion in terms of hiv and/or aids awareness, the adolescents in this at-risk rural community showed some insight into the fact that hiv and/or aids is an infectious transmittable disease that can cause death but can also be prevented. a study by oyo-ita et al.,25 which aimed to establish the impact of hiv and/or aids awareness programmes among secondary school adolescents in nigeria, indicates similar findings, with the majority (90%) of the participants in that study knowing that hiv and/or aids can be transmitted through sexual intercourse. surprisingly though, some participants indicated that they were not aware of hiv and/or aids or specific information related to the pandemic. this apparent lack of awareness is most probably rather an indication of denial among some adolescents in the community, to possible reasons such as them not having dealt with the death of their parents, or fearing their own hiv and/or aids status. this is a mere hypothesis that requires further investigation; however, against the background of hiv and/or aids information being frequently reported in the mass media,26 the chances of adolescents having no knowledge on the topic seem rather slim. in their study, oyo-ita et al.25 indicate television and the radio as primary sources of information on hiv and/or aids. even though these authors propose follow-up, the information sessions by, for example, teachers and/or parents, basic information is seemingly conveyed via mass media, also in far-off remote and rural communities. detailed information seems to be limited to only a percentage of children, as indicated by oyo-ita et al.25 who found that only 22.6% of adolescents receive information from teachers and 2.2% receive information from parents. the current study established that the majority of the participants in this study possess accurate knowledge on hiv and/or aids prevention and infection. these findings are supported by singh and jain20 who also indicate that a large number of adolescents know that hiv and/or aids is preventable, by, for example, abstaining from sexual relationships, or having a single, uninfected and faithful partner.20 other studies similarly indicate that the majority of adolescents possess the correct knowledge about hiv and/or aids.27 in a recent study by mwamwenda21 that assessed the level of hiv and/or aids knowledge of high school adolescents in kenyait, it was concluded that, even though the level of hiv and/or aids knowledge was high, some misconceptions existed, which would justify the continued promotion of public education regarding hiv and/or aids. the study furthermore showed that public education does produce dividends in the prevention of hiv and/or aids transmission and the spread of the pandemic.21 the finding that some of the participants in the current study (however limited) showed a lack of awareness of hiv and/or aids emphasises the need for re-enforced school hiv and/or aids education. in addition, adolescents – especially orphaned adolescents living in poor communities – should receive life skills training. by equipping vulnerable adolescents with basic skills such as problem-solving skills, conflict management techniques, self-awareness and self-protection, goal setting and career planning, they may be empowered to protect themselves from being exploited or harmed. in this way, the danger of transactional sexual exploitation and abuse may be combated. at present, south african children receive life skill training as part of the national curriculum; however, the need for practical skills application remains. even though teachers play a pivotal role in imparting knowledge, the use of multi-pronged methods, such as films, group discussions, dramas, puppet shows and role plays, can also be incorporated with success, as proven by harvey et al.28 it is, however, also important to provide the necessary resources to sustain such programmes or interventions and to obtain more evidence on the effect on behaviour, by, for example, determining changes in behaviour and hiv and/or aids incidence following such interventions.28 the current study furthermore indicates that parents who died of aids or hiv and/or aids-related illnesses tend not to disclose their status to their children despite adolescents becoming aware of the status of their parents through different sources. this finding is supported by naswa and marfatia,3 who found that disclosure of hiv and/or aids is associated with multifaceted challenges. as adolescence implies emotional vulnerability, the way in which children from this age group will respond to a disease status can never be predicted. key considerations mentioned by the who29 relate to stigma being a major barrier to parents or caregivers disclosing their hiv and/or aids status to their children, fearing that children may be stigmatised. furthermore, the manner in which disclosure takes place varies from culture to culture and from place to place, depending on available resources and caregivers’ desires and concerns.29 the decision to disclose to children involves weighing the pros and cons of disclosing against one another. delaney et al.30 assert that this decision is often based on the child’s perceived ability to handle the information without being psychologically harmed. another alternative relates to people potentially fearing that disclosure could disrupt their current or future relationships.31 disclosure may thus be avoided if people fear abandonment, rejection, discrimination or upsetting family members. as such, parent’s disclosure of his or her hiv and/or aids status to children may potentially affect the child’s adjustment or the parent–child relationship. even if children are not informed of the status of their parents, they may, however, intuitively know that something is wrong with their parents or even notice them taking medication. the current study confirms this possibility as some children became aware of their parents’ hiv and/or aids status when seeing their parents’ medical clinic cards or through observation of physical symptoms such as their parents’ loss of weight and the presence of pimples. despite murphy et al.32 observing that parents often choose not to disclose to their children in order to avoid negative responses, research shows (dane cited in qiao et al.33 dolly and dillon cited in armistead et al.34 and murphy et al.35) that there are many benefits when children are aware of their parents’ hiv status. even though participating adolescents in the current study were not directly asked about this, it appeared as if they wished that their parents had made them aware of their illness before they passed away. murphy et al.32 confirm that children may initially respond negatively to disclosure, but that parents and healthcare providers can guide children to accept such a diagnosis by validating their emotional responses, clarifying any misperceptions about the disease and providing emotional support. it should be noted, however, that the findings of this study do not imply that parents who had died of hiv and/or aids-related illnesses never disclosed their hiv and/or aids status to anybody, as this was not explored. in their study, ramdas et al.36 found that, according to patients’ records, most patients (90.7%, n = 54) disclosed their hiv and/or aids status. women prefer to disclose to relatives (82.1%, >n> = 28) rather than to partners (28.6%, n = 28). a few participating adolescents in the current study also revealed that relatives (grandmothers) and partners of their parents informed them about the hiv and/or aids status of their parents after they had died. conclusion this study shows that the majority of adolescents in at-risk rural community in south africa are knowledgeable about hiv and/or aids infection and prevention, thereby confirming related studies in this field. even though preventative and informative-focused interventions and campaigns therefore seem to reach far-off rural communities, whether through mass media or other avenues, it is also argued that continued educational campaigns are required, for example, to also guide parents in terms of discussions on hiv and/or aids with their children, including discussions of their own status. recommendations can furthermore include information on disclosure of hiv and/or aids status in ways and by people that can potentially reduce the possibility of stigma and discrimination. community health workers, nurses, social workers and counsellors can fulfil supporting roles in enhancing parents’ and caregivers’ skills to communicate about hiv and/or aids with children. more intervention is furthermore needed to address stigma and discrimination against people living with hiv and/or aids and their families. this need for change has been an ongoing priority in research on hiv and/or aids37 and remains to require urgent attention. acknowledgements this study was supported by the faculty of health sciences of the university of fort hare in terms of transport during data collection period. competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions s.t. made conceptual contribution including project instruments, data collection and analysis. r.f. was responsible for project design, presentation of results, implications and conclusion. references unaids. unaids global statistics report [homepage on the internet]. c2015 [cited 2015 nov 11]. available from http://www.unaids.org/sites/default/files/en/media/unaids/contentassets/documents/factsheet/2014 avert. averting hiv and aids: hiv and aids in south africa [homepage on the internet]. c2013 [cited 2015 feb 20]. available from http://www.avert.org/professionals/hiv-around-world/sub-saharan-africa/south-africa naswa s, marfatia s. adolescent hiv and/or aids: issues and challenges. indian j sex transm dis. 2010;31:1–10. http://dx.doi.org/10.4103/0253-7184.68993 betancourt t, meyers-ohki s, charrow a, hansen n. mental health and resilience in hiv and/or aids-affected children: a review of the literature and recommendations for future research. j child psycho psychiatry. 2013;54(4):423–444. http://dx.doi.org/10.1111/j.1469-7610.2012.02613.x durojaiye co. knowledge, perception and behaviour of nigerian youths on hiv and/or aids. internet j health. 2009;9(1). unaids. report on the 2008 global epidemic. geneva: joint united nations programme on hiv and aids; 2008. ebeniro cd. knowledge and beliefs about hiv and/or aids among male and female students of nigerian universities. j comp res anthropol sociol. 2010;1(1):121–131. cluver l, orkin m, boyes m, gardner f, meinck f. transactional sex amongst aids-orphaned and aids-affected adolescents predicted by abuse and extreme poverty. j acquir immune defic syndr. 2011;58(3):336–343. http://dx.doi.org/10.1097/qai.0b013e31822f0d82 statistics south africa. statistical release po302. pretoria: statistics south africa; 2014. sinelela n, venter fwd, pillay y, baron p. a political and social history of hiv in south africa. new york: springer: 2015. brown l, rice j, neil b, et al. psychosocial benefits of a mentoring program for youth-headed households in rwanda. horizons research summary, washington, dc: population council; 2007. mpanju-shumbusho w. a historic overview of the progression of hiv and/or aids epidemic in ssa and its impact on women and children. conference paper presented at nih in botswana, gaborone, march; 2001. njogu w, martin tc. the persisting gap between hiv and/or aids knowledge and perception among kenyan youth. genus. 2003;62(2):135–168. hartell cg. hiv and/or aids in south africa: a review of sexual behavior among adolescents. adolescence. 2005;40:171–181. unaids. report on the 2006 global aids epidemic. geneva: joint united nations programme on hiv and aids; 2006. statistics south africa. methodological report on rebasing of national poverty lines and development on pilot provincial poverty lines. pretoria: statistics south africa; 2015. statistics south africa. report po211, quarterly labour force survey, september 2015. pretoria: statistics south africa; 2015. proudlock p. the case of child ss and 1.1 million others like him – orphan children in need of social assistance. paper presented at the “towards carnegie3: strategies to overcome poverty & inequality” conference, 2012 sep 3–7; cape town, south africa; 2012. benton td, lachman a, seedat s. hiv and/or aids. addressing the mental health needs of affected children and families. in: rey jm, editor. iacapap e-textbook of child and adolescent mental health. geneva: international association for child and adolescent psychiatry and allied professions; 2013. singh a, jain s. awareness of hiv and/or aids among school adolescents in banaskantha district of gujarat. health popul perspect issues. 2009;32(2):59–65. mwamwenda ts. hiv and/or aids knowledge of high school adolescents in kenya. j aids hiv res. 2013;5(12):472–478. srivastava a, mahmood se, mishra p, shrotriya vp, iram shaifali i. adolescence awareness: a better tool to combat hiv and/or aids. natl j community med. 2011;2(1):85–90. kaiser k. protecting respondent confidentiality in qualitative research. qual health res. 2009;19(11):1632–1641. http://dx.doi.org/10.1177/1049732309350879 thanh nc, thanh tt. the interconnection between interpretivist paradigm and qualitative methods in education. am j educ stu. 2015;1(2):24–27. oyo-ita ae, ikpeme bm, etokidem aj, offor jb, okokon eo, etuk sj. knowledge of hiv and/or aids among secondary school adolescents in calabar-nigeria. ann afr med. 2005;4(1):2–6. anochie ic, ikpeme ee. prevalence of sexual activity and outcome among female secondary school students in port hartcourt, nigeria. afr j reprod health. 2001;5:63–67. http://dx.doi.org/10.2307/3583431 sathe ag, sathe s. knowledge, behaviour and attitudes about sexuality amongst adolescents in pune: a situational analysis. indian j fam wel. 2005;51(1):49–60. harvey b, stuart j, swan t. evaluation of a drama-in-education program to increase aids awareness in south african high schools: a randomized intervention trial. int j std aids. 2000;11(2):105–111. http://dx.doi.org/10.1258/0956462001915453 who. guideline on hiv disclosure counselling for children up to 12 years of age. geneva: who press; 2011. delaney ro, serovich jm, lim jy. reasons for and against maternal hiv disclosure to children and perceived child reaction. aids care. 2008;20(7):875–880. who. gender dimensions of hiv status disclosure to sexual partners: rates, barriers and outcomes. geneva: who; 2004. murphy da, austin el, greenwell. correlates of hiv-related stigma among hiv-positive mothers and their uninfected adolescent children. women health. 2006;44(3):19–42. http://dx.doi.org/10.1300/j013v44n03_02 qiao s, li x, stanton b. theoretical models of parental hiv disclosure: a critical review. aids care. 2013;25(3):326–336. armistead l, tannenbaum l, forehand r, morse e, morse p. disclosing hiv status: are mothers telling their children? j paediatr psych. 2001;26(1):11–20. http://dx.doi.org/10.1093/jpepsy/26.1.11 murphy da, roberts kj, hoffmann d. regrets and advice from mothers who have disclosed their hiv-positive serostatus to their young children. j child fam stud. 2003;12:307–318. http://dx.doi.org/10.1023/a:1023939827449 ramdas n, meyer cj, cameron d. factors associated with retention in hiv care at sediba hope medical centre. south afr hiv med. 2015;16:1. http://dx.doi.org/10.4102/hivmed.v16i1.347 xu t, yan z, rou k, wang c, ye r, duan s, wu z. disclosure of parental hiv and/or aids to children in rural china. vulnerable child youth stud. 2007;2(2):100–105. http://dx.doi.org/10.1080/17450120701335791 make up march 2007 55 it is with more than a twinge of nostalgia that i write this editorial for journal 26. the first issue of the journal of hiv medicine was distributed at the internal aids society conference, durban 2000. this issue will be distributed at the national aids conference, durban 2007. once again there is a wide variety of articles spanning epidemiology, guidelines and clinical case studies. i am happy in the knowledge that the journal has found a place on the desks and in the hearts of practitioners in our region. it has i believe, achieved, a unique branding, look and feel. i am standing down as editor with this edition, but i am secure in the knowledge that the journal will continue to flourish in the very capable hands of the new editor, professor linda-gail bekker. i wish her and her editorial team the very best for the future. des martin editor from the editor it’s been a topsy-turvy few months in the hiv prevention world. two major circumcision trials were interrupted because the benefit of male circumcision was so marked. at the same time, two microbicide trials were stopped, one because of a low hiv incidence rate, making the trial impossible to complete, and another more recently that suggested no benefit from microbicides, and possibly even harm. the media storm over the ending of the microbicides trials is unfortunate, as the news reports referred to ‘guinea pigs’ and poor oversight, though there was no real proof of any wrongdoing by the scientists. all this is very frustrating, leaving clinicians and public health policy makers with very few biological interventions to prevent hiv. mother-to-child prevention works well but is poorly implemented, ditto for postexposure prophylaxis for sexual assault; condoms work if used consistently, but very few people use them consistently; and circumcision is still trying to find its place. a useable vaccine looks years away. luckily, a novel microbicide made of seaweed (!) is being tested in phase three trials, and results are expected by the end of the year. in the wake of the microbicide criticism in some of the media, we must continue to insist on rigorous clinical trials. our countries have been under siege by nonscientific quacks and opportunists for too long to retreat from good science. francois venter president m e s s a g e f r o m t h e e x e c u t i v e t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e m a r c h 2 0 0 7 make up march 2007 30/3/07 11:26 am page 5 article information author: max kroon1 affiliation: 1division of neonatal medicine, department of paediatrics, university of cape town, south africa correspondence to: max kroon email: max.kroon@westerncape.gov.za postal address: highkloof, 8 timberlost lane, hout bay 7806, south africa dates: received: 23 jan. 2015 accepted: 05 mar. 2015 published: 20 may 2015 how to cite this article: kroon m. recognising and managing increased hiv transmission risk in newborns. s afr j hiv med. 2015;16(1), art. #371, 7 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.371 copyright notice: © 2015. the authors. licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. recognising and managing increased hiv transmission risk in newborns in this forum... open access • abstract • introduction • quantifying risk    • maternal factors    • infant factors • post-exposure prophylaxis reduces transmission risk • post-exposure combination antiretroviral therapy reduces transmission risk in increased-risk situations • post-exposure combination antiretroviral therapy options and recommendation for south africa • conclusion • acknowledgements    • competing interests • references • appendix 1: recognising and managing increased hiv transmission risk in newborns abstract top ↑ prevention of mother-to-child transmission (pmtct) programmes have improved maternal health outcomes and reduced the incidence of paediatric hiv, resulting in improved child health and survival. nevertheless, high-risk vertical exposures remain common and are responsible for a high proportion of transmissions. in the absence of antiretrovirals (arvs), an 8to 12-hour labour has approximately the same 15% risk of transmission as 18 months of mixed feeding. the intensity of transmission risk is highest during labour and delivery; however, the brevity of this intra-partum period lends itself to post-exposure interventions to reduce such risk. there is good evidence that infant post-exposure prophylaxis (pep) reduces intra-partum transmission even in the absence of maternal prophylaxis. recent reports suggest that infant combination arv prophylaxis (carp) is more efficient at reducing intra-partum transmission than a single agent in situations of minimal pre-labour prophylaxis. guidelines from the developed world have incorporated infant carp for increased-risk scenarios. in contrast, recent guidelines for low-resource settings have rightfully focused on reducing postnatal transmission to preserve the benefits of breastfeeding, but have largely ignored the potential of augmented infant pep for reducing intra-partum transmissions. minimal pre-labour prophylaxis, poor adherence in the month prior to delivery, elevated maternal viral load at delivery, spontaneous preterm labour with prolonged rupture of membranes and chorioamnionitis are simple clinical criteria that identify increased intra-partum transmission risk. in these increased-risk scenarios, transmission frequency may be halved by combining nevirapine and zidovudine as a form of boosted infant pep. this strategy may be important to reduce intra-partum transmissions when pmtct is suboptimal. introduction top ↑ in south africa, prevention of mother-to-child transmission (pmtct) programmes have been very successful in reducing the vertical transmission of hiv, with resultant gains in maternal, infant and child health and survival.1,2 complete elimination of mother-to-child transmission (mtct) remains elusive, primarily because of incomplete programme uptake – owing to suboptimal patient care-seeking behaviour and inadequate health care access – but also because no current antiretroviral therapy (art) regimen, even when started early in pregnancy, is 100% effective in preventing transmission. maternal treatment failure resulting from inadequate adherence or drug resistance may also compromise pmtct programme efficacy. in high-prevalence populations and serodiscordant partners, primary hiv infection in pregnancy (and breastfeeding), after initial negative hiv screening, may contribute disproportionately to transmission.3 delayed art initiation and apparent incident infection may also be a consequence of false-negative initial testing, owing to procedural and quality issues with rapid antibody screening tests. finally, resistance to non-nucleoside reverse transcriptase inhibitors (nnrtis) may compromise the efficacy of infant post-exposure nevirapine (nvp) ‘mono-prophylaxis’. although further gains are possible by improving programme coverage and uptake (and this should be encouraged), high-risk vertical exposures at birth remain common and are responsible for a high proportion of transmissions. recognition of increased-risk scenarios, enhanced labour management (including intra-partum antiretrovirals [arvs] and caesarean section before labour), infant post-exposure combination arv prophylaxis (carp) and a more aggressive testing schedule may all reduce transmission risk and improve the linkage of hiv-infected infants to definitive management. whilst it is also important for increased risk to be recognised and managed in pregnancy and labour, it is beyond the scope of this article to review obstetric management. in the developing world, as capacity has grown, pmtct programmes have evolved from simple, single-dose infant and maternal mono-prophylaxis, focused on intra-partum risk through targeted maternal combination art (cart), to the universal, lifelong ‘treatment-as-prophylaxis’ defined by the 2013 world health organization (who) guidelines. each step in this evolution has resulted in progressive reductions in vertical transmission and improvements in maternal care. infant prophylaxis has grown from post-exposure prophylaxis (pep) for intra-partum risk to include post-partum peri-exposure prophylaxis (peep) intended to render breastfeeding safer. in the developing world, with the focus on reducing transmission during breastfeeding, little consideration has been given to quantification of the intra-partum risk or to boosting infant pep for increased intra-partum risk scenarios. in contrast, developed-world pmtct guidelines routinely quantify intra-partum risk and recommend boosted infant pep for increased-risk scenarios. in the event of no or minimal pre-labour prophylaxis, national institutes of health guidelines recommend the addition of 3 doses of infant nvp in the first week of life to the standard 6 weeks of infant zidovudine (azt).4 british hiv association (bhiva) guidelines recommend triple arv prophylaxis for infants when the maternal viral load (vl) is > 50 copies/ml, and only recommend azt mono-therapy if the maternal vl is fully suppressed from 36 weeks’ gestation.5 both guidelines acknowledge a growing body of expert opinion that the benefits of infant post-exposure carp exceed its risks when transmission risk is increased. ironically, pre-2010 south african guidelines provided for routine infant dual prophylaxis with single-dose nvp (sdnvp) and one week of azt, and infants whose mothers had less than 4 weeks of pre-labour prophylaxis were assigned to sdnvp and 4 weeks of azt.6 this policy incorporated an element of risk recognition and response and was based on findings of the ‘thai long-short, short-long’ and nvaz studies.7,8 quantifying risk top ↑ cart initiated early in pregnancy, with a resultant suppressed vl, and avoidance of breastfeeding virtually eliminate vertical transmission. however, even in the developed world, transmissions occur because of suboptimal antenatal care, failure of maternal and infant prophylaxis and primary hiv infection in pregnancy. these factors argue for an augmented approach to infant management in such increased-risk settings. consequently, guidelines emanating from the developed world have incorporated elements of risk assessment and response. in the absence of arvs, hiv transmission rates are approximately 5% – 10% during pregnancy, 10% – 20% during the intra-partum period, and 10% – 20% during extended mixed breastfeeding.9 whilst transmission is minimal in early pregnancy, the frequency of infection increases significantly in the third trimester towards term, and peaks at 10% – 20% during the 8–12 hours of labour and delivery, making the latter the most intense risk period.10 the intensity of risk is very low throughout breastfeeding, but the cumulative risk over time may be high. factors strongly associated with increased transmission risk are: high maternal vl, low maternal cd4 count, the absence of maternal art, and preterm labour with prolonged rupture of membranes.11 whilst the first three factors are associated with increased transmission in all risk periods, preterm labour, especially with prolonged rupture of membranes, appears only to increase intra-partum transmission risk. the women and infant transmission study (wits) found intra-partum transmission to be associated significantly with a lack of art, an increased vl, a low cd4 percentage, young gestational age, low birth weight (lbw), prolonged rupture of membranes and hard drug use. overall transmission, particularly the intra-partum proportion, has declined significantly over time, reflecting the success of peri-partum maternal interventions and infant pep.12 consequently, the proportion of in utero transmissions is higher. in south africa, the proportion owing to transmission during breastfeeding remains uncertain, as the uptake and duration of breastfeeding are unknown, and long-term follow-up to ascertain postnatal transmission rates has been difficult to achieve. intensity of risk varies during pregnancy and breastfeeding according to the timing of art initiation, the duration of art and the impact on vl by the time of delivery and breastfeeding. for example, a woman who is newly diagnosed immediately after delivery will be at high risk for transmission in the antenatal and intra-partum periods and will have some risk during early breastfeeding until maternal cart takes effect. in this scenario, infant arv prophylaxis is critical for reducing transmission during labour and delivery, and exclusive breastfeeding, maternal cart and infant peep are vital for risk reduction in the first 3 months of breastfeeding. heat-treatment of breast milk until an adequate duration of maternal cart or viral suppression has been achieved is an option to eliminate breastfeeding transmission risk entirely. this is especially important to preserve breastfeeding as an option for preterm/lbw infants who are more likely to experience serious adverse events in the first 6 months of life if replacement fed, even if not hiv exposed.13 in contrast, a woman who initiates art from 34 weeks’ gestation, has good adherence, is virally suppressed and delivers at 40 weeks’ gestation will have some risk of transmission during pregnancy, but very little risk during labour and breastfeeding. whilst a polymerase chain reaction (pcr) test at birth is indicated to detect pre-labour transmissions, infant carp does not add much benefit and there is no real benefit in extending pep beyond 6 weeks. it would be wrong to recommend replacement feeding in this case, unless the conditions for safe formula feeding were met. it is difficult to incorporate this degree of risk assessment nuance into pmtct programmes, and it may be better to have a binary approach where any non-low-risk scenario, irrespective of risk period, attracts an enhanced response for intra-partum management, infant testing and carp. the introduction of universal pcr testing at birth would simplify the issue and allow the focus to be solely on flagging increased intra-partum risk exposures for infant carp. the definition of ’non-low risk’ and extent of the response will need to be balanced against its cost and available resources. if this approach is adopted, then it is important to guard against the perception that all non-low-risk infants should avoid breastfeeding. many infants in this category are at particularly high risk of formula-feeding-related morbidity and mortality; therefore, exclusive breastfeeding should be encouraged unless the criteria for safe replacement feeding are met. the community living with hiv has had significant exposure to nnrtis as part of first-line treatment and as single doses administered during labour. nnrti resistance develops rapidly after limited exposure, requiring only a single base pair mutation, and vertical transmission of resistant virus has been described.14,15 primary and acquired resistance is not uncommon and, when nnrti resistance is likely, it seems unwise to rely on nvp mono-therapy for infant pep when intra-partum risk is increased, even if the mechanism of prophylaxis is different to that of treatment. in contrast, azt resistance requires numerous mutations and takes longer to develop. therefore, azt is important to enhance infant pep in order to reduce intra-partum transmission risk when maternal virus is likely to be nnrti resistant. nnrti resistance is likely in women who are failing, or have failed, first-line art, or are on secondor third-line regimens. in such circumstances, it seems logical, at least, to combine infant nvp with azt if the maternal vl is not suppressed by delivery. the 2013 south african paediatric standard treatment guidelines recommend expert consultation if resistance is possible, but do not provide advice on reducing the peak risk during labour and delivery with boosted infant pep.16 the following factors are likely to increase vertical transmission risk: maternal factors duration of maternal art < 8 weeks (especially if no pre-labour art) maternal vl > 1000 copies/ml close to term (not always available) maternal viral rebound (treatment interruption, poor adherence, true resistance) maternal co-morbidity (tb, opportunistic infections, chorioamnionitis) incident infection (initial hiv test negative, subsequently tests positive) likely nnrti resistance (second-line art, failing first-line art; several sdnvp previously) adolescent pregnancy (recent/incident/vertically trans­mitted infection, more likely to have problems with follow-up) maternal substance abuse (alcohol or drugs). infant factors symptomatic (severe growth restriction, lymphadenopathy, hepatosplenomegaly, thrombocytopaenia, pancytopaenia, congenital cytomegalovirus, congenital syphilis, neonatal tuberculosis) preterm delivery (regardless of cause) and/or lbw infants (< 2500 g; < 37 weeks‘ gestation) abandoned infants (if alere determine or enzyme-linked immunosorbent assay [elisa] positive). pcr testing soon after birth will identify infants infected in utero, facilitate linkage to definitive care and, hopefully, reduce early mortality. those not infected in utero will, in many instances, also have an increased intra-partum transmission risk and may benefit from enhanced infant pep. in contrast to the peak risk intensity in labour and delivery, transmission risk intensity per breastfeeding session is extremely low but, owing to a relatively high cumulative risk over time, tends to be overstated. therefore, the need for enhanced infant peep for breast milk exposure is less urgent than pep for high-risk intra-partum exposure, and the cornerstone of risk reduction in this period remains the urgent optimisation of maternal cart. there is currently no evidence that infant carp reduces breastfeeding transmission. post-exposure prophylaxis reduces transmission risk top ↑ arv pep, soon after hiv exposure in various settings, is well established as routine management to prevent transmission: in 1997 a case-control study reported that post-exposure azt mono-prophylaxis reduces transmission in occupational exposures.17 since then, post-exposure carp has become the standard of care for occupational exposures. without prophylaxis, the risk of hiv infection from a penetrating injury with an hiv-contaminated needle is estimated at 0.3% compared with an estimated 15% vertical transmission risk in labour. post-exposure carp is established as the standard of care after sexual assault and after inadvertent exposure of an infant to another mother's hiv-infected breast milk. according to wade et al. in 1998, when azt was started before 48 hours of life for pmtct, transmission was 9.3% (4.1% – 17.5%) and, when started on day 3 of life or later, it was 18.4%. transmission was 26.6% (21.1% – 32.7%) in the absence of azt.18 a study of hiv-exposed, formula-fed infants whose mothers received no prophylaxis before delivery reported that infant sdnvp or 6 weeks of azt were equally efficient at reducing vertical transmission. at 6 weeks, transmission was 5.3% with sdnvp and 6.4% with azt – both considerably less than anticipated without prophylaxis.19 infant prophylaxis probably contributes little to reducing transmission risk when maternal cart is started early and viral suppression is optimal by the last weeks of pregnancy. extended or augmented infant pep cannot compensate for suboptimal antenatal prophylaxis, and early maternal art with vl suppression remains critical to prevent transmission at all times. ideally, patients with an increased risk of intra-partum transmission should be flagged for possible elective caesarean section to avoid intra-partum exposure. when maternal prophylaxis is suboptimal, the intra-partum risk peak is a critical opportunity for intervention and, importantly, its relative brevity makes it amenable to infant pep. in non-breastfeeding settings, infant pep targets intra-partum risk alone and is the key intervention for reducing intra-partum transmission when there has been no pre-delivery prophylaxis. in breastfeeding settings, infant carp must include an arv that reduces breast milk transmission risk (peep) as well. infant azt treatment has not been shown to be effective in this regard. pep is usually only effective if initiated within 48–72 hours of delivery. infant pep is not effective in reducing in utero transmission, but should be commenced as soon as possible after birth to reduce intra-partum transmission. in most situations, pep duration is typically 4 weeks but, in the context of pmtct, azt for 6 weeks was established as standard by the pactg 076 study.20 in non-breastfeeding settings, there is no real evidence that azt pep for 6 weeks is superior to 4 weeks, and the shorter option may be associated with a lower incidence of anaemia and neutropaenia. pundits for the longer course cite slow decay of transferred intracellular maternal virus as a reason for extending infant pep. post-exposure combination antiretroviral therapy reduces transmission risk in increased-risk situations top ↑ outside of pmtct settings, exposures of considerably lower risk (occupational, sexual assault and inadvertent breastmilk exposures) routinely attract carp. whilst infant carp for increased-risk mtct scenarios is routine in the developed world, little consideration has been given to boosting infant pep to prevent vertical transmission in the developing world. if viral suppression by the onset of labour is suboptimal, the risk of intra-partum transmission is increased, and the relatively short duration of labour and delivery makes infant carp an option for reducing transmissions. whilst data to support this approach are limited, there is some direct evidence that infant carp is more effective than a single agent: in infants where maternal pre-labour arvs were absent or minimal, the addition of 3 doses of infant nvp to the standard 6 weeks of azt reduced intra-partum transmission from 4.8% (confidence interval [ci] = 3.2–7.1) to 2.2% (ci = 1.2–3.9; p = 0.046).21 a study in malawi by taha et al. reported that the addition of 1 week of azt to sdnvp reduced intra-partum transmission from 12.1% to 7.7% (p = 0.03).22 post-exposure combination antiretroviral therapy options and recommendation for south africa top ↑ there are two main potential benefits of carp: reduced intra-partum transmission prophylaxis as very early treatment of hiv-infected infants while awaiting pcr results. a potential disadvantage is consequent difficulty in confirming infection owing to the effect on vl, but this is already an issue with extended nvp mono-therapy in infants. a higher rate of anaemia owing to extended infant azt argues for restricting the azt component to 4 weeks. selection of appropriate arvs for combination prophylaxis is problematic as there are limited pharmacokinetic, safety and efficacy data for the use of many agents in the neonatal period, and more so in combination and with preterm babies. whilst the imperative of early treatment justifies the use of some of these agents in neonatal cart for newborns infected in utero, it is more difficult to justify their use as carp in hiv-exposed neonates who, for the most part, remain uninfected. the 2008 south african pmtct programme recommended sdnvp and azt extended to 1 or 4 weeks. since 2010, extended infant daily nvp up to 12 months has been used as pep and breastfeeding prophylaxis. azt, lamivudine (3tc) and nvp as infant prophylaxis are the most used and studied agents globally. there are good study data on the safety and efficacy of these agents as part of comprehensive pmtct regimens.23,24,25 bhiva guidelines recommend these three drugs in combination for infant pep when transmission risk is not minimal. if drug resistance is likely, consideration needs to be given to other agents not usually used for infant pep, and then only under expert guidance and preferably with resistance genotyping.26 lopinavir/ritonavir (lpv/r) has been associated with very significant toxicity and is not recommended for use before 42 weeks’ corrected gestational age, limiting its usefulness as an option in carp.27 where multidrug resistance is identified by maternal virus genotyping prior to delivery, serious consideration may need to be given to lpv/r use as infant carp, but then only in a strictly controlled environment. as extended infant nvp facilitates safer breastfeeding by hiv-infected infants, it makes sense to retain nvp as the core of infant prophylaxis and add 4 or 6 weeks of azt and possibly 3tc. there is no evidence that extending azt or 3tc beyond 6 weeks confers any further intra-partum transmission reduction, or that it affects breastfeeding risk. both lpv/r and 3tc as single agents extended to 12 months of breastfeeding have recently been reported in the promise pep study to reduce hiv transmission during breastfeeding to very low levels.28 currently, in south africa, the two main options for carp are for a two(azt, nvp) or three-drug (azt, 3tc, nvp) approach. there is little evidence to support one over the other and, indeed, the three-drug approach in hptn040 showed no clear benefit over the two-drug approach. dosage tables for nvp (table 1) and azt (table 2) are given below. these tables are modified from the western cape 2014 pmtct guidelines, include doses for preterm infants, and differ slightly from doses provided in the current national guidelines. table 1: nevirapine doses for post-exposure prophylaxis in the first 6 weeks of life. table 2: zidovudine doses for post-exposure prophylaxis. the recommended dosage for 3tc is 2 mg/kg for the first 4 weeks of life, irrespective of gestational age at birth. conclusion top ↑ the most intense period of risk for mtct is during labour and delivery. this is accentuated by suboptimal maternal viral suppression and limited pre-labour cart duration. an increased risk of intra-partum hiv infection can be reduced by boosted infant pep. newborns at increased risk can be identified by clinical and laboratory parameters at birth, be tested early, and receive post-exposure carp if the birth pcr test is negative. risk of transmission during breastfeeding is low but, because of the cumulative risk over the whole breastfeeding period, tends to be overstated. breastfeeding risk per month is very low with maternal cart and infant peep. in high-risk scenarios, maternal art/adherence must be optimised urgently to reduce breastfeeding transmission risk and improve maternal health and survival. there are no data on the efficacy of carp to prevent breastfeeding transmission of hiv in high-risk situations, and the potential toxicity of extended carp means it cannot be recommended for this purpose. pcr testing at birth is recommended for infants commencing carp and when in utero transmission risk is high, to respectively exclude hiv infection and facilitate prompt linkage of infected infants to definitive treatment. appendix 1 contains commentary on the new south african consolidated guidelines for pmtct and the management of hiv in children, adolescents and adults that were released after the writing of this article. acknowledgements top ↑ competing interests the author declares that he has no financial or personal relationships that may have inappropriately influenced him in writing this article. references top ↑ millennium development goals, country report, 2013. pretoria: statistics sa; 2013. goga ae, dinh th, jackson dj, for the sapmtcte study group. evaluation of the effectiveness of the national prevention of mother-to-child transmission (pmtct) programme measured at six weeks postpartum in south africa, 2010. south african medical research council, national department of health of south africa and pepfar/us centers for disease control and prevention; 2012. johnson lf, stinson k, newell ml, et al. the contribution of maternal hiv seroconversion during late pregnancy and breastfeeding to mother-to-child transmission of hiv. j acquir immune defic syndr. 2012;59:417–425. http://dx.doi.org/10.1097/qai.0b013e3182432f27 recommendations for use of antiretroviral drugs in pregnant hiv-1 infected women for maternal health and interventions to reduce perinatal hiv transmission in the united states. [cited 16 april 2014]. available from: http://aidsinfo.nih.gov/guidelines/html/3/perinatal-guidelines/0 taylor gp, clayden p, dhar j, et al. british hiv association guidelines for the management of hiv infection in pregnant women 2012. hiv med. 2012;13 suppl. 2: 87–157. http://dx.doi.org/10.1111/j.1468-1293.2012.01030.x policy and guidelines for the implementation of the pmtct programme. pretoria: south african national department of health; 11 february 2008. lallemant m, jourdain g, le coeur s, et al. single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of hiv-1 in thailand. n engl j med. 2004;351:217–228. http://dx.doi.org/10.1056/nejmoa033500 lallemant m, jourdain g, le coeur s, et al. a trial of shortened zidovudine regimens to prevent mother-to-child transmission of human immunodeficiency virus type 1. perinatal hiv prevention trial (thailand) investigators. n engl j med. 2000;343:982–991. http://dx.doi.org/10.1056/nejm200010053431401 de cock km, fowler mg, mercier e, et al. prevention of mother-to-child hiv transmission in resource-poor countries: translating research into policy and practice. jama. 2000;283:1175–1182. http://dx.doi.org/10.1001/jama.283.9.1175 rouzioux c, costagliola d, burgard m, et al. estimated timing of mother-to-child human immunodeficiency virus type 1 (hiv-1) transmission by use of a markov model. the hiv infection in newborns french collaborative study group. am j epidemiol. 1995;142:1330–1337. kuhn l, abrams ej, matheson pb, et al. timing of maternal-infant hiv transmission: associations between intrapartum factors and early polymerase chain reaction results. new york city perinatal hiv transmission collaborative study group. aids. 1997;11:429–435. http://dx.doi.org/10.1097/00002030-199704000-00005 magder ls, mofenson l, paul me, et al. risk factors for in utero and intrapartum transmission of hiv. j acquir immune defic syndr. 2005;38:87–95. http://dx.doi.org/10.1097/00126334-200501010-00016 doherty t, jackson d, swanevelder s, et al. severe events in the first 6 months of life in a cohort of hiv-unexposed infants from south africa: effects of low birth weight and breastfeeding status. trop med int health. 2014;19:1162–1169. http://dx.doi.org/10.1111/tmi.12355 johnson va, petropoulos cj, woods cr, et al. vertical transmission of multidrug-resistant human immunodeficiency virus type 1 (hiv-1) and continued evolution of drug resistance in an hiv-1-infected infant. j infect dis. 2001;183:1688–1693. http://dx.doi.org/10.1086/320697 moodley d, esterhuizen t, reddy l, et al. incident hiv infection in pregnant and lactating women and its effect on mother-to-child transmission in south africa. j infect dis. 2011;203:1231–1234. http://dx.doi.org/10.1093/infdis/jir017 standard treatment guidelines and essential drugs list for south africa 2013. hospital level, paediatrics. pretoria: national department of health; 2013. cardo dm, culver dh, ciesielski ca, et al. a case-control study of hiv seroconversion in health care workers after percutaneous exposure. new engl j med. 1997;337:1485–1490. http://dx.doi.org/10.1056/nejm199711203372101 wade na, birkhead gs, warren bl, et al. abbreviated regimens of zidovudine prophylaxis and perinatal transmission of the human immunodeficiency virus. n engl j med. 1998;339:1409–1414. http://dx.doi.org/10.1056/nejm199811123392001 gray ge, urban m, chersich mf, et al. a randomised trial of two postexposure prophylaxis regimens to reduce hiv-1 mother-to-child transmission in infants of untreated mothers. aids. 2005;19:1289–1297. http://dx.doi.org/10.1097/01.aids.0000180100.42770.a7 connor em, sperling rs, gelber r, et al. reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. pediatric aids clinical trials group protocol 076 study group. n engl j med. 1994;331:1173–1180. http://dx.doi.org/10.1056/nejm199411033311801 nielsen-saines k, watts dh, veloso vg, et al. three postpartum antiretroviral regimens to prevent intrapartum hiv infection. new engl j med. 2012;366:2368–2379. http://dx.doi.org/10.1056/nejmoa1108275 taha te, kumwenda ni, gibbons a, et al. short postexposure prophylaxis in newborn babies to reduce mother-to-child transmission of hiv-1: nvaz randomized clinical trial. lancet. 2003;362:1171–1177. http://dx.doi.org/10.1016/s0140-6736(03)14538-2 shetty ak, coovadia hm, mirochnick mm, et al. safety and trough concentrations of nevirapine prophylaxis given daily, twice weekly, or weekly in breastfeeding infants from birth to 6 months. j acquir immune defic syndr. 2003;34:482–490. http://dx.doi.org/10.1097/00126334-200312150-00006 capparelli ev, mirochnick m, dankner wm, et al. pharmacokinetics and tolerance of zidovudine in preterm infants. j pediatr. 2003;142:47–52. http://dx.doi.org/10.1067/mpd.2003.mpd0335 de waal r, kroon sm, holgate sl, et al. nevirapine concentrations in preterm and low birth weight hiv-exposed infants: implications for dosing recommendations. pediatr infect dis j. 2014;33:1231–1233. http://dx.doi.org/10.1097/inf.0000000000000453 british hiv association guidelines for the management of hiv infection in pregnant women 2012 (2014 interim review). london: bhiva; may 2014. aids info. guidelines for the use of antiretroviral agents in pediatric hiv infection. [cited 01 july 2014]. available from: http://aidsinfo.nih.gov/guidelines/html/2/pediatric-treatment-guidelines/0 nagot n, kankasa c, meda n, et al. for the promise-pep trial protocol anrs 12174. abstract 70 croi 2014. paper presented at: conference on retroviruses and opportunistic infections; 3–6 march 2014; boston, ma. appendix 1: recognising and managing increased hiv transmission risk in newborns top ↑ in january 2015, the south african national department of health (ndoh) issued the new consolidated guidelines for pmtct and the management of hiv in children, adolescents and adults. this document includes risk criteria linked to more intensive testing and prophylaxis regimens. immediate pcr testing including birth testing is now recommended for many increased risk situations. infant post-exposure carp with azt and nvp for increased intra-partum risk is recommended for 6 weeks when the most recent maternal vls are > 1000 copies/ml. if maternal art duration is < 4 weeks or the diagnosis of maternal hiv is made during labour or after delivery, infant breastfeeding peep with nvp as a single agent is extended to 12 weeks. unfortunately, carp is not recommended for the very situation where evidence for risk reduction is strongest: when there is no pre-labour art and a current vl result is not available. another important omission is the use of carp for suspected maternal virus nnrti resistance in instances where it does not make sense to rely solely on nvp for prevention. curiously, maternal seroconversion during breastfeeding does attract temporary carp with azt for 1 week and extended nvp, but this advice seems illogical and the evidence for benefit is lacking. unlike the 2013 who consolidated guidelines, the ndoh guidelines make no mention of arv prophylaxis dosing for preterm and lbw infants. the nvp dosing schedule recommends 20 mg for all infants > 6 weeks old. many preterm infants may weigh < 2 kg at 6 weeks, and the 20 mg dose may be too high. moreover, the simplified azt dosing schedule does not include recommendations for infants weighing < 2 kg. whilst the consolidated guidelines are a step in the right direction, they could be improved further, and clinicians should carefully consider whether patients with increased-risk intra-partum hiv exposure may benefit from enhanced prophylaxis. the adoption of universal birth pcr testing would simplify risk management and the selection of infants for carp. point-of-care nucleic acid testing in delivery facilities has great potential for routine maternal vl testing to determine intra-partum transmission risk and to facilitate universal birth pcr testing for hiv-exposed newborns. article information authors: john ashmore1 ruth henwood2 affiliations: 1doctors without borders/médecins sans frontières, cape town, south africa 2doctors without borders/médecins sans frontières, khayelitsha, south africa correspondence to:     john ashmore email: jdashmore@gmail.com postal address: unit 23b, no. 14 waverly business park, wyecroft road, mowbray 7700, western cape province, south africa dates: received: 12 jan. 2015 accepted: 21 may 2015 published: 02 july 2015 how to cite this article: ashmore j, henwood r. choice or no choice? the need for better branded public sector condoms in south africa. s afr j hiv med. 2015;16(1), art. #353, 3 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.353 copyright notice: © 2015. the author(s). licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. choice or no choice? the need for better branded public sector condoms in south africa in this forum... open access • abstract • introduction    • background • condoms in khayelitsha • recommendations • acknowledgements    • competing interests    • authors’ contributions • references abstract top ↑ condoms are one of the cornerstones to any response to the hiv epidemic. however, targeted marketing strategies that make condoms more attractive to people at high risk of infection are often overlooked. the south african national department of health has recently purchased more attractive condoms to distribute in higher-education settings free of charge, targeting at-risk youth including young women. the authors applaud this move but note the importance of expanding better branded condoms to young people elsewhere – for example, via youth clinics and in high schools. exploratory, routine data from médecins sans frontières in khayelitsha are presented, showing the popularity of alternatives to the government's ‘choice’ brand. introduction top ↑ background condom distribution, promotion and social marketing represent a highly cost-effective hiv prevention strategy, given the low cost of condoms and their strong prevention efficacy. self-reported condom usage is around 80% effective at preventing hiv for heterosexual couples, 70% effective for men who have sex with men (msm), and much higher under laboratory conditions.1 condoms are advisable even for seroconcordant couples, to help prevent other sexually transmitted infections and unwanted pregnancy.2 lubricant is also advised for use with condoms. according to the world health organization, water-based lubricants are associated with either a decrease or no change in the rate of condom slippage or breakage. female condoms are also considered safe.3 the latest human sciences research council behaviour survey,4 however, found that self-reported condom use at time of last sex significantly declined in south africa, from 45.1% (95% confidence interval [ci] 43.3–47.0) of adults in 2008, to 36.2% (95% ci 34.5–37.9) in 2012. this decline is in spite of increases in the total number of male condoms distributed by the public sector, over the same period, from 283 000 5 to 501 000.6 female condoms still represent a small fraction of total condoms distributed. importantly, greater distribution of condoms does not ensure their increased and proper use, especially if divorced from a well-considered, segmented social marketing campaign. such a campaign would ideally: (1) research the needs and preferences of high risk and general populations, (2) deliver heterogeneous products branded differently for different target groups and (3) provide public messaging promoting healthy behaviour appealing to the target audience.7,8 the south african government's free ‘choice’ brand condoms, meanwhile, do not target any specific population or form part of any official marketing strategy. the main condom brands available at present are choice (80% of the market) followed by population service international's subsidised ‘trust’ and ‘lovers+’9 brands. partly in response to such issues, minister of health dr motsoaledi announced in april 2014 that free, colourful and flavoured condoms would be provided in south african tertiary education institutions. the minister noted that this was to combat ‘condom fatigue’, referring to a lack of enthusiasm amongst young people for choice.10 since this announcement, the national department of health awarded a tender for 50 million rebranded condoms for universities and further education and training colleges and has begun distributing them. however, by the age of 21, 50% of young people are not employed or enrolled in any form of education (20% at age 18) and thus do not benefit equally.11 school age adolescents, particularly young women, are also vulnerable to hiv infection. a recent development is that the department of basic education has drafted a policy to provide condoms in schools but faces backlash from school boards and religious groups who see this as encouraging sex,12,13 rather than safe sex, despite a lack of evidence supporting this claim.14 the present editorial calls for the further expansion of attractively branded and marketed condoms via the public sector, especially to meet the needs of young, marginalised people, many of whom are not enrolled in tertiary education. exploratory, routine data are presented from médecins sans frontières (msf) in khayelitsha that adds weight to these arguments. condoms in khayelitsha top ↑ khayelitsha township has one of the most successful condom distribution programmes in the country, with approximately 1 million choice condoms distributed per month by the treatment action campaign to a population of 391 749.15 with permission from the city of cape town, msf conducted a trial on the popularity of alternatives to choice in a youth clinic in khayelitsha, using condoms donated by the organization ‘condomize’. four condom types (choice, condomize regular with bright packaging, condomize strawberry flavoured, and condomize extra-large [figure 1]) were placed in identical glass containers in the reception area of site c youth clinic. condom containers were refilled under the supervision of msf's patient support team. placing the condoms in the waiting area of the clinic allowed youth access with minimal interference from health workers. clients could take as many or as few individually packed condoms as desired. figure 1: photo's of (a) condomize regular, (b) flavoured and (c) extra-large. as shown in figure 2, flavoured condoms proved the most popular, followed closely by extra-large condoms. interestingly, even the regular condoms in bright packaging were far more popular than choice, although their popularity seemed to decline slightly over time. only 6% of condoms taken from the youth clinic were choice condoms. figure 2: cumulative total of condoms taken in site c youth clinic: moving average. in discussions with youths about the new condoms at the clinic, the overall feeling was one of satisfaction. they preferred the colourful packaging, smell, fit and feel which some described as ‘lighter’. further remarks were ‘choice condoms are too thick and oily’, ‘we experienced pain due to the poor fit’, and ‘the old ones smelled awful and didn’t fit well’. some young women indicated that their boyfriends would sometimes buy condoms rather than use the freely available choice condoms. this anecdotal evidence implies higher acceptability of alternative brands to choice, at least in the short term. recommendations top ↑ although the experience of khayelitsha may not be generalisable to elsewhere in south africa, changes to packaging and marketing of government condoms may nevertheless prove popular with south african youth. repackaged, flavoured and extra-large condoms, in particular, appear to show some promise. the south african government should be praised for their introduction of such condoms to tertiary education institutions but must ensure wider distribution and reconsider their overall marketing strategy. msf has seen high demand in its projects for alternative condoms, along with family planning, amongst school age adolescents. in terms of introducing condoms in schools and other outlets such as youth clinics, it is time to leave behind moralistic arguments about sex and focus on addressing the public health crisis at hand. the costs of rebranding and marketing condoms should be weighed against the potential benefits of increased popularity and use. in general, more research is needed to explore condom market dynamics in south africa and elsewhere, including focusing on differences in design preference by gender, age and hiv risk. it is also important to identify whether alternative designs are preferred in the long term or whether there is a need for regular design changes to maintain novelty. such research should inform a national condom marketing strategy that maximises the impact of free government condoms which might no longer capture the imagination of their intended users. young people, but also sex workers, msm and prisoners, may all require their own strategies, along with a new approach for the general population. lubricant should also be considered for distribution along with condoms, especially for msm, while there is also much scope for social marketing messages that promote correct and consistent condom use. it is unknown at present how many people who collect the various brands of condoms will actually use them. this point may be particularly important to consider in a setting where intimate partner violence and the inability of women to negotiate condom access are linked to hiv infection.16 acknowledgements top ↑ competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions j.a. (msf) oversaw the project, analysed the data, and wrote most of the manuscript. r.h. (msf) oversaw collection of routine data including patient feedback, and contributed significantly to the manuscript as well as project conception. references top ↑ smith dk, herbst jh, zhang xj, et al. condom effectiveness for hiv prevention by consistency of use among men who have sex with men (msm) in the us. j acquir immune defic syndr. 2013; e-publication ahead of print. bertozzi s, padian ns, wegbreit j, et al. hiv/aids prevention and treatment. in: jamison dt, breman jg, measham ar, et al., editors. disease control priorities in developing countries. 2nd ed. washington: department of global health, university of washington; 2006. [cited 20 december 2014]. available from: http://www.dcp-3.org/dcp2/ world health organization. use and procurement of additional lubricants for male and female condoms: who/unfpa/fhi. advisory note 12.43, 2012. geneva: world health organization; 2012. [cited 20 december 2014]. available from: http://apps.who.int/iris/bitstream/10665/76581/1/who_rhr_12.34_eng.pdf shisana o, rehle t, simbayi lc, et al. south african national hiv prevalence, incidence and behaviour survey. cape town: hsrc press; 2012. department of health annual report 2008/09. pretoria: national department of health; 2009. department of health annual report 2012/13. pretoria: national department of health; 2013. knerr w. does condom social marketing improve health outcomes and increase usage and equitable access? reproductive health matters. 2011;19:166–173. http://dx.doi.org/10.1016/s0968-8080(11)37558-1 wedel m, kamakura w. market segmentation: conceptual and methodological foundations. 2nd ed. massachusetts: kluwer academic publishers; 2006. pallin sc, meekers d, lupu o, et al. south africa: a total market approach – psi/unfpa joint studies on the total market for male condoms in six african countries. pretoria: population sciences international/united nations population fund; 2010. [cited 18 december 2014]. available from: www.psi.org/total-market-approach enca news. flavours and colours to fight condom fatigue. 2 april 2014. [cited 10 may 2014]. available from: http://www.enca.com/south-africa/flavours-and-colours-fight-condom-fatigue statistics south africa. social profile of vulnerable groups: 2002-2012. pretoria: statistics south africa; 2012. [cited 07 may 2015]. available from: http://www.statssa.gov.za/publications/report-03-19-00/report-03-19-002012.pdf the new age. condom drive stirs south africa's worries. 19 october 2012. [cited 05 january 2015]. available from: http://www.sabc.co.za/news/a/30557c0044ba2398a317fb3bfe17c0b1/condoms-to-be-distributed-in-schools-next-year-20141407 sabc news. condoms to be distributed in school next year. sabc news, 14 july 2014. [cited 04 january 2015]. available from: http://www.sabc.co.za/news/a/30557c0044ba2398a317fb3bfe17c0b1/condoms-to-be-distributed-in-schools-next-year-20141407 smoak nd, scott-sheldon laj, johnson bt, carey mp. sexual risk reduction interventions do not inadvertently increase the overall frequency of sexual behavior: a meta-analysis of 174 studies with 116, 735 participants. j acquir immune defic syndr. 2006;41:374–384. http://dx.doi.org/10.1097/01.qai.0000185575.36591.fc statistics south africa. census 2011: khayelitsha. pretoria: statistics south africa; 2011. [cited 19 december 2014]. available from: http://www.capetown.gov.za/en/stats/2011censussuburbs/2011_census_ct_suburb_khayelitsha_profile.pdf jewkes rk, dunkle l, nduna m, shai n. intimate partner violence, relationship power inequity, and incidence of hiv infection in young women in south africa: a cohort study. lancet. 2010;376:41–48. http://dx.doi.org/10.1016/s0140-6736(10)60548-x article information author: gayle g. sherman1,2 affiliations: 1department of paediatrics and child health, university of the witwatersrand, south africa 2centre for hiv and sti, national institute for communicable diseases, south africa correspondence to: gayle sherman email: gayles@nicd.ac.za postal address: po box 79722, senderwood 2145, south africa dates: received: 01 dec. 2015 accepted: 10 feb. 2015 published: 24 apr. 2015 how to cite this article: sherman gg. hiv testing during the neonatal period. s afr j hiv med. 2015;16(1), art. #362, 3 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.362 copyright notice: © 2015. the authors. licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. hiv testing during the neonatal period in this forum... open access • introduction • effect of evolving prevention of mother to child transmission interventions on 6-week hiv polymerase chain reaction diagnostic performance • diagnostic performance of hiv pcr at birth • when should birth and early neonatal hiv pcr be considered? • optimal response to a birth or early neonatal hiv pcr result that is positive • further testing if birth or early neonatal hiv pcr test result is negative • acknowledgements    • competing interests • references introduction top ↑ testing for hiv in the neonatal period has been routinely recommended for all hiv-exposed infants in the developed world for over two decades. in 2015, birth testing for certain asymptomatic hiv-exposed infants was included in the south african national consolidated guidelines for the first time.1 questions remain concerning the optimal recommendations for and implementation of hiv testing in neonates to achieve improved outcomes for hiv-infected infants in south african and other low-resource settings. effect of evolving prevention of mother to child transmission interventions on 6-week hiv polymerase chain reaction diagnostic performance top ↑ the notion that a single hiv polymerase chain reaction (pcr) test performed at 6 weeks of age would detect virtually all in utero and intrapartum hiv-infected infants failed to recognise: the hiv-related mortality that occurs prior to testing at 6 weeks of age2,3,4 the reduced sensitivity of hiv pcr tests as a consequence of the increase in the number and duration of drugs used for prevention of mother-to-child transmission of hiv (pmtct) prophylaxis. there is increasing evidence that both fixed dose combination (fdc) maternal pmtct prophylaxis and daily dose nevirapine (nvp) infant prophylaxis (option b or b+) contribute towards reduced detection of perinatal hiv infection at 6 weeks of age. the literature demonstrates that: a single perinatal dose of nvp reduced viral load to below the limit of detection in 38% and 17% of in utero infected infants at 5 days and 2 weeks of age respectively.5,6 no hiv pcr sensitivity data for 6-week-old hiv-exposed infants, tested at discontinuation of 6 weeks of daily dose nvp, are available. the probability of a positive hiv pcr at age 6 weeks in perinatally hiv-infected infants is decreased with multi-drug maternal and/or infant pmtct prophylaxis7 in non-breastfed infants, hiv dna and rna pcr sensitivity at 1 month of age for perinatally infected infants was 89%8 in formula-fed infants who received 6 weeks of postpartum zidovudine (azt), with or without other antiretrovirals, 32% of intrapartum-infected infants tested hiv dna pcr negative at 6 weeks of age but tested positive at 3 months of age9 prophylaxis reduces hiv dna concentrations at birth complicating early identification of infected infants for initiation of early treatment10 there are case studies illustrating the challenges of ‘false negative’ and ‘indeterminate’ hiv pcr results in early infant diagnosis in the context of current pmtct prophylaxis and calling for revised diagnostic guidelines.11,12 the 6-week test, conveniently scheduled at the same time as the 6-week expanded programme for immunisation (epi) visit, is therefore too late and too early to detect all in utero and intrapartum hiv infections in the context of current pmtct interventions. it is too late to diagnose infants who die prior to 6 weeks of age and to achieve early combination antiretroviral therapy (cart) initiation by 7.4 weeks of age as was done on the children with hiv early antiretroviral therapy (cher) trial to reduce early morbidity and mortality.13 it is too early to diagnose in utero and intrapartum infections suppressed by daily dose nvp and/or maternal prophylaxis via the placenta and/or breastmilk. diagnostic performance of hiv pcr at birth top ↑ the hiv pcr sensitivity at birth for detecting perinatal hiv infections (viz. in utero and intrapartum hiv infections) can never approach 100% because it detects in utero infection only and cannot detect intrapartum infection, namely an infection transmitted at the time of labour and delivery and essentially in the window period at birth. prior to the implementation of pmtct and the use of standardised hiv assays, dunn et al.’s meta-analysis demonstrated that 38% of all perinatal infections were detectable at birth.14 with world health organization (who) option a prophylaxis and a single dose of nvp at birth for infants, lilian et al. demonstrated that 76% of all early hiv infections were detectable at birth.15 this increase was attributed to more sensitive viral detection assays and a proportional increase in in utero to intrapartum infections as a result of pmtct prophylaxis targeting intrapartum infections during late pregnancy and delivery. as the majority of women deliver in health facilities in south africa, identifying all hiv-infected women at delivery coupled with birth hiv pcr testing would yield three-quarters of all perinatal hiv infections with close to 90% coverage. with option b or b+ including daily dose nvp for 6 weeks to the infant, the ratio of in utero to intrapartum infections detectable at birth and 6 weeks of age is not known but is likely to be similar to option a. when should birth and early neonatal hiv pcr be considered? top ↑ because hiv testing of neonates is not performed unless a neonate is symptomatic, the hiv-related neonatal mortality rate in south africa is unknown. in the presence of vertical transmission and without a birth diagnosis, it is neither possible to detect neonatal hiv infection nor to reduce hiv-related neonatal mortality by initiating antiretroviral therapy. approximately 20% of infants known to be hiv-infected at birth in johannesburg either died or were lost to follow-up by the time that 6-week hiv pcr testing was conducted.4 modeling the ideal timing of hiv pcr tests in early infant diagnosis for south africa,16 considering birth, 6-, 10and 14-week epi visits, demonstrated that: when using 1 hiv pcr test, the same number of hiv-infected infants are identified when testing at birth or at 6 weeks of age when using 2 hiv pcr tests, the most hiv-infected ­infants can be identified by testing at birth and 10 weeks of age. additional evidence for the assumptions made in the model would assist in refining the optimal timing of hiv pcr tests. the 2014 south african national consolidated guidelines recommend targeted birth testing, namely hiv pcr testing of only those hiv-exposed neonates identified as being at high risk of hiv transmission.1 ‘high risk’ includes all premature (born before 37 weeks’ gestational age), low birth weight (lbw < 2500 g) or symptomatic hiv-exposed neonates and those born to women who were unbooked or received a late diagnosis of hiv (e.g. at delivery) or received < 4 weeks of antiretroviral pmtct prophylaxis or had viral loads > 1000 copies per millilitre or were co-infected with tuberculosis during pregnancy. the western cape pmtct guidelines also recommend targeted birth testing that include additional and slightly modified high-risk factors.17 these high-risk factors predict vertical transmission but not necessarily in utero transmission, and therefore the birth hiv pcr test may be negative. universal birth testing of all hiv-exposed infants may be simpler to implement than targeted birth testing. the cost of performing two early hiv pcr tests, to detect in utero and intrapartum infections, on every hiv-exposed infant can be offset by following 2010 who guidelines to use hiv rapid tests (hrt) from 9 months of age.18 as the majority of hiv-exposed, uninfected infants demonstrate seroreversion by 9 months of age by testing hrt negative, only those with positive hrt would require hiv pcr tests.19 this approach reduces the number of hiv pcr tests required for symptomatic infants or those requiring testing post-cessation of breastfeeding. optimal response to a birth or early neonatal hiv pcr result that is positive top ↑ to avoid morbidity and mortality, all positive hiv pcr results require urgent action to (1) confirm the hiv-infected status on a second blood sample and (2) initiate cart. healthcare facilities require good communication with the laboratory to access positive results within 2–7 days and systems for patient follow-up to see all hiv pcr-positive patients as soon as possible. as neonates usually return to their primary healthcare clinic and not the maternity unit for follow-up after birth, ensuring that birth hiv pcr test results reach patients will be pivotal to successful implementation of birth testing. point of care (poc) hiv diagnosis would facilitate same-day identification of hiv-infected neonates. the results of the second, confirmatory viral detection assay should not delay cart initiation but should be obtained as early as possible because, once cart is initiated, it becomes progressively more difficult to detect hiv either by hiv pcr or viral load testing. the availability of two different poc assays for detection of hiv would facilitate same-day identification and confirmation of hiv infection in neonates. further testing if birth or early neonatal hiv pcr test result is negative top ↑ if the birth hiv pcr test is negative, an hiv pcr test at 10 weeks of age is recommended to detect as many cases of intrapartum infection as possible. if the hiv pcr test is repeated at 6 weeks of age, as per national guidelines,1 fewer cases of intrapartum infection may be identified owing to the viral load lowering effect of the daily dose nvp infant prophylaxis. the 2014 national consolidated guidelines cater for this in high-risk infants only by recommending a third hiv pcr at 16 weeks of age where prolonged infant prophylaxis (e.g. daily dose nvp for 12 weeks) has been used.1 the probability that the sensitivity of diagnostic virological assays is affected by antiretroviral prophylaxis has prompted american guidelines to recommend an additional hiv pcr test be performed 2–4 weeks after combination antiretroviral infant prophylaxis has been discontinued if negative hiv pcr results were obtained during prophylaxis.20 as for all hiv-exposed and uninfected infants, hiv pcr testing is recommended whenever clinical features suggestive of hiv infection are present and 6 weeks after cessation of breastfeeding (if < 18 months old). if, at 6 weeks after weaning, the child is ≥ 18 months old, a hrt or hiv enzyme-linked immunosorbent assay (elisa) test should be performed instead of an hiv pcr test. in an evolving pmtct environment, ongoing monitoring is necessary to assess the impact of early diagnosis of hiv infection in neonates and to ensure that an evidence-based, effective diagnostic algorithm is deployed. acknowledgements top ↑ competing interests the author declares that she has no financial or personal relationship(s) which may have inappropriately influenced her in writing this article. references top ↑ national department of health. national consolidated guidelines for the prevention of mother-to-child transmission of hiv (pmtct) and the management of hiv in children, adolescents and adults. pretoria: department of health; 24 december 2014. bourne de, thompson m, brody ll, et al. emergence of a peak in early infant mortality due to hiv/aids in south africa. aids. 2009;23:101–106 http://dx.doi.org/10.1097/qad.0b013e32831c54bd marston m, becquet r, zaba b, et al. net survival of perinatally and postnatally hiv-infected children: a pooled analysis of individual data from sub-saharan africa. int j epidemiol. 2011;40:385–396. http://dx.doi.org/10.1093/ije/dyq255 lilian rr, kalk e, technau kg, sherman gg. birth diagnosis of hiv infection in infants to reduce infant mortality and monitor for elimination of mother-to-child transmission. pediatr infect dis j. 2013;32:1080–1085. http://dx.doi.org/10.1097/inf.0b013e318290622e mphatswe w, blanckenberg n, tudor-williams g, et al. high frequency of rapid immunological progression in african infants infected in the era of perinatal hiv prophylaxis. aids. 2007;21:1253–1261. http://dx.doi.org/10.1097/qad.0b0 13e3281a3bec2 lilian rr. identifying interventions to improve outcomes of the south african prevention of mother-to-child transmission programme. dissertation for mscmed, faculty of health sciences, university of the witwatersrand; 2013. shapiro de, balasubramanian r, fowler mg, et al. time to hiv dna-pcr positivity according to maternal/infant antiretroviral prophylactic regimen in non-breastfed hiv-infected infants in populations with predominantly non-b hiv subtype: a collaborative analysis of data from cohorts in thailand, south africa, botswana and the united kingdom [tuab0203]. presented at: 6th ias conference on hiv pathogenesis, treatment and prevention. rome, italy: 17–20 july 2011. burgard m, blanche s, jasseron c, et al. performance of hiv-1 dna or hiv-1 rna tests for early diagnosis of perinatal hiv-1 infection during anti-retroviral prophylaxis. j pediatr. 2012;160:60–66.e1. nielsen-saines k, watts dh, veloso vg, et al. three postpartum antiretroviral regimens to prevent intrapartum hiv infection. n engl j med. 2012;366:2368–2379. http://dx.doi.org/10.1056/nejmoa1108275 mitchell c, dross s, beck ia, micek ma, frenkel lm. low concentrations of hiv-1 dna at birth delays diagnosis, complicating identification of infants for antiretroviral therapy to potentially prevent the establishment of viral reservoirs. clin infect dis. 2014;58:1190–1193. http://dx.doi.org/10.1093/cid/ciu068 haeri mazenderani af, du plessis nm, thomas wn, venter e, avenant t. loss of detectability and indeterminate results: challenges facing hiv infant diagnosis in south africa’s expanding art programme. s afr med j. 2014;104:574–577. http://dx.doi.org/10.7196/samj.8322 connolly md, rutstein rm, lowenthal ed. virologic testing in infants with perinatal exposure to hiv receiving multidrug prophylaxis. pediatr infect dis j. 2013;32:e54–61. http://dx.doi.org/10.1097/inf.0b013e3182787c29 violari a, cotton mf, gibb dm, et al. early antiretroviral therapy and mortality among hiv-infected infants. n engl j med. 2008;359:2233–2244. http://dx.doi.org/10.1056/nejmoa0800971 dunn dt, brandt cd, krivine a, et al. the sensitivity of hiv-1 dna polymerase chain reaction in the neonatal period and the relative contributions of intra-uterine and intra-partum transmission. aids. 1995;9:f7–11. http://dx.doi.org/10.1097/00002030-199509000-00001 lilian rr, kalk e, bhowan k, et al. early diagnosis of in utero and intrapartum hiv infection in infants prior to 6 weeks of age. j clin microbiol. 2012;50:2373–2377. http://dx.doi.org/10.1128/jcm.00431-12 lilian rr, johnson lf, moolla h, sherman gg. a mathematical model evaluating the timing of early diagnostic testing in hiv-exposed infants in south africa. j acquir immune def syndr. 2014;67:341–348. http://dx.doi.org/10.1097/qai.000 0000000000307 department of health. western cape pmtct clinical guidelines. june 2014. cape town: western cape government department of health; 2014. world health organization. who recommendations on the diagnosis of hiv infection in infants and children. c2010 [cited 04 february 2015]. available from: http://www.who.int/hiv/pub/paediatric/diagnosis/en/ sherman gg, lilian rr, coovadia ah. the performance of 5 rapid hiv tests using whole blood in infants and children: selecting a test to achieve the clinical objective. pediatr infect dis j. 2012;31:267–272. http://dx.doi.org/10.1097/inf.0b013e31823752a0 panel on antiretroviral therapy and medical management of hiv-infected children. guidelines for the use of antiretroviral agents in pediatric hiv infection. c2014 [cited 29 july 2014]. available from: http://aidsinfo.nih.gov/guidelines the southern african journal of hiv medicine                                                          october  2009 the interaction between hiv infection and psychiatric illness is complex, with many authors suggesting that psychiatric disorders in hiv-positive individuals are frequently under-recognised and under-treated.2,3 it is well established that there is an increase in the prevalence of a number of psychiatric disorders in hiv-infected individuals, internationally4,5 and in south africa.6,7 there may also be changes in the clinical picture in patients with psychiatric disorders after hiv infection8 and an interactive effect between hiv infection and vulnerability to psychiatric illness.9 in patients on art who may require psychotropic medication important considerations include possible sideeffects of existing antiretroviral medications, as well as potential interactions between art and psychotropics. psychosis, mania, agitation and suicidal ideation have all been associated with art. the antiretroviral agents most commonly implicated include abacavir, efavirenz and nevirapine.10 although in most cases it would appear that the psychiatric adverse effects occurred shortly after initiation of the antiretroviral agent, cases occurring over a year after commencement have also been reported. drug interactions between art and psychotropic medication, as well as with other medications the patient may be receiving, is another area that must be approached with some caution. a number of psychotropic agents that are potent enzyme inducers are contra indicated for use with almost all antiretroviral agents as they can seriously compromise antiretroviral therapy; these include carbamazepine, phenytoin, primidone and st john’s wort. caution is also advised when using certain selective serotonin re-uptake inhibitors (ssris) and benzodiazepines (see below). with regard to the antiretrovirals, a wide range of interactions with psychotropic agents have been described, and careful observation in the first weeks to months after any change of these medications is required. all the protease inhibitors, as well as the non-nucleoside reverse transcriptase inhibitors, are metabolised by the cytochrome p450 system and may therefore possess enzyme-inducing or inhibiting properties. in the south african setting, the commonly used agents that require the most caution are efaverinz, which may induce or inhibit cyp3a4, and nevirapine, which may induce cyp3a4. many other antiretrovirals have been reported as interacting with psychotropics, and a more comprehensive list of interactions can be obtained at the hiv insite database of antiretroviral drug interactions (http://www. hivinsite.com/11).10 it is also critical to take into account a wide range of psychosocial factors that may adversely affect the individual patient’s willingness and capacity to take medication correctly and for the required duration. n many hiv-positive patients may already be on complex drug regimens. n patients are often going through a complex process of adjustment to and acceptance of a lifelong diagnosis of hiv/aids with associated stigmatisation. n many of these patients will be suffering from some degree of cognitive impairment. n in many psychiatric disorders, particularly those associated with psychosis, insight may be lacking or may fluctuate. when these issues are considered in their entirety, it becomes clear that the importance of selecting the simplest possible regimens, the provision of regular psycho-education and counselling, and the recruitment of family members or others as treatment partners for all the medications the patient may be receiving cannot be emphasised too strongly. while this review is based as far as possible on the existing evidence base for psychotropic medication use in psychotropic prescribing in hiv c l i n i c a l : p r e s c r i b i n g john parker, mb bch, fcpsych (sa) department of psychiatry and mental health, university of cape town and lentegeur hospital, cape town the use of psychiatric medication in patients with hiv infection is a complex area, but given the high rates of psychiatric disorder in this population – possibly as high as 50%1 – it deserves further consideration. a number of issues need to be thought about, including the nature of both the psychiatric illness and the hiv infection, the use of antiretroviral therapy (art), and patient-related factors. psychiatric illness in hiv patient-related issuesantiretroviral therapy (art) psychotropic use in specific disorders 44 the southern african journal of hiv medicine                                                        october  2009 hiv/aids, it is important to note that empirical evidence is limited in many instances. data often come from studies outside sub-saharan africa, and in turn the applicability of such evidence to south african populations may require interrogation. anxiety disorders the vast majority of the existing literature on the treatment of these disorders in hiv-positive patients describes the use of psychotherapeutic approaches rather than medication. as an initial approach, this is perhaps appropriate in general populations. benzodiazepines have been shown to provide rapid symptomatic relief from acute anxiety states, but they should be used with caution in post-traumatic stress disorder (ptsd) and panic disorders, and they have severe limitations in terms of their capacity to produce tolerance and dependence.12 there is no reason to believe that the situation differs in hiv. further caution must be applied with the use of alprazolam, midazolam and triazolam, which are dependent on cyp3a4 for metabolism, so that inhibitors of this enzyme system may increase the halflife of these drugs, possibly causing over-sedation and respiratory depression. additionally, cyp3a4 inducers may lower serum levels and reduce the effect of these drugs.13 perhaps safer choices are benzodiazepines such as oxazepam, lorazepam, and temazepam, which are metabolised by glucuronidation.3 however, a cautious approach is required in all cases, with careful titration of initial doses and observation for accumulation. there is some evidence in support of buspirone as an anxiolytic in hiv-positive individuals, as reported in two small studies.14,15 however there are also reports of dyskinesias, myoclonus, psychosis and mania in hiv-positive patients. lastly, and perhaps of most clinical relevance, it should be noted that the ssris are widely recommended as first-line treatment for a variety of anxiety disorders, including ptsd, generalised anxiety disorder (gad), panic disorder and obsessive-compulsive disorder in the general population.10 there is little evidence to suggest this is not the case in hiv-infected individuals, and the use of these drugs is discussed below. in using the ssris to treat anxiety disorders it is useful to initiate medication at smaller doses than is usual for the treatment of depression, and in some cases the brief use of small doses of benzodiazepines during the initial period may be helpful. alternative hypnotics, such as zopiclone and zolpidem, should be used with caution as interactions with cyp3a4 have been reported. beta-blockers are sometimes used in the treatment of gad, but in the context of hiv, consideration must be given to the possibility of respiratory disorders and peripheral neuropathies, in which case these agents are best avoided. depression depressive disorders and their treatment in hiv-positive populations have received far more attention than other psychiatric disorders. a particular area of concern has been raised by studies indicating poor adherence to art regimens16 and increased morbidity17 in hiv-positive patients with untreated depression. despite this, a systematic review and meta-analysis of controlled trials to examine efficacy of antidepressant treatment among hiv-positive depressed individuals18 identified only seven studies, almost all of which involved white males in first-world populations. of these, only three (involving fluoxetine, paroxetine and imipramine) reported significant effects. looking more broadly at the literature on tricyclic antidepressants (tcas), there is evidence to suggest that response rates are similar to those in hiv-negative populations19 and that these agents are as effective as ssris in depressed hiv-positive patients.20 it would therefore seem that tcas are an appropriate choice in this context. it is, however, important to consider a number of issues relating to the side-effects of these drugs, particularly anticholinergic effects (which may lead to dry mucous membranes and an increased vulnerability to mucocutaneous candidiasis), alpha-adrenergic blockade (which can result in problematic postural hypotension, particularly in patients with neuropathies and other systemic illnesses), and prolongation of the qtc interval. other issues such as the potential for sedation and weight gain may be problematic or beneficial, depending on the particular circumstances. with regard to the ssris, although the best evidence for efficacy to date favours fluoxetine and paroxetine, these agents are potentially problematic in conjunction with art (in particular nevirapine and ritonavir) as both are metabolised by cyp2d6, while fluoxetine also inhibits cyp3a4; there is therefore an increased risk of serotonin syndrome, as well as of changes in levels of antiretrovirals. although the quality of evidence for the efficacy of both citalopram and sertraline in hiv-positive populations is less compelling, some evidence does exist21,22 and there is little to suggest interaction with cyp2d6 or cyp3a4. possible side-effects that may be of concern with this class of drugs include gastro-intestinal disturbances and increased anxiety. these can, however, be mitigated by initiating therapy with low doses and slowly increasing to therapeutic levels. there is weak evidence to support the efficacy of newer-generation antidepressants in treating depression in hiv-infected patients.23 mirtazapine has minimal effect on cyp2d6 or cyp3a410 and has proved a popular choice because of its relatively sedating effects and tendency to improve appetite and promote weight gain.3 there is currently little evidence on the use of venlafaxine and duoloxetine in depressed hiv-positive patients, 45 the southern african journal of hiv medicine                                                          october  2009 and metabolism by cyp2d6 and inhibition of this system would argue against their use as a first-line treatment. bupropion has been studied in one open trial for depression in hiv-positive patients and was found to be effective,22 but there are concerns that efavirenz, ritonavir and nelfinavir may increase levels by inhibiting bupropion hydroxylation.3 a number of alternative agents for the treatment of depression have been studied quite extensively in hiv. concerns have been expressed about potential interactions between st john’s wort and various antiretrovirals,24 so this is best avoided. testosterone may be of use in men with hypogonadism, which may occur as a result of hiv infection,25 but is not broadly effective as an antidepressant. with regard to psychostimulants, their potential side-effect profile, which includes psychosis, mania, weight loss, anxiety, insomnia and cognitive deficits, would mitigate against their use as first-choice agents. finally, the use of electroconvulsive therapy should not be overlooked in cases of treatment resistance or where medication has not been tolerated. although not well studied in hiv, there are reports of its beneficial use26,27 and it should not be refused simply on the basis of hiv status. bipolar disorder and mania manic episodes, either as part of bipolar disorder or as a secondary complication of hiv infection,5,28 are well described in hiv. in a first manic episode it may be preferable to avoid the immediate use of a mood stabiliser in favour of an antipsychotic (see ‘psychosis’, below), with short-term use of benzodiazepines (see ‘anxiety disorders’, above) if necessary. in established bipolar disorder, recurrent or relapsing secondary mania, or where this initial approach has proven inadequate, the use of mood stabilisers is indicated. in bipolar mania the preferred first-line mood stabilisers are lithium and sodium valproate, with carbamazepine as a second choice.10 as mentioned earlier, however, the potent enzyme induction attributed to carbamazepine makes it a poor choice in hiv. there are mixed reports on the use of lithium in hivpositive patients. concerns have been expressed regarding possible increased sensitivity to side-effects29 and worsening of cognitive impairment;30 however, a recent study31 demonstrated quite the opposite, with improvements in hiv-associated neurocognitive impairment on lithium. this may be related to its capacity, together with sodium valproate, for the inhibition of glycogen synthase kinase 3 beta (gsk-3 beta), a survival-regulating enzyme.32,33 lithium is excreted unchanged in the urine, so interactions with art are unlikely. its narrow therapeutic index, however, is of some concern, particularly when diarrhoea is likely, and extreme caution is required with medications that may reduce the glomerular filtration rate. it can therefore be concluded that lithium may be a reasonable choice, provided that it is well tolerated on initiation and that excellent compliance can be guaranteed. valproate (available as sodium valproate or valproic acid) is generally considered to be better tolerated than lithium and safer with regard to therapeutic index, but neutropenia, hepatic failure and the potential for teratogenesis in women of child-bearing age remain a concern.10 its potential to inhibit cyp3a4 may result in interactions with some antiretrovirals, and caution is advised when using it in combination with nevirapine and efaverinz. it has also been shown to inhibit gsk-3 beta.33 early reports raised some concerns that it may increase viral loads by stimulating replication.34 more recently it was suggested that this effect, in combination with art, may lead to the possibility of cure by depleting latent viral stores,35 but unfortunately this has not been substantiated.36 whether sodium valproate may lead to cognitive decline in hiv-positive individuals or not is not entirely resolved, however, with some studies showing no decline37,38 but one study suggesting problems with longer-term use at higher doses.39 this concern is supported by a fairly extensive literature pointing to adverse neurocognitive effects of valproate in individuals with cognitive impairment, although it should be noted that valproate is not unique in this effect either (e.g. gualtieri and johnson40). while valproate is therefore probably a reasonable choice of mood stabiliser in this setting, it would seem prudent to exercise caution with higher doses and to monitor cognitive function carefully, shortly after initiation as well as in the longer term. psychosis the older ‘classic’ antipsychotics, haloperidol in particular, have been shown to be safe and effective in studies of hiv-infected patients with schizophrenia8 as well as those with hiv-associated psychotic disorder.41,42 however, these patient groups have increased susceptibility to extrapyramidal side-effects (epse) and possibly to tardive dyskinesia (td) and neuroleptic malignant syndrome.10 although chlorpromazine may be less likely to produce epse and is helpful in restless patients when benzodiazepines are not well tolerated, this is similarly limited to a lower dosage range. further problems include the well-established side-effects of neutropenia, alpha-adrenergic blockade and anticholinergic effects. it can therefore be concluded that these agents may be useful and, where psychosis or delirium with psychotic symptoms are present, a trial, at initial doses of not more than 1 mg of haloperidol, or the equivalent, is indicated; at higher doses, epse can be expected. it is also worth noting that an adequate trial of any anti-psychotic requires at least a week of treatment at any dosage increment, if not longer. given the high risk of epse and td, the newer, second-generation or ‘atypical’ antipsychotics may be a 46 the southern african journal of hiv medicine                                                        october  2009 reasonable first-line approach, and are clearly a rational second line when epse have become apparent. theoretically, at least, an additional advantage of these agents is their high potency as serotonin 5ht2a receptor antagonists, which may be a useful effect as pro-phylaxis against, and treatment of, progressive multifocal leucoencephalopathy.43 risperidone was shown to be effective in the treatment of hiv-associated psychotic and manic symptoms in one series of 17 cases,44 where a particularly good response in patients with manic symptoms was noted. epse can however be a problem, even in low doses,45 and severe complications as a result of interactions with ritonavir have been described.46 there is very little literature of substance on the use of other second-generation agents, other than for short-term, symptomatic use in delirium. some care must be taken with olanzapine, owing to metabolism by cyp2d6 (the same may be said of clozapine), but the low risk of epse and growing evidence of their efficacy as mood stabilisers10 make these agents compelling choices. the use of clozapine may be considered in hiv-positive patients with treatment-resistant schizophrenia, but given this drug’s association with neutropenia it is best used as a last resort in settings where cd4 counts remain high and white cell counts can be closely monitored. delirium as mentioned at the outset, the most critical step in managing delirium in the setting of hiv infection is to vigorously identify and treat possible causes (see the article on assessment and treatment of psychosis in hivinfected individuals in this issue). the short-term use of low-dose antipsychotics and/or benzodiazepines may be considered if clinically indicated to manage behavioural disturbance. hiv-associated dementia as described elsewhere in this issue, the mainstay of treatment of hiv-associated dementia is art, but shortterm, symptomatic use of antipsychotics and mood stabilisers may be helpful. references 1. bing e, burman m, longshore d, fleischmann j, sherbourne c, london a. psychiatric disorders and drug use among human immunodeficiency virusinfected adults in the united states. arch gen psychiatry 2001; 58: 721-728. 2. evans d, staab j, ward h, et al. depression in the medically ill: management consideration. depress anxiety 1996; 4: 199-208. 3. thompson a, silverman b, dzeng l, treisman g. psychotropic medications and hiv. clin infect dis 2006; 42: 1305-1310. 4. angelino at, treisman gj management of psychiatric disorders in patients infected with human immunodeficiency virus. clin infect dis 2001; 33: 847-856 5. lyketsos c, hanson a, fishman m. manic episode early and late in the course of hiv. am j psychiatry 1993; 150: 326-327. 6. kagee a. symptoms of depression and anxiety among a sample of south african patients. j health psychol 2008; 13: 547-577. 7. olley b. psychopathology and coping in newly diagnosed hiv/aids patients. s afr med j 2003; 93: 928-931. 8. mauri m, fabiano l, bravin s, ricci c, invernizzi g. schizophrenic patients before and after hiv infection: a case-control study. encephale 1997; 23(6): 437-441. 9. robinson r. primary mania versus hiv-related secondary mania of hiv/aids in uganda. am j psychiatry 2006; 163(8): 1309-1311. 10. taylor d, paton, c, kerwin, r. the south london and maudsley nhs foundation trust and oxleas nhs foundation trust prescribing guidelines. london: informa healthcare, 2007: 454-461. 11. insite h. database of antiretroviral drug interactions. 2006. http://www. hivinsite.com/ 12. davidson j. use of benzodiazepines in social anxiety disorder, generalized anxiety disorder, and post traumatic stress disorder. j clin psychiatry 2004; 65: 29-33. 13. wynn g, cozza k, zapor m, wortmann g, armstrong s. antiretrovirals, part iii: antiretrovirals and drugs of abuse. psychosomatics 2005; 46: 79-87. 14. hirsch d, fishman j, jacobsen p, breitbart w, emery m, schwimmer j. treatment of anxiety in hiv positive asymptomatic men with buspirone. international conf aids 1990; 6: 184. 15. kastenholz k, crisman m. buspirone, a novel, non-benzodiazepine anxiolytic. clin pharm 1984; 3: 600-660. 16. gordillo v, del amo j, soriano v, gonzalez-lahoz j. sociodemographic and psychological variables influencing adherence to antiretroviral therapy. aids 1999; 13: 1763-1769. 17. macdaniel j, 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disorder in hispanic hiv and aids patients: a prospective study. psychosomatics 2004; 45(3): 210-216. 23. elliot a, roy-byrne pp. mirtazapine for depression in patients with human immunodefficiency virus. j clin psychopharmacol 2000; 20: 265-267. 24. mills e, montori v, perri d, phillips e, koren g. natural health product-hiv drug interactions: a systematic review. int j std aids 2005; 16(3): 181-186. 25. amiaz r, seidman s. testosterone and depression in men. curr opin endocrinol diabetes obes 2008; 15(3): 278-283. 26. schaerf f, miller r, lipsey j, mcpherson r. ect for major depression in four patients infected with human immunodefficiency virus. am j psychiatry 1989; 146(6): 782-784. 27. kessing l, labianca j, bolwig t. hiv-induced stupor treated with ect. convuls ther 1994; 10(3): 232-235. 28. nakimuli-mpungu e, musisi s, katabira e. primary mania versus secondary mania of hiv/aids in uganda. am j psychiatry 2006; 163: 1349-1354. 29. el-mallakh r. mania in aids: clinical significance and theoretical considerations. int j psychiatry med 1991; 21: 383-391. 30. tanquary j. lithium neurotoxicity at therapeutic levels in an aids patient. j nerv ment dis 1993; 181: 518-519. 31. letendre s, woods s, ellis s, atkinson e, masliah e. lithium improves hivassociated neurocognitive impairment. aids 2006; 20: 1885-1888. 32. dou h, ellison b, bradley j, et al. neuroprotective mechanisms of lithium in murine human immunodeficiency virus-1 encephalitis. j neurosci 2005; 25(37): 8375-8385. 33. dewhurst s, maggirwar s, schifitto g, gendelman h, gelbard h. glycogen synthase 3 beta (gsk-3 beta) as a therapeutic target in neuroaids. j neuroimmune pharmacol 2007; 2(1): 93-96. 34. moog c, kuntz-simon g, caussin-schwemling c, obert g. sodium valproate, an anticonvulsant drug, stimulates human immunodeficiency virus type 1 replication independently of glutathione levels. j gen virol 1996; 77(9): 19931999. 35. lehrman g, hogue i, palmer s, et al. depletion of latent hiv-1 infection in vivo: a proof of concept study. lancet 2005; 366: 549-555. 36. sagot-lerolle n, lamine a, chaix m, et al. prolonged valproic acid treatment does not reduce the size of latent hiv reservoir. aids 2008; 22(10): 1125-1129. 37. schifitto g, peterson d, zhong j, et al. valproic acid adjunctive therapy for hivassociated cognitive impairment: a first report. neurology 2006; 66: 919-921. 38. ances b, letendre s, buzzell m, et al. valproic acid does not affect markers of human immunodeficiency virus disease progression. j neurovirol 2006; 12: 403406. 39. cysique l, maruff p, brew b. valproic acid is associated with cognitive decline in hiv-infected individuals: a clinical observational study. bmc neurol 2006; 6: 42. 40. gualtieri c, johnson l. comparative neurocognitive effects of 5 psychotropic anticonvulsants and lithium. medgenmed 2006; 8(3): 46. 41. hriso e, kuhn t, masdeu j, grundman m. extrapyramidal symptoms due to dopamine-blocking agents in patients with aids encephalopathy. am j psychiatry 1991; 148: 1558-1561. 42. breitbart w, marotta r, platt m, et al. a double-blind trial of haloperidol, chlorpromazine, and lorazepam in the treatment of delirium in hospitalized aids patients. am j psychiatry 1996; 153: 231-237. 43. altschuler e, kast r. the atypical antipsychotic agents ziprasidone, risperidone, and olanzapine as treatment for and prophylaxis against progressive multifocal leukoencephalopathy. med hypoth 2005; 65(3): 633-634. 44. singh a, golledge h, catalan j. treatment of hiv-related psychotic disorders with risperidone: a series of 21 cases. j psychosom res 1997; 42(5): 489-493. 45. meyer j, marsh j, simpson g. differential sensitivities to risperidone and olanzapine in a human immunodefficiency virus patient. biol psychiatry 1998; 44: 191-194. 46. jover f, cuadrado j, andreu l, merino j. reversible coma caused by risperidoneritonavir interaction. clin neuropharmacol 2002; 25: 251-253. 47 sajhiv 1010 reflections within minutes from mseleni to cape town … a k nelson, mb chb corresponding author: a k nelson (aurelie.nelson@gmail.com; msfocb-khayelitsha-eid@brussels.msf.org) dr aurélie nelson is the early infant diagnosis project manager for médecins sans frontières, khayelitsha, cape town, south africa ‘it’s impossible to roll out antiretrovirals in africa!’ i clearly remember hearing this on a daily basis while studying in canada 13 years ago. and there were strong points made: too expensive, not enough doctors, risk of resistance, how to monitor patients in resource-limited settings, and so forth. thankfully, not everyone believed this and we advocated and pressured from all around the world, and the price of antiretroviral therapy (art) did come down, by more than ten times. ten years later, after studying medicine in the united kingdom (uk), i moved to mseleni hospital in northern kwazulu-natal for my ‘voluntary community service’. the medical director of the hospital had been there for more than 30 years and started rolling out art unlawfully before march 2004. he had developed some outreach clinics and managed to have his hospital very well staffed with local and international doctors. with some basic teaching in hiv and tuberculosis (tb), we (the uk doctors) were very soon thrown into the deep end. the first three months of practising were a steep learning curve, particularly in hiv medicine. we were working in the outpatient department where aids patients often presented very late, and on the ward where we had very complex co-infected tb/hiv patients with poor referral systems. the mortality due to hiv/tb was often very high. despite some hiv-positive patients still presenting very late (particularly men), we had good statistics on testing people and good prevention of mother-to-child transmission (pmtct) coverage. as part of my duties, i was visiting an outreach clinic weekly called manaba clinic. most of my work there was to initiate patients on art and to follow up problematic cases. i recall the particular case of a 9-year-old boy who had virological failure on art, despite adherence reinforcement. after only a few months of working with hiv and art, and without access to resistance testing, i felt quite out of my depth. extraordinarily, however, i was able to get advice from an hiv specialist paediatrician in cape town within minutes via the national hiv hotline. following his advice, i started the little boy on lamivudine (3tc) monotherapy as a bridging measure, while waiting for new paediatric formulations to be made available. a few months later, i saw the same 9-year-old boy and his mother for a follow-up appointment. his viral load was now nearly suppressed and i was going to continue the 3tc monotherapy as per the advice i had received, when mum (via a translator) started objecting. she had always been told that her child must take three antiretrovirals, so why was he taking only one drug? wasn’t there a risk of resistance? she made me realise how far we had come in ten years: art was being rolled out to places hundreds of kilometres from the nearest city; patients with basic education were gaining a good understanding of a complex disease; and expert help from thousands of kilometres away was available within minutes over the phone. against all odds, what a long way hiv treatment had come! s afr j hiv med 2014;15(1):13. doi:10.7196/sajhivmed.1010 hiv march make up 01 march 2006 the southern african journal of hiv medicine8 pathophysiology lactate is normally produced by all the body’s cells, as part of anaerobic metabolism. certain cells (such as erythrocytes) lack mitochondria for aerobic respiration and are obligate lactate producers, while other cells will switch to predominant lactate production if the aerobic cycle is compromised, because of either a lack of available cellular oxygen or compromised mitochondrial oxidative phosphorylation. the liver is a key organ for the removal of lactate from the circulation, along with the kidneys. the steady state of lactate production and removal is usually only compromised when there is significant over-production and compromised liver function. impairment of renal function seems to increase the risk. nrtis suppress hiv replication by inhibiting the viral enzyme reverse transcriptase. however, this class of drugs also has the potential to directly inhibit the human enzyme mitochondrial dna polymerase gamma (�), which is responsible for mitochondrial dna synthesis. reduced dna synthesis results in less synthesis of essential mitochondrial proteins. the consequence is the formation of mitochondria which are structurally and functionally impaired, resulting in decreased oxidative capacity of each mitochondrium. lactate overproduction and cellular dysfunction result. different nrtis have different risk profiles for causing hyperlactataemia. their risk is directly proportional to their inhibitory effect on polymerase �, in the following order (highest to lowest risk): 1. combination of didanosine (ddi) and stavudine (d4t) 2. ddi 3. d4t 4. zidovudine (azt) 5. lamivudine (3tc), abacavir (abc) and the nucleotide reverse transcriptase inhibitor, tenofovir (tdf). these drugs are usually only implicated if used in combination with higher-risk drugs. other manifestations of nrti mitochondrial toxicity are hepatic steatosis, peripheral neuropathy, lipoatrophy, pancreatitis, myopathy, cardiomyopathy, hiv-associated neuromuscular weakness syndrome (a guillain-barré-like syndrome that occurs secondary to nrtis3) and cytopenias. definitions a normal venous lactate level is less than 2.5 mmol/l and arterial lactate less than 2.0 mmol/l. hyperlactataemia is present when lactate is raised but blood ph is > 7.35 and standard bicarbonate > 20 mmol/l, and may be asymptomatic or symptomatic. asymptomatic hyperlactataemia is common in patients on nrtis (occurs in up to 25% of patients), but does not predict for the symptomatic form of the disease. it represents a state of physiological compensation. symptomatic hyperlactataemia carries a good prognosis if recognised early and if there is no liver dysfunction. g u i d e l i n e s . . . c l i n i c a l guidelines for the prevention, diagnosis and management of nrtiassociated symptomatic hyperlactataemia and lactic acidosis southern african hiv clinicians society expanding access to antiretrovirals (arvs) in southern africa has dramatically impacted on the lives of those hiv-infected people who are able to obtain these drugs. highly active antiretroviral therapy (haart) has been shown to significantly reduce hiv-related morbidity and mortality in developed and developing world settings.1,2 however, arvs, like most pharmaceutical agents, can result in side-effects and toxicities that in some instances may be life-threatening, especially if there is delay in their recognition. one of the most challenging and dangerous side-effects is symptomatic hyperlactataemia that may evolve to lactic acidosis, a toxicity that may result from treatment with the nucleoside reverse transcriptase inhibitors (nrtis). the first cases were described in the late 1980s, with fatalities being described in 1993. important: the management of this condition is complex and these guidelines are based on expert experience rather than prospective clinical trials. clinical common sense is advised in all cases. guidelines may change as better evidence becomes available. march 2006 the southern african journal of hiv medicine10 lactic acidosis is diagnosed when ph < 7.35 and/or standard bicarbonate < 20 together with raised lactate. the lactate level in this setting is typically > 5. reaching this stage means that significant failure of the physiological compensating mechanisms is present, and this carries a much worse prognosis. in lactic acidosis the ph may be in the normal range (due to respiratory compensation) but the standard bicarbonate is always < 20. there is invariably multiple organ dysfunction, especially hepatic. symptomatic hyperlactataemia occurs in 0.4 9% of patients on nrti therapy, whereas lactic acidosis occurs in 0.1 0.4%.4 risk factors the following have been identified as risk factors: ■ high body mass index (bmi) – evidence from one of the south african cohorts suggests that rapid weight gain is also a risk factor. ■ gender – women are at greater risk. ■ pregnancy – a high risk of lactic acidosis has been noted in pregnancy when the ddi and d4t combination has been used. ■ underlying liver disease – this may impair lactate clearance. ■ age – symptomatic hyperlactataemia/lactic acidosis appears to be unusual in younger children, as are the other manifestations of mitochondrial toxicity, although cases have been reported in south africa. it is unclear whether co-administration with metformin is a risk factor. metformin can also cause lactic acidosis in patients with organ dysfunction. however, it is a key drug in the treatment of diabetes, and its co-administration with nrtis that have a high potential for hyperlactataemia (i.e. ddi, d4t) needs to be considered carefully, weighing the risks and benefits in the individual patient. diagnosis apply the rule: if you consider the diagnosis, do the laboratory investigation immediately. delays in diagnosis may be lifethreatening. many conditions (table i) may result in raised lactic acid and acidosis. hyperlactataemia/lactic acidosis secondary to nrtis is therefore a diagnosis of exclusion. symptoms may be very nonspecific and vague, and have generally been present and getting worse for weeks and occasionally months. key symptoms and signs include: ■ unintentional loss of weight (low) (especially > 5%). ■ gastrointestinal (git) symptoms, including nausea, vomiting, loss of appetite, abdominal pain and hepatomegaly. ■ weakness and fatigue. ■ dyspnoea, tachypnoea without respiratory cause. ■ unexplained tachycardia. ■ myalgia. ■ peripheral oedema. ■ peripheral neuropathy and lipoatrophy often herald the onset of symptomatic hyperlactataemia. the diagnosis is often missed initially, with symptomatic therapy being prescribed for git complaints. it is essential to maintain a high index of suspicion. symptomatic hyperlactataemia/lactic acidosis usually occurs after patients have been on nrtis for several months (median 9 months). typically the patient has initially experienced resolution of hivand opportunistic infection-related symptoms, has gained weight in the months after starting haart and is virologically suppressed, then experiences a deterioration with the onset of hyperlactataemia and its associated weight loss and symptoms. however, we have documented rare cases in our cohorts that have occurred after only 2 months. it is unusual for symptomatic hyperlactataemia/lactic acidosis to develop after 2 years on therapy, but we have seen exceptions to this. clinical assessment should include evaluation of respiratory rate, abdominal examination and assessment for peripheral neuropathy. tachypnoea in the absence of a respiratory cause is suggestive of metabolic acidosis. the diagnosis is made by measuring venous or arterial lactate. the blood sample should be taken without the use of a tourniquet in a sodium fluoride tube and should reach the laboratory within 20 minutes on ice. however, if the sample is centrifuged on site and serum separated the serum sample then has 24 hours to reach a central laboratory. point-of-care devices for lactate measurement are particularly useful for primary care and rural facilities where access to a laboratory that is able to measure lactate is difficult. these devices have been validated in icu settings and reliably determine lactate levels within ± 1 mmol/l of the laboratory measurement.5 however, they have not yet been validated in a busy clinic setting. it is important that the blood used for the measurement is taken by venepuncture without a tourniquet and is not a fingerprick sample – the latter method has been shown to falsely elevate the lactate level at sites using these devices. when doing blood gas sampling it is important to expel all residual heparin from the syringe before taking the sample. failure to do this will cause a false lowering of ph. liver function tests, creatinine kinase, lipase and lactate dehydrogenase may be elevated in association with the lactate, but these do not have the necessary sensitivity or ■ sepsis ■ severe cardiac failure ■ severe anaemia ■ severe dehydration ■ hepatic failure ■ thiamine deficiency ■ renal failure ■ other drugs (e.g. inh overdose, ■ pancreatitis metformin) table i. causes of hyperlactataemia/lactic acidosis other than nrtis march 2006 the southern african journal of hiv medicine12 specificity to be used as reliable diagnostic tests. it is, however, important to check lipase and liver functions in all patients with confirmed symptomatic hyperlactataemia/lactic acidosis to assess for coexistent pancreatitis and steatohepatitis. blood gas levels should also be checked in all patients with symptomatic hyperlactataemia to confirm or exclude metabolic acidosis. once nrti-associated lactic acidosis is established, it represents a profound metabolic insult. when the nrtis are removed, it takes weeks to months to resolve. differential diagnosis other causes for low and abdominal pain may mimic or coexist with hyperlactataemia/lactic acidosis. other causes for low to consider: ■ opportunistic infections (ask about tuberculosis symptoms). ■ lipoatrophy. ■ chronic diarrhoea with malabsorption. ■ virological failure. ■ depression. ■ malignancy. ■ undiagnosed diabetes. ■ poor diet and poor social circumstances. ■ hyperthyroidism. other causes for abdominal pain/symptoms to consider: ■ pancreatitis (check lipase). ■ hepatitis/steatohepatitis (check alt/alkaline phosphatase and assess for hepatomegaly). ■ opportunistic infections or immune reconstitution inflammatory syndrome (iris) (e.g. abdominal tb). ■ git intolerance of medication, especially if on concomitant tb treatment. hyperlactataemia is often incorrectly diagnosed as this. gi intolerance to drugs rarely develops after months of therapy. ■ unrelated causes (e.g. pregnancy, diabetic ketoacidosis, appendicitis, peptic ulcer disease, pelvic inflammatory disease, urinary tract infections, pneumonia). other causes of tachypnoea and tachycardia, with or without the above: ■ respiratory conditions. ■ cardiac conditions. ■ anaemia. ■ sepsis. ■ diabetic ketoacidosis. ■ hyperthyroidism. ■ hypoperfusion due to diarrhoea, vomiting or inadequate fluid intake. confounders there are several causes of lactic acidosis other than nrtis that need to be considered before the diagnosis is made (see table i). hiv-infected patients frequently present with infective gastroenteritis with diarrhoea and vomiting. if severe this may result in profound dehydration with poor tissue perfusion and a raised lactate level. in this situation once the patient is resuscitated with fluids the lactate will normalise. if the lactic acidosis is incorrectly attributed to the nrtis in this situation an inappropriate interruption and switch in therapy may result. this may compromise future haart options. similarly, septicaemia and other bacterial infections (e.g. pneumonia) may result in lactic acidosis that will resolve with fluid resuscitation, appropriate antibiotics and other supportive therapies. however, to complicate matters further opportunistic infections and bacterial sepsis may unmask mitochondrial toxicity and precipitate a presentation with hyperlactataemia/lactic acidosis. even with adequate fluid resuscitation and appropriate treatment for their infection these patients have persistently raised lactate levels. the presence of an infection therefore does not exclude the fact that the lactic acidosis is contributed to by the nrtis. prevention recognising the syndrome before the person becomes acidotic is the most effective prevention, and symptoms tend to occur long before severe laboratory abnormalities are present. the mortality and morbidity of the condition dramatically increases in the presence of acidosis. the mortality rate with lactic acidosis is 30 60%. a practical approach is to educate patients to report any loss of weight, abdominal pain or vomiting lasting more than a few days, excessive fatigue, lipoatrophy or peripheral neuropathy symptoms (see addendum – patient education poster, p. 15). weights should be monitored at every clinic visit, and when they drop by > 5% the lactate level should be measured, even if no other symptoms are present. any patient with a severe or rapidly progressive nrti-induced neuropathy (typically due to d4t or ddi) should also have the lactate level measured. there is evidence that reducing the dose of d4t is associated with less toxicity (including hyperlactataemia) and equal efficacy. patients developing other d4t-induced side-effects (e.g. peripheral neuropathy) should have their dose reduced (e.g. from 40 mg bd to 30 mg bd for those weighing > 60 kg, and from 30 mg bd to 20 mg bd in those < 60 kg) or switched to azt. another preventive strategy is to start women with a bmi > 28 on nrtis with a lower risk of hyperlactataemia (3tc, abc or tdf – but in the south african public sector azt rather than d4t in the first-line regimen) or to switch them to these nrtis if they gain weight to a bmi > 28 on haart. this is a particularly high-risk group. it is prudent to avoid using ddi and d4t in the same haart regimen as this combination carries the highest risk for mitochondrial toxicity. this combination should only be used if there are no other options available. routine lactate measurement in asymptomatic patients is not recommended, as the correlation with the development of the southern african journal of hiv medicine march 2006 symptoms is poor. up to 25% of patients on nrtis have asymptomatic hyperlactataemia with mild elevations in lactate levels, but only a minority will develop symptoms. elevated lactate levels in the absence of symptoms are not a good predictor of symptomatic hyperlactataemia. management once the diagnosis is confirmed (raised lactate and exclusion of other causes), the following guidelines are suggested. different facilities will have different treatment and monitoring options. stop the regimen even before the diagnosis is biochemically confirmed if you have a high index of suspicion. do not stop the nrtis alone – stop the entire regimen. it is better to interrupt a regimen for a short period than to continue a toxic regimen in the presence of suspected lactic acidosis. the treatment guidelines presented below are largely based on anecdotal experience with the condition, by local and international clinicians and other published guidelines.4,6-8 there are no prospective studies on the treatment of hyperlactataemia/lactic acidosis, and caution and common sense is urged by the guideline authors in all cases. these guidelines are based on the experience in south africa being that most cases of symptomatic hyperlactataemia/lactic acidosis are caused by d4t in first-line therapy. we strongly urge that you consult an experienced treater in all cases, especially if d4t is not the offending drug. mild hyperlactataemia and minimal symptoms (lactate 2.5 5 and no metabolic acidosis standard bicarbonate > 20) the nrti regimen should be switched to agents that are less likely to cause lactic acidosis (3tc, abc or tdf if available – in the south african public sector switch from d4t to azt in the first-line regimen) and the lactate rechecked within 3 days and then weekly until normalised. if symptoms are severe or the lactate continues to rise, or symptoms get worse despite the switch, haart should be stopped and an expert treater consulted regarding the decision as to which haart to restart when the lactate level has normalised. if the lactate cannot be monitored in the way described, treatment should be stopped and treatment restarted when the lactate level has normalised and symptoms have resolved, following the guidelines below. moderately severe hyperlactataemia/moderate metabolic acidosis (lactate 5 10 and/or standard bicarbonate 15 20) these patients should stop haart, be observed as an inpatient for 1 2 days, and given oral vitamins (vitamin b complex 2 tablets bd and thiamine 100 mg bd), be well hydrated (orally or ivi) and have sepsis/opportunistic infections excluded. the lactate level should be rechecked, and when it is falling the patient can be discharged for outpatient follow-up provided he or she is clinically stable. haart should only be recommenced when lactate and bicarbonate have normalised (this may take months), and the decision regarding what regimen to restart should be discussed with an experienced treater. the choice as to what to recommence is one of: 1. azt, 3tc and non-nucleoside reverse transcriptase inhibitor (nnrti) with lactate monitoring at 2 weeks, 4 weeks and then monthly for a further 2 months and at any time symptoms recur. this is not an option if the patient had metabolic acidosis (standard bicarbonate < 20). it is important to note that there is limited evidence for the safety of recommencing azt in this setting.6 2. tdf/3tc/nnrti or abc/3tc/nnrti with lactate monitoring as above. 3. nnrti with kaletra (kaletra dose here is 4 capsules bd due to nnrti induction of kaletra metabolism). lactate monitoring not required. 4. dual-boosted pi regimen (e.g. kaletra + saquinavir). lactate monitoring not required. this option is preferable to (3) if nnrti resistance is documented or strongly suspected, but the option is not available in many southern african public sector programmes. this decision is based on the prior haart history, clinical picture, lactate level, arterial blood gas, degree of steatohepatitis at presentation and ability to monitor lactate on recommencement. patients with more severe disease should be recommenced on (3) (or (2) or (4) if available in the private sector), whereas those with a milder syndrome could be recommenced on (1). if a metabolic acidosis was present (1) should not be recommenced. there is no risk of recurrence of hyperlactataemia with (3) or (4), whereas with (1) there is a risk that azt may cause relapse of hyperlactataemia (although the risk is lower than with d4t). there is less of a risk of recurrence with (2) than with (1), as abc, tdf and 3tc have been infrequently associated with hyperlactataemia and usually when used in combination with a drug that is more likely to cause mitochondrial toxicity. also, the decision as to when to restart haart is a balance between the patient’s nadir cd4, their current cd4 and the severity of the hyperlactataemia/lactic acidosis. patients with low nadirs should not have haart withheld for too long, as they run the risk of acquiring new opportunistic infections. if lactate levels are persistently elevated in a patient with a low nadir cd4 count, a regimen without a risk of occurrence (nnrti/kaletra or dual-boosted protease inhibitor (pi)) should be considered and can be commenced before lactate has normalised. patient education is critical. patients with hyperlactataemia/lactic acidosis being rechallenged with a safer nrti should understand the need for regular follow-up. patients who live far from the health care facility, have transport difficulties, are unreliable or have follow-up compromised in any way, should not have nrtis reintroduced. 1 3 march 2006 the southern african journal of hiv medicine14 severe hyperlactataemia (lactate > 10 without metabolic acidosis) or significant lactic acidosis (raised lactate regardless of level and significant metabolic acidosis – standard bicarbonate < 15) these patients should preferably be managed in a high-care facility as follows: ■ stop haart ■ ivi thiamine 100 mg 12-hourly and b-complex vitamins 1 amp 12-hourly. ■ ivi fluids. ■ blood culture/urine culture/septic search and broadspectrum antibiotic (e.g. third-generation cephalosporin or co-amoxyclav). this is important because sepsis may mimic or precipitate nrti-associated lactic acidosis. ■ consider ivi nahco3 if profound acidosis (e.g. 150 ml of 8.5% sodium bicarbonate added to a vacolitre of 5% dextrose water and infused at 80 100 ml per hour). ■ consider ventilation if respiratory fatigue occurs. ■ dialysis, inotropes and other supportive measures as necessary. ■ coenzyme q, l-carnitine and other mitochondrial cofactors are used by some when available, but have very limited evidence for efficacy. ■ if pancreatitis is present patients should be kept nil per mouth. ■ monitor lactate, blood gas, lipase, alt and alkaline phosphatase. some of these patients demonstrate a biphasic course with initial improvement and then deterioration, often when they develop a superimposed pancreatitis. these patients should be recommenced on kaletra (lopinavir/ritonavir) 4 capsules bd and nnrti or a dual boosted pi regimen (options (3) and (4) above) when lactate has normalised (this may take months). other regimens that could potentially be used in these patients with less severe presentations are tdf/3tc/nnrti or abc/3tc/nnrti with lactate monitoring on rechallenge as described above (option (2) above). covering the ‘nnrti tail’ with lopinavir/ritonavir (kaletra) when a haart regimen containing an nnrti (nevirapine or efavirenz) is stopped the nnrti persists in the plasma for 1 2 weeks because of the long half-life of these drugs, unlike the nrti component. this ‘nnrti tail’ means that there is effective monotherapy with the nnrti after the haart is stopped, which predisposes to the development of nnrti resistance. provided patients are not vomiting and do not have either significant steatohepatitis or pancreatitis, it is suggested that when an nnrti-containing regimen is stopped because of hyperlactataemia or lactic acidosis, 7 days of kaletra (lopinavir/ritonavir) 4 tablets bd are prescribed to cover the nnrti tail, thereby preventing effective monotherapy and the risk of nnrti resistance developing. paediatric hyperlactataemia/lactic acidosis initially paediatric symptomatic hyperlactataemia/lactic acidosis was considered very rare, but several local cases have been reported. experience with this group is very limited, but symptoms and signs similar to those in adults seem to be present, although the differential diagnosis may be different. management is similar to that of adults in terms of cessation of treatment and supportive measures. however, specialist advice should be sought in all cases. prognosis poor prognostic markers are high lactate level, severe acidosis and coexistent pancreatitis. patients who require ventilation and/or dialysis appear to have an extremely poor prognosis. switching to azt when d4t is switched to azt it is frequently forgotten that monitoring for azt haematological toxicity is required. the full blood count and differential count should be checked at baseline, then at 1, 2, 3 and 6 months, then 6-monthly. do not start azt in patients with a haemoglobin concentration < 8 g/dl. the future broader availability of tdf and abc may make hyperlactataemia/lactic acidosis less common in the future. until then, the availability of hand-held lactate monitors makes onsite diagnosis and monitoring a reality in public sector clinics. increased access to these devices is encouraged. references 1. pallela fj, delaney km, moorman ac, et al. declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. n engl j med 1998; 338: 853-860. 2. coetzee d, hildebrand k, boulle a, et al. outcomes after two years of providing antiretroviral treatment in khayelitsha, south africa. aids 2004; 18: 887-895. 3. simpson d, estanislao l, evans s, et al. hiv-associated neuromuscular weakness syndrome. aids 2004; 18: 1043-1412. 4. calza l, manfredi r, chiodo f. hyperlactataemia and lactic acidosis in hivinfected patients receiving antiretroviral therapy. clin nutr 2005; 24(1): 5-15. 5. brinkert w, rommes jh, bakker j. lactate measurements in critically ill patients with a hand-held analyser. intensive care med 1999; 25: 966-969. 6. lonergan jt, barber re, mathews wc. safety and efficacy of switching to alternative nucleoside analogues following symptomatic hyperlactatemia and lactic acidosis. aids 2003; 17: 2495-2499. 7. british hiv association (bhiva) guidelines for the treatment of hiv-infected adults with antiretroviral therapy. 2005. http: //www.bhiva.org/guidelines/ 2005/hiv/hiv05frameset.html (last accessed 20 february 2006). 8. grunfeld c, kotler dp, mulligan k, powderly wg, saag ms, management of metabolic complications associated with antiretroviral therapy for hiv-1 infection: recommendations of an international aids society-usa panel. j acquir immune defic syndr. 2002; 31(3): 257-275. contact number. if there are any queries contact the medicines information centre hiv hotline (south africa) (021) 406-6782. acknowledgement. this article is based on the practical experience of a large number of southern african clinicians as well as published evidence. guideline committee. convenor: graeme meintjes; committee: francois venter, francesca conradie, june fabian, gary maartens, douglas wilson. the southern african journal of hiv medicine march 2006 1 5 addendum. patient education poster risk factors: on d4t or ddl (occasionally occurs with azt) overweight (but can be normal weight) on arvs > 2 months (usually > 6) female neuropathy exclude other causes of acidosis – sepsis, severe anaemia, renal or hepatic failure, pancreatitis, congestive cardiac failure (ccf), severe dehydration, thiamine deficiency, diabetic ketoacidosis (dka), other drugs suspicious symptoms and signs • unintentional recent loss of weight • anorexia • abdominal pain • nausea and vomiting • dyspnoea, tachypnoea without respiratory cause • unexplained tachycardia lactate < 2.5 check lactate hyperlactataemia excluded, investigate for other causes in patients with raised lactate check • blood gas • lipase • lft stop haart and admit supportive therapy and maintain adequate hydration (po or ivi) investigate for sepsis, opportunistic infections and pancreatitis in patients who are acutely ill do blood culture and start broad spectrum antibiotic see guidelines for drug choices for restarting haart once lactate has normalised. consult expert. never use d4t or ddl again switch d4t to azt, tdf or abc as available repeat lactate in 3 days, then weekly until normal rather stop haart and get expert advice if: 1. lactate cannot be monitored 2. symptoms severe 3. nrti other than d4t causative 4. symptoms worsen or lactate continues to rise after switch mild lactate 2.5 5, minimal symptoms and bicarb > 20 moderately severe lactate 5 10, and/or bicarb 15 20 severe lactate > 10 and/or bicarb < 15 august 2001-----------the southern african journal of hiv medicine student training hiv education and health care students where are we going? ever-changing perceptions of health care students successful post-exposure prophylaxis (pep) and the commonplace occurrence of occupational hiv exposure incidents recently seems to have diminished the extent of the often expected horrified reaction to occupational exposure. worrying as that statement may be, health care students' everyday and repetitive encounter with the tragedy of hiv!aids may well evoke a dangerous and complacent attitude and a possible non-caring ethos akin to 'hiv fatigue:' health educators and all members of this profession need to rise to this challenge and ensure health care quality in the age of a changing infectious disease status. although this argument may not be a new concept and problem for health care students and practising professionals, the overwhelming nature and high prevalence rate of this epidemic, and its ramifications that involve individual, family and community suffering and the socio-economic and human rights aspects, place the approach to this infection in a unique light. there can be no doubt that students will work with hivinfected individuals, and each one will be affected by this disease and long-term illness. initially and in the recent past, students expressed a variety of feelings and attitudes in their approach to infected patients' dread of acquiring the infection as a result of workplace exposure, fear of potential exposure to concomitant and opportunistic infections in immunosuppressed patients, and the lack of skills and emotional burden of dealing with terminally impact of hiv as the 20th anniversary of the first report of an aids case in 1981 approaches, hiv poses one of the greatest public health challenges of this era.' whether or not it is or will be the greatest health challenge for mankind remains to be seen or debated; nonetheless the hiv pandemic is of herculean proportion. it has been estimated that more than 40 million people globally were infected with this virus by the end of the year 2000.' in addition, 70% of those infected live in sub-saharan africa.' analysis of the data from the unlinked anonymous 1999 south african hiv seroprevalence survey of women attending publicly funded antenatal clinics has submitted the following conclusions: • hiv in south africa is one of the fastest growing epidemics worldwide • the highest prevalence rates are in women aged 20 30 years, and • the hiv prevalence differs for each province, with kwazulu-natal exhibiting a rate of 32.5%.' the current status of hiv/aids statistics for southern africa highlights and elevates the plight of health care students, already burdened by the specific nature of their training under the peculiar circumstances now prevailing in south african hospitals and training centres. the everyday and repetitive encounter with the tragedy of hiv/aids may well evoke a dongeraus and complacent attitude on the part of health care students and a possible non-coring ethos akin to 'hiv fatigue: health educators and all members of this profession need to rise to this challenge and ensure health core quality in the age of a changing infectious disease status. it is not unreasonable to expect that 60 70% of beds in publicly funded and tertiary hospitals may be occupied by hiv-infected patients. south african health care workers remain at high risk of occupational hiv exposure, illustrated partly by this high hiv prevalence rate. this high risk elevates the plight of health care students, already burdened by the specific nature of their training under the peculiar circumstances now prevailing in south african hospitals and training centres. although there still exists a dread of acquiring this bloodbarne virus, the availability of lynne m webber, mb ehb, mmedpath (viro!), dth department of medical virology, university of pretoria penelope a richards, phd depart11lellt of anatomy, university of pretoria somarie v grey, dsc deputy dean, faculty of medicine, university of pretorm the southern african journal of hiv medicine ----------august 2001 diseased young people appeared to be the most dominant emotions.' this hiv epidemic is continuing to evolve in south africa; it has not yet peaked and students will continue to see its ravages for a considerable period. in turn, the epicentre of the aids epidemic is still awaited and health care students will have to be prepared to handle a large and growing number of terminally ill young patients and children as a natural part of their training and future direction. the recent media attention during and after the xlilth international aids conference in durban focused attention firmly on the fact that little has been done to awaken the south african government from its torpor.' in addition, a recent comment in a renowned international journal, noture medicine, entitled 'south african government continues policy of inactivity', alluded strongly to issues that were not scientifically addressed, such as reduction of mother-to-child transmission' reading about such worrying approaches to matters that form critical components of their training and future attitudes, points to the fact that students need constructive support in order to shape their caring and professional ethos. real issues have to be tackled by students wherein they deal regularly with hiv-infected patients denied access to treatment and intenention strategies proven to be successful but financially beyond the reach of most infected individuals. most health care curricula expect the student to know about the latest developments in hiv management, therapy and intenention, yet little may be in place to teach them how to apply this knowledge and the facilities to patients.' these attitudes, together with the possible ethos of hiv fatigue creeping insidiously into the south african health care profession, will impact significantly on student perceptions. in addition, perceptions of a killer disease that is crippling the infrastructure within south africa will change from the junior to the senior student. these problem areas and others, such as the following, have already been identified by health care educators and students.'.' should hiv-positive health care students be allowed to continue their training? this question tends to assess the rights of both the student and patient can health care training institutions turn down or stop the training of an individual in a given health care field should they contract hiv/aids? should such institutions, in recognising the potential risk hiv/aios poses, be insisting on compulsory hiv testing on a regular basis, despite the individual's constitutional rights) do patients have the right to refuse treatment or contact with an hiv-infected student? do only those patients who can afford private care have the right to choose who will care for them? although most of the questions have clear-cut answers or directions according to the constitutional rights of each south african, they still pose dilemmas that require thought, debate and action. who should be responsible for insuring the student against hiv? the question begs to be asked should such insurance be compulsory? considering the economic devastation of this infection coupled with individual expense, it is not unreasonable to expect the training institution to provide such insurance for all individuals in training. ideally, this cost should be borne by the training institution as part of the safe environment for students. in turn, in the absence of the provision of a safe environment, through no fault of the student, the institution should be prepared to find alternative safeguards.' by whom and when should a national pouc be devised to address these emotive issues? any national policy should be inclusive, therefore it is mandatory that all stakeholders be involved in this process. as students are at the forefront of this issue, strong student leadership is essential. in addition, health care educators, administrators and health care professionals must be consulted. a top-down policy is doomed to failure should bottom-up buy-in not be sought. when one considers all the currently available hiv/aios statistics in south africa, such a policy appears to be long overdue. how can educational values be reinforced) a major paradigm shift is required among health care educators in order to alter attitudes of students working in surgical and internal medicine environments where hiv/aids may feature commonly. truly integrated curricula, with an emphasis on community and evidence-based health care, go a long way towards encouraging an educationally sound basis to attitude transformation. however, how do health care educators identify solutions to these problems and still keep such education healthy? the role forward for health care educators the faculty of medicine at the university of pretoria has recently devised various action plans to address pertinent issues such as the provision and cost bearing of chemoprophylaxis following occupational exposure to hiv, and voluntary membership for all students and staff of a specifically designed hiv insurance scheme (this was cancelled at the last moment because of technicalities that arose after the promulgation of the new medical schemes act, which caused the underwriters of the scheme to withdraw their support), and it has drawn up a policy references august 200 i -----------the southern afr.ican jour.nal of hiv medicine 1 l~vl j the public health challenges of the hiv epidemic (editorial). am j public health 2000; 90: 1023-1024. 2. alien om, simelela np, makuabalo l epidemiology of hiv/aids in soum africa the southern african journal ofhivmroicine 2000; 1: 9-11. 3. kramer s. aids still more mmp!ace.(\~? health and hygiene 2cklo; 11: 26. 4. pantanowitz l, connel! l attitudes and perceptions of medical and allied m~ical students towards hiv/aids. south afr j epidemio/lnfect 1996; 11; 99103. 5. missed opportunities in durban [editorial). nature medicim: 2000; 6: 839. 6. birmingham k. south african government continues policy of inactivi[)'. nature medicine 2000; 6: 843. 7. webber w, richards pa, grey w. hiv prophylaxis: afe south african healthcare students bl"ing negll"ctl"d7 safrj sei 2000; 96: 295-296. 8. dl"partment of education. annual report. 1999. pretoria: doe, 2000: 157 161. conclusion the correct and caring altitudes of health care students and professionals must be cherished and should be deemed an urgent and necessary goal for all involved in health care education in south africa. considering the health care of infected students and professionals.' yet this is only the beginning, and monitoring of these actions and new directives is required. relevant data must be compiled, rationally analysed and the knowledge gained fed through to all students and professionals using a continuous reporting system. quality of health care education can be maintained and improved even in times of change, but this will require a detailed research agenda: partnerships must also be nurtured and involve input and output from other faculties and universities. a system must exist for the support of all levels of students and all ranks of professional staff members, incorporating the continuous feedback reporting service that is kept open for discussion (c coombes, 'hiv/aids and the education sector strategic plan: education sector planning learning to live with aids' paper prepared for the educator sector strategic plan first annual rev·,ew meeting, maputo, may 1999). finally, a support structure should also be in place to support and guide hiv-infected students and professionals as well as those burdened and crippled by the impact of hiv on their families, communities and peers. an annual report from the department of education has cited that there are 300 000 university students, 190000 technikon students and close to 73 000 other and support personnel within the education system' in turn, there are just over 12 million pupils at school (50.5ofa female), supported by about 375 000 teachers' not only are many of these destined to become health care students or participants within the health care system, but many will become victims of this system. accordingly the impact of hiv/aids as a whole on education in south africa needs to be addressed. recently, the youth aids project was launched and has been described as a non-profit project with a board of directors consisting of the deans of the medical schools. or atholl kent, national director of the project, has .cited the aims in the executive summary, namely to reduce the spread of hiv!aids among young south africans, and to provide them with tools to be compassionate and effective in dealing with hiv/aids in their lives and communities. as another part of the project, medical students will be afforded the opportunity of informing other young south africans about hiv/aids. this project, and many other initiatives in south africa and africa, offer hope, optimism and encouragement. however, attitudes of complacency and hopelessness must be guarded against and again, feedback and data analysis must be readily and frequently available. education in south africa make up march 2007 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e m a r c h 2 0 0 7 53 since the begining of hiv pandemic 25 years ago, kaposi’s sarcoma (ks) has been detected in aids patients, and it is considered an aids-defining illness.1,2 the first report on disseminated ks in younger homosexual men from the usa contrasted with the three forms of ks previously described in elderly persons from mediterranean countries, in children and adults from the sub-saharan countries, and in post-transplant patients receiving corticosteroid and immunossupressive therapies.3 ks in aids patients assumed a more aggressive pattern, disseminating into the viscera and being associated with a greater likehood of death. ks in aids or ‘epidemic’ ks has been detected worldwide and is related to mode of hiv transmission: high frequencies of ks have been observed among homosexual men and low frequencies among haemophiliacs, suggesting that a sexually transmitted agent could account for the tumour.4-6 in fact, in 1994 a novel human herpesvirus provisionally called kaposi’s sarcoma-associated herpesvirus (kshv) and more recently named human herpesvirus 8 (hhv-8) was detected in ks lesions from aids patients.7 the same herpesvirus was subsequently detected in all forms of ks, classic, endemic, and iatrogenic.3 interestingly, after the introduction of haart, a reduction in the number of ks/aids cases was observed in the western world.8 in vitro and in vivo studies supported the benefit of antiretroviral therapy in controlling hhv-8 growth and disease development and progression.9-12 the tat protein of hiv was implicated in enhancing the entry of hhv-8 into endothelial cells, and/or in increasing hhv-8 viral load by reactivation of hhv-8 from a latent state.12,13 antiretroviral therapy could therefore have a synergistic effect on ks/aids, allowing immune reconstitution and the clearance of hiv and consequently of hhv-8. in 1994, antiretroviral treatment in aids patients was started in brazil, first with transcriptase inhibitors, and from 1996 also with protease inhibitors. since then, a decrease in the number of ks/aids cases has been detected by the brazilian ministry of health. in são paulo, brazil, a seroepidemiological study conducted by our group in hiv/aids patients receiving antiretroviral therapy revealed 17% hhv-8-seropositive cases, and a 5-year follow-up showed that only 2% of these patients developed ks.14 this result contrasts with the 20% prevalence of ks in aids patients detected in the same region before the haart era. taking these data into account, we advocated the use of antiretroviral therapy in developing countries where ks is endemic, such as in sub-saharan africa, in order to fight both hiv and hhv-8 infections and diseases.15 since then we have been trying to detect hhv-8 infection in several populations from brazil, searching for at-risk individuals, the hhv-8 subtypes, and the routes of virus transmission/acquisition. by means of in-house serological assays we were able to detect hhv-8-endemic populations among amerindians from amazonia,16 homosexual/ bisexual men and promiscuous women,14,17-19 and hiv-infected children.20 using dna sequencing of hhv-8 orf k1 we were able to detect the three most common hhv-8 subtypes described around the world (a, b and c) in hiv/aids patients from são paulo, south-east brazil, and subtype b in a similar population from salvador (north-east brazil).21-23 these data may reflect the ethnic background of the individuals who live in these regions; são paulo received european and asiatic immigrants during its colonisation and has a mixed race/colour population, while salvador was colonised by black individuals from africa during the african slave trade, so black/mullatto is the predominant population. furthermore, among indians from the amazon region (northern brazil) we detected hhv-8 subtype e, which is phylogenically related to subtype d (australasia) and subtype hok (north of japan), along with hhv-8 subtype a.23 we o p i n i o n the fight against kaposi’s sarcoma in aids – lessons from brazil adele caterino-de-araujo, phd instituto adolfo lutz, immunology department, são paulo, brazil this article presents a brief review on ‘epidemic’ kaposi’s sarcoma (ks), an aids-defining illness, and laboratory data obtained by a group of researchers from são paulo, brazil, concerning the aetiological agent of ks (human herpesvirus 8, hhv-8). brazil earned international acclaim in the fight against aids, providing universal free access to antiretroviral treatment for all patients and promoting education programmes for blocking virus transmission/acquisition. drawing on her experience, the author suggests the use of highly active antiretroviral therapy (haart) to combat aids and ks in countries where both diseases are epidemic. the lessons learned by brazil, a developing country, and the techniques used there might help sub-saharan countries to fight hiv and ks/aids, decreasing morbidity and mortality in these geographical regions. make up march 2007 30/3/07 11:29 am page 53 m a r c h 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e54 speculated that there could have been prehistoric migration of hhv-8-infected native populations from asia through north america, reaching the north region of brazil, resulting in the maintenance of hhv-8 subtype e in isolated populations from brazil, but this hypothesis needs to be confirmed by phylogenetic analysis of several isolates. of interest was our finding of an alternative method for hhv8 subtyping that utilises a restriction fragment length polymorphism analysis of orf k1 (vr1) instead of sequencing assay.21,22 this technique is able to rapidly subtype hhv-8, and it could be used in developing countries because of its low cost. we still do not know whether there is a correlation between hhv-8 subtype and virus pathogenicity, but we are attempting to correlate hhv-8 subtype and tumour aggressiveness. on the other hand, it seems evident that the routes of virus transmission differ between endemic and epidemic hhv-8 regions; sexual virus transmission could account for ks infection in adults from endemic and epidemic areas, and horizontal transmission for infection in children and infants from endemic areas.3 using nested pcr for detecting several dna segments of hhv8, we confirmed hhv-8 shedding in blood, saliva, and urine from hiv/aids patients with and without ks, and suggested virus transmission/acquisition by these body fluids.24 in addition, we recently found hhv-8 shedding in urine and suggested virus transmission in populations living in poor socioeconomic and sanitary conditions,25 as previously demonstrated in a study conducted among ugandan families with limited access to water and consequently poor hygiene.26 several sanitary practices that prevent contact with saliva and urine could therefore be employed in developing countries to avoid virus transmission/acquisition. brazil and africa share several sociodemographic characteristics and sanitary conditions: south america and africa are both large continents, their populations are educationally and socioeconomically diverse, rural and urban areas in both have very different populations and sanitary conditions, and both experience a large number of tropical and infectious diseases. in spite of this, brazil has earned international acclaim in the fight against aids by a series of programmes including prevention and free access to antiretroviral treatment for all patients.27,28 the lessons learned in brazil, our experiences and the data we have gathered could therefore help developing countries to fight and control hiv/aids, especially in africa where ks is endemic. references 1. friedman-kein ae. disseminated kaposi’s sarcoma syndrome in young homosexual men. j am acad dermatol 1981; 5: 468-471. 2. goedert jj. the epidemiology of acquired immune deficiency syndrome malignancies. semin oncol 2000; 27(4): 390-401. 3. hengee ur, ruzicka t, tyring sk, et al. update on kaposi’s sarcoma and other hhv-8 associated diseases part 1: epidemiology, environmental predisposition, clinical manifestations, and therapy. lancet infect dis 2002; 2(5): 281-292. 4. haverkos hw, drotman dp. prevalence of kaposi’s sarcoma among patients with aids. n engl j med 1985; 312: 1518. 5. beral v, peterman ta, berkelman rl, jaffe hw. kaposi’s sarcoma among persons with aids: a sexually transmitted infection? lancet 1990; 335: 123-128. 6. tappero jw, conat ma, wolfe sf, berger tg. kaposi’s sarcoma. epidemiology, pathogenesis, histology, clinical spectrum, staging criteria and therapy. j am acad dermatol 1993; 28(3): 371-395. 7. chang y, cesarman e, pessin ms, et al. identification of herpesvirus like dna sequences in aids-associated kaposi’s sarcoma. science 1994; 266: 1865-1869. 8. jones jl, hanson dl, dworkin ms, jaffe hw. incidence and trends in kaposi’s sarcoma in the era of effective antiretroviral therapy. j acquir immune defic syndr 2000, 24(3): 270-274. 9. lebbé c, blum l, pellet c, et al. clinical and biological impact of antiretroviral therapy with protease inhibitors on hiv-related kaposi’s sarcoma. aids 1998; 12: f45-f49. 10. cattelan am, calabrò ml, gasperini p, et al. acquired immunodeficiency syndrome–related kaposi’s sarcoma regression after highly active antiviral therapy: biologic correlates of clinical outcome. j natl cancer inst monogr 2000; 28: 44-49. 11. rezza g, dorrucci m, serraino d, et al. incidence of kaposi’s sarcoma and hhv8 seroprevalence among homesexual men with known dates of hiv seroconversion. aids 2000; 14: 1647-1653. 12. aoki y, tosato g. hiv-1 tat enhances kaposi sarcoma-associated herpesvirus (kshv) infectivity. blood 2004; 104(3): 810-814. 13. harrington w jun, sieczkowski l, sosa c, et al. activation of hhv-8 by hiv-1 tat. lancet 1997; 349: 774-775. 14. caterino-de-araujo a, carbone phl, martinelli flb, et al. absence of an association between the presence of hhv-8 antibodies and the development of kaposi’s sarcoma in hiv-1-infected patients receiving antiretroviral therapy. aids 2000; 14: 1455-1457. 15. caterino-de-araujo a, carbone phl, martinelli flb, et al. lack in detecting an association between the presence of human herpesvirus 8 antibodies and the development of kaposi’s sarcoma in hiv-1-infected patients receiving antiretroviral therapy. paper presented at the xiii international aids conference, durban, south africa, 2000. abstract book volume ii, weora474, p. 4. 16. cunha amg, caterino-de-araujo a, costa scb, et al. increasing seroprevalence of human herpesvirus 8 (hhv-8) with age confirms hhv-8 endemicity in amazon amerindians from brazil. j gen virol 2005; 86(9): 2433-2437. 17. caterino-de-araujo a, calabrò ml, santos-fortuna e, suleiman j, chiecobianchi l. searching for human herpesvirus 8 antibodies in serum samples from patients infected with human immunodeficiency virus type 1 and blood donors from são paulo, brazil. j infect dis 1999; 179: 1591-1592. 18. caterino-de-araujo a, cibella sel. searching for antibodies to hhv-8 in children born to hiv-1 infected mothers from são paulo, brazil. relationship to maternal infection. j trop pediatr 2003: 49 (4): 247-250. 19. caterino-de-araujo a, santos-fortuna e, carbone phl, cibella se, moreira aa. human herpesvirus 8 (hhv-8) antibodies among women from são paulo, brazil. association with behavioral factors and kaposi’s sarcoma. braz j infect dis 2003; 7(6): 395-401. 20. avelleira j c r, lupi o, caterino-de-araujo a, santos-fortuna e. seroprevalence of hhv-8 infection in the pediatric population of two university hospitals in rio de janeiro, brazil. int j dermatol 2006; 45: 381-383. 21. caterino-de-araujo a, moreira aa. diversity of hhv-8 subtypes in ks-aids patients from são paulo, brazil: presentation of a new hhv-8 subtyping method. paper presented at the xiv international conference on aids, barcelona, 2002. abstract book vol ii, thpec7534, p. 469. 22. moreira aa. pesquisa de sítios de restrição enzimática em segmento da orf k1 do genoma de herpesvírus humano tipo 8 (hhv-8) em isolados clínicos de são paulo: relação com subtipos virais e implantação da técnica de rflp (restriction fragment length polymorphism analyses) para determinar subtipos virais. são paulo, 2003. [dissertação de mestrado. faculdade de ciências farmacêuticas da universidade de são paulo]. p.150. http://www.teses.usp.br (in portuguese). 23. cunha amg, costa scb, costa ff, caterino-de-araujo a, galvão castro b. serological and molecular detection of hhv-8 in brazilian populations. 2 international symposium on oncovirology, 2004, salvador. braz j infect dis 2005; 9(5): 442. 24. santos-fortuna e. herpesvírus humano tipo 8 (hhv-8): estudo de segmentos alvo do genoma viral em amostras de sangue, saliva e urina de pacientes infectados pelo hiv/aids, com e sem sarcoma de kaposi. doctoral thesis, faculdade de ciências farmacêuticas da universidade de são paulo, 2005, p. 146. http://www.teses.usp.br (in portuguese) (abstract in english). 25. santos-fortuna e, caterino-de-araujo a. confirming shedding of human herpesvirus 8 in urine from brazilian infected patients. j clin microbiol 2005; 43(2): 1008. 26. mbulaiteye sm, biggar rj, pfeiffer rm, et al. water, socioeconomic factors, and human herpesvirus 8 infection in ugandan children and their mothers. j acquir immune defic syndr 2005; 38(4): 474-479. 27. chequer p, marins jrp, possas c, et al. aids research in brazil. aids 2005; 19 (suppl 4): s1-s3. 28. okie s. fighting hiv – lessons from brazil. n engl j med 2006; 354: 1977-1981. make up march 2007 30/3/07 11:29 am page 54 article information authors: estelle lawrence1,2 patricia struthers1 geert van hove3 affiliations: 1school of public health, university of the western cape, south africa 2department of health, provincial government of the western cape, south africa 3department of special education, ghent university, belgium correspondence to: estelle lawrence email: estelle.lawrence@westerncape.gov.za postal address: western cape department of health, 1st floor the norton rose house, 8 riebeeck street, cape town 8001, south africa dates: received: 01 may 2015 accepted: 04 sept. 2015 published: 05 nov. 2015 how to cite this article: lawrence e, struthers p, van hove g. hiv counselling and testing in secondary schools: what students want. s afr j hiv med. 2015;16(1), art. #390, 6 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.390 copyright notice: © 2015. the authors. licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. hiv counselling and testing in secondary schools: what students want in this original research... open access • abstract • introduction • methodology    • setting    • sample    • data collection    • data analysis strategy • results    • theme 1: where we want hiv counselling and testing to be done    • theme 2: how we want hiv counselling and testing to be done       • we do not want to be seen going for hiv counselling and testing       • we want hiv counselling and testing to be done in a place that provides privacy       • we want information about hiv counselling and testing before testing takes place       • we want confidentiality guaranteed       • we do not want to be asked ‘too many questions’       • we want those who test positive to be supported    • theme 3: who should do the counselling       • we want to be counselled by staff whom we feel we can easily communicate with       • we want to be counselled by staff who are competent to work with youth       • we want hiv counselling and testing to be done by someone who is ‘young’ • discussion and implications • acknowledgements    • competing interests    • authors’ contributions • references abstract top ↑ background: hiv counselling and testing (hct) is an essential element in the response to the hiv epidemic. there are still major research gaps about the best ways to provide hct, especially to the youth, and school-based hct is a model that has been suggested. to make hct youth friendly and to enhance access to the service, the particular needs of the youth need to be addressed. aim: to explore the expressed needs of students about school-based hct service provision. method: the study was conducted in 6 secondary schools in cape town where a mobile hct service is provided by a non-governmental organisation. in each school, two mixed-gender focus groups were held, one with grades 8 and 9 students and one with grades 10 and 11. a total of 91 students aged 13–21 were involved. the focus groups were conducted in the students’ home language. all groups were audio-recorded, transcribed verbatim and translated into english. results: content data analysis was done and the following themes emerged: (1) where the students want hct to be done, (2) how they want hct to be done and (3) who should do the counselling. most students want hct to be provided in schools on condition that their fears and expressed needs are taken into account. they raised concerns regarding privacy and confidentiality, and expressed the need to be given information regarding hct before testing is done. they wanted staff providing the service to be experienced and trained to work with youth, and they wanted students who tested positive to be followed up and supported. conclusion: to increase youth utilisation of the hct service, their expressed needs should be taken into account when developing a model for school-based hct. introduction top ↑ hiv counselling and testing (hct) has been advocated as a critical entry point for care and treatment services, including prevention and clinical management of hiv-related illnesses, and psychosocial support.1,2,3,4,5 however, despite a national hct campaign from 2010 to 2012 in south africa, only 50.6% of youth aged 15–24 years reported testing, compared with 78.2% of adults aged 25–49 years.6 as part of the national hct campaign, the south african departments of basic education and health announced that they intended to launch an hct campaign specifically targeting secondary school students.7 this announcement was met with widespread concern from child rights, human rights and aids organisations, who argued that the school setting was not conducive to providing hct in a way that does not violate the rights of youth. owing to these legal and ethical concerns, the department of basic education put the campaign on hold until policies guiding hct in schools could be developed. little research has been done on the school-based model of providing hct, and it is not known if this model meets the needs of youth. school-based models have been described in uganda, where the kitovu mission hospital has provided a mobile hct service in schools,8 and the tholulwazi uzivikele hct programme in manguzi, south africa, where hct was offered in schools; drama used to raise awareness and encourage testing amongst the students.9 however, these studies were descriptive and did not evaluate the acceptability or effectiveness of the programmes. the objective of the present study was to explore the expressed needs of secondary school students regarding hct provision at schools, and to add the voice of youth to the discussion regarding school-based hct. methodology top ↑ setting the study was done with a non-governmental organisation (ngo) in cape town, south africa, which had been providing a school-based hct service since 2005 (before the south african government announced the hct campaign) in an attempt to make hct more accessible to youth. the ngo provided mobile school-based hct to schools that requested their service. with consent, students were tested class by class in the school hall (or similar space). they received individual preand post-test counselling and were tested by a nurse using a finger-prick rapid hiv test. results were given 15 minutes after the test, and students who were found to be hiv-positive were referred to a health facility of their choice for further management. the team usually tested for a number of days at one school, depending on the size of the school and the demand for testing (personal communication with ngo project manager, 2010). sample six public secondary schools were purposively selected from a list of schools where the ngo provided the school-based hct service. the six schools were selected so as to obtain the views of youth from diverse backgrounds in terms of their home language, ethnicity and school quintile. one school was selected from quintiles 1–4 (schools a, b, c and d) and two schools from quintile 5 (schools e and f) because, even though they were in the same quintile, the socio-economic status and racial backgrounds of the students at the two quintile 5 schools were very different (table 1). at the time of sampling, the ngo was not doing hct at any quintile 1 secondary schools; however, one quintile 1 school was selected (school a), to gather the perspective of students who had not previously been exposed to hct at school. table 1: profile of selected schools. the life orientation (‘the study of the self in relation to others and to society. it addresses skills, knowledge, and values about the self, the environment, responsible citizenship, a healthy and productive life, social engagement, recreation and physical activity, careers and career choices’10) teacher of each school was informed about the study purpose and asked to select students for two focus-group discussions (fgds) at each school, one with grades 8 and 9 students and one with grades 10 and 11 students. the inclusion criteria were: students who were confident in groups; students who were able to express themselves well; and students who were not all leaders. the life orientation teacher was asked to select students from diverse population groups (where possible), and to ensure a similar number of male and female participants. data collection in each of the six schools, two fgds were conducted with students, with a total of 91 student participants (table 2). all the groups were mixed-gender except for the grades 10 and 11 group at school d. none of the male students arrived for the fgd, even though they had signed consent to participate. their reason for not attending was not established; the life orientation teacher felt that it was because the fgd was held after school hours. table 2: sex and age of focus-group discussions participants. each fgd was conducted in the students’ home language by a trained facilitator, who focused on the discussion process (guiding the discussion and encouraging equal participation by all students), and an assistant who took comprehensive notes and documented non-verbal communication. the fgds were held in one of the classrooms at the school involved. at the beginning of the fgd, a role-play was used to trigger the students’ thinking. students were divided into two teams and were asked to create a role-play which illustrated what they think happens when students go for school-based hct. once the teams had watched each other's role-play, the two teams came together for the fgd. a set of questions linked to the role-plays guided the discussion: what do you think will make students want to use this testing service? what do you think will make students not want to use this testing service? what would you like to experience when you go for hct at school? do you think the school is a good place to do hct? why do you say that? ethical clearance was obtained from the university of the western cape senate ethics committee, and permission to conduct the study was given by the western cape education department as well as the schools’ principals. students ≥ 18 years old gave written informed consent to participate; those < 18 years gave assent, and written informed consent was obtained from their parents or guardians. data analysis strategy transcripts of the audio-recordings of the fgds were loaded into nvivo 8 and an inductive approach of content analysis was used to analyse the data. this involved close reading of the text, identifying segments related to the research question, coding these texts and assigning them to categories. a process of refining and revising the categories continued until three main themes emerged: (1) where we (the students) want hct to be done, (2) how we want hct to be done and (3) who should do the counselling (table 3). table 3: themes which emerged during data analysis. to improve the accuracy and validity of the coding and interpretation of the data, an independent researcher was asked to code the data, and member checks were done with the students who participated in the fgds. results top ↑ the students’ expressed needs were similar across schools, gender, age and grade, except where mentioned in the findings. there was also no difference between responses from the school where no hct had ever taken place, and those schools where it had taken place. the responses from the all-female group were similar to the mixed-gender groups. theme 1: where we want hiv counselling and testing to be done when asked whether they thought their school was a good place to have testing done, most students stated that they would prefer to have hct provided at their school during school hours. they explained that they would not find time after school to attend a clinic for testing. they also found it difficult to get to clinics because they were often located far from where they live: ‘it is easy if it's done here at school, ’cause i would have never gone for testing if it wasn’t.’ (female student, age 14) students also would prefer testing at school rather than at a clinic, as they feared being seen at the clinic by community members who might tell their parents that they had gone for testing: ‘… [t]he other woman is going to say, “oh no! your child was at the clinic! what was she doing there? she was sitting on the other side for people who go to test.”’ (female student, age 17) a few students felt that they would prefer being tested at a clinic. reasons included not wanting to be seen by other students when going for testing; concerns about confidentiality at school; and perceiving the quality of service at the clinic as being better. one student felt that he would prefer being tested at home, as it was more private. theme 2: how we want hiv counselling and testing to be done when stating that they would like to be tested at their school, students invariably added the proviso that it must be done ‘in a right way’. we do not want to be seen going for hiv counselling and testing when describing what they meant by ‘in a right way’, students said that they did not want other students and teachers to know that they were going for hct. they had huge concerns about what their peers and teachers would think of them if they were to be seen going for testing: ‘young people, they don’t want this kinda thing [going for hct] to be seen by others.’ (female student, age 17) ‘as a young person … something that is extremely important for us, is what people think about us.’ (female student, age 16) reasons for concern about ‘what people think’ differed amongst the schools, which might have been linked to the students’ racial groupings. students from schools d (only mixed race students), e and f (students from various racial groups) were concerned that others would assume that they were sexually active if they went for testing. in contrast, students from schools a, b and c, where all the students were black, were concerned that, if they went for testing, others would assume that they were hiv-positive: ‘…[b]lack people … if you do go for a test, it's not because you want to know your status. it's because you are definitely [hiv] positive’. (female student, age 15) a 15-year-old black male student at school a pointed out that male students do not want female students to see them go for testing, because it would be assumed that they were hiv-positive, and suggested that male students be tested on a separate day from female students: ‘if you queuing there and you see a girl that you like … you are going to get shy if you are also there to test. you are going to think, “no, no.”’ a 16-year-old black female student in the same fgd corroborated what he said: ‘if maybe [he] goes in there to test, most girls are going to distance themselves from him, thinking that he is already positive … that is how most girls think.’ to avoid being seen, students suggested going for testing one at a time rather than class by class in the school hall (some suggested an appointment system). we want hiv counselling and testing to be done in a place that provides privacy the need for a space that provided visual and auditory privacy during the hct process was consistently mentioned. students specifically did not want to be tested in the school hall (the site where hct took place at each of the schools). they explained that tents or cubicles were erected in the hall to try to provide visual and auditory privacy. however, they felt that the degree of privacy provided was not adequate, and preferred counselling in separate rooms: ‘about the privacy, i do think they need a room, like different rooms for each counsellor … this cubicle thing is just too open. it's just too public … the whole grade [is] behind you, like a few meters behind you … and there you’ve just heard that you’re positive, and the person [is] right behind you.’ (male student, age 16) after receiving their results, they had to face students waiting to be tested, and were afraid that they would not be able to hide the fact if they had just been told that they were hiv-positive: ‘when i get told that i am positive, even if i keep quiet about it, i will have a facial expression that i make. if i am coming out, they are going to first look at me in the face, what facial expression i’m going to make, and then they know that if i am crying i am hiv-positive, and if i am smiling they know that i am not.’ (female student, age 16) some students proposed that the counselling area should have a separate exit so that, after receiving their results, students did not have to face other students waiting in the queue. we want information about hiv counselling and testing before testing takes place students attributed an ‘it won’t happen to me’ attitude towards hiv as a reason for not testing. they believed that many students thought hiv and aids only affected older people, and thought it was necessary for students to be informed about the benefits, importance and procedure of hct prior to testing taking place. others felt that the fear of testing positive was a barrier to testing, and suggested that information be given about what to do if one should test hiv-positive, as they felt that this would reassure students and alleviate some of these fears. we want confidentiality guaranteed students mentioned confidentiality as an important part of doing the testing ‘in the right way’. they wanted staff to promise confidentiality up front, and preferred that only counsellors (not nursing and administrative staff) knew the hiv results and that no ‘paper trail’ was kept of results. we do not want to be asked ‘too many questions’ in many of the fgds, students said that they felt uncomfortable with being asked questions about sexual activity. they considered these questions to be ’private’ and wanted their privacy respected: ‘sometimes they ask too much questions. maybe they ask you now, “are you sexually active?” now you say, “yes,” then they ask you, “when last did you have sex?” you had sex yesterday last … you dunno how to tell her, because she's a big person [an adult] and you telling her now.’ (female student, age 17) we want those who test positive to be supported students felt it important that those who test positive be followed up and given support by the ngo. they wanted assistance with disclosing to family members, emotional support and encouragement with adherence if needing to take antiretrovirals: ‘if they say you are positive … they should do check-ups to see … if you are coping.’ (female student, age 17) theme 3: who should do the counselling we want to be counselled by staff whom we feel we can easily communicate with students said they wanted the counsellors to be people who are easy to talk to and who would make them feel comfortable. they felt it was essential that the counsellors were friendly, non-judgemental and treated youth with respect. they wanted the counsellors to be patient, and expressed the need to have enough time with the counsellor to have things explained properly, and to have the opportunity to ask questions. we want to be counselled by staff who are competent to work with youth it was important to students that the counsellor was experienced, behaved professionally and had received training to provide a youth-friendly health service (yfhs); ‘the counsellor should be taught … about teenagers of today and how they function.’ (female student, age 17) we want hiv counselling and testing to be done by someone who is ‘young’ some students preferred the counsellor to be young (they defined ‘young’ as someone between the ages of 20 and 30). they felt that a younger counsellor would be easier to relate to, and would better understand them (‘older people don’t know what we are going through.’ [female student, age 17]). some students preferred an older counsellor (they defined ‘older’ as someone in their 30s). those who preferred an older counsellor felt that an older person would have more knowledge and experience, and therefore be better able to give advice. students in one fgd favoured a counsellor under the age of 20 years, whereas other students in the same fgd specified that, though they preferred a younger counsellor, they did not want to be counselled by someone their own age, as they felt that their peers would only have as much knowledge as they did. discussion and implications top ↑ findings suggest that most students (across socio-economic groups, racial groups, gender, age and grade) consider school-based hct to be more accessible and convenient than a health facility-based hct service, which is similar to the findings of henry-reid et al.,11 who proposed that school-based hct services are more accessible and acceptable to youth than other formal health settings; and madiba and mokgatle12 who found that the acceptability of hct at schools in gauteng and north-west provinces, south africa, was high. the students made it clear, however, that if hct were to be offered at school, it has to be provided in a manner that takes into account their needs. they had very specific ideas about what they wanted and did not want. most of their expressed needs were based on fear: fear of being seen going for testing, fear of testing positive, fear of their hiv-positive status being known and the stigma associated with it, fear of not being supported if they tested positive, and fear of being judged and not being understood. in fact, the few students who preferred testing at a health facility or at home favoured these settings owing to concerns regarding privacy and confidentiality at school. similar fears about being seen going for hct have been expressed by african youth in other studies.12,13,14,15 the need for auditory and visual privacy during counselling was also expressed by adolescents attending clinics that were part of a yfhs project in zambia.16 the guarantee of confidentiality was also mentioned as an important need by youth in studies done in other african countries investigating youth needs regarding yfhs.16,17 the students’ concerns about not receiving ongoing counselling for dealing with a positive diagnosis and to assist with access to treatment is echoed in the findings of macphail et al.15 in their study with adolescents in two south african townships. students’ anxieties that they would be judged, disrespected and not understood by hct service providers have also been described in previous studies.15,17,18,19 similarly, in a systematic review, healthcare providers’ attitudes, communication skills and competency were cited by youth as indicators of youth-friendly health care.20 the expressed needs of students regarding school-based hct, as described in the present study, coincide with some of the characteristics of a yfhs described by the world health organization (who)21; namely, that the service should have policies that guarantee privacy and confidentiality; that service providers are easy to relate to, non-judgemental, have good interpersonal and communication skills, and are competent to work with youth; and that testing facilities offer privacy. to be noted is the fact that students in the present study did not mention youth involvement in service provision and assessment. similarly, in the survey carried out by erulkar et al.18 amongst kenyan and zimbabwean youth, youth involvement was also not mentioned as a priority for providing a yfhs. a number of limitations exist in the present study. all the groups, except one, were of mixed-gender, and all the facilitators were female, which might have affected responses by students. however, one group comprised only female students and their responses were similar to the responses in the mixed-gender groups. also, all the schools were urban schools; therefore, findings might be different with students from rural schools. because of these limitations and the fact that a purposeful sample was selected, data from the present study are not readily generalisable. however, care was taken to select schools and students that mirror the population groups in the area, and therefore the data allow valuable insights into the needs of students regarding school-based hct. one of the most important contributions that the present study could make is to afford youth a voice which has been lacking in discussions about the provision of hct in schools. it should further contribute to the debate around the ethics and feasibility of providing hct in south african schools, and can be used by governmental and ngo providers of hct in schools to provide a youth-friendly service. lastly, the present research adds to the limited existing body of literature regarding models of hct provision to youth. if hct is to be provided in schools, service providers need to (1) address students’ concerns regarding privacy and confidentiality, (2) provide information regarding hct to students before hct takes place, (3) ensure that staff are experienced and trained to work with youth and (4) that students who test positive are followed up and supported. acknowledgements top ↑ we thank de vlaamse interuniversitaire raad (vlir) for awarding the dynamics of building a better society (dbbs) scholarship to enable this research. competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions e.l. (western cape department of health) designed the study, conducted the focus-group discussions, interpreted the data and wrote the manuscript. p.s. (university of the western cape) and g.v.h. (ghent university) supervised the development of the study, and helped in data interpretation and manuscript evaluation and editing. references top ↑ djanssen rs, holtgrave dr, valdiserri ro, shepherd m, gayle hd, de cock km. the serostatus approach to fighting the hiv epidemic: prevention strategies for infected individuals. am j public health. 2001;91:1019–1024. pmid: 11441723, http://dx.doi.org/10.2105/ajph.91.7.1019 mshana gh, wamoyi j, busza j, et al. barriers to accessing antiretroviral therapy in kisesa, tanzania: a qualitative study of early rural referrals to the national program. aids patient care stds. 2006;20:649–657. pmid: 16987051, http://dx.doi.org/10.1089/apc.2006.20.649 nsigaye r, wringe a, roura m, et al. from hiv diagnosis to treatment: evaluation of a referral system to promote and monitor access to antiretroviral therapy in rural tanzania. j int aids soc. 2009;12:31. pmid: 19906291, http://dx.doi.org/10.1186/1758-2652-12-31 perbost i, malafronte b, pradier c, et al. in the era of highly active antiretroviral therapy, why are hiv-infected patients still admitted to hospital for an inaugural opportunistic infection? hiv med. 2005;6:232–239. pmid: 16011527. sabin ca, smith sj, gumley h, et al. late presenters in the era of haart: uptake of and responses to antiretroviral therapy. aids. 2004;18:2145–2151. pmid: 15577647. shisana o, rehle t, simbayi lc, et al. south african national hiv prevalence, incidence and behaviour survey, 2012. cape town: hsrc press; 2014. south african department of basic education. school hiv counselling and testing (hct) campaign. 2011 [cited 24 apr 2015]. available from: http://www.gov.za/school-hiv-counselling-and-testing-hct-campaign boswell d, baggaley r. voluntary counselling and testing and young people: a summary overview. c2002 [cited 30 apr 2015]. available from: http://ocw.mit.edu/courses/edgerton-center/ec-s11-engineering-capacity-in-community-based-healthcare-fall-2005/readings/mitec_s11f05_vct_toolkit_fhi.pdf pfaff c, de beer j. expanding access to hiv counselling and testing at schools – the manguzi experience. south afr j hiv med. 2011;12:16–18. south african department of basic education. national curriculum statement. curriculum and assessment policy statement. grades 10–12 life orientation. 2011b. pretoria: government printer; 2011. henry-reid lm, rodriguez f, bell ma, martinez j, peera a. youth counseled for hiv testing at schooland hospital-based clinics. j natl med assoc. 1998;90:287. pmid: 9617069, http://dx.doi.org/10.1016/1054-139x(96)81212-2 madiba s, mokgatle m. ‘students want hiv testing in schools’ a formative evaluation of the acceptability of hiv testing and counselling at schools in gauteng and north west provinces in south africa. bmc public health. 2015;15:388. pmid: 25887602, http://dx.doi.org/10.1186/s12889-015-1746-x denison ja, nalakwanji l, dunnett-dagg w, mccauley a, sweat md. social relationships and adolescents – hiv counseling and testing decisions in zambia. horizons research summary. c2006 [cited 30 apr 2015] available from: www.popcouncil.org/pdfs/horizons/zambvctyth.pdf lindberg c, lewis-spruill c, crownover r. barriers to sexual and reproductive health care: urban male adolescents speak out. issues compr pediatr nurs. 2006;29:73–88. pmid: 16772237, http://dx.doi.org/10.1080/01460860600677577 macphail c, pettifor ae, coates t, rees h. ‘you must do the test to know your status’: attitudes to voluntary counselling and testing for hiv among south african youth and their parents. health educ behav. 2008;35:87–104. pmid: 16870815, http://dx.doi.org/10.1177/1090198106286442 mmari kn, magnani rj. does making clinic-based reproductive health services more youth friendly increase service use by adolescents? evidence from lusaka, zambia. j adolesc health. 2003;33:259–270. pmid: 14519567, http://dx.doi.org/.1016/s1054-139x(03)00062-4 atuyambe l, mirembe f, johansson a, kirumira ek, faxelid e. experience of pregnant adolescents: voices from wakiso district, uganda. afr health sci. 2005;5:304–309. pmid: 16615840. erulkar as, onoka cl, phiri a. what is youth friendly? adolescents’ preferences for reproductive health services in kenya and zimbabwe. afr j reprod health. 2005;9:51–58. pmid: 16623189. senderowitz j. making reproductive health services youth friendly. focus on young adults. c1999 [cited 15 apr 2015]. available from: http://www.pathfinder.org/publications-tools/pdfs/making-reproductive-health-services-youth-friendly.pdf?x=79&y=19 ambresin ae, bennett k, patton gc, sanci la, sawyer sm. assessment of youth-friendly health care: a systematic review of indicators drawn from young people's perspectives. j adolesc health. 2013;52:670–681. pmid: 23701887, http://dx.doi.org/.10.1016/j.jadohealth.2012.12.014 world health organization. adolescent friendly health services: an agenda for change. c2002 [cited 05 mar 2015]. available from: http://whqlibdoc.who.int/hq/2003/who_fch_cah_02.14.pdf make up sept 2006 the southern african journal of hiv medicine september 2006 3 5 there is a specific context for women that must be carefully considered when assessing which models of hiv testing will be most effective. despite a plethora of laws and policies that provide for equality and non-discrimination, south african society continues to be characterised by high levels of inequality between men and women, and disturbingly high levels of violence against women. this context suggests that programmes intended to facilitate greater access to hiv testing and treatment for women, especially poor women who rely on the public health system, will not be successful unless they take these realities into account. in the context of sexual violence, research internationally and locally has affirmed the importance of access to adequate psycho-social care for survivors of gender-based violence, and activists and service providers continue to emphasise the importance of this access as part of the healing process for women. the lack of resources committed to providing this care has been a source of ongoing advocacy and lobbying. the value of counselling is starkly illustrated by research2 conducted into adherence to postexposure prophylaxis (pep) after sexual assault, in gauteng hospitals and clinics. this research reveals that pep services are significantly undermined and weakened if they are not supported by access to counselling and properly integrated into other services for women. the research also shows that women themselves see counselling as necessary and important to their health and well-being. the provision of counselling should be therefore be seen as an essential part of a package of care for poor women who may suspect that they have hiv. for many women, this fear is exacerbated and reinforced by additional fears of violence, abandonment and loss. although there is also little empirical research regarding the true extent of hiv-related stigma and discrimination, there is sufficient anecdotal evidence to show that it continues to be a major problem that must be addressed. pre-test counselling represents one of the very few opportunities for poor women to access any form of psychosocial care where they can discuss their fears and concerns regarding their health status and the consequences of a positive test result for themselves and their families, and where they are able to develop strategies to cope with hiv and its potential impact on their lives. post-test counselling plays an equally important role – for those women who are negative, it is a chance to receive and discuss information that could save their lives; for those who are not, it is a safe space to begin the process of coming to terms with having a lifethreatening illness. for many poor women, vct may also have an important symbolic value. living in deeply sexist societies, for many it is the first opportunity where their rights to autonomy and agency are respected and encouraged. so, rather than eliminating vct, it should adequately resourced so that it is more widely accessible and effective – some research has suggested that the quality of counselling is weak. it should also be integrated more holistically into health services so that it can support and strengthen health services generally. references 1. briefing paper, ‘outcomes of the symposium on hiv testing and human rights, 24-25 october 2005’, canadian hiv/aids legal network. 2. vetten l. ‘factors affecting adherence to post-exposure prophylaxis in the aftermath of sexual assault: key findings from seven sites in gauteng province’, 2004. p e r s o n a l s t o r y living positively with hiv/aids geddes m nala in 1985 my employer, scaw metals, appointed me as a candidate to attend a course as a non-departmental advisor. the course was run by the department of health and population development at their training centre in west fort, pretoria. the objective of the 2-week course was to train both departmental and non-departmental advisors in hygiene, high blood pressure, diabetes, family planning, obesity, stds, communicable diseases and hiv/aids. after completing the course successfully, i would then impart the knowledge to my co-workers. together with the nursing sister who was in charge of our medical centre, we gathered as many teaching aids as we could lay our hands on. we borrowed a range of videotapes from chris hani baragwanath hospital and acquired audiovisual materials, booklets and posters from various health centres. we then played the self-explanatory videotapes on the medical centre tv for employees who had come to see the doctor, while they were waiting. we also conducted health sessions at the company’s hostel after work. never did it dawn on me that i would be the carrier of the virus one day. today i am living with hiv. the reason why i disclose my status is that i know what i am talking about. in 1999 i became very sick. i was losing weight drastically and always felt tired. i also had night sweats and was short of breath. i had september 2006 the southern african journal of hiv medicine 3 6 become very thin and very dark. i ate very little and preferred fruit when i did eat. during this time my younger brother phoned to inform me of the death of my elder sister’s sister-in-law. the funeral would take place on the saturday of that same week at the local methodist church at about 8 am, and we would leave for the cemetery at 1 pm. i left early on saturday morning and arrived by 9 am. i did not see any of my family, as the church was jampacked, and it was only at the cemetery that i saw my younger brother and sister standing side by side. i went to join them, but to my surprise it took them longer than usual to recognise me. tears began to roll down my younger sister’s face. i was driven home immediately after the funeral. my brother took me to the doctor, who examined me and, through a syringe, took two watery samples from my back (between the shoulderblades) and poured them into two small bottles. he told my brother that he suspected tb and warned him to take me and the samples to hospital no later than the following monday. he then gave me treatment to help me through the weekend. on monday morning at the hospital, x-rays and further tests were conducted. i did indeed have tb. i was hospitalised, and further tests revealed that i was hiv positive; i only knew this through a counsellor before i was finally discharged. i want to give credit to this gentle lady and thank her, for after putting me at ease, she said, ‘to be hiv positive is not a death sentence. you must read a lot about issues relating to hiv/aids. this will help you to cope with the situation, and if you find other problems, remind the virus this is my body that you are living in. i will kick you out if you misbehave.’ it really did the trick, and i believe contributed towards my acceptance of my situation. she was a true professional. after this intensive and sincere counselling, she gave me a letter referring me to the clinic. i decided to take the letter to the company’s medical centre for convenience. the doctor then referred me to another health centre, where further xrays and other tests were done, before i was finally put on treatment. i was told that this treatment would last for 9 months. i returned to work exactly 4 months later. the doctor recommended that i be put on a much lighter job. i then helped in the hr department with some filing and other personnel duties. after a few months i found a permanent position as a clerk in the design and development department. although i completed my tb treatment. i continued to fall ill from time to time. it would be pneumonia one day and influenza the next. i was in and out of hospital most of the time. my time-keeping also deteriorated. i could not sleep well because of night sweats and coughs. i would doze off at dawn and wake up late. i decided to disclose my status to my colleagues and boss. this required a lot of courage, but i had to do it. it would in turn relieve me of the stress of having to account for poor time-keeping and performance. word went around that the company would be rolling out arvs in the near future. the doctor had informed me about it and had promised to put me on the art programme once it was implemented. but when the clinic sister gave me the consent form to read and sign, i had chickened out and declined the treatment. i was not going to be a ‘guinea pig’. i would not be the first one to experiment with a drug that had become so notorious for its toxic and other side-effects. in 2003 i had to change my mind. in july i became so sick that everyone had written me off. i could not walk as much as 3 metres. i had lost a lot of weight. i was a skeleton and very, very dark. one would not even take a second look at me. i was finished . . . the doctor informed me that i had pneumonia and referred me to hospital. there i was wheel-chaired to the consulting rooms and once examined, i was admitted immediately. i was taken to ward 2. there was something interesting about this ward. it looked like a club-house. all of the patients there looked exactly like me. they were very thin, very dark and every one was on a drip. eventually when i sat on my bed i thought. ‘well this is a club all right, i just wonder which position i am going to fit into.’ so much was happening in this ward: patients using food trolleys to carry them to the toilet, patients refusing to eat because of sores in their mouths, patients refusing to take a bath because of being powerless. saddest was the mortality rate in the ward. i do get along with my ex-wife, although we are divorced. i had phoned to inform her and my son that i was in hospital. she in turn passed on the message to my mom. she visited me often thereafter, bringing me food and prayers. she was also there when the rest of my family visited as well. i was having a good time. my niece had brought me food and fruit. as usual the southern african journal of hiv medicine september 2006 3 7 i was my jovial self and everyone was laughing. then it was my sister’s turn. she said, ‘geddes, my brother, you must get me correctly. i do not say that it will be like that, but there have been problems before. we are still struggling to sort out problems regarding my sister-in-law who recently passed away as we did not ask for her financial details while she was alive. please understand we would not want to repeat the same mistake. now, in case you die, where would you like to be buried? we would also appreciate it if you could provide us with your banking details and company benefits.’ although it was not surprising, i did not expect it so soon. after taking a deep breath to settle down, i obliged and gave her the information and referred her to a friend and colleague for other benefits such as the numsa membership. before they left, we said a prayer after which i accompanied them to their car and said goodbye. i returned to the ward and threw myself on my bed and my sister’s words came back to me loud and clear, ‘you are about to die!’ i jumped up and said aloud (to the surprise of other patients and nurses), ‘not i, not now!’ on friday in the second week of august i was discharged from hospital. i went straight to our medical centre and asked the sister to give me the consent form, and signed it. i did not have to waste time and read it now. i had nothing to lose. i had tasted death, so why not arvs this time? blood samples were taken and sent to the laboratory for analysis. after my final examination at the hospital, i was put on the art programme on 28 august 2003. i have been on combivir and efavirenz treatment ever since. before i took the treatment, my cd4 count was below 50 and my weight was below 40 kg. i was dead, dead ‘finish and klaar’. today my cd4 count is well over 250 and my weight ranges between 73 and 76 kg. i am healthy and strong. it is interesting to note that before i took the treatment i was treated for high blood pressure, but for unknown reasons since i started taking arvs my bp is normal and i have been taken off its treatment. what has actually prompted me to come out and talk is that i know what i am talking about. i felt guilty about remaining silent while other people were suffering and even dying from a situation that i had miraculously survived. i believed that it would haunt me until the last day of my life if i did not talk. that is why i appeal frankly and sincerely to all of you to go for vct. let our motto be ‘take action now, know your status’. the most dangerous thing about hiv/aids is the stigma. people refuse to go for testing for the following reasons: ■ stigmatisation ■ they are to afraid to know that they are hiv positive ■ they do not believe that there is such a thing as hiv/aids ■ they believe that hiv/aids is taboo ■ culture and religion ■ many years ago hiv-positive people were isolated and even killed. there is nothing wrong with hiv/aids. a speaker once said, ‘there are over 127 “viruses” like tb etc. and hiv is one of them.’ people prefer to admit that they suffer from tb or pneumonia rather than accept that they are hiv positive. is it because the first two are curable, or is it because celebrities like or former state president nelson mandela and bishop desmond tutu have publicly admitted to have been treated for tb, and it’s not bad to suffer from what great men have once suffered from? as madiba himself once said, ‘aids is no longer is a disease but a human right.’ we must put all the resources that we have together and intensify our fight against hiv/aids, just like we did in our struggle against apartheid. we must unite in the war against this pandemic in this country. we bury people who die from aids-related ailments daily. this is far above the statistics we receive through the media regarding the middle east. what makes our battle even more complex is that it is abstract in nature. let us all go for vct. this process is not time-consuming. before testing you are put at ease through counselling, and after the test you are once more comforted. your test results are strictly confidential. your employer cannot force you to go for a test, and at the same time cannot victimise you for your status. if you test positive, do accept it, and leave with a positive attitude to your status. as one doctor said to his patient after testing positive, ‘two situations occur when you test hiv positive. the first one is that you deny and die long before you are buried. the second one is you accept and takr it as a wake-up call.’ it is therefore very important for us to encourage people to go for testing and know their status. we should convince them that being hiv positive is not a ‘death sentence’. for those who test negative, we must encourage them to remain so by maintaining good lifestyles and practising protected sex. in conclusion, i would like to thank my company for its compassion towards its employees. i would also appeal to other companies and public sectors to join in this campaign for the betterment of our country and all who live in it. abstract introduction methods study design results discussion limitations conclusion acknowledgements references about the author(s) nnamdi o. ndubuka department of health studies, university of south africa, south africa northern inter-tribal health authority, prince albert, south africa hyun j. lim department of community health and epidemiology, college of medicine, university of saskatchewan, canada dirk m. van der wal department of health studies, university of south africa, south africa valerie j. ehlers department of health studies, university of south africa, south africa citation ndubuka no, lim hj, van der wal dm, ehlers vj. health-related quality of life of antiretroviral treatment defaulters in botswana. s afr j hiv med. 2016;17(1), a475. http://dx.doi.org/10.4102/sajhivmed.v17i1.475 original research health-related quality of life of antiretroviral treatment defaulters in botswana nnamdi o. ndubuka, hyun j. lim, dirk m. van der wal, valerie j. ehlers received: 24 mar. 2016; accepted: 05 sept. 2016; published: 31 oct. 2016 copyright: © 2016. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: antiretroviral therapy (art) improves patients’ health-related quality of life (hrqol). defaulting from art has detrimental consequences, including the development of viral resistance, treatment failure and increased risks of disease progression. little is known about the quality of life of art defaulters and reasons for discontinuing their art. objectives: this study sought to measure the hrqol of art patients in botswana who were on art for up to 5 years but had discontinued treatment for at least 3 months, and to identify factors associated with art defaulting. method: we conducted a cross-sectional study with 104 eligible respondents in four art clinics in south eastern botswana. we assessed respondents’ hrqol using the world health organization quality of life questionnaire for hiv short form. clinical information was obtained from respondents’ medical records. data were analysed using sas version 9.2. results: reasons for discontinuing art were inaccessible clinics (22.4%), feeling better (21.4%), running out of pills (11.2%), depression (8.2%), lack of care and/or support (8.2%), failure to understand instructions (7.7%), medications’ side effects (6.1%) and alcohol abuse (3.1%). in multivariate analyses, respondents aged 36–45 years had a 0.03 lower independence hrqol score compared to those aged 35 and younger (β = -0.03; 95% confidence interval: -1.72, -1.66). despite defaulting from their art, respondents’ calculated hrqol scores were moderate. conclusion: this study highlights the need to enhance art adherence in order to improve the hrqol of people living with hiv and/or aids. introduction background human immunodeficiency virus (hiv) is no longer a fatal disease because antiretroviral therapy (art) has become available. art reduces hiv-related morbidity and mortality and suppresses viral replication, thus increasing the individual’s cd4 counts and decreasing their viral load. botswana was the first country in africa to provide art to people living with hiv and/or aids (plwha) through a national programme. according to the united nations joint programme on hiv and/or aids,1 new hiv infections in botswana decreased from 15 000 in 2005 to 9100 in 2013 and aids-related deaths decreased from 14 000 in 2005 to 5800 in 2013, and an estimated 213 953 out of a possible 320 000 plwha received art in botswana.1 the world health organization (who)2 defined quality of life (qol) as ‘… an individual’s perception of his/her position within the context of culture and value systems in which he/she lives in relation to the individual’s goals, expectations, standards, and concerns’. qol could also be regarded as a person’s satisfaction and happiness with his or her daily life.3 health-related quality of life (hrqol) is an important aspect that determines the level of well-being of plwha because art adds years to these individual’s lives. art improves the hrqol of plwha, according to recorded clinical evidence.4 however, art adherence is essential to derive maximum benefits and an improved hrqol over time.5,6,7,8 although there are other definitions of hrqol, those provided by who were accepted for the purpose of this study. non-adherence to the prescribed art regimen has serious consequences for plwha, for their communities and for healthcare services. consequences of art non-adherence include the development of hiv resistance to antiretrovirals (arvs), necessitating the use of expensive and complicated secondor third-line art regimens with increased chances of developing side effects. other consequences of art non-adherence involve the risk of disease progression to aids, developing opportunistic infections, decreased hrqol, increased chances of infecting other people with hiv, and death.9,10,11,12 consequently, art services should identify defaulters and their reasons for discontinuing art so as to institute timely interventions to retain patients on art regimens and to improve their hrqol. previous studies addressed the hrqol of plwha in botswana, but limited information is available about the hrqol of art defaulters as the latter group comprises a largely inaccessible population. this study therefore attempted to measure the hrqol of botswana patients on art for at least 5 years who had defaulted art for at least 3 months and to identify reasons why these patients discontinued their art. methods study setting, population and sample data collection was conducted at four art clinics in four different health districts in south eastern botswana. the study population comprised adult art patients (aged 21 or older) who had commenced art from january 2002 to december 2007, and who had stopped taking arvs for at least 3 months. art patients younger than 21 years of age or who had defaulted their art for less than 3 months were excluded. from the four participating art clinics’ registers, 362 adult patients who had been on art for at least 5 years and who had discontinued their treatment for at least 3 months were identified. of these 362 art defaulters, 128 could be approached, but 18.8% (f = 24) refused to participate in the study. thus, a total of 104 eligible respondents participated in the study across four study sites between 01 september and 15 november 2012. the response rate was therefore 81.2% (n = 104). study design this was a cross-sectional, quantitative and exploratory study to describe art defaulters’ hrqol at one point in time when data collection for this study took place. measures and instrument three trained research assistants read the items to the art defaulters and recorded their responses on the questionnaires. this was done due to concerns regarding potential low literacy rates. the instrument comprised a 45-item questionnaire, designed by the researchers, and the who quality of life questionnaire for hiv short form (whoqol-hiv bref). a bilingual expert translated both instruments into the local language setswana, and then back translated these into english to ensure that the meaning of the english and setswana items corresponded. section a of the questionnaire requested information about art patients’ socio-demographic characteristics including age, gender, marital status, number of children, educational level, religion, employment status and hiv status disclosure. clinical aspects such as the most recent cd4 cell count and viral load, the year when art commenced, the year of hiv diagnosis, duration on art, reasons for discontinuing art and opportunistic infections were obtained from respondents’ medical records. cronbach’s alpha coefficient for the questionnaire was 0.75, indicating an acceptable level of internal consistency. the whoqol-hiv bref instrument is a short version of the whoqol-100 instrument developed by the who hiv and/or aids quality of life group for cross-cultural applications. it has 31 items representing six domains: physical (4 items), psychological (5 items), level of independence (4 items), social relationships (4 items), environment (8 items), spirituality (4 items) and two additional items (overall hrqol and general health).13,14 it is available in more than 20 languages and can be used in different settings, but ‘… the results are comparable across different cultural settings’.2 all the individual items are rated on a 5-point likert scale, where ‘1’ indicates the lowest level of feelings and ‘5’ indicates the highest level of feelings. this instrument asks questions about ‘how satisfied, how much, how completely, how bothered’ art defaulters felt about different aspects of their lives during 2 weeks preceding data collection. for example, in response to the question ‘how satisfied are you with your capacity to work?’, 1 would indicate ‘very dissatisfied’ and 5 would indicate ‘very satisfied’. these responses to individual aspects within the six domains are reported in terms of mean scores, with 5 being the maximum score. in this study, the calculated domain and overall qol scores were based on the whoqol-hiv bref scoring and coding methodology. the mean scores of all items in each domain were multiplied by four in order to make domain scores directly comparable with the scores used in the whoqol-100. the domain scores therefore ranged from the lowest count of four to the highest count of 20. the maximum total hrqol score for the six domains combined was therefore 120. three research assistants, fluent in both english and setswana and trained as hiv counsellors, were recruited and trained by the first author. they asked every person the same questions in the same order in his or her preferred language (english or setswana) and completed the questionnaire on behalf of the art defaulter. the questionnaire was pretested on three eligible art defaulters who met the inclusion criteria. these three persons encountered no problems in answering the questions, and the research assistants encountered no challenges in recording the answers on the questionnaires. the results of these three completed questionnaires were excluded from the data analysis of the actual study. ethical considerations the research proposal was approved by botswana’s ministry of health with reference number ppme-13/18/1 vol vii (318). managers of the four participating art clinics also approved the proposal and granted permission for data collection at their clinics. the higher degrees committee of the department of health studies, university of south africa, granted ethical approval for the study with reference number hshdc/7/2012. every art defaulter provided informed written consent. refusal to participate in the study did not affect their treatment in any manner whatsoever. unique code numbers were used instead of respondents’ names to ensure confidentiality and anonymity of respondents. all completed questionnaires were securely locked up. all information was entered into a password-protected computer to which only the researchers had access. the completed questionnaires and the computer records will be destroyed after acceptance of the research report. statistical analysis descriptive statistics were used to describe the demographics and health characteristics of the art defaulters with means, ranges, frequency distributions, percentages and standard deviations. mean estimates with standard deviations of the hrqol outcome domains (physical, psychological, level of independence, social relationships, environment and spirituality) were reported. spearman’s correlation coefficients were used to identify the relationship between dependent and independent variables. to understand the factors associated with hrqol among art defaulters, a series of bivariate associations were performed, selecting key variables related to respondents’ demographic and clinical characteristics such as their coping experiences with life’s challenges, art adherence levels and healthcare system-related issues. all the independent covariates were initially tested for potential relationships with each hrqol outcome and with the total qol. all significant independent covariates at univariate regression analyses were examined and only significant covariates were included in subsequent multivariate regression models. also stepwise forward model building strategies were used. interactions between variables in the multivariate models were examined. statistical significance was set at p < 0.05. all statistical analyses were performed using the sas version 9.2 programme.15 results socio-demographic and clinical characteristics of the study population of 128 contacted art defaulters, 104 eligible art defaulters participated in the study, resulting in a response rate of 81.2%. (participation was voluntary and no reasons were provided by the 24 art defaulters for refusing to participate.) of the 104 respondents, 51 (49.0%) were females, 53 (51.0%) were males, the mean age was 37.9 years and the standard deviation (sd) was 11. of the respondents, only 4 (3.9%) were married, 29 (28.2%) had completed primary education and 5 (4.9%) had completed college or vocational training. regarding restarting art, 53.5% of respondents who defaulted had restarted their art at the time of data collection. the respondents’ reasons for discontinuing art included inaccessible clinics (22.4%), feeling better (21.4%), running out of pills (11.2%), depression (8.2%), lack of care and/or support (8.2%), failure to understand instructions (7.7%), medications’ side effects (6.1%) and alcohol abuse (3.1%). of the respondents, 93.1% correctly understood that art adherence implies taking arvs at the right time and the right doses as prescribed, while 6.9% lacked adequate knowledge about art adherence. other characteristics of respondents are summarised in table 1.16 table 1: socio-demographic and disease-related characteristics of respondents (n = 104). with regard to art defaulters’ coping experiences, only 17.8% had previous experiences with overcoming difficulties other than being hiv-positive. most of the respondents (87.3%) did not belong to any community-based support groups. health-related quality of life scores of respondents figure 1 presents the hrqol mean scores across the various qol dimensions (with a maximum score of 20 in each dimension) among respondents. the higher hrqol scores were observed in the physical (mean = 15.3, standard deviation [sd] = 3.2), psychological (mean = 15.0, sd = 2.8) and spirituality (mean = 14.7, sd = 2.2) domains, while lower scores were observed in level of independence (mean = 13.7, sd = 4.1), social relationships (mean = 13.9, sd = 3.7) and environment (mean = 11.9, sd = 3.4) domains. the overall mean hrqol score of respondents (across all domains with a maximum score of 120) was relatively high (mean = 84.6, sd = 14.8). figure 1: mean quality of life domains (n = 104). factors associated with hrqol scores of respondents table 2 shows the association between respondents’ characteristics and hrqol domain scores. multivariate analyses indicate that respondents’ ages, incomes, coping experiences and the number of people disclosed about their hiv-positive status were significant variables in the independence hrqol domain. respondents aged 45 years and older had a 2.27 lower independence hrqol score compared to those aged 35 and younger (β = -2.27; 95% confidence interval (ci): -4.18, -0.36). table 2: factors associated with hrqol of respondents (n = 104). the respondents’ mean education level was significantly associated with psychological (β = -1.53; 95% ci: -2.61, -0.44), social relationship (β = -1.35; 95% ci: -2.69, -0.02) and environmental (β = -2.79; 95% ci: -4.07, -1.51) hrqol mean scores, but not with the other scores. respondents’ employment status was associated with their mean scores in the physical (β = -1.37; 95% ci: -2.51, -0.23) and social relationship hrqol domain (β = -1.34; 95% ci: -2.59, -0.09). in relation to the psychological domain, only education and previous coping experiences were associated with psychological hrqol mean scores. the psychological hrqol mean scores of respondents with no education were 1.53 points lower compared to those who had some education, after controlling for previous coping experiences (95% ci: -2.61, -0.44). the psychological hrqol mean scores of respondents with previous coping experience were 2.41 points lower compared to those with no coping experiences (95% ci: -3.72, -1.11). regarding the level of independence domain, respondents whose monthly incomes exceeded bwp2000 showed 3.56 higher independence hrqol mean scores compared to those with monthly incomes of less than bwp2000 (95% ci: 1.44, 5.69) after controlling for other significant factors (age, previous coping experience and the number of persons to whom respondents had disclosed their hiv-positive status). respondents with previous coping experiences had a 2.39 lower independence hrqol mean score compared to those with no coping experiences, after controlling for the other significant factors (95% ci: -4.31, -0.47). concerning the environmental domain, the multivariate regression analysis showed that only education was associated with the environmental hrqol mean score. respondents who had no education had a 2.79 lower environmental hrqol mean score compared to those with some education (95% ci: -4.07, -1.51). in the spirituality domain, respondents who had other people taking art in their homes showed a 1.45 higher spirituality mean score than those who did not have other persons taking arvs in their homes (95% ci: 0.45, -2.45) (table 2). discussion despite defaulting from their art, respondents in this study obtained moderate hrqol mean scores. the low hrqol mean score findings in the social and environmental domains might signify inadequate social support structures, stigma, poor financial resources, poor physical living conditions and insecurity. art defaulters in this study might have discontinued their art when they became more focused on spirituality and religion as coping mechanisms, but this could not be confirmed nor denied based on the available information. ntshakala17 studied the qol of art patients in swaziland and found that spirituality conflicted with art adherence. other researchers reported similar associations between spirituality and hrqol.8,17,18 in our study, only 17.8% of respondents had coping experiences with overcoming previous difficult situations. previous studies reported that plwha who experienced challenges in coping with art had poorer art adherence levels and poorer hrqol mean scores compared to plwha without such challenges.17,19 the respondents of this study reported various reasons for defaulting art. most of the respondents were unemployed and even the employed ones had limited incomes. lack of financial resources might have caused hardships to pay for transport to clinics to receive their monthly supplies of arvs. the results of this study appear to be congruent with those of other studies identifying transportation costs, running out of pills and living far from clinics as reasons for defaulting art.20,21,22 similar to findings reported by other botswana studies, respondents in this study reported depression as a reason for defaulting art. ehlers and tshisuyi23 studied the factors that affected art adherence among 300 art patients in rural botswana and found that depression was one of the top three reasons why respondents missed arv doses. lewis et al.24 reported that 48% of hiv-positive women (n = 62) in their botswana study had been diagnosed with depression. limitations of 362 art defaulters identified from the participating clinics’ registers, only 128 (35.4%) could be contacted and comprised the accessible population for this study. as people in the rural areas of botswana change locations frequently, most art defaulters could not be traced at their previous addresses or phone numbers. the 24 art defaulters who were contacted but refused to participate provided no reasons for their refusal. consequently, no information could be obtained about art defaulters who could not be contacted and those who refused to participate in the study. these inaccessible art defaulters might have had different experiences than those who agreed to participate in the study. our study did not analyse the art defaulters’ hrqol scores over time, and thus possible time-dependent hrqol changes were not identified. the who hrqol bref instrument has not been tested extensively in botswana for its cultural applicability. however, the respondents of this study did not encounter problems in replying to any item of this instrument. conclusion the low hrqol mean scores in the social and environmental domains might signify inadequate family support, poor financial resources, poor physical living conditions and insecurity. the most common reason for art defaulting was the inaccessibility of the clinics. respondents were more likely to discontinue their treatment if art clinics were far from their homes and if they felt better, ran out of arvs, were depressed and did not have support. addressing these issues could optimise the benefits of art adherence and improve the hrqol of plwha in botswana. further prospective studies using the same measures are required to confirm our study findings. although all respondents discontinued art for at least 3 months, their calculated hrqol scores were moderate. acknowledgements competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions n.o.n. was the project leader who conceived the need for the study. n.o.n., j.h.l., d.m.v.d.w. and v.j.e. developed the data collection instruments. n.o.n. organised the data collection procedures. n.o.n. and j.h.l. performed the statistical calculations. n.o.n., j.h.l., v.j.e., d.m.v.d.w. interpreted the data and wrote the research report. n.o.n. and v.j.e. drafted the current paper but j.h.l. and d.m.v.d.w. rendered inputs. v.j.e. was the corresponding author. references united nations joint program on hiv and/or aids. the gap report [homepage on the internet]. geneva; 2014 [cited 2015 may 04]. available from: http://www.unaids.org/sites/default/files/media_asset/unaids_gap_report_en.pdf world health organization quality of life group. introducing the whoqol instruments. department of mental health and substance dependency [homepage on the internet]. geneva: who; 1998 [cited 2011 mar 16]; pp. 1, 2. available from: http://depts.washington.edu/yqol/docs/whoqol_info.pdf tiwari mk, verma s, agrawal d, et al. quality of life of patients with 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antiretroviral therapy in 5 east african countries: an urgent need for standards. j int assoc phys aids care. 2008;7(4):193–199. rachlis b, ahmad f, van lettow m, et al. using concept mapping to explore why patients become lost to follow up from an antiretroviral therapy program in the zomba district of malawi. biomedcentral health serv res [serial online]. 2013 [cited 2013 jun 30];13:210. available from: http://www.biomedcentral.com/content/pdf/1472-6963-13-210.pdf van cutsem g, ford n, hildebrand k, et al. correcting for mortality among patients lost to follow up on antiretroviral therapy in south africa: a cohort analysis. plos one [serial online]. 2011 [cited 2013 apr 13];6(2):e14684. available from: http://www.plosone.org/article/info%3adoi%2f10.1371%2fjournal.pone.0014684 skevington sm, norweg s, standage m et al. predicting quality of life for people living with hiv and aids: international evidence from seven cultures. aids care. 2010;22(5):614–622. world health organization quality of life hiv group. whoqol-hiv quality of life assessment among people living with hiv and aids: results from the field test. aids care. 2004;16(7):882–889. sas institute inc. base sas® 9.2 procedure guide. cary, nc; 2009. ndubuka no. quality of life of art patients in botswana: coping with challenges [unpublished d lit et phil thesis]. pretoria: university of south africa; 2015. ntshakala tt. quality of life of people living with hiv and aids in swaziland who are on antiretroviral therapy [unpublished d lit et phil (health studies) thesis]. pretoria: university of south africa; 2006. fatiregun aa, mofolorunsho kc, osagbemi kg. quality of life of people living with hiv and/or aids in kogi sate, nigeria. benin j postgrad med [serial online]. 2009 [cited 2014 feb 22];11(1):21–27. available from: http://www.ajol.info/index.php/bjpm/article/view/48823/35172 mugavero m, ostermann j, whetten k, et al. barriers to antiretroviral adherence: the importance of depression, abuse, and other traumatic events. aids patient care stds. 2006;20(6):418–428. deribe k, hailekiros f, biadgilign s, et al. defaulters from antiretroviral treatment in jimma university specialised hospital, southwest ethiopia. trop med int health [serial online]. 2008 [cited 2013 jul 11];13(3):328–333. available from: http://onlinelibrary.wiley.com/store/10.1111/j.1365-3156.2008.02006.x/asset/j.1365-3156.2008.02006.x.pdf?v=1&t=hj59bl9x&s=5c65d50c49fc362d1ac659516fb8f027b43bec38 mcguire m, munyenembe t, szumilin e, et al. vital status of pre-art and art patients defaulting from care in rural malawi. trop med int health. 2009;15(suppl. 1):55–62. sendagala s. factors affecting the adherence to antiretroviral therapy by hiv positive patients treated in a community based hiv/aids care programme in rural uganda: a case of tororo district [unpublished mph (health studies) dissertation]. pretoria: university of south africa; 2010. ehlers vj, tshisuyi et. adherence to antiretroviral therapy by adults in a rural area in botswana. curationis. 2015;38(1):1–8. lewis el, mosepele m, seloilwe e, et al. depression in hiv-positive women in gaborone, botswana. health care women int [serial online]. 2012 [cited 2014 aug 30];33(4):375–386. available from: http://www.tandfonline.com/doi/pdf/10.1080/07399332.2011.603871 a b s t r a c t s 156 december 2014, vol. 15, no. 4 sajhivmed abstracts ‘excelling in clinical care’: southern african hiv clinicians society conference cape town, 24 27 september 2014 first place this abstract includes the updated data presented by dr goven der at the conference; these data are not included in the printed conference programme. cryptococcal screen-and-treat in gauteng province, south africa: update from the first 2 years of implementation, 2012 2014 n govender,1* v chetty,1 d spencer,2 b montoedi,3 d clark,4 r smith,5 a ahlquist-cleveland,5 m roy,5 b park,5 t chiller,5 o oladoyinbo,6 a adelekan,6 t maotoe,7 l coetzee,8 w stevens,8 d glencross8 1 national institute for communicable diseases, centre for opportunistic, tropical and hospital infections (a division of the nhls) 2 right to care 3 gauteng department of health 4 the aurum institute 5 centers for disease control and prevention 6 centers for disease control and prevention (sa) 7 usaid (sa) 8 national health laboratory service *neleshg@nicd.ac.za category: non-tuberculosis opportunistic infections background. screening for early cryptococcal disease is recommended to reduce morbidity/mortality related to hivassociated cryptococcal meningitis (cm). our objective was to describe the cascade of care among patients with a positive plasma cryptococcal antigen (crag) test, in two gauteng districts. methods. screening started in september 2012 at 21 facilities in johannesburg, and in april 2013 at 87 ekurhuleni facilities. rem nant plasma from any routinely collected ethylenediaminetetraacetic acid (edta) sample with a cd4+ count <100 cells/µl was tested with crag lateral flow assay (immunomycologics, usa). at 45 enhanced surveillance (es) facilities, surveillance officers reviewed medical records of plasma crag-positive patients from september 2012 to august 2014. cases of incident cm were reported to national surveillance. crag screening and cm surveillance data were cross-matched to determine whether screened patients had prior cm. incident antigenaemia (ia) was defined as a patient with a positive plasma crag test and no prior cm. results. during the evaluation, 18 357 patients were screened, 820 (4%) of whom were plasma crag-positive. of 624 diagnosed at an enhanced surveillance facility, 457 (73%) had data available for cm and ia diagnosis. of these, 207 (45%) had prior cm. of 250 (53%) with ia, symptom data were available for 244. of these, 99 (41%) had headache and/or confusion, and 145 (59%) were asymptomatic. lumbar puncture (lp) was performed for 56 (57%) and 48 (32%) symptomatic and asymptomatic patients with ia, respectively. cm was confirmed among 79% (33/42) and 26% (8/31) of symptomatic and asymptomatic patients with ia (with available lp results), respectively. excluding those with confirmed cm, available data showed that almost all patients with ia (symptomatic: 41/42 and asymptomatic: 98/99) were prescribed fluconazole. of 48 art-naive patients with ia and known art status, 47 initiated art a median of 15 days (interquartile range 13 29) post screening. conclusions. approximately 40 patients with cd4+ count <100 cells/µl needed to be screened to detect an ia case. most with ia were initiated on antifungal treatment and art. outcomes in hiv-infected and -uninfected drug-resistant tuberculosis patients in khayelitsha, south africa s moyo,1 j hughes,1 j daniels,1 o muller,1 a shroufi,1 g van cutsem,1 v cox,1* h cox2 1 msf khayelitsha 2 university of cape town *msfocb-khayelitsha-coord-deputy@brussels.msf.org category: tuberculosis background. there are limited data on outcomes of hivinfected, drug-resistant tuberculosis (dr-tb) patients who are on antiretroviral therapy (art). we compared outcomes among hiv-infected and -uninfected patients treated for drtb in khayelitsha, south africa. methods. routine data of patients diagnosed with dr-tb in khayelitsha from january 2008 to december 2011 were analysed retrospectively. outcomes until december 2013 were included. results. a total of 875 patients were diagnosed with drtb. overall, 607 (69%) were hiv-positive, 232 (27%) hiv-negative, with status unknown in 36 (4%). among hiv-positive patients, 96 (16%) had preand extensively drug-resistant tb (xdr-tb), 373 (61%) had multidrugthe top nine best abstracts from the biennial southern african hiv clinicians society conference, held in september 2014, are provided here. presentations from the conference may be viewed online: http://sahivsoc2014.co.za/2014-speaker-presentations/ s afr j hiv med 2014;15(4):156-159. doi:10.7196/sajhivmed.1124 a b s t r a c t s december 2014, vol. 15, no. 4 sajhivmed 157 resistant tb (mdr-tb), 129 (21%) had rifampicin monoresistance, and 9 (1%) had presumed dr-tb. among the hiv-positive patients, 34 (15%) had preand xdr-tb, 144 (62%) had mdr-tb, 28 (12%) had rifampicin monoresistance and 26 (11%) had presumed dr-tb. a total of 139 (16%) patients did not start dr-tb treatment; 64/139 (46%) died before treatment initiation (55 hiv-positive, 7 hivnegative; p<0.001). among those who started dr-tb treatment, 507/736 (69%) were hiv-positive. of these 507 patients, 470 (93%) were on art, with 236 (47%) already on art at dr-tb diagnosis; median cd4+ count was 120 cells/mm3 (interquartile range 55 250). among those with final outcomes (642), treatment was successful in 213/440 (48%) and 88/189 (47%) of hiv-positive and hiv-negative patients, respectively. more hiv-negative patients were lost from treatment (lft) (37% hiv-negative v. 27% hiv-positive, p=0.01). mortality was greater among hiv-positive patients (18% hivpositive v. 9% hiv-negative, p=0.004) during treatment. there was no difference in treatment failure: 26/440 (6%) hiv-positive and 14/189 (7%) hiv-negative patients failed treatment (p>0.05). patients who subsequently died included 31/120 hiv-positive and 15/70 hivnegative patients who were lft, and 21/26 hiv-positive and 7/14 hiv-negative patients with treatment failure. there was no significant difference in overall mortality: 19/100 person-years (95% confidence interval (ci) 16 22) hiv-positive; 17/100 person-years (95% ci 12 22) hiv-negative; incidence rate ratio 1.14 (95% ci 0.80 1.67). conclusions. in the presence of art, treatment success, treatment failure and long-term mortality were similar in hiv-positive and hivnegative dr-tb patients. hiv-positive patients on art experienced greater mortality prior to and during dr-tb treatment. lft masked mortality in both hiv-positive and hiv-negative patients, with more lft among hiv-negative patients and 20% mortality thereafter. more effective treatment regimens and strategies for reducing lft are needed to reduce mortality in dr-tb patients. a case series of antiretroviral therapy-associated gynaecomastia c njuguna-obwolo,* a uys, b chisholm, m blockman, g maartens, k cohen, a swart university of cape town *cw.njuguna@uct.ac.za category: antiretroviral treatment background. gynaecomastia is associated with antiretroviral therapy (art). there are few data about the clinical characteristics of patients with art-associated gynaecomastia and optimal management of this adverse drug reaction (adr). the national hiv and tb hotline at the medicines information centre offers the following standard advice for art-associated gynaecomastia: measure free testosterone to exclude hypoandrogenism and substitute efavirenz. objective. to describe the clinical characteristics, management and clinical outcomes of reported gynaecomastia cases. methods. we identified all cases of gynaecomastia in hiv-infected patients on art reported to the hotline between june 2013 and jan 2014. we collected data on actions taken and clinical outcomes. results. twenty-nine suspected gynaecomastia cases were reported, representing 11% (29/274) of total adr queries received during this period. all were on efavirenz-based regimens, and median age was 33 years (interquartile range (iqr) 1740). the median onset of gynaecomastia post efavirenz initiation was 19 months (range 2 99). twelve patients (41%) had bilateral gynaecomastia, 8 (28%) had unilateral gynaecomastia and 9 (31%) were unknown. five (17%) patients were on additional drugs associated with gynaecomastia: 1 on amlodipine and 4 on isoniazid. we obtained follow-up information on 21 (72%) patients, with a median follow-up of 62 days (iqr 39 97). free serum testosterone was performed in 13 of 21 patients; 11 had normal testosterone and 2 were unknown. of patients with followup, 18 substituted efavirenz, of whom 4 (22%) improved, 1 (5%) deteriorated, 5 (28%) remained unchanged and 8 (44%) had unknown status. among patients continuing efavirenz (n=3), 2 were unchanged and 1 had unknown status. conclusion. efavirenz-associated gynaecomastia was frequently reported to the hotline. improvement of gynaecomastia after substitution was variable, and since efavirenz is a component of the preferred firstline art regimen, more evidence to guide optimal management of this adr is needed. usefulness of free testosterone level testing requires further study. determinants of resistance to second-line protease inhibitor-based antiretroviral therapy in the southern african private sector k cohen,1 a stewart,1 r leisegang,1 m coetsee,2 s maharaj,2 l dunn,2 m hislop,2 l regensberg,2 g meintjies,1 g van zyl,3 g maartens1* 1 university of cape town 2 aid for aids management (pty) ltd 3 stellenbosch university *gary.maartens@uct.ac.za category: antiretroviral treatment background. in the south african public sector, 11% of patients failing second-line protease inhibitor (pi)-based antiretroviral therapy (art) have pi resistance. we explored predictors of pi resistance in patients on second-line art in a private sector cohort from 2004 to 2013. methods. we categorised patients as having pi resistance if their genotype included ≥1 major resistance mutations to their current pi. we constructed a multivariate logistic regression model, including age, sex, pi duration, adherence by pharmacy claims for 4 months prior to resistance test, and viral load (vl) closest to resistance test. results. there were 339 patients with at least 4 months of secondline pi-based art. mean age was 42 (standard deviation 8) years, 211 (62%) were female, and 309 (91%) were on lopinavir and 30 (9%) on atazanavir. there were ≥ 1 major pi-resistance mutations in 147/339 (43%). median duration on pi-based art before genotype was 2.5 years (interquartile range (iqr) 1.4 4.4). median vl before genotyping was 85 586 copies/ml (iqr 18 893 242 103). having a major pi-resistance mutation was independently associated with age (odds ratio (or) for 10-year age increase 2.0, 95% ci 1.4 2.8), highest quartile of art duration (or 2.7, 95% ci 1.4 5.3), and with the highest three adherence quartiles (or 2.1, 95% ci 1.0 4.3; or 2.4, 95% ci 1.1 4.9; or 2.6, 95% ci 1.3 5.2 for 66 93%, 94 98% and 99 100% adherence, respectively). sex and vl at the time of resistance testing were not associated with pi resistance. conclusion. in this private sector cohort, the proportion with pi resistance was higher than in public sector studies, which may reflect a longer duration of second-line art. these results suggest that patients with longer duration of pi-based art or adherence >65% may be most likely to benefit from genotyping. a b s t r a c t s 158 december 2014, vol. 15, no. 4 sajhivmed a b s t r a c t s gender differences and the effect of pregnancy on antiretroviral treatment outcomes amongst adolescents in south africa g fatti,1* n shaikh,1 e mothibi,1 b eley,2 a grimwood1 1 kheth’impilo, cape town, south africa 2 department of paediatrics and child health, university of cape town, cape town, south africa *geoffrey.fatti@khethimpilo.org category: children and adolescents background. adolescence is an important age group for hiv care and treatment programmes, as adolescents have a high rate of hiv acquisition, and perinatally infected children are transitioning into adolescence. relatively little data comparing gender differences in adolescent art outcomes in low-income settings are available. objectives. to investigate gender differences in baseline characteristics and antiretroviral therapy (art) outcomes in a large multicentre cohort in south africa (sa). methods. routine clinical data from 82 public art facilities in four provinces in sa were analysed. art-naive adolescents (ages 9 19 years) starting art between 2004 and 2011 were included. the outcomes were: mortality, loss to follow-up (ltfu), viral suppression (<400 copies/ml) and virological failure (two consecutive viral loads >1 000 copies/ml) after starting art. competing risks regression and generalised estimating equations were used to analyse outcomes controlling for individual and site-level confounding. results. a total of 3 175 adolescents were included, of whom 2 123 (66.9%) were adolescent girls. pregnancy among girls who started art increased progressively over time, and reached 25.3% by 2011. the median baseline cd4+ cell count of pregnant girls was substantially higher than for non-pregnant girls (205 v. 143 cells/µl; p=0.0001). ltfu was substantially higher in pregnant girls, adjusted subhazard ratio=1.94 (95% confidence interval (ci) 1.03 3.65; p<0.040). viral suppression on art was lower in pregnant girls, adjusted odds ratio=0.58 (95% ci 0.39 0.86; p=0.006). confirmed virological failure was substantially increased among pregnant girls, adjusted hazard ratio=4.85 (95% ci 1.78 13.1; p=0.002). conclusion. there were high levels of pregnancy among adolescent girls who started art, and they had less-advanced hiv disease, likely owing to earlier diagnosis at maternal facilities. however, pregnant girls had increased ltfu and poorer virological outcomes. programmes to reduce adolescent pregnancy and increased art adherence support for pregnant adolescents may be important interventions to improve outcomes of adolescents and to reduce vertical hiv transmission. hiv is the primary exclusion criterion in a prepex male circumcision device introductory study in mozambique m mahomed,1 h muquingue,1 b cummings,2 j come,3 d bossemeyer,1 t ferreira,1* l nhambi,1 e necochea,4 k curran4 1 jhpiego, mozambique 2 centers for disease control (mozambique) 3 ministry of health mozambique 4 jhpiego, eua *thais.ferreira@jhpiego.org category: prevention background. voluntary medical male circumcision (vmmc) reduces female to male hiv transmission by ~60%, and is recommended by the world health organization (who) and the joint united nations programme on hiv/aids (unaids) as a priority intervention in highhiv prevalence settings. in mozambique, vmmc for hiv prevention start ed in november 2009; >300 000 males were surgically circumcised by march 2014, with a goal of 2 million by 2016. prepex could potentially reduce procedure time and increase acceptability of vmmc because it does not require injectable anaesthesia or suturing. in 2013, an introductory study of the prepex device was conducted in maputo, mozambique, to assess acceptability among providers and clients. methods. adult clients presenting for vmmc at the study site in maputo were offered surgical or prepex device circumcision. those who preferred prepex were screened for inclusion criteria. exclusion criteria were recorded. the current guidelines excluding infected men from device circumcision are from the who. results. during the study, 752 clients aged ≥18 years presented for vmmc and were offered the choice of prepex or conventional surgery; 116 (15.4%) preferred surgical vmmc. of the 636 clients who chose prepex, 132 (20.8%) were ineligible. hiv infection was the primary reason for exclusion, restricting 85 (64%) interested seropositive clients. phimosis or narrow foreskin was present in 17 (13%) of the ineligible clients. sixteen clients (12%) were unable to communicate in portuguese and 8 (6%) lacked communication means (cellphone), which were study requirements. the remaining 6 (5%) were excluded due to an active sexually transmitted infection, sexual dysfunction or previous penile surgery. conclusions. one-third of adult clients offered prepex either did not want device circumcision or were ineligible under current guidelines, which exclude hiv-positive men. an integrated programme offering both device and surgical vmmc remains the best service delivery option. however, there is a need to assess the safety of prepex among hiv-positive clients, as hiv testing in mozambique is recommended but not required in routine vmmc service delivery. analysis of the antiretroviral treatment clinical outcomes in south africa from 2004 to 2012 m magoro,1* p barron,1 c white,2 r pretorius,1 n ntuli,1 y pillay1 1 national department of health, south africa 2 clinton health access initiative *magoro@health.gov.za category: antiretroviral therapy objectives. to analyse loss to follow-up (ltfu), retention on antiretroviral treatment (art), viral load (vl) suppression and increase in cd4+ counts on adult patients in the south african public sector national art programme. methods. this was a cohort study including all patients who started art in the south african public sector facilities from 2004 to 2013. art data were collected routinely through the national tier.net database and exported to the district health information system (dhis) in the form of excel pivot table workbooks. national analysis of data by financial years was conducted to determine improvements in retention on art, cd4+counts, vl suppression and ltfu. results. data summarised patient clinical outcomes for 435 323 adult patients who started receiving art from april 2004 to june 2013. adult patients starting art increased exponentially from 2 189 in 2004/5 to 119 827 in 2012/13. the proportion of patients with a cd4+ count of between 200 350 cells/µl increased from 8.9% in 2004/5 to 46.7% in 2012/13, while the proportion of patients with a cd4+ count <100 cells/ µl a b s t r a c t s december 2014, vol. 15, no. 4 sajhivmed 159 decreased to 25.2% in 2012/13. the 2004/5 and 2005/6 cohorts had 89% of clients remaining on art at 12 months, while the later cohorts such as the 2011/12 had 76% of clients remaining on art at 12 months. on average, 39% of adult patients had a vl done from 12 months to 108 months; meanwhile, 79% of adult patients who had a vl done had viral particles that were suppressed. the 2004/05 cohort had 2.5% of adult art clients ltfu at 3 months, which increased over a period of time to 27% at 96 months. the 2012/13 cohort had 13% of adult art clients ltfu at 3 months, which increased exponentially to 17% at 6 months. conclusion. this national art cohort data study showed that adult art patients who formed part of the 2004/05 cohort had better prospects compared with all later cohorts. the opposite was evident with ltfu, where higher rates of ltfu were observed in adult art clients who were part of the later cohorts, when compared with the 2004/05 cohort. innovative interventions to improve clinical outcomes in patients on art in south africa are critical, particularly in new patients starting art. detection of primary or early hiv-1 infections in pretoria (preliminary results) s mayaphi,1* t rossouw,2 sas olorunjuc,3 d martina1 1 medical virology department, university of pretoria; and tshwane academic division of nhls, pretoria, south africa 2 immunology and family medicine departments, university of pretoria, south africa 3 biostatistics unit, medical research council, pretoria, south africa *sim.mayaphi@up.ac.za category: prevention background. primary hiv infection (phi) is the highly infectious stage of hiv, as it is associated with very high viral loads (vls) in the blood and genital secretions. tests that detect viral particles are highly sensitive at this stage, and those that only detect hiv antibodies, such as rapid hiv strips, have poor sensitivity. objective. to evaluate the phi incidence in pretoria. methods. this is a preliminary report of a cross-sectional study that enrolled 2 524 participants who tested negative on rapid hiv tests. a questionnaire was used to assess the participants’ hiv risk behaviour. the study sites were tshwane district hospital voluntary counselling and testing (vct) and f f ribeiro clinics. pooled nucleic acid testing (nat) was employed using the roche hiv vl assay. individual sample testing was done from pools that had detectable vl. fourth-generation hiv testing was done in all participants who tested positive on nat. results. the study enrolled and tested 2 524 individuals, with a median age of 27 years (interquartile range (iqr) 24 33); females formed a larger proportion (70.9%, n=1 789). seventeen participants tested positive on nat; hiv elisa was positive in 16 of these participants. follow-up rapid tests were positive at a median time of 4 weeks (iqr 2.5 8). hiv incidence was 0.7% in the whole study, and slightly higher in the pregnant subgroup. questionnaire data showed that infections were only in the groups that sometimes used or never used condoms. conclusion. these data show a feasibility of detecting primary or early hiv-1 infections in south africa. pooled nat could be affordable when used in combination with a questionnaire tool that identifies those at high risk of hiv. hiv elisa or repeat rapid hiv tests at 4 weeks could be more affordable alternatives of identifying early hiv-1 infections. outcomes of infants starting antiretroviral therapy in southern africa, 2004 2012 m porter,1* m davies,1 m mapani,2 h rabie,3 s phiri,4 j nuttall,5 h moultrie,6 k technau,7 k stinson,8 r wood,9 m wellington,10 a haas,11 j giddy,12 p mutevedzi,13 b eley5 1 university of cape town 2 centre for infectious disease research in zambia 3 tygerberg academic hospital 4 lighthouse trust clinic, malawi 5 red cross war memorial children’s hospital and university of cape town 6 wits reproductive health and hiv institute and harriet shezi children’s clinic 7 rahima moosa mother and child hospital and university of the witwatersrand 8 khayeltisha art programme, médecins sans frontières and university of cape town 9 gugulethu community health centre and desmond tutu hiv centre, university of cape town 10 newlands clinic, harare, zimbabwe 11 university of bern 12 mccord hospital, durban 13 hlabisa hiv care and treatment programme *mireilleporter@gmail.com category: children and adolescents background. there are limited published data on the outcomes of infants starting antiretroviral therapy (art) in routine care in southern africa. we described baseline characteristics and outcomes of infants initiating art at 11 sites contributing to the international epidemiologic database to evaluate aids in southern african (iedea-sa). methods. art-naive, hiv-infected infants <12 months of age at initiation of ≥3 antiretroviral drugs after 2003 were included. kaplanmeier estimates were calculated and cox proportional hazards models stratified by site were used to determine baseline characteristics associated with outcomes mortality and virological suppression. loss to follow-up (ltfu) was defined as no visit for >9 months prior to site database closure. results. the median age of 4 945 infants who initiated art was 5.9 months (interquartile range (iqr) 3.7 8.7). median follow-up time was 11.2 months (iqr 2.8 20.0). at art initiation, 75% of infants had world health organization (who) clinical stage 3 or 4 disease, and 85% met the 2006 who definition of severe immunosuppression. threeyear mortality probability was >15% and ltfu 29%. severe immune suppression (adjusted hazard ratio (ahr) 2.19, 95% confidence interval (ci) 1.44 3.35), who stage 3/4 (ahr 1.36, 95% ci 1.04 1.78), anaemia and lower weight-for-age z-score were associated with higher mortality. initiation of treatment after 2009 was associated with lower mortality (ahr 0.75, 95% ci 0.59 0.94). the probability of virological suppression at 6 months and 12 months was 28% and 56%, respectively. initiation of treatment after 2009 was the only predictor of virological suppression. conclusion. the proportion of infants initiating art with baseline disease severity and high probability of mortality and especially ltfu is a concern. however, the majority of those remaining in care had good virological responses on art. hiv 987 is it lawful to offer hiv self-testing to children in south africa? a e strode, 1,2 llm; h van rooyen, 3 phd; t makusha, 3 phd 1 school of law, university of kwazulu-natal, pietermaritzburg, south africa 2 hiv/aids vaccines ethics group, school of applied human sciences, university of kwazulu-natal, pietermaritzburg, south africa 3 human sciences research council, south africa corresponding author: a e strode (strodea@ukzn.ac.za) health-facility-based hiv counselling and testing does not capture all children and adolescents who are at risk of hiv infection. self-testing involves conducting an hiv test at home or in any other convenient space without the involvement of a third party. it is increasingly being argued that it should be incorporated into national hiv-prevention programmes as one of a range of hiv counselling and testing approaches. although this model of hiv testing is being seen as a new way of reaching under-tested populations, no studies have been conducted on offering it to children. hiv self-tests are now available in south africa and are sold without the purchaser having to be a certain age. nevertheless, all hiv testing in children must comply with the norms set out in the children’s act (2005). here we explore whether offering self-testing to children would be lawful, by outlining the four legal norms that must be met and applying them to self-hiv testing. we conclude that, although children above the age of 12 years could consent to such a test, there would be two potential obstacles. firstly, it would have to be shown that using the test is in their best interests. this may be difficult given the potential negative consequences that could flow from testing without support and the availability of other testing services. secondly, there would need to be a way for children to access preand post-test counselling or they would have to be advised that they will have expressly to waive this right. the tests are more likely to be lawful for a small sub-set of older children if: (i) it assists them with hiv-prevention strategies; (ii) they will be able to access treatment, care and support, even though they have tested outside of a health facility; and (iii) psychosocial support services are made available to them via the internet or cell phones. s afr j hiv med 2013;14(4):151-154. doi:10.7196/sajhivmed.987 globally, in 2010, 3.4 million children aged <15 years were hiv-positive, 90% of whom were living in sub-saharan africa.1 in 2011, unaids estimated that in south africa (sa) alone there were about 460 000 children aged 0 14 years living with hiv. health-facility-based hiv counselling and testing (hct) does not capture all children and adolescents who are at risk of hiv infection.2-5 the large number of children not treated suggests that there are still relatively low rates of testing among children.6 children are either being missed by the prevention of mother-to-child transmission of hiv (pmtct) services, are surviving past two years of age without being tested, or are infected after birth through child abuse or health-service-acquired infection. in addition, children aged >12 years may be at increased risk because of their own sexual activity.7-9 similarly, rates of testing among adolescents are particularly low, especially among young males, despite this being an at-risk population.9 this highlights the need for new, targeted, innovative, age-appropriate counselling and testing services for children and adolescents.10 low uptake of hiv testing is attributed to both supply and demand factors. on the supply side, key factors include inconvenient clinic hours, the inaccessibility of health facilities and the high cost of travelling to clinics.11 in terms of demand, even if testing services are available, these do not always translate into willingness to test.12 research has shown that deep-seated concerns regarding stigma, discrimination and the fear of positive results act as barriers to increased uptake of hiv-testing services in high hiv prevalence settings.13 hiv self-testing (hst) refers to the performance of a simple saliva or blood-based test similar to a pregnancy test in the privacy of a home or in any other convenient space without the involvement of a third party.14 , 15 richter et al.16 point to four potential benefits of such testing; it could: encourage regular hiv testing, allay fears of stigma and possible breaches of confidentiality, decrease the overall costs of hiv testing through removing the need for face-to-face counselling, and facilitate earlier diagnosis and access to treatment. based on increasing evidence from feasibility and acceptability studies, activists and public health policy-makers have argued that hst should be incorporated into national hiv-prevention programmes as one of a range of community-based hct approaches.17 , 18 community-based hct models such as home-based and mobile testing have significantly improved testing uptake and have reached higher rates of first-time testers in sub-saharan africa.19-23 hiv self-tests are now available in sa. they sell for approximately r100 at pharmacies and have a shelf-life of two years. they can also be ordered via the internet.24 detailed instructions are in the packaging and they generally require the user to place a drop of blood on a test strip; if a dark line develops on the strip, it indicates that the person is hiv-positive. 24 highly accurate oral self-test kits exist with a sensitivity of 92% and a specificity of 99.9%. 17 , 24 while some hiv self-tests are available in sa, the distribution and use of these tests is largely unregulated as the country’s legal and policy frameworks do not specifically allow for their dissemination.16 this means that there are no specific regulatory restrictions on the sale of such products to persons aged <18 years. nevertheless, all hiv testing in children must comply with the norms set out in the children’s act (2005), and accordingly, regardless of the model of testing, must meet these minimum standards.25 although this innovative model of hiv testing is being seen as a new way of reaching under-tested populations, no studies have been conducted on offering hst to children. there has also not been any conceptual work exploring: (i) whether this is an appropriate model of testing to offer to children; and (ii) if it was found to be acceptable, whether there would be country-specific legal barriers to providing it to them. here we explore whether offering self-testing to children would be lawful in terms of the children’s act, by outlining the four legal norms that must be met and by applying them to hst. the legal framework the children’s act (2005) describes the rights of children to consent independently to a number of health interventions.26 it provides expressly for when and how hiv testing may be done with children. the drafters of the act considered hiv testing to be an area in which children’s rights were being abused and special protection was needed. accordingly, sections (s) 130 133 of the children’s act create four norms regulating hiv testing. these are that a child: (i) may only be tested for hiv in specific circumstances (s 130(1)(a) (b); (ii) must be counselled before and after the hiv test (s 130(1)(a) and 132); (iii) can consent independently to an hiv test from the age of 12 years (s 130(2)); and (iv) has a right to privacy regarding their hiv status (s 133). the circumstances in which a child may be tested for hiv parliament has expressly limited the circumstances in which hiv testing may be undertaken with children.25 the act provides that, other than in exceptional circumstances, hiv testing in children will only be lawful if it is in the best interests of the child and is undertaken with consent.25 this means that, unlike most other health interventions where children of a certain age or with a particular level of capacity can autonomously choose the intervention, with hiv testing it must be demonstrated that taking the test is in their best interests.26 our courts have generally held that in determining the best interests of the child, an effort must be made to establish if a decision will promote a child’s physical, moral, emotional and spiritual welfare.27 furthermore, it should be seen as a flexible standard which is applied with due consideration to the individual circumstances of the child. 28 the children’s act gives substance to this assessment by listing a number of factors that should be used in such an analysis. these include: the effect that the decision will have on the child’s circumstances, its impact on their physical and emotional security, as well as the need to protect the child from physical or psychological harm.25 if we apply these principles to hiv testing generally, we would argue that testing undertaken for prevention or treatment purposes would be in the best interests of the child as it promotes their right to basic healthcare services in terms of s 28 of the constitution.29 however, hiv testing aimed at discovering a child’s hiv status and using this information to discriminate against the child, by e.g. withholding a bursary for tertiary education, would be contrary to the child’s best interests. if we apply these principles to hst specifically, we submit that the following factors would need to be taken into account in establishing whether it could be in the child’s best interests: (i) the emotional impact of a child discovering their hiv status on their own, and potentially without support; (ii) the possibility that adults could use self-testing to coerce children to be tested for hiv; (iii) the confidential nature of such testing, which may meet the needs of some adolescents with privacy concerns; (iv) the availability and accessibility of other forms of hiv testing; (v) the child’s age, level of maturity and ability to cope with this particular form of testing; (vi) the views of the individual child on hst; and (vii) the capacity of the child to consent to the hiv test. if we weigh and balance the above factors, we would argue that hst could not be considered to be in the ‘best interests’ of all children. our reasons are: firstly, several authors have suggested that many would be too young to cope with the impact of receiving an hiv test result on their own. secondly, others have suggested that in the absence of pre and post-counselling there is potentially a risk of suicide for an individual who might be distressed.30 thirdly, a study conducted in kenya31 revealed that the main challenge of a self-testing programme was providing links to support services. napierala mavedzenge et al.32 highlight how hst delinks testing and counselling, potentially depriving individuals of access to a range of critical services.32 furthermore, if other testing services are accessible and available, it would seem more appropriate that young children use such services where they can be assured of both support and access to treatment. fourthly, there are some concerns in the literature that self-testing may not be in the best interests of children in that it could be used in a coercive way in the home environment and could possibly result in an abuse of individual rights. it appears that the authors are alluding to the possibility of the test being used by adults to test children at home as, e.g., ‘punishment’ for being sexually active. given that the test is done in private, it would always be difficult to ensure that it is not being undertaken for the benefit of third parties. however, there are no data available to support this potential risk.32 , 33 nevertheless, it is possible that for certain older children (aged ≥16 years) who are at high risk of hiv infection, this may be a testing model that appeals. we base this on the emerging evidence on self-testing for adults. several studies have documented high acceptability, uptake and accuracy of oral self-testing.20 , 34 furthermore, adult users of hiv self-tests have found them easy to use, the instructions comprehendible,35 and that they have a high level of accuracy (99.2%).20 this model of testing offers high levels of personal control to children with the capacity to consent to testing and privacy for those who wish to establish their hiv status without the involvement of a third party. if accompanied by alternative forms of support such as telephone counselling or internet-based advice, children may not necessarily be lost to care. consent the children’s act states that children aged >12 years can consent independently to an hiv test.26 given that there is no express capacity requirement for hiv testing, it is presumed that all children aged >12 years can make this decision.27 if we apply these principles to hst, it means that children as young as 12 years could theoretically consent without assistance to an hiv self-test, provided that the other obligations in the children’s act relating to the best interests of the child and counselling are met. one issue raised in the literature is the possibility of such consent being coerced. 33 accordingly, it has been submitted that to avoid this possibility, laws and policies should be put in place to ensure that vulnerable groups such as children are not tested against their will.36 preand post-test counselling the children’s act (s 132) requires preand post-test counselling by an appropriately trained person. the act does not describe the manner in which the counselling should be provided or the information that must be given to children during the counselling processes. mcquoid-mason37 submits that this provision simply means that ‘during pre-test counselling the benefits, risks and social implications of an hiv test must be explained to the child, while during post-test counselling the implications of the results must be explained’. the lack of accompanying counselling is a key concern in the literature on self-testing.36 it has been argued that pre-test counselling provides an opportunity to make informed decisions on whether to test or not, while post-test counselling informs individuals of their hiv status, provides information on hiv prevention, encourages them to test regularly, reduces the risk of hiv transmission to others, and offers psychosocial or referral support to hiv-positive clients.36 counselling is a mandatory requirement in the children’s act, which means that testing without counselling is unlawful unless a child waives their right to this service. this therefore serves as an obstacle to self-testing by sa children. the act does not specify the nature of the counselling; thus, it is possible that, e.g., telephone counselling could suffice. the national hiv counselling and testing policy also does not specify that counselling must be face to face. instead, it provides a list of the minimum information that should be provided in pre-and post-test counselling sessions.38 confidentiality the children’s act (s 133) provides that children have the right to confidentiality regarding their hiv status.26 furthermore, information on a child’s hiv-positive status may only be disclosed with the consent of that child if they are aged >12 years.37 a key strength of the self-testing approach is that it ensures that confidentiality is maintained. a study conducted in singapore39 found that confidentiality was a key reason why people preferred to buy over-the-counter hiv test kits. the right to confidentiality in the children’s act is therefore not a barrier to self-testing. conclusion there is some preliminary evidence that hst could be a valuable new hiv-prevention strategy in that it gives persons at risk of hiv infection another way of discovering their hiv status. although no research has been undertaken on whether this model is suitable for children, we argue that this work needs to be done as a matter of urgency, as they are a group at high risk of hiv infection. this review of the sa legal framework has shown that the law does not expressly prohibit or regulate the offering of self-tests to children. nevertheless, the way in which self-testing was offered would have to comply with the children’s act. this means that only children aged >12 years could use an hiv self-test on their own, as below this age they do not have the capacity to consent. furthermore, there would be two potential legal obstacles. firstly, it would have to be shown that using an hiv self-test is in their best interests. this standard may be hard to meet, given the potential negative consequences that could flow from testing without support and the availability of other forms of hiv testing. secondly, there would need to be a way for children to access preand post-test counselling or for children to be advised that they will expressly have to waive this right. thus, simply offering self-hiv tests to all children aged >12 years would not be lawful, unless it could be shown that it was in their best interests and that counselling was provided. given these legal obstacles, we would suggest that it is only a small sub-set of children for whom such testing would be considered lawful. we argue that for older children (aged >16 years) self-testing may be in their best interests if: (i) it assists them with hiv-prevention strategies; (ii) they will be able to access treatment, care and support even though they have tested outside of a health facility; and (iii) psychosocial support services are made available to them via the internet or cell phones. it is submitted that although self-testing in children is an under-explored issue, it requires further debate and discussion. policy guidance is needed on when a self-test would be in a child’s best interests and how children who choose such a testing model can receive counselling and appropriate referral to services, if required. acknowledgements. this article was made possible by funding from the national institutes of health (nih) awarded to the hiv aids vaccines ethics group (haveg) via the desmond tutu hiv foundation (dthf) (1ro1 a1094586) champs (choices for adolescent methods of prevention in south africa). the opinions expressed herein are the views of the authors. they do not represent any position or policy of the nih. references 1. who, unicef, unaids. global hiv/aids response. epidemic update and health sector progress towards universal access. progress report. geneva, switzerland: who unicef, unaids, 2011. 1. who, unicef, unaids. global hiv/aids response. epidemic update and health sector progress towards universal access. progress report. geneva, switzerland: who unicef, unaids, 2011. 2. bwambale f, ssali s, byaruhanga s, kalyango j, karamagi c. voluntary hiv counselling and testing among men in rural western uganda: implications for hiv prevention. bmc public health 2008;8(1):263. 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[http://dx.doi.org/10.1097/qad.0b013e32835fd7a0] 17. myers je, el-sadr wm, zerbe a, branson bm. rapid hiv self-testing: long in coming but opportunities beckon. aids 2013;27(11):1687-1695. [http://dx.doi.org/10.1097/qad.0b013e32835fd7a0] 18. krause j, subklew-sehume f, kenyon c, colebunders r. acceptability of hiv self-testing: a systematic literature review. bmc pub health 2013;13:735. [http://dx.doi.org/10.1186/1471-2458-13-735] 18. krause j, subklew-sehume f, kenyon c, colebunders r. acceptability of hiv self-testing: a systematic literature review. bmc pub health 2013;13:735. [http://dx.doi.org/10.1186/1471-2458-13-735] 19. van dyk ac. client-initiated, provider-initiated, or self-testing for hiv: what do south africans prefer? j assoc nurses aids care 2013 (in press). 19. van dyk ac. client-initiated, provider-initiated, or self-testing for hiv: what do south africans prefer? j assoc nurses aids care 2013 (in press). 20. choko a, desmond n, webb e, et al. the uptake and accuracy of oral kits for hiv self-testing in high hiv prevalence setting: a cross-sectional feasibility study in blantyre, malawi. plos med 2011;8(10):e1001102. [http://dx.doi.org/10.1371/journal.pmed] 20. choko a, desmond n, webb e, et al. the uptake and accuracy of oral kits for hiv self-testing in high hiv prevalence setting: a cross-sectional feasibility study in blantyre, malawi. plos med 2011;8(10):e1001102. [http://dx.doi.org/10.1371/journal.pmed] 21. frith l. hiv self-testing: a time to revise current policy. lancet 2007;369(9557):243-245. 21. frith l. hiv self-testing: a time to revise current policy. lancet 2007;369(9557):243-245. 22. ganguli i, bassett i, dong k, walensky r. home testing for hiv infection in resource-limited settings. curr hiv/aids rep 2009;6(4):217-223. 22. ganguli i, bassett i, dong k, walensky r. home testing for hiv infection in resource-limited settings. curr hiv/aids rep 2009;6(4):217-223. 23. wright aa, katz it. home testing for hiv. n engl j med 2006;354(5):437-440. 23. wright aa, katz it. home testing for hiv. n engl j med 2006;354(5):437-440. 24. egenie. hiv home test kits. http://testforhiv.egenie.co.za/index.php?hur=87 (accessed 8 november 2013). 24. egenie. hiv home test kits. http://testforhiv.egenie.co.za/index.php?hur=87 (accessed 8 november 2013). 25. government of south africa. children's act: no. 38 of 2005. pretoria: government of south africa, 2005. 25. government of south africa. children's act: no. 38 of 2005. pretoria: government of south africa, 2005. 26. strode a, slack c, essack z. child consent in south african law: implications for researchers, service providers and policy-makers. s afr med j 2010;100(4):247-249. 26. strode a, slack c, essack z. child consent in south african law: implications for researchers, service providers and policy-makers. s afr med j 2010;100(4):247-249. 27. mccall v mccall, 1994 (3) sa 201 (c). 27. mccall v mccall, 1994 (3) sa 201 (c). 28. s v m (centre for child law as amicus curiae, 2008). 28. s v m (centre for child law as amicus curiae, 2008). 29. grant k, lazarus r, strode a, van rooyen h, vujovic m. legal, ethical and counselling issues related to hiv testing of children hiv testing of children: legal guidelines for implementers. pretoria: human sciences research council, 2012. 29. grant k, lazarus r, strode a, van rooyen h, vujovic m. legal, ethical and counselling issues related to hiv testing of children hiv testing of children: legal guidelines for implementers. pretoria: human sciences research council, 2012. 30. world health organization. report on the first international symposium on self-testing for hiv: the legal, ethical, gender, human rights and public health implications of hiv self-testing scale-up. geneva: who, 2013. 30. world health organization. report on the first international symposium on self-testing for hiv: the legal, ethical, gender, human rights and public health implications of hiv self-testing scale-up. geneva: who, 2013. 31. kalibala s, tun w, muraah w, cherutich p, oweya e, oluoch p. “knowing myself first”: feasibility of self-testing among health workers in kenya. nairobi: population council, 2011. 31. kalibala s, tun w, muraah w, cherutich p, oweya e, oluoch p. “knowing myself first”: feasibility of self-testing among health workers in kenya. nairobi: population council, 2011. 32. napierala mavedzenge s, baggaley r, corbett el. a review of self-testing for hiv: research and policy priorities in a new era of hiv prevention. clin infect dis 2013;57(1):126-138. 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[http://dx.doi.org/10.1016/j.annemergmed.2011.03.029] 34. gaydos ca, hsieh y-h, harvey l, et al. will patients “opt in” to perform their own rapid hiv test in the emergency department? ann emerg med 2011;58(suppl 1):s74-s78. [http://dx.doi.org/10.1016/j.annemergmed.2011.03.029] 35. lee vj, tan sc, earnest a, seong ps, tan hh, leo ys. user acceptability and feasibility of self-testing with hiv rapid tests. j acquir immune defic syndr 2007;45(4):449-453. 35. lee vj, tan sc, earnest a, seong ps, tan hh, leo ys. user acceptability and feasibility of self-testing with hiv rapid tests. j acquir immune defic syndr 2007;45(4):449-453. 36. gardner j. hiv home testing – a problem or part of the solution? south african journal of bioethics and law 2012;5(1):15-19. 36. gardner j. hiv home testing – a problem or part of the solution? south african journal of bioethics and law 2012;5(1):15-19. 37. mcquoid-mason dj. the effect of the new children's act on consent to hiv testing and access to contraceptives by children. s afr med j 2007;97(12):1252. 37. mcquoid-mason dj. the effect of the new children's act on consent to hiv testing and access to contraceptives by children. s afr med j 2007;97(12):1252. 38. national department of health. national hiv counselling and testing (hct) policy guidelines. pretoria: ndoh, 2010. 38. national department of health. national hiv counselling and testing (hct) policy guidelines. pretoria: ndoh, 2010. 39. ng ot, chow all vj, chen mi, et al. accuracy and user-acceptability of hiv self-testing using an oral fluid-based hiv rapid test. plos one 2012;7(9). [http://dx.doi.org/10.1371/journal.pone.0045168] 39. ng ot, chow all vj, chen mi, et al. accuracy and user-acceptability of hiv self-testing using an oral fluid-based hiv rapid test. plos one 2012;7(9). [http://dx.doi.org/10.1371/journal.pone.0045168] d e c e m b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e when to initiate antiretroviral therapy (art) in children and adults has been determined by disease stage and cd4 count or percentage. the starting criteria were based on cohort data and clinical experience. the main groups determining paediatric guidelines are from the usa, europe (penta paediatric european network for treatment of aids) and the world health organization (who).1-3 with the advent of effective triple therapy from 1995, guidelines have adapted to new data. initial staging clinical and immunological criteria were those of the centers for diseases control and prevention (cdc).4 the staging criteria were based on north american experience and were not always appropriate for africa. for example, failure to thrive, bronchiectasis and pulmonary tuberculosis were not adequately addressed. although the cdc classification included cd4 depletion, it was only with the hiv prognostic markers collaborative study (hpmcs), representing the combined data of 3 941 hiv-infected infants and children from the usa and europe in the pre-highly active antiretroviral therapy (haart) era, that the relationship between age and cd4 percentage became clearer.5 the study showed that the younger the infant, the higher the cd4 percentage or absolute count at which there was a high risk of disease progression or death within the next 12 months. as the cd4 count normally declines with age until 5 years of age and the cd4 percentage remains stable, the cd4 percentage is used as a guideline until then (in the absence of lymphopenia). however, the cd4 count is an extremely accurate pre dictor of outcome.6 these findings were subsequently incorporated into all paediatric guidelines. the establishment of a who classification system in 2006 helped to focus on conditions more frequently encountered in africa.7 the system has 4 stages, with art recommended for stages 3 and 4. the special vulnerability of young infants to rapid disease progression and death was not fully appreciated at this time, although allowance was made for initiating art in hiv antibody-positive infants with severe disease before confirmation by hiv dna polymerase chain reaction (pcr). the decision on when to initiate art in infants and child ren has always been influenced by fears of long-term toxicity or antiretroviral (arv) resistance if therapy is started too soon. also, arv choices for children are far more limited than for adults. second-line therapy is especially unsatisfactory. however, there is increasing realisation, especially from adult data, that delaying art until the cd4 cell count falls below 350 cells/µl is associated with increased morbidity and mortality.8,9 art is therefore recommended at higher cd4 thresholds than previously. mortality in hiv-infected infants is exceedingly high. the first data came from a study of combined outcome in nine vertical transmission prevention (vtp) studies conducted in sub-saharan africa.10 thirty-five per cent of hiv-infected infants had died by 1 year of age and 52.5% by 2 years of age. the zvitambo study in zimbabwe showed a similar but slightly higher mortality in the first 2 years of life.11 for both studies, co-triwhen to start antiretroviral therapy in infants and children c l i n i c a l mark f cotton, fcpaed (sa), phd, dtm&h, dch (sa), cert id (sa) helena rabie, fcpaed (sa), mmed (paed) department of paediatrics and child health and kid-cru, tygerberg children’s hospital and faculty of health sciences, stellenbosch university, tygerberg, w cape ute feucht, fcpaed (sa), mmed (paed), dip hiv man (sa), cahm department of paediatrics, kalafong hospital and university of pretoria avy violari, fcpaed (sa) perinatal hiv research unit, chris hani baragwanath hospital, soweto, johannesburg we review the background and key studies that inform decisions on when to initiate antiretroviral therapy (art) in infants and children. the world health organization staging system from 2006 was based on conditions commonly seen in africa and provided an impetus for advancing art in children. because of poor predictive value of cd4 counts in infancy and inability to predict risk of death or disease progression, we recommend initiating art in all infants under a year of age. cd4 thresholds for initiating therapy decline as children become older. who stage 3 and 4 should trigger art regardless of cd4 count. over 5 years of age, a cd4 count <350/µl requires art. 50 infants below 12 months of age t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e d e c e m b e r 2 0 0 9 moxazole prophylaxis for prevention of pneumocystis pneumonia (pcp) was not given. the children with hiv early antiretroviral (cher) trial is the first arv trial to prospectively evaluate art strategies to inform arv guidelines.12 before this, limited cohort studies favoured early art. for example, faye et al. reported an improved outcome in 40 infants commencing art before 6 months of age compared with 43 starting later. in the early group there was no disease progression versus 7 events, including 3 cases of encephalopathy, in those treated later.13 cher commenced in july 2005 in two south african sites, the perinatal hiv research unit (phru) in soweto and the children’s infectious diseases clinical research unit (kid-cru) at tygerberg in the western cape. the hypothesis of the study is that early art will have long-term benefit by delaying the need for continuous therapy. at the time of planning and initiation, the standard practice in infants was to initiate art for a low cd4 percentage (<20% until august 2006 and 25% thereafter, in the first year of life) or evidence of severe clinical disease.3,14 in the first part of the study, infants with baseline cd4 >25% were randomised to deferred art (arm 1), where art was initiated once treatment criteria were reached (cd4 <20% until august 2006 and <25% thereafter or severe hiv disease), or early art commencing before 12 weeks of age until either the first (arm 2) or second (arm 3) birthdays, with interruption of art until indicated through cd4 depletion (<20% after the first birthday) or clinical disease progression. for the first year of the study, deferred art (arm 1) was compared with early art (arms 2 and 3). on 20 june 2007, after the study had been open for 2 years, the data safety monitoring board for cher, noting significantly improved survival in subjects in the early art arms, recommended that no infants be randomised to deferred art and that data until this time point be released.12 the difference in mortality and disease progression is shown in fig. 1. a key finding in cher was high early mortality, mainly in the deferred arm, which diminished as the infants became older (table i). also of note, however, is that mortality was also higher early on in the early art group, diminishing over time in the first year of the study. subsequently, arv guidelines for children throughout the world incorporated the findings of cher and recommended that all hiv-infected children below 12 months of age start art irrespective of cd4 status or disease progression.1, 2,15 more recently, a study by bourne and colleagues, using birth and death data from statistics south africa between 1997 and 2002, showed a peak in post-neonatal mortality, rising each year directly proportional to the rising hiv antenatal seroprevalence.16 these data are shown in fig. 2. also of note is that neonatal deaths are not addressed. it is possible that hiv may contribute significantly to neonatal deaths as well. these data, together with cher, illustrate the enormous dilemma and problems for child health programmes. in cher the diagnostic hiv dna pcr was done from 4 weeks of age with a 7-day turnaround time. in the public sector, the pcr is done at 6 weeks of age, to coincide with the 6-week immunisation visit. turnaround time for the test results and then communication to the caregiver all take time during a period of great vulnerability. one of the main problems is identifying hiv-infected children early and getting them into care. because of 51 fig. 1. deferred art is associated with a) a higher probability of death or b) first hiv event in the cher trial. death rate per 100 person years (95% ci) weeks on study* early art deferred art 0 13 9.8 (3.6 21.4) 40.6 (21 71) >13 26 3.7 (0.4 13.2) 19.7 (6.4 45.9) >26 52 3.1 (0.4 11.2) 6.8 (0.8 24.7) *infants were <12 weeks of age at study entry.12 table i. high early mortality rate in the cher study fig. 2. early peak in infant mortality proportional to rising antenatal hiv seroprevalence, 1997 2002 (reproduced with permission from aids16). d e c e m b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 52 the importance of the caregiver in giving arvs, previous guidelines emphasised adequate preparation and training over a number of weeks. because of the new recognition of early infancy as a period of high mortality, there is a need to ‘fast-track’ preparation and also to continue training and support after having initiated arvs. practical difficulties are illustrated by experience in the tshwane district. in 2009, 82% of children newly referred to the kalafong art site had stage 3 or 4 disease, the majority being referred from the inand outpatient service. of the 14 000 22 000 hiv-infected children thought to be in tshwane, only between 3 000 and 4 000 are receiving art or are in care. in this group there is less certainty on when to initiate art. ideally, decisions must be based on randomised studies. the predict is underway in thailand and cambodia and will assess the cd4 thresholds for therapy in children between 1 and 12 years of age. all guidelines recommend using absolute cd4 counts from 5 years of age. for simplicity, the who regards 1 5 years of age as a single group, while the penta guidelines have 1 3 and 3 5 years of age. this group of children also represents a wide age spectrum. clinical disease stage is extremely important and the majority of children are symptomatic. the dissociation of cd4 from disease severity has been well documented in south african children.17 the hpmcs data, although showing a low risk of disease progression for higher cd4 percentages, still showed notable death and disease progression with cd4 >30% up to 6 years of age.5,6 initial data suggested that young children show excellent immune restoration once art is initiated, but more recent studies suggest a poorer response if therapy is delayed to cd4 <15%. initial reports also suggested that viral suppression was difficult to achieve, especially in younger infants with extremely high viral loads. however, potent regimens and a better understanding of pharmacokinetics have improved outcomes. importantly, health care providers caring for children often do not fully appreciate the extent of end-organ damage. mild cognitive and behavioural changes, milder forms of chronic lung disease, renal and hepatic disease and poor growth may easily be overlooked, leading to irreversible organ damage, growth failure and delayed puberty. in the 3c4kids, 2 510 children over a year of age from africa and brazil contributed 357 deaths and 3 769 child-years at risk.18 none had access to art, with 81% follow-up occurring on co-trimoxazole. the 12-month risk of death was higher than in the hpmcs for cd4 count and percentage. most importantly, when anaemia and failure to thrive were included, the cd4 thresholds for predicting death or severe disease were much higher (fig. 3). both of these conditions are markers for advanced hiv disease. most importantly, there was a real risk of death at high cd4 counts and percentages. for these reasons, our guidelines favour earlier art between 1 and 5 years of age, in keeping with current us recommendations.2 there has been much progress in refining and improving arv guidelines for children. more changes can be expected as knowledge advances. most important, however, is the realisation that each child is unique and his or her individual and family circumstances need to be considered for maximum benefit. references 1. the penta 2009 guidelines for the use of antiretroviral therapy in paediatric hiv-1 infection. hiv medicine 2009; 10: 591-613. 2. working group on antiretroviral therapy and medical management of hivinfected children. guidelines for the use of antiretroviral agents in pediatric hiv infection; 2008. 28 february 2008. http://aidsinfo.nih.gov/contentfiles/ pediatricguidelines.pdf (accessed 1 march 1 2008). 3. world health organization. antiretroviral therapy of hiv infection in infants and children in resource-limited settings: towards universal access. recommendations for a public health approach. geneva: who, 2006. 4. centers for disease control and prevention. revised classification system for human immunodeficiency virus infection in children less than 13 years of age. mmwr morb mortal wkly rep 1994; 43: 1-10. 5. hiv paediatric prognostic markers collaborative study group. short-term risk of disease progression in hiv-1-infected children receiving no antiretroviral therapy or zidovudine monotherapy: a meta-analysis. lancet 2003; 362: 1605-1611. 6. hiv prognostic markers collaborative study. predictive value of cd4 count and viral load for disease progression in untreated hiv-infected children. aids 2006; 20: 1289-1294. 7. world health organization. who case definitions of hiv for surveillance and revised clinical staging and immunological classification for hiv-related disease in adults and children. geneva: who, 2006. 8. kitahata mm, gange sj, abraham ag, et al. effect of early versus deferred fig. 3. estimated risk of death within 12 months for a child on co-trimoxazole prophylaxis by age, weight-for-age zscore and haemoglobin and cd4 percentage or count. (a) cd4% at 2 years of age; (b) cd4% at 5 years of age; (c) cd4 count at 2 years of age; and (d) cd4 count at 5 years of age (reproduced with permission from aids18 ). children >12 months of age conclusion t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e d e c e m b e r 2 0 0 9 antiretroviral therapy for hiv on survival. n engl j med 2009; 360: 1815-1826. 9. sterne ja, may m, costagliola d, et al. timing of initiation of antiretroviral therapy in aids-free hiv-1-infected patients: a collaborative analysis of 18 hiv cohort studies. lancet 2009; 373: 1352-1363. 10. newell ml, coovadia h, cortina-borja m, rollins n, gaillard p, dabis f. mortality of infected and uninfected infants born to hiv-infected mothers in africa: a pooled analysis. lancet 2004; 364: 1236-1243. 11. marinda e, humphrey jh, iliff pj, et al. child mortality according to maternal and infant hiv status in zimbabwe. pediatr infect dis j 2007; 26(6): 519-526. 12. violari a, cotton mf, gibb dm, et al. early antiretroviral therapy and mortality among hiv-infected infants. n engl j med 2008; 359(21): 2233-2244. 13. faye a, le chenadec j, dollfus c, et al. early versus deferred antiretroviral multidrug therapy in infants infected with hiv type 1. clin infect dis 2004; 39(11): 1692-1698. 14. world health organization. scaling up antiretroviral therapy in resource limited settings: guidelines for a public health approach. april 22, 2002. http://www. helid.desastres.net/?e=d-0who--000--1-0--010---4-----0--0-10l--11es-5000--50-packc-0---01131-010-mulpqgf842f94771000000004ab19d67-0-0-0&a= d&c=who&cl=cl2.1.5&ld=js2888e (accessed 18 november 2009). 15. world health organization. report of the who technical reference group, paediatric hiv/art care guideline group meeting who headquarters, geneva, switzerland; 2008 june 18, 2008. http://www.who.int/hiv/pub/paediatric/who_ paediatric_art_guideline_rev_mreport_2008.pdf (accessed 19 june 2008). 16. bourne de, thompson m, brody ll, et al. emergence of a peak in early infant mortality due to hiv/aids in south africa. aids 2009; 23(1): 101-106. 17. van kooten niekerk nk, knies mm, howard j, et al. the first 5 years of the family clinic for hiv at tygerberg hospital: family demographics, survival of children and early impact of antiretroviral therapy. j trop pediatr 2006; 52(1): 3-11. 18. duong t, gibb dm, dunn dt, et al. (3cs4kids). markers for predicting mortality in untreated hiv-infected children in resource-limited settings: a meta-analysis. aids 2008; 22: 97-105. 53 june 2006 make up june 2006 the southern african journal of hiv medicine1 8 madwaleni’s hiv/arv programme madwaleni was accredited as an arv site by the eastern cape department of health on 14 february 2005 on condition that a pharmacist was employed prior to rollout. anemari buitendach joined madwaleni in may 2005 as both the hospital and hiv programme pharmacist. the arv rollout began on 28 june 2005 after the first batch of arv drugs was received on 27 june 2005. the staff complement has increased dramatically from 3 staff members in january 2005 (site co-ordinator, doctor, nurse) to 22 staff members, including 2 doctors, 3 nurses, 1 site coordinator, 1 administrator, 1 data capturer, 1 hospital pharmacist, 1 hospital social worker, 5 community health workers, 6 peer educators and a driver. in addition, a community service physiotherapist has joined madwaleni for the first time and also works with the hiv programme patients. two more pharmacy assistants joined the programme in mid-may 2006. madwaleni's hiv/arv programme centres around the support groups run by counsellors (community health workers and peer educators) and nurses at madwaleni and 6 primary health care clinics. based on support group attendance, patients join the hiv/arv programme and receive regular and continuing counselling irrespective of their cd4 counts. patients with cd4 counts lower than 200 cells/µl begin to prepare for arv readiness and are put on arv treatment. a vct outreach programme was started in which counsellors do ‘door to door’ hiv awareness in the communities c o m m u n i t y a r v s e r v i c e s the madwaleni hiv/arv programme richard cooke, bbus sci, mb bch lynne wilkinson, ba llb madwaleni hospital, e cape richard cooke and lynne wilkinson sought out a deep rural hospital in the old transkei area of the eastern cape to attempt to set up a holistic hiv programme including access to antiretrovirals (arvs). they looked for a hospital difficult to access by road, where the majority of the people were unemployed and where hiv-positive people currently have minimal health and social support. they identified madwaleni hospital, a 220-bed district hospital built as a missionary hospital in the early fifties. it is approximately 30 km south-east of a small town called elliotdale (approximately 80 km south-east of mthatha). district statistics indicate that the hospital serves a population of approximately 256 000. madwaleni is approximately 110 km (including 30 km of dirt road) from its referral centre, nelson mandela hospital complex (nmh) in mthatha. madwaleni has a small operating theatre, an x-ray facility and a laboratory, and patients are referred to nmh for all specialist consultations, and for surgery other than minor operations and caesarean sections. by car or ambulance this route takes approximately 1� 1 2 � hours, but for patients who are referred and need to use public transport, it takes closer to 2� 1 2 � hours. madwaleni has a total of 5 doctors (including hiv/arv programme doctors) and 117 nurses (including 46 professional nurses) at the time of writing in 2006. it has a small nursing college on site. at the beginning of 2005 madwaleni's hiv programme, as at many rural government hospitals, was run by a single nurse and included hiv voluntary counselling and testing (vct) for people coming to the hospital and specifically requesting to be tested, a small hiv support group started the previous year, prophylactic treatment (when available) for those patients requesting assistance, prevention of mother-to-child transmission (pmtct) counselling and provision of nevirapine to some of the hivpositive women accessing the hospital's services, and provision of formula feed (when available) for mothers who chose to formula feed upon receiving pmtct counselling. where is madwaleni? 1 9 surrounding the hospital. thereafter nurses do hiv testing in the communities on days arranged with the local headman/chief, often coinciding with government grant collection days. an infant follow-up clinic (ifc) for hiv-exposed infants and a paediatric hiv wellness and arv programme for hiv-positive children is run on a wednesday and is closely co-ordinated with the maternity ward in the hospital and the antenatal clinics at the primary health care clinics. the most recent initiative has been the integration of tuberculosis (tb) inpatients into the hiv programme. this aims to fast-track inpatients diagnosed with tuberculosis into the hiv programme, and where applicable put them on arv treatment (art). disease profile in the hiv/arv programme the most common presenting signs and symptoms are productive coughing, weight loss, dermatological conditions (especially papular pruritic eruptions, ringworm, fungal lesions and herpes zoster), and peripheral neuropathies. chronic diarrhoea is common in aids patients and arvs are now an option where management by repeated rehydration and antibiotics fails. common diagnosis on clinical grounds include oral and vaginal candidiasis, genital condylomas and herpes simplex virus (hsv) 1 and 2. tuberculosis is by far the most common disease affecting patients at madwaleni and remains a major problem. common who stage 4 conditions seen include cryptococcal meningitis and kaposi’s sarcoma, but relatively few cases of pneumocystis jiroveci pneumonia (pjp) are seen. conditions such as cervical dysplasia diagnosed on pap smear and extrapulmonary tuberculosis (eptb) are under-diagnosed. it is therefore necessary that hiv/aids patients are actively screened for these conditions, the latter when clinically indicated. neurological conditions are also under-diagnosed and patients often present on anticonvulsant medication with a longstanding ‘epilepsy’ diagnosis written in the opd card. neurocysticercosis is common in this part of south africa and is frequently treated empirically. owing to culture/language barriers faced by english-speaking doctors, counsellors are encouraged to recognise signs of confusion and mental deterioration through repeat counselling sessions. counsellors can prove valuable in referring neurological cases that could be hiv encephalopathy or organic cns pathology. early indications are that syphilis does not have a high prevalence in the current programme. of 376 baseline serological tests, 28 (7.4%) tested positive for syphilis, but 24 were only weakly reactive (false positives occurring at low titres). the first 90 patients started on arvs at madwaleni hiv clinic were staged according to the who classification as follows: stage 1 – 4%; stage 2 – 30%; stage 3 – 52%; stage 4 – 13%. a further 60 patients were staged on entry to the hiv wellness programme: stage 1 – 43%; stage 2 – 20%; stage 3 – 30%; stage 4 – 7%. side-effects and adverse events the majority of patients report initial dizziness on efavirenz which improves after a week. two patients – a man and a woman – presenting with psychiatric symptoms were switched from efavirenz to nevirapine. while the man is doing well, the woman had a stevens-johnson drug reaction to cotrimoxazole/nevirapine progressing to toxic epidermal necrolysis (ten), and died at the referral hospital. women of child-bearing age are encouraged to take the nevirapine-containing regimen, allthough more blood sampling for drug safety monitoring is required. only one woman has fallen pregnant after starting arvs, but this will increase as general health and quality of life continue to improve. family planning is encouraged and every woman is counselled on injectable contraceptive options. high alanine transaminase (alt) levels are common (see table i), but only one patient on nevirapine discontinued medication, owing to an isolated drug hepatitis. she is soon to commence regimen 2 arv treatment. two patients on regimen 1b were screened for hyperlactaemia. both are women, obese and with high cd4 counts. both had lost weight . a handheld lactate meter indicated a lactate level of 8.2 mmol/l in in the first patient and 3 mmol/l in the second. serial measurements were similar. the first was switched to zidovudine (azt), and her condition appeared to settle. unfortunately she was transferred to another site before the switch could be assessed properly, including haematological toxicity. the second settled on symptomatic treatment alone. known causes of death on arvs include 1 case of ten (see above), 1 case of proven multidrug-resistant (mdr) tb, 1 patient in whom a computed tomography (ct) scan of the brain revealed a pontine lesion (tuberculoma/lymphoma), 1 pulmonary tuberculosis (ptb) retreatment failure (sputum positive at 5 months), and 1 case of tuberculous meningitis (immune reconstitution). four died of unknown causes – in each case the baseline cd4 count was below 50 cells/µl, including a 5-year-old child with a cd4% of 0.24%. the first two patients with virological failure are soon to start on regimen 2. the southern african journal of hiv medicine june 2006 the madwaleni hiv/arv team. june 2006 the southern african journal of hiv medicine2 0 successes community involvement intensive community involvement has led to specific successes for the madwaleni hiv/arv programme. as stated above, there are 5 community health workers and 6 peer educators (hivpositive members of the programme) who work permanently on the programme with the further assistance of certain community health workers at the clinics. this has allowed intimate access to patient attitudes, feelings and expectations. in addition, their contribution has been invaluable in lightening the workload of the remaining staff (especially nurses) without compromising patient relationships and care. the counsellors are involved at all levels of the programme, which also ensures their full participation, including running support groups (group counselling), individual ongoing counselling of hiv wellness programme patients, preparing patients for arvs from an individual commitment perspective, at end march 06 notes total people tested for hiv at 4 119 the monthly average for the last 6 months is 445 madwaleni (since jan 05) and 6 clinics (madwaleni and clinics) (since oct 05) hiv prevalence rate 23.7% jan 05 mar 06 june 05 april 06 total no. of adults on hiv/arv programme 513 % of adults with cd4 < 200 cells/µl 57.1% total no. of children on hiv/arv programme 42 % of children with cd4% < 15% 51.7% adults initiated on arv treatment male 63 (33%) female 128 (67%) total 191 children initiated on arv treatment male 6 (55%) female 5 (45%) total 11 average no. of patients initiated on arv treatment 20 per month % adults on regimen 1a 64.9% % adults on regimen 1b 28.2% mean absolute cd4 in 'decision to treat' 105.03 n = 178 (excludes children on arv treatment and (dtt) group (cells/µl) patients transferred in from other sites) mean cd4% in ddt group 8.9% n = 178 (excludes children on arv treatment and patients transferred in from other sites) adults on arv treatment for 6 months 7 patients, of whom 3 patients n = 62 (excluding deaths before 6 months, transfers that have not achieved undetectable have < 1 log decrease out before 6 months, patient stopped on arv viral loads (< 400/ml) treatment, missed or still outstanding viral loads) adults on arv treatment for 6 months – mean n = 61 (excludes deaths before 6 months, transfers increase in absolute cd4 count (cells/µl) out before 6 months, patient stopped on arv baseline 118.52 treatment, missed or still outstanding cd4 counts) 6 months 250.41 increase 131.89 adults on arv treatment for 6 months – mean n = 61 (excludes deaths before 6 months, transfers out increase in absolute cd4% before 6 months, patient stopped on arv treatment, baseline 8.89% missed or still outstanding cd4 counts) 6 months 16.51% increase 7.62% patients died on arv treatment 9 includes 1 child see notes arv patients lost to follow-up 1 patients in whom arvs discontinued 2 hepatotoxicity related to nevirapine (n = 56) any > uln 44.6% alt > 3 x uln 10.7% alt > 5 x uln 3.6% uln = upper limits of normal; alt = alanine transaminase. table i certification of adherence counsellors. 2 1 assisting in the selection of patients ready for arv treatment and doing ongoing adherence counselling. they also conduct home visits to prepare the patient’s family for his/her arv treatment, to report any socio-economic problems to the social worker. the counsellors are involved with the adult, child and pregnant women components of the programme. in addition to the counsellors, the programme is supported by many 'hiv programme activist’ support group members who assiduously attend the support group, get involved in every initiative that the programme presents, counsel people in their homes and villages and introduce new members to their support groups on a weekly basis. these people are key to spreading the programme's 'follow-up' net widely. as a result, of over 200 patients on arv treatment in the programme, only 1 has been lost to follow-up. rural hospital staff motivation much criticism is levelled at public sector nurses in south africa with regard to lack of motivation and work ethic. this is often unfair, as it is rarely the nurses themselves who are the root cause of the problem. nurses are frustrated by years of isolation in rural district hospitals, unsupported by management and administrative functions, with few career development paths or remuneration incentives. consequently they adopt attitudes of resignation and defeat. at madwaleni patient and counsellor enthusiasm and participation in the programme have served as catalysts for renewed involvement of the nurses and improved performance. co-ordination function lynne wilkinson (an attorney by profession) has taken on the role of project manager for the programme. many rural programmes are left either to doctors or to nurses to set up and manage in addition to their many clinical duties. the programme has greatly benefited from having a dedicated person to set up administrative and data systems, staff management, funder reporting, government liaison and coordination of tasks within the programme. this system has allowed dr richard cooke to head the clinical programme and cover general hospital responsibilities. private-public partnerships in the eastern cape, government budgets support employment, arv drugs and laboratory costs. operating budgets are small, however, and in many instances extremely difficult to utilise through general hospital procurement and payment systems. it was intended that the madwaleni hiv/arv programme would be set up as a government accredited and funded site for purposes of long-term sustainability and that private funding would be brought in only to facilitate and accelerate the building up of the programme. in addition to government funding, the madwaleni hiv/arv programme has been funded by the rural health initiative (rhi), difaem, a few private individuals, and since october 2005, the aurum institute for health research (pepfar funding). this has allowed us to accelerate the implementation of the programme. challenges hiv and tb co-infection while many opportunistic infections can be managed routinely, the tb epidemic is a challenge of huge proportions. madwaleni's tb beds (80 of 220) are normally full to capacity. the dots system is ineffectively implemented and large numbers of patients needing retreatment are admitted to hospital for daily streptomycin injections. during 2005, 75 inpatients died. multidrug-resistant (mdr) tb is an increasing problem: in 2005, 16 of 500 inpatients were identified as having mdr tb. adult tb prophylaxis regimens are not provided by the central pharmacy depots. of the patients on arvs, 103 (54%) have a history of tb (29% of these 103 are retreatment cases). of the patients on arvs 57 (30%) were on tb treatment at the time they started on arvs (39% of these 57 were retreatment cases); 10 patients (9.7%) were started on tb treatment while on arvs. these figures support channelling of resources to diagnose tb as early as possible. if extending national guidelines on hiv/tb co-infection is not the answer, then district hospital staff must be in regular consultation with expert clinicians with respect to management of hiv/tb co-infections. strict monitoring of patient symptoms by counsellors, regular weight monitoring, regular sputum collection and a screening chest x-ray are helpful for diagnosing pulmonary/pleural tb. more tb cultures are now done routinely in smear-negative pulmonary tuberculosis diagnosed clinically and radiothe southern african journal of hiv medicine june 2006 our pharmacist and nurse explain the complexities of arv treatment to a patient. the madwaleni hiv support group in full swing. june 2006 the southern african journal of hiv medicine2 2 graphically, but the required 4 6-week waiting period is unhelpful. extrapulmonary tb is under-diagnosed in this resource-limited setting. with the recent arrival of an ultrasound machine (supplied by government), doctors must now acquire skills to aid ultrasound diagnosis of abdominal tb in addition to the regular obstetric and gynaecological investigations. unfortunately the high turnover of short-term community service doctors means that the benefit of this training is short lived. to address the high hiv prevalence among tb inpatients, the hiv/arv programme has been extended to the tb ward by fast-tracking patients assessed clinically and identified by the ward doctor. counsellors then provide hiv education, assess individual commitment and provide adherence counselling so that patients can be started on arv treatment while in the ward. further emphasis is placed on education of all tb/hiv patients before discharge to ensure continued participation in the arv programme on an outpatient basis. owing to the high prevalence of tb among the arv programme members, adherence to tb medicine needs to be included in arv adherence counselling, especially in view of the high pill burden for tb/arv patients. however, this does not solve the problem of tb patients who do not form part of the programme, which needs to be addressed with tb ward staff and clinic staff. no arv programme can be successful without an effective tb programme. medicine interactions and toxicity patients often present with multiple pathologies, but in resource-constrained hospitals too many conditions are treated empirically. madwaleni is no exception. faulty diagnostic tools (e.g. unavailability of x-rays or laboratory reagents out of stock), lost/delayed results, and lack of specialist guidance all contribute to this practice, which has the negative consequences of medication interactions, toxicities and high financial costs. madwaleni is attempting to address this in part by outsourcing a specialist one day a month to guide junior doctors. doctors are also increasingly trying to stop prophylactic co-trimoxazole as early as possible. while useful for ‘adherence practice’, co-trimoxazole is religiously swallowed (960 mg daily) to the extent that doctors struggle to convince patients to stop when their immune systems improve. the introduction of single-drug tb medicine formulations at district hospital level will go some way towards improving our management of tb drug toxicities. increased diagnosis does not always increase management capability as a service is built up and more clinical diagnoses are made, it is frustrating when treatment/management capabilities do not increase in tandem. for example, the women's health clinic is identifying more genital condylomas and abnormal pap smears, but unreliable equipment and an imperfect referral system result in too few cauterisations and colposcopies. similarly, our laboratory offers the full range of basic tests, as well as investigations such as liver function tests and cryptococcal/bacterial antigen tests. cd4 cell counts, polymerase chain reaction assays, viral loads, biochemistry and many others are done in mthatha. others including cytology investigations have to be done in east london (4 hours’ drive away). blood cultures are not routinely available at madwaleni. arv drug formulations while arv drug supply has been good, it is maintained by programme staff fetching the orders. in addition, in the months of december and january limited numbers of new patients could be started on arv treatment because the mthatha depot had no electrical power and placement of new orders was therefore difficult. changes in dosage formulations causes frustration. intensive adherence counselling is hampered by an abrupt change in pill colour. lamivudine, for example, changed from white to red and stavudine from orange/brown to red/yellow. similarly, unavailability of certain dosage formulations such as efavirenz 600 mg meant that madwaleni was supplied with 200 mg tablets. a number of the arv patients on the programme are illiterate, and changing colours and number of pills raises concerns about adherence and increased pill burdens. this problem was solved by selecting 10 highly adherent and focused patients to receive the 3 x 200 mg dosage of efavirenz until the stocks ran out, while other patients were kept on the simpler single-pill regimen. similarly, 20 mg stavudine tablets have repeatedly been unavailable, resulting in paediatric patients having to take ridiculously large quantities of the liquid formulation. increasing our knowledge of traditional xhosa medicine counsellors encourage support group members not to use traditional xhosa medicine without first consulting our clinical hiv education in our communities. mothers in the support group bring their children for testing. june 2006 the southern african journal of hiv medicine2 4 staff rather than forbidding them to do so. the support group members themselves have adopted a negative attitude towards traditional medicine, often as a result of their own personal experiences, and convey these stories and attitudes to new support group members. as a result, clinicians are not currently experiencing problems on the hiv programme with xhosa medicine interaction with arv drugs. staff, however, do not have a full understanding of the patients' opinions relating to xhosa medicine and their interaction with their arv drugs, and this needs to be studied further. poor access to health care access to both the hospital and the primary health care clinics is hindered by many factors including impassable dirt roads, few ambulances and limited taxi routes. the direct impact on the programme is manifested by a low conversion rate of vctpositive individuals onto the hiv/arv programme through the support group ‘gateway’, as well as precious resources spent on ensuring patient follow-up: clinic visits by doctors, database monitoring of follow-up visits, a driver transporting counsellors on home visits and patient searches. building a one-stop shop the intention is to provide a comprehensive primary arv service. the programme will need to be adapted in the future when the breadth of service itself becomes a barrier to increasing the numbers on the programme. currently new adult patients are initiated onto arvs on only one day per week as a result of stretched resources. other hiv/aids services provided by the hospital include a vct service, an infant follow-up clinic, a paediatric arv treatment clinic, peripheral clinic hiv wellness and arv readiness programmes, (during which the doctor rotates through three clinics per day), a prenatal clinic, and a women's health clinic. doctors are also involved in all areas of rural medicine, including ward rounds, opd work and theatre time. while this system is not currently limiting access to arv treatment, in that the programme is coping with the demand for arv treatment (no waiting list), this is likely to change in the future and a further day would then need to be considered. increased nurse participation in clinical monitoring of arv patients would also be of assistance. a further difficulty to overcome is that a patient who falls into a number of categories (e.g. she is on arv treatment, her child is part of the infant follow-up (ifc) and she requires a pap smear) cannot be expected to attend a number of different days in a week. decentralising the programme decentralising the programme to the clinics, including the wellness and arv programmes, improves health care access but more resources are needed to implement, monitor and maintain the programme at this level. at present patients join the hiv wellness programme and are prepared for arvs at the clinics. they are, however, required to go to madwaleni for their arvs. the arv patient follow-up and monitoring is only done by the largest of the clinics or at madwaleni. the programme's aim is to ensure that this takes place at all clinics, and newly appointed pharmacy assistants are in the process of being trained to assist the nurses with dispensing repeat medication. when resources allow, it is envisaged that the initial arv take up will also be done at the clinics with the assistance of the clinic doctor. palliative and home-based care: underprepared the increasing numbers of patients accessing hospital treatment and the madwaleni arv programme may have two negative consequences in the long term: the hospital will not have the resources to cope, and the number of treatment failures will grow. facilities to improve the palliative care of these chronically ill patients are urgently needed. such a facility could provide intensive short-term step-up treatment and care. it could also serve as a training venue for relatives and counsellors, enabling early discharge into home care. the programme has motivated the eastern cape health department to include such a facility as part of the planned hospital revitalisation. sustaining hiv-positive support groups currently the main motivation for attendance at an hiv support group is gaining an understanding of hiv, living with hiv, and arv treatment. this is crucial but will not provide experienced members with an incentive to continue attending on a weekly basis. resources need to be found to support income generation and education or training opportunities to sustain the support groups. conclusion the hiv/arv team realises that success is ultimately dependant on sustaining the programme. with continued district, provincial, hospital and, most importantly, community support, this is an achievable goal. egg-catching on teambuilding day. the local countryside. june 2006 make up 3 5 matlosana is a district of the southern region of the nwp and was previously referred to as kosh (klerksdorp, orkney, stilfontein and hartebeesfontein). the southern and bojonala regions have the highest hiv anc prevalence rates in the province (31.1% and 30.4% respectively, the provincial rate being 26.7%) (fig. 1). possible reasons for these figures include a highly mobile population: ■ klerksdorp is located along the n12, a major truck route to the northern cape, namibia and botswana. ■ klerksdorp is a major trading post for surrounding areas that lack services such as retail, health, academic and training institutions. ■ there is a high proportion of migrant workers (goldminers who are often not unionised contract workers and hence have no mine medical cover). klerksdorp-tshepong hospital complex (ktc) resembles most secondary-level hospitals in south africa in that it provides primary hospital care for those living in the immediate vicinity (matlosana), secondary care for patients from all primary care hospitals in the southern and bophirima regions, limited tertiary services for the entire nwp (renal unit, mdr tb unit, oncology unit, burns unit) and on occasion quaternary care (highly infectious unit for outbreaks of viral haemorrhagic fevers such as congo fever). large numbers of public secondary-level institutions are seeing increased numbers of patients, have severe budgetary constraints, face shortages of skilled personnel, particularly senior clinical and auxiliary staff (senior medical officers, general specialists, psychologists, social workers, senior nurses, senior pharmacists, etc.) and lack diagnostic and therapeutic tools. junior staff, mainly interns and community service doctors, are often called upon to provide a wide range of services as these institutions are inundated with complicated and difficult cases referred from their primary referral sites. the rollout of the south african government’s plan for comprehensive care for hiv/aids in the public health sector has created new challenges that have shaken the practice of medicine. an old cliché that not only defines health as a physical state of wellness but also includes social, psychological and economic sufficiency can best be realised by the goal of the comprehensive care package. ‘hiv medicine’ is no longer a clinical entity. it forces us to consider other pertinent issues in relation to the growing pandemic, which include a study of interpersonal relations, sexuality in diverse cultures, death and dying and being culturally sensitive, the right to and access to disability/support grants, early identification of families in dire need, orphans and their support, food security, home-based care availability, and a host of other no less important local issues (informal settlements, water, sanitation, etc.). not only do ‘hiv clinicians’ have to deal with ‘non-medical’ issues, hiv as a disease also confounds the most astute of pure clinicians because of its multi-system manifestations. these include autoimmune phenomena (idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, haemolysis, etc.), opportunistic infections (tb, mycobacterium avium complex, cryptococcal meningitis, pneumocystis pneumonia, etc.), malignancy (kaposi’s sarcoma, lymphoma, etc.) and antiretroviral therapy (art) with its complications. furthermore hiv can be a coincidental finding in patients with other diseases (hypertension, diabetes, cardiac, pulmonary, renal, etc.), often leading to diagnostic and therapeutic dilemmas. often extensive (expensive, difficult and timeconsuming) investigations and procedures are undertaken to diagnose a patient’s presenting condition. these range from radiological (x-rays, ultrasound, computed tomography scans) and laboratory (histology for biopsies, cultures of material/specimens, serology, etc.) to invasive procedures (bronchoscopy, endoscopy). doctors who work in high hiv prevalence areas become familiar with hiv-associated illnesses that were previously rare or uncommon (pcp/crypto), or common diseases (such as extrapulmonary tuberculosis or the southern african journal of hiv medicine june 2006 b r a n c h e s profile: hiv in north west province, south africa e variava specialist physician, head of internal medicine and wellness unit, klerksdorp-tshepong complex, north west north west province (nwp) has one of the highest hiv prevalences in south africa. it is further challenged by severe poverty, a huge surface area housing a scattered community, and limited human resources. despite this, it is one of the provinces that have successfully initiated large-scale arv access in south africa. this article describes the challenges and solutions that the province has grappled with to improve access to care for people with hiv. june 2006 the southern african journal of hiv medicine3 6 pneumonias) presenting differently. sub-specialist support for diagnosis and therapy is lacking at most secondary hospitals, and this further frustrates the clinician. with increasing access to antiretrovirals (arvs), a more endemic/chronic form of hiv now coexists leading to newer disease entities including multidrug-resistant or mutant hiv, lactic acidosis, lipoatrophy, lipodystrophy, metabolic syndromes, reconstitution disease (tuberculosis, crypto, hepatitis, mai, etc.) and other toxicities induced by art. clinicians working in areas where the prevalence of hiv is high, specialist support is scarce and arv rollout is expanding require ongoing training, as a patient can incidentally be found to be hiv positive (asymptomatic or on therapy) and present with a non-hiv-related ailment or with various ‘sub-specialist complaints’ (pericardial tb, spinal tb, renal failure, etc.) directly attributable to hiv or its related opportunistic diseases or effects of therapy. tshepong hospital is located in a high hiv prevalence region (31.1%) (nwp anc seroprevalence study, 2004) and the department of medicine deals with large numbers of acutely ill hiv-infected individuals (accounting for 60% of admissions). an average of 250 new cases of hiv are diagnosed each month (local hospital statistics), many present with advanced (stage iii/iv) disease and cd4 counts of < 200/µl, and many are malnourished. our crude fatality rate averages 16% (3 5 deaths a day), and hiv-related disease was found to be a major contributor. an audit presented at the 2005 aids congress in durban showed that 45% of deaths were confirmed as hiv positive, another 20% were clinically positive, in 30% hiv status was unknown, and only 5% were confirmed hiv negative (mortality analysis in the department of medicine, klerksdorp/tshepong hospital complex, july 2003 – june 2004). the department of medicine is responsible for 160 acute medical beds and 80 step-down beds with a bed occupancy rate of 80% and an average length of stay of 8 days. the stepdown unit provides palliative, recuperative and rehabilitative care. while the department of health in nwp prepared its rollout plan in october 2003, ktc began setting up a wellness unit. with help from local business, renovations to the site were undertaken and the site was officially opened by our previous mec for health (dr sefularo). partnerships with ngos including hospice, lifeline and seboka facilitated recruitment and training of lay counsellors. faith-based organisations assisted with provision of food security for the destitute. provincial support for a local hiv seminar in 2003 provided the original impetus for the training of doctors and nurses. rhrufig. 2. quarterly review, april 2004 – march 2006. fig. 1. north west province: district and local municipalities (source: municipal demarcation board, 2002). quarterly review 15.4% 26.3% 31.1% 30.4% population: 3.6 million districts: 4 sub-districts: 22 3 7 and later aurum consolidated the training. partnering with our district primary care team enabled us to develop staging sites at local clinic level and strengthened the referral process. provincial will and support led to the wellness unit with its multidisciplinary team being fully established at the point of official accreditation in july 2004. in line with the provincial plan, ktc assisted other sites with their programme implementation by assisting with staff training, accreditation and treatment of patients from these sites. taung, vryburg, ganyesa and potch have all been accredited and patients from these areas were successfully referred back. as the programme is rapidly growing (initiating arvs in an average of 240 patients per month) (wellness unit stats, ktc quarterly reviews – table i) the need to refer stable patients (with good immunological and clinical response) to their local clinics has become more apparent. clinics that were originally staging sites are now seeing and distributing medication for the down-referred patients (pre-packed for each patient and delivered to the clinic by the hospital pharmacy). a pilot programme for down-referral is referring stable patients to a local gp network (funded by broadreach) where the gps receive a capitation fee for following up these patients. downreferred patients return to hospital 6-monthly for ongoing tests. as a result more space at the wellness centre has been created, enabling us to continue with initiating newer patients on arvs. there are also cases in which earlier initiation or hospital-based initiation of arvs needs to be considered. the logical next phase would be the initiation of arvs in stable patients at the phc level. plans are being developed and it is hoped that by 2007 selected clinics may begin initiating arvs provided they meet requirements for accreditation. the complexities of hiv and a rapidly expanding hiv programme mean a growing need to form strategic partnerships. with this in mind we at ktc have pursued partnerships with rhru, aurum, broadreach, hospice, lifeline, seboka, primary care clinics, the local gp network and other care providers in matlosana. the formation of the hiv clinicians society has given us a means of disseminating medical information to caregivers in our areas. thanks to the persistent tanya nielson, an enthusiastic pharmacist who worked hard in setting up our branch, our inaugural launch (attended by 100 care providers) was a success. attendees included doctors, pharmacists, dieticians, primary care nurses, social workers and home-based care groups, all part of a multidisciplinary team needing to understand hiv from authorities in their field. dr francois venter presented an overview of the rollout programme and the challenges posed by arv provision. professor churchyard presented a talk on tb and hiv and how arv will impact on the tb epidemic. a second meeting was held in may and again this was enthusiastically supported, encouraging us to continue. the north west provincial department of health, ktc management, and the staff of the wellness unit all need to be thanked for the success of the unit. the southern african journal of hiv medicine june 2006 apr july oct janapr july oct jan jun 04 sept 04 dec 04 mar 05 jun 05 sep 05 dec 05 mar 06 total total initiated 25 124 548 667 704 851 785 566 4 270 total adm. 0 4 26 6 50 47 50 183 total deaths 4 2 14 41 31 23 27 40 182 transferred out 48 168 183 168 67 634 gp 110 214 324 clinics 100 138 127 365 stopped art 0 0 6 3 6 9 5 8 37 lost to follow-up 0 0 1 0 2 13 0 6 22 total follow-up 2 706 table i. summary of quarterly stats for the wellness unit, presented at ktc quarterly reviews the southern african journal of hiv medicine                                                        october  2009 5 i am delighted to introduce you to our guest editors, who have done a sterling job in pulling together this ‘mental health in hiv’ edition. they are two capetonian colleagues who i am also fortunate to consider friends: john joska is a psychiatrist and landon myer is a public health specialist. john joska is a senior specialist and lecturer in the department of psychiatry and mental health at the university of cape town. he is head of the division of neuropsychiatry, western cape provincial programme manager for hiv psychiatry, and director of the gshhiv mental health group. the latter is a newly formed group of mental health professionals who are providing service and investigating the effects of hiv on people living with hiv/aids (plwha) from a mental health point of view. current research projects include investigations into neurocognitive disorders in hiv, screening for mental disorders in hiv, and brief psychological interventions in plwha with depression. landon myer is an associate professor in the school of public health and family medicine at the university of cape town. his research focuses on the roles of hiv/ aids and other infectious diseases in shaping individual and population health in southern africa. he is particularly interested in how the hiv epidemic influences other areas of population health, including mental health and women’s reproductive health. in investigating these topics, his research incorporates biological mechanisms, individual behaviours and exposures, as well as structural socio-economic and health service conditions. i am sure you will agree that with their colleagues they have provided a feast of important reading for you all in this edition. linda-gail bekker editor f r o m  t h e  e di torf r o m t h e e di tor the journal is starting to feel like men’s health, what with posters, guidelines and now a state-of-the art science update, hiv treatment bulletin, falling out of it. exco is pleased to announce an important and strategic partnership with hiv ibase, who publish hiv treatment bulletin. we are distributing the southern african version of their excellent newsletter, which will exclusively focus on the scientific reports and resources that have local relevance – with a strong focus on paediatrics and maternal health. hiv treatment bulletin neatly complements the journal, providing the snobbish clinician and scientist with the most hot-off-the-press analysis of recent clinical trials and basic science research. policy makers can authoritatively pronounce at their guidelines meetings, clinicians can expand their patients’ options, and, most importantly, you can show off at ward rounds. thanks to all the people at i-base, this is a major step forward for quality information sharing. we wish the new health minister, barbara hogan, all the best. she has very small shoes to fill, but a mammoth task ahead of her to repair south africa’s woeful health service. at the time of writing, she and her deputy, dr molefi sefularo, have been very impressive, dealing with a cholera disaster, drug stock-outs, issues of prevention, releasing controversial reports that were stuck on her predecessor’s desk for months, and a dozen other complex health problems. finally, the exco welcomes two new members based in durban, professor yunus moosa and dr henry sunpath, both highly respected clinicians and part of the team responsible for an excellent hiv clinical conference held in october. francois venter president this spring edition brings 2008 to a close. and what a year it has been. not many breakthroughs in hiv or tb, but a lot of activity in terms of understanding early infection better, really getting to grips with early immune responses, and again thinking through our prevention options. in 2008 the concept of antiretrovirals for prevention as well as treatment has come to the fore with second-generation microbicides, pre-exposure prophylaxis and the notion that we may be able to ‘treat our way out of the epidemic’ becoming possibilities. gratifyingly, this year also saw a record number of people being tested and accessing art, and roll-out for both testing and treatment is truly scaling up. as chairperson of the 4th southern african hiv conference i must encourage every one of you to think seriously about coming to durban on 31 march. it promises to be a critical conference where we will really formulate the key steps in getting pmtct, treatment, testing and prevention out there on a scale that will begin to turn the sa statistics around. (i promise that it will also be loads of fun!) please note the early date this year: 31 march to 3 april. this is to ensure brilliant kzn weather! in this edition, we already begin to examine some of these key scale-up questions: jerome singh explores the ethics and legality of traditional healers performing hiv testing (i know many have asked why this has to be the domain of nurses only). francesca esposito and her team examine changes in body composition in women taking antivirals in a kzn clinic. we look at the role of mobile phones in the hiv response with william mapham, and polly clayden gives us pointers to starting infants on art. the role of a liver biopsy in diagnosis of opportunistic infections is described by mark sonderup and colleagues. the vexed question of when it is deemed safe to start haart in patients co-infected with tb is discussed by robin wood, and francois venter and colleagues give a practical view on new antiretrovirals on the horizon for south african practitioners. no guidelines in this issue, but i will whet your appetites – look out for guidelines on prevention of tb occupational exposure for hiv-infected health care workers and on the non-infertile hiv infected couple, hot stuff coming up in the new year! happy reading and every best wish for a restful and peaceful festive season from the whole editorial team. see you next year! linda-gail bekker editor m e s s a g e f r o m t h e e x e c u t i v e msg from the executive.indd 5 12/17/08 3:16:23 pm addressing mental health in routine hiv care and treatment as this journal’s readers are well aware, hiv has complex and wide-ranging impacts on the health of infected individuals. much of this complexity is due to the nature of host-virus interactions and the pathophysiology of the virus and its sequelae in different organ systems over time. other aspects are linked to the profound impact an hiv diagnosis has on the life of an infected individual, both through physical morbidity and the psychological and social consequences of a lifelong illness. the area of mental health is a critical example of the diverse impacts of hiv on patients’ health and well-being. the links between hiv and mental health are multiple: risk taking associated with hiv acquisition is more common among individuals with mental disorders; common mental disorders (such as anxiety, depression and alcohol/substance disorders) are often caused in part by the stress of an hiv diagnosis and related stigma; psychotic states are a relatively common presentation of hiv infected individuals; and neurocognitive manifestations of hiv infection such as hiv-associated dementia emerge later in the course of disease. taken together, mental disorders may be viewed as their own class of ‘opportunistic’ conditions affecting hiv-infected individuals in a unique manner. dealing with the various mental health impacts of hiv infection is a core component of effective hiv care and treatment. anxiety and depression among hiv-infected individuals can negatively impact on medication adherence; in these situations, management of mental disorders can help facilitate the management of hiv disease over the long term. the neurocognitive manifestations of hiv disease are a significant cause of morbidity; increasingly we are recognising that these disorders may e di tor i a l m e s s a g e   f r o m    t h e   e x e c u t i v e the large international aids society meeting has come and gone from cape town. the agenda was dominated by a new big idea, an audacious mathematical model by a group of brave world health organization modellers showing that giving antiretroviral therapy to every one with hiv, immediately, could make the epidemic disappear. we’ve known for a long time that viral load correlates with infectiousness, whether it is sexual contact, pmtct or other forms of exposure. art is so highly effective in reducing viral load that the swiss created an uproar a year ago by claiming that someone on art with an undetectable viral load (and no std) could not transmit hiv sexually. the who researchers essentially argue that if we diagnose hiv quickly and treat everyone who is hiv positive, irrespective of cd4 count, we can arrest sexual transmission early and pretty much eradicate hiv within 10 years. subsequent papers have even postulated that we could reverse the tb epidemic, as hiv drives this like fuel on a fire. finally, early economic work has shown ‘test and treat’ to be cost saving, despite significant initial investment. there is broad acknowledgment that hiv prevention programmes have been very disappointing, and that even effective interventions such as male circumcision and good pmtct are unlikely to eradicate the epidemic alone. it is exciting that researchers are thinking creatively, and that models showing we can reverse things are out there. but to implement this incredibly ambitious model would require a complete restructuring of health systems. we would need to do hiv testing aggressively and provide adequate, easily available art services, as broadly as possible. the health system would have to be transformed from the lumbering unfriendly giant it is at the moment to a responsive and effective service deliverer. the reality is that we need this anyway, even if the modellers are wrong. francois venter president be managed effectively, including by early initiation of antiretroviral therapy, to improve the prognosis of affected individuals. in short, basic mental health care is part of good hiv management. in this context, there is a clear need to make the diagnosis and management of mental disorders more feasible in general hiv care and treatment settings. at the primary and secondary levels of the health care system, medical officers and physicians must be able to identify patients with a possible mental disorder and work up these patients to arrive at a preliminary diagnosis, make management decisions, and follow up patients over time. support from specialist psychiatrists is necessary in some instances, but most cases do not require specialist referral, and the availability of psychiatric services to support hiv care and treatment is limited in most settings across the region. this special issue of the journal aims to address this need through a series of focused contributions from leaders in hiv mental health from across south africa. the first two pieces focus on anxiety and depression in hiv in broad terms (thom) and post-traumatic stress disorder specifically (pingo). following this, the topic of psychotic presentations in hiv is dealt with by an algorithm for the diagnosis and management of psychosis in hiv (jonsson) and then an extended case study (boyles) to help reinforce key concepts. the topic of neurocognitive impairment in hiv/aids is discussed in detail (singh) with a short report on the white matter changes that take place in the brain over the course of hiv disease (hoare) as well as a piece of empirical research investigating the clinical utility of one commonly used tool to identify neurocognitive deficits in hiv (ogunrin). the final piece deals with cross-cutting issues of prescribing psychotropic medications in the context of hiv infection (parker). throughout, these pieces aim to address issues in mental health faced by front-line hiv clinicians on a daily basis, with practical strategies for investigation and management. it is our hope that the contents of this issue may make some contribution towards helping hiv clinicians to better recognise and treat mental disorders in their patients. landon myer john joska guest editors the southern african journal of hiv medicine                                                          october  20096 make up march 2007 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e m a r c h 2 0 0 7 7 ‘southern african hiv clinicians society, penny penhall speaking, how may i help you?’ countless numbers of members who telephoned the society would have been greeted by those words. behind them was a person who dealt with a diverse range of requests, complaints and enquiries, always in a polite, caring and helpful way. i have received countless compliments on how helpful penny had been in resolving an issue. it is difficult even to begin describing what she has meant to the society, and the crucial role she has played in its development and maturation – her contribution has been enormous. penny comes from a nursing background, where she excelled, having received a number of academic awards. her desire to contribute in the larger health care arena led her to become interested in the field of hiv/aids. it was fortuitous, therefore, that at the establishment of the society in 1998 she was available to become involved in the crucial early phases. the beginning was humble – penny started work in a shared office, and as i was president of the society at the time, we would meet two mornings a week for a couple of hours to carry out the necessary administration. as the society grew, a permanent office was secured and penny started working full time for the society. in the early days penny did everything, and i mean everything! answering the telephone, office administration, secretarial duties, writing grant proposals, arranging society meetings, dealing with funders, organising conferences – she did the lot! her work on the journal, however, deserves special mention. this became our special project and i, as editor, benefited enormously from penny’s expertise in the editing and publishing arena. the look and feel of the journal as it is today is largely due to penny’s vision and expertise. over time the society grew to its present size with 11 000 members and 29 active branches. the society’s activities expanded, and it became necessary to increase our capacity. samantha klusener, pat and jean solan and more recently venie pillay came on board to assist in the activities that hitherto had been carried out by penny alone. if i were to reflect on penny’s strengths they would include patience, meticulous attention to detail, an enormous work ethic and readiness always to ‘go the extra mile’. this was particularly evident in dealing with the editorial deadlines of the journal. penny has decided to take a break (she so richly deserves a rest) and would like to explore other challenges in the future. i know that whatever she decides to do she will give it her all and make it a success. for me it has been a privilege working with penny for the past eight years. she has taught me an enormous amount, and i know that i am joined by francois, the members of the executive committee and all society members in wishing her well in the future. des martin editor penny penhall make up march 2007 30/3/07 11:26 am page 7 the southern african journal of hiv medicine                                                                july  2009 17 although the hiv pandemic is not a new phenomenon, there are still significant gaps in knowledge that influence progress in prevention and treatment strategies. most of these gaps involve the first few days and weeks of infection, i.e. the period of acute hiv infection. acute hiv infection (ahi) is usually defined as the time from entry of the virus into the body to completion of seroconversion, while early-stage hiv infection generally refers to the interval between seroconversion and the establishment of the viral load set point. the magnitude of the viral set point is prognostic for disease progression.1 tests such as rapid hiv tests are initially negative in acute hiv as there is a delayed immune response. seroconversion can occur as late as 6 months after exposure, while detectable levels of viraemia and p24 antigenaemia develop over the first 3 4 weeks of infection.2,3 evolution of symptoms of the acute retroviral syndrome usually coincides with high levels of viraemia and the host’s initial immunological response. the classic mononucleosis-like symptoms of acute hiv-1 infection (fever, joint pain, inguinal lymphadenopathy and night sweats) may last several days to weeks and are found in at least 47% of patients with ahi.4,5 several studies suggest that individuals with acute hiv infection can be identified in sexually transmitted infection (sti) clinics and perhaps other high-risk settings.5,6 the detection of acute hiv infection is important not only from a research and prevention point of view but because it may also allow for early treatment that could modify the natural history of the disease.7 medline and pubmed databases were searched using the keywords ‘acute hiv’, ‘natural history of hiv’, ‘hiv in africa’ and ‘immunology of hiv’. more recent articles were focused on, i.e. those published after 2000. the diagnosis of acute hiv infection is important from a public health point of view.8 patients are highly infectious and hiv transmission occurs readily owing to a massive viral burden in the blood and genital secretions.9 acute hiv may therefore account for a disproportionate amount of hiv transmission. patients may be unaware that they are infected and continue to engage in risky behaviour, putting others at risk. the differential d iagnosis of an unexplained viral syndrome in a sexually active adult should always include acute hiv.10 a study in heterosexual couples in the rakai district of uganda showed an increased risk of hiv transmission in the period just following hiv acquisition. in 10 out of 23 initially uninfected couples both partners seroconverted within the same 10-month follow-up period. a ‘per-act transmission rate’ of 0.0082 was calculated for this ‘early transmission’ group by dividing the total number of transmission events by the total number of sex acts reported by the 23 couples. a much smaller transmission rate was obtained for couples who were serodiscordant at enrollment.11 another study from botswana showed that identification of acute hiv was possible in a public health setting. this was viewed as an important part of reducing the epidemic in this country in combination with early use of haart, risk reduction counselling, partner notification and contact tracing.12 the natural history of hiv-1 has been well characterised in industrialised countries. a cohort study of homosexual men showed a steep decline in cd4+ tcell counts after seroconversion. hiv rna load at the acute hiv: what is new and do we treat? c l i n i c a l claire von mollendorf, mb bch, bsc med sc hons technical advisor maternal health, reproductive health and hiv research unit, university of the witwatersand, johannesburg health care providers are faced with a number of challenges with regard to acute hiv infection. the first of these is recognition, because the acute retroviral symptoms mimic a number of other viral infections. the second challenge is treatment, as treating early hiv has a number of benefits and risks both on an individual and a public health level. this review hopes to address some of these questions. methods public health issues natural history of ahi july  2009                                                                 the southern african journal of hiv medicine                                                   first hiv-seropositive visit (~3 months after seroconversion) was highly predictive of aids, with prognosis correlating with subsequent hiv rna measurements. the cd4+ t-cell decline was generally more severe in patients with higher cd4+ t-cell count levels before infection, which may reflect greater hiv replication.1 a subgroup of patients from a swiss and australian cohort showed that both the incubation period of ahi (time between hiv infection and ahi) and duration of ahi were associated with the late prognosis of hiv infection. the incubation period of ahi was independently associated with progression towards aids.13 information regarding the natural history of hiv-1 infection in africa is limited. in a prospective cohort study of female sex workers in mombasa, kenya, the survival rate was similar to that for hiv-1-infected individuals in developed countries before the introduction of highly active antiretroviral therapy (haart). this was supported by a review of african studies from uganda and malawi. a higher viral load set point and more severe acute hiv-1 illness predicted faster progression to death. disease in an african cohort, however, did not progress faster to aids than an industrialised country cohort.14,15 it is estimated that between 40% and 90% of patients with ahi experience an acute retroviral syndrome (ars). symptoms usually occur 2 6 weeks after exposure to hiv-1 and typically last 14 days, but may persist for as long as 10 weeks.4 the significance of the severity of seroconversion symptoms is not known, but the presence of seroconversion symptoms has been correlated with more rapid disease progression.4,14 common symptoms include fever (>80 90%), fatigue (>70 90%), pharyngitis (50 70%), weight loss, night sweats (50%), lymphadenopathy (40 70%), arthralgia or myalgia (50 70%), headache (32 70%), skin rash (>40 80%), and nausea, vomiting and diarrhoea (30 60%). the rash is typically maculopapular and usually involves the trunk. it may be difficult to detect in black african cohorts. other less frequent symptoms include aseptic meningitis (24%), oral ulcers (10 20%) and genital ulcers (5 15%), while frequent nonspecific laboratory findings include leukopenia (40%), thrombocytopenia (45%) or mild transaminitis (21%).16 other unusual presentations include myopericarditis, acute renal failure, cranial nerve vii palsy, radiculopathy and opportunistic infections such as candidiasis, cytomegalovirus infection, and pneumocystis jirovecii pneumonia.4 the nonspecific nature of acute retroviral symptoms and the extensive differential diagnosis often make the identification of this syndrome challenging. it is important to consider this diagnosis in order to obtain an appropriate history, perform an appropriate risk factor assessment, perform a thorough physical examination, and order appropriate diagnostic tests.4,17 in an article by fiscus et al., ahi was considered to be present if hiv rna results were positive and one of the following conditions were met: (i) rapid antibody tests both negative; (ii) rapid antibody tests discordant and western blot results negative or indeterminate; and (iii) rapid antibody tests discordant and western blot results weakly positive with subsequent band evolution.18 in contrast, hoen et al. used three laboratory criteria to confirm the diagnosis of primary hiv infection: (i) positive p24 antigenaemia; (ii) negative hiv enzyme-linked immunosorbent assay (elisa) or positive elisa in a patient who could be confirmed hiv negative within the past 3 months; and (iii) <3 bands in the western blot test.19 the p24 band is usually the first to become positive in the western blot test during seroconversion. if this is the only band present the hiv antibody test is considered to be indeterminate. this result should be correlated with the hiv-1 plasma rna level.4 as cd4+ t-cell counts can briefly decrease during acute infection, they are generally not reliable markers of immune status during the first 6 months of infection.4 the value of initiating antiretroviral therapy during ahi is uncertain. there are no randomised control trials examining the long-term effects of early treatment on the clinical course and prognosis of hiv infection. results from studies are conflicting, and some evidence shows that early treatment may not alter the viral set point consistently following interruption.4,20 the benefits and risks of initiating therapy for ahi continue to be discussed. potential benefits include the control of acute retroviral symptoms, prevention of abnormal helper t-cell function and reduction in the pace of decline, delaying or preventing decreased immune function and vulnerability to opportunistic infections, decreasing the initial viral load set point, which may decrease transmission, limiting viral evolution and diversity, potential slowing of the rate of disease progression among patients with a genetic predisposition, and decrease in the size of the latent hiv pool.4,20 presenting signs and symptoms diagnosis of ahi treatment 18 the southern african journal of hiv medicine                                                                july  2009 risks include increased cost, adverse effects and abnormal metabolic findings, drug resistance, long-term challenges to adherence, and unknown long-term toxicities or expected duration of benefit.4 a us study in 47 patients showed that initiation of haart within 90 days of hiv-1 infection was associated with reduced hiv-1 virus levels, improved cd4+ t-cell counts and immune conservation, decreased opportunistic infections, and decreased frequency of respiratory and mucocutaneous conditions when used for 78 weeks. rapid progression to aids also was avoided. however, side-effects of combination therapy were commonly reported in this study.21 immunological effects of art in patients with ahi the limited benefit of antiretroviral therapy initiated during ahi may be explained to some degree by the early depletion of lymphocyte reservoirs in the gastrointestinal tract reported in some studies. this may also help to explain the conflicting evidence between early observations demonstrating apparent immunological benefit with early antiretroviral treatment with the inability to control viral replication after treatment interruption.20 only a few reports describe the effects of haart on hiv-specific t-cell responses during acute hiv infection.22,23 however, limitations such as small sample size, short duration of follow-up and lack of concomitant virological data need to be taken into account when interpreting these results.23 in a cohort of 16 hiv-1infected individuals who received their diagnosis at the time of seroconversion and who were started on haart within 72 hours, a robust hiv-1-specific cd4+ t-cell proliferative response was observed and viraemia was contained.22 one prospective cohort study followed up participants from the time of acute infection and examined different virological profiles related to various treatment interventions. no correlation was observed between baseline viral load and hiv-specific cd4+ and cd8+ t-cell responses. subjects who started haart at the time of acute infection had no better hiv-specific tcell responses than those who started therapy after seroconversion, and the absence of any treatment or the incomplete virological control did not prevent the development of an hiv-specific cd4+ t-cell response. this may imply that early therapy aimed at preserving the hiv-specific immune response may not be necessary in all subjects.23 when to start treatment the period during which treatment for acute hiv should be given is not clear. benefits have being shown up to 3 4 months after infection, but long-term effects on morbidity and mortality are unknown. most clinicians would choose to treat within the first 6 months after seroconversion.4 guidelines for initiation of therapy for patients in whom acute hiv-1 infection has been diagnosed are often vague and lack consensus. the us department of health and human services (dhhs) guidelines recommend consideration of treatment for patients who received their diagnosis <6 months after infection. these guidelines consider treatment to be optional as clinical trials information is limited and benefits and risks of treatment need to be weighed up when considering initiating treatment.24 the british hiv association (bhiva) guidelines recognise that there are inconsistent study results on treatment in acute hiv. the justification for treating ahi is to preserve specific anti-hiv immune responses, reduce morbidity associated with high viraemia and cd4+ tcell depletion and reduce the risk of hiv transmission. these guidelines recommend treatment of ahi for the relief of symptoms of ars with neurological involvement, for any aids-defining illness or a cd4+ t-cell count persistently <200 cells/ml. bhiva guidelines recommend that there is currently insufficient evidence to support treatment for other indications.25 both the international aids society–usa panel recommendations and south african hiv clinicians society guidelines do not currently recommend art for ahi as there is no definitive evidence supporting this therapy.26,27 reasons not to treat patients with ahi include no proven efficacy of treatment in this period, drug toxicity, and the potential development of drug resistance. treatment should only be considered in a research trial or in the presence of very severe symptoms after consultation with an expert hiv clinician.27 expected outcomes of early treatment the time taken to achieve viral suppression in ahi may be dependent on a number of host factors. high initial viral loads may prolong the time to viral suppression, while the relatively intact immune system and lower total body viral burden in patients may decrease time to suppression.4 subjects from a multicentre acute infection and early disease research program cohort were enrolled in a study within 6 months of hiv seroconversion and selfselected whether to initiate haart. cd4+ t-cell counts at 24, 48 and 72 weeks were compared between treated and untreated groups. initiation of haart within 2 weeks of seroconversion was associated with viral load and cd4+ t-cell count benefits for 24 weeks after ter19 july  2009                                                                 the southern african journal of hiv medicine                                                   mination of haart. later initiation of haart showed less benefit in cd4+ t-cell counts, but viral load benefit lasted till week 72. the limitations of the study included a lack of random allocation of treatment, variation in duration of treatment, lack of statistical significance of the cd4+ t-cell count and viral load benefits at 72 weeks, the small sample size, and the need for longer follow-up to assess the durability of the apparent benefit.28 the application of haart treatment for ahi is limited by high costs, drug resistance, and drug-related toxicities. new treatment options such as supervised treatment interruption (sti) are being investigated as alternative options. with the sti strategy, haart is intermittently stopped once viral load has been reduced to a low level, in order to boost natural immunity by brief exposure to the virus.29 in a longitudinal open-label study of sti in 14 patients with acute hiv-1 infection, only transient control of viraemia was achieved after drug interruption. a gradual increase in viraemia and decline in cd4+ t-cell counts was observed in most patients, even after a year or more of viral containment.29 data from the smart (strategies for management of anti-retroviral therapy) trial provided evidence that episodic use of art based on cd4+ t-cell levels was inferior to use of continuous therapy for treatmentexperienced patients and therefore should not be routinely recommended. there was no evidence that interrupting drug exposure was related to fewer adverse events such as myocardial infarction, stroke and renal and liver disease.30 the follicular dendritic cell network (fdc) in lymphoid tissues is the major site of hiv storage in the presymptomatic and late stages of disease. in a review of 21 patients from 4 sites, there was no correlation between the duration of infection and accumulation of hiv into the fdc network. the data suggested that a large pool of infectious virus is established soon after infection and that initiation of antiretroviral therapy when symptoms of primary hiv infection are recognised is unlikely to prevent substantial accumulation of virus in the fdc network. early treatment might, however, maintain immune responses by preserving cd4+ t cells and reducing the fdc virus pool.31 while it is important on an individual and public health level to identify acute hiv infections, uncertainty still remains regarding the treatment of these identified infections. on a case-by-case basis there may be benefit in treating individuals who present with severe symptoms or persistently low cd4+ t-cell counts to maintain immune system integrity. with regard to the public health benefits, the reduction in transmission needs to be weighed up against the cost and toxicity of widespread treatment. other strategies such as vaccines and microbicides also need to be considered in this context in the prevention of transmission and infections. references 1. lyles rh, munoz a, yamashita te, et al. natural history of human immunodeficiency virus type 1 viraemia after seroconversion and proximal to aids in a large cohort of homosexual men. j infect dis 2000; 181: 872-880. http://www.journals. uchicago.edu/doi/pdf/10.1086/315339 (accessed 2 february 2009). 2. busch mp, satten ga. time course of viraemia and antibody seroconversion following human immunodeficiency virus exposure. am j med 1997; 102: 117126. 3. lindback s, thorstensson r, karlsson ac, et al. diagnosis of primary hiv-1 infection and duration of follow-up after hiv exposure. karolinska institute primary hiv infection study group. aids 2000; 14: 2333-2339. http://www. aidsonline.com/pt/re/aids/pdfhandler.00002030-200010200-00014.pdf (accessed 2 february 2009). 4. kassutto s, rosenberg es. primary hiv type 1 infection. clin infect dis 2004; 38: 1447-1453. http://www.journals.uchicago.edu/doi/pdf/10.1086/420745 (accessed 2 february 2009). 5. bollinger rc, brookmeyer rs, mehendale sm, et al. risk factors and clinical presentation of acute primary hiv infection in india. jama 1997; 278: 20852089. http://jama.ama-assn.org/cgi/reprint/278/23/2085 (accessed 11 february 2009). 6. stevens w, akkers e, myers m, et al. high prevalence of undetected, acute hiv infection in a south african primary care clinic. abstract, 3rd international aids society (ias) conference on hiv pathogenesis and treatment, rio de janeiro, brazil, 24-27 july 2005. 7. pilcher cd, eron jj jr, galvin s, gay c, cohen m. acute hiv revisited: new opportunities for treatment and prevention. j clin invest 2004; 113: 937-945. http://www.jci.org/articles/view/21540/pdf (accessed 24 february 2009). 8. janssen rs, holtgrave dr, valdiserri ro, shephard m, gayle hd, de cock km. the serostatus approach to fighting the hiv epidemic: prevention strategies for infected individuals. am j public health 2001; 91: 1019-1024. http://www.ajph. org/cgi/reprint/91/7/1019 (accessed 24 february 2009). 9. pilcher cd, eron jj jr, vemazza pl, et al. sexual transmission during the incubation period of primary hiv infection. jama 2001; 286(14): 17131714. http://jama.ama-assn.org/cgi/content/extract/286/14/1713 (accessed 11 february 2009). 10. geise r, maenza j, celum cl. clinical challenges and diagnostic approaches to recognizing acute human immunodeficiency virus infection. am j med 2001; 111: 237-238. http://linkinghub.elsevier.com/retrieve/pii/s0002934301008877 (accessed 24 february 2009). 11. wawer mj, gray rh, sewankambo nk, et al. rates of hiv-1 transmission per coital act, by stage of hiv-1 infection, in rakai, uganda. j infect dis 2005; 191: 1403-1409. http://www.journals.uchicago.edu/doi/pdf/10.1086/429411 (accessed 24 february 2009). 12. novitsky v, woldegabriel e, wester c, et al. identification of primary hiv1c infection in botswana. aids care 2008; 20(7): 806-811. http://www. pubmedcentral.nih.gov/articlerender.fcgi?artid=2605733 (accessed 24 february 2009). 13. vanhems p, hirschel b, phillips an, et al. incubation time of acute human immunodeficiency virus (hiv) infection and duration of acute hiv infection are independent prognostic factors of progression to aids. j infect dis 2000; 182: 334-337. http://www.journals.uchicago.edu/doi/pdf/10.1086/315687 (accessed 9 march 2009). 14. lavreys l, baeten jm, chohan v, et al. higher set point plasma viral load and more-severe acute hiv type 1 (hiv-1) illness predict mortality among high-risk hiv-1-infected african women. clin infect dis 2006; 42: 1333-1339. http:// www.journals.uchicago.edu/doi/pdf/10.1086/503258 (accessed 2 february 2009). 15. bull world health organ 4004; 82(6): 462-469. http://www.who.int/bulletin/ en/ (accessed 10 february 2009). 16. kahn jo, walker bd. acute human immunodeficiency virus type 1 infection. n engl j med 1998; 339: 33-39. http://content.nejm.org/cgi/content/full/339/1/33 (accessed 24 february 2009). 17. lavreys l, thompson ml, martin hl, et al. primary human immunodeficiency virus type 1 infection: clinical manifestations among women in mombasa, kenya. clin infect dis 2000; 30: 486-490. http://www.journals.uchicago.edu/ doi/pdf/10.1086/313718 (accessed 2 february 2009). 18. fiscus sa, pilcher cd, miller wc, et al. rapid, real-time detection of acute hiv infection in patients in africa. j infect dis 2007; 195: 416-424. http://www. journals.uchicago.edu/doi/pdf/10.1086/510755 (accessed 2 february 2009). 19. hoen b, dumon b, harzic m, et al. highly active antiretroviral treatment initiated early in the course of symptomatic primary hiv-1 infection: results of the anrs 053 trial. j infect dis 1999; 180: 1342-1346. http://www.journals.uchicago. edu/doi/pdf/10.1086/315002 (accessed 2 february 2009). conclusion the author would like to thank dr vivian black for her critical review of the article. 20 the southern african journal of hiv medicine                                                                july  2009 20. hicks cb, gay c, ferrari g. acute hiv infection: the impact of anti-retroviral treatment on cellular immune responses. clin exp immunol 2007; 149: 211-216.s. http://www3.interscience.wiley.com/cgi-bin/fulltext/117996335/pdfstart (accessed 17 february 2009). 21. berrey mm, schacker t, collier ac, et al. treatment of primary human immunodeficiency virus type 1 infection with potent antiretroviral therapy reduces frequency of rapid progression to aids. j infect dis 2001; 183: 14661475. http://www.journals.uchicago.edu/doi/pdf/10.1086/320189 (accessed 2 february 2009). 22. rosenberg es, altfeld m, poon sh, et al. immune control of hiv-1 after early treatment of acute infection. nature 2000; 407: 523-526. http://www. kendallasmith.com/follow/walker_nature_9_28_00.pdf (accessed 17 february 2009). 23. lacabaratz-porret c, urrutia a, doisne jm, et al. impact of antiretroviral therapy and changes in virus load on human immunodeficiency virus (hiv)-specific t cell responses in primary hiv infection. j infect dis 2003; 187: 748-757. http://www. journals.uchicago.edu/doi/pdf/10.1086/368333 (accessed 17 february 2009). 24. panel on antiretroviral guidelines for adults and adolescents. guidelines for the use of antiretroviral agents in hiv-1-infected adults and adolescents. department of health and human services. november 3, 2008; 1-139. http:// aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf (accessed 11 february 2009). 25. gazzard bg (bhiva treatment guidelines writing group). british hiv association guidelines for the treatment of hiv-1-infected adults with antiretroviral therapy 2008. 2008 british hiv association. hiv med 2008; 9: 563-608. http://www. bhiva.org/files/file1030835.pdf (accessed 11 february 2009). 26. hammer sm, eron jj, reiss p, et al. antiretroviral treatment of adult hiv infection: 2008 recommendations of the international aids society–usa panel. jama 2008; 300(5): 555-570. http://jama.ama-assn.org/cgi/reprint/300/5/555 (accessed 9 march 2009). 27. maartens g, venter f, meintjes g, cohen k. hiv clinicians society guidelines: antiretroviral therapy in adults. southern african journal of hiv medicine 2008; jan: 18-31. http://www.sajhivmed.org.za/index.php/sajhivmed/article/ view/68/34 (accessed 15 february 2009). 28. hecht fm, wang l, collier a, et al. a multicenter observational study of the potential benefits of initiating combination antiretroviral therapy during acute hiv infection. j infect dis 2006; 194: 725-733. http://www.journals.uchicago. edu/doi/pdf/10.1086/506616 (accessed 2 february 2009). 29. kaufmann de, lichterfeld m, altfeld m, et al. limited durability of viral control following treated acute hiv infection. plos med 2004; 1(2): 137-148. http:// medicine.plosjournals.org/archive/1549-1676/1/2/pdf/10.1371_1549-1676_ 1_2_complete.pdf (accessed 2 february 2009). 30. jülg b, goebel fd. treatment interruption in hiv therapy: a smart strategy? infection 2006; 34: 186-188. http://www.springerlink.com/content/ 573032284h528150/ (accessed 2 march 2009). 31. schacker t, little s, connick e, et al. rapid accumulation of human immunodeficiency virus (hiv) in lymphatic tissue reservoirs during acute and early hiv infection: implications for timing of antiretroviral therapy. j infect dis 2000; 181: 354-357. http://www.journals.uchicago.edu/doi/pdf/10.1086/315178 (accessed 2 february 2009). 21 c p d  q u e s t i o n s journal 35 two cpd points are awarded for the correct completion and submission of the questions below. cpd questionnaires must be completed online via www.cpdjournals.org.za. after submission you can check the answers and print your certificate. questions may be answered up to 6 months after publication of each issue. this programme is available free of charge to members of the hiv clinicians society and sama only. 1. true (a) or false (b) – click on the correct answer: intrusive recollections, avoidance/numbing, and hyperarousal are significant symptoms in post-traumatic stress disorder (ptsd). 2. true (a) or false (b) – click on the correct answer: benzodiazepines are important first-line agents in the management of ptsd. 3. true (a) or false (b) – click on the correct answer: efavirenz is the most commonly implicated antiretroviral causing drug-induced psychosis in hiv, and this usually manifests early after drug initiation. 4. true (a) or false (b) – click on the correct answer: in an hiv-infected individual, a diagnosis of delirium generally does not require further work-up. 5. true (a) or false (b) – click on the correct answer: in an hiv-infected individual presenting with an acute psychotic episode, the possibility of an underlying primary psychiatric disorder (that is unrelated to hiv infection) warrants consideration. 6. true (a) or false (b) – click on the correct answer: hiv-associated psychosis always requires a lumbar puncture and computed tomography scan of the brain as part of routine work-up. 7. true (a) or false (b) – click on the correct answer: haloperidol (starting dose 0.5 2.5 mg/day) is commonly used in the management of hiv psychosis. 8. true (a) or false (b) – click on the correct answer: hiv crosses the blood-brain barrier during acute infection and infects neurons only. 9. true (a) or false (b) – click on the correct answer: hiv-associated dementia typically involves the basal ganglia (i.e. is a subcortical dementia), and is therefore more likely to present with motor deficits compared with alzheimer’s dementia (a cortical dementia). 10. true (a) or false (b) – click on the correct answer: hiv may lead to subtle but measurable deficits in neurocognitive function that occur early in the course of hiv disease in otherwise asymptomatic patients. 11. true (a) or false (b) – click on the correct answer: antiretroviral therapy is not an effective treatment for hivassociated dementia. 12. true (a) or false (b) – click on the correct answer: the hiv dementia scale has a low sensitivity in detecting hivassociated dementia. 13. true (a) or false (b) – click on the correct answer: depression is more common in hiv-infected individuals than in those without hiv/aids. 14. true (a) or false (b) – click on the correct answer: insomnia and wide-ranging somatic complaints in the absence of a low mood are rare presentations of depression. 15. true (a) or false (b) – click on the correct answer: a clinician with special psychiatric training is required to diagnose and treat depression in an hiv-infected patient at primary care level. 16. true (a) or false (b) – click on the correct answer: in a patient on antiretroviral therapy with poor adherence who is diagnosed with depression, effective treatment of the depression may improve treatment adherence. 17. true (a) or false (b) – click on the correct answer: screening for suicidality is important in hiv primary care. 18. true (a) or false (b) – click on the correct answer: a 6-week course of selective serotonin reuptake inhibitors (ssris) should be adequate to treat most depressive episodes. 19. true (a) or false (b) – click on the correct answer: fluoxetine is safe and effective for treatment of depression in hiv infection, but the potential for drug-drug interactions requires consideration. 20. true (a) or false (b) – click on the correct answer: lithium is generally a better choice than valproate as a mood stabiliser for hiv-infected individuals with bipolar mood disorders as it has a safer therapeutic index. abstract introduction research design results discussion conclusion acknowledgements references about the author(s) razia gaida department of pharmacy, nelson mandela metropolitan university, south africa ilse truter department of pharmacy, nelson mandela metropolitan university, south africa drug utilisation research unit, nelson mandela metropolitan university, south africa christoffel grobler department of pharmacy, nelson mandela metropolitan university, south africa citation gaida, r, truter, i, incidence of neuropsychiatric side effects of efavirenz in hiv-positive treatment-naïve patients in public-sector clinics in the eastern cape. s afr j hiv med. 2016;17(1), a452. http://dx.doi.org/10.4102/sajhivmed.v17i1.452 original research incidence of neuropsychiatric side effects of efavirenz in hiv-positive treatment-naïve patients in public-sector clinics in the eastern cape razia gaida, ilse truter, christoffel grobler received: 17 nov. 2015; accepted: 16 may 2016; published: 30 june 2016 copyright: © 2016. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: it is acknowledged that almost half of patients initiated on efavirenz will experience at least one neuropsychiatric side effect. objectives: the aim was to determine the incidence and severity of neuropsychiatric side effects associated with efavirenz use in five public-sector primary healthcare clinics in the eastern cape. method: the study was a prospective drug utilisation study. a total of 126 medical records were reviewed to obtain the required information. after baseline assessment, follow-up reviews were conducted at 4 weeks, 12 weeks and 24 weeks from 2014 to 2015. results: the participant group was 74.60% female (n = 94), and the average age was 37.57±10.60 years. there were no neuropsychiatric side effects recorded for any patient. after the full follow-up period, there were a total of 49 non-adherent patients and one patient had demised. a non-adherent patient was defined as a patient who did not return to the clinic for follow-up assessment and medication refills 30 days or more after the appointed date. some patients (n = 11) had sent a third party to the clinic to collect their antiretroviral therapy (art). the clinic pharmacy would at times dispense a two-month supply of medication resulting in the patient presenting only every two months. conclusion: further pharmacovigilance studies need to be conducted to determine the true incidence of these side effects. healthcare staff must be encouraged to keep complete records to ensure meaningful patient assessments. patients being initiated on art need to personally attend the clinic monthly for at least the first 6 months of treatment. clinic staff should receive regular training concerning art, including changes made to guidelines as well as reminders of side effects experienced. introduction in 2013, an estimated 10% of the south african population was hiv-positive which amounted to 5.26 million people.1 this increased to 10.2% in 2014 which amounted to 5.51 million people.2 efavirenz forms part of the first-line treatment of hiv in south africa and is used as part of the fixed-dose combination (fdc) of triple therapy. it is acknowledged that almost half of patients initiated on efavirenz will experience at least one neuropsychiatric side effect.3,4,5 commonly reported side effects include dizziness, insomnia, headache, abnormal dreams and impaired concentration.4,6,7 these side effects tend to occur within the first few weeks of treatment and spontaneously resolve within that time.3 it has also been shown that these side effects may persist longer than a few weeks after the initiation of efavirenz.5 they may in fact persist for up to 2 years and this may influence the long-term adherence to efavirenz.8,9 the plasma levels of efavirenz as well as genetic polymorphisms in certain populations are thought to be the cause of these neuropsychiatric side effects.3,10,11 there have been several studies7,12,13,14,15 comparing efavirenz with various other treatments such as nevirapine, protease inhibitors, etravirine and raltegravir. in all instances, efavirenz was seen to induce neuropsychiatric side effects more frequently than these other treatments. the side effects presented most commonly during the first few weeks of treatment and resolved spontaneously after 6 weeks. however, the studies did note that there were instances of late-emergent side effects and recommend that monitoring be an ongoing process. efavirenz is effective in reducing viral load in hiv-positive patients. this was shown by gulick et al.16 who compared a regimen containing three nucleoside reverse-transcriptase inhibitors (abacavir, lamivudine and zidovudine) with efavirenz-containing regimens. the results of the study showed that efavirenz-containing regimens were virologically superior to those without. another study17 showed that efavirenz treatment resulted in an increase in cd4 cell count and was associated with fewer hypersensitivity reactions and hepatitis than nevirapine. these are some of the reasons for efavirenz being selected as part of the first-line treatment for hiv in south africa.7 however, in light of the problems caused by efavirenz, patient adherence may be affected and treatment interrupted which is undesirable for conditions such as hiv where consistent long-term therapy is required. the south african guidelines18 do acknowledge the neuropsychiatric side effects caused by efavirenz and indicate that previous or current depression or other mental disorders would increase the likelihood of these side effects occurring. the guidelines do not however provide guidance as to how to manage these side effects once they manifest. before efavirenz is initiated, patients need to be screened for a history of, or a current mental illness, as such patients may be at a higher risk of developing neuropsychiatric side effects. a south african study conducted in 200819 showed that the prevalence of hiv in people between the ages of 15 and 49 years at the time was 16.9% and that of this population, 43.7% had some kind of mental disorder. the study showed that mild depressive disorder was the most common amongst males (28.1%) and females (30.5%). this was followed by major depressive disorder and alcohol abuse in both sexes.20 another study,21 conducted in that same year, included 465 hiv-positive patients and found a mental disorder prevalence of 19%. the aim of this study was to determine the incidence and severity of neuropsychiatric side effects associated with efavirenz use in hiv-positive patients in a public-sector primary healthcare setting. research design study setting and population the study was designed as a prospective drug utilisation study. five public-sector primary healthcare clinics in the eastern cape were used as locations for the study. each of these sites had both an hiv clinic as well as a psychiatric clinic which ensured that patients would be treated at the same facility and not referred. patients themselves were not directly involved in the study, and there was no patient contact. instead, the medical records were reviewed to obtain the required information. patients were chosen through purposive sampling. the patient files were evaluated to determine whether or not patients met the inclusion criteria. all of the patients who met the outlined criteria were included. patients who were 18 years or older and diagnosed hiv-positive were included in the study. all of the selected patients were treatment-naïve upon initiation of antiretroviral therapy (art) and were prescribed efavirenz as part of the triple therapy regimen. patients with current or previous tuberculosis (tb) infection were also included as were pregnant women. patients who were previously non-adherent (missed 30 days or more of treatment) and subsequently restarted on art were excluded. the total sample amounted to 126. for the purposes of this study, the term ‘patient’ will refer to a patient file or medical record. the data capturers at each of the clinics were contacted to obtain access to files. data capturers are administrative staff at the clinics who electronically capture information concerning hiv-positive patients recorded by nurses. patients were enrolled between july 2014 and november 2014 and were selected based on the inclusion criteria. ethical consideration the study was granted ethics approval by the nelson mandela metropolitan university research ethics committee (human) (reference number: h14-hea-pha-001) as well as the eastern cape department of health and was conducted according to the principles outlined in the declaration of helsinki.20 the necessary permissions were obtained from the management of each individual clinic. measurements, outcomes and follow-up procedures in the public sector of south africa, hiv medical records are standardised across the country and contain a number of questions to be asked by the healthcare professional to obtain a baseline picture of the patient’s condition. this form was used to obtain the baseline information required for the study. a self-developed data collection tool was used to extract the required information. the information required included age, gender, weight, date of hiv diagnosis, cd4 count at art initiation, tb infection, pregnancy status, world health organization (who) stage, whether the patient was a substance abuser and a history of, or current, psychiatric condition. the primary outcome was the incidence and severity of neuropsychiatric side effects associated with efavirenz use as well as the subsequent management of the patient. after the baseline information was obtained, follow-up was conducted at 4, 12 and 24 weeks. in standard practice, patients receive counselling before the hiv test is performed. the healthcare workers explain the significance of a positive result or provide counselling to encourage the continuation of safe practices if the result is negative. for those who test hiv-positive, the patient is counselled to provide an understanding of what measures need to be taken in order to ensure their future well-being. healthy living, disclosure of status and, if the patient qualifies for art, the medication and the importance of adherence is discussed with the patient. once the patient is considered ‘art-ready’, the patient is initiated on treatment. the time lapse between testing and the initiation of treatment varies between patients. after art has been initiated, patients present at the clinic on a monthly basis for follow-up assessments and to collect medication. at each visit, the patient would be seen by the wellness clinic nurses for the clinical assessment and the information would be recorded in the file. at the 4-, 12and 24-week follow-up visits, the file was reviewed by the researcher using the data collection tool. statistical analysis the data were captured in microsoft excel® and analysed using descriptive statistics. results subjects at baseline a total of 126 patients were followed through the 24-week study period. the participant group was 74.60% female (n = 94). the average age was 37.57±10.60 years with females being, on average, younger (35.66±9.83 years) than males (43.19±10.91 years). the difference was seen to be statistically significant (p < 0.05). the baseline data are summarised in table 1. table 1: baseline data of patients. there were 14 (14.89%) female patients who were pregnant at the start of the study, five of whom were in the first trimester, four in the second semester and two in the third trimester. the trimester was not indicated for three patients. all of these women were initiated on efavirenz before the national department of health had published an updated guideline7 stating that efavirenz could be prescribed to pregnant women regardless of trimester. patients were also screened for a history of psychiatric disorders. this was done by means of a single ‘yes’ or ‘no’ question on the standardised medical record asking if the patient had a history of psychiatric illness. one patient had a current symptomatic mental illness and one patient had a history of depression. patients were treatment-naïve before the initiation of the efavirenz-containing regimen. the majority of patients (96.83%; n = 112) received efavirenz in the form of the fdc tablet. two patients were not receiving the fdc, one was receiving efavirenz in combination with lamivudine and abacavir, and the other efavirenz in combination with lamivudine and zidovudine. all patients, except one, were receiving efavirenz 600 mg daily. that patient was switched to a lower dose of 400 mg of efavirenz due to weight loss resulting in a total body weight of less than 40 kg. just over half (53.17%; n = 67) of the study population was diagnosed with hiv in 2014. there were 14 patients (11.11%) diagnosed as hiv-positive before 2008 but were initiated on art only in 2014. this could be due to the cd4 count remaining above the specified threshold of 350 cells/mm3 which, according to the south african guidelines7 at that time, was the point at which the patient must be initiated on art. the majority of patients (44.40%; n = 56) were classified as being in clinical stage 1 of the who staging and 23.0% (n = 29) being classified as stage 3. of the patients classified as being stage 3, 62.07% (n = 18) were suffering from a concurrent tb infection. more than half (55.56%) of the patients had a cd4 count of less than 350 cells/mm3. this is in keeping with the previous guidelines22 which stated that patients with a cd4 count of 350 cells/mm3 or less regardless of the clinical stage must be started on art. the guidelines have since changed to state that patients with a cd4 count of 500 cells/mm3 or less must be started on art regardless of the clinical stage.18 there were 10 patients who were initiated on art with a cd4 count of more than 350 cells/mm3. there were three patients in this group with active tb infection at baseline and another three who were pregnant at baseline. pregnant patients and those with tb must be initiated on life-long art regardless of the cd4 count.18 substance abuse was not well documented. the standardised medical record includes a ‘yes’ or ‘no’ question querying if the patient is a current ‘drug abuser’. there were 59 (46.83%) patients for whom no response was documented. alcohol abuse is also in the form of a ‘yes’ or ‘no’ question asking if the patient is a current alcohol abuser and is questioned separately from substance abuse. there were 60 (47.62%) patients for whom no response concerning alcohol abuse was documented. only one patient admitted to being a substance abuser and six patients admitted to abusing alcohol. not many patients were seen to have comorbidities. there were 13 (10.32%) patients each with hypertension and asthma, five (3.97%) patients with diabetes and two (1.59%) patients with epilepsy. three patients suffered from diabetes and hypertension, one patient suffered from hypertension and asthma, and one patient suffered from hypertension, asthma and epilepsy in addition to hiv. follow-up there were no neuropsychiatric side effects recorded in the medical records for any patient. one patient reported experiencing a headache; however, this was accompanied by other influenza symptoms and was therefore unlikely to have been caused by efavirenz. there were non-adherent patients (defined as a patient who did not return to the clinic for follow-up assessment and medication refills 30 days or more after the appointed date) at each follow-up, and this number increased throughout the follow-up period. there were 27 (21.43%), 39 (30.95%) and 49 (38.89%) non-adherent patients after 4, 12 and 24 weeks, respectively. at each follow-up point, there were more female non-adherent patients than male non-adherent patients. after 24 weeks, there were 35 (73.47%; n = 49) female non-adherent patients as compared with 14 (28.57%; n = 49) male non-adherent patients; however, this was not found to be statistically significant. there were nine patients transferred to different facilities over the follow-up period. some patients (n = 11) sent a third party to the clinic to collect their art for the month and did not personally present themselves. the clinic pharmacy would also, at times, dispense a 2-month supply of medication resulting in the patient presenting only every 2 months. by the end of the 24-week follow-up, one patient had demised and the cause of death was unknown. considering the non-adherent patients more closely (table 2), six patients were diagnosed with tb co-infection, two were diagnosed as being hypertensive and three were diagnosed as being asthmatic. one patient had both hypertension and asthma. although patients with comorbidities were prescribed medication for their chronic or infectious diseases, adherence to the medication cannot be guaranteed. of the 49 non-adherent patients, more than half (56%; n = 28) were between the ages of 18 and 35 years. as cd4 cell counts are checked only 12 months after initiation of art, there were no new results available during the follow-up period. table 2: characteristics of non-adherent patients. discussion according to the literature, at least half of the patients who are initiated on efavirenz will experience at least one neuropsychiatric side effect. the clinic records show zero incidence of neuropsychiatric side effects. this could mean that patients were not reporting side effects, clinic staff were not enquiring about side effects or the side effects were not being recorded in the medical records. there were instances of information not being documented in the medical records. this included information such as previous tb infection, whether or not the patient was a substance abuser or whether the patient had a history of a psychiatric disorder. the questions contained in the standardised medical record for hiv patients were not extensive. a history of psychiatric illness is an important factor in determining the art regimen, but only a single ‘yes’ or ‘no’ question is devoted to this topic asking the patient if they have a history of psychiatric illness. the patient may not be willing to divulge information concerning a previous mental illness, may not recognise it in themselves or it may not be asked by the healthcare worker. this section should be reviewed, and follow-up questions could be asked in order to determine a history, or current feelings, of depression. it is known that mental illness, particularly depression, serves as a barrier towards adherence.23 the ‘yes’ or ‘no’ questions with regard to substance and alcohol abuse may elicit a feeling of shame and the patient may therefore answer in the negative. the south african guidelines18 are not expansive in terms of preparing the patient for art. it states that the patient must be screened for nutritional status, comorbidities and possible drug interactions and any mental health and substance abuse issues must be addressed.18 further elucidation is not provided concerning the specific questions to be asked or clinical assessments to be done. the way these issues are addressed seems to be at the discretion of individual provinces or facilities. the 2010 hiv guidelines of swaziland24 dedicate a chapter to mental health and substance abuse. it states that these are underdiagnosed conditions and not properly managed. it recommends that healthcare workers at the primary care level conduct a basic mental health screen and refer patients who appear to have any issues or are at risk of suicide. the swaziland guidelines24 stress that mental illness may affect adherence to art and is an important issue to consider before initiating treatment. an extensive list of questions is provided to assist healthcare workers in detecting various mental illnesses such as anxiety, depression and suicide risk. in order to provide more comprehensive mental illness screening in south africa, a similar tool could be adopted. some patients did not return to the clinic each month. patients should be encouraged to personally present themselves at the clinics on a monthly basis for assessment and collection of art. third parties should not be allowed to collect medication on behalf of the patient, especially during the first 6 months of therapy when side effects may manifest and this in itself may present barriers to adherence. this also denies the patient any adherence counselling that may be done at these visits. kranzer et al.25 found that the rate of non-adherence to art was highest during the first 6 months of treatment and thereafter declined. it can be understood that the clinics dispense a 2-month supply to patients in order to reduce the patient burden on the dispensary. however, to encourage new patients to come to the clinic, only 1-month supply of medication should be dispensed for at least the first 6 months of treatment in order to ensure retention of the patient. a study26 conducted with patients across south africa showed an adherence of only 40% after an average of 29 months of treatment. a study focused in the eastern cape27 showed 37.5% poor compliance to treatment, but no patient discontinued treatment. another study28 set in cape town showed only 12.8% non-adherence of a cohort of 242 patients. this shows that adherence varies between provinces in south africa. it was interesting to note that in this study there were more female non-adherent patients than male non-adherent patients. however, even though the number of female non-adherent patients exceeded the number of male non-adherent patients, the percentage of male non-adherent patients (43.75%) was higher. kranzer et al.25 stated that male patients were at higher risk of being non-adherent, whereas female non-adherent patients were more likely to subsequently restart therapy. a retrospective analysis29 carried out in south africa stated that gender was not a predictive factor in terms of non-adherence which shows that there are conflicting ideas surrounding gender as a risk factor for non-adherence to art. it was also noteworthy that the majority (20.41%; n = 10) of patients who were non-adherent by the end of the 24-week follow-up period had initial cd4 counts of below 150 cells/mm3. studies30,31 have been conducted in south africa to determine the reasons behind non-adherence to art. reasons put forth by patients include transport costs, not obtaining time off from work to attend the clinic, transfers between clinics being difficult to complete and resulted in lost paperwork as well as other administration problems.30,31 suggestions have been made to provide patients with vouchers for transport, providing transport to and from the clinic, extending clinic hours for patients who work or providing mobile clinic services in order to decrease the distance patients need to travel to reach the clinic.30,31 a study conducted in rural rwanda32 showed that by providing nutritional support, healthcare worker visits to patients’ homes to supervise treatment and a transportation allowance resulted in a 92.3% retention rate. this study showed that high retention rates can be achieved in resource-limited settings. it was noted that overall the standardised medical record sheet used by the public-sector clinics is not sufficient. the form only allows the most elementary screening of comorbid conditions that would affect the choice of art prescribed to the patient. complex conditions such as psychiatric illnesses as well as substance abuse disorders cannot be comprehensively determined by means of single questions. this calls for more integrated healthcare services with psychiatric services performing a more thorough screening of a patient’s mental state. patients need to be adequately screened to determine those at risk for developing side effects to prevent future hospitalisation. these medical records need to be re-evaluated and a more integrated healthcare service provided to patients. conclusion record-keeping at the public-sector clinics is not currently optimal. healthcare staff must be encouraged to keep complete records in order to ensure meaningful patient assessments with more attention being paid to mental illness, neuropsychiatric side effects, substance abuse and emotional well-being of the patients. patients being initiated on art need to personally attend the clinic for monthly assessments at least for the first 6 months of treatment in order to increase the likelihood of retention in care. suggestions made by other studies to retain patients should be taken into consideration. these included home visits by healthcare workers, extended clinic hours and mobile clinics as well as providing patients with transport or remuneration for transport to attend the clinics. the medical information sheet used to obtain the patient’s medical history should be re-examined and improvements made where necessary. clinic staff should receive regular training concerning art including changes made to guidelines as well as reminders of side effects experienced and suggestions for questions to be asked when the patient attends follow-up sessions. limitations the small sample size serves as a limitation to the study as well as the fact that the patients were contained in a single district within the province. the inclusion of patients stretching across a broader location would be desirable. the record-keeping at these facilities has not proven optimal, and improvement in this regard would serve to improve future studies. acknowledgements competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions all authors contributed towards the conceptualisation and design of the study. r.g. was responsible for the acquisition of the data, data analysis and interpretation of the data. i.t. and c.g. were responsible for critically revising for intellectual content, proofreading and editing of the final manuscript. references statistics south africa. mid-year population estimates. pretoria: statistics south africa; 2013. statistical release p0302. statistics south africa. mid-year population estimates. pretoria: statistics south africa; 2014. statistical release p0302. gutierrez-valencia a, viciana p, palacios r, et al. stepped-dose versus full dose efavirenz for 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o u r n a l o f h i v m e d i c i n e1 8 in 1999, bristol-myers squibb company and bristol-myers squibb foundation launched a programme called secure the future (stf ) to support the development and evaluation of cost-effective, sustainable and replicable models for providing care and support for people living with hiv/aids (plwha) in africa. the programme was first launched in southern africa (botswana, lesotho, swaziland, namibia and south africa), and by 2004 had expanded to east and west africa (burkina faso, cote d'ivoire, mali, senegal, uganda and malawi). during the first 3 years of the stf programme, funding was provided to more than 160 projects addressing critical areas of need in community outreach and education and medical research. this phase of broad-based grant making put resources directly into the hands of small, community-based organisations that were the ‘first responders’ to the hiv/aids crisis and created innovative models of care. the programme also supported african researchers who studied the development of low-cost diagnostic and disease monitoring tools and conducted trials on locally relevant topics such as diagnosis of smear-negative tuberculosis (tb) and the efficacy of prevention of mother-to-child transmission (pmtct) medication given to the newborn infant only, in cases when the mother presented at the hospital after delivery. by 2002, the international community and many national governments in sub-saharan africa began working towards providing free antiretroviral therapy (art) to the hiv-infected population. at its biannual meeting in april 2002, the technical advisory committee endorsed the recommendation of stf staff that the programme redefine its role and join this effort. in the following months, stf staff consulted extensively with national governments in southern africa on challenges and gaps in rolling out art. a commonly raised issue related to roll-out to remote communities where health care infrastructure, capacity and other resources were limited. many regarded these communities as too challenged by poverty, lack of healthcare infrastructure and healthcare worker capacity, lack of food security, unemployment, and high levels of stigma to establish and sustain long-term efficacious treatment. there was not only concern about how to guarantee equity in art roll-out, but also the need for innovative models and comprehensive actions to make sure art could also be provided in poor communities. using these consultations and drawing on lessons from the grants made in the first 3 years of the programme, the community-based treatment support (cbts) programme model was developed. the cbts model (fig. 1) emphasises that plwha in resourcelimited settings need both clinical services and community services to effectively enhance their quality of life and outcomes. the model also places equal emphasis on supporting the needs of plwha receiving art and patients whose disease has not yet progressed to the need for treatment. the model, therefore, employs supportive services like nutrition support and home-based care to help plwha manage their chronic hiv disease outside the clinic and in their homes and communities. the model leverages the strengths of government, private sector and community-based organisations to offer a true continuum of care, or as stf refers to it, ‘231/2 hours’ of disease management and psychosocial support that takes place in the patient’s home and community following a ‘half hour’ of medical care in the clinic. the resulting stf programme was launched at five sites in southern africa, chosen after consultation with the respective governments. and the effectiveness of the cbts model has been demonstrated by a 3-year operational research study conducted at the five sites: namely katima-mulilo in namibia, bobonong in botswana, maseru in lesotho, mbabane in swaziland and ladysmith in south africa. c o m m u n i t y secure the future: seven steps to involve the community in hiv/aids treatment support programmes richard sebastian wanless, md, phd senior medical director, bristol-myers squibb, secure the future in this issue of the southern african journal of hiv medicine, secure the future is pleased to present in cd form the manual, seven steps to involve the community in hiv/aids treatment support programmes. the manual is the product of 4 years of intensive work on the implementation of a programme of community-based treatment support for patients with hiv/aids. its overall purpose is to guide any group in how to integrate medical care with the power of community mobilisation and community services provided to patients in their homes and communities. t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u n e 2 0 0 7 1 9 clinical outcomes and the added value of community support were evaluated by rigorous collection of data according to protocols developed by bms and family health international. full details of the methodology and analysis are to be found in the manual itself, but the following is a summary of key findings. ■ increased voluntary counselling and testing and clinical uptake. overall, the uptake of vct increased approximately 10-fold within 2 3 months from the start of community mobilisation. uptake of clinic services mirrored this. by november 2006, more than 16 000 patients had been enrolled ■ excellent adherence. at 12 months, 84.5% of patients were still more than 95% adherent. ■ the added value of community support: ■ cd4 counts increased significantly more and to significantly higher levels in patients on arvs who accessed community support than those who did not: from median values of 129 and 127 to medians of 326 and 268 respectively. ■ patients satisfied with the level of community support they received also experienced better quality of life and adhered better to their arv medication than those who were not satisfied. ■ food security and home-based care were the two services statistically related to better adherence. ■ the lost-to-follow-up rate in stf cbts programmes was only 5.1%. in swaziland’s pmtct programme, all 224 women and their babies were accounted for up until 12 months of the child’s age, thanks to community workers who intensively tracked defaulters. ■ community services helped prepare patients for art and ‘levelled the playing field’ by dealing with psychosocial problems, inadequate nutrition and logistical issues, such as transport to the clinic and disclosure of status to a significant other. in summary, with community mobilisation and support, a patient is more likely to present for testing and treatment, will be better prepared to begin and adhere to art, is less likely to default and is more likely to have a better clinical outcome. and the impact at a community level was dramatic. for example, approximately 66 000 people live in the bobirwa subdistrict of botswana. the bobonong primary hospital, where the cbts model was established, is the only hospital serving this population. by 2006, 2 years after the cbts model was adapted and implemented in the sub-district, 1 546 patients were on arvs and the following notable results were achieved: ■ hospital bed occupancy by hiv patients decreased from 93% to 52% ■ in-hospital mortality due to hiv/aids decreased from 25% to 13%. the model is now presented in the manual as a partnership involving government, the private sector and communitybased organisations, using a seven-step implementation process as illustrated in fig. 2. the manual also includes 22 technical tools and resources to assist the provision of quality services to clients, as well as case study profiles of five southern african community-based treatment sites, outlining their adaption and implementation of the programme. these case studies illustrate the flexibility of the model. the manual is intended for public health officials, project managers, service providers, aids service organisations, funders and communities seeking to initiate, enhance or expand comprehensive hiv/aids treatment and care programmes in resource-limited settings. the steps outlined in the manual will allow a logical, optimal and effective path to implementation. the key objectives, expected outcomes and lessons learnt according to stf are detailed below. fig. 1. community-based treatment support model of care. j u n e 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e2 0 step 1: engage government and community the first step recognises the critical need of obtaining government support for introduction of the cbts model. it guides the implementer in how to advocate for establishment of an integrated, community-based approach for hiv/aids care and treatment, which includes the government, private sector and community in multidisciplinary teams. at the end of this step, a business case for the programme will have been created and government buy-in secured. stf learnt that governments can be engaged if the cbts programme and model align with national policies and address critical challenges. engagement should now be eased because of the positive data included in the manual, attesting to the effectiveness of the community-based approach. step 2: establish leadership and management structure this step leads to the appointment of a skilled and preferably experienced project manager, as strongly recommended by stf, and to the development of a project charter that specifies objectives and deliverables as well as a management structure with clear roles, responsibilities, and reporting relationships through collaborative and transparent workshops. another key learning by stf was that for the cbts programme to succeed, it is important to place equal importance on the role of all partners and give them equal say in planning and implementation. step 3: adapt the community-based treatment support model the cbts model is flexible. indeed adaptation is essential and is described in this step, which leads to selection of clinical sites and of community services, the elaboration of a patient flow map, the development of a patient documentation system and an implementation plan. perhaps the most important learning of this step is that a carefully designed patient flow map is the key to quick and accurate adaptation of the model to any particular programme location. step 4: build partner capacity this step describes how to train and build capacity of all stakeholders to deliver services and other skills dictated by the shared goals of the project. capacity building is not just about training, but can be facilitated by providing appropriate, sometimes innovative upgrades or modifications to workplaces and other physical structures. stf also learnt that training personnel to understand the cbts concept itself is necessary for effective implementation. step 5: deliver services the first objective of this step is mobilisation of the community to support and engage in new and improved services, particularly newly accessible art and community services integrated with art. thereafter attention is paid to how to deliver high quality, accessible and integrated clinical and community services to the targeted numbers of patients, how to prepare patients who need art for treatment and how to track and retain them in the programme. the manual also fig. 2. the seven-step process. in namibia, an ngo village was constructed inexpensively employing indigenous construction techniques. more than 5 000 people attended the public launch of the achiva programme at ladysmith provincial hospital in kwazulu-natal, south africa, in 2004. t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u n e 2 0 0 7 2 1 addresses how to provide community support for patients not yet clinically eligible for arvs. stf learnt the importance of this, because inattention to these patients can demotivate them and they may then drop out of the programme. stf also learnt that selection of patients for arv therapy should be based largely on clinical criteria and remain uninfluenced by social discrimination, because social and psychological problems can usually be managed. in terms of community services, home-based care was found to be one of the most important for hiv/aids patients and has been shown to impact on clinical outcomes. the job description of home-based care workers has been transformed with the advent of arv therapy from palliative care to supportive care. in addition, adequate nutrition is essential for optimal response to treatment, but it is important to encourage selfsufficiency by teaching patients how to grow their own food. step 6: monitor and evaluate and step 7: revise services step 6 guides the development of a monitoring and evaluation framework while step 7 explains how to reflect on progress, successes and challenges, making use of monitoring and evaluation data. corrective action can be taken with input and agreement from relevant partners. in publishing the manual, it is the hope of stf that the experience gained and lessons learnt can be utilised by others wishing to provide holistic and effective care and support to patients with hiv/aids in resource-limited settings. ‘buddies’ trained by the ngo cocepwa in gaborone, botswana, prepare to go to work. food security in action: workers in their community garden in lesotho. in the bristol-myers squibb, secure the future manual: seven steps to involve the community in hiv/aids treatment support programme (cd included), page 4 of tool #11 is reprinted with the permission of actknowledge and the aspen institute roundtable on community change. www.theoryofchange.org. a woman in bobonong, botswana, proudly tends her doorsized garden. the souther.n african journal of iiiv medicine ----------august 200 i foundation for professional development and south african rn clinicians society medical education self-study the face-ta-face tuition will be presented by leading national and international experts and will take place over a 3-day period in the format of outcome-based workshops focusing on the practical integration of the knowledge acquired through the self-study guide. workshops will avoid a didactic approach and use case studies, roleplaying and interactive methodology. workshops course format successful participants will be awarded an attendance certificate for the workshop in the management of hiv/aids by the foundation for professional development. certification leading national experts will customise a comprehensive easy-ta-use self-study manual based on the international aids society's share programme. the study material will be provided to participants prior to the workshop in order for them to prepare. the study material eliminates the need for supportive textbooks and will include material on: • basic immunology and physiology • economic and epidemiological information • disease management strategies for stds and hiv/aids, including diagnosis, treatment (inclusive of therapy, monitoring efficacy, side-effects, compliance monitoring, primary resistance, drug failure) and referral options • vaccine development and trials • ethical considerations surrounding hiv/aids testing and management • counselling (lifestyle, compliance, terminal, preand post-test counselling) • the role of health care professionals in community mobilisation • living, coping and working with hiv. participants will need to score 7rfj1o for the multiple-choice questionnaire in order to ensure compliance with the selfstudy requirements of the course. the course will combine self-study and face-ta-face (workshop) tuition. the objective of the programme is to establish comprehensive training and support for health care professionals in the southern african region geared at: • ensuring a critical mass of trained health care professionals within a relatively short time • providing health care professionals with comprehensive skills in order to enable them to diagnose and manage hiv/aids and stds and all related clinical conditions including referral to specialist and support services • providing targeted sectors of the health care profession with appropriate and meaningful information to prevent them from becoming infected • establishing a support structure that will keep alumni of the programme updated with new developments in the field, and • creating an expanded organised community of health care professionals dedicated to responding to the hiv/aids epidemic given the current state of knowledge on hiv/aids management and the fact that antiretroviral therapy (art) is now more 'affordable, it is feasible to approach hiv!aids as a chronic medical condition. this implies that all healthcare professionals need to acquire knowledge on the management of this condition as a matter of urgency. the objective of the course in the management of hiv/aids is, through a combination of self-study and the workshop, to enable health care professionals to: • diagnose hiv/aids and stds • manage and refer hiv/aids patients • do counselling in the management of the patient • empathise with people 'living with hiv • fulfil their role as health care professionals in community mobilisation • understand vaccine development and trials. the foundation for professional development (fpd), the educational division of the south african medical association (sama), in association with the south african hiv clinicians society, a sama special interest group, is offering a course in the management of hiv/aids conditions with the support of an educational grant. objectives introducing the hiv!aids course management of hn/aids course -------------th~ sou'"~pe~ m~ ca~ jour',4l o~ hili .1toicin~ proposed provisional workshop schedule for the hiv/aids course day 2 (hiv/aids theory in practice) the role of health care professionals in communiiy mobilisation tea time case studies: participanis (in syndicates) are to diagnose (including diagnostic tesis), refer and treat [including patient education) in the simulated learning opportuniiy lunch. allowance for jumah prayers to allow muslim delegates to attend mosque case study feedback tea time case study feedback (continue) summary (overall approach in the managemen of patienis with hn/aidsj day 1 (hiv/aids overview conceptualising) introduction tea time basic immunology and physiology of aids lunch epidemiological and economic overview tea time clinical management of hiv/aids (inclusive of initiation of therapy, monitoring efficacy, side-effecis, compliance monitoring, primary resistance, drug failure) day 3 (hiv/aids reality) vaccine development and trials tea time uving, coping and working with hiv/aids lunch ethical considerations surrounding hiv/aids testing and management tea time counselling [iifesiyle, compliance, terminal, preand post-test) self-assessment and closure time 13hoo 14hoo 14hoo 15hoo 15hoo 15h30 15h30 17hoo time 08h30 09h30 09h30 10hoo lohoo 13hoo 12h30 14hoo 09h30 lohoo lohoo 13 hoo 08h30 09h30 14h00 15hoo 15hoo 15h30 15h30 16h30 16h30 17hoo 13hoo 14hoo 14hoo 15hoo time 08h30 09h30 09h30 10hoo lohoo 13hoo 16h30 17hoo 15hoo 15h30 15h30 16h30 registration please send completed registration forms to the course co-ordinator management of hiv/aids course foundation for professional developmeni po box 74789 lynnwood ridge 0040 tel: (012) 481-2032/3 fax: (012) 481-2083 e-mail: foundation@samedical.org both the workshop and the self-study before the workshop will be submitted for accreditation for cpd poinis. we will keep you informed of any progress. an estimated 36 cpd points might be allocated for the course. you will never get this opportuniiy again because the course is heavily subsidised! further details on cost will soon be released. further information on dares and venues will be provided as soon as the demand is established. augus t ~oo booking form management of hiv/aids course surname initials title rrstname preferred name for nametag male female contact numbers tel{w) tel{h) fm cellphone number e-mail address postal address business name & address postal code postal code present occupation sama or denosa membership no have you attended any other fpd courses? 1. 2. 3. would you uke to receive more information on other please indicate at which venue you wish to attend the fpd courses? workshop: 0 management and business courses 0 medical ethics (distance education) c johannesburg o cpt'" and icd-l0 o cape town 0 medical terminology and anatomy o durban :j management of obesity o pretoria :::j rheumatology o port euzabeth 0 medical examination on proressional drivers c bloemfontein 0 mental health o nelspruit 0 debt collecting 0 practice pathology to ensure your place on the workshop please fak or post this form to fpd, po box 747b9, lynnwood ridge 0040, or fak to 012-481 2083 the foundation for professional development is a division of the sa medical association and is supported by an educational grant from nedbank professional bankiing [he southern african journal or hiv medic ne -----------august 200 i sajhiv 1025 reflections reflections on a decade of delivering pmtct in khayelitsha, south africa k stinson, mph, phd; j giddy, mb chb, mfammed; v cox, md; r burton, mrcog (uk), fcp (sa), cert id phys (sa); m ibeto, mb chb; c cragg, mb chb; g van cutsem, md, dtm&h, mph; k hilderbrand, bsc, msc; a boulle, mb chb, phd; d coetzee, mb bch, fcphm; e goemae re , md, dtm&h, phd corresponding author: k stinson (kathryn.stinson@uct.ac.za) kathryn stinson, vivian cox, maryirene ibeto, gilles van cutsem and eric goemaere represent médecins sans frontières, cape town, south africa. kathryn stinson, gilles van cutsem, katherine hilderbrand, andrew boulle, david coetzee and eric goemaere are affiliated with the centre for infectious disease epidemiology and research, school of public health and family medicine, university of cape town, south africa. janet giddy and carol cragg hail from the provincial department of health (metro district health services), khayelitsha and eastern substructure, western cape, south africa. rosie burton is from the khayelitsha district hospital, khayelitsha, cape town, south africa. implementation of a flagship pmtct programme in khayelitsha great progress has been made in the prevention of mother-to-child transmission (pmtct) of hiv in the past ten years in south africa, and this is reflected in the achievements of the health services in khayelitsha. located 56 km from the centre of cape town, khayelitsha has an estimated population of 500 000, with a 38% unemployment rate. forty-five per cent of the population live in formal housing. antenatal (anc) hiv seroprevalence increased from 19.3% in 2000 to 37% in 2011 and is the highest in the western cape.1 the provincial government of the western cape (pgwc) started the first pmtct programme in south africa in khaye­litsha as a primary-healthcare-level demonstration project on 4 january 1999, despite opposition by the national ministry of health. the school of public health and family medicine at the university of cape town was tasked with the monitoring of this pilot, and in september 1999, médecins sans frontières (msf) added technical support. voluntary counselling and testing (vct) was provided at one midwife obstetric unit (mou) and short-course zidovudine (azt) was dispensed by midwives from 36 weeks of gestation and during labour. later the pilot was extended to a second mou, and in 1999, 74% of pregnant women agreed to testing and 16% were found to be hiv-infected.2 initially, antiretrovirals were provided only to prevent transmission to the child. maternal azt was stopped after delivery and no further hiv services were available for treating the mother. continuity of care was poor as anc and postnatal child health services were fragmented and provided by different health authorities. a clinician at the time recalled, ‘on learning they were hiv-positive, women would commonly ask, “when am i going to die?” all we had to offer was treatment to reduce the risk of the baby being infected, but no treatment to keep the mother alive, to see her child grow up.’ after complex negotiations in february 2000, msf opened the first service for pregnant, hiv-infected women requiring antiretroviral therapy (art) in site b. msf extended the hiv services and art to everyone who was eligible, according to world health organization (who) guidelines, and to two further sites in khayelitsha. however, legal and regulatory barriers to generic antiretroviral imports delayed service implementation and drug supplies until 2001. postnatal women from the pmtct programme initially constituted the majority of art referrals.3 nine postnatal clinics provided free formula milk for those who elected to perform replacement feeding.2 , 4 despite scientific evidence on the effectiveness of pmtct, the aids-denialist views of president thabo mbeki and health minister manto tshabalala-msimang led to a significant delay in the development of the national pmtct programme, resulting in thousands of infant infections and subsequent deaths. in a landmark court case brought against the government by the treatment action campaign (tac), nevirapine (nvp) was made available nationally by order of the constitutional court in 2002 and a national pmtct programme was implemented. nvp was the regimen established in two ‘pilot sites’ per province. the implementation of the national programme was slow, with wide geographical variation. by this time, the khayelitsha pmtct sites were well established, and vct coverage was over 95%.3 implementation of more efficacious pmtct regimens the western cape was also the first to launch a province-wide pmtct programme by 2002/2003. faced with a difficult choice between national policy at that time (single-dose nvp) and the more complex regimens, such as azt from 28 weeks of gestation with the addition of single-dose nvp, a technical meeting was held with policy makers, researchers and clinicians, including representation from the perinatal hiv research unit (phru) and the french national agency for aids research (anrs). it was decided that both interventions were equally effective. the msf-supported khayelitsha sites moved to the more complex regimen in 2003, consisting of azt from 28 weeks of gestation and single-dose nvp given to all hiv-positive mothers in labour and to infants post delivery. the effectiveness of this programme at a primary care level was demonstrated in khayelitsha in 2004, when pmtct coverage was reported to be 77% and mother-to-child transmission 8.8%. 5 while the national pmtct programme continued to supply single-dose nvp for pregnant women, the western cape provided both azt and nvp in 2004 and enhanced the pmtct programme by expanding it throughout the province as a nurse-driven service within anc services and the mous. lessons learnt from programme implement­ation assisted the early development of art services for adults and children in the province.6 following delivery, women were referred to the three msf-supported art sites in khayelitsha, and new sites were established in 2003 in khayelitsha, langa and gugulethu, in addition to secondary and tertiary facilities. when the national provision of art was announced in 2004, organisations within the western cape had already changed priorities from demonstrating feasibility to targeting scale up and service integration. towards an integrated model of care for pregnant women requiring art in 2004, the western cape pmtct protocols were changed to include cd4+ count testing and referral of pregnant women with a cd4+ count ≤200 cells/µl, or who stage 4, defining conditions for art initiation. the treatment and care of pregnant women with advanced disease had been a part of global pmtct strategy since 2002, yet there was little evidence on the best approach for implementing art for pregnant women within vertical anc services in resource-poor settings. integrating the initiation of life-long art in pregnant women into anc services at a primary care level posed several challenges, including laboratory monitoring requirements, multiple anc visits, linkage to postpartum art, and clinical skills to manage both pregnancy and hiv. initially, pregnant women were referred to an existing art clinic before delivery. however, many women failed to link to care or did not receive art timeously. patients also complained of the burden of additional visits to fetch their treatment, as well as of transport challenges. msf thus began a pilot project to initiate eligible pregnant women on art within two khayelitsha mous in december 2004. this provided a fast-track system that streamlined services for providers and clients, and allowed late presenters to be initiated on art within a week. incorporating art services within the anc service was uncommon at the time, but it decreased loss to follow-up and limited delays by removing complex referral processes between facilities. pregnant women with a cd4+ count ≤200 cells/µl were fast-tracked for art through weekly preparation visits, which included intensified adherence counselling and routine art work-up. msf trained and supported a midwife, an enrolled nurse, counsellors, and an outreach team of two obstetric medical officers provided by msf and mowbray maternity hospital (mmh).7 implementation of nimart in pregnancy there were a number of challenges associated with the provision of art within mous, including staff shortages and turnover that required human resource planning and training. visiting community obstetricians from mmh did not get involved in art provision, as few were experienced in prescribing art. the integration model demonstrated functional separation, as a vertical art initiation service was provided by a medical officer in a separate room in the mou on specific days of the week. midwife-managed art initiation had been the objective of the integrated mou model, but it took six years to achieve this, despite well-managed and effective nurse-driven art services at adjoining art clinics. staff saw the provision of art at the anc consultation as an extra task to perform in an already busy service. however, a different approach was required when new national guidelines were released in 2010. the cd4+ threshold for eligibility for art was raised (to 350 cells/µl), thus increasing the proportion of women who qualified for art in pregnancy. this required task shifting and extending the prescribing capacity of midwives from dual regimens to providing art. following a successful pilot of nurse-driven art in lusikisiki and lesotho, where there was a scarcity of doctors,8 msf partnered with the pgwc to implement a nurse-initiated management of art (nimart) mentorship programme in khayelitsha in december 2011, with the first nimart-trained midwives providing art at the site b mou in may 2012. early on, midwives were initiating 95% of clients within a week of first presentation.9 there was strong support from midwives, and facility, programme and sub-district managers, and hiv integration and nimart became policy. midwives were excited by the nimart training: ‘for me, nimart is very interesting, in that it’s not something you do as a midwife. it puts you on another level. you see a patient; you diagnose and manage them. this is not what i was doing in the labour ward. i learnt a lot – about hiv, the drugs, everything.’ implementing option b+ in khayelitsha the announcement on world aids day in 2012 that south africa would shift from option a (azt for women with a cd4+ count >350 cells/µl) to option b (art for all pregnant and breastfeeding women irrespective of cd4+ count), highlighted the importance of nimart mentorship for nurse midwives and anc nurses. in july 2013, the site b mou in khayelitsha implemented option b+ (life-long art for pregnant and breastfeeding women), including fixed-dose combinations, a new counselling model to support same-day initiation, and more attention to viral load (vl) monitoring in pregnancy, using vl as a predictor of transmission. the rationale behind the introduction of option b+ was not only to prevent the transmission of hiv to the infant, but to create an entry point for lifelong art care for women and their families. with this change, the linkage of hiv-exposed infants to care, retention in care for mothers receiving art, as well as the provision of services which cater for male partners’ needs have become even more of a priority. the implementation of option b+ has been remarkably smooth. since 1 july 2013, an average of 70 80 women have been initiated on art monthly at the site b mou, and less than five women have refused to initiate treatment during this time. the fixed-dose combinations (fdcs) have made it easier for both staff and women. the adaptation of adherence counselling has led to shorter sessions that allow for same-day initiation, with increased post-initiation counselling being piloted in khayelitsha. despite the increased workload, midwives feel empowered and are passionate about their new role: ‘nowadays we manage their pregnancy and we also manage their hiv. i’m so committed that i don’t care if i’m the one who leaves last – i don’t mind. as long as i leave after seeing that every women who is eligible is initiated.’ the new challenge is to retain women on art and achieve sustained virological suppression. an evaluation of the option b+ programme is underway to study these outcomes. as more women who enter anc services are already receiving art (a quarter of the monthly new anc attendees with hiv), an adapted model to prevent, detect and manage treatment failure is needed. conclusion a large part of the success of the pmtct programme in khayelitsha has been due to progressive provincial policies, and a successful partnership between the provincial and local authority health services, academic institutions and non-governmental organisations such as msf and the tac, as well as dedicated managers and staff. khayelitsha is a severely disadvantaged and resource-limited area, and yet the pmtct programme has remained at the forefront of innovation and has evolved in line with advances in global best practice in art care. there is hope that in the not-too-distant future, paediatric hiv infection will become a disease of the past, read about in textbooks. acknowledgements. we thank the staff of the site b mou for their support in the compilation of this article. references 1. provincial department of the western cape. western cape antenatal hiv prevalence survey, 2011. cape town: provincial department of the western cape, 2011. 1. provincial department of the western cape. western cape antenatal hiv prevalence survey, 2011. cape town: provincial department of the western cape, 2011. 2. coetzee d, hilderbrand k, boulle a, et al. outcomes after two years of providing antiretroviral treatment in khayelitsha, south africa. aids 2004;18(6):887-895. [http://dx.doi.org/10.1097/01.aids.0000125925.87797.38] 2. coetzee d, hilderbrand k, boulle a, et al. outcomes after two years of providing antiretroviral treatment in khayelitsha, south africa. aids 2004;18(6):887-895. [http://dx.doi.org/10.1097/01.aids.0000125925.87797.38] 3. médecins sans frontières, university of cape town, western cape provincial department of health. antiretroviral therapy in primary health care: experience of the khayelitsha programme in south africa: case study. geneva: word health organization, 2003. 3. médecins sans frontières, university of cape town, western cape provincial department of health. antiretroviral therapy in primary health care: experience of the khayelitsha programme in south africa: case study. geneva: word health organization, 2003. 4. abdullah f. the arv programme in the western cape: best practice. continuing medical education 2005;23(5):261-263. 4. abdullah f. the arv programme in the western cape: best practice. continuing medical education 2005;23(5):261-263. 5. coetzee d, hilderbrand k, boulle a, draper b, abdullah f, goemaere e. effectiveness of the first district-wide programme for the prevention of mother-to-child transmission of hiv in south africa. bull world health organ 2005;83(7):489-494. 5. coetzee d, hilderbrand k, boulle a, draper b, abdullah f, goemaere e. effectiveness of the first district-wide programme for the prevention of mother-to-child transmission of hiv in south africa. bull world health organ 2005;83(7):489-494. 6. draper b, abdullah f. a review of the prevention of mother-to-child transmission programme of the western cape provincial government, 2003 2004. s afr med j 2008;98(6):431-434. 6. draper b, abdullah f. a review of the prevention of mother-to-child transmission programme of the western cape provincial government, 2003 2004. s afr med j 2008;98(6):431-434. 7. médecins sans frontières, university of cape town, health coctdo, western cape provincial department of health. comprehensive tb/hiv services at primary health care level: khayelitsha annual activity report, 2007 2008. cape town: médecins sans frontières, 2008. 7. médecins sans frontières, university of cape town, health coctdo, western cape provincial department of health. comprehensive tb/hiv services at primary health care level: khayelitsha annual activity report, 2007 2008. cape town: médecins sans frontières, 2008. 8. cohen r, lynch s, bygrave h, et al. antiretroviral treatment outcomes from a nurse-driven, community-supported hiv/aids treatment programme in rural lesotho: observational cohort assessment at two years. j int aids soc 2009;12:23. [http://dx.doi.org/10.1186/1758-2652-12-23] 8. cohen r, lynch s, bygrave h, et al. antiretroviral treatment outcomes from a nurse-driven, community-supported hiv/aids treatment programme in rural lesotho: observational cohort assessment at two years. j int aids soc 2009;12:23. [http://dx.doi.org/10.1186/1758-2652-12-23] 9. cox v, ibeto m, giddy j, stinson k. reasons for delay in antiretroviral treatment initiation after nurse midwife hiv/antenatal care integration in khayelitsha, south africa. sixth south african aids conference; june 2013; durban, south africa. 9. cox v, ibeto m, giddy j, stinson k. reasons for delay in antiretroviral treatment initiation after nurse midwife hiv/antenatal care integration in khayelitsha, south africa. sixth south african aids conference; june 2013; durban, south africa. s afr j hiv med 2014;15(1):30-32. doi:10.7196/sajhivmed.1025 hiv 850 original article hiv risk behaviour among public primary healthcare patients with tuberculosis in south africa k peltzer,1,2,3 phd, dr habil 1 hiv/aids/sti and tb (hast), human sciences research council, pretoria, south africa 2 department of psychology, university of limpopo, turfloop, south africa 3 asean institute for health development, mahidol university, salaya, thailand corresponding author: k peltzer (kpeltzer@hsrc.ac.za) objective. to identify factors associated with hiv in tuberculosis (tb) patients in a public primary healthcare (phc) setting in south africa (sa). method. among 4 900 consecutively selected tb patients (54.5% men; women 45.5%) from 42 public phc clinics in 3 districts in sa, a cross-sectional survey was performed to assess new tb and new tb retreatment patients within one month of anti-tb treatment. results. the sample comprised 76.6% new tb patients and 23.4% tb retreatment patients. of those who had tested for hiv, 59.9% were hiv-positive; 9.6% had never tested for hiv. in multivariate analysis, older age (odds ratio (or) 5.86; confidence interval (ci) 4.07 8.44), female gender (or 0.47; ci 0.37 0.59), residing in an informal settlement (or 1.55; ci 1.13 2.12), being a tb retreatment patient (or 0.55; ci 0.42 0.72), occasions of sexual intercourse with condom use (or 1.07; ci 1.02 1.13) and having a sexual partner receiving antiretroviral treatment (art) (or 7.09, ci 4.35 11.57) were associated with an hiv-positive status in tb patients. conclusion. this study revealed high hiv risk behaviour (e.g. unprotected last sexual intercourse and alcohol and drug use in the context of sexual intercourse) among tb patients in sa. various factors were associated with hiv risk behaviour. condom use and substance use risk reduction need to be considered as hiv-prevention measures when planning such strategies for tb patients. s afr j hiv med 2013;14(3):125-130. doi:10.7196/sajhivmed.850 south africa (sa) has 0.7% of the world’s population and 28% of the world’s population of hiv/tuberculosis (tb) co-infected individuals. 1 it has been estimated that approximately 60% of people with tb are co-infected with hiv. 1 co-infected patients have almost double the chance of acquiring multidrug(mdr-tb) and extensively drug-resistant tb (xdr-tb), and have a high mortality rate.2 several studies have found a high level of hiv risk behaviour (e.g. multiple sexual partners, lack of condom use, intravenous drug use) among tb/hiv co-infected patients receiving anti-tb treatment.3-6 factors associated with hiv status in tb patients have included female gender, age 26 35 years, unmarried marital status, a higher income, belonging to a specific population group and engaging in high-risk practices.3 , 4 , 7 the aim of this study was to identify factors associated with hiv in tb patients in public primary healthcare (phc) in sa. methods a cross-sectional survey was conducted among tb patients in public phc clinics in sa, in the three provinces with the highest tb caseload. one district with the highest tb caseload per province (n=3) was ultimately included in the study: siyanda in the northern cape, nelson mandela metropole in the eastern cape, and ethekwini in kwazulu-natal. within each district, 14 phc facilities (phc clinics or community health centres) were selected (n=42) on the basis of the highest tb caseload per clinic. healthcare providers identified all new tb treatment and retreatment patients aged ≥18 years, informed them about the study and referred them for participation, if interested. recruited patients were consecutively interviewed within one month of anti-tb treatment. interviews were conducted by trained external research assistants over a period of 6 months in 2011 in all 42 clinics. the research assistants asked for permission/consent from the recruited patients to participate in the interview. ethical approval was granted by the research ethics committee of the human sciences research council (protocol rec 1/16/02/11) and by the national department of health. measures socioeconomic characteristics a researcher-designed questionnaire was used to record information on participant age, gender, educational level, marital status, income, employment status, dwelling characteristics and residential status. poverty was assessed with 5 items on the availability or non-availability of shelter, fuel or electricity, clean water, food and cash income in the past week. response options ranged from 1 = ‘not one day’ to 4 = ‘every day of the week’. poverty was defined as having a higher score on non-availability of essential items. the total score ranged from 5 to 20; 5 = low, 6 12 = medium and 13 20 = high poverty. cronbach’s α for the poverty index was 0.89 in this sample. psychological distress the kessler psychological distress scale (k-10) was used to measure global psychological distress, including significant pathology that did not meet the formal criteria for a psychiatric illness.8 , 9 the following symptoms were assessed by asking: ‘in the past 30 days, how often did you feel: nervous; so nervous that nothing could calm you down; hopeless; restless or fidgety; so restless that you could not sit still; depressed; that everything was an effort; so sad that nothing could cheer you up; worthless; tired out for no good reason?’ the frequency with which each of item was experienced was recorded using a five-point likert scale ranging from 0 = ‘none of the time’ to 5 = ‘all the time’. this score was summed, with increasing scores reflecting an increasing degree of psychological distress. this scale serves to identify individuals who are likely to meet formal definitions of anxiety and/or depressive disorders, as well as to identify individuals with sub-clinical illness who may not meet formal definitions for a specific disorder.8 the scale has been validated in hiv-positive individuals in sa.10 there was significant agreement between the k-10 and the mini-defined depressive and anxiety disorders. a receiver operating characteristic (roc) curve analysis indicated that the k-10 showed agreeable sensitivity and specificity in detecting depression (area under the roc curve (auc) 0.77), generalised anxiety disorder (auc 0.78) and post-traumatic stress disorder (auc 0.77).10 the k-10 scale was used as a binary variable comparing scores ≥30 or <30. the internal reliability coefficient for the k-10 was α=0.92. alcohol consumption the 10-item alcohol use disorders identification test (audit)11 assesses alcohol consumption level (3 items), symptoms of alcohol dependence (3 items) and problems associated with alcohol use (4 items). heavy episodic drinking is defined as the consumption of ≥6 standard drinks (10 g alcohol) on a single occasion.11 a standard drink in sa is equivalent to 12 g of alcohol. because the audit is reported to be less sensitive at identifying risk drinking in women, as recommended by freeborn et al.,12 the cut-off point for binge drinking in women (4 units) was reduced by one unit compared with that for men (5 units). responses to items on the audit are rated on a 4-point likert scale from 0 to 4 (maximum score 40 points). a higher audit score indicates a more severe level of risk: a score ≥8 indicates a tendency to problematic drinking. the audit has been validated in hiv-positive patients in sa, showing excellent sensitivity and specificity in detecting mini-defined dependence/abuse (auc 0.96),13 and among tb and hiv patients in phc in zambia, demonstrating good discriminatory ability in detecting mini-defined current alcohol use disorders (audit 0.98 for women and 0.75 for men).14 cronbach’s α for the audit in this sample was 0.92, indicating excellent reliability. tobacco use two questions were asked about the use of tobacco products: (i) ‘do you currently use one or more of the following tobacco products (cigarettes, snuff, chewing tobacco, cigars, etc.)?’ (response options were ‘yes’ and ‘no’); and (ii) ‘in the past month, how often have you used one or more of the following tobacco products (cigarettes, snuff, chewing tobacco, cigars, etc.)?’ (response options were: ‘once or twice’, ‘weekly’, ‘almost daily’ and ‘daily’). current tobacco use was defined as having used any tobacco product in the past month. perceived general health participants were asked: ‘in general, would you say your health is: excellent, very good, good, fair or poor?’ this measure was categorised based on participant response (very good = excellent/very good; good; and poor = fair/poor). tb treatment, hiv and antiretroviral therapy (art) status were assessed by self-report and from medical information. hiv risk behaviour was assessed in terms of the following: whether or not the participant was sexually active in the past 3 months; whether or not the last occasion of sexual intercourse was unprotected; the number of occasions of sexual intercourse with condom use in the past 3 months; the number of occasions of sexual intercourse without condom use in the past 3 months; alcohol use before sexual intercourse in the past 3 months; illegal drug use before sexual intercourse in the past 3 months; whether or not the participant had disclosed his/her hiv status to the sexual partner; the hiv status of the sexual partner; and the art status of the sexual partner. data analysis data were analysed using spss software (version 19.0). frequencies, means and standard deviations (sds) were calculated to describe the sample. data were checked for normality distribution and outliers. for non-normal distribution, non-parametric tests were used. associations of hiv status were identified using logistic regression analyses. following each univariate regression, multivariate regression models were constructed. independent variables from the univariate analyses were entered into the multivariate model if significant at p<0.05. for each model, the r2 values were calculated to describe the amount of variance explained by the multivariate model. a p-value <0.05 was regarded as statistically significant. results from the sample (n=4 935) approached for inclusion in the study, 35 (0.7%) patients declined the request to participate. the final sample included 4 900 patients (54.5% men; 45.5% women) of mean age 36.2 years (sd ±11.5; range 18 93). almost two-thirds (65.2%) were aged 25 44 years, most (72.7%) were never married, 27.7% had completed secondary education, 17% scored high on the poverty index, 24.2% had a formal salary as a main household income, and 58.9% were unemployed. a significant number of participants (15.3%) lived in informal settlements (table 1). health and hiv risk characteristics of the total sample, 76.6% were new tb patients and 23.4% were tb retreatment patients. of those who had tested for hiv, 59.9% were hiv-positive; 9.6% had never tested for hiv. more than 1/4 patients (27.6%) were current (past month) tobacco users, 26.3% had severe psychological distress, and 46.3% perceived their health status as fair or poor. regarding sexual risk behaviour, 54.9% had had unprotected sexual intercourse on the last occasion thereof, and 20.9% had used alcohol and 9.3% illegal drugs before sexual intercourse in the past 3 months. two-thirds (63.9%) of the participants had disclosed their hiv status, 27.2% had a sexual partner who was hiv-positive and 11.1% had a sexual partner who was receiving art (table 2). hiv status, socioeconomic factors, health status and hiv risk behaviour in univariate analysis, the following were associated with an hiv-positive status among tb patients: older age; female gender; not being poor; black race; residing in an informal settlement; being a tb retreatment patient; poor perceived health status; not currently using tobacco products; not being sexually active in the past 3 months; having unprotected sexual intercourse on the last occasion thereof; the number of occasions of sexual intercourse with condom use; hazardous or harmful alcohol use; alcohol use before sexual intercourse in the past 3 months; drug use before sexual intercourse in the past 3 months; and having a sexual partner who was receiving art. in multivariate analysis, the following were associated with an hiv-positive status in tb patients (table 3): older age; female gender; residing in an informal settlement; a tb retreatment status; number of occasions of sexual intercourse with condom use; and having a sexual partner who was receiving art. discussion this study revealed a high prevalence (59.9%) of co-infection with hiv among a large sample of tb patients in public phc in sa, similar to the findings of other studies (60%).1 further, there was a high level of hiv risk behaviour (last occasion of sexual intercourse unprotected, and alcohol and drug use in the context of sexual intercourse), in agreement with other studies.3-6] this is alarming, given the high rate of hiv/tb co-infection at a national level in sa.1 the dual epidemics of hiv and tb have become a public health priority, and this is beginning to receive increasing attention from the national department of health as specified in the national strategic plan 2012 2016.15 tb cannot, therefore, be managed as a single disease entity. a comprehensive treatment and prevention programme for tb, hiv and indeed other co-morbid disorders is required to meet this public health challenge. in the context of this study, condom use and substance use risk reduction need to be considered as hiv-prevention measures when planning hiv-prevention programmes for tb patients. in multivariate analysis, older age, female gender, residing in an informal settlement, being a tb retreatment patient, occasions of sexual intercourse with condom use, and having a sexual partner receiving art were associated with hiv-positive status in tb patients. in agreement with other studies,3 sociodemographic variables (female gender and older age) were associated with hiv status in tb patients. in contrast, unlike in other studies,3 , 4 , 7 marital status, income, population group and engaging in high-risk practices were not associated with an hiv-positive status. furthermore, tb retreatment patients were more likely to be hiv-positive than new tb treatment patients. these data provide information to inform hiv-prevention strategies. study limitations caution should be taken when interpreting the results of this study because of certain limitations. as this was a cross-sectional study, causality between the compared variables cannot be concluded. a further limitation was that most variables were assessed by self-report and desirable responses may have been given. the population surveyed originated predominantly from urban areas, and may not be representative of other settings in sa. conclusion this study revealed a high hiv risk behaviour among tb patients in sa. various factors were identified associated with this behaviour, providing information for hiv-prevention strategies. condom use and substance use risk reduction need to be considered as hiv-prevention measures when planning hiv-prevention programmes for tb patients. acknowledgement. this study was funded by a national department of health tender (‘ndoh: 21/2010-2011 implementation and monitoring of screening and brief intervention for alcohol use disorders among tuberculosis patients’) awarded to the human sciences research council. references 1. world health organization. global tb control report 2010. geneva, switzerland: who, 2010. 1. world health organization. global tb control report 2010. geneva, switzerland: who, 2010. 2. national department of health. tuberculosis strategic plan for south africa, 2007 2011. pretoria: doh, 2007. 2. national department of health. tuberculosis strategic plan for south africa, 2007 2011. pretoria: doh, 2007. 3. talbot ea, kenyon ta, moeti tl, et al. hiv risk factors among patients with tuberculosis – botswana 1999. int j std aids 2002;13(5):311-317. 3. talbot ea, kenyon ta, moeti tl, et al. hiv risk factors among patients with tuberculosis – botswana 1999. int j std aids 2002;13(5):311-317. 4. theuer cp, hopewell pc, elias d, et al. human immunodeficiency virus infection in tuberculosis patients. j infect dis 1990;162(1):8-12. 4. theuer cp, hopewell pc, elias d, et al. human immunodeficiency virus infection in tuberculosis patients. j infect dis 1990;162(1):8-12. 5. degefa t. survey of protective behaviour practiced against hiv/aids in adult tb patients at almata zonal hospital. ethiop med j 2006;44(2):105-112. 5. degefa t. survey of protective behaviour practiced against hiv/aids in adult tb patients at almata zonal hospital. ethiop med j 2006;44(2):105-112. 6. mankatittham w, likanonsakul s, thawornwan u, et al. characteristics of hiv-infected tuberculosis patients in thailand. southeast asian j trop med public health 2009;40(1):93-103. 6. mankatittham w, likanonsakul s, thawornwan u, et al. characteristics of hiv-infected tuberculosis patients in thailand. southeast asian j trop med public health 2009;40(1):93-103. 7. todd cs, barbera-lainez y, doocy sc, et al. prevalence of human immunodeficiency virus infection, risk behavior, and hiv knowledge among tuberculosis patients in afghanistan. sex transm dis 2007;34(11):878-882. [http://dx.doi.org/10.1097/olq.0b013e318095068a] 7. todd cs, barbera-lainez y, doocy sc, et al. prevalence of human immunodeficiency virus infection, risk behavior, and hiv knowledge among tuberculosis patients in afghanistan. sex transm dis 2007;34(11):878-882. [http://dx.doi.org/10.1097/olq.0b013e318095068a] 8. kessler r, andrews g, colpe lj, et al. short screening scales to monitor population prevalences and trends in nonspecific psychological distress. psychol med 2002;32:959e976. 8. kessler r, andrews g, colpe lj, et al. short screening scales to monitor population prevalences and trends in nonspecific psychological distress. psychol med 2002;32:959e976. 9. kessler rc, barker pr, colpe lj, et al. manderscheid rw, walters ee, zaslavsky am. screening for serious mental illness in the general population. arch gen psychiatry 2003;60(2):184e189. 9. kessler rc, barker pr, colpe lj, et al. manderscheid rw, walters ee, zaslavsky am. screening for serious mental illness in the general population. arch gen psychiatry 2003;60(2):184e189. 10. spies g, kader k, kidd m, et al. validity of the k-10 in detecting dsm-iv-defined depression and anxiety disorders among hiv-infected individuals. aids care 2009;21(9):1163-1168. [http://dx.doi.org/10.1080/09540120902729965] 10. spies g, kader k, kidd m, et al. validity of the k-10 in detecting dsm-iv-defined depression and anxiety disorders among hiv-infected individuals. aids care 2009;21(9):1163-1168. [http://dx.doi.org/10.1080/09540120902729965] 11. babor tf, higgins-biddle jc. brief intervention for hazardous and harmful drinking a manual for use in primary care. geneva, switzerland: world health organization department of mental health and substance dependence, 2001. 11. babor tf, higgins-biddle jc. brief intervention for hazardous and harmful drinking a manual for use in primary care. geneva, switzerland: world health organization department of mental health and substance dependence, 2001. 12. freeborn dk, polen mr, hollis jf, senft ra. screening and brief intervention for hazardous drinking in an hmo: effects on medical care utilization. journal of behavioral health services research 2000;27(4):446-453. 12. freeborn dk, polen mr, hollis jf, senft ra. screening and brief intervention for hazardous drinking in an hmo: effects on medical care utilization. journal of behavioral health services research 2000;27(4):446-453. 13. myer l, smit j, roux ll, parker s, stein dj, seedat s. common mental disorders among hiv-infected individuals in south africa: prevalence, predictors, and validation of brief psychiatric rating scales. aids patient care stds 2008;22(2):147-158. [http://dx.doi.org/10.1089/apc.2007.0102] 13. myer l, smit j, roux ll, parker s, stein dj, seedat s. common mental disorders among hiv-infected individuals in south africa: prevalence, predictors, and validation of brief psychiatric rating scales. aids patient care stds 2008;22(2):147-158. [http://dx.doi.org/10.1089/apc.2007.0102] 14. chishinga n, kinyanda e, weiss ha, patel v, ayles h, seedat s. validation of brief screening tools for depressive and alcohol use disorders among tb and hiv patients in primary care in zambia. bmc psychiatry 2011;11:75. [http://dx.doi.org/10.1186/1471-244x-11-75] 14. chishinga n, kinyanda e, weiss ha, patel v, ayles h, seedat s. validation of brief screening tools for depressive and alcohol use disorders among tb and hiv patients in primary care in zambia. bmc psychiatry 2011;11:75. [http://dx.doi.org/10.1186/1471-244x-11-75] 15. national department of health. national strategic plan for hiv and aids, stis and tb, 2012 2016. pretoria: doh, 2011. http://www.doh.gov.za/docs/stratdocs/2012/nspfull.pdf (accessed 1 july 2013). 15. national department of health. national strategic plan for hiv and aids, stis and tb, 2012 2016. pretoria: doh, 2011. http://www.doh.gov.za/docs/stratdocs/2012/nspfull.pdf (accessed 1 july 2013). hiv editorial_in.indd september 2014, vol. 15, no. 3 sajhivmed 75 e d it o r ia l �is edition of the journal, released to coincide with the southern african hiv clinicians society’s biannual conference, showcases local clinical research in keeping with the conference theme, ‘excelling in clinical care’. in their forum article, geffen et al.[1] open the issue with a call for two potentially significant adaptations to the ‘one size fits all’ policies that characterise many public sector services, to deliver antiretroviral therapy across southern africa. paediatric neurological and psychiatric complications are an area of particular complexity in hiv management, and to help primary care providers investigate, diagnose and manage children, nassen et al.[2] have produced simple yet comprehensive guidelines. two submissions explore the prevention of mother-to-child transmission of hiv from very different perspectives. first, pillay et al.[3] investigate the potential role of dc-sign and related molecules in the vertical transmission of hiv. shifting from molecular methods to health systems perspectives, ibeto et al.[4] explore the patientand service-level factors that may contribute to hiv transmission at a population level. two articles showcase strong examples of local clinical research. working in kwazulu-natal, kudsk-iversen et al.[5] describe the challenges in diagnosing and managing patients presenting with diarrhoea in a district hospital, pointing to the need for clearer guidelines – a possible future focus of the society. sogbanmu et al.[6] document the challenges in implementing guidelines for the management of cryptococcal meningitis in the eastern cape. these two articles demonstrate the importance of locally appropriate guidelines to support clinical care. i hope that you enjoy this issue of the journal and the conference. for those of you who cannot attend the sessions in cape town, we will run the best abstracts from the meeting in the december edition. happy reading. landon myer school of public health & family medicine university of cape town landon.myer@uct.ac.za references 1. ge�en n, robinson r, venter f, low m. one size doesn’t �t all: tailoring adult antiretroviral treatment. southern african journal of hiv medicine 2014;15(3):77-78. [http://dx.doi.org/10.7196/sajhivmed.1095] 2. nassen r, donald k, walker k, et al. management of mental health disorders and central nervous system sequelae in hiv-positive children and adolescents. southern african journal of hiv medicine 2014;15(3):8196. [http://dx.doi.org/10.7196/sajhivmed.1091] 3. pillay k, cloete m, mcleod h. expression of dc-sign and dc-signr in placentas of hiv-positive patients. southern african journal of hiv medicine 2014;15(3):97-101. [http://dx.doi.org/10.7196/sajhivmed.1094] 4. ibeto m, giddy j, cox v. closing the gaps: steps towards elimination of mother-to-child transmission of hiv. southern african journal of hiv medicine 2014;15(3):108-109. [http://dx.doi.org/10.7196/sajhivmed.1047] 5. kudsk-iversen s, gilbert jp, azarath a. management of patients presenting with diarrhoea to a regional emergency department in kwazulu-natal: call for clearer, more relevant guidance. southern african journal of hiv medicine 2014;15(3):102-103. [http://dx.doi.org/10.7196/sajhivmed.1082] 6. sogbanmu oo, john ma, lalloo u. management of cryptococcal meningitis in adults at mthatha hospital complex, eastern cape, south africa. southern african journal of hiv medicine 2014;15(3):104-107. [http://dx.doi.org/10.7196/sajhivmed.991] m e s s a g e s message from the editorn o n e s h a l l b e d e n i e d s4 reg. no. 44/20.2.8/0779 odimune tenofovir df 300 mg emtricitabine 200 mg efavirenz 600 mg “simplify, simplify.” henry david thoreau fdc philosopher cipla medpro (pty) ltd. reg. no. 1995/004182/07, building 9, parc du cap, mispel street, bellville, 7530, rsa. tel (021) 943 4200, fax (021) 914 4699. e-mail: medicalpa@ciplamedpro.co.za website: www.cipla.co.za customer care: 080 222 6662 who pre-qualified 3-in-1 once daily fixed dose combination r390.001 fda approved recommended as preferred 1st line regimen by national and international guidelines 2,3 reference: 1. sep excl. vat as per pcd february 2014. 2. the use of antiretroviral drugs for treating and preventing hiv infection (who guidelines-june 2013). 3. the south african antiretroviral treatment guidelines 2013. t~f sout~hin mrican journal of ~iv mfoicinf ----------novfmefr 2000 care access m jheywood, ba hof/s (oxford university> head: aids low projecf, and centre for applied legal studies, university of the witwatersralld the capacity of sa's health infrastructure to expand access to treatment during the management of most hiv-infected people, clinicians will reach a point where 'care' requires access to prophylaxis for the treatment of opportunistic infections (ols), and ideally to antiretroviral (arv) therapy at the moment, however, only two groups of people are able to access effective arv treatment: the small minority who can afford it and a small minority of poor people who are taking part in clinical trials. in the context of the current scientific knowledge about the benefits of effective management of ols and the proper use of arvs, this is a profound challenge to the principles of medicine and public health. regrettably, when calls are made by groups such as the treatment action campaign [tac) to expand access to arv treatment, hiv/aids clinicians, government officials and regrettably, however, the provision of pre-test counselling remains the exception rather than the rule. in reality the unlawful malpractice of private and public clinicians often coincides from different vantage points. in the private sector it seems that the objective of getting people in and out of the surgery door within pre-set times does not allow for effective counselling. this occurs particularly in relation to antenatal screening. in the public sector, in contrast, the genuine lack of trained counsellors and the pressure of large numbers of patients are used to justify the frequent argument that obtaining informed consent is 'not realistic: the consequence is that many people are diagnosed with hiv without an understanding of their status. these people are later accused of causing new hiv infections because of their inability to disclose their hiv status to their sexual partners; something that could have been avoided if they had been properly pre-test counselled. the same arguments could be made in relation to confidentiality. the promise of confidentiality (even if not absolute) is necessary to encourage wider take-up of hiv testing and treatment. yet breaches of confidentiality and a profound lack of appreciation of its importance even from a medical perspective remain the norm. it is therefore vital for the hiv clinicians society to take a very public stand on these psychotherapeutic ingredients of good practice, and to defend confidentiality and informed consent as essential aspects in the care and management of people with hiv. among other things this means lobbying for increased public health expenditure and sufficient resources for the provision of counsellors, as well as ensuring knowledge of and compliance with the guidelines of the hpcsa.' hiv testing confidentiality and informed consent hiv/aids presents a health and development emergency of unprecedented proportions. in the words of epidemiologist kevin de cock, it 'threatens to do more to undermine development in africa in the 21st century, than slavery did in the nineteenth' (comments made at the unaids!who consultation on hiv reporting and disclosure, october 1999). faced with this threat an extraordinary duty faits on health professionals. the formation of the southern african hiv clinicians society has been a very important step in the regional response to the aids epidemic, and the emergence of this institution invites a frank discussion of the responsibilities of 'clinicians' who work in the field of hiv/aids. the aim of this article, therefore, is to elucidate some of these responsibilities from a human rights perspective and to argue that clinicians must more visibly confront different responsibilities at different ends of the spectrum in the continuum of care for people with hiv/aids. the aids epidemic dictates that clinicians engage with public health, and not just confine themselves to medicine' underlying this discussion is an appeal for better collaboration between 'activists' and clinicians around a plan to improve understanding of hiv in society as rapidly as possible and to discuss treatment possibilities. this is a necessary step in the campaign to extend access to effective treatment against hiv to all people with hiv!aids in south africa. in this context three major issues must be considered: • the clinician's duties in relation to hiv testing, particularly in relation to confidentiality and informed consent; • the suitability of the available health care infrastructure with regard to expanding access to treatment; and • the role that clinicians should play in advocacy directed at pharmaceutical companies and the government. clinicians as public health advocates: the need for health professionals to be more vocal in campaigns to extend access to effective hivjaids treatment hiv is an unusual disease. because of the long asymptomatic phase of hiv infection, infection with hiv requires a higher degree of self-management and understanding of the condition on the part of the person infected than is the case in many other illnesses. this is one reason for the emphasis that has evolved on pre-test counselling, a duty that has not only become a part of medical ethics (first elaborated in 1993 in the south african medical and dental council guidelines on the management of patients with hiv and aids), but also a legal requirement' there is no dispute that with regard to hiv the continuum of care starts before the hiv test is even performed with thorough counselling. novf:mefr ;jooo -----------m southhln african journal of hiv medicine pharmaceutical companies respond with a joint refrain: 'insufficient infrastructure and the dangers of poor adherence in developing countries: however, as recent research in poor communities in the usa and brazil has shown, there is no inherent barrier to drug adherence among poor people pointing to an important role for clinicians. where an effort is made to raise the level of understanding with regard to hiv disease and treatment by assisting community-based organisations to raise levels of 'treatment literacy', compliance is improved. 'infras ructure', on the other hand, is evoked to draw attention to a lack of capacity to diagnose hiv and to counsel and monitor compliance, as well as to lack of sophisticated laboratory facilities to measure cd4+, viral load and drug resistance. this response does not stand up to scrutiny. health infrastructure should not be assessed using the lowest common denominator. debates about infrastructure should not exclude the capacity of the private health sector to provide services and treatment. in 199b, south africa had 162 private hospitals [with a total of 21 000 beds): 6b regional hospitals, 281 district hospitals, and approximately 3 000 clinics. there is also an extensive network of private laboratory services. if we are really dealing with a national emergency, all of these resources should be marshalled towards assisting with hiv prevention and care. if a horizontal approach is taken towards available infrastructure (i.e. if one that looks in all directions rather than merely up and down), then the reality quickly emerges that south africa already has surplus capacity with which to expand access to hiv testing, counselling and effective medicines. between 1990 and 1998 the private hospital sector grew by 33%, and increased by 8 000 beds.' this is evidence that health infrastructure can be quickly expanded particularly if the expansion is dictated by the need to prevent and treat illness rather than by profitability. on this basis, with government commitment and commitment on the part of the private sector and private practitioners to a genuine partnership against aids, it would be possible to expand access to treatment immediately. the brazilian experience is relevant to this discussion from a number of perspectives. like south africa, brazil is a developing country. it, too, has only recently emerged from years of dicta orship and its government faces a legacy of foreign debt, wide income disparities and a profound disjuncture between the metropolitan and rural areas. in many ways the brazilian and south african epidemics have followed similar courses. both epidemics began in the early 1980s among men who have sex with men [msm) (and in brazil also among injecting drug users), and moved increasingly into the rest of the population, particularly among the poor and marginalised' however, brazil differs from south africa in its consistent response to aids a response that has by no means halted the epidemic, but has slowed it down and made it more manageable. what is unique about brazil's response has been its commitment to integrating and expanding access to treatment into its general hiv/aids prevention strategy. in a recently published unaids best practice booklet this is described as 'a degree of national daring ... that goes against many of the recommendations on how a developing country ought to manage the epidemic:table i provides a brief chronology of significant developments in brazil. the last decade of the brazilian experience proves conclusively that health infrastructure is not created in a vacuum. it is created by need. in the words of unaids, infrastructure developed 'on becoming indispensable instruments in the clinical laboratorial follow-up of hiv patients under antiretroviral therapy .. (and) contributed to the optimization and more rational use of medicines'.8 in other words, public infrastructure develops when a government acts on the recognition that access to all dimensions of health care is a human right as well as a public health imperative in hiv prevention.' other very tangible benefits have accrued from treating aids. most obvious has been the government's ability to manufacture essential medicines and bring down imported drug prices once it embarked upon a real as opposed to a theoretical programme of treatment." finally, the public health benefits of these policies are indisputable. in sao paulo and rio de janeiro there has been a 48% reduction in the number of deaths among male patients since 1995. throughout brazil there has been a reduction in rate of hospital admissions, length of stay, and incidence of opportunistic infections, with tangible cost savings such as an 11% drop in the total national consumption of ganciclovir between 1996 and 1998." in order to achieve this government expenditure on drugs has been high us$356 million in 1999. however, in addition to the impact that access to treatment has had on human life and dignity, the programme has resulted in estimated savings for the government public health network of us$422 million between 1997 and 1999. in the words of the brazilian government: :.. the savings on internments, on welfare and on the number of years-of-life gained show clear signs of a guaranteed sound cost-benefit ratio: the outcomes of this 'daring' policy are evident. in 1997 brazil (6bth) was relatively close to south africa (90th) in its ranking on the united nations development programme's annually-revised human development index (hdi), which includes in its measurement average life expectancy. public expenditure on health was 2.b% as opposed to 3.2% in south africa. at that time aids cases per 100 000 people were 6 and 6.8% respectively. however, by the year 2000 the picture had changed dramatically. south africa's position on the hdi had dropped to 103rd, a decline that the undp attributes squarely to 'the drop in life-expectancy due to aids" cunictans as treatment advocates the brazilian experience is provided to try to convince health professionals to become better advocates for a public policy to expand access to treatment. groups such as the south african medical association (sama) need to be more outspoken in identifying and confronting the obstacles to expanded treatment access. the durban declaration is an example of an intervention that was both strategic and timely. although the declaration was literally trashed by the south africa government, it was not adversarial, merely a clear statement of medical science with regard to the virology of hiv and the aetiology of hiv and aids. a similar consensus statement on the efficacy of drugs used to treat hivand the imperative to overcome obstacles to treatment would be welcome. but this would compel clinithe southhln african journal of hiv medicine ----------november 2000 table i. actions speak louder than words: a short chronology of brazil's commitment to expanding treatment 1988 after years of military dictatorship brazil adopts a new democratic constitution that defines health care as a social right 1991 the national programme for std and aids decides to buy and distribute arv medicines. 1996 in the immediate aftermath of the vancouver international aids conference. which reported on breakthroughs in the use of highly active arv therapy (haard. a law is passed establishing the right to free medication. the objective is to 'ensure access to arvs to l()()qij of identified hiv patients in the country'.17 1996measures are taken to train health professionals, manufacture generic drugs. and 2000 to develop infrastructure for drug distribution and monitoring. the decision to provide treatment also created a necessity to establish a national system of quality of laboratory tests for std and aids and a system of logistic control of medicines. 1999 87 500 public patients are in receipt of aids-related drugs. 1999 270 services in the country have arvs available and outpatient follow-up for people with hiv. by july 1999 the national cd4+ network had 70 units, while the viral loads network had 55 units, performing 252000 and 165 000 tests a year. cians to break their silence on the unjustifiably high price of patented drugs. a recent report by medecins sans frontieres (msf) illustrates how pricing affects access" the report states the obvious: 'doctors need drugs to care for hiv infected people. without them they are simply managing decline and death. these drugs must be available, affordable and properly used: advocacy concerning affordability is not a political issue. it is an issue of social policy and the common good. it does not require that clinicians adopt a stance that is anti patent or anti-profit rather one that is ardently pro public health. drastic and unconditional price reductions would allow the most rational distribution and allocation of medicine according to need and capacity to distribute and dispense." unfortunately, the impression is that many hiv clinicians are unwilling to do this. the reasons are not too hard to decipher. to practice medicine it is necessary to have access to medicines. thus far, government has failed to supply clinicians with this indispensable tool for practice. consequently many clinicians have been drawn to the private health sector, or while continuing to work in the public sector, they have entered into relationship with phar-maceutical companies, with access to certain drugs achieved through conducting clinical trials." a relationship of almost feudal vassalage is at risk of . developing. forthright and sustained criticism of the price of drugs becomes difficult when major pharmaceutical companies are sponsoring clinical trials and scientific conferences. hence, the inclination to adopt the infrastructure escape clause, rather than confront the issue of pricing.'" conclusion dn 9 july 2000 in durban the global march for access to treatment handed over a memorandum to the minister of health, the director of unaids and the president of the international aids society (ias). a section of this memorandum saluted the contribution of clinicians to understanding hivand to research into treatments and vaccines. it called on clinicians to 'make your voices heard side-by-side with us in demanding additional public funding and the best use of medicines for the greatest number of people' and to 'publicly quantify and demand the funds that you consider necessary for urgent and relevant vaccine research, the development of effective microbicides and antiretroviral therapies that are easier to use by children and adults in countries where there is a shortage of food, water and electricity: it also requested the ias to 'initiate and coordinate an international scientific collaboration on a plan and timeframe for research: the southern african hiv clinicians society has an important part to play in these efforts. we believe that clinicians must base their actions on south africa's constitutional obligation to respect equality and promote and progressively realise the 'right of access to health care services: an alliance with public health activists around advocacy, improving treatment literacy and expanding access to treatment is a sure way of achieving these objectives. end notes 1. jonathan mann distinguished medicine from public health as follows: 'public health identifies and measures threats to the health of populations, develops governmental policies in response to these: concerns, and seeks to assure ct'rtain health and related services. in contrast, medical care focuses upon individuals diagnosis, treatment, relief of suffering, and rehabilitation: medicine and public health, ethics and human rights, health and human rights: a &ader, eds mann, gruskin, grodin, annas, 1999, routledge. 2. in a case known as cvminister of correctionoiservices, the judge found that 'it is axiomatic that there can only be consent if the person appreciates and understands what the object and purpose of the test is, what an hiv positive result entails and what the probability of aids occurring thereafter is: the 1993 samdc guidelines are currently being revised by the health professions council. 4. 1998 south african health review, health systems trust, 1998, p. 148. 5. hst, 199b. 6. see: unalds 8est practicesthe brazilian response to hiv/alds, 200cl, chapt 2, epidemiology. the initial profile of transmission, characterised by the predominant spread of hiv among educated msm of a high socio-economic level. similar to north america and europe, gradually altered in the direction of heterosexual transmission concentrated in marginalised and impoverished sections of the population: p. 19. 7. unalds. the brazilian response to hiv/a1ds, 2000, p. 15. 8. see: unalds, the brazilian response to hlv/a1ds, 200cl, especially chapt 3, care and treatment; also ministry of health, the brazilian std and aids programme. care and treatment, 200cl. 9. it is important to underline here that the approach adopted by the sa government, whereby 'prevention is the only cure', excludes from the national effort all those who are already infected and is a disinct'fltive for voluntary hiv testing. by contrast the prospect of expanded access to treatment will encourage testing and thus play a direct part in prevention. 10. the annual cost of double therapy with nudeoside analogues decreased on average by 8~ between 1996 and 2000... for triple therapy the cost reduction was 36llb over the same period: unaids, report of the global hlvfalds epidemic, june 2000, p. 102. 11. unalos, the brazilian response to hlvfalds, p.45. 12. undp human development report 2000,150. 13. hlvfalds medicines pricing report setting objectives: is there political will? msf, july 2000. 14. drug donations are lsometimesl welcome. but they do not address underlying issuesdonations to the public sector, such as the recent restrictive offer of free dlflucan by pfizer, ignore the fact that many poor people seek health care through the private sector. restricting donations to the public providers risks adding to the disjuncture between public and private health care, as poor people afe compelled to turn back to the public sector in order to ~s essential medicines15. 1998 health systems trust sa health review shows how 'most recent graduates are employed in the public sector, and nolo of all doctors who qualified in the previous 5 years are working in this sector. in contrast 10 years following qualification, the majority are working in the private sector. p. 150. 16. this situation creates a self-perpetuating vicious circle whose adverse consequences for medicine are enormous. willing buyers are created among clinicians through the advertising and sponsorship campaigns of research-based pharmacetjocal companiessimilarly, clinicians are placed in situations of very dubious ethics when they engage in 'short-course' drug trials to find a regimen of reasonable efficacy, where the main rationale for the trial is to try to make the intervention affordable something that could be done much more easily by reducing drug prices17. unalds, the brazilian response to hiv/alos, 200cl, p_ 41 december 2009                                                          the southern african journal of hiv medicine                                                  20 in resource-limited settings, infant feeding is the weakest link in programmes to prevent mother-to-child transmission of hiv. although new perinatal hiv infections have been almost eliminated in resource-rich settings, elimination of new paediatric infections remains elusive in resource-limited settings, where hiv transmission through breastmilk accounts for approximately 40% of new infections. 1 over the past 5 years, rigorously designed research, using varied study designs, has increased our knowledge about hiv transmission through breastmilk almost exponentially. however, implementing these findings has lagged far behind. a review of data shows that challenges to implementing current policies on infant feeding and hiv can be categorised into four main areas: (i) health care provider confusion about infant feeding and the risks of hiv transmission through breastfeeding; 2,3 (ii) poor support for infant feeding counsellors – qualitative research from tanzania revealed a high level of stress and frustration among nurse counsellors, who were confused about the appropriateness of infant feeding options in the context of hiv; 4 (iii) poor counselling skills 5,6 – in three south african sites, structured observations of 22 counsellors and exit interviews with 60 mothers attending prevention of mother-to-child transmission (pmtct) clinics showed that only 2 of 34 (5.9%) hiv-positive mothers were asked about essential conditions for safe formula feeding during counselling on infant feeding options, and fewer than a quarter of mothers expressed confidence in implementing their feeding decisions; 6 and (iv) a disjunction between feeding recommendations and the socio-cultural context within which feeding occurs 4,7-11 – in south africa exclusive feeding practices recommended by current guidelines are not practised unless intense support is provided, 10-12 and in tanzania nurse counsellors perceived both exclusive breastfeeding (ebf) and exclusive formula feeding as culturally and socially unacceptable, and therefore expressed a lack of confidence in their ability to counsel about hiv and infant feeding. 4 this paper aims to contribute to the debate on how postnatal hiv transmission can best be minimised, infant feeding and hiv towards a new policy and implementation plan for minimising postnatal hiv transmission and maximising infant hiv-free survival review ameena ebrahim goga, fcpaed, msc mch, msc (epidemiol) health systems research unit, medical research council, and department of paediatrics and child health, university of limpopo, medunsa campus, ga-rankuwa, pretoria recent studies on antiretroviral prophylaxis during breastfeeding show that maternal highly active antiretroviral therapy (haart) (alone or with 1, 4 or 24 weeks’ infant prophylaxis) or infant prophylaxis alone for 6, 14 or 24 weeks (with limited maternal prophylaxis) reduces hiv transmission through breastmilk (postnatal transmission). maternal postnatal regimens appear to be as efficacious as infant postnatal regimens, although one study shows a trend favouring infant nevirapine over maternal haart (both used from 1 week to 6 months after delivery). these new findings necessitate a review of existing interventions to prevent mother-to-child transmission of hiv (pmtct) , and the immediate implementation of regimens that reduce postnatal transmission – where this is feasible – to save children’s lives. in the public sector, while stakeholders engage in discussions about which is the best regimen to minimise postnatal transmission, sssupport should be given to all hiv-positive women to improve infant outcomes and reduce postnatal transmission, as follows: screen all women for hiv, send off cd4 cell counts on all hiv-positive women, screen all hiv-positive women for afass using a standardised tool (e.g. table ii/fig. 2 below); understand the woman’s personal and socio-cultural context; promote exclusive or predominant breastfeeding if all afass criteria are not met; promote exclusive formula feeding if all afass criteria are met; organise supplies of formula milk and co-trimoxazole; review mothers and infants in the first 3 days after delivery, in the first 2 weeks postnatally, and monthly thereafter, and review health and feeding practices, regardless of feeding choice, at every visit; lastly treat all pregnant women with haart if they meet national criteria for haart initiation. the southern african journal of hiv medicine                                                        december 2009   21 and how current recommendations on hiv and infant feeding can be implemented, in a southern african context. the paper is divided into three sections: the first provides a historical overview of infant feeding in the context of hiv (for readers new to the field of infant feeding and hiv), summarises new research on postnatal prophylaxis, and discusses the implications thereof; the second section summarises existing international and national recommendations on hiv and infant feeding; and the third section focuses on how we can implement existing, and possibly new, feeding recommendations in the context of hiv. historical overview of infant feeding in the context of hiv, and implications of recent findings table i summarises the key studies that have contributed towards the body of knowledge on hiv and infant feeding. the recent groundbreaking studies on maternal or infant prophylaxis during breastfeeding (table i) 13-19 yield data that should prompt immediate action and a review of existing guidelines on infant feeding and hiv. however, as highlighted by mofenson, 20 the perfect regimen to minimise postnatal hiv transmission through breastmilk is still difficult to identify as studies have major differences. these include differences in antepartum antiretroviral drug administration and duration, the duration of prophylaxis during breastfeeding, maternal cd4 cell counts at study entry, and rates of ebf. mofenson also points out that several studies do not specify breastfeeding duration, and hence the time at risk for postnatal hiv transmission, while others do not provide infant hiv status at birth, making it difficult to compare the incremental benefit of antiretroviral prophylaxis during breastfeeding. 20 despite these differences, the main message from recent studies on prophylaxis during breastfeeding is that maternal highly active antiretroviral therapy (haart) alone 16 or with 1 week, 14 4 weeks 18 or 24 weeks of infant prophylaxis, 13 or infant prophylaxis alone (with limited maternal prophylaxis – i.e. no haart) for 6 weeks, 19 14 weeks 17 or 24 weeks, 15 reduces postnatal hiv transmission (i.e. breastmilk transmission). maternal postnatal regimens appear to be just as efficacious as infant postnatal regimens, although the breastfeeding, antiretroviral and nutrition (ban) study suggests that at 28 weeks there was a trend favouring infant nevirapine over maternal haart (both used from 1 week to 6 months after delivery). 13 the post exposure prophylaxis to the infant (pepi) study showed that, when risk factors were adjusted for (maternal cd4 cell count, maternal presentation, sex of infant and infant birth weight), 9month hiv-free survival was higher among infants who received 14 weeks’ postnatal prophylaxis compared with control infants who only received 1 week’s antiretroviral (arv) cover (table i). 17 both the pepi and six week extended dose nevirapine (swen) studies show that the protective effect of infant postnatal prophylactic arv regimens on breastmilk hiv transmission stops once the regimens stop being taken. 17,19 implications of recent findings these messages suggest that any of the new regimens highlighted in table i could be implemented without further delay among breastfeeding hiv-positive mothers to reduce transmission where the human resource, financial and socio-cultural capacity exists to do this, e.g. in private sector facilities, despite the inherent inequity in this approach. even one new paediatric infection is one too many! the ideal regimen for a national public health policy still needs to be decided upon, and should be guided by data. the choice is between prophylactic maternal haart antenatally and thoughout breastfeeding, similar to regimens used in kesho bora 14 or mitra-plus 16 (table i), a modified ban regimen (table i) with maternal dual prophylaxis (modified ban) with or without tail cover and infant nevirapine for 6 months, 13 or a modified swen 19 or pepi 17 regimen, with better maternal prophylaxis and nevirapine for 6 14 weeks. for women who start haart for their own health antenatally, there is currently little debate about the postnatal regimen as haart will continue postnatally and will consequently cover the breastfeeding period if the mother breastfeeds. for resource-limited public health settings or countries, including south africa, that are seeking to minimise postnatal hiv transmission, three main issues need to be considered when deciding on which arv regimen to include in a national policy: (i) the basic science: efficacy and possible effectiveness of various postnatal prophylactic regimens using hiv transmission and hivfree survival as the main outcomes; (ii) the feasibility of each regimen from a user perspective, i.e. for pregnant women, for mothers who may need treatment after delivery, and for infants who may need treatment after delivery; and (iii) feasibility of each regimen from a health system/service perspective, including cost, cost-benefit, procurement, packaging and delivery systems. work needs to be undertaken urgently to examine the issues raised above, so that appropriate, effective and feasible new regimens that minimise postnatal hiv transmission can be instituted in the public health system without further delay. it is likely that the most appropriate policy for postnatal prophylaxis would be one that starts early, ensures that mothers who need haart for their own health receive treatment early, ensures that the postnatal regimen would not compromise any subsequent treatment needed by mother or infant (by increasing resistance, thus decreasing maternal treatment options), is feasible from a health system and community perspective, and is costdecember 2009                                                          the southern african journal of hiv medicine                                                  22 year, author, setting, study design, and characteristics of population regimens mother baby results and major contribution 1997 ekpini et al.36 abidjan poc all bf none none hiv transmission rate till 6 months: 28% (19 39%) for children born to hiv-1-infected women and 18% (9 30%) for children born to hiv-2-infected women hiv transmission rates after 6 months for hiv-1and hiv-2-infected women: 12% (3 23%) and 6% (0 14%), respectively, adjusting for loss to follow-up main messages: the risk of transmission continues throughout the bf period. early cessation of bf at 6 months of age is a possible intervention to reduce postnatal hiv transmission 1999 miotti et al.37 malawi poc all bf none none 7% of the 672 infants became hiv infected while bf. no infant became hiv positive after bf had stopped. the cumulative risk of infection for infants continuing to bf after 1 month to the end of months 5, 11, 17, and 23 was 3.5%, 7%, 8.9% and 10.3%, respectively. however, hiv infection rates per person per month were 0.7% in months 1 5, 0.6% in months 6 11, 0.3% in months 12 17, and 0.2% in months 18 23 (p=0.01), suggesting that hiv transmission decreases significantly as the child gets older main messages: breastmilk transmission continues throughout the bf period, but decreases as the child gets older, and stops when bf stops 1999 semba et al.38 blantyre, malawi poc all bf none none mothers of hiv-infected infants have significantly greater breastmilk viral load than mothers of uninfected infants mastitis – probably as a result of poor bf technique – and breastmilk viral load were independently associated with mtct of hiv-1 at 6 months (or 2.38, 95% ci 1.26 4.42, and or 2.97, 95% ci 1.23 7.18, respectively) main messages: higher breastmilk viral load increases transmission risk through breastmilk. mastitis also increases risk of hiv transmission, independently of breastmilk viral load 2001 nduati et al.39 nairobi, kenya rct women randomised to bf or ff (clean water available and formula subsidised) none none the cumulative probability of hiv-1 infection at 23 months was 36.7% (95% ci 29.4 44%) in the bf arm and 20.5% (95% ci 14 27%) in the formula feeding arm, p=0.001 the estimated rate of transmission (excess risk of transmission) was 16.2% (95% ci 6.5 25.9%). 44% of hiv-1 infection was attributable to breastmilk kaplan-meier estimates of the 2-year mortality rate were similar in the bf arm (24.4% (95% ci 18.2 30.7%) and formula feeding arm (20.0% (95% ci 14.4 25.6%)), p=0.30. the 2-year hiv-free survival rate was significantly lower in the bf arm (58%) compared with the formula feeding arm (70%), p=0.02 main messages: most breastmilk transmission seemed to occur early during bf; however, transmission risk difference continued to increase throughout the bf period. hiv-free survival at 2 years was better in the formula feeding arm table i. key studies that have contributed to the body of knowledge on hiv and infant feeding the southern african journal of hiv medicine                                                        december 2009   23 year, author, setting, study design, and characteristics of population regimens mother baby results and major contribution 2001 coutsoudis et al.24 cato manor – urban area, south africa unexpected findings from a vitamin a rct women self-selected to ebf or eff none none cumulative probabilities of hiv detection were similar among never and exclusive breastfeeders up to 6 months (0.19, 95% ci 0.14 0.26 and 0.19, 95% ci 0.13 0.27, respectively). probabilities among mixed breastfeeders surpassed both groups, reaching 0.26 (95% ci 0.21 0.32) by 6 months cumulative probability of hiv infection by 15 months was 0.25 (95% ci 0.16 0.34). this was still lower than among other breastfeeders – 0.36 (95% ci 0.27 0.45). in multivariate analysis ebf was associated with a significantly lower risk of hiv infection (adjusted hr 0.56, 95% ci 0.22 1.42) than mixed bf (adjusted hr 0.87, 95% ci 0.33 2.33) main messages: pattern of infant feeding affects transmission; ebf was associated with a lower risk of hiv transmission than mixed feeding 2003 richardson et al.40 nairobi, kenya prospective rct nested case control study within rct of bf and ff none none mother’s cd4 count <400/µl was associated with 3-fold higher breastmilk infectivity per litre of breastmilk ingested and per day of bf by the infant compared with cd4 cell count ≥400 main messages: breastmilk infectivity remains high throughout the bf period. lowering breastmilk viral load during bf is a potential strategy to reduce breastmilk infectivity 2004 bhits study group41 meta-analysis, 9 randomised placebo-controlled trials none none overall estimated risk of late postnatal (negative at or before 4 weeks followed by positive results) hiv transmission was 8.9 transmissions per 100 child-years of bf the cumulative probability of late postnatal transmission at 18 months was 9.3% main messages: cases of postnatal transmission continued to occur throughout the bf period. breastmilk transmission remained fairly constant throughout the bf period 2005 illiff et al.25 zimbabwe rct mothers randomised to 1 of 4 vitamin a treatment groups all mothers bf none none compared with ebf, early mixed feeding was associated with a 4.03 (95% ci 0.98 16.61), 3.79 (95% ci 1.40 10.29) and 2.60 (95% ci 1.21 5.55) greater risk of postnatal hiv transmission at 6, 12 and 18 months, respectively predominant bf was associated with a 2.63 (95% ci 0.59 11.66), 2.69 (95% ci 0.95 7.63, and 1.61 (95% ci 0.72 3.64) trend towards greater postnatal transmission risk at 6, 12 and 18 months, respectively, compared with ebf main messages: ebf was associated with a lower risk of hiv transmission compared with mixed feeding. predominant bf also tended to carry higher risks of transmission compared with ebf 2006 mashi study30 botswana rct azt for 6 months ff bf infant azt main messages: ff was associated with significantly higher rates of infant mortality and severe pneumonia and diarrhoea by 6 months, particularly among hiv-infected children 24-month hiv-free survival did not differ between arms with the exception of grade 3/4 pneumonia and in the context of weaning at 6 months by the bf arm, differences by feeding arm were attenuated by 24 months table i. key studies that have contributed to the body of knowledge on hiv and infant feeding (continued) 24 year, author, setting, study design, and characteristics of population regimens mother baby results and major contribution 2007 coovadia et al.23 hlabisa – rural area, south africa poc afass-guided feeding sd nvp sd nvp 14.1% (95% ci 12.0 16.4) of exclusively bf infants were infected with hiv-1 by age 6 weeks and 19.5% (17.0 22.4) by 6 months transmission risk was significantly associated with maternal cd4 cell counts below 200 cells/µl (adjusted hr 3.79; 2.35 6.12) and birth weight less than 2 500 g (1.81, 1.07 3.06). kaplan-meier estimated risk of acquisition of infection at 6 months of age was 4.04% (2.29 5.76) bf infants who also received solids were significantly more likely than ebf children to acquire infection (hr 10.87, 1.51 78.00, p=0.018), as were infants who at 12 weeks received both breastmilk and formula milk (1.82, 0.98 3.36, p=0.057) cumulative 3-month mortality in ebf infants was 6.1% (4.74 7.92) v. 15.1% (7.63 28.73) in infants given replacement feeds (hr 2.06, 1.00 4.27, p=0.051) main messages: early introduction of solids increased transmission risks, as did mixed feeding. 3-month mortality was highest in infants receiving no breastmilk compared with infants who were ebf; low maternal cd4 cell count increased risk of infant hiv acquisition 2007 kuhn et al. (zebs)26 zambia epidemiological study nested within a rct evaluating the safety and efficacy of early weaning sd nvp sd nvp postnatal hiv transmission before 4 months was significantly lower (p=0.004) among ebf (0.040, 95% ci 0.024 0.055) than non-ebf infants (0.102, 95% ci 0.047 0.157); time-dependent relative hazard (rh) of transmission due to non-ebf = 3.48 (95% ci 1.71 7.08) there were no significant differences in the severity of disease between ebf and non-ebf mothers, and the association remained significant (rh=2.68, 95% ci 1.28 5.62) after adjusting for maternal cd4 count, plasma viral load, syphilis screening results and low birth weight main messages: non-ebf more than doubles the risk of early postnatal (by 4 months) hiv transmission. early cessation of breastfeeding increases morbidity and mortality risks 2008 swen19 ethiopia, uganda and india 3 similar rcts all bf c: sd nvp int: sd nvp c: sd nvp int: sd nvp + extended daily nvp until 6 weeks there was a 46% decrease in postnatal hiv infection at age 6 weeks in infants uninfected at birth, with extended nevirapine compared with the control arm. there was a continued risk of postnatal hiv transmission after the regimens were discontinued in infants who continued to be breastfed; however this risk was similar in both arms main messages: postnatal infant nvp for 6 weeks reduced transmission compared with sd nvp, and improved 6-month hiv-free survival. transmission risk continued after nvp was stopped 2008 post exposure prophylaxis to the infant (pepi) trial17 malawi rct all bf c: sd nvp int 1: sd nvp int 2: sd nvp c: sd nvp + 1 week azt int 1: sdnvp + 14 weeks daily nvp int 2: sd nvp + 14 weeks nvp and azt at 9 months, the estimated rate of hiv-1 infection (the primary end-point) was 10.6% in the control group compared with 5.2% in the extended-nevirapine group (p<0.001) and 6.4% in the extended-dual-prophylaxis group (p=0.002). there were no significant differences between the two extended-prophylaxis groups. there was a continued risk of postnatal hiv transmission after the regimens were discontinued in infants who continued to be breastfed; however this risk was similar in both arms main messages: extended prophylaxis with nvp or with nvp and azt for the first 14 weeks of life significantly reduced postnatal hiv-1 infection in 9-month-old infants. 9-month hiv-free survival was higher among infants who received 14 weeks’ postnatal prophylaxis compared with control infants who only received 1 week’s arv cover (adjusted hr=0.001 for the 14-week postnatal infant nvp prophylaxis group, and adjusted hr=0.004 for the 14-week postnatal infant nvp + azt prophylaxis group – both compared with control) table i. key studies that have contributed to the body of knowledge on hiv and infant feeding (continued) the southern african journal of hiv medicine                                                        december 2009   25 year, author, setting, study design, and characteristics of population regimens mother baby results and major contribution 2008 mitra study15 dar es salaam, tanzania poc all bf azt/3tc to mothers from 36 weeks’ gestation to 1 week postpartum azt/3tc to infants for 1 week followed by daily 3tc to infants for a maximum of 6 months cumulative hiv transmission was 3.8% at 6 weeks and 4.9% at 6 months of age. the risk of postnatal infection from 6 weeks to 6 months was 1.1% main messages: infant prophylaxis for 6 months resulted in a low risk of hiv transmission through breastmilk 2009 kesho bora14 5 sites in burkina faso, kenya and south africa hiv-infected women with cd4 200 500 cells/µl randomised rct all bf c: azt started 28 36 weeks + sd nvp at labour + 1 week pn azt/3tc int: haart started 28 36 weeks preg. through 6 months postpartum sd nvp + 1 week azt in both arms the rates of hiv infection at birth were similar in both arms: 1.8% in the haart arm versus 2.2% in short-course azt arm at age 6 months cumulative hiv infection rates were 4.9% in the maternal haart arm, compared with 8.5% in the short-course azt arm between 6 weeks and 6 months the postnatal infection rate was 1.6% in the maternal haart arm compared with 3.7% in the short-course azt arm without extended prophylaxis the rate of infection after the prophylaxis/haart was discontinued was similar in both arms main messages: a maternal haart arm was more efficacious than short-course regimens 2009 mma bana18 botswana rct hiv-infected pregnant women with cd4 cell counts >200 cells/µl were randomised. rct all bf int 1: triple nucleoside haart regimen int 2: protease inhibitor-containing haart regimen started 26 34 weeks through 6 months of bf sd nvp + 4 weeks azt rates of viral suppression at delivery and during breastfeeding were similar between the 2 haart regimens. the cumulative infant hiv infection rate at age 6 months was 1% (95% ci 0.5 2%) with only 2 infections (0.4% transmission) in 553 infants with no difference between the 2 arms main messages: maternal haart regimens were efficacious in reducing postnatal transmission in mothers with cd4 cell count >200 cells/µl 2009 mitra plus16 dar es salaam, tanzania poc all bf haart to pregnant women starting at 34 weeks and continuing through 6 months of breastfeeding cumulative risk of hiv infection was 5% at 6 months and 6% at 18 months of age. the risk of postnatal infection between 6 weeks and 6 months was only 1% main messages: maternal haart during bf reduced postnatal transmission through breastmilk 2009 breastfeeding, antiretrovirals and nutrition (ban) study13 malawi rct women with cd4 cell counts >250 cells/µl at delivery and no previous antenatal prophylaxis c: intrapartum sd nvp + 1 week azt/3tc int 1: c regimen + haart from 1 week till 6 months postpartum int 2: c regimen c: sd nvp + 1 week azt/3tc int 2: daily infant nvp from 1 week to 6 months postpartum the cumulative probability of hiv infection at age 6 months in infants uninfected with hiv at birth was 6.4% in the control arm, 3.0% in the maternal haart arm (p=0.0032 v. controls), and 1.8% in the infant nvp arm (p<0.001 v. control arm). the rates were not statistically different between the 2 intervention arms, although the study was not powered to detect a difference between the arms main messages: maternal haart for 6 months and infant nvp for 6 months were equally efficacious in reducing postnatal hiv transmission through breastmilk at 6 months, although the data suggest a trend favouring infant nvp from 1 to 6 months over maternal haart from 1 week to 6 months (p=0.0698) poc = prospective observational study; rct = randomised controlled trial; cc = case control study; c = control group; int = intervention group; bf = breastfeeding; ff = formula feeding; ebf = exclusive breastfeeding; eff = exclusive formula feeding; nvp = nevirapine; azt = zidovudine; 3tc = lamivudine; sd = single-dose. table i. key studies that have contributed to the body of knowledge on hiv and infant feeding (continued) december 2009                                                          the southern african journal of hiv medicine                                                  26 beneficial and supported by exclusive or predominant breastfeeding to maximise infant hiv-free survival. one of the current gaps in the literature is that no study has examined whether hiv-free survival differs between hiv-exposed infants who appropriately avoid all breastfeeding, and breastfeeding hiv-exposed infants who receive postnatal prophylaxis to reduce postnatal transmission. this work still has to be done. while regimens to minimise postnatal hiv transmission are still being finalised (particularly in the public sector), health care providers and mothers need to be supported so that current feeding recommendations maximise hiv-free survival. these recommendations are explained in the next section. current international and national feeding recommendations, and the basis thereof in 2005 the lancet child survival series showed that universal coverage with ebf for 6 months and continued breastfeeding – i.e. breastmilk and complementary foods – up to 1 year may prevent 13% of under-5 deaths globally, even in the presence of hiv. 21 subsequently the lancet nutrition series showed that in the first 6 months of life ebf has far greater child survival benefits compared with predominant breastfeeding (feeding breastmilk and non-nutritive liquids), partial breastfeeding and not breastfeeding for all-cause mortality (odds ratio (or) 1.48 (95% confidence interval (ci) 1.13 1.92), or 2.85 (95% ci 1.59 5.10), or 14.40 (95% ci 6.09 34.05), respectively), diarrhoea mortality (or 2.28 (95% ci 0.85 6.11), or 4.62 (95% ci 1.81 11.77), or 10.53 (95% ci 2.80 39.64)) and pneumonia mortality (or 1.75 (95% ci 0.48 6.43), or 2.49 (95% ci 1.03 6.04), or 15.13 (95% ci 0.61 373.84)) in resource-limited settings. 22 despite these benefits of ebf, research highlighted in table i also shows that any breastfeeding (including ebf) carries a risk of postnatal hiv transmission, which is largest for mixed feeding and smallest for ebf. 23-26 hiv infection therefore presents new challenges for infant feeding, which have often been explained as two sides of a scale – one side is weighed down by the risk of hiv transmission through breastfeeding, and the other is weighed down by the risk of morbidity and mortality from common childhood illnesses as a result of not breastfeeding. this risk of mortality as a result of not breastfeeding has been documented among hiv-exposed infants in numerous sub-saharan settings, including south africa. 23, 27-30 furthermore, doherty et al. show that inappropriate decisions to formula feed and inappropriate decisions to breastfeed were associated with an increased hazard of hiv or death compared with appropriate decisions to formula feed (adjusted hazard ratio (hr) 3.63 (95% ci 1.48 8.89) and 3.35 (95% ci 1.25 8.96) compared with 1, respectively). 31 current recommendations in an attempt to be pragmatic, to minimise breastmilk transmission of hiv and maximise hiv-free survival, the world health organization (who), unicef and interagency task team (iatt) recommended between 2006 and november 2009 that feeding decisions in hivpositive women should depend on the mother’s health status, the local situation, the health services available and the counselling support she is likely to receive. 32 until 30 november 2009 the iatt recommended that ebf for 6 months should be instituted unless replacement feeding (avoiding breastmilk) is acceptable, feasible, affordable, sustainable and safe (commonly referred to as the afass criteria). at 6 months, if replacement feeding is still not afass, continuation of breastfeeding with additional complementary foods is recommended. all breastfeeding in hiv-positive women should stop once a nutritionally adequate and safe diet without breastmilk can be provided. on 30 november 2009, the who released revised rapid guidance on hiv and infant feeding (available from http://www.who.int/child_ adolescent_health/documents/9789241598873/en/ index.html). these state, inter alia, that mothers known to be hiv infected (and whose infants are hiv uninfected or of unknown hiv status) should exclusively breastfeed their infants for the first 6 months of life, introducing appropriate complementary foods thereafter, and continue breastfeeding for the first 12 months of life. breastfeeding should then only stop once a nutritionally adequate and safe diet without breastmilk can be provided. mothers known to be hiv infected who decide to stop breastfeeding at any time should stop gradually within 1 month. mothers or infants who have been receiving arv prophylaxis should continue prophylaxis for 1 week after breastfeeding is fully stopped. stopping breastfeeding abruptly is not advisable. mothers known to be hiv infected should only give commercial infant formula milk as a replacement feed to their hivuninfected infants or infants who are of unknown hiv status, when specific conditions are met (referred to as afass – affordable, feasible, acceptable, sustainable and safe – in the 2006 who recommendations on hiv and infant feeding). while the iatt 2006 2009 recommendations have been accepted by most resource-limited countries, countries still need to discuss the 2009 revisions and then amend their policies. fig. 1 lists the current south african pmtct guidelines on infant feeding in the context of hiv.33 these are similar to the guidelines followed in many resourcelimited countries. the southern african journal of hiv medicine                                                        december 2009   27 the iatt 2006 2009 recommendations need to be implemented while countries finalise their new policies on postnatal prophylaxis and infant feeding. although new policies – which will stem from recent evidence (table i) and the who rapid guidance – still need to be debated and finalised, aspects of the iatt 2006 2009 recommendations on infant feeding and hiv will still be relevant henceforth. for example, if women meet the afass criteria they should still be advised not to breastfeed so that postnatal hiv transmission is eliminated; if women do not meet the afass criteria then the new policy may advise breastfeeding for 6 months with an arv regimen that continues throughout the breastfeeding period. from a child survival perspective ebf has been recommended for mothers who do not meet the afass criteria. however, in most african settings ebf is not a normative cultural practice in the absence of intense support. ghuman et al. showed that the ebf rate among women of unknown hiv status – living in a high-hiv prevalence area – was 18% at 14 weeks, 10 and goga et al. showed that only 18% of hiv-positive breastfeeding women practised ebf at 12 weeks in a pmtct programme setting. 11 bland et al. (the vertical transmission study) were able to increase ebf rates to 40% at 6 months following an intense peer counselling intervention comprising approximately 20 home-based visits starting antenatally (4 visits) until 6 months after delivery. 12 however, it is questionable whether this intervention is replicable in a programmatic setting. more recently a pooled analysis of data from the vertical transmission study (south africa) and ditrame plus study (cote d’ivoire) showed that postnatal hiv transmission rates were not significantly different among infants who had been exclusively breastfed or predominantly breastfed for the same time period; however, infants exposed to solids at least once during the first 2 months of life were 2.9 (95% ci 1.1 8.0) times more likely to become hiv infected postnatally compared with infants who had never received solids this early. 34 this analysis did not compare hiv-free survival among predominantly or exclusively breastfed infants, but it does suggest that if ebf is not socially or culturally feasible among breastfeeding hiv-positive mothers, the next best option is predominant breastfeeding. mixed feeding with the early introduction of solids is the most risky for transmission. the following section provides recommendations on how to implement feeding recommendations that assess the appropriateness of feeding options (afass), as this has been a stumbling block. it also suggests how safe (exclusive or predominant) infant feeding can be supported. how to implement the feeding recommendations in view of recent data highlighting the risks of inappropriate feeding choices with regard to hiv-free survival, 31 much attention needs to be given to how hivpositive women make their feeding choices. to assess afass a checklist can be used (table ii). if there is any ‘no’ in the ‘ebf for 6 months’ column, advise the mother to exclusively breastfeed for 6 months. if all responses are ‘yes’, advise her to avoid all breastfeeding. in a recent review of solutions to operational challenges in pmtct,35 a novel ‘5-finger approach’ to assess afass and facilitate appropriate infant feeding choices has been described by coutsoudis and kroon. an example of the 5-finger approach, which is based on current literature, 31 is illustrated in fig. 2 and can be used by doctors, nurses and lay counsellors. fig. 2 is in the process of being revised by coutsoudis and kroon so that the ‘breast is best’ logo is not so prominent. readers interested in using fig. 2 should contact coutsoudis and kroon for updated versions. regardless of the method used to assess afass, appropriate infant feeding choices should be encouraged to maximise child survival in the context of pmtct. hiv-negative women • at every antenatal visit hiv-negative women or women of unknown hiv status (every effort should be made to get all pregnant women tested or re-tested as stated in the testing section of this document) should be counselled to exclusively breastfeed their babies during the first 6 months of life and continue breastfeeding for at least 2 years. hiv-positive women • at every antenatal visit hiv-positive women should be counselled on infant feeding options. • each pregnant hiv-positive woman should receive at least four antenatal counselling sessions on infant feeding. • the feeding options for the first 6 months of life are exclusive breastfeeding or exclusive formula feeding. all hiv-positive infants should continue breastfeeding for at least 2 years, regardless of whether the mother meets the afass criteria. • for each woman, the acceptability, feasibility, affordability, safety and sustainability criteria (afass) should be assessed and discussed, and the woman should be assisted to make the feeding choice that would be most appropriate for her individual situation. fig. 1. current (2008) south african pmtct feeding recommendations.33 december 2009                                                          the southern african journal of hiv medicine                                                  28 lastly, the acronym sssupport (table iii) should be taught or displayed in all health facilities to remind health workers about their responsibilities towards optimising child survival through appropriate infant feeding counselling in the context of hiv. summary and conclusions postnatal maternal or infant arv regimens reduce postnatal hiv transmission through breastmilk. maternal postnatal regimens appear as efficacious as infant postnatal regimens; however, data suggest that there may be a trend favouring infant nevirapine over maternal haart (both used from 1 week to 6 months after delivery). the protective effect of regimens stops once the regimens stop, if breastfeeding continues. any of the new regimens should be implemented among breastfeeding hiv-positive mothers without further delay where the human resource, financial and sociocultural capacity exists to do this, e.g. in private sector facilities, despite the inherent inequity in this approach. for resource-limited public health settings three main issues need to be considered when deciding on which arv regimen to include in a national policy: (i) the basic science: efficacy and possible effectiveness of various postnatal prophylactic regimens using hiv transmission and hiv-free survival as the main outcomes; (ii) the feasibility of each regimen, from a user perspective; and (iii) the feasibility of each regimen from a health system/service perspective. work needs to be undertaken urgently to examine these issues. while stakeholders engage in discussions about which is the best regimen to include in national policy on minimising postnatal transmission, sssupport should be given to all hiv-positive women to improve infant outcomes and reduce postnatal transmission: screen all women for hiv; send off cd4 cell counts on all hivpositive women; screen all hiv-positive women for afass using a standardised tool (e.g. table ii/fig. 2); understand the woman’s personal and socio-cultural context; promote exclusive or predominant breastfeeding if all afass criteria are not met; promote exclusive questions that can be used to assess afass most suitable feeding option ebf for 6 months if no to any of these questions avoiding all breastfeeding: exclusive formula feeding for 6 months if yes to all of these questions can the mother avoid all breastfeeding in her current social and cultural context? no yes does the family/person the woman stays with know that she is hiv positive? no yes can the woman overcome or deal with any stigma or discrimination if she were to choose to avoid all breastfeeding? no yes will the woman be able to go to the clinic to collect formula milk regularly? no yes will the woman have money for transport to collect milk or to buy milk if the supply runs out or to take the infant to a clinic if he/she gets diarrhoea? no yes does the woman or caregiver have enough time, knowledge, skills, resources and support to correctly prepare breastmilk substitutes? no yes will the woman be able to prepare night feeds easily? no yes is the mother able to feed the infant 8 12 times in 24 hours? no yes will the woman be able to regularly buy utensils needed to prepare formula milk? no yes will the woman be able to get a continuous, uninterrupted supply of formula milk and water and fuel? no yes is there piped water in the house or yard that can be accessed regularly? no yes will the woman be able to wash her hands before preparing each feed and prepare each feed with boiled water and clean utensils? no yes will the woman be able to store formula milk correctly and hygienically? no yes table ii. assessing afass criteria the southern african journal of hiv medicine                                                        december 2009   29 formula feeding if all afass criteria are met; organise supplies of formula milk and co-trimoxazole; review mothers and infants in the first 3 days after delivery, in the first 2 weeks postnatally and monthly thereafter, and review health and feeding practices, regardless of feeding choice, at every visit; and lastly treat all pregnant women with haart if they meet national criteria for haart initiation. references 1. world health organization. guidance on global scale-up of the prevention of mother-to-child transmission of hiv: towards universal access for women, infants and young children and eliminating hiv and aids among children. 2007. http:// www.unicef.org/aids/index_documents.html (accessed 1 october 2009). 2. doherty t, mccoy d, donohue s. health systems constraints to optimal coverage of the prevention of mother-to-child transmission programme in south africa: lessons from implementation of the national pilot programme. afr health sci 2005; 5(3): 213-218. 3. shah s, rollins n, bland r for the child health group. breastfeeding knowledge amongst health workers in rural south africa. j trop pediatr 2005; 51(1): 33-38. 4. leshabari s, blystad a, de paoli m, moland k. hiv and infant feeding counselling: challenges faced by nurse-counsellors in northern tanzania. human resources for health 2007; 5(18). published online 2007 july 24. doi: 10.1186/1478-4491-5-18. 5. rea mf, dos santos rg, sanchez-moreno cc. quality of infant feeding counselling for hiv+ mothers in brazil: challenges and achievements. acta paediatr 2007; 96(1): 94-99. 6. chopra m, jackson, d, ashworth a, doherty t. preventing hiv transmission to children: an evaluation of the quality of counselling provided to mothers in three pmtct pilot sites in south africa. acta paediatr 2005; 94: 357-363. 7. bland rm, rollins nc, coutsoudis a, coovadia hm. breastfeeding practices in an area of high hiv prevalence in rural south africa. acta paediatr 2002; 91: 704-711. 8. doherty t, chopra m, nkonki l, jackson d, greiner t. effect of the hiv epidemic on infant feeding in south africa : ‘when they see me coming with the tins they laugh at me’. bull world health organ 2005; 84(2): 90-96. 9. doherty t, chopra m, nkonki l, jackson d, persson l-a. a longitudinal qualitative study of infant-feeding decision making and practices among hiv-positive women in south africa. j nutr 2006; 136: 2421-2426. 10. ghuman m, saloojee h, morris g. infant feeding practices in a high hiv prevalence rural district of kwa-zulu natal. south african journal of clinical nutrition 2009; 22(2): 74-79. 11. goga a. improving child survival in south africa – a case study on pmtct: the special case of infant feeding. presentation at child health priorities conference, durban, 3 4 december 2007. 12. bland r, little k, coovadia h, coutsoudis a, rollins n, newell m-l. intervention to promote exclusive breast-feeding for the first 6 months of life in a high hiv prevalence area. aids 2008; 4: 27. 13. chasela c, hudgens m, jamieson d, et al. both maternal haart and daily infant fig. 2. a 5-finger method of assessing afass criteria developed by anna coutsoudis and colleagues (department of paediatrics and child health, ukzn) and max kroon, mowbray maternity hospital, western cape. note that this 5-finger approach is evolving, and is being amended to reduce the size of the ‘breast is best’ caption and text. readers should contact coutsoudis and kroon for updated versions. support without prophylaxis to reduce postnatal transmission through breastmilk additional steps if prophylaxis to reduce postnatal hiv transmission through breastmilk becomes policy s s s screen all women for hiv send off cd4 cell counts on all hiv-positive women screen all hiv-positive women for afass u understand the mother’s personal and socio-cultural context p promote exclusive or predominant breastfeeding if all the afass criteria are not met plus start postnatal prophylactic regimens to minimise postnatal hiv transmission p promote exclusive formula feeding if all the afass criteria are met o organise supplies: of formula milk if mothers meet afass and choose to formula feed of co-trimoxazole for infants from 6 weeks plus supplies: of prophylactic antiretrovirals if mothers do not meet afass r review mothers and infants in the first 3 days postnatally, in the first 2 weeks postnatally and monthly thereafter review mother’s and infant’s health, and infant feeding practices/techniques, regardless of feeding choice plus adherence to any regimens t treat all mothers and children with antiretroviral therapy according to updated recommendations adapted from goga et al. 11 and jackson et al. 42 table iii. key message to promote safe infant feeding and improve hiv-free survival december 2009                                                          the southern african journal of hiv medicine                                                  30 nevirapine (nvp) are effective in reducing hiv-1 transmission during breastfeeding in a randomised trial in malawi: 28 week results of the breastfeeding, antiretroviral and nutrition (ban) study (welb c103). presentation at 5th international aids society conference on hiv pathogenesis, treatment and prevention, 19 22 july 2009, cape town. 14. de vincenzi i, kesho bora study group. triple antiretroviral prophylaxis during pregnancy and breastfeeding compared with short-arv prophylaxis to prevent mother-to-child transmission of hiv-1: the kesho-bora randomised controlled trials in 5 sites in burkina faso, kenya and south africa (lbpe c01). presentation at 5th international aids society conference on hiv pathogenesis, treatment and prevention, 19 22 july 2009, cape town. 15. kilewo c, karlsson k, massawe a, for the mitra study team. prevention of mother-to-child transmission of hiv-1 through breastfeeding by treating infants prophylactically with lamivudine in dar es salaam. j acquir immune defic syndr 2008; 48: 315-323. 16. kilewo c, karlsson k, ngarina m. prevention of mother-to child transmission of hiv-1 through breastfeeding by treating mothers with triple antiretroviral therapy in dar es salaam, tanzania. the mitra-plus study. j acquir immune defic syndr 2009; on line at www.jaids.com, october 2009. 17. kumwenda n, hoover d, mofenson l, et al. extended antiretroviral prophylaxis to reduce breastmilk hiv-1 transmission. n engl j med 2008; 359: 119-129. 18. shapiro r, hughes m, ogwu a, et al. the mma bana study: randomised trial comparing highly active antiretroviral therapy regimens for virologic efficacy and the prevention of mother-to-child transmission of hiv transmission amongst breastfeeding women in botswana (welb b101). presentation at 5th international aids society conference on hiv pathogenesis, treatment and prevention, 19 22 july 2009, cape town. 19. six week extended dose nevirapine (swen) study team. extended dose nevirapine at 6 weeks of age for infants to prevent hiv transmission via breatsfeeding in ethiopia, india and uganda: an analysis of 3 randomised controlled trials. lancet 2008; 372: 300-313. 20. mofenson l. prevention of breastmilk transmission: the time is now. j acquir immune defic syndr 2009; on line at www.jaids.com, october 2009. 21. jones g, steketee rw, black re, bhutta za, morris ss. how many child deaths can we prevent this year? lancet 2003; 362: 65-71. 22. maternal and child undernutrition: global and regional exposures and health consequences. 2007. www.thelancet.com (accessed 18 january 2008). 23. coovadia h, rollins n, bland r, et al. mother-to-child transmission of hiv1 infection during exclusive breastfeeding in the first 6 months of life: an intervention cohort study. lancet 2007; 369: 1107-1116. 24. coutsoudis a, pillay k, kuhn l, et al. method of feeding and transmission of hiv-1 from mothers to children by 15 months of age: prospective cohort study from durban, south africa. aids 2001; 15(3): 379-387. 25. illif p, piwoz e, tavengwa v, et al. early exclusive breastfeeding reduces the risk of postnatal hiv-1 transmission and increases hiv-free survival. aids 2005; 19(7): 699-708. 26. kuhn l, sinkala m, kankasa c, et al. high uptake of exclusive breastfeeding and reduced early post-natal hiv transmission. plos one 2007; 12 (e1363). 27. creek t, arvelo w, kim a, et al. a large outbreak of diarrhoea among non-breastfed children in botswana, 2006 – implications for hiv prevention strategies and child health. presentation at 14th conference on retroviruses and opportunistic infections (croi), 25 28 february 2007, los angeles. 28. kafulafula g, thigpen m, hoover dr, et al. post-weaning gastroenteritis and mortality in hiv uninfected african infants receiving antiretroviral prophylaxis to prevent mtct-1 of hiv. presentation at 14th conference on retroviruses and opportunistic infections (croi), 25 28 february 2007, los angeles. 29. sinkala m, kuhn l, kankasa c, et al. no benefit of early cessation of breastfeeding at 4 months on hiv-free survival of infants born to hiv infected mothers in zambia: the zambia exclusive breastfeeding study. presentation at 14th conference on retroviruses and opportunistic infections (croi), 25 28 february 2007, los angeles. 30. thior i, lockman s, smeaton l, et al. breastfeeeding plus infant zidovudine prophylaxis for 6 months vs formula feeding plus infant zidovudine for 1 month to reduce mother to child transmission of hiv in botswana. a randomised trial: the mashi study. jama 2006; 296(7): 794-805. 31. doherty t, chopra m, jackson d, goga a, colvin m, persson l-a. infant feeding choices of hiv-positive women: do the who/unicef guidelines improve infant hiv-free survival. aids 2007; 21: 1792-1797. 32. world health organization. who hiv and infant feeding technical consultation held on behalf of the inter-agency task team (iatt) on prevention of hiv infections in pregnant women, mothers and their infants, geneva, october 25 27, 2006. http://www.who.int/child-adolescent-health/new_publications/nutrition/ consensus_statement.pdf (accessed 20 march 2007). 33. policy and guidelines for the implementation of the pmtct programme. 2008. www.doh.gov.za (accessed 1 october 2009). 34. becquet r, bland r, leroy v, et al. duration, pattern of breastfeeding and postnatal transmission of hiv: pooled analysis of individual data from west and south african cohorts. plos one 2009; 4: e7397. 35. goga ae, woldesenbet s, solomon w, rohde s (medical research council), jackson d (university of the western cape), national department of health, unicef. solutions to operational challenges in pmtct implementation in south africa: selected experiences and case studies. national department of health, october 2009, revised november 2009. 36. ekpini e, wiktor s, satten g, et al. late postnatal mother-to-child transmission in abidjan, cote d’ ivoire. lancet 1997; 349: 1054-1059. 37. miotti pg, taha te, kumwenda ni, et al. hiv transmission through breastfeeding: a study in malawi. jama 1999; 282(8): 744-749. 38. semba r, kumwenda n, hoover d, et al. human immunodeficiency virus load in breast milk, mastitis, and mother-to-child transmission of human immunodeficiency virus type 1. j infect dis 1999; 180(1): 93-98. 39. nduati r, john g, mbori-ngacha d, et al. effect of breastfeeding and formula feeding on transmission of hiv-1: a randomized clinical trial. jama 2000; 283(9): 1167-1174. 40. richardson b, john-stewart g, hughes j, et al. breast-milk infectivity in human immunodeficiency virus type 1-infected mothers. j infect dis 2000; 187(5): 736740. 41. breastfeeding and hiv inernational transmission study group. late postnatal transmission of hiv-1 in breast-fed children: an individual patient data metaanalysis. j infect dis 2004; 189(12): 2154-2166. 42. jackson d, goga a, doherty t, chopra m. an update on hiv and infant feeding issues in developed and developing countries. j obstet gynecol neonatal nurs 2009; 38(2): 219-229. july 2000------------thf southfrn african journal of hiv mfoicinf care and support geneous and unproblematic entities, while little thought is given to the tasks involved in mobilising them. this is especially so in south africa, where households and communities have been systematically disrupted by apartheid. moreover, evaluations in various southern african countries have dispelled the idea that home-based care is necessarily a quick fix and a cheap alternative to hospital-based care. 5 despite these considerable challenges, a number of non-governmental organisation (ngol, community and religious-based projects, attempting to grapple with hiv/aids care and support needs at community level, have emerged across south africa. a review of these projects was conducted during the latter half of 1999, the aim of which was to identify the models of community-based hiv/aids activities being implemented, the challenges facing them and the possible role of government in promoting such activities. this article gives findings from the review. the review methods included a literature review, 68 key informant interviews, and visits to 20 projects across the country. key informants and projects were identified through a snowball sampling strategy, starting with a list of 15 contacts known to the researchers. we defined aids community-based care and support as being all aids activities that are based outside conventional health facilities (hospital, clinic, health centre), but which may have linkages with the formal health and welfare sector; and all aids activities that address any aspect of the 'continuum of care and support', from time of infection through to death and impact on survivors. over the past few years, the previously largely silent hiv epidemic in south africa has shifted to a visible aids epidemic. the impact on health services, families and communities is emerging rapidly. in 1997, 20% of all patients admitted to the paediatric wards at chris hani baragwanath hospital were hiv-infected,' and in 1998, more than half (54%) of the admissions to the medical wards at king edward viil hospital in durban were hivrelated.' by the year 2005, conservative predictions are that there will be nearly 1 million children orphaned by aids in the country,' clearly overwhelming the current capacity of the welfare system. in an attempt to deal with impacts, it is common practice for healthcare facilities to ration services to people with hiv. much of the burden of hiv care in developing countries is now falling onto households and communities, and in south africa home-based care has become a national policy priority. any discussion of aids care and support therefore inevitably turns to a consideration of how to achieve greater community participation, both in minimising impacts on the formal health sector and in meeting the needs of people infected and affected by hiv. community mobilisation is often described as the key to the sustainability and success of care and support strategies.' however, decades of experience in implementing primary health care have shown that meaningful community involvement in health services is not easy to develop and sustain, and is especially hard to institutionalise on a wide scale. communities are often assumed to be homohelen schneider, me chb, mmed, michele russell, ba, msw; ms centre for health policy, university of the wir.oatersrand, johannesburg models of community-based hiv/aids care and support in south africa thf southtrn african journal of hiv mfoicinf ------------july 2000 models of care and support in south africa although it was not possible to quantify the presence of community-based services across the country, it was very evident from discussions and visits that coverage by community care and support for people with aids (pwas) is very patchy, and most often lacking. however, in almost all parts of the country evidence could be found of attempts to initiate activities and programmes. many initiatives did not refer to themselves as 'aids' organisations, but rather as \palliative care' projects, and many were still in their infancy, operating with little external support and with uncertain prospects of sustainability. some have benefited from contact with, and the materials of, projects in other parts of southern africa, such as the family aids caring trust (fact) in mutare, zimbabwe,' and the aids support organisation <tasq) in uganda! five 'general' and four orphan care and support models were identified and are summarised in table i. general models type of activity 1. funding, technical assistance umbrella structures and support programmes channelling funds, providing technical assistance and monitoring and evaluating functions 2. advocacy and community community structures to mobilisation protect the rights of individuals and facilitate access to health and welfare services and schooling 3. drop-in centres/support physical facility that groups provides a space to run support group and income generating activities 4. home visiting programmes home visiting, assistance with chores and psychological support 5. comprehensive home-based package involving palliative care care and well-developed referral network to health facilities and welfare agencies models for placement of orphans extended family child-headed households 'create a family' or 'cluster foster care' placing responsible adults in the homes of orphaned children funding, technical assistance and support programmes two examples of funding, technical assistance and support programmes encountered in the review were the aids foundation in kwazulu-natal and the mpumalanga project support association (m psal. these organisations are ngos providing a support function to community-based organisations (cbos) with regard to mobilising and channelling funds, providing technical assistance and training for home-based care, project management, report writing, and project monitoring and evaluation. such structures could be one vehicle for public-ngo partnerships to promote the development of community-based action, and could also play a coordination and standard-setting role. advocacy and community mobilisation projects an example of this is the thandanani project in pietermaritzburg. thandanani has created community child care committees (ccccs) comprised of community leaders and residents, whose task is to identify children who are abandoned, abused or at risk of being orphaned. the cccc will not only protect the rights of the child but will also help in accessing child welfare grants, medical and home-based care and schooling. the ccccs do not themselves provide services, but have created linkages and referral relationships with social, medical, nutritional, child welfare and other support service providers. community mobilisation programmes are often perceived as being easy to develop. however, they are a timeconsuming endeavour requiring specific skills in the areas of motivating and sustaining community involvement, developing partnerships and linkages, and creating opportunities where all participants feel equally respected and able to make a valued contribution. drop-in centres/support groups this model is perhaps the most common form of community-based care and support. it consists of a simple facility where people can receive hiv counselling and education, and can participate in support group activities. most providers felt that the traditional support group model centred on verbal problem exploration and psychosocial counselling was not sufficient, and combined it with an income-generating activity (lgal. this has a twofold benefit participants are engaged in an activity that facilitates conversation, and the activity has the potential to generate some income. the iga activities included beaded ribbons, paper bowls, hats from plastic bags, tablecloths, gardening, chicken farming and making foodstuffs. in practice very few projects actually manage to generate income, and as one person put it, 'i have a room full of things people have made but we can't sell them. they're just packed in there.' one project had acquired maize-grinding and fence-making machines, an oven for baking bread, juice-making equipment and battery-recharging facilities. with the income generated they were able to fund the activities of the drop-in centre. support groups were reported to build self-confidence, help people cope with their diagnosis, overcome depression and create social networks for people who are isolated. bonds formed outside of the group often result in sick members being assisted with small chores. through support group activities, hiv-infected adults can also be engaged in discussions about the future placement of their july 2000------------m southhln acrican journal of hv medici t children, and can acquire the documentation necessary to access welfare grants. home visiting drop-in centre activities may include a home or \friendly' visiting service. volunteers visit patients in their homes and spend time talking and educating patients and their family about basic care needs. they also provide support with cooking, cleaning and helping with errands, including accompanying patients to health facilities. they may also arrange access to food parceis and other material support. comprehensive home·based care in addition to the above, comprehensive home-based care programmes provide varying degrees of palliative care. these programmes tend to be run by more established ngos (such as hospice, the red cross society and church-linked groups). a number of such relatively large projects, catering for hundreds as opposed to tens of clientsl were identified in the review. training of caregivers includes supportive counselling, cleaning and dressing of wounds, oral hygiene, supervision of drug taking and in certain instances necrotic wound care/ pain management and diagnosis of opportunistic infections. the package of services also often includes oots (directly observed treatment, shortcourse) for tuberculosis. at least two projects had been trained in and adopted the zimbabwean 'fact' model. this has a strong spiritual component, and many of the volunteers are recruited from the church. all projects had invested considerable energy in creating partnerships and referral networks. relationships are formed with the local welfare department, schools, businesses, hospitals, respite care facilities and clinics. building these partnerships is time-consuming. however, once created, the package of services that can be offered to clients is comprehensive. care of orphans many community-based hiviaids care and support programmes visited had been confronted with the needs of orphaned children, and felt they had no option but to address these needs. the models of care and support for orphaned children included: 1. the extended family approach: a family member is identified to care for orphans after death of the parents. often this family member is a grandmother. 2. child-headed househoids: when parents die and there is a sibling 15 years or older, social services may work with that chiid to keep the family together. the younger siblings remain in their home, with the older sibling acting as a parent. they may receive support from volunteers who will visit the household to ensure that they are coping and to resolve problems. 3. 'create a family' or 'cluster foster care.' this intervention, based in durban, involves identifying a surrogate mother, who is hired to care for six orphans in the community. she is provided with a home, in which they all live, and she raises the children as though they were her own. with the assistance of the durban child welfare society, foster care grants are accessed to pay for school fees and uniforms, and the foster parent receives a stipend. this model serves as a job creation opportunity for women. 4. placing adults (usually older women) in the homes of orphaned children: this approach has worked successfully in the masoyi project (mpumalangaj. this approach benefits both the children and the adult, as often the latter lives in the poorest of housing (mud shacks) while the children tend to live in better quality brick houses. the key tasks in child care and support programmes are accessing welfare benefits (child care and foster grants), including the documents required for grants, maintaining children in school, and ensuring that basic necessities, such as food and clothes, are provided. challenges to community-based care and support managing avolunteer base with a few notable exceptions, most organisations had only one or two paid staff members, with the bulk of services provided by volunteers, who mayor may not receive a stipend. recruiting and maintaining commitment from volunteers is one of the main challenges facing projects and many programme managers admitted to struggling with this aspect. interviewees reported high turnovers of volunteers who, once trained, moved on to other opportunities, dropped out, or were unreliable. conversely, if a significant stipend was provided, a major concern was its sustainability over the long term. non-financial incentives, such as a sense of belonging a supportive work environment opportunities to gain skills and passing a rigorous screening process all appear to be crucial to maintaining volunteer commitment. as one project interviewee put it: 'the volunteers in these projects undergo a 4 to 6 month training, and not everyone makes it ...' organisational structure, staff capacity and access to resources project readiness and ability to provide services differed widely among the projects visited. programmes started by and within poor communities seemed to have the most difficulty developing strong and sustainable programmes. although many of these community-based organisations had great intentions, they did not have sufficient internal capacity to implement those ideas. they also lacked thf southtrn african journal of hiv mfoicine ------------july 2000 resources. in many cases, the project managers accessed some initial funding (such as pension payouts) to get started, but experienced difficulty as this money ran out. they did not have sufficient knowledge on how to maintain documentation and how to account fori or manage, funds. one retired nurse commented: \i'm a nurse ~ not an administrator. i don't know about budgeting and administration. [know how to take care of people.' another nurse voiced her frustration: \we work from hand to mouth.' the larger ngos with a sizeable infrastructure, history of programme development, and connections with players locally and internationally, appeared to be in a much better position. they were able to provide services over a larger area, at a higher level, and possibly with greater efficiency <through economies of scalel than some of the smaller projects visited. ability to form linkages and partnerships programmes that were able to develop partnerships or referral relationships with other service and care agencies were more successful than those that did not. relationships with welfare agencies, hospitals and clinics were cited as being particularly important. several projects had agreements with clinic and hospital providers, facilitating admissions to hospital or access to prescriptions and medications. in some cases, programmes also negotiated supplies of antiseptic solution, gloves, bandages and other home~based care necessities from hospital and clinic partners, in exchange for providing care to discharged patients in the community. some projects were also able to engage local businesses to provide food parcels, soup kitchens, transport or office supplies. lack of standardisation there was little standardisation across projects with regard to training and the quality of services provided. some programrnes sent their volunteers and staff to formally established training programmes, while others conducted their own in~house training. hence, the content and quality of care varied enormously. conclusions while a rich base of experience in community~based care and support is being developed in south africa, access to these services is still far from universal. large~scale technical assistance and capacity~building programmes, networking and co~ordinating opportunities, development and dissemination of standards/guidelines, and the establishment of monitoring and evaluation systems are all essential to the creation of an effective and sustainable community~based care and support movement. there are still many unanswered questions as to the feasibility of extending community~based care and support activities to all parts of the country, both in terms of being able to mobilise activities on a wide scale and the costs of programmes. it is clear that government has an important role to play in supporting and facilitating wider access to community-based care and support, and in ensuring a basic health and welfare safety net. perhaps the biggest challenge will be the ability to form meaningful partnerships between government at all levels and the nongovernmental sector. this may necessitate a paradigm shift in the minds of many health and welfare professionals, 'from the assumption that counselling, treatment and care of patients can only be done by highly technical personnel, to an appreciation that in every family and community there is some level of counselling and caring. scientists must cease perceiving themselves as custodians but... rather as facilitators. llo references 1. zwi kj, pettifor jm, soderlund rn. paediatric hospital admissions at a south african urban regional hospital: the impact of hiv 1992 1997. ann trop paediatr 1999; 19: 135-142. 2. colvin m, kleinschmidt r. the impact of hiv and aids on the medical wards of a tertiary hospital in kwazulu-natal, south africa. draft report prepared for the department of health. durban: medical research council <undated). 3. abdool karim q, matthews c, gutmacher s, wilkinson 0, abdool karim ss. hiv/aids and stos in south africa. appendix 15, volume 3. in: frolich j, ed. comprehensive report: the south african national std/hiv/aids review 4 ~ 18 july 1997. pretoria: medica! research council, 1997. 4. mutangadura g, mukurazita 0, jackson h. a review of household and community responses to the hiv/aids epidemic in the rural areas of sub-saharan africa. geneva: unalds, 1999. 5. hansen k, woelk g, jackson h, et al. the cost of home-based care for hivjaids patients in zimbabwe. aids care 1998; 10: 757-758. 6. foster g, nyaruwa t, muchaneta l. increased scope and decreased costs of home care. safaids news 1999; 70): 6-9. 7. kaleeba n, kalibala s, kaseje m, et al. participatory evaluation of counselling, medical and social services of the aids support organisation (tasol in uganda. aids care 1997; 9(1): 13-26. 8. mhloyi m. care in africa. plenary address to the 11th international conference on aids and stds in africa. lusaka, 16 21 september 1999. the southern african journal of hiv medicine                                                          winter  2008 m e s s a g e f r o m t h e e x e c u t i v e you will, i hope, be reading this at or immediately after the durban aids conference, an extravaganza held every two years and hosted this year by the journal editor, professor linda-gail bekker. a huge amount of work goes into these conferences, and we hope this one is a massive success. the society, funded by a generous grant from mtn, is supporting the skills-building workshops. the free state antiretroviral crisis is still not over, but appears to be a microcosm for the rest of south africa. under-funding of the health system, appalling oversight by the previous minister of health and the south african cabinet, loss of health care staff and increasing costs of medical care have created multiple crises at various levels. combined with a cholera outbreak that paradoxically has nothing to do with the health department and everything to do with crumbling municipal water infrastructure, things look grim for south africa, especially when compared with some of its neighbours. botswana boasts an antiretroviral programme that would be the envy of some developed world countries. the society asked its members to filter through any reports of rationing or drug stock-outs, triggering a deluge of emails, faxes and phone calls, not just from the free state but from across the country. reports of other stock-outs, as well as staff shortages, have been fed to the department. in late february our new minister of health, barbara hogan, met with members of the society, the aids law project, the treatment action campaign and the south african national aids council (sanac) after we raised issues regarding the free state problems. we were deeply impressed with her frankness and commitment, as well as the extent of her grasp of the problem. she has requested help in the form of reporting problems, and we are hoping to institute a more formal ‘problem helpline’ in the future. the minister needs help to fix the south african health care system. the society is determined to give her whatever help we can. francois venter president summer  2009                                                            the southern african journal of hiv medicine                                                   dr francois venter (hiv clinicians society), jonathan berger (aids law project), mark heywood (alp, south african national aids council), minister barbara hogan (department of health), adila hassan (alp), and professor helen rees (sanac, reproductive health and hiv research unit). f r o m t h e e di tor what an exciting time we are having in terms of hiv meetings in south africa this year! i can't wait to finally get to the 4th sa hiv conference in durban, and in july we will be back here in the fairest cape at the hiv pathogenesis conference – always very worth while in terms of the new findings and new thinking it attracts. both conferences have had an excellent number of abstracts, so peer reviewed input at both is going to be great. this edition of the journal is the usual smorgasbord of hiv issues from guidelines to clinical, ethics and debate. it will be available at the durban conference. honermann and colleagues explore the ethicolegal aspects of labour practices related to hiv-infected employees, and in particular the stance that the military took on hiv-infected recruits. firnhaber and colleagues re-look at hepatitis b and hiv co-infection and review diagnosis, management and outlook. osih and venter give us a rapid-fire tour de force of the recent conference on retroviruses and opportunistic infections held in montreal in february. polly clayden, a favourite author, brings us a clear review on the state of art in relation to pregnancy. the clinician's society and a number of other groups present their consensus statement of timing for initiation of art and who in our patient load should receive expedited art commencement – an important reminder that despite the pervasive notion of ‘there is no emergency in hiv’, unnecessary delays in treatment can result in a great deal of morbidity and mortality. practitioners need to be sure that perfection (taking many weeks to get a patient to the point of perfect ‘readiness’) does not become the enemy of the good. we have two excellent pulmonary clinical case studies, one adult and one paediatric, and on the prevention front kenyon and badri explore the role of concurrency in sti and hiv prevalence – watch this space: i think we will be hearing much more about multiple concurrent partnerships in durban and beyond. soul city is currently also launching their ‘one love’ campaign. finally, a cheerful project report from hofmeyr and colleagues on the keiskamma aids treatment programme in the eastern cape is a lesson on what can be done at primary community level to save lives and turn bad statistics around. wishing you good reading and great conferencing! linda-gail bekker editor � message from the executive.indd 5 3/16/09 2:17:56 pm abstract introduction research design results discussion conclusion potential study limitations acknowledgements references about the author(s) thandiwe manjati division of haematology, department of pathology, stellenbosch university, south africa division of haematopathology, national health laboratory service, tygerberg hospital, cape town, south africa bongani nkambule division of haematopathology, national health laboratory service, tygerberg hospital, cape town, south africa department of physiology, school of laboratory and medical sciences, university of kwazulu-natal, south africa hayley ipp division of haematology, department of pathology, stellenbosch university, south africa division of haematopathology, national health laboratory service, tygerberg hospital, cape town, south africa citation manjati t, nkambule b. immune activation is associated with decreased thymic function in asymptomatic, untreated hiv-infected individuals. s afr j hiv med. 2016;17(1), a445. http://dx.doi.org/10.4102/sajhivmed.v17i1.445 original research immune activation is associated with decreased thymic function in asymptomatic, untreated hiv-infected individuals thandiwe manjati, bongani nkambule, hayley ipp received: 10 nov. 2015; accepted: 25 may 2016; published: 28 july 2016 copyright: © 2016. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: reduced thymic function causes poor immunological reconstitution in human immunodeficiency virus (hiv)-positive patients on combined antiretroviral therapy (cart). the association between immune activation and thymic function in asymptomatic hiv-positive treatment-naive individuals has thus far not been investigated. aims and objectives: to optimise a five-colour flow cytometric assay for measurement of thymic function by measuring recent thymic emigrants (rtes) in treatment-naive hiv-infected patients and healthy controls and correlate results with levels of immune activation, cd4 counts and viral load. methods: blood obtained from 53 consenting hiv-positive individuals and 32 controls recruited from hiv prevention and testing clinic in cape town, south africa. rtes were measured (cd3+/cd4+/cd45ra+/cd31+/cd62l+) and levels were correlated with cd4 counts of hiv-infected individuals, log viral load and levels of immune activation (cd8+/cd38+ t-cells). results: hiv-infected individuals had reduced frequencies of rtes when compared to controls (p = 0.0035). levels of immune activation were inversely correlated with thymic function (p = 0.0403), and the thymic function in hiv-infected individuals showed no significant correlation with cd4 counts (p = 0.31559) and viral load (p = 0.20628). conclusions: there was impaired thymic function in hiv-infected individuals, which was associated with increased levels of immune activation. the thymic dysfunction was not associated with cd4 counts and viral load. immune activation may result in inflammatory damage to the thymus and subsequent thymic dysfunction, and cd4 counts and viral load may not necessarily reflect thymic dysfunction in hiv. introduction background human immunodeficiency virus (hiv) infection is characterised by depletion of naive and memory cd4 t-cells due to its ability to damage both thymic and peripheral t-cell homeostasis. in addition, there is evidence of direct infection of thymocytes by hiv, which results in defective thymopoiesis and apoptosis of cd4 t-cells.1,2 within a year of initiation of combined antiretroviral therapy (cart), the thymus of adult hiv-positive patients on cart expands,3 and evidence has shown that infected adults’ thymuses are still functional despite physiological involution. therefore, the thymus plays a role in immune recovery or contributes to the lack of immune reconstitution in hiv-infected patients.4 in some studies, it has been shown that immune reconstitution in adults is mainly from the memory t-cell pool, whereas in children, it is mainly from the naive t-cell subset.5 literature review most studies that have assessed thymic output in hiv patients have shown reduced output prior to initiating cart and significant thymic output increase after therapy initiation.4,5,6,7 the ongoing viraemia prior to cart initiation may cause proliferation of recent thymic emigrants (rtes) and result in differentiation to memory t-cells, which are more susceptible to hiv-1 infection than naive t-cells. this, in addition to reduced thymic function, reduces the number of rtes in hiv infection.8 in addition to improved thymic function, another mechanism for the increase seen after initiation of cart is the release of lymphocytes that have been sequestered in lymphoid tissue during hiv replication.7 the effect of the increase due to memory t-cells redistributed from lymph nodes wanes after a few weeks of therapy, and the increase due to the production of new naive t-cells derived from thymopoiesis is maintained for a longer period.6,9 this entrapment of rtes in lymphoid tissue was particularly seen in individuals with high viral loads.10 immune activation in hiv infection chronic infections such as hiv infection are associated with chronic inflammation that may be systemic, affecting the whole body and leading to persistent immune activation with cd4 t-cell activation and turnover.11,12 immune dysregulation causes a sustained increase in pro-inflammatory cytokines and erosion of immune defences. persistent t-cell activation accelerates their maturation, cell growth and division. immune activation in hiv leads to premature t-cell ‘burn out’ or clonal exhaustion and apoptosis.11,12 an important mechanism contributing to immune activation is the early damage to the gastrointestinal mucosa, which results in the ongoing translocation of microbes and microbial products into the systemic circulation.12 this is one of the causes of poor immune recovery after cart.1,12,13 chronic immune activation in hiv results in poor immune recovery and thus poor outcome and faster disease progression as well as end organ complications.12 chronic immune activation in hiv causes increased proliferation of thymocytes, which in the long term causes clonal exhaustion of t-cells and inflammatory damage to the lymphoid tissue.1,12 patients with a large thymus have shown a better immune reconstitution when compared with those with a small thymus; therefore, thymopoiesis is important in immune reconstitution. initiating therapy whilst thymic function is still good may be important in order to improve clinical outcomes.13 there are only few studies that have linked immune activation to thymic dysfunction in hiv-infected people.14 cd31 and cd62l cell markers cd31 is a cell surface marker expressed preferentially by naive, t-cell receptor excision circle (trec)-rich t-cells that have undergone a low number of t-cell divisions; therefore, cd31 can be used as a marker for rtes.15,16,17,18,19 it is a 130-kda transmembrane glycoprotein expressed by endothelial cells, platelets, monocytes, neutrophils and certain t-cell subsets. the average trec content in cd3+/cd4+/cd45ra+/cd31+/cd62l+ t-cells is 18 times higher than in cd3+/cd4+/cd45ra+/cd31-/cd62l+ t-cells confirming the strong correlation between cd31-expressing naive cd4 t-cells and the presence of trec.15 cd31 is downregulated on the majority of cd4 t-cells upon their transition to the memory phenotype.15 a progressive decrease of percentages and absolute numbers of rtes has been found associated with ageing, and in addition, cd31 is downregulated during homeostatic expansion of naive t-cells.13 cd62l (l-selectin) is an adhesion molecule that allows t-cells to enter secondary lymphoid tissues via high endothelial venules. early studies showed that bright cd62l expression was also a marker found on rtes.20,21,22 it is expressed by naive t-cells and central memory t-cells and is absent on effector memory t-cells. it is upregulated by thymocytes23 and plays an essential role in lymphocyte homing to lymphoid tissue and sites of inflammation.23,24 immune activation at the thymic site may result in inflammatory damage to the thymus and subsequent thymic dysfunction.1 this study investigated hiv-positive individuals who were not yet started on cart and measured thymic function using flow cytometry (cd31 and cd62l) as well as levels of immune activation (cd38 expression on cd8 t-cells). research design research approach and methods this was a cross-sectional study of 53 consenting, untreated asymptomatic hiv-infected black south african adults and 32 uninfected controls aged > 21 years. the study was approved by the university of stellenbosch, faculty of health sciences, human research ethics committee (hrec n07/09/197). patients and controls were recruited from an hiv prevention and testing clinic in cape town, south africa. all individuals gave informed consent prior to their involvement in the study. whole blood samples of 4 ml were collected from patients and controls into a heparin tube for measurement of rtes and levels of immune activation, and 5 ml of blood was collected into an edta tube for cd4 count and viral load. measurement of recent thymic emigrant frequency using flow cytometry the cell surface molecule expression was monitored by staining cells with the following fluorochrome-labelled monoclonal antibodies: cd31 fitc 5.6e, cd4 pe 13b8.2, cd45ra ecd j.33, cd62l pc5 dreg56 and cd3pc7 ucht1. the optimal volumes of each antibody were mixed in a 5 µl cocktail and titrated in dilution experiments. the samples with 50 µl of heparinised blood and antibody cocktail were then incubated in the dark for 15 min at room temperature. five hundred microlitres of phosphate-buffered saline (pbs) staining buffer was added and samples were analysed immediately. data acquisition was done using the beckman coulter fc500 five-colour flow cytometer calibur and cxp software. gating strategy the cell type and size were identified by size, granularity and positive expression of surface markers cd31, cd62l and cd45ra specific for rtes on cd4 t-cells. initial gating was performed on cd3-positive population with low side scatter (t-cells). secondary gating of cd45ra-positive cells and cd4-positive cells from the cd3-positive t-cells was done. cd3/cd45ra/cd4-positive naive t-cells were further analysed for cd31and cd62l-positivity (rtes). controls or populations of cells negative for cd31 and cd62l were used to establish the ‘cut-off’ values for cd31and cd62l-positivity. rtes were described as cd3+/cd4+/cd45ra+/cd31+/cd62l+ t-cells. levels of expression of these markers were correlated with cd4 counts, viral loads, levels of activation and patient’s age using spearman’s r test. cd4 t-cell count and viral load measurements the bd multitest cd3-fitc/cd8-pe/cd45-percp/cd4-apc reagent and bd trucount tubes (bd biosciences, san jose, ca) were utilised for the measurement of cd4 t-cell count. for viral load measurements, blood samples were collected into 5 ml edta tubes, which were centrifuged at 20°c at 300 g for 12 min. one millilitre of plasma was transferred into a greiner bio-one cryotube (greiner bio-one gmbh, frickenhausen, germany) and sent for viral load testing. the viral load assay performed was a nuclisenseasyq® hiv-1 v1.2 viral load test (biomerieux inc., boxtel, the netherlands), which has a detection range of 1.60–6.7 log10 copies/ml. both these tests were performed at the division of medical virology, faculty of health sciences, stellenbosch university, which is accredited by the south african national accreditation system (sanas). measurements of the percentage of cd8+ t-cells expressing cd38 this measurement was performed using flow cytometry. briefly, 50 µl of heparinised whole blood was stained with a titrated monoclonal antibody cocktail containing cd8 per-cp, cd38 apc and cd3 fitc (bd biosciences, san jose, ca). data acquisition was performed using a bd facs calibur instrument, and analysis was done using the bd cell quest pro (version 2) software. statistical analysis the software used for statistical analysis was graph pad prism version 5.0 for windows, graph pad software, ca, usa. mann–whitney u test was used to determine % cd38+/8+ t-cells (levels of immune activation) and reported as the median and interquartile range, and unpaired t-test was used to determine % cd3+/cd4+/cd45ra+/cd62l+/cd31+ t-cells (rtes) between the hiv-infected and control groups and reported as mean and standard deviation. non-parametric data of hiv-positive individuals were analysed using spearman’s r correlations. all p-values were considered as significant when < 0.05. these analyses were performed as single experiments. results the cohort consisted of 85 consenting individuals with similar ages and demographics. of these, 53 were hiv-infected individuals and 32 uninfected controls with median ages (in years): control group 27 [23–34] versus hiv group 28 [25–35], p = 0.2113). despite being clinically asymptomatic, the hiv-positive group had significantly lower cd4 counts when compared to the control group (p < 0.0001) as shown in table 1. table 1: participants’ demographics and disease parameters. rtes were significantly reduced in the hiv-infected group, with mean % value of 40.13 ± 21.72 in hiv-positive group versus 54.96 ± 20.10 in control group (p = 0.0035) (as shown in figure 1). immune activation levels were significantly increased in the hiv group as determined by the marker of activation, cd38+/8+-positive t-cells, which was increased in the hiv-infected group (26.1) versus control group (8.610) with a p-value of < 0.0001 (as shown in figure 2). figure 1: baseline levels of per cent of cd4+/cd45ra+/cd62l+/cd31+ t-cells in hiv-positive versus control groups. figure 2: baseline levels of % of cd38+/cd8+ t-cells in hiv-positive versus control groups. further analysis of hiv group was done using spearman’s r correlations for non-parametric data (as shown in table 2). table 2: spearman’s r correlations for hiv group. log viral load correlated inversely with the cd4 counts, whereas there was a direct correlation between log viral load and levels of immune activation (r = 0.431, p = 0.0027). the cd4 count correlated inversely with levels of immune activation (r = -0.397, p = 0.0035). levels of immune activation correlated inversely with the number of rtes (p = 0.0403) in this hiv-positive group. there were no significant correlations between age in the hiv-positive cohort and other parameters such as cd4 counts, viral load, levels of immune activation and rtes in this group, and rtes did not show a significant correlation with the cd4 counts or the log viral load. discussion rtes refer to t-cells that have undergone only a few cellular divisions after leaving the thymus.25,26 these naive t-cells have recently exited the thymus and have not undergone peripheral t-cell proliferation and antigen selection. they have high trecs and their numbers in peripheral blood depend on the magnitude of thymic export.17 therefore, measuring the number of rtes allows assessment of the thymic contribution to the peripheral t-cell pool. trec concentrations in rtes are affected by factors such as lymphopenic conditions, where absolute numbers of trecs can be influenced by dilution factors due to peripheral expansion of naive and memory t-cells, for example, after haematopoietic stem cell transplantation or in hiv-infected patients after cart15; ageing also decreases the number of trecs 50–100 fold.15 however, controversy exists as to whether trec concentrations are a good marker for rte, because trec concentrations are also affected by peripheral t-cell turnover events, such as t-cell division and death.17,27,28 in hiv infection and other lymphopenic diseases, t-cell homeostasis is maintained by the ability of the thymus to export new naive t-cells.29 therefore, thymic function can be monitored in conditions that influence t-cell depletion and reconstitution, such as hiv-1 infection, bone marrow transplantation and immunosuppressive therapy.30 in this study, we measured rtes using flow cytometry, with particular use of the marker cd31. we designed and optimised a flow cytometry panel that could be used as a measure of thymic function in asymptomatic, treatment-naive hiv-infected patients. we showed that rtes were significantly decreased in this group, even with cd4 counts median of 354 cells/mm3 (which is > 350 cells/mm3). the treatment cut-off value in south africa had been below 350 cells/mm3 until recently. furthermore, we showed for the first time to our knowledge, levels of rtes by flow cytometry correlated inversely with immune activation levels in untreated hiv-infected individuals. this supports the concept that ongoing immune activation has a damaging effect on thymic function in untreated hiv infection. interestingly, rte levels did not correlate with viral load nor cd4 count suggesting that these parameters do not necessarily reflect thymic dysfunction at this stage of the disease. most studies that have assessed thymic output in hiv patients have shown reduced output prior to initiating cart and significant thymic output increase after therapy initiation.4,6,7 however, these studies have not shown the difference between hiv-positive individuals and uninfected controls, and cd4 counts were lower (200–300 cells/mm3) and viral log levels were higher (4.8–5.0 log copies/ml) in comparison with our hiv-positive group. in addition, the studies that compared untreated hiv-positive individuals with uninfected controls were conducted in children. the results of our study have highlighted previous literature findings, wherein untreated hiv-positive individuals have increased immune activation when compared to uninfected controls.11,31 furthermore, we showed that the higher levels of immune activation (as demonstrated by the increased percentage of cd38+/cd8+ t-cells) were significantly associated with lower cd4 counts and higher viral loads. in untreated hiv-positive individuals, the activation marker cd38 indicates rapid clinical progression of disease and death more strongly than cd4+ t-cell counts and plasma hiv rna levels.32 there is evidence that thymic output is required to maintain efficient gut mucosal defence.32 bourgeois et al. showed in a mouse model of chemical thymomectomy that loss of gut immunity in hiv infection, particularly th17 cells, leads to loss of barrier integrity and subsequent bacterial translocation and microbial products into circulation, which results in chronic immune activation.29 these findings suggest that augmenting thymic output can be used to correct aberrant activation caused by hiv infection or hiv-induced microbial translocation.29,32 our study findings highlight the concept that ongoing immune activation impacts thymic production of naive t-cells thus resulting in depletion of the naive t-cell pool seen in hiv infection. this is supported by a study conducted by bandera et al. of ex-vivo thymuses from hiv-positive individuals and uninfected controls.1 they analysed markers of t-cell differentiation and activation at different stages of thymopoiesis and found a significantly higher proportion of activated and proliferating thymocytes at all stages of thymopoiesis in hiv-infected patients compared to controls. they suggested that this increased activation and proliferation of thymocytes at the thymic site might in the long term cause clonal exhaustion of t-cells (‘burn out’) and damage to lymphoid tissue.1 the immune activation at the thymic site is likely caused by bystander mechanisms and sustained by homeostatic proliferation and may result in inflammatory damage leading to thymic dysfunction.1 some studies have reported that hiv can directly infect the thymus thereby compromising its integrity.2,33 reduced t-cell restoration has been reported to be caused by the effects of atrophy or shrinkage of the thymus. using the simian immunodeficiency virus-infected rhesus macaques, wykrzykowska et al. showed that in the first 7 days of infection, the thymus has a regenerative capacity with increased cell proliferation; however, from 24 weeks after infection there was evidence of severe thymic damage.2 this group concluded that the regenerative capacity of the thymus is limited in hiv infection. early thymic dysfunction in children is also related to rapid progression to acquired immune deficiency syndrome (aids).34 middle-aged people with hiv showed evidence of immunosenescence (ageing of the immune system) resembling that of hiv-negative individuals two decades older. the ongoing immune activation and inflammation due to constant stimulation by hiv or other chronic infections accelerates the process of immunosenescence.11,35 our findings showed an association between thymic function in hiv infection and levels of immune activation. there seems to be a vicious cycle that results from immune activation causing damage to the thymus and thus causing dysfunctional thymic output. in turn, the reduced thymic output results in immune activation due to loss of mucosal barrier integrity and subsequent bacterial translocation and microbial products into circulation. conclusion there is mounting evidence of the contribution by the adult thymus to immune reconstitution in hiv infection.1,35 larger thymic size was associated with higher cd4 counts and higher thymic outputs.35 we therefore suggest that initiating cart in patients with poor thymic function could be associated with poor immunological response. this study supports earlier initiation of cart, before thymic damage or irreversible dysfunction sets in. this use of flow cytometry markers of rtes in conjunction with a marker of immune activation would be a valuable addition to the assessment of thymic function in these individuals. this panel could then be used to follow up thymic output after initiation of therapy. other methods used to estimate thymic function include measurements of thymic volume using computed tomography (ct) scan and evaluation of trec-bearing cells by quantitative polymerase chain reaction (pcr).3 however, these techniques are expensive and trec data may be difficult to interpret.36 this study presents a robust alternative method that can be used simultaneously to measure the levels of immune activation. further studies on the measurement of thymic function and levels of immune activation in hiv-positive patients with cd4 counts > 500 cells/mm3 are recommended. this would further establish whether immune dysfunction due to decreased thymic output is occurring at even earlier stages of the infection. these studies would support the earlier intervention with art for the protection of thymic function and better immunologic recovery. it will be important to develop novel therapeutic strategies to limit immune activation and in doing so, protect the thymus from inevitable damage and dysfunction. potential study limitations this study was conducted on the black south african population group and therefore may not be representative of other racial groups in south africa. the hiv cohort consisted of more females versus males. it is not known whether the hormonal differences between the two sexes can influence thymic function. it was also unknown how long each hiv-positive patient had been infected without treatment, and therefore, we do not know if the length of infection influences thymic output. the hiv-infected individuals are defined as being asymptomatic. symptoms were determined by clinical questioning and examination but no further special investigations such as cxr were performed; so subclinical infections may have been missed. finally, this was a small study group and a follow-up study on a larger cohort is considered. acknowledgements this work was supported by a grant from the national health laboratory service, south africa. the principal funding recipient is dr hayley ipp. the authors thank the participants and health workers for their involvement in this study. the authors especially thank their external reviewers for their drafts. the authors also acknowledge university of stellenbosch, beckman coulter flow cytometry research and training laboratory facility at tygerberg hospital, south africa, who provided the flow cytometer calibur used in this study. competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions tsm is the main author and corresponding author. she contributed to the conception and design of the study, acquisition of data (carried out flow cytometry assays), as well as analysis and interpretation of data. she also drafted the manuscript and carried out the corrections. hi participated in conception and design of the study, analysis and interpretation of data, critically revising the script and giving the final approval of the version to be published. bn participated in acquisition of data (carried out 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2010;1:4–10. http://dx.doi.org/10.1007/s11904-009-0038-4 papiernik m, brossard y, mulliez n, et al. thymic abnormalities in fetuses aborted from human immunodeficiency virus type 1 seropositive women. pediatrics. 1992;2:297–301. kourtis, ap, ibegbu c, nahmias aj, et al. early progression of disease in hiv-infected infants with thymus dysfunction. n engl j med. 1996;19:1431–1436. http://dx.doi.org/10.1056/nejm199611073351904 kolte l. thymic function in hiv-infection. dan med j. 2013;4:b4622. de boer rj. estimating the role of thymic output in hiv infection. curr opin hiv aids. 2006;1:16–21. http://dx.doi.org/10.1097/01.coh.0000194105.12816.6a j u ly 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e ‘i have twelve minutes to give this talk, but i can make my point in twelve seconds: there’s a lot of tb in our hiv services and we need to do something about it!’ said dr steve lawn of the desmond tutu hiv centre at the university of cape town at the start of the ‘3i’s satellite symposium’ held on 31 march 2009, just before the 4th south african aids conference (saac). hiv-infected individuals, especially those requiring antiretroviral therapy (art), are at a greatly increased risk of developing active tuberculosis and one consequence of this has been the resurgent tb epidemic in sub-saharan africa and other settings with a high burden of hiv. people working in hiv/art services can reduce the risk of tb in people with hiv by performing three activities that the world health organization (who) has promoted as the ‘3i’s’ strategy: infection control (measures to reduce the spread of tb, especially in health facilities); intensified case finding to proactively identify tb in people with hiv; and isoniazid preventive therapy to prevent active tb. south africa and other countries have endorsed the 3i’s strategy as policy, but implementation has been slow and somewhat limited. for this purpose, the 3i’s symposium, sponsored by the aurum institute, thibela, and the consortium to respond effectively to the aids tb epidemic (create), was held to increase awareness of these measures to reduce hiv-associated tb and to encourage the implementation of existing guidelines. ‘just do it should be the mantra of this symposium,’ professor gavin churchyard of the aurum institute told the standing-room-only audience. but to show just how to do it, more than a dozen experts at the meeting spoke about the gaps between policy and present practice, identified the barriers to implementation and offered possible solutions. several recently completed or ongoing research studies were described that could help guide future policy and implementation. speakers shared their hands-on experience about on how to put the 3i’s into practice. there has been a threefold jump in mortality in south africa over the past several years, and although there is often an underlying disease, such as hiv, ‘tb has been the most commonly reported cause of death on the death certificate’, according to professor anton stoltz of the foundation for professional development, ‘and it is killing people in the prime of their lives.’ globally south africa ranks fifth in the absolute number of people with new smear-positive tb, but the countries with heavier burdens (such as china, india and indonesia) are far more populous. swaziland and south africa have the highest incidence rates per capita in the world (with close to 1 000 cases per 100 000 people), according to 2006 data from the who. at the same time, the type of tb being diagnosed in south africa has changed over the past decade with a dramatic increase in smear-negative tb, extrapulmonary tb, retreatment tb and now increasingly drug resistant tb. professor stoltz listed multiple factors that could contribute to the tb epidemic, starting with overpopulation, climate change and malnutrition, as well as conflict and turmoil leading to displacement and migration. lack of strong political will to provide adequate support of the health system has resulted in low cure rates, high default rates and inadequate follow-up of patients, ultimately spawning an epidemic of drug-resistant tb. poor infection control practice in health facilities has led to the spread of tb (drug-susceptible and drug-resistant) to other patients and to health care workers. economic hardship and poor living conditions lead to spread of tb in communities as well. the 3i’s satellite symposium: reducing the risk of tuberculosis in hivinfected individuals 4th southern african aids conference, 31 march 2009, durban c o n f e r e n c e r e p o r t gavin j churchyard, mb bch, phd aurum institute for health research, johannesburg lois j eldred, drph johns hopkins university school of medicine, baltimore, md, usa overview of tb/hiv in south africa in the hiv and tb clinics 38 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u ly 2 0 0 9 ‘poor people living in shacks with little air circulation are at high risk of infecting each other,’ said professor stoltz. ‘but by far the biggest driver of tb is hiv.’ nowhere is this more evident than in the western cape of south africa, where dr lawn said that ‘three oceans have come together, the atlantic ocean on the west and indian ocean on the east; and in between the two there is a vast ocean of tb and hiv’. in fact, in one of the peri-urban communities where dr lawn works, tb notifications exceed 2 000 per 100 000 rates unprecedented in the era of modern multidrug chemotherapy despite a model local tb programme. everyone living in this resource-strapped community is at substantial risk of tb, but the risk is greatest in people with hiv, even when they are on art. ‘the burden of tb among people with hiv before, during and after art initiation is huge,’ according to dr lawn. in one analysis of the cumulative burden of tb in people arriving into an art clinic in gugulethu, ‘more than half have had one or more episodes of tb before they even set foot in the door. another quarter of the patients either have active tb on treatment or previously undiagnosed tb. so, at baseline, two thirds of the people either have had or have tb currently,’ said dr lawn. most of the previous tb cases occurred within the 2 3 years before initiating art. in another study of 235 patients enrolling into the art programme, dr lawn and colleagues actively screened for tb using culture instead of induced sputum. they found that 25% (n=58) had culture-positive tb and the risk was even greater (at 38%) in those with cd4 counts below 100.1 but in the absence of culture it would have been difficult to identify everyone with tb 22% of those with culture-positive tb had no tb symptoms (cough, fever, night sweats or weight loss), 30% had no sign of tb on chest radiograph, and fluorescent smear microscopy was positive in only 14%. culture, while sensitive, took over 3 weeks to produce a diagnosis, and drug sensitivity testing (via lowensteinjensen medium) took 3 months. once on art, the risk of tb is extremely high during the first 3 months, probably due to unmasking of tb missed by baseline screening.2 during the first year on art in the gugulethu study, about 11% developed incident tb after which the risk plateaued at around 4 5% per year. even after 3 years on art, the tb incidence remained four or five times higher than the background rate in the hiv-negative p opulation. the key determinant of tb risk is a person’s cd4 cell count, and those with poor immune recovery on art are at even higher risk. in the gugulethu cohort, for every rise of 100 cells/µl, there was a 25% reduction in risk of tb. even with optimal cd4 cell count recovery (over 500 cells/µl), the incidence of tb remains about twice the background rate in the hiv-negative population. conversely, many people are only diagnosed with hiv after they have been placed on treatment for active tb. globally, about 1.4 million tb cases are co-infected with hiv leading to about 0.5 million deaths each year while in south africa there are about 350 000 co-infected cases of tb (for an hiv infection rate of about 70% among tb patients). since there are drug interactions and overlapping toxicities between art and tb treatment, ‘one of the most critical questions in this population has been when the optimal time is to initiate antiretrovirals in people on tb treatment’, said dr kogie naidoo of the centre for the aids programme of research in south africa (caprisa). to answer this question, dr naidoo and colleagues conducted a randomised trial of 642 patients with hiv and cd4 cell counts below 500 cells/µl who were on standard tb treatment. patients began art in one of three time periods: n during the first 2 months of intensive tb treatment (early integrated treatment) n after the 2-month intensive phase of tb treatment was completed (later integrated treatment), or n after the entire 6 8-month course of tb treatment is completed (sequential treatment). an interim safety monitoring committee review of the data found that patients in the two integrated treatment arms had a 56% lower death rate than those in the sequential treatment arm. the sequential treatment arm was subsequently terminated, though the two integrated treatment arms of the study are ongoing. of note, ‘tb outcomes were similar in both arms mortality in the sequential treatment arm occurred late in tb treatment and after tb treatment was completed, hence the tb programme may not be aware of the higher mortality,’ said dr naidoo. the programmatic implications include offering every tb patient hiv testing and counselling, and those with tb-hiv (and cd4 <500) should be started on art while they are still taking tb treatment. dr francois venter of johannesburg hospital said this would probably mean that tb nurses should be initiating patients on art. if south africa were to do this widely, dr naidoo estimated that 150 000 more tb patients would be placed on art and about 10 000 deaths prevented annually. but even though concurrent art improves tb outcomes, the management of active tb is still quite complicated in people with hiv. tb remains the leading key cause of death in art services probably more than we know, since much tb goes undiagnosed.3 despite art, people with prevalent or incident tb and hiv are two 39 j u ly 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e or three times more likely to die than their hiv-negative counterparts. in addition, people with hiv and tb contribute to onward transmission in the community and the clinic. although many cases of tb in people with hiv are sputum smear-negative, dr lawn noted that ‘smear-negative does not mean non-infective ... smear-negative tb cases may be contributing substantially to tb transmission within the clinic, [especially] because patients with hiv are exquisitely susceptible to infection.’ ‘we need adjunctive strategies to prevent tb upstream of art services,’ he said. that is, strategies such as the 3i’s the first and perhaps most fundamental of which is infection control. ‘tb infection control is the strongest preventive tool we have; it is crucial that we get this basic step right in the first place,’ said lesley odendal, an ic co-ordinator for médecins sans frontières (msf) in khayelitsha, and one of three speakers on the subject at the symposium. ic measures are essential to prevent the spread of mycobacterium tuberculosis to vulnerable patients, health care workers, the community and those living in congregate settings. the concept of ic has been around ever since florence nightingale wrote that hospitals ‘should do the sick no harm’. for years, tb ic measures were standard policy in health care settings until they fell out of practice with the advent of tb chemotherapy. since the outbreak of extensively drug-resistant tb (xdr-tb) where there were clear indications of transmission at the church of scotland hospital in tugela ferry in kwazulu-natal tb ic has once again become a public health priority.4 ‘high rates of tb infection and disease in health care workers have been demonstrated in a number of studies, implicating nosocomial transmission,’ said dr lilanganee telisinghe of the aurum institute. these include a recent literature review by menzies et al. that ‘found that latent tb infection was consistently associated with ... occupational exposure,’ she said.5 those who worked longer in some areas had consistently higher rates of tb than that of the general population, plainly making tb ic an occupational safety issue ‘and a human rights issue,' ms odendal pointed out. there is an established hierarchy of controls to reduce the risk of tb transmission, beginning with administrative and workplace measures to reduce the generation of infectious tb particles in the facility and prevent the spread of the disease by quickly identifying, separating and investigating suspects and treating the tb cases; environmental control measures to reduce the concentration of infectious tb particles in a facility by ventilation or air cleaning; and personal respiratory protection to decrease or prevent inhalation of infectious tb particles by staff and clients. administrative and workplace control measures include a written infection prevention and control plan for each facility. procedures in the plan need administrative support, including quality assurance, as well as training and supervision of staff. patients and the community need to be made aware of how tb is transmitted (and taught cough etiquette). finally, every facility needs to communicate and work closely with the tb programme to co-ordinate these efforts. although menzies et al. reported that administrative controls may be less effective in lower middle-income countries than in high-income settings (where training and resources may improve implementation), dr sidney parsons, an engineer specialising in ic at the council for scientific and industrial research (csir), said that administrative measures remain the very foundation of ic. ‘fundamentally, everything starts and ends with the infection control plan,’ he said, noting that generic ic plans or templates alone are inadequate. ‘we’ve got to develop a specific plan for every facility because every facility is unique, and we need to make certain that the plan is in writing, easy to understand, and accessible. the plan must be practical, affordable, comprehensive and creative but in line with the accepted hierarchy of controls.’ speakers alluded to a document released by the who last year to help countries and programmes prioritise tb ic interventions: ‘essential actions for effective tb infection control: safety without stigma’ (http://www.stoptb.org/wg/tb_hiv/assets/documents/ 10%20essential %20actions%20for%20effective%20t b%20infection%20control.pdf). these steps highlight community engagement, developing a facility ic plan, safe sputum collection, promoting cough etiquette, triaging tb suspects, rapid diagnosis and treatment, improved room ventilation, protecting health care workers, capacity building and monitoring ic practices. ‘with the exception of improving room ventilation, these are all administrative policy measures,’ dr parsons reiterated. environmental tb ic measures may include engineering solutions, such as mechanical ventilation or air filtration systems, which are expensive to install and costly to maintain. dr telisinghe described experiments by dr rod escombe and colleagues showing that low-cost measures, such as natural ventilation and ultraviolet germicidal irradiation (ugi), could help reduce the risk of tb infection in facilities in resource-limited settings. a peruvian study found that simply opening the wintb infection control (ic) 40 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u ly 2 0 0 9 dows could work better than mechanical ventilation.6 more recently, using guinea pig studies and mathematical models, escombe et al. concluded that the use of uv lights could significantly reduce tb infection and disease provided there is adequate mixing of room air (to enhance air movement, and hence the transportation of droplet nuclei, through the upper-room uv disinfecting zone).7 once environmental and administrative controls are in place, personal respiratory protection wearing an n95 or ffp2 respirator mask to prevent inhalation of infectious tb particles may offer additional benefit. ‘the evidence for using n95 masks comes from mathematical modelling, laboratory testing ... and expert opinion,’ said dr telisinghe. there is little epidemiological evidence demonstrating effectiveness in the field. still, the case is strong enough for health care workers to wear them in high-risk settings. however, masks are often not available or used in health facilities, ms odendal noted. ‘you need all three components and all require education for patients and training for health care workers.’ she added that tb treatment, isoniazid preventive therapy and art are all part of tb ic. a mathematical model for xdr-tb transmission in rural south africa published in the lancet estimated that the combination of ic measures with tb treatment could avert 48% of facility-based xdr-tb cases (range 34 50%) by the end of 2012.8 the combined measures included early discharge of patients from hospitals, enforced respirator and mask use, improved natural ventilation, isolation of patients into 5-bed units, rapid drug sensitivity testing (and appropriate treatment), hospitalbased hiv testing and counselling, and art use. of note, although respirators would only prevent 2% of the total cases, consistent use would prevent about two-thirds of the cases among health care workers. msf and the western cape department of health are working on improving tb ic at all nine of the clinics providing tb services in khayelitsha. dr telisinghe described site assessments of the risk of tb infection in different clinic areas that found that while some tb ic was in place, there was room for improvement. ms odendal described the steps subsequently taken, including the establishment of ic committees at each facility, training and provision of information materials, implementing triage and intensified case-finding, and the provision of respirator masks for staff, and paper masks for cough hygiene to all clients in waiting areas. they have improved natural ventilation by installing wind-driven air extractors (whirly-birds) on existing buildings, and established outdoor waiting rooms that have roofs but are otherwise open though they have heaters and blankets to make patients more comfortable. finally, sputum collection booths have been moved outside. unfortunately, many designs for new health facilities lack natural ventilation and rely on forced ventilation systems, according to dr parsons. ‘is this the way to go in resource-limited settings with unreliable electricity?’ he asked. ‘on the other hand, are we going to try to use “simple” solutions that we know won’t work? we need to design appropriately.’ he cautioned the audience against assuming that ‘simple’ measures are always adequate. ‘i was in peru with rod escombe for some of his tests’, he said, ‘and the rooms he investigated had five metre high ceilings and [high] windows-to-floor ratios ... do you find that in all the facilities in our hospitals? no you don’t. it’s not that i don’t agree with the open window policy, in fact, i really support opening windows, but i think we need to put it in the appropriate context.’ ‘we need to act in a multidisciplinary group to resolve these issues,’ he said, adding that engineers and architects need to be engaged, and often have better access to the national legal and regulatory framework that should guide tb ic in facilities. for example, the national infection prevention and control policy and strategy (april 2007) makes reference to a long list of regulations in south africa, including the occupational health and safety act 85 of 1993, which mandates that hazards in the workplace be analysed and responded to appropriately, with the regulations regarding hazardous biological agents addressed in notice r1390. ‘anybody who runs or manages a health facility and does not adhere to the regulations embedded in the occupational safety health act is actually culpable,’ he said. dr parsons also referred to new proposed building codes of which many health care workers may not be aware (see appendix 1). these codes need to be enforced at every type of health facility, he stressed, ‘not just at the multidrug resistant tb facilities’, because people with tb could be encountered anywhere within the health system. but the provincial departments of health have to be held accountable to upgrade health facilities. ‘four hundred million rand has been made available per year for 3 4 years to the provinces to address infection control in facilities. we can only account for something like 110 million,’ he said, and urged the audience to find out what was going on in their province. tb ic also needs to be addressed within the home and community, according to ms odendal. ‘the hype around drug-resistant tb is actually driving the tb epidemic underground because people don’t 41 j u ly 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e want to go for diagnosis if there is a chance they have drug-resistant tb and will be isolated,’ she said. community-based treatment of drug-resistant tb would offer one solution, ‘but the lack of guidance regarding tb ic in homes and communities has been a big barrier.’ msf is pioneering community-based drug-resistant tb treatment in khayelitsha. to reduce the risk of transmission in the home between starting treatment and sputum culture conversion, the following measures have been adopted in households. first, there is an initial assessment of crowding and ventilation in the home, and the vulnerability of household members. then a risk reduction plan is developed, involving education about tb transmission and cough hygiene, and separate sleeping arrangements when necessary. patients and other household members are given at least two ic education sessions and follow-up, and patients are given paper masks to be worn in overcrowded and closed conditions. most households have been able to minimise contact between the patient and vulnerable household members, by arranging separate sleeping for patients and improving natural ventilation, according to ms odendal. ‘once they have been provided with information and support, people are more than willing to make necessary changes and able to reduce the risk of tb transmission. if a safe environment could not be brought about, patients are hospitalised until culture conversion,’ she said. in the meantime, they are trying to address tb ic in the community through treatment literacy campaigns to encourage community acceptance and support for ambulatory treatment. they are also engaging taxi associations and drivers in the taxi ranks with the goal of increasing ventilation on public transport, and promotion of cough hygiene. they hope to expand these efforts to other overcrowded settings such as prisons, mines, schools and detention centres. another measure that could help with tb ic efforts in the community is icf since more aggressive and earlier case detection could reduce the period of time during which people are unwittingly spreading tb in the community. dr celine gounder of johns hopkins university described study after study demonstrating that case detection rates are too low in many settings where tb is common. for example, professor robin wood and colleagues in the western cape found that the prevalence of pulmonary tb among people with hiv was 7.6% but passive case-finding (waiting for people to come in to have their illness investigated) only resulted in a third of the smear-positive tb diagnoses.9 dr liz corbett reported that icf detected a prevalence of 3.8% of previously undiagnosed pulmonary tb among hiv-positive goldminers.10 other icf studies have found high rates among hiv-positive pregnant women, and contacts of other smear-positive cases. studies where people attending art clinics are routinely screened for tb have found even higher rates of case detection. icf in communities in zambia and south africa also detects large numbers of previously undiagnosed tb cases, according to musonda simwinga, manager of the zambian aids-related tb (zamstar) study. the trial involves randomly allocating 24 whole communities across zambia and south africa to receive one of two public health interventions: community-enhanced case-finding (increasing access to diagnostic services within the community), or targeting households of tb patients and counselling the whole household to make better use of diagnostic services within the existing health system. according to simwinga, prevalence studies for the trial demonstrated a huge burden of tuberculosis, with a culture-positive prevalence of 960/100 000 in two zambian sites and 2 200/100 000 in two south african sites (14 894 adults). ‘many adults with a chronic cough have never sought care in their local health centre, and even when they have, they have often not been offered available diagnostic tests,’ he said. or they may present quite late for diagnosis and care. ‘patients who are identified through passive case-finding are picked up much later in the course of their disease,’ dr gounder said, ‘and as a result, their illness is often more severe.’ for instance, a study in the western cape found higher frequencies of major symptoms such as weight loss among cases detected through passive case-finding.11 late recognition also leads to poorer outcomes: professor churchyard found a higher case fatality rate after initiating treatment among goldminers whose tb was detected by passive case-finding rather than icf.12 ‘intensified case finding should also have an impact on disease duration and thereby transmission of disease,’ said dr gounder, noting that in another study by professor wood ‘87% of the total person years of untreated sputum smear-positive tb is among people with hiv so people with hiv are a very significant source of disease transmission within the community.’ the who recommends that people living with hiv, their household contacts, groups at high risk for hiv and those in congregate settings should be regularly intensified case-finding (icf) 42 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u ly 2 0 0 9 screened for tb whenever they come into contact with the health services. but even though 109 countries have adopted icf as part of their national tb/hiv policy, implementation has been limited. ‘are our hiv care services, our art services, our vct service points aware of intensified case finding or that they should implement it? probably not; if they are, they are not convinced that it is their responsibility. they say it is for somebody working within the tb clinic,’ said dr kgomotso vilakazi-nhlapo of the national department of health, who added that ‘the communities aren’t demanding it yet. and there is also a lack of training on screening for tb in hiv-positives.’ but one of the key barriers is the lack of agreed-upon tools that can be used by trained counsellors and health care workers to screen for tb in people with hiv. ‘the difficulties screening for tb in hiv-infected patients are well known’, said dr salome charalambous of the aurum institute, ‘and include the lack of typical symptoms, an increase in smear-negative tb, atypical chest x-ray changes, a large incidence of extrapulmonary disseminated tb and also the presence of other pulmonary disease [such as pneumocystis jirovecii pneumonia]. so for symptom screening, we don’t really know which symptoms are the best to use. sputum microcopy is rapid and cheap, but patients are smear-negative ... and we must be careful not to overstretch our laboratories. with chest x-rays, there are issues with access and interpretation.’ dr charalambous described several studies exploring optimal screening methods. she noted conflicting data on usefulness of chest x-rays. in botswana’s ipt programme, a pilot study suggested that x-rays didn’t add much to screening, but more recent experience has suggested that x-rays do indeed detect some cases of tb in asymptomatic patients. in one study in south african goldminers, adding a chest x-ray to a symptom screening tool (night sweats, cough and weight loss) improved sensitivity from around 60% to 90%.13 in another study, 381 patients at tshepong wellness clinic in north west province were screened for active tb before starting art. tb was diagnosed in 31.6%. ‘using a symptom screen alone would miss one quarter of the tb cases, while chest radiography improved sensitivity substantially,’ said dr charalambous. ‘one thing i’d like to emphasise, is that [in this study] 62.5% of patients had tb symptoms, so even if we are just screening with symptoms, we would still have to further screen these patients with sputum microscopy and culture, which would lead to overstretching our laboratory facilities. that’s a problem that we’re going to have to deal with.’ south africa’s national guidelines state that tb screening should take place before initiating art and that tb should be suspected if any two symptoms are observed (including weight loss of 1.5 kg or more, cough >2 weeks, night sweats over 2 weeks or fever >2 weeks). the diagnosis should then be confirmed by smear microscopy or culture. before initiating ipt, sputum should be sent for microscopy and culture if there are one or more symptoms. in practice this does not seem to happen, according to an analysis dr charalambous conducted in aurum’s clinics. even when clinic visit forms (with a checklist of symptoms) have been filled out and show that patients had two or more symptoms of tb, sputum was very rarely sent in for microscopy or culture. ‘only about 1.8% was screened correctly according to south african national guidelines,’ she said. as a result, they are recommending changes to the screening form. ‘clinical data systems we use should facilitate care by prompting care providers to screen for tb.’ a range of screening tools are needed at the different points where people with hiv enter into care, according to dr vilakazi. ‘one size does not fit all different settings have particular needs. you can’t have the same tools for prevention of mother-to-child transmission (pmtct) as you have for prisons, community screening, household contacts,’ she said. but if icf is to be rolled out at vct clinics, effective referral mechanisms need to be established to make certain that someone who is screened by a counsellor as a tb suspect makes it to a tb clinic for diagnosis. ‘referral systems between hiv [services] and tb diagnostic and treatment centres are mostly only verbal. patients are referred, but not properly “encouraged” to reach services. how do we follow up? how do we ensure the patient has been screened?’ she noted that patients often don’t follow through on the referral because they are too sick or busy. ‘so we need to promote the use of hiv resources to strengthen tb diagnostics capacity at all levels. we need to address long laboratory turn-around times and promote tb diagnostic capacity in all of our art clinics.’ ‘we need to develop practical guidelines at national level to operationalise icf,’ she said. ‘national policy should emphasise icf as the gatekeeper for ipt and ic. to implement ic, you need to know how to exclude tb so that you can triage the patients. and you cannot say a person should start ipt without first excluding tb.’ 43 j u ly 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e access to isoniazid to prevent tb is even more limited, even though a cochrane meta-analysis of seven major studies conclusively showed that its use would reduce active tb by about one-third in people with hiv.14 ‘in the global tb report that came out last year from the who, it was reported that only 29 000 people were started on ipt globally. that’s less than 0.1% of the estimated 33 million people estimated to be infected with hiv globally compared with 3 million people on art globally and 2.1 million on art in sub-saharan africa,’ said professor harry hausler of the tb/hiv care association. ‘if you think about art versus ipt, 10 20% of people who are hiv positive are eligible for antiretroviral therapy, but close to 40% of people who are hiv positive are eligible for ipt. so we should be looking at 6 million people on ipt globally rather than 29 000.’ in south africa, only 6 818 out of the 455 150 people who tested positive last year (1.5%) were put on ipt. the current department of health ipt guidelines may partly be to blame for the low uptake, as people on art are not eligible while a positive tuberculin skin test (tst) is required to qualify for ipt. ‘tst is in fact an obstacle to ipt,’ said another speaker, dr kerrigan mccarthy of the reproductive health and hiv research unit (rhru). ‘firstly there’s the hassle of the supply chain management of tst (for tuberculin syringes, ppd rt23/cold chain management).’ an appreciable percentage of clients don’t return to have their tst interpreted. in addition, dr mccarthy said that johannesburg clinics reported wide variations in the promotion of tsts interpreted as positive, indicating lack of consistency in performing and interpreting the test. ‘quality control of tst is impossible; if the quality of a test cannot be controlled, that test should not be used.’ even when patients who are eligible under the current guidelines are identified, many health care providers are reluctant to administer ipt, because they fear it may cause drug resistance or severe toxicity, or they believe it is not needed in someone on art. at present there is very little evidence to suggest that ipt promotes drug-resistant disease, according to professor harry hausler of the tb/hiv care association, who chaired the session on ipt at the symposium. ‘when active tb occurs among those given ipt, standard four-drug first-line therapy works,’ he added, citing evidence from one 2006 meta-analysis that included over 18 000 people on ipt showing a slight increase in inh resistance but a fairly low relative risk (1.45, 95% confidence interval (ci) 0.85 2.47).15,16 however, the authors recommend ongoing surveillance to exclude an increase in inh resistance with the roll-out of large-scale ipt programmes. if inh is used appropriately not given to people with active liver disease or to those who abuse alcohol, with monthly monitoring and vitamin b6 severe toxicity is rare. finally, at least one open-label study suggests that art and ipt synergistically decrease tb when given together.17 preliminary data from the first 6 months of the botswana ipt study seem to support that ipt can be safely and effectively administered even to rather ill patients, according to dr tefera agizew, senior medical research officer, tb/hiv research, botusa. during the first 6 months of the study, all eligible participants received open-label inh with vitamin b6 (after which point they were randomised to continue with 30 months of placebo or inh). of 1 995 subjects enrolled in the trial, only 7 (0.35%) were diagnosed with active tb (3 of whom were culture positive). there was no evidence of inh resistance. adherence was also good by pill count: 91% took more than 80% of the pills. severe adverse events were seen in 28 (1.4%) of participants: 19 were due to hepatitis (for a rate of 0.95% compared with an expected range of 0.5 5.3%), 5 were rashes, and 4 were other events. there was 1 death, due to hepatic encephalopathy. most of the hepatitis was asymptomatic. however, a couple of factors, such as having a cd4 cell count below 200 cells/µl, and a problem with alcohol, were significant risk factors for severe hepatitis. ‘alcohol dependence screening is recommended to reduce the risk of hepatitis,’ said dr agizew. however, in the much larger thibela tb study in south african goldmines, comparing the effectiveness of community-wide ipt in addition to standard tb control, hepatitis has been quite rare in preliminary findings, according to professor churchyard. ‘isoniazid is safe,’ he said. ‘and this is a group of men that are elderly and drink i wouldn’t say excessively, but they drink and have a high rate of hepatitis b and use traditional medicine. and yet despite all this, in an analysis of almost 13 500 individuals, we only had 3 cases of hepatitis only one of which was severe -and the patient fully recovered.’ (other events included hypersensitivity, which was seen in 55 participants, and peripheral neuropathy in 41 of the first 13 425 patients.)18 initially, adherence wasn’t quite as good in this study, with only about 40 50% adherence by 6 months, but this has now been improved to about 80%. professor churchyard also presented some of the first resistance data from the study so far (table i). isoniazid preventive therapy (ipt) 44 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u ly 2 0 0 9 ‘we would expect to see a higher proportion of inh resistance in people taking ipt, as inh won't work against inh-resistant tb,’ said professor churchyard. ‘and although it is slightly higher in terms of inh resistance, it is not significantly higher.’ similarly, dr neil martinson of the perinatal hiv research unit reported that ipt did not drive resistance in a study he conducted comparing different tb preventive therapy regimens, including ipt for 6 months, and continuous ipt. there was no resistance in 14 out of 19 tb cases out of 328 patients who received 6 months of isoniazid (specimens were not available for 5), and only 1 case of mdr tb in the 7 breakthroughs out of 164 people on the continuous ipt arm. that being said, dr martinson stressed that it was very important to exclude active disease but he wasn’t certain that chest x-rays would really be appropriate in the field. ‘i would recommend not doing a chest x-ray. i think it’s really an excuse just to keep people away from receiving isoniazid preventive treatment, especially when we consider that ipt is meant for well people,’ he said. ‘clearly asymptomatic tb in hiv-infected individuals is a concern, but my experience is that tb is a fairly malignant disease in people who are hiv-infected. if you have at least two visits, one month apart, before giving ipt, most patients/most people who are hiv-infected and who have got active tb are not going to be walking around feeling good for more than a month.’ however, he also said he thought ‘that anyone who is hiv-infected should have a tb culture’. dr martinson set some targets for the future, calling for cd4 counts to be routinely available at the time of hiv diagnosis (perhaps with point-of-care testing): for at least 20% to be investigated with a tb sputum culture; for 60% of those who do not yet qualify for art to be put onto ipt; for an 80% adherence rate; and for less than 2% breakthrough tb cases. as dr vincent tihon of the sa department of health noted, putting this into operation in clinics will take real-world models and tested tools but these are currently being developed. dr mccarthy described the development and implementation of a systematic method of integrating tb/hiv services at urban clinics in johannesburg. before starting the effort, ‘there was no systematic screening. ipt uptake was limited and in 2007, less than 100 people in the entire city of johannesburg had tst done,’ she said. ‘now to do this we used what we call the "roadmap of care" a framework for integrated tb/hiv services that uses a "provider-initiated testing and counselling register" and a "wellness register"; as well as other materials to facilitate implementation' (for copies contact padma dayah, pdayah@rhru.co.za). data collection in the registers is manual, which increases staff workload, so staff training in data collection is critical. however, now ‘we are able through the register, to track and understand all of the factors involved in tb and hiv integration and see month by month, exactly, the progress towards implementation’. after successful piloting in four inner city clinics, the roadmap of care is being rolled out on a larger scale in johannesburg, north west province and ekurhuleni. ‘ipt in fact represents a success for tb/hiv integration. it’s not only just the value of the preventive efficacy of inh this represents the tip of the iceberg of the population that is reached through hiv services,’ she said. ‘ipt will not only do those individuals a service by preventing tb, but we access the entire spectrum of the population for hiv testing, tb screening and all of the other services that go along with it.’ good followup mechanisms are also essential to ensure adherence, detect cases of active tb if any are missed, and appropriately treat and monitor those patients. ‘political commitment to ipt is essential, and community and activist awareness as well as promotion of tb prevention activities are critical. client awareness of ipt can drive prevention efforts and improve health seeking behaviour,’ she said. ‘community mobilisation has also supported the rapid and large-scale uptake in thibela,’ said professor churchyard. ‘it creates the awareness of both tb and ipt and it has created a demand for ipt, and strong support for this study. communication is essential to the community mobilisation and underpins all of those processes.’ active tb ipt (n=66) comparison (n=129) first episodes, n=53 retreatment, n=13 first episodes, n=97 retreatment, n=32 % (95% ci) % (95% ci) % (95% ci) % (95% ci) any inh 7 1 8 8 13.2% (5.5 25.3) 7.4% (1.9 36.0) 8.2% (3.6 15.6) 25% (11.5 43.4) mdr 1 1 3 4 1.9% 7.7% 3.1% 12.5% table i. preliminary drug susceptibility of tb on ipt 45 j u ly 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e as for political commitment, the meeting’s final word came from the south african department of health. ‘the political commitment has increased significantly in the past few months where tb and hiv have really gone high on the agenda,’ said dr tihon. first, the department is considering several proposed changes to the ipt policy that may remove some of the barriers to access. these include removing the tst requirement; considering ipt for pregnant women with hiv, as benefits outweigh the risks; and considering ipt for patients who have been stable on art for 6 or more months who have no signs and symptoms of tb. ‘it is quite critical to start talking about how we are going to implement it,’ he added. consequently, the department of health has instructed the provinces to develop clear operational plans for ipt implementation. ‘it will require training, standard operating procedures, technical guidance that is very practical, how to exclude tb, who is eligible and how to monitor people who are starting on ipt,’ he said, noting that rhru’s work could serve as a model. but ultimately, he said, successful implementation of ipt will be dependent upon the delivery of quality hiv services, effective tb screening, adherence support and follow-up. ‘the hiv programme really has to take the responsibility and the leadership in strong collaboration with the tb programme so that people will say: it works, it’s safe and let’s just do it!’ references 1. edwards d, vogt m, bangani n, et al. baseline screening for tb among patients enrolling in an art service in south africa. 16th conference on retroviruses and opportunistic infections, 8 11 february 2009, montreal, canada. abstract 780. 2. lawn s, myer l, edwards d, et al. shortand long-term risks of tb associated with cd4 cell response to art in south africa. 16th conference on retroviruses and opportunistic infections, 8 11 february 2009, montreal, canada. abstract 788. 3. lawn sd, myer l, orrell c, et al. early mortality among adults accessing a community-based antiretroviral service in south africa: implications for programme design. aids 2005; 19(18): 2141-2148. 4. gandhi nr, moll a, strum a, et al. extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and hiv in a rural area of south africa. lancet 2006; 368 (9547): 1575-1580. 5. menzies d, joshi r, pai m. tuberculosis among health-care workers in lowand middle-income countries: a systematic [occupational lung disease in highand low-income countries, ed. m chan-yeung, no. 5 in the series]. int j tuberc lung dis 2007; 11(6): 593-605. 6. escombe ar, oeser cc, gilman rh, et al. natural ventilation for the prevention of airborne contagion. plos med 2007; 4(2): e68. 7. escombe roderick a, moore daj, et al. upper-room ultraviolet light and negative air ionization to prevent tuberculosis transmission. plos med 2009; 6(3): e1000043. 8. basu s, andrew jr, poolman em, et al. prevention of nosocomial transmission of extensively drug-resistant tuberculosis in rural south african district hospitals: an epidemiological modelling study. lancet 2007; 370: 1500-1507. 9. wood r, middelkoop k, myer l, et al. undiagnosed tuberculosis in a community with high hiv prevalence: implications for tuberculosis control. am j respir crit care med 2007; 175(1): 87-93. occupancy minimum outdoor air requirements pressure relative to adjacent area air changes per hour l/s per person health care facilities surgical and critical care operating theatres and suites 20 positive wound intensive care (burns) 6 positive critical and intensive care, treatment and delivery rooms 6 positive trauma, er waiting rooms, radiology waiting rooms and triage 12 negative diagnostics and treatment areas bronchoscopy, sputum collection, examination and treatment room (general) 12 negative medication room 4 negative physical therapy and hydrotherapy 6 negative inpatient nursing areas general wards, paediatric wards and labour/delivery/recovery/postpartum rooms 2 positive airborne infection/protective environment wards and anterooms or airlocks 12 negative laboratories microbiological (molecular) 6 positive bacteriological p1 6 negative bacteriological p2, p3 and p4 12 negative general biochemistry, cytology, histology, nuclear medicine, pathology and serology 6 negative radiology general radiology areas 6 negative appendix 1. sa building codes of practice, the proposed sans 10400, section 0, para 4.4.10 we thank the chairs and presenters for sharing their expertise. mr theo smart is thanked for preparing the final report. 46 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u ly 2 0 0 9 10. corbett el, charalambous s, moloi vm, et al. human immunodeficiency virus and the prevalence of undiagnosed tuberculosis in african gold miners. am j respir crit care med 2004; 170(6): 673-679. 11. den boon s, verver s, lombard cj, et al. comparison of symptoms and treatment outcomes between actively and passively detected tuberculosis cases: the additional value of active case finding. epidemiol infect 2008; 136: 1342-1349. 12. churchyard gj, kleinschmidt i, corbett el, et al. factors associated with an increased case-fatality rate in hiv-infected and non-infected south african gold miners with pulmonary tuberculosis. int j tuberc lung dis 2000; 4(8): 705-712. 13. day jh, grant ad, charalambous s. screening for tuberculosis prior to isoniazid preventive therapy among hiv-infected gold miners in south africa. int j tuberc lung dis 2006; 10(5): 523-529. 14. woldehanna s, volmink j. treatment of latent tuberculosis infection in hiv infected persons. cochrane database syst rev 2004; (1): cd000171. 15. nolan cm, goldberg sv. treatment of isoniazid-resistant tuberculosis with isoniazid, rifampin, ethambutol, and pyrazinamide for 6 months. int j tuberc lung dis 2002; 6(11): 952-958. 16. mitchison da, nunn aj. influence of initial drug resistance on the response to short-course chemotherapy of pulmonary tuberculosis. am rev respir dis 1986; 133(3): 423-430. 17. golub je, saraceni v, cavalsante sc, et al. the impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in hiv-infected patients in rio de janeiro, brazil. aids 2007; 21: 1441-1448. 18. mngadi k, churchyard gj, grant a, et al. 38th iuatld conference, 8 12 november 2007, cape town. abstract ps-71835-10. 47 article information authors: pieter barnardt1 martha relling1 affiliations: 1department of medical imaging and clinical oncology, division of radiation oncology, university of stellenbosch, tygerberg campus, south africa correspondence to: pieter barnardt email: pieterb@sun.ac.za postal address: private bag x3, tygerberg 7505, south africa dates: received: 15 aug. 2014 accepted: 13 may 2015 published: 03 july 2015 how to cite this article: barnardt p, relling m. gestational trophoblastic neoplasm and women living with hiv and/or aids. s afr j hiv med. 2015;16(1), art. #344, 4 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.344 copyright notice: © 2015. the author(s). licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. gestational trophoblastic neoplasm and women living with hiv and/or aids in this case report... open access • abstract • introduction • ethics approval • case presentation    • case 1    • case 2 • discussion • conclusion • acknowledgements    • competing interests    • authors’ contributions • references abstract top ↑ the 2011 world health organization global report on hiv and/or aids estimated that sub-saharan africa comprised 67% of the global hiv burden, with a current estimate of 5.9 million cases in south africa. since the introduction of antiretroviral therapy, there has been an increase in the incidence of non-aids-defining cancers. gestational trophoblastic neoplasm (gtn) is a rare pregnancy-related disorder with an incidence ranging from 0.12–0.7/1000 pregnancies in western nations. the overall cure rate is about 90%. response to treatment for gtn is generally favourable; but the sequelae of hiv and/or aids, the resultant low cd4 counts, comorbidities, poor performance status and the extent of metastatic disease in patients receiving chemotherapy, compromise the prognosis and survival. introduction top ↑ infection with the human immune deficiency virus (hiv) in sub-saharan africa affected an estimated 22.5 million people, of whom 5.9 million were in south africa, however, in the recent 2014 unaids progress report, for the first time since 2009, a 17% decline was reported in the rate of newly diagnosed hiv cases for women of reproductive age, living in sub-saharan africa.1 may et al. found that, between 1996 and 2008, the life expectancy of people receiving antiretroviral therapy (art) had increased by an average of 15 years.2 people with hiv infection live longer as a result of art, and consequently are at risk of developing illnesses associated with ageing, chronic illnesses and malignancies. kaposi’s sarcoma (ks), non-hodgkin’s lymphoma (nhl) and cervical cancer are the most observed aids-defining cancers. in the era of art, a significant decrease in the incidence of aids-defining illnesses has been observed, whilst non-aids cancers (nadcs) are on the increase. an estimated 30% – 40% of hiv-infected patients are likely to develop a cancer during the duration of their disease.3 an increased incidence was observed for anal, lung, certain head and neck cancers, and hepatocellular carcinoma, as well as hodgkin’s disease, whilst no increased risk was observed for breast, prostate and colorectal cancer in the hiv-positive cohort. no clearly established association between hiv and/or aids and gestational trophoblastic neoplasm (gtn) exists. data from the swiss hiv cohort study showed that 19% of all cohort deaths in the art area were attributable to nadcs.4 gtn is a rare pregnancy-related disorder that derives from placental tissue and is clinically diagnosed if the b-hcg level fails to decrease or normalise in women when a normal pregnancy is excluded, and collectively includes: invasive mole, choriocarcinoma and placental site trophoblastic tumour (pstt) that can lead to death if left untreated. potential risk factors for the development of gtn include a history of a previous molar pregnancy, partial mole (0.5% risk) and a complete mole (15% risk), maternal age and a post-evacuation, persistent raised b-hcg level. management includes careful dilatation and curettage (d&c), and the need for systemic treatment is guided by the international federation of gynecology and obstetrics (figo)/who score that predicts if either single agent or combination chemotherapy is required. gtn is now one of the most curable solid tumours, with cure rates of more than 90% even in the presence of metastatic disease.5,6 the occurrence of malignancy amongst people living with hiv and/or aids represents a management challenge. we present here two choriocarcinoma case studies of women with hiv and/or aids. ethics approval top ↑ the human research ethics committee (hrec) of stellenbosch university approved the present report. case presentation top ↑ case 1 a 33-year-old woman (gravida 5, para 2, miscarriage 3) presented post-evacuation for a miscarriage with persistent vaginal bleeding and a raised b-hcg value. she was living with hiv and/or aids and had been established on art for one year. clinical examination confirmed an abdominal uterine mass of 22 weeks’ gestation with a foul-smelling vaginal discharge. staging examinations included a computed tomography (ct) scan of the lungs, abdomen and pelvis and confirmed several bilateral lung metastases and an extensive tumour that involved the uterus and extended into the anterior abdominal wall (figure 1). abnormal laboratory studies revealed haemoglobin 4 g% (12.5 g% – 15 g%),a serum b-hcg level of 115 544 iu/l (<5 iu/l), and cd4 count of 290 cells/μl, (500 cells/μl – 2010 cells/μl). she was diagnosed as having a figo stage iii:12 high-risk choriocarcinoma. figure 1: computer tomographic scan of the abdomen demonstrating a grossly enlarged uterus and tumour mass extending through the anterior abdominal wall to the subcutaneous tissue. management included continuation with art (tenofovir, efavirenz and lamivudine), intravenous antibiotics (piper­acillin and amikacin), and low-dose chemotherapy with the alternating regime of methotrexate 50 mg alternative days (d1, 3, 5, 7) with leucovorin rescue. she completed one cycle without any adverse effects. however, a week post-chemotherapy she developed a neutropaenic fever. abnormal laboratory studies then confirmed serum-creatinine 10.7 mmol/l (2.1 mmol/l – 7.1 mmol/l), urea 151 μmol/l (49 μmol/l – 90 μmol/l), and a pancytopaenia: white blood cells 0.13 × 109/l (4.00–10.00 ×109/l), haemoglobin 6.6 g%, and platelets 15 × 109/l (178–400 ×109/l). a follow-up cd4 count decreased to 29 cells/μl and the b-hcg value decreased to 50 296 iu/l. supportive management included granulocyte-stimulating factor (g-csf) and intravenous antibiotics according to the sensitivity of a positive blood culture (klebsiella pneumonia). a vaginal pus swab cultured candida species. the outcome for the patient was unfortunate as she died owing to severe neutropaenic sepsis from a resistant klebsiella and candida sepsis that resulted in acute renal failure and severe immune suppression. case 2 a 20-year-old woman (gravida 2, para 0, miscarriage 1) presented with a history of haemoptysis, grade iv dyspnoea and a raised b-hcg level. she was known to have had a previous molar pregnancy, diagnosed three years previously. on clinical examination, symptoms and signs of thyrotoxicosis were present. staging examinations included a lung ct that confirmed numerous bilateral, diffuse soft-tissue nodules throughout both lung fields in keeping with metastatic disease (figure 2). abnormal laboratory studies revealed a b-hcg value >898 400 iu/l (<5 iu/l), t4: 47 pmol/l (10.3 pmol/l – 21.9 pmol/l), and a cd4 count of 200 cells/μl (500 cells/μl – 2010 cells/μl); a hiv enzyme-linked immunosorbent assay (elisa) test was positive. direct microscopy for acid-fast bacilli was negative. she was diagnosed with a figo stage iii:15 high-risk choriocarcinoma in a newly diagnosed hiv-positive patient. figure 2: computer tomographic scan of the lung demonstrating bilateral diffuse soft-tissue nodules in keeping with metastatic disease. note the large cavitating lesion in the left lower lobe, found in metastases from choriocarcinoma and resulting from tumour haemorrhage. management included commencement with art (tenofovir, efavirenz and lamivudine) with the addition of trimetroprim-sulfamethoxazole for pneumocystis jiroveci prophylaxis (pcp) as her cd4+ count was ≤200 cells/μl, intravenous antibiotic (clindamycin) and acute thyrotoxicosis therapy consisting of carbimazole and propranolol. low-dose chemotherapy with methotrexate 50 mg alternated with leucovorin rescue on days 1, 3, 5 and 7 was initiated. however, she required admission into a high-care facility when spontaneous breathing became problematic and a continuous positive airway pressure (cpap) support system was needed. a standard blood culture confirmed gram-positive cocci and a coagulase negative staphylococcal organism was isolated sensitive to vancomycin. a urine specimen cultured positive for candida albicans. when severe oxygen decompensation occurred, she was admitted to the icu facility and intubation was necessitated. she died secondary to poor performance status, severe immune suppression, metastatic choriocarcinoma and a staphylococcus and candida sepsis when she developed acute respiratory distress syndrome (ards). discussion top ↑ malignancy tends to occur at a younger age in people living with hiv and/or aids, and presents with atypical presentations, widespread metastatic disease, and aggressive tumour behaviour. in patients with immunodeficiency, physiological principles for the development of malignancy exist: (1) the lack of autoimmune surveillance, (2) an imbalance between cellular differentiation and proliferation and (3) a repeat antigenic stimulation by an oncogenic virus leads to the emergence and proliferation of abnormal cells. amongst hiv-infected individuals, a 30% – 40% increase in the incidence of nadcs has been observed, and this contributes to morbidity and mortality in hiv-infected patients, now that survival is prolonged with the use of art.3,7 established chemotherapy regimens have resulted in a favourable response to gtn, and more than 90% of cases will be cured. choriocarcinoma is generally associated with pregnancy but an estimated 25% occur after miscarriage, 25% after term pregnancy and the rest after a molar pregnancy. choriocarcinoma is an aggressive form of gtn owing to its rapid growth and metastatic potential. in women, a high index of suspicion is needed to make a diagnosis based on an unexplained high b-hcg level in the presence of metastases in the lung, liver or brain. a high hcg level can also cause thyrotoxicosis. delay in diagnosis with delay in starting chemotherapy treatment is a common cause of early death in patients with metastasis.6 using the who/figo scoring system, patients are grouped into lowand high-risk categories. high-risk patients require combination chemotherapy as they are unlikely to be cured with a single agent. in high-risk patients, 50% of deaths occur within the first four weeks of initial treatment. early deaths are attributed to respiratory compromise, haemorrhage secondary to a heavy tumour burden within the thorax, and rapid tumour destruction associated with full-dose chemotherapy treatment. intubation in patients with very poor respiratory function should be avoided as far as possible as high ventilator pressures might trigger fatal intrapulmonary haemorrhage owing to friable tumour vasculature; and hence the introduction of low-dose therapy in the initial treatment of high-risk patients to gradually reduce tumour volume and significantly reduce the risk of haemorrhage to minimise the risk of early death.8,9 because of extensive comorbidities, low-cd4 counts, poor performance status and the extent of metastatic disease, both our patients were offered initial low-dose chemotherapy to debulk tumour load. in the first case study, our patient developed post-chemotherapy neutropaenic sepsis. the outcome for her resulted in death secondary to a poor performance, severe immune suppression (cd4 count decrease from 290 cells/μl to 29 cells/μl), neutropaenic sepsis and extensive metastatic choriocarcinoma that resulted in acute renal failure. in the second case, the patient experienced severe oxygen desaturation owing to extensive lung metastases that necessitated intubation and icu admission. the outcome for her was dismal as she died secondary to a poor performance status, severe immune suppression, sepsis and extensive metastatic choriocarcinoma when she developed ards. both our patients experienced severe immune suppression, had extensive metastatic disease and developed associated post-chemotherapy neutropaenia that increased their susceptibility to developing severe and fatal infections. our cases also highlight previous findings of reported studies on gtn and hiv that confirm an associated poor outcome related to chemotherapy in women with hiv and/or aids if they present with low cd4 counts, have a poor performance status and an associated poor tolerance to chemotherapy treatment.10,11 conclusion top ↑ response to gtn is generally favourable with cure rates in excess of 90%. however, in patients with advanced immune suppression, medical management of non-aids-defining cancers can be compromised owing to their extent and aggressive tumour behaviour with associated treatment-related complications. acknowledgements top ↑ we express our sincere gratitude to professor m.h. botha for reviewing the manuscript. competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions p.b. (stellenbosch university) was responsible for the design, concept and preparation of the manuscript and was the project leader. m.r. (stellenbosch university) also made conceptual contributions and was involved in preparation of the manuscript, and edited it. references top ↑ 2014 progress report on the global plan. [cited 2014 jun 24] available from: http://www.unaids.org/en/resources/documents/2014/jc2681 may m, gompels m, delpech v, et al. impact of late diagnosis and treatment on life expectancy in people with hiv-1: uk collaborative hiv cohort (uk chic) study. br med j. 2011;343:6016. http://dx.doi.org/10.1136/bmj.d6016 barnardt p. pregnancy in a patient with advanced human immunodeficiency virus (hiv) and kaposi’s sarcoma. j womens health, issues care. 2013;2:2. http://dx.doi.org/10.4172/2325-9795.1000105 weber r, ruppik m, rickenbach, et al. decreasing mortality and changing patterns of causes of death in the swiss hiv cohort study. hiv med. 2013;14:195–207. http://dx.doi.org/10.1111/j.1468-1293.2012.01051 lurain jr. gestational trophoblastic disease i: epidemiology, pathology, clinical presentation and diagnosis of gestational trophoblastic disease, and management of hydatidiforme mole. am j obstet gynecol. 2010;06:531–539. http://dx.doi.org/10.1016/j.ajog.2010.06.073 tse ky, chan kl, ngan hy. an update on gestational trophoblastic disease. obstet gynecol reprod med. 2011;22:7–15. http://dx.doi.org/10.1016/j.ogrm.2011.10.004 wroblewska i. non-aids-defining cancers in the light of recent research. hiv & aids review. 2010;9:7–10. http://dx.doi.org/10.1016/s1730-1270(10)60091-4 alifrangis c, agarwal r, short d, et al. ema/co for high-risk gestational trophoblastic neoplasia: good outcomes with induction low-dose etoposide-cisplatin and genetic analysis. j clin oncol. 2013;31:1–7. http://dx.doi.org/10.1200/jco.2012.43.1817 kenny l, seckl mj. treatments for gestational trophoblastic disease. expert rev obstet gynecol. 2010;5:215–225. http://dx.doi.org/10.1586/eog.10.13 moodley m, budham s, connolly c. profile of mortality among women with gestational trophoblastic disease infected with the human immunodeficiency virus (hiv): argument for a new poor prognostic factor. int j gynecol cancer. 2009;19:289–293. http://dx.doi.org/10.111/igc.ob013e31819bd212 tayib s, van wyk l, denny l. gestational trophoblastic neoplasia and human immunodeficiency virus infection: a 10-year review. int j gynecol cancer. 2011;21:1684–1691. http://dx.doi.org/10.1097/igc.0b013e31822d8ffd make up sept 2007 s p r i n g 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e4 6 to date historians have not generally engaged with the hiv/aids epidemic, and we are not sure why – perhaps because thinking has been premised on the assumption that it is ‘just another epidemic’. comparisons with the black death abound. this can mislead. aids won't kill such a large proportion of the global population as the 14th-century catastrophe, nor will it kill with the same speed. in some settings, however, mortality may over time approach that experienced in parts of europe. there are two significant differences: aids mortality will take place over decades, so mortality of any given cohort will exceed levels experienced in all but history’s most severe demographic disasters; and aids selects for age and gender, the majority of those dying being between 25 and 50, with more women than men falling victim. in this article, however, we shall focus primarily on the idea of aids as an event of such magnitude and with such implications that it assumes the proportions of a ‘darwinian event’. what does it mean to describe something as a darwinian event? it is a provocative but, we hope, a productive idea to interpret the hiv/aids pandemic in this way. we need however to begin with some definitions. in the context of this paper: ■ aids is the acquired immunodeficiency syndrome, the name given to the grouping of diseases caused by the human immunodeficiency virus (hiv). the disease was first recognised only in 1981. ■ darwinian means that process of evolution by natural selection first described by charles darwin.* here we mean that there is a struggle for survival in each generation; there is individual variation in the population; and the variation has a hereditary component. all this means that there will be gradual variation in a population with those characteristics associated with greater survival ability dominating. ■ an event is shorter term than a process. in this context an event is something where we can clearly say ‘this happened and had these effects’. the classic example of a darwinian event is the pollution arising from the industrial revolution that resulted in the dark form of peppered moths (biston betularia) predominating over the light form.† the darwinian framework provides a powerful set of hypotheses for the evolution of both the hiv/aids epidemic o p i n i o n a n d d e b a t e aids: a darwinian event? alex de waal global equity initiative, harvard university, boston, usa alan whiteside health economics and hiv/aids research division, university of kwazulu-natal, durban the hiv/aids epidemic is the biggest natural event in the history of our species for the last 500 years. professor roy anderson, who has modelled the likely path of the epidemic, estimates that hiv/aids is a 130-year event.1 this, we contend, is an underestimate. hiv/aids has already put an indelible mark on the most affected societies, and that effect will certainly be felt for generations. in addition, anderson’s model – like all such mathematical exercises – measures what can be measured, leaving other factors as hypothetical zeros. the hiv/aids epidemic is a complex systemic change in human ecology. it is unleashing secondary impacts that have demographic and epidemiological consequences, which in turn create feedback loops into the dynamics of the epidemic itself. hiv/aids is certainly an historic event. it may also be a ‘darwinian event’. we argue that historians have two particular responsibilities with regard to this epidemic. firstly history should provide us with ideas, paradigms and methodologies for understanding and responding to the disease. secondly there is an awful predictability about hiv/aids and what it has the potential to do. historians have the experience of seeing an event of unparalleled significance unfold before their eyes. to some extent this history can be written in advance as a wake-up call as to what might happen. certainly there must be lessons from the past that we can apply to this epidemic. * we are well aware of the rich debate about darwin and darwinism elegantly evidenced in the writings of stephen jay gould, stephen pinker, richard dawkins and many others, and the existence of darwinian discussion groups such as that at the london school of economics (http://www.lse.ac.uk/depts/ cpnss/darwin/). our use of the term darwinian is intentional. † before 1845 near birmingham peppered moths were primarily light-coloured, but some had darker wings and were called the melanic or carbonaria forms. before the industrial revolution birds ate the darker moths – they were easier to see. in the 1850s, about 98% of uneaten peppered moths were the light variety. industrialisation meant that trees darkened and so birds more easily ate the light moths. by the 1950s, 98% of the peppered moths were the dark variety. some argue this is a ‘proof of evolution’; others say there can be light-peppered moths and dark-peppered moths – but they are all still peppered moths, variations within a single species. (http://www.pathlights.com/ce_ encyclopedia/09nsel05.htm#peppered%20moths). we would accept the argument that this was the beginning of an evolution that would change peppered moths. ironically the clean air acts reversed this in the 1950s. make up sept 2007 11/21/07 10:15 am page 46 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s p r i n g 2 0 0 7 4 7 and human responses to it. it raises far more issues than can possibly be addressed in a short chapter. at this point, the most that we can attempt is to put forward our ideas and hypotheses to stimulate debate, inspire disciplines new to the study of the epidemic to research the epidemic and its consequence, and postulate the value of this approach to understanding the hiv/aids pandemic. we hope historians will be among those who engage. the framework for analysis here we shall pursue the darwinian hypothesis to its limits. this requires us to apply versions of universal darwinism to social phenomena. this is not a resuscitation of social darwinism, but a wider application of darwinian principles, as they are currently understood in the scientific community. we recognise that this is hard to grasp in dealing with a disease like aids, and all the baggage it carries – as dawkins says, ‘nature is not cruel, only pitilessly indifferent. this is one of the hardest lessons for humans to learn. we cannot admit that things may be neither good nor evil, neither cruel nor kind, but simply callous – indifferent to all suffering, lacking all purpose.’2 let us begin by identifying different possible interpretations and then following through on the logic. 1. the principle of natural selection is the most famous of darwin's ideas, and the subsequent discovery of genetic inheritance and dna means that this too is closely identified with genetic selection. a ‘darwinian event’ could be one where those that pass on their genes are selected for certain genetic traits. the converse is that those who die before they breed successfully are also ‘selected’: they are selected out. this is the ‘survival of the fittest’ scenario. we will ask, below, whether hiv/aids fits this scenario. we would note here one important point: survival of the fittest does not mean survival of the strongest or most ‘intelligent’, it means survival of the best adapted. 2. darwinism is commonly associated with biology’s replicator, genes. however, natural selection is a principle of evolution and not a specifically genetic theory. any systematic encoder of information that has the traits of replicability, fecundity and durability, along with a degree of imperfection or variation in offspring, can serve as a darwinian replicator. while genes are biology's replicator, memes are a ‘second replicator’ operating where there are human brains that can host them.3 any significant cultural or technological change (especially with regard to communications) has an impact on the replication and hence ‘evolution’ of memes. within this vast area, we focus on memes that have a direct impact on survival and reproduction, and higher-level complex social memes such as religions and organisational systems. 3. lastly, we have to look at homo sapiens not just as an organism but also as part of an ecological framework. thus, a ‘darwinian event’ could be a change in the ecological or evolutionary framework within which homo sapiens exists. we exist not just as a species but as part of the web of nature, a web that includes the entire biosphere from microbes to ecosystems – and also our social environment. under this ‘ecology change’ scenario, a ‘darwinian event’ for humankind can be a change in that framework that affects us, leading us into a new collective adaptation. we will see that any genetic or memetic adaptation is necessarily an ecological change. this paper will study each of these in turn. each provides a fruitful point of departure for understanding the likely trajectory of the hiv/aids epidemic and assessing if it is indeed a darwinian event. why hiv? hiv is a retrovirus, meaning that it is one of the first known viruses to transcribe dna (deoxyribose nucleic acid) from an rna (ribose nucleic acid) template.* in order to exist, the virus has to enter a cell and insert itself into the cell’s dna to reproduce itself. hiv is hard to transmit. the fact that heterosexual transmission is the main way in which hiv is transmitted, followed by mother-to-child transmission, may have far-reaching implications. evolutionary theorists argue that our primary function is to reproduce and our existence is geared towards this end. we do not explore this but suggest it deserves attention. hiv is a simple virus, replicates rapidly and so can mutate equally rapidly. people are infectious for many years, but most do not know that they are infected. a pathogen must transmit its progeny from one host to another. success may come from taking a long time to disable the host, giving plenty of time for contact with other potential victims; surviving for a long time outside the body; and being easily transmissible. hiv falls in the first category. aids will not wipe out people in the way western diseases killed the ‘immunologically naïve’ indigenous populations of the americas, australasia and parts of africa from the middle of the last millennium. lacking defences against common european diseases such as smallpox, typhus, measles and influenza, these populations fell ill faster and diseases were more virulent. the result was massive depopulation – whole peoples disappeared, and others were so seriously depleted as to have been written out of history. the role of disease in human history has been charted by a number of authors: initially by mcneil,4 who argues that disease is key, and more recently by diamond,5 who sees disease as part of broader geographical determinism. the interaction of disease, famine and political crisis has also been investigated, notably with regard to the ‘late victorian holocausts’ that overtook the emergent third world in the last * the science around the aids virus is clearly explained in many books and articles, one of the most accessible being christopher wills, plagues (london, flamingo, 1997). make up sept 2007 11/21/07 10:15 am page 47 s p r i n g 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e4 8 quarter of the 19th century.6 from these experiences we can identify a nexus of complex disaster, with different factors including climate, epidemic disease, conflict and social disorder all reinforcing one another to cause a decline in life expectancy and population stagnation and, in some cases, population collapse. these are cases of populations under severe stress, but how selection pressures might operate so that we could fairly describe such events as ‘darwinian’ remains speculative. it is clear from the history of epidemics that there are some populations at sub-regional, regional or continental level that are more susceptible to infection. there are also subtypes in a population who are more likely to be infected. does this also apply to hiv/aids? if it does, then the argument that aids is a darwinian event is supported. it has been suggested that at the population level those whose ancestors experienced the plague may be genetically resistant to hiv. the plague bacillus attached to the same receptor on the cell that hiv attaches to. if this were the case, then mapping the plague and movement of people whose genes carry this measure of protection would allow us to predict where the most serious hiv epidemics will and won’t be experienced. it might help explain why the genetically naïve populations of sub-saharan africa are experiencing such a severe epidemic.7 recently aids appears to be increasingly a disease of the poor and marginalised. what this means for humankind needs to be explored. we don’t know if the disease will have a greater impact on certain groups – are entrepreneurs in business and political leadership also more likely to be entrepreneurial in their sex lives? will hiv disproportionately affect them, and will this have any impact on our gene pool? in work done as a scenario building exercise for shell south africa we noted that some populations were experiencing higher levels of infection than others, with people in particular areas and particular occupation groups at high risk. newly prosperous people are often at risk, as are sex workers, mobile workers, soldiers, miners and others in hazardous occupations, as well as the unemployed. those who habitually think only in the shortterm are at high risk. fig. 1 was developed in a scenario planning exercise for shell south africa. is there any validity in this? those who survive the epidemic long enough to breed successfully create the future gene pool. as dawkins notes, ‘to the extent that differences between individuals are due to genes (which may be a large extent or a small one), natural selection can favour some quirk of embryological origami or embryological chemistry and disfavour others’.8 a characteristic influenced by genes – thinking in an entrepreneurial manner or being sexually attractive – can be favoured or disfavoured by natural selection. if it increases the chance of passing the genes on (through successful breeding), then these genes may be passed on, at the expense of others. the demographic impact of hiv/aids we would argue that aids is a darwinian event because of its demographic impact. it is a demographic shock. demographic consequences are felt in a number of ways, but most immediately through increased mortality and decreased fertility. in a scientific meeting on the demographic and sociofig. 1. some populations harder hit by hiv/aids than others (slide developed for shell south africa by b heinzen and heard, 2001). make up sept 2007 11/21/07 10:15 am page 48 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s p r i n g 2 0 0 7 4 9 economic impact of aids, in durban in 2003, available evidence was assembled and assessed. ‘in the worst affected countries the probability of a 15-year old dying before reaching the age of 60 years has risen dramatically, from a range of 10 to 30% in the mid-1980s, to a range of 30 60% at the turn of the century.’9 population size and structure mortality rises among those infected. five community-based studies in east africa found that mortality among infected adults was 10 20 times higher than among uninfected adults.10 child mortality rises both among hiv-positive children, infected through mother-to-child transmission (in the absence of treatment most hiv infected children die before their fifth birthday – newell et al., quoted by zaba et al.10), and among hiv-negative children who have an infected mother. a summary of the key demographic impacts of this disease is shown in table i. these data are taken from the normally conservative united nations. only in the very worst-affected countries (the un report specifically mentions botswana, lesotho and south africa) is the population expected to start declining after 2005. this is due to increased mortality, reduced fertility and the disruption of society. infected women are less likely to fall pregnant and carry a child to term, and premature mortality means there will be fewer women of childbearing age. for uganda it was estimated that the number of births was reduced by approximately 700 000, corresponding with almost 5.9% of all births that would have occurred during the last two decades.12 cohort mortality may be very high. fig. 2 looks at lifeexpectancy for today’s 15-year-old boys in a number of african countries.19 according to these conservative analyses, in countries where 15% of adults are currently infected, around a third of today’s 15-year-olds will die of aids. where adult prevalence rates exceed 15%, the lifetime risk of dying of aids is much greater. in south africa the medical research council has tracked the steady increase in deaths using the death certificates collected by the south african department of home affairs. south africa is one of the few countries where there is death registration and in 2000 over 90% of adult deaths were registered. between 1998 and 2003 there was a 150% increase in deaths of women aged 20 49 years, and this is adjusting for population growth and possible improvement in registration.14 an increase in mortality is also recorded for young people. in botswana under-5 mortality is expected to have risen to 104/1 000 live births; in the absence of aids it was projected to decrease to 45/1 000 live births. aids causes the majority of these ‘extra’ deaths11 (pp. 2 15). the structure of the population will change both in terms of age cohorts and in gender ratios. life expectancy for women is worse affected than that for men. we know that there are more women infected than men, in sub-saharan africa women are 30% more likely to be infected than men, and this is even more marked at younger ages. a 15 24-year-old woman is 3.4 more times more likely to be infected than her male counterpart.15 orphaning the increase in orphaning is a demographic impact, but it will have social and economic consequences. unicef estimates that by 2010 20 million children in africa will have lost one or both parents to hiv/aids. however, it is not just the numbers that are important. we also need to look at affected children as a percentage of all children. unicef estimates that in some settings up to 25% of children may be orphaned. for over 80% of orphans in the worst-affected countries the cause will be 53 countries where hiv/aids impact indicator included in 2002 un estimates* 7 countries with prevalence > 20% 1995 2000 2010 2015 2020 2025 1995 2000 2010 -2015 2020 2025 number of deaths (millions) without aids 159 174 193 3 3 4 with aids 170 207 231 5 10 9 percentage difference 7 19 20 71 193 142 life expectancy at birth (years) without aids 63.9 68.4 70.8 62.3 67 69.6 with aids 62.4 64.2 65.9 50.2 37.6 41 percentage difference 2.4 6.1 6.9 19.3 43.9 41.1 child mortality rate (per 1 000) without aids 93.9 68.8 56.1 80.2 56.9 44.8 with aids 98.8 75.8 62.3 108.8 100.2 84.3 percentage difference 5.3 10 11.1 35.7 76.2 88.4 * these countries are listed in the report and include the usa, russian federation, india and china. table i. summary of estimated and projected impact of hiv/aids on mortality indicators11 make up sept 2007 11/21/07 10:15 am page 49 s p r i n g 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e5 0 hiv/aids. these children face severe stress, they are less likely to attend school, more likely to be exploited and experience premature mortality, and they also have a more pessimistic outlook on life.16 life expectancy and child mortality rates have been widely used as markers for improvements in the welfare of populations. in botswana, life expectancy at birth is now estimated to be 39 years as opposed to 71 without aids. we would argue that demographic impact of this magnitude is certain to have far-reaching economic, social and political consequences. will these also be darwinian? perhaps; it is certainly something we need to consider, and it would merit thought by other disciplines. survival of the fittest? human beings evolved in africa several hundreds of millennia ago. our genome evolved in response to the constraints and opportunities of that environment. indeed, the entire theory of evolution is premised on historical contingency and the possibility of novelty. there can be a new species, and there can also be an extinction, and even a single new species or extinction can reshuffle the whole deck of phenotypical* cards. could a pathogen such as hiv wipe out the entire human race? the theoretical possibility is there, but such a pathogen would have to possess remarkable microbial and epidemiological characteristics. currently, neither hiv nor the headline-hitting ebola and sars fit this bill. notable is that disease is given short shrift in martin rees’ doomsday prognoses for the human race.17 rather, rees sees our main collective threat as our own technology run amok, or sufficiently abusing the planet as to make it uninhabitable. there is plentiful evidence that genetic factors can influence susceptibility and virulence. mutual adaptation between homo sapiens and pathogens has occurred through one of three channels. the first is through immunity acquired at the level of the individual (and thus acquired anew every generation). examples include measles and smallpox. a second channel is the extinction of the pathogen itself by burn-out in its intermediate hosts. a probable case of this is the plague, which may well have died out in europe because it killed rats too quickly. burn-out in intermediate hosts does not apply to hiv/aids. a third is the evolution of the pathogen itself into a less virulent form. a likely though still disputed case of this is syphilis, which showed exceptional virulence in its first century. it has been widely noted that emergent diseases have particularly florid manifestations in their first few years, after which they reduce in virulence. it is an epidemiologist’s rule of thumb that the first epidemic to strike a virgin population is the most devastating. in the case of hiv/aids, the way this would operate is that a certain genetically specified sub-group within the population would be ‘rapid progressors’, developing aids within 2 or 3 years of contracting hiv. these individuals would demonstrate particularly extreme symptoms (of opportunistic infections) and would be more likely to die off before they can transmit the virus onwards. one implication of the recent character of our common ancestry is that as a species we lack genetic diversity, and hence suffer greater collective susceptibility to infectious diseases. most epidemic infectious diseases have emerged since the invention of agriculture in the last 10 000 years, associated with population density and proximity to domestic animals.5 this is a very short time period for genetic selection to operate. * the visible characteristics of an organism resulting from the interaction between its genetic makeup and the environment. fig. 2. lifetime risk of aids death for 15-year-old boys, assuming unchanged or halved risk of becoming infected with hiv, selected countries. make up sept 2007 11/21/07 10:15 am page 50 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s p r i n g 2 0 0 7 5 1 for various reasons, hiv seems especially unlikely to succumb to evolutionary pressure for lower virulence. for a pathogen to be sustainable in a population, for every currently infected host there must be a greater-than-one chance of infecting a new host. in epidemiologists' algebraic parlance, r0 must be greater than one. for many infectious diseases such as measles, cholera and whooping cough, r0 is in the tens. for hiv, it is only slightly above one. the disease has a high degree of lethality and the host is infectious for many years, so this low transmission ratio is sustainable. hiv also has a high rate of mutation and recombination, and uses the human immune system to replicate itself. in summary, this means that ‘hiv may be evolutionarily free of constraints that reduce its virulence and increase its susceptibility’.18 in theory hiv could reach saturation in a host population, infecting and killing every individual, without jeopardising its onward transmission. in such a process, in the host population there could be selection for the genetic traits that make for slow progression from hiv to aids. but this is unlikely to be significant because of the mode of transmission and the fact that the virus is not easily transmitted. in most populations there will be those who are not exposed to infection (don’t have sex, stick to one partner who sticks to them) and those who will simply not be infected (30% of couples are discordant, meaning that one is infected and the other is not). any selection pressures would take generations to work through. because of the unique way in which hiv causes immunosuppression, it also has other implications for the evolution of pathogens and their human host. a human population with a large proportion of immunocompromised individuals is a new ecosystem for infectious diseases, marked by greater ease of transmission of infectious agents, and lesser vulnerability to the human immune system. the current pandemic of tb is an example of this, but there is no reason why epidemics of other infectious agents should not also seize upon this opportunity. given the normal functional relationship between transmissibility and virulence, this would imply that infectious agents would (mostly) evolve in the direction of higher transmission levels but lower virulence. concluding this tour d’horizon of the genetic evolutionary implications of hiv/aids, it is evident that the pandemic has intriguing, novel and potentially far-reaching impacts. some models for the impacts of hiv/aids imply immense adverse outcomes, and others imply modest impacts. so far, empirical data to substantiate models are scarce. they are novel, because of the peculiar capacity of hiv to retain its lethality, which means that we face the need for a new kind of accommodation to a pathogen. they are far-reaching, because hiv/aids will be with us for generations, and it may change our entire disease environment. ‘memetic evolution’ what are ‘memes’? the human brain has the capacity for receiving, encoding and transmitting information. replicable bits of information are ‘memes’. insofar as the packets of information have a capacity for replication (like genes themselves), they will do so, and thus become replicators along a new dimension. having a capacity for variation and recombination, they are themselves able to evolve in a darwinian manner. simple examples of memes are tunes, games and the skills necessary to make shoes; examples of complex combinations of memes (or memeplexes) are religious beliefs. there is no special reason why dna should be the sole darwinian replicator: any information coding system can do it. susan blackmore19 describes the gene-meme relationship as like a man walking a dog: at first the dog (memes) is on a tight leash, but increasingly it is able to steer its former master, so that it is not clear who is in charge. memeticists describe the relationship between memes and genes as purely an analogy, but it is one that allows us to lend some analytic rigour to the interaction of society and biology in the context of hiv/aids. also, insofar as we are exploring the limits of hiv/aids as a ‘darwinian event’, the least we can do is give the hypothesis the best run for its money. this section analyses two memes that are especially relevant to the case of hiv/aids: male circumcision and risk-taking. male circumcision an instance of a meme that features prominently in the literature is male circumcision. this was cited by richard dawkins in his introduction to susan blackmore’s the meme machine,19 with reference to his old school: ‘[a] martian geneticist, visiting the school during the morning cold bath ritual, would have unhesitatingly diagnosed an "obvious" genetic polymorphism. about 50 per cent of the boys were circumcised and 50 per cent were not. the boys, incidentally, were highly conscious of the polymorphism and we classified ourselves in roundheads versus cavaliers…. it is, of course, not a genetic but a memetic polymorphism. but the martian’s mistake is completely understandable; the morphological discontinuity is of exactly the kind that one normally expects to find produced by genes. ‘in england at that time, infant circumcision was a medical whim, and the roundhead/cavalier polymorphism at my school probably owed less to longitudinal [inter-generational] transmission than to differing fashions in the various hospitals where we happened to have been born – horizontal memetic transmission, yet again. where circumcision is religiously or traditionally based, the transmission will follow a longitudinal pattern of heredity, very similar to the pattern for true genetic transmission, and often persisting for many generations. our martian geneticist would have to work quite hard to discover that no genes are involved in the genesis of the roundhead phenotype.’ unlike, for example, tattooing or navel piercing, circumcision is a meme that is less often widely transmitted horizontally. this particular meme is important to our case because male circumcision appears to protect against hiv transmission by as much as a 40% reduction in risk. in short, it is a meme that has come to provide a very clear survival advantage to its possessors. until now, its replicatory capacity has been related almost wholly to its attachment to certain religious and cultural memes or ‘memeplexes’. but in the era of aids, circumcision now also provides a survival advantage. make up sept 2007 11/21/07 10:15 am page 51 s p r i n g 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e5 2 this is of both theoretical and practical interest. the protective effect of male circumcision should logically result in populations that practise it suffering lower hiv rates than those that do not, and thus surviving better. it could also result in the meme of male circumcision itself being adopted by other populations – i.e. spread horizontally. also relevant is to ask what determines circumcision in a society. the circumcision meme is closely associated with religious beliefs, and these may in turn be associated with other social practices that are correlated with hiv risk. examples might include polygamy and early marriage of girls. risk-taking another memetic trait is propensity to take risks. in the field of sexual behaviour, this has been studied, concluding that there is a genetic basis to unfaithfulness to one’s partner. but it is also a gene-meme interaction, with some individuals or subgroups more prone to risk-taking than others on the basis of their genetic profile. in the absence of hiv/aids or a similar sti, risk taking in the field of sexual encounters, especially numbers of sexual partners, is genetically adaptive. men who have higher numbers of partners will have more offspring. women who have illicit affairs are more likely to select those kinds of men as lovers, and to conceive children as a result of such casual flings, rather than through regular sexual intercourse with their long-term partners, and as many as 10% of all children in western societies are not in fact fathered by their ‘fathers’.20 there is some historical-anthropological evidence on which to build a theory of memetic change. many melanesian and some native american societies were, in marshall sahlins’ formulation, ‘aphrodisian’ in their traditions of sexual generosity, including routinely offering sexual favours to guests, traders and diplomats. the arrival of western explorers, missionaries and traders unleashed catastrophic epidemics on these societies, including syphilis. the low fertility, high mortality, and the sheer disfigurement and suffering caused by the disease contributed to population plunges and a thorough-going social demoralisation.21 these societies simply could not adapt their sexual practices quickly enough to deal with threat of stis. in the era of aids, sexual risk-taking undoubtedly increases risk of hiv, and as such negatively selects for survival. this is a new phenomenon in the history of our species. as a result, we can anticipate a new dynamic between natural and sexual selection. christian fundamentalists are, strictly speaking, correct in advocating that the a and b of aids prevention (abstinence and faithfulness to one lifetime partner) are sufficient, spurning the c for condoms. in the absence of condoms or other preventive technologies, over the generations, those who faithfully pursue the a and b would survive, while the rest of humanity would become steadily less numerous. the efficacy of a and b would be strongly associated with their connection to other memetic factors, notably religious faith, implying that such a hypothetical society would be much more religious. implications the cases of potential memetic ‘evolution’ in response to hiv/aids point to the complexity of the impacts of the epidemic. no part of human life is untouched. some memes have clear advantages or disadvantages for survival – and may as a consequence be selected for. how long this will take, we cannot speculate. the impacts of the epidemic compel human populations to explore elements of their wired-in behavioural capacities that have not recently been in evidence (such as selfishness under energy stress). other memes have their own autonomous logics, which may prevail despite their maladaptation to the realities of the epidemic. ‘ecology change’ the preceding discussion has necessarily veered away from simple evolutionism into examining the role of individual human host, human society and the hiv in a complex framework that encompasses all. any change to one part of the system necessarily impacts on others. to this extent, many ‘ecological’ issues have already been addressed. others follow. for example, as barnett and blaikie observed in uganda in the late 1980s, hiv/aids causes changes in land use, which in turn have other consequences for agrarian society.22 this is an example of the way in which it is necessary to analyse hiv/aids as an historic event. the question that remains is, how do hiv’s adaptation to its host and homo sapiens’ response to hiv interact with one another? what future will be jointly created by our genes and memes, and hiv and its parallel and inter-linked evolution? let us begin with hiv, as it is in the driving seat. as mentioned, hiv has unique evolutionary features, which enable it to bypass or render ineffective the pressures for lower virulence. this occurs at various levels, from the microbial to the collectivity of the host population. it is a fractal characteristic. at the population level, the key factor is the 7 10-year time lag between hiv infection and the development of aids, which enables r0 to be sustained without loss of lethality. we know that hiv is evolving. it does this by mutation and recombination, creating new strains that have differing transmissibility, virulence and vulnerability to treatments. the most likely outcome of genetic change in hiv is to increase resistance to treatment and to increase r0 by increasing the transmission rate. in populations already at saturation level (above 40% adult prevalence) the latter might be a maladaptive trait, insofar as a new variant of hiv that achieved still higher levels of prevalence among young women would actually begin to create a below-replacement fertility regimen in the host population. in evolutionary terms, this is a credible scenario. turning to the human response to hiv, we can identify three main types of reaction. the first is the impact of the epidemic on social functioning, including poverty, food security and social reproduction. aspects of this have been explored above. make up sept 2007 11/21/07 10:15 am page 52 s p r i n g 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e5 4 an additional element to the ‘new variant famine’ hypothesis, first put forward by de waal and whiteside, is the way in which responses to the stress of hunger and destitution become maladaptive in the context of hiv/aids. this is because survival strategies such as migration or commercial sex work increase the risk of hiv transmission. this is perhaps the most alarming implication of the ‘new variant famine’ hypothesis: that it has a feed-back loop into hiv transmission itself, helping to sustain high prevalence. if it occurs – and so far we have only anecdotal evidence that it does – this would be a far-reaching revision to the roy anderson projection of aids as a 130-year event. another potential feedback loop is the adverse impact of lower levels of girls’ education on hiv risk. educational performance is declining because of children (especially girls) being withdrawn from school to help with sustaining the household, and because of the lower standards of schools that are stricken with high educator morbidity and mortality. low female educational achievement is in turn associated with higher risk of hiv. it is a commonplace of population history that a demographic shock such as a famine or war creates greater vulnerability to a second shock such as an epidemic. disasters rarely come singly. what is different about hiv/aids is that it is a longwave event, with structural implications for human ecology, which in turn implies that its secondary impacts will themselves be structural and sustained. we could, in short, see a new viral-human ecological framework in which hiv saturation combines with poverty, hunger and social dislocation in a new kind of socioepidemiological trap. populations that pass a threshold of compounded distress may simply be unable to recover. in a globalised world, ambitious individuals can escape and live elsewhere, bringing up their families in richer low-hiv societies, leaving the poorest and most entrapped populations to continue a downward spiral of misery. a bifurcation of global life chances along these lines, determined in large part by hiv prevalence, cannot be ruled out. the second human response to hiv is the medical-scientific response. in two decades, scientists have learned more about hiv than almost any other pathogen. but, in the absence of a magic bullet, what has this meant for the virus? history counsels us to be cautious about the impact of human intervention – including medical science – on the life of a pathogen. some of the medical responses to hiv/aids, such as antiretroviral therapy (art), may in fact prove to be adaptive for the virus. this would happen if art extends the infective period of the person living with hiv, and thereby increases the number of his or her risky sexual encounters, by a greater degree than it reduces infectivity. if the proportional increase in the life expectancy of people living with hiv/aids from the moment of infection on art is a, and the proportional decrease in infectivity (through lower viral load) is b, then if a exceeds b, then r0 increases. note that this assumes no change in sexual behaviour: simply living longer implies more sexual partners. in addition, there are some indications that the availability of art may also increase risky behaviour, because hiv becomes seen as a treatable condition. on the other hand, the voluntary counselling and testing associated with art provision may lead to behaviour change in the opposite direction, lowering transmission. art is not, therefore, a block to the odyssey of hiv. it brings many desirable outcomes, such as prolonging the lives of those living with hiv and aids, and potentially blunting some of the disastrous secondary impacts such as reducing the numbers of children orphaned by aids. but this is managing or containing the epidemic, not halting it. the third human response is what we may call the ‘political economic’ response: the whole cluster of institutional measures put in place to manage and (optimistically) solve the problem posed by hiv/aids. international institutional responses have their own independent logic, driven by the need to appear to be managing the problem in such a way that the institutions themselves are protected and can reproduce themselves. scanning human responses to hiv/aids, what we see is the extent to which we have already adapted to accommodate the killer in our midst. we are sharing our habitat with hiv, and our society, institutions and even our prized science are quietly accommodating this specialist predator. conclusion in june 2004 the copenhagen consensus project released their list of priorities for the ten great global challenges. ‘these challenges, selected from a wider set of issues identified by the united nations, are: civil conflicts; climate change; communicable diseases; education; financial stability; governance; hunger and malnutrition; migration; trade reform; and water and sanitation.’23 the panel of economic experts was asked to address this and decide the best ways of advancing global welfare, especially that of developing countries, supposing an additional $50 billion of resources was available. the aids epidemic was identified as the first priority: ‘the panel assigned the highest priority to new measures to prevent the spread of hiv/aids. spending assigned to this purpose would yield extraordinarily high benefits, averting nearly 30m new infections by 2010. costs are substantial, estimated at $27 billion. even so, these costs are small in relation to what stands to be gained. moreover, the scale and urgency of the problem – especially in africa, where aids threatens the collapse of entire societies – are extreme’.23 writing in 1987, when the implications of the hiv/aids epidemic were first being absorbed by the scientific community, the evolutionary theorist stephen jay gould wrote: ‘the evolutionary perspective is correct, but utterly inappropriate for our human scale. yes, aids is a natural phenomenon, one of a recurring class make up sept 2007 11/21/07 10:15 am page 54 s p r i n g 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e5 6 of pandemic diseases. yes, aids may run through the entire population, and may carry off a quarter or more of us. yes, it may make no biological difference to homo sapiens in the long run: there will still be plenty of us left and we can start again. evolution cares as little for its agents – organisms struggling for reproductive success – as physics cares for individual atoms of hydrogen in the sun. but we care. the atoms are our neighbors, our lovers, our children, and ourselves. aids is both a natural phenomenon and, potentially, the greatest natural tragedy in human history.’24 seventeen years later, we have no reason to dispute his verdict that we care, but there is evidence stacking up to suggest this may make a biological difference to homo sapiens. we asked if hiv/aids was a darwinian event. we looked at the evidence and suggested that its demographic consequences were such that, for this reason alone, it merits this description. however, it has social and economic consequences as well. this paper was originally presented at a historical conference. we concluded that aids is an event of historical significance, not least because we must respond to it in a (short) historical time frame. it is therefore high time that new disciplines become engaged in looking at the epidemic, drawing comparisons from other epidemics and demographic disasters, and applying frameworks from evolutionary science. historians can both contribute to the debate and help us influence our future. george orwell wrote: ‘he who controls the past commands the future. he who commands the future conquers the past’. this is worth thinking about. references 1. anderson r. keynote address. report of the scientific meeting on the empirical evidence for the demographic and socio-economic impact of aids. durban, 2628 march 2003. 2. dawkins r. river out of eden. london: weidenfeld & nicolson, 1995: 96. 3. blackmore s. the meme machine. oxford: oxford university press, 1999. 4. mcneil wh. plagues and people . garden city, ny: doubleday, 1976. 5. diamond j. guns, germs and steel: the fates of human societies. new york: norton, 1999. 6. davis m. late victorian holocausts: el nino famines and the making of the third world. london: verso, 2001. 7. hunter s. who cares? aids in africa. london: palgrave macmillan, 2004: 187. 8. dawkins r. river out of eden. london: wiedenfield & nicolson, 1995: 28. 9. timæus i, jasseh m. adult mortality in sub-saharan africa: evidence from the demographic and health surveys. paper presented at the conference on empirical evidence for the demographic and socio-economic impact of aids, durban, 26-28 march 2003. 10. zaba b, whiteside a, ties boerma j. demographic and socio-economic impact of aids: taking stock of empirical evidence. aids 2004; 18: suppl, 1-7. 11. united nations secretariat, department of economic and social affairs, population division. the impact of aids, esa/p/wp. 185, 2 september 2003. 12. lewis j.jc, ronsmans c, ezeh a, gregson s. the population impact of hiv on fertility in sub-saharan africa. aids 2004; 18: suppl 2, s35-43. 13. baba z. in: unaids. report on the global hiv/aids epidemic. new york: unaids, 2000: 26. 14. bradshaw d, laubscher r, dorrington r, bourne de, timæus im. unabated rise in the number of adult deaths in south africa. s afr med j 2004; 94: 278-279. 15. unaids. 2004 report on the global aids epidemic. geneva: unaids, 2004: 40. 16. unicef. africa’s orphaned generation. new york: unicef, 2003. 17. rees m. our final century: will the human race survive the twenty-first century? london: heinemann, 2003. 18. hutchinson j, hiv and the evolution of infectious diseases. in: ellison g, parker m, campbell c, eds. learning from hiv and aids. cambridge: cambridge university press, 2003: 50. 19. blackmore s. the meme machine. oxford: oxford university press, 1999: xii-xiii. 20. baker r, sperm wars: infidelity, sexual conflict and other bedroom battles. london: fourth estate, 1996. 21. crosby aw. hawaiian depopulation as a model for the amerindian experience. in: ranger t, slack p, eds. epidemics and ideas: essays on the historical perception of pestilence. cambridge: cambridge university press, 1992. 22. barnett t, blaikie p. aids in africa: its present and future impact. london: john wiley; new york: guilford press, 1992. 23. copenhagen consensus. http://www.copenhagenconsensus.com/files/filer/cc/ pressuk/copenhagen_consensus_result_final.pdf (last accessed 3 june 2004). 24. gould sj. the terrifying normalcy of aids. new york times magazine 1987; 19 april. reproduced in: bull c, ed. while the world sleeps: writing from the first twenty years of the global aids plague. new york: thunder’s mouth press, 2003: 46-47. make up sept 2007 11/21/07 10:15 am page 56 march hiv issue 1-16 march 2005 the southern african journal of hiv medicine 1 8 antiretroviral therapy in adults southern african hiv clinicians society march 2005 sub-saharan africa has just over 10% of the world’s population but is home to more than 60% of all people living with hiv (approximately 25.4 million people). prevalence rates in southern africa’s antenatal clinics surpass 25%, the highest in the world. south africa is host to the highest number of hiv-infected people in the world (5.3 million, unaids/who aids epidemic update, december 2004) with considerable regional variation and an annual increase in all but two provinces (free state and gauteng). the free state, mpumalanga and kwazulu-natal have prevalence rates among pregnant women attending public sector antenatal clinics of > 30% while the remaining provinces have a range of between 15% and 17.5%. four other countries in the region have very high antenatal prevalence rates, often exceeding 40%: botswana, lesotho, namibia and swaziland (39%). elsewhere in the sub-region hiv infections in pregnant women appear to be stabilising at lower levels, e.g. malawi (18%), zambia (16%) and zimbabwe (25%). uganda’s prevalence, though still high, has dropped in the last decade to 5 6%. angola is the exception in the region, having had very low prevalence levels for some years, possibly owing to the war which restricted civilian movement. prevalence remains at about 3% at luanda’s antenatal clinics; however, sex workers have an incidence of 33%, fuelling fears of a widespread and rapid spread in this country. most sub-saharan countries have antiretroviral roll-outs, albeit at different stages and levels of delivery. in july 2004, the health systems trust, reported in the first south african health review (sahr) that aids was responsible for 39% of deaths in south africa in 2000. gearing up for the national antiretroviral (arv) roll-out in early 2003, the south african government estimated that about half a million south africans with aids were in urgent need of arv treatment (art). in march 2003 the department of health commenced the national roll-out at a handful of pre-selected, designated pilot sites, aiming to treat 53 000 hiv-infected south africans (cd4+ counts of < 200/µl) with arvs by march 2004, and expanding the number of sites over time. to date progress has been slower than planned. national art guideline regimens are advised in these guidelines. the primary goals of arv therapy are: improvement of quality of life reduction of hiv-related morbidity and mortality maximal and durable suppression of viral load, and restoration and/or preservation of immunological function. this is achieved by suppressing viral replication as intensely as possible for as long as possible by using tolerable and sustainable treatment for an indefinite period of time. by doing so, the impact of hiv on the immune system may be minimised and the morbidity and mortality associated with hiv infection can be improved. effective combination arv therapy has been shown to reduce the number of new cells infected by hiv and to impede the ability of the virus to evolve drug resistance. maximally suppressive arv regimens should be used in order to obtain the best clinical results and to prevent resistance. in the region there is still widespread use of non-suppressive regimens such as dual nucleoside reverse transcriptase inhibitor (nrti) therapy. initiation of such therapy should be strongly discouraged. regimens to prevent transmission of hiv non-suppressive regimens are effective in preventing hiv transmission in prevention of mother-to-child trans1. goals of therapy 2. standard of care g u i d e l i n e s march hiv issue 17-48 4/16/05 10:42 am page 18 march 2005 the southern african journal of hiv medicine 2 0 mission (pmtct), post-exposure prophylaxis for health care workers following occupational exposure, and following sexual exposure. refer to appropriate guidelines. currently available arv agents inhibit one of two key viral enzymes required by hiv for intracellular viral replication (table i, below): reverse transcriptase, which is essential for completion of the early stages of hiv replication, and protease, which is required for the assembly and maturation of fully-infectious viral progeny. notes on currently available arvs: always refer to the most current version of the guidelines as new treatments regularly become available for clinical use. different fixed-dose combinations are increasingly being made available. the oldest combination is azt/3tc, but 2and 3-drug fixed combinations are now available throughout southern africa. side-effects remain as described above. increasingly, low-dose ritonavir is being used to ‘boost’ the blood levels of certain pis, routinely with lopinavir, and usually with indinavir and saquinavir; it is not used in combination with nelfinavir, where boosting has little impact on blood levels. dosages, risk factors and special precautions in pregnancy, renal failure, and liver failure risk factors in pregnancy are set out in table iii (p. 22).i art dosages in renal failure are set out in table iv (p. 22). for peritoneal dialysis the dose given under creatinine clearance < 10 should be given daily. for haemodialysis the dose given under creatinine clearance < 10 should be given daily, but it must be given after dialysis on dialysis days or else the drug will be dialysed out. art dosages in liver impairment are set out in table v (p. 23). patient readiness for therapy is as important as the medical indications for commencing therapy. patient must demonstrate insight. patient must be informed that lifelong therapy is essential. patient must be aware of importance of adherence. patient must have been adequately informed about side-effects. patient must have established the ability to attend reliably and have attended at least two or three visits before commencing therapy. active depression or substance abuse should be dealt with. support, e.g. disclosure, support groups, treatment ‘buddies’. personal treatment plan including drug storage and strategies for missed doses. life-skills, crisis intervention and family planning counselling life-skills and crisis counselling should take place in a locale where privacy and time are available to the counsellor and the patient. where time and opportunity do not permit, the physician should refer to an appropriately skilled caregiver. treatment/management-related counselling many patients are afraid of starting art. reassure the patient that the drugs work and that side-effects are usually minor and manageable. the commencement of art 3. classes of arv agents and their mechanisms of action 4. arv agents currently available in southern africa and common adverse events (table ii, p. 21) classification of antiretroviral agent abr. mechanism of action specific action nucleoside & nucleotide* nrtis / reverse transcriptase inhibition mimics the normal building reverse transcriptase ntrti blocks of hiv dna inhibitors non-nucleoside nnrtis reverse transcriptase inhibition directly inhibits reverse transcriptase reverse transcriptase inhibitors protease inhibitors pis protease inhibition inhibits late stages of hiv replication fusion inhibitors† entry inhibition binds to gp41 *tenofovir – not yet registered in south africa. †not yet available in the region and prohibitively expensive. table i. classes of arv agents and their mechanism of action 5. readiness for therapy 6. support and counselling march hiv issue 17-48 4/16/05 10:42 am page 20 the southern african journal of hiv medicine march 2005 2 1 class dosage generic name of drug (and pill burden) common adverse events zidovudine (azt)* nrti 300 mg bid bone marrow suppression, gastrointestinal (gi) (2 tabs daily) upset, headache, myopathy, hyperlactataemia/ steatohepatitis (medium potential) didanosine (ddi) nrti 200 mg bid (125 mg bid peripheral neuropathy, pancreatitis, nausea, if < 60 kg) or 300 400 mg qd diarrhoea (take on empty stomach), (4 tabs daily) hyperlactataemia/steatohepatitis (high potential) zalcitabine (ddc) nrti 0.75 mg tid peripheral neuropathy, pancreatitis, oral ulcers, (3 tabs daily) hyperlactataemia/steatohepatitis (high potential), lamivudine (3tc) nrti 150 mg bid anaemia, gi upset, myalgia, pancreatitis (rarely), (2 tabs daily) hyperlactataemia/steatohepatitis (low potential) stavudine (d4t) nrti 40 mg bid (30 mg bid peripheral neuropathy, lipo-atrophy, if < 60 kg) (2 caps daily) hyperlactataemia/steatohepatitis (high potential) abacavir nrti 300 mg bid gi upset, hypersensitivity reaction 5%, (2 tabs daily) hyperlactataemia/steatohepatitis (low potential) tenofovir* nucleotide 300 mg qd (1 tab daily) asthenia, headache, gi upset and tubular rti (ntrti) nephropathy, ddi concentrations increased 30 60% nevirapine (nvp) nnrti 200 mg qd for 14 days then rash, hepatitis 200 mg bid (2 tabs daily) or 400 mg od efavirenz (efv) nnrti 600 mg od (3 tabs daily, rash, central nervous system symptoms, elevated new single tablet now available) transaminases nelfinavir pi 750 mg tid or 1 250 mg bid diarrhoea (take with food), hyperglycaemia, 9 (tid)/10 (bid) caps daily dyslipidaemia indinavir pi 800 mg q 8 h (6 caps daily) take on kidney stones, unconjugated hyperbilirubinaemia, an empty stomach; now commonly gi disturbances, hair loss, hyperglycaemia, used with decreased dosage, comheadache, dyslipidaemia bined with ritonavir – recommended 800 mg bid with100 200 mg ritonavir bid, no food restrictions ritonavir pi 600 mg bid (12 caps daily) gi upset, circumoral and extremities paraesthesias, – very rarely used as sole pi diarrhoea, fatigue, hepatitis, taste perversion, in adults hyperglycaemia, dyslipidaemia saquinavir (hard pi 600 mg bid, 1 200 mg tid gi disturbances (mild) (take with a fatty meal, or and soft gel formu(9 caps daily); when combined up to 2 hours after meal), headache, elevated lations) with ritonavir, dose at 400 mg transaminases, hyperglycaemia, dyslipidaemia combined with ritonavir 400 mg, both bid atazanavir pi 400 mg qd (2 tabs daily); unconjugated hyperbilirubinaemia, combinations with ritonavir hyperglycaemia, dyslipidaemia (low potential) being explored amprenavir* pi 1 200 mg bid rash, headache, gi upset, hyperglycaemia, (16 tabs daily) dyslipidaemia lopinavir/ritonavir boosted pi 400/100 mg bid (6 caps daily) asthenia, headache, gi upset, hyperglycaemia, dyslipidaemia *not yet registered in south africa. table ii. arv agents currently available in southern africa and common adverse events march hiv issue 17-48 4/16/05 10:42 am page 21 march 2005 the southern african journal of hiv medicine 2 2 is never a medical emergency: let the patient voice a desire to start therapy and indicate their commitment to take medication and to follow up as instructed. never coerce the patient into starting the treatment. give the patient a treatment plan. this should include the reasons for commencing therapy and which drugs are to be used. the names of the drugs must be mentioned and specific detail given including the appearance of each drug, when and how they are to be taken, and a brief indication of anticipated side-effects and toxicity. the medication requires adherence of the order of 95 100%. poor adherence and non-compliance result in the development of drug resistance. the desire to stop therapy or alter the number or timing of the drugs must be avoided. the patient must be encouraged to discuss drug-related issues with his/her doctor before any changes are made. lifestyle, nutrition, traditional medication and supplements in hiv various adjuncts to therapy are widely used in the community. these include specific diets, food/nutritional supplements, vitamins and so-called immune ‘boosters’. scientific evidence to support the use of these is largely absent. some herbs, trace elements and the excessive dosing of certain vitamins may cause harm and ought to be discouraged. fawzi et al. have recently shown survival benefit in tanzanian women given a supplement of vitamins b, c and e over a period of 5 years. this study needs further confirmation but does form the basis of a general view that these vitamins can be used safely in patients who are hiv infected. a healthy lifestyle is recommended, including a balanced diet, plenty of exercise, regular clinic follow-up and a positive outlook on the future. malaria, travel and hiv travellers to areas endemic for malaria and yellow fever need to be cautioned. the forested regions where contact with the mosquito vector and the virus is possible must be avoided. drug interactions between antimalarials and antiretrovirals: among drugs used for chemoprophylaxis, there are no clinically significant pharmacokinetic interactions between antiretrovirals and mefloquine or doxycycline. however, mefloquine and efavirenz both cause frequent neuropsychiatric side-effects. class, drugs fda category* nrtis abacavir c didanosine b lamivudine c stavudine c tenofovir b zalcitabine c zidovudine c nnrtis efavirenz d† nevirapine c pis amprenavir c indinavir c lopinavir-ritonavir (in combination) c nelfinavir b ritonavir b saquinavir b notes: * the fda codes for a b, c and d are listed below. the coding assigned to the drugs is based on package inserts; fda, briggs gg, freeman rk, yaffe sj, drugs in pregnancy and lactation 6th edition 2002; or expert opinion. † efavirenz has been shown to be teratogenic in primates, causing craniofacial abnormalities. there have been three human case reports of myelomeningocele in infants following intrauterine exposure to efavirenz. fda codes a: controlled studies have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of risk in later trimesters), and the possibility of harm appears remote. b: either animal-reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the first trimester (and there is no evidence of risk in later trimesters). c: either animal studies have revealed adverse effects on the fetus (teratogenic or embryocidal or other) and there are no controlled studies in women, or studies in women and animals are not available. drugs should be given only if the potential benefit justifies the potential risk to the fetus. d: there is positive evidence of human fetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g. if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective). x: studies in animals or humans have demonstrated fetal abnormalities and/or there is evidence of fetal risk based on human experience, and the risk of use of the drug in pregnant women clearly outweighs any possible benefit. the drug is contraindicated in women who are or may become pregnant. table iii. risk factors in pregnancy creat. clearance creat. clearance drug 10 50 < 10 zidovudine unchanged 300 mg daily didanosine > 60 kg 200 mg daily >60 kg 100 mg daily < 60 kg 150 mg daily < 60 kg 75 mg daily lamivudine 150 mg daily 50 mg daily stavudine > 60 kg 20 mg > 60 kg 20 mg daily 12-hourly, < 60 kg < 60 kg 15 mg daily 15 mg 12-hourly abacavir unchanged unchanged tenofovir avoid avoid zalcitabine 0.75 mg 12-hourly 0.75 mg daily pis unchanged unchanged nnrtis unchanged unchanged sources: bartlett jg. medical care of patients with hiv infection 2003, and the sanford guide to antimicrobial therapy 2003. formula to estimate creatinine clearance: 140 – age x ideal weight 0.82 x serum creatinine women: multiply total by 0.85 march hiv issue 17-48 4/17/05 11:17 am page 22 the southern african journal of hiv medicine march 2005 2 3 doxycycline is therefore the preferred chemoprophylactic agent for patients on efavirenz. levels of atovaquone, used in a fixed-dose combination with proguanil (malanil), are reduced by pis, the significance of which is uncertain. however, it would be prudent to avoid malanil use in patients on pis. quinine levels are increased by pis. quinine is the drug of choice for severe malaria, but is a toxic drug with potential for life-threatening adverse effects. pis should therefore be discontinued until the course of quinine has been completed, and monitoring for quinine adverse effects (hypoglycaemia and arrhythmias) is essential. yellow fever vaccination poses a risk to the hiv traveller whose cd4 level is below 200 cells/µl. encourage the traveller to make alternative arrangements or to travel with documentation that permits travel without prior vaccination. immunisations hiv infection is associated with a suppression of both humoral and cell-mediated immune response, which may impair the response to vaccinations, reducing their efficacy especially if the cd4 count is < 200 cells/µl. the safety of live attenuated vaccination is also modified by hiv infection and live vaccines are contraindicated in symptomatic hiv disease or if the cd4 count is < 200 cells/µl. the decision to use a vaccine must be based on best assessment of risks and benefits. it is mandatory to report all suspected vaccine-related adverse events and vaccine failures. opportunistic infections (ois) ois must be avoided through the use of appropriate prophylaxis. local and international guidelines should be consulted, e.g. the southern african hiv clinicians society’s oi guidelines. initiation of highly active antiretroviral therapy (haart) is never an emergency unless used as postexposure prophylaxis. art should be deferred until patients are prepared to commit themselves to long-term treatment and to maintaining good adherence to treatment. drug prescribing with liver impairment nrtis abacavir reduce adult dose to 200 mg bd for mild to moderate liver impairment. contraindicated in severe hepatic impairment didanosine use with caution. recent reports implicate ddi use as a risk factor for the development of hepatic decompensation in patients being treated for cirrhosis due to hepatitis c. avoid co-administration of ddi with d4t in patients with liver disease in view of increased risk of lactic acidosis lamivudine 3tc should be used with caution in patients with chronic hepatitis b infection as there is a risk of rebound hepatitis after treatment stavudine avoid co-administration of ddi with d4t in patients with liver disease in view of the risk of lactic acidosis tenofovir acute exacerbations of hepatitis b have been reported in patients who are co-infected with hiv and have discontinued tenofovir zalcitabine may be associated with exacerbation of hepatic dysfunction, especially in individuals with pre-existing liver disease or with a history of alcohol abuse. such patients should be closely monitored and dose reduction or interruption of drug therapy should be considered if necessary. avoid co-administration with either ddi or d4t in patients with liver disease in view of the likely increased risk of lactic acidosis zidovudine decrease dose by 50% or double dosage interval nnrtis efavirenz caution should be exercised in administering efavirenz to patients with liver disease nevirapine contraindicated in severe hepatic impairment; accumulation may occur with moderate hepatic impairment but no specific recommendations on dose reductions can be made owing to limited data pis indinavir reduce adult dose to 600 mg 8-hourly in mild to moderate hepatic impairment lopinavir/ lopinavir is highly metabolised in the liver and concentrations may be increased in patients with hepatic ritonavir impairment. pharmacokinetic studies have not been done, but reduced adult dose to 2 tablets bd should be considered in severe liver disease nelfinavir dose reduction advised – limited data suggest doses of 500 mg bd to 750 mg bd ritonavir no adjustment for mild hepatic impairment or moderate impairment (monitor closely). no data on severe impairment saquinavir avoid. there have been reports of worsening liver disease and development of portal hypertension after starting saquinavir in patients with severe liver disease table v. art dosages in liver impairment 7. indications for starting art (table vi, p. 24) march hiv issue 17-48 4/17/05 11:18 am page 23 march 2005 the southern african journal of hiv medicine 2 6 all infected individuals, including those on effective art, should be viewed as potentially infectious. adequate counselling about safer sex practices must be provided to encourage prevention of new infections and re-infection. primary infection the recommendation to treat primary infection has been removed owing to lack of evidence, and primary infection should only be treated in a carefully monitored research environment, or in the presence of significant acute symptoms, in careful consultation with an expert and with a fully informed patient. there are compelling reasons to defer therapy, including lack of proven efficacy, drug toxicity, and the potential for drug resistance. patients with severe primary infection progress more rapidly, and this is an indication for careful follow-up. tuberculosis and haart the following should be kept in mind when a patient presents with tuberculosis (tb) before commencing haart: tb should always be managed by public sector tb clinics. if the patient is already on art the regimen should be changed, if possible, to be compatible with rifampicin. when art is commenced the patient’s symptoms may temporarily worsen as part of immune reconstitution. if the patient’s cd4+ count is > 200 cells/µl commence art after completing tb therapy (providing the patient fulfils the criteria above). in other words, the cd4 count must be < 350. if the cd4+ count is < 200 cells/µl delay art until after the intensive phase of tb therapy (2 months) unless the patient has other serious hiv-related illness or has a very low cd4+ count (< 50 cells/µl), in which case art should be introduced only once the patient is stabilised on tb therapy. interactions of arv agents with rifampicin are set out in table vii. shared side-effects of tb and art are set out in table viii. viral loads are expensive and are not always available in resource-poor settings. however, viral loads are strongly recommended to monitor therapy. we recommend that they be done at the following times: baseline 6 8 weeks after commencement of therapy thereafter every 4 6 months. cd4+ counts should be done at the time of viral load testing. symptomatic patient treatment presence of severe hivart recommended related symptoms (who clinical stage 3 or 4)* asymptomatic patient treatment cd4+ count < 200 art recommended cd4+ count 200 350 art should be considered on an individual basis† cd4+ count > 350 defer treatment * who clinical staging is currently being revised. initiation of tuberculosis therapy and haart should not be commenced simultaneously (see below). † two cd4+ counts in this stratum should be done before a decision is made. individuals with high viral loads (> 100 000) or with rapidly declining cd4+ counts or troublesome hiv-related symptoms that are not covered in the staging system should commence art without delay, while others can wait until their cd4+ count approaches 200. table vi. indications for starting art arv interaction nrtis no significant interactions efavirenz (nnrti) mild reduction in efavirenz levels; recommended to use conventional dose nevirapine (nnrti) moderate reduction in nevirapine levels – limited experience – concern about shared hepatotoxicity; recommended to use conventional dose, but with close monitoring ritonavir (pi) (full no significant interaction dose, rarely used) lopinavir/ritonavir add ritonavir 300 mg bid (3 tablets bid) (boosted pi) 400 mg/100 mg bid (kaletra) ritonavir + saquinavir no significant interaction; do not both 400 mg bid* use saquinavir without ritonavir all other pis marked reduction in pi levels – avoid * a recent study of ritonavir 100 mg plus saquinavir 1 000 mg bid was associated with a high incidence of hepatotoxicity. caution is advised when using the combination of ritonavir + saquinavir both 400 mg bid, with frequent monitoring of liver function tests. table vii. art interactions with rifampicin side-effects art tuberculosis treatment nausea didanosine, pyrazinamide zidovudine, pis hepatitis nevirapine, efavirenz rifampicin, isoniazid, pyrazinamide peripheral stavudine, isoniazid neuropathy didanosine rash nevirapine, rifampicin, isoniazid, efavirenz pyrazinamide modified from 2004 national antiretroviral treatment guidelines, 1st ed; table vii; page 18. patients should be counselled before therapy about the following: • treatment for tb together with art involves taking a large number of tablets. patients may struggle with adherence. • when art is commenced, the patient’s tb symptoms may temporarily worsen as part of immune reconstitution. table viii. shared side-effects of tb and art 8. laboratory monitoring march hiv issue 17-48 4/17/05 11:18 am page 26 the southern african journal of hiv medicine march 2005 2 7 haematological toxicity (table ix) patients on zidovudine, stavudine or co-trimoxazole may experience abnormalities in their full blood counts. significant bone marrow toxicity from co-trimoxazole generally only occurs with high doses used for treating opportunistic infections – it is reversible with folinic acid (not folate). long-term monitoring of full blood counts is only necessary with zidovudine – this should be monitored monthly for the first 3 months of therapy and thereafter 3-monthly. the main problem is anaemia and neutropenia – platelet counts generally rise with zidovudine. hepatotoxicity (table x) liver function tests (lfts) should be done at art initiation and thereafter tailored to individual drug regimens. all arv agents may cause hepatotoxicity, but the most common is nevirapine (laboratory monitoring shows 10 15% of patients to be affected but only 1% present with clinical hepatitis). hepatotoxic drugs should be discontinued at high levels of lft abnormality (table x) or at low levels if any symptoms of hepatitis appear. a common cause of fatty liver is nrti use, especially stavudine. there is divided opinion that routine monitoring of alts is necessary but a full lft is recommended for patients on nevirapine at baseline, and thereafter only the alt need be monitored: at 2 weeks; 4 weeks; 2 months; and then 3-monthly (national guidelines say 6 months) if no problems are detected. if ggt, alkaline phosphatase or conjugated bilirubin is elevated, a liver ultrasound scan should be done to exclude biliary obstruction. an ultrasound or ct scan may suggest fatty infiltration, but a liver biopsy may be necessary for a definitive diagnosis and assessment of the severity of the condition. isolated unconjugated hyperbilirubinaemia (druginduced gilbert’s syndrome) is generally benign and associated with some pis (indinavir and atazanavir) and is more marked after fasting. note: patients with underlying hepatitis b and c infection frequently experience a ‘flare-up’ of hepatitis when art is commenced, as part of the immune reconstitution syndrome. hepatitis b can also flare when arvs that have activity against hepatitis b (lamivudine and tenofovir) are discontinued. many other drugs can cause hepatotoxicity, notably anti-tuberculosis therapy (including prophylactic isoniazid) and azoles. hyperlactataemia elevated lactate is common in patients treated with nrtis (up to 20%) but is generally asymptomatic. if asymptomatic, elevated lactate does not appear to predict the development of lactic acidosis and it is therefore unnecessary to monitor levels in asymptomatic patients. lactic acidosis is a serious, rare but potentially fatal side-effect of nrtis (most commonly associated with d4t, particularly when combined with ddi). it occurs in about 0.1% of patients, when it presents as a lifethreatening acute illness with acidosis. symptomatic hyperlactataemia without acidosis occurs in 1 – 2% of patients per annum. the combination of didanosine and stavudine is associated with a high risk of symptomatic hyperlactataemia or lactic acidosis, particularly in pregnancy (when the combination should be avoided). risk factors for hyperlactataemia include: • female gender • obesity hb > 8 g/dl 7 7.9 6.5 6.9 < 6.5 monitor repeat 4 weeks repeat 2 stop reduce azt: weeks azt 200 mg bd reduce azt: 200 mg bd neutro1 1.5 x 0.75 1 0.5 0.75 < 0.5 phils 109/l repeat 4 repeat 2 weeks repeat 2 stop weeks weeks azt reduce azt: 200 mg bd table ix. guidelines for managing haematological toxicity (mainly zidovudineinduced) 9. toxicity monitoring < 2.5 × uln 2.5 – 5 × uln 5 – 10 × uln >10 × uln alt monitor repeat 1 week discontinue relevant drug(s) discontinue all drugs ggt/alk. phos. monitor repeat 2 weeks ultrasound, ? biopsy ultrasound, ? biopsy bilirubin repeat 4 weeks repeat 2 weeks discontinue relevant drug(s) discontinue all drugs uln = upper limit of normal. table x. guidelines for managing hepatotoxicity the potential of nrtis to cause elevated lactate is: zalcitabine/stavudine/didanosine > zidovudine > lamivudine/abacavir march hiv issue 17-48 4/17/05 11:20 am page 27 march 2005 the southern african journal of hiv medicine 2 8 • prolonged use of nrtis • development of nrti-induced peripheral neuropathy or fatty liver. hyperlactataemia and lactic acidosis generally occur after months of nrti treatment. symptoms include: nausea and vomiting, abdominal pain, dyspnoea, fatigue and weight loss. a raised lactate level* of > 5 mmol/l, increased anion gap and metabolic acidosis confirm the diagnosis of lactic acidosis. associated abnormalities include elevated ast and alt, lactate dehydrogenase and creatinine kinase. if there is hyperlactataemia without acidosis and lactate levels < 5 mmol/l, it may be possible to manage the patient as an outpatient. therapy should be adjusted in symptomatic patients to nrtis that are less associated with elevated lactate (see box on previous page). symptoms and serial lactate levels should be done for several months (note that lactate levels decrease slowly over weeks). if there is hyperlactataemia (> 5 mmol/l) with acidosis, art must be discontinued and the patient should be admitted, preferably to an intensive care unit. the following signs may be present: • hypotension • respiratory failure • stupor/coma. treatment is supportive. bicarbonate replacement is controversial, but most experts would partially correct severe acidosis with bicarbonate. high-dose riboflavin (50 mg) and l-carnitine may be useful (no evidence for either intervention). in lactic acidosis nrtis should be discontinued and not used again. hyperlipidaemia pis can cause fasting hypertriglyceridaemia and elevated ldl cholesterol. diet and lifestyle modification should always be advised. marked hypertriglyceridaemia can cause pancreatitis. when treating hypertriglyceridaemia with lipidlowering drugs, the fibrates should be considered the drugs of choice as they are more effective than the statins for hypertriglyceridaemia, do not interact with pis and are effective against hypercholesterolaemia as well. many statins have interactions with pis which can lead to potentially toxic levels of statin, with the exception of pravastatin (levels of which are unaffected by pis). atorvastatin levels are significantly raised by pis but lower doses (5 – 20 mg) can be used. of the statins, only pravastatin or low-dose atorvastatin (10 mg) are recommended. see table xi for management of hyperlipidaemia in patients on pis. * a lactate level is performed on venous blood collected after the tourniquet has been released and placed in a tube containing sodium fluoride (grey top). bloods should be sent on ice and processed as quickly as possible. lipodystrophy long-term use of pis and some nrtis may cause chronic lipodystrophic changes including raised cholesterol and triglyceride levels and a change in body fat distribution (central obesity, peripheral and facial wasting or lipo-atrophy). the redistribution of body fat may cause distress on a cosmetic level. lipo-atrophy may improve when stavudine is substituted with an nrti less associated with such adverse effects, e.g. abacavir. exercise is of some assistance in reducing abdominal fat. there may be some reversal on cessation of therapy but changes are very slow, and rarely complete. ideally, substitution should be considered at the earliest onset of symptoms. hypersensitivity rash with nnrtis is common (more severe and frequent with nevirapine) in the first 6 weeks of therapy. if the rash is accompanied by systemic features (especially fever), elevated liver enzymes/hepatitis, or mucosal involvement/blistering discontinue the nnrti immediately and do not rechallenge. if the rash occurs without these features, the nnrti can be continued and the rash treated symptomatically with antihistamines and possibly also topical steroids, although the latter is controversial. systemic steroids should not be used. patients who develop rashes during the low dose nevirapine ‘lead in’ phase (200 mg daily) must not have the dosage increased to 200 mg bd until the reaction has completely resolved. this ‘treat-through’ approach is only acceptable if the patient can be carefully observed; otherwise substitute with a drug from a different class. patients who develop nevirapine rashes at the higher dosage should have their nevirapine dose lowered to 200 mg daily until the rash resolves. there is an approximately 50% cross-reaction between nevirapine and efavirenz and they are therefore not recommended as substitutes for one another in cases of severe hypersensitivity. triglyceride 2 5.5 mmol/l > 5.5 mmol/l diet diet and fibrate ldl cholesterol 3 4.8 mmol/l > 4.8 mmol/l low ihd risk diet diet and fibrate/statin ldl cholesterol 3 3.3 mmol/l > 3.3 mmol/l high ihd risk diet diet and fibrate/statin schambelan m et al. management of metabolic complications associated with antiretroviral therapy for hiv-1 infection: recommendations of an international aids society–usa panel. j aids 2002; 31: 257-275 table xi. management of hyperlipidaemia in patients on pis march hiv issue 17-48 4/16/05 10:44 am page 28 the southern african journal of hiv medicine march 2005 2 9 abacavir hypersensitivity is primarily a systemic reaction occurring within the first 8 weeks of therapy in 3% of cases. fatalities may occur. therapy must be discontinued, and never rechallenge as fatalities may occur. the manifestations of hypersensitivity include fever, rash, fatigue and abdominal or respiratory symptoms. if there is any doubt about the diagnosis, e.g. if the patient has a cough with fever, then the patient should be admitted for observation. symptoms progress if hypersensitivity is present. criteria for treatment success a decline in viral load of at least 1 log from pretreatment levels by 6 8 weeks after initiating art. a decline in viral load to < 400 rna copies/ml by 24 weeks after commencement of therapy. note: a sustained viral load of < 50 rna copies/ml (or undetectable viral load) is associated with the most durable virological benefit. criteria indicative of treatment failure several factors can influence the measurement of hiv viral load. it is strongly recommended that the decision to alter therapy should be based on the results of repeat testing after 1 3 months following intensive adherence counselling. inadequate patient adherence to the prescribed regimen remains one of the most common reasons for treatment failure. virological failure (as defined in these guidelines): primary virological failure. a decline in viral load of less than 1 log (10-fold) 6 8 weeks after commencing art. secondary virological failure. a sustained increase in viral load > 5 000 copies/ml. immunological failure is defined as a 30% drop in cd4+ count from peak value or a return to pre-art baseline or lower. a significant minority of patients on art fail to achieve a significant rise in cd4+ count despite viral suppression, particularly if the cd4+ count is very low at baseline. good viral load suppression should be seen as a good response in this percentile even if cd4+ counts remain low. clinical failure is defined as progression of disease with the development of ois or malignancy occurring 3 months or more after initiation of art. note that cd4 counts may rise, even in the presence of incomplete viral suppression and drug resistance. similarly, ois may occur despite excellent viral suppression and immunological recovery. all three parameters need to be closely monitored. initial regimens for treatment-naïve patients should consist of combinations of drugs that are expected to achieve the abovementioned treatment goals. individualised vs. standardised regimens the traditional approach in choosing drug regimens in countries where art has been widely used has been to select a combination of appropriate drugs that suits a patient’s individual requirements and preferences. the world health organization (who) advocates an approach to ‘standardise and simplify art, much like tb treatment in national tb control programmes, while acknowledging the relative complexity of hiv treatment, bearing in mind the needs of health systems that often lack sophisticated manpower and monitoring facilities, without compromising the quality and outcomes of the treatments offered’. department of health guidelines (doh, south africa) two art regimens are recommended in the south african public sector (table xii, p. 30). patients failing both regimens are referred to art specialists for individual evaluation. new developments in art will determine options for salvage therapy. substitution of drugs for toxicities can be made. drug swaps between regimens can be made for toxicity. in general, private sectors should tailor their programmes to the public sector guidelines if possible. botswana, lesotho, zambia, zimbabwe and swaziland all follow who guidelines. optimal use should be made of available drugs. particular consideration should be given to those factors which may affect patient adherence, such as the regimen’s pill burden, dosing frequency, food requirements, convenience, toxicity and drug interaction profile. the importance of adherence must be clearly explained to the patient and reinforced at every visit. practitioners should take sufficient time and care to prepare themselves and the patient for an intervention that may be life-long. in accordance with who and unaids recommendations, these guidelines endorse the use of nrtis and nnrtis as first-line therapy. 9. outcomes of art 10. initial arv regimens for the previously untreated patient advantages of standardised regimens: simplified training and education of providers and patients simplified monitoring for toxicity predictable patterns of resistance predictable and standardised sequence of drug combinations, assisting mass procurement and prescribing limited number of drugs to procure and manage march hiv issue 17-48 4/16/05 10:44 am page 29 march 2005 the southern african journal of hiv medicine 3 0 the use of d4t in first-line therapy makes the choice of second line easier and less toxic (the combination of ddi and d4t should in general be avoided because of the risk of peripheral neuropathy and symptomatic hyperlactataemia). treatment should only be changed as soon as possible in the following situations: patient intolerance despite adequate and appropriate intervention significant side-effects treatment failure, as defined in 9 on previous page. careful consideration should be taken before changing therapy because of limited number of drugs. indications for changing regimens should be limited to toxicity (the offending drug should be substituted), intolerance or failure (the entire regimen should be changed). table xiii contains recommendations for changing therapy in drug intolerance, and table xiv (p. 31) recommendations for changing nrtis when drug resistance emerges; the caveats listed above apply. changing nnrtis in the presence of resistance there is broad cross-resistance between nevirapine and efavirenz. resistance to one precludes the use of the other, unless resistance test data indicate the contrary (very rare). regimen drugs indications regimen 1 regimen 1a d4t/3tc/efv men, and women who are not of childbearing potential or are using injectable contraception plus condoms regimen 1b d4t/3tc/nvp women who are unable to guarantee reliable contraception while on therapy regimen 2 azt/ddi and for patients lopinavir-ritonavir virologically failing regimen 1 despite demonstrating adherence table xii. art regimens in the south african public sector 12. options for changing therapy 11. indications for changing therapy regimen toxicity drug substitution d4t/3tc/efv d4t-related neuropathy or pancreatitis switch d4t to azt efv-related persistent cns toxicity switch efv to nvp lactic acidosis consult expert d4t/3tc/nvp d4t-related neuropathy or pancreatitis switch d4t to azt nvp related severe hepatotoxicity switch nvp to efv (except early pregnancy) nvp-related severe rash (but not life-threatening) switch nvp to efv nvp-related life-threatening rash switch nvp to efv or lopinavir/ritonavir stevens-johnson syndrome switch nvp to lopinavir/ritonavir lactic acidosis consult expert azt/ddi/lopinavir/ azt-related anaemia or neutropenia switch azt to d4t ritonavir ddi-related git side-effects switch ddi for enteric-coated ddi ddi-related pancreatitis or hepatitis consult expert lactic acidosis consult expert lpv/r-related git symptoms symptomatic management lpv/r-related hyperlipidaemia see section 9 lipodystropy consult expert impaired glucose tolerance antidiabetic agents (warning: metformin increases risk of acidosis) note: • in the event of virological failure a change of regimen is advised. • the clinician may choose to be guided by genotypic or phenotypic resistance testing. this must be done in close consultation with a specialist. table xiii. recommendations for changing therapy in drug intolerance march hiv issue 17-48 4/16/05 10:44 am page 30 the southern african journal of hiv medicine march 2005 3 1 individuals who fail an nnrti-containing regimen are candidates for a pi-containing regimen, or a triplenucleoside nnrti combination (there is serious concern, however, that triple nnrti combinations are more likely to fail). changing pis in the presence of resistance a major reason for regimens that contain pis failing is suboptimal pharmacokinetics and inadequate drug exposure as a result of poor adherence (often due to intolerance). this needs to be considered carefully before deciding to introduce an alternative pi-containing regimen. secondline pi alternatives may exhibit reduced activity owing to extensive cross-resistance within this class of drugs. ritonavir-boosted pis are preferred because they are more potent, have less frequent dosage intervals, are less susceptible to food-related changes in absorption, and are durable. exceptions are unboosted nelfinavir in pregnancy and atazanavir, which has a more favourable metabolic side-effect profile. if a patient fails a pi-containing regimen: if no nnrti has been used previously, replace with an nnrti. if this is not an option, if the pi is ‘unboosted’, consider using another pi with ritonavir boosting. if failing a boosted pi, consider resistance testing. if not available, use a different pi, also with boosting. some clinicians use two pis, and then boost both with ritonavir (e.g. lopinavir/saquinavir). there is some evidence that amprenavir may be useful after failure of pis. obtain expert help in all these cases. avoid triple nrti regimens in patients who have failed picontaining regimens – it is likely that significant nrti resistance mutations will be present, and it is unlikely that these combinations will be effective. because of limited availability of drugs third and fourth regimens should only be prescribed by a specialist treater. in south africa we think that genotyping should be done by a specialist because of cost. indications would be failed second-line therapy and good adherence. rational definition of a third-line regimen is difficult without genotyping. newer drugs we would like to see are tenofovir and tipranavir. severe depression, suicidal talk, domestic violence and psychotic and irrational behaviour, must be regarded seriously. patients and their families must be assisted with obtaining the help they need. if a patient is planning to fall pregnant and is taking art, her art may need to be changed. efavirenz, indinavir and the combination of stavudine and didanosine are contraindicated in pregnancy. where art has failed repeatedly or there is no access to such therapy, and death becomes a looming and unavoidable issue, living with grief and loss needs to be addressed by qualified individuals, with sensitivity and without time constraints. patients are frightened by the prospect of losing control and the constellation of disabling symptoms of advanced aids. palliative symptom control should be aggressively pursued, as it is rare that significant relief is unobtainable. both the caregiver and the recipient may need help. support groups and a longterm relationship with the patient and his/her family may make this time easier. religious workers, palliative care nurses and doctors, and supportive members of the patient’s community may need to be called in. for specific advice and assistance in using these guidelines, please contact the southern african hiv clinicians society by e-mail: sahivsoc@sahivsoc.org initial agent new agent zidovudine stavudine* stavudine zidovudine* didanosine lamivudine lamivudine didanosine* zalcitabine abacavir, stavudine or zidovudine or other as determined by resistance testing abacavir determined by resistance testing *may exhibit cross-resistance. table xiv. changing nrtis in the presence of resistance 13. third and fourth regimens 14. psychological support for patients and caregivers 15. treatment decision support disclaimer: specific recommendations provided in this document are intended only as a guide to clinical therapy, based on expert consensus and best current evidence. treatment decisions for patients should be made by their responsible clinicians, with due consideration for individual circumstances. the most current version of this document should always be consulted. chairperson of adult guidelines committee dr des martin expert panel members steven andrews, gary maartens, robin wood, douglas wilson, des martin, leighton mcdonald, dave spencer, francois venter, zackie achmat international reviewers pedro cahn, david cooper, brian gazzard, stefano vella march hiv issue 17-48 4/16/05 10:44 am page 31 hiv 995 guideline management of mental health disorders in hiv-positive patients by the southern african hiv clinicians society g jonsson (chair), n davies, c freeman, j joska, s pahad, r thom, k thompson, n woollett (panel members), j furin, g meintjes (reviewers) mental health guidelines committee, southern african hiv clinicians society, johannesburg, south africa corresponding author: g jonsson (gregory.jonsson@wits.ac.za) disclaimer. specific recommendations provided in this document are intended only as a guide to clinical therapy, based on expert consensus and best current evidence. treatment decisions for patients should be made by their responsible clinicians, with due consideration for individual circumstances. the most current version of this document should always be consulted. these guidelines are intended as a reference document to assist hiv nurse and doctor clinicians in managing mental health disorders. it is intended to improve awareness, knowledge and capacity to support patients living with hiv and mental health disorders. s afr j hiv med 2013;14(4):155-165. doi:10.7196/sajhivmed.995 1. introduction ‘there is no health without mental health’.1 , 2 mental disorders are highly prevalent among people living with hiv/aids (plwha), with major depressive disorder (mdd) occurring almost twice as frequently among this group than in the general population.3 mental disorders may increase an individual’s risk for hiv infection through increased social vulnerability, altered risk behaviour, associated substance misuse and loss of control within sexual relationships. conversely, such disorders may also arise as a direct result of hiv neuro-invasion or psychosocial stressors, or due to complications of antiretroviral therapy (art). 4 , 5 despite their prevalence, mental disorders are often under-diagnosed or inadequately managed in plwha. the impact of untreated mental disorders on health outcomes is substantial. it is imperative that clinicians caring for hiv-positive individuals actively screen for, diagnose and manage mental disorders in this population.6 2. overview of the guideline this guideline is intended to improve primary care hiv clinicians’ knowledge and capacity to manage mental health disorders. it is also intended to heighten hiv clinicians’ awareness of the need to integrate hiv and mental healthcare within their daily practice.7 the following conditions and issues are addressed here: • hiv testing in the context of mental disorders • common mental disorders (cmds) • severe mental disorders (smds) • hiv-associated neurocognitive disorders (hands) • grief • healthcare worker (hcw) burnout and vicarious trauma. these guidelines do not encompass substance use disorders or triple diagnosis (hiv/mental disorder/substance use disorder), or mental disorders among children and adolescents; these topics will be covered in separate, future guidelines. 3. principles of hiv testing in patients with mental disorders • all patients with mental disorders (in-/out-patients, volun­tary/involuntary patients admitted under the mental health care act) should be offered hiv testing, hiv-prevention/risk-reduction education and access to condoms • the presence of a mental disorder does not automatically equal incapacity to consent to hiv testing • capacity to consent to hiv testing must therefore be assessed on an individual basis, particularly in patients with smds • for capacity to consent, patients should be able to: • understand why they are being tested • understand and report on the consequences of a negative or positive test result • report how they are likely to respond to either result • patients should be included in decision-making about their hiv testing, as far as possible in all cases • if the patient is assessed as being incapable of giving informed voluntary consent (e.g. active psychosis, dementia), then proxy consent may be sought • proxy consent • consent is given by someone else acting in the best interests of the patient, e.g. a senior clinician in charge of the case • the reasons for testing and the process must be docu­mented carefully • if the patient regains capacity, then disclosure of the results is paramount • there may be a need to disclose the results to the carer, if the patient has irreversible neurocognitive impairment, with cognisance of potential stigma/discrimination • disclosure • all medical information should be kept confidential at all times • information should preferably be released only with patient con­sent, unless the information is relevant to clinical management/medical aid pro­cedures • the procedure to follow when testing for hiv in patients with mental disorders is shown in fig. 1.8 , 9 fig. 1. testing for hiv in patients with mental disorders.8 , 9 4. assessment and diagnosis of cmds the term ‘common mental disorder’, used to describe disorders that are highly prevalent in the general population (usually occurring at rates >10%), typically includes: • depressive disorders • anxiety disorders • substance use disorders (not included in this guideline).10 box 1 provides an overview of cmd pre­valence. in south africa (sa), 26 38% of plwha have a cmd (v. 12.6% of the general population).6 cmds have not decreased in prevalence with the introduction of art. box 1. overview of cmd prevalence • two-fold increase in prevalence in hiv-positive individuals3 , 8 • in sa, 26 38% of plwha have a cmd (v. 12.6% of the general population)9 • some 20 60% of plwha are affected by some form of psychiatric disorder10 (depressive disorders are most common) • cmds are not decreasing in the art era • cmd prevalence is influenced by viral central nervous system (cns) pathology, concomitant psychosocial stressors and the nature of hiv as a life-threatening and stigmatised illness • cmds often go undiagnosed and untreated in this population 4.1 screening clinicians should screen routinely for cmds, because patients rarely volunteer information about their mental state. box 2 includes three questions to ask patients. due to the high prevalence of gender-based violence (gbv) in sa, we recommend clinicians also incorporate screening for gbv.11 box 2. screening for depression and gbv brief routine screening questions for depression • how have you been in the past month/since your last visit? • have you been feeling more stressed than usual? • have you been feeling down, low, heart-sore or depressed? brief screening questions for gbv • how are things going in your relationship with your partner? • have you ever been emotionally, sexually or physically victimised? certain patients may require more intensive screening, including: • those at their first art assessment • those responding poorly to art (detectable viral load (vl)/adherence issues) • those exhibiting worrying behaviour (look­ing anxious/depressed, expressing sui­cidal ideation or self-harm). patients who respond positively to one of the brief screening questions should be administered a validated screening tool that is appropriate for primary healthcare settings, such as the patient health questionnaire (phq)-9 (fig. 2).12 fig. 2. patient health questionnaire (phq)-9. 4.2 risk assessment it is important to assess suicide risk. clinicians should always ask about suicidal ideation in patients with depressive symptoms. high risk is indicated by: • a clear plan for ending life • an identified lethal method • a previous suicide attempt • a lack of social support • severe (psychotic) depressive disorder. see also the ‘sad persons’ scale (fig. 3).13 fig. 3. ‘sad persons’ scale (yes for any letter = 1 point). 4.3 mental state assessment assessing the patient’s mental state is as important as a physical examination. clini­cians should conduct and document a ‘mental state examination’ (box 3) at each visit. box 3. recording the mental state examination document the mental state examination, as for physical examination: • appearance and behaviour: grooming, eye contact, motor activity, etc. • level of consciousness: orientation for time, person, place • cognitive function (see section 6: hands) • mood: objectively euthymic, depressed, elevated • speech, form and content of thinking: flow of speech, coherence and content of thinking (delusions, pre-occupations, ruminations) • perceptual abnormalities: evidence of hallucinations • insight into own condition 4.4 depression in plwha (including mdd and less severe types) up to 25% of plwha in sa are thought to suffer from some form of depression during the course of the illness. severe depression, also known as mdd, occurs in about 5 10% of patients, while minor depressive disorders are diagnosed in about 15 20%.6 , 10 even mild depression can lead to erratic adherence, poor care engagement and ultimately to more serious outcomes. major depression is diagnosed by the presence of five or more of the symptoms listed in section 4.4.1 for at least two weeks, while minor depression is diagnosed when fewer symptoms are present and/or for shorter periods. 4.4.1 symptoms of depressive disorders depressive disorder is characterised by five or more of the following occurring together in a two-week period: • either: depressed mood almost all day every day • or: loss of interest or enjoyment of usually pleasurable activities for most of the day • and (occurring nearly every day): • significant weight loss when not dieting or due to medical illness, or weight gain (e.g. >5% body weight change in a month), or decreased/increased appetite • insomnia or hypersomnia • psychomotor agitation or retardation (observ­able by others, not merely sub­ject­ive feelings of restlessness or of being slowed down) • fatigue or loss of energy • feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) – not merely self-reproach or guilt about being sick • diminished ability to think or concen­trate, or indecisiveness (either by sub­jective account or as observed by others) • recurrent thoughts of death (not just fear of dying), recurrent suicidal idea­tion without a specific plan, or a suicide attempt or a specific plan for committing suicide.14 psychotic symptoms may occur in severe depressive disorders. these usually consist of delusions (guilt, nihilistic, of death, occasionally paranoid) and occasionally hallucinations (these are usually transient). if the screen is positive for a cmd, conduct and document a mental state examination (see box 3). 4.4.2 differential diagnosis of depression • minor or sub-threshold depressive dis­orders are characterised by the presence of some symptoms, but do meet all criteria for mdd • major depression • adjustment disorder: a depressive reaction to psychosocial stressors including hiv diagnosis • bereavement (see section 7) • mood disorder secondary to a medical condition/substance, e.g. hiv, hypothyroidism, efavirenz (efv), alcohol • bipolar disorder: there is usually history of a previous episode of elevated mood resulting in abnormal behaviour, e.g. reduced sleep, increased energy/libido/risk-taking, etc. 4.4.3 management of mdd (moderate to severe depression according to the phq-9) 4.4.3.1 hospitalisation the patient requires hospitalisation: • if there is a high suicide risk • in complex cases: the presence of psychosis and/or minimal social support and/or a poor response to out-patient treatment and/or a diagnostic dilemma • in complex medical comorbidity (to monitor antidepressant medi­cation) • in the event of severe psychomotor retardation or no eating/drinking. 4.4.3.2 initiation of antidepressant treatment the initiation of antidepressant therapy in patients with cmds is based on a step-wise approach, using the phq-9 as a guide to diagnosis, management and follow-up (box 4). it is essential to remember that one ‘starts low and goes slow’ as patients with hiv/aids are often more sensitive to side-effects of medication. box 4. introducing an antidepressant: ‘start low and go slow’ * • initiate 20 mg fluoxetine (or similar) at the lowest available dose and refer to psychosocial support services where available • reassess using the phq-9 at 2 4 weeks and for side-effects (e.g. irritability, nausea, headache, disturbed sleep patterns); most side-effects settle within 2 weeks • if after a total of 6 8 weeks there is no/minimal improvement, then increase the dose and reassess with the phq-9 in 4 6 weeks • if after reassessment there is still no improvement, then up-refer * fluoxetine and amitriptyline are the only antidepressants on the primary-level essential drugs list. nurses are not currently permitted to prescribe – refer to a doctor. if unsure at any point, then phone the referral centre for advice. if the depression worsens at any point, or if suicide risk increases, then refer the patient. 4.4.5 psychotherapy 15 • if available, patients should be referred for psychological assessment and treatment • evidence-based psychotherapy interventions for plwha and de­press­ion include: • cognitive-behavioural therapy (cbt): a form of psychotherapy addressing dysfunctional emotions and maladaptive ideas through a goal-directed systematic process • interpersonal therapy (ipt): a form of psychotherapy that is time-limited and encourages patients to regain control of mood and functioning through the therapeutic alliance • group ipt (ipt-g): a form of therapy that employs the same basic structure and focus of individual ipt, though modified to capitalise on the group format • key determinants of successful therapy include the motivation of patients to attend multiple sessions and the access to clinics/times. 4.5 anxiety disorders anxiety disorders in plwha are common. some studies report that between 20% and 60% of hiv-positive adults suffer from some form of psychiatric disorder. the most recent general population study of the prevalence of mental disorders in sa was the sash study, which reported a combined 12-month prevalence of depressive and anxiety disorders of 12.6%. 6 it is important to recognise and treat anxiety disorders as they have been associated with increased rates of poor treatment compliance and high-risk behaviour. quality of life is also adversely affected by anxiety disorders (table 1). 5. smds and hiv/aids these disorders occur less frequently in the general population (usually at rates <5%) and include: • schizophrenia • bipolar mood disorder • mdd with psychotic features. box 5 describes the prevalence and impact of smds. box 5 . prevalence and impact of smds prevalence • hiv among those with smds: 2.6 59.3% in sub-saharan africa8 • smds in the hiv-positive population: up to 15% • new-onset psychosis among the hiv-positive population: 0.2 15.2%16 impact • smds lead to an increased risk of acquiring and transmitting hiv • smds may impact adherence to psychiatric treatment and art • hiv disease progression can be associated with secondary psychiatric disorders, which often improve with art • integrated care of both conditions improves outcomes7 • successful art is more likely if there is: • no substance abuse • no history of homelessness/incarceration • retention in psychiatric care • adherence to psychiatric treatment16 • regular mental health visits decrease the risk of art discontinuation 5.1 diagnosis of smds smds in plwha can often be classified as ‘primary’ or ‘secondary’. primary smds often occur prior to hiv infection while secondary smds arise as a consequence of hiv infection. both are responsive to a combination of psychotropic medication and art. a careful approach will help to differentiate primary smds (with comorbid hiv) (fig. 4a) from secondary smds resulting directly from hiv or an opportunistic infection (fig. 4b). fig. 4. recognising (a) primary and (b) secondary smds. (bmd = bipolar mood disorder; smd = severe mental disorder; had = hiv-associated dementia; amc = another medical condition; hand = hiv-associated neurocognitive disorder; art = antiretroviral therapy; mdd = major depressive disorder; sga = second-generation antipsychotic; fga = first-generation antipsychotic.) clinicians must: • conduct a thorough history: presenting symptoms, temporal relation­ship to hiv diagnosis, family/past psychiatric history • conduct a comprehensive physical and neurological examination: this is essential to exclude underlying medical causes for psychiatric symptoms, e.g. opportunistic infections (particularly cns pathology – toxoplasmosis/tuberculosis or cryptococcal meningitis), delirium or medication side-effects • perform the following investigations: vital signs, urine dipstix, blood glucose, full blood count (fbc), creatinine and estimated glomerular filtration rate (egfr), cd4+ count, lumbar puncture; may also perform alanine transaminase (alt)/liver function tests (lfts), syphilis serology, thyroid stimulating hormone (tsh), vl testing and a computed tomography (ct) scan, if these are indicated on the basis of history and examination findings. 5.2 management of smds • requires a multidisciplinary team approach, and where possible, integrated care including the involvement of community members and allied professionals • adherence support via treatment supporter/support groups and careful monitoring are key; patients should be educated/counselled regarding mental disorders and hiv to improve insight • poly-pharmacy (antidepressants, anticonvulsants, antipsychotics and art): try as far as possible to rationalise to once daily dosing; patients on complex regimens should be reviewed regularly with a view to simplification • patients are more vulnerable to medication side-effects (e.g. extra-pyramidal side-effects while receiving antipsychotics) and should be monitored closely. • see table 2. 5.3 starting art in smd: use of efv clinicians should follow standard national guidelines when initiating patients with smds on art. efv can often be used safely in patients with cmds and in most with smds.17 routinely avoiding efv for fear of worsening psychosis/depression is not warranted, especially since efv has a more favourable side-effect profile, lower pill burden and fewer drug-drug interactions with psychiatric medications than other available alternatives (nevirapine and lopinavir/ritonavir). milder neuropsychiatric side-effects of efv (vivid dreams, dizziness), which typically resolve within 2 4 weeks, can be managed with re­assurance.18 should a patient develop new-onset or worsening of pre-existing psychosis with a temporal relationship to efv introduction, and the psychosis persists despite psycho-pharmacological management, then the clinician should consider switching from efv to an alternative agent. if a patient cannot tolerate efv side-effects, then it may be necessary to switch to an alternative arv. the use/initiation of efv in patients who are currently psychotic or severely depressed remains controversial. if available, consider alternative regimens as there currently is no published literature on the outcomes of efv in psychotic/depressed individuals. if alternatives are unavailable, contraindicated or involve significant drug-drug interactions, then initiate efv and monitor carefully. 5.4 diagnosis and management of secondary smds it is helpful to establish whether the smd (psychosis or manic epi­sode) is due to an underlying primary mental disorder or is secondary to hiv infection. primary disorders require the initiation of psycho­tropic treatment and an assessment of whether hiv disease is currently contributing to the disorder. if patients do not meet national department of health (ndoh) criteria for art initiation and are not considered to have hiv-associated smd, then they can be referred to out-patient hiv services when discharged. where the smd is either thought to be secondary to hiv or where a primary smd is being aggravated by hiv, art and psychotropic treatment should be given in hospital. 5.5 smds secondary to hiv infection • smds secondary to hiv infection are often associated with: • cognitive impairment (memory deficits and psychomotor slowing) • significant immune-compromise: stage iii/iv who disease, cd4+ counts <350 cell/µl and/or high vls • some atypical mental state features, e.g. irritability, non-auditory hallucinations (i.e. visual or other), and a lack of personal or family history of mental disorders (i.e. no or little genetic loading) • no/poor response to psychotropic treatment. • management includes: • commencing art in line with the ndoh guidelines • using low-dose anti-psychotics (haloperidol, risperidone, quetia­pine) for psychosis • patients with mania due to hiv may respond well to second-generation antipsychotics (sgas) (risperidone, quetiapine, olanzapine, aripiprazole) • considering mood stabilisers in persistently manic patients (consult with a psychiatrist). 6. hiv-associated neurocognitive disorders hiv-associated neuropathological disease presents with a characteristic sub-cortical deficit pattern including: psychomotor slowing, impaired memory, attention, language, executive functioning and behavioural apathy. in patients receiving art, a mixed cortical-subcortical picture is observed (less psychomotor slowing, more executive function, language and visuo-spatial difficulties). classification into various hand categories (box 6) is determined by the extent of neurological and functional impairment: • mild neurocognitive disorder (mnd) • hiv-dementia (hiv-d).21 box 6. mnd v. hiv-d incidence • hiv-d in untreated hiv: 35/1 000 person years • hiv-d in patients receiving art: 3/1 000 person years prevalence (sa) • mnd, pre-art: 42.4% • mnd, while receiving art: 25.4%22 impact • hiv-associated neuro-invasion results in a spectrum of neurological effects, ranging from subclinical to advanced dementia • milder (or subclinical) hand, which often persists during art, has significant effects on functional outcomes, e.g. poor adherence, unemployment • increasing hiv testing uptake, earlier access to art and adherence support will positively impact rates of hand in hiv-positive populations 6.1 screening • without screening (excluding hand suffer­ers presenting to hospital with con­fusional states/psychosis), many patients with gradual neurodegenerative changes are undiagnosed due to infrequent self-reporting of functional impairment/ decline • such milder hand needs to be detected as it may precede to further neurodegeneration that can potentially be prevented by art • in pre-art patients with cd4+ counts >350 cells/µl, screening should be performed in wellness clinics approximately annually; patients with clear neurocognitive disorder should be referred for confirmation and initiation of art • at art initiation, patients with cognitive problems may require additional treatment support; a baseline assessment allows track­ing over time of progress/recovery • once receiving art, patients with hand may require additional adherence support • hand may progress or fail to recover despite art • should be offered as part of adherence support or may be offered annually, or where resources are limited, reserved for those with clinical problems (treatment failure, poor ad­her­ence, on-going depression, self-reported functional impair­ment). 6.2 approaches to screening for hand • there is no globally accepted screening policy or practice • an ultra-brief symptoms-based tool23 may detect more severe cases (see table 3) • other tools proposed for use include: • international hiv dementia scale (ihds) (validated in sa) (http://www.europeanaidsclinicalsociety.org/guidelines/g2_pc.htm) • montreal cognitive assessment (moca) (http://www.mocatest.org) • the hiv-dementia scale (http://www.turkpsikiyatri.org/arsiv/category/3-eng.html?...93:hiv-dementia) • cognitive assessment tool – rapid ver­sion (awaiting validation) (http://www.hivmentalhealth.co.za/.../cognitive-assessment-tool-paper-version2.pdf) • a positive screen does not equate to a diag­nosis of hand; three further steps are required for clinical confirmation (table 4). 6.3 management (fig. 5) fig. 5. screening and management of hands. (cpe = cns penetration effectiveness.) • pre-art, with confirmed hand: comm­ence art, irrespective of cd4+ count; engage family/partner for treatment support; and diagnose and treat confounding conditions • receiving art, with hand: usually mild/moderate disease but, with ageing popula­tions, more advanced disease may develop • routine vl monitoring with enhanced support, if adherence is poor • screen and treat comorbidities including age-related dementia • adjusting the arv regimen to en­hance cns penetration (cpe) is not recommended, as the evidence in this regard is conflicting • measure the cerebrospinal fluid vl if viral compartmentalisation is suspected (low cd4+ nadir, severe impairment, confusional symptoms, increased tone and psychomotor slowing despite viral suppression in plasma) • augmentation strategies, including meman­tine, are not recommended due to the lack of robust supporting evidence and cost • sodium valproate or lithium may be used if there is neuropsychiatric comorbidity. 7. grief and loss in the context of hiv grief is a normal, non-pathological response to any type of loss, not just death. the grief response is highly individualised as it is influ­enced by individual, cultural, religious, familial, community and societal factors. grief arising from a loss related to hiv may be particularly complicated; complicated grief is defined as a prolonged period of intensified grief symptoms that disrupt daily functioning.24 7.1 screening • screen for common symptoms of grief: • emotional: enduring sadness, shock, anger, anxiety, loneliness, yearning, guilt, fear, withdrawal, feeling worthless, apathy, irritability, appetite disturbances • physical: fatigue, tightness in the chest, shortness of breath, lack of energy, numbness, nausea, body aches, panic attacks, insomnia • psychological/cognitive: disbelief, con­fu­sion, sense of presence, lack of concen­tration, auditory hallucinations (hearing the voice of the deceased), intrusive thoughts, anxiety about death, mental fatigue • spiritual distress: questioning faith or the meaning of being a survivor • explore the nature and relationship of the loss/death and its impact • assess if the grief reaction is appropriate for the setting/cultural context • assess the griever’s coping style, support network, and previous experiences of loss or death • assess for barriers to effective grieving, e.g. a lack of support, multiple losses, mental health issues, a complex relationship with the deceased, the manner of death, etc. • the screening of children and adolescents needs to be age-appropriate and cognisant of the multiple subsequent losses that can arise following parental/caregiver death, e.g. separation from siblings, new school/friends, new home, etc. • clinicians may have trouble distinguishing grief and bereavement from depression (see table 5; refer to fig. 6 for the management of acute grief and bereavement) fig. 6. management of grief and bereavement. 26 8. burnout and vicarious trauma hcws may also experience emotional and psychological effects from exposure to cumulative challenges within the health sector. while taking care of oneself is a prerequisite to taking good care of others, stigma persists for hcws acknowledging burnout and vicarious trauma. table 6 highlights key symptoms indicative of burnout and vicarious trauma.29 8.1 burnout • prolonged involvement in emotionally demanding situations results in gradual progression towards: (i) emotional ex­haus­tion; (ii) depersonalisation; and (iii) a re­­duc­ed personal accomplishment and commit­ment to one’s profession • risk factors include: a high patient load; difficult patient circumstances; hcw em­­pathy, own experiences, age, training, lack of control and failure to care for oneself; and organisational characteristics (a lack of support/recognition/fairness, low salaries) • failure to recognise burnout may lead to depression or chronic fatigue27 • burnout can be assessed officially using the maslach burnout inventory (mbi) (http://www.mindgarden.com/products/mbi.htm) or the oldenburg burnout inventory (obi) (http://www.bma.org.uk/burnoutquestionnaire ). 8.2 vicarious trauma repeated exposure to patients’ traumatic stories may result in intrusive imagery, avoidance/hyperarousal, experiencing symp­toms similar to the patients’ trauma response (confusion, tearfulness, iso­lation, anger, irrita­bility, powerlessness, hope­less­ness), increased vulnerability and/or sur­vivor guilt.28 8.3 management • the individual clinician can manage burnout by following the 3 ‘r’ approach:30 • recognise: watch carefully for signs of burnout • reverse: undo damage by using stress-management techniques and employing support from fellow hcw and family • resilience: build resilience to stress by looking after your physical and mental health • when recovering from burnout: slow down; re-evaluate goals and priorities; and get support. conflict of interest. all expert panel members completed and submitted conflict of interest disclosure forms. disclosure information represents the previous three years (updated 15 november 2013) and includes relationships with pharmaceutical companies and medical aids. c freeman has received support to attend a conference from bristol-myers squibb; g jonsson has received support to attend conferences from janssen-cilag, research support from bristol-myers squibb and honoraria for speaking engagements from toga laboratories; j joska has received an in-kind donation to support research from norgine pharmaceutircals and honoraria for speaking engagements from sanofi aventis; and g meintjes has received honoraria for speaking engagements from sanofi aventis and serves as a consultant for aid for aids. n davies, j furin, s pahad, r thom, k thompson and n woollett report no conflicts of interest.    acknowledgement. this work is supported and funded by the southern african hiv clinicians society through an educational grant from atlantic 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francis, 1993. 27. maslach c. burnout: a multi-dimensional perspective. in: schaufeli c, mslach t, marek t, eds. professional burnout: recent developments in theory and research. washington dc: taylor & francis, 1993. 28. sexton l. vicarious traumatisation of counsellors and effects on their workplaces. br j guid counc 1999;27:393-403. 28. sexton l. vicarious traumatisation of counsellors and effects on their workplaces. br j guid counc 1999;27:393-403. 29. mccann il, pearlman la. vicarious traumatisation: a framework for understanding the psychological effects of working with victims. journal of traumatic stress 1990;3:131-149. 29. mccann il, pearlman la. vicarious traumatisation: a framework for understanding the psychological effects of working with victims. journal of traumatic stress 1990;3:131-149. 30. smith ma, segal j, segal r. preventing burnout. 2013. http://www.helpguide.org/mental/burnout_signs_symptoms.htm (accessed 26 august 2013). 30. smith ma, segal j, segal r. preventing burnout. 2013. http://www.helpguide.org/mental/burnout_signs_symptoms.htm (accessed 26 august 2013). cpd questionnaire vol. 14, no. 3 hiv risk behaviour among primary care patients with tubercu losis (tb) in south africa (sa) 1. when counselling tb patients, condom use and alcohol/ substance use risk reduction need to be considered as hivprevention measures. child privacy rights in hiv-prevention research 2. while children are entitled to privacy, in some cases, their expectation of privacy may be limited and may not be deemed reasonable by the healthcare provider. chylothorax associated with non-endemic kaposi’s sarcoma (ks) 3. chylothorax is a common complication in patients infected with hiv and with ks. 4. the most common cause of chylothorax in and hivinfected patient is tb. 5. ks-associated chylothorax carries a poor prognosis. 6. treatment of chylothorax in patients affected by advanced hiv and ks is best considered a palliative measure. analysis of hiv-related mortality data in a tertiary south african neurology unit from 2006 to 2012 7. neurological complications of hiv infection are rare in sa. 8. after bacterial and fungal meningitis, encephalitis is the most common neurological presentation in hiv-infected patients requiring hospitalisation. 9. the incidence of neurological diseases such as hiv-associated dementia and central nervous system opportunistic infections may be decreasing due to antiretroviral therapy (art). combined art/anti-tb drug resistance after incarceration 10. sa is responsible for a quarter of the world’s burden of hiv-associated tb. 11. prisons act as reservoirs of tb, including drug-resistant tb that poses a threat to public health control. 12. in settings with a high burden of drug resistance, screening using xpert mtb/tif has little role in reducing the transmission of drug-resistant tb. 13. patients receiving art and/or tb treatment who become incarcerated may be at high risk of defaulting treatment and/or developing treatment resistance. management of drug-induced liver injury (dili) in hivinfected patients treated for tb 14. dili occurs in <0.1% of patients receiving tb treatment and art. 15. some of the individual risk factors for dili in patients receiving tb treatment or art are younger age, children, hepatitis b surface antigen positivity, malnutrition and use of alcohol. starting art following cryptococcal meningitis (cm) – the optimal time has yet to be defined 16. patients with cm in southern africa typically present with cd4+ counts >100 cells/μl. 17. there is clear evidence that art should be initiated no more than 2 weeks after initiation of cm treatment. native valve endocarditis due to candida parapsilosis in a an adult patient 18. a high index of suspicion as well as aggressive diagnostic modalities and therapy are essential in patients with candidaemia to decrease mortality. 19. candidiasis is the most common opportunistic infection in hiv-infected patients with cd4+ counts <200 cells/μl. 20. the most prevalent presentation of candidiasis is invasive candidiasis. c p d q u e s t io n a ir e five cpd points are awarded for the correct completion and submission of the questions below. cpd questionnaires must be completed online via www.cpdjournals.co.za. after submission, you can check the answers and print your certificate. this programme is available free of charge to members of the sa hiv clinicians society and sama only. instructions 1. read the journal. all the answers will be found there. 2. go to www.cpdjournals.co.za to answer the questions. accreditation number: mdb001/011/01/2013 (clinical) http://www.cpdjournals.co.za http://www.cpdjournals.co.za make up march 2007 m a r c h 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e8 the seven-point plan 1. rapid surveys to assess the current prevalence of xdr tb the only comprehensive survey for south africa conducted during the current hiv pandemic produced figures of 39% for mdr tb and 6% for xdr tb.3 these figures were for a single small region in kwazulu-natal, and until comprehensive surveys are conducted nationally one can only speculate on the true extent of the problem in south africa. hospital budgets are stretched and the further financial burden of routine culture and drug sensitivity testing on all cases of suspected tb cannot be borne by individual institutions. limiting tb culture and susceptiblity testing of patients with persistent acid-fast bacilli (afb) and retreatment cases in accordance with the national guidelines will not provide the information required. in the kwazulu-natal series the median time from sputum collection until death for xdr tb cases was 16 days, leaving no time to fail treatment. fiftyfive per cent of the xdr tb cases had no history of prior tb. central funding is required for the culture and drug sensitivity testing of all suspected tb cases nationwide to define the true extent and location of the problem. any intervention aimed at addressing a problem the extent and distribution of which is unknown will not be able to be assessed and may squander time and money. the cost of conducting a comprehensive national surveillance programme may be better spent on improving the current tb treatment programmes. this strategy will decrease drug resistance even if the extent of the problem is not known. 2. enhance local laboratory capacity to carry out culture and drug resistance testing laboratories are already strained by the current load of specimens and need to honestly assess their capacity to deal with a much larger volume if routine culture and susceptibility testing is to be advocated. quality assurance and reproducibility is imperative so that clinicians may have confidence in the laboratory results. laboratories should have the expertise and equipment available to perform the services they offer. there is currently no system whereby clinicians are provided with a monthly list of culture-positive results for their hospital. lack of this seemingly basic information means that hospitals are unable to identify and trace culture-positive patients who have not returned for follow-up. laboratory services need to take more responsibility with regard to the notification of clinicians or hospitals of positive tb culture results. a step in the right direction is the fact that the laboratory now contacts the clinician if a culture is found to be mdr tb. this needs to be extended to all positive tb cultures. 3. increased training of public health staff to identify, investigate and treat xdr outbreaks training and education needs to involve staff who manage tb patients and needs to focus on the control of all tb and not just xdr tb, as our tb incidence of 718/100 0004 suggests that d e b a t e tb or xdr tb, should that be the question? andrew black, bsc, mb bch, fcp (sa), cert pulm (sa), fccp (usa) department of medicine, chris hani baragwanath hospital, johannesburg the emergence and recognition of extensively drug-resistant tuberculosis (xdr tb) in south africa led to a wave of panic fuelled by media hype. the response was predictable: meetings, circulars and finally a seven-point emergency action plan.1 fortunately mycobacterium tuberculosis (tb) replicates slowly, as very little seems to have happened in the 5 months since the proposal of the seven-point plan. the seven-point emergency action plan for xdr tb is based on the seven-point plan devised for mdr tb in the 1990s.2 the emergence of xdr tb is a consequence of the earlier plan’s failure. are we doing any better this time? xdr tb is defined as an isolate of tb resistant to isoniazid (inh) and rifampicin (multidrug-resistant tuberculosis) plus any fluoroquinolone and at least one of three injectable second-line agents (i.e. amikacin, kanamycin or capreomycin). make up march 2007 30/3/07 11:26 am page 8 m a r c h 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e10 south africa’s national tb control programme is not functioning. without routine surveillance and a central point for all culture results, outbreaks of xdr tb will be missed because no specific clinical features have yet been identified that may alert clinicians to suspect xdr tb. 4. implementation of infection control precautions infection control should be more than just a sign on the door. public sector hospitals often face a large tb burden, and are required to manage an excessive number of patients with limited resources. as an illustration, a large tertiary hospital in gauteng province registered 6 992 cases of tb for 2006 – just under 20 new tb cases daily (personal communication). at this hospital over 100 medical patients are admitted daily via a 32bed admission ward. only 6 single-bed cubicles are available for the isolation of general medical patients. medical staff at this hospital have no access to p95 masks. there are no ultraviolet lights or ventilatory control systems in any of the medical wards. given the patient numbers and available facilities, no meaningful infection control is possible. 5. increased research support for drugs to treat xdr tb we currently have highly effective short-course therapy available to treat tb. in south africa nationally we achieve only a 54% cure rate for new smear-positive tb cases.4 some provinces are unable to cure a third of their tb cases. there is an urgent need to develop drugs to treat the few patients with confirmed xdr tb. however, more drugs and more complex regimens will be of little use overall until we start to treat new smear-positive cases adequately. the introduction of new drugs into an already failing programme is likely to result in more resistant cases than they would treat. 6. development of rapid diagnostic tests for tb cost will be the deciding factor when these tests are developed. improved diagnosis is, however, of little benefit if the tb diagnosed is not treated adequately and cured. 7. access to antiretroviral therapy antiretroviral therapy (art) decreases the incidence of tb dramatically. this decrease is dependent on the absolute cd4 count.5 to decrease the incidence of tb in south africa we need to increase voluntary counselling and testing (vct), clear backlogs at art clinics, shorten the time from hiv diagnosis to commencement of art, and campaign for a cd4 count higher than the current 200 to qualify for art. art in prisons, which are notorious for high tb incidence, is essential. other considerations include assessing whether we are not inadvertently encouraging resistance through well-meaning practices. the use of fluoroquinolones not only delays the diagnosis of tb but may promote the resistance to this class of second-line tb agents.6 these findings are worrying given the liberal use of ciprofloxacin for diarrhoea in hiv-positive patients. isoniazid (inh) prophylaxis is highly effective, but the risk of inducing resistance needs to be seriously considered, particularly in a population group where proving a patient does not have active tb is as difficult as proving they do. there are still questions that need to be answered with regard to the current treatment regimens in our patient population. rifampicin may not be as well absorbed when part of fixeddrug formulations as when administered as a single agent.7 rifampicin’s absorption is significantly decreased in hiv seropositive patients, particularly those with chronic diarrhoea.8 the possible induction of widespread rifampicin mono-resistance would make short-course therapy ineffective. large pharmacokinetic and pharmacodynamic studies are needed in our patient population to determine whether we are achieving the desired drug concentrations. xdr tb is the end of a spectrum of a man-made problem and a result of poor tb treatment. the mdr/xdr tb problem can be overcome (even without quantifying it) by treating tb and hiv adequately, ensuring patient compliance with directly observed therapy, and practising adequate infection control measures in our clinics, hospitals, prisons and communities. these measures have been shown to not only decrease overall tb incidence but also decrease the prevalence of mdr tb in both hiv-seropositive and seronegative patients.9 references 1. sa health info, report from the expert consultation on drug-resistant tuberculosis (sept 7-8, 2006). http://www.sahealthinfo.org/tb/expert.htm (accessed 8 january 2006). 2. van rie a, enarson d. xdr tuberculosis: an indicator of public health negligence. lancet 2006; 368: 1554-1556. 3. gandhi nr, moll a, sturm aw, et al. extensive drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and hiv in a rural area in south africa. lancet 2006; 368: 1575-1580. 4. global tuberculosis control: surveillance, planning, financing. who report 2006. www.who.int/tb (accessed 10 january 2007). 5. lawn sd, myer l, bekker lg, wood r. burden of tuberculosis in an antiretroviral treatment programme in sub-saharan africa: impact on treatment outcomes and implication for tuberculosis control. aids 2006; 20 (12): 1605-1612. 6. wang jy, hsueh pr, jan is, et al. empirical treatment with a fluoroquinolone delays the treatment for tuberculosis and is associated with a poor prognosis in endemic areas. thorax 2006; 61(10): 903-908. 7. iseman md. tuberculosis chemotherapy, including directly observed therapy. in: iseman md, ed. a clinician’s guide to tuberculosis. philadelphia: lippincott williams & wilkins, 2000: 271-322. 8. gurumurthy p. decreased bioavailability of rifampin and other antituberculosis drugs in patients with advanced human immunodeficiency virus disease. antimicrob agents chemother 2004; 48 (11): 4473-4475. 9. frieden tr, fujiwara pi, washko rm, hamburg ma. tuberculosis in new york city – turning the tide. n engl j med 1995; 333: 229-233. make up march 2007 30/3/07 11:26 am page 10 article information authors: alan whiteside1,2 jamie cohen3 michael strauss4 affiliations: 1balsillie school of international affairs, waterloo, canada 2college of law and management studies, university of kwazulu-natal, south africa 3harvard school of public health, boston, united states 4health economics and hiv and aids research division, university of kwazulu-natal, south africa correspondence to:     michael strauss email: straussm@ukzn.ac.za postal address: private bag x54001, durban 4000, south africa dates: received: 27 jan. 2015 accepted: 13 may 2015 published: 02 july 2015 how to cite this article: whiteside a, cohen j, strauss m. reconciling the science and policy divide: the reality of scaling up antiretroviral therapy in south africa. s afr j hiv med. 2015;16(1), art. #355, 5 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.355 copyright notice: © 2015. the author(s). licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. reconciling the science and policy divide: the reality of scaling up antiretroviral therapy in south africa in this forum... open access • abstract • introduction • governance • human resources for health capacity • infrastructural capacity • financial capacity • treating the region? • the hiv endgame: an aids-free generation • conclusion • acknowledgements    • competing interests    • authors’ contributions • references abstract top ↑ with the world’s largest national treatment programme and over 340 000 incident cases annually, the response to hiv in south africa is hotly contested and there is sometimes a dissonance between activism, science and policy. too often, policy, whilst well intentioned, is informed only by epidemiological data. the state of the healthcare system and sociocultural factors drive and shape the epidemic and its response. by analysis of the financial, infrastructural, human resources for health, and governance landscape in south africa, we assess the feasibility and associated costs of implementing a universal test and treat programme. we situate a universal test and treat strategy within the governance, fiscal, human resources for health, and infrastructural landscape in south africa. we argue that the response to the epidemic must be forward thinking, progressive and make the most of the benefits from treatment as prevention. however, the logistics of implementing a universal test and treat strategy mean that this option is problematic in the short term. we recommend a health systems strengthening hiv treatment and prevention approach that includes scaling up treatment (for treatment and prevention) along with a range of other prevention strategies. introduction top ↑ south africa currently has the world’s highest national incidence of hiv and aids, with 6.4 million people infected and over 340 000 incident cases annually.1 the history of the epidemic and the political, economic and policy response has been well documented by academics.2,3,4 in brief, the government refused from 1999 to 2004 to provide antiretroviral therapy via public facilities. the then head of state, thabo mbeki, aided and abetted by minister of health manto tshabalala-msimang, a few members of his cabinet and some of the provincial governments, questioned the causal link between the hi virus and aids, the effects of antiretroviral therapy (art), and the motives of pharmaceutical companies.5 despite this opposition, drugs were made available by progressive provincial governments, health workers and activist organisations. since those bleak days of aids denialism, and increasingly from 2005,5 south africa has expanded its hiv services and today has the world’s largest art programme, reaching about 2.1 million people.1 like most countries in sub-saharan africa, south africa tries to base its health policy on world health organization (who) recommendations. their guidelines are based on the best available scientific evidence, but do not always speak to economic and social realities, especially regarding hiv and aids. the first who hiv treatment guidelines were released in 2002, and updated in 2006, 2010 and 2013. the latest who clinical recommendations promote treatment initiation for adults and adolescents > 10 years old whose cd4 count falls below 500 cells/mm3 and immediate treatment for persons with active tb disease; hepatitis b virus (hbv) co-infection with severe chronic liver disease; pregnant and breastfeeding women with hiv; and those who are hiv-positive in a serodiscordant partnership.6 the south african national department of health adopted the 2010 recommendations to start adults on treatment at a cd4 cell count ≤ 350 cells/mm3, and in 2015 partially adopted the new guidelines.7 the only who recommendation not adopted in the new south african art guidelines is the recommendation to initiate serodiscordant couples regardless of cd4 count; the discussion of whether or not to include this is ongoing. however, the government is hesitant to start all hiv-infected individuals on treatment irrespective of cd4 level. historically, who recommendations drive policy. in the light of the delayed and discrepant policy change in south africa, it is worth examining the who recommendations and process with careful consideration of context. whilst scientific evidence provides the foundation for the who’s guidance on expanded treatment eligibility, scientific literature tends to be produced in a vacuum. increasing the cd4 threshold has implications that reverberate across sectors: it affects budgets, infrastructure and human resources. in the present article, we examine how policy has changed and existing constraints on the south african government. the policy debate has been articulated in the pages of this journal, but it is noteworthy that this is the only place where we have seen these arguments7,8 as they are generally seen as politically incorrect and going against international norms. we argue that policymakers must consider the possibility that a ’one-size-fits-all’ approach to treatment may not be the most beneficial for patients’ health and adherence to treatment, or the most cost-effective for the national budget.7 decisions to change the cd4 threshold in south africa are not taken lightly, but we are not convinced that there has been sufficient consideration of the implications regarding capacity, adherence and the health of the population. we argue that the treatment agenda has been set outside the country and to unrealistic levels reflecting a dissonance between activism, science and policy.9 the success in translating evidence into practice depends on local context, resources, priorities and data. it is our view that the south african government’s position is that it, reluctantly, has to change policy if not practice. this works for a relatively well-off country with a powerful political leadership, reasonable public health system, low (and falling) dependence on donors, and a reasonable public platform for debate. in many other settings, governments and ministries of health may be adversely affected by the decrees from geneva or global capitals. the present article identifies two major challenges faced in south africa. first, modelling studies are being given too much emphasis and should not be used, in isolation, to dictate policy. second, the issue of when to provide art is being conflated with treatment-based prevention. it is important, however, to understand the two pressures for treatment. first, it is seen by some as a ‘right’ that hiv-positive people should get the best available treatment, without considering the broader health context and the need to make choices. second is the pressure of treatment as prevention. the seminal hptn 052 study showed the effectiveness of art in reducing hiv transmission in discordant heterosexual couples.10 this study was a key driver for the who to revise its guidelines for art initiation.11 art is recommended for hiv–positive, pregnant, breastfeeding women; all children under the age of five; people with tb or hepatitis b; and hiv–positive people with hiv-negative partners.6 for clarity, we include working definitions of universal access and universal test and treat art rollout strategies as well as treatment as prevention (tasp) (see panel). papers12,13,14,15 that model the cost-effectiveness of universal test and treat in south africa, using various inputs and assumptions, yield different results. we include an overview of the findings and conclusions of these studies to show the different predicted outcomes and costs of universal test and treat. models are a mixed blessing – they can generate useful cost-effectiveness data if they are based on realistic assumptions and up to date biomedical data. however, achieving this often proves to be difficult, especially for long-term analyses, because even small inaccuracies or unforeseen costs may lead to very different results. meyer-rath and over15 warn about the shortcomings of art scale-up models that do not account for the flexibility of costs over time. their model showed that small-scale inefficiencies could lead to far higher costs in the long run. although prevention necessarily results from any treatment programme,16 it is important when developing policy not to conflate tasp with universal test and treat. we critique universal test and treat in the context of governance, human resources for health, and infrastructural and fiscal constraints in south africa. the response to the epidemic must be forward thinking, progressive and to make the most of the benefits from tasp. the logistics of implementing a universal test and treat strategy mean that this option is problematic in the short term. we recommend a health systems strengthening hiv treatment and prevention approach, which includes scaling up treatment (for treatment and prevention) along with a range of other prevention strategies. governance top ↑ south africa’s constitution established three spheres of government–national, provincial, and local. health policy is developed nationally and adapted to fit provincial needs. healthcare funding, including that for hiv and aids, is allocated to provincial departments of health. this system has created and exacerbated health inequities between provinces. the political, socioeconomic and historical context in the nine provinces varies significantly, which affects service delivery (see table 1).17 we illustrate this point with data from the best and worst provinces: the well-resourced and well-governed western cape, and limpopo which has a largely rural population, fewer human resources per capita and inefficient government. table 1: provincial inequality. the health profile in south africa’s nine provinces varies between these two extremes. hiv prevalence ranges from 4.75% in the western cape to 24.7% in kwazulu-natal – nearly double that in limpopo. the number of annual new hiv infections varies by a factor of 30.18 in this context, one-size-fits-all interventions cannot work; the gaps in health service facilities, especially staffing levels, are too great. a blanket universal test and treat strategy would be difficult to apply. human resources for health capacity top ↑ human resources are a significant limitation on the ability to effectively deliver health and hiv services. progress has been made; the number of public sector doctors increased from 7645 in 2003 to 13 614 in 2013, and the number of professional nurses registered with the south african nursing council from 96 715 to 129 015.19 the number of doctors and professional nurses per 100 000 people exceeds the who minimum. box 1: definitions and models. the problem is the uneven distribution of human resources for health (hrh) across provinces; between urban and rural areas; and between the public and private sectors.19 only 12% of the country’s doctors and 19% of its nurses work in rural facilities, serving 43.6% of the population.20 these additional strains on an already overstretched health labour force compromise the ability of the health system to provide equal access and increased coverage of treatment and care for people with hiv. health facilities face other human resource problems. the real unit costs of labour have almost doubled over the last 15 years.19 put simply, this means that compensation has gone up more than productivity, hence more money has to be spent to achieve the same result. attrition owing to aids and emigration has worsened the ratio of professional and enrolled nurses and doctors to population size in the public sector. there is an historical trend of a substantial proportion of doctors who qualified in south africa emigrating to work abroad, and many leave the public sector to work in private practice.20 responses include expanding and auditing the quality and relevance of training to meet the demand for health services, task shifting and developing strategies for ensuring an equitably distributed, long-term supply of hrh. government’s training targets may enable south africa to reach universal art, if the skewed distribution of hrh is addressed in conjunction with innovative, task shifting measures. building human resource capacity to meet the needs of a universal test and treat programme will be a significant challenge in south africa and will need to be an increasing priority as the treatment programme expands. infrastructural capacity top ↑ south africa’s healthcare infrastructure has improved since 1994, but regional and sectoral discrepancies persist (table 1). fifteen per cent of poor rural households live more than one hour away from the closest clinic, and 20% live more than one hour away from the closest hospital.21 the fragility of the health system was clearly illustrated in december 2012 when médecins sans frontières had to step in to supply the mthatha medical depot with arvs for 50 000 hiv-infected patients. an estimated 5494 adults taking arvs went at least one day without treatment owing to severe drug supply and delivery disruptions.22,23 this service delivery crisis was a symptom of long-standing and systemic infrastructural, human resource capacity and financial mismanagement issues, which continue today.24 a universal test and treat programme would place strain on a fragile system, possibly particularly compromising rural healthcare where there may be fewer staff members, and also a dependence on urban-based supply chains. south africa’s public health infrastructure must be strengthened to support the demands of universal art and the proposed national health insurance (nhi) plan. financial capacity top ↑ a good understanding of south africa’s healthcare spending shows additional constraints. overall expenditure on public health grew from r16.4 billion in 2008/2009 to over r30 billion in 2013/2014.25 a key component of the expanded health budget is the nhi plan, to be phased-in over 14 years. this plan aims to restructure and strengthen the public health system and improve quality of care. the nhi will require significant financial expenditure, imposing a further fiscal burden on taxpayers. nhi-related public spending increased from r119.3 million in 2008/2009 to r491.8 million in 2013/2014, and is expected to increase to r650.1 million by 2016/2017.25 this expense must be seen against a backdrop of rising hiv spending. public spending on hiv and aids increased from r3.36 billion in 2008/2009 to r10.97 billion in 2013/2014.25 clinical care and treatment support from the president’s emergency plan for aids relief (pepfar), south africa’s largest bilateral donor, will come to an end in 2017, and the focus of this funding is already shifting from treatment to support and technical assistance. the government committed to increase its financing of the national strategic plan for hiv, stis and tb (nsp) from r9.57 billion in 2012 (71% of nsp) to r15.2 billion in 2017 (88% of nsp).26 despite this outlay, the government is forecasting a widening funding gap; in 2013/2014 it was r2.67 billion. by 2015/2016 the projections are: resource needs of r29.86 billion, government funding of r19.8 billion, and development partners providing r5.02 billion – leaving a gap of over r5 billion.27 a universal test and treat strategy does not currently fit into south africa’s available financial resources and spending priorities. although nhi expenditure will strengthen hiv services, it crowds out the feasibility of investment in a universal test and treat programme unless significant new money is allocated; this could come from re-allocation of national budgets but would require political will. treating the region? top ↑ there is evidence of an increasing burden on existing health resources because of ’medical tourists’ in south africa, especially from neighbouring countries. in 2012 there were 6 689 105 african or middle eastern visitors to south africa, of whom 260 875 or 3.9% were defined as medical tourists. not all are seeking public health; middle-class visitors may be coming for elective procedures or be covered by insurance; and some regional governments refer (and pay for) patients to attend specialised medical facilities and this is covered under the 1999 southern african development community (sadc) health protocol.28 there is evidence to show that, as art coverage improves across the border, so the number of people trying to access treatment in south africa declines. in the case of botswana, medical tourists grew from 40 000 to just over 50 000 between 2003 and 2008. thereafter, the numbers fell to less than 20 000 in 2012. for mozambique, the number of medical tourists grew rapidly from 8000 in 2003 to about 180 000 in 2010. with the expansion of art coverage in mozambique, the numbers fell and in 2012 were just less than 100 000.28 the exception may be zimbabweans who are primarily in south africa for employment, and who are accessing art. of course, there is also evidence that south africans are making it difficult for visitors to access treatment in the public sector, and the appalling april 2015 xenophobic attacks sent a message that foreigners are not welcome in the country for any reason. nevertheless, providing art to all makes public health sense. the hiv endgame: an aids-free generation top ↑ significant scientific advances coupled with political will have endowed the world with effective biomedical, behavioural and structural interventions. the conversation is shifting towards a foreseeable end to the epidemic. in the absence of a vaccine or cure, navigating the ‘endgame’ will be costly and ineffective if plans are designed without context and foresight. the hiv epidemic in south africa is driven by deeply entrenched social and structural factors including gender inequality, poverty and migration.29,30 even if the structural inadequacies of the healthcare system are addressed, a one-size-fits-all approach to hiv treatment and prevention will not work. the complexity of the epidemic necessitates a diverse range of interventions which are effective within the south african epidemiological and resource context. too often, health policy recommendations are prescribed with good intention but based primarily on modelled outcomes or international ‘norms’, with little attention paid to local context. successful programmes that will make a real impact hinge on much more. fiscal, infrastructural and human resources for health, political and sociocultural factors drive and shape the epidemic and should inform its response. given these constraints, it is clear that a universal test and treat strategy, and a combination prevention and treatment approach that includes a strengthening of the health system, are mutually exclusive in the short term. a premature move to a one-size-fits-all policy will undermine the importance of other interventions that work. rolling out a comprehensive treatment and prevention programme for hiv based on evidence for efficacy, cost-effectiveness and country-specific context must become a priority. strengthening the health system and increasing capacity for hiv treatment must remain high on the agenda, but a universal test and treat strategy cannot be pursued exclusively or to the detriment of other interventions that work, as we have shown elsewhere that there is the potential for a virtuous cycle to begin but it must be properly planned.31 in addition to medical interventions, there must be increased emphasis on gender relations and empowering women, especially young women. there needs to be social change, and it may be that requiring some form of payback for treatment – not financial but perhaps in terms of volunteerism – will contribute to this. conclusion top ↑ south africa is achieving significant progress in the form of dramatically lower rates of mother-to-child-transmission, falling new infections in young adults, decreasing hiv-related mortality, and expanding art coverage. we cannot risk derailing this momentum with premature policy decisions. universal access should be the primary goal and, in this context, treatment will necessarily lead to prevention. acknowledgements top ↑ competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions a.w. (balsillie school of international affairs) developed an initial conceptual framework for this article. a.w. and j.c. (harvard school of public health) and m.s. (university of kwazulu-natal) participated in conceptual development, literature search, writing and finalising of the article. references top ↑ shisana o, rehle t, simbayi l, et al. south african national hiv prevalence, incidence and behaviour survey, 2012. cape town: hsrc press; 2014. nattrass n. mortal combat: aids denialism and the struggle for antiretrovirals in south africa. durban: university of kwazulu-natal press; 2007. fourie p, meyer m. the politics of aids denialism: south africa’s failure to respond. farnham: ashgate; 2010. šehović ab. hiv/aids and the south african state: sovereignty and the responsibility to respond. farnham: ashgate; 2014. nattrass n. the aids conspiracy: science fights back. new york: columbia university press; 2012. who. march 2014 supplement to the 2013 consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection: recommendations for a public health approach. geneva: world health organization; 2014. geffen n, robinson m, venter f, sa fcp, low m. one size doesn’t fit all: tailoring adult antiretroviral treatment. s afr j hiv med. 2014;15:77–78. http://dx.doi.org/10.7196/sajhivmed.1095 geffen n. world health organization guidelines should not change the cd4 count threshold for antiretroviral therapy initiation. s afr j hiv med. 2013;14:6–7. http://dx.doi.org/10.7196/sajhivmed.906 coutsoudis a, goga a, desmond c, barron p, black v, coovadia h. is option b+ the best choice? lancet. 2013;381:269–271. http://dx.doi.org/10.1016/s0140-6736(12)61807-8 cohen ms, chen yq, mccauley m, et al. prevention of hiv-1 infection with early antiretroviral therapy. n engl j med. 2011;365:493–505. http://dx.doi.org/10.1056/nejmoa1105243 who. programmatic update: antiretroviral treatment as prevention (tasp) of hiv and tb. geneva: world health organization; 2012. granich r, kahn jg, bennett r, et al. expanding art for treatment and prevention of hiv in south africa: estimated cost and cost-effectiveness 2011-2050. 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abstract introduction discussion conclusion acknowledgements references about the author(s) theresa m. rossouw department of immunology, university of pretoria, south africa sonia hitchcock department of family medicine, university of pretoria, south africa kalafong provincial tertiary hospital, south africa mariëtte botes muelmed hospital, pretoria, south africa citation rossouw tm, hitchcock s, botes m. the end of the line? a case of drug resistance to third-line antiretroviral therapy. s afr j hiv med. 2016;17(1), a454. http://dx.doi.org/10.4102/sajhivmed.v17i1.454 case reports the end of the line? a case of drug resistance to third-line antiretroviral therapy theresa m. rossouw, sonia hitchcock, mariëtte botes received: 09 dec. 2015; accepted: 03 apr. 2016; published: 31 may 2016 copyright: © 2016. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract hiv drug resistance has been described in all antiretroviral drug classes and threatens the long-term success of hiv treatment. here, we describe the first reported case of acquired resistance to the integrase strand transfer inhibitors in south africa. this case illustrates the dilemma of treatment in the context of inadequate adherence and poor psychosocial support and highlights the potential risk of transmission of multidrug-resistant virus. introduction the development of drug resistance is one of the biggest concerns in the long-term management of hiv-infected patients. an increasing number of confirmed cases of drug resistance to second-line antiretroviral treatment (art) has prompted the south african national treatment programme to introduce third-line treatment. this is, to the best of our knowledge, the first report of drug resistance to third-line therapy in the south african public sector. the research ethics committee of the faculty of health sciences of the university of pretoria approved the case study and granted a waiver of consent. patient presentation the patient tested hiv-positive in 2006 at the age of 8 years. her exposure to perinatal art is unknown. she started her first art regimen consisting of stavudine, lamivudine and efavirenz in the private sector in 2006 after completing a course of treatment for pulmonary tuberculosis. in 2007, she was transferred to the state sector. here, she was changed to the standard second-line regimen in use at the time – zidovudine (azt), didanosine and ritonavir-boosted lopinavir – because of virological treatment failure in october 2008. she initially responded well, but her viral load became detectable again in september 2009 and she was referred to an academic art clinic in march 2010 because of virological failure. her art regimens, cd4 counts and hiv viral load results are shown in figure 1. figure 1: antiretroviral treatment and monitoring data from 2006 to 2015. management and outcome at the time of the referral, the patient was 12 years old and living in pretoria with her aunt. her mother lived in limpopo and was also using art. the patient was aware of her hiv status and it was known to all her close adult family members. she reported poor adherence with her art treatment because it was unpalatable. she had three genotypic drug resistance tests (drts) over the next 2 years and the mutations evolved from low-level resistance to ritonavir-boosted lopinavir to extensive three-class resistance during this time (table 1). she moved again to a private general practitioner in 2012 where she had another drt performed at a private laboratory which confirmed the results of the second test. she was then changed to third-line therapy consisting of tenofovir (tdf), emtricitabine (ftc), ritonavir-boosted darunavir, raltegravir (ral) and etravirine. the arvs were delivered monthly from june 2012 to february 2015 by courier pharmacy and no parcels were returned. she attended all monitoring visits and initially had an excellent response to the third-line regimen. table 1: hiv genotypic drug resistance test results for 2011, 2012 and 2015. however, by 2013 the patient was not coping well and had developed urinary and faecal incontinence without a physiological cause. she had nearly been raped, had failed grade 9 and had become socially isolated. by december 2013, her viral load reflected the impact of the psychological problems on her adherence. her mother passed away in 2015 and with that the patient lost her medical aid benefits and was referred back to the state sector. a fourth drt (table 1) showed that resistance to the non-nucleoside reverse transcriptase inhibitors and protease inhibitors had worsened and also now included resistance to the integrase strand transfer inhibitors (instis). currently, neither the patient nor the family seem to have grasped the seriousness of her condition. despite multiple adherence counselling sessions and even contracting with the family that her pill-taking will be supervised, there is still inadequate supervision. she has poor coping skills, has not entirely accepted her illness and is ambivalent about taking her art. she is now on a holding regimen consisting of ftc, tdf, azt and abacavir (abc). a tropism assay predicted that ccr5-antagonists are likely to be effective. discussion this patient has come to the end of the line in terms of available art. the virus displays intermediate to high-level resistance to all the available arvs (either in the second or the third genotype) and even low-level resistance to the new insti, dolutegravir (dtg) and the new-generation protease inhibitor (pi), tipranavir. a potential new regimen should therefore preferably include an entry inhibitor (e.g. maraviroc) and tipranavir, together with tdf, ftc and dtg. the cost, however, is prohibitive and apart from tdf/ftc, none of the medications are available in the public sector at this time. this case raises the question about the positioning of dtg in the treatment guidelines once it becomes available in south africa. a considerable minority of patients develop cross-resistance to dtg after exposure to ral and elvitegravir, while resistance has only rarely been reported in patients exposed to dtg as the first integrase inhibitor.1,2 this case also illustrates the complexity of the long-term management of hiv in the context of poor psychosocial support and suboptimal adherence. it raises concerns about the addition of drug classes in the face of ongoing non-adherence and highlights how management is complicated, and unnecessary costs incurred, when patients move between health sectors without an electronic patient record. this case also raises the issue of potential transmission of extensively drug-resistant virus in a teenager who is bound to become sexually active in the foreseeable future. transmitted multiclass (including insti) resistance has been reported in the united states,3,4,5 and clinicians have called for insti resistance testing for patients with an unexpectedly high number of pre-art drug resistance mutations and for contacts of heavily treatment-experienced patients.6 this may become a reality in south africa if efforts to prevent the emergence of resistance are not prioritised. conclusion this case of acquired multiclass resistance, including resistance to instis, in a teenager in south africa illustrates the complexity of the long-term management of hiv in contexts where inadequate adherence and poor psychosocial support abound and highlights the importance of the appropriate positioning of dtg in the national treatment programme. acknowledgements the authors thank the clinic staff who assisted with managing this patient. competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions t.m.r. was the clinician in charge of interpreting the hiv drug resistance results and wrote the patient study. s.h. and m.b. managed the patient’s clinical care and helped to edit and approve the final manuscript. references mesplède t, wainberg ma. resistance against integrase strand transfer inhibitors and relevance to hiv persistence. viruses. 2015;7(7):3703–3718. http://dx.doi.org/10.3390/v7072790 fourati s, charpentier c, amiel c, et al. cross-resistance to elvitegravir and dolutegravir in 502 patients failing on raltegravir: a french national study of raltegravir-experienced hiv-1-infected patients. j antimicrob chemother. 2015;70(5):1507–1512. http://dx.doi.org/10.1093/jac/dku535 fransen s, young b, frantzell a, et al. control of viral replication following transmission of hiv-1 exhibiting resistance to reverse transcriptase, protease and integrase inhibitors [abstract a56] antivir ther. 2010;15:a67. young b, fransen s, greenberg k, et al. transmission of integrase strand-transfer inhibitor, multidrug resistant hiv-1: case report and natural history of response to raltegravir-containing antiretroviral therapy. antivir ther. 2011;16(2):253–256. http://dx.doi.org/10.3851/imp1748 boyd s, maldarelli f, sereti i, et al. transmitted raltegravir resistance in an hiv-1 crf_ag-infected patient. antivir ther. 2011;16(2):257–261. http://dx.doi.org/10.3851/imp1749 hurt cb. transmitted resistance to hiv integrase strand-transfer inhibitors: right on schedule. antivir ther. 2011;16(2):137–140. http://dx.doi.org/10.3851/imp1750 o r ig in a l a r t ic l e 144 december 2014, vol. 15, no. 4 sajhivmed o r ig in a l a r t ic l eoriginal article safety of the surgeon: ‘double-gloving’ during surgical procedures o a arowolo,1 fwacs; e a agbakwuru,1 fmcs; g c obonna,1 fwacs; c u onyia,2 mbbs; a a akinkuolie,1 fwacs; j g olaogun,2 mbbs 1 department of surgery, faculty of clinical sciences, obafemi awolowo university, ile-ife, nigeria 2 department of surgery, obafemi awolowo university teaching hospitals complex, ile-ife, nigeria corresponding author: a o adeolu (arowolodoctor1@yahoo.com) background. in the face of increasing hiv/aids prevalence in subsaharan africa, we evaluate the effectiveness of ‘doublegloving’ during surgery as a means of protecting the surgeon operating on patients with a known or unknown hiv status. methods. a prospective study was conducted to determine the rate of glove puncture and intraoperative injury in categories of patients with known positive, known negative or unknown hiv status. results. the surgeon and the first assistant double-gloved in all the 1 050 procedures performed between 2009 and 2013, and a total of 8 400 surgical gloves were used. sixty-nine patients (6.6%) were hiv-positive, 29 patients (2.8%) were hiv-negative, and the hiv status was unknown for the remaining 952 patients (90.7%). the overall glove puncture rate in the study was 14.5%. the glove puncture rate was 0%, 31% and 15% for hiv-positive, hiv-negative and hiv status unknown, respectively, and this difference was statistically significant. the mean operating time in the group with glove punctures was 148 min (95% confidence interval (ci) 135 161), while mean operating time in the group without glove puncture was 88 min (95% ci 84 92). conclusion. double-gloving offers protection against intraoperative injury. knowing the hiv status of the patient offers additional protection to the operating surgeon. while we recommend routine double-gloving for surgeons working in hivprevalent patient populations, we also advocate for the routine screening for hiv in all surgical patients. s afr j hiv med 2014;15(4):144-147. doi:10.7196/sajhivmed.1050 surgical gloves were originally developed to protect the patient from organisms on the physician’s hands.[1] recently, the protection of physicians and other medical personnel from the percutaneous transmission of hiv, hepatitis-b virus and other pathogens by direct contact with infected patients has become a major concern of the medical community.[2-6] since medical history and examination cannot reliably identify all patients harbouring blood-borne pathogens, universal precautions during exposure to blood and body fluids are now mandatory. intact surgical gloves can help to prevent hiv transmission, but breaches in glove material may expose operating room staff to risk of infection, particularly if there are cuts or abrasions on the skin. breached gloves do not only indicate the potential for infection via the skin, but also indicate the possibility of needlestick injury and thus inoculation with infected blood.[6,7] there have been numerous reports on the rising prevalence of hiv infection in subsaharan africa, especially in nigeria. [8,9] the reason for this rising prevalence has partly been due to the widespread use of antiretroviral drugs, which has increased the life expectancy of hiv-infected patients. stemming from this increasing prevalence, it is expected that more hiv-infected patients will be presenting with conditions needing surgical intervention in the near future, thus increasing the surgeon’s exposure to this group of patients. owing to lack of clear guidelines and comprehensive policy formulation on patients with hiv infection,[8-10] patients undergoing surgery in nigeria and many other african countries are not routinely screened for hiv. coupled with this is the lack of a full complement of protective armamentaria against hiv infection for surgeons who are working in low-resource countries such as nigeria, leaving them more vulnerable to contracting this disease from their patients. the principle for most practising surgeons in this region is to take full universal precautions while performing surgery on all patients, as if they are already infected with hiv. the problem with this attitude is that taking full precautions when operating on all patients is likely to become a routine exercise that may be taken for granted. it is therefore questionable if the routine application of universal precautions can offer maximum protection to surgeons practising in such an environment. if a patient is known to be hiv-infected, the attending surgeon will definitely take more-than-routine universal precautions while performing surgery. it is believed that part of the additional precautions to be taken while carrying out surgical operations on patients with hiv/aids infection is for the surgeon to ‘double-glove’ – wear two standard gloves on each hand. while this is common practice, there are few data on the rate of surgical glove puncture while performing surgery on patients of known or unknown hiv status. several studies have shown that doubleo r ig in a l a r t ic l e o r ig in a l a r t ic l e december 2014, vol. 15, no. 4 sajhivmed 145 gloving protects the surgeon from bloodborne diseases more than a single glove, and this has led to routine use of double-gloving by operating surgeons. [11-13] studies on the effect of awareness of patient’s hiv status on the rate of perforation and puncture of the operating glove during surgery remain sparse. we examined whether awareness of the hiv status of a patient by the operating surgeon affects the glove puncture rate. we also assess the efficacy of double-gloving in preventing glove puncture and perforation injury while operating on patients with or without hiv infection. methods this prospective study was carried out at the general surgery unit of obafemi awolowo university teaching hospitals complex (oauthc), comprising the ife hospital unit (ihu) in ile-ife, and the wesley guild hospital (wgh) in ilesha, both in the southwestern region of nigeria. the hospitals serve as referral centres to the rural and semi-urban agrarian communities in this part of nigeria, cover ing a population of ~7.7 million people. the study period spanned a 4-year period from march 2009 to march 2013. with ethical approval from our institutional ethics board, consecutive patients with elective or emergency general surgical procedures were recruited into the study. the patients were not routinely screened for hiv status as part of the study, but where there was clinical indication to do so, patients were screened accordingly. this meant that there were three categories of patients in terms of hiv status: negative, positive and unknown. the hiv status (or lack of knowledge thereof ) of the patient was made known to the operating surgeon and all other theatre staff. however, only the surgeon and the first assistant were included in the study. the gloves used in all surgical cases were made of latex, and the surgeon and the assistant double-gloved in all the cases. after surgery, the used inner and outer gloves were tested separately in accordance with the water-infusion method of the food and drug administration to detect perforation. [7] the gloves were filled with 1 000 ml of water and were suspended from the occluded cuff 5 ft (15.2 m) from the ground. the digits were pressurised differentially when a volume of water was squeezed into each one, and were observed for perforations. with this technique, even minute punctures were detected. in addition, at the end of the surgical procedure, an independent observer inspected the hands of the surgeon and the first assistant for the presence of blood or body fluids as evidence of a break in the integrity of the latex gloves. results a total number of 8 400 surgical gloves used in 1 050 surgical procedures were analysed. the surgeons double-gloved during all the surgical procedures performed (table 1). breast lump excision was the most common surgical procedure, accounting for 142 cases (13.5%). table 2 outlines the indications and surgical procedures performed on the hiv/aidspositive patients. pyomyositis (n=18 (26%)) and appendicitis (n=10 (14.5%)) were the most common surgical conditions in the hiv/ aids patients. as a result, incision, drainage table 1. types of surgical procedure performed during the study period type of surgical procedure n percentage (%) breast lump excision 142 13.5 appendectomy 89 8.5 uncomplicated inguinal herniorrhaphy 86 8.2 simple mastectomy and axillary dissection 68 6.5 thyroidectomy 60 5.7 surface lump excision 48 4.6 right hemicolectomy and ileo-transverse anastomosis 40 3.8 splenectomy 30 2.9 colostomy closure 25 2.4 exploratory laparotomy for drainage of intraperitoneal abscess 24 2.3 others 438 41.7 total 1 050 100 table 2. indications and surgical procedures performed on hiv/aids-positive patients diagnosis procedure frequency, n (%) duration (min) glove status pyomyositis incision and drainage 18 (26) 30 no puncture acute appendicitis appendectomy 10 (14.4) 70 no puncture peripheral lymphadenopathy excision biopsy 8 (11.6) 30 no puncture ruptured appendicitis and gangrenous caecum right hemicolectomy and ileo-transverse anastomosis 7 (10.2) 120 no puncture spontaneous primary peritonitis exploratory laparotomy drainage of abscess 11 (15.9) 80 no puncture typhoid ileal perforation exploratory laparotomy and closure of ileal perforation 3 (4.4) 75 no puncture obstructive jaundice secondary to tumour of head of pancreas triple bypass 2 (2.9) 125 no puncture uncomplicated inguinal hernia inguinal herniorrhaphy 1 (1.5) 60 no puncture parotid gland tumour superficial parotidectomy 1 (1.5) 180 no puncture breast cancer modified radical mastectomy 1 (1.5) 160 no puncture o r ig in a l a r t ic l e 146 december 2014, vol. 15, no. 4 sajhivmed and appendectomies were the most common surgical procedures performed on these patients. out of the 1 050 patients operated on during the study period, 98 patients were tested for hiv infection based on clinical suspicion, and 69 patients (6.8%) tested positive. the remaining 952 patients (88%) were not tested (table 3). the overall glove puncture rate in this study was 152 (14.5%) across the three groups of patients. in the group of patients who were hivinfected, no glove puncture was recorded. the glove puncture rate was 9 (0.86%) in the group of patients who tested negative for hiv, and 143 (13.6%) in the group with an unknown hiv status (table 3); the difference in these rates was statistically significant (p<0.001). the mean operating time in the group with a punctured glove was 148 min (95% confidence interval (ci) 135 161), while mean operating time in the group without glove puncture was 88 min (95% ci 84 92). the pattern of glove puncture in the surgeon and assistants’ hands is shown in table 4. the surgeon’s left-hand outer glove was the most punctured (n=127), accounting for 12.1% of the total glove punctures recorded in the study. the most common site of glove perforation was on the index finger of the left hand (n=114), accounting for 76% of all perforations recorded. the second most common was the left middle finger (n=11), accounting for 7.3% of total perforations (table 5). discussion glove perforation is relatively common during surgery. the overall glove puncture rate per numbers of patients operated upon was 152 (14.5%) (table 3), while the overall glove perforation observed per total number of gloves used was 197 (18.8%) (table 4), which is consistent with perforation rates reported in other studies, with the frequency ranging from 18 to 61% during various surgical procedures. [11-14] the rate of glove puncture has been extensively docu mented in different operative scenarios, including singlegloving and double-gloving.[13,15] the highest frequencies of glove puncture have been reported in orthopaedic, trauma and thoracic surgery; this is likely to be because in these fields the surgeon handles sharp fractured bones or bony structures.[12,16,17] the rate of glove puncture in hand and foot surgery has also been documented. [18,19] studies on glove puncture rates while operating on hiv-infected patients were largely lacking in the literature. in 1987, the centers for disease control issued guidelines, called ‘universal precautions’, designed to minimise the risk of transmission of hiv in the table 3. analysis of glove puncture and hiv status* hiv status glove puncture during surgery, n (%) total, n (%)punctured not punctured not known 143 (15) 809 (85) 952 (100) negative 9 (31) 20 (69) 29 (100) positive 0 (0) 69 (100) 69 (100) total 152 (14.5) 898 (85.5) 1,050 (100) * overall p<0.001. table 4. pattern of glove puncture injury in surgeon and assistant glove area punctured, n percentage (%) not punctured, n percentage (%) surgeon left hand outer 127 12.1 923 87.9 inner 36 3.4 1 014 96.6 surgeon right hand outer 13 1.3 1 037 98.8 inner 1 0.1 1 049 99.9 1st assistant left hand outer 14 1.3 1 036 98.7 inner 1 0.1 1 049 99.9 1st assistant right hand outer 4 0.4 1 046 99.6 inner 1 0.1 1 049 99.9 total 197 18.8 table 5. digits most frequently involved in the puncture injury digit frequency, n percentage of total (%) percent of punctured finger (%) index 114 10.9 76.0 middle 11 1.0 7.3 thumb 10 0.5 6.7 ring 5 0.5 3.3 thumb and index 3 0.3 2.0 thumb and little finger 2 0.2 1.3 index and middle finger 2 0.2 1.3 between ring and middle finger 2 0.2 1.3 total 150 15.1 100 laurie cross-out laurie inserted text per cent o r ig in a l a r t ic l e december 2014, vol. 15, no. 4 sajhivmed 147 healthcare setting.[4] these guidelines are also appropriate for reducing the transmission of other blood-borne infections.[20] however, there are few studies from lowand middle-income countries documenting the rate of glove puncture during surgery when operating on patients with known or unknown hiv status, with universal precautions applied in both settings. as a result, there are no data on the efficacy of universal precautions in preventing glove punctures and hiv transmission in the operating surgery environment, which has recently witnessed an upsurge in the prevalence and incidence of hiv infection. in this study, the rate of glove puncture while operating on patients with a known preoperative status of hiv-positive was zero (0%), compared with the rates of 143 (13.6%) and 9 (0.9%) in patients with unknown preoperative hiv status and patients with negative preoperative hiv status, respectively. this should be interpreted with caution, bearing in mind the small sample size of hiv-infected patients in this study, which limits statistical power. in most other studies, there has been a relatively small and stable number of hiv-infected patients undergoing surgery. [21-23] however, the prevalence of hiv-infected patients undergoing surgery in nigeria and many other parts of africa is expected to increase significantly, because of the efficacy and widespread use of antiretroviral drugs. as hiv-infected patients live longer, more will present in hospital with surgical conditions. in turn, there is need for anticipatory policies that will protect surgeons operating in the environments with high hiv prevalence. that there was no glove puncture while performing surgery in the group of patients who were hiv-infected suggests that awareness of a patient’s hiv status may enhance the intraoperative safety of surgeons. the problem of glove perforation remains a major cause of exposure to contaminated body fluids and is yet to be solved satisfactorily.[24] our study re-emphasises that double-gloving offers significantly better protection than single-gloving. the outer glove alone was punctured in 119 cases (11.3%), while both gloves were punctured in 29 cases (2.8%). therefore, in 8.6% of cases, when the outer glove was perforated, the inner glove protected the surgeon’s hand from contamination; subsequent visible skin contamination would also be much lower with double gloves. these are similar to observations in other studies.[7,17-19] this study also showed that the majority of glove perforation occurred in the index finger of the left hand, which accounted for 10.9% of total perforation, followed by perforation in the left middle finger (1.6%) and left thumb (1.0%) (table 5). this has also been reported in similar studies.[7,17-19] the reason for this may be due to the fact that the index finger and the thumb are more actively used during tissue dissection and during hand exploration than other fingers. as the majority of glove perforations go unnoticed, we recommend the routine use of double gloves in all surgical procedures, or where chances of needlestick injury are high. conclusion these data point to the potential benefits of double-gloving during surgery in settings where hiv is prevalent. more generally, we recommend a comprehensive review of policy frameworks that guide surgeons operating in high-hiv prevalence environments, such as nigeria and other african countries, in order to allow for the routine screening of patients in addition to taking universal precautions, which on their own are not adequate for optimal protection of the surgeon. references 1. misteli h, weber wp, reck s, et al. surgical glove perforation and the risk of surgical site infection. arch surg 2009;144(6):553-558. [http://dx.doi.org/10.1001/ archsurg.2009.60] 2. sanders r, fortin p, ross e. helfest d. outer gloves in orthopaedic procedures. cloth compared with latex. j bone joint surg am 1990;72(6):914-917. 3. grady gf. hepatitis b from medical professions. how rare? how preventable. n engl j med 1977;296(17):995-996. 4. kelen gd, digiovanna ta, celentano dd, et al. adherence to universal (barrier) precautions during interventions on critically ill and injured emergency department patients. j acquir immune defic syndr 1990;3(10):987-994. 5. dxodds rd, guy pj, peacock am, et al. surgical glove perforation. br j surg 1988;75(10):966-968. 6. zhang m, wang h, miao j, du x, li t, wu z. occupational exposure to blood and body fluids among healthcare workers in a general hospital, china. am j ind med 2009;52(2):89-98. [http://dx.doi.org/10.1002/ajim.20645] 7. thomas s, agarwal m, mehta g. intraoperative glove perforation: single v. doublegloving in protection against skin contamination. postgrad med j 2001;77(909):458460. [http://dx.doi.org/10.1136/pmj.77.909.458] 8. adebamowo ca, ezeome er, ajuwon ja, ogundiran to. survey of the knowledge, attitude and practice of nigerian surgery trainees to hiv-infected persons and aids patients. bmc surg 2002;2:7. [http://dx.doi.org/10.1186/14712482-2-7] 9. owotade fj, ogunbodede eo, sowande oa. hiv/aids pandemic and surgical practice in a nigerian teaching hospital. trop doct 2003;33(4):228-231. 10. adelekan ml, jolayemi so, ndom rj, et al. caring for people with aids in a nigerian teaching hospital: staff attitudes and knowledge. aids care 1995;7(suppl 1):s63-s72. 11. yinusa w, li yh, chow w, et al. glove punctures in orthopaedic surgery. int orthop 2004;28(1):36-39. [http://dx.doi.org/10.1007/s00264-003-0510-5] 12. laine t, aarnio p. how often does glove perforation occur in surgery? comparison between single gloves and a double-gloving system. am j surg 2001;181(6):564566. [http://dx.doi.org/s0002-9610(01)00626-2.] 13. na’aya hu, madziga ag, eni ue. prospective randomised assessment of single v. double-gloving for general surgical procedures. niger j med 2009;18(1):73-74. 14. sebold ej, jordan lr. intraoperative glove perforation. a comparative analysis. clin orthop relat res 1993;297:242-244. 15. alrawi s, houshan l, satheesan r, et al. glove reinforcement: an alternative to double-gloving. infect control hosp epidemiol 2001;22(8):526-527. [http://dx.doi. org/10.1086/501947] 16. driever r, beie m, schmitz e, et al. surgical glove perforation in cardiac surgery. thorac cardiovasc surg 2001;49(6):328-330. [http://dx.doi.org/10.1055/s-2001-19006] 17. maffulli n, capasso g, testa v. glove perforation in pediatric orthopaedic surgery. j pediatr orthop 1991;11(1):25-27. 18. maffulli n, testa v, capasso g. glove perforation in hand surgery. j hand surg am 1991;16(6):1034-1037. 19. maffulli n, testa v, capasso g. glove perforation in foot surgery. foot ankle 1991;11(4):228-230. 20. bennett nt, howard rj. quantity of blood inoculated in a needlestick injury from suture needles. j am coll surg 1994;178(2):107-110. 21. adeolu aa, malomo ao, shokunbi mt, shokunbi wa, obajimi mo, komolafe eo. cranial computed tomographic (ct) findings in hiv-positive nigerian patients presenting for neurosurgical evaluation. west afr j med 2006;25(1):69-74. 22. čačala sr, mafana e, thomson sr, smith a. prevalence of hiv status and cd4 counts in a surgical cohort: their relationship to clinical outcome. ann r coll surg engl 2006;88(1):46-51. [http://dx.doi.org/10.1308/003588406x83050] 23. ukponmwan cu, egbagbe ee, osahon ai. prevalence of human immunodeficiency virus in ophthalmic surgical patients. niger j clin pract 2009;12(2):120-123. 24. nelson jb, mital, a. an ergonomic evaluation of dexterity and tactility with increase in examination glove thickness. ergonomics 1995;38:723-733. article information authors: danna flood1 melissa wallace2 kimberly bloch2 james kublin1 linda-gail bekker2 affiliations: 1hiv vaccine trials network, fred hutchinson cancer research center, united states 2the desmond tutu hiv centre, university of cape town, south africa correspondence to: danna flood email: dflood@hvtn.org postal address: 1100 fairview ave n, e3-300, seattle, wa 98109, united states dates: received: 19 feb. 2015 accepted: 28 sept. 2015 published: 19 nov. 2015 how to cite this article: flood d, wallace m, bloch k, kublin j, bekker l-g. attracting, equipping and retaining young medical doctors in hiv vaccine science in south africa. s afr j hiv med. 2015;16(1), art. #364, 6 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.364 copyright notice: © 2015. the authors. licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. attracting, equipping and retaining young medical doctors in hiv vaccine science in south africa in this original research... open access • abstract • introduction • methods    • sampling    • data collection    • data analysis • ethical considerations • results    • attracting young doctors to research       • exposure to research early in medical training:       • career development pathway:       • comparable employment packages and job security:       • increase awareness of the hiv prevention field:    • equipping and retaining doctors for careers in research       • skill building, infrastructure and academic resources:       • mentorship:       • adequate funding for research:    • clinician investigator development programmes • the south african/hvtn aids early stage investigator programme • discussion    • study limitations • acknowledgements    • competing interests    • authors’ contributions • references abstract top ↑ background: hiv remains a significant health problem in south africa (sa). the development of a preventive vaccine offers promise as a means of addressing the epidemic, yet development of the human resource capacity to facilitate such research in sa is not being sustained. the hiv vaccine trials network (hvtn) has responded by establishing south african/hvtn aids early stage investigator programme (shape), a programme to identify, train and retain clinician scientists in hiv vaccine research in sa. objectives: the present study sought to identify factors influencing the attraction and retention of south african medical doctors in hiv vaccine research; to understand the support needed to ensure their success; and to inform further development of clinician research programmes, including shape. methods: individual interviews and focus groups were held and audio-recorded with 18 senior and junior research investigators, and medical doctors not involved in research. recordings were transcribed, and data were coded and analysed. results: findings highlighted the need for: (1) medical training programmes to include a greater focus on fostering interest and developing research skills, (2) a more clearly defined career pathway for individuals interested in clinical research, (3) an increase in programmes that coordinate and fund research, training and mentorship opportunities and (4) access to academic resources such as courses and libraries. unstable funding sources and inadequate local funding support were identified as barriers to promoting hiv research careers. conclusion: expanding programmes that provide young investigators with funded research opportunities, mentoring, targeted training and professional development may help to build and sustain sa's next generation of hiv vaccine and prevention scientists. introduction top ↑ africa (sa) has one of the highest hiv prevalence rates globally.1 despite promising new developments in non-vaccine prevention modalities, a preventive vaccine against hiv offers the best hope to end the epidemic.2 several large-scale hiv vaccine, and other prevention, trials will begin in sa in 2016.3, 4 these trials will utilise the strengths of south african investigative teams, requiring a wide breadth of research capacity. whilst senior-level south african hiv vaccine researchers have developed enormous expertise, the number of junior clinician investigators entering the field has lagged. since the early 1990s, sa has seen a decrease in the number of clinical researchers and an ageing of publishing scientists.5, 6 a concerted effort is required to increase the number of young medical doctors entering the hiv prevention and vaccine field to ensure the country's ongoing contribution to this critical effort. in 2010, responding to the challenge, the hiv vaccine trials network (hvtn), with support from the national institute of allergy and infectious diseases (niaid) and the fogarty international center (fic), established the south african/hvtn aids early stage investigator programme (shape), a peer-reviewed medical doctors/phd programme that recruits and supports young clinician investigators as they become independent investigators. components of the programme, coordinated by the desmond tutu hiv centre at the university of cape town, include 3-year salaried appointments at hvtn clinical trial sites; financial support for a mentored research project and research-related costs; targeted training and tuition for a concurrent phd programme; travel to hvtn meetings and international hiv conferences; and facilitated integration into the hvtn scientific community via participation on scientific and governance committees. to inform the shape programme and future efforts, formative research was conducted to: (1) understand facilitators and barriers to attracting, equipping and retaining young south african medical doctors in careers in hiv vaccine research, (2) develop recommendations to address identified challenges and (3) inform the design of clinician investigator development programmes, including shape. methods top ↑ sampling during 2011, participants were recruited from clinical research sites and via referrals throughout sa. target participants comprised a small group of specialised individuals and therefore purposive sampling with specific criteria was used. these groups were defined as: (1) senior investigators (si) – those who led research teams and held the role of ‘principal investigator’ (pi) for at least 5 years, (2) junior investigators (ji) – those who had medical degrees and worked at clinical research sites for 10 years or less without assuming the role of pi and (3) young medical doctors (md) – those who had received medical degrees no more than 12 years ago and expressed interest in research but had not pursued research careers. data collection we used a qualitative approach and conducted semi-structured interviews and focus groups. k.b. underwent comprehensive training and utilised interview and focus group schedules to guide the sessions. fifteen one-on-one, semi-structured, confidential telephone interviews were conducted, lasting approximately 1 hour and included five jis, five sis, and five mds. data collected during the interviews informed semi-structured questions used for three face-to-face focus groups, lasting approximately 1.5 hours and included four sis, three jis and four mds in separate groups. all interviews and focus groups were conducted in english, recorded using a hand-held audio recorder, and transcribed in english. demographics questionnaires were completed by those who participated in focus groups. data analysis three investigators independently coded five interview transcripts and then met as a team to review codes, resolve differences in coding by consensus, and create a codebook. the codebook was used to analyse subsequent interview and focus group transcripts, and generate new codes. subsequent transcripts were assigned to three of the authors who independently cleaned and coded them using the codebook. the three investigators reconvened again to resolve differences in coding by consensus, analyse the transcripts, discuss patterns in the data and organise identifiable themes in atlas.ti.6.2.25 (gmbh berlin). data and investigator triangulation were utilised to enhance validity of the findings.7 ethical considerations top ↑ all participants were over 18 years old and provided written informed consent. the study was approved by the university of cape town's human research ethics committee (ir file #128/2011) and the fred hutchison cancer research center institutional review board (ir file #7448). results top ↑ participants (n = 18) were sis (n = 5), jis (n = 6), and mds (n = 7). sociodemographic characteristics of study participants are shown in table 1. the following themes were identified for each research objective and were endorsed by participants from all groups (ji, si, md) unless otherwise stated. table 1: sociodemographic characteristics of study participants. attracting young doctors to research exposure to research early in medical training: most participants believed there is little exposure to research in medical training and a majority of young doctors are not aware that research is a viable career option: ‘[clinical research] is an unconsidered job because … it's not explored in medical school.’ (md) many participants indicated that even brief exposure to research (e.g. an investigator presenting their research to students and professors) can spark interest in a research career. there was wide agreement that incorporating research methodology courses and hands-on research with medical training early in the curriculum would help doctors to better understand research and fuel interest in this career option: ‘… integrate clinical researchers back into [university] departments. … people … could see … what fun research is and how research changes people's lives and become excited about doing this…’ (si) suggestions for supporting these activities included providing students with small mentored research projects, offering stipends to support projects, and combining a medical degree with a master's or phd degree. several participants indicated that better integration of researchers into university academic departments would provide them with greater access to funding support, training and academic resources, whilst providing medical schools and other departments with faculty to teach research methodology, and opportunities for students to gain research experience: ‘clinical researchers are incredibly isolated in the university; even though they are driving the publications of the university and … the research agenda … [they] are isolated from [their] peers.’ (si) career development pathway: most participants, particularly mds, highlighted a lack of clarity around the career development pathway for clinical researchers as a deterrent to pursuing a career in this field: ‘… there isn’t really a … [formal] progression… there's no hierarchy. either, you’re … the pi or you’re not the pi …’ (ji) this is in contrast to the well-defined and regimented career pathway for clinical medicine: ‘[in clinical medicine]… determining your path is much more strict and clearly defined… [clinical research] has a lot of uncertainties…’ (md) comparable employment packages and job security: nearly all participants agreed that, to attract and retain top research doctors, employment packages in clinical practice and research need to be comparable. perceptions of researcher v. non-researcher salaries varied. to the best of our knowledge, there are no definitive data comparing salaries of medical doctors in clinical practice v. research. all sis agreed that salaries have been historically lower for researchers, but recent efforts have been made to align salaries more closely; increasing awareness of this trend could help to attract doctors to research: ‘… making comparable salaries [to doctors in clinical practice is] important … we are really struggling to find doctors [to bring] into research…’ (si) increase awareness of the hiv prevention field: many investigators reported that the subject of hiv prevention sparked their interest in research, citing the urgency and magnitude of the hiv epidemic and their desire and ability to make a difference in people's lives. many participants suggested that increasing awareness amongst the medical community about developments in hiv prevention modalities, particularly vaccines, could stimulate interest in the field. suggestions included presentations at medical conferences and in media frequented by clinicians: ‘… show [doctors] what the future holds for hiv/aids. to be able to see … the result, the impact in the community … it can be very satisfying for a career.’ (ji) equipping and retaining doctors for careers in research there was considerable overlap in themes identified as important for equipping and retaining doctors; therefore they are combined here. skill building, infrastructure and academic resources: to effectively equip jis, sis noted that they need specialised training. most participants highlighted the importance of acquiring research knowledge and skills through academic courses in ‘… epidemiology, statistics, immunology… ethics … [and] research methods…’ (si). some suggested courses in ‘laboratory methods.’ most sis recommended intensive training in ‘… manuscript and proposal writing …’ and ‘[giving] presentations’. participants also mentioned the importance of collecting data in the field and working in research units. nearly all participants agreed that, to train and retain new investigators, the investigators need access to academic resources such as journal subscriptions, educational opportunities, research symposia and networking to foster ‘collaboration … [with a] wider scope of people …’ (si). mentorship: structured mentoring was raised by most participants as a significant facilitator to equipping, retaining and supporting career progression for new investigators. nearly all participants proposed that fostering an environment with structure, clear objectives, dedicated time, and positive personal relationships is essential for a successful mentor-mentee experience: ‘[we need a] formal structure … the mentor and the mentee [should] draw up a contract that spells out … purpose… goals and targets … time frames … to guide this relationship.’ (ji) despite the acknowledged importance of mentorship, most participants identified that lack of time hinders the mentoring process. all sis emphasised that sufficient time for mentoring requires specific funding allocated for mentorship activities, but acknowledged the difficulty of earmarking research funding for mentorship. many investigators noted that they themselves had not been mentored and, as a result, some sis conceded that they did not feel capacitated for this role. several participants suggested the development of a mentorship training programme for all investigator levels to address this challenge: ‘… we need support. … mentors need coaching about how to be a good mentor because … [we’ve] never had one.’ (si) participants noted the importance of the ji and si relationship in ensuring career progression and enhancing retention in the field. jis mentioned the critical role that sis play in providing linkage to resources, people and networks which can assist them in furthering their career. most sis and jis recognised that if an si was unwilling or unable to facilitate ji development and ‘make space at the top’, it could jeopardise career progression: ‘… if that chief person [the si] … has no spirit of “look, i’m on top, now i can pull you up to come join me.” if that doesn’t exist, it's a serious barrier.’ (ji) adequate funding for research: all sis and jis expressed concerns about the inherently unstable nature of grant funding and thought it deterred doctors from entering, progressing in, and retaining research careers because, in contrast, clinical practice salaries are thought to be ‘guaranteed’. in addition, the limited availability of consistent and sustained government and university research funding in sa was a frequent theme: ‘if you look at research, in general it's something that's run by donors, and if you go into that kind of career … you are not sure whether that job is secure…’ (ji) because much research funding is sourced internationally and tends to be on a project or grant basis, the ability for long-term planning is affected. financial concerns are perceived to hamper career progression, because the need to secure funding is constantly prioritised above the ‘science’: ‘… instead of spending my time thinking what's the next interesting research question, i’m thinking how the hell do i keep this funded? sure, that dilutes efforts quite a lot.’ (si) some participants suggested seeking alternative funding sources, particularly from the south african government, to establish a more stable funding base to supplement grants: ‘if the government is proactive in leading research … the private sector will also move in and pour in funds when they see there is commitment from the government.’ (ji) clinician investigator development programmes most participants believed that it was critical for the clinical research field to create more clinical investigator development programmes that provide structured mentored research, training, and professional development opportunities: ‘[programmes like shape offer] something that is necessary. … people have to be given this opportunity, otherwise i don’t see them paying their way through this kind of programme…’ (ji) several participants emphasised that development programmes must provide the opportunity for young investigators to experience the full range of activities, and hone the practical skills needed to be a successful investigator: ‘you’re gonna need to give people the experience of doing all of it … if they’re going to become the next generation pis they do actually need to have that exposure and be able to do it.’ (ji) ‘… things like regulatory [agency research review requirements], to understand how that process works … the practical experience of how to go about that.’ (si) the south african/hvtn aids early stage investigator programme top ↑ participants were asked to reflect on the design of the shape programme and comment on the strengths and weaknesses of this model, and provide input on ways to improve the programme. most participants were enthusiastic about the shape programme and agreed that it served an important role in providing an opportunity not previously available: to recruit and train young doctors in research. participants identified shape's strengths as providing a mentored research project and full-time salaries, incorporating a phd degree programme, offering experience as a clinical trial doctor, and opportunities for travel to research meetings and conferences. lack of awareness of the programme by the medical community was often identified as the most significant weakness: ‘… i’m actually thinking about [applying to shape] … nobody approached me before personally and said … this is what it entails … are you interested? personal contact is the best [way to recruit].’ (md) participants suggested several ways to improve shape. most advocated greater involvement from sis and jis in publicising the programme and presenting research findings at medical schools and hospitals to increase interest in hiv vaccine research. most participants agreed that the best recruitment approach is multi-pronged and includes ‘personal outreach’, ’national publicity’ and advertising through the ‘provincial departments of health’, ‘newspapers’, ‘major medical journals’ and ‘medical association websites’. a few participants also advocated use of social media such as facebook (si), direct sms (md) and email (md). some participants suggested expanding the programme to support independent research for mid-career hiv vaccine investigators. a few suggested increasing the number and location of sites where scholars can work. discussion top ↑ the present study identified factors influencing the attraction and retention of south african medical doctors into hiv prevention research; increasing the understanding of the resources and support needed to ensure their success; and eliciting suggestions to inform design of clinical research development programmes, such as shape. of note is that findings were largely applicable to hiv prevention research generally and clinical research more broadly, increasing their value and impact in informing recommendations and future practice. overwhelmingly, there was recognition from all groups that research was not adequately represented in the medical training curriculum and that this limited exposure discouraged interest in, understanding of, and entrance into this field. the overall shortage of doctors in primary healthcare is critical in sa8,9, 10 and requires urgent redress.11 as a result, medical education has renewed its focus on primary healthcare.12,13 whilst necessary, this focus on primary healthcare has had a detrimental effect on the development of clinical research capacity and solid grounding in research skills12; and although medical schools may include training on evidence-based medicine, it is not prioritised as a critical part of the curriculum. our study's findings highlight the need for a more clearly defined career pathway for mds entering research, which includes research skill development, senior researcher mentorship, academic resource access, and networking opportunities. these findings mirror those of the academy of science of south africa (assaf) report, which reviewed the overall state of clinical research in sa and indicated the inadequacies of these resources for clinical research.12 a major barrier to the attraction, retention and career progression of doctors in research is the perceived lack of secured and ongoing funding. with limited financial support from the south african government and academic institutions, the large amounts of money required to conduct hiv prevention trials are sourced outside sa. this project-based funding is competitive, subject to exchange rate fluctuations, and often short-term and unstable. based on these findings, several recommendations can be made. exposure to research: enhance academic research modules, and develop more programmes where students at all levels can gain hands-on experience to spark interest in clinical research, including hiv vaccine research. expand the number of programmes offering a combined mbbch and phd degree. foster an awareness of research, particularly hiv prevention research and its impact, amongst both medical professionals and the broader community. training and mentorship: develop coordinated training programmes for hiv clinical researchers at all levels, as well as a structured mentorship programme supporting researchers vertically and horizontally. provide training on effective mentoring for jis and sis. develop a more objective, standardised and clearly defined career development pathway for jis with clear expectations, milestones and incentives (e.g. promotions, awards) and promote it widely. funding: increase local/national funding (e.g. government, industry, corporate, donor). address funding allocation to support projects, the researcher and designated time for mentorship activities. ensure that salaries are comparable across research and clinical practice positions, and publicise this widely. clinical investigator development programmes: expand programmes such as shape that provide comprehensive support. promote via personal outreach in medical schools, registrar programmes, hospitals and conferences. advertise in journals, social media, medical bulletins, sms and email from trusted sources. create advancement opportunities for jis. for example, create new pi roles at research sites, faculty positions and opportunities for independent research. incorporate ji development programmes in networks, universities and other collaborative research environments to leverage research and academic infrastructures. study limitations there are several limitations to the present study. the sample size was small, comprising 18 participants, most of whom took part in both one-on-one interviews and focus groups. whilst this is considered an adequate sample size for qualitative research,14 it possibly limits the generalisability of the present results. however, notably two of the three groups included in this study (sis and jis) are, by definition, small in size. hiv vaccine research is a specialised field and it is partly because of the small number of doctors entering this field that the present research was conducted. consequently, particularly for sis, our sample included a significant proportion of the total si population involved in hiv vaccine research in sa. in addition, given the small size of this research community in sa, it is possible that participants did not feel comfortable speaking freely and honestly, out of concern that they would be recognised, despite removal of identifiers. this risk might have been an issue particularly during focus groups, as many investigators are colleagues and collaborators. nevertheless, all participants expressed an interest in and recognition of the importance of the topic, and were aware of the value of the research process, and it is hoped that this encouraged openness and honesty throughout. finally, factors identified by participants as significant in attracting, equipping and retaining doctors in hiv prevention science research were largely representative of their own needs rather than a broader impression of what might be required overall. whilst inevitable, this may be viewed as a limitation. acknowledgements top ↑ we thank michele andrasik for her feedback on the manuscript and assistance with atlas.ti., and mindy miner for editing the manuscript. this research was funded by the hvtn (nih um1 a1068614) supported by the national institutes of allergy and infectious disease, us national institutes of health, and in collaboration with the desmond tutu hiv centre. competing interests d.f., j.k. and l.g.b. were part of the hiv vaccine trials network that funded the present research. the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions d.f. (hiv vaccine trials network) conceived the research study. d.f. and m.w. (desmond tutu research centre) were project leaders and led the qualitative study design, implementation, data analysis, interpretation and the writing of this article. d.f., m.w. and k.b. (desmond tutu research centre) coded transcripts. k.b. performed the interviews and led the focus groups, and assisted with data analysis and interpretation. l-g.b. (desmond tutu research centre) and j.k. 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publications; 1998. hiv march make up 01 march 2006 the southern african journal of hiv medicine24 g u i d e l i n e s . . . d i a g n o s t i c revised guidelines for diagnosis of perinatal hiv-1 infection in south africa w stevens, mb bch, mmed (haem), fcpath (haem) g sherman, mb bch, dch (sa), dtm&h, mmed (haem) department of molecular medicine and haematology, university of the witwatersrand, johnnesburg, and national health laboratory services, south africa m cotton, mb chb, fcpaed (sa), mmed (paed), phd, dtm&h, dch (sa) department of paediatrics and child health, stellenbosch university, tygerberg,w cape l gerntholtz aids law project, centre for applied legal studies, university of the witwatersrand, johannesburg l webber, mb chb, mmedpath (virol), dth lancet laboratories, johannesburg the diagnosis of hiv-1 infection in infants begins with identifying hiv-1 infection in women before and during every pregnancy; this awareness should also identify the infant at risk for hiv-1 infection.2,3 nonetheless, perinatal hiv-1 diagnosis presents challenges such as: ■ difficulty in establishing an early and rapid diagnosis in exposed infants due to the persistence of transplacentally acquired maternal igg hiv-1 antibodies. these may remain present in the blood for 15 18 months.4 ■ timing of hiv-1 transmission from mother to child, which directly affects the sensitivity and specificity of available hiv-1 diagnostic assays. ■ the risk of the infant being exposed to hiv-1 throughout the duration of breastfeeding. ■ whether to use quantitative and/or qualitative hiv-1 nucleic acid-based virological assays. ■ the utility and role of detecting p24 antigen for diagnosis and prognosis. ■ the global existence of multiple clades or subtypes of hiv1 and its effect on assay performance.5-10 clinical acumen should prevail in interpreting hiv-1 test results; for example, hiv-1 infection can be ruled out in children ≥ 18 months of age with negative hiv-1 serology, a history of either no breastfeeding or breastfeeding that ceased at least 6 weeks previously, no clinical symptoms of hiv-1 disease and no hypogammaglobulinaemia.4 rapid hiv tests should perform as well in children >18 months as in adults. algorithms are in the process of being validated locally. in turn, all women should be encouraged to undergo voluntary counselling and testing (vct).2 as per national treatment guidelines for infants,11 testing may only be conducted on infants following pre-test counselling and only once informed consent has been obtained from parents, legal guardians or primary caregivers. this document should be read in conjunction with the testing algorithm summarised in fig. 1. introduction the need for expanded testing practices for the early diagnosis of hiv in exposed infants is now well established, hence the urgent need for review of these infant diagnostic guidelines. early diagnosis is critical to facilitate: ■ comprehensive care of infected children including arv treatment ■ evaluation of prevention of mother-to-child transmission (pmtct) programmes, and ■ added social benefits such as a reduction in maternal anxiety,12 stratification of health care services, and recommendations for appropriate infant feeding practices. hiv-infected children under 24 months of age are a particularly vulnerable group. a recent natural history study showed that approximately 35% of infected children in africa died before 1 year of age and that more than 52% have died by their 2nd birthday.13 early diagnosis has the potential to reverse this situation, provided that primary care services are adequately capacitated to provide these children with appropriate care including nutritional support, co-trimoxazole prophylaxis, clinical and cd4 count monitoring and timely referral for antiretroviral therapy. these guidelines for best practice under both ideal and resource-constrained conditions are intended to provide guidance for health care professionals regarding the laboratory diagnosis of hiv-1-infected infants and young children. resources, circumstances and decisions will differ across the wide range of clinical settings occurring in southern africa and other developing countries. these serve as an update of guidelines published in this journal in 2001.1 the southern african journal of hiv medicine march 2006 2 5 age < 18 months mother hiv positivemother’s status unknown, child has features of symptomatic hiv positive negative child infected start co-trimoxazole prophylaxis if indicated child uninfected if child still breastfed, repeat hiv elisa 6 weeks after breastfeeding has stopped repeat hiv dna-pcr if child is asymptomatic hiv dna pcr positive hiv dna pcr positive hiv dna pcr negative hiv elisa positivehiv elisa negative child uninfected • stop co-trimoxazole prophylaxis • investigate for other cause of illness child hiv-infected. manage as per guidelines. • stop co-trimoxazole prophylaxis if not breastfeeding • child uninfected if breastfeeding stopped • if child still breastfeeding, repeat hiv dna pcr 6 weeks after breastfeeding cessation. or, if > 18 months repeat hiv elisa 6 weeks after stopping • infants less than 6 weeks of age presenting with clinical features suggestive of hiv infection should have an hiv-1 dna pcr test performed. infants with rapidly progressive disease require early initiation of antiretroviral therapy and may die if the pcr test is delayed. should this test be negative, a repeat test is recommended at or after 6 weeks of age. • any time clinical features are discordant with hiv test results, re-testing is indicated. • start co-trimoxazole prophylaxis if child is ≥ 6 weeks • perform hiv antibody test on mother (with consent), or • test child’s hiv elisa (with consent) if mother cannot be tested • do hiv pcr if ≥ 6 weeks of age • start co-trimoxazole prophylaxis age > 18 months hiv elisa test fig. 1. hiv infant testing algorithm (modification of the testing algorithm from the national department of health, national antiretroviral treatment guidelines, 1st ed., april 2004). based on recent antenatal hiv prevalence figures of 29.5%14 and assuming there are a million births per year in south africa, approximately 300 000 infants require access to early diagnosis. previously, protocols in resource-poor settings have recommended that infants be followed up for 1 year on cotrimoxazole prophylaxis from 6 weeks of age and then tested using hiv enzyme-linked immunosorbent assay (elisa) testing strategies at 12 months of age. the reality of this practice is illustrated by experience in johannesburg, south africa, where over 60% of infants were lost to follow-up by 6 weeks and 85% by 12 months of age during a 24-month period (october 2001 september 2003).15,16 the absence of a diagnosis, and the death of 40% of hiv-infected infants by 12 months of age, severely limits children’s access to comprehensive care.17 furthermore, a diagnostic algorithm incorporating a single hiv dna polymerase chain reaction (pcr) test at 6 weeks of age costs society less than one that uses an hiv elisa test at 12 months of age.18 much emphasis has been focused on choosing the appropriate technology to allow for timeous diagnosis. important considerations include: ■ sample volume ■ mode of specimen collection ■ required turnaround ■ laboratory technical skills, and ■ cost. recent work in johannesburg has confirmed the potential value of two diagnostic assays for early infant diagnosis of hiv: ■ roche hiv dna pcr assay version 1.5, and ■ the ultrasensitive heat-denatured p24 antigen quantitation assay.19 in summary, 627 non-breastfed hiv-exposed infants (58 hiv positive) had their hiv status determined according to centers for disease control (cdc) guidelines. a single hiv dna pcr using the roche amplicor assay version 1.5 at 6 weeks of age had a sensitivity of 98.8% and specificity of 99.4%.20 the use of the 6-week visit coincides with the first immunisation visit and thus fits in well with the continuum of care. the performance of the roche hiv dna pcr assay has been confirmed in other regions as summarised in table i. data on the second option, the ultrasensitive heat-denatured p24 antigen assay at 6 weeks, yielded satisfactory results in south africa with a sensitivity and specificity of 97.7% and 100% respectively when compared with hiv dna pcr testing.25 the performance of this assay for infant diagnosis has been confirmed in other studies and is summarised in table ii. in remote settings, difficulties have been experienced with sample collection and transport for infant diagnostic specimens. this has been overcome with the use of dried blood spots followed by extraction and the roche hiv dna pcr assay. the roche hiv dna version 1.5 pcr assay performed on unmodified filter paper at 6 weeks of age yielded an accurate diagnosis of hiv infection with a sensitivity and specificity of 100% and 99.6% respectively compared with pcr conducted on whole-blood samples.31 preliminary data suggest that dbs from capillary (e.g. heel prick) versus venous blood also yields highly accurate hiv dna pcr results (personal communication – g sherman). the ultrasensitive p24 ag assay has recently been modified for use on dried plasma32 and dried blood spots.33 in the south african context, owing to the sheer numbers of samples needing diagnosis, automated testing methodologies for assays such as the roche hiv dna pcr assay have been explored. to date the automation of the extraction method for this assay has been optimised using the roche magnapure analyser. when comparing this approach with the conventional whole-blood manual extraction method 100% concordance was noted (w stevens – personal communication). this method also reduced the number of equivocal results and internal control failures to 1 2% of samples run. preliminary data suggest that this method works well for dried blood spots using the magnapure lc dna isolation kit iii (w stevens – personal communication) and the data will be published shortly. definition of an hiv-1-uninfected infant/child a child should not be labelled as hiv positive simply if the mother is hiv positive; the correct terminology in this situation is hiv-exposed. an hiv-1-uninfected infant/child can be defined as an infant/ child with a negative hiv-1 serological or virological test region prevalent sensitivity reference subtype and specificity zimbabwe c 100%; 100% zijenah et al.21 tanzania a, c, d lyamuya et al.22 rwanda a 100%; 98% fischer et al.23 table i. summary of performance of roche amplicor hiv dna pcr assay version 1.5 in different subtypes region prevalent sensitivity reference subtype and specificity tanzania a, d 99%, 100% lyamuya et al.26 switzerland; b 97 98% sensivity/ nadal et al.;27 us 98 99% specificity respess et al.28 thailand and e 97 98% sensitivity/ sutthent et al.,29 cambodia 97 99% specificity nouhin et al.30 table ii. summary of performance of ultrasensitive heat-denatured p24 antigen quantitation assay for infant diagnosis of hiv march 2006 the southern african journal of hiv medicine26 where clinical features are not discordant. the following modifiers apply to age categories: ■ for children older than 18 months of age a negative hiv1 serological test based on the elisa method confirms absence of hiv-1 infection, provided that breastfeeding ceased at least 6 weeks before the first test. ■ for infants between 6 weeks and 18 months of age, one negative hiv dna pcr test result indicates non-infection provided that breastfeeding ceased at least 6 weeks before the test. confirmation of an infant’s hiv infection status using an hiv elisa test at 15 18 months can be done. hiv-1 diagnostic techniques are more difficult to interpret in infants and young children than in older children or adults because of the persistence of maternal antibodies up to 12 18 months of age. the hiv-1 dna pcr detects the integrated hiv virus dna (‘provirus’) into the genome of mononuclear cells, and is considered the test of choice for establishing the diagnosis of perinatally acquired hiv-1 infection.34 this pcr is a diagnostic qualitative reaction, distinct from the rna quantitative reaction (viral load test) used for the prognostic staging or clinical monitoring.35 the hiv-1 dna pcr is a rapid and accurate method for identification of hiv-1 infection in infants and young children under 18 months of age. currently the only assay with extensive validation in south africa is the roche amplicor dna assay version 1.5. however, pcr amplification is prone to contamination and testing should take place strictly according to the manufacturer’s instructions and only in areas dedicated for pcr work. hiv-1 dna pcr methods are considered reliable when standardised and performed in laboratories following good laboratory practices. these tests have been accurate for all known hiv-1 subtypes but ongoing molecular surveillance is necessary to confirm their performance for novel subtypes. ■ an hiv-1 dna pcr test should be performed on infants between 6 weeks and 18 months of age for diagnosis. if the hiv-1 dna pcr is positive infection is established, and if the infant is currently being breastfed this may be continued and the infant should receive prophylaxis for opportunistic infections such as pneumocystis jiroveci. ■ infants under 6 weeks of age presenting with clinical features suggestive of hiv infection should have an hiv-1 dna pcr test performed. infants with rapidly progressive disease require early initiation of antiretroviral therapy and may die if the pcr test is delayed. should this test be negative, a repeat test is recommended at or after 6 weeks of age ■ in infants over 18 months of age, a positive hiv elisa assay as per the national testing algorithm confirms diagnosis of hiv infection. ■ whenever clinical features are discordant with hiv test results, re-testing is indicated. determination of hiv infection in abandoned/orphaned infants ■ perform an hiv elisa to assess hiv exposure at birth if results for the mother are not available. if you have confirmation of a positive hiv elisa result for the mother this test may be omitted. ■ if hiv antibody assay for mother or infant is positive, perform an hiv dna pcr assay at 6 weeks. this may be repeated on a second sample at any stage to confirm the 6-week result and comply with the hiv testing requirements of adoption agencies. legislation regarding hiv testing in infants the final version of the bill is not yet available but will be shortly and posted at http://www.gov.za and called the children’s act. in summary, the following important information will be included: ■ informed consent to hiv testing may be obtained from a child aged 12 years or older without the assistance of the parents/caregivers provided the child is sufficiently mature to understand the implications of the test. if the child is under 12 years of age but is sufficiently mature to understand the implications of the test, consent may be obtained without the assistance of parents/caregivers. ■ if the child is under 12 years of age and cannot understand the implications of the test, and has no parents and caregivers, consent is to be obtained from the provincial head of social development. ■ if the child is under 12 years of age and not mature, options are as follows: ■ the child protection agency arranging the placement of the child can consent, or ■ the medical superintendent/person in charge of the hospital – if no parents/caregiver and no child protection agency is involved, or ■ the children’s court – if consent is being withheld (by anyone capable of giving consent, not just parents) or if child and parents are not able to give consent. ■ in the case of an abandoned child who has obviously been deserted by parent/s, legal guardian or caregiver or who has had no contact with parent/s, legal guardian or caregiver for 3 months for no apparent reason, a caregiver may give consent. a caregiver is defined as the individual who actually cares for a child and may include a foster parent, kinship carer, person who cares for a child in temporary safe care, head of shelter, child protection or youth agency, child or youth care worker who cares for a child without appropriate care in the community, and child who is head of a child-headed household. ■ consent to hiv testing also cannot be withheld unreasonably. definition of an hiv-1-infected infant/child and recommendations on the use of hiv tests the southern african journal of hiv medicine march 2006 2 7 march 2006 the southern african journal of hiv medicine other points to consider ■ in south africa, the quantitative hiv rna (viral load) test has not been validated as a diagnostic tool but should be reserved for assessing prognosis and further management of the patient. the reasons for this recommendation include the following: ■ workflow issues within local laboratories, and ■ delayed transport from remote areas causing deterioration of rna. ■ the measurement of hiv-1 p24 antigen in blood is sensitive enough for early diagnosis of hiv infection in infants and young children only if the ultrasensitive heatdenatured p24 antigen quantitation assay described by schupbach and colleagues. (ledergerber et al.19) is used. until a consistent reagent and buffer for this assay have been obtained, it should not be widely used. ■ whether to test all infants at 6 weeks of age or delay testing in breastfed infants until 6 weeks after breastfeeding has ceased, remains controversial. ■ the current national diagnostic algorithm recommends antibody tests after 18 months of age despite the fact that many uninfected infants serorevert (lose maternal hiv antibodies) between 9 and 12 months of age. it is reasonable to use hiv antibody tests earlier than 18 months of age provided health care workers understand that a positive hiv elisa test under 18 months of age may indicate hiv exposure and not hiv infection. references 1. weber lm, cotton m, stevens w. diagnosis of perinatal hiv-1 infection in south africa. southern african journal of hiv medicine 2001; issue 5, 21-26. 2. gray ge, mcintyre ja, jivkov b, violari a. preventing mother-to-child transmission of hiv-1 in south africa; recommendations for best practice. southern african journal of hiv medicine 2001; issue 4, 15-26. 3. davis sf, byers rh jun, et al. prevalence and incidence of vertically acquired hiv infection in the united states. jama 1995; 274: 952-955. 4. nielsen k, bryson yj. hiv/aids in infants, children and adolescents. paediatr clin north am 2000; 47 (1): 39-58. 5. dickover r, dillon m, leung km, et al. early prognostic indicators in primary perinatal hiv-1 infection: importance of viral rna and the timing of transmission on long-term outcome. j infect dis 1998; 178: 375-387. 6. dunn dt, newell ml, ades ae, peckham cs. risk of human immunodeficiency virus type 1 transmission through breastfeeding. lancet 1992; 340: 585-588. 7. ekpini er, wiktor sz, satten ga, et al. late postnatal mother-to-child transmission of hiv-1in abidjan, cote d’ivoire. lancet 1997; 349: 1054-1059. 8. palumbo pe, kwok s, waters s, et al. viral measurement by polymerase chain reaction-based assays in human immunodeficiency virus-infected infants. j pediatr 1995; 126: 592-595. 9. martin d, sim j. the laboratory diagnosis of hiv infection. s afr j med 2000; 90: 105-109. 10. daar es, little s, pitt j, et al. diagnosis of primary hiv infection. ann intern med 2001; 134: 25-29. 11. national department of health. national antiretroviral treatment guidelines. 1st ed., april 2004. http://www.doh.gov.za/docs/factsheets/guidelines/ artguide04-f.html (last accessed 23 february 2006). 12. varga, ca, sherman gg, maphosa j, jones sa. psychosocial consequences of early diagnosis of hiv status in vertically exposed infants in johannesburg, south africa. health care women int 2005; 26(5): 387-397. 13. newell ml, coovadia h, cortina-borja m, rollins n, gaillard p, dabis f; ghent international aids society (ias) working group on hiv infection in women and children. mortality of infected and uninfected infants born to hiv-infected mothers in africa: a pooled analysis. lancet 2004; 364(1): 1236-1243. 14. department of health, 2005. national hiv and syphilis antenatal seroprevalence survey in south africa 2004. www.doh.gov.za/docs/reports/2004/ hiv-syphilis.pdf (last accessed 23 february 2006). 15. sherman gg, jones sa, coovadia ah, urban mf, bolton kd. pmtct from research to reality – results from a routine service. s afr med j 2004; 94: 289292. 16. jones sa, sherman gg, varga ca. exploring socio-economic conditions and poor follow-up rates of hiv-exposed infants in johannesburg, south africa. aids care 2005; 17(4): 466-470. 17. jones sa, sherman gg, coovadia ah. can clinical algorithms deliver an accurate diagnosis of hiv infection in infancy? bull world health organ 2005; 83(7): 559-560. 18. sherman gg, matsebula tc, jones sa. is early hiv testing of infants in poorly resourced prevention of mother to child transmission programmes unaffordable? trop med int health 2005; 10: 1108-1113. 19. ledergerber b, flepp m, boni j, et al. hiv-1 p24 concentration measured by boosted elisa of heat-denatured plasma correlates with decline in cd4 cells, progression to aids, and survival: comparison with viral rna measurement. j infect dis 2000; 181: 1280-1288. 20. sherman gg, cooper pa, coovadia ah, et al. polymerase chain reaction for diagnosis of hiv infection in infancy in low resource settings. pediatr infect dis j 2006; 24: 993-997. 21. zijenah ls, humphrey j, nathoo k, et al. evaluation of the prototype roche dna amplification kit incorporating the new ssk145 and skcc1b primers in detection of human immunodeficiency virus type 1 dna in zimbabwe. j clin microbiol 1999; 37(11): 3569-3571. 22. lyamuya e, olausson-hansson e, albert j, mhalu f, biberfeld g. evaluation of a prototype amplicor pcr assay for detection of human immunodeficiency virus type 1 dna in blood samples from tanzanian adults infected with hiv-1 subtypes a, c and d. j clin virol 2000; 17(1): 57-63. 23. fischer a, lejczak c, lambert c, et al. simple dna extraction method for dried blood spots and comparison of two pcr assays for diagnosis of vertical human immunodeficiency virus type 1 transmission in rwanda. j clin microbiol 2004; 42(1): 16-20. 24. sherman gg, stevens ws, stevens g, galpin js. diagnosis of human immunodeficiency virus infection in perinatally exposed orphaned infants in a resource poor setting. pediatr infect dis j 2000; 19: 1014-1015. 25. sherman g, stevens g, stevens w. affordable diagnosis of human immunodeficiency virus infection by p24 antigen detection. j pediatr infect dis 2004; 23: 173-176. 26. lyamuya e, bredberg-raden u, massawe a, et al. performance of a modified hiv-1 p24 antigen assay for early diagnosis of hiv-1 infection in infants and prediction of mother-to-infant transmission of hiv-1 in dar es salaam, tanzania. jaids 1996; 12: 421-426. 27. nadal d, boni j, kind c, et al. prospective evaluation of amplification-boosted elisa for heat-denatured p24 antigen for diagnosis and monitoring of pediatric hiv-1 infections. j infect dis 1999; 180: 1089-1095. 28. respess r, cachafeiro a, fiscus s, et al. evaluation of a commercially available ultrasensitive p24 antigen (upta) viral load assay in samples from patients infected with genetically diverse hiv-1 from different geographic settings. 10th conference on retroviruses and opportunistic infections, boston, 10-14 february 2003. abstract 669. 29. sutthent r, gaudart n, chokpaibulkit k, tanliang n, kanoksinsombath c, chaisilwatana p. p24 antigen detection assay modified with a booster step for diagnosis and monitoring of hiv-1 infection. j clin microbiol 2003; 41: 10161022. 30. nouhin j, nguyen m, reynes jm, henin y. evaluation of p24 ultrasensitive assay for the diagnosis of hiv-exposed infants. abstract weppb2057. 15th international aids conference, bangkok, thailand, 11-16 july 2004. 31. sherman g, stevens g, jones s, horsfield p, stevens w. dried blood spots for hiv diagnosis of infants: improving access to care for hiv affected infants in low resource settings. j aids 2006 (in press). 32. de baets aj, edidi bs, kasali mj, et al. pediatric human immunodeficiency virus screening in an african district hospital. clin diagn lab immunol 2005; 12(1): 86-92. 33. patton j, sherman gg, coovadia ah, stevens ws, meyers tm. ultrasensitive human immunodeficiency virus 1 p24 antigen type assay modified for use on dried whole-blood spots as a reliable, affordable test for infant diagnosis. clinical and vaccine immunology 2006; 13: 152-155. 34. martin d, sim j. the laboratory diagnosis of hiv infection. s afr j med 2000; 90: 105-109. 35. kuritzkes dr. clinical application of virus load monitoring and resistance assays. in: armstrong d, cohen j, eds. infectious disease. london: harcourt, 1999. 28 abstract introduction patients and methods ethical consideration results illustrative cases discussion conclusion acknowledgements references about the author(s) ahmed i. bhigjee department of neurology, nelson r mandela school of medicine, university of kwazulu-natal, south africa anandan a. moodley department of neurology, greys hospital, pietermaritzburg, south africa department of neurology, university of kwazulu-natal, south africa izanne roos department of neurology, inkosi albert luthuli central hospital, university of kwazulu-natal, south africa cait-lynn wells department of neurology, nelson r. mandela school of medicine, university of kwazulu-natal, south africa pratistadevi ramdial department of anatomical pathology, nhls, inkosi albert luthuli central hospital, south africa monika esser immunology unit, nhls tygerberg, tygerberg hospital, south africa citation bhigjee ai, moodley aa. the neuromyelitis optica presentation and the aquaporin-4 antibody in hiv-seropositive and seronegative patients in kwazulu-natal, south africa. s afr j hiv med. 2017;18(1), a684. https://doi.org/10.4102/sajhivmed.v18i1.684 original research the neuromyelitis optica presentation and the aquaporin-4 antibody in hiv-seropositive and seronegative patients in kwazulu-natal, south africa ahmed i. bhigjee, anandan a. moodley, izanne roos, cait-lynn wells, pratistadevi ramdial, monika esser received: 30 aug. 2016; accepted: 14 nov. 2016; published: 31 jan. 2017 copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the association of the anti-aquaporin-4 (aqp-4) water channel antibody with neuromyelitis optica (nmo) syndrome has been described from various parts of the world. there has been no large study describing this association from southern africa, an hiv endemic area. hiv patients often present with visual disturbance or features of a myelopathy but seldom both either simultaneously or consecutively. we report our experience of nmo in the era of aqp-4 testing in hiv-positive and hiv-negative patients seen in kwazulu-natal, south africa. methods: a retrospective chart review was undertaken of nmo cases seen from january 2005 to april 2016 in two neurology units serving a population of 7.1 million adults. the clinical, radiological and relevant laboratory data were extracted from the files and analysed. results: there were 12 hiv-positive patients (mean age 33 years), 9 (75%) were women and all 12 were black patients. of the 17 hiv-negative patients (mean age 32 years), 15 (88%) were women and 10 (59%) were black people. the clinical features in the two groups ranged from isolated optic neuritis, isolated longitudinally extensive myelitis or combinations. recurrent attacks were noted in six hiv-positive patients and six hiv-negative patients. the aqp-4 antibody was positive in 4/10 (40%) hiv-positive patients and 11/13 (85%) hiv-negative patients. the radiological changes ranged from longitudinal hyperintense spinal cord lesions and long segment enhancing lesions of the optic nerves. three patients, all hiv-positive, had tumefactive lesions with incomplete ring enhancement. conclusion: this study confirms the presence of aqp-4-positive nmo in southern africa in both hiv-positive and hiv-negative patients. the simultaneous or consecutive occurrence of optic neuritis and myelitis in an hiv-positive patient should alert the clinician to test for the aqp-4 antibody. it is important to recognise this clinical syndrome as specific therapy is available. we further postulate that hiv itself may act as a trigger for an autoimmune process. introduction neuromyelitis optica (nmo) or devic’s disease is a central nervous system inflammatory disorder originally described as a monophasic illness but recurrent cases have been noted.1 nmo has been described in different ethnic and racial groups worldwide.2 one of earliest reported cases of nmo in south africa was by hift and moodley.3 cosnett speculated that nmo might be a variant of multiple sclerosis (ms) in black people.4 dean et al. in describing ms in black south africans and zimbabweans clearly included cases of nmo in their case series.5 a link between nmo and pulmonary tuberculosis was suggested in 1990 and more recently in 2014.6,7 modi et al. recognised the opticospinal presentation as a distinct disorder in black patients.8 a recent global study reported that the prevalence of nmo in south africa is 5/100 000, which together with paraguay is the highest in the world.9 in 1991, wingerchuk et al. studied the clinical course of nmo of 71 patients and devised a set of criteria for a more accurate diagnosis of nmo.10 hiv-positive patients commonly present with visual disturbance or myelopathy, but seldom both either simultaneously or consecutively. when we see this combination, we consider the possibility of nmo. we, therefore, undertook a retrospective analysis of all nmo cases seen in the neurology units based at inkosi albert luthuli central hospital in durban and greys hospital in pietermaritzburg from january 2005 to april 2016. the two units serve an adult population (over the age of 15 years) of approximately 7.1 million in kwazulu-natal.11 patients and methods the records of patients with the diagnosis of nmo were reviewed from each hospital’s repository. for each patient the clinical, laboratory and radiological data were extracted and entered into an excel spreadsheet. although a number of laboratory tests were performed on each patient, the focus was on the following tests: hiv and human t-lymphotropic virus 1 (htlv-1) antibodies, rapid plasma reagin (rpr), anti-nuclear factor (anf), serum aqp-4 antibody, serum angiotensin converting enzyme (sace), routine csf chemistry and cell count, csf microscopy, culture and pcr for tuberculosis, csf fluorescent treponemal assay (fta) and oligoclonal bands in the csf. in the hiv-positive patients, the csf was tested for cryptococcal antigen, together with pcr for varicella zoster (vzv), herpes simplex (hsv), cytomegalovirus (cmv) and enteroviruses. the cd4 count and viral load were also included where available. the mri scans were reviewed for spinal and brain lesions by ahmed i. bhigjee and anandan a. moodley. the aqp-4 antibody test was performed by a private laboratory in three cases but the rest were performed at a national health laboratory in the western cape. the cell-based euroimmun ag (lübeck, germany) assay was used at both centres. this test has a claimed sensitivity and specificity of 80% and 100%, respectively (euroimmun ag package insert). ethical consideration the study was approved by the biomedical research ethics committee of the university of kwazulu-natal. results a total of 12 hiv-positive patients and 17 hiv-negative patients were identified. their demographic details are summarised in table 1. table 1: demographic data. in the hiv-positive group, 9/12 (75%) were women. the age range varied from 19 to 42 years (mean ± sd 33 + 9.7). all patients were black people. the duration of illness at the time of first presentation varied from 2 weeks to 2 years in 11 patients and not stated in one. the first presentation was visual impairment in six, spinal in five and not stated in one. recurrent attacks were noted in six patients. in the hiv-negative group, 15/17 (88%) were women. the age range varied from 17 to 58 years (mean ± sd 33 ± 10.3). there were ten black patients, five indians and two patients of mixed ancestry. the duration of illness at the time of first presentation varied from 5 days to 14 years. the first presentation was visual impairment in six and spinal in the rest. recurrent attacks were recorded in six patients. routine laboratory tests were unhelpful in both groups of patients except for other autoantibodies. the more relevant laboratory results are summarised in table 2. in the hiv-positive group, one patient has a positive anf at a titre of 1:2560 with positive anti-dsdna. in the hiv-negative group, four had a positive anf with titres ranging from 1:50 to 1:640. two had a positive anti-ro antibody as well. there was a third patient who was anf-negative but anti-ro positive. one patient had anti-gad antibodies and another patient was anti-ma2 antibody positive. none of the anf-positive patients exhibited any clinical features of systemic lupus erythematosus (sle). in the hiv-positive group, the anti-aqp-4 antibody test was performed in ten, four of whom returned a positive result. htlv-1 antibodies were not detected in any of the 10 patients tested. oligoclonal bands were absent in all six patients who were tested. table 2: laboratory data. in the hiv-negative group, of the 13 patients in whom the test was performed, 11 (85%) had anti-aqp-4 antibodies. six of these eleven aqp-4 antibody positive cases had recurrent attacks. three of the patients in whom the test was not performed were seen at a time when the test was not available to us. one of these patients, a 53-year-old black woman, was htlv-1 positive. oligoclonal bands were absent in all 10 patients who had the results of this test available. the neuro-imaging findings are summarised in table 3. table 3: neuro-imaging findings. the mri features ranged from typical caudal medulla to upper cervical hyperintensity (figure 1a–c), thoracic longitudinally extensive transverse myelopathy (letm), cord atrophy and long segment enhancement of the optic nerve. for example, figure 2a and b shows intense enhancement of the right optic nerve extending to the chiasm. there was minimal enhancement of the left optic nerve. figure 1: (a) and (b) are t2 sagittal images showing high intensity signal in the lower medulla and upper cervical cord; (c) is post-contrast t1 image showing enhancement of the lesion; (d) is a chest radiograph showing features consistent with tuberculosis. figure 2: a) and (b) are orbital mri views post-contrast. they show diffuse enhancement of the right optic nerve extending to the chiasm (arrows). minimal enhancement of the left optic nerve is also present (right arrow in (b)). in the hiv-positive group, three of the brain mri scans showed tumefactive lesions (e.g. figure 3a and b). in none of these patients was there fever or specific cerebral symptoms such as confusion and seizures to suggest a diagnosis of acute disseminated encephalomyelitis. figure 3: images from an hiv-positive patient (a) and (b) are t2 and t1 post-contrast images of the brain, respectively, showing tumefactive lesions. figure (c) and (d) are corresponding images of the spinal cord. illustrative cases case 1 (hiv-negative) a 55-year-old woman of mixed ancestry presented in march 2011 with a 3-month history of acute onset of nausea, vomiting, diplopia and incoordination of her limbs. examination revealed normal visual acuity and optic fundi. the tone, power and tendon reflexes were normal. joint position sense was impaired at the toes, vibration sense was abnormal up to the anterior superior iliac spine and there was patchy pinprick sensory loss in the legs. there was bilateral horizontal gaze evoked nystagmus and incoordination of all four limbs. the mri showed an irregular hyperintense lesion from the medulla to the c3 vertebral level (figure 1a). there was minimal enhancement of the lesion. the csf was acellular with a protein of 0.54 g/l and a glucose level of 3.3 mmol/l. oligoclonal bands were not detected in the csf. whilst in the ward, the patient spontaneously started to improve. no treatment was instituted. when reviewed 4 months later, she was much better and ambulant with mild disability, and a repeat mri showed shrinkage of the medullary cervical lesion. she presented again in april 2014 with acute worsening of her incoordination and loss of sensation in the right hand. examination revealed marked bilateral incoordination, normal tone and power but depressed tendon jerks in the right arm and knee. a repeat mri showed worsening of the cervico-medullary lesion with extension now down to the c6 vertebral level (figure 1b). enhancement was present (figure 1c). a repeat csf was again not helpful. serum ace was normal. hiv test was negative. the anf was positive 1:640 with a speckled pattern. the double-stranded anti-dna and anti-ena were negative. the aqp-4 antibody was negative. a chest radiograph showed cavitatory lesion in both lung fields. (figure 1d). the genexpert test on a bronchial aspirate was positive for mycobacterium tuberculosis. the patient was started on antituberculous therapy and given a 5-day course of 500 mg intravenous methylprednisolone followed by oral prednisone. the patient improved. at follow-up, she maintained her improvement. in december 2014, she was admitted quadriplegic, pyrexial and in respiratory distress. klebsiella pneumoniae was isolated from a bronchial aspirate. the aqp-4 antibody was now positive. the patient was intubated, ventilated and given appropriate antibiotics but died soon thereafter. case 2 (hiv-positive) a 40-year-old hiv-seropositive woman on antiretroviral therapy presented in 2016 with weakness of the arms, shock-like pain in the limbs and cramps in the legs for about 3 months. in 2014, she had an episode of left-sided weakness which partially resolved. she had no visual symptoms. on examination, her mental state and cranial nerves were normal. the visual acuity in both eyes was normal. power in the right arm and leg was normal. on the left side, there was a 4/5 weakness in a pyramidal distribution. the tendon reflexes were brisker on the left. the abdominal reflexes were absent and both plantar responses were equivocal. the outstretched arms demonstrated ‘piano playing’ with gross proprioceptive loss. there was patchy pinprick impairment in the limbs. there were no features to suggest sle. routine blood tests were normal apart from mildly deranged liver enzymes and an anf titre of 1:2560. the cd4 count was 712 cells/µl. the aqp-4 antibody was positive. the mri of the spine showed a hyperintense signal extending from the caudal medulla to c7. in the axial slices, the hyperintensity was posteriorly located. the mri of the brain was normal. the csf was acellular, with a glucose level of 3.5 mmol/l and protein level of 0.36 g/l. the pcr for viruses was negative. other tests that were negative in the csf included smear, genexpert and culture for tuberculosis, cryptococcal antigen and the csf fta. the patient was commenced on prednisone and azathioprine and was due for a follow-up appointment. discussion hiv-seropositive group there were 12 hiv-seropositive patients who had a nmo presentation. the anti-aqp-4 antibody was positive in 4 of 10 patients tested. there have been isolated reports of hiv and nmo presentations, summarised in table 4. table 4: literature survey of neuromyelitic presentation in hiv-seropositive patients. although visual disturbance in hiv infection is common, the underlying cause is usually an opportunistic infection. examples include cmv, hsv, vzv, toxoplasmosis, syphilis, cryptococcal and candida infection. in all these cases, the underlying problem is a neuroretinitis or uveoretinitis. isolated optic neuritis or optic neuropathy is rare.16,17,18 some have been shown to respond to steroids or highly active anti-retroviral therapy (haart).16,17,18 yet others may develop optic neuropathy whilst on haart especially stavudine and didanosine. in these instances, it is believed that haart unmasks leber’s hereditary optic neuropathy.19 in contrast, the optic neuritis in the nmo cases is usually severe, does not respond to haart or may partially respond to steroids. similarly, the cause of an letm in an hiv-seropositive patient is usually an opportunistic infection. examples include herpes virus infection, tuberculosis, syphilis and htlv-1.20 hiv itself may cause a transverse (short segment) partial myelopathy at seroconversion and the well-documented vacuolar myelopathy. letm, if it does occur, must be a very rare manifestation of hiv itself. it follows then that the co-occurrence of optic neuritis and ltem because of hiv itself is unlikely. there are several possible explanations for the nmo presentation in hiv-positive patients. because of high hiv prevalence in the population, the patients may have anti-aqp-4-related nmo and incidental hiv infection. the four aqp-4-positive patients we describe above may fall into this category. yet others may have the same autoimmune-related nmo but maybe seronegative for aqp-4 antibody, as the test has a variable sensitivity of 70% – 80%.21,22 some of the patients may have the uncommon anti-myelin oligodendrocyte glycoprotein (mog)-mediated disease which presents in a similar manner. we did not test for this antibody. another postulate is that hiv acts as a trigger for the autoimmune process. this has been seen with pulmonary tuberculosis6,7 and antecedent or recent viral infections.10,23,24 hiv-seronegative group all 17 patients fulfilled the nmo diagnostic criteria for adult patients25 and none had the imaging ‘red flags’ suggestive of ms.25 further, ms is rare in black subjects. the clinical course in this group of patients was typical and recurrent attacks were noted in 6 of the 17 patients. anti-aqp-4 antibodies were detected in 11 of 13 patients tested. four of these patients were noted to have recurrent attacks, and six had a monophasic illness at the time of the last follow-up. the two anti-aqp-4 antibody-negative patients were a man who developed a testicular tumour and a woman who had recurrent attacks. anti-mog antibody testing was not available.26 a 53-year-old woman who did not have an anti-aqp-4 antibody test was seropositive for htlv-1. this must be a very rare presentation as we could find only one report, and in our experience of over 200 cases of htlv-1-associated myelopathy, we have not had a single patient with an opticospinal presentation.27 nmo as a paraneoplastic presentation following the discovery of the anti-aqp-4 antibody, pittock et al. identified a thymic carcinoma in an nmo patient.28 a subsequent review by the mayo group found an association between nmo and a variety of other malignancies including breast, bronchus, thyroid, carcinoid and lymphoma.29 the indian man in our series presented with nmo first and became aware of a testicular mass about 17 months later. the anti-aqp-4 antibody test performed at the time of his neurological presentation was negative. the neurological deficits improved on steroids and azathioprine. he underwent orchidectomy and chemotherapy and currently has no evidence of tumour. his anti-ma2 antibody test was positive. an underlying malignancy should be considered in any patient with an unexplained nmo presentation. conclusion our study has all the limitations of a retrospective analysis, the most important being that of missing data. it does not have long-term follow-up on some of the patients. thus, we cannot be certain whether each had a monophasic or recurrent illness. we did not test for anti-mog antibodies which occurs in some nmo patients who are negative for anti-aqp-4 antibodies.26 nonetheless, this study is probably the largest one to emerge from africa in the hiv era where anti-aqp-4 testing is available. recognition of the nmo presentation is important as patients respond to immunosuppressant and immunomodulatory therapy. ongoing therapy is also necessary to prevent recurrent attacks. acknowledgements competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions a.i.b. was responsible for concept, design, acquisition and interpretation of data, and drafting of the manuscript. a.a.m. undertook acquisition of data and review of the manuscript. i.r. undertook acquisition and interpretation of data and statistical analysis. c.d.w. undertook acquisition of data. p.k.r. undertook acquisition of data and critical review of the manuscript. m.e. undertook acquisition of data and critical review of the manuscript. references jarius s, wildemann b. the history of neuromyelitis optica. j neuroinflammation. 2013;10:8. http://dx.doi.org/10.1186/1742-2094-10-8 pandit l, asgari n, apiwattanakul m, et al. demographic and clinical features of neuromyelitis optica: a review. mult scler j. 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http://dx.doi.org/10.1016/j.clineuro.2013.03.007 feyissa am, singh p, smith rg. neuromyelitis optica in patients with co-existing human immunodeficiency virus infection. mult sclerj. 2013;19(10):1363–1366. http://dx.doi.org/10.1177/1352458513483891 sweeney bj, manji h, gilson rj, harrison mj. optic neuritis and hiv-1 infection. j neurol neurosurg psychiatry. 1993;56:705–707. http://dx.doi.org/10.1136/jnnp.56.6.705 babu k, murthy k, rajagopalan n, satish b. vision recovery in human immunodeficiency virus-infected patients with optic neuropathy treated with highly active antiretroviral therapy: a case series. indian j ophthalmol. 2009;57:515–518. http://dx.doi.org/10.4103/0301-4738.53062 burton bjl, leff ap, plant gt. steroid-responsive hiv optic neuropathy. j neuroophthalmol. 1998;18:25–29. http://dx.doi.org/10.1097/00041327-199803000-00006 moodley a, bhola s, omar f, mogambery j. antiretroviral therapy-induced leber’s hereditary optic neuropathy. s afr j hiv med. 2014;5(2):69–71. http://dx.doi.org/10.7196/sajhivmed.1056 bhigjee ai, madura s, bill pla, et al. spectrum of myelopathies in hiv seropositive south african patients. neurology. 2001;57(2):348–351. http://dx.doi.org/10.1212/wnl.57.2.348 paul f, jarius s, aktas o, et al. antibody to aquaporin 4 in the diagnosis of neuromyelitis optica. plos med. 2007;4:e133. http://dx.doi.org/10.1371/journal.pmed.0040133 kang es, min j-h, lee kh, kim bj. clinical usefulness of cell-based indirect immunofluorescence assay for the detection of aquaporin-4 antibodies in neuromyelitis optica spectrum disorder. ann lab med. 2012;32:331–338. http://dx.doi.org/10.3343/alm.2012.32.5.331 ghezzi a, bergamaschi r, martinelli v, et al. clinical characteristics, course and prognosis of relapsing devic’s neuromyelitis optica. j neurol. 2004;251:47–52. http://dx.doi.org/10.1007/s00415-004-0271-0 koga m, takahashi t, kawai m, et al. a serological analysis of viral and bacterial infections associated with neuromyelitis optica. j neurol 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http://dx.doi.org/10.1001/archneur.65.5.629 abstract case discussion strategies to improve hypoxaemia acknowledgements references about the author(s) gladness nethathe intensive care unit, chris hani baragwanath academic hospital, south africa nirav patel department of pediatric surgery, university of the witwatersrand, south africa citation nethathe g, patel n. survival after pneumocystis jirovecii pneumonia requiring ventilation: a case report. s afr j hiv med. 2016;17(1), a474. http://dx.doi.org/10.4102/sajhivmed.v17i1.474 case report survival after pneumocystis jirovecii pneumonia requiring ventilation: a case report gladness nethathe, nirav patel received: 23 mar. 2016; accepted: 05 sept. 2016; published: 31 oct. 2016 copyright: © 2016. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract pneumocystis pneumonia (pcp) in patients with the human immunodeficiency virus (hiv) is associated with a high mortality rate, which increases substantially with the need for mechanical ventilation. local experience of patients with pcp admitted to the intensive care unit has revealed mortality rates close to 100%. we present a case of a 39-year-old hiv-infected man diagnosed with pcp who was successfully weaned from mechanical ventilation after presenting with respiratory distress and severe hypoxaemia. a short review of the literature will also be presented. case a 39-year-old man presented to the emergency department complaining of a 3-day history of shortness of breath and dry cough. he had no known significant co-morbidities and did not report any further associated symptoms. he reported that he was treated with antibiotics for a lower respiratory tract infection (lrti) by a private physician in the previous 3 days with no improvement in symptoms. he was unsure of his hiv status and was not on antiretroviral therapy (art). his admission vitals were a blood pressure of 123/70 (82) mmhg, heart rate of 116 beats per minute, respiratory rate of 30 breaths per minute and a temperature of 36.9 °c. on examination, he had no significant lymphadenopathy and was not found to have mucosal or skin lesions associated with advanced hiv. no other obvious stigmata of advanced hiv were noted. he was in severe respiratory distress with scattered bilateral predominantly basal crackles on auscultation. wheezing was not present on auscultation. he had an oxygen saturation of 62% on a partial rebreather mask with an inspired oxygen fraction (fio2) of 80%. laboratory investigations revealed a white cell count (wcc) of 14.5 × 109 cells/l, haemoglobin (hb) of 11.6 g/l, platelets of 298 × 109 cells/l, urea of 6.3 mmol/l, creatinine of 108 μmol/l, c-reactive protein (crp) of 102 mg/l and beta-d-glucan (bdg) of > 500 pg/ml. his admission blood gas showed a mixed respiratory and metabolic acidosis with type ii respiratory failure and a markedly increased alveolar-arterial gradient (ph = 7.36, pco2 = 34.7, po2 = 64.8, hco3 = 19.2, be = -4.9, spo2 = 96.9, hb = 13.4, lac = 4.4). his chest x-ray (cxr) showed diffuse bilateral alveolar infiltrates and granular opacities. a transthoracic echocardiogram performed at the time of admission showed normal left ventricular function, no evidence of pulmonary embolus and normal heart valves. based on clinical suspicion, hypoxaemic respiratory failure with typical chest radiograph changes, the patient’s normal echocardiogram, elevated bdg, and the relative absence of clinical signs usually associated with a multilobar pneumonia, the diagnosis of pneumocystis pneumonia (pcp) was considered. on the basis of his clinical condition and investigations, the patient was intubated, ventilated and admitted to the intensive care unit (icu) for respiratory support. he was empirically started on treatment for partially treated community acquired pneumonia (cap) (piperacillin and tazobactam and a macrolide) as well as pcp, on the basis of clinical case definition as suggested by the world health organisation (who), with high-dose intravenous trimethoprim-sulfamethoxazole (tmp-smx) and high-dose intravenous corticosteroids (hydrocortisone). he consented to hiv testing on admission and was found to be hiv-infected with a cd4 count of 7 cells/μl. additional sputum and blood investigations for mycobacterium tuberculosis (tb) including tb culture (sputum and blood) and auramine o stain, real-time polymerase chain reaction (pcr) (tb genexpert), sputum gram stain and bacterial culture and direct fluorescence antigen test for pcp were negative. standard aerobic and anaerobic blood cultures yielded no pathogenic organisms. the patient was intubated and ventilated for 3 days and spent a week in our unit. during this period, we adopted a lung protective ventilation strategy, permissive hypoxaemia as well as meticulous fluid management. through his week-long admission, he had a cumulative fluid balance of -332 ml. initial pre-admission ventilator settings of fio2 = 1, peep = 14 and δp = 8 were successfully weaned to fio2 = 0.6, peep = 10 and δp = 10 on day one of admission. we accepted oxygen saturations in the region of 70%–80% and pao2 measurements in the region of 50 mmhg – 60 mmhg whilst maintaining tidal volumes of 4 ml/kg – 6 ml/kg. on day four of admission, despite oxygen saturations in the region of 80%, the patient was successfully extubated and placed on non-invasive ventilation (niv). he required niv (positive end expiratory pressure of 6 cm h2o and pressure support of 6 cm h2o) for a total of 3 days before being weaned onto oxygen supplementation with an fio2 of 0.4. he maintained oxygen saturations in the region of 85%–90%. he was discharged to the ward on nasal cannula after a 7-day icu stay. discussion literature search a pubmed search was conducted to identify english language studies that have evaluated the icu management of hiv-infected patients with pcp. search terms used were ‘pneumocystis pneumonia and intensive care management and pcp and ventilatory management and hiv’. we additionally searched in the reference lists of relevant articles to identify further relevant literature. pcp, once considered rare in africa, is one of the most common opportunistic infections found in patients infected with hiv in developing countries.1,2,3,4 the prevalence of the disease in sub-saharan african adults varies widely in clinical studies3 with more recent reports suggesting a high rate of clinical disease in african children.5,6 hospital survival in hiv-infected adult patients with pcp ranges from 10% to 90%.7,8 the organism is classified as an opportunistic fungal pathogen of the genus pneumocystis sp. it is an atypical fungus as it has a cell wall that contains cholesterol instead of ergosterol and does not grow in fungal culture.9 it exists in three forms, namely pre-cystic, cystic and trophic.10 of the four species of pneumocystis, pneumocystis jirovecii is thought to be pathogenic only in humans, although p. jirovecii cannot be cultured in vitro.11 the acronym pcp is still used to refer to the clinical manifestation of the disease (pcp). prior to the advent of hiv and/or aids pcp was usually only seen in immunosuppressed adults with malignancies or on corticosteroid therapy. more recently, the incidence of pcp has declined in developed countries as a result of widespread use of pcp prophylaxis and art.12,13 in hiv-infected patients, the risk factors associated with p. jirovecii infection are cd4+ cell depletion as evidenced by cd4+ t-lymphocyte cell count < 200 cells/μl (200 × 106 per l), previous p. jirovecii infection and other aids-defining illness.14 pathogenesis and clinical presentation pcp typically presents as a non-productive cough, shortness of breath, fever and hypoxaemic respiratory failure with radiographic changes of alveolar infiltrates. this said, pcp may also present as a lobar pneumonia on chest radiography with few features of systemic inflammation. after inhalation, the organism attaches to type one alveolar cells resulting in injury to the alveolar epithelium.15 this attachment and the release of degradative enzymes from the pathogen is thought to play a role in initial alveolar damage.16 initial damage to the epithelium results in an increase in alveolar capillary membrane permeability, which is in turn associated with an influx of inflammatory mediators such as neutrophils. neutrophil-mediated mechanisms, such as the production of reactive oxygen species (ros) (superoxide and hydrogen peroxide) and non-oxidative mechanisms, have been implicated in the pathogenesis of lung injury in pcp. ultimately, pcp infection results in the production of an eosinophilic infiltrate, which fills the alveoli leading to impairment in oxygenation and resultant hypoxaemia, interstitial thickening and eventual fibrosis.17,18 increasing experimental and clinical evidence supports the idea that lung damage occurring during pcp is the result of the type and extent of the host-mediated inflammatory response to infection rather than direct damage by the organism. of particular note is the controversy surrounding the role of neutrophils and ros in the inflammation and subsequent fibrosis observed in patients with pcp. observations from human studies are that the severity of the disease correlates with the number of neutrophils in samples obtained through bronchoalveolar lavage (bal) in both hiv-infected and non-hiv-infected patients with pcp.19,20 however, there is evidence to suggest that although neutrophils as well as their ros are correlative markers of lung damage during pneumocystis infection, they do not necessarily contribute to tissue damage.21 the clinical manifestation of the disease differs in immunosuppression from hiv compared to that from patients with other immunosuppressive conditions such as haematological malignancies.22 pcp in hiv-infected patients occurs at a time of profound immunosuppression from cd4+ t-cell depletion, whereas in patients receiving chemotherapy pcp typically occurs during the maintenance phase.23 the ability of patients without hiv-related illness or disease to mount an immune response may be associated with an exacerbated inflammatory response.24 diagnosis the gold standard for diagnosing pcp is bronchoscopy with bal and microscopic visualisation of the organism’s cystic or trophic forms using immunohistochemical stains.25 p. jirovecii cannot be cultured. pcp pcr assays are available and can be used in combination with bal as well as on oral sputum or oral wash.26,27,28,29 although p. jirovecii pcr sensitivity is reportedly high, it is non-specific as p. jirovecii colonisation or subclinical carriage is common.11 the use of biomarkers such as the bdg assay, a component of the cell wall of a number of medically important fungi, has also gained recent interest.25 in a study by desmet et al.,30 bdg reactivity tested in serum samples from 28 patients with pneumocystis jirovecii pneumonia (pcp) and 28 controls showed a sensitivity and specificity of bdg detection of 100% and 96.4%, respectively, using a cut-off value of 100 pg/ml. a limitation of this assay is that other fungal diseases may result in significantly raised levels.30 a negative serum bdg in hiv patients has been suggested as sufficient to rule out pcp.31 other differentials that should be considered and excluded in this setting include mycobacterial infection (tuberculous and non-tuberculous), viral infections, toxoplasmosis and kaposi’s sarcoma. therapeutic options treatment for pcp should be started empirically if there is a high clinical suspicion. confirmation of the diagnosis may be limited by factors such as availability of diagnostic tests. in such cases, the response to therapy may be used to guide management. trimethoprim and sulfamethoxazole (tmp-smx) is the treatment of choice for pcp as well as adjunctive corticosteroids for patients who present with hypoxaemia (pao2 < 70 mmhg).32 the breakdown and clearance of the microbe may result in a severe inflammatory response in the lungs. corticosteroid therapy has been shown to blunt this response and improve oxygenation.33 the widespread use of tmp-smx prophylaxis allows for the possibility of resistance to sulphur drugs owing to mutations of the pneumocystis dihydropteroate synthase gene. these mutations have been identified in up to 56% of p. jirovecii strains identified in south africa.14 the clinical significance of this is unclear, and it is an area of debate whether this should alter pharmacological therapy.34,35 clindamycin plus primaquine, atovaquone, pentamidine and trimetrexate are other effective options that may also be used.36,37 p. jirovecii is highly resistant to standard antifungal therapy such as azoles and amphotericin b because of the lack of ergosterol biosynthesis.37 echinocandins, however, have activity against the cyst forms of the fungus as they target glucan synthesis in these fungal forms. glucan presence is low in the trophic forms of the fungus.38 the trophic form is the predominant form during an infection. the use of art is associated with decreased mortality in hiv-infected patients with pcp.39,40 our patient was not on art at the time of presentation. strategies to improve hypoxaemia changes in the ventilatory and non-ventilatory management of patients with acute respiratory distress syndrome (ards) have improved survival in the last few decades. the use of lower tidal volumes and higher levels of positive end expiratory pressure in conjunction with other ventilatory (such as permissive hypercapnoea) and non-ventilatory strategies (such as fluid restriction) saw survival from ards improve from approximately 40% in 1991 to 60% in 1993 in developed regions.41 patients with pcp-associated ards who require ventilation should be ventilated according to the ards network guidelines using low tidal volumes and plateau pressures. the use of high flow nasal oxygen is emerging with new clinical applications and may provide an alternate method of oxygenation to niv in this group of patients.42 its use specifically in the management of hypoxaemia from pcp has not been adequately studied and was also not an available option in our unit at the time. in patients with pcp, the prognosis is poor if ventilation is required, with a mortality rate that ranges from 40% to 100%.40,41 early extubation may minimise superinfection, ventilator-associated pneumonia and other deleterious effects of intubation. the employment of permissive hypoxaemia may be prudent to minimise oxygen toxicity. lower mortality rates of patients with pcp admitted to the icu with respiratory failure are noted in patients from developed regions though this may be due to differing admission criteria.11,39,40 the use of non-invasive mechanical ventilation as an alternative to endotracheal mechanical ventilation has been suggested as another possible explanation for the low 30-day mortality (33%) reported in some centres.2 in south africa, pcp requiring ventilation is a suggested exclusion criterion for interventions such as extra-corporeal membrane oxygenation.43 the morbidity and mortality associated with pcp also appear to be related to the underlying cause of immunosuppression with patients with hiv-related illness or disease seeming to have much better outcomes than other groups of immunosuppressed patients such as those with malignancies or on corticosteroids.24,44,45 the prognosis of pcp has also been correlated with markers of inflammation supporting the idea that immune-mediated inflammation may be contributory to the pathogenesis of pcp.39 sub-saharan african literature on outcomes of hiv-associated respiratory failure from pcp requiring ventilation is limited. interventions that can modify the disease process and improve outcomes of hiv-infected patients with pcp who require mechanical ventilation still need to be identified and further investigated. management strategies such as permissive hypoxaemia, avoiding endotracheal intubation where possible, lung protective ventilation and meticulous fluid management seem to be appropriate in the management of hypoxaemia in this group of patients. other strategies such as the use of high flow nasal oxygen in this group of patients require further exploration. acknowledgements competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions g.n. and n.p. contributed to project design, data collection and analysis, and drafting and critical revision of the article. references mayer kh, fisk dt, meshnick s, kazanjian ph. pneumocystis carinii pneumonia in patients in the developing world who have acquired immunodeficiency syndrome. clin infect dis. 2003;36(1):70–78. http://dx.doi.org/10.1086/344951 zahar jr, robin m, azoulay e, fieux f, nitenberg g, schlemmer b. pneumocystis carinii pneumonia in critically ill patients with malignancy: a descriptive study. clin infect dis. 2002;35(8):929–934. http://dx.doi.org/10.1086/342338 zar hj, maartens g, wood r, hussey g. pneumocystis carinii pneumonia in hiv-infected patients in africa – an important pathogen. s afr med j 2000;90(7):684–688. de armas ry, wissmann g, müller a, et al. pneumocystis jirovecii pneumonia in developing countries. parasite j société fr parasitol. 2011;18(3):219–228. ansari na, kombe ah, kenyon ta, et al. pathology and causes of death in a series of human immunodeficiency virus-positive and -negative pediatric referral hospital admissions in botswana. pediatr infect dis j [serial online]. 2003;22(1). available from: http://journals.lww.com/pidj/fulltext/2003/01000/pathology_and_causes_of_death_in_a_series_of_human.13.aspx nathoo kj, 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kogulan p, et al. development and evaluation of a quantitative, touch-down, real-time pcr assay for diagnosing pneumocystis carinii pneumonia. j clin microbiol. 2002;40(2):490–494. http://dx.doi.org/10.1128/jcm.40.2.490-494.2002 larsen hh, huang l, kovacs ja, crothers k, silcott va, morris a, et al. a prospective, blinded study of quantitative touch-down polymerase chain reaction using oral-wash samples for diagnosis of pneumocystis pneumonia in hiv-infected patients. j infect dis. 2004;189(9):1679–1683. http://dx.doi.org/10.1086/383322 harris jr, marston bj, sangrujee n, duplessis d, park b. cost-effectiveness analysis of diagnostic options for pneumocystis pneumonia (pcp). plos one. 2011;6(8):e23158. desmet s, van we, maertens j, et al. serum (1-3)-β-d-glucan as a tool for diagnosis of pneumocystis jirovecii pneumonia in patients with human immunodeficiency virus infection or hematological malignancy. j clin microbiol. 2009;47(12):3871–3874. http://dx.doi.org/10.1128/jcm.01756-09 li w-j, guo y-l, liu t-j, wang k, kong j-l. diagnosis of pneumocystis pneumonia using serum (1-3)-β-d-glucan: a bivariate meta-analysis and systematic review. j thorac dis. 2015;7(12):2214. limper ah, knox ks, sarosi ga, et al. an official american thoracic society statement: treatment of fungal infections in adult pulmonary and critical care patients. am j respir crit care med. 2011;183(1):96–128. http://dx.doi.org/10.1164/rccm.2008-740st bozzette sa, sattler fr, chiu j, et al. a controlled trial of early adjunctive treatment with corticosteroids for pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. n engl j med. 1990;323(21):1451–1457. http://dx.doi.org/10.1056/nejm199011223232104 navin tr, beard cb, huang l, et al., effect of mutations in pneumocystis carinii dihydropteroate synthase gene on outcome of p. carinii pneumonia in patients with hiv-1: a prospective study. lancet. 2001;358(9281):545–549. http://dx.doi.org/10.1016/s0140-6736(01)05705-1 helweg-larsen j, benfield tl, eugen-olsen j, lundgren jd, lundgren b. effects of mutations in pneumocystis carinii dihydropteroate synthase gene on outcome of aids-associated p carinii pneumonia. lancet. 1999;354(9187):1347–1351. http://dx.doi.org/10.1016/s0140-6736(99)03320-6 masur h. management of patients with hiv in the intensive care unit. proc am thorac soc. 2006;3(1):96–102. http://dx.doi.org/10.1513/pats.200511-122jh joffrion tm, cushion mt. sterol biosynthesis and sterol uptake in the fungal pathogen pneumocystis carinii: sterol biosynthesis and sterol uptake in p. carinii. fems microbiol lett. 2010;311(1):1–9. http://dx.doi.org/10.1111/j.1574-6968.2010.02007.x cushion mt, collins ms. susceptibility of pneumocystis to echinocandins in suspension and biofilm cultures. antimicrob agents chemother. 2011;55(10):4513–4518. http://dx.doi.org/10.1128/aac.00017-11 morris a, wachter rm, luce j, turner j, huang l. improved survival with highly active antiretroviral therapy in hiv-infected patients with severe pneumocystis carinii pneumonia. aids [serial online]. 2003;17(1). available from: http://journals.lww.com/aidsonline/fulltext/2003/01030/improved_survival_with_highly_active.10.aspx miller rf. improved survival for hiv infected patients with severe pneumocystis jirovecii pneumonia is independent of highly active antiretroviral therapy. thorax. 2006;61(8):716–721. http://dx.doi.org/10.1136/thx.2005.055905 monnet x, vidal-petiot e, osman d, hamzaoui o, durrbach a, goujard c, et al. critical care management and outcome of severe pneumocystis pneumonia in patients with and without hiv infection. crit care. 2008;12(1):r28–r28. http://dx.doi.org/10.1186/cc6806 frat j-p, thille aw, mercat a, girault c, ragot s, perbet s, et al. high-flow oxygen through nasal cannula in acute hypoxemic respiratory failure. n engl j med. 2015;372(23):2185–2196. http://dx.doi.org/10.1056/nejmoa1503326 richards ga, joubert i. extracorporeal membrane oxygenation (ecmo). south afr j crit care. 2013;29:7–9. http://dx.doi.org/10.7196/sajcc.161 azoulay é, thiéry g, chevret s, et al. the prognosis of acute respiratory failure in critically ill cancer patients. medicine (baltimore) [serial online]. 2004;83(6): 360–370. http://dx.doi.org/10.1097/01.md.0000145370.63676.fb mori s, sugimoto m. pneumocystis jirovecii infection: an emerging threat to patients with rheumatoid arthritis. rheumatol oxf engl. 2012;51(12):2120–2130. http://dx.doi.org/10.1093/rheumatology/kes244 roger bacon, 1214-1294 leon jlevin, mb bc/i, fcpaed (sa), dtm&h mcot@gerga.sun.ac.za gray@pixie.co.za ethbil@netactive.co.za e-mail e-mail e-mail mark cotton: glenda gray: lean levin: references [as suggested by one of the international experts), but it was felt that a unique guideline was desirable for southern african paediatricians. the international guidelines are lengthy and often difficult to follow, particularly for those who are inexperienced in arv therapy. it is hoped that the local guidelines will prove useful for those who are starting to use arv therapy and it is hoped that it will also encourage paediatricians to further their knowledge in this fascinating, complex and ever-changing field. in this vein, it is perhaps sad that there are so few paediatricians in south africa actively involved in treating patients with arv drugs. the paediatric subcommittee of the southern african hiv clinicians society is uniquely poised to help transport our paediatricians 'beyond the guidelines'. lectures and workshops on arv therapy, run by experienced paediatricians and other clinicians, are available through the society on request. additionally, the society is happy to respond to any queries that might arise on paediatric arv therapy, and has access to an extensive network of international paediatricians for consultation. it is hoped that the paediatric hiv treatment guidelines will prove a useful companion in practice. 1. the working group on antiretroviral therapy and medical management of hiv-infected children convened by the national pediatric and family hiv resource (enter [nphrci. the health resources and sef\lices administration ihrsai. and national institutes of health [nih). guidelines for the use af antiretroviral agenrs in pediatric hlv infection. published and updated r~ularly on the web. www.hivatis.arg. 2 luzuriaga k, et al. jvira/2000; 74:6984-6991. for more information on the activities of the paediatric subcommittee of the hiv clinicians society, contact the society directly, or the following: medical men don't know the drugs thet) use nor their cost.' comment paediatric antlretroviral therapy beyond the guidelines thf southtrn african journal of hiv mfoicinf -----------novfmhtr 2000 the truth of the above quotation has not dated in 800 years. nowhere in clinical medicine today is it more relevant than in the treatment of hiv patients using antiretroviral (arv) therapy. in the south african setting, the cost issue is clearly important and very often limits the treatment that can be prescribed. therefore, when drawing up the paediatric hiv treatment guidelines for the southern african hiv clinicians society, consideration was given to the fact that treatment options might vary from state-of-the-art combinations to cheaper options suitable for use in a resqurcelimited setting. indeed, it is felt that in some aspects these guidelines are, more progressive than the american guidelines. a recent exciting development, addressed in the society's guideline but not elsewhere, is the treatment of infants under 3 months of age. since most of these patients acquire their infection at around the time of birth, we really are dealing with acute primary hiv infection. these children have a good response to therapy, and viral suppression may be so significant that they develop a normal, functioning immune system. at the age of about 18 months, when infected children normally lose their maternal hiv antibodies, the hiv elisa can become negative [the dna pcr, however, remains positive). this reflects the extent to which their virus is suppressed and hidden from the immune system, thus minimising an antibody response.' although the numbers of children are small, there is a definite suggestion that these results are achieved more readily with a 4-drug regimen than a 3-d rug regimen ik luzuriaga personal communication); hence the inclusion of a 4-drug regimen in the guidelines for patients under 3 months of age. another important difference in the society's guideline is that the dosage regimens incorporate the latest pharmacokinetic data and therefore dosages occasionally differ from those found in the drug package inserts. because infants and children metabolise their drugs at a faster rate than adults, relatively larger dosages are necessary in this patient group. consideration was given to utilising the international guidelines, with modifications, for the south african setting hiv 979 case report mrsa bacteraemia complicating amphotericin b treatment of cryptococcal meningitis j scriven,1,2 mb chb, mrcp, mres, dtm&h; j cirot a,3 mb chb; c viljoen,3 mb chb; j black,4 mb chb, fcp (sa), dip hiv man (sa); g meintjes,1,4,5 mb chb, fcp (sa), mrcp, dip hiv man (sa), mph, phd 1 clinical infectious diseases research initiative, institute of infectious disease and molecular medicine, faculty of health sciences, university of cape town, south africa 2 liverpool school of tropical medicine, liverpool, united kingdom 3 department of medicine, faculty of health sciences, university of cape town, south africa 4 division of infectious diseases and hiv medicine, department of medicine, faculty of health sciences, university of cape town, south africa 5 department of medicine, imperial college london, united kingdom corresponding author: j scriven (james.scriven@liverpool.ac.uk) intravenous amphotericin b is a key component of the antifungal therapy for cryptococcal meningitis recommended in south african and international guidelines. unfortunately, its use is associated with significant toxicity including deterioration in renal function, electrolyte disturbance, anaemia and infusion reactions. chemical phlebitis is common following administration via peripheral cannulae. this can be complicated by bacterial infection, resulting in localised cellulitis or bacterial sepsis. here we describe two patients with cryptococcal meningitis who developed methicillin-resistant staphylococcus aureus (mrsa) bacteraemia during, or shortly after treatment with amphotericin b. these cases illustrate the dangers of line-related sepsis in hospitalised individuals and some of the difficulties encountered during treatment of this condition. s afr j hiv med 2013;14(3):144-146. doi:10.7196/sajhivmed.979 intravenous (iv) amphotericin b is a key component of the antifungal therapy for crypto­coccal meningitis (cm) recom­mended in both south african (sa) and international guide­lines.1 , 2 unfortunately, its use is asso­ciated with significant toxicity including deterioration in renal function, electrolyte disturbance, anaemia and infusion reactions.3 chemical phlebitis is commonly seen following its administration via peripheral cannulae. this can be complicated by bacterial infection, resulting either in localised cellulitis or bacterial sepsis. here we describe two patients with cm who developed methicillin-resistant staphylococcus aureus (mrsa) bacteraemia during, or shortly after treatment with amphotericin b. these cases illustrate the dangers of line-related sepsis in hospitalised individuals and some of the difficulties encountered during treatment of this condition. case 1 a 42-year-old, hiv-positive man presented to hospital with a one-week history of headache and vomiting. he was not receiving antiretroviral therapy (art) and had a cd4+ count of 23 × 106 cells/l. cm was diagnosed following lumbar puncture (positive india ink, cryptococcal antigen test and culture) and he was treated with 1 mg/kg/day amphotericin b (iv) and 800 mg/day fluconazole (oral) for 14 days. during this time he had frequent episodes of phlebitis at peripheral cannula sites. on day 13 following admission, the patient deteriorated, developing fever and tachycardia. his right forearm was markedly swollen with frank pus discharging from an old cannula site. a diagnosis of bacterial sepsis secondary to drip-site infection was made, a blood culture was performed and iv vancomycin was administered. within one day, s. aureus was identified from a blood culture. resistance testing confirmed this to be methicillin-resistant, but vancomycin susceptible (minimum inhibitory concentration (mic) 0.5 µg/ml). vancomycin was continued with regular monitoring of trough levels. the patient’s fever gradually settled, and a repeat blood culture after 7 days of therapy was negative. there were no clinical signs suggestive of complicated bacteraemia and the patient was discharged after 14 days of vancomycin therapy. he has since started art and remains well 6 months later. case 2 a 50-year-old hiv-positive man receiving first-line art (tenofovir, lamivudine and efavirenz) presented to hospital with a 3-week history of headache, vomiting and blurred vision. he was diagnosed with cm following lumbar puncture (positive india ink, cryptococcal antigen test and culture) and treated with 1 mg/kg/day amphotericin b (iv) and 800 mg/day fluconazole (oral). two weeks after discharge, he was seen in the infectious diseases clinic. deemed to have failed first-line art (cd4+ count 2 × 106 cells/l, hiv viral load 60 414 copies/ml), he was switched to zidovudine, lamivudine and ritonavir-boosted lopinavir. he re-presented a further 3 weeks later with a recurrence of meningeal symptoms. lumbar puncture was performed and raised intracranial pressure was noted (opening pressure 33 cmh2o). amphotericin b was re-started, but discontinued after 7 days when cerebrospinal fluid fungal cultures showed no growth. the patient was diagnosed with cm immune reconstitution inflammatory syndrome (cm-iris) and treated with 90 mg/day prednisone, with good resolution of symptoms. during both admissions, phlebitis was noted at amphotericin infusion sites, but this settled following removal of the cannula. when seen in the outpatient clinic 2 weeks after his admission for iris, he complained of a 5-day history of fever and rigors. on examination, there was a tender, fluctuant mass over the inferior part of his sternum, but no signs of infection around any of his previous cannula sites. s. aureus was identified from a blood culture and needle aspirate of the mass; iv vancomycin was commenced pending sensitivities. a computed tomography (ct) scan of his chest revealed lytic destruction of the caudal end of the sternum with an adjacent soft-tissue collection (34 × 28 × 15 mm) (fig. 1). lung lesions suggestive of multiple septic emboli were also noted. a transthoracic echocardiogram showed no evidence of endocarditis, and a bone scan revealed no other areas of bone involvement. antibiotic susceptibility testing demonstrated methicillin resistance, but susceptibility to vancomycin (mic 1 µg/ml). incision and drainage of the chest wall abscess was performed and vancomycin was continued, but with little clinical improvement. repeat blood cultures after 7 days of therapy remained positive for mrsa, and despite treatment, he deteriorated with ongoing fevers and worsening renal and respiratory failure. he died a week thereafter. fig. 1. cross-sectional computed tomography (ct) of the anterior chest (case 2). a lytic lesion in the sternum and overlying soft tissue mass is marked by the red oval. a needle aspirate of the collection grew methicillin-resistant staphylococcus aureus (mrsa), as did 3 blood cultures. limited views of the lungs showed multiple lesions highly suggestive of septic pulmonary emboli (not shown here). discussion s. aureus bacteraemia is a serious infection with significant associated mortality. the organism is highly pathogenic and should never be assumed to be a blood culture contaminant, even in a patient who appears systemically well. the infection seeds haematogenously to distant organs in approximately 40% of cases, leading to endocarditis, septic arthritis, osteomyelitis and other deep-tissue abscesses.4 the second case presented here is an illustration of this. in the cases described, both patients developed mrsa bacteraemia during, or shortly after treatment for cm; the likely portal of entry being peripheral venous cannulae used to administer amphotericin b and iv fluids. in the first case, the bacteraemia was accompanied by obvious signs of infection at a cannula site. in the second, no evidence of localised infection was found at the time of bacteraemia, but phlebitis (attributed to amphotericin b) had been noted during the recent admission. although studies from north america report the risk of blood-stream infection (bsi) associated with peripheral iv devices to be low (0.5 bsi/1 000 ivd days),5 the risk could be higher in the sa setting, especially in this vulnerable group of patients, with advanced hiv infection receiving prolonged iv amphotericin b therapy. diagnosing bacterial infection at iv cannula sites in patients with cm can be difficult, especially given the frequent chemical phlebitis seen following amphotericin b administration (fig. 2). both chemical and infective phlebitis result in erythema and pain, and in our experience, infective phlebitis may occur as a complication at the site of chemical phlebitis. fever and systemic upset, or the presence of pus at the cannula site, are very suggestive of bacterial infection and should be investigated further. blood cultures should be taken prior to the use of any antibiotics, and swabs sent for investigation if any exudate or pus is present.6 in the absence of these features, it is reasonable to remove the cannula, elevate the limb, apply ice and observe. bacterial infection should be considered if there is no significant improvement in 24 hours, or it there is an expanding area of cellulitis. fig. 2. ‘chemical’ phlebitis complicating amphotericin b infusion (photograph courtesy of dr t a bicanic). this inflammation occurred during the 4-hour amphotericin b infusion and presented as redness and tenderness tracking up the cannulated vein. in such cases, the cannula should be removed once the infusion is completed and the site monitored closely for infection and the patient for fever. this is not an indication for immediate antibiotics. if signs of systemic infection are present, then once blood cultures are taken, empirical iv antibiotic therapy should be commenced. antibiotic choice should ensure adequate coverage of s. aureus.6 given the high rates of methicillin resistance among nosocomially acquired isolates in sa (30 60%),7 , 8 iv vancomycin should be used until microbiology results are available. if blood cultures are negative, antibiotics can be stopped after 5 days. if blood cultures are positive for s. aureus, then more prolonged antibiotic treatment is required. the infectious diseases society of america (idsa) recommends treating uncomplicated mrsa bacteraemia for at least 2 weeks with iv vancomycin, with target trough levels of 15 20 μg/ml. due to high rates of unrecognised endocarditis, the idsa recommends echocardiography in all patients – an impractical option in many sa settings. a pragmatic approach is to risk stratify patients by taking repeat blood cultures after 2 4 days of antibiotic therapy. patients with no implantable prostheses, no clinical evidence of endocarditis or metastatic infection, who have a negative repeat blood culture and resolution of fever within 72 hours of initiating effective therapy, can be treated for 2 weeks with iv vancomycin (monitoring trough levels and creatinine). patients at high risk of complicated infection, such as those with prosthetic cardiac material, should be investigated with echocardiography (transoesophageal is preferred over transthoracic). if neither is available, high-risk patients should be treated as having complicated bacteraemia, with careful clinical follow-up to exclude a relapse of infection or complications of prosthetic-valve endocarditis. patients with persistent fevers, positive repeat blood cultures or clinical features suggestive of metastatic infection, should be considered as complicated cases and investigated for endocarditis, osteomyelitis and deep-tissue abscesses.4 , 9 , 10 the management of complicated mrsa bacteraemia should be discussed with an expert wherever possible. surgery may be required to drain an abscess or remove a focus of infection, and antibiotic therapy should continue for approximately 4 6 weeks depending on the extent of the infection and response to treatment.10 with regard to patients with cm, it is important that clinicians are aware of this additional complication of amphotericin b treatment. cannula sites should be monitored regularly and any patient who develops a new fever should be evaluated carefully for signs of drip-site-related infection. finally, efforts should be made to reduce the incidence of nosocomial infections as a whole, through increased emphasis on infection-control practices such as handwashing and aseptic technique. although it is now more than 100 years since the pioneering work of semmelweis, his lessons remain pertinent today. acknowledgement. we are grateful to prof. g maartens for critical re­view of the manuscript and dr t a bicanic for the photograph in fig. 2. references 1. perfect jr, dismukes we, dromer f, et al. clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. clin infect dis 2010;50(3):291-322. 1. perfect jr, dismukes we, dromer f, et al. clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. clin infect dis 2010;50(3):291-322. 2. govender n, meintjes g, bicanic t, et al. guideline for the prevention, diagnosis and management of cryptococcal meningitis among hiv-infected persons: 2013 update. southern african journal of hiv medicine 2013;14(2):76-86. 2. govender n, meintjes g, bicanic t, et al. guideline for the prevention, diagnosis and management of cryptococcal meningitis among hiv-infected persons: 2013 update. southern african journal of hiv medicine 2013;14(2):76-86. 3. sawaya bp, briggs jp, schnermann j. amphotericin b nephrotoxicity: the adverse consequences of altered membrane properties. j am soc nephrol 1995;6(2):154-164. 3. sawaya bp, briggs jp, schnermann j. amphotericin b nephrotoxicity: the adverse consequences of altered membrane properties. j am soc nephrol 1995;6(2):154-164. 4. fowler vg, olsen mk, corey gr, et al. clinical identifiers of complicated staphylococcus aureus bacteremia. arch intern med 2003;163(17):2066-2072. 4. fowler vg, olsen mk, corey gr, et al. clinical identifiers of complicated staphylococcus aureus bacteremia. arch intern med 2003;163(17):2066-2072. 5. maki dg, kluger dm, crnich cj. the risk of bloodstream infection in adults with different intravascular devices: a systematic review of 200 published prospective studies. mayo clin proc 2006;81(9):1-13. 5. maki dg, kluger dm, crnich cj. the risk of bloodstream infection in adults with different intravascular devices: a systematic review of 200 published prospective studies. mayo clin proc 2006;81(9):1-13. 6. mermel la, allon m, bouza e, et al. clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the infectious diseases society of america. clin infect dis;49(1):1-45. 6. mermel la, allon m, bouza e, et al. clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the infectious diseases society of america. clin infect dis;49(1):1-45. 7. bamford c, bonorchis k, elliott e, et al. antimicrobial susceptibility patterns of selected bacteraemic isolates from south african public sector hospitals, 2010. southern african journal of epidemiology and infection 2011;26(4):243-250. 7. bamford c, bonorchis k, elliott e, et al. antimicrobial susceptibility patterns of selected bacteraemic isolates from south african public sector hospitals, 2010. southern african journal of epidemiology and infection 2011;26(4):243-250. 8. shittu ao, lin j. antimicrobial susceptibility patterns and characterization of clinical isolates of staphylococcus aureus in kwazulu-natal province, south africa. bmc infect dis 2006;6(1):125. 8. shittu ao, lin j. antimicrobial susceptibility patterns and characterization of clinical isolates of staphylococcus aureus in kwazulu-natal province, south africa. bmc infect dis 2006;6(1):125. 9. kaasch aj, fowler vg, rieg s, et al. use of a simple criteria set for guiding echocardiography in nosocomial staphylococcus aureus bacteremia. clin infect dis 2011;53(1):1-9. 9. kaasch aj, fowler vg, rieg s, et al. use of a simple criteria set for guiding echocardiography in nosocomial staphylococcus aureus bacteremia. clin infect dis 2011;53(1):1-9. 10. liu c, bayer a, cosgrove se, et al. clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant staphylococcus aureus infections in adults and children. clin infect dis 2011;52(3):e18-e55. 10. liu c, bayer a, cosgrove se, et al. clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant staphylococcus aureus infections in adults and children. clin infect dis 2011;52(3):e18-e55. article information author: mary-ann davies1 affiliation: 1centre for infectious disease epidemiology and research, school of public health and family medicine, university of cape town, south africa correspondence to: mary-ann davies email: mary-ann.davies@uct.ac.za postal address: uct faculty of health sciences, anzio road, observatory 7925, cape town dates: received: 17 jan. 2015 accepted: 16 mar. 2015 published: 20 may 2015 how to cite this article: davies m-a. research gaps in neonatal hiv-related care. s afr j hiv med. 2015;16(1), art. #375, 6 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.375 copyright notice: © 2015. the authors. licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. research gaps in neonatal hiv-related care in this forum... open access • abstract • research gaps in neonatal hiv-related care    • what is the best way to manage newborns at increased risk of intrapartum hiv transmission?    • what are the optimal algorithms for early infant diagnostic?       • what is the best time for a follow-up hiv-polymerase chain reaction test?       • is it efficient to test all infants routinely at birth, or should this be restricted to those at high risk of transmission?       • how feasible is implementation of birth testing in routine care settings?       • how do we ensure that patients return for results and initiate antiretroviral therapy if indicated?    • what is the best management for hiv-infected neonates?       • how soon after birth should antiretroviral therapy be started?       • which regimen should be used in the neonatal period?       • how do we initiate and retain children on antiretroviral therapy from the neonatal period onwards? • future directions • acknowledgements    • competing interests • references abstract top ↑ the south african prevention of mother to child transmission programme has made excellent progress in reducing vertical hiv transmission, and paediatric antiretroviral therapy programmes have demonstrated good outcomes with increasing treatment initiation in younger children and infants. however, both in south africa and across sub-saharan african, lack of boosted peri-partum prophylaxis for high-risk vertical transmission, loss to follow-up, and failure to initiate hiv-infected infants on antiretroviral therapy (art) before disease progression are key remaining gaps in neonatal hiv-related care. in this issue of the southern african journal of hiv medicine, experts provide valuable recommendations for addressing these gaps. the present article highlights a number of areas where evidence is lacking to inform guidelines and programme development for optimal neonatal hiv-related care. research gaps in neonatal hiv-related care top ↑ the south african (sa) prevention of mother to child transmission (pmtct) programme has made excellent progress in reducing vertical hiv transmission.1,2 in addition,1 paediatric antiretroviral therapy (art) programmes have demonstrated good outcomes with increasing treatment initiation in younger children and infants, in response to south african and world health organization (who) guidelines expanding recommendations for immediate art from infants to all children < 5 years old.2,3,4,5,6,7,8,9,10 however, both in sa and across sub-saharan african, lack of boosted peri-partum prophylaxis for high-risk vertical transmission, loss to follow-up (ltfu) for early infant diagnostic (eid) hiv-polymerase chain reaction (pcr) testing and receipt of results, and failure to initiate hiv-infected infants on art before disease progression are key remaining gaps in neonatal hiv-related care.11,12,13 the expert reviews on recognising and managing vertical transmission risk in the peri-partum period,14 hiv diagnostic testing of newborns15 and provision of neonatal art16 provide valuable recommendations for addressing these coverage gaps. they also highlight a number of areas where evidence is lacking to inform guidelines and programme development for optimal neonatal hiv-related care. what is the best way to manage newborns at increased risk of intrapartum hiv transmission? for many years, guidelines from developed countries17,18,19 included identification of neonates at high risk of vertical transmission,20,21 recommending multi-antiretroviral (multi-arv) post-exposure prophylaxis (pep) for these neonates. while two studies provide direct evidence that multi-arv pep is more effective than a single drug,22,23 data are lacking on the best choice, number and duration of drugs. research is needed to inform guidelines that balance the prophylactic benefit of multi-arv pep with risks of toxicity and resistance that may increase with duration, as well as the programmatic challenges associated with effectively implementing more complex regimens for longer periods. furthermore, longer-duration multi-arv pep may suppress hiv viral load,23,24,25 making hiv diagnosis more challenging, with implications for eid algorithms. in wealthy countries with low maternal hiv prevalence, reduced sensitivity of hiv-pcr is of less concern as guidelines recommend eid testing at numerous time points in exposed infants. in contrast, in south africa, routine testing in otherwise well infants will probably be restricted to two hiv-pcr tests per infant at most, hence the impact of reduced sensitivity of hiv-pcr testing is critical. research needs include determining the effectiveness of routine programmes in accurately identifying high-risk infants in need of multi-arv pep, as well as retention, adherence and transmission in routine care. for example, monitoring and evaluation of the implementation of the national and western cape provincial guidelines for multi-arv pep could provide valuable data to inform programme development. what are the optimal algorithms for early infant diagnostic? south african 2014 pmtct guidelines provide for hiv-pcr testing at birth of hiv-exposed infants at high risk of vertical hiv transmission, including low-birthweight and premature infants as well as those born to mothers on art for < 4 weeks or with hiv-rna > 1000 copies/ml.26 in addition, a who technical expert panel in 2013 reviewed the optimal timing of eid testing, and consideration was given to recommending either universal or risk-based birth testing.27 given the shift towards a greater proportion of in utero infections with improved coverage of more effective pmtct regimens such as option b/b+, and the proven efficacy of hiv-pcr at birth to identify 75% of infections detectable by 6 weeks of age, birth eid could be pivotal in mitigating against the high ltfu for eid testing and delays in starting infected infants on art.23,28 however, there are a number of questions regarding optimal eid guidelines. what is the best time for a follow-up hiv-polymerase chain reaction test? birth testing necessitates a follow-up test, as 25% of early hiv infections are undetectable at birth.23,28 evidence is needed to inform the optimal timing of follow-up testing, which depends on test performance, morbidity and mortality without art (and the effect of art in reducing this), retention strategies and operational considerations of aligning follow-up with routine child health visits.27,29 whilst mathematical modelling suggests that, with two hiv-pcr tests per infant, the greatest number of infections can be identified at birth and 10 weeks of age, there is a need for more evidence to inform the model assumptions, such as the probable loss of hiv-pcr sensitivity owing to nevirapine pep.30 of note, no studies to date have examined hiv-pcr test performance at birth and thereafter, now that triple art is mandated for all women during pregnancy and breastfeeding together with extended infant nvp prophylaxis. these factors may all reduce test sensitivity at birth31 and at 6 weeks of age.25 for this reason, the 2014 south african pmtct guidelines defer pcr testing to 16 weeks of age in infants who need 12 weeks of nvp pep.26 however, more data are needed on the duration and extent of reduced sensitivity post-pep.24 delaying testing will improve sensitivity; however, attrition is likely to increase at longer post-partum durations.32 the extent to which such attrition would be exacerbated by false reassurance of a negative result at birth is unknown. in addition, the model assumes that art very early in life is associated with improved survival. however, there are little data on the magnitude of the mortality benefit when art is initiated very early, for example in the first days or weeks of life, especially in premature low-birthweight infants, compared with the benefit seen in the children with hiv early antiretroviral (cher) trial where the median age of art initiation in the early group was 7.4 weeks.33 is it efficient to test all infants routinely at birth, or should this be restricted to those at high risk of transmission? whilst the mathematical modelling study demonstrates a nearly 50% increase in the number of life years saved when adding a routine birth test to a single test at 10 weeks of age, more tests increase costs and reduce efficiency (measured in terms of new diagnoses per pcr) by approximately 35%.30 the efficiency of restricting birth testing to those at high risk of transmission is unknown and may be programmatically more difficult to implement effectively. in particular, more data would be needed to identify easily implementable high-risk criteria that are predictive of a high likelihood of a positive birth test. although the specificity, and therefore positive predictive value (ppv) of currently used eid tests is very high, the proportion of false-positive tests increases with reduced transmission rates. follow-up confirmatory testing with hiv-pcr or viral load may be difficult to interpret in infants on prophylactic therapy,25 with careful counselling needed. research is needed on how best to manage patients with false-positive or indeterminate test results, which may be resource-intensive and difficult outside specialist facilities. how feasible is implementation of birth testing in routine care settings? eid testing at 6 weeks and follow-up for results at the 10-week immunisation visit is currently performed at immunisation clinics. for a birth pcr, delivery facilities would be responsible for birth testing. the very high proportion of facility-based deliveries in sa favours birth testing, and routine postnatal follow-up within a few days of birth at many delivery facilities could facilitate receipt of results. however, the extent to which the additional workload can be absorbed by delivery facilities is unclear. this consideration is particularly important for high-burden facilities where women may be discharged within hours of delivery so that counselling and birth tests may need to be performed after hours or on weekends. there are encouraging early data from a pilot study comparing birth testing of high-risk infants in primary (khayelitsha, cape town) and tertiary (tygerberg hospital, cape town) care delivery facilities, supporting the feasibility of implementing birth testing at primary care level.34 there was no difference in median time-to-test results between the facilities despite no on-site laboratory at the primary care facility.34 however, additional research staff supported the study and testing was limited to high-risk infants (about 25% of all exposed infants), therefore the results may not be generalisable to all infants in routine care settings. research is also needed on how best to counsel mothers of infants whose birth test is negative about the need to return for an additional test. systems to ensure follow-up for a subsequent test require development. this approach may be challenging, especially in the absence of unique patient identifiers across the health service, as subsequent tests in infants born at a single delivery facility would probably occur in many different immunisation clinics. how do we ensure that patients return for results and initiate antiretroviral therapy if indicated? irrespective of the timing of testing, there is a need to develop and evaluate systems for ensuring that positive infant results are received and art is successfully initiated. interestingly, in the modelling study, changing the timing of a second hiv-pcr test between 6 and 14 weeks of age had only a small effect on the proportion of perinatal infections diagnosed,30 whereas the greatest reduction in missed diagnoses (11%) was seen if 100% of caregivers received test results, compared with the assumption of 66% based on previous studies.35,36 data from the western cape reassuringly suggest that the proportion of infected infants linked to hiv care has increased from 54% to 71% between 2005 and 2010.37 it is likely that there have been further improvements, with rapid alerts of positive tests from laboratories to sub-district pmtct co-ordinators and immunisation clinics, with follow-up tracing of infants. (van niekerk, personal comm.). in contrast, in rural kwazulu-natal in 2012, 45% of infants with positive hiv-pcr diagnoses never started art and a number of challenges in tracing infected infants were identified, highlighting the need for better linkage systems in a range of settings.38 point-of-care (poc) tests could maximise the proportion of infants receiving results, with a number of platforms currently under investigation.29 a recent mozambique study demonstrated 98.5% sensitivity and 99.9% specificity, comparing a poc nucleic acid test implemented in primary care clinics with laboratory tests.39 similar encouraging results were reported for a poc nucleic acid test in cape town, south africa, with overall sensitivity of 97% and specificity of 100% for correctly identifying hiv-infected infants.40 sensitivity was slightly lower (93%) and the test error rate higher (10%) among 90 infants tested at < 7 days old.40 further studies of birth poc tests are ongoing. in addition, the throughput time for a single poc test may limit its use in busier facilities, especially if testing is done on all infants, and not only those at high risk. despite the research gaps and challenges described, implementation of routine birth testing in all infants with nearly 100% coverage could itself provide much-needed evidence of the real effectiveness of the pmtct programme and monitor progress towards virtual elimination of vertical transmission of hiv. mother to child transmission is probably currently under-estimated both by routine statistics and dedicated studies, as a high proportion of hiv-infected infants may be ltfu or deceased by 6 weeks of age.2,28 similarly, owing to current under-diagnosis of all neonatal infections, the true neonatal mortality in hiv-infected infants is unknown.15 what is the best management for hiv-infected neonates? how soon after birth should antiretroviral therapy be started? there is a spectrum of arguments favouring early infant art ranging from the more conventional aims of reducing morbidity and mortality through effective therapy to the potential for modifying persistent hiv to facilitate later treatment-sparing or even eradication strategies.41,42,43,44,45 evidence for the traditional goal of reducing morbidity and mortality includes the high early mortality and rapid disease progression in hiv-infected infants,46,47,48 the lack of prognostic markers for mortality in infants49 and the substantial reductions in morbidity, mortality, neurodevelopmental delay and other hiv-related complications demonstrated in the cher randomised controlled trial.33,50,51 in addition, cohort studies report better growth, neurocognitive outcomes, immunological response and virological control in infants starting therapy at earlier ages than amongst older infants and children.45,52,53,54,55,56,57,58,59 whilst early virological control in infancy is important for the conventional treatment goals of optimal long-term outcomes on art, it may also moderate chronic hiv infection by reducing the latent hiv reservoir, paving the way for treatment-sparing strategies.41,45,53,60 the case of the ‘mississippi child’, who received triple therapy within hours of birth with early virological control and subsequent prolonged virological remission off art,61 has sparked interest in treatment-sparing or cure approaches. the final results of the cher trial found that early therapy followed by interruption after either 40 or 96 weeks on art had superior clinical and immunological outcomes and less overall time on art than deferred continuous therapy.44 however, it is not known whether longer duration or uninterrupted early therapy would have even better outcomes. in addition, detailed studies on the virological and immunological consequences of interruption, and predictors of the need to restart therapy in the interrupted groups, are still under way. luzuriaga et al.53 recently showed that early treatment at < 2.6 months of age with sustained virological control through to adolescence is associated with limited circulating pro-viral and replication competent virus with continuous decay of viral reservoirs, not seen in children starting art at older ages. nevertheless, whilst early virological control in infants may allow for later treatment interruptions or eradication strategies, it does not guarantee prolonged absence of viral rebound, which has occurred within days to weeks of stopping treatment.62,63 it is easy to merge the spectrum of arguments in favour of early infant art into the general dictum ‘the sooner, the better’, especially with a shift towards birth eid testing. indeed, the rapid disease progression and mortality in hiv-infected infants by 2–3 months of age and high mortality even in the early treatment arm of the cher trial suggests that art initiation before a median of 7.4 weeks of age should be beneficial.33,46,64 however, we really do not know how soon is soon enough. there is no clear evidence on the optimal timing of art between birth and 7.4 weeks for either reducing morbidity and mortality on art, or later treatment-sparing approaches. importantly, this evidence is also needed for pre-term and low-birthweight infants who comprise a substantial proportion of infants at risk of vertical transmission.21,65,66 of note, low-birthweight infants (< 2kg) were excluded from the cher study.33 in addition, as studies demonstrating benefits of early infant art to date have not distinguished between in utero and intrapartum infection, the optimal timing of art initiation in these groups may differ.47,67 which regimen should be used in the neonatal period? the optimal timing of neonatal art initiation must balance the benefits and risks of early therapy, and hence the lack of appropriate formulations or pharmacokinetic, dosing, safety and effectiveness data for drugs in neonates, especially premature neonates, as outlined in the companion article by nuttall,16 are research gaps. in particular, the use of a nevirapine-based regimen in neonates < 2 weeks of age is a concern with high prevalence of non-nucleoside reverse-transcriptase inhibitors (nnrti) resistance, even in the absence of reported pmtct exposure.68 prevalence of resistance may be even higher than previously reported if more sensitive testing methods are used.69 there is mixed evidence on the benefit of more aggressive regimens that hasten virological control, for example four-drug regimens.54,70,71 studies are warranted on the safety and effectiveness of different regimens, including triple-class four-drug regimens and integrase inhibitors. the role of these regimens may be particularly important if the goal of therapy is to allow for later treatment-sparing strategies.41 in addition, as adult art programmes mature, choice of regimen in infants born to mothers failing first-line art is an emerging research need. evidence for which drugs to initiate should consider the likely characteristics and comorbidities in infants infected despite a comprehensive high-coverage pmtct programme. in a case series of 20 infants initiating art within the first 6 weeks of life at rahima moosa mother and child hospital in johannesburg, 70% had congenital infections and other illnesses requiring treatment.72 prematurity (70%), low birthweight (50%), and pre-treatment thrombocytopaenia (30%), anaemia (40%) and renal dysfunction (10%) were not uncommon.72 illnesses requiring treatment included congenital pneumonia, congenital syphilis, cmv and tb.72 similar results have been reported from a case series of infants diagnosed at birth at mowbray maternity hospital, cape town.73 drug interactions may occur and drugs may require administration via nasogastric or orogastric tubes in sick pre-term infants, affecting dose delivery.65 given the lack of data on many drugs in the neonatal period and probable comorbidities in infected infants, appropriate safety and dose monitoring requires determination. for example, published studies of treated premature neonates have closely monitored drug levels to determine dosing, and the extent to which this is required routinely is unclear.65 similarly, the optimal intensity of safety monitoring is unknown both for sick neonates in hospital as well as for those who are clinically well who could be treated in primary care settings.74 how do we initiate and retain children on antiretroviral therapy from the neonatal period onwards? there are substantial challenges with initiating and retaining hiv-infected newborns on treatment. the mothers of hiv-infected infants will frequently have either never accessed pmtct or been lost to care;75,76,77 consequently, the likelihood of poor infant retention and adherence after art initiation is high. studies from both wealthy countries78 and resource-limited settings79 report substantial loss to follow-up and poor adherence on art in infected infants, despite high coverage of an effective pmtct programme. in a johannesburg research cohort of 30 infants initiating art at a median 16 weeks of age, < 50% were in care 68 weeks later, with four deaths.79 the challenges that the caregivers of these infants may already face with accessing and remaining in care may be exacerbated by the tremendous stress experienced with eid.80,81,82,83 significant research gaps include understanding the tensions between maternal needs in the post-partum period, including the psychosocial readiness of the mother to initiate art for her infant, and how neonatal art services are delivered. research is needed to investigate approaches to eid and neonatal art initiation, such as the use of heath navigators, that best support engagement and long-term retention in care. future directions top ↑ as practice changes towards birth diagnosis and early infant art, there is an opportunity to collect both programme-level and individual patient data to address some of the research questions related to early neonatal hiv care.84 just as studies of the first paediatric art programmes in resource-limited settings were used to inform treatment guidelines and programme development,85,86,87 careful collection and analysis of observational data from pmtct, eid and neonatal art programmes will provide valuable evidence to inform neonatal hiv care. collaborative research across different sites and settings is needed owing to the small numbers of patients at individual sites and transfer of infants from pmtct programmes to neonatal/paediatric and primary care art programmes. such observational research conducted within south africa and in other resource-limited settings will be relevant both locally and globally.84 acknowledgements top ↑ competing interests the author declares that she has no financial or personal relationships which may have inappropriately influenced her in writing this article. references top ↑ barron p, pillay y, doherty t, et al. eliminating mother-to-child hiv transmission in south africa. bull 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2012;160:60–66. http://dx.doi.org/10.1016/j.jpeds.2011.06.053 haeri mazanderani af, du plessis nm, thomas wn, venter e, avenant t. loss of detectability and indeterminate results: challenges facing hiv infant diagnosis in south africa’s expanding art programme. s afr med j. 2014;104:574–577. http://dx.doi.org/10.7196/samj.8322 national consolidated guidelines for the prevention of mother-to-child transmission of hiv (pmtct) and the management of hiv in children, adolescents and adults. c2014 [cited 15 january 2015]. available from: http://www.health.gov.za/policies.php march 2014 supplement to the 2013 consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection. recommendations for a public health approach. c2014 [cited 01 april 2014]. available from: http://www.who.int lilian rr, kalk e, bhowan k, et al. early diagnosis of in utero and intrapartum hiv infection in infants prior to 6 weeks of age. j clin microbiol. 2012;50:2373–2377. 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a public sector antiretroviral treatment programme for hiv-infected children and their infected parents. s afr med j. 2004;94:643–646. fassinou p, elenga n, rouet f, et al. highly active antiretroviral therapies among hiv-1-infected children in abidjan, cote d’ivoire. aids. 2004;18:1905–1913. http://dx.doi.org/10.1097/00002030-200409240-00006 sutcliffe cg, van dijk jh, bolton c, persaud d, moss wj. effectiveness of antiretroviral therapy among hiv-infected children in sub-saharan africa. lancet infect dis. 2008;8:477–489. http://dx.doi.org/10.1016/s1473-3099(08)70180-4 abstract introduction methods results discussion conclusion acknowledgements references appendix 1 about the author(s) magdel e. rossouw department of paediatrics and child health, family clinical research unit, stellenbosch university, tygerberg campus, south africa morna cornell school of public health and family medicine, university of cape town, south africa mark f. cotton department of paediatrics and child health, family clinical research unit, stellenbosch university, tygerberg campus, south africa monika m. esser department of pathology, national health laboratory service immunology unit (nhls), stellenbosch university, tygerberg campus, south africa citation rossouw me, cornell m, cotton mf, esser mm. feeding practices and nutritional status of hiv-exposed and hiv-unexposed infants in the western cape. s afr j hiv med. 2016;17(1), a398. http://dx.doi.org/10.4102/sajhivmed.v17i1.398 original research feeding practices and nutritional status of hiv-exposed and hiv-unexposed infants in the western cape magdel e. rossouw, morna cornell, mark f. cotton, monika m. esser received: 09 june 2015; accepted: 13 nov. 2015; published: 13 may 2016 copyright: © 2016. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: optimal infantand young child–feeding practices are crucial for nutritional status, growth, development, health and, ultimately, survival. human breast milk is optimal nutrition for all infants. complementary food introduced at the correct age is part of optimal feeding practices. in south africa, widespread access to antiretrovirals and a programme to prevent mother-to-child transmission of hiv have reduced hiv infection in infants and increased the number of hiv-exposed uninfected (heu) infants. however, little is known about the feeding practices and nutritional status of heu and hiv-unexposed (hu) infants. objective: to assess the feeding practices and nutritional status of hiv-exposed and hiv-unexposed (hu) infants in the western cape. design: prospective substudy on feeding practices nested in a pilot study investigating the innate immune abnormalities in heu infants compared to hu infants. the main study commenced at week 2 of life with the nutrition component added from 6 months. information on children’s dietary intake was obtained at each visit from the caregiver, mainly the mother. head circumference, weight and length were recorded at each visit. data were obtained from 6-, 12and 18-month visits. world health organization feeding practice indicators and nutrition indicators were utilised. setting: tygerberg academic hospital, western cape. mothers were recruited from the postnatal wards. subjects: forty-seven mother–infant pairs, 25 heu and 22 hu infants, participated in this nutritional substudy. eight (17%) infants, one hu and seven heu, were lost to follow-up over the next 12 months. the heu children were mainly xhosa (76%) and hu were mainly mixed race (77%). results: the participants were from poor socio-economic backgrounds. in both groups, adherence to breastfeeding recommendations was low with suboptimal dietary diversity. we noted a high rate of sugarand salt-containing snacks given from a young age. the hu group had poorer anthropometric and nutritional indicators not explained by nutritional factors alone. however, alcohol and tobacco use was much higher amongst the hu mothers. conclusion: adherence to breastfeeding recommendations was low. ethnicity and cultural milieu may have influenced feeding choices and growth. further research is needed to understand possible reasons for the poorer nutritional and anthropometric indicators in the hu group. introduction background observational studies show that exclusive breastfeeding in the early months of life and continued breastfeeding with timely transition to high-quality complementary foods deliver physiological and economic benefits to mothers and maximise nutrient intake, growth, development and survival of children.1,2,3,4,5 the world health organization (who) recommends exclusive breastfeeding for the first 6 months of life.6,7 introduction of fluids other than breast milk is associated with increased morbidity and mortality during the first 6 months of life.8,9,10 complementary foods should be introduced from 6 months.11 continued breastfeeding up to 24 months is advised.11 in the absence of interventions, 5% – 20% of infants born to hiv-infected mothers acquire hiv through breastfeeding.11 given the need to reduce the risk of hiv transmission, whilst minimising other risks for morbidity and mortality, current who guidelines state that when replacement feeding is acceptable, feasible, affordable, sustainable, and safe, hiv-infected mothers should avoid breastfeeding completely.11 if not feasible, hiv-infected mothers should exclusively breastfeed for the first few months and gradually stop breastfeeding, provided that conditions for replacement feeding are in place.12 the 2015 south african national programme to prevent mother-to-child transmission of hiv (pmtct) supports exclusive breastfeeding for 6 months and continued up to 12 months. maternal antiretroviral therapy (art) should continue until the infant is fully weaned.13 formula milk was provided at public health facilities solely for pmtct until 2013. optimal feeding practices are crucial for the nutritional status, health and survival of infants.14 anthropometric measurements are screening tools for assessing nutritional status. the three main indicators used to define undernutrition are as follows: stunting, underweight and wasting. stunting is associated with repeated exposure to adverse economic conditions, poor sanitation and the interactive effects of poor intake and infection.15,16,17 underweight indicates a history of poor health or nutritional insult, whilst wasting is associated with recent illness and failure to gain weight or a loss of weight.18 knowing the levels of stunting, underweight and wasting is important in determining the overall health of the community. in contexts of high hiv prevalence such as south africa, it is important to understand how feeding patterns impact on the health of hiv-exposed uninfected children (heu). the success of the pmtct programme has decreased hiv infection in infants, conversely increasing the number of heu infants. to date, there has been no comparison of feeding practices between heu and hiv-unexposed (hu) children in the western cape. in this study, we explored feeding practices and nutritional status in heu and hu children over 12 months. participants had been recruited for a pilot study of innate immune abnormalities in 2009, when antenatal dual art was provided unless combination art was indicated in the mother for either who stage 3 or 4 disease or a cd4 count at below 200 cells/ml.19 the aim of the study was to assess the feeding practices and nutritional status of heu and hu infants. methods hiv-infected and -uninfected mothers and their infants were recruited from the postnatal maternity wards of tygerberg academic hospital, which serves patients from lower socio-economic communities in the western cape. the aim of the study was to compare infectious disease morbidity and vaccine responses in heu and hu infants over 24 months.20,21 fifty-five infants, 27 heu and 28 hu, were enrolled at 2 weeks of age in the main study. the prospective substudy on feeding practices commenced in october 2009 after 6 months on study. five (9%) mother–infant pairs, two with heu infants and three hu, were lost to follow-up over the first 6 months of the main study. three (5%) heu infants became infected and were excluded. forty-seven mother–infant pairs (85%), comprising 25 heu infants and 22 hu infants, participated in this nutritional substudy. eight (17%) infants, one hu and seven heu, were lost to follow-up over the next 12 months. a trained staff nurse consented the mothers for the nutrition study. data were obtained from 6-, 12and 18-month visits. a staff nurse and medical professionals conducted the nutritional questionnaire (appendix 1) at each visit. the human research ethics committee, faculty of medicine and health sciences at stellenbosch university (n08/10/289) approved the study protocol. nutritional information was obtained from the caregiver, generally the mother. weight, length and head circumference were recorded at each visit. sociodemographic questions were included in the nutrition questionnaire. caregivers were asked to answer yes or no to questions regarding nonnutritional foods, that is, salty snacks and sugar-containing snacks and drinks, given to the infant and the current alcohol and tobacco (smoking) use of the caregiver (the mother). we used simple rapid-assessment techniques with the who indicators22 to assess feeding practices. world health organization indicators22 early initiation of breastfeeding the proportion of children who were put to the breast within 1 hour of birth. exclusive breastfeeding under 6 months the proportion of infants 0–5 months of age who were fed exclusively with breast milk. continued breastfeeding at 1 year the proportion of children 12–15 months of age who were fed breast milk. introduction of solid, semisolid or soft foods the proportion of infants 6–8 months of age who received solid, semisolid or soft foods. minimum dietary diversity the proportion of children 6–23 months of age who received foods from four or more food groups per day. the seven foods groups used for this indicator were grains, roots and tubers, legumes and nuts, dairy products (milk, yoghurt and cheese), flesh foods (meat, fish, poultry and liver or organ meats), eggs, vitamin a–rich fruits and vegetables and other fruits and vegetables. children ever breastfed the proportion of children who were ever breastfed. bottle-feeding the proportion of children 0–23 months of age who were fed with a bottle, regardless of whether the infant was breastfed. milk-feeding frequency for non-breastfed children proportion of non-breastfed children 6–23 months of age who received at least two milk feedings per day. the who anthropometric calculator application (version 3.2.2, january 2011) was used for z-score calculations of weight/age, length/age, weight/length and head circumference/age. anthropometry defined23 as underweight: below -2 standard deviations (sd) from median weight for age of reference population; wasting: below -2 sd from median weight for height of reference population; and stunting: below -2 sd from median height for age of reference population. feeding practices and nutritional status indicators were reported as median (med) and interquartile range. results participants were recruited over a 16-week period from march to june 2009. forty-seven mother–infant pairs (25 heu and 22 hu infants) participated in this nutritional substudy (table 1). eight (17%) infants, one hu and seven heu, were lost to follow-up over the next 12 months on the nutrition substudy. table 1: sociodemographic characteristics of hiv-exposed uninfected and hiv-unexposed infants at enrolment in nutrition study at 6 months of age. the heu children were mainly xhosa (76%) and hu were mainly mixed race (77%). occupation density and number of young children in the households were similar. nearly half of the households had running water and ablution facilities inside the house. more hu mothers smoked (73% versus 28%) and used alcohol (23% versus 4%). in the heu group, only one mother initiated breastfeeding and was still breastfeeding at 18 months (table 2). in the hu group, all mothers initiated breastfeeding with over half starting within an hour of delivery. at 12 and 18 months, 62% and 52% of the hu mothers were still breastfeeding. no infant was exclusively breastfeeding at 6 months. in the heu group, there was 100% adequate formula milk frequency at 6 months, dropping to 80% at 12 and 18 months. the hu group had a similar trend but with a later time decline (100% at 12 months and 80% at 18 months). table 2: feeding practices by world health organization indicators 19 of hiv-exposed uninfected and hiv-unexposed children. no information was available on bottle-feeding at 6 months because of misinterpretation of the survey question. however, all but one heu infant were assumed to bottle-feed, as only one mother was breastfeeding. almost all heu infants were bottle-fed from 12 to 18 months. amongst the hu infants, 72% and 79% were bottle-fed at 12 and 18 months. at 6 months, 96% of hu and 76% heu infants had solid, semisolid or soft foods introduced. at 6 months, 46% of hu and 20% heu had minimum dietary diversity. by 12 months, it was 65% for heu and 56% for hu and by 18 months it was 61% and 67%, respectively, for heu and hu. sixty-eight percent of hu and 32% of heu infants were fed nonnutritional foods at 6 months increasing to all hu and about half the heu infants at 12 months. by 18 months, all infants were receiving nonnutritional foods. the hu group had poorer anthropometry (table 3) and nutritional indicators than the heu group at 6 and 18 months (table 4). no heu infants were underweight at any time point. amongst the hu, 2 (9%) were underweight at 6 months, 3 (14%) at 12 months and 2 (10%) at 18 months. amongst hu, 6 (27%) were stunted at 6 months, declining to 4 (19%) at 12 and 18 months. one heu infant was wasted at 12 months and one hu infant was wasted at 6 months. table 3: anthropometry of hiv-exposed uninfected and hiv-unexposed infants. table 4: nutritional indicators of hiv-exposed uninfected and hiv-unexposed infants. discussion in this small study, we documented detailed feeding history in heu predominantly xhosa infants and hu predominantly mixed race infants. in both groups, adherence to breastfeeding recommendations was low and there was suboptimal dietary diversity. however, there were significant differences between groups in the practices and outcomes. breastfeeding occurred in all hu and in one heu infant(s). the mainly formula-fed heu infants had a significant decrease in milk frequency after 6 months, coinciding with no access to free formula after this age. we noted a high rate of sugarand salt-containing snacks given from a young age in both groups. the hu group had poorer anthropometric and poorer nutritional indicators not explained by nutritional factors alone. alcohol and tobacco use were much higher amongst the hu mothers. all these factors (ethnicity, smoking and alcohol use) may have played a role in the difference in anthropometric and nutritional indicators between the two groups. because of these confounding factors and small sample size, statistical analyses were not included. the rate of breastfeeding was extremely low in heu infants, possibly because free formula milk through public health facilities for the first 6 months of life for all heu was standard of care at the time. all hu infants were initiated on breastfeeding, whilst the provincial average was 87.1% in 2003–2004,24 suggesting some success of the baby-friendly initiative.25 in contrast, the proportion of mothers reporting initiation of breastfeeding within an hour after birth was lower than the provincial figure (55% versus 69.3%)24 and the 95%26 found in another western cape study, whilst other studies reported that few infants were breastfed within 1 hour after birth.27 late initiation is a concern as neonatal mortality may increase markedly with increasing delay in initiating breastfeeding.28 in this study, no infant was exclusively breastfed at 6 months. this is lower than the national average of 8.5%24 of infants exclusively breastfed until just under 6 months. it is generally accepted that the proportion of children who are exclusively breastfed until just under 6 months of age is lower than the number derived from the indicator of current status at 6 months,22 which may explain our finding. south africa has one of the lowest rates of exclusive breastfeeding in the world.29,30 reasons for this low rate are complex but include longstanding cultural practices, historical lack of promotion of breastfeeding because of high hiv prevalence and the provision of free formula milk through the pmtct programme.31 continued breastfeeding at 1 year was similar to the national proportion.24 our study does not include data at 20–23 months, the who indicator for continued breastfeeding at 2 years. however, over 50% of hu infants were still breastfed at 18 months compared with 30.6% at 2 years nationally.32 in contrast, in the developing world, about 86% of infants 6–11 months were still breastfed, ranging from 92% and 88% in africa and asia, respectively, to 60% in latin america and the caribbean.30 for children 12–23 months of age, the prevalence of continued breastfeeding dropped to about 70% and 72% in africa and asia, respectively.30 adequate milk frequency for heu infants decreased significantly from 100% at 6 months to 80% at 12 and 18 months. this may have been due to the provision of free formula milk to all heu infants for the first 6 months of life at the time of the study. poorer caregivers may struggle to pay for formula milk thereafter26 or may have chosen to spend their money on other forms of nutrition. the current policy puts more emphasis on social circumstances (replacement feeding only when it is acceptable, feasible, affordable, sustainable and safe) and should help to prevent inadequate milk frequency for heu infants in future. the proportion of infants bottle-fed in the study exceeded national figures; 72% of hu infants at 12 months compared to 40% nationally at 12–15 months. furthermore, 79% of this group were bottle-fed at 18 months compared to 27% at 16–19 months nationally.32 information on bottle-feeding is useful because of the potential interference of bottle-feeding with optimal breastfeeding and the association between bottle-feeding and increased diarrhoeal disease morbidity and mortality.22 early introduction of complementary food is common in many developing countries33,34 and in this study. the lower percentage in the heu group might reflect nutrition counselling input from the clinic staff as these mothers had monthly clinic visits for formula supply in addition to immunisation visits. dietary diversity was inappropriate during the first few months after weaning. dietary diversity is essential as inadequate complementary feeding at 6 months of age is associated with impaired growth and increased stunting during the next 12 months.35 children aged 6–24 months are at the greatest risk from poor feeding practices.36,37 minimum dietary diversity was better in the hu group compared to heu at 6 months, poorer at 12 months, and almost equal at 18 months. the later introduction of complementary food in the heu group might explain the poorer dietary diversity at 6 months. all the hu were given snacks and/or drinks containing sugar and salt at 12 months and heu infants by 18 months. the widespread use of such goods at a young age may increase risk of elevated blood pressure38 and obesity later in life.39 high-sugar foods displace whole foods (e.g. soft drinks displace milk and juice consumption) and contribute to nutritional deficiencies, adding empty kilojoules40 as they reduce dietary diversity. furthermore, sugar contributes to dental caries.41 the road to health booklet already contains basic health promoting messages. health professionals at primary care should highlight this advice to mothers. the hu group had poorer nutritional and anthropometric indicators than the heu group, despite the higher infectious morbidity already described in the heu group.21 the higher infectious morbidity by 12 months may be attributed to deficient immunity rather than their diet. in a recent study of premature infants from the same demographic area, the heu infants also had better anthropometric indicators than the hu group.42 no difference in 2-year rates of adverse health outcomes between early-weaned breastfed and formula-fed children born to hiv-infected mothers has been reported.43 a study from latin america found the association between stunting and feeding practices generally weaker and less consistent during the first year of life, increasing gradually with age.44 stunting was more prevalent in both groups studied as observed in the national food consumption survey in 1999 where 10.3% children 1–9 years were underweight and 21.6% were stunted.45 a much higher proportion of the mothers in the hu group (23% versus 4%) reported alcohol use. excessive alcohol consumption remains a serious social and public health problem in the western cape. the prevalence of risky drinking (more than two drinks per day for women) is higher in the western cape province than in all the other provinces (9% compared with ≤ 5%), with mixed race women having higher levels than other communities (12.6% compared with ≤ 2%).30 evidence regarding the negative effects of heavy drinking in pregnancy is well established. even low levels of maternal alcohol consumption have a negative association with foetal growth.46 in our study, 73% of the mothers of hu infants compared to 28% of the heu group reported smoking. the western cape province has the highest prevalence of smoking of all the provinces: 44.7% of men and 27% of women including a large proportion of pregnant women.47 smoking reduces weight, length and head circumference at birth48 and during the first 2 years of life, independent of several confounding factors.49 ethnicity and the habits of the mother (smoking and alcohol use) during pregnancy and breastfeeding likely affected the difference in anthropometry and nutrition indicators between the two groups. limitations this study had a small sample size with various confounding factors in both groups. interviewer standardisation and guidelines for use of questionnaires were not strictly controlled and some misinterpretation of the questionnaire is possible. in our opinion, even though the data are from 2009, it remains relevant to feeding practices and social issues impacting on healthy growth in the current social and economic climate. conclusion the study found disturbing information regarding feeding patterns and growth in two different cultural groups with similar economic surroundings. infants in both groups received nonnutritional foods with high sugar and salt content, emphasising a general lack of nutritional awareness. more education and more counselling are imperative. further research is needed to understand reasons for the poorer nutritional and anthropometric indicators in the hu group. the role of smoking and alcohol use during pregnancy and breastfeeding and other potential confounders require further investigation. acknowledgements the authors thank students of the hochschule niederrhein, university of applied sciences, faculty of food, nutrition and hospitality sciences, germany, who developed the questionnaire. the authors acknowledge the dedication shown by sister s. sylvester who helped with administering of questionnaires, performed anthropometric measurements and co-ordinated follow-up visits and the participants and their mothers. competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions m.e.r. was the primary author of the article. m.c. and m.f.c. made significant conceptual contributions. m.m.e. was the study leader and responsible for the project protocol and gave valuable comments. references de zoysa i, rea m, martines j. why promote breastfeeding in diarrhoeal disease control programmes? health policy plan. 1991;6(4):371–379. http://dx.doi:10.1093/heapol/6.4.371 cunningham as, jelliffe db, jelliffe ef. breast-feeding and health in the 1980’s: a global epidemiologic review. j pediatr. 1991;118:659–666. http://dx.doi.org/10.1016/s0022-3476(05)80023-x newman j. how breast milk protects newborns. sci am. 1995;273:76–79. http://dx.doi.org/10.1038/scientificamerican1295-76 cohen rj, brown kh, dewey kg, canahuati j, landa rivera l. effects of age of introduction of 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western cape department of health, 2011 [cited 2014 july 23]. available from: http://www.westerncape.gov.za/general-publication/wellness-summit-2011-kelvin-gr zaren b, lindmark g, gebre-medhin m. maternal smoking and body composition of the newborn. acta paediatr. 1996;85(2):213–219. http://dx.doi.org/10.1111/j.1651-2227.1996.tb13995.x kanellopoulos ta, varvarigou aa, karatza aa, beratis ng. course of growth during the first 6 years in children exposed in utero to tobacco smoke. eur j pediatr. 2007;166(7):685–692. http://dx.doi.org/10.1007/s00431-006-0308-8 appendix 1 pilot study of innate immune abnormalities in hiv-exposed uninfected infants. march hiv issue 1-16 the southern african journal of hiv medicine march 2005 4 1 news the low registration of patients on hiv management programmes has received a fair amount of negative publicity recently. however, research suggests that enrolment of those who stand to gain the most benefit from accessing treatment is relatively high. in addition, the inclusion of antiretroviral therapy into the hiv prescribed minimum benefits (pmbs) will have a limited effect on medical schemes. this is according to rodney cowlin, managing director for aid for aids, a medscheme initiative that has been in operation for almost seven years. ‘aid for aids has looked critically at number of beneficiaries registered on hiv programmes in relation to the estimated hiv prevalence within medical schemes,’ he says. to ensure accuracy, the analysis was carried out on several medical schemes covering 680 000 lives and the hiv prevalence for these schemes was calculated to be 10% as of early 2005. ‘to date, 2.7% of beneficiaries from these schemes are enrolled on afa (1.9% are receiving antiretroviral therapy). this includes people at all stages of the disease,’ says cowlin. ‘while this enrolment may sound low, it is unlikely that all hiv-positive beneficiaries would enrol on an hiv management programme, either because the disease is in its early stages, and they have no or few symptoms and are unaware of their hiv status, or because of the perception that there is no reason to register on hiv management programmes until antiretroviral therapy is required.’ an alternative approach to analysing statistics would be to look at the number of hiv-positive beneficiaries who have joined hiv management programmes as a percentage of the number that should be on antiretroviral therapy (art). ‘based on data from the world health organization (who), we estimate that at least 21% of hiv-positive patients should be on art. using the 10% prevalence indicated by the modelling exercise, this equates to 2.1% of the 680 000 lives. currently, 1.9% of lives are actually on art, which is close to the estimated number who should be on treatment,’ cowlin says. the data therefore suggest that enrolment of those who stand to gain most benefit from registering on afa and accessing treatment is relatively high. ‘however, this does not mean that management programmes should not continue to make every effort to enrol as many hivpositive beneficiaries as possible. early enrolment provides a valuable educational opportunity and enables art to be commenced at the optimal time.’ from 1 january 2005 the pmbs related to hiv infection have include the provision of art and appropriate monitoring tests. however, a 2002 report from the centre for actuarial research, university of cape town showed that 90% of medical aid beneficiaries already had access to highly active antiretroviral therapy (haart). ‘currently all 32 of the medical schemes contracted to afa make provision for haart across all benefit options.’ as a result, the new regulations are likely to have little impact on the industry as a whole. the provision of haart will in fact improve the financial position of those schemes that did limit access to haart in the past, as a result of the favourable impact on hospital admissions. further benefit is possible if the scheme makes use of an hiv management programme. ‘analysis of hiv-related expenditure incurred by the schemes referred to in the afa modelling exercise shows that the monthly cost of treating a patient who requires art (first-line therapy) is r935.00. this includes art, consultations, monitoring tests, preventive antibiotics and the management of common associated conditions,’ cowlin says. generally speaking, mediumto high-contribution medical scheme options offer good benefits of up to r25 000 per beneficiary per annum, which is more than adequate to cover treatment costs for a year (haart, including second-line and salvage therapy, pep and pmtct, related medicines and pathology tests). ‘furthermore,’ says cowlin, ‘anticipated reductions in the cost of drugs and monitoring tests will assist schemes to continue providing reasonable benefits for the treatment of hiv/aids.’ medical schemes overcoming hiv/aids hurdles inclusion of art into the hiv pmbs march hiv issue 17-48 4/16/05 10:46 am page 41 t·f sou hfhn mhican jouhnal o~ hi meoicl f -----------august 200 i clinical guideline recommendations for best practice under ideal and resource-constrained conditions clinical acumen should prevail in interpreting hiv test results, for example hiv infection can be ruled out in children 18 months of age or older who have negative hiv serology, a history of no breast-feeding or breast-feeding that ceased at least 3 months previously, no clinical symptoms of hiv disease and no hypoor hypergammaglobulinaemia' in turn, all women should be encouraged to undergo voluntary counselling and testing lvcn' when hiv-exposed infants and young children have been identified, health care professionals still need to determine whether they are indeed hiv-infected or not. such information is critical for the implementation of adequate medical care that musl address monitoring of t-cell subsets, lhe viral load and institution 0 warranted prophylaclic therapies." an n-uninfemd in'an child can 2. definition of an hn-uninfecfed infant/child nonetheless, perinatal hiv diagnosis presents challenges such as: • difficult, early and rapid diagnosis in exposed infants because of the persistence of transplacental passage of malernal immunoglobulin g (lgg) hiv antibodies • timing of hiv transmission from mother to child that affects the sensitivity and specificity of available hiv diagnostic assays • the risk of the infant being exposed to hiv throughout the duration of breast-feeding • the use and role of quantitative and qualitative hiv virological assays • the use and role of the immune complex-dissociated (icd) p24 antigen detection assay for diagnosis and prognosis • the global existence of multiple c1ades or subtypes of hiv and the impact on assay detection.'·5-," 1. introducnon diagnosis of perinatal hiv-l infection in south africa lynne m webber, mmedpath (viml), dth department of medical virology, institute at pathology, univmity of pretorio. mark cotton. fcpa,d, mm,d rpaed), dtm&h, dch rsa) department of paediatrics and child health, university of stellenbosch and tygerberg children's hospital, w cape wendy stevens, mb beh, mlvfed (haem) department of haematology, university of the witwatersrand, johannesburg these guidelines for best practice under both ideal and resource-constrained conditions are intended to provide guidance for health care professionals on the laboratory diagnosis of hiv-l-infected and non-infected infants and young children. resources, circumstances and decisions will differ across the wide range of clinical settings in south africa. these guidelines have therefore been formulated recognising the following needs: • diagnosis of hiv infection in infants and young children born to mothers of unknown hiv serostatus or changing hn serostatus in the perinatal or breastfeeding period • management of hiv-infected or hiv-exposed infants and children with regard to implementation of prophylaxis for opportunistic infections • early identification of hiv infected infants critical for clinical management and initiation of antiretroviral therapy • decisions regarding the continuation or cessation of breast-'eeding practices and the possible implementation of alternative feeding practices • early diagnosis of hiv infection in infants considered for adoption • revised and updated guidelines as new data on laboratory techniques and the management of hiv infeclion are acquired:') rates of hiv in ection among pregnant women are still increasing and rhe perinaral lransmission of hiv in south africa remains a perlinent and critical issue: (refer to the guidelines on preventing mother-to-child transmission of hiv-l in south africa, southern african journal of hiv medicine, issue 4, may 2001.) the diagnosis of hiv infection among infants should begin with identifying hiv infeclion in women before and during every pregnancy and rhis awareness shoul also identify rhe hi -in'ecred infant:' the souther mrica journal of hiv medicine ----------august 2001 diagnosis of perinatally acquired hiv infection. i breast-fed or mixed i i non-breast-fed i ~ ~ dna pcr + dna pcri i dna pcr + i dna pcri i i• • confirmatory stop breast-feeding confirmatory repeat dna pcr dna pcr+ for 3/12 then repeat dna pcr + 3 months laterdnapcr ~ /~ /~ continue breastfeeding + + l ~ ~ confirmatory confirdna pcr+ matory not j. dna infected pcr+ prophylaxis for opportunistic repeat /infections dna pcr consider for antiretroviral therapy 3 months prophylaxis for later opportunistic infections consider for antiretroviral therapy • ! ! referral for clinical management referral for clinical management i • in resource-poor settings: (a) serial ellsa antibody assays may be done at 3-monthly intervals from 6 months of age (b) serum p24 antigen assays (with icd) may be useful in symptomatic subjects. • two +ve dna pcrs are diagnostic of hiv infection. • an hiv rna quantitative assay may be used as the second confirmatory test. indicate non-infection [if under 15 months of age, eusa tests should be at least a month apart). • for infants younger than 12 months yet older than 6 weeks of age, provided breast-feeding has ceased 3 months previously, two negative hiv dna polymerase chain reaction (per) test results would indicate noninfecllon. be defined as an infant/child who has undergone two negative hiv serological or virological tests; such children can be classified into two distinct age categories: • for children older than 12 months of age, provided breast-feeding has ceased 3 months previously, two negative hiv serological tesls based on the enzymelinked immunosorbent assay (eusa) method would august 200 i -----------the southhtn african journal o~ hiv medicine 3. definition of an hiv-infected infant/child and recommendations on the use of hiv tests hiv diagnostic techniques are difficult in infants and young children as a result of the persistence of maternal antibodies up to 18 mo'nths of age."" the hiv dna pcr detecting the dna proviral form of the integrated virus into the genome of peripheral blood cells, is considered the test of choice for the diagnosis of perinatally acquired hiv infection.') the pcr is a diagnostic qualitative reaction compared with the rna quantitative reaction (viral load) which is applied in the prognostic staging or clinical monitoring of patients.' the hiv dna pcr is a rapid and accurate method for identification of hiv infection in infants and young children less than 18 months of age and two tests performed on separate samples are 98.5ofa accurate in identifying infection status after 28 days of age." however, pcr amplifications can be prone to carry over contamination and testing should take place strictly according to the manufacturer's instructions and only in areas dedicated for pcr work. hiv dna pcr methods are commercially available and reliable when standardised and performed in laboratories following good laboratory practices. these tests have been accurate for all known hiv-l subtypes but ongoing molecular surveillance is necessary should novel subtypes emerge. two hiv dna pcr tests should be performed on infants between 6 weeks and 12 months of age. if the hiv dna pcr is positive, breast-feeding should continue where applicable and the infant should receive prophylaxis for opportunistic infections, such as pneumocystis carinii pneumonia (pcp). reports have indicated that the hiv rna quantitative detection assays were more sensitive for early detection of hiv infection in infants born to hiv-infected women than the hiv dna pcr assay. nonetheless, a quantitative assay should not be used as a diagnostic tool and its clinical applications are clearly related to prognosis and further management of the patient"ln infants with a positive hiv dna pcr resul~ the quantitative rna assay may confirm hiv infection and provide additional data relevant to prognosis and as a baseline before antiretroviral therapy." measurement of hiv p24 antigen in blood is not sensitive enough to be used for early diagnosis of hiv infection in infants and young children, even if immune complexdissociated methods are used for sample preparation."" however, repeatedly positive hiv p24 antigen tests could be diagnostic of hiv infection and may be utilised in a resource-constrained setting, but use of a single positive result as a sole diagnostic test must be discouraged. the western blot assay and the cd4 count should not be used for diagnostic purposes. the cd4 count as a diagnostic tool remains unreliable until local reference ranges for infants and young children have been studied and established. 4. recommendations for special circumstances hiv testing for abandoned infants and infants for adoption there is an urgent need to diagnose early hiv infection in abandoned infants, especially those considered for adoption. often the experience has been that hiv-positive infants remain at the institutions for extended periods before a final diagnosis of infection or non-infection is made. in turn, if these children are already older than 1year it is more difficult to find foster or permanent homes for them. it is therefore recommended that these guidelines on diagnosis of perinatal hiv infection in south africa be applied in these circumstances. hiv testing for sexually abused infants and young children the management of sexually abused infants and young children is another area of controversy and uncertainty; however, it is recommended that these guidelines be applied in these circumstances." references 1. gray ge. mclntyre la, jivkov b, violari a preventing mother-ta-child transmission of hiv-l in south africa; recommendations for best prae:tiet=. southun african journal ofhn medicine 2001; 4: 15-26. 2 nielsen k, bryson yj. hiv/aids in infants, children and adolescents. pediatt oin northam 2000; 47 (l): 39-58. 3. bertolli j, st louis me, simonds rj, etal. estimating the timing of mother-tochild transmission of human immunodenciency virus in a breast-feeding population in kinshasa. lfnfectdis 1996; 174: 722-726. 4. davis5f, byers rhjun,lindegren ml cafdwelj b. karon jm, gwinn m. preval~nc~ and incidenet' of vertically acquired hiv infection in the united stat~ lama 1995; 274: 952-955. 5dick.ov~r r, dillon m, leung k-m, etal. early prognostic indicators ill primary perinatal hiv-l infenion: importanc~ of viral rna and th~ timing of transmission on long-t~rm outcome. 1 infect dis 1998; 178: 375-387. 6. dunn or, new~1i ml, adts a£, ~k.ham cs. risk. of human immunodefici~ncy virus type 1 transmission through breastfeeding_ lancer 1992; 340: 585-588. 7. ekpini er. wik.tor sz. san~n ga, et 01. late postnatal mother-to-chlld transmission of hiv-i in abidjan, cote d'lvoire. lancerl997; 349: 1054-1059. 8. palumbo pe, kwok. 5, waters 5, et 01. viral measurement by polym~rase: chain reaction-base:d assays in human immunodeficiency virus-infected infants. j fediocr 1995; 126: 592-595. 9. martin d, sim 1. the laboratory diagnosis of hiv infection. safr medl 2000; 90: 105-109. 10. daar es, little 5, pin j. et 01. diagnosis of primary hiv infection. ann intern med 2001; 134: 25-29. 11. children in working group on antireuoviral therapy and medical management of hn-i infected children. guidelines for the use of antiretroviral agents" in fbediotric hn infection. washington, dc: national paediatric and family hiv resource centre, health resources and servict's administration and the national institutes of health, 15 april 1999: 1~49. 12. haverns pl diagnosis of hiv in newborns. in: armsttong d, cohen 1. infectious diseases. london: harcourt, 1999_ 13. guay la, horn dl, kabengera sr, er 01. hiv-1 icd p24 antigen detettion in ugandan infants: use in early diagnosis of infection and as a marker of disease progression. j med viroi2coj; 62: 426-434. 14. kuritzkts dr. clinical application of virus load monitoring and resistance assays. in: armstrong d, cohen j, eds. infectious diseases. london:harcourt, 1999. 15 cunningham cj<, charbonneau tt, song k, et 01. comparison of human immunodeficiency virus 1 dna polymerase chain reaction and qualitative and quantitative rna polymerase chain reaction in human immunodeficiency virus i-exposed infants. pediarrlnfecrdis1 1999; 18: 30-3516. southern african hiv oinicians society. clinical guideline on antiretroviral therapy in children. southern african journal ofhnmedicine 2txxj; nov: 19-30. untitled j u n e 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e8 process of writing the subsequent consultative process, ostensibly co-ordinated through the south african national aids council (sanac) but in reality co-ordinated by health officials and key civil society members with some political guidance from sanac, engaged in a laborious but highly participatory series of sectoral discussions, engaging labour, gender groups, traditional leaders, the disabled, business and academia, as well as many other sectors, including education and prisons. ready access to e-mail meant a large number of submissions from a range of organisations and individuals were submitted electronically. interestingly, the process of writing was made significantly more complex by recognition that in several areas related to hiv – including poverty, housing and tb – there were existing government policy and targets, and the process of harmonising these with the new plan was not always possible. the writing of the final 159-page report was a consensus event by a few key individuals, and the final version was released at the time of writing, in june 2007. structure of the plan the structure of the document broadly follows the original 2000 version, with four key areas: ■ prevention ■ treatment, care and support ■ research, monitoring, and surveillance ■ human rights and access to justice n e w s – n a t i o n a l the south african national strategic plan: what does it mean for our health system? w d francois venter, fcp (sa) reproductive health and hiv research unit, department of medicine, university of the witwatersrand south africa has a new and highly ambitious guiding document to comprehensively deal with hiv over the next 5 years, the national strategic plan (nsp)1 (table i). the country has an hiv problem resulting in huge mortality and morbidity, with an associated tuberculosis crisis, a growing orphan population, and a range of well-documented adverse social and economic impacts.2 in 2000 the south african government, under siege internationally for its denialist president and combative health minister, hurriedly unveiled its 5-year programme for hiv. the plan was vague and committed the government to very little of substance, and its soft wording contrasted with the strong and clearly defined advocacy campaigns around prevention of mother-to-child transmission (pmtct) and antiretroviral therapy (art) provision, nutrition and unscientific supplements. in 2003, the release of the art component of the operational plan for comprehensive hiv and aids care, management, and treatment resulted in the provision of antiretroviral treatment throughout the country over the next 4 years.3 the original plan expired in 2005, but it was only when the absence of an updated version was highlighted in the media, that the department of health began responding by drawing up a new plan. an initial very rough draft, released after some consultation with special interest groups in the middle of 2006, rapidly attracted civil society interest and mobilisation, as well as strong media interest. the primary aims of the nsp are to: • reduce the rate of new hiv infections by 50% by 2011. • reduce the impact of hiv and aids on individuals, families, communities and society by expanding access to appropriate treatment, care and support to 80% of all hiv positive people and their families by 2011. table i. primary aims of the nsp j u n e 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e1 0 the intention is that ‘all government departments and sectors of civil society will use this plan as a basis to develop their own hiv and aids strategic and operational plans to achieve a focused, coherent, country-wide approach to fighting hiv and aids’. an introduction and overview sketches the epidemic with all the usual sobering indicators, and has a sanitised description of the various conflicts over the last few years between government and sectors of society. the epidemiology descriptions are a useful summary of the evolution and current status of the epidemic, and the discussion on the drivers of transmission is necessarily cursory but frank. there is a section on the process of development of the plan, and a description of the formal governmental political process that overviews the aids agenda. the bulk of the document sketches targets in the four key areas, with objectives, interventions, timelines for implementation, and lead agencies. the final section details the significant cost projections, and some key implementation suggestions, including the establishment of district committees. strengths of the plan undoubtedly, the strength of the plan relates to the setting of aggressive targets (see table ii). in the old plan, provinces were left to set their own targets, often with no measure against local prevalence rates or population size. this led to a situation where some provinces, with very high prevalence, had set themselves low targets, which could easily be met. it also allowed for priority setting in the wrong areas, often because managers and policy makers lacked the skills to identify critical concerns. in some instances, politicians used this unfocused approach to follow an unscientific and denialist agenda, channelling resources to interventions that are not evidence based. south africa has excellent epidemiological provincial data, and extrapolating these targets set by the new plan down to a district level will not be difficult. our unapologetically hardnosed treasury has held government departments accountable for their budgets against outputs, and it would appear that local health departments will be pushed to achieve targets once they are given adequate funding. the wide consultative process for the new plan brings with it unprecedented support from a broad panel of stakeholders. the inclusion of experts from throughout the country has also meant that a variety of ideas were checked against current scientific consensus. the restructuring of the health care system will require creativity and patience from all stakeholders. the consultative process may allow for some of this patience. there is a strong emphasis on monitoring and evaluation, and adequate and committed resources are suggested for this component. ‘core’ indicators are currently being developed, with other measured priorities also reviewed regularly but less often. there is commitment to supporting research, mirrored by a consultative research colloquium at the time of the plan’s launch. there is significant focus on the specific needs of women and children, as well as special groups such as sex workers. testing strategies and the specific issues of pregnancy are recognised, with specific indicators measuring the impact of interventions in each group. continuity of care is also stressed, and regular cd4 measurements for people not needing art are one of the targets. the budget for the plan was drawn up under difficult conditions, with many details of the plan unclear or in the process of being written. however, the treasury has allocated significant resources to the health department, and will no doubt allocate more if the plan appears to be successful. what are the challenges of the plan? a more accurate title for the plan would have been national strategic targets, as the plan gives little guidance on implementation. this may be a necessary tactic to produce a final document, but does leave provinces in a similar position to before, with little guidance on how to implement multiple complex and integrated programmes. there is no order of priorities within the plan. this may also be a function of the consensus building process, as well as the fact that in some cases it may truly be difficult to prioritise (how does one weigh poverty reduction against treatment?), but again leaving it up to individual provincial interpretation may lead to key targets not being met. achieving targets in one area may be seen as permission to underachieve in target 2007 2011 pep for sexual assault survivors 30% coverage 90% coverage % of pregnant women tested for hiv 70% 95% % of hiv-positive women given pmtct 60% 95% adult population tested annually 7% 25% new adult initiates on art 120 000 420 000 % adult initiates started on art outside hospital setting 30% 70% % adult initiates started by nurses on art 10% 80% % hiv exposed children screened by pcr 45% 90% new child initiates on art 17 000 40 000 % of tb patients screened for hiv 40% 90% pep = post-exposure prophylaxis; pcr = polymerase chain reaction. table ii. selected targets t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u n e 2 0 0 7 1 1 another. the implementation process will require clear national leadership and active monitoring. multiple government departments are responsible for many of the targets. achieving buy-in from non-health and social welfare departments has been notoriously difficult. sanac, tasked with the multi-sectoral response, will have its work cut out to ensure adequate commitment of energy from departments that do not see hiv as their primary focus. prevention is a major part of the plan. to an hiv doctor, the ambitious and noble target of reducing infection rates by 50% is, on the face of it, something to be applauded. however, the interventions are disturbingly short on detail, especially considering that current prevention efforts are having little or any impact. behavioural interventions listed are vague and contain little evidence base. some of the language within the prevention section borders on rhetoric, and it is unclear why continuing with current approaches would make an impact, especially an impact as great as a halving of incidence. mechanisms for measuring new infections, which is difficult, are unclear, although the regular hsrc survey, using bed assays, may be one solution. the xdr outbreak of tuberculosis in tugela ferry has triggered a much-needed interrogation of south africa’s tb programme. the nsp attracted strong submissions suggesting that strengthening the tb programme should be integrated within the document. however, there was disagreement, and the position was taken that tb has its own programme that the nsp should support, rather than that the nsp should guide the tb programme. there has been criticism of this approach, especially as the prior separation of tb and hiv has compromised both programmes. finally, at the time of the release of the plan, 2007 was half over. the 2007 targets are modest ‘stretch targets’, and failure to achieve our initial aims would be very demoralising. so what does this all mean for the south african health system? taken individually, hiv testing, pmtct and art targets individually would each involve an enormous refocusing of health systems. the targets collectively are phenomenally ambitious, and references to 'stretch targets' peppered all the consultative meetings. however, a radical restructuring in the way that health care is delivered will be required to ensure delivery. conclusion the targets throughout the plan are very ambitious. the prevention targets appear to be unrealistic without a more creative and aggressive approach to the issue of behaviour. however, the testing and treatment targets, and the strong commitment to a human rights agenda and societal mitigation and stigma reduction, allows for the planning process to continue on a provincial and local level with firm treatment goals in mind. government will need all the help it can get, however, and it will be time for civil society, health care workers and policy makers to fully commit to the new plan. south africa has a long history of producing policy papers that look good but fail to facilitate delivery due to lack of implementation. it must not happen with the national strategic plan. references 1. hiv & aids and sti strategic plan for south africa 2007-2011. pretoria: department of health, 2007. 2. anderson ba., phillips he. adult mortality (age 15-64) based on death notification data in south africa: 1997-2004. report no. 03-09-05. pretoria: statistics south africa, 2006. www.statssa.gov.za 3 south african department of health, full report of the joint health and treasury task team charged with examining treatment options to supplement comprehensive care for hiv/aids in the public health sector, november 2003. http://www.gov.za/issues/hiv/careplan19nov03.htm (last accessed 5 june 2007). august 200 i -----------the southern african journal of hiv medicine eisabe klinck legal advisor, south african medical association legal and ethical issues those held by a private sector facility. apart from this, there are two further differences between access to information held by public and private bodies: public bodies have to appoint so-called 'information officers', and also have to have a process of internal appeal if the requester is not satisfied. refusal of access to information may only take place on the grounds prescribed by the act (sections 34 45 in the case of public, and sections 63 69 in the case of private bodies). if part of a record may be refused, and part of it not, the principle of severability states that such parts should be deleted, photocopied out of severed from the parts to which access should be granted. therefore the mere fact that part of a record contains information that may be refused may not serve as a reason to refuse access to the rest of the record. a person requesting information has to do so on the prescribed form (found in the regulations to the act), and there are two types of fees payable. the act distinguishes between 'personal requesters' and 'requesters: a per'sonal requester is a person requesting information about him/herself. such a person does not have to pay the standard fee of r35 (in the case of information requested from a public body) or r50 (in the case of information requested from a private body). all other requesters have to pay that fee. when access is to be given, there are three more types of fees that all requesters have to pay, i.e. reproduction fees (for photocopying, computer disks, etc.l. search and preparation fees (r 15 per hour or part thereof in the case of public bodies and r30 per hour or part thereof in the case of private bodies), and actual postage. the act does not provide for faxing costs, i.e. a requester would either have to receive the information by mail, collect it personally, or the private or public body could fax it, if s/he so wishes, at the requester's expense. refusal of access some of the most pertinent grounds for refusal concern the protection of privacy of a third party and the protection of confidentiality agreements. this means that private information may not be unreasonably disclosed to a third party. personal information includes medical information, financial information, ete. as it is uncertain as to what 'unreasonable' disclosure entails, it is advisable that medical requests made in terms of the act information in the possession of any facility can fall into one of two categories: information automatically available, and information available on request, as explained below. as a first step, all health care facilities [including private practices), irrespective of whether they are private or public, have to decide which information is to be made available 'voluntarily and automatically' to the public at large for free and for sale. all other information has to be made available as set out below and at the fees described below. information automatically available has to be listed and included in a manual, available to the public, in which every facility should also describe the manner of access (and price) of certain categories of information (sections 14 and 51). a body can also request the minister of justice to exempt certain types of information from the application of the act. all facilities should have a policy on the retention of records, as well as when records may be disposed of, ete. the promotion of access to information act of 2000 (the act) came into operation in march this year. the act purports to give effect to the human right of access to information. it contains very detailed prescriptions on procedure, forms and types of access. it also sets time frames within which the person or institution holding information has to respond to a request for access to information. the department of justice administers the act the act overrides any other act that provides for more restrictive access to information. in this regard concern has been expressed in relation to its suitability for the health sector and its relationship with the proposed national health bill. introduction decision regarding information automatically available the right of access to information some ramifications for the health sector a person requesting access to records or information held by a private body has to show that s/he is requesting the information in order to protect or exercise his/her rights. a person requesting information from a public body does not have to show that s/he is requesting it in pursuance of their rights. this creates a rather strange anomaly in that persons will have easier access to health care information (or even their own records) held by state health care facilities, than the southern african journal of hiv meoicine -----------practitioners do not provide any information relating to a patient to any third party without the patient's informed consent. alternatively, medical practitioners may conclude confidentiality agreements with their patients, if, for example, they want to protect the medical information of a minor from being accessed by a parent (this may be the case where child abuse is suspected, or where the minor has legally obtained a termination of her pregnancy, has legally consented to medical tests or treatment, etc.). medical aid funds, pharmaceutical companies, researchers, etc. all request patient information from health care practitioners from time to time. even though such information may be de-indentified, it may still constitute a violation of privacy. in order to protect themselves from possible legal action, medical practitioners should in all cases obtain the informed consent of patients regarding the specific requesters to whom specified information will be divulged. if a medical aid fund requests information from a medical practitioner, only information as delineated in the medical schemes act of 1998 may be given to medical aid funds, and then only under the prescribed circumstances. these circumstances include that the information has to serve the purpose of managed care and that access has to take place in terms of an agreement between the medical aid fund and the service provider. other grounds for refusal include commercial information on and of a third party where the disclosure of such information would cause disadvantage in contractual or other negotiations, priviledged legal information and the commercial information on and of a private body. it should be noted that the list for grounds of refusal in relation to public bodies differs from those listed for refusal by private bodies. information relating to police dockets in bail proceedings, for example, may be refused under certain circumstances listed in the act. south african revenue service (sars) records are also protected by this list. medical records that do not fall within one of the grounds for refusal, but which contain information likely to cause serious physical or mental harnl to the patient requesting it, have to be dealt with in terms of a specific procedure set out in the act. in short, the patient must be asked to nominate a health practitioner who may then be consulted regarding possible serious harm of such information to the patient, and who can ensure that adequate arrangements are made for counselling of the patient. mandatory disclosure • despite falling within the grounds for refusal, the act states that certain information has to be disclosed. such disclosure must take place if it reveals a substantial contravention or failure to comply with the law or an imminent and serious public safety risk, and if the public interest in the disclosure clearly outweighs the possible harm. this may be very risky terrain, as some people may feel that disclosing the hiv status of a person falls within the ambit of this section. however, it should be borne in mind that the act only applies to where information is requested. it does not apply where information is volunteered. in such cases the laws in relation to the protection of privacy, as well as the relevant ethical considerations, still apply. if information is requested and it is possible that it falls within this ambit, it is advisable to first obtain legal advice on this matter. operation of the act in practice in practice, the act will operate as follows: 1. a person will request access on the prescribed form. in the case of public bodies the information officer will take responsibility for the request; the head of a private body has to duly delegate a person to fulfil this function. the information officer must open a file for every requester, so as to keep track of the flow of correspondence on the matter. 2. the information officer writes the requester a letter stating that the request has been received and a decision will be made within 30 days. this period may be extended if the search or request concerns a large number of documents, etc. in this case, however, the requester must consent to such an extension. if the record concerns a health record that may pose serious harm to the requester, the requester must be asked in this letter to nominate a health care practitioner. 3. if the request is granted, written notice must be given to the requester of the access fee (r3s or rso) and the fees in relation to searches, reproduction and postage. it is advisable that a table sets out exactly how this is calculated. the letter should include reference to the fact that the requester may approach a relevant court of law if not satisfied with the outcome. in the case of a public body, the requester must be made aware of the internal appeal procedure. 4. if the request is denied, written notice must be given with full particulars as to the grounds, as specified in the act. on which access is refused. again, information has to be given as to the rights of appeal or review. 5. if a record was lost, destroyed, could not be found or does not exist, the requester must be informed as such. an affidavit or affirmation to that effect has to be made and attached to the letter. the affidavit must state all the steps taken in order to find the document and it is advisable that the policy of the facility in relation to the retention, destruction, etc. of records be attached to such affidavit and letter. destroying or losing a document so as to evade the provisions of the act constitutes an offence for which a fine or up to 2 years' imprisonment may be given. 6. if records are requested for which the consent of a third party first has to be obtained [sections 47ff and sections 71 ff), those procedures and time frames have to be adhered to. august 200 i j u ly 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e over 35 participants from four african nations, the usa, the uk and the european union – 21 of whom gave oral presentations – were brought together for this satellite conference, the first such to accompany the south african aids conference. this executive summary reviews the conference proceedings in each of the following categories: new msm research and challenges, current lgbt programmes overview and needs assessment, and developing advocacy and funding strategies. current research outputs underscored what we know to be a very difficult situation. among men who have sex with men (msm) in south africa, kenya and malawi there are documented high-risk sexual behaviours; limited access to water-based lubricants; low knowledge of hiv; fatalistic views of hiv, sickness, and death; barriers to accessing care, hiv testing, antiretrovirals (arvs) and support; vulnerability to homoprejudice and sexual violence; a lack of general security; and the most vulnerable being least connected to resourced gay communities.1-5 research challenges included developing standardised protocol definitions to produce comparable data outputs across sites, obtaining and verifying more representative samples, recruitment of high-risk msm to research studies and delivery services, identifying and accessing bisexual men, and mapping the crossover of disparate hetero and homosexual hiv epidemics.6-11 lesbian, gay, bisexual, and transgender (lgbt) advocates, service providers and support organizations outlined plans to mainstream lgbt-sensitive and specific health care into general health systems, with sex-positive and holistic care packages.12-14 there was a call to better understand msm populations; create an lgbt sexual health training manual for clinicians; recognise the role of religion in sexual-identity formation; and address the almost complete lack of current biand trans-specific research and programming.12-19 underscored was the need for more and better resourced lgbt safe-spaces, and action against sexual violence targeting lgbt folk.12,13,16 outside of south africa, the paramount issue was an urgent need to de-criminalise homosexuality.1,4,11,15,19 advocacy tools and funding strategies require the anticipation of research outcomes and the preparation of targeted advocacy packages for specific audiences, such as government and religious leaders.20,21 data outputs should be used more effectively to leverage secure funds for continued and better research.22,23 advocacy ‘champions’ within the lgbt community need to be identified and groomed to liaise with donors in meeting funding goals.20,24 especially in this time of global financial downturn, the focus must be on value for money, prioritising quality research projects and evidence-based interventions, while adopting flexible programme development and step-wise approaches to roll-out.20,22-24 throughout the satellite, researchers and advocates alike expressed a need for more open dialogue in order to develop a single framework with which to approach shared goals. there is a need to work collectively towards security for african lgbt people, engaging all levels of government in discourse around negativerights legislation, while also holding them accountable. more streamlined approaches to research and service delivery must be developed, delegating responsibilities to those best suited to the task. and lastly, programme expansion must be informed by sound scientific research and guided by rigorous monitoring and evaluation, an ideal opportunity for lgbt research-advocate partnership. references 1. dhaliwal m. msm in southern africa … intersections of policy, human rights, and public health. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 2. rispel l. the johannesburg/ethekwini men’s study (jems): lessons learnt and future pointers. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 3. dladla s. rds prevalence study in soweto, south africa. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 4. sanders e. high-incidence cohort in kilifi, kenya. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 5. burrell e. new hiv prevention research: the cape town prep studies. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 6. nel j. levels of empowerment and emerging lgbt communities in south africa. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 7. reddy v. is aids a death sentence? preliminary outcomes of a survey among tshwane’s msm. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. sa aids 2009 msm satellite conference, research and advocacy: sharing the strength, bridging the gap 30 31 march 2009, durban c o n f e r e n c e r e p o r t e burrell, mph desmond tutu hiv foundation, cape town 48 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u ly 2 0 0 9 8. struthers h. diversity, definitions, and directions. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 9. burrell e. recruiting high-risk msm for a hiv prevention clinical trial in cape town, south africa. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 10. metcalf c. ‘eish, but the whites are scarce!’: jems research challenges. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 11. muhaari a. experiences of working with msm in mombassa. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 12. nel d. service delivery to vulnerable groups. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 13. valentine m. multidimensional approach to msm sex and its impact on risk behaviour. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 14. rebe k. health4men: a clinical service for msm in cape town. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 15. trapence g. an overview of msm programs in malawi. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 16. mkhize n. drop-in lgbt centre in durban. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 17. hendricks p. hiv and muslim msm. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 18. bowley c. an assessment of male to female transgender person’s needs who are msm in south africa. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 19. chibwezo w. sexual reproductive health and msm in malawi. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 20. avertt s. integrating research outcomes into advocacy (agitating for a better world). sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 21. swartz i. research as advocacy tool: making the evidence work for us. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 22. mah t. resources for hiv prevention for msm. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 23. seale a. resources, tools, and strategic considerations for funding strategies for msm and lgbti programmes and services. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 24. avertt s. negotiate safely with your funders: three observations. sa aids 2009 msm satellite conference, 30 31 march 2009, durban. 49 acknowledgements references about the author(s) michelle moorhouse wits reproductive health and hiv institute, johannesburg, south africa francesca conradie right to care and clinical hiv research unit, university of the witwatersrand, south africa francois venter wits reproductive health and hiv institute, johannesburg, south africa citation moorhouse m, conradie f, venter f. what is the role of cd4 count in a large public health antiretroviral programme? s afr j hiv med. 2016;17(1), art. #446, 3 pages. http://dx.doi.org/10.4102/sajhivmed.v17i1.446 original research what is the role of cd4 count in a large public health antiretroviral programme? michelle moorhouse, francesca conradie, francois venter published: 12 feb. 2016 copyright: © 2016. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. hiv clinicians have relied on the cd4 count for more than three decades as being central to key issues in managing hiv-positive patients. the cd4 count is an important predictor of disease progression1,2,3,4,5 and death,6,7,8 and has informed us when to start antiretroviral therapy (art), opportunistic infection (oi) risk stratification (especially in late presenting patients), when to start and stop oi prophylaxis or management, as well as in monitoring response to treatment.8,9,10 however, in areas where viral loads are readily available and patients are virologically suppressed and stable, the question arises – is there a role for continued cd4 count monitoring in this setting? this question merits consideration. south africa bears 20% of the global hiv burden, with approximately 3 million people accessing arvs and a similar number still in need of art. with such large numbers of people accessing care through a public health programme, cost remains a critical factor that needs to be considered with regard to each and every aspect of the programme. savings that may seem miniscule considered on an individual basis, are not inconsiderable when scaled up to the size of south africa’s arv programme. the south african department of health (doh) guidelines, which are evidence-based, have traditionally followed the world health organization (who) recommendations. the first doh guidelines, in 2004, recommended treatment initiation at cd4 count < 200 cells/mm3. in 2009, the cd4 threshold for treatment was increased to 350 cells/mm3. the haiti study, published in nejm in 2010, was a randomised, controlled trial that demonstrated reduced mortality and incident tuberculosis (tb) in patients starting art at a cd4 count threshold of < 350 cells/mm3 (compared with patients waiting to commence therapy at a threshold of < 200 cells/mm3).11 the previous who recommendation of treatment initiation at cd4 counts < 500 cells/mm3 was adopted into the south african doh guidelines in january 2015. however, the evidence supporting the 500 cells/mm3 cd4 threshold has been less clear because, until recently, no randomised, controlled trial (rct) had definitively shown any benefit in initiating art at a cd4 count higher than 350 cells/mm3. data from observational studies suggested reduced morbidity (especially from non-hiv-related events) and mortality with art initiation at higher cd4 counts. the temprano and start studies are rcts investigating optimal cd4 count initiation thresholds. data from temprano are more difficult to interpret, due to the study methodology that, in two of the four study arms, shifted cd4 initiation thresholds several times. the reason for this was that national guidelines in the countries in which temprano was conducted changed according the who guideline recommendations.12 hptn 052 is an rct that showed reduced morbidity, but not mortality, associated with starting art at a cd4 count of 350 cells/mm3 – 550 cells/mm3 (compared with < 250 cells/mm3). despite the fact that mortality was not reduced in hptn 052, the major benefit demonstrated in the study was a 96% reduction in hiv infection amongst serodiscordant couples in which the hiv-positive partner was initiated at the higher cd4 count threshold, as opposed to delaying to cd4 < 250 cells/mm3.13 these data are a compelling argument for moving towards ‘test and treat’ (art initiation independent of cd4 count), as recommended in the latest iteration of who guidelines (2015).14 the start study, an rct, compared early art initiation in asymptomatic patients with cd4 counts > 500 cells/mm3 to deferred initiation at cd4 count ≤ 350 cells/mm3. the study commenced in 2009 and enrolled over 4000 participants. the start study was stopped prematurely, in 2015, and a press release was issued by the national institute of allergy and infectious diseases based on the recommendations of the study’s independent data and safety monitoring board (dsmb). following their review of interim study data, the dsmb found that the risk of developing serious illness or death in the early treatment arm was reduced by 53%, compared to the results for those in the deferred treatment arm. start study, therefore, provides robust evidence that it is beneficial to patients to initiate art irrespective of their cd4 count and whether or not they are asymptomatic.15 these findings have global implications, in that we now have proof of the double impact of early art initiation: the benefit to the health of the hiv-infected individual as proven in start, as well the reduction of hiv transmission risk, as proven in hptn052. in its 2014–2015 hiv treatment guidelines, the doh endorses the use of the viral load as the preferred test for monitoring response to art, a shift that aligns with current who guidelines. the viral load detects virological failure before immunological or clinical failure become apparent and is one of the main reasons for the shift towards the viral load as the preferred test for monitoring response art in hiv-infected patients. one of the barriers to viral load monitoring is the cost. by reducing the overall cost of laboratory testing, for example by stopping routine cd4 count monitoring in virologically suppressed patients, will significantly increase the amount of money available which could be channeled to covering the costs of increasing numbers of viral loads as the size and cost of south africa’s arv programme increases as we strive for 90:90:90. the evidence supports moving away from using cd4 counts as a means for monitoring art. data from rcts and observational studies suggest that, once virological suppression is achieved, in the majority of patients, cd4 counts remain stable over time,16 and this conclusion is supported by cohort data from high hiv prevalence areas, namely south africa and uganda. the south african cohort showed that cd4 counts tend to be maintained over 200 cells/mm3 in more than 92% of patients to 10 years. moreover, those who did experience cd4 decreases, these were self-limiting in more than 90% of cases16. the ugandan cohort had similar findings, in that amongst virologically suppressed patients with cd4 counts ≥ 200 cells/mm3, less than 5% of patients experienced cd4 declines to < 200 cells/mm3; in those whose subsequent cd4 counts were measured, more than 80% were transient.17 currently, waiting for a cd4 count to confirm eligibility for art in patients may in fact be a barrier to treatment and delay art initiation. yet, we have seen, for example, in south africa’s prevention of mother-to-child transmission (pmtct) programme, that it is possible to initiate art without waiting for a cd4 count result. the very test that may be the key criterion for treatment eligibility should not also, ironically, function as the barrier to treatment. until such times as south africa moves towards ‘test and treat’, which is supported by start data, the main role of cd4 count monitoring will be in determining eligibility for art, as well as oi prophylaxis or management, and assisting clinicians in deciding when oi prophylaxis/treatment should be discontinued, to avoid prolonged administration of drugs with not insubstantial side effect profiles and toxicity in otherwise healthy patients. in the scenario of ‘test and treat’, cd4 count testing will still continue to play an important role in the baseline assessment of patients to inform initial clinical management decisions, particularly for those presenting late to care, as well as those on art where clinical deterioration or virological failure is suspected or evident. the southern african hiv clinicians society is of the opinion that the cd4 count retains an important role in the care of hiv-infected patients. the society also believes that the role of the cd4 count is changing, as new rct evidence becomes available to guide optimal patient care that is balanced, out of necessity, against cost concerns in a public health programme of the magnitude of south africa’s antiretroviral programme. going forward, the optimal use of the cd4 count in south africa’s programme would be to guide the initiation and discontinuation of oi prophylaxis/management and in assessing late presenting patients, or patients on art when clinical or immunological failure is suspected. once patients are initiated onto art, we recommend that one further cd4 count be checked, at 6 months, to guide decisions regarding oi prophylaxis/management, and thereafter only if clinically indicated. in terms of monitoring the response to art, the preferred test remains the viral load. in stable, virologically suppressed patients, the cd4 count offers little value and contributes significantly to costs in an arv programme as large as that found in south africa. acknowledgements competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions the piece was researched and written by m.m. and reviewed by f.c. and f.v. references polk bf, fox r, brookmeyer r, et al. predictors of the acquired immunodeficiency syndrome developing in a cohort of seropositive homosexual men. n engl j med. 1987;316:61–66. goedert jj, biggar rj, melbye m, et al. effect of t4 count and cofactors on the incidence of aids in homosexual men infected with human immunodeficiency virus. jama. 1987;257:331–334. fahey jl, taylor jm, detels r, et al. the prognostic value of cellular and serologic markers in infection with human immunodeficiency virus type 1. n engl j med. 1990;322:166–172. phillips an, lee ca, elford j, et al. serial cd4 lymphocyte counts and development of aids. lancet. 1991;337:389–392. fauci as, macher am, longo dl, et al. nih conference. acquired immunodeficiency syndrome: epidemiologic, clinical, immunologic, and therapeutic considerations. ann intern med. 1984;100:92–106. pedersen c, gerstoft j, tauris p, et al. trends in survival of danish aids patients from 1981 to 1989. aids. 1990;4:1111–1116. saah aj, hoover dr, he y, kingsley la, phair jp. factors influencing survival after aids: report from the multicenter aids cohort study (macs). j acquir immune defic syndr. 1994;7:287–295. hogg rs, yip b, chan kj, et al. rates of disease progression by baseline cd4 cell count and viral load after initiating triple-drug therapy. jama. 2001;286: 2568–2577. department of health and human services and henry j. kaiser family foundation. guidelines for the use of antiretroviral agents in hiv-infected adults and adolescents. mmwr recomm rep. 1998;47:43–82. world health organization. scaling up antiretroviral therapy in resource-limited settings: guidelines for a public health approach. geneva: who; 2002. severe p, juste ma, ambroise a, et al. early versus standard antiretroviral therapy for hiv-infected adults in haiti. n engl j med. 2010;363(3):257–265. available from: http://dx.doi.org/10.1056/nejmoa0910370. temprano anrs 12136 study group. a trial of early antiretrovirals and isoniazid preventive therapy in africa. n engl j med. 2015;373:808–822. cohen ms, chen yq, mccauley m, et al. prevention of hiv-1 infection with early antiretroviral therapy. n engl j med. 2011;365(6):493–505. available from: http://dx.doi.org/0.1056/nejmoa1105243. insight start study group, lundgren jd, babiker ag, et al. initiation of antiretroviral therapy in early asymptomatic hiv infection. n engl j med. 2015;373:795–807. ford n, meintjes g, pozniak a, et al. the future role of cd4 cell count for monitoring antiretroviral therapy. lancet infect dis. 2015;15:241–247. ford n, stinson k, davies m-a, et al. is it safe to drop cd4 monitoring among virologically suppressed patients: a cohort evaluation from khayelitsha, south africa. aids. 2014;28:2003–2005. reynolds s, sempa j, kiragga a, et al. is cd4 monitoring needed among ugandan clients achieving virologic response to treatment? abstract 56, 2014 conference on retroviruses and opportunistic infections; 2014 mar 03–06; boston, usa. hiv 883 conference report ‘feedback: where data finally get thrilling’ – tools for facility managers to use data for improved health outcomes in the prevention of mother-to-child transmission of hiv and antiretroviral therapy j murphy,1 mph; c-h mershon,2 mph; h struthers,1 msc, mba; j mcintyre,1,3 mb chb, frcog 1 anova health institute, johannesburg, south africa 2 gillings school of global public health, university of north carolina at chapel hill, usa 3 school of public health and family medicine, university of cape town, south africa corresponding author: j murphy (murphy@anovahealth.co.za) data use and data quality continue to be a challenge for government sector health facilities and districts across south africa. led by the national department of health, key stakeholders, such as the anova health institute and district health management teams, are aligning efforts to address these gaps. coverage and correct implementation of existing tools – including tier.net, routine data collection forms and the south african district health information system – must be ensured. this conference report provides an overview of such tools and summarises suggestions for quality improvement, data use and systematic evaluation of data-related interventions. s afr j hiv med 2013;14(3):131-134 doi:10.7196/sajhivmed.883 there is increasing recognition of the impor­t­ance of a functional information-manage­ment system to improve health outcomes in south africa (sa). this is gaining attention through a number of local and international policy docu­ments, including the sa district health management information system (dhmis) policy (2011),1 the aid effectiveness framework (2012) 2 and the us president’s emergency plan for aids relief (pepfar) partnership framework.3 with ongoing evaluation and improvement of the sa district health information system (dhis), patients, clinicians and policymakers are ideally positioned to benefit from the improved quality and increased use of routinely collected data at facility, sub-district and district levels. in the case of hiv services, the dhis can be particularly valuable in determining the number of clients receiving antiretroviral therapy (art) and in identifying gaps in the prevention of mother-to-child transmission (pmtct) of hiv services. the anova health institute (anova) recently gathered 160 delegates in johannesburg for the symposium ‘feedback: where data finally get thrilling’, to provide an overview of best practice for information use in assessment and improvement of health services, with an emphasis on hiv treatment and pmtct. the target audience included facility managers across gauteng province, with a focus on johannesburg. anova partnered with information and programme managers from provincial and district government, as well as a variety of non-governmental organisations (ngos), to maximise expertise and objectivity on the issue. magnitude of the issue the dhmis policy calls for more than just addressing data quality; it denotes that information should be used in programme planning and in clarifying the main roles and responsibilities ‘for ensuring data completeness, data quality, and data use and “ownership” at all levels of the health system.’4 one finding of this symposium was voiced by those in attendance: the dhmis policy is not available or followed by all facility managers, especially in the areas of data use for programme decisions and feedback between all levels (facility to sub-district/district and vice versa). the dhis, which since 1996 has been the sole government repository of health-related data in sa, has not reached optimal levels of quality, as documented5 and anecdotally reported. this holds true for pmtct as documented by mate et al.,6 as well as for art data which are not as well documented. particular areas of concern include data accuracy, completeness and reliability. fortunately, the national department of health (ndoh), facility managers, district doh structures and ngo partners have begun the implementation of tools like tier.net, the prevention of mother-to-child transmission action framework and the district health barometer (dhb) to interrogate and better utilise information. in this context, this conference report is not a declaration of success, but rather a brief description of the status of our progress in using tools to strengthen data quality and ease of use. conference content keynote speaker, winnie moleko from the wits reproductive health and hiv institute (wrhi)/ndoh, presented ‘data feedback towards quality improvement in service delivery’. moleko discussed the state of data quality in sa and the role that this plays in quality improvement and implementation of the national core standards.7 practitioners and policy makers can use data to identify gaps in service delivery, resources and facility needs. for data to be useful, they must be correct and accurate; data that are incorrect or presented misleadingly can be detrimental to service delivery and planning. one suggestion that moleko made, which can be implemented in service facilities, is to post the facility’s data on improvements and achievements in a public place in the facility. this allows staff and clinicians to engage the public and clients in the facility’s data-improvement process. all presentations are available online (http://www.anovahealth.co.za/resources/entry/feedback_where_data_finally_gets_thrilling/ ). table 1 summarises the lessons learnt for clinicians and facility managers working in the field of hiv. the body of the symposium covered three main areas: (i) review of data quality and challenges; (ii) best practice review of data use for quality improvement; and (iii) data tools available to facilities, clinicians and policy makers. review of data quality and challenges mokgadi morokolo represented johannesburg health information and gave an overview of the dhmis. she reminded the facility managers in the audience of their responsibility for the data signoff process. this includes a review of the source data such as facility registers, critical analysis of the data outputs, and timely submission of reports and corrections. she emphasised that this is the responsibility of sub-district managers, district directors and hospital chief executive officers (ceos). these managers are also responsible for improving their knowledge of indicators and maintaining current data-collection tools. district directors are responsible for ensuring that facilities have the current and correct stationery. goodwill kachingwe and nowinile dube presented recent district-level data and highlighted where data can and should be used at all phases of the programme cycle (fig. 1). data are used in the conceptual phase to help determine what health outcomes need to be addressed through the programme. data can be used in the planning phase to provide insight into where resources need to be distributed or to provide a baseline for future evaluation. in the implementation phase, data are used to monitor the programme implementation or to ensure that target populations are being reached by the programme. in the termination phase, data are used to evaluate the success of the programme, or to determine how the programme has contributed to district, provincial or national targets. fig. 1. flowchart indicating where data can and should be used at all phases of the dhmis programme cycle. best practice review of data use for quality improvement maria sibanyoni from the wrhi reported on the implementation of a quality-improve­ment inter­vention in johannesburg. 8 the intervention incorporated quality-improve­ment meetings with staff, collaborative learning workshops, process mapping and a data dashboard to improve initiation and adherence to art. this effort succeeded in creating an inter-facility referral network and focused on data-driven processes that provided clear and achievable targets for meeting client needs. these achievements can be replicated in other locations. theunis hurter, from anova’s cape winelands project, demystified tier.net reporting for the audience. tier.net is being expanded into facilities throughout the country (fig. 2 shows its growing use in johannesburg). in the winelands, tier.net has helped clinicians and policy makers at facilities and the district level to identify defaulters, track and trace patients, and even identify pmtct programme gaps. specific to pmtct, hurter and doh colleagues in the cape winelands identified, through the use of routine data, that facilities in the district had initiated art in more under-2-year-olds than had been offered pmtct services – a clear service-delivery gap. like this example, one key element in using data for effective programme and data quality improvement is the presence of facility managers who empower their data capturers and others to give feedback on the data and make note of any trends, issues or remarkable issues in the data. fig. 2. mapping tier.net progress in johannesburg, may 2012. 9 existing data tools available to facilities, clinicians and policy makers existing tools, organisations and methodologies are in abundance, but greater coverage and use of these tools is still needed. the dhis, for example, can be used to identify data quality issues through min/max out-of-range graphs and data completeness reports. the prevention of mother-to-child transmission action framework is effective for target-setting and monitoring programme performance. as much of this information was new to the conference audience, we suggest that raising awareness of these tools is still necessary. mashudu rampilo shared the results of an informal data quality audit comparing source documents (registers) to facility reports and dhis data specific to hiv testing, the pmtct programme and art in mopani, limpopo province. although from a different setting, the audience was both familiar and shocked with the results. rampilo’s results showed wide variation and regular disagreement between each of the three data points (the source, facility report and the dhis). as noted in the dhmis overview, data accuracy is the responsibility of the staff at facility, sub-district and district level. one method to improve service delivery at the facility level is treatment-gap modelling. this uses baseline data, national targets and comparisons between people receiving treatment and those eligible for treatment, to estimate where the biggest gaps in service coverage exist, and where more needs to be done to meet local, provincial and national health indicator targets. this approach was adapted from the work of barker and venter.10 the available, but under-utilised (as remarked from conference attendees) dhb contains a comprehensive set of indicators to inform planning at all levels in the government and ngo sectors. candy day from the health systems trust highlighted how the dhb can be used to provide an overall view of district health performance at the primary healthcare level, and to provide comparative data to monitor the overall quality of service within a district. one final strategy for data use is the three tier art monitoring and evaluation (m&e) strategy, of which the art m&e standard operating procedures (sops) are a key element. catherine white presented this tool, which is essential to quality data collection and use of m&e of art. recommendations while facilitating the final discussion, dr cephas chikanda, anova’s head of health systems strengthening, and prince dulaze, anova’s m&e co-ordinator for johannesburg, solicited participant feedback to consolidate the key points that the audience had derived from the day’s presentations. the participants’ recommendations included: • there is a need for better communication about the data within facilities between clinicians, facility managers and data collectors, as well as between the different levels of the health system. for example, facility and district managers need to communicate what the data tell them about service delivery and resources. • accountability for the data is the re­sponsi­bility of everyone, from facility and district data collectors, to district managers and policy makers at the national level. accountability includes knowing the data elements, what the data reveal about health service delivery and outcomes, and how to accurately and efficiently use data to improve the health system. • the continuous revision of data-collection tools and systems is a concern. standardisation of tools and systems according to the dhmis would facilitate correct and timely completion of collection tools, assist users in becoming familiar and comfortable with the data tools, and make it easier for users and collectors to identify issues and errors. standardisation is one way to contribute to continuous quality improvement, as well as the development and use of tools and strategies for the immediate and long-term. • in order for the health system to use data most efficiently for its best effect, it is important to value good quality data as central to quality healthcare provision and worthy of investing time and resources. this includes sharing the results of data collection and interpretation with health services and the public. data must also be prioritised within the system to highlight its worth as a valuable tool to improve health service delivery. acknowledgement. the conference was funded by pepfar through the united states agency for international development (usaid) under co-operative agreement 674-a-00-08-00009-00 to the anova health institute. the opinions expressed herein are those of the authors and do not necessarily reflect the views of usaid/pepfar. references 1. national department of 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[http://dx.doi.org/10.1136/bmjqs-2011-000381] 9. measure evaluation. excel2googleearth (e2g). chapel hill: measure evaluation. http://www.cpc.unc.edu/measure/tools/monitoring-evaluation-systems/e2g (accessed 1 march 2012). 9. measure evaluation. excel2googleearth (e2g). chapel hill: measure evaluation. http://www.cpc.unc.edu/measure/tools/monitoring-evaluation-systems/e2g (accessed 1 march 2012). 10. barker pm, venter f. setting district-based annual targets for haart and pmtct: a first step in planning effective intervention for the hiv/aids epidemic. s afr med j 2007;95:916-917. http://www.ihi.org/knowledge/pages/tools/southafricahaartcalculator.aspx (accessed 1 april 2012). 10. barker pm, venter f. setting district-based annual targets for haart and pmtct: a first step in planning effective intervention for the hiv/aids epidemic. s afr med j 2007;95:916-917. http://www.ihi.org/knowledge/pages/tools/southafricahaartcalculator.aspx (accessed 1 april 2012). hivmed_17(1)_2016_reviwer acknowledgement.indd the editorial team of southern african journal of hiv medicine recognises the value and importance of the peer reviewer in the overall publication process – not only in shaping the individual manuscript, but also in shaping the credibility and reputation of our journal. we are committed to the timely publication of all original, innovative contributions submitted for publication. as such, the identification and selection of reviewers who have expertise and interest in the topics appropriate to each manuscript are essential elements in ensuring a timely, productive peer review process. we would like to take this opportunity to thank all reviewers who participated in shaping this volume of southern african journal of hiv medicine. we appreciate the time taken to perform your review successfully. in an effort to facilitate the selection of appropriate peer reviewers for southern african journal of hiv medicine, we ask that you take a moment to update your electronic 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black brian eley candice fick charles feldman david spencer evan shoul francois venter gary maartens gert van zyl gillian hunt godspower akpomiemie graeme meintjes gregory jonsson helena rabie jeanette wessels jonathan stadler kevin b. rebe kim roberg kuben vather lee fairlie malcolm davies maria papathanasopoulos melanie pleaner mervyn mer michelle a. moorhouse mo archary mohammed majam mopo radebe nicola wattrus nicolette du plessis nomathemba chandiwana remco peters rob freercks samantha a. nicholson sean wasserman shafiya coovadia shanene olivera shayne loubser susan j. randall tammy meyers theresa m. rossouw tim tucker vivian cox wendy burgers open accesshttp://www.sajhivmed.org.za page iii of iii reviewer acknowledgementpage 1 of 1 southern african journal of hiv medicine hiv message message from the executive mid-year and the cold is settling in. the hype about the introduction of fixed-dose combinations (fdcs) has passed. we have started giving these combinations to the first priority group; so newly diagnosed hiv-infected patients and pregnant women are starting on one tablet once a day. while this is very exciting and without a doubt the way forward, there are still reports of stock-outs of other medications. the southern african hiv clinicians society is actively engaging and forming links with other southern african countries. i spent a very fruitful weekend in harare for the inaugural meeting of the reconstituted zimbabwean branch. over 70 keen healthcare workers attended a full-day meeting packed with lots of teaching and discussion. what i personally love about travelling and meeting other hiv clinicians is seeing the same drive and passion to find solutions. we are all part of a massive movement of healthcare workers who simply want solutions to the health crisis. formal barriers have been broken down as we share what we have done and learn what others are doing. the ultimate vision of the society is to engage with all the ministries of health in the region and come up with one unified response to hiv and tb. francesca conradie president southern african hiv clinicians society fconradie@witshealth.co.za abstract introduction methods results discussion conclusion acknowledgements references about the author(s) leigh f. johnson centre for infectious disease epidemiology and research, university of cape town, south africa rob e. dorrington centre for actuarial research, university of cape town, south africa haroon moolla centre for infectious disease epidemiology and research, university of cape town, south africa citation johnson lf, dorrington re, moolla h. hiv epidemic drivers in south africa: a model-based evaluation of factors accounting for inter-provincial differences in hiv prevalence and incidence trends. s afr j hiv med. 2017;18(1), a695. https://doi.org/10.4102/sajhivmed.v18i1.695 original research hiv epidemic drivers in south africa: a model-based evaluation of factors accounting for inter-provincial differences in hiv prevalence and incidence trends leigh f. johnson, rob e. dorrington, haroon moolla received: 21 sept. 2016; accepted: 01 june 2017; published: 28 july 2017 copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: hiv prevalence differs substantially between south africa’s provinces, but the factors accounting for this difference are poorly understood. objectives: to estimate hiv prevalence and incidence trends by province, and to identify the epidemiological factors that account for most of the variation between provinces. methods: a mathematical model of the south african hiv epidemic was applied to each of the nine provinces, allowing for provincial differences in demography, sexual behaviour, male circumcision, interventions and epidemic timing. the model was calibrated to hiv prevalence data from antenatal and household surveys using a bayesian approach. parameters estimated for each province were substituted into the national model to assess sensitivity to provincial variations. results: hiv incidence in 15–49-year-olds peaked between 1997 and 2003 and has since declined steadily. by mid-2013, hiv prevalence in 15–49-year-olds varied between 9.4% (95% ci: 8.5%–10.2%) in western cape and 26.8% (95% ci: 25.8%–27.6%) in kwazulu-natal. when standardising parameters across provinces, this prevalence was sensitive to provincial differences in the prevalence of male circumcision (range 12.3%–21.4%) and the level of non-marital sexual activity (range 9.5%–24.1%), but not to provincial differences in condom use (range 17.7%–21.2%), sexual mixing (range 15.9%–19.2%), marriage (range 18.2%–19.4%) or assumed hiv prevalence in 1985 (range 17.0%–19.1%). conclusion: the provinces of south africa differ in the timing and magnitude of their hiv epidemics. most of the heterogeneity in hiv prevalence between south africa’s provinces is attributable to differences in the prevalence of male circumcision and the frequency of non-marital sexual activity. introduction south africa’s hiv epidemic is highly heterogeneous, with population hiv prevalence levels ranging between 5.0% in the western cape and 16.9% in kwazulu-natal in 2012.1 in such settings, it has been suggested that policymakers should focus hiv prevention efforts on the regions in which hiv incidence is greatest, in order to make efficient use of limited hiv resources.2,3,4 it is therefore important to produce robust estimates of provincial hiv prevalence and incidence. models may also be required to estimate hiv prevalence at district levels for the purpose of district-level treatment coverage estimation and resource allocation. although previous studies have estimated district hiv prevalence from antenatal hiv survey data,5 antenatal survey data are known to be biased.6,7,8 it is likely that the extent of the bias differs between districts as a result of differences in the factors that account for the bias (e.g. patterns of health-seeking behaviour, contraception, epidemic stage and age distributions). it is therefore important to assess the extent of differences in antenatal bias between regions so that resource allocation is not unfairly skewed towards those districts in which the antenatal bias is greatest. lastly, an understanding of the factors that explain geographical differences in hiv prevalence is important in identifying epidemic drivers, which in turn is important in developing effective hiv prevention strategies. previous studies have speculated that geographical variation in hiv prevalence within sub-saharan africa may be explained by differences in rates of marriage,9 male circumcision,10,11,12,13 migration,11 concurrency13,14 and other sexually transmitted infections.15 however, few attempts have been made to identify the factors that account for inter-provincial differences in hiv prevalence in south africa. this study aims to estimate hiv incidence and prevalence trends in each of south africa’s provinces, and to identify the key epidemiological factors that account for these differences. methods the thembisa model of the south african hiv epidemic was applied to each of the nine provinces in south africa. detailed descriptions of the national model16 and the province-specific adjustments to the national model17 have been published previously. briefly, thembisa is a combined demographic and epidemiological model, which simulates changes in the population profile and hiv disease burden over time, starting in 1985. demographic estimates of the 1985 population profile, fertility rates, non-hiv mortality rates and migration were adapted from province-specific demographic estimates from the earlier actuarial society of south africa (assa) 2008 model,18 updated to ensure consistency with the 2011 census,19 vital registration statistics20,21 and the 2010 national burden of disease study.22,23 sexual behaviour is modelled by dividing the sexually experienced population into two broad classes: ‘high risk’ (individuals who have a propensity for concurrent partnerships and commercial sex) and ‘low risk’. within these two classes, individuals are divided into sub-classes on the basis of their marital status and (if they are high-risk women) current engagement in commercial sex. the national assumption about the fraction of individuals who are high risk (35% for males and 25% for females) is adjusted by a multiplicative factor, which differs by province. because of the uncertainty regarding this adjustment, a bayesian approach is adopted, with prior distributions being specified to represent the range of uncertainty around the appropriate adjustment factor, for each province (table 1). the mean and standard deviation of each prior distribution were chosen based on provincial differences in male reporting of concurrent partnerships24 and multiple partnerships in the last year.25 similar multiplicative adjustments are made to national assumptions about rates of marriage, based on provincial differences in estimates of the age at first marriage.26 table 1: prior distributions a sexual mixing parameter determines the extent of sexual contact between the high-risk and low-risk groups, with this parameter varying between 0 (no contact) and 1 (random sexual mixing).27 in the national model, the parameter was set to 0.47, but in initial attempts to fit the model to province-specific data, best-fitting parameter values ranged between 0.1 and 0.6 (average value of 0.35). to represent the uncertainty around the sexual mixing parameter in each province, a prior distribution was therefore assigned, with a mean of 0.35 and a standard deviation of 0.15 (table 1). rates of partnership formation, coital frequency and condom use are assumed to differ by age, sex, risk group and relationship type. rates of condom use are also assumed to change over time, in response to hiv communication programmes, and are assumed to increase following hiv diagnosis. national assumptions about probabilities of condom use are adjusted by province-specific multiplicative factors. prior distributions are specified to represent the uncertainty around these adjustments (table 1), with means and standard deviations being chosen based on survey estimates of differences in condom use between provinces.1,28,29 the model distinguishes between the ‘background’ rate of male circumcision (the rate that would be expected in the absence of campaigns to promote male circumcision as an hiv prevention strategy) and the rate of medical male circumcision (mmc) associated with campaigns promoting mmc. the annual background rate of male circumcision differs by age and province, with the age pattern being determined by assumed fractions of males circumcised during infancy, fractions of males who ever get circumcised and median ages at circumcision post-infancy. these assumptions are set to match the patterns of male circumcision in each of south africa’s language groups in 200230 and are weighted by the province-specific proportions of the population in each language group19 in order to obtain average provincial background rates of circumcision. rates of mmc uptake through campaigns are assumed to be proportional to men’s probability of engaging in non-marital relationships, and are estimated from annual numbers of mmc operations reported by the department of health,31,32 distributed between provinces in proportion to numbers of uncircumcised men and in proportion to stated levels of mmc acceptability, which again differ by language.33,34,35,36,37 in each province, the epidemic is seeded by specifying an initial level of hiv prevalence in high-risk women aged 15–49 in 1985 and a relative level of prevalence in men aged 15–49. the uncertainty regarding the former is represented by prior distributions (table 1). these prior distributions are determined by calculating the rate of growth in antenatal hiv prevalence over the first five survey years (1990–1994) and back-projecting the likely antenatal prevalence in 1985. sexual transmission of hiv after 1985 is modelled based on assumed probabilities of transmission per act of unprotected sex, which differ according to age, sex, relationship type and the disease stage of the hiv-positive partner. female-to-male transmission rates are reduced by 60% if the male partner is circumcised,38 and transmission rates are reduced by 90% if a condom is used. hiv transmission probabilities per act of sex are assumed to be the same across all provinces. untreated hiv-positive adults are stratified according to their cd4 count and hiv testing history, while treated adults are stratified according to their baseline cd4 count at antiretroviral treatment (art) initiation and time since first art initiation. assumptions about rates of cd4 decline and hiv mortality are the same for all provinces. however, assumptions about rates of hiv testing and art initiation differ by province, based on reported numbers of hiv tests performed39 and numbers of patients who are on art by province.40 the model also allows for differences between provinces in rates of antenatal hiv testing,41 uptake of prophylaxis against mother-to-child transmission, breastfeeding by hiv-positive mothers and uptake of polymerase chain reaction (pcr) screening after birth.42,43 each provincial model is fitted to province-specific hiv prevalence data from the 1990–2013 antenatal surveys44 and household surveys conducted in 2005, 2008 and 2012.1 a detailed description of the method used to calculate the likelihood function is provided in the online appendix. because the antenatal surveys represent only women using public antenatal facilities, and because of other biases, an antenatal bias parameter is specified for each province to represent the average difference between the true hiv prevalence in pregnant women and that measured in the survey. prior distributions are specified to represent the uncertainty around these biases (table 1), with the prior means and standard deviations being set based on the biases estimated when fitting the national model, adjusted to take into account provincial differences in the fraction of adults who are members of private medical schemes.29 posterior estimates of the best-fitting parameter values were calculated using incremental mixture importance sampling.45 results differences in the provincial assumptions about male circumcision led to the modelled fraction of 15–49 year old men who were circumcised in 2000 varying between 19% in kwazulu-natal and 64% in limpopo (figure 1a). after fitting the model to hiv prevalence data, a number of the other parameters were also found to differ substantially between provinces. the high-risk adjustment factor was significantly below the national average in northern cape (0.56, 95% ci: 0.51–0.63) and western cape (0.58, 95% ci: 0.51–0.67), but significantly above the national average in free state, gauteng, kwazulu-natal and mpumalanga (figure 1b). the sexual mixing parameter ranged between 0.11 (95% ci: 0.04–0.23) in gauteng and 0.55 (95% ci: 0.42–0.68) in kwazulu-natal (figure 1c). condom usage was significantly below the national average in northern cape and western cape, but not significantly different from the national average in other provinces (figure 1d). initial hiv prevalence in women aged 15–49 in 1985 was highest in gauteng (0.051%, 95% ci: 0.043%–0.062%) and lowest in the provinces in the southern and western parts of the country (figure 1e). finally, the extent of the antenatal bias was greatest in gauteng and western cape (figure 1f). prior and posterior estimates of each parameter are compared as shown in online appendix figure 1. figure 1: male circumcision rates and posterior estimates of sexual behaviour parameters, initial hiv prevalence and antenatal bias. panel (a) shows the modelled prevalence of male circumcision in men aged 15–49 years in 2000 (prior to mmc promotion campaigns); (b) multiplicative adjustment to high risk proportion; (c) sexual mixing parameter; (d) multiplicative adjustment to condom usage; (e) initial hiv prevalence in women aged 15–49 years (initial hiv prevalence in high-risk women multiplied by the fraction of women in the high-risk group); (f) antenatal bias (on logit scale). panels (b)–(f) show posterior means of the input parameters for which prior distributions have been specified (table 1), and error bars represent the 95% confidence intervals from the posterior distributions. in all panels, the dashed line represents the national average. figure 2 shows that the model estimates of antenatal hiv prevalence over the 1990–2013 period are generally in close agreement with the survey data. however, some of the early antenatal surveys in north west and mpumalanga produced erratic trends, with the result that there are wide confidence intervals around the model estimates. in addition, the model tends to under-estimate hiv prevalence in gauteng in the early 2000s. in sensitivity analyses that excluded antenatal data collected prior to 1997 (before the introduction of standard sampling protocols), average model estimates of hiv prevalence over the 1997–2013 period were virtually unchanged, but confidence intervals were substantially narrower in north west and mpumalanga (online appendix). the model fit to the gauteng data was not improved in sensitivity analyses that considered different priors on the sexual behaviour parameters (online appendix). figure 2: hiv prevalence levels in pregnant women attending public antenatal clinics: (a) eastern cape; (b) free state; (c) gauteng; (d) kwazulu-natal; (e) limpopo; (f) mpumalanga; (g) northern cape; (h) north west; (i) western cape. dark blue lines represent posterior means and shaded light blue areas represent posterior 95% confidence intervals (model estimates have been adjusted to reflect the modelled antenatal bias). dots represent antenatal survey estimates (95% confidence intervals for survey estimates prior to 1998 are not shown, as the reported confidence intervals did not account for survey design effects). hiv incidence trends differed substantially by province (figure 3a). incidence in 15–49-year-olds peaked in kwazulu-natal in 1997–1998 at 3.97% per annum (95% ci: 3.81%–4.13%) and subsequently declined to 1.83% (95% ci: 1.71%–1.93%) in 2012–2013. in contrast, incidence in the western cape peaked in 2003–2004 at 0.92% (95% ci: 0.84%–0.99%) and declined to 0.64% (95% ci: 0.53%–0.75%) by 2012–2013. hiv prevalence trends reflect similar inter-provincial differences (figure 3b); by mid-2013, hiv prevalence in 15–49-year-olds varied between 9.4% (95% ci: 8.5%–10.2%) in western cape and 26.8% (95% ci: 25.8%–27.6%) in kwazulu-natal. although hiv prevalence has been steadily increasing in all provinces over the last five years, the pace of increase has been greater in western cape, limpopo and eastern cape, reflecting the slower pace of hiv incidence decline in these provinces. figure 3: hiv incidence: (a) and prevalence (b) trends in 15–49-year-olds. lines represent posterior means (95% confidence intervals not shown). to assess the relative importance of different parameters in explaining inter-provincial prevalence differences, the parameters estimated in each provincial model were substituted into the national model in a series of one-way sensitivity analyses (figure 4). hiv prevalence in 2013 in 15–49-year-olds varied between 18.2% when substituting the free state marriage rates into the model and 19.4% when substituting the kwazulu-natal marriage rates into the model (figure 4a). prevalence varied between 15.9% when substituting the gauteng sexual mixing parameter into the model and 19.2% when substituting the kwazulu-natal sexual mixing parameter into the model (figure 4b). in contrast, prevalence was highly variable when substituting province-specific high-risk adjustments, ranging from 9.5% when using the western cape parameter to 24.1% when using the mpumalanga parameter (figure 4c). although provincial differences in initial hiv prevalence (in 1985) accounted for much variation in prevalence during the 1990s and early 2000s (figure 4d), prevalence in 2013 was relatively insensitive to the initial prevalence, ranging between 17.0% when substituting the western cape initial prevalence and 19.1% when substituting the gauteng initial prevalence (figure 4d). in contrast, provincial differences in condom use accounted for little variation in prevalence during the 1990s, but accounted for more variation in prevalence in 2013: prevalence in this year varied between 17.7% when substituting the free state condom use and 21.2% when substituting northern cape condom use. finally, prevalence was very sensitive to the assumed levels of male circumcision prior to mmc promotion, varying between 12.3% when substituting the limpopo parameters and 21.4% when substituting the kwazulu-natal parameters into the national model. figure 4: effect on adult hiv prevalence (15–49 years) in the national hiv model of substituting province-specific parameter values: (a) substituting provincial marriage rates; (b) substituting provincial sexual mixing parameters; (c) substituting provincial high risk proportions; (d) substituting provincial initial hiv prevalence levels; (e) substituting provincial rates of condom use; (f) substituting provincial male circumcision rates. for panels (b)–(e), province-specific parameters substituted into the national model are the posterior means shown in figure 1. discussion this analysis confirms the heterogeneous distribution of hiv within south africa and advances our understanding of the factors that account for this heterogeneity. most of the current inter-provincial variation in hiv prevalence in south africa is attributable to two factors: differences in the prevalence of male circumcision and differences in the fraction of the population in the high-risk group. because the model assumes that rates of marriage are the same in the high-risk and low-risk groups, but rates of non-marital sex (short-term relationships and sex worker–client contacts) differ between high-risk and low-risk, the provincial differences in the high-risk fraction are equivalent to differences in the frequency of non-marital sex. our findings of relatively low rates of non-marital sex in western cape and northern cape are consistent with the findings of sexual behaviour surveys, which show that the fraction of men reporting multiple or concurrent partnerships is lowest in these two provinces.24,25 rates of male circumcision are highly variable between south african ethnic groups. the pedi and venda ethnic groups, which account for the majority of the population in limpopo, have high rates of circumcision, and circumcision typically occurs in early adolescence.14,30 the xhosa, which comprise 79% of the eastern cape population,19 also have high rates of male circumcision, but circumcision occurs at later ages than in other ethnic groups,30,33 with the result that there is less hiv prevention benefit. the zulu, which account for 78% of the population in kwazulu-natal, had the lowest fraction of men circumcised in 2002 (14.5%),30 which partially accounts for the severity of the hiv epidemic in this province. ethnicity may also be an important factor explaining provincial differences in sexual mixing patterns. it is interesting to note that the sexual mixing parameter is lowest in gauteng, the most ethnically heterogeneous province, and is highest in eastern cape and kwazulu-natal, which are ethnically relatively homogeneous (figure 1c). although the sexual mixing parameter is defined to represent the extent of mixing between high-risk and low-risk groups, the model-fitting procedure may effectively be identifying mixing in relation to other dimensions of hiv risk (such as ethnicity and socioeconomic status). to the extent that individuals tend to be ethnically and socioeconomically homogamous,46,47,48 one might expect to observe less sexual mixing in the provinces in which there is greater ethnic/socioeconomic heterogeneity. this is important because mathematical models suggest that hiv epidemics develop differently depending on sexual mixing patterns: when there is little sexual mixing between high-risk and low-risk groups, hiv spreads more rapidly at first but levels off at a lower rate (figure 4b),49,50,51 and the greater degree of heterogeneity in hiv risk means that interventions have less of an impact on hiv incidence.52 thus the relatively rapid levelling off in hiv prevalence seen in gauteng is likely to be because of the low level of sexual mixing in this province rather than any unusually successful hiv intervention. differences in the timing of peak hiv incidence are largely explained by differences in the prevalence of hiv in 1985, which is a proxy for the age of the epidemic. consistent with earlier analyses,53 we find that the hiv epidemic started later in eastern cape, northern cape and western cape than the other provinces (figure 1e), and hiv incidence therefore peaked later in these provinces (figure 3a). however, in recent years differences in epidemic timing account for relatively little inter-provincial variation. this analysis suggests that antenatal bias differs substantially between provinces, being most extreme in the provinces in which use of private healthcare is greatest. caution is therefore required when using antenatal hiv prevalence data to draw conclusions about differences in hiv burden between provinces or districts. ideally, such comparisons should rely on hiv prevalence data from household surveys, but the cost of such surveys and the difficulty in obtaining adequately precise estimates for small geographical units often make this impractical. there have been few previous attempts to model the role of different factors in explaining inter-provincial hiv variation within south africa. the assa models explained differences in hiv prevalence across provinces primarily in terms of provincial differences in initial hiv prevalence, proportions of the population in different risk groups and population group profile (for example, the low prevalence of hiv in the western cape was partly explained by the relatively small proportion of black south africans living in this province).54 however, the models did not consider directly the role of factors such as male circumcision or marriage. another modelling study noted that provincial differences in measures of hiv incidence and epidemic growth did not correlate strongly with the prevalence of male circumcision, and hence concluded that male circumcision was not a significant driver to hiv spread in south africa.55 however, this study did not consider the role of provincial differences in sexual behaviour patterns. understanding reasons for inter-provincial differences in hiv prevalence requires a model that is sophisticated enough to simulate each of the major epidemic drivers simultaneously. a strength of this analysis is that it relies on a parsimonious model-fitting procedure, with only a few key parameters being used to explain the differences in hiv prevalence between provinces. unlike the approach in other hiv model-fitting studies,56,57 these parameters relate to observable measures of behaviour and hiv risk, allowing an understanding of the factors that are most influential in driving hiv. however, the parsimony of the model-fitting procedure is also a limitation, as there may be important epidemic drivers that we have not been able to identify because of the simple model structure. for example, drug and alcohol use may be important determinants of hiv risk behaviour,58,59 but are not currently considered in the model. there are also variables that might not be important in explaining inter-provincial hiv differences, but which are nevertheless important as epidemic drivers. for example, differences in marriage rates account for relatively little variation in hiv prevalence between provinces (figure 4a), but this may be because marriage rates in south africa are uniformly low in comparison to the rates in most other african countries.9 another limitation associated with the relatively parsimonious model-fitting procedure is that the model fit to the antenatal survey data is not always as good as might be hoped for, especially in the case of gauteng. this implies that there is some uncertainty around the hiv incidence estimates, particularly in the most recent years. incorporating other data sources, such as recorded death data, in the calibration procedure could potentially lead to more precise estimates. however, recorded death data have not been used in the calibration of the provincial models because of current uncertainty regarding provincial differences in the fractions of deaths that are recorded,60 and the possibly substantial fraction of individuals who die outside of the province in which they are normally resident.60,61 another limitation of this study is that uncertainty regarding the prevalence of male circumcision is not considered in the model-fitting procedure. assumptions about the prevalence of male circumcision were considered more robust than the assumptions about sexual behaviour, the former having been validated using data from various nationally representative surveys.62,63 there is also uncertainty regarding relative levels of risk behaviour in circumcised and uncircumcised men. consistent with most published studies,64,65,66,67 the model assumes that male circumcision is not associated with any change in hiv risk behaviour. however, one south african study found a univariate association between traditional male circumcision and reduced hiv risk perception, as well as a univariate association between mmc and reporting of multiple partnerships.62 another cape town study found that hiv risk behaviours in traditionally circumcised men were related to knowledge of the protective effects of male circumcision.68 however, even if it is true that increased awareness of the protective effects of male circumcision is leading to increased risk behaviour in circumcised men, this does not diminish the importance of male circumcision in explaining inter-provincial hiv prevalence differences in the period up to 2005, before the protective effect of male circumcision was widely known. although this analysis does not consider provincial differences in hiv testing and art coverage as factors explaining differences in hiv prevalence, we have shown that levels of hiv diagnosis are similar across provinces,17 and thus they would be unlikely to account for hiv prevalence differences. art reduces hiv incidence, but the impact that this has on hiv prevalence is completely offset by the impact on mortality in the short term.69 the net effect of provincial differences in art access on provincial hiv prevalence is therefore also likely to be relatively small. conclusion the conclusion that the low prevalence of male circumcision and high prevalence of multiple/concurrent partnerships are important in driving the high hiv prevalence in southern africa, is not new.13 however, advances in new hiv prevention and treatment strategies have meant that these factors have received relatively less attention in recent hiv prevention debates. it is important that these epidemic drivers are not neglected in the push towards the ‘90-90-90’ targets,70 and that hiv communication programmes continue to promote male circumcision and risk awareness in the context of non-marital relationships. acknowledgements this research was funded by the south african national aids council. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions l.j. developed the mathematical model, set the epidemiological input parameters for each province and drafted the first version of the article. r.d. set the demographic parameters for each province. h.m. ran the model simulations and assisted in data collection. all authors assisted in the drafting of the article. references shisana o, rehle t, simbayi lc, et al. south african national hiv prevalence, incidence, and behaviour survey, 2012 [homepage on the internet]. cape town: human sciences research council. 2014 [cited 2014 apr 16]. available from: http://www.hsrc.ac.za/en/research-outputs/view/6871 anderson sj, cherutich p, kilonzo n, et al. maximising the effect of combination hiv prevention through prioritisation of the people and places in greatest need: a modelling study. lancet. 2014;384(9939):249–256. https://doi.org/10.1016/s0140-6736(14)61053-9 gerberry dj, wagner bg, garcia-lerma jg, heneine w, blower s. using geospatial modelling to optimize the rollout of antiretroviral-based pre-exposure hiv interventions in sub-saharan africa. nat commun. 2014;5:5454. https://doi.org/10.1038/ncomms6454 verguet s. efficient and equitable hiv prevention: a case study of male circumcision in south africa. cost eff resour alloc. 2013;11(1):1. https://doi.org/10.1186/1478-7547-11-1 bor j, brennan a, fox m, et al. district prevalence of unsuppressed hiv in south african women: monitoring programme performance and progress towards 90-90-90 [abstract tuac0205]. 21st international aids conference; 2016 jul 18–22; durban, south africa. eaton jw, rehle tm, jooste s, et al. recent hiv prevalence trends among pregnant women and all women in sub-saharan africa: implications for hiv estimates. aids. 2014;28(suppl. 4):s507–s514. https://doi.org/10.1097/qad.0000000000000412 montana ls, mishra v, hong r. comparison of hiv prevalence estimates from antenatal care 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https://doi.org/10.1177/0956462412472455 gullickson a, torche f. patterns of racial and educational assortative mating in brazil. demography. 2014;51(3):835–856. https://doi.org/10.1007/s13524-014-0300-2 jacobson ck, amoateng ay, heaton tb. inter-racial marriages in south africa. j compar fam stud. 2004;35(3):443–458. hertog s. heterosexual behavior patterns and the spread of hiv/aids: the interacting effects of rate of partner change and sexual mixing. sex transm dis. 2007;34(10):820–828. https://doi.org/10.1097/olq.0b013e31805ba84c gupta s, anderson rm, may rm. networks of sexual contacts: implications for the pattern of spread of hiv. aids. 1989;3(12):807–817. garnett g, anderson r. factors controlling the spread of hiv in heterosexual communities in developing countries: patterns of mixing between different age and sexual activity classes. philos trans r soc lond b. 1993;342:137–159. johnson lf, hallett tb, rehle tm, dorrington re. the effect of changes in condom usage and antiretroviral treatment coverage on hiv incidence in south africa: a model-based analysis. j roy soc interface. 2012;9(72):1544–1554. williams b, campbell c. understanding the epidemic of hiv in south africa. analysis of the antenatal clinic survey data. s afr med j. 1998;88(3):247–251. dorrington re. the assa2000 suite of models. paper presented at actuarial society of south africa convention; somerset west, south africa; 24–25 october, 2000. garenne m. long-term population effect of male circumcision in generalised hiv epidemics in sub-saharan africa. afr j aids res. 2008;7(1):1–8. https://doi.org/10.2989/ajar.2008.7.1.1.429 brown t, bao l, eaton jw, et al. improvements in prevalence trend fitting and incidence estimation in epp 2013. aids. 2014;28(suppl. 4):s415–s425. https://doi.org/10.1097/qad.0000000000000454 hogan dr, zaslavsky am, hammitt jk, salomon ja. flexible epidemiological model for estimates and short-term projections in generalised hiv/aids epidemics. sex transm infect. 2010;86(suppl. 2):ii84–92. https://doi.org/10.1136/sti.2010.045104 nkosi s, rich ep, morojele nk. alcohol use, sexual relationship power, and unprotected sex among patrons in bars and taverns in rural areas of north west province, south africa. aids behav. 2014;18(11):2230–2239. https://doi.org/10.1007/s10461-014-0764-5 kalichman sc, simbayi lc, kagee a, et al. associations of poverty, substance use, and hiv transmission risk behaviors in three south african communities. soc sci med. 2006;62(7):1641–1649. https://doi.org/10.1016/j.socscimed.2005.08.021 johnson lf, dorrington re, laubscher r, et al. a comparison of death recording by health centres and civil registration in south africans receiving antiretroviral treatment. j int aids soc. 2015;18:20628. welaga p, hosegood v, weiner r, hill c, herbst k, newell ml. coming home to die? the association between migration and mortality in rural south africa. bmc public health. 2009;9:193. https://doi.org/10.1186/1471-2458-9-193 zungu np, simbayi lc, mabaso m, et al. hiv risk perception and behavior among medically and traditionally circumcised males in south africa. bmc public health. 2016;16:357. https://doi.org/10.1186/s12889-016-3024-y shisana o, simbayi lc, rehle t, et al. south african national hiv prevalence, incidence, behaviour and communication survey, 2008: the health of our children [homepage on the internet]. cape town; 2010 [cited 2010 aug 7]. available from: http://www.hsrc.ac.za/research_publication-21767.phtml auvert b, taljaard d, rech d, et al. association of the anrs-12126 male circumcision project with hiv levels among men in a south african township: evaluation of effectiveness using cross-sectional surveys. plos med. 2013;10(9):e1001509. https://doi.org/10.1371/journal.pmed.1001509 kong x, kigozi g, nalugoda f, et al. assessment of changes in risk behaviors during 3 years of posttrial follow-up of male circumcision trial participants uncircumcised at trial closure in rakai, uganda. am j 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therapy on hiv incidence in south africa. plos med. 2012;9(7):e1001245. https://doi.org/10.1371/journal.pmed.1001245 unaids. ambitious treatment targets: writing the final chapter of the aids epidemic [homepage on the internet]. geneva. 2014 [cited 2014 aug 19]. available from: http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2014/jc2670_unaids_treatment_targets_en.pdf sajhiv 1031 reflections building on the first decade of art g maartens, mb chb, fcp (sa), dtm&h, mmed; e goemaere, md, dtm&h, phd corresponding author: g maartens (gary.maartens@uct.ac.za) professor gary maartens hails from the division of clinical pharmacology, department of medicine, university of cape town (uct), south africa. dr eric goemaere is affiliated with médecins sans frontières, south africa, and the school of public health and family medicine, uct. there is much to celebrate at the end of the first decade of south africa’s public sector antiretroviral therapy (art) programme. an estimated 2 million south africans had started art by 2012, making ours the largest art programme globally. art coverage in adults, according to current guidelines, was estimated at 81% in 2012.1 the prevalence of hiv is increasing, because people receiving art are living longer.2 in rural kwazulu-natal, adult life expectancy increased from 49.2 years in 2003, just before the beginning of the art programme, to 60.5 years in 2011.3 tremendous strides have been made in the prevention of mother-to-child transmission (pmtct) of the virus. almost 90% of pregnant, hiv-infected women access antiretrovirals (arvs) either for their own health or for pmtct, resulting in a 67% decline in new infections in children from 2009 to 2012.4 further declines in new infections in children should be seen with the new pmtct guidelines, which include prolonged arvs for infants during breastfeeding, and combination art for all mothers irrespective of cd4+ counts. art access in eligible children has increased from 17% in 2009 to 67% in 2012.4 we have even started a third-line art programme. the birth of our art programme was difficult, to say the least. we should never forget the tragic loss of hundreds of thousands of south african lives as a result of delays in starting our art programme. the aids-denialist views of former president mbeki, including the absurd notion that arvs, not hiv, were the cause of mortality, and the ill-informed promotion of nutrition as treatment for hiv by then health minister, manto tshabalala-msimang, were bitter pills to swallow for people living with hiv, grieving relatives, and healthcare workers. civil society, notably the treatment action campaign (tac) and the aids law project, played a major role in forcing the government to implement arvs for pmtct, and later an art programme. however, once the green light was reluctantly given to scale-up art, the public sector responded well. donors contributed significantly to the setting up and running of our art programme, but unlike other african countries (except for botswana), our art programme is largely funded out of the national budget. the us president’s emergency plan for aids relief and the global fund to fight aids, tuberculosis and malaria have played key roles in funding our art programme and providing technical assistance. less well acknowledged is the critical role that donor-funded pilot art projects have played in establishing the feasibility of public health art programmes. particularly noteworthy was the khayelitsha project, which was jointly funded by médecins sans frontières and the western cape government. three art clinics were opened in 2000 despite opposition from national government. generic arvs were imported from brazil in 2001, provoking a statement from president mbeki’s spokesman, smuts ngonyama, that this was tantamount to biological warfare. the high rates of virological suppression and retention in care of the first two years of the khayelitsha art project5 were influential in the initial scale-up of art nationally and internationally. a reduction in arv costs has been one of the biggest achieve­ments of the last decade. south africa is a major global market player given the size of its national art programme, and the department of health has been able to negotiate lower drug prices, to the benefit of other lowand middle-income countries. in 2000, art cost around us$10 000 per year, while the currently used fixed-dose combination single tablet for first-line art costs only us$129 per year. south africa has the world’s highest number of people living with hiv, estimated to be 6.1 million in 2012,1 nearly all of whom will require art in the next decade. the estimated number of new hiv infections in south africa decreased from 640 000 in 2001 to 370 000 in 2012, which is gratifying, but most people infected in the next decade will also need art. major challenges lie ahead to achieve the expansion of the art programme, particularly if south africa adopts the new world health organization (who) art initiation criterion of a cd4+ count <500 cells/µl. task-shifting, such as nurse-initiated management of art (nimart), has increased access to art, but there is a need to train more nurses. innovative models of patient care, such as adherence clubs,6 should be developed, adapted to local contexts, and rolled out. the biggest challenge for scaling up art for the next decade will be retention in care. we know that over 2 million south africans have started art, but how many are still in care? loss to follow-up increased with time and increasing clinic population size in a large south african art programme,7 suggesting that the massive art programme expansion needed in the next decade will be accompanied by high attrition rates. measures of retention in care at the facility level need to be collected routinely. electronic pharmacy refills are increasingly being used and could easily identify people who are defaulting. retention in care and rates of virological suppression according to years receiving art should be used to identify poorly functioning clinics and regions. the initial role for patient activist groups such as the tac was crucial, given the state opposition to rational treatment for people living with hiv. some might have thought that the job of activists was done once the national art programme was launched and the current progressive minister of health was appointed. unfortunately, the general lack of accountability in the public health services, as demonstrated by ongoing drug stock-outs, demonstrates the need for independent civil society groups to monitor service delivery, and where necessary, exert pressure on the health services to deliver their mandate. finally, more resources need to be made available for operational research to support the art programme. south african hiv researchers have been very productive, but almost all of their major achievements have been completed using resources from international grant agencies. budgets were made available for research to support the national hiv programmes in the mid-2000s, but this was not sustained. the medical research council has made good progress in leveraging extra funding for clinical research, indicating that political will exists to support more resources for research. references 1. unaids. report on the global aids epidemic 2013. http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2013/gr2013/unaids_global_report_2013_en.pdf (accessed 12 january 2014). 1. unaids. report on the global aids epidemic 2013. http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2013/gr2013/unaids_global_report_2013_en.pdf (accessed 12 january 2014). 2. zaidi j, grapsa e, tanser f, newell ml, barnighausen t. dramatic increases in hiv prevalence after scale-up of antiretroviral treatment: a longitudinal population-based hiv surveillance study in rural kwazulu-natal. aids 2013;27(14):2301-2305. [http://dx.doi.org/10.1097/qad.0b013e328362e832] 2. zaidi j, grapsa e, tanser f, newell ml, barnighausen t. dramatic increases in hiv prevalence after scale-up of antiretroviral treatment: a longitudinal population-based hiv surveillance study in rural kwazulu-natal. aids 2013;27(14):2301-2305. [http://dx.doi.org/10.1097/qad.0b013e328362e832] 3. bor j, herbst aj, newell ml, barnighausen t. increases in adult life expectancy in rural south africa: valuing the scale-up of hiv treatment. science 2013;339(6122):961-965. [http://dx.doi.org/10.1126/science.1230413] 3. bor j, herbst aj, newell ml, barnighausen t. increases in adult life expectancy in rural south africa: valuing the scale-up of hiv treatment. science 2013;339(6122):961-965. [http://dx.doi.org/10.1126/science.1230413] 4. unaids. 2013 progres report on the gloval plan towards the elimination of new hiv infections among children by 2015 and keeping their mothers alive. http://www.unaids.orgenmediaunaidscontentassetsdocumentsunaidspublication201320130625_progress_global_plan_en.pdf (accessed 12 january 2014). 4. unaids. 2013 progres report on the gloval plan towards the elimination of new hiv infections among children by 2015 and keeping their mothers alive. http://www.unaids.orgenmediaunaidscontentassetsdocumentsunaidspublication201320130625_progress_global_plan_en.pdf (accessed 12 january 2014). 5. coetzee d, hildebrand k, boulle a, et al. outcomes after two years of providing antiretroviral treatment in khayelitsha, south africa. aids 2004;18(6):887-895. 5. coetzee d, hildebrand k, boulle a, et al. outcomes after two years of providing antiretroviral treatment in khayelitsha, south africa. aids 2004;18(6):887-895. 6. luque-fernandez ma, van cutsem g, goemaere e, et al. effectiveness of patient adherence groups as a model of care for stable patients on antiretroviral therapy in khayelitsha, cape town, south africa. plos one 2013;8(2):e56088. [http://dx.doi.org/10.1371/journal.pone.0056088] 6. luque-fernandez ma, van cutsem g, goemaere e, et al. effectiveness of patient adherence groups as a model of care for stable patients on antiretroviral therapy in khayelitsha, cape town, south africa. plos one 2013;8(2):e56088. [http://dx.doi.org/10.1371/journal.pone.0056088] 7. boulle a, van cutsem g, hilderbrand k, et al. seven-year experience of a primary care antiretroviral treatment programme in khayelitsha, south africa. aids 2010;24(4):563-572. [http://dx.doi.org/10.1097/qad.0b013e328333bfb7] 7. boulle a, van cutsem g, hilderbrand k, et al. seven-year experience of a primary care antiretroviral treatment programme in khayelitsha, south africa. aids 2010;24(4):563-572. [http://dx.doi.org/10.1097/qad.0b013e328333bfb7] s afr j hiv med 2014;15(1):7-8. doi:10.7196/sajhivmed.1031 june 2006 make up 4 7 twelve years have passed since the establishment of south africa’s new democracy. over this period the country's hiv prevalence has grown from 3% to 11 17%. maternal prevalence rates and those of several provinces are higher.5, 6 a recent report detailing the hiv prevalence among 17 088 south african teachers indicated that 12.7% were infected and that 52% of these had cd4 cell counts below 350 µl and 22% counts below 200/µl.7 most governments are ill prepared to cope with disasters of the magnitude of the aids epidemic. the new south african government has fortunately enjoyed the support of the international community and has had two decades of scientific knowledge upon which to draw. with fewer resources, uganda reduced hiv prevalence from over 20% in 1993 to 5 8% currently. thailand, like south africa a ‘middle-income’ country, has maintained its 3% prevalence over the same period.8-10 despite the goodwill of scientists locally and abroad, the south african government has frequently chosen to follow an independent route with regard to public discussion and the management of the epidemic. dissidents who dispute the science of hiv have openly advised government and continue to do so.11, 12 mr mbeki has at times based his remarks upon insights from the internet, a source of unregulated data, opinion and bias.12,13 cabinet advocacy for the play ‘sarafina ii’ and the so-called aids cure, virodene, was premature and inappropriate: ‘instead of emerging victorious with a new african miracle cure, the government’s reputation was harmed by the strong aroma of sleaze which permeated the virodene episode and by the fact that it ignored scientific checks and balances. instead of accepting the recommendations of the medicines control council (mcc), the government undermined the body by removing the chairperson and replacing him and others with more compliant members.’13 herbs, vegetables, so-called ‘immune boosters’, various ‘diets’ and vitamin concoctions have been advanced as benefiting the infected.14, 15 evidence-based support for these assertions is largely absent, anecdotal, speculative or simply misinformation. scientific data promoting the use of vitamins and trace elements in the hiv patient is limited. where deemed to be indicated, vitamins and trace elements are not viewed as alternatives to the antiretroviral (arv) drugs.16, 17 nutritionists and researchers agree that patients require access to healthy diets, and that where nutrition is needed this ought to be provided in the form of food.18, 19 support by public figures of homespun ‘remedies’ has led to general confusion and in some cases to patients refusing life-saving therapy with consequent loss of life.20 the southern african journal of hiv medicine june 2006 e t h i c s medical ethics and the politics of the south african hiv/aids epidemic dave spencer johannesburg, south africa ‘who among us shall dwell with the devouring fire? who among us shall dwell with everlasting burnings?’ he who walks righteously and speaks uprightly. he who despises the gain of oppression, who gestures with his hands refusing bribes. who stops his ears from hearing of bloodshed and shuts his eyes from seeing evil.’1 politics has been defined as the ‘art and science of government’ and ethics as ‘moral principles, the science of morals in human conduct, rules of conduct’.2, 3 the reader would know politics by its public face – its leaders, their words, their actions: ‘levelling the playing fields’, ‘quiet diplomacy', ‘kill the farmer, kill the boer’, ‘shifting the goal posts’, ‘redressing the imbalances’, ‘playing the race card.’ ethical issues in health are familiar too: triaging survivors, prioritising limited budgets, maintaining confidentiality, obtaining informed consent, deciding upon ventilator/dialysis access, euthanasia and embryo research. making choices has never been easy. writing from prison in 1945, bonhoeffer commented upon ethics: 'rarely has any generation shown so little interest in any kind of theoretical or systematic ethics. our period of history is oppressed by an abundance of ethical problems. today, there are once more villains and saints. these emerge from the primeval depths to open the infernal or divine abyss and allow us to see briefly into mysteries of which we had never dreamed. what is worse than doing evil is being evil. it is worse for a liar to tell the truth than for a lover of the truth to lie. a falling away is of infinitely greater weight than a falling down. one is distressed by the failure of reasonable people to perceive the depths of evil or the depths of the holy. with the best of intentions they believe that a little reason will clamp together the parting timbers of their house…’4 4 9 ethics in the context of government moral principles should govern behaviour in government and in health care. we use ethical language when addressing political and health matters: ‘primum non nocere’ (first do no harm), autonomy, beneficence, non-maleficence, justice and futility, and we contrast altruism with self-interest. the application of these ideas to society underlies the day-to-day running of government: utilitarianism – ‘the greatest happiness of the greatest number’ (jeremy bentham, 17481832), human rights (individual v. community rights), communitarianism – the building of a good and just society.38, 39 the anc government of 1994 inherited an imperfect health care system.30 regional health has deteriorated for years: life expectancy in south africa has fallen for the past 40 years and current levels are below those of 1960.40 the aids epidemic has played a part in this, but one must also acknowledge the persistence of poverty, inadequate education, poor rural and urban living conditions and the fractured health infrastructure that grew out of the apartheid system. ‘history’, says roberts, ‘has many examples of people who sought to impose their vision of a good society by force – from the crusades to the khymer rouge to the taliban. moving from coercion to coexistence, tolerance, and mutual learning requires a degree of openness that many find inconsistent with the certainty of their own vision.’38 do governments harm the health of their citizens? sadly, many do. living in south africa before 1994 ensured unequal access to health care. we live with this legacy. ‘the nazi doctors made hell’, is elie wiesel’s commentary on life in europe during the 1930s and 1940s.41 lenin wrote of 'purging the russian soil of all kinds of harmful insects’.42 mao, according to the authors of a recent biography, ‘was responsible for well over 70 million deaths in peacetime'.43 zimbabwe: ‘its ambulance fleet includes nine ox-drawn carts, introduced in july (2004) as part of the struggle against climbing maternal mortality rates. life expectancy at birth – according to the undp human development report for 2004, is 33.9 years.’44 south africa: ‘between 1995 and 2000 the public health sector in the western cape was downsized by 3 601 hospital beds (24.4%) and by 9 282 health and support personnel (27.9%), while the local population grew by 8%.’ benatar continues, ‘public tertiary health services have been severely eroded... the failure of the (south african) government to promote a prevention campaign over the past decade and an initial focus on ineffective treatments have contributed to sustained and pervasive denial of the existence of the hiv pandemic as well as perpetuation of the stigma associated with hiv and aids.'30 politicians are salaried public servants and are answerable to the community they serve. our government has been reelected twice and tasked with the provision of equable care to all its citizens – including those who carry the hi virus. ‘unemployment insurance, old age pensions, workmen’s liability acts and other similar legislation represent the effort of political society to mitigate the inequalities which are created by the process of economic development … the economic system heaps up profits in the hands of the owners of property and the state uses the power of taxation to reduce these profits and to assist the worker...’45 but as niebuhr observes, even democratically elected governments have their own agendas: 'the creeds and institutions of democracy have never become fully divorced from the special interests of the commercial classes who conceived and developed them.'46 1994 ushered into power those who were once the objects of the abuse of power. has such a perspective resulted in better government? is the altruism demanded of the newly qualified health worker who is obliged to complete community service matched by a similar altruism of the politician? how ought the south african public to view ‘floor-crossing’, the failure of municipalities to deliver basic services, unspent budgets, scandals – ‘armsgate’, ‘oilgate’, ‘travelgate’? is this altruism or self-service? who audits government? where political opposition is weak most governments are left to audit themselves. ‘the moral attitudes of the dominant and privileged classes are characterized by self-deception and hypocrisy... the most common form of hypocrisy among the privileged classes is to assume that their privileges are the just payments with which society rewards specially useful and meritorious functions.’47 governments and most human beings lack the moral clarity to judge themselves without bias. what of the health workers themselves? a recent review of nursing care in two eastern cape hospitals reported serious irregularities. the nurses and doctors had been trained in the management of severe malnutrition in children. their performance was studied from april 2000 to april 2001. the authors comment: 'despite the shortcomings in care, most aspects of the world health organization (who) guidelines were feasible, even with scarce resources … the researchers visited each hospital about 6 times per month. visits were unannounced and unobtrusive. a high proportion of deaths were due to doctor error ... but weaknesses in support and supervision from local and central management gave rise to a lax environment, exemplified by nurses fabricating pulse and respiration rates and some night nurses giving antibiotics hours ahead of schedule.’48 the training of health workers is not enough to ensure good medical care. researchers note that ‘for decades it was assumed that poor performance was due to a lack of knowledge and skill. the use of oral rehydration salts greatly increased during the 1980s and 1990s. however after more than 2 000 training courses on the management of diarrhoea and the provision of supervision from 1988-93 in more than 120 countries, the median percentage of children correctly rehydrated by health workers as assessed in 22 surveys, was only 20%.’49 these researchers draw the conclusion that poor the southern african journal of hiv medicine june 2006 june 2006 the southern african journal of hiv medicine5 0 health worker practices contribute to the low use of health facilities by vulnerable populations. among reasons cited by poor kenyans for failure to access health facilities were ‘lack of money’ and ‘the belief that hospital staff have insufficient understanding of and tolerance for the patient’s social and economic circumstances and language, and that facilities and drugs might be inadequate to assist their sick child.50 this perception seems to be held by the south african public too: ‘ms n.m. had been at the helen joseph hospital in johannesburg, since 6.30am. she had resigned herself to spending the day at the hospital. “i travel from soweto to come here and get my pills because the service is better than at baragwanath. there, the nurses scold us and will not help you if you don’t have money to pay. the nurses go out for lunch and tea breaks, leaving us sitting here and when they come back they shout at us. i don't know why. and there is nothing we can do because we are poor.”‘51 the south african minister of health after a recent visit to chris hani baragwanath hospital is quoted as saying, ‘judging by what i have seen, i would not encourage people to use public health facilities’.52 what ought to be done? what ought to be done to respond to the ethical and political issues surrounding the provision of care to the hiv-infected community of south africa? activism aids activism in north america and europe resulted in an expanded access to arvs, price reduction and the promotion of research: 'decisions about the allocation of resources are inherently political and are thus amenable to effective lobbying'.53 locally, the treatment action campaign has garnered support from city and township dwellers and rural communities. in so doing it has become a legitimate voice of the people.54, 55 how might the ordinary health worker respond to perceived inadequacies or injustice? withholding their vote or voting for an alternative party, drafting and supporting petitions, joining ngos and activist groups or forming new groups – it was particularly the mass movements of the 1980s that led to the demise of the apartheid regime. there are issues that need to be addressed: speeding the process of new drug registration, enhancing access of indigent patients to arvs, addressing the low morale of health workers in arv rollout programmes, assisting in projects that aim to build the numbers and competency of staff employed in rollout centres. those health care facilities that persist in rendering inadequate service must be identified and pressured to change. corrupt health workers and disinterested officials must be weeded out of the system. the promises of government and local authorities must be matched by performance. allocated budgets must be spent. concerned bodies such as the hiv clinicians society might consider closer links with activist groups and networking with the trade union movement and with grassroots communities across the country. dealing with denial preventive strategies were defined decades ago. universally acceptable treatment guidelines have been in the public domain for many years. yet both transmission and mortality continue to increase. denial has fed this situation. ‘aids is here to stay. it is like the day after hiroshima (or after 9/11!). the world has changed and will never be the same again. the new virus will be a fact of life for our children's children; much can be done to moderate its force, but it cannot be made to disappear.’56 asked about the value of garlic, olive oil, etc., the health minister commented, ‘no one said these diets cure hiv. however they boost the immune system. i have met over 100 patients who ‘got-up-and-walked’ after following this dietary advice.’57, 20 a truthful understanding of the epidemic has been scuttled by a belief in non-science, folklore and dissident opinions. where truth is muddied and denied, society will not find solutions to the epidemic. has this denial been deliberate? do the politicians really believe what they say? are politicians able to envision alternatives to the situations they are tasked to deal with? can they work outside the box of their own value system and world view? ‘it is the vocation of the prophet to keep alive the ministry of imagination, to keep on conjuring and proposing alternative futures.’58 few would credit the religious community of our day as having the status to provide such leadership. prophets appear largely to have passed into the realm of antiquity and obscurity. nevertheless we need them. ‘any justice which is only justice soon degenerates into something less than justice. it must be saved by something which is more than justice. the realistic wisdom of the statesman is reduced to foolishness if it is not under the influence of the moral seer.’59 politicians need ethics and the ethical scholar to guide them. opposition to apartheid drew strength from tough religious people and those communities that refused to accept the status quo. we need such people today. the issue of denial needs to be faced both at the level of government and by the community. infection with the hiv virus is perceived as shameful and evokes disgust, revulsion and rejection by many in the community. exposure in the early days of the epidemic led to censure, harassment and in some cases the death of the infected person.60 only openness and honesty will deal with these inappropriate attitudes. several political leaders have spoken of their sorrow concerning the loss of family members from this disease. but those who are themselves infected and enjoy prominence within our society need to become role models for society: seen to be taking medication, living well, dealing with life in a humble but challenging manner. we lack these heroes. why do governments fail to confront aids adequately? sexual transmission is the dominant vehicle of spread in africa. ‘safe sex’ means abstinence, or being persistently faithful to one's spouse/partner, and using condoms to prevent exposure to body fluids. a core responsibility of government is to ensure that those most likely to spread disease adopt preventive behaviour.61 recent data suggest that some young people influenced by the 'lovelife' campaign 5 1 may be altering lifestyles. however, there is little evidence that viral transmission in the southern african region as a whole is diminishing. can a nation or a continent change its culture? at the core of this epidemic is the vulnerability of our youth, particularly adolescent girls between the ages of 15 and 19 years. the hiv prevalence among this group far outnumbers that of boys of the same age. older males transmit the virus to these teenagers. this culture of abuse clearly needs to change.62, 63 but some customs are part of everyday life in africa: long engagement periods necessitated by inflated bride prices, premarital sex to confirm fertility, conjugal rights of widows to males within the extended family or tribe. to these add poverty and sex for money, poor acceptability of condoms, single-parent homes, fathers and husbands who work long distances from their families and seldom return home. if this epidemic will be heard, it is saying that society has to change in significant ways. this perhaps is the central 'meaning' of this epidemic. what politician has shown any determination to confront this goliath? ‘the man with a conscience fights a lonely battle against overwhelming forces of inescapable situations which demand decisions. evil comes upon him in countless respectable and seductive guises so that his conscience becomes timid and unsure of itself, till in the end he is satisfied if instead of a clear conscience he has a salved one, and lies to his own conscience in order to avoid despair. a man whose only support is his conscience can never understand that a bad conscience may be healthier and stronger than a conscience which is deceived.’64 ron bayer: 'there are no simple answers that address the needs both for trust and candor in intimate relationships and for security in the era of aids. systematic behavioral research is essential, as is searching inquiry into the ethical and psychological underpinnings of intimate relationships. nonetheless, these questions make it clear that matters of sexual ethics are not moralistic diversions. they are at the heart of aids prevention.'65 case isolation, quarantine, contact identification, notification and the provision of treatment underpin the effective public health response to a serious communicable disease.8 with regard to the prevention of hiv, south africa took its lead from europe and north america where so-called hiv 'exceptionalism' had taken root.66 notification and identification were deemed to be an infringement of the individual's rights and likely to drive the epidemic underground. perhaps the memory of the 'pass laws' and the abuse of personal freedom prompted this position, or the fact that in its earliest days the south african epidemic was focused on the white, middle-class gay community and thus not unlike that of europe and the usa. without notification, the south african government has been able to query prevalence data and contradict research findings.67, 68 ‘governments’, say ainsworth and teokul, ‘will do those things that are not viewed as controversial and that can be expected to have widespread support.’61 would the 'public health' model of disease prevention be appropriate to south africa? can a government police its entire population? cuba's approach has been dramatically successful: the hiv prevalence in cuba is currently 0.03%, only 4 000 infected in a population of more than 13 million.69, 70 it took a traditional public health approach incorporating isolation, quarantine and notification of exposed partners. how would one quarantine 6 million infected south africans? is it not time to end this hiv exceptionalism? several experts suggest that it may be.8,66,71 de kock argues for performing mandatory, voluntary and routine testing and testing where patients present with specific hiv-related illnesses such as tb and sexually transmitted diseases (stds). it is stressed that such testing must be done in an open manner while maintaining strict confidentiality. in support of this approach he argues, ‘what if the hiv prevalence were 30% in geneva or new york?’8 he notes that aids awareness is now huge in most of sub-saharan africa and that evidence of benefit from extensive pre-test counselling for hiv in this region 'is lacking'. other researchers remind their readers that the political costs of promoting a public health approach include 'offending both sides of the political establishment’. they continue, 'controlling epidemics is a fundamental responsibility of government, working in concert with physicians, patients and communities. until we implement prevention programs with proven efficacy more widely, make voluntary screening and linkage to care a normal part of medical care and expand screening in community settings, and improve treatment, risk reduction, monitoring, and partner notification, we will continue to miss opportunities to reduce the spread of hiv infection.'71 while the south african government and society fail to address the underlying cultural and ethical issues that orbit around this epidemic there is little likelihood that we in south africa will follow these recommendations. what of the health worker whose conduct is unprofessional? how does one change the low morale of our nurses and doctors? denial and disinformation – untruth – have perpetuated the spirit of futility that has characterized much of the government's response to this epidemic. health workers, we are told, are 'burnt-out and demoralised'.72 but the epidemic is not yet over. indeed the virus is likely to remain with us for many generations. arthur frank speaks of the rebuilding of czech society in the 1990s: 'vaclav havel realized that the success of any institutional reform in postcommunist czechoslovakia depended on individual moral work.'73 the principles are no different in africa. ‘individual moral work.’ ethics and the practice of health care are inseparable. ethics and the practice of good governance are inseparable. the control of the epidemic with vaccines and various 'magic bullets' are unrealistic dreams at this time. a cure is not around the corner. hard work and difficult choices lie ahead. inadequacies in the prevention of transmission need to be reviewed. the debate over appropriate public health strategies requires further thought. cultural mores and norms that do the nation a disservice must be openly debated and change embraced where appropriate. clear-thinking leadership, truthfulness and humility on the part of our politicians and goodwill on the part of our scientists may help to bring the country out of the dark tunnel it is in. the the southern african journal of hiv medicine june 2006 june 2006 the southern african journal of hiv medicine5 2 plundering of this nation's life will only be halted when citizens and government listen to the lessons the epidemic is teaching. references 1. isaiah 33:14,15. the holy bible, new king james version. 2. politics. in: concise oxford dictionary. 8th ed. oxford: oxford university press, 1990: 922. 3. ethics. in: concise oxford dictionary. 8th ed. oxford: oxford university press, 1990: 401. 4. bonhoeffer d. ethics. scm press, 1955: 46, 47. 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(originally published in german in 1949.) 65. bayer r. aids prevention – sexual ethics and responsibility. n engl j med 1996; 334: 1540-1542. 66. bayer r. public health policy and the aids epidemic: an end to hiv exceptionalism? n engl j med 1991; 324: 1500-1504. 67. ramsay s. ‘shocking’ aids data released in south africa. lancet 2001; 358: 1345. 68. baleta a. confusion over mandela's ‘support’ of anc hiv policy. lancet 2002; 359: 855. 69. susman e. us could learn from cuban aids policy. notes and quotes. aids 2003; 17: n7-n8. 70. hsieh y-h, chen cws, lee s-m, de arazoza h. on the recent sharp increase in hiv detections in cuba. aids 2001; 15: 426-428. 71. frieden tr, das-douglas m, kellerman se, henning kj. applying public health principles to the hiv epidemic. n engl j med 2005; 353: 2397-2402. 72. kapp c. hiv overshadows south african health advances. lancet 2004; 363: 1202-1203. 73. frank aw. the renewal of generosity. illness, medicine and how to live. london: university of chicago press, 2004: 29. sajhiv 1033 reflections reflections on hiv care and art – a view from pietermaritzburg c armstrong, bsc (hons), mb chb, mrcp (uk), dtm&h, da (sa), diphivman corresponding author: c armstrong (carolinejarmstrong@gmail.com) dr caroline armstrong hails from edendale hospital in pietermaritzburg, kwazulu-natal province, south africa i held her hand; her wasted arm revealing the anatomy of every bone and muscle. her eyes were closed, weighed down by the burden of disease. she lay upon the bed in my consulting room and there, with no fanfare, she breathed her last breath, passing effortlessly from life into death. ironically, it was 1 december 2000, world aids day. the patient was a nursing sister and her decline in the face of no antiretroviral therapy (art) had been harrowing. at times like these, the futilty of working in an hiv clinic was overwhelming, and i fought tears as i turned with a heavy heart to deal with the devastated family as best i could. i had arrived in kwazulu-natal from my native britain in 1997 to work for two years. i soon realised that the numbers of hiv-infected people were growing inexorably, but that no-one really knew what to do with those individuals who had summoned the courage to take an hiv test and had a positive result. triple-drug art was new, even in europe, and virtually unheard of in the hospitals in which i was working. knowledge about the natural course and management of hiv was limited, even among healthcare professionals. on the wards if a patient had ‘the label’ (coded in various subtle ways in the doctors’ notes), then doctors and nurses would often not fully address whatever the presenting problem was – even if it was unrelated to hiv. there would be hushed tones on the ward round, a shrugging of shoulders and a general feeling that there was nothing much more that could be done. little wonder that time and again patients would refuse to be tested, even in the face of all the stigmata of advanced hiv infection. because, at that time, to test positive meant that your medical team might have looked no further for what was actually wrong with you. in effect, you would have been sent home to die. it seemed that we doctors hated the diagnosis almost as much as the patients did. it called us failures; it labelled us as incompetent, inept, ineffectual; it mocked our training and humbled us as we fought to cope with the burgeoning numbers inundating our services. we had no oral antifungal agents – just gentian violet. amphotericin b was extremely difficult to obtain and cryptococcal meningitis, when the diagnosis was actually made, was almost universally fatal. there were virtually no hiv services, and patients were often literally neglected as they trod the terrifying path of opportunistic infections to their death. in 1999, i started working at a government hospital in pieter­maritz­burg. there, an insightful and committed physician had started an hiv clinic (one of the first in kwazulu-natal) and i remember clearly how incredulous and excited i was about this! someone was willing to see these patients; someone actually wanted to see these patients! someone felt they had something to offer in the face of the hiv monster which had thus far defeated all the doctors i knew! i was captivated by the thought and it was not long before i joined the clinic. although we had no antiretrovirals (arvs), we provided something that these patients hadn’t hitherto experienced: a place where they were welcomed because of their hiv status. elsewhere in society and in the healthcare system at that time, people living with hiv were rejected and ostracised. but in an hiv clinic, they were embraced. we got to know and care about our patients; we treated their opportunistic infections; we obtained disability grants for them; and we spent many hours counselling about death and dying, allowing people to explore and verbalise their fears. we encouraged mothers to make memory boxes for their children and we galvanised patients to put their affairs in order before they died. we tried to read as much as we could about hiv manage­ment; we gave isoniazid and cotrimoxazole prophyl­axis and we obtained a supply of ketoconazole for oesophageal candidiasis. there were so many things we didn’t know. the internet was limited and we relied heavily on our manuals to teach ourselves hiv medicine. it became increasingly obvious that arvs were going to be the only solution for our burdened country. how many heated discussions were had around this topic! many people felt that such an expense could never be borne by a middle-income country with such a vast hiv epidemic. in 2000, we started prescribing the cheapest arv drugs in a desperate attempt to do something that could slow down the disease progression. and so bongani, weak and wasted, with histoplasmosis of the palate, was our first patient to receive didanosine (which he paid for) and hydroxyurea (which we supplied). amazingly, he blossomed on what is now considered substandard, toxic dual therapy, and we marvelled in wonder at his improved health! this was the first time we had ever seen the disease checked and reversed. next, didanosine and stavudine became available for us$1 per day. this was affordable to a number of patients and it worked! it was relatively durable and we saw people rally. very few people in south africa at this time knew much about hiv treatment. we constantly felt like isolated and lonely pioneers, chasing the pipedream of triple therapy. those were the days when the government dragged its collective feet in almost everything concerning the treatment of hiv and the treatment action campaign had to force them into the courts. later, the advent of relatively cheap efavirenz meant that at last we could initiate patients on really effective art. the caveat of course was that they had to pay r700 for one month’s supply. those who could afford it sat side by side with those who couldn’t, which was a huge source of frustration for all of us. we continued to be astounded by the effect that these drugs had on our patients. after so many years of losing countless lives, at last we had a weapon with which to fight back, and it was a glorious feeling. we still lacked adequate monitoring (it was difficult to convince people to spend r750 testing their viral load privately) and we learnt hard lessons as we saw peripheral neuropathy, lactic acidosis and drug-related deaths. early in 2003 the air was thick with rumours that soon the government would introduce a national art programme. when the moment actually arrived, it was a cause of great celebration. the package was comprehensive and at last we could monitor patients’ responses to therapy. our kwazulu-natal department of health seemed really committed, with our minister of health, dr zweli mkhize, even coming to work at the clinic on monday mornings! i still work with hiv – having been privileged to have witnessed the enormous mobilisation of resources and commitment that has brought us to where we stand today as a country. the hiv story of south africa continues to evolve, but for me, the battle will never be as fierce again. s afr j hiv med 2014;15(1):16-17. doi:10.7196/sajhivmed.1033 july 2000------------th£ southtrn african journal of hiv m£oicin£ prevention james mcintyre, mrcog, glenda gray, mb chb, fcpaeds (sa) perinatal hiv research unit, university of the wirujafersrmzd and clzris hani baragwanath hospital. johannesburg placebo. arm a received zdv and 3tc from 36 weeks' gestation} during labour and for 1 week postpartum (mother and child). arm b received zdv and 3tc from the onset of labour and for 1 week postpartum (mother and childl. arm c received zdv and 3tc during labour only. interim early efficacy results have been reported, showing that the risk of transmission by 6 weeks of age was 8.6% in arm a, 10.8% in arm 8/ 17.7% in arm c and 17.2% in the placebo group." nevirapine is a fast-acting and potent antiretroviral, with a long half-life. the hivnet 012 trial in uganda" investigated the use of a single 200 mg dose of nevirapine administered orally to women at the onset of labour and a single dose of 2 mg/kg administered to infants within 72 hours of birth, compared with intrapartum zdv and 1 week of infant zdv treatment. almost all babies were breast-fed. in the nevirapine treatment group the transmission rate at 14 16 weeks was 13.1 % compared with 25.1 % in the comparison group. the efficacy of nevirapine was 47% (95% cl 20 64l. side-effects were similar for the two regimens, both of which were well tolerated." the south african intrapartum nevirapine trial (saint) is investigating intrapartum and postpartum duction in mtct" a second random-ised trial of the zdv regimen was conducted in 260 women in c5te d'ivoire. this resulted in a 37% reduction in transmission in the treatment group by the time the infants were 3 months of age." in contrast to the thai study, over 95% of the infants in the c5te d'ivoire trial were breast-fed. another trial of short-eourse zov was conducted among 350 women in burkina faso and c5te d'ivoire. the trial com-pared placebo with oral zdv started at between 36 and 38 weeks' gestation at 300 mg twice daily. this was followed by a single loading dose of 600 mg at the onset of labour and oral zdv 300 mg administered to mothers twice daily for 7 days after delivery. in this trial over 85% of infants were breast-fed for longer than 3 months. the efficacy of zdv was estimated at 38% (95% confidence intervals (cl) 5% 60%) when infants were 6 months of age,lz and at 30% when they were 15 months old." the pet ra study, " conducted in five african sites in south africa, tanzania and uganda, investigated different regimens of a combination of zdv and 3tc (iamivudine) in over 1 700 women. this trial compared the effectiveness of three different drug regimens with preventing mother-to-child transmission of hn african solutions for an african crisis the use of antiretroviral treatment during pregnancy has resulted in a dramatic decline in the number of perinatal hiv infections in the usa and europe. transmission rates in los angeles have dropped from 30% to 10%, and in north carolina from 21 % to 8.5%.4 reported transmission rates in the usa and france declined by between one-half and twothirds within the first 3 years of routine use of zidovudine (zdv) in pregnancy.'·' further reductions have been seen, with transmission rates of less than 5% now recorded.' astudy in france" showed that hiv-positive women who received this zdv regimen and who had an elective caesarean section had a transmission rate of 0.8%. when the results of the pactg 076 trial became available in 1994,' it was obvious that the expensive regimen would not be feasible in most developing countries in the short term. african and asian scientistsl with international collaborators, commenced a series of trials to investigate the efficacy of shorhourse antiretroviral therapy in late pregnancy. the first trial results, from thailand, demonstrated that 4 weeks of zdv given in late pregnancy produced a 50% rethe issue of mother-to-child transmission (mtct) of hiv has become increasingly politicised in south africa, with accusations and counter-accusations from all sides. oinicians and activists, unable to comprehend the government's decisions not to provide inexpensive treatment to prevent mtct, accuse it of child murder, while the president and minister of health claim concern about the safety of the drugs and make sweeping statements about mothers being killed. amid all the political noise, scientific findings seem to be forgotten. the south african president has called for a 'search for specific and targeted responses to the specifically african incidence of hiv-aids',' but it appears that some of the evidence already collected by african scientists and their collaborators, with the participation of african women and children, has been ignored. hiv seroprevalence in pregnant women in south africa averages 23%, rising to 33% in the worst-hit provinces. some south african studies' have reported mtct rates of over 35% in the absence of any intervention and where breast-feeding is practised. with a conservative estimate of 800 000 births per year in south africa, this suggests 70000 infants are affected annually. the head of the medical research council, professor malegapuru makgoba, wrote in a recent science editorial' that the decision not to use antiretrovirals for the prevention of mtct 'poses serious moral and ethical dilemmas in a nation where maternal-fetal transmission of hlv accounts annually for 10% of the total hlv disease burden'. the need for an effective and affordable strategy to reduce mtct of hlv is a matter of urgency. 'i am convinced that our urgent task is to respond to the specific threat that faces us as africans.' president thabo mbekj' antiretroviral therapy thf southfrn african journal of hiv mfdlcinf -----------july 2000 nevirapine compared with the arm b reqimen from the petra study, with results expected in mid-2000. these trials of antiretroviral interventions have included several thousand african mother-infant pairs. to date, none of these trials has demonstrated significant toxicity or serious side-effects in mothers or infants. a small study in uganda" has demonstrated the development of a nevirapine-resistant virus in 3 of 14 women who received only one intrapartum dose of nevirapine. further studies on the development of resistance are in progress. infant feeding concern remains about the effect of infant feeding choice on transmission, infant survival and the efficacy of antiretroviral interventions. while breastfeeding may be the major detenminant for the difference in transmission rates between developed and developing countries, safe replacement feeding options are not always available. the additional risk of transmission via breast-feeding is estimated at between 7% and 22%, and the additional risk of transmission for women who become infected during the breast-feeding period is close to 30%. international guidelines recommend that hiv-positive women should be given the infonmation to make an infonmed choice about the risks and benefits of breast and replacement feeding, and that they should be supported in their choice. in malawi, miotti et al." showed a 0.7% per month incidence of breastfeeding transmission in infants from 2 to 6 months of age, and a 0.3% incidence from 12 to 24 months, equivalent to about 3% additional risk from 12 to 24 months. a randomised controlled trial comparing breast-feeding and replacement feeding in nairobi showed that at 24 months of age infants had a 36.7% cumulative probability of hiv infection in the breastfeeding anm and a 20.5% probability in the fonmula-feeding anm." forty-four per cent of hiv infection in breast-fed infants was attributable to breast-milk. although the 2-year mortality rates were similar in the two groups, hiv-free survival was significantly lower in the breast-feeding anm (58% v. 70%, p = 0.02). in work from durban, coutsoudis et al." proposed an influence of infant feeding pattern on the rate of transmission. in this subanalysis of motherinfant pairs enrolled into a vitamin a supplementation study, transmission rates in exclusively breast and formula-fed infants were simila~ while infants who received mixed feeding had higher rates of infection. these findings are interesting and require further investigation in a larger trial. ongoing research several ongoing studies in africa will add to our knowledge of prevention strateqies. in malawi, a trial of treatment for chorioamnionitis and sexually transmitted infections in pregnancy is underway. a study in soweto is assessing escalating concentrations of chlorhexidine for birth canal cleansing during labour, in the hope that a safe higher concentration will improve on the results from malawllo in durban and zimbabwe, an initial study of nevirapine administered to breast-fed infants will lead the investigation into ways to make breast-feeding safer, while in pretoria a low-technology pasteurisation method for breast-milk is being studied. several trials in south africa, uganda and other centres aim to fine-tune the antiretroviral interventions to make them more cost-effective. pilot studies underway in eight african countries under the auspices of unicef, unaids and the who will take the research findings into practice and provide invaluable infonmation on implementation issues. botswana, cote d'ivoire, rwanda and zimbabwe are taking the lead in this regard. in south africa, pilot projects in soweto, the western cape and three other provinces will add to this experience. the way forward there is no doubt that african solutions to the african crisis of mtct of hiv have been found and are starling to be implemented. these are 'specific and targeted responses', which have not tried to implement western approaches blindly, but have been tailored to meet the needs and challenges of the continent. they come from the dedication and commitment of african research teams and of african women prepared to contribute to the research efforts. several years back, at the height of the controversy about placebo-<:ontrolled trials, a participant in a trial at chris hani baragwanath hospital was asked why she would risk participation in a study. she replied 'i am not only doing this for myself, i am doing it for my sisters who also face this terrible epidemic.' it will be an ongoing tragedy if policy makers across the continent ignore these solutions and the needs of hivpositive women and their families. references 1. anonymous. south african president addresses aids in africa. washington post. iq april 2000. 2. bobat r, moodley d, coutsoudis a, coovadia h. breastfeeding by hiv-l-infected women and outcome in their infants: a cohort study from durban, south africa aids lqq7; 11: 1627-1633. 3. makgoba mw. hivlaids: the pedl of pseudoscience (editorial). science 2000; 288: non. 4. fiscus sa, adimora aa, schoenbach vj, et al. perinatal hiv infection and the effect of zidovudine therapy on transmission in rural and urban counties. jama lq96; 275: 1483-1488. 5. simonds rj, ste etee r, nesheim s, et af. impact of zidovudine use on risk and risk factdrs for perinatal transmission of hiv. perinatal aids collaborative transmission studies. aids lqq8; 12: 301~308. 6. mayallx mj, teglas jp, mandelbrot l, er al. accept.ability and impact of zidavudine for prevention of mother-to<hild human immunodeficiency virus-l trans-mission in france. j pedialrlqq7; 131: 857-862. 7. fowler mg, simonds rj, roongpisuthipoll9 a. update on perinatal hiv transmission. pediav clin north am 2000; 47(1): 21-38. 8. mandelbrot l, le chenadec j, berrebi a, er al. perinatal hiv-l transmission: interaction between zidovudine prophylaxis and mode of delivery in the french perinatal cohort. jama 1998; 280(1): 55-60. 9. connor em, sperling rs, gelber r, et at reduction of matemal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. pediatric aids clinical trials group protocol 076 study group. n cngl j med 19q4; 331: 1173-1180. 10. shaffer n, chuachoowong r, mock pa, et al. short-eourse zidovudine for perinatal hiv-l transmission in bangkok, thailand: a randomised controlled trial. bangkok collaborative perinatal hiv transmission study group. lancet 1999; 353: 773-780. 11. wiktor s2, ekpini e, karon jm, et al. short· course oral zidovudine for prevention of motherto-child transmission of hiv-l in abidjan, cote d'ivoire: a randomised trial. lancet 1999; 353: 781-785. 12. dabis f, msellati p, meda n, et aj. 6-month efficacy, tolerance, and acceptability of a short regimen of oral zidovudine to reduce vertical transmission of hiv in breastfed children in cote d'lvoire and burkina faso: a double-blind placebo-ecnttrolled multicenve trial. ditrame study group. diminution de la transmission mere-enfant. lancet lqq9; 353: 786-7q2. 13. 15-morrth efficacy of matemaj oral zidovudine to decrease vertic.aj transmission of hiv-i in breastfed african children. ditrame anrs 049 study group. lancet im; 354: 2050-2051. 14. saba j, petra study group. current status of the pet ra sbjdy. 2nd conference on global strat.egies for the prevention of hiv transmission from mothers to lnfarns, montreal, quebec, canada, 2 september 1999. 15. guay la, musoke p, fiemi~ t, et al. intrapartum and neonatal single-dose nevirapioe compared with zidovudioe for prevention of mother-to-child transmission of hiv-l in kampala, uganda: hivnet 012 randomised trial. lancer 1999; 354: 795-802. 16. seeker-pergola g, guay l, mmiro f, er al. selection of the ki03n nevirapine rt5ista:nee mutation in ugandan women receiving nvp prophylaxis to prevent hiv-l vertic.aj transmission (hivnet-q06). 7th conference on retroviruses and opportunistic infections, san francisco, 2000. 17. miotti pg, taha te, kumwenda ni, et al. hiv transmission through breast-feeding: a study in malawi. jama lqqq; 282: 744-749. 18. nduati r, john g, mbori-ngacha d, et al. effect of breastfeeding and formula feeding on transmission of hiv-l: a randomized clinical trial. jama 2000; 283: 1167-1174. 19. coul$oudis a, pillay k, spooner e, kuhn l, coovadia hm.lnfluence of infant-feeding patterns on early mother-to-ehild transmission of hiv-l in durban, south africa: a prospective cohort study. south african vitamin a study group. lancet 19qq; 354: 471-476. 20. bigqar rj, mioni pg, taha te, et al. perinatal intervention trial in africa: effect of a birth cana1 cleansing intervention td prevent hiv transmission. lancet 19%; 347: 1647-1650. abstract introduction materials and methods results discussion conclusion acknowledgements references about the author(s) neil k. morris department of forensic medicine, university of pretoria, south africa lorraine du toit-prinsloo department of forensic medicine, university of pretoria, south africa lynne webber department medical virology, university of pretoria, south africa gert saayman department of forensic medicine, university of pretoria, south africa citation morris nk, du toit-prinsloo l, webber l, saayman g. the prevalence of hiv in the sudden, unexplained and unexpected death population at the pretoria medico-legal laboratory. s afr j hiv med. 2016;17(1), a424. http://dx.doi.org/10.4102/sajhivmed.v17i1.424 original research the prevalence of hiv in the sudden, unexplained and unexpected death population at the pretoria medico-legal laboratory neil k. morris, lorraine du toit-prinsloo, lynne webber, gert saayman received: 21 sept. 2015; accepted: 22 mar. 2016; published: 31 may 2016 copyright: © 2016. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract purpose: to determine the prevalence of hiv in the sudden, unexplained and unexpected (suu) death population admitted to the pretoria medico-legal laboratory. methods: this study was conducted at the pretoria medico-legal laboratory. blood samples were obtained from decedents who died suddenly and/or unexpectedly, during autopsy, by a forensic pathologist. sample collection continued until 100 valid samples were analysed for hiv antibodies. the data collected included demographic details and case-related information. results and conclusion: suu deaths accounted for 14% of all cases admitted to the pretoria medico-legal laboratory. the hiv prevalence in the suu deaths was 43%, which is 17% higher than the general mortuary population in pretoria (p = 0.0045). the majority of these deaths were due to respiratory disease processes, with 12 cases having hiv/tb co-infection. introduction there are numerous definitions for sudden deaths. all of the definitions include two main parameters. they relate to the time from the onset of symptoms and signs, and the time of death.1 these times vary between zero, 1, 6 and 24 h.1 the who defines a sudden death as a death occurring within 24 hours after the onset of symptoms.2 byard classified these deaths into three categories: those individuals who were apparently completely well and died suddenly; those who were mildly unwell; and those with known serious disease processes but were stable on treatment.1 the admission of cases of sudden, unexpected and/or unexplained deaths (suu-deaths) to medico-legal mortuaries is a well-known worldwide phenomenon, and in many of these cases an inadequate history is present at the time of the investigation.3 in south africa, the performance of medico-legal autopsies is regulated by the inquests act (no. 58 of 1959). the definition of unnatural deaths is in the regulations regarding the rendering of forensic pathology service (r636) in accordance with chapter 11 of the national health act (no. 61 of 2003). these include cases ‘where the death is sudden and unexpected, or unexplained, or where the cause of death is not apparent’. suu-deaths are considered to be some of the most challenging autopsies that can be conducted by pathologists.3 in many of these cases, it is difficult to ascertain whether or not the person died from a disease process found at autopsy or as a result thereof.4 hiv can cause death of an individual in numerous different ways including aids, accelerated cardiovascular disease, malignancies and opportunistic infections.5 aids is regarded as being the number one cause of death in hiv patients.6 tseng et al. indicated that sudden cardiac deaths in hiv-positive individuals accounted for 86% of all cardiac deaths with a mean rate of 2.6 per 1000 person-years.6 antiretroviral therapies have been associated, in a number of studies, with the increased risk of cardiovascular disease.7,8 it was documented that: ‘increased exposure to protease inhibitors is associated with an increased risk of myocardial infarction, which is partly explained by dyslipidaemia’.9 tb and hiv co-infection may also be linked to suu-death. tb and hiv co-infected patients have a five times greater risk of dying within 2 years of receiving tb treatment.10 other studies have determined that 31% of all new tb cases in the african region can be attributed to hiv infection: ‘tb was the cause of 11% of all adult aids-related deaths’. in south africa, it was estimated that there were 2 million co-infected adults in 2003.11,12 south africa has a jaded past with misinformation and the stigmatisation of hiv-positive individuals.13,14 due to these social factors, the disclosure of an accurate medical history is not forthcoming in cases of suu-death. this ends up hindering the medico-legal investigation of the death. south africa had a population of 49 320 500 people as of mid-2009, and 10.6% of the population was hiv-positive.15 the burden of the disease on the state is large and costly. in order to minimise the consequences of the pandemic, every possible chance to understand and refine the information, used to make important prevention and treatment decisions, needs to be implemented and assessed. this study seeks to provide relevant statistical information on the hiv prevalence rate in the suu-death population of the pretoria medico-legal laboratory (mll). the results of this study could also provide additional insight into the epidemiology of the virus and the suu-death population. this can facilitate a protocol change in the handling of the suu-death population admitted to the pretoria mll. this would be to implement standardised hiv testing in suu-death cases, which, in turn, will have budgetary and policy implications for the forensic pathology service (fps). materials and methods study population this study was conducted at the pretoria mll. pretoria is the capital city of south africa with a population of approximately 2 553 648.16 the pretoria mll admits approximately 2500 cases each year, and full autopsies are conducted in more than 90% of the cases admitted. a previous study conducted at the pretoria mll indicated that the hiv prevalence of the general mortuary population was 26%.17 the suu-death population makes up 14% of the general mortuary population. samples were collected until the study had obtained 100 valid results. method blood samples were obtained from decedents who died suddenly and/or unexpectedly. this was done during autopsy, by a forensic pathologist. sample collection continued until 100 valid samples were analysed. a study and funding limitation was that only 100 samples were to be collected. the processing of blood samples was done by the following standardised testing procedures developed and used in the nhls tshwane virology research department: after centrifugation of whole blood, the serum was used to run the test in order to minimise the effect that haemolysed blood has on test strips. the screening test used was the determine™ hiv-1/2 ag/ab combo assay, and the confirmatory test used was the hiv combi, cobas e, elecsys and modular (roche).18 exclusionary criteria the following cases were excluded: if age was less than 9 months because of the possible residual positive reaction to the mothers’ antibodies in the child19,20; and if it was not possible to obtain a sample due to post-mortem changes (decomposition) or charring of the remains. data collection and analysis the data collected included demographic details and case-related information. confidentiality was ensured, and the study proposal was approved by the university of pretoria’s faculty of health sciences research ethics committee and the msc committee. the statistical analysis was done in conjunction with the department of statistics at the university of pretoria. the null hypothesis was that the prevalence of hiv in the pretoria mll suu-death population should not deviate from that of the general pretoria mll population. the statistical programme sas® was used for the analysis of data. results the data collection took approximately 10 months to complete in 2009. a total of 130 samples were collected, of which 100 samples yielded a valid hiv result. the remaining 30 samples when tested provided an invalid result on the test (the absence of a test result). this was discussed in a previous study, and it could be caused by an increased post-mortem interval.17 demographic details table 1 lists the results of the hiv screening and confirmatory testing that was done at the nhls tshwane medical virology laboratory. a total of 30 invalid test results were documented; these translate into 25% of all samples. of the viable samples, 43 (43%) were hiv-positive and 57 (57%) were hiv-negative. table 1: total sudden, unexplained and unexpected death cases and hiv prevalence information in the pretoria medico-legal laboratory. table 2 lists the gender and race distribution of the hiv-positive cases. twenty-one per cent (21 cases) of the suu-death sample population was female and 79% (79 cases) was male. of the female demographic fraction, the hiv-positive cases made up 62% (13 cases) of the total valid samples. in the male demographic fraction, the hiv prevalence rate was 38% (30 cases). table 2: gender and race demographics for sudden, unexplained and unexpected death cases. the race demographics for the suu-death cases are listed in table 2. of the total sample population, asian individuals made up 2% (2 cases), with none of them being documented as hiv-positive. black population group made up 79% (79 cases), and the prevalence of hiv was 51% (40 cases). no individuals classified as ‘mixed race’ were documented in this study. white south africans made up 19% (19 cases) of the suu-death population, and the hiv prevalence is 16% (3 cases) in this group. the age of individual cases in this study ranged from 9 months to 74 years (figure 1). data were divided into categories with a 5-year interval between the groupings. positive hiv immune assay results were obtained only from samples in the 9 months – 74 years range, resulting in a 43% rate of infection across the entire pretoria mll suu-death population. the average age for the valid sample population was 43 years. the average age for females was 39.0 years and for males 44.9 years. the average age in the males from the black population group was 45.5 years and in the males from the white population group was 42.6 years. the average age in the females from the white and black population groups was 37.2 years and 39.3 years, respectively. figure 1: age distribution of the valid sudden, unexplained and unexpected death samples and the hiv-positive results. cause of death the causes of death are summarised in table 3 below. the majority of the deaths were due to respiratory disease processes (31 in total) with 12 cases of tb, 15 cases of bronchopneumonia, 2 pulmonary thrombo-embolism cases and 1 each of asthma and small-cell lung carcinoma (19 cases of pulmonary disease). cardiovascular disease processes included six cases of ischaemic heart disease, two cases of myocarditis and nine cases of cardiomyopathy. in the central nervous system, one case each of meningitis and sudden unexpected death in epilepsy (sudep) and two cases of haemorrhagic cerebrovascular incident were present; only one case was signed out as being due to aids. in 11 cases which presented as sudden unexpected deaths, unnatural causes of death was identified, which included acute alcohol poisoning, carbon monoxide poisoning and trauma. table 3: causes of death. the prevalence of both the general populations hiv statistics (previously conducted study17) and the suu-death populations hiv statistics were compared in table 4 with a chi-squared analysis, which yielded a statistically significant p-value of 0.0045.17 table 4: chi-square analysis of the general population hiv statistics and sudden, unexplained and unexpected death hiv prevalence statistics. discussion the hiv prevalence in the suu-death population at the pretoria mll is 43%. this is significantly higher than the hiv prevalence in the general mortuary population at the pretoria mll (26%), translating into a 17% difference in prevalence between the two groups.17 this was determined to be statistically significant. white south africans account for 18% of the general mortuary population and their hiv prevalence was 8% in the general mortuary population.17 however, in the suu-death population they accounted for an unexpected 19% of the population and had an hiv prevalence of 16%. black south africans accounted for 76% of the general mortuary population with an hiv prevalence of 32%.17 in the suu-death population, black south africans accounted for 79% of the population but had an hiv prevalence of 51%. the concerning factor is that there are such large numbers of hiv-positive cases being admitted to the pretoria mll and that hiv is not being routinely tested for in the mortuary setting. in contrast to the study by christiansen in which he found the top three causes of suu-death – cardiovascular, malignancy and infection, the majority of our cases died from respiratory disease processes followed by cardiovascular disease. tb accounted for 12 of the 31 respiratory disease-related deaths. in south africa’s millennium development goals, goal 6 declares that there is a co-infection rate of 70% with tb and hiv.21 in a report by statistics south africa in 2009, tb accounted for 12% of all deaths, influenza and/or pneumonia 7.5% and hiv 3.1%,22 thus giving us a context for this difference in profile. tb–hiv co-infection and antiretroviral treatment side effects are two possible explanations that warrant further investigation in this subpopulation. tseng et al. indicated that sudden cardiac deaths in hiv-positive individuals accounted for 86% of all cardiac deaths with a mean rate of 2.6 per 1 000 person-years.6 in our study, cardiovascular diseases accounted for 17% of the cases with the majority being due to cardiomyopathy. suu-deaths are a challenging autopsy and need to be approached with caution and the right amount of scepticism. the purpose of these autopsies is firstly to rule out an unnatural cause of death and secondly to provide, if possible, the cause of death even if it is natural. the value of post-mortem hiv testing as an ancillary investigative technique to assist in the decision-making process and diagnosis of the cause of death should be further investigated. these cases are often admitted with no available history as the next of kin is not known or the medical history is incomplete. an hiv test can be helpful in determining the cause of death. unfortunately in south africa, hiv has not been routinely tested for in the suu-death cases, and as a result statistics and observations regarding this challenging autopsy population have left a number of unanswered questions. this research study has attempted to address these questions and has shown that the analysis and observations provided by this testing provide an accurate well-documented source of information to facilitate the complex decisions that need to be taken in determining the cause of death and ultimately in our fight with regard to the hiv pandemic. if medical records, post-mortem hiv test results and eyewitness testimony are made available before autopsy, a death scene investigator (dsi) can collect the relevant records and information and present them to the forensic pathologist along with the hiv test results. this would simplify the post-mortem examination for the forensic pathologist and facilitate a possible reduction in the number of suu-death cases admitted to the pretoria mll for a full autopsy. a reduction in suu-death cases could save the fps a considerable amount of money and decrease the workload. this will ultimately streamline the provision of fpss in the pretoria mll. a spin-off of testing for hiv routinely would be that there is a database of results that could be used to better understand hiv in the pm setting. conclusion suu-deaths accounted for 14% of all cases admitted to the pretoria mll. the hiv prevalence in the suu deaths was 43%, which is 17% higher than the general mortuary population in pretoria (p = 0.0045). the majority of these deaths were due to respiratory disease processes with 12 cases having hiv–tb co-infection. this study demonstrates the value of testing the suu-death population for hiv at autopsy. further research recommendations are that research should be conducted in the implementation of routine hiv testing and testing for which stage of infection the hiv-positive suu-death cases are in. screening for resistance and antiretrovirals could also be undertaken to determine if the person was on treatment at the time of death. acknowledgements competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions n.k.m. was the project leader, did all the sample collection, analysed the data and prepared the manuscript. l.d.t-p. was the supervisor and made conceptual and editorial contributions. l.w. assisted in the hiv testing and made conceptual contributions. g.s. made conceptual and editorial contributions. references byard rw. sudden death in the young. new york: cambridge university press; 2010. world health organisation. international classification of diseases. 2010 [cited 2011 dec 08]. available from: http://www.who.int/classifications/icd/en/ christiansen lr, collins ka. natural death in the forensic setting: a study and approach to the autopsy. am j forensic med pathol. 2007;28(1):20–23. http://dx.doi.org/10.1097/01.paf.0000233553.19938.a0 republic of south africa. regulations regarding the rendering of forensic pathology services. national health act (61 of 2003); 2005. spencer dc. the clinical practice of hiv medicine. johannesburg, south africa: goldstream books; 2005; p. 99, p. 139. tseng zh, secemsky ea, dowdy d, et al. sudden cardiac death in patients with human immunodeficiency virus infection. j am coll cardiol. 2012;59(21):1891–1896. http://dx.doi.org/10.1016/j.jacc.2012.02.024 dad study group. cardiovascular disease risk factors in hiv patients association with antiretroviral therapy. aids 2003;17(8):1179. http://dx.doi.org/10.1097/00002030-200305230-00010 koppel k, görana b, jovanb r. sudden cardiac death in a patient on 2 years of highly active antiretroviral treatment: a case report. aids. 1999;13(14):1993. http://dx.doi.org/10.1097/00002030-199910010-00033 dad study group. class of antiretroviral drugs and the risk of myocardial infarction. n engl j med. 2007;356:1723–1735. http://dx.doi.org/10.1056/nejmoa062744 elliott am, halwiindi b, hayes rj, et al. the impact of human immunodeficiency virus on mortality of patients treated for tuberculosis in a cohort study in zambia. trans r soc trop med hyg. 1995;89(1):78–82. djoba siawaya jf, ruhwald m, eugen-olsen j, walzl g. correlates for disease progression and prognosis during concurrent hiv/tb infection. int j infect dis. 2007;11(4):289–299. http://dx.doi.org/10.1016/j.ijid.2007.02.001 corbett e, watt cj, walker n, et al. the growing burden of tuberculosis. global trends and interactions with the hiv epidemic. arch intern med. 2003;163:1009. http://dx.doi.org/10.1001/archinte.163.9.1009 van rijn k. the politics of uncertainty: the aids debate, thabo mbeki and the south african government response. soc hist med. 2006;19(3):521. http://dx.doi.org/10.1093/shm/hkl077 keikelame mj, murphy ck, ringheim ke, woldehanna s. perceptions of hiv/aids leaders about faith-based organisations on hiv/aids stigma in south africa. ajar. 2010;9(1):63. http://dx.doi.org/10.2989/16085906.2010.484571 statistics south africa. mid-year population estimates for 2009. 27 july 2009;p0302. the demographics chapter â institute of race relations; 2014 [cited 2014 dec 27]. available from: http://irr.org.za/reports-and-publications/south-africa-survey/south-africa-survey-2012/01-demographics morris n, du toit-prinsloo l, webber l, saayman g. the prevalence of hiv in pretoria’s medico-legal laboratory cases, rsa, in 2009. occup health south afr. 2014;20(2):4. ly td, laperche s, brennan c, et al. evaluation of the sensitivity and specificity of six hiv combined p24 antigen and antibody assays. j virol methods. 2004 12/15;122(2):185–194. sherman gg, lilian rr, coovadia ah. the performance of 5 rapid hiv tests using whole blood in infants and children: selecting a test to achieve the clinical objective. pediatr infect dis j. 2012;31(3):267–272. http://dx.doi.org/10.1097/inf.0b013e31823752a0 world health organization. who recommendations on the diagnosis of hiv infection in infants and children. 2010 [cited 2016 feb 04]. available from: http://whqlibdoc.who.int/publications/2010/9789241599085_eng.pdf council sana. the hiv & aids and sti strategic plan for south africa 2007–2011. 2009 [cited 2014 oct 27]. available from: http://beta2.statssa.gov.za/mdg/2010_mdg_goal_6_combat_hiv_aids_malaria_and_other_diseases.pdf statistics south africa. p0309.3 mortality and causes of death in south africa: findings from death notification, 2009. statistics rsa; 2009 [cited 2014 nov 06]. available from: http://www.statssa.gov.za/publications/statsdownload.asp?ppn=p0309.3&sch=5097 he is married, with 4 children and 5.5 grandchildren spread throughout the diaspora, including new york and toronto. th£ southfrn mrican journal of hiv m£oicin£ ------------may 200 i 'never throw blood away' the bubble really burst in 1985 after a blood test became available tha could detect hiv infection. stored bloods taken 'ram the group in 1983 were tested. results showed that 11% of the group had been infected at the time of giving blood. two men, employees of south african airways, had died in the interim. following calls to professor koornhof and reuben sher in this regard, bee/d published a front-page article on hiv accompanied by a photograph of the face that was to become synonymous with the battle against hiv/aids that of professor ruben sher. thrombocytopenic condition which his son developed. in 1980 he gained a phd from wits and registered as a microbiologist in 1984. 'a new disease' while visiting a number of usa cities in the early 1980s, ruben heard of a 'new disease' afflicting gay men. he travelled to atlanta, georgia, where he met with members of the centers for disease control (cdc) and other us pioneers in the aids field. he voiced his concern about gay men working for south african airways and frequenting usa gay establishments what was the likelihood of their becoming infected] on his return to south africa reuben offered to research the local incidence of aids by taking histories and bloods from, and following up, a small group of 250 gay men . personality profile currently director of hivcare international, he has held seven academic appointments and served as principal investigator on six major hiv studies. a son of johannesburg, born 16 june 1929, professor ruben sher is most widely known as head of the aids research unit at the south african institute for medical research (saimr), johannesburg. a pioneer in aids research, he was a founder member of many south african aids bodies, including the southern african hiv clinicians society. ruben is recipient of many accolades including the wits alumni honour award in 1987 for rendering exceptional service to the community, both the paul harris fellowship and the vocational service award from rotary in the early 1990s, and the salus award (silver) from the department of health in 1993. remembering the beginning before becoming the local media's medical face of aids, he was a pill-counter, served as a pilot in the infant israel, completed a phd, registered as a specialist pathologist (microbiology), and qualified as a sangoma. after an unsuccessful application to the university of the witwatersrand medical school in 1947, ruben marked time as a pharmacist [his second choice) before joining a number of other young south african, british and american zionists training as pilots for the defence of the newly established state of israel. his active service, . mostly ferrying paratroopers and military goods in b17s, dakotas, stearmans and rapides [fitted out like small ambulances)', continued until 1953. reuben says that his subsequent intense interest in pathology was largely the result of a rare he returned home older, wiser and armed with a loan from the zionist federation, to knock again at wits's medical school door, this time successfully. as a reward for 6 years of unremitting study came the mandatory period of hard labour and sleep deprivation which seems to be an integral part of medical training worldwide. after his internship ruben did some time as a general practitioner and later became medical officer at the johannesburg fever hospital. may 200 i -------------the southern african journal of hiv meoicine ruben and his small group of supportive colleagues saw increasing numbers of gay men become sick as a result of this disease. in response, reuben started a centre for aids at the saimr where he recalls working closely with or dennis sifris, a well-known johannesburg general practitioner. the two men offered educational talks providing slides and visuals. first international aids conference in 1985 the first international conference on hiv took place in atlanta. gay men manned the few stands and distributed pamphlets to the 2 000 delegates, mostly medical scientists. ruben, the only south african to attend, remembers a young gay doctor who was dying of aids being given a standing ovation after his presentation. those of us fortunate enough to have attended the aids 2000 conference in durban last year recall a city filled to capacity with medical professionals of every discipline, impressive opening and closing ceremonies, a poor response from government, and an exceedingly informed and moving presentation by judge cameron. in 1986 the national institute of virology (niv) joined the arena by testing serum that had been taken from the mining community during the period 1970 1974. they found no evidence of hiv in mineworkers originating from a variety of sadc countries including angola, zambia and malawi. in the same year, a major study involving 30 000 mineworkers revealed a 3.76% hiv incidence in malawians from the same group. lone ralngers ruben remembers the next 2 5 years as a period during which few doctors were prepared to get involved in what had become almost a lone crusade. during these di icult 'apartheid days' ruben recalls, with gratitude, how he managed to cultivate and maintain friendships with experts in the uk, france and the usa (the cdc, and the national institutes of health (nih)) in an attempt to find answers to pressing hiv questions. ruben had by now established the first hiv clinics, first at johannesburg hospital, followed by the hillbrow hospital clinic in 1988/89. the nightmare of hiv exposed the death throes of an intolerant and conservative apartheid south africa. the disease was stigmatised by the 'type of people' who transmitted it and vilified by the 'immoral means of transmission' collectively creating a press bonanza. unwittingly ruben sher had become the darling of the media. aids advisory group only a small handful of local experts were able to respond to the growing crisis. in anticipation of the looming pandemic they formed the 'aids advisory group' to educate and inform colleagues and other health professionals, stimulate local research and try to find local solutions to the pressing problems of service delivery and attitudes. professor jack metz was chairman and members included professor barry schoub, professor anton heyne~ professor john moodie, professor tom bothwell, or m hendricks, or leon du toit, or j h lombard, or horst kustner, or coco du plessis, professor denis pudifin, professor n padayachie and or fspracklen. public recognition was shown to ruben in the form of a convocation medal for services to humanity from the university of witwatersrand. on government response 'i think the government is doing very little in terms of contributing. it is not just about wearing a red ribbon. it is about action: mass education; medical professional training; destigmatisation, and service provision. never mind a state of emergency they should declare a state of war against aids! 'they are rejecting pharmaceutical companies' heavily cut-priced antiretrovirals, e.g. the boehringer and glaxosmithkline offers. 'there are 1 600 new infections a day! 'to complicate matters the disease has attracted too many inappropriate opportunists hell-bent on empire building with no desire to put something back into the community: on offering solutions 'i think locally designed educational programmes are very important the models that we used at the beginning were designed for us white, gay men not heterosexual people with very different customs and value systems. local education should include local leaders, sangomas and african practices, e.g. non-penetrative sex. 'medical schools should invest more time on compulsory aids training courses, and communities should be independent and critical of political policies and make their needs heard at senior government level: the southern african journal or hiv medicine -----------may 200 i vacci nes collaboration bilateral south african-italian collaborative projects were established last year to accumulate baseline data on the possible use of a tat-based preventive and therapeutic hiv vaccine in south africa. these projects were funded by the south african aids vaccine initiative [saavi). it is hoped that phase i trials will be done first in rome at the iss towards the end of 2001. if the vaccine is found to be safe, phase 11 trials could begin soon after in south africa and italy. 'separate trial enrolment requirements are required to be able to measure the preventative and therapeutic outcomes of the vaccine, i.e. negative and positive 'it was decided to have two independent south african sites because of the potential biological diversity of the soweto and durban populations and probable virological diversity; says dr vardas. the south african sites will do both preventive and therapeutic phase i1 trials, while the iss will probably only do the preventive phase ii trial. currently in development is a new collaborative application to be submitted to unaids by the insituto superiore di sanita (iss), the hiv/aids vaccine division at the perinatal hiv research unit (phru) in soweto and the medical research council in durban to expand the existing collaboration and begin preparing south african sites for phase 11 clinical testing of a tatbased vaccine. the overall principal investigator is or barbara ensoli from the iss, and the principal investigators from the two south african sites are dr eftyhia vardas, director of the hiv/aids vaccine division at the phru, and dr mark colvin of the mrc. michelle rotchford galloway, mphi[ ('oum) south african hn vaccine action cnmpaign (sa hivacj hiv vaccines can be preventive (preventing infection in the first place) or therapeutic (slowing down disease progression in infected individuals by keeping viral load low and cd4 counts high) or both. most research so far has been aimed at developing a safe, effective, preventive vaccine for use in hiv-negative individuals to prevent infection. however, there is also a focus on developing a safe, cross-subtype reactive, therapeutic hiv vaccine that can be used in people who are already infected. collaboration between italian and south african scientists on a tat-based hivvaccine therapeutic vaccines are particularly important for south africa because there are already large numbers of people living with hiv (the latest antenatal survey results estimate that 4.7 million, or one in nine, south africans are already infected), who are unable to access expensive antiretroviral treatments. the urgent need to find an effective hiv vaccine, and the challenges this presents, have forced scientists to investigate various innovative approaches. most of the attempts made in the last 15 years have focused on the structural proteins of hiv aiming at inducing immunity by blocking virus entry. however, the failure of this approach so far has led some scientists to investigate strategies aimed at controlling viral replication and blocking disease onset recent approaches aimed at eliciting immunity against the hiv regulatory gene products tat rev and nef have shown good results. tat vaccination appears capable of controlling primary infection with highly pathogenic shiv (simian hiv) viruses providing evidence of crossprotection in non-human primates. the tat gene is relatively well conserved in its immunogenic regions among most subtypes of hiv-1 and therefore may lead to the development of a vaccine that could be used globally. therapeutic vaccines article information authors: clifford kendall1 lore claessens2 jienchi dorward1 gloria mfeka1,3 kelly gate1,3 affiliations: 1bethesda hospital, umkhanyakude district, kwazulu-natal, south africa 220,000 plus partnership, university of kwazulu-natal, south africa 3department of family medicine, university of kwazulu-natal, south africa correspondence to: jienchi dorward email: jienchino@gmail.com postal address: private bag x602, ubombo 3970, south africa dates: received: 09 may 2014 accepted: 15 feb. 2015 published: 28 apr. 2015 how to cite this article: kendall c, claessens l, dorward j, mfeka g, gate k. reasons for failure of prevention of mother-to-child hiv transmission in a rural south african district hospital. s afr j hiv med. 2015;16(1), art. #365, 3 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.365 copyright notice: © 2015. the authors. licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. reasons for failure of prevention of mother-to-child hiv transmission in a rural south african district hospital in this scientific letter... open access • abstract • introduction • methods    • ethics approval • results • discussion • conclusion • acknowledgements    • competing interests    • authors’ contributions • references abstract top ↑ further reduction of mother-to-child transmission (mtct) of hiv requires improved understanding of the reasons for mtct. we reviewed maternal and infant case notes for hiv-positive infants diagnosed by polymerase chain reaction at bethesda hospital. nineteen cases were analysed. median gestation at first antenatal consultation (anc) was 22.5 (interquartile range [iqr] 19.25–24). eleven (57.9%) mothers were hiv positive at first anc, whilst eight tested negative and later positive (2 antepartum, 6 postpartum). median maternal cd4 was 408 cells/μl (iqr 318–531). six (31.6%) received no antenatal antiretroviral therapy (art) because they were diagnosed as hiv positive postpartum; 9 (47.3%) received antenatal art and 3 (15.8%) were never initiated on art. at 6 weeks postpartum, 5 infants (26.3%) were not on prophylactic nevirapine (nvp) because their mothers had not yet been diagnosed. maternal seroconversion in pregnancy and breastfeeding, and possibly false-negative hiv tests, were important reasons for prevention of mother-to-child transmission (pmtct) failure. introduction top ↑ in 2010, the south african department of health (doh) prevention of mother-to-child transmission (pmtct) guidelines recommended world health organization option a (prophylactic zidovudine [azt] for women with a cd4+ count > 350 cells/μl and combination antiretroviral therapy [cart] for all pregnant women with cd4 < 350 cells/μl, with subsequent infant nevirapine [nvp] for a minimum of 6 weeks).1 option b (cart for all pregnant and breastfeeding women irrespective of cd4 count and postnatal infant nvp prophylaxis) was introduced in april 2013.2 using these guidelines, mother-to-child transmission (mtct) in kwazulu-natal, south africa, dropped from 20.8% at 6 weeks postpartum in 2005 to 2.1% in 2011,3,4 with a national target of less than 2% by 2016.5 further reduction will require a better understanding of the reasons for pmtct failure in local facilities. seroconversion in pregnancy or breastfeeding, hiv diagnosis in pregnancy compared with diagnosis prior to conception, and health system-related factors have all been found to play a role in pmtct failure.6,7,8 bethesda is a rural district hospital serving approximately 115 000 people in umkhanyakude district, kwazulu-natal province, with an hiv prevalence of 41.1% amongst pregnant women in 2011.9 hiv polymerase chain reaction (pcr) positivity at 6 weeks postpartum in 2013 was 2.3% for bethesda hospital (personal comm., facility information officer, n.d.) and its eight peripheral primary healthcare clinics. our aim was to identify reasons for these pmtct failures. methods top ↑ we retrospectively reviewed maternal and infant case notes for hiv-positive infants identified by hiv pcr between february and september 2013 at bethesda hospital and its clinics. ethics approval ethics approval for the study was granted by the university of kwazulu-natal biomedical research ethics committee and the kwazulu-natal health research committee. results top ↑ a total of 25 cases of mtct were identified in the study period. data were available for analysis in 19 cases (table 1). notes were often incomplete, meaning data were not available for all 19 cases for some variables. median maternal age was 22 years (interquartile range [iqr] 20.5–28). median gestation at first antenatal consultation (anc) was 22.5 weeks (iqr 19.25–24) and 9 (47.3%) women were known to have had their first anc after 20 weeks’ gestation. five (26.3%) women were known to be hiv positive preconception. a further 6 (31.6%) tested hiv positive at first anc. eight (42.1%) tested hiv negative at first anc, but two of these subsequently tested positive antenatally (1 and 3 weeks before delivery respectively). the remaining 6 (31.6%) women tested hiv positive postpartum. median maternal cd4 at baseline was 408 cells/μl (iqr 318–531). of the 13 who were known to be hiv positive before delivery, 1/13 (7.7%) had unknown antenatal antiretroviral therapy (art) status, 3/13 (23.1%) were never initiated on art before delivery, 3/13 (23.1%) were already on cart pre-conception, and 6/13 (46.2%) were initiated on art antenatally (cart = 4, azt monotherapy = 2) at a median of 28 weeks’ gestation (iqr 26–30) and 0 days (iqr 0–16) after being diagnosed as requiring pmtct. one of these patients had a documented history of poor adherence/defaulting. the six patients diagnosed postpartum did not have information on maternal art initiation available. of the three patients on cart pre-conception, 2 had viral loads taken antenatally and both were greater than 400 copies/ml. five women had caesarean sections. figure 1: period of maternal hiv diagnosis and initiation table 1: maternal and infant characteristics. regarding infants, 5 (26.3%) were not on nvp at their 6-week postnatal follow-up visit because their mothers had not yet tested hiv positive. of the remaining 14 subjects, only 8/14 (57.1%) infants were documented to be on nvp prophylaxis, with 6/14 (42.9%) having no record of nvp administered. two (10.5%) infants were documented as receiving mixed feeding at 6 weeks. one (5.3%) infant died before cart initiation, and 13 (68.4%) were known to have been initiated on cart at a median 5 (iqr 3–11) weeks after diagnosis. discussion top ↑ maternal and infant art have consistently been shown to be highly efficacious for pmtct; consequently, omitting or delaying art exposes infants to unnecessary hiv transmission risks.10 in the present study, we repeat findings elsewhere6,8 that initially testing hiv negative and subsequently positive in pregnancy or breastfeeding (leading to delays in art initiation) is a major cause of pmtct failure, occurring in 8 (42.1%) of the pmtct failure cases in our study. we could not determine whether this was because of an initial false-negative test, or maternal seroconversion in the majority of cases. current pmtct guidelines advocate a confirmatory second hiv rapid test if the initial test is positive. however, there is no confirmatory test if the first test is negative.2 a study of 967 adults presenting for hiv testing in a clinic in durban found that 2.1% of patients with a negative rapid hiv test had either acute hiv infection (which was missed by the rapid test because of falling within the ‘window period’) or chronic hiv infection (i.e. a false-negative rapid test).11 in the context of further reducing mtct to below 2%, potentially misdiagnosing 2% of mothers living with hiv is significant. strategies to increase detection of all positive cases could include a second confirmatory rapid test as routine in all pregnant women (with an hiv elisa confirmatory test for all discordant results). furthermore, regular 3-monthly maternal hiv testing throughout the duration of pregnancy and breastfeeding, in accordance with doh guidelines,2 or even reducing the repeat testing interval to 1or 2–monthly, will be crucial to ensure that maternal seroconversion is detected as soon as possible. not documenting infant nvp prophylaxis when it is known to be indicated occurred in 6 (42.9%) cases in our study. however, this is probably higher than the true value as, from clinical experience, we note that infant nvp is often administered but poorly documented. late booking after 20 weeks’ gestation (also leading to late initiation of maternal art) occurred in 9 (47%) of cases, although 75% of cases had booked before 24 weeks which should allow time for viral suppression by the time of delivery, assuming art is initiated promptly.10,12 omitting maternal art when it is known to be indicated occurred in 3 (15.8%) cases (we were unable to ascertain why), and virological failure despite maternal cart occurred in 2 (10.5%) cases. both these cases had repeated viral loads > 400 copies/ml more than 1 month apart but were not switched to second-line cart. the third case had no viral load sampling during pregnancy. weaknesses of our study include lack of a control group, small sample size and incomplete or unavailable case notes. data were too incomplete for analysis of several important variables (e.g. duration and means of rupture of membranes, elective versus emergency caesarean section, instrumental delivery, postpartum maternal art adherence). only descriptive analysis was possible and our results must be interpreted with caution. conclusion top ↑ pmtct remains a focus programme in the south african healthcare sector. better understanding of the reasons for mtct can assist further reduction of mtct rates to the target of less than 2%. several causes for the failure of pmtct in our sub-district have been identified. these correspond with reasons for mtct from previous studies and available literature. late first anc, delayed or omission of maternal cart initiation, and poor management of women on cart contributed, amongst other factors, to our mtct cases. maternal seroconversion or an initial false-negative hiv test occurs frequently in pmtct failures in our clinics, with subsequent late maternal art initiation. this fact highlights the importance of preventing and promptly detecting maternal hiv infection in pregnancy and breastfeeding if mtct is to be further reduced. further research is needed to characterise the frequency of false-negative hiv testing in operational pmtct programmes, and to identify cost-effective testing strategies to ensure early detection of acute maternal hiv infection in pregnancy and breastfeeding. acknowledgements top ↑ the 20,000 plus partnership team is gratefully acknowledged for their technical support. we also thank staff at bethesda hospital and its peripheral clinics who assisted with data collection. competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions c.k. (bethesda hospital), l.c. (university of kwazulu-natal) and k.g. (bethesda hospital) designed the study. c.k., l.c., j.d. (bethesda hospital), g.m. (bethesda hospital) and k.g. collected data. c.k., l.c. and j.d. analysed the data. all authors were involved in drafting and critically reviewing the manuscript. references top ↑ department of health. the south african antiretroviral treatment guidelines 2010. pretoria: department of health; 2010. department of health. revised anti-retroviral treatment guideline: update for frontline clinical health professionals. pretoria: department of health; 2013. rollins n, mzolo s, little k, et al. hiv prevalence rates amongst 6 week old infants in south africa: the case for universal screening at immunization clinics. toronto: xvi international aids conference; 13–18 august 2006. abstract no. thac0104. goga a, dinh t, jackson d, for the sapmtcte study group. population-level impact of the national pmtct programme: 2010 and 2011. johannesburg: pmtct symposium; 23–24 october 2012. department of health. national strategic plan on hiv, stis and tb: 2012–2016. pretoria: department of health; 2011. johnson lf, stinson k, newell ml, et al. the contribution of maternal hiv seroconversion during late pregnancy and breastfeeding to mother-to-child transmission of hiv. j acquir immune defic sundr. 2011;31:474–480. http://dx.doi.org/10.1097/qai.0b013e3182432f27 onono m, bukusi e, owuor k, et al. pmtct failure: the role of maternal and facility-related factors. cape town: 17th international conference on aids and stis in africa; 2013. abstract ads067. technau k, kalk e, coovadia a, et al. timing of maternal hiv testing and uptake of prevention of mother-to-child transmission interventions among women and their infected infants in johannesburg, south africa. j acquir immune defic syndr. 2014;65:e170–e178. http://dx.doi.org/10.1097/qai.0000000000000068 department of health. the 2011 national antenatal sentinel hiv & syphilis prevalence survey in south africa. pretoria: department of health; 2012. hoffman rm, black v, technau k, et al. effects of highly active antiretroviral therapy duration and regimen on risk for mother-to-child transmission of hiv in johannesburg, south africa. j acquir immune defic syndr. 2010;54:35–41. http://dx.doi.org/10.1097/qai.0b013e3181cf9979 bassett iv, chetty s, giddy j, et al. screening for acute hiv infection in south africa: finding acute and chronic disease. hiv med. 2011;12:46–53. http://dx.doi.org/10.1111/j.1468-1293.2010.00850.x patel d, cortina-borja m, thorne c, et al. time to undetectable viral load after highly active antiretroviral therapy initiation among hiv-infected pregnant women. clin infect dis. 2007;44:1647–1656. http://dx.doi.org/10.1086/518284 article information authors: marlene knight1,2 robyn l. van zyl2 ian sanne3 jean bassett4 annelies van rie5 affiliations: 1clinical hiv research unit, university of the witwatersrand, south africa 2department of pharmacy and pharmacology, university of the witwatersrand, south africa 3right to care, johannesburg, south africa 4witkoppen health and welfare centre, johannesburg, south africa 5department of epidemiology, university of north carolina, united states correspondence to: annelies van rie email: vanrie@email.unc.edu postal address: mcgavran greenberg hall, suite 2104f, chapel hill, nc27514, united states dates: received: 09 jan. 2015 accepted: 06 aug. 2015 published: 08 oct. 2015 how to cite this article: knight m, van zyl rl, sanne i, bassett j, van rie a. impact of combination antiretroviral therapy initiation on adherence to antituberculosis treatment. s afr j hiv med. 2015;16(1), art. #346, 6 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.346 copyright notice: © 2015. the authors. licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. impact of combination antiretroviral therapy initiation on adherence to antituberculosis treatment in this original research... open access • abstract • introduction • methods    • study setting and population    • study procedures    • adherence measures    • statistical analysis • results    • study cohort characteristics    • adherence to tb treatment before and after antiretroviral therapy initiation    • reasons for suboptimal adherence    • factors associated with optimal adherence to tb treatment after antiretroviral therapy initiation • discussion • conclusion • acknowledgements    • competing interests    • authors’ contributions • references abstract top ↑ background: healthcare workers are often reluctant to start combination antiretroviral therapy (art) in patients receiving tuberculosis (tb) treatment because of the fear of high pill burden, immune reconstitution inflammatory syndrome, and side-effects. object: to quantify changes in adherence to tuberculosis treatment following art initiation. design: a prospective observational cohort study of art-naïve individuals with baseline cd4 count between 50 cells/mm3 and 350 cells/mm3 at start of tb treatment at a primary care clinic in johannesburg, south africa. adherence to tb treatment was measured by pill count, self-report, and electronic medication event monitoring system (emems) before and after initiation of art. results: art tended to negatively affect adherence to tb treatment, with an 8% – 10% decrease in the proportion of patients adherent according to pill count and an 18% – 22% decrease in the proportion of patients adherent according to emems in the first month following art initiation, independent of the cut-off used to define adherence (90%, 95% or 100%). reasons for non-adherence were multifactorial, and employment was the only predictor for optimal adherence (adjusted odds ratio 4.11, 95% confidence interval 1.06–16.0). conclusion: adherence support in the period immediately following art initiation could optimise treatment outcomes for people living with tb and hiv. introduction top ↑ adhering to a lengthy course of medication is difficult and poses a challenge to achieving health in people with chronic diseases. poor adherence to treatment for infectious disease poses a risk to both the individual and community as it can lead to prolonged infectiousness, development of drug resistance, and poor treatment outcomes. tuberculosis (tb) and the human immunodeficiency virus (hiv) present particular challenges as both are chronic diseases that mainly affect disadvantaged populations and involve complex treatment regimens with potentially severe side-effects.1 treatment adherence for tb and hiv is also affected by beliefs about the origins and transmission of tb and hiv, which can result in stigmatisation of those affected.2 the 2012 world health organization (who) and 2015 south african antiretroviral therapy (art) guidelines recommend initiating art in people with tb as soon as possible, within the first 2 weeks of initiating tb treatment for those with profound immunosuppression (cd4 counts < 50 cells/mm3) and within the first 8 weeks of treatment in all tb patients.3 whilst initiating art greatly improves the survival and quality of life of tb patients living with hiv,4 it also poses challenges to patients and healthcare workers.5 early initiation of art can result in clinical deterioration related to immune reconstitution inflammatory syndrome (iris), toxic effects of drugs, or drug interactions, and increased pill burden. the high pill burden of four anti-tb drugs, antiretroviral drugs, and antimicrobial prophylaxis (cotrimoxazole and fluconazole) against opportunistic infections, as well as possible drug interactions and toxic effects, may jeopardise the patient's adherence to treatment.6 as a result, healthcare workers are often reluctant to start art in patients receiving tb treatment. in 2012, only 57% of tb patients with hiv were started on art,7 and in the latter group, initiation of art was often delayed.8 in the present study, we aimed to quantify changes in adherence to tb treatment associated with initiation of art by prospectively measuring adherence to tb drugs immediately before and after initiation of art. methods top ↑ study setting and population the study took place at witkoppen health and welfare centre, a primary care clinic in johannesburg, south africa. adults (> 18 years old) diagnosed with pulmonary tb who were art-naïve at the time of initiation of tb treatment and had a cd4 count between 50 cells/mm3 and 350 cells/mm3 were eligible for enrolment. those with rifampicin-resistant tb (defined by xpert mtb/rif or culture-based drug susceptibility testing) were excluded as they are referred for care. those with cd4 counts < 50 cells/mm3 were excluded because art should be initiated as an emergency, limiting the possibility of reliably establishing the level of adherence to tb treatment before art initiation. those with cd4 counts > 350 cells/mm3 were excluded as these individuals were not eligible for art, according to the 2010 south african guidelines, which were current at the time of the study. all care provision for tb and hiv, including the decision on timing of art initiation, was performed by the routine clinic staff, without any input from study staff. study procedures eligible patients who signed informed consent completed a questionnaire collecting information on socio-demographic information, occurrence of side-effects, and adherence support. medical files were reviewed to collect details of weight, height, results of tb diagnostics (xpert mtb/rif, smear microscopy and culture), tb treatment outcome, art regimen and start date, and cd4 count and viral load (vl) at baseline and during the first 6–12 months of art. ethical approval was obtained from the institutional review board of the university of north carolina (10–2317) and the university of the witwatersrand's human research ethics committee (m10925). adherence measures participants were prospectively monitored for adherence, using pill count (primary measure of adherence), self-report, and an electronic medication event monitoring system (emems). participants received their tb medication in a securitainer fitted with an emems lid (emum, geomed, stellenbosch, south africa). participants were seen by study staff at each clinic visit; the number of visits varied and was determined by the routine clinic care provider. at each visit, the date of visit, number of pills distributed for tb treatment, and prescribed dosage were recorded. at each return visit, the number of pills remaining in the container was recorded, the emems lid was connected to a computer to download data pertaining to when the securitainer was opened, and the patient was asked, ‘in the last week, have you missed any of your doses?’ participants with suboptimal adherence (according to self-report, pill count or emems) were asked the reasons for non-adherence. to reduce the effect of factors other than art initiation on adherence to tb treatment, the primary outcome measure was adherence during the 28 days before and 28 days after art initiation. the number of days included varied by participant because art could be initiated sooner than 28 days after starting tb treatment, and the number of days between visits was not always exactly 28 days. pill count was used to calculate several adherence measures: percentage of the prescribed doses taken (100 × [number of pills dispensed minus the number of pills returned]/[number of days between clinic visits] × [daily dose]) and three binary indicators: whether adherence equalled 100%, ≥ 95% and ≥ 90%. emems data were used to calculate additional measures of adherence: percentage of the prescribed doses taken (100 × number of days with bottle openings/number of days between clinic visits) and three binary indicators: whether adherence was 100%, ≥ 95% and ≥ 90%. the number of daily bottle openings were truncated to one to avoid overestimating adherence. data from follow-up visit questionnaires were used to calculate the self-reported adherence (100 × [1 minus the number of missed doses]/number of days between clinic visits) and three binary indicators: whether adherence was 100%, ≥ 95% and ≥ 90%. statistical analysis participant characteristics are presented as absolute and relative frequencies for categorical variables and as medians and interquartile ranges (iqr) for continuous variables. the effect of art initiation on adherence to tb treatment was evaluated in two different ways. firstly, the median change in percentage of prescribed doses of tb drugs taken before and after art initiation was compared for each of the three continuous adherence measures (pill count, emems and self-report) using the wilcoxon matched-pair signed ranks test. secondly, using the exact mcnemar test for paired samples, the proportion of participants adherent to tb treatment before and after art initiation was compared for all three binary adherence measures for each of the three methods (pill count, emems and self-report). to determine factors predictive of optimal adherence (100% adherence) in the first month after art initiation, we first performed bivariate analysis to estimate crude odds ratios (or) and 95% confidence intervals (ci). we subsequently ran a saturated logistic model containing all selected covariates to estimate adjusted ors (aor), and used stepwise backwards elimination to generate a final (reduced) predictive model. we conducted a sensitivity analysis to explore the effect of broadening the definition of optimal adherence to ≥ 95% and ≥ 90% adherence post art. crude ors and aors are presented with standard wald 95% ci. all analyses were conducted using stata 12.1 (texas, usa). results top ↑ study cohort characteristics between september 2011 and october 2012, 83 art-naïve individuals initiating first-line drugs for pulmonary tb gave informed consent for study participation (figure 1). of these, 14 were excluded from the analysis for not meeting all inclusion criteria: cd4 count < 50 cells/mm3 (n = 9), cd4 count > 350 cells/mm3 (n = 3), erroneous tb diagnosis (n = 1), or mdr-tb diagnosis (n = 1). prior to art initiation, another 18 were excluded owing to loss to follow-up (n = 6), transfer to another facility (n = 7), hospitalisation (n = 1), refusal to start art (n = 1), missing pill count (n = 2), and withdrawal of consent (n = 1). one additional participant was excluded because of missing pill count post art initiation. figure 1: study flow chart. among the 50 patients included in the analysis, median age was 32.5 years (iqr 30–38), 56% were female, 58% were unemployed, and almost half (48%) were not of south african nationality. the diagnosis of tb was bacteriologically confirmed in 80%. median cd4 count was 124 (iqr 94–193). the median time to art initiation was 27 days (iqr 13–48), and almost all (92%) participants initiated an art regimen containing efavirenz, lamivudine and tenofovir. tb treatment outcome was successful in 82%. only 56% of participants achieved viral load suppression, defined as a viral load < 400 copies/ml in the 6–12 months of art (table 1). table 1: characteristics of 50 individuals included in the analysis of the impact of initiation of antiretroviral treatment on adherence to tuberculosis treatment. adherence to tb treatment before and after antiretroviral therapy initiation when measured by pill count or self-report, the median percentage of prescribed tb drug doses taken was 100% before and after art initiation (table 2). when measured by emems, median percentage of prescribed tb drug doses taken was 93% before, and 82.5% (iqr 55–96) after, art initiation. there was no change in the percentage of tb medication taken before and after art initiation, with a median percentage change of 0 (iqr −4, +1) for pill count, 0 (iqr 0–0) for self-report, and minus 1.5 (iqr −25, +3) for emems (all p values > 0.30). table 2a: adherence to tuberculosis treatment before and after initiation of antiretroviral treatment. table 2b: hundred percent adherence to tuberculosis treatment before and after initiation of antiretroviral treatment. table 2c: ninety-five percent adherence to tuberculosis treatment before and after initiation of antiretroviral treatment. table 2d: ninety percent adherence to tuberculosis treatment before and after initiation of antiretroviral treatment. when measured by pill count, the proportion of participants who were 100% adherent to tb treatment before and after art initiation was 64% (41.7–70.3) versus 56.0% (50.2–77.8); increased to 68.0 (54.6–81.4) versus 78% (66.1–89.9) when adherence was defined as 95% of prescribed doses taken, and 78.0 (66.1–89.9) versus 88.0% (78.7–97.3) when adherence was defined as 90% of doses taken. self-reported adherence was high, with 100% of participants being adherent before and after art initiation when adherence was defined as taking ≥ 90 or ≥ 95% of prescribed doses, and 96.0% (90.4–100) and 94.0% (87.2–100) being adherent before and after art initiation, respectively, when adherence was defined as 100% of prescribes doses. owing to technical errors, power failures, equipment failures, and misunderstandings by pharmacists and patients, adherence data by emems were only available for 21 participants pre art, 20 participants post art, and 14 both before and after art initiation. the proportion of participants adherent to tb treatment after art initiation was consistently lower than adherence before art initiation: 10.0% (0.4–24.4) versus 38.1 (15.4–60.7); 30.0 (8.0–52.0) versus 47.6 (24.3–70.9) and 40.0 (16.5–63.5) versus 61.9 (39.3–84.6) when adherence was defined as 100%, 95% or 90% of prescribed doses taken, respectively. reasons for suboptimal adherence leaving house without tablets (n = 8) and running out of tablets between visits (n = 8) were the most frequently stated reasons for missing doses (n = 8), followed by forgetfulness (n = 3), dosing errors (n = 3), taking medication as prescribed whilst not using the emems lid (n = 3), distractions (n = 2), medication side-effects (n = 2) and lack of transport money (n = 1). factors associated with optimal adherence to tb treatment after antiretroviral therapy initiation employment status was the only factor associated with optimal (100%) adherence following art initiation. compared with those not employed, participants who were employed had four times greater odds (aor 4.11, 95% ci 1.06–16.0) of being fully adherent to tb treatment. age and gender tended to be associated with optimal adherence, with a 13% (95% ci −1, +29%) increased odds for every year increase in age and men being less likely to optimally adhere to tb treatment (aor 0.32, 95% ci 0.08–1.29), but these associations did not reach statistical significance. in sensitivity analyses, age and employment status were factors associated with 95% and 90% adherence, respectively (table 3). table 3: factors associated with optimal adherence (100% of prescribed doses) following initiation of antiretroviral treatment in patients receiving treatment for active tuberculosis (pe 0.05; pr 0.15). discussion top ↑ in the present study of art-naïve hiv-infected individuals receiving treatment for active tb, we observed a trend of decrease in adherence to tb treatment in the first month following art initiation, with an 8% – 10% decrease in the proportion of patients adherent according to pill count and an 18% – 22% decrease in the proportion of patients adherent according to emems, independent of the cut-off used to define adherence (90%, 95% or 100% of prescribed doses taken). the finding of reduced adherence soon after the introduction of art is clinically relevant, as suboptimal adherence has been associated with poor treatment outcomes and development of resistance, especially in the early phases of treatment when the bacillary load is highest. whilst many have speculated that the increased pill count in patients with tb initiating art could reduce adherence,5,6,9 we could not compare our findings with others as we could not find published reports assessing this association. similar to findings of other studies,2 reasons for non-adherence reported by patients were multifactorial and few independent predictors for optimal adherence could be identified. except for employment, with those being employed having four times higher odds of remaining fully adherent when initiating art, we could not identify patient factors associated with adherence. in the present study, we used three different methods to measure adherence: self-report of missed doses, pill count, and emems. we observed that adherence by self-report was always highest, pill count gave intermediate estimates, and emems consistently resulted in the lowest estimates. poor correlations between different adherence measures have been reported. for example, in a study of adherence to art, holzemer found that there was minimal correlation amongst adherence as measured by pharmacy refill, self-report, mems and pill count.10 overestimation of adherence by self-report is a consistent finding, probably related to social desirability or recall error.11 emems, on the other hand, can underestimate adherence when several doses of medications are removed from bottles at a single time, as was observed in the present and other studies.12,13 similar to what was observed in our cohort, self-reported rates of adherence are higher than the rates derived from electronic monitoring; however, the 40% – 50% difference between the two measures is greater than the 10% – 30% reported in other settings.14,15 this result may be owing to limited validity of the emems data, given the numerous challenges when implementing emems into routine care in a resource-limited setting, including batteries of emems caps running flat, power cuts during the transfer of emems data to computer, errors made by pharmacists when filling the containers, and breakage of the container lids. in addition, some patients forgot or lost their securitainer. the present study has several limitations. firstly, the small sample resulted in imprecise estimates and a lack of power to detect statistically significant differences, even when the differences observed were probably of clinical relevance. secondly, the time between starting tb treatment and art initiation in the study participants was short, (median of 27 days), and did not vary greatly between participants (iqr 13–48). as such, we could not assess the impact of timing of art initiation on adherence. it is possible that delay of art initiation until the end of the intensive phase, when patients feel better and side-effects of tb treatment have subsided, could lower the negative impact of art initiation on adherence to tb treatment. this possibility would need to be weighed against the risk of poor treatment outcomes owing to the delay of art initiation, and may therefore only be possible for patients with high cd4 counts at the time of tb diagnosis. thirdly, we limited our assessment to the 28 days immediately before and after art initiation to assess the impact of art initiation on adherence to tb drugs. we could therefore not assess whether the observed changes in adherence were temporary or persisted throughout the tb treatment period. finally, the clinic did not perform clinic-based directly observed treatment (dot). findings of the present study may therefore not be generalisable to settings where dot is systematically implemented for all patients receiving tb treatment. conclusion top ↑ in the present small prospective cohort study, we observed a trend to decreased adherence to tb treatment following the initiation of art. our findings suggest that adherence interventions in the period following art initiation may be needed to optimise treatment outcomes for people living with tb and hiv. acknowledgements top ↑ this work was supported by pepfar and the national institutes of health grant um1 ai069463, the united states agency for international development grants to right to care: 674-a-00-08-00007 and 674-a-12-00020 and by the university of the witwatersrand, faculty of health sciences research committee. we are also thankful to jacques de vos (geomed) for providing the emems and securitainers®. we are grateful to the study participants, the staff at witkoppen health and welfare center (bridgette moatlhodi, katerina roussos), rightmed pharmacy (coreen barker) and the medical research council (prof piet becker). competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions m.k. (university of the witwatersrand) collected the data and wrote the first draft. r.l.v.z. (university of the witwatersrand) was involved in project design, i.s. (right to care) made conceptual contributions, j.b. (witkoppen health and welfare centre) was involved in data collection, and a.v.r. (university of north carolina) was involved in project design and statistical analysis. all authors reviewed the manuscript and gave scientific input. references top ↑ world health organization. adherence to long-term therapies – evidence for action. geneva: world health organization; 2003. munro sa, lewin sa, smith hj, engel me, fretheim a, volmink j. patient adherence to tuberculosis treatment: a systematic review of qualitative research. plos med. 24 july 2007;4(7):e238. pmid: 17676945, http://dx.doi.org/10.1371/journal.pmed.0040238 world health organization. who policy in collaboratove tb/hiv activities: guidelines for national programmes and other stakeholders. geneva: world health organization; 2012. havlir dv, kendall ma, ive p, et al. timing of antiretroviral therapy for hiv-1 infection and tuberculosis. n engl j med. 2011;365:1482–1491. pmid: 22010914, http://dx.doi.org/10.1056/nejmoa1013607 naidoo k, baxter c, abdool karim ss. when to start antiretroviral therapy during tuberculosis treatment? curr opin infect dis. 2013;26:35–42. pmid: 23188213, http://dx.doi.org/10.1097/qco.0b013e32835ba8f9 torok me, farrar jj. when to start antiretroviral therapy in hiv-associated tuberculosis. n engl j med. 2011;365:1538–1540. pmid: 22010921, http://dx.doi.org/10.1056/nejme1109546 world health organization. global tuberculosis report. geneva: world health organization; 2013. varma jk, nateniyom s, akksilp s, et al. hiv care and treatment factors associated with improved survival during tb treatment in thailand: an observational study. bmc infect dis. 2009;9:42. pmid: 19364398, http://dx.doi.org/10.1186/1471-2334-9-42 swaminathan s, padmapriyadarsini c, narendran g. hiv-associated tuberculosis: clinical update. clin infect dis. 2010;50:1377–1386. pmid: 20388036, http://dx.doi.org/10.1086/652147 holzemer wl, bakken s, portillo cj, et al. testing a nurse-tailored hiv medication adherence intervention. nurs res. 2006;55:189–197. pmid: 16708043, http://dx.doi.org/10.1097/00006199-200605000-00005 wagner g, miller lg. is the influence of social desirability on patients’ self-reported adherence overrated? j acquir immune defic syndr. 2004;35:203–204. pmid: 14722455, http://dx.doi.org/10.1097/00126334-200402010-00016 ailinger rl, black pl, lima-garcia n. use of electronic monitoring in clinical nursing research. clin nurs res. 2008;17:89–97. pmid: 18387881, http://dx.doi.org/10.1177/1054773808316941 kalichman sc, amaral cm, cherry c, et al. monitoring medication adherence by unannounced pill counts conducted by telephone: reliability and criterion-related validity. hiv clin trials. 2008;9:298–308. pmid: 18977718, http://dx.doi.org/10.1310/hct0905-298 thirumurthy h, siripong n, vreeman rc, et al. differences between self-reported and electronically monitored adherence among patients receiving antiretroviral therapy in a resource-limited setting. aids. 2012;26:2399–2403. pmid: 22948266, http://dx.doi.org/10.1097/qad.0b013e328359aa68 liu h, golin ce, miller lg, et al. a comparison study of multiple measures of adherence to hiv protease inhibitors. ann intern med. 2001;134:968–977. pmid: 11352698, http://dx.doi.org/10.7326/0003-4819-134-10-200105150-00011 ---------may 200 i 11 des martin editor, southern african journal of hiv medicine president, southern african hiv clinicians society the global aids epidemic has witnessed its 'characters', and this issue honours one of the first physicians in south africa to recognise, confront and do something about what was then a novel syndrome. professor ruben sher is honoured by our society and it is therefore appropriate that he be the first person to appear in the newly established 'profile' section of the journal. drugs and the importance of adherence to these regimens in order to prevent drug resistance, and they must be familiar with issues relating to the sequencing of therapies. it is not just a matter of 'provide drugs, and everything else will fall into place'. education is of paramount importance, and a prime objective of the society is to provide the profession with the necessary education in this regard. providing therapeutic guidelines is seen as important; these have appeared in previous issues of the journal, and in this issue guidelines addressing mother-ta-child transmission appear. continuing medical education also takes place at monthly meetings in the regions where the society is represented. it is hoped that in the near future these regional initiatives will be strengthened. a further important initiative is announced in this issue an educational programme commencing in partnership with the foundation for professional development of the south african medical association and the international aids society (iasj, which will provide courses in hiv medicine for medical practitioners. these courses are based on the share programme of the ias. this programme is specifically formulated for developing countries and will be customised by the society for southern african practitioners. from the editor recent weeks have borne witness to controversies relating to the pricing of antiretroviral drugs, and it is heartening that at long last the voice of reason has prevailed and access to optimal therapies for our patients is on the horizon. the availability of cheap drugs, although crucial to treatment access initiatives, is by no means the only prerequisite that needs to be in place before patients get treatment. a confident and knowledgeable cadre of treaters together with an infrastructure of other health care professionals needs to be developed. these professionals must be able to counsel their patients regarding their therapies, the side-effects of a plethora of the southern african journal of hiv medicine abstract introduction methods results discussion conclusion acknowledgements references about the author(s) natasha khamisa department of public health, monash south africa, south africa maboe mokgobi department of psychology, monash south africa, south africa citation khamisa n, mokgobi m. risky sexual behaviour and human immunodeficiency virus (hiv) and acquired immune deficiency syndrome (aids) among healthcare workers. s afr j hiv med. 2018;19(1), a744. http://doi.org/10.4102/sajhivmed.v19i1.744 original research risky sexual behaviour and human immunodeficiency virus (hiv) and acquired immune deficiency syndrome (aids) among healthcare workers natasha khamisa, maboe mokgobi received: 03 mar. 2017; accepted: 02 oct. 2017; published: 26 jan. 2018 copyright: © 2018. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: south africa is known to have one of the highest prevalence rates of human immunodeficiency virus (hiv) and acquired immune deficiency syndrome (aids) globally, with one in seven healthcare workers being hiv-positive. an hiv-positive healthcare workforce is less equipped to respond to the increasing spread of the epidemic. objectives: assessment of the factors contributing to high hiv prevalence rates among healthcare workers is important in planning the development of human resources. this review sought to identify and understand predominant risky sexual behaviours among healthcare workers in hiv and aids-affected countries. methods: this study reviewed articles focusing on sexual behaviour among healthcare workers. major health science databases (e.g. proquest, cochrane, pubmed and cinahl) were searched for combinations of keywords including ‘healthcare workers’, ‘risky sexual behaviour’ and ‘hiv and aids’. articles from a range of countries met inclusion and exclusion criteria. results: findings of the study revealed three main contributing factors: unprotected sex, multiple sex partners and sexual violence. sexual violence emerged as the dominant risk factor in the majority of the studies. most research was conducted in developed countries where the hiv infection rate is much lower than it is in developing countries. conclusion: more research needs to be conducted in developing countries and appropriate strategies should be implemented to reduce sexual violence among healthcare workers. appropriate procedures on reporting sexual violence coupled with education on hiv and aids as well as influencing attitudes and belief systems could assist in reducing the spread of hiv and aids within the healthcare workforce while minimising the effect on patient care. introduction human immunodeficiency virus (hiv) and acquired immune deficiency syndrome (aids) are considered to be a global crisis, with healthcare systems being at the core of response efforts. however, an hiv-positive healthcare workforce is less equipped to respond to the increasing spread of the epidemic in affected countries.1 south africa is known to have one of the highest prevalence rates of hiv and aids globally, with 12.6% of the population being hiv-positive.2 with hiv prevalence increasing from 4.02 million in 2002 to 6.19 million in 2015, there has been an impact on supply and demand of healthcare workers.2 this is likely to be exacerbated by the hiv prevalence among healthcare workers in south africa, whereby limited research shows that among a sample of healthcare workers in south africa, 11% are reported to be hiv-positive. additional research reports that one in seven nurses is hiv-positive.3 in zambia, research among a sample of healthcare workers confirms that up to 30% are lost annually to hiv and aids.4 it is also reported that high hiv prevalence among healthcare workers affects attrition, absenteeism and productivity, increasing costs and strain within the health sector.5 assessment of risky sexual behaviours among healthcare workers is important in maintaining necessary human resources in hiv and aids-affected countries. studies have reported associations between risky sexual behaviour and hiv infection. one such study reported significant associations between inconsistent condom use and hiv infection (adjusted odds ratio [aor] 1.41; 95% confidence interval [ci] 1.04–1.90). there was an association between increase in the number of sexual partners and hiv infection. men reporting more than four partners were 4–12 times more likely to become infected with hiv and women reporting more than four partners were three to five times more likely to become infected with hiv.6 in another study exploring risk perception and hiv, participants were 17 times more likely to test hiv-positive when their perception of risky sexual behaviour was associated with multiple types of sex partners, sex preceded by alcohol use and unprotected sex (odds ratio [or] 17.14; 95% ci 3.28–89.72, p < 0.001).7 a study in eight countries with generalised hiv epidemics showed that a change in risky sexual behaviours can reduce hiv prevalence by up to 20%.8 limited research implies that risky sexual behaviour is attributed to higher hiv rates among healthcare workers. one such study showed that 21% of hiv-positive healthcare workers reported having sex with non-regular partners over the period of one year. of these, 10% engaged in sex with multiple partners.9 although risky sexual behaviour is recognised as a contributing factor to hiv and aids among healthcare workers, occupational exposure has been more widely studied with findings suggesting that only a small percentage (10%) of hiv among healthcare workers is attributable to exposure at work.10 this leaves a gap in understanding about the actual contribution of risky sexual behaviours to hiv and aids among healthcare workers. sociocultural norms play a role in increasing risky sexual behaviour, but this is rarely considered in the formation of behavioural intentions. sociocultural contexts disrupted by stressful situations are believed to incite maladaptive behaviour. such disruption compromises cultural identities, which then affects decision-making processes, thereby increasing the likelihood of risky sexual behaviour.11 sociocultural norms influence normative and attitudinal aspects of behavioural intentions by shaping dispositions in response to situational and contextual stressors. gender norms, for instance, may influence gender power relations in smaller subcultures of a society, where members share similar cultural beliefs and values. this may trigger risky sexual behaviours (including sexual violence as means of exerting power and discipline to subordinates).12 such effect on behaviour at a sociocultural level rather than on an individual level may explain why healthcare workers engage in risky sexual behaviours despite possessing knowledge about it. the aim of this review is to identify and understand predominant risky sexual behaviours among healthcare workers in hiv and aids-affected countries. it is expected that risky sexual behaviour among healthcare workers can be better understood through sociocultural considerations. this is important because healthcare workers expressing risky behaviours have severe consequences for the health system, with an infected workforce being unable to respond to the increasing prevalence of hiv and aids among the general population.13 the health system relies on healthcare workers to inform patients of their hiv status, provide prevention education as well as treat and care for infected patients. this creates the perception of healthcare workers as privileged service delivery agents resulting in less attention being paid to hiv and aids among this population.1 given the dearth of research on hiv and aids among healthcare workers, they are not beneficiaries of existing interventions. identifying the risky sexual behaviours of healthcare workers will inform appropriate interventions aimed at them, thereby preventing the loss of healthcare workers to hiv and aids, while maintaining service delivery to patients. methods the authors searched four major health science databases (i.e. proquest, cochrane, pubmed and cinahl) for multiple combinations of keywords including ‘healthcare workers’, ‘risky sexual behaviour’ and ‘hiv and aids’. a further manual search of the reference lists for articles obtained from the database search was also conducted by an independent reviewer. articles were excluded or retained based on specific inclusion and exclusion criteria. emerging themes were then consolidated by the authors and an independent reviewer. inclusion criteria included full-text peer-reviewed journal articles involving quantitative studies published within the last 15 years in english. only articles focusing on risky sexual behaviour and hiv and aids among samples of healthcare workers were retained. articles published in languages other than english in conference proceedings and newspapers more than 10 years ago were excluded. articles focusing on risky sexual behaviour of sex workers, adolescents and patients were also excluded. in addition, articles including insufficient details about the sample and context as well as articles focused on other health outcomes were excluded. this is illustrated in figure 1. figure 1: a flow chart describing the search strategy. results after applying inclusion and exclusion criteria, 16 articles were retained and analysed according to country, sample and findings (table 1). table 1: country, sample and results of identified studies. of the 16 studies included, 11 studies (69%) focusing on risky sexual behaviour among healthcare workers have been conducted in developed countries and only five studies (31%) in developing countries. of the 16 studies included, 12 studies identified sexual violence as one of the risky sexual behaviours among healthcare workers. of these, eight studies confirmed that doctors are often the perpetrators of sexual violence, with only four studies showing that sexual violence was perpetrated by nurses. eight studies showed that nurses are often victims of sexual violence. four studies confirmed unprotected sex as one of the risky sexual behaviours among healthcare workers. more educated healthcare workers reported less unprotected sex, whereas healthcare workers from rural areas reported more unprotected sex. three studies confirmed multiple sex partners as one of the risky sexual behaviours among healthcare workers. education had no effect on the number of sexual partners with healthcare workers in rural areas having a higher number of sexual partners. additional details on the above-mentioned findings are included in table 1. discussion the aim of the study was to assess factors contributing to high hiv infection rates in the healthcare workforce by reviewing studies conducted in various countries. the reviewed studies reported risk factors contributing to an increase in hiv infection rate among healthcare workers, which could be summarised under three main themes: unprotected sex, multiple sex partners and sexual violence. it is worth noting that only four studies reported unprotected sex and multiple sex partners as the main risk factors. sexual violence emerged as the dominant risk factor in the majority of the studies and includes doctor-on-doctor sexual violence, doctor-on-nurse sexual violence or nurse-on-nurse sexual violence. the majority of sexual violence seems to be perpetrated by doctors.14,16,18,20 doctors perpetrating sexual violence against other healthcare workers could be explained by power dynamics. doctors are, by virtue of the organogram of the healthcare system, ‘superior’ to other healthcare workers who take orders or instructions from them. these power imbalances render other healthcare workers vulnerable to doctors, making them less likely to report sexual violence for fear of reprisals or victimisation by the doctors.14 a similar explanation of power dynamics could be proffered for doctor-on-doctor violence, where a senior doctor perpetrates sexual violence on a junior doctor. such behaviour has been conceptualised as a natural socialisation process commonly considered a salutary rite of passage as reported in a number of studies.28 sexual violence is also viewed as an issue of gender norms. the majority of healthcare workers on the lower end of the hierarchy are women, which makes them more vulnerable to sexual violence.29 studies have reported that women are seven times more likely to experience sexual violence compared to men.30 male sex role socialisation influencing sexual beliefs is expressed in the form of sexual violence as a means of attaining masculinity and dominance.31 other factors are associated with working environments and working conditions.32 any form of sexual violence has serious negative consequences, which include, but are not limited to, loss of confidence in clinical abilities and mental health issues, known to have adverse consequences on patient care.16 this in the context of high hiv prevalence in developing countries could diminish the healthcare workforce and place further strain on the supply and demand of healthcare workers.3 it is important to note that sexual violence is an unwanted and unreciprocated sexual behaviour, to which victims do not consent. research suggests that experiencing sexual violence has been associated with an increase in risky sexual behaviours, whereby victims are more likely to have unprotected sex with multiple sex partners. this is attributed to a loss of sexual decision-making power and increases susceptibility to hiv infection.21,23 studies have shown that many healthcare workers reported not using condoms regularly, despite some having multiple sex partners. it has been found that many healthcare workers believe condoms are ineffective in preventing hiv infection, with 60% confirming their beliefs about the effectiveness of condom use in preventing the spread of hiv.1 such findings are attributed to a lack of knowledge about hiv and aids on the part of many healthcare workers, with only 46% of healthcare workers participating in a study on knowledge, attitude and practice about aids and condom utilisation, having adequate knowledge about aids.23 this is further supported by findings showing that more educated healthcare workers are less likely to engage in unprotected sex.15 healthcare workers in rural areas report having more multiple sex partners. this has been attributed to poor social support and separation from families when rural healthcare workers move to urban areas for work.9 several gaps have been identified in the literature. most research was conducted in developed countries where the hiv infection rate is much lower than it is in developing countries. no studies were found for south africa in particular, which is reported to be the significantly impacted by hiv and aids. only a few of the studies included in this review focus on hiv and aids prevention among healthcare workers. the majority of the studies available mostly focus on other samples including sex workers, adolescents and patients. limitations it is acknowledged that 16 articles may limit the generalisability of findings in this review. furthermore, with the majority of existing research focusing on risky sexual behaviours among healthcare workers in developed countries, it is difficult to address policy implications for developing countries where hiv and aids is more prevalent. however, given the dearth of research on risky sexual behaviours among healthcare workers, this handful of articles provides a unique insight into sexual behaviours of healthcare workers as well as related outcomes (hiv). further research exploring risky sexual behaviours among healthcare workers is important in reducing hiv and aids among this population, especially in developing countries. recommendations it is recommended that research should focus more on exploring the factors contributing to high hiv rates among healthcare workers in developing countries. appropriate implementation strategies overcoming the challenges posed by power imbalances are necessary to empower healthcare workers to make a formal complaint without experiencing stigma, discrimination or intimidation. at a national level, recognition and action are required from governments and professional regulatory bodies, while improving healthcare practice and organising community action at a local level.33 at organisational level, it must be ensured that complaints are taken seriously and treated fairly, despite being directed against doctors.18 working environments and working conditions must be improved in order to address the context within which the problem occurs.34 similar prevention strategies have been shown to reduce sexual violence in the workplace by 40%.21 solutions must also be centred on challenging female vulnerability. the cognitive appraisal theory emphasises promoting women’s action on sexual violence by educating them on recognising cues associated with sexual violence, understanding psychological barriers to effective resistance and self-defence training. these types of interventions allow women to assess the situation in preparation for response.35 healthcare workers should be educated on the consequences of risky sexual behaviour, including condom use especially with multiple sex partners. such education should be targeted at both the perpetrators and victims of sexual violence.23 education has been found to be an effective strategy in reducing hiv and aids.36 interventions involving training on ethics and sexual rights as well as communication and mutual respect are important in addressing sexual violence in the workplace.33 supportive working environments for rural healthcare workers in urban areas are important in addressing risky sexual behaviours associated with multiple sex partners. studies have confirmed reduced risky sexual behaviours among people living with hiv and aids through support interventions within working environments as well as through social and community support.37 conclusion hiv and aids remains a global crisis with south africa bearing the brunt of its prevalence. healthcare workers are not immune to this condition, which stifles efforts to effectively combat the disease. sexual risk behaviours, especially sexual violence among healthcare workers, can only exacerbate the problem by increasing infection rates and compromising availability of human resources. appropriate procedures on reporting sexual violence coupled with education on hiv and aids as well as influencing attitudes and belief systems could assist in reducing the spread of hiv and aids within the healthcare workforce while minimising the effect on patient care. acknowledgements we would like to acknowledge and thank the independent reviewer for assisting with the search strategy and consolidation of the emerging themes. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions n.k. was responsible for conceptualisation, methodology, search and compilation of findings as well as write-up of the article. m.m. was responsible for some interpretation of findings as well as write-up of the discussion section of the article. references kiragu k, ngulube t, nyumbu m, njobvu p, eerens p, mwaba c. sexual risk-taking and hiv testing among health workers in zambia. aids behav. 2007;11(1):131–136. https://doi.org/10.1007/s10461-006-9091-9 statistics south africa. mid-year population estimates [homepage on the internet]. statssa publication 0302; 2017 [cited 2017 feb 02]. available from: www.statssa.gov.za/publications/p0302/p03022017.pdf connelly d, veriava y, roberts s, et al. prevalence of hiv infection and median cd4 counts among health care workers in south africa: original article. s afr med j. 2007;97(2):115–120. 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https://doi.org/10.1177/0361684311404137 mbeba mm, kaponda cp, jere dl, et al. peer group intervention reduces personal hiv risk for malawian health workers. j nurs sch. 2011;43(1):72–81. https://doi.org/10.1111/j.1547-5069.2011.01384.x qiao s, xiaoming l, stanton, b. social support and hiv related risk behaviours: a systematic review of the global literature. aids behav. 2014;18(2):419–441. https://doi.org/10.1007/s10461-013-0561-6 untitled j u n e 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e5 0 the hiv clinicians society has joined forces with the popular multimedia ngo soul city to help prevent hiv infection in south africa. the soul city tv series has consistently been in the top five most-watched tv programmes in south africa, with about 60% of the country watching each episode since 1994. soul city is an entertaining tv series that uses researched edutainment techniques to deliver health information and cause changes in health and social behaviour. independent research has shown it to have a powerful impact on south african society. the hiv clinicians society and soul city have worked together on the next series to turn fiction into reality. during the tv series characters phone the aids helpline to find out where they can get tested and treated for hiv. behind the scenes the society, lifeline and soul city are working together to create the first geographical database of hiv testing and treatment sites in south africa. you will soon be able to call one number (or search one website) and get directions from where you are standing to your nearest hiv services. the tv series also focuses on ways to prevent hiv infection, the damaging effects of alcohol in society and how to have a healthy pregnancy. soul city imparts information and impacts on social norms, attitudes and practice. its impact is aimed at the level of the individual, the community and the sociopolitical environment. while the tv show is on air, radio talk shows will be broadcast in all nine african languages, and three million booklets on hiv, alcohol and maternal health will be released and distributed nationally, mainly through newspapers. we aim to create an enabling environment empowering audiences to make healthy choices, both as individuals and as communities. the tv series will be supported by a robust marketing campaign which includes advertising and publicity, to draw maximum audiences, create excitement and keep bums on seats throughout the 13-week broadcast period. the new soul city series will be broadcast on sabc 1 from 4 september to 27 november 2007. n e w p a r t n e r s h i p s telling stories to change the country – a combined effort by the hiv clinicians society and soul city reach and reported impact of specific tv programmes reported reach: per cent who say they have ever watched each programme higher reach, higher impact higher reach, lower impact lower reach, higher impact lower reach, lower impact soul city soul buddyz tsha tsha zola 7 generations zone 14 isidingo take 5 siyanqoba heart lines 7 de laan city sesia viewer reported impact: per cent of viewers who say they have personally learned a lot about hiv and related sexual behaviours from programme overall reported impact: per cent of all youth who watch and say they have learned a lot about hiv from programme source: young south africans. broadcast media, and hiv/aids awareness. kaiser family foundation and south african broadcasting corportion, 2005. 72% 55% 57% 74% 81% 59% 52% 40% 22% 22% 40% 9% 91% 83% 72% 55% 29% 35% 42% 67% 86% 73% 25% 41% 65% 46% 41% 40% 24% 21% 22% 27% 19% 16% 10% 4% t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u n e 2 0 0 7 5 1 bonnie henna, who plays one of the main roles as the nurse zanele, is holding a poster for the mothers 2 mothers project. the project aims to support women through the process of pmtct (prevention of mother to child transmission of hiv). schoolchildren campaign against the abuse of alcohol and alcohol advertising near their school. zuko and his friend mandla play with condoms in preparation for ‘the real thing’. in this series mandla and his girlfriend naledi decide that they would like to start sleeping together, but they want to be 100% safe and 100% sure. watch to see how they do it. skosana, the mother of a child with fetal alcohol syndrome. she is now pregnant and drinking again! watch the series to see how, with help from friends and nurses, she learns to cope with her problems in a healthier way. simphiwe, the baby, is hiv-positive and has been adopted by his uncle odwa and aunt maria. his teenage mother, portia, died just after childbirth due to complications arising from hypertension during pregnancy. in this scene you find out how portia, who was only 15, became infected with hiv. make up march 2007 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e m a r c h 2 0 0 7 27 1. preamble providing hiv-related services to displaced populations is a difficult yet critical undertaking, which is firmly rooted in international human rights law. protection offered under this law and, in particular, article 12 of the international covenant on economic, social and cultural rights, confirms ‘the right of everyone to the enjoyment of the highest attainable standard of physical and mental health’. this right requires health workers to take steps that are necessary for ‘the creation of conditions which would assure to all medical service and medical attention in the event of sickness’.1 in addition, health workers who treat displaced persons are guided by the same principles that govern the treatment of any patient, irrespective of nationality or ethnic origin, which include an intrinsic respect for human life and an oath to act in the patient’s best interest when providing medical care. nonetheless, displaced persons are a unique group with special needs. they are often stigmatised, marginalised and discriminated against, making them highly vulnerable and insecure in their host country. those in need of treatment are often denied care. however, since the rollout of affordable antiretroviral therapy (art) worldwide, there has been an international push to recognise every individual’s right to treatment and to ensure universal access to art. displaced persons often come from communities that are least likely to have access to art, and health workers will be following international law and practice by providing treatment to them. for those who are already on treatment, health workers often need guidance regarding complications that may arise due to differences in regimens or, if initiated in the host country, due to different conditions the individual may face at the site they will be going to. the management of art in displaced populations requires health workers to make strategic choices regarding the best care for the individual who may be further displaced. these guidelines outline key principles to guide the health worker in making these sometimes complex choices. scope of application this policy is intended to offer guidance to clinicians, nongovernmental organisations (ngos) and governments on the provision of art among displaced populations, including prevention of mother-to-child transmission (pmtct), postexposure prophylaxis (pep) and long-term art. these guidelines are not meant to replace national guidelines but to provide additional guidance to health workers to deal with the specific needs of these populations. as with all hiv and aids policies and programmes, art must be linked to prevention, care and support programmes. art should not be implemented as a parallel intervention but rather as part of an integrated programme that is in itself linked to other existing services (e.g. reproductive health, nutrition, education and social services). the guidance set out in this document applies to all displaced populations, including refugees, asylum seekers, internally displaced persons and migrants. specific guidance is necessary not only because of the unique characteristics of these populations, but also because of their specific vulnerabilities and frequent exclusion from hivand aids-related services. it is widely recognised that the failure to provide hiv prevention and care to displaced persons not only undermines effective hiv prevention and care efforts, but also undermines effective hiv prevention and care for host country populations. 2. background southern africa is host to approximately 300 000 refugees and asylum seekers, the majority of whom are hosted in south africa and zambia. most refugees and asylum seekers are currently coming from countries with lower hiv prevalence, such as the democratic republic of the congo (drc), and moving to countries with higher hiv prevalence, such as south africa. their vulnerability to hiv infection therefore increases upon arrival. in general, they also come from areas where access to art is limited. g u i d e l i n e s 2007 clinical guidelines on antiretroviral therapy management for displaced populations ‘they see refugees as a threat, as competing for their jobs and women. nobody sees them as a victim of circumstances.’ refugee in johannesburg referring to local services make up march 2007 30/3/07 11:28 am page 27 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e m a r c h 2 0 0 7 29 the number of migrants in the region is difficult to estimate accurately, as there are no official mechanisms for recording these figures. however, every country in southern africa is affected by migration, either as a source or destination country. 3. responsibility of the health worker it is the role of health workers to act, within a legal framework, as advocates for access to health care, and not to restrict or ration care. the ethical duty of a health worker is to treat patients in a manner that serves the patient’s best interest. medical assistance should ensure the ‘right of everyone to the enjoyment of the highest attainable standard of physical and mental health’2 and must be offered without discrimination. people in need of health care should not be denied hiv care because of their nationality. 4. medical management all people, including displaced persons, should be encouraged to test for hiv regularly. retesting for hiv should occur in all patients who report being hiv positive. this must be done with their informed consent. counselling should be made available if results from re-testing are negative and confirmatory testing/expert consultation sought. as is the case with the general population, people from displaced communities may present late with aids-defining illnesses, as well as for pep and antenatal care. advanced presentation is not a reason to deny care. earlier diagnosis should be pursued at every opportunity. mythbusters ‘conflict always increases hiv’ on the contrary, despite the sexual violence, trauma and breakdown of family and community structures, evidence suggests that there are ‘protective’ factors in a refugee setting that may offset these risks. furthermore, displaced persons often come from countries of origin with lower hiv prevalence and move to countries of asylum with higher hiv prevalence.3 thus, these populations often have lower hiv prevalence than their surrounding host communities, particularly in southern africa.4 ‘displaced persons engage in high risk behaviour’ while displaced persons are vulnerable to exploitation and abuse, they have often benefited from the assistance of international organisations. for example, dedicated hiv awareness programmes and training in many refugee camps have resulted in a high level of skills and knowledge with less risky behaviour. displaced people can use this knowledge in their country of asylum as well as upon return to their home country.5 ‘high mobility among displaced persons prohibits good adherence’ displaced persons are often denied access to care because of fear that they are too mobile. however, by the end of 2003, refugee populations remained on average in their host country for 17 years.6 even within a country, they are far less mobile than many assume and may move around less than local clients who work far from home.5 ‘providing care will bring on a flood across the border’ as hivand aids-related care is made increasingly available in the region and as more people can access such services, the more they tend to stay where they are. in countries that have provided free art to refugees, there has not been an increase in movement across borders. ‘displaced persons never have support structures’ there are often tight and extensive support networks of similarly affected people within the host community; these may, however, not involve family, friends or more traditional support networks. often innovative ways of ensuring adherence to art, such as using clinical staff, counsellors and support groups, have proven effective. ‘conflict is limited to a short period’ unfortunately, most conflict lasts for years and even decades, resulting in conditions that force displaced people to remain in their host countries for extended periods. definitions ■ refugee: a person who flees his/her own country because of race, religion, nationality, membership of a particular social group, political opinion or civil unrest/war, and who cannot return home for fear of persecution. ■ asylum seeker: a person who has applied for asylum and is awaiting a decision on his/her case. ■ internally displaced person: person who has been forced to flee his/her home suddenly or unexpectedly due to armed conflict, internal strife, systematic violations of human rights or natural disasters, and who is still within the territory of his/her country. ■ economic migrant: person who moves to another country seeking economic opportunities. ■ undocumented migrant (often negatively referred to as ‘illegal immigrant’): person who has entered another country and remains without the required legal documentation. make up march 2007 30/3/07 11:28 am page 29 m a r c h 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e30 displaced persons may be anxious that disclosure of their hiv status will have implications for their residency, resettlement and other legal consequences. the reality is that hiv status does not have an impact on the legal status of a displaced person in the southern african region. despite this, displaced persons may be anxious about disclosing their hiv status. some refugees may wish to remain anonymous for a myriad of reasons, including very real security concerns. it is up to the health worker to deliver care in a manner that does not put them or their families in danger. health workers must reassure patients that their privacy and confidentiality in this regard will be respected. a full history, clinical, psychosocial and available laboratory evaluation should be done for all patients according to the national protocol. 4.1 antiretroviral therapy (art) art is a life-saving intervention. in principle, art should be lifelong and sustainability should therefore be key. however, even if sustainability is not guaranteed or is uncertain, immune reconstitution on art, even for short periods, can yield significant clinical benefits. furthermore, provision of art is rapidly evolving in the region, and is increasingly accessible even in very poorly resourced areas. hence, starting someone on art for even a limited period of time may allow them to access more sustainable treatment at a later stage. however, there is substantial evidence that art interruptions may be harmful, and this option must be carefully weighed and generally only considered in severe disease. adherence support needs of displaced persons may be very different from those of the local community. a displaced person may not have the traditional support of family or friends, although there may be strong cohesion among displaced communities who share similar reasons for displacement. as the circumstances of displaced persons often change without warning, assistance needs should be constantly assessed, and appropriate counselling and support provided where necessary. 4.1.1 initiation criteria for patients with no art history patient preparedness patients must make an informed decision to begin and be adherent to art and, as with other patients, proper counselling is key to ensuring the displaced person’s understanding of these principles. counselling in an appropriate language and with due regard for cultural differences is crucial. unhcr has translation resources available for refugees. counselling should also take into consideration the particular background and human rights context of the displaced person. the possibility of treatment interruptions should they be further displaced must be specifically addressed during counselling, e.g. if they travel to a different area, they may need to find an alternative drug supply and hiv care network. the possibility of interruption should not be used by the health worker as a reason to deny access to care. instead, strategies should be explored with the displaced person to find solutions. in the event of informed refusal of art, as with any other patient, continued counselling is required. furthermore, access to other interventions including prophylaxis and treatment of opportunistic infections should not be withheld. country-specific exclusion criteria for art these criteria should be viewed very critically, taking into consideration the specific circumstances of displaced persons. certain criteria may need to be modified to include displaced persons in art programmes. for example, some programmes ask for a ‘treatment buddy’, which can be a challenge for displaced persons who are often alone or separated from traditional support structures. imaginative solutions are usually available and should be explored (see ‘solutions’ box). biological criteria for initiation of art national guidelines should be adhered to, where these are available. where there are no national guidelines, world health organization (who) guidelines should be followed. the absence of laboratory facilities should not be used to exclude hiv-infected people from treatment. for example, if a displaced person does not have access to or cannot afford cd4 testing at initiation, who guidelines clearly state that clinical staging is an acceptable indicator for art initiation. if return to country of origin or further movement is imminent the following considerations should govern the decision to commence art immediately: i. art is a lifesaving treatment and should be carefully evaluated in each case, regardless of whether return or further displacement is imminent. ii. in many cases, the conditions and access to art at the site being travelled to are unknown. information may be out of date in many cases, especially as art access has expanded so rapidly. conflict may interrupt access to previously accessible health services. displaced persons may therefore return to hiv care systems that may be either stronger or weaker than they, or the assessing health worker, anticipated. iii. stage of disease and anticipated availability of treatment at the site being travelled to should guide the urgency of initiation. ‘from what i have seen, compliance among foreigners is good, better than south african citizens.’ south african doctor make up march 2007 30/3/07 11:28 am page 30 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e m a r c h 2 0 0 7 31 iv. if patients have advanced clinical disease (severe aidsdefining disease or a low cd4 count (< 50 cells/μl)), they should be advised to delay their departure and art commenced immediately. however, clinical discretion is required in all cases. v. if the patient is who stage 3 or healthy, with a good cd4 count (if available) and ■ treatment is available at the site being travelled to: the site of initiation (either at the current health site, or at the site being travelled to) should be determined by the following factors: timing of departure, duration of travel, art regimen at the receiving site (if known), anticipated side-effects and conditions on arrival (e.g. local waiting time to access art). all these need to be discussed with the patient so an informed decision can be made. ■ treatment is not available at the site being travelled to: the displaced person should be encouraged to remain where they are and initiate art for at least 3 months to monitor potential side-effects and adherence, and subsequently be provided with a stock of medication for 3 6 months if possible. ■ the individual insists on leaving immediately or in the near future: these individuals must receive comprehensive advice on options available (see below). all should be considered sub-optimal. options include: a) leaving with no art b) initiation for a short period prior to leaving together with additional art stock c) leaving with a supply to be initiated at the site being travelled to (with referral letters and extensive preadherence counselling). the guidelines group felt that options (b) and (c) were dangerous, and should only be considered in exceptional circumstances. in many situations, the person will be going to an area with poor or limited health care, limited or no access to clean water or accommodation and food insecurity. in this situation, option (a) may be more appropriate. for other individuals who are going to better conditions and have a good understanding of hiv and art, options (b) and (c) may be considered if this is the only option. consequences of initiating art in the (b) and (c) scenarios may include developing side-effects in an unsupported environment, possible development of art resistance due to the lack of adherence support, and the difficulties of initiating and maintaining treatment during a stressful and unstructured time. these consequences must be fully explained to the patient. vi. there may be additional reasons for delaying treatment initiation, other than those listed above, such as patient readiness, practical considerations (such as side-effects during travel and reintegration), concurrent medical conditions that may worsen on art (e.g. immune reconstitution diseases may present catastrophically and the receiving site may not have the resources to manage them), and other considerations. the risks and benefits of deferring treatment must be carefully weighed against immediate initiation; options should be discussed with the patient, including delaying departure. vii. this decision-making may require significant art expertise, and the health worker should consult if not confident that s/he has the expertise to give adequate counsel. viii. choice of regimen. in general, try to match the regimen to the one the individual is most likely to be on over the next year. if return or displacement is likely to be soon, try wherever possible to match the regimen to that available in the area the person is going to. 4.1.2 patient presents on art or with history of previously taking art in circumstances where the displaced person is either currently on art, or has a history of previously being on art, the following is recommended: ■ a repeat hiv test to confirm their infection. ■ if the individual is currently on art, continue treatment with no interruption. solutions to problems encountered when initiating patients on art problems solutions cd4 count is unavailable ■ who clinical staging is or unaffordable simple, and relatively sensitive and specific. treatment buddy is required ■ use a friend, companion, by national guidelines family member, support group, local health worker, or local faith-based or non-governmental organisation (ngo) member. no counsellor is available ■ contact unhcr for list who speaks the language of translators. payment, lab costs, ■ displaced persons must transport costs are an be assisted with a waiver obstacle process if one exists; others can be referred to ngos and social welfare organisations, which are also resources in many areas. refugees can be referred to unhcr. geographical exclusion ■ if outside treatment criteria exist, but patient catchment area, patient is unable to return to must demonstrate ability home site to regularly attend appointments and then assisted to negotiate for inclusion with the relevant authorities. make up march 2007 30/3/07 11:28 am page 31 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e m a r c h 2 0 0 7 33 ■ if possible, a viral load and cd4 count should be done at the time of the first visit. if the viral load is raised adherence intensification is usually warranted. expert opinion should be sought before ordering resistance testing, if available. ■ if there has been a treatment interruption, try to restart treatment as soon as possible, after careful assessment of the reasons for the interruption (see below). the viral load may be high if the interruption is significant. ■ adherence counselling and support should be undertaken in light of the new circumstances. choice of regimen if currently on art in general, most patients in sub-saharan africa are currently initiated on d4t or azt, 3tc and a non-nucleoside reverse transcriptase inhibitor (nnrti), either nevirapine or efavirenz. ■ if on same regimen as national programme: continue same regimen. ■ if on different regimen from national programme: if the national guideline supports the different regimen, continue with this regimen and initiate monitoring according to the local algorithm. occasionally, the national regimen protocols may offer better treatment options, or new treatment options may become available, and these cases should be assessed with suitable expertise. if the national guideline does not support the regimen, the following possibilities should be considered, as they may not allow patients to go on to the regimen indicated under the national protocol: ■ history of side-effects and co-morbidities ■ history of possible virological, immunological or clinical failure ■ use of concomitant medication. in this case, select the best available regimen from available drugs. ■ if on unknown regimen, with minimal history: in general, these patients should be initiated on the national guideline’s first-line therapy, and followed closely. where possible, a viral load after 6 weeks of treatment should be used to indicate efficacy and a significant drop in viral load (1-log) should be anticipated if the regimen remains effective. choice of regimen if art was interrupted establish the cause of the interruption. note that displaced persons are at greater likelihood of treatment interruption due to factors beyond their control, e.g. conflict resulting in displacement from their normal art site. routine evaluation: ■ if adherence is an issue, this needs to be explored. however, there is no evidence that displaced persons are less adherent than local populations. ■ if virological failure was the reason, treat as per national protocols, which may mean accessing second-line regimens, if available. ■ if due to side-effects, subsequent drug choices should be carefully evaluated. ■ if interruption was due to drug supply issues, and there were no adherence, resistance or toxicity issues, art should be reinitiated as soon as possible. ■ if the previous regimen was the same as the national programme, restart art. nevirapine deserves special consideration in the event of the patient having a high cd4 count, as it is associated with significantly increased toxicity. if nevirapine is restarted after an interruption of > 1 week, recommence with the 2 week lead-in dose, and monitor alanine transaminase closely for the first 3 months of treatment, if laboratory monitoring is available. if the previous regimen is different from the current recommended regimen, considerations should be as above. 4.1.3 contingency planning displaced persons can be affected by unforeseen events, causing them to move unexpectedly. this needs to be explored at every visit. discuss the provision of a personal art stock where assessed to be necessary (2 4 weeks will allow for time to make alternative plans for art access). all patients should have a clinical hiv summary, such as a treatment card, which includes their drug regimens, prior toxicity, illness history and laboratory results. all patients should also be aware of their basic medical history and be able to relate it verbally. this assists continuity of treatment in the event of unplanned displacement. if on a non-nucleoside reverse transcriptase inhibitor (nnrti) regimen (which have a long half-life) and treatment is stopped with no possibility of immediate restocking of drugs, consider ‘covering the tail’ (the long half-life of nnrtis) by continuing dual nucleosides for a week after stopping the nnrti, to prevent possible nnrti resistance. in the event of unplanned displacement, patients should be cautioned on non-reputable sources of treatment, including counterfeit drugs, cheaper but less effective regimens (such as dual therapy), inconsistent sources of drugs, and poorly trained health worker advice. they should be counselled to seek continued care only through a public or reputable programme. sharing of art and dose reduction/interruption to extend the stock lifespan must be discouraged. ‘they saved my life.’ migrant in johannesburg on art through faith-based organisation make up march 2007 30/3/07 11:28 am page 33 m a r c h 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e34 4.1.4 art-specific challenges the choice of art should take the following into account: ■ national guidelines should be used. within this, try to match this regimen to the possible regimen in the area being travelled to, if travel is anticipated soon. ■ some arvs (e.g. ritonavir) require refrigeration. assess availability of refrigeration during travel and at the site they are travelling to and adapt art accordingly. ■ some arvs require food intake for optimal absorption. many regimens require twice-daily dosing. displaced persons may not have sufficient food available and should be told to take their medications despite lack of food, and warned of possible increased gastrointestinal side-effects. at the same time, food aid should be sought for these persons. ■ in many cases, patients may be on fixed-dose combinations (fdcs) in their prior art site, and this may mean a higher pill burden in their new site if the fdc is not available. the changes should be carefully explained during adherence counselling. ■ if the art choice requires more frequent monitoring, consider the ease and cost of access to the displaced person. as with local populations, transport costs are often a barrier to regular visits. ■ arvs requiring reconstitution (some paediatric formulations) depend on access to clean water, which may not be easily available to displaced persons. ■ the absence of access to laboratory monitoring (either due to lack of facilities or cost) in the current site or site being travelled to should not be used to exclude people from art. minimum standards for laboratory monitoring are outlined in the who and national guidelines, and should be adapted as much as possible to enable access. if the art choice requires more frequent monitoring, consider ease and cost of access. for example, a nevirapine regimen should ideally have liver function monitoring in the initiation phase, which may increase the frequency and cost of visits. however, in many cases, nevirapine is the only nnrti available, and no liver function testing is available, in which case the drug should be initiated with extensive patient counselling. 4.1.5 management of children initiation of treatment should be based on national guidelines. in certain cases, if diagnostic and monitoring facilities are not available, refer to the who guidelines for hiv diagnosis that are based on a positive hiv antibody test and clinical findings. syrup formulations have large volumes, and can be difficult to carry and refrigerate. this may be particularly relevant to those travelling long distances and should be taken into consideration when making clinical decisions. in children < 18 months who are diagnosed clinically, parents should be counselled to seek confirmatory testing after 18 months of age with conventional antibody tests. this is particularly important where further displacement is possible. unaccompanied minors are a special issue, and may need to follow a special legal process or agreed upon guardian/ caregiver arrangements. these need to be expedited as quickly as possible, so as not to delay art. for refugee children, contact unhcr for assistance. 4.1.6 post-exposure prophylaxis (pep) in populations affected by conflict, gender-based violence and assault is common throughout the cycle of displacement. sexual exploitation is also common among female migrants, who can be victims of trafficking. pep should be considered for displaced persons in need; however, assessment often takes place after the efficacy of pep has passed. pep includes hiv, sexually transmitted disease and pregnancy prevention. trauma and adherence counselling is essential in all cases. national and who/unhcr7 pep guidelines should be followed. if national guidelines exclude displaced persons, treatment should be accessed wherever possible (e.g. from rape crisis centres, ngos, faith-based organisations, private practitioners). for refugees who cannot access pep through a local service, contact unhcr urgently. mythbusters ‘resistance to arvs is caused by suddenly stopping art’ stopping art suddenly is rarely associated with resistance; poor dosing, poor drug quality and poor adherence are far more common causes. there is concern about stopping nnrtis along with other classes of drugs, as they have a long half-life. this is discussed above. ‘access to monitoring is poor and hence art should not be started’ if laboratory monitoring is not available, clinical monitoring, although sub-optimal, is sufficient to start art. ‘access to guaranteed lifelong therapy is a reason not to start art’ treatment may allow a person to live long enough to access more sustainable sources of art, especially as broader availability increases throughout the region. however, there are dangers in interrupting treatment, and this must be avoided wherever possible. ‘people are surprised to see me looking so well. before they were advising me to save my mealiemeal for my funeral.’ namibian refugee in botswana, on art through a faithbased organisation make up march 2007 30/3/07 11:28 am page 34 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e m a r c h 2 0 0 7 35 4.1.7 prevention of mother-to-child transmission (pmtct) pmtct services may not be available in the prior site, and hence women may not have been counselled regarding pmtct. pregnant women may require counselling on testing, treatment and feeding options available in the host health care environment. in cases of moving to sites with unknown or poor access to care, similar to treatment for tuberculosis in pregnancy, the pregnant woman and her family should be advised to delay moving until after delivery in order to complete the pmtct programme. in cases of moving to sites with established pmtct programmes, the patient should be advised to immediately seek out local pmtct programmes on arrival. however, due consideration to the stage of pregnancy, duration/mode of travel and conditions on arrival must be discussed. a clear referral letter is important at all times, in both the antenatal and postnatal period. provision of pmtct drugs to pregnant women about to move should be considered in case labour occurs during travel or the woman arrives in an area where there is no pmtct programme. take note of the considerations described in the section that deals with individuals in need of art who are facing imminent departure (see section 4.1.1, ‘if return to country of origin or further movement is imminent’) to counsel appropriately. 4.2 non-art considerations 4.2.1 tuberculosis (tb) treatment, and primary and secondary prophylaxis for opportunistic infections including co-trimoxazole, fluconazole and isoniazid national guidelines should be followed. interruption of prophylaxis should be avoided through rapid referral to local sites providing these drugs. people with tb should be encouraged to complete tb treatment before further movement. co-trimoxazole demonstrates significant benefit in areas affected by malaria and bacterial infections, as well as in people with who stage 2, 3 and 4 disease. co-trimoxazole should be strongly considered, in line with national and who guidelines. a contingency stock of prophylactic medications, as for art, is recommended for people at risk of unplanned movement (2 4 weeks supply, like art). 4.2.2 other illnesses malaria is extremely common in the region, but typhoid, trypanosomiasis, viral hepatitis, cholera, amoebiasis, measles and other diseases that can affect travellers should be considered, and appropriate prevention advice given. be aware of other countries’ endemic aids-defining diseases that may not be common in the host country (e.g. kala-azar in somalia, histoplasmosis in zimbabwe). 4.2.3 language using family members or community members as interpreters carries risks regarding respect for confidentiality and inappropriate disclosure, and should be avoided where possible. furthermore, information may be less forthcoming through a third party if the party is known to the person. all efforts should be made to have an independent interpreter who has been trained in issues of confidentiality. ongoing adherence counselling is a challenge if no ready interpreter is readily available. for refugees, do not refer them to their country’s embassy, as that may jeopardise their asylum status. this may however be an option for other displaced persons, e.g. economic migrants. for help with refugees, contact unhcr, who may be able to identify suitable interpreters. 4.2.4 referral letter note that owing to language issues, the health worker at the distant site may not speak or read the referring site’s language, and may not be able to read the referral letter or treatment card of the referring site. use generic names and terms such as stavudine, tuberculosis, cryptococcal meningitis and internationally agreed upon abbreviations or acronyms such as pmtct or vct (voluntary counselling and testing). referral letters may get lost. therefore, explain the contents of the letter to the patient, so they can relay information verbally if necessary. 4.3 other important issues 4.3.1 cultural issues the background and culture of a displaced person may be different to that of the host country. health workers should be culturally sensitive and non-judgemental. regardless of cultural traditions or practices, the health worker should maintain professional standards and practices, although this may require additional time and effort. for example, if a man insists on knowing the hiv test results of his spouse without her consent, as this is his ‘right’ according to his culture, a more detailed explanation of the principles of confidentiality and disclosure may be required. 4.3.2 alternative treatments as with many local communities, displaced persons may seek alternative treatments. encourage them to share this ‘people come to us frustrated and disillusioned after being turned away from the hospitals repeatedly.’ south african ngo working with displaced persons make up march 2007 30/3/07 11:28 am page 35 m a r c h 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e information with the health worker, so that informed treatment decisions can be made. in almost all cases, drug interactions between art and alternative medication are unknown, and alternative medication should be discouraged where possible. 4.3.3 psychosocial and mental health8 displaced persons, particularly those coming from conflict areas, may have experienced trauma and violence, including sexual violence, and therefore may be in need of specific psychosocial support. these issues should be explored sensitively and efforts to refer to specialised services should be made. history taking may provoke anxiety, depression and stress responses. appropriate counselling should be made available. 4.3.4 prevention southern africa is an area of very high hiv prevalence. in some cases, displaced persons will be moving into a high hiv risk or higher prevalence environment (e.g. from somalia to south africa). displaced persons should be made aware of increased hiv risk. some populations have very limited knowledge of prevention methods, such as condoms, and health workers must not assume core knowledge exists. for those already living with hiv, prevention messages must be re-emphasised to avoid further infections. prevention messages, verbal or written, must be communicated where possible in the displaced person’s language. the essential linkage between prevention and treatment is as relevant in this situation as with the host general population. 4.3.5 reproductive health9 family planning availability needs to be carefully explained. issues such as access to contraception, termination of pregnancy, emergency contraception and availability of ante/postnatal care should be outlined for all displaced persons. specific care options may not be known to the person due to unavailability in area of origin (e.g. contraceptive methods, pap smears); these new options should be explained. 4.3.6 gender-based exploitation and violence10 sexual violence often accompanies conflict and consequent displacement. displaced persons are often economically vulnerable, and may be at increased risk of sexual exploitation and abuse. in particular, women and girls may be more susceptible to hiv due to gender discrimination and violence, insufficient access to hiv prevention information and services, inability to negotiate safer sex and lack of female-controlled hiv prevention methods. information anticipating this, especially regarding pep and psychosocial support, should be provided. a careful and sensitive history should be taken in all cases. in cases of prior sexual assault, appropriate systematic care, support and treatment should be initiated, as per national guidelines. 4.3.7 orphans, separated and vulnerable children the nature of displacement often results in family separation. there may be an increase in orphans due to conflict and a related increase in communicable diseases. displaced children may also be accompanied by a relative or another adult who is not a relative. if there are any concerns regarding the guardianship or care arrangements for the child, refer directly to social services for assessment. specialised counselling may be required for these children. red cross/red crescent and other organisations facilitate tracing of family members and return of children to their country of origin. consent issues are covered in the paediatric treatment section (see section 4.1.5). 4.3.8 end-of-life care treatment options closer to the person’s home may need to be explored in the event of limited mobility. palliative care options vary, and support is often available in the host country through government programmes and ngos. refugees wishing to return to their country of origin should contact unhcr. 4.3.9 death and body disposal body transport across borders may be expensive, logistically complex and bureaucratic. international organisations rarely facilitate the transport of a body to the home country, although faith-based organisations may. in the case of terminal patients, this information should be sensitively explained to the patient and their family members, and any available support offered. 4.4 advocacy health workers should advocate for non-discriminatory medical practices, and must play an active role in reducing discriminatory attitudes and dispelling myths regarding displaced persons. concerning refugees and asylum seekers, many countries in southern africa, such as namibia, south africa and zambia, have specific policies that include these groups in their public sector art programmes. others, such as mozambique, malawi and zimbabwe, do not specifically exclude refugees or asylum seekers from public sector art. as at march 2007, botswana is the only country with a policy that specifically excludes nonnationals from the art programme. however, unhcr and other organisations are advocating the government to lift this restriction. 36 make up march 2007 30/3/07 11:28 am page 36 m a r c h 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e40 where policy restrictions exist precluding art access in the public sector, migrants, refugees and others should be referred to ngo, faith-based or private sector art programmes. 5. case studies case 1: thembi thembi is a botswana national who has a work permit for south africa (sa) and is working there as a cashier. she has just arrived in south africa, after spending a year on the botswana national programme. she has lost her referral letter and only plans to return to botswana in 6 months. she says she is on tenofovir, 3tc and nevirapine, dosed daily, and is considering having a child with her south african husband. she was previously on d4t, but developed a peripheral neuropathy and was switched to tenofovir. she has sufficient medication for an additional week. she is refused access to the art site in the government programme in sa, as it is not available to economic migrants. she goes to a private practitioner, but does not have money to pay for a viral load or cd4 count. the practitioner is unable to obtain the records from the botswana site. clinically she is well. she claims complete adherence and says that her previous viral load, taken 6 months ago, was ‘ok’. the practitioner advises her that tenofovir is not yet readily available in sa. d4t is not an option, due to her previous peripheral neuropathy, nor is ddi, both substitutes for tenofovir. azt and abacavir are options as substitutes, although abacavir remains very expensive, and azt ideally requires haematological monitoring, with attendant costs. introducing a single new drug to replace tenofovir in the face of a virologically failing regimen carries the risk of resistance to that drug, if no viral load is obtained to confirm suppression. the practitioner persuades thembi to pay for a single viral load, funded through her local church. the result comes back undetectable. he substitutes tenofovir with azt, carefully explaining the new twice-daily dosing she now requires. she asks why other patients are on efavirenz, and why she isn’t. the practitioner explains that established nevirapine is very safe, and that a switch is not advised, especially if she plans to have a baby, due to concerns regarding the teratogenicity of efavirenz. he asks her to try to obtain her past medical records as soon as possible. thembi is advised to return if she experiences any sideeffects, and is asked to see if the church has further resources to pay for haemoglobin and further viral load monitoring. case 2: machozi machozi is a 28-year-old married woman from eastern drc. like most of the women in her area, she has never been to school. four years ago, she was working in her fields when a group of soldiers moved through the area. seeing her in the field, they took her hostage and forced her to carry their goods. they then forced her to ‘marry’ one of the commanders. over the next 4 months she was repeatedly raped. finally she was able to escape her captors, and in fear of being recaptured, she fled over the border of zambia. she settled in a small town and made a meagre living selling items in the market. then over several months, she started to lose weight. she noticed as well that her skin had broken out in a rash that wouldn’t go away. at first she thought she had been poisoned by one of the market women but finally the nurse at the health centre convinced her to have an hiv test. the test was positive and she was referred to the hiv clinic. the doctor who saw machozi at the clinic evaluated her as clinically who stage 3. he prescribed co-trimoxazole and ordered a cd4 count. the cd4 came back as 124, and the doctor decided to start preparing machozi to start art. however when he discussed this with machozi, she didn’t seem to understand. in fact, she told the doctor that she had decided to return home, and therefore could not come back to the clinic. the doctor explained how important it was to stay in zambia and start art. machozi nodded, but still insisted that she must go home. she told the doctor she would take the pills home with her if they were so important. the doctor considered this option. machozi was newly diagnosed and while she seemed to understand her diagnosis, the doctor could not be sure, given the language difference and the short time he had known her. a pill count of her co-trimoxazole showed that she had some pills left over. he asked machozi to describe the health care in her home village. machozi described the small basic health centre with a single nurse in the town one hour’s walk away. she described how much it cost to see the nurse and how often there were no drugs in the health centre. considering machozi’s current state of preparedness for art, the uncertainty that lay ahead when returning home, and the poor level of the local health care system, the doctor decided not to start machozi on art before leaving. instead, he advised her to try and seek out an ngo hiv programme when she returned home. he gave her a 3-month stock of cotrimoxazole tablets and reviewed again with her how to take the pills correctly. finally he wrote a letter describing her medical history and explained its contents to her. make up march 2007 30/3/07 11:28 am page 40 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e m a r c h 2 0 0 7 41 6. key documents united nations high commissioner for refugees. note on hiv/aids and the protection of refugees, idps and other persons of concern. geneva: unhcr, 2006. joint united nations programme on hiv/aids, united nations high commissioner for refugees. strategies to support the hiv-related needs of refugees and host populations. geneva: unaids best practice collection, 2005. inter-agency standing committee (iasc). guidelines for hiv/aids interventions in emergency settings. geneva: iasc reference group, 2004. united nations high commissioner for refugees. antiretroviral medication policy for refugees. unhcr, 2007. http://www.unhcr.org/hiv-aids united nations high commissioner for refugees. sexual and gender-based violence against refugees, returnees and internally displaced persons: guidelines for prevention and response. unhcr, 2003 united nations high commissioner for refugees. protracted refugee situations, standing committee 30th meeting. ec/54/sc/crp.14. geneva: unchr, 10 june 2004. world health organisation. antiretroviral therapy for hiv infection in adults and adolescents: recommendations for a public health approach. who, 2006. http://www.who.int/hiv/ pub/guidelines/artadultguidelines.pdf antiretroviral therapy of hiv infection in infants and children in resource-limited settings: towards universal access. who, 2006. http://www.who.int/hiv/pub/guidelines/whopaediatric. pdf southern african hiv clinicians society guidelines: adult and paediatric art, and pre-art guidelines. http://www.sahiv clinicianssociety.org/ 7. contacts members of guidelines committee and affiliation convenors: dr w d francois venter president, southern african hiv clinicians society director, reproductive health and hiv research unit (rhru), university of the witwatersrand johannesburg, south africa dr paul b spiegel chief, hiv, health and nutrition unit, unhcr geneva, switzerland members of expert panel: laurie bruns senior regional hiv/aids co-ordinator, unhcr pretoria, south africa prof ames dhai director, steve biko centre for bioethics, university of the witwatersrand medical school johannesburg, south africa dr gagoitsewe saleshando specialist physician, university of pennsylvania-botswana botswana hiv clinicians society gaborone, south africa dr gerard prithiviraj dental surgeon, ministry of health & social welfare general-secretary, lesotho medical association lesotho dr flavia mugala-mukungu namibia hiv clinicians society windhoek, namibia dr leslie shanks medical co-ordinator, msf operational centre amsterdam goma, drc celicia m serenata treatment liaison specialist, centers for disease control and prevention (cdc) pretoria, south africa sanja gohre medical writer, southern african hiv clinicians society johannesburg, south africa references 1. international covenant on economic, social and cultural rights, art 12, para 2 (d). 2. international covenant on economic, social and cultural rights (icescr), art 12, para 1. 3. spiegel pb. hiv/aids among conflict-affected and displaced populations: dispelling myths and taking action. disasters 2004; 28(3): 322-339. 4. unhcr/us centers for disease control and prevention/zambian ministry of health. zambia antenatal clinical sentinel surveillance report, kala and mwange refugee camps, 2005. 5. unhcr. behavioural surveillance survey among refugees and surrounding host communities, kakuma, kenya, 2004; unhcr. hiv and aids behavioural surveillance survey, marratane refugee camp, mozambique. 2005; unhcr/ great lakes initiative on hiv/aids. behavioural surveillance survey, uganda, 2006. 6. united nations high commissioner for refugees. protracted refugee situations, standing committee 30th meeting. ec/54/sc/crp.14. geneva, 10 june 2004. 7. who/unhcr. clinical management of rape survivors: developing protocols for use with refugees and internally displaced persons. revised edition, 2005; unhcr’s antiretroviral medication policy for refugees, 2007. 8. inter-agency standing committee (iasc). iasc guidelines on mental health and psychosocial support in emergency settings. geneva: iasc, 2007. 9. unhcr/who/unfpa. reproductive health in refugee situations: an interagency field manual, 1999. 10. inter-agency standing committee (iasc). guidelines for gender-based violence interventions in humanitarian settings. geneva: iasc taskforce on gender in humanitarian assistance, 2005; unhcr. sexual and gender-based violence against refugees, returnees and internally displaced persons: guidelines for prevention and response, 2003. make up march 2007 30/3/07 11:28 am page 41 c p d  q u e s t i o n s journal 34 two cpd points are awarded for the correct completion and submission of the questions below. cpd questionnaires must be completed online via www.cpdjournals.org.za. after submission you can check the answers and print your certificate. questions may be answered up to 6 months after publication of each issue. this programme is available free of charge to members of the hiv clinicians society and sama only. 1. true (a) or false (b) – click on the correct answer: acute hiv infection (ahi ) is usually defined as the time from entry of the virus into the body to completion of seroconversion. 2. true (a) or false (b) – click on the correct answer: early-stage hiv infection generally refers to the interval between seroconversion and the establishment of the viral load set point. 3. true (a) or false (b) – click on the correct answer: the magnitude of the viral set point has no influence on the prognosis of disease progression. 4. true (a) or false (b) – click on the correct answer: fortunately, rapid hiv tests are initially invariably positive because of the rapid immune response. 5. true (a) or false (b) – click on the correct answer: the classic mononucleosis-like symptoms of acute hiv-1 infection may last days to weeks. 6. true (a) or false (b) – click on the correct answer: because of the high viral burden in the blood and genital secretions in ahi, a disproportionate amount of hiv transmission may occur during this time. 7. true (a) or false (b) – click on the correct answer: the period during which treatment should be given for ahi is not clear. 8. true (a) or false (b) – click on the correct answer: the south african hiv clinicians society guidelines do not currently recommend art for ahi as there is no definite evidence supporting this therapy. 9. true (a) or false (b) – click on the correct answer: cervical cancer is one of the most common cancers in women worldwide. 10. true (a) or false (b) – click on the correct answer: after breast, colon and lung cancers, cervical cancer is the next most common cause of cancer death among women. 11. true (a) or false (b) – click on the correct answer: cervical cancer and its precursor lesions are caused by infection with the human papillomavirus (hpv). 12. true (a) or false (b) – click on the correct answer: hpv is associated with both squamous and glandular dysplasia. 13. true (a) or false (b) – click on the correct answer: a strong relationship exists between hiv and hpv, two sexually transmitted viruses. 14. true (a) or false (b) – click on the correct answer: invasive cervical cancer in hiv-positive women tends to occur 10 15 years earlier than in their hiv-negative counterparts. 15. true (a) or false (b) – click on the correct answer: primary prevention of cervical cancer includes adopting safe sex practices and hpv vaccination. 16. true (a) or false (b) – click on the correct answer: south africa and swaziland have the highest incidence rates per capita of tuberculosis (tb) in the world. 17. which one of the following is false? factors that could contribute to the tb epidemic are: a) overpopulation b) economic hardship and poor living conditions c) halitosis d) conflict and turmoil leading to displacement and migration. 18. true (a) or false (b) – click on the correct answer: in south africa, by far the biggest driver of tb is hiv. 19. true (a) or false (b) – click on the correct answer: a person’s cd4 cell count has little influence on tb risk. 20. true (a) or false (b) – click on the correct answer: a cochrane meta-analysis showed that the use of isoniazid would reduce active tb by about one-third in people with hiv. southern african hiv clinicians society application / renewal form membership fees for 2009 annual membership fees: private sector r290 / public sector r145 / associate member r115 renewal fees are valid for 12 months from date of receipt of payment. payments may be made by cheque or electronic transfer payable to: ‘southern african hiv clinicians society’, nedbank campus square, branch code: 158-105 account no: 1581 048 033. please fax proof of payment to the database manager on 086 682 2880 or post to: suite 233, postnet killarney, private bag x2600, houghton, 2041 tel: + 27 (0) 11 341 0162 e-mail: sahivsoc@sahivsoc.org. website: www.sahivsoc.org nb! please print legibly for accurate entry into the database in order to ensure receipt of services: first name: initials: surname: title: specialty: practice address postal address: city: state/province: country: postal code: hpcsa.no: tel.no fax: cell: e-mail: please tick relevant box: • do you practice in the private sector or in the public sector or both • would you like to be added to the society’s provider network for hiv patient referrals? yes no • would you like your quarterly journal, the southern african journal of hiv medicine, to be posted to you? yes: no (i will read journals on-line, on the society website: http://www.sajhivmed.org.za) • preferred method for receiving your quarterly newsletter transcript: e-mail post • name(s) of hiv training courses successfully completed:………………………………………………………………………………… . ……………………………………………………………………………………………………………………………………………………… method of payment: electronic transfer: direct deposit: post/cheque: cash: amount paid: payment date: society services: quarterly issues of southern african journal of hiv medicine quarterly newsletter transcript cpd points for: branch meetings, journal questionnaires, published submissions hiv/aids cme: courses/alumni programme as training for dip. hiv med.advocacy & day-time telephonic consultancy conference information and discounts regional and international representation specialty sub-groups local and international guidelines advocacy the durban declaration in july 2000, seventeen years after the discovery of the human immunodeficiency virus (hiv), thousands of individuals 'rom around the world gathered in durban, south africa, to attend the xlllth international aids conference. approximately 34 million people worldwide are estimated to be living with hiv or aids, 24 million of them in sub-saharan africa.' last year alone, 2.6 million people worldwide died of aids, the highest yearly death rate since the start of the epidemic. if current trends continue then southern and south-east asia, south america and regions of the former soviet union will bear a very heavy burden in the next two decades. like many other diseases (e.g. tuberculosis, malarial that cause illness and death in underprivileged and impoverished communities, aids spreads by infection. hiv-l, which is responsible for the aids pandemic, is a retrovirus closely related 10 a simian immunodeficiency virus [siv) infecting chimpanzees. hiv-2, which is prevalent in west africa and has spread to europe and india, is almost indistinguishable from an siv infecting sooty mangabey monkeys. hiv first arose as a zoonosis' an infection transmitted from animals to humans although it now spreads among humans through sexual contact from mother to infant and via contaminated blood. an animal source for a new epidemic is not peculiar to hiv. the plague came from rodents. both influenza and the new nipah virus epidemic in south-east asia reached humans via pigs, while variant creutzfeldt-jakob disease in the uk came from 'mad cows: once hiv became established in humans, it followed human habits and movements. like other viruse~ hiv recognises no social, political or geographical boundaries. the scientific evidence that aids is caused by hiv-l or hiv-2 is overwhelming." the data providing proof that hiv is the cause of aids fulfil exactly the same criteria as for other viral diseases such as polio, measles and smallpox: • all patients with aids, regardless of where they live, are infected with hiv." • most patients with hiv infection show signs of aids within 5 10 years" hiv infection is identified in blood by detecting antibodies or gene sequences. these tests are as reliable as any used for detecting other virus infections. • all children who develop aids are born to hiv-infected mothers. the higher the viral burden in the mother the greater the risk of the child becoming infected.' • persons who received hiv-infected blood developed hiv/ aids, whereas those who received umainted or screened blood did not' • in the laboratory hiv infects the exact type of white blood cell [cd4+ iymphocytes) that becomes depleted in persons with aids. drugs which block hiv replication in the test tube delay progression to aids when given to patients. treatment can greatly reduce aids mortality' • chimpanzees experimentally infected with hiv1 have developed aids. monkeys inoculated with cloned siv dna become infected and develop aids." further compelling data are available." for all these reasons it is our considered conclusion that hiv causes aids. it is therefore most unfoftunate that some people cominue 0 doubt the cause of aids. this position will cost lives. in different regions of the world hiv/aids can show altered patterns 0' spread and symptoms. in africa, for example, hivinfected persons are 11 times more likely to die within 5 years,' and over loo times more likely than uninfected persons 10 develop kaposi's sarcoma, a cancer caused by yet another virus. ll as with any other chronic infection, various co-factors play a role in determining the risk of disease. persons who are malnourished, who already suffer other infections or who are older, tend to be more susceptible to the rapid development of aids following hiv infection. however, none of these factors weaken the scientific evidence that hiv is the sole cause of aids. in his global emergency, prevemion of hiv infection must be our greatest worldwide public health priority. the knowledge and tools to prevent infection are available. the sexual spread of hiv can be slopped by monogamy, by abstinence or by using condoms. blood transmission can be prevented by screening blood products. mother-to-child transmission can be reduced by so'\b or more by short courses of antiviral drugs and other measures.'2.13 limited resources and the crushing burden of poverty in many parts of the world constitute formidable challenges to the control of hiv infection. people already infected with hiv can be helped using treatment with life-saving drugs. but their high cost puts these treatments out of reach for most people. it is crucially important to develop new antiviral drugs that are easier 10 take, have fewer side-effects and are far less expensive, 50 that millions more can benefit from them. there are many ways of communicating the crucial information on hiv/aids, and what works best in one country may not necessarily be appropriate in another. however 10 tackle the disease, everyone must firs[ understand that hiv is the enemy. research, not myths, will lead 10 the developmem of more effective and cheaper treatments, and hopefully a vaccine. there is no end in sight to the aids pandemic, but by working together to prevent hiv infection we have the power to reverse the tide of the epidemic. science will one day triumph over aids, just as it did over smallpox, and curbing the spread of hiv will be the first major step. until then, reason, solidarity, political will and courage must be our partners. referencts 1. unalds' aids epidemic update. dererbef 1999. w",,,,ul'losds.ol'~i~,.,,:asm~!!!ttl!5.html 2. harn bh, shorn gm, lk cock km, sr.arp pm. alos as a zoonosis; 'iclffitific gm pjll: c health ;rr:p' c;;ti~ soffiet 2oco, 287: 607-614 3. wriss ra, ja"'e tfn djtsoo'g. hlv a~.ci aids. notult 1990; 345: ss9-6&). 4 n.alo (19961. hlv as the cause of aids. 1nww.r;,ald./ljlgavj5potf;hrfr,i.nj/~fulo,r..hrmj s. o'bf el'l sj. goeoffi 11 hn ca;lseio aids: kod'!'s postu acts ful;eo. curropin/mr"nd 1956; 8: 61).61& 6. daroy se e(a~ f.~om wbcore"liq atttr hfif inftctjofi in ut colt.p e:e uk pooj.auon of hdetropr ac:s.. nafulf 1995; 377: 79-82 7. n~nn al, ~tal ~40r0' rtassoaatea wth hf\i-lln~on 0vt1 fi'lt ~rs:n a rural u9andan popu'atian: coroft s!uay. bm) 1997; 31 s: 767-711. 8. spertng rs, fret ma:err.aj vira' :oad, liliovulllnf treatment, ar!! thf risil. 0" trat\sffljssion of r<!r":ilfl iml"1urooefiofrey virus typf i from mother to ,nfant n fngl j med 199£; ]35: 1678-1680. 9. centres for o,sme cor1o"01 and ?re'lention [coe!. hr.j!a1ds sumi1lance report 1999; 11: 1-44. 10. liska v, ~r al. viremla ana aids in rhesus macaque!; after intramuscu~ar inoculation of plasmid dna encoding fuii·length sn mac 239. aids re-s hum retroviruse; 1999; 15: 44s· 450. 11. s tas f, eral antiqodes aga:nsr human herpes virus bin b'ac( south african pauents with can~r. n&g/j med 1999; 340: 1863-1871. 12 sha~~r n. et al 51'0f{ ro<!rs~ zidovl.d'ne for perirataj hn·i transmission in bargkok tnaland, a rarcorr: lee comrol ed trial lanetr 1999; 35]: 773-780_ 13. guay la, e, al inrratlaf:jm iira near;;:;;] sorgc-{lose i'f'jir.;p ne compared w;m le!", jd re "or pr~tian 0" mother-:o-cn ,a trars!"' ssion 0" rn-in k<:"'p'o-a, ugaraa hn\et 012 rarlla~'sed :rill lancet 19'?3: 3)4, 79s-802. untitled the mood of clinicians working in the field of hiv medicine has been heartened by reports in the press of recent statements by both the deputy president and deputy minister of health. both of these eminent individuals have advocated increased access to antiretroviral drugs and a speeding up of the antiretroviral roll-out programme. the national strategic plan for 2007 2011 is eagerly awaited, as this document will spell out the detail of how this will be achieved. one model is to decentralise hiv/aids care to remove the load from overburdened central facilities. the article by nathan ford et al. outlines the lusikisiki model of decentralised hiv care. attention should be paid to this type of initiative and satellite peripheral centres of excellence need to be established throughout rural south africa. the initiative of the society to forge closer links with the rural doctors association of south africa (rudasa) will go a long way in facilitating the establishment and support of such centres. new drugs are eagerly awaited in south africa in the fight against hiv. the tardiness of the medicines control council (mcc) in registering such drugs, e.g. tenofovir, is disappointing. it is hoped that the registration of this drug will take place soon and that it will be available to the committee advising the national strategic plan so that we may have less toxic regimens. the expertise of the clinicians society has been offered to the mcc to facilitate expert opinion regarding registration of new drugs. the editor and staff of the journal would like to wish all our readers the best wishes during the season of goodwill and every good wish for the year 2007. des martin editor from the editor hiv march make up 01 march 2006 the southern african journal of hiv medicine16 gate-keeping by medical researcher/practitioners: a case study the wider cape town metropolitan area is home to several antiretroviral treatment and vaccine initiatives funded by ngos and pharmaceutical companies. all of these entail collaboration with the western cape government (which has de jure ownership of the clinics). most of the projects have strong links with university-based medical researchers, some of whom also offer medical or related support services to the projects. many hiv clinicians are thus simultaneously medical practitioners and researchers. in this world of overlap between service provision and research interests, patients on antiretroviral treatment are both beneficiaries and research subjects. they enter a world entirely controlled by medical practitioner/researchers. although the clinics are technically under the control of the government, decision-making power in effect is ceded to the largely foreign-funded doctors and researchers who run the interventions. they decide who can be on the premises, what research is ‘acceptable’, and who can interview the patients. this gatekeeper role has serious implications for social scientists trying to conduct research – as one of my phd students discovered to her cost. the student, a trained and registered clinical psychologist, wanted to conduct research into the psychological well-being and coping strategies of low socio-economic status mothers on antiretroviral treatment. her research entailed recruiting 75 hiv-positive mothers and interviewing them when they started treatment, and then again after 4, 12 and 24 weeks. a sample of 75 hiv-negative mothers from the community was to be recruited as the comparison group. the aim of the research was to explore the challenges to women’s care-giving and psychological well-being posed by negotiating the multiple roles of living with hiv, caring for young children and dealing with the general stressors associated with poverty. she was particularly interested in drawing out the implications of these multiple roles for women’s adherence to antiretroviral therapy. in addition to interviewing the women, the student stated her intention to ask the participants for permission to access their medical files so that she could collect data on cd4 counts, viral loads, clinical staging and adherence information. she stressed that this information would only be collected at the convenience of the clinic. in her research protocol, she acknowledged that she would need the help of clinic staff in accessing the files, but argued that this cost was small in relation to the benefits of her study. she pointed out that she and her researchers are clinically trained (and registered with d e b a t e when hiv clinicians prevent social scientists from accessing ‘their’ patients: some ethical concerns nicoli nattrass aids and society research unit, centre for social science research, university of cape town there is an understandable tension between medical researchers and social scientists when it comes to aids-related research at clinic level. clinics offering antiretroviral treatment exist primarily to assist patients – but many of them also provide ‘data’ for medical researchers. this may involve a randomised controlled trial, or simply the collection of data on adherence. a social scientist wishing to access patients to conduct interviews or focus groups thus (inevitably) appears to the hiv clinician as at best a disruption to an already over-stretched operation, and at worst a potentially confounding factor in his or her own research. given that the medical practitioner/researchers effectively control the clinics, the temptation to deny social scientists access to patients must be strong. as discussed below, this was the case with regard to two cape town clinics that prevented a clinical psychologist (working in my research unit) from conducting social science research. although understandable, such unaccountable exercise of power denies patients the opportunity to participate in other research projects that may be of benefit to them (or society) in ways that hiv clinicians do not necessarily appreciate. as such, it violates the principle of informed consent. it is also problematic in that it restricts the aids research agenda to biomedical concerns. this is particularly worrying with regard to aids, where it is widely accepted (by social scientists and hiv clinicians alike) that social and psychological factors matter a great deal for hiv prevention and treatment interventions. the southern african journal of hiv medicine mrrch 2006 1 7 the health professions and social work councils) and thus in a position to provide useful feedback to the clinic on patients who were deemed to be at risk for poor adherence owing to their mental health and social difficulties. she also pointed out that some of the empirical indicators being developed in her study could potentially become useful tools for the counsellors associated with the treatment programme to use in the future should they wish to assess the extent to which a patient's psychological well-being places them at risk for poor adherence: ‘more broadly, the research aims to make recommendations about the kinds of psychosocial services which can enhance women patients’ quality of life and psychological well-being, as well as enhancing their adherence to treatment’ (student research protocol). the student approached a clinic in a local african township for permission to invite potential respondents to participate in her study. the medical practitioner/researchers associated with the antiretroviral treatment project at the clinic considered her request – but rejected it. as can be seen from the three reasons listed below, the fact that the research and treatment intervention was funded in part through a large pharmaceutical company seemed to pose particular problems. 1. ‘the population is over-researched and your study is not the primary focus of the research’ (‘the research’ referring, of course, to the research already being conducted by the medical doctors/researchers linked to the clinic); 2. ‘none of the (pharmaceutical company ) exco members are senior authors of the project’ (i.e. the student’s doctoral project); and 3. ‘it has not been approved by the same ethics committee as the other (pharmaceutical company ) projects’ (written response to the student). the student was then referred to another clinic in a different african township, but was again turned down by the gatekeeper committee of medical practitioner/researchers. this time she was turned down principally because: 1. there were insufficient ‘direct and tangible benefits to the clinic patients’; 2. they were concerned about the ‘amount of time’ respondents would have to spend on the study; and 3. they did not ‘feel that the research addresses the needs which they have as a clinic at this point in time, and only want to permit research which does so’ (response to the student). the student responded to the main research gatekeeper of this clinic by reiterating that her research could be of potential direct and immediate benefit to the counsellors who work with people on antiretroviral treatment as well as to the patients themselves: ‘depending on the clinic’s need, feedback from the research could either be restricted to liaising with the counselling team, or direct input could also be given to the other members of the clinic team if relevant and useful. whichever approach minimises the negative impact of our presence on the running of the service, while maximising the support and benefits, is desirable for me’ (response by the student). she never got a reply to this correspondence. she made several phone calls (all to no effect) and eventually gave up. fortunately, a local clinic run by absolute return for kids (ark) came to the rescue and let her conduct her research there. the fact that it was not linked to either a pharmaceutical company or a major research project no doubt helped … this story of her rejection by the first two clinics is interesting in several respects. firstly, with regard to both clinics she approached, the medical practitioner/researchers prioritised their own research interests and used their effective control over the clinic to prevent other research from taking place. the blocking of research by the first clinic on the grounds that only research linked to the pharmaceutical company that was funding it would be acceptable was breath-taking in its blatant self-interest. secondly, it is clear from the reasons provided by the second clinic that non-medical interventions were not regarded as potentially being of value to the patient. this reflects an uncritical adoption of a strictly biomedical notion of health promotion which is particularly worrying given the obvious social and psychological determinants of adherence to antiretroviral therapy. it also demonstrates a lack of understanding that even when the ‘benefits’ of social science research for a particular individual patient are not obvious, the research may nevertheless inform the development of relevant future social policies. a narrow application of the requirement that the research ‘benefits’ the research subject is therefore necessarily always going to be biased against the social scientist. thirdly, the story demonstrates a paternalistic approach on the part of medical practitioner/researchers to who is in the best position to judge whether a project is, or is not, in the best interests of the patient. this, in my view, runs counter to the spirit of the principle of informed consent. although the principle of informed consent was designed to ensure that prospective research subjects have the right to refuse to participate, it surely also protects these same subjects from others deciding on their behalf that it is not in their best interests to participate. the principle should surely be that research subjects have the right to decide whether they want – or do not want – to participate. in my experience of conducting surveys and qualitative in-depth interviews, research subjects often enjoy being interviewed and having the opportunity to discuss matters of concern to them (see also pahl1). this is, of course, not true for all participants. some get irritated by the research process, but they can always refuse to participate at any point (as is typically – if not always – pointed out in consent forms). ultimately, it must be up to the potential research participant to decide whether the risks (which, in social science research, typically entail little more than the opportunity cost of the time taken up by the interview) outweigh the benefits. medical 18 practitioner/researchers are not in an appropriately informed position to make the judgement call. some ethical concerns most research ethics codes are silent on the issue of ensuring that potential research subjects have the right to choose whether they do or do not want to participate in research. the european group on ethics in science and new technologies2 and the nuffield council on bioethics (uk)3 note that in some local contexts, it may be appropriate to obtain familyor community-level agreement before approaching research subjects (see discussion in ncob,4 p. 73). however, this is a concession to local culture – it cannot be used to justify giving medical practitioner/researchers the right to make decisions on the behalf of their patients, especially in cases where these same medical practitioner/researchers are not disinterested observers. before 1947, when the nuremburg code of ethics for medical research highlighted the need for informed consent,5 the prevailing ‘hippocratic’ approach assumed that medical researchers and doctors were the only agents capable of making appropriate judgements about medical research.6 refusing to allow patients on antiretroviral therapy the opportunity to make their own decision as to whether they wish to participate in a psychological study or not amounts to a reversion to this old paternalistic approach. some attention has been paid to the problem of ‘dual loyalty’ – i.e. when a clinician experiences a role conflict between their professional duties to a patient and the obligations, expressed or implied, real or perceived, to the interests of a third party (see physicians for human rights and university of cape town health sciences faculty7). however, as singh points out,8 this problem has yet to be applied to dual loyalty in medical research – especially when the roles of clinician and researcher merge: ‘in the practice-research context this translates to the physician-researcher’s primary interest (duty of care towards the patient-subject) being undermined by secondary factors (such as loyalty to the study/sponsor)’ (p. 395). furthermore, clinicians may deny social scientists access to ‘their’ patients not because they are worried about the adverse implications of the social science research for the patients, but because they do not want any other research (besides their own) being conducted on the patients. disciplinary differences like this would not matter except for the fact that medical practitioner/researchers are in a powerful position to dictate the research agenda largely because they have access to extraordinarily large budgets to treat and research their patients. in a very real sense, these medical practitioner/researchers do indeed control ‘their’ patients/research subjects – and as discussed above, they can use this power and deny others research access to them. with about a fifth of the adult population hiv-positive, and given the government’s reluctance to roll out antiretroviral therapy with any sense of urgency, there is substantial pressure (both in terms of resources and emotional energies) on hiv clinicians. their irritation with social science research is therefore in some way understandable. however, as the aids crisis is both a social and health crisis, and given that social scientists are often better placed than medical practitioners to understand the social and behavioural context governing individual adherence to antiretroviral therapy, the effective control of medical practitioner/researchers over access to research subjects is highly problematic. there needs to be a more tolerant and constructive attitude towards social science research on the part of hiv clinicians who control access to patients on antiretroviral therapy. references 1. pahl j. ethics review in social care research. paper presented at the emerging ethical issues in social science and cross-cultural research, university of sussex, brighton, may 2005. 2. european group on ethics in science and new technologies (ege). opinion nr 17 on the ethical aspects of clinical research in developing countries. 2003. available on http://europa.eu.int/comm./european_group_ethics/docs/ avis17_ en.pdf. 3. nuffield council on bioethics (ncob). the ethics of research related to healthcare in developing countries. april 2002. available on http://www. nuffieldbioethics.org/developingcountries. 4. nuffield council on bioethics (ncob). the ethics of research related to healthcare in developing countries: a follow-up discussion paper based on a workshop held in cape town, south africa, 12 14 february, 2004. 2005. nuffield council on bioethics, london. see also http://www.nuffieldbioethics. org. 5. hoeyer k, dahlager l, lynoe n. conflicting notions of research ethics: the mutually challenging traditions of social scientists and medical researchers. soc sci med (in press). 6. alderson p. ethical codes in social science and medicine. paper presented at the emerging ethical issues in social science and cross-cultural research, university of sussex, brighton, may 2005. 7. physicians for human rights and university of cape town health sciences faculty. dual loyalty and human rights in health professional practice: proposed guidelines and institutional standards. 2003. available on http://www. phrusa.org/healthrights/dual_loyalty.html. 8. singh j. the impact on ethics. in: karim s, karim q, eds. hiv/aids in south africa. cape town: cambridge university press, 2005: 384-404. march 2006 the southern african journal of hiv medicine erratum there was an error in the article entitled ‘staging of hiv disease in children – towards pragmatism?’, which appeared in the november 2005 issue of the journal (issue 21). in table ii (p. 16), hepatosplenomegaly should have been listed as a stage 2 and not a stage 1 event. hiv 972 case report native valve endocarditis due to candida parapsilosis in an adult patient k moodley, mb chb, fcpath (micro); c n govind, mb chb, fcpath (micro); a k c peer, msc, mb chb, mmed (micro); s dawood, mb chb, fcp (sa); m h hassim, mb chb, fcp (sa); j deonarain, mb chb, fcpath (anat) lancet laboratories, kwazulu-natal, south africa corresponding author: k moodley (krishnee.moodley@lancet.co.za) candida endocarditis is rare, but associated with a high mortality. the most common species implicated is candida albicans. the epidemiology of invasive candida infections is changing, with a predominance of non-albicans species causing invasive disease. we describe a case of candida parapsilosis endocarditis in an hiv-positive patient with pre-existing mitral valve disease and renal failure on haemodialysis. the patient presented with fever and malaise. clinical examination revealed pulmonary oedema and severe mitral regurgitation. blood cultures were positive for c. parapsilosis. β-d-glucan assay levels were elevated. an echocardiogram showed large, friable vegetations on the mitral valve. c. parapsilosis was cultured from the haemodialysis tip and the vegetations. the patient responded well to mitral valve replacement and antifungal therapy. a high index of suspicion and aggressive diagnostic modalities and therapy are essential in patients with candidaemia, to decrease mortality due to this condition. s afr j hiv med 2013;14(3):138-140. doi:10.7196/sajhivmed.972 fungal endocarditis accounts for 2 4% of all endocarditis cases. of these cases, 25% are attributed to candida albicans, other candida species account for 25%, and aspergillus species and other fungi account for the remainder.1-3 predisposing factors for candida parapsilosis endocarditis include prosthetic valves, intravenous (iv) drug use, parenteral nutrition, abdominal surgery, immunosuppression, treatment with broad-spectrum antibiotics and pre-existing valvular disease.4 mortality for candida endocarditis is high (67%), with a lower mortality in younger patients with a history of iv drug use.5 we present a case of native valve c. parapsilosis endocarditis, which to our knowledge, is the first reported case in south africa. case presentation a 46-year-old hiv-positive man with a history of hyper­tension and renal failure presented with fever and malaise. the patient was receiving antiretroviral therapy (art) and haemodialysis. clinical examination of the patient revealed fever, pulmonary oedema and severe mitral regurgitation. blood cultures, β-d-glucan assays and a full blood count were undertaken. the patient remained febrile after 48 hours and antifungal therapy was commenced. laboratory findings upon admission, white blood cell and cd4+ counts were 11.37 x 109 cells/l and 435 cells/µl, respectively. the hiv viral load on admission was undetectable, as it had been for the previous 6 months. blood cultures were positive for c. parapsilosis, which was susceptible to all antifungals tested (amphotericin b, fluconazole, voriconazole and caspofungin). fungal identification and susceptibility testing were performed using the vitek 2 (biomerieux, france) automated system. the patient was treated with iv fluconazole in view of the impaired renal function and susceptibility of the isolate to this agent. blood cultures taken 48 hours after commencing fluconazole were positive. the haemodialysis catheter was removed and replaced. culture of the catheter tip revealed c. parapsilosis with susceptibilities corresponding to the blood culture isolate. β-d-glucan assay results were elevated (>523 pg/ml) on the day of the initial blood culture. the patient was referred for cardiology assessment. the echocardiographic examination demonstrated large, friable mitral valve vegetations, in keeping with fungal infective endocarditis (fig. 1). fig. 1. echocardiogram showing the size and position of the vegetation. the patient underwent mitral valve resection and tissue was submitted for microbiological and histological evaluation. the tissue culture isolate corresponded to the admission blood culture and catheter tip culture findings. histological evaluation showed fibrotic, hyalinised heart valve, with stromal neovascularisation, suggesting a pre-existing chronic valvulitis (fig. 2a). friable surface vegetations composed of fibrin, degenerating neutrophils and numerous fungal yeast forms were noted (fig. 2b). blood cultures performed 2 weeks after surgery were negative. repeat β-d-glucan assays remained elevated 4 weeks after therapy. the patient was re-evaluated, but remained clinically stable. treatment doses of fluconazole were discontinued after 6 weeks, and oral suppressive fluconazole therapy was continued. two months following diagnosis, the patient remains clinically stable, and continues haemodialysis, fluconazole suppressive therapy and art. fig. 2. histological examination of the infected mitral valve with vegetations showing pre-existing fibrosis and infected vegetation. discussion this report presents an uncommon disease in a patient with several predisposing factors: renal failure, in situ iv catheter, admission broad-spectrum antimicrobial agents, pre-existing valvular heart disease and hiv infection. a catheter-related portal of entry has been reported in 80% of cases of c. parapsilosis endocarditis in one series of candida endocarditis cases.5 other described risk factors include abdominal surgery, iv drug use and prosthetic heart valves. candidiasis is the most common opportunistic infection in hiv-positive patients with cd4+ counts <200 cells/µl. the most prevalent presentation is mucocutaneous candidiasis, although invasive candidiasis has been reported.6 highly active antiretroviral therapy (haart) has been shown to decrease the rate of candidiasis in this population.7 although this patient was hiv-positive, his disease state was controlled on art at the time of diagnosis. thus, the propensity for c. parapsilosis to adhere and form biofilms, together with the indwelling haemodialysis catheter, broad-spectrum antimicrobials on admission and chronic valvular disease, were more significant in the pathogenesis of endocarditis in this case. the epidemiology of invasive candida infection has changed. improvements in medical therapy have resulted in increased survival of critically ill patients who are exposed to longer durations of broad-spectrum antimicrobial therapy. the incidence of non-albicans candidaemia has also increased, in some situations accounting for a higher percentage of isolates compared with c . albicans candidaemias. 8 this change is reflected in our local setting as well, where surveillance data from 2009 to 2012 from selected sites in sa were analysed. the data showed a predominance of non-albicans candidaemia in 4/6 sites, with c. parapsilosis being the most common non-albicans species (unpublished data, dr n govender, national institute of communicable diseases, south africa, 2012). this suggests a higher propensity for invasive disease, such as fungal endocarditis, to be caused by this species. the clinical presentation of candida endocarditis is non-specific. fever and cardiac failure may be absent and embolic phenomena may be the presenting feature.5 most patients have a risk factor for invasive candidiasis. documented predisposing factors in c. parapsilosis endocarditis present in this patient included in situ haemodialysis catheter, probable pre-existing chronic valve disease, admission broad-spectrum antibiotics, and immunosuppression mediated by hiv and renal failure. the aortic valve is most commonly affected.4 mitral valve involvement in this instance was likely due to pre-existing chronic valve disease. due to the non-specific clinical features, correct diagnosis requires a high index of suspicion in patients with known risk factors. persistant candidaemia, as in this case, should prompt further clinical evaluation, as well as early transoesophageal echocardiography, as recommended by the european society clinical microbiology and infectious diseases guidelines for non-neutropenic adult patients with candidaemia.9 the value of the β-d-glucan assay in diagnosis of invasive candidiasis has been reviewed.5 the assay measures components of the fungal cell wall present in the bloodstream. this assay may be positive before the traditional culture results are available. it has a high sensitivity (77%) and specificity (83%).10 the β-d-glucan assay levels were found to be significantly higher in patients infected with c. parapsilosis, candida tropicalis and candida guilliermondii endocarditis, than with c. albicans endocarditis.5 there are no formal recommendations regarding the use of this assay as a diagnostic tool; however, the β-d-glucan assay has a role in negating a diagnosis with a high negative predictive value and supporting a positive diagnosis where other clinical and laboratory features are in keeping with a fungal endocarditis.3 , 9 interestingly, the β-d-glucan assay remained elevated after commencement of treatment and following negative follow-up blood cultures. this has been described previously, where elevated levels during the early phase of the disease do not always return to baseline during the early stages of antifungal therapy.5 , 10 this assay is also positive in patients with pneumocystis jiroveci pneumonia. thus, a positive assay must be interpreted with caution and correlated with the clinical picture in immunocompromised patients. this patient did not have any clinical features supporting a diagnosis of p. jiroveci infection. β-d-glucan assay levels may be elevated falsely in patients on haemodialysis where cellulose membranes have been utilised.11 , 12 this patient’s dialysis was performed using synthetic polysulfone membranes, which do not significantly elevate the assay.12 treatment of fungal endocarditis includes medical or surgical interventions or a combination thereof. although combined medical and surgical therapy has decreased the mortality of patients with candida endocarditis, the mortality remains high.1 recommended first-line therapy includes early surgery plus liposomal amphotericin b or an echinocandin.3 , 13 the source of c. parapsilosis in this patient was most likely the haemodialysis catheter. in patients with candidaemia, early removal of the catheter is recommended; however, this is not always possible. these situations require therapy with either amphotericin b or an echinocandin.9 individual case reports have shown successful medical treatment of candida endocarditis using the echinocandins without surgical intervention;14-16 however, there is insufficient experience with these agents to make a recommendation for medical management alone. the use of fluconazole in this patient was initially empirical and subsequently based on antimicrobial susceptibility results. early aggressive surgical therapy combined with medical treatment resulted in a positive outcome. long-term oral fluconazole therapy may be continued following iv therapy; however, the duration of suppressive therapy is not clearly defined, with some patients remaining on lifelong therapy.3 , 16 conclusion we describe a case of c. parapsilosis endocarditis in a patient with significant risk factors. the changing epidemiology of invasive fungal disease indicates that invasive disease due to this species may be more frequent. a high index of suspicion as well as aggressive diagnostic modalities and therapy are essential to decrease mortality due to this condition. the persistence of elevated β-d-glucan levels in the presence of negative blood cultures suggests that this test is not reliable as a marker for response to therapy. although individual case reports suggest that the echinocandins offer promise as sole medical therapy, if surgery is not possible, then further evidence is required before this modality of therapy is pursued. acknowledgement. this article was approved for submission by the institutional review board for lancet laboratories, the lancet publications committee (lpc). references 1. mandell gl. principles and practice of infectious diseases. in: mandell gl, bennett je, dolin r, eds. principles and practice of infectious diseases. usa: churchill livingstone elsevier, 2010:1081-1087. 1. mandell gl. principles and practice of infectious diseases. in: mandell gl, bennett je, dolin r, eds. principles and practice of infectious diseases. usa: churchill livingstone elsevier, 2010:1081-1087. 2. baddley jw, benjamin dk, patel m, et al., candida infective endocarditis. eur j clin microbiol infect dis 2008;27(7):519-529. [http://dx.doi.org/10.1007/s10096-008-0466-x] 2. baddley jw, benjamin dk, patel m, et al., candida infective endocarditis. eur j clin microbiol infect dis 2008;27(7):519-529. [http://dx.doi.org/10.1007/s10096-008-0466-x] 3. gould fk, denning dw, elliott tsj, et al. guidelines for the diagnosis and antibiotic treatment of endocarditis in adults: a report of the working party of the british society for antimicrobial chemotherapy. j antimicrob chemother 2012;67(2):269-289. [http://dx.doi.org/10.1093/jac/dkr450] 3. gould fk, denning dw, elliott tsj, et al. guidelines for the diagnosis and antibiotic treatment of endocarditis in adults: a report of the working party of the british society for antimicrobial chemotherapy. j antimicrob chemother 2012;67(2):269-289. [http://dx.doi.org/10.1093/jac/dkr450] 4. garzoni c, nobre va, garbino j. candida parapsilosis endocarditis: a comparative review of the literature. eur j clin microbiol infect dis 2007;26(12):915-926. 4. garzoni c, nobre va, garbino j. candida parapsilosis endocarditis: a comparative review of the literature. eur j clin microbiol infect dis 2007;26(12):915-926. 5. lefort a, chartier l, sendid b, et al. diagnosis, management and outcome of candida endocarditis. clin microbiol infect 2012;18(4):e99-e109. [http://dx.doi.org/10.1111/j.1469-0691.2012.03764.x] 5. lefort a, chartier l, sendid b, et al. diagnosis, management and outcome of candida endocarditis. clin microbiol infect 2012;18(4):e99-e109. [http://dx.doi.org/10.1111/j.1469-0691.2012.03764.x] 6. anwar kp, malik a, subhan kh. profile of candidiasis in hiv infected patients. iran j microbiol 2012;4(4): 204-209. 6. anwar kp, malik a, subhan kh. profile of candidiasis in hiv infected patients. iran j microbiol 2012;4(4): 204-209. 7. alvaro-meca a, jensen j, micheloud d, et al., rate of candidiasis among hiv-infected children in spain in the era of highly active antiretroviral therapy (1997-2008). bmc infect dis 2013;13:115. [http://dx.doi.org/10.1186/1471-2334-13-115] 7. alvaro-meca a, jensen j, micheloud d, et al., rate of candidiasis among hiv-infected children in spain in the era of highly active antiretroviral therapy (1997-2008). bmc infect dis 2013;13:115. [http://dx.doi.org/10.1186/1471-2334-13-115] 8. horn dl, neofytos d, anaissie ej, et al. epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry. clin infect dis 2009;48(12):1695-1703. [http://dx.doi.org/10.1086/599039] 8. horn dl, neofytos d, anaissie ej, et al. epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry. clin infect dis 2009;48(12):1695-1703. [http://dx.doi.org/10.1086/599039] 9. cornely oa, bassetti m, cornely oa, et al. escmid* guideline for the diagnosis and management of candida diseases 2012: non-neutropenic adult patients. clin microbiol infect 2012;18(suppl 7):19-37. [http://dx.doi.org/10.1111/1469-0691.12039] 9. cornely oa, bassetti m, cornely oa, et al. escmid* guideline for the diagnosis and management of candida diseases 2012: non-neutropenic adult patients. clin microbiol infect 2012;18(suppl 7):19-37. [http://dx.doi.org/10.1111/1469-0691.12039] 10. mikulska m, furfaro e, del bono v, et al. persistence of a positive (1,3)-beta-d-glucan test after clearance of candidemia in hematopoietic stem cell transplant recipients. clin vaccine immunol 2011;18(3):518-519. [http://dx.doi.org/10.1128/cvi.00513-10] 10. mikulska m, furfaro e, del bono v, et al. persistence of a positive (1,3)-beta-d-glucan test after clearance of candidemia in hematopoietic stem cell transplant recipients. clin vaccine immunol 2011;18(3):518-519. [http://dx.doi.org/10.1128/cvi.00513-10] 11. kanda h, kubo k, hamasaki k, et al. influence of various hemodialysis membranes on the plasma (1,3)-beta-d-glucan level. kidney int 2001;60(1):319-323. 11. kanda h, kubo k, hamasaki k, et al. influence of various hemodialysis membranes on the plasma (1,3)-beta-d-glucan level. kidney int 2001;60(1):319-323. 12. kato a, takita t, furuhashi m, et al. elevation of blood (1-->3)-beta-d-glucan concentrations in hemodialysis patients. nephron 2001;89(1):15-19. 12. kato a, takita t, furuhashi m, et al. elevation of blood (1-->3)-beta-d-glucan concentrations in hemodialysis patients. nephron 2001;89(1):15-19. 13. pappas pg, kauffman ca, andes d, et al. clinical practice guidelines for the management of candidiasis: 2009 update by the infectious diseases society of america. clin infect dis 2009;48(5):503-535. [http://dx.doi.org/10.1086/596757] 13. pappas pg, kauffman ca, andes d, et al. clinical practice guidelines for the management of candidiasis: 2009 update by the infectious diseases society of america. clin infect dis 2009;48(5):503-535. [http://dx.doi.org/10.1086/596757] 14. bacak v, biocina b, starcevic b, et al. candida albicans endocarditis treatment with caspofungin in an hiv-infected patient case report and review of literature. j infect 2006;53(1):e11-e14. 14. bacak v, biocina b, starcevic b, et al. candida albicans endocarditis treatment with caspofungin in an hiv-infected patient case report and review of literature. j infect 2006;53(1):e11-e14. 15. rajendram r, alp nj, mitchell ar, et al. candida prosthetic valve endocarditis cured by caspofungin therapy without valve replacement. clin infect dis 2005;40(9):e72-e74. 15. rajendram r, alp nj, mitchell ar, et al. candida prosthetic valve endocarditis cured by caspofungin therapy without valve replacement. clin infect dis 2005;40(9):e72-e74. 16. talarmin jp, boutoille d, tattevin p, et al. candida endocarditis: role of new antifungal agents. mycoses 2009;52(1):60-66. [http://dx.doi.org/10.1111/j.1439-0507.2008.01533.x] 16. talarmin jp, boutoille d, tattevin p, et al. candida endocarditis: role of new antifungal agents. mycoses 2009;52(1):60-66. [http://dx.doi.org/10.1111/j.1439-0507.2008.01533.x] hiv march make up 01 5 the editorial staff of the southern african journal of hiv medicine would like to take this opportunity to congratulate dr francois venter on his election as president of the southern african hiv clinicians society. i am sure that under francois’ vigorous leadership the society will continue to expand and become even more significant in the field of hiv medicine on our continent. francois is an experienced clinician in the field and is currently working in the public sector. he thus provides a bridge between the public sector and the private sector and would be an important catalyst in developing and promoting public-private sector partnerships. this issue of the journal provides clinicians with two important guidelines in the field of antiretroviral (arv) therapies, namely the issue of nucleoside reverse transcriptase inhibitor (nrti)associated lactic acidosis and arv drug resistance. ironically the former is associated in most instances with our extremely adherent patients and the latter with our least adherent patients. stavudine, which at the present time is included as a first-line drug in most regimens in the developing world, is included for very good reasons: it is effective, inexpensive and easy to take. regrettably, however, it has been linked to a number of conditions associated with mitochondrial toxicities, lipoatrophy, peripheral neuropathy and lactic acidosis to name but a few. the time has come when this drug needs to be replaced in regimens in the developing world. we eagerly await the registration of tenofovir in south africa, which will go a long way towards alleviating the distressing side-effects of stavudine. until this happens clinicians need to have a heightened awareness of lactic acidosis and institute appropriate laboratory monitoring and prompt management in order to avoid the not insignificant morbidity and mortality associated with the condition. resistance of hiv to arv therapies is an issue in both the developed and developing world. the difference between these situations, however, is that in the developed world there are many more options with regard to both testing and sequencing of therapy. in the developing world, where options for drug therapies are limited, the clinicians’ guide published in this issue will provide immeasurable support for the treating doctor. des martin editor from the editor on behalf of the newly elected executive, i would like to extend my thanks to the 10 500 members of the southern african hiv clinicians society for all your support. we are going to need it, as the challenges posed by the epidemic appear to be getting greater with each passing year. as part of an overall review, the new executive will be taking an intensive look at our activities in the light of expanded access to care across the southern african region. new branches are cropping up across the region, and a major role for the society is maintaining our massive database so that, no matter where our members are, effective communication is possible to ensure that those on the ground have the information they need to do the best job possible. in terms of immediate activities, we will be revamping the journal and transcript, our major method of communication. the previous president, professor des martin, will remain as the journal’s editor and ms penny penhall will continue editing transcript, with more scope to stimulate debate and controversy! the website will also be changing, and will be freely accessible to all in future, led by dr steve andrews. professor gary maartens will be co-ordinating the colleges of medicine’s highly successful hiv management diploma, and the society will be encouraging as many of you to write it as possible. the society’s extremely successful collaboration with the foundation for professional development is set to continue – thousands of health care workers have been trained through their courses, and the society will continue to ensure the quality of this course and its relevance to the southern african context. dr david spencer will be leading the society’s advocacy wing, strengthening our ties with civil society. other responsibilities will be allocated as needed. i welcome any suggestions going forward, and will be calling on members to assist us where possible. finally, much thanks to the previous executive, as well as penny penhall, the society’s manager, pat solan, responsible for the database, and jean solan, who manages our finances, for making this one of the biggest medical organisations in the world. i look forward to meeting many of you through branch meetings and events and i hope we are able to do great things in 2006. francois venter president message from the executive the southern african journal of hiv medicine march 2006 article information authors: aurélie nelson1 jean maritz2 janet giddy3 lisa frigati4 helena rabie4 gilles van cutsem5,6 tabitha mutseyekwa1 nomfusi jange1 jonathan bernheimer1 mark cotton4 vivian cox1 affiliations: 1médecins sans frontières, khayelitsha, cape town, south africa 2department of medical virology, national health laboratory service, university of stellenbosch, tygerberg campus, south africa 3western cape department of health, khayelitsha and eastern substructure, cape town, south africa 4department of paediatrics and child health, university of stellenbosch, tygerberg campus, south africa 5médecins sans frontières, cape town, south africa 6centre for infectious disease epidemiology and research, university of cape town, south africa correspondence to: aurelie nelson email: aurelie.nelson@gmail.com postal address: po box 27401, rhine road 8050, south africa dates: received: 23 feb. 2015 accepted: 17 mar. 2015 published: 28 apr. 2015 how to cite this article: nelson a, maritz j, giddy j, et al. hiv testing and antiretroviral therapy initiation at birth: views from a primary care setting in khayelitsha. s afr j hiv med. 2015;16(1), art. #376, 4 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.376 copyright notice: © 2015. the authors. licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. hiv testing and antiretroviral therapy initiation at birth: views from a primary care setting in khayelitsha in this forum... open access • background • cases of positive hiv polymerase chain reaction: lessons learnt    • case 1    • case 2    • case 3 • conclusion • acknowledgements    • competing interests    • authors’ contributions • references background top ↑ despite 95% coverage via the prevention-of-mother-to-child-transmission (pmtct) programme, 14 000 children in south africa became hiv-infected in 2012.1 there are many reasons for this gap in pmtct efforts. late maternal diagnosis of hiv, late antenatal antiretroviral therapy (art) initiation, seroconversion in pregnancy, and inadequate adherence to art during gestation singly and collectively increase the risk of transmission. early initiation of art in the first few weeks of life significantly reduces the hiv-associated morbidity and mortality in hiv-infected infants, compared with deferred initiation2,3 and may reduce the latent hiv-1 reservoir in children.4 furthermore, a recent south african study documents that 76% of babies who would have tested hiv positive via polymerase chain reaction (pcr) by 6 weeks could have been diagnosed at birth.5 therefore, the western cape province (wcp) department of health adopted new guidelines6 in june 2014 (and the south african department of health in december 20147) to test ‘high-risk’ infants at birth. infants testing pcr-positive are started on art as soon as possible. in march 2014, médecins sans frontières, in collaboration with the university of stellenbosch, started a pilot project in a community healthcare centre in khayelitsha to establish the impact of very early infant diagnosis on art initiation and to establish the feasibility of implementation in a primary care setting. to establish routine testing of high-risk hiv-exposed infants at the primary care level, the following steps were taken: training and mentorship of healthcare staff at the healthcare centre (midwives, nurses, doctors, counsellors) on the new guideline recommendations; the identification and management of high-risk infants; and the clinical management of art initiation in a newborn routine counselling and consent from mothers for birth pcr testing initiation of nevirapine (nvp) and zidovudine (azt) post-exposure prophylaxis on day one in high-risk infants pcr and confirmatory viral load testing via the routine courier system to the referring national health laboratory service (nhls) laboratory, with results available within 48 hours counselling all mothers regarding the pcr results at 48 hours of life, when the mother and infant return to the health centre for routine post natal care: if the pcr result is negative, the mother is advised of the necessity to keep the infant in care for repeat hiv testing as per wcp guidelines as well as to continue post-exposure prophylaxis if the infant is hiv positive, the nurse caring for the mother/infant pair provides standardised art initiation counselling and ensures the infant is seen by a medical officer the same day initiation of art on the same day as diagnosis for clinically well infants, according to interim infant art treatment guidelines developed in consultation with infectious disease paediatricians, and referral to the district hospital for clinically unwell infants close follow-up of the infants on art: weekly until 6 weeks of age and monthly until 2 years of age, including routine monitoring bloods and a repeat viral load at 4 months of age monitoring of further hiv test results in hiv-exposed infants testing negative at birth, to identify further hiv-positive infants and to assess the coverage of hiv testing per guidelines to 18 months of age. by the end of december 2014, we had identified 138 high-risk infants delivered at the primary healthcare centre and we tested 132 high-risk infants (95% of high-risk infants delivered at the centre had a birth pcr) of whom 3 had a positive hiv pcr. the 3 cases are summarised in table 1 and the lessons learnt from them are described below. table 1: demographics and early outcomes of three hiv-positive infants diagnosed at birth in a primary care setting. cases of positive hiv polymerase chain reaction: lessons learnt top ↑ case 1 case 1 was complicated by a mother struggling with numerous psychosocial difficulties: low socioeconomic status, fear of stigmatisation and of disclosure to her partner/family, and deep mistrust of the healthcare system. despite repeated attempts to contact her, she only returned to care when the infant was 9 days old after her perception of her baby being healthy changed after the infant developed conjunctivitis. this case was a good illustration of how barriers at the individual level (low socioeconomic background and psychological factors such as fear of disclosure and stigma) can prevent access to art for the infant.8 by addressing these barriers through individual counselling by healthcare providers and peer support from an organisation experienced in supporting hiv-positive mothers, the mother and infant returned to care and have remained in care to date (10 months later). they are both showing good adherence and viral suppression. case 2 case 2 confirmed the higher risk of transmission with a presumed hiv incident infection in the mother, as reported in other studies such as that by drake et al.9 good support and counselling allowed the mother to overcome her initial shock and to accept the need to initiate her infant on art. she and her baby are suppressed and doing very well. case 3 case 3 illustrates the importance of early booking as intrauterine hiv transmission to the infant could have been prevented if the mother had been diagnosed and started on art earlier in the pregnancy. in this instance, too, extensive support and counselling assisted the mother in accepting the diagnosis and starting treatment for the infant. both are now virologically suppressed. so far, we have demonstrated that testing high-risk infants at birth is possible in a primary care setting, with 129 out of 130 mothers eager for their infants to be tested at birth (other high-risk infants were not tested for other reasons such as already being enrolled in another study, mother missed, etc.). although concerns were expressed by healthcare providers and counsellors on the psychosocial readiness of the mothers to initiate art, we found that it was possible and sustainable, with structured art initiation counselling and adherence support. art programmes aimed at the implementation of early infant diagnosis strategies should consider modification of the existing three pre-art routine counselling sessions as essential, given the timing of art initiation in newborns and the early challenges that both mother and infant are likely to experience in the first months on art. prior to starting the pilot study, we had concerns about the timing of sample transport from the primary care setting to the central laboratory. in fact, the average turnaround time for pcr results has been 48 hours, allowing prompt initiation of babies on art after birth. programmatically, it may be more difficult in rural areas, where there may be a longer turnaround time to obtain results. furthermore, in our pilot project, about 22% of women did not come back for the results of the baby's birth pcr. using a point of care (poc) pcr machine at birth, with good sensitivity and specificity, could reduce the attrition of patients not returning for results and improve early management of hiv-exposed infants. more research is needed to look into which poc platform would be optimal and the feasibility of its use at a primary care level. art initiation in this pilot project was undertaken by a general medical officer in a primary care setting, with the telephonic support of infectious disease paediatricians. as described in an article by nuttall10 in the present issue of the southern african journal of hiv medicine, initiating art in a neonate is more intricate than for a 6-week-old infant in terms of available drugs, dosage and monitoring. an initial lack of confidence to initiate neonates on art was observed during the mentorship of primary care medical officers, mostly related to lack of experience in calculating paediatric dosages and in blood draws in neonates. with the guidance of infectious disease paediatricians at our tertiary referral centre, we designed an interim guide on art initiation at birth where we attempted to simplify blood tests for monitoring and the calculation of dosages. modelled on existing art drug dosing charts, the guide reduces the complexity of neonatal art initiation and thus increases the confidence of clinicians managing well infants on art at primary care level. in addition to being well received by primary care doctors, mentorship on primary care art initiation for stable infants was well received by the local district hospital, as it reduces the burden on their overstretched services. furthermore, from the patient's point of view, previous studies show that accessing local clinics rather than distant referral hospitals leads to better retention in care,8,11 which is what we experienced on the ground, with the above three patients’ mothers being compliant with their appointments. the mother builds a trusting relationship with one or two health workers, which probably additionally promotes her retention in care. as we observed, assisting the very vulnerable mother-infant pair through the initial phase of art may greatly assist long-term compliance with clinic visits. the major difficulty encountered with art initiation was for the mother to understand the dosage of syrups appropriately, particularly with the high number of changes in the first few months of treatment. this finding is corroborated by other msf projects in which paediatric treatment failure has been linked directly to under-dosage by the caregiver (internal source). to overcome this difficulty, sufficient time must be spent counselling the mother on how to administer syrups; visual methods on how much of each syrup to give (using colour stickers and marked syringes) can be very helpful for mothers to understand the measurements. assigning specific responsibility to the pharmacist, counsellor, nurse or doctor for this education on medication dosing is crucial for art initiation in neonates to be rolled out effectively in a primary care setting. finally, whilst following up the birth pcr-negative babies, we observed that most women take their infants for a ‘6-weeks pcr’ but very few of them actually come to clinics in the right time frame (6–8 weeks). most of the ‘6-weeks pcr’ tests are done at random times, showing that mothers return to clinics when it suits them, not when they are given a date. further studies are needed to evaluate the impact of this observation as well as the reasons behind it, and how to adapt the existing system to the needs and demands of new mothers. conclusion top ↑ we started a pilot project in a primary care centre in khayelitsha in march 2014 to establish the impact of very early infant diagnosis in reducing the age at art initiation, and to investigate the feasibility of implementing both early diagnosis and early art initiation in a primary care setting. so far, we have diagnosed 3 hiv-positive infants out of 129 high-risk hiv-exposed babies tested, and all 3 babies were initiated on art from 2 days to 2.5 weeks after birth. they are currently doing well: all 3 infants are adherent to their medication and are virologically suppressed on art. overall, we have established the feasibility of testing newborns for hiv at birth and initiating art in the first days of life in a primary care setting with appropriate mentorship of healthcare providers and consistent adherence support for mothers. by promoting a decentralised model of early infant diagnosis at birth, programmes will ensure access to care for some of the most vulnerable patients with hiv infection. acknowledgements top ↑ competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions a.n. (médecins sans frontières) contributed to the conception, design, data acquisition, interpretation, and co-drafting of the paper. j.m. (university of stellenbosch) drafted the ethics protocol and contributed to the conception, intervention implementation and critical review of the paper. j.g. (western cape department of health) contributed to the critical review of the paper. l.f. (university of stellenbosch) contributed to the intervention implementation and critical review of the paper. h.r. (university of stellenbosch) contributed to the intervention implementation and critical review of the paper. g.v.c. (médecins sans frontières) contributed to the conception and critical review of the paper. t.m. (médecins sans frontières) contributed to the intervention implementation and critical review of the paper. n.j. (médecins sans frontières) contributed to the intervention implementation and critical review of the paper. j.b. (médecins sans frontières) contributed to the critical review of the paper. m.c. (university of stellenbosch) contributed to the intervention implementation and critical review of the paper. v.c. (médecins sans frontières) contributed to the conception, design and co-drafting of the paper and approved it for publication. references top ↑ evaluation of the effectiveness of the national pmtct programme measured at six weeks postpartum in south africa. durban: sapmtcte study group, mrc, ndoh & pepfar/us centers for disease control and prevention; 2012. violari a, cotton mf, gibb dm, et al. early antiretroviraltherapy and mortality among hiv-infected infants. n engl j med. 2008;359:2233–2244. http://dx.doi.org/10.1056/nejmoa0800971 wamalwa d, benki-nugent s, langat a, et al. survival benefit of early infant antiretroviral therapy is compromised when diagnosis is delayed. pediatr infect dis j. 2012;31:729–731. http://dx.doi.org/10.1097/inf.0b013e3182587796 persaud d, palumbo pe, ziemniak c, et al. dynamics of the resting cd4(+) t-cell latent hiv reservoir in infants initiating haart less than 6 months of age. aids. 2012;26:1483–1490. http://dx.doi.org/10.1097/qad.0b013e3283553638 lilian rr, kalk e, technau kg, sherman gg. birth diagnosis of hiv infection in infants to reduce infant mortality and monitor for elimination of mother-to-child transmission. pediatr infect dis j. 2013;32:1080–1085. http://dx.doi.org/10.1097/inf.0b013e318290622e western cape government department of health pmtct clinical guidelines update. cape town: western cape department of health; june 2014. national consolidated guidelines for the prevention of mother-to-child transmission of hiv (pmtct) and the management of hiv inchildren, adolescents and adults. pretoria: national department of health; december 2014. gourlay a, birdthistle i, mburu g, iorpenda k, wringe a. barriers and facilitating factors to the uptake of antiretroviral drugs for prevention of mother-to-child transmission of hiv in sub-saharan africa: a systematic review. j int aids soc. 2013;16:18588. http://dx.doi.org/10.7448/ias.16.1.18588 drake a, wagner a, richardson b, john-stewart g. incident hiv during pregnancy and postpartum and risk of mother-to-child hiv transmission: a systematic review and meta-analysis. plos med. 2014;11:e1001608. http://dx.doi.org/10.1371/journal.pmed.1001608 nuttall jjc. antiretroviral therapy during the neonatal period. southern african journal of hiv medicine. in press 2015. scanlon m, vreeman r. current strategies for improving access and adherence to antiretroviral therapies in resource-limited settings. hiv aids (auckl). 2013;5:1–17. abstract introduction research design results discussion conclusion and recommendations acknowledgements references about the author(s) lennart p. maljaars desmond tutu hiv centre, university of cape town, south africa amsterdam institute of global health and development, the netherlands katherine gill desmond tutu hiv centre, university of cape town, south africa philip j. smith desmond tutu hiv centre, university of cape town, south africa glenda e. gray south african medical research council, south africa perinatal hiv research unit, university of witwatersrand, south africa janan j. dietrich perinatal hiv research unit, university of witwatersrand, south africa gabriela b. gomez amsterdam institute of global health and development, the netherlands department of global health, academic medical centre, the netherlands linda-gail bekker desmond tutu hiv centre, university of cape town, south africa citation maljaars lp, gill k, smith pj, gray ge, dietrich jj, gomez gb. et al. bekker l-g. condom migration after introduction of pre-exposure prophylaxis among hiv-uninfected adolescents in south africa: a cohort analysis. s afr j hiv med. 2017;18(1), a712. https://doi.org/10.4102/sajhivmed.v18i1.712 original research condom migration after introduction of pre-exposure prophylaxis among hiv-uninfected adolescents in south africa: a cohort analysis lennart p. maljaars, katherine gill, philip j. smith, glenda e. gray, janan j. dietrich, gabriela b. gomez, linda-gail bekker received: 08 dec. 2016; accepted: 01 june 2017; published: 21 sept. 2017 copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: approximately 3 million adolescents and young adults (aya), between the ages of 15 years and 24 years, are living with hiv in sub-saharan africa. the use of pre-exposure prophylaxis (prep) may be a promising hiv prevention tool to bridge the high-risk years of aya between sexual debut and adulthood. objectives: concerns have been raised that the use of prep could lead to an increase in sexual risk behaviour and sexually transmitted infections in general and less condom use in particular among adolescents. methods: this study assesses condom use among south african adolescents enrolled on a demonstration prep study, called pluspills, being conducted in cape town and soweto. a questionnaire on sexual risk behaviour was administered at baseline and after 4, 8 and 12 weeks. three different questions on condom use were asked at each visit. unless all answers indicated condom use at all times, a participant was scored ‘at risk’. mcnemar’s tests and a cochran’s q test were used to investigate changes in condom use over time. results: we interviewed 148 adolescents (66% female) at baseline. eighty-nine participants completed all visits. in this group, an increase in condom use was observed over the period of 12 weeks. most participants who reported behavioural changes mentioned an increase in condom use. conclusion: there was no sign of sexual risk compensation in the 12 weeks of the study. observed increase in condom use can be explained by an increased awareness of personal hiv risk or by social desirability or recall biases. in future research, additional data including other biomarkers of unprotected sex and longer follow-up time would be useful to help understand the relationship between prep use, sexual risk perception and consequent behaviours, especially in adolescents. introduction background hiv incidence reduction has plateaued in the recent years with some population sub-groups still being affected disproportionately.1 one of these key populations is adolescents and young adults (aya) with approximately 2.9 million living with hiv in sub-saharan africa between the ages of 15 years and 24 years.2 research shows that, because of a number of developmental, psychological, social and structural transitions that converge in this period of the lifespan, aya are at increased risk of hiv acquisition.3 moreover, a growing body of neurobiological research and imaging studies suggest that adolescents may be prone to engage in risk behaviours, including sexual risk taking and substance abuse, because of developmental changes.4 risk factors for hiv acquisition seen in south african youth are the early age of sexual debut, a high number of sexual partners and inconsistent use of condoms.5,6 objectives at the end of 2015, the south african medicines control council approved a fixed-dose combination of tenofovir disoproxil fumarate and emtricitabine for pre-exposure prophylaxis (prep) of hiv, a new prevention tool in the fight against hiv.7 previous research showed the benefits of prep if it is prioritised to high-risk populations, is adhered to and does not lead to an increase in risk behaviour.8,9,10 therefore, the use of prep may be beneficial in preventing hiv infection during the high-risk years of youth, as prep could offer a time-limited strategy to bridge the developmental period in at-risk adolescents from sexual debut to adulthood. however, there is a concern that its use may result in risk compensation,11 that is, prep use might inhibit the uptake of safer behaviours by reducing people’s perception of their risk of infection.12 trends in the past, the potential introduction of other hiv prevention technologies, such as vaccines, barrier methods,13 antiretroviral treatment for prevention, male circumcision14 and vaginal microbicides,15,16 raised the same public health concern. yet, previous research has not found evidence for sexual risk compensation in adults using prep17,18,19,20,21,22 or post-exposure prophylaxis (pep).23 contribution to the field to date, there has been no research into sexual risk compensation among adolescents following the introduction of prep. with the ongoing roll-out of prep programmes and an upcoming united nations children’s fund (unicef) funded project for prep implementation for adolescents in south africa, this research question has become urgent. in particular there is potential concern that condom use may decrease in the short-term as a result of being substituted by another prevention intervention, also known as ‘condom migration’.15 in this article, we aim to explore short-term changes in condom use among hiv-uninfected adolescents using prep in south africa. research design setting this analysis was part of the pluspills study24,25 which evaluates the use and effectiveness of prep among hiv-uninfected adolescents in south africa. the pluspills study is an open-label, single-arm cohort study to evaluate patterns of prep use and patterns of condom use among adolescents aged 15 years to 19 years. design the aim was to evaluate the change in condom use (condom migration) among participants starting prep for a period of 12 weeks. all participants received prep (ftc/tdf) as part of a combination prevention package. this package consisted of an individualised adherence plan for prep, risk reduction counselling, free condoms and condom counselling, screening and treatment for sexually transmitted infections (stis) and counselling and referral for other hiv prevention interventions (e.g. pep, voluntary male circumcision). sampling in the study was stratified by gender, because women are more vulnerable to hiv acquisition in this setting. community engagement via the adolescent community advisory board (cab) and a consent education discussion group prior to screening was done at both sites. the discussion groups enabled the study team to explain the prevention package, including prep, to participants and enabled participants to engage with the study team. after these meetings, participants were invited to enrol in the pluspills study. the following inclusion criteria had to be met: participants must be aged between 15 years and 19 years old, willing to provide assent or consent, have a guardian willing to provide consent, able to provide adequate locator information, hiv-uninfected, sexually active, have negative pregnancy test, effective method of contraception, no intention to relocate, no activities that require long absences from the area and willing to undergo all study-required procedures. at enrolment, participants were asked to initiate prep as part of a comprehensive prevention package for at least three months. thereafter individuals were allowed to opt out of prep use should they wish to, whilst remaining in the study. the choice to opt out was posed at each three-monthly visit. participants were counselled at every visit as part of the combination prevention package. counsellors and clinicians offered participants condoms at each visit. condoms were also available in the bathrooms of each clinic. procedure a behavioural questionnaire was administered at baseline and at each subsequent visit. the questionnaire aimed to collect information on sexual behaviour, risk taking and changes over time. measurements and coding the three questions on condom use (consistency of condom use, condom use during last sexual act and frequency of condom use) were coded as ‘at risk’ (=1) and ‘not at risk’ (=0). only an explicit confirmation of condom use on all three questions was scored as ‘not at risk’. inconsistent condom use was defined as any uncertainty in the self-report on condom use. if a participant scored 1 on any of the three questions she/he was considered ‘at risk’. participants were also asked if and how they changed their sexual behaviour between the different time points. self-reported change was used to assess participants’ perception of sexual risk. participants were screened for stis (herpes simplex virus-2, chlamydia trachomatis and neisseria gonorrhoeae) at baseline and week 12. statistical analyses baseline condom use data were compared with data points after 4, 8 and 12 weeks and these were also compared with each other. mcnemar’s tests and a cochran’s q test were used to look for change in condom use over time. in particular, the mcnemar’s test was used to see if change in condom use (=condom migration) was random or because of the intervention. data were analysed using stata 13.0. ethical consideration this study was approved by the division of aids (daids), independent ethics committees, and south africa’s medicines control council prior to implementation. this study was conducted according to the protocol as well as the international conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (ich) and south african good clinical practices. results demographic information eighty-nine participants completed all subsequent visits (see tables 1 and 2): 41 participants at the desmond tutu hiv foundation youth centre in masiphumelele, cape town and 48 participants at the perinatal hiv research unit in soweto, johannesburg. of the participants who completed all visits, 58 (65%) were females, as per design. all participants were of black ethnicity and lived in the townships of masiphumelele or soweto. at baseline 75% of the participants attended school and 11% attended a tertiary education institute. eighty percent of the sample lived with, at least one of their parents; the other 20% lived with their grandparents, other family or a guardian. two-thirds of the sample reported inconsistent condom use at baseline. female participants reported more inconsistent condom usage than male participants at baseline. the sti numbers were high, with 37% of the participants having an sti at baseline. stis were more prevalent in female participants than in male participants, respectively 47% versus 16%. table 1: baseline characteristics. table 2: age and average grade of participants. follow-up sexually transmitted infections in the follow-up, data regarding sti screening were only available for 81 out of the 89 participants. of the participants, 30% had an sti (table 3), and 19% had an sti at both time points. at week 12, five participants had an sti despite reporting consistent condom use on all intermediate time points. table 3: sexually transmitted infections. condom migration mcnemar’s tests showed an increase in condom use between baseline and week 8, baseline and week 12, and week 4 and week 12 (see table 4). the cochran’s q test with all data points also showed an increase in condom use over time (see table 4). approximately 28% of the participants reported a change in sexual behaviour between the different visits. of them, 87% (81% – 92%) reported using condoms more often than before. during the follow-up period, fewer participants were classified ‘at risk’ because of more consistent condom use reported over time (see figure 1). figure 1: condom migration (n = 89). table 4: change in condom use. discussion outline of the results we did not see a reduction in condom use over this relatively short period of time in a south african adolescent population commencing prep. reported condom use was similar to previous research of condom use patterns in adolescents in south africa.5,26 what is more is that in this relatively small sample we observed an increase in self-reported condom use. we can hypothesise multiple explanations for this finding. firstly, this reporting is valid and may be because of the benefits of repeated risk reduction counselling, provision of condoms, enhanced awareness of potential risk because of provision of prep and more partner support because of enrolment in a study. secondly, this finding can be false reporting as a result of social desirability or recall biases in self-reported condom use. whilst ongoing surveillance of sexual risk compensation is warranted in prep implementation, these data are at least encouraging. limitations a total of 148 participants completed the baseline visit, but only 89 participants completed all three subsequent visits. whilst a comparison of demographic baseline data and baseline reported sexual behaviour between participants who attended their visits and the ones who missed a visit showed no difference, the analysis was carried out only in those who attended all three survey time points. this limited the number of participants in the study. secondly, a limitation of the study was that condom use was based on self-report which can be influenced by social desirability or recall biases. using other biomarkers of unprotected sex may be a more reliable measure of current risk behaviour.27 sti rates can be a surrogate to validate self-reported condom use. despite self-reported consistency in condom use, five participants had an sti after 12 weeks, perhaps raising some questions around the validity of consistent condom use. conclusion and recommendations to our knowledge, this is the first study of condom migration among adolescents on prep. three months is a relatively short period, although this is the time that all adolescents were expected to consistently be using daily prep in pluspills. whilst more research is needed to understand the relationship between prep use, sexual risk behaviour, perception of risk and consequent behaviours, especially among adolescents, these preliminary and limited results are encouraging. whilst prep may well be a very important intervention prevention addition to the tool box for adolescents, it is also understood that it should always be administered as part of a broader package that also includes risk reduction counselling, condom provision, contraception and sti screening as part of adolescent-friendly services. acknowledgements competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions l.p.m. was responsible for the first draft. it was part of his thesis for his master’s degree in medicine. all authors were responsible for conceptualisation and designing of the study, proofreading and editing. l-g.b. and g.b.g. were the supervisors of the project. references unaids. prevention gap report [homepage on the internet]. geneva; 2016 [cited 2016 oct 10]. available from: http://www.unaids.org/sites/default/files/media_asset/2016-prevention-gap-report_en.pdf unaids. the gap report [homepage on the internet]. geneva; 2014 [cited 2016 jul 14]. available from: 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[2016 dec 08]. available from: http://programme.aids2016.org/abstract/abstract/10633 macphail c, campbell c. ‘i think condoms are good but, aai, i hate those things’: condom use among adolescents and young people in a southern african township. soc sci med. 2001;52(11):1613–1627. https://doi.org/10.1016/s0277-9536(00)00272-0 mauck ck, doncel gf. biomarkers of semen in the vagina: applications in clinical trials of contraception and prevention of sexually transmitted pathogens including hiv. contraception. 2007;75:407–419. https://doi.org/10.1016/j.contraception.2007.02.007 --------august 200 i from the editor clinicians working in the field of hiv medicine welcome the accelerated treatment access programmes that are providing standard of care to hiv-infected individuals. this has occurred as a result of the dramatic price reduction of antiretroviral therapies. a vast amount of education is required to bring health care professionals in our country up to speed regarding the toxicities, drug interactions and other complexities inherent in the wider use of antiretroviral drugs. one of the major issues related to the increasing use of these drugs is the question of viral the southern african journal of hiv meoicine resistance. the virus has an enormous capacity to mutate and in the presence of sub-optimal drug concentrations resistance may manifest with surprising rapidity. in this issue the place of resistance testing is addressed by or pierre schoeman. in the management of patients, research has shown that patients who have had access to resistance testing have fared better than patients offered management based on clinical judgement alone. it is important to emphasise that the laboratory results should be interpreted in consultation with the clinician, where current clinical status, viral load, cd4 count and prior treatment history are important in formulating future treatment options. the issue of drug resistance, however, goes beyond the individual case and has rapidly become a global public health issue. the incidence of transmission of drugresistant isolates has risen alarmingly; between 1999 and 2000, 5.8% of patients infected with hiv acquired strains resistant to two classes of antiretroviral drugs, compared with just 0.4% 5 years previously. one in 7 newly infected persons in the usa now acquires a strain resistant to at least one class of antiretroviral. clearly the situation in south africa is not nearly as worrying. there is, however, an urgent need to track resistance patterns in south africa and the establishment of a registry will facilitate this. this will require a collaboration between academia, the public sector and the private sector, where the most drug resistance is currently occurring. des martin editor, southern african journal of hiv medicine president southern african hiv clinicians society 11 d e c e m b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e in 2007, only 8% of the estimated 1 800 000 children (0 14 years) living with hiv in sub-saharan africa were receiving antiretroviral therapy (art). coverage will need to be expanded greatly if the goal of providing art to 80% of children in need by 2010 is to be met.1 moreover, recent evidence highlights early initiation of art as particularly critical for infants with hiv.2 clinical guidelines issued by the world health organization (who) now recommend immediate initiation of art for all hiv-infected infants.3 paediatric art management involves a complex process of interactions between patients, families, health care providers and the antiretrovirals (arvs) themselves. barriers to the delivery of effective treatment occur both within the health care system and in the home. these include delayed diagnosis, limited availability of health care providers trained in paediatric art, few available paediatric arv formulations, complicated regimens and dosing schedules, and poor palatability of some arvs. difficulties in the home include overcrowding, difficult work schedules of the parents and the stresses associated with parental disclosure in the home. unlike adults, children require changes in antiretroviral dose as they grow and become older, and rely upon adult caregivers to administer medicines.4 children have traditionally been dosed according to body surface area (bsa) (e.g. zidovudine (azt), didanosine (ddi), lopinavir/ritonavir (lpv/r)), weight (mg/kg) (e.g. stavudine (d4t), lamivudine (3tc), abacavir (abc), nevirapine (nvp)) or dose per weight band (efavirenz (efv)). manufacturers’ recommendations for some arv drugs (e.g. lpv/r) include both bsa and weight-based dosing methods.5 the calculation of bsa generally requires accurate measurement of the child’s weight and length or height (ideally with a stadiometer or measuring box), and a normogram or mathematical formula (e.g. mosteller formula).6 for both bsa and mg/kg weight-based dosing approaches, the calculated dose of each arv drug must be rounded up or down as a ‘best-fit’ dosage according to which solid or liquid formulations of the arv drug are available. this may lead to confusion and uncertainty on the part of the prescriber. in resource-limited settings (rls), primary care doctors and nurses rather than paediatricians are responsible for the majority of paediatric art initiation and follow-up. lack of accurate measuring equipment and the relative complexity of bsa dosing may inhibit initiation of art in infants and young children or mean that inappropriate doses are given. while the most ‘accurate’ dosing may be obtained with the use of liquid formulations, large volumes of solutions (which may require refrigeration, e.g. d4t solution) may be challenging for caregivers to administer to young children, particularly if palatability is poor (e.g. lpv/r). art simplification strategies are required to help health care providers manage art in children, and to help caregivers and children adhere to therapy. interventions include the use of adult or preferably paediatric fixed-dose combinations (fdcs), selection of doses based on weight band rather than individual mg/kg or bsa doses, prescription of pills or capsules rather than liquids, and identification of reliable oncedaily regimens. weight-band dosage tables assist health care providers by assigning a fixed dose of medication for a particular weight range (e.g. 1.5 ml of lpv/r solution for children weighing 4 9.9 kg, or half a 150 mg 3tc tablet for children weighing 14 19.9 kg). in large public sector weight-band dosing tables: simplifying paediatric art c l i n i c a l james j c nuttall, mb chb, dtm&h paediatric infectious diseases unit, red cross children’s hospital and university of cape town one of the obstacles to scaling up paediatric antiretroviral therapy (art) coverage in resource-limited settings is the relative complexity of paediatric dosing. there is a need to simplify art in order to facilitate treatment initiation and ongoing management of infants and children by health care providers, as well as to support adherence in the home. this article reviews the development of weight-band dosing tables as a strategy for simplifying the delivery of paediatric art. 62 moving from bsa and weight-based dosing approaches to weight-band dosage tables t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e d e c e m b e r 2 0 0 9 treatment programmes, tables can reduce the time and risk of dosing errors involved in calculating multiple arv doses by weight or bsa. they can also facilitate easier checking of doses against weight gain by clinicians, nurses, pharmacists or adherence counsellors. under-dosing of arvs, due in part to a lack of regular dose adjustments for ongoing growth, has been described in a large cohort of children in the uk and ireland.7 a study in thailand found that 17 of 18 doctors using a standardised drug dosage table avoided miscalculations and reported more confidence with prescriptions.8 in 2006, the who published simplified weight-band dosing tables on all arv drugs for which there were available paediatric indications, formulations or sufficient information and evidence to provide guidance on prescribing and doses.9 decisions about dosing were based upon manufacturers’ information, arv formulation choices, available data from clinical studies and expert paediatric pharmacology consultation. what was considered to be the ‘optimal’ dose for a particular weight band, given the limitations imposed by currently available drug formulations, was selected. weightband doses were determined by using bsa values calculated from median height-for-weight from international growth charts using the following formula: bsa = square root [[weight (kg) × height (cm)]/3 600]. the dosing tables are directed at rls and are based on the following principles: 1. it is preferable to use one formulation or fixed combination of any given drug(s). 2. syringes or other standardised devices of various sizes should be available to support accurate dosing of liquid formulations. 3. large volumes of liquid or syrup formulations should be avoided where possible. 4. in general, children should be switched to available solid formulations as soon as possible or as soon as they are tolerated. 5. if liquids or syrups are difficult because of storage, large volumes required or palatability, solid dosage formulations are preferable. 6. if solid formulations of first-line and second-line drugs developed for children are unavailable, solid formulations currently used for adults can be used. 7. many tablets, but not all, may be divided in half but not beyond as drug content cannot be guaranteed. scored tablets are more easily split. some tablets cannot be split, and the who recommends that where possible tablet splitting be done in the dispensing pharmacy using appropriate tablet cutters. 8. some adult fdcs may result in under-dosing of individual components in children. this is of concern, particularly with drugs such as nnrtis and 3tc where there is a low threshold for resistance. nvp requires a ‘lead-in’ dosage. during the first 2 weeks, therefore rather use individual components of the regimen. 9. different dosing between a.m. and p.m. should be avoided where possible. however, in order to keep all regimens to no more than twice daily, there are instances where different quantities of solid dosage forms can be administered a.m. as opposed to p.m. 10. the doses in the tables are presented in weight bands, accepting that some deviation from target dosing will occur. 11. children have to be weighed at each clinic visit, and dose changes are required as children grow and/or gain weight. 12. when capsules are opened or tablets dissolved or crushed and added to food or liquid, it is important that the entire volume/amount of vehicle be taken to ensure administration of the full dose. the dosing tables are based on standardised weight bands starting from 5 kg body weight for the individual arv drugs (excluding efv, which starts from 10 kg) and 10 14 kg for the fixed-dose combinations (azt + 3tc, d4t + 3tc, azt + 3tc + abc, d4t + 3tc + nvp). the weight bands are in 1 kg divisions from 5 to 11 kg, and 2 5 kg divisions from 12 to 35 or 40 kg. dosing tables may be adapted according to the specific drug formulations available to a regional or national treatment programme. for example, dual (d4t + 3tc) or triple (d4t or azt + 3tc + nvp) fdcs play an important role in paediatric art in many countries (e.g. thailand and many african countries), but are not widely used in south africa. satisfactory early clinical and immunological outcomes have been described following the use of fractions of generic adult fdcs in children dosed according to a weight-band table method in thailand.10 in another project, a visual dosing aid (vda) incorporating coloured dosing bands for five first-line arv drugs was developed to assist clinicians in prescribing paediatric art consisting of syrups, generic adult tablets or a combination. it compared well with generic paediatric fdc tablets and could help facilitate paediatric art roll-out in rls.11 the south african national guidelines for the management of hiv-infected children (2005) incorporate a weight-band dosing chart12,13 developed by the centers for disease control and prevention (cdc) and a number of international paediatric aids programmes 63 adapting weight-band dosing tables for different settings d e c e m b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 64 prior to the more widespread availability of fdcs. bsa dosing recommendations were converted to weightband doses using approximations of weight-for-age and height-for-age derived from standardised growth charts of girls from birth to 36 months and 20 years in the usa (national center for health statistics). dose for each weight band was based on the practicality of the available dosage forms for each drug, and practical storage and dosing instructions were included with the chart. the chart lacks dose recommendations for children weighing less than 5 7 kg and for hiv-tb co-infection. the western cape antiretroviral drug dosing chart for children (2007), based on the 2006 who recommendations, was developed by the author and colleagues as a pilot project for the hiv directorate of the western cape (south africa) provincial health department. the chart was directed at both clinicians and pharmacists involved in prescribing and dispensing art for children, and it was successfully piloted at a number of hiv clinics before being distributed across the province. it was produced as a laminated a4 colour copy. standard firstand second-line art regimens (including regimens compatible with rifampicin-based tb treatment) as well as general comments relating to storage, administration and common drug interactions and sideeffects of the individual arv drugs were printed on the reverse side. only arv formulations available at public sector treatment facilities were included (no fdcs were available), and there was an emphasis on the early introduction of solid formulations where possible. fractions of tablets (not less than half a tablet) were only incorporated for scored tablets. the target dose in mg/ kg or mg/m2 for each drug as well as the formula for calculating bsa was included to facilitate comparison of dosing methods when necessary. the following local practices were incorporated: 1. the off-label ‘opened capsule’ d4t dosing method whereby a d4t capsule is opened and the powder contents dispersed in a standardised volume of water and the required dose drawn up with a syringe and administered to the child (e.g. to administer a standardised d4t dose of 10 mg for the weight bands 7 9.9 kg, a 20 mg d4t capsule is opened and dispersed into 5 ml of water and 2.5 ml is withdrawn with a syringe and administered and the remaining 2.5 ml is discarded). the rationale for this method is to minimise the use of stavudine solution (1 mg/ml when reconstituted), which is expensive, requires refrigeration, and results in relatively large medication volumes for administration to young infants at the usual dosing schedule (1 mg/kg/dose). there are now data based on high-performance liquid chromatography analysis of active drug concentration in dispersed capsule solutions, supporting the accuracy of this method for certain brands of d4t capsules.14 2. standardised doses of ritonavir used for pharmacological boosting of lpv/r (in order to achieve a ratio of 1:1) in children receiving concurrent lpv/r and rifampicin-based tb treatment.15 3. colour coding of arvs on the chart corresponding to colour coding methods used in the pharmacy for medication containers and syringes to assist parents and caregivers with correct dosing. 4. the chart incorporated co-trimoxazole and multivitamin syrup dosing according to weight bands. 5. since there were no standard weight-band dosing recommendations for infants weighing <5 kg in the who document (2006), it was recommended that a clinician experienced in arv prescribing be consulted for such cases. there are a number of approaches to validation of weight-band dosing. direct methods include pharmacokinetic (pk) studies and therapeutic drug monitoring. indirect methods include comparison of weight-based with bsa doses, and safety and efficacy studies. qualitative studies assessing the usefulness of a weightband dosing table to prescribing clinicians and dispensing pharmacists should be undertaken. differing growth rates and the prevalence of malnutrition could have a significant impact on the accuracy of weight-band dosing of drugs that are usually dosed by bsa. a study comparing the calculated bsa dose range with who weight-band doses for azt, ddi, nvp and lpv/r using actual heights and weights of 601 children at the time of arv initiation was undertaken at a tertiary hospital in south africa in 2007.16 the median age was 28 months (interquartile range 13 62), 49% of children weighed <10 kg, and 59% and 63% of children had weight-for-age and height-for-age z-scores <–2 (moderate to severe underweight or stunting), respectively. children with body weight <5 kg were excluded as weight-based dosing recommendations were unavailable for this category, and children <6 months of age were excluded as lpv/r bsa dosing recommendations are different in this age group. the bsa dose ranges used were azt 180 240 mg/m2, ddi 90 120 mg/m2, nvp 160 200 mg/m2, and l/r 230 300 mg/m2. results are presented in table i. the conclusion of this study was that the 2006 who simplified weight banddosing method effectively avoided under-dosing children in relation to existing bsa dose recommendations for azt, nvp and lpv/r suspensions. however, the authors noted that the risk of over-dosing is greater with weight-band recommendations for existing capsule or tablet formulations of these arvs. further studies are recommended for the who weight-band dosing method. validation of weight-band dosing tables t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e d e c e m b e r 2 0 0 9 65 weight-band dose relative to calculated bsa dose range (n=601 children) (using anthropometric data arv drug, bsa dose range, at time of starting art) formulations assessed under-dosing (% of children) over-dosing (% of children) azt 180 240 mg/m2 oral solution (10 mg/ml) 2 0.5 capsules (100 mg) 8.5 19 ddi 90 120 mg/m2 tablets (25, 50, 100 mg, chewable or dispersable in water) 0 87 nvp 160 200 mg/m2 oral suspension (10 mg/ml) 0 53 tablets (200 mg) 0 61 lopinavir/ritonavir 230 300 mg/m2 oral solution (80/20 mg/ml) 1.2 26 capsules (133.3/33.3 mg soft) 0 38 table i. weight-band dose relative to calculated body surface area dose range a vda to facilitate dosing calculations in response to children’s growth and weight during arv treatment developed by callens et al.11 was evaluated using anthropometric data from 55 children from the usa and 324 children from the democratic republic of congo (drc). in comparison with who-recommended dosing, the authors noted a relative dosing difference of >20% in <3% of children for nvp, azt and d4t but in 20% of children for 3tc, over-dosing being more frequent.11 a detailed review of pk studies and clinical outcome, safety and efficacy studies undertaken in children treated with individual or fdc arv drugs dosed according to weight bands is beyond the scope of this article. there are no reported pk or clinical studies directly comparing weight band with mg/kg or bsa dosing approaches. in july 2008, the who published a revised weightband dosing table for individual arvs as well as dual and triple fdcs applicable to children >6 weeks of age, indicating the number of tablets or millilitres of solution to be administered twice daily by weight band from 3 kg to 34.9 kg (fig. 1).17 the table focuses on arvs used in first-line regimens and was developed by the who paediatric antiretroviral working group using the 2006 who treatment recommendations, target doses and weight bands as a benchmark and reviewing currently available published and unpublished data to assess dosing. ddi is not included in the dosing table. key supporting references are provided in the document.18 see table ii for target doses or dosing ranges. a who generic tool was used to assess and evaluate the expected dose delivered of any product in relation to intended target doses. for all formulations, changes in the number of pills and switches from one formulation to another occur at the same weight bands. there was an attempt to avoid dosing any single arv component below 90% of the intended delivered dose and not more than 25% above the intended dose (or dose range for products with an established dose range). for nvp, the aim was to avoid dosing below 100% of the minimum of the dose range (150 mg/m2). discrepancies between dose delivered and intended dose were justified based on available pk data, consideration of toxicity, and threshold for development of hiv drug resistance. higher dosing for children who would fall into the lower weight bands (under 3 years) was accepted for drugs with known increased metabolism or clearance in the young child (nvp, 3tc, d4t, abacavir, lpv/r). in south africa, the antiretroviral drug dosing chart (2009) is an update of the 2007 western cape version and incorporates elements of the who 2008 table; in particular, dosing recommendations for weight bands 3 3.9 kg and 4 4.9 kg (fig. 2). many of the formulations in the who table, in particular the fdcs, are not currently available to public sector treatment programmes in south africa and so are excluded. the registration and availability of the paediatric strength heat-stable lpv/r tablet (aluvia; 100 mg lopinavir/25 mg ritonavir) is still awaited, but it has been included. local dosing practices described in the 2007 chart have been retained with modification, e.g. the d4t openedcapsule method is now used from 5 kg body weight. a comparative analysis of the revised weight band dosing in comparison with bsa dosing for azt, nvp and l/r has been completed but not yet published. an analysis of the dose of lpv/r solution in mg/m2 that revised who weight band dose recommendations would provide, using anthropometric data on 976 children initiating art at median age of 11.2 months, indicated doses considerably in excess of 300/75 mg/m2, particularly for children <6 months of age.19 a protocol for an infant pk study using the revised who weight-band dosing current weight-band tables d e c e m b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 66 fi g. 1 . p ae di at ric a nt ire tr ov ira l d os in g ta bl e, w or ld h ea lt h o rg an iz at io n (2 00 8) .17 n u m b e r o f ta b le ts o r m l b y w e ig h t b a n d ( tw ic e d a il y ) c h il d re n 6 w e e k s o f a g e a n d a b o v e (0 .7 5 b d i s d e li v e re d a s 1 t a b le t a m a n d 0 .5 t a b le ts p m a n d 1 .5 b d i s d e li v e re d a s 2 t a b le ts a m a n d 1 t a b le t p m ) n u m b e r o f ta b le ts b y w e ig h t b a n d ( tw ic e d a il y ) d ru g s tr e n g th o f ta b (m g ) o r li q u id m g /m l 3 -3 .9 k g 4 -4 .9 k g 5 -5 .9 k g 6 -6 .9 k g 7 -7 .9 k g 8 -8 .9 k g 9 -9 .9 k g 1 0 1 0 .9 k g 1 1 1 1 .9 k g 1 2 1 3 .9 k g 1 4 1 6 .9 k g 1 7 1 9 .9 k g 2 0 2 4 .9 k g s tr e n g th o f a d u lt t a b (m g ) 2 5 2 9 .9 k g 3 0 3 4 .9 k g a z t 6 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 3 0 0 1 1 a z t ( n e w a n n e x e ) 3 0 0 ; 1 0 m g /m l 6 m l 6 m l 6 m l 9 m l 9 m l 9 m l 9 m l 1 2 m l 1 2 m l 1 2 m l 0 .5 0 .5 0 .7 5 3 0 0 1 1 a z t /3 t c 6 0 /3 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 3 0 0 /1 5 0 1 1 a z t /3 t c /n v p 6 0 /3 0 /5 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 3 0 0 /1 5 0 /2 0 0 1 1 a b c 6 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 3 0 0 1 1 a b c ( n e w a n n e x e ) 3 0 0 ; 2 0 m g /m l 3 m l 3 m l 3 m l 4 m l 4 m l 4 m l 4 m l 6 m l 6 m l 6 m l 0 .5 0 .5 0 .7 5 3 0 0 1 1 a b c /3 t c 6 0 /3 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 3 0 0 /1 5 0 1 1 a b c /3 t c /n v p 6 0 /3 0 /5 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 3 0 0 /1 5 0 /2 0 0 1 1 a b c /a z t /3 t c 6 0 /6 0 /3 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 3 0 0 /3 0 0 /1 5 0 1 1 3 t c 3 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 1 5 0 1 1 3 t c ( n e w a n n e x e ) 1 5 0 ; 1 0 m g /m l 3 m l 3 m l 3 m l 4 m l 4 m l 4 m l 4 m l 6 m l 6 m l 6 m l 0 .5 0 .5 0 .7 5 1 5 0 1 1 d 4 t 6 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 3 0 1 1 d 4 t ( n e w a n n e x e ) v a ri o u s ; 1 m g /m l 6 m l 6 m l 6 m l 9 m l 9 m l 9 m l 9 m l 1 x 1 5 m g 1 x 1 5 m g 1 x 1 5 m g 1 x 2 0 m g 1 x 2 0 m g 1 x 2 0 m g 3 0 1 1 d 4 t /3 t c 6 /3 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 3 0 /1 5 0 1 1 d 4 t /3 t c /n v p 6 /3 0 /5 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 3 0 /1 5 0 /2 0 0 1 1 n v p 5 0 1 1 1 1 .5 1 .5 1 .5 1 .5 2 2 2 2 .5 2 .5 3 2 0 0 1 1 n v p ( n e w a n n e x e ) 2 0 0 ; 1 0 m g /m l 5 m l 5 m l 5 m l 8 m l 8 m l 8 m l 8 m l 1 0 m l 1 0 m l 1 0 m l 0 .7 5 0 .7 5 0 .7 5 2 0 0 1 1 l o p in a v ir /r it o n a v ir 1 0 0 /2 5 n /r n /r n /r n /r n /r n /r n /r 1 .5 1 .5 1 .5 2 2 2 .5 1 0 0 /2 5 * (p a e d ) 3 3 l o p /r it ( n e w a n n e x e ) 8 0 /2 0 m g /m l 1 m l 1 .5 m l 1 .5 m l 1 .5 m l 1 .5 m l 1 .5 m l 1 .5 m l 2 m l 2 m l 2 m l 2 .5 m l 2 .5 m l 3 m l 8 0 /2 0 m g /m l 3 .5 m l 4 m l * 3 t a b le ts b d o f 1 0 0 /2 5 m a y b e s u b s ti tu te d w it h 2 t a b le ts a m a n d 1 t a b le t p m o f 2 0 0 /5 0 n o te : h ig h e r d o s e s o f l o p /r it m a y b e r e q u ir e d w h e n c o -a d m in is te re d w it h e n z y m e -i n d u c in g d ru g s s u c h a s n v p , e f v ; fo s a m p re n a v ir , ri fa m p ic in . t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e d e c e m b e r 2 0 0 9 table and incorporating safety and efficacy end-points has been developed. the use of weight-band arv dosing approaches, adapted in accordance with locally available formulations and treatment programme conditions, is a key component of simplifying paediatric art for health care providers as well as children and their caregivers, and will contribute to expanding treatment coverage for hiv-infected infants and children. references 1. unicef, unaids, who and unfpa. children and aids: third stocktaking report, 2008. geneva: unicef, 2009. http://www.childinfo.org/files/stocktakingreport08.pdf (accessed 29 september 2009). 2. violari a, cotton m, gibb d, et al. early antiretroviral therapy and mortality among hiv-infected infants. n engl j med 2008; 359: 2233-2244. 3. world health organization. report of the who technical reference group, paediatric hiv/art care guideline group meeting who headquarters, geneva, switzerland, 10 11 april 2008. http://www.who.int/hiv/pub/paediatric/who_ paediatric_art_guideline_rev_mreport_2008.pdf (accessed 8 october 2009). 4. sohn a, ananworanich j. how can we simplify antiretroviral therapy in children? curr opin hiv aids 2007; 2: 426-430. 5. package insert for abbott kaletra®, abbott laboratories, june 2005. 6. mosteller rd. simplified calculation of body-surface area. n engl j med 1987; 317: 1098. 7. menson e, walker a, sharland m, et al. underdosing of antiretrovirals in uk and irish children with hiv as an example of problems in prescribing medicines to children, 1997-2005: cohort study. bmj 2006; 332: 1183-1187. 8. ponnet m, frederix k, petdachai w, et al. a drug dosage table is a useful tool to facilitate prescriptions of antiretroviral drugs for children in thailand. int j std aids 2005; 16: 420-426. 9. world health organisation. antiretroviral therapy of hiv infection in infants and children in resource-limited settings, towards universal access: recommendations for a public health approach. 2006. http://www.who.int/hiv/pub/guidelines/en/ (accessed 8 october 2009). 10. o’brien dp, sauvageot d, zachariah r, humblet p. in resource-limited settings good early outcomes can be achieved in children using adult fixed-dose combination 67 drug target dosing range considerations abc 8 10 mg/kg/dose twice daily clearance in children <3 years old is increased, but recent data on once-daily dosing in children from 3 months of age suggest favourable pk profile azt 180 240 mg/m2 /dose twice daily twice-daily dosing is acceptable and preferred dosing at the upper end of the range is recommended for central nervous system hiv disease; dosing at the lower end may be preferred in settings where anaemia is prevalent d4t 1 mg/kg/dose twice daily needed as a priority product despite well-recognised longer-term toxicities (lipodystrophy), as it is initially well tolerated, is safer to use in anaemia than azt, and has lower laboratory monitoring requirements avoid over-dosing wherever possible (noting recent revision to adult dosing recommendation to reduce dose) and especially for extended periods to minimise toxicity ddi <3 months of age: 50 mg/m2/dose; enteric-coated formulations are preferred over the buffered form >3 months: 120 mg/m2/dose twice daily needs to be given 1 hour before or 2 hours after food once-daily dosing accepted over 6 years of age 3tc 4 mg/kg/dose twice daily clearance in children <3 years old is increased, and minimal observed toxicity allows for higher dosing in younger children (up to 5 mg/kg/dose twice daily) nvp a bsa dose range of 150 200 mg/m2/dose under-dosing must be avoided wherever possible owing to low twice daily is used to generate weight-band dosing barrier development of hiv drug resistance a reduced dose (150 200 mg/m2/dose once daily) is recommended for the first 2 weeks when initiating nvp treatment regimens young children require a higher nvp dose relative to the nrti components than delivered in current adult fdcs efv by weight band (15 18.75 mg/kg/dose dosing not established for children <3 years solid formulation or 19.5 mg/kg/dose suspension, suspension is over 30% less bio-available than solid formulations once daily) lpv/rtv approved dose is 230/75.5 mg/m2/dose twice daily; clearance in children <2 years is increased 300/75 mg/m2/dose is recommended in children actual exposure depends on metabolism and inter-patient vari <2 years of age, if taken with nnrti, or for ability, which is considerable pi-experienced patients heat-stable paediatric formulation recently approved (awaiting registration in sa) rtv co-formulated with lopinavir (l:r ratio 4:1) needed for use as a pharmacological booster with pi-based treat for patients receiving rifampicin, additional rtv ment and for children receiving rifampicin-based antituberculosis dosed at 0.75 x l/r dose to achieve l:r ratio of 1:1 therapy table ii. dosing considerations for individual antiretroviral drugs included in the revised who dosing table (2008) and adapted for the antiretroviral drug dosing chart (2009)18 conclusion acknowledgements for assistance with the development, analysis and implementation of the western cape antiretroviral drug dosing chart (2007): shenaaz raiman (pharmacist), heather jaspan, brian eley, mary-ann davies, brenda smuts, david pienaar, heli moeng, staff at the hiv clinic at red cross war memorial children’s hospital, cape town and nolungile hiv clinic, khayelitsha. d e c e m b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 68 t ar ge t do se st av ud in e (d 4t ) l am iv ud in e (3 t c ) z id ov ud in e (a z t ) d id an os in e (d di ) a ba ca vi r (a b c ) e fa vi re nz (e f v ) n ev ir ap in e (n v p ) l op in av ir /r it on av ir (l p v /r tv ) r it on av ir bo os ti ng (r t v ) c otr im ox az ol e m ul ti vi ta m in s t ar ge t do se 1m g/ kg /d os e t w ic e d ai ly 46m g/ kg /d os e t w ic e d ai ly 24 0m g/ m 2 /d os e t w ic e d ai ly 90 -1 20 m g/ m 2 /d os e t w ic e d ai ly 8m g/ kg /d os e t w ic e d ai ly b y w t. ba nd o n c e d ai ly 15 0m g/ m 2 /d os e * t w ic e d ai ly 30 0/ 75 m g/ m 2 /d os e l pv /r tv t w ic e d ai ly ** o n l y a s bo os te r f or l pv /r tv w he n on r if am pi ci n t w ic e d ai ly o n c e d ai ly o n c e da ily a va ila bl e fo rm ul at io ns so l. 1m g/ m l c ap s 15 ,2 0, 30 m g so l. 10 m g/ m l t ab s 15 0m g (s co re d) so l. 10 m g/ m l c ap s 10 0m g t ab s 30 0m g (n ot s co re d) t ab s 25 ,5 0, 10 0m g (d is pe rs ib le in 30 m l w at er ) c ap s 25 0m g e c so l. 20 m g/ m l t ab s 30 0m g (n ot s co re d) c ap s 50 , 20 0m g t ab s 50 , 2 00 , 60 0m g (n ot s co re d) so l. 10 m g/ m l t ab s 20 0m g (s co re d) so l. 80 /2 0m g/ m l t ab s 20 0/ 50 m g, 10 0/ 25 m g so l. 80 m g/ m l so l. 40 /2 00 m g/ 5m l t ab s 80 /4 00 m g (s co re d) so l. t ab s (b c o) a va ila bl e fo rm ul at io ns w t. (k g) w t. (k g) <3 c on su lt w ith a c lin ic ia n ex pe ri en ce d in p ae di at ri c a r v p re sc ri bi ng fo r n eo na te s (< 28 d ay s of a ge ) a nd in fa nt s w ei gh in g <3 kg 2. 5m l 2. 5m l <3 33. 9 6m l 3m l 6m l av oi d 3m l d os in g <1 0k g no t es ta bl is he d 5m l 1m l ** 1m l 33. 9 44. 9 1. 5m l ** 1. 2m l 44. 9 55. 9 7. 5m g: o pe n 15 m g ca ps ul e in to 5 m l w at er : gi ve 2 .5 m l & di sc ar d re st 2x 25 m g ta bs 5m l o r ½ ta b 55. 9 66. 9 4m l 9m l 8m l 66. 9 77. 9 10 m g: o pe n 20 m g ca ps ul e in to 5 m l w at er : gi ve 2 .5 m l & di sc ar d re st 4m l 77. 9 88. 9 88. 9 99. 9 99. 9 10 -1 0. 9 15 m g: o pe n 15 m g ca ps ul e in to 5 m l w at er 6m l 12 m l 1x 50 m g+ 1x 25 m g ta bs a m ; 2x 25 m g ta bs p m 6m l 20 0m g ca p/ ta b 10 m l 2m l t w ic e da ily o r 10 0/ 25 m g ta bs : 2 ta bs a m , 1 ta b pm ** 1. 5m l 5m l 10 -1 0. 9 11 -1 1. 9 1x 50 m g+ 1x 25 m g ta bs 11 -1 1. 9 12 -1 3. 9 12 -1 3. 9 14 -1 6. 9 20 m g: o pe n 20 m g ca ps ul e in to 5m l w at er ½ ta b 2 ca ps a m ; 1 ca p pm 2x 50 m g ta bs a m ; 1x 50 m g+ 1x 25 m g ta bs p m 7m l 20 0m g ca p/ ta b + 50 m g ca p/ ta b 1 ta b am ; ½ ta b pm 2. 5m l t w ic e da ily o r 10 0/ 25 m g ta bs : 2 ta bs tw ic e da ily ** 2m l 10 m l o r 1 ta b 14 -1 6. 9 17 -1 9. 9 2x 50 m g ta bs 8m l 17 -1 9. 9 20 -2 4. 9 20 m g am ; 30 m g pm 1 ta b am ; 1/ 2 ta b pm 2 ca ps 1x 10 0m g ta b+ 1x 25 m g ta b tw ic e da ily o r 1x 25 0m g e c c ap on ce d ai ly 10 m l 20 0m g ca p/ ta b + 2x 50 m g ca ps /ta bs 3m l t w ic e da ily o r 10 0/ 25 m g ta bs : 3 ta bs a m , 2 ta bs p m ** 2. 5m l 20 -2 4. 9 25 -2 9. 9 30 m g 1 ta b 1 ta b 1 ta b 20 0m g ca p/ ta b + 3x 50 m g ca ps /ta bs 1 ta b 3. 5m l t w ic e da ily o r 20 0/ 50 m g ta bs : 2 ta bs a m , 1 ta b pm ** 3m l 25 -2 9. 9 30 -3 4. 9 2x 20 0m g ca ps /ta bs 4m l t w ic e da ily o r 20 0/ 50 m g ta bs : 2 ta bs a m , 1 ta b pm 2 ta bs 1 ta b 30 -3 4. 9 35 -3 9. 9 5m l t w ic e da ily o r 20 0/ 50 m g ta bs : 2 ta bs tw ic e da ily ** 4m l 35 -3 9. 9 >4 0 60 0m g ta b >4 0 b od y su rf ac e a re a (b sa ) m 2 = m as s (k g) x h ei gh t ( cm ) 36 00 n ee d h el p ? c a ll n a ti o n a l h iv h c w h o tl in e 08 00 2 12 5 06 / 0 21 4 06 6 78 2 o r se n d a n s m s o r “ p le as e ca ll m e” m es sa g e to 07 1 84 0 15 72 * a le ad -i n do se o f n ev ir ap in e is g iv en fo r th e fir st 1 4 da ys o f t re at m en t e qu iv al en t t o ha lf o f m ai nt en an ce d os e i.e . u su al m ai nt en an ce d os e bu t g iv en o nc eda ily . i nc re as e to fu ll m ai nt en an ce d os e af te r 14 d ay s if n o ra sh d ev el op s. c om pi le d by j . n ut ta ll & s . r ai m an fo r th e p ae di at ri c h iv /t b p ol ic y r ef er en ce g ro up , w es te rn c ap e. a da pt ed fr om w or ld h ea lt h o rg an is at io n gu id el in es , 2 00 6 & 2 00 8. a n ti re tr o vi ra l d ru g d o si n g c h ar t fo r c h il d re n ( 2 0 0 9 ) fi g. 2 . a nt ire tr ov ira l d ru g do si ng c ha rt fo r c hi ld re n (2 00 9) (c op ie s av ai la bl e vi a n at io na l h iv h ea lt h ca re w or ke r h ot lin e 08 00 2 12 5 06 ). t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e d e c e m b e r 2 0 0 9 antiretroviral therapy. aids 2006; 20: 1955-1960. 11. callens sf, westreich d, kitetele f, et al. a visual dosing aid for first-line pediatric antiretroviral treatment in resource-poor settings. j trop pediatr 2008; 55: 135137. 12. national department of health, south africa. guidelines for the management of hiv-infected children. 1st ed. national department of health, south africa, 2005. 13. weidle pj, abrams ej, gvetadze r, rivadeneira e, kline mw. a simplified weight-based method for pediatric drug dosing for zidovudine and didanosine in resource-limited settings. pediatr infect dis j 2006; 25: 59-64. 14. innes s, smuts m, cotton m, seifart h, rosenkranz b. comparative study of different brands of stavudine capsules for the off-label ‘opened capsule’ method recommended for hiv-infected infants and children in resource-limited settings. south african journal of child health 2009; 3: 44-47. 15. ren y, nuttall j, egbers c, et al. effect of rifampicin on lopinavir pharmacokinetics in hiv-infected children with tuberculosis. j acquir immune defic syndr 2008; 47: 566-569 16. nuttall j, eley b, davies m. comparison of body surface area-based dosing and a simplified weight-based dosing method for zidovudine, didanosine, nevirapine and lopinavir/ritonavir in children starting antiretroviral therapy. paper presented at the 3rd south african aids conference, 5 8 june 2007, durban (abstract 538). 17. world health organization. annex e: simplified weight based paediatric dosing for antiretroviral medicines http://www.who.int/hiv/topics/paediatric/technical/en/ index.html (accessed 17 november 2009). 18. world health organization. report of the who expert working group meeting to determine preferred arv medicines for treating and preventing hiv infection in younger children, 2008 http://www.who.int/hiv/topics/paediatric/technical/en/ index.html (accessed 17 november 2009). 19. nuttall j, eley b, davies m-a. how well do the revised world health organization weight-based dosing guidelines for lopinavir/ritonavir in infants and children correlate with body surface area-based dosing recommendations? paper presented at the 5th international aids society conference on hiv pathogenesis, treatment and prevention, 19 22 july 2009, cape town (abstract moab105). 69 hiv 897 forum child privacy rights: a ‘cinderella’ issue in hiv-prevention research a strode,1,2 ba, llb, llm; c slack,2 ba (hons), ma (clin psych) 1 school of law, university of kwazulu-natal, pietermaritzburg, south africa 2 hiv/aids vaccines ethics group, school of applied human sciences, university of kwazulu-natal, pietermaritzburg, south africa corresponding author: a strode (strodea@ukzn.ac.za) legal debates regarding child participation in hiv research have tended to focus on issues of informed consent. however, much less attention has been given to privacy; accordingly, we classify this as a ‘cinderella issue’ that has been excluded from ‘the ball’ (academic debate). here we argue that privacy issues are as important as consent issues in hiv-prevention research. we describe a child’s right to privacy regarding certain health interventions in south african law, and identify four key norms that flow from the law and that could be applied to hiv-prevention research: (i) children cannot have an expectation of privacy regarding research participation if they have not given independent consent to the study; (ii) children may have an expectation of privacy regarding certain components of the study, such as hiv testing, if they consent independently to such services; (iii) children’s rights to privacy in health research are limited by mandatory reporting obligations; (iv) children’s rights to privacy in hiv-prevention research may be justifiably limited by the concept of the best interests of the child. we conclude with guidelines for researchers on how to implement these principles in hiv-related research studies. s afr j hiv med 2013;14(3):108-110. doi:10.7196/sajhivmed.897 health research among children (age <18 years), including hiv-prevention and -treatment re­search, is legally complex, because they have limited legal capacity and laws require them to be protected against their lack of experience and knowledge.1 to date, legal debates have tended to focus on informed consent for child research. as a result, much of the literature has dealt with questions such as which parties should give consent to child research,2-5 and what forms of research risk can be consented to on behalf of, or by children.6-10 this article uses the analogy of cinderella to describe the ‘exclusion’ of child privacy rights from academic debates on health research. it suggests that like cinderella, who was left to clean the house rather than being invited to the ball, privacy has been overlooked or viewed as less important than the ‘two ugly stepsisters’ of who can consent and to what can be consented in child research. it is argued here that the privacy rights of children participating in hiv-related research are as important as the consent rights for several reasons. firstly, every child has the right to privacy.11 it is argued that this right extends to ensuring that children have confidentiality regarding certain aspects of research participation. secondly, south african courts have recognised that the failure to protect private medical information can have a direct public health impact, because without confidentiality, individuals are discouraged from seeking medical treatment or divulging personal information to healthcare providers.12 it is argued, likewise, that undermining the confidential nature of the research relationship may erode public trust in research and researchers. in previous articles, we argued that the privacy rights of adolescents (age 12 17 years) will have to be delineated carefully in hiv-prevention trials.1 , 7 this article attempts to build on earlier work, by comprehensively setting out the nature and sources of a child’s right to privacy regarding health interventions, and by developing four key norms which can be applied to a range of hiv-prevention studies. adolescents are at risk of hiv infection, and in order to make new hiv-prevention products available to them, they will need to be enrolled in hiv-prevention trials – provided that rigorous ethical criteria are met.13 for example, it is possible that, within the next 24 months, adolescent females will be enrolled in a clinical trial of a microbicide gel (facts 002), once sufficient safety and efficacy data have been obtained from adult participants.14 there are also many other behavioural studies exploring aspects of hiv prevention in adolescents, e.g. explorations of knowledge, attitudes and practices among teenagers. there are many complexities raised by a child’s right to privacy within the context of trials of hiv-prevention products, as well as in related social-behavioural studies. parents or guardians, who are aware of their child’s involvement in such research through the consent process, may have expectations that personal health information reported to, or identified by researchers will be disclosed to parents. however, adolescents aged ≥12 years who have the capacity to consent independently to certain health interventions (such as testing for sexually transmitted infections) may have expectations of privacy regarding such interventions.1 , 3 , 7 the right to privacy in health-related matters according to section 14 of the constitution of the republic of south africa, everyone has a right to privacy.11 this right enables individuals to be left alone or not to be observed by others.15 it only extends to those aspects of a person’s life that they and society believe should be kept private.16 thus, an individual’s right to privacy will exist if they have an expectation that the information would be kept private, and if such an expectation is regarded as reasonable by society.16 whether information can reasonably be regarded as private is established through an assessment of the impact of the violation on the individual’s autonomous identity.17 the right to privacy is also shaped by the grounds of justification. if a ground of justification exists (such as consent to the disclosure, necessity or where the law limits the right), the invasion of privacy will not be unlawful.18 a child’s right to privacy in health-related matters constitutional and other rights apply in most instances to adults and children equally.16 by implication, children are entitled to the right to privacy. however, a child’s expectation of privacy may be limited, and in some instances, society would not recognise their expectation as reasonable.1 , 7 national health act (2003) currently, there is no legal guidance on how the right to privacy applies to child research participants, because the national health act (nha) 19 is silent on this issue. however, section 14(1) of the nha provides that a user (patient) has the right to confidentiality regarding health information, ‘including information relating to his or her health status’. 19 however, such information may be disclosed in certain defined circumstances where the act regards the disclosure as justifiable (section 14(2)(a)-(c) and 15(1), nha).19 it appears that the nha does not create an independent right to privacy for children who do not have the capacity to consent to medical treatment, because if a parent or guardian consents on behalf of a child, then the parent/guardian is granted all the rights of the user, including the right to confidentiality (section 1, nha).19 this means that children, who cannot consent independently to a medical intervention would not have a right to keep information about such an intervention from the adult providing proxy consent. children’s act (2005) the children’s act, in contrast, provides that all children have a self-standing right to privacy regarding their ‘health status’ (section 13(1)(d), children’s act).20 ‘health status’ is not defined, but it is assumed that this refers to a child’s medical condition or diagnosis. the act also provides that ‘children are entitled to privacy from the age of 12 years regarding access to condoms, contraceptives and contraceptive advice’ (sections 13(1)(d) and 134(3), children’s act).20 furthermore, no person may disclose that a child is hiv-positive without the consent of the child (if they are aged ≥12 years), or another responsible adult if they are aged <12 years (section 133(1), children’s act).20 the children’s act provides that a child’s rights to privacy regarding their health status may be limited where this is in their best interests (section 13(d), children’s act).20 such rights may also be indirectly limited through mandatory reporting obligations. these require certain individuals such as medical practitioners, to report children who are abused, neglected or in need of care/protection (section 110, children’s act).1 , 7 , 20 the definitions of abuse, neglect and children in need of care and protection are very broad. resultantly, reporting is required if, among others, children: (i) are performing child labour (i.e. working while aged <15 years); (ii) are dependent on drugs and they are ‘without any support to obtain treatment for such dependency’; (iii) are being exploited, e.g. used by adults to commit crimes; or (iv) have been physically or sexually abused (section 150(2), children’s act).7 , 20 the choice of termination of pregnancy act (1996) the choice of termination of pregnancy act (ctpa) also deals expressly with the right to privacy, by providing that the ‘identity of a woman who has requested or obtained a termination of pregnancy shall remain confidential at all times unless she herself chooses to disclose that information’ (section 7(5), ctpa).21 woman in this context means a ‘female person of any age’ (section 1(xi), ctpa).21 this provision is tempered by section 5(3), which provides that minors must be advised to ‘consult with their parents, guardian, family members or friends’ before the termination (section 5(3), ctpa).3 , 21 the criminal law (sexual offences and related matters) amendment act (2007) the sexual offences act (2007) limits a child’s right to privacy by requiring the mandatory reporting of all sexual offences committed against children, including consensual crimes (section 54(1), sexual offences act).22 applying privacy laws to adolescent hiv-prevention studies we argue that by applying the law on privacy to hiv-prevention studies, the following norms emerge: a child does not have a right to privacy regarding participation in an hiv prevention study unless they have consented independently to research participation. it is submitted that older adolescents may have expectations of privacy regarding participation in an hiv-prevention trial as they may have been recruited while independently accessing health services. however, this would not be regarded as reasonable given that ethical guidelines require parental consent for clinical trials,23 and for more than minimal risk research.24 recently, section 71 of the nha was operationalised, requiring parental or guardian consent for all forms of health research with minors.19 while the section 71 requirements are overly broad, we argue that in the case of clinical trials, children do not have the right to keep their involvement private, because a parent or legal guardian should provide proxy consent. in low-risk studies related to hiv prevention in adolescents, it is possible that research ethics committees (recs) may grant approval for independent consent by adolescents despite the implementation of section 71 of the nha, and in such cases, adolescents would also have an expectation of privacy for their enrolment in such studies. it is submitted that in this instance, such an expectation would be regarded as reasonable given that the rec has recognised their capacity to act without parental assistance. an older child has the right to privacy regarding certain therapeutic health interventions that form part of the hiv-prevention study. we argue that where hiv-prevention studies involve a range of health services, older children may be entitled to privacy regarding these, for a number of reasons.25 firstly, in some circumstances the law specifies that children are entitled to privacy (see section above). as a result, children have the right to confidentiality regarding condoms, contraceptives and contraceptive advice, and their hiv status, from age 12 years.3 , 20 , 25 girl children are entitled to privacy regarding a termination of pregnancy at any age.21 secondly, in other situations, although the law does not expressly set out that a child is entitled to confidentiality for that health intervention, e.g. medical treatment, it nevertheless provides that all children have the right to privacy regarding their health status.20 this considered, it is argued that when the law specifies that children have the capacity to consent independently to a particular intervention, they should have a corresponding right to privacy regarding their health status. we argue that in such a situation the child would have an expectation of privacy, given their right to confidentiality regarding their health status, and that society would regard this as reasonable, as they are able to access the service without assistance.1 , 25 thirdly, in all other situations (where the law is silent on a child’s right to privacy or it does not specify that they have the capacity to consent independently), the general principles regarding the right to privacy would have to be applied. this issue is discussed elsewhere.1 , 25 a child’s right to privacy in the hiv-prevention study (where it exists) is limited by mandatory reporting obligations for abuse, neglect and sexual offences, and in some instances , ethical obligations to protect children. the children’s act provides indirect limitations on a child’s right to privacy by requiring the mandatory reporting of children who are abused, neglected, or those who are in need of care and protection.1 , 7 , 20 this includes children performing child labour (i.e. working when aged <15 years) or those who are dependent on drugs and are not receiving any support for their addiction.20 the children’s act does not extend this obligation to report children in need of care and protection to third parties, i.e. other children whom child participants themselves may identify as being in a crisis situation. for example, if an adolescent research participant reports that a third party has been the ‘victim’ of a crime, or has ‘committed’ a crime, site staff will not have to report this information.25 however, they may have ethical obligations to intervene if a child is in clear and imminent danger, e.g. from a violent and abusive parent. in such a case, they should assist the child participant to report this information to the appropriate authorities (local police or social workers) for further investigation.25 the sexual offences act22 also requires the mandatory reporting of sexual offences against children and this may affect a child’s privacy rights within an hiv-prevention study.25 this is discussed in detail elsewhere.26 a child’s right to privacy regarding health status in hiv-prevention research may be limited by the concept of the best interests of the child. the right to privacy regarding a child’s health status may be limited where maintaining confidentiality is not in the best interests of the child.20 the children’s act does not envisage an absolute concept of privacy, but rather a flexible approach in which a range of individual factors would need to be considered in establishing whether privacy is appropriate in the circumstances. for example, maintaining confidentiality – and not informing the child’s parents – regarding a child’s truancy from school may not be in the best interests of the child, because parents are under a legal duty to ensure that their children attend school until the end of the year in which they turn 15 years.25 conclusion it is argued that a child’s right to privacy in research is a cinderella issue that has received little direct attention in the literature, unlike the two consent stepsisters. this article has attempted to act as privacy’s fairy godmother and present this as a significant issue that requires urgent attention, to ensure that the privacy rights of adolescent participants are maintained without undermining their best interests. we recommend that hiv-prevention researchers consider the following guidelines: (i) children should be advised during the recruitment stage of hiv-prevention trials or studies that they will have a limited right to privacy regarding their overall participation in the research if parental consent for enrolment is required; (ii) if parental consent is required, parents should be informed during the informed-consent process that, despite their consent, they will not receive direct feedback from researchers regarding many key components, because their children have legal rights to privacy for such components; (iii) standard operating procedures should be developed on the circumstances in which a child’s right to privacy will be limited by mandatory reporting obligations.1 , 25 it is likely that some parents will not agree to enrolment because this approach may not be consistent with their values or preferences.27 however, it is also likely that many will be willing to enrol their children in such studies when they receive assurances that children will be linked to appropriate counselling, support and health interventions to assist them. acknowledgement. funding for this article was received from the european and developing countries clinical trials partnership (edctp). the views expressed herein are not necessarily those of the edctp. references 1. slack c, strode a, mamashela m. ethical-legal challenges in adolescent hiv vaccine trials. southern african journal of hiv medicine 2007;2:12-13. 1. slack c, strode a, mamashela m. ethical-legal challenges in adolescent hiv vaccine trials. southern african journal of hiv medicine 2007;2:12-13. 2. pope a. hiv preventative research and minors. salj 2007;124(1):165-187. 2. pope a. hiv preventative research and minors. salj 2007;124(1):165-187. 3. strode a, slack c, essack z. child consent in south african law: implications for researchers, service providers and policy makers. s afr med j 2010;100(4):247-249. 3. strode a, slack c, essack z. child consent in south african law: implications for researchers, service providers and policy makers. s afr med j 2010;100(4):247-249. 4. singh ja, abdool karim ss, abdool karim q, et al. enrolling 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[http://dx.doi.org/10.1371/journal.pmed.0030180] 4. singh ja, abdool karim ss, abdool karim q, et al. enrolling adolescents in research on hiv and other sensitive issues: lessons from south africa. plos med 2006;3(7):e180. [http://dx.doi.org/10.1371/journal.pmed.0030180] 5. van oosten f. the law and ethics of information and consent in medical research. thrhr 2000;63(1):5-31. 5. van oosten f. the law and ethics of information and consent in medical research. thrhr 2000;63(1):5-31. 6. burchell j. therapeutic medical research on children. salj 1978;95(2):193-216. 6. burchell j. therapeutic medical research on children. salj 1978;95(2):193-216. 7. slack c, strode a, fleischer, t gray g, ranchod c. enrolling adolescents in hiv vaccine trials: reflections on legal complexities from south africa. bmc medical ethics 2007;8:5. 7. slack c, strode a, fleischer, t gray g, ranchod c. enrolling adolescents in hiv vaccine trials: reflections on legal complexities from south africa. bmc medical ethics 2007;8:5. 8. stobie ml, strode ae, slack c. the dilemma of enrolling children in hiv vaccine research in south africa: what is in a child’s best interest? in: van niekerk aa, kopelman lm, eds. aids in africa. cape town: david philip/new africa books, 2005:190-207. 8. stobie ml, strode ae, slack c. the dilemma of enrolling children in hiv vaccine research in south africa: what is in a child’s best interest? in: van niekerk aa, kopelman lm, eds. aids in africa. cape town: david philip/new africa books, 2005:190-207. 9. slack c, kruger m. the south african medical research council's guidelines on ethics for medical research implications for hiv-preventive vaccine trials with children. s afr med j 2005;95(4):269-271. 9. slack c, kruger m. the south african medical research council's guidelines on ethics for medical research implications for hiv-preventive vaccine trials with children. s afr med j 2005;95(4):269-271. 10. van wyk c. hiv preventive vaccine research on children: is this possible in terms of south african law and research guidelines? thrhr 2005;68(1):35-50. 10. van wyk c. hiv preventive vaccine research on children: is this possible in terms of south african law and research guidelines? thrhr 2005;68(1):35-50. 11. republic of south africa. constitution of the republic of south africa, 1996. 11. republic of south africa. constitution of the republic of south africa, 1996. 12. nm and others v smith and others (freedom of expression institute as amicus curiea). 12. nm and others v smith and others (freedom of expression institute as amicus curiea). 13. nelson rm, lewis ll, struble k, wood sf. ethical and regulatory considerations for the inclusion of adolescents in hiv biomedical prevention research. j acquir immune defic syndr 2010;54(suppl 1):s18-s24. 13. nelson rm, lewis ll, struble k, wood sf. ethical and regulatory considerations for the inclusion of adolescents in hiv biomedical prevention research. j acquir immune defic syndr 2010;54(suppl 1):s18-s24. 14. follow on african consortium of tenovifir studies (facts). 14. follow on african consortium of tenovifir studies (facts). 15. govindjee a. the right to privacy. in: govindjee a, vrancken p, eds. introduction to human rights. durban: lexisnexis butterworths, 2009:101-107. 15. govindjee a. the right to privacy. in: govindjee a, vrancken p, eds. introduction to human rights. durban: lexisnexis butterworths, 2009:101-107. 16. currie i, de waal j. the bill of rights handbook. 5th ed. johannesburg: juta, 2005. 16. currie i, de waal j. the bill of rights handbook. 5th ed. johannesburg: juta, 2005. 17. burnstein and others v bester no 1996 (2) sa 751 (cc) para 67. 17. burnstein and others v bester no 1996 (2) sa 751 (cc) para 67. 18. neethling j, potgieter jm, visser pj, knobel jc. the law of delict. 5th ed. durban: lexisnexis butterworths, 2006:323-324. 18. neethling j, potgieter jm, visser pj, knobel jc. the law of delict. 5th ed. durban: lexisnexis butterworths, 2006:323-324. 19. republic of south africa. national health act, no. 61 of 2003. 19. republic of south africa. national health act, no. 61 of 2003. 20. republic of south africa. children’s act, no. 38 of 2005. 20. republic of south africa. children’s act, no. 38 of 2005. 21. republic of south africa. choice of termination of pregnancy act, no. 92 of 1996. 21. republic of south africa. choice of termination of pregnancy act, no. 92 of 1996. 22. republic of south africa. criminal law (sexual offences and related matters) amendment act, no. 32 of 2007. 22. republic of south africa. criminal law (sexual offences and related matters) amendment act, no. 32 of 2007. 23. department of health. guidelines for good practice in the conduct of clinical trials in human participants in south africa. pretoria: doh, 2006. 23. department of health. guidelines for good practice in the conduct of clinical trials in human participants in south africa. pretoria: doh, 2006. 24. department of health. ethics in health research: principles, structures and processes. pretoria: doh, 2004. 24. department of health. ethics in health research: principles, structures and processes. pretoria: doh, 2004. 25. strode a, slack c. selected ethical-legal norms in child and adolescent hiv prevention research: consent, confidentiality and mandatory reporting [revised]. durban, south africa: european and developing countries clinical trials partnership (edctp), 2012. 25. strode a, slack c. selected ethical-legal norms in child and adolescent hiv prevention research: consent, confidentiality and mandatory reporting [revised]. durban, south africa: european and developing countries clinical trials partnership (edctp), 2012. 26. strode a, slack c. sex, lies and disclosures: researchers and the reporting of underage sex. southern african journal of hiv medicine 2009;10(2):8-10. 26. strode a, slack c. sex, lies and disclosures: researchers and the reporting of underage sex. southern african journal of hiv medicine 2009;10(2):8-10. 27. emanuel e, wendler d, killen j, grady c. what makes clinical research in developing countries ethical? the benchmarks of ethical research. j infect dis 2004;189(5):930-937. [http://dx.doi.org/10.1086/381709] 27. emanuel e, wendler d, killen j, grady c. what makes clinical research in developing countries ethical? the benchmarks of ethical research. j infect dis 2004;189(5):930-937. [http://dx.doi.org/10.1086/381709] abstract introduction what is photosensitivity? pathogenesis photosensitive drug reactions chronic actinic dermatitis actinic lichenoid leukomelanoderma of hiv lichenoid photoeruptions pellagra porphyria cutanea tarda management of photosensitive dermatoses ethical considerations conclusion acknowledgements references about the author(s) karen koch wits university donald gordon medical centre, johannesburg, south africa citation koch k. photosensitive disorders in hiv. s afr j hiv med. 2017;18(1), a676. https://doi.org/10.4102/sajhivmed.v18i1.676 overview photosensitive disorders in hiv karen koch received: 09 aug. 2016; accepted: 05 feb. 2017; published: 31 aug. 2017 copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract photosensitive disorders are common, affecting up to 5% of hiv-positive patients. hiv itself induces photosensitivity but photoaggravated drug reactions, porphyria cutanea tarda and nutritional disorders such as pellagra are also more common in patients with hiv. in south africa, actinic lichenoid leukomelanoderma of hiv is a unique photosensitive disorder which is associated with advanced hiv. it is important to be able to recognise these conditions and withdraw photosensitising medications wherever possible. introduction hiv is known to cause photosensitivity, and approximately 5% of patients with hiv have some form of photosensitive dermatitis.1 these conditions include photosensitive drug reactions, chronic actinic dermatitis (cad), pellagra, lichenoid photoeruptions, porphyria cutanea tarda (pct), pseudoporphyria, photoaggravated granuloma annulare and actinic prurigo.2 actinic lichenoid leukomelanoderma of hiv – a photosensitive dermatological condition specific to south africa – represents a possibly unique entity seen in our clinical setting.3,4 what is photosensitivity? photosensitivity is an inflammatory reaction caused by an abnormal response to ionising radiation. photosensitive rashes (as depicted in figure 1)5 affect sun-exposed areas and are more pronounced on the face, ears, scalp, posterior neck, upper back, the ‘v’ area of the chest, extensor surface of arms and dorsal hands. the key in identifying photosensitivity is involvement of sun-exposed areas with sparing on the face of the nasolabial folds, eyelids and submental areas. some skin disorders are primarily related to ionising radiation, whilst others are simply aggravated by sun exposure.5 figure 1: photosensitive distribution. pathogenesis the pathogenesis of photosensitivity in hiv is multifactorial. ultraviolet (uv) radiation causes the production of reactive oxygen species in the skin, resulting in dna damage and cell destruction. oxygen-free radical scavenging pathways are dysfunctional in hiv because of a host of factors, including a relative glutathione and thioredoxin deficiency, alterations in the dietary absorption of elements such as vitamins and flavonoids, and liver damage secondary to medications.2 certain medications such as trimethoprim-sulphamethoxazole, non-steroidal anti-inflammatory drugs (nsaids) and antiretrovirals can be photosensitising and may increase the risk of photodermatitis.1,6 photosensitivity typically occurs in patients with a cd4 t-lymphocyte count less than 200 cells/µl and often below 50 cells/µl7 and is 6.68 times more likely to occur in african americans.1 photosensitive drug reactions photosensitive drug reactions can be either photoallergic or phototoxic, both of which occur more frequently in the setting of hiv. both drug reactions can result from oral or topical medications. prescribed, over-the-counter medications and herbal supplements may all be inciting agents.8 a phototoxic reaction is a non-immunologic reaction that looks like exaggerated sunburn, whilst a photoallergic drug reaction is an eczematous immune-mediated reaction to medications.8 phototoxic drug reactions (figure 2) occur because of a variety of medications. in the setting of hiv, sulphonamides (sulphamethoxazole and trimethoprim) and nsaids are the most likely causative agents. phototoxic reactions usually occur within minutes to hours of exposure. the rash causes a burning sensation rather than pruritus. the rash is typically clearly limited to areas of sun exposure.9 figure 2: phototoxic drug reaction. photoallergic drug reactions are mediated by type iv delayed hypersensitivity and occur 24 h – 48 h after uv exposure. in the setting of hiv, they are most likely to be caused by sulphonamides, nsaids or pyridoxine. efavirenz has also been reported to cause photoallergic dermatitis.10 clinically, the lesions occur on sun-exposed sites but are not as well demarcated as phototoxic reactions. they are also eczematous and pruritic.9 treatment involves identifying and removing the causative agent, strict sun protection, use of potent topical corticosteroids and symptomatic relief. when selecting an antihistamine, it is important to avoid using older generation medications such as promethazine as these can cause or aggravate a phototoxic or a photoallergic drug reaction.11 chronic actinic dermatitis cad encompasses a spectrum of photodistributed conditions including photosensitive eczema, actinic reticuloid photosensitive eczema and persistent light reaction.8 some authors believe it to be the end stage of ongoing photosensitivity or persistent light reactivity in the absence of any known photosensitisers. it may occur in association with ultraviolet a (uva) or ultraviolet b (uvb) exposure (figure 3).12 figure 3: chronic actinic dermatitis. it usually presents as thickened scaling patches and plaques, often becoming confluent to involve large areas of the body. the condition is common in men over the age of 50 and with dark complexion. it may progress to involve unexposed sites on the body, resulting in erythroderma. it often heals with marked depigmentation resembling vitiligo. it may be an early sign of hiv.2,8 histologically, a spongiotic reaction pattern is often seen.13 photosensitising agents need to be excluded in order to make the diagnosis. treatment is difficult. strict sun avoidance, barrier-type sunscreens containing zinc or titanium, topical corticosteroids and oral h1-type antihistamines all form part of the treatment.12 actinic lichenoid leukomelanoderma of hiv actinic lichenoid leukomelanoderma (figure 4) of hiv has been described in both johannesburg and bloemfontein.3,4 unfortunately, both case series have not been published. the condition presents in the setting of advanced hiv and in the absence of exposure to any photosensitising medications. figure 4: actinic lichenoid leukomelanoderma (a and b) of hiv. the skin lesions resemble discoid lupus erythematosus, with well-circumscribed scaly plaques arranged symmetrically in photodistributed areas. the plaques normally start as violaceous hyperpigmented macules which progress to have central vitiligo-like depigmentation or erythematous discolouration with peripheral hyperpigmentation. the central area of the plaques may be quite thickened.3,4 histologically, the skin lesions differ from lupus with lichenoid changes, including irregular acanthosis, saw-toothing of rete ridges, an interface dermatitis with necrotic keratinocytes, pigment incontinence and dermal inflammation.3,4 the condition is associated with low cd4 counts, and treatment with antiretroviral therapy will theoretically result in improvements. van rensburg and sinclair reported a good response to topical corticosteroids and oral chloroquine at a dose of 200 mg daily.4 strict broad-spectrum photoprotection is essential, as it remains unclear whether uva, uvb or both are responsible for triggering this condition. in patients already on antiretrovirals, it is important to check for drug compliance or viral resistance. lichenoid photoeruptions lichenoid photoeruptions (figure 5) present as violaceous, flat-topped papules and plaques that resemble lichen planus. it occurs on the face, dorsum of the forearms, hands and the lower lip. it spares the mucosa and this can be helpful in distinguishing it from lichen planus.14 figure 5: lichenoid photoeruption. lichenoid photoeruptions may be idiopathic but have been linked to the use of nsaids or sulphamethoxazole and trimethoprim. histologically, a lichenoid pattern aids in the diagnosis.14 the skin lesions most often progress from red to slatey grey colour. the final dark pigmentation of the skin tends to persist for several months even after withdrawal of the offending agent. strict sun avoidance and sunscreen are important in recovery. patients need to be advised of lengthy recovery process.7 pellagra pellagra (figure 6) is caused by a deficiency of niacin (also known as vitamin b3) or its active metabolites. hiv infection alone as well as isoniazid and pyrazinamide treatment have both been shown to cause pellagra-like disease.15 figure 6: pellagra. niacin is produced in the body from the amino acid tryptophan. in hiv, oxidation of tryptophan along the kynurenine pathway, because of chronic inflammation, is considered to be the main cause of tryptophan depletion and hence niacin deficiency. in addition, malnutrition as a result of malabsorption and chronic diarrhoea in patients with hiv may also contribute to the disease. in south africa, tryptophan deficiency has been associated with lower cd4 counts and patients not yet on art.16 niacin is essential for numerous processes including glycolysis, amino acid metabolism and the formation of high-energy phosphate bonds. this is why niacin deficiency tends to affect areas of rapid cell turnover including the skin and the gastrointestinal system. the classic triad of pellagra is diarrhoea, dermatitis and dementia.17 in the initial phase, pellagra may resemble severe sunburn with erythema and blistering in sun-exposed areas. these skin lesions resolve leaving red–brown discolouration. typically, the patient has symmetrical superficial scaling and pigmentary discolouration on the face, neck and forearms. the characteristic discolouration over the neck and upper chest is also known as casal’s necklace.8 left untreated, hallucinations, psychosis, seizures, dementia, neurologic degeneration and coma may develop. the disease may be fatal.8 there are currently no tests or laboratory markers to diagnose pellagra. a high index of suspicion is required to make the diagnosis.17 niacin supplementation as well as the use of antiretrovirals has been shown to reverse hiv-associated niacin deficiency.18 nicotinamide at a dose of 100 mg three to four times daily should be used until clinical symptoms have completely resolved.17 porphyria cutanea tarda pct is the commonest of the porphyrias and is because of reduced enzymatic activity of uroporphyrinogen decarboxylase (figure 7).7 figure 7: porphyria cutanea tarda. accumulation of photosensitising uroporphyrins within the skin causes a blistering rash with secondary scarring on sun-exposed sites, particularly the dorsum of the hands. other symptoms include pruritus, increased skin fragility, hypertrichosis and sclerodermoid changes.19 the mechanism of pct in hiv is thought to be hiv-induced changes in porphyrin metabolism and liver injury in the setting of co-infection with hepatitis c.20 the diagnosis of pct is largely aided by a skin punch biopsy for histology and direct immunofluorescence. however, measuring actual porphyrin levels in the blood, urine or stool is critical to make an accurate assessment.21 the differential diagnosis of pct is pseudoporphyria, a phototoxic drug reaction which clinically and histologically mimics pct. pseudoporphyria occurs most commonly because of nsaids and is more common in patients on dialysis or infected with hiv.11 patients should be managed in conjunction with a haematologist. any medications potentially causing liver injury should be avoided as should any alcohol consumption. underlying hepatitis must be sought and treated. treatment consists of twice weekly low-dose chloroquine (125 mg per week) or phlebotomy to reach a target haemoglobin of 10g/dl. strict sun avoidance is required. patients with pct react to visible light rather than uv, making photoprotection particularly challenging. physical barrier sunscreens containing titanium dioxide or zinc oxide are preferable.21 management of photosensitive dermatoses it is important to exclude drug-related causes in any form of photosensitive skin condition. an antinuclear antibody (ana) test should be done to exclude cutaneous or systemic lupus erythematosus. a skin punch biopsy and immunofluorescence can be helpful in establishing a diagnosis. photo-patch testing should be used if a photoallergic drug reaction is suspected. photoprotection, sun avoidance and strict sunscreen use are essential in all forms of photoaggravated skin conditions. sunscreens should be both uvb and uva protective. the labelling of sunscreens can be confusing. ‘broad spectrum’ does not necessarily mean uva cover. a higher sun protection factor (spf) indicates the degree of uvb cover and not the degree of uva protection. sunscreens which contain physical photoprotective agents like titanium or zinc are preferable. directed therapies will depend on the exact nature of the skin condition. use of a mild cleanser and emollients can help soothe the skin. topical corticosteroids are useful during the acute phase of most photosensitive skin conditions. antihistamines are important in relieving pruritus but second-generation agents are safer. patients should be advised that post-inflammatory hyperpigmentation resulting from any photosensitive condition may take many months to entirely resolve. ethical considerations the patients participated by providing their signed consent. conclusion photosensitive disorders are common in patients with hiv affecting as many as 5% of all people. photosensitivity can cause significant distress, often healing with disfiguring hyperpigmentation. photosensitivity can herald a more serious underlying issue such as porphyria cutanea tarda or pellagra. early recognition of a photosensitive drug reaction can allow for drug withdrawal and early treatment, alleviating the degree of skin damage. acknowledgements competing interests the author declares that she has no financial or personal relationships which may have inappropriately influenced her in writing this article. references bilu d, mamelak aj, nguyen rh, et al. clinical and epidemiologic characterization of photosensitivity in hiv-positive individuals. photodermatol photoimmunol photomed. 2004;20(4):175–183. https://doi.org/10.1111/j.1600-0781.2004.00101.x cockerell cj, calame a. cutaneous manifestations of hiv disease. london: manson publishing; 2012. wolfowitz k. actinic lichenoid leukomelanoderma of hiv infection. annual congress of the dermatological society of south africa; august 2005; sun city, north west province, south africa. van rensburg e, sinclair w. actinic lichenoid leukomelanoderma (allmd) in hiv+ patients – a retrospective case series. university of the free state; 2014 (unpublished). wolff k, johnson r. fitzpatrick’s color atlas and synopsis of clinical dermatology. 6th ed. new york, ny: mcgraw-hill education/medical; 2009; p. 232–270. rodwell ge, berger tg. pruritus and cutaneous inflammatory conditions in hiv disease. clin dermatol. 2000;18(4):479–484. https://doi.org/10.1016/s0738-081x(99)00143-1 vin-christian k, epstein jh, maurer ta, mccalmont th, berger tg. photosensitivity in hiv-infected individuals. j dermatol. 2000;27(6):361–369. https://doi.org/10.1111/j.1346-8138.2000.tb02185.x james w, berger tg, elston d. andrew’s diseases of the skin: clinical dermatology. london: saunders/elsevier; 2011. fitzpatrick j, morelli j. dermatology secrets lus. 5th ed. philadelphia, pa: elsevier; 2010. yoshimoto e, konishi m, takahashi k, et al. the first case of efavirenz-induced photosensitivity in a japanese patient with hiv infection. intern med. 2004;43(7):630–631. https://doi.org/10.2169/internalmedicine.43.630 bolognia jl, jorizzo jl, schaffer jv. dermatology. 3rd ed. philadelphia, pa: elsevier saunders; 2012. meola t, sanchez m, lim hw, buchness mr, soter na. chronic actinic dermatitis associated with human immunodeficiency virus infection. br j dermatol. 1997;137(3):431–436. https://doi.org/10.1111/j.1365-2133.1997.tb03753.x norris pg, hawk jl. chronic actinic dermatitis. a unifying concept. arch dermatol. 1990;126(3):376–378. https://doi.org/10.1001/archderm.1990.01670270108018 berger tg, dhar a. lichenoid photoeruptions in human immunodeficiency virus infection. arch dermatol. 1994;130(5):609–613. https://doi.org/10.1001/archderm.1994.01690050077013 murray m. niacin as a potential aids preventive factor. med hypotheses. 1999;53(5):375–379. https://doi.org/10.1054/mehy.1999.0908 bipath p, levay pf, viljoen m. tryptophan depletion in context of the inflammatory and general nutritional status of a low-income south african hiv-infected population. j health popul nutr. 2016;35:5. https://doi.org/10.1186/s41043-016-0042-4 piqué-duran e, pérez-cejudo ja, cameselle d, palacios-llopis s, garcía-vázquez o. pellagra: a clinical, histopathological, and epidemiological study of 7 cases. actas dermosifiliogr. 2012;103(1):51–58. https://doi.org/10.1016/j.ad.2011.05.001 murray mf, langan m, macgregor rr. increased plasma tryptophan in hiv-infected patients treated with pharmacologic doses of nicotinamide. nutrition. 2001;17(7–8):654–656. https://doi.org/10.1016/s0899-9007(01)00568-8 hall j, cockerell c. hiv/aids in the post-haart era: manifestations, treatment, and epidemiology. shelton, ct: pmph-usa; 2011. coburn pr, coleman jc, cream jj, hawk jl, lamb sg, murray-lyon im. porphyria cutanea tarda and porphyria variegata unmasked by viral hepatitis. clin exp dermatol. 1985;10(2):169–173. https://doi.org/10.1111/j.1365-2230.1985.tb00547.x schulenburg-brand d, katugampola r, anstey av, badminton mn. the cutaneous porphyrias. dermatol clin. 2014;32(3):369–384, ix. https://doi.org/10.1016/j.det.2014.03.001 gonçalo, m. phototoxic and photoallergic reactions. in: johansen j., frosch p., lepoittevin jp, editors. contact dermatitis. berlin: springer, 2010. from the editor in the minds of many clinicians the management of patients infected with hiv has a narrow focus involving antiretroviral therapies, high-tech laboratory monitoring, and so on. in the field of medicine generally, and in the field of hiv medicine in particular, this approach falls short of the mark. the broader issues of a more holistic approach to the comprehensive management of the patient are highlighted in this issue of the journal. in an excellent review on the nutritional management of hiv patients steenkamp and dannhauser [po 31) make the the southern afr.ican jour.nal of hiv medicine point that there is a significant risk of nutritional deficit at all stages of the disease and that this can compromise the function of the immune system. they provide a practical approach to deal with nutritional management in different settings; at the level of basic care, when limited resources are available, and lastly in the optimal setting. they make specific recommendations regarding each of the stated goals of nutrition support, namely prevention of protein energy malnutrition, immune system support, preservation of gastrointestinai function, and improvement of psychosocial well-being. it should also be remembered that patients who are going onto antiretroviral agents need nutritional advice, in that many of these agents have specific accompanying dietary requirements and many have adverse effects on gastrointestinal function. guidelines for palliative care [po 15) benefit from a new expanded definition for the discipline. health care professionals are frequently guilty of shedding responsibility for the care of the patient, with an attitude of 'there is nothing more that can be done: these guidelines will, it is hoped, empower health care professionals to provide a caring and humane approach to their patients, particularly those in end-stage disease. the challenges of providing a community-based home-care programme are outlined in an article by or laura campbell (p. 9), who has outlined experiences emanating from port shepstone hospital and the south coast hospice team. their experiences, recommendations and ongoing review process provide a template for other similar national programmes. des martin editor, southern africon journal of hiv medicine president, southern african hivclinicians society december. 200 i abstract case report ethical consideration acknowledgements references about the author(s) lauren m. golden wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa lee fairlie wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa freda might wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa stina mojela wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africaaurum institute, south africa dorothy motsamai wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa suzan motshepe wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa enoch manyame wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa craig parker wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa helen rees wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa gloria maimela wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa matthew f. chersich wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa citation golden lm, fairlie l, might f, et al. hiv retesting in pregnant women in south africa: outcomes of a quality improvement project targeting health systems’ weaknesses. s afr j hiv med. 2018;19(1), a784. https://doi.org/10.4102/sajhivmed.v19i1.784 original research hiv retesting in pregnant women in south africa: outcomes of a quality improvement project targeting health systems’ weaknesses lauren m. golden, lee fairlie, freda might, stina mojela, dorothy motsamai, suzan motshepe, enoch manyame, craig parker, helen rees, gloria maimela, matthew f. chersich received: 05 july 2017; accepted: 17 apr. 2018; published: 12 july 2018 copyright: © 2018. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract introduction: south africa is moving towards achieving elimination of mother-to-child transmission (emtct) but gaps remain in emtct programmes. documenting successful outcomes of health systems interventions to address these gaps could encourage similar initiatives in the future. methods: we describe the effectiveness of a quality improvement project (qip) to improve hiv retesting rates during pregnancy among women who had previously tested negative by redesigning the clinic process. eight poorly-performing clinics were selected and compared with eight better-performing control clinics in a subdistrict in north west province. over nine months, root cause analysis and testing of change ideas using plan-do-study-act cycles were used to identify and refine interventions. analysis of patient flow showed that women were referred for retesting following their nurse-driven antenatal visits, and many left without retesting as this would have further prolonged their visit. processes were redesigned and standardised, where a counsellor was charged with retesting patients before antenatal consults. staff were mentored on data collection and interpretation process. quality improvement nurse advisors monitored indicators bi-weekly and adjusted interventions accordingly. results: retesting in intervention clinics rose from 36% in the three months pre-intervention to full coverage at month nine. at the end of the study, retesting in intervention clinics was 20% higher than in controls. retesting also increased in the subdistrict overall. conclusion: service coverage and overall impact of hiv programmes can be raised through care-process analysis that optimises patient flow, supported by targeted qi interventions. these qi methodologies may be effective elsewhere for identifying new hiv infections in pregnant/breastfeeding women, and possibly in other services. case report in south africa, great strides have been made towards the elimination of mother-to-child transmission (emtct) of hiv.1,2 currently, a treat all approach is in place, including emphasising repeated hiv testing for women testing negative during pregnancy/breastfeeding, and lifelong antiretroviral treatment (art) for hiv-positive women.3 despite large investments in actualising these policies, some gaps in implementation remain.2,4 hiv retesting, in particular, needs strengthening given that incident hiv infection in women during pregnancy raises the risks of infant hiv transmission several fold.5 interventions to strengthen health systems using quality improvement methodologies are key to raising programme performance and policy implementation6 and have been applied by pepfar partners in several districts.7,8,9 documenting the effectiveness of these initiatives will further encourage their replication. we describe the effectiveness of a quality improvement project (qip) to raise the performance of antenatal hiv retesting in the north west province, where the hiv prevalence among pregnant women is around 29%.2,10 the study compares eight intervention and eight control clinics in one subdistrict (figure 1), set in an urban area surrounded by several large mines. to optimise the project’s impact, we purposively selected intervention sites, aiming to include those with low levels of retesting and high patient loads (selection based on data from the preceding three months). while selecting clinics with larger patient loads might optimise the interventions’ impact, it could bias comparisons between control and intervention sites as effectiveness of interventions may vary by clinic size. in the intervention clinics, the retest rate (number of hiv-negative women retested during pregnancy ÷ hiv-negative women at first antenatal visit) was 36% compared to 66% in control sites (figure 2). the average number of women presenting to antenatal clinics (ancs) was 3948 per month in intervention clinics and 3094 in controls. also, the proportion of women attending anc prior to 20 weeks gestation was 42% in intervention sites and 56% in controls. figure 1: antenatal clinics retesting rate in four subdistricts. figure 2: antenatal clinics retest rate intervention versus control clinics. a quality improvement team was established in each facility to conduct a qip on retesting, which was implemented from january 2014 to september 2014. the ‘model for improvement’ was used to design the qips in intervention clinics.11 root cause analysis was conducted using a fishbone tool and a process map, and plan-do-study-act (pdsa) cycles were used to test and adapt change ideas (interventions) over the 9-month period.11 typically, a root cause analysis took 1–2 h, and often more than one session was required if there were many issues to ‘root out’. quality improvement teams consisted predominately of facility staff (facility managers, nurses, counsellors, data capturers and clerks) and also local area managers, a data improvement advisor and a quality improvement nurse advisor (qia). quality improvement nurse advisors, who were mentors trained in implementation of quality improvement methodologies, were each assigned two of the intervention clinics. these advisors also worked in four of the control clinics, but on interventions other than retesting. the quality improvement team met weekly to review process outcomes, identify additional issues that needed to be ‘rooted out’ and rediscuss change ideas. change ideas went through repeated testing cycles, which were monitored through a quality improvement tracker, which included process measures maintained by facility staff and qias including the use of diaries and allocation schedules. the key finding of the root cause analysis was that, across all sites, women were being lost after referral to the counsellors for retesting, as this only took place following the women’s nurse-driven antenatal consultation. by then, women had already spent considerable time in the anc and understandably did not wish to further prolong their visit. the main intervention, therefore, was to effect process redesign, whereby a counsellor was allocated to the anc to identify and test eligible women as an integrated service within the clinic, and before women had their antenatal consultation. women identified as hiv-positive in retesting commenced art at that visit. other interventions included in-service training on updated pmtct guidelines, and mentorship provided by the data improvement advisor on recording, interpreting and reporting data. while the qip methodology was standardised across intervention facilities, as was the process redesign, many other changes were specific to individual facilities, and evolved through repeated cycles of testing and adapting of changes until the desired results were achieved. the antenatal clinic hiv retest rate indicators were monitored monthly using routinely collected district health information system (dhis) data for each facility, as well as for the subdistrict as a whole. run charts were plotted monthly for intervention and control clinics. data were not available on whether women identified as hiv-infected on retesting began art as this is not measured as a separate indicator on the dhis (these women are subsumed in the total antenatal clients initiated on art). post-intervention, the average anc retest rate rose steadily from pre-intervention levels to about half that of control clinics to reach parity six months into the intervention. at month nine, retesting rates had reached full coverage in intervention clinics and were 20% higher than the controls, a difference that persisted for six months post-intervention (figure 1). moreover, many women who had not been retested in the period preceding the intervention now accessed these services (hence, figures exceeded 100%). notable changes also took place in the retesting rates for the subdistrict as a whole, as well as in other subdistricts (figure 2). at baseline, retesting rates were the lowest in the study subdistrict but had become the highest of the subdistricts at month nine. although it is plausible that rises in rates in other subdistricts were related to the intervention, this cannot be ascertained with available data. it is encouraging that improvements were sustained in the six months following the intervention, but long-term follow-up data are needed. following the intervention, the qip teams turned to providing support for pmtct services more generally. as the facility staff had become proficient in qip methodology, it is hoped that they would continue to not only apply qip methods to retesting but also to other interventions that require strengthening. in conclusion, the study indicates that process mapping, and simple, targeted qip interventions were able to improve service coverage in the intervention clinics and the subdistrict as a whole. these findings are important as they again show the impact of health system interventions, especially those involving existing clinic staff, and address semi-urban settings, which are often understudied. counsellor-based hiv testing prior to an antenatal consultation streamlined patient care, raised retesting rates and, by identifying women early after hiv infection, likely enabled timely initiation of art for these women. this suggests that quality improvement approaches to health systems strengthening, such as that presented here, are central to efforts to raise the overall performance and impact of hiv programmes. ethical consideration the authors obtained ethical approval from the university of the witwatersrand human research ethics committee (ref r14/49, protocol no. m151184) and the district health management team gave permission for study activities. acknowledgements the authors are grateful to l. badenhorst, m. seheri, z. motala, c. randeree and all facility managers and staff in the intervention clinics. funding for the project was provided under usaid health systems strengthening grant, wits rhi. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions l.m.g. wrote the first draft and was the project lead. m.f.c. and l.f. reviewed the first draft and assisted with development of the manuscript. f.m., s.m., d.m., s.m., e.m. and c.p. assisted with data acquisition and conceptualising the article. all authors contributed to data analysis and writing of the manuscript, and gave final approval of the version to be published. references unaids. on the fast-track to an aids-free generation. 2016. http://www.unaids.org/sites/default/files/media_asset/globalplan2016_en.pdf goga ae, dinh th, jackson dj, et al. population-level effectiveness of pmtct option a on early mother-to-child (mtct) transmission of hiv in south africa: implications for eliminating mtct. j glob health. 2016;6:020405. https://doi.org/10.7189/jogh.6.020405 national department of health south africa. national consolidated guidelines for the prevention of mother-to-child transmission of hiv (pmtct) and the management of hiv in children, adolescents and adults. 2015. http://www.sahivsoc.org/files/art%20guidelines%2015052015.pdf woldesenbet s, jackson d, lombard c, et al. missed opportunities along the prevention of mother-to-child transmission services cascade in south africa: uptake, determinants, and attributable risk (the sapmtcte). plos one. 2015;10:e0132425. https://doi.org/10.1371/journal.pone.0132425 drake al, wagner a, richardson b, john-stewart g. incident hiv during pregnancy and postpartum and risk of mother-to-child hiv transmission: a systematic review and meta-analysis. plos med. 2014;11:e1001608. https://doi.org/10.1371/journal.pmed.1001608 who. everybody’s business: strengthening health systems to improve health outcomes: who’s framework for action. 2007. http://www.who.int/healthsystems/strategy/everybodys_business.pdf usaid. quality improvement in hiv/aids care, prevention of mother-to-child transmission and related services: collaboration between the ministry of health and social welfare and usg-supported partners. 2008 http://www.urc-chs.com/resources/quality-improvement-hivaids-care-prevention-mother-child-transmission-and-related-services institute for healthcare improvement. plan-do-study-act (pdsa) worksheet. cambridge, ma; 2017. http://www.ihi.org/resources/pages/tools/plandostudyactworksheet.aspx usaid. health care improvement project (hci) | south africa. 2013. http://www.urc-chs.com/projects/usaid-health-care-improvement-project-hci-south-africa massyn n, day c, peer n, et al. district health barometer 2013/14. durban: health systems trust; 2014. langley gl, moen r, nolan km, nolan tw, norman cl, provost lp. the improvement guide: a practical approach to enhancing organizational performance. 2nd ed. san francisco, ca: jossey-bass publishers; 2009. august 200 i -----------the southern african journal of hiv medicine legal and ethical issues steve andrews, me chb, mcfp (sa) brooklyn medical centre, cape rerum further, the concept of informed consent has slightly different meanings when viewed legally (a viewpoint surrounding physician liability in failing to inform, disclose and assess correctly) and when viewed morally (an ethical view regarding respect fa" individual autonomy). the viewpoints are not exclusive: but it is ·important to separate them if the process of obtaining informed consent is not to become a legalistic ritual. it is also of importance that this schema does not assign an overriding importance to autonomy, and certain autonomy rights may be less pressing in the face of more weighty moral demands (for example justice, and the constraints and requirements of resource allocation). this does not invalidate the concept of autonomy, or that of informed consent, but emphasises the interrelatedness of these ideas at a societallevel. threshold elements (preconditions) • competence (to understand and decide) • voluntariness (in deciding) influences as to what is best for you because of your status as a self-determining individual'). autonomy has value in its own right, but also has instrumental value, as it promotes individual well-being. beauchamp and childress' define an approach to informed consent by dividing elements of the concept into those relating to information and those relating to consent. they also refer in their definition to the preconditional elements relating to individual competence and voluntariness in making decisions. informational elements • disclosure (of material information) • recommendation of (a plan) • understanding (of disclosed information and proposed plan) consent elements • decision (in favour of or against a plan) • authorisation/rejection (of plan) some of the specific issues raised by hiv will be analysed in the light of this model, presenting theoretical and practical applications to the dilemmas presented. first, however, it is historically, the term informed consent is a relatively recent one. from ancient times until the 1950s, disclosure and consent-seeking behaviour were largely governed by a beneficence model. this is well stated in the writings of hippocrates: 'declare the past, diagnose the present, foretell the future; practise these acts. as to disease, make a habit of two things to help, or at least do no harm~' 'both the low ond morality require thot 0 heolth professionol obtoin 0 patient's voluntory, informed consent before providing medical treotment" a review of the topic with reference to the particular problems posed by the hiv pandemic what is informed consent? informed consent and hiv the above statement would seem to be a fairly uncontroversial one. few health care professionals would argue with the need to obtain informed consent before intervening in any patient's life. the extent and meaning of the terms 'informed', and 'consent', however, cause significant debate. this paper will address a concept and definition of informed consent, and illustrate that schema with particular aspects of hiv-related problems in the application of the principle in day-to-day clinical practice. it is hoped that the arguments presented will alter the perception of informed consent as being a signature on a piece of paper legally indemnifying the professional from litigation, to one of a dynamic process vital in the strengthening of the ongoing doctor-patient relationship. further, it should be seen as one of the tools for the breaking down of the terrible secrecy that surrounds this illness, and which hampers the effective use of available methodologies for prevention and treatment of hiv and aids. driven by the nuremberg judgements on the nazi atrocities of world war ii and the emergence of the legal concept of informed consent in 1957, various external socio-political forces, and the emergence of a new schema of medical ethics, shifted the emphasis of disclosure and consent. beneficence-based models of ethics ('because of my medical knowledge i know what is best for you, and you will do it') shifted to those centred on patient autonomy ('i respect your right to decide and to act without controlling the southern african journal of iiiv mhicine -----------important to decide whether this framework is applicable to the specific situation we find ourselves in. this schema has been challenged as being founded on an individualistic philosophy of personal autonomy, one which may be at odds with certain cultural value systems, particularly in the context of communitarian societies. this argument, known as cultural relativism, implies different moral values across societies, and must be seriously considered before entertaining the application of an individual autonomy-based doctrine of informed consent in as diverse a cultural environment as south africa. this is particularly true when considering issues surrounding hiv, which have significant personal as well as community implications. rachels' challenges the general concept, arguing that while the application of principles may differ between societies, the basic moral principles themselves do not change because of the basic existence requirements of societies themselves. lindegger and richter; argue more specifically in the south african setting regarding the issue of autonomy and informed consent in hiv. they present data from phase i vaccine trial work in kwazulu-natal which suggest that, as regards informed consent, individual and collective interests are never mutually exclusive. it is apparent that within collectivist societies an individual sense of self is not lost, but may in fact be made more powerful. an autonomy-based practice should be applied in a culturally sensitive manner, but universal firstperson consent should not be ignored. community involvement should be invited only with explicit consent of the person concerned. it is also important to avoid the problems of treating cultural norms as absolute, at the risk of violating other ethical principles. given the aforementioned arguments, applying the beauchamp and childress' model in the south african setting would appear appropriate. hiv and informed cdnsent threshold elements (preconditions) beauchamp and childress' define two conditions that must be met before entering into an informed consent process with any patient. these are an assessment of the patient's competence to decide, and his or her voluntariness, or degree of separation from others' coercive infiuences. competence is essentially a legal term, referring to a court determination. it is widely used, however, as it is less cumbersome than 'decisional capacity:' in practical terms, it refers to the assessment of whether a patient will be able to enter a consent process competently. in the setting of hiv, this relates to situations such as where patients are delirious or partially or totally demented as a result of hiv disease. this may include patients presenting in a conscious or semi-conscious state with any combination of opportunistic infections, substance abuse and/or trauma. obtaining consent for interventions and procedures under these circumstances, and in particular assessing competence to provide informed consent to testing and procedures, is compromised. morally and legally, this would constitute an exception to the requirement for first-person consent, as would the setting where emergency care was immediately necessary to prevent serious harm. this problem is further complicated by the doctrine of substituted judgement, where another person makes an emergency decision on behalf of the index patient, supposedly in the best interests of the temporarily incompetent person. in the setting of hiv illness, the association with sexual and maternal transmission, as well as the stigma society assigns to the illness, may have serious ramifications for such surrogates, calling into question their ability to make objective decisions in such situations. these issues must be considered by clinicians when entering into diagnostic and therapeutic relationships with patients, and may necessitate delays in instituting interventions until the patient is considered sufficiently autonomous to provide consent personally. in the usa, the federal patient self determination act (effective december 1991) recognises that institutions are responsible for enabling patients to plan for the eventuality that they may later lack decision-making capacity' the problem of voluntariness is also important as a precondition to consent procedures, and sets a requirement that the patient enter the health care relationship without undue coercion. this is obviously an impossible to meet criterion if set absolutely no person is entirely free from coercive infiuences. but the requirement of voluntariness calls for substantial autonomy and substantial freedom from overt and subtle coercive forces. this can be difficult to assess, but it must be remembered that a consent given in a non-voluntary fashion is neither morally nor legally binding. here overt issues ['my employer sent me for the hiv test') and more subtle ones ('i'm not yet comfortable with haart, but my friends all say i should, so i suppose i should start therapy') should be recognised by the alert clinician. informational elements these elements of the informed consent procedure can cause significant problems both in understanding and in application. the decision regarding how much to disclose (should all possible side-effects of a drug be disclosed, for example?) and how to deal with the tension between beneficence and autonomy inherent in the process of recommendation is at the heart of the patient-professional, dialogue. this tension is not easily resolved, but of help is the reminder that informed consent is not static, but rather an ongoing process. disclosure should involve sufficient august 200 i august 2001-----------information so that the patient can make an informed decision, and should form part of an ongoing process. in discussing antiretroviral therapy, for example, known major side-effects should be initially disclosed, as well as requirements for dosing, cost implications, etc. the discovery of new long-term side-effect profiles (for example mitochondrial toxicities associated with the nucleoside reverse transcriptase inhibitors,' and the lipodystrophy syndrome primarily associated with the protease inhibitors') can be incorporated into the ongoing dialogue between doctor and patient in a similar way, recommendation of plans is an ongoing process involving both parties in the decisions undertaken. both disclosure and plan-making should be undertaken from a central platform of respect for the patient's right to selfgovernance, and the questions 'what do you want to know?' and 'what do you want to do?' are of great value in this assessment. it is also important that the patient has an adequate understanding of the information disclosed, and the plan proposed. faden and beauchamp' formulate their definition of understanding as follows: 'a person has a full and complete understanding of an action if there is a fully adequate apprehension of all the relevant propositions or statements (those that contribute in any way to obtaining an appreciation of the situation) that correctly describe (1) the nature of the action, and (2) the foreseeable consequences and possible outcomes that might follow as a result of performing and not performing the action: a detailed exposition of the concept of understanding is not within the scope of this paper. however, language and cultural barriers to understanding are among the most common problems encountered in the process of informed consent in the local setting. clinicians should attempt to deal with complex issues as simply as possible, and in the patients' mother tongue if he or she is not fluent in the physician's own language. further, the complexities and rapid changes in the field, coupled with the multitude of social myths surrounding hiv and aids need to be considered and incorporated into the thinking surrounding disclosure and planning. patients should be given adequate time to consider options, and to ask questions regarding diagnostics and therapy. consent elements actual consent or refusal of consent follows the preceding threshold and informational elements. initially, this involves the decision of the substantially autonomous patient for or against the plan proposed, and the subsequent authorisation for the intervention to proceed, or the rejection of such intervention. a very difficult aspect of informed consent can be the acceptance by the clinician of the patient's decision not to follow what is, in the mind of the doctor, the best and most appropriate course of action (for example, a refusal to commence antiretroviral therapy). it has been argued that in such cases doctors should make judgements as to what is best for their patients, and convince them of the correctness of such judgements. -, others, however, have seen this as mere paternalism," and argue, as does the author, that the emphasis on autonomy and patient choice must form the centre of any doctor-patient relationship, and further, must include the option of choice in opposition to the doctor's chosen plan. this does not imply passive agreement on the part of the clinician, but rather an active respect for the autonomous action of the patient. in conclusion, informed consent can be seen as a very active part of the doctor-patient relationship. far from being a mere legal notion, static and situational, it carries great moral significance, and impacts greatly upon the day-to-day management of disease. in the management of the hiv-infected patient, this broader moral concept of informed consent provides a powerful tool for the empowerment of the individual, the strengthening of the doctor-patient relationship, and for the successful management and prevention of hiv. references 1. lverson '(ji etal~ eds.lverson kv, sanders ab. mathieu o. autonomy and info(m~ consent. in: ethics in emergency medicine. tucson: galen press. 1995: 51. 2. fadet1 rr. be:auchamp tl a history and theory of informed coflse1lt. n~ york: oxford univttsity press. 1986: 62 3. eltauchamp n. childros je principles of biomedical ethics. 4th ed. nl:'w york: oxford university pr~ 1994. 4. rachds j. the challenge of cultural relativism. in: the elements of moroj philosophy. 3rd ed. boston: mcgrawhiil. 1999. 5. tindegger g. richter l cross-cultural issues in the implementation of inform~ consent in hfii vaccine uials in south africci. oral sessions, world alds conference. durban, july 2000, thore6s3. 6. nessa j. malterud k. tell me what's wrong with me: a discourse analysis approacn [q the concept of patiet1t autonomy. jmed ethics 1998; 24: 394400. 7. swam mn. mitochondrial toxicity new adverse drug eff~ts. n engl j med 1995; 333: 11~1148. 8. martinez e, macroft a. gatcia-viejo ma, er al risk of lipodystrophy in hiv-l infected patients treated with protease inhibitors: a prosp«tive cohort study. lancet 2001 ; 357; 592-598. 9. faden rr, beauchamp tl a hisroryand theory of informed consent new york: oxford univ(:rsity press. 1986: 252. 10. savulescu 1. rational non-interventional paternalism: why doctors ought to make judgements of what is best for their patients. j mtd ethics 1995; 21: 327-331. 11. madder h. existential autonomy: why patients should make their own choices. j med emics 1997; 23; 221-225. the southfrn african journal of hiv mfolcinf abstract introduction objective methods results discussion conclusion acknowledgements references about the author(s) naseem cassim national health laboratory service, national priority programmes, south africa department of haematology and molecular medicine, university of johannesburg, south africa lindi m. coetzee national health laboratory service, national priority programmes, south africa department of haematology and molecular medicine, university of the witwatersrand, south africa kathryn schnippel right to care, johannesburg, south africa department of clinical medicine, university of the witwatersrand, south africa deborah k. glencross national health laboratory service, national priority programmes, south africa department of haematology and molecular medicine, university of the witwatersrand, south africa citation cassim n, coetzee lm, schnippel k, glencross dk. compliance to hiv treatment monitoring guidelines can reduce laboratory costs. s afr j hiv med. 2016;17(1), a449. http://dx.doi.org/10.4102/sajhivmed.v17i1.449 original research compliance to hiv treatment monitoring guidelines can reduce laboratory costs naseem cassim, lindi m. coetzee, kathryn schnippel, deborah k. glencross received: 13 nov. 2015; accepted: 12 mar. 2016; published: 31 may 2016 copyright: © 2016. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: panel tests are a predetermined group of tests commonly requested together to provide a comprehensive and conclusive diagnosis, for example, liver function test (lft). south african hiv antiretroviral treatment (art) guidelines recommend individual tests for toxicity monitoring over panel tests. in 2008, the national health laboratory services (nhls) request form was redesigned to list individual tests instead of panel tests and removed the ‘other tests’ box option to facilitate efficient art laboratory monitoring. objectives: this study aimed to demonstrate changes in laboratory expenditure, for individual and panel tests, for art toxicity monitoring. method: nhls corporate data warehouse (cdw) data were extracted for hiv conditional grant accounts to assess art toxicity monitoring laboratory expenditure between 2010/2011 and 2014/2015. data were classified based on the tests requested, as either panel (lft or urea and electrolytes) or individual (alanine transaminase or creatinine) tests. results: expenditure on panel tests reduced from r340 million in 2010/2011 to r140m by 2014/2015 (reduction of r204m) and individual test expenditure increased from r34m to r76m (twofold increase). a significant reduction in lft panel expenditure was noted, reducing from r322m in 2010/2011 to r130m in 2014/2015 (60% reduction). conclusion: changes in toxicity monitoring guidelines and the re-engineering of the nhls request form successfully reduced expenditure on panel tests relative to individual tests. the introduction of order entry systems could further reduce unnecessary laboratory expenditure. introduction diagnostic laboratory services are considered an integral part of the public health system in south africa.1 laboratory testing plays a pivotal role across the hiv continuum of care, including screening of asymptomatic individuals to identify risk for developing disease, detecting disease at the earliest stages, selecting safe and effective treatments, planning disease management strategies, monitoring treatment response throughout the course of care and identifying adverse reactions.2 the national health laboratory service (nhls) is the diagnostic pathology service provider to the public health sector as mandated by act 37 of 2000.3 the nhls currently provides laboratory services coverage up to 80% of the population through a national network of over 260 laboratories. its mandate is to provide diagnostic laboratory services, research, teaching and training.4 annual laboratory expenditure has increased by 45% from r3.1 billion in 2010/2011 to r4.5bn by 2013/2014.4 annual state price increases during this period accounted for only 18%, the remainder being due to changes in test volumes and test mix. total laboratory test volumes increased from 80.2 million tests in 2011/2012 to 86 million tests in 2013/2014. this sharp increase in expenditure and test volumes could be attributed to growth in the priority public health programmes, that is, hiv, tb and cervical cancer screening, as well as state price increases.4 pressures on public health expenditure therefore require the application of evidence-based laboratory medicine (eblm) that integrates clinical decision-making and laboratory investigations, to improve patient outcomes and ensure the effective use of healthcare resources.5 the eblm approach includes eliminating laboratory tests with limited clinical value and introducing laboratory tests where published evidence proves their efficacy and effectiveness.5 for all antiretroviral treatment (art)-related testing, the hiv and aids conditional grant funds are used. the conditional grant for comprehensive care, management and treatment of hiv and aids (ccmt) is allocated by the national government to provinces.6 provincial departments of health reimburse the nhls on a fee-for-service billing arrangement, a payment model in which the service provider is reimbursed for specific service or services provided to a patient.7 in this payment model, laboratory expenditure is itemised as tariff code or codes. each test or set of tests is allocated a tariff code, for example, tariff code 02960 for the creatinine test. panel or profile tests are a predetermined group of diagnostic tests that are commonly requested together to provide a comprehensive and conclusive diagnosis, for example, urea and electrolytes (u&e) and liver function tests (lft) for the assessment of renal and liver functions, respectively. each panel consists of related individual (discrete) tests. if one of the individual tests can provide sufficient information for clinical management, replacing the more expensive panel test with specifically directed individual tests could reduce laboratory costs without negatively affecting patient outcomes or clinical interventions. however, where an lft panel is motivated by a clinician to exclude symptoms suggestive of hepatitis, the test should be performed in line with the current art guidelines. art can cause a wide range of toxicities, from low-grade intolerance that may be self-limiting to life-threatening side effects. art toxicity can be monitored clinically, as well as by a limited number of laboratory tests. the south african art guidelines list the art regimens used, as well as the routine laboratory tests required for monitoring for drug toxicity.8 since 2004, guidelines have recommended individual tests over panel tests. the current 2015 art guidelines recommend alanine transaminase (alt) testing to monitor nevirapine (nvp) toxicity and creatinine testing for tenofovir (tdf) toxicity.9 one of the early challenges was the availability of the ‘other tests’ option, which healthcare workers to order laboratory tests, including panels, on the ccmt request form. since 2008, a demand-management strategy was implemented by listing only tests prescribed by the art guidelines on the ccmt request form and removing the box for ‘other tests’, to limit the latter practice not prescribed in the art guidelines. objective the aim of the study is to review hiv & aids conditional grant laboratory expenditure for art toxicity monitoring by comparing expenditure attributable to costs of panel versus individual prescribed test ordering over a 5-year period. methods laboratory billing and expenditure conditional grant laboratory expenditure allocation is managed through a dedicated (ccmt) request form. health facilities use the ccmt request form when tests are requested for screening and art monitoring. each province has either one or more ‘zarv’ accounts on the nhls billing systems (based on provincial requirements) to which conditional grant laboratory expenditure is allocated. currently, eight provinces are using conditional grants to pay for art-related toxicity monitoring. however, it was not possible to extract conditional grant expenditure data for the kwazulu-natal province as they do not make use of a provincial conditional grant account. instead, all expenditure is allocated to the health facility without the possibility of flagging ccmt-related toxicity monitoring. laboratory expenditure data were extracted from the nhls corporate data warehouse (cdw) for art (nvp and tdf)-related toxicity monitoring (refer to table 1) between 2010/2011 and 2014/2015. table 1: classification of conditional grant tariff codes based on the tests requested to differentiate individual and panel testing. the data extract included the established tariff codes for each test performed,4 for example, 02685 for alt. additional variables captured from the cdw included the province, billable account number, customer name, financial period, test volume and laboratory expenditure. laboratory expenditure data were categorised into profiles and individual tests based on the test or tests requested and collated over the described 5-year period. for example, where an u&e test was requested (tariff code 02661), expenditure was classified as a panel test. similarly, where an alt test was requested (tariff code 02685), expenditure was classified as an individual test (refer to table 1 for the categorisation criteria used to identify panels and individual tests). the individual 2014/2015 creatinine test is charged at r27.32 compared to r76.78 for the u&e panel (64% less expensive); the alt individual test is charged r40.91 compared to r277.38 for the lft panel (85% less expensive). results conditional grant laboratory expenditure on individual and panel tests conditional grant laboratory expenditure on individual tests in 2010/2011 contributed 9% (r34 million) of the total expenditure for nvp and tdf toxicity monitoring. this increased each year, ultimately contributing 35% (r76m) by 2014/2015 (figure 1). in 2010/2011, expenditure on panel tests comprised 91% (r340m) of toxicity monitoring expenditure, reducing by over 26% to 65% by 2014/2015 (r140m). the overall expenditure on panel tests reduced from r340m in 2010/2011 to r140m by 2014/2015. similarly, expenditure on individual tests increased from r34m to r76m (twofold increase). a total reduction of r200m in laboratory expenditure incurred through panel testing was achieved in 2014/2015. figure 1: annual laboratory expenditure for nevirapine and tenofovir toxicity monitoring of antiretroviral treatment patients 2010/2011 to 2014/2015 by panel (liver function test and urea and electrolytes) and individual testing (antiretroviral treatment and creatinine), zar millions. there was a significant reduction in nvp-related panel testing, reducing from r322m in 2010/2011 to r130m in 2014/2015 (reduction of r192m) (figure 1). with the introduction of tdf in 2010, tdf-associated individual test expenditure increased from r16m in 2010/2011 to r56m in 2014/2015 (more than a three-fold increase). a reduction in laboratory expenditure of r192m was achieved through reduced nvp-related panel testing in 2014/2015. percentage of provincial conditional grant laboratory expenditure on panel tests overall, the free state province reported the lowest percentage of expenditure on panel testing reducing from 48% in 2010/2011 to 21% by 2014/2015 (figure 2). the western cape province reduced from 56% in 2010/2011 to 36% by 2014/2015. the gauteng and limpopo provinces also made significant progress in reducing panel tests to below the national average by 2014/2015. the gauteng province reduced the percentage of laboratory expenditure on panel tests from 85% in 2010/2011 to 70% by 2011/2012 (15 percentage point change). similarly, the limpopo province reduced from 92% in 2010/2011 to 75% by 2011/2012 (17 percentage point change). by 2014/2015, the gauteng province had reduced expenditure on panel tests to 50%, whilst limpopo had decreased to 62%. the overall reduction in panel testing between 2010/2011 and 2014/2015 varied between 12% (northern cape) and 35% (gauteng) with a median of 23%, with averaged reduction in laboratory expenditure of r200m attributable to guideline adherence in 2014/2015. figure 2: annual laboratory expenditure for nevirapine and tenofovir toxicity monitoring of antiretroviral treatment patients 2010/2011 to 2014/2015, by individual or panel category, zar millions. discussion laboratory expenditure on art toxicity monitoring (nvp and tdf) reported a significant reduction in the relative proportion of panel testing compared to individual tests between 2010/2011 and 2014/2015, from 91% panel testing to 65% panel testing. a significant reduction in the number of lft panels ordered, decreasing laboratory expenditure from r322m in 2010/2011 to r130m in 2014/2015, aligns with change in first-line art regimens during the period away from nvp. thus, laboratory services demand-management facilitating art guidelines, together with the request form refinement, were effective in reducing laboratory tests requests and hence, expenditure. however, despite art guidelines recommending use of the individual tests and with the demand-management request form in place, there is still substantial panel test laboratory expenditure present in 2014/2015 (r140m), especially for nvp monitoring (r130m), leaving room for additional savings. recommendations to achieve further efficiencies to further reduce laboratory expenditure of panel tests and to facilitate appropriate guideline-based testing, two options are available. the first alternative involves stopping inappropriately requested tests before they reach the laboratory network, unless the panel test is motivated for by a consultant.10 this will enable clinicians to request the panel test in patients with symptoms suggestive of hepatitis. these preventative strategies involve a focus on education for clinicians and nurses on appropriate test ordering based on the latest art guidelines.10 these interventions include healthcare worker training on appropriate test requesting and the inclusion of interpretative comments on laboratory test results,10 for example, ‘an lft is not indicated for patients on art, please request an alt as stipulated by the current art guidelines’. the second intervention to manage appropriate test requesting involves the development of order entry (oe) applications on existing electronic health records and hospital information systems, to flag inappropriate test requests before venesection commences at the health facility. this is the most effective option and alerts (and educates) the healthcare worker requesting an inappropriate test, upfront, by offering more appropriate and cost-effective tests. westbrook et al. reported that one of the main advantages of computerised oe systems is the ease of extracting and reviewing the impact of laboratory demand-management strategies by using real-time data to feedback to clinicians and nurses.11 to describe this further, computerised oe refers to an application that enables healthcare workers to order laboratory tests using a computer system at or near patient-care areas.12 additionally, oe can provide a platform that streamlines the logistical processes before the samples get to the laboratory, standardises ordering of laboratory tests, promotes adherence to guidelines and delivers decision support alerts.12 additional benefits of oe include the reduction of duplicate test orders for same patient.12,13 the removal of panel tests on the oe screen itself can reduce panel orders and increase individual test orders. oe systems may be confused with electronic gate keeping (egk), which in comparison, is a rule-based mechanism employed on laboratory information systems to reject tests based on agreed criteria when they reach the laboratory. the aim of egk is to prevent or minimise irrational and wasteful use of laboratory services. the challenge with egk is that tests are rejected at the laboratory, initially unbeknown to the attending clinician, whereas with oe the decision support alerts are generated at the health facility, enabling the healthcare worker to immediately respond. oe also supports the electronic delivery of laboratory results for integration into the patient’s record in the hospital information system.12 oe also saves wasted expenditure by removing the cost associated with pulling the sample and sending it to the laboratory in the first place (approximately r2.58 for the vacutainer tube, specimen plastic bag and request form). implementing oe systems in south africa will require adequate information technology (it) infrastructure, which is currently lacking. the combination of these interventions could act to unlock additional reductions in laboratory expenditure on toxicity monitoring and meaningfully reduce public health expenditure on providing art services. limitations due to the exclusion of the kwazulu-natal province, this study is not representative of national toxicity monitoring expenditure. from the data extract, we were unable to differentiate test orders from hospitals and primary healthcare clinics to assess differences in laboratory expenditure patterns by level of care. additionally, it was not possible to differentiate between routine toxicity monitoring versus testing following an adverse event. however, hospital expenditure is funded through the provincial equitable share and not the hiv conditional grant, and therefore, this bias is not likely to be substantial. conclusion although there have been significant cost reductions in panel testing reported here following some fairly simple interventions, widespread use of these interventions is necessary to fully exclude unnecessary laboratory expenditure and maximise cost-efficiency in delivering laboratory services required for monitoring art toxicity. the introduction of an oe system could play a significant role in this regard to reduce inappropriate laboratory test requests and public health expenditure in south africa. additionally, the introduction of oe would improve the appropriate utilisation of laboratory services across all disciplines to further reduce public health expenditure. acknowledgements the authors wish to thank sue candy and manfred tepper of nhls cdw for their assistance and support to extract laboratory expenditure data. competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions d.k.g. was the project leader and supervised the study. n.c. and k.s. designed the study, developed the methodology, prepared, analysed and interpreted the data. l.m.c. helped with data interpretation and manuscript evaluation. all authors contributed to the manuscript development. references national health laboratory service (nhls). nhls strategic plan 2010–2015. johannesburg: nhls; 2010. the lewin group i. the value of laboratory screening and diagnostic tests for prevention and health care improvement. washington, dc: american clinical laboratory, association & advanced medical technology association (advamed); 2009. contract no.: pcdocs #: 490607. national health laboratory service act (act no. 37,2000), 2000. national health laboratory service (nhls). national health laboratory service annual report 2013–14. johannesburg, south africa: national health laboratory service (nhls); 2014. horvath ar. from evidence to best practice in laboratory medicine. clin biochem rev. 2013;34(2):47–60. section 27. health budgeting and hiv: a budget and expenditure monitoring forum fact sheet. 2010. [cited n.d.]. available from http://www.section27.org.za/wp-content/uploads/2010/05/budgetingactivistpamphlet.pdf mma work group to advance health care reform. five payment models: the pros, the cons, the potential. 2015. [cited n.d.]. available from http://www.minnesotamedicine.com/past-issues/past-issues-2011/february-2011/five-payment-models-the-pros-the-cons national department of health (ndoh). the south african antiretroviral treatment guidelines. in: (ndoh) ndoh, editor. pretoria, south africa; 2010. p. 8. national department of health (ndoh). national consolidated guidelines for the prevention of mother-to-child transmission of hiv (pmtct) and the management of hiv in children, adolescents and adults. pretoria, south africa: ndoh; 2015. fryer a, smellie w. managing demand for laboratory test:a laboratory toolkit. j clinl pathol. 2012;66:62–72. http://dx.doi.org/10.1136/jclinpath-2011-200524 westbrook ji, georgiou a, dimos a, germanos t. computerised pathology test order entry reduces laboratory turnaround times and influences tests ordered by hospital clinicians: a controlled before and after study. j clin pathol. 2006;59(5):533–536. http://dx.doi.org/10.1136/jcp.2005.029983 baron jm, dighe as. computerized provider order entry in the clinical laboratory. j pathol inform. 2011;2:35. http://dx.doi.org/10.4103/2153-3539.83740 krasowski md, chudzik d, dolezal a, et al. promoting improved utilization of laboratory testing through changes in an electronic medical record: experience at an academic medical center. bmc med inform decis mak. 2015;15(1):137. http://dx.doi.org/10.1186/s12911-015-0137-7 make up sept 2007 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s p r i n g 2 0 0 7 2 5 introduction and background while the developed world has seen a substantial decline in incidence rates of cc after the advent of highly active antiretroviral treatment (haart),1-3 the enormity of the burden of aids on the african sub-continent and the anticipated delays in achieving full coverage of antiretroviral therapy (art) programmes imply that cc will continue to cause mortality among our population for years to come. the prognosis of patients with cryptococcal meningitis was very poor prior to the availability of art,4-6 but present survival rates in the context of art co-administration are much improved.7-9 consequently it has become essential to improve the initial acute management of cc in order to maximise the patient’s chances of initial survival and subsequent entry into the art treatment programme. existing international guidelines for the management of cryptococcosis10-14 are written for different geographical and clinical contexts and may be impracticable for implementation in sub-saharan africa given limited availability of drugs and other resources. objective and target audience of guidelines the objective of these guidelines is: ■ to set best practice standards for prevention, diagnosis, management and treatment of hiv-associated cc. ■ to provide practical guidance for doctors working without specialist support who encounter cc in their routine practice. ■ to identify gaps in the evidence base to guide further research. g u i d e l i n e s guidelines for the prevention, diagnosis and management of cryptococcal meningitis and disseminated cryptococcosis in hiv-infected patients convenors: kerrigan mccarthy reproductive health and hiv research unit, university of the witwatersrand graeme meintjes division of infectious diseases and hiv medicine, university of cape town and g f jooste hospital members of writing committee: beth arthington-skaggs mycotic diseases branch, centers for disease control, atlanta, usa tihana bicanic st george’s hospital medical school, london mark cotton department of paediatrics, stellenbosch university tom chiller epidemiology unit, mycotic diseases branch, centers for disease control, atlanta, usa nelesh govender mycology reference unit, national institute for communicable diseases tom harrison department of infectious diseases, st george’s hospital medical school, london alan karstaedt department of medicine, university of the witwatersrand gary maartens division of clinical pharmacology, department of medicine, university of cape town ebrahim varavia department of medicine, tshepong hospital, north west province francois venter reproductive health and hiv research unit, university of the witwatersrand hester vismer promec unit, medical research council, tygerberg international reviewers: david lalloo liverpool school of tropical medicine, uk robert a larson department of medicine, university of southern california, usa somnuek sungkanuparph mahidol university, bangkok, thailand acknowlegements: brian eley and helena rabie for comments on management of paediatric cryptococcosis. a note on definitions: cryptococcal meningitis (cm) refers to meningo-encephalitis resulting from infection; disseminated cryptococcosis refers to infection of multiple body sites; and cryptococcosis (cc) refers to infection of any body site, with an organism from the genus cryptococcus, including cryptococcus neoformans and c. gattii (formerly c. neoformans var. gattii). where the term ‘cryptococcosis’ (cc) is used in this document, it refers to either cryptococcal meningitis or disseminated cryptococcosis. pfizer supported the cost of the guideline writing committee and the poster supplied as an insert to this issue of the journal. make up sept 2007 11/21/07 10:14 am page 25 s p r i n g 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e2 6 these guidelines do not provide guidance for the management of cc in hiv-negative persons, or pulmonary cryptococcosis, or cryptococcosis with limited organ involvement. cryptococcosis rarely occurs in hiv-uninfected individuals and there are important differences in the management of these patients. hiv-positive patients with apparently limited organ involvement due to c. neoformans (e.g. cutaneous cryptococcosis) almost always have disseminated disease. structure of the guidelines ■ part 1 comprises guidelines presented as a statement in a text box followed by explanatory notes. ■ part 2 (to be found on the hiv society website, www.sahivsoc.org) presents a justification of or explanation for the guideline, quoting available evidence. part 1: guidelines with explantory notes when to consider the diagnosis of cc suspect cryptococcosis in all patients presenting with meningitis: ■ cryptococcosis is a common cause of meningitis in the aids era. ■ patients may not be aware of their hiv status and may be in a good state of health without features of hiv or aids at time of presentation with cc. clinical presentation of patients with cryptococcosis may include: ■ symptoms and signs related to raised intracranial pressure: headache, confusion, altered level of consciousness, 6th cranial nerve palsies with diplopia and visual impairment, papilloedema ■ fever of unknown origin ■ encephalitic symptoms including memory loss and newonset psychiatric symptoms ■ cutaneous lesions (fig. 1) ■ pulmonary involvement including cavitation, infiltration and consolidation. patients with cm may not have neck stiffness. lumbar puncture and ct brain lp is essential in order to establish an aetiological diagnosis of suspected meningitis. lp may also alleviate symptoms such as headache, altered level of consciousness and 6th nerve palsies which are a result of raised intracranial pressure. focal neurological signs in cm are relatively uncommon; where available, ct brain should be performed first in order to exclude the presence of space-occupying lesions. in resourceconstrained settings where ct brain is not immediately available or likely to be significantly delayed, lp may be done without prior ct brain. at lp, in suspected cc: ■ measure opening csf pressure (normal <20 cm csf) (see fig. 2). ■ request the following investigations routinely: microscopy (cell count, gram stain and india ink stain), chemistry (protein, glucose), bacterial culture, fungal culture. ■ cryptococcal antigen (crag) detection should be requested only if the india ink test is negative. recommendation 1: the diagnosis of cryptococcosis 1. when to consider the diagnosis consider in all patients (whether known or not known to be hiv-seropositive) with the following: headache, unexplained fever, nausea and vomiting, neck stiffness, confusion, seizures, abnormal behaviour, new-onset psychiatric symptoms, altered level of consciousness, focal neurological signs, diplopia, unexplained blindness or coma. 2. the role of lumbar puncture (lp) and computed tomography (ct) scan of the brain in the investigation of patients with suspected cm lp is necessary to establish an aetiological diagnosis of meningitis. occasionally, patients with cm present with focal neurological signs: where possible, these patients should have a ct scan of the brain to ensure that lp is safe. 3. the diagnosis of recurrent cc all patients with a history of a prior episode of cc and symptoms suggesting a recurrence should have an lp to confirm cc, to exclude concurrent pathology, to have an isolate for susceptibility testing and to identify and manage raised intracranial pressure. fig. 1. cryptococcal skin rash demonstrating the typical umbilicated nodules and papules. it is caused by haematogenous dissemination of the organism. make up sept 2007 11/21/07 10:14 am page 26 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s p r i n g 2 0 0 7 2 7 ■ consider the following investigations: adenine deaminase (ada), smear and culture for mycobacterium tuberculosis (requires at least 5 ml csf), tpha for syphilitic meningitis, toxoplasma gondii igg and igm. ■ retain a tube of csf at room temperature in event of laboratory error. ■ if insufficient csf is submitted, the laboratory will prioritise tests to be performed. ■ contact details for procurement of csf manometer sets may be found in appendix 2. recurrent cc a recurrent episode of cc is defined as: 1. re-appearance of symptoms of cryptococcosis (headaches, neck stiffness and/or other neurological manifestation) after symptoms had fully resolved following treatment for the initial episode with 2. appropriate laboratory confirmation of the diagnosis – refer to recommendation 2 below. in our context, recurrent cc may be a consequence of: ■ inadequate treatment of the first episode of cryptococcosis (through administration of fluconazole in the intensive phase, or insufficient dose/duration of fluconazole in the consolidation phase or failure to manage raised intracranial pressure appropriately) ■ failure to adhere to secondary prophylaxis (due to patient or health care service provider factors) ■ in the context of art, immune reconstitution inflammatory syndrome (iris) ■ development of microbiological ‘resistance’ to fluconazole. patients with suspected recurrence of cc require a lumbar puncture. clinicians should not assume that symptoms are indicative of a recurrence. lp has the following advantages: ■ the lp identifies the aetiological agent of meningitis and will provide a diagnosis of other infections if present. ■ the lp provides the laboratory with an isolate for susceptibility testing if this is available. ■ the lp establishes a diagnosis of raised intracranial pressure, and facilitates appropriate management thereof. recommendation 2: initial treatment of cryptococcosis 1. antifungal treatment of a first episode of cc induction phase: amphotericin b 1 mg/kg/dose ivi for 2 weeks (minimum 1 week). consolidation phase: fluconazole 400 mg po daily for 8 weeks. secondary prophylaxis: fluconazole 200 mg po daily for life or until cd4 >200 cells/µl for more than 6 months on art (at least 12 months’ fluconazole in total). 2. antifungal treatment of a subsequent episode* of cc that is thought to be due to fluconazole ‘resistance’: induction phase: amphotericin b 1 mg/kg/dose ivi for 2 -4 weeks or until csf is sterile. consolidation phase: fluconazole 800 mg po daily for 8 weeks with or without weekly amphotericin b 1 mg/kg. secondary prophylaxis:† fluconazole 400 mg po daily for life (at least 12 months’ fluconazole in total) or weekly amphotericin b 1 mg/ kg/dose or weekly amphotericin b 1 mg/ kg/dose plus daily fluconazole 400 mg. secondary prophylaxis can be discontinued if cd4 count is >200/µl for 6 months on art. 3. management of raised intracranial pressure (>20 cm csf) alleviate pressure initially by draining not more than 20 30 ml of csf (to decrease opening pressure by 20 fig. 2. measurement of csf opening pressure using manometer. make up sept 2007 11/21/07 10:14 am page 27 s p r i n g 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e2 8 antifungal treatment of a first episode of cc infectious diseases society of america (idsa) guidelines10 and other international guidelines recommend induction phase treatment with 0.7 1 mg/kg/dose amphotericin b and 100 mg/kg/day 5-flucytosine; unfortunately the latter drug is not available in southern africa. in head-to-head trials, the combination 5-fc with amphotericin b 0.7 mg/kg/dose is superior to amphotericin b 0.7 mg/kg/dose alone16 in terms of early fungicidal activity. in the absence of 5-flucytosine, the writers believe that southern african patients should be treated with the higher dose of amphotericin b 1 mg/kg/dose. in south african adults amphotericin b 1 mg/kg/dose is well tolerated.17 amphotericin b in the induction phase should be given for 2 weeks; however, 7 10 days may suffice.18 where amphotericin b is unavailable or cannot be given safely, transfer the patient to a centre where amphotericin b is available. if this is not possible, substitute amphotericin b induction phase treatment with fluconazole 800 mg po daily for 4 weeks followed by fluconazole 400 mg daily for 8 weeks (continuation phase). amphotericin b is superior to fluconazole at lower fluconazole doses.17,19,20 there are no studies comparing higher dose fluconazole with amphotericin b, but given that fluconazole is fungistatic, amphotericin b should always be the drug of first choice. give fluconazole intravenously in patients who are vomiting or comatose and unable to take it orally. refer for palliative care those patients who fail to respond to antifungal therapy and management of raised intracranial pressure, once other pathologies have been excluded. antifungal treatment of a subsequent episode of cc establish whether the patient was adherent to secondary prophylaxis. if not adherent, address the reasons, and treat as for the first episode of cc. if the patient is on art, this episode of cc may meet the definition for iris, in which case recommendation 5 should be followed. management of raised intracranial pressure csf opening pressure should be measured with every lp that is performed (fig. 2). patients with raised intracranial pressure experience considerable relief of symptoms following therapeutic lp. patients with persistent pressure symptoms that fail to respond to serial lumbar punctures may require lumbar drain insertion or shunting procedures. neurosurgical consultation should be sought. patients with cm should not be treated with adjunctive steroids as this may adversely affect the prognosis. laboratory-based surveillance for cc south africa has an active surveillance programme for cc. (refer to appendix 3.) recommendation 3: role of the laboratory in the diagnosis and treatment of cc 1. the laboratory diagnosis of cryptococcosis a case of cryptococcosis may be diagnosed definitively by culture or presumptively by tests indicating the presence of cryptococcus species, including a positive india ink (fig. 3) or cryptococcal antigen detection test on any specimen or mucicarmine-stained histopathological sections revealing the organism. 2. the role of antifungal susceptibility testing (afst) in management of cc afst of c. neoformans against amphotericin b has no role in patient management. afst against fluconazole is not advised in first episodes of cc, but may have value in recurrent or unresponsive cases where testing is available. 50%) at initial lp. thereafter the need for pressure relief should be dictated by recurrence of symptoms of raised intracranial pressure. patients may require daily lps. 4. pain and symptom management reduction of intracranial pressure alleviates headache and confusion. residual pain may be managed with paracetamol and mild opiates (who level 1 and 2 analgesics15). non-steroidal anti-inflammatory drugs should be avoided in patients receiving amphotericin b because concomitant administration may increase potential for nephrotoxicity. *patients who are not adherent to secondary prophylaxis may be treated with the regimen above for treatment of a first episode of cc. †these combinations are not evidence-based. fig. 3. india ink microscopy stain demonstrating encapsulated cryptococcal yeasts, some of them budding. make up sept 2007 11/21/07 10:14 am page 28 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s p r i n g 2 0 0 7 2 9 laboratory diagnostic tests for cc the india ink test has good sensitivity (80 98%)7,21 and specificity in arv-naïve and fluconazole-naïve populations, but may have lower sensitivity in patients who are receiving fluconazole for other reasons (commonly mucocutaneous candidiasis), who present early in the course of disease and who have low fungal burden in the csf. a negative india ink test does not exclude the diagnosis. crag detection by latex agglutination has excellent sensitivity and specificity, but is expensive, especially when titres are performed. the test should be performed on neat and at least one titred specimen (preferably 1:8 dilution) in order to exclude false-negative results due to the ‘prozone phenomenon’. use this test only in the following circumstances: ■ for all csf when the india ink test is negative (unless an alternative diagnosis has been made e.g. bacterial meningitis) ■ for non-csf specimens such as blood or serum or urine if csf is not obtainable. culture of c. neoformans is the gold standard for the diagnosis of cc. culture may take up to 2 weeks to appear; therefore keep culture plates for 14 days before reporting specimens as negative (liaise with the laboratory service to ensure that this is done). laboratories that offer antifungal susceptibility testing may wish to preserve cultures of c. neoformans from incident cases. antifungal susceptibility testing of c. neoformans antifungal susceptibility testing requires specialised laboratory services and trained laboratory personnel, both of which are not often available to routine general hospital services. clinicians should be wary of indiscriminate reporting of antifungal susceptibility testing results and should interpret these results with specialist consultation. clinically reliable and objective values for interpretation of susceptibility testing (mic breakpoints) of c. neoformans against fluconazole have not been established; therefore although testing can be done, results may not be predictive of clinical response and outcome. microbiological resistance to fluconazole may be present when a recurrent isolate of c. neoformans has a higher mic (at least 2 dilutions) than the incident isolate when the afst has been done in parallel (i.e. at the same time), using e-test or clsi m27-a2 methodology and where control strains have been included. given that afst can only be done in this manner after management of the patient’s recurrent episode has commenced, afst results are not expected to impact significantly on initial management of relapse episodes. susceptibility testing methodology of c. neoformans against amphotericin b is not sufficiently developed for applicability to the clinical setting. counselling of patients diagnosed with cryptococcosis patients, their relatives and caregivers should be counselled regarding cryptococcosis: ■ that the initial treatment phase will last 10 weeks, and ■ that secondary prophylaxis will be required for an extended period of time. clear written instructions regarding the patient’s medication schedule should be provided. all patients who do not know their hiv status should be strongly advised to undergo testing as part of providerinitiated testing and counselling (pitc). a diagnosis of cc represents an opportunity for enrollment into hiv services. in the context of art, patients with cryptococcosis have a reasonable prognosis for survival. sample drugs (fluconazole, antiretroviral drugs, cotrimoxazole) including the dispensed containers and pills are helpful aids for counselling the patient. patients who are confused should be counselled when their level of consciousness has improved, and ideally a family member or caregiver should be involved in the counselling. concurrent opportunistic infections patients with cc are profoundly immunosuppressed and often have concurrent opportunistic infections including tuberculosis. clinicians should ensure that patients who have symptoms suggestive of tb (fevers, cough, night sweats, loss of weight) are appropriately investigated as pulmonary cryptococcosis may mimic pulmonary tb. microscopy and culture for tuberculosis of sputum and other clinical specimens should be performed where indicated. recommendation 4: supplementary managment of cc 1. counselling of patients diagnosed with cc all patients who are diagnosed with cc should be counselled (once fully conscious) regarding: • the need for compliance with fluconazole therapy (both consolidation and secondary prophylaxis) • the urgent need for hiv testing (if hiv status unknown) and lifelong art. 2. concurrent opportunistic infections including tuberculosis in patients with cc diagnose and treat concomitant opportunistic infections in patients with cc, particularly pulmonary and extrapulmonary tuberculosis, pneumocystis pneumonia (pcp), bacterial pneumonia, and chronic diarrhoea. all patients with cc should have a chest xray. make up sept 2007 11/21/07 10:14 am page 29 s p r i n g 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e3 2 prevention of cc art should be initiated after patients have been screened for the presence of opportunistic infections by clinical history and examination, with or without laboratory investigations as indicated. screening for cc by performing serum crag testing in patients with low cd4 counts and evidence of systemic illness prior to commencement of art may have a role in preventing the development of cc soon after art initiation22-24 (see below). primary prevention of cc with fluconazole may have a limited role in patients with cd4 counts below 100 cells/µl where delays in access to art are anticipated.25 initiation of art in arv-naïve clients with cc all hiv-positive patients who develop cc are eligible for cotrimoxazole preventive therapy (cpt) and art. evidence for the optimal timing of art initiation is not available: we believe art is most appropriately started 2 4 weeks after treatment for cc has commenced. although no prospective evidence exists in this regard, given these patients’ advanced immunosuppression, delaying art introduction beyond 4 weeks to reduce the risk of iris may increase the risk of mortality. the long in-hospital stay associated with amphotericin b therapy should facilitate pre-art counselling, identification of a treatment supporter and early referral to an art centre. patients who are initiated on art should be counselled regarding the risk of development of iris. if a patient is referred to another facility for art, the need for fluconazole maintenance therapy should be communicated. antiretroviral regimens including nucleoside and nonnucleoside reverse transcriptase inhibitors are appropriate. caution should be observed when using nevirapinecontaining art regimens as fluconazole increases nevirapine levels and may result in hepatotoxicity with fluconazole coadministration. immune reconstitution inflammatory syndrome patients who are receiving art may develop iris related to infection with cryptococcus species in the following scenarios: ■ ‘unmasking’ iris occurs in patients not known to have cc who are commenced on art and develop an incident episode of cc within the first 3 months of art. these episodes of cc usually meet the definition for a diagnosis of cc (recommendation 3) and should receive antifungal therapy according to recommendation 2. patients who are eligible for art should have opportunistic infections excluded; serum crag testing may identify patients at risk for ‘unmasking’ iris. ■ ‘paradoxical’ iris occurs in patients who have a diagnosis of cc before starting art and have responded to antifungal therapy. the most common presentation of paradoxical iris is recurrent meningitis associated with raised intracranial pressure, but other manifestations like enlarging cryptococcomas, encephalitis and lymphadenitis are described. recommendation 5 advises on paradoxical iris. recommendation 6: cc in special populations 1. cryptococcosis in the pregnant patient no alterations in the management of cryptococcosis are required for treatment of cryptococcosis in pregnancy. recommendation 5: the role of antiretroviral therapy in patients with cc role of art art is the most effective intervention to treat aids, and is the most potent mechanism to prevent both primary and secondary recurrences of cc. commence patients (according to relevant local guidelines) on art a matter of urgency. 1. art all patients with hiv and cc require art and cotrimoxazole prophylactic therapy. art should be commenced 2 4 weeks after initiation of antifungal therapy using relevant national guidelines for drug regimens and monitoring. 2. immune reconstitution inflammatory syndrome (iris) and cc management of a patient with suspected paradoxical iris requires the following: • continuation of art • lumbar puncture to exclude additional pathology, to obtain an isolate for susceptibility testing to fluconazole and to measure intracranial pressure • ct scan of the head when focal neurological signs are present • appropriate antifungal therapy • culture-positive cases should receive treatment according to recommendation 2 • culture-negative cases should continue with their consolidation phase treatment or secondary prophylaxis (clinicians should ensure adherence) as appropriate • oral steroid therapy with prednisone 1 mg/kg daily for at least a week if symptoms fail to respond after appropriate management of raised intracranial pressure and symptomatic treatment. some patients require prolonged courses of steroids to control iris manifestations. make up sept 2007 11/21/07 10:14 am page 32 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s p r i n g 2 0 0 7 3 3 cryptococcosis in children cryptococcosis in children is uncommon, but does occur with a bimodal distribution, firstly in neonates and young infants where the mode of acquisition is possibly vertical, and secondly in school-going and adolescent children who acquired hiv infection in early childhood or infancy. the latter group presents very similarly to adult cc. drug interactions administration of fluconazole in patients on concurrent intensive phase tb treatment appears to be a risk factor for drug-induced hepatitis.26 patients should be monitored both clinically and with laboratory testing. because of rifampicin induction of fluconazole metabolism, some clinicians consider increasing the dose of fluconazole by 50% during continuation phase and secondary prophylaxis. 1. drug information refer to text below, and appendix: amphotericin b information sheet for clinical staff 2. additive drug toxicities, interactions and required alterations of dose in patients receiving fluconazole together with other anti-infective agents fluconazole is an enzyme inhibitor and may cause levels of concomitantly administered drugs to increase. concurrent medication (with drug interaction/ required fluconazole) additive toxicity alteration pyrazinamide, drug-induced none (clinical isoniazid hepatitis and laboratory monitoring is indicated) rifampicin reduced levels consider of fluconazole increasing the secondary drug-induced fluconazole hepatitis prophylaxis dose by 50%*. clinical and laboratory monitoring is indicated regarding the potential for hepatotoxicity nevirapine drug-induced none (clinical hepatitis monitoring with laboratory investigation if indicated). some clinicians would not exceed a fluconazole dose of 400 mg daily. *see caveat below. although fluconazole is teratogenic, the high mortality of the condition necessitates optimal management of the mother. 2. fluconazole prophylaxis in women of child-bearing age fluconazole is teratogenic. women of childbearing age and potential who require fluconazole in the course of treatment for other conditions should be counselled regarding the need for appropriate contraception. 3. cryptococcosis in paediatric patients cryptococcosis in children should be suspected, diagnosed and treated according to guidelines for adults with the following exceptions as listed below: antifungal treatment of cc in paediatric patients induction phase: amphotericin b 1 mg/kg/dose ivi for 2 weeks (relapse episodes should be treated for 4 8 weeks, preferably until csf fungal culture is negative). adequate hydration during amphotericin b treatment should be maintained. consolidation phase: fluconazole 12 15 mg/kg once daily for a further 8 weeks (the maximum dose should not exceed 400 mg). secondary prophylaxis: fluconazole 6 10 mg/kg once daily for life. in children over the age of 2 years who have evidence of sustained immune reconstitution on art (2 6 years old: cd4 percent > 25%, more than 6 years old: cd4 count >200 cells/µl) and who are asymptomatic with their last episode of cryptococcosis having been more than 12 months previously, secondary prophylaxis can be stopped. management of raised intracranial pressure recommendations for management of intracranial pressure in adults apply to children (i.e. repeated lumbar punctures). for refractory raised intracranial pressure, referral to or discussion with a specialist centre is advised. recommendation 7: drug information, toxicities and interactions in patients treated for cc make up sept 2007 11/21/07 10:14 am page 33 s p r i n g 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e3 4 co-administration of fluconazole with nevirapine increases nevirapine levels and consequently the potential for hepatotoxicity. drug information amphotericin b (see also detailed information sheet for clinical staff in appendix 1) 1. dosage and administration a) controlled infusion over 4 hours of amphotericin b at 1 mg/kg in 1 litre of 5% dextrose water should be given after prehydration with 1 litre normal saline containing 20 mmol kcl (1 ampoule). a ‘test dose’, previously common practice, need not be given if the daily dose is run slowly over the first half hour of administration. 2. prevention and management of side-effects a) major side-effects include renal impairment due to renal tubular toxicity, usually in the second week of therapy, hypokalaemia, hypomagnesaemia and renal tubular acidosis, anaemia, febrile reactions and chemical phlebitis. b) nephrotoxicity and electrolyte abnormalities may be prevented by avoiding amphotericin b in patients with renal impairment, by prehydration, by avoiding concurrent use of other nephrotoxins (non-steroidal anti-inflammatory agents (nsiads), aminoglycosides including streptomycin) and by routine administration of potassium and magnesium supplements. c) phlebitis may be prevented by rotation of the drip site every 2 3 days and by flushing of lines after the amphotericin b infusion is complete. d) febrile reactions may be prevented when subsequent doses of amphotericin b are given by administration of paractetamol 1 g 30 minutes prior to dose. severe febrile reactions may require hydrocortisone 25 mg ivi at the start of the infusion. e) if nephrotoxicity occurs, manage as follows: i) if creatinine increases by 2-fold or more, omit a dose and/or increase prehydration to 1 litre 8-hourly ii) if creatinine fails to decrease after the above intervention, stop amphotericin b therapy and use fluconazole. fluconazole 1. dosage and administration. fluconazole has excellent bioavailability when administered orally; intravenous administration is rarely required. csf penetration is >80% of serum levels. 2. prevention and management of side-effects fluconazole is well tolerated. patients with renal impairment require dose adjustment according to glomerular filtration rate (gfr): ■ gfr 10 50 ml/min, reduce dose by up to 50% ■ gfr <10 ml/min, give 25% of dose. calculate gfr using formula as follows: 140 � age � ideal weight 0.82 � serum creatinine women: multiply total by 0.85 side-effects include nausea and vomiting, abdominal pain, rash and drug-induced hepatitis. clinical monitoring for symptoms of hepatitis (nausea and vomiting, abdominal pain and jaundice) should be performed, with laboratory testing (alanine transaminase, alt) if these symptoms occur. fluconazole may be teratogenic: women of child-bearing potential should be advised regarding the need for effective contraception while on the drug. fluconazole is an enzyme inhibitor and may increase levels of certain drugs. clinically relevant drug interactions requiring interventions are listed in recommendation 7 above. flucytosine flucytosine is not available in southern africa. flucytosine is included in international guidelines10 for the management of cc in the context of induction phase and co-administration with amphotericin b. new antifungal agents and their role in the management of cryptococcosis 1. echinocandins (caspofungin/micafungin) have no activity against c. neoformans.27 2. voriconazole has excellent activity against c. neoformans,28,29 but is not available in the public sector in southern africa and is expensive. appendix 1: intravenous amphotericin b: information sheet for clinical staff dosage and administration intravenous amphotericin b is prescribed for once-daily administration according to the patient’s weight (dose = 1 mg/kg). total doses will usually range between 25 mg and 80 mg. prehydrate patients with 1 litre of normal saline containing 1 ampoule (20 mmol) of kcl infused over 2 hours before the amphotericin b infusion. this reduces the risk of renal toxicity and hypokalaemia, both side-effects of amphotericin b. amphotericin b comes in a vial that contains 50 mg of powder. each vial is reconstituted with 10 ml of sterile water. the appropriate dose is then drawn up according to the table on p. 35. the total dose must then be injected into a 1-litre bag of 5% dextrose or 10% dextrose and shaken to mix. once mixed, the bag must be administered within 24 hours or discarded. protection of the infusion from light (with brown bag) is not necessary provided it is administered within 24 hours of preparation. the amphotericin b should never be mixed with normal saline or half normal saline as it will precipitate. the line that is used for amphotericin b should not be used for administering any other drugs. the infusion must be given over 4 hours and not faster otherwise it can cause cardiac problems. once the infusion is complete the line should be flushed with 100 ml normal saline. make up sept 2007 11/21/07 10:14 am page 34 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s p r i n g 2 0 0 7 3 5 side-effects: how to avoid and manage them nephrotoxicity and electrolyte abnormalities may be prevented by prehydration with normal saline containing potassium (as above). nephrotoxicity usually occurs in the second week of therapy with amphotericin b; baseline and twice-weekly monitoring of creatinine, potassium and magnesium is appropriate. if creatinine doubles, consider omitting a dose of amphotericin b or increasing prehydration to 1 litre 8hourly. if creatinine remains elevated, stop amphotericin and use fluconazole. oral potassium and magnesium supplementation may be given pre-emptively to prevent electrolyte abnormalities. phlebitis is very common in patients receiving amphotericin b and increases the risk of localised cellulitis as well as potentially fatal septicaemia. to minimise risk of phlebitis, flush lines with 100 ml normal saline after amphotericin b infusion is complete. do not leave the empty bag of amphotericin b hanging overnight attached to the patient’s drip. remove the drip if the patient spikes a fever having been previously apyrexial, or at first sign of redness or patient discomfort at site. rotate drips routinely every 2 – 3 days. anaemia may occur in patients receiving amphotericin; however be sure to exclude other treatable causes. monitor haemoglobin weekly. febrile reactions may occur; during the first infusion run the drip at a slow rate over first half hour and observe the patient closely. if febrile reactions occur, treat with paracetamol 1 g 30 minutes before infusion or if severe, hydrocortisone 25 mg ivi at the start of subsequent infusions. appendix 2: contact details for ordering manometry sets in southern africa appendix 3: contact details for germs-sa surveillance for cc surveillance for cc is performed by the germs-sa laboratory network that is co-ordinated by the national institute for communicable diseases (nicd). all cases (india ink or crag or culture positive cases) and all cultures of cryptococcus species should be referred to the nicd. dr nelesh govender (neleshg@nicd.ac.za; 011 386-6000) may be contacted for assistance pertaining to submission of isolates and cases. references 1. mirza sa, phelan m, rimland d, et al. the changing epidemiology of cryptococcosis: an update from population-based active surveillance in 2 large metropolitan areas, 1992-2000. clin infect dis 2003; 36(6): 789-794. 2. friedman gd, jeffrey fw, udaltsova nv, hurley lb. cryptococcosis: the 19812000 epidemic. mycoses 2005; 48(2): 122-125. 3. dromer f, mathoulin s, dupont b, laporte a. epidemiology of cryptococcosis in france: a 9-year survey (1985-1993). french cryptococcosis study group. clin infect dis 1996; 23(1): 82-90. 4. heyderman rs, gangaidzo it, hakim jg, et al. cryptococcal meningitis in human immunodeficiency virus-infected patients in harare, zimbabwe. clin infect dis 1998; 26(2): 284-289. 5. bogaerts j, rouvroy d, taelman h, et al. aids-associated cryptococcal meningitis in rwanda (1983-1992): epidemiologic and diagnostic features. j infect 1999; 39(1): 32-37. 6. moosa my, coovadia ym. cryptococcal meningitis in durban, south africa: a comparison of clinical features, laboratory findings, and outcome for human immunodeficiency virus (hiv)-positive and hiv-negative patients. clin infect dis 1997; 24(2): 131-134. 7. schaars cf, meintjes ga, morroni c, post fa, maartens g. outcome of aidsassociated cryptococcal meningitis initially treated with 200 mg/day or 400 mg/day of fluconazole. bmc infect dis 2006; 6: 118. 8. dromer f, mathoulin-pelissier s, fontanet a, ronin o, dupont b, lortholary o. epidemiology of hiv-associated cryptococcosis in france (1985-2001): comparison of the preand post-haart eras. aids 2004; 18(3): 555-562. 9. manosuthi w, sungkanuparph s, thongyen s, et al. antifungal susceptibilities of cryptococcus neoformans cerebrospinal fluid isolates and clinical outcomes of cryptococcal meningitis in hiv-infected patients with/without fluconazole prophylaxis. j med assoc thai 2006; 89(6): 795-802. 10. saag ms, graybill rj, larsen ra, et al. practice guidelines for the management of cryptococcal disease. infectious diseases society of america. clin infect dis 2000; 30(4): 710-718. 11. bohme a, ruhnke m, buchheidt d, et al. treatment of fungal infections in hematology and oncology – guidelines of the infectious diseases working party (agiho) of the german society of hematology and oncology (dgho). ann hematol 2003; 82 suppl 2: s133-s140. 12. masur h, kaplan je, holmes kk. guidelines for preventing opportunistic infections among hiv-infected persons – 2002. recommendations of the u.s. public health service and the infectious diseases society of america. ann intern med 2002; 137(5 pt 2): 435-478. 13. berenguer j, laguna f, lopez-aldeguer j, moreno s. prevention of opportunistic infections in adult and adolescent patients infected with the human immunodeficiency virus in the era of highly active antiretroviral therapy. recommendations of the grupo de estudio del sida (gesida/plan national sobre el sida). enferm infecc microbiol clin 2000; 18(9): 457-468. 14. mofenson lm, oleske j, serchuck l, van dr, wilfert c. treating opportunistic infections among hiv-exposed and infected children: recommendations from cdc, the national institutes of health, and the infectious diseases society of america. mmwr recomm rep 2004; 53(rr-14): 1-92. 15. gabriel s. cancer pain relief; a guide to opioid availability. 2nd ed. geneva: world health organisation, 1996. 16. brouwer ae, rajanuwong a, chierakul w, et al. combination antifungal therapies for hiv-associated cryptococcal meningitis: a randomised trial. lancet 2004; 363: 1764-1767. 17. bicanic t, meintjes g, wood r, et al. fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviralexperienced patients treated with amphotericin b or fluconazole. clin infect dis 2007; 45(1): 76-80. 18. tansuphaswadikul s, nantawat w, phonrat b, boonpokbn l, mctm ag, pitisuttithum p. comparison of one week with two week regimens of amphotericin b both followed by fluconazole in the treatment of cryptococcal meningitis among aids patients. j med assoc thai 2006; 89(10): 1677-1685. 19. saag ms, powderly wg, cloud ga, et al. comparison of amphotericin b with fluconazole in the treatment of acute aids-associated cryptococcal meningitis. the niaid mycoses study group and the aids clinical trials group. n engl j med 1992; 326(2): 83-89. 20. larsen ra, leal ma, chan ls. fluconazole compared with amphotericin b plus flucytosine for cryptococcal meningitis in aids. a randomized trial. ann intern med 1990; 113(3): 183-187. 21. mccarthy km, morgan j, wannemuehler ka, et al. population-based surveillance for cryptococcosis in an antiretroviral-naive south african province with a high hiv seroprevalence. aids 2006; 20(17): 2199-2206. 22. micol r, lortholary o, sar b, et al. prevalence, determinants of positivity, and clinical utility of cryptococcal antigenemia in cambodian hiv-infected patients. j acquir immune defic syndr 2007; 45: 555-559. 23. french n, gray k, watera c, et al. cryptococcal infection in a cohort of hiv-1infected ugandan adults. aids 2002; 16(7): 1031-1038. 24. desmet p, kayembe kd, de vc. the value of cryptococcal serum antigen screening among hiv-positive/aids patients in kinshasa, zaire. aids 1989; 3(2): 77-78. 25. chang lw, phipps wt, kennedy ge, rutherford gw. antifungal interventions for the primary prevention of cryptococcal disease in adults with hiv. cochrane database syst rev 2005; 3: cd004773. 26. pukenyte e, lescure fx, rey d, et al. incidence of and risk factors for severe liver toxicity in hiv-infected patients on anti-tuberculosis treatment. int j tuberc lung dis 2007; 11(1): 78-84. 27. cappelletty d, eiselstein-mckitrick k. the echinocandins. pharmacotherapy 2007; 27(3): 369-388. 28. pfaller ma, zhang j, messer sa, et al. in vitro activities of voriconazole, fluconazole, and itraconazole against 566 clinical isolates of cryptococcus neoformans from the united states and africa. antimicrob agents chemother 1999; 43(1): 169-171. 29. scott lj, simpson d. voriconazole: a review of its use in the management of invasive fungal infections. drugs 2007; 67(2): 269-298. zenith surgical cc telephone and e-mail postal address: street address: tel: 011 991-7011 po box 1264 14 6th avenue fax: 011 472-1270 fontainebleau maraisburg zenithsurgical@tiscali.co.za 2032 roodepoort johannesburg total volume drawn no. of vials prescribed dose up from vial(s) required 25 mg 5 ml 1 30 mg 6 ml 1 35 mg 7 ml 1 40 mg 8 ml 1 45 mg 9 ml 1 50 mg 10 ml 1 55 mg 11 ml 2 60 mg 12 ml 2 65 mg 13 ml 2 70 mg 14 ml 2 75 mg 15 ml 2 80 mg 16 ml 2 make up sept 2007 11/21/07 10:14 am page 35 make up sept 2007 5 well, spring has sprung and this bumper spring edition is the final for 2007. what a year it has been! important circumcision trial results push us to ask about the implementation logistics, and equally important negative results in hiv vaccine, microbicide and diaphragm research make us realise that the road to efficacious prevention modalities will be a long one. in the meantime safer sex, more testing and positive prevention are what we must rely on to curb the epidemic. we must also continue to hone our expertise in treating both hiv and the myriad of opportunistic infections associated with hiv. this edition highlights fungal infections, with excellent laboratory insights from govender, a terrific cryptococcal review by jarvis et al., and of course our signature guidelines, in this edition focusing on cryptococcal management. thanks to the guideline committee led by graeme meintjies for this. a case study illustrating just how complex multiple opportunistic infections can be is also presented. we also highlight the 3rd south african hiv conference, held mid-year in durban. it focused on consensus building with the launch of the conference declaration (www.saaidsconference.com), and featured here are some of the highlights as captured by the track rapporteurs and a synopsis of a plenary on positive prevention by kalichman. as the epidemic moves into its 3rd decade, we pay tribute to reuben sher, a great stalwart and warrior of the south african epidemic. we also feature a thought-provoking article by whiteside et al. entitled ‘aids: a darwinian event?’, in which the authors question why historians have not written about the hiv epidemic as a history-changing event and make a convincing case for this. at the end of 2007, with its highs and lows, its politics and its triumphs (not least those in green and gold), despite having an hiv epidemic of unprecedented proportion and much work to be done, it is good to be in south africa! linda-gail bekker editor from the editor t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s p r i n g 2 0 0 7 there’s never a dull moment on the south african hiv scene. the dramatic firing of the deputy minister of health was greeted with shock by many of us, and elicited a strong reaction from the society, as well as many other organisations. deputy minister nozizwe madlala-routledge gave hope and inspiration to many health care workers after years of arrogance and disregard by senior political officials within the department of health. the society extends its gratitude for her contribution to the national strategic plan, and we hope her political future is bright. the society has a new website (http://www.sahivsoc.org/) which i urge you to visit, where you can find electronic copies of the journal and lots more. we also have a major and evolving project, our karabo website, which is intended to be a map-based directory of all hiv services, including testing, cd4 access and art availability. check it out at http://www. karabo.org.za/#home. francois venter president m e s s a g e f r o m t h e e x e c u t i v e 5 make up sept 2007 11/21/07 10:12 am page 5 99 sajhivmed june 2013, vol. 14, no. 2 cpd questionnaire vol. 14, no. 2 true (a) or false (b): regarding 'men who have sex with men (msm)-appropriate' health services in south africa (sa): 1. local evidence suggests that there are high rates of hiv among the population of msm. 2. biologically, unprotected vaginal sex is more likely than unprotected receptive anal sex to transmit hiv. 3. for a health-provision site to be considered msm-appropriate, services need to be friendly, sensitive and competent. with regard to managing aids-related kaposi’s sarcoma (ks) and pregnancy: 4. in sub-saharan africa, ks with pulmonary manifestations generally has an associated life expectancy of <6 months. 5. patients with a favourable prognostic index should be treated with a combination of antiretroviral therapy (art) and systematic chemotherapy immediately. 6. liposomal doxorubicin and a taxane group constitute the backbone of current systemic chemotherapy against ks in the developed world. regarding screening for suicide risk among hiv-infected persons in the immediate post-diagnosis period: 7. hiv-infected individuals are at higher risk of suicidality than the general population in sa. 8. a number of psychometric, clinical and biological measures to detect suicide risk have made it simple to measure and predict this risk accurately. 9. self-reported screening tools provide an adequate evaluation of suicidality. regarding the challenges to delivering quality care in a prevention of mother-to-child transmission (pmtct) of hiv programme in soweto, sa: 10. knowledge of pmtct interventions in sa is high among pregnant women and healthcare providers. 11. challenges in scaling up pmtct services in the sa public healthcare sector relate to coverage at different steps of the pmtct cascade, and also to the quality of care rendered in the pmtct services. 12. art initiated pre-conception decreases the risk of motherto-child transmission of hiv significantly. 13. disclosure of hiv status is unrelated to pmtct intervention uptake and adherence among women. regarding hiv sero-conversion during late pregnancy and when to retest: 14. pregnancy poses an increased risk for hiv acquisition by women. 15. high viral loads during primary hiv infection increase risk of vertical transmission in utero, peripartum and post partum. 16. the two hiv tests recommended during pregnancy – one at the first antenatal visit and one at 32 weeks of gestation – are adequate to identify all new hiv infections in pregnant women. regarding hiv/human t-cell lymphotropic virus type 1 (htlv-1) co-infection: 17. co-infections, previous splenectomy, and lymphoproliferative disorders are among the pathophysiological causes for a normal or raised cd4+ count in the background of a progressive hiv infection. 18. hiv-1/htlv-1 co-infected patients have been found to progress to advanced clinical disease with a high hiv viral load but in the presence of a normal or higher than normal cd4+ count. regarding parental presence within households and the impact of art in khayelitsha, sa: 19. young adults with advanced hiv disease are likely to rely on and live with their families for support, but this can be reversed after initiation of art. regarding art adherence clubs as a long-term retention strategy for clinically stable patients receiving art: 20. the art adherence club model leads to better adherence and long-term retention in care for clinically stable art patients compared to usual clinical services. c p d q u e s t io n a ir e five cpd points are awarded for the correct completion and submission of the questions below. cpd questionnaires must be completed online via www.cpdjournals.co.za. after submission, you can check the answers and print your certificate. this programme is available free of charge to members of the sa hiv clinicians society and sama only. instructions 1. read the journal. all the answers will be found there. 2. go to www.cpdjournals.co.za to answer the questions. accreditation number: mdb001/011/01/2013 (clinical) 2013/04/29 3:21 pm hiv message from executive message from the executive there is little doubt that 2012 ended on a high note. the inaugural conference of the southern african hiv clinicians society was a resounding success; with over 950 attendees and excellent speakers (both local and international), i believe that we achieved our aim of ‘striving for clinical evidence.’ even before the dust had settled on the conference, dr aaron motsoaledi, south african minister of health minister, announced two very important strides for our national antiretroviral therapy (art) programme. firstly, for the first time, fixed-dose combinations (fdcs) are going to be introduced. this means that most south africans who are receiving first-line therapy will be taking one tablet a day. the price for the combination of tenofovir, emtricitabine and efavirenz is r89.37 – one of the lowest in the world. in the coming months, the society will be training and educating healthcare workers and patients on when and how to change to fdcs.  if that was not enough good news, at the same press conference motsoaledi announced that all hiv-infected pregnant women will be given triple therapy – usually the single-dose fdc – irrespective of their cd4+ cell count. the work is not over. let’s get these fdcs out there, enrol as many hiv-pregnant women on therapy as possible, and eradicate mother-to-child transmission of hiv. f conradie president southern african hiv clinicians society johannesburg fconradie@witshealth.co.za hiv march make up 01 h o r i z o n s trials and tribulations the medical maxim of 'first do no harm' is never more relevant than during development of a medicinal agent or intervention, whether it be drug, vaccine, diagnostic or procedure. over many years a phased clinical trial process has been developed along with safety and monitoring processes to ensure human subject dignity, privacy and autonomy, and the minimisation of risk as well as research integrity. before any testing in human subjects the process involves pre-clinical work, including toxicity studies, wherever possible in animal models. human subject testing then follows with phase 1 trials, often in small numbers (10 100) of adult volunteers who may or may not have the condition under consideration, and under very carefully monitored trial conditions. this phase tests safety only. phase 2 is conducted in slightly larger groups (100s) of individuals (now possibly involving the target population), again mostly testing safety, but also ideal dose and possibly some indicators of activity. in phase 3, the well-known efficacy studies, much larger groups (100s 1 000s) of the target population are included and while safety should still be carefully monitored the main question is efficacy. efficacy can be tested most rigorously if a comparison group is included, usually receiving the ‘standard of care’ in order to allow the trial to be performed adequately and without unfair disadvantage to the experimental group. every phase of the process requires careful review by independent regulatory and ethical groups to ensure that all considerations of safety and indicators to move forward are met. in dose escalation studies, safety pauses should again be incorporated. where possible independent safety monitoring groups should have access to trial data to ensure that safety is reviewed objectively and studies modified or stopped for reasons of safety and/or efficacy. this process is incorporated within the concept of ‘good clinical practice’, and i would contend that somehow gcp has got lost in the minutiae of whether our case report forms are filled out perfectly in black or blue ink. while detail is important and an important element of clinical research, the primary purpose of gcp is to meet the highest levels of human subject protection while conducting well-designed clinical trials that inform the developmental process. two events in the last week have highlighted these issues. first is the recent disaster at northwick park hospital, london. six healthy young men – including british asians, an australian, a new zealander, and a south african, contracted by the us drug testing company parexel to test the anticancer drug tgn1412 – went into sudden multiple organ failure as a result of unexpected massive inflammatory reactions. why did the rigorous rules laid down by the medicines and healthcare products regulatory agency (mhra) fail to halt these dreadful events? the mhra has begun an investigation into the calamity, which should provide answers to these questions. it may be months before any inquiries give answers, and in the meantime these previously healthy volunteers are fighting for their lives. there are three reported questionable aspects to this disaster: 1. the drug is a monoclonal antibody that targets the cd28 site on the surfaces of t cells, kick-starting the body’s immune system into action. one could argue for a trial design for early phase 1 studies to be conducted not in healthy volunteers whose immune systems are normal and vigorous but in cancer patients or individuals with autoimmune disorders. because the monoclonal is humanised it is not always easy to interpret animal toxicity data. finally, new technology involving microdosing where local systems are set up in blisters on the skin may give more information in trials of this kind before proceeding to normal dosing. 2. secondly, the dose escalation in this study was reportedly performed inordinately rapidly and, some would argue, without sufficient safety pause. 3. finally, the study participant recompensation for the trial was apparently in the order of £2 000 each, and it has been argued that inducements of this magnitude may cloud volunteers’ ability to judge personal risk and lead to non-disclosure of pre-existing medical conditions, etc. the next item of news is local: weekend papers ran a story on senior members of government who have supported use of unproven traditional medicines for aids, and this at the expense of clinically tried and tested licensed antiretroviral agents. ubhejane is the secret recipe of zeblon gwala, a former truck driver from kzn who claims that its ingredients came to him in a dream from his healer grandfather. apparently he personally collects the 89 herbal ingredients from all over south africa and mixes them manually. it is then sold in unlabelled 2-litre plastic bottles for r342 each and lasts 2 weeks. more seriously, aside from any possible toxicity, patients commencing use of ubhejane are reportedly encouraged to stop or not use prescribed antiretrovirals. the sunday times reported that kzn minister of health, the ethekwini mayor and the special advisor to the kzn premier have openly encouraged people to take this product despite no evidence of conventional clinical testing for either safety or efficacy. if this is true it is both dangerous and unethical, particularly if it is recommended as a substitute for a proven life-saving treatment. mr gwala claims that he has records of all patients on this treatment, but could not supply details to the sunday times. gwala is quoted as saying: ‘i do keep files but there are so many and i don’t know which has these things in it’. with 5 6 million south africans infected with hiv we would be ecstatic if ubhejane or some other indigenous medicine could be found to be part of the armamentarium against hiv, but in order to prove any new product’s worth and safety, and before wild claims of efficacy are made to a desperate public, we need to follow drug testing protocols developed to protect the public. linda-gail bekker managing editor 7the southern african journal of hiv medicine march 2006 abstract introduction research aim and objectives methodology results discussion conclusion acknowledgements references about the author(s) ivo n. azia school of public health, university of the western cape, south africa ferdinand c. mukumbang school of public health, university of the western cape, south africa brian van wyk school of public health, university of the western cape, south africa citation azia in, mukumbang fc, van wyk, b. barriers to adherence to antiretroviral treatment in a regional hospital in vredenburg, western cape, south africa. s afr j hiv med. 2016;17(1), a476. http://dx.doi.org/10.4102/sajhivmed.v17i1.476 original research barriers to adherence to antiretroviral treatment in a regional hospital in vredenburg, western cape, south africa ivo n. azia, ferdinand c. mukumbang, brian van wyk received: 30 mar. 2016; accepted: 25 july 2016; published: 30 sept. 2016 copyright: © 2016. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: south africa currently runs the largest public antiretroviral treatment (art) programme in the world, with over 80% of people living with hiv and/or aids on art. however, in order to appreciate the benefits of using art, patients are subject to uncompromising and long-term commitments of taking at least 95% of their treatment as prescribed. evidence shows that this level of adherence is seldom achieved because of a multilevel and sometimes interwoven myriad of factors. objective: we described the challenges faced by patients on art in vredenburg with regard to art adherence. methods: a descriptive qualitative research design was used. eighteen non-adhering patients on art in the vredenburg regional hospital were purposefully selected. using a semi-structured interview guide, we conducted in-depth interviews with the study participants in their mother tongue (afrikaans). the interviews were audio-taped, transcribed verbatim and translated into english. the data were analysed manually using the thematic content analysis method. results: stigma, disclosure, unemployment, lack of transport, insufficient feeding, disability grants and alternative forms of therapy were identified as major barriers to adherence, whereas inadequate follow-ups and lack of patient confidentiality came under major criticisms from the patients. conclusion: interventions to address poverty, stigma, discrimination and disclosure should be integrated with group-based art adherence models in vredenburg while further quantitative investigations should be carried out to quantify the extent to which these factors impede adherence in the community. introduction background south africa has one of the largest hiv epidemics globally. of the estimated 35 million people living with hiv and/or aids (plwha) in the world by the end of 2014, south africa accounted for over 6.8 million cases, with more than 370 000 new infections and 240 000 deaths linked to aids.1 in 2007, the south african government made a commitment towards combating its aids epidemic by implementing a national strategic plan, which had as one of its principal objectives, the provision of antiretroviral (arv) medications to 80% of all people eligible for treatment by 2011.2 south africa now runs the largest public antiretroviral treatment (art) programme in the world, with over 80% of plwha eligible for art already initiated on treatment in the country.3,4 although art does not cure hiv/aids, it is known to significantly reduce the viral loads of plwha and thus forms an integral part of the comprehensive approaches used in curbing aids epidemics worldwide.5 however, to appreciate the benefits associated with the use of arv drugs, patients are required to focus on long-term commitments of taking at least 95% of the treatment as prescribed, given that poor adherence is linked with multidrug resistance and even death resulting from opportunistic infections.6,7,8 practically, adherence to art is a complex and dynamic process. several barriers to adherence to art have already been established by numerous studies in both developed and developing countries.9,10,11 demographic variables such as age, gender and ethnicity are known to be inconsistent in predicting good adherence to art.12 literature has consistently revealed that socio-economic variables such as unemployment, poverty, food insecurity and transport costs are implicated in poor adherence to arv medications.13,14 socially related variables, such as stigma and discrimination, disclosure and lack of social support, have also been identified to negatively influence the adherence of patients to art.15,16,17 human resource constraints in developing countries are reported to cause congestion and long waiting times in art centres and thus deter many art users from accessing treatment.18 poor healthcare provider practices, including inadequate counselling sessions, abuse of patient confidentiality, lack of adherence follow-ups and drug stock-outs have been demonstrated as major health systems barriers to adherence.19,20 the complex nature of art regimens with a high burden of pills, food and fluid restrictions is also a well-established barrier to adherence.21 patient-related factors such as forgetfulness, side effects, feeling better, mistrust and myths regarding arv medication are well documented for inhibiting many patients from adhering to treatment.22,23,24 the use of substances such as alcohol and illicit drugs while on art has been found to promote non-adherence to art in many patients.25 in sub-saharan africa, the increasing use of traditional concoctions, holy water, as well as prayers as a cure for hiv and/or aids is reported as barrier to art adherence.26,27 research problem poor art adherence rates (taking less than 95% of medications as prescribed) are empirically proven to have negative outcomes such as medication failure, viral mutations and the development of drug resistance, which further complicate the already limited secondand third-line treatment options available for patients.6,7,8 to better understand and address issues of inadequate art adherence, factors that influence adherence have also been investigated.16,23,28 however, there is a paucity of behavioural research on adherence to art in the peri-urban/semi-rural settings of the western cape province. this information could be relevant in planning and implementing tailored programmes and strategies to address problems faced by patients receiving art in vredenburg and similar settings. research aim and objectives aim the aim of the study was to describe the barriers to adherence to art among patients in the vredenburg regional hospital in the western cape. specific objectives the specific objectives of the study were: to describe the experiences of hiv and/or aids patients in vredenburg about accessing art to describe the social, structural, economic and cultural factors that influence adherence to art in vredenburg. definitions of key concepts antiretroviral therapy: standard arv therapy consists of a combination of arv drugs to maximally suppress the hiv virus and stop the progression of hiv to aids and also prevent the onward transmission of hiv in the population.29 adherence: is defined as the ability of patients to follow treatment plans, take medications at prescribed times and frequencies and also follow restrictions regarding lifestyles, food and other medications.29 non-adherence: is defined as the inability of patients to follow treatment plans, take medications at prescribed times and frequencies and also follow restrictions regarding lifestyles, food and other medications.29 methodology study design a descriptive qualitative study approach was used. according to pope and mays,30 the qualitative approach is well suited for studies exploring health behaviours. the choice of a qualitative approach was motivated by the fact that the researchers were interested in obtaining a deeper understanding of issues surrounding patients’ adherence or non-adherence to art in vredenburg, based on their experiences and perspectives. study population and sampling all plwha who were registered in the art programme in the vredenburg general hospital for more than 6 months prior to the inception of this study constituted the study population. the non-adhering patients were identified through patients’ medical records by health practitioners working in the art programme. after identifying the non-adhering patients, those who could be contacted and were also physically and mentally able to undergo an in-depth interview were approached by a doctor or a nurse working in the art programme for their possible recruitment into the study. we held several briefing sessions with the doctor and the non-adhering patients about the nature of the study and how they were going to participate and contribute in the study. twenty-two patients initially accepted to take part in the study, but finally only 18 were interviewed. the demographic characteristics of the participants are summarised in table 1. table 1: demographic characteristics of the participants. data collection we used a semi-structured interview guide to conduct the in-depth interviews. the interview guide was used throughout the study to ensure standardisation and consistency across the interviews. the interviews were conducted in the language of the participants’ choice in a suitable private setting where the respondents could talk freely. the interviewers were guided by the participants’ responses to probe for the emerging themes. each interview session lasted between 55 and 65 minutes. data analysis the data were analysed manually using the thematic content analysis guided by the five stages of thematic analysis as illustrated by pope et al.31 namely: familiarisation stage, theme identification stage, indexing stage, charting stage, and the mapping and interpretation stages. using these five steps of thematic content analysis, we discovered themes and subthemes, winnowed the themes to a manageable few and constructed hierarchies of themes.32 a consensus was reached among the investigators on the themes identified after an interactive discursive process. finally, the subthemes obtained were deductively represented under economic, social, health team and system, therapy-related, patient-related and cultural factors. trustworthiness the trustworthiness of the study was addressed through enforcing credibility, transferability, dependability and conformability as guided by lincoln and guba.33 the investigators held several meetings during which the approach to data collection and interpretation was carefully selected. dependability in the results was ensured by sharing the transcripts with experienced researchers at the university of the western cape who independently reviewed the coding frame with the data transcripts. we later on reconciled the differences in coding decisions. ethical considerations ethical approval was sought from the senate research committee of the university of the western cape. participation in the study was voluntary, and the participants were free to withdraw from the study without being penalised in any way. a participant information sheet with a brief explanation of the purpose and nature of the study was provided to the participants and explained in their language of choice. they were asked to sign a consent form before participating in the study. anonymity in the study was ensured by keeping all data secure throughout the study. results the data obtained from the interviews with the 18 participants were organised around the following themes: (1) economic barriers, (1) social barriers, (3) health team and system barriers, (4) therapy-related barriers, (5) patient-related barriers and (6) cultural barriers. table 2 shows the themes, subcodes and codes that emerged from the data analysis. table 2: themes, subcodes and codes obtained from the data analysis. economic barriers the economic factors that were identified by respondents to interfere with their ability to take art as prescribed were poverty and unemployment, lack of money for transport, lack of food and disability grants. poverty and unemployment many respondents reported that they sometimes failed to take their art because they are poor and unemployed; therefore, they could not raise enough money to buy food and eat properly before taking the medication. this was captured in the excerpt below: ‘i don’t work, i’m not eating properly, i don’t have food, i don’t have money and those things and the baby is … you see for me why would i drink the pills if it doesn’t help me at the end of the day.’ [female respondent, aged 38 years] lack of money for transport it was reported that taxi fare to and from the art centre at that time of this study was r36. a 63-year-old female respondent complained that the vredenburg clinic was too far for her to pick up her medication; so she sometimes missed her art appointments because she did not always have money for transport. another female respondent expressed her challenges of securing transport in the following words: ‘there are sometimes that i will need to go to the clinic and have no money so i will ask for assistance from my children and sometimes when i have no money for transport i hike to the art clinic.’ [female respondent, aged 60 years] disability grants it was reported that some patients deliberately discontinued taking their arts to enable them lower their cd4 counts and become very sick. the patients then used their low cd4 count and the severity of their sickness to persuade the doctors to qualify them for a disability grant. this is what a 33-year-old female participant reported in connection with securing a disability grant: ‘maybe you will qualify for a grant when the doctor will see you don’t have an income and you can’t work and you are weak. so most of them, they just uh…stop with the medication because they want to receive a grant.’ [female respondent, aged 33 years] social barriers socially related factors that were identified by the respondents to hamper adherence to art were fear of unintended disclosure when using the art clinic, fear of unintended disclosure when seen interacting with community hiv-care providers, fear of unintended disclosure leading to the secret trade on art, fear of being stigmatised and discriminated against by community members and finally, the fear of being humiliated by some community members if a patient’s hiv status was unintentionally disclosed. fear of unintended disclosure of hiv status a number of patients reported that they discontinued accessing the art clinic because they were afraid that their status could be unintentionally disclosed if they were seen queuing up at the art clinic regularly. one 60-year-old female respondent pointed out that if someone was often seen in the community having lengthy discussions with any hiv-care provider, that person’s hiv status was automatically assumed and this caused some patients to miss important appointments with hiv-care providers: ‘so if they see someone from the community speaking with these art workers for a long time, they will assume that the person speaking with them is hiv positive.’ [female respondent, aged 60 years] another 33-year-old female respondent mentioned in the quotes captured below that some patients in the community stopped going to the art clinic because they did not want others to know about their hiv status. as a result of the fear of disclosure, the patients were going behind the backs of the healthcare providers and instigating those patients accessing the art clinic to sell to them some of their medications collected from the art clinic: ‘i heard that other people saying maybe if, i am working now and i have a friend who is hiv now and who does not want to come to the doctor then maybe i should steal the tablets here and then i take them to her to buy.’ [female respondent, aged 33 years] stigma and discrimination stigma and discrimination were identified from the data as social barriers to medication adherence. some patients admitted discontinuing their treatment when they started drinking to cope with the emotional depression that they had developed from being stigmatised and discriminated against by their friends and some family members. the following experiences were given by a 25-year-old female respondent on how she was stigmatised and discriminated against by her friends and some of her family members: ‘some of my friends…, they ignore me or if i came to her she will say, oh, i want to go there or there or say something like that. so the experience was that some of the people do not want you because of the sickness that you have. they do not want to drink in your cups or eat out of your bowl. my mother was doing that, because i was having my own glass, my own cup and my own plate, it made me feel like i never wanted to live anymore. so that is why i started drinking.’ [female respondent, aged 25 years] ‘i stopped taking my pills for about 2 weeks because my boyfriend humiliated me openly that i was an hiv patient.’ [female respondent, aged 32 years] health system barriers health system–related factors that were found to obstruct medication adherence were the poor treatment literacy, the lack of follow-up of patients, dissatisfaction about the quality of the art services provided, lack of confidentiality in the way patients’ hiv results were handled, long waiting times at art clinics and the fear of picking up other infections from other patients in the outpatient department. poor treatment literacy a 36-year-old male respondent confessed that he did not take his pills accurately because he was often confused and unable to recall exactly the time and the right number of pills to be taken. this is what he said: ‘then i asked her sister hmm, why do you give me this one in the morning and this one in the afternoon, you say when i am going to sleep? she said ‘i learned that from the doctor that you must drink the two in the morning and when you go to sleep say before 12 pm.’ [male respondent, aged 36 years] the 38-year-old male respondent also reported how he sometimes skipped taking his pills at night before sleeping because of exhaustion or because he overslept: ‘wednesday, thursday i was working so hard, sometimes when i come back home and sit down, i fall asleep immediately.’ [male respondent, aged 38 years] lack of follow-up a respondent testified of missing his art schedules because of inadequate follow-up by the nurse in charge at the rehabilitation unit. consequently, his medication supply ran out without the nurse realising and he missed his pills for 4 days before they were finally replenished. this is what he said in connection to the lack of follow-up on his arvs by the nurse in charge: ‘when i was leaving, all the pills were finished. so i left, i was there for 4 days, without them.’ [male respondent, aged 38 years] therapy-related barriers two therapy-related factors that hindered adherence to art identified by the respondents were side effects and feeling better after commencing treatment. side effects a 38-year-old female respondent was the only respondent who stopped taking her art for 3 weeks because she got fed up with the pruritus (itches) she experienced when she started taking the treatment. the respondent said she experienced side effects and discomfort in the following ways: ‘i said doctor, i just stopped my pills for three weeks i got fed up of with these pills, you know what i am saying and now i experienced the itching and all those things and i was stressed out because of all those things.’ [female respondent, aged 38 years] feeling better feeling better was identified as a barrier to medication adherence in some patients. a 25-year-old female respondent testified that when she experienced improvements in her health after commencing treatment, she stopped taking her medications and carried on socialising with her friends as she did prior to her initiation in the art programme. this is what she had to say: ‘i was not taking them, and the weekend i was not taking them, because i was for a year and two months without, without my pills…. it was on my birthday when i started drinking with my friends, july month.’ [female respondent, aged 25 years] patient-related barriers the respondents pointed out the following patient-related factors to have negatively affected their adherence to treatment: alcohol abuse and smoking, emotional distress, forgetfulness, confusion, fatigue and hard labour. alcohol abuse and smoking alcohol is known to impair peoples’ reasoning and can therefore negatively affect adherence. most respondents who started drinking and smoking while on art reported that heavy drinking and smoking hindered them from taking their art as prescribed. while those who drank and smoked only occasionally during weekends and birthday parties also reported that they missed taking their art after drinking heavily. a 25-year-old female respondent made the following testimony: ‘i was on my own, started drinking and smoking again and that is why i dropped my pills and now i am back on treatment.’ [female respondent, aged 25 years] emotional distress emotional distress can disrupt peoples’ moods and their ability to concentrate on taking their art. according to some respondents, they did not concentrate on taking their art as prescribed because they were emotionally distressed either by a broken relationship or by stigmatisation and rejection at home. a 38-year-old male respondent had this to say with regards to being emotionally distressed while on art: ‘something that happened between us; so we were not married… so i decided to leave her alone. i could not use that medication and i came to the doctor and told him but-but this woman, what she has done to me i cannot take it any longer so i, i started drinking heavily.’ [male respondent, aged 38 years] forgetfulness forgetfulness was found by some respondents to have caused them to sometimes miss doses sometimes. a 38-year-old male respondent, in the quote below, explained how he missed taking his art because he sometimes forgot about them especially when he overslept and did not take note of the reminder from his alarm clock or cell phone: ‘you see that happened to me, not so far away from 7 o’clock, it happened once with me, in the morning at 7 o’clock i drank my pills but later at the same time it was 7 o’ clock again…i forgot and it was to 8.’ [male respondent, aged 38 years] cultural barriers the simultaneous use of concoctions from traditional healers while on antiretroviral treatment a culturally related factor that was found to have been negatively affecting adherence to art was the simultaneous use of concoctions from traditional healers while on art. it was reported that some respondents were still using concoctions prepared by traditional healers for cleansing their bodies internally as well as taking art medications. a 38-year-old female respondent made this testimony on her simultaneous use of art and concoctions from traditional healers: ‘no, no… i am using the mixtures, it is the mixtures that must make me like this, and it is cleaning me. that is my concern.’ [female respondent, aged 38 years] a 38-year-old female respondent mentioned that she was of the opinion that one could take mixtures from traditional healers while on art as long as one informed both parties about using both types of treatments. this is how she expressed her opinion regarding the use of traditional healers’ concoctions while on arts: ‘you have to take both of them, and you have to tell the doctor and your traditional healers that you are also on arvs.’ [female respondent, aged 38 years] discussion financial constraints in our study, many respondents missed hospital appointments and/or their doses either because they were unable to raise enough money for transport fares or because they were unable to buy food and eat properly to enable them to take their medications as prescribed. this is consistent with literature that patients on higher incomes have less difficulty with adherence compared to patients with low-income levels.34 although art programmes are presently making them more affordable to users by providing them free of charge at the points of delivery, in south africa, unemployment, transportation cost, childcare, school fees and lack of food as well as loss of earnings are still major concerns that hinder patients from adhering optimally to treatment.35 disclosure of hiv status disclosure of one’s hiv status and the readiness to live with the disease is a difficult process. a number of patients in our study skipped their doses or missed hospital appointments because they were afraid that their hiv status could unintentionally be disclosed if they were seen in queues at the art clinics regularly. these findings are common to those obtained in a south indian study in which patients who did not disclose their hiv-positive status, travelled long distances to obtain anonymous treatment and hid or skipped pills to ensure that family members and employers did not know about their hiv status.36 nonetheless, disclosure was also found to play both a negative and positive role in adherence in this study, given that those patients who intentionally disclosed to family members, friends or religious groups, gained some form of social, physiological, economical and spiritual support, which motivated them to step up their adherence to art as compared to those who did not. stigma and discrimination stigma was found to be pivotal in driving discrimination against people living with aids in the community and thus negatively influenced adherence in our study. stigma and discrimination have been reported as two important variables well documented for greatly contributing to low rates of disclosure and thus poor adherence to art.37 in this study, stigma was found to have provoked discrimination, rejection and the isolation of people living with aids. hiv stigma created the emotional distress that pushed some patients to skip doses and to take up heavy drinking as a way of providing some self-comfort. inadequate follow-up and dissatisfaction in antiretroviral treatment services a study from tanzania found that long waiting hours (>10 hours) in a hospital setting to access art, reduced clinic attendance and consequently hindered adherence.38 however, in our study long waiting times was not a major concern but inadequate follow-ups and lack of confidence in health officials were reported as major concerns with a potential of interrupting patients’ abilities to access art treatment in future. side effects and discomfort while therapy-related variables such as the complex nature of arv regimens, with a high number of pills, foods and fluids restrictions and the difficulty of fitting regimens into daily living activities was reported in malangu28 to have negatively influenced adherence in pretoria south. in our study only one respondent reported that she stopped taking her medications for 2 weeks because of the unbearable itches that she experienced. this suggests that side effects, pill burden, and food and fluid restrictions are not major barriers to adherence in vredenburg. feeling better and the hope to live longer feeling better in this study was like a double-edged sword that positively and negatively influenced adherence in some patients. while some art users believed in the treatment because they were sure to regain their health after the treatment, others took advantage of the improvement in their health and deliberately stopped taking their treatment in order to carry on with their past risky social lifestyles. the hope to live longer and the disastrous consequences of poor adherence to art, experienced by some patients, was found to have motivated them to step up their adherence. this result matches those obtained by watt et al.39 in a study in tanzania in which men were motivated to adhere to treatment because it provided them with an opportunity to return to their work, support their families and care for their children. substance abuse, forgetfulness and fatigue in this study, we also found that most of our respondents who started drinking heavily and smoking while on art reported that heavy drinking and smoking hindered them from taking their art as prescribed. substance abuse in patients taking art has been noted to have far-reaching consequences on their ability to adhere to therapy, as it makes it difficult for them to receive any form of social and family support, which can motivate them to adhere properly to therapy.35 although alcohol and smoking were found to negatively influence adherence, other factors associated with substance abuse such as forgetfulness, fatigue and confusion were also recorded to have negatively influenced adherence in this study. the use of alternative therapy the use of traditional medicines while on art has been previously reported as a potential barrier to art adherence in uganda.26 in this study, many respondents also reported to have been using concoctions prepared by traditional healers for cleansing their bodies. others said that they could also take mixtures from traditional healers while on art, if they informed both parties about the different treatments that they were using. this suggests that the concomitant use of traditional mixtures while on art could be a barrier to art adherence in the community. it is worth mentioning that some respondents were still visiting traditional healers and religious prophets for prayers and other solutions to their hiv problem. these findings are in line with those from an ugandan study,26 which found that believing in divine healing was found to be a barrier to art adherence in 1.2% of the patients in the study. limitations of the study time and financial constraints hindered the researchers from conducting all the interviews. thus, the interviews were also conducted by research assistants. this could also have influenced the quality of the data collected and also the results of the study. secondly, the study did not include some of the adhering patients in the same facility of vredenburg who may have had similar experiences as those included in the study. in that case, the investigators would have explored what made them adherent despite the challenges or how they overcame the challenges. therefore, we might have missed valuable lessons for incorporation into adherence messages to help those who were non-adherent. recommendations this study revealed that patients in vredenburg are still facing significant barriers to art adherence, such as stigma, discrimination, poverty and disclosure. therefore, poverty, stigma and disclosure are recommended to remain at the forefront of the art programme implementation in vredenburg, while further quantitative investigations are also recommended to quantify the extent to which the above-mentioned factors impede art adherence in vredenburg. conclusion although barriers to art adherence, such as financial constraints, substance abuse, alternative therapy use, disclosure and recklessness in healthcare services obstructed adherence in this study, hiv and/or aids has been a stigmatised illness since its onset in the early 1980s, and these results highlight that poverty, disclosure and stigma are yet to dissipate in the community of vredenburg. acknowledgements competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in 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associated with poor adherence to anti-retroviral therapy in patients attending a rural health centre in south africa. eur j clin microbiol infect dis. 2010;29(8):947–953. http://dx.doi.org/10.1007/s10096-010-0949-4 joglekar n, paranjape r, jain r, et al. barriers to art adherence & follow ups among patients attending art centres in maharashtra, india. indian j med res. 2011;134:954–959. http://dx.doi.org/10.4103/0971-5916.92642 chesney m. adherence to haart regimens. aids patient care stds. 2003;17:169–177. http://dx.doi.org/10.1089/108729103321619773 wanyama j, castelnuovo b, wandera b, et al. belief in divine healing can be a barrier to antiretroviral therapy adherence in uganda. aids. 2007;21(11):1486–1487. http://dx.doi.org/10.1097/qad.0b013e32823ecf7f peltzer k, preez nf, ramlagan s, fomundam h, anderson j, chanetsa l. antiretrovirals and the use of traditional, complementary and alternative medicine by hiv patients in kwazulu-natal, south africa: a longitudinal study. afr j 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[cited 2016 march 29]. available from: http://www.who.int/chp/knowledge/publications/adherence_introduction.pdf pope c, mays n. qualitative research: reaching the parts other methods cannot reach: an introduction to qualitative methods in health and health services research. bmj. 1995;311:42–45. http://dx.doi.org/10.1136/bmj.311.6996.42 pope c, ziebland s, mays n. qualitative research in health care: analysing qualitative data.bmj. 2000;320:114–116. http://dx.doi.org/10.1136/bmj.320.7227114 ryan gw, bernard hr. techniques to identify themes. field meth. 2003;15(1):85–109. http://dx.doi.org/10.1177/1525822x02239569 lincoln ys, guba eg. naturalistic inquiry. 1st ed. beverly hills, ca: sage; 1985. rosen s, ketlhapile m, sanne i, desilva b. cost to patients of obtaining treatment for hiv/aids in south africa. s afr med j. 2007;97:524–529. kagee a. adherence to antiretroviral therapy in the context of the national roll-out in south africa: defining a research agenda for psychology. s afr j psychol. 2008;38:413–428. http://dx.doi.org/10.1177/008124630803800211 balasundaram a, sarkar s, hamide a, lakshminarayanan s. socioepidemiologic profile and treatment-seeking behaviour of hiv/aids patients in a tertiary-care hospital in south india. j health popul nutr. 2014;32(4):587–594. dlamini ps, wantland d, makoae ln, et al. hiv stigma and missed medications in hiv-positive people in five african countries. aids patient care stds. 2009;23(5):377–387. http://dx.doi.org/10.1089/apc.2008.0164 mshana gh, wamoyi j, busza j, et al. barriers to accessing antiretroviral therapy in kisesa, tanzania: a qualitative study of early rural referrals to the national program. aids patient care stds. 2006;20(9):649–657. http://dx.doi.org/10.1089/apc.2006.20.649 watt mh, maman s, earp ja, et al. ‘it’s all the time in my mind’: facilitators of adherence to antiretroviral therapy in a tanzanian setting. soc sci med. 2009;68(10):1793–1800. http://dx.doi.org/10.1016/i.socscimed.2009.02.037 abstract introduction research method and design ethical consideration results discussion conclusion acknowledgements references about the author(s) damilola awolesi department of family medicine, university of kwazulu-natal, south africa mergan naidoo department of family medicine, university of kwazulu-natal, south africa mohammed h. cassimjee department of family medicine, university of kwazulu-natal, south africa citation awolesi d, naidoo m, cassimjee mh. the profile and frequency of known risk factors or comorbidities for deep vein thrombosis in an urban district hospital in kwazulu-natal. s afr j hiv med. 2016;17(1), a425. http://dx.doi.org/10.4102/sajhivmed.v17i1.425 original research the profile and frequency of known risk factors or comorbidities for deep vein thrombosis in an urban district hospital in kwazulu-natal damilola awolesi, mergan naidoo, mohammed h. cassimjee received: 22 sept. 2015; accepted: 28 jan. 2016; published: 13 may 2016 copyright: © 2016. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: although deep vein thrombosis (dvt) is a preventable disease, it increases the morbidity and mortality in hospitalised, patients, resulting in considerable economic health impact. the identification and primary prevention of risk factors using risk assessment and stratification with subsequent anti-thrombotic prophylaxis in moderateto severe-risk categories is the most rational means of reducing morbidity and mortality. aim and setting: the aim of the study was to describe the profile and frequency of known risk factors or comorbidities of hospitalised medical patients with ultrasound-diagnosed dvt in an urban district hospital in kwazulu-natal. methods: a retrospective review of clinical notes of all medical patients (age ≥ 13 years) admitted to the hospital with ultrasound-diagnosed dvt between july and december 2013. results: the median age was 40 years (interquartile range 32–60 years) and female preponderance was 72.84%. hiv and tuberculosis emerged as the prevalent risk factors, accounting for 51.85% and 35.80%, respectively. other risk factors observed were recent hospitalisation (34.57%), smoking (25.93%), previous dvt (19.75%) and congestive cardiac failure (18.52%). conclusion: dvt in our study occurred predominantly in young female patients unlike previous studies where patients were generally older. furthermore, hiv and tuberculosis were the two most common known risk factors or comorbidities observed. clinicians should have a heightened awareness of venous thromboembolism in patients with either condition or where both conditions occur together and appropriate thromboprophylaxis should be administered. introduction deep vein thrombosis (dvt), with an average annual incidence of 48 per 100 000 persons, accounts for more than half of venous thromboembolic events in the united states and 52 per 100 000 persons in australia.1,2 in india, an overall incidence of confirmed dvt has been shown to be 17.46 per 100 000 patients with 64% occurring in non-surgical non-trauma patients.3 over 200 000 south africans suffer from dvt each year, and because most dvt is occult, the true incidence is unknown.4 according to statistics south africa, thromboembolic disease is responsible for 20 000 deaths per annum in south africa.5 however, there are currently no studies describing the prevalence of dvt in kwazulu-natal. the economic impact of venous thromboembolism (vte) is enormous, as shown in a systematic review conducted in high-income countries (hic) which showed that the economic impact on the healthcare system was because of the initial vte diagnosis and treatment as well as the costs involved in managing recurrent hospitalisations.6 although dvt is a preventable disease in hospitalised patients, morbidity and mortality associated with dvt is still high in these patients.7 there are several well-defined studies documenting risk in medical patients and the impact of thromboprophylaxis.8 in adults, several clinical conditions have been documented to predispose to vte, and these include increasing age, stroke or paralysis, previous vte, congestive heart failure, acute infection, pregnancy or puerperium, cancer and its treatment, prolonged immobility, dehydration, hormonal treatment, varicose veins, long-distance air travel, acute inflammatory bowel disease, rheumatological disease and nephrotic syndrome.9 oral contraceptive pills, especially those that contain third-generation progestins, also increase the risk of vte.10 there is a strong association between recent respiratory infection and vte as described by clayton et al.11 there are many well-described anomalies predisposing hiv-infected patients to developing vte.11 genetic factors such as primary coagulation abnormalities (e.g. deficiency of proteins c and s, anti-thrombin iii, factor v leiden, prothrombin 20210a) have also been documented to increase the risk of vte.12 recent reports suggesting increased risk of dvt amongst patients with hiv and tuberculosis (tb) point to the increasing role of these infections in the development of dvt. given the high burden of hiv in south africa, it is not surprising that many of the medical patients admitted with dvt are infected with hiv. many researchers have documented the positive correlation between thrombosis and hiv infection because hiv predisposes to a hypercoagulable state, particularly those with severe immunosuppression (cd4 < 200 cells/ml).13,14 a study conducted in 2009 at nelson mandela hospital, mthatha, showed that the prevalence of dvt was 12.5% amongst hiv-positive patients admitted to the medical wards.15 identification of suspected dvt cases is difficult and sometimes these are missed.16 however, administering prophylaxis to all patients admitted to hospital is not cost-effective, especially in lowand middle-income countries.17 the high economic burden and increased morbidity and mortality associated with vte make it important that primary prevention of dvt with risk assessment or stratification and subsequent anti-thrombotic prophylaxis in the moderateto severe-risk category of patients is the most rational means of managing such patients. the padau prediction score, which assesses the risk of vte and identifies potential high-risk hospitalised medical patients for appropriate thromboprophylaxis, makes use of clinical components to arrive at this scores.18 a score of < 4 is categorised as low risk whilst a score of ≥ 4 is regarded as high risk.18 likewise, the wells scoring system, which is a clinical prediction rule for estimating pretest probability of dvt and further subsequent diagnostic testing developed in 1997 by wells et al.,19 has nine clinical components with a possible score range of -2–8, and this was risk stratified into three groups, namely, high risk (≥ 3 points), intermediate risk (1–2 points) and low risk (< 1 point). it was later modified in 2003 with the addition of a further component (previously documented dvt) which was observed to increase the risk of dvt, giving a possible score range of -2–9.20 this version reduced the risk categories into two groups, namely, likely (≥ 2 points) and unlikely (< 2 points), based on the symptoms, signs and risk factors. with the emergence of hiv and its well-documented predisposition for coagulopathy, hiv is yet to be considered as an additional risk factor in any tool aimed at assessing the risk category for thromboprophylaxis administration. tables 1 and 2 show the modified wells and padau prediction scoring systems, respectively, with the assigned points for each clinical feature or component. a definitive diagnosis is made by doppler ultrasound scan for patients stratified as likely, and the most reliable indicator of the presence of a thrombus within a vein is direct visualisation of intraluminal thrombus or non-compressibility of the vein during ultrasound.21 these operator-dependent techniques are highly accurate in the diagnosis of dvt with a weighted mean sensitivity and specificity of 97% and 94%, respectively, for proximal dvt.22 use of clinical signs and symptoms alone for diagnosis of dvt cannot be relied upon because they do not reliably predict which patients have dvt.16 the sensitivity of clinical signs and symptoms alone ranges from 60% to 96% and the specificity from 20% to 72%; therefore, it is not recommended without objective non-invasive diagnosis.16 table 1: the modified wells scoring chart. table 2: the padau prediction scoring chart. table 3: demographic and clinical profile of the patients. given the burden of hiv and tb amongst the patients seen in our study setting, we were interested in exploring the possible impact of these infections on the profile of patients presenting with dvt in our hospital. therefore, the aim of the study was to describe the profile and frequency of risk factors of medical patients admitted with non-invasive ultrasound-diagnosed dvt. research method and design this was a retrospective descriptive study done by reviewing clinical notes at an urban district hospital in kwazulu-natal. the study topic was selected based on the researcher’s observation of an increased number of medical patients being admitted with dvt. the clinical records of all medical patients aged ≥ 13 years who were admitted to the medical wards with ultrasound-diagnosed dvt between 1 july and 31 december 2013 were retrospectively reviewed and relevant data were extracted using a pre-defined data extraction tool.15 patients’ records were identified using the ultrasound unit register and the hospital admission or discharge register. further review of clinical records and laboratory data (accessed from the national health laboratory service database) was done in order to extract relevant parameters for the study. the data extraction tool used was developed from a validated tool used in a previous study.15 data were captured onto microsoft excel spreadsheet and imported into stata version 13 for analysis. frequency and proportional tables, mean, median, and standard deviation were generated to describe the findings. ethical consideration ethical approval was obtained from university of kwazulu-natal biomedical research ethics committee (ref.be214/14) as well as kwazulu-natal department of health and the management of the hospital where the study was conducted. results from the hospital records, a total of 118 patients with suspected dvt based on their clinical history, signs and symptoms were sent for ultrasound scans during the study period. eighty one (68.64%) of these patients had confirmed dvt, whilst 37 (31.36%) had negative ultrasound scan results. of the 81 who had ultrasound-confirmed dvt, 52 (64.2%) presented at the emergency unit with signs and symptoms, whilst 29 (35.8%) developed dvt in the ward during admission for other medical conditions. the age distribution of those with confirmed dvt ranged from 19 to 80 years, with median age of 40 years (interquartile range [iqr] 32–60 years). amongst those with confirmed dvt, 22 were male patients (27.16%), whilst 59 were female patients (72.84%). the study showed that 78 patients (96.30%) had dvt of the lower extremity. the remaining three patients (3.7%) had upper extremity dvt: two were in the neck (internal jugular vein) and one in the right subclavian vein. the most common clinical presentation found in the study sample was swelling and pain, accounting for 76/81 (93.83%) and 74/81 (91.36%), respectively. fever was seen in 16 patients (16/81, 19.75%), whilst other presentations like shortness of breath, cold limb and skin changes were recorded in only 9 patients (9/81, 11.11%). table 3 shows the demographic and clinical profile of the patients. the most common risk factors identified in this study were hiv (n = 42) and tb (n = 29), whilst recent admission (n = 28), smoking (n = 21), previous dvt (n = 16) and congestive cardiac failure (n = 15) were other risk factors seen. risk factors like myocardial infarction, pregnancy, recent surgery, immobility (unable to perform activities of daily living for ≥ 3 days), oral contraceptive pills (ocp) and hormone replacement therapy (hrt) accounted for a negligible proportion. table 4 depicts the observed risk factors. table 4: observed risk factors. analysis of haematological profile of the patients showed mean haemoglobin level of 9.76 g/dl (standard deviation 1.92) for female patients and median haemoglobin level of 13.1 g/dl (iqr 9.02 g/dl – 13.80 g/dl) for male patients. the median albumin level was 28.0 g/dl (iqr 23 g/dl – 36 g/dl). d-dimer was done in 31 (38.37%) patients, 30 of whom had elevated levels. baseline international normalised ratio (inr) was done in 78/81 (93.71%) patients, of whom 51 (65.38%) had a range of 0–1.0, whilst inr on discharge was done in 69/81 (85.16%) patients. the discharge inr was in the therapeutic range (inr 2–3) for 23 patients (23/81, 28.4%), it was sub-therapeutic (inr < 2) for 39 patients (39/81, 48.1%), and for 7 (7/81, 8.61%) patients inr was > 3. there was a 97.5% compliance with the south african standard treatment guidelines (2012) for adults for whom warfarin and low molecular weight heparin (lmwh) or low-dose unfractionated heparin (as an alternative where cost precludes the use of lmwh) were started simultaneously.23 however, only 34.18% had weight-based dosing of lmwh as majority of the patients had no documentary evidence of their weight. it was noted that the clinicians preferentially prescribed a convenient dosing of 80 mg twice daily of the lmwh (as majority of the patients [60.2%] were given this dose), possibly because of the non-documentary evidence of the weight. warfarin was commenced at a low dose of 2.5 mg daily for 37 of the patients (37/81, 45.68%) and was titrated upward according to the baseline inr level to achieve a therapeutic range in only 23(of 81, 28.4%) of the patients. discussion the most common associated factors in the case series were hiv and tb. although these findings differ from the risk factors identified in studies done in hic, it is similar to the findings of a study conducted in gf jooste hospital in cape town, where hiv and tb were also identified as the most common risk factors accounting for 64.0% and 55.0%, respectively.9,10,24 that study showed that 97% of the dvt occurred in the lower limb, which is consistent with our finding of 96.3% of the dvt occurring in the lower extremity. a retrospective study conducted by saber25 in mount sinai hospital, new york, in 2001 showed that hiv infection increases the risk of dvt, especially in the lower extremity by 10-fold. a similar study by matta,26 which analysed data from the national hospital discharge survey from 1990 through 2005, also concluded that the incidence of vte in patients with hiv infection was higher than in non-hiv patients. considering this context-specific prevalence of hiv in south africa and the documented strong association between hiv and thrombosis, it is not surprising that the risk of dvt would be increased in this population. there is also evidence to support the occurrence of dvt in patients with tb infection and this may be accounted for by the fact that tb is the most common opportunistic infection in hiv-infected people in africa accounting for the synergistic effect causing an increased risk of developing dvt.27,28,29 in addition, many of these patients with hiv and tb coinfections may have had prolonged illnesses at home that may have contributed to their immobility, further predisposing them to dvt. it is important to note that both padau predictive rule and wells criteria may need to be further modified for validation within south africa to reflect the additional risk for dvt associated with these infections because they exclude hiv and tb, which were the two most common observed known risk factors in this study population. further studies using appropriate designs and incorporating these scoring tools, which score hiv as risk factor, are recommended to test the validity of these tools for the local south african setting. despite existing evidence that age has a direct correlation with the formation of dvt resulting in an exponential increase in the incidence rate with increasing age, analysis of our study showed median age of 40 years (ior 32–60 years).30,31 this finding is in keeping with studies done in similar setting with median age of 37 years (iqr 15–88 years).24 similarly, the findings of olubanwo15 showed that 68.6% of the dvt cases were found in those aged < 40 years. this could be explained by the fact that hiv is most prevalent in age group 15–49 years, which constituted the age group of the majority of our study sample (69.1%).32 recent hospitalisation, smoking, previous dvt and congestive cardiac failure were the other risk factors observed in the study. however, risk factors such as malignancy, use of ocp, hrt and obesity were not common in the study and accounted for only 1.23% – 6.15%, which is consistent with the study of levine et al.33,34,35 recent hospital admissions occurred within the preceding 1 month in 28 patients (34.57%) of which the majority were because of hiv/aids and opportunistic coinfections. the results of studies investigating the relationship of smoking with vte remain inconsistent and controversial. whilst a prospective epidemiological study by meyer-michel samama (the sirius study)36 observed smoking as a protective factor for dvt, a systematic review and meta-analysis by cheng et al.,37 which examined the link between smoking and vte in the general population, found that smoking was associated with an absolute risk of 24.3 cases of vte per 100 000 person-years. they concluded that smoking is associated with a slightly increased risk of vte.37 the preponderance of female gender in our study population is in keeping with findings from earlier studies but inconsistent with the finding of levine et al.35 of male predominance of 60%.24,33,38 the result showed that 29 patients (35.8%) developed dvt during admission for other medical conditions of which hiv accounted for the majority. this may have been prevented with appropriate pharmacologic thromboprophylaxis. the lack of recommendation for clear thrombosis treatment guideline for this growing sub-population (hiv-infected population) leaves the decision to the attending clinicians to either administer thromboprophylaxis or not, although guidelines advocate that any sick patient who is non-ambulant receive thromboprophylaxis, unless contraindicated (south african guideline).39 further investigation using these suggested modified scoring tools to assess risk and identify potential high-risk hospitalised medical patients for appropriate thromboprophylaxis is required. proactive management of these patients may reduce morbidity and mortality associated with dvt. baseline inr was done in 78/81 (93.71%) patients, of whom 51 (65.38%) had a range of 0–1.0, whilst inr on discharge was done in 69/81 (85.16%) patients. the discharge inr was in the therapeutic range (inr 2–3) for 23 patients (23/81, 28.4%); sub-therapeutic (inr < 2) for 39 patients (39/81, 48.1%) and inr was > 3 for 7 patients (7/81, 8.61%). the practical implications of optimising the inr in a busy district hospital in which staff are constantly pressured to make beds available because of the large burden of disease in south africa sometimes contributes to the suboptimal care in that many patients are discharged before optimisation of the inr. patients should ideally have inrs in the range of 2–3 before discharge but only a minority of patients were discharged with inrs in the therapeutic range. outpatient management to obtain optimal inrs are done in first-world countries, but this is not feasible in the public sector in south africa because of limited resources.40,41 the gap identified in the study will thus lend itself to a quality improvement project to improve the management of patients with dvt. limitations of the study information bias existed in the study as it was not possible to standardise the quality of the patients’ clinical notes because of the retrospective nature of the study, therefore missed or improper documentation could not be completely ruled out. furthermore, the study was done in an urban district hospital in a high prevalence of hiv and tb area, it is not possible to generalise the findings of the study. recommendations further review of the modified wells criteria to include hiv with a possible score of 1 and validated for use in a population with high burden of hiv infection, for example, sub-saharan africa. the authors propose that all sick, hospitalised hiv-infected patients should be considered for thromboprophylaxis, particularly if non-ambulant, and until such time as they are fully weight-bearing ambulant. it is important that practicing clinicians ensure that all hospitalised patients with vte should be adequately anticoagulated prior to discharge and ideally followed up at an anticoagulation clinic. conclusion the review of the profile and risk factors of patients with dvt in our study setting shows predominantly young patients with female preponderance. tb and hiv are well-recognised risk factors, either alone or in conjunction. clinicians should have a heightened awareness of vte in patients with either condition or where both conditions occur together and appropriate thromboprophylaxis should be administered. acknowledgements competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing the article. authors’ contributions d.a. was the principal researcher with the conceptualisation 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[cited 2015 nov 18] available from: http://www.hsrc.ac.za/en/research-outputs/view/4176 heit ja, silverstein md, mohr dn, petterson tm, o’fallon wm, melton li. risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. arch intern med. 2000;160(6):809–815. hansson po, welin l, tibblin g, eriksson h. deep vein thrombosis and pulmonary embolism in the general population. ‘the study of the men born in 1913’. arch intern med. 1997;157(15):1665–1670. shisana o, rehle t, simbayi l, et al. south african national hiv prevalence, incidence and behavior survey, 2012. cape town: hsrc press; 2014. miah t, hoque aa, rashid hu, mahmood t, khan rr, sarkar s. clinical profile and risk association of dvt. j med. 2007;8:7–9. van hylckama vlieg a, helmerhorst fm, vandenbroucke jp, doggen cjm, rosendaal fr. the venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the mega case-control study. bmj. 2009;339:1–8. levine m, gent m, hirsh j, et al. a comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. n engl j med. 1996;334(11):677–681. samama m, for the sirius study group. an epidemiologic study of risk factors for deep vein thrombosis in medical outpatients: the sirius study. arch intern med. 2000;160(22):3415–3420. http://dx.doi.org/10.1001/archinte.160.22.3415 cheng y-j, liu z-h, yao f-j, et al. current and former smoking and risk for venous thromboembolism: a systematic review and meta-analysis. plos med. 2013;10(9):e1001515. http://dx.doi.org/10.1371/journal.pmed.1001515s naess ia, christianse sc, romundstad p, cannegieter sc, rosendaal fr, hammerstrom j. incidence and mortality of venous thrombosis: a population-based study. j thromb haemost. 2007;5(4):692–699. jacobson, bf, louw s, büller h, et al. venous thromboembolism: prophylactic and therapeutic practice guideline. s afr med j. 2013 [cited 2015 dec 21]; 103(4):260–267. available from: http://www.samj.org.za/index.php/samj/article/view/6706/5002. http://dx.doi.org/10.7196/samj.6706 spyropoulos ac. outpatient-based treatment protocols in the management of venous thromboembolic disease. am j manag care. 2000;6(20 suppl):1034–1044. dunn as, coller b. outpatient treatment of deep vein thrombosis: translating clinical trials into practice. am j med. 1999;106:660–669. abstract introduction msm, transwomen and hiv in southern africa initiation of pre-exposure prophylaxis risk reduction counselling risks and side-effects hiv prevention package for pre-exposure prophylaxis users stopping pre-exposure prophylaxis other notes for pre-exposure prophylaxis prescribers special clinical considerations the future of pre-exposure prophylaxis acknowledgements references about the author(s) linda-gail bekker the desmond tutu hiv centre, university of cape town, south africa kevin rebe anova health institute, johannesburg, south africa francois venter wits reproductive health and hiv institute, johannesburg, south africa gary maartens department of medicine, university of cape town, south africa michelle moorhouse wits reproductive health and hiv institute, johannesburg, south africa francesca conradie right to care and clinical hiv research unit, university of the witwatersrand, south africa carole wallis barc, johannesburg, south africa lancet laboratories, johannesburg, south africa vivian black wits reproductive health and hiv institute, johannesburg, south africa beth harley city health, city of cape town, south africa robyn eakles wits reproductive health and hiv institute, johannesburg, south africa citation bekker l-g, rebe k, venter f. southern african guidelines on the safe use of pre-exposure prophylaxis in persons at risk of acquiring hiv-1 infection. s afr j hiv med. 2016;17(1), art. #455, 11 pages. http://dx.doi.org/10.4102/sajhivmed.v17i1.455 original research southern african guidelines on the safe use of pre-exposure prophylaxis in persons at risk of acquiring hiv-1 infection linda-gail bekker, kevin rebe, francois venter, gary maartens, michelle moorhouse, francesca conradie, carole wallis, vivian black, beth harley, robyn eakles published: 15 mar. 2016 copyright: © 2016. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract the southern african hiv clinicians society published its first set of oral pre-exposure prophylaxis (prep) guidelines in june 2012 for men who have sex with men (msm) who are at risk of hiv infection. with the flurry of data that has been generated in prep clinical research since the first guideline, it became evident that there was a need to revise and expand the prep guidelines with new evidence of safety and efficacy of prep in several populations, including msm, transgender persons, heterosexual men and women, hiv-serodiscordant couples and people who inject drugs. this need is particularly relevant following the world health organization (who) consolidated treatment guidelines released in september 2015. these guidelines advise that prep is a highly effective, safe, biomedical option for hiv prevention that can be incorporated with other combination prevention strategies in southern africa, given the high prevalence of hiv in the region. prep should be tailored to populations at highest risk of hiv acquisition, whilst further data from studies in the region accrue to guide optimal deployment to realise the greatest impact regionally. prep may be used intermittently during periods of perceived hiv acquisition risk, rather than continually and lifelong, as is the case with antiretroviral treatment. recognition and accurate measurement of potential risk in individuals and populations also warrants discussion, but are not extensively covered in these guidelines. introduction pre-exposure prophylaxis pre-exposure prophylaxis (prep) involves taking a pharmaceutical agent prior to an exposure to prevent an outcome (e.g. infection by a microbe, such as malaria). prep for hiv involves the use of antiretroviral (arv) medications to prevent hiv infection. research into the use of existing and novel prep agents, as well as various delivery systems, including topical gels and rings (microbicide) and oral (tablet) and long-acting injectable formulations, is ongoing. tenofovir (tdf) and tenofovir/emtricitabine (tdf/ftc) in a single tablet fixed-dose combination (fdc) are the oral arv agents used in oral prep studies to date. the present guidelines support the use of tdf/ftc in combination for effective prep. tdf-containing prep is recommended by the world health organization (who) for people at substantial risk of hiv infection.1 in december 2015, the tdf/ftc combination pill was approved for use as prep by the medicine control council, in combination with safer sexual practices.2 the aim of the this prep guideline is to: explain what prep is outline current indications for its use outline steps for appropriate user selection provide guidance to monitor and maintain prep users. prep is indicated for hiv-negative men who have sex with men (msm), transgender persons, heterosexual men and women (including adolescents) and people who inject drugs (pwid), who are assessed to be at high risk for hiv acquisition. prep should be used as part of a package of hiv prevention services (which may include regular hiv testing, condoms, lubrication, contraception, sexually transmitted infection [sti] management and risk reduction counselling). prep is also applicable to individuals at risk of hiv acquisition because they are unwilling or unable to consistently use male or female condoms, especially if in serodiscordant relationships. the user must be counselled on ongoing pregnancy and sti risk. prep can also be effective as part of a broader prevention package for people who use and inject drugs (pwid) in the comprehensive setting of needle and syringe exchange and opioid substitution programmes and access to art for injecting networks. harm reduction is an extensively proven hiv prevention intervention for pwid, but is not discussed further in these guidelines. recommendations daily prep may be used intermittently during periods of perceived hiv acquisition risk, rather than continually and lifelong, as is the case with arv treatment. hiv testing, estimation of creatinine clearance, pregnancy screening, and sti and hepatitis b screening are recommended as baseline investigations. hepatitis b vaccination should be offered to susceptible individuals. daily oral tenofovir/emtricitabine (tdf/ftc) as fdc, along with effective use support, can then be prescribed for eligible users. prep should not be given to those with abnormal renal function, nor should it be commenced in individuals with acute viral symptoms. an initial three-drug post-exposure prophylaxis (pep) approach may be used whilst confirming hiv-negative status in an individual presenting with acute viral symptoms and a concomitant history of recent potential hiv exposure. an alternative hiv risk reduction method should be used until hiv-negative status is confirmed. once hiv-negative status is confirmed, switching to prep can be discussed. three-monthly follow-up visits to assess hiv status, pregnancy, tolerance, renal function, adherence and ongoing eligibility is recommended. six-monthly sti screens and annual creatinine levels to estimate creatinine clearance are also recommended. hepatitis b vaccination should be provided to susceptible clients. headache and gastro-intestinal symptoms with weight loss are relatively common although usually mild and self-limiting, occurring for the first 4–8 weeks after initiating prep. these can be managed with counselling support and provision of symptomatic relief. although uncommon, arv resistance is most likely to occur amongst those who initiate prep with undiagnosed acute hiv infection. there is ongoing potential for resistance development among those with sub-optimal prep use who become hiv-infected while on prep. prep, if taken correctly and consistently, will offer protection from hiv infection but not from other stis or pregnancy, and clinicians should continue to support prep users to be aware of sti symptoms and other components of combination prevention. research is ongoing to assess optimum dosing regimens, potential long-term effects and alternative prep medications. recommendations for the use of prep among other at-risk individuals, and the components of these recommendations, will be informed by future evidence. background development of pre-exposure prophylaxis tenofovir disoproxil fumarate (tdf) alone or in combination with emtricitabine (ftc) was chosen for the evaluation of prep because of its high level of activity in inhibiting hiv replication; its acceptable safety profile; its high barrier to generating resistant virus; and its low levels of side-effects.3 the protective activity of tdf and ftc has been shown in animal models, with best efficacy when both agents were used together.4,5 in clinical trials, however, it has been shown that the difference in efficacy between tdf/ftc and tdf alone is insignificant. the use of tdf monotherapy for hiv prevention has not been investigated in some key populations such as msm. the global iprex trial was the first randomised controlled trial to report decreased risk of hiv acquisition amongst at-risk msm and transgender persons.6 these findings were further confirmed in the ipergay and proud studies.7,8 ipergay used an ’on-demand’ dosing strategy. however, as yet there are no data to support such a dosing strategy in other at-risk populations, and the writing group recommends daily prep in all at-risk groups until further data emerge supporting ‘on-demand’ dosing. the partners prep and tdf2 trials were both conducted in africa and showed high levels of protection with daily oral tenofovir-based prep in heterosexual men and women including those in serodiscordant couples.9,10 the bangkok tenofovir study was conducted using tenofovir only as prep amongst pwid.11 the risk overall in the study was reduced by 49%, and by up to 74% amongst those with detectable levels of tenofovir in their blood. to date there have been 10 randomised controlled trials of tdf-based prep reporting hiv outcomes. the studies have involved more than 17 000 people and have demonstrated an overall reduction in hiv acquisition risk of 51% (women rr 0.57 [95% ci 0.34–0.94] and men rr 0.38 [95% ci 0.2–0.6]). three studies in which there was high adherence to the study product (> 70% of drug detection) showed prep was most efficacious but hiv infection was also significantly reduced in those studies in which drug detection levels were moderate (41% – 70% detection). unfortunately in the two studies with lowest adherence (< 40% drug detection), involving heterosexual women in southern and east africa, prep had no effect.12,13 the reasons for the particularly low uptake and use of oral prep in these two studies have been speculated on elsewhere and a range of potential reasons have been suggested, including structural, behavioural and/or psychological factors. unfortunately this has led to some controversy around the effectiveness of oral prep in black african women. it is important to note, however, that two of the three studies considered by the us food and drug administration (fda) prior to licensure of prep as a prevention modality included women from uganda, kenya and botswana. what does emerge clearly from all these studies is the fact that protection strongly correlates with adherence to the study drug, assessed in most studies by random tenofovir drug levels. additional open-label demonstration projects and implementation science studies amongst different at-risk populations are ongoing (http://www.avac.org/ht/a/getdocumentaction/i/3113) and confirm high rates of protection amongst the individuals with best effective use. no rcts of tenofovir-based prep are currently underway, although alternative arvs, new longer-acting formulations and alternative topical applications are planned or are still in earlier phase studies (figure 1). figure 1: effectiveness and adherence in trials of oral and topical tenofovir-based prevention. msm, transwomen and hiv in southern africa msm is a behavioural term that describes msm, regardless of social identity (gay, bisexual, heterosexual) or whether they also have sex with women.14 msm and transgender persons have been shown to be at disproportionately high risk of hiv acquisition and transmission.15,16 biological susceptibility (efficiency of rectal hiv transmission), behaviours (including condomless sex, anal intercourse and multiple partners) as well as structural and social factors (including homophobia and discrimination) have been associated with increased vulnerability to hiv.16 condomless receptive anal intercourse is the main risk factor for sexual transmission of hiv among msm.17 the high concentration of rectal cells vulnerable to hiv-1 infection (macrophages, t-cells and dendritic cells) and the single-cell layer of rectal mucosa, results in a per-act risk for hiv transmission that is 10–20 times greater than unprotected vaginal intercourse.17,18,19 there is emerging and consistent evidence about the high hiv burden amongst msm in southern africa.20 unfortunately, little data exist on the trans populations in south africa. hiv prevalence amongst msm sampled in cross-sectional surveys in south africa has ranged from 10% – 50%.21,22,23,24 however, owing to the lack of accurate population size estimates, it is hard to assess attributable risk.25 a 2009 modelling study on the modes of hiv transmission in south africa estimated that 8% of all new hiv infections in south africa occur among msm.26 high-risk sexual practices (including unprotected anal intercourse, multiple and concurrent partnerships, and sex work) and limited knowledge about hiv and substance use (alcohol, methamphetamines and heroin) have been associated with increased risk for hiv infection amongst msm in south africa.15,22,23,24,27,28,29 many msm also have female sexual partners. almost half (49%) of the participants in a soweto-based msm study reported recent female sexual partners.23 homophobia, stigma and discrimination (including criminalisation of same-sex behaviours in some southern african countries), healthcare worker ignorance (about msm and transgender vulnerability to hiv and appropriate management of msm clients) and the heterosexual focus of the hiv response have been contributing factors to the failure of southern african public health services to address the health needs of msm and transgender persons.15,25,30,31,32,33,34,35,36,37 motivation for a pre-exposure prophylaxis guideline the initial iprex trial results contributed to an earlier version of these guidelines and the development of interim guidance on the use of prep amongst msm by the united states centers for disease control and prevention.38 these revised guidelines include all at-risk populations consistent with all accrued clinical evidence, the cdc guidelines39 and recent (2015) who recommendations.1 southern african guidelines will assist practitioners who may be considering, or are already, prescribing prep to people at risk. identification of potential pre-exposure prophylaxis users providers should educate and counsel potential prep users about prep and conduct an individualised risk-benefit assessment to assess eligibility (box 1). the eligibility assessment requires that providers have developed sufficient client rapport to effectively assess risk based on these self-reported behaviours. box 1: risk behaviour assessment for sexual hiv acquisition. indications for the use of pre-exposure prophylaxis prep should be considered for people who are hiv-negative and at significant risk of acquiring hiv infection (see boxes 2 and 3). prep may be suitable for: any sexually active hiv-negative msm or transgender person who wants prep those with hiv-positive sexual partner(s) who are not confirmed virologically suppressed partner(s) of unknown hiv status recent sti multiple sexual partners history of inconsistent or no condom use commercial sex work recurrent pep users history of sex whilst under the influence of alcohol or recreational drugs heterosexual women and men who want prep, targeting especially those with hiv-positive sexual partner(s) who are not confirmed virologically suppressed partner(s) of unknown hiv status recent sti multiple sexual partners history of inconsistent or no condom use commercial sex work serodiscordant couples trying to conceive recurrent pep users history of sex whilst under the influence of alcohol or recreational drugs people who inject drugs hiv-negative pwid with hiv-positive/unknown status injecting partner(s) share injecting needles and drug preparation equipment all of the above groups include adolescents and sex workers, which each constitute special groups meriting specific consideration especially vulnerable are young msm and adolescent girls. box 2: indications for the use of pre-exposure prophylaxis. box 3: eligibility criteria for pre-exposure prophylaxis use. prep should be provided as part of a combination prevention package. contraindications to pre-exposure prophylaxis hiv-1 infected or evidence of possible acute infection suspicion that patient might be in the window period for hiv testing following potential exposure adolescents < 35 kg or < 15 years of age who are not tanner stage 3 or greater should not be given tdf poor renal function (estimated creatinine clearance < 60 ml/min) tdf should not be co-administered with other nephrotoxic drugs, for example, aminoglycosides unwilling or unable to return for 3-monthly hiv testing, counselling and safety monitoring visits pregnant or breastfeeding women2 (see section below entitled special clinical considerations). initiation of pre-exposure prophylaxis steps for the screening/baseline visit, prep initiation visit and maintenance of prep are described below. baseline investigations after documenting eligibility and motivation for prep use, mandatory baseline investigations should be completed (table 1). the minimum package of tests offered should include: table 1: mandatory baseline investigations for pre-exposure prophylaxis initiation. assessment of hiv status: preferably use laboratory elisa. if not available, use a fourth generation rapid test. always repeat a positive test with a confirmatory test. if a fourth generation test is not available, defer prep commencement, use rapid test available in facility and repeat in 2–4 weeks whilst counselling client on risk reduction. if this subsequent test is negative and there is no reported recent risk and no symptoms, prep may be initiated where history of recent exposure, consider pep per guidelines before initiating prep check creatinine and calculate creatinine clearance syndromic sti screen or, if resources allow, a full sti panel regardless of symptoms. treat any stis detected as appropriate, according to the relevant local guidelines hepatitis b surface antigen and antibody – if both negative, vaccinate against hepatitis b virus (hbv). acute or chronic hbv is not a contraindication to prep but monitoring of lfts is advised, especially if considering cycling off prep pregnancy screen. condoms and condom-compatible lubrication should be provided, and arrangements made for follow-up. problems with using rapid hiv tests in the field there are several point of care (poc) or rapid tests available for detection of hiv in the field. rapid and accurate diagnosis of hiv is needed in the setting of prep. this on-site detection of hiv removes the risk of loss to follow-up and decreases the time of individuals taking prep if they are hiv-positive. a major downfall of poc hiv diagnostic tests is that they have a larger window period for hiv diagnosis at prep commencement than molecular-based assays and are also more prone to inaccurate reporting. there is a growing need to ensure that optimal conditions for rapid hiv testing are followed, ensuring that the highest level of quality and sensitivity is achieved.40 this includes improved training of both technical and clinical staff; improvement of testing space in the clinic; improvement of laboratory information systems for management of the patient results; and the need to implement external quality programmes covering all steps of the assay. implementing pre-exposure prophylaxis the prep initiation visit should take place no longer than one month after the screening/baseline visit. at this visit, review lab elisa results, repeat the rapid hiv test and do a review for acute viral symptoms. review results from baseline investigations and confirm that estimated creatinine clearance is > 60 ml/min. commence hbv vaccination if susceptible and provide sti treatment as required (refer to latest national guidelines). educate the user about potential prep side-effects and their management, as well as signs and symptoms of acute hiv infection (and the need to return for urgent hiv testing). hiv testing should be repeated every 3 months. initiate an effective prep use plan (box 4) and provide a one-month tdf/ftc 300/200 mg (fdc) prescription (one tablet orally daily) together with a one-month follow-up date (table 2). those individuals with a recent high-risk exposure (e.g. a sex worker) can transition from pep to prep. box 4: what if users ask about stopping condom use while on pre-exposure prophylaxis? table 2: summary of pre-exposure prophylaxis visits and procedures. it is important to bear in mind that msm initiating prep need 7 days of daily dosing to reach adequate anal/rectal tissue levels, whilst women need up to 20 days of daily dosing to achieve protective vaginal tissue levels of prep drugs. during this period, other protective precautions must be used, such as abstinence or condoms. this should also be borne in mind in users who stop and start prep according to their periods of risk. prep medications should be continued for 28 days after the last potential hiv exposure in those wanting to cycle off prep. risk reduction counselling risk-reduction counselling is a behavioural intervention that attempts to decrease an individual’s chances of acquiring hiv and other stis,41 and should be implemented together with effective use counselling and contraceptive counselling at follow-up visits for prep users. the main objective of risk-reduction counselling is for clients to set a realistic goal for behaviour change that could reduce their risk of contracting hiv. this is most effective when it is non-prejudicial and user-centred. risk reduction counselling can be provided by any trained healthcare provider and should address the following points: explore the context of the user’s specific sexual practices, and assist in recognising which of their behaviours are associated with higher risk of hiv infection. clinicians should also be aware that clients might not always perceive their own risk, or may be in denial about it identify the sexual health protection needs of the user and reflect on what their main concerns appear to be strategise with the user on how they can manage these concerns or needs agree on which strategies the user is willing to explore, and guide the user to decide on how to implement the strategy (box 4). for effective use support, see box 5. box 5: ‘adherence’ versus ‘effective use’. adherence to daily prep medication, as shown in the iprex study and other prep trials, is a challenge. effective use counselling should be implemented at each visit where prep prescriptions or distributions are made. in iprex, participants who took prep more consistently and had evidence of drug detection in their blood, had higher levels of protection than those who did not.3 these findings have been duplicated in other prep studies in different study populations. users will need to be made aware of the fact that drugs only work if present at adequate levels in tissues and, preferably, that drug levels should be adequate before and after exposure to hiv has occurred. the use of cellphone reminders, pillboxes, and linking pill taking with a daily routine activity are currently being evaluated for their impact on improving prep effective use. clinicians and clients could use any of these or other strategies to assist in maximising effective use (see box 6 on tips to support effective use). any trained healthcare worker can implement effective use counselling. a client-centred approach is recommended. drug level testing for tenofovir levels in plasma is available, but is expensive. drug level testing may be useful to assess effective use in the future. box 6: tips to support effective use. managing abnormal screening results clients with abnormal renal function (estimated creatinine clearance < 60 ml/min) should not be placed on prep. an abnormal estimated creatinine clearance result could be rechecked after 2 weeks and, if renal function returns to normal and other prep eligibility criteria are met, prep may be initiated. those who are susceptible to hepatitis b should be immunised. clients with acute or chronic hepatitis b can be safely initiated onto prep but may require lft monitoring.6 clients with a history of pathological bone fracture, a family history of osteoporosis, or decreased bone mineral density on dexa scanning, should be educated on ways to improve bone health, such as weight-bearing exercise and avoiding alcohol, tobacco and recreational drugs.43 clients who are ineligible for prep require support to access other prevention options (see hiv prevention text box). treat stis syndromically as per national guidelines.44 consider empiric gonorrhoea and chlamydia treatment for msm who are highly sexually active, even in the absence of symptoms (especially where sti laboratory screening is not feasible). most msm with gonorrhoea and chlamydial infection are more likely to be asymptomatic than symptomatic.45,46 and can be managed in line with sti treatment guidelines (refer to latest national guidelines). safety monitoring and maintenance prep users require an initial one-month follow-up to assess ongoing eligibility, tolerance, safety and effective use. hepatitis b vaccination and sti treatment (as appropriate), condoms and condom-compatible lubricant, contraceptive services, risk reduction counselling, effective use support, a 3-month prescription for tdf/ftc fdc and a follow-up date should be provided at this visit. thereafter, 3-monthly visits are recommended (table 3). check the creatinine at the first-month and fourth-month visits, and thereafter 12-monthly. check rapid hiv every 3 months. table 3: hepatitis b immune status and pre-exposure prophylaxis eligibility. each visit should be viewed as an opportunity for counselling and risk assessment. discuss with the user at each visit whether prep is still needed. emphasise the importance of effective use of prep to gain maximum ongoing benefit from prep. by mutual agreement, prep should be stopped if: hiv test is positive; the client no longer meets eligibility criteria; the client does not need prep; the client feels that adherence to prep is too onerous; or it is perceived by the clinician that the risks of prep outweigh potential benefits. users who are ineligible for prep require support to access other prevention options (see hiv prevention text box). prep users should be reminded that prep is not conceptualised as a life-long therapy. it should be used while there is risk of sexual or other exposure to hiv. prep users are therefore expected to cycle on and off prep as dictated by their current level of sexual risk. a reminder should be given that, if restarting prep, adequate protection only occurs after 7 days of dosing for anal sex and 20 days of dosing for vaginal sex or needle risk in pwid. hiv-negative status should be confirmed before restarting prep. if stopping prep, medication should be taken for 28 days after the last potential exposure to hiv. managing abnormal follow up visit results prep should be stopped if estimated creatinine clearance < 60 ml/min. repeat creatinine clearance should be rechecked after 2 weeks; if renal function returns to normal and other prep criteria are met, prep may be restarted. stis should be treated syndromically (refer to latest national guidelines). risks and side-effects antiretroviral resistance at the time of writing the guideline, the only hiv resistance documented to date amongst prep users has been amongst clients who initiated prep when they were already hiv infected (during acute hiv infection). predictably, the ftc resistance mutation m184v was the first to occur.3 to prevent the risks of developing arv resistance, clinicians must focus on not commencing or reinitiating prep after a break, during acute hiv infection (box 7). box 7: strategies to reduce the likelihood of antiretroviral resistance. hiv testing should be done 3-monthly, and should be accompanied by an hiv exposure assessment, symptom screen and a targeted examination to exclude acute hiv infection (box 8). hiv testing should also be repeated whenever symptoms of a viral illness are present. clinicians should advise clients on the need for an hiv test before resuming prep if it was stopped, particularly if they have potentially been exposed to hiv during this period. box 8: hiv prevention for pre-exposure prophylaxis users. side-effects there is a large tdf/ftc fdc safety database derived from millions of hiv-positive individuals receiving art.6 in addition, the 17 000 individuals exposed during the clinical trials and an increasing number of individuals in demonstration projects confirm the extremely good safety profile of tdf/ftc fdc use in hiv-negative individuals.6 the major toxicities associated with tdf/ftc have been extremely rare in prep exposure to date. minor side-effects have been relatively common, but mild and self-limiting (approximately 1 in 10 individuals in the first 1–2 months). gastrointestinal side-effects the side-effects related to tdf/ftc fdc use in prep trials (nausea, weight loss) were mostly self-limiting mild start-up symptoms (first month), but these may adversely affect persistent prep effective use. supportive counselling and symptomatic treatment (anti-emetics) of these symptoms is often sufficient to assist the user to persist beyond the first month, after which the symptoms tend to subside. this may also be accompanied by mild headache and some malaise. rates of other git symptoms (bloating, abdominal tenderness, flatulence) amongst prep trial participants who took tdf/ftc fdc were not significantly different from those who took placebo.6 renal toxicity modest, transient increases in serum creatinine have been noted in completed prep studies, but these did not persist after stopping prep nor recur on rechallenge. proteinuria, decreasing glomerular filtration rate (gfr) and fanconi’s syndrome have been described in the setting of art, and decreased gfr has been described in the setting of prep but has not caused clinical harm.6 renal function needs to be measured prior to commencement and monitored in clients using prep by measuring serum creatinine and calculating the estimated creatinine clearance. these parameters should be measured at baseline, at month 1, month 4 and then annually thereafter. hypertensives, diabetics and those with existing glomerulonephropathies (if the benefit of prep is still deemed to outweigh clinical risk) should be monitored more frequently. tdf/ftc fdc-based prep should be avoided in patients who require the use of other nephrotoxic drugs, such as aminoglycosides for the treatment of drug-resistant tuberculosis (tb). clients with creatinine clearance < 60 ml/min should not be placed on prep and, if found during maintenance, prep should be discontinued. decreased bone mineral density decreases in bone mineral density associated with tdf and ftc/tdf fdc have been observed in completed prep trials. decreases were less than those observed in hiv-infected individuals treated with the same drugs, and appeared to stabilise over time.49,50 no difference in fracture rates was seen. recreational drugs (amphetamines and inhalant use) were associated with reductions in bone mineral density in hiv-negative msm taking tdf, suggesting some synergistic impact. hepatitis b management tdf and ftc both have hepatitis b antiviral activity. the potential risk exists that exposure to these antivirals may treat unidentified chronic hepatitis b infection, with a consequent viral flare (rebound) upon drug withdrawal that can result in severe liver injury.51 this phenomenon has not been described with prep use to date. however, it is recommended that screening for hepatitis b surface antigen and antibodies occurs prior to prep commencement. it is recommended that, if hepatitis b surface antigen (hbsag) is positive, the client be investigated prior to commencement of short-term prep (table 3). prep is not contra-indicated in those with hbv but we recommend that additional liver function monitoring should be performed. prep users with persistently elevated or abnormal liver function tests should be referred for assessment. a possible approach to those with chronic hepatitis b infection may be to prescribe long-term tdf/ftc fdc. liver function tests should be checked after stopping prep in those with chronic hepatitis b infection. users who are negative for both hbsag and hepatitis b surface antibody (hbsab) should commence a hepatitis b vaccine schedule. people with chronic hepatitis b infection may choose to continue using tdf and ftc to control their hepatitis, even if they do not require these drugs any longer for the indication of prep. users with a history of injecting drug use should be screened for hepatitis c and, if positive, referred for further care. other side-effects hyperpigmentation may occur as a side-effect to ftc. the clinician should explain that this is not harmful. lamivudine (3tc) can be substituted but this will increase the pill burden, which may have an impact on effective prep use. prep studies to date have used either tdf or tdf in combination with ftc, rather than 3tc. risk compensation this term refers to the theoretical risk that individuals commencing prep will neglect other safer-sex measures, and put themselves at increased risk of hiv exposure. to date, evidence of this has not been borne out in prep trials. it may be, however, that during counselling it is apparent that a client may not be able to or simply cannot use condoms or other safer-sex modalities. in these cases, prep if used consistently during hiv exposure may significantly reduce hiv infection. providers should gauge this during risk reduction and effective use counselling opportunities. hiv prevention package for pre-exposure prophylaxis users the prevention of hiv acquisition requires a comprehensive approach, inclusive of a combination of biomedical and behavioural/psychosocial interventions tailored to individual needs. where feasible, condoms and condom-compatible lubrication are key components of all hiv prevention packages, supported by contraceptive services, sti detection and treatment, appropriate use of art (pep), and counselling around the identification of high-risk practices and ways to circumvent or reduce risk. individuals should be encouraged to understand what each component of the prevention package offers and, together with the provider, should devise the optimal package for their own lifestyle. stopping pre-exposure prophylaxis prep should be stopped: (1) whenever an hiv test is positive, (2) at client request, (3) for safety concerns (particularly if creatinine clearance < 60 ml/min) and (4) if the risks of prep outweigh the potential benefits. ongoing linkage to appropriate hiv prevention services and contraceptive services should be encouraged, as well as the use of other hiv prevention strategies, as needed. the duration of prep use may vary and individuals are likely to start and stop prep depending on their risk assessment at different periods in their lives – including changes in relationship status, behaviours and ability to adhere to a prep maintenance programme. clients should be advised that an hiv test at minimum should be done before prep is recommenced. clinicians may want to discuss the options of when to discontinue prep with their clients. other notes for pre-exposure prophylaxis prescribers pre-exposure prophylaxis will not suit all users prep should be considered for clients who are most likely to benefit from this specific prevention strategy, ideally as part of a package of hiv prevention services (box 9). box 9:  pre-exposure prophylaxis usage requires commitment usage will require commitment from both the provider and the user to ensure success. providers may need to be innovative in providing support to prep users and also find ways to make participation in a prep programme as easy and convenient as possible. this requires ensuring that structural, logistical barriers are minimised as much as possible and that participants are provided with an encouraging and positive approach from providers. special clinical considerations women who become pregnant or breastfeed on pre-exposure prophylaxis hiv-negative women in serodiscordant relationships are at risk of acquiring hiv infection whilst trying to conceive through unprotected sex. pregnancy itself is also associated with an increased risk of becoming infected with hiv. the use of prep around the time of conception and during pregnancy offers a means of protection to the uninfected partner. unfortunately, data relating to the safety of prep specifically with regard to the developing foetus are limited, and consequently the onus is on the clinician to discuss potential risks and benefits of prep initiation or maintenance during pregnancy with the client. prep trials involving heterosexual women excluded pregnant women from enrollment, and those who fell pregnant during the conduct of the study were discontinued from prep. one study of 46 uninfected women in serodiscordant relationships demonstrated no adverse effects on the pregnancy or cases of hiv transmission when tdf was used around the time of conception. there are several ongoing demonstration projects that will allow women to continue prep if they fall pregnant, which will provide some data to inform future recommendations. in addition, the antiretroviral pregnancy registry shows no evidence of adverse outcomes amongst infants exposed to these medications when used as antiretroviral therapy in utero. in serodiscordant couples, the infected partner should be initiated on art and virologically suppressed, ideally for 6 months, before any attempts to conceive. in south africa, the use of tdf/ftc as prep in pregnant or breastfeeding women is contra-indicated. however, as the risk of seroconversion during pregnancy is high, the risks and benefits of prep should be discussed with potential prep users, allowing these women at high risk of hiv acquisition to make an informed decision regarding prep use.2 exposure to prep via breast milk has not been extensively studied. however, hiv-negative babies born to hiv-positive mothers on pmtct b+ programmes and lifelong art are exposed to tdf/ftc. the risk of hiv infection against the risk of arv exposure to the infant should frame a discussion with a potential prep user who is pregnant or is planning conception. the future of pre-exposure prophylaxis whilst recommendations for safe and effective prep use in correctly identified users to prevent hiv acquisition are strong, questions still remain on optimising the user selection, the ideal distribution platform and optimal monitoring schedule. ongoing health service research aims to address these knowledge gaps. for more information, consult the avac website http://www.avac.org/prevention-option/prep. please report adverse events occurring on prep to the national adverse drug event monitoring centre, which is housed in the division of pharmacology at the university of cape town. the reporting guideline is available at: http://www.mccza.com/genericdocuments/2.11_adr_reporting_jun11_v2.doc. acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions m.m. is the corresponding author and prepared the first draft of the manuscript. l-g.b. and k.r. co-chaired a meeting of the prep guideline development committee, where the principles of the guideline were agreed upon. the remaining authors were involved in the discussions that guided the development of the manuscript and also reviewed the first draft. all authors developed the recommendations. references world health organization. guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for hiv. geneva: world health organization; 2015. gilead sciences. truvada package insert. foster city, ca: gilead sciences; 2015. grant rm, buchbinder s, clarke e, et al. promote hiv chemoprophylaxis research, don’t prevent it. science. 2005;309:2170–2171. cranage m, sharpe s, herrera c, et al. prevention of siv rectal transmission and priming of t cell responses in macaques after local pre-exposure application of tenofovir gel. plos med. 2008;5:e157. garcia-lerma j, otten r, qari s, et al. prevention of rectal shiv transmission in macaques by daily or intermittent prophylaxis with emtricitabine and teonofovir. plos med. 2008;5:e28. grant rm, lama jr, anderson pl, et al. preexposure chemoprophylaxis for hiv prevention in men who have sex with men. n engl j med. 2010;363:2587–2599. grohskopf la, chillag kl, gvetadze r, et al. randomized trial of clinical safety of daily oral tenofovir disoproxil fumarate among hiv-uninfected men who have sex with men in the united states. j acquir immune defic syndr. 2013;64:79–86. mccormack s, dunn d. pragmatic open-label randomised trial of preexposure prophylaxis: the proud study. conference on retroviruses and opportunistic infections; 2015 feb 23–26; seattle, wa. baeten jm, donnell d, ndase p, et al. antiretroviral prophylaxis for hiv prevention in heterosexual men and women. n engl j med. 2012;367:399–410. thigpen mc, kebaabetswe pm, paxton la, et al. antiretroviral preexposure prophylaxis for heterosexual hiv transmission in botswana. n engl j med. 2012;367:423–434. choopanya k, martin m, suntharasamai p, et al. antiretroviral prophylaxis for hiv infection in injecting drug users in bangkok, thailand (the bangkok tenofovir study): a randomised, double-blind, placebo-controlled phase 3 trial. lancet. 2013;381:2083–2090. marrazzo jm, ramjee g, richardson ba, et al. tenofovir-based preexposure prophylaxis for hiv infection among african women. n engl j med. 2015;372:509–518. van damme l, corneli a, ahmed k, et al. preexposure prophylaxis for hiv infection among african women. n engl j med. 2012;367:411–422. unaids. unaids terminology guidelines. geneva: world health organization, 2011; p. 1–31. baral s, sifakis f, cleghorn f, beyrer c. elevated risk for hiv infection among men who have sex with men in lowand middle-income countries 2000–2006: a systematic review. plos med. 2007;4:e339. beyrer c, wirtz al, walker d, johns b, sifakis f, baral sd. the global hiv epidemics among men who have sex with men. washington, dc: the world bank; 2011. vittinghoff e, douglas j, judson f, mckirnan d, macqueen k, buchbinder sp. per-contact risk of human immunodeficiency virus transmission between male sexual partners. am j epidemiol. 1999;150:306–311. baggaley rf, white rg, boily m-c. hiv transmission risk through anal intercourse: systematic review, meta-analysis and implications for hiv prevention. int j epidemiol. 2010;39:1048–1063. leynaert b, downs am. heterosexual transmission of human immunodeficiency virus. am j epidemiol. 1998;148:88–96. baral s, trapence g, motimedi f, et al. hiv prevalence, risks for hiv infection, and human rights among men who have sex with men (msm) in malawi, namibia, and botswana. plos one. 2009;4:e4997. baral s, burrell e, scheibe a, brown b, beyrer c, bekker l-g. hiv risk and associations of hiv infection among men who have sex with men in peri-urban cape town, south africa. bmc public health. 2011;11:766. burrell e, mark d, grant r, wood r, bekker l-g. sexual risk behaviours and hiv-1 prevalence among urban men who have sex with men in cape town, south africa. sex health. 2010;7:149–153. lane t, raymond hf, dladla s, et al. high hiv prevalence among men who have sex with men in soweto, south africa: results from the soweto men’s study. aids behav. 2011;15: 626–634. doi: http://dx.doi.org/10.1007/s10461-009-9598-y. rispel lc, metcalf ca. the johnannesburg/ etwikini mens’ study. a rapid assesment of the hiv epidemic among men who have sex with men. information leaflet. pretoria: hsrc; 2009. desmond tutu hiv foundation. key populations, key responses. a gap analysis for key populations and hiv in south africa. pretoria: sanac; 2011. sacema. the modes of transmission of hiv in south africa. stellenbosch: sacema; 2009. lane t, shade sb, mcintyre j, morin sf. alcohol and sexual risk behavior among men who have sex with men in south african township communities. aids behav. 2008;12:s78–s85. knox j, sandfort t, yi h, reddy v, maime s. social vulnerability and hiv testing among south african men who have sex with men. int j std aids. 2011;22:709–713. sandfort tgm, nel j, rich e, reddy v, yi h. hiv testing and self-reported hiv status in south african men who have sex with men: results from a community-based survey. sex transm infect. 2008;84:425–429. nel j, judge m. exploring homophobic victimisation in gauteng, south africa: issues, impacts and responses. acta criminol. 2008;21:19–37. rispel lc, metcalf c. breaking the silence: south african hiv policies and the needs of men who have sex with men. reprod health matters. 2009;17:133–142. lane t, mogale t, struthers h, mcintyre j, kegeles sm. ‘they see you as a different thing’: the experiences of men who have sex with men with healthcare workers in south african township communities. sex transm infect. 2008;84:430–433. cegaa. south africa consolidated national aids spending assessment. report. cape town: cegaa; 2011. south african national aids council. south african hiv epidemic, response and policy synthesis. pretoria: sanac; 2011. seale a. heteronormativity and hiv in sub-saharan africa. development. 2009;52:84–90. smith ad, tapsoba p, peshu n, sanders ej, jaffe hw. men who have sex with men and hiv/aids in subsaharan africa. lancet. 2009;374:416–422. cloete a, simbayi lc, kalichman sc, strebel a, henda n. stigma and discrimination experiences of hiv-positive men who have sex with men in cape town, south africa. aids care. 2008;20:1105–1110. united states centers for disease control and prevention. interim guidance: preexposure prophylaxis for the prevention of hiv infection in men who have sex with men. mmwr morb mortal wkly rep. 2011;60:65–68. us public health service. preexposure prophylaxis for the prevention of hiv infection in the united states – 2014 clinical practice guideline. washington, dc: us public health service; 2014. clinical and laboratory standards institute. quality management system: development and management of laboratory documents; approved guidelines. 6th ed. wayne, pa: clinical and laboratory standards institute; 2013. world health organization. prevention and treatment of hiv and other sexually transmitted infections among men who have sex with men and transgender people. recommendations for a public health approach. geneva: world health organization; 2011. r amico k, mcmahan v, goicochea p, et al. supporting study product use and accuracy in self-report in the iprex study: next step counselling and neutral assessment. aids behav. 2012;16:1243–1259. http://dx.doi.org/10.1007/s10461-012-0182-5. mccomsey g. tebas p, shane e, et al. bone disease in hiv infection: a practical review and recommendation for hiv care providers. clin infect dis. 2010;51:937–946. lewis da, maruma e. revision of the national guideline for first-line comprehensive management and control of sexually transmitted infections: what’s new and why? s afr j epidemiol infect. 2009;24:6–9. rebe k, lewis d, myer l, et al. a cross sectional analysis of gonococcal and chlamydial infections among men-who-have-sex-with-men in cape town, south africa. plos one. 2015;10:e0138315. http://dx.doi.org/10.1371/journal.pone.0138315. world health organization. consolidated guidelines on hiv prevention, diagnosis, treatment and care for key populations. c2014 [cited 2015 aug 25]. available from: http://www.who.int/hiv/pub/guidelines/keypopulations/en. gilbert d, moellering r, eliopoulos g, saag m, chambers h. course of hiv infection in adults, clinical decision points. in: the sandford guide to hiv/aids therapy. sperryville: antimicrobial therapy, inc., 2009: p. 22, 23. wilson d, cotton c, bekker l-g, meyers t, venter f, maartens g. handbook of hiv medicine. 2nd ed. cape town: oxford southern africa, 2002; pp. 185–267. liu ay, vittinghoff e, sellmeyer de, et al. bone mineral density in hiv-negative men participating in a tenofovir pre-exposure prophylaxis randomized clinical trial in san francisco. plos one. 2001;6:e23688. mulligan k, glidden d, gonzales p, et al. effects of emtricitabine/tenofovir on bone mineral density in seronegative men from 4 continents: dexa results of the global iprex study. paper presented at: 18th conference on retroviruses and opportunistic infections; 2011 mar; boston, ma. honkoop p, de man r, niesters h, zondervan p, schalm s. acute exacerbation of chronic hepatits b virus infection after withdrawl of lamivudine therapy. hepatology. 2000;32:635–639. abstract introduction materials and methods ethical consideration results discussion conclusion strengths and limitations acknowledgements references about the author(s) brian t. flepisi department of medical biosciences, university of the western cape, south africa patrick bouic department of medical microbiology, stellenbosch university, south africa gerhard sissolak department of medicine, division of clinical haematology, stellenbosch university, south africa bernd rosenkranz department of medicine, division of clinical pharmacology, stellenbosch university, south africa citation flepisi bt, bouic p, sissolak g, rosenkranz b. b-cell and t-cell activation in south african hiv-1-positive non-hodgkin’s lymphoma patients. s afr j hiv med. 2018;19(1), a809. https://doi.org/10.4102/sajhivmed.v19i1.809 original research b-cell and t-cell activation in south african hiv-1-positive non-hodgkin’s lymphoma patients brian t. flepisi, patrick bouic, gerhard sissolak, bernd rosenkranz received: 25 oct. 2017; accepted: 04 july 2018; published: 07 nov. 2018 copyright: © 2018. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: altered immune mechanisms play a critical role in the pathogenesis of non-hodgkin’s lymphoma (nhl). hiv-1 (hiv) infection is associated with a state of excessive t-cell activation, which can lead to increased t-cell turnover and lymph node fibrosis. objectives: this study aimed to determine the serum levels of circulating b-cell activation markers, and the expression of t-cell activation and regulatory markers in hiv-positive nhl patients. method: the serum levels of circulating soluble(s) scd20, scd23, scd27, scd30 and scd44 molecules, all of which are biomarkers of b-cell activation, were determined by enzyme-linked immunosorbent assays (elisa), while biomarkers of t-cell activation (cd8+cd38+) and regulation (foxp3) were determined by flow cytometry in 141 subjects who were divided into five groups: combination antiretroviral therapy (art)-naïve hiv-positive patients; art-treated hiv-positive patients; hiv-negative nhl patients; hiv-positive nhl patients on art; and healthy controls. results: hiv-positive nhl patients had significantly higher serum levels of scd20, scd23, scd30 and scd44 than hiv-negative nhl patients, while all five biomarkers were significantly elevated in hiv-positive nhl patients when compared with art-treated hiv-positive patients. hiv-positive nhl patients had higher cd8+cd38+ and lower foxp3 expression than hiv-negative nhl and art-treated hiv-positive patients. conclusion: b-cell activation is increased in hiv-positive nhl patients and is associated with reduced regulatory t-cell populations and increased cd8+ t-cell activation. introduction non-hodgkin’s lymphoma (nhl) refers to a heterogeneous group of haematopoietic malignancies originating in the lymphocytes.1,2,3 non-hodgkin’s lymphoma is the second most common malignancy affecting hiv-1 (hiv)-infected individuals.4 altered immune mechanisms play a critical role in the pathogenesis of nhl, as evidenced by increased rates of nhl among hiv-positive patients, transplant recipients and autoimmune disease patients.5,6 hiv infection has also been associated with a state of excessive t-cell activation, which has been shown to be a strong prognostic indicator for disease progression at different stages of hiv infection.7 chronic immune activation during hiv infection leads to increased t-cell turnover and exhaustion and may precipitate lymph node fibrosis.8 the increased levels of both soluble biomarkers of inflammation and markers of t-cell activation have been shown to be associated with and predictive of increased morbidity and mortality in treated hiv infection.9 previous studies indicated that those patients with the most marked b-cell activation are at increased risk of developing hiv-associated nhl.10,11 b-cell activation is characterised by lymphocyte proliferation, class switch recombination and somatic hypermutation, all of which are prone to dna mutations that may lead to lymphomagenesis.5 there are two ways by which b-cell activation may occur: (1) interactions with activated t-cells, whose t-cell receptor recognises antigen presented by the b-cells or (2) activation by t-cell independent antigens. in the current study, we examined serum levels of circulating b-cell activation markers and the expression of t-cell activation and regulation markers in hiv-positive nhl patients and in several comparison groups. chronic immune activation has been suggested to be one of the mechanisms leading to the development of nhl in hiv-infected patients.12 increased expression of cd38+ on cd8+ t-cells (cd8+cd38+) has been previously associated with immune activation, progression of hiv disease and death.13 in addition, cd8+cd38+ has been previously shown to function as a signalling molecule in b-cell chronic lymphocytic leukaemia (b-cll) and has been linked with disease pathogenesis.14,15 cd8+cd38+ expression has been shown to be an important prognostic marker in b-cll that is stable over time and is not significantly influenced by chemotherapy.16 materials and methods study population patients diagnosed with hiv infection (art-treated and naïve) and a cd4+ t-cell count of ≤ 350 cells/µl, patients with hiv-associated nhl, hiv-negative nhl patients and a healthy control group were included in this study. study subjects were recruited from tygerberg hospital and groote schuur hospital, both tertiary hospitals in cape town, south africa, between october 2012 and february 2014. blood samples were drawn. all subjects signed informed consent forms. all subjects were aged 18 years and older. a total number of 141 subjects (61 males and 80 females) were recruited in the study. the study sample consisted of the following five ageand gender-matched groups: 16 healthy controls, 34 hiv-negative nhl patients, 31 hiv-positive nhl patients on combination antiretroviral therapy (art), 28 art-naïve hiv-positive patients and 32 art-treated hiv-positive patients (table 1). the mean age was 40 years. there were 53 black, 61 mixed race and 27 caucasian subjects. there were 48 active smokers, while 93 were non-smokers. the mean hiv viral load was 4905 copies/ml in hiv-positive nhl patients, 1044 copies/ml in art-treated hiv-positive patients and 19 008 copies/ml in art-naïve hiv-positive patients. the mean duration of art treatment was 24 months in both art-treated hiv-positive patients and hiv-positive nhl patients, while the mean duration of chemotherapy was three cycles in both nhl groups. table 1: subject demographic characteristics. determination of the t-cell activation and regulation markers cd8+cd38+ expression the expression of cd38+ on cd8+ t-cells (cd8+cd38+) was determined by flow cytometry as follows: 20 µl each of monoclonal antibodies anti-cd3 percp, anti-cd8 fitc and anti-cd38 pe (the scientific group and becton dickinson (bd) pty ltd, johannesburg, south africa) were added into labelled bd falcon tubes and mixed with 50 µl of whole blood. the tubes were vortexed gently and the samples incubated in a dark cupboard for 15 min at room temperature. facs lysing solution (450 µl) was added, and samples were again incubated for 15 min under the same conditions. all samples were analysed on a bd facscanto ii flow cytometer instrument by facs canto diva software immediately following incubation. foxp3 expression foxp3 expression was determined by flow cytometry as follows: 20 µl of anti-cd45-fitc, anti-cd3-percp and anti-cd4-apc (the scientific group and becton dickinson (bd) pty ltd, johannesburg, south africa) were added to bd falcon tubes labelled for each sample and standards of lymphocyte subsets (lymphosures) low and normal.17 the sample and lymphosures (100 µl) were added to the tubes containing antibodies, vortexed and incubated in a dark cupboard for 20 min at room temperature (20 °c – 25 °c). following the incubation, 900 µl of facs lysing solution was added, and samples were vortexed and incubated for 15 min under the same conditions. samples were then centrifuged for 5 min at 2000 rpm. the supernatant was decanted and the resultant pellet was resuspended in the residual volume of facs lyse by vortexing gently. phosphate-buffered saline (pbs) (2 ml) was added to all samples which were centrifuged at 2000 rpm for 5 min. the supernatant was decanted and the resultant pellet was resuspended in the residual volume of pbs. the foxp3 buffer c (500 µl) was added to all samples, and samples were vortexed and incubated in a dark cupboard for 30 min at room temperature. samples were then centrifuged, the supernatant decanted and the resultant pellet resuspended in the residual volume of buffer c. foxp3 pe antibody (20 µl) was added, and samples were vortexed and incubated in a dark cupboard for 30 min at room temperature. pbs (2 ml) was added, and samples were centrifuged at 2000 rpm for 5 min. the supernatant was decanted and the resultant pellet was resuspended in the residual volume of pbs. then 5% fixative (50 µl) was added to all samples which were analysed within 24 h. determination of serum levels of circulating b-cell activation markers the serum levels of the following b-cell activation markers were assessed by enzyme-linked immunosorbent assay (elisa) kit: scd20 and scd27 (cusabio, houston, usa); scd23, scd30 and scd44 (biocom africa [abcam], pretoria, south africa). all assays were carried out according to the manufacturer’s protocol. all samples from each case and matched (age and gender) controls were tested together. the following basic principles of elisa were followed: (1) coating/capture: direct or indirect immobilisation of antigens to the surface of polystyrene microplate wells. (2) plate-blocking: addition of irrelevant protein or other molecule to cover all unsaturated surface-binding sites of the microplate wells. (3) probing/detection: incubation with antigen-specific antibodies that affinity-bind to the antigens. (4) signal measurement: detection of the signal generated via the direct or secondary tag on the specific antibody. data and statistical analysis all data were captured and analysed using microsoft excel and graph pad prism version 5 (san diego, usa). statistical analysis of in-transformed data was performed using one-way analysis of variance (anova) with bartlett’s test for equal variances. analysis of the primary endpoint was performed using a kruskal-wallis with dunn’s posthoc test. the study populations were regarded as independent variables and the specific marker value was regarded as dependent variable. relationships between two continuous variables were analysed by logistic regression analysis and the strength of the relationship measured with the pearson correlation, or spearman correlation. a p-value of < 0.05 represented statistical significance in hypothesis testing and 95% confidence intervals were used to describe the estimation of unknown parameters. ethical consideration this study was approved by the health research ethics committees of stellenbosch university (n12/03/015) and university of cape town (076/2013). all participants completed and signed the informed consent forms, which were available in english, afrikaans and xhosa. results cd8+cd38+ expression cd8+cd38+ expression (%) was significantly upregulated in hiv-positive nhl patients on art (hiv-1+nhl) as compared to art-treated hiv-positive patients (hiv-1+ art) (mean ± s.d.: 10.8 ± 7.80 vs. 7.36 ± 6.90; p = 0.0104) (figure 1). however, there was no significant difference between hiv-positive nhl patients on art and hiv-negative nhl (nhl) patients. hiv-negative nhl patients had higher cd8+cd38+ expression than controls (mean ± s.d.: 9.56 ± 5.53 vs. 3.65 ± 1.48; p < 0.0001). antiretroviral therapy-treated hiv-positive patients had significantly lower cd8+cd38+ expression than art-naïve hiv-positive patients (mean ± s.d.: 7.36 ± 6.90 vs. 15.95 ± 8.81; p < 0.0001). antiretroviral therapy-naïve hiv-positive patients had higher cd8+cd38+ expression than controls (mean ± s.d.: 15.95 ± 8.81 vs. 3.65 ± 1.48; p < 0.0001). figure 1: cd8+cd38+ expression (t-cell activation). hiv-positive nhl, hiv-positive non-hodgkin lymphoma patients on combination antiretroviral therapy (art); nhl, hiv-negative non-hodgkin lymphoma patients; hiv-positive art, art-treated hiv-positive patients; art-naive hiv-positive, art-naïve hiv-positive patients; controls, healthy control subjects. dimension: cd8+cd38+ = percentage (%). foxp3 expression the expression of foxp3 (%) was significantly downregulated in hiv-positive nhl patients on art (hiv-positive nhl) as compared to both hiv-negative nhl (nhl) patients (mean ± s.d.: 4.28 ± 1.87 vs. 6.37 ± 2.04; p < 0.0001) and art-treated hiv-positive patients (hiv-positive art) (mean ± s.d.: 4.28 ± 1.87 vs. 5.02 ± 0.91; p = 0.0171) (figure 2). hiv-negative nhl patients had significantly lower foxp3 expression than controls (mean ± s.d.: 6.37 ± 2.04 vs. 7.59 ± 1.70; p = 0.0251). as compared to art-naïve hiv-positive patients, art-treated hiv-positive patients had significantly higher foxp3 expression (mean ± s.d.: 5.02 ± 0.91 vs. 4.02 ± 1.28; p = 0.0059). in addition, art-naïve hiv-positive patients had significantly lower foxp3 expression than controls (mean ± s.d.: 4.02 ± 1.28 vs. 7.59 ± 1.70; p < 0.0001). figure 2: foxp3 expression (t-cell regulation). hiv-positive nhl, hiv-positive non-hodgkin lymphoma patients on combination antiretroviral therapy (art); nhl, hiv-negative non-hodgkin lymphoma patients; hiv-positive art, art-treated hiv-positive patients; art-naive hiv-positive, art-naïve hiv-positive patients; controls, healthy control subjects. dimension: foxp3 = percentage (%). serum levels of circulating b-cell activation markers the serum levels (ng/ml) of circulating b-cell activation markers were significantly higher in hiv-positive nhl patients on art (hiv-1+nhl) as compared to hiv-negative nhl (nhl) patients (scd20 [mean ± s.d.: 5.62 ± 1.69 vs. 3.92 ± 0.63; p < 0.0001], scd23 [mean ± s.d.: 3.39 ± 1.53 vs. 2.47 ± 1.56; p = 0.0192], scd30 [mean ± s.d.: 0.57± 0.25 vs. 0.38 ± 0.17; p = 0.0052], scd44 [mean ± s.d.: 7.25 ± 1.23 vs. 6.03 ± 1.41; p = 0.0014]) except scd27, as well as when compared to art-treated hiv-positive patients (hiv-positive art) (scd20 [mean ± s.d.: 5.62 ± 1.69 vs. 4.75 ± 1.34; p = 0.0359], scd23 [mean ± s.d.: 3.39 ± 1.53 vs. 2.31 ± 2.17; p < 0.0001], scd27 [mean ± s.d.: 22.80 ± 11.20 vs. 13.71 ± 4.09; p = 0.0007], scd30 [mean ± s.d.: 0.57 ± 0.25 vs. 0.27 ± 0.26; p < 0.0001], scd44 [mean ± s.d.: 7.25 ± 1.23 vs. 4.84 ± 1.57; p < 0.0001]) (table 2). table 2: serum levels of b-cell activation markers (mean ± s.d.). however, hiv-negative nhl patients had significantly higher serum levels of b-cell activation markers than controls (scd20 [mean ± s.d.: 3.92 ± 0.63 vs. 3.04 ± 0.84; p = 0.0025], scd23 [mean ± s.d.: 2.47 ± 1.56 vs. 1.56 ± 0.59; p = 0.0178], scd27 [mean ± s.d.: 22.28 ± 12.87 vs. 12.21 ± 1.87; p = 0.0033], scd30 [mean ± s.d.: 0.38 ± 0.17 vs. 0.24 ± 0.12; p = 0.0078], scd44 [mean ± s.d.: 6.03 ± 1.41 vs. 4.30 ± 1.37; p = 0.0013])] (table 2). as compared to art-naïve, hiv-positive patients, art-treated hiv-positive patients had significantly higher serum levels of scd23 (mean ± s.d.: 2.31 ± 2.17 vs. 1.15 ± 0.81; p = 0.0074), lower serum levels of scd27 (mean ± s.d.: 13.71 ± 4.09 vs. 19.74 ± 9.48; p = 0.0038) and scd44 (mean ± s.d.: 4.84 ± 1.57 vs. 6.08 ± 2.61; p = 0.0130), while there was no significant difference in serum levels of scd20 and scd30. when compared to the controls, art-naïve, hiv-positive patients had significantly higher serum levels of scd20 (mean ± s.d.: 5.11 ± 1.49 vs. 3.04 ± 0.84; p < 0.0001), scd27 (mean ± s.d.: 19.74 ± 9.48 vs. 12.21 ± 1.87; p = 0.0025) and scd44 (mean ± s.d.: 6.08 ± 2.61 vs. 4.30 ± 1.37; p = 0.0030), lower serum levels of scd23 (mean ± s.d.: 1.15 ± 0.81 vs. 1.56 ± 0.59; p = 0.0452), while there was no significant difference in scd30. associations between t-cell activation, regulation and b-cell activation the expression of cd8+cd38+ was negatively associated with foxp3 expression (r = −0.2033, p = 0.0078) (figure 3a). the serum levels of circulating scd20 were negatively correlated with foxp3 (r = −0.3604, p < 0.0001) expression (figure 3b), while they correlated positively with cd8+cd38+ expression (r = 0.172, p = 0.0203) (figure 3c). the serum levels of circulating scd27 were negatively correlated with foxp3 (r = −0.164, p = 0.0260) expression (figure 3d), while they associated positively with cd8+cd38+ (r = 0.201, p = 0.0082) (figure 3e) expression. the serum levels of circulating scd44 were positively associated with cd8+cd38+ (r = 0.1676, p = 0.0235) expression (figure 3f). no significant correlation was observed between scd23, scd30 and biomarkers of t-cell activation and regulation. figure 3: t-cell activation/regulation versus b-cell activation associations. (a) cd8+cd38+ (%) versus foxp3 (%); (b) scd20 (ng/ml) versus foxp3 (%); (c) scd20 (ng/ml) versus cd8+cd38+ (%); (d) scd27 (ng/ml) versus foxp3 (%); (e) scd27 (ng/ml) versus cd8+cd38+ (%); (f) scd44 (ng/ml) versus cd8+cd38+ (%). discussion levels of cd8+ t-cell activation in the current study, there was no significant difference in the expression of cd8+cd38+ between hiv-positive nhl patients on art and hiv-negative nhl patients. however, although there was no significant difference, there was a trend towards increased cd8+cd38+ expression in hiv-positive nhl patients on art. in addition, hiv-positive nhl patients on art had significantly elevated t-cell activation as compared to art-treated hiv-positive patients. furthermore, as compared to the controls, hiv-negative nhl patients had increased cd8+cd38+ expression. the increased cd8+ t-cell activation observed in hiv-negative nhl patients may have been caused by epstein-barr virus (ebv) infection which has been associated with nhl or anti-tumour immune responses. cd8+ t-cell activation may be necessary for killing malignant lymphoma cells in nhl.18 to confirm if hiv infection leads to increased t-cell activation, the levels of t-cell activation between art-naïve hiv-positive patients and control subjects were compared. t-cell activation was significantly elevated in art-naïve, hiv-positive patients as compared to the controls and art-treated hiv-positive patients. these results suggest that hiv increases t-cell activation and the art initiation decreases t-cell activation. deeks and colleagues19 reported that the initiation of art during early hiv infection reduces the level of cd8+ t-cell activation. in addition, almeida and colleagues20 showed that prior to art, cd38+ expression was increased on peripheral blood cd8+ t-cells, and art initiation significantly decreased cd38+ expression. furthermore, the increased cd8+cd38+ expression was negatively associated with foxp3 expression in the current study. this suggests that the increased t-cell activation observed in the current study may have been because of decreased t-cell regulation. the expression of foxp3 which normally inhibits t-cell activation is reduced; thus, t-cell activation occurs continuously without regulation. levels of t regulatory cells foxp3 plays an important role in regulatory t-cell (t-reg) function, development and maintenance.21 t-reg cells have been implicated in the suppression of t-cell activation, proliferation and cytokine production.22,23 dysregulated t-reg cell expression has been associated with a number of pathological conditions including cancer, infectious and autoimmune diseases.21 in the current study, the expression of foxp3 in hiv-positive nhl patients on art was significantly downregulated as compared to hiv-negative nhl patients as well as when compared to art-treated hiv-positive patients. the reduced foxp3 expression observed in hiv-positive nhl patients on art may have been caused by hiv infection, as the levels of foxp3 expression were higher in hiv-negative nhl patients and art-treated hiv-positive patients. this may have detrimental effects on t-cell regulation and activation. foxp3 expression was also downregulated in hiv-negative nhl patients as compared to the controls. this may have been caused by the direct effect of ebv on foxp3 or the detrimental effect of immunosuppressive drugs such as cyclophosphamide, hydroxydaunomycin, oncovin and prednisone (chop) in the immune system. in a study conducted by el-sayed and colleagues,24 it was shown that mrna transcripts as well as percentages of foxp3 were significantly increased in b-cell nhl patients before receiving chop, when compared to healthy controls. however, after six cycles of chop treatment, foxp3 expression decreased significantly. these results suggest that t-cell regulation is impaired in both nhl and hiv-positive state. as mentioned previously, one of the hallmark features of nhl is chronic immune activation. this may be because of suppressed t-cell regulation. in addition, the reduced t-reg cell expression observed in hiv-negative nhl patients may be beneficial as they may lead to increased immune activation and anti-tumoural responses, while the increased t-reg cell expression could limit the anti-tumour immune response, favouring tumour growth and development.24,25 to investigate the effect of art on t-cell regulation, the levels of foxp3 expression between art-treated hiv-positive patients and art-naïve hiv-positive patients were compared. the expression of foxp3 was significantly increased in art-treated hiv-positive patients than art-naïve hiv-positive patients. thus, art may have increased the expression of foxp3 in this population group. consistent with the current findings, andersson and colleagues26 reported suppressed foxp3 expression in art-naïve hiv-positive patients; however, upon initiation of art, the levels of foxp3 normalised. antiretroviral therapy-naïve hiv-positive patients also had decreased foxp3 expression as compared to the controls. this confirms that hiv infection decreases t-cell regulation, leading to chronic t-cell activation. t-reg cells have been shown to be susceptible to hiv infection.27 levels of b-cell activation soluble biomarkers of b-cell activation (scd20, scd23, scd27, scd30 and scd44) were elevated in hiv-positive nhl patients on art in the present study. biomarkers of b-cell activation were also elevated in art-naïve, hiv-positive patients, which indicates that chronic b-cell activation also occurred in untreated hiv-positive patients and art may reduce b-cell activation. these results suggest that b-cell activation is increased in hiv-associated nhl as evidenced by increased b-cell activation markers investigated in this study. the increased b-cell activation has been previously observed in hiv-infected patients and was associated with a more rapid disease progression and poor survival.8,10,14 breen and colleagues28 reported that serum scd23, scd27 and scd30 levels were significantly elevated in hiv-positive nhl patients as compared to hiv-positive controls. depleted foxp3 expression was associated with increased t-cell activation. increased b-cell activation was positively associated with increased t-cell activation and decreased t-cell regulation. the current findings indicate that chronic immune activation may have been a result of decreased immune regulation in hiv-positive nhl patients. immune regulation is necessary in the control of immune activation and the prevention of auto immunity. t-reg cells are known to suppress t-cell activation, proliferation and cytokine production.22,23 in the absence of immune regulation, sustained immune activation occurs without monitoring. however, art use was associated with improved immunity, increased regulatory t-cells and decreased t-cell activation. the increased t-cell activation observed in hiv-positive nhl patients may have also caused chronic b-cell activation. it has been reported that chronic b-cell activation may be caused by related interaction with activated t-cells, whose receptor recognises antigen presented by the b-cells, or activation by t-cell-independent antigens.29 in addition, there is growing evidence that hiv virus can directly contribute to b-cell activation via direct interactions with b-cells.14 chronic b-cell activation is known to increase the risk of hiv-associated nhl development.5,10,30 it has been previously shown that elevated serum levels of sc23, scd27 and scd30 are associated with subsequent diagnosis of hiv-associated nhl.31 the downstream effects of chronic b-cell activation with ongoing engagement of the b-cell receptor complex on lymphomagenesis are numerous and include the accumulation of oncogene mutations and translocations resulting from aberrant expression and gene targeting of the dna mutating enzyme, activation-induced cytidine deaminase (aicda).31 b-cell activation leads to the expression of aicda, a dna editing enzyme that mediates immunoglobulin gene class switch recombination and somatic hypermutation.32 it has been shown that aicda is overexpressed before the development of hiv-associated nhl which is consistent with a direct role for this molecule in the pathogenesis of nhl.32 conclusion although cd4+ t-cell activation was not investigated, cd8+ t-cell activation is increased in nhl, as evidenced by increased cd8+cd38+ expression in hiv-positive nhl patients on art as compared to art-treated hiv-positive patients as well as in hiv-negative nhl patients as compared to controls. the influence of hiv infection on t-cell activation in hiv-positive nhl patients was not clearly defined in the current study, as there was no significant difference between hiv-positive nhl patients on art and hiv-negative nhl patients. however, the current findings confirm that t-cell activation is greatly increased in untreated hiv infection. the observed chronic t-cell activation in hiv-infected patients may have been caused by a decreased regulatory t-cell expression as evidenced by decreased foxp3 expression. this may lead to increased t-cell turnover and exhaustion, resulting in immune dysfunction. antiretroviral therapy decreases t-cell activation while increasing its regulation. b-cell activation is increased in hiv-positive nhl patients as evidenced by increased b-cell activation markers investigated in this study and is associated with reduced t-cell regulation and increased t-cell activation. the increased immune activation in this patient population group may have been caused by persistent hiv infection, as well as suppressed immune regulation. these findings confirm that b-cell activation is increased in untreated hiv-positive patients and in nhl patients. the serum levels of circulating b-cell activation markers are elevated in hiv-positive nhl patients and art-naïve hiv-positive patients, and art may decrease them. these data provide additional support for the recommendation that early art initiation in all hiv-positive patients could be beneficial. strengths and limitations the sample size investigated in the current study was small; however, this was substantiated by formal statistical sample size calculation. the studied population groups were genetically diverse. hiv-positive patients had low cd4+ counts of ≤ 350 cells/µl, and cd4+ t-cell activation was not measured. hiv viral load was much lower in hiv-positive nhl patients and the mentioned ebv was not confirmed in nhl patients. b-cell activation was not measured directly; only soluble biomarkers of b-cell activation were measured. the current study provides important information on the levels of immune activation in south african hiv-positive, nhl patients. acknowledgements the authors acknowledge the assistance by dr zainab mohamed and the hospital nurses in the recruitment of patients in tygerberg and groote schuur hospitals and the assistance by synexa life sciences and their laboratory technologists in sample analysis. the project was financially supported by the harry crossley foundation, the columbia-south africa (d43) training programme for research on hiv-associated malignancies and the joint national research foundation-german dfg-irtg project 1522 ‘hiv/aids and associated infectious diseases in southern africa’ (nrf-irtg). competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions b.t.f. was responsible for experimental and project design, experiments, data analysis and writing of the manuscript. p.b. 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https://doi.org/10.1615/critrevimmunol.v23.i3.10 purdue mp, lan q, martinez-maza o, et al. a prospective study of serum soluble cd30 concentration and risk of non-hodgkin lymphoma. blood. 2009;114(13):2730–2732. https://doi.org/10.1182/blood-2009-04-217521 hussain sk, hessol na, levine am, et al. serum biomarkers of immune activation and subsequent risk of non-hodgkin b-cell lymphoma among hiv-infected women. cancer epidemiol biomarkers prev. 2013;22(11):2084–2093. https://doi.org/10.1158/1055-9965.epi-13-0614 vendrame e, hussain sk, breen ec, et al. serum levels of cytokines and biomarkers for inflammation and immune activation, and hiv-associated non-hodgkin b-cell lymphoma risk. cancer epidemiol biomarkers prev. 2014;23(2):343–349. https://doi.org/10.1158/1055-9965.epi-13-0714 abstract introduction key messaging from the who normative guidelines on hiv self-testing hiv self-testing rapid diagnostic tests implementation acknowledgements references appendix 1 appendix 2 appendix 3 about the author(s) francois venter hiv management cluster, wits reproductive health and hiv institute, johannesburg, south africa mohammed majam hiv management cluster, wits reproductive health and hiv institute, johannesburg, south africa lauren jankelowitz southern african hiv clinicians society, johannesburg, south africa siraaj adams southern african hiv clinicians society, johannesburg, south africa michelle moorhouse southern african hiv clinicians society, johannesburg, south africa wits reproductive health and hiv institute, university of the witwatersrand, south africa sergio carmona national health laboratory service, johannesburg, south africa wendy stevens national health laboratory service, johannesburg, south africa department of haematology, university of the witwatersrand, south africa busisiwe r. msimanga world health organization, south africa david allen bill and melinda gates foundation, johannesburg, south africa pooja balani southern african hiv clinicians society, johannesburg, south africa zwoitwaho nevhutalu south african national aids council, pretoria, south africa naleni rhagnath wits reproductive health and hiv institute, university of the witwatersrand, south africa amir shroufi médecins sans frontières, southern africa walter devillé ndlovu care group, groblersdal, south africa utrecht university medical center, utrecht university, the netherlands victoria kazangarare psi, johannesburg, south africa society for family health, johannesburg, south africa renee van der wiel wits institute for social & economic research, university of the witwatersrand, south africa hugo templeman ndlovu care group, groblersdal, south africa adrian puren national institute for communicable diseases, johannesburg, south africa tim tucker strategic evaluation, advisory and development consulting (sead), johannesburg, south africa gilles van cutsem médecins sans frontières, southern africa department of medicine, university of cape town, south africa francesca conradie southern african hiv clinicians society, johannesburg, south africa krista dong iteach, denton, united states massachusetts general hospital, boston, united states thato chidarikire national department of health, pretoria, south africa andy gray discipline of pharmaceutical sciences, university of kwazulu-natal, south africa citation venter f, majam m, jankelowitz l, adams s, moorhouse m, carmona s, et al. south african hiv self-testing policy and guidance considerations. s afr j hiv med. 2017;18(1), a775. https://doi.org/10.4102/sajhivmed.v18i1.775 guidelines south african hiv self-testing policy and guidance considerations francois venter, mohammed majam, lauren jankelowitz, siraaj adams, michelle moorhouse, sergio carmona, wendy stevens, busisiwe r. msimanga, david allen, pooja balani, zwoitwaho nevhutalu, naleni rhagnath, amir shroufi, walter devillé, victoria kazangarare, renee van der wiel, hugo templeman, adrian puren, tim tucker, gilles van cutsem, francesca conradie, krista dong, thato chidarikire, andy gray copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract the gap in hiv testing remains significant and new modalities such as hiv self-testing (hivst) have been recommended to reach key and under-tested populations. in december 2016, the world health organization (who) released the guidelines on hiv self-testing and partner notification: a supplement to the consolidated guidelines on hiv testing services (hts) and urged member countries to develop hivst policy and regulatory frameworks. in south africa, hivst was included as a supplementary strategy in the national hiv testing services policy in 2016, and recently, guidelines for hivst were included in the south african national strategic plan for hiv, sexually transmitted infections and tuberculosis 2017–2022. this document serves as an additional guidance for the national hiv testing services policy 2016, with specific focus on hivst. it is intended for policy advocates, clinical and non-clinical hts providers, health facility managers and healthcare providers in private and public health facilities, non-governmental, community-based and faith-based organisations involved in hts and outreach, device manufacturers, workplace programmes and institutes of higher education. introduction background hiv represents the primary burden of disease in south africa, with an estimated national prevalence of 12.2% in 2012. the hiv annual incidence among individuals aged between 15 years and 49 years is estimated at 1.9%, and 2.3% among youth aged between 15 years and 24 years. the country has a generalised and maturing hiv epidemic, with the highest number of people (6.4 million) living with hiv in the world. the prevalence of hiv in south africa remains high. it is estimated that approximately 3 million people are on antiretroviral treatment (art), making it the largest programme in the world. this can be attributed to the rapid scale-up and success of the art programme. in south africa, the proportion of people who have had an hiv test and are aware of their status has increased from 50% in 2008 to 66.5% in 2014. in the country there still remains a gap in hiv testing, and new approaches must be considered. according to the world health organization (who), hiv self-testing (hivst) is defined as the process whereby an individual collects their own specimen (blood or oral fluid), performs hiv testing using an hiv rapid diagnostic test (rdt) and interprets the result themselves either assisted or unassisted.1 hivst does not provide a definitive diagnosis. a reactive (positive) result always requires a further confirmatory testing from a trained health professional using the relevant validated national hiv testing algorithm, typically performed at a clinic. self-testing may also be termed ‘self-screening’. in december 2016, the who released the guidelines on hiv self-testing and partner notification: a supplement to the consolidated guidelines on hiv testing services (hts).1 these globally recognised guidelines have paved the way for in-country policy and guidance development on hivst. in tandem, the who diagnostics prequalification team released a technical specifications guidance document (tss-1)2 for manufacturers who wish to apply for who prequalification and diagnostic assessment of their hivst product. through this process, the who prequalification sets the baseline for safety, quality and performance following international standards. hiv self-testing has the potential to impact the first ‘90’ of the unaids 90-90-90 targets, which have been adopted by south africa, by increasing access and acceptability for traditionally under-tested populations. (un 90-90-90 targets: by 2020, 90% of all people living with hiv will know their hiv status, 90% of all people with diagnosed hiv infection will receive sustained art and 90% of all people on art will have viral suppression.3). this includes key at-risk populations (serodiscordant couples, men, adolescents, female sex workers and men who have sex with men) who may require frequent or routine testing. hivst is not intended to displace the confirmatory facility-based hiv test; rather hivst is a complementary approach to existing htss, with the benefit of reaching previously untested, hard-to-reach and test-averse populations. hivst has been shown to be widely acceptable among untrained users in various settings, particularly in key populations.2,3 to support the use of hivst, guidelines for hivst have recently been included in the south african national strategic plan for hiv, sexually transmitted infections (stis) and tuberculosis (tb) 2017–2022.4 this comes after hivst was included as a supplementary strategy in the national hiv testing services policy for south africa in 2016. the majority of hiv kits for self-testing are based on hiv rdts for professional use that have been modified and repackaged for an untrained layperson. professional use hiv rdts should not be used as an hivst kit for the layperson without some level of modification, as there is a risk of misunderstanding or misinterpreting the instructions for use or test results. these tests should be validated for self-testing prior to use as such. the ideal hivst should be easier to use than the current hiv professional use tests. self-test kits need to be made more ‘user-friendly’ and appropriate for an untrained, non-professional layperson. these modifications may include: revising the instructions for use to have fewer words and more pictures; simplifying specimen collection and transfer; reducing the number of process steps; achieving a faster time to results; ensuring that results remain stable for a longer period; making the test result easier to read and interpret; and optimising packaging and general instructions, including making this language-level and literacy-level appropriate. each product must include referrals for assistance (telephone hotline, social media, local counsellor, phone application) with interpreting the results and linkage to care. innovations in information tools for referrals, such as online videos and apps, may improve test performance and linkage to confirmatory testing, prevention, treatment and care. with a few early hiv rdts for self-testing already on the market more international hivst products are emerging (homemed: http://www.homemed.co.za/hiv-1-or-2-single-test-kit/?p=zz0xjmfw ptemcd0x). however, substantial entry into the south african market has been inhibited by several barriers. until recently,5 the most significant barrier has been the uncertainty around a national policy on hivst, which has inhibited manufacturers from bringing high-quality products to the market. in the 2016 updated hiv counselling and testing guidelines, hivst was recommended as a new approach for hiv testing (national hiv testing services policy 2016).6 the hivst agenda has moved rapidly and the evidence base to support hivst has grown significantly (www.hivst.org). a glossary of terms used is provided in appendix 1, and a list of acronyms and abbreviations in appendix 2. rationale for hiv self-testing guidelines these guidelines serve as additional guidance for the national hiv testing services policy 2016 with specific focus on hivst. there is a global initiative to accelerate universal access to hiv prevention, treatment and care. hiv testing remains the key point of entry in the continuum of care for any individual living with hiv. the gap in hiv testing remains significant and new modalities such as hivst have been recommended as alternative approaches to traditional htss to reach key and under-tested populations. the who’s formal recommendation states1: ‘hiv self-testing should be offered as an additional approach to hiv testing services (strong recommendation, moderate quality evidence)’. in south africa, hiv tests are available for purchase, through online channels, retail outlets and private community pharmacies. the quality of some of these tests is unknown. in february 2016, the south african pharmacy council lifted the ban on the sale of hivst by pharmacists and has since published draft guidance on the provision of such tests by pharmacists.7 the medicines control council, which will shortly become the south african health products regulatory authority (sahpra), has published regulations on medical devices and in vitro diagnostics.8 a risk-based approach will be followed in applying these new regulations, and hiv tests are expected to receive priority attention. the who has urged member countries to develop policy and regulatory frameworks for hivst. these include adapting, developing and harmonising existing national policies on hiv testing to incorporate hivst, such as: laws permitting the sale, distribution, advertisement and use of quality-assured rdts for hivst age of consent to self-test human rights laws, policies and regulations to protect individuals and address misuse of hivst national policies on how to confirm an individual’s hiv status following hivst quality assurance and post-market surveillance systems for rdts used for hivst. target audience this document is intended for policy advocates, clinical and non-clinical hts providers, health facility managers and healthcare providers in private and public health facilities, non-governmental, community-based and faith-based organisations involved in hts and outreach, device manufacturers, workplace programmes and institutes of higher education. the department of health, medical aids, non-governmental organisations, faith-based organisations and other organisations have to balance complex decisions around resource allocation, cost-effectiveness and expanded access to hard-to-reach populations. guiding principles all forms of htss, including hivst, should adhere to the who 5cs: consent, confidentiality, counselling, correct test results and connection. these guiding principles are found in the national hiv testing services policy 2016.6 key messaging from the who normative guidelines on hiv self-testing the selected key points summarise the who’s hivst guidelines1: hivst is considered a test for triage (a0) (figure 1) because a single rdt is not sufficient to make an hiv-positive diagnosis. a reactive (positive) self-test result always requires further testing and confirmation from a trained tester starting from the beginning of a validated national testing algorithm. clear messages are essential to ensure users understand that hivst does not provide a definitive hiv-positive diagnosis, and they are aware of what to do after a reactive self-test result. interpretation of a non-reactive (negative) self-test result will depend on the ongoing risk of hiv exposure. individuals at high ongoing risk, or who test within six weeks of possible hiv exposure, should be encouraged to re-test. hivst is not recommended for users with a known hiv status who are taking antiretroviral drugs, as this may lead to an incorrect self-test result (false non-reactive). hivst is acceptable to many users across different contexts and can, therefore, increase uptake and frequency of hiv testing, particularly among populations at high ongoing risk of hiv, who may be less likely to access testing or test less frequently than recommended. hiv rdts used by self-testers can perform as accurately as when used by a trained tester, provided the hivst products meet quality, safety and performance standards. in-person demonstrations and other support tools, such as videos, may also enhance the performance of hivst. hivst can be delivered through various approaches in the public and private sectors, including community-based, facility-based and internet-based channels. approaches may also offer the option of using an oral-fluid-based or blood-based hiv rdt for self-testing. as such, different populations can benefit from a range of choices when self-testing for hiv. figure 1: hiv self-testing algorithm. hiv self-testing rapid diagnostic tests evidence has shown that hivst has a high level of test accuracy, in terms of both sensitivity and specificity, when quality-assured products are used in the hands of untrained users. the technology landscape is driving towards ensuring that hivst products are fit for purpose and can demonstrate high accuracy when compared to use by a trained user. target product profile adapted from the global target product profile (tpp)9 is a set of characteristics that the ‘ideal’ hivst should exhibit. device manufacturers must strive towards achieving and demonstrating the following: high-quality manufacturing standards, according to iso 9001 acceptable analytical performance in laboratory settings high clinical sensitivity and specificity in the hands of untrained users pictorial instructions for use with any text-based instruction translated into local languages low number of test steps with simple sample transfer simple-to-interpret test results fast time to result stable test results. technology landscape there are now several countries in which hivsts are available in the open market. these include usa, uk, brazil, australia and france. the products that are available for sale and distribution in these countries have been approved by a member of the global harmonization task force such as the fda in the usa, and ce mark in europe. the fda is widely considered to have the most stringent regulatory framework globally. each member regulatory body sets out individual standards for product performance that must be met. in south africa, until the new regulatory framework for medical devices and in vitro diagnostics is fully operative and has addressed hivsts, the national department of health (ndoh) recommends that only hivsts that have been approved for the purposes of hivst by the who prequalification programme should be procured or sold. under the requirements of the programme, manufacturers have to demonstrate high analytical performance, usability and clinical performance in the hands of untrained users. the full list of hivsts in the pipeline and those that have been approved can be viewed at: http://unitaid.eu/assets/hiv_rapid_diagnostic_tests_for_self-testing_-_semi-annual_update-december_2016.pdf. guidance for hiv self-testing in south africa based on the international guidelines above, a committee was convened on 17 november 2016 to establish guidelines appropriate for south africa. representatives at this meeting are included in table 1-a3 available in appendix 3. the proposed guidelines for hivst follow, towards an overarching goal of ensuring that high-quality, safe and effective products are available in the market: south africa, through the health products regulatory authority, will develop a regulatory framework for medical devices, which will include hivsts. until the development of this framework, hivsts must comply with the requirements of this guidance document. products should strive to meet all of the requirements of the target product profile, as per section ‘target product profile’ above. stable test results within the specified read window. the need for appropriate, validated, clear and concise instructions for use. this is critical in terms of a product’s usability to ensure that critical errors are minimised and accuracy is maximised. manufacturers must demonstrate reasonable usability of their products in the region where they are marketed. instructions for use and packaging materials must be translated and available in local languages, as well as in english. clear messaging: users must understand that a reactive or positive result must be confirmed through further testing by a healthcare worker, as well as where to access services. manufacturers should include a ‘care card’ with the packaging that the user can take to a local clinic as evidence of having self-tested. care card information should include the ndoh logo, the contact details for the national aids helpline, the hivst website (www.hivselftesting.co.za) or the manufacturer’s website that can provide any additional information on linkage to care as needed. verification and certification of medical devices or in vitro diagnostic devices (ivds) before they are placed on the market by manufacturers – all products must be accredited on the basis of a conformity assessment certificate issued by a conformity assessment body, a body corporate or other legal entity, locally or internationally, accredited either by the south african national accreditation system (sanas) or an international body recognised by the medicines control council, according to a standard determined by the council, as competent to carry out the assessment. post-marketing surveillance and lot number tracking to ensure device failures can be reported, lot numbers may be recalled and manufacturing quality can be assured. all kits must clearly show the expiry date of the product. all hivst devices must provide disposal instructions and disposal supplies, e.g. sealable plastic bags. implementation implementation considerations to maximise the benefit of hivst, it is important not only to consider the products used but also how this modality may be implemented or scaled up. there are several mechanisms through which the service may be delivered, but there are also key considerations for all stakeholders such as linkage to care, quality control and monitoring and evaluation (m&e). there are several models through which hivst may be delivered and will depend on the target population: these would include primary healthcare facilities, hospitals and pharmacies. less traditional access points could be through internet distribution, workplace programmes and vending machines. in terms of community-based outreach, self-testing can be offered as part of a package to clients visiting pre-exposure prophylaxis facilities, centres for voluntary medical male circumcision, sexual and reproductive health, outreach clinics for stis and tb and multi-disease prevention campaigns. secondary distribution includes peer-to-peer, and couples and partners. within the spectrum of channels for distribution of hivst, there are also varying levels and types of support that can be offered to self-testers. these include: brief demonstrations on kit usage and result interpretation, face-to-face assistance during initial testing, and instructions for use. the following tools can be utilised for assistance or demonstration: pictorials videos hotline apps multimedia sms. to facilitate linkage into care for individuals who receive a reactive self-test result, a care card bearing the ndoh logo should be implemented and standardised across the country, and should read (suggested wording): dear sister in-charge, this participant has screened for hiv using an hiv self-test and may have received a reactive (positive) result. please ensure that the individual is provided with confirmatory testing and counselling should they require. (twg) monitoring and evaluation hiv self-testing provides some unique challenges in terms of m&e, and globally there are not many systems outside of research-controlled environments that can effectively provide this. this is an area that the technical working group of the who is actively pursuing. the mere notion of a self-test shifts the focus away from a healthcare facility to an individual. measurement of uptake cannot be inextricably linked to usage, as individuals who receive a test may not necessarily use it. the following have been proposed as minimum m&e during the initial roll-out of hivst: periodical assessment of the hotline for hivst-related calls requesting information, assistance, counselling and support reporting of adverse events to the national hotline, on dedicated web and social media platforms post-marketing surveillance data of companies linkage to care through e-health platforms. implementation messaging successful implementation of hivst requires clear messaging for both healthcare providers and end-users. the following messaging should be considered during implementation: an hivst is a screening test. an initially reactive or positive self-test result requires further testing and confirmation from a trained tester. clear messages are essential to ensure users understand that hivst does not provide a definitive hiv-positive diagnosis, and they are aware of what to do after a reactive self-test result. a non-reactive or negative self-test result does not always indicate that a person is hiv-negative, depending on the test used, window period and also possible errors in performing the self-test or interpreting results, and, as with all hiv testing, individuals who have had a high-risk encounter in the preceding three months should be advised to re-test. individuals at high, ongoing risk should be advised to re-test frequently. if an individual is on antiretroviral drugs for treatment or pre-exposure prophylaxis, this may lead to a false non-reactive or negative result, particularly if using an oral fluid-based rdt. to minimise social harm, test kits or care cards or packaging must contain the following statements: this test is private, confidential and voluntary. if you are concerned about the outcome of the result or uncomfortable using the test do not use it. go to a clinic for testing. if you require assistance telling your partner your result, then call the helpline or go to your nearest clinic. warning about disinhibition if hiv-negative and risk. emphasis must be placed on the correct disposal of used hivsts. acknowledgements the society gratefully acknowledges the receipt of funding from the south african medical research council (www.mrc.ac.za) for the development and printing of these guidelines. reviewer: cheryl johnson (who). the activities of the twg was funded by the sa hiv clinicians society and the wits reproductive health and hiv institute. no ethical approval was required for this paper. competing interests the donor did not participate in or influence the process of guideline development. a.g. is a member of the medicines control council (which will regulate in vitro diagnostics, including hivst), and the national essential medicines list committee. he chairs the unitaid proposal review committee, which has called for submissions to support supply-side interventions and demand-generation for hivst (see https://www.unitaid.eu/call-hiv-self-testing/). m.m., m.m. and f.v. hail from the wits reproductive health and hiv institute, which receives grants unattached to device manufacturers to facilitate registration, technical assistance and implementation of self-testing in south africa. authors’ contributions m.m. wrote the first and final draft. f.v. reviewed the final draft. all other members of the technical working group contributed to the various drafts. all authors read and gave approval of the final manuscript. references world health organization (who). guidelines on hiv self-testing and partner notification. supplement to consolidated guidelines on hiv testing services [homepage on the internet]. geneva, switzerland: who; 2016 [cited 2017 may 22]. available from: http://www.who.int/hiv/pub/vct/hiv-self-testing-guidelines/en/ world health organization (who). technical specifications series or submission to who prequalification – diagnostic assessment. tss-1: human immunodeficiency virus (hiv) rapid diagnostic tests for professional use and/or self-testing [homepage on the internet]. geneva, switzerland: who; 2016 [cited 2017 may 22]. available from: http://apps.who.int/iris/bitstream/10665/251857/1/9789241511742-eng.pdf the joint united nations programme on hiv/aids (unaids). 90-90-90 – an ambitious treatment target to help end the aids epidemic [homepage on the internet]. geneva, switzerland: unaids; 2014 [cited 2017 may 22]. available from: http://www.unaids.org/en/resources/documents/2017/90-90-90 national department of health (ndoh). south african national strategic plan for hiv, stis and tb 2017–2022. pretoria, south africa: ndoh; 2017. south african pharmacy council (sapc). rules relating to good pharmacy practice [homepage on the internet]. board notice 194 of 2016. government gazette no. 40522, 23 november 2016. arcadia, south africa: sapc; 2016 [cited 2017 may 22]. available from: http://www.gov.za/sites/www.gov.za/files/40522_bn194.pdf national department of health (ndoh). national hiv testing services: policy 2016 [homepage on the internet]. pretoria, south africa: ndoh; 2016 [cited 2017 may 22]. available from: http://www.health.gov.za/index.php/gf-tb-program/332-national-hiv-testing-services south african pharmacy council. rules relating to good pharmacy practice [homepage on the internet]. board notice 193 of 2016, government gazette no. 40522, 23 december 2016. [cited 2017 may 22]. available from: http://www.gov.za/sites/www.gov.za/files/40522_bn193.pdf minister of health. regulations relating to medical devices and in vitro diagnostic medical device (ivds) [homepage on the internet]. government notice no. 1515, government gazette no. 40480, 9 december 2016. [cited 2017 may 22]. available from: http://www.gov.za/sites/www.gov.za/files/40480_gon1515.pdf path. target product profile: hiv self-test version 4.1: a white paper on the evaluation of current hiv rapid tests and development of core specifications for next-generation hiv tests [homepage on the internet]. seattle, wa: path; 2014 [cited 2017 may 22]. available from: http://www.path.org/publications/files/ts_hiv_self_test_tpp.pdf appendix 1 glossary of terms acute infection: the period in which an individual becomes hiv-infected and before hiv antibodies can be detected by a serological assay. assay: a complete procedure for detecting the presence or concentration of an analyte, including all the components of a test kit used to identify hiv p24 antigen or hiv-1/2 antibodies, in the case of hiv. confirm: to issue a report on hiv status. initially reactive test results, including reactive self-test results, need to be confirmed according to the national validated testing algorithm. directly assisted hiv self-testing (hivst): refers to when individuals who are self-testing for hiv receive an in-person demonstration from a trained provider or peer before or during hivst, with instructions on how to perform a self-test and how to interpret the self-test result. this assistance is provided in addition to the manufacturer-supplied instructions for use and other materials found inside hivst kits. harm or social harm: any intended or unintended cause of physical, economic, emotional or psychosocial injury or hurt from one person to another, a person to themselves, or an institution to a person, occurring before, during or after testing for hiv. hiv self-testing: a process in which a person collects his or her own specimen (oral fluid or blood) and then performs a test and interprets the result, often in a private setting, either alone or with someone he or she trusts. hiv status: is the final report that is given to the patient; it is the final interpretation of the patient disease state and is based on a collection of testing results generated from one or more assays. hiv status may be reported as hiv-positive, hiv-negative or hiv-inconclusive. hiv test result: the result from a single test on a given assay. in vitro diagnostic medical device: a medical device, used alone or in combination, intended by the manufacturer for the examination of specimens derived from the human body solely, or principally, to provide information for diagnosis, monitoring or determining compatibility. for example, an in vitro diagnostic medical device can be used for: diagnosis, as an aid to diagnosis, screening, monitoring, predisposition, prognosis, prediction and determination of physiological status. key populations: defined groups who, because of specific higher-risk behaviours, are at increased risk of hiv irrespective of the epidemic type or local context. these guidelines refer to the following groups as key populations: men who have sex with men, people who inject drugs, people in prisons and other closed settings, sex workers and transgender people. non-reactive test result: a test result that does not show a reaction indicating the presence of analyte, which in the context of hiv refers to hiv-1 p24 antigen or hiv-1/2 antibodies. point-of-sex testing: refers to when individuals use an hiv rdt for self-testing to screen potential sex partners and determine his or her own hiv status and their partner(s)’ hiv status. quality assurance: part of quality management focused on providing confidence among stakeholders that quality requirements will be fulfilled. quality control: is the set of procedures designed to monitor the test method and results to ensure appropriate test system performance. it includes testing control materials, charting the results and analysing them to identify source of error, and evaluating and documenting any remedial action taken as a result of this analysis. quality improvement: an element of quality management focused on increasing the ability to fulfil quality requirements. quality management system: a system to direct and control an organisation with regard to quality. systematic and process-oriented efforts are essential to meet quality objectives. principles of quality management include categories such as documents and records, organisation, personnel, equipment, purchasing and inventory, process control, information management, occurrence management, assessments (external and internal), process improvement, customer services and facilities and safety. rapid diagnostic test: in vitro diagnostic medical device of immunochromatographic or immunofiltration format for the detection of hiv-1/2 antibodies or hiv p24-1 antigen in the context of hiv. reactive test result: a test result that shows a reaction indicating the presence of analyte, which in the context of hiv includes hiv-1 p24 antigen or hiv-1/2 antibodies. repeat testing: a situation in which additional testing is performed for an individual immediately following a first test, during the same testing visit, because of hiv-inconclusive status or discordant test results. the same assay(s) is used and, where possible, the same specimen. re-testing: refers to certain situations in which individuals should be re-tested after a defined period of time: (1) hiv-negative people with recent or ongoing risk of exposure; (2) people with an hiv-inconclusive status; and (3) hiv-positive people before they enrol in care or initiate treatment. reasons for re-testing before initiation of care or treatment include: ruling out laboratory or transcription errors, and ruling in or ruling out seroconversion. sensitivity: denotes the probability that an hiv assay or algorithm will correctly identify all specimens that contain hiv-1/2 antibodies or hiv-1 p24 antigen. seroconversion: is when an individual’s immune system produces a quantity of hiv-1/2 antibodies sufficient to be detectable on a given hiv serology assay. serodiscordant couple: a couple in which one partner is hiv-positive and one partner is hiv-negative. serology assay: refers to an assay that detects the presence of antibodies in human specimens. such assays typically use serum or plasma, but also capillary or venous whole blood and oral fluid. for example, rdts, immunoassays and certain supplemental hiv assays are serology assays. specificity: denotes the probability that the assay or algorithm will correctly identify specimens that do not contain hiv-1/2 antibodies or hiv-1 p24 antigen. testing algorithm: the combination and sequence of specific assays used within hiv testing strategies. unassisted hiv self-testing: refers to when individuals self-test for hiv using only a self-test kit that includes manufacturer-provided instructions for use. as with all self-testing, users may be provided with links or contact details to access additional support, such as telephone hotlines or instructional videos. window period: the period between hiv infection and the detection of hiv-1/2 antibodies using serology assays, which marks the end of the diagnostic window period and the end of seroconversion. appendix 2 aids, acquired immune deficiency syndrome anc, antenatal care art, antiretroviral treatment elisa, enzyme-linked immunosorbent assay fda, united states food and drug administration ghtf, global harmonization task force hct, hiv counselling and testing hiv, human immunodeficiency virus hivst, hiv self-testing hts, hiv testing services ivds, in vitro diagnostic (medical devices) m&e, monitoring and evaluation ndoh, national department of health pep, post-exposure prophylaxis pmtct, prevention of mother-to-child transmission qa, quality assurance qc, quality control rdt, rapid diagnostic test sahpra, south african health products regulatory authority sanac, south african national aids council sti, sexually transmitted infection tb, tuberculosis tpp, target product profile unaids, joint united nations programme on hiv/aids vct, voluntary counselling and testing who, world health organization whopq, who prequalification appendix 3 table 1-a3: attendees: hiv self-testing guidance development group meeting, 17 november 2016, johannesburg, south africa. abstract introduction background changing guidelines a mathematical model causes a stir treatment as prevention observational data strategic timing of antiretroviral treatment (start) discussion conclusion acknowledgements references about the author(s) nathan geffen department of computer science and centre for social science research, university of cape town, south africa marcus o. low spotlight magazine, cape town, south africa citation geffen n, low mo. when to start antiretroviral treatment? a history and analysis of a scientific controversy. s afr j hiv med. 2017;18(1), a734. https://doi.org/10.4102/sajhivmed.v18i1.734 original research when to start antiretroviral treatment? a history and analysis of a scientific controversy nathan geffen, marcus o. low received: 28 jan. 2017; accepted: 18 aug. 2017; published: 05 dec. 2017 copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: since 1987 hiv scientists and activists have debated the optimal point to start antiretroviral treatment. positions have varied between treating people with hiv as soon as they are diagnosed, based on biological, modelling and observational evidence, versus delaying treatment until points in disease progression at which clinical trial evidence has shown unequivocally that treatment is beneficial. objectives: examining the conduct and resolution of this debate may provide insight into how science works in practice. it also documents an important part of the history of the hiv epidemic. method: we describe clinical trials, observational studies, models and various documents that have advanced the debate from 1987 to 2015. results and conclusion: evidence accumulated over the past decade, especially from randomised controlled clinical trials, has shown that immediate treatment both reduces the mortality and the risk of hiv transmission; it benefits both public health and the individual patient. by mid-2015, the debate was resolved in favour of immediate treatment. introduction since the publication of the first antiretroviral trial in 1987, scientists and patient advocates have debated the optimal time for people with hiv to start antiretroviral treatment. guidelines, both national and international, have changed back and forth on this question, reflecting changes in expert opinion and new scientific developments. we describe the when-to-start debate and its resolution in mid-2015. this debate exemplifies the problem of deciding policy when the evidence is still being collected, or how ‘technological decision making’ is done when there is ‘scientific uncertainty’.1 while much has been written about the debate over the cause of aids, a consequence mainly of former south african president thabo mbeki’s views, little has been written on the when-to-start debate. yet, there is more to be learnt about how science works from the when-to-start debate. this is because it was genuinely hard to determine public health policy from the limited evidence. by contrast, the science that hiv is the cause of aids was clear, and that debate was fuelled not by legitimate scientific disagreements, but by politics and ideology. the question of when-to-start treatment was contested not only between scientists, but also between aids activists. participants with reasonable claims to expertise who for the most part were familiar with the same scientific literature reached opposing conclusions on what treatment guidelines should recommend. the participants in the debate differed in their assessments of the value of observational versus clinical trial data. they also differed on whether the public health benefits of reducing hiv transmission by treating people earlier outweighed the unknown harms to individual patients because of side effects of drugs, difficulties with adherence to lifelong medication and the development of drug resistance. and they differed on how much value to assign mathematical models and observational data. the stakes were high: the contestants understood that settling the question of when-to-start treatment might have considerable effects on life expectancy and the incidence of hiv. if we think about the when-to-start debate as a court case, then the main exhibits were a mathematical model by granich et al.2 which showed that a policy of universal testing followed by immediate treatment of people with hiv would lead to the eradication of the disease; a clinical trial that showed that people with hiv on antiretroviral treatment are unlikely to transmit the virus3; several observational studies, with inconsistent results, which compared what happened to patients who started treatment at different stages of hiv infection; and a massive multinational clinical trial called strategic timing of antiretroviral treatment (start).4 besides these exhibits, there were many others that either supported or contested some of the main ones. the publication of results of the start trial in august 2015, a year-and-a-half ahead of schedule, effectively resolved the question of when-to-start treatment, generating broad scientific consensus on the question. but it did not and could not resolve differences in values and methodologies of the debate’s participants. these differing values and methodologies in the approach to resolving medical science questions will continue, perhaps indefinitely, to be the subject of sociological and philosophical enquiry. background the results of the first randomised controlled antiretroviral clinical trial, bw002, were published in 1987.5 for 24 weeks, people with aids received azidothymidine (now better known as azt or zidovudine) or placebo. of the 145 participants who received azt, one died, compared to 19 out of 137 who received placebo. despite this promising result, the trial was too short to show that monotherapy soon results in drug resistance followed by most patients developing aids illnesses again. new combination treatments were needed to reduce the risk of resistance. new antiretrovirals went to trial and were approved by the united states food and drug administration (fda) through the 1990s: didanosine (1991), zalcitabine (1992), stavudine (1994) and lamivudine (1995). it was, however, the development of protease inhibitors and non-nucleoside reverse transcriptase inhibitors – such as saquinavir (1995), ritonavir (1996), indinavir (1996) and nevirapine (1996) – which changed the nature of hiv treatment.6 arts and hazuda6 write, ‘the advent of combination therapy, also known as haart, for the treatment of hiv-1 infection was seminal in reducing the morbidity and mortality associated with hiv-1 infection and aids’. people with hiv on combination therapy, typically three antiretrovirals taken daily for life, who adhere to their regimen have a very small risk of resistance. the virus can remain suppressed indefinitely restoring near-normal life expectancy.7 today there are about 25 individual antiretroviral drugs spread over six different classes (i.e. differing modes of action) approved by the fda.8 but it was only in the second half of 2015, 28 years after the completion of the first randomised controlled antiretroviral trial that the answer to the when-to-start question was settled. changing guidelines the two main criteria in treatment guidelines for determining when to start treatment have been symptoms of aids and cd4 t-lymphocyte count. the ‘to and fro’ of treatment guideline changes has previously been described.9 when azt was approved in 1987, the us department for health and human services (dhhs) set the cd4 threshold at 500 cells/µl. in april 2001, it was reduced to 350, and then to 200 in 2003. in 2007, it was raised to 350, and then 500 in 2009. in 2013, cd4 count was removed as a criterion for determining when-to-start treatment. in 2003, the world health organization (who) guidelines – produced for resource-limited settings – set the cd4 threshold at 200 cells/µl. this increased to 350 in 2010 and then 500 in 2013, with a recommendation that some groups of patients start irrespective of cd4 count. changes over time in the cd4 initiation threshold can be found in the south african department of health’s, british hiv association’s and european aids clinical society’s guidelines. and often, they were not in sync with each other. for example, in 2012, these differed from the dhhs guidelines by retaining the 350 threshold. south africa’s guidelines have changed from 200 cells/µl to 350 to 500, followed by treatment irrespective of cd4 count. one of the reasons why many scientists, clinicians and activists in the late 1990s and the early 2000s were reluctant to endorse early treatment for people was the surprising results of the concorde trial.10 symptom-free people with hiv were enrolled in the trial from 1988 to 1991. follow-up of the patients continued until they died or end of 1992, whichever came first. when the trial began, azt was the only antiretroviral available. participants were randomly assigned either to receive azt immediately or to defer treatment until they developed aids symptoms or had persistently low cd4 counts. the trial was blinded: the deferred group received placebo, but upon developing signs of aids, participants were unblinded and offered azt if they were on placebo. there was no statistical difference in the primary outcome between the two arms: on the immediate arm, 176 of 877 people died or progressed to aids versus 171 of the 872 on the deferred arm. by starting treatment before they were ill, the immediate arm participants found no more benefit from azt than those who deferred, and they were more likely to have become resistant to the drug so that by the time they did become ill, it was no longer beneficial. that it was disadvantageous to start early was confirmed by a long-term follow-up of the trial participants who showed statistically significant worse survival in the immediate arm. but even then matters were not straightforward, because by pooling the results of a similar trial that was conducted at about the same time as concorde, there was no significant difference between the deferred and immediate strategies.11 even though these discouraging results were based on monotherapy, and the drug resistance this approach caused, concorde was a warning about jumping to the conclusion that early combination treatment would be beneficial. with the growing success of combination therapy, ho published an article in the new england journal of medicine (nejm) in 1995 provocatively titled ‘time to hit hiv, early and hard’. he wrote that recent scientific findings and therapeutic development favoured an ‘aggressive interventional strategy early in the course of hiv-1 infection’.12 but the scientific findings ho referred to were based on improved understanding of the pathogenesis of the disease. for some, this was unconvincing because it was not based on clinical data and did not consider drug side effects and long-term adherence challenges. in an article published in the lancet entitled ‘hit hiv-1 hard, but only when necessary’ by harrington and carpenter,13 the authors argued for caution and a cd4 threshold of 350 cells/µl. they stated that: [n]o available regimen can eradicate hiv-1; all currently effective regimens may cause undesirable, sometimes life-threatening, toxic effects; and, unless regimens are strictly adhered to, multidrug resistance can develop, limiting future treatment options. through the 2000s, as various randomised controlled clinical trials were conducted, the when-to-start debate became increasingly nuanced. a trial showed that treating infants upon diagnosis reduced mortality by 76% and hiv progression by 75%.14 two trials in adults showed that a threshold of 350 cells/µl resulted in better outcomes than 250 or 200.15,16 but the question of whether to treat adults irrespective of cd4 cell count, or to wait until it declined to some optimal value remained unanswered, at least in clinical trials. a mathematical model causes a stir studies of antenatal transmission of hiv as well as observational data showing that sexual transmission was more likely if the infected partner’s viral load was higher suggested that antiretroviral treatment could be used to reduce new infections.17 based on these findings, granich et al.2 published results of two mathematical models. they found that if a policy of universal testing coupled with the offer of immediate treatment to people who were found to be hiv-positive was introduced in south africa, incidence and mortality because of the disease could be reduced to ‘less than one case per 1000 people per year by 2016, or within 10 years of full implementation of the strategy’. they wrote that the prevalence of hiv could be ‘less than 1% within 50 years’. the authors included leading who researchers, including kevin de cock, the director of its hiv department. its publication, while not responsible for starting the discussion on whether the cd4 count initiation criterion should be dispensed with and a policy of universal testing and immediate treatment should be pursued, certainly escalated the intensity of the debate. at the time of writing the article has been cited over 1600 times according to google scholar. this is extraordinarily high for mathematical models, the details of which most scientists, activists and policymakers are unlikely to understand, even though these were relatively simple models, which was part of their appeal. the article’s findings were first presented ahead of world aids day in 2008, and the response to it was divided. email correspondence at the time by leaders of the treatment action campaign (tac), the leading aids activist organisation in south africa, conveyed both the excitement and scepticism the article generated. the organisation’s leader, zackie achmat wrote, ‘this is going to overwhelm us with calls. [our policy department] will draft a statement. the heavens are opening up’ (achmat z, personal communication, n.d.). another leader of the organisation, mark heywood, wrote: i heard kevin de cock present this paper in geneva … i have serious concerns about it, as does peter piot and most at unaids! it has the potential to create a great deal of confusion, so our statement will have to be very careful. you should also be aware that in meetings to justify the paper de cock is also claiming it has the support of activists… (heywood m, personal communication, n.d.). heywood was a co-signatory on a statement by a group of ‘independent experts advising unaids on hiv and human rights’ published on world aids day 2008. while welcoming ‘a model that proposes the attainment of universal access to hiv treatment and hiv testing’, that ‘confirms the critical link between hiv prevention and hiv treatment’, the authors wrote the study did not ‘really address’ the problems of stigma and discrimination which could be exacerbated by potentially coercive approaches. they wrote: to be both effective and just, programmes to scale-up hiv testing and treatment must be based on evidence and must protect the human rights of both the non-infected and the infected. they cautioned about ‘the application of theoretical models to fictitious populations’.18 the publication of the granich et al. article was accompanied by letters from accomplished researchers in various fields of hiv who criticised various aspects of the model: the ‘hypothesis that suppressive antiretroviral therapy can reduce hiv transmission within a sexual relationship is plausible, but unproven’, wrote cohen et al.,19 scientists who within a few years would indeed prove the protective effect of treatment within a sexual relationship. they underestimated infectiousness in early infection and overestimated the number of partners south africans report having, wrote harvard demographers.20 harold jaffe, who was at the forefront of the discovery of the aids epidemic, and his colleagues pointed out that the risks and benefits of treating people with a cd4 count above 350 cells/µl were unknown. they wrote, ‘trials of therapy for patients with higher counts are yet to begin. within the field of communicable diseases, we are aware of little precedent for the approach of “treating for the common good”.’21 ethiopian public health officials described the difficulties of implementing mass testing in a resource-limited setting.22 more complex models were developed in the aftermath of the granich et al. article, though none achieved as much public discussion. twelve models, including one of the granich et al. ones, were described in an article by eaton et al.23 the model results were compared under a set of similar assumptions about how universal testing and treatment would be carried out versus if the south african treatment guideline criteria at the time (with a cd4 initiation threshold of 350 cells/µl) were used. the authors concluded that although the models evaluating the impact of treatment ‘vary substantially in structure, complexity, and parameter choices’, all suggested that treatment at ‘high levels of access and with high adherence’ would reduce new infections. although there ‘was broad agreement regarding the short-term epidemiologic impact of ambitious treatment scale-up’, the models varied on their ‘longer term projections’ and ‘in the efficiency with which treatment can reduce new infections’. one of the most sophisticated set of models aimed at determining the effect of universal testing and treatment on the epidemic was published by hontelez et al.24 explaining the motivation for their study, they wrote: there are as many different conclusions as there are models that investigated the issue. as models are profoundly different in many aspects – structure, parameterization, and assumptions about the intervention – it is difficult to determine which factors are responsible for the differences in the model predictions. (p. 2) the period since the publication of the granich et al. model had also produced new evidence that the authors relied upon. the authors developed nine structurally different models of increasing complexity, starting with one that resembled that of granich et al. in contrast to the set of relatively simple differential equations that characterised the granich et al. model, their most complicated models simulated people (usually referred to as agents in simulation literature) with complex algorithms for choosing sexual partners. their results confirmed that ‘universal testing and immediate treatment at 90% coverage’ would eliminate the hiv epidemic in south africa. but they also found that their models, which they claimed were more realistic, ‘show that elimination is likely to occur at a much later point in time than the initial model suggested’. they also found that universal testing and treatment is cost-effective, but less so than calculated by granich et al. most interestingly, they found that ‘the current south african … treatment policy alone could already drive hiv into elimination’.24 however, it is controversial whether adding complexity to models improves them. one of the authors of the granich et al.’s article, brian williams, a leading figure in mathematical modelling of infectious diseases, has written a response questioning their methodology. he writes: hontelez et al. suggest that the current scale-up of art at cd4 cell counts less than 350 [cells/µl] will lead to elimination of hiv in 30 years. i disagree … and believe that their more complex models rely on unwarranted and unsubstantiated assumptions.25 williams’ view was that there was already sufficient evidence to make treatment universally available. he wrote: the challenge now is to mobilize the political will and the financial support to make early treatment available to all that want it in order to save lives, save money and stop aids.25 treatment as prevention observational studies published between 2006 and 2011 showed that people with hiv on antiretroviral treatment were likely less infectious.26,27,28,29 but a clinical trial was needed to remove the possibility of confounding factors and estimate the magnitude of the effect. in july 2011, the results of the hptn 052 study were presented to a standing ovation at the meeting of the international aids society in rome. a month later the results were published. in this multinational randomised controlled trial of 1700 sero-discordant couples, the partner with hiv was randomly assigned to receive treatment immediately or to delay until 250 cells/µl. this partner also had to have a cd4 count between 350 cells/µl and 550 cells/µl at enrolment, which took place between 2007 and 2010. using genetic analysis, the authors found that in the immediate group, there was only one transmission to the hiv-negative partner. in the deferred group, there were 27 such transmissions, meaning that the transmission rate in the immediate group was 96% lower.3 to date, this remains the most beneficial hiv sexual transmission prevention effect found in any randomised controlled clinical trial. the study also found that there were clinical benefits for patients who started earlier, but as the initiation threshold was 250 cells/µl, a point already known to be lower than optimal (although the most convincing clinical trial showing this had not yet completed at the time hptn 052 enrolled), it did not resolve the when-to-start debate, at least not from the perspective of the individual patient. however, it did result in the who publishing guidelines that recommended immediate treatment – for the purpose of prevention – for hiv-positive people with hiv-negative sexual partners.30 the debate on when-to-start swung noticeably towards earlier treatment after the publication of hptn 052. here is some of the discussion that followed. joseph sonnabend, a physician, wrote a blog expressing caution against immediate treatment of anyone who tested positive and had a cd4 count above 350 cells/µl: the recent demonstration that antiretroviral treatment can prevent transmission of hiv among sero-discordant heterosexual couples is great news. however, when the person offered treatment has not yet been shown to personally benefit from it, an ethical issue needs to be addressed.31 in an interview, the study’s principal investigator, myron cohen, stated his support for the earlier treatment recommendations made to the us guidelines following hptn 052. ‘that’s a pretty big change’, he said, ‘and it respects the accrued benefits, which are very, very strong’.32 in a critical response to cohen, aids activist simon collins33 wrote: a radical public health approach to hiv care is presented as self evident, while neglecting to discuss the lack of important data or presence of contradictory evidence. this is a serious omission in an historical context of guideline recommendations that have been wrong on this question more often than they have been right. he further wrote: even with the best intentions, guidelines produced by experts, can be wrong. the limited evidence and lack of randomised data, restricts the ability to know the risks as well as the benefits.33 given the state of uncertainty about the optimal initiation threshold and that many sexually active people would want to start treatment to reduce their infectiousness, collins and geffen wrote: the decision of when to start must be taken by the hiv-positive person in consultation with their health worker based on accurate information. that choice will vary depending on a person’s individual health, their reason to want to treat and the resources of the health-care facility.9 observational data in april 2009, two large studies were published that had a considerable impact on the when-to-start debate. both used observational data to calculate the effect on mortality of different cd4 count initiation thresholds.34,35 kitahata et al.34 studied over 17 000 canadian and us patients. they found a substantial increase in the risk of death for people who deferred treatment below a cd4 count of 500 cells/µl. those who deferred to below 350 cells/µl had the highest risk of death. however, the study used novel methods that introduced bias in favour of earlier treatment. the authors were criticised for this in several subsequent letters to the editor. they responded that even taking these concerns into account, their data still supported earlier treatment. an accompanying editorial pointed out that the strengths of this study: included its relatively large size, the use of advanced statistical methods that attempted to analyze the data in a fashion similar to that of a randomized trial, and the use of survival … as the end point.36 nevertheless: the results of the … study cannot be considered definitive evidence that everyone with hiv should start receiving antiretroviral therapy. this was not a randomized trial, and the patients who chose to begin therapy early might have differed in other important ways from those who chose to defer therapy – ways that improved survival but were not measured.36 the editorial concluded that if five years previously an asymptomatic patient with hiv with a cd4 cell count above 500 cells/µl wished to start treatment, most experienced clinicians ‘could have made an excellent case’ for deferring treatment. today, if a similar patient were eager to start, we should be ready and willing to prescribe therapy – with ongoing careful monitoring of toxic effects that could arise during decades of treatment.36 but the uk funded when-to-start consortium,35 which looked at over 21 000 patient records, had less convincing results with less controversial methods. the authors found that deferring therapy to a cd4 count of 250–350 cells/µl was associated with higher rates of a composite endpoint of aids or death than deferring to 351–450. however, when mortality alone was considered, there was no statistical significance. and at stepwise comparisons of higher cd4 count ranges, they could find no significant difference in the primary outcome. the authors noted, ‘the evolution of guidelines has been compared to the swings of a pendulum’. they motivated for a 350 cells/µl threshold. subsequently, uk and us guidelines diverged, with the latter taking steps in subsequent editions that promoted earlier treatment. jain and deeks37 summarised the situation at the time: although the debate regarding when to start antiretroviral therapy has been present for over two decades, consensus on this question has been hard to achieve. this lack of clarity continues in the current era, with major guidelines recommending very different treatment strategies. all agree, however, that the pendulum has swung back in favor of more aggressive approaches to therapy. the philosophy of delaying potentially toxic medications as long as possible has increasingly shifted toward a philosophy of initiating therapy as soon as possible. this shift was evident when unaids published its 90–90–90 strategy in october 2014.38 the second of the three 90s referred to having 90% of people diagnosed hiv-positive on sustained antiretroviral treatment by 2020 – a target that amounts to an endorsement of test and treat. but this was at odds with the who’s treatment guidelines, which at the time only recommended treatment initiation at cd4 counts of 500 cells/µl or below.39 in his budget vote speech in july 2014, shortly after returning from the 20th international aids conference in melbourne australia, south africa’s minister of health endorsed the 90–90–90 targets and treatment irrespective of cd4 count. while he endorsed test and treat, he only went as far as announcing that the treatment initiation threshold would be raised from 350 cells/µl to 500 cells/µl.40 in response, the tac’s policy director criticised motsoaledi for recommending earlier treatment initiation without consulting activists.41 strategic timing of antiretroviral treatment (start) members of the trial’s community advisory board wrote that the strategic timing of antiretroviral treatment (start) trial: is a study that has been driven by community demand that the optimal clinical initiation threshold for [antiretroviral treatment] be determined by clinical trial evidence rather than expert opinion informed primarily by observational data.42 start was conceived in the mid-2000s to resolve definitively the question when it would be best to start treatment from the perspective of a patient with hiv. the trial was randomised but open-label because a placebo arm would have created insurmountable practical and ethical problems.4 nearly 4700 people enrolled in the trial at 215 sites in 35 countries between april 2009 and december 2013. to participate, patients had to be antiretroviral treatment naive, and have a cd4 cell count greater than 500 cells/µl. participants were randomised either to begin treatment immediately or to wait until their cd4 counts dropped to 350, or treatment was clinically indicated. the primary endpoint was a composite of any serious aidsor non-aids-related event, or death.43 support for the trial was not universal. franco and saag44 wrote that the balance of data strongly supported starting treatment in nearly everyone regardless of cd4 count. they cited the availability of better drugs that were now available, the current understanding of hiv biology and pathogenesis and evidence from observational data. they conceded that a small group of people who ‘have undetectable virus in the absence of antiretroviral therapy’ might be exceptions. but for: everyone else, to wait on randomized clinical trial data could well be doing harm. the time spent waiting is time that the patients cannot get back and the long-term damage associated with waiting could well be irreversible.44 by the time they wrote this, however, start was well underway. contrast this with a view expressed by some of the main researchers involved in the publication of the observational data, after the us guidelines changed. phillips et al.45 wrote ‘we are concerned that some may interpret the new recommendations as implying that the deferral group of this trial [start] is no longer ethical. such an interpretation would endanger the future of the trial in the usa’. after explaining the problems with the observational data, they concluded: we therefore do not believe that there is convincing evidence to conclude that deferral of initiation of art to a cd4 count of 350 causes net harm, particularly in terms of mortality, compared with starting at any higher level. we strongly support continued enrolment into start. large randomised studies represent the only means of eventually obtaining the definitive result we need to properly inform future patient care. the trial was only expected to produce results in late 2016 or early 2017. but in may 2015, the trial’s independent data and safety monitoring board informed the main sponsor that the question had been answered. it recommended that the findings be ‘immediately disseminated’. the primary endpoint occurred in 42 people in the immediate arm versus 96 in the deferred one, meaning the risk of serious illness or death was less than half in the immediate one (though for an hiv cohort, patient outcomes were good in both arms). even at high cd4 counts, treatment reduced the risk of aids illnesses.43 at about the same time as start, a smaller trial (2076 participants) called temprano was run in côte d’ivoire. primarily concerned with the effect of earlier treatment in an area with high tuberculosis, it had a similar primary endpoint to start. its findings, which also showed the benefit of immediate treatment, were made public shortly before start’s were. however, the details of the study were presented at the international aids conference in vancouver on the same day as start’s and both studies were published in the same journal on the same day.46 the last outstanding piece of evidence in the when-to-start controversy had now been answered. discussion there were two main points of contention in the when-to-start debate. first, there was disagreement over what constituted sufficient evidence that early treatment was beneficial. there was an implicit hierarchy of evidence, with biological plausibility and mathematical models constituting the lowest evidence, followed by observational data. for many, this was sufficient to make the case for immediate treatment. but those who considered observational data to be too uncertain and prone to confounding demanded a randomised clinical trial. they were concerned by the additional adherence demanded of patients who started treatment early in their hiv infection, the side effects primarily associated with earlier generations of antiretroviral drugs, the unfortunate experience of concorde and the fluctuations of guideline recommendations in the absence of compelling evidence. there was also concern that the public health concern of the reduced infectiousness of people with hiv was taking precedence over the uncertainty about the benefit of immediate treatment for the health of individuals with hiv. the publication of the start results resolved these points of contention. conclusion there are no accepted criteria for resolving scientific debates with policy repercussions when the evidence is still being gathered. in contrast to the destructive and irrational debate on the cause of aids that took place in south africa in the 2000s, the protagonists on both sides of the when-to-start debate included leading experts in hiv science who could draw on substantial evidence to make their arguments. in the case of aids denialism, one side of the debate shunned the immense body of evidence, preferring conspiracy theories instead, whereas on the question of when-to-start, the science truly was in dispute (see1,47,48,49 for further discussion on this). now that all the data, including the gold standard of medical science – a randomised controlled trial – support immediate treatment, continuing to advocate for delayed treatment on medical grounds would be irrational. acknowledgements thank you to nicoli nattrass and martin weinel for comments. competing interests n.g. is a member of the community advisory board of insight which runs the start trial. both authors have been members of the treatment action campaign which has been involved in the debates described here. authors’ contributions n.g. conceived and drafted the article. both authors reviewed and edited the article. n.g. is the corresponding author. references weinel m. technological decision making under scientific uncertainty [homepage on the internet] [phd thesis]. cardiff: cardiff university; 2010 [cited 2015 nov 10]. available from: http://orca.cf.ac.uk/55502/1/u564796.pdf granich rm, gilks cf, dye c, de cock km, williams bg. universal voluntary hiv 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saag ms. when to start antiretroviral therapy: as soon as possible. bmc med. 2013;11(1):147. https://doi.org/10.1186/1741-7015-11-147 phillips a, costagliola d, sabin c, sterne j. early initiation of treatment for hiv infection. lancet. 2010;375(9715):639. https://doi.org/10.1016/s0140-6736(10)60269-3 the temprano anrs 12136 study group. a trial of early antiretrovirals and isoniazid preventive therapy in africa. n engl j med. 2015;373(9):808–822. https://doi.org/10.1056/nejmoa1507198 geffen n. debunking delusions: the inside story of the treatment action campaign. 1st ed. auckland park, south africa: jacana media; 2010. 256 p. nattrass n. defending the boundaries of science: aids denialism, peer review and the medical hypotheses saga. sociol health illn. 2011;33(4):507–521. https://doi.org/10.1111/j.1467-9566.2010.01312.x nattrass n. the aids conspiracy: science fights back. 1st ed. new york, ny: columbia university press; 2012. 240 p. abstract introduction method results discussion conclusion acknowledgements references about the author(s) hoosain f. paruk department of neurology, nelson r mandela school of medicine, university of kwazulu-natal, south africa ahmed i. bhigjee department of neurology, nelson r mandela school of medicine, university of kwazulu-natal, south africa suzaan marais department of neurology, nelson r mandela school of medicine, university of kwazulu-natal, south africa citation paruk hf, bhigjee ai, marais s. a comparative study of human t-cell lymphotropic virus-associated myelopathy in hiv-positive and hiv-negative patients in kwazulu-natal. s afr j hiv med. 2017;18(1), a746. https://doi.org/10.4102/sajhivmed.v18i1.746 original research a comparative study of human t-cell lymphotropic virus-associated myelopathy in hiv-positive and hiv-negative patients in kwazulu-natal hoosain f. paruk, ahmed i. bhigjee, suzaan marais received: 06 mar. 2017; accepted: 20 july 2017; published: 06 dec. 2017 copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: kwazulu-natal is an endemic area for hiv and human t-cell lymphotropic virus (htlv) infection. the main neurological manifestation of htlv is htlv-associated myelopathy/tropical spastic paraparesis (ham/tsp). the effect of hiv co-infection in patients with ham/tsp is not well documented. aims: to determine the prevalence of hiv seropositivity in patients with ham/tsp and compare the clinical, laboratory and radiological features of patients mono-infected with htlv and those dually infected with htlv and hiv. methods: adult patients referred to the neurology department at inkosi albert luthuli central hospital in kwazulu-natal, south africa, for the period 01 january 2004 to 31 december 2015 with a positive htlv serology were identified from the national health laboratory service database. a retrospective chart review was conducted to identify all patients who had a diagnosis of ham/tsp and to record their hiv status. clinical, laboratory and radiological data were compared for hiv-positive and hiv-negative patients. results: a total of 52 patients with ham/tsp were identified. hiv results were available in 44 patients of whom 23 (52%) patients were hiv co-infected. patients who were hiv-positive had a younger age of presentation compared to hiv-negative patients (median: 31 vs 50 years, p = 0.002). hiv-positive patients had a median duration of symptoms at presentation of 12 months compared to 16 months for hiv-negative patients, but the difference did not reach statistical significance (p = 0.082). the cd4 cell counts of hiv-positive patients were well preserved with a median count of 781 cells/µl. conclusions: hiv co-infection is commonly seen in the setting of ham/tsp in kwazulu-natal. an interaction between the viruses may accelerate the development of ham/tsp, leading to a younger age of presentation. co-infection may have treatment implications because of cd4 counts being preserved in these patients. introduction the human t-cell lymphotropic virus (htlv) is a retrovirus that is structurally similar to human immunodeficiency virus (hiv).1 two htlv types (htlv-1 and htlv-2) were identified to cause disease in humans prior to the identification of hiv. htlv is spread in a manner similar to hiv, vertically and horizontally. the main form of spread of htlv-1 is through sexual transmission and sharing of contaminated needles for htlv-2.2 human t-cell lymphotropic virus-1 is found in endemic clusters in various regions of the world, including kwazulu-natal. a population-based study performed in kwazulu-natal in 1992 on 1018 individuals showed a prevalence rate of 2.6% (95% confidence interval (ci) 1.62–3.58).3 in this study, only one case of htlv-2 was identified. the hiv-positive rate in the same cohort was 3.5% (95% ci 2.4–4.68) and the relative risk of co-infection in the 15–24 year age group was 1.16 (95% ci 1.08–1.24). htlv-1 is associated with the development of neurological disease, the most important of which is htlv-1-associated myelopathy/tropical spastic paraparesis (ham/tsp). hiv leads to neurological complications in more than 40% of infected patients, including vacuolar myelopathy, a condition that clinically resembles ham/tsp.4 the occurrence of co-infection is not unexpected in areas endemic for both viruses and considering their common modes of transmission. one of the earliest reports of retroviral co-infection found that 7% of patients with aids were seropositive for htlv.5 of the 90 patients who were identified with ham/tsp during the initial epidemiological study in kwazulu-natal in 1992, six (6.6%) were co-infected with hiv.3 in a more recent retrospective analysis,6 24% of samples tested positive for htlv. this limpopo analysis included 170 hiv-positive samples collected during 2007 and 2008. the consequences of co-infection on viral replication, pathogenicity and susceptibility to antiretroviral therapy (art) are critical issues, which require investigation. early studies of retroviral co-infection, in particular with htlv-1, performed before the era of art suggested that htlv seropositivity accelerated the progression of hiv to aids.7,8,9,10 the lifetime risk of developing ham/tsp in htlv-1 seropositive individuals is estimated to be around 3% – 5%, but a report of ham/tsp developing in three out of four patients with co-infection in the pre-art era was the first to suggest that myelopathy risk is increased with co-infection.11,12 ascertaining the cause of myelopathy in such patients can be challenging because of the similarities in clinical presentation. whilst the cd4 cell count is used as a marker for immunosuppression in hiv infection, htlv has been shown to have lymphoproliferative effects.13 this complicated management in resource-constrained settings when the decision to commence art in hiv-positive patients was based on the peripheral blood cd4 count. a direct comparison of ham/tsp in hiv-positive and negative patients has only been reported in one retrospective study that examined the records of nine dually infected patients and 11 htlv mono-infected patients with ham/tsp.14 the study suggested that patients with ham/tsp present earlier in dually infected patients. art has not been shown to be effective in the treatment of ham/tsp; also the response of the hiv viral load in the setting of dually infected patients is not well documented.15 thus, despite the potential clinical significance, the possibility of co-infection is often overlooked by clinicians as htlv is not routinely tested in hiv outpatient settings. the aim of this hospital-based study was to determine the prevalence of hiv seropositivity in patients with ham/tsp and compare the clinical, laboratory and radiological features of patients mono-infected with htlv and those dually infected with htlv and hiv. method patients the inkosi albert luthuli central hospital (ialch) is one of the two neurology referral centres in the province of kwazulu-natal which has an adult population of 7.5 million individuals over the age of 15 years. this hospital is the referral centre for the northern and southern parts of kwazulu-natal, an area that is endemic for htlv infection. a record of all seropositive htlv results for patients referred to the neurology department at ialch for the period 01 january 2004 to 31 december 2015 was obtained from the national health laboratory services (nhls) electronic database. the nhls uses an architect rhtlv-i/ii elisa test to detect htlv seropositivity. this method has a sensitivity of 100% (95% ci 99.10–100) and specificity >99.95% (95% ci 99.84–99.99). it does not distinguish between htlv-1 and htlv-2. it is assumed that most, if not all, of the cases represent htlv-1 infection considering that htlv-2 is an infrequent cause of myelopathy and that only one case of htlv-2 was detected in a previous epidemiological study in kwazulu-natal.3 a chart review was performed on all patients with a positive htlv serology result to identify patients who had a diagnosis of ham/tsp. the diagnosis was based on a combination of clinical, radiological and laboratory findings. investigations to exclude an alternative cause for myelopathy that were performed included the following: (1) blood tests including vitamin b12 levels and syphilis serology, (2) cerebrospinal fluid (csf) analysis, including biochemistry, cytology, microbiology (including microscopy and culture for fungi, pyogenic bacteria and mycobacterium tuberculosis), syphilis serology and cryptococcus latex agglutination titre and (3) magnetic resonance imaging (mri) of the spine. patients without myelopathy or with myelopathy because of other causes were excluded. hiv status of the patients was also ascertained where available. the clinical, laboratory and radiological features of these patients were extracted from the patient records using a structured data sheet. mri spine was reported by radiologists and subsequently reviewed by the study team (all qualified neurologists). data analysis the data collected were analysed using prism version 6. descriptive statistics such as frequencies, percentages, medians and interquartile ranges were used to summarise results. continuous and categorical variables were analysed using mann–whitney u test and fischer’s exact test, respectively. a p-value of <0.05 was considered statistically significant. results a total of 121 patients had a positive htlv serology result during the study period; 52 patients had a diagnosis of ham/tsp and were included in the study. hiv results were available for 44 of these patients. twenty-three (52%) patients were hiv-positive and the rest were hiv-negative. demographic characteristics demographic and clinical features are summarised in table 1. patients who were hiv-positive had younger age of presentation compared to hiv-negative patients (median age: 31 vs. 50, p = 0.002). there were proportionately more females in both groups, with 17 (67%) and 14 (67%) in the hiv-positive and hiv-negative groups, respectively. table 1: demographic and clinical features of human t-cell lymphotropic virus-associated myelopathy/tropical spastic paraparesis patients. clinical features there was a trend for the duration of symptoms prior to diagnosis to be shorter in hiv-positive patients compared to hiv-negative patients, but this did not reach statistical significance (p = 0.082). there was no significant difference in the power grading or proportion of patients who remained ambulant in the two groups. however, there was a significantly increased frequency of sensory and sphincter disturbance in hiv-negative patients compared to hiv-positive patients (p = 0.037, p = 0.04). four patients were receiving art. investigations the csf parameters are summarised in table 2. there was a trend for hiv-positive patients to have higher protein and lower glucose values than the hiv-negative patients. in addition, polymorphonuclear cells were only detected in patients who were hiv-positive. cd4 cell counts were available in 16 of the hiv-positive patients (median: 781 cells/µl, range: 47 – 1993). table 2: cerebrospinal fluid findings of human t-cell lymphotropic virus-associated myelopathy/tropical spastic paraparesis patients. thoracic spinal cord atrophy, which was determined subjectively, was noted on mri in eight out of 23 hiv-positive patients and seven (33.3%) out of the 19 hiv-negative patients who had imaging available. a hyperintense intramedullary signal was noted in six (25%) patients who were hiv-positive and none of those who were hiv-negative. discussion the occurrence of ham/tsp in the setting of patients co-infected with htlv and hiv was first described by berger et al.12 four of 241 hiv-positive patients were confirmed to be seropositive for htlv during the course of a longitudinal survey of neurological complications of hiv. three of the four patients, two htlv-1 and one htlv-2, had a progressive myelopathy that clinically resembled ham/tsp.16 subsequently, other studies have also showed increased rates of ham/tsp in co-infected patients. a study in the pre-art era by harrison et al. did not diagnose ham/tsp but described clinical evidence of myelopathy in 11 of 15 (73%) patients with hiv/htlv-1 co-infection as compared to 10 of 62 (16%) patients with hiv mono-infection.17 beille et al. screened 3600 hiv-positive patients at an outpatient clinic in the united states between 1993 and 2002 and confirmed 62 and 141 hiv/htlv-1 and hiv/htlv-2 co-infections, respectively. four of the 62 (9.7%) hiv/htlv-1-infected patients were diagnosed with ham/tsp; two of the patients were receiving zidovudine monotherapy.18 art does not appear to decrease the risk of ham/tsp, as a study by silva et al. reported myelopathy in 12 of 47 (25.5%) co-infected patients on art.19 casseb et al. diagnosed ham/tsp in six out of 38 (18%) dually infected patients and found that htlv-1 proviral loads were significantly higher in patients with ham/tsp compared to asymptomatic co-infected patients (p = 0.012).20 our study confirms a high frequency of hiv co-infection in patients with ham/tsp in kwazulu-natal. dual infection is associated with a younger age of clinical presentation and shorter duration of symptoms prior to presentation. we postulate that the presence of hiv infection in htlv-infected individuals predisposes them to developing ham/tsp and that the disease course is of a more accelerated nature. the possibility of a more aggressive disease would also explain our finding of spinal cord hyperintensity which was only observed in patients who were also hiv-infected. atypical mri findings such as hyperintensity and contrast enhancement have been associated with more acute progression in ham/tsp.21 however, there was no significant difference in the power grading or proportion of patients who remained ambulant between the two groups, and the increased frequency of sensory and sphincter impairment in the htlv mono-infected group is unexplained. the differences in the csf findings of higher protein, lower glucose and increased white cells in hiv-positive patients are potentially a reflection of the chronicity of hiv infection and do not necessarily imply more aggressive disease. the proportion of ham/tsp patients found to be hiv-positive in this study is much higher than what was initially observed in kwazulu-natal province (52% vs. 6.6%). this is not unexpected given that the previous survey of ham/tsp patients in the region was conducted in the early 1990s, a period which signalled the beginning of the hiv epidemic in south africa. the finding is similar to that of a more recent south african study that investigated hiv co-infection in ham/tsp patients in which nine of 21 (42.8%) patients with ham/tsp were found to have concurrent hiv infection.14 schutte et al. reported similar findings to ours with respect to age at presentation and duration of symptoms. however, a statistically significant difference was not demonstrated with regard to age at presentation, which might have been related to small sample size. cd4 counts in our cohort tended to be relatively preserved with the median count being 781 cells/µl, which differs from the study of schutte et al. in which 56% of patients had counts less than 350 cells/µl. it should be noted that although preserved, these cd4 cells are functionally impaired and art should be considered regardless of the cd4 counts in these patients.22,23 hiv leads to increased htlv protein expression.24,25 these effects may be a possible explanation as to how htlv is more readily able to overcome the immune response. both hiv and htlv infect endothelial cells and astrocytes, resulting in blood-brain barrier damage.26 the proportional contribution of each of the viruses to the development of myelopathy has been debated; however, an early pathological study of two patients with co-infection suggested that the myelopathy was because of htlv as no evidence of hiv-associated vacuolar myelopathy was found.27 in a further post-mortem examination of a dually infected patient with hiv dementia and ham/tsp, co-infection of a single-cell phenotype could not be demonstrated.28 hiv was found in macrophages or microglia, whilst htlv was found in astrocytes, suggesting that mechanisms other than co-infection of the same cell play a role in the development of neurological disease in co-infected patients. whilst hiv-associated neurocognitive disorder (hand) has been well characterised, there is much less information regarding the effects of htlv or retroviral co-infection on the brain and cognition. limitations of this study include the retrospective design, the inability to ascertain the sequence of viral infection and the unavailability of longitudinal data. we could not ascertain if art offers any protection, nor could we determine whether art alters the progression of disease. we also did not have any data regarding hiv and htlv viral and proviral loads, respectively. conclusion to date this study is the largest that directly compares ham/tsp in hiv-positive and hiv-negative patients and suggests that htlv-1 and hiv have a synergistic effect with regard to the development of neurological complications. cd4 cell counts tend to be relatively well preserved in co-infected patients. further longitudinal studies of mono-infected and dually infected patients with monitoring of viral loads and clinical outcomes are required to enhance the understanding and impact of hiv/htlv co-infection. areas known to be endemic for both viruses provide a unique and ideal opportunity to perform community-based screening of asymptomatic patients. ascertaining the sequence of infection, clinical 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mondal d, eloby-childress s, winsor el, beilke ma. upregulation of htlv-1 and htlv-2 expression by hiv-1 in vitro. j med virol. 2008;80(3):494–500. https://doi.org/10.1002/jmv.21089 beilke ma, japa s, vinson dg. htlv-i and htlv-ii virus expression increase with hiv-1 coinfection. j acquir immune defic syndr hum retrovirol. 1998;17(5):391–397. https://doi.org/10.1097/00042560-199804150-00002 afonso pv, ozden s, cumont mc, et al. alteration of blood-brain barrier integrity by retroviral infection. plos pathog. 2008;4(11):e1000205. https://doi.org/10.1371/journal.ppat.1000205 rosenblum mk, brew bj, hahn b, et al. human t-lymphotropic virus type i-associated myelopathy in patients with the acquired immunodeficiency syndrome. hum pathol. 1992;23(5):513–519. https://doi.org/10.1016/0046-8177(92)90128-p levin mc, rosenblum mk, fox ch, jacobson s. localization of retrovirus in the central nervous system of a patient co-infected with htlv-1 and hiv with ham/tsp and hiv-associated dementia. j neurovirol. 2001;7(1):61–65. https://doi.org/10.1080/135502801300069719 article information authors: lynne wilkinson1 helene duvivier2 gabriela patten1 suhair solomon1 leticia mdani1 shariefa patel3 virginia de azevedo3 saar baert4 affiliations: 1médecins sans frontières, khayelitsha project, south africa 2médecins sans frontières, south african mission, south africa 3city of cape town health department, khayelitsha, south africa 4médecins sans frontières, south african medical unit, belgium correspondence to: lynne wilkinson email: lynneswilkinson@yahoo.com postal address: unit 23b, no. 14 waverly business park, wyecroft road, mowbray 7700, western cape province, south africa dates: received: 01 mar. 2015 accepted: 13 may 2015 published: 02 july 2015 how to cite this article: wilkinson l, duvivier h, patten g, et al. outcomes from the implementation of a counselling model supporting rapid antiretroviral treatment initiation in a primary healthcare clinic in khayelitsha, south africa. s afr j hiv med. 2015;16(1), art. #367, 7 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.367 copyright notice: © 2015. the authors. licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. outcomes from the implementation of a counselling model supporting rapid antiretroviral treatment initiation in a primary healthcare clinic in khayelitsha, south africa in this original research... open access • abstract • introduction • methods    • study design    • study setting    • antiretroviral treatment management    • antiretroviral treatment preparation education and counselling    • study participants    • data collection and analysis    • ethics approval • results • discussion • conclusion • acknowledgements    • competing interests    • authors’ contributions • references abstract top ↑ background: lengthy antiretroviral treatment (art) preparation contributes to high losses to care between communicating art eligibility and initiating art. to address this shortfall, médecins sans frontières implemented a revised approach to art initiation counselling preparation (integrated for tb co-infected patients), shifting the emphasis from pre-initiation sessions to addressing common barriers to adherence and strengthening post-initiation support in a primary healthcare facility in khayelitsha, south africa. methods: an observational cohort study was conducted using routinely collected data for all art-eligible patients attending their first counselling session between 23 july 2012 and 30 april 2013 to assess losses to care prior to and post art initiation. viral load completion and suppression rates of those retained on art were also calculated. results: overall, 449 patients enrolled in the study, of whom 3.6% did not return to the facility to initiate art. of those who were initiated, 96.7% were retained at their first art refill visit and 85.9% were retained 6 months post art initiation. of those retained, 80.2% had a viral load taken within 6 months of initiating art, with 95.4% achieving viral load suppression. conclusions: adapting counselling to enable rapid art initiation is feasible and has the potential to reduce losses to care prior to art initiation without increasing short-term losses thereafter or compromising patient adherence. introduction top ↑ one-third of antiretroviral treatment (art)-eligible patients are estimated to be lost to care between communicating art eligibility and initiating art1 – the so-called ‘third stage’ of pre-art care2 – increasing the risk of morbidity and mortality.3 whilst patient education and adherence counselling are recommended to improve long-term adherence,4,5 lengthy preparation processes before starting art cause delays during this pre-art stage, contributing to high losses to care.6,7 in practice, there are wide-ranging approaches to patient art preparation within the south african public sector.6 in 2012, the south african national department of health released a circular that recommended fast-tracking patients onto art without unnecessary delay. it further recommended that patients with cd4 counts < 200 cells/mm3 and pregnant women be started on the same day that art eligibility is ascertained. some facilities now provide minimal art preparation owing to prioritising fast-tracking, whilst others continue to require prior attendance of 3 (and sometimes more when co-infected with tb) education and adherence counselling sessions. médecins sans frontières (msf), along with its partners (see acknowledgements), developed a revised approach to art initiation counselling which supports rapid initiation without failing to adequately prepare a patient for lifelong adherence to treatment, including those who are co-infected with tb or pregnant. the overall aim of the revised approach is to reduce the loss of patients prior to art initiation without increasing losses post art initiation or reducing adherence amongst such patients. the aim of the present study is to describe the intervention and determine the retention outcomes during the third stage of pre-art care and post art initiation of patients who underwent this model of counselling. secondary outcomes include viral load completion and suppression rates of those retained on art. methods top ↑ study design this was an observational cohort study using routinely collected data. study setting khayelitsha is a peri-urban township on the outskirts of cape town, south africa. it has a population of approximately 500 000 with high burdens of both hiv and tb. in 2011, the antenatal hiv prevalence was 34.3%8 and the tb case notification rate at least 1500 per 100 000 population per year.9 the study site (kuyasa clinic) is a general primary healthcare facility run by the city of cape town's health department. hiv and tb related services include: hiv counselling and testing (hct), pre-art, art initiation, art management, art adherence clubs10 and both drug-susceptible and drug resistant tb services. according to 2013/2014 records, the clinic tests each month approximately 466 patients for hiv (2014), initiates approximately 50 patients on art (2014), starts tb treatment for approximately 37 patients (2013) and had 2766 art patients retained in care at the end of june 2014, with 772 (28%) receiving their treatment and care through art adherence clubs. antiretroviral treatment management in south africa, art eligibility is determined by world health organization clinical staging combined with cd4 cell count. western cape hiv clinical guidelines provided that, from august 2011, patients with who stage 4 disease or those with a cd4 count < 350 cells/mm3 were eligible to start art. patients are due for their first and second viral loads at 4 and 12 months on art respectively. antiretroviral treatment preparation education and counselling prior to july 2012, the art initiation counselling model in place at kuyasa clinic consisted of three counselling sessions, scheduled at weekly intervals after communication of art eligibility, followed by art initiation. co-infected tb/hiv patients were also required to undergo 3 tb counselling sessions, which at the time were not integrated within the art preparation counselling process. where a clinician indicated a need to rapidly initiate hiv or tb treatment for clinical reasons, counselling was condensed into fewer sessions. counsellors were not trained on how to appropriately condense sessions – specifically on what information remained pertinent and necessary. counselling was provided by lay counsellors, employed by a nongovernmental organization (ngo) funded by the western cape's department of health (wcdoh). the counsellors were trained by the wcdoh's aids training, information and counselling centre (aticc) according to egan's ‘skilled helper’ model of counselling.11 from july 2012, msf supported the implementation of a revised art initiation counselling model at kuyasa clinic. in summary, the lay counsellor provides a total of four counselling sessions: 1 session prior to art initiation (‘session 1’) on the date when art eligibility is communicated to the patient, 1 session on the day of art initiation (‘session 2’), and two sessions post art initiation ('sessions 3 and 4’) on subsequent clinic appointment/art refill dates. where the patient indicates at the end of session 1 that he/she is not ready to start, a further ‘not ready to start’ session is scheduled ('session 1c’) that specifically aims to work through patient-identified barriers to initiating art. where it is appropriate for clinical reasons to initiate art on the day that art eligibility is assessed, it is possible to carry out the first two sessions on the same day. where a patient is diagnosed with tb and hiv, one additional counselling session is added prior to session 1 to prepare the patient for starting and adhering to tb treatment. each counselling session is designed to take 12 min – 18 min. figure 1 outlines session timing. where a patient is not able to return to the clinic 2 weeks after art initiation, sessions 3 and 4 are combined and provided at the first art refill date, which is 28 days after art initiation. figure 1: timing of counselling sessions. the counselling approach is based on the life steps intervention to hiv medication adherence12,13 in which cognitive behavioural, problem solving, and motivational interviewing techniques are used to enhance motivation and assist hiv-positive patients to develop better skills for adhering to hiv treatment. this model has shown favourable results in different settings.14 the life steps model was simplified and adapted to barriers and adherence planning requirements identified by msf through its work with patients attending a second-line failure clinic in khayelitsha.15,16 patient education is limited to essential information to initiate art and tb treatment, supported through the use of a visual aid and a take-home leaflet. the 14 most common barriers to start art and adherence (box 1) are addressed with all patients and are documented in each patient's adherence plan. the approach focuses on creating a patient-oriented motivation for commitment to lifelong treatment. box 1: adherence steps addressed in antiretroviral treatment initiation counselling model. session guides were developed, defining the content to address per session, and served as a working tool for both counsellor and counsellor supervisor. both counsellors were trained, and fidelity to the intervention was assured through regular supervision by observation of sessions using a standardised observation checklist, and review of patients’ adherence plans and counsellors’ paper registers recording patients enrolled and counselling sessions provided. this supervision was performed by an ngo counsellor supervisor who covered a number of clinics and msf staff. for further details on the model, including session plans and tools, see art/tb/pmtct initiation counselling model report and toolkit at http://bit.ly/197vdfb. study participants from 23 july 2012 to 30 april 2013, all hiv-positive patients found to be eligible for art initiation who attended session 1were enrolled in the study. data collection and analysis all data were collected (other than viral load results) at the end of january 2014, providing a minimum of 9 months of follow-up. viral load data were collected on 30 september 2014. variables collected included age, sex, cd4 count, tb at art start, tb treatment start date, attendance of counselling sessions, art initiation date, last visit date to the clinic for art refill, reported transfers and deaths, and dates of first viral load and first viral load outcome. study outcomes were time taken and retention from session 1 to art initiation, short-term retention on art at 28 days (first art refill) and 6 months (183 days) post art initiation, viral load completion and suppression within 6 months of art initiation, and viral load suppression at first viral load. we defined retention at 1 month and 6 months as those patients whose last visit to the clinic or documented transfer date was more than 28 days and 6 months after the date of art initiation. viral load suppression was defined as < 400 copies/ml. descriptive analyses were done in stata version 13.17 ethics approval ethics approval was obtained from the university of cape town human research ethics committee. permission to do the study was obtained from the city of cape town research committee. results top ↑ a total of 449 patients attended session 1 from 23 july 2012 to 30 april 2013, thereby enrolling in the study, of whom 300 (66.8%) were female and 137 (30.5%) of whom had tb at enrolment. median age was 31 years (interquartile range [iqr] 26–37 years) and median cd4 count 242 cells/mm3 (iqr 147 cells/mm3 – 308 cells/mm3) at enrolment. a further breakdown of age and cd4 count categories is set out in table 1. table 1: demographic and clinical characteristics of patients included in study at enrolment. figure 2 presents a summary of counselling session completion. of those patients who enrolled in the study, 427 (95.1%) completed session 2, of whom two did not proceed to initiate art. session 3 was completed by 392 (92.2%) of those who completed session 2 and initiated art and 329 (86.4%) of those patients who returned to the study site for their 28-day art refill, completed session 4. figure 2: counselling session completion. figure 3 details retention in care from enrolment to 6 months post art initiation. art was initiated by 433 (96.4%) patients. median time to the start of art for all enrolled patients from session 1 was 5 days (iqr 2–14 days). forty-nine (11%) patients started art on the same day as session 1, indicating fast-tracking for clinical reasons including pregnancy, whilst 32 (7%) took more than 28 days to start (see further breakdown of time to art start in table 2 below). patients with a concurrent tb diagnosis took a median of 18 days (iqr 14–29 days) from start of tb treatment to initiate art. after excluding patients with documented transfers to other facilities, 412 (96.7%) and 353 (85.9%) patients were retained respective at 1 and 6 months post art initiation. figure 3: retention and viral load outcomes. table 2: time from enrolment (session 1) to antiretroviral treatment start and first viral load. the median time to first viral load was 4.4 months (134.5 days [iqr 114–174 days]). of those patients retained at the study clinic, 283 (80.2%) had a viral load taken within 6 months of initiating art, with 270 (95.4%) achieving viral load suppression. by 30 september 2014, 342 (96.9%) had their first viral load taken, with a 94.4% suppression rate. see table 2 for a further breakdown of time to first viral load. discussion top ↑ by adapting art initiation education and counselling to expedite the start of treatment, whilst addressing common barriers to patients’ readiness to start art, only 3.6% of patients were lost from care between their first counselling session and art initiation. the proportion of patients initiating art after being informed of their eligibility for treatment is substantially higher than estimates reported previously in south africa and elsewhere in the region.1,18 our findings are comparable to the outcomes of a randomised controlled trial by rosen et al. which reported pre-art losses when rapid (2%) versus standard art initiation (28%) took place.19 reducing losses to care prior to art initiation carries a potential risk of increased losses immediately after art start, if patients are uncomfortable with starting quickly or are insufficiently prepared. our study found limited losses immediately after art start, with 2.6% of those initiated not returning for their 1-month art refill appointment. at 6 months after art initiation, 85.9% of patients were retained, which is comparable to elsewhere in south africa20 and sub-saharan africa.21,22 whilst cohorts that started art prior to 2008 in khayelitsha were reported to have higher 6-month retention outcomes,23 a recent study reporting on msf cohorts has shown higher losses to care in more recently initiated cohorts, with the 2011 cohort retaining 85.5% (95% ci 84.5% – 86.4%) at this time point.22 it is worth noting that it may not be appropriate to compare retention reported in older versus more recently initiated cohorts; this point is due to increasing unaccounted-for self-transfers hidden within the lost to follow-up (ltfu) outcome24 and a bias towards better retention outcomes in older cohorts introduced by longer follow-up times, which allow transient treatment interrupters to return to care.25 it took less than a week for patients to initiate art from starting art preparation counselling. whilst there is extensive evidence on the delay between ascertaining art eligibility (date of cd4 count) and initiating art, with a recent systematic review reporting a range of 22–108 days,18 we could find no routine programme evidence specifically measuring the time from starting art preparation counselling to art initiation. high rates of both viral load completion and suppression were achieved. these were higher than those previously reported for art patients in khayelitsha.23 focusing the art initiation counselling sessions on making practical plans to overcome the most commonly experienced barriers to maintaining good treatment adherence, together with educating and motivating patients towards the goal of achieving an undetectable viral load, might have contributed to these high completion and suppression rates. the use of motivational interviewing has been recommended to ensure behaviour change related to art adherence26 but, in resource-limited settings, major challenges exist to make lay counsellors proficient in using these more complex counselling techniques.27,28 whilst this model was based on principles of motivational interviewing, by engaging with all patients on planning around the same common barriers to adherence, the counselling model did not require lay counsellors to use more complex counselling techniques. barriers to address with patients were predefined, and each adherence barrier was addressed in a standardised way by setting the goal, identifying the possible barriers to reaching that goal, and concluding on a plan per adherence barrier. our experiences with the art initiation counselling model suggest that this may provide a feasible approach to enhancing the counselling skills of lay counsellors, whilst taking their limitations into account. the present study is not comparable with a recently published study in south africa that found no difference in patient adherence or virological suppression outcomes when assessing those who received only didactic education with those who received both didactic education and counselling utilising motivational interviewing skills.29 our study was carried out in an operational setting, provided a maximum of one session prior to the day of art initiation, sessions were considerably shorter in length, and sessions were carried out by existing lay counsellors only, and not nursing staff. our results should be considered in the light of the following strengths and limitations: the principle strength of the study is demonstration of feasibility within an operational setting utilising existing lay counselling staff. there were a number of limitations, the first three relating to the study constraint of limited pre-art routine data. firstly, we were unable to provide a comparison group as a result of poor routine pre-art data collection prior to implementation of the revised art initiation counselling model, including attendance of art counselling preparation sessions. secondly, the date of baseline cd4 counts was not accurately captured, often reflected as the same date as art initiation, limiting our capacity to calculate length of time from eligible cd4 count to art start. thirdly, whilst the intervention was designed for patients to attend session 1 immediately after being informed of their art eligibility, we were unable to verify the date on which such communication took place. further limitations should be noted: during the evaluation period described by the present study, the counselling model had not yet been specifically adapted for pregnant women initiated on art. whilst these women were enrolled in the study and accounted for some of the same-day art initiations with high cd4 counts, we were unable to reliably identify those starting art for pmtct purposes. their inclusion in the study cohort might have increased overall short-term losses to care as reported elsewhere.30,31 lastly, despite basic interventions to ensure fidelity, no specific data were collected to report on fidelity to the piloted model. the present study highlights useful directions for future research. most importantly, further evidence is required to determine the optimal art initiation counselling model that can feasibly be implemented in settings with lay counsellors, who have no formal professional or paraprofessional degree in counselling and high numbers of art patients. these models should ideally also evaluate preand post art retention outcomes. to provide a better understanding of the counselling model, components such as timing, counselling provider, session length, content and measures to ensure fidelity to the intervention should always be described. in addition to counselling model research, more studies are required that report on the extent of delays and losses to care attributable to lengthy art preparation processes prior to art initiation. lastly, whilst there is substantial evidence on optimal timing for starting art after tb treatment initiation from a clinical perspective,32,33 competing risk analysis would benefit from studies reporting on losses to care caused by delaying art initiation for tb co-infected patients. conclusion top ↑ adapting initiation education and counselling to enable the rapid start of art, by addressing common barriers to adherence and strengthening post-initiation support, is feasible. it has the potential to reduce losses to care prior to art initiation without increasing short-term losses thereafter or compromising patient adherence. art programmes should consider adjusting their art initiation counselling to limit delays but ensure that fast-tracking does not result in patients receiving inadequate adherence support with possible negative long-term consequences. acknowledgements top ↑ the structured support sessions adapted a counselling approach known as ‘life steps’, developed by steven safren (massachusetts general hospital, harvard medical school and fenway community health), and michael otto and jonathan worth (massachusetts general hospital and harvard medical school).11 we also acknowledge and thank a working group (lena andersen, karien conradie; pff john joska, jean nashega and ashraf kagee; david pienaar, kevin stoloff, sarah dewing and cathy matthews) who provided input for the design of the model. in addition, we thank our implementation partners in khayelitsha: the city of cape town health department, tb/hiv care and kuyasa clinic staff and patients. competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions l.w. (msf) was involved in intervention design, paper conception, data acquisition, data analysis, interpretation and drafting the paper. h.d. (msf, south african mission) was involved in intervention design, implementation and critical review of the paper. g.p. (msf) did data acquisition and critical review of the paper. s.s. (msf) and l.m. (msf) were involved in intervention implementation and critical review of the paper. s.p. (city of cape town health department khayelitsha) was involved in intervention design, implementation, and critical review of the paper. v.d.a. (city of cape town health department) undertook a critical review of the paper. s.b. 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patient retention? am j epidemiol. 2014;180:1208–1212. http://dx.doi.org/10.1093/aje/kwu295 lundahl b, moleni t, burke bl, et al. motivational interviewing in medical care settings: a systematic review and meta-analysis of randomized controlled trials. patient educ couns. 2013;93:157–168. http://dx.doi.org/10.1016/j.pec.2013.07.012 dewing s, mathews c, schaay n, et al. the feasibility of implementing a sexual risk reduction intervention in routine clinical practice at an arv clinic in cape town: a case study. aids behav. 2011;15:905–910. http://dx.doi.org/10.1007/s10461-010-9718-8 mash r, baldassini g, mkhatshwa h, sayeed i, ndapeua s. reflections on the training of counsellors in motivational interviewing for programmes for the prevention of mother to child transmission of hiv in sub-saharan africa. south african family practice. 2008;50:53–59. http://dx.doi.org/10.1080/20786204.2008.10873697 van loggerenberg f, grant ad, naidoo k, et al. individualised motivational counselling to enhance adherence to antiretroviral therapy is not superior to didactic counselling in south african patients: findings of the caprisa 058 randomised controlled trial. aids behav. 2015;19:145–156. http://dx.doi.org/10.1007/s10461-014-0763-6 tweya h, gugsa s, hosseinipour m, et al. understanding factors, outcomes and reasons for loss to follow-up among women in option b+ pmtct programme in lilongwe, malawi. trop medint health. 2014;19:1360–1366. http://dx.doi.org/10.1111/tmi.12369 clouse k, pettifor a, shearer k, et al. loss to follow-up before and after delivery among women testing hiv positive during pregnancy in johannesburg, south africa. trop med int health. 2013;18:451–460. http://dx.doi.org/10.1111/tmi.12072 mfinanga sg, kirenga bj, chanda dm, et al. early versus delayed initiation of highly active antiretroviral therapy for hiv-positive adults with newly diagnosed pulmonary tuberculosis (tb-haart): a prospective, international, randomised, placebo-controlled trial. lancet infect dis. 2014;14:563–571. http://dx.doi.org/10.1016/s1473-3099(14)70733-9 lawn sd, meintjes g, mcilleron h, harries ad, wood r. management of hiv-associated tuberculosis in resource-limited settings: a state-of-the-art review. bmc med. 2013;11:253. http://dx.doi.org/10.1186/1741-7015-11-253 personality pro file miller's training in pathology stimulated an enduring interest in the pathogenic process and resultant biological and clinical response of the human hosr to disease. it is therefore not surprising that dr miller was one of the first a 2-year stint as a registrar in cardiothoracic surgery in utrech , holland came to an end when, ironically, miller's father became ill with a genetic cardiovascular disorder and he decided to return to south africa to be with his family. the time was not wasted though, as dr miller learnt to speak fluent dutch. to his disappointment registrar posts in cardiothoracic surgery were difficult to obtain at the time but fortunately miller had developed an interest in endocarditis and heart valve infections. a career in clinical microbiology seemed a reasonable option so he joined the south african institute for medical research where he subsequently qualified as a clinical microbiologist it was during this time that he developed an interest in teaching, particularly undergraduates and postgraduates. he began an intense crusade to ta e microbiology out of the laboratory into the related clinical medical areas to bring south africa in line with the rest of the world. he was appointed associate professor of clinical microbiology in 1989, shortly before he entered private practice. hospital (recently renamed the helen joseph hospital) in auckland park, johannesburg. this led to his fifth-year elective being spent in houston, texas with internationally renowned cardiovascular surgeon, professor denton courey. his interest in this specially did not waver throughout an internship at the johannesburg general hospi al in 1978. steven miller as a medical student steven's sights were set on cardiotheracic surgery and he spent all of his free time in ward 17 or the caroiothoracic unit at the j g strydom steven miller was born, bred and educated in johannesburg. anyone who has met him, attended one of his lectures or read one of his many papers will not be surprised that at sc 001 he excelled in languages and initially aspired to be a teacher of latin and english. his later decision to study medicine eventually enabled him to fulfil the wish to teach clinical microbiology in beautifully enunciated king's english! or miller's involvement in hiv medicine and research dates back to 1984 when he helped to establish the hiv clinic at the johannesburg hospital. since then he has lectured and published widely on hiv infection and has served on a number of local and national aids planning committees. he is a founder member of the hiv clinicians' society of southern africa and is chairman of its treatment guidelines committee. he has been principal investigator of several international collaborative cfinical triols and cantinues to play an active role in cfinical research. or steven miller is a consultant in clinical micrabialogy ond infectious disease in private practice in johonnesburg. he is medicol director of innovirlnstitute, an organisation praviding state-of-the-art laboratory diagnostics, cfinicol triol opportunities ond patient care services far persons with hiv/aids. or miller is a graduate of the witwatersrand university medicol school. following a period of postgraduate training overseas in cardia thoracic surgery, he returned to johannesburg and joined the south african institute for medical research where he qualified as a cfinical micrabiolagist. he was appointed associote prafessar ofcfinical micrabiolagy in 1989, shortly before he entered private practice. -----------/-if sou/nf ahuan jour al of hi mfoicinf of a small number of south african experts to become involved in the new and mystifying hiv/aids disease when it reared i15 head in johannesburg in 1982, particularly as the causative organism had not yet been identified. miller's participation in related research coupled with an interest in the diagnosis and clinical care of people infected with hiv led to his involvement in the establishment of the hiv clinic at the johannesburg hospital in 1984. dr miller comments that he feels honoured to have been associated with the southern african hiv epidemic from the outset he says that he has learnt a great deal from the experience as it is in this field that the most significant discoveries regarding global infectious diseases of the 20th century have been made. when asked what he feels should be done to deal with the present south african scenario, he says that four specific components are needed to deal with it adequately: • treat people with hiv using internationally accepted standards of treatment and care • devise and implement an effective preventive programme • train medical and health care professionals to manage hiv/aids • set up a national infrastructure to provide testing, counselling and monitoring and to distribute drugs for prophylaxis and treatment finally, he says that all of the above should be carried out with systems in place to monitor accountability. he believes thal in the presence of a political will this is achievable, but at present local practitioners need to be reassured that government and health authorities continue to support and implement appropriate interventions. the sad reality is that until that happens an infected individual's fate depends on financial resources and economic standing. there are two very distinct categories of patients: the 'haves', who can access appropriate care largely confined to the private sector and who will remain well, and the 'have nots', who rely on public sector services and will continue to get sick and die as people did 20 years ago at the beginning of the epidemic: asked about 'uture objectives dr miller said his major medical objective is to assist south africa to embrace infectious disease as a recognised specialty in line with the rest of the world. he is currently collaborating on establishing guidelines for its inception and gives a little insight into the high standards that are being proposed. he believes that the present specialist training is too narrow and that the broader-based system used in the past, which incorporated more clinical training, provided greater atjgtj;200 insight into how the disciplines integrate. a personal objective will be to find time to play his piano he is a licentiate in music and if time can be suetched so far, extend his grasp of german. untitled 55 the journal this quarter is, as usual, jam packed with relevant and valuable information. among others, we have a description of the ethical and legal difficulties of involving adolescents in prevention research from slack et al., a timely consideration as we assimilate the implications of the newly promulgated child bill and sexual offences bill. meyer-rath gives a hard-to-ignore cost-effectiveness argument for rolling out treatment and prevention. wanless and the secure the future group again highlight the good work being done by this charitable funding and the importance of community involvement. the society president alludes to the excellent quality of information disseminated at the recently held south african hiv conference. i was impressed at how practitioners and caregivers have progressed in terms of knowledge and understanding of the complexities of hiv care. in this issue we showcase a series of south african abstracts accepted and presented at the very competitive conference on retroviruses and opportunistic infections held earlier this year in los angeles. in each case we have asked the authors to describe the relevance and implications for the south african epidemic. in the next issue we will highlight presentations from the south african conference, and include a summary of wood’s state-of-the-art review of diagnostics for tuberculosis at a symposium hosted by roche at this conference. finally, as has become our tradition, we have guidelines for you in the centre pages. in this edition, spencer and the nutrition focus group have outlined the first two chapters of the nutritional guidelines – more to follow. in addition, venter has summarised the national strategic plan and the exciting partnership between the clinicians society and soul city is described. well done to francois and the team who have also recently launched the new and exciting website. we are working hard to have articles from this journal online as soon as possible after the distribution of the hard copy. finally, we are happy to announce that articles can now be submitted to the journal online: go to www.sajhivmed.org.za and follow the instructions. you will be able to track the progress of your submission and we will be able to more efficiently keep track of all the incoming copy. please get writing! linda-gail bekker editor t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u n e 2 0 0 7 from the editor the south african aids conference has just finished as i’m writing this, amidst a new dawn for the rejuvenated south african national aids council, the release of the ambitious national strategic plan, and a provocative world health organization document on provider-initiated hiv testing. the conference, held every 2 years, had a very strong scientific programme with some excellent presentations. the society had a strong presence, and we ran several highly successful skills workshops during the conference as well as a hugely entertaining debate on circumcision. we were delighted that sponsorship from cipla-medpro enabled us to send a large number of rural doctors to the conference, and hope that we can continue to support attendance in this way. i would like to congratulate linda-gail bekker for two reasons – she is our new journal editor, and she will be chair of the conference in 2009. moreover, her home town, cape town, will host the prestigious 2009 international aids society conference. add to this the highly anticipated botswana aids conference next year, and no one need leave our shores in the near future to access the best scientific presentations and debates. francois venter president m e s s a g e f r o m t h e e x e c u t i v e fatima hassan of the aids law project and francois venter of the society get tested at new start, after debating provider-initiated hiv testing at the 3rd south african aids conference. olive shisana, head of the human sciences research council, takes an hiv test at the 3rd south african aids conference as part of the sunday times campaign to get more people to do an hiv test. hiv 903 hiv seroconversion during late pregnancy – when to retest e kalk,1 mb bch, phd, dip hiv man; a slogrove,1,2 mb chb, fcpaed (sa), mmed; d p speert,2 md, frcp(c); j a bettinger,3 phd, mph; m f cotton,1 mb bch, fcpaed (sa), phd; m esser,4 mb bch, mmedpaed (rheum) 1 children’s infectious diseases research unit (kidcru), department of paediatrics and child health, stellenbosch university, stellenbosch, south africa 2 department of pediatrics, university of british columbia, canada 3 vaccine evaluation center, british columbia children’s hospital and university of british columbia, canada 4 national health laboratory service and department of pathology (immunology), stellenbosch university, stellenbosch, south africa corresponding author: e kalk (kalk@sun.ac.za) the south african national prevention of mother-to-child transmission of hiv programme has resulted in significant reductions in vertical transmission, but new infant hiv infections continue to occur. we present two cases of hiv seroconversion during late pregnancy, demonstrating the limitations of the current programme. these could be mitigated by expanding the programme to include maternal testing at delivery and at immunisation clinic visits as we pursue the elimination of mother-to-child transmission. s afr j hiv med 2013;14(2):90-92. doi:10.7196/sajhivmed.903 in order to identify hiv-infected women and offer antiretroviral (arv) prophylaxis, the south african national prevention of mother-to-child transmission (pmtct) of hiv programme recommends 2 hiv tests during pregnancy: at the first antenatal visit and at 32 weeks of gestation.1 we present two cases that suggest that additional hiv testing strategies are needed to help eliminate the mother-to-child transmission of hiv. in a longitudinal study on hiv-exposed infants, we recruited infants whose mothers were known to be hiv-infected post partum along with a control group of infants born to hiv-negative women. all women delivering at the kraaifontein midwife obstetric unit were eligible for enrolment. hiv-exposed infants were matched with hiv-unexposed controls within one month of birth. mother-infant pairs were recruited within three days of delivery and a cd4+ t-cell count was performed on all women regardless of hiv status. in accordance with the study protocol, the infants were reviewed at 2 weeks of age and regularly thereafter. at the 2-week visit, the hiv status of the uninfected mothers was confirmed with an hiv rapid assay using finger-prick blood (alere determine hiv 1/2). recently, hiv infection was identified on the rapid tests at the 2-week visit in 2 women (table 1). according to antenatal clinic documentation, both tested negative during pregnancy: at booking (at 21 weeks and 28 weeks of gestation, respectively) and at 32 weeks of gestation, as recommended in the national guideline.1 neither infant was born before 38 weeks of gestation. the hiv rapid assay in use in the antenatal clinic at the time was the first response hiv1-2-0 card test (premier medical corporation ltd, india). according to policy, only a single test is required to screen for hiv. positive screening tests are confirmed with a second rapid assay (abon hiv 1/2/0 tri-line hiv rapid test device). both women elected to breastfeed, although one mother switched to infant formula after one week owing to poor feeding. her cd4+ t-cell count at delivery was 680 x 106 cells/l. her infant was symptomatic at age 2 weeks and was immediately hospitalised, requiring transfer to the intensive care unit. an hiv dna polymerase chain reaction (pcr) test (amplicor hiv-1 dna prototype assay 1.5) at 2 weeks was positive. the cd4+ count of the second woman was 157 x 106 cells/l at delivery. her baby was well and the hiv dna pcr at 2 weeks was negative. daily nevirapine (nvp) for the infant was initiated and the mother was referred for combination antiretroviral therapy (cart) which was commenced within 2 weeks. discussion these two cases raise concerns about antenatal hiv screening and the implications for vertical transmission. as expected, neither woman received any arv prophylaxis. a recent medical research council (mrc) report on the effectiveness of the national pmtct programme in south africa2 demonstrated that, among mothers who reported being hiv-negative, 4.1% had infants who were hiv-exposed at 4 8 weeks (measured by the presence of hiv antibodies in the infants’ blood). a 2007 surveillance study in kwazulu-natal (kzn) found that 6.9% of infants whose mothers reported a negative hiv status had similar evidence of exposure (i.e. the presence of hiv antibodies in the infants’ blood).3 of concern is that the vertical transmission rate in this group was high (31% v. an overall rate of 20.2% at that time). it is possible that some women knew, but did not admit their hiv-positive status. however, the kzn study was anonymous, and the mrc report demonstrated a high uptake of hiv testing and disclosure, making it unlikely that this scenario contributed significantly to the observations.2 , 3 moreover, the two subjects described here each had hiv-negative results for rapid tests on two different occasions. alternatively, there may have been a problem with the hiv rapid antibody assay, including that the tests were conducted within the window period. antibodies to hiv can be detected at 2 3 weeks after infection by fourth-generation laboratory enzyme-linked immunosorbent assay (elisa) tests, which detect both antibody to hiv and p24ag (fiebig stage ii and iii). 4 the third-generation rapid tests have a window period of three to four weeks post infection (fiebig stage iii).4 , 5 testing during this time will yield a false-negative result. the reported sensitivity and specificity of the first response hiv 1-2-0 card test are 100% and 98.8% when used correctly5 within the who recommended range of >98%.6 in our subjects, this explanation could only apply to the second assay at 32 weeks, and would indicate recent acquisition of infection. the rapid assay may have recorded a false-negative result for the second test. all batches of rapid tests are validated by the national institute for communicable diseases (nicd) on a panel of laboratory samples, but they have not been validated in pregnant women specifically or in the field. assay sensitivities have been reported between 87% to 95% in clinics depending on the product.2 , 7 more data are therefore required to assess and validate hiv rapid assays in pregnant women, and to ensure the quality of testing at clinic level. importantly, there is no quality-control procedure for negative rapid tests. the most likely explanation for our findings is true acquisition of hiv during pregnancy and breastfeeding. pregnancy poses an increased risk for hiv acquisition by women, even after adjustment for behavioural and other factors; it is possible that the hormonal and other biological changes associated with pregnancy play a role.8 high viral loads during primary hiv infection increase the risk of vertical transmission in utero, peri partum and post partum,9 , 10 especially in the absence of arv prophylaxis. in studies in botswana and sa, new mothers with negative hiv test results or of unknown hiv status were tested immediately post partum or at infant immunisation visits. the results demonstrated a seroconversion rate of 2.4 7.9% during pregnancy and post partum. 2 , 7 , 11 , 12 these women are at high risk of vertical transmission.13-15 in addition, they are more likely to use mixed feeding practices, placing their infants at greater risk for hiv infection. 2 , 16-18 ‘mixed feeding’ refers to the use of breast milk in addition to other fluids (infant formula, water, tea) for infant feeding. the increased incidence of mixed feeding observed in these women is presumably because, having tested hiv-negative, they perceive no risk. repeat hiv testing of mothers during late pregnancy, at delivery or at the clinic immunisation visits, would identify women who acquire hiv during pregnancy and in the early post-partum period. the hiv diagnosis of infants whose mothers tested negative during pregnancy is often delayed,18 with significant implications for morbidity and mortality.19 most sa women deliver at a healthcare facility20 and 99% attend the 6-week vaccination visit.2 moreover, testing at these time-points shows high uptake,11 , 21 , 22 while offering hiv tests to both partners may identify discordant couples and allow counselling on hiv prevention.2 a proviso to this is increasing evidence that, even within discordant partnerships, a significant number of new hiv infections arise from extra-couple transmission.23 conclusion while the elimination of mother-to-child transmission of hiv is feasible, it will require a modification of current protocols/guidelines to include repeat hiv testing of women at delivery and/or post partum, a quality-control strategy for laboratory testing of a small percentage of negative rapid tests, involvement of male partners in testing and counselling, and an emphasis on exclusive feeding practices, regardless of hiv status. ethics approval. the mother infant health study (mihs) is approved by the ethics committees of stellenbosch university and the university of british columbia. conflict of interest. none. funding acknowledgement. the mihs is supported by the peter wall institute of advanced studies, university of british columbia. as receives funding from the canadian institute of health research canada-hope. acknowledgements. the authors thank the ever-motivated mihs team at kid-cru and kraaifontein mou in cape town; and tobias kollmann, arlene kallos and kim marty from the team in vancouver. references 1. national department of health, south african national aids council. clinical guidelines: prevention of mother-to-child transmission. pretoria: national department of health, 2010. 1. national department of health, south african national aids council. clinical guidelines: prevention of mother-to-child transmission. pretoria: national department of health, 2010. 2. goga ae, jackson dj. evaluation of the effectiveness of the national prevention of mother-to-child transmission (pmtct) programme measured at six weeks postpartum in south africa, 2010: medical research council of south africa, national department of health, pepfar/us centers for disease control and prevention, 2012. 2. goga ae, jackson dj. evaluation of the effectiveness of the national prevention of mother-to-child transmission (pmtct) programme measured at six weeks postpartum in south africa, 2010: medical research council of south africa, national department of health, pepfar/us centers for disease control and prevention, 2012. 3. rollins n, little k, mzolo s, et al. surveillance of mother-to-child transmission prevention programmes at immunization clinics: the case for universal screening. aids 2007;21:1341-1347. 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[http://dx.doi.org/10.1097/01.aids.0000166093.16446.c9] 17. iliff pj, piwoz eg, tavengwa nv, et al. early exclusive breastfeeding reduces the risk of postnatal hiv-1 transmission and increases hiv-free survival. aids 2005;19:699-708. [http://dx.doi.org/10.1097/01.aids.0000166093.16446.c9] 18. kalk e, zunza m, cotton mf. abstract p80: reasons for failure of vertical transmission prevention in the western cape, south africa – a retrospective descriptive study. first southern african hiv clinicians society conference, cape town, south africa, november 2012. 18. kalk e, zunza m, cotton mf. abstract p80: reasons for failure of vertical transmission prevention in the western cape, south africa – a retrospective descriptive study. first southern african hiv clinicians society conference, cape town, south africa, november 2012. 19. violari a, cotton mf, gibb dm, et al. early antiretroviral therapy and mortality among hiv-infected infants. n engl j med 2008;359:2233-2244. [http://dx.doi.org/10.1056/nejmoa0800971] 19. violari a, cotton mf, gibb dm, et al. early antiretroviral therapy and mortality among hiv-infected infants. n engl j med 2008;359:2233-2244. [http://dx.doi.org/10.1056/nejmoa0800971] 20. myer l, harrison a. why do women seek antenatal care late? perspectives from rural south africa. j midwifery womens health 2003;48:268-272. [http://dx.doi.org/10.1016/s1526-9523(02)00421-x] 20. myer l, harrison a. why do women seek antenatal care late? perspectives from rural south africa. j midwifery womens health 2003;48:268-272. [http://dx.doi.org/10.1016/s1526-9523(02)00421-x] 21. lu l, legwaila k, motswere c, et al. hiv incidence in pregnancy and the first post-partum year and implications for pmtct programs, francistown, botswana, 2008. 16th conference on retroviruses and opportunistic infections, montreal, canada, 2009. 21. lu l, legwaila k, motswere c, et al. hiv incidence in pregnancy and the first post-partum year and implications for pmtct programs, francistown, botswana, 2008. 16th conference on retroviruses and opportunistic infections, montreal, canada, 2009. 22. lu l, motswere-chirwa c, legwaila k, et al. abstract 15: hiv incidence in women during the first postpartum year: implications for pmtct programs, francistown, botswana, 2010. third international workshop on hiv pediatrics. rome, italy. 22. lu l, motswere-chirwa c, legwaila k, et al. abstract 15: hiv incidence in women during the first postpartum year: implications for pmtct programs, francistown, botswana, 2010. third international workshop on hiv pediatrics. rome, italy. 23. bellan se, fiorella kj, melesse dy, et al. extra-couple hiv transmission in sub-saharan africa: a mathematical modelling study of survey data. lancet. 2013 (in press). [http://dx.doi.org/10.1016/s0140-6736(12)61960-6] 23. bellan se, fiorella kj, melesse dy, et al. extra-couple hiv transmission in sub-saharan africa: a mathematical modelling study of survey data. lancet. 2013 (in press). [http://dx.doi.org/10.1016/s0140-6736(12)61960-6] 927 clinical challenge: deteriorating liver function in tb and hiv co-treatment f venter,1 fcp (sa); n masingi,2 mb bch; s stacey,2 mb bch, fcp (sa), cert id (sa); s fidler,3 bsc, mbbs, frcp, phd 1 wits reproductive health & hiv institute, university of the witwatersrand, johannesburg, south africa 2 charlotte maxeke academic hospital, department of medicine, university of the witwatersrand, johannesburg, south africa 3 faculty of medicine, imperial college, london, united kingdom editor’s note: in this section of the journal, we present complex, real-world hiv medicine cases to two experienced clinicians working in very different environments, and ask them to describe the approach that they would take if they saw the case in their local hospital setting. in our first edition, a patient with deteriorating liver function is presented by prof. francois venter and dr ntsakisi masingi, and then discussed by dr sarah stacey in johannesburg and dr sarah fidler in london. s afr j hiv med 2013;14(2):95-97. doi:10.7196/sajhivmed.927 case prof. f venter and dr n masingi a 30-year old male taxi driver (cd4+ count 5 cells/μl) presented with a vague history of weight loss and night sweats. he had received tuberculosis (tb) treatment (rifampicin, isoniazid, pyrazinamide and ethambutol) for one month. he was initiated on antiretroviral therapy (art) including tenofovir, lamivudine and efavirenz. the clinician involved was concerned about the low cd4+ cell count, and brought the patient back for follow-up after 4 weeks. at that time, the patient said he felt much better. objectively, the patient had gained 4 kg and was slightly jaundiced. he had no hepatomegaly and there were no other clinical findings. the clinician phoned the patient after receiving his 4-week blood test results, and asked him to return for follow-up. his blood test results before and after art initiation are summarised in table 1. five weeks after art initiation, the clinical examination results were unchanged. the patient refused inpatient care, as he had to drive his taxi. with this background, we put the following questions to our clinical experts in johannesburg and london: • how would you practically manage this patient at your institution, with available resources? • what would be your top differential diagnoses? • what would make you change your management plan, if anything, as you implement it? • is there anything that may emerge over time that would worry you? response dr s stacey (johannesburg) i would consider, as possible causes of this common problem: • a drug reaction to: • tb therapy • art • prophylactic co-trimoxazole • tb-iris reaction • ingestion of other hepatotoxic sub­stances including traditional med­icines • acute viral infections. i would prefer to investigate and manage the patient as an inpatient in the infectious diseases ward, especially because of the long waiting list for outpatient investigations, but would not insist on admission if the patient adamantly refused. i would stop the tb therapy and co-trimoxazole and repeat the liver function tests (lfts) after 5 7 days. co-trimoxazole can cause a cholestatic picture alone or a hepatocellular and cholestatic pattern together. due to the very rapid rise in liver enzymes, i would also stop art. although i think the prescribed antiretrovirals (arvs) are the less likely suspects and he is asymptomatic, he is also jaundiced and his enzymes are more than five times the baseline value. efavirenz has been associated with liver failure and liver fatalities. other blood tests would include repeat viral hepatitis serology for types a, b and c to exclude recently acquired acute hepatitis, a cytomegalovirus (cmv) polymerase chain recation (pcr) test, full blood count and differential and inflammatory markers. i would question the patient about the use of over-the-counter and traditional medicines and alcohol, and advise him to discontinue their use. in the meantime, i would use a liver-sparing regimen for tb therapy, consisting of an aminoglycoside, moxifloxacin and ethambutol. i have chosen these drugs because although none of them are as effective as rifampicin or isoniazid (inh), i would like to ensure that i am still providing a combination that is effective in the continuation phase. i would substitute dapsone for co-trimoxazole, because dapsone is not associated with liver injury. if the patient's liver enzymes showed signs of improvement on this regimen, i would wait until they approached normal and then reintroduce the tb drugs one at a time (although we are usually anxious to restart full tb therapy as soon as possible because we believe that liver-sparing treatment is less effective than standard therapy). we still do not restart pyrazinamide in these patients, but i would attempt to reintroduce both inh and rifampicin, although we have noticed that some patients tolerate reintroduction of full tb therapy with the fixed-dose combination (fdc). it is also much more practical to prescribe the fdc, as single drugs are only available at tertiary sites and, even there, are not stocked consistently. if the patient tolerated tb therapy, i would attempt to reintroduce art using the same regimen. i would request an ultrasound of the liver as well, but booked on an outpatient basis, this investigation may be several weeks away at our hospital. hypodense lesions in the liver, associated with lymphadenopathy, and splenic lesions could suggest tb-immune reconstitution inflammatory syndrome (tb-iris), although the initial diagnosis of tb was sufficiently vague to make other  (unmasked) infections of the liver worth considering, such as fungal infections, non-tuberculous mycobacterial infections and viral infections like cmv. depending on the results of the ultrasound, i would proceed to recommend a liver biopsy and/or magnetic resonance cholangiopancreatography (mrcp) if the patient's liver functions did not improve off medication. response dr s fidler (london) first, i would take a full history – plus a sexual history – to exclude other sexually transmitted infections (stis) that could affect liver function (e.g. hepatitis b and c virus, which could be acute infections even though he was initially antibody-negative), and ask about travel to consider other acquired co-infections, other family or close contacts who were unwell, other medications, over-the-counter medications, recreational drugs and especially alcohol. i would ask about malaena, gastrointestinal symptoms, nausea, vomiting and fevers. blood tests to add: repeat hepatitis a, b and c; cmv pcr; epstein-barr virus (ebv); toxoplasmosis; sti screen; syphilis; drug levels (efavirenz, rifampicin); and bacterial and mycobacterial blood cultures. my differential diagnosis would include: a drug reaction to either co-trimaoxazole, any tb drug or art – most likely efavirenz or tenofovir, alcohol or other medication not disclosed. other causes, if all of the above were excluded, could include lymphoma (a very low cd4+ cell count suggests long-standing untreated hiv). i would admit the patient to hospital for investigation and observation, exclude other causes, and treat as diagnosed. if he declined admission and his liver dysfunction continued, i would advise him to stop driving his taxi – especially if alcohol abuse was suspected, or lft results were increasingly abnormal. if he continued to decline admission, i would repeat his lfts and clotting three times a week. i would arrange an urgent liver ultrasound scan, and potentially magnetic resonance imaging (mri), depending on the outcome of the ultrasound. i would do a regular review of the patient in the outpatient clinic to ensure that there was no clinical evidence of hepatic failure or encephalopathy. if there was any evidence of liver failure, i would admit the patient. as the patient's lfts were increasingly abnormal, i would stop all drugs. the goal is to reintroduce drugs, preferably individually, prioritising tb treatment first, but preventing other opportunistic infections in view of the patient's severe immunosuppression. i would anticipate that once all drugs were stopped, the lft results would return to within normal limits. i would then review the patient's treatment options for both tb and hiv. this would include the use of genexpert for determining tb drug sensitivities and hiv genotyping, including integrase and tropism (this should be available from the baseline sample taken on all new hiv-positive individuals) prior to restarting therapy. the first priority would be tb treatment: based on the test results, i would restart an effective regimen for tb, introducing single agents with close monitoring of lfts and clotting (three times weekly). once the patient was established on tb treatment, i would re-start his art regimen: i would check the viral genotype to confirm whether or not there was any drug resistance and determine the potential for other art options. ideally, tenofovir/emtricitabine/efavirenz would be the preferred option in view of tb drug interactions and available safety data, but i would monitor lfts and therapeutic drug levels. if efavirenz was the potential cause of abnormal lfts, i would consider triple nucleosides while the patient was receiving tb drugs or potentially, but cautiously, raltegravir with tenofovir/emtricitabine, although there are fewer data on interactions, so the patient would require close monitoring of viral load (vl). i would avoid pis altogether due to drug interactions. if, despite starting art, there was clinical or ultrasound evidence suggestive of tb-iris, i would consider adding steroids to treat the suspected iris, while continuing tb treatment and arvs unchanged. final outcome prof. f venter and dr n masingi we elected to continue the arvs and tb continuation phase treatment, phoning the patient daily to make sure he was alright. we were a little suspicious about the use of traditional medicines (he seemed unsure when we asked him), so we asked a counsellor to speak to him, who agreed that he may be using something. we then gave him general counselling about unknown drug interactions, and showed him his lft results and how they were deteriorating. we were worried about the patient driving a taxi (on efavirenz, potentially encephalopathic), but he had no objective signs of liver failure, his international normalised ratio (inr) remained normal, suggesting his liver synthetic function was still alright – and he was not prepared to stop driving. an ultrasound three weeks later showed liver and splenic micro-abscesses, so the patient could also have had a tb-iris reaction. he is fine now, with a cd4+ count >300 cells/µl, an undetectable vl 8 months later, he is still driving his taxi, but we never proved tb. these cases are hard, but access to additional and repeated laboratory investi­gations and rapid radiology can help. the differential diagnosis of drug toxicity, tb-iris, toxin or new opportunistic illness all look alike, and if the patient's lfts had continued to decline, we would have stopped all treatment and slowly re-introduced his tb medication, then art, once his lfts had settled. article information authors: louise kuhn1,2 max kroon3 affiliations: 1gertrude h. sergievsky center, college of physicians and surgeons, columbia university, united states 2department of epidemiology, mailman school of public health, columbia university, united states 3division of neonatal medicine, department of paediatrics, university of cape town, south africa correspondence to:    louise kuhn email: lk24@columbia.edu postal address: sergievsky center, columbia university, box 16, 630 w 168th street, new york 10032, united states dates: received: 02 mar. 2015 accepted: 17 mar. 2015 published: 20 may 2015 how to cite this article: kuhn l, kroon m. breastfeeding and the 2015 south african guidelines for prevention of mother-to-child transmission of hiv. s afr j hiv med. 2015;16(1), art. #377, 5 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.377 copyright notice: © 2015. the authors. licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. breastfeeding and the 2015 south african guidelines for prevention of mother-to-child transmission of hiv in this forum... open access • hiv-infected neonates • preterm and low birthweight neonates • neonates of mothers who are non-adherent or have drug-resistant virus • conclusion • acknowledgements    • competing interests    • authors’ contributions • references breastfeeding, especially exclusive breastfeeding in the first months of life, is the cornerstone of good infant nutrition, health and survival. the various health benefits include the mother and also extend beyond infancy to protection against common noncommunicable diseases in adult life. these benefits take on even greater salience in low-resource settings. mother-to-child transmission (mtct) of hiv through breastfeeding and the centers for disease control's initial recommendation that hiv-infected women avoid breastfeeding their infants, threatened this key child health-promoting activity. support for breastfeeding by hiv-infected women is steadily being reinstated, however. this change was prompted by numerous reports that formula feeding incurred significant harm1 and was also facilitated by a 1999 report that showed significantly reduced postnatal hiv transmission if breastfeeding was exclusive.2 further impetus came from a demonstration that postnatal transmission is almost eliminated if maternal combination antiretroviral treatment (cart) or extended infant antiretroviral peri-exposure prophylaxis (peep) is provided during breastfeeding.3 in 2012, even the british hiv association (bhiva) guidelines permitted breastfeeding under tightly controlled circumstances, if mothers insisted. the 2010 south african prevention of mother-to-child hiv transmission (pmtct) guidelines incorporated this evidence and were broadly supportive of hiv-infected women breastfeeding their infants, but stopped short of adopting breastfeeding as the programme's default feeding choice. the tshwane declaration in august 2011 shifted south africa squarely onto the breastfeeding restoration path. besides promoting, protecting and supporting breastfeeding generally, the declaration specifically adopts breastfeeding as the default feeding method for hiv-exposed infants and promotes human milk banks to support breastfeeding and breast milk feeding. the tshwane declaration was followed by the promulgation of regulations (r991/2012) to enforce the international code on marketing of breast milk substitutes. nevertheless, south africa still lags behind many other african countries in the uptake and duration of breastfeeding and the duration of exclusive breastfeeding.4 new guidelines to improve pmtct in south africa have recently been released and recommend lifelong cart for all pregnant women and those who have delivered in the preceding 12 months, irrespective of disease and laboratory criteria. four important new dimensions provide greater attention to neonates, namely (1) birth polymerase chain reaction (pcr) testing of high-risk neonates, (2) extended infant antiretroviral (arv) prophylaxis if early breastfeeding risk is increased owing to inadequate duration of maternal cart, (3) combination infant arv prophylaxis (carp) if intrapartum transmission risk is increased and (4) very early initiation of cart in infected neonates. in the present article, we discuss the implications of these new programme and policy developments for breastfeeding. the first issue is the specific counselling needs of women whose infants are hiv-infected. the new birth pcr testing programmes will identify most hiv-infected infants much earlier than the old 6-weeks pcr testing programmes.5 this approach provides a valuable opportunity for strengthening support for breastfeeding, which is essential to the survival and well-being of hiv-infected infants. hiv-infected infants should be breastfed for 2 years or more. secondly, by design, the new, targeted birth testing programmes will encompass a large proportion of preterm and low birthweight (lbw) neonates. many challenges exist to maintain optimal breastfeeding and clinical care for this high-risk group, regardless of hiv exposure status. hiv clinicians will need to improve their skills and expertise in this area as caring for more of these vulnerable infants becomes their responsibility. in turn, neonatologists and paediatricians already caring for this clinical population will need to strengthen their skills and expertise in hiv-related interventions. thirdly, risk estimation linked to targeted testing or augmented infant prophylaxis will identify women with suboptimal cart, including those who have not yet accessed care, those who deliberately avoided care, those who are non-adherent, those who are failing cart, late starters, etc. counselling around infant feeding for this group will need to balance hiv transmission risks against the adverse and potentially fatal outcomes associated with abstinence from breastfeeding, particularly in preterm and lbw infants. hiv-infected neonates top ↑ infant feeding counselling in pmtct programmes has mostly ignored the scenario of known hiv-infected neonates. typically, counselling has been directed at hiv-infected women with infants of unknown hiv status. whilst antenatal counselling still has to keep this focus, postnatal counselling will now have the benefit of much earlier diagnosis of hiv infection than was previously possible. if a sample for a pcr test is collected at birth, the mother should be able to learn her infant's hiv status in a matter of days, depending on the turnaround time of the laboratory and the schedule of follow-up visits. this time could be reduced to a few hours if point-of-care (poc) tests are used routinely in the clinical setting. for an infant diagnosed as infected, earlier diagnosis offers a valuable opportunity for strengthening support for breastfeeding. breastfeeding is crucial for the wellbeing of hiv-infected infants who are at exceedingly high risk of mortality.6 breastfeeding for two years or more can be unequivocally recommended and supported for the infected infant, as the risk of hiv transmission is no longer a consideration. however, learning the infant's diagnosis is challenging for mothers. many are distressed and experience feelings of guilt. they should be reassured that any ‘re-infection’, should it even occur, will not accelerate disease progression in their infant and that the protective benefits of breastfeeding in an hiv-infected child far outweigh the minuscule possibility of harm. very early diagnosis also provides a window of opportunity to begin or restart breastfeeding for those who either decided to forgo all breastfeeding or who stopped before the infant's diagnosis. healthcare workers and the community are often quite ignorant of the reversible nature of infant feeding decisions. an innovative programme in soweto demonstrated that a modest relactation counselling program had reasonable success in achieving full lactation after infant hiv diagnosis, even in mothers who had abstained entirely from breastfeeding until infant diagnosis around 12 weeks of age.7 preterm and low birthweight neonates top ↑ preterm and lbw infants are generally at higher risk of perinatal hiv transmission than term, normal birthweight infants. they also may have biological reasons for increased susceptibility to enteral acquisition of hiv from breast milk. in addition, preterm birth before adequate passive transfer of maternal neutralising antibodies may cause reduced protection against postnatal hiv infection. this is why preterm birth and/or lbw is included as one of the criteria for targeted birth testing and, in the western cape, for carp. few studies of extended infant prophylaxis include preterm infants, despite their higher risk of infection, and special dosage considerations are required in this group.8 nevertheless, combining infant peep with maternal cart is advisable in this group, as avoidance of breastmilk feeding increases morbidity and mortality significantly. the immature, preterm gut is nowhere near as robust as the term gut with, initially, relative hypomotility, underdeveloped microvilli and brush border enzymes predisposing to malabsorption, stasis, bacterial overgrowth and inflammation, particularly if fed injudiciously. very gentle graduated feeding with human milk reduces the risk of intestinal inflammation and necrotising enterocolitis (nec). nec is three times more common with formula milk than with donated human milk feeding.9 gut inflammation is likely to increase the number of cd4 cells and ccr5 receptor expression and increase vulnerability to hiv transmission. additionally, hiv-exposed infants may be more at risk of developing nec, worse grades of progressive nec and mortality from nec with worse outcomes after surgery.10 consequently, whilst human milk feeding is critical to better outcomes in hiv-exposed preterm neonates, it may involve the risk of hiv transmission despite arv prophylaxis. it may be advisable to complement infant peep and maternal cart to further reduce transmission risk. consideration should be given to heat treatment of the infant's own mother's milk or feeding with human milk from an hiv-negative donor at least temporarily whilst feeds are being established and preterm gut matures in the first few weeks of life. over-reliance on donated human milk should be discouraged, as this does not facilitate sustained breastfeeding after discharge whilst heat treatment of own mother's milk does. human milk banks have a critical role in supporting breastmilk feeding, and the south african department of health is currently developing regulations on milk banking. some provinces and non-governmental organisation (ngos) have already developed milk banks and milk bank networks. one of the postulated mechanisms for the increased rate of transmission in mixed breastfeeding infants is that cow's milk protein or solid food causes low-grade gut inflammation, thus increasing susceptibility. this possibility may be especially true for the immature gut. preservation of exclusive breastmilk feeding may be facilitated by the temporary use of donated human milk until lactation is fully established or the next batch of own mother's milk is brought from home. there are some data to suggest that heat treatment of expressed breast milk (ebm) at home may be implementable but this complicated approach requires a great deal of motivation from family and adequate support from the health service. the approach is worth considering in preterm neonates in hospital with additional risk factors such as mothers who fail therapy or who are drug resistant. the bulk of feeds would initially be by gastric tube, and this facilitates heat treatment of ebm. cup feeding of heat-treated ebm may also be considered. it is probably safe to transition to suckling directly from the breast with extended infant arp and maternal cart cover once the gut has matured and full enteral feeds are established and well tolerated. minimally nutritive suckling may accelerate oro-motor maturation and should be encouraged. sustaining lactation in mothers of preterm infants can be challenging, particularly when faced with meagre lodging facilities, prolonged maternal-infant separation especially because of severe maternal illness, infrequent visiting owing to poverty or substance abuse, and inadequate support for sibling care especially in recently migrated impoverished families. in addition, postnatal depression and poor advice from healthcare workers may undermine sustained breastfeeding. mothers should be informed that fortification of their milk to meet the increased nutrient demands of the preterm infant is preferable to special preterm formula. whilst some infrastructure issues may be dealt with at a health systems level, commitment to the mother and baby friendly initiative (mbfi) principles, kangaroo infant care and promotion of routine early and regular emptying of breasts by manual and mechanical expression are vital to support and sustain breastfeeding. pharmacological interventions to optimise milk expression may also be helpful but, by and large, the most important component is parental education and ‘buy-in’ of the benefits of breastfeeding. an institutionalised belief that breastfeeding is a critical component of preterm care goes a long way to reverse the tendency to rely on formula milk as a short-term, quick-fix option. this complex subset of preterm and lbw infants neonates poses many challenges for ensuring optimal and sustained breastfeeding and care whilst preventing hiv infection. hiv clinicians, neonatologists and paediatricians will have to rise to this challenge as these babies become the focus of intensified risk-based prophylaxis and, if infected, cart in the first weeks of life. some hospitals have sophisticated programmes to help support breastfeeding of preterm infants including kangaroo infant care, heat-treatment stations and active milk banks. other hospitals, however, need to establish this capacity as soon as possible. neonates of mothers who are non-adherent or have drug-resistant virus top ↑ infants whose mothers have had suboptimal arv exposures will constitute the majority of high-risk infants identified for targeted testing or carp. this group includes women who have only recently learned their hiv status; those who have deliberately absented themselves from programmes, are non-adherent or defaulters and those not yet able to access appropriate services. all of these characteristics point to challenging social circumstances. ensuring that the mothers of these high-risk infants obtain hiv-related care and arvs necessary for their own health is as important as ensuring the best available prophylaxis for their infants. given the probable social disadvantage of women who are partially adherent to cart, the new advice that women who are failing secondor third-line treatment should formula feed is, in most circumstances, ill-advised. there are no special reasons to avoid breastfeeding in this group. the same risk/benefit considerations for breastfeeding in all hiv-exposed infants apply to this subgroup, and many will have social circumstances that could amplify the adverse consequences of avoiding breastfeeding. invoking risk of transmission of drug-resistant virus through breastfeeding as the motivation for avoiding it is not logical. concerns about transmission of drug resistance in this situation are overstated and confused. almost all infants who fail pmtct (i.e. become infected despite being exposed to arvs) have virus resistance to a number of first-line arvs.11 the paediatric treatment guidelines already address this by recommending initiation with ritonavir-boosted lopinavir (lpv/r)-based cart for hiv-infected infants from 42 weeks’ corrected gestational age and young children under 3 years of age. mtct of resistance to lpv/r is exceedingly rare. we are aware of one report of transmitted lpv/r resistance to an infant via perinatal rather than postnatal transmission.12 trials using lpv/r for pmtct have not observed frequent emergence of lpv/r resistance in either mothers or infants.13 even if it were to occur, the small risk of resistance applies only to the small population of infants who are infected. avoiding breastfeeding for the benefit of a tiny minority places the majority of hiv-exposed uninfected infants at risk of poor health and development. fear of hiv transmission during breastfeeding looms large, and fear of transmission of drug-resistant hiv even larger. this fear seems to blind providers to the immediate risks of poor growth, pneumonia and diarrhoea, significantly more likely to be worse or fatal in the non-breastfed infant.1 the risks of postnatal hiv transmission are almost 20 times less than during the pregnancy and delivery. arvs given to the mother or to the infant reduce risks via all of these routes by a factor of more than 10 (figure 1). in the event of suboptimal adherence to arvs, the risk of hiv transmission does not exceed that observed in the absence of arvs. risks of transmission in this partially adherent group will be less than the risks when no arvs are given. figure 1: risks of hiv transmission with (in red) and without (in purple) antiretroviral drugs occurring during the intrauterine, intrapartum and during months 1–9 via breastfeeding. the risks of transmission amongst mothers who are non-adherent, failing therapy or drug resistant are likely to lie between these two estimates. the social circumstances and health service access issues associated with this subgroup tend to exacerbate the adverse effects of abstinence from breastfeeding. formula feeding should only be considered in this group if all options of ensuring access to arvs for mother and infant have been exhausted or there are absolutely no prospects of breastfeeding because serious maternal substance addiction will grossly interfere with it. conclusion top ↑ risk recognition linked to improved testing and infant prophylaxis may further reduce transmission, diagnose infection earlier and improve linkage to definitive care and treatment. there is a danger that when transmission risk is increased, replacement feeding may be considered to prevent postnatal transmission despite breastfeeding being critical to infant health and survival. the few paediatric infections averted will be at the expense of harm to the majority who are hiv-exposed but uninfected. even with imperfect prophylaxis, less than 1% of infants become infected in each month of breastfeeding. promoting replacement feeding denies breastfeeding benefits to the more than 99% of hiv-exposed infants who remain uninfected. importantly, these benefits would also be denied to the high-risk infants infected during birth and only diagnosed at 6 weeks of age or older. clinicians may struggle to keep this in mind when counselling the individual ‘high-risk’ patient on feeding choices, and should avoid inflating the real but tiny risk of transmission and understating the real harm from not breastfeeding. at a public health level, occasional individual infections via breastfeeding are a small price to pay for a compelling benefit to the majority. the low frequency of transmission during breastfeeding, even when risk is increased, allows time to optimise maternal cart to reduce risk rather than promoting formula feeding. a weak point in the old early infant diagnosis programme was a tendency towards early termination of breastfeeding around 10–12 weeks when receiving the negative result from the 6-weeks test. this pattern suggested a missed opportunity to support breastfeeding at this critical juncture. it is unclear whether counselling specifically encouraged women to stop breastfeeding or whether messaging around the need for retesting inadvertently failed to convey the importance of continued breastfeeding. vigilance is needed when counselling mothers about the meaning of negative birth pcr tests to ensure that this counselling does not inadvertently discourage breastfeeding. breastfeeding and breastmilk feeding remain the best feeding method to optimise health outcomes in pmtct, even when mothers are failing firstand second-line treatment. the counselling messages after birth testing must include clear support for breastfeeding if we are to leverage the full health benefits of very early hiv diagnostic testing and strengthened prophylaxis. acknowledgements top ↑ competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions the authors co-wrote the article. references top ↑ kuhn l, aldrovandi g. pendulum swings in hiv-1 and infant feeding policies: now halfway back. adv exp med biol. 2012;743:273–287. http://dx.doi.org/10.1007/978-1-4614-2251-8_20 coutsoudis a, pillay k, spooner e, kuhn l, coovadia hm. influence of infant-feeding patterns on early mother-to-child transmission of hiv-1 in durban, south africa: a prospective cohort study. south african vitamin a study group. lancet 1999;354:471–476. http://dx.doi.org/10.1016/s0140-6736(99)01101-0 mofenson lm. antiretroviral drugs to prevent breastfeeding hiv transmission. antivir ther. 2010;15:537–553. http://dx.doi.org/10.3851/imp1574 tylleskar t, jackson d, meda n, et al. exclusive breastfeeding promotion by peer counsellors in sub-saharan africa (promise-ebf): a cluster-randomised trial. lancet. 2011;378:420–427. http://dx.doi.org/10.1016/s0140-6736(11)60738-1 lilian rr, kalk e, technau kg, sherman gg. birth diagnosis of hiv infection in infants to reduce infant mortality and monitor for elimination of mother-to-child transmission. pediatr infect dis j. 2013;32:1080–1085. http://dx.doi.org/10.1097/inf.0b013e318290622e kuhn l, aldrovandi gm, sinkala m, et al. effects of early, abrupt weaning on hiv-free survival of children in zambia. new engl j med. 2008;359:130–141. http://dx.doi.org/10.1056/nejmoa073788 nyati m, kim hy, goga a, violari a, kuhn l, gray g. support for relactation among mothers of hiv-infected children: a pilot study in soweto. breastfeed med. 2014;9:450–457. http://dx.doi.org/10.1089/bfm.2014.0049 mugabo p, els i, smith j, et al. nevirapine plasma concentrations in premature infants exposed to single-dose nevirapine for prevention of mother-to-child transmission of hiv-1. s afr med j. 2011;101:655–658. quigley m, mcguire w. formula versus donor breast milk for feeding preterm or low birth weight infants. cochrane database syst rev. 2014;4:cd002971. http://dx.doi.org/10.1002/14651858.cd002971.pub3 karpelowsky js, van mil s, numanoglu a, leva e, millar aj. effect of maternal human immunodeficiency virus status on the outcome of neonates with necrotizing enterocolitis. j pediatr surg. 2010;45:315–318; discussion 8. http://dx.doi.org/10.1016/j.jpedsurg.2009.10.068 paredes r, marconi vc, lockman s, abrams ej, kuhn l. impact of antiretroviral drugs in pregnant women and their children in africa: hiv resistance and treatment outcomes. j infect dis. 2013;207 suppl 2:s93–s100. http://dx.doi.org/10.1093/infdis/jit110 kuhn l, hunt g, technau kg, et al. drug resistance among newly diagnosed hiv-infected children in the era of more efficacious antiretroviral prophylaxis. aids. 2014;28:1673–1678. http://dx.doi.org/10.1097/qad.0000000000000261 shapiro rl, hughes md, ogwu a, et al. antiretroviral regimens in pregnancy and breast-feeding in botswana. new engl j med. 2010;362:2282–2294. http://dx.doi.org/10.1056/nejmoa0907736 hiv message from executive message from the executive fellow hiv clinicians, by now i am sure that most of you know that the world health organization (who) issued new guidelines. one of the most important differences is that these guidelines suggest initiating hiv-positive individuals on antiretroviral therapy (art) at a cd4+ count of 500 cells/µl. this has caused much debate. with fixed-dose combination (fdc) treatment (one pill once daily) and medications with low side-effect profiles now available, many of the arguments for delayed therapy have fallen away. however, there is no clear clinical evidence of a benefit to starting art earlier. there is a transmission-prevention benefit in discordant couples as shown in the hptn 052 study. the national department of health has not yet adopted the who guidelines, and for those of you who treat patients in the private sector, our advice is to provide careful adherence counselling, as you would to anyone initiating art. if a patient has a cd4+ count of 350 500 cells/µl and is committed to therapy, has thought through the issues around lifelong adherence and is committed, then – if funding permits – start. however, if there is any doubt about the capacity of an individual to adhere to treatment, delay art until he/she is ready.   this edition contains a consensus statement on drug-induced liver injury (dili) resultant from tuberculosis (tb) therapy. this statement has been a long time coming. we gathered together a group of specialists in the area, which was much like herding cats. we debated the various strategies and weighed the evidence, which is not extensive. a consensus was reached; we hope that you will find the statement useful. we will review the statement every couple of years; undoubtedly, there will be changes in the future. as we went through this process, i was struck by the paucity of research in the area of tb. anyone of us who has treated tb has seen a case of dili, but there are so few high-quality studies to help chose the best strategy for management.   finally, i know it seems far away, but the southern african hiv clinicians society’s second clinical conference is scheduled for 24 27 september 2014. please add this event to your diary and make plans to attend. the last one was outstanding and we are already working very hard to ensure that the next one is even better … francesca conradie president southern african hiv clinicians society fconradie@witshealth.co.za abstract introduction methods results discussion conclusion acknowledgements references about the author(s) ferdinand c. mukumbang school of public health, university of the western cape, south africa department of public health, institute of tropical medicine, belgium citation mukumbang fc. actions of female sex workers who experience male condom failure during penetrative sexual encounters with clients in cape town: implications for hiv prevention strategies. s afr j hiv med. 2017;18(1), a698. https://doi.org/10.4102/sajhivmed.v18i1.698 original research actions of female sex workers who experience male condom failure during penetrative sexual encounters with clients in cape town: implications for hiv prevention strategies ferdinand c. mukumbang received: 26 sept. 2016; accepted: 05 feb. 2017; published: 04 apr. 2017 copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: condom failure has always been found to coexist with condom usage, especially among sex workers. objective: to describe the actions of female sex workers when they are faced with situations of condom failure. methods: using the survey design, the participants were selected through the snowball sampling method. their responses were obtained using a structured questionnaire. a total of 100 questionnaires were analysed. results: with respect to the immediate actions of sex workers after condom failure, 36% of the respondents continued with the sexual encounter after noticing that the condom was broken. another 36% stopped immediately when they noticed that the condom had failed, but replaced the condom; 13% of the participants stopped the sexual encounter completely; 3% applied vaginal spermicidal foam; and 5% of the respondents stopped immediately and took a douche when they had the chance. for the actions within the next 24 hours of experiencing condom failure with a client, 53% of the participants did nothing; 4% sought counsel from a professional; 3% of the respondents took alcohol or drugs to forget the incident, 25% went to the clinic for assistance and 8% offered other responses. conclusion: while continuing the sexual encounter without replacing the condom, taking alcohol and drugs or doing nothing could increase the risk of contracting hiv; however, actions like stopping the sexual encounter completely and visiting a clinic or a professional could make a difference between staying hiv negative or seroconverting. there is a need for targeted intervention to address issues of inappropriate behaviours after experiencing condom failure. introduction the global hiv prevalence among female sex workers is estimated at 11.8%, with the highest prevalence of 36% registered in sub-saharan africa.1 the rates of hiv among sex workers are relatively higher compared to the corresponding general population, making them disproportionately affected by the hiv pandemic.2 an integrated biological and behavioural survey of hiv prevalence and treatment rates among sex workers in south african cities conducted in 2015 revealed that an estimated 70% of sex workers in johannesburg are hiv positive, while durban’s sex workers have a 53% hiv infection rate and cape town’s almost 40%.3 it is, therefore, estimated that the hiv prevalence among sex workers is about 12 times greater than that among the general population.4 in south africa, sex workers, their sexual partners and clients account for approximately 20% of all new hiv infections.5 consequently, commercial sex is identified to play a significant role in the hiv epidemic in many developing countries, and it is progressively recognised as an essential part of hiv programming.1 thus, they form part of the key target (most at risk) populations in the fight against the hiv pandemic globally.6 working in the sex industry, biologically, structurally and behaviourally, predisposes female sex workers to acquire and thereby transmit hiv at a higher rate than the general population.7 as women are anatomically more predisposed to contracting hiv than their male counterparts, they are biologically more vulnerable. according to research, the delicate nature of the vaginal walls makes women, in general, three times more susceptible than men to sexually transmitted infections (stis).8 as sex work is characterised by multiple sex partners and frequent coitus9 and also because sex workers sometimes indulge in ‘condomless’ sex with clients for more money,10,11 they are vulnerable from a behavioural perspective. another important behavioural component that further exposes female sex workers is the fact that apart from indulging in commercial sexual activities, they also have non-commercial sex partners which in turn increase their exposure. as sex workers work in unsafe conditions and constantly encounter barriers to accessing condoms or negotiate condom use, they are at risk from a structural perspective.2 this is compounded by the ‘illegal’ status of sex work in south africa. physical and sexual violence from both clients and police have also been identified as conditions that propagate the transmission of hiv and/or aids in the sex industry as it compromises the ability of the sex workers to negotiate condom use. because female sex workers are intimidated by their male clients, are terrified by violence and have limited access to women’s healthcare and prevention, they tend to practice inadequate hiv protection with their clients.11 therefore, programmes designed to prevent the spread of the hiv infection in the sex industry should adopt strategies that address these components in a comprehensive manner.12 sex worker–led prevention initiatives usually include sex education, training on stis and hiv and/or aids, voluntary counselling and testing, and condom distribution and advocacy services. most intervention packages contain at least three of the above-mentioned services and condom distribution forms an integral part of these packages.4 therefore, condoms are considered an important component in the strategy to prevent the transmission of stis, including hiv, in the sex industry as well as in general.13 trends effective condom use is recommended for people who engage in sex with multiple sexual partners14 such as sex workers; hence, condom use is highly recommended and encouraged within the sex industry. although sex workers and their clients are exclusively responsible for their sexual health, working in the sex industry places the female sex workers at a higher risk of contracting hiv during commercial sex. the heightened risk that they face places more responsibility on the female sex workers to ensure that condoms are appropriately and effectively used.11 the effectiveness of condoms is based on the fact that they provide a more direct protection to both the sex workers and their clients. the emphasis on condom use is based on its practicability and its reported effectiveness in providing protection against stis including hiv.15 although male condoms are reported to be up to 98% efficient in preventing stis including hiv with perfect use, condom failure has been identified to considerably interfere with the protective functionality, thus compromising its effectiveness. common condom problems include breakage, slippage and leakage.16 observational and prospective studies have estimated failure rates at 1%–13% during condom use.17 condom failure is likely to occur in situations of poor condom fit; rough, lengthy or intense intercourse; diminished lubrication; or if the condom comes in contact with sharp edges.18 higher rates of condom failure are identified among less-experienced users,19,20 anal sex and men having sex with men,21 situations of sex-perpetuated violence22 and among frequent users.23 the above-mentioned circumstances are common features of the sex industry. consequently, condom failure is identified as an issue that should receive due consideration, especially among sex workers. definition of terms sex worker: a person who indulges in sexual activities for a financial or material benefit, wherein sex is considered a revenue-generating activity rather than a deviant or criminal activity.24 condom breakage: total breakage is defined as the number of condoms that reportedly open or split any time from opening the package to removing the condom from the penis, divided by the total number of condoms opened. condom slippage: partial or complete fall-off of a condom from a penis. study objective while many studies have explored issues around male condom failure among sex workers,18,22,25 an evidence gap was found with regard to what female sex workers do when they encounter circumstances of condom failure during penetrative sex with male clients. this study sought to describe the actions of female sex workers within the first 24 hours of experiencing male condom failure with a male client during penetrative sex. contribution to field these findings could inform national government departments and on-profit organisations (ngos) working with sex workers such as sex worker education and advocacy taskforce (sweat) and sisonke to design interventions that address issues around condom failure. their programmes should focus on empowering and equipping sex workers on what to do when faced with circumstances of condom failure and for possible lobbying for better and need-specific services such as healthcare facilities that can meet the needs in case of unanticipated exposure of sex workers to stis including hiv. methods a cross-sectional, descriptive design was used for this exploratory pilot study. the study was designed as a small-scale version in preparation for a major study.26 the study catchment population included all the female sex workers who conduct sex work around the cape town metropole. this includes both the roadside and the brothel-based female sex workers. a sampling method known as the snowball sampling was employed.27 the first 10 participants included self-identified sex workers who are registered with sweat (seed participants). the seed participants were asked to recommend other self-identified sex workers willing to participate in the study. the investigator calculated the sample size using the estimate of 7500 for the cape town metropole.28 using the raosoft® sample size calculator, the investigator estimated the margin of error at 5%, confidence interval at 95% and the response distribution at 90%. using these modalities, a minimum recommended sample size for the study was estimated at 136. of the 142 participants recruited, only 100 questionnaires were completed correctly and admitted for analysis. although the snowballing method of data collection was employed to recruit the participants, the investigator ensured some degree of representativeness of the female sex workers’ population by making sure that participants were selected from the various areas renowned for sex trade. the investigator identified these sex work ‘hot spots’ from a sex worker population mapping that was done by sweat et al.28 the investigator recorded the regions the participants came from and using the sex work population mapping, identified those regions that were poorly represented. although it is impossible to include a representative sample of all the communities sought,29 the investigator encouraged participants to recruit potential participants from the areas that had not been represented. the study participants were recruited during the months of december 2013 and january 2014 from the following sex trade ‘hot spots’: bellville, parow, goodwood, observatory, brooklyn, mitchell’s plain and khayelitsha. a r40 transportation fee was given to the participants who came in from the various areas to the sweat premises. the investigator used self-administered questionnaires to collect the data in a standardised manner. the questionnaire used in this study comprised four sections. the first section explored the demographics of the study participants. the second section was related to substance use by the female sex workers. the third section dealt with their sex work experiences and the final section was based on condom use, condom failure (breakage and slippage) and actions of the sex workers after experiencing condom failure. this questionnaire was designed to gauge the actions of sex workers when they experienced condom breakage or slippage with their male clients. these questions explored the actions of the study participants immediately after they realised that the condom had failed as well as within the next 24 hours of the incident. this was based on the consideration that the first 72 hours are the most critical with regard to adopting actions that could mitigate seroconversion if a sex worker became infected as a result of condom failure. to ensure the reliability of the questionnaire, simple and straightforward questions were used to reduce the chances of ambiguity and confusion. the questionnaire was adapted from an online commercial sex survey.30 the advantage of using instruments that have already been used by others is that they are recognised by the research community as effective measures in terms of conveying the meaning of the enquiry exactly as the research intended.31 secondly, a copy of the questionnaire was verified by a research delegate of sweat for its appropriateness and completeness. thirdly, the designed questionnaire was piloted among six participants who fitted the inclusion criteria. this pilot tested their comprehension of the questions to ensure that the questions were pitched at a level comprehensible to all the participants, including those who did not have any formal education. after the pilot study, corrections were made to the questionnaire to rephrase questions that were poorly understood by the pilot participants. ethical considerations this study received ethical approval from the stellenbosch ethical research council and permission from sweat. to guarantee a meaningful participation of the sex workers during the investigation, the study was conducted under the auspices of sweat. according to stella (a sex work–focused research institute),32 while conducting research involving sex workers, their participation under the ambit of a protecting body is important because it can prevent further stigmatisation and abuse of the sex workers. the study participants were asked to sign a consent form confirming that their participation in the study is completely voluntary and that they understood the benefits and risks that were associated with their participation before responding to the questionnaires, which did not require any identification of the participants. results a total of 142 self-administered questionnaires were collected. of the 142 questionnaires, 42 were incompletely filled and were thus discarded. the remaining 100 questionnaires were analysed using the ibm spss version 21. the results of the analyses are described under the following headings: demographics of the sample, condom use among the female sex workers, condom breakage and slippage, and actions of sex workers after condom failure. the actions of the sex workers are further divided into two parts: immediate actions and actions within the next 24 hours. demographics of the sample the demographics of the study participants are represented in terms of their age, marital status, educational background and race. table 1 summarises the demographics of the study participants. table 1: key demographics of study participants. condom use among female sex workers to assess the rates of condom use, the investigator used the following parameters: frequently, sometimes, rarely and never. almost all of the sex workers who participated in the survey (99%) indicated using condoms during their last sexual encounter with a male client during penetrative sexual intercourse (vaginal or anal). however, it is clear that consistent condom use is still an issue among sex workers working in the cape town metropole. almost half (44%) of the respondents attested to sometimes having sex without a condom for more money. another 8% said that they frequently engaged in unprotected sex, while 10% indicated that they rarely engaged in unprotected sexual intercourse with their male clients. therefore, 62% of the study participants at one point or the other of their sex work life had engaged in unprotected sexual encounters with their clients for more money. nevertheless, 38% of the respondents reported that they had never engaged in unprotected sexual intercourse with their clients for more money. figure 1 displays the results. figure 1: responses of participants on condom usage. condom breakage and slippage figure 2 represents the distribution of responses with regard to condom breakage and slippage. more people reported frequently experiencing condom breakage compared with condom slippage. the ‘sometimes’ responses of the participants are almost on par when asked how often they experienced condom failure or slippage. more people ‘rarely’ or ‘never’ had condom slippage compared to breakage. figure 2 displays the responses of the participants on condom breakage. figure 2: responses of study participants on condom breakage and slippage. meanwhile, 90% of the participants confirmed having experienced condom breakage at some point or the other while working as sex workers, and 85% reported encountering situations of condom slippage. these findings mean that condom failure is a common occurrence in sex work among female sex workers. actions of sex workers after condom failure the first part focuses on the actions taken by the sex workers immediately after they noticed condom breakage or slippage. the second part focuses on their actions up until the 24th hour. the response percentages of the participants with regard to the immediate actions and actions within the next 24 hours of experiencing condom failure with a client are displayed in table 2. table 2: actions of female sex workers faced with condom failure during penetrative sexual encounters with clients in cape town. immediately after exposure regarding the actions of the sex workers immediately after they noticed that the condom was broken off or had slipped during the sexual encounter with a male client, the questionnaire offered six possible (options) actions (see table 2). the participant responses showed that 36% of the respondents continued the sexual encounter with their clients to the end, even after noticing that the condom was broken or had slipped off. the same number stopped immediately after they noticed that the condom was broken or had slipped and put on a new condom, continuing the encounter to the client’s satisfaction. around 13% of the participants told that they stopped the sexual encounter completely after noticing that the condom was broken or had slipped out during the sexual encounter. three per cent revealed that they applied vaginal spermicidal foam immediately after experiencing condom breakage or slippage. about 5% of the respondents said that they stopped immediately and took a douche. none of the participants took any other action when faced with condom breakage and slippage. finally, 7% did not offer any response because they had previously indicated that they had never experienced condom breakage or slippage while working as sex workers. within the next 24 hours the second part of the action of sex workers was explored using the following question and response options: what do you do when you notice that the condom has slipped or broken when having sex with a client after the encounter is over until the next day? the response options are displayed in table 2. slightly more than half (53%) of the participants reported doing nothing within the next 24 hours after noticing that the condom had failed. meanwhile, 4% of the participants attested to seeking counsel from a professional after an experience of condom breakage or slippage, and 3% of the respondents revealed that they simply drank alcohol or took drugs to forget about the incident. a quarter of the participants (25%) indicated that they went to the clinic for help when they experienced condom breakage and slippage. the 8% who suggested other actions mentioned taking the morning-after pill for the prevention of pregnancy; however, they did not make a mention of anything they did to prevent the transmission of hiv. the last 7% offered no response as they had stated that they had never ever experienced condom breakage or slippage while having sex with a client. discussion condom use among female sex workers the findings of this study revealed that many sex workers are making efforts towards using male latex condoms during penetrative sexual intercourse with their male clients. nevertheless, most of these sex workers are ready to compromise their safety by engaging in unprotected sexual relations with their male clients for better pay rates. this fact is espoused by the finding that only 38% of the respondents reported never having unprotected sexual intercourse with their male clients for better pay. the other 62% of the respondents sometimes, rarely or frequently engaged in unprotected sexual intercourse for more money, representing the sex workers who use condoms inconsistently with their clients. these findings do not, however, tally with the findings of a study conducted by sweat et al.28 that explored the rates of condom use among sex workers in cape town. they observed that of the sex workers that engaged in vaginal sex with male clients, 64.3% reported using a condom at all sexual encounters with their clients. notwithstanding, according to the same study, 45.6% of sex workers reported engaging in penetrative sex with a client without a condom. this figure is not far from the 38% of participants who admitted to indulging in unprotected sexual relations with male clients for better pay. disparities of this nature are frequent because in most studies as in this one, condom use is self-reported and, therefore, potentially subject to bias. although there is a disparity between the exact percentage of sex workers who used condoms every time they had sex with a client, there is a substantial number of sex workers who are still engaging in unprotected sexual intercourse with their clients. although other socio-cultural factors such as accessibility of condoms, client violence and forced unprotected sex, working under the influence of alcohol,33 substance use among sex workers34 and the influence of gatekeepers35 may contribute to the practice of unprotected sex, a factor that stands out is the need for financial stability.36,37 in essence, financial gain is the main reason why people employ themselves in the sex industry. also, sex workers who are addicted to drug use are likely to engage in unprotected sexual intercourse for more money to pay for their habits, and so they need to secure more clients.38 evidence accrued to date also links binge drinking, chronic alcohol use and other alcohol use disorders with unsafe sex and hiv transmission, and these disorders are common among sex workers.39 alcohol and drug use are identified to compromise the thinking and decision-making capacities of the user. this explains why sex workers working under the influence of alcohol are likely to neglect using condoms during sex trade or perhaps do nothing when a condom breaks. another important underlying factor that has been identified in the literature is power relations between the sex workers and their clients. because the client pays for the sex act, they are perceived to hold more power in the condom-negotiation process, requiring negotiation skills on the part of the sex worker to tilt the power balance. if the sex worker is unsuccessful in the negotiation process, they will likely experience problems such as inability to resist the client’s pressure for unprotected sex.40 condom breakage and slippage this study showed very high rates of condom breakage (90%) and slippage (85%) among sex workers in cape town. a study conducted in china revealed the prevalence of condom slippage and condom breakage during the three months before the survey was conducted at 36.2% and 34%, respectively.22 although the rates of condom failure are different in both studies, there is a fundamental understanding that condom failure remains a prevalent problem against hiv preventive efforts in the sex industry. although hiv prevention interventions have positively influenced the prevalence of condom use among sex workers in cape town, the risk of transmission of hiv among this population may remain relatively high as ‘unsafe’ sex stemming from condom failure remains prevalent. the situation is even more dire as mastery of condom use skills is always assumed among sex workers because of the understanding that they practice sex regularly. unfortunately, condom failure always coexists with condom usage and condom use errors. the findings of this study revealed that condom breakage and slippage (condom failure) is fairly common among female sex workers in cape town. in a qualitative study conducted by gurav et al.,18 sex workers identified rough sex in different forms – over-exuberance to violence – resulting from clients’ inebriation and use of sexual stimulants causing tumescence. they also identified excessive thrusting and sex that lasts longer than usual as the main causes of condom failure. according to a study conducted by sweat et al.,28 high levels of condom failure are associated with the choice® condom brand, the condom brand that is distributed by the south african government as a campaign against hiv transmission. while this study points to condom brands being a contributing factor in condom failure to an extent, studies have also shown that condom failure is more associated with condom use skills21,41,43,44 than the condom brand. actions of sex workers after condom failure it is recommended that if a condom breaks or slips off during sexual intercourse and before ejaculation, the parties involved should stop the sex act immediately and put on a new one before continuing.16 if ejaculation occurred, the receptive partner (female sex worker in this case) should squat and squeeze with vaginal muscles to remove excess semen, then wash their vulva, anus and surrounding areas with soap and water immediately, to reduce the risk of acquiring an sti including hiv.45 inserting an applicator full of spermicide into the vagina as soon as possible is highly recommended. the spermicide in the applicator will help eliminate some of the organisms causing stis. females are warned against performing a douche because washing the inside of the vagina can alter the useful bacteria that protect the vagina from infection, and further push any sperm and bacteria into the cervix, thus increasing the chances of unwanted pregnancies and the transmission of hiv and stis.45 after these required immediate actions, female sex workers are advised to visit a clinic or their doctor for further support. immediately after exposure according to the survey, a third of the respondents continued their sexual encounter to the end, even after noticing that the condom had broken. this situation constitutes a very high-risk sexual activity, for both parties involved, as they are unaware of each other’s hiv status. based on biomedical evidence and calculations, the risk of hiv infection is determined by the number of hiv-infected partners, the efficiency of hiv transmission and the number of unprotected sex acts with each hiv-infected partner.5 inconsistent condom use, the length of working hours in the sex industry, a higher number of clients and high rates of condom failure are identified as proxy markers to the risk of hiv acquisition. consequently, continuing a sexual encounter with a client after the condom has broken or slipped off is similar to having unprotected sex with the client. therefore, the chances of contracting hiv, according to the biomedical formula, increases. another third of the population reported that they stopped immediately after noticing that the condom had broken or slipped and that they put on a new condom to continue the sexual encounter to the end. although this is better than the first option of continuing the sexual encounter in spite of the condom breaking or slipping, it still carries some elements of risk because of the prior mixing of the biological fluids. participants reported that they stopped the sexual encounter completely when they realised that the condom was broken or had slipped out during the sexual encounter. while this is identified as the best measure to prevent the spread of hiv and other stis in the case of condom failure, it should be recognised that stopping the sexual encounter entirely at this stage is greatly influenced by the sex worker–client power dynamics. when a sex worker feels that they are in control of the situation, they could stop the sexual encounter completely and explain to the clients about the risks involved in continuing with the sexual activity. conversely, if the sex worker feels less in control and intimidated by the client considering that she already has collected the clients’ money, the situation is left to the client’s discretion. this situation is potentially precarious because there is a high chance that the client will opt to continue the sexual encounter without any condom. this possibility is substantiated by a large number of studies portraying clients’ resistance to using condoms during the sexual transaction,9,46 supported by their willingness to pay more for unprotected sex.5 according to gould and fick,47 the demand for unprotected sex by clients creates most of the significant problems of sex workers. gay et al.48 reported that most violence perpetrated on sex workers by their clients is based on their refusal to comply with the clients’ demands for unprotected sex, and up to a third of street-based sex workers have reported being raped by their clients. therefore, violence or fear of violence has a role to play in determining what the sex workers do when faced with a situation of condom failure with a client. a few of the participants revealed that they apply vaginal spermicidal foam after noticing that the condom had broken or had slipped off, while others said that they stopped immediately and took a douche. a survey, which was done among brothel and non-brothel-based sex workers, revealed that over 90% of sex workers washed their vagina with water mixed with dettol® or soda or turmeric after sex with their clients.49 this is a common practice among sex workers. although, these practices could prevent sex workers from becoming pregnant, they might not be effective in preventing the transmission of the hiv virus and other stis. on the contrary, taking a vaginal douche with hygienic substances eliminates the protective bacteria and alters the vaginal ph, thus exposing the vaginal lining to easy viral transmission. martino and vermund50 explained that the normal acidity of the vaginal environment can partly inactivate the hiv virus, which means that altering this ph level would expose the individual to various stis including hiv. consequently, the risk of contracting hiv after performing these acts remains higher, as the basis of these actions are at best myths. those who said they took other measures than those suggested in the questionnaire indicated that they took the morning-after pills. some people believe that taking a birth control pill could prevent them from contracting hiv. according to wilton, ‘the evidence, investigating the link between hormonal contraceptives and hiv transmission is inconsistent and limited’.51 nevertheless, research shows that the progesterone contained in the birth control pills can increase the chances of contracting hiv in two ways. firstly, it is suggested that progesterone can cause changes to the vaginal lining (decrease the thickness), which may increase a woman’s susceptibility to hiv infection. research also shows that progesterone can increase the amount of virus (or viral load) in the vaginal fluid of women living with hiv, increasing their chances of transmitting hiv to others.48 within the next 24 hours the responses offered by the sex workers in this category represent their actions within the next 24 hours after a condom failure incident. the most popular response from the study participants indicated that the participants did nothing after the incident of condom failure with a client. although it is unclear why they do nothing at all, a reasonable assumption is that they do not actually know what to do or where to go in situations of condom failure constituting high-risk exposure to hiv and other stis. although interventions to prevent hiv among sex workers have shown some success, they have had little impact on hiv transmission dynamics because they are implemented on very small scale, that most sex workers who need the prevention services do not have them available.6 in a study conducted by parry et al.,52 they uncovered that many of the sex workers in cape town know about the treatment for hiv but they did not know where to go to get access to the antiretroviral medication. this is supported by gay et al.48 who noted that most prevention interventions targeting sex workers focus on condom use and that just a few have advocated for sex workers to have equal access to antiretroviral medication. they also noted that sex workers have faced many of barriers to accessing healthcare. according to scheibe et al.,53 discrimination, stigma and violence by police officers, clients, healthcare service providers, family members and community members have adverse impacts on the health and well-being of sex workers and thereby increases their vulnerability to hiv. insensitive health workers might cause sex workers to avoid health facilities.54 sex workers may have difficulties accessing both, post-exposure prophylaxis and legal services in situations of rape.48 these barriers could adversely impact on the health service–seeking behaviours of sex workers. three per cent of the respondents indicated that they indulged in the use of drugs (including alcohol, hormones and imageand performance-enhancing drugs) to forget about the incident that took place with the client. the association between alcohol use and sexual risks among female sex workers has been established.55 in addition, there is evidence that alcohol use by female sex workers and their clients can present problems for safer sexual and social interactions, which might lead to difficulty using condoms.56 although the sex workers were aware of the dangers they faced with condom failure with a client, they indulged in drugs and alcohol to forget about the incident. sex workers have reported using alcohol and other drugs to lower inhibitions and give them the courage they need to approach the clients.52 nevertheless, as revealed by some of the sex workers in this study, those who had developed drug and alcohol dependency had the propensity to use these substances to drown their worries and escape from the reality of their problems. thus, according to chen et al.,55 alcohol use in commercial sex should be considered an occupational hazard that requires immediate intervention. notwithstanding, a fair number of sex workers reported having attended a clinic (27%) and making use of the services of a professional (4%) within 24 hours of experiencing condom failure. this makes a total of 31% of the participants who displayed positive actions within the 24 hours following an experience with condom failure. this behaviour is also reported by richter, 57 who observed some positive attitudes of the sex workers towards healthcare services tailored to sex workers’ needs, such as sex worker consultation, peer education and empowerment initiatives. she explained that strategies to mitigate sex workers’ risk for hiv and ill health by ensuring access to proper and sensitive healthcare and education in rustenburg were successful. limitations on the study the snowball sampling method limits the possibility of generalising the research finding to the general population identified because it has a high possibility of producing biased samples.29 this method had its downfall in that generally, participants tend to refer only those who might have similar preferences, dislikes and behavioural patterns, thus the sample may include an over-representation of individuals with numerous social connections who share similar characteristics.58 another limitation of this study is related to the sample size. some potential problems with studies done on sex workers using self-administered questionnaires are that the respondents are likely to be biased when responding to questions on topics such as condom use and drug habits.59 to minimise the chances of this, the participants were reminded of the importance of responding to the questions with honesty and the promise of anonymity throughout the study. while the quantitative study could provide us with the spread of the problem, a qualitative study could provide us with participants’ perceptions and why they think and behave in a particular way with respect to the phenomenon in question.60 conclusion condom failure has always been found to coexist with condom usage and is often associated with condom use errors. this study explored what female sex workers do when a male condom fails during a sex act with a male client. meanwhile, some of the actions such as continuing the sexual act without a new condom, taking alcohol and drugs or doing nothing at all could expose the sex workers more to contracting hiv; other actions such as stopping the sexual completely, paying a visit to a nearby clinic or visiting a professional could be the difference between staying hiv-negative or becoming hiv-positive. unfortunately, many sex workers did nothing in the circumstance, avoiding seeking medical attention or specialised advice when they are faced with situations that increase their vulnerability to hiv. although the national sex worker hiv plan for 2016–2019 for south africa provides for the reduction of risk behaviours and the creation of an environment for sex work that is safe for sex workers and clients including the provision of pre-exposure prophylaxis (prep) medication for sex workers, there is a need to understand the actions of sex workers when faced with circumstances that predispose them to contracting hiv for successful programming. acknowledgements the author would like to acknowledge prof. jan du toit of the africa centre for hiv and aids management in stellenbosch university for his support in conducting this study. the author is grateful to the entire staff of the sweat for their support and also for providing their offices to conduct the study. the author thanks dr gordon isaacs of sweat for facilitating the process of obtaining the first participants for the study and leka asila alindekane for assisting with the data collection process. competing interests the author declares that he has no financial or personal relationships which may have inappropriately influenced him in writing this article. references world health organization. prevention and treatment of hiv and other sexually transmitted infections for sex workers in lowand middle-income countries: recommendations for a public health approach. geneva, switzerland: world health organization; 2012. shannon k, strathdee sa, goldenberg sm, duff p. global epidemiology of hiv among female sex workers: influence of structural determinants. lancet. 2015;385(1):55–71. https://doi.org/10.1016/s0140-6736(14)60931-4 ucsf, anova health institute, wrhi. south african health monitoring study (sahms), final report:the integrated biological and behavioural survey among female sex workers, south africa 2013–2014. san francisco, ca: ucsf; 2015. unaids, aphiaplus. hiv education and health 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principles and practice in the australian context. aust nz j publ health. 2007;31(4):388–389. https://doi.org/10.1111/j.1753-6405.2007.00097.x hiv 841 towards ‘men who have sex with men-appropriate' health services in south africa k b rebe,1 mb chb, fcp (sa), dtm&h, dip hiv man (sa); g de swardt,1 ba, mw; h struthers,1 mba; j a mcintyre,1,2 mb chb, frcog 1 anova health institute, johannesburg and cape town, south africa 2 centre for infectious diseases epidemiology and research, school of public health and family medicine, university of cape town, south africa corresponding author: k b rebe (rebe@anovahealth.co.za) health programming for men who have sex with men (msm) in south africa has been ignored or absent until fairly recently, despite this population being at high risk for hiv acquisition and transmission. anova health institute, with support from the us president's emergency plan for aids relief (pepfar)/united states agency for international development (usaid) and in collaboration with the south african national department of health, launched the first state sector msm-targeted sexual health clinic in 2010. the clinic has been successful in attracting and retaining msm in care, and lessons learned are described in this article. components contributing to the creation of msm-appropriate healthcare services are discussed. s afr j hiv med 2013;14(2):52-57. doi:10.7196/sajhivmed.841 until fairly recently, the healthcare needs of men who have sex with men (msm) have been under-researched and under-resourced in south africa (sa).1 this has occurred despite emerging local evidence confirming high rates of hiv among this key population. notwithstanding inclusion in the country’s previous national strategic plan for hiv and aids, stis and tb (2007 2011), services for msm were not scaled up nationally, although impressive strides have been made in some provinces such as the western cape and gauteng. evidence from modelling studies shows that in settings where concentrated hiv epidemics exist among key populations in countries with generalised heterosexual epidemics, failure to provide targeted and tailored hiv prevention and treatment programmes to key populations negatively affects hiv rates among the general population.2 msm in sa comprise of a diverse group of men who share only one behavioural commonality: they have sex with other men.3 many msm in sa do not identify with gay culture, which may be viewed as a eurocentric cultural construct often considered foreign and ‘un-african’.4 the behaviour of msm has, however, occurred across all cultures and all times, including in sa, and is therefore well described in african oral histories. colonial oppressors were largely responsible for the criminalisation of sodomy on the continent.5 homosexual activity in sa therefore often remains clandestine, with msm identifying as heterosexual and dismissive of westernised gay culture.3 this has implications for health messaging as non-gay-identifying msm are not targeted in either mainstream heterosexual or gay media platforms and remain invisible in healthcare settings. for multi-factorial reasons, msm are at particular risk for hiv acquisition and transmission.6 biologically, unprotected receptive anal sexual intercourse is about 16 times more likely to transmit hiv than unprotected vaginal sexual intercourse. 7 this is due to the friable nature of the rectal mucosa, which does not contain mucous-producing cells like the thicker, self-lubricating lining of the vagina. the vulnerability of msm is further increased by structural factors such as a lack of funding for msm-appropriate services, lack of specific skills training of health providers, and institutionalised stigma within the public healthcare sector. msm patients generally avoid being identified as msm, culminating in their elevated risk of hiv acquisition, transmission being overlooked, and a lack of counselling about the risks associated with unprotected anal sex.8 organisations such as the anova health institute, through it’s innovative health4men project, and the desmond tutu hiv foundation have been active in addressing these concerns in sa. in 2009 the anova health institute, with support from the us president's emergency plan for aids relief (pepfar)/united states agency for international development (usaid), launched the first state sector clinic dedicated to msm in the country. a further 6 sites have subsequently become operational across multiple provinces. invaluable lessons have been learned through this process, which will undoubtedly serve as a template for the ongoing expansion of such services.4 , 9-11 msm experience mainstream state sector healthcare services as unfriendly and prejudiced, which creates a barrier to accessing such services.12 many local healthcare centres have become friendly to women at the exclusion of men. women are a captive audience in these clinics, which they attend for antenatal care, childhood vaccinations, completion of children’s road-to-health growth charts and other services. clinics respond by improving their female-specific skills and services. it is not unusual to find most of the educational materials in hiv clinics focusing on issues such as breastfeeding and female contraception, thereby alienating hiv-positive men. other barriers to msm healthcare access include fears about confidentiality related to their hiv status and sexual behaviour. the local catchment area of primary healthcare services is also often problematic; msm who experience community-based stigma are unlikely to attend a clinic where they are known to other patients or staff members. for a health provision site to be considered msm-appropriate, a number of criteria need to be met. firstly, most msm require more than a friendly service (often incorrectly referred to as an msm-sensitised service); they expect competence regarding their specific sexual healthcare needs. services therefore need to be both sensitive and competent if they are to attract and retain msm in care.4 the ivan toms centre for men’s health (itcmh), a clinic of the anova health institute in partnership with the western cape department of health (doh) and funded by pepfar through usaid, was inaugurated in february 2010 in cape town. it has since provided care to over 3 800 msm. there are a few features which have contributed to the success of this clinic. there is buy-in and commitment by the provincial and national doh.13 the service is marketed as a sexual health clinic for men. it is neither an hiv nor an antiretroviral therapy (art) clinic, which means that patients in the waiting room cannot be identified as hiv-positive. approximately half of the clients in the cohort are hiv-positive and half of those are receiving art. other msm attend for hiv and sexually transmitted infection (sti) screening, syndromic sti management, counselling and other mental healthcare services, harm-reduction services for msm who use drugs, or for research and information purposes. this model assists in providing an enabling space that promotes feelings of anonymity regarding the reason for attendance, and allays fears of being identified as gay or hiv-infected when attending the clinic. clinic staff have received extensive sensitivity and competency training and are accepting of the diversity of msm. they have become accustomed to providing service to msm with either a feminine or masculine gender-identity, as well as to transgendered individuals. all staff are accustomed to referring to clients by their preferred name and pronoun (as opposed to their legal name). the scope of practice encompasses holistic sexual health, including sti and hiv prevention, diagnostic and treatment services, as well as in-house access to mental healthcare services provided by staff who have specific experience in providing such care to msm. staff have been intensely trained in the specific features of sexual health pertaining to msm. medical staff have an expert understanding of how sti presentations, diagnosis and management plans differ in msm, compared with heterosexual men. a good example is training in physical examination to detect and diagnose anal and pharyngeal presentations of stis. a package of care has been developed for the clinic and a clinical manual is available for guidance both in print format and online (http://www.anovahealth.co.za). 4 it is understood that clinics may not be able to provide an optimal level of msm healthcare due to resource constraints; therefore, a package of minimal and optimal services has been developed (see tables 1 3). some specific features of the itcmh that have worked well include the provision of msm-sensitive hiv screening. counsellors are trained to ask about male and female partners, to identify specific sexual behaviours and their risks (e.g. receptive unprotected anal intercourse), and to avoid adopting a hetero-normative attitude to counselling (such as asking an msm couple which is the man and which is the women in a relationship). msm are also encouraged to screen for hiv together with their partners.14 since msm are at an elevated risk of acquiring and transmitting hiv, prevention technologies assume particular importance. condoms, although generally available via the state, are mainly marketed through heterosexually-targeted campaigns that do not address the risks of unprotected anal sex. condom-compatible lubricant required for comfortable anal sex is largely unavailable. medical male circumcision is likely to fail to protect msm to the same degree as heterosexual men, which leaves a deficit of effective prevention interventions.15 available hiv-prevention resources that are evidence-based – such as condoms, lubricants, postand pre-exposure prophylaxis (pep and prep), and early treatment for positive msm – should be prominent at all msm-targeted sites. fig. 1. the ukwazana (getting to know each other) campaign. an example of hiv risk-reduction messaging designed to reach msm though township taverns/shebeens where msm congregate. fig. 2. an example of hiv risk-reduction messaging designed to reach gay-identified msm through gay-targeted publications (the pink press). marketing msm-appropriate services is challenging, especially in areas where msm do not disclose their sexual behaviours and remain hidden to the healthcare system. it has taken time for msm groups to develop trust in the clinic and the most effective marketing has occurred by word of mouth via clients who have had a positive health-affirming experience at the clinic. health4men employs peer educators, and key individuals in msm communities from specific geographical areas have been recruited as ambassadors for the programme. marketing and information, education and communication (iec) materials have been developed through testing with msm focus groups to ensure that the language is locally understood and contextually correct. health information, referral links and interactive questions and answers are also available from the health4men’s mhealth programme ‘health4men connect’ (h4m.mobi) and the programme’s website. the itcmh was followed by the launch of the simon nkoli centre for men’s health in soweto and, more recently, the khayelitsha male clinic (cape town), the zola and chiawelo clinics (both in soweto) and the yeoville clinic (central johannesburg). these sites have built on the evidence and experience gained from providing services at the itcmh. guidelines for the management of common msm health problems have been developed and packaged into an intensive training package, which can be delivered at healthcare facility level to improve staff attitudes and skills and better allow for the provision of non-judgemental, appropriate msm-targeted healthcare. over time, once enough state clinics have received such training, it is hoped that msm-specific healthcare services can be mainstreamed in 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[http://dx.doi.org/10.1136/sti.2008.031567] 4. de swardt g, rebe k. from top to bottom: a sex-positive approach for men who have sex with men – a manual for healthcare providers. johannesburg: anova health institute, 2010. http://www.anovahealth.co.za/resources/entry/toptobottom/ (accessed 22 apr 2013) 4. de swardt g, rebe k. from top to bottom: a sex-positive approach for men who have sex with men – a manual for healthcare providers. johannesburg: anova health institute, 2010. http://www.anovahealth.co.za/resources/entry/toptobottom/ (accessed 22 apr 2013) 5. delius p, glaser c. sex, disease and stigma in south africa; historical perspectives. african journal of aids research 2005;4:29-36. 5. delius p, glaser c. sex, disease and stigma in south africa; historical perspectives. african journal of aids research 2005;4:29-36. 6. baral s, sifakis f, cleghorn f, beyrer c. elevated risk for hiv infection among men who have sex with men in lowand middle-income countries 2000 2006. plos medicine 2007;4(12):1901-1911. [http://dx.doi.org/10.1371/journal.pmed.0040339] 6. baral s, sifakis f, cleghorn f, beyrer c. elevated risk for hiv infection among men who have sex with men in lowand middle-income countries 2000 2006. plos medicine 2007;4(12):1901-1911. [http://dx.doi.org/10.1371/journal.pmed.0040339] 7. baggaley r, white r, boily m. hiv transmission risk through anal intercourse, systematic review, meta-analysis and implications for hiv prevention. int j epidemiol 2010;39(4):1048-1063. [http://dx.doi.org/10.1093/ije/dyq057] 7. baggaley r, white r, boily m. hiv transmission risk through anal intercourse, systematic review, meta-analysis and implications for hiv prevention. int j epidemiol 2010;39(4):1048-1063. [http://dx.doi.org/10.1093/ije/dyq057] 8. carceres cf, konda k, segura er, lyerla r. epidemiology of male same-sex behaviour and associated sexual health indicators in lowand middle-income countries: 2003 2007 estimates. sex transmit infect 2008;84:i49-i56. [http://dx.doi.org/10.1136/sti.2008.030569.] 8. carceres cf, konda k, segura er, lyerla r. epidemiology of male same-sex behaviour and associated sexual health indicators in lowand middle-income countries: 2003 2007 estimates. sex transmit infect 2008;84:i49-i56. [http://dx.doi.org/10.1136/sti.2008.030569.] 9. rebe kb, de swardt g, pienaar d, struthers h, mcintyre j, eds. an african clinic providing targeted healthcare to men-who-have-sex-with-men. 18th international aids conference, july 2010, vienna. http://pag.aids2010.org/abstracts.aspx?aid=5583 (accessed 22 april 2013). 9. rebe kb, de swardt g, pienaar d, struthers h, mcintyre j, eds. an african clinic providing targeted healthcare to men-who-have-sex-with-men. 18th international aids conference, july 2010, vienna. http://pag.aids2010.org/abstracts.aspx?aid=5583 (accessed 22 april 2013). 10. rebe kb, struthers h, de swardt g, mcintyre ja. hiv prevention and treatment for south african men who have sex with men. s afr med j 2011;101(10):708-710. 10. rebe kb, struthers h, de swardt g, mcintyre ja. hiv prevention and treatment for south african men who have sex with men. s afr med j 2011;101(10):708-710. 11. de swardt g, rebe k, eds. msm in your pocket. 1st ed. johannesburg: anova health institute, 2010. http://www.anovahealth.co.za/resources/entry/msm_in_your_pocket/ (accessed 22 april 2013). 11. de swardt g, rebe k, eds. msm in your pocket. 1st ed. johannesburg: anova health institute, 2010. http://www.anovahealth.co.za/resources/entry/msm_in_your_pocket/ (accessed 22 april 2013). 12. parry c, peterson p, dewing s, et al. rapid assessment of drug-related hiv risk among men who have sex with men in three south african cities. drug alcohol depend 2008;1(95):45-53. [http://dx.doi.org/10.1016/j.drugalcdep.2007.12.005] 12. parry c, peterson p, dewing s, et al. rapid assessment of drug-related hiv risk among men who have sex with men in three south african cities. drug alcohol depend 2008;1(95):45-53. [http://dx.doi.org/10.1016/j.drugalcdep.2007.12.005] 13. south african national aids council (sanac). national strategic plan on hiv, stis and tb: 2012 2016. pretoria: sanac, 2012. http://www.doh.gov.za/docs/stratdocs/2012/nspfull.pdf (accessed 22 april 2013). 13. south african national aids council (sanac). national strategic plan on hiv, stis and tb: 2012 2016. pretoria: sanac, 2012. http://www.doh.gov.za/docs/stratdocs/2012/nspfull.pdf (accessed 22 april 2013). 14. stephenson r, sullivan p, salazar lf, gratzer b, allen s, seelback e. attitudes towards couples-based hiv testing among msm in three us cities. aids behavior 2011;15:s80-s87. [http://dx.doi.org/10.1007/s10461-011-9893-2] 14. stephenson r, sullivan p, salazar lf, gratzer b, allen s, seelback e. attitudes towards couples-based hiv testing among msm in three us cities. aids behavior 2011;15:s80-s87. [http://dx.doi.org/10.1007/s10461-011-9893-2] 15. lane t, raymond hf, dladla s, et al., eds. lower risk of hiv infection among circumcised msm: results from the soweto men's study. 5th international aids society conference on hiv pathogenesis, treatment and prevention, cape town, 2009. http://www.ias2009.org/pag/abstracts.aspx?aid=2185 (accessed 22 april 2013). 15. lane t, raymond hf, dladla s, et al., eds. lower risk of hiv infection among circumcised msm: results from the soweto men's study. 5th international aids society conference on hiv pathogenesis, treatment and prevention, cape town, 2009. http://www.ias2009.org/pag/abstracts.aspx?aid=2185 (accessed 22 april 2013). make up sept 2007 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s p r i n g 2 0 0 7 7 it was in 1983 that i received a call from a man named ruben sher at my rooms in jeppe street in johannesburg. we had spoken once previously when he was doing research on hepatitis b prevalence among gay men, and he was now contacting me about the mysterious ‘gay plague’ that was hitting gay men in america. it was a simple, straightforward call. he was pursuing his doctorate in virology, and since i had a large gay practice, he asked if i would help him conduct a prevalence study, collecting bloods and medical histories of many of my patients. we began the study, not certain exactly what we meant to be looking for. but two years later, when a commercial test did become available, we found that over 12% of the subjects were, in fact, hivpositive. ruben took this news as he would any other piece of distressing medical research: a thoughtfully furrowed brow, a slight shake of the head, following by a soft, exasperated ‘acch’. it was not so much the action of a steely-eyed researcher. there was an instinctive empathy, a sincerity, that preceded the inevitable rolling up of the sleeves. the call to get down to business; to get back to work. ruben was neither a fiery activist nor a hardened political creature, but somehow he managed to inhabit both of those worlds. one has to remember that back in the early ’80s, the hiv community was divided into two camps: the stone-jawed, robert gallo politicos on one side and the angry, confrontational act-up gays on the other. while i tended to fall into the latter, myself hiv-positive, ruben couldn’t understand all the fuss or lack of co-operation. ‘let’s just get down to work,’ he would persist, half-frustrated. ‘let’s just do it.’ and do it he so often did. during those years, ruben would drag me into the halls of the walter reid hospital in washington or to some top-level research conference, his hand outstretched like a battering ram to the likes of gallo, luc montangier, and others. he had what i would often call an ‘aggressive affability’. he was humble, everyone liked him, but he clearly wasn’t there to score points. ruben always had an agenda – sometimes large, sometimes to clarify a simple issue that confounded him. i remember back in 1985 going with ruben to a research lab in bethesda, maryland (i can’t recall which), where he simply dropped in, as for tea, and announced that he ‘really could use some htlv-3 culture’. the researcher, clearly off-footed, handed ruben a test tube sample, which he carried back to south africa – and right through customs – in his shirt pocket. as artless as all this might seem, ruben never ruffled any feathers. he used common sense and humility where others would confront or manoeuvre. to ruben, it didn’t matter if it was a gay issue, a black issue, or a rich/poor issue. the facts were clear. people were getting ill. people were dying. there was no need to argue. what do we do now? upon ruben’s passing, many in the media have christened him ‘mr aids’. it’s one of those dual-edged distinctions, particularly when for nearly 20 years it brought him more derision and frustration – from an unmoving government and, at times, his own medical colleagues – than respect. at the same time, there’s a strange tradition in the medical community: watching an elder colleague as the science progresses and proclaiming, in hushed tones, that they’ve somehow ‘lost it’. in looking at ruben’s slides from the ’80s (yes, slides, no powerpoint), it’s clear that in his simple educational message – condoms, test, treat – ruben really never lost it. it’s a message that’s just as urgent and relevant as ever, a chilling reminder of how far we have to go and how much we still have to learn. dennis sifris t r i b u t e remembering ruben sher make up sept 2007 11/21/07 10:13 am page 7 the editorial team of the southern african journal of hiv medicine recognises the value and importance of peer reviewers in the overall publication process – not only in shaping individual manuscripts, but also in shaping the credibility and reputation of our journal. we are committed to the timely publication of all original, innovative contributions submitted for publication. as such, the identification and selection of reviewers who have expertise and interest in the topics appropriate to each manuscript are essential elements in ensuring a timely, productive peer review process. we would like to take this opportunity to thank the following reviewers who participated in shaping this volume of the southern african journal of hiv medicine. we appreciate the time taken to perform your review(s) successfully. in an effort to facilitate the selection of appropriate peer reviewers for the southern african journal of hiv medicine, we ask that you take a moment to update your electronic portfolio on https:// sajhivmed.org.za for our files, allowing us better access to your areas of interest and expertise, in order to match reviewers with submitted manuscripts. if you would like to become a reviewer, please visit the journal website and register as a reviewer. to access your details on the website, you will need to follow these steps: 1. log into the online journal at https:// sajhivmed.org.za 2. in your ‘user home’ [https://sajhivmed.org. za/index.php/hivmed/ user] select ‘edit my profile’ under the heading ‘my account’ and insert all relevant details, bio statement and reviewing interest(s). 3. it is good practice as a reviewer to update your personal details regularly to ensure contact with you throughout your professional term as reviewer to the southern african journal of hiv medicine. please do not hesitate to contact us if you require assistance in performing this task. publisher: publishing@aosis.co.za tel: +27 21 975 2602 tel: 086 1000 381 mohendran archary pooja balani sanjay bhagani tom h. boyles nomathemba chandiwana matthew f. chersich admire t. chikandiwa jeane cloete kalysha closson richard court vivian cox lauren de kock nicole delahunt janan j. dietrich sipho dlamini thozama dubula jason ensor candice fick joel francis robert freercks nathan geffen louise gilbert paul a. goldberg kerry gordon siphamandla gumede kapila hari nadine harran lucas hermans andrew m. hill pauline howell leigh f. johnson suzanne johnson samanta lalla-edward shayne loubser thandinkosi e. madiba vuyolwethu magasana gloria d. maimela pino mavengere tammy meyers jade c. mogambery michelle a. moorhouse kagiso motse nicolette p. naidoo jeremy s. nel nobubelo ngandu adam nosworthy james j. cnuttall catherine orrell josephine otchere-darko shenaaz pahad faeezah patel oscar radebe mohammed s. rassool rachael rawlinson kevin b. rebe shobna sawry clara schutte geoff setswe sudhir sharma dennis sifris mark w. sonderup david c. spencer jonathan stadler david stead mohammed tikly julia turner brian van wyk francois venter michelle venter michelle viljoen marnie vujovic corinna m. walsh sean wasserman nicola wattrus nicola wearne michelle wong open accesshttp://www.sajhivmed.org.za page iii of iii reviewer acknowledgementpage 1 of 1 acknowledgement to reviewers https://sajhivmed.org.za https://sajhivmed.org.za https://sajhivmed.org.za https://sajhivmed.org.za https://sajhivmed.org.za https://sajhivmed.org.za mailto:publishing@aosis.co.za http://www.sajhivmed.org.za hiv 898 forum is option b+ the best choice? a coutsoudis, a goga, c desmond, p barron, v black, h coovadia department of paediatrics & child health, university kwazulu-natal, durban a coutsoudis, phd medical research council, pretoria a goga, fc (paeds) school of clinical medicine, university of the witwatersrand, johannesburg c desmond, phd school of public health, university of the witwatersrand, johannesburg p barron, ffch wits reproductive health and hiv institute, university of the witwatersrand, johannesburg v black, mb bch match, university of the witwatersrand, johannesburg h coovadia, md corresponding author: a coutsoudis (coutsoud@ukzn.ac.za) this article is reprinted from the lancet, with permission from elsevier: coutsodis a, goga a, desmond c, barron p, black v, coovadia h. is option b+ the best choice? lancet 2013;381(9863):269-271. [http://dx/doi.org/10.1016/s0140-6736(12)61807-8] the success of prevention of mother-to-child transmission (pmtct) programmes (options a and b) in middle-income countries, together with clinical trial data on antiretroviral (arv) treatment as prophylaxis, has emboldened un agencies to aggressively promote lifelong arvs for pmtct (option b+). unsubstantiated claims submit that option b+ is cost-effective at population-level, will protect hiv-negative male partners, improve maternal and infant health, and increase arv coverage. we provide counterfactual arguments about the ethics, medical safety, programme feasibility and economic benefits of option b+. option b+ offers no advantage to pmtct and there are social hazards associated with privileging pregnant woman for treatment over men and non-pregnant women, especially with the absence of data to suggest that discordant relationships are more frequent among pregnant women or that they contribute disproportionately to the horizontal hiv transmission. the benefits and safety of long-term arvs – including adherence and resistance – in mothers who do not need treatment for their own health, need to be considered, as well as, crucially, health service costs. the assumption that a decrease in efficiency caused by inappropriate targeting is compensated for by lower recruitment costs, is untested. lives could be saved instead with appropriately targeted interventions. countries should make individual decisions based on their hiv epidemiology, resources, priorities and local evidence. s afr j hiv med 2013;14(1):8-10. doi:10.7196/sajhivmed.898 advocacy of the extreme antiretroviral therapy (art) option b+ for pregnant women by some organisations and international agencies,1 , 2 particularly at the aids 2012 conference in washington dc, usa,3 with little consultation, debate and discussion, is worrying. supporters of option b+ argue that it is superior, owing to additional art coverage (because cd4 cell count results are not needed), additional maternal health benefits, and protection of discordant male partners. however, these benefits have not been validated due to the fast pace and single-mindedness of advocacy. the business case,2 which supports the use of option b+ in resource-limited settings, does not fully address four critical considerations: ethics, medical safety and benefits, programme feasibility, and economic concerns (table 1). table 1. summary of pmtct options and concerns with option b+ pmtct options option a mother • cd4 count ≤350 cells/μl: triple arvs starting as soon as diagnosed; continued for life • cd4 count >350 cells/μl: • antepartum: azt from 14 weeks’ gestation • intrapartum: single-dose (sd) nvp and azt + 3tc • postpartum: azt + 3tc for 7 days. infant • daily sd nvp for 6 weeks in non-bf infants or mother receiving art or until 1 week after all bf has stopped. option b mother • all pregnant women will be started on triple arvs regardless of cd4 cell count. • cd4 count ≤350 cells/μl: triple arvs will be continued for life • cd4 count >350 cells/μl: triple arvs will be started as early as 14 weeks’ gestation, continued intrapartum and through childbirth and stopped if not breastfeeding or continued until 1 week after cessation of all breastfeeding. infant • daily nvp or azt from birth to 4 6 weeks of age. option b+ mother • all pregnant women will be started on triple arvs regardless of cd4 cell count and this will be continued for life. infant • daily nvp or azt from birth to 4 6 weeks of age. • concerns with option b+ ethical • should pregnant women be prioritised for treatment for reasons other than the immediacy of their medical condition? • have the implications of introduction or exacerbation of intra-household and community tensions because of different treatment access been adequately considered? • should selective test-and-treat interventions be considered ahead of achieving universal access for patients with cd4 counts <350 cells/μl? • is it ethical to give women with high cd4 cell counts treatment for life without fully understanding the long-terms benefits and risks? • will the rollout of arvs for a selected group within the population compromise the provision of arvs for other groups who need it for their own health in resource-limited settings or settings with drug-supply restrictions? medical • are there benefits for mother-to-child transmission and long-term infant hiv-free survival? • are the benefits for maternal health worth the potential increase in drug resistance? • will long-term exposure to arvs in mothers reduce horizontal transmission and change the trajectory of the hiv epidemic? • do we have enough evidence to suggest that pregnant women and new mothers are a risk group who have discordant relationships and contribute to the hiv epidemic? programmatic • can b+ be implemented in strained health systems without disruption of the introduction of treatment programmes? • will the implementation of b+ need scarce resources such as personnel, laboratory support and drugs to be diverted from the drive towards universal access to hiv treatment or universal access to treatment for other non-hiv life-threatening conditions or infectious diseases? • will the necessary levels of adherence be maintained? economic • is the assumption valid that economies of scope will favour this 3-in-1 intervention (i.e. pmtct, treatment and treatment-as-prevention)? • if retention rates are not high, will the economic argument in favour of b+ be invalid? options a, b and b+ have similar protective benefits with respect to the prevention of mother-to-child transmission (pmtct) of hiv.4 , 5 data suggest that triple art may provide maternal health benefits even up to cd4 cell counts of 600 cells/μl,5 , 6 and that it reduces hiv transmission between discordant couples.7 however, these data alone do not justify favouring pregnant woman for treatment over men and non-pregnant women. if option b+ is used because it may decrease mortality and disease progression in hiv-infected mothers with cd4 counts >350 cells/μl, then the justification should extend to the families, partners, friends and community of the pregnant women, and the whole hiv-infected population. the application of different treatment thresholds in sub-populations could create tensions between people with and those without access to treatment. if option b+ is a phase-in of a universal test-and-treat goal, then this should be made explicit, and the ethics of early treatment initiation in the context of unmet need warrant discussion. option b+ is being considered only in resource-limited settings with a high hiv burden, to target pregnant women for non-pregnancy-related interventions such as treatment-as-prevention and early treatment initiation. there are no data to suggest that pregnant women have above-average involvement in discordant relationships or that pregnant women contribute disproportionately to the horizontal transmission of hiv. the medical benefits and safety of long-term antiretrovirals (arvs) need to be considered, including adherence and resistance, in sub-populations of mothers and infants who do not need treatment for their own health. for example, increased exposure to art, as will be experienced with options b or b+, may increase adverse pregnancy outcomes such as pre-term delivery and low birth weight.8 in resource-limited settings this may increase risk for infant death. increased exposure to tenofovir may also increase potential for renal toxicity in mothers9 and poor growth outcomes in infants.10] additionally, option b+ is costly, owing to the need for additional drugs, laboratory tests, human resources and other health-system expenditures. furthermore, experience of option b+ is restricted to malawi and rwanda; this is insufficient to measure universal feasibility. the success of option b+ depends on the retention of women in treatment programmes, which increases pressure on already strained health systems.11 , 12 recent data show that adequate adherence drops from 75.7% (95% ci: 71.5 79.7%) during pregnancy to 53% (95% ci 32.8 72.7) postpartum among women who meet present art criteria.13 the public health implications (including resistance and potential for future treatment) of reduced adherence in options b and especially b+ are unknown and likely to be concerning. finally, although higher treatment thresholds may be necessary, particularly in regions with high fertility rates, it is unclear whether universal provision of art for pregnant women only is appropriate. the business case for option b+ assumes that economies of scope are generated by implementation of the triple combination of pmtct of hiv, treatment and treatment-as-prevention. if each intervention were to be introduced separately, except for pmtct, then the targeting of pregnant women only would not be appropriate. the recommendation of option b+ is based on the untested assumption that the decrease in efficiency caused by inappropriate targeting is compensated for by lower recruitment costs. similar to the economic analysis of test-and-treat,14 small changes to assumptions, particularly relating to retention, have large implications. indeed, if the scope assumptions are incorrect, option b+ will cost lives, which could have been saved with appropriately targeted treatment and treatment-as-prevention. advocacy is critical, and reliance only on what has been scientifically proven would result in slow progress. however, with so many unknowns, the strong push for countries to switch to option b+ is premature. a switch now would be dangerous, ignoring severe ethical, safety, feasibility and economic concerns. countries should make their own decisions based on their local situation, resources, priorities and evidence. international agencies should guide, but not pressure, ministries into making decisions, particularly where evidence is weak. a clear decision-making process is essential. acknowledgements. this article is reprinted from the lancet, with permission from elsevier: coutsodis a, goga a, desmond c, barron p, black v, coovadia h. is option b+ the best choice? lancet 2013;381(9863):269-271. [http://dx/doi.org/10.1016/s0140-6736(12)61807-8] conflict of interest. ac is a member of the protocol team of the promise study, which is investigating the research questions associated with option b v. option a. hc has received funding for breastfeeding research from the welcome trust and nih. other authors declared no conflicts of interest. references 1. world health organization hiv/aids programme. use of antiretroviral drugs for treating pregnant women and preventing hiv infections in infants. executive summary. geneva: who, 2012. http://www.who.int/hiv/pmtct_update.pdf (accessed 8 october 2012). 1. world health organization hiv/aids programme. use of antiretroviral drugs for treating pregnant women and preventing hiv infections in infants. executive summary. geneva: who, 2012. http://www.who.int/hiv/pmtct_update.pdf (accessed 8 october 2012). 2. unicef. a business case for options b and b+ to eliminate mother to child transmission of hiv by 2015. a discussion document for the global steering group presented by the business leadership council and unicef, in collaboration with the clinton health access initiative. new york: unicef, 2012. http://eptctasiapacific.org/content/business-case-options-b-and-b-eliminate-mother-child-transmission-hiv-2015-model-methodology (accessed 3 october 2012) 2. unicef. a business case for options b and b+ to eliminate mother to child transmission of hiv by 2015. a discussion document for the global steering group presented by the business leadership council and unicef, in collaboration with the clinton health access initiative. new york: unicef, 2012. http://eptctasiapacific.org/content/business-case-options-b-and-b-eliminate-mother-child-transmission-hiv-2015-model-methodology (accessed 3 october 2012) 3. aids 2012. washington dc. july, 2012. http://aids2012.org/webcontent/file/aids2012_plenary_media_ release_25_july_2012_en.pdf (accessed 8 october 2012) 3. aids 2012. washington dc. july, 2012. http://aids2012.org/webcontent/file/aids2012_plenary_media_ release_25_july_2012_en.pdf (accessed 8 october 2012) 4. shapiro r, hughes m, oguwa a. antiretroviral regimens in pregnancy and breast-feeding in botswana. n engl j med 2010;362(24):2282-2294. 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[http://dx.doi.org/10.1097/qad.0b013e328352d135] 10. siberry g, williams p, mendez h, et al.; pediatric hiv/aids cohort study (phacs). safety of tenofovir use during pregnancy: early growth outcomes in hiv-exposed uninfected infants. aids 2012;26(9):1151-1159. [http://dx.doi.org/10.1097/qad.0b013e328352d135] 11. rosen s, fox m, gill c. patient retention in antiretroviral therapy prorams in sub-saharan africa: a systematic review. plos med 2007;4(10):1691-1701. [http://dx.doi.org/10.1371/journal.pmed.0040298] 11. rosen s, fox m, gill c. patient retention in antiretroviral therapy prorams in sub-saharan africa: a systematic review. plos med 2007;4(10):1691-1701. [http://dx.doi.org/10.1371/journal.pmed.0040298] 12. unge c, södergård b, marrone g. long-term adherence to antiretroviral treatment and program drop-out in a high-risk urban setting in sub-saharan africa: a prospective cohort study. plos one 2010;5(10):1-12. [http://dx.doi.org/10.1371/journal.pone.0013613] 12. unge c, södergård b, marrone g. long-term adherence to antiretroviral treatment and program drop-out in a high-risk urban setting in sub-saharan africa: a prospective cohort study. plos one 2010;5(10):1-12. [http://dx.doi.org/10.1371/journal.pone.0013613] 13. nachega j, uthman o, anderson j, et.al. adherence to antiretroviral therapy during and after pregnancy in low-, middleand high-income countries: a systematic review and meta-analysis. aids 2012;26(16):3039-3052. [http://dx.doi.org/101097/qad0b013e328359590f] 13. nachega j, uthman o, anderson j, et.al. adherence to antiretroviral therapy during and after pregnancy in low-, middleand high-income countries: a systematic review and meta-analysis. aids 2012;26(16):3039-3052. 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[http://dx.doi.org/10.1371/journal.pone.0041212] abstract introduction objectives research design and methodology findings discussion conclusions acknowledgements references about the author(s) barbara a. hanrahan department of nursing, university of the witwatersrand, south africa adri williams edupark, polokwane, south africa citation hanrahan ba. williams a. prevention of mother-to-child transmission of hiv guidelines: nurses’ views at four primary healthcare facilities in the limpopo province. s afr j hiv med. 2017;18(1), a690. https://doi.org/10.4102/sajhivmed.v18i1.690 original research prevention of mother-to-child transmission of hiv guidelines: nurses’ views at four primary healthcare facilities in the limpopo province barbara a. hanrahan, adri williams received: 05 sept. 2016; accepted: 25 apr. 2017; published: 28 june 2017 copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: when new guidelines for existing programmes are introduced, it is often the clinicians tasked with the execution of the guidelines who bear the brunt of the changes. frequently their opinions are not sought. in this study, the researcher interviewed registered nurses working in the field of the prevention of mother-to-child transmission (pmtct) of human immunodeficiency virus (hiv) to gain an understanding of their perspectives on the changes introduced to the guidelines. the guideline changes in 2014 were to move from the world health organization (who) option b to option b + which prescribes lifelong antiretroviral therapy (art) for all hiv-positive pregnant women regardless of cd4 cell count. objective: to determine what the registered nurses’ perspectives are on the pmtct programme as implemented at four phc facilities in the limpopo province. method: for this qualitative investigation, a descriptive research design was implemented. the data were collected during semi-structured interviews with nurses from four primary healthcare facilities in the limpopo province of south africa. data were analysed using thematic analysis. results: challenges preventing effective implementation (e.g. increased workloads, viz. staff shortages; poor planning of training; equipment and medication shortages and long lead times; poor patient education) were identified. conclusion: in spite of the successes of the pmtct programme, considerable challenges still prevail; lack of patient education, poor facilities management and staff shortages could potentially influence the implementation of the pmtct guidelines negatively. introduction background and literature review frequently, policy is determined by committees removed and distant from the actual sites of implementation, that is, a top-down approach. on the other hand, policy may be determined by the eventual beneficiaries, that is, a bottom-up approach. however, bhuyan, jorgensen and sharma1 recommend including more role players, that is, ‘moving away from top-down or bottom-up dichotomies to a centrist approach emphasising how actors from different institutional contexts influence what gets implemented’. in the context of this research, the focus was on inputs gleaned from the perceptions of registered nurses (rns) in the community-based health service. the study was conducted on the implementation of the south african prevention of mother-to-child transmission (pmtct) of human immunodeficiency virus (hiv) guidelines. the focus was on the evaluation of the implementation of the pmtct guidelines, from the perspective of rns within the context of primary healthcare (phc) facilities. the provision of antiretroviral therapy (art) is an important part of the strategy to manage hiv infection. the guideline changes were announced in july 2014, published in december 2014 and implemented in january 2015.2,3 these changes were authorised for implementation for specific groups, for example, pregnant and breastfeeding women; infants and early adolescents; and late adolescents and young adults. the changes to the pmtct programme prescribe that all hiv-positive women who are pregnant, breastfeeding or who are within one year postnatal are immediately initiated on lifelong art – regardless of their cd4 cell count. art is often initiated by a registered or phc nurse, and this is known as nurse initiated and managed antiretroviral therapy (nimart).4 nimart is credited for distinct benefits, such as earlier, quicker patient uptake with improved patient retention, enhanced patient outcomes, greater access to care (especially for those in rural communities) and reduced travel expenses to patients.5 the effectiveness of this programme depends on various factors as shown in other studies. in a study executed in uganda, the challenges experienced during the implementation of the pmtct programme were investigated.6 the study concluded that there was a lack of infant testing and early diagnosis, patients’ non-adherence to medical instructions, staff shortages, inadequate facilities and equipment that impede the implementation of the programme. in a study in mozambique, it was found that the integration of the pmtct programme, voluntary counselling and testing (vct) and highly active antiretroviral therapy (haart) services caused an increase in the duty burden of the nurses, resulting in a staff shortage. it was also found that the nurses lacked cultural sensitivity, which made patient education ineffectual – which in turn led to the impairment of the implementation of the various programmes.7 a third study in kwazulu-natal, south africa, focused on the implementation of programmes implemented at 27 phc sites (peri-urban and rural).8 it found that the pmtct programme had shown significant improvements and achieved high coverage of interventions during pregnancy and delivery, but coverage of interventions for infants remained poor. many phc facilities had designated health workers for the pmtct programme, but fragmentation of services created challenges with regard to patient access. the fourth study was conducted in eastern cape and in gauteng to evaluate health system weaknesses in accessing pmtct services in south africa.9 the study revealed weaknesses within the implementation of the programme such as shortages in staff, shortages of supplies, delayed hiv testing and treatment, delayed payment to lay hiv counsellors, delays in the receipt of laboratory results and the initiation of antiretroviral (arv) therapy. a lack of healthcare worker education and fragmentation of services also caused delays in hiv diagnosis and care.9 it is clear from the abovementioned studies that existing information is outdated because of the changes that have taken place in the pmtct guidelines, and does not reflect the quality of the programme from the perspective of nursing responsibilities. objectives the study’s main aim was to determine what the rns’ perspectives are on the pmtct programme as implemented at four phc facilities in the limpopo province in order to discover whether any improvements could be suggested to guide management in its strategies to provide quality pmtct healthcare service. research design and methodology this study followed the format of a qualitative, descriptive research design. the data were collected during semi-structured interviews using an interview guide. open-ended questions were used, followed by more targeted open-ended probe questions.10 the study sites were purposively selected, and four phc facilities in the polokwane district, of the limpopo province, were chosen. these sites were chosen because they were easily accessible and considered safe to access. the four sites each serve the general population in polokwane, as well as villages in the district and serve approximately 5000 patients per month (i.e. individual patients visited these phc facilities for all the various services provided, not only for pmtct services). the sites that were visited included three remote sites, varying in services that are available to the areas’ patients. polokwane is the capital of the limpopo province and the selected facilities are typical phc facilities in the district. a pilot study was undertaken before implementing the final research. the interview guide was tested on a small sample of five participants and resulted in a few small adjustments to the interview protocols. the sample for the study was purposively selected and participants were chosen based on the inclusion criteria.11 twenty-one participants (n = 21) were identified and interviewed until data saturation was reached (table 1). it was decided that data saturation occurred when the same responses were recorded 10 times. the sample size constituted approximately 40% of all the available registered nursing staff members across all four facilities. included in the study were rns with at least one years’ experience in pmtct implementation, who agreed to participate in the study. the interviews were then conducted and data were collected in july 2014. the audio recordings with their accompanying field notes were transcribed, and the data from the interviews were analysed using thematic analysis.12 table 1: the demographic data of participants (n = 21) in a qualitative study of the prevention of mother-to-child transmission programme in the polokwane district. the trustworthiness and credibility of the research was accomplished by prolonged engagement, referential adequacy and member checks with the participants to ensure the correct interpretation. to ensure dependability and confirmability, a subject specialist from the department of health (doh) and social development in limpopo province was consulted to audit the study. a clearance certificate (m131164) to conduct the study was obtained from the university of the witwatersrand human research ethics committee (medical), as well permission from the limpopo doh and social development, and the ceo of the polokwane/mankweng hospital complex. all participants provided written informed consent. findings demographic data the demographical data of the participants are depicted in table 1. to record and analyse the perspectives of the registered nurses on the successes on the implementation of the national prevention of mother-to-child transmission guidelines the majority (n = 16) of the participants were of the opinion that the pmtct programme is working effectively, and half (n = 8) of them thought that there is now an earlier antenatal-booking trend amongst patients. the term ‘early booking’ refers to when a patient first seeks healthcare during her pregnancy. hiv-positive women are then initiated on art on the same day, regardless of their gestation or cd4 cell count. it is pertinent that the majority (n = 15) of the participants were of the opinion that there is a decreased rate in positive polymerase chain reaction (pcr) rates in infants at the time of the study. in limpopo, a decline was shown in the mother-to-child transmission of hiv (mtct) rates for the period 2013/14 where the transmission rates for infants (at 6–8 weeks) was 2.3%.13 five of the participants (n = 5) viewed the education of the staff members as a contributing factor to the successes of pmtct, as was their effective teamwork (n = 7) and positive attitude and commitment (n = 6). a substantial number (n = 19) of participants verbalised that they have updates on the pmtct programme, as well as the pmtct policies and guidelines, available to them. other factors were also mentioned: nurses felt that they educated patients and that their effective communication with the patients and the doh (monthly site visits from the doh delegate) were key in the success of the pmtct programme. to record and analyse the perspectives of the registered nurses on the challenges on the implementation of the national prevention of mother-to-child transmission programme guidelines four main themes under challenges were identified, namely: ‘staffing’, ‘late bookings’, ‘patient education’ and ‘resources’. under ‘staffing’, the main challenge that was experienced was staff shortages because of various reasons, such as a general nursing shortage (n = 7) and a time-consuming programme (assessing patients) (n = 5). other challenges were that participants were not given advance notice of planned continuous education (n = 3). even though a majority of participants (n = 19) were of the opinion that they received the necessary timely updates on the pmtct guidelines, there were a few participants who felt that they did not receive regular continuous education from the doh (n = 3). the second theme under challenges was ‘late bookings’. there were participants who felt that there are prevailing problems when it came to the timing of patients’ booking for antenatal care. some of the participants felt that human migration contributed to a late booking tendency (n = 10), and others believed that patients’ cultural convictions (n = 7) prevented them from seeking care early in pregnancy. the participants also thought that teenagers (n = 6) were less likely to seek antenatal care early in pregnancy. the last contributing factor to late bookings that was identified by the participants as a lack of support systems (n = 5) and that patients who do not have a supportive family or community around them tend to book later for pmtct care. the third theme ‘patient education’ indicated that there were challenges that could be linked to the patients’ misconception or misunderstanding of hiv, hiv treatment and the general intention of pmtct. some of the participants were of the opinion that patients still experienced a fear of being stigmatised (n = 6) by their communities and denied their hiv status. two participants commented that patients did not adhere to the treatment that was prescribed and that patients experienced information overload (n = 2) when diagnosed. participants also experienced language as a barrier (n = 2) when interacting with immigrant patients, and some of the participants felt that patients did not breastfeed exclusively, and mixed the feedings (n = 2). other patient education issues discussed by the participants included the following: patients did not follow-up or were late in following up on testing of their infants at 18 months (n = 1) and that traditional remedies (n = 1) are still being used in conjunction with art. the fourth theme identified under challenges was ‘resources’ and could be classified as facility management problems. a number of participants felt that there were general equipment shortages (n = 4). the nurses also felt that their facilities were in a state of disrepair (n = 3). other challenges experienced were medication shortages (n = 2) and overdue blood results (n = 1). the third main finding identified is ‘possible solutions’ there are four themes under ‘possible solutions’. the first theme, ‘staffing’ indicated that participants felt that the nursing shortage can be addressed by the recruitment of more staff members (n = 5). advance notice of upcoming training (n = 1) and employing limited-period contract nurses (n = 1) in the phc facilities in the event that permanent nurses are assigned for extended periods of training, also featured. the second theme is ‘education’. participants (n = 8) thought that national campaigns using the media (radio, television and billboards) could address both late bookings and the lack of patient knowledge. participants (n = 6) also felt that involving the communities – for example, during imbizos (or community meetings) – in educational campaigns could address the lack of knowledge on hiv and hiv treatment and improve the general understanding of the objectives of the pmtct programme. in addition to these suggestions, the participants (n = 6) also felt that school education programmes could help solve the late booking tendencies amongst pregnant teenagers. the third theme is ‘immigration: home affairs and stakeholders’. the participant who suggested this felt that the department of home affairs could convene stakeholder meetings to address late bookings because of human migration (immigration), by educating immigrants on the importance and availability of antenatal care. theme four ‘computer database’ was identified when a participant recommended that a national computer database could streamline appointments and facilitate patient follow-up regardless of where they might relocate. other participants (n = 4) were of the opinion that the employment of tracing teams could help locate patients who do not follow-up with pmtct care or could actually find pregnant women who are not seeking antenatal care. discussion this study found, according to the perceptions of the nurses working at the implementation level of the pmtct guidelines, that the pmtct programme is effective and that there is a definite tendency of pregnant women to report earlier for antenatal care. the pmtct programme has made significant advances and is available at approximately 98% of the phc facilities across the country. importantly, according to the participants, fewer hiv-positive infants are born. with the steady increase in mothers taking part in the programme, the south african mtct rates have dropped significantly to 1.3% in 2014.3 this supports the participants’ opinions. nurses feel that their education and commitment is instrumental in the success of the pmtct programme. the study found that an overwhelming number of the participants agreed that they had received the necessary timely education (n = 5), support manuals and guidelines from the doh (n = 19) to implement the pmtct programme. a few participants (n = 3) did, however, mention that they did not receive regular continuous education on the pmtct programme from the doh. this could suggest fragmentation of learning scheduling at either the doh or the phc facility level. however, in spite of the efficacy of the programme, the participants were of the opinion that their patients and the communities they come from have a significant lack of knowledge where it pertains to hiv and hiv treatment. this lack of understanding prevented women from seeking care earlier in pregnancy and reduced their adherence to the prescribed treatment. therefore, it was concluded that communities in the limpopo province still need more education on hiv, hiv treatment and the pmtct programme. with the increased burden of nimart, nurses feel overwhelmed at times, having to spend a great deal more time per patient. there is an increased work burden, but no additional support is given. this staff shortage could lead to longer waiting periods for patients at phc facilities and decreased morale amongst staff members. in this study, it was found that 19% of the nurses were already at the generally accepted retirement age, and 38% of the nurses will be at retirement age in under 10 years. according to sanc,14 18% of rns in south africa are at retirement age (60 years to > 69 years), and 30% are close to retirement age (50 years to 59 years). more overwhelmingly, only 5% of rns nationally are under the age of 30 years; that is, the cadre of younger nurses is alarmingly small (figure 1). figure 1: age distribution of registered nurses in south africa in december 2016. it is clear that the nursing population at the sites studied is aging, and this could be a contributing factor to the nursing shortage currently experienced at these phc facilities. in this study, the participants stressed that the ineffective management of facilities, dilapidated buildings and shortages of working equipment could lead to protracted patient visits. according to ho,15 this particular problem is also relevant in the mpumalanga province (gert sibande district) where buildings and facilities are inadequate, unhygienic and unsafe, resulting in substandard patient care. rutter16 also referred to the mounting evidence of inefficiencies and undignified conditions patients in the free state are subjected to. the findings of the people’s commission of inquiry into the free state healthcare system, indicate that facilities are often in disrepair and equipment broken or unavailable. the facility management challenges seem to be a countrywide problem and do not only influence the implementation of the pmtct programme but other healthcare programmes as well. during the interviews, participants were asked how they would address the challenges that they experienced. a general idea that emerged from this study is that the communities around the polokwane district needed more education and that this could be addressed by launching more national and community campaigns to increase adherence to the pmtct programme and encourage earlier bookings. it was also found that the participants believed the nursing shortage could be addressed by staff recruitment and the implementation of support services like tracing teams. limitations data were only collected at four phc facilities in the polokwane district of the limpopo province. because of the small sample size, it will not be possible to generalise conclusions to all phc facilities in the limpopo province, and these conclusions may not be applicable to all south african phc facilities. the language barrier was partly addressed by the use of a fieldworker who was able to assist in the clarification of any questions and responses of the participants and the researcher. this was accomplished by communicating in the mother tongue of the participants. in some cases, however, it appeared that the participants comprehended the questions fully but, on analysing the responses, some doubt may be cast on this assumption. during data analysis, it became evident that the fieldworker had simplified some of the questions to the effect that the questions were not as open-ended as originally intended. this may have limited the participants’ responses. managerial suggestions several suggestions flowed from this study: research could be done on the intake of new nurse trainees who are supposed to supplement and eventually replace the aging nursing population in south africa. this could render a better explanation for the current reasons for the nursing shortage in south africa and possibly discover ways to encourage young school leavers to choose nursing as a career. further research is suggested to ascertain workload (nurse–patient ratios) at phc facilities in the limpopo province. it is unclear whether these ratios are monitored, which prompts the researcher to propose this recommendation. this will ensure that nurses are not overburdened and, where needed, that more staff appointments could be made. it may also be considered to develop individual staff members within the aegis of personal and professional practice to potentially balance the stress of perceived staff shortages. a continued, increased effort from the doh should be made to increase the south african citizens’ knowledge on the hiv and pmtct by initiating national, community and school campaigns. on a more practical and selective level, the researcher saw the need for more personalised patient education. patients should be issued with a ‘take-home’ information booklet by the nurses. this booklet should contain general information on hiv (emphasising the importance of viewing hiv as a chronic medical problem), the patient’s treatment regimen how to correctly take medication, as well as how to improve health and well-being. this information booklet could be a useful tool in supporting and educating patients and their immediate family members and may combat information overload and confusion. clinic facilities, that is, buildings and equipment should be improved. the sites visited were in a state of disrepair and needed improvement and regular maintenance (as mentioned by the participants). this could be addressed by training the facility managers, as well as conducting an audit of the infrastructure that could reveal the extent of the maintenance required to repair those buildings that are in disrepair. another audit is recommended to highlight the essential equipment that should be acquired in order to reduce patient waiting times. advance notice of training from the doh should be ensured, and nurse managers at the sites should communicate effectively with personnel to ensure that the staff members are informed of the planned training dates. pmtct training requires frequent updated training and this should feature in the in-service and development plan each facility compiles annually. the implementation of a national computer database is suggested to ensure a better monitoring system. this will eliminate the unnecessary repetition of tests and treatment of migrating patients, resulting in a reduction of costs and ensuring that there is an accurate audit trail on all known patients throughout south africa. this will also ensure a reduction of ‘loss to follow-up’ because of the improved patient tracking and tracing. this will require a significant financial investment in a real-time computer documentation system, so that information is directly available to any nimart practitioner at any given time. conclusions mtct rates have dropped significantly to 1.3% in 2014.2 in spite of the successes of the pmtct programme, considerable challenges still prevail; lack of patient education, poor facilities management and staff shortages could potentially influence the implementation of the pmtct guidelines negatively. the findings and commentary in this study call for further research about the perspectives of nurses on the pmtct policies and guidelines, as well as other national healthcare guidelines which could result in policy changes and improvements on a national level. national policy and guideline committees need to take cognisance of the suggestions made by the healthcare workers on the ground. this requires a commitment to change management in order to accept the views expressed by the nurses working at the proverbial coalface. acknowledgements competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions a.w. has completed an msc in nursing at the university of the witwatersrand in august 2016. she did the research, data analysis and the compilation of the research dissertation. b.a.h. is a supervisor and nursing lecturer at the university of the witwatersrand, and she was the supervisor of a.w. during the entire course of this study. references bhuyan a, jorgensen a, sharma s. taking the pulse of policy: the policy implementation assessment tool. washington, dc: future group, health policy initiative, task order 1; 2010. peteke m. dealing with hiv the smart way. nursing update. the magazine for the caring profession. denosa. 2015; p. 20–21. south africa department of health. national consolidated guidelines for the prevention of mother-to-child transmission of hiv (pmtct) and the management of hiv in children, adolescent and adults. pretoria: government printer; 2014. cameron d, gerber a, mbatha m, mutyabule j, swart h. nurse initiation and maintenance of patients on antiretroviral therapy: are nurses in primary care phc facilities initiating art after attending nimart training? s afr med j. 2012;102(2):98–100. https://doi.org/10.7196/samj.5195 davies necg, homfray m, venables ec. nurse and manager perceptions of nurse initiated and managed antiretroviral therapy (nimart) implemented in south africa: a qualitative study. bmj open access [serial on the internet]. c2013 [cited 2015 may 7]. available from: http://www.bmjopen.bmj.com nuwagaba-biribonwoha h, mayon-white rt, okong p, carpenter lm. challenges faced by health workers in implementing the prevention of mother-to-child hiv transmission (pmtct) programme in uganda. j public health. 2007;29(3):269–274. https://doi.org/10.1093/pubmed/fdm025 agadjanian v, hayford sr. pmtct, haart, and childbearing in mozambique: an institutional perspective. springerlink [serial on the internet]. c2009 [cited 2012 june 2]; 13(1):103–112. available from: http://link.springer.com/article/10.1007/s10461-009-9535-0 horwood c, haskins l, vermaak k, phakathi s, subbaye r, doherty t. prevention of mother to child transmission of hiv (pmtct) programme in kwazulu-natal, south africa: an evaluation of pmtct implementation and integration into routine maternal, child and women’s health services. trop med int health. 2010;15(9):992–999. https://doi.org/10.1111/j.1365-3156.2010.02576.x sprague c, chersich mf, black v. health system weaknesses constrain access to pmtct and maternal hiv services in south africa: a qualitative enquiry. 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treatment action campaign & section27. rutter l. free state province: is there any hope left? 14th ed. p. 42–47. johannesburg: treatment action campaign & section27. abstract introduction acute kidney injury and chronic kidney disease tenofovir disoproxil fumarate-associated nephrotoxicity risk factors for tenofovir disoproxil fumarate-associated nephrotoxicity diagnosis of acute kidney injury management of acute kidney injury conclusion acknowledgements references about the author(s) michael t. boswell department of medical immunology, university of pretoria, south africa nuffield department of medicine, university of oxford, united kingdom theresa m. rossouw department of medical immunology, university of pretoria, south africa citation boswell mt, rossouw tm. approach to acute kidney injury in hiv-infected patients in south africa. s afr j hiv med. 2017;18(1), a714. https://doi.org/10.4102/sajhivmed.v18i1.714 overview approach to acute kidney injury in hiv-infected patients in south africa michael t. boswell, theresa m. rossouw received: 09 dec. 2016; accepted: 14 july 2017; published: 28 nov. 2017 copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: hiv-infected patients have an increased risk of renal disease. current first-line antiretroviral therapy contains tenofovir disoproxil fumarate (tdf), which has nephrotoxic potential, characterised by proximal tubular cell injury. this may result in acute kidney injury, chronic kidney disease or partial or complete fanconi syndrome. objectives: we reviewed the existing literature on acute kidney injury and tdf-associated nephrotoxicity with the aim of providing an approach to diagnosis and management, which is relevant to a general medical practitioner. methods: we performed a broad literature search of biomedical databases including pubmed and sciencedirect. our search terms included, but were not limited to, ‘tenofovir’, ‘nephrotoxicity’, ‘hiv’, ‘acute kidney injury’ and ‘renal tubular acidosis’. our aim was not to generate a systematic literature review with weighted evidence, but rather to provide a review of best practice from a variety of sources. where published studies were not available from the above databases, we relied on relevant textbooks and professional guidelines. results: potential nephrotoxicity is not an impediment to the widespread use of tdf in treating hiv infection, because most patients will tolerate the medication well. however, patients with advanced disease, low body weight, advanced age, pre-existing kidney disease and concomitant use of other nephrotoxic medications are at increased risk of adverse renal events and may develop severe complications if not appropriately managed. these risk factors are unfortunately common in patients initiating antiretroviral therapy in south africa. conclusion: prevention of renal damage by means of careful screening and monitoring of high-risk patients is of paramount importance. increased awareness of this problem and knowledge of how to manage kidney disease should be emphasised for general medical practitioners who work with hiv-infected patients. introduction hiv is south africa’s leading health problem. approximately 7 million people are thought to be hiv-infected and the prevalence is increasing because of improved life expectancy on combination antiretroviral therapy (art).1 current estimates suggest that approximately 3.4 million south africans are receiving art, and this number is expected to increase dramatically with the country adopting the 2015 world health organization (who) guidelines recommending that all hiv-infected patients receive art regardless of cd4 count. because of constraints on resources, the options available for art in the public health services are relatively limited. the national department of health recommends a first-line regimen consisting of a nucleotide/nucleoside reverse transcriptase inhibitor (ntrti/nrti) backbone together with efavirenz, with the backbone consisting of a combination of tenofovir disoproxil fumarate (tdf) and lamivudine (3tc) or emtricitabine (ftc). one major concern regarding such widespread use of tdf is nephrotoxicity. this article gives an overview of the causes and management of renal dysfunction in hiv-infected patients, with special emphasis on acute kidney injury (aki) and tdf-associated nephrotoxicity. our aim is to provide primary healthcare practitioners with a working system for managing aki in the context of hiv. acute kidney injury and chronic kidney disease hiv infection is associated with an almost four-fold increased risk of renal disease, attributable to a variety of causes of aki as well as chronic kidney disease (ckd).2 the most common causes are summarised in table 1.11 aki can be caused by pre-renal (haemodynamic alterations), renal (nephritis, nephrosis, tubulopathies and necrosis) and post-renal (crystal nephropathy) factors. in hiv-infected patients, acute tubular necrosis (atn) secondary to hypotension or sepsis is the most common cause of aki, with who stage iv disease, low cd4 counts and hypoalbuminaemia all associated with higher mortality.3 many commonly used medications have nephrotoxic potential (table 2)12, varying from predictable, cumulative dose-dependent nephrotoxicity to idiosyncratic dose-independent toxicity, or both.4 table 1: common causes of acute kidney injury and chronic kidney disease in hiv-infected patients. table 2: medication with nephrotoxic potential. acute kidney injury (aki) is defined as an increase in serum creatinine by 26.5 mmol/l within 48 h; or an increase in serum creatinine to 1.5 times baseline, which is known or presumed to have occurred within the prior seven days; or a urine volume < 0.5 ml/kg/h for 6 h (this can, however, also occur with fluid restriction in the absence of aki).5 some studies have shown that complete recovery of renal function occurs in only 59% of hiv-infected patients presenting with aki, with 2% of patients progressing to end-stage renal disease (esrd).3 in practice, it may be difficult to distinguish aki from ckd at presentation, because multiple biochemical abnormalities are common to both entities, including electrolyte abnormalities and proteinuria. chronic kidney disease is defined as abnormalities of kidney structure or function, present for at least three months, with implications for health. classification is based on cause, glomerular filtration rate (gfr) and albuminuria category.6 aki is a significant risk factor for the development of ckd and vice versa. a common feature is the disruption of normal renal architecture in the setting of a variety of adaptive immunological or vascular events, the interactions of which determine recovery or decline of renal function. a full discussion of the spectrum of ckd associated with hiv infection is beyond the scope of this article. both aki and ckd are associated with cardiovascular disease, which has become a leading cause of morbidity and mortality in hiv-infected populations.7 hiv-infected patients are known to be at increased risk of cardiovascular disease because of increased prevalence of traditional risk factors (e.g. smoking, hypertension and dyslipidaemia), direct viral effects, chronic inflammation and art use.8 tdf is especially important in this regard because it can decrease gfr and impair the activation of vitamin d in the renal proximal tubules, leading to vitamin d deficiency. both decreased gfr and vitamin d deficiency have been associated with increased cardiovascular risk.9,10 tenofovir disoproxil fumarate-associated nephrotoxicity the proximal tubular cells of the kidney are especially vulnerable to potential tdf toxicity because their unique cell membrane transporters promote entry of the drug into the cells.14 in addition, limited anaerobic adenosine triphosphate-generating capacity makes these cells vulnerable to mitochondrial dysfunction.15 even though tdf is considered a weaker inhibitor of mitochondrial dna polymerase γ than the nrtis, the main pathophysiological mechanism underlying tdf nephrotoxicity appears to be mitochondrial damage.16 the proximal tubules are responsible for most of the tubular transport of molecules such as glucose, activation of 25-dihydroxycholecalciferol and release of ammonia necessary for proton secretion into the urine by distal segments. mitochondrial damage will therefore negatively impact molecular transport and vitamin d activation, as well as urinary acidification.14 the resultant features include low serum levels of uric acid, phosphate and bicarbonate, together with high urine levels of glucose, low-molecular-weight proteins (e.g. β2-microglobulin), uric acid or phosphorus.14 the clinical spectrum of tdf-associated proximal tubular dysfunction is shown in table 3.17 table 3: spectrum of tenofovir disoproxil fumarate-associated proximal tubular dysfunction. pharmacokinetic studies have shown a correlation between exposure to higher tdf concentrations and an increased risk of ckd over time. two possible mechanisms contributing to increased tdf levels have been suggested: (1) polymorphisms in genes coding for cellular transport mechanisms may promote the accumulation of tdf in tubular cells and (2) decreased excretion brought about by low gfr may increase tdf plasma concentrations.18,19 tdf-induced renal toxicity may manifest as aki, ckd or proximal tubular injury, including fanconi syndrome, isolated hypophosphataemia and decreased bone mineral density.20,21,22 proximal tubular dysfunction may result in an increase in serum creatinine in the absence of aki because of a decrease in excretion of creatinine by this segment of the nephron.23 the risk for aki on tdf therapy has been estimated to be approximately 1% in clinical trials and almost 2% in cohort studies. a recent meta-analysis found a significantly faster loss of kidney function in patients receiving tdf compared with controls.24 most studies have, however, not found a significantly higher risk of proteinuria, ckd or esrd requiring dialysis, and the above meta-analysis did not find an increased risk of hypophosphataemia, decreased bone mineral density or bone fractures in patients on tdf.24,25,26,27 the authors concluded that the overall risk was modest and it supported the routine use of tdf in settings where appropriate monitoring was available. on a cautionary note, however, the meta-analysis mostly included patients from resource-rich countries with advanced medical systems and early initiation of art. this is attested to by the fact that the median cd4 count was 364 cells/µl. in addition, the studies excluded patients with advanced disease and medical comorbidities and are therefore unlikely to accurately reflect the reality in sub-saharan africa, where late presentation and advanced disease at the time of art initiation are still the norm.28 as a result of the complex pathologies present in advanced hiv, it is often very difficult to discern a single cause for aki in many patients. a recent study in south africa showed an incidence of renal impairment of a little below 3% during the first 12 months of tdf-containing art in primary care populations,29 while another south african study of patients hospitalised with aki reported tdf therapy to be associated with more rapid worsening of renal function, a higher likelihood of proteinuria and acidosis, and delayed renal recovery.30 the latter study highlights the poor prognosis of aki in hiv-infected individuals in the context of limited access to renal replacement therapy, as more than a quarter of the patients in this cohort died.30 risk factors for tenofovir disoproxil fumarate-associated nephrotoxicity the main risk factors for tdf nephrotoxicity include pre-existing renal impairment, older age, low body weight, advanced hiv disease (low cd4 count or aids), comorbidities (especially diabetes, hypertension and hepatitis c co-infection), concomitant use of nephrotoxic drugs and protease inhibitors.14,23,31 countries in sub-saharan africa can expect to experience a large proportion of patients in whom the above-mentioned risk factors are present at art initiation. a significant proportion of patients are underweight28,32 and a recent review of patients initiated on art in south africa between 2010 and 2014 reported a median cd4 count of only 213 cells/µl (interquartile range (iqr) 117–324 cells/µl).33 in addition, cryptococcus neoformans is the leading cause of meningitis in south africa, with the consequence that many patients will receive amphotericin b.34 the large number of patients co-infected with mycobacterium tuberculosis may also contribute to increased risk because of rifampicin-related nephrotoxicity and interstitial nephritis induced by immune reconstitution inflammatory syndrome.30 tenofovir disoproxil fumarate-associated nephrotoxicity generally, manifests within the first 3 to 9 months of treatment35,36,37 but a progressive decrease in egfr has been demonstrated up to five years on art, especially in patients with low body weight.31 serum creatinine in the first four months of art has a low predictive value for a change in egfr after a year on art29 and it is therefore essential that renal function in patients on tdf be monitored over the long-term. questions remain about the ideal timing and tests to be used. diagnosis of acute kidney injury early detection of nephrotoxicity and withdrawal of offending drugs are key to avoiding irreversible renal damage.14 it is, however, equally important to remember that tdf is not the only cause of renal disease and that failure to consider other causes may result in a missed opportunity for the diagnosis of a significant underlying condition requiring intervention.38 initial evaluations, which may be used to determine whether tdf nephrotoxicity is present, include the following: serum urea, electrolytes, creatinine and egfr serum calcium, magnesium and phosphate urine phosphate and urea (if possible, fractional excretion of phosphate should be done as it is a more accurate measurement of proximal tubular function) spot urine protein to creatinine ratio urine dipstick for glycosuria. the aim of these investigations is to give an indication of the extent of renal damage, as well as to differentiate between glomerular and tubular dysfunctions. glomerular dysfunction presents with proteinuria with or without haematuria and is usually an indication of hiv-related renal disease (e.g. hiv-associated nephropathy [hivan]) or other chronic diseases, such as diabetes mellitus. drug toxicity commonly presents with tubular dysfunction characterised by glycosuria, hyperphosphaturia and hypophosphataemia. isolated haematuria is often indicative of an extra-renal problem with pathology localised to the ureter, bladder or prostate.38 because the effect of tdf on glomerular function is believed to be mild, measuring only egfr and albuminuria is not an appropriate screening strategy and is unlikely to detect early tdf nephrotoxicity. the presence of tubular proteinuria is thought to be the most sensitive test for proximal tubule dysfunction, and a spot urine protein to creatinine ratio or the urinary retinol-binding protein to creatinine (rbp:cr) ratio has been suggested as a useful marker and screening tool for tdf-associated tubular toxicity.23,39 further validation of the latter test is needed, and until it is routinely available, measuring the spot urine protein to creatinine ratio or less sensitive, but well-established, markers of proximal tubule dysfunction, such as increased fractional excretion of phosphate and glycosuria, are the most appropriate alternatives. all patients should have an egfr calculated before initiation of any art. patients with an egfr > 60 ml/min do not warrant further investigation and can be monitored routinely. patients with the above risk factors should, however, receive closer monitoring for tdf nephrotoxicity, as demonstrated in the proposed algorithm in figure 1.23 it should be kept in mind that egfr calculated by means of the modification of diet in renal disease (mdrd) or cockcroft–gault formula may underestimate the degree of renal dysfunction if a patient’s muscle mass is lower than the age and sex standards,40 in which case a 24-h urine specimen for creatinine clearance calculation would be more appropriate. the ckd-epi equation has been proposed as a replacement to the mdrd formula because of its greater accuracy in estimating gfr.41 figure 1: algorithm for initiation of tenofovir disoproxil fumarate and monitoring of tenofovir disoproxil fumarate-associated nephrotoxicity. should multiple risk factors for tdf toxicity be present in a patient, closer monitoring may be desirable. management of acute kidney injury the specific cause and clinical context of the patient determines the management of aki. a general approach, based on the kdigo 2012 aki guidelines,5 is shown in figure 2.5 three common clinical scenarios can be foreseen, which are discussed below. figure 2: algorithm for management of acute kidney injury, based on the kdigo 2012 acute kidney injury guidelines. patients not yet on antiretroviral therapy who present with acute kidney injury patients with aki should be evaluated promptly to determine the cause, with special attention to reversible causes, and the need for renal replacement therapy must be assessed. hospitalisation will frequently be required and, where available, specialist referral is advised.5 patients should be managed according to stage and cause and assessed after three months to determine if the aki has resolved or progressed to ckd. in patients with pre-existing ckd, a 3-month follow-up is used to monitor for further deterioration in renal function. initiation of art should be deferred until aki has resolved with creatinine clearly on a downward trend and an egfr suitable for the selected art.42 should a patient have aids, cd4 count < 50 cells/µl or severe hiv-related disease such as thrombotic thrombocytopaenic purpura, initiation of art may be the overriding therapeutic goal even if aki has not yet resolved. in such cases, the patient should preferably be discussed with a specialist and art be restricted to non-nephrotoxic drugs, for example, abacavir (abc), provided that the pre-treatment viral load (vl) is below 100 000 copies/ml; zidovudine (azt), provided that the patient is not anaemic; or, alternatively, as a short-term option, stavudine (d4t).42 patients who have been initiated on tenofovir disoproxil fumarate and now have acute kidney injury current local guidelines recommend that tdf be substituted when a patient’s egfr is < 50 ml/min (calculated using either the cockcroft–gault formula or the mdrd formula).42 in patients with aki, dosages of nrtis and some other commonly used drugs should be adjusted based on egfr (table 4).42,45,46 tdf should be interrupted even if it is not thought to be the cause of aki and substituted with an alternative nrti. once there is clear evidence that renal function is improving (creatinine on downward trend), nrti dosages should be readjusted to standard dosages to avoid under-dosing.42 we recommend that additional screening should be undertaken to evaluate proximal tubule function and exclude renal fanconi syndrome. in addition, if no reversible cause for aki is identified, it is reasonable to assume that tdf is the cause and it should be either discontinued or monitoring increased as appropriate. table 4: medication adjustments in acute kidney injury and/or chronic kidney disease. tenofovir disoproxil fumarate may be continued in patients with chronic hepatitis b infection at a reduced dose (see package insert) because of the risk of a hepatic flare on withdrawal of the drug.42 however, if renal function declines on tdf or if there is severe dysfunction, then it is reasonable to replace tdf with an alternative nrti and continue 3tc monotherapy, with or without pegylated interferon-α, for the management of hepatitis b.42 assessment of hepatitis b surface antigen is therefore mandatory in all patients before tdf is discontinued and patients testing positive should be maintained on renally adjusted doses of tdf if possible (table 4). reassuringly, patients who had their art changed from tdf to an alternative nrti because of nephrotoxicity showed high rates of recovery of renal function.43 those who discontinued tdf were more likely to regain renal function compared to those who reinitiated tdf and there were no differences in virological outcomes between study groups. patients initiated on tenofovir disoproxil fumarate with biochemical or clinical features of tenofovir disoproxil fumarate nephrotoxicity but preserved glomerular filtration rate subclinical tubular dysfunction is much more common than overt renal failure, but the long-term significance for kidney function and bone health is uncertain. in such cases, it may be reasonable to discontinue tdf and replace it with an alternative nrti such as abc. however, substituting tdf should be balanced not only against the increase in pill burden caused by providing an alternative art regimen which is not available in a fixed, single dose combination, but also against the cost to the health sector. if a patient requires other potentially nephrotoxic medication such as aminoglycosides or amphotericin b, tdf should be replaced with abc, azt or d4t to avoid precipitating severe aki. tdf can then be reinstituted on cessation of the nephrotoxic agent.44 conclusion hiv-infected patients have a greatly increased risk of renal disease, a situation that is exacerbated by the frequent use of potentially nephrotoxic medication. appropriate screening and monitoring of renal function in all hiv-infected patients is therefore essential. considering that south africa has limited capacity to care for patients with esrd, managing other conditions which are known to cause aki and ckd, such as hypertension and diabetes mellitus, is of paramount importance. lack of integrated care and limited access to non-hiv-related medication in art clinics result in many hiv-infected patients needing to attend multiple clinics, adding considerable cost and inconvenience to both patients and the health sector. fragmented care also leads to duplication of tests, as well as the possibility of polypharmacy and prescription errors. the lack of definitive care for patients with esrd in south africa means that only approximately 10% of those who would benefit from dialysis are receiving this therapy47 and as noted by moosa et al.:11 the current stark reality in sa and many developing countries is that most people with eskd [end-stage kidney disease] and hiv die as a result; some have limited access to dialysis. most clinicians deal with advanced stages of ckd in hiv and prevention or early detection of renal disease in this population is neglected. primary healthcare practitioners need a working system for screening, early detection and referral. 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https://doi.org/10.4172/2155-6113.1000379 kenyon c, wearne n, burton r, meintjes g. the risks of concurrent treatment with tenofovir and aminoglycosides in patients with hiv-associated tuberculosis. s afr j hiv med. 2011;12(1):43–45. https://doi.org/10.4102/sajhivmed.v12i1.214 who. companion handbook to the who guidelines for the programmatic management of drug-resistant tuberculosis. geneva: world health organization; 2014. (who/htm/tb/2014.11). rossiter d, editor. south african medicines formulary. 12th ed. cape town, (western cape, south africa): health and medical publishing group; 2016. gerntholtz t, paget g, hsu p, meyers am. management of patients with chronic kidney disease. s afr med j. 2015 mar;105(3):237. article information authors: michelle moorhouse1 linda g. bekker2 vivian black1 francesca conradie3 beth harley4 pauline howell5 gary maartens6 tari papavarnavas7 kevin rebe8 gillian sorour9,10 francois venter1 carole l. wallis11,12 affiliations: 1wits reproductive health and hiv institute, johannesburg, south africa 2the desmond tutu hiv centre, university of cape town, south africa 3right to care and clinical hiv research unit, university of witwatersrand, south africa 4city health, city of cape town, south africa 5wits health consortium, university of witwatersrand, south africa 6department of medicine, university of cape town, south africa 7helen joseph hospital, right to care, south africa 8anova health institute, johannesburg, south africa 9gauteng department of health, gauteng, south africa 10president's emergency plan for aids relief, wits reproductive health & hiv institute, south africa 11barc, johannesburg, south africa 12lancet laboratories, johannesburg, south africa correspondence to: michelle moorhouse email: mmoorhouse@wrhi.ac.za postal address: 22 esselen street, hillbrow, johannesburg 2001, south africa how to cite this article: moorhouse m, bekker lg, black v, et al. guideline on the management of occupational and non-occupational exposure to the human immunodeficiency virus and recommendations for post-exposure prophylaxis: 2015 update. s afr j hiv med. 2015;16(1), art. #399, 14 pages. http://dx.doi.org/10.4102/sajhivmed.v16i1.399 note: this guideline was compiled by the southern african hiv clinicians society. disclaimer: specific recommendations provided here are intended only as a guide to clinical management, based on expert consensus and best current evidence. treatment decisions for patients should be made by their responsible clinicians, with due consideration for individual circumstances. the most current version of this document should always be consulted. update of: bekker lg, black v, myer l, et al. guideline on safer conception in fertile hiv-infected individuals and couples. s afr j hiv med. 2011;12(2), art. #196, 14 pages. http://dx.doi.org/10.4102/sajhivmed.v12i2.196 copyright notice: © 2015. the authors. licensee: aosis openjournals. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. guideline on the management of occupational and non-occupational exposure to the human immunodeficiency virus and recommendations for post-exposure prophylaxis: 2015 update in this guidelines... open access • abstract • key summary points    • clinical approach    • drug selection    • public health issues • introduction • scale of the problem • core principles of post-exposure prophylaxis    • balancing risks and benefits in post-exposure prophylaxis • prevention of exposure    • prevention of hiv exposure in the workplace • special situations: healthcare situations • other situations    • sexual exposure outside of a relationship, where disclosure concerning the exposure is not desired    • children • selecting patients for antiretroviral interventions    • potentially infectious material    • selecting antiretroviral regimens for post-exposure prophylaxis       • recommended post-exposure prophylaxis antiretroviral regimen       • justification for three versus two drugs and for choice of antiretrovirals preferred for post-exposure prophylaxis       • justification for choice of antiretrovirals preferred for preferred for post-exposure       • justification for duration preferred for post-exposure • routine baseline and follow-up investigations    • investigating the source individual       • hiv testing       • hiv and hepatitis b virus testing       • hepatitis c virus testing       • other blood-borne pathogens    • investigating the exposed individual       • hiv testing       • hepatitis b testing       • hepatitis c virus testing       • other blood-borne pathogens       • sexually transmitted infections       • pregnancy       • tetanus    • follow-up: monitoring for adverse drug reactions       • side-effects       • comorbidities       • medical comorbidities and antiretroviral selection for preferred for post-exposure       • drug safety in pregnancy    • key issues regarding counselling       • adherence       • anxiety management       • risk-taking interventions • acknowledgements    • competing interests    • authors’ contributions • references abstract top ↑ this guideline is an update of the post-exposure prophylaxis (pep) guideline published by the southern african hiv clinicians society in 2008. it updates the recommendations on the use of antiretroviral medications to prevent individuals who have been exposed to a potential hiv source, via either occupational or non-occupational exposure, from becoming infected with hiv. no distinction is made between occupational or non-occupational exposure, and the guideline promotes the provision of pep with three antiretroviral drugs if the exposure confers a significant transmission risk. the present guideline aligns with the principles of the world health organization pep guidelines (2014), promoting simplification and adherence support to individuals receiving pep. key summary points top ↑ southern africa differs from other regions, particularly in terms of very high hiv and hepatitis b virus (hbv) seroprevalence. post-exposure prophylaxis (pep) guidelines lack a substantive evidence base to guide advice. it is unlikely that this will change considerably, as randomised studies of different drug regimens for pep are not feasible owing to the complexity of exposure, low event rate, and inability to ethically have a placebo group. evolving basic science understanding, along with further studies on animals and prevention of mother-to-child transmission (pmtct) findings, will continue to guide policy makers. in addition, data from pre-exposure prophylaxis (prep) studies will also provide valuable data relevant to pep interventions. pep guidelines prior to the southern african hiv clinicians society's 2008 pep guideline were not user friendly and rarely acknowledged the complex range of situations that occur with hiv. selecting patients for appropriate pep administration must be simplified. algorithmic approaches for antiretroviral treatment (art) regimens have simplified antiretroviral management at the treatment and management levels. the same approach is possible for pep regimens in this region. the approach to occupational, sexual and other forms of hiv exposure (bites, assaults, trauma, injecting drug use, etc.) is similar. cases of exposure are often not simple, do not lend themselves to simple categorisation, and require an individualised approach. however, concepts to guide the attending clinician are relatively simple and allow an effective intervention in most cases. clinical approach animal data, case control studies and pmtct data suggest that pep is highly effective if taken correctly for the full duration prescribed. similarly, prep studies have indicated that, with high levels of adherence, prep is a highly effective intervention in the prevention of hiv transmission. the key outcome in hiv pep is successful completion of one month of uninterrupted appropriate prophylaxis. side-effect management is critical to completion, and is often under-managed. zidovudine (azt) and protease inhibitor (pi)-based regimens are associated with significant side-effects, and are therefore not preferred drugs in pep regimens, except in special circumstances. the number of drugs used to treat pep is often the focus of clinician attention. whilst number of drugs and specific antiretroviral (arv) prescribing are important, completing the full course, through active side-effect and anxiety management, remains the cornerstone of successful management. side-effects owing to art appear to be more common and severe in hiv-negative exposed people than in hiv-positive patients initiated on treatment, especially amongst healthcare workers (hcws). there have been few documented failures of pep. many of these failures have been associated with poor adherence, suboptimal dosing or delayed art. anxiety management of the exposed individual must be actively addressed. drug selection where art is felt to be justified, a three-drug regimen should be used. however, this must never be at the expense of adherence. singleor dual drug regimens are known to be effective and can be used as an alternative where necessary (e.g. to increase adherence when a three-drug regimen is not well tolerated). the preferred nucleoside reverse transcriptase inhibitor (nrti) backbone for pep is tenofovir (tdf) with lamivudine (3tc) or emtricitabine (ftc), preferably as a fixed-dose combination (fdc). the preferred third drug is raltegravir (ral). owing to a lack of safety data regarding the use of ral in pregnancy, atazanavir/ritonavir (atv/r) is the preferred third drug in pregnancy. azt-containing pep regimens are associated with significant side-effects, whereas stavudine (d4t) is well tolerated for short-term administration; in patients where tdf cannot be used, d4t should be given preferentially to azt. nevirapine (nvp) should never be used for pep owing to its potentially severe side-effects. boosted pis should be used in cases where arv resistance is suspected, with nrti choices based on medication to which the patient has not been exposed. expert guidance should be sought in these situations. hepatitis b prophylaxis, often not considered after hiv exposure, must form part of any assessment. follow-up must be actively pursued. advice on further hiv and hepatitis testing; when it is safe to commence unprotected sex; and subsequent primary prevention, are critical. post-exposure hiv status should be assessed through serial enzyme-linked immunosorbent assay (elisa) testing at 6 weeks and 3 months after exposure occurred. polymerase chain reaction (pcr) testing does not currently have a role in pep assessment. public health issues occupational exposure is usually avoidable. all cases should be investigated with a view to improving infection control. all health and allied institutions where exposure is an occupational risk should have clear, public and accessible pep protocols. hepatitis b vaccination programmes must be encouraged in all occupational health settings, as primary prophylaxis is very effective. introduction top ↑ in 2008, the southern african hiv clinicians society published guidelines on pep, which were bold, specifically with regard to three key recommendations: the removal of the distinction between occupational versus non-occupational exposure; the use of triple prophylaxis; and treatment for all exposures.1 these points were in contrast to all other international guidelines at the time, and in fact it is only in the latest world health organization (who) pep guideline that a similar approach to pep has been promulgated.2 the present guideline updates the recommendations on the use of antiretroviral medications to prevent individuals who have been exposed to a potential hiv source, via either occupational or non-occupational exposure, from becoming infected with hiv. as in the 2008 guideline, no distinction is made between occupational or non-occupational exposure, and the guideline promotes the provision of pep with three antiretroviral drugs if the exposure confers a significant transmission risk. there are strong recommendations with regard to the prevention of occupational exposure and the use of simplified approaches to pep, with an emphasis on managing both the anxiety of the exposed individual, as well as a pro-active approach to side-effect management. see table 1 for a summary of guideline recommendations. table 1: summary of guidelines on post-exposure prophylaxis for hiv in adults, adolescents and children. unfortunately, most of the data on which pep guidelines are based are from different settings to the southern african region, and are largely derived from non-randomised control trial (rct) data (except in the case of some of the pmtct studies and more recently, the prep studies). much of the data rely on retrospective register analysis, as well as extrapolation from animal data and individual clinical case studies. it is important to remember that these data from developed-world studies, where hiv epidemiology is significantly different and hiv prevalence considerably lower, may underestimate the risk of exposures in the southern african setting. however, due to ethical considerations and the numbers that would be needed to obtain rct data, in the context of the relatively low rate of transmission associated with occupational exposure (if all parenteral exposures are considered together, the transmission risk is 0.3% per exposure),3 we are unlikely to obtain much additional or quality ’pure pep’ data than what we currently have. in addition, prep studies consistently show that prep works when used properly, making it ethically questionable to conduct studies with pep as a sole prevention intervention. in fact, there is a shift towards combination approaches to the prevention of hiv infection, of which pep is only one component in a complex of prevention interventions. previous guidelines differentiated between occupational and non-occupational exposures. given the very high background prevalence of hiv infection in the southern african region, hiv exposure risk outside the occupational setting is high, and the distinction between occupational and non-occupational exposure is less helpful for decision-makers. further complicating the problem is the high rate of sexual assault in south africa, and the large number of individuals with acute or primary hiv infection within the community. the generalised nature of the epidemic creates differences in risk group demographics that must be accommodated by local pep guidelines. finally, ‘non-traditional’ exposures, such as pre-mastication, tattoos, cuts from roadside barber's shears and other exposures listed below, often require clinician advice. whilst the actual management of exposure is the same whether the exposure was occupational or non-occupational, it is essential to document and manage occupational exposures appropriately, for possible subsequent compensation (including completion of the appropriate compensation for occupational injuries and diseases act [coida] forms). this is also important in cases of sexual assault where legal and criminal proceedings may ensue. the present update to the pep guidelines seeks to harmonise with the who pep guidelines (2014) by alignment with who principles, and promoting simplification and adherence support to individuals receiving pep (see figure 1). the guidelines do not address pmtct settings, prep or the comprehensive management of sexual assault. local guidelines should be consulted as appropriate. figure 1: care pathway for individuals exposed to hiv. scale of the problem top ↑ about 3 million percutaneous exposures to bloodborne viruses occur globally amongst hcws annually. a survey of more than 2400 usa hcws showed that more than half had experienced a percutaneous injury in their career, and almost a quarter in the last year.4 a study in northern india demonstrated exceedingly high exposure rates, with 63% of participants reporting a percutaneous injury in the previous year, compared with the us data above.5 mucocutaneous and percutaneous exposures over the previous week in the indian study were reported at 11% and 30% respectively. these figures are not uncommon in lower income countries, with 55% of hcws in uganda and 57% of injection providers in mongolia experiencing a percutaneous exposure in the last year.6,7 data from the southern african region are limited and poor. the largest study from three west african countries documented that 45% of hcws had sustained at least one accidental blood exposure, over 60% of which went unreported.8 in 2001, 69% of interns at chris hani baragwanath hospital in gauteng, south africa, had sustained at least one percutaneous injury, and 45% had sustained a mucocutaneous blood risk exposure.9 again in this cohort, over 60% of exposures were not officially reported. at tygerberg hospital, cape town, 91% of junior doctors reported needlestick exposures in the prior year, three-quarters of these ‘after hours’ or during calls.10 despite regulatory frameworks being in place in some countries, management oversight regarding occupational accidental blood exposure is largely lacking in southern african institutions, especially as far as the handling of sharps disposal and training in safe exposure practices are concerned. in terms of non-occupational exposure, hiv transmission data for rape (a common experience for women, children and not a few men) are poor. there are almost no data on other forms of exposure; however, the continued high incidence and prevalence of hiv in southern africa amongst the general population suggests that exposure is ongoing and high risk. advice is frequently sought from clinicians regarding pep following assault, traffic accidents and other trauma-related events where blood exposure occurs. core principles of post-exposure prophylaxis top ↑ occupational exposure prevention requires strong management oversight in all settings. non-occupational exposure requires an understanding of core transmission principles, combined with clinical common sense. in the southern african setting, all unknown source exposures should be assumed to be hiv-positive. evidence regarding occupational and non-occupational risks of transmission for southern africa is limited, and may underestimate transmission risk in our setting. triple arv regimens in treatment settings have been proven superior to mono or dual therapy regimens. however, in the setting of pmtct and prep, mono and dual drug regimens have proven effective. it is recognised, however, that additional arvs increase the potential side-effect and adherence burden. risk of adverse effects and toxicities must be weighed against benefit in administering arvs in the pep setting. however, with increasingly well tolerated arvs that are available, side-effects are becoming less of a problem. nonetheless, side-effects must be treated rapidly, effectively and, where possible, avoided entirely. ensure that the individual is aware of potential side-effects and has been advised how to deal with any that may arise. patients should be advised that when in doubt they should rather see a healthcare provider as soon as possible and should only discontinue pep under the guidance of a healthcare provider. pep should be administered as soon as possible after exposure; efficacy after 72 hours is highly unlikely. to facilitate administering the first pep dose as soon as possible after exposure, any arv drug combination that is easily available can be used for the first dose, but the patient should not leave without a full month's supply (or prescription for a full month's supply) of the recommended regimen, namely tdf + ftc/3tc + ral or tdf + ftc/3tc + atv/r in pregnancy. starter packs are not recommended owing to the high rate of default, as the exposed individual is often lost to care and does not return for the rest of the one-month supply. all pep regimens must be administered for 28 days. animal and case control studies suggest that administration for less than 2 weeks is associated with minimal efficacy; administration for more than 28 days confers no added benefit. most arvs are in packs of 30 tablets, and the full pack should be dispensed at the first visit. regimens need to be selected using locally available arvs. a comprehensive infrastructure of counselling and support for the exposed party is necessary to facilitate adherence to pep regimens. exposure is associated with substantial anxiety for most people; this must be dealt with actively. in many cases, anxiety is most significant for those who do not need pep. counselling must be available to deal with side-effects on an ongoing basis. azt and pis are commonly associated with side-effects. balancing risks and benefits in post-exposure prophylaxis people with hiv infection have a near-normal lifespan provided that art is not started too late, so the risks of pep need to be more carefully considered than in the past. on the other hand, newer antiretroviral drugs are considerably safer than most of the older agents. most international guidelines on pep, including those of the southern african hiv clinicians society, recommend three antiretroviral drugs for both lowand high-risk exposures. there are no controlled data on the efficacy of any pep regimen. there are also limited controlled data on the safety of arvs in hiv-uninfected people, except for tdf + ftc from pre-exposure prophylaxis trials. it cannot be assumed that antiretroviral safety will be similar in hiv-infected and hiv-uninfected people, as illustrated by the severe toxicity of nvp when used in pep. therefore it is not possible to accurately determine risk-to-benefit ratios for pep. life-threatening adverse drug reactions from currently recommended antiretroviral drugs are uncommon, probably occurring in about 1 in 1000 people, except for ftc and 3tc, which are considerably safer. people on the month-long course of pep are at risk of life-threatening reactions, as many of them occur early (e.g. acute renal failure from tdf, severe hypersensitivity reactions). therefore the number needed to harm (with life-threatening adverse drug reactions) may be similar to or lower than the number needed to treat to prevent one hiv infection when three-drug pep is used following low-risk exposures. in the absence of definitive data, clinical judgement needs to be exercised when balancing risks and benefits for pep. it is reasonable to start three-drug pep following an hiv exposure event. however, clinicians should have a low threshold to switch or stop offending antiretroviral drugs, should potentially severe adverse drug reactions occur. there may still be a place for two-drug pep for very low-risk exposures. prevention of exposure top ↑ awareness of the risks and activities related to transmission of hiv, as well as availability of pep and support, is critical, especially in an occupational setting. hcws in traditional exposure environments often receive training regarding this hazard. other potential areas where pep should be available include, but are not restricted to, home-based carers, day centres and crèches, schools and prisons, where pep exposure and treatment training are often poorly available. exposure to hiv occurs in a variety of situations, which hcws should be aware of (see box 1). box 1: potential hiv exposure situations. prevention of hiv exposure in the workplace prevention of exposure to hiv and other blood-borne viruses in the workplace is the responsibility of both employer and employee. it is a legal requirement in many southern african countries for employers to provide a safe working environment and to ensure that employees adhere to workplace guidelines for infection control. south africa has an extensive legal framework and comprehensive codes and guidelines dealing with this issue. employers have specific and numerous responsibilities with regard to workplace safety and staff support. the meticulous recording and reporting of incidents is critical; this responsibility usually rests with a medical practitioner. a broad range of professionals practising within the healthcare service and outside the department of health is at occupational risk of blood-borne viral exposure (see box 2). box 2: who is at risk of occupational exposure to blood-borne viruses? special situations: healthcare situations top ↑ occupational exposure involves potentially hazardous exposure to blood-borne viruses in the workplace: all occupational exposure should be regarded as preventable and hence deserving of investigation until proven otherwise. standard precautions should be practiced in every setting where blood or infectious body fluid contact is possible. gloves should be worn and, where appropriate, protective eyewear. clean water or saline should be available to immediately irrigate any mucosal exposure or percutaneous injury. use non-caustic soap. only use water or saline if the exposure involves the eye. needles should not be re-sheathed, and manipulation of the needle following withdrawal from the patient must be kept to the absolute minimum. wherever possible, safety equipment for blood taking should be available, particularly in the hospital and clinic setting where the risk of exposure to hiv-infected blood is highest. it is imperative that the cost of cheaper equipment and disposal must be weighed against the potential increased risk of exposure that using such equipment entails. needles and tools for any surgical practice, including traditional circumcision, should never be re-used without rigorous chemical disinfection/sterilisation according to national or local guidelines. all needles and sharp objects should be disposed of into a dedicated biohazard sharps bin. syringes and other blunt instruments should not be disposed of in these bins, but rather in regulation biohazard bins for disposal of blunt biohazard objects. the number of sharps bins allocated to each workplace area will depend on the setting and the resources available. it is recommended that, in hospital settings, designated areas of high throughput of patients who require a large number of invasive procedures, such as intensive care and emergency departments, should have a ratio of sharps bins to beds of either 1:1 or 1:2. isolation rooms should have their own sharps bins, as should any clinic area in which blood taking or invasive procedures are undertaken. the ratio of sharps bins to beds in open wards should ideally be 1:2, but at least one bin per bay. once three-quarters full, the sharps bin should be sealed and disposed of to prevent obstruction of the opening; overfull bins are a risk factor for injury during subsequent sharps disposal (figure 2). in resource-poor settings where sharps bins are unavailable, the safest and most practical method of sharps disposal should be practiced as per local or national guidelines. within the hospital or clinic environment, it is the ultimate responsibility of that institution's infection control team to monitor and ensure that sharps bins are sealed when three-quarters full and disposed of correctly. however, on a day-to-day basis, this responsibility falls to the nursing sister in charge of the ward or clinic. outside the healthcare setting, employers must take responsibility for such monitoring and enforce standard practice as laid out above. best practice should be enforced with the aid of unions within the framework of occupational law to ensure that employers and employees create a safe working environment regarding prevention of blood-borne disease acquisition. figure 2: unsafe sharps bin. other situations top ↑ post-sexual exposure prophylaxis is indicated for those who present within 72 hours of unprotected risky sexual activity including, but not limited to, penetrative intercourse and including, but not limited to, survivors of sexual assault. as a public health intervention, equal access to treatment of all sexual exposures, including rape, is essential to equality of prophylaxis and minimisation of hiv transmission: there is often considerable variation in clinical presentation of exposure situations, making it almost impossible to establish standard operating procedures for control of exposure, as may be possible in healthcare settings. the complications of criminal, civil and medico-legal elements, particularly in the case of criminally defined rape, are specialised elements of care that are beyond the scope of the present guideline. applicable local guidelines should be consulted in such cases. pep should be given as part of a package of care to women subjected to sexual assault, including support, emergency contraception and prophylaxis for additional sexually transmitted infections (stis) in combination with psychological interventions (the details of this package of care are beyond the scope of this guideline – please consult applicable local guidelines). other people who have been sexually assaulted need to have psychosocial issues addressed in combination with pep as part of a package of care; this would include men, children and adolescents who have been sexually assaulted. given the emotional and psychological trauma experienced by many of the patients who present after sexual assault, hiv-specific counselling may be appropriately delayed for 24–48 hours after onset of pep regimens. it is recognised that the post-sexual assault situation has a high rate of therapy default, complicating all aspects of management. the choice of arvs when several other agents are being utilised for pregnancy prophylaxis, sti syndromic management, and various medications to treat side-effects of trauma, is complicated. despite the strong empirical arguments for triple arv prophylaxis in this setting, a default to dual therapy with minimal short-term side-effects may be considered in individuals where there are concerns regarding adherence, or where an integrase inhibitor is not available as a third drug, with full disclosure of the potential risk of this strategy to the patient. alternatively, more arvs with better tolerability profiles are available and consideration should be given to switching the offending agent to a different one. there is no real evidence that a third drug in pep gives any additional protection. in addition, prophylactic management, such as anti-emetics and antidiarrhoeals, should be considered as upfront therapy, given the high rate of pep defaulters. sexual exposure outside of a relationship, where disclosure concerning the exposure is not desired this is a common and thorny problem faced by clinicians, with ethical and social implications. marriage and long-term relationships are almost always assumed within our society to be monogamous, although ‘straying’ from the relationship is very common in all communities. whilst a single episode of unsafe sex overall carries a low risk of hiv exposure, they may, should the exposed partner become positive, have a very high viral load during the seroconversion phase, and unprotected sex will carry a very high risk to the regular partner, whether pep is given or not. we advise providing pep for people who have had unprotected sex with a partner of known hiv-positive or unknown hiv status. sudden cessation of regular sexual relationships or introduction of condoms can cause relationship disruption, and the exposed partner may be reluctant to do this. this situation raises issues concerning the duty of the hcw to disclose to the partner, and requires a very careful and individual approach. any decision to disclose against the wishes of the exposed person to the partner must be carefully discussed with colleagues, representative organisations and medical defence organisations. patients may require help with strategies around disclosure. where the exposed individual is not putting their sexual partners at risk, for example by consistently using condoms, disclosure is not strictly necessary. where the exposed individual is placing others at risk, the issue of disclosure or facilitated disclosure becomes relevant. children principles around exposure for children are biologically similar to those for adults. as in pregnancy, newer agents have often not been tested in children and dosages might not have been determined. therefore, recommended medications and dosages may differ and it is important to check doses carefully. psychological and legal consent issues may differ from adults, and clinicians should be guided by local legislation. children often do not give accurate histories, and anxious parents, especially in the context of possible sexual assault, may require significant counselling and careful referral. pre-mastication of food is commonly practised in both developed and developing countries, and several cases of transmission from caregivers to children have been described in the usa. this practice should be actively discouraged. another source of potential infection, through breast milk, is using wet nurses, as well as milk kitchens (the practice of pooling breast milk, and then transferring to bottles in healthcare facilities). finally, children are exposed to other children's behaviours, which may theoretically have transmission risks, such as biting. most cases of biting do not pose a risk of hiv transmission in children, but if there is blood in the mouth of the biting individual (e.g. bleeding gums owing to gingivitis), or if the skin of the bitten child is breached, there is a theoretical risk of transmission. principles of pep in children are the same as in adults, although managing parent anxiety is often a huge challenge. selecting patients for antiretroviral interventions top ↑ potentially infectious material the following should be regarded as infectious material: blood (and any bloodstained fluid, tissue or material) sexual fluids vaginal secretions penile pre-ejaculate and semen tissue fluids any fluid drained from a body cavity, including ascites; cerebrospinal, amniotic, rectal, peritoneal, synovial, pleural or pericardial fluids; and wound secretions breast milk. parenteral or mucosal exposure requires antiretroviral pep intervention, as described in the present guideline. in the absence of super-contamination with the above fluids, the following may be considered non-infectious: sweat tears saliva and sputum urine stool. exposure to hiv occurs in a vast variety of situations, which healthcare professionals (hcp) should be aware of (see box 2). exposure to non-infectious material requires reassurance but no pep. a special circumstance involves human bites and punching. where a bite or a punch has resulted in opening of the skin, pep should be advocated, bearing in mind that in the case of human bites, the possibility that both the person bitten and the person who inflicted the bite were exposed to blood-borne pathogens. pep should be offered and initiated as early as possible after exposure, ideally within 72 hours, to all individuals with exposure that poses a risk for hiv transmission, and should be continued for one month. in exceptional cases involving high-risk exposures, pep may be considered up to 7 days after exposure. it is advisable to discuss such cases with an experienced hiv clinician. selecting antiretroviral regimens for post-exposure prophylaxis recommended post-exposure prophylaxis antiretroviral regimen the choice of pep combinations is based on available evidence in both prevention (including prep and pmtct) and treatment settings; side-effect profiles; ease of use; local guidelines; and availability. in addition, the present pep guidelines are aligned with the latest who pep guidelines, released in december 2014, which now recommend three drugs as the preferred option for pep, and no differentiation in regimen according to the type of exposure, namely occupational versus non-occupational. this approach is part of a move towards simplification of prescribing to improve availability of pep and to reduce the time to pep initiation. with the availability of less toxic and better tolerated drugs, providing a three-drug regimen supports simplified prescribing by removing the need to evaluate the risk of resistance, which was the basis upon which the decision to initiate twoversus three-drug pep was previously made. while pep completion rates are generally less than optimal, there is evidence that completion rates are similar when comparing two-drug to three-drug pep (see box 3). box 3: post-exposure prophylaxis recommendations. justification for three versus two drugs and for choice of antiretrovirals preferred for post-exposure prophylaxis as in the previous guideline, the present update recommends that, where pep is to be provided, three drugs should be administered. the basis of this recommendation is manifold. current north american centers for disease control and prevention (cdc) and uk guidelines are based on risk assessments in low-prevalence settings, with presumed exclusive clade b data. in contrast, the southern african situation is one of extremely high hiv prevalence (clade c), high volumes of patients, and an attendant very high number of exposures. the individual and cumulative risk of hiv transmission in this setting has never been quantified. there are limited data suggesting that clade c is more infectious in the sexual exposure setting. we assume that this risk is significantly higher than in other settings, and the exposed individual should therefore be treated appropriately. for key populations, such as men who have sex with men (msm), intravenous drug users, prison populations and others, the risk is even higher than penile-vaginal penetration, which adds further weight to this recommendation. whilst previous guidelines advocated two or three drugs based on clinician assessment of risk, the sa hiv clinicians society has recommended three drugs in all exposure situations since 2008. there is no evidence backing the use of two drugs over the single-agent azt. we further note that the pmtct trials suggest no added advantage of adding 3tc to azt, a finding replicated in various cohort pmtct studies. several prep studies have shown tdf + ftc to be superior to tdf alone in preventing hiv infection occurring in study participants. in addition, the use of triple-therapy art regimens has been shown to have significant benefit in comparison with dual therapy in treatment settings. whilst no evidence exists to support the use of such combinations in humans in pep scenarios, all current pep guidelines advocate triple prophylaxis regimens in ‘high-risk scenarios’. the argument is therefore not one of two or three drugs, but of what constitutes ‘high-risk scenarios’. southern africa, with its high prevalence, large numbers of patients and high number of exposures, should be considered a high-risk scenario. of particular contention are mucous membrane exposures and oral sex scenarios, which are associated with lesser risk. the cdc guideline is based on a single known transmission out of almost 10 000 reported incidents. again, no evidence of risk is available in our setting, but evidence of significantly higher exposures in comparison to the us setting (blood spatters on eyeglasses, masks in low-, mediumand high-risk procedures) is available. furthermore, blood risk exposures are chronically underreported, a factor that is likely to be particularly true of injuries that are deemed to carry a lesser risk, meaning the incidence may be greater than we think. for these reasons, coupled with the known high background hiv prevalence, we advocate three-drug pep in these scenarios. however, the extremely low risk of transmission via these routes should be discussed with the exposed individual. on the other hand, the advocated pep triple regimen is very well tolerated compared with previously used regimens, and the exposed individual may opt to take the pep regimen despite the low risk of transmission via mucous membrane exposure. finally, the risk of side-effects increases when additional agents are added to pep regimens. three-drug regimens carry more risk of side-effects than two-drug regimens. with the availability of more tolerable drugs, potential side-effects are fewer, and can be anticipated and managed proactively, to ensure the full month of pep is completed. integrase inhibitors have minimal side-effects, and are a well tolerated third drug option. justification for choice of antiretrovirals preferred for preferred for post-exposure azt-containing regimens carry such a significant side-effect profile that this agent should be avoided, and with the reduction in cost of tdf combinations, the recommended nrti backbone is now tdf with ftc/3tc, preferably in a fdc. there is no evidence that prevention of hiv transmission by azt in the setting of pep is effected by anything other than its inhibition of viral replication. this supports the use of tdf, whose potency of action is equivalent to azt, yet which is far better tolerated over one month of therapy, as a recommended nrti in pep. whilst the risk of adverse events is undeniably real, it must be balanced against the often unquantifiable but equally real risk of transmission associated with high hiv prevalence, high individual viral load levels, and high levels of exposures in occupational and non-occupational settings. tdf is usually avoided in patients on art with renal failure or egfr < 50 ml/min. in the setting of pep, the duration of tdf administration is short. comparative data from three randomised trials for art and prep and from observational studies with pep support the use of tdf + ftc/3tc as the preferred backbone in pep. indirect comparisons between azt + 3tc versus tdf + ftc/3tc across 15 studies demonstrate less pep discontinuation due to adverse events in individuals receiving tdf + ftc/3tc than azt + 3tc. however, where there are concerns regarding the use of tdf, d4t is very well tolerated when it is used for short periods and, given the poor tolerability of azt in pep regimens, would be the recommended nrti to use in such cases. there may be a risk of hepatic flares in individuals chronically infected with hbv who discontinue pep containing tdf, 3tc or ftc, as has been seen in some patients on art who switch away from these drugs. such individuals should be monitored for hepatic flare if these drugs are not continued for hbv treatment. where hbv testing is available, those with unknown hbv status should be tested for active hbv infection, to assess the need for ongoing hbv therapy. in terms of third drug options, there are many agents which may be suitable for use in pep but which may have limitations such as cost and availability in lowand middle-income countries, such as in the southern african region. there are studies that provide data on lopinavir + ritonavir (lpv/r), atv/r, darunavir + ritonavir (drv/r) and raltegravir (ral) as part of triple-combination pep, but offer little guidance on their efficacy. the present guideline recommends using ral as the third drug, with atv/r, lpv/r, drv/r or efavirenz (efv) as alternatives where ral is not available or cannot be used. ral in combination with tdf + ftc/3tc (as an fdc) is the preferred pep regimen on account of its tolerability, potency, convenience and minimal drug interactions. this regimen differs from who recommendations, which advocate the use of lpv/r or atv/r as the third drug in pep, as they are currently used in art and are widely available in lowand middle-income countries, which is not always the case with ral or drv/r because of the higher cost of these agents. if the three recommended drugs are not immediately available, this should not delay the initiation of pep. it is imperative that pep is started as soon as possible after exposure; in cases where the recommended 3 drugs are not immediately available, an alternative 3-drug combination can be given immediately. however, the patient must not leave without a full month's supply of the recommended 3 drugs. there are other newer drugs that might be useful as part of a pep regimen, but there are no data supporting their use in pep specifically. the drugs include dolutegravir (high potency, tolerability and once-daily dosing); rilpivirine (high tolerability and low cost) and elvitegravir (tolerability and convenient coformulation). once dolutegravir becomes available in south africa, it is likely to replace ral as the third drug of choice in pep, with advantages being once-daily dosing (compared with ral which is twice a day) and the possibility of dolutegravir-containing fdcs. efv is currently the preferred third drug in first-line art, and is generally well tolerated in the long term; however, it is associated with early nervous system and psychiatric side-effects that limit its use in pep. owing to the possibility of high levels of anxiety in the exposed individual, efv should only be used as the third drug where other drugs cannot be used. nevirapine (nvp) and abacavir (abc) are not recommended for pep, on account of their risk of serious side-effects. justification for duration preferred for post-exposure a one-month prescription for arvs should be provided for pep. this is supported by animal study data that demonstrate that a full 28-day course is necessary to achieve maximum benefit from the intervention and prevent seroconversion. before the widespread availability of rapid hiv tests, starter packs of pep were dispensed to ensure testing and counselling could be completed, accommodating the longer turnaround time of the available tests. however, it is now recommended that the full one-month course is dispensed to improve completion rates, which are lower amongst those exposed who received partial prescriptions than those receiving the full course at the initial visit. providing the full course removes the need for a 3-day follow-up visit, reducing the burden on facilities, as well as being more convenient for exposed individuals. however, they should be fully informed about the side-effects of the pep regimen, and advised to return to the facility if they have any concerns, side-effects or adherence problems prior to their scheduled follow-up visit. a follow-up appointment for 2 weeks should be scheduled, and at this visit any side-effects should be proactively identified and managed, and appropriate counselling provided. the next appointment should be scheduled for 6 weeks post-exposure, where appropriate laboratory tests will be done (as per table 4). table 2: selecting patients for preferred for post-exposure interventions. table 3: doses of antiretrovirals for hiv preferred for post-exposure in adults and adolescents. table 4: timing of bloods preand post-preferred for post-exposure. routine baseline and follow-up investigations top ↑ investigating the source individual where the source individual is known, every effort must be made to gain their voluntary, informed consent to have the necessary laboratory tests performed, in accordance with health professions council of south africa (hpcsa) guidelines and national policy regarding hiv testing. if the source individual is unknown, unavailable for testing, or refuses testing after appropriate counselling, the default position should be that the source is seropositive for hiv. if a source individual is unable to give consent because of an impaired level of consciousness, national guidelines allowing testing in such circumstances should be followed. testing of the source should be undertaken as soon after the injury as possible. testing of needles, sharps or other samples that have been implicated in the exposure is not recommended, even when the source is unknown or refuses testing. such investigations are unreliable and pose a risk of further exposure to the hcws undertaking the testing. the tests that should be performed on blood from the source individual are shown in table 4. if the source is found to be positive on any of the tests undertaken, they should receive post-test counselling and either be treated or referred to their local healthcare facility for further management. hiv testing a nationally approved hiv test should be performed by a hcw who is trained in this procedure, with preand post-counselling, and formally documented. a positive rapid test should be confirmed, as per national guidelines, and the source patient managed as per guidelines. if the diagnosis of hiv is confirmed in the source patient, they must be linked with treatment and care services immediately. for source patients on antiretrovirals, hiv rna pcr should be performed where available. if the viral load is not fully suppressed, genotypic testing should be considered, although this is of uncertain value. this test should, however, not delay initiation of pep. detectable viral load results should be discussed with an expert. if viral load testing and/or genotyping are not available, and if resistance is suspected, a boosted pi should always be used as the third drug. as the plasma viral load measures only the level of cell-free virus in peripheral blood and so an undetectable viral load does not exclude low-level viraemia, the possibility of transmission from a source patient with an undetectable viral load is not eliminated. in such cases, the exposed individual should still be offered pep and appropriate follow-up. hiv and hepatitis b virus testing testing of the source for hepatitis b surface antigen (hbsag) can be omitted when the exposed individual is known to be protected from hepatitis b acquisition by natural immunity or vaccination. hepatitis c virus testing hepatitis c virus (hcv) is rare in sa and we do not recommend testing unless the source individual is an intravenous drug user, msm, haemophiliac or from a high hcv prevalence setting, or where the source is unknown. in such cases, the source should be tested for hcv ab. if the source is hcv-negative, the exposed individual should be tested at baseline to assess their own hcv status, and no further hcv testing will be necessary in further follow-up. however, where the source is hcv-positive and the exposed individual is hcv-negative at baseline, hcv pcr testing should be done at 6 weeks. other blood-borne pathogens syphilis: routine testing of source should be performed. malaria: malaria blood films should not be routinely sent from source patients, unless there is clinical suspicion that the source has malaria. investigating the exposed individual it is strongly recommended that any investigation on the blood of an exposed person should be requested and taken by an independent third party. if infection is proven, baseline investigation for blood-borne viruses forms a vital part of any future compensation claim. hiv testing preand post-test counselling should be offered to all exposed persons at all testing facilities. a baseline hiv rapid test, followed by 4th-generation elisa as confirmation should be performed and the results carefully documented. as many cases have medico-legal or occupational claims implications, it is recommended that formal laboratory testing be done in all cases. confirmatory testing of a positive result should be undertaken per standard guidelines. follow-up testing for hiv seroconversion should be undertaken at 6 weeks and 3 months post-exposure. we do not advocate routine testing of an exposed worker at 6 or 12 months, as current elisa tests (4th generation) have reduced the window period considerably. in exposed individuals, testing beyond 3 months is advised in the following settings: ongoing high-risk behaviour a specific exposure incident within the last few months can be identified hiv status at 3 months is indeterminate. viral load or p24 antigen testing is not recommended in the setting of pep. quantitative viral loads may yield false-positive results, and may cause substantial anxiety. seroconversion on pep is extremely rare; any exposed individual thought to be experiencing a seroconversion illness on pep should be discussed with an hiv specialist physician for advice. if an exposed individual tests hiv-positive at any stage, they should be linked to treatment and care services as soon as possible. hepatitis b testing the risk of transmitting the hbv is higher than that of hiv in most exposures, especially in the healthcare environment. if the exposed worker has had prior hbv infection or has been vaccinated and is a known responder, then no investigation or post-exposure therapeutic intervention for hbv is required. if the source individual tests hbsag-negative and the exposed individual is not vaccinated or does not know their vaccination/antibody status, they should be referred to a local facility for testing and vaccination. in the case of exposure to an hbsag-positive source, the options for management of unvaccinated individuals or those whose status is unknown are as detailed in table 5. table 5: management of an individual exposed to an hbsag-positive or unknown source. hepatitis c virus testing only if the source individual is an intravenous drug user, msm, haemophiliac or from a high hcv prevalence setting, or where the source is unknown. in such cases, the source should be tested for hcv ab. if the source is hcv-negative, the exposed individual should be tested at baseline to assess their own hcv status, and no further hcv testing will be necessary in further follow-up. however, where the source is hcv-positive and the exposed individual is hcv-negative at baseline, hcv pcr testing should be performed at 6 weeks. other blood-borne pathogens malaria: routine testing of an individual who has been exposed to a source is not recommended unless the source is symptomatic. sexually transmitted infections in cases of sexual exposure, exposure to other sexually transmitted infections might have occurred. if symptomatic, manage syndromically. otherwise, appropriate prophylaxis should be provided to the exposed individual. however, these guidelines do not deal with the comprehensive management of sexual assault. appropriate guidelines should be consulted for sexual assault cases. pregnancy all exposed women should be screened for pregnancy at the time of the incident and subsequent follow-up. emergency contraception should be offered to all women of childbearing age who present after accidental exposure or sexual assault, in line with relevant guidelines. tetanus individuals who have wounds such as abrasions, cuts or bites should be asked about their tetanus immunisation status, and be offered immunisation if appropriate. follow-up: monitoring for adverse drug reactions side-effects the present guideline's emphasis on appropriate choice of agents to minimise side-effects, on close management of the individual patient through the pep process, and on the aggressive prophylactic and therapeutic management of side-effects, allows a great deal of amelioration of the side-effect risk. this approach then tips the risk/benefit balance back towards the use of the most virologically potent regimens available, namely three-drug regimens. management guidelines to minimise exposure risk also form a large part of the present guideline, but once exposure has occurred, management of side-effects is almost always achievable, whilst the attendant risks are not. for common side-effects with the preferred and alternative pep antiretroviral agents, see table 6. mainly shorter-term side-effects such as nausea, vomiting and headaches which are transient or can be managed have been included in the table. longer-term toxicities that are unlikely to be seen with one-month pep regimens are not included (e.g. lipoatrophy, hyperlactataemia, steatohepatitis). table 6: common or severe adverse drug reactions of antiretrovirals that may be used for preferred for post-exposure. comorbidities patients with significant comorbidities should have regular monitoring of any relevant investigations during therapy. no additional investigations are warranted in otherwise healthy individuals. medical comorbidities and antiretroviral selection for preferred for post-exposure although many of the comorbid conditions listed in table 7 do not preclude the use of certain arvs, increased monitoring of the comorbid condition may be necessary during the one-month course of pep. moreover, whenever a safer regimen is available with equal efficacy, that regimen should be used in preference. table 7: comorbidities affecting choice of antiretrovirals for preferred for post-exposure. drug safety in pregnancy in pregnancy, the benefits of arvs must be weighed against the risks of adverse events to the woman, foetus and newborn. data regarding the use of most arvs during pregnancy are limited, and usually not of high quality. much of the information regarding the use of arvs in pregnancy is from the antiretroviral pregnancy registry that, by virtue of the voluntary nature of registration, introduces a selection bias. as there is less information regarding the use of ral in pregnancy than atv/r, the present guideline recommends that atv/r be the third drug of choice for pep during pregnancy. both atv/r and ral are food and drug administration (fda) pregnancy category c. table 8 provides information on the use of the drugs recommended for pep during pregnancy. table 8: drug safety in pregnancy. key issues regarding counselling adherence pep studies report low completion rates, often less than 60% for all populations, but especially adolescents, and pep following sexual assault. adherence counselling has been shown to improve adherence in hiv-positive individuals starting art. three rcts comparing standard care counselling to enhanced adherence packages in improving adherence to pep were identified and reviewed. the enhanced package included individual baseline needs assessments, adherence counselling, and education sessions and telephone calls. the combined effect of the enhanced intervention improved adherence and completion rates compared with standard of care counselling. based on this finding, it is likely that some of the methods used to improve art adherence may well be effective in pep, such as peer support, alarms, text messages and phone calls. anxiety management anxiety should not simply be dismissed as baseless with simple reassurance. hiv remains a ‘dread disease’, despite the success of art, because it is sexually transmitted, still accounts for significant mortality and morbidity, and has extensive stigma associated with it. anxiety management must be part of the adherence or follow-up support, and may need several interventions. simple telephonic contact and reassurance is almost always adequate. the intervention must be individualised, but the following approaches should be integrated: contextualise the risk: emphasise that acquisition of hiv is unusual through a single exposure, unless the injury is severe (sexual assault, blood transfusion of an infected unit, severe penetrating injury with infected tissue). even in the case of severe exposure or injury, where pep is used timeously and the course completed, the risk of transmission is extremely low. risk-taking interventions counselling should be non-judgemental, practical and solution-focussed. pep is an ideal time to deal with risk-taking environments, whether unsafe sex (e.g. a one-night stand with unprotected sex), poor occupational health (e.g. overfull sharps bins) or other (e.g. injecting drug use). addressing occupational risk must be practical (e.g. report overfull bins to infection control, do not tell an exhausted nurse to ‘be more careful’). secondary prevention to prevent harm to others (e.g. risk to a spouse after sex with a third party) must be addressed. exposed individuals should be counselled on how to prevent transmission to others, until they undergo the three-month post-exposure test following pep: use of condoms to protect sexual partners to prevent mother-to-child-transmission (mtct), avoid pregnancy (provide emergency contraception if necessary) and avoid breastfeeding if possible (high risk of transmission via breast milk during the 3 months following seroconversion demonstrated in a study from zimbabwe) safe injecting practices avoid blood and tissue donation. consider offering prep to exposed individuals where chronic exposure to hiv is unavoidable or likely to continue (e.g. sex workers). current evidence indicates that prep is effective as part of combination prevention approaches, provided it is used correctly. for more information, consult the southern african hiv clinicians society guidelines on the safe use of prep in msm and the us department of health and human service dhhs clinical practice guideline.11,12 acknowledgements top ↑ the previous iteration of the southern african clinicians society pep guidelines was convened by dr steve andrews, and we acknowledge his contribution to hiv care and treatment in south africa. the format of the previous guideline has been preserved, with additional information included, and the content updated in line with current evidence and recommendations. competing interests all expert panel members have completed and submitted conflict of interest disclosure forms. disclosure information represents the previous 3 years (updated 10 june 2014) and includes relationships with pharmaceutical companies and medical aids: l.g.b. has received honoraria from merck (msd) for participating in consultative meetings. v.b. has received research support from standard diagnostics and served as a consultant to novartis. f.c. has received support from abbvie, aspen and mylan to attend conferences; research support from janssen; honoraria for speaking engagements from abbvie, glaxosmithkline, janssen and msd; and acted as a consultant to sanofi aventis. m.m. has received honoraria for speaking engagements from aspen and msd. f.v. has received support to attend conferences from adcock ingram, msd and aspen; received honoraria for speaking engagements from msd, aspen, abbott, novogen, adcock ingram and glaxosmithkline; served on advisory boards for johnson and johnson, mylan and tibotec; and received drug donations for research projects from gilead and mylan. c.l.w. has received support from roche molecular to attend conferences; honoraria for speaking engagements from abbvie, msd and janssen; and acted as a consultant to celera. b.h., p.h., g.m., n.s.p., k.r. and g.s. report no conflicts of interest. authors’ contributions m.m. (wits reproductive health & hiv institute) is the first author, undertaking preparation of the first draft of the manuscript. the remaining authors were involved in the discussions that guided the development of the manuscript and also reviewed the first draft. all authors developed the recommendations. references top ↑ southern african hiv clinicians society. post-exposure prophylaxis. s afr j hiv med. 2008;9(3):36–45. world health organization. guidelines on post-exposure prophylaxis for hiv and the use of co-trimoxazole prophylaxis for hiv-related infections among adults, adolescents and children: recommendations for a public health approach: december 2014 supplement to the 2013 consolidated arv guidelines. geneva: world health organization; 2014. bell dm. occupational risk of human immunodeficiency virus infection in healthcare workers: an overview. am j med. 1997;102(5b):9–15. pmid: 9845490, http://dx.doi.org/10.1016/s0002-9343(97)89441-7 hersey jc, martin ls. use of infection control guidelines by workers in healthcare facilities to prevent occupational transmission of hbv and hiv: results from a national survey. infect control hosp epidemiol. 1994;15:243–252. pmid: 8207191 kermode m, jolley d, langkham b, thomas ms, crofts n. occupational exposure to blood and risk of bloodborne virus infection among health care workers in rural north indian health care settings. am j infect control. 2005;33(1):34–41. pmid: 15685133, http://dx.doi.org/10.1016/j.ajic.2004.07.015 newsom dh, kiwanuka jp. needle-stick injuries in a ugandan teaching hospital. ann trop med parasitol. 2002;96:517–522. pmid: 12194713, http://dx.doi.org/10.1179/000349802125001186 logez s, soyolgerel g, fields r, luby s, hutin y. rapid assessment of injection practices in mongolia. in: who. pilot-testing the who tools to assess and evaluate injection practices: a summary of 10 assessments coordinated by who in seven countries (2000–2001). 2003;whoibct/03.1o. tarantolaa a, koumare a, rachline a, et al. a descriptive, retrospective study of 567 accidental blood exposures in healthcare workers in three west african countries. j hosp infect. 2005;60:276–282. pmid: 16021690, http://dx.doi.org/10.1016/j.jhin.2004.11.025 karstaedt as, pantanowitz l. occupational exposure of interns to blood in an area of high hiv seroprevalence. s afr med j. 2014;104:732–735. pmid: 11236300 marais bj, cotton m. occupational exposure to hiv in paediatricians – a previously undescribed high risk group. abstract no. mopec3515. proceedings of the xiv international aids conference; 2002 jul 7–12; barcelona, spain. southern african hiv clinicians society. southern african guidelines for the safe use of pre-exposure prophylaxis in men who have sex with men who are at risk for hiv infection. s afr j hiv med. 2012;13:40–55. us public health service. preexposure prophylaxis for the prevention of hiv infection in the united states – 2014 clinical practice guideline; 2014. abstract introduction cases ethical consideration discussion conclusion acknowledgements references about the author(s) vhudzani tshisevhe lancet laboratories, rustenburg, south africa department of medical microbiology, faculty of health sciences, university of pretoria, pretoria, south africa nontombi mbelle department of medical microbiology, faculty of health sciences, university of pretoria, pretoria, south africa department of medical microbiology, tshwane academic division, national health laboratory service, pretoria, south africa remco p.h. peters department of medical microbiology, faculty of health sciences, university of pretoria, pretoria, south africa department of medical microbiology, school for public health and primary care, university of maastricht, maastricht, the netherlands anova health institute, johannesburg, south africa citation tshisevhe v, mbelle n, peters rph. cutaneous tuberculosis in hiv-infected individuals: lessons learnt from a case series. s afr j hiv med. 2019;20(1), a895. https://doi.org/10.4102/sajhivmed.v20i1.895 case report cutaneous tuberculosis in hiv-infected individuals: lessons learnt from a case series vhudzani tshisevhe, nontombi mbelle, remco p.h. peters received: 03 aug. 2018; accepted: 05 feb. 2019; published: 12 mar. 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract introduction: extrapulmonary tuberculosis (tb) causes a significant burden of disease worldwide, especially among hiv-infected individuals and those with other immunosuppressive conditions. cutaneous tb is an important manifestation of extrapulmonary tb but is uncommonly reported in south africa despite the high burden of hiv and tb co-infection. there is a paucity of published data on clinical presentation and outcome of cutaneous tb in this context. raising awareness of this condition among clinicians is imperative to improve early diagnosis and optimise treatment outcomes. patient presentation: in this series, we present three cases of cutaneous tb, two adults and one child, referred to a tertiary hospital from two primary healthcare centres and from a general practitioner. we demonstrate that the clinical presentation is diverse, ranging from papular lesions to abscesses, and that concordant pulmonary tb may be present. management: in particular, we show the importance of performing diagnostic procedures (e.g. aspiration) in individuals presenting with an abscess that does not respond to broad spectrum antimicrobial treatment, particularly in those with advanced immunosuppression. outcome and conclusion: the outcome of our three patients was poor, highlighting the need for earlier diagnosis in this who stage 4 condition and intensive management of clinical cases. keywords: hiv-medicine; retro-viral disease; mycobacteria; tuberculosis; multidrug resistance; cutaneous tuberculosis; cutaneous disease; immunocompromised. introduction cutaneous mycobacterium tuberculosis (mtb) infection is a form of extrapulmonary tuberculosis (tb) that is uncommon: it accounts for less than 2% of all cases of tb.1,2 the incidence of cutaneous tb has been reported to decrease in india while increasing incidence was reported in mexico; there are no time trend data for south africa available.2,3,4 the human immunodeficiency virus (hiv) epidemic is an important driver of the occurrence of cutaneous tb; other important factors are the increased rates of tb in specific settings such as healthcare facilities, prisons and homeless shelters; intravenous drug use; diabetes mellitus; and immunosuppressive therapy.5,6,7,8,9 the diagnosis of cutaneous tb is often challenging. firstly, the clinical presentation of cutaneous tb is non-specific and variable. furthermore, microbial diagnosis is complicated for reasons including the paucibacillary nature of the skin lesions, requirements for prolonged incubation period of culture in the laboratory and the difficulties in extracting and detecting mycobacteria from biopsy material.2,5,10 lastly, in our experience, the awareness of cutaneous tb among health practitioners is low, which may result in delays. as a result, cutaneous tb is often diagnosed relatively late and may have poor outcomes, despite the availability of effective anti-tb treatment. there is a paucity of data on the clinical and microbiological features of cutaneous tb and its clinical outcomes in sub-saharan africa. to improve treatment outcomes, increased awareness of this condition and the appropriate diagnostic work-up among healthcare workers is required. here, we describe three cases of cutaneous tb and present lessons learnt to improve daily clinical practice. cases case 1 a 34-year-old hiv-infected man, who had been on antiretroviral therapy (art) for eight months, presented to hospital with a skin abscess on his lower back of more than 1 month’s duration. he had been treated with amoxicillin-clavulanic acid at a nearby primary healthcare (phc) facility on first presentation. upon return to the phc facility one month later, the abscess had increased in size, and the patient was referred to the hospital. aspirates were taken from the abscess and submitted to the laboratory of medical microbiology, where both the xpert® mycobacterium tuberculosis (mtb)/rif and line probe assay detected m. tuberculosis. based on these two tests, the strain was determined to be resistant to rifampicin and sensitive to isoniazid. second-line drug susceptibility testing revealed that the strain was sensitive to second-line injectable drugs and fluoroquinolones. of note is that the patient completed treatment for drug-sensitive pulmonary tb 6 months prior to presenting with the skin abscess and had no concomitant signs or symptoms of pulmonary tb when he presented with the skin abscess. it is not known if the pulmonary tb was cured. his cd4+ count was 122 cells/µl when art was initiated and 30 cells/µl at the time of cutaneous tb diagnosis. he was initiated on kanamycin, moxifloxacin, ethionamide, terizidone, ethambutol, isoniazid and pyrazinamide for cutaneous rifampicin-resistant tb (regimen used in 2016). the patient died at home two weeks after tb treatment initiation; cause of death could not be determined. case 2 a 21-month-old male paediatric patient on art for eight months presented with multiple abscesses on the forearms and torso. his mother was on drug-sensitive tb treatment at the time of the patient’s presentation, and a year prior, the father had died of pulmonary tb. the patient received bacillus calmette-guérin vaccine at birth. he had first presented at the general practitioner (gp) with a week’s history of intermittent cough, papular lesions on the torso and failure to thrive. the treatment given by the gp included amoxicillin, trimethoprim-sulfamethoxazole and vitamin b complex syrup. gastric aspirates tested negative for tb with ziehl-neelsen and mycobacteria growth indicator tube (mgit) culture. the patient returned to the gp a month later, and the papular lesions had formed abscesses and extended to the forearms. the patient was transferred to the hospital for further management. mycobacteria growth indicator tube culture of the abscess aspirate grew m. tuberculosis, and line probe assay confirmed the organism as sensitive to rifampicin and isoniazid. two respiratory specimens collected at different times after cutaneous tb diagnosis tested negative for m. tuberculosis. hospital records showed poor adherence to hiv treatment as evident by hiv viral load of 260 000 copies/ml six months after art initiation and missed follow-up appointments. the patient was initiated on rifampicin, isoniazid, pyrazinamide and ethambutol for cutaneous tb. he died four weeks after starting treatment from respiratory tract infection, the cause of which was not determined, as the patient died on arrival at the hospital and no autopsy was done. case 3 a 42-year-old hiv-positive female patient who had never been on art presented to her local hospital with a 2-month history of a non-healing cold abscess on the right forearm. the patient had been treated with flucloxacillin and trimethoprim-sulfamethoxazole by her local gp, whom she consulted on three occasions prior to hospital presentation. incision and drainage was also done by the gp during her last visit. abscess aspirates were collected and submitted to a microbiology laboratory, where m. tuberculosis was detected by mgit culture and confirmed by line probe assay. the patient was initiated on a first-line anti-tb regimen: rifampicin, isoniazid, pyrazinamide and ethambutol. pulmonary tb was also diagnosed a month later following new onset of cough, loss of weight and a positive xpert® test on sputum. both the cutaneous and pulmonary m. tuberculosis strains were susceptible to rifampicin and isoniazid; and the initial treatment was continued following the diagnosis of pulmonary tb. the patient was lost to follow-up and thus the outcome is unknown. ethical consideration ethical approval was obtained from the faculty of health sciences research ethics committee of the university of pretoria (ethics reference number: 145/2018). discussion cutaneous tb can be acquired through direct infection of the skin (exogenous tb) or from haematogenous spread of tb elsewhere in the body.11 it may not always be obvious how the patient acquired the cutaneous tb. haematogenous spread of tb may be the most likely cause in the first patient, as he had recently been treated for pulmonary tb and presented with low cd4+ count, putting him at increased risk for disseminated infection. direct infection of the skin could have occurred in the second patient, although haematogenous spread of asymptomatic pulmonary infection is more likely because children are more prone to disseminated tb. the mode of acquisition is unclear in the third patient. it is clinically important, however, to assess patients with cutaneous tb for the presence of pulmonary infection, especially because these infections may be caused by strains with different resistance profiles.12 despite the strong association with hiv, cutaneous tb is rarely reported in south africa, the country with the largest hiv–tb epidemic in the world.11,13 most likely, under-diagnosis and under-reporting occur because of the limited awareness of this condition. the clinical presentation of cutaneous tb is non-specific and variable. the cases presented illustrate that skin lesions may occur on different parts of the body, can be single or multiple and could evolve from papular lesions to abscesses.14 all patients had initially been treated with broad spectrum antibiotics, without success. correctly, the clinicians referred these patients to the hospital for further diagnostics and management, where cutaneous tb was confirmed through abscess aspiration. it is noteworthy that tissue biopsies can also be used for cutaneous tb diagnosis using xpert® mtb/rif.15 these cases highlight the importance of sampling any lesion that does not respond to initial broad spectrum antimicrobial treatment. as we show in our case series, this holds particularly true for those at highest risk of cutaneous tb: hiv-infected individuals with advanced immunosuppression.6 the same applies to cutaneous lesions in children, as infancy is another known risk factor that may be further enhanced by other individuals with pulmonary tb in the household.5,14,16,17 as such, a diagnosis of cutaneous tb is an important indicator for further investigations and management of other conditions, in particular hiv-associated advanced immunosuppression. while our cases presented with abscesses; it is important to note that cutaneous tb can present in various forms depending on bacillary load. the varieties include the multibacillary forms such as tuberculous chancre, scrofuloderma, orificial tb and tuberculous gumma and paucibacillary forms such as verrucosa cutis and lupus vulgaris.5,16 there are also skin lesions associated with immune hypersensitivity reactions to m. tuberculosis antigens. these lesions are of three variants, which include papulonecrotic tuberculid, lichen scrofulosorum and erythema induratum. the outcome of cutaneous tb is rarely reported in the literature, but two of our patients died and the third was lost to follow-up. however, cutaneous tb generally occurs in a vulnerable group because of high level of immunosuppression, young age and various comorbidities. intensive follow-up of tb care as well as intensive management of all other underlying conditions is required to ensure optimal outcome. conclusion the diverse clinical presentation of cutaneous tb requires a high index of suspicion when patients present with skin lesions that do not respond to broad spectrum antibiotics, especially in the presence of other risk factors such as hiv infection. abscess aspiration is an essential diagnostic procedure. acknowledgements competing interests the authors declare that they have no financial or personal relationship(s) which may have inappropriately influenced them in writing this article. authors’ contributions all authors equally contributed to the research and writing of this article. references kumar b, kaur s. pattern of cutaneous tuberculosis in north india. indian j dermatol venereol leprol. 1986;52:203–207. chopra d, chopra v, sharma a, chopra s, aggarwal s, goyal d. unusual sites of cutaneous tuberculosis: a report of two cases. case rep dermatol med. 2017;2017:1–4. https://doi.org/10.1155/2017/ sehgal nh, srivastava g, khurana vk, sharma vk, bhalla p, beohar pc. an appraisal of epidemiologic, clinical, bacteriologic, histopathologic, and immunologic parameters in cutaneous tuberculosis. int j dermatol. 1987;26(8):521–526. https://doi.org/10.1111/j.1365-4362.1987.tb02294.x yasmeen n, kanjee a. cutaneous tuberculosis: a three-year prospective study. j pak med assoc. 2005;55(1):10–12. frankel a, penrose c, emer j. cutaneous tuberculosis: a practical case report and review for the dermatologist. j clin aesthet dermatol. 2009;2(10):19. bravo fg, gotuzzo e. cutaneous tuberculosis. clin dermatol. 2007;25(2):173–180. https://doi.org/10.1016/j.clindermatol.2006.05.005 fariña mc, gegundez mi, piqué e, et al. cutaneous tuberculosis: a clinical, histopathologic, and bacteriologic study. j am acad dermatol. 1995;33(3): 433–440. https://doi.org/10.1016/0190-9622(95)91389-0 macgregor rr. cutaneous tuberculosis. clin dermatol. 1995;13(3):245–255. https://doi.org/10.1016/0738-081x(95)00019-c bhutto am, solangi a, khaskhely nm, et al. clinical and epidemiological observations of cutaneous tuberculosis in larkana, pakistan. int j dermatol. 2002;41(3):159–165. https://doi.org/10.1046/j.1365-4362.2002.01440.x thakur bk, verma s, hazarika d. a clinicopathological study of cutaneous tuberculosis at dibrugarh district, assam. indian j dermatol. 2012;57(1):63–65. https://doi.org/10.4103/0019-5154.92685 van zyl l, du plessis j, viljoen j. cutaneous tuberculosis overview and current treatment regimens. tuberculosis. 2015;95(6):629–638. https://doi.org/10.1016/j.tube.2014.12.006 lai cc, liu wl, tan ck, et al. differences in drug resistance profiles of mycobacterium tuberculosis isolates causing pulmonary and extrapulmonary tuberculosis in a medical centre in taiwan, 2000–2010. int j antimicrob agents. 2011;38(2):125–129. https://doi.org/10.1016/j.ijantimicag.2011.03.016 mclachlan i, visser wi, jordaan hf. skin conditions in a south african tuberculosis hospital: prevalence, description, and possible associations. int j dermatol. 2016;55(11):1234–1241. https://doi.org/10.1111/ijd.13355 handog eb, gabriel tg, pineda rt. management of cutaneous tuberculosis. dermatol ther. 2008;21(3):154–161. https://doi.org/10.1111/j.1529-8019.2008.00186.x scott le, beylis n, nicol m, et al. the diagnostic accuracy of xpert mtb/rif on extra pulmonary tuberculosis specimens: establishing a laboratory testing algorithm for south africa. j clin microbiol. 2014;12:jcm-03553. https://doi.org/10.1128/jcm.03553-13 santos jb, figueiredo ar, ferraz ce, oliveira mh, silva pg, medeiros vl. cutaneous tuberculosis: epidemiologic, etiopathogenic and clinical aspects – part i. an bras dermatol. 2014;89:219–228. https://doi.org/10.1590/abd1806-4841.20142334 almaguer-chávez j, ocampo-candiani j, rendón a. current panorama in the diagnosis of cutaneous tuberculosis. actas dermo-sifiliográficas (english edition). 2009;100(7):562–570. https://doi.org/10.1016/s1578-2190(09)70124-6 abstract introduction rilpivirine for the management of hiv infection: efficacy and tolerability rilpivirine for the management of hiv infection: other important considerations for programmatic settings role of rilpivirine in programmes using efavirenz-based first-line therapy role of rilpivirine as programmes move to dolutegravir-containing first-line therapy dolutegravir in combination with rilpivirine: a nucleoside-sparing treatment option rilpivirine in long-acting injectable antiretroviral regimens the role of rilpivirine in hiv prevention: pre-exposure prophylaxis the role of rilpivirine in hiv prevention: post-exposure prophylaxis ethical consideration conclusion acknowledgements references about the author(s) michelle a. moorhouse wits reproductive health and hiv institute, university of the witwatersrand, johannesburg, south africa karen cohen division of clinical pharmacology, department of medicine, university of cape town, cape town, south africa citation moorhouse ma, cohen k. the role of rilpivirine in southern africa. s afr j hiv med. 2019;20(1), a825. https://doi.org/10.4102/sajhivmed.v20i1.825 opinion paper the role of rilpivirine in southern africa michelle a. moorhouse, karen cohen received: 22 dec. 2017; accepted: 03 apr. 2019; published: 29 may 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract rilpivirine, a second-generation non-nucleoside reverse transcriptase inhibitor (nnrti), is included as an option in first-line antiretroviral therapy (art) for antiretroviral-naïve individuals in treatment guidelines in high-income countries, including the united states and many european countries. rilpivirine is available in a single-tablet fixed-dose combination, has a favourable tolerability profile and is of relatively low cost. however, rilpivirine has reduced efficacy in patients commencing art at high viral loads. therefore, baseline viral load testing is required before commencing rilpivirine, and it is not recommended for patients commencing therapy with a viral load greater than 100 000 copies/ml. rilpivirine is not included in the treatment regimens recommended by the world health organization (who), which form the basis of treatment guidelines in many lowerand middle-income countries. some patients commencing standard first-line regimens experience treatment-limiting toxicity. a low-cost rilpivirine-containing fixed-dose combination would potentially be a useful addition to treatment options available in south africa and other countries in the region, for patients who do not tolerate standard first-line art. in this article, we explore the utility of rilpivirine as an option in art in south africa and the region in the context of current public-sector regimens. we consider what role rilpivirine might play if first-line therapy moves to a dolutegravir-based regimen, as has already happened in some lowerand middle-income countries, including botswana, kenya and brazil. finally, we describe emerging evidence for rilpivirine in the prevention of hiv transmission. keywords: hiv; rilpivirine; antiretrovirals; non-nucleoside reverse transcriptase inhibitor; southern africa. introduction rilpivirine, a second-generation non-nucleoside reverse transcriptase inhibitor (nnrti), is currently approved for the treatment of hiv-1 infection in more than 80 countries around the world. it is included as an option in first-line antiretroviral therapy (art) for antiretroviral-naïve individuals in treatment guidelines in high-income countries, including the united states and many european countries.1,2 rilpivirine is available in a single-tablet fixed-dose combination, has a favourable tolerability profile and is relatively low cost.3 because of reduced efficacy in patients commencing art at high viral loads, baseline viral load testing is required before commencing rilpivirine, and it is not recommended for patients commencing therapy with a viral load greater than 100 000 copies/ml. rilpivirine has not been included in the treatment regimens recommended by the world health organization (who), which form the basis of treatment guidelines in many lowerand middle-income countries. south africa has the largest antiretroviral programme in the world, and purchases antiretrovirals in quantities similar to both the president’s emergency program for aids relief (pepfar) and the global fund. a low-cost, well-tolerated, single-tablet regimen would potentially be a useful addition to treatment options available in south africa and other countries in the region. the suitability of any antiretroviral agent for use within large-scale treatment programmes is determined by a number of factors. these include efficacy; tolerability profile, preferably with no need for laboratory monitoring for safety issues; interactions with commonly prescribed drugs, especially those used to treat coinfections such as tuberculosis and hepatitis viruses; convenience and availability of fixed-dose combinations; availability of paediatric formulations; safety in pregnancy; and affordability. in this article, we explore the utility of rilpivirine as an option in art in south africa and the region, in the context of current public-sector regimens. we consider what role rilpivirine might play if first-line therapy moves to a dolutegravir-based regimen, as has already happened in some lowerand middle-income countries, including botswana, kenya and brazil. finally, we describe emerging evidence for rilpivirine in the prevention of hiv transmission. rilpivirine for the management of hiv infection: efficacy and tolerability the efficacy and tolerability of rilpivirine compared to efavirenz in antiretroviral-naïve individuals was explored in a phase 2b dose-finding study,4,5 in the phase 3 echo6 and thrive7 studies (data from these two registrational studies were pooled for analysis at weeks 48 and 96)8,9,10,11 and the single-tablet regimen (star) study.12 in all of these studies, with the exception of the phase 2b dose-finding study, rilpivirine was associated with fewer adverse events leading to treatment discontinuation than efavirenz (including neuropsychiatric events, rash and dyslipidaemia). the phase 2b study explored three different doses of rilpivirine compared to efavirenz 600 mg. the rilpivirine doses explored were 25 mg, 75 mg and 150 mg, and the study was powered to detect a dose response across the arms at a 5% significance level.5 the study was extended to follow participants out to 192 weeks from 96 weeks and found similar viral suppression and immunological efficacy across the rilpivirine and efavirenz arms, and the rilpivirine 25 mg dose was taken forward into phase 3. the echo and thrive studies demonstrated non-inferior efficacy of rilpivirine compared to efavirenz overall. however, in these studies, which compared rilpivirine 25 mg with efavirenz 600 mg, both in combination with two nucleoside reverse transcriptase inhibitors (nrtis), rates of virological failure and emergence of viral resistance were higher in individuals with high baseline viral loads (> 100 000 copies/ml) receiving rilpivirine than efavirenz at both 4813 and 96 weeks.10 in the echo and thrive studies, 23/686 (3%) of participants taking rilpivirine discontinued because of an adverse event, versus 52/682 (8%) taking efavirenz.13 in a systematic review of randomised clinical trials, comparing safety and neuropsychiatric adverse events of efavirenz with other agents, participants had double the risk of discontinuation because of adverse drug reactions with efavirenz-containing art regimens than with rilpivirine-containing regimens (rr: 2.0, 95% confidence interval [ci]: 1.0 to 3.8; rd: 4.1, 95% ci: 1.3 to 6.8).14 side effects of rilpivirine were uncommon; the two most common side effects were headache in 2% and insomnia in 2% of participants.15 in the star study, both rilpivirine and efavirenz were administered in combination with tenofovir disoproxil fumarate (tdf) and emtricitabine (ftc) as single-tablet regimens. star stratified participants at randomisation according to their baseline viral load (≤ or > 100 000 copies/ml) and demonstrated superiority of the rilpivirine arm at weeks 48 and 96 overall at viral loads below 100 000 copies/ml (for higher viral loads, the rilpivirine arm was non-inferior).12,15 the switching at low hiv-1 rna into fixed-dose combinations (salif) study demonstrated non-inferior efficacy of rilpivirine (rpv)/tdf/ftc in maintaining virological suppression at 48 weeks compared to efavirenz (efv)/tdf/ftc (both administered as a single tablet regimen [str]) in people living with hiv who were virologically suppressed on a nnrti-based regimen prior to randomisation. in the salif study, there were more discontinuations and treatment-limiting adverse events in the rilpivirine arm. this most likely reflects the effect of being switched to a new rilpivirine-containing regimen, as opposed to continuing on an efavirenz-based regimen (randomisation ensured a balance of participants who were previously on nevirapine regimen across both arms, approximately 45%).16 observational data from the swiss hiv cohort followed up patients who were initiated on or switched to the rpv/tdf/ftc str for two years. the main reasons for switches were for regimen simplification or efavirenz-related neuropsychiatric adverse events. the study population were mainly antiretroviral-experienced and virologically suppressed. at 24 months, 96% of treatment-experienced and 100% of treatment-naïve patients remained virologically suppressed. among those who were switched because of neuropsychiatric adverse events, 78.3% experienced improvement at 12 months.17 these results were similar to those of other observational cohorts assessing switches to the str.18,19,20 in summary, rilpivirine has lower efficacy than efavirenz in patients with high viral loads at art initiation. this limits the usefulness of rilpivirine-based regimens in first-line art in resource-constrained settings. most large programmes in lowerand middle-income countries do not routinely quantify viral load at baseline, and adding this test in large programmes would add considerable treatment costs. however, switch studies of virologically suppressed patients have shown good efficacy of rilpivirine in maintaining suppression.16,17,18,19,20,21 rilpivirine may therefore be a useful option for patients needing to switch for tolerability issues, especially those relating to neuropsychiatric adverse events. rilpivirine for the management of hiv infection: other important considerations for programmatic settings drug interactions rilpivirine is mainly metabolised by cytochrome p450 3a4, rendering it vulnerable to the effects of drugs that are cytochrome p450 3a4 inhibitors or inducers. its solubility and therefore absorption are ph dependent, requiring a low ph. because of this, rilpivirine cannot be co-administered with proton pump inhibitors, and when prescribed with histamine-2 receptor antagonists and antacids, doses need to be separated to allow rilpivirine absorption.22 rilpivirine cannot be administered with rifampicin-containing regimens, which are still the mainstay of tuberculosis management in many lowerand middle-income countries where the burden of tuberculosis is the highest. rifampicin may reduce the rilpivirine concentrations substantially,23 putting patients at risk of virological failure. there is a similar interaction with rifabutin.22 this means that all patients on rilpivirine who develop rifamycin-sensitive tuberculosis would need to be switched to alternative art. this adds to programmatic complexity, as well posing a risk to patients who may be switched to a less well-tolerated regimen, potentially risking virological failure. however, this is not a problem unique to rilpivirine, as many arvs require either a treatment change (such as atazanavir) or a change in dose (such as ritonavir-boosted lopinavir and dolutegravir) when co-administered with rifampicin. with the move to ‘test and treat’ resulting in earlier art initiation at higher cd4+ counts, and with increased rollout of various tb prevention therapies, this may become less of an issue as incident tb rates are likely to decline. convenience fixed-dose combinations are preferred in large programmes, not only for their benefits in terms of adherence but also for the benefits they offer in terms of simplicity of supply chain, distribution, stock management, storage and prescription. internationally, both rilpivirine and efavirenz are available co-formulated with either tdf and ftc, or tenofovir alafenamide (taf) and ftc. taf is a prodrug of tenofovir, which is potentially associated with less bone and renal toxicity than tdf because of lower plasma tenofovir exposure.24,25 unfortunately, none of the rilpivirine fixed-dose combinations, or formulations of either drug containing taf, are currently available in south africa. paediatric formulations currently, there are no specific paediatric formulations of rilpivirine available and the adult formulation can only be used in children from 12 years and weighing 35 kg or more. where possible, within large-scale programmes, harmonisation of adult and paediatric regimens is preferred. this is not currently possible with rilpivirine. safety in pregnancy pregnancy can affect rilpivirine concentrations by its effect on cardiac output, protein binding, volume of distribution and cytochrome p450 3a4 activity.26 rilpivirine concentrations are reduced during pregnancy, especially during the third trimester,26,27 as is seen with many other antiretrovirals. in two studies that investigated the pharmacokinetic characteristics of rilpivirine in pregnant women, nearly all the women had rilpivirine concentrations above the ic90 (the concentration of drug required to inhibit viral replication by 90%). this suggests that no dose adjustment is required despite the reduced rilpivirine exposures during pregnancy. in both studies, the women maintained virological suppression and the infants were not hiv-infected.26,27 the antiretroviral pregnancy registry (apr) still has relatively low numbers of rilpivirine-exposed pregnancies. for first trimester exposures to rilpivirine, there was one birth defect in 202 pregnancies (0.5%; 95% ci: 0.0%, 2.7%); for second trimester exposures, there were three birth defects in 247 pregnancies (1.2%; 95% ci: 0.3%, 3.5%).28 no specific teratogenic concerns have emerged to date. affordability in south africa, rilpivirine currently has a ‘single exit’ price of around zar 50.00 (around us $3.70) for a 30-day supply versus zar 175.00 (around us $13.00) for efavirenz.29 efavirenz is unlikely to decrease in price any further and is therefore unlikely to achieve price parity with rilpivirine. this does not include any costs related to managing side effects related to the use of efavirenz, which is associated with higher adverse event-related discontinuations compared to rilpivirine across several studies.14 role of rilpivirine in programmes using efavirenz-based first-line therapy internationally, treatment guidelines have moved to recommending art initiation irrespective of who clinical stage or cd4+ count.30 benefits of art initiation are modest for those with earlier stage disease, and need to be weighed up against the potential harms, which include side effects and toxicity from art when initiated in asymptomatic patients at high viral loads. a systematic review including 42 randomised controlled trials found that the relative risk for discontinuations because of adverse events was higher for efavirenz compared to most other first-line options, including low-dose efavirenz (400 mg), rilpivirine, tdf, atazanavir and maraviroc, and that neuropsychiatric adverse events were common with efavirenz.14 notably, most of the studies included were conducted in predominantly white populations. black africans have a much higher prevalence of efavirenz slow metaboliser genotypes than white people (17% vs. 3% in south africa),31 which may result in more frequent efavirenz-related neuropsychiatric adverse events. efavirenz is superior to rilpivirine for programmatic use in a standard first-line art regimen because it has higher virological efficacy at high viral loads, is available in fixed-dose combination formulations, can be prescribed with rifampicin and is safe in pregnancy. rilpivirine cannot be prescribed with rifamycin-containing tb treatment. although rilpivirine is cheap, it has reduced efficacy at high baseline viral loads and cannot therefore be used for first-line therapy without pre-art initiation viral loads. pre-art viral loads are not routinely performed in southern african art programmes and would considerably increase total cost to the healthcare system of the first-line regimen. in addition, data on rilpivirine use in pregnancy are limited and the reduction in rilpivirine exposure during the third trimester of pregnancy is concerning.26,27,32 however, for patients with a contraindication to efavirenz (e.g. history of psychosis) or who experience severe neuropsychiatric side effects on efavirenz, alternatives are currently limited. nevirapine cannot be prescribed for women initiating art with cd4+ counts above 250 cells/µl or men initiating art with cd4+ counts above 400 cells/µl because of the risk of severe hepatotoxicity. in addition, nevirapine is associated with a higher frequency of severe adverse events, particularly treatment discontinuations, than efavirenz.8 the only other alternative in current guidelines for patients with high cd4+ counts is to initiate ritonavir-boosted lopinavir. as ritonavir-boosted lopinavir is used in second-line therapy, this limits future treatment options. as rilpivirine has better tolerability than efavirenz,14 a rilpivirine-based regimen would be a very useful alternative for patients with contraindications to efavirenz or treatment-limiting toxicity once initiated on efavirenz-based art. role of rilpivirine as programmes move to dolutegravir-containing first-line therapy dolutegravir is newly included in current who guidelines as a recommendation for first-line art and is starting to be rolled out across several lowerand middle-income countries. dolutegravir has demonstrated robustness with a formidable barrier to resistance, good tolerability and superiority to both efavirenz and ritonavir-boosted lopinavir in clinical trials, in both antiretroviral-naïve and experienced patients.33,34 in these studies, dolutegravir’s tolerability is likely to have contributed to the superior efficacy demonstrated. the main dolutegravir-related treatment-emergent adverse event reported in these studies was insomnia.33,34 dolutegravir was found to be protective of discontinuations because of adverse events in a network meta-analysis that included 34 032 patients on first-line art.35 dolutegravir was also shown to have superior efficacy to both efavirenz and rilpivirine in the network meta-analysis.35 because of the relatively small number of carefully selected participants included in registrational studies of newer antiretrovirals, more information regarding the safety profile may emerge only after registration, once the use of the antiretroviral becomes more widespread. since dolutegravir’s approval, observational cohorts have reported neuropsychiatric adverse events, including depression, anxiety and suicidal ideation in patients receiving dolutegravir.36,37,38,39 this has been seen with other integrase inhibitors and has been postulated as a possible class effect.40,41,42,43 more recently, data have suggested44 that dolutegravir may also be associated with weight gain in a number of cohorts as well as clinical studies. potentially, rilpivirine could be used in people living with hiv who experience intolerance to dolutegravir as the transition to dolutegravir-based first-line art rolls out. furthermore, a prospective study was set up in botswana to quantify the incidence of neural tube defects with efavirenz exposure. this cohort also considers other birth outcomes and includes a number of patients on dolutegravir. it recently showed a worrying signal of increased incidence of neural tube defects with periconception use of dolutegravir.45 if confirmed, this signal will raise a dilemma regarding the use of dolutegravir in women at risk of falling pregnant. dolutegravir in combination with rilpivirine: a nucleoside-sparing treatment option recent data from the sword 1 and 2 studies of dolutegravir in combination with rilpivirine suggest that this dual therapy regimen may be effective maintenance regimens in virologically suppressed patients.46 the sword studies randomised virologically suppressed participants with no history of virological failure to continue their current art regimen or switch to dolutegravir and rilpivirine. switching to the dual therapy regimen was found to be non-inferior to continuing the initial regimen over 48 weeks. this is despite the inherent bias of the switch study design against the drug being studied, where switching may result in adverse events that could result in virological failure because of non-adherence. in addition, observational data from several cohorts have demonstrated the efficacy of this regimen in achieving and maintaining virological suppression in patients with varying degrees of antiretroviral experience.47,48,49 a fixed-dose combination of rilpivirine and dolutegravir was recently approved by the food and drug administration (fda),50 based on the results of the sword studies. however, the inability to co-administer with rifamycin-containing tb treatment limits the usefulness of this coformulation in lowerand middle-income settings with high tb burdens. rilpivirine in long-acting injectable antiretroviral regimens the combination of long-acting rilpivirine and the integrase inhibitor cabotegravir is being studied in an injectable therapy for the treatment and prevention of hiv-1 infection. the phase 2b latte 2 study randomised patients to oral cabotegravir plus abacavir plus lamivudine and long-acting cabotegravir plus rilpivirine injected 4 weekly, and found that the injectable dual therapy regimen was well tolerated and had efficacy similar to the oral regimen.51 further studies, such as first long-acting injectable regimen (flair) and art as long-acting suppression (atlas), are currently underway to evaluate this dual therapy injectable regimen. however, there is still significant research needed before this regimen could be considered for programmatic use in lowerand middle-income countries. this would need to include data on tb co-infected and pregnant patients. the role of rilpivirine in hiv prevention: pre-exposure prophylaxis currently the only approved and who-recommended pre-exposure prophylaxis (prep) option is oral tenofovir-based prep,30 which has demonstrated its efficacy in preventing hiv infection in multiple randomised controlled trials52 and demonstration projects in different target populations, with more evidence continuing to accumulate. however, there are those for whom oral tenofovir-based prep is not an appropriate option, either on account of contraindications to the drug itself, or on account of other factors related to oral formulation or the requirement to take pills regularly. for such individuals, alternative prep options are essential. early studies of long-acting rilpivirine (alone or in combination with a long-acting integrase inhibitor, cabotegravir) confirmed the initial safety, acceptability and pharmacokinetic characteristics of the formulation.53,54 plasma, rectal and cervical fluid sampling and limited rectal and vaginal biopsies after single doses of 300 mg – 1200 mg long-acting rilpivirine in one of these studies demonstrated prolonged rilpivirine exposure in plasma as well as the genital tract for 84 days. in this study, one female participant subsequently experienced incident hiv-1 (wild-type virus) infection after a single episode of unprotected vaginal intercourse approximately 41 days after she received the 300 mg rilpivirine injection. viraemia peaked on day 115, and at this point, a mixed population of 101 k/e was detected and art was initiated. resistance was selected by high levels of viral replication in the face of low rilpivirine concentrations. the viral population reverted to predominantly wild-type by day 199. this incident infection illustrates the risk of subtherapeutic concentrations of long-acting agents that are not high enough to prevent infection but are sufficient to select for resistance.56 a subsequent phase 1 study enrolled 36 hiv-negative participants and alternately assigned them to receive one intramuscular dose of long-acting rilpivirine, either 1200 mg or 600 mg. the safety and acceptability findings were in line with previous studies. these findings were confirmed in a multiple dose phase of this study.57 hptn 076 is a double-blind, randomised study, which compared the safety of long-acting rilpivirine1200 mg every 8 weeks to placebo, following a 4-week run-in oral phase, for prep in low-risk, sexually active hiv-uninfected women. the study demonstrated no significant differences between the two arms with respect to adverse events. it also showed that for 92% of participants, plasma rilpivirine concentrations were above the protein-adjusted ic90. currently, hptn 076 study has only reported safety, acceptability and pharmacokinetic findings,58,59 and the long-acting rilpivirine will not be taken forward into prep efficacy studies at this stage. to date, no studies using rilpivirine oral formulations as prep have been conducted, except where it has been used as an initial run-in phase to establish tolerability prior to progressing onto the administration of injectable formulations. the role of rilpivirine in hiv prevention: post-exposure prophylaxis while a number of prep randomised controlled trials have been conducted with various drug regimens, there are no randomised studies on antiretroviral regimens for post-exposure prophylaxis (pep). most data supporting the use of pep are derived from animal transmission models, prevention of mother-to-child transmission trials, observational studies of healthcare workers receiving pep following occupational hiv exposure, and observational cohorts and case studies of pep following potential sexual exposure. adherence to the full 28-day course of pep has been shown to be poor, with only 56.6% (95% ci 50.9–62.2%; t2 0.25) of those eligible completing the course,60 and lower in adolescents than in adults. a significant proportion of pep discontinuation is related to adverse events, indicating that better tolerated pep regimens are needed. a systematic review of observational data concluded that tenofovir-based pep regimens were better tolerated than those using zidovudine, while the optimal third drug to use was a little less clear. while raltegravir was well tolerated, other factors such as twice daily dosing, availability and cost were identified as limitations to the use of raltegravir as the third drug, particularly in resource-limited settings.61 subsequently, a number of pep observational studies using newer antiretrovirals have been undertaken. one single-arm study and one observational cohort used rilpivirine for pep. the single arm study used a str of rilpivirine combined with tdf and ftc for 28 days in 100 hiv-uninfected men who have sex with men. post-exposure prophylaxis completion rates were high at 92% and adherence rates at 98.6% (standard deviation [s.d.], 2.4) by pill count. discontinuations for adverse events were low (1%).62 these results are similar to the findings of a french observational cohort study including 129 participants, which evaluated the safety, tolerability, adherence and efficacy of a 28-day course of single-tablet rpv/tdf/ftc commenced within 48 hours of potential exposure to hiv.63 in these studies, adverse events were commonly reported by participants but were of low grade, and there were no seroconversions. with the high number of participants completing their pep regimens in these studies, rilpivirine is an attractive option as a third drug for pep regimens, offering the advantages of cost and coformulation (although the coformulation is not available in many countries). with more lowerand middle-income countries introducing dolutegravir into first-line art, another potential advantage of rilpivirine-based pep is the lack of overlapping resistance profiles between rilpivirine and dolutegravir. ethical consideration this article followed all ethical standards for a research without direct contact with human or animal subjects. conclusion many lowerand middle income countries use efavirenz-based regimens for first-line art. efavirenz has good efficacy and relatively good tolerability, is available in fixed-dose combination str at low cost, is safe in pregnancy and can be used concomitantly with rifampicin-containing tb treatment. however efavirenz causes treatment-limiting toxicity in some individuals and should be used with caution in psychiatric disease. rilpivirine cannot replace efavirenz in standard first-line therapy. rilpivirine is not optimal for patients with high baseline viral loads because of reduced efficacy, and cannot be prescribed with rifampicin. in addition, there is a paucity of rilpivirine safety data in pregnancy, and the decrease in rilpivirine concentrations during pregnancy is concerning: more data in pregnancy are required to inform recommendations on use in pregnancy. however, rilpivirine is generally well tolerated and may be a useful alternative for people living with hiv who cannot tolerate efavirenz or in whom it is contraindicated. if rilpivirine is initiated in treatment-naïve patients, a baseline viral load is mandatory because of reduced efficacy at high viral loads in phase 3 trials, and if the baseline viral load is more than 100 000 copies/ml, an alternative drug is preferable. with increasing use of dolutegravir as more country programmes transition to dolutegravir-based first-line art, emergent neuropsychiatric adverse events are being reported, suggesting an overlapping toxicity profile with current efavirenz-based regimens. for patients who experience neuropsychiatric or other toxicity or with contraindications to current or future first-line art regimens, rilpivirine may be a useful alternative. acknowledgements competing interests dr michelle moorhouse has received speaker fees and honoraria from gilead sciences, abbvie, cipla, mylan and janssen, and has received conference sponsorship from bd, gilead, janssen, merck, cipla and mylan. her work forms part of art optimisation collaborations and receives funding from usaid, unitaid and the south african medical research council (samrc) and study drug donations from viiv healthcare and gilead sciences for art optimisation studies. prof karen cohen has no conflicts of interest to declare. authors’ contributions m.a.m. and k.c. conceived the scope and structure of the article together. m.a.m. completed the first draft. k.c. assisted with refining the article for submission. references williams i, churchill d, anderson j, et al. british hiv association guidelines for the treatment of hiv1-positiveadults with antiretroviral therapy 2012 (updated november 2013). hiv med. 2014;15(suppl 1):1–85. european aids clinical society. eacs guidelines 2017 [homepage on the internet]. 2017 [updated october 2017]. version 9.0. available from: http://www.eacsociety.org/files/guidelines_9.0-english.pdf meintjes g, moorhouse m, carmona s, et al. southern african hiv clinicians society adult antiretroviral therapy guidelines 2017. s afr j hiv med. 2017;18(1):a776. https://doi.org/10.4102/sajhivmed.v18i1.776 wilkin a, pozniak al, morales-ramirez j, et al. long-term efficacy, safety, and 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https://doi.org/10.1097/qad.0000000000001145 van’t klooster g, hoeben e, borghys h, et al. pharmacokinetics and disposition of rilpivirine (tmc278) nanosuspension as a long-acting injectable antiretroviral formulation. antimicrob agents chemother. 2010;54(5):2042–2050. https://doi.org/10.1128/aac.01529-09 verloes r, deleu s, niemeijer n, crauwels h, meyvisch p, williams p. safety, tolerability and pharmacokinetics of rilpivirine following administration of a long-acting formulation in healthy volunteers. hiv med. 2015;16(8):477–484. https://doi.org/10.1111/hiv.12247 jackson ag, else lj, mesquita pm, et al. a compartmental pharmacokinetic evaluation of long-acting rilpivirine in hiv-negative volunteers for pre-exposure prophylaxis. clin pharmacol ther. 2014;96(3):314–323. https://doi.org/10.1038/clpt.2014.118 glaubius rl, parikh um, hood g, et al. deciphering the effects of injectable pre-exposure prophylaxis for combination human immunodeficiency virus prevention. open forum infect 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review. clin infect dis. 2015;60(suppl 3):s170–s176. https://doi.org/10.1093/cid/civ092 foster r, mcallister j, read tr, et al. single-tablet emtricitabine-eilpivirine-tenofovir as hiv postexposure prophylaxis in men who have sex with men. clin infect dis. 2015;61(8):1336–1341. https://doi.org/10.1093/cid/civ511 allavena c, bonnet b, merrien d, et al. compliance to and safety of tenofovirdf/emtricitabine/rilpivirine in post-exposure prophylaxis. 9th ias conference on hiv science; 23–26 july 2017; paris, france; 2017. abstract introduction relevance objectives research design and method results discussion conclusion acknowledgements references appendix 1 about the author(s) delarise m. mulqueeny school of nursing and public health, university of kwazulu-natal, south africa myra taylor school of nursing and public health, university of kwazulu-natal, south africa citation mulqueeny dm., taylor m. patients’ recommendations for a patient-centred public antiretroviral therapy programme in ethekwini, kwazulu-natal. s afr j hiv med. 2017;18(1), a677. https://doi.org/10.4102/sajhivmed.v18i1.677 original research patients’ recommendations for a patient-centred public antiretroviral therapy programme in ethekwini, kwazulu-natal delarise m. mulqueeny, myra taylor received: 11 aug. 2016; accepted: 20 jan. 2017; published: 31 mar. 2017 copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the south african antiretroviral therapy (art) programme, which is in its second decade of existence, includes many successes and challenges. this study provides patients’ recommendations to address the challenges they currently experience at four antiretroviral (arv) clinics based in urban public hospitals in order to provide a patient-centred service. objectives: to use patients’ recommendations to develop intervention strategies to improve patients’ experiences of the public art programme. method: a three-stage, sequential, mixed-method study was implemented. stage 1 recruited five patients from the four sites to formulate and test a structured questionnaire prior to data collection. stage 2 recruited a stratified random sample of 400 patients (100 from each hospital) to complete the administered structured questionnaire. stage 3 purposively selected 12 patients (three from each of the four sites) to participate in in-depth audio-recorded interviews using an interview schedule. results: the 412 patients prioritised six recommendations, which are as follows: waiting areas should be enclosed to protect patients from the elements (rain, sun, lightening, wind and cold); patients should not have to return their files to the main hospital or arv clinic themselves; stable patients should collect their arv drugs every three months; pharmacy opening and closing times should be revised to suit patients’ needs; hiv-positive patient representatives should be elected at each arv clinic to address patients’ concerns and/or challenges to ensure that the programme could be more patient-centred and arv clinic operating times should be extended to open later during weekdays and over weekends. conclusion: patients living with hiv have a valuable contribution to make in assessing service delivery and making recommendations to create a patient-centred healthcare environment, which will feasibly increase their adherence to art. introduction in 2003, the south african department of health initiated a much welcomed antiretroviral therapy (art) rollout programme for patients.1 subsequent advancements in treatment as well as changes to the eligibility criteria have increased the availability of art, resulting in people living with hiv (plhiv) establishing families, living longer and enjoying meaningful employment.2,3 plhiv require comprehensive hiv care, which includes management of opportunistic infections, nutritional deficiencies, antiretroviral (arv) side effects and co-morbidities as well as assistance with psychosocial, spiritual and socio-economic challenges.4,5 this assistance must be ongoing for arv adherence, to avoid drug resistance and promote retention, which is essential for the success of the art programme and patients’ well-being.6,7 the public art programme is perceived by many as successful.8,9 however, it is also affected by challenges,10,11 which include all plhiv receiving quality treatment, adherence, sustaining patients on art, closing the gap between urban and rural health services and addressing operational problems (strikes, staff and drug shortages, infrastructure challenges, overburdened staff and training and upscaling of staff).12,13,14,15 the national hiv counselling and testing campaigns16 and the south african health minister aaron motsoaledi’s announcement that as from september 2016 all hiv-positive patients could access art irrespective of their cd4 count is likely to increase the number of patients attending the public art programme and may further challenge the quality of patient care.17,18,19 relevance this study reports patients’ recommendations based on their experiences, which serve as a patient-driven interventional component, to improve the local public art programme. involving patients in assessments of service quality and delivery is a growing trend and becoming a global phenomenon.20 such a study is lacking in south africa and could be beneficial to policy makers, programme directors and patients and serve as a catalyst to achieve patient-centred care within the current public art programme and health systems, both locally and nationally. objectives this study investigated what could be implemented to enable the art programme to be more patient-centred at four urban public hospitals. the objectives are to describe patients’ recommendations to improve the public art programme, enhance treatment adherence and retention, reduce morbidity and mortality rates and ensure patient-centred care. research design and method a sequential, mixed-method, multi-site approach was employed to provide reliable and valid results.21 initially, the study utilised structured questionnaires and thereafter face-to-face, in-depth interviews (idis) to provide recommendations to improve the quality of care at four arv clinics, based in hospitals within ethekwini district, kwazulu-natal. the reason for the study taking place in this province is that it has the second largest population in south africa and is at the epicentre of the south african hiv epidemic.22,23,24 initially, five experienced and articulate art patients of both sexes and different ages, a minimum of one from each facility, who did not participate in further data collection, described their experiences and the challenges they encountered and together formulated a total of 41 recommendations to ensure a patient-centred art programme at their facility. these were included in the questionnaire. a stratified random sample of patients (400), 100 from each clinic from four public hospitals in the ethekwini district, participated in the administered structured questionnaires. every fourth patient visiting the clinic was systematically and randomly selected starting with the first patient attending the clinic daily. the quantitative sample comprised 161 men and 239 women of different ages, ethnicity and sexual orientation. twelve respondents (three from each site) for the idis were purposively recruited to achieve gender, race and sexual orientation representation. six female and six male patients, aged between 18 and 67 years, participated in the interviews, with seven respondents identifying as heterosexual, four as gay and one as bisexual. all 412 hiv sero-infected patients met the study criteria as they were aged 18 years or older and had accessed the art programme at one of the four arv clinics for at least one year or more. completion of all the questionnaires and interviews took place in and around the outpatient arv clinics within the hospital grounds. informed consent and confidentiality was explained to ensure voluntary participation in the study. no refusals were documented, and all 412 respondents signed informed consent forms prior to the data collection process. this took place from august to november 2015. all the questionnaires were administered by the principal investigator (pi) and two research assistants who were fully conversant in zulu, afrikaans and english. the patients requested the interviews be held in english; however, the trilingual research assistants were also present during the process. no language challenges were reported. the researcher conducted the idis with an interview schedule and utilised probes where and when necessary. data analysis questionnaires were checked prior to the patients leaving the site, and the data were entered into epidata software and analysed utilising the statistical package for the social sciences (spss 22) software. the interview transcripts were read several times to ensure a thorough understanding of the information and context. open-coding techniques were used for the content analysis of each transcript to identify themes and sub-themes based on recurring ideas and concepts.25 reliability and validity a sequential, mixed-method design was appropriate to provide reliable, valid results, which johnson and onwuegbuzie26 describe as important as ‘research approaches should be mixed in ways that offer the best opportunities for answering important research questions’ (p. 16). to ensure all data were accurately captured, dual recording took place during the interviews. the transcripts were read several times by the researcher and coded using thematic analysis to identify differences and similarities of respondents’ answers to ensure the dependability and trustworthiness of the data. coded questionnaires and interview transcripts ensured anonymity, which provided valid results. the process was continuously discussed and checked by the co-author. potential benefits and hazards all respondents were allowed to ask questions regarding the questionnaires and interviews prior, during and subsequent to data collection taking place, to ensure all respondents understood the research process. the sensitive nature of the research study dictated that confidentiality and privacy were respected at all times. patients were offered follow-up sessions with a social worker or counsellor to avoid any psychological or emotional harm.27 to respect busy arv clinics, continuous communication with the clinic staff took place.28 all completed anonymous questionnaires, electronic records, tape recordings and transcripts were stored in a locked cupboard for the duration of the study and will be destroyed five years after study completion. ethical consideration the biomedical research ethics committee (bfc089/15) and the kwazulu-natal department of health (hrkm158/15) granted ethical clearance, while site clearance was obtained from the four hospital managers prior to the commencement of the study. results change, the only constant to ensure patient-centred care five patients from public arv clinics, together with the pi, formulated 41 recommendations, to ensure that the art programme at all four hospitals is patient-centred. patients were required to choose six primary recommendations for the purpose of this study. the quantitative data are presented in figure 1. figure 1: patient recommendations. recommendations from the in-depth interviews the six most popular recommendations from the idis were similar to those chosen by respondents who answered the questionnaires. physical space and infrastructure respondents reported discomfort with open waiting areas as follows: ‘they should put an urn outside so we can make ourselves some tea in winter or provide us with sandwiches while we wait outside.’ [participant 12, female, 57 years] ‘we have been sitting like this for too long. this waiting area needs to be closed up.’ [participant 7, male, 38 years] ‘government and staff should work with private companies to find money to improve this clinic.’ [participant 9, male, 50 years] patient files the recommendations below expose an inadequate filing system: ‘the filing system must be improved because our files keep getting lost.’ [participant 5, female, 67 years] ‘they should invest in a computerised filing system.’ [participant 11, male, 40 years] ‘hiring qualified staff in the filing department would help.’ [participant 1, female, 62 years] antiretroviral drugs collection outsourcing of pharmacies, flexibility of pharmacy operation times and dispensing processes and reduction in the costs of arv drugs collection are highlighted below: ‘it would be so much better if our meds were delivered to our home or work.’ [participant 2, female, 26 years] ‘the quicker they outsource the arv pharmacy the better. it would be much better to collect our medication at private pharmacies such as dischem or clicks as we can collect on weekends and after work.’ [participant 5, female, 67 years] ‘surely it would save the staff time, money and irritation if they give us our medication once every three months. i know all the patients would be happy because we would save taxi fare.’ [participant 6, male, 18 years] patient representation and satisfaction respondents’ need for patient involvement, engagement and representation are expressed below: ‘i feel we should have a representative, representing us. we should do anonymous forms and hand it in outside this clinic.’ [participant 1, female, 62 years] ‘if we had one of our own representing us i think the service would improve for us.’ [participant 2, female, 26 years] ‘patients should be involved because patients tell other patients the truth, not staff. they need our input so they should employ us as patient therapists because we are the experts.’ [participant 3, male, 46 years] ‘a representative should sit in on hospital meetings so our problems are put forward.’ [participant 6, male, 18 years] ‘we need to be involved in this programme so that service improves all the time.’ [participant 8, female, 29 years] ‘patients must be represented so we know and understand our rights.’ [participant 9, male, 50 years] ‘i don’t think a patient rep will make a difference, we are just hiv patients.’ [participant 10, male, 46 years] ‘even though we receive good service from the clinic staff i think it is important for a representative to discuss the pharmacy story. they should hire patients as role-models.’ [participant 7, male, 38 years] these responses emphasise patients’ need for a trustworthy, engaging and empowering environment and a programme that promotes patients’ self-worth and rights. all these recommendations promote and embody patient-centred care. pharmacy operational times the responses below articulate patients recommending outsourcing of the arv pharmacies and revision of operational times: ‘they should close this pharmacy and let us go to private chemists to collect.’ [participant 4, male, 35 years] ‘if they don’t want to change the weekday times they should let us collect on the weekend or from private chemists.’ [participant 8, female, 29 years] ‘the pharmacy is an area of concern at this clinic. if they can sort it out, then this would be a clinic that other medical staff could learn a thing or two from the staff at this clinic.’ [participant 7, male, 38 years] the latter response highlights the respondents’ satisfaction with service delivery and even suggests learning opportunities for other arv clinic staff. this latter respondent accesses treatment at hospital 3, which has inconsistent pharmacy opening times. antiretroviral clinic operational times extension of clinic operational times and inclusion of signage to suit patients’ needs are recommendations provided below: ‘we should be able to attend a clinic after hours. [participant 4, female, 35 years] ‘signs should be put up of how long it’s going to take us in this clinic.’ [participant 5, female, 67 years] ‘weekends are the solution as most working people are off work.’ [participant 10, male, 46 years] ‘all clinics should open at 7 o’clock and close at 5 pm so that we can be seen before or after work.’ [participant 11, male, 40 years] worth noting was that the majority of the patients arrived at the hospital between 4:00 and 7:00, which entailed them leaving their homes very early to meet their scheduled 7:00 appointments. respondents required arv clinics operational times to be extended to open earlier, close later and include weekends. discussion patient-centred care places patients at the centre of their healthcare journey.29 hence, patients recommending improvements and changes to ensure a patient-centred arv clinic is both empowering and inclusive to the patient healthcare dynamic.30 the six most popular recommendations focus on improvement to the physical space and infrastructure, patients’ files, arv drug collection frequency, patient representation and satisfaction, pharmacy operational times and the arv clinic operational times. physical space and infrastructure the majority of the questionnaire respondents (72%) recommended enclosed waiting areas, which concurs with an evaluation of the art programme in kwazulu-natal, south africa, which highlighted the ‘mismatch between supply and demand’.31 a comfortable safe environment where patients are not concerned about the elements and being seen by others should be a priority for all sites as is the case with hospital 1.32 patient files the results concur with the findings of an assessment of public arv clinics conducted between june and november 2009 and another study conducted at a johannesburg clinic, which highlighted challenging filing systems as new files were opened and such challenges lead to loss to follow-up.33,34 an electronic or improved filing system could improve patient turnaround time and lessen the opportunity for files being lost. the study highlighted the inconsistency and variability of services and processes between sites, which requires further interrogation. antiretroviral drug collection and pharmacy operational times arv stock-outs, transportation costs and lengthy waiting times are challenges that patients are confronted with when collecting their arv drug and other chronic medication. the study results concur with a study conducted at a public hospital, which concluded that arv drugs are provided free of charge; however, the cost of attaining them (transport, time off work) is high and could affect adherence.35,36 the introduction of the central chronic medicine dispensing and distribution programme (ccmdd) is an attempt at alleviating such challenges. this programme allows patients to collect their chronic medication from designated pharmacies and healthcare facilities. these facilities operate after hours and on weekends and would be meaningful and cost-effective for patients on arv drugs, as they would be able to access their medication nearer to their homes and/or workplace at times that are convenient for them.37 however, the data collection process took place in 2015 and this intervention had not been implemented at the four study sites. during 2016 some sites have introduced the programme. hence a follow-up study on the impact of the ccmdd programme might yield different results. patient representation and satisfaction respondents viewed themselves as ‘patient therapists’, ‘role-models’ and ‘experts’ who should be involved and/or employed at arv clinics to assist other patients and play an active role in improving systems and processes to enhance patient care.38 these findings concur with a study conducted at 18 sub-saharan health facilities to assess the degree of patient involvement at hiv care hospitals, which concluded that patient involvement was a necessity towards improving service delivery.34 a malawian study also highlighted the benefits of involving plhiv in treatment programmes.39 our study results also highlighted patients’ internalised and healthcare workers’ stigma and disrespect, which contradicts the findings of kieft et al. 2014.40 antiretroviral clinic operational times most patients were in the arv clinic for between one and two hours from the time they entered to the time they exited. this timeframe did not include collecting their arv drugs as three arv pharmacies are separate from the arv clinics. the refurbishments at hospital 2’s arv clinic included a pharmacy inside the clinic, which was unique and saved patients’ time. the pharmacy and clinic operational times have been documented as challenges to patients in other studies.41,42 hence, patients’ recommendations of flexible and extended operational hours, which include earlier and later closing times and weekends, could be beneficial. the rollout of the central chronic medicine dispensing (ccmd) and implementation of flexible, extended hours could improve patients’ experiences. some recommendations can be implemented at the hospital level, whereas others require provincial and national intervention in terms of budgetary and human capital resources. these would promote patient-centred care through strengthened patient–provider relationships; improved and extended pharmacy and operational times; warm, nurturing clinics; continuous improvement; qualified, patient-friendly and respectful staff; empowering and engaging systems; reciprocal communication; improved outsourcing services; patient representation and satisfaction; destigmatised clinical environments; and updated filing systems and processes. the recommendations further provide opportunities for staff to learn best practices from each other and other clinics to improve their systems and processes. however, inasmuch as these six recommendations did not prioritise waiting times, waiting areas, staff attitudes, patient–provider relationships, staff training, stock-outs and financial assistance, the other recommendations did and are discussed in subsequent papers. the patients’ six recommendations and the 35 that are included in appendix 1 would result in a patient-centred clinic that patients approve of and signify an ideal arv clinic. limitations of the study the study was conducted at four hospitals within ethekwini district; therefore, more studies at other hospitals and primary health care (pch) facilities could yield further recommendations for improvement of the current art programme in kwazulu-natal. recommendations staff perceptions and experiences of the public art programme as well as their recommendations for patient-centred arv clinics could be explored in future studies. conclusion as patients are the cornerstone of the south african art programme, it is important and relevant to understand their needs 12 years after the rollout of the public art programme. the findings are concerning for sites within a large metro; however, room for change and improvements to the programme were highlighted. the study also emphasised that the patients were prepared to assist in improving the status quo by offering recommendations that could be feasibly implemented to improve the current art programme. the results presented patients’ willingness to participate as ‘patient therapists’, ‘role-models’ and ‘expert’ patients. this study concurs with other relevant studies regarding patient experiences of the public art programme and healthcare system but goes further to provide recommendations for improvement. acknowledgements the authors would like to thank all the patients for participating in this study. competing interests the authors declare that they have no financial or personal relationships, which may have inappropriately influenced this article. authors’ contributions d.m.m. was a phd candidate and m.t. the supervisor while writing this article. references nyasulu jcy, muchiri e, mazwi s, ratshefola m. nimart rollout to primary healthcare facilities increases access to antiretrovirals in johannesburg: an interrupted time series analysis. s afr med j. 2013;103(4):232–236. https://doi.org/10.7196/samj.6380 green k, dix o, mwangi-powell f, horne c, luyirika e. where’s the care in the post-art era? afr health. 2012:19–21. hoa dm. antiretroviral therapy (art) adherence among people living with hiv/aids (plhiv) in the north of vietnam: a multi-method approach [phd thesis]. brisbane, australia: school of public health, faculty of health and institute of health and biomedical innovation, queensland university of technology; 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physical environmental factors on users. build environ. 2012;58:70–80. https://doi.org/10.1016/j.buildenv.2012.06.016 kinkel hf, adelekan am, marcus ts, wolvaardt g. assessment of service quality of public antiretroviral treatment (art) clinics in south africa: a cross-sectional study. bmc health serv res. 2012;12(228):1–12. https://doi.org/10.1186/1472-6963-12-228 shumba cs, atukunda r, memiah p. patient-centred quality care: an assessment of patient involvement. int j med public health. 2013;3(2):77–80. https://doi.org/10.4103/2230-8598.115159 rosen s, ketlhapile m, sanne i, desilva mb. cost to patients of obtaining treatment for hiv/aids in south africa. s afr med j. 2007;97(7):524–529. maskew m, macphail p, menezes c, rubel d. lost to follow-up: contributing factors and challenges in south african patients on antiretroviral therapy. s afr med j. 2007;97(9):853–857. health systems trust [homepage on the internet]. 2016 [cited 2016 sep 11]. available from: http://www.hst.org.za/projects/central-chronic-medicine-dispensing-and-distribution-programme-ccmddcmddp mwai gw, mburu g, torpey k, frost p, ford n, seeley j. role and outcomes of community health workers in hiv care in sub-saharan africa: a systematic review. j int aids soc. 2013;16(1):18586. https://doi.org/10.7448/ias.16.1.18586 tenthani l, cataldo f, chan ak, bedell r, matiniuk alc, van lettow m. involving expert patients in antiretroviral treatment provision in a tertiary referral hospital hiv clinic in malawi. bmc health serv res. 2012;12:140. https://doi.org/10.1186/1472-6963-12-140 kieft r, de brouwer b, francke a, delnoij d. how nurses and their work environment affect patient experiences of the quality care: a qualitative study. bmc health serv res. 2014;14:249. https://doi.org/10.1186/1472-6963-14-249 mathibe md, hendricks sh, bergh a. clinician perceptions and patient experiences of antiretroviral treatment integration in primary health care clinics, tshwane, south africa. curationis. 2015;38(1). https://doi.org/10.4102/curationis.v38i1.1489 peltzer k. patient experiences and health system responsiveness in south africa. bmc health serv res. 2009;9:117. https://doi.org/10.1186/1472-6963-9-117 appendix 1 table 1-a1: other recommendations. hiv 976 guideline consensus statement: management of drug-induced liver injury in hiv-positive patients treated for tb e jong,1 md, phd; f conradie,1 mb bch, dtm&h, dip hiv man; r berhanu,2 md, dtm&h, dip hiv man; a black,3 bsc, mb bch, fcp (sa), cert pulm (sa); m-a john,4 mb chb, fcpath (micro), dip hiv man, dtm&h; g meintjes,5 mb chb, mrcp (uk), fcp (sa), dip hiv man, mph, phd; c menezes,6 md, mmed, dip hiv man, dtm&h, fcp (sa) 1 clinical hiv research unit, department of medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa 2 tb focal point, right to care, johannesburg, south africa 3 wits reproductive health and hiv institute, department of medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa 4 durban international clinical trials unit, university of kwazulu-natal, durban, south africa 5 institute of infectious disease and molecular medicine, and department of medicine, faculty of health sciences, university of cape town, south africa 6 division of infectious diseases, department of medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa corresponding author: f conradie (fconradie@witshealth.co.za) disclaimer. this consensus statement represents a consultative process with the authors and other experts in the field. at the time of publishing, this represented the best possible advice based on the data and experience of the group. we acknowledge that as more information is collected, both from randomised controlled trials and cohort data, this consensus statement will need to be updated. there will be at least a biennial review of the document. drug-induced liver injury (dili) in hiv/tuberculosis (tb) co-infected patients is a common problem in the south african setting, and re-introduction of anti-tb drugs can be challenging for the healthcare worker. although international guidelines on the re-introduction of tb treatment are available, the definition of dili is not uniform, management of antiretroviral therapy (art) in hiv co-infection is not mentioned, and the guidance on management is not uniform and lacks a practical approach. in this consensus statement, we summarise important aspects of dili and provide practical guidance for healthcare workers for different patient groups and healthcare settings on the re-introduction of anti-tb drugs and art in hiv/tb co-infected individuals presenting with dili. s afr j hiv med 2013;14(3):113-119. doi:10.7196/sajhivmed.976 1. background globally, 34 million (31.4 35.9 million) people were living with hiv at the end of 2011. south africa (sa) carries the highest burden, with 5.6 million people infected.1 a major scale-up of public sector antiretroviral therapy (art) has seen 1.6 million people start such therapy, and an increasing proportion of eligible individuals initiate treatment.2 sa has the third highest tuberculosis (tb) burden in the world and the fourth highest multidrug-resistant (mdr) tb rate.3 an estimated 60 80% of new tb cases in sa are hiv co-infected.3 , 4 tb remains an important cause of morbidity and mortality among hiv-infected individuals, and undiagnosed tb is a major cause of death in the first months of art.5 adherence to tb treatment is an important determinant of a favourable treatment outcome, and those who default treatment, especially if soon after treatment initiation, continue to be a source of infection and transmission within the community.6 , 7 a two-fold higher relative risk of adverse events has been reported in hiv-infected individuals.8 , 9 drug-induced liver injury (dili) is a well-recognised adverse drug reaction of tb treatment and art. dili complicates tb treatment in 5 33% of patients. first-line anti-tb drugs associated with hepatotoxicity are isoniazid (inh), rifampicin (rif) and pyrazinamide (pza). depending on the regimen, dili develops in 9 30% of patients receiving art.11 transaminitis can be associated with most art, although nevirapine (nvp) is associated with the highest risk of dili. a retrospective, observational study from sa showed an in-hospital and 3-month mortality among tb treatment or art-associated dili patients of 27% and 35%, respectively.12 given the high hiv prevalence and tb incidence, dili in tb/hiv co-infected patients is a common problem in the sa setting, and the re-introduction of anti-tb drugs can be challenging for the healthcare worker. although international guidelines on the re-introduction of tb treatment are available, the definition of dili is not uniform, management of art in hiv co-infection is not mentioned, and the guidance on management is not uniform and lacks a practical approach. in this consensus statement, we aim to summarise some important aspects of dili and provide practical guidance for healthcare workers, for different patient groups and healthcare settings, on the re-introduction of anti-tb drugs and art in hiv/tb co-infected individuals presenting with dili. 2. mechanism of dili hepatotoxicity may result from direct toxicity of the primary compound, a metabolite, or from an immunologically mediated response, affecting hepatocytes, biliary epithelial cells and/or liver vasculature. predictable dili is generally characterised by certain dose-related injury and tends to occur rapidly. injurious free radicals cause hepatocyte necrosis in zones furthest away from the hepatic arterioles. unpredictable or idiosyncratic reactions account for most types of dili. these hypersensitivity reactions occur mostly independent of dose and relatively rarely for each drug, and may result in hepatocellular injury and/or portal tract inflammation with cholestasis. rif may occasionally cause dose-dependent interference with bili­rubin uptake, resulting in subclinical, unconjugated hyper­bilirubin­aemia or jaundice without hepatocellular damage.10 this may be transient and occur early in treatment or in some individuals with pre-existing liver disease.10 hepatocellular injury appears to be rare. pza may induce both dose-dependent and idiosyncratic hepatotoxicity. pza may induce hypersensitivity reactions with eosinophilia and liver injury or granulomatous hepatitis in a limited number of cases. inh is cleared mostly by the liver, primarily by acetylation by n-acetyltransferase 2. mono-acetyl hydrazine is one of the main metabolites; its reactive metabolites are probably toxic to liver tissue through free radical generation. inh hepatotoxicity occurs generally within weeks to months, rather than days of starting the drug, as seen with hypersensitivity reactions. unlike a classic hypersensitivity reaction, inh rechallenge does not always elicit a rapid recurrence of hepatotoxicity.10 hepatotoxicity due to art may be a result of immune restoration and the development of acute liver injury related to an enhanced immune response to tb or hepatitis b virus (hbv) immune reconstitution inflammatory syndrome (iris). hbv-iris presents as an acute hepatocellular injury, whereas tb-iris presents with an obstructive picture. nucleoside reverse transcriptase inhibitors (nrtis) are associated with a risk of mitochondrial toxicity and hepatic steatosis. non-nucleoside reverse transcriptase inhibitors (nnrtis) are also associated with hepatotoxicity. the hypersensitivity reaction observed with nvp can also include severe transaminitis.11 nvp-dili may be accompanied by a rash and fever. hepatotoxicity is also observed with efavirenz (efv), but the mechanism seems to be different.13 the mechanism of protease inhibitor (pi)-associated hepatotoxicity is not known. some studies have suggested an impaired drug metabolism, especially in individuals with underlying liver disease.14 to complicate matters, the hiv/tb co-infected patient is often exposed to other potentially hepatotoxic drugs and is prone to conditions associated with liver injury. co-trimoxazole may be prescribed as preventive therapy or treatment for pneumocystis jirovecii or toxoplasmosis. cholestatic jaundice and hepatic necrosis are known side-effects and could be part of a systemic drug hypersensitivity syndrome that occurs independent of plasma drug concentrations.15 bacterial sepsis can also induce liver injury by various mechanisms, including the release of peroxynitrite by leucocytes, resulting in damage to the cell membranes; apoptosis of lymphocytes and gastrointestinal epithelial cells; and tissue ischaemia due to microvascular obstruction triggered by the release of pro-inflammatory mediators.16 the pattern is generally mixed with increased bilirubin levels. tb itself and tb-iris can involve the liver. hepatic tb-iris is probably more common than is appreciated clinically. approximately 56% of patients with tb-iris have clinical hepatomegaly.17 the hepatomegaly in tb-iris is frequently tender and patients may have symptoms of right-upper quadrant pain, nausea and vomiting.18 the typical pattern of liver enzyme abnormality is mixed with moderate elevation of transaminases, but a far more significant rise in the canalicular enzymes.18 gamma-glutamyl transferase (ggt) is substantially more elevated in tb-iris patients than in hiv-negative patients with tb involving the liver. while bilirubin may increase, clinical jaundice is uncommon.18 differentiating hepatic tb-iris from dili attributed to a tb drug, art or co-trimoxazole, poses a clinical conundrum. unfortunately, there are no features absolutely predictive of either iris or dili. tender hepatomegaly, the preponderance of an elevation of the canalicular enzymes, the absence of jaundice, maintained synthetic liver function and tb-iris features in other organ systems may suggest tb-iris rather than dili. the more definitive diagnostic route is to perform liver biopsy. however, this procedure is invasive and not readily available. histological features observed in patients with tb-iris include significantly increased numbers of granulomas per liver core with abundant eosinophils palisading around these granulomas.18 when there is doubt as to whether the liver function test (lft) abnormalities represent tb-iris or dili, it is safer to manage as dili and monitor the response. 3. risk factors for dili risk factors for dili in patients receiving tb treatment or art are well described in the literature. the most important risk factors in individuals receiving tb treatment are: age >35 years; being a child; perhaps female gender; hepatitis b surface antigen (hbsag) positivity, particularly if eag-positive; use of alcohol; slow acetylator status; extensive tb disease; increase in baseline alanine transaminase (alt); malnutrition; hepatitis c virus (hcv) co-infection; and hiv co-infection.10 , 19 , 20 however, most data on tb-dili in hiv-infected individuals come from observational studies or treatment trials, generally before the advent of effective art. definitions of hepatotoxicity and methodology varied among studies, and most lacked hiv-negative control groups. the overall influence of hiv infection alone on dili during tb treatment was difficult to assess, but appeared to be slight, with the exception of one study where other confounding causes of dili were present, such as injection drug use, alcoholism, art and viral hepatitis.10 one study from ethiopia looked at tb-dili in a population grouped by hiv status;21 i.e. biochemical tb-dili in hiv-positive and hiv-negative individuals. hiv-infection (odds ratio (or) 3.6; 95% confidence interval (ci) 1.5 8.5), concomitant drug intake (or 2.7; 95% ci 1.2 5.8) and a lower cd4+ count (0 50 cells/µl: or 21.3 (95% ci 2.2 204.9); cd4+ 51 100 cells/µl: or 5.2 (95% ci 0.6 46.0); cd4+ 101 200 cells/µl: or 4.3 (95% ci 0.4 42.4)) relative to a cd4+ count >200 cells/µl, were identified as factors significantly associated with biochemical tb-dili.21 risk factors associated with severe art-related hepatotoxicity were a baseline elevation in serum aminotransferases, concomitant hepatotoxic medication, thrombocytopenia, renal insufficiency, chronic hbv or hvc co-infection and female gender.22-25 4. definition of dili the definition of tb-dili, according to the commonly used management guidelines, is summarised in table 1. asymptomatic transaminase elevations occur in 20% of patients started on standard anti-tb regimens prior to, or immediately after the start of treatment. usually these elevations resolve spontaneously.26-28 rif may occasionally cause dose-dependent interference with bilirubin uptake, resulting in subclinical, unconjugated hyperbilirubinaemia or jaundice without hepatocellular damage. this may be transient and occur early in treatment or in some individuals with pre-existing liver disease. although similarities exist between the major guidelines, there are also differences. to achieve a uniform approach to dili, a clear definition is required. none of the guidelines recommend routine monitoring of liver function in patients in whom there is no reason to suspect liver dysfunction. the definition for dili in table 2 has been advocated in the sa setting. this definition applies to all tb patients including those with hiv co-infection. although most guidelines suggest baseline lft and laboratory monitoring of risk groups including hiv-positive individuals, this is generally not performed in low-resource countries with a high tb burden because of additional costs and low detection rates. nevertheless, a healthcare worker should always enquire whether baseline laboratory parameters are available. in patients with a baseline alt >120 iu/l or total bilirubin >40 μmol/l, it is recommended to start standard tb treatment and monitor closely, or to omit pza initially in severe cases. if lfts worsen on tb treatment, an alternative regimen should be started. elevated ggt and alkaline phosphatase (alp) levels are not included in the dili-definition of any of the major tb guidelines. cholestasis is frequently observed in hiv-infected individuals and the cause can be multifactorial e.g. tb of the liver, tb-iris, drugs, opportunistic infections and fatty liver, but also hiv-related malignancies and biliary tract disease.32 ggt and alp levels should not be monitored routinely. elevations of ggt alone do not reflect liver injury. 5. management of tb-dili: existing guidelines and studies guidelines on the management of tb and adverse drug reactions have been published by the american thoracic society (ats); the british thoracic society (bts); the task force of the european respiratory so­ciety (ers), the who and the international union against tuberculosis and lung disease (iuatld); and the hong kong tuberculosis service (hktbs).10 , 29-31 , 33 most guidelines are based on expert opinion from a multidisciplinary team supported by literature searches. good quality studies with adequate sample sizes on the preferred tb treatment regimen in patients presenting with dili are scarce and will be discussed later. in the case of confirmed moderate or severe drug-induced hepatotoxicity, treatment should be interrupted and re-introduced after hepatotoxicity has resolved. when and how tb drugs should be re-introduced according to the various guidelines is summarised in table 3. however, in the sa setting, hiv/tb co-infected patients with dili often have significant immune suppression and large mycobacterial loads, and the clinician may initiate a tb treatment backbone that excludes the first-line hepatotoxic drugs while the lfts settle and until the patient is ready for rechallenge. only the bts guideline29 provides guidance for these cases. also, it is not clear what approach should be followed when the healthcare worker fails to re-introduce some of the first-line drugs, especially inh or rif. the bts guideline is reasonable and advises consultation with a fully trained physician, which is not always feasible in the southern african setting. few published studies have focused on different re-introduction regimens of tb drugs.34-37 all excluded hiv-positive patients and only two were randomised trials. a trial by tahaoglu et al.35 randomised 45 patients to inh, rif, ethambutol (emb) and streptomycin (str) by gradually increasing the number and dosage of the drugs (n=20) or the standard regimen (inh, rif, emb and pza) in the same dosage from the start of the rechallenge (n=25). hepatotoxicity recurred in 0 and 6 (24%) patients (p=0.021), respectively. the time from withdrawal of tb drugs to resolution of hepatotoxicity was 18.7 days (standard deviation ±11.4). 35 sharma et al. 36 randomised 175 patients with tb-dili to one of three predefined re-introduction regimens. in the first arm, patients were given inh, rif and pza simultaneously at full dosage from day 1. in the second arm, drugs were re-introduced according to the ats guideline with rif at maximum dosage from day 1, inh at maximum dosage from day 8, and pza at maximum dosage from day 15. in the third arm, drugs were administered in accordance with the bts guidelines with 100 mg/day inh from day 1, (maximum dosage from day 4), 150 mg/day rif from day 8 (maximum dosage from day 11) and 500 mg/day pza from day 15 (maximum dosage from day 18). the recurrence rates were not significantly different between the three arms (around 10%). the median time from withdrawal of the tb drugs to resolution of hepatotoxicity was 18 days (interquartile range 14 28). 36 some studies have looked at the use and safety of fluoroquinolones in tb-dili patients. in these studies, the use of fluoroquinolones did not result in additional hepatotoxicity; however, the potential hepatotoxicity associated with fluoroquinolones (although infrequent) is something of which clinicians should be aware.38 , 39 szklo et al.38 reported a cure rate of 85% and no treatment failures or relapses after 2 years of follow-up with fluoroquinolone regimens in patients who had dili. 6. management of tb-dili in a high hiv burden setting: recommendations • check tb diagnosis. • check results of tb culture and drug susceptibility testing. • reconsider tb diagnosis if not confirmed. if the patient has had a clinical response to the tb treatment including weight gain, improvement of symptoms that were compatible with a tb diagnosis and/or chest x-ray improvements, then the diagnosis can be assumed to be correct. • check if the patient is on the intensive or continuation phase of tb treatment. • consider other causes such as chronic alcohol consumption, pre-existing liver disease, viral hepatitis, other hepatotoxic medications, tb involvement of the liver, iris and bacterial sepsis. 6.1 group 1: intensive phase of tb treatment 6.1.1 mild dili: clinically well with elevated alt <200 iu/l and total bilirubin <40 μmol/l • continue tb drugs in the event of confirmed or probable tb. • continue art if the patient is receiving art. • repeat alt and bilirubin in one week. • if alt and bilirubin have improved or normalised, stop laboratory monitoring. • if alt and bilirubin remain elevated but stable for 4 consecutive weeks, consider the other causes listed above, abdominal sonar and referral for further workup of liver dysfunction. • if alt and bilirubin increase further and meet the dili definition, then move on to the relevant section below. 6.1.2 moderate dili: clinically well and elevated alt >200 iu/l irrespective of total bilirubin • discontinue the standard tb regimen. • start str, moxifloxacin (mox) and emb (note: str is contra­indicated if the glomerular filtration rate (gfr) is <60 ml/min). • discontinue co-trimoxazole prophylaxis and other hepatotoxic drugs. • stop art. if the patient is on an nnrti-based regimen, stop the nnrti first and the nrtis after 5 7 days. if the patient is on a pi-based regimen, stop all drugs at once. if the patient has been on a stable art regimen for >6 months, consider continuing the therapy, as it is less likely that art is the cause. • repeat alt and bilirubin in 2 3 (inpatient) or 7 days (outpatient). • when alt is <100 iu/l and total bilirubin is normal, start the rechallenge. • day 1: rif 450 or 600 mg daily, depending on weight. • day 3: check alt. • day 4 6: add 300 mg inh daily. • day 7: check alt. • day 8: consider a pza rechallenge (especially in the case of tb menin­­gitis or intolerance/resistance to other drugs) and check alt at day 10. • once rechallenged, follow the guidance in table 4. • monitor alt weekly for 4 weeks after the rechallenge. 6.1.3 moderate dili: isolated jaundice (alt <120 iu/l and total bilirubin >40 μmol/l) • continue art. • stop co-trimoxazole prophylaxis if alp and ggt are also elevated. • stop rif (rif is the most likely cause of isolated jaundice). • continue inh, pza and emb and add mox. • repeat alt and bilirubin after 7 days. if bilirubin does not settle, then consult an expert. • if the bilirubin settles, then follow the guidance in table 4. • the clinician may consider a full-dose rif rechallenge 2 3 weeks after stopping rif. • repeat alt and bilirubin after 7 days. if alt and bilirubin are stable, then stop mox and continue with standard rif, inh, pza and emb for 2 months, followed by 4 months of rif and inh. • if bilirubin increases to >40 μmol/l, stop rif and continue inh, pza, emb and mox. follow the guidance in table 4. • monitor alt and bilirubin weekly for 4 weeks after the rechallenge. • if alt increases to >120 iu/l, perform abdominal ultrasound and refer for further investigation. follow the guidance in sections 6.1.1 or 6.1.2. 6.1.4 severe dili: clinically not well (nausea, vomiting, abdominal pain), meets dili definition (table 2) • admit the patient. • consult an infectious diseases or tb-treatment specialist, if available. • assess liver synthetic function with an international normalised ratio (inr) and monitor blood glucose (hypoglycaemia can complicate liver failure). • stop standard tb treatment, co-trimoxazole prophylaxis and all other hepatotoxic drugs. • if the patient is on an nnrti-based regimen, stop the nnrti first and the nrtis after 5 7 days. however, if the patient is in liver failure, stop all art immediately. • if the patient is on a pi-based regimen, stop all drugs at once. • start emb, str and mox (note: str is contraindicated if the gfr is <60 ml/min). • repeat alt and bilirubin after 2 3 days. • rechallenge tb drugs when alt is <100 iu/l and bilirubin is normal. • day 1: rif 450 or 600 mg daily depending on weight. • day 3: check alt (should improve or become stable). • day 4 6: add 300 mg inh daily. • day 7: check alt (alt should improve or become stable). • stop str and follow the guidance in table 4. • consider pza re-challenge (especially in the case of tb meningitis or intolerance/resistance to other drugs). • monitor alt weekly for 4 weeks after rechallenge. 6.1.5 management if rif is not tolerated after rechallenge • stop rif. • check alt after 2 3 days. • if alt is <100 iu/l and bilirubin is normal, add 300 mg inh daily. • check alt after 2 3 days. • if alt is stable, follow the guidance in table 4. • if alt is worsening, stop inh and continue treatment in consultation with an infectious diseases or tb-treatment specialist. • consider pza rechallenge where rif has not been tolerated. • monitor alt weekly for 4 weeks after rechallenge. 6.1.6 management if inh is not tolerated after rechallenge • stop inh. • check alt after 2 3 days. • continue rif, mox and emb for 12 months in total. • consider pza rechallenge in this setting where inh has not been tolerated. • monitor alt weekly for 4 weeks after rechallenge. 6.2 group 2: continuation phase of tb treatment • confirm the start date and response to art/tb treatment. • consider other diagnoses. • if asymptomatic with elevated alt <200 iu/l and bilirubin <40 μmol/l, then follow the approach in 6.1.1. • if the patient has isolated jaundice (alt <120 iu/l and total bilirubin >40 μmol/l), stop rif, continue inh, emb and mox. follow the guidance in table 4. • continue art. stop co-trimoxazole prophylaxis if alp and ggt are also elevated. • the clinician may consider full-dose rif rechallenge 2 3 weeks after stopping rif. • if the patient has moderate dili (asymptomatic and elevated alt >200 iu/l irrespective of total bilirubin) or severe dili, then discontinue the standard tb regimen, co-trimoxazole prophylaxis and other hepatotoxic drugs. • if the patient has severe dili, assess liver synthetic function with an inr and monitor blood glucose. • stop art. if the patient is on an nnrti-based regimen, stop the nnrti first and the nrtis after 5 7 days (however, if the patient is in liver failure, stop all art immediately). if the patient is on a pi-based regimen, stop all drugs at once. • monitor alt and bilirubin in 2 3 days (inpatient) or 7 days (outpatient). • rechallenge tb drugs if alt is <100 iu/l and bilirubin is normal. • day 1: 450 600 mg rif daily depending on weight. • day 3: check alt (alt should be stable). • day 4 6: add 300 mg inh daily. • day 7: check alt. • continue rif and inh to complete the continuation phase. • if alt and/or bilirubin worsen after rif rechallenge, treat with inh, emb and mox. further diagnostic tests and treatment duration in consultation with an infectious diseases or tb-treatment specialist may be needed. • if alt and/or bilirubin worsen after inh rechallenge, then treat with rif, emb and mox. further diagnostic tests and treatment duration in consultation with an infectious diseases or tb-treatment specialist may be needed. • monitor alt weekly for 4 weeks after rechallenge. 6.3 general comments for all tb-dili patients • the re-introduction of first-line tb drugs in patients with tb-dili is preferred over the use of second-line drugs. • rechallenge is not recommended for those who have had fulminant hepatitis (defined as hepatic encephalopathy with coagulopathy). once alt is <100 iu/ml and bilirubin has normalised, treat with an mdr-tb regimen, avoiding pza and substituting pza with emb (i.e. str or kanamycin, emb, mox, ethionamide and terizidone). • if the patient cannot tolerate mox, high-dose levofloxacin should be used. ciprofloxacin should not be used in the treatment of tb. • if str is not available, then kanamycin or amikacin should be used. • if the intensive phase of tb treatment is interrupted for any period, restart the full treatment course starting from the day that the alternative tb regimen is successfully re-introduced. • re-challenge with pza was previously not recommended, but a recent trial has shown that most patients tolerate it.36 pza re-challenge should be considered in patients with severe tb (e.g. miliary, meningitis), drug resistance or intolerance to inh or rif. transaminase levels, especially alt, should be monitored frequently (e.g. 3 times weekly) during rechallenge and weekly for a month following rechallenge. • patients with low body weight (<40 kg) should have their maximal doses calculated according to body weight. • monitor vision in all patients requiring a modified regimen, including signs of emb toxicity. • art is indicated for all tb/hiv patients independent of cd4+ cell count. 6.4 rechallenge or initiation of art 6.4.1 patients who develop dili while receiving tb medication only, not on art 6.4 .1.1 art-naive • cd4+ count <100 cells/µl: start art as soon as the complete standard or alternative regimen of tb drugs is re-introduced.40 • cd4+ count >100 cells/µl: art can be delayed until after the intensive phase of tb treatment, unless the patient has other serious hiv-related conditions (e.g. kaposi’s sarcoma or hiv encephalopathy).40 • after art initiation, monitor alt every 2 weeks for 2 months. 6.4.1.2 art-experienced • collect information on treatment history, treatment response and reason for treatment interruption. • discuss the appropriate regimen with an infectious diseases or hiv-treatment specialist. • after art initiation, monitor alt every 2 weeks for 2 months. 6.4.2 patients who develop dili while receiving tb treatment and art • if dili developed on an nnrti-based regimen with nvp, then rechallenge with an nnrti-based regimen with efv after the tb drug rechallenge.13 , 40 • if dili developed on nnrti-based regimen with efv, then rechallenge efv in the case of mild dili after the tb drug rechallenge. in the case of severe or recurrent dili, start a pi-based regimen with lopinavir/ritonavir (lop/r) (with dose adjustment if receiving rif). • if the patient has mild dili on efv and lfts resolve within 5 7 days after interrupting efv, the clinician may consider restarting efv before the tb drug rechallenge in order to avoid stopping art. • if dili developed on pi-based regimen with double-dose lop/r, then the preferred approach is to replace rif with 150 mg rifabutin on alternate days and use this with atazanavir/ritonavir (or a standard dose of lop/r). if this option is not available and double-dose lop/r with rif is used, then this should be recommenced with slow-dose escalation over 2 weeks: i.e. day 1 – 400/100 mg 12-hourly; day 7 – 600/150 mg 12-hourly; day 14 – 800/200 mg 12-hourly. this should be done after the tb drug rechallenge. note: there is no need for double-dose lop/r if there is no rif in the final tb treatment regimen. • in the case of all other regimens including newer pis or drugs from other drug classes, discuss the approach with an infectious diseases or hiv-treatment specialist. • after art rechallenge, monitor alt every 2 weeks for 2 months. 6.5 rechallenge of co-trimoxazole co-trimoxazole therapy should not be rechallenged in hiv/tb patients taking primary or secondary co-trimoxazole prophylaxis and who experience severe liver toxicity. dapsone should be used instead, but is less effective than co-trimoxazole in preventing p. jirovecii pneumonia and also lacks the broad antimicrobial activity of co-trimoxazole. it is therefore desirable to attempt rechallenge of co-trimoxazole in patients with previous p. jirovecii pneumonia and with mild dili after re-introduction of tb treatment and art. monitor alt and bilirubin weekly for 1 month after rechallenge. conflict of interest. all authors submitted conflict of interest disclosure forms. authors were required to report on financial support received from pharmaceutical companies and medical aids over the previous three years (updated 19 august 2013). f conradie has received support from aspen pharmacare to attend conferences, research support from janssen pharacetic, and honoraria for speaking engagements from msd, and acted as a consultant to discovery health. g meintjes has received honoraria for speaking engagements from sanofi aventis and serves as a consultant for aid for aids. r bernhau, a 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[http://dx.doi.org/10.1371/journal.pone.0001809] 22. uberti-foppa c, de bona a, morsica g, et al. pretreatment of chronic active hepatitis c in patients coinfected with hiv and hepatitis c virus reduces the hepatotoxicity associated with subsequent antiretroviral therapy. j acquir immune defic syndr 2003;33(2):146-152. 22. uberti-foppa c, de bona a, morsica g, et al. pretreatment of chronic active hepatitis c in patients coinfected with hiv and hepatitis c virus reduces the hepatotoxicity associated with subsequent antiretroviral therapy. j acquir immune defic syndr 2003;33(2):146-152. 23. martin-carbonero l, nunez m, gonzalez-lahoz j, soriano v. incidence of liver injury after beginning antiretroviral therapy with efavirenz or nevirapine. hiv clin trials 2003;4(2):115-120. 23. martin-carbonero l, nunez m, gonzalez-lahoz j, soriano v. incidence of liver injury after beginning antiretroviral therapy with efavirenz or nevirapine. hiv clin trials 2003;4(2):115-120. 24. servoss jc, kitch dw, andersen jw, et al. predictors of antiretroviral-related hepatotoxicity in the adult aids clinical trial group (1989 1999). j acquir immune defic syndr 2006;43(3):320-323. [http://dx.doi.org/10.1097/01.qai.0000243054.58074.59] 24. servoss jc, kitch dw, andersen jw, et al. predictors of antiretroviral-related hepatotoxicity in the adult aids clinical trial group (1989 1999). j acquir immune defic syndr 2006;43(3):320-323. [http://dx.doi.org/10.1097/01.qai.0000243054.58074.59] 25. wit fw, weverling gj, weel j, et al. incidence of and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy. j infect dis 2002;186(1):23-31. [http://dx.doi.org/100.1086/341084] 25. wit fw, weverling gj, weel j, et al. incidence of and risk factors for severe hepatotoxicity associated with antiretroviral combination therapy. j infect dis 2002;186(1):23-31. [http://dx.doi.org/100.1086/341084] 26. girling dj. the hepatic toxicity of antituberculosis regimens containing isoniazid, rifampicin and pyrazinamide. tubercle 1978;59(1):13-32. 26. girling dj. the hepatic toxicity of antituberculosis regimens containing isoniazid, rifampicin and pyrazinamide. tubercle 1978;59(1):13-32. 27. ormerod lp, horsfield n. frequency and type of reactions to antituberculosis drugs: observations in routine treatment. tuber lung dis 1996;77(1):37-42. 27. ormerod lp, horsfield n. frequency and type of reactions to antituberculosis drugs: observations in routine treatment. tuber lung dis 1996;77(1):37-42. 28. sharifzadeh m, rasoulinejad m, valipour f, et al. evaluation of patient-related factors associated with causality, preventability, predictability and severity of hepatotoxicity during antituberculosis treatment. pharmacol res 2005;51(4):353-358. [http://dx.doi.org/10.1016/j.phrs.2004.10.009] 28. sharifzadeh m, rasoulinejad m, valipour f, et al. evaluation of patient-related factors associated with causality, preventability, predictability and severity of hepatotoxicity during antituberculosis treatment. pharmacol res 2005;51(4):353-358. [http://dx.doi.org/10.1016/j.phrs.2004.10.009] 29. joint tuberculosis committee of the british thoracic society. chemotherapy and management of tuberculosis in the united kingdom: recommendations 1998. thorax 1998;53(7):536-548. 29. joint tuberculosis committee of the british thoracic society. chemotherapy and management of tuberculosis in the united kingdom: recommendations 1998. thorax 1998;53(7):536-548. 30. migliori gb, raviglione mc, schaberg t, et al. tuberculosis management in europe. task force of the european respiratory society (ers), the world health organization (who) and the international union against tuberculosis and lung disease (iuatld) europe region. eur respir j 1999;14(4):978-992. 30. migliori gb, raviglione mc, schaberg t, et al. tuberculosis management in europe. task force of the european respiratory society (ers), the world health organization (who) and the international union against tuberculosis and lung disease (iuatld) europe region. eur respir j 1999;14(4):978-992. 31. tam ww, leung c, chan yc. monitoring for hepatotoxicity during antituberculosis treatment: general recommendations. a consensus statement of the tuberculosis control coordinating committee of the hong kong department of health and the tuberculosis subcommittee of the coordinating committee in internal medicine of the hospital authority, hong kong. http://wwwinfogovhk/tb_chest/doc/drugheppdf (accessed 1 july 2013). 31. tam ww, leung c, chan yc. monitoring for hepatotoxicity during antituberculosis treatment: general recommendations. a consensus statement of the tuberculosis control coordinating committee of the hong kong department of health and the tuberculosis subcommittee of the coordinating committee in internal medicine of the hospital authority, hong kong. http://wwwinfogovhk/tb_chest/doc/drugheppdf (accessed 1 july 2013). 32. te hs. cholestasis in hiv-infected patients. clin liver dis 2004;8(1):213-228. 32. te hs. cholestasis in hiv-infected patients. clin liver dis 2004;8(1):213-228. 33. national department of health. national tuberculosis management guidelines. pretoria: doh, 2011. 33. national department of health. national tuberculosis management guidelines. pretoria: doh, 2011. 34. singh j, garg pk, tandon rk. hepatotoxicity due to antituberculosis therapy. clinical profile and reintroduction of therapy. j clin gastroenterol 1996;22(3):211-214. 34. singh j, garg pk, tandon rk. hepatotoxicity due to antituberculosis therapy. clinical profile and reintroduction of therapy. j clin gastroenterol 1996;22(3):211-214. 35. tahaoglu k, atac g, sevim t, et al. the management of anti-tuberculosis drug-induced hepatotoxicity. int j tuberc lung dis 2001;5(1):65-69. 35. tahaoglu k, atac g, sevim t, et al. the management of anti-tuberculosis drug-induced hepatotoxicity. int j tuberc lung dis 2001;5(1):65-69. 36. sharma sk, singla r, sarda p, et al. safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment-induced hepatotoxicity. clin infect dis 2010;50(6):833-839. [http://dx.doi.org/10.1086/650576] 36. sharma sk, singla r, sarda p, et al. safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment-induced hepatotoxicity. clin infect dis 2010;50(6):833-839. [http://dx.doi.org/10.1086/650576] 37. agal s, baijal r, pramanik s, et al. monitoring and management of antituberculosis drug induced hepatotoxicity. j gastroenterol hepatol 2005;20(11):1745-1752. [http://dx.doi.org/10.1111/j.1440-1746.2005.04048.x] 37. agal s, baijal r, pramanik s, et al. monitoring and management of antituberculosis drug induced hepatotoxicity. j gastroenterol hepatol 2005;20(11):1745-1752. [http://dx.doi.org/10.1111/j.1440-1746.2005.04048.x] 38. szklo a, mello fc, guerra rl, et al. alternative anti-tuberculosis regimen including ofloxacin for the treatment of patients with hepatic injury. int j tuberc lung dis 2007;11(7):775-780. 38. szklo a, mello fc, guerra rl, et al. alternative anti-tuberculosis regimen including ofloxacin for the treatment of patients with hepatic injury. int j tuberc lung dis 2007;11(7):775-780. 39. ho cc, chen yc, hu fc, et al. safety of fluoroquinolone use in patients with hepatotoxicity induced by anti-tuberculosis regimens. clin infect dis 2004;48(11):1526-1533. [http://dx.doi.org/10.1086/598929] 39. ho cc, chen yc, hu fc, et al. safety of fluoroquinolone use in patients with hepatotoxicity induced by anti-tuberculosis regimens. clin infect dis 2004;48(11):1526-1533. [http://dx.doi.org/10.1086/598929] 40. meintjes g, maartens g, boulle a, et al. guidelines for antiretroviral therapy in adults by the southern african hiv clinicians society. southern african journal of hiv medicine 2012;13(3):114-133. [http://dx.doi.org/10.7196/sajhivmed.862] 40. meintjes g, maartens g, boulle a, et al. guidelines for antiretroviral therapy in adults by the southern african hiv clinicians society. southern african journal of hiv medicine 2012;13(3):114-133. [http://dx.doi.org/10.7196/sajhivmed.862] d e c e m b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 70 immune reconstitution inflammatory syndrome (iris) refers to an ‘unexpected’ and paradoxical clinical deterioration in the period immediately after initiation of antiretroviral therapy (art). diagnosis of iris relates to the time frame after initiation of antiretroviral therapy art, response to art and exclusion of alternative diagnoses. boulware et al. proposed criteria for children.1 there are fewer data on incidence, prevalence and clinical descriptions in infants and children than in adults. studies report a prevalence of up to 21% in south african infants.2 iris is commonly associated with mycobacterial infections, mainly bacille calmette-guérin (bcg), mycobacterium tuberculosis and non-tuberculous mycobacteria (ntm).2-5 other conditions such as skin disease, herpes simplex, cryptococcal meningitis and immune diseases such as guillain-barré syndrome are also reported.1,3 age and geographical location are important determinants of the risk for each disease. table i summarises the most pertinent paediatric literature. m. tuberculosis iris epidemiological considerations in hivinfected children tuberculosis (tb) is a common opportunistic infection in hiv-infected african children. rates of 53.3 cases/100 patient-years are reported in children not on highly active antiretroviral therapy (haart).6 high rates of exposure to potentially infectious source cases are well documented in hiv-exposed infants7 and rates of disease of 1 596 cases per 100 000 hiv-infected infants are documented in cape town.8 young age and hiv-related immunosuppression contribute to this high disease burden. recurrent episodes of tb are well documented and are caused by both relapse and re-infection.9 in a cohort studied before and after widespread availability of art, 30% of children with hiv and culture-confirmed tb had received prior tb therapy.6 rates of drug-resistant tb vary between settings. drug resistance was reported in 17% of hiv-infected children with tb, 6.8% having resistance to both rifampicin and isoniazid.10 children with prior tb therapy are at higher risk of resistance.11 there may be an incomplete therapeutic response to 6 months of standard anti-tb therapy.9 up to a third of children initiating haart may be on anti-tb therapy.6,12 cohort data from low-resource settings indicate that the majority of children still initiate haart at very low cd4 counts and with significant clinical disease.13 these children are at high risk for iris and incident tb from new exposure to m. tuberculosis. with improved access to haart, an up to 70% reduction in the incident tb can be achieved.6,14 diagnostic considerations the diagnosis of tb in hiv-infected children remains difficult. signs and symptoms overlap with advanced hiv. clinical scoring tools have poor specificity in hiv-infected children.15,16 sputum is difficult to collect in young children, and gastric washings are frequently not performed.17 culture yields from gastric washings and induced sputa are low in children. although yields of up to 40%18 have been reported in research settings, the yield in clinical settings is immune reconstitution inflammatory syndrome in children c l i n i c a l helena rabie1, fcp (paed) tammy meyers2, fcp (paed) mark f cotton1, phd 1department of paediatrics and child health, tygerberg children’s hospital and stellenbosch university, tygerberg, w cape 2harriet shezi paediatric arv clinic, chris hani baragwanath hospital, johannesburg paradoxical deterioration due to immune reconstitution inflammatory syndrome (iris) occurs in up to 21% of children initiating antiretroviral therapy. mycobacterial diseases are the most common, with bcg-vaccine adenitis predominating in infants and mycobacterium tuberculosis (tb) in older children. the difficulty of diagnosing tb in hiv-infected children and the increasing risk of drug-resistant tb complicate the diagnosis and management of both paradoxical iris and post-antiretroviral therapy tb. history and clinical assessment remain key strategies in the management of these infants and children. there are no prospective studies investigating diagnostic criteria and therapeutic strategies in children. t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e d e c e m b e r 2 0 0 9 71 lower.19 in children with a high index of suspicion for tb, microbiological confirmation can be obtained in 55%, increasing to 80% with significant pulmonary infiltration.16 chest radiographs are difficult to interpret owing to ubiquitous chronic underlying hiv-associated lung disease. tuberculin skin tests have a reduced sensitivity despite adjusting the extent of induration from 10 mm to 5 mm.20 the value of interferon-gamma release assays in hiv-infected children is still under study. negative results do not exclude tb,21 and tests are expensive. although failure of therapy for an opportunistic infection is considered an exclusion criterion for iris, iris has been diagnosed in adults with inadequately treated drug-resistant tb.22 as the diagnosis of tb is seldom confirmed by culture and drug sensitivity is often not available, it may be difficult to differentiate iris from poor response to treatment and drug resistance. it may not be possible to confirm a response to haart because of lack of access to virological testing. if events occur soon after initiation of therapy, significant reductions in viral load and clinical responses may not yet have occurred. therapeutic considerations current dosages of anti-tb medicines, especially isoniazid and rifampicin, are insufficient in all children; this is probably exacerbated in children with hiv, in whom malabsorption is common.23-25 rifampicin reduces exposure to protease inhibitors (pis) and non-nucleoside reverse transcriptase inhibitors (nnrtis), thereby compromising haart efficacy. ritonavir-based haart, previously recommended for cotreated children on pis, has been associated with poorer virological outcomes.26 post-haart tb and unmasking iris besides the general principles proposed by boulware,1 there are no proposed criteria to distinguish true iris from incident tb or missed disease prior to haart initiation. adult clinicians have suggested that all cases of tb after initiation of haart should be termed post-haart tb, with only cases occurring in the first 3 months accompanied by heightened clinical features classified as iris.27 data from cohort studies report tb rates of 3.4 6.2% in african children after initiating haart6,28 (table i). in infants tb-iris is thought to be less common than bcg-iris.2 clustering of these cases in the first 100 days after haart initiation is reported from cohort studies. in a large ugandan study, a 2.7fold increase in risk for tb was observed early after the initiation of haart.28 this could be due to inadequate screening procedures, as the converse was noted in a study where active screening was done.6 few studies provide detailed assessment of the severity of disease, an essential component in distinguishing between iris, incident tb and disease missed prior to initiating haart. zampoli et al. described 7 children with post-haart pulmonary tb iris, and 1 with additional extrapulmonary disease.29 three (43%) had received therapy prior to the initiation of haart. culture was positive in 4 of the 7 cases. of these, 1 had multidrug resistance, having stopped anti-tb therapy 3 weeks before initiating haart. all chest radiographs showed significant adenopathy with airways compression, extensive parenchymal infiltration and pleural reactions.29 although all iris is associated with significant inflammatory response, radiological findings are similar in hiv-infected children not on haart.10 clinicians therefore need to judge the relative severity of these conditions. exposure to m. tuberculosis shortly after initiation of haart could conceivably present as posthaart tb iris.30 this is especially relevant in children immunologically primed by receiving bcg at birth. iris caused by both bcg and tb in the same patient is now well documented in two prospective paediatric cohorts. in the neverest study 50% of children with tb also had bcg iris.2 in the cher cohort, 19% of children with bcg iris adenitis also had tb iris.31 paradoxical iris delaying the initiation of art in tb cases with severe immunodeficiency is associated with increased hiv-related mortality.32 currently the world health organization (who) recommends that children with severe immune suppression or stage 4 disease should initiate art 2 8 weeks after the initiation of anti-tb therapy.33 the basic diagnostic criteria for iris1 should be met first when diagnosing paradoxical iris. the proposed case definitions for tb paradoxical iris, although appropriate for well-resourced settings, are problematic in lower-resource settings. this is due to the diagnostic uncertainty of tb in hiv-infected children and difficulty in excluding alternative diagnoses and confirming a response to art because of inability to measure cd4 counts or viral load, especially in rural areas. few data exist on the risk of paradoxical iris. the study from uganda reports only 2 cases of paradoxical iris.27 zampoli et al. recently described the clinical events in 4 children receiving anti-tb therapy for 21 59 days before initiation of art, who subsequently developed tb iris between 6 and 105 days later. skin test conversion was documented in 1 child and was positive at the time of exacerbation in another. two children presented with deterioration of pulmonary tb, 1 developed local adenitis and another abdominal adenitis. one child died.29 there is little information on clinical features and management of neurological paradoxical iris in children. in adults these account for 12% of cases of paradoxical tb iris.34 similarly, intra-abdominal tb iris is comd e c e m b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 72 mon in adults, occurring in 37% of cases.35 although paediatric cases do occur (helena rabie – unpublished data), little is known about the prevalence in children. it is challenging to exclude drug-resistant tb and failure of tb therapy for other reasons in these children. resistance was common in an adult series from cape town.22 the case in fig. 1 illustrates the diagnostic difficulties in a setting of paradoxical iris and resistance to tb therapy. general evaluation contact with a source case has been documented in 30 54% of hiv-infected children with tb.6,10 tb can therefore be prevented and detected through a careful history looking for a source case in the household and extended social circle. in older children and adolescents transmission may occur outside the family due to social mobility, and it is likely that a history of contact will be a less sensitive marker to distinguish incident tb from iris. reviewing adherence to anti-tb therapy and art is essential to evaluate children with suspected paradoxical tb iris. documentation of suspected contact with a source patient who may have drug-resistant tb is also crucial. in w al te rs e t al .6 a ll tb sm it h et a l.2 a ll ir is pu th an ac it e t al .3 a ll ir is n ut ta ll et a l.4 6 bc g o nl y za m po li et a l.2 9 tb o nl y an d as pe ct s of b cg a ge (a ll) 8 m on th s 7. 9 ye ar s 8 12 1 m on th s 23 .5 m on th s ep is od es /c hi ld re n (% ) 34 e pi so de s /1 69 c hi ld re n (2 1% ) 32 e pi so de s/ 15 3 ch ild re n (1 9% ) 21 e pi so de s /3 31 c hi ld re n (6 .3 % ) 11 c as es 10 u nm as ki ng t b , 4 pa ra do xi ca l a ge , c as es v . c on tr ol s (p -v al ue ) 7 m on th s v. 1 0 m on th s (0 .0 07 ) 8. 2 ye ar s v. 7 .8 y ea rs (0 .5 0) 5 m on th s v. 2 7 m on th s (< 0. 00 1) c d 4% , c as es v . c on tr ol s (p -v al ue ) 3. 1 v. 5 .5 (0 .0 2) 12 .3 % v . 1 2. 0% (0 .5 5) 10 .3 % (c as es o nl y) a bs ol ut e c d 4 co un t, ca se s v. co nt ro ls (p -v al ue ) 74 1 v. 1 0 75 (0 .0 14 8) lo g ba se lin e h iv r n a c op ie s/ m l, ca se s v. c on tr ol s (p -v al ue ) 5. 37 v . 5 .3 7 h iv r n a c op ie s/ m l ( 0. 96 ) 6. 1 v. 5 .6 (0 .0 01 ) vi ra l l oa d > 75 0 00 0 (% ) 79 % v . 5 5% (0 .0 44 ) ti m e to e ve nt (m ea n (r an ge )) 16 d ay s (7 1 15 ) 6 w ee ks (2 2 1) 34 d ay s (1 5 60 ) b c g 24 /3 4 2/ 32 21 /2 1 tb 6/ 34 3/ 32 11 /1 1, 4 p ar ad ox ic al ir is 14 /1 4 tb a nd b c g 6/ 34 m a c 4/ 32 n tm 5/ 32 h er pe s zo st er 7/ 32 h er pe s la bi al is 1/ 34 6/ 32 h er pe s en ce ph al it is 1/ 32 c ry pt oc oc ca l m en in gi ti s 3/ 32 c yt om eg al ov ir us 1/ 34 pc p 1/ 34 se bo rr ho ei c de rm at it is 1 b ac te ri al s ep si s 2 g b s 1/ 32 b c g = b ac ill e c al m et te -g ué ri n; t b = t ub er cu lo si s; m a c = m . a vi um -i nt ra ce llu la re ; n tm = n on -t ub er cu lo us m yc ob ac te ri a; p c p = p ne um oc ys ti s pn eu m on ia ; g b s = g ro up b s tr ep to co cc al d is ea se . ta bl e i. co m pa ri so n o f st u d ie s il lu st ra ti n g a sp ec ts o f pa ed ia tr ic ir is t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e d e c e m b e r 2 0 0 9 73 adults diagnosed with paradoxical tb iris, resistance is a major clinical confounder.22 weight gain on therapy may be an important and measurable clinical marker supporting iris rather than clinical deterioration. this information, together with clustering in the first 100 days, may allow for a possible differentiation between incident tb and iris in younger children. culture for m. tuberculosis and drug sensitivity testing should be conducted whenever possible. clinical judgement should guide clinicians as to additional investigations needed to exclude additional diagnoses such as acute bacterial infections, drug reactions and other opportunistic infections or malignancies. management children are at higher risk than adults of death and hospitalisation in the period immediately after haart initiation. mortality of 17.4/100 000 patient-years in the first 3 months of therapy has been reported. up to 30% require hospitalisation in the first 6 months on therapy. two-thirds of the admissions are related to bacterial infection and pneumonia.36,37 withholding antibiotic therapy and other interventions at initial presentation is therefore very dangerous when tb iris is suspected. as in adults, therapy for tb iris includes the anti-tb therapy and continuation of haart. however, if the iris event is life-threatening or likely to cause permanent disability (i.e. tb meningitis with clinical deterioration), haart may be discontinued temporarily. children on pis can stop all drugs simultaneously. there is a significant risk for resistance when stopping efavirenz or nevirapine.38 clinicians need to weigh the risk of inducing nnrti resistance against that of continuing either nrtis or boosted lopinavir/ritonavir for 7 14 days. the safety of these strategies is unknown in this scenario. steroids improve outcomes for adults with moderate to severe tb iris, but there are no randomised studies in children.39 as in adults, clinicians must weigh the risk of resistant tb prior to starting steroid therapy. other modalities used (but not studied) include non-steroidal anti-inflammatory drugs (nsaids), thalidomide and leucotriene receptor antagonists.40-44 despite the lack of data, it is reasonable to stratify the use of supportive therapy as follows: nsaids for mild to moderate disease, and steroids for severe disease. in cases where there is a prior indication, i.e. meningitis, steroids should always be used. it is unclear whether pre-emptive steroids or nsaids can prevent iris (a trial in adults is underway). bcg-related iris bcg is the most common mycobacterial iris in infants given bcg at birth.2 vaccine site ulceration and abscess formation, ipsilateral adenitis and exacerbation of disseminated disease occur.45 where art is delayed until clinically indicated, 6% of all children and 14% of infants experience bcg-related adverse events. in this setting, age at initiation is the most important risk factor.2,46 when children access therapy early and at a younger age, a low cd4 count is the most important predictor.45 although there is a significant reduction in the risk of iris with early initiation of art adverse events are common in these infants also.31 fig. 1. drug-resistant tb presenting as paradoxical iris in a 12-year-old girl with pulmonary and abdominal tb and severe immune suppression (chest radiograph a). she was sputum smear positive and had a cd4 count of 31 cells/µl. anti-tb therapy with four drugs was initiated and she responded well, smear conversion taking place within 3 weeks. art was started 3 weeks after initiation of tb therapy, and 7 days later she developed a high fever, severe abdominal pain and food intolerance. the sputum smear was now positive, and a chest radiograph (b) suggested miliary tb. steroids were added with some clinical improvement. rifampicin resistance was confirmed after 48 days on tb therapy and 27 days on art. a b d e c e m b e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 74 the diagnosis of iris remains clinical. where systemic disease is suspected, extensive investigation may be required. although no prospective studies have been conducted, it is likely that local and regional iris requires no specific therapy. however, disseminated disease requires aggressive therapy that should be discussed with an expert. danish strain bcg is resistant to current standard doses of isoniazid as well as to pyrazinamide and ethionamide.47 induction of resistance in inappropriately treated cases with systemic disease has been documented.48 non-tuberculosis mycobacteria one study from thailand reports on non-tuberculosis mycobacterial iris in children. of 153 children initiating therapy at a median age of 7.9 years, 9 had iris caused by non-tuberculosis mycobacteria, 2 with paradoxical deterioration and 7 with unmasking disease. the rate was 5.9 cases per 100.5 there are no data for south african children, although cases do occur (helena rabie unpublished data). iris involving skin changes skin changes are the most common form of iris in adults, but there are fewer data in children. unpublished data from kwazulu-natal reported by boulware in a review on iris indicated that 53% of children had a new onset of rash after the initiation of haart.1 these included molluscum contagiosum (8%), tinea capitis (20%), warts (16%), impetigo (12%), herpes zoster (5%), and other fungal rashes (24%).1 earlier cohorts reported that 11% of children developed herpes zoster. children at risk were negative for varicella antibody despite a previous history of varicella and had severe immunodeficiency before treatment.49 exacerbation of warts and molluscum contagiosum is commonly seen. if areas such as the face are involved, this disfigurement can be very disruptive and may lead to non-adherence. other phenomena cryptococcus neoformans is common in south african adults50 but less common in children. in children <15 years of age, the incidence is 1 per 100 000 population.51 c. neoformans iris of both the central nervous system and the lungs occurs occasionally.52 guillain barré syndrome, myocardial dilatation, exacerbation of jc virus progressive multifocal leucoencephalopathy, leprosy, kaposi’s sarcoma, cytomegalovirus, pneumocystis pneumonia (pcp), opsoclonus-myoclonus syndrome, toxoplasmosis and other entities have been reported in adults and in children.3,41,53-55 conclusion iris is common in children. bcg is important in infants and tb is more prevalent in older children. although the morbidity is thought to be low, iris may be diagnostically challenging and carry a high morbidity. a higher drug burden may result in decreased therapeutic success, with possible non-adherence and more potential for drug interactions as well. a careful history and clinical review remain important tools in the diagnosis and management of these conditions. references 1. boulware dr, callens s, pahwa s. pediatric hiv immune reconstitution inflammatory syndrome. curr opin hiv aids 2008; 3: 461-467. 2. smith k, kuhn l, coovadia a, et al. immune reconstitution inflammatory syndrome among hiv-infected south african infants initiating antiretroviral therapy. aids 2009; 23: 1097-1107. 3. puthanakit t, oberdorfer p, akarathum n, wannarit p, sirisanthana t, sirisanthana v. immune reconstitution syndrome after highly active antiretroviral therapy in human immunodeficiency virus-infected thai children. pediatr infect dis j 2006; 25: 53-58. 4. puthanakit t, oberdorfer p, punjaisee s, wannarit p, sirisanthana t, sirisanthana v. immune reconstitution syndrome due to bacillus calmette-guerin after initiation of antiretroviral therapy in children with hiv infection. clin infect dis 2005; 41: 1049-1052. 5. puthanakit t, oberdorfer p, ukarapol n, et al. immune reconstitution syndrome from nontuberculous mycobacterial infection after initiation of antiretroviral therapy in children with hiv infection. pediatr infect dis j 2006; 25: 645-648. 6. walters e, cotton m, rabie h, schaaf h, walters l, marais b. clinical presentation and outcome of tuberculosis in human immunodeficiency virus infected children on anti-retroviral therapy. bmc pediatr 2008; 8: 1. 7. cotton mf, schaaf hs, lottering g, weber hl, coetzee j, nachman s. tuberculosis exposure in hiv-exposed infants in a high-prevalence setting. int j tuberc lung dis 2008; 12: 225-227. 8. hesseling ac, cotton mf, jennings t, et al. high incidence of tuberculosis among hiv-infected infants: evidence from a south african population-based study highlights the need for improved tuberculosis control strategies. clin infect dis 2009; 48: 108-114. 9. schaaf hs, krook s, hollemans dw, warren rm, donald pr, hesseling ac. recurrent culture-confirmed tuberculosis in human immunodeficiency virusinfected children. pediatr infect dis j 2005; 24: 685-691. 10. schaaf hs, marais bj, whitelaw a, et al. culture-confirmed childhood tuberculosis in cape town, south africa: a review of 596 cases. bmc infect dis 2007; 7: 140. 11. schaaf hs, marais bj, hesseling ac, et al. surveillance of antituberculosis drug resistance among children from the western cape province of south africa – an upward trend. am j public health 2009; 99: 8: 1486-90 12. moultrie h, yotebien m, kuhn l, meyers t. mortality and virological outcomes of 2105 hiv-infected children receiving art in soweto, south africa. presented at the16th conference on retroviruses and opportunistic infections, 8 11 february 2009, montréal (abstract 97). 13. sutcliffe cg, van dijk jh, bolton c, persaud d, moss wj. effectiveness of antiretroviral therapy among hiv-infected children in sub-saharan africa. lancet infect dis 2008; 8: 477-489. 14. martinson na, moultrie h, van niekerk r, et al. haart and risk of tuberculosis in hiv-infected south african children: a multi-site retrospective cohort. int j tuberc lung dis 2009; 13: 862-867. 15. hesseling ac, schaaf hs, gie rp, starke jr, beyers n. a critical review of diagnostic approaches used in the diagnosis of childhood tuberculosis. int j tuberc lung dis 2002; 6: 1038-1045. 16. marais bj, graham sm, cotton mf, beyers n. diagnostic and management challenges for childhood tuberculosis in the era of hiv. j infect dis 2007; 196: suppl 1: s76-85. 17. eamranond p, jaramillo e. tuberculosis in children: reassessing the need for improved diagnosis in global control strategies. int j tuberc lung dis 2001; 5: 594603. 18. zar hj, hanslo d, apolles p, swingler g, hussey g. induced sputum versus gastric lavage for microbiological confirmation of pulmonary tuberculosis in infants and young children: a prospective study. lancet 2005; 365: 130-134. 19. hatherill m, hawkridge t, zar hj, et al. induced sputum or gastric lavage for community-based diagnosis of childhood pulmonary tuberculosis? arch dis child 2009; 94: 195-201. 20. schaaf hs, geldenduys a, gie rp, cotton mf. culture-positive tuberculosis in human immunodeficiency virus type 1-infected children. pediatr infect dis j 1998;17: 599-604. 21. davies ma, connell t, johannisen c, et al. detection of tuberculosis in hiv-infected children using an enzyme-linked immunospot assay. aids 2009; 23: 961-969. 22. meintjes g, rangaka mx, maartens g, et al. novel relationship between tuberculosis immune reconstitution inflammatory syndrome and antitubercular drug resistance. clin infect dis 2009; 48: 667-676. 23. schaaf hs, parkin dp, seifart hi, et al. isoniazid pharmacokinetics in children treated for respiratory tuberculosis. arch dis child 2005; 90: 614-618. 24. schaaf hs, victor tc, engelke e, et al. minimal inhibitory concentration of isoniazid in isoniazid-resistant mycobacterium tuberculosis isolates from children. eur j clin microbiol infect dis 2007; 26: 203-205. t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e d e c e m b e r 2 0 0 9 75 25. schaaf hs, willemse m, cilliers k, et al. rifampin pharmacokinetics in children, with and without human immunodeficiency virus infection, hospitalized for the management of severe forms of tuberculosis. bmc med 2009; 7: 19. 26. reitz ca, meyers t, hu c-c, strehlau r, sherman g, abrams ej, kuhn l. virologic response to protease-inhibitor-based antiretroviral therapy among children less than 2 years of age co-treated for tuberculosis in south africa. presented at the 16th conference on retroviruses and opportunistic infections, 8 11 february 2009, montréal (abstract 910). 27. meintjes g, lawn sd, scano f, et al. tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. lancet infect dis 2008; 8: 516-523. 28. bakeera-kitaka s, kekitiinwa a, dhabangi ae, et al. tuberculosis immune reconstitution syndrome among ugandan children. presented at the infectious diseases society of america annual conference, 4 7 october 2007, san diego (abstract 921). 29. zampoli m, kilborn t, eley b. tuberculosis during early antiretroviral-induced immune reconstitution in hiv-infected children. int j tuberc lung dis 2007; 11: 417-423. 30. innes shs, cotton mf. cavitation of the ghon focus in an hiv infected infant who acquired tuberculosis after the initiation of haart. southern african journal of hiv medicine 2009; 10(1): 44-48. 31. rabie h, violari a, madhi s, gibb dm, steyn j, van niekerk r, et al. complications of bcg vaccination in hiv infected and uninfected children: evidence from the children with hiv early antiretroviral therapy (cher) study. presented at the 15th conference on retroviruses and opportunistic infections, 3 6 february 2008, boston (abstract 600). 32. karim sa, naidoo k, grobler a, et al. initiating art during tb treatment significantly increases survival: results of a randomized controlled clinical trial in tb/hiv-coinfected patients in south africa. presented at the 16th conference on retroviruses and opportunistic infections, 8 11 february 2009, montréal (abstract 36a). 33. world health organization. antiretroviral therapy of hiv infection in infants and children: towards universal access. 2006 http://www.who.int/hiv/pub/guidelines/ paediatric020907.pdf (accessed 20 november 2009). 34. pepper dj, marais s, maartens g, et al. neurologic manifestations of paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome: a case series. clin infect dis 2009; 48: e96-107. 35. lawn sd, myer l, bekker lg, wood r. tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in south africa. aids 2007; 21: 335-341. 36. bolton-moore c, mubiana-mbewe m, cantrell ra, et al. clinical outcomes and cd4 cell response in children receiving antiretroviral therapy at primary health care facilities in zambia. jama 2007; 298: 1888. 37. puthanakit t, aurpibul l, oberdorfer p, et al. hospitalization and mortality among hiv-infected children after receiving highly active antiretroviral therapy. clin infect dis 2007; 44: 599-604. 38. cressey tr, green h, khoo s, et al. plasma drug concentrations and virologic evaluations after stopping treatment with nonnucleoside reverse-transcriptase inhibitors in hiv type 1-infected children. clin infect dis 2008; 46: 1601-1608. 39. meintjes gwr, morroni c, pepper d, et al. randomized placebo-controlled trial of prednisone for the tb immune reconstitution inflammatory syndrome. presented at the 16th conference on retroviruses and opportunistic infections, 8 11 february 2009, montréal (abstract 34). 40. kestens l, seddiki n, bohjanen pr. immunopathogenesis of immune reconstitution disease in hiv patients responding to antiretroviral therapy. curr opin hiv aids 2008; 3: 419-424. 41. rapose a, sarvat b, sarria jc. immune reconstitution inflammatory syndrome presenting as pericarditis and pericardial effusion. cardiology 2008; 110: 142-144. 42. schoeman jf, fieggen g, seller n, mendelson m, hartzenberg b. intractable intracranial tuberculous infection responsive to thalidomide: report of four cases. j child neurol 2006; 21: 301-308. 43. schoeman jf, springer p, ravenscroft a, et al. adjunctive thalidomide therapy of childhood tuberculous meningitis: possible anti-inflammatory role. j child neurol 2000; 15: 497-503. 44. skiest dj, hester lj, hardy rd. cryptococcal immune reconstitution inflammatory syndrome: report of four cases in three patients and review of the literature. j infect 2005; 51: e289-297. 45. hesseling ac, rabie h, marais bj, et al. bacille calmette-guerin vaccine-induced disease in hiv-infected and hiv-uninfected children. clin infect dis 2006; 42: 548558. 46. nuttall jj, davies ma, hussey gd, eley bs. bacillus calmette-guerin (bcg) vaccineinduced complications in children treated with highly active antiretroviral therapy. int j infect dis 2008; 12: e99-105. 47. ritz n, tebruegge m, connell tg, sievers a, robins-browne r, curtis n. susceptibility of mycobacterium bovis bcg vaccine strains to antituberculous antibiotics. antimicrob agents chemother 2009; 53: 316-318. 48. hesseling ac, schaaf hs, hanekom wa, et al. danish bacille calmette-guerin vaccine-induced disease in human immunodeficiency virus-infected children. clin infect dis 2003; 37: 1226-1233. 49. tangsinmankong n, kamchaisatian w, lujan-zilbermann j, brown cl, sleasman jw, emmanuel pj. varicella zoster as a manifestation of immune restoration disease in hiv-infected children. j allergy clin immunol 2004; 113: 742-746. 50. bicanic t, meintjes g, rebe k, et al. immune reconstitution inflammatory syndrome in hiv-associated cryptococcal meningitis: a prospective study. j acquir immune defic syndr 2009; 51: 130-134. 51. the burden of cryptococcosis in south africa: statistical notes february 2008. http://www.doh.gov.za/docs/stats/2008/cryptococcosis.pdf (accessed 20 november 2009). 52. van toorn r, kritzinger f, rabie h. acute demyelinating encephalomyelitis (adem), cryptococcal reactivation and disseminated herpes simplex in an hiv infected child following haart. eur j paediatr neurol 2005; 9: 355-359. 53. kharkar v, bhor uh, mahajan s, khopkar u. type i lepra reaction presenting as immune reconstitution inflammatory syndrome. indian j dermatol venereol leprol 2007; 73: 253-256. 54. nuttall jj, wilmshurst jm, ndondo ap, et al. progressive multifocal leukoencephalopathy after initiation of highly active antiretroviral therapy in a child with advanced human immunodeficiency virus infection: a case of immune reconstitution inflammatory syndrome. pediatr infect dis j 2004; 23: 683-685. 55. van toorn r, rabie h, warwick jm. opsoclonus-myoclonus in an hiv-infected child on antiretroviral therapy possible immune reconstitution inflammatory syndrome. eur j paediatr neurol 2005; 9: 423-426. g u id e l in e december 2014, vol. 15, no. 4 sajhivmed 121 o r ig in a l a r t ic l eguideline adult antiretroviral therapy guidelines 2014 by the southern african hiv clinicians society g meintjes (chairperson) j black, f conradie, v cox, s dlamini, j fabian, g maartens, t manzini, m mathe, c menezes, m moorhouse, y moosa, j nash, c orrell, y pakade, f venter, d wilson (expert panel members) correspondence: southern african hiv clinicians society (sahivsoc@sahivsoc.org) disclaimer: specific recommendations provided here are intended only as a guide to clinical management, based on expert consensus and best current evidence. treatment decisions for patients should be made by their responsible clinicians, with due consideration for individual circumstances. the most current version of this document should always be consulted. these guidelines are intended as an update to those published in the southern african journal of hiv medicine in 2012. since the release of the previous guidelines, the scale-up of antiretroviral therapy (art) in southern africa has continued. cohort studies from the region show excellent clinical outcomes; however, art is still being initiated late (in advanced disease) in some patients, resulting in relatively high early mortality rates. new data on antiretroviral drugs have become available. although currently few, there are patients in the region who are failing protease-inhibitor-based second-line regimens. to address this, guidelines on third-line therapy have been expanded. s afr j hiv med 2014;15(4):121-143. doi:10.7196/sajhivmed.1130 1. key principles while many antiretroviral therapy (art) guidelines are available inter nation ally, the current guidelines have been written to address issues relevant to southern africa. the following general principles underpinned the writing process: • south africa (sa) is a middle-income country, whereas certain other countries in the region are low-income countries; therefore, affordability was taken into account. • only treatment and diagnostic options available in southern africa were included. • we recognised the need to bridge the gap in treatment recommendations between public and private sector programmes, considering that many patients transition between the two sectors for treatment. • while it is acknowledged that certain recommendations are aspirational for poorly resourced settings, the unavailability of diagnostic/monitoring tests should not pose a barrier to providing art to those in need. • there has been a shift to view art as a means of hiv prevention. the clinical trial evidence base for this exists for serodiscordant couples; recommendations in this regard are included in these guidelines and additional data from randomised community studies are awaited. 2. goals of art the primary goals of art are to: • improve quality of life • reduce hiv-related morbidity and mortality • provide maximal and durable suppression of viral load (vl) • restore and/or preserve immune function. these goals are achieved by suppressing viral replication completely for as long as possible, using well-tolerated and sustainable treatment taken with good adherence. with prolonged viral suppression, the cd4+ lymphocyte count usually increases, which is accompanied by a restoration of pathogen-specific immune function. for most patients, this results in a dramatic reduction in the risk of hiv-associated morbidity and mortality. it is still unclear whether immune function ever returns to full normality. long-term cohorts show that patients who adhere well to art have a near-normal life expectancy.[1] 3. standard of care maximally suppressive art regimens should be used in hivpositive individuals to obtain the best results and to prevent resistance. however, non-suppressive regimens have a role in hiv prevention, e.g. in the prevention of mother-to-child transmission (pmtct) (infant prophylaxis), in post-exposure prophylaxis (pep) for healthcare workers following certain lowrisk occupational exposures, and in pre-exposure prophylaxis (prep). furthermore, these regimens are probably effective in hiv-negative individuals following low-risk sexual exposures. for further guidance see: southern african hiv clinicians society. post-exposure prophylaxis. s afr j hiv med 2008;9(3):36-45. (an update will be published in 2015.) g u id e l in e 122 december 2014, vol. 15, no. 4 sajhivmed g u id e l in e 4. antiretroviral (arv) agents: classes and mechanisms of action there are currently five classes of arvs available in southern africa (table 1). the most commonly used arv agents inhibit one of three key hiv enzymes required by the virus for intracellular replication: • reverse transcriptase: essential for completion of the early stages of hiv replication • protease: required for the assembly and maturation of infectious viral progeny • integrase: required for the integration of proviral dna into the host chromosomal dna. 5. arv agents currently available in southern africa the arv agents currently available in southern africa are summarised in table 2. different fixed-dose combinations (fdcs) are increasingly being made available. the oldest combination is zidovudine (azt)/lamivudine (3tc), but a number of other two and three-drug fdcs are now available in the region. these fdcs reduce the burden of multiple pills and may improve treatment adherence. 6. indications for initiating art indications for art initiation are summarised in table 3. art initiation is hardly ever an emergency, unless used for pep or pmtct. however, patients with profound immunosuppression are at significant risk of opportunistic infections (ois) and associated mortality, and should be assessed rapidly and initiated on art within 1 2 weeks once adherence counselling has been initiated. in patients with higher cd4+ counts, art should be deferred until patients are prepared to commit to long-term treatment and are main taining good treatment adherence. however, in eligible patients, efforts should be made to avoid lengthy indecision that may result in avoidable clinical deterioration and death. 6.1 rationale for these guidelines 6.1.1 cd4+ threshold all patients with a cd4+ count <350 cells/μl should be advised and encouraged to start art without delay. there is clinical evidence that this reduces mortality: a randomised trial in haiti demonstrated reduced mortality and incident tuberculosis (tb) in patients starting art at a cd4+ count threshold of <350 cells/µl (compared with patients waiting to commence therapy at a threshold of <200 cells/ μl).[2] evidence is less clear concerning individual patient benefit when in creasing the cd4+ count threshold for art initiation to 500 cells/ μl. no clinical trial has shown improved patient survival from starting art at a cd4+ count >350 cells/μl. such trials are ongoing. some observational data suggest that reduced morbidity and mortality are associated with starting art earlier (at cd4+ count thresholds of ≥500 cells/μl).[3-6] however, these data are derived from retrospective studies with methodological issues and probable residual confounding. if there is benefit to patients starting art at cd4+ counts >350 cells/μl, the benefit is likely to be small, since hivrelated events at high cd4+ counts are rare. a randomised controlled trial (rct) (hiv prevention trials network 052 (hptn052)) showed reduced morbidity but not mortality associated with starting art at a cd4+ count of 350 550 cells/µl (v. <250 cells/μl).[7] however, again the absolute benefits were small. definitive evidence regarding earlier art initiation is awaited from ongoing rcts, including the start (strategic timing of art; http://clinicaltrials.gov/ct2/show/ nct00867048) and temprano (early antiretroviral treatment and/or early isoniazid prophylaxis against tuberculosis in hivinfected adults) trials. however, there is evidence that starting art at higher cd4+ counts reduces hiv transmission within couples where one partner is hivnegative (hptn052) (see below),[7] and wider art coverage appears to reduce the risk of hiv transmission at a community level.[8] thus, consideration should be given to starting art in patients with a cd4+ count of 350 500 cells/μl.  however, it must be remembered that table 1. classes of arv agents class abbreviation mechanism of action specific action nucleoside and nucleotide reverse transcriptase inhibitors nrtis and ntrtis reverse transcriptase inhibition nucleic acid analogues mimic the normal building blocks of dna, preventing transcription of viral rna to dna non-nucleoside reverse transcriptase inhibitors nnrtis reverse transcriptase inhibition alter the conformation of the catalytic site of reverse transcriptase and directly inhibit its action protease inhibitors pis protease inhibition inhibit the final maturation stages of hiv replication, resulting in the formation of non-infective viral particles integrase inhibitors (also termed integrase strand transfer inhibitors) instis inhibition of viral integration prevent the transfer of proviral dna strands into the host chromosomal dna entry inhibitors entry inhibition bind to viral gp41 or gp120 or host cell cd4+ or chemokine (ccr5) receptors arv = antiretroviral; ccr5 = c-c chemokine receptor type 5. december 2014, vol. 15, no. 4 sajhivmed 123 g u id e l in e table 2. dosage and common adverse drug reactions of arv agents available in southern africa generic name class of drug* recommended dosage common or severe adr† tenofovir (tdf)‡ ntrti 300 mg daily renal failure, tubular wasting syndrome, reduced bone mineral density, hyperlactataemia/steatohepatitis (very low potential) lamivudine (3tc) nrti 150 mg 12-hourly or 300 mg daily anaemia (pure red cell aplasia) (rare), hyperlactataemia/ steatohepatitis (very low potential) emtricitabine (ftc) nrti 200 mg daily palmar hyperpigmentation, hyperlactataemia/ steatohepatitis (very low potential) not available as a single drug in sa, only co-formulated. abacavir (abc) nrti 300 mg 12-hourly or 600 mg daily hypersensitivity reaction, hyperlactataemia/steatohepatitis (very low potential) zidovudine (azt)‡ nrti 300 mg 12-hourly anaemia, neutropenia, gi upset, headache, myopathy, hyperlactataemia/steatohepatitis (medium potential), lipoatrophy stavudine (d4t)‡ nrti 30 mg 12-hourly note: higher doses for >60 kg are no longer recommended peripheral neuropathy, lipoatrophy, hyperlactataemia/ steatohepatitis (high potential), pancreatitis, hivassociated neuromuscular weakness syndrome (rare), dyslipidaemia didanosine (ddi)‡ nrti 400 mg daily (250 mg daily if <60 kg) taken on an empty stomach (entericcoated formulation preferred) peripheral neuropathy, pancreatitis, nausea, diarrhoea, hyperlactataemia/steatohepatitis (high potential) efavirenz (efv) nnrti 600 mg at night (400 mg at night if <40 kg) central nervous system symptoms (vivid dreams, problems with concentration, dizziness, confusion, mood disturbance, psychosis), rash, hepatitis, gynaecomastia nevirapine (nvp) nnrti 200 mg daily for 14 days then 200 mg 12-hourly rash, hepatitis rilpivirine (rpv) nnrti 25 mg daily with food rash, hepatitis, central nervous system symptoms (all uncommon) etravirine (etv) nnrti 200 mg 12-hourly rash, hepatitis (both uncommon) atazanavir (atv) pi 400 mg daily (only if art-naive) or 300 mg with ritonavir 100 mg daily (preferable) with tdf, always 300/100 mg daily and with efv 400/100 mg daily unconjugated hyperbilirubinaemia (visible jaundice in minority of patients), dyslipidaemia (low potential), renal stones (rare), hepatitis (uncommon) lopinavir/ritonavir (lpv/r) boosted pi 400/100 mg 12-hourly or 800/200 mg daily (only if pi-naive). gi upset, dyslipidaemia, hepatitis darunavir (drv) pi 600 mg 12-hourly with 100 mg ritonavir 12-hourly or 800/100 mg daily (only if pi-naive) gi upset, rash, dyslipidaemia, hepatitis (uncommon) contains sulphonamide moiety (use with caution in patients with sulpha allergy) saquinavir (sqv) (rarely used)§ pi 1 000 mg with 100 mg ritonavir 12-hourly, or 1 600 mg with 100 mg ritonavir daily (only if pi-naive) take with a fatty meal, or up to 2 h after meal gi disturbance (mild), hepatitis, hyperglycaemia, dyslipidaemia indinavir (idv) (rarely used)§ pi 800 mg 12-hourly with 100 mg ritonavir 12-hourly no food restrictions maintain high fluid intake kidney stones, unconjugated hyperbilirubinaemia (visible jaundice in minority of patients), gi disturbances, hair loss, hyperglycaemia, headache, dyslipidaemia raltegravir (ral) insti 400 mg 12-hourly headache, gi disturbance, hepatitis and rash (rare), rhabdomyolysis (rare) maraviroc (mvc) ccr5 blocker 150 mg, 300 mg or 600 mg 12-hourly (doses depends on concomitant medication and interactions) rash, hepatitis, fever, abdominal pain, cough, dizziness, musculoskeletal symptoms (all rare) continued ... 124 december 2014, vol. 15, no. 4 sajhivmed g u id e l in e many of these patients are completely well; starting lifelong medication that needs to be taken with 100% adherence and which may have side-effects in some may be a difficult undertaking. consequently, we support an individualised approach in patients with a cd4+ count of 350 500 cells/μl: after a discussion about the potential benefits, uncertainties, side-effects and need for impeccable adherence, patients should only be prescribed art in this cd4+ range if they are motivated for lifelong art with the required adherence. if they do not yet feel ready, art should be deferred until their cd4+ count is <350 cells/μl, with a plan in place for ongoing follow-up and cd4+ monitoring. our guidance, therefore, for patients with a cd4+ count in the range of 350 500 cells/μl is that if the patient has two cd4+ count measurements in this range and is motivated to start art, then this therapy should be commenced. however, if the patient has a cd4+ count within this range and is not yet motivated to start lifelong art, then the clinician can defer initiation, with follow-up and 6-monthly cd4+ monitoring planned. if the cd4+ count is <350 cells/μl, or if there is any clinical indication (table 3), then the clinician should strongly recommend that the patient does not defer art initiation. 6.1.2 treating world health organization stages 3 and 4 all patients with world health organization (who) stage 3 or 4 conditions are eligible for starting art. in particular, we advise that an episode of hiv-associated tb (i.e. tb diagnosed at the time of a seropositive hiv test) is a sufficient criterion for commencing art, but not remote episodes of tb when the patient’s hiv status was unknown. many observational studies have shown that tb accelerates hiv disease progression and increases mortality.[10] 6.1.3 serodiscordant couples the hptn052 trial showed that treating the hiv-positive partner in a serodiscordant relationship with art was associated with a 96% reduction in transmission risk to the uninfected partner.[7] patients who do not meet other criteria for art initiation may want to initiate art to protect their partner(s). this should be encouraged if the patient understands the need for adherence and is motivated. 6.2 commencing art in patients with tb decisions regarding the timing of art in patients with tb should be made on the basis of the cd4+ count. table 2 (continued). dosage and common adverse drug reactions of arv agents available in southern africa arv = antiretroviral; adr = adverse drug reaction; ntrti = nucleotide reverse transcriptase inhibitor; nrti = nucleoside reverse transcriptase inhibitor; sa = south africa; gi = gastrointestinal; nnrti = non-nucleoside reverse transcriptase inhibitor; pi = protease inhibitor; art = antiretroviral therapy; insti = integrase inhibitor (integrase strand transfer inhibitor); ccr5 = c-c chemokine receptor type 5; rtv = ritonavir; fdc = fixed-dose combination; vl = viral load. *all pis may be associated with cardiac conduction abnormalities (especially pr interval prolongation). this seldom results in clinically significant effects, but caution should be taken when coprescribing other drugs that cause delayed cardiac conduction, such as macrolides. †life-threatening reactions are indicated in bold. ‡arv combinations to be avoided include: (i) azt + d4t (antagonism); (ii) tdf + ddi (associated with poorer virological and immunological responses and increased toxicity); and (iii) d4t + ddi (associated with a very high risk for mitochondrial toxicities such as lactic acidosis and peripheral neuropathy). §the following three pis are recommended for use: lpv/r, atv/r and drv/r. patients receiving older pis (e.g. sqv and idv) should be switched to the recommended pis (consult an expert if the patient’s vl is not suppressed). we recommend against regimens containing dual rtv-boosted pis, as there is no evidence for superior efficacy[9] and more side-effects are likely. pis are almost always combined with rtv to boost the pi concentration. in rare situations, atv without boosting is used in first-line therapy. low-dose rtv is used to ‘boost’ the concentration of other pis. it is always used with lpv (in fdc) and is strongly encouraged with all other pis. table 3. indications for art* clinical diagnosis (irrespective of cd4+ count) who clinical stage 3 and 4† art recommended other severe hiv-related disorders, e.g.:‡ • immune thrombocytopenia • thrombotic thrombocytopenic purpura • polymyositis • lymphocytic interstitial pneumonitis art recommended non hiv-related disorders:§ • malignancies (excluding localised malignancies) • hepatitis b co-infection¶ • hepatitis c co-infection art recommended any condition requiring long-term immunosuppressive therapy art recommended cd4+ counts <350 cells/µl art recommended 350 500 cells/µl (two counts in this range) art recommended if patient is ready and motivated to start >500 cells/µl defer art hiv-infected partner in serodiscordant relationship regardless of cd4+ count or clinical diagnoses offer art and discuss safe sex (discussion should ideally involve all partners) art = antiretroviral therapy; who = world health organization. *note that either listed clinical diagnoses or cd4+ strata would be an indication for art. †see appendix. note that symptomatic hiv-associated nephropathy (hivan) is a who stage 4 condition and therefore a criterion for starting art. in many settings it may be difficult to obtain a renal biopsy to confirm the diagnosis of hivan, and in such settings any patient with chronic renal impairment and/or significant proteinuria should be considered as eligible for art. ‡specialist input required. note that this list is not exhaustive – any other severe hiv-related disorder should be considered an indication for art. §specialist input required. other disorders that may benefit from improvement in immune function should also be considered as an indication to start art. also, given that untreated hiv appears to be a risk factor for vascular disease, patients with symptomatic vascular disease or diabetes mellitus can be considered for earlier art. ¶hepatitis b surface antigen positive (see section 16.5 for recommended art regimens). december 2014, vol. 15, no. 4 sajhivmed 125 g u id e l in e • cd4+ count ≤50 cells/µl: art should be regarded as urgent, with the aim to start therapy 2 weeks following the commence ment of tb treatment. three rcts[11-13] have demonstrated that this approach reduces aids progression and mortality. it is advised to commence art after it is clear that the patient’s tb symptoms are improving and that tb therapy is tolerated. • cd4+ count >50 cells/µl: art can be delayed until 8 weeks after starting tb treatment, but no later. however, if the patient has other who stage 4 conditions, art should also be initiated 2 weeks after tb treatment is started. the exception to this is in the case of cryptococcal meningitis (cm) (see below; defer 4 6 weeks from cm diagnosis). the longer delay before commencing art in this group is anticipated to reduce the risk of shared toxicity (as the patient will then be receiving fewer tb drugs) and to reduce the risk of immune reconstitution inflammatory syndrome (iris) (see section 18). the aforementioned rcts did not show a higher risk of aids progression/ mortality in this group when art initiation was delayed until ~8 weeks after starting tb treatment.[11-13] • there is clinical trial evidence showing that patients with higher cd4+ counts (>= 220 cells/μl) can delay art until after tb treatment completion, without excess morbidity or mortality;[14] however, in programmatic settings, the concern is that patients not initiated on art during tb treatment may be lost to follow-up in the health system after tb treatment completion, without starting art. for this reason, we support starting these patients on art during tb treatment as above. • there are important drug interactions and shared side-effects when art is co-administered with tb therapy (section 16.1). • when art is commenced, patients should be warned that tb symptoms or signs may temporarily worsen and new features may occur in the first 3 months as a result of tb-iris. • unless contraindicated, co-trimoxazole ( ctx) prophylaxis should be initiated in patients with hiv-associated tb. • in patients with tb meningitis (tbm), starting art immediately or at 2 months following diagnosis was shown to have similar high mortality, with more complications in the former. [15] we recommend starting art 4 8 weeks after tbm diagnosis. 6.3 starting art in patients with other ois and acute illnesses with most ois (e.g. pneumocystis or bacterial pneumonia), if the patient has a cd4+ count <200 cells/μl, then the clinician should aim to start art within 2 weeks of commencing treatment for that infection.[16] in patients with severe kaposi’s sarcoma and lymphoma, art counselling should be expedited and art should be initiated as soon as possible. in a patient diagnosed with an oi in hospital, it is important to ensure referral and linkage to outpatient services for art initiation without delay. (refer to supplementary material: ‘starting art in hospital’ and ‘high-risk patients’.) for patients with cm, the optimal time to start art is 4 6 weeks from the time of cm diagnosis. the c oat (cryptococcal optimal art timing) trial demonstrated 15% higher mortality in patients who started art in hospital 1 2 weeks after cm diagnosis than in those starting 5 6 weeks after diagnosis.[17] regarding hiv-positive patients admitted to the intensive care unit (icu): if the patient is receiving art, then this should be continued (through nasogastric tube, if necessary) and only interrupted if the gastrointestinal tract is not functional (e.g. ileus); if the patient is not yet receiving art, then it should not be commenced if the reason for admission is an acute critical illness or injury. there are several potential problems associated with commencing art in this setting: lack of adequate counselling, gastrointestinal dysfunction, malabsorption and possible development of resistance. there are no intravenous options for an art regimen. in patients admitted to the icu for prolonged periods for an hiv-related condition, art initiation in the unit should be considered after multiorgan failure has resolved. 6.4 patient readiness for art patient readiness for therapy is as important as the medical indications for commencing therapy. • conventionally, art is not initiated at the first visit. rather, to accommodate counselling, two or three visits are required, staggered closely together. prolonged delays in commencing art should be avoided. art should be delayed only if concerns about adherence are severe enough to outweigh the risk of hiv disease progression. • the patient should be provided with details on the following key information: • the benefits of art • that art is life-long therapy • the importance of good adherence • a list of art side-effects, including what to do and who to contact if serious side-effects occur. • active depression or substance abuse should actively be detected and treated. • a personal treatment plan should be formulated for each patient, specifying drug storage, strategies for missed doses and how to integrate taking medication into t heir daily routine. the patient must be made aware of scheduling in terms of clinical follow-up. • disclosure of hiv status (to a partner and/or other household members) should strongly be encouraged. this has been shown to be an important determinant of treatment adherence and assists in the provision of patient-directed support. disclosure also identifies exposed contacts for screening and support. this issue needs to be handled sensitively in situations where disclosure may have harmful consequences, particularly for women. • the patient should be encouraged to join a support group and/or identify a treatment ‘buddy’. however, neither disclosure nor support group participation are prerequisites for good adherence in all patients, and should not be a reason for deferring art. • clinicians should ensure that they have the contact details of each patient and their treatment buddy. • counselling should cover safe-sex practices and address issues related to reproductive health (i.e. family planning, contraception, condom use, pregnancy and pmtct). (refer to supplementary material: ‘common art misconceptions’, and ‘practical measures for monitoring and enhancing adherence and retention in care ’.) 6.5 art in primary hiv infection several recent studies have suggested that starting art during seroconversion is associated with slower subsequent disease progression. a subgroup of patients who started art during seroconversion and were treated for 3 years showed virological control for several years after interrupting art.[18] we recommend initiating standard first-line therapy in patients diagnosed during seroconversion, if adherence requirements are met. art should be continued for at least 3 years, but consideration should be given to continuing lifelong 126 december 2014, vol. 15, no. 4 sajhivmed g u id e l in e art in these patients. commencing therapy during seroconversion is likely to limit the size of the hiv reservoir. diagnosing seroconversion is facilitated by having a recent negative hiv test that then becomes positive on a subsequent test. otherwise, the following are suggestive: the compatible clinical syndrome, an indeterminate enzyme-linked immunosorbent assay (elisa) test result that then becomes positive on a subsequent test, and a very high vl. 7. investigations prior to starting art the following investigations are recommended prior to initiating art: • alanine transaminase (alt) • full blood count (fbc): avoid azt if haemoglobin (hb) is <8 g/dl • serum creatinine and calculation of creatinine clearance (crcl): avoid tenofovir (tdf) if crcl is <50 ml/min; other nucleoside reverse transcriptase inhibitors (nrtis), except abacavir (abc), require dose adjustment if crcl is <50 ml/min (either using the estimated glomerular filtration rate (egfr) provided by the laboratory or calculating using the modified cockgraft-gault equation, table 9) • urinalysis for proteinuria • hepatitis b surface antigen (hbsag) • cd4+ count • baseline vl • syphilis serology • serum cryptococcal antigen test in patients starting art at a cd4+ count <100 cells/μl (to screen for early cryptococcal disease and to initiate pre-emptive treatment if p osit ive). if hiv diagnosis has been made using two rapid tests performed out side of a laboratory setting, then we advise confirming the positive serostatus using a laboratory test prior to commencing lifelong art. a detectable vl result would be sufficient (note that it may be undetectable in <1% of patients not receiving art, i.e. ‘elite controllers’), but if unaffordable/unavailable, then an elisa should be performed. 8. initial art regimens for the previously untreated patient the preferred first-line regimen is tdf + emtricitabine (ftc) (or 3tc) + efavirenz (efv). there are situations where this regimen cannot be used and these are discussed below. 8.1 nnrti component of first-line regimen in accordance with international recommendations, we recommend the use of a non-nucleoside reverse transcriptase inhibitor (nnrti) and two nrtis as the first-line art regimen. in comparison with protease inhibitors (pis), nnrtis are better tolerated in the long term and are at least as potent when combined with an appropriate dual nrti combination.[19] in addition, we do not recommend pis in firstline therapy owing to the associated cost and role in subsequent lines of therapy. for the same reasons, we do not recommend integrase inhibitors (integrase strand transfer inhibitors (instis)) in first-line therapy. however, intolerance or contraindications to nnrtis may dictate their use. an affordable insti-based first-line regimen may feature in future guidelines. however, in the interests of harmonising public and private sector guidelines, our opinion is that nnrti first-line regimens are currently preferable. many patients transition between the two sectors, and we have advised the use of insti in third-line therapy, as used in the public sector. either efv, rilpivirine (rpv) or nevirapine (nvp) may be selected as the nnrti; efv is preferred. owing to its neuropsychiatric sideeffects, efv should be avoided in those with active psychiatric illness or a history of severe psychiatric disease, in night-shift workers and in those operating heavy machinery or industrial vehicles. nvp should be avoided in women with a cd4+ count >250 cells/μl and men with a cd4+ count >400 cells/μl who are initiating art for the first time, because of the increased risk of rash-associated hepatitis. it should be noted, however, that this side-effect can occur with any cd4+ count. clinicians should consider avoiding nvp in patients who may encounter difficulties obtaining rapid medical attention should rash or hepatitis symptoms occur. nvp should also be avoided in patients with pre-existent liver disease. rpv should not be used in patients with a vl >100 000 copies/ ml, as clinical trials have shown that rpv-based regimens have higher virological failure rates in patients with higher vls compared with efvbased regimens.[20] in patients with a vl ≤100 000 copies/ml, outcomes are comparable overall with efv-based regimens, with rpv being better tolerated.[21] when efv, nvp and rpv are contraindicated (e.g. after a life-threatening nnrti hypersensitivity reaction), raltegravir (ral) or a pi could be substituted. any patient starting an nnrti should be told to report a rash, jaundice or symptoms of hepatitis immediately. a 400 mg dose of efv was non-inferior in terms of virological suppression compared with a 600 mg dose in the encore trial.[22] if there are significant non-resolving central nervous system side-effects, then the clinician should consider reducing the dose to 400 mg. a drawback of this is that there are no fdcs containing 400 mg of efv. this efv dose reduction should not be done for patients receiving tb treatment or who are pregnant, as the efficacy of this dose has not been studied in these patient groups (efv concentrations are reduced in pregnancy). etravirine (etv) use is not advised in first-line regimens, as this has not been studied in rcts and the drug has many significant drug interactions. 8.2 nrti component of first-line regimen any of the following two-drug nrti combinations are recommended for use with the nnrti: • tdf + emtricitabine (ftc – a cytidine analogue very similar to 3tc – is combined with tdf in an fdc or with the addition of efv as a triple-drug combination pill) • tdf + 3tc • abc + 3tc we favour regimens that include fdcs and allow once-daily dosing. tdf is the favoured nrti to use with 3tc or ftc, as it aligns with public sector programmes, is widely available as an fdc, and is very well tolerated. however, patients with a crcl <50 ml/min should not start tdf and should rather start abc. certain clinical trials suggest that abc-containing (v. tdf-containing) first-line regimens are associated with lower rates of virological suppression in patients with a baseline vl >100 000 copies/ml.[23,24] however, a recent meta-analysis shows that virological suppression is equivalent with abcand tdf-containing first-line regimens regardless of baseline vl.[25] given this finding, we now recommend that abc can be used in patients with a vl >100 000 copies/ml, without concerns regarding virological efficacy. abc has been associated with an increased risk of myocardial infarction in some cohort studies,[26,27] but the association was not confirmed in a meta-analysis of rcts.[28] nevertheless, caution december 2014, vol. 15, no. 4 sajhivmed 127 g u id e l in e is recommended when considering abc for patients at significant risk of, or with established ischaemic heart disease. abc, which does not require dose adjustment in renal failure, is specifically recommended for use in chronic renal failure, as tdf is nephrotoxic and azt could aggravate the anaemia of renal failure. we now recommend that azt or short-term stavudine (d4t) are only used in special circumstances in first-line therapy. if both tdf and abc are unavailable or contraindicated, then azt should be used, provided that the hb level is >8 g/dl. as it is considerably more toxic than other nrtis, d4t is no longer recommended. nonetheless, there is still a role for d4t in selected patients, when it is used in the short term in patients with contraindications to other nrtis. a common example is a patient with renal dysfunction and anaemia at baseline, who could be initiated on d4t for 3 6 months if abc is unavailable, and then switched to azt or tdf depending on resolution of the anaemia and/or renal dysfunction. in addition, if there is a need for concomitant nephrotoxic medications, e.g. aminoglycosides to treat multidrug-resistant (mdr)tb, then abc, azt or short-term d4t are preferable to tdf during the period of exposure to the other nephrotoxic medication. patients usually tolerate short-term d4t well. severe d4t side-effects, such as hyperlactataemia, lipoatrophy and other mitochondrial toxicities, typically occur after 6 months, although peripheral neuropathy can develop earlier. 9. laboratory monitoring for art efficacy 9.1 vl 9.1.1. timing of vl monitoring vl monitoring should be performed: • at baseline (before commencing art) • at 3 months after the commencement of art (this early vl is desirable to detect adherence problems early, before resistance develops. a subset of patients who start with a very high vl may not be fully suppressed at 3 months despite 100% adherence, but such patients would have had a >2log 10 drop in vl from baseline; therefore, the 3-month result should be interpreted in relation to the baseline vl. all patients who have a detectable vl at 3 months should receive additional adherence interventions.) • at 6 months and thereafter every 6 months. (in patients who have an undetectable vl for >12 months, and who demonstrate reliable adherence and follow-up, it may be acceptable to reduce the frequency of vl monitoring to annually.) if vl is >50 copies/ml, then the patient should receive counselling and interventions should be implemented to improve adherence. a repeat measurement of vl should then be done in 2 3 months. 9.1.2 interpreting vl results a vl >50 copies/ml while receiving art should be an indication for urgent action to improve adherence. a subsequent art change must be considered if the patient meets the criteria for a switch to a second-line art regimen at the subsequent 2 3-month follow-up vl measurement (section 11, ‘indications for changing art’). vl monitoring is key to the success of art. decisions to change art made on the basis of virological failure, rather than on clinical or immunological failure alone, result in better patient outcomes. if the vl is undetectable, then the virus cannot mutate and develop resistance. a sustained vl of <50 copies/ml is associated with the most durable benefit. isolated detectable hiv vls that are <1 000 copies/ml, which are followed by an undetectable vl, are termed ‘viral blips’ and do not indicate an increased risk of virological failure. 9.2 cd4+ counts cd4+ counts should be performed every 6 months. in patients being monitored with vl measurements, once the cd4+ count is >200 cells/ μl, provided that the vl is suppressed, routine cd4+ testing can be stopped, as it adds little to management. data to support this have recently been summarised.[29] however, if virological or clinical failure occurs, then a cd4+ count should be repeated, as ctx prophylaxis should be commenced if the count falls to <200 cells/μl while receiving art. 10. defining art failure in resource-limited settings where vls are unavailable, the who has devised criteria for defining art failure on the basis of cd4+ count responses or clinical disease progression. studies have shown that switching art regimens using these criteria results in a significant proportion of patients switching very late (with progressive accumulation of resistance mutations) and switching inappropriately (as the cd4+ count response may be poor in some patients, despite optimal virological suppression).[30] 10.1 virological criteria for treatment success treatment success is defined by: • a decline in vl of at least 2 log 10 from pretreatment levels 3 months after initiating art • a decline in vl to <50 copies/ml within 6 months of commencing art, and sustained thereafter. 10.2 virological criteria for treatment failure treatment failure is defined by a confirmed vl of >1 000 copies/ml in two measurements taken 2 3 months apart. several factors can influence the measurement of the vl. the decision to alter art should therefore be based on the results of repeat testing after 2 3 months, following intensive adherence counselling. inadequate patient adherence to the prescribed regimen remains the most common reason for treatment failure. other important causes include: prior use of single-dose nvp for pmtct; drug interactions that decrease art concentrations; and transmitted drug resistance, which is currently uncommon in the region (<5%).[31] 10.3 cd4+ response typically, the cd4+ count increases rapidly in the first month of art, by approximately 75 100 cells/μl, with a more gradual rise thereafter (50 100 cells/μl/year).[32] most, but not all, patients achieve a cd4+ count >500 cells/μl after several years of art, provided that the vl remains suppressed.[33-35] however, cd4+ responses are highly variable and may fail to increase despite virological suppression in about 10 20% of patients.[36,37] such patients have a delayed or absent cd4+ response to art despite viral suppression, which is termed an ‘immunological discordant response to art’. certain studies suggest that older patients are at higher risk. there is no evidence that such patients benefit from a change in art regimen; therefore, the same regimen should be continued. ctx prophylaxis should be continued if the cd4+ count remains <200 cells/μl. there is evidence that the prognosis of such patients is worse than in those who have a cd4+ 128 december 2014, vol. 15, no. 4 sajhivmed g u id e l in e response, but better than that of patients not receiving art. if patients with an immunological discordant response to art are clinically unwell, then tb or lymphoma should be considered as the cause of persistent cd4+ lymphopenia. cd4+ counts may continue to rise or remain stable in the presence of incomplete viral suppression (which will result in the emergence of drug resistance) in patients receiving pi-based art until the vl is high (approximately ≥10 000 copies/ml).[38] 11. indications for changing art individual art drugs may be substituted in the event of toxicity (section 17), provided that the vl is suppressed or art was initiated within the preceding 6 months. changing the first-line art regimen to a second-line regimen is a major step. the drugs used in secondline regimens are often not as well tolerated and are more expensive. for this reason, clinicians tend to switch to second-line art after a prolonged period of virological failure, causing a progressive increase in the accumulation of resistance mutations. if the vl is detectable, it is essential to step up adherence interventions, as discussed above. we advise a switch to a second-line regimen without undue delay when two vl measurements have been >1 000 copies/ml, preferably with the measurements taken 2 3 months apart, with at least 4 weeks of an intensified adherence intervention in between. in patients with low cd4+ counts (<100 cells/μl), this process should be expedited. some patients have persistently detectable vls at low levels (200 1 000 copies/ml). if patients have low-level viraemia for a prolonged period (>1 year), or persistently low cd4+ counts (<100 cells/μl) together with low-level viraemia despite adherence interventions, then they should be switched to second-line art. 12. second-line art regimens 12.1 resistance testing for selecting secondline art a resistance test at first-line failure should be considered if resources permit. however, in many settings in the region, this is unaffordable and/or unavailable. the benefits of such testing include that it may be able to differentiate between adherence problems (when the resistance test shows no resistance mutations) and the development of resistance, and may be informative regarding etv or rpv mutations in subsequent third-line regimens. it will help in deciding which nrtis to use in second-line therapy, although the recently published earnest (europe-africa research network for evaluation of secondline therapy) trial shows that even without the use of a resistance test to decide upon which nrtis to use in second-line therapy, virological outcomes are good and equivalent to a pi + ral regimen.[39] 12.2 recommended second-line art regimen we recommend a regimen of two nrtis and a ritonavir (rtv)-boosted (/r) pi. boosting of pis involves the addition of low-dose rtv, which inhibits pi metabolism, thereby boosting pi plasma concentration and prolonging half-life. we recommend against the use of unboosted pis. 12.3 rtv-boosted pi in the second-line regimen based on clinical trials demonstrating superior tolerability,[40,41] we suggest that the preferred pi in second-line therapy should be atazanavir (atv) 300 mg/rtv 100 mg daily. the benefits of atv/r over lopinavir (lpv)/r include that it is better tolerated in terms of gastrointestinal side-effects, has a more favourable lipid profile, and is taken once daily. drawbacks of atv/r are: it cannot be used with rifampicin (rif)-based tb treatment; there is no fdc containing rtv registered in sa; rtv capsules are not heat stable; and there are important drug interactions with drugs that reduce stomach acidity such as proton pump inhibitors. an alternative rtv-boosted pi rather than atv/r should be used in the following situations: • patients who do not tolerate atv/r (e.g. cosmetically unacceptable jaundice): use lpv/r • patients who do not own a fridge (to store rtv capsules): use lpv/r • patients receiving rif-based tb treatment: double-dose lpv/r should be used while receiving the tb treatment. other rtv-boosted pi options in second-line therapy are lpv/r and darunavir (drv)/r. lpv is coformulated with rtv in a heat-stable tablet (aluvia) and is the better option in patients without a refrigerator (other pis require rtv-boosting with a separate rtv capsule that ideally requires refrigeration, although rtv capsules are stable at room temperature for 30 days). this is also an option with rif when doubledosed. drv/r is taken twice daily, currently, and is more costly. when the 400 mg formulation becomes available, the 800/100 mg daily dose will be a feasible option in second-line art, with fewer side-effects than the twice daily dosing. indinavir (idv) is significantly more toxic than other pis. saquinavir (sqv) is less robust in terms of resistance than the three options listed. idv and sqv confer no benefit over other options, and are therefore not recommended. 12.4 selecting second-line dual nrtis because boosted pis are robust drugs (i.e. resistance develops slowly) in pi-naive patients, it is very likely that virological suppression will be achieved with good adherence, even if the two nrtis used in secondline therapy are partially compromised by nrti resistance mutations (tables 4 and 5).[42] this is supported by findings of the earnest trial, which showed good virological suppression rates of second-line lpv/r and nrti regimens, even in patients with significant nrti resistance. [39] certain nrti combinations are contraindicated for toxicity reasons (e.g. d4t + didanosine (ddi), or tdf + ddi). tdf + abc is not recommended for second-line art, as these agents share resistance mutations. nrti combinations advised for second-line regimens include either azt + 3tc, or tdf + 3tc (ftc can be substituted for 3tc), depending on the likely mutational profile selected during the patient’s first-line nrti combination. even if 3tc (or ftc) was used in a failed first-line regimen and may, therefore, have selected for the m184v mutation, which confers resistance to the agent, 3tc (or ftc) can be reused in second-line therapy because of the capacity of the m184v mutation to partially restore susceptibility to azt, d4t and tdf in the presence of thymidine analogue mutations (tams), and to partially restore susceptibility to tdf in the presence of the k65r mutation. the m184v mutation also reduces the replicative capacity of the virus. 12.5 selecting second-line art in patients who received a first-line pi regimen if a patient was receiving a first-line combination of two nrtis and a pi (boosted or unboosted), it is best to discuss the choice of second-line december 2014, vol. 15, no. 4 sajhivmed 129 g u id e l in e regimen with an experienced hiv clinician, and to perform a genotype resistance test. second-line nnrti + nrti regimens are often not effective in such patients because of nrti resistance mutations. the regimen choice is therefore best guided by resistance testing. 13. third-line art regimens third-line art (also referred to as ‘salvage’ therapy) is used when a patient has experienced virological failure on drugs from the nrti, nnrti and pi classes, and has documented pi resistance. before considering third-line therapy, adherence interventions should be intensified, and then adherence checked (e.g. check that pharmacy refills are all collected over a 6-month period). if there is still no viral suppression, then a resistance test should be performed to confirm the presence of resistance to the pi being used in secondline therapy. we advise doing this only after patients have been on a pi-based second-line regimen for a period of longer than 1 year, as the development of resistance earlier than this is very uncommon, unless there has been a medication error (e.g. giving standarddose lpv/r with rif). the resistance test is very expensive and the patient must be receiving the failing art at the time, as ‘wild-type’ hiv is more fit and outgrows the resistant mutant population which therefore cannot be detected within some weeks after cessation of art. however, third-line regimens are also extremely expensive and are not justified if the patient does not have resistance necessitating such a switch. currently, data show that most patients failing secondline regimens in the sa public sector have no pi mutations. in these patients, improved adherence is required rather than third-line regimens. the decisions regarding treatment choices in third-line therapy are complex and need to be guided by resistance patterns found on resistance testing. it is essential that resistance tests are interpreted by an expert in conjunction with a full art history. in recent years, a number of new drugs for use in third-line art have become available (e.g. instis together with newer pis (darunavir (drv) and tipranavir (tpv)) and nnrtis (etv and rpv)).[43] these provide an opportunity for effective viral suppression with third-line therapy in the majority of patients, provided that adherence is optimal. drv, etv, rpv, ral (an insti) and maraviroc (mvc) are now registered in sa. no firm recommendations for a generic third-line regimen can be made and regimen choice should be individualised. an expert treater should always be consulted. a few guidelines regarding third-line art regimens are: • there is a need for specific adherence counselling in patients preparing to start third-line art, with a frank discussion that this regimen is likely to be their last option for the foreseeable future. • first-generation nnrtis (nvp and efv) have no place in third-line therapy as they do not impair viral fitness. • a boosted pi with the broadest resistance profile should be selected (this is currently drv).[44] drv must be used twice daily in this context (600 mg 12-hourly with 100 mg rtv 12-hourly). lpv may be used if the drug is still active based on a resistance test (e.g. if the patient failed second-line atv therapy). • the addition of 3tc (or ftc) is recommended as the m184v mutation that it selects for impairs viral replication. other nrtis (the most active based on resistance testing) should also be added. • consideration of the addition of other salvage drugs (e.g. ral[45] and/ or etv[46,47] or rpv) will depend on the results of genotype resistance testing and cost issues. ral is preferred because it belongs to an entirely new class with no risk of cross-resistance from prior art exposure in firstand second-line therapy. because most patients are not receiving an nnrti at the time of failing second-line therapy when a genotype resistance test is typically performed, prior nnrti mutations related to first-line nnrti failure may be archived at this time. therefore, it is difficult to be certain from this genotype whether etv is compromised; however, data from sa suggest that the majority of patients who have failed nvp or efv are still susceptible to etv.[48] • we advise against double rtv-boosted pis.[9] • if viral suppression is not achieved on salvage therapy, then there is still benefit in continuing failing art, because of the residual partial activity and ‘crippling’ effect of such art. ‘crippling’ describes the fact that mutant viruses often have less replicative capacity. provided that the vl can be maintained at <10 000 copies/ml, the cd4+ count will usually be maintained or even increase.[38] • mvc (a ccr5 blocker) is a consideration for salvage therapy; however, it is currently extremely costly and can only be used after a tropism test demonstrates that the patient’s circulating virus has sole tropism for the ccr5 coreceptor. we advise only considering this for a salvage regimen when there is intermediateor high-level resistance to all pis, all nnrtis and all nrtis. for further guidance, consult the southern african hiv clinicians society art resistance guideline: southern african hiv clinicians society. the 2012 southern african arv drug resistance testing guidelines. s afr j hiv med 2012;13(4):162-167. 13.1 stopping art structured treatment interruptions are not advised as they have been shown to increase mortality (smart study).[49] sometimes, patients need to stop therapy for reasons beyond the control of the patient and clinician. if life-threatening toxicity occurs (e.g. hepatitis with liver failure), all drugs should be stopped at once, but in most cases of toxicity, a continuation of art should be attempted while switching the culprit drug to an alternative. if stock-outs occur, it may also be necessary to stop art. with pi and insti regimens, it is possible to stop all drugs simultaneously. with an nnrti regimen, it is necessary to cover the tail with 5 7 days of two nrtis (not needed if tdf/ftc are the nrtis). we advise against 3tc monotherapy ‘holding regimens’ in patients who have virological failure. such regimens can be associated with a rapid fall in cd4+ count. the objective when prescribing art should always be to provide a regimen that is most likely to achieve virological suppression. 14. patients who return after defaulting therapy we recommend restarting the same regimen if patients return to care after defaulting therapy. a vl should preferably be performed before restarting. we then recommend that the vl is measured 3 months after restarting art; switching to a second-line regimen should be considered if the vl is not <1 000 copies/ml at this point. in patients with multiple episodes of interruption, particularly beyond the first year of art, many clinicians would consider switching to a secondline regimen, making the assumption that the multiple interruptions resulted in first-line resistance. reasons for defaulting should be addressed and adherence support increased. 130 december 2014, vol. 15, no. 4 sajhivmed g u id e l in e hospitalisation with an aids-defining condition and a cd4+ count of <50 cells/μl represents another situation where a patient may be restarted immediately on second-line art when returning to care after defaulting; the reason being that the patient is considered to be at high risk of mortality if restarted on a first-line therapy to which their virus may be resistant, and that they require a guaranteed effective art regimen immediately. this decision should usually be taken by the clinicians at a hospital level. performing a resistance test after the patient has been off art for longer than 4 weeks is of limited value, as many resistance mutations are overtaken by wild-type virus when art is stopped. 15. drug interactions there are many important drug interactions between arv agents and other medications, as well as between certain arv agents themselves. these interactions occur because of the metabolism of arv drugs by cytochrome p450 in the liver and intestine, and the induction or inhibition of arvs by this and other enzyme systems and drug transporters. some of these drug interactions are discussed in these guidelines (e.g. the interaction between rif and nnrtis, pis and ral). the list of all potential drug interactions is, however, very long and beyond the scope of this document. knowledge of drug interactions is constantly evolving. clinicians are advised to consult the package inserts of arv agents and concomitant medications to assess for drug interactions, in addition to the following websites, which provide up-to-date information on drug interactions and the actions required to account for them: • university of liverpool drug interactions charts: http://www.hiv-druginteractions.org • university of cape town medicines information centre arv interactions table: http://www.mic.uct.ac.za/?page_id=47 we advise that clinicians assess for potential drug interactions whenever patients start or switch to new arv drugs or regimens, and start new concomitant medications. in addition, herbal medications may also have interactions with arvs. 16. art in special populations 16.1 tb the art regimen should be modified if necessary for compatibility with rif. rif is a critical component of the tb regimen that substantially reduces the risk of relapse after completing tb treatment. efv is the preferred nnrti for use with rif. nvp is an alternative in patients with contraindications for efv (e.g. psychosis), but it carries a higher risk of hepatitis and virological failure when used with rif. the plasma concentrations of all boosted pis are reduced to subtherapeutic ranges with rif. dose adjustment of lpv/r can overcome this induction (table 6), but there is a risk of hepatotoxicity. the patient will require counselling and alt should be monitored frequently. an alternative approach is to replace rif with rifabutin (rfb). however, rfb is expensive and not currently widely available at public sector tb clinics. also, rfb is not coformulated with other tb drugs, and the evidence base for rfb in the treatment of tb is much less substantial than that for rif.[51] there is also uncertainty regarding the optimal dose of rfb with boosted pis; these guidelines recommend 150 mg on alternate days (table 7). rfb may be considered in patients who are not tolerating cotreatment with lpv/r and rif-based antitubercular therapy (patients unable to tolerate the increased lpv/r dose due to hepatotoxicity or gastrointestinal side-effects) or in art-experienced patients on an art regimen that is not compatible with rif (e.g. third-line art with drv/r). if rfb is unavailable and adjusted doses of lpv/r are poorly tolerated in patients receiving second-line art, then ral may be substituted for the pi or triple nrti therapy may be considered. triple nrti art is, however, inferior to conventional art, and ral is less table 4. mutations selected by first-line nrti combinations* first-line nrtis nrti mutations selected 3tc or ftc select for m184v, which compromises both 3tc and ftc, and slightly impairs the activity of abc and ddi, but increases susceptibility to azt, d4t and tdf azt selects for tams, which may compromise all nrtis† d4t selects for tams, which may compromise all nrtis in a minority of patients, d4t may select for k65r, which compromises tdf, abc and ddi, but increases susceptibility to azt tdf selects for k65r, which compromises tdf, abc and ddi, but increases susceptibility to azt abc selects for l74v, which compromises abc and ddi may also select for k65r, which compromises tdf, abc and ddi, but increases susceptibility to azt selects for y115f, which decreases its susceptibility nrti = nucleoside/nucleotide reverse transcriptase inhibitor; 3tc = lamivudine; ftc = emtricitabine; abc = abacavir; ddi = didanosine; azt = zidovudine; d4t = stavudine; tdf = tenofovir; tams = thymidine analogue mutations. *these mutations accumulate with time – the longer the patient has virological failure, the more of these mutations are likely to be selected. † the presence of ≥3 tams, including m41l and l210w, confer intermediateto high-level tdf resistance. table 5. choice of second-line nrtis in relation to first-line nrtis used first-line nrtis used second-line nrti combination advised azt + 3tc tdf + 3tc* d4t +3tc tdf + 3tc* (preferably genotype first, given the increased risk of k65r on d4t in subtype c[50]) tdf + 3tc* azt + 3tc abc + 3tc azt + 3tc nrtis = nucleoside reverse transcriptase inhibitors; azt = zidovudine; 3tc = lamivudine; tdf = tenofovir; d4t= stavudine; abc = abacavir; ftc = emtricitabine. *3tc is interchangeable with ftc. december 2014, vol. 15, no. 4 sajhivmed 131 g u id e l in e robust than a pi in second-line therapy. nevertheless, short-term use over 6 months is probably preferable to treating tb without rif, which has a high risk of failure or relapse. art and tb medication share many side-effects (table 8). 16.2 pregnancy aids is the most frequent cause of death in pregnant women in many southern african countries,[52] and is a significant cause of morbidity and mortality in children born to hiv-positive women. even where children are born hiv-negative to hiv-positive mothers, their mortality is significantly increased. traditionally, the focus on hiv and pregnancy has centred on the transmission of hiv to children. this has lead to complex regimens to address concerns about efficacy and resistance. these guidelines attempt, where possible, to simplify this approach, to decrease transmission in both pregnant and breastfeeding mothers, and facilitate the continuum of care. 16.2.1 nnrti and pi choice in pregnancy based on the accumulated evidence, we endorse the who guidance that efv can be used in pregnancy and in women who intend to fall pregnant. this is in contrast to our previous guidance. the fda category d classification should be discussed with women, explaining that this was based on animal studies; human cohort studies have not demonstrated an increased risk of con geni tal abnormalities, but that there is a background low risk of congenital abnormalities table 6. art interactions with rif and recommendations for co-administration class arv agent interaction dose of art drug with rif nrti all in class no significant pharmacokinetic interactions no dose adjustment required nnrti efv mild reduction in efv concentrations in some patients on tb treatment, efv concentrations may increase no dose adjustment required (600 mg nocte) nvp moderate reduction in nvp concentrations with increased risk of virological failure compared with efv use standard dosing, but omit the lead-in dose phase and start 200 mg nvp 12-hourly etv and rpv marked reduction in concentrations do not prescribe concomitantly with rif pi lpv/r lpv plasma concentrations significantly decreased the preferable strategy is to double the dose of lpv/r to 800/200 mg 12-hourly alternatively, add 300 mg rtv 12-hourly to standard dose of two tablets of lpv/r 12-hourly there is an increased risk of hepatotoxicity with these strategies these dose adjustments can be made gradually over 1 2 weeks* all other pis marked reduction in pi concentrations do not prescribe concomitantly insti ral reduction in concentrations, but a clinical trial showed that standard dosing results in adequate virological suppression no dose adjustment required (i.e. ral 400 mg 12-hourly) art = antiretroviral therapy; rif = rifampicin; arv = antiretroviral; nrti = nucleoside reverse transcriptase inhibitor; nnrti = non-nucleoside reverse transcriptase inhibitor; efv = efavirenz; nvp = nevirapine; etv = etravirine; rpv = rilpivirine; pi = protease inhibitor; lpv = lopinavir; lpv/r = lopinavir/ritonavir; rtv = ritonavir; insti = integrase inhibitor (integrase strand transfer inhibitor); ral = raltegravir. *the double-dosing regimen is preferred as it is better tolerated. dose adjustments should be continued for 2 weeks after rif is stopped. table 8. shared side-effects of art and tb treatment side-effects art tb treatment nausea azt, ddi, pis pyrazinamide, ethionamide hepatitis nvp, efv, pis (nrtis can cause steatohepatitis) rif, inh, pyrazinamide and many second-line drugs, including quinolones peripheral neuropathy d4t, ddi inh, ethionamide, terizidone/ cycloserine renal impairment tdf aminoglycosides, rif (rare) rash nvp, efv, ral rif, inh, pyrazinamide, ethambutol, streptomycin and many second-line drugs, including quinolones neuropsychiatric problems efv terizidone/cycloserine, quinolones, inh art = antiretroviral therapy; tb = tuberculosis; azt = zidovudine; ddi = didanosine; pis = protease inhibitors; nvp = nevirapine; efv = efavirenz; nrtis = nucleoside reverse transcriptase inhibitors; rif = rifampicin; inh = isoniazid; d4t = stavudine; tdf = tenofovir; ral = raltegravir. table 7. dosing of arvs and rfb when prescribed concomitantly arv dose arv change rfb dosage efv none increase to 450 mg/day nvp none 300 mg/day atv or rtv-boosted pis none decrease to 150 mg every second day arvs = antiretrovirals; rfb = rifabutin; efv = efavirenz; nvp = nevirapine; atv = atazanavir; rtv = ritonavir; pis = protease inhibitors. 132 december 2014, vol. 15, no. 4 sajhivmed g u id e l in e in all pregnancies, unrelated to drugs. efv has been shown to be teratogenic in primates, resulting in craniofacial abnormalities in exposed offspring. there have been isolated human case reports of myelomeningocoele (neural tube defects) in infants following intrauterine exposure to efv. the drug is classified by the us food and drug administration (fda) as a category d drug, meaning that ‘there is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g. if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).’ it should be noted, however, that data supporting this classification are not supported by findings in cohorts of pregnant women exposed to efv. in a meta-analysis, the incidence of neural tube defects and all congenital abnormalities among women exposed to efv in the first trimester was similar to that of the general population.[53] who guidance is that efv can be used throughout pregnancy; their review of current data on efv safety and risk of teratogenicity is reassuring and, from a public health perspective, the need for simplicity and the toxicity associated with nvp are considered to outweigh concerns regarding unproven risks associated with efv.[ 54] studies have shown that total lpv concentrations are significantly reduced in pregnancy, but unbound lpv concentrations are not affected.[55] therefore, dose adjustment of lpv/r is not recommended in pregnancy. however, once-daily dosing of lpv/r should not be used in pregnancy. similarly, concentrations of boosted atv are reduced in pregnancy, but trough concentrations are adequate and dose adjustments are not recommended in pregnancy.[56] an exception is in patients who are also receiving tdf, as tdf may reduce atv concentrations: atv/r dose should be increased to 400 mg/100 mg daily in such patients during the third trimester of pregnancy. unboosted atv is not recommended in pregnancy. 16.2.2 general points fertility choices in the context of hiv treatment are complex. clinicians should check these choices at every patient visit to minimise risks. adequate access to safe and effective contraception should be provided. for further guidance: southern african hiv clinicians society. guideline on safer conception in fertile hiv-infected individuals and couples. s afr j hiv med 2011;12(2):31-44. in particular: • clinicians should be aware that women may fall pregnant unintentionally, but that the response may still vary from welcoming the pregnancy to wanting a termination. • in general, far too few women in the southern african region receive prophylaxis for pmtct. every effort must be made to ensure rapid ascertainment of hiv status and access to appropriate pmtct with art. • sa data suggest that most hiv transmissions to babies occur from hiv-positive mothers with cd4+ counts <350 cells/μl. rapid art initiation for the mother at this level will have a large effect on both maternal and child health. • all pregnant women of unknown hiv status or who were previously hiv-negative should be offered an hiv test, irrespective of previous sexual activity, marital status, social group or perceived hiv risk status. hiv testing should be repeated 3-monthly throughout pregnancy and breastfeeding. some studies have suggested a greater hiv acquisition risk during pregnancy. • the study of mtct is a rapidly evolving field, and international guidelines should be monitored for major changes. 16.2.3 recommendations for women who are hiv-infected and pregnant and not receiving art, the following is recommended as the best standard of care in situations where resources are available: • all hiv-infected pregnant women should be initiated on triple-drug art, if adequately prepared, irrespective of cd4+ count and vl. • cd4+ count testing and staging must be done quickly and art adherence counselling should be accelerated, with the aim to initiate women on treatment within 2 weeks of the first visit (and more rapidly in the third trimester of pregnancy). women who are being initiated onto art for pmtct should ideally be initiated after the first trimester, but women with a cd4+ count <200 cells/μl or with severe hiv morbidity should be started in the first trimester. • women who elect to breastfeed should continue art until weaning has occurred. • women with baseline cd4+ counts <350 cells/μl should have their art continued lifelong. • in women with a cd4+ count >350 cells/μl after pregnancy and who have completed breastfeeding, lifelong art should be discussed; if the patient is motivated, she should continue art lifelong, otherwise stop safely and continue to have her cd4+ count monitored (section 13.1). • if a woman presents during labour and is not receiving art, singledose nvp should be given to mother and baby, with additional azt and 3tc for 1 week, or single-dose tdf/ftc to the mother to reduce the risk of developing nnrti resistance (nvp has a very long half-life). an alternative is to start triple-drug art. • refer to pmtct guidelines for recommended regimens for the baby. 16.3 renal failure 16.3.1 arv dosages renal function is estimated either by the modified cockgraft-gault equation (table 9) or the modification of diet in renal disease (mdrd) method, which most laboratories report as egfr. the results of these formulae differ slightly, but either can be used for clinical management. for peritoneal dialysis, the dose given with a crcl <10 ml/min should be given daily. for haemodialysis, the dose given with a crcl <10 ml/ min should be given daily, but must be given after dialysis on dialysis days, to prevent the drug from being dialysed out. 16.3.2 arv choice and dosing in patients on chronic haemodialysis patients with hiv may develop end-stage renal failure requiring chronic haemodialysis owing to hiv-associated nephropathy or an hiv-unrelated cause. in patients on chronic haemodialysis, there are a number of important art issues that arise. the nrti class is eliminated through the kidneys, and thus doses of most nrti drugs need to be adjusted in patients on dialysis (table 9). although tdf can be used in patients on chronic haemodialysis, dosing is once weekly, which can be difficult for patients to remember. azt is generally avoided because of anaemia associated with chronic renal failure. daily dosages or the evening doses of a twice-daily regimen of arvs on the day of haemodialysis should be given after the haemodialysis session. nnrti drugs do not require dose adjustment. december 2014, vol. 15, no. 4 sajhivmed 133 g u id e l in e we recommend the following first-line option for patients on chronic haemodialysis: • abc 600 mg daily • 3tc 50 mg first dose and thereafter 25 mg daily (on the days when haemodialysis is performed, the dose should be given after the haemodialysis session) • efv 600 mg nocte. atv concentrations are reduced in patients on haemodialysis to a greater degree than lpv, and thus atv is preferably not used in treatment-experienced patients. lpv/r should be used with twice daily dosing in patients on haemodialysis. we recommend an lpv/ r-based second-line regimen with the nrtis in the regimen selected after genotype resistance testing and consideration of issues related to nrtis in patients on dialysis as discussed above. drv/r and ral may be used at standard dosages. it is suggested that patients on chronic haemodialysis (who generally receive ongoing medical care in a dialysis unit) are reviewed by a clinician experienced in arv management at least 6-monthly, to monitor treatment efficacy and side-effects, and to adjust the regimen when needed. 16.3.3 arvs in patients with acute kidney injury (aki) in patients with aki, dosages of nrti drugs should be adjusted based on estimated crcl calculation (table 9). tdf should be interrupted even if it is not thought to be the cause of the aki. once there is clear evidence that renal function is improving (creatinine on downward trend), nrti dosages should be readjusted to standard dosages to avoid underdosing. in patients with aki who are not yet receiving art, initiation is preferably deferred until aki has resolved. 16.4 arv dosages in liver impairment unlike in renal impairment, there is no blood test that can accurately quantify liver impairment. child-pugh class c may require dose adjustment for the relevant arvs listed in table 10. in general, the combination of tdf with 3tc (or ftc) and ral (or efv, which can be hepatotoxic) is regarded as the least hepatotoxic. if the patient has active hepatitis b, discontinuation of arvs that have activity against hepatitis b (tdf, 3tc and ftc) can cause severe flares of hepatitis. 16.5 hepatitis b co-infection hepatitis b is a common co-infection with hiv in southern africa, with significant implications for progression to cirrhosis, as well as for treatment options. clinicians are encouraged to support current efforts in the region to vaccinate all children for hepatitis b, and to extend coverage to eligible adults. access to vaccination, lab oratory resources and treatment options is limited to some extent in southern african countries, and the recommendations below should each be considered in the light of the local context. all hiv-positive patients should be screened for active hepatitis b (limiting screening to those with liver function abnormalities will miss many cases, as liver enzymes are often normal in hepatitis b infection). hbsag is an appropriate screening test. hepatitis b vl correlates with disease progression and may be used to monitor antihepatitis b therapy, but it is expensive and availability is limited. hepatitis b/hiv co-infection is associated with: • an increased risk of chronic liver disease • a higher hepatitis b vl • diminished responses to hepatitis b vaccine • poorer responses to interferon-alpha treatment • an increased incidence of drug-induced hepatotoxicity (particularly with nvp) • a flare of hepatitis within 3 months of commencing art (due to hepatitis b-iris, which is difficult to differentiate from drug hepatotoxicity). drugs directed against hepatitis b that have no/ minimal antihiv activity (e.g. entecavir and telbivudine) are largely unavailable or extremely expensive in our region. for practical purposes, the only available therapy is to use arvs that also have antihepatitis b activity (tdf + 3tc/ftc). as with hiv, these drugs suppress hepatitis b, but do not eradicate it. effective treatment prevents or slows progression to cirrhosis. all patients who are hiv-infected and hbsagpositive are eligible for art irrespective of cd4+ count. the art regimen should include table 9. arv dosage adjustments in renal failure* drug crcl (ml/min)‡§ haemodialysis (dose after dialysis) peritoneal dialysis10 50 <10 tdf avoid avoid 300 mg once weekly unknown abc unchanged unchanged unchanged unchanged 3tc 150 mg daily 50 mg daily† 50 mg first dose and thereafter 25 mg daily† 50 mg first dose and thereafter 25 mg daily† azt unchanged 300 mg daily 300 mg daily 300 mg daily d4t 15 mg 12-hourly 15 mg daily 15 mg daily unknown ddi >60 kg body weight: 200 mg daily <60 kg body weight: 150 mg daily >60 kg body weight: 125 mg daily <60 kg body weight: 75 mg daily >60 kg body weight: 125 mg daily <60 kg body weight: 75 mg daily >60 kg body weight: 125 mg daily <60 kg body weight: 75 mg daily nnrtis unchanged unchanged unchanged unchanged pis unchanged unchanged unchanged unchanged instis unchanged unchanged unchanged unchanged arv = antiretroviral; crcl = creatinine clearance; tdf = tenofovir; abc = abacavir; 3tc = lamivudine; azt = zidovudine; d4t = stavudine; ddi = didanosine; nnrtis = non-nucleoside reverse transcriptase inhibitors; pis = protease inhibitors; instis = integrase strand transfer inhibitors; egfr = estimated glomerular filtration rate; nrtis = nucleoside reverse transcriptase inhibitors. *this table was developed using: (i) bartlett jg. medical care of patients with hiv infection 2010; (ii) the sanford guide to antimicrobial therapy 2012; and (iii) hiv medicine association of the infectious diseases society of america. clinical practice guideline for the management of chronic kidney disease in patients infected with hiv: 2014 update. clin infect dis 2014;59(9):e96-e138. †some experts recommend that the lowest available tablet dose of 150 mg 3tc daily be used in patients with advanced renal disease (creatinine clearance <10 ml/min) and patients on dialysis so as to avoid having to use the liquid formulation of 3tc, and because of the favourable safety profile and lack of data to suggest 3tc dose-related toxicity.*(iii) this is particularly relevant if the 3tc liquid formulation is unavailable or not tolerated. ‡the modified cockgraft-gault equation: creatinine clearance (crcl)** = (140 age × ideal weight) ÷ serum creatinine **for women, multiply the total by 0.85. §many laboratories report the egfr calculated using a variation of the modification of diet in renal disease (mdrd) formula. this result can be used (in place of the calculated creatinine clearance) to make decisions regarding the use of tdf and for modification of the dose of other nrtis based on this table. 134 december 2014, vol. 15, no. 4 sajhivmed g u id e l in e tdf and 3tc (or ftc). using 3tc without including tdf leads to hepatitis b resistance in 80 90% of patients after 5 years of treatment. if a patient meets the criteria for switching to a second-line art regimen (to treat hiv), this combination (tdf + 3tc/ftc) should be continued to suppress hepatitis b infection, as interruption of tdf and/ or ftc/3tc has been associated with flares of life-threatening hepatitis. the second-line art regimen should be shaped around these two drugs in consultation with an experienced hiv clinician. nvp should be avoided in patients with hepatitis b co-infection. in patients with hepatitis b and renal dysfunction, the use of tdf may be considered with dosing frequency adjustment based on crcl (see package insert) and more frequent creatinine monitoring. if renal dysfunction is severe or renal function deteriorates with tdf, then 3tc monotherapy (with or without pegylated interferon-alpha, which is very costly) should be considered. 16.6 malaria there are several drug interactions between antimalarials and arvs: artemether-lumefantrine (coartem) can safely be administered with nvp. efv significantly lowers the concentrations of artemether (and its active metabolite) and lumefantrine, which is likely to increase the risk of failure of therapy. there is no clear guideline on how to overcome this interaction, but some experts recommend repeating the 3-day course of coartem (i.e. treat for 6 days). boosted pis dramatically increase the plasma concentrations of lumefantrine, but a dose reduction is not recommended, as the toxicity threshold of lumefantrine seems to be high. close monitoring for toxicity is recommended when coadministering artemether-lumefantrine with art. quinine concentrations are significantly decreased by lpv/r, probably owing to induction of metabolism by rtv. it is likely that quinine concentrations will also be reduced by efv and nvp; therefore, quinine should be avoided in patients receiving pis or nnrtis. patients with severe malaria should receive artesunate, if this is available, and those with milder malaria should be treated with artemether-lumefantrine. among drugs used for chemoprophylaxis, there are no clinically significant pharmacokinetic interactions between arvs and mefloquine or doxycycline. however, mefloquine and efv both cause frequent neuropsychiatric side-effects; therefore, doxycycline is the preferred chemoprophylactic agent for patients receiving efv. there are several interactions with atovaquone-proguanil (malanil). atovaquone concentrations are reduced by pis and efv. it is also table 10. prescribing arvs in liver impairment class drug prescribing notes nrtis tdf in patients with chronic hepatitis b, there is a risk of rebound hepatitis when tdf is discontinued ftc in patients with chronic hepatitis b, there is a risk of rebound hepatitis when ftc is discontinued or if hepatitis b resistance to ftc develops 3tc in patients with chronic hepatitis b, there is a risk of rebound hepatitis when 3tc is discontinued or if hepatitis b resistance to 3tc develops azt decrease dose by 50% or double dosage interval if significant liver disease abc reduce adult dose to 200 mg bd for significant liver impairment. contraindicated in severe hepatic impairment d4t use with caution and never combine d4t and ddi in patients with liver disease ddi use with caution: reports implicate use as a risk factor for the development of hepatic decompensation in patients being treated for cirrhosis due to hepatitis c nnrtis efv caution should be exercised in administering efv to patients with liver disease; therapeutic drug monitoring should be done if available nvp avoid if significant hepatic impairment or active hepatitis b or c etv use with caution in severe liver disease (child-pugh class c) as dosage recommendation has not been established rpv use with caution in severe liver disease (child-pugh class c) as dosage recommendation has not been established pis atv avoid in severe hepatic impairment lpv/r lpv is highly metabolised in the liver and concentrations may be increased in patients with hepatic impairment; therapeutic drug monitoring should be done if available drv use with caution or avoid if significant liver disease idv reduce unboosted adult dose to 600 mg 8-hourly if significant hepatic impairment sqv avoid: there have been reports of worsening liver disease and development of portal hypertension after starting sqv in patients with severe liver disease insti ral no dosage adjustment necessary in mild-to-moderate hepatic insufficiency ccr5 blocker mvc concentrations likely to be increased with hepatic impairment arvs = antiretrovirals; nrtis = nucleoside reverse transcriptase inhibitors; tdf = tenofovir; ftc = emtricitabine; 3tc = lamivudine; azt = zidovudine; abc = abacavir; bd = twice daily; d4t = stavudine; ddi = didanosine; nnrtis = non-nucleoside reverse transcriptase inhibitors; efv = efavirenz; nvp = nevirapine; etv = etravirine; rpv = rilpivirine; pis = protease inhibitors; atv = atazanavir; lpv/r = lopinavir/ritonavir; drv = darunavir; idv = indinavir; sqv = saquinavir; insti = integrase inhibitor (integrase strand transfer inhibitor); ral = raltegravir; ccr5 = c-c chemokine receptor type 5; mvc = maraviroc. december 2014, vol. 15, no. 4 sajhivmed 135 g u id e l in e likely that nvp decreases atovaquone concentrations. proguanil concentrations are also reduced by pis and efv. use of atovaquoneproguanil is therefore best avoided in patients receiving pis or nnrtis. 17. arv toxicity monitoring and management currently recommended art is generally well tolerated. many adverse drug reactions are mild and occur only in the first few weeks of therapy. if toxicity does not resolve or is severe, then the offending drug should be substituted as indicated below. it is important to ensure that the vl is suppressed before substituting a single drug for toxicity, otherwise resistance may develop to the new drug, consequently compromising future regimens. however, single-drug substitutions can be done in the first few months of art without measuring the vl, as the vl may take up to 6 months to suppress. it is rarely necessary to stop the entire art regimen due to toxicity. it is advised to switch only the culprit drug and continue the rest of the art regimen. in certain life-threatening situations (e.g. hepatitis with liver failure or lactic acidosis), it may be necessary to cease use of all arvs. 17.1 haematological toxicity cytopenias occur commonly in hiv infection without exposure to art. patients receiving azt, d4t or ctx may experience abnormalities in their fbcs. significant bone marrow toxicity from ctx generally only occurs with high doses used for treating ois. patients receiving prophylactic ctx rarely develop isolated neutropenia. fbc monitoring is necessary with azt; this should be performed monthly for 3 months, then after 6 months of therapy and thereafter if clinically indicated (it is unusual to see haematological toxicity occurring after 6 months). the main problem arising from azt use is anaemia and neutropenia; platelet counts generally rise with use of the drug. management guidelines are provided in table 11. macrocytosis is usual with d4t and azt therapy; there is no need to measure vitamin b12 and folate concentrations unless there are other indications that these may be deficient. pure red cell aplasia, which presents with severe anaemia and low reticulocyte production index, has rarely been associated with 3tc. a bone marrow examination should be performed to confirm the condition. parvovirus b19 infection should be excluded (a polymerase chain reaction (pcr) test should be requested on blood sent in an ethylenediaminetetra-acetic acid (edta) tube). 17.2 hepatotoxicity • liver function tests (lfts) should be performed at art initiation and the measurement intervals should be tailored thereafter to individual drug regimens. the full panel of lfts is expensive; therefore, it is recommended that only alt is monitored, as this is the most sensitive indicator of drug-induced liver injury (dili). the full lft profile should be requested in patients with symptoms suggestive of hepatitis. all arv classes have been associated with hepatotoxicity – most commonly nnrtis. nrtis very rarely present with acute hepatitis. mild alt elevations occur very commonly and usually transiently with many drugs in general. alt elevations >5× the upper limit of normal (uln) are significant in the absence of symptoms. in the presence of symptoms of hepatitis, alt elevations >2.5× uln are significant. • ideally, in patients starting nvp, alt should be monitored at 2, 4, 8 and 12 weeks after initiation. if monitoring is performed, a system should be in place to obtain the result and contact the patient; routine alt monitoring makes little sense in settings where the result will only be available when the patient is seen in 2 4 weeks, or where the patient cannot be contacted. it is essential to educate all patients starting nvp about the symptoms of hepatitis (nausea, vomiting, anorexia, malaise, jaundice and right-upper-quadrant pain) and drug rash, which is frequently associated with hepatitis. hepatitis often follows the rash after about 10 days. if such symptoms develop, alt should be determined urgently. • hepatotoxic drugs should be discontinued at high levels of lft abnormality (table 12) or at lower levels if any symptoms of hepatitis appear and an alternative arv agent substituted. rechallenge may be considered in selected cases; a specialist should be consulted. if hepatitis occurs together with a rash or fever, or with other systemic involvement, then rechallenge with nnrtis, abc or ctx should not be attempted. • prolonged use of nrtis, especially d4t and ddi, may cause fatty liver. typically, alt concentration is more significantly elevated than ast, and the concentrations of canalicular enzymes (gammaglutamyl transferase (ggt) and alkaline phosphatase (alp)) are more elevated than those of the transaminases. non-tender hepatomegaly may be present. ultrasound or computed tomography (ct) imaging may show decreased hepatic density. the condition is not benign and fibrosis has been reported with long-term ddi use. patients should be advised to avoid alcohol. patients receiving d4t or ddi should be switched to safer nrtis. • in patients with severe hepatitis or jaundice, the international normalised ratio (inr) and serum glucose should be assessed, as well as features of hepatic encephalopathy (i.e. features of hepatic failure). • if the concentration of canalicular enzymes is more significantly elevated than that of alt, or if conjugated bilirubin is elevated, an ultrasound of the liver should be conducted to exclude biliary obstruction. • isolated unconjugated hyperbilirubinaemia (drug-induced gilbert’s syndrome) is associated with certain pis (idv and especially atv). in this case, all other lfts are normal and the patient has no other symptoms of hepatitis. although this is a benign condition (it does not reflect liver injury, but isolated competitive inhibition of the enzyme in the liver which conjugates bilirubin), it is often cosmetically unacceptable to patients. • patients with underlying hepatitis b or c infection may experience a flare of hepatitis when art is commenced, as a consequence of iris. hepatitis b can also flare when arvs that have activity against it (tdf, 3tc and ftc) are discontinued or when hepatitis b resistance develops. • many other drugs can cause hepatotoxicity, notably antitb agents (including prophylactic isoniazid) and azoles. ctx is an uncommon cause of hepatitis, often as part of a systemic hypersensitivity reaction. • recommendations for the management of dili in patients receiving tb treatment have been published by the society in 2013: • jong e, conradie f, berhanu r, et al. consensus statement: management of drug-induced liver injury in hiv-positive patients treated for tb. s afr j hiv med 2013;14(3):113-119. 17.3 hyperlactataemia this side-effect has become less common with fewer patients starting art with d4t and with the use of lower doses of d4t. it can also occur occasionally with azt, but clinicians should be aware that this side-effect can occur with all other nrtis, although it is very rare with abc, tdf, 136 december 2014, vol. 15, no. 4 sajhivmed g u id e l in e 3tc and ftc. mildly elevated lac tate is not uncommon in patients treated with nrtis, but is generally asymptomatic. asymptomatic elevated lactate does not predict the development of lactic acidosis; it is therefore unnecessary to monitor levels in asymptomatic patients. • lactic acidosis is a serious, rare, potentially fatal side-effect of nrtis, most commonly associated with d4t, particularly when combined with ddi. symptomatic hyperlactataemia without acidosis is more common, but seldom seen with the safer nrtis that are currently recommended. • the combination of d4t and ddi is associated with a high risk of symptomatic hyperlactactaemia or lactic acidosis, particularly in pregnancy. this combination should therefore be avoided. • symptoms are nonspecific and include nausea and vomiting, abdominal pain, dyspnoea, fatigue and weight loss. • risk factors for hyperlactataemia include: • female gender • obesity • the use of nrtis for >6 months • the development of nrti-induced peripheral neuropathy or fatty liver. • a raised lactate of >5 mmol/l together with metabolic acidosis confirms the diagnosis of lactic acidosis. low serum bicarbonate (<20 mmol/l) is the most sensitive marker of acidosis. associated abnormalities include elevated ast and alt, lactate dehydrogenase and creatinine kinase. treatment is supportive. the management of symptomatic hyperlactataemia depends on lactate and bicarbonate concentrations: • lactate <5 mmol/l and bicarbonate >20 mmol/l: nrtis should be switched to agents less frequently associated with hyperlactataemia: tdf/abc + ftc/3tc. symptoms and serial lactate should be monitored for several months (lactate levels decrease slowly over weeks). • lactate >5 mmol/l and bicarbonate >15 mmol/l: patient should be admitted and nrtis should be discontinued. if the patient is on an nnrti regimen, then a boosted pi should be added. if the patient has already failed an nnrti and is on a boosted pi, then ral and/or etv should be added, if available, or the patient should be continued on the boosted pi only. when lactate has normalised, the patient should be switched to tdf/abc + 3tc/ftc, as above. • lactate >5 mmol/l and bicarbonate <15 mmol/l: the patient should be admitted, preferably to an icu, and nrtis should be discontinued. if the patient is on an nnrti regimen, a boosted pi should be added. if the patient has already failed an nnrti regimen and is receiving a boosted pi, then ral and/or etv should be added, if available, or the patient should be continued on a boosted pi only. bicarbonate replacement is controversial, but most experts would use this strategy to partially correct severe acidosis. broad-spectrum antibiotics are recommended as sepsis can mimic nrti-induced lactic acidosis (this can be discontinued if procalcitonin is normal). on recovery, all nrtis should be avoided in future regimens, although some experts would recommend a trial of safer nrtis with lactate monitoring, as above. for further guidance: southern african hiv clinicians society. guidelines for the prevention, diagnosis and management of nrti-hyperlactataemia and lactic acidosis. s afr j hiv med 2006;7(1):8-15. the potential of nrtis to cause elevated lactate varies (from most likely to least likely): d4t/ddi > azt > tdf/ftc/3tc/abc 17.4 dyslipidaemia • pis, with the exception of unboosted atv, can cause fasting hypertriglyceridaemia and elevated l o w d e n s ity lipoprotein (ldl) cholesterol. boosted atv is associated with less severe dyslipidaemia; d4t can cause mild hypertriglyceridaemia, and efv can cause elevated total cholesterol and mild hypertriglyceridaemia. • diet and lifestyle modification should always be advised. diet is more effective for controlling hypertriglyceridaemia than hypercholesterolaemia. other cardiovascular risk factors should be addressed. • if patients receiving pis develop dyslipidaemia that warrants lipid-lowering therapy, then they should be switched to boosted atv, if possible, rather than adding therapy for the dyslipidaemia. switching the pi to ral is another option, because ral has a favourable lipid profile. however, ral should only be used in a regimen with two other arvs known to be fully active. • marked hypertriglyceridaemia (>10 mmol/l) can cause pancreatitis and requires urgent treatment with diet, fibrates and switching to boosted atv (fibrates can be stopped after 1 month, followed by reassessment). indications for statin therapy table 11. guidelines for managing haematological toxicity (mainly azt-induced) hb (g/dl) >8: monitor 7.0 7.9: repeat 4 weeks reduce azt 200 mg bd or consider switching from azt 6.5 6.9: repeat 2 weeks consider switching from azt <6.5: switch from azt neutrophils (× 109/l) 1.0 1.5: repeat 4 weeks 0.75 0.99: repeat 2 weeks 0.50 0.74: repeat 2 weeks consider switching from azt <0.5 switch from azt azt = zidovudine; hb = haemoglobin; bd = twice daily. table 12. guidelines for managing hepatotoxicity elevation uln* <2.5 × uln 2.5 5 × uln >5 × uln alt monitor repeat at 1 week discontinue relevant drug(s) alp monitor repeat at 2 weeks ultrasound; consider biopsy bilirubin repeat at 1 week discontinue relevant drug(s) discontinue relevant drug(s) uln = upper limit of normal; alt = alanine transaminase; alp = alkaline phosphatase. *any elevations with symptoms of hepatitis (nausea, vomiting, right upper quadrant pain) should be regarded as an indication to stop the relevant drugs. december 2014, vol. 15, no. 4 sajhivmed 137 g u id e l in e in hiv-positive patients should be the same as in hiv-negative patients, according to the framingham heart disease risk score. many statins have interactions with pis that can lead to potentially toxic statin concentrations, with the exception of pravastatin and fluvastatin. atorvastatin concentrations are significantly raised by pis, but low doses (e.g. 10 mg daily) can be used with monitoring for symptoms of myalgia. lovastatin and simvastatin should not be coadministered with pis, as their concentrations are dramatically increased and severe rhabdomyolysis has been reported. • we suggest assessing lipids after 3 months on a pi regimen. if normal at this stage, reassessment should be performed only in those with other cardiovascular risk factors. 17.5 lipodystrophy • long-term art use may cause changes in body fat distribution (lipodystrophy). this can present with fat accumulation (visceral obesity, breast enlargement, ‘buffalo hump’ or lipomata) or subcutaneous fat loss (lipoatrophy, most noticeable in the face, limbs and buttocks), or with both forms of lipodystrophy. • the thymidine analogue nrtis (azt and especially d4t) are associated with fat loss. • lipoatrophy improves when d4t/azt are substituted with tdf or abc, but resolution is very slow and often incomplete; therefore, it is important to recognise lipoatrophy early or, better still, to use nrtis that are not associated with the condition. • previously, pis were thought to be the cause of lipohypertrophy. however, more recent studies have shown that all classes of arvs are associated with fat gain to the same extent. furthermore, longitudinal studies comparing hiv-negative people with hiv-positive people on long-term art have demonstrated that the extent and distribution of fat gain are similar. a systematic review of rcts concerning switching arvs for fat accumulation failed to show any benefit.[57] these data indicate that fat gain is a consequence of treating hiv rather than a drug-specific side-effect. telling the patient that the arvs are causing fat gain is not only incorrect, but may result in the patient discontinuing art. the appearance of the fat gain is particularly unsightly when accompanied by subcutaneous fat loss. • there is no good evidence to support the switching of arvs in patients with fat accumulation. healthy diet and exercise should be advocated, as in the hiv-negative population. surgery should be considered in selected cases with focal fat gain (e.g. those with prominent ‘buffalo humps’). metformin modestly reduces weight and improves insulin resistance in patients with the metabolic syndrome or isolated dysglycaemia. • visceral fat accumulation is associated with insulin resistance and dyslipidaemia. other cardiovascular risk factors should be addressed in all patients. 17.6 hypersensitivity • rash with nnrtis is common (more severe and frequent with nvp) in the first 6 weeks of therapy. if the rash is accompanied by systemic features (e.g. fever, elevated alt or hepatitis), mucosal involvement or blistering, then the nnrti should be discontinued immediately and rechallenge must not be performed as these are features of lifethreatening reactions. if the rash is mild and occurs without these features, then the nnrti can be continued and the rash can be treated symptomatically with antihistamines, and possibly topical steroids. systemic steroids should not be used. • in patients who develop mild rashes during the low-dose nvp lead-in phase (200 mg daily), the dosage must not be increased to 200 mg 12-hourly until the reaction has resolved. this ‘treatthrough’ approach is only acceptable if the patient can be observed carefully, otherwise nvp should be substituted. • there is a possible cross-reaction between nvp and efv, although most studies report no evidence of this. it is acceptable to substitute efv for nvp in the event of hypersensitivity, unless the reaction was severe. there are hardly any data on substituting nvp for efv in the event of hypersensitivity; therefore, this substitution is not recommended. • abc hypersensitivity is primarily a systemic reaction occurring within the first 8 weeks of therapy in ~3% of cases. fatalities may occur on rechallenge. therapy must be discontinued and never reintroduced. the manifestations of hypersensitivity include fever, rash, fatigue and abdominal or respiratory symptoms. if there is any doubt concerning the diagnosis (e.g. if the patient has a cough with fever), then the patient should be admitted for observation. symptoms progress if hypersensitivity is present. the hypersensitivity reaction has been shown to occur on a genetic basis, being confined to people with the hla-b*5701 allele, which is very uncommon in africans. it is thus less frequent in patients of african descent. if testing is affordable and available, this allele should be excluded prior to using abc. • other arvs, notably ral and drv, can occasionally cause hypersensitivity rashes, including life-threatening rashes. • ctx is a common cause of cutaneous and systemic hypersensitivity reactions, indistinguishable from hypersensitivity reactions to arvs. ctx should be interrupted when treating mild suspected nnrti cutaneous hypersensitivity rashes, and permanently discontinued if severe hypersensitivity reactions occur. 17.7 nephrotoxicity analysis for serum creatinine and urine proteinuria must be performed at baseline in all patients to detect subclinical renal disease, as there is an increased risk of renal failure in hiv infection due to a variety of causes. the dose of nrtis needs to be adjusted in renal failure (table 9). in a minority of patients, tdf may cause a tubular wasting syndrome (including wasting of phosphate and potassium). if patients receiving tdf develop muscle weakness or other muscle symptoms, then potassium and phosphate levels must be assessed. tdf can also cause acute renal failure, but this is uncommon. tdf should be discontinued immediately in patients with acute renal failure and should generally never be restarted (switch to abc or another nrti). consider recommencing with careful monitoring when the renal failure has resolved only if an alternative cause of renal failure is established and tdf was considered not to have contributed. we recommend that it is essential to estimate the crcl before commencing tdf, which should not be used if the egfr or crcl is <50 ml/min. for patients receiving tdf, creatinine should be monitored at 3 months, 6 months and then 6-monthly thereafter. in high-risk patients (particularly those with coexistent hypertension or diabetes), creatinine should also be checked at 1 and 2 months. long-term use of tdf with other nephrotoxic agents (e.g. aminoglycosides or non-steroidal antiinflammatory agents (nsaids)) should be avoided. where tdf is avoided because crcl is <50 ml/min at baseline, it may be possible to switch to tdf at a later point if renal function improves. this is often the case where patients had diarrhoea or other ois at the time of art initiation. 138 december 2014, vol. 15, no. 4 sajhivmed g u id e l in e 17.8 neuropsychiatric toxicity azt and ral frequently cause headaches when started, but this usually resolves. efv frequently causes neuropsychiatric effects in the first few weeks of therapy, typically presenting with insomnia, vivid dreams and dizziness. both dysphoria and euphoria may occur. fortunately, these features subside in the majority of patients within the first 4 6 weeks. psychosis may occasionally occur. if the neuropsychiatric effects of efv are not tolerated, then the patient should be switched to rpv, nvp (if the cd4+ count is <250 cells/μl in women or <400 cells/μl in men; if virologically suppressed, then efv can be switched to nvp at higher cd4+ counts as this is not associated with increased risk of rash-associated hepatitis), lower dose efv (400 mg daily) or ral. patients starting efv should be warned about these symptoms, and reassured that they resolve in most patients continuing the drug, but if not, that an alternative can be substituted. 17.9 dysglycaemia the older pis, notably idv, may cause diabetes. however, the newer pis (atv, drv and lpv) do not. efv, azt and d4t are associated with small increased risks of dysglycaemia. visceral fat gain, which occurs to a similar extent with all arv classes, is associated with insulin resistance. blood glucose should be assessed serially in these patients as part of a cardiovascular risk assessment. 17.10 gynaecomastia gynaecomastia involves the development of breast tissue in men. this is not related to lipodystrophy. it may be bilateral or unilateral. serum testosterone should be measured and replacement therapy given if this is low. gynaecomastia is most consistently associated with efv, so suppressed patients should be switched to rpv or nvp. 18. iris approximately 10 20% of patients who start art with advanced immunosuppression experience clinical deterioration during the first months due to iris. two forms are recognised: • unmasking iris occurs in patients who have an unrecognised oi when art is initiated, and who then present with exaggerated inflammatory features of that infection during early art due to it being ‘unmasked’ by recovering immunity. • paradoxical iris occurs in patients who are being treated for an oi when they start art, but who develop an immune-mediated worsening or recurrence of features of that infection after starting art. iris is most frequently described in association with tb and cm. skin conditions such as molluscum contagiosum and kaposi’s sarcoma may also worsen due to iris. the diagnosis of iris can be difficult, mainly because there is no confirmatory diagnostic test. diagnosis relies on recognition of the characteristic clinical presentation, ensuring that ois are correctly diagnosed, and excluding alternative causes for deterioration, such as drug resistance (e.g. mdr-tb). case definitions for tb and cryptococcal iris have been published.[58,59] it is important to ensure that the underlying oi is treated appropriately. art should be continued, unless iris is life-threatening (e.g. neurological involvement in tb-iris with depressed level of consciousness). corticosteroids have been shown to reduce morbidity and improve symptoms in paradoxical tb-iris,[60] and can be used in mycobacterial and fungal forms of iris when other causes for deterioration have been excluded, and particularly when iris features are severe. for paradoxical tb-iris, prednisone can be commenced at a dose of 1.5 mg/kg/day and weaned over 4 weeks, but a longer course may be required if symptoms recur on weaning. steroids should not be used in patients with kaposi’s sarcoma. practical guidance for tb-iris management has been published.[61] 19. support and counselling the patient should be informed about the benefits of art and that side-effects are usually minor and transient, or manageable. the patient should be given a treatment plan, specifying the reasons for commencing therapy and the drugs to be used (with names and details including the appearance of each drug, when and how they are to be taken, and a brief indication of anticipated side-effects and toxicity). adherence in the order of ≥90% is required for virological suppression. poor adherence results in the development of drug resistance. there is a bell-shaped relationship between adherence and resistance: patients with very poor resistance may not acquire resistance because of insufficient drug pressure to select for resistance. the patient should be encouraged to discuss drug-related issues with his/her clinician. 20. prophylaxis in patients receiving art 20.1 ois the use of appropriate prophylaxis (primary or secondary) is essential in patients initiating art. in general, prophylaxis can be discontinued once the cd4+ count has increased to 200 cells/μl (but certain minimal durations of prophylaxis apply for secondary prophylaxis – local and international guidelines should be consulted). 20.2 isoniazid preventive therapy (ipt) a recent clinical trial conducted in sa showed that ipt has an additive effect with art in preventing incident tb in hiv-positive patients.[62] there was a 37% reduction in incident tb when patients receiving art were prescribed ipt (v. placebo) for 12 months. this benefit applied irrespective of tuberculin skin test (tst) status, and the trial included patients established on art. all patients receiving art should be considered for ipt and screened for active tb using a symptom screen[63] – defer ipt and investigate for active tb if any of the four symptoms (current cough, fever, night sweats or weight loss) are present. consider sputum tb culture in all patients with a cd4+ count <200 cells/μl before ipt initiation where feasible. in patients receiving ipt, monitor for neuropathy and hepatitis symptoms. routine alt monitoring is not indicated. the duration of ipt depends on tst and art status as outlined in table 13. funding and support. this work is supported and funded by the southern african hiv clinicians society. table 13. indications for and duration of ipt  tst pre-art on art not done ipt for 6 months ipt for 12 months negative ipt not indicated ipt for 12 months positive ipt for at least 36 months ipt for at least 36 months ipt = isoniazid preventive therapy; tst = tuberculin skin test; art = antiretroviral therapy. december 2014, vol. 15, no. 4 sajhivmed 139 g u id e l in e conflicts of interest. all expert panel members have completed and submitted conflict of interest disclosure forms. disclosure information represents the previous 3 years (updated 1 december 2014) and includes relationships with pharmaceutical companies and medical aids. f conradie has received support from abbvie, aspen and mylan to attend conferences; research support from janssen; honoraria for speaking engagements from abbvie, janssen and msd; and acted as a consultant to sanofi aventis. t manzini has received support from mylan and cipla to attend conferences. m mathe has received support from janssen to attend conferences and honoraria from janssen for speaking engagements. g meintjes has received honoraria for speaking engagements from sanofi aventis and serves as a consultant for aid for aids. m moorhouse has received honoraria for speaking engagements from aspen and msd. y moosa has received honoraria for speaking at conferences from abbvie, msd and mylan, and acted as a consultant for mylan and pfizer. c orrell has received support to attend conferences from tibotec and honoraria from abbott for a speaking engagement. y pakade has received support from aspen to attend a conference. f venter has received honoraria for speaking engagements from msd, novogen, aspen and adcock-ingram; has served on advisory boards for abbott, pfizer, johnson and johnson, mylan and tibotec; and has received study drug for investigator-led studies from gilead. j black, v cox, s dlamini, j fabian, g maartens, c menezes, j nash and d wilson report 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[http://dx.doi.org/10.1097/qai.0b013e3181c990bf] 42. hamers r, sigaloff k, wallis c, et al.; and pharmaccess african studies to evaluate resistance (paser). patterns of hiv-1 drug-resistance after first-line art failure and response to second-line art in a multi-country cohort: sub-saharan africa. 19th conference on retroviruses and opportunistic infections. seattle, 5-8 march 2012. abstract 104. 43. yazdanpanah y, fagard c, descamps d, et al. high rate of virologic suppression with raltegravir plus etravirine and darunavir/ritonavir among treatment-experienced patients infected with multidrug-resistant hiv: results of the anrs 139 trio trial. clin infect dis 2009;49(9):1441-1449. [http://dx.doi.org/10.1086/630210] 44. arastéh k, yeni p, pozniak a, et al. efficacy and safety of darunavir/ritonavir in treatment-experienced hiv type-1 patients in the power 1, 2 and 3 trials at week 96. antivir ther 2009;14(6):859-864. [http://dx.doi.org/10.3851/1301] 45. steigbigel rt, cooper da, teppler h, et al. long-term efficacy and safety of raltegravir combined with optimized background therapy in treatmentexperienced patients with drug-resistant hiv infection: week 96 results of the benchmrk 1 and 2 phase iii trials. clin infect dis 2010;50(4):605-612. [http:// dx.doi.org/10.1086/650002] 46. lazzarin a, campbell t, clotet b, et al. efficacy and safety of tmc125 (etravirine) in treatment-experienced hiv-1-infected patients in duet-2: 24-week results from a randomised, double-blind, placebo-controlled trial. lancet 2007;370(9581):39-48. [http://dx.doi.org/10.1016/s0140-6736(07)61048-4] 47. madruga jv, cahn p, grinsztejn b, et al. efficacy and safety of tmc125 (etravirine) in treatment-experienced hiv-1-infected patients in duet-1: 24-week results from a randomised, double-blind, placebo-controlled trial. lancet 2007;370(9581):2938. [http://dx.doi.org/10.1016/s0140-6736(07)61047-2] 48. stevens ws, wallis cl, sanne i, venter f. will etravirine work in patients failing non-nucleoside reverse transcriptase inhibitor-based treatment in southern africa? j acquir immune defic syndr 2009;52(5):655-656. [http://dx.doi.org/10.1097/ qai.0b013e3181ba1b00] 49. el-sadr wm, lundgren j, neaton jd, et al.; strategies for management of antiretroviral therapy (smart) study group. cd4+ count-guided interruption of antiretroviral treatment. n engl j med 2006;355(22):2283-2296. [http://dx.doi. org/10.1056/nejmoa062360] 50. wainberg ma, zaharatos gj, brenner bg. development of antiretroviral drug resistance. n engl j med 2011;365(7):637-646. [http://dx.doi.org/10.1056/nejmra1004180] 51. davies g, cerri s, richeldi l. rifabutin for treating pulmonary tuberculosis. cochrane database syst rev 2007;(4):cd005159. [http://dx.doi. org/10.1002/14651858.cd005159.pub2] 52. bradshaw d, chopra m, kerber k, et al. every death counts: use of mortality audit data for decision making to save the lives of mothers, babies, and children in south africa. lancet 2008;371(9620):1294-1304. [http://dx.doi.org/10.1016/s01406736(08)60564-4] 53. ford n, calmy a, mofenson l. safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. aids 2011;25(18):2301-2304. [http://dx.doi.org/10.1097/qad.0b013e32834cdb71] 54. world health organization. technical update on treatment optimization. use of efavirenz during pregnancy: a public health perspective. geneva: world health organization, 2012. 55. patterson kb, dumond jb, prince ha, et al. protein binding of lopinavir and ritonavir during 4 phases of pregnancy: implications for treatment guidelines. j acquir immune defic syndr 2013;63(1):51-58. [http://dx.doi.org/10.1097/ qai.0b013e31827fd47e] 56. eley t, bertz r, hardy h, burger d. atazanavir pharmacokinetics, efficacy and safety in pregnancy: a systematic review. antivir ther 2013;18(3):361-375. [http:// dx.doi.org/10.3851/imp2473] 57. de waal r, cohen k, maartens g. systematic review of antiretroviral-associated lipodystrophy: lipoatrophy, but not central fat gain, is an antiretroviral adverse drug reaction. plos one 2013;8(5):e63623. [http://dx.doi.org/10.1371/journal. pone.0063623] 58. haddow lj, colebunders r, meintjes g, et al. cryptococcal immune reconstitution inflammatory syndrome in hiv-1-infected individuals: proposed clinical case definitions. lancet infect dis 2010;10(11):791-802. [http://dx.doi.org/10.1016/ s1473-3099(10)70170-5] 59. meintjes g, lawn sd, scano f, et al. tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resourcelimited settings. lancet infect dis 2008;8(8):516-523. [http://dx.doi.org/10.1016/ s1473-3099(08)70184-1] 60. meintjes g, wilkinson rj, morroni c, et al. randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. aids 2010;24(15):2381-2390. [http://dx.doi.org/10.1097/ qad.0b013e32833dfc68] 61. meintjes g, sonderup mw. a practical approach to the diagnosis and management of paradoxical tuberculosis immune reconstitution inflammatory syndrome. continuing medical education 2011;29(10):410-417. 62. rangaka mx, wilkinson rj, boulle a, et al. isoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trial. lancet 2014;384(9944):682-690. [http://dx.doi.org/10.1016/s01406736(14)60162-8] 63. getahun h, kittikraisak w, heilig cm, et al. development of a standardized screening rule for tuberculosis in people living with hiv in resourceconstrained settings: individual participant data meta-analysis of observational studies. plos med 2011;8(1):e1000391. [http://dx.doi.org/10.1371/journal. pmed.1000391] supplementary material s1. starting art in hospital starting art in eligible patients in an inpatient setting can be considered in certain circumstances, and should strongly be considered during prolonged hospitalisation, where adherence, toxicity management and other support can be directly provided. however, limited data have shown what many experienced clinicians predicted: that patients who are initiated on art within hospital have high default rates. this may be due to several factors: patients who wait to become severely ill and enter hospital may still have high levels of denial; they may be too ill to take in adherence counselling; and discharge may not be managed well. the clinician must carefully weigh up the high risk of deferring art in terms of mortality and morbidity, and the risk for the individual patient of default, which cannot be predicted easily. if a patient is considered for initiation in hospital, the following should be attended to: s1.1 in hospital • before discharge, the patient must understand the reasons for art initiation. • if the patient is too ill or not mentally competent, then a caregiver and/or family member who will act as a directly observed therapy supporter should be involved. • care should be exercised regarding art drug interactions with concomitant medication. s1.2 on discharge • give very clear art clinic directions, with a referral letter and details of documentation needed by the clinic. • patients should be encouraged to attend the art clinic as soon as possible for an appointment and should be informed of reasonable clinic appointment waiting times. • sufficient medication must be provided to last until the art clinic december 2014, vol. 15, no. 4 sajhivmed 141 g u id e l in e visit. • these patients are often discharged on newly initiated tb treatment; few programmes as yet offer integrated tb/art clinical services, and the need for separate clinical visits should be explained carefully. • discharging patients directly into the care of adequately counselled family members can be invaluable. s2. high-risk patients patients who are at high risk for early mortality, iris and art sideeffects include patients with: • a low body mass index, anaemia and low albumin levels • newly diagnosed ois, especially tb and cm • low cd4+ counts. these patients should be initiated on art as quickly as possible after any underlying ois have been addressed (note the specific guidelines regarding art timing in tb and cm in the guidelines), and should be counselled about the risk of iris, which may be misinterpreted as a sign of art side-effects. ideally, patients should have access to rapid referral systems, in the events of experiencing complicated iris or side-effects. in addition, patients with any of the following are at high risk of default or inadequate adherence: • uncontrolled depression • poverty • ambivalence about their hiv status • distrust of the formal health sector • lack of home support or high levels of community stigma • alcohol or other substance abuse • postpartum women. adherence issues are addressed in the southern african antiretroviral resistance treatment guidelines, and include: attention to treating mental illness and substance use; giving access to support groups; addressing potential workplace-related issues including drug toxicity issues; additional counselling if denial is an issue; honest discussions about alternative health providers and churches that may undermine adherence; better postpartum integration of women/child hiv services; and actively linking poorer patients to poverty alleviation programmes. s3. common art misconceptions • you cannot take art if you do not have food available. none of the commonly used firstand second-line options have meaningful food restrictions (although rpv should be taken with food). patients should be warned that their appetite may return and that this may even be uncomfortable. however, food insecurity should be managed actively through rapid referral, and this should never be a reason to delay art initiation. • doses need to be taken at precisely the same time each day. this myth was especially prevalent in the earlier days of art, with anecdotes of patients returning to clinic in despair, after having interrupted their therapy for several weeks after missing a dose due to oversleeping by an hour. encouraging patients to establish a routine helps with adherence, but delayed dosing is rarely a problem, even if out by many hours. most of the drugs have long half-lives, and patients should be told simply to take their dose once they remember to do so. • you must never drink alcohol again. heavy alcohol use may affect adherence, and may potentiate the hepatic toxicity of art and other hepatic pathology. however, data do not support the commonly held notion that alcohol speeds up the progression to aids, nor is there any evidence that moderate alcohol use has any negative effect on the health of hiv-positive individuals. local guidelines for the general population around responsible alcohol use should be followed; prohibition is not advocated. • disclosure is a prerequisite for art. this myth probably followed early experiences with highly rationed art, where all possible adherence strategies were aggressively pursued to optimise outcomes, and bringing in a ‘treatment buddy’ was required to access art. however, it became a form of punishment by some unsophisticated counsellors and clinicians, often under the pretext of preventing transmission, through making hiv status public. this tactic is almost certainly illegal and is certainly unethical, and while disclosure may assist patients with support and adherence, this should be suggested and based on the patient’s individual circumstances. forced disclosure can result in violence at the hands of a partner or community, and undermines confidence in confidentiality within the entire health system. patients should be counselled about the pros and cons of disclosure, and assisted through the process as needed. • unprotected sex causes virological failure. this myth probably emerges from a convoluted understanding of the transmission of resistant virus. theoretically, unprotected sex with someone who is failing art may allow for the passage of resistant virus, but this is unusual. patients should be counselled about safe sex; however, unprotected sex itself will not result in virological failure. s4. practical measures for monitoring and enhancing adherence and retention in care the success of an individual’s art hinges on how well the tablets are taken. at least 90%, preferably more, of treatment doses need to be taken as prescribed and gaps in therapy avoided in order to prevent the development of resistance. most people will need support in maintaining high levels of treatment adherence. the areas below reflect adherence measures that are evidence based and should be in place for all those receiving art. s4.1 causes of poor adherence these are often complex and linked to social issues. common causes include: • inadequate treatment literacy. most hiv programmes have extraordinary adherence rates compared with other chronic diseases; this is largely due to efforts to ensure that patients understand hiv. if a patient fails therapy, some examination of the preart counselling may be merited. • side-effects. side-effects are a very common reason for patients to default therapy. a careful history of often subtle but distressing side-effects (bad dreams, sleepiness, poor concentration, nausea, loss of appetite, change of body shape), in conjunction with a work history (shift work in particular) may allow for drug substitutions. subtle lipoatrophy changes from d4t and azt are often not taken seriously by healthcare providers, until disfiguring. regular enquiry and immediate drug substitutions where possible should form part of every healthcare worker encounter. • depression and other mental illnesses. undiagnosed or undertreated 142 december 2014, vol. 15, no. 4 sajhivmed g u id e l in e depression and other mental illness (the frequency of major depression is twice as high in hiv-positive subjects than in matched hiv-negative subjects) may undermine adherence. patients with depression usually respond well to an antidepressant medication in combination with non-pharmaceutical interventions. if they do respond, then the medication should be given for at least 6 months. • poverty and food insecurity. both of these have been related to poor adherence and increased missed clinic visits. patients often lose their jobs due to ill health during the period leading up to art initiation, and should be encouraged to return to the job market as soon as feasible or to seek support. this may lead to moving away from the art clinic, and referral must be facilitated. access to available grants, social support and employment non-governmental organisations (ngos) may provide additional support. • work-related issues. these include shift work and the ability to visit clinics on weekdays. they are a major cause of poor adherence. long clinic waiting times, including monthly pick-ups, may render maintaining employment untenable, especially with an unsympathetic employer. clinicians should try to encourage clinics to be flexible, run smoothly for healthy patients, and provide 3 6-monthly pharmacy refills. • substance use. excessive alcohol use may cause significant problems with adherence. in addition, other recreational drugs may cause problems in certain parts of the country, and use fluctuates according to availability and fad. • social problems. these include stigma and poor social support networks. perceived stigma is correlated with poor adherence; this may manifest in a fear of tablets being found, an inability to solicit family or partner support, or anxiety regarding an employer, neighbours or a community. social support groups may assist. s4.2 pretreatment preparedness anyone commencing art needs to be prepared for treatment. this can be done on a one-toone basis or in a group session, by a trained doctor, nurse or counsellor. while treatment preparation involves imparting information on hiv and art to the patient, sessions should also include identifying an individual’s barriers to therapy (e.g. depression, alcohol use, nondisclosure or food security (table s1)) and addressing any misconceptions about art. the minimum information should include: • that art is beneficial, but it is lifelong therapy • the importance of excellent adherence to tablet-taking and to care • side-effects of the current regimen, and a plan for what to do and who to contact if serious side-effects occur. a flipchart to highlight key points in treatment preparedness session can be accessed at: http://sahivsoc.org/topics?page=1&curre ntfilter=adherence%20and%20hiv%20 drug%20resistance. this information can be given over two to three sessions around the time of treatment commencement. s4.3 on-treatment monitoring adherence must be monitored during therapy. ideally both subjective and objective adherence should be assessed at every visit. two easy subjective measures include selfreport (asking the number of doses missed in the last 3 days or 1 week) or a visual analogue scale (fig. s1). subjective methods are not sensitive (most people do not admit to missing doses), but are specific (if a missed dose is noted, adherence issues are very likely and should be addressed). pharmacy refill is a reliable method of assessing adherence. most medications are refilled monthly and assessing how many months of medication are collected over a fixed period (6 or 12 months) is a sensible way of determining adherence (fig. s2). couriering medication unfortunately removes this method of assessment. s4.4 using vl there is a growing body of evidence to show that resuppression of vl after an initial raised vl on treatment is possible in 56 68% of individuals. any raised vl after >3 months on art should be treated urgently and an adherence intervention must be implemented. 0 5 8 10 ask the patient to mark how well they have taken their medication in the last month: 0 means no treatment taken; only 10 is perfect. any other score identi�es an adherence issue and should be addressed. fig. s1. an example of a visual analogue scale. table s1. possible reasons for poor adherence individual provider medication depression alcohol or substance use non-disclosure adolescence pregnancy food insecurity stock-outs inaccessible clinics (both in place and time) high pill burden frequent dosing (>once per day) adverse effects calculate the number of claims/times that the patient has collected medication since the start of art (or from 12 months prior to the current date if the patient has received art for some years). e.g. a patient who started art on 15 july 2011 had collected medication a total of 30 times according to the medical aid between then and june 2014. divide by the number of complete months since the start of art until the current date (or 12 months if only using the preceding year). e.g. there are 35 complete months between july 2011 and june 2014. the calculation would be 30/35 = 0.86. express as percentage. e.g. 0.86 x 100 = 86% this is lower than what is ideal and should trigger adherence support. fig. s2. calculating pharmacy refill adherence. g u id e l in e december 2014, vol. 15, no. 4 sajhivmed 143 this intervention would include exploration of adherence practices and further education on viral resistance and failure. any issues from table s1 that were not completely addressed should be identified, and disclosure to at least one other person who could act as a treatment supporter should actively be encouraged. a pillbox or other reminder system should be implemented, if not already in use. art should be dispensed monthly, to allow more frequent contact with art staff, until the vl is <50 copies/ml. ideally, a vl measurement should be repeated 2 3 months after commencing this adherence intervention. s4.5 noticing if patients miss visits each provider should have a system in place in order to notice when a patient misses a visit or does not collect their arvs. rapid follow-up within a few days of a missed visit with a phone call or a home visit by a counsellor may serve to prevent a gap in treatment. s4.6 watching for high-risk groups be aware that certain subsets of people are at higher risk of poor adherence and loss to follow-up. these include pregnant women, children and adolescents, and the mentally ill (including those who are depressed). these groups should be monitored more closely and managed actively. this may include monthly attendance to see a counsellor for additional support and monitoring of adherence, or referral to specific support groups or services (e.g. mothers to mothers to be, alcoholics anonymous, an adolescent-friendly clinic or psychological services), as appropriate. s4.7 practical adherence tools tools such as pillboxes, diaries and setting alarms may help patients to remember to take their medication. having an emergency supply of a single dose on hand (e.g. in the handbag or workbag) may be useful for situations when patients have unexpected delays in getting home. medicine formulations and trade names may change, and patients should be educated to recognise the generic name of their current regimen to avoid confusion. additional adherence and resistance educational resources from the southern african hiv clinicians society are available at: http:// sahivsoc.org/topics?page=1&currentfilter=adherence%20and%20 hiv%20drug%20resistance references • bärnighausen t, chaiyachati k, chimbindi n, peoples a, haberer j, newell ml. interventions to increase antiretroviral adherence in sub-saharan africa: a systematic review of evaluation studies. lancet infect dis 2011;11(12):942-951. [http://dx.doi.org/10.1016/s1473-3099(11)70181-5] • thompson ma, mugavero mj, amico kr, et al. guidelines for improving entry into and retention in care and antiretroviral adherence for persons with hiv: evidence-based recommendations from an international association of physicians in aids care panel. ann intern med 2012;156(11):817-833. [http://dx.doi. org/10.7326/0003-4819-156-11-201206050-00419] • bonner k1, mezochow a, roberts t, ford n, cohn j. viral load monitoring as a tool to reinforce adherence: a systematic review. j acquir immune defic syndr 2013;64(1):74-78. [http://dx.doi.org/10.1097/qai.0b013e31829f05ac] appendix: who stage 3 and 4 conditions (2006 revision) who stage 3 conditions • unexplained severe weight loss (>10% of presumed or measured body weight) • unexplained chronic diarrhoea persisting for longer than 1 month • unexplained persistent fever (intermittent or constant for longer than 1 month) • persistent oral candidiasis • oral hairy leukoplakia • pulmonary tb (current) • severe bacterial infections (e.g. pneumonia, empyema, pyomyositis, bone or joint infection, meningitis, bacteraemia, severe pelvic inflammatory disease) • acute necrotising ulcerative stomatitis, gingivitis or periodontitis • unexplained anaemia (<8 g/dl), neutropenia (<0.5 × 109/l) and/ or chronic thrombocytopenia (<50 × 109/l). who stage 4 conditions • hiv wasting syndrome • pneumocystis pneumonia • recurrent severe bacterial pneumonia • chronic herpes simplex virus infection (orolabial, genital or anorectal of more than 1 month’s duration, or visceral at any site) • oesophageal candidiasis (or candidiasis of trachea, bronchi or lungs) • extrapulmonary tb • kaposi’s sarcoma • cytomegalovirus infection (retinitis or infection of other organs) • cns toxoplasmosis • hiv encephalopathy • extrapulmonary cryptococcosis including meningitis • disseminated non-tuberculous mycobacteria infection • progressive multifocal leukoencephalopathy • chronic cryptosporidiosis • chronic isosporiasis • disseminated mycosis (extrapulmonary histoplasmosis, cocci dio mycosis) • recurrent septicaemia (including non-typhoidal salmonella) • lymphoma (cerebral or b-cell non-hodgkin’s) • invasive cervical carcinoma • atypical disseminated leishmaniasis • symptomatic hiv-associated nephropathy • symptomatic hiv-associated cardiomyopathy abstract introduction patient presentation discussion conclusion acknowledgements references about the author(s) hayati demiraslan department of infectious diseases and clinical microbiology, erciyes university, turkey kemal deniz department of pathology, erciyes university, turkey mehmet doganay department of infectious diseases and clinical microbiology, erciyes university, turkey citation demiraslan h, deniz k, doganay m. multiple papular lesions in a patient with hiv and/or aids and coinfected with hepatitis b virus: amyloidosis. s afr j hiv med. 2017;18(1), a735. https://doi.org/10.4102/sajhivmed.v18i1.735 case reports multiple papular lesions in a patient with hiv and/or aids and coinfected with hepatitis b virus: amyloidosis hayati demiraslan, kemal deniz, mehmet doganay received: 01 feb. 2017; accepted: 05 june 2017; published: 30 aug. 2017 copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract introduction: the most common form of systemic amyloidosis is amyloid a induced by a chronic inflammation. in hiv-infected patients, elevated serum amyloid a levels might be associated with chronic inflammation. patient presentation: a 43-year-old male patient was admitted to hospital with a complaint of papular lesions around his eyes, existing for four months. the patient is receiving antiretroviral therapy. hiv rna was undetectable, and the cd4 count was 770 cells/mm3. he suffered from a bladder carcinoma for four years. on examination, periocular, perioral and anogenital papules, papular lesions in the meatus of external auditory canal, and intranasal polyps were observed. management: microscopic examination of the biopsy material taken from the periocular lesion and then from perianal polyps revealed eosinophilic deposition, and stained positively by congo red. serum amyloid a level was negative. antiretroviral therapy was continued. conclusion: a rare form of amyloidosis in a patient with hiv and/or aids and coinfected with hepatitis b virus (hbv) was presented here with cutaneous and mucosal lesions. introduction the most common form of systemic amyloidosis is amyloid a induced by a chronic inflammation or chronic infections such as tuberculosis, chronic osteomyelitis, familial mediterranean fever and rheumatoid arthritis. in hiv-infected patients, elevated serum amyloid a levels have been reported to be associated with chronic inflammation.1,2 hiv infection may cause amyloidosis by either direct action of hiv or its immunosuppressive effect.3,4 clinical presentation depends on systemic organ involvement by amyloid fibrils, and the most common clinical manifestations proteinuria that leads to renal insufficiency.5 here, a rare clinical presentation of amyloidosis in a patient infected with hiv was reported. written informed consent was also taken from the patient, and the case report was approved by erciyes university local ethics committee (no: 352/2017). patient presentation a 43-year-old male patient with hiv and/or aids was admitted to the infectious diseases department for the investigation of papular lesions around his eyes in november 2014. the patient was diagnosed with hiv and/or aids and hepatitis b virus (hbv) coinfection in 2004 and antiretroviral therapy was initiated with a combination of lamivudine, zidovudine and lopinavir and ritonavir. this regimen was given between 2007 and 2010. later, the therapy regimen was switched to tenofovir and emtricitabine and efavirenz. a bladder carcinoma was diagnosed in 2011 and he received mitomycin c in cycles. he denied fever and pain but sometimes complained of bleeding from his perianal polyp, and he claimed the lesion colour changed from pale to violet. on physical examination, periocular, perioral and anogenital papules and papular lesions in the external auditory canal and intranasal polyps were present. the lesions were lilac-coloured, soft and painless (figure 1a, 1b, 1c and 1d). his body mass index was 21 kg/m2. figure 1: appearence of (a, b) multiple nodular lesions around the eyes and within both nostrils (c) on the right external ear canal (d) and the lesions on the lower lip. management and outcome routine blood count and biochemistry tests were within normal limits. urinalysis showed microscopic haematuria and proteinuria (3 g/day). the creatinine clearance was calculated to be 80 ml/min according to the cockroft–gault equation. abdominal ultrasound examination showed an echogenic stone of 8 mm diameter in the lower pole of the left kidney. the size of both kidneys was found to be within normal limits. a biopsy was performed from the periocular lesion in 2014 and from the perianal polyp in 2016. histopathologic examination revealed eosinophilic deposition in the tissues and a positive staining with congo red showing amorphous eosinophilic deposition (figure 2). apple green birefringence was visualised under polarised light. serum amyloid a level was negative. renal biopsy could not be performed because the patient refused the procedure. hiv rna was undetectable (< 20 copies/ml), and the cd4 count was 770 cell/mm3. the patient is currently receiving an antiretroviral regimen consisting of dolutegavir and lamivudine, and additional oral colchicine therapy. figure 2: photomicrograph showing typical amorphous extracellular congo red–positive amyloid deposition within the dermis (congo red, x100). ethical considerations verbal and written consent were taken from the patient for his clinical presentation and outcome. the case report was also approved by erciyes university local ethics committee (no: 352/2017). discussion serum amyloid a is an acute-phase protein produced by the liver and it is related to high-density lipoprotein particles.1 one cause of systemic inflammation may be mitochondrial dysfunction, which is induced by nucleoside reverse transcriptase inhibitors.6 amyloid may be induced by chronic inflammation and cancer.1 the presented case had hiv infection and hbv coinfection since 2004 and bladder carcinoma since 2011. either of these might lead to secondary amyloidosis. a limited number of cases have been reported of secondary amyloidosis in hiv patients who had nephrotic syndrome.7,8 in this case, renal biopsy could not be performed because the patient refused the biopsy. the most common clinical presentation of amyloidosis is related to renal disease, which includes nephritic syndrome.3,7,8 although this patient had nephrotic renal disease with proteinuria of 3 g/day; however, the patient’s main presenting complaint was related to cutaneous involvement periocular, intranasal and perioral papules. conclusion in conclusion, unusual presentations of amyloidosis with multiple cutaneous involvement may be seen in hiv patients especially complicated with cancer and hbv coinfection. acknowledgements competing interests all authors declare that there is no conflict of interest. the authors further declare that they have no financial or personal relationship which may have inappropriately influenced them in writing this article. this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. authors’ contributions all three authors were involved in preparing, follow-up and writing of the article. h.d. and m.d. were involved in redacting of the article. references eklund kk, niemi k, kovanen pt. immune functions of serum amyloid a. crit rev immunol. 2012;32:335–348. https://doi.org/10.1615/critrevimmunol.v32.i4.40 hoffman hm, throne ml, amar nj, et al. long-term efficacy and safety profile of rilonacept in the treatment of cryopryin-associated periodic syndromes: results of a 72-week open-label extension study. clin ther. 2012;34:2091–2103. https://doi.org/10.1016/j.clinthera.2012.09.009 jung o, haack hs, buettner m, et al. renal aa-amyloidosis in intravenous drug users – a role for hiv-infection? bmc nephrol. 2012;13:151. https://doi.org/10.1186/1471-2369-13-151 real de asua d, costa r, galvan jm, filigheddu mt, trujillo d, cadinanos j. systemic aa amyloidosis: epidemiology, diagnosis, and management. clin epidemiol. 2014;6:369–377. https://doi.org/10.2147/clep.s39981 lachmann hj, goodman hj, gilbertson ja, et al. natural history and outcome in systemic aa amyloidosis. n engl j med. 2007;356:2361–2371. https://doi.org/10.1056/nejmoa070265 manfredi aa, rovere-querini p. the mitochondrion – a trojan horse that kicks off inflammation? n engl j med. 2010;362:2132–2134. https://doi.org/10.1056/nejmcibr1003521 jatem e, loureiro j, agraz i, curran a. secondary amyloidosis in a hiv patient. nefrologia. 2011;31:759–760. cozzi pj, abu-jawdeh gm, green rm, green d. amyloidosis in association with human immunodeficiency virus infection. clin infect dis. 1992;14:189–191. https://doi.org/10.1093/clinids/14.1.189 untitled t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u n e 2 0 0 7 7 professor des martin was the visionary who in 1998 saw a need and pulled together a group of hiv specialists who became the founder members of the hiv clinicians society of south africa. it has become the largest interest group of the south african medical association and now has branches throughout the sadc region. this phenomenal growth is a tribute to des’s extraordinary ability to inspire and challenge others to take up the cudgels and fight the good fight. the mushrooming number of branches in other countries in this region also speaks to des’s passion for africa and his deepseated commitment to see capacity grow throughout the continent. he has personally visited most of these branches at their inaugural meetings and then singlehandedly nurtured them to independence. many branches now provide some of the most critical support and continuing medical education to hiv doctors in their areas. des is no stranger to hard work. born and bred in johannesburg, educated at wits, he started his career as a general practitioner first in johannesburg but then moving to the ‘eastern transvaal’ where he became a household name among the farmers and townspeople of the nelspruit area. he devoted 20 years to general practice before heeding the call to academia and returning to wits to specialise in clinical virology. subsequently des has held pivotal posts in the national institute of virology and national pathology structures. he is currently a consultant virologist at toga laboratories, and a senior member of the departments of virology at wits and the university of pretoria. des launched the southern african journal of hiv medicine as president of the society in august 2000. from the first distinctive edition with its bold design and eye-catching colour the journal has gone from strength to strength. remarkably, des has involved world-renowned hiv specialists on the editorial board and forged important and strategic partnerships with a wide range of people, institutions, funders and organisations. des has a wonderful ability to spot talent, especially in younger members, and has framed the careers of many who now play important roles in south african hiv and virology. encouraged by des, francois venter took over the reins as president of the society in 2005, and linda-gail bekker stepped into his shoes as editor just in the last two months. des is a hard act to follow. he describes himself as a ‘fence sitter’, but in fact it is his masterful diplomacy and artful chairmanship of meetings, especially in the presence of strong personalities and opinions, that (together with an incorrigible sense of fun and outstanding sense of humour) have made him stand out as a statesman of note. des is a devoted family man, father to five grown children and some grandchildren, and loves nothing better than to spend time on the golf course, or at their holiday home in kwazulunatal, with his talented wife lori. he is a sportaholic who can be relied upon to know the score of most cricket and rugby matches while they are still being played. professor des martin, the society and the editorial team salute you for all your years of commitment and service. we wish you well as you take a little more time for relaxation, but greatly appreciate your ongoing wisdom with so much still to be done in combating the hiv epidemic in south africa. linda-gail bekker editor des martin – a tribute make up march 2007 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e m a r c h 2 0 0 7 1 9 a ‘think tank’ meeting on aids prevention in the high hiv prevalence countries in southern africa, convened in lesotho in may 2006 by sadc and unaids, concluded that ‘high levels of multiple and concurrent sexual partnerships by men and women with insufficient consistent, correct condom use, combined with low levels of male circumcision are the key drivers of the epidemic in the sub-region.’1 the top two ‘key priority interventions’ recommended by the hiv-aids, reproductive health, epidemiological and other experts participating in the think tank meeting were: (i ) ‘significantly reduce multiple and concurrent partnerships for both men and women’, and (ii ) ‘prepare for the potential national roll out of male circumcision … depending on the outcome of the [now successfully completed] kenya and uganda randomized trials’. various other factors in the region’s hiv epidemic, including a range of gender issues, especially the need for greater male involvement in hiv prevention, high prevalence of sexual violence, low hiv risk perception, and pervasiveness of transactional sex among young people, especially young women, were also discussed, and continued promotion of primary abstinence, greater access to hiv counselling and testing and access to condoms, especially in high-risk situations, were also recommended. this paper, however, focuses on the evidence underlying the prevention think tank meeting’s two main conclusions. the highly generalised hiv epidemic in southern and parts of east africa is uniquely severe. elsewhere, hiv transmission continues to be strongly associated with especially high-risk activities, namely use of injectable drugs, male-to-male anal sex, and sex work, and the most effective means of prevention are now generally recognised.2 although hiv has been present for nearly two decades in much of asia, latin america and eastern europe, extensive heterosexual spread has seldom occurred in those regions.3-6 while there is concern over the possibility that it could still occur, for the foreseeable future southern africa will certainly remain by far the most severely affected region of the global pandemic.6-9 although there has been some decline in hiv in parts of eastern africa, rates remain extremely high in much of southern africa.2,7-9 the overwhelming burden of hiv is still concentrated in this region, home to less than 2% of the global population but at least one-third of all hiv-infected people. infection rates among adults in south africa, swaziland, botswana and western kenya range from 20% to at least 30%, roughly an order of magnitude higher than anywhere else in the world, outside of africa.2 what might account for this pervasive discrepancy? the now conclusive body of epidemiological and biological evidence confirming the strong association between lack of male circumcision and hiv10-15 is increasingly understood to explain much of the roughly fivefold difference in hiv rates between southern and western africa7,16 (fig. 1). in 2005, a randomised clinical trial of male circumcision for hiv prevention in orange farm, south africa, found that the procedure reduced a man’s risk of infection by at least 60%, and two similar clinical studies in kenya and uganda were recently halted prematurely, also due to such robust findings.17-19 however, this key driver does not explain why hiv has spread so much more extensively in southern africa than in india or in europe, where circumcision is similarly uncommon. although sexual cultures do vary from region to region,20 these differences have not been studied in sufficient depth and their significance is not so obvious. for example, demographic and o p i n i o n why is hiv prevalence so severe in southern africa? the role of multiple concurrent partnerships and lack of male circumcision: implications for aids prevention daniel t halperin, phd, ms harvard university center for population and development studies, cambridge, mass, usa helen epstein phd, ma princeton university center for health and wellbeing, princeton, nj, usa fig. 1. male circumcision and hiv in africa. regions in africa where most men are uncircumcised men typically uncircumcised cities where men are traditionally circumcised but where large populations of uncircumcised men have recently migrated: high hiv levels men were not circumcised until recently highest percentage of hiv cases scientific american 1996 m a r c h 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e2 0 health surveys and other studies suggest that, on average, african men typically do not have more sexual partners than men elsewhere.21 a comparative study of sexual behaviour, conducted by the world health organization (who) in the 1990s, found that men in thailand and rio de janeiro were more likely to report five or more casual sexual partners in the previous year than were men in tanzania, kenya, lesotho, or zambia. and very few women in any of these countries reported five or more partners a year.22,23 men and women in africa report roughly similar, if not fewer, numbers of lifetime partners than do heterosexuals in many western countries.21,24-26 of increasing interest to epidemiologists is the observation that in africa men and women often have more than one – typically two or perhaps three – concurrent partnerships that can overlap for months or years. for example, according to the who study, 18%, 22% and 55% of men in tanzania, lusaka (zambia) and lesotho, respectively, reported having two or more regular, ongoing (lasting at least a year) sexual partnerships in the previous year, compared with only 3% and 2% of men in thailand and sri lanka. among women, 9%, 11% and 39% in tanzania, lusaka and lesotho reported two or more regular partnerships in the previous year, compared with just 0.2% and 1% of women in thailand and sri lanka22,23 (fig. 2). this pattern of concurrent partnerships differs markedly from that of the pattern of serial monogamy more common in the west – i.e. the tendency to have one relatively long-term (a few months or longer) partner after another – or the more ‘one-off’ casual and commercial sexual encounters that occur everywhere.23,27,28 morris and kretzschmar used mathematical modelling to compare the spread of hiv in two populations, one in which serial monogamy was the norm and one in which long-term concurrency was common.28 although the total number of sexual relationships was similar in both populations, hiv transmission was much more rapid with long-term concurrency – and the resulting epidemic was some 10 times greater. the effect that morris and kretzschmar measured was due to the impact of sexual networking alone; they assumed that the infectiousness of hiv did not vary over time. however, it is now established that viral load, and thus infectivity,15 is much higher during the ‘acute infection’ window period (typically about 3 weeks long) initially following hiv infection.27,29,30 the combined effects of sexual networking and the acute infection spike in viral load means that as soon as one person in a network of concurrent relationships contracts hiv, everyone else in the network is placed at risk. in lesotho, for example, according to a national reproductive health survey conducted in 2002, 20% of men and nearly 10% of women reported having two or more partners during the past 4 weeks31 (fig. 3). and in the 2005 national, population-based ‘nelson mandela’ serosurvey in south africa, among youth aged 15 24 about 40% of males and almost 25% of females reported having more than one current sexual partner. in contrast to this pattern of concurrent partnerships, serial monogamy traps the virus within a single relationship for months or years, so when a new partner is engaged the acute infection period of unusually high hiv infectivity has usually passed. morris subsequently studied sexual networks in uganda, thailand, and the usa.28 she found that ugandan men reported fewer lifetime sexual partners than thai men, but while the thais mainly had one-off encounters with sex workers, the ugandan men’s relationships tended to be of much longer duration. given that the per-act probability of heterosexual hiv transmission is, on average, very low,15 the much higher number of cumulative sexual acts – and hence the likelihood of transmission – within any given relationship was much greater in uganda than in thailand or the usa. in addition, except for sex workers, very few asian women have concurrent partners, whereas a larger proportion of african women do. even though the ugandan women in morris’s study reported fewer concurrent relationships than ugandan men, the multiple partnerships that some of them did have helped importantly to maintain the extensive interlocking sexual networks which facilitate the generalised spread of hiv.23,28 although most african women in concurrent partnerships are not sex workers, such relationships often include a powerful element of sexual-economic exchange, related to issues of gender and income inequality, sexual culture, poverty, and the globalisation of consumerism.32,33 a recent study from malawi found that among some 1 000 adult villagers, whose sexual fig. 2. concurrent partnerships globally. fig. 3. ‘acute infection’ and concurrence. 5 4 3 2 1/25 1/1,000 1/50 1/1,000 1/100 1/1,0001/100 1/1,000 risk of transmission three weeks seroconversion (acute infection) asymptomatic infection hiv progression (falling cd4 count) aids disease stage 0 20 40 60 80 100 percent of sexually active 12-54 year old males reporting two or more partners in the past four weeks percent of sexually active 12-49 year old females reporting two or more partners in the past four weeks concurrence: lesotho 2002 reproductive health survey months to years sources: m. carael 1995: halperin and epstein 2004 singapore thailand manila kenya tanzania lusaka cote d’ivoire lesothosri lanka t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e m a r c h 2 0 0 7 2 1 relationships were carefully mapped by researchers over a 2year period, some 65% were ‘connected up’ in the same sexual network34 (fig. 4). unfortunately the investigators did not inquire whether the sexual relationships were of a concurrent or serial nature, although data from similar populations in southern africa suggest the likelihood that concurrency also plays a key role in that malawi population.1,2 although polygamy, and therefore a type of concurrency, is common in much of north and west africa, as well as in other muslim regions of the world, hiv infection rates tend to be considerably lower there. the most likely explanation is twofold: first, in most of west africa and in all muslim countries, nearly all men are circumcised.5,6,9,13 secondly, largescale heterosexual concurrency networks can only emerge if a significant proportion of women are also engaging in multiple, longer-term relationships. but in muslim societies generally, women’s sexual behaviour tends to be under strict surveillance, which limits the extent of sexual networks. such differing patterns of sexual behaviour and the resulting differences in sexual networks have important implications for hiv prevention programmes and outcomes. consistent use of condoms has been effectively promoted in asia's organised brothels, most notably in thailand and cambodia, as well as, for example, in the sonagachi project in calcutta,35 and among sex workers in the dominican republic, abidjan, senegal, harare and elsewhere.36-38 yet, from the gay communities of australia and san francisco to the market towns of uganda, it has proved much more challenging for people in ongoing longer-term relationships to consistently use condoms37-43 (fig. 5). in southern africa – unlike in most of asia or latin america – such longer-term relationships are typically the ones in which hiv transmission takes place. for years, condom promotion has been a mainstay of donor-funded hiv prevention in africa, yet a comprehensive review commissioned by unaids concluded that, although condoms are highly effective when used correctly and consistently, ‘no clear examples have emerged yet of a country that has turned back a generalized epidemic primarily by means of condom promotion.’37 furthermore, a large experts’ meeting convened by who in july 2006 concluded that, although treatment of sexually transmitted (bacterial) diseases continues to be an important public health measure, the impact on preventing hiv transmission, especially in high hiv prevalence, more generalised epidemics, is likely to be fairly minimal31 (who report forthcoming). and perhaps even more sobering, several meta-analyses and other rigorous reviews of the data on the impact of hiv testing and counselling on preventing hiv infection, particularly in africa, so far tend to similarly suggest the likelihood of limited impact (especially for individuals who test hiv negative), although access to testing is clearly very important for various other reasons, including as an entry point for care and treatment.44-46 thus while condoms (and sti treatment and hiv testing) remain important interventions, there is considerable evidence that people worldwide are more likely to use condoms during commercial and casual sexual encounters than in longer-term relationships, in which there is a sense of commitment and trust.1,37-40,42,43 also, because hiv can spread so efficiently through populations in which concurrent partnerships are common, everyone’s risk is thereby increased, including persons who are commencing a sexual relationship, those who are monogamous with a partner who is not, or people who practise ‘serial monogamy’. it is hoped that wider understanding of the dangers of longer-term concurrency could lead to a shift in social norms emerging from a deeper appreciation of the importance of avoiding and addressing concurrency, not only for those whose behaviour is ‘risky’ according to conventional standards, but also for those whose behaviour is not considered risky, such as monogamous women. although clearly no simple solution exists to this complex problem, it appears imperative that in addition to condom availability and other prevention approaches in africa, there needs to be franker discussion and concerted public-health efforts addressing the dangers of having more than one longer-term sexual partner at a time, or of having a partner who has more than one longer-term partner. because most africans do not have high numbers of partners, they may not realise the special dangers of having long-term concurrent partners, especially in regions of high hiv prevalence. in much of southern africa, even people with only two lifetime partners – hardly high-risk behaviour by western standards – need to appreciate just how risky that one extra partner can be, for themselves and others, if the relationships are longterm and concurrent. males females fig. 4. largest connected component. n = 685. it comprises more than 65% of the population of the 7 villages surveyed. ■■ a fifth of population in exclusive dyadic relationships ■■ two-thirds linked by a single chain of infections over past 3 years ■■ networks not linked by sex workers or other ‘high-frequency transmitters’ ■■ linked by decentralised, complex, robust chains of sexual relationships fig. 4. sexual networking in likoma, malawi. 80 70 60 50 40 30 20 10 0 67% ... with casual patners ... with a boyfriend/girlfriend ... with a spouse 33% 2% just as some drugs don’t cross the blood brain barrier; we have a very difficult time getting condoms to cross the marriage and relationship barriers. nigeria: percentage of respondents who ‘always’ use condoms ... fig. 5. condom use in longer versus shorter-term relationships. so ur ce s: d s ta nt on 2 00 6; va n ro ss em e t a l.a id s ed uc a nd p re v. 20 01 m a r c h 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e2 2 at a sadc/unaids-organised regional consultation on social change communication for hiv prevention, held in swaziland in october 2006, it was concluded that the focus of communications programmes across the region over the next 5 years should be on partner limitation.47 because in many african countries cultural practices and traditional policies allow and sometimes even encourage multiple partnerships for men, communications programmers will need to work closely with local leaders in order to get the messages right. in addition, it was agreed that expanded and improved male circumcision services will need to be placed within a broader framework of male reproductive and sexual health.1,47 future communications programming will also need to emphasise that while male circumcision is protective, it certainly is not fully protective. therefore messages which combine information about male circumcision along with promotion of partner limitation and consistent condom use will be essential. it may seem simplistic to expect people to change their sexual behaviour, once they learn how dangerous it is to have multiple concurrent partnerships in areas of high hiv prevalence. there are, after all, numerous social, cultural and economic reasons why multiple concurrent partnerships exist. in many societies, having multiple partners is a powerful signifier of masculinity, and a relatively wealthy man may even be expected to have more than one wife or girlfriend as long as he can afford to do so.48 it is also the case that many women in africa – especially poor women – may be compelled to rely on multiple partners for support, and often have little power to negotiate with their partners about the timing of sex, use of condoms, etc. a detailed exploration of sexual culture in southern africa is beyond the scope of this paper, but any hiv prevention strategy to address partner reduction and faithfulness should also take place within a wider campaign to address gender issues and to raise the status of women generally.49 despite such important limitations, there is evidence that focused, clearly articulated partner reduction campaigns can make a difference, even in countries where traditional norms would seem to militate against behaviour change. the ‘zero grazing’ (partner reduction and faithfulness) campaign in uganda,31,33,37,39,50-53 coupled with evidence from other places such as kenya and addis ababa,54,55 suggests that fundamental society-wide changes in sexual norms and resulting declines in hiv rates can occur in africa, just as they did in highly affected communities in north america and europe in the 1980s.56,57 large surveys conducted in uganda by who/the global programme on aids indicate that between 1989 and 1995 there was a 60% decline in the percentage of people reporting two or more sexual partners in the past 12 months.41,50 the proportion of men reporting three or more partners fell even more dramatically41,51 (fig. 6). these behavioural changes are believed to explain much of the decline in hiv prevalence that occurred during the 1990s, which modelling studies suggest was preceded by a steep decline in incidence – or the rate of new infections – during the late 1980s, when the zero grazing campaigns were at their height.8,50-53 a sampling of newspaper articles on hiv-aids in kampala’s main english language paper, the new vision, between 1987 and 1992 found that of 20 articles in the period 1987-1989, 12 mainly addressed behaviour change (partner reduction-related issues in particular), whereas of 25 articles from 1990 to 1992, only 2 did so (although several in the latter period addressed issues such as increasing the condom supply). for example, a long piece on ‘zero grazing’ and other ‘b’ types of behaviour change, titled ‘slim [aids] is forcing people to change social habits’, from 23 october 1987, contained this anecdote: ‘in bugolobi, a young housewife with three children declared, with a gleam in her eye, “my husband stays at home much more. and i encourage him to do so by enthusiastically keeping him informed of the latest gossip about slim victims.”‘51 an 11 november 1989 editorial in the new vision concluded, ‘aids has no cure. protect yourself by zero-grazing.’ recently, attention has been drawn to the reversal of the prevention success in uganda, where there are some indications that hiv prevalence has increased.2 this has been variously attributed to temporary shortages of condoms, or the expansion of abstinence-until-marriage programmes conducted by evangelical churches that may promote unrealistic standards of sexual behaviour.58,59 however, the stagnant and worsening trends in uganda date from about 2000, significantly before either the condom shortages or the proliferation of such abstinence-only programmes. another possibility is that these negative hiv trends are due, at least in part, to the phasing out of the ‘zero grazing’ and other partner reduction/fidelity-focused campaigns of the late 1980s.60-62 indeed, demographic and health surveys conducted between 1995 and 2005 suggest that there has been a considerable increase in the number of sexually active adults reporting multiple partners. the recognition that partner reduction has been neglected in uganda's more recent prevention programmes, and that it must be a central theme of future campaigns, was emphasised in the final recommendations of a 3-day research symposium, organised by makerere and harvard universities, which was held in kampala in december 2006.63 the ugandan case is not unique. in kenya, where hiv prevalence has also declined considerably, albeit more recently,2 the percentage of men reporting two or more sexual fig. 6. behavioural and hiv trends in uganda. 40 30 20 10 0 20 15 10 5 0 1989 1995 1989 1995 men with one or more ‘casual’ partners in past year women with one or more ‘casual’ partners in past year men with three or more ‘non-regular’ partners in past year 35 16 15 15 6 3 15 6.7 adult hiv prevalence adult hiv prevalence source:who/gpa surveys 1991 2005 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e m a r c h 2 0 0 7 2 3 partners in the last year fell very sharply, according to demographic and health surveys conducted between 1993 and 2003.31,38 a study in rural zimbabwe found an approximately 50% decrease in the percentage of men reporting a new sexual partner in the last month over a roughly 3-year period, coinciding with a significant decline in hiv prevalence and incidence64 (fig. 7). in swaziland, where the government recently began aggressively promoting messages such as ‘i choose to have only one sexual partner’ and ‘your secret lover can kill you’, preliminary data from large surveys conducted in 2005 and 2006 found that after only 1 year, the percentage of adults reporting two or more partners in the last 4 weeks had fallen by approximately half.65-67 this 4-week indicator roughly covers the ‘acute infection’ period, also approximately 3 4 weeks, and so may provide some measure of the degree of sexual networking in the population and the potential for highly efficient transmission of hiv. in conclusion, although partner reduction/faithfulness approaches have received relatively little attention in most of africa,68,69 they appear to be feasible and epidemiologically crucial. the experiences of uganda and some other places, where campaigns emphasising ‘b’ appear to have been associated with population-wide declines in hiv,31,33,38,39,41,50-53 suggest there is empirical validity to the common-sense notion of emphasising partner limitation – in addition to other crucial approaches, such as the promotion of consistent condom use and increased access to safe and affordable voluntary male circumcision – for hiv prevention.70,71 references 1. experts think tank meeting on hiv prevention in high-prevalence countries in southern africa. southern african development community (sadc) meeting report, may 2006. gaborone: sadc hiv and aids unit. http://www. sadc.int/attachments/news/sadcprevbrochure.pdf 2. unaids. global report on hiv-aids, 2006. geneva: unaids. http://www. unaids.org/en/hiv_data/2006globalreport/default.asp 3. chin j, bennett a, mills s. primary determinants of hiv prevalence in asianpacific countries. aids 1998; 12 (suppl b): s87-91. 4. kumar r, jha p, arora p, et al. trends in hiv-1 in young adults in south india from 2000 to 2004: a prevalence study. lancet 2006; 367: 1164-1172. 5. short rv. 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http://www.ingentaconnect.com/content/els/14733099/2001/00000001/00000 004/art00117 12. weiss ha, quigley ma, hayes rj. male circumcision and risk of hiv infection in sub-saharan africa: a systematic review and meta-analysis. aids 2000; 14: 2361-2370. 13. halperin dt, bailey rc. male circumcision and hiv infection: ten years and counting. lancet 1999; 354: 1813-1815. http://www.circumcisioninfo.com/ halperin_bailey.html 14. donoval ba, landay al, moses s, et al. hiv-1 target cells in foreskins of african men with varying histories of sexually transmitted infections. am j clin pathol 2006; 125: 386-391. 15. quinn tc, wawer mj, sewankambo n, et al. viral load and heterosexual transmission of human immunodeficiency virus type 1. n engl j med 2000; 342: 921-929. 16. potts m. male circumcision and hiv infection. lancet 2000; 355: 926. 17. auvert b, taljaard d, lagarde e, sobngwi-tambekou j, sitta r, puren a. randomized, controlled intervention trial of male circumcision for reduction of hiv infection risk: the anrs 1265 trial. plos med 2005; 2: 1-11. http:// medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/ journal.pmed.0020298 18. mcneil d. circumcision’s anti-aids effect found greater than first thought. new york times 2007; february 23. http://www.nytimes.com/2007/02/23/ science/23hiv.html 19. williams bg, lloyd-smith j o, gouws e, et al. the potential impact of male circumcision on hiv in sub-saharan africa. plos med 2006; 3: e262. http:// medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/ journal.pmed.0030262 20. caldwell jc, caldwell p, quiggin p. the social context of aids in sub-saharan africa. popul dev rev 1989; 15: 185-234. 21. wellings k, collumbien m, slaymaker e, singh s, hodges z, patel d, bajos n. sexual behaviour in context: a global perspective. lancet 2006; 368: 1706-1728. 22. carael m. sexual behaviour. in: cleland jg, ferry b, eds. sexual behaviour and aids in the developing world. london: taylor & francis, 1995. 23. halperin d, epstein h. concurrent sexual partnerships help to explain africa’s high hiv prevalence: implications for prevention. lancet 2004; 363: 4-6. 24. santelli js, brener nd, lowry r, et al. multiple sexual partners among u.s. adolescents and young adults. fam plann perspect 1998; 30: 271-275. 25. morris m. a comparative study of concurrent sexual partnerships in the united states, thailand and uganda. published abstract, american sociology association annual meeting, anaheim, california, 18 21 august 2002: session 409. fig. 7. behaviour change among males in manicaland, zimbabwe. page 24 f/p f/c roche lactate new ad t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e m a r c h 2 0 0 7 2 5 26. pettifor ae, rees hv, steffenson a, et al. hiv and sexual behavior among young south africans: a national survey of 15 24-year olds. reproductive health research unit, university of the witwatersrand, johannesburg, 2004. http://www.rhru.co.za/site/publications.asp 27. hudson cp. aids in rural africa: a paradigm for hiv-1 prevention. int j std aids 1996; 7: 236-243. 28. morris m, kretzschmar m. concurrent partnerships and the spread of hiv. aids 1997; 11: 681-683. 29. pilcher cd, tien hc, eron jj, et al. brief but efficient: acute hiv infection and the sexual transmission of hiv. j infect dis 2004; 189: 1785-1792. 30. wawer mj, gray rh, sewankambo nk, et al. rates of hiv-1 transmission per coital act, by stage of hiv-1 infection, in rakai, uganda. j infect dis 2005; 191: 1403-1409. 31. halperin dt. evidence-based behavior change hiv prevention approaches for sub-saharan africa. presentation at harvard medical school, 17 january 2007. http://www.globalhealth.harvard.edu/hupaseminar_halperin.html 32. leclerc-madlala s. transactional sex and the pursuit of modernity. social dynamics 2003; 29: 1-21. 33. epstein h. the fidelity fix. new york times magazine 2004; 13 june: 54-59. 34. helleringer s, kohler hp. the structure of sexual networks and the spread of hiv in sub-saharan africa: evidence from likoma island (malawi). university of pennsylvania population aging research center, working paper series 06-02. 35. jana s, bandyopadhyay n, mukherjee s, dutta n, basu i, saha a. std/hiv intervention with sex workers in west bengal, india. aids 1998; 12 (suppl b): s101-108. 36. ghys pd, diallo mo, ettiegne-traore v, et al. increase in condom use and decline in hiv and sexually transmitted diseases among female sex workers in abidjan, cote d'ivoire, 1991-1998. aids 2002; 16: 251-258. 37. hearst n, chen s. condom promotion for aids prevention in the developing world: is it working? stud fam plann 2004; 35: 39-47. 38. shelton j. confessions of a condom lover. lancet 2006; 368: 1947-1949. 39. green ec. rethinking aids prevention. westport, conn: praeger, 2003. 40. ahmed s, lutalo t, wawer m, et al. hiv incidence and sexually transmitted disease prevalence associated with condom use: a population study in rakai, uganda. aids 2001; 15: 2171-2179. 41. bessinger r, akwara p, halperin dt. sexual behavior, hiv and fertility trends: a comparative analysis of six countries; phase i of the abc study. chapel hill, north carolina: measure evaluation, 2003. http://www.cpc.unc.edu/measure/ publications/pdf/sr-03-21b.pdf 42. meekers d, klein m, foyet l. patterns of hiv risk behavior and condom use among youth in yaounde and douala, cameroon. aids behav 2003; 7: 413-420. 43. flood m. lust, trust and latex: why young heterosexual men do not use condoms. culture health sexuality 2003; 5: 353-369. 44. glick p. scaling up hiv voluntary counseling and testing in africa: what can evaluation studies tell us about potential prevention impacts? evaluation review 2005; 29: 331-357. 45. matovu jk, gray rh, makumbi f, et al. voluntary hiv counseling and testing acceptance, sexual risk behavior and hiv incidence in rakai, uganda. aids 2005; 19: 503-511. 46. corbett el, makamure b, cheung yb, et al. hiv incidence during a clusterrandomized trial of two strategies providing voluntary counselling and testing at the workplace, zimbabwe. aids 2007; 21: 483-489. 47. sadc regional consulation on social change communication for hiv prevention. 3 4 october 2006, ezulwini, swaziland. meeting report. gaborone: sadc hiv and aids unit. 48. hunter m. cultural politics and masculinities: multiple-partners in historical perspective in kwazulu-natal. culture, health and sexuality 2005; 7: 389-403. 49. epstein h, kim j. fighting back against gender violence in south africa. new york review of books. january 2007. http://www.nybooks.com 50. stoneburner r, low-beer d. population-level hiv declines and behavioral risk avoidance in uganda. science 2004; 304: 14-18. http://www.sciencemag.org/ cgi/data/304/5671/714/dc1/1 51. shelton j, halperin dt, nantulya v, potts m, gayle hd, holmes kk. partner reduction is crucial for balanced ‘abc’ approach to hiv prevention. bmj 2004; 328: 891-894. http://bmj.bmjjournals.com/cgi/content/full/bmj;328/7444/891 52. green ec, halperin dt, nantulya v, hogle, ja. uganda’s hiv prevention success: the role of sexual behavior change and the national response. aids and behavior 2006; 10: 335-346. http://www.springerlink.com/content/h00r4n 6521805w27/fulltext.html 53. slutkin g, okware s, naamara w, et al. how uganda reversed its hiv epidemic. aids and behavior 2006; 10: 351-360. http://www.springerlink.com/content/ 7024v857p67q0220/fulltext.pdf 54. cheluget b, baltazar g, orege p, ibrahim m, marum lh, stover j. evidence for population level declines in adult hiv prevalence in kenya. sex transm infect 2006; 82: suppl 1, i21-26. 55. mekonnen y, sanders e, aklilu m, et al. evidence of changes in sexual behaviours among male factory workers in ethiopia. aids 2003; 17: 223-231. 56. becker mh, joseph jg. aids and behavioral change to reduce risk: a review. am j public health 1988; 78: 394-410. 57. winkelstein w jr, wiley ja, padian ns, et al. the san francisco men’s health study: continued decline in hiv seroconversion rates among homosexual/ bisexual men. am j public health 1988; 78: 1472-1474. 58. bass e. fighting to close the condom gap in uganda. lancet 2005; 365: 11271128. 59. good in parts: the latest unaids report suggests a little hope is justified. the economist 2006; 21 november. 60. epstein h. god and the fight against aids. new york review of books 2005; 52: 28 april. http://www.nybooks.com/articles/17963 61. epstein h. the invisible cure: africa, the west and the fight against aids. new york: farrar straus & giroux. in press, may 2007. 62. symposium resolutions and recommendations. african successes: can behavior-based solutions make a crucial contribution to hiv prevention in sub-saharan africa? meeting held 17-20 december, kampala, uganda. http://ugandasymposium.jot.com/wikihome 63. timberg t. uganda's early gains against hiv eroding; message of fear, fidelity diluted by array of other remedies. washington post 2007; 29 march, p. a1. w w w. w a s h i n g t o n p o s t . c o m / w p d y n / c o n t e n t / a r t i c l e / 2 0 07 / 0 3 / 2 8 / a r 2007032802510. html?referrer=email 64. gregson s, garnett gp, nyamukapa ca, et al. hiv decline associated with behavior change in eastern zimbabwe. science 2006; 311: 664-666. 65. halperin d, andersson n, mavuso m, bicego g. assessing a national hiv behavior change campaign focusing on multiple concurrent partnerships in swaziland. international aids conference oral presentation abstract, toronto, august 2006. http://www.iasociety.org/abstract/ show.asp?abstract_ id=2199617; http://today.reuters.co.uk/news/articlenews.aspx?type=health news&storyid=2006-08-15t132307z_01_col548149_rtridst_0_healthmultiple-partnerships-dc.xml&archived=false 66. irin news service. swaziland: aids campaign induces behaviour change. irin, 27 october 2006. http://www.alertnet.org/thenews/newsdesk/irin/bee9c 252234ff045d1275451934ae1c5.htm 67. timberg c. in swaziland, ‘secret lovers’ confronted in fight against aids. washington post 2006; 29 october, p. a15. http://www.washingtonpost. com/wp-dyn/content/article/2006/10/28/ar2006102800445.html 68. timberg c. speeding hiv's deadly spread: multiple, concurrent partners drive disease in southern africa. washington post 2007; 2 march, p. a1. http://www. washingtonpost.com/wp-dyn/content/article/2007/03/01/ar2007030101607. html 69. epstein h. africa's lethal web net of aids: the quiet acceptance of informal polygamy is spreading the risk. los angeles times 2007; 15 april. http://www.latimes.com/news/opinion/commentary/la-op-epstein15apr15,0, 4906338.story?coll=la-news-comment-opinions 70. halperin dt, steiner m, cassell m, green ec, hearst n, kirby d, gayle h, cates w [149 signers in total]. the time has come for common ground on preventing sexual transmission of hiv. lancet 2004; 364: 1913-1915. http://www. iasociety.org/images/upload/lancet%20hiv%20prevention.pdf 71. mcneil d. w.h.o. urges circumcision to reduce spread of aids. new york times 2007; march 29. http://www.nytimes.com/2007/03/29/health/29hiv.html?ei= 5070&en=4f962a3432644116&ex=1176091200&adxnnl=1&adxnnlx=11759938 26-3ezsrzjkphqukxlhqfu/+q (also: http://www.sfgate.com/cgi-bin/article. cgi?f=/c/a/2007/03/29/mng5lotiv21.dtl&hw=circumcision&sn= 002&sc= 772) untitled j u n e 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e2 2 1. nutrition, weight loss and hiv in africa 1.1 introduction the hiv epidemic affects large numbers of people living in the southern african region.2 despite more than 2 decades of research, a cure remains elusive.3 the implementation of proven preventive interventions has had limited success; and the uptake of antiretroviral (arv) drugs has lagged far behind the estimated numbers in need.4 furthermore, the production of food in africa may well be adversely influenced both by the epidemic itself and by global warming.5 nutrition, specifically the use of food, special diets, micronutrients and so-called immune boosters and supplements, has been suggested as an affordable and practical means of ’delaying the onset of advanced hiv infection’.6 is this true? and if it is, how secure is access to food and good nutrition in africa? floods, drought, famine, poverty, war and political instability define much of the everyday life of millions on this continent. secure and reliable access to food is extremely important in these circumstances. in some instances, sex will be exchanged for food and employment far from home may result in risky sexual behaviour. the science of nutrition is more than the science of food itself.5 it is about people, their access to food of a suitable quality and quantity, and in addition it is about the production of food and its utilisation. it is also about maintaining access to food over decades so as to ensure that the children and adults of africa – including those who are hiv-infected – grow and realise their full potential. discussion about food and diet in the hiv era also requires that due attention be given to the interactions and toxicities of the arv group of drugs. these have revolutionised the management of hiv infection. sooner or later all who are infected will need to take these agents. some arvs are best given on an empty stomach, some with food and others with a fatty meal. many give rise to metabolic alterations, such as insulin resistance and glucose intolerance, fat abnormalities (lipodystrophy, hyperlipidaemia), lactic acidosis, liver enzyme abnormalities, anaemia and osteopenia.7 certain herbs and foods interfere with the bioavailability of the arvs. various micronutrients have been shown to benefit the hiv-infected. home-grown diets, herbal concoctions and vitamin supplements have been advanced by some as alternatives to the arvs and as cures of the disease, but without providing evidence of their benefit.8 where denial and stigma and commercial interests have dictated the political and social response to this epidemic, it has been a simple matter to add nutritional nonsense and personal economic gain to the general confusion that has defined public discussion.9 the science of nutrition and hiv infection intersect at several strategic levels. evidenced-based research confirms the following four concepts: ■ weight loss predicts death.10 ■ energy and nutrient needs are increased in the hivinfected.11 ■ adequate food – and not just vitamins and so-called immune boosters – constitutes an appropriate supplement for those in need.12 ■ nutritional security: food alone is not enough. children and adults who are malnourished, whether they are infected, exposed or affected, need comprehensive medical and nutritional care and social support.13 these concepts will be discussed in detail in later chapters. 1.2 epidemiology and basic science the human immunodeficiency virus (hiv) crossed into the human race from its primate host in the early decades of the 20th century.14 since that time it has spread throughout the globe and has caused more than 20 million deaths worldwide.15 sub-saharan africa has borne the greatest burden of the infection. without access to arv drugs average g u i d e l i n e s nutrition and hiv/aids nutritional guidelines for hiv-infected adults and children in southern africa: meeting the needs d c spencer, c harman, t naicker, s gohre, for the nutrition focus group of the sa hiv clinicians society reviewers: n rollins, d labadarios, m visser ‘despite progress in boosting democracy, ending wars and improved economic growth, africa is the only region in the world becoming less able to feed itself’.1 members of the nutritional focus group: d c spenser (chair), c harman, c egbers, a caradas, e hefer, t j dlamini, b ndzungu, c julsing, z makasi, t naicker, s gohre, f venter, m yssel, t robinson. t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u n e 2 0 0 7 2 3 survival is about 10.3 10.8 years.16 the hiv virus is spread from human to human via direct contact with sexual fluids and blood (blood products) and to infants and children during pregnancy and lactation.17 since the mid-1990s, drugs called antiretrovirals (arvs) have been used to control viral replication, and to prevent neonatal transmission and accidental exposure to the virus. these interfere with the growth cycle of the virus. some prevent the virus from entering the human cell (viral entry inhibitors), while others inhibit viral enzymes that assist in the reproduction of the virus: the nucleoside and nucleotide reverse transcriptase inhibitors (nrtis and ntrtis) and the non-nucleoside reverse transcriptase inhibitors (nnrtis). the protease inhibitors (pis) block the assembly of newly formed viral proteins. a further class of arvs, the integrase inhibitors, impair the integration of viral dna into the human genome. interactions with food and other drugs, including herbs and the so-called immune boosters, are well documented. these interactions may impair viral control by a variety of mechanisms. the virus targets the cells of the immune system, particularly the cd4 lymphocyte (the 'helper-t cells’).18 despite the increased production of these cells, they are ultimately sacrificed to the virus. eventually this progressive immune deficiency leads to life-threatening infections and cancers: the acquired immunodeficiency syndrome (aids). once within a cell, hiv-1 reproduces rapidly. from a single infected cell thousands of new viral particles are released into the bloodstream. in the laboratory this is measured as the viral load. nevertheless, most of the virus remains undetectable within the cells of the body.19 together with the medical history and examination, the measurement of the cd4 cell count and the viral load (vl) provide a platform from which to assess the patient. because of the effect of the infection on nutritional status, this assessment should include the nutritional evaluation of the patient. what does growth failure and loss of weight mean in hiv-infected children and adults? 1.3 weight loss in hiv-infected children and adults weight loss is a strong predictor of death in hiv-infected adults and children.20 during the 1980s and early 1990s, ‘slim disease’ was a term used throughout central africa to characterise a patient with end-stage hiv infection or aids.21 indeed, weight loss is used in both the world health organization (who) and the centers for disease control (cdc) adult staging systems: unintentional weight loss of < 10% = who stage ii and > 10% = stage iii and cdc stage c, i.e. is aids defining.22 in children older than a year, weight loss resulting in a fall of 2 or more percentile lines is aids defining if accompanied by chronic diarrhoea or fever. also aids defining is a child in the 25th percentile of weight-for-height (on consecutive measurements separated by more than 30 days).23 severe wasting in adults is defined by the cdc as a body mass index (bmi) < 18.5 (kg/m)2 or unintentional weight loss of > 5% of usual body weight within 6 months.24 growth faltering and stunting are common in children with hiv infection and occur early in life.25-27 in children, wasting is particularly associated with the loss of lean body mass and failure to gain height.27 in adults both lean mass and fat are lost, though the loss of lean mass predominates.24 in contrast, starvation leads primarily to fat loss.24 both the loss of lean mass and poor linear growth in hiv-infected children are closely associated with poor survival and protecting lean body mass prolongs survival.24, 27 weight loss in the hiv-infected is the sum of a number of causes. energy requirements are increased even in the asymptomatic state.28, 29 these needs soar under periods of stress and during malnutrition.29 cytokines such as tumour necrosis factor-� (tnf-�) and interleukin-1 (il-1) released during episodes of infection and even during the ‘asymptomatic’ phase of hiv infection, promote increased metabolism, glucose recycling, muscle catabolism and negative nitrogen balance.29, 30 they may also reduce appetite even when there is no overt opportunistic disease. this results in the characteristic wasting associated with aids.31 levels of interferon-� (inf-�) are persistently elevated in full-blown aids.29, 31 apart from these underlying metabolic factors, the inability to eat or to swallow food and the increased loss of dietary nutrients from vomiting and diarrhoea will lead to wasting and malnutrition. wasting also accompanies the opportunistic infections and cancers of advanced hivinfection. 1.4 weight loss: its causes and increased energy requirements (table 1.1) 1.4.1 increased and often unmet energy requirements during all stages of hiv infection energy requirements are likely to increase by 10% just to maintain body weight and normal physical activity in asymptomatic hiv-infected adults and to maintain normal growth in asymptomatic, infected children. during symptomatic stages and particularly during aids (opportunistic diseases) these energy requirements increase by 20 30%. energy needs may even increase to levels of 50 100% above weight = heaviness measured in kilograms lean body mass = the total of all body components except storage lipid (fat) and bone fat-free mass = the same as lean body mass weight loss predicts death • low weight reflects advancing disease • weight loss often indicates opportunistic infections or progressive disease • weight loss should be a warning to the doctor/nurse to initiate investigations and treatment t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u n e 2 0 0 7 2 5 normal in children who are severely malnourished and who are experiencing weight loss.28, 29 when enriched with various fats (peanut butter) or oils (olive, canola), food will provide greater ‘energy content’. this ‘enriched’ food is needed to supplement the daily, baseline dietary requirements if the malnutrition and weight loss are to be corrected. 1.4.2. decreased energy intake and the increased loss of nutrients anorexia, nausea, gingivitis, oral sores and dysphagia will impair food intake and promote weight loss. at times the arvs and the anti-tb drugs are poorly tolerated – nausea, anorexia, and vomiting. fortunately this situation is generally shortlived and usually restricted to the first weeks after the start of therapy. depression and anxiety suppress appetite and result in weight loss. religious and cultural practices that require regular fasting, purging and dietary restrictions may be harmful in the context of advanced hiv infection. food access and food security can be significantly affected when material resources are lost income, the inability to work. chronic diarrhoea and malabsorption may cause wasting: direct viral invasion of gastrointestinal cells (hiv-enteropathy) can be demonstrated in some patients.32 both localised gastrointestinal and overwhelming generalised infections are frequent in africa. pulmonary and extra-pulmonary tb, salmonella, escherichia coli, cryptosporidia and isosporiasis may present with fever, anorexia, nausea, vomiting and diarrhoea. undiagnosed and untreated, these infections will lead to wasting and ultimately death. the prevention and treatment of weight loss is a priority for patients who are hiv-infected. what can be done for patients who are at risk? 1.5 weight loss. assessment and treatment 1.5.1 assessing weight loss all infected children and adults must be regularly followed up. this includes taking a medical and nutritional history. the patient must be thoroughly examined. it goes without saying that in southern africa, every effort must be made to identify the infected so as to offer them protection from advancing hiv disease and facilitate the control of the epidemic. the following measurements are essential: weight, height/length in children, the mid-upper arm circumference (muac) and the cd4 and viral load. muac is a useful means of assessing lean body mass. additional investigations are discussed in a subsequent section. 1.5.2 managing weight loss attention must be given to the causes of weight loss and the diagnosis and control of anorexia. poverty, food insecurity and related socio-economic issues ought to be recognised and managed in as practical a way as possible. the timeous provision of arv therapy is a very appropriate means of preventing weight loss and the secondary opportunistic infections associated with it.33 provide food. provide nutritional counselling. provide support – but aim to make the patient and their family independent of food parcels and short-term solutions. a team approach (nurse, doctor, dietician and trained nutritional advisor) works best. diagnose and treat intercurrent disease. check the cd4 and viral load and any other relevant tests as suggested by the clinical examination. consider starting arv therapy where appropriate. ‘the best way to achieve protein repletion in clinically severe hiv/aids is to establish effective arv therapy.’34 once an adult has achieved his/her normal body weight, discourage further weight gain in those on arvs. obesity is to be avoided. fat redistribution, hyperglycaemia and insulin resistance, the metabolic syndrome, hyperlipidaemia and cardiovascular disease are recognised complications.35-37 wasting and severe malnutrition may require enteral and parenteral feeding. this is usually undertaken in a hospital or clinic. nutritional supplements such as fortified porridges and food itself ought to be accessed on behalf of the patient. the use of specific micronutrients generally follows recommendations for the population at large. safety, tolerability and cost are the important drivers in this regard.24 the role of individual supplements will be discussed later. exercise – including resistance training – has been found to improve the patient’s quality of life, to build up lean body mass, and in those on managing weight loss effectively • record weight at each visit, usually 3 4 visits annually. • identify the reason for the weight loss • control the hiv infection where indicated: arvs may be needed • treat malnutrition: food, supplements, micronutrients where needed • diagnose and treat opportunistic disease • symptomatic control of: nausea, anorexia, vomiting, diarrhoea • examine the oral cavity: treat thrush, gingivitis and oral ulcers • stop smoking, alcohol abuse and recreational drug use • exercise and strength training may have a role in some • exclude hypogonadism (rare) and consider use of appetite ‘stimulants’ such as megesterol acetate, anabolic steroids and dronabinol for nausea where appropriate (benefit controversial) • involve social support mechanisms: social worker, income grants, ngos including faith-based groups that provide nutritional support, exclude depression and anxiety, consider incorporating a family member or ‘concerned other’. hivenergy positive phase adults and adolescents asymptomatic 10% symptomatic (mild) 20 30% children asymptomatic 10% symptomatic (mild) 20 30% symptomatic (moderate to severe) 50 100% * *in the presence of severe malnutrition. table 1.1. increased energy needs of hiv-infected adults, adolescents and children28, 29 ➝ ➝ ➝ ➝ ➝ j u n e 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e2 6 arvs, to improve serum lipid profiles.38, 39 the simplest monitor of nutritional recovery in adults is the measure of sequential weight gain. but weight alone will not discriminate between the return of lean muscle and/or fat, or for that matter indicate the return of good health. other measurements in addition to that of weight will be needed. references 1. christian science monitor. hunger is spreading in africa. august 01, 2005. http://www.csmonitor.com/2005/0801/p01s02-woaf.html 2. merson mh. the hiv-aids pandemic at 25 – the global response. n engl j med 2006; 354: 2414-2417. 3. hammer 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modelling and projections. aids 2002; 16: w1-w14. 17. schreibman t, friedland g. human immunodeficiency virus infection prevention: strategies for clinicians. clin infect dis 2003; 36: 1171-1176. 18. rosenberg es, walker bd. hiv type 1-specific helper t cells: a critical host defence. aids research human retrovir 1998; 14 (suppl 2): s143-s147. 19. kilby jm. human immunodeficiency virus pathogenesis: insights from studies of lymphoid cells and tissues. clin infect dis 2001; 33: 873-884. 20. tang am, forrester j, spiegelman d, knox ta, tchetgen e, garbach sl. weight loss and survival in hiv-positive patients in the era of highly active antiretroviral therapy. j acquir immune defic syndr 2002; 31: 230-236. 21. serwadda d, mugerwa r, sewankambo n. slim disease: a new disease in uganda and its associations with htlv-iii infection. lancet 1985; 2: 849-852. 22. the who international collaborating group for the study of the who staging system. proposed ‘world health organisation staging system for hiv infection and disease’: preliminary testing by an international collaborative crosssectional study. aids 1993; 2: 711-718. 23. bailey rc, et al. growth of children according to maternal and child hiv, immunological and disease characteristics: a prospective cohort study in kinshasa, democratic republic of the congo. int j epidemiol 1999; 28: 532-540. 24. grinspoon s, mulligan k. weight loss and wasting in patients infected with human immunodeficiency virus. clin infect dis 2003; 36 (suppl 2): s69-78). 25. bobat r, coovadia h, moodley d, coutsoudis a, gouws e. growth in early childhood in a cohort of children born to hiv-1 infected women from durban, south africa. ann trop paediatr 2001; 21; 203-210. 26. miller tl et al. growth and body composition in children infected with the human immunodeficiency syndrome virus-1. am j clin nutr 1993; 57: 588-592. 27. arpadi sm. growth failure in hiv-infected children. who consultation on nutrition and hiv/aids in africa: evidence, lessons and recommendations for action. durban, 10-13 april 2005. geneva: world health organization, 2005. 28. food and nutrition technical assistance (fanta) project. hiv/aids: a guide for nutritional care and support. 2nd ed. washington, dc: academy for educational development, 2004: 86. 29. hsu j w-c, pencharz pb, macallan d, tomkins a. macronutrients and hiv/aids: a review of current evidence. who consultation on nutrition and hiv/aids in africa: evidence, lessons and recommendations for action. durban, 10-13 april 2005. geneva: world health organization, 2005: 1, 2. 30. roubenhoff r, grinspoon s, skolnik pr, et al. role of cytokines and testosterone in regulating lean body mass and resting energy expenditure in hiv-infected men. am j physiol endocrinol metab 2002; 283: e138-145. 31. hazenberg md, otto sa, van benthem bhb, et al. persistent immune activation in hiv-1 infection is associated with progression to aids. aids 2003; 17: 18811888. 32. kotler dp. hiv infection and the gastrointestinal tract. aids 2005; 19: 107-117. 33. gazzard b. antiretroviral therapy for hiv: medical miracles do happen (editorial). lancet 2005; 366: 346-347. 34. shevitz ah, knox ta. nutrition in the era of highly active antiretroviral therapy. clin infect dis 2001; 32: 1769-1775. 35. grunfeld c, feingold kr. metabolic disturbances and wasting in the acquired immunodeficiency syndrome. n engl j med 1992; 327: 329-337. 36. dube mp. disorders of glucose metabolism in patients infected with human immunodeficience: effects on parameters related to fatigue, dyspnea, weight and body composition in hiv-infected adults. aids 2001; 15: 693-701. 39. roubenoff r, mcdermott a, weiss l, et al. short-term progressive resistance training and lean body mass in adults infected with human immunodeficiency virus. aids 1999; 13: 231-239. 2. nutrition, hiv and clinical measurement 2.1 nutrition: taking a dietary history ‘a simple nutritional assessment is available to all and requires only an interview, a scale and a tape measure.’1 this assessment begins with history taking: ‘what do you eat on a typical day?’ ‘when last did you have a meal?’ ‘tell me everything you’ve had to eat or drink in the last 24 hours.’ the nutritional history needs to give the interviewer a clear sense of the client’s diet, its contents, amounts of food taken, regular and reliable access to good food, and in the context of the hiv epidemic, the stage of the infection and use by the client of prescribed medication, herbs and traditional or so-called complementary treatments. it may be helpful to use actual plates, cups and spoons to estimate the size of food portions. a diary card may be helpful: ‘record everything you eat and drink for the next week. add in the amounts that you consume …’2 if the patient is an infant, enquire as to what feeds are being given. formula? breast? exclusive or mixed breastfeeds? how is the food prepared? what understanding does the client have of hygiene and food? arv drugs may cause physical changes: ask about weight loss and breast enlargement and the loss of fat on the face, arms and legs. what is the stage of hiv infection? have opportunistic diseases such as tb been experienced? comorbid conditions such as diabetes, liver and cardiovascular disease will require dietary advice and the outlining of potential arv drug and food interactions.3, 4 ‘do you or the family ever go without food?’ enquire about the patient’s access to an income and food. in busy public clinics trained caregivers from the community can assist with history taking, and the weighing and measuring of patients. the goal of the dietary analysis is to prevent weight loss and optimise nutrition: the counselling that takes place will foster the patient-doctor/nurse relationship and improve communication.5,6 however, providing specific advice is difficult. diets vary between and within populations. familiarity with local foods, food preparation and the culture and traditions of a t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u n e 2 0 0 7 2 7 community will root any advice offered within the context of the patient’s life. dietary advice needs to be culture sensitive and feasible. see also appendices 1 and 2 for action to be taken in response to nutritional risk. 2.2 nutrition: measurement medical science is built upon practices that have measurable and reproducible outcomes. the measurement of human nutrition is based upon anthropometric, biochemical, clinical and dietary parameters – the so-called ‘abcd’ of nutritional assessment.7, 8 included in the anthropometric measurement are body weight, length or height, the body mass index (bmi) and the mid-upper arm circumference (muac). if performed reliably, these form a baseline from which to judge growth failure or abnormality. often the measurements can be carried out by a trained non-medical clinic or community member. results must be tabulated in the clinic file at each visit, preferably before the patient is seen by the nurse or doctor. a reduction in lean body mass in children is detectable before a deceleration in linear growth (length/height) and is important to document and act upon.9 waist circumference is a measure of cardiovascular risk, type 2 diabetes, hypertension and increased cholesterol risk in non-hiv infected adults. this may also be a helpful measurement in patients on arvs at risk for the metabolic complications of therapy.10 paediatric growth charts record both height and weight: height-for-age, weight-for-age, and weight-for-height. all three measurements must be plotted at each visit.8 in young children, body length will replace height. muac and subscapular and triceps skin-fold thickness reflect lean body mass and fat stores in adults and children older than 1 year. about 50% of body fat is subcutaneous.11,12 muac is generally the preferred measurement. muac is an essential component of malnutrition assessment and is routinely used in world health organization (who) and unicef-sponsored relief programmes.6 intercurrent illness will alter these measurements: repeated measurement reveals the emergence of trends and the early onset of new disease. in adults the body mass index, bmi = weight (kg)/height (m)2 (table 2.1), is a sensitive measure of both under and over nutrition. (the bmi can be read directly from a nomogram – usually present in most practices, or worked out from the above equation.) diet history a diet history is a detailed dietary record that may include a 24hour recall, a food frequency questionnaire and other information such as weight, history, previous dietary changes, the use of supplements and known food intolerance. nutritional questionnaire question 1. baseline assessment. what is your usual weight and height (adult)? is the child being regularly weighed and having his/her height/length measured at the clinic? may i see the child's clinic card, please? question 2. weight loss: have you recently lost weight? do your clothes still fit? have you noticed weight gain and body changes on the antiretrovirals (arvs)? question 3. appetite: has your appetite changed? question 4. digestion: do you have any of the following: • difficulty with swallowing? • discomfort or pain in the mouth? • nausea and vomiting? • diarrhoea? question 5. food access and food security: in the past week have you missed any meals? do you or your children ever go hungry? are you able to eat meat or fish regularly? how often? question 6. non-prescription medication. do you take any immune boosters, vitamin supplements or traditional medicines? how much alcohol and/or recreational drugs do you take each day or each week? question 7. prescription medication. do you know which of your arvs need to be taken with or without food/a meal? what medicines other than arvs are you taking? question 8. stage of hiv infection: have you been admitted to hospital or been diagnosed with tuberculosis in the last 3 to 5 years? do you know your most recent cd4 level? muac in adults and children by convention the tape is placed around the left upper arm midway between the tip of the acromion process (shoulder) and the olecranon (elbow). values in adult men of < 23 cm and women of < 22 cm represent malnutrition. paediatric measurements vary with age and will be detailed in the (later) paediatric chapter. weighing the patient subjects are weighed in light underclothing without shoes. heavy items of jewellery, wallet, keys, etc. should be removed and the patient advised that a large meal just prior to the measurement and a full bladder at the time of measurement will increase the reading. where available a beam or lever balance is more reliable. bathroom scales are generally unreliable. the scale must be regularly serviced and checked, preferably monthly. babies are weighed naked and without their nappies. classification bmi (kg/m2) severe undernutrition < 16 underweight < 18.5 normal 18.5 24.9 overweight 25.0 29.9 obesity, class i 30.0 34.9 obesity, class ii 35.0 39.9 extreme obesity, class iii > 40 source: national heart, lung and blood institute, national institutes of health, usa. clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. nih publication no. 98-4083. table 2.1. the body mass index (bmi) – a measure of the risk of undernutrition and obesity j u n e 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e2 8 2.3 nutrition: the laboratory laboratory tests in hiv patients are restricted to those with clinical value. the cd4 cell count and viral load are essential and provide a direct measure of the patient's immune system and the virus. often included in the routine workup are tests that indicate whether vital organs are functioning normally: blood, the full blood count (fbc); liver – the alanine aminotransaminase (alt) level; and kidneys – urea or creatinine and urine dipstix. from time to time sophisticated diagnostic tests are indicated (blood cultures, malaria smears, sputum analysis for tb and urine microscopy), but tests that directly measure the micronutrient status of the patient are seldom required. in general, the clinical evaluation and anthropometric measurements discussed above will guide the clinician in deciding what additional investigations are necessary. 2.3.1 anaemia anaemia is an independent predictor of mortality in hiv patients. it is therefore important to document and to follow and act upon.13 the common nutritional deficiencies associated with anaemia are iron, folate and vitamin b12. however the most common cause of anaemia in hiv-infected patients is 'the anaemia of chronic disorders', an anaemia seen in many chronic inflammatory or infective conditions and not related to any nutritional deficiency.14 the haemoglobin, red cell mass and haematocrit are decreased. the laboratory will provide a comment on the peripheral blood smear and record the mean corpuscular volume (mcv), a measure of the size of the red cell. the mcv is usually normal in the anaemia of chronic disorders (normocytic anaemia), while in iron deficiency the red cells are small and the mcv is less than normal (microcytic anaemia). in folate and b12 deficiencies, the mcv will usually be elevated (macrocytic anaemia). other causes of anaemia are occasionally present: red cell haemolysis, drug-induced toxicity (the arvs: zidovudine, combivir), bone marrow infiltrate (e.g. tumour or infection such as tb) or infection with hiv itself. not every hiv-infected person requires iron supplementation. indeed most have an excess of storage iron (ferritin), and added iron may be harmful.15,16 nevertheless during pregnancy and lactation supplementation with iron, folate and multivitamins is given to both hiv-infected and non-infected women. in other circumstances, iron supplementation should only be provided if iron deficiency has been confirmed on laboratory testing. in many parts of africa malaria and hookworm infestation are common. these must be excluded in any investigation of anaemia in patients from rural or endemic areas.17 2.3.2 serum micronutrients in the hiv-infected patient the persistent presence of the virus in the human host ensures that the immune system is chronically stimulated. hence the frequently elevated total proteins in hiv-positive patients – resulting from the chronic overproduction of gamma globulins, including antibodies. intercurrent illnesses cause additional inflammatory stress. an ‘acute-phase response’ follows. for the clinician, elevated erythrocyte sedimentation rate (esr) and c-reactive protein (crp) level help to define such periods.18,19 local and systemic cytokine levels rise and fall. micronutrient concentrations mirror these changes. some increase, others decrease.20, 21 some micronutrients such as vitamins a, c and e, and zinc may behave as antioxidants. low serum levels may therefore indicate utilisation rather than an underlying deficiency.22, 23 blood levels are an incomplete measurement of the body's micronutrient status. without the clinical context of the patient and knowledge of the micronutrient status of the community, the meaning of an individual result is of limited value.24 studies from the cape and kwazulu-natal confirm generally low levels of micronutrients among hiv-infected south african children and adults.25-27 furthermore, micronutrient supplementation with vitamin a reduces morbidity, growth failure and death, while zinc supplementation reduces the duration of diarrhoea and associated fluid losses in young hiv-positive children.27,28 selenium and zinc also behave as acute-phase reactants: their levels fluctuate during infection. the value of observational and cross-sectional micronutrient studies and studies that ignore the acute-phase phenomenon remain difficult to interpret.29-31 any measurement of individual micronutrients must place the result within its clinical context. where these issues are ignored, clinical studies fail to provide convincing data.29 the routine measurement of micronutrients is expensive, difficult to interpret and generally not warranted in the southern african situation. but it goes without saying that well-planned clinical studies in this area are urgently needed to supplement the sparse data currently available. 2.3.3 liver function tests: albumin and serum alt a low serum albumin level may indicate poor nutrition, and indeed low serum albumin predicts both death and length of stay in hospitalised hiv-positive patients.5 but malnutrition is just one of several causes of low albumin: liver disease with decreased protein synthesis, renal disease with protein loss (albuminuria), enteric infections with chronic diarrhoea and malabsorption are also associated with low albumin levels. in addition, as an acute-phase reactant, a low albumin level may simply behave as a marker of an active inflammatory state. liver-related disease has become a significant cause of death of patients on long-term arv therapy.32 prolonged survival on arvs has increased exposure to the following: ■ persistent liver damage resulting from uncontrolled hepatitis b or c virus infection.33 ■ non-alcoholic steatohepatitis (nash) may result from hiv infection itself and from exposure to the metabolic sideeffects of the arvs.34, 35 ■ direct drug toxicity. all drugs are potential hepatotoxins but certain arvs are more frequently associated with liver toxicity, e.g. nevirapine in women with cd4 counts > 250 cells/µl and men with cd4 counts > 400/µl, the combination of stavudine and didanosine, and the protease inhibitor ritonavir.32, 35, 36 elevated transaminases, e.g. alt, may accompany liver damage and must be checked two or three times a year while on the t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u n e 2 0 0 7 2 9 arvs. elevated transaminases ought to direct the physician to excluding alcohol (ggt>>ast >>alt) and the activity of the hepatitis viruses (hbv and hcv) as possible causes.37, 38 elevated alkaline phosphatise and gamma-gluteryl transferase (ggt) may suggest an infiltrative process including the presence of hepatic granulomas, e.g. tb or cotrimoxazoleinduced hepatitis.39 2.3.4 miscellaneous tests amylase levels are checked in symptomatic patients with suspected pancreatitis: abdominal pain, nausea, vomiting while taking didanosine or the combination of didanosine and stavudine, and rarely, lamivudine in children. concomitant use of alcohol, pentamidine, hydroxyurea and steroids including anabolic steroids, will increase the risk.40 serum amylase is not tested routinely. fasting plasma cholesterol and triglycerides, glucose (or urine dipstix) are suggested at baseline assessment and annually in patients with known risk factors for cardiovascular disease, diabetes, etc. patients on arvs associated with lipodystrophy are at an increased risk of cardiovascular disease and insulin resistance. these will also need annual or bi-annual fasting lipids and sugars.4 2.4 nutrition: the clinical assessment see also appendices 1 and 2. the assessment of the nutritional status of hiv-infected patients begins with the initial interview. a clinical examination follows. this is combined with measurements that are repeated during subsequent follow-up visits: weight, height/length to enable a bmi measurement to be made, muac, and in patients on lipid-altering arvs, waist nutritional assessment of the hiv-infected patient7 laboratory tests (baseline assessment history examination and as indicated clinically thereafter) weight loss weight full blood count and haemoglobin (anaemia) dietary history height or length serum iron studies only if significantly access to food and food security body mass index (bmi) (normal anaemic, hb < 8 10 g/dl stage of hiv infection value: 18.5 24.9 kg/m 2) otherwise clinically indicated use of medication including the mid-upper arm circumference (muac) viral hepatitis serologies (hbv, hcv) antiretrovirals (normal values: adult males > 23 cm; and additional liver tests as clinically indicated pregnancy, lactation and the adult females > 22 cm; plasma fasting cholesterol and triglyceride ‘child under 5’ pregnant females > 23 cm) plasma fasting blood glucose micronutrient and vitamin use waist circumference, 'at risk values' the albumin level, and specific micronutrient family and/or community support (adult males ≥ 102 cm, levels are not routinely assessed adult females ≥ 88 cm) serum amylase not routinely assessed clinical examination of the patient: signs of wasting, evidence of stunting in children, signs of advanced hiv infection, signs of specific nutritional deficiency syndromes, signs of treatment-related fat redistribution what to do? history: examination laboratory tests identify food insecurity weight loss is significant and is anaemia, low serum albumin levels indicate assist families/patients with associated with mortality in the an increased risk of death in the hiv infected. accessing government support hiv infected. check measurements all abnormal investigations must be explained and welfare grants to exclude significant weight loss and and acted upon identify lack of nutritional malnutrition (weight, bmi) anaemia: check the mcv and find the likely knowledge lower than normal muac levels: cause and correct this refer to counsellor to assist with loss of lean body mass serum iron, % saturation, transferrin practical support of the mother/ correct underlying malnutrition and and ferritin levels may be helpful if iron child/patient ensure virus is brought under control deficiency is suspected identify a responsible assess food access, intake and utilisation elevated alt: check the ast, alkaline home or community member who examine patient to exclude active phosphatase, ggt and hbv, hcv antibody can assist opportunistic disease and uncontrolled tests. decide whether this is a medicationidentify opportunities to hiv infection related toxicity or an opportunistic process. if prevent hiv transmission increased abdominal circumference: necessary follow up with a hepatic ultrasound assist the pregnant patient with check which arvs are being used and to exclude a space-occupying lesion, fatty liver making informed choices including confirm metabolic abnormalities with or nash, enlarged abdominal lymph nodes exclusive breastfeeding appropriate investigations where weight loss is confirmed, give dietary advice and refer where examine and investigate to exclude available to dietician opportunistic disease, e.g. tuberculosis, weight reduction and exercise advanced hiv programme may be indicated j u n e 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e3 0 circumference can be considered. baseline and follow-up blood and urine tests complete the assessment and permit clinical staging of the patient. at this time the patient will want to know whether arv drugs are needed and what if any, is the role of diet, micronutrient supplements and vitamins. these topics will be addressed in the next chapter. references 1. shevitz ah, knox ta. nutrition in the era of highly active antiretroviral therapy. clin infect dis 2001; 32: 1769-1775. 2. truswell as. measuring nutrition. bmj 1985; 291: 1258-1262. 3. nerad j, romeyn m, silverman e, et al. general nutrition management in patients infected with human immunodeficiency virus. clin infect dis 2003; 36 (suppl 2): s52-62. 4. grinspoon s, carr a. cardiovascular risk and body-fat abnormalities in hivinfected adults. n engl j med 2005; 352: 48-62. 5. souba ww. nutritional support. n engl j med 1997; 336: 41-48. 6. young h, borrel a, holland d, salama p. public nutrition in complex emergencies. lancet 2004; 364: 1899-1909. 7. knox ta, zafonte-sanders m, fields-gardner c, moen k, johansen d, paton n. assessment of nutritional status, body composition and human immunodeficiency virus-associated morphologic changes. clin infect dis 2003; 36 (suppl 2): s63-68. 8. jones jm. the methodology of nutritional screening and assessment tools. j hum nutr dietet 2002; 15: 59-71. 9. arpadi sm. growth failure in hiv-infected children. who consultation on nutrition and hiv/aids in africa: evidence, lessons and recommendations for action. durban, 10-13 april 2005. geneva: world health organization, 2005: 4. 10. hadigan c, meigs jb, corcoran c, et al. metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. clin infect dis 2001; 32: 130-139. 11. american dietetic association. hiv/aids medical nutrition therapy protocol: medical nutrition therapy across a continuum of care. chicago, iii.: american dietetic association, 1998. 12. heller ls. nutrition support for children with hiv/aids. j am diet assoc 1997; 97: 473-474. 13. weinberg ga, boelaert jr, weinberg ed. iron and hiv infection. in: friis h, ed. micronutrients and hiv infection. boca raton: crc press, 2001: 135-157. 14. weiss g, goodnough lt. anemia of chronic disease. n engl j med 2005; 352: 1011-1023. 15. boelaert jr, weinberg ga, weinberg ed. altered iron metabolism in hiv infection: mechanisms, possible consequences and proposals for management. infect agents dis 1996; 5: 36-46. 16. gangaidzo it, moyo vm, mvundura e, et al. association of pulmonary tuberculosis with increased dietary iron. j infect dis 2001; 184: 936-939. 17. spivak jl. the blood in systemic disorders. lancet 2000; 355: 1707-1712. 18. feldman jg, goldwasser p, holman s, dehovitz j, minkoff h. c-reactive protein is an independent predictor of mortality in women with hiv-1 infection. j acquir immune defic syndr 2003; 32: 210-214. 19. munford rs. statins and the acute-phase response (editorial). n engl j med 2001; 344: 2016-2018. 20. tomkins a. assessing micronutrient status in the presence of inflammation. j nutr 2003; 133; 1649s-1655s. 21. grunfeld c, feingold kr. metabolic disturbances and wasting in the acquired immunodeficieincy syndrome. n engl j med 1992; 327: 329-336. 22. halliwell b, gutteridge jm. the antioxidants of human extracellular fluids. arch biochem biophys 1990; 280: 1-8. 23. nike e. antioxidants in relation to lipid peroxidation. chemistry and physics of lipids 1987; 44: 227-253. 24. brown kh et al. potential magnitude of the misclassification of a population's trace element status due to infection: example from a survey of young peruvian children. am j clin nutr 1993; 58: 549-554. 25. eley bs, sive aa, abelse l, kossew g, cooper m, hussey gd. growth and micronutrient disturbances in stable, hiv-infected children in cape town. ann trop paediatr 2002; 22: 19-23. 26. visser me, maartens g, kossew g, hussey gd. plasma vitamin a levels in hiv infected adults in cape town, south africa. br j nutr 2003; 89: 475-482. 27. bobat r, coovadia h, stephen cv, et al. safety and efficacy of zinc supplementation for children with hiv-1 infection in south africa: a randomised double-blind placebo-controlled trial. lancet 2005; 366: 18621867. 28. coutsoudis a, bobat r, coovadia h, huhn l, tsai w, stein z. the effects of vitamin a supplementation on the morbidity of children born to hiv infected women. am j public health 1995; 85: 1076-1081. 29. truswell as. levels and kinds of evidence for public-health nutrition. lancet 2001; 357: 1061-1062. 30. nichol c et al. changes in the concentrations of plasma selenium and selenoproteins after minor elective surgery: further evidence for a negative acute phase response? clin chem 1998; 44: 1764-1766. 31. lawlor da, smith gd, bruckdorfer kr, kundu d, ebrahim s. those confounded vitamins: what can we learn from the differences between observational versus randomised trial evidence? lancet 2004; 363: 1724-1727. 32. morcroft a, soriano v, rockstroh j, et al. is there evidence for an increase in the death rate from liver-related disease in patients with hiv? aids 2005; 19: 21172125. 33. bonacini m, louie s, bzowej n, wohl ar. survival in patients with hiv infection and viral hepatitis b or c: a cohort study. aids 2004; 18: 2039-2045. 34. pol s, lebray p, vallet-pichard a. hiv infection and hepatic enzyme abnormalities: intricacies of the pathogenic mechanisms. clin infect dis 2004; 38 (suppl 2): s65-72. 35. duval x, journot v, leport c, et al. incidence and risk factors for adverse drug reactions in a prospective cohort of hiv-infected adults initiating protease inhibitor-containing therapy. the antiprotease cohort, aproco. clin infect dis 2004; 39: 248-255. 36. van leth f, andrews s, grinszteyn b, et al., for the 2nn study group. the effect of baseline cd4 cell count and hiv-1 viral load on the efficacy and safety of nevirapine or efavirenz-based first-line haart. aids 2005; 19: 463-471. 37. pratt ds, kaplan mm. evaluation of abnormal liver-enzyme results in asymptomatic patients. n engl j med 2000; 342: 1266-1271. 38. kew m. serum aminotransferase concentrations as evidence of hepatocellular damage. lancet 2000; 355: 591-592. 39. kreisberg r. clinical problem solving. n engl j med 1995; 332: 945-949. 40. dube m. disorders of glucose metabolism in patients infected with hiv. clin infect dis 2000; 31: 1467-1475. the following chapters of this guideline will appear in subsequent issues of the journal. t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u n e 2 0 0 7 3 1 entry and exit criteria: adults > 14 years nutrition risk score if the total score exceeds 6 points, the patient can be seen as nutritionally at risk and requires food and to be provided with long-term nutritional support and access to government or ngo assistance or welfare grants. where practical, the patient should be referred to a dietician for appropriate nutritional intervention. date and score 1. weight loss in 3 months • none 0 • 3 kg (< 1clothes size) 1 • 3 6 kg (1 2 clothes size) 2 • > 6 kg (> 2 clothes size) 3 2. bmi • ≥ 18.5 0 • 17.0 18.4 1 • 16.0 16.9 2 • ≤ 16 3 3. appetite • good (most of plate) 0 • poor (half of plate eaten) 1 • unable to eat (no food in 2 days) 2 4. ability to eat • no problems 0 • mild vomiting/diarrhoea 1 • difficult swallowing/chewing 2 • severe vomiting/diarrhoea 2 • need help feeding 3 5. stage of infection (who stage classification) • stage i 0 • stage ii 1 • stage iii 2 • stage iv 3 6. other problems • none 0 • tb 2 • pregnant/lactation 2 • social problems 2 total score source: harman c. nutritional assessment chart. nutrition unit, department of paediatrics, chris hani baragwanath hospital, soweto, 2007. appendix 1 j u n e 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e3 2 entry and exit criteria: children < 14 years nutrition risk score if the total score exceeds 6 points, the child is nutritionally at risk and needs to be given food and provided with long-term nutritional support and access to government or ngo assistance or grants. where practical, the patient should be referred to a dietician for an appropriate nutritional intervention. where acute malnutrition is diagnosed, this child must be admitted to hospital and provided with appropriate formula feeding as per who guidelines. rthc = road to health chart. date and score is this child malnourished? 1. present weight: 0 3 years (rthc) • following a curve on the rthc 0 • inadequate weight gain, growth faltering 2 • ≤ 3rd percentile rthc 4 • ≤ 60% of expected weight on the rthc 6 2 14 years bmi • ≥ 50th percentile 0 • < 50th percentile 2 • ≤ 25th percentile 4 • < 3rd percentile 6 3. appetite • good (5 meals a day) 0 • poor (less than 3 meals daily) 2 • unable to eat (no food in 2 days) 4 4. ability to eat • no problems 0 • mild vomiting/diarrhoea 1 • difficult swallowing/chewing 2 • severe vomiting/diarrhoea 4 5. stage of infection • stage i 0 • stage ii 1 • stage iii 2 • stage iv 3 6. other problems • none 0 • tb 2 • pregnant/lactation 2 • social problems 2 total score source: harman c. nutritional assessment chart. nutrition unit, department of paediatrics, chris hani baragwanath hospital, soweto, 2007. appendix 2 abstract introduction materials and methods results discussion conclusion and recommendation acknowledgements references about the author(s) samuel nambile cumber department of nursing and public health, college of health sciences, university of kwazulu-natal, south africa joyce m. tsoka-gwegweni department of nursing and public health, college of health sciences, university of kwazulu-natal, south africa citation cumber sn, tsoka-gwegweni jm. knowledge and practice of condom use as well as perceived barriers among street adolescents in cameroon. s afr j hiv med. 2016;17(1), a479. http://dx.doi.org/10.4102/sajhivmed.v17i1.479 original research knowledge and practice of condom use as well as perceived barriers among street adolescents in cameroon samuel nambile cumber, joyce m. tsoka-gwegweni received: 31 mar. 2016; accepted: 05 sept. 2016; published: 03 nov. 2016 copyright: © 2016. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract introduction: street children in cameroon are adolescents, vulnerable to sexually transmitted infections (stis) and hiv and/or aids. the level of knowledge and practice of condom use among this population is unknown. objective of the study: to assess the knowledge, practice and barriers to condom use in cameroon. materials and methods: the study was an analytical cross-sectional survey conducted in 2015. questionnaires were administered to street children in a quiet location. recruitment was made using the snowball technique with the help of peers. results: more than 90% of participants knew of condoms, but only about 6% reported to have used a condom during their last sexual encounter. most of the participants did not know that condoms could prevent hiv; only a few (15.5%) knew about this. conclusion: street adolescents in cameroon seem to know about condoms, but have insufficient information on the importance of their regular use. the main barriers for the low practice of condom use reported by this population were the following: condoms hinder sexual pleasure; are costly; and it is embarrassing to buy, use or propose to use a condom. introduction street children are mostly adolescents in most african countries.1 they are often children under the age of 18 years living in difficult circumstances on the streets as has been identified by the united nations children’s fund (unicef).2,3 concerns have also been drawn by unicef regarding their growing numbers on urban streets in lowand middle-income countries around the world.2,3 the existing estimate of street children in urban cities remains that of uniceef, which suggested that there are tens of millions of street-based children in urban cities and their number continues to rise more rapidly in lowand middle-income countries around the world.2,3 the increase of street children in these countries may be because of rapid urbanisation, migration, population growth, the hiv and/or aids epidemic and other health challenges of parents.3,4 while on the streets, they go around without any form of proper adult supervision; thus, the framework of a family is absent – a framework which is believed to foster healthy development and growth in children. while on the streets, these children are pushed by circumstances to engage in any risky form of activity in order to survive life on the streets.3,4 as most of them lack basic education and skills, they are more likely to beg; tell lies; steal; engage in car washing, shoe shining, plate washing in restaurants, scavenging and other activities for their survival.3,4,5 in cameroon, their number is unknown, but they can be seen wandering the urban streets in dirty torn clothes, with some looking pale and sick.4,6,7 despite their appearance in urban cities in cameroon, no adequate supervision or support from the community or government has been given to them; thus, they are completely left to survive on their own, despite their vulnerability on the streets.4,6,7 the population of young people under the age of 18 years is estimated to be 9 573 563, almost half of the country’s total population.7 total yearly deaths in cameroon is estimated to be 117 415 and daily deaths to be 564.7 the estimated total life expectancy at birth for both sexes in cameroon is 54.4 years, 53.5 years for males and 55.3 years for females.7 however, despite the poorly estimated figures given above, the cameroon health system has no published data on the health of street children and there are no existing policies which give street children any priorities when they seek healthcare.6,7 furthermore, the public healthcare services in cameroon are not freely available to all because of its service fee policy without which one cannot receive primary healthcare in both private and state-owned healthcare facilities across the country.6,7 the policies towards street children and the high hospital cost for treatment all weigh much more on street children who are faced with the harsh realities on the streets in cameroon.6,7 they are more likely to experience sexual abuses and physical violence on the streets at night, exposing them to the risk of acquiring sexually transmitted infections (stis), and pregnancy among females.6,7 furthermore, to survive on the streets, many of them engage in risky behaviours such as sex work, substance abuse and multiple sexual partners, among others, which increase their risk of acquiring stis including hiv and/or aids.5,6 we reported elsewhere that more than 80% of street children, in the three main cities of cameroon, reported to have stis in the past.8 condoms are well-known contraceptives that are used during sexual intercourse to reduce the probability of pregnancy and the spread of stis including hiv and/or aids.9,10,11 condoms have gained more importance in the prevention of the spread of aids; yet a large section of the population of street children still have unprotected sexual intercourse and continue to have multiple sexual partners.9,10,11 one of the biggest problems with the use of condoms is that they are not used consistently, especially among street children.9,10,11 perceived barriers to condom use by street children may include factors such as high prevalence of rape, the unfavourable economic position of street children and their inability to insist on the use of condoms, which hampers their ability to negotiate during sex as the timing of sexual intercourse and the conditions under which it occurs are all to the disadvantage of street children.9,10,11 personal factors, individual perceptions, lack of efficiency, notions, constraints and condom-related problems are likely to influence condom use among street children; this especially affects girls, who account for 25% of the street children, as many of them take to prostitution as a means of survival.9,10,11 most of their clients do not want to use condoms and offer additional money for unprotected sexual intercourse; thus, they end up with common stis, hiv or become pregnant for which they lack the means to seek medical aid.9,11 acute alcohol consumption and the use of other drugs by street children significantly predicts their perceived likelihood of having sexual intercourse without condoms.12,13 both a feeling of emotional closeness and an increased sexual arousal are associated with the consumption of psychoactive substances.12,13 the aim of this study is to document the knowledge and practice of condom use among street children in three cameroonian cities. specific objectives are to assess their knowledge regarding the use of condoms, describe the practice of condom use and identify barriers to condom use. in cameroon, little is known about condom use among street children, and the barriers to condom use among them are unknown as no study has published such information.7 this information is very important for the government and all stakeholders in order to address the barriers faced by these children regarding condom use. materials and methods this study was part of a comprehensive cross-sectional survey conducted during a 3-month period from 01 january to 30 march 2015 to investigate the level of knowledge and practice of condom use as well as perceived barriers among 399 street children (320 boys and 79 girls), who were below the age of 18 years during the time of the study and resided in bamenda, douala or yaoundé urban city in cameroon. the study used the phrase ‘street children’ in order to refer to children living on the streets in urban cities, and considers a street child to be any child, boy or girl, below the age of 18 years, who has taken to the streets (including wastelands, unoccupied dwellings and unfinished buildings) as their habitual abode and source of livelihood without proper adult supervision. because the participants had no identity cards to prove their age, the study relied only on self-reported ages, which was reported orally by the participants. the study selected three urban cities which accounted for accommodating large numbers of street children. bamenda is the most populated english-speaking city in cameroon, douala is the economic capital of cameroon and yaoundé is the administrative capital of the republic of cameroon. douala and yaoundé are french-speaking cities and are the most populated among the french-speaking cities in cameroon. in the absence of data on street children in cameroon, a 50% prevalence value was used for calculating the sample size, using the following formula: where n = target sample size; z = statistics for a level of confidence (here z = 1.96, i.e. for a 95% confidence interval); p = estimated proportion of street children; d = absolute precision, that is, the width of the confidence interval to be 5% (0.05); and deff (design effect): used a clustered-randomised study where the different cities are the primary sampling units. the same number of participants was used in the different cities of the study, giving a design effect to be 1. therefore: also, based on assumption, about 5% of the questionnaires would be wrongly filled in or incomplete. for this reason, 20 more questionnaires (i.e. 0.05*385) were added, giving a total of 405 targeted participants (street children) for this study. participation in the study was voluntary. all participants were 12–17 years of age at the time of the study and must have been living on the streets for not less than 1 month prior to the onset of this study. the pilot study showed more family contact with children less than a month on the street. this does not mean that those who are less than 1 month on the street are not street children, but the authors believed those who are more stable and have accepted the street to be their new home will have more to contribute towards the study objectives. recruitment and enrolment took place at the local catholic church facilities, which provided a quiet and natural location for data collection. data collection was done by administering questionnaires to the participants because it is believed that most of the street children cannot read or write. the questionnaires were administered using pidgin english and french (pidgin english is a language that is widely spoken in west africa). the children were first contacted at identified gathering points for street children (e.g. bus stations, railway stations, market and city centres, and in front of movie houses). the questionnaires were administered by six research assistants who were given a 2-day training course to ensure that they all understood the questionnaire on the same level. questions asked included demographic details, knowledge regarding condom use, perceived barriers to condom use, history of condom use and the source of condoms. a non-probability technique (snowball sampling) was used to get participants with the help of peers on the street. this is a process whereby each recruited participant led the researcher to other participants. snowball was used because of the highly mobile lifestyle of street children. in total, 405 street children were recruited; however, six participants were excluded before analysis because of incomplete information, resulting in 399 participants. to protect the identity of the participants as all were minors, no names were written on the questionnaires; however, unique numbers were assigned to each participant for the purpose of the research only. only the primary researcher had access to the collected data. obtaining permission from parents and/or guardians in the case of street children was not possible. thus, only written informed consent form was obtained. the children were first approached by the research team at their meeting point and the entire study was explained to them including their rights and the freedom to withdraw from the study at any time they feel uncomfortable. after administering of the questionnaires, food was given to the participating street children but no monetary incentive was provided. the study received ethical approval from the biomedical research ethics committee, university of kwazulu-natal, durban, south africa and the cameroon bioethics initiative. after data collection and cleaning, data were captured in a microsoft excel (2010) spreadsheet and imported to spss statistical package version 19 for windows (ibm corp., armonk, ny, usa) for analysis. descriptive statistics such as frequency distributions and cross-tabulations were used to summarise the data. a normal distribution test was performed to determine whether the data were normally distributed or not. chi-squared test of association was used to assess whether there was any association between region and other categorical variables related to condom use. all the chi-squared tests were conducted at 5% significance level; thus, a p-value less than 0.05 meant that there was some significant variation in the variable of interest. a pilot study was conducted using a preliminary version of the authors’ self-designed questionnaire. the questionnaire was tested on a small sample of street children in a different city, after which the authors improved on the training given to research assistants and amended some questions to be more simple. the study has many strengths including the fact that up to 79 girls were recruited, making it the only study to have recruited this number of street girls in cameroon. also because of the large sample size (399 street children), six research assistants were employed for this study. the main weakness of the study was that it relied mainly on self-reported data and it was not possible to verify the responses provided by participants about their present living conditions and family background. also, there was no identification papers presented to determine their actual age. the lack of sufficient finance made it difficult to collect data in all 10 regions of cameroon. results demographic information in total, 399 adolescents were interviewed. of the sample, 320 (80.2%) were boys and 79 (19.8%) were girls. the age group 15–17 years made up 77.7% of participants, and was evenly distributed in all three cities. as presented elsewhere by cumber and tsoka-gwegweni8, the age range 12–17 had a mean age of 15.4±1.27 years. over 80% of participants reported they were christians, and less than 10% said they were either muslims or traditional and/or non-religious, with yaoundé having the highest proportion of muslims. regarding the educational status of the participants, 21.3% had never been to school, 77.4% had primary education and 1.3%, from douala, studied up to secondary school. the reason for school dropout was reported as family poverty, hatred for school, bullying and maltreatment by teachers. all the demographic variables analysed revealed significant differences between the cities, except for the age groups of participants. more than 80% of participants reported having suffered from a sti, with the highest percentage coming from douala and yaoundé. all participants reported being sexually active (table 1). table 1: the demographic characteristics of participants by city. knowledge of condom use by city table 2 presents results of knowledge regarding condom use in the three cities of cameroon. it should be noted that more than 90% of participants said they had knowledge of condoms even before ever having sex, but only about 10% reported being aware of the importance of regular use of condoms. also, only 15.5% of participants knew that condoms could prevent hiv and/or aids. table 2: knowledge regarding condom use by city. more than 60% of participants thought that condoms could be reused, with a significantly higher frequency in the city of bamenda. about 69.2% knew that condoms should be put on before ejaculation, with the highest frequency in bamenda (81.6%). also 47.4% of participants reported that the penis should be withdrawn immediately after ejaculation when using a condom, with still a significantly higher frequency in the city of bamenda (82.4%). practice of condom use among street children stratified by city all the participants reported not having used a condom during their very first sexual intercourse (figure 1). a similar response was received when participants were asked about condom use during their last sexual activity, as only 6% of participants reported to having used a condom during their last sexual intercourse. the responses were much lower in douala and yaoundé compared to that in bamenda. less than half of the participants reported to ever having used a condom in the past as shown in figure 1. figure 1: history of condom use among street children stratified by region. the figure shows percentages based on each city, for example, 68% of participants only in bamenda have used condoms in the past. more than half of the participants reported using condoms, although it was not regular. higher frequencies were reported in yaoundé and douala. it should also be reminded that a significant percentage of participants reported to have never using a condom before (figure 2). figure 2: frequencies of participants who never used condoms. perceived barriers to condom use different reasons were given by participants for not using condoms. a considerable proportion of the participants mentioned the discomfort and painful nature of the condom as a reason of not using it. some participants reported that they were shy to ask partners to use a condom, while the very few who reported not being shy to buy or use condoms were more concerned or were afraid of the aggressive reaction of their partners if they proposed the use of condoms. participants also reported some common reasons identified as barriers which contributed to not using condoms, such as: ‘i did not think about condoms’, ‘my partner did not care’, ‘i do not have hiv and/or aids’, ‘condoms hinder sexual satisfaction’, ‘i had no condom’ and ‘i was drunk and forgot’, among others (table 3). table 3: perceived barriers to condom use. in general, 30% of participants have heard information about hiv and/or aids, but only a few of them actually implemented prevention. furthermore, even the few who had knowledge of hiv and/or aids never used the information (like to insist on the use of condoms) to protect themselves (figure 3). figure 3: relationship between information and condom use for prevention of hiv and/or aids. discussion this study focused primarily on three aspects: the knowledge, practice and barriers, of condom use among street children in three urban cities (bamenda, douala and yaoundé) in cameroon. their demographic details, living conditions and risky sexual behaviours were gathered through self-reports rather than document review and/or medical examinations. self-reports may be regarded as less reliable sources; however, with the challenges surrounding the mobile lifestyle of street children, we believe that our results are a true reflection of their knowledge, practice and perceived barriers in using condoms. this belief is based on the fact that the study results concur with other similar studies in africa.3,4,5 this study also confirmed directly or indirectly that the street presents opportunities for work for these children, despite the adverse circumstances they have to endure on the streets. thus, the results are similar to those from other studies conducted in kinshasa, egypt, addis ababa, ghana and rwanda.9,10,11,12,14 this study further confirmed that street children belong to a group with multiple vulnerabilities and at high risk for hiv infection because of their lifestyle and other risky behaviours such as unprotected sex, sex work, multiple sexual partners, among others, as a means to survive the harsh realities on the streets. unlike studies from rwanda,14 further data to support public health interventions were beneficial. however, public health interventions have not included street children in cameroon; thus, there are no existing data on previous public health interventions on this population.7 no study conducted in cameroon had addressed specifically the knowledge, practice and barriers to condom use among street children in cameroon. for this reason, the ministry of public health in cameroon has called for papers which can describe the current knowledge, practice and common barriers to the use of condoms among this population.7 because of no current data, this study aims at presenting the situation using a descriptive approach so as to provide data on the present situation, which will enable decision-makers and other stakeholders working with street children to be able to design sustainable interventions to help the growing number of vulnerable street children. the results reveal that all participants, irrespective of the city setting, had limited knowledge of the importance of condoms. also a high proportion of respondents (street children) did not know about the correct routes of hiv transmission and this could be one reason for the irregular use of condoms alongside other barriers (such as high cost, shyness and fear, among others) as outlined in the results. poor knowledge may also be a result of their source of information which includes mainly their peers and other street friends. the results also revealed that all 399 participants reported to be sexually active and some, though mostly girls, engaged in commercial sex with adults in the community without the use of condoms. this suggests that the efforts made by the government and other community-based organisations to fight hiv and/or aids in cameroon are not reaching the population of street children, thereby contributing to the high aids mortality among street children in cameroon hospitals.7 the findings of this study showed very low levels of condom use among street children, as well as low levels of knowledge among the adolescents included in the study. multiple barriers have been highlighted above in the results section. additional analyses also revealed that street adolescents with more knowledge on condoms were more likely to have history of condom usage although regular usage scored zero percentage. the percentage of participants who have never used a condom was higher in the city of bamenda, as compared to the other two cities. this could be because of the strong stereotype behaviour towards persons who freely buy condoms in public places. this is also backed by a considerably higher percentage of participants who reported to be embarrassed buying or using condoms. the percentage could be higher in bamenda because it is a cultural traditional city with cultural norms very much in place as compared to douala and yaoundé which are, respectively, the economic capital and the administrative capital of cameroon, the two most populated cities in cameroon and where culture and tradition does not easily come to play a role.4,6,7 the results further showed that hindrance of sexual pleasure, feeling embarrassed to buy or use condoms and other reasons were identified by participants as barriers to condom use. these results are similar to other studies conducted on street adolescents in some african countries such as kinshasa, egypt, addis ababa, ghana and rwanda.3,9,10,11,12,14 the circumstances that make street children more vulnerable than children who live in homes are similar to those reported in studies from other african countries such as egypt, addis ababa, ghana and rwanda, which highlighted scanty knowledge and misconceptions about condoms.3,9,10,11,12,14 a study from egypt and ghana reported that about half of street children knew that unprotected sex was the primary mode of hiv transmission, but that did not affect their level of engaging in risky sexual behaviours (unprotected sex).10,12 sexual debut was reported to be from 12 years as all participants reported being sexually active, but similar results were reported among street children in other countries, some having had sex even from the age of 8 years.3,9,10,11,12,14 furthermore, cultures in west africa overlook early sexual intercourse for males, and because of their young ages their initiation in most cases is with prostitutes, which puts them at risk of contracting stis and hiv because condoms are not being used.3,9,10,11,12,14 future interventions should primarily strengthen the knowledge of street adolescents, target the various age groups as well as gender to obtain a better understanding of their knowledge, practice and perceived barriers to condom use. conclusion and recommendation the survey showed a clear insight into street children in cameroon regarding their condom use and barriers to the use of male condoms. the results showed that the street children know about condoms but have insufficient information regarding the importance of regular use of condoms. although not being able to afford condoms can be seen as a strong barrier, the push and determination to use condoms was not seen as a priority and the government and non-governmental organisations have completely neglected street children during their intervention campaigns. more programmes should target street children specifically in cameroon. the authors of this study suggested that condom vending machines and increasing the number of distributing points of free condoms in the community will help ease the stress of buying condoms. interventions from all stakeholders should tailor their messages to eliminate barriers or reduce them to a minimum, and this can be achieved through creating stronger and trustful relationships with street children, providing free condoms to them and improving their knowledge regarding what condoms can prevent. thus, intervention programmes should intensify condom education with street children. the government and non-government agencies should also intensify public campaigns targeting the entire community, promoting condoms as sexual diseases preventive measures because street children do not only have sex with street children but also with people in the community. acknowledgements competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions s.n.c. was responsible for the project. it was part of his phd study. j.m.t-g. was the supervisor of the project and phd supervisor. s.n.c. and j.m.t-g. both worked on the proposal and study designed. s.n.c. collected the data. both authors contributed in writing of the manuscript. references who/unaids. global standards for quality health care services for adolescents: a guide to implement a standards driven approach to improve the quality of health care services for adolescents. geneva: world health organization; 2015. unicef. street and unsupervised children of africa [homepage on the internet]. c2003 [cited 2015 apr 30]. available from: http://www.unicef.org/africa/street_children_report_eng.pdf pandey gk, dutt d, nair ns, subramanyam m, nagaraj k. interventions to modify sexual risk behaviors for preventing hiv infection in street children and youth people in developing countries (protocol). cochrane database syst rev. 2015;(4):10. tchombe tm, nuwanyakpa m, etmonia t. street children in cameroon: problem and perspectives. j psychol afr. 2001;11(2):101–125. karmacharya d, yu d, dixit s, et al. a study of the prevalence and risk factors leading to hiv infection among a sample of street children and youth of kathmandu. aids res ther. 2012;9(1):1. http://dx.doi.org/10.1186/1742-6405-9-25 nsagha ds, thompson rb. integrated care of orphans and vulnerable children in ekondo titi and isangele health areas of cameroon. j hiv aids soc serv. 2011;10(2):161–173. http://dx.doi.org/10.1080/15381501.2011.572740 nsagha ds, marcelin nn, assob jcn, njundah al. a public health model and framework to mitigate the impact of orphans and vulnerable children due to hiv and/or aids in cameroon. world j aids. 2014;4(1):27–37. http://dx.doi.org/10.4236/wja.2014.41004 cumber sn, tsoka-gwegweni jm. characteristics of street children in cameroon: a cross-sectional study. afr j prm health care fam med. in press. mudingayi a, lutala p, mupenda b. hiv knowledge and sexual risk behavior among street adolescents in rehabilitation centres in kinshasa; drc: gender differences. pan afr med j. 2011;10:23. http://dx.doi.org/10.4314/pamj.v10i0.72233 nada kh, sulimanel da. violence, abuse, alcohol and drug use, and sexual behaviors in street children of greater cairo and alexandria, egypt. aids. 2010;24:s39–s44. http://dx.doi.org/10.1097/01.aids.0000386732.02425.d1 habtamu d, adamu a. assessment of sexual and reproductive health status of street children in addis ababa. j sex transm dis. 2013;524076. http://dx.doi.org/10.1155/2013/524076 oppong ak, meyer-weitz a, petersen i. substance use and risky sexual behaviours among street connected children and youth in accra, ghana. subst abuse treat prev pol. 2014;9:45. http://dx.doi.org/10.1186/1747-597x-9-45 bal b, mitra r, mallick ah, chakraborti s, sarkar k. nontobacco substance use, sexual abuse, hiv, and sexually transmitted infection among street children in kolkata, india. subst use misuse. 2010;45(10):1668–1682. http://dx.doi.org/10.3109/10826081003674856 mthembu s, ndateba i. exploration of knowledge, attitudes and behaviours of street children on the prevention of hiv and aids in the huye district, rwanda. east afr j publ health. 2014;9(2):74–79. abstract introduction methods results discussion conclusion acknowledgements references about the author(s) somya gupta international association of providers of aids care, new delhi, india reuben granich international association of providers of aids care, washington dc, united states citation gupta s, granich r. when will sub-saharan africa adopt hiv treatment for all? s afr j hiv med. 2016;17(1), a459. http://dx.doi.org/10.4102/sajhivmed.v17i1.459 original research when will sub-saharan africa adopt hiv treatment for all? somya gupta, reuben granich received: 14 jan. 2016; accepted: 28 july 2016; published: 31 aug. 2016 copyright: © 2016. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the world health organization (who) hiv treatment guidelines have been used by various countries to revise their national guidelines. our study discusses the national policy response to the hiv epidemic in sub-saharan africa and quantifies delays in adopting the who guidelines published in 2009, 2013 and 2015. methods: from the internet, health authorities and experts, and community members, we collected 59 published hiv guidelines from 33 countries in the sub-saharan african region, and abstracted dates of publication and antiretroviral therapy (art) eligibility criteria. for these 33 countries, representing 97% regional hiv burden in 2015, the number of months taken to adopt the who 2009, 2013 and/or 2015 guidelines were calculated to determine the average delay in months needed to publish revised national guidelines. findings: of the 33 countries, 3 (6% regional burden) are recommending art according to the who 2015 guidelines (irrespective of cd4 count); 19 (65% regional burden) are recommending art according to the who 2013 guidelines (cd4 count ≤ 500 cells/mm3); and 11 (26% regional burden) according to the who 2009 guidelines (cd4 count ≤ 350 cells/mm3). the average time lag to who 2009 guidelines adoption in 33 countries was 24 (range 3–56) months. the 22 that have adopted the who 2013 guidelines took an average of 10 (range 0–36) months, whilst the three countries that adopted the who 2015 guidelines took an average of 8 (range 7–9) months. conclusion: there is an urgent need to shorten the time lag in adopting and implementing the new who guidelines recommending ‘treatment for all’ to achieve the 90-90-90 targets. introduction the rapid expansion of antiretroviral therapy (art) has been a cornerstone in transforming the acquired immunodeficiency syndrome (aids) response globally. in march 2015, the ’15 by 15’ target set out in the 2011 united nations political declaration on hiv and aids was achieved ahead of the deadline.1 the greatest gains in access to art occurred in sub-saharan africa, a region with 25.5 million people living with hiv.2 however, treatment coverage remains relatively low. in 2015, only 12.1m (47%) people living with hiv in the region were accessing art.2 there were 1.4m (range 1.1m–1.6m) new hiv infections and 800 000 (range 640 000–990 000) aids-related deaths.2 barring unforeseen events, the aids epidemic will continue to outrun the response and these figures are likely to rise.3 to end the aids epidemic by 2030, the joint united nations programme on hiv/aids (unaids) has established the 90-90-90 targets for 2020 (i.e. 90% of people living with hiv to know their status; 90% of people diagnosed with hiv to be accessing treatment; and 90% of those on art achieving viral suppression) that will prevent an estimated 21m aids-related deaths and 28m new hiv infections worldwide by 2030.3 shortly after these targets were established, the u.s. president’s emergency plan for aids relief (pepfar) adopted them as part of the pivot to pepfar 3.0.4 achieving these targets would require countries to align their national guidelines and programmes with the latest scientific evidence that demonstrates the benefits of immediate art in reducing the risk of hiv-related morbidity, mortality, transmission and costs.5,6,7,8,9,10,11,12,13,14 translating scientific discovery into policy and then service delivery generally takes years. however, delays translate into missed public health opportunities to prevent illness, death and transmission and deny millions of people timely access to life-saving treatment. since 2003, the world health organization (who) has updated its treatment guidelines to reflect expert consensus on when to initiate hiv treatment. whilst the who 2003 guidelines recommended art at cd4 count ≤ 200 cells/mm3 for adults and adolescents living with hiv,15 the 2006 guidelines additionally recommended considering art at cd4 count ≤ 350 cells/mm3.16 in 2009 and 2013, who guidelines updated the art eligibility criteria to cd4 count ≤ 350 cells/mm3 and cd4 count ≤ 500 cells/mm3, respectively.17,18 recently, based on results from the hptn 052,5 the insight-start6 and the temprano trial,7 the who issued an early release to its guidelines in september 2015 to recommend immediate art at all cd4 counts.19 most of the countries in sub-saharan africa use the internationally accepted who guidelines as a reference to revise their national guidelines. our study looks at the national art policy response to the hiv epidemic in sub-saharan african countries, and quantifies delays in national level adoption of the who art guidelines published in 2009, 2013 and 2015. methods from the international association of providers of aids care’s (iapac) national policy database,20 we collected the latest national treatment guidelines for adults and adolescents for 48 countries in sub-saharan africa. this database (www.hivpolicywatch.org) is current as of july 2016 and has been constructed over a 5-year period using quarterly internet searches and direct submissions from ministries of health, who, unaids, centers for disease control and prevention, united states agency for international development, pepfar, non-governmental organisations, hiv experts and members of the community. in addition to the iapac database, an internet search was also done for previously published guidelines using the keywords ’country name’ and ’hiv treatment or antiretroviral’ and ’guidelines’. as pdf versions of national guidelines before 2005 were often not available or links to these guidelines had expired, we restricted the analysis to calculating the time lag in adoption of the who 2009, 2013 and 2015 guidelines. of the 48 countries in the sub-saharan african region, we found 92 published national guidelines from 37 countries, representing 98% of regional hiv burden in 2015 (referred to as regional burden henceforth).2 for four countries, guidelines recommending art according to the who 2009, 2013 or 2015 guidelines were not available (an old version recommending art at cd4 count ≤ 200 cells/mm3 was available for each country) and they were excluded from further analysis. we screened the remaining 88 guidelines from 33 countries (97% regional burden) and excluded the 29 guidelines that did not contribute to calculating the time to adoption of the who 2009, 2013 or 2015 guidelines (they recommended art at cd4 count ≤ 200 cells/mm3 or 250 cells/mm3). from the remaining 59 guidelines for 33 countries (97% regional burden), we abstracted information on (1) month and year of publication of the guidelines, and (2) art eligibility criteria for asymptomatic adults living with hiv. in cases where the month of publication was not known, we assumed that the guidelines were published in june of the same calendar year. the date of adoption of a who guideline was defined as the date of publication of the first national guideline that was consistent with the who guideline recommendation. using the who guidelines publication date (i.e. october 2009, june 2013 and september 2015), the time lag was calculated as the number of months taken by a country to adopt the who guidelines. the average time lag in who guidelines adoption was defined as the total number of months taken to adopt who guidelines divided by the number of countries. delay was calculated separately for the who 2009, who 2013 and who 2015 guidelines according to the available published national guidelines for that period. we also estimated the delay in moving to the who 2013 guidelines for all 33 countries by assuming that the countries that are yet to move to cd4 count ≤ 500 cells/mm3 will do so by august 2016. results according to the latest available published national guidelines from 33 countries, 3 countries (6% regional burden) are recommending art according to the who 2015 guidelines (treatment for all). a total of 19 countries (65% regional burden) are recommending art according to the who 2013 guidelines (cd4 count ≤ 500 cells/mm3) and 11 countries (26% regional burden) are still recommending art according to the who 2009 guidelines (cd4 count ≤ 350 cells/mm3) (figure 1). figure 1: art eligibility criteria in 33 countries in sub-saharan africa as of august 2016 (who recommendation: irrespective of cd4 count). countries in white are the countries from north africa and the 15 countries from sub-saharan africa without publicly available national guidelines. time lag in adopting the who 2009 guidelines the who 2006 guidelines recommended art at cd4 count ≤ 200 cells/mm3, but additionally considered treatment at cd4 counts between 200 and 350 cells/mm3. guidelines from eight countries (4% regional burden) released between january 2006 and october 2009 were already recommending art at cd4 count ≤ 350 cells/mm3 before the who 2009 guidelines were released. these countries were not included in the analysis of the delay in adopting the who 2009 guidelines (figure 2). figure 2: timeline showing the date of release of the who guidelines and national guidelines from 33 countries in sub-saharan africa (january 2006–august 2016). of the 33 countries, 21 (91% regional burden) are known to have moved to cd4 count ≤ 350 cells/mm3 after publication of the who 2009 guidelines (figure 2). on average, these countries took 24 (range 3–56) months to revise their national guidelines in line with the who 2009 guidelines (table 1). for the remaining 4 countries (1% regional burden), national guidelines that adopted the who 2009 guidelines were not available. table 1: time lag in adopting the who guidelines published in 2009, 2013 and 2015 in 33 countries in sub-saharan africa. time lag in adopting the who 2013 guidelines none of the countries in sub-saharan africa moved to the cd4 ≤ 500 cells/mm3 recommendation before the release of the who 2013 guidelines (figure 2). of the 33 countries, 22 (92% regional burden) moved to cd4 count ≤ 500 cells/mm3 after publication of the who 2013 guidelines (or earlier) (figure 2). these countries took an average of 10 (range 0–36) months to revise their national guidelines in line with the who 2013 recommendations (table 1). eleven countries (26% regional burden) have not yet adopted the who 2013 guidelines. assuming these 11 countries adopt the who 2013 guidelines by august 2016, average time lag would be 19 (range 0–38) months. time lag in adopting the who 2015 guidelines none of the countries in sub-saharan africa moved to art irrespective of cd4 count before the release of the who 2015 guidelines (figure 2). of the 33 countries, 3 (6% regional burden) moved to art irrespective of cd4 count after publication of the who 2015 guidelines (figure 2). these countries took an average of 8 (range 7–9) months to revise their national guidelines in line with the who 2015 recommendations. discussion the national treatment guidelines are vital tools for programme design and management of people living with hiv. timely adoption of international best practices and normative guidelines as national policies, and successful dissemination and implementation of these policies, are critical for accelerated access to art. guideline revisions can be complex and often involve consensus building around technical and operational issues and negotiations with internal and external stakeholders regarding budget prioritisation. our study suggests that adoption of national treatment guidelines from sub-saharan african countries has been very slow, with countries taking an average of 2 years to move to cd4 ≤ 350 cells/mm3 after release of the who 2009 guidelines. it has been 3 years since the release of the who 2013 guidelines, but 11 countries, including many high-burden countries such as nigeria and mozambique, have not yet adopted these guidelines. as of august 2016, after 11 months, only three countries in the region had adopted and published national guidelines reflecting the who 2015 recommendations, which were published in september 2015. recent public announcements about plans to adopt ’test and treat’ suggest that adoption of the who 2015 guidelines may be more rapid than for the who 2009 and 2013 guidelines.21 however, implementation of national guidelines takes additional time which threatens to increase the delay to many years before the who 2015 guidelines become actual practice in the countries. understanding these delays and considering ways to shorten the time lag from science to guideline adoption to delivery of hiv services is essential to more rapidly expand access to treatment for people living with hiv and achieving the 90-90-90 targets. countries with low hiv prevalence and higher hiv spending are more likely to adopt the who guidelines.22 this is evident from the global trends – treatment for all has been the standard of care in 18 highand middle-income countries with low hiv prevalence for some years.20 on the other hand, lesotho, malawi and botswana have adopted this recommendation recently.20 also, patterns of hiv spending in high-burden countries do not consistently reflect the new science around ‘treatment as prevention’. many sub-saharan african countries are allocating less than 50% of their total hiv spending on care and treatment.23 hiv spending on art per person living with hiv is below us$200 in most of these countries.23 adoption and implementation of the who 2015 guidelines will pay off with improvement in art coverage and reductions in illness, aids-related deaths and hiv transmission, and save health and other costs.5,6,7 with nearly 2200 aids-related deaths and 3800 new infections each day,2 translating the new science into action more quickly needs to become a major public health priority for the sub-saharan african region. the countries in this region, which are already struggling to provide art, will require additional funds and/or more efficient resource utilisation to make a timely move to ‘treatment for all’. given that international funding has flat-lined, countries will need to commit more funds from domestic or innovative financing sources and allocate more resources for care and treatment.21 additionally, investments in innovative service delivery models (e.g. community-based testing and drug dispensing, nurse-initiated art), decreased use of cd4 count for art initiation and monitoring, and advances in antiretroviral regimens and technology will allow more people to be on treatment with the same or even less resources. limitations of the study our study has several limitations. we concentrated solely on published national guidelines to determine the date of adoption of the who recommendations. written policies might not reflect practice in countries or might have been published after a recommendation was implemented, suggesting that we might have overestimated the time lag in some cases. even though we did a comprehensive search for all national guidelines, we might have missed some guidelines; and some guidelines may be outdated or in the process of being updated. conclusion since 2000, hiv treatment has dramatically changed the natural history of the hiv epidemic. the new science showing the benefits of treatment for all5,6,7 along with other prevention interventions has provided the opportunity to end aids by 2030. however, our study shows that it takes years for national policies to reflect the latest science and international standard of care. even if published guidelines reflect new normative standards, implementation and access to the best care may lag. aids response is at a crucial juncture; the new science around treatment and the health and human rights obligation of governments calls for strategic use of resources to rapidly translate new science regarding hiv treatment into action.24,25 an estimated 13.4m people living with hiv are eligible but not on treatment.2 the hiv epidemic is by no means over, and there is an urgent need to move away from the traditional ’one step at a time, business as usual’ approach to guidelines production, dissemination and revision. the present analysis, which benchmarks the current pace of policy adoption, may help global and national accountability to expedite the adoption and implementation of ‘treatment for all’ in sub-saharan africa to win the fight against hiv. acknowledgements competing interests the authors declare that they have no financial or personal relationships, which may have inappropriately influenced them in writing this article. authors’ contributions r.g. was the project leader; r.g. and s.g. were responsible for project design; s.g. collected the data and performed the calculations; r.g. made conceptual contributions; and s.g. and r.g. prepared the manuscript. references how aids changed everything mdg 6: 15 years, 15 lessons of hope from aids response [homepage on the internet]. geneva, switzerland: joint un programme on hiv/aids (unaids); 2015. available from: http://www.unaids.org/sites/default/files/media_asset/mdg6report_en.pdf aidsinfo database [database online]. geneva, switzerland: joint un programme on hiv/aids (unaids); 2016. available from: http://aidsinfo.unaids.org/ 90-90-90: an ambitious treatment target to help end the aids epidemic. geneva, switzerland: joint un programme on hiv/aids (unaids); 2014. available from: http://www.unaids.org/sites/default/files/media_asset/90-90-90_en_0.pdf pepfar 3.0 controlling the epidemic: delivering on the promise of an aids-free generation. the u.s. president’s emergency plan for aids relief, united states, 2014 [homepage on the internet]. available from: http://www.pepfar.gov/documents/organization/234744.pdf cohen ms, chen yq, mccauley m, et al. prevention of hiv-1 infection with early antiretroviral therapy. n engl j med. 2011;365(6):493–505. group iss, lundgren jd, babiker ag, et al. initiation of antiretroviral therapy in early asymptomatic hiv infection. n engl j med. 2015;373(9):795–807. group tas, danel c, moh r, et al. a trial of early antiretrovirals and isoniazid preventive therapy in africa. n engl j med. 2015;373(9):808–822. attia s, egger m, muller m, zwahlen m, low n. sexual transmission of hiv according to viral load and antiretroviral therapy: systematic review and meta-analysis. aids. 2009;23(11):1397–1404. granich rm, gilks cf, dye c, de cock km, williams bg. universal voluntary hiv testing with immediate antiretroviral therapy as a strategy for elimination of hiv transmission: a mathematical model. lancet. 2009;373(9657):48–57. montaner js, hogg r, wood e, et al. the case for expanding access to highly active antiretroviral therapy to curb the growth of the hiv epidemic. lancet. 2006;368(9534):531–536. montaner js, lima vd, harrigan pr, et al. expansion of haart coverage is associated with sustained decreases in hiv/aids morbidity, mortality and hiv transmission: the ‘hiv treatment as prevention’ experience in a canadian setting. plos one. 2014;9(2):e87872. quinn tc, wawer mj, sewankambo n, et al. viral load and heterosexual transmission of human immunodeficiency virus type 1. rakai project study group. n engl j med. 2000;342(13):921–929. suthar ab, lawn sd, del amo j, et al. antiretroviral therapy for prevention of tuberculosis in adults with hiv: a systematic review and meta-analysis. plos med. 2012;9(7):e1001270. tanser f, barnighausen t, grapsa e, zaidi j, newell ml. high coverage of art associated with decline in risk of hiv acquisition in rural kwazulu-natal, south africa. science. 2013;339(6122):966–971. scaling up antiretroviral therapy in resource-limited settings: treatment guidelines for a public health approach [homepage on the internet]. geneva, switzerland: world health organization (who); 2003. available from: http://www.who.int/hiv/pub/prev_care/en/arvrevision2003en.pdf?ua=1 antiretroviral therapy for hiv infection in adults and adolescents: recommendations for a public health approach [homepage on the internet]. geneva, switzerland: world health organization (who); 2006. available from: http://www.who.int/hiv/pub/guidelines/artadultguidelines.pdf antiretroviral therapy for hiv infection in adults and adolescents [homepage on the internet]. geneva, switzerland: world health organization (who); 2010. available from: http://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection. geneva, switzerland: world health organization (who); 2013. available from: http://apps.who.int/iris/bitstream/10665/85321/1/?9789241505727_eng.pdf guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for hiv. geneva, switzerland: world health organization (who); 2015. available from: http://www.who.int/hiv/pub/guidelines/earlyrelease-arv/en/ global hiv policy watch [database online]. international association of providers of aids care; 2015 [updated 2016 june]. available from: http://www.hivpolicywatch.org/ south africa moves to ‘test and treat’ [newpaper article]. health e-news: the south african health new service, may 2016. available from: https://http://www.health-e.org.za/2016/05/10/south-africa-moves-test-treat/ gupta s, granich r, suthar ab, et al. global policy review of antiretroviral therapy eligibility criteria for treatment and prevention of hiv and tuberculosis in adults, pregnant women, and serodiscordant couples. j acquir immune defic syndr. 2013;62(3):e87–e97. granich r, gupta s, montaner j, williams b, zuniga jm. pattern, determinants, and impact of hiv spending on care and treatment in 38 high-burden lowand middle-income countries. j int assoc provid aids care. 2016;15(2):91–100. kavanagh m, cohn j, mabote l, et al. evolving human rights and the science of antiretroviral medicine. health hum rights. 2015;17(1):e76–e90. montaner js, socias me. restricting access to hiv-related services: a bad public health and economic policy. enferm infecc microbiol clin. 2015;33(7):435–436. introduction conclusion acknowledgements footnote about the author(s) andrea s. mendelsohn the desmond tutu hiv centre, university of cape town, south africa citation mendelsohn a.s. empowering patients, empowering clinicians: how the lessons of hiv can inform chronic disease management across the primary healthcare system. s afr j hiv med. 2017;18(1), a692. https://doi.org/10.4102/sajhivmed.v18i1.692 opinion paper empowering patients, empowering clinicians: how the lessons of hiv can inform chronic disease management across the primary healthcare system andrea s. mendelsohn received: 12 sept. 2016; accepted: 13 mar. 2017; published: 31 may 2017 copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. introduction a 39-year-old virally suppressed man on antiretrovirals presented to hannan crusaid arv centre in gugulethu with a complaint of frequent urination and weight loss. after telling him that he is a type 2 diabetic, he looked at me with concern and asked, ‘can i pass this on to my daughter?’ since moving to south africa, i have been struck by how much healthcare and people’s understanding of health in south africa is shaped by hiv. clearly, the experience of so many young people dying was culturally traumatic for both ordinary citizens and healthcare providers alike. however, i have also been impressed by the public health infrastructure that has proactively and thoughtfully risen to respond to the epidemic. the crisis, and consequent national and international funding, gave south africans a chance to stop and think of what the best way is to deliver chronic primary care services, rather than simply trying to get through the deluge of patients on a day-to-day basis. as a result, over three million people are receiving counselling, antiretrovirals (arvs), adhering to medication and living positive healthy lives, not an insignificant accomplishment in a resource-limited context. i think that many of the successes of hiv-related healthcare service delivery can be applied to the management of chronic diseases in south africa more broadly by empowering both primary care clinicians and patients. empowering patients: that newly-diagnosed diabetic was concerned that – like hiv can pass from mother to child or tuberculosis (tb) within household – he could go home and infect his 3-year-old child with diabetes. his understanding of diabetes was poor, and his general health literacy level low, but his understanding of his hiv was excellent. he could recount how hiv is transmitted, what medications he took and the importance of adherence. he understood the concept of taking medication to lower blood sugar within the framework of taking arvs to suppress one’s viral load. the three treatment readiness classes, hiv counselling and home visits had an impact – he understood the significance of the medication and was able to make his own healthcare decisions related to hiv from an informed vantage. i think that similar group education and treatment support, such as a culturally appropriate diabetes self-management curriculum taught by community health workers, could equally improve outcomes of other chronic diseases, including diabetes, asthma and hypertension. the days of paternalistically prescribing medication with minimal explanation are over. patients need to be treatment ready and empowered for the self-management of all diseases. hiv has provided a model of how teams of healthcare workers, in collaboration with busy clinicians who often do not have the time for extensive education and community follow-up, can be locally viable and successful. simplifying treatment: one lesson from hiv is that less is more, decreasing pill burden is key to success. the same lesson could be applied to other primary care protocols. for instance, the current western cape guidelines favour starting a low dose diuretic and adding an angiotensin-converting-enzyme (ace) inhibitor and then calcium channel blocker, before titrating any individual medication to the maximum dose. while scientifically this approach is valid, many patients end up on a higher pill burden than possibly necessary. maximally titrating diuretics or calcium channel blockers as first-line agents might serve to decrease the overall pill burden of anti-hypertensives, thereby increasing adherence. likewise, exploring generic combination anti-hypertensive agents in the public sector, such as combinations of diuretics and ace-inhibitors, might also simplify patients’ regimens. empowering clinicians: by developing clear hiv/tb treatment guidelines and nurse initiated management of antiretroviral therapy (nimart) training programmes, nurses are able to provide the bulk of hiv/tb care in south africa. this enables medical officers (mos) to focus on complicated cases. mos are given a fair amount of latitude to switch from firstto secondto even third-line regimens, with the approval of a specialist’s review only in the final case. in the case of non-communicable diseases, mos are able to perform caesarean sections and stabilise trauma patients, but they are only allowed to prescribe first-line agents for basic medical conditions. second-line agents and the corresponding laboratory investigations require the approval of a specialist. primary care mos should, for example, be able to prescribe proton pump inhibitors for short term gastro-oesophageal reflux symptoms not requiring a gastroscope, high dose corticosteroids for severe eczema not responding to weaker topicals, tamsulosin for men with history and physical examination consistent with benign prostatic hypertrophy, lipid lowering agents other than simvastatin in the case of drug-interactions (such as aluvia), or long acting beta-agonists (labas) for uncontrolled asthmatics already on inhaled corticosteroids. given the overall shortage of specialists and financial travel barriers for patients, such restrictions create a significant barrier to care. many patients are left sub-optimally controlled because they are not sick enough to warrant a specialist referral or their care is unnecessarily fragmented making for a higher likelihood of errors. general medical patients would benefit if primary care nurse-doctor teams were as empowered as their hiv colleagues. nurses are highly capable of following detailed clinical protocols, such as the western cape’s 2015 practical approach to care kit (pack),1 to prescribe first-line treatment and refer to mos only for patients failing treatment or with multiple co-morbidities. mos should be entrusted to appropriately prescribe a broader variety of agents and order medical work-ups at the primary care level, in consultation with a family physician or on-call specialists if necessary. mos would still refer cases in which a specialist consultation or procedure was warranted. however, empowering primary care nurse-doctor teams to optimally medically manage their patients with the full range of treatment options available in the public sector would, at the very least, improve patient care by offsetting the demand for specialist referrals and might even arguably result in cost savings by keeping people healthier at baseline. if primary care is the heart of the south african system, give community nurses and doctors the tools to maximise their effectiveness and take ownership of their patients’ care. conclusion i am sure that primary care providers in south africa have had dreams of improved delivery systems for years, filled with community health workers and educators all working together in a team to complement the clinician’s care. it is not as if anyone wants to keep prescribing medication after medication to an uncontrolled diabetic without seeing any improvement, yet not having the time to really figure out why the patient is not getting better or to discuss lifestyle changes. hiv was so tragic, that it forced south african healthcare workers to take the time to figure out a better way to deliver chronic care, a process that was enabled by massive international funding. this is not to say that hiv management is perfect, or the delivery of care cannot be improved. however, as an outsider looking in, it seems that south africans used creativity and hard work to develop novel, multidisciplinary approaches to improve the management of a single chronic disease on a massive scale. now is the time to apply those locally grown lessons more broadly to the treatment of all chronic diseases in the public sector. acknowledgements competing interests the author declares that he has no financial or personal relationships which may have inappropriately influenced him in writing this article. footnote 1.primary care guidelines for adults 2015, western cape edition. abstract introduction methods results discussion conclusion acknowledgements references appendix 1: supplementary material about the author(s) taygen edwards africa health research institute, somkhele, south africa liggins institute, university of auckland, auckland, new zealand ntombizodumo mkwanazi human and social capabilities division, human sciences research council, durban, south africa dsi-nrf centre of excellence in human development, faculty of health sciences, university of the witwatersrand, johannesburg, south africa joanie mitchell lentegeur psychiatric hospital, department of health, government of the western cape, cape town, south africa ruth m. bland royal hospital for sick children, glasgow, scotland institute of health and wellbeing, university of glasgow, glasgow, scotland school of public health, university of the witwatersrand, johannesburg, south africa tamsen j. rochat dsi-nrf centre of excellence in human development, faculty of health sciences, university of the witwatersrand, johannesburg, south africa samrc developmental pathways to health research unit (dphru), faculty of health sciences, university of the witwatersrand, johannesburg, south africa citation edwards t, mkwanazi n, mitchell j, bland rm, rochat tj. empowering parents for human immunodeficiency virus prevention: health and sex education at home. s afr j hiv med. 2020;21(1), a970. https://doi.org/10.4102/sajhivmed.v21i1.970 original research empowering parents for human immunodeficiency virus prevention: health and sex education at home taygen edwards, ntombizodumo mkwanazi, joanie mitchell, ruth m. bland, tamsen j. rochat received: 19 mar. 2019; accepted: 24 nov. 2019; published: 29 june 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: improving health literacy amongst human immunodeficiency virus (hiv)-positive mothers could strengthen child and adolescent hiv prevention. the amagugu intervention included health literacy materials to strengthen maternal communication and has demonstrated success in low-resource hiv-endemic settings. objectives: our aims were to (1) evaluate whether amagugu materials improved health literacy leading to changes in parental behaviour towards communicating on topics such as hiv, health behaviours and sex education, and (2) explore what additional information and materials mothers would find helpful. method: the amagugu evaluation included 281 hiv-positive mothers and their hiv-uninfected children (6–10 years). process evaluation data from exit interviews were analysed using content analysis and logistic regression techniques. results: of 281 mothers, 276 (98.0%) requested more educational storybooks: 99 (35.2%) on moral development/future aspirations, 92 (32.7%) on general health, safety and health promotion, and 67 (23.8%) on hiv and disease management. compared to baseline, mothers reported that the materials increased discussion on the risks of bullying from friends (150; 53.4%), teacher problems (142; 50.5%), physical abuse (147; 52.3%) and sexual abuse (126; 44.8%). most mothers used the ‘hiv body map’ for health (274; 97.5%) and sex education (267; 95.0%). the use of a low-cost doll was reported to enhance mother–child communication by increasing mother–child play (264; 94.3%) and maternal attentiveness to the child’s feelings (262; 93.6%). conclusion: parent-led health education in the home seems feasible, acceptable and effective and should be capitalised on in hiv prevention strategies. further testing in controlled studies is recommended. keywords: health education; sex education; intervention materials; hiv prevention; hiv-uninfected children; parent–child communication. introduction prevention of paediatric and adolescent human immunodeficiency virus (hiv) is a global priority.1 in south africa, substantial investment in reducing vertical transmission of hiv has led to more children being born hiv-negative.2 however, the rate of new infections, particularly amongst adolescents, remain high.3,4 children who are hiv-negative but have an hiv-positive parent are especially vulnerable. some evidence has shown that parental hiv may be associated with increased sexual risk behaviour and hiv infection amongst hiv-exposed or hiv-affected adolescents.5,6 although the process by which these risks may be conferred (i.e. parenting, parental illness, parental death) is still unclear, it is plausible, given international evidence, that at least some of these effects may occur as a consequence of parenting capacity or the absence thereof.7,8,9,10 the proportion of south african children who live with a parent infected with hiv is large4 and the burden on the south african health system is high,11 thus limiting the feasibility of providing parental health literacy training in primary health or hiv treatment care settings.12 therefore, it is important to consider task shifting to lay workers as a means to deliver training and education that enable hiv-positive parents to use developmentally appropriate health literacy strategies in the home setting.11 in turn, this could increase preadolescent children’s capacity to remain free from hiv in later life.10 utilising caregivers to strengthen hiv prevention in the home during the preadolescent years, before the onset of the high-risk adolescent period, has substantial potential but has been underexploited and under-researched in south africa. in south africa, the predominant hiv health literacy strategies are implemented in school-based education models which tend to target older children aged 14–16 years.13 these strategies have been moderately successful in targeting hiv risk behaviours and increasing hiv-related knowledge in lowand middle-income countries.14 however, the quality and delivery of hiv, health and sex education in rural south african schools are considered to be poor, and inconsistent, as the teachers themselves often lack the capacity to fulfil this educational role.15 evidence has shown that targeting the caregiver in the home setting is a cost-effective response to increasing health education, in particular, in resource-scarce settings.16 globally, interventions which target parents in the home are on the increase, for example, countries such as france, the netherlands, australia and the united states are increasingly focused on parental capacity as a strategy for promoting healthy ideas around reproductive health in young people.17,18 research to date has shown that caregivers have an influential role in hiv prevention and in ensuring the optimal development of children.8,18 central to achieving increased health promotion by caregivers is providing them with the necessary skills and training. health promotion is broadly defined as a process of enabling people to increase control over and improve their health.19 the world health organisation includes three key elements in its definition of health promotion: (1) governance to ensure the removal of structural barriers to adequate access to health; (2) healthy cities which limit geographical hindrances to health and (3) most relevant to this study is to ensuring health literacy. health literacy refers to the knowledge, skills and information individuals need to make healthy choices and central to improving health literacy is ensuring that individuals have the capacity to obtain, process and understand health information.20 more recently, the literature has begun to emphasise the need to go beyond simply providing health information and to move towards ensuring capacity to change behaviour, which from a psycho-social perspective is critical.21 however, very little is available to support parent’s health literacy, with many parents reporting that they feel ill-equipped to provide education to their children with hiv or sex education.22 in response, the south african national strategic plan for hiv, tuburculosis (tb) and sexually transmitted infections (sti) 2017–2022 has included a focus on early parenting interventions to support resilience in children.23 however, these focus predominantly on the early years, while little is known about the support needs of caregivers in contexts of parental hiv in south africa, and almost no interventions have focused on primary school-aged children.11,24 one maternal hiv-disclosure intervention (amagugu) focused on supporting maternal disclosure to hiv-uninfected primary school-aged children has been shown to be effective in improving mother-led health behaviours and health promotional activities (such as taking children to clinic to learn about health services); in improving maternal hiv-disclosure rates; and in strengthening the quality of the mother-child relationship in south africa.11,24,25,26 this manuscript undertakes a detailed analysis of the amagugu process evaluation with the aims of (1) evaluating whether amagugu materials improved health literacy leading to changes in parental behaviour towards communicating on topics such as hiv, health behaviours and sex education, and (2) identifying what additional informational needs (over and above existing amagugu content) might be helpful for parents. methods study design and intervention the amagugu intervention was based on a health literacy and promotion conceptual framework that was informed by an extensive body of literature.10 in summary, the conceptual framework hypothesised that the relationship between parental hiv and child outcomes was mediated through parenting and that parent–child communication is central to improving parent-led health promotion. specifically, amagugu hypothesised that non-disclosure and avoidant coping leads to low-quality parent–child communication which, in turn, decreases the likelihood of health and sex education. these children then enter adolescence with a diminished capacity for healthy behaviours resulting in increased risk-taking and adverse outcomes such as hiv infection. the conceptual framework has been described in detail elsewhere.10 the intervention model (see figure 1) was designed to disrupt these risk pathways by targeting the avoidant behaviour, facilitating maternal hiv-disclosure thereby improving parent–child communication, and fostering parent-led health education, engagement with primary healthcare services and custody planning for their child. mothers were supported to disclose their hiv status to their child at a level with which they felt comfortable. this included either ‘partial disclosure’ using the word ‘virus’, or ‘full disclosure’ using the word ‘hiv’.25,27 figure 1: the amagugu intervention materials sourced from and reproduced with permission from the authors.10 amagugu involved six home-based sessions delivered by experienced lay counsellors.11,25 lay counsellors had completed high school, had previous counselling experience and were trained on amagugu.11 the intervention package (figure 1) included low-cost, age-appropriate materials that were given to the mother to use with her child. the health literacy materials supported hiv disclosure and education, health information on the importance of nutrition, hygiene, physical activity and health promotion activities which encouraged parental engagement with health services through a series of parent-led activities undertaken in a primary healthcare setting.10 a central part of the amagugu approach involved training parents in health literacy and encouraging change in parental behaviour towards health promotion and communication. as such, counsellors did not interact directly with children, but rather the mothers were trained on the use of the materials so that they could lead the activities with their child without the involvement of the counsellor. this aimed to ensure the transfer of learning, encourage behaviour change and increase parental confidence. each mother–child pair received one intervention package consisting of 17 materials. the health literacy materials included a variety of activity cards, educational games and storybooks, such as the ‘family treasures story book’, an illustrated 14-page english-isizulu storybook designed to foster closeness between the mother and child; the ‘disclosure safety hand’, which served as a tool to create a confidante circle for the child that helped discourage the child’s disclosure of maternal hiv status to others beyond her confidante circle, in a way easily understood by the child. the tool also encouraged the child to feel safe to disclose any risks at home or school to ‘safety hand’ adults in the household; an ‘hiv body map’, a tool for sex and health education including how to explain hiv to a child; and a culturally appropriate doll which facilitated play and parent–child communication. non-index children in a household were also given a doll. the families were able to keep the intervention materials after the intervention had ended.11 amagugu has been implemented successfully in a pilot study with 24 mothers11; in a large-scale evaluation with 281 mothers25,26 and in a randomised controlled trial with 464 mothers.24 this analysis used data from the large-scale evaluation; specifically, the process evaluation data collected during the exit interviews with the 281 mothers. study setting and population this study was conducted between 2010 and 2012 at the africa health research institute, previously known as the africa centre for population health (‘africa centre’), situated in a rural community in northern kwazulu-natal with a high hiv prevalence rate.28 a prevention of mother-to-child transmission (pmtct) programme was implemented in 2001,29,30 followed by a decentralised hiv treatment and prevention programme in 2004.30,31,32 the sample for the amagugu evaluation was purposively recruited from an existing cohort in the vertical transmission study (vts; 2001–2006), a non-randomised intervention study which supported exclusive breastfeeding for the first 6 months post-birth.33 prior participation in the vts study meant that the mothers’ hiv status during the perinatal period, and hence the child’s hiv exposure status, was known. at the time of vts, these mothers had given consent to be re-contacted at a later date and for the purpose of this amagugu study, they were physically traced and invited to participate.25 inclusion criteria were that the mothers were hiv-positive, and their children were hiv-uninfected and between the ages of 6–10 years. in addition, the mother–child pair needed to be in reasonable physical and mental health and reside in the study area. in cases where the mother migrated for work, to be eligible for enrolment, she needed to be staying with her child for a minimum of two nights per week.10 the consort diagram is shown in figure 2. out of a total available pool of 525 mothers who consented to be contacted at the end of the vts, 375 women were approached, of whom 291 were enrolled and 281 completed follow-up. figure 2: the consort diagram showing women enrolled in the study sourced from and reproduced with permission from the authors.10 data collection data in the amagugu evaluation were collected by questionnaires at 4 time-points: a baseline and post-intervention assessment to collect outcome data. a further two process evaluation semi-structured interviews were completed: the first immediately after disclosure (a post-disclosure interview) and the second conducted 1 week after a health clinic promotion visit (post-clinic visit).11,25 this study reports on data from the baseline questionnaires and process evaluation interviews. during the baseline assessment, data were collected using questionnaires (collected in an interview format) covering information on maternal and child characteristics, including socio-economic, demographic and health information. this included treatment status and cd4 count; partner hiv status and previous hiv disclosure to the index child and family. process evaluation data included disclosure outcome and type (‘partial’; ‘full’); and post-disclosure questions and reactions of the children. informational needs of the mothers were derived from the open question of ‘would you like more storybooks for you and your family? if so, what topics would you like to be covered?’ which was asked in the context of the ‘family treasures story book’. at the end-line assessment, questionnaires (collected in an interview format) also collected data on intervention material usefulness including a pre–post evaluation question on whether the ‘disclosure safety hand’ had helped the mothers to talk to their children about the risk of bullying from friends, teacher–child problems, or physical and sexual abuse; whether the participant thought that the ‘hiv body map’ could be used to teach about health or sex education. lastly, information was gathered about whether there were any dolls in the household before the intervention; if the child played with the doll provided by amagugu; and whether the doll helped the mother to spend more time with her child, listen to her child more and know when her child was worried, happy or excited. other data collected in this amagugu evaluation are detailed and published elsewhere.25,26,34 analysis we used a process evaluation design to analyse data which has not previously been analysed. data were transformed, coded and analysed in two phases to address each research aim. in phase 1, we analysed the qualitative data collected through end-line questionnaires on intervention resource use to evaluate which materials in their current form fostered mother–child communication about hiv, health behaviours and sex education. we used descriptive statistics including cross-tabulations and chi-square tests to investigate whether there were significant differences amongst mothers who chose to use the intervention materials, whether those materials were used to discuss healthand sex-related topics with their children, and whether it fostered mother–child communication and maternal attentiveness to the child’s feelings. where a cross-tabulation contained multiple cells, adjusted standardised residuals were calculated to determine which cells did not differ by chance. the analysis was undertaken using stata version 13.35 in phase 2, we analysed and reported on the process evaluation data collected during the two semi-structured interviews on what other storybook topics the mothers would like to be trained on, to identify additional information that would be useful to mothers. the data were systematically categorised and quantified using content analysis36 with the following steps: the third author repeatedly read the data and identified recurrent codes of informational topics requested by the mothers, once an exhaustive codebook was finalised through review by the third and last author to check consistency and saturation of codes, all of the responses were re-analysed and coded. thereafter the first author independently reviewed the coded data and queries and discrepancies were resolved by consensus between first, third and last authors. secondly, the codes were then grouped into categories by the first and third author and were reviewed together with the last author. the analysis was conducted using microsoft excel. because some mothers provided more than one response for future storybook topics, a z-test was conducted to determine whether there was a significant difference between the first and all responses. logistic regression models were computed to test for the effects of maternal characteristics, child characteristics, post-disclosure reactions of children and post-disclosure questions of children on the likelihood of mothers asking for more information on each of the categories derived from the content analysis. regression models were run controlling for disclosure type (partial; full), with and without controls. ethical consideration ethical approval was obtained from the biomedical research ethics committee (brec) of the university of kwazulu-natal (ref: bf 144/010). results sample characteristics table 1 shows the sample characteristics by post-intervention disclosure level.26 all mothers had engaged in some degree of disclosure at that time, with 110 (39%) mothers reporting ‘partial’ and 171 (61%) reporting ‘full’ disclosure to their child.26 almost all had completed at least some primary school education, were in a current relationship and did not have a regular source of income. a large proportion of the mothers were in relatively good health, defined both objectively (having a cd4 count above the eligibility criteria for antiretroviral therapy [art] at that time of 350 cells/ml) and subjectively (perceiving their current health to be ‘excellent’), although over half of the sample was not yet on art. the median age of children was 7.0 (interquartile range [iqr] = 7–8) years, and most had a father who was still alive and contributed financially to their care. disclosure to children prior to the intervention was low. table 1: sample characteristics. the descriptive results suggested that the intervention materials in their current form improved parental capacity for health and sex education. table 2 shows descriptive statistics on whether the ‘disclosure safety hand’ increased mother–child communication during the amagugu evaluation on the topics of risks of bullying from friends, teacher–child problems and physical or sexual abuse. overall, the findings indicated that the intervention material did increase communication across all categories. the intervention material facilitated maternal discussion amongst approximately half of the mothers post-intervention who had never engaged in such discussions pre-intervention with their boy children. child sex was associated with differences for the categories of ‘talked before and talked during’ and ‘did not talk before or during’ on communication about the risks of sexual abuse (p < 0.01). the category of ‘talked before and during’ for communication about the risks of physical abuse (p < 0.05) also differed by child sex. table 2: cross tabulation of parental talks on challenging topics with the use of the ‘disclosurs hand’. most of the mothers reported having used the ‘hiv body map’ for sex (n = 267; 95.0%), and health education (n = 274; 97.5%) with no gender differentials being observed. when reporting on the use of the amagugu doll, only 94 (33.6%) mothers reported that there had been a doll in the household pre-intervention. after the introduction of the intervention doll, almost all mothers reported that their child had played with the doll (n = 270; 96.4%). most mothers reported that since receiving the doll they had played with their child more (n = 264; 94.3%). in relation to whether the doll helped foster mother–child communication, mothers reported that the doll had helped them listen to their child more (n = 262; 93.6%), and to know when their child was worried (n = 256; 91.4%), or happy or excited (n = 257; 91.8%). encouragingly, the doll was equally popular with both boy and girl children as no gender differences were observed (p > 0.05). in total, 276 (98.6%) mothers responded that they would like more educational storybooks. in response to the question of what topic they would like for future books, 281 mothers gave 363 suggestions, excluding ‘missing’ or ‘not applicable’ responses. these topics were coded and grouped into three main categories and further broken down into three sub-categories: ‘hiv and disease management’ (hiv and tb education and caregiving/disclosure/stigma); ‘general health, safety and health promotion’ (health education/health promotion/sex education); and ‘family, moral development and aspirations for the future’ (aspirations and family values/morals and social norms/parenting skills). table 3 shows categories of story book topics suggested by the mothers. the most popular topics amongst mothers were those relating to ‘family, moral development and aspirations’. mothers expressed interest in learning parenting skills with topics such as ‘how to have a good relationship with children’, ‘raising children and how to treat children’ and ‘talk about love as a parent’ being requested for future books. the second most requested category comprised topics related to ‘general health, safety and health promotion’. in this category, requests for books covering health and sex education were prominent with examples, including ‘what to do when you are sick…’, ‘learn about drug abuse’, ‘child abuse and rights’, ‘sexually transmitted diseases’ and ‘encouraging children to talk when they are abused’. the category with the least counts was ‘hiv and disease management’, which covered topics related to the aetiology, prevention and treatment of hiv/tb, maternal and family disclosure, and stigma surrounding illness, with parents’ requests ranging from ‘how hiv is transmitted to babies’, ‘more about disclosing in the family’ and ‘any topics related to not stigmatising someone else’. table 3: maternal suggestions for additional story book topics for the family. maternal and child characteristics, post-disclosure reactions and post-disclosure questions were regressed against the outcome of storybook category. no characteristics were found to be significant predictors of storybook topic selection, and therefore the results were not included in this article. discussion this study showed that the mothers found the current amagugu intervention materials to be useful in leading communication with their preadolescant children around hiv and health behaviours which may include sex education as part of reproductive health and hiv prevention.8 these results suggest that parents may be able to overcome their expressed discomfort, embarrassment and lack of knowledge on how to engage their children in discussions about sex-related matters with appropriate and user-friendly materials.8,15 these results are encouraging because discussing sex-related issues with children is often reported to be a taboo in many settings.8,15,22 building parental capacity for sex education has been identified in the literature as a key method through which increased health education and prevention occurs in the family context.8,18 this involves providing parents and caregivers with the necessary practical tools for laying the early foundation in health needed for a positive trajectory over the life course.18 the literature suggests that because family, especially parents, plays an important role in the sexual socialisation of children, their role should be capitalised upon when designing programmes to improve the sexual and reproductive health of children and adolescents.37,38 although research on parent–child communication regarding sexuality with younger children is limited, a multi-site study conducted with adolescents in burkina faso, ghana, malawi and uganda demonstrated parental influence on adolescents’ sexual and reproductive health.37 it is promising that studies in other parts of the world have demonstrated that parents also agree that the basis for sex education should be the home, supplemented by external facilities such as schools.39 in a study conducted in a rural area of the united states, 80% of parents believed that the family should provide sex education to children; 94% reported to have talked to their children about sex, and 87% regarded themselves as the primary source of sexual information for their adolescents.39 this research is one of the first to demonstrate that south african hiv-positive mothers are willing and interested in being involved in providing such health education (including education on hiv and sexuality) to their preadolescent and adolescent children. most studies on parent–child communication on sexual issues have been conducted in the united states, europe and australia.8,15 according to the world health organization, studies on parent–child communication on sexual matters in sub-saharan africa are limited, but there is a growing literature on this issue.38 our findings align with existing research which suggests that if parents are equipped with adequate support, they can communicate with their children about hiv/aids and sexuality matters.8 this would, in turn, assist in hiv prevention in young people who may also be exposed to multiple risks as they enter adolescence, including ill-health, depression and substance abuse.38 parent–child communication is a recognised protective factor during the high-risk developmental stage of adolescence, especially concerning hiv infection, and other sexual and reproductive health outcomes.8,24,37 the amagugu evaluation was shown to increase mother–child communication on topics, including the risks of bullying from friends, teacher–child problems, physical abuse and sexual abuse. this finding is important as these childhood events have been linked to adverse outcomes, including behavioural problems,40 mental health disorders,41,42,43 substance abuse disorders, sexual risk behaviour and increased risk of hiv infection and interpersonal violence,41 especially amongst hiv-affected children who are particularly vulnerable to bullying and abuse.44,45 it is encouraging to note that in comparison to baseline, mother–child communication increased for all topics. importantly, we also found that there were gender-specific and significant increases amongst mothers with boys, towards increased education of the potential risk for sexual abuse amongst their boy children. this is an important finding given that a recent national representative cross-sectional study of sexual abuse in south africa found that 10% of boys and 14% of girls aged between 15 and 17 years reported some sexual victimisation in their lifetime.46 this risk of early sexual abuse amongst boys has also been shown in longitudinal research in south africa to start early.47 thus, intervention such as amagugu, which encourage communication with boy children about the risk of sexual abuse, has important potential beyond the context of hiv. conversely, we found no gender differentials in the use of the ‘hiv body map’ for sex education. this is encouraging as the finding suggests that the distribution of educational resources has the potential to make sex education more gender-inclusive, and overcome the accepted norm that the education of boys is often regarded as the responsibility of the father or male caregiver. this is particularly relevant in the context of rural south africa, not only where patriarchal gender norms pervade but also where the role of education falls to the mother because the father may often be absent from the household.48 a plausible explanation for our finding is that the age-appropriate resources boost a mother’s confidence and empowers her to undertake this task.49 an important finding was that a simple tool such as a doll could foster parent–child communication and strengthen the parent–child relationship. this is because a doll can build parental capacity by providing an opportunity for interactive play, and insight into a child’s emotions and thoughts, fundamental to capacitating mothers as agents of early prevention.50 based on existing evidence on the usefulness of dolls in counselling with children, it may also provide children with a valuable tool for expressing concerns about emerging risks to which the child is exposed, which they feel afraid to disclose, but may disclose inadvertently through play.51,52 for example, illustrating to the parent through projective play concerns about bullying at school or undisclosed sexual abuse. in contexts of parental hiv in south africa, there is very little information on what practical support mothers may need to support them in optimising health education with their children.11,24 this study provided novel insights into the type of informational needs the mothers themselves identified to be important for their children as they entered into adolescence. this included requests for more information on family, moral development and aspirations for the future, in addition to information on health and sex. this is an original finding as prior evidence has mainly been restricted to its exploration of parent-led educational topics to the domain of sexual and reproductive health.50,53 in comparison, our results, which allowed parents to use an open-ended question to define the topics, illustrate the importance of considering a more value-based approach to health education because this emerged as a parental priority and preference. interventions which are responsive to this parental desire may benefit from increased engagement and motivation amongst parents to undertake what can be a challenging task. it is important to consider these parental preferences within the context of south africa and the culture of the study population. the black south african zulu population have a sense of pride in traditional values which emphasise morality. broadly, in african cultures, values emphasise collectivist consciousness where the value of the individual (self-achievement) is not as important as the value of one’s relationship with others and how it contributes to a collective or societal achievement, known as ‘ubuntu’ which represents a moral philosophy of life.54 this may explain why mothers considered the moral developmental of children as important requesting material on topics about the importance of family, culture and traditions, as well as education. with regard to the latter, it is also possible that given the south african history of exclusion and discrimination, parents would be particularly motivated to ensure that their children succeed in post-apartheid south africa.55 practical implications the under-utilisation of caregivers in health education and disease prevention in current approaches is a missed opportunity. these findings provide insight into how parental capacities can be strengthened in a cost-effective way which may guide both researchers and policy makers. targeting mothers in the home context has the potential to be a feasible and cost-effective point of entry for intervention in early prevention of disease. specific tools may be useful in engaging and encouraging parental education in areas which are traditionally difficult for parents to handle. limitations of the study limitations include that sample size was small and context-specific, thereby limiting generalisability. the sample was also restricted to mothers, a practical decision because as mentioned previously, children in rural south africa are mostly raised by their mothers.48 hence, we are not able to determine whether fathers would find such approaches helpful or appropriate. however, amagugu is easily adapted to target fathers and other family members24 if it were demonstrated to be acceptable to them. an additional limitation was that because the data in this evaluation study were based on self-report, social desirability bias may have influenced the responses of the mothers regarding health communication and the usefulness of the materials in achieving behavioural change towards increased communication. the amagugu evaluation is thus limited in its ability to determine the extent to which the intervention materials or activities played a direct role in changing parental behaviours. this is because the data on disclosure and communication outcomes were not measured objectively, and there was no control group. however, the descriptive findings of the analysis do suggest that the intervention materials in their current form helped to improve the mothers’ capacity for health and sex education, contributing to their (the mothers) capacity for making behavioural changes towards increased health communication. it is thus plausible to infer that potentially the content and activities of the package could have led, at least in part, to the increased rates of disclosure and health education that were reported at the end line assessment. this is particularly so because additional research on the amagugu intervention using a randomised controlled design has since, indeed, demonstrated efficacy in changing parent behaviour towards disclosure and health promotion.24 recommendations a long-term follow-up study, when the children in the sample will reach adolescence, would provide further information about whether amagugu is an effective intervention for hiv prevention in later life. moreover, studies should be conducted to ascertain whether these findings are replicated in other population settings. national surveys such as the national attitudes survey56 could help illuminate parental perceptions in this area and determine broader acceptability. a partial economic evaluation should be conducted to make a stronger case for investment in prevention at home. conclusion this study provided valuable information on what hiv-positive mothers need to support their hiv-uninfected children’s health education as well as the type of interventional resources they found useful in leading communication around health and sex. the capacity of hiv-positive mothers to lead health and sex education in the home should be capitalised on in hiv prevention strategies. the intervention materials were low cost and administered by lay counsellors, which suggests that early prevention does not have to be a costly and complicated endeavour. acknowledgements the authors wish to thank the amagugu team including samu dube, hlengiwe mtolo, bonnie gumede and philani sithole (field team); colin newell (database design and management); dickman gareta and siyabonga nxumalo (data extraction team); and the africa centre community liaison office and the community advisory board for their assistance in this research. they would also like to acknowledge all the mothers and families who agreed to participate in amagugu without whom this study would not have been possible. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions t.e. contributed to the analysis and interpretation of data, drafted and revised the article. n.m. contributed to drafting the article and critically revised the final version. j.m. contributed to the coding of the data and reviewed the final version. r.b. contributed to drafting of the article and critically reviewed the final version. t.j.r. contributed to the article concept, interpretation of the data and critically reviewed the article. funding information this study was funded by the canadian international development agency (cida). t.e. receives salary support from the africa health research institute. n.m. receives a post-doctoral scholarship from the dst-nrf centre of excellence in human development, university of the witwatersrand. t.j.r is a wellcome trust intermediate fellow in public health and tropical medicine and recieves salary support from the wellcome trust. data availability statement data is available on the africa health research institute data repository for researchers who meet the 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profile: mamanengane or the africa centre vertical transmission study. int j epidemiol. 2010;39(2):351–360. https://doi.org/10.1093/ije/dyp165 rochat tj, mitchell j, lubbe am, stein a, tomlinson m, bland rm. communication about hiv and death: maternal reports of primary school-aged children’s questions after maternal hiv disclosure in rural south africa. soc sci med. 2017;172:124–134. https://doi.org/10.1016/j.socscimed.2016.10.031 statacorp. stata statistical software: release 12. college station, tx: statacorp lp; 2011. hsieh h-f, shannon se. three approaches to qualitative content analysis. qual health res. 2005;15(9):1277–1288. https://doi.org/10.1177/1049732305276687 biddlecom a, awusabo-asare k, akinrinola b. role of parents in adolescent sexual activity and contraceptive use in four african countries. int perspect sex reprod health. 2009;35(2):72–81. https://doi.org/10.1363/3507209 who. helping parents in developing countries improve adolescents’ health [homepage on the internet]. 2007 [cited 2019 feb 18]. available from: https://apps.who.int/iris/bitstream/handle/10665/43725/9789241595841_eng.pdf;jsessionid=4343d19a7b9b649b3ec58ac02fe1931d?sequence=1 jordan tr, price jh, fitzgerald s. rural parents’ communication with their teenagers about sexual issues. j sch health. 2000;70(8):338–344. https://doi.org/10.1111/j.1746-1561.2000.tb07269.x o’connor ee, dearing e, collins ba. teacher-child relationship and behavior problem trajectories in elementary school. am educ res j. 2011;48(1):120–162. https://doi.org/10.3102/0002831210365008 anda rf, felitti vj, bremner jd, et al. the enduring effects of abuse and related adverse experiences in childhood. eur arch psychiatry clin neurosci. 2006;256(3):174–186. https://doi.org/10.1007/s00406-005-0624-4 takizawa r, maughan b, arseneault l. adult health outcomes of childhood bullying victimization: evidence from a five-decade longitudinal british birth cohort. am j psychiatry. 2014;171(7):777–784. https://doi.org/10.1176/appi.ajp.2014.13101401 ttofi mm, farrington dp, lösel f, loeber r. do the victims of school bullies tend to become depressed later in life? a systematic review and meta-analysis of longitudinal studies. j aggress confl peace res. 2011;3(2):63–73. https://doi.org/10.1108/17596591111132873 cluver l, bowes l, gardner f. risk and protective factors for bullying victimization among aids-affected and vulnerable children in south africa. child abuse negl. 2010;34(10):793–803. https://doi.org/10.1016/j.chiabu.2010.04.002 cluver l, orkin m, boyes m, gardner f, meinck f. transactional sex amongst aids-orphaned and aids-affected adolescents predicted by abuse and extreme poverty. j acquir immune defic syndr. 2011;58(3):336–343. https://doi.org/10.1097/qai.0b013e31822f0d82 ward cl, artz l, leoschut l, kassanjee r, burton p. sexual violence against children in south africa: a nationally representative cross-sectional study of prevalence and correlates. lancet glob health. 2018;6(4):e460–e468. https://doi.org/10.1016/s2214-109x(18)30060-3 richter lm, mathews s, kagura j, nonterah e. a longitudinal perspective on violence in the lives of south african children from the birth to twenty plus cohort study in johannesburg-soweto. s afr med j. 2018;108(3):181–186. https://doi.org/10.7196/samj.2018.v108i3.12661 richter l, chikovore j, makusha t. the status of fatherhood and fathering in south africa. child educ. 2010;86(6):360–365. https://doi.org/10.1080/00094056.2010.10523170 schuster ma, corona r, elliott mn, et al. evaluation of talking parents, healthy teens, a new worksite based parenting programme to promote parent-adolescent communication about sexual health: randomised controlled trial. bmj. 2008;337:a308. https://doi.org/10.1136/bmj.39609.657581.25 wamoyi j, fenwick a, urassa m, zaba b, stones w. parent-child communication about sexual and reproductive health in rural tanzania: implications for young people’s sexual health interventions. reprod health. 2010;7(1):1–18. https://doi.org/10.1186/1742-4755-7-6 rozentals-thresher r, hemmens r, stone j. play with us: bringing hope and healing to kwazulu-natal’s children. in: bunston w, jones sj, editors. supporting vulnerable babies and young children: interventions for working with trauma, mental health, illness and other complex challenges. london: jessica kingsley publishers, 2019; p. 175–190. mkwanazi nb, rochat tj, bland rm. the amagugu intervention: a qualitative investigation into maternal experiences and perspectives of a maternal hiv disclosure support intervention in rural south africa. health policy plan. 2017;32(9):1231–1240. https://doi.org/10.1093/heapol/czx056 turnbull t, van wersch a, van schaik p. parents as educators of sex and relationship education: the role for effective communication in british families. health educ j. 2011;70(3):240–248. https://doi.org/10.1177/0017896911398817 gade cbn. what is ubuntu? different interpretations among south africans of african descent. s afr j philos. 2012;31(3):484–503. https://doi.org/10.1080/02580136.2012.10751789 barbarin oa, richter lm. mandela’s children: growing up in post-apartheid south africa. london: routledge; 2001. pillay u, roberts b, rule sp. south african social attitudes: changing times, diverse voices. cape town: hsrc press; 2006. appendix 1: supplementary material table 1-a1: parental suggestions for additional story book topics for the family by category and response. hiv 933 case report chylothorax associated with non-endemic kaposi’s sarcoma k verma,1 dmrt, dnb; m haverkamp,2 md, mph; m kayembe,3 md; z musimar,4 mb bch 1 department of oncology, princess marina hospital, gaborone, botswana 2 hiv care and support, botswana-upenn partnership, gaborone, botswana 3 department of pathology, national health laboratory, gaborone, botswana 4 department of oncology, princess marina hospital, gaborone, botswana corresponding author: k verma (kv_erma@yahoo.com) chylothorax is a rare cause of pleural effusion, seen in approximately 2% of cases. in hiv-positive patients with kaposi’s sarcoma (ks), the development of chylothorax presents as a diagnostic challenge with an aggressive course and poor, often lethal outcome. in this clinical scenario, the aetiology of chylothorax may include infections and malignancy, while pleural fluid examination and computed tomography of the mediastinum may fail to establish a cause. we present a case of ks-associated non-traumatic chylothorax resulting in death, and a review of available literature on this condition. s afr j hiv med 2013;14(3):141-143. doi:10.7196/sajhivmed.933 in hiv-positive patients with kaposi’s sarcoma (ks), chylothorax is a rare complication. ks is related to human herpesvirus-8 (hhv8), and striking reductions in incidence and improvements in survival have been reported after the introduction of highly active antiretroviral therapy (haart). 1 with prolonged survival, the sequelae as well as related complications of ks pleural effusions are increasingly being noted. however, in settings of high tuberculosis (tb) prevalence and limited clinical resources, patients with pleural effusions are typically treated empirically for tb, often with little consideration for ks. the limited availability of diagnostic testing in many settings to investigate unresolving pleural effusion despite tb treatment often presents a diagnostic dilemma. chylous pleural effusion is an uncommon complication secondary to pathology of the thoracic duct; however, determining the aetiology of chylothorax in hiv-positive patients with ks and/or tb is a significant challenge. the contribution of infectious, malignant and iatrogenic causes needs to be investigated to determine the appropriate management strategy. case a 40-year-old man sought medical attention for shortness of breath on mild exertion with dry cough of 1 month’s duration. he had no significant past medical, social or family history. physical examination revealed dullness to percussion at both bases, but no significant lymphadenopathy. a chest x-ray revealed bilateral pleural effusion without any infiltration. his sputum was negative twice for acid-fast bacilli (afb). he tested positive for hiv with a cd4+ count of 119 cells/µl (6%). he was started on emtricitabine, tenofovir and efavirenz as a fixed-dose combination, pneumocystis jerovii prophylaxis, and 6 months of standard treatment for pulmonary tb. after 2 months of this therapy, he reported with violaceous lesions on both legs and his chest wall. skin biopsy revealed ks and he completed 6 cycles of chemotherapy with doxorubicin, bleomycin and vincristine. after 6 months of art, he was virologically suppressed; however, he had immunological failure with a cd4+ count of 41 cells/µl (5%). shortness of breath responded to this therapy, but he had radiological persistence of bilateral pleural effusions (table 1). repeated thoracocentesis revealed straw-coloured fluid with protein >3 g/dl, and inflammatory cells with a lymphocytic predominance without any atypical cells. despite multiple attempts, no bacterial pathogens or afb were isolated from the pleural effusion. his skin lesions decreased in size, but he developed woody oedema of the left leg that responded to lower-hemibody irradiation of 800 cgy in a single fraction. table 1 presents a summary of the major investigations and findings. due to persistent bilateral pleural effusions, the patient received 6 cycles of 150 mg/m2/day etoposide (injection) from day 1 through day 3 for treatment of pulmonary ks, with a temporary relief in his cough and shortness of breath. he still required repeated thoracocentesis to relieve his episodes of breathlessness. three months after completion of chemotherapy, he developed a worsened shortness of breath and productive cough. the whitish sputum was negative upon ziehl-neelsen smear. contrast-enhanced computed tomography (ct) of the chest confirmed bilateral pleural effusions with consolidation of the right lower zone of the lung, but no pulmonary nodules, mediastinal or hilar lymphadenopathy (fig. 1). the patient underwent bilateral intercostal chest drainage, revealing thick brownish fluid (fig. 2). sputum and pleural fluid were negative for afb cultures and mycobacterium tuberculosis polymerase chain reaction (pcr) (genexpert), but bacterial cultures from pleural fluid grew staphylococcus aureus. these were identified as methicillin-resistant s. areus (mrsa) and the coverage was narrowed down to vancomycin only. after 5 days of vancomycin therapy, pleural fluid draining from both sides turned milky white in colour. the fluid triglyceride level was 3.1 mmol/l (247 g/dl), protein was 2.2 g/ dl, cholesterol was 0.1 mmol/l and lactate dehydrogenase (ldh) was 1 344 mol/l. the patient was diagnosed with bilateral chylothorax and underwent blind pleural biopsy to rule out other aetiologies of persistent bilateral pleural effusion aside from ks-induced scarring of the thoracic duct. diagnostic bronchoscopy revealed normal trachea and bronchi. the respiratory mucosa was inflamed and red, but visibly normal with no evidence of endobronchial lesions. there were profuse, whitish secretions in the trachea-bronchial tree, which were washed out and sent for microscopy, culture and sensitivity, as well as tb and fungal investigations. bilateral thoracoscopy revealed empyema with loculations with beefy, inflamed, thick-walled visceral and parietal pleurae. in the presence of low cd4+ counts, this was regarded as a relapse of pulmonary tb, and anti-tubercular treatment was started. the patient developed sepsis from extended spectrum β-lactamase (esbl) gram-negative bacteria and died after several days in the intensive care unit. fig. 1. computed tomography scan of the chest showing bilateral pleural effusions with consolidation of the right lower zone of the lung with thickened pleura and intercostal drainage tube in place. no significant pulmonary nodules or lymphadenopathy are visible. fig. 2. chest x-ray posteroanterior view showing bilateral pleural effusions with intercostal drainage tube in place. discussion this patient was diagnosed with hiv with non-endemic ks and pulmonary tb manifesting as bilateral pleural effusion with s. aureus empyema with bilateral chylothorax. bilateral pleural effusions persisted even after empirical anti-tubercular treatment for 6 months. the presence of advanced hiv disease, pulmonary tb and disseminated ks synchronously posed a difficult diagnostic scenario, and the aetiology of bilateral chylothorax in this patient was unclear. in the setting of hiv-associated ks, the underlying aetiology for bilateral chylothorax may include primary tumour (ks with involvement of pleura or thoracic nodes), infections (related to immunocompromised status and multi-agent chemotherapy) or an unrelated aetiology. diagnostic bronchoscopy revealed no evidence of endobronchial lesions and ruled out pleuropulmonary ks as the cause for chylothorax. chyle consists of lymph of intestinal origin, which is a milky and opalescent fluid rich in lymphocytes, protein, triglycerides and chylomicrons. chyle is conducted from intestinal lymphatics to the cisterna chyli, which eventually drains into the left subclavian vein via the thoracic duct through the posterior mediastinum. disruption of flow in the thoracic duct results in mediastinal collection of chyle, which can leak into the pleural space resulting in chylothorax. this manifests as shortness of breath and chest discomfort due to compression of the lung by the collection of chyle. drainage of milky-white pleural fluid suggests chylothorax that can be confirmed by pleural fluid examination. a level of pleural fluid triglycerides >110 mg/dl and a pleural fluid/serum cholesterol ratio <1 is diagnostic of chylothorax.2 normally, the average flow of chyle is about 2 l/day; following meals it may increase to a rate of 4 l/day.3 continued loss of chyle leads to depletion of protein, fat and lymphocytes. the four main causes of chylothorax include: malignancy; trauma; idiopathic; and miscellaneous causes such as thrombosis of the superior vena cava or subclavian vein, cirrhosis and rarely, pulmonary lymphangiomyomatosis.4 ks is one of the most common causes of pleural effusion in patients with aids. the pathological diagnosis of pleural ks requires a characteristic architectural appearance and not a particular neoplastic cell type.5 the sampled fluid (usually serosanguineous or haemorrhagic exudate) is unlikely to contain diagnostic cytological material. since ks tends to involve only the visceral pleura, closed pleural biopsy is often non-diagnostic and the diagnosis requires thoracoscopy with the characteristic multiple cherry-red to purple appearance of the ks lesions on the visceral pleura.6 in most cases, the clinical picture and the characteristic bronchoscopic appearance of the lesions help to make a presumptive diagnosis and may obviate the need for biopsy.7 a study describing the clinical course and pleural fluid findings in patients with aids-associated pleural ks showed that 21/105 (20%) cases had pleuropulmonary ks involvement. of these, 13 (62%) had pleural effusions and only 2 had chylothorax. neither cytological examination nor needle biopsy of the parietal pleura was able to establish the diagnosis. at autopsy, patients with pulmonary ks have multiple cherry-red to purple lesions on the visceral, but not on the parietal pleural surface. the reported median survival from ks diagnosis to death was 205 days for patients with pleuropulmonary ks.6 in another series, 29/53 (55%) patients had pleural effusions including 76% bilateral.8 currently, the exact aetiology of chylothorax in patients affected by advanced hiv with ks is unclear, and few cases have been described in the literature.[8-­­10] most cases reported evidence of lymphatic obstruction via ks involvement of the mediastinal nodes and/or prominent pulmonary ks, and the treatment included palliative measures such as pleural drainage, pleural sclerosis, fluid shunting and/or chemotherapy directed at ks. the treatment was largely unsuccessful, and patients in whom the outcome was noted, died within a few weeks to months. average survival after diagnosis of ks pleural disease is around 4 months. 6 the potential cause of chylothorax in hiv-positive patients also includes tb, but chylothorax appears to be rare in patients with tb, and ks remains the leading concern in the differential diagnosis. 11 chylothorax is also rare in patients with ks without hiv infection (endemic ks) and only a single case of ks-related chylothorax in an hiv-negative patient was reported in past years.12 the pathogenesis of most effusions due to malignancy has been attributed to blockade of the lymphatic drainage system located in the parietal pleura, but this is unlikely in patients with ks-related pleural effusions, since their parietal pleura is not involved. the ks-related effusion may be due to the elaboration of vascular endothelial growth factor (vegf). vegf promotes angiogenesis and microvascular hyper-permeability to produce extravascular fluid that appears bloody.13 in patients with ks, the pleural effusion is a chylothorax in about 2% of cases, which suggests involvement of the thoracic duct by the tumour. ks-related chylothorax is postulated to develop from metastases to the thoracic duct. more recently, however, it was demonstrated by the co-expression of hhv-8, cd34 and d2-40 on lesional cells, that chylothorax may arise due to the development of in situ ks in this region.14 the patient described here had no clinical, radiological or cytological indication of pleuropulmonary ks. there was no mediastinal lympha­denopathy, nor any history of chest trauma. thus, the aetiopathogenesis of his bilateral chylothorax was not clinically or radiologically evident. in this scenario, the reason for chylothorax appeared to be involvement of the thoracic duct by ks, leading to obstruction and a resultant leakage of chyle from the thoracic duct. the process might have been exacerbated by post-chemotherapy fibrosis of mediastinal nodes and/or lymphatic involvement by mycobacteria. this can be evaluated by radioisotope lymphangiography, magnetic resonance imaging or positron emission tomography; however, these investigations are unfortunately not widely available. further, thoracoscopy with biopsy of mediastinal nodes and a visceral pleural biopsy may help to differentiate ks from tb as the underlying aetiology. patients immunocompromised by hiv infection and chemotherapy are at high risk for infection-related effusions. a concomitant infection must be ruled out in patients with ks-related pleural effusion, as a failure to treat a concomitant infection carries a high short-term mortality. in this patient, isolation of mrsa from pleural fluid was probably related to pleurocentesis-related iatrogenic empyema. conclusion ks-associated chylothorax may present a diagnostic challenge and carries a poor prognosis. current literature is sparse and a congregation of such cases can provide more insight into the aetiopathogenesis of non-endemic ks-related chylothorax. references 1. tam hk, zhang zf, jacobson lp, et al. effect of highly active antiretroviral therapy on survival among hiv-infected men with kaposi's sarcoma or non-hodgkin's lymphoma. int j cancer 2002;98(6):916-922. 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[http://dx.doi.org/10.1378/chest.94.6.1316b] 10. schulman ll, grimes mm. metastatic kaposi’s sarcoma and bilateral chylothorax. ny state j med 1986;4:205-206. 10. schulman ll, grimes mm. metastatic kaposi’s sarcoma and bilateral chylothorax. ny state j med 1986;4:205-206. 11. singh s, girod jp, ghobrial mw. chylothorax as a complication of tuberculosis in the setting of the human immunodeficiency virus infection. arch intern med 2001;161(21):2621. 11. singh s, girod jp, ghobrial mw. chylothorax as a complication of tuberculosis in the setting of the human immunodeficiency virus infection. arch intern med 2001;161(21):2621. 12. fife km, talbot dc, mortimer p, isher c, smith ie. chylous ascites in kaposi's sarcoma: a case report. br j dermatol 1992;126(4):378-379. [http://dx.doi.org/10.1111/j.1365-2133.1992.tb00683.x] 12. fife km, talbot dc, mortimer p, isher c, smith ie. chylous ascites in kaposi's sarcoma: a case report. br j dermatol 1992;126(4):378-379. 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[http://dx.doi.org/10.1186/1472-6890-6-7] s u m m e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 10 biology hepatitis b is a dna virus classified as a hepadnavirus, which replicates in the liver but is found in other sites of the body.7 a simplified version of the very complicated hbv life cycle begins with the dna virus entering into the hepatocyte’s nucleus, which then produces and releases rna into the cell’s cytoplasm. a nucleoside reverse transcriptase enzyme is necessary to revert into dna strand for viral packaging and release from the hepatocyte for further infection. hence the effectiveness of the nucleoside reverse transcriptase inhibitors (nrtis) in the use of both hiv and hepatitis b treatment (fig. 1). as with hiv, hbv has a high mutation rate. the reverse transcriptase enzyme lacks the proof-reading function that is seen with most dna polymerases. there are three important clinical mutations in the hb virus: tryosinemethionine-aspartate-aspartate mutant (more commonly known as the ymdd mutant), n236t mutant precore mutants, and core promoter mutants. the first two are important for nucleoside reverse transcriptase drug resistance and the last one is important in diagnosis and prognosis of hbv infection. these mutants will be described in more detail further on.8 hbv is classified into eight different genotypes using alphabetical nomenclature (a h). the different genotypes are represented in different geographical locations, and genotype can influence both the prognosis of clinical disease and treatment response rates. in south africa the common genotypes seen are a1 and e. in asia b and c genotypes are seen. genotype c has been noted not to respond as well to interferon treatment as genotypes hepatitis b and hiv co-infection in south africa: just treat it! clinical cynthia s firnhaber1,2, md prue ive1, fcp (sa) 1clinical hiv research unit, university of the witwatersrand, johannesburg 2right to care, johannesburg there are an estimated 350 million hepatitis b carriers worldwide. the prevalence of mono-infection with hepatitis b in south africa has been estimated at approximately 10% for the rural population and 1% in urban areas.1,2 the transmission routes of hepatitis b and hiv are similar, but hepatitis b is more efficient. co-infection with hiv and hepatitis b is therefore not unusual. recent studies have shown that the prevalence of hiv/hbv co-infection (using hbv surface antigen (hbsag) as a marker for hbv) in south africa ranges from 4.8% to 17%, depending on the population studied.3-5 the guidelines for the south african hiv comprehensive care, management and treatment (ccmt) programme do not include viral hepatitis studies.6 hepatitis b serology is usually done only if serum aminotransferases are evaluated in the absence of another known cause (e.g. tuberculosis and concomitant medications). the clinical sequelae of hiv/hbv co-infection are multiple and can cause an increase in morbidity and mortality. awareness of hbv/hiv co-infection with appropriate diagnosis and management is imperative for improved care of our hiv patients. fig.1. simplified life cycle comparison of hbv and hiv– use of reverse transcriptase enzyme in viral reproduction. hepatitus b.indd 10 3/16/09 2:16:16 pm t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s u m m e r 2 0 0 9 11 a and d. c has also been reported to have an increased tendency to be associated with liver failure and hepatocellular carcinoma.8-10 transmission transmission of hbv follows the same blood/body fluid patterns of hiv, but is much more efficient. for example, the rate of hiv transmission from a needle stick is 0.03%, whereas the rate of transmission of hepatitis b can be as high as 30%. serum but also semen and saliva are effective infectious agents.7,11 horizontal transmission due to close contact between young children is a major modality of hbv spread in southern africa.12,13 perinatal transmission is very important in asia and is thought to occur mainly during delivery and not during breastfeeding.7 most of these data come from the literature on hbv mono-infection. hiv-related immunosuppression increases the viral replication and viral load of hbv. hiv/hbv co-infected people have higher hbv viral loads, so co-infection would be likely to make transmission of hbv more efficient.14 serology and diagnosis the diagnosis of hepatitis b disease is complicated, and multiple laboratory evaluations of serology, hbv viral load, hepatic transaminase levels and/or histological studies are often required. serological markers have been the standard method of diagnosis of hbv infection for more than 30 years and have been the cause of great confusion among many an intern over this time. the traditional interpretation of serological markers is as follows: n anti-hbs – antibody to hepatitis surface antigen confers immunity (either through the vaccine or through exposure). anti-hbs alone is seen with immunity acquired through vaccination. anti-hbs + anti-hbc is usually seen with immunity acquired through hbv infection. n hbsag – hepatitis b surface antigen (infectious agent) is the first serological marker to appear after infection, and persistence for more than 6 months indicates chronic hbv infection. n anti-hbc – antibody to the hepatitis core antigen becomes positive when exposed to hepatitis b virus. n hbeag – e antigen represents active replication of hepatitis b (it can be viewed as a poor man’s hbv viral load). n anti-hbeag – antibody of e antigen indicates that hbv replication is not occurring and has been considered an end-point of hbv treatment. precore and promoter mutants these mutations occur in the wild-type hepatitis b replicating virus in the precore and/or promoter regions of the virus. in these regions there are mutations leading to changes in the dna code which form stop codons in the templates, preventing hbeag production. a replicating hbv that should be producing the e antigen therefore cannot do so, and is called hbeag-negative chronic hepatitis b.8 with the wider availability of sensitive molecular biological techniques for detecting hbv dna in serum and liver tissue, increased attention is being paid to occult (silent) hbv infection. occult hbv dna is defined as dna found in liver or serum in hbsag-negative patients, and detection of two regions of the hepatitis virus dna via pcr is required for an infection to be considered occult. the clinical importance of occult hbv infection is unclear and debated. in a co-infected hiv/occult hepatitis b cohort in philadelphia, no significant increase in liver transaminases was seen after controlling for confounders such as alcohol exposure and hepatitis c. 15 an italian cohort found an increased frequency of elevated liver transaminases in hiv-seropositive patients who were co-infected with occult hepatitis b. there was a statistically significant increase in hepatitis flares during highly active antiretroviral therapy (haart). in addition, with the discontinuation of lamivudine in these co-infected patients, there were hepatic exacerbations (defined as greater than twofold increase in transaminases from basesline) when compared with hiv-seropositive patients who did not have occult hbv dna (64.7% v. 24.6%, p<0.005).16 if occult hbv dna in hiv is found to be clinically significant, the greater prevalence of hiv/hbv co-infection will have significant consequences for the antiretroviral (arv) treatment programme in resource-poor settings such as southern africa. department of health and human services (dhhs) guidelines and world health organization (who) recommendations for the treatment of hbv include the use of more than one medication active against hbv in combination therapy for hiv infection.17 as mentioned above, diagnosis of chronic hepatitis b may need a variety of testing for accuracy, and serological studies alone may not be adequate. hbv pcr is not readily available in south africa and is very expensive, but could be considered if there is concern about possible occult infection or hbeag-negative chronic hepatitis b. raised levels on liver function tests can be helpful, but ‘normal’ liver function test results do not rule out chronic hepatitis b infection.18 clinical complications of hiv/hbv coinfection as with most co-infections with hiv, there are interactions between the viruses that can affect the clinical course. hiv increases the risk of an acute hepatitis b infection progressing to a chronic active infection (defined as positive hbsag for over 6 months) by at least threefold. these co-infected individuals will have significantly higher hbv viral loads, and hiv-infected individuals will have a higher risk of reactivating the latent hbv infechepatitus b.indd 11 3/16/09 2:16:18 pm s u m m e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 12 tion. occult hepatitis b infection is also seen more commonly in hiv-positive individuals and co-infection may escape diagnosis, especially in resource-limited countries where it is not possible to measure the hbv dna viral load. clinically these viral interactions lead to an increased risk of hepatic cirrhosis caused by hepatitis b and of hepatic-related deaths in hiv patients (hepatocellular carcinoma and cirrhosis) if not treated.14 hepatitis b per se does not interfere with the disease course of hiv, as cd4 immune reconstitution and viral load suppression in patients on haart are similar to those in hepatitis b-negative patients. however, hbv co-infection can increase complications with treatment of hiv patients with haart or other concomitant medications. a retrospective study in miners in south africa showed that hepatotoxicity was more likely to occur with haart initiation if the baseline hbv dna was above 1×104 copies/ml, and a higher proportion of these patients had hepatotoxicity 12 weeks after initiating haart.19 the hiv/hbv-co-infected patients who had the highest degree of hepatotoxicity were taking haart and antituberculosis treatment. patients who were hbsag positive had 100% increase in hepatotoxicity (0.11 to 0.22 proportion of patients) compared with patients on tb medication without hbsag during the first 6 months of tb/arv treatment.3 these hepatic exacerbations can be related to several mechanisms: direct drug-related liver damage, seroconversion from hbeag or hbsag positivity, immune reconstitution in patients with hbsag, and an hbv viral load rebound after effective arv therapy (tenofovir/lamivudine) for hiv/hepatitis b is withdrawn. co-infected patients can also be at increased risk of hepatic steatosis and lactic acidosis from arvs.12,14 careful observation is needed in the co-infected patient if anti-hepatitis b antiretroviral drugs are removed. significant hepatic exacerbations (alanine aminotransferase >200 u/l) were reported in 4% of a european hiv/hbvco-infected cohort, and 1/147 deaths from fulminant hepatic failure (0.7%) occurred. hepatitis exacerbations were seen about 5 8 weeks after removal of the antiretroviral agent. re-institution of the agent in these situations is the treatment of choice.20 clinical follow-up hbv viral load is the major factor that determines progression to liver cirrhosis, hepatocellular carcinoma and death in patients with chronic hepatitis b. however, serum hepatitis b dna is costly and not routinely performed in south africa, especially in the public sector. the degree of liver fibrosis is also important in determining prognosis and treatment decisions. as in mono-infections, the patient with hepatic cirrhosis carries a high risk of developing hepatocellular carcinoma. liver biopsy has been used to stage fibrosis, but more recently new non-invasive methods such as elastometry and serum biochemical indices have been used. neither of these methods is well validated in co-infected patients.21 in the south african public sector context hbv/hiv coinfected patients should have liver function tests 1, 3 and 6 months after initiation of haart, and close monitoring should be performed with any change or discontinuation of haart. education regarding transmission of hepatitis b (including condom use), avoidance of alcohol and herbal medications is needed. all concomitant medications should be reviewed for hepatic toxicity and if possible switched to a less hepatotoxic drug. partners of hbv-infected hiv patients should be evaluated for hbv. if seronegative, they should be vaccinated. serum hbeag and anti-hbe can be used as a limited surrogate marker for hbv dna replication, and a clinical history and examination, measurement of the serum albumin, prothrombin time and platelet count, and an abdominal ultrasound scan can be done to evaluate for liver cirrhosis.14,22 treatment treatment for hbv in hiv-seropositive patients is usually not curative because viral reserves are not eradicated. treatment is done to reduce the hbv dna viral load with the goal of preventing or reducing the risk of liver disease progression, cirrhosis and hepatocellular carcinoma. there are several drugs available for treatment of hepatitis b mono-infection: interferon-alpha, lamivudine, adefovir, tenofovir, emotricitabine, entecavir, telbivudine and interferon.8,14 in public sector ccmt sites in south africa only lamivudine and tenofovir are available for treatment. as the majority of people in south africa come in for evaluation of their hiv late in the disease (the average cd4 count on initiation at the helen joseph clinic is approximately 90 cells/µl), most will need treatment for their hiv. dhhs guidelines recommend treatment for hbv when the viral load is >20 000 iu/ml in hbeag-positive patients and 2 000 copies/ml in hbeag-negative patients.14 however, since hbv dna is not readily available, the clinician should just treat for both infections. patients who need treatment for hbv infection should also be started on a fully suppressive antiretroviral regimen that contains nrtis with activity against hbv including dual therapy for hepatitis b to prevent resistance: for example, tenofovir plus either emtricitabine or lamivudine. monotherapy with lamivudine for hepatitis b in co-infected patients will result in resistance in 60 80% of patients within 12 months. if tenofovir cannot be used, another agent with anti-hbv activity should technically be used in combination with lamivudine or emtricitabine for treatment of hbv infection. however, in the public health sector other drugs are not available.17 hepatitis b infection in hiv-seropositive patients may respond poorly to interferon-alpha, and this drug should not be used in any patient with cirrhosis as it can trigger fulminant liver failure. when patients have failed the first-line therapy for hiv with treatment containing lamivudine, hepatitus b.indd 12 3/16/09 2:16:20 pm s u m m e r 2 0 0 9 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e 14 it is recommended that lamivudine be included in the second-line therapy.8,14 in instances when hiv treatment is not an option or is not desirable, pegylated interferon-alpha (excluding cirrhosis) may be used for the treatment of hbv infection, as it does not lead to the emergence of hiv or hbv resistance. adefovir dipivoxil is active against hbv but not against hiv at the 10 mg dose; however, there is a theoretical risk of development of hiv resistance, as it has anti-hiv activity at higher doses and is related to tenofovir. adefovir is not available in the public sector.17 vaccination benjamin franklin’s ‘an ounce of prevention is worth a pound of cure’ could not have been more prophetic than in the situation of hiv/hbv. with the addition of the hepatitis b vaccination to the expanded programme on immunization (epi) in 1995 for all infants at 6, 10 and 14 weeks, hbv/hiv coinfection will begin to decrease.13 for those who were born before 1995, vaccination is imperative for prevention. in those already infected with hiv, the vaccine is not as effective. with a cd4 count >500 cells/µl the response rate is 87%, and with a count of 200 500 cells/µl it falls to 33%. vaccination is recommended when the cd4 count is above 350 cells/µl. however, vaccination should not be delayed if the cd4 count is low, as there are some patients who do respond with lower cd4 counts. vaccination response rates improve when the hiv viral load is suppressed to <50 copies/µl on haart. doubling the dose of the vaccine from 20 µg to 40 µg per injection or adding a fourth immunisation also helps response rate.22 conclusion hepatitis b co-infection is prevalent in our population and can make haart more complicated. however, most of our patients tolerated haart without difficulty, and with close monitoring the simple combination of tenofovir/lamivudine with efavirenz is very effective in treating both hiv and hepatitis b and should be considered first-line therapy in these patients. references 1. kramvis a, kew mc. epidemiology of hepatitis b virus and its genotypes in africa, and the clinical associations of the genotypes. hepatol res 2007; 37: 9-9. 2. shisana o, rehle t, simbayi l, et al. south african national hiv prevalence, hiv incidence, behaviour and communication survey, 2005. cape town: hsrc press, 2005. 3. hoffmann c, charalambous s, thio c, et al. hepatotoxicity in an african antiretroviral therapy cohort: the effect of tuberculosis and hepatitis b. aids 2007; 21: 1301-1308. 4. lodenyo h, schoub b, ally r, kairu s, et al. hepatitis b and c virus infections and liver function in aids patients at chris hani baragwanath hospital, johannesburg. east afr med j 2000; 77(1): 13-15. 5. firnhaber c, reyneke a, schulze d, et al. the prevalence of hepatitis b co-infection in a south african (sa) urban government hiv clinic. s afr med j 2008; 98: 541544. 6. tshabalala-msimang me, mbewu a, simelela n, et al. operational plan for comprehensive hiv and aids care, management and treatment for south africa. 19 november 2003. 7. dienstag jl. acute viral hepatitis. in: fauci a, braunwald e, kasper d, et al., eds. harrison’s principles of internal medicine. 17th ed. new york: mcgraw-hill, 2008: 1932-1949. 8. keeffe, e, dieterich d, han h, et al. a treatment algorithm for the management of chronic hepatitis b virus infection in the united states. clin gastroenterol hepatol 2004; 2(2): 87-106. 9. owiredu wk, kramvis a, kew mc. molecular analysis of hepatitis b virus genomes isolated from black african patients with fulminant hepatitis. br j med virol 2001; 65(3): 485-492. 10. kimbi gc, kramvis a, kew mc. distinctive sequence characteristics of subgenotype a1 isolates of hepatitis b virus from south africa. j gen virol may (85) 2004 12111120. 11. management of disease control and prevention: updated us public health service guidelines for the management of occupational exposures to hiv and recommendations for postexposure prophylaxis. mmwr morb mortal wkly rep 2005; 54: 1-11. 12. dibisceglie am, kew mc, dusheiko gm, et al. prevalence of hepatitis b virus infection among black children in soweto. bmj 1986; 292: 1440-1442. 13. burnett rj, francois g, kew mc, et al. hepatitis b virus and human immunodeficiency virus co-infection in sub-saharan africa: a call for further investigation. liver int 2005; 25(2): 201-213. 14. thio c. hepatitis b virus infection in hiv-infected persons. current hepatitis reports 2004; 3: 91-97. 15. lo re v 3rd, frank i, gross r, et al. prevalence, risk factors, and outcomes for occult hepatitis b virus infection among hiv-infected patients. j acquir immune defic syndr 2007; 44(3): 315-320. 16. filippini p, coppola n, pisapia r, et al. impact of occult hepatitis b virus infection in hiv patients naïve for antiretroviral therapy. aids 2006; 20: 1253-1260. 17. dhhs panel on clinical practices for treatment of hiv infection. guidelines for the use of antiretroviral agents in hiv-1 infected adults and adolescents, november 2008. http://aidsinfo.nih.gov/guidelines (accessed 13 february 2009. 18. bhattacharya d, katzenstein d, wong a, et al. alanine aminotransferase levels are not significantly elevated in patients with hiv/hbv co-infection and lamivudine resistance. int j std aids 2008; 19(11): 780-781. 19. hoffmann c, charalambous s, martin d, et al. hepatitis b virus infection and response to antiretroviral therapy (art) in a south africa art program. clin infect dis 2008; 47: 1479-1485. 20. bellini c, keisen o, chave jp, et al. liver enzyme elevation after lamivudine withdrawal in hiv-hepatitis b virus co-infected patients: the swiss hiv cohort study. hiv med 2009; 10(1): 12-18. 21. soriano v, puoti m, peters m, et al. care of hiv patients with chronic hepatitis b: updated recommendations from the hiv-hepatitis b virus international panel. aids 2008; 22(12): 1399-1410. 22. dhhs guidelines for prevention and treatment of opportunistic infections in hivinfected adults and adolescents, june 2008. http://aidsinfo.nih.gov (accessed 13 february 2009). hepatitus b.indd 14 3/16/09 2:16:21 pm hiv 902 challenges to delivering quality care in a prevention of mother-to-child transmission of hiv programme in soweto c n mnyani,1 ba, mb chb, fcog (sa); j a mcintyre,1,2 mb chb, frcog 1 anova health institute, johannesburg, south africa 2 centre for infectious diseases epidemiology and research, school of public health and family medicine, university of cape town, cape town, south africa corresponding author: c n mnyani (mnyani@anovahealth.co.za) background. there has been little focus on the quality of care provided in the prevention of mother-to-child transmission (pmtct) of hiv services in south africa (sa). objective. to assess the quality of care in pmtct services in soweto, sa, focusing on the knowledge and experiences of healthcare workers and hiv-infected pregnant women accessing the services. methods. a cross-sectional survey was conducted in november december 2009. a total of 201 hiv-infected pregnant women and 80 healthcare workers from 10 antenatal clinics were interviewed using standardised questionnaires. results. among the hiv-infected pregnant women, the median gestational age was 20 weeks at the first antenatal visit and 32 weeks at the time of the interview. the majority of the women interviewed (71.5%) discovered that they were hiv-infected in the index pregnancy, and 87.9% disclosed their hiv status. overall, 97.5% received counselling and 33.5% were members of a support group. knowledge of antenatal and intra-partum pmtct interventions was accurate in 62.7% and 43.3% of the women, respectively. support group membership and current use of antiretroviral prophylaxis did not impact on the quality of knowledge. of the healthcare workers, 43.8% were professional nurses and 37.5% were lay counsellors. the majority (80.0%) felt satisfied with their knowledge of the pmtct guidelines and 96.3% felt competent in managing hiv-infected pregnant women. yet, there were important deficiencies in the knowledge of the guidelines. conclusion. in our study, the knowledge of pmtct interventions was low in both clients and healthcare workers. this points to the need to improve quality of care in pmtct services, especially with increasingly complex pmtct interventions recommended by international policies. s afr j hiv med 2013;14(2):64-69. doi:10.7196/sajhivmed.902 in the past few years, south africa (sa) has made significant progress in the provision of prevention of mother-to-child transmission (pmtct) of hiv services, both in the delivery of more efficacious pmtct interventions and also an increase in the proportion of women receiving the interventions.1 according to a unaids report, ~95% of hiv-infected pregnant women in sa received some antiretroviral therapy (art) intervention for pmtct in 2010.2 while progress has been made, there are still several challenges in scaling up pmtct services in the sa public healthcare sector. these relate to coverage at different steps of the pmtct cascade, and also to the quality of care rendered in the services. according to a qualitative study documenting women’s experiences of accessing art and pmtct programmes in several facilities in sa, health system weaknesses impacted negatively on access.3 healthcare system and patient factors are important in the scale-up and success of hiv programmes (including pmtct) 4-7 and the availability of interventions alone is not sufficient to guarantee appropriate implementation and uptake.4-5 , 8-9 healthcare facilities need to be well-resourced with competent and motivated staff to provide the services, and there needs to be service uptake and treatment adherence by patients.4-7 the providers’ and patients’ knowledge and attitudes are also important.7 , 8 there is evidence to suggest that the patient-provider relationship may have an effect on decision-making during the antenatal period, and on the uptake of pmtct interventions.10 yet, quality of care has not been a focus in most pmtct services in sa; most are focused on increasing coverage in the pmtct cascade. several reviews have found poor performance and coverage in pmtct programmes, despite the simplicity of some interventions; hence, the focus has been on increasing coverage.5 , 11 , 12 we conducted a cross-sectional survey to investigate key aspects of the quality of care in pmtct services in antenatal clinics in soweto, sa, focusing on the pmtct programme knowledge and experiences of (i) healthcare workers and (ii) hiv-infected pregnant women accessing the services. this was performed against the backdrop of recently updated pmtct guidelines in 2008, when zidovudine (azt) monotherapy became available for prophylaxis.13 methods the study was approved by the human research ethics committee of the university of the witwatersrand. all participants signed written informed consent to participate. until march 2008, all antenatal clinics in soweto had only intrapartum single-dose nevirapine (nvp) for pmtct for pregnant women who were not eligible for life-long art. azt was rolled out in phases across the antenatal clinics in march october 2008. prior to implementation of the guidelines, staff at the antenatal clinics, including lay counsellors, were trained on the new guidelines. the pmtct service at each clinic was staffed by a professional nurse – a ‘pmtct co-ordinator’ in charge of pmtct services, including supervision of lay counsellors. the study was conducted in november december 2009; all facilities had at least 12 months of routine services under the 2008 pmtct guidelines. participating clinics were a mixture of lowand high-volume clinics, with 50 300 pregnant women presenting to each clinic per month. the hiv prevalence was 29% in 2009, and 15 20% of pregnant women were eligible for art under the guidelines in place at the time (criterion: cd4+ count ≤200 cells/μl). hiv-infected pregnant women using consecutive sampling, art-eligible and -ineligible hiv-infected pregnant women presenting to the selected antenatal clinics for repeat visits were interviewed using a structured questionnaire. their experiences of being hiv-infected and their knowledge of available pmtct interventions were determined. eight key-knowledge questions were selected; each was assigned a score of 1 for a correct answer and 0 for an incorrect answer (maximum score of 8). healthcare workers healthcare workers from the same clinics were interviewed using a different questionnaire assessing their opinions and experiences of working in a pmtct programme and their knowledge of the pmtct guidelines. consecutive sampling was used to select participants. similar to the knowledge score devised for patients, a scoring system based on eight key questions was formulated. all interviewers received training on the questionnaire, and all were fluent in the local vernacular languages. data analysis data were analysed using stata version 12.0. descriptive statistics used employed means and standard deviations (sds) or medians and interquartile ranges (iqrs) (for continuous variables) and proportions (for categorical variables). we compared knowledge scores on subgroups using student’s t-tests and fisher’s exact tests. all statistical tests were two-sided (alpha=0.05). results hiv-infected pregnant women a total of 201 hiv-infected pregnant women were interviewed (table 1). the mean age was 27.7 years (sd ±4.8); median gestational age was 20 weeks (iqr 16 24) at the first antenatal visit and 32 weeks (iqr 24 32) at the time of the interview. the majority of women (71.5%) discovered that they were hiv-infected in the index pregnancy. of the women diagnosed in a previous pregnancy, 84.1% (37/44) had previously taken single-dose nvp for pmtct. a baseline cd4+ cell count was available for 92.0% of the participants: median 395 cells/μl (iqr 294 500); mean 420 cells/μl (sd ±190). overall, 87.5% (175/200) of the women had disclosed their hiv status; the majority (90.9%; 159/175) had done so to their partners. this finding did not differ according to timing of hiv diagnosis. of the women who discovered that they were hiv-infected in the index pregnancy, 68.0% had disclosed their status. there were various reasons for non-disclosure to the partner, including fear that the partner would leave, be violent, or accuse the woman of being unfaithful and infecting him with hiv. less than half (45.3%) of the women knew their partner’s hiv status. there was a significant difference in the knowledge of the partner’s hiv status between women who had, and those who had not disclosed their hiv status: 89 (50.9%) v. 0 (0%) knew the partner’s hiv status, respectively (p<0.001). of the partners with known hiv status, 81.3% were hiv-infected. of the women, 62.7% and 43.3% had accurate knowledge on antenatal and intra­partum prophylaxis, respectively. overall, 97.5% (196/201) had received some counselling, 67.7% had received more than one counselling session, 88.6% (178/201) felt that the time spent on counselling was adequate, and 33.5% were part of a support group. there was no significant difference in knowledge between pregnant women who were members of a support group (mean score 5.29; sd ±0.98)), and those who were not (mean score 5.18; sd ±1.41) (p=0.542) (table 2). there was a significant difference in knowledge between women who were already receiving azt prophylaxis (mean score 5.44; sd ±1.18) and those who were not (mean score 4.94; sd ±1.34) (table 3) (p=0.005). healthcare workers of the healthcare workers interviewed, 43.8% were professional nurses and 37.5% were lay counsellors; the majority (81.3%) had been in their current position for longer than a year (table 4). less than a half (47.5%) were satisfied with their working conditions. the most dissatisfaction was in terms of remuneration; only 28.8% were satisfied with their salary. in terms of workload, 80.0% of the workers felt that the new pmtct programme increased their workload, and 92.5% felt that there was a need for more staff for the programme. most healthcare workers were satisfied with their knowledge of the pmtct guidelines (80.0%) and with their general knowledge of hiv/aids (91.3%). in managing hiv-infected pregnant women, 96.3% were satisfied with their competence. training received on the new guidelines was perceived to be adequate by 63.6%. the mean score for the workers’ knowledge of the pmtct guidelines was 5.15 (sd ±1.85): 5.41 (sd ±1.56) for professional nurses v. 5.19 (sd ±1.89) for lay counsellors (p=0.586). there was no significant difference between the mean score of those who were satisfied with their knowledge of the guidelines (5.29; sd ±1.88) and those who were not (4.56; sd ±1.63) (p=0.157) (table 5). there was also no difference between the mean score of healthcare workers who thought that the training they received was adequate (5.10; sd ±1.9) and those who did not (5.14; sd ±1.7) (p=0.926). a high percentage of healthcare workers (86.3%) thought that hiv-infected pregnant women did not disclose their hiv status. there were a number of adverse opinions about hiv-infected women having children: 21.3% of healthcare workers thought that hiv-infected individuals should not have children; 53.8% thought hiv-infected individuals were having too many children; and 46.3% thought that social grants were an incentive for hiv-infected women to have children. discussion in this cross-sectional survey, several challenges were identified in the soweto pmtct programmes. the majority of pregnant women discovered that they were hiv-infected during pregnancy, and although disclosure to partners was high, less than half knew their partner’s hiv status. there were important deficiencies in the women’s knowledge of the available pmtct interventions, despite receiving counselling and their perception that the counselling that they received was adequate. neither the number of counselling sessions received, nor participation in a support group, had an impact on the quality of knowledge. staff in the pmtct programme felt well prepared and well informed prior to the rollout of the updated pmtct programme. the majority thought that the training received was adequate and almost all felt confident about managing hiv-infected women; yet, there were several important gaps in the knowledge of the pmtct guidelines. job satisfaction was low, mostly in terms remuneration. moreover, several staff members expressed negative opinions about hiv-infected women having children. the findings of this cross-sectional survey have important implications for pmtct programmes in sa. routine hiv testing for women, and men, of reproductive age needs to be encouraged, and linkages to care provided for those who test hiv-positive. this is especially important in women who are art-eligible, as they carry a high risk of mother-to-child transmission, and art initiated preconception decreases this risk significantly.14 it will be important to assess the impact of the sa national hiv counselling and testing (hct) drive on testing outside of pregnancy.15 unpublished data from the soweto pmtct programmes indicate that the number of pregnant women presenting for antenatal care with a known hiv-positive status and already receiving art has increased in the past 2 years (c mnyani, unpublished data). the rate of disclosure among hiv-infected pregnant women in this survey was higher than that reported for most of sub-saharan africa, but similar to the findings of another study conducted in sa.16-18 disclosure has been shown to be important in women’s uptake and adherence to pmtct interventions.16 our data on the women’s knowledge of pmtct interventions suggest that the quality of counselling given can be improved. incorrect information, and hence incorrect practices, will be harmful in the context of pmtct and may significantly increase the risk of mother-to-child transmission. while health knowledge is only one component of quality of care, there is evidence to suggest that poor quality of counselling, which translates to poor patient knowledge, is an important contributing factor to non-adherence to pmtct interventions. 5 , 19 poor quality of counselling has been reported even in well-functioning pmtct sites where counsellors, some nurses, had received structured training. 20 the sa public healthcare sector depends on the services of lay counsellors who receive a stipend, and also receive variable training. counselling services are often interrupted, and there is evidence to suggest that this has a negative effect on pmtct services.21 as we scale up pmtct programmes and introduce more complex interventions, staff preparedness, including knowledge, needs to be improved.22 , 23 there needs to be a review and standardisation of training providers, and also of training content. support using trained peers who are experts in hiv care and management has been shown to be an important intervention in building capacity.6 negative staff attitudes towards hiv-infected women also need to be addressed. there is evidence that hiv-infected women who fear and/or experience stigmatisation may avoid participating in pmtct programmes.24 study limitations while our findings do have im­portant implications, there are several limitations to this survey. like all questionnaire-based research, the results may have been influenced by reporting biases. in this case, participants may have felt social desirability to report satisfaction with their pmtct-related knowledge, but this potential bias was unlikely to have influenced their ability to report factual knowledge correctly. in addition, although the study was conduced under a different set of pmtct policy guidelines, the findings are particularly noteworthy given the subsequent implementation of more complex pmtct guidelines in sa and many other parts of africa. the study was conducted in one urban community of high hiv prevalence and with established pmtct services, and the results should be generalised to other settings with caution. healthcare workers were generally reluctant to be interviewed, and this warrants further investigation. also, we used a consecutive sampling strategy; although routine in this form of health services research, this may be more prone to bias than random sampling strategies. there are plans to perform a similar survey to assess experiences with, and knowledge of the latest sa pmtct guidelines. despite the limitations, there are strengths to the survey that warrant merit, including the large number of pregnant women and different categories of staff who were interviewed. conclusion there are still several challenges in pmtct services. most importantly, knowledge of pmtct interventions is surprisingly low in both clients and healthcare providers, and there is a need for enhanced interventions to improve the quality of care in pmtct services. this is particularly important as pmtct interventions become more complex during the anteand postnatal periods. acknowledgements. the anova health institute's soweto pmtct programme is supported by the us president’s emergency plan for aids relief (pepfar) via the us agency for international development (usaid) (cooperative agreement no. 674-a-00-08-00009-00). the views expressed here do not necessarily reflect those of pepfar or usaid. we acknowledge the patients and staff at all the antenatal clinics sampled in soweto. conflict of interest. the authors declare no conflicts of interest. no external funding was used for this study. references 1. unicef 2010. south africa: pmtct. new york: unicef, 2010. http://www.unicef.org/aids/files/safrica_pmtctfactsheet_2010.pdf (accessed 18 november 2011). 1. unicef 2010. south africa: pmtct. new york: unicef, 2010. http://www.unicef.org/aids/files/safrica_pmtctfactsheet_2010.pdf (accessed 18 november 2011). 2. unaids 2011. world aids day report 2011. geneva: joint united nations programme on hiv/aids (unaids) and world health organization (who). http://www.unaids.org/en (accessed 18 november 2011). 2. unaids 2011. world aids day report 2011. geneva: joint united nations programme on hiv/aids (unaids) and world health organization (who). http://www.unaids.org/en (accessed 18 november 2011). 3. sprague c, chersich mf, black v. health system weaknesses constrain access to pmtct and maternal hiv services in south africa: a qualitative enquiry. aids res ther 2011;8:10. [http://dx.doi.org/10.1186/1742-6405-8-10] 3. sprague c, chersich mf, black v. health system weaknesses constrain access to pmtct and maternal hiv services in south africa: a qualitative enquiry. aids res ther 2011;8:10. [http://dx.doi.org/10.1186/1742-6405-8-10] 4. delva w, draper b, temmerman m. implementation of single-dose nevirapine for prevention of mtct of hiv – lessons from cape town. s afr med j 2006;96(8):706-709. 4. delva w, draper b, temmerman m. implementation of single-dose nevirapine for prevention of mtct of hiv – lessons from cape town. s afr med j 2006;96(8):706-709. 5. nkonki ll, doherty tm, hill z, et al. missed opportunities for participation in prevention of mother-to-child transmission programmes: simplicity of nevirapine does not necessary lead to optimal uptake, a qualitative study. aids res ther 2007;4:27. 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[http://dx.doi.org/10.1002/hpm.950] 23. youngleson ms, nkurunziza p, jennings k, et al. improving a mother-to-child hiv transmission programme through health system redesign: quality improvement, protocol adjustment and resource addition. plos one 2010;5(11):e13891. [http://dx.doi.org/10.1371/journal.pone.0013891.s001] 23. youngleson ms, nkurunziza p, jennings k, et al. improving a mother-to-child hiv transmission programme through health system redesign: quality improvement, protocol adjustment and resource addition. plos one 2010;5(11):e13891. [http://dx.doi.org/10.1371/journal.pone.0013891.s001] 24. rahangdale l, banandur p, sreenivas a, et al. stigma as experienced by women accessing prevention of parent-to-child transmission of hiv services in karnataka, india. aids care 2010;22(7):836-842. [http://dx.doi.org/10.1080/09540120903499212] 24. rahangdale l, banandur p, sreenivas a, et al. stigma as experienced by women accessing prevention of parent-to-child transmission of hiv services in karnataka, india. aids care 2010;22(7):836-842. [http://dx.doi.org/10.1080/09540120903499212] abstract introduction case report ethical consideration discussion acknowledgements references about the author(s) leanne swart department of molecular medicine and haematology, national health laboratory service, university of the witwatersrand, south africa elise schapkaitz department of haematology, national health laboratory service, university of the witwatersrand, south africa anima baiden department of molecular medicine and haematology, national health laboratory service, university of the witwatersrand, south africa citation swart l, schapkaitz e, baiden a. a case of a drug reaction to sulfasalazine in a patient infected with hiv. s afr j hiv med. 2018;19(1), a829. https://doi.org/10.4102/sajhivmed.v19i1.829 case report a case of a drug reaction to sulfasalazine in a patient infected with hiv leanne swart, elise schapkaitz, anima baiden received: 03 jan. 2018; accepted: 04 july 2018; published: 03 dec. 2018 copyright: © 2018. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract introduction: the diagnosis of drug reaction with eosinophilia and systemic symptoms (dress) in human immunodeficiency virus (hiv) patients on multiple drugs with concomitant disorders presents a diagnostic challenge. patient presentation: we describe a case of a drug reaction to sulfasalazine in a 46 year old hiv-infected female with concurrent rheumatoid arthritis which presented atypically with a marked peripheral blood plasmacytosis mimicking a lymphoproliferative neoplasm. management and outcome: a diagnosis of dress was made in conjunction with the laboratory and clinical presenting findings. sulfasalazine was immediately discontinued. the mucocutaneous rash and systemic symptoms (which included fever, lymphadenopathy and multi-organ dysfunction) resolved with supportive treatment. this included topical and systemic corticosteroids. conclusion: in conclusion, it is important to consider drug reactions when evaluating patients infected with hiv. introduction drug reaction with eosinophilia and systemic symptoms (dress) is a severe adverse drug reaction. drug hypersensitivity reactions are common in patients infected with human immunodeficiency virus (hiv), secondary to drugs prescribed for the treatment of hiv and for the prevention of opportunistic illnesses. the diagnosis of dress in hiv patients on multiple drugs with concomitant disorders presents a challenge. we present an unusual case of a drug reaction to sulfasalazine in a patient infected with hiv with concurrent rheumatoid arthritis (ra), which presented as a marked peripheral blood plasmacytosis. case report a 46-year-old female patient with ra, known to the charlotte maxeke academic hospital’s rheumatology outpatient department, presented with a one-week history of fever (> 38 °c) and a generalised skin rash requiring hospitalisation. she gave a history of starting sulfasalazine two weeks prior, for the management of ra. she had no known allergies. on past medical history, she was also hiv-positive with an absolute cd4+ count of 411 cells/µl and a lower than detectable viral load. other chronic medications (for > 3 months) included hydroxychloroquine for ra, risperidone for psychiatric manifestations of hiv, and antiretroviral therapy, namely tenofovir, lopinavir with ritonavir, and lamivudine. on examination, she was found to have significant (> 1.5 cm) bilateral cervical and left submental lymphadenopathy associated with severe periorbital oedema. on skin and mucosal examination, her palms and soles were indurated, her lips showed superficial mucosal erosions and there were widespread urticarial papules and target lesions on her face, trunk and extremities. a differential diagnosis including erythema multiforme major, vasculitis and acute drug eruptions such as steven-johnson syndrome and toxic epidermal necrolysis were considered. baseline laboratory investigations were performed (table 1). the full blood count (fbc) revealed a leucocytosis with a lymphocytosis and eosinophilia. the peripheral blood smear (pbs) demonstrated 31% atypical lymphocytes and plasmacytoid lymphocytes (figure 1). a lymphoproliferative neoplasm associated with hiv infection was considered. flow cytometry of the peripheral blood was performed. immunophenotypic analysis revealed a population of 20% – 25% reactive plasma cells with a range of cd138 (dim to +++) expression (figure 2) and no light chain restriction (figure 3). in addition, there were ~26% – 28% reactive t-cells and ~8% polyclonal b-cells (figure 3). polymerase chain reaction analysis for the immunoglobulin heavy-chain gene rearrangement studies was polyclonal. these findings demonstrate no evidence of a b-cell lymphoproliferative disorder. figure 1: giemsa-stained peripheral blood smear at ×100 magnification showing plasmacytoid (arrow) and atypical lymphocytes (circle). lymphocytes ranged from small to intermediate in size with deeply basophilic cytoplasm, eccentric nuclei and nuclear folding. figure 2: immunophenotypic analysis of the peripheral blood performed on a dual laser facscalibur equipped with cellquest pro and paint-a-gate pro software. cd19 is the monoclonal antibody on fitc and cd138 is the monoclonal antibody on pe. there is a population of ~20% – 25% plasma cells (yellow) which express a range of cd138 and cd19, and a population of ~20% b-cells (red) as defined by cd19 expression only. figure 3: immunophenotypic analysis of the peripheral blood performed on a dual laser facscalibur equipped with cellquest pro and paint-a-gate pro software. kappa is the monoclonal antibody on fitc, and lambda is the monoclonal antibody on pe. there is a population of polyclonal plasma cells (yellow population), polyclonal b-cells (violet population) and t-cells (cyan). table 1: baseline laboratory investigations. further laboratory and radiologic investigations supported the diagnosis of dress syndrome (table 2).1 the chest x-ray revealed bilateral interstitial lung infiltrates in keeping with pneumonitis. the liver function tests (lft) were abnormal (table 1). serology for hepatitis studies was negative. additional viral studies and a skin biopsy were not performed, at the discretion of the treating physician. table 2: clinical and laboratory presentation criteria. sulfasalazine was immediately discontinued. administration of promethazine, montelukast as well as intravenous and topical hydrocortisone led to a dramatic improvement. the clinical manifestations resolved and the patient was discharged. on outpatient follow-up, laboratory investigations, namely fbc, pbs and lft, had returned to baseline. ethical consideration ethics was indeed obtained from the university of the witwatersrand’s ethics committee. this was a retrospective case report and consent was therefore not a requirement. discussion drug reaction with eosinophilia and systemic symptoms, also known as drug-induced hypersensitivity syndrome, is an adverse drug reaction commonly associated with numerous drug classes, including anticonvulsants, sulphonamides, antidepressants, anti-inflammatory drugs, antibiotics, angiotensin-converting enzymes and beta blockers.1 the last drug prescribed may not always be the offending drug, as the hypersensitivity reaction has a delayed onset of up to three months. this is often difficult in patients infected with hiv on multiple drugs. further, these patients are at high risk of developing concomitant opportunistic infections, and dress often mimics non-specific infections. it is thus always important to keep drug history in mind when evaluating patients infected with hiv. drug hypersensitivity reactions are common in patients infected with hiv. drugs prescribed for the treatment of hiv, namely reverse transcriptase inhibitors and protease inhibitors, as well as drugs for the prevention of opportunistic illnesses, namely sulphonamides, dapsone and anti-tuberculosis drugs, predispose these patients to drug reactions.2,3 in addition, there are numerous reports of adverse drug hypersensitivity reactions in this patient population to other drug classes. drug reaction with eosinophilia and systemic symptoms associated with sulfasalazine in a patient infected with hiv to our knowledge has not been previously reported. sulfasalazine is a modified sulphonamide composed of sulfapyridine covalently linked to 5-aminosalacyclic acid for the treatment of ulcerative colitis and ra. the pathogenesis of dress is not fully understood. in most drugs implicated in dress, an association with lymphocyte activation, genetic drug metabolising enzyme defects or eosinophilic tissue infiltration has been described.4,5 a deficiency of detoxifying enzymes results in the accumulation of drug metabolites.4 certain human leucocyte antigen (hla) alleles may predispose to drug reactions because of naïve t-cells recognising a hla–hapten complex on an antigen-presenting cell with a subsequent hyperactive immune response.2 more recently, reactivation of human herpes virus family has been associated with the diagnosis of a more severe form of dress, namely drug-induced hypersensitivity syndrome.6 the diagnosis of dress is based on laboratory and clinical criteria. however, there is a significant overlap with other reactive and malignant disorders. classical haematologic abnormalities include a leucocytosis, eosinophilia and atypical lymphocytosis.7 reactive plasma cells in the peripheral blood have been described in single case reports; however, a marked plasmacytosis as described in this case is rare. a marked peripheral blood plasmacytosis is characteristically associated with haematological malignancies such as plasma cell neoplasms and terminally differentiated mature lymphoproliferative b-cell neoplasms. in the setting of hiv, plasmacytoid and atypical lymphocytes are frequently described; however, plasma cells on pbs are also a rare finding.8 infections with other viruses such as epstein-barr virus, parvovirus, hepatitis or cytomegalovirus should also be excluded. the most common clinical findings are a mucocutaneous rash with or without systemic symptoms which include fever, lymphadenopathy and multi-organ dysfunction. as described in this patient, the most commonly involved internal organ is the liver.5 other organs such as the kidney, lungs, heart or central nervous system are rarely involved.3 this is associated with a significant morbidity and a mortality of up to 10%, if the precipitating drug is not immediately discontinued.3 supportive treatment, which depends on the severity of the clinical signs, is the mainstay of treatment. isolated mucocutaneous involvement usually responds to topical corticosteroids, whereas systemic corticosteroids may be indicated in the presence of severe mucocutaneous lesions or other organ involvement. the role for systemic corticosteroids in patients with liver impairment, however, is not well established.4 counselling of family members for a possible genetic susceptibility to dress is also advised. in conclusion, this case report describes a drug reaction to sulfasalazine which presented atypically with a marked peripheral blood plasmacytosis mimicking a lymphoproliferative neoplasm. the diagnosis of dress in hiv-positive patients on multiple drugs with concomitant disorders presents a diagnostic dilemma. it is important to consider drug reactions when evaluating patients infected with hiv. acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions l.s., e.s. and a.b. contributed to the writing of the article. l.s. and e.s. contributed to the concept and design and interpretation of this study. references kardaun sh, sidoroff a, valeyrie-allanore l, et al. variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a dress syndrome really exist? br j dermatol. 2007;156(3):609–11. https://doi.org/10.1111/j.1365-2133.2006.07704.x criado pr, criado rfj, avancini j, santi cg. drug reaction with eosinophilia and systemic symptoms (dress)/drug-induced hypersensitivity syndrome (dihs): a review of current concepts. an bras dermatol. 2012;87(3):435–449. https://doi.org/10.1590/s0365-05962012000300013 cacoub p, musette p, descamps v, et al. the dress syndrome: a literature review. am j med. 2011;124:588–597. https://doi.org/10.1016/j.amjmed.2011.01.017 choudry s, mcleod, m, romanelli, p. drug reaction with eosinophilia and systemic symptoms (dress) syndrome. j clin aesthet dermatol. 2013;6(6):31–37. kano y, shiohara t. sequential reactivation of herpesvirus in drug-induced hypersensitivity syndrome. acta derm venereol. 2004;84:484–485. https://doi.org/10.1080/00015550410016976 yoshikawa t, fujita a, yagami a, et al. human herpesvirus 6 reactivation and inflammatory cytokine production in patients with drug induced hypersensitivity syndrome. j clin virol. 2006;37 suppl 1:s92–s96. https://doi.org/10.1016/s1386-6532(06)70019-1 gentile i, talamo m, borgia g. is the drug-induced hypersensitivity syndrome (dihs) due to herpesvirus 6 infection or to allergy-mediated viral reactivation? report of a case and literature review. bmc infect dis. 2010;10:49. https://doi.org/10.1186/1471-2334-10-49 opie j. haematological complications of hiv infection. s afr med j. 2012;102(6):465–468. https://doi.org/10.7196/samj.5595 abstract introduction methods ethical consideration results discussion conclusion acknowledgements references about the author(s) geoffrey jobson anova health institute, south africa moyahabo mabitsi anova health institute, south africa jean railton anova health institute, south africa cornelis j. grobbelaar anova health institute, south africa james a. mcintyre anova health institute, south africa school of public health and family medicine, university of cape town, south africa helen e. struthers anova health institute, south africa division of infectious diseases and hiv medicine, department of medicine, university of cape town, south africa remco p.h. peters anova health institute, south africa citation jobson g, mabitsi m, railton j, et al. targeted mentoring for human immunodeficiency virus programme support in south africa. s afr j hiv med. 2019;20(1), a873. https://doi.org/10.4102/sajhivmed.v20i1.873 original research targeted mentoring for human immunodeficiency virus programme support in south africa geoffrey jobson, moyahabo mabitsi, jean railton, cornelis j. grobbelaar, james a. mcintyre, helen e. struthers, remco p.h. peters received: 18 may 2018; accepted: 16 nov. 2018; published: 14 feb. 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: mentoring is a required component of health systems strengthening technical assistance interventions in lowand middle-income countries (lmics). mentoring is useful because it does not necessarily compromise service delivery and promotes the sharing of newly acquired knowledge and skills. however, there is a lack of research on the implementation of mentoring in the context of the hiv epidemic in southern africa. objectives: this qualitative evaluation focussed on understanding the implementation process of targeted mentoring for clinical practice, data management and pharmacy management, at public health care facilities in south africa; and on identifying critical factors influencing the effectiveness of mentoring as a technical assistance intervention in this context. methods: purposive sampling was used to select participants from public health facilities in three south african provinces. participants were invited to take part in structured interviews. datawere analysed using thematic analysis, and two core themes were identified: mentoring as knowledge and skills transfer; and mentoring as psychosocial support. results: in terms of knowledge and skills transfer, the sequential implementation of proactive and reactive mentoring was critical. initial proactive mentoring involved mentors initiating training and developing professional relationships with mentees. thereafter, a reactive mentoring phase allowed mentees to request support when required. this enabled mentors to leverage real-world problems faced by health workers to support their implementation of new knowledge and skills. the availability and accessibility of mentors alongside the relationships between mentors and mentees provided psychosocial support for health care workers which facilitated their self-efficacy in implementing new knowledge and skills. conclusion: these findings suggest that the success of mentoring programmes in lmics may require specific attention to both knowledge transfer and the management of interpersonal relationships. introduction the mentoring of clinical staff has become an important aspect of the human immunodeficiency virus (hiv) response in many lowand middle-income countries (lmics). using mentors to support local staff enables implementing agencies and governments to target specific cadres of health workers to develop and entrench the skills and knowledge required to successfully implement interventions.1 mentoring has also played an important role in supporting task shifting of particular functions from doctors to mid-level staff such as nurses, counsellors and medical officers.1 using mentoring as a component of technical assistance interventions is beneficial because it does not compromise service delivery and promotes the sharing of newly acquired knowledge and skills.2 ndwiga et al. also note that workplace mentorship has been found to increase confidence and self-esteem, decrease stress and conflict, and improve job satisfaction among mentees.2 while mentoring has the potential to significantly improve service provision, there are a number of important features of the mentor-mentee relationship that may affect the relative success of such programmes. straus et al. for example, found that successful mentoring relationships were characterised by reciprocity, mutual respect, clear expectations, a personal connection and shared values.3 factors related to the context of local health systems may also affect the success or failure of mentoring initiatives. in kenya, for example, ndwiga et al. found that the effectiveness of mentoring was affected by erratic supplies of medication and commodities, high client caseloads and staff shortages.2 mentoring programmes supporting the scale-up of hiv treatment in sub-saharan africa (ssa) have frequently focussed either on mentoring clinical staff or on supporting administrative and logistical processes.1,4,5,6 while these programmes have shown impressive results, their focus on either clinical or administrative processes may lead to constraints in their effectiveness. therefore, we explore the role of targeted mentoring using a needs-based approach to support both clinical and some administrative processes as part of a technical assistance package targeting hiv and tuberculosis (tb) services at public healthcare facilities in three provinces of south africa. methods study setting the study was conducted at selected health facilities in limpopo, gauteng and the western cape. facilities in limpopo and the western cape were situated in rural districts, while the gauteng facilities were located in peri-urban townships. all facilities had been receiving technical assistance from anova health institute (hereafter referred to as ‘the implementing agency’) since 2010, and most had previously been sites where the agency had directly provided hiv-related services. the implementing agency’s hiv and tb-related health systems strengthening (hss) support activities were primarily funded by usaid/pepfar. in 2009, pepfar’s focus shifted away from direct service provision towards technical assistance and hss.7 hence, the focus of the implementing agency’s work between 2009 and 2014 was on hss and the provision of technical support to the south african government’s hiv response, with staff mentoring forming a central aspect of this support. mentoring was provided to nurses to assist with the implementation of nurse initiated and managed art (nimart); to data capturers and administrators to assist with managing the art (antiretroviral therapy) programmes reporting requirements; and to pharmacy staff to support efficient stock control and pharmacy management. theoretical framework this study was informed by literature focussing on mentoring as a broad approach to individual and organisational development in various contexts,8,9 as well as research focussing more specifically on mentoring in the context of technical assistance programmes in lmics.2,5,10 this literature was reviewed in reference to the world health organization’s 200611 recommendations on the use of clinical mentoring to support hiv programme implementation in resource-limited settings. study design this study is a qualitative evaluation of the role of mentoring as part of a technical assistance package targeting hiv and tb services as provided by the implementing agency at public healthcare facilities in three south african health districts. structured interviews to explore health workers’ perceptions of the implementing agency’s mentoring programme were conducted by independent consultants with 74 participants (both male and female) from government health facilities in limpopo province, gauteng and the western cape. interviews were conducted in person, in private rooms at individual facilities, between october 2014 and july 2015. refusal rates were very low, with only five participants refusing to participate in interviews as a result of repeatedly being unavailable or having to attend to urgent medical problems in their facilities. participants were purposively selected based on their involvement in the technical assistance programme. interviews were conducted with facility managers and their deputies, nurses, pharmacists and data staff. while the evaluation included questions relating to the entire technical assistance package, this article focusses on understanding healthcare workers’ perceptions of the mentoring component of the package. signed informed consent was obtained from all participants prior to their participation. to maintain anonymity of respondents, no identifying information was collected. the study protocol and materials were approved by the university of the witwatersrand’s human research ethics committee (m120625). data analysis interviews were audio-recorded and transcribed verbatim. data were managed using nvivo 1112 and were analysed using a thematic analysis approach.13 firstly, interview transcripts were read carefully while paying particular attention to discussion related to the mentoring programme. once the two authors responsible for data analysis were familiar with the data set, initial coding was conducted independently by each author to identify units of text with relevance to the research topic. text units dealing with the same issue were grouped together in an initial set of themes and 48 basic themes were interpreted from the data in this stage. the same unit of text could be included in more than one theme. these themes were then discussed and refined in relation to both the coded content of the basic themes, and the data set as a whole, in order to create a coherent set of organising themes. five organising themes were produced in this stage of analysis. finally, these organising themes were analysed to develop two main themes related to the role of the implementing agency’s mentoring programme in implementing hiv-related services. these were: (1) targeted mentoring as knowledge and skills transfer and (2) mentoring as psychosocial support. ethical consideration signed informed consent was obtained from all participants. the study protocol was approved by the university of the witwatersrand’s human research ethics committee (reference number: m120625). results mentoring as knowledge and skills transfer the targeted mentoring programme focussed on supporting three main aspects of the south african department of health’s (doh) antiretroviral therapy (art) scale up. these were: nimart, pharmacy management and data management. the mentoring programme adopted a two-stage approach, which we classified as proactive and reactive mentoring.14 proactive mentoring proactive mentoring involved scheduled visits to health facilities by mentors. during these visits, several activities took place, which were noted as important by the doh staff. for professional nurses being trained to initiate art, an important feature of the mentoring visits was having nurse-mentors accompany them during consultations with patients. in this role, mentors were able to provide bridging support between off-site training courses and the actual implementation of the skills learnt on these courses. this was particularly important because initiating and managing art was a significant increase in nurses’ responsibilities in the context of hiv treatment and care: ‘i think the mentoring system is good and it is needed … art initiation is difficult so the mentoring has helped.’ (nurse 1, johannesburg) supporting nurses in learning to initiate art, and to manage the care of patients on art, was a critical feature of participants’ discussions about the role of the mentoring programme, and several participants discussed the knowledge they had gained through the training and mentoring process as empowering them to take on a more active role in treating hiv-positive patients required by the nimart programme: ‘… before i was scared of patients who had hiv/aids, i was scared and immediately after i was trained i had power and now i can do it and even critically ill patients are living healthy lives.’ (deputy facility manager 1, limpopo) several participants also discussed support from the implementing agency in terms of their mentors’ roles in assessing and evaluating their practice. in this context, the mentors’ presence facilitated the application of the skills learnt through nimart training: ‘and [mentors] come for mentoring us for treatment and checking if we have difficulties. if i have a patient and want to initiate and i am taking the baseline to find the patient is in bad condition they check if we are coping.’ (nurse 3, limpopo) the mentors’ roles in assessing participants’ progress was also discussed by pharmacists, pharmacy assistants and data staff as an important aspect of the mentoring programme. in assessing the application of knowledge and skills, the mentors created a platform from which to provide ongoing training and support to these staff. this process of ‘checking’ was an important means of jointly identifying areas in which staff needed more support: ‘… mostly [mentors] come to check how we pack treatment and make sure that if over-stocking arrange the drugs so we use the old ones first, and they come and check the data capturer …’ (deputy facility manager 2, johannesburg) ‘they do the stock checks of arvs and the other stock. they also available on the phone to help with stock control. [name] helps to ensure the stock in the pharmacy is arranged logically.’ (pharmacist 1, winelands) ‘we get support from [the implementing agency]. when they come and check the computers and check the data and check the data is clear.’ (data capturer 1, johannesburg) while proactive mentoring was generally appreciated by the doh staff, for the mentoring programme to operate successfully in this role, clear interpersonal communication and relationship management on the part of the mentors were critical. where these factors were perceived to be absent, the doh staff found the programme less useful: ‘you just see them here and they say they here for support visit but there is no programme around their visits as we don’t know when they are coming and cannot plan around it. they just come and you might not be ready for them and therefore the visit does not become fruitful. if we knew when they were coming then we could plan the problems we are having.’ (facility manager 1, limpopo) ‘they don’t consult with me and that is one of the challenges.’ (facility manager 1, johannesburg) ‘they have not told us that they are not capturing the data anymore.’ (data capturer 2, johannesburg) a further challenge in terms of proactive mentoring occurred when implementing agency staff took on a direct service delivery role, and in doing so prevented the doh staff from applying their training. a participant in the winelands, for example, reported that the nurse mentor tended to do the clinical work herself, rather than allowing her mentees to practice and gain experience: ‘[name] does the work but does not explain what she is doing … she does more clinical work than a mentor should do.’ (facility manager 3, winelands) reactive mentoring a second theme highlighted from study participants’ discussion around the mentoring programme related to mentors’ roles as problem solvers and sources of on-demand support. we termed this reactive mentoring.14 to facilitate this, mentors provided mentees with their contact information to enable them to ask for assistance as and when they needed it. this aspect of the mentoring programme was important as an enabling mechanism for participants, particularly for nurses who were beginning to initiate and manage patients on art: ‘… we phone if we have problems and when they come there are issues we ask them and they come frequently and help us with problems and how do we deal with it.’ (facility manager 4, johannesburg) ‘[the mentor] gives technical support whenever i have a problem, i call or they visit and whatever challenges i face they come.’ (data capturer 2, limpopo) in this reactive role, mentors were able to facilitate skill building and knowledge transfer by ensuring that they were available to assist the doh staff when the need arose; and participants noted that mentors used the opportunities provided by the doh staff contacting them to build on the knowledge they gained through training: ‘last week there was a patient here and we called [name] and she consulted with another doctor and came back to me to do in-service training and teach us about the hiv virus and how deal with the patients.’ (facility manager 1, limpopo) ‘[name] is my mentor and she regularly comes to check my defaulter list – every problem i come across she is there to help … there was a duplication of patients and she helped.’ (data capturer 3, gauteng) while the doh staff clearly valued the role of the implementing agency’s mentors, the implementation of reactive mentoring required careful attention to the level and type of assistance requested by healthcare workers to ensure that mentees continued to develop their own skills and did not become overly dependent on their mentors, for example: ‘they help me with a lot of things i cannot work without them.’ (nurse 4, johannesburg) a second challenge in terms of reactive mentoring was that because they were each responsible for several health facilities, mentors were sometimes unavailable when their help was needed. this had the potential to become problematic as it could result in a breakdown in trust between mentors and mentees: ‘they used to come but now that they have to service other clinics it is minimal.’ (nurse 7, limpopo) both proactive and reactive mentoring contributed to the ability of the doh staff to implement the knowledge and skills gained through attending training courses and workshops. however, in addition to this, our interpretation of participant interviews suggested that the mentorship programme also played an important empowering role for staff by providing a source of psychosocial support as they took on new responsibilities. mentoring and psychosocial support the role of mentors in providing psychosocial support was most important among nurses who were beginning to initiate art. there were several ways in which the mentorship programme provided psychosocial support to these staff. firstly, simply knowing that mentors were available to assist in problem-solving was important in enabling participants to implement their training. the idea that their mentors were ‘just a phone call away’ allowed them to take on this role without undue fear that they would cause harm to their patients: ‘with complicated cases i like to know that [i] can phone [the implementing agency].’(facility manager 1, johannesburg) ‘i’m being mentored at the moment, and it really helps to know the doctor is there.’ (nurse 3, johannesburg) participants’ willingness to contact their mentors when they experienced problems was also a result of trust and support that mentors built up when interacting with the doh staff when they were asked for help: ‘and when my mentors come and evaluate me they don’t complain, they just guide.’ (nurse 2, limpopo) ‘they give us a listening ear … they do not come to find mistakes but to give us support and information to have team work spirit.’ (deputy facility manager 2, limpopo) these quotes also point to the importance of developing personal relationships between mentors and mentees which in turn meant that participants felt comfortable enough to contact their mentors when they needed help. a second important way in which the mentoring programme provided psychosocial support to the doh staff was by facilitating an improvement in health workers’ self-efficacy for implementing their training and managing the initiation of art without having doctors present: ‘i am like a doctor in the clinic as i can initiate.’ (nurse 5, limpopo) ‘i feel it empowered me through what i learnt and learn every day.’ (nurse 7, limpopo) finally, several nurses discussed how their mentors provided an emotional outlet, which allowed them to deal with the stress of taking on the responsibility of initiating and managing patients on art: ‘and the mentors come and encourage us as sometimes we get depressed when patients stop taking drugs.’ (nurse 2, limpopo) ‘their support is helpful, and if we are feeling stressed we offload.’ (nurse 1, limpopo) discussion the use of mentoring as an integral part of the implementing agency’s technical assistance programme appears to be successful in facilitating healthcare workers’ implementation of knowledge and skills gained through training. based on our interpretation of evaluation interviews conducted with healthcare workers, we suggest several attributes of the programme contributed to this success. firstly, the mentoring programme used a multifaceted approach to supporting the health system. the implementing agency’s prior service delivery in the three provinces led them to identify key bottlenecks to art implementation, and the mentoring programme was therefore designed to support the clinical, administrative and pharmacy facets of the health system simultaneously. chien et al. studied a similar approach to mentoring in malawi and found that supplementing clinical mentoring with support for facility and district-level systems improved the overall impact of the mentoring programme.15 our findings suggest that health facility staff value these broader approaches to mentoring that include non-clinical staff as they may facilitate an overall improvement in services available to patients while simultaneously limiting constraints to the impact of clinical mentoring resulting from administrative or pharmacy-related problems. however, this approach does not address broader health system management issues, which edwards et al. suggest may further improve patient outcomes.6 a second important attribute of the mentoring programme was the fact that the programme adopted a sequential proactive and reactive approach, which allowed mentors to leverage real-world problems faced by health workers to support their implementation of new knowledge and skills. the sequence of implementing the proactive and reactive aspects of the programme directly affected the effectiveness of mentoring. it was important that initial proactive mentoring occurred to build trust and relationships between mentors and mentees. based on these relationships, health workers were comfortable enough to ask for help (i.e. to initiate reactive mentoring) when they needed it. where mentors did not build relationships with mentees sufficiently, there appeared to be less willingness to ask for support. the development of trusting relationships between mentors and mentees as a prerequisite for successful mentoring relationships is a common finding in the mentoring literature.3,16,17,18 in the context of hss in ssa, edwards et al.6 found that mutual trust between implementing agency and mozambique doh staff based on an open and collaborative relationship was a critical enabling factor supporting the success of health management mentoring. the importance of developing trusting mentoring relationships during proactive mentoring phases of programme implementation should therefore be emphasised to mentors during the preparatory stages of these programmes. finally, mentors played an important role in providing psychosocial support to nurse mentees in particular. psychosocial support was important because it helped nurses to develop the self-confidence to apply their nimart training and to take responsibility for managing the ongoing care of patients on art without direct supervision. there were several ways in which the mentoring programme was able to provide this type of support. simply having the knowledge that mentors were available if they needed them enabled nurses to initiate patients onto art without excessive anxiety about managing side effects or complications. mentors also played an important role in providing psychosocial support by providing a means for nurses to deal with the stress of managing patients on art. here, the personal relationships between mentors and mentees were critical, and several participants noted how important their mentors’ caring and supportive attitudes were in helping them to gain confidence in implementing their new skills and knowledge. although psychosocial support has long been recognised as a critical aspect of mentoring relationships, there is relatively little research conducted on the role of psychosocial support for mentees in health system-related interventions in lmics.8 more broadly, however, eller et al. found that a ‘caring personal relationship’ was an important aspect of effective mentoring relationships among nurses in the us, and the emotional support provided by mentors in other contexts has been found to improve mentees’ self-efficacy and emotional well-being.18,19 our findings support the value of the mentor-mentee relationship as a source of psychosocial support. this suggests that the effectiveness of art scale-up using mentoring programmes could potentially be improved by paying particular attention to the development of supportive relationships within these interventions. there are some limitations to our study that may have affected our interpretation of the data. firstly, our data only included interviews with the doh staff; as such it is possible that we would have reached different conclusions if interview data were available from mentors and other implementing agency staff. secondly, the authors are employed by the implementing agency, and while we made a conscious effort to remain objective, it is possible that our interpretations of the data were skewed by our personal investment in the mentoring programme. in spite of these limitations, this study is among the first to examine the role of mentoring in strengthening hiv and tb programmes in south africa. by identifying key factors supporting and limiting the success of the mentoring programme, this study may provide important lessons for the implementation of similar programmes elsewhere. conclusion mentoring is a well-recognised and frequently used means of providing technical assistance in health-related interventions around the world.6 however, the likelihood of success of mentoring programmes depends on the dual role of mentors as supporting the proactive and reactive transfer of knowledge and skills to mentees, while simultaneously providing the psychosocial support necessary for mentees to develop the confidence to apply these in practice. where this balance in mentors’ dual role is successfully achieved, mentoring is likely to be a powerful tool to improve healthcare globally. acknowledgements the authors wish to thank carmel marock and candice harrison-train for managing the data collection process. this study is made possible by the generous support of the american people through the us president’s emergency plan for aids relief (pepfar) through the united states agency for international development (usaid) under cooperative agreement number 674-a-12-00015 to the anova health institute. the contents are the responsibility of anova health institute and do not necessarily reflect the views of usaid or the united states government. the funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. competing interests the authors declare that they have no financial or personal relationship(s) which may have inappropriately influenced them in writing this article. authors’ contributions g.j. and r.p.p.h. conducted the data analysis. g.j. wrote the manuscript. m.m., j.r. and c.j.g. supported the data collection process and provided in-depth comments and reviews on the manuscript. h.e.s. and j.a.m. reviewed the manuscript and provided comments and input on all versions. references morris mb, chapula bt, chi bh, et al. use of task-shifting to rapidly scale-up hiv treatment services: experiences from lusaka, zambia. bmc health serv res. 2009;9:5. https://doi.org/10.1186/1472-6963-9-5 ndwiga c, abuya t, mutemwa r, et al. exploring experiences in peer mentoring as a strategy for capacity building in sexual reproductive health and hiv service integration in kenya. bmc health serv res [serial online; cited n.d.]. 2014;14:98. available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3942326&tool=pmcentrez&rendertype=abstract straus se, johnson mo, marquez c, feldman md. characteristics of successful and failed mentoring relationships: a qualitative study across two academic health centers. acad med. 2013;88(1):82–89. https://doi.org/10.1097/acm.0b013e31827647a0 fatti g, rundare a, pududu b, et al. an innovative approach to improve the quality of prevention of mother-to-child transmission of hiv programs through nurse … an innovative the quality of programs through nurse clinical mentoring in south. j acquir immune defic syndr. 2013;63(2):e76–e78. https://doi.org/10.1097/qai.0b013e31828f5a5c workneh g, scherzer l, kirk b, draper hr, tolle ma. evaluation of the effectiveness of an outreach clinical mentoring programme in support of paediatric hiv care scale-up in botswana. aids care. 2013;25(1):11–19. https://doi.org/10.1080/09540121.2012.674096 edwards lj, moisés a, nzaramba m, et al. implementation of a health management mentoring program: year-1 evaluation of its impact on health system strengthening in zambézia province, mozambique. int j heal policy manag [serial online; cited n.d.]. 2015;4(6):353–361. available from: https://doi.org/10.15171/ijhpm.2015.58 pepfar. pepfar transition 2009–2013. washington, dc: usaid; 2016. kram ke. mentoring at work. boston, ma: scott, foresman; 1985. eby lt, allen td, evans sc, ng t, dubois dl. does mentoring matter? a multidisciplinary meta-analysis comparing mentored and non-mentored individuals q. j vocat behav. 2008;72:254–267. https://doi.org/10.1016/j.jvb.2007.04.005 moon td, edwards lj, vermund sh. health management mentoring for health systems strengthening: a response to recent commentaries. kerman univ med sci [serial online; cited n.d.]. 2015;4(11):793–794. available from: https://doi.org/10.15171/ijhpm.2015.179 world health organization. who recommendations for clinical mentoring to support scale-up of hiv care, antiretroviral therapy and prevention in resource-constrained settings. geneva: who; 2006. qsr international pty. ltd. version 11. nvivo 11 qualitative data analysis software. london: qsr international; 2015. braun v, clarke v. using thematic analysis in psychology. qual res psychol [serial online; cited n.d.]. 2006;3(2):77–101. available from: http://www.tandfonline.com/doi/abs/10.1191/1478088706qp063oa ray ml, wilson mm, wandersman a, meyers dc, katz j. using a training-of-trainers approach and proactive technical assistance to bring evidence based programs to scale: an operationalization of the interactive systems framework’s support system. am j community psychol. 2012;50(3–4):415–427. https://doi.org/10.1007/s10464-012-9526-6 chien e, phiri k, schooley a, chivwala m, hamilton j, hoffman rm. successes and challenges of hiv mentoring in malawi: the mentee perspective. plos one. 2016;11(6):e0158258. https://doi.org/10.1371/journal.pone.0158258 barker er. mentoring – a complex relationship. j am acad nurse pract. 2006;18:56–61. https://doi.org/10.1111/j.1745-7599.2006.00102.x erdem f, aytemur jo. mentoring – a relationship based on trust: qualitative. public pers manage. 2015;37(1):55–65. https://doi.org/10.1177/009102600803700104 eller ls, lev el, feurer a. key components of an effective mentoring relationship: a qualitative study. nurse educ today [internet; cited n.d.]. 2014;34(5):815–820. available from: https://doi.org/10.1016/j.nedt.2013.07.020 israel m, kamman ml, mccray ed, sindelar pt. mentoring in action: the interplay among professional assistance, emotional support, and evaluation. except child. 2014;81(1):45–63. https://doi.org/10.1177/0014402914532231 abstract introduction methods ethical consideration results discussion conclusion acknowledgements references about the author(s) kudzaishe mangombe department of sociology and social anthropology, faculty of social sciences, great zimbabwe university, masvingo, zimbabwe ishmael kalule-sabiti department of population studies and demography, faculty of humanities, north-west university, mmabatho, south africa citation mangombe k, kalule-sabiti i. knowledge about male circumcision and perception of risk for hiv among youth in harare, zimbabwe. s afr j hiv med. 2019;20(1), a855. https://doi.org/10.4102/sajhivmed.v20i1.855 original research knowledge about male circumcision and perception of risk for hiv among youth in harare, zimbabwe kudzaishe mangombe, ishmael kalule-sabiti received: 17 apr. 2018; accepted: 05 feb. 2019; published: 30 apr. 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: male circumcision will require high uptake among previously non-circumcising countries to realise the impact of circumcising in preventing hiv. little is known about whether youths are knowledgeable about male circumcision and its relationship with hiv prevention and their perception of risk of hiv infection. objective: this article aimed to ascertain youth’s knowledge about male circumcision and perception of risk of hiv infection. methods: a quantitative study on 784 youth (men aged 15–35 years) was conducted in harare, zimbabwe, after obtaining their consent. multivariate analysis examined the associations between background characteristics and knowledge about male circumcision and the perception of risk of hiv infection. results: the results revealed that age was a significant predictor of knowledge about male circumcision among youth in harare, as was educational attainment and ever having tested for hiv. in addition, youth who had heard of voluntary medical male circumcision were more likely to have high knowledge of male circumcision compared to those who had never heard of it. the results also showed that male circumcision status was associated with higher knowledge about male circumcision compared to those who were not circumcised. the study also found that educational attainment, belonging to the shona ethnic group, never having tested for hiv and disapproval of voluntary counselling and testing prior to male circumcision were associated with the perception of risk of hiv infection. conclusion: the study provides two recommendations: the need to strengthen perceived susceptibility to hiv among the youth and the need for advocacy on the health benefits of male circumcision. keywords: knowledge about male circumcision; perception of risk to hiv; youth; zimbabwe; voluntary medical male circumcision; voluntary hiv counselling. introduction the aim of the study was to identify the sociodemographic factors associated with knowledge about male circumcision and the perception of risk of hiv infection among youth in harare, zimbabwe. male circumcision as a subject is at the helm of hiv prevention. the eastern and southern africa regions are most affected by hiv, with the number of people on treatment more than doubling since 2010, reaching nearly 10.3 million people, resulting in hivand aids-related deaths in the region decreasing by 36% since 2010.1 according to unaids, the region has also witnessed the largest reduction in new adult hiv infections. there were about 40 000 fewer new adult hiv infections in the region in 2015 than in 2010, a 4% decline.1 although strides have been made concerning improved sexual behaviour in most countries, some countries in sub-saharan africa have detected low condom use and an increase in the number of sexual partners in their surveys.2 recent reports show that sexually transmitted infections (stis) are increasing among certain population groups, including urban youth in harare.3 considering the higher levels of stis among the urban youth, there is need to focus attention on knowledge about male circumcision and the perception of risk of hiv infection research in urban areas as a way to curb further hiv and sexually transmitted infections. both observational and ecological studies have shown that male circumcision reduces female-to-male hiv transmission,4,5,6 and three randomised controlled trials7,8,9 have shown that male circumcision has the potential to significantly alter the hiv epidemic in countries with high hiv prevalence and low circumcision rates. thus, in sub-saharan africa, there is currently a push for male circumcision to reduce the risk of hiv infection in previously non-circumcising communities. one of the potential challenges in adopting male circumcision in non-circumcising countries has been a lack of knowledge regarding the benefits in reducing hiv transmission.10,11,12,13 studies on knowledge about male circumcision have been conducted previously,10,11,14,15 some of which have found that the perception of risk of hiv infection is a predisposition for willingness to circumcise.16,17,18,19,20 however, most of these studies did not exclusively cover male youth age 15–35 years who reside in urban areas. little is known about the impact of sociodemographic characteristics on knowledge about male circumcision and perception of risk of hiv infection among youth in zimbabwe despite the fact that this is a key population in the fight against hiv. this study confines itself to youth aged 15–35 years, which is in line with the african charter definition.21 methods design, setting and sample a cross-sectional study with a closed-ended questionnaire was conducted in harare among male youth. the sample was calculated using kish’s22 sample size determination. this yielded a target population of 853 men aged 15–35 years. a total of 783 youth were interviewed, yielding a response rate of 92%. the study used the 2012 zimbabwe census as the sampling frame, and a three-stage sampling design was employed. firstly, the process involved the selection of primary sampling units, which were the enumeration areas (eas). the second stage involved the selection of households as secondary sampling units (ssus). the last stage involved the selection of respondents within the households in the selected eas. an eligible participant was one male household member between the ages of 15 and 35 years. when multiple households existed within a single dwelling unit, a kish grid was used to randomly select a responding household, and one member of the selected household was eligible to participate. if the selected household had no eligible respondent, the next household within the same dwelling unit was selected. thus, a kish grid was used in the selection of a respondent in a multiple-respondent household and multiple-dwelling units. measures dependent variables knowledge about male circumcision was measured by 10 items measured at the nominal level. the responses for each item were coded 0 and 1, with 0 indicating that an individual did not have knowledge about that particular question and 1 indicating that an individual did have knowledge about it. a knowledge score was obtained by summing up the individual knowledge questions. the score ranged from 0 to 10. the knowledge score was dichotomised. previous studies have also dichotomised knowledge scores in a similar way.23 studies have confirmed that dichotomisation of continuous variables makes interpretation easy and helps in simplifying analyses or presentation of results.24,25 the dichotomisation was done at mean score (7.79). a value of 0–7.78 indicated that the respondents had low knowledge about male circumcision, and a score from 7.79 to 10 indicated that the respondents had high knowledge about male circumcision. for modelling purposes, a dummy variable was created, with 0 indicating respondents had low knowledge about male circumcision and 1 for those respondents who had high knowledge about male circumcision. perception of risk of hiv infection was created from responses to a direct question: ‘do you think you are at risk of hiv infection’? the responses were as follows: ‘yes, at higher risk’ (assigned a value of 3); ‘yes, at low risk’ (assigned 2); ‘no, not at risk at all’ (assigned 1). sociodemographic variables the respondents were asked about their age in completed years, and these were categorised into 5-year age groups: 15–19, 20–24, 25–29 and 30–35 years. education was categorised as primary, secondary and higher than secondary. marital status was categorised as never married, married or living together, and never formerly married. wealth status was measured using a household goods index, which was recoded into low, medium and high wealth status. the measure was derived from the presence of 10 household assets within the respondent’s household: generator, solar panel, radio, television, refrigerator, non-mobile telephone, computer, washing machine, car and electricity connected to the dwelling unit. employment status was classified into unemployed or employed. religion was categorised into mainline christian, pentecostal, apostolic sect, other christian and no religion, while ethnicity was categorised into shona or other. respondents were also asked whether they had ever tested for hiv. the responses were ‘yes’ or ‘no’. respondents were asked whether they approved of voluntary counselling and testing (vct) prior to circumcision (yes or no). lastly, respondents were asked whether they had ever heard of voluntary medical male circumcision (vmmc) (yes or no). data analysis data management and statistical analyses were performed using spss version 22. the chi-square independence test was used to compare the various sociodemographic and dependent variables. a binary logistic regression model was used to identify predictors of knowledge about male circumcision. multinomial logistic regression was used to predict the net effect of the predictor variables (background characteristics) on perception of risk to hiv infection. in the model, the reference category for the dependent variable was ‘no, not at risk at all’. ethical consideration ethical clearance was granted by the relevant ethics council (ethics number: north-west university [nwu 00210-14-a9] and medical research council of zimbabwe [mrcz/a/1848]). a written informed consent was obtained from all the study participants after describing the objectives of the study to them. in addition, the respondents were assured of confidentially and anonymity. results demographic characteristics of respondents table 1 presents the frequency distribution of background characteristics of the respondents. almost equal proportions were distributed in the four age groups. the highest proportion of the respondents had never been married (63%), had achieved secondary education (78.8%), were employed (56%) and had ever been tested for hiv (65.3%); 90.6% of the respondents were of the shona ethnic group, and most of them were not circumcised (84.9%). in addition, 33.8% of the respondents were mainline christians, 78.2% did not approve of hiv testing prior to circumcision, and almost all (96.8%) had ever heard vmmc. table 1: background characteristics of the study respondents (n = 784). table 2 presents the frequency distribution of the respondents’ knowledge about male circumcision. it is evident from the table that more than 9 in 10 respondents (94.1%) knew that it is recommended that a circumcised man still use a condom. moreover, 7.4% of the respondents knew that male circumcision should be integrated with other hiv prevention methods. about 8 in 10 (81.4%) of the respondents indicated that an hiv-negative woman can contract hiv after having unprotected sex with an hiv-positive uncircumcised man. reversing the question, about the same percentage (83.7%) indicated that an hiv-negative circumcised man could contract hiv after having unprotected sex with an hiv-positive woman. table 2: proportion of respondents who answered correctly to the knowledge questions about circumcision (n = 784). a little more than 8 in 10 (82.2%) of the respondents indicated that male circumcision was not as good as an invisible condom. on the other hand, 82.7% indicated that male circumcision reduces the chances of hiv transmission. with regards to male circumcision reducing penile cancer, 53.2% indicated that male circumcision reduces penile cancer. more than 9 in 10 (92.7%) indicated that male circumcision improves penile hygiene, and about the same proportion (92.6%) indicated that male circumcision alone can prevent hiv infection. fewer than half (46.8%) of the respondents were aware that it was recommended that circumcised men abstain from sexual intercourse for a minimum period of 6 weeks following circumcision. more than two-thirds (66.5%) of the respondents were able to define male circumcision. table 3 shows the bivariate relationship between the background characteristics and knowledge about male circumcision. the results showed that there was a significant association between age and knowledge about male circumcision. knowledge about male circumcision increased with age. a higher percentage of respondents who were aged 30–35 years had high knowledge about male circumcision (88.4%) compared to those who were aged 25–29, 20–24 and 15–19 (80.2%, 79.9% and 71.4%, respectively; p < 0.001). a higher proportion of respondents who had attained a higher level of education had high knowledge about male circumcision (93.8%) compared to those who had attained primary and secondary education (77.7% and 70.3%, respectively; p < 0.000). table 3: background characteristics by knowledge about male circumcision. high knowledge about male circumcision was more common in respondents in the high wealth status group (83.8%) compared to those who belonged to medium and low wealth status (80.6% and 75.7%, respectively; p < 0.060). with respect to employment status, 26.6% of respondents who indicated that they were unemployed had low knowledge about male circumcision as compared to 16.4% of respondents who indicated that they were employed. eighty-six per cent of the respondents who had ever tested for hiv had high knowledge about male circumcision, compared to 68.8% of those who had never tested for hiv. finally, 80.8% of the respondents who had heard of vmmc had high knowledge about male circumcision. predictors of knowledge about male circumcision table 4 shows the results of the binary regression examining the influence of sociodemographic characteristics and knowledge about male circumcision. the results concerning age and knowledge about male circumcision showed that men aged 25–29 years were significantly less likely to have high knowledge about male circumcision compared to those aged 30–35 years. the odds of young men aged 25–29 years having high knowledge about male circumcision were 42% lower (odds ratio [or] = 0.576, p < 0.1) compared to those aged 30–35 years. education was significantly related to knowledge about male circumcision. the results showed that the odds of youth with primary education having high knowledge of hiv were 78% lower (or = 0.223, p < 0.05) compared to those with higher education. in addition, youth who reported having secondary education and having high knowledge about male circumcision were 71% lower (or = 0.292, p < 0.05) compared to those with higher education and having high knowledge about male circumcision. table 4: predictors of knowledge about male circumcision. further, the odds of young men who reported ever having tested for hiv having high knowledge about male circumcision were 93% higher (or = 1.93, p < 0.05) compared to those who had never tested for hiv. with respect to ever having heard of vmmc, the odds of youth who had ever heard about vmmc compared to those who had not having high knowledge about male circumcision were 250% higher (or = 3.50, p < 0.05). youth who reported being circumcised were more likely (or = 1.78, p < 0.1) to have high knowledge about male circumcision compared to those who were uncircumcised, with 78% higher odds. table 5 presents the frequency distribution for respondents’ perception of risk for hiv infection. fifty-four per cent of the respondents perceived themselves not to be at risk of hiv infection compared to 10.4% who indicated that they were at a higher risk. about a third (35.6%) perceived themselves to be at low risk of hiv infection. table 5: perception of risk of hiv infection. table 6 shows that there was a significant association between the background characteristics and perception of risk to hiv infection. perception of low risk and high risk of hiv infection increased with increase in age. for example, 67.6%, 23.6% and 8.8% of young people aged 15–19 years indicated that they were at no risk, low risk and high risk to hiv infection, respectively. on the other hand, 44.2%, 42.5% and 13.3% of those aged 30–35 years indicated that they were at no risk, low risk and high risk for hiv infection, respectively. table 6: background characteristics by perception of risk to hiv infection. with respect to marital status, while about a third (30.8%) of formerly married men indicated that they were at high risk of hiv infection, only 10% of never-married men and the same proportion of men married or living together indicated that they were at high risk of hiv infection. forty-three per cent of married men indicated that they were at a low risk of hiv infection, while 31.9% of never-married men indicated that they were at low risk of hiv infection. there is a positive relationship between education and risk perception of hiv infection. nearly half (49.6%) of the respondents with higher levels of education indicated that they were at low risk of hiv infection compared to about a third (32.5%) of respondents with secondary education and close to two-fifths (37.8%) of those with primary education. there was a significant relationship between employment status and perception of risk of hiv infection (significant at p < 0.001). forty-one per cent of employed youth perceived themselves to be at low risk (40.8%), and 11.2% perceived themselves to be at high risk of hiv infection. on the other hand, 29% of the unemployed youth perceived themselves to be at low risk, compared to 9.6% who perceived themselves to be at high risk of hiv infection. a similar proportion of respondents who had ever tested for hiv (10.6%) and those who had never tested (9.5%) indicated that they were at a high risk of hiv infection. additionally, 42.1% of those who had ever tested for hiv reported that they were at a low risk. with those who had never tested for hiv, 47.3% and 9.5% indicated that they were at low risk and at high risk of hiv infection, respectively. predictors of perception of risk of hiv infection table 7 shows the results of a multinomial logistic regression model. the results show the relationship between the background characteristics and the perception of risk of hiv infection. in the model, the reference category for the dependent variable is ‘no, not at risk at all’. the results showed that holding other variables constant, the odds of a man perceiving himself to be at a higher risk of hiv infection, relative to perceiving himself to be at no risk of hiv, were higher (or = 3.13, p < 0.05) among formerly married young men than for never-married young men. youth with secondary education were significantly less likely (or = 0.535, p < 0.1) to perceive themselves to be at higher risk compared to those with higher education. in addition, youth with primary education were significantly less likely (or = 0.530, p < 0.05) to perceive themselves to be at low risk compared to those with higher education. table 7: predictors of perception of risk of hiv infection. with regard to religion, the odds of a pentecostal christian perceiving himself to be at higher risk were 66% (p < 0.05) lower compared to young men who did not profess any religious faith. on the other hand, the odds of apostolic sect youth perceiving themselves to be at low risk of hiv infection were lower by 49% (p < 0.05) compared to young men who did not belong to any religion. the odds of shona youth perceiving themselves to be at low risk of hiv infection compared to young men who belonged to other ethnic groups were 45% lower (p < 0.05). further, the odds of young men perceiving themselves to be at low risk of hiv infection relative to perceiving themselves to be at no risk were 102% higher (or = 2.01, p < 0.05) for those who had ever been tested for hiv than for those who had never been tested for hiv. the odds of youth who approved of vct prior to male circumcision were less likely (or = 0.486, p < 0.05) to perceive themselves to be at a higher risk of hiv infection compared to their counterparts who did not approve of it. discussion this study sought to examine youths’ knowledge about male circumcision and perception of risk of hiv infection on the one hand, and selected background characteristics, on the other. in the zimbabwean context, little is known about the impact of background characteristics on social variables related to knowledge of male circumcision and perception of risk of hiv infection among urban men aged 15–35 years, despite the fact that this is a key subpopulation in the fight against hiv. while some studies have looked at these social variables related to male circumcision,26 it is mostly among different subpopulations, only included as predictor variables or not as exhaustive and critically analysed as done in the present study. knowledge about male circumcision appeared to increase with age. youth aged 15–19, 20–24 and 25–29 years all were less likely to have high knowledge about male circumcision. however, only youth aged 25–29 years compared to those aged 30–35 years were less likely to have high knowledge about male circumcision. studies elsewhere show contrary findings. for example, one study in particular27 found no significant association between age and knowledge about male circumcision among young people and adults surveyed in rural uganda. the differences in these results could have been attributed to the differences in the context of the studies and the definition of youth. ‘youth’ in the study was defined as men aged 14–24 years and ‘adults’ as those aged 24 years and above. furthermore, the findings showed that youth with primary and secondary education were less likely to have knowledge about male circumcision compared to those with a higher level of education. one study observed similar relationships in zimbabwe among soccer players, with those with higher education levels having more knowledge about male circumcision compared to those with lower levels of education.28 educational attainment predisposes individuals to appreciate health programmes better.29 the findings from this study also showed that previously testing for hiv was associated with knowledge about male circumcision. respondents who had ever tested for hiv were more likely to be knowledgeable about male circumcision. this could be attributed to counselling sessions that happen before and after testing. in zimbabwe, vct centres disseminate information about male circumcision. male circumcision services have also been an integral part of male sexual and reproductive health programmes.30 information about the importance of reduction in the number of sexual partners, provision of condoms, delay in sexual debut and early diagnosis of stis is disseminated during vct sessions and in some cases male circumcision.3 the likelihood is that those who have ever been tested for hiv were informed or educated about the availability of male circumcision as an option to prevent hiv infection. in addition, ever having heard of vmmc was found to be statistically significantly associated with knowledge about male circumcision. youth who had ever heard of vmmc were more likely to have high knowledge of male circumcision compared to those had never heard of it. this could be a result of availability of different mass media advertisement about vmmc. according to a study in zimbabwe among respondents aged 15–49 years in rural and urban areas, a higher proportion of the respondents had heard of vmmc.26 as expected, youth who were circumcised were knowledgeable about male circumcision in comparison to those who were uncircumcised. the present findings are consistent with other research, which found that males who were circumcised were more likely to have high levels of knowledge about male circumcision.14 perhaps the reason why circumcised youth have high knowledge about male circumcision is as a result of intensive information dissemination by health professionals before circumcision takes place in health institutions in zimbabwe. the findings suggest marital status had a significant influence on perception of risk of hiv infection. for example, formerly married youths were more likely to perceive themselves to be at higher risk of hiv infection compared to those who had never married. however, previous findings have found that, in general, people tend to underestimate their risk of hiv.31,32 in addition, the present study found that education influences perception of risk of hiv infection. for instance, youth with secondary education were less likely to perceive themselves to be at a higher risk of hiv infection compared to respondents with higher education. however, youth with primary education were less likely to perceive themselves to be at low risk of hiv infection compared to those with both secondary and higher education. as education increases, the young men are more likely to perceive themselves to be at high risk of hiv infection, most likely because they understand the dynamics of hiv infection. however, these results are inconsistent with previous studies; for instance, a study among military personnel in nigeria found an inverse relationship between educational attainment and hiv risk perception.33 results from that study found that those with higher education were less likely to perceive themselves to be at high risk of hiv infection. furthermore, the results showed religious variations in perception of risk of hiv infection. youth who belonged to pentecostal churches and apostolic sects were less likely to perceive themselves to be at a higher risk of hiv infection compared to respondents with no religion. however, the findings of the current study do not support previous research, which found that these men perceived themselves to be at no risk for hiv infection.34 apostolic sect members usually put stringent restrictions on sexual behaviour, which make them believe that they are not at risk of hiv infection.34 for instance, they encourage intermarriage within the church, virginity tests for young girls, polygamy practices and use of the holy spirit to detect adultery. this has implications for young men affiliated to the apostolic sect’s perception of hiv infection. studies have shown that religion impacts on human behavioural and health outcomes.35 with regard to pentecostal christians, the findings of the current study are consistent with those of a previous study,35 which also found that pentecostal christians perceived themselves to be at low risk of hiv infection. plausibly, the association between low perception of risk of hiv infection and pentecostalism could be attributed to their teachings on nurturing religious experiences and strong synergies encouraged among members. socialisation of congregants towards more frequent and overlapping interactions can discourage members’ involvement in risky sexual behaviours and hence impact on their perception of risk of hiv infection.36 youth belonging to the shona ethnic group were less likely to perceive themselves to be at low risk of hiv infection compared to other ethnic groups, which perceived itself to be at no risk of hiv infection. perhaps the shona perception of risk of hiv infection is not surprising considering the fact that in zimbabwe and other sub-saharan africa communities they have cultural practices conducive to the spread of hiv such as wife inheritance, which involves relatives of the deceased husband marrying the widow.37 in most cases, condoms are not used in this new relationship, because they are not usually used among married couples.38 if the widow’s first husband died from hiv, she would be more likely to transmit hiv and/or stis to the new husband. the practice of wife inheritance is also prevalent in the bondo district in kenya.39 in addition, those who had ever tested for hiv were more likely to perceive themselves to be at low risk of hiv infection compared to those who had never tested. this relationship could be explained by the fact that hiv is highly stigmatised. hence, ever taking the test and obtaining negative hiv results makes men aged 15–35 years feel they are not at risk of hiv infection. with respect to approval of vct prior to male circumcision, respondents who approved of vct prior to circumcision were less likely to perceive themselves to be at risk of hiv infection compared to those who did not approve of it. perhaps those who approve of vct prior to circumcision are youth who regularly check their status and for that reason perceive themselves to be at low risk of hiv infection. conclusion the findings identified a knowledge deficit about male circumcision among youth with primary and secondary education, indicating the probability of low uptake of male circumcision as an hiv intervention measure in harare. furthermore, as education increases, youth are more likely to perceive themselves to be at high risk of hiv infection. the study recommends the need to strengthen perceived susceptibility to hiv across all educational levels, and advocacy is needed on health benefits of male circumcision. acknowledgements the authors would like to thank the following research assistants: tapiwa chirenje, washington dune, kudzai ndemera, josphat jekera and tapiwa mangombe. competing interests the authors declare that they have no financial or personal relationship(s) that may have inappropriately influenced them in writing this article. authors’ contributions k.m. made conceptual contributions, data analysis and led the writing process. i.k.-s. contributed substantially to the writing and reviewing of the article. references unaids. unaids global aids update. geneva: world health organization; 2016. unaids. unaids report on the global aids epidemic. geneva: world health organization; 2013. zimbabwe national aids council, zimbabwe ministry of health and child welfare, unaids, world food programme vam food security analysis, cdc. smart investment to end hiv/aids in zimbabwe [homepage on the internet]. harare; 2015. available from: http://www.nac.org.zw/sites/default/file/hot%20spot%20mapping%20report.pdf cameron dw, d’costa l, maitha g, et al. female to male transmission of 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south africa. j mod afr stud. 2000;38:41–69. https://doi.org/10.1017/s0022278x99003249 drew ds, foster g, chitima j. cultural practices associated with death in the north nyanga district of zimbabwe and their impact on widows and orphans. j soc dev afr. 1996;11:79–86. exavery a, kanté am, jackson e, et al. role of condom negotiation on condom use among women of reproductive age in three districts in tanzania. bmc public health. 2012;12:1097. https://doi.org/10.1186/1471-2458-12-1097 agot ke, vander stoep a, tracy m, et al. widow inheritance and hiv prevalence in bondo district, kenya: baseline results from a prospective cohort study. plos one. 2010;5:e14028. https://doi.org/10.1371/journal.pone.0014028 abstract introduction methods ethical consideration results discussion conclusion acknowledgements references about the author(s) chanté bisschoff department of paediatrics and child health, faculty of health sciences, university of the free state, bloemfontein, south africa jasmine coulon department of paediatrics and child health, faculty of health sciences, university of the free state, bloemfontein, south africa ziva isaacs department of paediatrics and child health, faculty of health sciences, university of the free state, bloemfontein, south africa lavinia van der linde department of paediatrics and child health, faculty of health sciences, university of the free state, bloemfontein, south africa linley wilson department of paediatrics and child health, faculty of health sciences, university of the free state, bloemfontein, south africa riana van zyl department of paediatrics and child health, faculty of health sciences, university of the free state, bloemfontein, south africa gina joubert department of biostatistics, faculty of health sciences, university of the free state, bloemfontein, south africa citation bisschoff c, coulon j, isaacs z, et al. hiv testing at birth: are we getting it right? s afr j hiv med. 2019;20(1), a951. https://doi.org/10.4102/sajhivmed.v20i1.951 original research hiv testing at birth: are we getting it right? chanté bisschoff, jasmine coulon, ziva isaacs, lavinia van der linde, linley wilson, riana van zyl, gina joubert received: 29 jan. 2019; accepted: 06 may 2019; published: 27 june 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: birth polymerase chain reaction (pcr) testing improves early detection of hiv and allows for early treatment initiation. national guidelines exist, but it is unknown whether these are being implemented correctly. objectives: to determine whether hiv-exposed infants at the mangaung university community partnership programme community health centre (mucpp chc) received pcr tests at birth, if hiv-positive infants were initiated on treatment, if follow-up dates were scheduled and the percentage of mothers or caregivers who returned to collect the results. methods: the study was a retrospective descriptive file audit (1304 files) of births from 01 january to 31 december 2016 at mucpp chc. the study sample was 428 infants born to hiv-positive mothers. the birth register was used to collect the infants’ hiv pcr test barcodes. the birth and 10-week pcr results were retrieved from an electronic database at the virology department, university of the free state. results: in total, 375 infants received a birth pcr test (87.6%) of which 4 (1.1%) tested hiv positive and 327 (87.2%) negative. follow-up tests were not scheduled. however, 145 (44.3%) hiv-negative infants returned for a 10-week test. irrespective of the pcr birth result, 157 (36.7%) infants were brought for a 10-week follow-up test at which time 3 (1.9%) tested positive and 151 (96.2%) negative. conclusion: the majority of hiv-exposed infants received a pcr test at birth; however, the clinic is below the national target (90%) for hiv testing. a record-keeping system of infants’ visits does not exist at mucpp chc, making it impossible to determine whether hiv-positive infants were started on antiretroviral treatment. keywords: birth hiv pcr testing; follow-up testing; prevention of mother-to-child transmission; national guidelines; documentation; communication introduction the risk of an infant being infected with hiv during pregnancy, delivery or breastfeeding can be reduced to 5% or less if the mother is on antiretroviral treatment (art).1 the highest mortality in an infant who has acquired hiv is between the ages of 6 weeks to 4 months; therefore, early infant diagnosis is imperative in identifying the status of the infant for early introduction of treatment.1,2,3,4 a south african trial conducted in hiv-positive infants showed improved short-term neurodevelopmental outcomes because of early initiation of art, in comparison to infants for whom treatment was delayed.5 violari et al.6 found that infant mortality was reduced by 76% and hiv progression by 75% when infants infected with hiv were diagnosed and placed on art before 12 weeks of age. the south african national department of health released the 2015 ‘national consolidated guidelines for prevention of mother-to-child transmission (pmtct) and the management of hiv in children, adolescents and adults’7 which makes provision for birth hiv polymerase chain reaction (pcr) testing for all hiv-exposed infants. the reason for the birth pcr was to promote immediate art and linkage to care. the infants must receive immediate art if they test positive with the first pcr test, and a second pcr test must be performed as a confirmatory test within 1 week after the first pcr test.7,8 at 10 weeks, all hiv-exposed but uninfected infants will have a repeat pcr. this is performed 4 weeks after the cessation of nevirapine administration. if the infant is still on nevirapine prophylaxis and the pcr test is performed, there is a possibility of a false negative or indeterminate result.9 a definite diagnosis of hiv in infants younger than 18 months of age needs two positive pcr results.7 the mangaung university community partnership programme community health centre (mucpp chc) in the free state is a large primary health care facility, which consists of an antenatal clinic, a maternity ward and a paediatric clinic, and provides comprehensive hiv management for adults and children. only uncomplicated normal vaginal deliveries (nvd) are performed on site, while complicated deliveries and caesarean sections are referred to the pelonomi academic hospital for specialist management. as mucpp chc uses the 2015 national guidelines,7 the authors were interested in how strictly these guidelines were adhered to. aim the aim of this study was to determine whether the neonatal component of the 2015 ‘national consolidated guidelines for pmtct of hiv and the management of hiv in children, adolescents and adults’7 was being implemented in the management of hiv-exposed infants on a phc level at mucpp chc in bloemfontein, free state. specific objectives included the following: whether all hiv-exposed infants received an hiv pcr test at birth whether the infants who tested hiv-positive were initiated on art within a week of diagnosis whether a follow-up date for the 10-week follow-up test was given to the mother or caregiver of the infant who tested hiv-negative at birth the percentage of mothers or caregivers who returned to collect the birth hiv pcr results. methods study design and sampling this was a retrospective descriptive file audit. the study population included all mothers who gave birth to a live baby via nvd at mucpp chc from 01 january 2016 to 31 december 2016. measurement the mothers’ files are kept at the maternity ward of mucpp chc. the researchers counted every file from 01 january to 31 december 2016. the mothers’ files were used to identify whether they were hiv-positive or not and whether they had an uncomplicated nvd. the mother’s age, parity and gravidity, hiv status and whether she was on art were captured on a data sheet. the 2016 birth register was used to collect the hiv-exposed infants’ pcr barcodes and any information that was missing from the mothers’ files, for example whether the mother was on art. the researchers collected the hiv pcr results using these pcr barcodes for the birth tests, while the date of birth and surname of the infant were used to obtain the hiv pcr test results, including the 10-week hiv pcr test results. this was performed using the national health laboratory system (nhls) electronic database at the department of virology, university of the free state (ufs). pilot study the pilot study was conducted at mucpp chc. the first 10 files of hiv-positive mothers of january 2016 with an uncomplicated nvd were selected. during the pilot study, it became clear that the information to achieve our objectives was not noted in the patient files and the methodology had to be amended to obtain pcr results from the virology database. it was thus not possible to determine whether infants who tested hiv-positive were initiated on art within a week of diagnosis, whether follow-up dates were given to mothers and whether mothers collected birth pcr results. changes were made to the data sheet, which included removing the fields for the infant’s weight, height and if the infant was on medication, because this information was found to be unavailable and did not contribute to the study aim. demographic information, hospital number, the option of ‘unknown’, the clinic’s name for antenatal care and dates of all the hiv pcr tests were added. the information gathered from the pilot study was included in the main study. analysis of data the researchers entered the data into microsoft excel. data were analysed by the department of biostatistics, faculty of health sciences, university of free state. numerical variables were summarised by medians and ranges because of skewed distributions. categorical variables were summarised by frequencies and percentages. the 10-week hiv pcr test results were categorised as follows: before 10 weeks (1–55 days) at 10 weeks (56–89 days) after 3 months (90+ days) ethical consideration the protocol was approved by the health sciences research ethics committee (hsrec) of ufs [hsrec-s 06/2017] and the free state department of health. the data were handled confidentially, and each patient file received a unique study number. access to the information on the nhls electronic database was granted by the head of the department of virology, ufs. results the file review showed that 1304 live babies were born via uncomplicated ndv during 2016. there were, however, 20 duplicate data entries and 10 cases were thus removed. eight incorrect entries were also removed leaving 1286 patient files. the number of deliveries per month ranged between 65 (minimum, recorded in july) and 151 (maximum, recorded in august). the study sample included 428 (33.3%) babies born to hiv-positive mothers. just over half of these babies were male (n = 214, 50.4%). the median age of the hiv-positive mothers was 23.3 years (range: 16.4–44.5 years). most mothers were between the ages of 20 and 35 years (82.6%). there were 31 (7.3%) teenage pregnancies (mothers < 18 years old) and 43 (10.1%) pregnancies in mothers aged 35 years and older. nearly half the mothers had been pregnant at least twice before (parity ≥ 2, 48.5%; gravidity ≥ 3, 45.5%). the art details were recorded for only 410 of the mothers of which 361 (88.0%) mothers were on art. figure 1 is a schematic representation of the hiv-exposed infants and their pcr testing and outcomes at birth and 10 weeks. figure 1: birth and 10-week polymerase chain reaction testing of hiv-exposed infants. the majority of hiv-exposed infants (87.6%) received an hiv-1 pcr test at birth, of whom 87.2% tested hiv-negative. when looking at month-specific percentages, during november, only 47.9% (23/48) of hiv-exposed infants received birth pcr tests. instead, a viral load test was performed on the mother. there was no outcome recorded for 11.7% of all infants tested at birth, because of either insufficient specimen or missing results. of the 22 infants born in july, 16 (72.7%) had an insufficient specimen. this is 48.5% of the total of 33 insufficient specimens at birth. of these 33 infants, only a third were retested at 10 weeks. of the 34 babies born to teenage mothers, 82.4% had an hiv-1 pcr test at birth. the birth pcr results were conclusive in 24 babies of whom 2 (7.7%) tested positive. of the 43 infants born to mothers aged 35 and older, 90.7% had an hiv-1 pcr test at birth, but none of these babies had a positive birth pcr test. of the infants who tested hiv-negative at birth, 44.3% had a repeat pcr at 10 weeks, of whom 1.4% tested hiv-positive. irrespective of the hiv pcr test outcome at birth (positive, negative or insufficient specimen), 43.1% of the infants (157/364) returned for a 10-week follow-up visit of whom 3 (1.9%) tested positive, 151 (96.2%) tested negative and 3 (1.9%) had an insufficient specimen for a result. the median number of days for the 10-week pcr testing was 73 days, and the mode was 70 days. of the 375 babies who had a birth pcr, 57.3% (n = 215) had a follow-up test at any date. twenty mothers or caregivers returned with their infants for follow-up testing before the 10-week time frame (i.e. ≤ 55 days after the birth hiv pcr test). the median number of days was 42 days (range: 7–46 days). eighteen infants tested negative, and two infants had an insufficient specimen. two infants were tested before 10 weeks and again at 10 weeks. one infant tested negative on both occasions. the second infant had an insufficient specimen before 10 weeks and tested negative at 10 weeks. fifty infants were tested only after 3 months (i.e. 90 or more days after the birth hiv pcr test).the median number of days was 119 days (range: 90–441 days). the pcr outcome for 49 of the infants was negative, and one infant had an insufficient specimen. four infants were tested before 10 weeks and again after 3 months. all four infants tested negative at both dates. nevirapine was given to 427 (99.8%) infants with one file having no record of this. discussion a third (33.3%) of the mothers who gave birth at mucpp chc during 2016 were hiv-positive. among these hiv-positive mothers, there were 7.3% teenage pregnancies and 10.1% pregnancies to women over the age of 35 years, also classified as post-maternal. pregnancies in either very young women (teenagers younger than 18 years) or women older than 35 years (advanced maternal age) are considered to be high-risk pregnancies.10 especially, teenage pregnancy and multiparity carry an increased risk of maternal hiv infection and vertical transmission. the percentage of hiv-positive mothers on art at mucpp chc is comparable to the 95.0% of pregnant hiv-positive women in south africa on art in 2016.11 the results showed that 87.6% (375/428) of hiv-exposed infants born at mucpp chc during 2016 received a birth pcr test. the national target for hiv testing in the general population in south africa is 90.0%.7 the 2015 national guidelines7 also state that all hiv-exposed infants should receive a birth pcr test as early diagnosis is essential to decrease hiv-related deaths in infants. it is possible that not all nurses were aware of the 2015 national guidelines7 and they still follow the 2010 national guidelines12 in which the first hiv pcr test is performed only at 6 weeks of age while the mother receives a viral load test of delivery. this practice seemed to be employed by staff working at the clinic during november. different staff members also seem to have differing levels of phlebotomy expertise, with those working in july having a particularly high percentage of insufficient specimens. four (1.2%) infants out of the 331 infants with birth pcr results tested hiv-positive at birth. any infant with a positive birth pcr result should be referred to or discussed telephonically with a paediatric hiv specialist for art initiation. as we found no record-keeping system of the infants’ visits, it was not possible to determine whether art was initiated in hiv-positive infants. the 2015 national guidelines7 state that all pcr results should be documented; however, this information is only recorded in the infant’s road to health (rth) booklet that stays in the mother’s or caregiver’s possession. only the mother’s details are recorded in the appointment book at the paediatric clinic. in the authors’ opinion, there is poor communication between the maternity ward and paediatric clinic at mucpp chc because the maternity ward was under the impression that the paediatric clinic received the infant pcr results, which was not the case. as a result, none of these departments recorded any information in their files about the pcr results or whether the infant was tested. thus, the researchers used the nhls electronic database to get this information. the maternity ward sister indicated to the researchers that the mothers or caregivers were contacted telephonically if the birth hiv pcr was positive. of the four infants who tested positive at birth, one was retested at 10 weeks and remained hiv-positive. we speculate that this infant was possibly not on art and that the birth result was lost, necessitating a repeat pcr. although the second test could have been confirmatory, the 2015 national guidelines7 state that the confirmatory test should be performed within 1 week of a positive birth pcr result. during the study, we could not find evidence that specific follow-up dates or a general time frame was given to the mother to return for the birth pcr results or repeat testing at 10 weeks. we postulate that mothers were informed at the first vaccination visit at 6 weeks that a repeat pcr should be performed at 10 weeks. a specific date should be given so that the mothers or caregivers know exactly when to come back. according to the national guidelines, 10 weeks is the correct follow-up date because it is essential to do the hiv pcr test 4 weeks after having stopped nevirapine prophylaxis. nevirapine use could produce a false negative or indeterminate result.7,9 of the mothers or caregivers who brought the infants back for a follow-up pcr test, either before, during or after the 10-week time frame, we speculate that these are the mothers or caregivers who collected the birth pcr results. possible reasons why the mother or caregiver did not bring the infant back for follow-up pcr testing are lack of transport, lack of money for transport, relocation, forgotten appointments and/or social and family issues. study limitations it was difficult to find the 10-week results via nhls. this may be because of the infant’s name, surname or residential address changing from the time of birth. no further information was captured for the 53 infants who were not tested at birth. conclusion the researchers found that 87.6% of hiv-exposed infants received a birth hiv pcr test, which approaches the national target of 90.0%. there were no follow-up dates given for infants who tested negative at birth. the mothers or caregivers of those who tested positive at birth were telephonically contacted to return so that initiation of art could commence, but no record was maintained. the authors speculate that 57.3% of mothers or caregivers who came back for a follow-up test received the birth pcr test results. therefore, mucpp chc is partially adhering to the 2015 national guidelines7 as the majority of hiv-exposed infants are being tested at birth. however, they do not ensure that negative cases are retested to identify intrapartum infection. as only the mothers’ details were recorded at the paediatric clinic, it could not be determined whether the infants who were hiv-positive were initiated on art or whether a confirmatory pcr test was performed. the national guidelines7 state that all hiv pcr results should be documented. however, this information is recorded in the rth booklet, which stays with the mothers or caregivers. as of 2017, a record-keeping system was initiated where the clinical staff of the paediatric clinic record the mother’s contact details; however, the infant’s treatment should also be recorded. recommendations the maternity ward and paediatric clinic at mucpp chc should establish a more detailed record-keeping system and improve the communication between the two departments to keep track of testing, results and patient follow-up to provide a continuum of care through the postnatal period. a written date for the 10-week follow-up test should be given on an appointment card to the mother or caregiver. the maternity ward and paediatric clinic should also record that the date was given to the mother or caregiver. a future study could be conducted to determine whether infants who tested positive at birth had a confirmatory test. in addition, infant follow-up testing through 18 months of age should be documented. feedback should be given to the clinic and hiv programme. this setting is ideal for a continuous quality improvement programme.13 acknowledgements the authors thank mrs p. meningwa and mrs o. mocumi at the mangaung university community partnership programme community health centre for allowing them access to the mothers’ files and birth register, and prof. j. goedhals and dr s. vawda, department of virology, university of the free state (ufs), for allowing them access to the nhls to collect data. they are also grateful to mrs a. bouwer, research coordinator, department of paediatrics and child health, ufs, for her assistance with the report, and ms t. mulder, medical editor and writer, faculty of health sciences, ufs, for preparation of the manuscript. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions c.b., j.c., z.i., l.v.d.l. and l.w. were the medical students who compiled the protocol, performed the data collection and wrote the first draft report of this study. r.v.z. was the study leader from the project’s inception. g.j. advised with the planning of the study, performed the analysis and assisted with the write-up. references unaids. children [homepage on the internet]. 2017 [cited 2018 feb 28]. available from: http://www.unaids.org/en/topic/children. anoje c, aiyenigba b, suzuki c, et al. reducing mother-to-child transmission of hiv: findings from an early infant diagnosis program in south-south region of nigeria. bmc public health. 2012;12:184. https://doi.org/10.1186/1471-2458-12-184 chiu a, modi s, rivadeneira ed, koumans eh. optimizing infant hiv diagnosis in resource-limited settings: modeling the impact of hiv dna pcr testing at birth. j acquir immune defic syndr. 2016;73(4):454–462. https://doi.org/10.1097/qai.0000000000001126 taylor d, durigon m, davis h, et al. probability of a false-negative hiv antibody test result during the window period: a tool for preand post-test counselling. int j std aids. 2015;26(4):215–224. https://doi.org/10.1177/0956462414542987 laughton b, cornell m, grove d, et al. early antiretroviral therapy improves neurodevelopmental outcomes in infants. aids. 2012;26(13):1685–1690. https://doi.org/10.1097/qad.0b013e328355d0ce violari a, cotton mf, gibb dm, et al. early antiretroviral therapy and mortality among hiv-infected infants. n engl j med. 2008;359(21):2233–2244. https://doi.org/10.1056/nejmoa0800971 national department of health. the national consolidated guidelines for the prevention of mother-to-child transmission of hiv (pmtct) and management of hiv in children, adolescents and adults. pretoria: department of health, republic of south africa; 2015. aids info. guidelines for the use of antiretroviral agents in paediatric hiv infection [homepage on the internet]. 2016 [update 2018 dec 14; cited 2016 dec 17]. available from: https://aidsinfo.nih.gov/guidelines/html/2/pediatric-arv/0. haeri mazanderani af, du plessis nm, thomas wn, venter e, avenant t. loss of detectability and indeterminate results: challenges facing hiv infant diagnosis in south africa’s expanding art programme. s afr med j. 2014;104(8):574–577. https://doi.org/10.7196/samj.8322 dekker b. evidence on: advanced maternal age [homepage on the internet]. evidence based birth®. 2016 [cited 2018 feb 26]. available from: https://evidencebasedbirth.com/advanced-maternal-age/. unaids. data 2017 [homepage on the internet]. 2017 [cited 2018 feb 28]. available from: http://www.unaids.org/sites/default/files/media_asset/20170720_data_book_2017_en.pdf. national department of health. clinical guidelines: pmtct (prevention of mother-to-child transmission) 2010. pretoria: department of health, republic of south africa; 2010. youngleson ms, nkurunziza p, jennings k, arendse j, mate ks, barker p. improving a mother to child hiv transmission programme through health system redesign: quality improvement, protocol adjustment and resource addition. plos one. 2010;5(11):e13891. https://doi.org/10.1371/journal.pone.0013891 references about the author(s) mukesh dheda pharmacovigilance centre for public health programmes, national department of health, south africa school of health science, university of kwazulu-natal, south africa citation dheda m. efavirenz and neuropsychiatric effects. s afr j hiv med. 2017;18(1), a741. https://doi.org/10.4102/sajhivmed.v18i1.741 advice document efavirenz and neuropsychiatric effects mukesh dheda copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. currently, efavirenz (efv) is widely prescribed as part of antiretroviral therapy (art) in south africa, and it is most frequently prescribed in fixed-dose combination (fdc) at a dose of 600 mg. efavirenz has been linked to early (two to six weeks1) transient as well as late neuropsychiatric effects, which include increased risk of suicidal ideation,2 encephalopathy,3 catatonia,4 psychosis and ataxia.5,6 all of these have been directly linked to efv toxicity. the risk for toxicity has been associated with loss of function polymorphisms of cytochrome 2b6, the main metabolising enzyme for efv.7 it is estimated that about 20% of sub-saharan africans are genetically slow metabolisers and may be at risk of efv toxicity.8 clinicians should be aware that weight is another factor that predisposes a patient to efv toxicity, and it is recommended that patients weighing less than 40 kg should be prescribed a reduced dose of 400 mg.5,9 there are no fdcs with a reduced efv dose available in south africa, and underweight patients are often over-dosed as healthcare workers often prescribe the fdc with standard doses of efv. efavirenz toxicity should be considered in patients who present with depression, psychosis, catatonia, encephalopathy or ataxia after the first few weeks of therapy when other causes are excluded. these include renal failure, liver failure, vitamin b12 deficiency, syphilis, meningitis and structural brain lesions. once suspected, it is recommended that efv be switched to lopinavir or ritonavir. if patients are on first-line tuberculosis medication, the dose of lopinavir or ritonavir needs to be increased, and this can be done over two weeks if gastrointestinal tract (git) side effects are a problem. healthcare professionals are requested to be vigilant and report any suspected adverse drug reaction (adr) when using antiretroviral (arv) drugs. please complete adverse drug reaction forms when adverse reactions are suspected. adverse drug reaction forms can be obtained from the national department of health pharmacovigilance centre for public health programmes. any comments and queries can be addressed to the email below: tel: +27 (0)12 395 9506/8099 fax2email: 086 241 2473 email: npc@health.gov.za references puzantian t. central nervous system adverse effects with efavirenz: case report and review. pharmacotherapy. 2002;22:930–933. https://doi.org/10.1592/phco.22.11.930.33624 mollan kr, smurzynski m, eron jj, et al. association between efavirenz as initial therapy for hiv-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data. ann intern med. 2014;161(1):1–10. https://doi.org/10.7326/m14-0293 kenyon c, mfolozi s, croxford r, colebunders r, cohen, k. severe efavirenz-induced vacuolar axonopathy complicated by fatal aspiration pneumonia. br j clin pharmacol. 2012;74(6):1070–1072. https://doi.org/10.1111/j.1365-2125.2012.04299.x sabato s, wesselingh s, fuller a, ray j, mijch a. efavirenz-induced catatonia. aids. 2002;16(13):1841–1842. https://doi.org/10.1097/00002030-200209060-00024 variava e, sigauke f, muchichwa p, maartens g, martinson n. 2016 efavirenz toxicity manifesting as cerebellar ataxia: case series from south africa. poster 963 croi. dept. of internal medicine, klerksdorp tshepong hospital complex and university of the witwatersrand, klerksdorp, south africa; 2016. hauptfleisch mpk, moore dp, rodda jl. efavirenz as a cause of ataxia in children. samj. 2015;105(11): 897–898. https://doi.org/10.7196/samj.2015.v105i11.9451 desta z, saussele t, ward b, et al. impact of cyp2b6 polymorphism on hepatic efavirenz metabolism in vitro. pharmacogenomics. 2007;8(6):547–558. https://doi.org/10.2217/14622416.8.6.547 nyakutira c, röshammar d, chigutsa e, et al. high prevalence of the cyp2b6 516g→ t (* 6) variant and effect on the population pharmacokinetics of efavirenz in hiv/aids outpatients in zimbabwe. eur j clin pharmacol. 2008;64(4):357–365. https://doi.org/10.1007/s00228-007-0412-3 nemaura t, nhachi c, masimirembwa c. impact of gender, weight and cyp2b6 genotype on efavirenz exposure in patients on hiv/aids and tb treatment: implications for individualising therapy. afr j pharm pharmacol. 2012;6(29):2188–2193. https://doi.org/10.5897/ajpp12.076 abstract introduction study population and methods results discussion acknowledgements references about the author(s) kathleen m. powis massachusetts general hospital, departments of medicine and pediatrics, united states harvard t. h. chan school of public health, department of immunology and infectious diseases, united states botswana harvard aids institute partnership, gaborone, botswana shahin lockman harvard t. h. chan school of public health, department of immunology and infectious diseases, united states botswana harvard aids institute partnership, gaborone, botswana brigham and women’s hospital, infectious disease division, united states gbolahan ajibola botswana harvard aids institute partnership, gaborone, botswana michael d. hughes harvard t. h. chan school of public health, department of immunology and infectious diseases, united states kara bennett bennett statistical consulting, inc, ballston lake, united states jean leidner goodtables data consulting, norman, united states oganne batlang botswana harvard aids institute partnership, gaborone, botswana kerapetse botebele botswana harvard aids institute partnership, gaborone, botswana sikhulile moyo botswana harvard aids institute partnership, gaborone, botswana erik van widenfelt botswana harvard aids institute partnership, gaborone, botswana joseph makhema botswana harvard aids institute partnership, gaborone, botswana chipo petlo ministry of health, gaborone, botswana haruna b. jibril ministry of health, gaborone, botswana kenneth mcintosh division of infectious diseases, boston children’s hospital, united states max essex harvard t. h. chan school of public health, department of immunology and infectious diseases, united states botswana harvard aids institute partnership, gaborone, botswana roger l. shapiro harvard t. h. chan school of public health, department of immunology and infectious diseases, united states botswana harvard aids institute partnership, gaborone, botswana citation powis km, lockman s, ajibola g, et al. similar hiv protection from four weeks of zidovudine versus nevirapine prophylaxis among formula-fed infants in botswana. s afr j hiv med. 2018;19(1), a751. http://doi.org/10.4102/sajhivmed.v19i1.751 note: presented in part: 2016 conference on retroviruses and opportunistic infections, boston, massachusetts, united states, 22–25 february (abstract 16-1677). original research similar hiv protection from four weeks of zidovudine versus nevirapine prophylaxis among formula-fed infants in botswana kathleen m. powis, shahin lockman, gbolahan ajibola, michael d. hughes, kara bennett, jean leidner, oganne batlang, kerapetse botebele, sikhulile moyo, erik van widenfelt, joseph makhema, chipo petlo, haruna b. jibril, kenneth mcintosh, max essex, roger l. shapiro received: 21 mar. 2017; accepted: 30 oct. 2017; published: 28 mar. 2018 copyright: © 2018. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the world health organization hiv guidelines recommend either infant zidovudine (zdv) or nevirapine (nvp) prophylaxis for the prevention of intrapartum mother-to-child hiv transmission (mtct) among formula-fed infants. no study has evaluated the comparative efficacy of infant prophylaxis with twice daily zdv versus once daily nvp in exclusively formula-fed hiv-exposed infants. methods: using data from the mpepu study, a botswana-based clinical trial investigating whether prophylactic co-trimoxazole could improve infant survival, retrospective analyses of mtct events and division of aids (daids) grade 3 or grade 4 occurrences of anaemia or neutropenia were performed among infants born full-term (≥ 37 weeks gestation), with a birth weight ≥ 2500 g and who were formula-fed from birth. zdv infant prophylaxis was used from mpepu study inception. a protocol modification mid-way through the study led to the subsequent use of nvp infant prophylaxis. results: among infants qualifying for this secondary retrospective analysis, a total of 695 (52%) infants received zdv, while 646 (48%) received nvp from birth for at least 25 days but no more than 35 days. confirmed intrapartum hiv infection occurred in two (0.29%) zdv recipients and three (0.46%) nvp recipients (p = 0.68). anaemia occurred in 19 (2.7%) zdv versus 12 (1.9%) nvp (p = 0.36) recipients. neutropenia occurred in 28 (4.0%) zdv versus 21 (3.3%) nvp recipients (p = 0.47). conclusions: both zdv and nvp resulted in low intrapartum transmission rates and no significant differences in severe infant haematologic toxicity (daids grade 3 or grade 4) among formula-fed full-term infants with a birthweight ≥ 2500 g. introduction previous studies have demonstrated that infant antiretroviral (arv) prophylaxis with zidovudine (zdv) or nevirapine (nvp), or both combined, have been efficacious in preventing intrapartum mother-to-child hiv transmission (pmtct).1,2,3,4,5 recent work has shown that infant nvp prophylaxis provides additional protection against mother-to-child hiv transmission (mtct) during breastfeeding.4,5 currently, the world health organization (who) recommends nvp prophylaxis for all hiv-exposed infants, but who guidelines do not preferentially support either zdv or nvp in formula-fed hiv-exposed infants.6,7 in fact, the strength of the recommendation for use of daily nvp or twice daily zdv from birth for 4–6 weeks among breastfed hiv-exposed infants was categorised as ‘strong’ based on ‘moderate’ evidence.6 however, the who prophylaxis recommendation for formula-fed hiv-exposed infants from birth was categorised as a ‘conditional’ recommendation with ‘low’ evidence, suggesting the need for data-driven evidence.6 formula feeding is an alternative to breastfeeding in lower infant-mortality settings where formula feeding is available and can be safely prepared; when breastfeeding cannot occur; and among those who wish to maximally reduce the risk of late hiv transmission. at present, formula feeding is widely practiced as a pmtct strategy throughout europe and the americas, and in some areas of asia and africa.8,9,10,11 the mpepu study, conducted in botswana from may 2011 through june 2015, permitted comparison of four weeks of infant prophylaxis consisting of either single-dose nvp (sdnvp) and zdv twice daily or nvp once daily among formula-fed hiv-exposed infants. the majority of infants born to women who consented prior to february 2013 received sdnvp and zdv prophylaxis. thereafter, most infants received nvp prophylaxis as a single-drug regimen. we performed a retrospective analysis evaluating mtct rates and haematologic safety of arv prophylaxis for full-term, normal birthweight, formula-fed infants who received 4 weeks of sdnvp plus zdv versus nvp. study population and methods study population and monitoring this retrospective study was conducted in botswana, a middle-income country with high hiv prevalence, estimated at 21.9% among persons aged 15–49 as of 2016.12 botswana was among the first countries with high hiv prevalence to promote pmtct, offering free antiretroviral treatment (art) to pregnant women living with hiv who qualified for treatment for their own health as early as 2002, while providing zdv monotherapy to pregnant women living with hiv if they did not yet qualify for hiv treatment. in 2012, botswana national hiv treatment guidelines were updated to recommend triple arv use among all pregnant women living with hiv, regardless of their hiv disease state.13 as of 2016, more than 95% of pregnant women living with hiv in botswana accessed art.14 this has contributed to significant reductions in mtct with a rate of 1.8%, despite the fact that hiv prevalence among pregnant women remains high at over 25%.15 up until 2016, botswana has promoted exclusive formula feeding in the first six months-of-life for hiv-exposed infants.13,16 in 2016, this policy changed to encourage breastfeeding of hiv-exposed uninfected (heu) infants so long as the mother is taking art and is virally suppressed.17 despite this policy change, the practice of providing free infant formula-fed during the first year of life to hiv-exposed infants remains an option. use of formula feeding for hiv-exposed infants has been widely adopted, with nearly 80% of women living with hiv in botswana opting to formula feed their infant. in this context, data were analysed retrospectively from the mpepu study to evaluate comparative efficacy of four weeks of sdnvp with zdv versus nvp. the mpepu study, a double-blinded randomised controlled trial, investigated prophylactic co-trimoxazole (ctx) versus placebo from 2 weeks to 15 months of age in heu infants, studying health outcomes including diarrhoeal illness, pneumonia and death (nct01229761). this study has previously been described.18 in brief, hiv-infected women were eligible for enrolment between 26 weeks gestation and 35 days postpartum. infants were enrolled from birth to 35 days-of-life. the study opened for enrolment in may 2011 and was conducted in the capital city (gaborone), the rural village of molepolole, located approximately 56 km from the capital city, and the peri-urban town of lobatse located approximately 67 km from the capital city. consistent with botswana’s pmtct guidelines,19 the initial study protocol followed government dosing of sdnvp (6 mg) within 72 h of birth and zdv [4 mg/kg twice daily for full-term infants (37 weeks) with a birth weight ≥ 2500 g] for four weeks. randomisation to ctx or placebo took place between 28 and 35 days-of-life. from february 2013, the protocol was amended to allow randomisation to ctx or placebo as early as 14 days-of-life for infants born full-term and weighing ≥ 2500 g. to avoid the possibility of overlapping haematologic toxicity from ctx with zdv with this protocol change, study infants were offered nvp (15 mg once daily for four weeks from birth). of note, the prevailing prophylaxis under national guidelines remained sdnvp with four weeks of zdv.20 therefore, some infants enrolled in the study after the protocol amendment received sdnvp and zdv initiated by government nursing staff at maternity wards where they were born. data were collected on the initiation and stop dates of infant arv prophylaxis. at infant enrolment and randomisation study visits, infant hiv-1 testing was performed using qualitative polymerase chain reaction (pcr) dna assay (amplicor hiv-1, roche diagnostic systems, new jersey, usa) for infants at the birth (enrolment) and randomisation study visits. over 95% of infant enrolment dna pcrs were collected in the first 72 h after infant birth. if an infant enrolment pcr was not available and a subsequent hiv-1 pcr test was negative, the enrolment pcr was imputed as negative. additional infant hiv dna pcr testing was performed at six weeks of life in government-run health facilities in accordance with botswana national pmtct guidelines with results documented in mpepu study records and by mpepu study clinicians at any visit where an infant was noted to have significant interim or current illness or insufficient weight gain. infants attending the 18-month study visit were retested for hiv status using enzyme-linked immunosorbent assay (elisa). a full blood count was drawn at randomisation (between 14 and 35 days-of-life), and 3and 6-month visits and included haemoglobin and absolute neutrophil count. infant haemoglobin and absolute neutrophil count (anc) values were graded using the division of aids (daids) table for grading and severity of adult and paediatric events, version 1.0, december 2004; clarification august 2009.21 haemoglobin or absolute neutrophil count results corresponding to daids grade 3 or grade 4 values were classified as anaemia or neutropenia. maternal verbal reports and clinical records were used to ascertain maternal arv use; all maternal arvs were provided through the government’s infectious disease care clinics. at mpepu study inception, the national policy endorsed triple arv for all hiv-infected women for pmtct (option b),19 transitioning from a policy where only women with cd4+ cell counts of < 350 cells/µl were eligible for triple arvs.20 however, option b was not fully operationalised until january 2013.22 study inclusion and exclusion criteria infants were eligible for this secondary analysis if they were born full-term (≥ 37 weeks gestation) with a birth weight ≥ 2500 g, received 25–35 days of zdv twice daily or nvp once daily and were exclusively formula-fed in the first 35 days-of-life based on maternal verbal report. where mixed feeding was reported, infants were excluded. national guidelines endorsed sdnvp within 72 h of birth for all infants receiving zdv prophylaxis. gestational age and birth weight restrictions were employed to avoid study-specific sources of bias in this secondary analysis, because preterm and low-birth-weight infants in the later study period were more likely to have received zdv prophylaxis. statistical methods sas, version 9.3 (sas institute, cary, north carolina, usa) was used for statistical analyses. maternal and infant characteristics were compared by infant arv prophylaxis group. continuous variables were compared using wilcoxon rank sum test. fisher’s exact testing was used for comparison of non-continuous variables and to assess mtct prevalence by infant hiv dna pcr results obtained between 14 and 35 days-of-life. exact (clopper–pearson) methods for binomial proportions were used to estimate the mtct confidence limits. time to first occurrence of infant anaemia or neutropenia in the first six months-of-life by arv prophylaxis group was compared using cox proportional hazard models, stratified by infant randomisation arm (ctx or placebo). all testing used a significance level of 0.05, with two-sided hypothesis testing. ethical consideration the health research development committee of botswana and the office of human research administration at the harvard t.h. chan school of public health approved the study protocol and amendments. women signed a written consent form approved by the ethical review boards for their and their infants’ participation. project research number: clinical trials.gov registration number: nct01229761. results of 3164 infants enrolled in the mpepu study, 1823 (58%) infants were excluded from this secondary analysis: 930 born preterm and/or with a birth weight < 2500 g, 203 evaluated only at birth, 420 breastfed infants, 69 without arv prophylaxis documentation, 95 with documentation of < 25 days of prophylaxis, 55 with extended prophylaxis (> 35 days) and 51 given dual zdv and nvp prophylaxis (figure 1). of the remaining 1341 (42%) infants, 695 received zdv prophylaxis for a median of 28 [interquartile range (iqr) 27–30] days, with 665 (95.7%) of the infants receiving zdv prophylaxis also having documentation of sdnvp dosing within 72 h of delivery. the remaining 646 infants received nvp for a median of 29 days (iqr 28–30). before the protocol change in february 2013, 2 (0.3%) infants received nvp prophylaxis, whereas 644 (86.6%) infants received nvp prophylaxis after the change. figure 1: consort diagram. characteristics of mother–infant pairs by prophylaxis regimen are presented in table 1. a significantly higher proportion of mothers of nvp recipients received triple arvs during pregnancy, as 99% of all nvp recipients were born after botswana’s national hiv treatment guidelines transitioned to option b. only 1.3% of mothers of nvp recipients received zdv monotherapy in pregnancy versus 21.4% of mothers of zdv recipients. the median days to hiv dna pcr testing at parent study randomisation (visit for initiation of ctx/placebo) was 29 days-of-life for zdv infants and 15 days-of-life for nvp infants, reflecting the earlier age at randomisation for nvp recipients after the protocol change. early closure of the lobatse site led to a higher proportion of lobatse enrolled infants receiving zdv. in all other respects, characteristics between groups were similar. table 1: comparison of mother–infant characteristic by infant antiretroviral prophylaxis. of the 1341 formula-fed infants, 9 (0.67%) represented potential intrapartum infections (hiv infection acquired during labour or delivery), having a first positive hiv dna pcr result > 72 h after delivery; 6 [0.86%; 95% confidence interval (ci): 0.32% – 1.87%] zdv recipients and 3 (0.46%; 95% ci: 0.10% – 1.35%) nvp recipients (p = 0.51). among these nine potential intrapartum infections, five were confirmed intrapartum infections, having documentation of an initial negative hiv dna pcr prior to a positive test result on a second hiv dna pcr test, two (0.29%; 95% ci: 0.04% – 1.04%) infants receiving zdv and three (0.46%; 95% ci: 0.04% – 1.12%) receiving nvp (p = 0.68). the remaining four infants, all receiving zdv prophylaxis (one without sdnvp dosing documentation), had their first hiv dna pcr test between 6 and 29 days-of-life, and it was positive. for these infants, the possibility of in utero transmission cannot be excluded. a total of 201 (15%) of the 1341 mother–infant pairs were at higher risk for vertical transmission, defined as no or < 28 days of maternal arv use during pregnancy, or maternal enrolment cd4+ cell count < 250 cells/µl. of these, 110 infants received zdv and 91 received nvp. four (2.0%) potential intrapartum transmission events occurred among high-risk infants; three (2.73%; 95% ci: 0.57% – 7.76%) zdv recipients and one (1.10%; 95% ci: 0.03% – 5.97%) nvp recipient (p = 0.63). two of the high-risk zdv recipients (one without sdnvp dosing documentation) were not confirmed intrapartum transmissions, as their first hiv dna pcr test was positive but was not drawn until more than two weeks after delivery. a total of 31 (2.3%) infants experienced at least one episode of anaemia, by daids grade 3 or grade 4 criteria, in the first six months: 19 (2.7%) zdv recipients and 12 (1.9%) nvp recipients (p = 0.36). because the parent study involved infant randomisation to ctx or placebo, and ctx can cause bone marrow suppression,23 cox proportional hazard models were used to evaluate time to first occurrence of anaemia or neutropenia by infant prophylaxis with stratification by infant randomisation arm (ctx or placebo). the adjusted hazard ratio for the time to first episode of anaemia among zdv recipients did not differ significantly from nvp recipients [ahr 1.51 (95% ci: 0.73–3.14), p = 0.26] after stratification. daids grade 3 or grade 4 neutropenia occurred more frequently than anaemia, with 49 (3.7%) infants experiencing at least one episode in the first six months; 28 (4.0%) zdv recipients and 21 (3.3%) nvp recipients (p = 0.47). time to first episode of neutropenia did not differ significantly for zdv recipients compared with nvp recipients [ahr 1.04 (95% ci 0.57–1.91), p = 0.90] after stratification by ctx versus placebo. discussion using data from the mpepu study, we provide the first comparative evaluation of vertical transmission and haematologic safety among full-term, normal birthweight, formula-fed hiv-exposed infants, analysing infant prophylactic regimens of sdnvp and zdv twice daily versus nvp once daily. whether including confirmed or potential intrapartum transmissions, the intrapartum mtct incidence was low in this cohort where over 80% of all women received triple arvs during pregnancy. reassuringly, vertical transmission was low for both infant prophylaxis regimens. even among mother–infant pairs at highest risk for mtct, both infant prophylaxis regimens achieved low vertical transmission outcomes. daids grade 3 and grade 4 anaemia and neutropenia events were each noted in fewer than 5% of infants, with no significant difference between prophylaxis groups in the first six months-of-life. this study reduced bias by reporting confirmed and potential intrapartum transmissions and utilising very similar comparison groups from each study era. however, the study design imposed some limitations to this secondary analysis. first, preterm and low-birth-weight infants in the mpepu study were more likely to receive zdv. unfortunately, this precluded analysis of transmission outcomes and haematologic safety among infants born at < 37 weeks gestational age or with a birth weight < 2500 g, excluding nearly 30% of the infants in the mpepu study. second, it is possible that some false-negative hiv dna pcr results may have occurred, because testing was performed at the time the infant was taking prophylaxis or within days of discontinuing prophylaxis. however, in a study conducted by burgard and colleagues evaluating the sensitivity of hiv dna pcr performed between 15 and 45 days-of-life among 1293 formula-fed hiv-exposed infants, the sensitivity of hiv dna pcr during this window when infants were taking or had recently completed arv prophylaxis was quite high (88%).24 mpepu study infants were referred for hiv dna pcr testing at six weeks of age under botswana’s national programme, with no positive tests known to the study team. furthermore, 48% of formula-fed children had an 18-month elisa through the study (the remaining 52% were not followed to 18 months owing to early closure of the study for futility, at the recommendation of the data safety and monitoring board); all but one of these children had a negative elisa at 18 months-of-life (the one infant with a positive elisa had documentation of a negative hiv dna pcr at three months-of-life, suggesting hiv acquisition from a source other than intrapartum hiv transmission, such as undisclosed breastfeeding). third, this analysis involved comparison of infants from two consecutive time periods. as such, temporal confounders may be present. for example, less extensive maternal art coverage in the earlier study era may explain the non-significant increase in overall (but not confirmed) intrapartum transmission events with zdv (6 vs. 3). in terms of haematological toxicity, we acknowledge that the mpepu testing schedule with a full blood count obtained between 14 and 35 days-of-life with follow-up at 3and 6 months-of-life may have missed the occurrence of anaemia or neutropenia shortly after the infant discontinued arv prophylaxis but before the 3-month visit. lastly, this is a retrospective analysis of a study specifically designed for other purposes. as such, it was not powered to detect prophylaxis efficacy between the two infant regimens. although a larger study with more complete birth pcr testing might have provided better discrimination between nvp and zdv, the very low overall occurrence of mtct in the mpepu study suggests that clinically meaningful differences in transmission were not missed. in conclusion, while formula feeding of hiv-exposed infants in resource-limited settings remains the exception, our study findings provide reassuring evidence that a 4-week infant prophylaxis regimen of either sdnvp plus zdv or ongoing nvp was similarly efficacious for pmtct among formula-fed, full-term, normal birthweight infants in the context of extensive maternal art use, without significant differences in haematologic adverse consequences. prior to this study, the who recommendation for the use of sdnvp plus zdv versus nvp was categorised as ‘conditional’ and based upon low evidence. our comparative analysis strengthens the evidence, supporting current who recommendations for use of either zdv or nvp as prophylaxis among hiv-exposed full-term infants in the first month of life to prevent intrapartum hiv acquisition. acknowledgements the mpepu study was supported by funding from the national institute of child health and human development and the national institute of allergy and infectious diseases (r01 hd061265). k.m.p. received salary support from the national institute of child health and human development (k23hd070774). competing interests the authors declare that they have no financial or personal relationship(s) that may have inappropriately influenced them in writing this article. authors’ contributions r.l.s. and s.l. were the principal investigators of the parent study, mpepu, and k.m.p. and g.a. were the study coordinators for the mpepu study. o.b. and k.b. (botswana harvard aids institute partnership) were mpepu study clinicians and k.m.p., g.a., o.b. and k.b. routinely interacted with women and infants enrolled in this study to collect data and specimens. e.v.w is the information technology manager at botswana–harvard aids institute partnership (bhp). he designed the electronic data capture systems for the mpepu study. both e.v.w. and j.l. assisted in the preparation of data sets for the secondary analysis presented in this manuscript. s.m. is the lab director at bhp and processed and resulted all the specimens or lab tests presented in the manuscript. k.m.p. designed the study and performed the primary statistical analyses for the manuscript, with k.b. (bennett statistical consulting, inc.) and m.d.h. providing validation of the statistical code and outcomes reported in the manuscript. k.m.p. wrote the first draft of the manuscript, with first draft editing support from r.l.s. and s.l. all co-authors of the manuscript, including j.m., c.p., h.b.j., k.m. and m.e. reviewed the final draft and provided meaningful edits to the final version of the manuscript submitted. references connor em, sperling rs, gelber r, et al. reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. pediatric aids clinical trials group protocol 076 study group. n engl j med. 1994;331(18):1173–1180. https://doi.org/10.1056/nejm199411033311801 thior i, lockman s, smeaton lm, et al. breastfeeding plus infant zidovudine prophylaxis for 6 months vs formula feeding plus infant zidovudine for 1 month to reduce mother-to-child hiv transmission in botswana: a randomized trial: the mashi study. jama. 2006;296(7):794–805. https://doi.org/10.1001/jama.296.7.794 six week extended-dose nevirapine study team, bedri a, gudetta b, et al. extended-dose nevirapine to 6 weeks of age for infants to prevent hiv transmission via breastfeeding in ethiopia, india, and uganda: an analysis of three randomised controlled trials. lancet. 2008;372(9635):300–313. https://doi.org/10.1016/s0140-6736(08)61114-9 chasela cs, hudgens mg, jamieson dj, et al. maternal or infant antiretroviral drugs to reduce hiv-1 transmission. n engl j med. 2010;362(24):2271–2281. https://doi.org/10.1056/nejmoa0911486 kumwenda ni, hoover dr, mofenson lm, et al. extended antiretroviral prophylaxis to reduce breast-milk hiv-1 transmission. n engl j med. 2008;359(2):119–129. https://doi.org/10.1056/nejmoa0801941 anitretroviral drugs for treating pregnant women and preventing hiv infection in infants: recommendations for a public health approach 2010 version [homepage on the internet]. world health organization; 2010 [cited 2017 oct 01]. available from: http://apps.who.int/iris/bitstream/10665/75236/1/9789241599818_eng.pdf world health organization. consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection: recommendations for a public health approach. 2nd ed. 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testing discussion conclusion acknowledgements references about the author(s) madeleine whalen johns hopkins hospital, united states pamela mda department of medicine, faculty of health sciences, walter sisulu university, south africa andy parrish department of medicine, faculty of health sciences, walter sisulu university, south africa department of internal medicine, frere and cecilia makiwane hospitals, south africa thomas c. quinn division of intramural research, national institute of allergy and infectious diseases, united states division of infectious diseases, johns hopkins school of medicine, unite states richard rothman department of internal medicine, frere and cecilia makiwane hospitals, south africa david stead department of medicine, faculty of health sciences, walter sisulu university, south africa department of internal medicine, frere and cecilia makiwane hospitals, south africa bhakti hansoti department of emergency medicine, johns hopkins university, united states citation whalen m, mda p, parrish a, et al. implementing emergency department-based hiv testing in a low-resource setting: the value of a structured feasibility assessment tool. s afr j hiv med. 2018;19(1), a793. https://doi.org/10.4102/sajhivmed.v19i1.793 original research implementing emergency department-based hiv testing in a low-resource setting: the value of a structured feasibility assessment tool madeleine whalen, pamela mda, andy parrish, thomas c. quinn, richard rothman, david stead, bhakti hansoti received: 28 july 2017; accepted: 17 apr. 2018; published: 16 july 2018 copyright: © 2018. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract introduction: hiv is a worldwide health problem with continuing high rates of new infections in many parts of the world. this lack of progress in decreasing overall incidence rates has sparked innovative hiv testing strategies, including expansion of testing into the emergency department (ed) setting. emergency departments have been shown to be high-yield testing venues in the united states and other developed world settings. the feasibility of expanding public health hiv services in the ed in limited-resource countries is unclear. methods: we performed a cross-sectional feasibility assessment of a convenience sample of four hospitals in the eastern cape, south africa. we administered three adapted interview tools from a previously field-tested survey instrument at each facility (total of 10 interviews) to gather an overview of the health facility, their hiv counselling and testing services, and their laboratory services. results: all of the health facilities had access to basic commodities such as water and electricity. many had severe human resource limitations and provided care to wide population catchment areas. in addition, there was little integration of hiv testing into current daily ed operations. hospital staff identified numerous barriers to future ed testing efforts. conclusions: although control of the hiv epidemic requires innovative testing strategies and treatment, specific assessments are warranted on how to incorporate routine hiv testing into an acute care facility like the ed, which typically has many competing priorities. the use of a prospective structured tool incorporating both barriers and benefits can provide valuable field-tested guidance for increased programme planning for hiv testing. introduction the joint united nations programme on hiv/aids (unaids) estimates that more than 10 million people worldwide have contracted hiv since 2011.1 despite public health efforts in key areas, such as west and central africa, declines in new hiv infection rates are ‘marginal’.2 to address stagnated hiv incidence, the world health organization (who), the united kingdom’s health protection agency and the united states’ centers for disease control and prevention (cdc) recommend expanded and integrated hiv testing strategies. this includes testing for all healthcare clients, including those utilising emergency services.3,4,5 the inclusion of the emergency department (ed) represents a viable and effective strategy for hiv testing in both the high-resource and resource-limited settings. emergency departments provide unrestricted access to large numbers of patients who may not otherwise interact with the healthcare system, and have been shown to effectively identify new hiv infections in high-resource settings.6,7,8 studies that have sought to quantify the effectiveness of ed-based hiv testing in low-resource settings are limited but have found an hiv prevalence of 2% – 43% with a proportion of 65% – 90% of previously undiagnosed hiv infection.9 in addition, eds care for key high hiv-risk populations, such as drug and alcohol users, young men and sex workers who are missed in more traditional settings such as antenatal clinics.1,10 despite the global hiv burden, national and international recommendations, as well as the demonstrated efficacy of ed-based testing in the united states, implementation has been inconsistent. a 2009 survey found that only 22% of eds provided routine hiv testing, and of those, less than a third followed the recommended ‘opt-out’ format in the united states.11 a 2013 meta-analysis of hiv testing in the united kingdom found that only 27.2% of eligible patients, as defined by the 2008 british hiv association guidelines, received hiv testing.12 likewise, south african national testing guidelines call for universal hiv testing in all health facilities, including the ed, with preand post-test counselling; however, it is rarely implemented.13 given this gap between practice and policy, a structured feasibility assessment may provide insight into barriers to implement effective and efficient ed-based hiv testing. feasibility assessments are a key early component of dissemination and implementation of science and can have a large effect on an intervention’s acceptability, which in turn influences adoption, penetration and sustainability.14 the use of an appropriate and efficient assessment tool addresses the implementation component of a theoretical recommendation and provides prospective data on human and physical resources that need to be developed or supplemented to truly incorporate hiv testing into sustainable standards of practice. in addition, the use of a tool goes above and beyond more common feasibility assessments which do not proactively gather data but rather implement screening and then retrospectively evaluate their success using testing uptake as a proxy for feasibility.15,16,17,18,19,20,21 assessment tools are available from the who, family health international, partners in health and other hiv/aids organisations.22,23,24,25 in this study, we seek to evaluate the usability and importance of a pre-implementation facility assessment tool in a low-resource setting where implementation of ed-based hiv testing is desperately needed. methods we performed a cross-sectional feasibility assessment of a convenience sample of four tertiary hospitals in the eastern cape of south africa. hospitals were selected in the eastern cape based on geographic accessibility, existing relationships with participating institutions and the prioritisation of research efforts by the medical research council of south africa. institutional review boards at johns hopkins university and walter sisulu university approved the study (irb number irb00105801). survey instrument we utilised three interview tools in accordance with guidelines from family health international’s health facility tools to assess preparedness for hiv service delivery.23 the guide consists of 13 tools that were designed to rapidly and comprehensively gather data regarding the availability and quality of essential elements of hiv services, organise and analyse the data, and plan for programme implementation. the guide has been field tested in cambodia, ethiopia, nigeria, kenya, senegal and zambia and was designed to be flexible for adaption to meet individual site needs.23 the interview tools in our study were selected by both international and local researchers (authors m.w., b.h. and p.m.) based on applicability to the south african ed setting. two of the tools were administered without change from the original text. the third tool, an assessment of laboratory services, was modified to only include information that could not be gathered from review of the national health laboratory service of south africa scope of services.26 the interview tools included yes/no, closedand open-ended questions, as well as interviewer observations. this specific feasibility assessment toolkit was chosen based on a review of available tools and its previous use in low-resource settings. an overview of each of the three tools can be seen in figure 1. the three tools in their entirety can be found at http://www.aidsdatahub.org/sites/default/files/documents/health_facility_tools_to_assess_preparedness_for_hiv_services_delivery_including_antiretroviral_therapy.pdf. figure 1: tools summary. data collection interviewees consented to using the provided script and delivered their responses orally or via email. in-person interviews were conducted in the interviewees’ private offices. all interviews were conducted in english by the johns hopkins university researcher (m.w.) with facilitation from the walter sisulu university research partner (p.m.). data analysis all answers were recorded on the paper survey tools and later entered into excel for side-by-side analysis of each question for all four sites. the majority of questions were closed-ended and direct responses were recorded. for open-ended questions, the researcher listed each response verbatim, then combined and tallied repeated answers. interviewees selected answers from a finite list regarding barriers and benefits to ed-based hiv testing as well as provided open-ended responses. these answers were then combined into one table. narrative answers that commented on the same problem, but with slightly different language (e.g. ‘manpower’ and ‘staff’), were grouped. results a total of 10 interviews were completed across four sites. information was gathered from four lab supervisors, three physicians and three nurses. interviewees are identified in table 1. table 1: interviewee role identification. facility characteristics all facilities are state-run tertiary academic hospitals and operate under walter sisulu university. all sites have 24-hour access to electricity (with back-up generators), water and computers. none of the eds have designated laboratory personnel to perform point-of-care testing, and only one site, lh, has an in-department, part-time pharmacist. in-depth facility descriptions are shown in table 2. table 2: facility descriptions. health services each of the four hospitals has inpatient and outpatient departments. in addition, all of the eds provide physician-initiated, targeted hiv testing. patients found to be hiv-positive are referred to their community antiretroviral (arv) clinic using a standard referral form with the exception of livingstone hospital, which performs direct doctor-to-doctor sign-out on referred patents. available health services at all hospitals include rapid and diagnostic hiv testing, arv clinic, social services, pharmacy and post-exposure prophylaxis for employees only. frere hospital, nelson mandela hospital and lh have on-site national health laboratories and are able to perform all hiv-related testing. cecilia makiwane hospital sends specimens offsite for testing. benefits and barriers to emergency department-based hiv testing in addition to concrete information regarding provision of services related to hiv in the ed, we gathered subjective information from key informants regarding benefits and barriers to hiv testing in the ed. responses to both open and closed-ended questions regarding testing barriers and potential benefits are included in table 3. each response is followed by the frequency it was listed in parentheses. table 3: opportunities and barriers to emergency department–based hiv testing. discussion the use of a structured feasibility assessment tool demonstrated concrete barriers to ed-based hiv testing that will need to be addressed at the institutional level prior to implementing an ed-based hiv testing strategy. however, some of the identified barriers are likely to spark controversy and will require strategies for improvement beyond the ed. use of a structured tool informed understanding of staffing shortages (mix as well as amount), the structure of ed services in the context of the institution and cultural barriers. the descriptive nature of these interview tools brings new illustrative information to the study of hiv testing implementation.27 this assessment clearly demonstrated the lack of available human resources to take on new responsibilities and projects, such as implementation of ed-based hiv testing. the number of full-time ed nurses ranged from 24 to 84 to serve large daily volumes of patients. emergency department physician staffing only ranged from 11 to 14 full-time providers to serve the same population. the shortage of nurses and doctors in south africa, specifically those with emergency training, is an ongoing problem and will need to be factored into any new programme implementation.8,28,29 in addition, none of the facilities has ancillary staff that could potentially take on the new responsibility of hiv testing and counselling, such as social workers, laboratory technicians or other cadres. these numbers demonstrate a clear barrier to ed-based hiv testing and help to create a more robust picture of the human resource constraints to successful implementation of the hiv testing policy. the question of availability and willingness of staff is cited in many accounts of ed-based hiv testing in both highand low-resource settings.20,30,31,32 the feasibility assessment tool provided a structured approach to garner information at each of the facilities and how the ed functions as a part of the whole. for all facilities, hiv testing has been systematically and purposefully shifted to outpatient and community arv clinics.13 this system of assigning a task to the most basic facility that can fulfil it has created both cultural and structural barriers to ed-based hiv testing, as well as missed opportunities to test new patients. none of the four eds provided universal hiv testing, and none currently has the resources to initiate arvs. this is problematic in the current hiv environment that calls for non-targeted testing and treatment regardless of symptoms, viral load or cd4+ count.33 in addition, the processing time for laboratory tests may not be conducive to the fast pace of the ed environment. finally, the structured interviews recorded perceived benefits and barriers to hiv testing. this information reinforced and illuminated much of the information gathered through the objective interview tools. gathering these data describes institutional knowledge and individual attitudes. items such as health and hospital policy need to be addressed in order to successfully introduce a change in practice and culture. in addition, the perception that the ed is not the venue for testing for communicable diseases appears to be ingrained in hospital culture, and a campaign to challenge this assumption may need to be incorporated into project planning. the prevalent themes of lack of provider knowledge, costs, insufficient time, insufficient space and linkage to care (ltc) issues are apparent in this setting and echo concerns noted in ed-barrier studies completed in the united states and the united kingdom.27,31,32,34,35,36 the overall concept of reframing the role of the ed in public health initiatives is a prevalent theme in both highand low-resource settings.20,31,35 in addition, mumma and suffaletto30 highlight the need for public health officials to recognise the many competing priorities of the ed and create a collaborative project that meets both the acute care and public health needs of the population.30 implementation of family health international’s interview guides was simple, and the language was accessible to the interviewees, including those for whom english was not a first language. some of the questions required both high-level institutional knowledge and department-level statistics (e.g. number of full-time and part-time employed nurses) that was difficult for some respondents to provide. the questionnaires are also lengthy which makes sustained quality data collection difficult, given that it requires interviews with key informants in busy leadership positions. in addition, the key question of funding a new hiv testing initiative is not addressed in this assessment. our study did not utilise family health international’s provider or client attitudes tools but rather incorporated a more in-depth attitudes interview that included healthcare provider stigma and patient hiv knowledge at fh that has been previously described in this journal.37 future pre-implementation efforts will need to continue to gather information on acceptability at all sites as it is a large component of cultural feasibility. the use of this feasibility assessment provided essential information at the hospital level that, if expanded, could be used to influence policy at the institutional, provincial, state and even national level. in addition, given the documentation of the shortages of physical and human resources as well as staff buy-in found in this, and other feasibility assessments, it may be unethical to mandate new hiv testing strategies without accompanying solutions.31,35 in order to further inform the feasibility of ed-based hiv testing in these facilities, it will be important to administer both patient and provider questionnaires at all sites to evaluate cultural barriers, including stigma.37 in addition, the cost-effectiveness and financial feasibility of implementing a novel hiv testing programme will need to be studied. given the time-prohibitive length of the surveys, it may also be beneficial to administer the tools in a setting that already provides ed-based hiv testing to determine which questions truly add value. this abbreviated questionnaire could then be validated. a priority matrix may also be a helpful prioritisation tool to organise results. as this study was performed with a small convenience sample of four hospitals, it is limited in its generalisability to other institutions. the range of hospital resources and capacity is widely varied not only throughout south africa but also across low-resource settings. in addition, interviewees provided information from their knowledge base and catchment areas; ed volumes, staffing numbers and laboratory times are estimates. finally, bias is inherent to qualitative interviewing techniques. structured interview guides were used to minimise interviewer level variation, but it cannot be completely eliminated.38 conclusion this feasibility assessment helped to inform the possibility of initiating ed-based hiv testing by establishing an anticipatory list of barriers that will need to be addressed prior to initiation of a new testing strategy. although potentially high yield, ed-based hiv testing in south africa will need to have dedicated resources to shift the cultural perception of acute care versus public health mandates, as well as physical limitations such as funding, staff and space. possible solutions to these obstacles could be incorporation of more traditional strategies, such as clinic-based testing, diverting testing resources to the inpatient setting owing to the captive audience of patients, or provision of at-home or self-testing kits to all ed patients.39,40 taking advantage of blood samples already sent to the laboratory for add-on testing may also increase hiv testing volumes while minimising performing point-of-care testing on frontline staff.41,42 acknowledgements this research was made possible by the staff and ceos of frere hospital, cecilia makiwane hospital, livingstone hospital, nelson mandela hospital, walter sisulu university, and supported in part by the division of intramural research, niaid, nih and johns hopkins department of emergency nursing. competing interests the authors declare no potential conflict of interest. authors’ contributions m.w. designed and conducted the study, analysed the data and drafted the manuscript. p.m. contributed to the study design and provided revisions to the manuscript. a.p., d.s., r.r. and t.c.q. contributed to the drafting and revision of the manuscript. b.h. oversaw the study and contributed to the study design, data analysis and 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literature. aids. 2007;21(12):1617–1624. https://doi.org/10.1097/qad.0b013e32823f91ff hecht cr, smith md, radonich k, kozlovskaya o, totten vy. a comparison of patient and staff attitudes about emergency department–based hiv testing in 2 urban hospitals. ann emerg med. 2011;58(1):s32.e4. world health organization. progress report 2016: prevent hiv, test and treat all: who support for country impact. geneva: world health organization; 2016. irvin cb, flagel bt, fox jm. the emergency department is not the ideal place for routine hiv testing. ann emerg med. 2007;49(5):722. https://doi.org/10.1016/j.annemergmed.2007.03.011 waxman mj, popick rs, merchant rc, rothman re, shahan jb, almond g. ethical, financial, and legal considerations to implementing emergency department hiv screening: a report from the 2007 conference of the national emergency department hiv testing consortium. ann emerg med 2011;58(1):s43. https://doi.org/10.1016/j.annemergmed.2011.03.021 hsieh y, jung jj, shahan jb, moring-parris d, kelen gd, rothman re. emergency medicine resident attitudes and perceptions of hiv testing before and after a focused training program and testing implementation. acad emerg med. 2009;16(11):1165–1173. https://doi.org/10.1111/j.1553-2712.2009.00507.x hansoti b, hill se, whalen m, et al. patient and provider attitudes to emergency department-based hiv counselling and testing in south africa. s afr j hiv med. 2017;18(1):1–7. broom a. using qualitative interviews in cam research: a guide to study design, data collection and data analysis. complement ther med. 2005;13(1):65–73. https://doi.org/10.1016/j.ctim.2005.01.001 liddicoat rv, horton nj, urban r, maier e, christiansen d, samet jh. assessing missed opportunities for hiv testing in medical settings. j gen intern med. 2004;19(4):349–356. https://doi.org/10.1111/j.1525-1497.2004.21251.x gaydos ca, hsieh y, harvey l, et al. will patients ‘opt in’ to perform their own rapid hiv test in the emergency department? ann emerg med. 2011;58(1):s78. https://doi.org/10.1016/j.annemergmed.2011.03.029 lyss sb, branson bm, kroc ka, couture ef, newman dr, weinstein ra. detecting unsuspected hiv infection with a rapid whole-blood hiv test in an urban emergency department. j acquir immune defic syndr. 2007;44(4):435–442. https://doi.org/10.1097/qai.0b013e31802f83d0 cornett jk, kirn tj. laboratory diagnosis of hiv in adults: a review of current methods. clinical infect dis. 2013;57(5):712–718. https://doi.org/10.1093/cid/cit281 several extraordinary people have been involved in taking the hiv clinicians society from a small group of interested clinicians to one of the largest medical interest groups in the world. mick graham arrived in south africa four years ago from drizzly london, and has made it his home. originally deployed to help non-governmental organisations sort themselves out, through the british-based volunteer services organisation (vso), mick joined the society during a staffing crisis. on his first day he was tasked with getting the society back on its feet, especially as we had just been given a major grant to help establish a range of new projects. deftly negotiating the complex politics that bedevil everything around hiv, mick efficiently improved on the organisational structures of the society while building up the staff complement to the stage where it is now selfsufficient. mick’s keen negotiation skills, honed while a justly feared trade union representative in his home country, were put to good use in getting great deals from publishers, sponsors and advertisers, all for the good of the society. in a very short time he established the society as a viable operation, with the journal, transcript, the guidelines and much of our commercial communication rapidly gaining financial independence. mick’s attention to organisational process has ensured that today the society is a much stronger and more robust organisation, well positioned for the challenges of the future. mick will always be the ideal dinnertime companion. conversations are liberally sprinkled with ‘as my good friend george bernard shaw said …’, when not regaling us with his lunches with prime minister tony blair and stories from northern england’s steelworks. we owe mick a large debt, and will miss his contribution to fighting hiv, less than efficient contractors, and bad white wine. the society, the general manager and the executive wish him well in his semi-retirement. francois, fatima, pat, natalie, jean, chloe, kerry, linda-gail 5 there is a strong feeling in the field that it is ‘back to the drawing board’ on prevention in hiv. perhaps the most compelling possibilities going forward involve the use of antiretrovirals for prevention. without doubt, next to prevention of vertical transmission the most emotive reasons for prevention include the immediate use of antivirals to prevent infection in those recently exposed. a large part of this spring edition is dedicated to post-exposure prophylaxis (pep). the reduction of mother-to-child transmission is evidence that antiviral therapy at the time when infection is occurring can abort the establishment of that infection. the pep guidelines as they appear in this edition may be thought of as controversial, and we welcome comments in this regard. there is an equally controversial legal take on the risks of hiv transmission in sport by verrier and tuson, and a short report on the importance of counselling and support for rape victims who are taking antivirals after rape. the issue also includes an account of the local experience of engaging with traditional healers in hiv programmes by wreford and esser, and some recommendations for completing death notification forms in the hiv era by smith. woods et al. describe the challenges of training health professionals, in particular nurses, to manage hiv, and present an innovative methodology for training. finally there are two instructive clinical case studies, one on rhabdomyolysis following a drug reaction in an infected patient by ramogi and the other the all too common problem of concurrent treatment of tuberculosis and hiv by conradie, with a second opinion from meintjes. it has been said that a week in politics is a lifetime, and this can seldom have been better illustrated than by the past few weeks in south africa. the political turbulence in our country has also seen the closing of the ‘manto’ era, and many, activists and practitioners alike, have voiced an array of sentiments about this in the last few days. those of us (and thankfully there are many) committed to seeing the countrywide, successful roll-out of pmtct, antiretrovirals, testing and a variety of prevention strategies, as well as solid operational research, wish health minister barbara hogan and her team strength, wisdom and tenacity in taking us forward with bold new steps. linda-gail bekker editor f r o m  t h e  e di tor the southern african journal of hiv medicine                                                          winter  2008 mick graham t r i b u t e from the editor.indd 1 10/14/08 9:48:59 am december 2014, vol. 15, no. 4 sajhivmed 119 o r ig in a l a r t ic l eletter managing the hiv-infected neonate: a rural doctor’s perspective to the editor: continued improvements for prevention of mother-to-child transmission (pmtct) of hiv have dramatically reduced the number of vertical infections. however, a number of risk factors for transmission are still seen. there is an increasing awareness that more should and could be done to prevent transmission in these cases, and that targeted early diagnosis (soon after delivery) adds significant value in some infants to prevent prolonged nevirapine exposure leading to resistance, allows for rapid initiation of antiretroviral therapy as per the current guideline, and retains the infant and mother in care. managing hiv-infected neonates is complex. few antiretrovirals have dosages for the first 4 weeks of life. lopinavir/ritonavir (lpv/solution, kaletra, abbott laboratories, south africa) is contraindicated for the first 42 weeks post conception. [1] with regard to nucleoside reverse transcriptase inhibitors, zidovudine is the only agent with adequate dosage information for term and premature infants, there is no dose for abacavir, and lamivudine dosage is lower than that for older infants. nevirapine is safer in neonates, although therapeutic dosage and need for induction dosage for 2 weeks are uncertain. in the longer term, kaletra is superior to nevirapine in infants regardless of prior nevirapine exposure, although there are few data in the first 2 3 weeks of life, with exposure being lower than in older infants.[2] the social issues that have caused poor/incomplete access to prevention programmes often persist and complicate management. many experienced paediatricians grapple with these issues, and there is currently no consensus on the best approach. rural doctors are often confronted with challenging cases with respect to initiating neonates and infants on highly active antiretroviral therapy (haart) and need to make pragmatic decisions. at ceres provincial hospital, we have begun screening for mothers at increased risk of transmitting hiv to their infants in the labour ward. their infants are given nevirapine plus zidovudine for postexposure prophylaxis, and we perform early polymerase chain reaction (pcr) tests. we recently identified our first infected neonate. the mother (a 28-year-old primigravida) booked early and rapid tests were negative at 8 and 32 weeks. she was retested during labour, and the rapid hiv test was positive. the mother received zidovudine, single-dose nevirapine and truvada in the labour ward. the baby was delivered through caesarean section for breech presentation. the mother starting receiving antiretroviral therapy (art) the next day. the baby received zidovudine and nevirapine at birth, and breastfeeding was commenced. an early diagnostic pcr was fast-tracked by contacting the national health laboratory service. fortunately, the mother was still hospitalised when we received the positive results; the baby was in its 5th day of life. we contacted the medicine information centre hiv hotline for further assistance, and were put in contact with a local paediatrician experienced in hiv care. as per telephonic advice, we initiated triple therapy with zidovudine, lamivudine and full doses of nevirapine on day 6 of life. kaletra was prescribed at the appropriate age. the mother was educated and instructed on how to give art correctly, and continued with her own medication and exclusive breastfeeding. mother and baby are being followed at the local well baby clinic and the regional hiv clinic; they attend regularly and are healthy with no side-effects. the doctor caring for the mother and infant communicates regularly with the nurses in the mother’s community. the viral load of the mother and infant will be measured at 4 months of therapy. the key lessons learned from this case are shown below: • healthcare providers should not be distracted by negative hiv tests in pregnancy. • pregnancy is associated with an increased risk of hiv acquisition. in addition, we should emphasise safe sex practices and recommend partner testing. • rural doctors and nurses can implement expanded prevention and early diagnosis to infants at increased risk. • there is still a need for point-of-care testing to allow for rapid management of infants and their mothers. • communication between staff at the different service points is essential to ensure good follow-up care. • although immediate access to art should be the goal, allowing space and time to come to terms with the diagnosis may be needed. • transfer of infants to specialist centres is unnecessary provided there is a specific doctor or nurse to assume responsibility for the infant, and specialist advice is readily available. • there is a need for pragmatic guidelines for the management of term and preterm infants. if we are unable to prevent vertical hiv transmission, the next best option is early recognition and rapid access to therapy. d demas,1 h rabie,2 m f cotton2 1 district health service (boland), ceres provincial hospital, ceres, south africa 2 department of paediatrics and child health, stellenbosch university, tygerberg hospital, cape town, south africa references 1. abbvie. lopinavir/ritonavir package information. http://www.rxabbvie. com/pdf/kaletratabpi.pdf (accessed june 2014) 2. palumbo p, lindsey jc, hughes md, et al. antiretroviral treatment for children with peripartum nevirapine exposure. n engl j med 2010;363(16):1510-1520. l e t t e r abstract introduction materials and methods ethical consideration results discussion conclusion summary acknowledgements references about the author(s) ridwaan essa department of otorhinolaryngology, university of the witwatersrand, johannesburg, south africa shivesh maharaj department of otorhinolaryngology, university of the witwatersrand, johannesburg, south africa kapila hari department of internal medicine, faculty of health sciences, university of the witwatersrand, johannesburg, south africa shahpar motakef department of otorhinolaryngology, university of the witwatersrand, johannesburg, south africa citation essa r, maharaj s, hari k, motakef s. tonsil histopathology in hiv-infected versus hiv-uninfected adults. s afr j hiv med. 2019;20(1), a936. https://doi.org/10.4102/sajhivmed.v20i1.936 original research tonsil histopathology in hiv-infected versus hiv-uninfected adults ridwaan essa, shivesh maharaj, kapila hari, shahpar motakef received: 29 nov. 2018; accepted: 26 feb. 2019; published: 28 may 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the relationship between hiv and tonsil malignancy has not been fully investigated and established. both of these diseases prominently feature in the otorhinolaryngology clinics. objective: there is minimal data available on the histopathology of tonsillectomy specimens in the hiv-infected population. this retrospective review compared tonsil histopathology between hiv-infected and hiv-uninfected patients. methods: of the 319 adult patients undergoing tonsillectomy (01 july 2005 to 30 june 2015), hiv results were available for 160. the histological findings were compared in the hiv-infected and hiv-uninfected subgroups. the effects of age, hiv status and cd4 count on the risk of malignancy were determined. results: there were 86 patients who were hiv-infected and 74 were uninfected. reactive lymphoid hyperplasia was the most common diagnosis in both groups (77%). malignancies were diagnosed in eight hiv-infected and six hiv-uninfected patients, an insignificant difference. conclusion: the majority of patients undergoing tonsillectomy had benign conditions. hiv status does not appear to be a specific risk factor for tonsil malignancies, but advanced age may be. keywords: hiv; malignancy; tonsil; tonsillectomy; hiv-infected patients; hiv-uninfected patients. introduction in resource-rich centres, histopathology assessments are performed routinely on adult tonsillectomy specimens.1 the merits of routine tonsillar histopathology in poorly resourced centres have been questioned.2 a recent systematic review by rokkjaer et al. (12 studies including 6434 patients) concluded that there is inadequate proof for routine histological examinations from patients who do not exhibit high-risk features.3 beaty et al. in 1998 identified certain features that were associated with an increased risk of tonsillar malignancy: history of cancer. tonsillar asymmetry. tonsil firmness. visible lesions. concomitant neck adenopathy. unexpected weight loss. constitutional symptoms (fatigue, night sweats, fever, anorexia).4 recent evidence suggests that hiv infection should be considered an additional risk factor for malignancy.1 in view of the limited data in our setting, especially in the adult population where the prevalence of hiv infection is high (18% in the adult population),5 we set out to determine whether tonsillar histological studies differed between the hiv-infected and hiv-uninfected patients. few studies have documented the effect of hiv infection on tonsillar histology. one nigerian study by adoga et al. reviewed 61 patients. the cohort comprised 35 children and 26 adults. they did not comment on the number of patients with hiv infection, although they did detect lymphoma in an adult patient with hiv. they concluded that a request for histopathology on tonsillectomy specimens should be based on the presence of established risk factors with consideration of the cost to patients and to spare histopathological resources.6 a south african study by von lierop et al. evaluated the impact of hiv on the incidence of adenotonsillar lesions in the paediatric population. of the 172 patients evaluated in their study, 50% were hiv-positive. they detected only one case of lymphoma, and the patient was hiv-negative. they concluded that, given the high cost of pathological examinations, routine pathology would not be cost effective.1 the palatine tonsils play an important role in immunologic surveillance and resistance to infection in the upper aero digestive tract. palatine tonsils taken from individuals infected with hiv-1 have shown infected lymphocytes localised to the surface of the tonsillar crypt epithelium. thus, hiv may replicate rapidly at this site because of the numerous t-cells and dendritic cells present. hiv is rarely transferred through the oral cavity and oropharynx as long as the mucosa is intact as demonstrated by a laboratory experiment, whereby minimal transfer of hiv was found after human tonsillar tissue was bathed in hiv semen with an intact mucosa.7 hiv infection is associated with an increased risk of a range of malignancies given as follows: acquired immunodeficiency syndrome (aids) defining (virus-related): kaposi sarcoma (ks). non-hodgkin’s lymphoma (nhl). cervical cancer. non-aids defining carcinomas (nadc): lung. liver. anal. tonsillar.8 in the case of tonsillar malignancies, co-infection with human papilloma virus (hpv) is thought to be responsible for the increase, but hiv itself may play a role.8 ks is a frequently reported mesenchymal neoplasm characterised by neoangiogenesis and endothelial-derived, spindle-shaped tumour cells in hiv-infected people, and it is caused by human herpes virus 8 (hhv8). ks is usually isolated to the skin and oral mucosa although it may also occur in the lungs, liver, stomach, bowel and lymph nodes. it has also been described in multiple mucosal sites, including the pharynx, larynx, nasal cavity, oral cavity and the palatine tonsil.9 lymphomas are the most common malignancy in hiv-infected individuals. they represent more than 50% of aids-related malignancies. hiv-associated lymphomas are usually: high grade clinically advanced at presentation associated with extra nodal disease. common nhls occurring with hiv are diffuse large b-cell lymphoma and burkitt’s lymphoma. hodgkin’s lymphoma does occur, but not as commonly as nhl.10 it has been shown that for nadc, the cd4 count does not appear to play a singular role in carcinoma development.8,11 it is thought that co-infection with certain viruses resulted in an increased incidence of malignancy. the viruses implicated are hpv, epstein–barr virus (ebv), hepatitis c and hhv 8.11 there is also a growing body of evidence that hiv has a direct effect on oncogenes and inactivates tumour-suppressor genes; it may even cause more susceptibility to the effects of the co-existing viral infections. it has been shown that cells involved in the immune system of hiv-positive patients have a shortening of the telomeres.10 this may indicate that hiv-positive patients have a more rapid rate of immunologic ageing predisposing to malignancy.10,11 materials and methods we reviewed our departmental theatre registries and identified 319 patients with tonsillar histopathology. the surgical procedures were performed between 01 july 2005 and 30 june 2015 at the chris hani baragwanath hospital, charlotte maxeke johannesburg academic hospital and helen joseph hospitals, johannesburg, south africa. these are teaching hospitals affiliated to the university of the witwatersrand. the patients’ histology and laboratory records were collected from the national health care laboratory database. in our cohort, we included adult patients with known hiv serostatus, and 160 patients were identified. in addition, we recorded other factors, including age, cd4 count and histology result. we did not record clinical data because of incomplete medical records. ethical consideration ethics approval was obtained in march 2016 from the university of the witwatersrand (ethical clearance number: m151140). results there were 160 patients in our cohort. all the statistical tests were carried out with a 5% significance level. all the analyses were carried out using the statistical packages for social sciences version 1. ages of patients the ages of the patients in the study range from 18 to 77 years old, with a mean age of 35 years. in the hiv-positive group, the mean age was 32.5 years and the range was 19–66 years. in the hiv-negative group, the mean age was 34 years and the range was 18–77 years. figure 1 indicates the distribution of tonsillar histopathology results in hiv-infected and hiv-uninfected patients in red and blue colour, respectively. in both groups, reactive lymphoid hyperplasia was found in 77% of patients. actinomycosis was found in 12% of patients in the hiv-infected group, while in the hiv-uninfected patients, it was observed in 11% of patients. figure 1: histology results in hiv-infected (red) and hiv-uninfected patients (blue). chi-square test of independence the majority of patients (both hiv-positive and negative) had benign pathology of their tonsils. in the hiv-infected patients, eight patients (9.3%) had a malignant pathology. in the hiv-uninfected group, six patients (8.1%) had a malignant pathology. we concluded that there was no statistical evidence that hiv infection conferred an increased risk for the development of malignant tonsillar disease (see table 1 and table 2). table 1: the association between malignancy and hiv status. table 2: logistic regression of malignancy at age and hiv results. logistic regression was performed to test the effects of age and hiv infection on the presence of malignant lesions. the results indicated that when controlling for the effect of age in the model, hiv-infected patients are 1.380 times more likely to have malignant tonsillar pathology than hiv-uninfected patients. the wald tests showed that only age significantly predicted the presence of malignant pathology (p = 0.017). hiv infection did not influence the risk of developing malignant pathology (p = 0.586). this result is in accordance with the chi-square test in table 3. table 3: cd4 count: effect of cd4 count on malignant lesions. patients with a lower cd4 count (< 200 cells/mm3) would be expected to have more severe hiv disease and, therefore, a greater chance of having an hiv-associated malignancy. in our study, a low cd4 count did not appear to affect the occurrence of malignant lesions (p = 0.928). discussion we reviewed 160 tonsillectomy specimens. the most common finding on histopathology was reactive lymphoid hyperplasia, which is a pattern of hyperplasia seen in tonsils secondary to an inflammatory or immune response.12 this was present in 123 patients (77%). the findings were the same in both the hiv-infected and hiv-uninfected groups. our findings are consistent with previously published studies, which found reactive lymphoid hyperplasia in the vast majority of patients.13,14 there are minimal data available on the histopathology of routine tonsillar specimens in the adult hiv-infected population. a south african study by lierop et al. reviewed the tonsil histology in 344 paediatric patients.1 reactive lymphoid hyperplasia was present in all their patients with hiv infection (four patients). our findings suggest that reactive lymphoid hyperplasia remains the most common finding in patients undergoing tonsillectomy, regardless of hiv status or age. dell’aringa et al. studied 250 patients between the ages of 2 and 34 years; the mean age was 7.3 years. of these, 245 (95%) had lymphoid hyperplasia or inflammation; 2 (0.8%) had tonsillar cysts and 2 (0.8%) had actinomycosis infection.15 our study, which was of a similar size, had an older population; the mean age was 35 years. we had greater proportions of patients with actinomycosis 45 (14%), squamous cell carcinoma (scc) 8(2.5), ks 7 (2.2%) and lymphoma 4 (1.3%) in our study. in both studies, granulomatous disease was present in only one patient. actinomyces are commonly found in the oral cavity where they are commensals. their role in the development of tonsillar disease has not been firmly established.16,17 in our study, actinomycosis was equally present in both patients with hiv (11.6%) and without hiv (10.8%). the presence of actinomycosis infection in tonsillectomy specimens is well described. rebechi et al. evaluated the routine histopathology of 281 patients who underwent tonsillectomy, most of whom had recurrent bouts of infection. they found evidence of chronic tonsillitis with colonies of actinomyces in 9.6% of their patients.18 in light of our findings, we concur with hasan et al., who suggested that actinomycosis is likely to have a causal association with recurrent tonsillitis and tonsillar hypertrophy.17 south africa has one of the highest burdens of tb in the world, with an estimated 450 000 active cases in 2013.19 we, however, did not detect any evidence of tb in the specimens that we reviewed. this is not unexpected as tonsillar involvement in tb infection is rare. ricciardello et al. looked at otorhinolaryngology-related tb in 304 patients. their study was conducted in naples. they found tonsillar involvement in only two patients.20 scc is the most common malignancy in patients with non-benign tonsillar lesions. it accounts for up to 7% of malignancies. courville et al. tested 1093 adult patients, and of these, 75 (7%) had scc.21 malignancies were suspected prior to the confirmatory histology in all of their patients. four of our patients had scc on pathological evaluation; three patients were hiv-uninfected and one patient had hiv infection. randall et al. found 22 patients with scc (0.04%). the relatively low overall prevalence in their study was probably because of the high number of paediatric tonsillectomy specimens (96%). in their adult population, scc was present in 25 patients (1.2%).22 lymphomatous lesions are well described in patients with tonsillar malignancy. their occurrence ranges from 0% to 1.74%.1,13,14,15,21,22 ikram et al. studied 200 patients between the ages of 4 and 49 years. they detected lymphoma in only one patient (0.5%).13 younis et al. evaluated the histopathology in 2438 routine tonsillectomy specimens. in the 339 adult specimens they reviewed, they detected lymphoma in six patients (1.74%). all their lymphoma patients had suspicious clinical findings preoperatively.14 we had four patients (1.3%) with lymphoma; one of these patients had concomitant hiv infection. the relationship between tonsillar malignancies and underlying hiv is not well established. we found 14 patients with malignancies, and of those patients, eight were hiv-infected and six were hiv-uninfected. the results showed no significant correlation between tonsil malignancy and hiv infection. hiv infection is associated with an increased risk of a range of cancers, including ks, nhl and cervical cancer, which are considered virus-related and aids-defining diseases. the spectrum and incidence of nadc (smokingand virus-related) has also been shown to be augmented. franzetti et al. found a higher than expected incidence of tonsil carcinoma in their review of 5924 hiv-infected patients.8 mitsuyasu reviewed the incidence of both aids-defining and nadc in the united states. he did not find an increased incidence of tonsillar malignancies.11 grulich et al. performed a meta-analysis of people with hiv/aids (444 172 patients). they found an increased incidence of oral cavity and pharyngeal tumours. unfortunately, they did not specify whether any of their patients had tonsillar malignancies.23 in our study, ks was detected in seven patients, all of whom were hiv-infected. there is an established strong correlation between hiv and ks, which has been borne out of the literature.8,11,24,25 hiv-infected individuals in southern africa have a higher risk of developing ks than their counterparts in europe.24 prior to the hiv epidemic, the prevalence of ks was low in africa. there has been a marked surge in the number of ks cases. hhv8 is implicated in this resurgence of ks. the mechanism of how hhv8 causes ks is not completely understood, but it is believed to be instigated by oncoprotein production and the inhibition of tumour-suppressor genes. it usually begins in the head and neck. this may be because of the fact that the oropharynx is the main reservoir for hhv8.25 franzetti et al. found a significant association between nadc and low cd4 counts (< 200 cells/mm3). they evaluated 5924 hiv-infected patients over a 26-year period. they used regression models to compare the cancer risk in their hiv-infected patients to ageand gender-matched individuals.8 we could not confirm this relationship. we cannot exclude the possibility that the retrospective nature of our study, the relatively small number of events and the large deviations of cd4 counts would make our results less reliable. advancing age was the only predictor of malignancy in both the hiv-infected and hiv-uninfected subgroups. study limitations the size of our study cohorts may be adequate, but is not ideal for a statistically powerful analysis. unfortunately, many patients were excluded because of the absence of hiv results. the lack of clinical data on the patients is not ideal as we were unable to establish the absence or presence of established high-risk features. the significance of our study lies in the findings that advancing age may be an additional risk factor to consider, and hiv status does not confer an added risk in the development of tonsillar malignancies. conclusion our study findings are consistent with current recommendations that there is inadequate proof for routine histological examinations from patients who do not exhibit high-risk features.3 previously identified features that carry an increased risk for malignancy include history of cancer, tonsil firmness, visible lesions, concomitant neck adenopathy, unexpected weight loss and constitutional symptoms (fatigue, night sweats, fever and anorexia).4 the additional risk factor that we identified was an advanced age; this needs to be further by larger studies. tonsil histology should probably be reserved for patients with clinically suspicious lesions independent of hiv status. summary there is minimal data on the histopathology of tonsillectomy specimens in the hiv-infected population. this retrospective review compared tonsil histopathology between hiv-infected and hiv-uninfected patients. there were 86 patients hiv-infected patients and 74 hiv-uninfected patients in this study. reactive lymphoid hyperplasia was the most common diagnosis in both groups (77%). malignancies were diagnosed in eight hiv-infected and six hiv-uninfected patients, an insignificant difference. the majority of patients undergoing tonsillectomy had benign conditions. hiv status does not appear to be a specific risk factor for tonsil malignancies, but advanced age may be. acknowledgements the research was part of the mmed research report for dr ridwaan essa, faculty of health sciences, university of the witwatersrand. competing interests the authors declare that they have no financial or personal relationship(s) which may have inappropriately influenced them in writing this article. authors’ contributions r.e. was responsible for the data collection and analysis. s.m. was responsible for the conceptualisation and data analysis. k.h. was responsible for the write-up and editing. s.m. was responsible for the literature review and editing. references lierop a, prescott j. is routine pathological examination required in south african children undergoing adenotonsillectomy? s afr med j [serial online]. 2009 [cited 2015 dec 01];99:805–809. available from: https://www.ncbi.nlm.nih.gov/pubmed/20218481 hajiioannou j, tsiouvaka s, exarchos s, et al. histopathologic examination of routine tonsillectomies in times of greek austerity. necessity or luxury? clin otolaryngol [serial online]. 2014 [cited 2016 jan 01];39:235–257. available from: www.ncbi.nlm.nih.gov/pubmed/24814402 rokkjaer m, klug e. malignancy in routine tonsillectomy specimens: a systematic review. eur arch oto rhino laryngol [serial online]. 2014 [cited 2016 feb 01];271:2851–2861. available from: https://www.ncbi.nlm.nih.gov/pubmed/24481924 beaty m, funk g, karnell l, et al. risk factors for malignancy in adult tonsils. head neck [serial online]. 1998 [cited 2016 feb 01];20:399–403. available from: https://www.ncbi.nlm.nih.gov/pubmed/966366 avert hiv, aids in south africa. [homepage on the internet]. c2016 [updated 2016 jun 06; cited 2016 aug]. available from: https://www.avert.org/professionals/hiv-around-world/sub-saharan-africa/south-africa adoga s, ma`an d, nuhu s. is routine histopathology of tonsil specimen necessary? afr j paediatr surg [serial online]. 2011 [cited 2016 mar 01];8:283–285. available from: https://www.ncbi.nlm.nih.gov/pubmed/22248890 lü f, jacobson r. oral mucosal immunity and hiv/siv infection. j dent res [serial online]. 2007 [cited 2016 jun 01];86:216–226. available from: https://www.ncbi.nlm.nih.gov/pubmed/17314252 franzetti m, adorni f, parravicini c, et al. trends and predictors of non–aids-defining cancers in men and women with h.i.v infection: a single-institution retrospective study before and after the introduction of h.a.a.r.t. j acquir immune defic synd [serial online]. 2013 [cited 2016 jan 01];62:414–420. available from: www.ncbi.nlm.nih.gov/pubmed/23274934 pittore b, pelagatti c, deiana f, et al. isolated kaposi sarcoma of the tonsil: a case report and review of the scientific literature. case report otolaryngology [homepage on the internet]. 2015 [cited 2016 jul 20]. available from: http://0-www.ncbi.nlm.nih.gov.innopac.wits.ac.za/pmc/articles/pmc4338387 dolcetti r, gloghini a, caruso a, carbone a. a lymphomagenic role for hiv beyond immune suppression? topics antiv med. blood. 2016 [cited 2016 feb 01];127:1403–1409. available from: https://www.ncbi.nlm.nih.gov/pubmed/26773045 mitsuyasu. non-aids-defining cancers. topics antiv med. 2013 [cited 2017 jan 01];22(3). available from: https://www.iasusa.org/sites/default/files/tam/22-3-660.pdf sharon d, mukerji s, pine h. tonsillectomy and adenoidectomy. pediatr clin n am. 2013 [cited 2016 jan 01];60:793–807. available from: www.sciencedirect.com/science/article/pii/s0031395516340743 ikram m, khan m, ahmed m, siddiqui t. the histopathology of routine tonsillectomy specimens: results of a study and review of literature. ear nose throat j. 2000 [cited 2017 jan 01]; 79(11): 880–882. available from: https://www.ncbi.nlm.nih.gov/pubmed/11107690 younis r, hesse s, anand v. evaluation of the utility and cost-effectiveness of obtaining histopathologic diagnosis on all routine tonsillectomy specimens. laryngoscope. 2001 [cited 2017 feb 01];111(12):2166–2169. available from: https://www.ncbi.nlm.nih.gov/pubmed/11802018 dell’aringa ar, juares aj, melo cd, et al. histological analysis of tonsillectomy and adenoidectomy specimens from january 2001 to may 2003. braz j otorhinolaryngol. 2005 [cited 2017 mar 01];71(1):18–22. available from: https://www.ncbi.nlm.nih.gov/labs/articles/16446886/ valour f, sénéchal a, dupieux c, et al. actinomycosis: etiology, clinical features, diagnosis, treatment, and management. infect drug resist. 2014 [cited 2016 dec 01];7:183–197. available from: https://www.ncbi.nlm.nih.gov/pubmed/25045274 hasan m, kumar a. actinomycosis and tonsillar disease. br med j case rep. 2011;2011:bcr0120113750. https://org/10.1136/bcr.01.2011.3750 rebechi g, ponte t, braga e, matos w, rebech f, matsuyama c. are histologic studies of adenotonsillectomy really necessary? int arch otorhinolaryngol. 2013;17(4):387–389. https://doi.org/10.1055/s-0033-1353441 soul city institute. literature review of tb in south africa [homepage on the internet]. 2015 [cited 2017 jul 01]. available from: http://www.soulcity.org.za/projects/tuberculosis/research/literature-review-on-tuberculosis-in-south-africa.pdf/view ricciardiello f, martufi s, cardone m, cavaliere m, errico p, lango p. otorhinolaryngology-related tuberculosis. acta otorhinolaryngol italy. 2006;26(1):38–42. courville e, lew m, sadow p. routine evaluation of adult tonsillectomy specimens: toward establishing a new standard of care. int j surg pathol. 2011 [cited 2016 jun 01];19:469–475. available from: https://www.ncbi.nlm.nih.gov/pubmed/21427094 randall d, martin p, lester d, thomson l. routine histologic examination is unnecessary for tonsillectomy or adenoidectomy. laryngoscope. 2007 [cited 2016 jun 01];117:1600–1604. available from: https://www.ncbi.nlm.nih.gov/pubmed/17762791 grulich a, leeuwen m, falster m, vajdic c. incidence of cancers in people with hiv/aids compared with immunosuppressed transplant recipients: a meta-analysis. lancet. 2007 [cited 2017 mar 01];370(9581):59–70. available from: https://www.ncbi.nlm.nih.gov/pubmed/17617273 robeya c, bower m. facing up to the ongoing challenge of kaposi’s sarcoma. curr opin infect dis. 2015 [cited 2017 jul 01];28(1):31–40. available from: https://www.ncbi.nlm.nih.gov/pubmed/25490104 amador v, saavedra g, martínez g. kaposi’s sarcoma of the head and neck: a review. 2010;46(3):135–145. make up sept 2007 s p r i n g 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e4 0 the history of hiv prevention has followed similar trajectories across cultures. soon after hiv is identified as a viable threat to a population there are efforts to disseminate educational and motivational messages to the masses. when clearly stated, behaviourally targeted and personally relevant generalised prevention messages do raise awareness and undoubtedly reduce high-risk behaviours in at least some population segments. however, many individuals at risk, perhaps those at greatest risk, are not reached by mass education efforts and remain unaffected by generalised prevention messages. a second phase of hiv prevention is then implemented that focuses on further enhancing motivation and developing risk reduction behavioural skills. interventions such as community-based voluntary counselling and testing (vct), risk reduction counselling and targeted community programming are examples of second-generation hiv prevention interventions, several of which have been demonstrated effective in southern africa.1-3 these intervention approaches are important because they engage people at high risk for hiv infection, including people who are hiv infected but have not yet tested hiv positive. in what is now a third phase of hiv prevention programming, there is a growing movement to implement hiv transmission risk reduction interventions for people who have tested hiv positive, referred to as positive prevention. the us centers for disease control and prevention (cdc) has declared positive prevention the focal point of us national aids prevention policy.4 there are also calls for the immediate adaptation and implementation of positive prevention for use in southern africa.5 in addition, the south african national strategic plan for hiv prevention has included positive prevention as one of its central recommendations.6 in this article, i review the research basis for positive prevention and discuss its potential utility in southern africa. i will focus on one intervention in particular that has been widely disseminated in the usa and is currently being adapted for use in africa. i conclude with recommendations for moving forward with positive prevention initiatives in southern africa. positive prevention interventions tested in research the first positive prevention interventions were tested in rigorous randomised clinical trials conducted in the usa. positive prevention has used several intervention delivery formats, including individual counselling, brief medical care provider messages, and small support-group style workshops. the interventions have also been designed for delivery in clinical and community settings and have been aimed to reduce risk in men and women with diverse hiv risk histories. table i summarises the interventions that have been shown c o n f e r e n c e p l e n a r y positive prevention: hiv transmission risk reduction interventions for people living with hiv/aids seth c kalichman, phd university of connecticut, storrs, ct, usa hiv prevention programmes require scaling up in southern africa, and interventions that target people living with hiv/aids (positive prevention) should be included in all comprehensive hiv prevention plans. positive prevention interventions have been tested in the usa and have been demonstrated effective in reducing hiv transmission risks. lessons learned from us trials can be used in selecting and adapting positive prevention interventions for use in southern africa. efforts to implement positive prevention will be enhanced by reducing institutionalised aids stigmas and culturally held aids denialism and by increasing access to hiv/aids care services including antiretroviral therapies and sexually transmitted infection detection and treatment. positive prevention should not replace, but rather should augment, generalised hiv prevention interventions targeting highrisk populations. this paper is based on a plenary presentation at the 3rd south african aids conference, durban 2007 and was supported by national institute of mental health grants r01-mh71164. correspondence should be addressed to seth kalichman, university of connecticut, department of psychology, 406 babbidge road, storrs, ct 06269, usa. phone (860) 208-3706, e-mail seth.k@uconn.edu make up sept 2007 11/21/07 10:14 am page 40 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s p r i n g 2 0 0 7 4 1 study target population intervention content intervention format kalichman et al.7 men and women of diverse risk healthy relationships, designed five 2-hour small support histories at a community-based to reduce sexual hiv transmission group style workshops with aids service organisation, risk behaviours in relation to 6 10 participants and atlanta, ga disclosure of hiv status to sex community-based group partners. grounded in social facilitators cognitive theory, uses coping effectiveness skills training focused on hiv-related stressors and sexual risk-producing situations; skills for self-disclosure decisions; development and maintenance of safer sex practices; and role-playing scenarios presented in popular films. margolin et al.8 substance use treatment patients harm reduction, weekly individual substance abuse all on aarv therapy and receiving individual substance abuse counselling, daily methadone, methadone maintenance in a counselling, case case management, and 48 substance abuse treatment management and methadone 1-hour sessions of harm programme, new haven, ct coupled with motivational reduction delivered over 24 interviewing; videos for modelling weeks and practice of needle cleaning and correct condom use; harm reduction negotiation role plays; and sharing information with peers. these standard intervention elements were integrated with additional group therapy that addressed medical, emotional and spiritual needs as well as harm-reduction skills to avoid substance use relapse and improve arv adherence. richardson et al.9 infectious disease clinic patients, partners in prevention, brief messages ongoing intervention with southern california grounded on social psychological messages delivered at each theory of message framing, messages clinic visit; each patient emphasised importance of patientreceived a minimum of provider teamwork; loss-framed 1 session; 3 5 min each, over prevention messages were most 10 11 months effective and were delivered along with brochures and posters. wingood et al.10 women attending health care willow, based on social cognitive four 4-hour small support clinics in alabama and georgia theory and theory of gender and group style workshops with power, the intervention discussed 6 10 women participants and gender pride, personal achievements, community-based peer managing abusive partners, identifying educators socially supportive people, transmission risk-behaviour education, debunking myths, safer sex communication and negotiation skills, condom use skills, distinguishing healthy from unhealthy relationships. rotheram-borus et al.11,12 adolescents and young clear, social action theory based: one-on-one counselling adults with substance abuse module 1, stay healthy (coping intervention delivered in 3 histories in new york, san with hiv; implementing new daily different modules, each francisco, los angeles routines to stay healthy; issues of module being 6 1.3-hour sessions. disclosure; participating in healthalso tested in a telephonecare decisions); module 2, act safe delivered format (reduce substance use and unprotected sex; identify risk behaviour triggers; modify patterns of substance use; increase selfefficacy for condom use and negotiation skills); and module 3, being together (identify values that define personal identity as a person living with hiv; reduce negative emotional reactions to hiv; increase perception of personal self-control; reduce selfdestructive motivations). table i. summary of positive prevention intervention content in five of the most promising approaches make up sept 2007 11/21/07 10:14 am page 41 s p r i n g 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e4 2 most effective in reducing hiv transmission risk behaviours among people living with hiv/aids as tested in randomised controlled trials. two meta-analyses of the positive prevention intervention literature concluded that the interventions described in table i demonstrate significant short-term and long-term reductions in unprotected intercourse, especially with uninfected sex partners and those whose hiv status is unknown.13-14 it should be noted that these effective interventions share several common features. all the effective interventions were based on sound theories of behavioural change, typically social cognitive theory that emphasises building behavioural skills. the interventions were also intensive, highly interactive, and aimed toward sustained behaviour change. although the approaches varied, their goals were clearly directed to reduce hiv transmission risks. the interventions did vary considerably in terms of their formats. some interventions were delivered in multiple small-group sessions, whereas others were delivered by care providers in routine clinical services. the two metaanalyses did examine several other interventions that reported risk behaviour outcomes, but they were not well focused on risk reduction and did not demonstrate substantial preventive outcomes. positive prevention in southern africa research is now demonstrating the need for and promise of positive prevention delivered in southern africa. studies conducted in uganda, botswana, south africa, and other countries in sub-saharan africa are showing that men and women who have tested hiv positive experience difficulty consistently practising safer sex. for example, bunnell et al.15 found that 47% of hiv-positive men and 21% of hiv-positive women were sexually active prior to initiating arvs, with 45% of these persons reporting unprotected intercourse in a 3month period. simbayi et al.16 found that 7% of hiv-positive men and women in cape town reported having recently engaged in unprotected intercourse with a partner who was not known to be hiv infected. importantly, it was more common for people to report unprotected sex with an uninfected partner to whom they had not disclosed their hiv status than with a partner who they had told. this finding was extended in a subsequent study that showed that the best predictor of failing to disclose hiv status to sex partners was experiencing aids-related stigma and discrimination. another critical factor in the continued practice of hiv transmission risk behaviours among people living with hiv/aids is their access to antiretrovirals (arvs). optimally, antiretroviral therapy (art) reduces hiv concentrations (viral load) in the genital tract that parallel reductions in the blood, potentially lowering hiv infectiousness. adherence to virussuppressing arv regimens can therefore play an important role in hiv prevention, especially in patients who do not have co-occurring sexually transmitted infections.17 in contrast to research conducted in europe and the usa, it appears that receiving arvs in southern africa is associated with lower rather than higher levels of hiv transmission risk behaviours. for example, a study conducted in cote d’ivoire18 compared hiv-related sexual risk behaviour among sexually active people being treated with arvs with that in people not being treated and found that fewer arv-treated sexually active patients had unprotected sexual intercourse during the previous 6 months. furthermore, more sexually active males and females who were on art than their counterparts who were not reported that they had used condoms during the last sexual intercourse. in a prospective analysis, bunnell et al.15 observed reductions in hiv transmission risk behaviours following the start of arvs. also simbayi et al.19 reported that nearly half of people with hiv in cape town who were not taking arvs engaged in unprotected sex with uninfected partners and failed to disclose their hiv status to their partners. fig. 1 shows a conceptual framework for linking institutional aids stigma and aids denialism to hiv/aids discrimination, barriers to disclosure, and failure to engage hiv treatment and care services, which in turn can foster continued hiv transmission risk behaviours. adapting positive prevention for use in south africa: healthy relationships effectively implementing positive prevention in southern africa will require multiple approaches delivered at individual and structural levels in clinical and community settings. one positive prevention intervention approach that is currently being adapted and tested in south africa and botswana is healthy relationships.7 the healthy relationships intervention has been widely distributed throughout the usa as a part of the cdc’s dissemination of effective behavioural interventions programme. research being conducted by the human sciences research council in cape town systematically adapted the intervention activities and video material for use in indigenous african communities. healthy relationship therefore represents one intervention in the us standard of care for positive prevention. using concepts derived from previous mental health and public health interventions for populations affected by aids, healthy relationships was designed to reduce hiv transmission risks in people living with hiv/aids. the intervention uses a highly interactive approach that includes fig. 1. association of institutionalised aids stigma and denialism with aids discrimination, disclosure, and engaging clinical services in relation to hiv transmission risk behaviours. institutionalised stigma and denialism increased hiv transmission risks aids discrimination fostering concealment/ non-disclosure failure to engage treatment and care make up sept 2007 11/21/07 10:14 am page 42 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s p r i n g 2 0 0 7 4 3 educational, motivational and behavioural skills building components. in addition, like all effective behavioural interventions the content is tailored for gender and risk behaviour history. the intervention content is also made personally relevant to people living with hiv/aids. for example, the intervention is framed around the challenges of establishing and maintaining healthy and satisfying relationships in the face of living with hiv/aids. table ii summarises the healthy relationships intervention content within the five group sessions. as suggested by a panel of community advisors, healthy relationships encapsulates hiv transmission risk reduction within the context of managing hiv disclosure decisions. initial skills for making effective hiv disclosure decisions are built in reference to disclosing hiv status to non-sex partners, particularly family members, friends and employers. the intervention content transitions to address issues of hiv disclosure to sex partners using the same principles and intervention techniques that were introduced in the initial disclosure skills-building activities, contextualised and reframed for disclosure to sex partners. healthy relationships does not promote or even encourage hiv status disclosure. rather the intervention explicitly targets reductions in transmission risk behaviours regardless of whether or not disclosure occurs. the final segment of the intervention addresses building skills for reducing hiv transmission risk behaviours. risk reduction strategies arise naturally in the context of disclosing hiv status, with different implications for practising protected and unprotected sex with hiv-positive partners, hiv-negative partners, and sex partners of unknown hiv status. skills building activities established in the two disclosure segments to specifically build skills for reducing hiv transmission risk behaviours are generalised for safer sex skills. the healthy relationships model attempts to build behavioural skills within an initial behavioural domain and then carries the skills forward to related behaviours ultimately addressing risk reduction strategies with partners of varying hiv statuses. the three behavioural domains of the intervention components (i.e. disclosure to non-partners, disclosure to partners, and safer sex) were conceptualised as potentially stress-producing situations for people living with hiv/aids and therefore framed the intervention activities accordingly as stress reduction skills and strategies. making effective decisions as to whether to disclose hiv status to family, friends, employers, or sex partners and reducing hiv transmission risk behaviours were therefore viewed as coping responses (fig. 2). healthy relationships therefore integrates a mental health conceptualisation to achieve behaviour changes that have public health implications. each of the intervention components was geared to build self-efficacy for either making effective hiv status disclosure decisions or reducing hiv transmission risks. the original randomised trial that tested healthy relationships demonstrated promising behavioural outcomes over a 6month follow-up period. results of the randomised trial showed that healthy relationships resulted in significantly less unprotected intercourse and greater condom use at the follow-up assessments. specifically, 34% of the healthy relationships group members reported non-hiv-positive sex session 1 welcome group members, state the goals of the group and agree on group rules; ice-breaker activity to establish group cohesion; initial discussion of stress and hiv status disclosure; provide prf for personal stress levels and disclosure experiences; group process of prf; view movie scenes for disclosure decision role play; continuum of risks for disclosure activity; light-comedy videotape to end group on upbeat note session 2 communication skills applied to disclosing hiv status to family and friends and other persons who are not sex partners: active listening and assertiveness; identifying and managing triggers and barriers for hiv status disclosure, establishing problem solving skills and decision making skills for hiv disclosure; integrating skills into action; skills practice in role plays setup within movie scenes session 3 review of hiv disclosure skills; applying disclosure decision skills to relationships with sex partners; risks of disclosing and not disclosing hiv status to sex partners; personalised feedback report for disclosure experiences; group discussion of issues of disclosing hiv to sex partners; applying listening skills, assertiveness, problem solving and decision; skills to disclosure situations for sex partners; role playing decisions to disclose to sex partners using movie scenes specified to gender and sexual orientation session 4 implications of decisions to disclose and to not disclose hiv status to sex partners; potential adverse reactions and problem solving; group discussion of safer sex in hiv-concordant and hiv-discordant relationships; pfr for sexual risk behaviours; sexual risk behaviour continuum activity; review of active listening skills, trigger identification and management, problem solving and decision making skills adapted to sex and safer sex behaviours session 5 continuum of safer sex decisions; condom use and the pros and cons of condoms; managing condom aversions and condom use anxiety – condom use desensitisation exercises; condom skills proficiency training; initiation, negotiation, and communication skills for safer sex; role plays within movie scenes to integrate disclosure decisions and safer sex skills table ii. session content for the social cognitive hiv risk reduction intervention healthy relationships fig. 2. social cognitive theory-based coping efficacy model for hiv risk behaviour change in the healthy relationships intervention. stress and risk reduction self-efficacy stress reduction coping responses risk reduction coping responses reduced emotional distress risk reduction skills risk reduction behaviour change make up sept 2007 11/21/07 10:14 am page 43 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e s p r i n g 2 0 0 7 4 5 partners at the 6-month follow-up relative to 42% of the control intervention, a significant difference. in addition, rates of unprotected vaginal and anal intercourse with non-hivpositive partners were significantly lower among the healthy relationships groups than the comparison intervention at the 3-month and 6-month follow-ups. mathematical modelling showed that hiv transmission risk behaviours with non-hivpositive sex partners would result in significantly fewer new hiv infections from the healthy relationships intervention relative to the time-matched control condition. reductions in potential new hiv infections were greater for hiv-positive men with male sex partners as well as for hiv-positive men with female sex partners. subsequent secondary analyses of the healthy relationships outcomes demonstrated that the intervention effects were at least partially accounted for by improvements in mental health and coping with emotional stress of living with hiv/aids. this finding supports the original model of healthy relationships, which specifies that risk reduction will be enhanced by increased stress management (fig. 2). the potential for healthy relationships to address mental health and coping in relation to transmission risk behaviours may be particularly well suited to south africa, where depression and other mental health challenges are observed in people living with hiv/aids. although previous research has shown a strong association between hiv/aids and depression in africa, much of this research predated the availability of art. however, it appears that depression is persistent among people with hiv/aids even in the arv era.20-21 the considerable amount of psychological distress reported by people infected with hiv is at least in part accounted for by internalised aids stigmas. depression is also part of the expected emotional reaction to learning one is infected with hiv. of course, depression is widely considered a predisposing risk factor for hiv infection among at-risk populations. a unique feature of the healthy relationships intervention is its explicit aim to reduce hiv transmission risk behaviours by addressing stigma experiences, disclosure, social support and other mental health issues. conclusions effectively implementing positive prevention in southern africa will require reductions in aids-related stigmas and denialism to allow people at risk to get tested and engage people with hiv/aids into care services. scaling up access to arvs can help to further reduce aids stigmas and normalise hiv infection as a chronic health condition. increasing arv uptake can have the added benefit of reducing hiv infectiousness when hiv-suppressive regimens are adhered to and patients receive aggressive sti detection and treatment services. positive prevention holds great promise to fill an important gap in hiv prevention programming. however, we must never delude ourselves by placing all of our prevention resources in just one strategy, especially not positive prevention. generalised epidemics demand interventions that will capture individuals who are hiv infected but have not yet been tested positive. positive prevention will only be effective when delivered side by side with effective primary prevention interventions that target high-risk populations, within which many people are untested hiv positive. hiv prevention programming must remain comprehensive and positive prevention should be considered an integral part of any comprehensive hiv prevention plan. references 1. voluntary hiv-1 counselling and testing efficacy study group. efficacy of voluntary hiv-1 counselling and testing in individuals and couples in kenya, tanzania, and trinidad: a randomized trial. lancet 2000; 356: 103-112. 2. kalichman sc, simbayi lc, vermaak r, cain d, jooste s, peltzer k. hiv/aids risk reduction counselling for alcohol using sexually transmitted infections clinic patients in cape town south africa. j acquir immune defic syndr 2007; 44: 594-600. 3. allen s, serufilira a, bogaerts j, et al. confidential hiv testing and condom promotion in africa: impact on hiv and gonorrhea rates. jama 1992; 268: 3338-3343. 4. centers for disease control and prevention. advancing hiv prevention: new strategies for a changing epidemic – united states. mmwr morb mortal wkly rep 2003; 52(15): 329-332. 5. bunnell r, mermin j, decock k. hiv prevention for a threatened continent: implementing positive prevention in africa. jama 2006; 296: 855-858. 6. south african department of health. hiv & aids and sti national strategic plan 2007-2011. pretoria: south african national aids council (sanac), 2007. 7. kalichman sc, rompa d, cage m, et al. effectiveness of an intervention to reduce hiv transmission risks in hiv positive persons. am j prev med 2001; 21: 84-92. 8. margolin a, avants sk, warburton la, hawkins ka, shi j. a randomized clinical trial of a manual-guided risk reduction intervention for hiv-positive injection drug users. health psychol 2003; 22: 223-228. 9. richardson jl, milam j, mccutchan a, et al. effect of brief safer-sex counselling by medical providers to hiv-1 seropositive patients: a multi-clinic assessment. aids 2004; 18: 1179-1186. 10. wingood gm, diclemente rj, mikhail i, et al. a randomized controlled trial to reduce hiv transmission risk behaviours and sexually transmitted diseases among women living with hiv: the willow program. j acquir immune defic syndr 2004; 37: s58-s67. 11. rotheram-borus mj, swendeman d, comulada s, weiss re, lightfoot m. prevention for substance using hiv positive young people: telephone and inperson delivery. j acquir immune defic syndr 2004; 37: s68-s77. 12. rotheram-borus mj, lee mb, murphy da, et al. efficacy of a preventive intervention for youths living with hiv. am j public health 2001; 91: 400-405. 13. crepaz n, lyle c, wolitski r, et al. do prevention interventions reduce hiv risk behaviours among people living with hiv? a meta-analytic review of controlled trials. aids 2006; 20: 143-157 14. johnson bt, carey mp, chaudoir sr, reid ae. sexual risk reduction for persons living with hiv: research synthesis of randomized controlled trials, 1993 to 2004. j acquir immune defic syndr 2006; 41(5): 642-650. 15. bunnell r, ekwaru j, solberg p, et al. changes in sexual behaviour and risk of hiv transmission after antiretroviral therapy and prevention interventions in rural uganda. aids 2006; 20: 85-92. 16. simbayi lc, kalichman sc, strebel a, cloete a, henda n, mqeketo a. disclosure of hiv status to sex partners and sexual risk behaviours among hiv positive men and women, cape town, south africa. sex transm infect 2007; 83: 29-34. 17. kalichman sc, diberto g, eaton le. associations among hiv concentration in blood plasma and semen: review and implications of empirical findings. sex transm dis (in press). 18. moatti jp, prudhomme j, traore dc, juillet-amari a, akribi ha msellati p, cote d’ivoire hiv drug access initiative soci-behavioural evaluation group. access to antiretroviral treatment and sexual behaviours of hiv-infected patients aware of their serostatus in cote d’ivoire. aids 2003; 17: s69-77. 19. simbayi lc, kalichman sc, cloete a, strebel a, henda n. morbidity, social support, depression and hiv risk behaviour among people living with hiv/aids receiving arv treatment in cape town, south africa. submitted, 2007. 20. olley bo, seedat s, stein dj. self-disclosure of hiv serostatus in recently diagnosed patients with hiv in south africa. afr j repr health 2004; 8: 71-76. 21. olley bo, zeier md, seedat s, stein dj. post-traumatic stress disorder among recently diagnosed patients with hiv/aids in south africa. aids care 2005; 17: 550-557. make up sept 2007 11/21/07 10:14 am page 45 make up march 2007 42 countries in southern africa host a variety of displaced populations: refugees and asylum seekers who have fled conflict or persecution in their country; internally displaced persons who are still within their country; and economic migrants moving in search of employment. regardless of the reason for displacement, all persons have the right to the ‘highest attainable standard of health’,1 including hiv-related care. however, the displaced person’s ability to access care can be fraught with challenges. they often do not speak the language in the area to which they have moved. they might not be familiar with local systems or services. they may have knowledge gaps, particularly related to hiv and aids, and have specific support needs owing to lack of traditional community and family support structures. but one of the greatest barriers to access to care is one that can easily be surmounted: reluctance on the part of health professionals, from nurses to clinicians, to make the extra effort necessary to deliver services to such individuals. the reasons for this reluctance are varied. certain myths about displaced persons persist, such as the belief that they are more likely to engage in high-risk behaviour, or that they are too mobile to adhere to antiretroviral therapy (art) and therefore pose a risk of developing resistance. none of the available evidence supports these perceptions; on the contrary, the evidence we have for refugee populations, for example, demonstrates fewer risky behaviours in comparison with the host community.2,3 however, every situation is context-specific and must be evaluated as such. by the end of 2003, refugee populations remained in their host country for an average of 17 years.4 furthermore, behavioural surveillance surveys show a high level of interaction between refugee and host communities; clearly the exclusion of displaced persons from local hiv and aids-related services is detrimental to efforts in hiv prevention, care and treatment to both displaced persons and the surrounding host communities.5 according to the world health organization (who), the largest threat for developing resistance to art is persons taking their medications in an incorrect manner;6 this threat is no larger for displaced populations than for other populations. differing treatment regimens and treatment interruption between area of origin and area of displacement may also pose a challenge to clinicians. however, clear guidance on this issue has been developed through a consultative process led by the southern african hiv clinicians society and unhcr (included in this issue of the journal). lack of awareness of the rights of displaced persons, together with xenophobia, can lead health professionals to deny care. in a survey conducted among urban refugees in south africa in 2003,7 30% of respondents who had been denied emergency medical care, which is guaranteed to everyone under the national constitution, reported that the denial came directly from a doctor or a nurse. the reasons given varied, but many practitioners showed a lack of familiarity with refugee rights, as well as a belief that such services were ‘only provided to south africans’. in fact, the hiv care needs of displaced persons are, for the most part, not different to those of local patients; a bit of empathy and creativity will go a long way towards finding ways of providing the same quality of services to these populations. in a number of countries in the southern african region, creative approaches to some of these challenges have already been employed. in botswana and south africa, local non-governmental organisations (ngos) maintain a roster of trained interpreters to help with communication and adherence support. in mozambique and namibia, unhcr and its ngo partners provide support for transport from refugee camps to the nearest art site. unhcr has also produced or translated existing hiv information materials into local refugee and migrant languages. these materials are a very effective means of educating patients, whether dealing with prevention, care or treatment. the only problem was language, which again, with a bit of initiative, has been quite easily overcome. displaced persons and hiv care: challenges and solutions laurie bruns, ms paul spiegel, md mph united nations high commissioner for refugees clinic in zambia serving refugees and locals, 2006 (j redden, unhcr). m a r c h 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e make up march 2007 30/3/07 11:28 am page 42 43 who, together with unhcr, unicef and other international organisations, recently held an expert consultation on delivering antiretrovirals in emergencies. in the consensus statement from this meeting, they conclude: ‘that emergencies … should not affect one’s access to hiv services and that the provision of such services is not only feasible, but an inalienable human right and a public health necessity.’8 hiv knows no borders, nor individuals. addressing the hivrelated needs of displaced persons in an equitable, nondiscriminatory manner is a critical intervention in the fight against hiv and aids, particularly in sub-saharan africa. references 1. international convenant on economic, social and cultural rights (icescr). 2. unhcr. hiv and aids behavioural surveillance survey, marratane refugee camp, mozambique. november 2005. 3. spiegel, pb. hiv/aids among conflict-affected and displaced populations: dispelling myths and taking action. disasters 2004; 28(3): 322-339. 4. unaids, unhcr. strategies to support the hiv-related needs of refugees and host populations. geneva: unaids best practice collection, 2005. 5. unhcr. antiretroviral medication policy for refugees. geneva, january 2007. 6. who. hiv drug resistance. geneva, 2006. http://www.who.int/hiv/drug resistance/en/ 7. japan international cooperation agency (jica) & unhcr. national refugee baseline survey: final report. november 2003. 8. who, unaids, unhcr, unicef, medecins sans frontieres, et al. consensus statement: delivering antiretroviral drugs in emergencies: neglected but feasible. 2006. displaced boy, luena, angola, 2006 (j redden, unhcr). 1/2 pg wits health ad t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e m a r c h 2 0 0 7 make up march 2007 30/3/07 11:28 am page 43 hiv message from editor message from the editor this issue features a diverse sampling of hiv medicine from across south africa (sa). several contributions provide a glimpse into the future of the hiv epidemic in the country, and in turn, our responses. in the area of the prevention of mother-to-child transmission (pmtct) of hiv, the use of triple-drug antiretroviral therapy (art) regimens in hiv-infected pregnant women is becoming standard of care – whether as short-term prophylaxis against mother-to-child transmission or as lifelong treatment. in europe and north america, the use of art in pregnancy has raised concerns around potential toxicities in hiv-exposed pregnancies and infants. it is important to remember that almost any such toxicity is likely to be uncommon in comparison to the risk of vertical hiv transmission. still, with more than 200 000 pregnant women exposed to art each year across sa, the possibility that in utero art exposure may contribute to adverse pregnancy or child health outcomes requires consideration. aniji et al.1 report the outcomes of a small cohort of hiv-exposed pregnancies from limpopo province. while the sample is small and there are limitations to the design, the findings for no association between early in utero art exposure and either prematurity or low birthweight appear somewhat reassuring. there are a number of major, ongoing studies across the country investigating these issues, and with the 2013 revisions to the pmtct guidelines in full implementation, additional evidence is eagerly anticipated. in thinking about health systems, we know that nurse-driven services form the basis of primary healthcare across sa, and most hiv-positive individuals are managed through nurse-initiated management of antiretroviral therapy (nimart) services. one of the core challenges to nimart services is providing appropriate clinical support to nurse practitioners. in this regard, the national hiv & tb health care worker hotline serves as a valuable resource. swart et al.2 present a descriptive analysis of the queries that the hotline has received recently from nurses. their report provides readers with valuable insight into the types of questions that arise in primary care, and with this, a valuable basis for future training interventions. there is considerable excitement in public health circles about human papillomavirus (hpv) vaccination across sa and its eventual impact on cervical cancer epidemiology, particularly in hiv-positive women. however, the manifestations of hpv in men have been largely neglected. delany-moretlwe et al.3 review the epidemiology and natural history of hpv in men, emphasising the role of circumcision and vaccination in future prevention efforts. in addition, self-testing for hiv infection has been controversial, both locally and internationally, as a strategy to increase awareness of individual hiv status. strode et al.4 comment on the ethico-legal aspects of hiv self-testing in adolescents, and raise important questions about the risks v. benefits of allowing self-testing in young people – clearly a double-edged sword. inevitably, the number of patients initiating second-line art regimens is growing in most parts of the region, and following from this, a small but increasing number of patients are found to be failing second-line regimens. failure of a second-line regimen is considered grounds for specialist referral in many settings, but this is certainly not always possible. this issue features two contributions regarding the management of patients on second-line regimens in primary care settings in cape town. first, in a group of 69 patients with sustained viraemia on a second-line regimen, garone and colleagues5 report that a substantial proportion appeared to re-suppress with targeted adherence support. in parallel with this, barnett et al.6 present a qualitative study using a unique photo-based methodology to suggest that the barriers to adherence in this group of patients vary notably between patients and providers, underscoring the complexity of supporting patient adherence. this research is from small, local studies, but is surely a harbinger of the kinds of issues that the national art rollout will face in the years to come. finally, few among us would question the role of mental health as part of long-term health outcomes in hiv-positive patients, including the interplay of mental disorders and treatment adherence, as well as the neurocognitive effects of hiv disease. however, many providers struggle with practical steps to support the mental health of their patients. to help fill this gap, the southern african hiv clinicians society has produced a valuable guideline7 on the management of different types of mental health disorders in hiv-positive patients. the guideline is at once comprehensive but accessible – an impressive feat given the breadth and complexity of mental disorders – and hopefully readers will be able to put it to good use in practice. happy reading. landon myer school of public health & family medicine, university of cape town landon.myer@uct.ac.za 1. anjii cd, towobola oa, hoque me, et al. impact of antiretroviral therapy on pregnancy outcomes. southern african journal of hiv medicine 2013;14(4):176-178. [http://dx.doi.org/10.7196/sajhivmed.834] 1. anjii cd, towobola oa, hoque me, et al. impact of antiretroviral therapy on pregnancy outcomes. southern african journal of hiv medicine 2013;14(4):176-178. [http://dx.doi.org/10.7196/sajhivmed.834] 2. swart am, chisholm bs, cohen k, et al. analysis of queries from nurses to the south african national hiv & tb health care worker hotline. southern african journal of hiv medicine 2013;14(4):179-182. [http://dx.doi.org/10.7196/sajhivmed.948] 2. swart am, chisholm bs, cohen k, et al. analysis of queries from nurses to the south african national hiv & tb health care worker hotline. southern african journal of hiv medicine 2013;14(4):179-182. [http://dx.doi.org/10.7196/sajhivmed.948] 3. delany-moretlwe s, chikandiwa a, gibbs j. human papillomavirus infection and disease in men: impact of hiv. southern african journal of hiv medicine 2013;14(4):183-188. [http://dx.doi.org/10.7196/sajhivmed.1002] 3. delany-moretlwe s, chikandiwa a, gibbs j. human papillomavirus infection and disease in men: impact of hiv. southern african journal of hiv medicine 2013;14(4):183-188. [http://dx.doi.org/10.7196/sajhivmed.1002] 4. strode ae, van rooyen h, makusha t. is it lawful to offer hiv self-testing to children in south africa? southern african journal of hiv medicine 2013;14(4):151-154. [http://dx.doi.org/10.7196/sajhivmed.987] 4. strode ae, van rooyen h, makusha t. is it lawful to offer hiv self-testing to children in south africa? southern african journal of hiv medicine 2013;14(4):151-154. [http://dx.doi.org/10.7196/sajhivmed.987] 5. garone db, conradie k, patten g, et al. high rate of virological re-suppression among patients failing second-line antiretroviral therapy following enhanced adherence support: a model of care in khayelitsha, south africa. southern african journal of hiv medicine 2013;14(4):166-169. [http://dx.doi.org/10.7196/sajhivmed.980] 5. garone db, conradie k, patten g, et al. high rate of virological re-suppression among patients failing second-line antiretroviral therapy following enhanced adherence support: a model of care in khayelitsha, south africa. southern african journal of hiv medicine 2013;14(4):166-169. [http://dx.doi.org/10.7196/sajhivmed.980] 6. barnett w, patten g, kerschberger b, et al. perceived adherence barriers among patients failing second-line antiretroviral therapy in khayelitsha, south africa southern african journal of hiv medicine 2013;14(4):170-176. [http://dx.doi.org/10.7196/sajhivmed.981] 6. barnett w, patten g, kerschberger b, et al. perceived adherence barriers among patients failing second-line antiretroviral therapy in khayelitsha, south africa southern african journal of hiv medicine 2013;14(4):170-176. [http://dx.doi.org/10.7196/sajhivmed.981] 7. jonsson g, davies n, freeman c, et al. management of mental health disorders in hiv-positive patients. southern african journal of hiv medicine 2013;14(4):155-165. [http://dx.doi.org/10.7196/sajhivmed.995] 7. jonsson g, davies n, freeman c, et al. management of mental health disorders in hiv-positive patients. southern african journal of hiv medicine 2013;14(4):155-165. [http://dx.doi.org/10.7196/sajhivmed.995] hiv 977 forum starting art following cryptococcal meningitis: the optimal time has yet to be defined t a bicanic,1 mb chb, md; j n jarvis,1,2 mb chb, phd; a loyse,1 mb chb, md; t s harrison,1 mb chb, md 1 cryptococcal meningitis group, research centre of infection and immunity, st george’s university of london, london, united kingdom 2 department of clinical research, faculty of infectious and tropical diseases, london school of hygiene and tropical medicine, london, united kingdom corresponding author: t a bicanic (tbicanic@sgul.ac.uk) ever since the public sector rollout of antiretroviral therapy (art) in 2004, the question of the optimal time to start art following diagnosis of an opportunistic infection has aroused controversy among south african hiv clinicians and researchers. s afr j hiv med 2013;14(3):105-106. doi:10.7196/sajhivmed.977 patients with cryptococcal meningitis (cm) in southern africa present with median cd4+ counts <50 cells/µl,1-4 with a high prevalence of co-morbidities such as tuberculosis (tb) and kaposi’s sarcoma. in this context, the challenge is to balance the competing risks of morbidity and mortality from each additional week of advanced immuno­suppression – well demonstrated in south african (sa) hiv cohorts waiting to start antiretroviral therapy (art)5 – with those from immune reconstitution inflammatory syndrome (iris) occur­r­ing within the confined space of the central nervous system, when art is commenced in the presence of a high fungal antigen load.6 , 7 the first southern african cm guide­line8 published in 2008 recommended treatment with 1 mg/kg/day amphotericin b for 2 weeks – a regimen known to drive down the cryptococcal burden rapidly in cerebrospinal fluid (csf), with many patients having sterile csf by day 14.1 at this time, given the lack of evidence regarding art timing in cm, it was recommended to start art 2 4 weeks after commencing amphotericin b.8 this window pragmatically coincided with the timing of hospital discharge, and the switch from amphotericin induction therapy to consolidation with fluconazole, with the aim of having asymptomatic patients with sterile or almost-sterile csf counselled and ready to start art at outpatient follow-up 4 weeks into antifungal therapy. since 2007, two randomised controlled trials (rcts) of art timing following cm have been completed in africa. in the first, conducted by makadzange et al. 9 in zimbabwe, patients receiving fluconazole monotherapy for cm were randomised to start art at <72 h v. 10 weeks.9 the study found excess mortality in the immediate art arm, most probably due to iris, although this information was not collected systematically.9 notwithstanding this trial’s small sample size and large early loss to follow-up,10-12 it confirmed the clinical impression that starting art extremely early was harmful, but it did not provide guidance on what to do in the context of amphotericin-based treatment, nor provide information on art timing between 3 days and 10 weeks, which represent a far earlier and far later art-initiation time-point, respectively, than most clinicians would consider in practice. the cryptococcal optimal art timing (coat) trial13 conducted in uganda and sa was designed to address these questions, randomising patients treated with amphotericin-based induction (1 mg/kg/day amphotericin b with 800 mg/ day fluconazole) to early (1 2 weeks, median 8 days) v. deferred (4 6 weeks, median 36 days) art. the trial was halted prematurely (n=177 patients randomised) due to excess mortality in the early art arm, with the most pronounced difference in mortality occurring between days 8 and 30 after cm diagnosis: 21/75 (28%) early art v. 8/80 (10%) deferred art (hazard ratio 3.1; p<0.01). this difference occurred despite an apparently similar incidence of cm-iris in the two groups (13% v. 10%).13 based on significant differences in mortality in an rct conducted in an african context following amphotericin treatment, the 2013 southern african hiv clinicians society guidelines committee felt compelled to move the recommended art start window to 4 6 weeks, in line with the delayed art group of the coat trial. this generated some debate among panel members, with some favouring the 4-week time-point. for all the clear advantages of rct data, the two art timing studies do not say anything about a preference between the better-performing study arm and intermediate time-points such as 2, 3 and 4 weeks – they only tell us that the worst-performing arms (i.e. during the first 2 weeks of induction therapy) do not represent the right time to start. ten weeks was not prioritised over 6 weeks in the makadzange et al. study,9 and 5 weeks was not prioritised over 3 or 4 weeks in the coat trial. we are unlikely to have any further art timing rcts for cm in the near future, given the large cohorts required to power an rct of art start at 2 v. 4 weeks post cm treatment. thus, we may need to edge towards a preferred time based on observational clinical cohort data. in successive sa clinical trial cohorts between 2005 and 2010,1-4 in which all patients received amphotericin-based induction treatment, with our sa partners we have gradually decreased the median time to art start from cm diagnosis from 6 weeks1 to just 23 days (in our latest trial).4 despite the concerns of confounding by historic trends in the severity of cm and hiv of patients at presentation, in all four studies1-4 the median cd4+ count was <50 cells/µl, the median baseline fungal burden was high (approximately 5 log10 cfu/ml in the csf), and the percentage of altered mental status – the most significant indicator of poor prognosis in cm – ranged from 13% to 37%, with the latest trial4 enrolling those with the highest rates. one-year survival analysis of the combined cohort from the four trials (n=171 patients), who started art at a median of 31 days (interquartile range 23 46) following a cm diagnosis, showed an earlier flattening of the survival curve in those who started art within 1 month compared with those who started beyond 1 month.7 despite an association of day-14 fungal burden and subsequent cm-iris, there was no association of earlier art initiation and iris, and patients who developed iris did not have a higher mortality. while cm was the presumed cause of 85% of the deaths in the first 2 weeks, the majority (67%) of deaths after 2 weeks were attributed to other illnesses related to advanced immunosuppression, which might have been prevented through earlier art initiation. the absence of rct evidence favouring the 2 4-week time-points does not translate into evidence against these time-points. our clinical cohort data and experience in managing hiv patients with cm in the sa setting makes us strong advocates of an art start time of 4 weeks from cm diagnosis: a time-frame that is being applied in a recently commenced phase iii randomised trial of cm treatment at four sites in africa (acta trial, isrctn 45035509), and which we believe represents a pragmatic approach based on a synthesis of all available evidence. references 1. bicanic t, meintjes g, wood r, et al. fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin b or fluconazole. clin infect dis 2007;45(1):76-80. 1. bicanic t, meintjes g, wood r, et al. fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin b or fluconazole. clin infect dis 2007;45(1):76-80. 2. bicanic t, wood r, meintjes g, et al. high-dose amphotericin b with flucytosine for the treatment of cryptococcal meningitis in hiv-infected patients: a randomized trial. clin infect dis 2008;47(1):123-130. [http://dx.doi.org/10.1086/588792] 2. bicanic t, wood r, meintjes g, et al. high-dose amphotericin b with flucytosine for the treatment of cryptococcal meningitis in hiv-infected patients: a randomized trial. clin infect dis 2008;47(1):123-130. [http://dx.doi.org/10.1086/588792] 3. loyse a, wilson d, meintjes g, et al. comparison of the early fungicidal activity of high-dose fluconazole, voriconazole, and flucytosine as second-line drugs given in combination with amphotericin b for the treatment of hiv-associated cryptococcal meningitis. clin infect dis 2012;54(1):121-128. [http://dx.doi.org/10.1093/cid/cir745] 3. loyse a, wilson d, meintjes g, et al. comparison of the early fungicidal activity of high-dose fluconazole, voriconazole, and flucytosine as second-line drugs given in combination with amphotericin b for the treatment of hiv-associated cryptococcal meningitis. clin infect dis 2012;54(1):121-128. [http://dx.doi.org/10.1093/cid/cir745] 4. jarvis jn, meintjes g, rebe k, et al. adjunctive interferon-immunotherapy for the treatment of hiv-associated cryptococcal meningitis: a randomized controlled trial. aids 2012;26(9):1105-1113. [http://dx.doi.org/10.1097/qad.0b013e3283536a93] 4. jarvis jn, meintjes g, rebe k, et al. adjunctive interferon-immunotherapy for the treatment of hiv-associated cryptococcal meningitis: a randomized controlled trial. aids 2012;26(9):1105-1113. [http://dx.doi.org/10.1097/qad.0b013e3283536a93] 5. lawn sd, harries ad, anglaret x, myer l, wood r. early mortality among adults accessing antiretroviral treatment programmes in sub-saharan africa. aids 2008;22(15):1897-1908. [http://dx.doi.org/10.1097/qad.0b013e32830007cd] 5. lawn sd, harries ad, anglaret x, myer l, wood r. early mortality among adults accessing antiretroviral treatment programmes in sub-saharan africa. aids 2008;22(15):1897-1908. [http://dx.doi.org/10.1097/qad.0b013e32830007cd] 6. boulware dr, meya db, bergemann tl, et al. clinical features and serum biomarkers in hiv immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. plos med 2010;7(12):e1000384. [http://dx.doi.org/10.1371/journal.pmed.1000384] 6. boulware dr, meya db, bergemann tl, et al. clinical features and serum biomarkers in hiv immune reconstitution inflammatory syndrome after cryptococcal meningitis: a prospective cohort study. plos med 2010;7(12):e1000384. [http://dx.doi.org/10.1371/journal.pmed.1000384] 7. bicanic t, jarvis jn, loyse a, et al. determinants of acute outcome and long-term survival in hiv-associated cryptococcal meningitis: results from a combined cohort of 523 patients. abstract 892. conference of retroviruses and opportunistic infections (croi), boston, usa, 27 february 2 march 2011. 7. bicanic t, jarvis jn, loyse a, et al. determinants of acute outcome and long-term survival in hiv-associated cryptococcal meningitis: results from a combined cohort of 523 patients. abstract 892. conference of retroviruses and opportunistic infections (croi), boston, usa, 27 february 2 march 2011. 8. mccarthy k, meintjes g, arthington-skaggs b, et al. guidelines for the prevention, diagnosis and management of cryptococcal meningitis and disseminated cryptococcosis in hiv-infected patients. southern african journal of hiv medicine 2008;8(3):25-35. 8. mccarthy k, meintjes g, arthington-skaggs b, et al. guidelines for the prevention, diagnosis and management of cryptococcal meningitis and disseminated cryptococcosis in hiv-infected patients. southern african journal of hiv medicine 2008;8(3):25-35. 9. makadzange at, ndhlovu ce, takarinda k, et al. early versus delayed initiation of antiretroviral therapy for concurrent hiv infection and cryptococcal meningitis in sub-saharan africa. clin infect dis 2010;50(11):1532-1538. [http://dx.doi.org/10.1086/652652] 9. makadzange at, ndhlovu ce, takarinda k, et al. early versus delayed initiation of antiretroviral therapy for concurrent hiv infection and cryptococcal meningitis in sub-saharan africa. clin infect dis 2010;50(11):1532-1538. [http://dx.doi.org/10.1086/652652] 10. bicanic t, jarvis jn, muzoora c, harrison ts. should antiretroviral therapy be delayed for 10 weeks for patients treated with fluconazole for cryptococcal meningitis? clin infect dis 2010;51(8):986-987. [http://dx.doi.org/10.1086/656437] 10. bicanic t, jarvis jn, muzoora c, harrison ts. should antiretroviral therapy be delayed for 10 weeks for patients treated with fluconazole for cryptococcal meningitis? clin infect dis 2010;51(8):986-987. [http://dx.doi.org/10.1086/656437] 11. boulware dr. safety, censoring, and intent-to-treat analysis: dangers to generalizability. clin infect dis 2010;51(8):985-986. [http://dx.doi.org/10.1086/656436] 11. boulware dr. safety, censoring, and intent-to-treat analysis: dangers to generalizability. clin infect dis 2010;51(8):985-986. [http://dx.doi.org/10.1086/656436] 12. grant pm, aberg ja, zolopa ar. concerns regarding a randomized study of the timing of antiretroviral therapy in zimbabweans with aids and acute cryptococcal meningitis. clin infect dis 2010;51(8):984-985. 12. grant pm, aberg ja, zolopa ar. concerns regarding a randomized study of the timing of antiretroviral therapy in zimbabweans with aids and acute cryptococcal meningitis. clin infect dis 2010;51(8):984-985. 13. boulware dr, meya d, muzoora c, et al. art initiation within the first 2 weeks of cryptococcal meningitis is associated with higher mortality: a multisite randomized trial. abstract 144. conference on retroviruses and opportunistic infections (croi), atlanta, usa, 6 march 2013. 13. boulware dr, meya d, muzoora c, et al. art initiation within the first 2 weeks of cryptococcal meningitis is associated with higher mortality: a multisite randomized trial. abstract 144. conference on retroviruses and opportunistic infections (croi), atlanta, usa, 6 march 2013. abstract introduction ethical considerations case report discussion conclusion acknowledgements references about the author(s) mohamed f. sacoor department of dermatology, nelson r mandela school of medicine, university of kwazulu-natal, south africa citation sacoor mf. disseminated cutaneous histoplasmosis with laryngeal involvement in a setting of immune reconstitution inflammatory syndrome. s afr j hiv med. 2017;18(1), a693. https://doi.org/10.4102/sajhivmed.v18i1.693 case reports disseminated cutaneous histoplasmosis with laryngeal involvement in a setting of immune reconstitution inflammatory syndrome mohamed f. sacoor received: 19 sept. 2016; accepted: 02 mar. 2017; published: 28 apr. 2017 copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract introduction: histoplasmosis is a systemic mycosis caused by the dimorphic fungus histoplasma capsulatum. we report a case of disseminated cutaneous histoplasmosis with mucocutaneous involvement in an aids patient paradigmatic of the multifaceted nature of the disease, which is an expression of the immune reconstitution inflammatory syndrome (iris). patient presentation: a 39-year-old man presented with a three month history of asymptomatic papules and nodules with necrotic centres involving the centrofacial region. the patient was diagnosed as being hiv-positive a month earlier and was commenced on antiretroviral treatment. two weeks after the development of skin lesions, the patient complained of a sore throat and hoarseness of his voice. a fibre-optic laryngoscopy and biopsies of the skin, larynx and liver were performed. management and outcome: the cd4 counts increased from 2 cells/µl to 124 cells/µl, whereas the viral load decreased from one million to less than 20 copies/ml. a fibre-optic laryngoscopy revealed a supraglottitis with ulceration on the epiglottis. histology of the liver, larynx and sections of the skin demonstrated pandermal necrotising granulomatous inflammation. grocott-gomori methenamine silver and periodic acid–schiff (pas) stains revealed a relative paucity of intracellular, narrow-neck budding fungal organisms. culture findings confirmed the diagnosis of histoplasmosis. the patient was treated with intravenous amphotericin b for two weeks followed by oral itraconazole 100 mg twice a day, with an excellent response to treatment. conclusion: we present this case to remind clinicians that disseminated histoplasmosis in aids patients may occur as an expression of iris. a sudden onset of hoarseness with cutaneous lesions in a patient with disseminated disease should alert one to possible laryngeal histoplasmosis. prompt recognition and treatment will avert the potential fatal complications of this disease. introduction histoplasmosis is a systemic mycosis caused by the dimorphic fungus histoplasma capsulatum. we report a case of disseminated histoplasmosis (dh) with mucocutaneous involvement in an aids patient paradigmatic of the multifaceted nature of the disease, which is an expression of the immune reconstitution inflammatory syndrome (iris). ethical considerations the sub-committee of the biomedical research ethics committee at the university of kwazulu-natal has given their full ethical approval for this study with brec reference number: be068/17. case report a 39-year-old man presented with a 3-month history of skin lesions involving the face, neck and extremities. the patient was diagnosed as being hiv-positive a month earlier and was commenced on antiretroviral treatment abacavir 300 mg bd, lamivudine 300 mg bd and efavirenz 600 mg once daily, because of impaired renal function or pre-renal failure. the patient was hydrated with an improvement in the renal function. two weeks after the development of the skin lesions, the patient complained of a sore throat and hoarseness of his voice. on clinical examination, the patient had multiple translucent, clustered, umbilicated papules and nodules in the centrofacial region and neck with necrotic centres. in addition, there were verrucous plaques and nodules on the ears and upper limbs (figure 1a and b). chest x-ray was normal with no lung, hilar or mediastinal lymph nodes. a fibre-optic laryngoscopy revealed a supraglottitis with ulceration on the lingual surface of the epiglottis (figure 1c). figure 1: (a) multiple pearly papules and nodules with necrotic centres on the face and neck, (b) well-circumscribed verrucous papules and plaques on the ear and (c) a supraglottitis with ulceration on the lingual surface of the epiglottis. routine blood investigations demonstrated elevation of the liver enzymes with an infiltrative pattern (ast-63/alt 70/alp -219/gamma gt-291). abdominal ultrasound revealed an enlarged liver with abnormal parenchyma. the kidneys and the rest of the abdomen were normal. the initial cd4 count performed prior to the commencement of antiretrovirals was 2 cells/µl with a viral load greater than one million copies/ml. a repeat test (eight weeks later) showed a cd4 count of 124 cells/µl with a viral load of less than 20 copies/ml. urinalysis and urine histoplasma antigen test were negative. histology of the liver, larynx and sections of the skin demonstrated pandermal necrotising granulomatous inflammation. grocott-gomori methenamine silver and pas stains revealed a relative paucity of intracellular oval, narrow-neck budding fungal organisms morphologically in keeping with histoplasma capsulatum var. capsulatum (figure 2a and b). fungal culture of liver, epiglottis ulcer and skin confirmed the diagnosis of histoplasmosis. figure 2: (a) haematoxylin–eosin 40x – shows features of a pandermal granulomatous inflammatory reaction comprising aggregates of epithelioid histiocytes and langerhans giant cells; (b) pas stain 40x reveals the presence of intracellular uninucleate oval yeast-like, narrow-neck budding fungal organisms; and (c) grocott-gomori methenamine silver stain 40x – shows a narrow-neck budding fungal organism. on the basis of the clinical presentation, initial worsening of the disease and rapid elevation of the cd4+ t-cell count with lowering of the hiv viral load, the patient most likely has histoplasmosis associated iris. the patient was commenced on intravenous amphotericin b (0.8 mg/kg/day) for two weeks and continued with his antiretroviral treatment. he had an excellent response to this treatment and was discharged on itraconazole 100 mg twice a day. discussion disseminated histoplasmosis is most frequently described among patients with cd4+ t-cell counts below 50 cells/mm3.1 it occurs in 5% – 75% of aids patients, with mucocutaneous manifestations seen among 11% – 25% of cases.2 cutaneous lesions can take a number of forms from inflammatory folliculitis, molluscum-like papules, verrucous plaques, erythema multiforme-like lesions, vasculitic lesions, exfoliative dermatitis, ulcers and nodular lesions.2,3 immune reconstitution inflammatory syndrome is an inflammatory disease and is the consequence of an exaggerated dysregulated immune antigen interaction following highly active antiretroviral therapy (haart) induced immune restoration.4 the disseminated clinical presentation may probably be due to a low cd4 count as well as a high antigen burden prior to haart initiation.4 nacher et al.5 reported that patients taking haart were more likely to develop dh than untreated patients. the exacerbation of skin and laryngeal symptoms in our patient after starting haart may be due to an exaggerated cell-mediated inflammatory response. iris is a diagnosis of exclusion. although it is the most likely diagnosis in our patient, the natural progression of a pre-existing opportunistic infection cannot be excluded.5 laryngeal histoplasmosis is a rare phenomenon.6 since 1952, when laryngeal histoplasmosis was initially described in the literature, less than 100 cases have been reported to date.7 common initial manifestations are pain when swallowing, hoarseness, gingival ulceration and dysphagia.7,8 firm, painful ulcers, with elevated borders, involving the oral mucosa and larynx are characteristic.7,8 amphotericin b and itraconazole are the antifungal agents that were noted to be effective in the treatment of histoplasmosis.9 treatment should be continued until clinical and laboratory findings are normal.9,10 however, 9% of patients will experience a relapse.10 according to the evidence-based guidelines for the management of dh presented by the infectious diseases society of america (idsa), it is recommended that patients with moderate to severe disease be treated with liposomal amphotericin b (3.0 mg/kg daily for 12 weeks), followed by oral itraconazole (200 mg three times daily for three days and then 200 mg twice daily for a total of at least 12 months).11 the deoxycholate formulation of amphotericin b (0.7 mg/kg – 1.0 mg/kg daily) is an alternative to a lipid formulation in patients who are at low risk for nephrotoxicity. for mild to moderate disease, itraconazole (200 mg three times daily for three days and then 200 mg twice daily for at least 12 months) is recommended.11 lifelong suppressive therapy with itraconazole (200 mg daily) may be required in immunosuppressed patients if immunosuppression cannot be reversed and in patients who relapse despite receipt of appropriate therapy.11 conclusion we are presenting this case to remind clinicians that dh in aids patients may occur as an expression of iris. a sudden onset of hoarseness with cutaneous lesions in a patient with disseminated disease should alert one to possible laryngeal histoplasmosis. prompt recognition and treatment will avert the potential fatal complications of this disease. acknowledgements competing interests the author declares that he has no financial or personal relationships which may have inappropriately influenced him in writing this article. references angius ag, viviani ma, muratori s, cusini m, brignolo l, alessi e. disseminated histoplasmosis presenting with cutaneous lesions in a patient with acquired immunodeficiency syndrome. j eur acad dermatol venereol. 1998;10:182–185. https://doi.org/10.1111/j.1468-3083.1998.tb00724.x ramdial p, mosam a, dlova n, satar n, aboobaker j, singh sm. disseminated cutaneous histoplasmosis in patients infected with human immunodeficiency virus. j cutan pathol. 2002;29:215–225. https://doi.org/10.1034/j.1600-0560.2002.290404.x radhakrishnan s, adulkar ng, kim u. primary cutaneous histoplasmosis mimicking basal cell carcinoma of the eyelid: a case report and review of literature. indian j pathol microbiol. 2016;59(2):227–228. https://doi.org/10.4103/0377-4929.182017 ogoina d, adekunle v, obiako r, umar a, akolawole m, ovosi j. disseminated infections due to immune reconstitution inflammatory syndrome after highly active antiretroviral therapy-report of 3 cases from nigeria. pan afr med j. 2011;9:38. https://doi.org/10.4314/pamj.v9i1.71216 sarazin e, nacher m, toure y, et al. dermatologic manifestations associated with immune reconstitution syndrome in hiv+ patients starting haart. bull soc pathol exot. 2005;98(3):187–192. solari r, corti m, cangelosi d, et al. disseminated histoplasmosis with lesions restricted to the larynx in a patient with aids. report of a case and review of the literature. rev iberoam micol. 2007;24(2):164–166. https://doi.org/10.1016/s1130-1406(07)70036-0 pochini sobrinho f, della negra m, queiroz w, ribeiro uj, bittencourt s, klautau g. histoplasmosis of the larynx. braz j otorhinolaryngol. 2007;73(6):857–861. https://doi.org/10.1016/s1808-8694(15)31187-3 sanmani l, randall cj, palfrey j, rowen d. hoarseness of voice in an aids patient: a rare presenting feature of disseminated histoplasmosis. int j std aids. 2011;22(2):115–116. https://doi.org/10.1258/ijsa.2010.010356 marques sa, silvares mr, camargo rm, marques me. cutaneous histoplasmosis disclosing an hiv-infection. an bras dermatol. 2013;88(3):420–423. https://doi.org/10.1590/abd1806-4841.20131812 assi ma, sandid ms, baddour lm, roberts gd, walker rc. systemic histoplasmosis: a 15-year retrospective institutional review of 111 patients. medicine (baltimore). 2007;86(3):162–169. wheat lj, freifeld ag, kleiman mb, et al. clinical practical guidelines for the management of patients with histoplasmosis: 2007 update by the infectious diseases society of america. clin infect dis. 2007;45:807–808. https://doi.org/10.1086/521259 hiv 1094_in.indd september 2014, vol. 15, no. 3 sajhivmed 97 o r ig in a l a r t ic l eoriginal article expression of dc-sign and dc-signrs in placentas of hiv-positive patients k pillay,1 mb chb, fcpath (sa), frcpath(uk), mmed anat path; m cloete,2 mb chb, fcog (sa), mmed o&g; h mcleod,1 mtech 1 department of anatomical pathology, university of cape town, and red cross children’s war memorial hospital, cape town, south africa 2 department of obstetrics and gynaecology, groote schuur hospital, university of cape town, south africa corresponding author: k pillay (komala.pillay@uct.ac.za) background. human dendritic cell-speci�c intracellular adhesion molecule-3 (icam3)-grabbing non-integrin (dc-sign) is a mannose-binding lectin that initiates interaction between dendritic cells and resting t-lymphocytes. dc-sign is highly expressed in placental tissue on dendritic cells and ho�auer cells, and it is suggested that hiv may become adsorbed to dc-sign on ho�auer cells as part of the mechanism of mother-to-child hiv transmission. a possible mechanism of transfer of the virus from the ho�auer cells to the fetus is the subsequent adsorption to dc-sign-related molecules (dc-signrs), present on immediately adjacent capillary vascular endothelium. however, data on dc-sign and dc-signr expression in the placenta are few. methods. forty term placentas from hiv-positive mothers and 21 term placentas from hiv-negative mothers underwent immunohistochemistry staining for dc-sign and dc-signr expression. five random sets of 10 villi were assessed, and the average number of positive cells were counted in each case. in addition, where possible, maternal and cord blood viral loads and maternal cd4+ counts were performed in the hiv-positive group only. results. �e median maternal cd4+ count was 377 cells/µl and 27% of participants had undetectable viral loads; the median detectable viral load was 3.72 log. most (97%) of the cord bloods tested in infants from hiv-positive mothers had lower than detectable viral loads. hiv-positive cases had signi�cantly greater expression of both dc-signrs (median values in hiv-positive cases, 14.5 positive cells/10 villi (pc/10villi), compared with 11 pc/10villi in hiv-negative cases, p=0.020) and dc-sign (median value in hiv-positive cases, 26.5 pc/10villi, compared with 23 pc/10villi in hiv-negative cases, p=0.037). dc-signr expression was also noted in ho�auer cells and decidual macrophages in addition to endothelium (reported currently). �ere was no di�erence in expression of dc-sign and dc-signrs in patients with or without chorioamnionitis, but there was an inverse relationship between dc-sign and dc-signr expression and maternal cd4+ counts in hiv-positive cases. conclusion. both dc-sign and dc-signr expression were higher in placentas from hiv-positive mothers compared with hiv-negative cases. �ese lectins may be potential new therapeutic targets for preventing vertical transmission of hiv. s afr j hiv med 2014;15(3):97-101. doi:10.7196/sajhivmed.1094 �e rate of vertical transmission of hiv is estimated at between 13% and 39% in nonbreastfeeding women.[1] most of these cases occur during the intrapartum period during vaginal delivery. however, a small percentage results from hiv infection across the placenta (1 2%). a possible mechanism for late-gestation hiv transmission may be maternal-fetal transfusions during labour, which is signi�cantly lower in elective caesarean sections (css).[2] reverse transcriptase inhibitors (azidothymidine/zidovudine (azt) and lamivudine) rapidly cross the placenta, and cord blood levels equal or exceed those in the maternal circulation at the time of delivery.[3] even a single dose of nevirapine, when administered during labour and to an infant after birth, can reduce vertical transmission by 50% because it rapidly crosses the placenta.[3,4] the use of highly active antiretroviral therapy (haart) throughout pregnancy and prophylactic cs have reduced the rate of vertical transmission in the us to <2%.[5] infants with a positive hiv polymerase chain reaction (pcr) test within 48 hours of birth are considered to have been infected in utero. however, infants who tested hiv-negative at birth but tested positive at 6 weeks or 12 weeks postnatally with pcr testing are considered to have been infected intrapartum or immediately post partum.[6] in addition, hiv has been demonstrated in second-trimester fetuses and second-trimester cord bloods with associated placental hiv infection supporting in utero transmission.[7-9] factors that may increase the risk of mother-to-infant transmission include advanced hiv-related illness, low cd4+ counts, high hiv-1 viral loads (vls), the presence of sexually transmitted diseases, viral phenotype, premature rupture of membranes, chorioamnionitis and absence of maternal autologous neutralising antibodies.[2] but even at the highest vls, only about half of exposed infants become infected with hiv.[2,4] it has been proposed that a breach in the trophoblast layer lining the chorionic villi may result in contact of hofbauer cells o r ig in a l a r t ic l e o r ig in a l a r t ic l e 98 sajhivmed september 2014, vol. 15, no. 3 (specialised fetal macrophages) with maternal blood and amniotic fluid. there may also be entry of hiv into the trophoblast layer with subsequent infection of the cell, or the virus could traverse the cells intact, following release at the basolateral surface and exposure to stromal cells. the two pathways are not mutually exclusive.[2] however, trophoblast cells are reported to be only ‘moderately susceptible’ to hiv infection in vitro.[10] it has been shown that tumour necrosis factor alpha (tnfα) significantly upregulated transcytosis of hiv-1 across the trophoblast layer whereas an anti-inflammatory drug (tenidap) significantly reduced transcytosis rates.[5] infection of trophoblast cells remains controversial.[11] c-c chemokine receptor type 5 (ccr5) and c-x-c chemokine receptor type 4 (cxcr4) were demonstrated on placental macrophages and lymphocytes, but not in trophoblast cells. mattern et al.[12] demonstrated p24 antigen within scattered hofbauer cells but not within trophoblast cells or vascular endothelium, in 5/19 term placentas (26%) from hiv-positive women. there was no association between p24 antigen detection and vertical transmission. [12] another study showed positive hofbauer cell staining for p24 in 4/9 (44%) placentas from hiv-positive mothers, but there was also decidual macrophage (n=1), intermediate trophoblast (n=1) and villous endothelium (n=1) positivity.[13] human dendritic cell-specific intracellular adhesion molecule-3 (icam3)-grabbing non-integrin (dc-sign) is a type ii mannose-binding lectin that initiates interaction between dendritic cells and resting t-lymphocytes. it is highly expressed in dendritic cells on mucosal tissue and has also been found to be highly expressed in placental tissue on maternal decidual cells and fetal hofbauer cells.[14] it has been proposed that hiv may become adsorbed to dc-sign on hofbauer cells and/or infect hofbauer cells. various mechanisms have been proposed that may allow transfer of the virus from the hofbauer cells to the fetus. one mechanism includes subsequent adsorp tion to dc-sign-related molecules (dcsignrs) present on immediately adjacent capillary vascular endothelium. [14] a dc-signr is a transmembrane lectin that binds mannose residues including the glycans of icam3 and hiv-1 and hiv-2. it is prominently expressed on endothelial cells derived from liver sinusoids, lymph node sinuses and placenta. [15] however, the possible role of dc-sign and dc-signrs in vertical transmission of hiv is still poorly understood. the purpose of this study was to assess the expression of dc-sign and dc-signrs in placentas of hiv-positive patients with the following objectives: to compare the expression of dc-sign and dc-signrs in placentas of hiv-positive and hiv-negative patients; to correlate the expression of dc-sign and dc-signrs with vls, history of antiretroviral therapy and evidence of in-utero hiv transmission (if possible); and to assess the placentas from hiv-positive patients for pathology, including chorioamnionitis and the presence of specific infective agents. methods forty placentas from hiv-positive patients at term gestation were collected from the department of obstetrics and gynaecology, mowbray maternity hospital, cape town, south africa. in addition, 21 placentas from hiv-negative patients were collected. ethical approval for the study was granted by the faculty of health sciences at the university of cape town and informed consent for research was obtained from the patients (rec ref 290/2005). the research included histology and immunohistochemistry of the placentas, performed in the division of anatomical pathology, groote schuur hospital, cape town. the placentas were fixed in 10% buffered formalin and analysed in the postmortem laboratory. the analysis included macroscopic description (with plate weight), serial sectioning and taking of three blocks, depending on the presence of macroscopic abnormality, which included umbilical cord, membranes, cord insertion site and a peripheral section of placenta. haematoxylin and eosin stained sections were analysed by k pillay and a placental histopathology report was issued. one suitable block was selected for immunohistochemistry. two micrometre sections were cut onto poly-l-lysine coated slides and stained with dc-sign (purified mouse antihuman cd209 antibody, dilution 1:40, bd biosciences, us) and dc-signrs (monoclonal antihuman cd209l antibody, dilution 1:40, r&d systems, us) using the envision kit. diaminobenzidine (brown) was used as chromogen. positive and negative controls were run simultaneously. five random sets of 10 villi were assessed and an average number of positive cells were counted in each case. maternal and fetal vls, with blood taken at the time of delivery, were performed for the hiv-positive group in the department of virology, groote schuur hospital, cape town. data were analysed using stata version 10.0 (stata corporation, us). median values of cd4+ cell count, hiv vl and dc-signr expression were compared using the wilcoxon rank-sum test; proportions were compared using fisher’s exact test; and correlations were analysed using spearman’s rho. results forty term placentas from hiv-positive mothers (mean age (range) 26 (14 38) years) and 21 term placentas from hiv-negative mothers (28 (16 40) years) were assessed. all hiv-positive mothers received antiretrovirals for the prevention of motherto-child transmission (pmtct). the majority started azt monotherapy in the third trimester (85%, n=34), 2 were on azt and nevirapine or lamivudine (5%) and 4 were on haart before pregnancy (10%). two of the 40 hiv-positive patients tested positive for syphilis (venereal disease research laboratory (vdrl)-positive) and received treatment for this, while none of the hivnegative mothers was vdrl-positive. most of the deliveries were by cs in both groups (table 1). there were 2/38 (5%) small for gestational age (sga) babies from hiv-positive mothers, one with a history of gestational proteinuric hypertension even though the placenta was histologically normal. there were 3/21 (14%) sga babies from the hiv-negative cases, two of whom showed ischaemic changes histologically. table 1. antenatal history and delivery hiv status vdrl-positive delivery sga hiv-positive (n=40) 2 10 nvd 2 30 cs hiv-negative (n=21) 0 5 nvd 3 16 cs vdrl = venereal disease research laboratory; nvd = normal vaginal delivery; cs = caesarean section; sga = small for gestational age. o r ig in a l a r t ic l e september 2014, vol. 15, no. 3 sajhivmed 99 in the hiv-positive group, the median maternal cd4+ count was 324.5 cells/µl (interquartile range 246 522) (n=38) and 27% of hiv-positive participants had undetectable vls; the median detectable vl was 3.59 log (n=33). in infants from hiv-positive mothers, 97% of the cord bloods tested had lower than detectable vls (30/31). the mother of the infant with the positive cord blood (n=1) had higher than median vl, lower than median cd4+ count, received azt, and the placenta showed chorioamnionitis with cord-vessel vasculitis and chronic deciduitis. in the hiv-positive group, 15 placentas showed chorioamnionitis (grade 1 n=7, grade 2 n=6, grade 3 n=2; stage 1 n=3, stage 2 n=9, stage 3 n=3). there was also plate-vessel vasculitis (n=9), cord-vessel vasculitis (n=7) and funisitis (n=2). in the hiv-negative group, there were three cases of chorioamnionitis (grade 2 n=2, grade 3 n=1; stage 1 n=1, stage 3 n=2) and two cases of mild cord-vessel vasculitis with no evidence of plate-vessel vasculitis or funisitis in this group. there was no significant difference in the incidence of chorioamnionitis between placentas from hiv-positive and hivnegative mothers (p=0.084). there were 9 cases of chronic deciduitis, 7 in hivpositive placentas and 2 in hiv-negative patients (p=0.704). there was no evidence of villitis or intervillositis, and no opportunistic infections (e.g. cytomegalovirus inclusions, toxoplasmosis or cryptococcosis) were noted on morphology. additional features that were noted on histology in the hiv-positive group included evidence of meconium exposure (n=10), focal infarct (n=1), focal decidual vasculopathy (n=1), dysmaturity (n=3), fetal thrombotic vasculopathy (n=1), chorangiosis (n=1), intervillous thrombus (n=2) and intervillous haemorrhage (n=3); and in the hiv-negative group, infarcts (n=2), decidual vasculopathy (n=1) and dysmaturity (n=2). dc-sign expression was noted in hofbauer cells (fig. 1) and decidual macrophages (fig. 2) while dc-signr expression was seen in endothelial cells (fig. 3), some hofbauer cells and decidual macrophages (fig. 4). decidual macrophage staining for dc-signrs has not been described previously in the literature. hiv-positive cases had significantly greater expression of both dc-signrs (median values in hiv-positive cases, 14.5 positive cells/10 villi (pc/10villi), compared with 11 pc/10villi in hiv-negative cases, p=0.020) and dc-sign (median values in hivpositive cases, 26.5 pc/10villi, compared with 23 pc/10villi in hiv-negative cases, p=0.037). in addition, the expression of dc-sign and dc-signrs was inversely associated with cd4+ count in hiv-positive cases (p<0.05 for both, fig. 5) but the relationship with maternal vl was not statistically significant. there was no significant difference in the expression of dc-sign (p=0.833) and dc-signrs (p=0.557) in placentas with or without placental membrane inflammation. there was also no association with mode of delivery (normal vaginal delivery v. cs). discussion in the placenta, no co-expression of dc-sign and dc-signrs was detected previously. [15] dc-signr expression was detected only on capillary endothelial cells, whereas dcsign was expressed only by ho� auer cells. [15] however, mummidi et al.[16] demonstrated expression of dc-sign on placental capillary endothelium as well. dc-signrs showed a low level of expression in the endometrium. [17] in this study, we demonstrated dc-signr expression on ho� auer cells and decidual cells as well. dc-sign and dc-signr lectins have been shown to mediate infection in cis (cells with dc-sign receptors e.g. dendritic cells) and trans (e.g. t-lymphocytes) cells.[18] currently, it is felt that dc-sign and dc-signrs represent the best candidate molecules for mediating intrauterine transmission.[10] dc-sign and dc-signrs appear to function fig. 1. a. dc-sign expression in hofbauer cells in an hiv-positive case with chorioamnionitis and a cd4+ count of 118 cells/µl; b. dc-sign expression in hofbauer cells in an hiv-negative case. (dcsign = human dendritic cell-speci� c intracellular adhesion molecule-3 (icam3)-grabbing nonintegrin.) a b fig. 2. dc-sign expression in decidual macrophages in an hiv-positive case with the only detectable viral load in the cord blood. (dcsign = human dendritic cell-speci� c intracellular adhesion molecule-3 (icam3)-grabbing nonintegrin.) fig. 3. dc-signr expression in endothelial cells and hofbauer cells in an hiv-positive case with maternal cd4+ count of 365 cells/µl and a viral load of 3.84 log. (dc-signr = human dendritic cellspeci� c intracellular adhesion molecule-3 (icam3)grabbing non-integrin-related molecule.) fig. 4. dc-signr expression in decidual macrophages in an hiv-positive case with maternal cd4+ count of 45 cells/µl. (dc-signr = human dendritic cell-speci� c intracellular adhesion molecule-3 (icam3)-grabbing non-integrinrelated molecule.) 100 sajhivmed september 2014, vol. 15, no. 3 o r ig in a l a r t ic l e as universal attachment factors for primate lentiviruses, namely hiv-1, hiv-2 and simian immunodeficiency viruses. [19] however, research in this field is still in progress and many studies are in vitro in nature. one such study has shown a decrease in dc-sign expression following infection with hhv6. [20,21] according to these papers, this may apply to the infection of hiv-1, or dc-sign expression may be up-regulated in the setting of hiv-1. another in-vitro study has shown that while dc-sign is up-regulated by type 1 and type 2 cytokines, there is no association between dc-sign expression and the degree of hiv-1 transmission from macrophages to cd4+ t-cells.[21] the situation in vivo may be different. a few studies have shown that antidc-sign reactive antibodies block hiv transmission to cells mediated by dc-sign. [22] if studies find a significant association between dc-sign expression and intrauterine transmission, then transplacental transmission of hiv may be retarded by the administration of dc-signand dc-signrblocking molecules. other lectin receptors include mannose receptor and langerin expressed on intradermal dendritic cells and langerhans cells (dc-sign negative), respectively, which may have hiv-binding affinity.[23] dc-sign on dendritic cells has been shown to bind and transfer hiv through its interaction with hiv gp120. disruption of this interaction represents a potential new therapeutic approach for preventing hiv transmission.[24] gurney et al.[24] found that dc-signpositive dendritic cells in the submucosa may be responsible for the transfer of hiv-1 from the periphery to the draining lymph nodes during primary sexual mucosal transmission of hiv-1. dc-sign-positive cells appear to be immature dendritic cells in that they did not express the dendritic cell maturation molecule cd83. the hofbauer cells have also been shown to be human leukocyte antigen (hla) ii+ , cd68+, cd14 low+, cd4+, and s100±, cd86– and cmrf-44–. [23,25] dc-sign is also expressed by some decidual cells with cd14high+ and s100-negative phenotype compared with the hofbauer cells. dc-sign-positive hofbauer cells co-express cd4+ and chemokine receptors ccr-5 and cxcr4.[23] gurney et al.[24] have demonstrated an increase in dc-sign-positive cells in the gut mucosa of hiv-positive patients (two fourfold greater). increased dc-sign expression in the gut mucosa correlated with a type 2 environment (increased interleukin (il)-10/ il-12 ratio) and a decrease in the levels of the costimulatory molecules cd86 and cd80. micro-array analysis experiments have shown that il-10-induced dendritic cells result in a dc-sign high-expressing subset. there is a shift in pregnancy towards the production of t-helper 2 (th2) cytokines, including il-4 and il-10, promoted by progesterone.[4] the th2 cytokines il-4 and il-13 play an important role in inducing dc-sign expression under specific conditions.[23] however, it has been shown that placentas from non-transmitting women maintain normal type 2 placental cytokines (il-4, il-10) whereas transmitting women have placentas that express type 1 cytokines (interferon-gamma, tumour necrosis factor beta).[11] other cytokines (tnfα, il-6, etc.) stimulate the hiv infection and facilitate transmission during pregnancy.[2] in this study, we found an increase in dc-sign expression in placentas from hivpositive patients, which may be due to the increased cytokine milieu. fig. 5. a. cd4+ v. dc-signrs (cd299) showing a statistically signi�cant inverse correlation, the higher the expression, the lower the cd4+ count; b. cd4+ v. dc-sign (cd209) showing a statistically signi�cant inverse correlation, the higher the expression, the lower the cd4+ count. (dc-signr = human dendritic cell-speci�c intracellular adhesion molecule-3 (icam3)-grabbing non-integrin-related molecules.) 0 10 20 30 cd299 mother cd4+ fitted values+ c d 4+ (c el ls /µ l ) 0 200 400 600 800 1 000 0 10 20 30 cd299 mother cd4+ fitted values+ 40 c d 4+ (c el ls /µ l) 0 200 400 600 800 1 000 b a september 2014, vol. 15, no. 3 sajhivmed 101 o r ig in a l a r t ic l e it has been shown that an anti-dc-sign antibody blocked virus binding to dendritic cells by almost 90%, with low viral inocula close to those found in seminal �uid from untreated hiv-positive patients.[24] in addition, when the hiv was exposed to the total mucosal mononuclear cells, about 40-fold more viruses were bound to the dc-sign-positive population compared with the total gut mononuclear cell population. �erefore, more than 90% of the bound virus was associated with the dc-sign-positive cells, which only constitute about 1 5% of the total mucosal mononuclear cell population. dc-sign is therefore a potential target for therapeutic intervention to reduce viral transmission (a�er sexual transmission and during vertical transmission).[14,24] �e ability of dc-sign to enhance infection markedly when virus levels are low may be of particular importance in the setting of prophylaxis against mother-to-child transmission and haart.[26] placental membrane inflammation comprises histological evidence of chorioamnionitis and/or funisitis with or without associated vasculitis. plasma cell (chronic) deciduitis is demonstrated by the presence of plasma cells in the maternal decidua.[27] jauniaux et al.[28] demonstrated a high incidence of chorioamnionitis (43%) in placentas from hiv-positive women, but villitis was absent. according to the study by schwartz et al.,[29] no histopathological finding occurred with increased frequency in placentas of transmitting women even though there was a trend towards increased frequency of plasma cell deciduitis. only 1/17 transmitting women had a placenta with low-grade neutrophilic inflammation. more uninfected women had villitis.[29] chandwani et al.[30] demonstrated no cases of villitis and a higher incidence of chorionitis in placentas from hiv-positive women and p24 antigen within trophoblastic cells, contrary to other studies.[30] in our study, we demonstrated no significant difference in placental membrane inflammation or chronic deciduitis between hiv-positive and hiv-negative women. there were no cases of villitis or intervillositis in any of the cases. in addition, there was no association of dc-sign or dc-signr expression with placental membrane inflammation. conclusion both dc-sign and dc-signr expression were higher in placentas from hiv-positive mothers compared with hiv-negative cases, and this was statistically signi�cant. dc-signr expression was also noted in ho�auer cells and decidual macrophages in addition to endothelium (reported currently). �ere was no association of dc-sign or dc-signr expression with the presence of placental membrane in�ammation, but there was a statistically signi�cant inverse relationship between dc-sign and dc-signr expression and maternal cd4+ counts in hiv-positive cases. �ere was possible in utero transmission of hiv in one of the 40 hiv-positive cases (3%). references 1. kourtis ap, lee fk, abrams ej, et al. mother-to-child transmission of hiv-1: timing and implications for prevention. lancet infect dis 2006;6(11):726-732. 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[http://dx.doi.org/10.1016/0046-8177(92)90088-k] 14. geijtenbeek tb, van vliet sj, van duijnhoven gc, et al. dc-sign, a dentritic cellspeci�c hiv-1 receptor present in placenta that infects t cells in trans: a review. placenta 2001;22(suppl a):s19-23. [http://dx.doi.org/10.1053/plac.2001.0674] 15. soilleux ej, morris ls, rushbrook s, et al. expression of human immunode�ciency virus (hiv)-binding lectin dc-signr: consequences for hiv infection and immunity. hum pathol 2002;33(6):652-659. [http://dx.doi.org/10.1053/ hupa.2002.124036] 16. mummidi s, catano g, lam l, et al. extensive repertoire of membrane-bound and soluble dendritic cell-speci�c icam-3-grabbing nonintegrin 1 (dc-sign1) and dc-sign2 isoforms. inter-individual variation in expression of dc-sign transcripts. j biol chem 2001;276(36):33196-33212. [http://dx.doi.org/10.1074/ jbc.m009807200] 17. soilleux ej, barten r, trowsdale j. dc-sign; a related gene, dc-signr; and cd23 form a cluster on 19p13. j immunol 2000;165(6):2937-2942. [http://dx.doi. org/10.4049/jimmunol.165.6.2937] 18. gummuluru s, kewalramani vn, emerman m. dendritic cell-mediated viral transfer to t cells is required for human immunode�ciency virus type 1 persistence in the face of rapid cell turnover. j virol 2002;76(21):10692-10701. [http://dx.doi. org/10.1128/jvi.76.21.10692-10701.2002] 19. pohlmann s, soilleux ej, baribaud f, et al. dc-signr, a dc-sign homologue expressed in endothelial cells, binds to human and simian immunode�ciency viruses and activates infection in trans. proc natl acad sci usa 2001;98(4):26702675. [http://dx.doi.org/10.1073/pnas.051631398] 20. niiya h, azuma t, jin l, et al. transcriptional downregulation of dc-sign in human herpesvirus 6-infected dendritic cells. j gen virol 2004;85(pt 9):2639-2642. [http://dx.doi.org/10.1099/vir.0.80095-0] 21. chehimi j, luo q, azzoni l, et al. hiv-1 transmission and cytokine-induced expression of dc-sign in human monocyte-derived macrophages. j leukoc biol 2003;74(5):757-763. [http://dx.doi.org/10.1189/jlb.0503231] 22. wu l, martin td, vazeux r, et al. functional evaluation of dc-sign monoclonal antibodies reveals dc-sign interactions with icam-3 do not promote human immunode�ciency virus type 1 transmission. j virol 2002;76(12):5905-5914. [http://dx.doi.org/10.1128/jvi.76.12.5905-5914.2002] 23. soilleux ej. dc-sign (dendritic cell-speci�c icam-grabbing non-integrin) and dc-sign-related (dc-signr): friend or foe? clin sci (lond) 2003;104(4):437446. [http://dx/doi.org/10.1042/cs20020092] 24. gurney kb, elliott j, nassanian h, et al. binding and transfer of human immunode�ciency virus by dc-sign+ cells in human rectal mucosa. j virol 2005;79(9):5762-5773. [http://dx.doi.org/10.1128/jvi.79.9.5762-5773.2005] 25. bockle bc, solder e, kind s, et al. dc-sign+ cd163+ macrophages expressing hyaluronan receptor lyve-1 are located within chorion villi of the placenta. placenta 2008;29(2):187-192. [http:dx.doi.org/10.1016/j.placenta.2007.11.003] 26. soilleux ej, morris ls, lee b, et al. placental expression of dc-sign may mediate intrauterine vertical transmission of hiv. j pathol 2001;195(5):586-592.[http:// dx.doi.org/10.1002/path.1026] 27. wabwire-mangen f, gray rh, miro fa, et al. placental membrane in�ammation and risks of maternal-to-child transmission of hiv-1 in uganda. j acquir immune de�c syndr 1999;22:379-385. [http://dx.doi.org/10.1097/00126334-199912010-00009] 28. jauniaux e, nessmann c, imbert mc, et al. morphological aspects of the placenta in hiv pregnancies. placenta 1988;9(6):633-642. [http://dx.doi.org/10.1016/01434004(88)90007-0] 29. schwartz da, sungkarat s, sha�er n, et al. placental abnormalities associated with human immunode�ciency virus type 1 infection and perinatal transmission in bangkok, �ailand. j infect dis 2000;182(6):1652-1657. [http://dx.doi. org/10.1086/317634] 30. chandwani s, greco ma, mittal k, et al. pathology and human immunode�ciency virus expression in placentas of seropositive women. j infect dis 1991;163(5):11341138. [http://dx.doi.org/10.1093/infdis/163.5.1134] hiv 957 case report combined antiretroviral and anti-tuberculosis drug resistance following incarceration k e stott,1 mb chb, msc; t de oliviera,1,2 bsc (hons), phd; r j lessells,1,3 bsc (medsci), mb chb, mrcp, dtm&h, dip hiv med 1 africa centre for health and population studies, university of kwazulu-natal, mtubatuba, south africa 2 research department of infection, university college london, london, united kingdom 3 department of clinical research, london school of hygiene and tropical medicine, london, united kingdom corresponding author: r j lessells (rlessells@africacentre.ac.za) we describe a case of hiv/tuberculosis (tb) co-infection from kwazulu-natal, south africa, characterised by drug resistance in both pathogens. the development of drug resistance was linked temporally to two periods of incarceration. this highlights the urgent need for improved integration of hiv/tb control strategies within prison health systems and within the broader public health framework. s afr j hiv med 2013;14(3):135-137. doi:10.7196/sajhivmed.957 the twin epidemics of hiv and tuberculosis (tb) have had a devastating impact on individuals, families and communities in south africa (sa) over the past two decades.1 sa alone is responsible for almost one-third of the global burden of hiv-associated tb.2 while much progress has been made in the last few years with robust responses to these epidemics, many challenges remain.3 antiretroviral and anti-tb drug resistance pose considerable threats to the control of these epidemics.4 , 5 the breakdown in hiv/tb control within prisons is another emerging threat.6 , 7 we describe one of the first reports of combined antiretroviral and anti-tb drug resistance, where the development of resistance was closely associated with two periods of incarceration. case report a 34-year-old unemployed male presented to a primary healthcare (phc) clinic in hlabisa sub-district, kwazulu-natal, in february 2012 with a cough, night sweats and weight loss. he had been diagnosed with hiv infection in 2002, but had not accessed hiv care until april 2009 when he presented with his first episode of smear-negative pulmonary tb. at that time, his cd4+ cell count was 85 cells/µl and he was initiated on a standard first-line antiretroviral therapy (art) regimen of stavudine (d4t), lamivudine (3tc), and efavirenz (efv). he achieved complete virological suppression (hiv viral load <50 copies/ml) and a good immunological response (cd4+ count 482 cells/µl) after 5 months of art (fig. 1). in may 2010, he was incarcerated (in a correctional facility approximately 50 km from home) and as a result of non-disclosure of hiv status to prison officials, his art was interrupted. following release in september 2010, he had re-engaged with care at the phc clinic and had been restarted on art (tenofovir (tdf), 3tc and efv). within 6 months, he was once again detained in prison and his art was interrupted once again for several months. he reported that he shared a cell with up to 50 people during this second spell in prison, several of whom were coughing and one had apparently stated that he had multidrug-resistant tb (mdr-tb). fig. 1. clinical course of art with results of viral load (vl) and cd4+ cell count monitoring and timing of treatment interruptions. xpert® mtb/rif was performed on sputum and detected myco­bacterium tuberculosis resistant to rifampicin. he was referred to the provincial drug-resistant tb unit (approximately 250 km from home) and was commenced on a standardised regimen of kanamycin, moxifloxacin, ethionamide, terizidone, pyrazinamide and isoniazid. two weeks later, he was re-initiated on art (tdf, 3tc and efv). he completed the intensive phase of drug-resistant tb treatment with a good treatment response (acid-fast bacilli smear and culture negative after 2 months) and no evidence of nephrotoxicity, but there was no virological response to art (viral load 390 845 copies/ ml 6 months after restarting art), despite documented good adherence. genotypic resistance testing was performed and revealed non-nucleoside reverse transcriptase inhibitor (nnrti) resistance mutations (k103n and v106m) and nucleoside reverse transcriptase inhibitor (nrti) resistance mutations (k65r and m184v), conferring high-level resistance to efv and 3tc, and intermediate-level resistance to tdf. hepatitis b surface antigen (hbsag) was negative and haemoglobin was 12.7 g/dl. as a result, he was switched to a second-line art regimen consisting of co-formulated zidovudine (azt) and 3tc with lopinavir/ritonavir (lpv/r). at this stage, the total number of pills taken daily was 27 (including co-trimoxazole and pyridoxine). as of june 2013, he continues to be followed up at his local phc clinic (2 km from home) and at the drug-resistant tb unit. consent written informed consent was given by the patient prior to publication. discussion the issue of tb control in sa prisons has recently received much attention, as a result of the successful legal action against the minister of correctional services by a former prison inmate who contracted tb while in a correctional facility awaiting trial.8 here we have described a case where acquisition of drug-resistant tb most likely occurred in prison and the clinical course was compounded by the emergence of antiretroviral drug resistance. this has significance, not only for individual health, with increased treatment complexity and adverse clinical outcomes, but also for the health of the wider community, with the risk of onward transmission of drug-resistant infections. the case here highlights the need for an improved and more integrated approach to hiv/tb prevention and care in prisons, as well as better linkage between prison health services and the public health system. the incidence of tb disease in prisons worldwide has been shown to be more than 20 times that of the general population.9 this is widely attributed to factors such as overcrowding, poor nutrition, insufficient ventilation and inadequate health services in prisons.7 , 10-12 the problem is amplified in countries with a high hiv burden, as hiv infection is the strongest individual risk factor for developing active tb.12-14 hiv prevalence is also often higher than that among the general population, with estimates of 40 45% in sa prisons.15 , 16 only 40% of sa correctional centres report segregating inmates on medical grounds, although drug-resistant tb has been cited as the most common reason for such segregation.17 ventilation is frequently poor;6 , 11 our patient described small, slit-like windows high up on one exterior wall of his cell. there is a shortage of medical personnel in prisons and delays in accessing care are frequently an issue;6 , 8 , 11 , 17 our patient stated that, during his second period of detention, he had reported his cough and night sweats to prison officials for 3 weeks before he was taken to the prison health facility. the epidemiology of communicable diseases within and outside prisons is closely related; large numbers of prisoners and staff enter and leave prisons on a daily basis, acting as potential sources of transmission to the community at large. in sa in 2011/ 2012, over 80% of remand detainees17 and 40% of those who received sentences were imprisoned for less than one year.18 thus, in sa, as elsewhere, prisons act as reservoirs of tb, and inevitably drug-resistant tb, that poses a threat to public health control.12 , 14 despite this, control measures for tb, hiv and other communicable diseases are often neglected, relative to measures directed at non-prison populations.19 many of the same factors that enhance the spread of tb in prisons encourage the emergence of drug resistance and subsequent transmission of drug-resistant tb.10 , 19 moreover, the failure to ensure prompt recognition and appropriate treatment of drug-resistant cases results in a prolonged infective period, such that transmission risks may be even higher than those associated with drug-susceptible tb.11 there are additional factors that may particularly promote the development of drug-resistant tb in prisons, such as: erratic drug supply and inadequate treatment; access to uncontrolled anti-tb drugs from staff and visitors; and chaotic lifestyles, including transfers between and within prisons. these enhance the likelihood of treatment interruption or default.19 while there is a paucity of data on antiretroviral drug resistance in prison populations, hiv-positive prisoners receiving art in brazil have been found to have high rates of acquired hiv drug resistance;20 and release from prison followed by re-incarceration has been shown to be associated with impaired virological and immunological outcomes while receiving art.21 unplanned treatment interruptions are known to promote resistance;22-24 and chaotic lifestyles,18 , 19 fear of stigmatisation18 , 25 and poor health services in prisons6 , 25 are likely to increase the frequency of treatment interruptions. in sa, most prisons do not have dedicated hiv care programmes and those that exist are delivered by external service providers.17 our patient did not disclose his hiv-positive status or use of art during either spell in prison, primarily due to fear of stigmatisation. while the timing of the development of art drug resistance cannot be ascertained definitively in this case, it is plausible that the unscheduled interruption of treatment during the first period of incarceration could have led to the initial emergence of resistance. certainly the interruption of art, the emergence of art drug resistance and the resultant drop in cd4+ cell count would have substantially increased the risk of developing tb disease.26 we cannot definitively reject the possibility that art resistance emerged prior to incarceration or that super-infection with a drug-resistant hiv strain occurred during incarceration. the interdependence of numerous transmission risk factors necessitates a multifaceted approach to tb control in prisons, involving improvement in case finding, reductions in overcrowding and improvements in environmental conditions such as ventilation and airflow.6 , 10-12 , 14 robust evidence for action already exists: a modelling analysis based on conditions for inmates awaiting trial in pollsmoor prison, cape town, suggested a potential reduction in tb transmission rates of 50% if active case finding and national minimum standards of cell occupancy were implemented; and a reduction of 94% if international environmental standards were adopted.11 screening and case detection in prisons worldwide has, until recently, been limited by suboptimal diagnostic tools and a lack of adequate laboratory facilities. 27 there is some evidence to suggest that screening prisoners using xpert mtb/rif could be a cost-effective means to reduce transmission of drug-resistant tb in settings with a high burden of drug resistance.28 the recent announcement that correctional facilities in sa will now be prioritised for deployment of xpert mtb/rif offers strong encouragement.29 however, research is needed to inform policies on the optimal use of xpert mtb/rif within prison health services, and any strategy must be linked to appropriate treatment programmes and proper segregation processes. furthermore, this case highlights that reducing the individual risk of tb disease should be as important, and optimising individual management of hiv disease, with the aim of virological suppression and prevention of antiretroviral resistance, should be a critical component of broader prison hiv/tb control strategies. no single intervention will adequately address the complex issues relating to tb and hiv in prisons. ultimately, there needs to be the political will and funding to deliver sustained improvements to prison conditions and health services. collaboration between the department of correctional services and the department of health is necessary to facilitate better integration of prison health services within the public health system. the high costs of managing drug-resistant tb and hiv disease should be a powerful incentive to implement measures to reduce the emergence and spread of drug-resistant tb and hiv.30-32 at a time when considerable progress is being made in the public health sector in sa,3 the failure to address tb and hiv in prisons has the potential to seriously undermine the control of these infectious diseases in the community. acknowledgement. this work was supported by the wellcome trust (grant 090999/z/09/z), european union (sante 2007 147–790), the united states centres for diseases control via the centre for the aids programme of research in south africa (caprisa) (project title: health systems strengthening and hiv treatment failure (hiv-tfc)) and the swiss south african joint research programme (ssjrp) research grant entitled ‘swiss prot/south africa: protein bioinformatics resource development for important health-related pathogens’. the funders had no role in data collection and analysis, decision to publish or preparation of the manuscript. author contributions. kes and rjl looked after the patient. kes wrote the first draft of the manuscript. all authors contributed to revision of the manuscript and approved the final version. references 1. abdool karim ss, churchyard gj, abdool karim q, lawn sd. hiv infection and tuberculosis in south africa: an urgent need to escalate the public health response. lancet 2009;374(9693):921-933. 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[http://dx.doi.org/10.1097/qad.0b013e32832d3b6d] 26. lawn sd, myer l, edwards d, bekker lg, wood r. short-term and long-term risk of tuberculosis associated with cd4 cell recovery during antiretroviral therapy in south africa. aids 2009;23(13):1717-1725. [http://dx.doi.org/10.1097/qad.0b013e32832d3b6d] 27. vinkeles melchers nvs, van elsland sl, lange jma, borgdorff mw, van den hombergh j. state of affairs of tuberculosis in prison facilities: a systematic review of screening practices and recommendations for best tb control. plos one 2013;8(1):e53644. [http://dx.doi.org/10.1371/journal.pone.0053644] 27. vinkeles melchers nvs, van elsland sl, lange jma, borgdorff mw, van den hombergh j. state of affairs of tuberculosis in prison facilities: a systematic review of screening practices and recommendations for best tb control. plos one 2013;8(1):e53644. [http://dx.doi.org/10.1371/journal.pone.0053644] 28. winetsky de, negoescu dm, demarchis eh, et al. screening and rapid molecular diagnosis of tuberculosis in prisons in russia and eastern europe: a cost-effectiveness analysis. plos med 2012;9(11):e1001348. [http://dx.doi.org/10.1371/journal.pmed.1001348] 28. winetsky de, negoescu dm, demarchis eh, et al. screening and rapid molecular diagnosis of tuberculosis in prisons in russia and eastern europe: a cost-effectiveness analysis. plos med 2012;9(11):e1001348. [http://dx.doi.org/10.1371/journal.pmed.1001348] 29. republic of south africa. address by deputy president of south africa kgalema motlanthe at the world tb day, pollsmoor management centre, cape town, 2013. http://www.thepresidency.gov.za/pebble.asp?relid=15108 (accessed 18 june 2013). 29. republic of south africa. address by deputy president of south africa kgalema motlanthe at the world tb day, pollsmoor management centre, cape town, 2013. http://www.thepresidency.gov.za/pebble.asp?relid=15108 (accessed 18 june 2013). 30. pooran a, pieterson e, davids m, theron g, dheda k. what is the cost of diagnosis and management of drug resistant tuberculosis in south africa? plos one 2013;8(1):e54587. [http://dx.doi.org/10.1371/journal.pone.0054587] 30. pooran a, pieterson e, davids m, theron g, dheda k. what is the cost of diagnosis and management of drug resistant tuberculosis in south africa? plos one 2013;8(1):e54587. [http://dx.doi.org/10.1371/journal.pone.0054587] 31. schnippel k, rosen s, shearer k, et al. costs of inpatient treatment for multi-drug-resistant tuberculosis in south africa. trop med int health 2013;18(1):109-116. [http://dx.doi.org/10.1111/tmi.12018]. 31. schnippel k, rosen s, shearer k, et al. costs of inpatient treatment for multi-drug-resistant tuberculosis in south africa. trop med int health 2013;18(1):109-116. [http://dx.doi.org/10.1111/tmi.12018]. 32. long l, fox m, sanne i, rosen s. the high cost of second-line antiretroviral therapy for hiv/aids in south africa. aids 2010;24(6):915-919. [http://dx.doi.org/10.1097/qad.0b013e3283360976] 32. long l, fox m, sanne i, rosen s. the high cost of second-line antiretroviral therapy for hiv/aids in south africa. aids 2010;24(6):915-919. [http://dx.doi.org/10.1097/qad.0b013e3283360976] abstract introduction methods ethical consideration results discussion conclusion acknowledgements references about the author(s) claire van deventer department of family medicine, university of the witwatersrand, south africa anne wright department of family medicine, university of the witwatersrand, south africa citation van deventer c, wright a. the psychosocial impact of caregiving on the family caregivers of chronically ill aids and/or hiv patients in home-based care: a qualitative study in zimbabwe. s afr j hiv med. 2017;18(1), a718. https://doi.org/10.4102/sajhivmed.v18i1.718 original research the psychosocial impact of caregiving on the family caregivers of chronically ill aids and/or hiv patients in home-based care: a qualitative study in zimbabwe claire van deventer, anne wright received: 10 jan. 2017; accepted: 20 july 2017; published: 05 dec. 2017 copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the family caregiver has a pivotal role to play in the management of the chronically ill hiv and/or aids patients. the wellbeing of caregivers is therefore crucial because impairment of their physical or mental health could impact negatively on the management of their hiv-positive family member. the purpose of this qualitative study was to explore the psychosocial impact of caregiving on the family caregiver of the chronically ill hiv and/or aids patients in home-based care. method: unstructured interviews were conducted with 11 caregivers recruited at an adult hiv clinic at united bulawayo hospitals, bulawayo, zimbabwe. relevant demographic information was collected from each participant. the interviews were then transcribed and analysed. results: caregivers’ biggest challenge was meeting care costs such as food, transport and medical costs. certain conditions relating to the care-recipient’s health and family issues, such as abandonment of the ill patient as well as that of orphans, added to the burden of care. carers also had to deal with their own health and physical problems. all the above resulted in a spectrum of emotions such as helplessness, sadness, anxiety and anger. despite this, caregivers also reported on the positive aspects regarding their caregiving role. conclusion: there were both negative and positive psychosocial experiences by caregivers of hiv and/or aids patients. the study highlighted practical areas where support could be provided. introduction the impact of caregiving on the wellbeing of carers has been studied in different communities across the world.1,2,3,4,5,6 the overall results revealed that these caregivers suffer from significant psychosocial problems. the problems encountered included depression, anxiety, loneliness, anger, fear, stigmatisation and economic difficulties. the extent of caregiving in these studies included assistance with activities of daily living (adl), management of the disease and medications, as well as emotional and financial support. in a botswana study,1 older women complained of exhaustion because they were often caring for multiple family members. their physical care for the ill patient as well as the general household chores like fetching firewood and water, cooking and cleaning resulted in neglect of their own health. the stigma of hiv extended to the carers and exacerbated the isolation they felt. a study which was performed exclusively with elderly caregivers in rural uganda6 showed similar results. additional factors in this group were their fear of contracting the illness through the caring process and a sense of futility. in rural namibia,7 diaries were kept by participants. these revealed, amongst others, that over time tensions arose between the caregiver and patient as well as in the household in general. this resulted in the carer becoming insensitive to and withdrawing from the patient. in contrast to these problem-saturated accounts, a qualitative study in malawi8 reported that nine out of 15 caregivers experienced no problems in their caregiver roles. many of these patients died within a few months, and this may explain why caregiver burnout did not occur. most carers in these african studies were women from rural, impoverished communities. however, in the united states and australia,9,10 where palliative care was more often given to gay men, it was found that male caregivers were more prevalent because of patient choice. zimbabwe, where the study was conducted, has been significantly affected by the aids pandemic. this country reported the 5th highest hiv prevalence in sub-saharan africa in 2015, at 15%.11 the adult prevalence has however almost halved from 29% in 1998.11 the number of adults receiving antiretroviral therapy (art) in 2014 was 89.7%.11 these indicators have all improved significantly in the last 10 years. there has been a strong commitment from government with various financial and political initiatives being implemented. these have, however, been countered by the general economic deterioration in the country. healthcare, as one of many sectors, has been affected by the financial situation, which led to the care of the chronically ill devolving largely to the family. in many other countries, home-based care is an integral part of the management of these patients. this is because of the additional human and economic burdens, protracted hospital admissions and the sheer numbers of very ill patients. no similar studies regarding carers of hiv and/or aids patients were found relating to zimbabwean citizens, which provided an opportunity for the researcher to contribute additional information. the study was carried out because encounters with caregivers in clinical practice often revealed feelings of despair. the researcher also observed impatience or anger between partners and also that elderly relatives were involved in many instances in fulfilling the role of carer. the aim of the research was to study the impact of caregiving on the psychosocial health of family caregivers of hiv and/or aids patients in home-based care, describing their demographic profile and their perspectives on the effects this role was having on them. methods design a qualitative study was performed because ‘human emotions are difficult to quantify; qualitative research seems to be more effective than quantitative research for investigating these emotional responses’.12 in particular, individual interviews were expected to contribute to this understanding regarding the topic and because of the site of the study, where many carers accompanied patients for their medial visits, this was considered to be a practically achievable method. study site the study was conducted at the opportunistic infection (oi) clinic at united bulawayo hospitals (ubh) in bulawayo, zimbabwe. the clinic was dedicated to managing hiv patients only. study population adult caregivers with any type of relationship to home-based chronically ill, adult hiv-positive patients who attended the oi clinic at ubh. sampling purposive sampling was performed, related to any accompanying caregivers at the clinic in the study period. inclusion criteria for participating in the study were the following: adults over 18 years, caregiving performed by these caregivers in the community, assistance with adl as opposed to simple visits, a period of caregiving for longer than two weeks, residing in bulawayo for accessibility and speaking english or shona fluently. child and adolescent carers were not included as they are in the minority and are faced with a different set of challenges. a total of 14 participants were recruited, but 11 were interviewed as three were not available when the interviews were conducted. the sample size was determined by saturation where the researcher found no new information emerging. measuring tools and data collection interviews took place at the caregiver’s home or the researcher’s office. informed consent was obtained with separate consent for the audiotaping. demographic information included age and gender of carer and patients, employment status, relationship of the carer with the patient, hiv status of the carer, duration of caregiving and the carer’s karnofsky score.13 this latter scale measures the incapacity of the patient, which influences the degree of caregiving required. after completion of the questionnaire, the participant was invited to share his or her experience of the caregiving process by the use of an unstructured one-on-one interview. the key introductory question was: ‘how are you finding the experience of taking care of your ill relative?’ additional questions were used only for the clarification of specific points as supported by qualitative research techniques.14,15,16 the interviewer employed the techniques of clarification, reflection and summarising in order to ascertain that the researcher had understood the participant’s full perspective and to encourage the flow of conversation between the interviewer and interviewee. the interview was recorded on audiotape, and some important points were captured in field notes in order to highlight issues such as non-verbal communication. the interviews were conducted exclusively by the researcher either in shona or english or a combination of both and lasted an average of an hour. each interview was then transcribed by the researcher on the same day to allow for better recall of the interview and other events surrounding it. bias the presence of the tape recorder may have intimidated some of the participants and could have affected the quality of the information shared. however, this did not seem to be a problem as none of the participants seemed to be paying any attention to the tape recorder. to pre-empt any preconceived ideas and opinions from the researcher, her own ideas regarding the research topic were explored by a qualitative research trainer before the research commenced. language limitations may have excluded the opinions of relevant caregivers. an attempt was made to contact the participants after the analysis of the data, to validate the findings. only five participants were able to do so as three had died and three were uncontactable. it is acknowledged that during the analysis of qualitative research data, the researcher’s bias may play a role in the selection of quotes and the presentation thereof. chenail makes it clear that ‘data from qualitative research are … rarely if ever conclusive. nevertheless the analysis process should be highly deliberate and systematic’.17 for this reason, triangulation was planned to confirm and validate the findings of the study. as indicated above, less than half the participants could be contacted for this step, which contributes to the possible bias. analysis taped interviews were transcribed as soon after they were conducted as possible. the key to qualitative data analysis is to familiarise or ‘immerse’ oneself in the information contained in the transcripts.18 as the transcripts of interviews were analysed, common themes emerged from the verbatim quotes of the interviewees and these were highlighted in different colours. these were then further analysed to create subthemes. the cut and paste method was subsequently used to move quotes to particular themes. limitations the obvious limitations are those of any qualitative study in that the findings are not easily transferable to another population because of the sample size and non-random sampling. analysis is also very dependent on the researcher’s skill and inherent subjective views19 as was mentioned earlier. triangulation of observer, theory and method14 would have strengthened the research, but this was not possible logistically. ethical consideration permission to conduct this study was obtained from the medical research council of zimbabwe, the ethics committee of the university of zimbabwe and the research and the ethics committee of the university of the witwatersrand. all participants received an information sheet emphasising that the study was entirely voluntary, confidentiality was protected and tapes and transcripts would be kept in safekeeping by the researcher. written consent was obtained from each participant. counsellors at the oi clinic were available for assistance in the event of emotional distress related to the interviews. results demographics the caregivers’ demographics are presented in table 1, with 10 of the 11 being women and seven of these over the age of 50. there were two spousal dyads. nine carers did not know their own hiv status. the remaining two were hiv-positive themselves. most of the carers interviewed had taken responsibility for one patient each, mostly direct relatives or spouses. the karnofsky score was more than 50 in only three patients, indicating a moderately heavy carer load for most of the caregivers as a karnofsky score of 50 indicates ‘moderately disabled; dependent. requires considerable assistance and frequent care’.13 lower scores indicate increasing disability and dependence. table 1: demographic data of participants. themes the seven main themes identified were the following: financial issues, caregivers’ physical/health problems, patients’ physical/health problems, religious aspects, family issues, emotional impact and an appraisal of the caregiver role. given the financial challenges facing zimbabwe, it was not surprising that financial difficulties were raised by all but one of the respondents. these were because of several factors most of which were expressed by the majority of participants: i do not have food or soap for washing her soiled linen. [p4, female, 59] and: isn’t it when the linen gets washed every day, it becomes old very quickly? [p4, female, 59] sometimes she can choose food, whatever, and maybe at that i would have bought food that is adequate for the family but then she can say she doesn’t want it, she wants something else when i don’t even have a cent. [p9, female, 40] so when the day we have to take her to the hospital comes and she is not able to walk…the money for the fuel is what’s hard to find, they charge a lot. [p8, female, 58] so it is a problem not to have an income when you are caring for someone who is ill because how do you help them and yourself? [p3, female, 56] additional burdens were where four of the caregivers were looking after the ill person’s children or orphans, some of whom were also ill. medical needs were also mentioned by three carers as part of the financial problem: yes the drugs are so expensive and sometimes i can’t afford some of the drugs the doctor says we should buy. [p9, female, 40] other financial issues that were mentioned related to the high inflation, lack of employment and the fact that household goods were being sold to make ends meet. caregivers’ health/physical issues most of the carers were older women with their own health problems and physical limitations. one carer acknowledged the limitations of her age: …when one is as ill as she is, it is difficult to lift her, i am old, am very old. [p1, female, 69] and another her physical exhaustion: …even during the day i always find that i’m always asleep, i sleep, myself always i sleep. i sit down, i’m asleep, at night i sleep. [p4, female, 59] there were also psychosomatic symptoms mentioned: i had sharp pains, i felt sharp pains when i was forcing her to eat, i just felt a stabbing pain, ah, and then my arm could no longer work. now how can you help someone else who is helpless when you have also become helpless? [p9, female, 40] a fear of contracting hiv was expressed: gloves are not available….what do you do? you just wash with your bare hands and end up catching hiv as well and also become ill. [p10, female, 64] the above quotes indicate to some extent the sacrificial role of the carers who have taken on burdens beyond their own, for whatever reasons. care-recipients’ physical/health-related issues untrained carers were faced with extreme situations where they simply felt they had to cope. situations included the following: …she couldn’t even go to the toilet by herself and i could take her to the toilet, sometimes if i came too late i’d find her messy. [p11, female, 50] and: i used to sleep with her at that time. i would wake up covered with her skin until i said it was better to separate… [p3, female, 56] the poor appetite often associated with aids seemed to cause a lot of distress probably because of the belief that the antiretrovirals prescribed would not work if the person was not eating well or vomiting: that is the problem that worries me a lot because if she spends the day without eating…, i can’t …, the pills, the tablets cannot work. [p3, female, 56] there were two participants who were caring for patients with mental confusion. although carers of people with mental impairment face additional challenges, one of these was coping but the other was clearly frustrated: what he wants to do, some of the things, ah, you can’t get it since he is ill; you don’t know what he wants or doesn’t want. sometimes you can do something good for him but he can say he doesn’t want it any more, he doesn’t want. [p10, female, 64] additional subthemes were concern for weight loss, deterioration of the patient’s condition and poor mobility, all of which added to the carer’s physical and mental burden. religious aspects all but one participant mentioned god during the interviews. some of the comments seemed to be casual, the ones which many people often make without it necessarily being a true reflection of their religious standing. however, with four participants mentioning god three or more times and one of them mentioning him seven times, it can be concluded that religion played an important role in the lives of these caregivers. the supportive role of god in this suffering was expressed: only god is helping me and i am truly grateful to him. i would have long died from bp because of thinking too much. [p1, female, 69] god is good to me because somehow i find myself with the transport. [p7, female, 58] i will be asking god for her to survive. [p2, female, 44] this was offset by two other carers who had a more fatalistic approach: …nothing can help me to make her well again unless god makes her well. me there is nothing i can do. [p3, female, 56] ah yes, if god decides to take him, he can take him. what can i do? [p6, female, 34] there was also some questioning of god: i am not lying to you but when i think of all this nearly every day i start to cry, asking god or is it satan why my daughter is going through all this when some people don’t do so. [p4, female, 59 years] together with this, one caregiver took her responsibility so seriously that a strong element of guilt is apparent: she is helpless there and you cannot help her as well so what you can do is to cry and ask god for help saying ‘god please help me, what did i do wrong?’ [p8, female, 58] family issues these were matters, which mostly exacerbated the burden of caregiving: i also have orphans. i have many orphans and the one left by his mother in 2004 is always ill. [p1, female, 69] there was a mother struggling with the taboo of washing her adult son because his own wife had abandoned him: it is difficult indeed because when he first fell ill it was too much for me to touch his body since he is an adult. [p7, female, 58] there was a mother caring for her daughter who was very upset with her other children for not supporting her financially because the daughter she was looking after had been her breadwinner: actually it is better to say i don’t have any other children to be honest because you can only consider a child who assists you in certain areas. [p4, female, 59] in contrast to this another caregiver said: but anyway, my relatives, my brothers and sisters they help me a lot. whenever i tell them that i have this problem they come forward and help me. [p9, female, 40] very few people raised the issue of disclosure within the family. one person said: the problem was telling our children what the pills were for. [p2, female, 44] emotional impact caregivers freely discussed the emotions they experienced regarding the challenges of the caregiving process. however, they were more reticent about those emotions experienced when witnessing the suffering of their relatives. this may be because of a particular type of resilience or an expectation of family support being non-negotiable within a culture of ubuntu. general worry, helplessness and despair were common: sometimes i despair so much that tears just flow on their own because i would be feeling so troubled. [p3, female, 56] and: not having things, you don’t have… then you worry about you can do about it, that’s troubling that’s troubling, that’s troubling. where can i go to now? [p10, female, 64 years] one of the mothers illustrated the extreme of her despair as follows: those who didn’t give birth are better. they don’t see all the things we are seeing. [p10, female, 64 years] at the other end of the spectrum of life and death was the hopeless comment: one day you can end up taking a rope and hanging yourself. [p9, female, 40] the pain of seeing loved ones suffering was expressed: it pains my heart very much because this is my only son. [p7, female, 58] firstly it is not easy, really, to see your daughter’s condition deteriorating day after day. so you develop a stress. also because you find yourself at times crying. [p11, female, 50] many tears were shed in the interviews themselves. there was occasionally an element of hope expressed: ah i see people who have been very ill surviving. so i have hope that she will survive, maybe as she takes the arvs she will survive. [p2, female, 44] appraisal of the caregiver role five caregivers talked about their perspectives on how they viewed their caregiving role. there was a sense of responsibility and obligation, which reflects the resilience and ubuntu mentioned above: there is nothing i can do because she is my child… [p3, female, 56] together with this, positive aspects that were vocalised were gratification linked to love for the recipient, a lack of blame and an experience of coping with this role: but it’s only that it’s difficult but i don’t blame anyone, i don’t blame her. [p8, female, 58] i am coping but it is difficult but i am coping, yes. [p11, female, 50] …but when it comes to looking after my wife it is hard but i am coping because of all the counselling i have had as you can see. [p5, male, 36] discussion the aim of this research was to try and understand the psychosocial impact on carers of hiv and/or aids patients through a qualitative process. both practical and psychological challenges were elicited as were some positive experiences. the themes analysed in the study reflect many similarities with other countries in the world. the day-to-day struggle for survival amidst poverty and the additional burdens of caregiving with little, if no additional, resources formed the background of most of the stories of caregivers. the prevailing economic hardships of high inflation and lack of employment in zimbabwe, which were often cited by participants, were a source of great distress for caregivers because of the financial implications for them. all the studies that were reviewed from africa also revealed that poverty had a major impact on the psychosocial wellbeing of carers.1,6,7,8,20,21,22 one mother in this study resorted to selling her household goods to raise money to provide for her ill daughter who previously was the sole breadwinner. this practice was reported in other aids caregiver studies.6,20 there was a high unemployment rate generally and many caregivers were retired and elderly.21 much of the poverty was compounded by the costs of chronic care including special foods, transport to hospital, washing detergents, etc. as reported in other studies as well,8,21 the lack of these distressed caregivers immensely as they felt this compromised the health of the ill. the health of both carers and patients influenced the psychosocial wellbeing of the carers. many of the older caregivers had hypertension, diabetes and arthritis, which they felt were being negatively affected by the increased physical role they were expected to play. for example, the limited financial resources did not allow one mother with diabetes to adhere to her diet. eighty-two per cent of latina family aids carers in the united states also reported chronic conditions such as asthma, hypertension and diabetes.23 tiredness and psychosomatic complaints from the caregivers were common in this and other studies.1,6,19 these included headache, abdominal pain, chest pain and anorexia. concerns regarding the contracting of hiv were raised in a number of studies.1,7,22 in botswana,1 it was found that elderly caregivers did not use the care package they were provided with because they felt that using gloves would imply that they do not love the person in their care. in contrast, caregivers in a namibian study7 expressed anger at the risk they were exposed to. the lack of gloves was also related to specific conditions of patients (e.g. incontinence). frustration was expressed regarding patient complaints specifically regarding poor appetite7,8 and mental illness,9 in common with other studies. poor mobility and deterioration of the physical condition was distressing to carers. the lack of improvement or worsening of the condition led, in many cases, to feelings of despair in the carers, and these emotions were part of anticipatory grief as found in a us study.9 religious issues similar to those of the study were found in other papers. fifty-seven per cent of aids caregivers in one study1 found religion to be a comfort and felt that their faith in god had increased as a result of the illness, while 17% no longer went to church or worshipped at home because of caregiving commitments. female caregivers in india went through the different stages of questioning god, anger towards him and finally hope and belief in his compassion. these are similar to emotions found in the study. family issues are common themes especially the care of orphans,1,6,24,25 but also abandonment6 and issues of taboos and disclosure.26 these are often linked to emotional aspects as well. some patients cried in the interviews while others admitted to crying often because of the difficulties they were encountering to make ends meet. it is not possible from the nature of the study to determine if some of the participants had overt depression, but it is possible considering the stressors they were experiencing, as well as the feelings of emotional pain that they expressed. on the contrary, when asked directly about how they felt about the prognosis of the ill person in their care, most of the participants said that they had hope that the arvs would help them make a full recovery because they had seen it happen to other people. other emotions like anger were found in a number of studies. a comparison between carers of hiv and/or aids and dementia patients2 found that the former were significantly more anxious and angrier than the latter. where one of the patients from the study was angry and unappreciative, this distressed her mother greatly. care dyad conflict has been reported in several studies and causes tensions arising from the mood changes of both partners.6,7,21 despite the challenges that were described by the caregivers some of them still reported that they were coping with the caregiving role. counselling has helped some of them. chimwanza and watkins8 postulated that the underplaying of the difficulties of caregiving could be what they termed ‘courtesy bias’ meaning that the participants may have felt that an admission of being troubled by their role as caregivers might be understood as not having enough love for the person they were caring for. this may explain why some of the participants in the study were quick to say they were coping. some carers indicated a sense of gratification and fulfilment in their roles, which was also found in other studies.1,2,8 there is a pervasive underlying theme of duty and the social expectation that relatives will be taken care of under all circumstances by somebody close to them. this ties up with the ubuntu culture of africa where the interdependence of all people is a priority. people’s being is thus determined by this concept of totality by means of which all internal and external dimensions of their existence (spirituality, religion, economy, judicial systems, politics, kinship, language, education, play, art, science, et cetera) are fused into purpose relationships.27 this may well be a subconscious driving force in carers who are barely coping with their circumstances. although much of the information elicited in the study is not new, it confirms that in zimbabwe, similar issues confront caregivers as those experienced in the rest of the world. the study also focuses on relevant recommendations that could assist the government with practical interventions such as those set out in the following section. the main thrust of the study is to shift the current focus from patients to include caregivers in a meaningful way. the following recommendations are made: campaigns by government in conjunction with non-governmental organisations to train and equip health workers to identify caregivers at risk. hiv support groups to set up parallel support groups for caregivers. religious groups to identify caregivers in their communities and offer home visits for prayers and other support. social services that provide grants to families with the chronically ill and orphans in their care to be re-established. re-establish effective home-based programmes that support family caregivers. these programmes could utilise humanitarian aid that is being offered to the country to provide services as well as care packages and food parcels. conclusion the study set out to find out the psychosocial impact of caregiving on family caregivers of chronically ill hiv and/or aids patients in bulawayo, zimbabwe. there were factors relating to the family, the health and physical aspects of the carers and the care-recipients that compounded the overriding financial burden. the participants experienced a spectrum of emotions from worry, helplessness and hopelessness, despair and sadness to feeling overwhelmed, but some had hope of the recovery of the ill person in their care. although the sample size was small, the researcher was able to gain a good insight into the experience of these caregivers because of the qualitative nature of the study. although some of the interviewees seemed to be at the end of their tether, it is a testament to the resilience of humans that all of them were coping with their burdensome role, with very little social support. the study was carried out in the hope that the findings would contribute towards more concrete support. acknowledgements the authors would like to thank dr natsayi matimba, mfammed (wits), who was involved as the researcher. competing interests the authors declare that they have no financial or personal relationship(s) which may have inappropriately influenced them in writing this article. authors’ contributions c.v.d. contributed the bulk of the written article. a.w. was the supervisor of the original research and edited the article. references lindsey e, hirschfeld m, tlou s, ncube e. home-based care in botswana: experiences of older women and young girls. health care women int. 2003;24:486–501. https://doi.org/10.1080/07399330390199384 flaskerud jh, tabora b. health problems of low-income female caregiver of adults with hiv/aids. health care women int. 1998;19:23–26. orner p. psychosocial impacts on caregivers of people living with aids. aids care. 2006;18(3):236–240. valjee l, van dyk ac. 2014, impact of caring for people living with hiv on the psychosocial well-being of palliative caregivers. curationis 37(1), art. #1201, 13 pages. kohli r, purohit v, karve l, et al. caring for caregivers of people living with hiv in the family: a response to the hiv pandemic from two urban slum communities in pune, india. plos one 2012;7(9):e44989. https://doi.org/10.1371/journal.pone.0044989 ssengonzi r. the plight of older persons as caregivers to people infected/affected by hiv/aids: evidence from uganda. j cross cult gerontol 2007;22:339–353. thomas f. stigma, fatigue and social breakdown: exploring the impacts of hiv/aids in patient and carer well-being in the caprivi region, namibia. soc sci med. 2006;63:3174–3187. https://doi.org/10.1016/j.socscimed.2006.08.016 chimwanza af, watkins sc. giving care to people with symptoms of aids in rural sub-saharan africa. aids care. 2004;16(7):795–807. munro i, edward k. the lived experience of gay men caring for others with hiv/aids: resilient coping skills. int j nurs pract. 2008;14:122–128. turner ha, catania ja, gagnon j. the prevalence of informal caregiving to persons with aids in the united states: caregiver characteristics and their implications. soc sci med. 1994;38(11):1543–1552. https://doi.org/10.1016/0277-9536(94)90116-3 zimbabwe ministry of health. garpr zimbabwe country progress report 2016. unaids, geneva, switzerland, 2016. burns n, grove sdk. evolution of research in building evidence-based nursing practice in: burns n, grove sdk, editors. the practice of nursing research; conduct, critique and utilisation. 4th ed. philadelphia: wb saunders company; 2001; p 26–27. crooks v, waller s, smith t, hahn tj. the use of the karnofsky performance scale in determining outcomes and risk in geriatric outpatients. j gerontol. 1991;46:m139–m144. de vos as, strydom h, fouche cb, delport csl. research at grassroots: for the social sciences and human service professions. 3rd ed. van schaik publishers; pretoria, 2016. taylor s j, bogdan r, devault m. introduction to qualitative research methods: a guidebook and resource. 4th ed. wiley, hoboken, nj; 2016. sofaer s. qualitative research methods. int j qual health care 2002;14(4): 329–336. chenail rj. interviewing the investigator: strategies for addressing instrumentation and researcher bias concerns in qualitative research. qual rep. 2011;16(1): 255–262. terre blanche m, durrheim k, kelly k. first steps in qualitative data analysis. in: terre blanche m, durrheim k, painter d, editors. research in practice: applied methods for social sciences. 2nd ed. south africa: university of cape town press, cape town 2006; p. 233–326. katzenellenbogen jm, joubert g, abdool karim ss. qualitative methodology: an introduction. in: joubert g, ehrlich r, editors. epidemiology: a manual for south africa. southern africa: oxford university press, cape town, 1997; p. 176–181. kipp w, matakula nt, laing l, jhangri gs. care burden and self-reported health status of informal women caregivers of hiv/aids patients in kinshasa, democratic republic of congo. aids care 2006;18(7):694–697. https://doi.org/10.1080/13548500500294401 katapa rs caretakers of aids patients in rural tanzania. int j stds aids. 2004;15:673–678. kang’ethe sm. challenges impacting on the quality of care to persons living with hiv/aids and other terminal illnesses with reference to kanye community home-based care programme. sahara j. 2009;6(1):24–32. https://doi.org/10.1080/17290376.2009.9724926 land h, hudson sm, stiefel b. stress and depression among hiv-positive and hiv-negative gay and bisexual aids caregivers. aids behav. 2003;7(1):41–43. caldwell jc. the impact of the african aids epidemic. health trans rev. 1997;7(supp2):169–188. leake m. hiv and aids care in the home. 2009 [homepage on the internet; cited 2017 oct.]. available from: http://www.avert.org/aids-home-care.htm mwinituo p. mill je. stigma associated with ghanaian caregivers of aids patients. west j nurs res 2006;28:369–382. https://doi.org/10.1177/0193945906286602 myburgh ac. anthropology for southern africa. pretoria: van schaik; 1981. abstract introduction methods results discussion acknowledgements references appendix 1 appendix 2 about the author(s) samantha kaplan   department of internal medicine, university of washington, seattle, united states katleho s. nteso  medical care development international, maseru, lesotho, south africa school of public health and family medicine, university of cape town, cape town, south africa nathan ford centre for infectious disease epidemiology and research, school of public health and family medicine, university of cape town, cape town, south africa andrew boulle centre for infectious disease epidemiology and research, school of public health and family medicine, university of cape town, cape town, south africa graeme meintjes institute of infectious disease and molecular medicine, faculty of health sciences, university of cape town, cape town, south africa citation kaplan s, nteso ks, ford n, boulle a, meintjes g. loss to follow-up from antiretroviral therapy clinics: a systematic review and meta-analysis of published studies in south africa from 2011 to 2015. s afr j hiv med. 2019;20(1), a984. https://doi.org/10.4102/sajhivmed.v20i1.984 note: additional supporting information may be found in the online version of this article as online appendix 1: https://doi.org/10.4102/sajhivmed.v20i1.984-1 and online appendix 2: https://doi.org/10.4102/sajhivmed.v20i1.984-2 review article loss to follow-up from antiretroviral therapy clinics: a systematic review and meta-analysis of published studies in south africa from 2011 to 2015 samantha kaplan, katleho s. nteso, nathan ford, andrew boulle, graeme meintjes received: 22 may 2019; accepted: 20 aug. 2019; published: 18 dec. 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: south africa has the largest antiretroviral therapy (art) programme in the world. to optimise programme outcomes, it is critical that patients are retained in care and that retention is accurately measured. objectives: to identify all studies published in south africa from 2011 to 2015 that used loss to follow-up (ltfu) as an indicator or outcome to describe the variation in definitions and to estimate the proportion of patients lost to care across studies. method: all studies published between 01 january 2011 and october 2015 that included loss to follow-up or default from art care in a south african cohort were included by use of a broad search strategy across multiple databases. to be included, the cohort had to include any patient art data, including follow-up time, from 01 january 2010. two authors, working independently, extracted data and assessed risk of bias from all manuscripts. meta-analysis was performed for studies stratified by the same loss to follow-up definition. results: forty-eight adult, 15 paediatric and 4 pregnant cohorts were included. median cohort size was 3737; follow-up time ranged from 9 weeks to 5 years. meta-analysis did not reveal an important difference in ltfu estimates in adult cohorts at 1 year between loss to follow-up defined as 3 months (11.0%, n = 4; 95% ci 10.7% – 11.2%) compared with 6 months (12.0%, n = 4; 95% ci 11.8% – 12.2%). only two cohorts reported reliable ltfu estimates at 5 years: this was 25.1% (95% ci 24.8% – 25.4%). conclusion: south africa should standardise a ltfu definition. this would aid in monitoring and evaluation of art programmes, with the broader goal of improving patient outcomes. keywords: hiv; antiretroviral therapy (art); loss to follow-up; disengagement; south africa. introduction as of 2016, over 7 million people in south africa were living with human immunodeficiency virus (hiv), of which 56% were receiving antiretroviral therapy (art). this represents the largest art programme in the world1: south africa’s art population accounts for 20% of people on art globally, and the country instituted updated national guidelines in 2016 to offer art to all patients with hiv. because of this rapid upscaling and increasing number of patients eligible for and starting lifelong art, a focus on retention in art care has become even more important. according to a review in south africa from 2008 to 2013, only ± 67% of patients who initiated art remained in care after 4 years, and 40% of those who were lost were attributed to known deaths.2 since the first availability of hiv treatment, studies have reported findings on retention after art initiation, usually as an indicator of programme effectiveness. there has not been a definitive temporal trend: some studies have concluded that loss to follow-up (ltfu) proportions are decreasing over time, but others concluded that rates have increased as the epidemic has grown, coinciding with the increase in numbers of patients enrolled at health centres that serve art patients.3,4,5,6 more recent studies have supported the notion that with increasing cd4 thresholds for art initiation and the adoption of ‘test and treat’, ltfu rates are increasing.7,8,9 however, a large part of the variation in reported outcomes is because of the lack of standardisation of definitions of ltfu and retention, as well as the bias in reporting interruptions in care.10,11,12 if patient retention is to be used as a key indicator of art programme effectiveness, there should be a standardised definition of ltfu so that art programmes can be more accurately compared within and between countries. the aims of this systematic review were to identify all studies published in south africa from 2011 to 2015 that used ltfu as an indicator or outcome, to describe the variation and diversity of definitions as justification for establishing a single standardised definition going forward, to summarise the findings using meta-analysis and to provide suggestions for ways to use ltfu as an indicator in a standardised fashion. reporting standards have evolved since art began to be provided in the south african public sector in 2004, as have treatment guidelines. this review focuses on the 5 years between 2011 and 2015, when there were more stringent requirements to start art; those who started had lower cd4 counts. since 2015, universal test and treat has been adopted in south africa and even more patients have been enrolled in art. based on the findings of this review, we provide suggestions for ways to use ‘ltfu’ as an indicator in a standardised fashion with an increasing population of patients on art. methods this systematic review was designed, conducted and reported in accordance with the preferred reporting items for systematic reviews (prisma) statement.13 the protocol was registered on prospero international prospective register of systematic reviews as #crd42015026466 (http://www.crd.york.ac.uk/prospero). eligibility criteria all studies found in the search engines and published between 01 january 2011 and october 2015 that included loss to follow-up or default from art care as an indicator or outcome in a south african art cohort were included, even if that cohort was part of an interventional trial. if the cohort was composed of a mix of pre-art and art patients, we only reported outcomes for art patients; cohorts that were not disaggregated were excluded. to be included, the cohort analysed had to (1) be published between january 2011 and october 2015 and (2) report any patient art data, including follow-up, from 01 january 2010; however, initial data could have been collected before this time point. these criteria were enacted so as not to include older data in the analysis if a manuscript was not published until much later. both adult and paediatric studies were included. if the article was multinational, it was included only if the data were disaggregated and reported south african data separately. systematic review articles were excluded, but their citation lists were reviewed for further eligible articles. modelling studies were excluded. interventional studies were included if they reported loss to follow-up, and risk of bias was assessed on the observational component of these studies. search strategy and information sources by use of a broad search strategy (appendix 1), one investigator (s.k.) worked independently to search medline via pubmed, embase via scopus, web of science, cinahl and africa-wide databases from 01 january 2011 to date of search. pubmed was searched on 05 october 2015, scopus and africa-wide on 07 october 2015, web of science on 14 october 2015 and cinahl on 15 october 2015. information specialists at the university of cape town medical library assisted with the literature search process. after obtaining lists of abstracts meeting the search criteria from each database, two investigators (s.k. and k.s.n.) reviewed the abstracts independently in duplicate and met to achieve consensus on final inclusions of full-text review. s.k. and k.s.n. supplemented database searches by screening bibliographies of all full-text articles screened for the review. figure 1 details the article selection process. figure 1: flowchart of article selection for inclusion in the study. data extraction data were extracted independently in duplicate (s.k., k.s.n.) using a standardised extraction form. data collection forms were crosschecked by both reviewers, and the reviewers discussed discrepancies, with differences resolved by a third investigator (g.m.). data were extracted on study design, dates, description and context of intervention, if applicable, participant characteristics (age, baseline cd4 count), programme characteristics (cohort size, number of clinics, eligibility criteria), length of follow-up, definition of outcomes, outcomes, missing data and study limitations. primary outcomes were ltfu and mortality. if a study reported these outcomes by sub-cohort instead of aggregate, then outcomes by sub-cohort were recorded. ltfu outcomes at 1 and 5 years were collected, when available, for meta-analysis. if raw numbers were not readily available from the text, the reviewers calculated it from the available text or figures and agreed on the numerator and denominator. if a study included both pre-art and art patients, the statistics were only calculated for art patients; pre-art patients were excluded. if the study did not provide a definition for ltfu or default, or had another issue needing clarification, s.k. contacted the corresponding author by email. assessment of study quality study quality and risk of bias were assessed by evaluating the selection of the cohort, ascertainment of outcomes, length of follow-up and the presence of missing data using a modified set of criteria based on the newcastle-ottawa domains14 (appendix 2). meta-analysis for a study to be included in the meta-analysis, it had to have raw data available for a total number of patients ltfu at 12 months and/or 5 years of art. some of these studies had overlapping data in that the data were collected from the same clinic population with some overlapping time periods. if it was not clear if the data were overlapping, the reviewers emailed the manuscript authors for verification. if the data did overlap, the reviewers selected the most recent cohort with the largest amount of data available. point estimates and 95% confidence intervals were calculated for the proportion of people ltfu and data were pooled following transformation using random-effects meta-analysis. differences in the definitions of ltfu (3 months vs. 6 months) and between patient groups (adults vs. children vs. pregnancy) were assessed through pre-planned subgroup analyses. point estimates and 95% confidence intervals were displayed visually on a forest plot to visually assess heterogeneity. all data were analysed with stata version 14.0. ethical considerations this article followed all ethical standards for research without direct contact with human or animal subjects. results during the primary database search, 2611 abstract citations were identified and 2324 were excluded. after removing duplicates, 163 full-text articles were screened for inclusion and six additional articles were included from a bibliography screen of these articles; 67 articles were included in the final review (figure 1). of the 67 eligible studies, 48 were adult cohorts, 15 were paediatric cohorts and four were focussed on pregnant women; 57 studies included study or follow-up time prior to 2010. mean cohort size was 10,711; median was 3737. only six studies were interventional; the rest were observational. seven studies (10%) utilised research data; the remainder of the studies utilised routinely collected data from art clinics. follow-up time ranged from 9 weeks to 5 years, with a large variation in how this was calculated. forty-six cohorts were solely in primary care clinics, while four were solely in clinics located in hospitals and 15 were in both primary care and hospital clinics. forty-five cohorts (67%) were in urban settings, 7 (10%) were in rural settings and 13 (19%) were in both urban and rural settings; 2 (3%) studies were missing this information. twenty-seven cohorts (40%) were in the gauteng province, 11 (16%) in the western cape, 7 in kwazulu-natal (10%), 1 (1%) in the free state, 1 (1%) in limpopo and 2 (3%) did not include the information; 18 studies (27%) included data from multiple provinces, which included gauteng, western cape, kwazulu-natal, mpumalanga, eastern cape, limpopo, free state and north west provinces. for the 33 adult cohorts that reported age in aggregate, the median age was 35.8 years, and for the 32 adult cohorts reporting cd4 count, the median baseline cd4 was 121 cells/µl. among the paediatric cohorts, the median age was 4.2 years at art initiation, and the median aggregate cd4 percentage was 12.5%. in the four pregnancy cohorts, the median age was 28 years (n = 3 cohorts reporting), and the median cd4 estimate was 239 cells/µl. in terms of definitions, 24 adult cohorts defined ltfu as 3 months without a clinic visit, 18 adult cohorts defined ltfu as 6 months without a clinic visit and 6 adult cohorts had other definitions, such as a different length of time without a clinic visit or no definition of ltfu included in the manuscript text. of the paediatric cohorts, 2 cohorts defined ltfu as 3 months without a clinic visit, 6 cohorts defined as 6 months without a clinic visit and 7 cohorts had other definitions. among the pregnancy cohorts, one defined ltfu as 3 months without a clinic visit and the other three had other definitions (online appendix 1 and 215,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81). of the 96 cohorts reporting mortality, encompassed within the 67 studies, the median mortality estimate was 7.9% (interquartile range [iqr] 4.1% – 11.4%; range 0% – 26%); range of time for reporting was 3 months to 5 years. there was significant variability in how these estimates were calculated; some were raw data reported at a certain endpoint; some were estimated using statistical methods; and some studies utilised linkage of patients to the national death registry. of those 17 estimates in the lowest quartile (< 4% mortality), all had n < 5000; nine (53%) had n < 1000. ten of these cohorts (41%) estimated mortality at < 2 years of follow-up, 6 (35%) did not standardise mortality estimates and the remaining 4 (24%) were paediatric studies with longer follow-up. of the 16 estimates in the highest quartile (> 11.4% mortality), 10 cohorts (63%) had n > 2000, 5 cohorts (31%) had n < 1000, of which 3 were paediatric studies. only five studies (29%) standardised a timeframe for mortality estimates, ranging from 1 to 4 years. two (12.5%) were interventional studies. of the total 19 cohorts reporting mortality at 1 year, the median mortality was 9.6% (range 3.8% – 17.4%). only three cohorts reported mortality at 5 years with a median of 9.0% (range 8.6% – 10.6%) (online appendix 2). of the 101 cohorts reporting ltfu, encompassed within the 67 studies, the median ltfu estimate was 12.8% (iqr 7.9% – 22.0%; range 0.2% – 43.1%); range of time for reporting was 3 months to 5 years. of those 14 estimates in the lowest quartile (< 7.9% ltfu), four cohorts (28.6%) had n < 2000; five (36.0%) had n < 5000. eight (57%) were paediatric studies, and 1 (7%) was an adult interventional study. half did not standardise their ltfu estimate; the other half estimated at 3 years or under. of the 20 estimates in the highest quartile (> 22% ltfu), 12 studies (60%) had n < 1000, and 4 (20%) had n < 100; 2 (10%) studies were paediatric cohorts, 4 (20%) studies were pregnancy cohorts and 1 (5%) study was an interventional pregnancy cohort. the timeline for estimating ltfu ranged from 6 months to 3 years, with 12 cohorts (60%) not reporting a standardised timeframe (online appendix 2). the vast majority of studies had reliable data collection (99%), an independent assessment of outcome (99%), and reported mortality (96%); 75% of cohorts were deemed definitely representative of the population, with only 9% definitely not or unclear. in terms of follow-up, seven studies (10%) had follow-up of greater than 3 years; the majority of studies had follow-up lengths between 1 and 3 years (n = 49; 73%); seven studies (10%) had follow-up shorter than 1 year, and four studies (6.0%) had follow-up of unclear length; 54% of studies had complete data, while 30% of studies were missing < 10% of data related to our primary outcomes, 10% of studies were missing > 10% of data related to our primary outcomes and 6% of studies did not state anything about the missing data in the manuscript. meta-analysis aggregate ltfu estimates at 1 year were 11.6 (95% ci 11.4% – 11.7%) for eight representative adult cohorts, 33.0% for three pregnancy cohorts (95% ci 28.7% – 37.4%) and 7.5% (95% ci 6.7% – 8.2%) for two paediatric cohorts (figure 2). the same analysis was performed after taking definitions of ltfu into account: ltfu estimates at 1 year for adult cohorts did not substantially differ between the 3-month definition (11.0%, n = 4; 95% ci 10.7% – 11.2%)15,16,17,18 and 6-month definition (12.0%, n = 4; 95% ci 11.8% – 12.2%) (figure 3).19,20,21,22,81 there were only two cohorts that reported reliable ltfu estimates at 5 years; in aggregate, this was 25.1% (95% ci 24.8% – 25.4%).22,81 statistical heterogeneity of ltfu was quite large as anticipated, as estimated by visual inspection of the forest plots. table 1 summarises the characteristics and key figures from each study included in the meta-analysis.15,16,17,18,19,20,21,22,34,66,70,77,79,81 figure 2: meta-analysis of proportion of patients loss to follow-up at 1 year, by study population. figure 3: meta-analysis of proportion of patients loss to follow-up at 1 year, by loss to follow-up definition (3 months vs. 6 months). table 1: characteristics of studies included in the meta analysis. discussion among the 67 studies reporting ltfu from art care in south africa that met our inclusion criteria, ltfu definitions and estimation methodologies were not standardised. our meta-analysis did not indicate any important difference in loss to follow-up estimates for those studies when using 3-month versus 6-month definitions. the median non-standardised ltfu estimate for all studies (12.8%) was similar to the aggregate ltfu estimate at 1 year from the meta-analysis (11.6%). both of these estimates are hard to compare to previous systematic reviews of studies published prior to 2011, again, because of varying definitions and methodologies. two large systematic reviews of studies published from lower-income countries estimated ± 20% ltfu in the first 6 months3 and 11% at 36 months,5 respectively. two south african studies, both of which reviewed data from ± 2002 to 2007, estimated 13% ltfu at 1 year,4 and 18.7% at a median of 2.4 years,6 respectively. it is also important to note that the studies included in this review were conducted during years when the earlier south african art guidelines were in place; the 2010 and 2013 guidelines utilised cd4 threshold for art initiation of 200 and 350, respectively. the 2015 guidelines expanded art to a cd4 threshold of 500, and more recently, universal test and treat has been adopted nationally. in more recent studies, bock et al.7 reported 26% ltfu at 2 years in three south african public sector clinics through 2016; grimsrud et al. reported 17% ltfu at 2 years in a similar patient population.8 while overall studies are reporting higher rates of ltfu as the art thresholds have changed, there is still not a widely adopted definition and standardisation of measurement of ltfu. it is therefore hard to draw definitive conclusions about trends of ltfu rates over time. previous studies have examined the need for standardisation of a ltfu definition in art programmes in sub-saharan africa, citing methodological concerns and a range of outcomes depending on the definition used.82,83,84,85 indeed, there have been a variety of study definitions with a vast diversity of ltfu estimates. a review from 2007 of art programmes in sub-saharan africa estimated 20% attrition at 6 months and between 25% and 75% at 2 years depending on the estimation method used.86 a subsequent review of studies from 2007 to 2009 estimated 29.5% attrition (death or ltfu) at 3 years; 59% of these patients were ltfu.87 a larger review by the same authors subsequently estimated 35% attrition in africa by 36 months.88 in south africa, a systematic review from 2014 estimated approximately 33% attrition by 4 years on art using studies published between 2008 and 2013.2 chi et al.10 performed a meta-analysis that included patients from 19 countries and 111 health facilities, concluding that a standard definition of 180 days since last clinic visit was most accurate in determining actual loss from care. grimsrud et al.11 examined the impact of using different definitions of loss to follow-up on programme outcomes using data from the international epidemiological databases to evaluate aids-southern africa, finding that utilising different definitions led to significantly different estimates of those ltfu, making it impossible to effectively compare rates from different programmes if the same definition is not used; these authors also recommended a standard definition of 180 days since last clinic visit. we support this standardised definition. a key limitation of this study was that despite including 67 studies that met our inclusion criteria, there was not large heterogeneity in terms of study locations. many of them were conducted in the same study site and often had overlapping dates. there were a disproportionate number of studies (two-thirds) in urban areas, primarily in gauteng and western cape provinces. fifteen (22%) of them came from a single clinic in johannesburg (themba lethu). this overlap led to a significant decrease in the number of studies we could include in our meta-analysis and therefore reduced the likelihood we could find significant statistical differences in ltfu. for instance, we did not find that variation in ltfu definition impacted overall ltfu estimates at 1 year in our meta-analysis, and this is likely because of several reasons. firstly, the small sample size of the analysis; once estimates were matched for definition and overlapping cohorts were removed, the sample size was relatively small. similarly, larger estimates of ltfu are notable in smaller cohorts likely because of outlier effects. secondly, there was a lack of standardisation of estimation methodologies for ltfu and mortality including length of follow-up time. thirdly, inclusion of paediatric cohorts likely also played a role in the observed variation. for instance, paediatric patients may be more likely to be retained in care given that they have caregivers. additionally, pregnant patients may be more likely to be lost to follow-up following childbirth, which has been demonstrated in several studies. this may be for a variety of reasons, including lifestyle changes postpartum as well as changing motivations after preventing hiv transmission to their infants.89,90,91 indeed, the differences in aggregate ltfu estimates at 1 year were different between adult versus paediatric versus pregnancy cohorts and largely follow this trend: pregnancy cohorts had higher ltfu (33.0%), and paediatric lower ltfu (7.5%) than adult cohorts (11.6%). a final limitation was that six randomised controlled studies were included, of which some of the interventions were designed to impact adherence and ltfu, which therefore could have biased the meta-analysis estimates. we likely underestimated and/or misrepresented true estimates of ltfu at 5 years in our meta-analysis because of including only two non-representative cohorts in our estimate after standardisation. however, both estimated ltfu at 5 years to be > 1 in five patients. fatti et al.22 defined ltfu as 187 days without a clinic visit and did not include those who had left care and returned later. grimsrud et al.81 similarly defined ltfu as 6 months without a clinic visit and also did not include patients who had left care and returned later. despite being high crude rates of ltfu, these are lower than estimated by large systematic reviews as described above. in conclusion, going forward in south africa, our data suggest that it would be helpful for policy-makers to recommend and programme managers to put into practice a system in which the definition of ltfu or ‘default’ from care is standardised across south african art programmes. such standardisation would not only aid in comparing outcomes across clinics and across the country, especially at defined timeframes, but also in planning broadly applicable interventions for patient retention. ideally, data from clinics could be monitored in real time using a standardised definition, with an actionable reporting system in place to identify patients who require re-engagement, or clinics that need interventions to improve patient retention. additionally, tracing patients after they are ltfu may improve outcomes and lower ltfu rates, as many art patients are mobile and receiving care at more than one clinic, and/or transfers to other clinics may not be sufficiently documented in current data systems.12,92,93,94 already a three-tiered monitoring system exists in the western cape province that aggregates paper and electronic systems into a single database for reporting purposes95; the ideal or goal is to scale this up to a national level and transition to an electronic medical record as resources allow. we hope that our data may be useful to south african art programmes in advancing these broader goals of improving art retention for patients across south africa. acknowledgements s.k. would like to thank the staff at the university of cape town health sciences library for assistance with literature searches and the staff at the university of cape town clinical research centre for assistance with organisation of data extraction. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions g.m., a.b. and s.k. conceived and designed the project. g.m. and a.b. provided the overall conceptual and design guidance. s.k. was the lead author and conducted literature searches and led data extraction efforts with the assistance of k.s.n. who aided in data extraction. n.f. provided conceptual input, conducted the meta-analysis and created figures 2 and 3. s.k wrote the manuscript with assistance from g.m. all authors reviewed the manuscript, provided edits and agreed with its final form. funding s.k. was supported by the national institutes of health office of the director; fogarty international center; office of aids research; national cancer center; national heart, blood, and lung institute; and the national institutes of health (nih) office of research for women’s health through the fogarty global health fellows program consortium comprising the university of north carolina, john hopkins, morehouse and tulane (r25tw009340). a.b. was supported by the nih (u01ai069924), médecins sans frontières and national research foundation (nrf) incentive funding. g.m. was supported by the wellcome trust (098316), the south african research chairs initiative of the department of science and technology, and nrf of south africa (grant no 64787), nrf incentive funding (uid: 85858) and the south african medical research council through its tb and hiv collaborating centres programme with funds received from the national department of health (rfa# samrc-rfa-cc: tb/hiv/aids-01-2014). the funders had no role in the study design, data collection, data analysis, data interpretation or writing of this report. the opinions, findings and conclusions expressed in this manuscript reflect those of the authors alone. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views 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programmes in lowand middle-income countries: systematic review and meta-analysis. trop med int health. 2015;20(3):365–379. https://doi.org/10.1111/tmi.12434 kaplan sr, oosthuizen c, stinson k, et al. contemporary disengagement from antiretroviral therapy in khayelitsha, south africa: a cohort study. plos med. 2017;14(11):e1002407. https://doi.org/10.1371/journal.pmed.1002407 osler m, hilderbrand k, hennessey c, et al. a three-tier framework for monitoring antiretroviral therapy in high hiv burden settings. j int aids soc. 2014;17:18908. https://doi.org/10.7448/ias.17.1.18908 appendix 1 pubmed search strategy (((((((((((((((((“hiv infections”[mesh]) or “hiv”[mesh]) or hiv*) or hiv-1) or hiv-2) or hiv1) or hiv2) or hiv infect*) or human immunodeficiency virus) or human immune deficiency virus) or human immuno-deficiency virus) or human immune-deficiency virus) or (((human immune*) and (deficiency virus)))) or acquired immunodeficiency syndrome*) or acquired immune deficiency syndrome*) or acquired immuno-deficiency syndrome) or acquired immune-deficiency syndrome) or (((acquired immun*) and (deficiency syndrome))) ((((((((((“anti-hiv agents”[mesh]) or “antiretroviral therapy, highly active”[mesh]) or haart) or cart) or art) or antiretroviral) or anti-retroviral) or anti-viral) or antiviral) or antiviral therapy) or arv ((((((((((((((((((((((((((“patient compliance”[mesh]) or “lost to follow-up”[mesh]) or “treatment outcome”[mesh]) or “treatment refusal”[mesh]) or “continuity of patient care”[mesh]) or retention) or nonadherence) or non-adherence) or adherence) or noncompliance) or non-compliance) or follow-up) or patient monitoring) or attrition) or patient elopement) or retain*) or (((loss*) and “follow-up”))) or ltfu) or “loss to care”) or “lost to follow-up”) or “loss to follow-up”) or “lost to care”) or “loss to program*”) or “lost to program*”) or default*) or engage*) or disengage* (“south african”) or “south africa*” #1 and #2 and #3 and #4 appendix 2 table 1-a2: modified newcastle-ottawa scale. hiv 1095_in.indd f o r u m september 2014, vol. 15, no. 3 sajhivmed 77 forum one size doesn’t fit all: tailoring adult antiretroviral treatment n geffen,1 msc; m robinson,2 bsc hons; f venter,3 fcp (sa); m low,4 ma, mphil 1 centre for social science research, university of cape town, south africa 2 department of molecular medicine and haematology, university of the witwatersrand, johannesburg, south africa 3 wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, johannesburg, south africa 4 policy department, treatment action campaign, cape town, south africa corresponding author: n geffen (nathangeffen@gmail.com) advances in antiretroviral treatment mean that patients in the public health system can be given more options in the management of their treatment. although public health programmes tend to offer one-size-fits-all approaches, patients might benefit from a more flexible approach. in particular, we propose that people with hiv should be given more choice with regard to when to start treatment, and patients who experience efavirenz side-effects should be encouraged to switch to other medications, which will be facilitated by faster registration and lower prices of newer antiretrovirals. s afr j hiv med 2014;15(3):77-78. doi:10.7196/sajhivmed.1095 in the past decade, the standard of care for hiv treatment in the public sector has improved considerably. our increased knowledge of antiretroviral (arv) medicines and the additional drugs in our treatment arsenal are an oppor tunity to give patients a greater number of options and improve the tolerability of treatment. when the state’s antiretroviral therapy (art) roll-out began in 2004, the cd4+ initiation threshold for adults was 200 cells/µl and the first-line regimen included stavudine, a drug associated with severe side-effects. a decade later, the cd4+ threshold is 350 cells/µl,[1] and will be increased soon to 500 cells/µl.[2] additionally, stavudine has been replaced with a safer alternative, tenofovir. while 10 years ago, adults on their first regimen had to take varied-dose combinations twice daily, today most patients are being prescribed one pill once daily. this progress has resulted in art that is easier to manage and maintain. public health programmes need to standardise the care offered to patients. but a one-size-fits-all approach can be too restrictive, resulting in some patients receiving suboptimal care. there is scope to offer more options to patients with hiv, at least in some facilities, with the prospect of improving their quality of life. this increased individualisation of treatment is unlikely to overburden the public health system. while there are a number of factors that affect individualising treatment, here we focus on two that we believe can be adapted in publicsector art programmes in south africa (sa): (i) efavirenz tolerability; and (ii) treatment initiation. efavirenz tolerability in 2014, art options are relatively plentiful, but several important ones are, for the most part, beyond the public sector. besides nucleoside and non-nucleoside reverse transcriptase inhibitors and protease inhibitors, integrase inhibitors are now also available in the private sector, but access is limited to specific research and clinical scenarios in public facilities. the current first-line regimen includes efavirenz, which is tolerated well by most patients. given that over 2.5 million patients are receiving treatment in the public sector, about 2 million are likely to be receiving efavirenz. but some patients endure debilitating neurocognitive side-effects from this drug; recent data suggest a doubling of the suicide rate in people treated with efavirenz over other regimens.[3] patients should have the opportunity to modify their regimen by switching efavirenz for a protease or integrase inhibitor. the concern is the price and availability of alternative drugs. the standard first-line efavirenz-containing regimen costs the state less than r100 per patient per month. protease inhibitors cost more, but have become increasingly affordable. raltegravir, however, is not readily available in the public sector, is on the state tender at r533 per patient per month,[4] and is currently dosed twice daily. new integrase inhibitors like the daily-dosed dolutegravir are not yet available in sa, and the local price is as yet unknown. the lag times between arvs being approved by the us food and drug administration, european medicines agency v. the medicines control council (mcc) are extraordinarily long, especially considering that there is much greater need in sa and other sub-saharan african countries than in north america or europe. to improve treatment options for patients, clinicians, researchers and activists need to put pressure on pharmaceutical companies and the mcc to prioritise registration here (and in other african countries). campaigning for lower prices of new arv drugs must continue. treatment initiation the hptn 052[5] and partner[6] studies show that hivpositive people with suppressed viral loads and who are receiving f o r u m once daily dosing for antiretroviral therapy experienced patients references: 1. aluvia approved package insert. 200/50 tablets. october 2013. storage conditions: store aluvia 200/50 tablets at room temperature (below 30ºc). keep well closed. s4 aluvia®. each film coated tablet contains 200 mg lopinavir and 50 mg ritonavir. reg. no. 41/20.2.8/0217 for full prescribing information refer to the package insert approved by the medicines regulatory authority. promo no. zaalu140099a date of publication: july 2014 abbott laboratories s.a (pty) ltd. abbott place 219 golf club terrace constantia kloof, 1709 important information aluvia should not be administered once daily in combination with carbamazepine, phenobarbital, or phenytoin. the recommended oral doses of aluvia film-coated tablets are as follows:1 adults • aluvia film-coated tablets 400/100 mg (given as two 200/50 mg tablets) twice daily, with or without food. • aluvia film-coated tablets 800/200 mg (given as four 200/50 mg tablets) once daily, with or without food, in patients with fewer than three lopinavir-associated mutations. there is insufficient data to support the use of once-daily administration of aluvia in adult patients with three or more lopinavir-associated mutations. protection for tomorrow, starts today. 78 sajhivmed september 2014, vol. 15, no. 3 f o r u m treatment will not transmit the virus to hiv-negative sexual partners. also, clinical trial evidence shows that it is clinically beneficial to initiate treatment at a cd4+ count of 350 v. 250 cells/µl.[7] but the optimal cd4+ threshold to initiate patients to maximise clinical benefit remains unknown. it is possible that the benefits of starting above 350 cells/µl may be undone by interrupted drug supplies or if poor adherence results in the emergence of drug resistance. within the next 3 years, the start[8] and temprano[9] clinical trials are likely to provide a clearer answer on the clinical benefits and risks of initiating treatment above 350 cells/µl. but without clear evidence that the clinical benefit of earlier treatment outweighs harm due to side-effects, patients should be given the opportunity to make an informed choice. their pathophysiology, preferences and circumstances should be taken into account to determine when it is appropriate to initiate treatment. the question of when to start treatment has become contentious, and many experts differ on this issue. this is understandable, given the current lack of evidence about the clinical and the public health benefits of suppressing viral load in sexually active people with hiv. there is increasing pressure on people with hiv to start treatment earlier, e.g. at 500 cells/µl. the world health organization raised the cd4+ threshold for initiating art to 500 cells/µl in its 2013 treatment guidelines.[10] the sa minister of health has announced that this threshold will also be used in sa from january 2015.[2] in response to the minister’s announcement, the southern african hiv clinicians society correctly wrote: ‘we … support an individualised approach in patients with a cd4+ count 350 500 [cells/µl]: after a discussion about the potential benefits, uncertainties, side-effects and need for impecable [sic] adherence patients should only be prescribed art in this cd4+ range if they are motivated for lifelong art with the required adherence. if they do not feel ready yet, art should be deferred until their cd4+ count is below 350 [cells/µl] with a plan in place for ongoing follow-up and cd4+ monitoring.’[11] furthermore, the threshold of 500 cells/µl is arbitrary and not based on clinical trial findings. we therefore propose the following approach: art should be offered to all people with hiv. as part of discussions between patients and providers, patients need to be given an informed choice. patients with cd4+ counts >350 cells/µl should be informed that the clinical benefits and risks of starting art at high cd4+ counts are, as yet, unknown, and that taking treatment daily is likely to be a life-long commitment. patients should also be informed that within a few years, more will be known about this. patients who are sexually active and want to minimise their risk of transmission to sexual partners should be informed that treatment can reduce the risk of transmitting hiv considerably, at least once viral load becomes undetectable. based on this information, patients who wish to start at a high cd4+ count should be allowed to do so. there are caveats: early art is not a reasonable option in facilities still using stavudine or zidovudine as first-line treatment, nor in facilities prone to stock-outs. in resourcestretched facilities with high patient loads, patients with cd4+ counts <350 cells/µl must be prioritised. ultimately, an approach that gives patients the opportunity to make informed choices respects the principle of patient autonomy. this could lead to increased adherence, and better outcomes for individual patient’s and the public’s health. conflict of interest. n geffen is on the insight community advisory board and receives a per diem for travel to insight meetings and an honorarium. insight is running the start trial. f venter is on the data safety monitoring board for the start trial. references 1. south african national department of health. the south african national antiretroviral treatment guidelines 2013. http://www.sahivsoc.org/upload/ documents/2013%20art%20guidelines-short%20combined%20final%20 draft%20guidelines%2014%20march%202013.pdf (accessed 25 august 2014). 2. green a, skosana i. motsoaledi reveals ‘progressive’ hiv treatment plans. mail & guardian, 24 july 2014. 3. mollan kr, smurzynski m, eron jj, et al. association between efavirenz as initial therapy for hiv-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data. ann intern med 2014;161(1):1-10. [http://dx.doi.org/10.7326/m14-0293] 4. department of health. contract number hp13-2013arv. http://www.health.gov. za/docs/contructs/hp13_2o13arv.pdf (accessed 24 july 2014). 5. cohen ms, chen yq, mccauley m, et al. prevention of hiv-1 infection with early antiretroviral therapy. n engl j med 2011;365(6):493-505. [http://dx.doi. org/10.1056/nejmoa1105243] 6. rodger a, bruun t, cambiano v, et al. hiv transmission risk through condomless sex if hiv+ partner on suppressive art: partner study. conference on retroviruses and opportunistic infections (croi 2014). boston, march 3 6, 2014. abstract 153lb. 7. when to start consortium, sterne jac, may m, costagliola d, et al. timing of initiation of antiretroviral therapy in aids-free hiv-1-infected patients: a collaborative analysis of 18 hiv cohort studies. lancet 2009;373(9672):1352-1363. [http://dx.doi.org/10.1016/s0140-6736(09)60612-7] 8. babiker ag, emery s, fatkenheuer g, et al. considerations in the rationale, design and methods of the strategic timing of antiretroviral treatment (start) study. clin trials 2013;10(10):s5-s36. [http://dx.doi.org/10.1177/1740774512440342] 9. early antiretroviral treatment and/or early isoniazid prophylaxis against tuberculosis in hiv-infected adults (anrs 12136 temprano) http:// clinicaltrials.gov/ct2/show/nct00495651 (accessed 1 june 2014) 10. who. consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection: recommendations for a public health approach june 2013. http://www.who.int/hiv/pub/guidelines/arv2013/en/ (accessed 27 august 2014). 11. southern african hiv clinicians society. position: initiation of art at a cd4 threshold above 350. http://www.sahivsoc.org/upload/documents/14%2007%20 23%20position%20art%20initiation%20greater%20than%20350.pdf (accessed 13 august 2014). references about the author(s) mukesh dheda pharmacovigilance centre for public health programmes, national department of health, south africa school of health science, university of kwazulu-natal, south africa citation dheda m. herbal slimming formulations or remedies interact with antiretroviral therapy. s afr j hiv med. 2017;18(1), a742. https://doi.org/10.4102/sajhivmed.v18i1.742 advice document herbal slimming formulations or remedies interact with antiretroviral therapy mukesh dheda copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. concurrent use of vitamins, supplements and herbs among people on antiretroviral therapy to help manage the side effects or improve their general health is very common in south africa. among these are various slimming herbs. many slimming products are complex mixtures of herbs that contain organic compounds that may induce or inhibit drug metabolising enzymes (e.g. cytochrome p450) and drug transporters (e.g. p-glycoprotein). these interactions may reduce or increase serum antiretroviral drug concentrations. subtherapeutic antiretroviral drug levels in patients lead to suboptimal viral control whilst increased concentration may lead to higher risk of toxicity.1,2 these products may also contain compounds that interfere with the absorption of the antiretrovirals. there are limited data from scientifically sound studies assessing the interaction between herbal slimming products and antiretroviral therapy. recently, during the pharmacovigilance training conducted by the national department of health pharmacovigilance centre for public health across south africa, healthcare professionals have expressed concerns regarding the safety of herbal slimming preparations when used concomitantly with antiretrovirals. healthcare professionals are requested to be vigilant and report any change in the patient’s condition when using slimming preparations concomitantly with antiretrovirals, especially when they are co-administered. please complete adverse drug reaction forms where adverse reactions are suspected. adverse drug reaction forms can be obtained from the national department of health pharmacovigilance centre for public health programmes. any comments and queries can be addressed to the below email: tel: +27 (0)12 395 9506/8099 fax to email: 086 241 2473 email: npc@health.gov.za references pandrea i, happel ki, amedee am, bagby gj, nelson s. alcohol’s role in hiv transmission and disease progression. alcohol res health. 2010;33:203–218. calmy a, hirschel b, cooper da, carr a. a new era of antiretroviral drug toxicity. antivir ther. 2009;14:165–179. abstract introduction methodology results discussion conclusion acknowledgements references about the author(s) mthokozisi a. cele department of paediatrics and child health, university of kwazulu-natal, durban, south africa moherndran archary department of paediatrics and child health, university of kwazulu-natal, durban, south africa citation cele ma, archary m, acceptability of short text messages to support treatment adherence among adolescents living with hiv in a rural and urban clinic in kwazulu-natal. s afr j hiv med. 2019;20(1), a976. https://doi.org/10.4102/sajhivmed.v20i1.976 original research acceptability of short text messages to support treatment adherence among adolescents living with hiv in a rural and urban clinic in kwazulu-natal mthokozisi a. cele, moherndran archary received: 31 mar. 2019; accepted: 16 july 2019; published: 03 oct. 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the use of mobile communication technologies (mhealth) has improved adherence and viral suppression among hiv-infected adults. adolescents have disproportionally lower levels of adherence and viral suppression compared with adults, potentially impacting the goal of 90% viral suppression by 2030. objectives: the aim of this study was to evaluate the acceptability of using short message service (sms)-based mhealth interventions as a tool to improve adherence in hiv-infected adolescents in a rural and urban clinic in kwazulu-natal (kzn). method: a cross-sectional study with a sample size of 100 participants was conducted in a rural and urban clinic in kzn, from january 2018 to june 2019. fifty participants were sequentially enrolled from each clinic. a questionnaire was self-administered with the assistance of the treating clinician depending on the adolescent’s level of understanding. informed consent was obtained from guardians and questionnaires were anonymised. appropriate descriptive and comparative statistics were used. results: the mean age of participants was 15 years, with 88% having access to a mobile device (mod). there was no significant difference in mod ownership between rural and urban participants. majority of participants (65%) were willing to receive sms-based adherence support with no difference between rural and urban area. conclusion: with high rates of mod ownership and acceptability (willingness to use mhealth to improve health status), sms-based mhealth interventions have the potential to improve adherence and viral suppression in adolescents living with hiv in both rural and urban kzn. further studies with a larger sample size need to be conducted to further explore these findings. keywords: adolescents on antiretroviral therapy; hiv; text messaging system; adherence support; retention cell phone technology; mhealth. introduction in 2015, an estimated 1.8 million adolescents worldwide were living with hiv,1 with over two-thirds living in sub-saharan africa (ssa).2 in 2018, an estimated 310 000 adolescents were living with hiv in south africa.3 the earlier initiation of antiretroviral treatment (art) in vertically hiv-infected children has resulted in more children surviving into adolescence potentially increasing these estimates in the future. with the aim of controlling the hiv epidemic, the world health organization (who) launched the 90-90-90 campaign, which aims for 90% of people living with hiv knowing their hiv status, 90% started on art and 90% with a suppressed hiv viral load.4 one of the challenges in achieving the 90-90-90 targets is the poor adherence among adolescents in africa.5 poor adherence is associated with lower rates of viral suppression both in adult and adolescent populations.6,7,8 a recent systemic review estimated that viral suppression ranged from 27% to 89% in africa.9 west and central africa had the lowest viral suppression rate (8%), while east africa had the highest (56%).10 in south africa, a study conducted in gauteng and mpumalanga found that adolescents were more likely to be unsuppressed by 12 months (risk ratio 2.30, 95% ci, 1.38–3.82) than adult patients.11 adolescents also have lower rates of retention in care compared with adults.12 an evaluation of lost to follow-up in adolescents starting art in four ssa countries was 20% at 3 months and 44% at 12 months.13 in a study conducted in a cohort of 241 adolescents in south africa between 2007 and 2015, 89% were retained in care and 81% achieved viral suppression. furthermore, adolescents attending designated adolescent clinics had higher retention rates (95%) compared with those attending paediatric clinics (85%). the needs of adolescents should be addressed differently from the general population,14 with individualised care associated with higher adolescent retention in care.15 mobile communication technologies in medical care (mhealth) have the potential to address some of these issues. mhealth refers to the use of mobile devices (mods), such as mobile phones to support practice of medicine and public health.16 there are several variations to mhealth interventions, including short messaging service (sms) reminders, gaming applications (apps) and interactive mobile apps. a mobile app study conducted in new england found improved motivation in taking antiretroviral therapy,17 while a medminder pill counter that generates automated sms to adolescents found that there was a significant increase in cd4 counts.18 a randomised controlled trial of a personalised sms reminder to promote adherence in adults in kenya improved adherence from 28% to 64% after 3 months.19 in studies conducted in uganda and kenya found that 97% of the surveyed participants thought that sms reminders would improve treatment adherence.19,20 a study conducted in ethembeni clinic in durban found that 98% of the adult participants remembered their medications and would recommend the service to a friend.21 concerns expressed regarding mhealth included privacy and security with unintentional sharing of personal information being of most concern.22 sharing of mods is common in africa and has implications on mhealth interventions. the majority (88%) of respondents from a study in mozambique felt that unauthorised access to text messages could result in accidental disclosure of their hiv status because they share mods.23 sharing of mods may also result in a delay in relaying of the message or message not being delivered to right person.20 intermittent and limited funding for public health and sustainable mhealth interventions is a major problem especially in resource-limited countries with competing priorities.24 the majority of mhealth studies have been based on an sms reminder that is sent as daily or weekly reminders. more research is needed to determine the optimal frequency of messages to support adherence. improvements in mobile technology have allowed interactive text messages that have been shown to help with emotional support and build patient knowledge and allowed the adolescents to ask questions.7 however, sms provides an easy, cheap and accessible technology for mhealth that is accessible even in remote areas with limited resources.25 an mhealth intervention (momconnect) in pregnant women was launched in south africa in 2014 and has been successfully implemented in the adult population. to our knowledge, there is limited data evaluating mhealth interventions in adolescent populations in kwazulu-natal (kzn), especially comparing rural and urban populations. the aim of our study was to evaluate the acceptability of using sms-based mhealth interventions as the tool for mhealth in adolescents living with hiv from kzn, comparing a rural and urban clinic, with the aim to support adherence and retention in care. furthermore, we explored the preferred type of mhealth support (peer support or daily or weekly reminders). methodology we conducted a cross-sectional observational survey in a rural and urban clinic in kzn from january 2018 to june 2019. the two study sites, a rural clinic (umbumbulu clinic) and an urban clinic (king edward viii hospital [keh]) were selected based on the geographic location and patient profile. umbumbulu clinic is in a deep rural area in a sub-district of kzn, 30 km south of durban. the umbumbulu clinic is a primary healthcare centre serving the marginalised community of umbumbulu, with a high rate of unemployment, poor transport system and patients have to walk 3 km – 5 km to access the clinic. umbumbulu clinic is a combined service serving children, adolescents and adults. the arv clinic (philani clinic) at keh, durban, serves an urban and peri-urban area, including patients from formal and informal housing in umbilo, cato manor, manor gardens and mayville. these communities include lowand middle-class families. population and sample we sequentially enrolled 100 adolescents (12–19 years of age) living with hiv on art from the adolescent clinics in the two sites. as an exploratory pilot study, the sample size of 100 was based on availability of limited resources and the patient numbers at each of the study sites. the sample size was powered to detect a difference in mhealth acceptability of 70% between the rural and urban sites with a power of 95% and alpha of 0.05. a further study with a larger sample size would need to be performed to determine smaller differences between the two groups. fifty participants were enrolled from each clinic with an equal distribution of males and females. informed consent to participate in the study was provided by the parent or guardian (telephonic consent was provided when the adolescent came alone), the adolescent provided signed assent and those above 18 years signed informed consent. s.n. at umbumbulu clinic and c.k. at keh recruited participants while registering their details before the doctor consultation. no patient incentives were provided for participation in the study as patients were recruited during scheduled visits and the questionnaire was completed while waiting for their consultations. the investigator conducted a 2-h workshop 2 months prior to the commencement of the study at both clinics, to engage with s.n. and c.k. and standardise the survey collection. participants were provided with a pen and questionnaire in the waiting area and answered the questionnaire while waiting for their consultation. after completion, the questionnaire was dropped in the box inside the consultation room. an anonymous questionnaire was used as a tool to collect data from the participants. the questions were divided in 10 sections, mainly containing information about age, language frequently used, sex, gender, level of education, mod ownership and perceptions about sms mhealth interventions. the questionnaire was available in isizulu and english. the questionnaire had been piloted at keh as part of the passages project. statistical analysis results were reported as means for continuous variables and as frequencies and percentages for categorical variables. chi-square tests for categorical data and student t-tests for continuous data were used to compare the difference in covariates between the rural and urban clinic sites. a chi-square test was also used to assess phone ownership and mobile health technology feasibility by level of education. if more than 25% of the cells had expected counts less than five, a fisher’s exact test was run in place of the chi-square test. this is necessary because having small expected counts violates an assumption of the chi-square test. analysis was performed using sas 9.4. ethical considerations approval for this study was obtained from the university of kwazulu-natal biomedical research ethics committee (brec number be480-17), the kzn department of health (kz_201801_031) and the two institutions. results the key demographics of this survey from both rural and urban areas are depicted in table 1. the mean age was 15 years (range 13–19 years). there was an almost equal distribution between males and females as per the study design. the majority of the population in this sample was black africans and the preferred language of communication was isizulu. there were significant differences between the participants in the urban and rural clinics with regard to age and level of education. table 1: demographic characteristics of the study population by clinic site (n = 100). access to an mod was high as shown in table 2, with 88% of adolescents surveyed having access to an mod. there was no statistical difference in mod ownership between rural and urban sites (92% vs. 84%, p = 0.2). the mod ownership was almost the same between males and females (88% vs. 83% p = 0.19). there was a high frequency of sms messages use in the rural site as compared to urban (40% vs. 26%, p = 0.08). despite high mod ownership, 48% of participants in the urban site had never sent an sms text message. the majority of the study population at both sites had not sent or received any form of text message from a medical provider; however, adolescents at both the rural and urban sites were willing to use mobile technology to access healthcare (table 2). table 2: feasibility of mobile health technology by clinic site (n = 100). feasibility of mhealth interventions was stratified by participant level of education (table 3). fifty per cent of the study population was attending secondary school with a statistically significant increase in mod ownership with higher level of education (p = 0.0016). only 38% of participants reported that they use sms every day; however, 34 % reported that they never sent an sms text message. use of mhealth was feasible particularly in adolescents who attend secondary school with high levels of mod ownership and 67% willing to receive sms regarding their health. table 3: feasibility of mobile health technology by education level (n = 83). discussion in this exploratory pilot study evaluating the acceptability of text messaging support for adolescents in an urban and rural clinic, we found no significant difference in mod ownership and acceptability of mhealth between the two sites. participants in both sites had high mod ownership, with more than 90% of adolescents in this cohort owning a mod. there are similar trends in mod ownership that have been noted in other studies from africa. a study of mod ownership among the youth population in malawi, ghana and south africa showed that 88% of youth owned an mod.26 despite the high levels of mod ownership, there is a possibility that adolescents share their mods with other family members, which increased the risks of accidental disclosures of confidential information regarding their health status.16 investing in improving sms-based mhealth interventions that do not divulge patient information and protecting individual privacy is urgently needed.16,27 while there have been different mhealth interventions studied in adult populations in developing and developed countries, these findings support the exploration of mhealth in adolescents residing in both rural and urban kzn. telecommunication technologies are emerging as an important means of extending healthcare to patients with limited direct access to a healthcare facility, with a cochrane review showing that there is growing interest in the use of cell phone technology.28 in this study, 65% of adolescents were willing to participate in a mhealth intervention. there are different communication tools that have been used for delivering mhealth, ranging from simple, for example sms, to more complicated, for example interactive apps. participants from both clinics found that communicating with a healthcare provider using sms text messages was an acceptable tool. one of the major potential benefits of mhealth is in improving adherence and retention to care. a study conducted in a rural area of kenya found that an sms-based mhealth intervention was associated with 90% improvement in adherence over 48 weeks.29 additional benefits include decreased need for regular follow-up appointments resulting in a positive financial effect for patients as most clinics are far from the community.18 several studies have found a correlation between high usage of mhealth and improvement of adherence.22,30,31 the high mod ownership and willingness to access mhealth at both sites indicate that there is a space for mhealth interventions among these communities. the higher usage of sms text messaging in the participants from the rural clinic compared to the urban clinic likely highlights the influence of different access to telecommunication technologies between the settings. the ready availability of internet-based messaging (e.g. whatsapp) in urban centres may account for the lower use of sms text messaging. this finding highlights the need for the use of simple technologies that can be accessed by both urban and rural communities when designing mhealth interventions. implementation of telecommunication technologies requires adequate infrastructure, sustained budget for operational costs and this will need involvement of public and private sector support for it to be sustainable.32 the frequency of preferred messages differs by country, with patients in developing countries preferring to receive messages once a week,20,29,30 compared to daily text messaging that was preferred by patients in some developed countries.33 this preference may be related to socio-economic status with adolescents in developing countries being more likely to share mods and less frequent messages would decrease the chances of accidental disclosure. other suggestions by youth to improve confidentiality of mhealth include the use of mods with access codes to increase security.22 in addition, daily sms might be intrusive, produce habituation and response fatigue.34 there is suggestion that a two-way text messaging may be better than a simple text message reminder. more evidence is warranted regarding the optimal frequency of messaging.35 the majority of adolescents attending school may have restriction placed on the use of mod both at school and at home during the school terms; this is important for the timing of sms. while the frequency of messaging is high among adolescents, only 12% of adolescents use cell phones for health-related information26; this is lower than previously thought. a study conducted in malawi, ghana and south africa showed that 29% use cell phone technology for health-related issues.26 the possible reasons that can be extrapolated for the low usage include that people struggle to differentiate between good and bad information from the internet about health and the prohibitively high cost of using data.26 text messaging and phone calls maybe unaffordable in certain very low resource settings.24 these challenges will need to be addressed to achieve adherence and retention. our study indicates that mhealth interventions hold promise, as 65% of adolescents are willing to use cell phone technology for health-related information. providing healthcare-related messages in a language that the recipient is comfortable with is very important. there are differences in languages used at home between participants in the urban and rural clinic, highlighting the need for the language to be customised to accommodate different ethnic and linguistic groups. the average age of the participants in this survey is 15 years, with the majority in secondary school. however, if mhealth interventions are to be implemented, then content of messages might need to be different to accommodate different age groups. these messages need to be individualised and free of abbreviations like hiv/aids to decrease risk of accidental disclosure.35 a limitation of this study was the small sample size, which limited the power of the study to detect smaller differences between the two populations. however, this analysis was aimed at exploring mhealth in rural and urban areas in kzn and provides a rationale for further research in this area. bias may arise as caregivers consented for enrolment into this survey, which may influence the responses, but assent was obtained and those adolescents who refused participation were not included. further participants may have shared information while waiting outside the consultation room, which can lead to contamination of the data. strategies like mhealth are in line with the fourth industrial revolution, as technology has become the focus. with dwindling international funding for provision of art globally, this is a key opportunity to use innovative technologies (such as mhealth) to support a sustainable art programme especially in vulnerable groups.36 however, as many african countries struggle with poverty, high unemployment rate and weak economic growth, it will be challenging to channel resources for implementation of such projects.24 conclusion this study has demonstrated that adolescents in this study population were willing to use simple sms technology to communicate their health status with the health system both in urban and rural areas. this demonstrates the acceptability of potential of mhealth interventions that might have positive impact in supporting adherence and retention in care. further studies are required to identify the most effective types of messaging, cost-effectiveness and sustainability especially in developing countries. this will require partnership with the private sector cellular phone networks while tailoring the intervention to the needs and information required by adolescents. acknowledgements the authors would like to thank sister sibongiseni ngubelanga from umbumbulu clinic and dr chirjeev kindra from keh philani clinic for their assistance in collecting the questionnaires and the adolescents for their participation in the study. competing interests the authors have declared that no competing interests exist. authors’ contributions m.a.c. did the literature review, summarised and interpreted data collection, and wrote the summary. m.a. assisted with corrections and did overall supervision of the project. funding this research received no specific grant from any funding agency in the public, commercial or not for profit sectors. data availability statement data can be shared upon permission from the authors. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references unicef. for every child, end aids: seventh stocktaking report, 2016. seventh stocktaking report 2016. 2016. [cited n.d.]. available from: https://www.unicef.org/publications/index_93427.html slogrove al, mahy m, armstrong a, davies ma. living and dying to be counted: what we know about the epidemiology of the global adolescent hiv epidemic. j int aids soc. 2017;20(suppl 3):4–15. https://doi.org/10.7448/ias.20.4.21520 unaids, aidsinfo. unaids 2019 estimates. 2019. [cited n.d.]. available from: https://aidsinfo.unaids.org/ joint united nations programme on hiv/aids (unaids). 90-90-90 an ambitious treatment target to help end the aids epidemic, 2014. 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2010;14(6):1294–1301. https://doi.org/10.1007/s10461-010-9720-1 whiteley l, brown l, lally m, heck n, van den berg jj. a mobile gaming intervention to increase adherence to antiretroviral treatment for youth living with hiv: development guided by the information, motivation, and behavioral skills model. jmir mhealth uhealth. 2018;6(4):e96. https://doi.org/10.2196/mhealth.8155 spratt es, papa ce, mueller m, et al. using technology to improve adherence to hiv medications in transitional age youth: research reviewed, methods tried, lessons learned. j gen med. 2017;1(1):1002. lester rt, ritvo p, mills ej, et al. effects of a mobile phone short message service on antiretroviral treatment adherence in kenya (weltel kenya1): a randomised trial. lancet. 2010;376(9755):1838–1845. https://doi.org/10.1016/s0140-6736(10)61997-6 rana y, haberer j, huang h, et al. short message service (sms)-based intervention to improve treatment adherence among hiv-positive youth in uganda: focus group findings. plos one. 2015;10(4):1–14. https://doi.org/10.1371/journal.pone.0125187 georgette n, siedner mj, zanoni b, et al. the acceptibility and percieved usefulnes of weekly sms. aids behav. 2017;20(11):2629–2638. https://doi.org/10.1007/s10461-016-1287-z saberi p, siedle-khan r, sheon n, lightfoot m. the use of mobile health applications among youth and young adults living with hiv: focus group findings. aids patient care stds. 2016;30(6):254–260. https://doi.org/10.1089/apc.2016.0044 nhavoto ja, grönlund å, klein go. mobile health treatment support intervention for hiv and tuberculosis in mozambique: perspectives of patients and healthcare workers. plos one. 2017;12(4):1–13. https://doi.org/10.1371/journal.pone.0176051 kliner m, knight a, mamvura c, wright j, walley j. using no-cost mobile phone reminders to improve attendance for hiv test results: a pilot study in rural swaziland. infect dis poverty. 2013;2(1):2–8. https://doi.org/10.1186/2049-9957-2-12 saberi p, johnson mo. technology-based self-care methods of improving antiretroviral adherence: a systematic review. plos one. 2011;6(11):e27533. https://doi.org/10.1371/journal.pone.0027533 hampshire k, porter g, owusu sa, et al. informal m-health: how are young people using mobile phones to bridge healthcare gaps in sub-saharan africa? soc sci med. 2015;142:90–99. https://doi.org/10.1016/j.socscimed.2015.07.033 crankshaw t, corless ib, giddy j, nicholas pk, eichbaum q, butler lm. exploring the patterns of use and the feasibility of using cellular phones for clinic appointment reminders and adherence messages in an antiretroviral treatment clinic, durban, south africa. aids patient care stds. 2010;24(11):729–734. https://doi.org/10.1089/apc.2010.0146 horvath t, azman h, kennedy ge, rutherford gw. mobile phone text messaging for promoting adherence to antiretroviral therapy in patients with hiv infection. cochrane database syst rev. 2012;(3):cd009756. https://doi.org/10.1002/14651858.cd009756 pop-eleches c, thirumurthy h, habyarimana jp, et al. mobile phone technologies improve adherence to antiretroviral treatment in a resource-limited setting: a randomized controlled trial of text message reminders. aids. 2013;25(6):825–834. https://doi.org/10.1097/qad.0b013e32834380c1 maduka o, tobin-west ci. adherence counseling and reminder text messages improve uptake of antiretroviral therapy in a tertiary hospital in nigeria. niger j clin pract. 2013;16(3):302–308. https://doi.org/10.4103/1119-3077.113451 kanters s, park jjh, chan k, et al. interventions to improve adherence to antiretroviral therapy: a systematic review and network meta-analysis. lancet hiv. 2017;4(1):e31–e40. https://doi.org/10.1016/s2352-3018(16)30206-5 avery m, mills sj, stephan e. real-time monitoring through the use of technology to enhance performances throughout hiv cascades. curr opin hiv aids. 2017;12(5):488–493. https://doi.org/10.1097/coh.0000000000000397 garofalo r, kuhns lm, hotton a, johnson a, muldoon a, rice d. a randomized controlled trial of personalized text message reminders to promote medication adherence among hiv-positive adolescents and young adults. aids behav. 2017;20(5):1049–1059. https://doi.org/10.1007/s10461-015-1192-x finitsis dj, pellowski ja, johnson bt. text message intervention designs to promote adherence to antiretroviral therapy (art): a meta-analysis of randomized controlled trials. plos one. 2014;9(2):e88166. https://doi.org/10.1371/journal.pone.0088166 amankwaa i, boateng d, quansah dy, akuoko cp, evans c. effectiveness of short message services and voice call interventions for antiretroviral therapy adherence and other outcomes: a systematic review and meta-analysis. plos one. 2018;13(9):1–20. https://doi.org/10.1371/journal.pone.0204091 mcgillen jb, sharp a, honermann b, millett g, collins c, hallett tb. consequences of a changing us strategy in the global hiv investment landscape. aids. 2017;31(18):f19–f23. https://doi.org/10.1097/qad.0000000000001669 m e s s a g e f r o m t h e e x e c u t i v e the pharmaceutical industry is a complex and highly political business. a friend of mine in the industry refers to them as ‘the new tobacco companies’ because of their recently acquired status as the world’s new industrial bad guys. in some cases this has been well deserved. in south africa, the battle to drive indefensible antiretroviral drug prices down was a sad part of our history that cost many lives. as new and novel compounds arrive on the market, with a tension between clinical need, affordability and reasonable profit, this battle is likely to continue. however, a new situation has now arisen. with the huge increase in the number of people on antiretroviral therapy (art) in southern africa, the need for sustainable (both in terms of supply and affordability) drug supply is an increasing concern. south africa alone has about 400 000 people on art. the annual ingredients for these drugs can be measured in tons, and many ingredients are only available from outside our borders. this makes our country extraordinarily vulnerable. if there is any interruption in the supply of these ingredients, or of the imported complete drug, we will face a major treatment interruption, with all the consequences of undermining adherence, promoting resistance and clinical progression. this threat is increasingly becoming a national security issue for the government, with hiv treatment a graphic illustration of the risks we face if we do not secure the industry. discussions are underway between the south african department of trade and industry and the local pharmaceutical industry with a view to supporting the industry, especially generic manufacturing, in securing local capacity. the new tenders for art in the south african state sector are looming fast, with huge orders. we need a robust, flexible and strong drug manufacturing industry in our region, to guarantee that our patients are not exposed to needless treatment interruption risks. francois venter president anglo’s dr brian brink, the department of health’s dr nomonde xundu and dr francois venter at aspen’s factory in port elizabeth on a fact-finding visit. the southern african journal of hiv medicine                                                         summer  2008 5 we are well into 2008, and government reports suggest that more than 400 000 south africans are now receiving life-saving antiretrovirals. this makes our programme the biggest in the world, but there is no room for complacency, with another 500 000 requiring therapy over the next few months. a daunting task, as initiation is just the beginning these patients need care for the rest of their lives. in this summer edition the adult treatment guidelines have been revised. anyone providing care for hiv-infected patients should familiarise themselves with these guidelines. the guidelines describe the proposed role of tenofovir in the south african art programme, and on p. 8 nathan ford and co-authors describe what needs to be done to bring its price into a range that would make it affordable and possible for first-line consideration. we are also delighted to feature the rest of the much sought-after nutritional guideline chapters. dr dave spencer has been the driving force behind these, and we thank him and the team for their commitment. we pay tribute to dave, who is retiring from the hiv clinicians society executive committee. he is much loved and respected in this country as a devoted and wise hiv treater and an exceptionally talented trainer. one of his memorable attributes is making any question sound like an excellent one! dr fabian and co-authors have contributed an excellent review on hiv and the kidney. again, with tenofovir on the cards, better understanding of the renal pathologies expected in hiv and the complications of drugs and drug dosing is paramount for good management. finally, in the roll-out of art and pmtct, a number of excellent community-led projects have developed throughout africa, often using the one resource we do not have a shortage of: people living with hiv. one such programme, which has grown from cape town and now extends throughout africa, is mothers2mothers, described in this edition by chloe teasdale. as we go to print, we have had the sad news that an hiv/ tb, public health and human rights warrior, dr ivan toms, passed away in cape town over the easter weekend. ivan, a colourful and passionate doctor who lived life to the full and never compromised, was a south african who will be sorely and sadly missed. i am sure you will again agree: a fabulous smorgasbord of information in this our summer edition. please keep articles rolling in – we have a series of critical guidelines coming up, but we need interesting and relevant original articles as well. articles are easily submitted by going to www. sahivmed.org.za and registering as an author. thereafter log in, proceed to 'user home', click on 'author' and follow the instructions for submission. linda-gail bekker editor f r o m t h e e di tor pg5.indd 1 4/4/08 9:05:07 am abstract introduction methods ethical consideration results discussion conclusion acknowledgements references about the author(s) nina e. diana division of nephrology, department of internal medicine, charlotte maxeke johannesburg academic hospital, johannesburg, south africa faculty of health sciences, university of the witwatersrand, johannesburg, south africa charles feldman division of pulmonology, department of internal medicine, charlotte maxeke johannesburg academic hospital, johannesburg, south africa faculty of health sciences, university of the witwatersrand, johannesburg, south africa citation diana ne, feldman c. measles in adults: a comparison of hospitalised hiv-infected and hiv-uninfected patients. s afr j hiv med. 2019;20(1), a877. https://doi.org/10.4102/sajhivmed.v20i1.877 original research measles in adults: a comparison of hospitalised hiv-infected and hiv-uninfected patients nina e. diana, charles feldman received: 22 june 2018; accepted: 22 feb. 2019; published: 13 aug. 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: although measles is traditionally a childhood illness, there are an increasing number of adult cases. despite both measles and hiv infection being endemic in sub-saharan africa, there are little data regarding outcomes in co-infected patients. objectives: compare demographic, clinical, laboratory and radiographic features, as well as outcome (length of hospital stay, complications and mortality) between hiv-infected and hiv-uninfected adult patients admitted with confirmed measles. methods: we conducted a retrospective record review of adult patients with confirmed measles who were admitted to the infectious diseases unit at the charlotte maxeke johannesburg academic hospital during the peak of the 2009 and 2010 south african measles outbreak. the data collected included demographic, clinical and laboratory parameters, as well as outcomes. results: of the 33 confirmed measles cases admitted, 24 patients were tested for hiv infection and 18 tested seropositive. there were no significant differences in the demographics, clinical findings or laboratory data when comparing the hiv-positive and hiv-negative cases. serious clinical manifestations were seen more frequently in hiv-positive patients (odds ratio [or] 5, 95% confidence interval [ci] 0.48–51.8, p = 0.34). one of the six patients testing hiv-negative developed pneumonia, while six of the 18 hiv-positive patients had a course complicated by pneumonia. five of these hiv-positive patients required admission to the intensive care unit, three developing respiratory failure necessitating mechanical ventilation. hiv-positive patients had several other manifestations, including acute kidney injury, purulent conjunctivitis, pancreatitis and encephalitis. hiv-positive patients had a significantly longer hospital stay (p = 0.03). there were three deaths in the hiv-positive group, but none in the hiv-negative group (or 2.9, 95% ci 0.13–65.3, p = 0.55). conclusion: our study provides data on the largest series of hospitalised adults infected with hiv and co-infected with measles. more severe consequences seemed to occur in hospitalised hiv-positive patients. keywords: measles; adults; complications; human immunodeficiency virus; infectious diseases. introduction measles is one of the most contagious of all human viruses,1 and infects approximately 10 million people annually, with an estimated mortality of 134 200 in 2015, occurring mainly in developing countries.2 although it is historically a childhood illness,1 reports have highlighted an increasing frequency of measles occurring in young adults.3,4,5,6 with the incorporation of measles vaccination into routine childhood vaccination programmes, there has been a ‘shift of disease burden’. it now occurs more commonly in older patients who missed vaccination as children.7,8 in addition, protection induced by the measles vaccine also seems to wane over a period of years (secondary vaccine failure), with the length of protection having been estimated to be approximately 25 years.9 factors affirming the theory that the hiv epidemic may enhance dissemination of measles include the high rates of primary and secondary measles vaccine failure in hiv-infected persons,10,11,12,13,14 atypical presentations of measles resulting in delayed diagnosis in hiv-infected individuals,15,16 as well as the association of hiv infection with prolonged measles viral shedding and delayed clearance of the measles virus (mv).17 serious complications have been described in hiv-positive patients co-infected with measles.18,19,20,21,22,23 all studies comparing hiv-positive and hiv-negative patients infected with measles have been conducted in the paediatric population only. moss et al.24 reported hiv-positive children to have a longer duration of illness (p = 0.03), a longer hospital stay (p = 0.0004) and a higher mortality (p < 0.01). however, in a report by sension et al.25 from kinshasa, there were similar rates of pneumonia, diarrhoea and death in the hiv-positive and hiv-negative children. in south africa, there have been three studies comparing hiv-positive and hiv-negative children infected with measles. morrow et al.26 concluded that although hiv-infected patients were 1.6 times more likely to be hospitalised, there was no difference in death rate between the two groups. le roux et al.27 documented that the length of hospital admission was longer, the number of re-admissions was greater and the odds ratio (or) of death was seven times higher in the hiv-positive group. pamacheche et al.28 described the clinical profile of children admitted with measles to a teaching hospital in johannesburg. there were two deaths, both in children that were hiv-negative. between 2009 and 2011, an outbreak of measles occurred in south africa that resulted in 18 431 laboratory-confirmed cases being reported to the national institute of communicable diseases of the national health laboratory service.29 during this outbreak, a number of cases were admitted to the adult infectious diseases ward at the charlotte maxeke johannesburg academic hospital (cmjah) in johannesburg and this afforded us the opportunity to describe the clinical features and outcome of adult patients with measles comparing the hiv-positive and hiv-negative cases. methods this was a retrospective record review of adult patients with confirmed measles, who were admitted to the infectious diseases unit (idu) at the cmjah during the peak of the 2009 and 2011 south african measles outbreak. the majority of cases occurred from week 37 in 2009 to week 24 in 2010. the study period was 29 september 2009 to 31 march 2010. the data collected included all available demographic and clinical features and laboratory parameters. patients with clinical features suggestive of measles were confirmed to have measles by serological testing, using the enzygnost anti-measles virus/igm assay (dade-behring, marburg, germany). hiv testing, using a chemiluminescent microparticle immunoassay for the simultaneous qualitative detection of hiv p24 antigen and antibodies to hiv type 1 and/ or type 2 (architect hivab/ag combo calibrator, abbott laboratories, wiesbaden, germany), was offered to all confirmed measles cases. the clinical characteristics and outcomes of these patients were compared in hiv-positive and hiv-negative cases. outcome measures were length of hospital stay, complications and mortality. the hiv-infected and hiv-uninfected groups were compared using the mann–whitney u test for continuous variables, and the fisher’s exact (two-tailed) test for categorical variables. analyses were done using graphpad instat version 3. a p-value < 0.05 was considered to be statistically significant. ethical consideration permission to conduct the study was obtained from the human research ethics committee of the university of witwatersrand (clearance certificate no. m10104). results a total of 51 adult patients with suspected measles were admitted to the idu of cmjah between 29 september 2009 and 31 march 2010. thirty-three (64.7%) of these patients were confirmed to have measles by serology. in 12 patients (23.5%), measles serology was negative and six patients (11.8%) were not tested. of the 33 patients confirmed to have measles by serology, 24 (72.7%) consented to a test for hiv infection. these 24 patients were studied further. figure 1 shows the study population included in this analysis. figure 1: flow diagram of the study patients. of the 24 patients, 13 were female and 11 were male. the mean (standard deviation) age of the hiv-positive group was 28.1 (5.6) years and of the hiv-negative group was 29.6 (9.0) years. of the 24 patients, 18 patients (12 females) tested seropositive for hiv infection. of the entire group, only one hiv-positive patient reported a measles contact and two patients in the hiv-positive cohort remembered previously being vaccinated against measles as a child. presenting features and examination findings are depicted in tables 1 and 2. there were no significant differences between the two patient groups. the median duration of symptoms was 4 days (range: 1–7 days) in the hiv-positive group and 3 days (range: 3–6 days) in the hiv-negative group. table 1: presenting symptoms in 24 adult patients with measles: comparison of hiv-positive and hiv-negative cases. table 2a: examination findings in 24 adult patients with measles: comparison of hiv-positive and hiv-negative cases. table 2b: examination findings in 24 adult patients with measles: comparison of hiv-positive and hiv-negative cases. laboratory investigations also revealed no significant differences between the two groups (table 3). in the hiv-positive group, the median cd4 count was 109 cells/mm³ (range: 18–599 cells/mm³) (16 patients had data), the hiv viral load (vl) was available for seven patients (with a median of 15 000 copies/ml) and three patients had a vl lower than the detectable limit. eight patients (44.4%) were newly diagnosed with hiv infection on this presentation and four patients were already on highly active antiretroviral therapy. table 3: laboratory findings in 24 adult patients with measles: comparison of hiv-positive and hiv-negative cases. serious clinical manifestations were seen more frequently in hiv-positive than hiv-negative patients (or 5, 95% confidence interval [ci] 0.48–51.8, p = 0.34). one of the six patients testing hiv-negative developed pneumonia, while six of the 18 hiv-positive patients had a clinical course complicated by pneumonia (or 2.5, 95% ci 0.23–26.5, p = 0.63). five of these hiv-positive patients required admission to the intensive care unit or high care unit, three developing respiratory failure necessitating mechanical ventilation. these three patients also developed acute kidney injury. hiv-positive patients had several other manifestations, including purulent conjunctivitis, pancreatitis and encephalitis (table 4). table 4: complications in 24 adult patients with measles: comparison of hiv-positive and hiv-negative cases. hiv-positive patients had a significantly longer hospital stay (p = 0.03). there were three deaths in the hiv-positive group, but none in the hiv-negative group. the or of death was 2.9 times higher in the hiv-positive group (or 2.9, 95% ci 0.13–65.3, p = 0.55). discussion in this study, there were no differences in demographic, clinical and laboratory parameters when comparing the hiv-positive and hiv-negative groups. there was a tendency for complications to be more common in the hiv-positive group; however, the only significant difference was a longer length of hospital stay. over the 6-month period, 51 adult patients were admitted with suspected mv infection. despite having clinical features suggestive of mv infection, 12 (23.5%) patients had negative mv serology. negative serological testing may be attributed to possible laboratory error, to patients not having mounted an adequate immune response because of underlying immunocompromise or to undetectable antibody levels within the first 72 h of the exanthem appearing.30 of the 13 females who consented to hiv serological testing, 12 tested hiv-positive. there were twice as many females as males in the subgroup infected with hiv. this may reflect the burden of hiv infection among women in the south african population.31 in 2012, the estimated adult (15–49 years) prevalence rate of hiv and/or aids in south africa was 18.8%.31 however, in our study the prevalence of hiv-positivity was 18 of 24 patients (75%). this higher rate of hiv infection among our measles cases may be the result of hiv-infected patients being at increased risk of acquiring measles and requiring hospitalisation26; firstly because hiv-induced immune deficiencies are compounded with the immune-suppressive effect of the mv and secondly because of an inferior response to measles vaccination.10,11,32,33,34,35 presenting symptoms, findings on clinical examination and laboratory results revealed no significant differences between the hiv-infected and hiv-uninfected subgroups. all of the patients infected with hiv presented with features typical of mv infection, including the occurrence of a morbilliform rash. this contrasts with published data documenting atypical findings in hiv-infected patients.15,16 furthermore, this is also despite the median cd4 cell count of 109 cells/mm³ in the hiv-infected subgroup, suggesting advanced retroviral disease and immunosuppression. measles is typically a self-limiting illness, but individuals who are immunocompromised are at increased risk of severe disease.24 this was mirrored in our study as half of the hiv-infected adults in our cohort developed complications related to mv infection, as compared to only one patient in the hiv-uninfected subgroup (or = 5, 95% ci 0.48–51.8, p = 0.34). the length of hospital stay was significantly higher in the hiv-infected subgroup (p = 0.03). all three deaths recorded in our cohort occurred in the hiv-infected subgroup (or = 2.9, 95% ci 0.13–65.3, p = 0.55), resulting in a case fatality rate of 16.7% in this group. possible limitations of this study include the following. firstly, there were small patient numbers and this may have limited our ability to show statistical significance in some of the endpoints. secondly, it was a retrospective study and so the datasets were not complete. thirdly, we included only patients confirmed to have measles on serological testing, thus excluding 12 cases with clinical features of measles that tested negative for measles by serology and which may have represented false-negative cases because of hiv co-infection with deficient antibody synthesis. fourthly, only patients with more severe disease were included as they were hospitalised patients. lastly, the cases were all from a single centre, and therefore the results may not be generalisable. however, our study provides data on the largest series of hospitalised adults infected with hiv and co-infected with measles. unlike other published literature, we were also able to provide a comparison of adult patients infected and uninfected with hiv, within the same cohort. conclusion our findings confirm that mv is still an important cause of morbidity and mortality, even among adult patients. co-infection with hiv may be associated with worse outcomes. future studies with larger patient numbers may substantiate this conclusion. hiv testing should be carried out in all adults with suspected mv infection. ‘mop-up’ vaccination campaigns should perhaps also target adults infected with hiv with the aim of attaining protective antibody levels and reducing the risk of developing disease. acknowledgements competing interests the authors have no conflict of interests. authors’ contributions n.e.d. conducted the study and wrote the manuscript. c.f. supervised the study and reviewed the manuscript. all authors have read and approved the final manuscript. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views expressed in the article are those of the authors and not an official position of the institution or funder. references babbott jr fl, gordon je. modern measles. am j med sci. 1954;228(3):334–361. https://doi.org/10.1097/00000441-195409000-00013 who/unicef. who/unicef joint annual measles report, 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https://doi.org/10.1093/infdis/158.2.480 kaplan lj, daum rs, smaron m, mccarthy ca. severe measles in immunocompromised patients. jama. 1992;267(9):1237–1241. https://doi.org/10.1001/jama.267.9.1237 permar sr, moss wj, ryon jj, et al. prolonged measles virus shedding in human immunodeficiency virus-infected children, detected by reverse transcriptase-polymerase chain reaction. j infect dis. 2001;183(4):532–538. https://doi.org/10.1086/318533 nadel s, mcgann k, hodinka rl, russtein r, chatten j. measles giant cell pneumonia in a child with human immunodefiency virus infection. pediatr infect dis j. 1991;10(7):542–544. https://doi.org/10.1097/00006454-199107000-00014 okamura a, itakura o, yoshioka m, kubota m, kikuta h, kobayashi k. unusual presentation of giant cell pneumonitis in a patient with acquired immunodeficiency syndrome. clin infect dis. 2001;32(3):e57–e58. https://doi.org/10.1086/318499 koppel bs, poon tp, khandji a, pavlakis sg, pedley ta. subacute sclerosing panencephalitis 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[cited november 2014]. available from: http://wiredspace.wits.ac.za/handle/10539/14305 ntshoe gm, mcanerney jm, archer bn, et al. measles outbreak in south africa: epidemiology of laboratory confirmed cases and assessment of intervention, 2009–2011. plos one. 2013:8(2):e55682. https://doi.org/10.1371/journal.pone.0055682 helfand rf, kebede s, mercader s, gary he jr, beyene h, bellini wj. the effect of timing of sample collection on the detection of measles-specific igm in serum and oral fluid samples after primary measles vaccination. epidemiol infect. 1999;123(3):451–456. https://doi.org/10.1017/s0950268899002988 simbayi lc, shisana o, rehle t, et al. south african national hiv prevalence, incidence and behaviour survey, 2012. cape town: hsrc press; 2014. kerdiles ym, sellin ci, druelle j, horvat b. immunosuppression caused by measles virus: role of viral proteins. rev med virol. 2006;16(1):49–63. https://doi.org/10.1002/rmv.486 griffin de. measles virus-induced suppression of immune responses. immunol rev. 2010;236(1):176–189. https://doi.org/10.1111/j.1600-065x.2010.00925.x avota e, gassert e, schneider-schaulies s. measles virus-induced immunosuppression: from effectors to mechanisms. med microbiol immunol. 2010;199(3):227–237. https://doi.org/10.1007/s00430-010-0152-3 arpadi sm, markowitz le, baughman al, et al. measles antibody in vaccinated human immunodeficiency virus type 1 infected children. pediatrics. 1996;97(5):653–657. hiv 921 revised parental presence within households and the impact of antiretroviral therapy in khayelitsha, cape town c jury, bbussci; n nattrass, dphil aids and society research unit, centre for social science research, university of cape town, cape town, south africa corresponding email: n nattrass (nicoli.nattrass@gmail.com) background. while household support is an important component of effective care and treatment in hiv/aids, there are few insights from southern africa into how household support arrangements change over time for patients starting antiretroviral therapy (art). objective. we hypothesised that patients initiating art are more likely to be living with family, especially their mothers, compared with the general population, but that over time these differences disappear. methods. a panel survey of art patients was matched by age, gender and education to a comparison sample drawn from adults in khayelitsha, cape town. results. the results show that there is a substantial potential burden of care on the families of patients starting art, particularly mothers, and that the use of art appears to reduce this burden over time. but, even after their health is restored, art patients are significantly less likely to have a resident sexual partner and more likely to be living in single-person households than their counterparts in the general population. s afr j hiv med 2013;14(2):70-74. doi:10.7196/sajhivmed.921 there is evidence that people living with hiv/aids (plwha) across sub-saharan africa rely on family members, especially parents, for ongoing care and support, particularly with the morbidity of advanced hiv disease. several studies have shown that terminally ill south african (sa) adults often return to the parental home to access care and support, primarily from their mothers.1-4 as haour-knipe5 points out, this is to be expected in many settings where extended family serves as the ‘primary social safety net’. a ugandan study found that elderly parents, especially mothers, were the main caregivers for plwha6 and similar dynamics have been reported in thailand.7 however, there are few studies exploring whether reliance on family and parental support changes after initiation of antiretroviral therapy (art). what sets southern africa – and especially sa – apart is the generally lower presence of fathers in households and the importance of ‘uterine kin’ (mothers, grandmothers and sisters) in providing social stability and care when necessary.8-10 this is a consequence of sa’s history of oscillating migration and apartheid, which separated families geographically, often for long periods of time. but, it is also a consequence of declining rates of marriage, to the point that it is no longer the norm.11 hunter argues that the rise of unemployment was the key factor behind this, as only the relatively well-off african men could afford to pay 'ilobolo' (bridewealth) or act as reliable providers for their families.12-14 under these circumstances, women become incentivised to form looser connections with men (sometimes several men) and closer bonds with siblings and mothers. the phenomenon of the ‘absent father’ has been well documented in sa.15-17 what this means in terms of the supporting role of fathers, however, is unclear. according to morrel and richter,15 paternal absence implies a lack of fatherly support for children’s care. however, other research emphasises how fathers can and often do maintain meaningful contact with children, even when they do not reside in the household,8 and that their role in providing care when they are in the household often goes unreported.18 , 19 we investigated aspects of living arrangements for art patients over time, at the time of art initiation and subsequently, and compared this with the living arrangements of people of similar age, gender and education in the general population of residents of khayelitsha, cape town. methods khayelitsha is a peri-urban settlement comprising about half a million predominantly xhosa-speaking residents. almost half of the working-age adults are without jobs and over a quarter of pregnant women are hiv-positive.20-22 between 2001 (when the first art pilot programme was established in khayelitsha) and 2008, more than 10 000 people were successfully initiated on art with over 93% retained in care.23 in 2004, 242 patients receiving art in khayelitsha were recruited into a panel study conducted by the aids and society research unit of the university of cape town. respondents were recruited through social networks, clinic support groups and by word of mouth; hence, the sample cannot be regarded as strictly representative. however, as two-thirds of the starting art cohort was recruited into the study, the sample can be regarded as broadly representative of the experience of the early art patients.24 the first round of the survey (wave 1) was conducted in 2004 and a second wave in 2006. retrospective questions were posed to respondents regarding their households and health at the time that they started art, thereby allowing us to construct a retrospective ‘wave 0’ (i.e. at the time of art initiation, when they were sick with aids) for all respondents. the panel study allowed examination of the changes in household characteristics of art patients over time, but we also needed to know how this compared with households in the general population. we therefore constructed a ‘quasi control’ dataset drawn from a survey of khayelitsha residents (which can be regarded as representative of adult african khayelitsha residents29 ), conducted in parallel with the art panel study. from this dataset we drew a sub-sample of 202 respondents matched (using a probit regression) by age, gender and education to respondents in the art sample. ethics approval for the studies was obtained from the ethics committee of the centre for social science research, in line with the ethics approval process of the university of cape town. results within the art panel study, loss to follow-up was 16% (of the 242 respondents interviewed in 2004, only 202 were present for all subsequent interviews). older respondents in wave 1 were more likely to be lost to follow-up (table 1), but the effect was small (for each additional year of age, the probability of loss to follow-up rose by 4%). those without jobs were more likely to be lost to follow-up (being employed cut the probability of loss to follow-up by one-half), but once controls were implemented for household income and other household characteristics, the effect of being employed became statistically insignificant. having a resident sexual partner reduced the probability of attrition, but this effect also became statistically insignificant once controls were implemented for other factors. in multivariate analysis, there were no systematic differences in socio-economic and demographic characteristics between those lost to follow-up and those retained in care, other than small differences in age. furthermore, the explanatory power of the regression models remained low in all specifications. the matching process resulted in a matched and balanced panel dataset of art patients and khayelitsha respondents, with almost identical average age, gender and educational profiles (table 2). respondents were asked to rank on a 10-point scale (with 10 being the best health that they had ever experienced) their current health status as well as their recollections of their health at the time that they initiated art, and three and six months later. the mean score for perceived health rose from 2.8 (standard deviation (sd) ±2.2) at art initiation to 5.3 (sd ±2.0) three months later and 7.8 (sd ±1.7) six months later – an increase in line with improvements in clinical markers (e.g. cd4 cell counts) and quality-of-life indicators found in other studies of the same khayelitsha cohort.20 , 25-28 given the potential for art to restore health and independence, we expected the art rollout to result in changes in household characteristics, especially involving mothers and sisters. accordingly, we hypothesised that mothers and sisters were more likely to be present in the households of patients initiating art. we found that maternal presence in the household decreased significantly from 31% to 19% between wave 0 (art initiation) and wave 2 (table 3). indeed, by wave 2, there was no significant difference between maternal presence in art-patient households and those of the matched khayelitsha residents. the trend was similar and statistically significant also for households with no mother but with a sister present. an analysis of changes in paternal presence are reported in table 3. we found that fathers were generally less present than mothers, in both the art and matched khayelitsha samples. however, as was the case with maternal presence, fathers were significantly more likely to be present in the household when art respondents were sick with aids, rather than later. whether fathers were actively playing any caring or supportive role could not be ascertained from the data. there was a statistically significant increase between wave 0 and wave 2 in the number of art respondents who were themselves household heads (table 4). more than half of the respondents in the art sample were household heads by wave 2. in addition, we examined changes in reported sexual partnerships over time, comparing art patients with the general population. there was indeed a statistically significant increase in the number of art patients with resident sexual partners (table 5), but this remained significantly lower than for the matched khayelitsha sample.  discussion we employed an innovative methodology to compare trends in a panel study of art patients in khayelitsha with a matched sample drawn from the local population. we confirmed the pattern found in the existing literature that people with aids rely on kin, especially mothers, for care and support.2-5 , 9 a limitation of our study was that we could not ascertain whether it was the patient or the caregiver that moved households. even so, we were able to establish that art patients were more likely to be living in parent-headed households when they initiated treatment than they were after their health had been restored by art. this implies that significant numbers had returned to the parental home to receive care when they were sick with aids. our study goes beyond the existing literature on the relationship between aids and household structure, by showing that art reverses the burden of care on kin. our analysis showed that by wave 2, i.e. when art patients had been stabilised on treatment, the art sample and the matched khayelitsha sample were indistinguishable with regard to the presence of mothers and sisters and parent-headed households. the shift in living arrangements away from parent-headed households and the declining presence of uterine kin is strongly indicative of the effect of art on restoring health and independence for young adults living with hiv. fathers were less present than mothers (consistent with the broader socio-economic literature11 , 12-17 ), but even so, art patients were more likely to be living in households with a father present when they were sick with aids than they were once their health had been restored. it is possible that all or some of these fathers were providing the kind of care and support found in other studies,8 , 18 , 19 but our data do not speak to this issue. there is some evidence to suggest that hiv stigma, rather than falling as a result of the art rollout, may well have risen in cape town in the earlyto mid-2000s. using data from the cape area panel study of young adults, maughan-brown31 found that aids stigma increased in the african population between 2003 and 2006 and that fear of infection was the key driver. we therefore hypothesised that the presence of sexual partners in the households of art patients was likely to have increased over time as health was restored, but in the context of ongoing aids stigma and fear of infection, art patients were probably less likely than their counterparts in the general population to be living with a sexual partner. this hypothesis was supported by the data. these results are consistent with what we know about the potential for art to restore health and promote greater independence for plwha. however, there may also have been push factors at work – notably, some art patients may have been forced/encouraged to leave by other household members once they were able to take care of themselves. the fact that there were statistically significantly more single-person households in wave 2 (compared with wave 0 of the art sample, and wave 2 of the khayelitsha sample) is consistent both with art patients exercising greater independence and potentially experiencing persistent stigma and subsequent social isolation. we found that the number of art patients with sexual partners rose over time, but compared with the matched comparison sample, art patients were more likely to be living alone and without sexual partners, even after their health had been restored. this is suggestive of the continued existence of stigma against plwha. medical professionals should remain alert to the possibility that stigma may be affecting some of their patients, especially those living alone, and that they may be suffering from social marginalisation. acknowledgements. we acknowledge celeste coetzee and takwanisa machemedze for help in drawing the matched and balanced sample. references 1. bachmann m, booysen f. economic causes and effects of aids in south african households. aids 2006;20:1861-1867. 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[http://dx.doi.org/10.1016/s0277-9536(02)00361-1] 8. denis p, ntsimane r. absent fathers: why do men not feature in stories of families affected by hiv/aids in kwazulu-natal? in: morrel r, richter l, eds. baba: men and fatherhood in south africa. cape town: human sciences research council, 2006:237-249. 8. denis p, ntsimane r. absent fathers: why do men not feature in stories of families affected by hiv/aids in kwazulu-natal? in: morrel r, richter l, eds. baba: men and fatherhood in south africa. cape town: human sciences research council, 2006:237-249. 9. harper s, seekings j. claims on and obligations to kin in cape town, south africa. cssr working paper no. 272. cape town: centre for social science research and university of cape town, 2010. http://www.cssr.uct.ac.za/publications/working-paper/2010/claims-and-obligations-kin-cape-town-south (accessed 1 april 2013). 9. harper s, seekings j. claims on and obligations to kin in cape town, south africa. cssr working paper no. 272. cape town: centre for social science research and university of cape town, 2010. http://www.cssr.uct.ac.za/publications/working-paper/2010/claims-and-obligations-kin-cape-town-south (accessed 1 april 2013). 10. preston whyte e. families without marriage: a zulu case study. in: argyle j, preston whyte e, eds. social system and tradition in southern africa. cape town, oxford university press, 1978:55-83. 10. preston whyte e. families without marriage: a zulu case study. in: argyle j, preston whyte e, eds. social system and tradition in southern africa. cape town, oxford university press, 1978:55-83. 11. seekings j. measuring the gendered consequences of aids: householding and poverty in south africa. in: klot j, nguyen v, eds. the fourth wave: an assault on women. gender, culture and hiv in the 21st century. new york: ssrc and geneva: unesco, 2011:423-443. 11. seekings j. measuring the gendered consequences of aids: householding and poverty in south africa. in: klot j, nguyen v, eds. the fourth wave: an assault on women. gender, culture and hiv in the 21st century. new york: ssrc and geneva: unesco, 2011:423-443. 12. hunter m. fathers without ‘amandla’: zulu speaking men and fatherhood. in: morrel r, richter l, eds. baba: men and fatherhood in south africa. cape town: human sciences research council, 2006:99-107. 12. hunter m. fathers without ‘amandla’: zulu speaking men and fatherhood. in: morrel r, richter l, eds. baba: men and fatherhood in south africa. cape town: human sciences research council, 2006:99-107. 13. hunter m. the changing political economy of sex in south africa: the significance of unemployment and inequalities to the scale of the aids pandemic. soc sci med 2007;64:689-700. 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[http://dx.doi.org/10.1186/1758-2652-13-s2-s5] 18. hosegood v, madhavan s. data availability on men’s involvement in families in sub-saharan africa to inform family-centred programmes for children affected by hiv and aids. j int aids soc 2010;13(s2/s5):s2-s5. [http://dx.doi.org/10.1186/1758-2652-13-s2-s5] 19. montgomery c, hosegood v, busza j, timaeus i. men's involvement in the south african family: engendering change in the aids era. soc sci med 2006;62(10):2411-2419. 19. montgomery c, hosegood v, busza j, timaeus i. men's involvement in the south african family: engendering change in the aids era. soc sci med 2006;62(10):2411-2419. 20. boulle a, van cutsem g, hilderbrand k, et al. seven-year experience of a primary care antiretroviral treatment programme in khayelitsha, south africa. aids 2010;24(4):563-572. 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[http://dx.doi.org//10.1016/j.socscimed.2009.09.041] hiv 978 book review ‘fash – focused assessment with sonography for hiv/tb – a practical manual’ by tom heller. london, uk: teaching-aids at low cost (talc), 2013. isbn: 978-0-9558811-8-3. the emergence of high quality, yet affordable portable ultrasound devices during the past decade has brought the ultrasound examination out of imaging services to the patients’ bedside. point-of-care (poc) ultrasound is increasingly practised throughout various medical disciplines. simplified and targeted ultrasound protocols, applied by the attending clinician or medical staff, allow instantaneous assessment of clinically relevant questions. time to diagnosis can be shortened, referrals can be avoided, and resources can be saved. poc ultrasound requires little training and is a safe and effective tool, with particular value for resource-limited settings where imaging modalities are often restricted. extra-pulmonary tuberculosis (eptb) is common in hiv-infected individuals, but diagnosis is a challenge, especially where access to adequate imaging diagnostics is limited. the value of ultrasound for diagnosing eptb has long been recognised, but its availability in primary care settings, where most hiv/tb-infected patients are seen, often remains restricted by the absence of appropriate equipment and/or radiological expertise. in 2010, infectious diseases physician and ultrasound expert, tom heller, developed 'focused assessment with sonography for hiv/tb (fash)' as a poc ultrasound protocol to improve the diagnosis of eptb in hiv-positive patients. it evolved on the basis of multiple years of experience in a rural district hospital in hlabisa, south africa. fash was a success thereafter: throughout the world, and especially in southern africa, fash was taught in short courses for practitioners working in the field. by now, heller’s method is an integral part of the emergency poc ultrasound curriculum for emergency medicine trainees in south africa and one of the most frequently taught modules in the country. the practical manual, fash – focused assessment with sonography for hiv/tb, comprises 84 pages and includes a cd. the book is organised in 13 chapters. the first three encompass a concise introduction to poc ultrasound, the hiv/tb pandemic, as well as the basics of ultrasound physics and ultrasound anatomy of the abdomen. seven core chapters address the bedside ultrasound evaluation of the main areas of interest in the context of hiv and tb: effusions, lymphadenopathy, spleen, liver, chest, eptb and the heart. three final chapters deal with other hiv-related pathologies, deep vein thrombosis and interventional ultrasound. chapters are well structured, allowing easy orientation through the sections of anatomy, normal ultrasound findings, pathophysiology of hiv/tb, differential diagnoses, diagnostic tests, clinical implications, tips and pitfalls, and references for further reading. all chapters are illustrated with ultrasound images that include probe positions, corresponding x-ray, computed tomography and/or magnetic resonance imaging findings, and coloured schematics to simplify learning. besides a digital copy of the manual, the cd provides video clips of both normal anatomy and pathological findings. the latter is a particularly useful addition for learners, as visual memory is the most helpful aid at the bedside. in summary, this low-cost manual is a comprehensive guide for practitioners in the field, providing very helpful instruction on bedside ultrasound evaluation even beyond the context of hiv/tb. applying fash on an everyday basis in the hospital, i wish to encourage practitioners to adopt ‘the concept of ultrasound as the stethoscope of the 21st century’. the manual will be a very useful companion! s bélard, md, msc, dtm&h institute of infectious disease and molecular medicine faculty of health sciences, uni­versity of cape town south africa sabine.belard@uct.ac.za hivmed_19(1)_2018_contents.indd http://www.sajhivmed.org.za open access table of contents i original research ‘scared of going to the clinic’: contextualising healthcare access for men who have sex with men, female sex workers and people who use drugs in two south african cities zoe duby, busisiwe nkosi, andrew scheibe, ben brown, linda-gail bekker southern african journal of hiv medicine | vol 19, no 1 | a701 | 19 january 2018 original research risky sexual behaviour and human immunodeficiency virus (hiv) and acquired immune deficiency syndrome (aids) among healthcare workers natasha khamisa, maboe mokgobi southern african journal of hiv medicine | vol 19, no 1 | a744 | 26 january 2018 original research modelling the human immunodeficiency virus (hiv) epidemic: a review of the substance and role of models in south africa nathan geffen, alex welte southern african journal of hiv medicine | vol 19, no 1 | a756 | 21 february 2018 original research similar hiv protection from four weeks of zidovudine versus nevirapine prophylaxis among formula-fed infants in botswana kathleen m. powis, shahin lockman, gbolahan ajibola, michael d. hughes, kara bennett, jean leidner, oganne batlang, kerapetse botebele, sikhulile moyo, erik van widenfelt, joseph makhema, chipo petlo, haruna b. jibril, kenneth mcintosh, max essex, roger l. shapiro southern african journal of hiv medicine | vol 19, no 1 | a751 | 28 march 2018 original research completeness of the road-to-health booklet and road-to-health card: results of cross-sectional surveillance at a provincial tertiary hospital harishia naidoo, theunis avenant, ameena goga southern african journal of hiv medicine | vol 19, no 1 | a765 | 10 april 2018 original research cognitive-behavioural theories and adherence: application and relevance in antiretroviral therapy adegoke o. adefolalu southern african journal of hiv medicine | vol 19, no 1 | a762 | 12 april 2018 original research the association between asymptomatic and mild neurocognitive impairment and adherence to antiretroviral therapy among people living with human immunodeficiency virus violet awori, peter mativo, gerald yonga, reena shah southern african journal of hiv medicine | vol 19, no 1 | a674 | 12 april 2018 original research risk factors and co-morbidities associated with changes in renal function among antiretroviral treatment-naïve adults in south africa: a chart review shirelle assaram, tivani p. mashamba-thompson, nombulelo p. magula southern african journal of hiv medicine | vol 19, no 1 | a770 | 12 april 2018 forum making ward-based outreach teams an effective component of human immunodeficiency virus programmes in south africa nireshni naidoo, jean railton, geoffrey jobson, nthabiseng matlakala, gert marincowitz, james a. mcintyre, helen struthers, remco p.h. peters southern african journal of hiv medicine | vol 19, no 1 | a778 | 12 april 2018 overview an overview of tenofovir and renal disease for the hiv-treating clinician willem d.f. venter, june fabian, charles feldman southern african journal of hiv medicine | vol 19, no 1 | a817 | 17 july 2018 opinion paper will the current national strategic plan enable south africa to end aids, tuberculosis and sexually transmitted infections by 2022? kathryn l. hopkins, tanya doherty, glenda e. gray southern african journal of hiv medicine | vol 19, no 1 | a796 | 04 october 2018 guidelines guidelines for the vaccination of hiv-infected adolescents and adults in south africa sipho k. dlamini, shabir a. madhi, rudzani muloiwa, anne von gottberg, mahomed-yunus s. moosa, susan t. meiring, charles s. wiysonge, eric hefer, muhangwi b. mulaudzi, james nuttall, michelle moorhouse, benjamin m. kagina southern african journal of hiv medicine | vol 19, no 1 | a839 | 23 may 2018 guidelines southern african hiv clinicians society guidance on the use of dolutegravir in first-line antiretroviral therapy michelle a. moorhouse, sergio carmona, natasha davies, sipho dlamini, cloete van vuuren, thandekile manzini, moeketsi mathe, yunus moosa, jennifer nash, jeremy nel, yoliswa pakade, joana woods, gert van zyl, francesca conradie, francois venter, graeme meintjes southern african journal of hiv medicine | vol 19, no 1 | a917 | 17 october 2018 guidelines appropriate clinical use of darunavir 800 mg michelle a. moorhouse, sergio carmona, natasha davies, sipho dlamini, cloete van vuuren, thandekile manzini, moeketsi mathe, yunus moosa, jennifer nash, jeremy nel, yoliswa pakade, joana woods, gert van zyl, francesca conradie, francois venter, graeme meintjes southern african journal of hiv medicine | vol 19, no 1 | a918 | 18 october 2018 guidelines guidelines to support hiv-affected individuals and couples to achieve pregnancy safely: update 2018 natasha e.c.g. davies, gail ashford, linda-gail bekker, nomathemba chandiwana, diane cooper, silker j. dyer, lauren jankelowitz, otty mhlongo, coceka n. mnyani, muhangwi b. mulaudzi, michelle moorhouse, landon myer, malika patel, melanie pleaner, tatiana ramos, helen rees, sheree schwartz, jenni smit, doreen s. van zyl southern african journal of hiv medicine | vol 19, no 1 | a915 | 18 october 2018 page i of ii table of contents i vol 19, no 1 (2018) issn: 1608-9693 (print) | issn: 2078-6751 (online)southern african journal of hiv medicine 1 59 67 72 87 93 103 110 120 7 15 21 29 31 33 http://www.sajhivmed.org.za open access table of contents ii original research barriers to hiv service utilisation by people living with hiv in two provinces of zimbabwe: results from 2016 baseline assessment taurayi a. tafuma, nyikadzino mahachi, chengetai dziwa, tafara moga, paul baloyi, gladys muyambo, auxilia muchedzi, tinashe chimbidzikai, getrude ncube, joseph murungu, tendai nyagura, katherine lew southern african journal of hiv medicine | vol 19, no 1 | a721 | 09 august 2018 original research the metabolic syndrome and renal function in an african cohort infected with human immunodeficiency virus edith phalane, carla m.t. fourie, aletta e. schutte southern african journal of hiv medicine | vol 19, no 1 | a813 | 20 september 2018 original research b-cell and t-cell activation in south african hiv-1-positive non-hodgkin’s lymphoma patients brian t. flepisi, patrick bouic, gerhard sissolak, bernd rosenkranz southern african journal of hiv medicine | vol 19, no 1 | a809 | 07 november 2018 original research prevalence and outcomes of central venous catheter-related bacteraemia in hiv-infected versus non-hiv-infected patients undergoing haemodialysis treatment for end-stage kidney disease nuria avila-danguillecourt, anand a. moodley, polycarpe makinga southern african journal of hiv medicine | vol 19, no 1 | a859 | 22 november 2018 original research sexual reproductive healthcare utilisation and hiv testing in an integrated adolescent youth centre clinic in cape town, south africa andrea s. mendelsohn, katherine gill, rebecca marcus, dante robbertze, claudine van de venter, eve mendel, landisiwe mzukwa, linda-gail bekker southern african journal of hiv medicine | vol 19, no 1 | a826 | 26 november 2018 original research human immunodeficiency virus infection and older adults: a retrospective single-site cohort study from johannesburg, south africa india butler, william macleod, pappie p. majuba, brent tipping southern african journal of hiv medicine | vol 19, no 1 | a838 | 29 november 2018 case report suicidal overdose of dolutegravir: a case report rahul daimari, lawrence kwape, anthony a. oyekunle southern african journal of hiv medicine | vol 19, no 1 | a799 | 18 june 2018 case report a case of a drug reaction to sulfasalazine in a patient infected with hiv leanne swart, elise schapkaitz, anima baiden southern african journal of hiv medicine | vol 19, no 1 | a829 | 03 december 2018 reviewer acknowledgement southern african journal of hiv medicine | vol 19, no 1 | a930 | 05 december 2018 original research the use of illustrated medication diaries to improve outcomes for children initiated on highly active antiretroviral therapy yashodhara kannigan, kevin b. spicer, fathima naby southern african journal of hiv medicine | vol 19, no 1 | a804 | 23 may 2018 original research evaluation of antenatal rapid human immunodeficiency virus testing in rural south africa tivani p. mashamba-thompson, pravi moodley, benn sartorius, paul k. drain southern african journal of hiv medicine | vol 19, no 1 | a771 | 23 may 2018 original research hiv care and treatment clinic performance following president’s emergency plan for aids relief-funded infrastructure improvement in tanzania boniphace m. idindili, simon j. king, kristen stolka, irene mashasi, philberth bashosho, happy karungula, florida chintowa, godfrey mwakabole, kimberly ashburn, barbara do, norman goco southern african journal of hiv medicine | vol 19, no 1 | a777 | 14 june 2018 original research human immunodeficiency virus infection predictors and genetic diversity of hepatitis b virus and hepatitis c virus co-infections among drug users in three major kenyan cities micah oyaro, john wylie, chien-yu chen, raphael o. ondondo, anna kramvis southern african journal of hiv medicine | vol 19, no 1 | a737 | 27 march 2018 original research hypertriglyceridaemia and the risk of pancreatitis six months post lopinavir/ritonavir initiation wilhelm p. greffrath, jesslee m. du plessis, michelle viljoen, marike cockeran southern african journal of hiv medicine | vol 19, no 1 | a766 | 26 june 2018 original research hiv retesting in pregnant women in south africa: outcomes of a quality improvement project targeting health systems’ weaknesses lauren m. golden, lee fairlie, freda might, stina mojela, dorothy motsamai, suzan motshepe, enoch manyame, craig parker, helen rees, gloria maimela, matthew f. chersich southern african journal of hiv medicine | vol 19, no 1 | a784 | 12 july 2018 original research implementing emergency department-based hiv testing in a low-resource setting: the value of a structured feasibility assessment tool madeleine whalen, pamela mda, andy parrish, thomas c. quinn, richard rothman, david stead, bhakti hansoti southern african journal of hiv medicine | vol 19, no 1 | a793 | 16 july 2018 original research development of a clinical prediction rule to diagnose pneumocystis jirovecii pneumonia in the world health organization’s algorithm for seriously ill hiv-infected patients gary maartens, annemie stewart, rulan griesel, andre p. kengne, felix dube, mark nicol, molebogeng x. rangaka, marc mendelson southern african journal of hiv medicine | vol 19, no 1 | a851 | 23 july 2018 page ii of ii 131 138 146 154 163 169 172 177 183 199 214 206 221 229 232 235 189 abstract introduction clinical data cut up ethical issues double pathology diagnostic challenges prognostic value the future conclusion acknowledgements about the author(s) carolina e. nel department of anatomical pathology, national health laboratory service, wits university, south africa citation nel ce. hiv and the histopathologist. s afr j hiv med. 2017;18(1), a680. https://doi.org/10.4102/sajhivmed.v18i1.680 opinion paper hiv and the histopathologist carolina e. nel received: 23 aug. 2016; accepted: 06 mar. 2017; published: 24 apr. 2017 copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract the practicing histopathologist is often a forgotten link in the management of hiv patients. this article aims to highlight the unique challenges faced by anatomical pathologists as well as focusing on the valuable contribution they can make to ensure prompt and accurate diagnoses that will ultimately benefit the patient. introduction as a practicing histopathologist working in the public sector, we are constantly exposed to cases where the patient is hiv-positive. often, pathologists are not seen as a crucial component in the treatment of the hiv-positive population. this opinion piece serves to highlight the crucial and important role of a histopathologist in the management of these patients as well as look at the challenges we face in our daily practice. clinical data the presence of an adequate clinical history cannot be stressed enough. the patient’s retroviral disease (rvd) status, antiretroviral (arv) status, cd4 count, viral load, drug history and presenting symptoms are crucial to provide a satisfying and useful pathology report. without these essential data, the assessment of the patient’s tissue cannot be optimal. histopathologists need to know the clinical status of the patient to render an accurate and reproducible report. an important aspect of this clinical history on the patient’s request form includes the provision of a clinical differential diagnosis. this information will guide the pathologist as to whether the clinical assessment of the pathology correlates with the pathological findings. an example of this is a clinical history of a possible pyogenic granuloma that is submitted for microscopic evaluation. the histological diagnosis of kaposi’s sarcoma by the pathologist would not be inconsistent with this clinical diagnosis, and the pathologist would be comfortable in authorising the report. another important aspect of a complete set of clinical data is the possibility of research that can be conducted in this sphere. academic research is essential to ensure improved management of the hiv-positive population. a complete set of clinical data will aid in providing clinically significant results. incomplete clinical information may hamper the impact that pathological findings may have in contributing to optimum treatment or management protocols. to have real clinical significance and impact, clinicians and pathologists should be embarking on prospective studies in our population as we are uniquely positioned in the public sector to provide guidance and academic data from which evidence-based medicine can be practiced. we should be providing the world with high-quality research material on hiv by collaborating with our clinical colleagues on a regular basis. cut up the discipline of anatomical pathology is a multi-step process with different individuals performing different tasks. the first contact with the specimen is in the laboratory during macroscopic assessment. the challenge for the anatomical pathologist, therefore, starts at the cut up of specimens where trainees, pathologists and laboratory staff are exposed to human tissue. the macroscopic evaluation of a specimen is an important adjunct to the assessment on the microscopic level. using knives and sharp equipment exposes laboratory staff to the virus. knowledge regarding the patient’s immune status becomes essential to ensure personal protective equipment is worn, and laboratory guidelines regarding potential infective agents are adhered to. providing the pathologist in the laboratory with the hiv status on the patient’s request form will alert them to look for specific hiv-related findings, for example, the presence or absence of caseous necrosis that can be observed macroscopically in lymph nodes or other organs. this finding can result in the immediate request of a ziehl–neelsen stain, which will speed up the diagnosis of tuberculosis. ethical issues should a pathologist raise the possibility of immunocompromise in his or her report if the patient’s hiv status is unknown? is it ethical not to mention this possibility? this is not a common scenario but becomes problematic as it may affect clinical decision-making and future management of the patient. personally, i feel that a histopathologist has a duty to the clinician and the patient to raise the issue of possible immunocompromise albeit not of hiv per se. this is where the histopathologist can assist in the multidisciplinary management of these patients. the role of a pathologist in the interdisciplinary meetings is of great value. double pathology in the era of hiv, the presence of double pathology has become a significant factor in our daily practice. the hiv-positive population are not just at risk of developing opportunistic infections but are also exposed to the usual risk factors of other malignancies and diseases of that specific gender and age group. often, the clinician is unsuspecting of double pathology, for example, lymphoma with a superimposed kaposi’s sarcoma or tuberculosis. this is not uncommon in our daily practice. diagnostic challenges the introduction of antiretroviral therapy (art) has changed not just the lives of clinicians but also those of the practicing histopathologist. this has resulted in a change in the pathology of diseases and evolution of infectious diseases. we have seen a significant increase in cases of syphilis, for example, which is a disease known to have a diverse clinical presentation. the explanation for this apparent increase may be twofold. the first is a higher index of suspicion for the infection from a diagnostic point of view. the second is the immune reconstitution inflammatory syndrome (iris) phenomenon that may unmask latent diseases including syphilis, tuberculosis and cryptococcosis. the availability of the immunohistochemical stain in the laboratory for routine detection of treponema pallidum organisms has contributed to the higher diagnostic yield of this disease. the histological presentation of syphilis remains non-specific, but a vigilant pathologist with a sharp clinician will result in an accurate diagnosis of this treatable infection. the diagnosis of many disease processes has been complicated by the hiv epidemic, but none as severe as its impact on haematolymphoid pathology. lymphomas driven by ebstein-barr virus (ebv) and human herpes virus-8 (hhv-8) are often difficult to classify adequately because of the deranged immune system in these patients. the grey zone between a reactive lymphoid population and a true haematolymphoid neoplasm has increased and remains a massive diagnostic challenge. prognostic value an important part of the management of the hiv-infected population is follow-up histology to assess the response to treatment or to assess disease progression. pathologists are in a unique position to assist clinicians in this regard. for instance, the persistence of squamous intra-epithelial lesions in the cervix is an example where pathologists can assist in decision-making regarding patient’s need for large loop excision of the transformation zone (lletz) procedures or hysterectomies. pathological findings are important not only from a diagnostic perspective but also from a prognostic point of view. histopathologists are able to provide essential information in a report regarding prognosis of a disease. assessment for bone marrow involvement is a useful tool used for staging purposes in many malignancies including lymphomas, carcinomas and other neoplasms such as small round blue cell tumours in children. an excellent example of prognostic value add in histopathology is the use of ki-67 (proliferation marker) in the assessment of lymphomas. a high proliferation index will indicate a more aggressive tumour with a possibly worse prognosis and resistance to standard chemotherapy. histologic grading of malignancies is also a function of the histopathologist which in turn has a direct impact on staging, prognosis and management protocols. the future pathologists in south africa are a crucial but often unrecognised part of the management team of the hiv population. we can add valuable research value in this area of hiv management and provide input with regard to disease progression, side effects of drugs and assist in diagnosis. the pathologist is often able to provide a quick and accurate provisional result in infective conditions long before culture results are available. antiretroviral therapy treatment has increased the life expectancy of hiv-positive patients. this has resulted in an emergence of a new spectrum of diseases not previously encountered in this population. a new era of paediatric hiv patients will also provide new challenges as certain disease processes have not been studied in this group. conclusion the histopathologist is perfectly positioned to assist in the management of both acute and chronic illnesses in the context of the hiv-infected patient. an accurate and detailed clinical history as well as a sound relationship with the treating clinician will go a long way in improving patient care. acknowledgements competing interests the author declares that she has no financial or personal relationships which may have inappropriately influenced her in writing this article. untitled j u n e 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e1 2 consent challenges no provision currently in operation sets out when children may provide their own independent consent to research. in the future, in terms of section 71 of the national health act (nha),2 consent for research participation will have to be obtained from a parent or legal guardian until the age of majority is reached. other caregivers or custodians will not have the authority to provide consent for child research. until 30 june 2007 minority ended at the age of 21.3 however, section 71 of the new children’s act4 was implemented on 1 july 2007 which lowered the age of majority to 18. a further complexity is that the nha provides that adolescents will consent with their parents if they have sufficient understanding. this means that researchers must anticipate how they will assess adolescent understanding to determine when adolescents possess the higher standard of competence required for consent. finally, in order for adolescent participation in these trials to be lawful in south africa, common law requirements must be met, namely, consent to such research must be legally permissible or in line with public policy.5 a key issue in making this determination is to establish if the research interventions pose acceptable standards of risk. ethical guidelines in south africa are approaching agreement on this issue – three out of four south african ethical guidelines6-8 assert that when the intervention or research does not hold out the prospect of direct benefit, the risk must be ‘minimal’ or ‘negligible’ (i.e. the risks of daily life or routine medical and psychological tests), although a minor increase over such risk is allowed. however, draft regulations9 are slightly more restrictive, i.e. they do not appear to permit non-beneficial research or interventions to exceed minimal risk, which is out of step with the majority of our guidelines. recs will have to make complex assessments about whether vaccine trial interventions meet acceptable risk standards in terms of our national framework. in addition, enrolling over-16-year-olds in an efficacy trial requiring them to be sexually active would not be contrary to public policy, given that sex over the age of 16 is lawful.10 privacy challenges adolescents in these trials will not consent independently to trial enrolment, but will be assisted by their parent or legal guardian. accordingly, a number of complex privacy issues must be managed. these include whether adolescents will enjoy confidentiality regarding their hiv status, sexually transmitted infection (sti) results, pregnancy test results and sexual risk information. unfortunately neither the current nor the future law deals directly with a child’s right to privacy in research. the lack of legal guidance means that the general legal principles relating to privacy must be applied to a research context to fill this vacuum. these principles provide r e s e a r c h a n d t h e l a w ethical-legal challenges in adolescent hiv vaccine trials catherine slack, ma clin psych hiv aids vaccines ethics group, university of kwazulu-natal, pietermaritzburg ann strode, llm mothokoa mamashela, llm faculty of law, university of kwazulu-natal south africa is likely to enrol adolescents into a phase iib proof of concept hiv vaccine trial in late 2007 or early 2008, which would make it the first country in the world to enrol adolescents into hiv vaccine trials. these healthy adolescents will be at high risk of hiv infection. they will have to undergo a general physical examination, answer questions about their personal hiv risk, be administered an experimental hiv vaccine or placebo via injection, have blood drawn for laboratory safety and immunogenicity testing, and have regular testing for hiv infection.1 many ethical/legal complexities exist, in part due to our fluctuating ethical-legal framework, the lack of legal guidance on issues such as adolescent privacy rights in research, and differing approaches towards child antonomy in child care and health legislation that enable children of a certain age to consent independently to medical treatment but not to research. against this backdrop, in 2005 a member of the uct research ethics committee (rec) initiated a process of research into the minimum legal requirements that need to be met to ensure that adolescent hiv vaccine trials are lawful. as a result, a unique collaboration was established between an ethics and law research unit, (the hiv/aids vaccines ethics group – haveg); members of the uct rec, and researchers at the desmond tutu hiv centre, cape town, and the perinatal hiv research unit, soweto. this collaboration resulted in the development of a roadmap of issues that ought to be addressed in order to promote the rights and welfare of adolescent participants in hiv vaccine trials, which was published in biomedical central: medical ethics in 2007.1 from november 2006 onwards, work began to apply these legal principles to a protocol for an adolescent hiv vaccine trial and its accompanying informed consent/assent forms. this article summarises the issues identified by this unique and on-going collaboration, published in an earlier article.1 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u n e 2 0 0 7 1 3 that the right to privacy only extends to those aspects of a person’s life that the person himor herself, as well as society, recognises should be kept private.11 this means that adolescents will have the right to privacy for sti results (for example) if it can be shown (i ) that they would expect these results to be private, and (ii ) that this is reasonable because they would have this right outside of the research context provided they were over the age of 14 and could consent independently to such tests. consent forms will need to delineate the boundaries of adolescent privacy rights. mandatory reporting challenges south african children often live with high levels of violence, poverty and abuse. the law has responded by providing special protections for children who may be facing abuse, illtreatment or neglect. the child care act requires medical practitioners, among others, to report suspected ill-treatment, abuse or neglect of children to the department of social development.12 failure to report is a criminal offence. additionally, the family violence act13 states that any person who examines, treats, attends to, advises, instructs or cares for any child, and suspects that the child has been ill-treated, must report this to a commissioner of child welfare, a social worker or the police. the future children’s act4 obliges any person to identify children in need of care and protection (e.g. living in a child-headed household, required to perform child labour, being maltreated, abused, or exploited) and to refer these to a social worker.1 site staff would have a legal duty to report abuse or ill-treatment disclosed by an adolescent in a trial. this means they would have to recognise when disclosures trigger a mandatory reporting response. consent procedures will have to inform parents and adolescents about this limit to confidentiality.1 approval challenges approval challenges relate primarily to (i ) the circumstances in which recs would regard such trials as ethical, and (ii ) the data that will be required by the medicines control council (mcc) before approving such research. regarding recs, the nha (section 73) sets out the current legal obligations of recs. it provides that recs must approve research where it meets the ethical standards of the committee. recs that will review adolescent hiv vaccine trial protocols will have to network with each other to build consensus about adolescent trials. in addition, they will have to debate their role in relation to establishing lawfulness, given that their primary brief is to ensure that protocols are ethical and they may already be burdened. in many cases, recs that comply with the principles set out in ethical guidelines may be simultaneously abiding by legal values, and researchers who craft their protocols with thoughtful attention to ethical guidelines may meet most, if not all, of the legal requirements. where the law is unclear, researchers should consult with their rec or get legal advice from a lawyer trained in research ethics and law.1 with regard to the mcc, in terms of the regulations on the control and conduct of clinical trials, all trials must be conducted in accordance with good clinical practice guidelines.14 the mcc has also prepared a set of guidelines for phase i trial applications.15 however, they have not issued any guidance on adolescents. they should be requested to articulate the data they will require, firstly to allow adolescents into trials and secondly to license an adolescent vaccine. finally, if such trials are classed as ‘non-therapeutic’, when section 71 of the nha is implemented, ‘non-therapeutic’ research on minors may not be done without first obtaining consent from the minister of health. this requirement has a number of ambiguities, including which research falls into its scope, and its place in the sequence of approvals.16 this detail is also not provided in the draft regulations.9 south african researchers will have to anticipate the public policy assessment that the minister will have to undertake by framing their protocols in a way that assists the minister, or a delegated authority, to make a speedy determination. they can do this by explicitly addressing the four factors the minister must consider in terms of the act when deciding whether to authorise such trials. conclusions this collaboration between researchers and law/ethics advisors has facilitated research into the minimum legal requirements for lawful research with adolescents, and consideration of how to apply these requirements in a way that facilitates research and protects participants’ rights. it has identified that south african investigators and recs will have to deal with: (i ) consent challenges (e.g. who must consent? what can be consented to?); (ii ) privacy challenges (determining the boundaries of adolescent privacy rights for sti, hiv and other test results); (iii ) challenges around obligations to protect children from abuse and maltreatment (e.g. responding to disclosures by adolescents that they have been raped); and (iv ) procedural challenges (e.g. need for guidance from the mcc and the impending ‘ministerial consent’ requirement). additional networking, tool development and training processes are needed to make sound adolescent trials a reality. references 1. slack c, strode a, fleisher t, ranchod c, gray g. enrolling adolescents in hiv vaccine trials: reflections on legal complexities from south africa. bmc medical ethics 2007; 8: 5. 2. national health act no. 61 of 2003. government gazette no. 27503, 18 april 2005. 3. age of majority act 1972, no. 57. 4. children’s act 2005, no. 38. http://ci.org.za/depts/ci/plr/pdf/bills/childrensact 38-2005.pdf 5. strode a, slack c, grant k, mushariwa m: ethical and legal challenges in enrolling adolescents in medical research in south africa: implications for hiv vaccine trials. s afr j sci 2005; 101: 224-228. 6. department of health. ethics in health research: principles, structures and processes. pretoria: doh, 2004 7. south african medical research council. guidelines on ethics of medical research: hiv preventative vaccine trials. cape town 2003. http://www. sahealthinfo.org/ethics/ethicsbook5.pdf 8. department of health. guidelines for good practice in the conduct of clinical trials in human participants in south africa. pretoria: doh, 2000. 9. republic of south africa. regulations relating to research on human subjects. government gazette no. 8629, 23 february, 2007. regulation no. 29637, regulations 10-16. 10. sexual offences act 1957, no. 23. 11. directorate for serious economic offences v hyundai 2001 (1) sa 545 (cc). 12. child care act 1983, no. 74. 13. family violence act 1992, no. 133, s4. 14. regulations 34(4) no. r 510. government gazette no. 24727, 10 april 2003. 15. medicines control council. guide to completing a clinical trial application of hiv vaccine. pretoria: mcc, 2003. 16. strode a, slack c, wassenaar d, singh j. one step forward, two steps back: requiring ministerial approval for all ‘non-therapeutic’ health research with minors. s afr med j 2007; 97: 200-202. haveg is funded by the south african aids vaccine initiative (saavi). the views expressed here do not necessarily reflect the views of saavi. the southern african journal of hiv medicine                                                        summer 2009   29 the traditionally measured sexual behaviour risk factors are only able to explain some of the elevated hiv prevalence in southern/eastern africa. for example, the most comprehensive international study of differences in sexual practices around the world, based on demographic and health surveys and other data, concluded that men and women in sub-saharan africa typically have a similar or lower number of lifetime partners than do their heterosexual counterparts elsewhere.1 similarly, within africa the prevalence of risky behaviours was unable to explain the difference in hiv spread between western and eastern/southern africa.2 what then are the current explanations for the high hiv prevalence in southern/eastern africa? a recent joint inquiry by the southern african development community and unaids concluded that ‘high levels of multiple and concurrent sexual partnerships by men and women, with insufficient, correct condom use, combined with low levels of male circumcision are the key drivers of the epidemic in the (southern african) region’. the putative mechanisms for how concurrency could be such a driving force in hiv spread are outlined in box 1 and fig. 1. concurrency may be defined as sexual partnerships overlapping in time, when one partnership starts before another terminates. outside of sub-saharan africa, concurrency has been shown to play an important role in the spread of stis such as syphilis,3 gonorrhoea,4 chlamydia5 and hiv.6 however, within africa a sero-linked study found no link between concurrency rates and hiv transmission.7 numerous problems with this study have been raised (reviewed in mah8). there are ecological data to support the link between hiv and concurrency. a world health organization-conducted international comparative study found that concurrency rates were considerably higher in sub-saharan africa (18 55%) than in other third-world areas such as south asia (2 3%) which had lower hiv rates.9 very few studies of the prevalence and effects of concurrency in south africa have been done. a survey in rural kwazulu-natal found that 40% of sexually active men reported having had more than one partner in the past 3 months, and it was considered likely that many of these were concurrent.10 a study of 15 26-year-olds in the eastern cape found that 55% of young men had engaged in one or more concurrent relationships in the past.11 a household survey in khayelitsha, cape town, found that 29% of men and 8% of women in sexual relationships reported that they had been sexually involved with individuals from outside their regular relationship in the last 12 months. the cape area panel survey (caps) is one of the first surveys to collect detailed information on respondent and partner concurrency. a secondary data analysis of the the role of concurrent sexual relationships in the spread of sexually transmitted infections in young south africans original article chris kenyon, mb chb, ba (hons), mph, fcp division of infectious diseases and hiv medicine, department of medicine, university of cape town motasim badri, msc (med) department of medicine, university of cape town we still do not know why the hiv prevalence in southern and eastern africa is an order of magnitude higher than anywhere else in the world. an article in this journal in 2007 argued that a key determinant was not so much the lifetime numbers of sexual partnerships, but rather the high proportion of these partnerships that are arranged concurrently. concurrency has been associated with elevated rates of sexually transmitted infections (stis) elsewhere, but this relationship has never been demonstrated in an african setting, where its effect is proposed to be greatest. we conducted a secondary data analysis from a representative survey of 14 25-year-olds living in cape town to test the hypothesis that concurrency is associated with self-reported symptoms of an sti. on logistic multiple regression analysis we found a modest but statistically significant relationship between self-reported sti symptoms and having had a partner who engaged in concurrency. the role of.indd 29 3/16/09 2:13:34 pm summer 2009                                                          the southern african journal of hiv medicine                                                  30 caps dataset found that 38% of black females (versus 14% of other racial/ethnic groups) report that at least one current or previous partner definitely had another sexual relationship during their relationship. the corresponding figures for males are 28% for blacks and 10% for the others. turning to whether or not the respondent ever had two simultaneous sexual relationships, this was the case for 41% of black males, and 4% and 21% for white and coloured males, respectively (kenyon c et al. – unpublished data). caps is not an hiv-serolinked study, but it did collect information on whether or not the respondent had symptoms of an sti in the past 12 months. since there are numerous studies in africa (and elsewhere) showing that self-reported symptoms of genital discharge and ulcers are associated with hiv infection,12-14 we conducted a multivariate logistic regression analysis to test the hypothesis that concurrency is associated with sti symptoms. data and methods we analysed data from the caps dataset to determine the distribution, prevalence and correlates of symptoms of stis. caps is a representative longitudinal study of adolescents aged 14 22 living in cape town;15 4 752 adolescents were interviewed in the first wave in 2002 and in the second wave in 2004. in the third wave, conducted in 2005, 3 324 of the initial 4 752 individuals were re-interviewed. all of our analyses are weighted with sampling weights correcting for sample design and appropriate wave non-response. applying these weights, coloureds comprised 59% of the total wave 1 sample, blacks 15% and whites 26%. as seen in table i, the attrition rates between 2002 and 2005 were considerably higher for whites (53%) than for blacks (36%) and coloureds (21%). the lower response rate for whites is typical of survey results in south africa.12 participants were interviewed about their socio-demographic, education, employment, health ailments and sexual behaviour histories. unfortunately questions pertaining to previous sti symptoms were only asked in wave 1 (2002) and detailed sexual behaviour histories were only investigated in wave 3 (2005). the analyses presented here were restricted to all persons who were sexually active in wave 1 and completed the wave 3 questionnaire – a total of 1 482 respondents. we examined the association of sti symptoms with various socio-demographic and sexual behaviour variables which we chose on the basis of our conceptual framework for understanding the spread of stis (fig. 3). the socio-demographic variables included age, educational attainment, wealth quintile, ethnic/race group, alcohol consumption in the last month, knowledge about sti prevention strategies, marital status and general mental state. the sexual behaviours evaluated were age at first sexual intercourse, lifetime number of sexual partners, an age gap of 4 or more years between sexual partners, condom use at last sex, ever pregnant, and partner or respondent ever engaged in a concurrent relationship. risk factors that were found to be associated with symptoms of an sti at a significance level of p<0.10 were included in the logistic regression analysis. analyses were conducted in stata version 10, utilising the survey methodology to adjust for the complex two-stage survey design. when appropriately weighted for over-sampling of blacks and whites, as well as nonresponse, the results are representative of metropolitan cape town. univariate and multivariate logistic regression was utilised to evaluate the strength of the association between sti symptoms and the independent variables. results table ii depicts the ongoing socio-economic deprivation of blacks and to a lesser extent coloureds, as measured in terms of income, educational attainment, parental employment and whether or not the youth live with their parents. in univariate analysis, the following were positively associated with sti symptoms: being female, black, coming from the poorest 20% of the population, poor educational outcomes, knowing someone who has died of hiv/aids, having consumed alcohol in the last month, ever been pregnant, ever been forced or hurt during sex, having a first sex partner who was 4 or more years older, having had a partner who had another concurrent refig. 1. the effect of sexual network configuration on hiv transmission in two hypothetical populations with the same number of lifetime partners, but differing concurrency patterns. population a has a pattern of serial monogamy, while most of population b are connected in a concurrent network. in both populations individual k (bottom left) contracts hiv in january. in a, the individual will have a high probability of transmitting the infection on to his january partner while in seroconversion and then a lower probability of passing it onto his next partners. the future partners of k’s infected january partner are also less likely to be infected owing to the reduced chances of their having sex during seroconversion. in b, the virus spreads rapidly through the network, as each person who becomes infected has a much higher probability of transmitting the virus on to another partner due to the fact that they are much more likely to have sex with the other partner/s during the seroconversion period (diagram based on one by epstein h. 2008. the invisible cure: africa, the west and the fight against aids. picador, 2008, reproduced with permission). k b: concurrency k fig. 1. the effect of sexual network configuration on hiv transmission in two hypothetical populations with the same number of lifetime partners, but differing concurrency patterns. population a has a pattern of serial monogamy, while most of population b are connected in a concurrent network. in both populations individual k (bottom left) contracts hiv in january. in a, the individual will have a high probability of transmitting the infection on to his january partner while in seroconversion and then a lower probability of passing it on to his next partners. the future partners of k’s infected january partner are also less likely to be infected owing to the reduced chances of their having sex during seroconversion. in b, the virus spreads rapidly through the network, as each person who becomes infected has a much higher probability of transmitting the virus on to another partner due to the fact that they are much more likely to have sex with the other partner/s during the seroconversion period (diagram based on one by epstein h. 2008. the invisible cure: africa, the west and the fight against aids. picador, 2008, reproduced with permission). a: serial monogamy the role of.indd 30 3/16/09 2:13:39 pm the southern african journal of hiv medicine                                                        summer 2009   31 lationship while in the relationship with the respondent, having used a condom at last sex, feeling generally unhappy, and feeling as if the future offered few or no opportunities. the only hiv-knowledge variable associated with sti symptoms was ‘limiting the number of sex partners’ – individuals who listed this as a strategy to decrease their risk of acquiring hiv had a lower rate of sti symptoms. education, income category, race, alcohol consumption in the last month, personally knowing someone who died of aids, feeling as if the future holds little or no opportunities, age of sexual debut, age difference with first partner and condom use at last sex all lose their significance in the multivariate analysis. only female gender, ever having been or made someone pregnant, having experienced coercion or force during sex, partner concurrency, not mentioning ‘limiting the number of sex partners’ as an hiv prevention strategy and feeling generally unhappy remain as significant predictors of stis on multivariate study (table iii). how does concurrency enhance hiv transmission? concurrent relationships result in an exponential acceleration of hiv transmission due to two main factors. firstly, concurrency has a dramatic effect on increasing the size of the ‘connected component’ – the number of persons who are directly or indirectly sexually connected at any point in time. morris and kretzschmar modelled the spread of hiv in two populations, one characterised by serial monogamy and the other by long-term concurrency.6 they modelled this in a way that kept the total number of sexual relationships the same in the two populations. despite this, the hiv prevalence after 5 years was 10 times higher in the population with concurrency, and the key mediating factor was the increased size of the concurrency-induced connected component. in a serial monogamy setting this component can never be greater than 2, but in situations of concurrency this number can be very large and the virus is therefore not trapped in a monogamous relationship after transmission. if we consider that hiv transmissibility is enhanced 10to 40-fold in the acute infection phase,24-26 then in a network characterised by concurrency, as soon as one person is infected everyone else in the connected component is at dramatically increased risk. by way of contrast, in serial partnerships, because of the monogamy during the relationship and the gaps between relationships, a recently infected person is less likely to expose another partner during this short high-viraemia-risk period and by definition is unable to expose a whole connected component of the population. if kretzschmar and morris had included this dramatically elevated hiv transmission rate during early disease in their analysis, then the modelled impact of concurrency would have been considerably greater.27 secondly, the infection-transmission-lowering effect of ‘partner-sequencing’ is lost.28 these dynamics are illustrated in fig. 2, which compares a serial monogamy dynamic with a concurrent sex network. in both, individual a has 5 partners and is exposed to hiv by his third partner, d. in the concurrency network, a is able to infect all 4 other partners with a relatively high probability during his seroconversion period – or as many as he has sexual relationships with during this period. in the serial monogamy network, c and b are protected by ‘partner-sequencing’, and only e is at high risk of hiv infection and even then only if the a e relationship occurs before a’s seroconversion period is over. f is at lower risk of hiv acquisition – approximately 1/1 000 per heterosexual coital act.29 based on this type of evidence, concurrency-induced connected components have been argued to act as core-groups or ‘superhighways’ for the spread of hiv. fig. 2. in the serial monogamy scenario, after a is infected by partner d, up to two partners are put at risk of hiv. in the concurrency scenario, all four other partners are placed at risk (black circle = hiv infected, grey circle = at risk of hiv infection) (figure based on wohlfeiler and potterat1 fig. 2. in the serial monogamy scenario, after a is infected by partner d, up to two partners are put at risk of hiv. in the concurrency scenario, all four other partners are placed at risk (black circle = hiv infected, grey circle = at risk of hiv infection) (figure based on wohlfeiler and potterat29). ethnic group wave component blacks coloureds whites total wave 1 completed interviews 2 126 (93%) 1 879 (87.5%) 747 (86%) 4 752 (89.6%) wave 2 completed interviews 1 807 (84.9%) 1 593 (84.7%) 506 (67.9%) 3 906 (82.2%) wave 3 completed interviews 1 519 (71%) 1 680 (84%) 337 (57%) 3 536 (75%) table i. response rates for waves 1, 2 and 3 (response rates are in parentheses) a: serial monogamy concurrency the role of.indd 31 3/16/09 2:13:43 pm summer 2009                                                          the southern african journal of hiv medicine                                                  32 while there is extensive evidence linking concurrency to increased sti risk, most of this is from a developed world setting. to the best of our knowledge, this is the first study to reproduce these findings in an african setting. of note, this analysis replicates the findings elsewhere that it is partner concurrency rather than respondent concurrency that facilitates sti spread.16 this is contrary to the findings of the four-cities study, which compared individual and ecological level risk factors in two high and two low hiv prevalence cities in africa. their finding was that levels of concurrency were not higher in the two high-prevalence cities. they did, however, find that there was a non-significant positive association between an individual’s propensity to concurrency and hiv in the two high-prevalence cities (or 2.02, ci 0.84 4.88 in kisumu; or 2.96, ci 0.96 9.11 in ndola). numerous problems have been raised about this study. 1. it was a cross-sectional study approximately 15 years into the hiv epidemic, and the epidemic may therefore have altered behaviour (such as reducing concurrency rates) in the high-prevalence cities, which would result in a weakening or loss of any association between concurrency and hiv. this supposition is supported by the sex behaviour (ro=b.c.d) contact rate (c) no. of sex partners pattern of sex partnerships including gaps between serial monogamy, concurrency mixing patterns size and connections of core groups age of sexual debut transmission efficacy (b) condom use circumcision status co-infections duration of infectiousness (d) access to and quality of therapy sti/hiv general mental state/ ability to respond to hiv/aids information • e.g. depression, self-esteem, negotiating skills, self-confidence individual level factors: livelihood options • access to quality education and subsequent employment opportunities • access to health care and health information societal and household level influences • home environment • household structure, e.g. parents cohabit • friendship networks • community and peer norms, e.g. drug use, age of sex debut, attitude to concurrency • gender relations health knowledge fig. 3. conceptual framework of the determinants of sti in young persons (based on hallman22). fig. 3. conceptual framework of the determinants of sti in young persons (based on hallman20). discussion ethnic group black coloured white p-value for difference between the races wealth quintiles 1 (poorest 20%) 47.7 13.4 1.2 <0.001 2 31.6 20.6 2.7 <0.001 3 12.5 26.1 0.3 <0.001 4 6.9 28.8 15.4 <0.001 5 (richest 20%) 1.4 11.2 80.4 <0.001 education level attained primary school education or less 8.3 9.9 0.6 <0.001 grade 8 11 65.7 53.4 35.3 <0.001 grade 12 19.9 26.4 26.1 <0.001 post-secondary education 6.1 10.4 38.0 <0.001 % of families living below poverty line 45 16 8 <0.001 mean age (yrs) 20.89 20.56 20.06 <0.001 % female 55.0 53.4 53.7 % married 4.0 8.5 1.2 <0.001 mother currently employed 30.0 48.6 75.8 <0.001 father currently employed 41.9 64.3 88.1 <0.001 live with mother 56.4 74.5 76.6 <0.001 live with father 27.0 44.1 59.6 <0.001 table ii. socio-demographic characteristics by race/ethnic group (%) the role of.indd 32 3/16/09 2:13:46 pm the southern african journal of hiv medicine                                                        summer 2009   33 fact that the low hiv prevalence cities had considerably higher rates of the ‘fragile stis’ – chlamydia and gonorrhoea – which are either self-limiting or easily treatable, whereas the high hiv prevalence cities also had higher rates of the other lifelong infection – herpes simplex virus 2.17 taken together, these suggest that there have been behaviour changes that have led to reductions in recently acquired stis in the high-prevalence cities. 2. models predict that concurrency is important in the generation but not the maintenance of sti epidemics.6 the four-cities survey may have been too late in the genesis of the epidemic to pick up the generative effect of concurrency. univariate analysis multivariate analysis factor category or 95% ci p-value or 95% ci p-value sex male 0.42 0.27 0.66 <0.001 0.52 0.32 0.87 0.014 age 1.01 0.90 0.13 0.911 race blacks reference group coloureds 0.74 0.49 1.13 0.165 1.00 0.56 1.77 0.988 whites 0.09 0.02 0.55 0.007 0.47 0.07 3.27 0.450 income quartile 1 (poorest) reference group quartile 2 0.87 0.57 1.33 0.533 0.91 0.56 1.48 0.711 quartile 3 0.71 0.42 1.40 0.202 0.87 0.47 1.63 0.665 quartiles 4 & 5 (richest) 0.27 0.13 0.53 <0.001 0.66 0.30 1.45 0.298 education (highest grade attained) grade 0 7 reference group grade 8 11 0.72 0.41 1.27 0.268 0.66 0.35 1.25 0.200 grade 12 0.41 0.23 0.79 0.007 0.64 0.31 1.31 0.221 post secondary 0.32 0.12 0.82 0.017 0.77 0.27 2.15 0.619 hiv prevention knowledge believe that limiting the number of sex partners is a way to decrease hiv risk 0.11 0.03 0.34 <0.001 0.15 0.04 0.59 0.006 affected by hiv/aids personally know someone who has died of hiv/aids 1.74 1.13 2.67 0.012 1.31 0.81 2.10 0.265 alcohol consumed alcohol in the last month 1.63 1.08 2.47 0.019 1.16 0.72 1.89 0.533 mental state feel unhappy about life in general 2.51 1.64 3.85 <0.001 2.14 1.35 3.40 0.001 opportunities feel as if the future holds poor or no opportunities 1.40 1.16 1.69 <0.001 1.11 0.91 1.34 0.306 pregnancy ever pregnant 2.91 1.92 4.41 <0.001 1.91 1.11 3.29 0.019 marital status married 1.02 0.75 1.38 0.89 age of sexual debut sexual debut ≤15 years old 1.41 0.98 2.08 0.067 1.54 0.98 2.40 0.056 sex duress have been forced to have sex or threatened or hurt during sex 2.01 1.19 3.34 0.008 1.90 1.08 3.31 0.024 number of sex partners 3 or more lifetime sexual partners 1.04 0.66 1.65 0.851 age difference with partner first sex partner 4 or more years older 1.64 1.09 2.48 0.016 1.15 0.71 1.85 0.559 partner concurrency any partner had concurrent sexual relationship while in relationship with the respondent 1.81 1.20 2.73 0.005 1.60 1.02 2.49 0.040 respondent concurrency respondent ever engaged in two or more simultaneous sexual relationships 1.02 0.67 1.55 0.941 condom use used condom at last sex 1.58 1.08 2.12 0.018 1.24 0.81 1.92 0.323 table iii. univariate and multivariate logistic regression model for association with symptoms of sti in 14 25-year-olds in cape town the role of.indd 33 3/16/09 2:13:48 pm summer 2009                                                          the southern african journal of hiv medicine                                                  34 3. the study only measured current concurrency, which may have led to an underestimate of concurrency.18 4. the much higher levels of circumcision in the lowas opposed to the high-prevalence cities may have provided such dramatic protection from hiv transmission as to obscure any relationship between concurrency and hiv transmission. one way to get around some of these problems is to look at risk factors for stis in adolescents, as their stis are the result of relatively recent behaviours. a secondary data analysis of 4 707 adolescents in the usa found that teens in concurrent relationships and serially monogamous relationships were 3.9 and 2.3 times respectively more likely to report an sti than teens who had only had a single relationship.19 the largest study to evaluate hiv prevalence and risk factors in south african youth found that the variable most strongly correlated with risk of hiv infection was race.12 multivariate modelling revealed that black african females and males were 8.3 and 2.6 times respectively more likely to have hiv infection compared with the other races. what then are the factors that mediate these differences? the multivariate model included lifetime number of sexual partners, always using a condom with the most recent partner (which led to a significant reduction in hiv for women, but an insignificant reduction in men) and circumcision (the beneficial effect of which only just reached statistical significance). the study did not, however, measure concurrency. our results suggest that the elevated sti rates in blacks may be related to higher concurrency rates; as in our study, the racial differential in sti symptoms found on univariate analysis disappeared in the multivariate analysis (which included partner concurrency). the association of sti symptoms with female sex, ever having been pregnant and having experienced coercion or force during sex provides further evidence of the role that vulnerability and gender violence may be playing in the spread of stis. although socio-economic position lost its significance in multivariate modelling, it is of interest that feeling generally unhappy remained a risk factor for sti symptoms. this is not, to the best of our knowledge, a relationship that has been found in previous adolescent sti research, but as a measure of general mental state it may have considerable utility. one’s general mental state impacts on how one accesses, integrates and operationalises safe sex messages and one’s ability to negotiate with partners on these matters (fig. 3).20 there is a notable body of qualitative research on sexual behaviour in south africa and elsewhere in which respondents have pointed out that concerns about daily survival trump concerns about health consequences in 10 years’ time.21,22 the caps data reveal a strong graded response between decreasing income and increasing levels of unhappiness. being generally unhappy is likely to be a marker of persons who, owing to economic or other factors, are less able to access the necessary safe sex information and less likely to have the psychological and social support resources necessary to implement these messages. our study has certain limitations, the most significant of which was the fact that the symptoms of sti were gathered in wave 1 in 2002 and many of the sexual behaviour variables were gathered in wave 3 in 2005. many of the variables gathered did however refer to the characteristics of the first sexual partner. wherever possible we utilised the variable pertaining to the first sexual partner – for example, when evaluating the age gap between all previous partners we limited our variable to the age gap in the first sexual relationship. the effect of this study design should serve to dilute any relationship between the dependent and independent variables. we were also able to utilise the recently released data from wave 4 of the caps where individuals were asked if they had had an abnormal genital discharge or genital ulcer in the last 30 days. because the reference period was only the last 30 days and not the last year as in wave 1, the proportion and numbers of symptomatic individuals (1.85%) were too low for multivariate analyses. individuals who noted symptoms of an sti in wave 1 were however more likely (4%) to note sti symptoms in the month before wave 4 than individuals who had no sti symptoms in wave 1 (1.6%) (p=0.06). this suggests that there is significant continuity in terms of the sti risk-promoting behaviours from wave 1 to wave 4. the outcome variable was respondent-declared symptoms of sti, which was not necessarily corroborated by medical examination or microbiological or serological testing. while this makes the variable prone to both false-positive and false-negative results, it is a validated methodology that has been used in other sti epidemiological research.23 we are also unable to establish the direction of causation –it is therefore possible that it was the sti that made the individuals generally unhappy. the high levels of concurrency found in this and related studies in southern africa, the way that the patterning of concurrency and hiv so neatly overlap within the racial/ethnic sexual networks within this region (kenyon c et al. – unpublished data) and the extensive evidence elsewhere linking concurrency to elevated sti transmission were sufficient grounds for unaids to declare that concurrency was a major determinant of hiv transmission. by showing that partner concurrency is linked to sti symptoms, this study supports these findings. much work now remains to be done to evaluate the link between hiv and concurrency in hiv-serolinked surveys with more complete network data, and to explore the upstream determinants of concurrency. references 1. wellings k, collumbien m, slaymaker e, et al. sexual behaviour in context: a global perspective. lancet 2006; 368: 1706-1728. 2. auvert b, buvé a, ferry b, et al.; for the study group on the heterogeneity of hiv epidemics in african cities. ecological and individual level analysis of risk factors for hiv infection in four urban populations in sub-saharan africa with different levels of hiv infection. aids 2001; 15: suppl 4, s15-s30. 3. koumans eh, farley th, gibson jj, et al. characteristics of persons with syphilis in areas of persisting syphilis in the united states: sustained transmission associated with concurrent partnerships. sex transm dis 2001; 28(9): 497-503. the role of.indd 34 3/16/09 2:13:50 pm summer 2009                                                          the southern african journal of hiv medicine                                                   4. ghani ac, swinton sj, garnett gp. the role of sexual partnership networks in the epidemiology of gonorrhea. sex transm dis 1997; 24(1): 45-56. 5. potterat jj, zimmerman-rogers hz, muth sq, et al. chlamydia transmission: concurrency, reproduction number, and the epidemic trajectory. am j epidemiol 1999; 150(12): 1331-1339. 6. morris m, kretzschmar m. concurrent partnerships and the spread of hiv. aids 1997; 11(5): 641-648. 7. lagarde e, auvert b, carael m, et al. concurrent sexual partnerships and hiv prevalence in five urban communities of sub-saharan africa. aids 2001; 15(7): 877-884. 8. mah t. concurrent sexual partnerships and hiv transmission in khayalitsha, south africa. centre for social sciences research working paper no. 225, august 2008, university of cape town. 9. carael m. sexual behaviour. in: cleland jg, ferry b, eds. sexual behaviour and aids in the developing world. london: taylor & francis, 1995. 10. colvin m, abdool karim ss, connolly c, hoosen aa, ntuli n. hiv infection and asymptomatic sexually transmitted infections in a rural south african community. int j std aids 1998; 9(9): 548-550. 11. jewkes r, dunkle k, mduna m, et al. factors associated with hiv seropositivity in young, rural south african men. int j epidemiol 2006; 35(6): 1455-1460. 12. pettifor ae, rees hv, kleinschmidt i, et al. young people's sexual health in south africa: hiv prevalence and sexual behaviors from a nationally representative household survey. aids 2005; 19: 1525-1534. 13. quigley m, munguti k, grosskurth h, et al. sexual behaviour patterns and other risk factors for hiv infection in rural tanzania: a case-control study. aids 1997; 11: 237-248. 14. carpenter l, kamali a, payne m, et al. independent effects of reported sexually transmitted infections and sexual behaviour of hiv-1 prevalence among adult women, men and teenagers in rural uganda. j acquir immune defic syndr 2002; 29: 174-180. 15. lam d, seekings j, sparks m. the cape area panel study: overview and technical documentation for waves 1-2-3. cape town: university of cape town, december 2006. 16. drumright ln, gorbach pm, holmes kk. do people really know their sex partners? sex transm dis 2004; 31(7): 437-442. 17. marie-claude b, lowndes c, gregson s. population-level risk factors for hiv transmission and "the 4 cities study": temporal dynamics and the significance of sexual mixing patterns. aids 2002; 16(15): 2101-2102. 18. mah tl, halperin dt. concurrent sexual partnerships and the hiv epidemics in africa: evidence to move forward. aids behav 2008; jul 22 (epub ahead of print). 19. kelley ss, borawski ea, flocke sa, et al. the role of sequential and concurrent sexual relationships in the risk of sexually transmitted diseases among adolescents. j adolesc health 2003; 32: 296-305. 20. hallman k. gendered socioeconomic conditions and hiv risk behaviours among young people in south africa. afr j aids res 2005; 4(1): 37-50. 21. marks s. an epidemic waiting to happen? the spread of hiv/aids in south africa in social and historical perspective. african studies 2002; 61(1): 13-26. 22. soul city, hiv prevention: multiple and concurrent sexual partnerships among youths and adults in south africa. http://www.soulcity.org.za/programmes/ research/target-audience-research/soul-city-series/south_africa_mcp_report_ final.pdf (accessed 19 november 2008). 23. manhart le, aral so, king k. sex partner concurrency measurement, prevalence, and correlates among urban 18 39-year-olds. sex transm dis 2002; 29(3): 133-143. 24. wawer mj, gray rh, sewankambo nk, et al. rates of hiv-1 transmission per coital act, by stage of hiv-1 infection, in rakai, uganda. j infect dis 2005; 191(9): 14031409. 25. pinkerton sd. probability of hiv transmission during acute infection in rakai, uganda. aids and behavior 2008; 12(5): 677-684. 26. pilcher cd, tien hc, eron jj, et al. brief but efficient: acute hiv infection and the sexual transmission of hiv. j infect dis 2004; 189: 1785-1792. 27. halperin dt, epstein h. why is hiv prevalence so severe in southern africa? the role of multiple concurrent partnerships and lack of male circumcision: implications for aids prevention. southern african journal of hiv medicine 2007; issue 26 (march):19-23. 28. kretzschmar m, morris m. measures of concurrency in networks and the spread of infectious disease. math biosci 1996; 133(2): 165-195. 29. wohlfeiler d, potterat ba. using gay men's sexual networks to reduce sexually transmitted disease/human immunodeficiency virus transmission. sex transm dis 2005; 32(10): suppl, s48-52. this woman found out she had mdr-tb while she was pregnant, and later the baby was also diagnosed. despite considerable challenges she and her daughter managed to complete the two years of mdr-tb treatment, both of them are now healthy, and she is working for médecins sans frontiers in khayelitsha as a community health worker. 36 the role of.indd 36 3/16/09 2:14:30 pm abstract background ethical consideration case discussion acknowledgements references about the author(s) rahul daimari department of internal medicine, university of botswana, botswana princess marina hospital, botswana lawrence kwape department of internal medicine, university of botswana, botswana princess marina hospital, botswana anthony a. oyekunle department of internal medicine, university of botswana, botswana princess marina hospital, botswana citation daimari r, kwape l, oyekunle aa. suicidal overdose of dolutegravir: a case report. s afr j hiv med. 2018;19(1), a799. https://doi.org/10.4102/sajhivmed.v19i1.799 case report suicidal overdose of dolutegravir: a case report rahul daimari, lawrence kwape, anthony a. oyekunle received: 03 sept. 2017; accepted: 17 apr. 2018; published: 18 june 2018 copyright: © 2018. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract dolutegravir (dtg) is the most recently introduced integrase inhibitor for the treatment of hiv infection and is preferred for its superior tolerability and efficacy in both new and pre-treated patients, and infrequent drug interactions. since january 2017, botswana has adopted a ‘treat-all’ approach with a dtg-based antiretroviral (arv) regimen as first-line treatment. we report a 29-year-old man with clinical stage 1 hiv infection who had been started on dtg, tenofovir and emtricitabine eight months prior, and who was admitted following a suicidal overdose of 1500 mg of dtg. he reported only minor symptoms including vomiting, epigastric pain and dizziness; which promptly resolved following supportive treatment. on admission, full blood count, liver function tests and electrocardiography were unremarkable. however, there was a non-progressive increase in serum creatinine. after a month off arvs, he was successfully restarted on antiretroviral therapy without any serious adverse effect. background integrase strand transfer inhibitors (instis) are the newest class of antiretroviral (arv) drugs approved for hiv treatment. combination therapy based on insti is one of the alternative first-line arv drugs recommended by the world health organization (who).1 dolutegravir (dtg) is the most recent insti and is preferred for its superior tolerability and efficacy in both new and treatment-experienced patients and infrequent drug-drug interactions.2,3 since june 2016, botswana has adopted the ‘universal test and treat’ approach for hiv-infected persons, with a dtg-based regimen.4 ethical consideration for this case report, the authors obtained ethical approval from the research and ethics committee (rec) of princess marina hospital, gaborone, and written informed consent from the patient. ethics approval number is pmh 5/79(1-4-2018). case we report a 29-year-old hiv-positive male truck driver, who was diagnosed with who clinical stage 1 hiv infection in may 2016, with a cd4+ count of 317 cells/µl, and was started on a triple regimen comprising dtg 50 mg and tenofovir (tdf) 300 mg and emtricitabine (ftc) 200 mg in september 2016. the tdf/ftc were in a fixed dose combination, and dtg was provided as a separate pill. he achieved virologic suppression, with a viral load < 400 copies/ml in december 2016. however, after an argument with his girlfriend, he ingested 30 tablets of dtg (1500 mg in total) with suicidal intention. he denied taking the other antiretroviral (arv) drugs (tdf/ftc). he arrived at our hospital about 2 h after the incident and complained of epigastric pain, dizziness and vomiting. there was no prior history of depression or psychiatric illness. he drank alcohol only over weekends but denied smoking and substance abuse. on examination, he was conscious and well-oriented, with stable vital signs. full blood count, liver and renal function tests were within reference ranges, although serum creatinine rose from 48 µmol/l (day 1) to 82 µmol/l on day 2 (table 1). serum level of dtg could not be done. electrocardiography was normal, including a normal qtc. he was managed with intravenous fluid, metoclopramide and an antacid, and was off of his arvs during his 3-day hospital stay. he was restarted on dtg and tdf/ftc after discharge, day 5 post-overdose. as per hospital protocol, he also had a psychological assessment and psychiatric consultation, which were unremarkable. cd4+ count on day 9 was 538 cells/µl. by day 28 follow-up he reported no serious adverse events and clinical assessment revealed no significant findings. serum creatinine had also decreased to 72 µmol/l. as at the last check-up 7 months after overdose, the cd4+ count had risen further to 828 cells/µl. table 1: changes in full blood count and serum chemistry during admission and follow-up. discussion integrase inhibitors are an essential addition to hiv treatment and act by blocking the incorporation of hiv dna into the host genome, thus preventing replication. drugs in this class include raltegravir, elvitegravir and dtg. dolutegravir is taken once daily (50 mg for adults), has a good tolerability profile and superior virologic activity. it is primarily metabolised by the udp glucuronosyltransferase (ugt1a1) pathway and excreted into bile. hepatic cytochrome p4503a also contributes to dtg metabolism through oxidation by a minor pathway.5 dolutegravir can thus be safely used in patients with significant renal dysfunction, without an expectation of renal impairment or dangerously high drug levels. even though dtg is not known to have any direct effect on glomerular filtration rate, it impairs renal creatinine secretion through inhibition of the organic cation transporter-2 (oct2) and may create an impression of deteriorating renal function.5,6 in addition, guttierrez et al. mentioned in their review that there was a slight but predictable increase in serum creatinine concentration and a decrease in estimated creatinine clearance (ecrcl) of about 15% among patients taking dtg at the pharmacologic dose and without an actual reduction in glomerular filtration rate.6 our patient experienced a non-progressive but significant increase in baseline serum creatinine, which may be attributable to this effect. hence, clinicians should be guided by other measures of renal function that are not known to be affected by dtg. the occurrence of psychiatric symptoms including suicidal ideations in hiv-positive patients receiving dtg was reviewed across five randomised clinical trials by fettiplace et al., and the authors concluded that similar to other arv drugs, these symptoms were infrequently reported.7 another review suggested that psychiatric symptoms may indeed be an insti class effect. literature reports of dtg overdose are sparse, and thus its likely effects remain unclear. lee m et al. reported a case of a suicidal overdose of a combination of dtg, tdf and ftc.8 in that case, the authors observed a non-progressive renal failure which was attributed to the effect of dtg, although tdf (a potentially nephrotoxic drug which the patient also used) may have contributed to the rise in serum creatinine. in our patient, where dtg alone was used, there was also a similar non-progressive elevation of serum creatinine. oct2 inhibition by dtg can readily explain these effects in both cases, and this ‘renal impairment’ is typically reversible without any permanent harm.8 to our knowledge, there are no independent research publications regarding single overdose of dtg either in humans or animals. an fda pre-approval review of non-clinical animal toxicity studies by the drug sponsor concluded that there were no significant adverse events after single-dose ingestion of 10 mg – 1500 mg among rats, mice and monkeys.9 however, animals developed gastrointestinal inflammation and haemorrhage in similar studies following repeated short-term, subchronic and chronic daily dosing, at 10–1500 mg/kg/day. in addition, hepatotoxicity was noted in male monkeys, and this included hepatocellular necrosis and diffuse hepatocellular hypertrophy and vacuolation.9 these studies also established that the plasma levels achieved by these animals after a maximum of 1500 mg/kg/day are approximately seven times what humans achieve after a 50 mg once daily dose. if the pharmacokinetic relationship between the oral dose and plasma dtg levels remain linear at such doses, it will imply that humans can be expected to experience similar effects after just about 350 mg once daily. therapeutic interventions are mostly supportive. patients are unlikely to benefit from dialysis following an overdose because dtg is highly bound to plasma proteins.3 in this index case, we found no significant adverse effect after an overdose of 1500 mg. his minor symptoms disappeared with supportive treatment. in conclusion, single-ingestion dtg overdose may be associated with minimal toxicity, as compared to repeated daily overdose, which may potentially result in gastrointestinal bleeding and hepatotoxicity. the apparent renal dysfunction noted in these cases is usually owing to oct2 inhibition by dtg and is reversible. however, as experience is limited to the likely range of toxicities that may develop, physicians are advised to adopt measures that will prevent any form of overdosing using arvs. acknowledgements competing interests the authors declare no potential conflict of interest. authors’ contributions r.d. and a.a.o. conceived and designed the study, and conducted literature review. all authors were involved with the care of the patient, obtaining consent, data collection, writing and approval of the initial and final manuscript draft. references who. consolidated guidelines on the use of antiretroviral drugs for treating and preventing hiv infection [homepage on the internet]. world health organization; 2016 [cited 2017 july 28]. http://www.who.int/hiv/pub/arv/arv-2016/en/ despiégel n, anger d, martin m, et al. cost-effectiveness of dolutegravir in hiv-1 treatment-naive and treatment-experienced patients in canada. infect dis ther. 2015;4(3):337–353. https://doi.org/10.1007/s40121-015-0071-0 taha h, das a, das s. clinical effectiveness of dolutegravir in the treatment of hiv/aids. infect drug resist. 2015;8:339–352. https://doi.org/10.2147/idr.s68396 handbook of the botswana 2016 integrated hiv clinical care guidelines [homepage on the internet]. [cited 2017 sept 24]. http://www.moh.gov.bw/publications/handbook_hiv_treatment_guidelines.pdf reese mj, savina pm, generaux gt, et al. in vitro investigations into the roles of drug transporters and metabolizing enzymes in the disposition and drug interactions of dolutegravir, a hiv integrase inhibitor. drug metab dispos. 2013;41(2):353–361. https://doi.org/10.1124/dmd.112.048918 gutiérrez f, fulladosa x, barril g, domingo p. renal tubular transporter-mediated interactions of hiv drugs: implications for patient management. aids rev. 16(4):199–212. [cited 2018 feb 14]. http://www.ncbi.nlm.nih.gov/pubmed/25350530 fettiplace a, stainsby c, winston a, et al. psychiatric symptoms in patients receiving dolutegravir. j acquir immune defic syndr. 2017;74(4):423–431. https://doi.org/10.1097/qai.0000000000001269 lee m, eyer f, felgenhauer n, klinker hh, spinner cd. overdose of dolutegravir in combination with tenofovir disaproxil fumarate/emtricitabine in suicide attempt in a 21-year old patient. aids res ther. 2015;12:18. https://doi.org/10.1186/s12981-015-0054-y fda. center for drug evaluation and research [homepage on the internet]. 2013 [cited 2018 jan 17]. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204790orig1s000pharmr.pdf abstract introduction method ethical consideration results discussion conclusion and recommendations acknowledgements references about the author(s) nuria avila-danguillecourt department of internal medicine, grey’s hospital, university of kwazulu-natal, south africa anand a. moodley department of medicine, university of the free state, south africa polycarpe makinga department of family medicine, ladysmith hospital, university of kwazulu-natal, south africa citation avila-danguillecourt n, moodley aa, makinga p. prevalence and outcomes of central venous catheter-related bacteraemia in hiv-infected versus non-hiv-infected patients undergoing haemodialysis treatment for end-stage kidney disease. s afr j hiv med. 2018;19(1), a859. https://doi.org/10.4102/sajhivmed.v19i1.859 original research prevalence and outcomes of central venous catheter-related bacteraemia in hiv-infected versus non-hiv-infected patients undergoing haemodialysis treatment for end-stage kidney disease nuria avila-danguillecourt, anand a. moodley, polycarpe makinga received: 24 apr. 2018; accepted: 13 sept. 2018; published: 22 nov. 2018 copyright: © 2018. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: central venous catheter (cvc) haemodialysis (hd) to implement renal replacement therapy is the preferred choice in the urgent setting. unfortunately, cvc placement is associated with multiple complications including nosocomial bloodstream infections. there is a paucity of data on the prevalence and pattern of pathogenic organisms in haemodialysed hiv-infected versus non-hiv-infected patients with end-stage kidney disease. method and results: we undertook a retrospective study of 228 patients who were dialysed using a cvc at a tertiary referral hospital in kwazulu-natal, south africa. seventy-eight patients (34.2%) complicated with bacteraemia and sepsis requiring antibiotics. removal of the catheter was necessary in 58 patients (74.0%). the most common organisms isolated were staphylococcus aureus (30.8%), staphylococcus epidermidis (24.4%) and klebsiella pneumoniae (15.4%). there was no statistically significant difference between hiv-infected and non-infected patients with regards to infection rate, time interval from insertion of cvc to infection and final outcome. however, hiv-infected patients took longer to recover; 54.3% of non-infected patients versus 10.3% hiv-infected patients had their sepsis controlled within one week. acidosis, hypotension, line malfunction and line discharge were infrequent signs of sepsis. fever, rigors and raised white cell count occurred in over 80.0% of patients. conclusion: the infection rate in cvc hd is not more frequent in hiv-infected patients, provided that cd4+ count is ≥ 200 cells/µl and the patient is virologically suppressed. outcomes following intravenous antibiotic and removal of the cvc are similar in hiv-infected and non-infected patients but response to treatment is slower in hiv-infected patients. a high index of suspicion is needed in detecting cvc-related bacteraemia. introduction the gold standard in management of chronic kidney disease (ckd) patients varies according to the stage of the disease. in early stages, the goal of management is to correct reversible insults and retard progression. however, in the late stages of the disease, renal replacement therapy (rrt) is needed to sustain and maintain life. in the south african setting this approach is not always possible owing to the late presentation of patients for medical care. hence, there is often a need for urgent and temporary vascular access. central venous catheter (cvc) haemodialysis (hd) to implement rrt is the preferred choice in the urgent setting. unfortunately, cvc is associated with multiple complications including nosocomial bloodstream infections. the infection rate of cvc is reported as high as 32.0% and mortality rate amongst the infected patients as much as 12.0% – 26.0%.1 the kidney disease outcomes quality initiative (kdoqi) has recommended the use of the arteriovenous fistula (avf) as the modality of choice for vascular access in end-stage kidney disease (eskd).2 this is not always possible in resource-constrained settings as well as in those situations where the quality of the vasculature and time constraints prevent avf formation. in such cases, long-dwelling intravenous catheters are used and remain a reliable option for hd despite the risk for infection. the three veins commonly used for cvc insertion are the femoral, internal jugular and subclavian veins. since its early days, cvc has undergone numerous advances in its design, insertion technique and ongoing care. however, the risk of infective complications remains higher in patients with cvc than in those with avf.3 a meta-analysis published in 2006 by pronovost et al. reported an incidence range of infection of between 1 and 3.1 per 1000 patients per day.4 south africa has the largest human immunodeficiency virus (hiv) epidemic in the world. in 2015 it was estimated that seven million people were living with hiv in south africa.5 at the same time south africa has the largest antiretroviral treatment programme in the world. despite having the largest antiretroviral programme, the prevalence of hiv remains high, the highest being in kwazulu-natal (40.0%) and the lowest in northern and western cape (18.0%).6,7 the hiv epidemic continues to burden the delivery of optimal healthcare in south africa. despite the availability of antiretroviral therapy (art), hiv-associated nephropathy (hivan) is still highly prevalent because of the virus itself and art, specifically tenofovir.8 hivan is characterised histologically by a collapsing form of focal segmental glomerulosclerosis, microcystic tubular dilation, interstitial inflammation and fibrosis.8 it is a result of the direct effect of hiv-1 and the expression of viral genes on the renal epithelial cells in a genetically susceptible host.9 other reported glomerular lesions in hiv-infected patients include cryoglobulinaemia, iga nephropathy, amyloidosis and a lupus-like immune complex glomerulopathy.10 in the pre-art era, hivan was characterised by rapid progression to kidney failure and eskd, leading to the need for dialysis. hiv infection is not a contraindication for inclusion into the chronic renal programme in south africa as long as the patient’s cd4+ count is ≥ 200 cells/µl and the patient is virologically suppressed.1 this encouraging development has brought new challenges to the management of hiv-infected patients with eskd. conceivably, the risk of infection in haemodialysed hiv-infected patients even with mild immunosuppression should be higher than the non-immunocompromised population. when line sepsis is suspected, patients are started empirically on antibiotics until culture and antibiotic sensitivity results are obtained. there is a paucity of data on the prevalence and pattern of pathogenic organisms in the haemodialysed hiv-infected group, specifically with relation to cvc-related infections. there is no study conducted in south africa to determine whether the rate of central venous catheter-related bacteraemia (cvc-rb) in hiv-infected patients is comparable to that of non-infected patients. the spectrum of pathogens implicated in cvc-rb varies across different data sources. according to data from the usa, the common pathogens causing cvc-rb are coagulase negative staphylococcus (32.0% – 45.0%), staphylococcus aureus (22.0% – 29.0%) and enterococcus (9.0% – 13.0%).11 in a south african study by bisiwe et al., staphylococcus spp. were the most common pathogens isolated, but no comparison was made between hiv-infected and non-infected individuals.12 we undertook a retrospective chart review to address this by investigating the prevalence of cvc-rb in hiv-infected and non-infected patients with eskd at grey’s hospital, a tertiary hospital based in kwazulu-natal, south africa. our aim was to determine the commonest microbial agents implicated in cvc-rb, in hiv-infected versus non-hiv-infected subjects, and to compare the outcome of the current treatment protocols in hiv-infected versus non-infected subjects. our study population included patients with eskd treated with hd via a cvc and complicated by cvc-rb. method a retrospective cross-sectional chart review was conducted in the renal unit of grey’s hospital, a 494-bed tertiary hospital in pietermaritzburg, south africa. the hospital serves an urban population of 860 000 people and a rural population of approximately four million. patients diagnosed with eskd are referred to grey’s hospital for rrt from its referring hospitals. the majority of these cases present late in the course of the disease and often require urgent dialysis. the cvc placement is done as an emergency procedure in many cases. on average 80–90 patients are dialysed monthly with about 600 sessions of hd per month. the study population in this case comprised all patients with eskd attending grey’s hospital. all patients with eskd receiving hd treatment via cvc at grey’s hospital between 01 january 2013 and 31 december 2015 were eligible for inclusion in the study. participants had to be 12 years of age or older and only cases with a first episode of infection related to cvc were considered. all patients with suspected line sepsis are treated empirically with antibiotics. the renal unit protocol at grey’s hospital is vancomycin 1 g stat intravenously and, depending on the stability of the patient, additional antibiotics are given. for stable patients, intravenous coamoxiclavulanate 1.2 g eight-hourly and for unstable patients intravenous meropenem 1 g eight-hourly with or without intravenous gentamicin 240 mg daily is given. despite the renal failure, infection control takes precedence as it is lifesaving. infection control is defined as response to treatment by clinical and laboratory markers. if the patient’s temperature, pulse rate, blood pressure, white cell count and c-reactive protein normalise, the infection is regarded as controlled. if after seven days of intravenous antibiotics, there is persistence of fever, hypotension, tachycardia and neutrophilia, antibiotics are continued. when culture and sensitivity results are available, appropriate changes to treatment are made. a delayed response is considered if infection control occurs beyond 10 days of antibiotic usage. the catheters are removed if the infection does not subside, there is poor quality dialysis or the catheter is non-functioning as a result of the infection. furthermore, if there is abscess formation at the insertion site, then removal of the catheter promotes infection control. this protocol is followed equally for hiv-infected and non-hiv-infected patients. patients with acute renal failure, those whose source of infection was found not to be cvc-related and those whose hd was delivered through avf were excluded from analysis. only patients with long-dwelling cvc were included in the analysis. several data sources were consulted for both the sample selection and the actual data collection. these included the renal unit patient database, the infectious disease patient database, the national health laboratory services database and patients’ medical records. data were collected using a predesigned structured data collection sheet. after collection, data collection sheets were checked for accuracy and completeness and were entered into a computer database by a single data-capturer, and where discrepancies were found data cleaning was performed. statistics: data were analysed using ibm® spss® (version 21) software. descriptive statistics in the form of frequency tables, proportions and summary statistics for continuous variables were computed. the chi-square tests of association and student’s t-test were computed to assess associations and compare means at the significance level of 5.0%. the fischer exact test was also computed for comparative analysis with a significance level of 5.0%. ethical consideration ethical clearance was obtained from the ethics committee of the university of kwazulu-natal. given that this was a retrospective chart review using records of patients seen at the hospital two – three years ago, the consent to use these records was obtained from the hospital management and not from individual patients. information collected from these records was kept confidential. results there were 725 patients admitted for renal impairment in grey’s hospital during the two-year study period. of these, 236 patients (32.6%) were diagnosed as having ckd. of the 236 patients with ckd, 228 patients (96.6%) had hd through a cvc. of the 228 who had cvc, microscopy, culture and sensitivity were performed on 92 (40.4%) patients, from which 78 (84.8%) patients were culture infected and had organisms identified. the remaining 14 (15.2%) had no growth (figure 1). figure 1: patient selection. these 78 patients with cvc-rb were further analysed. sixty-two (79.5%) patients had internal jugular catheters, 10 (12.8%) patients had subclavian catheters and six (7.7%) patients had femoral catheters. in the group of patients with cvc-rb, 29/78 (37.0%) were hiv-infected and 49/78 (63.0%) were not hiv-infected. there was no significant difference in the cvc insertion site between the hiv-infected and non-infected patients. the sample was predominately male (56.4%). the mean age of participants was 38.1 years (s.d. = 14.6) with a range from 13 to 78 years. about 35.9% of patients were employed while only 5.1% were on a government-funded pension. the rest of the participants were either scholars or unemployed. all 29 (37%) hiv-infected patients were on first-line art and were virologically suppressed. first-line art in the south african public health sector includes tenofovir, lamivudine (or emtricitabine) and efavirenz.6 viral suppression was defined as viral load undetectable or < 50 copies/ml. all patients had a cd4+ count ≥ 200 cells/µl. fifteen patients had a cd4+ count of > 500 cells/µl.6 the commonest comorbidities were anaemia of chronic diseases (68 patients), secondary hypertension (22 patients) and hypercholesterolaemia (six patients). there was no significant difference in the comorbidities between the hiv-infected and non-infected groups. table 1 shows the aetiology of eskd in the two groups. the cause of eskd was unknown in eight patients; related to hiv infection alone in 12/29 (41.0%) patients; diagnosed on biopsy in five patients; and on ultrasound and clinical grounds in seven patients. ten (34.0%) hiv-infected and 12 (24.0%) non-infected patients had multiple causes of eskd as detailed in table 1. table 1: aetiology of end-stage kidney disease. before blood culture was performed to confirm the diagnosis of bacteraemia, infection was suspected on the basis of clinical and laboratory markers. the clinical and laboratory markers present in more than 75.0% of patients were as follows: raised white cell count in 78 patients (100.0%), raised neutrophils in 76 patients (97.4%), rigors in 72 patients (92.3%), fever in 65 patients (83.3%) and tachycardia in 59 patients (75.6%) (table 2). in hiv-infected patients, the erythrocyte sedimentation rate is commonly elevated and therefore not considered a useful marker of sepsis in this group. table 2: clinical and laboratory findings suggestive of sepsis. three specimens were collected from each patient: one from the peripheral line, one from the cvc and the third from the tip of the catheter when the catheter was removed. the proportions of patients who had an infected growth on specimens from one, two and three sites were 50.0%, 44.9% and 5.1%, respectively. of the 78 cases with cvc-rb, blood from the peripheral line yielded infected growth in 17/78 (21.8%), from the cvc in 54/78 (69.2%) and from the tips of the catheter in 54/58 (93.1%). in 58 cases the catheter was removed and a specimen from the tip was cultured (figure 2). figure 2: percentage of positive blood cultures from different sites in 78 cases. fifty-eight patients had the catheter removed. the incidence rate of bacteraemia events was 2.7 per 1000 catheter-days for hiv-infected individuals, 3.7 per 1000 catheter-days for non-infected individuals and 3.2 per 1000 catheter-days for the entire sample of 78 patients, as shown in table 3. the frequently isolated pathogens were staphylococcus aureus in 24 patients (30.8%), staphylococcus epidermis in 19 patients (24.4%), klebsiella pneumoniae in 12 patients (15.4%), staphylococcus haemolyticus in eight patients (10.3%), escherichia coli in four patients (5.1%) and pseudomonas aeruginosa in four patients (5.1%) (table 4). where the fischer exact tests could be computed, no statistical difference in the occurrence of these organisms between the hiv-infected and non-infected groups could be found. table 3: incidence of bacteraemia. table 4: the prevalence and antibiotic sensitivity of isolated microorganisms. the mean lag time between the insertion of the catheter and the onset of bacteraemia was 373.7 days (s.d. 251.6) for the hiv-infected group and 272.2 days (s.d. 262.5) for the non-infected group. this too was not significantly different (p = 0.99). the management of patients with cvc-rb required that a decision be made to remove or preserve the catheter, depending on the clinical circumstances. after such a decision was made, the patient was then put on single or combination antibiotics, given orally or intravenously. the majority of patients were treated by removing the catheter and commencing intravenous antibiotics. fifty-eight (74.4%) patients had the cvc removed. eleven patients (14.1%) were treated with triple therapy antibiotics while 48 (61.5%) and 19 (24.4%) were on dual therapy and monotherapy, respectively. in this unit, vancomycin was the commonest antibiotic used, both as single agent and in combination with other antibiotics. of the 75 patients who had their infections controlled (determined on the basis of both laboratory and clinical grounds), 28 patients (37.3%) had their infection controlled within the first week of treatment while 41.3% and 21.3% needed two and more than two weeks, respectively. the stratification according to the hiv status presented in table 5 shows that hiv-infected patients required more time to control infection than non-infected patients. for instance, 54.3% of non-hiv-infected patients versus 10.3% of hiv-infected patients had their infection controlled within one week. only 15.2% of hiv non-infected patients versus 31.0% of hiv-infected patients required more than two weeks to control their infection. the pearson chi-square test showed a statistically significant association between the patient’s hiv status and the time required to control infection: (χ2 = 14.73, p = 0.00), implying that the control of infection in hiv-infected patients took longer than in non-infected patients. table 5: treatment outcomes of bacterial infection: hiv-positive versus hiv-negative. discussion catheter-related bacteraemia is a serious complication that can lead to adverse clinical outcomes for the patient on hd. the prevalence rate of bacteraemia in hd patients with cvc was 34.1% at grey’s hospital, pietermaritzburg, a 494-bed tertiary hospital serving a population of just under 5 million. this rate is more or less similar to the 32.0% found by bisiwe et al. at universitas academic hospital, bloemfontein.12 only patients who exhibit some clinical signs of infection warrant blood culture to exclude infection. a low threshold in ordering blood culture is paramount to diagnosing sepsis early. anaemia of chronic disease, hypertension (primary and secondary) and hypercholesterolaemia emerged as common comorbidities in 66 (87.2%), 30 (38.5%) and six (7.7%) patients, respectively. this result is in keeping with findings of other studies conducted in south africa.12 anaemia is a known complication of eskd. renal impairment leads to reduced production of erythropoietin by the failing kidney. other causes of anaemia included blood loss (in cases of high incidence of bleeding, uraemic gastritis and hd) and reduced iron storage (iron deficiency anaemia). the causes and consequences of anaemia were not investigated in this study. further research is needed to investigate in detail this important comorbidity in haemodialysed hiv-infected patients. the common causes of eskd were hivan (12 patients; 15.4%), the combination of hypertension and diabetes (nine patients; 11.5%), nephrotic syndrome (eight patients; 10.3%), autoimmune diseases (eight patients; 10.3%), hypertension (seven patients; 8.0%), non-steroidal anti-inflammatory drugs (nsaids) (five patients; 6.4%), nsaids and hivan (five patients; 6.4%) and nsaids and hypertension (one patient; 1.3%) as seen in table 1. the role of tenofovir and hivan in the aetiology of eskd may be difficult to distinguish in hiv-infected patients. this too was not investigated in detail in this study but may be of interest for further study. of the 12 cases that had nephrotoxic drug use as cause of eskd in isolation or in combination with other causes, tenofovir was the offending drug in eight cases, nsaids in three cases and herbal medicines in one case. acidosis cannot be relied on when diagnosing or suspecting infection as it was only present in 12/46 (26.0%) of patients. clinical and laboratory signs present in more than 50.0% of patients were raised white cell count, raised neutrophils, rigors, fever, tachycardia and raised c-reactive protein. clinicians should rely more on these signs to diagnose or suspect sepsis instead of acidosis, hypotension, line discharge or line malfunction, which were present in less than 75.0% of patients. in certain circumstances, line malfunction is not because of infection. other causes of line malfunction include mechanical obstruction, line kinks, misplaced sutures, catheter migration, drug precipitation, catheter cracks and patient’s position.2,13 these factors should be kept in mind and ruled out before ordering blood culture for line malfunction. raad et al. suggest that local catheter site inflammation is associated with a sensitivity of ≤ 3% for infection or may exist in the absence of cvc-rb and therefore cannot be relied upon. patients with systemic signs of infections such as fever and chills should have their blood drawn for blood culture.14 staphylococcus aureus remains the commonest pathogen in both hiv-infected and non-infected patients. this is in keeping with findings of several studies.11,12,15,16 in this study, it was difficult to make meaningful comparisons of the predominance of specific bacteria between the hiv-infected and non-infected groups, owing to the wide variety of organisms detected and small numbers. mokrzycki et al. found a statistically significant fivefold increased risk of hiv-infected patients having a gram-negative organism.15 klebsiella pneumoniae, e. coli and p. aeruginosa were the most commonly isolated gram-negative bacilli in this study but not statistically more common in the hiv-infected group. surprisingly, the mean lag time between the time of catheter insertion and the onset of bacteraemia was slightly longer in the hiv-infected (373.7 days) than in the non-infected (272.2 days) patients. however, this difference was not statistically significant. the lack of difference in this lag time can be attributed to the fact that most (51.7%) hiv-positive patients enrolled in this study had a cd4+ count > 500 cells/µl, with the remainder having a cd4+ count of 200 cells/µl to 500 cells/µl, and their viral load was undetectable; hence there were fewer people profoundly immunosuppressed. the data do indicate that there was a statistically significant dependency between time needed to control sepsis and hiv status. the time required to control sepsis was longer in hiv-infected than in non-infected patients. apart from the ongoing inflammatory process in hiv-infected patients we postulate that drug interactions between art and antibiotics might also account for the delayed response. in addition to antibiotic use, 58 patients (74.4%) had their catheter removed. according to the 2015 kdoqi clinical practice guidelines update, it is recommended that the catheter be replaced in most instances (guideline 7.4.3).2 in our setting, this has become a standard of care in the majority of cases; however, conservative management is used on patients with poor or previously damaged vasculature and good response to antibiotics. of the 12 patients who either died, developed complications or whose infection was not controlled, only five were hiv-infected, 11 had their catheter removed, two were on antibiotic monotherapy, five on dual therapy and five on triple therapy. there was no association between hiv status and the treatment outcome (χ2 = 5.27, p = 0.15). the infection was controlled in 82.8% (24/29) of hiv-infected patients versus 85.7% (42/49) of non-infected patients. the remaining 7.2% (5/29) of hiv-infected patients had complications or their sepsis was not controlled, while only 14.3% (7/49) of non-infected patients had complications or died. hiv infection does not impact negatively on outcome when the cd4+ count is ≥ 200 cells/µl and patients are virologically suppressed. limitations: the major limitations of the study were as follows: firstly, this was a retrospective study and some patients’ files were not obtainable. secondly, only hiv-infected patients with a cd4+ count ≥ 200 cells/µl and who were virologically suppressed were included in the study, as this is a requirement for a patient to be admitted to the chronic renal programme. severely immunocompromised patients are excluded from the chronic renal programme and therefore could not be part of the study sample. thirdly, the number of patients from which specific microorganisms were isolated was too small to allow meaningful comparison between the hiv-infected and non-infected groups for a specific microorganism. nevertheless, we do believe that the data presented are useful for making reliable estimates of the differences and similarities between hiv-infected and non-infected patients with eskd, dialysed via cvc. much to our surprise, hiv-infected patients complicated as much and recovered as much as non-infected patients. conclusion and recommendations based on this study our conclusions and recommendations are as follows: the cvc-related bacteraemia at grey’s hospital renal unit is 34.1%, which is similar to findings at universitas hospital in the free state. such a high prevalence warrants regular check-up and screening for sepsis during follow-up of these patients. hiv status should not be used as the basis of exclusion of hiv-infected patients from rrt as long as these patients are virologically suppressed with a cd4+ count ≥ 200 cells/µl. this view is supported by gupta et al.17 and the south african guidelines for chronic renal dialysis.1 no significant difference in bacteraemia rate, organisms implicated or outcome was noted between the hiv-infected and non-infected groups apart from the fact that hiv-infected patients took longer to recover from sepsis. the clinical and laboratory markers present in more than 50.0% of patients with line infection were raised white cell count, raised neutrophils, rigors, fever, tachycardia and raised c-reactive protein. erythrocyte sedimentation rate is an unreliable marker, especially in hiv-infected patients where elevation is indicative of an ongoing inflammatory response. acidosis is also uncommon and cannot be relied upon to detect sepsis in these patients. similar antibiotic protocols for the treatment of cvc-rb in both hiv-infected and non-infected patients are encouraged. this study did not reveal major differences between the two groups with regard to the aetiology, the lag time to the onset of bacteraemia and the outcome, although hiv-infected patients took longer to clear their sepsis. there should be a low threshold for the removal of infected catheters. this policy has resulted in similar low morbidity and mortality in our population when compared to statistics from other parts of the world. protocols that facilitate timely initiation of an elective, safe, optimal and permanent vascular access on patients with ckd stage four must be implemented to minimise the need for emergency dialysis, which carries a higher risk for bacteraemia by using temporary vascular access. acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions n.a.d. and a.m. were responsible for conception and design of the work. n.a.d. did data collection. data analysis and interpretation were performed by n.a.d., a.m. and p.m. drafting of the article was done by n.a.d. and a.m. a.m. and p.m. made critical revision of the article. n.a.d., a.m. and p.m. provided final approval for the version to be published. references department of health – south africa. guidelines for chronic renal dialysis. clin guidelines [serial online]. 2009 [cited 2018 jan 26]. available from: http://www.kznhealth.gov.za/medicine/dialysisguide.pdf national kidney foundation. kdoqi clinical practice guideline for hemodialysis adequacy: 2015 update. am j kidney dis. 2015;66(5):884–930. https://doi.org/10.1053/j.ajkd.2015.07.015 tokars j, miller e, stein g. new national surveillance system for haemodialysis associated infections: initial results. ajic. 2002;30:288–295. pronovost p, needham d, berenholtz s, sinopoli d, chu h, cosgrove s, et al. an intervention to decrease catheter-related bloodstream infections in the icu. new engl j med. 2006;355:2725–2732. https://doi.org/10.1056/nejmoa061115 naicker s. end-stage renal disease in sub-saharan africa and south africa. kidney int. 2003;63(suppl. 83):s119–s22. https://doi.org/10.1046/j.1523-1755.63.s83.25.x south african national aids council (sanac), national department of health (ndoh). global aids response progress report: republic of south africa. pretoria: south african national aids council; 2012. unaids. the gap report [homepage on the internet]. 2014 [cited 2018 jan 26]. available from: http://www.aidsdatahub.org/gap-report-2014-unaids roling j, schmid h, fischereder m, draenert r, goebel fd. hiv-associated renal diseases and highly active antiretroviral therapy-induced nephropathy. clin infect dis. 2006;42(10):1488–1495. https://doi.org/10.1086/503566 medapalli r, he j, klotman p. hiv-associated nephropathy: pathogenesis. curr opin nephrol hypertens. 2011;20(3):306–311. https://doi.org/10.1097/mnh.0b013e328345359a foy m, estrella m, lucas g, tahir f, fine d, more r. comparison of risk factors and outcomes in hiv immune complex kidney disease and hiv-associated nephropathy. clin j am soc nephrol. 2013;8:1524–1532. https://doi.org/10.2215/cjn.10991012 mitchell d, krishnasami z, alton m. catheter-related bacteraemia in haemodialysis patients with hiv infection. nephrol dial transplant. 2006;21(1):3185–3188. https://doi.org/10.1093/ndt/gfl425 bisiwe f, van rensburg b, barett c, van rooyen, van vuuren c. haemodialysis catheter-related bloodstream infections at universitas academic hospital, bloemfontein: should we change our empiric antibiotics? s afr j inf dis. 2015;30(1):29–33. https://doi.org/10.1080/23120053.2015.1103960 chan m. hemodialysis central venous catheter dysfunction. semin dial. 2008;21(6):516–521. https://doi.org/10.1111/j.1525-139x.2008.00495.x raad i, hanna h, maki d. intravascular catheter-related infections: advances in diagnosis, prevention, and management. lancet infect dis. 2007;7:645–657. https://doi.org/10.1016/s1473-3099(07)70235-9 mokrzycki m, schroppel b, von gersdorff g, rush h, zdunek m, feingold r. tunneled-cuffed catheter associated infections in hemodialysis patients who are seropositive for the human immunodeficiency virus. j am soc nephrol. 2000;11(11):2122–2127. saxena a, panbotra b. haemodialysis catheter-related bloodstream infections: current treatment options and strategies for prevention. swiss med weekly. 2005;135:127–138. gupta s, eustace j, winston j, boydstun i, ahuja t, rodriguez r, et al. guidelines for the management of chronic kidney disease in hiv-infected patients: recommendations of the hiv medicine association of the infectious diseases society of america. clin infect dis. 2005;40:1559–1585. https://doi.org/10.1086/430257 abstract introduction methods results discussion conclusion acknowledgements references about the author(s) ernest kateule zambia field epidemiology training program, ministry of health, lusaka, zambia tropical diseases research centre, ndola, zambia ramya kumar zambia aids related tuberculosis projects, lusaka, zambia david mwakazanga tropical diseases research centre, ndola, zambia modest mulenga tropical diseases research centre, ndola, zambia victor daka tropical diseases research centre, ndola, zambia gershom chongwe school of public health, university of zambia, lusaka, zambia citation kateule e, kumar r, mwakazanga d, et al. a cross-sectional study of the factors associated with male circumcision status among college youth in ndola, zambia, 2016. s afr j hiv med. 2019;20(1), a952. https://doi.org/10.4102/sajhivmed.v20i1.952 original research a cross-sectional study of the factors associated with male circumcision status among college youth in ndola, zambia, 2016 ernest kateule, ramya kumar, david mwakazanga, modest mulenga, victor daka, gershom chongwe received: 01 feb. 2019; accepted: 05 apr. 2019; published: 20 june 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: new cases of hiv are increasing among young adults in zambia; yet voluntary medical male circumcision (vmmc) coverage as an hiv prevention measure remains low. despite having the highest hiv burden in the province, ndola district had a vmmc coverage of 23% in 2015 compared to the national target of 80% among high-risk groups. objectives: to determine predictive factors associated with circumcision status among male students in ndola district. methods: we conducted a cross-sectional study in may 2016 among students aged 18–35 years enrolled in five conveniently sampled colleges. we administered a structured questionnaire to assess the knowledge, attitudes and perceptions about vmmc. we used multivariable logistic regression to determine factors associated with male circumcision (mc) status. results: of 136 students interviewed, 63% were circumcised, and of those, 96% were medically circumcised. half of all students were aged 21–24 years. those who perceived the circumcision procedure to be ‘safe’ (adjusted odds ratio [aor] = 5.13; 95% ci: 2.09–14.82), and knew that it reduced female to male hiv transmission risk (aor = 3.65; 95% ci: 3.12–11.67), were more likely to be circumcised. the perception that mc promotes ‘promiscuous behaviour’ (aor = 0.20; 95% ci: 0.07–0.61), and that sexual sensitivity is the ‘same’ regardless of circumcision status, were associated with not being circumcised (aor = 0.13; 95% ci: 0.02–0.80). conclusion: students had adequate knowledge about the safety of medical circumcision, and the subsequent risk reduction of hiv infection. interventions aimed at addressing negative sexual perceptions about circumcision may increase vmmc coverage among college students. keywords: college students; ethnicity; hiv; voluntary medical male circumcision; ndola; zambia. introduction in zambia, hiv prevalence remains high, with a prevalence of 12.3% and an overall hiv annual incidence among men and women aged 15–49 years of 70 per 10 000 population.1 in an effort to combat the high hiv burden, zambia initiated programmes to expand the provision of voluntary medical male circumcision (vmmc) in 2007.2 this policy change was based on evidence from three randomised controlled trials conducted in kenya, uganda and south africa, which showed that male circumcision (mc) reduced the risk of sexual transmission of hiv from women to men by approximately 60%.3 an assessment of the potential impact and costs of scaling-up mc in zambia found that if the government had expanded mc coverage to 80% of all adolescent and adult males by 2015, it would have averted an estimated 486 000 new hiv infections (approximately 50% of all new infections) and would result in substantial cumulative net savings for the public health sector. for these reasons, a national programme to make high-quality and safe mc services available and accessible on a voluntary basis to all hiv-negative men aged 15–49 years was implemented.4 zambia had set an ambitious target of scaling-up vmmc programmes to achieve 80% vmmc coverage by december 2015.5 although there had been significant progress in scaling up high-impact hiv preventive interventions, zambia fell short of the vmmc coverage goal. the country only managed to circumcise 1 005 424 out of eligible 1 864 396 men during 2012–2015, thus achieving a national vmmc coverage of 54%, instead of the 80% target.4 nevertheless, the new 2016–2020 vmmc operational plan is built on the existing momentum and aims to reach an ambitious target of 90% coverage of men aged 10–49 years, with a focus on those aged 15–29 years. this is also in line with the unaids 90-90-90 strategy to combat the hiv/aids pandemic, and the ultimate elimination of new hiv infections by 2030.6 the scale-up of vmmc in zambia is constrained by the low demand for mc services, especially from young men.3 studies conducted in sub-saharan africa and other parts of the world have suggested various barriers to seeking vmmc services. studies have suggested that gaps in knowledge regarding vmmc services, misconception, myths and negative influences from different sources such as the community and families affect the acceptability of vmmc.7,8,9 confusion of vmmc with female genital mutilation, fear of pain, cultural and religious beliefs, cost, the risk of medical complications and adverse effects, and the possibilities that mc would result in increased sexual risk behaviours or behavioural disinhibitions all influence vmmc uptake rates.7 other barriers and risks include the lack of regular access or no access to healthcare at all, expected time away from employment in order to heal, lack of spousal support, a reduction in penile sensitivity and size, and fear of a lessened capacity to engage in sexual intercourse.10,11,12 to date, few studies in zambia have been conducted to determine the mc status and identify predictive factors associated with vmmc uptake among male college youth. a study conducted in one college in mansa district, a rural part of zambia, found that respondents ranked enhanced sexual performance and pleasure as the most important reason why they would choose circumcision.13 almost all (97%, n = 25) male respondents thought that loss of penile sensitivity was beneficial because it allowed both men and women to enjoy sex for longer periods.13 however, this study sampled from a non-circumcising community, and the lack of variability in sociodemographic characteristics among participants, limited the investigators’ ability to make comparisons across traditionally circumcising and non-circumcising communities. factors associated with vmmc uptake may differ between rural and urban areas. thus, we conducted a study targeting male college and university students aged 18–35 years in an urban setting in order to determine attitudes and knowledge levels around mc, as well as to explore sociocultural factors that influence young men to elect for vmmc services. methods study design a cross-sectional survey study was conducted to determine the prevalence and correlates of mc uptake among males aged 18–35 years. this study design was preferred to a mixed-methods study because there was inadequate time to conduct the extensive follow-up required for a cohort study or focus group discussions (fgds), as students were time-constrained because of full course loads. timeframe the study was conducted within a duration of 1 month, from 02 to 27 may 2016. population the targeted population was about 12 710 students in ndola district. the sample comprised students from ndola college of biomedical sciences, zambia information communication and technology college, northern technical college, zambia electricity supply company (zesco) training centre and the copperbelt university ndola campus. setting ndola is the third largest city in zambia, with a population of 451 246. it is the industrial and commercial centre of the copperbelt, zambia’s copper-mining region, and capital of copperbelt province. nearly half (49.4%) of the population are men and the majority (223 020; 58.4%) are aged 15–64 years. the youth (15–24 years) represents 23.5% of the urban population, while the overall median age is 18.5 years. sample size and sampling procedure to estimate the knowledge of vmmc among the students with a 95% confidence level, and assuming a prevalence of 95% ± 4%, using kirsh’s (1965) method of sample size calculation, the minimum required sample size was 115. we obtained a sample size of 176 after adjusting for a non-response rate of 35%. we assumed uniform design effect across the colleges as the targeted colleges were in the same district and within a 5 km radius of each other. we introduced the study to the heads of institutions or departments at each of the colleges, who then went on to formally announce the study to their respective student bodies. students who fulfilled the inclusion criteria (male, aged 18–35 years) were approached in their lecture halls typically at the end of their lectures and asked if they would like to participate in the study. respondents who met the inclusion criteria were enrolled regardless of the year of study or hiv status. students who did not consent to participate in the study were excluded. we did not expect differences to occur in characteristics between those who consented to participate in the study and those who refused as only those that fitted the same recruitment criteria were approached for consent. the number of respondents recruited at each study site was obtained using the probability proportional to size approach. data collection we administered a standardised questionnaire to eligible participants through in-person interviews. the questionnaire was piloted on five students at one college in order to improve the reliability and validity of the questionnaire. the data collection instrument consisted of three sections: the participant’s sociodemographic characteristics, knowledge about vmmc and attitudes towards vmmc as a prevention strategy against hiv transmission. in this study, our outcome variable was the reported mc status among college youth. we collected data on exposure variables such as demographics (age, marital status, religion, year of study and ethnicity/tribe), knowledge (awareness about medical mc services, reduced risk of hiv infection, reduced risk of other sexually transmitted infections [stis], safety of procedure and penile hygiene) and attitudes or perceptions (access to and costs of mc services, fear of pain, fear of hiv testing, sexual dissatisfaction or satisfaction, promiscuousness, and stigma). the questionnaire was self-developed based on a literature review of various published studies, such as the zambian demographic and health surveys, as well as unpublished reports.3 the 10–15 min interviews were conducted by trained research assistants who were fluent in both english and bemba, which are the primary local languages. to minimise bias during data collection, we ensured age–sex matching, that is, only male research assistants administered the questionnaire after lecture hours in private rooms identified at each of the five campuses. data management the paper-based questionnaires were physically checked for completeness and consistency before data were entered into epi infotm (centers for disease prevention and control, atlanta, ga, us; version 3.5.1). we used epi info to conduct checks on data range, values and consistency. data were then exported to spss version 22.0 for further statistical analyses. for clearer interpretation of results, ordinal variables were recorded to binary form; responses ranging from ‘very important’ to ‘important’ were recoded to ‘yes’, whereas ‘somewhat important’ and ‘not important’ were recoded to ‘no’. the resulting data set included both categorical and continuous variables. statistical analyses we generated means with their standard deviations to describe continuous variables, and frequency and percentage distributions to describe categorical variables. we used univariable logistic regressions to assess individual statistical significance of association between factors and mc status, and multivariable logistic regression to adjust for other factors. the multivariable logistic regression model was determined in two stages. firstly, cross tables of the factors associated with vmmc were done; at this point, chi-square test or fisher’s exact-based p-values, as appropriate, equal to or less than 0.10 were deemed indicative of a significant association. secondly, factors found to be significantly associated with vmmc at the first stage were taken into the multivariable logistic regression model. the wald chi-square test-based p-values equal to or less than 0.05 were deemed indicative of a significant association in the multivariable model. ethical consideration this study was conducted after approval from eres converge research ethics board (reference number 00005948) was obtained. a written informed consent was obtained after explaining the purpose of the study to prospective participants. this was a low-risk single-contact study using a structured questionnaire and participants were free to withdraw from the study or decline to answer questions any time without consequences. the interviews were conducted in a private environment. results of the total target sample of 176 male participants, 136 consented, with a response rate of 77.2%. the majority were aged between 21 and 24 years (50.0%). of the participants interviewed, 28% were from northern technical college, followed by the copperbelt university (24.4%) and zambia ict college (12.6%). most of the respondents reported that they were not in committed relationships (85.1%), although half reported having sexual partners (50.8%). the majority reported identifying with traditionally non-circumcising cultural groups (82.1%), such as bemba, lozi, tonga and ngoni (table 1). the overwhelming majority of study participants identified as christian (99.2%, n = 133), a religion that does not generally promote circumcision on religious grounds. table 1: demographic characteristics, circumcision status and awareness about medical male circumcision services (n = 136). of the 131 students who responded to a question about their circumcision status, 82 (62.6%) reported being circumcised. the majority (81.5%) of the circumcised students reported being single. the vast majority of medically circumcised respondents believed that vmmc should be promoted in non-circumcising communities (98.6%), and 74.5% of uncircumcised respondents reported that they were considering circumcision in the future. regardless of circumcision status, 97.6% (n = 126) of respondents recommended mc as an additional strategy to prevent hiv and other stis. awareness of vmmc was almost universal, with 97.7% (n = 133) of the respondents reporting having seen or heard messages about it (table 1). many respondents ranked government hospitals and clinics among the top two places where one could get circumcised (88.0% and 63.2%, respectively), and the majority knew that the services at those locations were free (96.8%). most respondents reported that they were able to easily access vmmc sites (75.2%, n = 131). about one in five (22.3%, n = 121) did not know what time during the day these services were provided (table 1). with regard to knowledge and attitude towards vmmc, circumcised participants ranked the following as reasons, in order of importance, why they decided to get circumcised: (1) it reduces the chances of contracting hiv (90%, n = 80), (2) it reduces the chances of contracting other stis (88.8%, n = 80), (3) it improves penile hygiene (93.2%, n = 74), (4) these services were provided for free (87.3%, n = 79), and (5) facilities were nearer to their residences (87.2%, n = 78) (table 2a and table 2b). other respondents reported that mc reduces the risk of developing penile cancer (90.0%), while some reported that the services were safe (96.2%) and of good quality (90.4%). nearly two-thirds (n = 80) of students ranked enhanced sexual pleasure as an important reason for accepting the procedure. eight exposure variables (such as the safety of procedure, costs, the quality of mc services, perceptions on promiscuous behaviour, sexual enhancement, sexual sensitivity being the ‘same’ regardless of circumcision status, reduced chance of hiv and other stis) met the level of statistical significance in the univariate model and were then taken into the multivariate model (table 3). table 2a: exposure variables for male circumcision status among college youth, ndola – 2016 (n = 136). table 2b: exposure variables for male circumcision status among college youth, ndola – 2016 (n = 136). table 3: factors associated with circumcision status among male college students, ndola, zambia (n = 136). uncircumcised respondents ranked the following, in order of importance, as reasons why they decided not to get circumcised: (1) surgery complications or safety of mc (70.0%, n = 40), (2) mc does not guarantee 100% protection against hiv and other stis (62.2, n = 37), (3) pain during and after surgery (57.1%, n = 42), (4) post-surgery abstinence from sex for 6 weeks (62.5%, n = 40), and (5) long healing time after mc (64.1, n = 39) (table 2a and table 2b). having the knowledge that mc reduces the risk of female to male hiv transmission (aor = 3.65; 95% ci: 3.12–11.67) and the belief that the medical procedure is safe (aor = 5.13; 95% ci: 2.09–14.82) were two statistically significant factors that were associated with being circumcised after controlling for all other factors (table 3). the perceptions that mc promotes promiscuous behaviour (aor = 0.20; 95% ci: 0.07–0.61) and that sexual sensitivity is the same for both circumcised and uncircumcised men (aor = 0.13; 95% ci: 0.02–0.80) were both associated with being uncircumcised after controlling for all other factors. discussion of the total 136 students who consented to participate in the study, 63.0% were circumcised, and of those, 96.0% were medically circumcised. half of all students were aged 21–24 years. nearly all the students (97.7%) were aware about medical mc and the majority (96.8%) knew that mc services in government health facilities were free. those who perceived the circumcision procedure to be ‘safe’ and knew that it reduced female to male hiv transmission risk were more likely to be circumcised. the perceptions that mc promotes ‘promiscuous behaviour’ and that sexual sensitivity is the ‘same’ regardless of circumcision status were associated with not being circumcised. one encouraging finding of this study was that knowledge about vmmc was higher compared to studies conducted in botswana, tanzania and zimbabwe.10,12,14 however, the observed differences in levels of vmmc acceptability in other studies could be explained by the diverse cultural settings.15 in addition, participants from higher learning institutions are more likely to be exposed to information on vmmc. our study further confirms the assertion from previous reports that males with more knowledge about benefits and risks of vmmc services are more likely to accept circumcision compared to those with less knowledge.13,16,17 therefore, targeting information, education and communication (iec) materials about vmmc services to college or university students would further encourage adolescents and young men to take up mc. additionally, we found that the college population was generally young, single or in uncommitted relationships. this could be explained by the fact that at the time of interviews, we did not find older age groups doing full-time block lectures. most students aged 30 years and older attend school part-time because they are also engaged in full-time employment. therefore, the study could not establish the proportion of the males aged above 35 years; hence, further studies may be required to ascertain this age group’s views around mc. this study found that respondents who had knowledge of the partial protective effect of mc against female to male hiv transmission were more likely to be medically circumcised. it follows that gaps in knowledge of the protective effect of mc against hiv and other stis could be one reason for the low vmmc uptake among uncircumcised hiv-negative, young males. similarly, a study in swaziland documented that the reduced risk of hiv infection was the most important reason for undergoing vmmc (55.4%), followed by reduced risk of other stis (43.5%) and improved genital hygiene (21.1%).16 similar studies have shown that having the knowledge that ‘vmmc reduces the risk of getting stis’ had a significant effect on the acceptability of vmmc.13,16,17 uncircumcised respondents who had this knowledge were found to be four times more likely to accept vmmc compared to their counterparts.16 therefore, interventions to increase the awareness of reduced risk of hiv infection may serve to motivate men to undertake vmmc. previous studies have documented a strong association between perceptions of safety and vmmc service uptake. similarly, the ‘cost and quality’ of vmmc services are among well-described factors associated with acceptance levels of medical circumcision in the literature.10,12,16,18 in our study, the perceived costs of the procedure had no bearing on respondents’ mc-seeking behaviours. this finding contrasts with a previous study conducted in zambia, which found that the majority of uncircumcised participants reported that unacceptable medical service conditions and concerns about the quality at vmmc sites were reasons why they did not get circumcised.15 believing that the mc procedure is safe was associated with being medically circumcised. because this is a cross-sectional study, we cannot say what the temporal relationship is between believing that the mc procedure is safe and actually undergoing vmmc. other studies conducted in kenya, uganda and zimbabwe found that if men and their parents believed that circumcision leads to high rates of complications, then uptake is likely to be low.9,11,12,14,17 for instance, it was noted that parents of uncircumcised boys would be willing to take their sons for circumcision only after the assurance of good treatment and safety of the procedure.10 the safety of the procedure is of critical importance to a man’s decision to undergo mc because it is a permanent surgery with potentially significant effects on an individual’s sexual health. thus, men’s fears about the safety and quality of the procedure should be acknowledged and reassured. the zambian ministry of health along with public health partners should continue to educate individuals that safe, high-quality vmmc services are freely available in government health facilities. more sensitisation on the safety of procedure could correct the negative perceptions around free mc being of poor medical quality.5,18 men considering mc should also be informed about how the procedure is done, what they need to do to prepare for the surgery and how to ensure proper healing post-surgery. circumcision is not traditionally practised in the majority of zambian tribes, which in turn influences societal perceptions and an individual’s decision to seek mc. studies have documented that men from ethnic communities that do not traditionally circumcise expressed strong feelings against mc. this is because mc is not part of their culture, and they did not want to adopt a practice that their forefathers never had.10,19 this could explain the finding in our study that some students perceive circumcision to be an ‘unnatural’ modification of the body organ. it can be expected however that such attitudes may perhaps change gradually with access to accurate information about mc and its benefits.19,20 our study found that some students from non-circumcising tribes were not concerned about their mc status because they believed that both circumcised and uncircumcised men are the same in all aspects, including sexual sensitivity. it is possible that the self-reported preference to undergo mc among circumcised students was because of its protective effect against hiv, and not necessarily whether the respondent’s tribe traditionally practised circumcision or not.10,19 therefore, vmmc programmes should reach out to tribal elders within non-circumcising communities in order to combat some of the negative cultural perceptions and beliefs about vmmc, which could be preventing some men from undergoing mc. the possibility of suspicion in sexual relationships was reported by some participants in this study. specifically, uncircumcised men believed that if they underwent circumcision, their partners would perceive them as being more likely to engage in multiple sexual relationships because of the protective effect of mc against stis including hiv. this phenomenon is known as ‘behavioural disinhibition’.10 a study in zambia noted that almost all male respondents thought that loss of penile sensitivity was beneficial because it allowed both men and women to enjoy sex for longer periods.10,13 the reported enhanced sexual satisfaction in men, however, could explain the belief that women have a preference for circumcised men, hence the perception that mc promotes promiscuous behaviour among circumcised males.9,19,21 a future study should be conducted to assess zambian women’s perceptions of vmmc for their spouses and sons. a study among kenyan urban women aged 18–35 years found that women who were exposed to positive vmmc messages were able to discuss the procedure with their partners, while others made a joint decision for the men to go for vmmc.22 this suggests that vmmc programmes could involve women as positive motivators for circumcision, especially because of the indirect benefits to women, including reduced risk of human papillomavirus infection, which is a strong risk factor for cervical cancer. study limitations in this study, information bias was a possible limitation because the circumcision status was self-reported, and respondents might not have reported their true circumcision status for various reasons. the use of convenient sampling procedures could limit the study’s capacity to appropriately estimate the prevalence of mc among respondents. the study was conducted among college youth, thereby limiting the generalisability to the general population because older age groups may hold different opinions about vmmc. as our sample was restricted to men, we could not capture women’s opinions and were thus unable to make inferences about the role of women in vmmc uptake. however, these anticipated biases were handled by ensuring confidential interviews with male research assistants, and the use of a ‘proportionate to size’ sampling approach to enrol an adequate number of respondents from each of the five campuses. given the high response rate (77%), our study therefore provides important evidence on the factors associated with mc status among college students in ndola, zambia, and provides essential information for programme implementers to effect policy adjustments. the study also offers some baseline information, which is necessary for future research on mc using other contextual approaches. conclusion consistent with other studies in african nations, this study showed that most male college students in ndola district of zambia had knowledge about the benefits of mc. believing that the circumcision procedure was safe and that it had a short healing time were factors associated with accepting vmmc services among respondents. the perception that mc promotes promiscuous behaviour, and that sexual sensitivity in circumcised and uncircumcised men is the same were two factors associated with men who self-reported being uncircumcised. although our study found the level of mc among college students to be higher than the national prevalence, there is a need for the ministry of health and its implementing partners to create more awareness about the safety and quality of services in government health facilities. in addition, educating the public that mc reduces the female to male transmission risk of hiv could lead to an increased uptake of vmmc services. there is also a need to carry out similar studies among non-college educated individuals, including females, to determine the knowledge and perceptions about vmmc among both men and women with lower education levels. acknowledgements this research article was conducted with financial and material support from the president’s emergency plan for aids relief (pepfar) through the centers for disease control and prevention (cdc) zambia field epidemiology training program (fetp), tropical diseases research centre (tdrc), ministry of health (moh)’s directorate of disease surveillance control and research and zambia national public health institute. the authors would like to thank the staff and management of ndola college of biomedical sciences, zambia information communication and technology college, northern technical college, zesco training centre and the copperbelt university. they extend special regards to kip h. baggett, dorothy l. southern and nicole bellows for scientific writing instruction and critical review of this article. competing interests this research was supported by cooperative agreement number u36oe000002 from the centers for disease control and prevention (cdc) and the association of schools and programs of public health (aspph). authors’ contributions e.k., d.m. and v.d. conceived the investigation, participated in its design and coordination, drafted the manuscript, initiated the investigation, interpreted the results and drafted the final manuscript. r.k. conducted data entry checks, interpreted the data and analysed the findings. r.k., g.c. and m.m. revised the methods, guided the discussion and wrote up the manuscript. all authors read and approved the final manuscript. references ministry of health, zambia. zambia population-based hiv impact assessment (zamphia) 2016: first report. zambia, ministry of health. december 2017 [homepage on the internet]. lusaka, zambia: ministry of health, zambia; 2017 [cited]. available from: https://phia.icap.columbia.edu/wp-content/uploads/2017/11/final-zamphia-first-report_11.30.17_ck.pdf national aids council. voluntary medical male circumcision (vmmc) | national hiv/aids/sti/tb council | zambia [homepage on the internet]. 2016 [cited 2019 apr 3]. available from: http://www.nac.org.zm/?q=voluntary-medical-male-circumcision-vmmc central statistic office. zambia sexual and behavioral survey – 2013–2014 [homepage on the internet]. 2015 [cited 2019 apr 3]. available from: https://www.google.com/search?source=hp&ei=lnmkxp_vbjlsxgpxkwq&q=zambia+sexual+and+behavioral+survey+&btnk=google+search&oq=zambia+sexual+and+behavioral+survey+&gs_l=psy-ab.3…981.981..2562…0.0..0.771.1248.4-1j0j1……0….2j1..gws-wiz…..0.kakqt9hxqso ministry of health (moh), national aids council (nac). zambia national voluntary medical male circumcision communication and advocacy strategy 2012–2015 | clearinghouse on male circumcision [homepage on the internet]. 2016 [cited 2019 apr 3]. available from: https://www.malecircumcision.org/resource/zambia-national-voluntary-medical-male-circumcision-communication-and-advocacy-strategy kripke k, chen p-a, vazzano a, et al. cost and impact of voluntary medical male circumcision in south africa: focusing the program on specific age groups and provinces. plos one [serial online]. 2016 jul 13 [cited 2019 apr 3];11(7):e0157071. available from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157071 usaids, who. 90–90–90 – an ambitious treatment target to help end the aids epidemic [homepage on the internet]. 2017 [cited 2019 apr 3]. available from: http://www.unaids.org/en/resources/documents/2017/90-90-90 chiringa io, ramathuba du, mashau ns. factors contributing to the low uptake of medical male circumcision in mutare rural district, zimbabwe. afr j prim health care fam med [serial online]. 2016 may 31 [cited 2019 mar 30];8(2). available from: https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4913440/ rosenberg ms, gómez-olivé fx, rohr jk, kahn k, bärnighausen tw. are circumcised men safer sex partners? findings from the haalsi cohort in rural south africa. plos one [serial online]. 2018 aug 1 [cited 2019 mar 30];13(8):e0201445. available from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0201445 jones dl, rodriguez vj, butts sa, et al. increasing acceptability and uptake of voluntary male medical circumcision in zambia: implementing and disseminating an evidence-based intervention. transl behav med [serial online]. 2018 nov 21 [cited 2019 mar 30];8(6):907–916. available from: https://academic.oup.com/tbm/article/8/6/907/5053244 muhangi d. factors that influence decisions to seek medical male circumcision services: a report of qualitative research in kampala, kayunga, pallisa, kasese and mbale districts-uganda. kampala, uganda: health communication partnership; 2010. skolnik l, tsui s, ashengo ta, kikaya v, lukobo-durrell m. a cross-sectional study describing motivations and barriers to voluntary medical male circumcision in lesotho. bmc public health. 2014;14(1):1119. https://doi.org/10.1186/1471-2458-14-1119 hatzold k, mavhu w, jasi p, et al. barriers and motivators to voluntary medical male circumcision uptake among different age groups of men in zimbabwe: results from a mixed methods study. plos one. 2014;9(5):e85051. https://doi.org/10.1371/journal.pone.0085051 mlewa aj. acceptability of medical male circumcision among uncircumcised young men at mansa college of education, zambia: influence of perceptions about effects on male sexuality. phd thesis. stellenbosch: stellenbosch university; 2013. mndzebel sl, tegegn ga. knowledge, attitude and acceptance of voluntary male medical circumcision among male students attending botswana university. j public health epidemiol. 2015;7(1):6–14. https://doi.org/10.5897/jphe2014.0671 price je, phiri l, mulenga d, et al. behavior change pathways to voluntary medical male circumcision: narrative interviews with circumcision clients in zambia. plos one. 2014;9(11):e111602. https://doi.org/10.1371/journal.pone.0111602 tsvere m, pedzisai c. attitudes of university students towards male circumcision. int j innovative res dev. 2014;3(2):236–242. herman-roloff a, otieno n, agot k, ndinya-achola j, bailey rc. acceptability of medical male circumcision among uncircumcised men in kenya one year after the launch of the national male circumcision program. plos one. 2011;6(5):e19814. https://doi.org/10.1371/journal.pone.0019814 bautista-arredondo s, sosa-rubi sg, opuni m, et al. influence of supply-side factors on voluntary medical male circumcision costs in kenya, rwanda, south africa, and zambia. plos one [serial online]. 2018 sep 13 [cited 2019 mar 30];13(9):e0203121. available from: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0203121 humphries h, van rooyen h, knight l, barnabas r, celum c. ‘if you are circumcised, you are the best’: understandings and perceptions of voluntary medical male circumcision among men from kwazulu-natal, south africa. cult health sex. 2015;17(7):920–931. https://doi.org/10.1080/13691058.2014.992045 evens e, lanham m, hart c, loolpapit m, oguma i, obiero w. identifying and addressing barriers to uptake of voluntary medical male circumcision in nyanza, kenya among men 18–35: a qualitative study. plos one. 2014;9(6):e98221. https://doi.org/10.1371/journal.pone.0098221 westercamp n, bailey rc. acceptability of male circumcision for prevention of hiv/aids in sub-saharan africa: a review. aids behav. 2007;11(3):341–355. https://doi.org/10.1007/s10461-006-9169-4 lanham m, l’engle kl, loolpapit m, oguma io. women’s roles in voluntary medical male circumcision in nyanza province, kenya. plos one. 2012;7(9):e44825. https://doi.org/10.1371/journal.pone.0044825 hiv 931 ‘hiv & tb drug resistance & clinical management case book’ by t rossouw, r j lessells, t de oliveira. cape town: south african medical research council, 2013. isbn 978-1-920014-91-9. south africa (sa) is home to the highest number of hiv-infected people in any country, and has the largest hiv treatment program worldwide, with 2 million patients currently receiving combination antiretroviral therapy (art). the country also has a massive tuberculosis (tb) epidemic, and tb/hiv co-infection is a common challenge for clinicians. the increasing number of patients who are infected with drug-resistant strains of tb and/or hiv in southern africa poses a mounting threat to successful treatment. drug-resistance testing for patients failing therapy is available at reference laboratories, which contrasts the situation in many countries in sub-saharan africa. this provides an important tool to protect the sustained effectiveness of available tb and hiv therapies; however, interpretation of drug resistance reports is complex and expert guidance to clinicians may be required for optimal clinical management. in this context, the recently published hiv & tb drug resistance & clinical management case book by rossouw, lessells and de oliveira, is an important aid to clinicians in sa and beyond, who are managing complex cases of patients with hiv and tb drug resistance. it provides a comprehensive background to the development of drug resistance as well as up-to-date clinical knowledge on how to diagnose and manage drug-resistant infections. the book uses an instructive case-based learning approach, with 14 hiv and 6 tb cases. after a brief review of technical details, each clinical case is presented in a structured manner. the description of the case is followed by the clinical chart and drug-resistance results. the drug-resistance report is translated into a clear and evidence-based recommendation for clinical management. lessons from each case are excellently summarised in ‘key learning points’. the cases cover diverse and illustrative examples of adult and paediatric patients with therapy failure, thus addressing actual problems that clinicians will deal with in daily practice. many of the cases in the book highlight errors in management that contributed to the emergence of drug resistance. these ‘preventable’ cases of drug resistance provide important lessons; avoiding these mistakes will advance clinical practice and benefit patients. preventing acquired drug resistance in patients receiving treatment will also have major public health consequences, as these cases are the source of onward transmission of drug resistance to newly infected individuals. a common feature of the hiv cases is that they used the saturn regadb drug resistance database to construct a complete clinical chart and resistance report for each patient. this database conveniently summarises all clinical and laboratory information into a clinical chart including treatment history, cd4 counts and viral load results. it also interprets the drug-resistance genotype using the stanford hivdb algorithm. the saturn information management system provides an excellent example of how bioinformatics tools can be utilised to the benefit of the physician and patient. in conclusion, this book is an excellent practical compendium of knowledge in the field of hiv and tb drug resistance, set in the highly relevant context of southern africa where drug-resistant strains of hiv and tb are increasingly reported. it provides expert guidance in difficult clinical situations and explains the steps to be taken to prevent the emergence and transmission of drug resistance. this book highlights the fact that education and training are fundamental steps in the implementation of technologies such as viral-load and drug-resistance testing, so that they can be used to full advantage. k c e sigaloff, md, phd r l hamers, md, phd department of global health, academic medical center of the university of amsterdam, amsterdam institute for global health and development, amsterdam, the netherlands conflict of interest. both authors are clinicians and investigators in the pharmaccess african studies to evaluate resistance (paser) network established in sub-saharan africa to monitor hiv drug resistance. http://www.sajhivmed.org.za open access southern african journal of hiv medicine issn: (online) 2078-6751, (print) 1608-9693 page 1 of 1 corrigendum read online: scan this qr code with your smart phone or mobile device to read online. authors: barbara a. hanrahan1 adri williams1 affiliations: 1department of nursing education, university of the witwatersrand, south africa corresponding author: barbara hanrahan, barbara.hanrahan@wits.ac.za dates: published: 14 dec. 2017 how to cite this article: hanrahan ba, williams a. corrigendum: prevention of mother-to-child transmission of hiv guidelines: nurses’ views at four primary healthcare facilities in the limpopo province. s afr j hiv med. 2017;18(1), a821. https://doi.org/10.4102/ sajhivmed.v18i1.821 copyright: © 2017. the authors. licensee: aosis. this work is licensed under the creative commons attribution license. in the version of this article initially published, the affiliations for barbara a. hanrahan and adri williams were incorrect. the correct affiliations for both authors is the department of nursing education, university of the witwatersrand, south africa. the error has been corrected in the pdf version of the article. the author apologises for any inconvenience that this omission may have caused. corrigendum: prevention of mother-to-child transmission of hiv guidelines: nurses’ views at four primary healthcare facilities in the limpopo province read online: scan this qr code with your smart phone or mobile device to read online. note: doi of original article: https://doi.org/10.4102/sajhivmed.v18i1.690 http://www.sajhivmed.org.za mailto:barbara.hanrahan@wits.ac.za https://doi.org/10.4102/sajhivmed.v18i1.821 https://doi.org/10.4102/sajhivmed.v18i1.821 http://crossmark.crossref.org/dialog/?doi=10.4102/sajhivmed.v18i1.821=pdf&date_stamp=2017-12-14 foreword key game changers between 2011 and 2018 introduction discussing fertility and childbearing with hiv-affected women and men hiv-affected clients who express a desire to have a child clients with no immediate plans for a child additional considerations for optimising prepregnancy health acknowledgements references appendix 1: prepregnancy counselling – checklist and key messages appendix 2: determining a woman’s fertile window appendix 3: low-technology sperm collection and self-insemination techniques about the author(s) natasha e.c.g. davies wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa gail ashford wits donald gordon medical centre, south africa linda-gail bekker the desmond tutu hiv centre, institute of infectious disease and molecular medicine, university of cape town, south africa department of medicine, faculty of health sciences, university of cape town, south africa nomathemba chandiwana wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa diane cooper school of public health, university of western cape, south africa silker j. dyer department of obstetrics and gynaecology, groote schuur hospital, faculty of health sciences, university of cape town, south africa lauren jankelowitz southern african hiv clinicians’ society, south africa otty mhlongo kwazulu-natal department of health, south africa coceka n. mnyani department of obstetrics and gynaecology, school of clinical medicine, university of the witwatersrand, south africa muhangwi b. mulaudzi southern african hiv clinicians’ society, south africa michelle moorhouse wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa landon myer division of epidemiology and biostatistics, school of public health and family medicine, university of cape town, south africa malika patel department of obstetrics and gynaecology, groote schuur hospital, faculty of health sciences, university of cape town, south africa melanie pleaner wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa tatiana ramos southern african hiv clinicians’ society, south africa helen rees wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa sheree schwartz wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa department of epidemiology, johns hopkins school of public health, united states jenni smit department of obstetrics and gynaecology, school of clinical medicine, university of the witwatersrand, south africa doreen s. van zyl private practitioner, south africa citation davies necg, ashford g, bekker l-g, et al. guidelines to support hiv-affected individuals and couples to achieve pregnancy safely: update 2018. s afr j hiv med. 2018;19(1), a915. https://doi.org/10.4102/sajhivmed.v19i1.915 guidelines guidelines to support hiv-affected individuals and couples to achieve pregnancy safely: update 2018 natasha e.c.g. davies, gail ashford, linda-gail bekker, nomathemba chandiwana, diane cooper, silker j. dyer, lauren jankelowitz, otty mhlongo, coceka n. mnyani, muhangwi b. mulaudzi, michelle moorhouse, landon myer, malika patel, melanie pleaner, tatiana ramos, helen rees, sheree schwartz, jenni smit, doreen s. van zyl received: 17 sept. 2018; accepted: 20 sept. 2018; published: 18 oct. 2018 copyright: © 2018. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. foreword in june 2011, the southern african hiv clinicians’ society, together with an expert working group, developed the guidelines on safer conception in fertile hiv-infected individuals and couples.1 since then, interventions to manage and prevent hiv have evolved and, similarly, options for safer conception have expanded. these updated guidelines provide healthcare providers with up-to-date information to support efforts to optimise safer conception care. key game changers between 2011 and 2018 safer conception has been incorporated into various national policies and strategies, including in south africa, kenya, uganda and botswana.2,3,4,5 in 2016, universal test and treat (utt) was adopted in south africa and other southern african countries.3,5,6 this makes provision for antiretroviral therapy (art) initiation when people test hiv-positive, regardless of their cd4+ count. utt improves health outcomes and contributes to treatment as prevention. mounting evidence indicates that an undetectable viral load (vl) means that a person is not infectious7,8,9,10 (with certain provisions, such as ongoing treatment adherence and absence of sexually transmitted infections [stis]). this is a key game changer that emphasises the importance of any hiv-positive partner being on art and virally suppressed before they start trying to achieve pregnancy. since 2013, option b+ has been rolled out in many countries to provide lifelong art for all hiv-positive pregnant and breastfeeding women to prevent mother-to-child transmission (mtct) of hiv.11,12,13 reassuring safety data are now available concerning art exposure during pregnancy and breastfeeding, including efavirenz use.14,15,16 however, a new safety alert has emerged for dolutegravir use in women around the time of conception, with an indication of increased risk of neural tube defects (ntds). further research is needed but, in the interim, providers are recommended to avoid the use of dolutegravir in any woman who expresses a desire for pregnancy now or in the near future and to counsel all women of childbearing potential about the possible risks of becoming pregnant while taking dolutegravir. providers should adhere to world health organization (who) or relevant local recommendations as they evolve. tenofovir/emtricitabine (truvada and equivalent generics) has been registered for use as pre-exposure prophylaxis (prep) for hiv prevention among individuals at high risk of hiv infection by the national regulatory authorities of kenya, lesotho, malawi, namibia, south africa, zambia and zimbabwe.17 approval is pending in botswana, nigeria and uganda, although their national health policies incorporate prep as a key prevention intervention.17 the who recently recommended that tenofovir-based prep should be continued for pregnant and breastfeeding women who remain at substantial risk of hiv acquisition during this period. this recommendation is accompanied by an emphasis on continued pharmacovigilance for any adverse maternal or infant outcomes.18 the combination of art initiation in the hiv-positive partner with prep coverage in the hiv-negative partner until the positive partner is confirmed virally suppressed (vl < 200 copies/ml) and has been on treatment for at least six months has been shown to completely remove the risk of hiv transmission where adherence to both art and prep is maintained.19 where the hiv-positive partner(s) are virally suppressed, then all other safer conception strategies become optional. couples may, however, still choose to use other options, so the full range of strategies should still be offered to all hiv-affected couples to enable their informed choice.20 for the purposes of this guideline, an undetectable vl is considered any vl that is 200 copies/ml or less to allow for variable sensitivity of viral load assays across the region.7 increasing evidence shows that there is little to be gained by offering other assisted reproductive technologies and/or sperm washing to avoid hiv transmission, if the hiv-positive partner is adhering to art and is confirmed to be virally suppressed.21 it is no longer considered necessary to refer couples with presumed normal fertility for assisted reproductive technologies such as sperm washing and intrauterine insemination (iui) unless this is their choice and they are made aware of the costs involved. there is wider availability and access to long-acting reversible contraceptives, such as the subdermal contraceptive implant and the intrauterine contraceptive device (iucd) – relevant because both allow immediate return to fertility on removal, unlike predominantly used hormonal injectables, which have a longer period for return to fertility. there are some drug interactions with art, which are discussed in more detail below.22 introduction in southern and sub-saharan africa, the majority of hiv-positive individuals are adults of reproductive age,23 many of whom desire children24,25,26,27,28 and between 30% and 50% of them have an hiv-negative partner,29,30 although many may remain unaware of their own or their partner’s status.31,32,33 attempting natural conception, without using any hiv risk reduction strategies, places hiv-affected couples at increased risk of hiv transmission.28 this likely contributes to regional estimates that up to 60% of new hiv infections occur in stable serodifferent couples.34 acknowledging the considerable overlaps between high hiv prevalence in reproductive-aged individuals, hiv transmission risks and active fertility desires, safer conception services need to be scaled up across the region.35,36 modern art, which is highly effective, with lower toxicities and pill burden, ensures that hiv can be managed as a lifelong, chronic disease and that mtct and infection of an hiv-negative partner can be almost entirely avoided if testing and treatment are effectively offered and utilised. with this in mind, the medical and ethical arguments previously used to deny the rights of hiv-positive women to become pregnant, or hiv-positive men to have biological children, are becoming increasingly irrelevant.33 healthcare providers need to actively engage with people living with hiv (plhiv), and their partners, to respect and support the fulfilment of their reproductive rights and desires. parenting should now be normalised for any individual or couple affected by hiv. these guidelines attempt to provide practical information about how this goal can be achieved safely, with optimal health and minimal hiv acquisition risks for any uninfected partner and the resulting child. the routine provision of appropriate contraception and safe prepregnancy planning support holds the potential to impact adult hiv testing and art uptake, vl outcomes, adult hiv prevention efforts and the achievement of elimination of mother-to-child transmission (emtct).35 it is one of the few cross-cutting interventions that can positively impact across numerous hiv and sexual and reproductive health programmes to the benefit of women, men and children. this requires accessible and safe fertility planning services and includes both the prevention of unplanned pregnancy through the use of appropriate contraceptive methods and the achievement of a planned, healthy pregnancy. scope of the guidelines the guidelines are designed to assist healthcare providers to, first, identify clients’ fertility desires and second, provide safe and effective pregnancy planning guidance to a presumed fertile couple who currently desire a child and where one or both partners are known to be living with hiv or are at possible risk of acquiring hiv because of having condomless sex with a partner(s) of unknown hiv status. both resource-limited settings, such as most public health sector facilities across the region, and resource-intensive clinical settings, including the private sector, where assisted reproductive technologies may be available, have been considered. however, even in resource-intensive settings, with effective art and other risk reduction strategies, costlier assisted reproductive technology, for example, sperm washing, iui and in vitro fertilisation (ivf), should no longer be considered necessary purely for the prevention of hiv transmission.20,21,35 it is important to recognise infertility and refer individuals or couples who are unable to achieve pregnancy; however these guidelines do not cover the management of infertility. it should be noted that much of what is covered in these guidelines is relevant to all couples desiring pregnancy. structure of the guidelines the guidelines are presented in four sections. the first section, ‘discussing fertility and childbearing with hiv-affected women and men’, discusses how providers can raise the issue of fertility planning and help identify the desires of hiv-affected women and men in relation to preventing an unwanted pregnancy or planning a desired pregnancy. the second section, ‘hiv-affected clients who express a desire to have a child’, focuses on the management of individuals and couples who desire pregnancy, with an emphasis on management of hiv and other comorbidities prior to attempting pregnancy. this section includes strategies for serodifferent and seroconcordant couples, as well as undisclosed individuals or individuals with an unknown status partner, to minimise risks of horizontal and vertical hiv transmission. the third section, ‘clients with no immediate plans for a child’, provides a very brief overview of contraceptive provision within the context of hiv for those who do not desire a child at present or in the future. the fourth section, ‘additional considerations for optimising prepregnancy health’, provides an overview of several additional service delivery issues, including prepregnancy counselling, basic assessment for underlying infertility, as well as management of comorbidities, pregnancy in older women and basic management if pregnancy is confirmed or a miscarriage occurs. special considerations for the provision of counselling for hiv-affected single women, same sex and transgender individuals and couples desiring pregnancy are briefly covered. a word on terminology used in the guidelines safer conception safer conception is the term used throughout these guidelines to refer to the overall process of choosing one or more risk reduction strategies to try and minimise hiv transmission and acquisition risks while attempting to achieve a healthy pregnancy. although in the field of fertility medicine the word conception is no longer used because it is not a distinct biological event,37 for the purposes of these guidelines it was felt important to maintain continuity with existing literature and guidelines, which speak to safer conception with particular reference to minimising hiv risks during the time when an hiv-affected couple is attempting pregnancy. hiv-affected individuals and couples the term hiv-affected individuals and couples includes a range of hiv relationship combinations, all of which require specifically tailored support to minimise hiv risk and to maximise the possibility of a safe pregnancy. couples may be in a mutually disclosed seroconcordant or serodifferent relationship, relationships where one or both partners have unknown hiv status or partnerships in which one individual is living with hiv and feels unable to disclose their status to their partner. hiv-positive and -negative individuals without a stable partner may also desire a child. hiv-affected men who have sex with men, women who have sex with women, bisexual and transgender individuals and couples may also have reproductive desires requiring the support of healthcare providers. in high hiv prevalence settings all hiv-negative individuals who have a known positive or unknown status partner fall within this definition of ‘hiv-affected’ and should be offered safer conception services if they desire a child. safe pregnancy safe or healthy pregnancy in this case refers to a minimised risk of hiv transmission to an uninfected partner and/or a foetus. horizontal hiv transmission the transmission of hiv from one sexual partner to another is called horizontal transmission. it can also occur between people who inject drugs if they share injecting equipment. vertical hiv transmission vertical transmission is the transmission of hiv from mother-to-child, either during pregnancy, labour and delivery or breastfeeding. condomless sex these guidelines specifically use the term condomless sex as opposed to unprotected sex because, with the availability of art and prep, when a couple undertake sexual intercourse without a condom they are not unprotected; they are simply using other measures to protect themselves and their partner from hiv transmission and acquisition. this distinction is important because the phrase unprotected or unsafe sex creates anxiety in couples and also implies unsafe and irresponsible behaviour when, in fact, many of these couples are very committed to doing everything possible to achieve pregnancy safely and reduce risk to the hiv-negative partner. timed condomless sex timed condomless sex is one safer conception strategy that individuals or couples may choose to use to reduce the total number of hiv risk exposures undertaken while trying to achieve pregnancy. with this strategy, condomless sex acts are limited to the peak fertile window, which occurs around the time that the female partner ovulates. this strategy has also been referred to as timed periovulatory unprotected intercourse. healthcare provider(s) this term refers to all clinicians, including doctors and nurses, and other staff such as counsellors and community healthcare workers who provide contraception, fertility planning and prepregnancy services for people affected by hiv, as defined by their scope of practice. serodifferent (serodiscordant) the guidelines use the term serodifferent instead of serodiscordant to describe relationships in which one partner is hiv-positive and the other is hiv-negative. other terms with the same meaning are seromixed, mixed status or magnetic couples. the term serodifferent is used in these guidelines rather than serodiscordant in response to the expressed preferences of plhiv and their partners. disclosure and partial disclosure in the context of these guidelines, disclosure is the process of revealing one’s hiv status to another person. disclosure may also involve telling another person about his or her hiv treatment, health status or vl. partial disclosure, for the purposes of this document, refers to a situation in which one partner has disclosed their hiv status but may not have told the other partner all of the details of their hiv history. this situation can commonly arise when an individual who already knows his or her status, and may be well established on arvs, chooses to disclose by attending for couples testing and counselling with their partner as if testing for the first time. partial disclosure may also refer to other aspects of a person’s history including previous pregnancies, children, miscarriages, terminations of pregnancy or failure to conceive with other partners. undetectable = uninfectious (u=u) u=u is an abbreviation for undetectable = uninfectious or untransmissible. over time, evidence has shown that if an hiv-positive person is well established on art, adherent to treatment and has a recently confirmed, undetectable plasma vl, this person is considered uninfectious and will not transmit hiv (untransmissible).8,9,10 this is discussed further in box 2. infertility infertility is defined as the failure to establish a clinical pregnancy after 12 months or more of regular, condomless sexual intercourse in a non-contracepting couple. infertility may be a result of an impairment of a person’s capacity to reproduce either as an individual or with his or her partner and can be a result of female factors, male factors or a combination of both.37 discussing fertility and childbearing with hiv-affected women and men despite improved quality of life and normal life expectancy resulting from effective art, many hiv-positive and hiv-affected clients remain reluctant to discuss sexual activity, fertility and childbearing with their healthcare providers.25,26,33 it is important for providers to provide culturally sensitive prepregnancy counselling (see appendix 1) and reproductive health services.2,27 providers should be able to confidently initiate the discussion, create a conducive environment for open discussion and be able to provide fertility planning services tailored to the individual’s or couple’s goals and choices (section ‘important points to note when discussing fertility choices and desires’, figure 1 and table 1). figure 1: approach to discussing fertility desires with hiv-affected individuals and couples. table 1: additional factors to consider when discussing fertility intentions. important points to note when discussing fertility choices and desires normalise the discussion: people may feel uncomfortable discussing sex, including their desire to prevent or plan for pregnancy, when one or both partners are hiv-positive. it is important to normalise this discussion, creating an honest and open atmosphere. ‘normalising’ the discussion includes pointing out that many other plhiv and uninfected people are grappling with these issues, and many have conceived. this communicates that the healthcare provider is non-judgemental and supportive of reproductive rights. frequent discussions about fertility choices make this a normal part of a consultation and acknowledge that fertility desires change over time. offer hiv testing: hiv testing and counselling for anyone with unknown hiv status (or repeat testing for those previously testing hiv-negative) should be revisited regularly over time. focus on both partners and be sensitive to dynamics within the relationship: discussions about fertility planning (both the desire to achieve pregnancy or to prevent pregnancy) often focus on female clients. however, it is important to engage male clients as many men living with hiv wish to have children.38 in some relationships, the male in the partnership has a strong influence over women’s fertility-related desires and decisions, often determining when the next child will be planned or whether a reliable form of contraception will be used.39,40 couple-based hiv testing and counselling should be routinely encouraged. efforts should be made to determine the hiv status of both partners; however, coercion and undue pressure should be avoided. although there are several advantages of involving partners, the provider needs to be sensitive to the fact that some women may not be able to convince their partner to come in; the provider should let the client make this decision. providers should be sensitive to issues relating to gender inequality and gender-based violence within relationships. it is important to provide a platform where both partners can agree on their desire to plan for, or prevent pregnancies, without any pressure being exerted on an unwilling partner. it can be helpful to have these discussions with each partner separately, as well as together, if possible, to ascertain if such imbalances are present. encourage informed decision-making: an important part of these discussions should be to ensure that all clients have a basic understanding of the menstrual cycle, hiv transmission, hiv prevention options and how to achieve pregnancy safely with reduced risks of horizontal and vertical hiv transmission, as well as how to prevent unplanned pregnancy for those not currently desiring pregnancy. the uptake of contraceptive and safer conception services should be promoted as appropriate. the provider should seek to assist clients to arrive at their own informed choice about their fertility desires. couples who are unsure of their fertility intentions should be encouraged and supported to access shorter-term contraception while they formulate a decision and discuss their plans during follow-up consultations. providers should be trained to offer a range of effective prevention alternatives, including viral suppression with art and prep. counselling about fertility intentions is not a once-off event: providers should reassure clients that fertility intentions can change over time, and that they are welcome to revisit their decision and discuss any changes in the future. providers should raise the issue of fertility intentions regularly and not rely on the client to do so.33 documenting decisions ensures continuity of care, particularly in busy public sector clinics where clients may be managed by different providers. concluding the discussion – different outcomes require different approaches individuals or couples who express a desire for pregnancy (see the section ‘hiv-affected clients who express a desire to have a child’) should be supported in starting the process of achieving pregnancy safely, utilising appropriate risk reduction strategies to minimise horizontal and vertical hiv transmission or acquisition risks. whatever the client’s expressed desire, he or she should be encouraged, where possible, to return to the facility with his or her partner to enhance the provision of couple-based fertility counselling and services. however, this should not be a prerequisite for future access to services. individuals and couples who do not currently desire a pregnancy (see the section ‘clients with no immediate plans for a child’) should be provided with information about available contraceptive methods, hiv testing and effective hiv prevention options or hiv treatment. they should be encouraged to discuss any changes in their plans over time with their provider. providers should also regularly revisit this discussion. individuals and couples who are not yet sure of their fertility desires may require further counselling and shorter-term contraception, and the issue should be revisited again in the near future. working with couples clients often attend consultations on their own. discussions regarding fertility and planning for pregnancy should be undertaken as appropriate – some clients may prefer one-on-one to couple-based sessions. there are several advantages to a couple-based approach as outlined in box 1. box 1: advantages to a couple-based approach. working with couples and disclosure engaging both partners together requires full hiv status disclosure. this can raise many issues about which a provider should be sensitive: where full disclosure has not yet happened, providers should consider the possibility of partial disclosure. partners should be consulted separately at least once to explore any undisclosed issues about which the healthcare provider should be aware. this may include hiv history (time of diagnosis and treatment initiation) and any previous terminations of pregnancy, miscarriages or failure to achieve pregnancy, with other partners. the provider should discuss with each partner individually what aspects may be relevant to disclose to their partner. in some situations, disclosure of hiv status is not possible and disclosure should not be considered a prerequisite of safer conception care and support. disclosure can be associated with risks, including intimate partner violence (particularly for women) and relationship breakdown, with loss of economic support.32,41 these issues need to be taken into account when encouraging disclosure. forced disclosure, or a judgmental approach towards non-disclosure, may cause the undisclosed individual to withdraw from care altogether, placing them and their partner at even higher risk of hiv transmission and poor health outcomes. risks can still be mitigated even where disclosure has not occurred and the individual who has not disclosed should be optimally managed within this context. couple-based hiv testing and counselling may represent a valuable opportunity to assist with supported disclosure, whereby the known positive individual tests with their partner as if for the first time. however, the resulting partial disclosure should be carefully noted to avoid inadvertent discussion of as yet undisclosed details about previous illnesses or arv treatment history to the other partner. despite the importance of a couple-based approach, it is not uncommon for providers to be approached by individuals who desire a child but either do not know the serostatus of their partner, may not have a regular partner or may have a partner who is not willing to engage in care. providers should develop an approach that ensures these individuals are also able to achieve pregnancy as safely as possible in a non-judgemental, supportive environment (see section ‘integrated package of care’, table 3). other issues relating to disclosure include previous pregnancies, miscarriages, abortions or difficulties in getting pregnant with other partners. these can be discussed with the client and support provided in his or her decision as to how much he or she chooses to disclose to his or her current partner. hiv-affected clients who express a desire to have a child between 30% and 50% of hiv-positive individuals desire a child.24,25,26,27 many may already be actively trying to achieve pregnancy at the time of clinical consultation. in supporting these individuals, there are a number of considerations that need to be taken into account. these guidelines focus on low-cost, low-technology strategies. for those clients who can access more resource-intensive options, such as sperm-washing with iui, ivf or intracytoplasmic sperm injection (icsi), these may also be considered. however, where there are no concerns about infertility, these interventions may not add any additional benefit, add extra cost and unnecessarily medicalise what can now be a safe, natural process.21,35 where available, these assisted reproductive technologies may provide additional options for couples who have suspected or confirmed underlying infertility. identifying such couples is discussed briefly in the fourth section, ‘additional considerations for optimising prepregnancy health’. utt and improved access to art provide an important option for hiv prevention in serodifferent couples – as explained in box 2. box 2: the concept of u=u. in the context of u=u, all other safer conception strategies and approaches discussed in the following represent additional safety measures that should be offered to all couples and may assist those couples who remain anxious and prefer to use additional strategies for their own peace of mind. however, these strategies do remain critically important options for those couples where viral suppression cannot be confirmed, because it is unavailable as a result of local resource constraints or where maintained vl suppression cannot be assured. they also apply during the period where the hiv-positive partner has not yet started or only recently started art and is not yet virally suppressed. it is essential that providers remain aware that many hiv-positive people may not be able to attain an undetectable vl because of barriers to treatment access or adherence; others may have art primary acquired drug resistance or secondary resistance as a result of previous art exposure, and some may choose not to access hiv testing or, once diagnosed, may not feel ready to start treatment.7 in these situations, these other strategies, including prep for the hiv-negative partner, provide important options. achieving pregnancy as safely as possible – choosing appropriate options figure 2 gives an overview of a range of strategies available to hiv-affected individuals or couples seeking to achieve pregnancy. the choice of strategies depends on what is appropriate, based on the hiv status of each partner, clinical considerations, available resources and, most importantly, client preferences (see section ‘integrated package of care’, table 3). table 4, at the end of this chapter following the section ‘medical male circumcision’, presents the recommended strategies for serodifferent, seroconcordant and sero-unknown couples in more detail. figure 2: prepregnancy counselling: prevention options. art with viral suppression and regular sti screening and management form the foundation of safer conception support. in cases where the partner’s serostatus or vl is unknown, other modalities such as prep become critical. antiretroviral therapy, viral suppression and pregnancy planning for couples who plan to achieve pregnancy through condomless sex, the most important determinant of hiv transmission risk is plasma hiv vl. effective art reduces the plasma and genital hiv vl in the infected individual to undetectable levels.43 plasma hiv levels generally correlate positively with the concentration of hiv in genital secretions, rectal mucosa and saliva, although inflammation can stimulate local replication,44 which is why screening for stis is such an important component of safer conception care. many hiv-affected couples still have much anxiety about trying to conceive in the context of hiv risk. it is important to share with them the robust evidence around u=u in order to provide evidence-based reassurance that they can, in fact, reduce the risk of hiv transmission between partners, and from mother-to-child, to zero if the positive partner or partners are established on art and confirmed virally suppressed with maintained high levels of adherence over the long-term (see box 2).7 antiretroviral therapy initiation as per globally accepted who guidelines, all newly diagnosed hiv-positive individuals, and those known to have hiv infection but not yet accessing art, should be counselled and initiated on art as soon as possible as part of the utt approach. the health benefits for the individual of starting art soon after diagnosis, regardless of cd4+ count, as well as the impact on hiv transmission risk, must be explained to the individual or couple.45 clients should be counselled about the importance of daily adherence to treatment. antiretroviral therapy initiation should be undertaken as per existing local guidelines, with appropriate screening for underlying opportunistic infections and considering any contraindications to first-line therapy, including renal dysfunction.13 clients should be reassured that use of art during pregnancy is considered safe. the benefits of sustained viral suppression far outweigh any potential minimal risks of abnormality in the foetus as a result of teratogenic effects.18,46 key information and recommendations regarding dolutegravir safety in the periconception period and early pregnancy at the time of writing (september 2018): preliminary findings from an observational study in botswana suggest an increased risk of ntds in infants born to women who conceived while taking dolutegravir.47 previous data concerning dolutegravir exposure in pregnancy, including antiretroviral pregnancy registry data, clinical trials and post-marketing surveillance, had not reported any increased risk of ntds. there is no evidence of safety concerns with dolutegravir use beyond eight weeks of the first trimester. women can be safely initiated on dolutegravir if they are already pregnant and beyond eight weeks. this dolutegravir safety signal highlights the importance of integrating routine fertility intentions screening into hiv care for women of childbearing potential. it is imperative that providers be aware of local guidelines relating to dolutegravir use around the time of conception and early pregnancy. as further evidence related to the safety of dolutegravir around the time of conception and early pregnancy is likely to emerge in the future, we strongly advise that readers consult the most recent national or international guidance on this specific question. this guideline promotes the woman’s right to choose whether to use dolutegravir or efavirenz, based on access to appropriate information about potential dolutegravir safety concerns and how this relates to her own fertility intentions. the southern african hiv clinicians’ society (sahcs) recommends that: a woman-centred approach should be adopted: healthcare providers should give women information and options to allow for informed choices about using lifelong art regimens. all women of childbearing potential who are being considered for dolutegravir initiation must be counselled about the possible risks of becoming pregnant while on dolutegravir and should be screened for active fertility intentions. all women of childbearing potential who do not have active fertility intentions should be advised about the importance of using a reliable contraceptive method and should be actively linked to the relevant services. these women should also be advised to discuss with their art provider should their fertility intentions change at any time in the future or if they are planning to discontinue a reliable form of contraceptive. women, including adolescents, of childbearing potential who desire pregnancy or are unable or choose not to access reliable contraception should be counselled about the potential risks and benefits of a dolutegravirversus efavirenz-based art regimen and offered the choice. documentation of this discussion, including consent for those choosing dolutegravir-based art, is essential. women, including adolescents, on effective contraception or not of childbearing potential may initiate dolutegravir-based first-line art. all pregnant (from eight weeks after conception) and breastfeeding women, including adolescents, may initiate dolutegravir-based first-line art. any hiv-positive woman of childbearing potential who is already on dolutegravir and plans to become pregnant should be adequately counselled about the potential risks and benefits of dolutegravirversus efavirenz-based art and offered the choice of dolutegraviror efavirenz-based art. this discussion should be documented, along with consent from those women opting for dolutegravir-based art. providers should make clinical notes of any discussion, particularly if a woman of childbearing potential chooses to start dolutegravir so that, in the event she does become pregnant on dolutegravir, there is documentation of ntd risk counselling. if pregnancy is confirmed in the first eight weeks while a woman is taking dolutegravir, she should be adequately counselled about the potential risks and benefits of dolutegravirversus efavirenz-based art and offered the choice of dolutegraviror efavirenz-based art. this discussion should be documented, along with consent from those women opting for dolutegravir-based art. the risk and benefits of switching during pregnancy should also be discussed. switching is associated with a small risk of viraemia in a previously virologically suppressed patient, which may result in risk of mtct and resistance. for those women opting for efavirenz-based art, once beyond eight weeks, a woman who does achieve pregnancy may consider switching to dolutegravir in order to benefit from its more robust nature throughout the rest of pregnancy, breastfeeding and lifelong. however, risk and benefits of switching during pregnancy should also be discussed. switching is associated with a small risk of viraemia in a previously virologically suppressed patient, which may result in risk of mtct and resistance. women who become pregnant on dolutegravir should be referred for evaluation of birth defects including ntds, using foetal ultrasound examination around 18–20 weeks gestation. should a ntd or other congenital abnormality be identified, counselling about the option to terminate the pregnancy should be provided. continuation or switch of dolutegravir will depend on the gestation at which pregnancy is confirmed. if the woman is already beyond eight weeks in the first trimester, dolutegravir can be safely continued. a specialist opinion should be sought for women taking dolutegravir as part of secondor third-line art regimens, where options to switch may be limited. any adverse outcome observed in a woman of childbearing potential who is on dolutegravir must be actively reported to the provider’s relevant pharmacovigilance or regulatory body so that more data pertaining to dolutegravir safety can be accumulated to inform future recommendations. where possible, all outcomes, including normal outcomes, should be reported to the relevant body to enable more rapid accumulation of safety data. recommended duration of antiretroviral therapy before attempting to achieve pregnancy several fertility guidelines recommend that the hiv-positive partner(s) should be on art for at least six months before attempting pregnancy to ensure sustained viral suppression.18,20,35 this is particularly important in settings without access to vl monitoring as those who start with higher vls pretreatment may need longer to suppress and there is no way to confirm this. it is important to counsel couples from the outset to manage their expectations around timelines and that the advice is, where possible, to wait until the hiv-positive partner has been on art for six months. short-term contraception should be offered to individuals or couples during this waiting period and consistent male or female condom use should be emphasised. some couples may find it difficult to wait this long. there are two options in this situation: where vl monitoring is available, the vl may be checked at three months on art. if viral suppression is confirmed, the couple may begin attempting pregnancy at this point, provided strict treatment adherence is emphasised. prep may be used as a prevention bridge for serodifferent couples to cover them until the hiv-positive partner has been on art for at least six months or until vl is undetectable (this is described further in the section ‘achieving pregnancy as safely as possible – choosing appropriate options’, table 2).19 clients already established on art: if available, the vl should be rechecked to confirm viral suppression before pregnancy attempts are undertaken. if not virally suppressed, treatment should be optimised as per current guidelines and the individual or couple should be encouraged to wait for viral suppression to be confirmed before attempting to achieve pregnancy. where possible, viral suppression should be confirmed after three months following a switch to any new art regimen. there should also be evidence of sustained high levels of adherence and immune reconstitution, where necessary, before the couple starts trying for pregnancy. where the hiv-positive partner is not virally suppressed despite more than six months on art, prep should be offered with caution because of the possibility that accumulating antiretroviral drug resistance may be driving the detectable vl. in this situation prep may not be effective as resistant virus may be transmitted to the hiv-negative partner, as has been seen in some case reports of prep failure.48,49,50 however, as these case reports emphasise, transmitted resistance remains very rare and prep has been proven effective for huge numbers of people at risk of hiv infection with very few failures reported globally to date. viral load monitoring and switching of regimen: in couples trying to achieve pregnancy, vl monitoring should be conducted at least six-monthly to ensure sustained viral suppression. in resource-intensive settings, this may be increased to three-monthly, in line with current prevention of mother-to-child transmission (pmtct) guidelines where pregnant and breastfeeding women are monitored every three months: viral load > 1000 copies/ml3: advise to wait until viral suppression is (re)established. explore barriers to adherence and resolve if possible. discuss the implications of a detectable vl, including possible transmission of drug resistance, and provide support for improved adherence. many clients will (re)suppress at this point if provided with adequate counselling and adherence support. a repeat vl should be taken after one month of supported adherence to confirm (re)suppression. if the second vl remains > 1000 copies/ml, or there has not been at least a one-log drop in the vl value, then the possibility of treatment failure because of drug resistance should be considered, and switching from first-line art to a recommended second-line option, as per current guidelines, should be undertaken.13 should a regimen switch be required, the couple should again be advised to wait until suppression of vl is established on the new regimen. consistent condom use should be encouraged and the risk of transmitting a resistant strain of virus explained to both partners, whether in a serodifferent or seroconcordant relationship, as reinfection with a resistant virus may occur. viral loads between the limit of detectability (assay dependent) and 1000 copies/ml are associated with a very low risk of transmission and hence a couple may be advised that they could continue trying to achieve pregnancy provided they are willing to accept this very low risk. condomless sex acts should be limited to the periovulatory fertile window to minimise risk exposure. information about assisting clients to determine their fertile window is provided later in this document (see appendix 2). the client should be provided with adherence support and his or her vl should be monitored more closely, preferably three-monthly, to ensure that the low-level viraemia is not the beginning of treatment failure with a subsequent rise in vl.51 the provider must also ensure comprehensive and regular sti screening as any concurrent, active sti in either partner would increase the risks of hiv transmission in this context.52 serodifferent couples in this situation may also choose to use prep as an additional strategy. table 2: overview of safer conception strategy options for individuals and couples according to hiv dynamic. antiretroviral drugs in pregnancy we recommend standard first-line, second-line and third-line regimens be used in pregnancy.6 based on the accumulated evidence, we endorse the who guidance that efavirenz can safely be used in pregnancy and in women who intend to become pregnant.14 their guidance was based on a meta-analysis that found that the incidence of ntds and all congenital abnormalities among women exposed to efavirenz in the first trimester was similar to that of the general population.15 the fda category d classification of efavirenz, and accompanying package insert, should be discussed with women, explaining that this was based on animal studies; human cohort studies have not demonstrated an increased risk of congenital abnormalities, but there is a background low risk of congenital abnormalities in all pregnancies, unrelated to drugs.53 providers are also referred to the section ‘key information and recommendations regarding dolutegravir safety in the periconception period and early pregnancy’ which presents recommendations pertaining to dolutegravir use in women of childbearing potential. providers are encouraged to maintain high levels of pharmacovigilance, reporting any adverse outcomes seen in women on any art drug during pregnancy (for either treatment or prevention) to their local art pregnancy registry. hiv-positive women not yet on antiretroviral therapy and confirmed pregnant many countries, including south africa, have implemented utt art guidelines so all people testing positive for hiv should be offered immediate art, regardless of their cd4+ count or clinical staging. prior to this, south africa had implemented the option b+ pmtct strategy, which made provision for any women commencing art during pregnancy to then continue art lifelong.13 any hiv-positive woman presenting pregnant before hiv diagnosis or art initiation should be initiated as soon as possible, preferably on the day that pregnancy is confirmed, and then reviewed in one week to follow up on baseline bloods and continue with treatment literacy and adherence counselling. refer for antenatal care (anc)/pmtct services as soon as pregnancy is confirmed or as early as possible in pregnancy. similar to horizontal transmission, viral suppression is critical to reduce the likelihood of vertical hiv transmission to the foetus in utero or to the infant during delivery. the longer a woman is on art during pregnancy, the better the outcomes – for herself and for her infant – because of an increased likelihood of an undetectable vl at delivery, thus preventing peripartum mtct.54,55 undetectable vl also reduces the risk of hiv transmission during breastfeeding as well as transmission to any serodifferent partner during this time. pre-exposure prophylaxis pre-exposure prophylaxis for serodifferent and sero-unknown couples it is recognised that for many women, the involvement of their male partners in couples counselling and testing or in any part of the health system remains a challenge.56,57,58 while health systems grapple with the challenge of developing male-attractive health services, it is important that hiv-seronegative women and their unborn offspring be protected even when there are demands for condomless sex. there is now considerable evidence that prep, in the form of tenofovir and emtricitabine, effectively prevents hiv transmission in serodifferent couples.59,60 studies have also shown efficacy with tenofovir alone, but to date who recommendations are for the combination of tenofovir and emtricitabine. prep may thus offer additional risk reduction for the hiv-negative partner in a serodifferent relationship or be the only protection option in some cases. however, evidence and careful modelling have shown that prep would be unlikely to provide additional risk reduction benefit where the hiv-positive partner has been on art for at least six months with optimal adherence or has confirmed viral suppression < 200 copies/ml by formal laboratory or point of care monitoring. in this situation, the risk of hiv transmission is already considered to be so low that prep would not add a further benefit.61 however, prep is advisable in the following circumstances: while the hiv-positive partner is becoming established on art, referred to as a ‘bridge’19 where the hiv-positive partner does not want to engage in care or refuses art where the hiv-negative partner has concerns about the reliability of their hiv-positive partner’s adherence to treatment where vl monitoring is not available and there are concerns that the hiv-positive partner may not be virally suppressed, for example if there are known to be occasional interruptions to drug supply that are beyond the individual’s control if the hiv-negative partner wishes for additional protection despite confirmed viral suppression and is concerned about condomless sex timed to the fertile window where the hiv-negative partner is unable to ascertain their partner’s hiv status and so may be exposed to unknown hiv risks if embarking on condomless sex in any situation where the hiv-negative partner in a serodifferent or sero-unknown relationship chooses, after counselling, to use prep because of personal preference. using pre-exposure prophylaxis for hiv prevention hiv-negative individuals opting to use prep should be managed according to existing prep guidelines.59 important points include the following: confirmation of hiv-negative status and screening for signs or symptoms of acute hiv seroconversion before prep initiation. screening for underlying renal dysfunction and hepatitis b infection. counselling about current recommendations on daily use of prep to ensure effectiveness. the pharmacokinetic modelling data that have been used to estimate the dosing period required before protection varies from seven to 21 days. this should be discussed with clients and, where possible, given the non-urgent situation, it would be advisable to recommend initiating prep at least 20 days prior to trying to achieve pregnancy.59 therefore, a lead in time of a minimum of 20 days is recommended for females and for male partners in heterosexual relationships who will be undertaking condomless vaginal-penile sex. no data currently exist concerning time to attain effective tissue levels in men who do not have sex with men.62,63,64 pre-exposure prophylaxis should be continued daily while trying to achieve pregnancy and for one month after returning to consistent condom use to cover a 28-day period since the last known hiv risk exposure. repeat hiv testing should be conducted at least three-monthly during prep use. pre-exposure prophylaxis and pregnancy where pregnancy is confirmed in a woman taking prep, the risks and benefits of continuing prep should be carefully discussed. there is currently no clear evidence of harmful effects resulting from significant in utero foetal exposure to tenofovir or emtricitabine. a systematic review that included studies observing hiv-negative and hepatitis b-positive women who took tenofovir and emtricitabine treatment throughout their pregnancies provided reassuring evidence including the following:65 no difference in low birth weights between tenofovir and control regimens no increase in reported birth defects (for both hiv-infected and not infected women) no significant difference in infant growth no significant impact on maternal health. however, increased neonatal mortality risk with tenofovir exposure has been noted in two studies in relation to significantly higher very preterm delivery (< 34 weeks) and associated neonatal mortality when women were taking a tenofovir-based art regimen compared to non-tenofovir art regimen.65,66 there also remains a need to assess longer-term infant growth and bone effects. a limited number of prep studies including hiv-negative women who became, or were already, pregnant when taking prep are starting to emerge with similarly reassuring data to that seen among women using tenofovir or tenofovir and emtricitabine (truvada) for hiv or hepatitis b treatment.18,67,68,69,70 based on the accumulating evidence, the risks for pregnant or breastfeeding hiv-negative women using prep for hiv prevention are thought to be minimal and are outweighed by the prevention benefit where the woman remains at substantial risk of acquiring hiv during this time.71 it is important to explain to women who are taking prep and are confirmed pregnant that most current evidence is based on women using tenofovir or tenofovir and emtricitabine (truvada) as a form of treatment for an existing infection (hiv or hepatitis b), not as a prevention strategy. the woman’s risk of hiv acquisition during pregnancy and breastfeeding should be carefully considered and, where a woman remains at substantial risk of hiv infection, sahcs, in alignment with recent who recommendations, advises that the woman be maintained on prep throughout pregnancy and during breastfeeding. this is particularly important for women who cannot negotiate consistent condom use and where the partner is either of unknown hiv status in a high hiv prevalence setting or known to be hiv-positive but not accessing care, not virologically suppressed or not adhering optimally to treatment. the benefits of continuing prep throughout pregnancy and breastfeeding in order to avoid seroconversion in the pregnant or breastfeeding woman, with consequent significant risk of mtct, are considered to far outweigh any potential risk of tenofovir or emtricitabine exposure to the foetus or breastfed infant.59,60,65 note for south african providers: currently the national south african department of health (doh) guidelines do not recommend prep during pregnancy because of regulatory issues as the medicines control council regulatory approval includes a paragraph stating that prep use is contraindicated in pregnancy. studies are currently underway to increase the exposure of pregnant and breastfeeding women to tenofovir-based prep and it is hoped that the doh guidelines will soon be updated to synchronise with who recommendations. in this context, the final decision should be made through full consultation between clinician and client with a balanced consideration of risks and benefits. oral tenofovir-based prep is also considered safe in breastfeeding because: transfer of tenofovir from maternal plasma to breast milk is limited. infant exposure was found to be > 200 times lower than the proposed infant therapeutic dose. tenofovir was not detected in 94% of infant plasma samples.71,72 note: pre-exposure prophylaxis use in pregnancy should be accompanied by high levels of pharmacovigilance. providers are strongly encouraged to report any adverse maternal or infant outcomes to their national regulatory authority and any established prep or art safety registry or committee. the importance of hiv retesting all hiv-negative partners, whether choosing to take prep or not, should be retested regularly for hiv. it is recommended that this be done at least every three months during pregnancy attempts. hiv acquisition during pregnancy, and immediately following pregnancy, remains high despite increased access to, and initiation of, art in the general population. in south africa, the maternal hiv incidence rate was 10.7 per 100 person years (py) and 12.4 per 100 py in urban health facilities in 2013.73,74 in a recent meta-analysis, mtct risk was significantly higher among women with newly acquired hiv infection during pregnancy or breastfeeding compared to those already known to be hiv-infected in the post-partum period (odds ratio [or] 2.9, 95% confidence interval [ci] 2.2–3.9) or in the pregnancy and post-partum periods combined (or 2.3, 95% ci 1.2–4.4).75 for females who achieve pregnancy, retesting should be continued at least three-monthly throughout pregnancy and breastfeeding, along with counselling about the continued use of risk reduction strategies to avoid seroconversion during pregnancy or the breastfeeding period, as this is associated with higher health risks to women (higher maternal morbidity and mortality) and very high risks of mtct because of the high vls seen during acute hiv infection.75 hiv-negative partners who have proven seroconversion at retesting should be initiated on art, as per the utt approach. as hiv self-screening becomes more widely available and acceptable,76 this provides an important alternative for hiv-negative partners who may not want to attend a clinic to access regular testing. education should be provided about reliable, quality assured self-screening brands as they become available in each country, as well as advice about how regularly to test and what to do should a self-screening result be positive. any positive self-screening result must be confirmed according to standard algorithms for facility-based or community-based testing.77 post-exposure prophylaxis post-exposure prophylaxis (pep) is recommended for accidental exposure to hiv, either occupational or non-occupational.78 it is, however, no longer recommended as a key strategy for persons trying to achieve pregnancy because of the repeated risk exposures usually required to achieve pregnancy, which then necessitates repeated rounds of pep. any individual trying to achieve pregnancy who presents for pep after condomless sex within the last 72 hours should be provided with a single course of pep as per existing guidelines. they should then be counselled and offered to transition to daily prep, if available, as a preferred prevention method because of the expectation of repeated hiv risk exposures as they continue to try and achieve pregnancy. other components of prepregnancy workup table 3 (see section ‘integrated package of care’) shows recommended basic investigations that may be undertaken in primary care facilities as part of prepregnancy workup in both resource-limited and resource-intensive settings. table 3: prepregnancy screening for hiv-positive individuals desiring a child in resource-limited and resource-intensive settings. integrated package of care integrated care should be strongly supported. clients should be counselled prior to their prepregnancy workup about these investigations and why they are important for their health. these investigations include the following: hiv-related investigations. syphilis and hepatitis b screening, haemoglobin measurement and physical examination including a full genital examination to identify any signs of stis. a papanicolau (pap) smear should be performed for all women who do not have a documented normal result within the recommended screening period, based on national cervical cancer screening guidelines. abnormal pathology, including high grade squamous intraepithelial lesions, should be managed according to national guidelines79 prior to trying to achieve pregnancy, and the couple should be advised to defer pregnancy attempts until the abnormal result has been managed further and any healing following excisional biopsy has taken place (which usually takes six weeks). should a woman require extensive excision, including cone biopsy, there may be a slightly increased risk of pregnancy loss, preterm delivery and preterm premature rupture of membranes, and the client should be counselled about this.80 good communication should be maintained between the cervical cancer screening and gynaecology team and the safer conception provider to ensure appropriate follow-up should pregnancy be achieved. national guidelines should be consulted to inform referral of women with abnormal pathology to the appropriate specialised services. basic investigations may be extended, where resources allow, to include a full screen for torch infections (toxoplasmosis, rubella, cmv, herpes simplex and other congenital infections), along with a full hepatitis screen and full blood count. sexually transmitted disease screening and treatment all males and females should be screened, using a basic questionnaire81 for new sti symptoms at each visit. if either partner is confirmed, or suspected, to have an sti then both partners should be managed according to local guidelines. the treatment course must be completed before pregnancy attempts begin. in most settings, sti screening and management will be based on the syndromic approach.81 however, because of the high rate of asymptomatic stis seen in many populations,82 if available, tests for chlamydia trachomatis, gonorrhoea (neisseria gonorrhoeae), trichomonas vaginalis, syphilis and herpes simplex virus-2 should be performed and any positive results managed by treating the client and his or her partner according to current treatment algorithms. effective sti screening is not only important for hiv transmission risk reduction but also to avoid the negative consequences of sti infections during pregnancy. these include higher risks of miscarriage, intrauterine growth retardation, premature labour and delivery, and the possibility of neonatal, congenital sti infection.83 timed condomless sex timed condomless sex is an additional safer conception strategy that may be used by some couples.35 it is recommended for all hiv-affected couples where an undetectable vl cannot be confirmed. the risk of sti transmission or acquisition when condoms are not used should always be noted. in those couples where u=u applies – one or both partners are hiv-positive with a sustained undetectable vl and maintained adherence – careful timing of condomless sex to the woman’s peak fertile days is no longer considered necessary. this is because correctly identifying the days of peak fertility can be difficult and restricting couples to certain days may not actually increase their chances of conceiving and may instead create confusion and/or stress within the relationship by disrupting their usual patterns of intercourse. in presumed fertile, u=u couples, it may be best to avoid such ‘meddlesome’ activity84 and leave the couple to have regular condomless sex without strict timing. although viral shedding in semen has been reported to occur even in men who are fully suppressed on art,85 recent evidence indicates that this detectable virus in seminal fluid may be particles of hiv rna or dna rather than entire, viable virions, which are required to be infectious; therefore, such detectable virus should not lead to hiv transmission.7 because some hiv-affected but u=u couples may prefer to reduce risk as much as possible, the pros and cons of timed coitus should be discussed with all couples. for seroconcordant and serodifferent couples where viral suppression is not possible, or cannot be confirmed, and for individuals with a partner of unknown hiv status, the option of having condomless sex timed to the window of ovulation in order to limit hiv risk exposure while trying to achieve pregnancy should be discussed. for most couples this is the most feasible risk reduction strategy available to them. partners must be aware of the potential risk of hiv transmission or reinfection and should understand that this risk increases on a continuum – the higher the vl, the higher the risk of hiv transmission per condomless sex act.86 couples should be offered information on how to time condomless intercourse to the peak fertile window (see appendix 2). couples should be informed that timed condomless sex should be combined with other risk reduction strategies, including art adherence and, where appropriate and available, prep (see section ‘medical male circumcision’, table 4). for hiv-positive seroconcordant couples, the possibility of reinfection, or transmission of different or resistant viral strains, should be discussed, particularly if one partner is not virally suppressed and there is a concern about treatment failure and possible art drug resistance. this may become more common as the hiv epidemic evolves and more individuals develop resistance to first-line therapy. table 4: summary of optimal risk reduction strategies for resource-limited and resource-intensive settings, according to the hiv status of the couple. self-insemination for male hiv-negative serodifferent couples an alternative to timed, condomless sex is intravaginal self-insemination.87 this technique is low cost, requiring only a clean, needleless syringe and a condom without spermicide or a clean specimen cup (see appendix 3). the healthcare provider can teach the couple how to do this procedure in their own home: couples should have timed sex using a condom (without spermicide), aspirate the semen from the condom using a needleless syringe and then insert the syringe into the vagina and slowly ‘inject’ the semen. the man can also masturbate and ejaculate into a clean specimen bottle from which the semen can be drawn up into the syringe and inseminated into the female’s vagina within the hour, being kept at body temperature if there is any delay between ejaculation and insemination. reassure couples that any child conceived will still be genetically the man’s child, as this has been raised as a concern in some qualitative studies exploring community perceptions of this option.38 alternatively, if the couple prefers, freshly collected semen can be brought to the clinic and vaginal insemination can easily be performed by the healthcare provider. the semen should be kept at body temperature in a clean specimen jar (not condom) and the couple should be helped at the clinic within the hour. other hiv-affected couples may choose this technique if there is anxiety about hiv transmission when trying to conceive using condomless sex. however, for these couples, there is no additional hiv risk reduction benefit gained from using this technique. it may be an option for couples who experience sexual dysfunction arising because of anxiety about having condomless sex. sperm washing in resource-intensive settings, a serodifferent couple with an hiv-positive male partner may opt to use sperm washing as a risk reduction strategy.88 following sperm washing, the couple would need to undergo iui, ivf or icsi, which are costly and invasive procedures when compared to natural conception. again, the pros and cons to this approach should be discussed with the couple. as the risk of timed condomless sex is now considered to be so low in the setting of viral suppression with art, even couples in resource-intensive contexts may prefer to opt for natural conception and avoid the costs, hospital visits and stress that can be associated with utilising iui or other assisted reproductive technologies. medical male circumcision hiv-negative men should be counselled on the benefits of male circumcision as an additional hiv risk reduction strategy.89 there is also possibly a smaller benefit for partners of hiv-positive men in serodifferent relationships as circumcision may slightly reduce male-to-female hiv transmission risk.90 medical male circumcision (mmc) also reduces the risks of some other stis and cervical cancer in female partners.90 if medical male circumcision is performed, the couple should wait before trying to achieve pregnancy for at least six to eight weeks or longer if there is still discomfort to ensure complete healing of the circumcision wound. note: across all groups, male and female partners (where engaged) should be screened regularly for stis as per existing syndromic screening and management guidelines (or as per available tests and protocols). if a new sti is detected in either partner, pause pregnancy attempts until both partners have completed treatment. clients with no immediate plans for a child couples and individuals who wish to prevent a pregnancy in the near future should be offered a reliable contraceptive method of their choice, within a rights-based framework, as per existing national2,91 or global22 contraceptive guidelines. although fertility may be reduced, particularly in advanced hiv disease, the overall incidence of pregnancy is seen to increase following access to art.92 importantly, the rate of unintended pregnancy remains high among hiv-positive women, just as seen in the general population.93 access to contraception contributes to the goals of emtct by strengthening pillar 2 of the pmtct programme (prevention of unplanned pregnancies), which remains one of the weakest areas of pmtct programme implementation in many countries. using contraception is also an option for couples who do wish to achieve pregnancy but where certain aspects of their health need to be optimised before pregnancy attempts are undertaken. initiating short-term contraception in this situation may help to prevent pregnancy being achieved under suboptimal conditions and different contraception options should be discussed. examples where this may be relevant include when the hiv-positive partner is taking treatment for an acute opportunistic infection such as tuberculosis or other infection such as bacterial sti; where the female’s cd4+ count is still low but expected to improve; where the positive partner is only just initiating on art and is not yet virally suppressed or where a new non-communicable disease is diagnosed and treatment is being optimised. an important consideration is to use a method with immediate return to fertility, as summarised in box 3 (‘special considerations when providing contraception to hiv-positive women’ section). these couples should be encouraged to continue using male or female condoms as part of dual protection. box 3: expected return to fertility with different contraceptive methods. important points to note when providing contraception services method selection will be based on medical eligibility,94 screening and information about contraceptive choices. clients should be encouraged to discuss any new plans to achieve pregnancy with their provider, so that contraception can be discontinued in conjunction with supportive interventions to ensure a safe, healthy pregnancy. informed decision-making is key. information about mechanisms of action, possible side effects and return to fertility after discontinuing a method should be provided. myths and misconceptions should be addressed, particularly those relating to contraceptive use as a cause of infertility. partner involvement should be discussed and supported if the woman requests; however, she may choose to make her decision independently of her partner. after a woman has given birth, a reliable method of post-partum contraception should be prioritised, with informed consent, to ensure that the next child, if desired, can be planned with appropriate spacing. all women should be encouraged to use dual methods, combining their contraceptive choice with the consistent use of male or female condoms to reduce the risk of hiv and stis. avoiding stis, via consistent condom use, is an important consideration for women who may wish to have a child later, as stis such as c. trachomatis are associated with both reduced fertility and risk of miscarriage and pregnancy complications, including intrauterine growth restriction, and premature labour and delivery.95 where an individual or couple communicates that they prefer not to use condoms, the following counselling messages should be covered:59 where the hiv-positive partner is virally suppressed and/or the hiv-negative partner is on prep, not using a condom still has risks: undetectable vls are dependent on art adherence and need to be monitored. undetectable vl and/or prep prevents hiv transmission but does not prevent other stis and pregnancy (unless reliable contraception is used). a regular sti screening and management plan should be confirmed with the client. vaccination against all vaccine-preventable stis, for example, hepatitis a and b and hpv, should be offered where possible. information about emergency contraception should be provided. information and counselling should be provided about rights and options in terms of safe abortion should an unintended pregnancy occur. special considerations when providing contraception to hiv-positive women a range of detailed resources are available that provide guidance on contraceptive provision, including for women living with hiv.22,94 key points are highlighted as follows: numerous effective contraceptive options are available for safe use by women living with hiv. these include barrier methods (male and female condoms), hormonal injectables such as depot medroxyprogesterone acetate (dmpa) or norethisterone enanthate (net-en), combined oral contraceptive pills (cocp), subdermal contraceptive implants, intrauterine contraceptive device (iucd) and levonorgestrel intrauterine system (lng-ius).2,91,94 long-acting reversible contraceptive options, particularly the iucd, should be encouraged where possible, especially among young women, because of fewer side effects, better adherence and immediate return to fertility following removal. the iucd is also a recommended option for women who have completed their families but do not wish to access permanent sterilisation. drug interactions, as per the who medical eligibility criteria (mec) and country guidelines, need to be considered, for example: the efficacy of subdermal implants in preventing pregnancy may be compromised because of drug interactions with certain antiretroviral drugs, such as efavirenz,96 and certain other enzyme-inducing tuberculosis (tb) and antiepileptic drugs.97 women who choose this as a method need to be counselled about the risks and the need for consistent male or female condom use as additional protection. however, there is no need to counsel against implant use or advise early removal of implants in women living with hiv. non-nucleoside reverse transcriptase inhibitors, particularly efavirenz, interact with the cocp such that there is a marginally higher rate of pregnancies seen in women on efavirenz and cocp, but the pregnancy rate observed was still considerably lower than among women on no form of modern contraception.96 women on protease inhibitors did not have a significantly higher rate of pregnancy.96,98 the cocp should, therefore, remain an option for women on these arvs and is preferable to being on no reliable contraception when the cocp is the woman’s preferred choice. however, as with the subdermal implant, more extensive interactions are seen with tb drugs, particularly rifampicin, as well as antiepileptic medications, so these interactions should be reviewed before proceeding with a final choice for women on one or more of these medications. again, dual prevention with consistent male or female condom use should be recommended to all women. there are various options for women and couples who do not want any further children in the future. these include long-acting reversible methods and voluntary male or female sterilisation. the latter should only be performed after thorough, non-coercive counselling to ensure there is full understanding that this option is permanent and not reversible and in compliance with national guidelines on voluntary male and female sterilisation. it is also important to note that for hiv-negative women there are concerns that dmpa/net-en hormonal injectable contraceptives may be associated with an increased risk of hiv acquisition and transmission.99 any hiv-negative female who chooses this contraceptive option should be counselled about the importance of consistent condom use to prevent hiv-infection, the option of treatment as prevention where her partner is on art and virally suppressed and the increasing availability of prep. figure 3: contraceptive methods for hiv+ individuals, including those on antiretroviral therapy. additional considerations for optimising prepregnancy health identifying and managing comorbidities both partners should be screened for any other comorbidities. it is strongly recommended that hiv-positive women should have a cd4+ count of 200 cells/ml or more before considering pregnancy so that their risk of opportunistic infections and deteriorating health during the pregnancy can be minimised. however, many women with a cd4+ count lower than this have successfully carried a healthy pregnancy to term and, for some women, waiting until their cd4+ count has risen to over 200 cells/ml following art initiation may not be possible, including if they have a slow response or are already over 35 years of age. in this situation the woman should be counselled about the risks of being pregnant with a lower cd4+ count and appropriate prophylaxis should be considered, including cotrimoxazole and isoniazid prophylactic therapy to prevent tb. hiv-positive partners should also be screened for opportunistic infections, in particular tb. should an opportunistic infection be detected that requires a finite period of treatment, the couple should be encouraged to defer pregnancy attempts until the treatment course is complete and the individual has returned to full health. hiv-positive women who are on fluconazole because of a history of cryptococcal meningitis or positive cryptococcal antigen should be alerted to the risk of craniofacial and skeletal deformities following first trimester exposure to high-dose fluconazole.101 clients in this situation should be encouraged to defer pregnancy attempts until cd4+ reconstitution has been confirmed to be at least between 100 cells/ml and 200 cells/ml on two separate occasions so that the fluconazole prophylaxis can be safely discontinued without risk of cryptococcal disease relapse.102 in the rare situation where cd4+ reconstitution above 100–200 cells/ml does not occur, the risks of continuing versus stopping fluconazole during the first trimester, if pregnancy is achieved, should be discussed. screening should also be offered, where available, for chronic co-infections such as hepatitis b. where hepatitis b infection is confirmed, this should be managed according to guidelines.103 if the couple is confirmed hepatitis b serodifferent then the hepatitis b-negative individual should be offered immunisation before pregnancy attempts are undertaken; the hepatitis b-positive individual should be established on effective therapy and, where possible, the hepatitis b vl should be confirmed to be undetectable. where the hepatitis b-positive individual is co-infected with hiv, the use of tenofovir and emtricitabine or lamivudine should prove sufficient for hepatitis b infection management as well. a female client with hepatitis b should have her hepatitis b vl monitored during pregnancy and the labour and delivery team should be alerted to the possibility of congenital hepatitis so that the newborn can be provided with immunoglobulin and immunisation, where available, as per current recommendations.103 where there is no evidence of hepatitis b infection or immunity (surface antigen and surface antibody negative) in either partner then vaccination should be considered, particularly in higher prevalence settings. female clients should be screened for non-communicable diseases including hypertension and diabetes mellitus. where present, blood pressure and/or glucose control should be optimised prior to pregnancy attempts being undertaken. complex cases should be referred to the relevant specialist for assistance with management optimisation. where feasible, acknowledging resource constraints, male clients should also be screened and managed for non-communicable diseases. obesity is increasing globally. should one or both partners be obese then possible ways to assist with appropriate weight reduction should be discussed. obesity is associated with reduced fertility in both men104 and women,105 and this may be an important motivational factor to encourage weight loss. obese clients, especially pregnant women, should be screened regularly for hypertension and diabetes mellitus. for all other chronic conditions that require treatment throughout pregnancy, it is important to review all medications for potential teratogenicity, for example, anticonvulsant therapy, and switch to alternatives where possible or counsel the female client about the risks of continuing or stopping therapy where alternatives do not exist. all chronic conditions should be optimally managed before pregnancy attempts are undertaken. prepregnancy counselling (see appendix 1) should also include information about a healthy lifestyle, as well as the negative impact of smoking, excessive alcohol intake and recreational drug use on both fertility and pregnancy outcomes. women who are 35 years and older should be counselled about the impact of advanced maternal age on fertility, first trimester miscarriage, pregnancy complications and pregnancy outcomes including stillbirth and chromosomal abnormalities, most notably trisomy 21 (down syndrome).106 prenatal screening for foetal abnormalities, and other higher-level care, may be offered based on maternal age according to routine national antenatal care guidelines. all women should have a full obstetric history taken as part of the prepregnancy workup. any woman with heightened obstetric risk should be referred to, or discussed telephonically with, a specialist obstetrician/gynaecologist, where available, to ensure risks with any future pregnancy can be managed. deferring pregnancy for hiv-positive individuals or couples – is it ever appropriate? ultimately the decision whether or not to achieve pregnancy rests with the client and providers should avoid personal judgements, especially concerning socio-economic or relationship status. however, there are medical circumstances in which a clinician should encourage the couple to consider deferring pregnancy, including the following instances: one or both partners are not virally suppressed, not consistently adherent to art for at least six months or prep is not in use. there is suspicion of infertility and there are available resources to investigate and manage any underlying condition. there are relative medical contraindications to pregnancy. there is harmful substance use with motivation to stop use of the substance, allowing time to access rehabilitation support. the woman had a recent miscarriage. the woman has a cd4+ count below 200 cells/ml and only recently started art, whereby there is still the possibility of immune reconstitution. in these instances, clients should be encouraged to attempt pregnancy only once health has been optimised. where absolute contraindications exist, making pregnancy permanently inadvisable, the couple needs to be counselled accordingly, including the availability of other options such as fostering and adoption. pregnancy should be avoided and other options sought when: there is evidence or confirmation of infertility. there are absolute medical contraindications to pregnancy. there is harmful substance use with no intention to stop substance use. expected time to pregnancy and fertility assessment trying to achieve pregnancy through condomless sex should only be undertaken if the couple are presumed fertile and expected to have a reasonable chance of achieving pregnancy. in contexts where resources are limited, this can be difficult to accurately assess. where fertility potential is untested, the couple should try for at least six months before investigations are considered. hiv itself can negatively impact male and female fertility.107 fertility, although improved with art, may not return to normal. in the female, hiv may be associated with anovulation, amenorrhoea and premature ovarian failure. in males, hiv may negatively impact testosterone levels, libido and may contribute to erectile dysfunction.107 expected time to pregnancy it is recommended that a presumed fertile, hiv-affected couple attempt pregnancy for at least six months before considering possible infertility.108 the best chance of pregnancy is seen in the first six months of attempting pregnancy.109 although infertility is defined as the failure to achieve pregnancy after one year of regular, condomless intercourse, hiv-affected couples should be referred sooner, where referral options exist, to avoid prolonged hiv risk exposure. failure to achieve pregnancy can be a considerable source of relationship stress so the provider should explain to any presumed fertile couple that, depending on age, up to 50% of couples in the general population will achieve pregnancy in the first six months, a further 30% – 40% of couples who continue trying will achieve pregnancy by 12 months and a further 5% – 15% will achieve pregnancy if they continue trying up to 24 months. up to 5% – 10% of couples will not achieve pregnancy, suggesting underlying infertility.110,111 pregnancy testing it is recommended that female clients perform a pregnancy test, using a home testing kit or by consulting with their provider for testing, if they miss their next expected menstruation. urine beta-human chorionic gonadotropin (bhcg) is a reliable test to confirm pregnancy. suspected infertility where infertility is suspected, it is important that couples understand that male and female causes of infertility are equally common and it should never be assumed that one partner is ‘responsible’ for difficulty in conceiving (see table 5).112 in 22% of couples the infertility is male cause only. in 31% it is female only, with secondary infertility being more common than primary. in 21% both partners have an underlying problem. in up to 14% of couples no cause is found and 12% of couples conceive while undergoing infertility investigations. table 5: causes of female infertility in sub-saharan africa. fertility assessment in low-resource settings a thorough history can detect warning signs of possible underlying fertility issues, including the following: previous history of sti no history of prior pregnancy despite regular condomless sex previous ectopic pregnancy possible male factor infertility (e.g. previous vasectomy; undescended testis). for guidance on how to take a detailed fertility history providers are referred to the following resource:84 http://www.fertilitytool.com/tools/basic-tool-4-diagnose-infertility/support-tool-4-how-to-diagnose-infertility/action-1-take-infertility-history/. (note: the figo fertility toolbox is an invaluable tool for providers working in all settings who find themselves managing clients with suspected or confirmed infertility.) where referral options for further investigation and management do not exist, couples should be counselled about the risks of trying, or continuing to try, to achieve pregnancy where infertility is suspected. alternative parenting options or adjusting to the possibility of childlessness should be discussed. fertility assessment in high-resource settings where resources are available, clients with a history indicative of infertility, or who have already tried to conceive for more than six months, may be referred to specialist fertility services for further workup, including hormone profiles in women and semen analysis for male partners. fallopian tube blockage is also a common cause of infertility, which can be readily investigated via a hysterosalpingogram and, if a uterine abnormality such as fibroids is suspected, then a pelvic sonar should be performed. where a couple is confirmed to be infertile, they may be candidates for assisted reproductive technologies such as ivf, iui or icsi, although these are often either unavailable or unaffordable for the majority of people living in high hiv prevalence settings. managing safer pregnancy outcomes when pregnancy is confirmed all female clients with confirmed pregnancy should be linked to their local antenatal care provider as soon as possible, preferably on the same day. hiv-positive female: repeat vl on the day pregnancy is confirmed to ensure sustained viral suppression. emphasise treatment adherence throughout pregnancy and breastfeeding, providing reassurance about the safety of art exposure during pregnancy. hiv-negative female: retest on the day of pregnancy confirmation and after the window period according to the last risk exposure. if the woman is on prep, discuss continuing versus returning to other hiv prevention strategies. regular retesting, at least three-monthly, should be encouraged throughout pregnancy and breastfeeding, and hiv prevention strategies, including consistent condom use, should be encouraged. hiv-positive male partner: ensure the male partner remains linked to routine art services. if eligible, he may benefit from joining an adherence club or other form of differentiated care for stable patients. hiv-negative male partner: retest on the day of pregnancy confirmation and at the end of the window period according to the last risk exposure. all couples should be encouraged to return to consistent condom use, not only for hiv transmission prevention but also avoidance of new stis. provide information about antenatal, intrapartum and postnatal care pregnancy confirmation provides the perfect opportunity to provide basic information about what to expect during the antenatal and postnatal periods in terms of vl monitoring or hiv retesting, management of the baby if they are hiv exposed and recommended infant feeding options. ongoing male partner involvement should be encouraged, and male involvement should be supported by a conducive environment being provided in antenatal and postnatal care services. male involvement has been shown to improve maternal and infant outcomes, overall and in terms of pmtct.113,114 provide information about safe infant feeding to lay a foundation for repeated counselling throughout pregnancy.115 the female (and if possible, her male partner) should be advised about post-partum contraception to avoid future unintended pregnancy and to support appropriate spacing should another child be desired in the future. couples who are engaged in safer conception care often become aware of their pregnancy very early on, sometimes at just 2–3 weeks gestation. miscarriage remains a significant risk up until around 14 weeks of pregnancy and couples should be counselled about this possibility but reassured that there is little that can be done to prevent miscarriage. if miscarriage does occur, they should return straight to the clinic for appropriate management. the woman should be encouraged to remain on folic acid supplementation throughout at least the first three months of her pregnancy. other antenatal supplements should be given as per local guidelines. counselling for those experiencing miscarriage if an individual or couple returns to report a miscarriage, appropriate counselling should be provided and the woman managed as per local guidelines. it is important to acknowledge the disappointment and grief associated with miscarriage and to emphasise to the couple that no one is to blame and that early pregnancy loss is usually a result of an abnormality that occurred during early development of the foetus. miscarriage is common, occurring in up to 25% of pregnancies. a couple is not at any increased risk of a further miscarriage unless they have had three or more miscarriages, at which point they should be referred to a specialist for further investigations. after a miscarriage, couples may want to start trying to conceive again straight away. it is recommended that the couple can start trying within three months from their loss, if they feel ready to do so.116 the preconception workup should be repeated to ensure that the couple are still ‘safe’ to start trying again. special situations what if an hiv-positive woman desires a child but does not have a partner? options include insemination from alternative sperm sources such as a sperm bank or known male sperm donor (hiv status should be known), surrogacy or adoption. it is worth knowing what resources exist in your area, what the stipulated eligibilities are and what financial resources would be required. a man or woman may also present without a stable partner, communicating their desire for a child. whether they have one or multiple current, but not necessarily long-term, partners, they should still be offered all the available risk reduction strategies without judgement. counselling should include a discussion about the increased risks associated with attempting to conceive via, or impregnate, multiple partners, if that is their chosen approach to fulfil their fertility intentions. men who have sex with men, transgender and female same sex couples options also exist for couples who may not be able to conceive naturally because they are in a same-sex relationship or one or both partners are transgender. where necessary, further advice should be sought from the appropriate specialist to support these couples to achieve their reproductive goals as they have the same reproductive rights as heterosexual couples. options include surrogacy for same-sex male couples and sperm donation for same sex female couples. a transgender male who is in a relationship with a cis-male (cis-male is a male whose gender identity corresponds to the biological identity assigned at birth) may still be able to conceive and carry the pregnancy to term and should remain engaged in care to appropriately manage hormone therapy throughout pregnancy. acknowledgements thanks to the wits reproductive health and hiv institute (wits rhi), in particular natasha davies and melanie pleaner, for their support in writing and editing these guidelines. thanks also to those working in the international safer conception community and the clients of safer conception services, who helped to inform these updated guidelines. competing interests no funding or assistance was provided for this process. and no authors have any conflict of interest to declare. authors’ contributions n.e.c.g.d. was the committee chair and primary author of the guidelines. all other authors either reviewed and contributed to the manuscript electronically and/or attended a full-day committee meeting where the guidelines were discussed and developed. t.r., m.p. and m.m. edited the document to produce the final version. references bekker l-g, black v, myer l, et al. guideline on safer conception in 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retrospective cohort study. plos one. 2013;8(6):e66517. https://doi.org/10.1371/journal.pone.0066517 world health organization. updates on hiv and infant feeding. geneva: world health organization; 2016. schliep kc, mitchell em, mumford sl, et al. trying to conceive after an early pregnancy loss: an assessment on how long couples should wait. obstet gynecol. 2016;127(2):204–212. epub 2016/03/05. https://doi.org/10.1097/aog.0000000000001159 brotman rm, klebanoff ma, nansel tr, et al. a longitudinal study of vaginal douching and bacterial vaginosis – a marginal structural modeling analysis. am j epidemiol. 2008;168(2):188–196. https://doi.org/10.1093/aje/kwn103 van oostrum n, de sutter p, meys j, verstraelen h. risks associated with bacterial vaginosis in infertility patients: a systematic review and meta-analysis. hum reprod. 2013;28(7):1809–1815. epub 2013/04/02. https://doi.org/10.1093/humrep/det096 mirmonsef p, krass l, landay a, spear gt. the role of bacterial vaginosis and trichomonas in hiv transmission across the female genital tract. curr hiv res. 2012;10(3):202–210. https://doi.org/10.2174/157016212800618165 appendix 1: prepregnancy counselling – checklist and key messages prepregnancy counselling should ensure an informed choice about reproductive options, including any risks and costs involved with each strategy, as well as the likely chances of success. prepregnancy counselling should include the following: a summary of available data on the safety of different strategies, and the impact of combining strategies to optimise risk reduction. all safer conception strategies are considered risk reduction strategies and no provider should guarantee a risk-free process. the importance of viral suppression for the hiv-positive partner with continued full adherence to art (undetectable equals uninfectious: u=u) should be clearly explained. because vl cannot be monitored continuously, full adherence is key to this approach, particularly if it is to be used in isolation, without any other strategy. should there be an interruption in art drug supply, or suboptimal adherence, at any point the client must alert their provider and pregnancy attempts should be deferred until viral suppression can be reconfirmed or other prevention strategies introduced. a discussion of prep as an option in certain situations, especially where viral suppression may not be guaranteed, for example, hiv-positive partner recently initiated art or concerns about adherence, not yet engaged in care or of unknown hiv status. the importance of regular sti screening. the need to assess for reduced fertility at an early stage to avoid the possibility of prolonged risk exposure during ongoing pregnancy attempts in the context of infertility where a couple has not conceived after at least six months of correctly timed pregnancy attempts. the risk of transmission to a non-infected partner and mtct if the female partner is hiv-infected, or becomes hiv-infected, and is not established on art with an undetectable vl. the importance of reporting any pregnancy as soon as possible to ensure early access to antenatal care so that maternal healthcare and pmtct interventions can be optimally provided throughout the pregnancy. information about available pmtct strategies for use throughout the pregnancy and breastfeeding period. the importance of lifelong adherence to art for any hiv-positive partner, for their own health and the prevention of horizontal and, for women living with hiv, vertical hiv transmission. all female partners, regardless of hiv status, should be started on folic acid supplementation, as per local guidelines, prior to undertaking pregnancy attempts. key counselling points about conception options prepregnancy counselling should include the presentation of all safer conception options so that the individual or couple can make an informed decision about which strategy, or combination of strategies, they would like to use: condomless intercourse, even without peak fertility timing, is now considered a very safe option in the setting of consistent art use with confirmed viral suppression (< 200 copies/ml), ongoing full adherence and sti screening for both partners, where possible. where viral suppression cannot be confirmed, explore additional strategies including limiting condomless intercourse to the peak fertile window, prep and mmc. in resource-intensive settings, explore pros and cons of undertaking more costly conception options, including sperm washing and iui, ivf or icsi. appendix 2: determining a woman’s fertile window the basics: ensure that clients understand how a woman’s reproductive cycle works. this is often poorly understood and forms the basis for optimising the strategy of timed condomless sex or self-insemination for safer conception. remember: for those hiv-affected couples who are u=u, precise timing of condomless sex to the fertile window is not considered necessary. if they are comfortable to do so, the couple should be advised to have regular, condomless sex, two or three times per week spread out equally over each week when the woman is not menstruating. for those couples who are anxious about multiple condomless sex acts, the strategy of timing condomless sex to limit them to the days of highest fertility can be explained. explain the following: when an hiv-affected couple is advised to, or chooses to, limit their condomless sex acts to peak fertility, determining a woman’s fertile period is necessary to establish the timing of periovulatory intercourse. there are various ways in which a woman’s fertile period can be determined. the methods described here presume normal fertility and require minimal resources. in situations where a woman’s fertility may be impaired, more resource-intensive methods such as day 21 progesterone measurements or serial ultrasound monitoring, with or without ovulation stimulation through clomiphene administration, may be used by a reproductive specialist. these more intensive methods may also be used in women living with hiv (who have presumed normal fertility) in order to increase their chance of fertility prediction. fertile dates the average normal duration of a menstrual cycle is 28 days. the first day of a woman’s menstrual period is considered to be day 1 of her menstrual cycle. ovulation is anticipated to occur 14 days before the next period is due to start. her fertile period would be from five days before predicted ovulation up until 1–2 days after ovulation. for example, in a woman whose cycle is 28 days long, ovulation would be assumed to occur on day 14. the woman’s fertile period would therefore occur between days 9 and 16 of her menstrual cycle. this creates a seven-day window. this may be narrowed down to a peak fertile window of four days if the couple would like to minimise risk exposure further. this would be calculated as two days before predicted ovulation, the day of ovulation and one day after predicted ovulation. however, menstrual cycle length may differ considerably between women and may even differ from month to month for an individual woman. it is therefore essential that a woman keeps a record of her menstrual cycle (typically taking into account the first day of her menstrual period) in order to determine an average menstrual cycle length. it is important to explain to patients that regular menstrual cycles may not necessarily indicate that ovulation has occurred. ovulation is less likely to be occurring in women whose cycle is 24 days or less or 35 days or longer. there are now several mobile phone applications that are available for free that can assist women to keep track of their cycles and to predict ovulation. this can be a very helpful resource. examples include cyclebeads™ and dot™. it may take up to four months to establish an average cycle length where cycles are irregular and the more months that are recorded the more accurate the timing can become when using this method. ovulation prediction kits (for urine and saliva) a number of over-the-counter products are available that enable ovulation prediction. these methods may utilise sampling and analysis of either urine or saliva and detect the surge of luteinising hormone that occurs immediately before ovulation. these test kits are becoming more affordable and can limit risk exposure to just two days per cycle because of their high levels of accuracy. the use of ovulation prediction kits can be particularly useful for women with irregular cycles where the calendar method is often not as helpful. in women where there may be a concern about anovulatory cycles, ovulation test kits may also help to identify if the luteinising hormone surge is not happening and there is a need for further investigation and management to promote ovulation. cervical mucus monitoring monitoring the cervical mucus changes that occur around the time of ovulation is also a useful means to identify peak fertility. during non-fertile days, the cervical mucus is thick and acidic. in contrast, during fertile days, the mucus undergoes a change to become thin, profuse, transparent and ‘stretchy’ (spinnbarkeit), like raw egg white. a woman’s awareness of these changes in her cervical mucus may help her to predict her fertile period and guide her pregnancy attempts. however, this method may not be as easy to use for some women, particularly those who use certain hygiene practices including douching or vaginal drying, as the cervical mucus is disrupted or washed away so changes in vaginal secretions may not be as easily observed. if the provider gathers a history of vaginal hygiene practices, it is advisable to counsel the client against such practices as there may be an association between vaginal douching or drying and increased rates of bacterial vaginosis,117 which in turn may be associated with increased rates of hiv transmission and pregnancy loss.118,119 appendix 3: low-technology sperm collection and self-insemination techniques artificial insemination is the process whereby semen is introduced into the female reproductive tract other than by sexual intercourse. it may be intrauterine or vaginal, the former being a specialist procedure. the latter is a low-risk procedure that can be carried out by a healthcare provider or at home by the patient herself or her male partner. it is advisable that vaginal insemination be attempted at the most fertile time in the menstrual cycle, as described above. semen needs to be provided in a clean receptacle, either by male ejaculation into a condom during intercourse or by male ejaculation into a clean specimen jar provided for the purpose. the semen (most men ejaculate 1.5 ml) should be inseminated as soon as possible, and within an hour of ejaculation. if the ejaculate is collected from a condom the couple must ensure that the condom is one that does not include spermicide and the transfer to syringe or clean jar should be done immediately, as latex condoms can cause sperm immobility if exposure is prolonged. other equipment to carry out the vaginal insemination would include a ‘turkey baster’, 5 ml or 10 ml plastic needleless syringe or plastic disposable pipette. these items should be supplied to prospective couples or individuals along with the instructions in the diagram. figure 1-a3: diagram of self-insemination. hiv 885 original article transitioning behaviourally infected hiv-positive young people into adult care: experiences from the young person’s point of view c katusiime, r parkes-ratanshi, a kambugu department of prevention, care and treatment, infectious diseases institute, college of health sciences, makerere university, kampala, uganda c katusiime, mb chb, pgdppm, miph r parkes-ratanshi, mbbs, ma, mrcp, phd department of research, infectious diseases institute, college of health sciences, makerere university, kampala, uganda a kambugu, mb chb, mmed corresponding author: c katusiime (katutina1@gmail.com) background. there is limited literature on the transition of young people living with hiv/aids (yplhiv) from adolescent/young adult hiv care to adult hiv care in sub-saharan africa. objective. we aimed to share the experiences of hiv-seropositive young adults transitioning into adult care, to inform best practice for such transitioning. methods. we conducted a retrospective evaluation of the transition of 30 young adults aged ≥25 years from our adolescent/young adult hiv clinic at the infectious diseases institute, makerere university, kampala, uganda, to adult hiv healthcare services between january 2010 and january 2012. results. six major themes emerged from the evaluation: (i) adjustment to adult healthcare providers, (ii) the adult clinic logistics, (iii) positive attributes of the adult clinic, (iv) transfer to other health centres, (v) perceived sense of stigma, and (vi) patient-proposed recommendations. a model for transitioning yplhiv to adult care was proposed. conclusion. there is a paucity of evidence to inform best practice for transitioning yplhiv to adult care in resource-limited settings. ensuring continuity in hiv care and treatment beyond young adult hiv programmes is essential, with provision of enhanced support beyond the transition clinic and youth-friendly approaches by adult-oriented care providers. s afr j hiv med 2013;14(1):20-23. doi:10.7196/sajhivmed.885 there are a growing number of behaviourally hiv-infected young people who require hiv care and treatment in resource-limited settings. with improved coverage of hiv care, survival among vertically hiv-infected children is increasing. consequently, an increase in the number of young people living with hiv/aids (yplhiv) who are in need of hiv care and treatment services is inevitable. yplhiv, especially adolescents, are usually managed in adult hiv care programmes by providers who are not trained in the provision of adolescent services. this poses a major challenge as providers are often not fully aware of the most common, adolescent-specific challenges of antiretroviral therapy (art) including adherence, drug-related toxicities (particularly lipodystrophy), hiv status disclosure, late presentation to care, and onset of sexual activity.1 across africa, there are few healthcare programmes tailored specifically for behaviourally hiv-infected young people; these yplhiv are consequently under-served by the healthcare system.2 , 3 furthermore, with improved survival among yplhiv, the need eventually arises to transition them into adult care services. challenges in relation to such transition include the establishment of trusting relationships, which make paediatricians reluctant to transfer yplhiv to physicians with adult-oriented healthcare models, and the difficulty most yplhiv face in disclosing their hiv status to their families and caregivers.2 despite this, there is a scarcity of published information on the challenges faced and successes of transition clinics and models in sub-saharan africa.3 in uganda, there are few adolescent healthcare services available outside of schools,4 , 5 yet there is a national adolescent health policy in place.6 here, to begin to address this gap between policy and practice, we report on the experiences of yplhiv who have been transited from our young adult hiv clinic into adult hiv care. methods the infectious diseases institute (idi) at the college of health sciences, makerere university, kampala, uganda, was awarded a grant from the civil society fund to provide specialised hiv/aids care to hiv-seropositive young adults. the weekly clinic, established and maintained since 2008, is run by a dedicated healthcare team comprised of doctors, nurses, counsellors and peer supporters specialising in adolescent/young adult hiv care. the main emphasis of the clinic is to bridge the gap between paediatric and adult hiv healthcare. this is achieved by offering hiv-seropositive young persons, aged 15 24 years, youth-friendly clinical services and psychosocial support. between january 2010 and january 2012, of 820 young persons enrolled in the young adult hiv clinic, 80 participants aged ≥25 years were transferred to adult healthcare services. approximately 95% of the young adults acquired hiv through horizontal transmission. the remainder were likely to have been infected perinatally. in february 2012 we performed a retrospective evaluation of the transition of 30 of these young adults, aged 25 29 years, from our young adult hiv clinic to our adult hiv clinic. the idi young adult transition process the idi transition process for young adults from the young adult hiv clinic to full adult hiv healthcare is shown in fig. 1. for participants, the transition commenced when the young adults reached 25 years of age; however, the timing of transfer was ultimately determined by patient readiness. the clinic counsellor conducted two exit-interview sessions with each young adult. the sessions, which lasted between 15 and 20 minutes on average, were conducted in the privacy of the counsellors’ rooms. the first exit session was a one-on-one interaction to acquaint the young person with the subject of transitioning to the adult hiv clinic. during the second exit session, which was also a one-on-one session, an exit questionnaire was completed. the purpose of these sessions was to discuss the transition and to assess patient expectations and readiness (appendix 1). fig. 1. the infectious diseases institute (idi) young adult hiv transition model. ya = young adult. data collection and analysis one year after transition, a group evaluation was held to assess the participants’ attitudes and perceptions of the transition process and to determine how they had adjusted to the adult hiv clinic. an evaluation during a peer-support meeting was selected as the best mode to conduct the research, because it closely resembled daily social interaction and was less intimidating than a one-on-one interview. the participants were contacted tele-phonically prior to the event. the evaluation was conducted at the idi premises and was facilitated by the co-ordinator and counsellors of the young adult hiv clinic. participants were reimbursed approximately us$5 each for transportation costs. the group evaluation lasted 4 hours and was audiotaped. discussion was initiated by an open-ended question on the participants’ experiences in the adult clinic. all participants provided written informed consent prior to the evaluation, and institutional ethical approval for the evaluation was obtained. audiotapes were subsequently transcribed verbatim, and qualitative thematic content analysis was conducted by two independent coders: the investigator and a graduate public health student. qualitative concepts were generated from the data from the evaluation. the two independent coders read the transcripts line-by-line and abstracted key ideas and themes. results of the 80 participants aged ≥25 years who were transited to adult hiv care between january 2010 and january 2012, 50 were unavailable for evaluation: 20 had provided incorrect telephone contact details and could not be reached; 15 had other obligations and could not attend the evaluation; 9 resided outside the kampala district and were therefore unable to attend the evaluation; and 6 had been transferred to other partner clinics. all 30 participants who attended the evaluation had acquired hiv through sexual transmission. nineteen (63%) of the 30 participants, aged 25 years, partook in the evaluation at approximately one year following the exit questionnaire interview. the remaining 11 (37%), aged 26 29 years, partook in the evaluation at 2, 3, 4 and 5 years, respectively, following the exit interview. six major themes emerged from the evaluation: (i) adjustment to adult healthcare providers, (ii) the adult clinic logistics, (iii) positive attributes of the adult clinic, (iv) transfer to other health centres, (v) perceived sense of stigma, and (vi) patient-proposed recommendations. adjusting to adult healthcare providers most of the participants expressed a sense of difficulty with terminating their relationships with their young adult healthcare providers, because most of them had grown attached to them: ‘the first time i came to idi, i was placed in the young adult clinic and it had become my dad, my mum, my uncle, my auntie, my friend, my family and my life. i was at home in the young adult clinic. you cannot just take my family away from me.’ (female, aged 25 years); ‘i feel like i am being separated from my mother … i have been at home in the young adult clinic … the doctors in the adult clinic now view me like an old man.’ (male, aged 26 years) some of the participants felt that they were not prepared appropriately for the changes in the adult clinic: ‘they need to tell us that the doctors will not treat us like young people anymore. the doctors give us no special attention. if you are not sick, then you are not a problem. they will not even try to find out how your life is.’ (female, aged 26 years) adult clinic logistics the young adults described some logistical issues with the adult hiv clinic compared with the young adult hiv clinic. specifically, they felt that the young adult clinic offered a less busy environment than the adult clinic: ‘the waiting hours in the adult clinic are too long and yet in the young adult clinic waiting hours are much shorter.’ (female, aged 27 years); ‘some of the health workers in the adult clinic are not youth-friendly and some bark at me. i am always worried about missing lunch.’ (female, aged 25 years) there were also logistical issues raised due to the large clinic size: ‘at one of my clinic appointments, i was told that my file had gotten lost and was told to sit and wait. i sat at the waiting benches for almost the whole day and yet i had come at 8 a.m. in the morning and left at 3 p.m. in the afternoon. this had never happened to me in the young adult clinic.’ (female, aged 28 years); ‘files begin to get lost when you are moved to the adult clinic and not when you are in the young adult clinic.’ (male, aged 26 years) positive attributes of the adult clinic although most of the young adults acknowledged difficulties in coping with the transition, some appreciated the adult clinic services, the specialised healthcare and the tools that were used to decongest the adult clinic: ‘ever since i was transited into the adult clinic i have gotten special care ... maybe it is because at the time of transition, i was pregnant. i was given a special doctor to attend to my needs. my baby and i are healthy and well. i am happy with the services.’ (female, aged 27 years); ‘i have not faced any difficulties since i started attending the adult clinic. when i come to the clinic, i cancel all the day’s programmes and devote the day to the clinic. i do not mind about the amount of time i spend at the clinic provided i have been seen by the doctor and gone home with my medications.’ (female, aged 26 years); ‘i have not had any problems in the adult clinic. as soon as i was transferred to the adult clinic, i was given a green card, which basically means that i see the health worker every 3 months. every other month i get my drugs from a prescription window.’ (male, aged 26 years) transfer to other health centres some of the young adults who had been transitioned from the young adult clinic expressed discontent when they had been transferred to other health centres: ‘i was not happy when i was transitioned to the adult clinic. as soon as i was transitioned i was told that i had to be transferred to another health centre outside idi. when i reported to that health centre, i was told that the centre only works on two days in a week and yet i have a job.’ (female, aged 26 years) perceived sense of stigma some participants associated the adult clinic with stigma: ‘i do not like the way the adult patients look at me in the adult clinic. they look at me in an accusing way … like i am someone who sleeps around.’ (female, aged 26 years) some participants conveyed a fear that the adults may be a frightening group: ‘it is very difficult for me to walk in the adult clinic … sit with adults and wait for my turn to see the doctor without being asked what i am doing in the clinic. i am a short, thin girl and usually get mistaken for being a teenager … when i sit in the adult clinic, i feel totally lost.’ (female, aged 25 years) patient-proposed recommendations some participants felt that the adult hiv clinic healthcare providers needed to acquire skills specific to the treatment and management of yplhiv: ‘some of the doctors in the adult clinic should work in the young adult clinic so that they can learn how to handle young people. some of them treat us like adults and yet we are not … we need more time.’ (female, aged 25 years) one of the participants still felt the need for additional support extending beyond the adolescent and young adult hiv/aids care programme: ‘i was among the first young adults to be exited from the young adult clinic. it would be good if you got us a special day – like thursday or friday – for the exited young adults, so that we can continue to meet others.’ (female, aged 29 years) discussion the transition process for yplhiv to routine adult hiv care is a complex, clinical and psychosocial process that varies from patient to patient. given the paucity of available data specific to this in resource-limited settings, we accordingly aimed to provide insight into and propose a model for such transitioning. as much as transition into adult care is possible for yplhiv, our evaluation showed that stigma still persists among these young people. the qualitative results of our study corresponded with similar findings by others when transitioning adolescents with other chronic diseases into adult healthcare in developed countries.4-8 in our study, adjusting to the concept of adult care, an adult-oriented clinic environment and a perceived sense of stigma were some of the challenges faced by young people transitioning into the adult services. these findings were similar to those of others when transitioning adolescents with perinatally acquired hiv infection into adult care.4-12 in contrast, a few participants acknowledged the benefits of the adult-oriented hiv clinic, reiterating that the process may vary for each patient. although the transition process itself did not involve caregivers, the importance of the social support system was emphasised during the exit process. the rationale for not involving caregivers in the transition process is to enhance patient autonomy. however, it is possible that involvement of the caregivers would have provided more insight into some of the challenges faced by the young adults during and after transfer to adult care. in the literature, there are a number of models that have been developed for transitioning adolescents and young adults with chronic health conditions into adult care. these models, however, have been developed in resource-rich, developed countries. the maestro project systems navigator model for diabetes mellitus and the young adults with rheumatic diseases (yard) clinic transition model are two examples of disease-specific transition care programmes that were designed to provide support for youths with chronic diseases.14 other transition models that are not disease-specific were designed to link young adults with chronic conditions in general to adult care.14 , 15 all of these models emphasise the importance of a social support system, including parents and families, in the transition care process. each model also differs, as the principles that govern transition across these models differ. for example, the maestro systems navigator model is governed by five principles: enhancement of patient autonomy, ensuring collaboration between healthcare providers, equipping with negotiation skills, providing community resources, and having a designated professional who takes responsibility for transition.14 other programmes emphasise the provision of developmentally appropriate care, shifting the responsibility to the adolescent, and the provision of a portable summary of the patient’s healthcare needs and a clear transition plan in the patient's file.14 with regard to adolescent hiv care, the 'movin" out' model was developed by a special adolescent clinical team in the united states.16 the model is essentially a transitioning protocol of 5 phases and is fluid, allowing a young person to revert to a prior phase or to become stagnant at a particular phase. the protocol necessitates that a multi-disciplinary transition team, comprising nurses, social workers, peer educators, psychologists and physicians, take charge of the process of transition.16 against this backdrop, we formulated a transition model that would provide guidance for transitioning yplhiv from young adult hiv programmes into adult hiv care in developing countries, on the basis of enhancing patient autonomy. despite the limitations, the key findings of the evaluation were that moving to the adult clinic is difficult for yplhiv. as an implication, there is the need for continual follow-up and for some of the adult care providers to be part of the adolescent/young adult team. study limitations the study had several limitations. all 30 participants who partook in the evaluation had acquired hiv through sexual transmission. it is possible that there could have been major differences between sexually infected young people and perinatally infected young people. the results may, therefore, not be generalisable to vertically infected young people transitioning into adult hiv care. secondly, there was a low response rate to participation in the evaluation (30/80; 38%); hence, the sample size was small. adding to this, the study was based on a single-centre evaluation (one facility). as much as we sought to illuminate the area of transitioning young hiv-positive people into adult hiv care in the study, the data obtained in our evaluation may not be generalisable to other young adult hiv cohorts. conclusion ensuring that yplhiv continue to access care beyond young adult hiv programmes is essential in assuring continuity in hiv care and treatment across africa. the directions emerging from this study are clear: the provision of enhanced support beyond the transition clinic and youth-friendly approaches by adult-oriented care-providers to young people are both key to continuity of care. funding acknowledgement. this study was funded by the civil society fund (csf); grant number csf/003/2010. acknowledgements. we thank the young adults who participated in the evaluation and shared their experiences with us. we acknowledge the young adult counsellors who helped in mobilisation: julian nkurayija, adelline twimukye and rachael nabaggala. we also wish to thank the young adult peer 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[http://dx.doi.org/10.1542/peds.2004-0458] 9. scal p, ireland m. addressing transition to adult health care for adolescents with special health care needs. pediatrics 2005;115(6):1607-1612. [http://dx.doi.org/10.1542/peds.2004-0458] 10. wiener ls, kohrt ba, battles hb, pao m. the hiv experience: youth identified barriers for transitioning from pediatric to adult care. j pediatr psychol 2011;36(2);141-154. [http://dx.doi.org/10.1093/jpepsy/jsp129] 10. wiener ls, kohrt ba, battles hb, pao m. the hiv experience: youth identified barriers for transitioning from pediatric to adult care. j pediatr psychol 2011;36(2);141-154. [http://dx.doi.org/10.1093/jpepsy/jsp129] 11. miles k, edwards s, clapson m. transition from paediatric to adult services: experiences of hiv-positive adolescents. aids care 2004;16(3):305-314. 11. miles k, edwards s, clapson m. transition from paediatric to adult services: experiences of hiv-positive adolescents. aids care 2004;16(3):305-314. 12. vijayan t, benin al, wagner k, romano s, andiman wa. we never thought this would happen: transitioning care of adolescents with perinatally acquired hiv infection from paediatrics to internal medicine. aids care 2009;21(10):1222-1229. [http://dx.doi.org/10.1080/09540120902730054] 12. vijayan t, benin al, wagner k, romano s, andiman wa. we never thought this would happen: transitioning care of adolescents with perinatally acquired hiv infection from paediatrics to internal medicine. aids care 2009;21(10):1222-1229. [http://dx.doi.org/10.1080/09540120902730054] 13. van staa al, jedeloo s, van meeteren j, latour jm. crossing the transition chasm: experiences and recommendations for improving transitional care of young adults, parents and providers. child care health dev 2011;37(6):821-832. [http://dx.doi.org/10.1111/j.1365-2214.2011.01261.x] 13. van staa al, jedeloo s, van meeteren j, latour jm. crossing the transition chasm: experiences and recommendations for improving transitional care of young adults, parents and providers. child care health dev 2011;37(6):821-832. [http://dx.doi.org/10.1111/j.1365-2214.2011.01261.x] 14. grant c, pan j. a comparison of five transition programmes for youth with chronic illness in canada. child care health dev 2011;37(6):815-820. [http://dx.doi.org/10.1111/j.1365-2214.2011.01322.x] 14. grant c, pan j. a comparison of five transition programmes for youth with chronic illness in canada. child care health dev 2011;37(6):815-820. [http://dx.doi.org/10.1111/j.1365-2214.2011.01322.x] 15. schwartz la, tuchman lk, hobbie wl, ginsberg jp. a social-ecological model of readiness for transition to adult-oriented care for adolescents and young adults with chronic health conditions. child care health dev 2011;37(6):883-895. [http://dx.doi.org/10.1111/j.1365-2214.2011.01282.x] 15. schwartz la, tuchman lk, hobbie wl, ginsberg jp. a social-ecological model of readiness for transition to adult-oriented care for adolescents and young adults with chronic health conditions. child care health dev 2011;37(6):883-895. [http://dx.doi.org/10.1111/j.1365-2214.2011.01282.x] 16. maturo d, powell a, major-wilson h, sanchez k, de santis jp, friedman lb. development of a protocol for transitioning adolescents with hiv infection to adult care. j pediatr health care 2011;25(1):16-23. [http://dx.doi.org/10.1016/j.pedhc.2009.12.005] 16. maturo d, powell a, major-wilson h, sanchez k, de santis jp, friedman lb. development of a protocol for transitioning adolescents with hiv infection to adult care. j pediatr health care 2011;25(1):16-23. [http://dx.doi.org/10.1016/j.pedhc.2009.12.005] untitled j u n e 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e3 4 severe hyperlactataemia complicating antiretroviral therapy with stavudine firstline therapy in south africa: incidence, risk factors and outcomes meg osler1,2, dave stead3, kevin rebe2,3, andrew boulle1,2, graeme meintjes2,3 1department of health, provincial government of the western cape, 2university of cape town, 3g f jooste hospital, cape town symptomatic hyperlactataemia (shl) and lactic acidosis (la)result from mitochondrial toxicity caused by nucleoside reverse transcriptase inhibitors (nrtis) (especially stavudine (d4t) and didanosine (ddi)). high rates of these conditions are being reported in the sa public sector art programme. we undertook this study to document the incidence, risk factors and outcomes of severe shl (defined as serum lactate ≥ 5 mmol/l) at one referral facility in cape town, g f jooste hospital. we also assessed the safety of re-challenge with azt (an nrti that carries a lower risk for mitochondrial toxicity than d4t) in a select group of patients with less severe presentations. g f jooste hospital is a public sector hospital which serves a population of approximately 1.5 million people. there are 6 primary care art clinics which refer to g f jooste. there were two parts to the study. the first was a retrospective observational study on patients referred to g f jooste hospital with severe shl. all patients with a lactate ≥ 5 mmol/l attributed to nrtis during the period 1 august 2003 to 30 november 2005 were included. we calculated cumulative exposure to art among patients attending the 6 art clinics to derive an estimated rate of referral. secondly, a matched casecontrol study which used incidence density sampling and was based on the cases sampled in the observational study outlined above was conducted. for practical reasons, controls were randomly selected from the same cohort (the same month commencing art and at the same clinic – i.e. matched on facility and duration on art) as each case. major findings observational study seventy-three patients were diagnosed with severe shl during the study period. during this period there was a cumulative exposure to art of 7 080 patient years at all 6 art clinics in the referral area, resulting in an estimated rate of referral for severe shl of 10/1 000 years of treatment. sixty-nine patients (95%) were female. all 73 patients were on d4t-containing regimens, or had been switched off d4t in the preceding few weeks. the median duration on art was 10 months (iqr = 8 11.3). the median serum lactate was 7.6 mmol/l. thirteen patients (18%) had standard bicarbonate (sbc) ≥ 20 mmol/l, 49 patients (67%) < 20 mmol/l (i.e. lactic acidosis), and in 11 (15%) sbc was not measured. eleven patients died acutely (15%), and 1 patient died 4 months later. sbc below 15 mmol/l was the only risk factor consistently associated with acute mortality in univariate and multivariate modelling (or = 35, p = 0.004, adjusted for age). management and outcome all patients were managed acutely according to a management guideline which included general supportive therapy, vitamin supplementation and treatment of complications. art was immediately interrupted in 66 patients. in the other 7 patients d4t was switched to azt and art was not immediately interrupted. however, in 5 of these 7 patients there was continued clinical or biochemical deterioration necessitating art interruption. thus 71 patients in total interrupted art. of the 62 initial survivors, 3 were lost to follow-up and 59 patients were re-established on safer art regimens. these included the 2 successful switches, plus 57 patients rechallenged with safer art regimens once lactate levels had normalised after a mean 87-day treatment interruption. the outcomes of those re-established on art were: 29 patients with less severe presentations (all these patients had lactates < 10.4 mmol/l and sbcs > 14 mmol/l and none had pancreatitis) were restarted on an art regimen which contained azt and 3tc, with lactate monitoring. one of these patients was lost to follow-up. the remaining 28 patients were still in care on the same regimen at the time of data censure, with no recurrence of hyperlactataemia. a cumulative follow-up of 1 137 weeks (mean = 39 weeks) was available on these patients without recurrence of shl. the other 30 more severe cases were reinitiated on a tenofovir-containing regimen or an nrtia b s t r a c t s croi 2007 the conference on retroviruses and opportunistic infections is held annually in the usa. this meeting, organised by the foundation on retroviruses and the centers for disease control, has a mission to provide a forum for basic scientists and clinicians to present, discuss, and critique their investigations into the biology and epidemiology of human retroviruses and the diseases they produce with the ultimate goal of translating laboratory and clinical research into progress against the aids epidemic. the 14th conference was held in los angeles from 25 to 28 february 2007. this conference is relatively small with steep competition to get abstracts accepted for posters and presentations, yet south africa has a growing representation at this prestigious and excellent meeting. the journal invited a selection of south african authors whose abstracts were accepted and published to describe the background and relevance of their work and contextualise their findings for us in south africa. j u n e 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e3 6 sparing regimen (i.e. kaletra + nnrti). there were no recurrences among these patients. matched case-control study demographic and clinical features at baseline associated with subsequent shl in multivariate analysis, compared with people with a baseline weight below 60 kg, those between 60 and 74 kg were 5 times more likely to experience severe shl (95% ci 1.6 15.4) while those over 75 kg had an increased 19-fold risk (95% ci 4.8 77.1). the odds ratio for females was 44.2, with a wide confidence interval due to the paucity of men in the study (95% ci 6.4 303.8). clinical variables associated with shl during follow-up in a regression model, patients having at least one of the listed major symptoms (abdominal pain, diarrhoea, nausea, and vomiting) within 80 days prior to case presentation were 18 times (95% ci 3.5 97.6) more likely to present with severe shl. weight gain of ≥ 6 kg in the first 3 months on art was a further clinical association with severe shl, with an odds ratio of 11 (95% ci 1.9 67.5). patients with weight loss of ≥ 3 kg during the last 3 months prior to diagnosis were 12 times (95% ci 2.2 62.1) more likely to present with severe shl. concurrent peripheral neuropathy was also found to be independently associated with developing severe shl (or 8.4, 95% ci 1.4 51.8). what are the implications for clinical practice? the rate of severe shl (referral rate of 10/1 000 patient treatment years) was higher than that reported from many developed-world settings. this is likely due to uniform use of d4t in first-line therapy, but may also be related to the risk factor profile of patients starting art in sa. in order to minimise the morbidity and mortality related to this condition it is important to develop strategies to address prevention, earlier diagnosis and appropriate management. preventive measures may include: ■ changes in drug regimens on a programme level: an example would be substituting d4t with tenofovir, a drug which has not by itself been associated with lactic acidosis. ■ dose reduction of d4t: the who now recommends d4t be dosed at 30 mg bd in all patients regardless of weight. this is anticipated to reduce mitochondrial toxicity rates. ■ strategies focusing on high-risk patients: our study identified female gender, higher weight and rapid weight gain after starting art as risk factors for severe shl. one strategy that has been advocated and is supported by these data is to start overweight women on azt (or tenofovir) rather than d4t and to switch those who become overweight on art from d4t to azt (or tenofovir). to facilitate early diagnosis it is essential that a high index of suspicion for shl is maintained. clearly those at highest risk (overweight women) should be monitored most closely. our study shows that symptoms such as abdominal pain, diarrhoea, nausea, and vomiting, weight loss ≥ 3kg as well as symptoms of neuropathy are important heralds of the condition. also, most patients (85%) in this study presented with severe shl after having been on art for between 6 and 14 months. this period is thus the critical time to monitor for symptoms of shl and weight loss. management of patients with severe shl involved stopping drugs and a range of supportive measures.1 it is worth noting that in 7 patients d4t was switched to azt and art was not immediately stopped. this strategy however failed with 5 of these patients deteriorating and requiring that art be stopped. it is thus advisable that in all patients presenting with shl and lactate > 5 mmol/l art be immediately stopped. once art was stopped it took a mean of 3 months for the lactate to normalise so that art could be re-initiated. we were encouraged to find that our practice of re-challenging with an azt-containing regimen in a group of 29 patients with less severe presentations (all had lactate < 10.4 mmol/l and sbc >14 mmol/l and none had pancreatitis) was well tolerated with no recurrences of shl. lactate levels and symptoms were closely monitored in these patients on rechallenge. this provides a kaletra-sparing alternative, while we wait for tenofovir to be available in the public sector, for carefully selected patients who can be monitored on rechallenge. reference 1. southern african hiv clinicians society. guidelines for the prevention, diagnosis and management of nrtj-associated symptomatic hyperlactataemia and lactic acidosis. southern african journal of hiv medicine 2006; issue 22; 8 15. assessing the risk of contamination between samples during their excision from dried blood spots for hiv-1 dna pcr testing glen driver1, janet patton1, jackie moloi2, eve akkers2, w stevens2, g sherman1,2 1witwatersrand paediatric hiv clinic,witwatersrand health consortium, johannesburg, 2national health laboratory service, university of the witwatersrand, johannesburg it is now well established that early infant diagnosis is critical for implementation of early antiretroviral (arv) treatment, stratification of health care services, monitoring the success of prevention of mother-to-child transmission (pmtct) programmes, and reducing maternal anxiety. the diagnosis of hiv below 15 18 months of age requires the use of virological nucleic acid testing strategies. qualitative dnabased assays such as the roche dna polymerase chain reaction (pcr) assay have stood the test of time in south africa, being conducted at 6 weeks of age with sensitivities and specificities of 98.8% and 99.4%, respectively.1 local work has also revealed that the collection method of choice for clinical sites is the dried blood spot (dbs), which facilitates easy collection by relatively unskilled staff and reduces transport difficulties. the performance of the roche pcr assay using dbs has been evaluated and demonstrates comparable results to those obtained on liquid blood samples.2 dbs prepared from capillary (e.g. heel prick) versus venous blood in 206 children also yields highly accurate hiv dna pcr results with a sensitivity of 98.3% and specificity of 98.7%.3 concerns have been raised over the following aspects of largescale implementation of this technology in south africa: (i ) t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u n e 2 0 0 7 3 7 the need for automation of this methodology; and (ii ) concerns of contamination when spots are punched out either manually or via an automated punch. the issue of automation has been addressed at several levels within the laboratory: (i ) automation of the punching step, using the bsd1000 genepunch; (ii ) at the extraction step, by conducting dna extraction from both liquid blood samples and dbs using automated extraction systems such as the roche magnapure instrument; and ( iii ) investigation of more automated amplification and detection systems, such as the roche taqman dna qualitative assay, which are ongoing studies. we investigated the second concern expressed by laboratory scientists, that of contamination. in this study, the risk of contamination between samples was assessed during the excision of dbs for hiv-1 dna pcr testing using a manual punch and an automated punching system. for both the manual and the automated punch, a spot from a known hiv-negative patient was excised after a spot from a known hiv-infected patient. for the hand-held punch, 3 to 4 ✕ 6 mm discs (± 50 µl) from a total of 372 samples using three different cleaning methods applied between each sample was evaluated. cleaning methods included: (i ) punch swabbed with virkon/ethanol; (ii ) punching a clean card; and (iii ) no cleaning (n = 124 for each method). for the automated punch investigation, 7 ✕ 3.2 mm discs were excised per spot (± 75 µl) from 202 samples and a clean card punched between each sample. this was followed by genomic dna extraction from the discs followed by amplification and detection using the roche amplicor hiv-1 dna assay version 1.5. the manual punching method produced no false-positive hiv dna pcr results. we obtained 1 and 3 equivocal results on hiv-negative samples with cleaning interventions (i ) and (ii ), respectively. this may represent a degree of contamination that was insufficient to affect the assay’s specificity. the automated punch yielded 2 equivocal and 2 false-positive results (specificity 98%). of the latter, 1 sample of dna extracted from the same disc produced a negative hiv dna pcr result, confirming that contamination had arisen downstream from the excision step. the other sample for which a false-positive result was obtained could not be retested (specificity 99%). we concluded that available punching methodologies for dbs excision present very low risks of contamination. the automated punch option, although working well, is complicated by cost and significant space requirement. this work, together with publications cited above, suggest there can no longer be any reason for not scaling up early infant diagnosis in south africa. references 1. sherman gg, cooper pa, coovadia ah, et al. hiv-1 dna polymerase chain reaction for diagnosis of hiv infection in infancy in low resource settings. pediatr infect dis j 2005; 24(11): 993-997. 2. sherman gg, stevens g, jones s, horsfield p, stevens w. dried blood spots improve access to hiv diagnosis and care for infants in low-resource settings. j acquir immune defic syndr 2005; 38(5): 615-617. 3. patton jc, akkers e, coovadia ah, meyers tm, stevens ws, sherman gg. evaluation of heelor finger-stick dried whole blood spots (dbs) as an alternative to venous blood collection for diagnosis of human immunodeficiency virus (hiv)-1 infection in vertically-exposed infants in the routine diagnostic laboratory. clin vaccine immunol 2007; 14(2): 201-203. early mortality among patients with hiv-associated tuberculosis in africa: implications for the time to initiation of antiretroviral treatment stephen d lawn1,2, landon myer3,4, linda-gail bekker1, robin wood1 1desmond tutu hiv centre, institute for infectious disease and molecular medicine, faculty of health sciences, university of cape town, 2clinical research unit, department of infectious and tropical diseases, london school of hygiene and tropical medicine, 3infectious diseases epidemiology unit, school of public health and family medicine, faculty of health sciences, university of cape town, 4department of epidemiology, mailman school of public health, columbia university, new york the hiv epidemic has been associated with major increases in tuberculosis (tb) notification rates in south african townships over the past 10 years, principally among young adults.1 not surprisingly, as antiretroviral treatment (art) clinics have been established in these communities, tb has emerged as a key challenge. the burden of tb within art clinics is very high. we have previously reported from an art service in gugulethu, cape town, that among patients enrolling in the clinic, 52% have previously been treated for one or more episodes of tb, 26% have an active diagnosis of tb and a further 10% develop tb during the first year of art.2 overall, during the first year from enrolment, approximately one-third of patients receive concurrent antituberculosis treatment and art. the impact of this huge burden of tb within art services in sub-saharan africa has not been fully characterised, but it might be expected to contribute to the high early mortality in programmes in the region.3 indeed, we have previously reported from the clinic in gugulethu that patients who have tb at entry to the programme have a 2-fold greater mortality risk in the first year of art compared with those who remain tb-free.2 while not altogether surprising, this observation nevertheless warrants careful examination to gain a better understanding of the factors contributing to this high early mortality as some deaths may be preventable. firstly, it might be expected that among patients receiving concurrent tb treatment and art, pharmacokinetic drug interactions and impaired treatment adherence (due to high pill burden, reduced regimen tolerability and overlapping toxicity profiles) would undermine responses to art and thereby increase mortality risk. however, we and others have found this not to be the case, with good immunological and virological responses being observed among patients receiving rifampicin-containing tb treatment and efavirenz-based art in standard dosages.2,4,5 secondly, concurrent use of rifampicin with nevirapine, another non-nucleoside reverse transcriptase inhibitor (nnrti), has been associated with reports of severe hepatotoxicity.6 however, in gugulethu where efavirenz is the nnrti routinely used and where monitoring of serum hepatic transaminases is available, no deaths attributable to efavirenz/rifampicin co-toxicity have occurred.7 thirdly, initiation of art among patients receiving treatment for tb is commonly associated with immune reconstitution disease (frequently referred to by clinicians as immune reconstitution j u n e 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e3 8 inflammatory syndrome or ‘tb iris’). however, although we have found that iris is common among patients with advanced immunodeficiency starting art early in the course of tb treatment in the gugulethu clinic, it is most commonly self-limiting and is an infrequent cause of death.8 indeed, iris associated with cryptococcal disease is a far more important cause of mortality than tb iris in this setting.9,10 none of the above factors therefore account for the high early mortality among tb patients accessing art. a further critical question, though, is whether the timing of initiation of art affects mortality risk among tb patients. this is potentially a very important variable, as it is one over which the clinician has direct control. we have previously shown that the mortality rate of patients entering the gugulethu art service is extremely high and even short delays in art initiation may potentially be associated with appreciable mortality risk.7,11 we therefore decided to study in more detail the early mortality among tb patients accessing art with a focus on the timing of treatment initiation and presented these data at croi.12 why was this study done? the aim of this study was to determine the mortality risk associated with tb among patients enrolling in the art service in gugulethu and to assess the association between mortality and the timing of art initiation during tb treatment. these analyses were done to provide insights into the appropriate timing of art in patients with hiv-associated tb. what did the researchers do and find? mortality occurring in the two intervals between programme enrolment, initiation of art and the first 16 weeks of treatment was prospectively studied among patients with (n = 213) and without (n = 675) tb accessing the art service in gugulethu, cape town. the mortality rate among those with tb was 1.8-fold (95% confidence interval (ci) = 1.62 2.80) greater than that of patients who were tb-free (40 versus 21 deaths/100 person-years; p = 0.003). when the tb patients were subdivided into those with active tb (n = 73) or inactive tb (n = 140), the mortality rate was significantly greater in both groups (44 and 37 deaths/100 person-years, respectively) compared with those who were tb-free (21 deaths/100 person-years) (p < 0.01 for each comparison). patients with tb, however, had lower cd4 cell counts than those who were tb-free, and this was potentially an explanation for the higher mortality rates observed. we therefore did multivariate analysis to assess risk factors for mortality in the whole cohort. in this analysis, tb (either active or inactive) was no longer significantly associated with mortality risk. instead, mortality risk was only independently associated with baseline cd4 cell count < 100 cells/µl (adjusted hazards ratio (ahr) = 2.85, 95% ci = 1.52 5.34) and who clinical stage 4 disease (ahr = 2.94, 95% ci = 1.80 4.82). this analysis therefore showed that the high excess mortality risk among patients with tb was largely explained by advanced immunodeficiency and not with tb disease activity or even with diagnoses of tb per se. this is consistent with findings in cohorts in zambia and malawi.13,14 since mortality risk is predominantly associated with immunodeficiency, delays in the initiation of art should be minimised. we next examined the association between the timing of art initiation in tb patients and mortality risk. of patients with tb diagnosed within the programme prior to art initiation (n = 73), 48 had received art by data censorship after a median of 42 days from tb diagnosis. a total of 14 patients died. just 4 deaths occurred after initiation of art of which 2 were due to immune reconstitution disease. however, 10 deaths (71%) occurred in patients waiting to commence art, most (n = 8) within the first 6 weeks of antituberculosis treatment. all those who died waiting to commence art had either a cd4 cell count < 100 cells/µl or who stage 4 disease. these data are observational (non-randomised) and therefore potentially subject to bias. however, baseline patient and disease characteristics did not differ when comparing those who died with those who survived or when comparing those who did or did not receive art. mortality risk was only associated with art status. however, if art were commenced earlier, it is not known what proportion of deaths might be prevented and also to what extent tb iris would become a greater problem. what does this mean? these data are important with regard to the optimal timing of commencement of art in patients with tb. there is no consensus between various national and international guidelines in respect of this timing. moreover, it will be several years before the results of randomised controlled trials will become available to address this issue definitively. in the interim, these observational data therefore provide important insights for patients being treated in south africa and elsewhere in sub-saharan africa. collectively these data indicate that patients with tb have high mortality risk due to advanced immunodeficiency and that with the current median delay of 42 days in this programme between tb diagnosis and starting art, many patients die waiting to start art. clearly, the mortality risk associated with delays in art in this service greatly exceeded any mortality risk associated with early initiation of art (e.g. due to tb iris). those at greatest risk of death were those with cd4 cell counts < 100 cells/µl and those with who stage 4 disease. such patients should be prioritised in respect of early initiation of art. the optimal time for art initiation cannot be determined from these non-randomised data. however, the current who guidelines for resource-limited settings recommend that tb patients with cd4 cell counts < 200 cells/µl should commence art between 2 and 8 weeks of art.15 data from this study strongly suggest that those with cd4 cell counts < 100 cells/µl and who stage 4 disease should commence art as early as possible within this time-frame (i.e. after 2 weeks of tb treatment). funding sources: sdl is funded by the wellcome trust, london, uk with grant 074641/z/04/z. rw is funded in part by the national institutes of health, usa, ro1 grant (a1058736-01a1). lm, lgb and rw are all funded in part by the national institutes of health through a cipra grant 1u19ai53217-01. conflicts of interest: the authors have no conflicts of interest. t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u n e 2 0 0 7 3 9 references 1. lawn sd, bekker lg, middelkoop k, myer l, wood r. impact of hiv infection on the epidemiology of tuberculosis in a peri-urban community in south africa: the need for age-specific interventions. clin infect dis 2006; 42: 1040-1047. 2. lawn sd, myer l, bekker lg, wood r. burden of tuberculosis in an antiretroviral treatment programme in sub-saharan africa: impact on treatment outcomes and implications for tuberculosis control. aids 2006; 20: 1605-1612. 3. braitstein p, brinkhof mw, dabis f, et al. mortality of hiv-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries. lancet 2006; 367: 817-824. 4. breen ra, miller rf, gorsuch t, et al. virological response to highly active antiretroviral therapy is unaffected by antituberculosis therapy. j infect dis 2006; 193: 1437-1440. 5. manosuthi w, kiertiburanakul s, sungkanuparph s, et al. efavirenz 600 mg/day versus efavirenz 800 mg/day in hiv-infected patients with tuberculosis receiving rifampicin: 48 weeks results. aids 2006; 20: 131-132. 6. sanne i, mommeja-marin h, hinkle j, et al. severe hepatotoxicity associated with nevirapine use in hiv-infected subjects. j infect dis 2005; 191: 825-829. 7. lawn sd, myer l, orrell c, bekker lg, wood r. early mortality among adults accessing a community-based antiretroviral service in south africa: implications for programme design. aids 2005; 19: 2141-2148. 8. lawn sd, myer l, bekker lg, wood r. tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in south africa. aids 2007; 21: 335-341. 9. lawn sd, bekker lg, myer l, orrell c, wood r. cryptococcocal immune reconstitution disease: a major cause of early mortality in a south african antiretroviral programme. aids 2005; 19: 2050-2052. 10. bicanic t, harrison t, niepieklo a, dyakopu n, meintjes g. symptomatic relapse of hiv-associated cryptococcal meningitis after initial fluconazole monotherapy: the role of fluconazole resistance and immune reconstitution. clin infect dis 2006; 43: 1069-1073. 11. lawn sd, myer l, harling g, orrell c, bekker lg, wood r. determinants of mortality and nondeath losses from an antiretroviral treatment service in south africa: implications for program evaluation. clin infect dis 2006; 43: 770-776. 12. lawn sd, myer l, bekker lg, wood r. early mortality in patients with hivassociated tuberculosis in africa: implications for time to initiation of treatment. programme and abstracts of the 14th conference on retroviruses and opportunistic infections (croi). los angeles, february 2007. abstract #0-126. 13. stringer js, zulu i, levy j, et al. rapid scale-up of antiretroviral therapy at primary care sites in zambia: feasibility and early outcomes. jama 2006; 296: 782-793. 14. zachariah r, fitzgerald m, massaquoi m, et al. risk factors for high early mortality in patients on antiretroviral treatment in a rural district of malawi. aids 2006; 20: 2355-2360. 15. world health organization. antiretroviral therapy for hiv infection in adults and adolescents: recommendations for a public health approach. 2006 revision. geneva: who, 2006. adolescents and hiv vaccine trials g gray, g de bruyn perinatal hiv research unit, soweto, johannesburg the incidence and prevalence of hiv infection among adolescents and young adults in south africa is extremely high, particularly among girls. data from national seroprevalence surveys estimate the prevalence of hiv to be 9.4% among 15 19-year-old girls and 23.9% in women aged 20 24.1 four young women between the ages of 15 and 24 are infected for every man in the same age group. despite current efforts, including hiv prevention programmes targeted to youth, hiv infection rates have shown no sign of decreasing. the lack of a substantial decline in hiv incidence among young women in south africa may be attributed to the marked changes in society seen since the transition from apartheid with concomitant rapid rates of urbanisation, disintegration of family structures, and a general lack of understanding of adolescent sexuality, current youth attitudes and practices. currently hiv prevention programmes within south africa have not been context-specific, which may have contributed to the lack of appreciable behaviour changes seen, despite high levels of hiv/aids awareness. as south africa will be the first country to enrol adolescents aged 16 18 years into a phase iib efficacy hiv vaccine trial (the hvtn 503 study), it is imperative to understand some of the challenges to adolescent enrolment in hiv vaccine trials. studies performed to date in soweto include a cross-sectional survey of knowledge and attitudes to hiv/aids and hiv vaccines and willingness among adolescents and their stakeholders to participate in a hypothetical study, as well as a small longitudinal cohort study that assessed sexual risk behaviour and knowledge and attitudes to hiv among soweto youth aged 12 21. adolescent involvement in vaccine trials a two-stage sampling procedure was used. the first-stage sampling units were all 72 public high schools in soweto. ten schools were randomly selected and the first four were approached regarding participation. all pupils in the selected schools from whom parental consent and child assent could be obtained were eligible for participation. a selfadministered, facilitated questionnaire was completed by participants. two hundred and seventy-seven school-going youth (mean age 16.2 years, range 10 25, 53.1% female) participated in this survey. of 240 responses to the willingness item, 84 (35%) indicated they were probably and 126 (52.5%) definitely willing to join a study of a vaccine to prevent hiv. there were no significant differences in willingness by gender, age, school grade, or institution. factors rated as ‘very important’ in determining willingness included receiving current information about hiv research (n = 209, 88.2%), getting free counselling and testing every 6 months (n = 168, 70%), indicating that participants would be doing something to honour people who have hiv/aids or have died of aids (n = 168, 70%), and that participants may receive some protection against hiv infection from the vaccine (n = 167, 70.5%). some misconceptions regarding vaccine research were common, particularly regarding placebo and potential eligibility criteria for vaccine trials. soweto school-going youth report high degrees of willingness to participate in hiv vaccine trials. whether hypothetical willingness translates into participation will await data from adolescent hiv vaccine trials. adults’ perceptions regarding adolescent participation in vaccine trials this study was conducted in soweto between august 2005 and march 2006. the participants for this study were recruited using convenience and snowballing techniques as well as through community outreach. a self-administered questionnaire in english was completed by participants, with facilitation by study staff. the sample size was 64 (mean age, 41.3 years), 57% of participants were women, 55 were parents and 9 were teachers. regarding adolescent sexual risk, of the 64 adults who participated in this research, 31 (55%) believed that the sexual debut of soweto children may be as early as age 9 and 39 (70%) believed that these children were vulnerable to hiv infection. sixty per cent (n = 33) of participants believed that adults spoke to their 9 10-yearolds about hiv. most adults indicated that they would want to know if their child is sexually active (91%) and that should their child participate in an hiv vaccine trial, they would want to know their hiv test results. a great concern to researchers involved in hiv vaccine research is the issue of ‘social harm’ that trial participation may cause. potential social harms that may impact on trial participation include the perception of being at high risk of hiv acquisition, or being thought to have aids. in this study, more than half the adults sampled did not believe that the perceived stigma of hiv vaccine trial participation would impact on their decision to allow their adolescents to j u n e 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e4 0 participate in a hiv vaccine trial (table i). the relationship between trial participation and stigma in this research did not distinguish between participation in phase i, ii or iib/iii trials and the potential distinction made in the trial eligibility criteria with regard to the sexual risk profile of participants. moreover, the figures presented here reflect attitudes of an uninitiated population. it is not beyond reason that attitudes towards hiv vaccine trial participation may change with better understanding of the clinical trial process. willingness to participate in a hypothetical hiv vaccine trial may not reflect participation in an actual trial. this notwithstanding, 44 (80%) indicated willingness (‘probably would’ (27%) or ‘definitely would’ (53%)) to allow adolescent participation and 51 (91%) indicated that they would also want to be involved in the research. of the respondents 48 (86%) indicated that they have confidence in medical research; however, 9 (16%) thought that hiv vaccine research was unsafe and 18 (32%) were unsure whether vaccine research is unsafe. factors cited as important for deciding on trial participation included potential benefits of participation, such as access to information and counselling; potential impact on risk behaviour; and potential protection against hiv from the vaccine. participation was also seen as altruistic and socially beneficial. access to counselling and testing, current information, and potential impacts on improving motivation to reduce risk behaviour were very important for determining willingness to participate. the soweto community, located within gauteng province where an estimated 14.5% of its population is estimated to be hiv infected,1 is heavily affected by hiv. it is therefore not surprising to see the high level of hiv discourse occurring and the low levels of reported stigma. most (49/50) of the adults we sampled had spoken to others about hiv, 43/48 had spoken to family members, 30/50 had ever been tested for hiv, and only 9/50 felt afraid of people with hiv while 12/50 felt uncomfortable around people with hiv. adolescent hiv prevention and vaccine preparedness study this study was conducted to demonstrate that adolescents could be retained in a longitudinal cohort study. this study also assessed over time: risk behaviour; willingness to participate in vaccine trials; knowledge and attitudes towards hiv/aids; and documented for the first time in an african setting, family and social networks of participants, enabling a more dynamic delineation of risk. from july 2005 to november 2005, 52 ‘index’ adolescents (adolescent initially contacted and enrolled) and 19 ‘alter’ adolescents (adolescents referred by the index from their family or social network) were enrolled into the study (table ii). overall, 69 participants were eligible for follow-up. more than 50% of participants were female. most (56) participants were in school, with the median year of schooling being approximately 10 years. only 5 participants had previously had access to hiv testing and counselling. most participants (56/65) were willing to undergo hiv testing and counselling. twenty-six (37.7%) participants reported that they had had penetrative sex. however, only 9 (35%) reported consistent condom use, with 3 (11.5%) reporting that they had never used a condom, and 5 (19%) reporting use of condoms for more or less half the time. birth control was not widely used, with only 10 (26%) participants using condoms as a birth control method, 1 participant using withdrawal as a contraceptive method, and 1 participant using hormonal contraception. one participant reported ever having been pregnant. preliminary data available from the 2-week post-prevention intervention session designed to deal with hiv vaccine research demonstrated that adolescents need more information and education to understand some of the fundamentals of hiv vaccine research. the concept of placebo was not fully understood; some adolescents (15%) believed that an hiv vaccine could give one hiv. the issue of vaccine-induced seropositivity appeared to be understood by most participants. approximately two-thirds of adolescents were willing to participate in hiv vaccine trials and almost 70% were comfortable about referring other adolescents or family members for participation in such trials. interestingly, most adolescents were willing to participate in future vaccine research. there appeared to be few barriers cited for vaccine trial participation. motivators for being involved in vaccine trials were mostly related to altruism or a desire to learn more about hiv/research. almost a quarter of participants indicated that receiving reimbursement for trial participation would be a reason to be involved in research. thirty per cent of adolescents indicated they would be wary of trial participation because of potential side-effects, 20% indicated that they needed more information before they could make up their minds regarding trial participation, and 60% agreed that they were at risk of hiv acquisition and therefore would consider trial participation. how important to decision? (n (%)) factor very somewhat slightly not at all my child may be 12 (22) 4 (7) 9 (16) 30 (55) discriminated against at school people may avoid 12 (22) 6 (11) 7 (13) 30 (55) my child people may think 5 (9) 8 (15) 4 (7) 38 (69) my child has hiv or aids people may think 5 (9) 9 (16) 10 (18) 32 (57) my child is at high risk of hiv or aids people may not 15 (27) 5 (9) 9 (16) 27 (58) want to have sex with my child table i. stigma and hiv vaccine trial participation index (n = 50) alter (n = 19) gender 25 female 11 female median (yrs) 16.68 17.05 soweto residents 45 17 ethnicity black = 50 black = 18* scholars 37 19 median years of education (iqr) 9.78 10.44 sexually active 18 8 drug use 6 1 alcohol use 32 14 *missing = 1. table ii. demographics of adolescents participating in the hiv prevention and hiv vaccine preparedness study t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u n e 2 0 0 7 4 1 conclusion taken together, these preliminary studies indicate a high degree of willingness to participate in hiv vaccine trials among soweto youth and adults. the need for regular risk reduction counselling was highlighted as an important benefit by both youth and adults, indicating the perceived need for developmentally and culturally tailored tools, as well as for services for youth. the adolescent vaccine preparedness study has been critical to developing site expertise in studies with adolescent participation. this programme also highlighted several key developmental issues that would require adaptation of existing risk reduction counselling formats and content to fully address the needs of soweto youth. reference 1. pettifor ae, et al. young people’s sexual health in south africa: hiv prevalence and sexual behaviors from a nationally representative household survey. aids, 2005; 19(14): 1525-1534. emerging hiv-1 drug resistance patterns from two johannesburg clinics on the south african arv roll-out programme carole wallis1, catherine bell1, ronan boulme2, maria a papathanasopoulos1, francois venter3, ivan sanne4 , wendy stevens1,5 1department of molecular medicine and haematology, university of the witwatersrand, 2abl sa/therapyedge inc., r&d unit, luxembourg, 3rhru, university of the witwatersrand, johannesburg, 4chru, university of the witwatersrand, johannesburg, 5national health laboratory service the south african government began the antiretroviral (arv) roll-out programme in april 2004, and over 250 000 aids patients have been enrolled to date. the programme uses two standardised regimens for all patients accessing care, with the first-line regimen consisting of lamivudine (3tc), stavudine (d4t), efavirenz (efv)/nevirapine (nvp) and the second line consisting of didanosine (ddi), zidovudine (azt) and kaletra. there are already reports of treatment failures in south african hiv-1 subtype c-infected patients accessing arv drugs, attributed to the emergence of drug-resistant viruses. however, there are currently no published data available on the development of arv drug resistance (dr) in south african hiv-1 infected individuals on the chosen public sector regimens. routine resistance testing is currently not available in south africa owing to prohibitive costs of current sequencing-based assays. there is no consensus yet in the literature about the possible effects of the genetic diversity of hiv-1 on the development of dr, although several publications describe subtype-specific dr mutations/polymorphisms. arv dr studies conducted in subtype c-infected individuals failing therapy from zimbabwe,1 brazil,2 ethiopia,3 and botswana4,5 revealed that hiv-1 subtype c developed similar arv mutation profiles to hiv-1 subtype b. however, comparisons of subtype c reverse transcriptase (rt) and protease (pr) sequences to subtype b sequences, and corresponding clinical data have revealed subtype c-specific polymorphisms that impact on treatment outcome. for example, v106m has previously been shown to be a subtype cspecific mutation in patients failing efv,6,7 and is a result of a natural polymorphism that occurs at this codon. the k65r mutation may emerge at a higher frequency in hiv-1 subtype c-infected patients on certain nucleoside reverse transcriptase inhibitor (nrti)-containing regimens,5 and its rapid emergence has been shown to confer resistance to tenofovir in cell culture.7 the k103n mutation occurred at a greater frequency and higher levels in women infected with subtypes c and d as opposed to subtype a.8 in addition, the pathways leading to non-nucleoside reverse transcriptase inhibitor (nnrti) and protease inhibitor (pi) resistance may be subtype-specific. for example, grossman et al.,9 and douella-bell et al.,5 showed that hiv-1 subtype c-infected patients on nelfinavircontaining regimens developed resistance to this pi through distinct mutational pathways from subtype b. a number of other studies have confirmed the presence of baseline polymorphisms in subtype c in the protease regions.10,11 these data confirm the need for continued evaluation of drug resistance patterns in hiv subtype c. in an effort to begin to understand the evolution of hiv-1 subtype c drug resistance (hivdr) in south africa, a pilot study was performed in patients demonstrating treatment failure in two johannesburg clinics. this study looked at hivdr patterns emerging in patients failing either the firstor second-line regimens or a combination thereof. one hundred and fifteen patient samples from the two johannesburg clinics were sent for hivdr testing. clinics 1 and 2 defined virological failure differently. clinic 1 defined it as hiv rna levels greater than 1 000 copies/ml on two consecutive visits, whereas at clinic 2 it was classified by a repeated viral load greater than 5 000 copies/ml. the average viral load from patients failing therapy at clinic 2 was found to be 0.8 log higher than clinic 1. the rt mutation patterns seen in our two cohorts have been documented previously in subtype b, with a few exceptions. the mutations that occurred at the highest frequencies (>10%) at both clinics were m184v, k103n, v106m, g190a, d67n and can be directly attributed to the arv drug pressure exerted from the prescribed regimens in south africa. however, the arv dr mutation profiles in patients failing therapy were different in the two clinics, with clinic 2 appearing to have significantly more complex resistance profiles for the rt-associated mutations. these complex mutation patterns may be a result of leaving patients on a failing regimen for an extended period of time. the higher frequency of the k65r mutation, 7.87% and 11.54% at clinics 1 and 2, respectively, is unusual as it is not commonly associated with the prescribed regimens. two factors may potentially be contributing to this increase in k65r. firstly, studies have shown that patients left on failing regimens accumulate several mutations, one of which is k65r, which may be the case in clinic 2. secondly, the bases at this codon are different from those in hiv-1 subtype b and may have resulted in a faster switch to the k65r mutation. there was also an increase of thymidine analogue mutations (tams) at clinic 2, which accumulate over time and confer cross-resistance to most nrtis, making salvage therapy difficult. previous studies have suggested that a delayed switching causes complex resistance patterns to arise (as seen in clinic 2), resulting in reduced susceptibility to most if not all nrtis and the pis being the only effective drug in the secondline regimen. as in other studies, both clinic 1 and 2 showed a high prevalence of secondary mutations and several naturally occurring polymorphisms in the pr region. the presence of these polymorphisms in hiv-1 subtype c pr region may have j u n e 2 0 0 7 t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e4 2 an impact on the efficacy of the pi drugs that will be included in future drug regimens. conclusion arv drug treatment failure in hiv-1 subtype c-infected patients is associated with the development of dr, and these mutation patterns are similar to subtype b. the data suggest that the longer the treatment is continued in the presence of drug-resistant viruses, the more dr mutations accumulate. viral load monitoring of hiv treatment may therefore be important even in resource-poor countries. high-level dr mutations that lead to broad-class dr for nrtis were demonstrated, providing concern for the use of tenofovir in second-line treatment, and strategies of recycling nrtis in second-line treatment. finally, these preliminary findings need to be further investigated and confirmed on a larger sample size in a controlled study. references 1. kantor rkd, gonzales m, sirivichayakul s, et al. influence of subtype and treatment on genetic profiles of hiv-1 rt and protease (rt-pr): do they act independently in predicting position-specific mutation probabilities in nonsubtype b sequences? antiviral research 2002; 7: s142. 2. couto-fernandez jc, silva-de-jesus c, veloso vg. et al. human immunodeficiency virus type 1 (hiv-1) genotyping in rio de janeiro, brazil: assessing subtype and drug-resistance associated mutations in hiv-1 infected individuals failing highly active antiretroviral therapy. mem inst oswaldo cruz 2005; 100. 73-78. 3. averbuch d, schapiro jm, lanier er, et al. diminished selection for thymidineanalog mutations associated with the presence of m184v in ethiopian children infected with hiv subtype c receiving lamivudine-containing therapy. pediatr infect dis j 2006; 25: 1049-1056. 4. doualla-bell f, gaseitsiwe s, ndungu t, et al. mutations and polymorphisms associated with antiretroviral drugs in hiv-1c-infected african patients. antivir chem chemother 2004; 15:.189-200. 5. douella-bell f, avalos a, gaolathe t, et al. impact of human immunodeficiency virus type 1 subtype c on drug resistance mutations in patients from botswana failing a nelfinavir-containing regimen. antimicrob agents chemother 2006; 50: 2210-2213. 6. brenner b, turner d, oliveira m. a v106m mutation in hiv-1 clade c viruses exposed to efavirenz confers cross-resistance to non-nucleoside reverse transcriptase inhibitors. aids 2003; 17: f1-5. 7. brenner bg, oliveira m, doualla-bell f, et al. hiv-1 subtype c viruses rapidly develop k65r resistance to tenofovir in cell culture. aids 2006; 12: f9-13. 8. flys ts, chen s, jones dc, et al. quantitative analysis of hiv-1 variants with the k103n resistance mutation after single-dose nevirapine in women with hiv-1 subtypes a, c, and d. j acquir immune defic syndr 2006; 15: 610-613. 9. grossman z, paxinos ee, averbuch d, et al. 2004. mutation d30n is not preferentially selected by human immunodeficiency virus type 1 subtype c in the development of resistance to nelfinavir. antimicrob agents chemother 2004; 48: 2159-2165. 10. cane pa, de ruiter a, rice p. resistance associated mutations in the human immunodeficiency virus type 1 subtype c protease gene from treated and untreated patients in the united kingdom. j clin microbiol 2001; 39: 2652-2654. 11. grossman z, vardinon n, chemtob d, et al. genotypic variation of hiv-1 reverse transcriptase and protease: comparative analysis of clade c and b. aids 2001; 15: 1453-1460. outcomes of children on non-nucleoside reverse transcriptase inhibitor versus protease inhibitor haart regimens in resourcelimited settings heather b jaspan1,2, andrew boulle3, alison berrisford2, paul roux1,2 1school of child and adolescent health, university of cape town, 2department of paediatrics groote schuur hospital, cape town, 3school of public health and family medicine, university of cape town few data exist as to the most effective highly active antiretroviral therapy (haart) regimens for children with vertically acquired hiv infection. most countries in southern africa have limited regimens based on nucleoside analog reverse transcriptase inhibitor (nrti) backbones combined with either a non-nrti (nnrti) or a protease inhibitor (pi). the world health organization (who) recommends nnrticontaining regimens as the first line for children despite the fact that nevirapine (nvp) is often used for vertical transmission prevention (pmtct) in these settings. in addition, recent evidence suggests that recommended dosing for nvp and efavirenz (efv) in children may be too low. why was this study done? 1. to evaluate the outcomes of children on haart in a resource-limited setting. 2. to compare laboratory and clinical outcomes of children on pi versus nnrti-containing regimens. 3. to determine the correlates of virological suppression (vs). what did the researchers do and find? this study describes the outcomes of a cohort of 389 children on haart treated in a public sector hospital-based antiretroviral programme. children were started on haart that included two nrtis, and either an nnrti (nvp or efv) or a pi (lopinavir/ritonavir or ritonavir). approximately 50% of the children received a pi (n = 199) v. nnrti (n = 188). few children in this group were exposed to nvp for pmtct. the median age at baseline was 26.3 (intraquartile range (iqr) 12.4 53.8) months, the median baseline cd4 percentage 13% (iqr 8.0 17.0%) and median viral load 5.5 log10 (iqr 4.8 6.0 log10). the median baseline weight-for-age z-score (waz) was –2.5. there was no significant difference in baseline characteristics of patients on the different regimens with viral load, cd4 percentage or waz; however infants initiating treatment with an nnrti were older (34.3 v. 21.8 months, p < 0.01). there were obvious improvements in the infants in all parameters after the initiation of haart. the overall increase in cd4% from baseline to 24 months on treatment was 13% (double that at baseline), and increase in waz of 1.8. an overall viral load log drop of 2.6 log10 occurred at 24 months of treatment. however, when comparing pi versus nnrti regimens, a significantly better virological response was seen among those children receiving a pi at all times through 48 months, although there were no differences in cd4%, waz or in survival. in a multivariate analysis predicting vs, pi-based regimens were independently associated with vs, as was cd4 percentage, waz, and age. this association was evident even when adjusting for year of starting haart. what do these findings mean? haart greatly improves the health of children in resourcelimited settings. however, despite profound improvements in outcomes, this study found nnrti-based regimens inferior to pi regimens in achieving and maintaining virological suppression. this difference did not seem to have clinical implications during the study period, since there was no difference on growth, immunological outcomes, or survival. nevertheless, the implications of detectable viraemia in we would like to thank the patients for participating in this study, and the nurses and clinicians from the two clinics. this study was made possible by funding received from the usaid and nih (usaid – award no. 674-a00-02-00018-00; cipra award 1u19 ai53217-01). t h e s o u t h e r n a f r i c a n j o u r n a l o f h i v m e d i c i n e j u n e 2 0 0 7 4 3 children are that resistance may develop and switches to second-line regimens may therefore occur sooner. in developing country settings where regimens are limited, the goal of haart should be to reach and maintain undetectable viral loads for as long as possible. the effectiveness of regimens containing nnrtis may be decreased in this setting because of less than optimal dosing, drug-drug interactions (such as tuberculosis therapy), or pmtct programmes. there is an urgent need to further explore optimal regimens, dosing, and pharmacokinetic interaction studies for children on haart in these settings. recruitment and sexual risk assessment of hiv-negative adolescents aged 14 17 years in preparation for hiv vaccine trials heather jaspan1,2, daniella mark1, landon myer3, alan flisher4, catherine mathews3,5, nosiphiwo soka1, keren middelkoop1, linda-gail bekker1 1desmond tutu hiv centre, institute of infectious diseases and molecular medicine, university of cape town, 2school of child and adolescent health, university of cape town, 3infectious diseases epidemiology unit, school of public health and family medicine, university of cape town, 4division of child and adolescent psychiatry, university of cape town, 5health systems research unit, medical research council, south africa the majority of new hiv infections in sub-saharan africa occur between ages 15 and 24 years, so adolescents are important targets for hiv preventive vaccination and must be included in hiv vaccine trials. to date no hiv vaccine trials have included adolescents, in part because of the challenges associated with hiv prevention research in young people, including issues of recruitment, informed consent, confidentiality, stigma, and potential for behavioural disinhibition. adolescents are likely to be ‘hard to reach’, and may be difficult to recruit into long-term studies. phase i to iii vaccine trials require participants of specific sexual risk, but adolescents may not freely admit their sexual behaviour. more information is needed to assess the feasibility of recruiting adolescents of varying sexual risk into hiv prevention research. why was this study done? ■ to assess the feasibility of recruiting hiv-negative 14 17year-olds, with parental consent, from a community in which hiv vaccine trials are planned. ■ to compare different methods of recruiting adolescents into hiv prevention research. ■ to assess self-reported hiv risk-related perceptions, knowledge and behaviours in this group. what did the researchers do and find? adolescents aged 14 17 were recruited from a peri-urban xhosa-speaking community. consent was obtained from all adolescents and a parent or legal guardian. hiv and syphilis testing was performed, and pregnancy testing where applicable. participants completed interviewer-assisted paper questionnaires on demographics, sexual risk behaviour, hiv knowledge, and perceived risk for hiv. there were 107 adolescents screened; 3 failed screening due to hiv infection and 3 due to pregnancy, and 1 was underage. the study was fully enrolled in 4 months. challenges arose in obtaining consent from parents, and required after-hours home visits. of the 100 adolescents enrolled, 98 were recruited through outreach activities. the mean age of the cohort was 15 years, and 70% were female. all participants were attending school with a median level of education of 8th grade. in general, hiv knowledge was high, except that only 78% knew that an infected person could test negative on routine hiv testing, and only 93% thought a person with hiv could look healthy. risky sexual behaviour was reported by the participants, with 43% reporting sexual activity, and 30% of these reporting more than one partner in the past year. only 19% knew the hiv status of their partner, yet 21% had never used a condom in the past 6 months. the adolescents perceived themselves to be at low risk of infection with hiv despite this behaviour, with only 3% reporting that they were at risk, and 63% believing that their bodies could fight off hiv. however, one-third felt that getting hiv would be bad for their futures and their family relationships. among the sexually active adolescents, condom use was not associated with perceived risk (p = 0.32). perceived risk was not associated with hiv knowledge (p = 0.30). females were more likely to perceive themselves as at high risk for hiv (p = 0.06); however, this association did not persist when adjusting for sexual activity. in a multivariate analysis predicting sexual activity, adjusting for hiv knowledge, perceived personal impact of hiv, and gender, only perceived risk for hiv was positively associated with sexual activity. what do these findings mean? recruitment for this study was relatively rapid, but required flexibility in clinic hours. recruitment via outreach activities seems to be far more effective than through voluntary counselling and testing (vct), a method often used for recruitment of adults. this may be due to the poor vct attendance of adolescents in this community. the high level of sexual risk-taking in this population suggests that young people are at substantial risk of hiv infection, yet these adolescents do not perceive themselves to be at high risk for hiv. this is not due to poor hiv knowledge, as the level of hiv knowledge among these adolescents was high. hiv prevention intervention studies will therefore need strong ageappropriate risk-reduction counselling. as shown in prior studies, young females are more often sexually active, and therefore at higher risk for hiv, than young males. yet these young women are also more aware of their hiv risk. there is an ethical imperative to facilitate inclusion of adolescents in hiv vaccine trials in order to ensure rapid licensure of a successful vaccine for this high-risk group. this work was supported in part by the kidzpositive family fund and the one to one children’s fund. this work was supported in part by the international maternal pediatric adolescent aids clinical trials network of the national institute of allergy and infectious diseases. hiv 930 guideline for the prevention, diagnosis and management of cryptococcal meningitis among hiv-infected persons: 2013 update by the southern african hiv clinicians society n p govender, g meintjes (chairpersons), t bicanic, h dawood, t s harrison, j n jarvis, a s karstaedt, g maartens, k m mccarthy, h rabie, e variava, w d f venter (expert panel members), d r boulware, t chiller, d b meya, j scriven (reviewers) corresponding author: n p govender (neleshg@nicd.ac.za) disclaimer: specific recommendations provided here are intended only as a guide to clinical therapy, based on expert consensus and best current evidence. treatment decisions for patients should be made by their responsible clinicians, with due consideration for individual circumstances. the most current version of this document should always be consulted. six years after the first society guidelines were published, cryptococcal meningitis (cm) remains an important cause of morbidity and mortality among hiv-infected adults in south africa. several important developments have spurred the publication of updated guidelines to manage this common fungal opportunistic infection. recommendations described here include: (1) screening and pre-emptive treatment; (2) laboratory diagnosis and monitoring; (3) management of a first episode of cm; (4) amphotericin b deoxycholate toxicity prevention, monitoring and management; (5) timing of antiretroviral therapy among patients with cm; (6) management of raised intracranial pressure; (7) management of relapse episodes of cm. s afr j hiv med 2013;14(2):76-86. doi:10.7196/sajhivmed.930 six years after the first society guidelines were published,1 cryptococcal meningitis (cm) remains an important cause of morbidity and mortality among hiv-infected adults in south africa (sa).2 several important developments have spurred the publication of updated guidelines to manage this common opportunistic fungal infection. first, for the first time in december 2011, the world health organization (who) published a rapid advice guideline focused on the management of hiv-associated cm in resource-limited settings.3 second, cryptococcal screening, an old strategy that has been revisited to detect cryptococcal disease earlier and pre-emptively reduce mortality, is being implemented in a phased manner in sa4 and is being considered in other african countries. third, the diagnostic landscape for cm has changed with the introduction of a united states food and drug administration (fda)-approved cryptococcal antigen (crag) lateral flow assay (lfa), which is simple, accurate and useful as a point-of-care test.5 finally, several clinical trials, many undertaken in southern africa, have improved our understanding of issues such as which first-line antifungal regimens are best suited to a resource-limited setting,6-9 when to start antiretroviral therapy (art),10 , 11 and how to safely administer amphotericin b deoxycholate,12 which has been used by many more sa clinicians as first-line induction-phase treatment for cm in the last 5 years.13 1. screening and pre-emptive treatment refer to table 1 for a summary of this recommendation. 1.1 background early diagnosis of hiv infection and early initiation of art before immunosuppression is the most important strategy to reduce the incidence of cm and associated mortality. in sa, patients should initiate art according to the current national guidelines.14 , 15 however, screening for early cryptococcal disease and pre-emptive antifungal treatment may be a useful adjunctive strategy, because the median cd4+ t-lymphocyte count among patients at the time of art initiation remains low in sa.16 the who, in their recently issued rapid advice guideline, indicated that routine screening for cryptococcal disease in art-naive adults with a cd4+ t-lymphocyte count <100 cells/µl may be considered prior to art initiation in populations with a high prevalence of cryptococcal antigenaemia. 3 in two art cohorts in sa, the prevalence of newly-diagnosed antigenaemia among patients with a cd4+ t-lymphocyte count <100 cells/µl was 4% and 7%, respectively. 17 this is greater than the threshold above which screening was found to be potentially cost-saving in a ugandan study. 18 , 19 to reduce disability and deaths associated with hiv infection, screening and pre-emptive antifungal treat­ment of cryptococcal disease has been suggested for routine implementation as part of the south african national strategic plan for hiv, stis and tb, 2012 2016.4 primary azole prophylaxis for cryptococcal disease, in the absence of a screening programme, is not routinely recommended by the who.3 1.2 detailed recommendations 1.2.1 who to screen hiv-infected adults with a cd4+ t-lympho­cyte count <100 cells/µl are recommended to be screened for cryptococcal antigenaemia. if screening is initiated by a clinician (medical practitioner or nurse trained in nurse-initiated management of art (nimart)) and not performed reflexively in the laboratory, then the expert panel recommends that screening be restricted to: art-naive adults with cd4+ t-lymphocyte count <100 cells/µl and no prior cm. although art-experienced patients with a cd4+ t-lymphocyte count that remains <100 cells/µl may also be at risk for cryptococcal disease,20 there is insufficient current evidence to routinely recommend screening art-ex­perienced adults. there are also insufficient data to recommend routine cryptococcal screening of hiv-infected children and adolescents, among whom the incidence of cm is much lower.3 , 21 1.2.2 screening strategies the most cost-effective screening strategy has not yet been defined. reflex laboratory screening, where blood samples with a cd4+ t-lymphocyte count <100 cells/ µl are auto­matically tested for crag, is being conducted at healthcare facilities in the gauteng and free state provinces in 2012/2013.4 screening initiated by clinicians is being conducted in other provinces such as the western cape.4 although the latex agglutination (la) test has been more extensively evaluated for diagnosis of cryptococcal disease, the rapid lfa is equally valid as a screening test. the laboratory turn-around time is short for the crag screening test; however, initiation of art should not be delayed unnecessarily while waiting for crag test results. 1.2.3 management of crag-positive patients the clinician should urgently evaluate crag-positive patients for symptoms and signs of meningitis, including headache and confusion (fig. 1). for the management of symptomatic crag-positive patients, refer to recommendations 3, 4, 5 and 6. patients without symptoms of meningitis may be offer­­ed a lumbar puncture (lp), if this is immediately accessible, to exclude early asymptomatic cm. for patients without suspected meningitis, oral fluconazole (800 mg for 2 weeks) followed by standard consolidation and maintenance treatment (refer to recommendation 3) is recommended; the same applies to patients with an lp that is cryptococcal test-negative. among patients without signs or evidence of meningitis, art is recommended to be started two weeks after antifungal therapy is initiated. as part of the screen-and-treat algorithm (fig. 1), crag-positive patients also need to be evaluated for the following clinical situations: fig. 1 screen-and-treat algorithm for art-naive adult patients with a cd4 + t-lymphocyte count <100 cells/µl. * symptomatic for meningitis if either of the following is present: headache; confusion. † special situations include: prior cryptococcal meningitis; pregnancy or breastfeeding mothers; clinical liver disease. § a lumbar puncture may be considered if available. fig. 2. laboratory procedure to set up and read the cryptococcal antigen lateral flow assay (immuno-mycologics, norman, ok) (source: immy crag lfa package insert; reprinted with permission). 1.2.3.1 prior cm patients with a history of cm do not need to be screened routinely as cerebrospinal fluid (csf) and blood specimens may remain crag-positive for months to years. however, if a patient with prior cm is screened and found to be crag-positive and has new symptoms or signs of meningitis, a full evaluation should be undertaken for relapse disease (refer to recommendations 2 and 7). if the patient does not have new symptoms or signs of meningitis, the clinician should ensure that the patient has received or is receiving adequate fluconazole maintenance therapy (refer to recommendation 3). the serum/plasma (and csf) crag test can remain positive for a prolonged period after successful treatment; therefore, if these tests are positive in the absence of symptoms and signs, this is not an indication of relapse. 1.2.3.2 pregnant/breastfeeding women fluconazole is teratogenic (category d).22 women of child-bearing age who screen crag-positive should have a pregnancy test prior to starting fluconazole; those who are not pregnant and are started on fluconazole should be advised to avoid becoming pregnant during treatment. crag-positive patients who are pregnant should be offered an lp before a decision is made regarding management. if the patient has laboratory evidence of cm, then she should be treated for cm with amphotericin b. the risks, benefits and alternative to fluconazole treatment (i.e. art and close clinical monitoring) should be discussed with the pregnant crag-positive patient without laboratory-confirmed cm and consultation with a medical practitioner who is experienced in the care of hiv-infected patients is recommended; in this context, consideration of factors such as the trimester and crag titre may be useful. for mothers who are breastfeeding, consultation with an experienced medical practitioner is also recommended as fluconazole can be transmitted in large amounts through breast milk to the infant.22 1.2.3.3 clinical liver disease patients with a history of liver disease or with evidence of clinical liver disease deserve careful monitoring because fluconazole may cause liver injury. consultation with a medical practitioner who is experienced in the care of hiv-infected patients is recommended. 2. laboratory diagnosis and monitoring refer to table 2 for a summary of this re­commendation. 2.1 background cryptococcus neoformans is the most commonly detected meningitis-causing pathogen in sa.23 all adults with suspected meningitis should be investigated for cm. patients with cm may present with fever as well as symptoms and signs related to inflamed meninges (including neck stiffness), raised intracranial pressure (including headache, confusion, altered level of consciousness, sixth cranial nerve palsies with diplopia and visual impairment, and papilloedema) and encephalitis (including memory loss and new-onset psychiatric symptoms).24 cutaneous lesions and pul­monary involvement (including cavitation, nodular infiltrates and consolidation) may also occur. symptomatic relapses are common and are most often a result of inadequate or premature cessation of maintenance flucona­zole treatment. 25 the incidence of cm is much lower among children;21 african children with cm may present with an acute onset of illness and focal neurological signs may be less common.26 2.2 detailed recommendations 2.2.1 diagnosis of first cm episode lp is required to establish an aetiological diagnosis of suspected meningitis. lp may also alleviate symptoms – such as headache, altered level of consciousness, and sixth cranial nerve palsies – that are a direct result of raised intracranial pressure. for a suspected first episode of cm, csf should be submitted to the laboratory for a rapid test (either india ink or crag test) and fungal culture. if the india ink test is performed as the only rapid test and is negative, the laboratory should then perform a crag test (either la or lfa). the sensitivity and specificity of crag tests (la and lfa) are higher than of india ink. 3 c. neoformans can be cultured within 72 hours from the csf of patients with a first episode. there is no need to routinely order a baseline csf crag titre; most patients are diagnosed when the csf fungal burden is high and antifungal treatment for a first episode is standardised and not influenced by the crag titre (refer to recommendation 3). if laboratory facilities are unavailable, a point-of-care lfa may be performed on csf at the bedside.5 , 27 antifungal susceptibility testing should not be requested for a first episode because antifungal drug minimum inhibitory concentrations (mics) are invariably very low at first diagnosis28 and, even if elevated, the relevance is difficult to interpret in this setting. if opening pressure was not measured at the time of the diagnostic lp, the lp should be repeated to measure the pressure once a diagnosis of cm is confirmed (refer to recommendation 6 for diagnosis and management of raised intracranial pressure). 2.2.2 diagnosis of cm if focal neurological signs are present or if lp is not immediately available focal neurological signs are relatively un­common in cm, except for sixth cranial nerve palsy. where focal neurological signs are present, a ct brain scan should be performed first to exclude the presence of space-occupying lesions. if a ct brain scan cannot be performed immediately in the case of focal neurological signs, or if lp is not immediately available to make a diagnosis of meningitis, then serum/plasma may be tested for crag to determine if the patient has disseminated cryptococcal disease. patients with a positive serum/plasma crag test and symptoms and signs of meningitis are very likely to have cm and should be started empirically on antifungal treatment (refer to recommendation 3). patients without focal neurological signs should then be referred to a centre where lp can be performed, while patients with focal neurological signs first need to have a computed tomography (ct) brain scan, followed by an lp (if this is not contra-indicated by ct brain findings). although aware that it may be difficult to access a ct brain scan in rural settings, the panel cannot recommend that an lp be performed in a patient with focal neurological signs without a scan. 2.2.3 diagnosis of a subsequent episode of cm a careful history should be taken including dates of previous episodes of cm and the patient should be assessed clinically for signs and symptoms of meningitis. an lp is indicated if the patient has signs and symptoms of meningitis. csf should be submitted for fungal culture with plates incubated for at least 14 days to detect slow fungal growth. rapid tests are not useful for diagnosis of subsequent episodes because both india ink and crag tests may remain positive for months to years even if treatment has been successful. antifungal susceptibility testing may be considered in certain circumstances (see below and refer to recommendation 7). 2.2.4 monitoring response to treatment resolution of symptoms and signs should be used to monitor response to treatment. lp should not be routinely performed after 14 days of antifungal treatment to document conversion of csf from culture-positive to culture-negative, because the expert panel advises routinely changing from induction to consolidation phase treatment at 14 days. given that the culture result takes several days (up to 14 days) to become available, the culture result will not affect the timing of this change. if symptoms persist at day 14, lp should be repeated to re-measure opening pressure, which may increase despite successful csf sterilisation. patients with raised intracranial pressure should be managed according to recommendation 6. csf crag may remain positive for months to years and crag titres are not recommended to be routinely measured to monitor response to treatment. serum/plasma crag titres are also not useful to monitor response to treatment.29 2.2.5 suspected antifungal drug-resistant isolate antifungal susceptibility testing may be considered if the patient has had more than one relapse episode and the causes listed in table 7 have been excluded. isolates with elevated fluconazole mics have been described occasionally from relapse episodes – especially where fluconazole monotherapy is initially given – and are unusual if amphotericin b-based induction treatment was administered during the first episode. as there are no established clinical breakpoints for c. neoformans and fluconazole, it is useful to test isolates from the initial and subsequent episodes in parallel at an academic or reference laboratory and document a four-fold (double-dilution) change in mic,14 , 16 which may suggest resistance. this requires storage of the initial isolate, which may not always be possible at a diagnostic laboratory. mics should be interpreted by an experienced clinical microbiologist, in conjunction with the clinical history. refer to recommendation 7 for the management of patients with fluconazole-resistant isolates. non-susceptibility to ampho­tericin b is very unusual and susceptibility testing to this drug should not be requested. 3. management of first episode of cm refer to table 3 for a summary of this re­commen­dation. 3.1 detailed recommendations the antifungal treatment of cm is divided into 3 phases: induction, consolidation and maintenance. 3.1.1 induction phase (2 weeks) guidelines of the infectious disease society of america (idsa) and the who recommend the first choice for induction-phase treatment as: amphotericin b (0.7 1.0 mg/ kg/ dose) and flucytosine (100 mg/ kg/ day).3 , 30 unfor­tunately, flucytosine is not currently available in southern africa. the panel supports international advocacy efforts to provide greater access to flucytosine in resource-limited settings, particularly in light of the findings of a recently-published clinical trial in vietnam showing improved survival among patients with cm treated with amphotericin b plus flucytosine v. amphotericin b alone.9 in the absence of flucytosine, the expert panel advocates that southern african patients should be treated with the following induction therapy for the first two weeks: amphotericin b deoxycholate (1 mg/kg/ day intravenous (iv) administration) plus flu­conazole (800 mg per os (po) daily). among sa adults, the 1 mg/kg/day dose of amphotericin b is well tolerated. 31 the panel advises adding fluconazole (800 mg/ day) during the induction phase in line with the who guideline; this is supported by evidence from a clinical trial that this combination is associated with a marginally superior rate of csf clearance compared with amphotericin b alone, and evidence from two trials showing a non-significant decrease in mortality and neurological morbidity.3 , 6 , 9 , 32 where amphotericin b is unavailable or cannot be given safely, the patient should be transferred to a hospital where amphotericin b is available. it is reasonable to give a fluconazole dose of 1 200 mg po daily while transfer is awaited. in countries where amphotericin b is unavailable, the panel would advise clinicians to follow the who guideline with respect to high-dose fluconazole options.3 however, in sa, all patients diagnosed with cm should have access to amphotericin b-based induction-phase treatment. 3.1.2 consolidation phase (further 8 weeks) the panel recommends 400 mg fluconazole po daily for 8 weeks. 3.1.3 maintenance phase this is also termed secondary prophylaxis. the panel recommends 200 mg fluconazole po daily for at least a further 10 months (i.e. until at least 12 months after treatment for cm was started). maintenance fluconazole should only be stopped when the cd4+ t-lymphocyte count is >200 cells/µl for at least 6 months and the most recent hiv-1 viral load is suppressed. patients with cm should have 6-monthly cd4+ t-lymphocyte measurements until flu­conazole can be stopped. 3.1.4 adolescents and children a dose of 1 mg/kg/ day amphotericin b should be prescribed during the induction phase. fluconazole doses should also be calculated according to body weight. induction phase: 12 mg/kg/day (up to 800 mg daily); consolidation phase: 6 12 mg/kg/day (up to 400 mg daily); maintenance phase: 6 mg/kg/day (up to 200 mg daily). 3.1.5 baseline renal impairment if patients have renal impairment at the time of diagnosis, this is not a contraindication to receiving amphotericin b deoxycholate at the standard dose (i.e. 1 mg/kg/day); however, creatinine should be monitored frequently and if it deteriorates significantly, then amphotericin b may need to be stopped and treatment continued with fluconazole monotherapy. when used as monotherapy during induction, the fluconazole dose would be 1 200 mg daily with normal renal function. with a creatinine clearance of 10 50 ml/min, the dose of fluconazole used as monotherapy should be reduced by 50% to 600 mg daily, and if creatinine clearance is <10 ml/ min, fluconazole should be reduced to 400 mg daily. if the baseline renal impairment is thought to be due to dehydration, then intensive iv rehydration efforts should occur while starting amphotericin b. for the prevention, monitoring and management of renal impairment that develops during amphotericin b deoxycholate administration, refer to recommendation 4. 3.1.6 patients receiving tb treatment in contrast to previous guidelines, the panel does not recommend a fluconazole dose increase in patients receiving rifampicin, as the induction of fluconazole metabolism by rifampicin causes only moderate reductions in fluconazole exposure,33 and because of the high doses of fluconazole that are initially being used. 3.1.7 adjunctive corticosteroid therapy the panel does not currently recommend adjunctive corticosteroid therapy in the initial management of cm. there is an ongoing international clinical trial that aims to address this question.34 refer to recommendation 7 for the use of corticosteroids in patients with immune inflammatory reconstitution syndrome (iris). 3.1.8 immunological failure on art in patients who develop immunological failure while receiving art and where the cd4+ t-lymphocyte count drops <200 cells/µl after secondary prophylaxis has been stopped, the panel advises restarting fluconazole at 200 mg daily. refer to the above section on maintenance-phase treatment for the duration of treatment. 3.1.9 non-adherence to maintenance treatment in patients who stop taking fluconazole maintenance prematurely and then return for care but are asymptomatic, the panel advises simply restarting fluconazole (200 mg daily) and monitoring closely for the recurrence of meningitis. refer to the above section on maintenance-phase treatment for the duration of treatment. 3.1.10 analgesia therapeutic lp is the best form of ‘analgesia’ for headaches associated with raised intra­cranial pressure. paracetamol can be used, but not non-steroidal anti-inflammatory drugs (nsaids), due to the nephrotoxicity concern with amphotericin b deoxycholate. morphine may also be appropriate and is not contraindicated in the presence of raised intracranial pressure. 4. amphotericin b toxicity prevention, monitoring and management refer to table 4 for a summary of this re­commendation.  4.1 background major adverse effects of amphotericin b deoxycholate include renal impairment due to renal tubular toxicity (usually in the second week of therapy), hypokalaemia, hypomagnesaemia, anaemia, febrile reactions and chemical phlebitis. nephrotoxicity and electrolyte abnormalities may be prevented by pre-hydration, by avoiding concurrent use of other nephrotoxins (e.g. nsaids and aminoglycosides) and by routine administration of potassium and magnesium supplements. phlebitis is very common in patients receiving amphotericin b and increases the risk of localised cellulitis as well as sepsis. anaemia commonly occurs among patients receiving amphotericin b and can be clinically significant, particularly among those with a low baseline haemoglobin level. haemoglobin decreases >2 g/dl occurred in 50 71% of patients over 2 weeks of treatment in an sa trial.7 it is important also to exclude other treatable causes of anaemia and consider transfusion in symptomatic patients. 4.2 detailed recommendations 4.2.1 administration of amphotericin b deoxycholate amphotericin b deoxycholate powder (50 mg vials) should be refrigerated between 2oc and 8oc and protected from light.35 the total daily dose of amphotericin b is calculated based on a dose of 1 mg/kg/day; amphotericin b deoxycholate powder from each 50 mg vial should be aseptically reconstituted in 10 ml of sterile water. the calculated volume of the concentrate (i.e. reconstituted drug in sterile water) should be injected into a 1 litre bag of 5% dextrose water and shaken to mix. amphotericin b deoxycholate should never be mixed with normal saline or half-normal saline as it will precipitate. once mixed, the solution (≤0.1 mg amphotericin b per 1 ml 5% dextrose water for infusion through a peripheral iv line22 ) must be infused within 24 hours of preparation or discarded. a test dose is not recommended.3 protection from light with a brown bag is unnecessary.35 the line that is used for amphotericin b infusion should not be used to administer other drugs simultaneously. the solution should be infused over 4 hours or more (infusion over <4 hours can result in cardiac complications). once the infusion is complete, the line should be flushed with normal saline. 4.2.2 prevention of amphotericin b deoxycholate-related toxicities patients should be pre-hydrated with 1 litre of normal saline containing 1 ampoule of potassium chloride (20 mmol k+ per 10 ml ampoule) infused over 2 hours before adminis­tration of amphotericin b deoxycholate. this reduces renal toxicity and hypokalaemia. patients should be given 1 200 mg of pota­ssium chloride twice daily (equivalent to 16 mmol of oral potassium, e.g. two slow-k 600 mg tablets twice daily, 8 mmol k+ per tablet) and up to one 500 mg magnesium chloride daily (e.g. two slow-mag 535 mg tablets daily, 5.33 mmol mg2+ per tablet) for the duration of treatment with amphotericin b deoxycholate. routine pre-emptive potassium supplementation should not be given to patients with pre-existing renal impairment or hyperkalaemia. to mini­mise the risk of phlebitis, lines should be flushed with normal saline after amphotericin b infusion is complete. the empty bag should not be left attached to the iv line. the iv line should be removed if the patient develops a fever after the infusion, or at the first sign of redness or discomfort at the insertion site. febrile reactions may occur; to prevent recurrence, the infusion should be administered at a slow rate over the first half-hour while observing the patient closely, as treatment such as paracetamol may be required. 4.2.3 clinical and laboratory monitoring at minimum, for the duration of amphotericin b deoxycholate treatment, baseline and twice-weekly monitoring of serum creatinine and potassium, and baseline and weekly monitoring of haemoglobin are recommended. renal toxicity is more likely to develop in the second week of treatment. fluid input and output should be monitored carefully. chemical phlebitis is often complicated by infection at the iv line insertion site, which can result in bacteraemia; the insertion site should be monitored by regular clinical examination, and febrile patients with a suspected insertion site infection should be appropriately investigated and managed. 4.2.4 management of toxicities for patients with significant hypokalaemia (serum k+ <3.3 mmol/l), iv replacement is required: 2 ampoules of potassium chloride (20 mmol k+ per 10 ml ampoule) in 1 litre of normal saline 8-hourly. among those who develop hypokalaemia, serum potassium should be monitored daily until resolved. if hypokalaemia remains uncorrected, serum magnesium should be checked (if this test is available) and/or oral magnesium supplementation doubled. iv magnesium sulphate may be considered for persistent hypokalaemia and hypomagnesaemia. if serum creatinine doubles from baseline, one dose of amphotericin b deoxycholate may be omitted and/or pre-hydration may be increased to 1 litre of normal saline 8-hourly; serum creatinine should then be monitored daily. if serum creatinine improves, amphotericin b may be restarted at a dose of 0.7 mg/kg/day and alternate-day treatment could be considered. if creatinine remains elevated or repeatedly rises, amphotericin b should be stopped and fluconazole used as suggested in recommendation 3 (baseline renal impairment section). if febrile reactions occur, paracetamol (1 g) may be given 30 minutes before infusion, or for severe reactions, hydrocortisone (25 mg iv) can be administered before subsequent infusions.22 5. timing of art among patients with cm refer to table 5 for a summary of this re­commendation. 5.1 detailed recommendations all hiv-infected patients who are diagnosed with cm are eligible for co-trimoxazole preventative therapy and art. the panel recommends commencing art 4 6 weeks after cm diagnosis, and strongly advises that art not be delayed beyond 6 weeks after diagnosis; some panel members advise that clinicians should aim to start exactly 4 weeks after diagnosis of cm. although most patients with cm have advanced immuno­suppression with very low cd4+ t-lymphocyte counts, two randomised clinical trials in sub-saharan africa have shown excess early mortality when art was commenced while patients were still receiving induction-phase treatment for cm.10 , 11 in the latter trial, conducted in uganda and sa, patients who started art 1 2 weeks after cm diagnosis had a 15% higher mortality rate than those who deferred art until 5 6 weeks.11 another small trial showed possible excess iris in those patients who started early.36 the long in-hospital stay associated with amphotericin b therapy should be utilised for pre-art counselling, identification of a treatment supporter and early referral to an art clinic. clinicians should aim to set up an art clinic appointment within one week of discharge from hospital; this prevents delays in art initiation beyond what is advised in this guideline. patients initiated on art should be counselled regarding the risk of developing iris. if a patient is referred to another facility for art, then the need for fluconazole maintenance therapy should be communicated. the panel recommends standard first-line art regimens among patients with cm.14 , 15 if nephrotoxicity occurred on amphotericin b, the renal function should be checked before starting art to ensure that it has improved (creatinine clearance >60 ml/ min) before commencing tenofovir. there are potential interactions between nevirapine and fluconazole, but studies have shown that these interactions do not affect the efficacy or toxicity of therapy.37 , 38 the panel recommends checking alt if symptoms of hepatitis or jaundice develop while patients are receiving fluconazole, but routine alanine transaminase (alt) monitoring is not indicated. the panel advises that, among patients who present with relapse of cm or a first cm episode after defaulting art, art is also restarted after 4 6 weeks. one situation where art may be delayed further is if a patient is still symptomatic with headaches at the visit when art is due to be started. in such a situation, an lp should be repeated to measure pressure and fungal culture should be used to exclude persistent culture-positivity. art should be deferred and such patients may require further lps or amphotericin b therapy to ensure control of symptoms before starting art. among patients who are serum/plasma crag-positive on screening, but do not have symptoms of meningitis and thus do not have an lp performed or have an lp that excludes cm, the panel advises starting art 2 weeks after starting fluconazole (fig. 1). 6. management of raised intracranial pressure refer to table 6 for a summary of this re­commendation. 6.1 background raised intracranial pressure occurs in ≤75% of patients with cm and is thought to result from obstruction of csf outflow, resulting in build-up of csf pressure.39 it may be present at diagnosis of cm or develop while the patient is receiving treatment. it may cause severe headaches, vomiting, confusion or a depressed level of consciousness, ophthalmo­plegia (particularly sixth cranial nerve palsies) and visual disturbance/loss. clinicians need to consider raised intracranial pressure as part of the differential diagnosis and act appro­priately if a patient exhibits these symptoms or signs at any stage of cm management. to alleviate raised pressure, therapeutic lps are indicated. new-onset hypertension may be a sign of increased intracranial pressure (i.e. cushing’s triad) and should prompt an lp to measure opening pressure instead of anti-hypertensive medications. 6.2 detailed recommendations it is good practice to measure the csf opening pressure whenever a diagnostic lp is done. however, in practice the opening pressure will not have been measured at the initial diagnostic lp in cm. thus, once the diagnosis of cm is made, an lp should be repeated to measure csf opening pressure, particularly if the patient still has a headache (which is usually the case). the pressure should be measured with the patient lying down and without excessive spinal flexion. if the opening pressure is raised (>25 cm h2o), then 10 30 ml of csf should be drained (to normalise pressure to <20 cm h2o or decrease the pressure by at least 50% – based on repeat measurements of closing pressure). thereafter, the need for pressure relief should be dictated by the recurrence of symptoms of raised intracranial pressure. patients may require daily lps. patients with raised intra­cranial pressure experience considerable relief of symptoms following therapeutic lps. approximately 15% of patients with initially normal intracranial pressure will develop raised intracranial pressure during treatment; therefore, all patients should be monitored daily for headache or signs of raised pressure that should prompt an lp. patients with persistent pressure symptoms and who fail to respond to serial lumbar punctures may require lumbar drain insertion or shunting procedures. neurosurgical consul­tation should be sought. in situations where manometers are not available, the panel suggests using a central venous pressure set manometer and attaching this to the lp needle using aseptic technique. in situations where this is also unavailable, if there are symptoms or signs of raised intracranial pressure due to cm (severe headache, drowsiness, sixth cranial nerve palsies), then the panel recommends performing an lp and removing 20 ml of csf and repeating daily, if necessary. manometers can be ordered from rocket medical plc (tyne and wear, uk) through summit surgical (gauteng) (email: phil@acroteq.co.za or jim@wycliffe.edu; fax: +27 (0)86 565 6347). 7. management of relapse episodes of cm there are several possible reasons for the recurrence of symptoms of meningitis in patients treated for cm. in certain cases, recurrence is due to microbiological relapse, but situations exist where there is symptom recurrence but csf fungal cultures are negative. the causes are summarised in table 7. when a patient presents with a recurrence, it is not always possible immediately to be sure of the aetiology. assessment should include: • assessment of adherence to fluconazole consolidation and maintenance-phase treatment (self-reported and pharmacy refill data) • to support an iris diagnosis, an enquiry as to whether the patient recently started art • an lp to measure opening pressure, assess csf inflammation and for a prolonged fungal culture (14 days) – there is no role for india ink staining or csf/serum/plasma crag assays in establishing the cause of recurrence, as these may remain positive for months (years even) in patients after successful treatment (refer to recommendation 2) • if the csf is culture-positive and non-adherence does not appear to be the cause, then fluconazole susceptibility testing should be considered (refer to recommendation 2) and should be performed in a reference laboratory; the panel recom­mends this especially when there has been more than one relapse, despite reported good adherence. if the cause of the recurrence is attributed to non-adherence, then the patient should be treated as for the first episode. the reasons for non-adherence should be explored and the patient should receive additional adherence counselling, preferably with a treatment supporter. if the patient also defaulted art, this should be re-initiated 4 6 weeks after presentation. art may need to be adjusted if there is concern that there has been virological failure on first-line art. paradoxical cryptococcal iris occurs among patients treated for cryptococcal disease who start art and develop a recur­rence or worsening of the clinical manifest­ations of cryptococcal disease. iris is thought to be the result of an immuno­pathological reaction directed at residual cryptococcal antigen at sites of the disease. 40 iris occurs, on average, 6 weeks after art is commenced, but delayed cases (even more than a year after art initiation) are described.41 iris affects approximately 20% of patients with cryptococcal disease who start art, and mortality may be substantial. 42 the most frequent manifestation is a recurrence of the symptoms of meningitis, often with raised intracranial pressure. typically, the csf fungal culture is negative at the time of iris presentation; iris represents an immunological reaction rather than a microbiological recurrence. however, in cases where induction therapy was recent (<2 months), the csf fungal culture may still be positive. other cryptococcal iris manifestations include lymphadenitis and cryptococcomas.40 in all patients with suspected paradoxical cm iris, an lp should be performed to measure pressure and obtain a fungal culture incubated for up to 14 days. it is not possible to make a diagnosis of iris with certainty prior to excluding microbiological relapse on csf fungal culture. if the symptoms are mild, the panel recommends performing therapeutic lps if there is raised intracranial pressure, providing analgesia and increasing the fluconazole dose to 1 200 mg daily with regular review and follow-up of the csf fungal culture result. if the csf fungal culture is negative, the dose of fluconazole can be reduced back to what it was (400 mg or 200 mg daily depending on the timing of the cm iris event). if patients with suspected cm iris have severe symptoms or deteriorate with the approach above, the panel recommends treating with amphotericin b (1 mg/kg/day iv) plus fluconazole (800 mg po daily) until the csf culture is confirmed as negative. if the csf culture is still negative after 7 days of incubation, amphotericin b can be stopped. if the fungal culture is positive by 7 days, then amphotericin b should be continued for 14 days. daily therapeutic lps may be required if the opening pressure is raised. a ct head scan should be considered, as mass lesions and cerebral oedema can occur with iris. analgesia should be provided. for patients with severe iris who do not respond to the above treatment, corticosteroids (e.g. prednisone 1mg/kg/day po or dexamethasone iv) should be considered. the panel recommends that corticosteroids preferably be used among patients with iris who are documented to be csf fungal culture-negative and when other aetiologies are excluded; however, if there is life-threatening neurological deterioration, corticosteroids should be started immediately. in patients with cm due to fluconazole-resistant isolates, subsequent management should be discussed with a medical practitioner experienced in the treatment of cm. such patients should receive induction therapy with amphotericin b again. consolidation and maintenance options depend on the fluconazole mic and include high-dose fluconazole with or without weekly amphotericin b infusions or voriconazole. in patients with multiple relapses, it is important to document the conversion of csf from culture-positive to culture-negative before stopping amphotericin b. such cases should be discussed with an experienced medical practitioner and fluconazole suscepti­bility testing should be performed (refer to recommendation 2). conflict of interest. t bicanic, j n jarvis, g maartens, k m mccarthy, t chiller and j scriven have declared no conflicts of interest. n p govender has received speaking-engagement honoraria from merck, and research support from pfizer (investigator-initiated grant) and immuno-mycologics (provision of cryptococcal antigen tests for studies). g meintjes is a senior clinical consultant for aid for aids. h dawood has received honoraria from msd-south africa and novartis-south africa for speaking engagements and a travel grant from novartis-south africa. t s harrison has received speaking-engagement honoraria from gilead sciences and research support from immuno-mycologics (provision of cryptococcal antigen tests for studies). h rabie is a consultant for aid for aids and has received honoraria from abbott abvie for speaking engagements. w d f venter has received conference travel support from adcock ingram and speaking-engagement honoraria from merck, jansen, tibotech and abbott. d r boulware has received research support from glaxosmithkline (investigator-initiated grant) and merck (medication for a clinical trial). d b meya has received research support. references 1. mccarthy k, meintjies g, arthington-skaggs b, et al. guidelines for the diagnosis, management and prevention of cryptococcal meningitis and disseminated cryptococcosis in hiv-infected patients. southern african journal of hiv medicine 2007;8(3):25-35. 1. mccarthy k, meintjies g, arthington-skaggs b, et al. guidelines for the diagnosis, management and prevention of cryptococcal meningitis and disseminated cryptococcosis in hiv-infected patients. southern african journal of hiv medicine 2007;8(3):25-35. 2. national institute for communicable diseases. germs-sa annual report 2011. johannesburg: national institute for communicable diseases, 2012. 2. national institute for communicable diseases. germs-sa annual report 2011. johannesburg: national institute for communicable diseases, 2012. 3. world health organization. rapid advice diagnosis, prevention and management of cryptococcal disease in hiv-infected adults, adolescents and children. geneva: world health organization, 2011. 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[http://dx.doi.org/10.1016/s1473-3099(10)70026-8] abstract introduction research methods and design results discussion conclusion acknowledgements references about the author(s) joseph sharp emory university school of medicine, atlanta, united states lynne wilkinson médecins sans frontières, cape town, south africa centre for infectious disease epidemiology and research, school of public health and family medicine, university of cape town, cape town, south africa international aids society, cape town, south africa vivian cox centre for infectious disease epidemiology and research, school of public health and family medicine, university of cape town, cape town, south africa carol cragg provincial department of health, western cape, cape town, south africa gilles van cutsem médecins sans frontières, cape town, south africa centre for infectious disease epidemiology and research, school of public health and family medicine, university of cape town, cape town, south africa anna grimsrud international aids society, cape town, south africa citation sharp j, wilkinson l, cox v, et al. outcomes of patients enrolled in an antiretroviral adherence club with recent viral suppression after experiencing elevated viral loads. s afr j hiv med. 2019;20(1), a905. https://doi.org/10.4102/sajhivmed.v20i1.905 original research outcomes of patients enrolled in an antiretroviral adherence club with recent viral suppression after experiencing elevated viral loads joseph sharp, lynne wilkinson, vivian cox, carol cragg, gilles van cutsem, anna grimsrud received: 30 aug. 2018; accepted: 17 apr. 2019; published: 11 june 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: eligibility for differentiated antiretroviral therapy (art) delivery models has to date been limited to low-risk stable patients. objectives: we examined the outcomes of patients who accessed their care and treatment through an art adherence club (ac), a differentiated art delivery model, immediately following receiving support to achieve viral suppression after experiencing elevated viral loads (vls) at a high-burden art clinic in khayelitsha, south africa. methods: beginning in february 2012, patients with vls above 400 copies/ml either on firstor second-line regimens received a structured intervention developed for patients at risk of treatment failure. patients who successfully suppressed either on the same regimen or after regimen switch were offered immediate enrolment in an ac facilitated by a lay community health worker. we conducted a retrospective cohort analysis of patients who enrolled in an ac directly after receiving suppression support. we analysed outcomes (retention in care, retention in ac care and viral rebound) using kaplan–meier methods with follow-up from october 2012 to june 2015. results: a total of 165 patients were enrolled in an ac following suppression (81.8% female, median age 36.2 years). at the closure of the study, 119 patients (72.0%) were virally suppressed and 148 patients (89.0%) were retained in care. six, 12 and 18 months after ac enrolment, retention in care was estimated at 98.0%, 95.0% and 89.0%, respectively. viral suppression was estimated to be maintained by 90.0%, 84.0% and 75.0% of patients at 6, 12 and 18 months after ac enrolment, respectively. conclusion: our findings suggest that patients who struggled to achieve or maintain viral suppression in routine clinic care can have good retention and viral suppression outcomes in acs, a differentiated art delivery model, following suppression support. keywords: differentiated care; retention; viral suppression; adherence; high-risk patients; art delivery. introduction the introduction of antiretroviral therapy (art) for the treatment of hiv has led to massive reductions in mortality and slowed the progression of disease and transmission of infection.1,2 these reductions are contingent upon strict adherence to art regimens and long-term retention in care.3,4 treatment programmes throughout the world are both expanding to meet the joint united nations programme on hiv/aids (unaids) 90-90-90 targets and continuing to mature, as the first patients initiated in some treatment programmes will soon enter their third decade on art.5 despite advances in the reduction of the costs of treatment,6 the stigma associated with infection7 and the need to integrate treatment into daily routines,8,9 increasing numbers of patients are interrupting care and experiencing viral rebound. while retention has been consistent between 74% and 78% at 12 months from 2005 to 2013,10 the number of patients in care globally has increased dramatically from 1.3 million in 200511 to over 21.7 million in 2017.12 this trend is evident in south africa where the treatment programme has grown from just less than 100 000 to over 4 million patients, and concurrently, the number of patients interrupting or abandoning care has also increased.13 models of care must adapt to focus on the needs of the growing population that has interrupted art while supporting quality care for the new patients eligible for art as countries adopt ‘test and start’ guidelines. differentiated art delivery models such as art adherence clubs (acs) have been shown to be successful and cost-effective in providing treatment, care and support.14,15,16,17 these models have traditionally been restricted to clinically stable patients, defined as patients on art for 12 months or more with two undetectable viral loads (vls). differentiated art delivery models promote adherence by reducing the frequency of visits and time spent in a clinic, allowing for increased peer and lay healthcare worker (lhcw) support and ensuring longer art supply.18,19,20,21,22,23 if such models of art delivery remain restricted to low-risk stable patients on first-line treatment, the growing cohort of patients struggling with adherence may be left behind, stuck in delivery models that already failed them. furthermore, it may be the patients who are not stable, those at risk of treatment failure, who stand to gain the most from simplifying their art refill delivery mechanism.24 while differentiated art delivery models have received widespread attention and have been incorporated into the world health organization’s treatment guidelines,25 they have been restricted to low-risk stable patients. data on the outcomes of patients at high-risk of experiencing viral rebound who access differentiated art delivery models do not currently exist. we describe the outcomes of patients referred directly to acs after viral suppression following specific adherence support. research methods and design study design a descriptive retrospective cohort study was undertaken using routine data collected under programmatic conditions at ubuntu clinic, khayelitsha, western cape, south africa, for patients who joined acs between february 2012 and february 2014 after viral suppression following the risk of treatment failure (rotf) intervention. setting the study was conducted at ubuntu clinic in khayelitsha, south africa. khayelitsha is a township in cape town with a population of approximately half a million people and high rates of hiv and tuberculosis (tb). in 2011, the antenatal hiv prevalence was 34%.26,27 the community is largely poor, with 55% of the population living in informal housing and 60% unemployment among working age individuals.28 in 2001, ubuntu clinic became the first public sector clinic in the country to provide art;29 by march 2017, 10 252 patients were retained in art care at ubuntu clinic, with close to 40 000 patients in art care in khayelitsha sub-district (a sub-district in the cape metro district). adherence club model and risk of treatment failure intervention the ac model has been described in detail previously.15,16,17,18 briefly, in the western cape, clients were initially regarded as stable and eligible for the ac model if on art for 12 months or more with two undetectable vls and no co-morbidities requiring frequent clinical assessment. in 2015, stability criteria changed to on art for 6 months or more with a single undetectable vl. adherence clubs were composed of approximately 30 patients who met with an lhcw five times a year (every 2 months except over year-end holidays when a 4-month art refill was provided) for a short symptom screen, peer support and distribution of pre-packed art refills. some acs were facility based and met at the ubuntu clinic, while others were decentralised to community venues. adherence club patients had an annual blood draw and an annual clinical consultation as part of their ac visit schedule. if a patient experienced viral rebound (vl > 400) in the ac, failed to attend their ac or became clinically unstable for any reason, the patient was referred back into routine clinic care for ongoing management. the ac model was brought to scale in the cape town health district with 40.9% (62 874 patients) of all art patients in the district accessing art care and support through acs by the end of 2016.30 twenty-four-month retention, annual vl completion and viral suppression outcomes31 were 89.3%, 88.1% and 97.2%, respectively. in 2012, the rotf intervention was piloted at ubuntu clinic by médecins sans frontières (msf) and the western cape department of health.32,33, the western cape department of health has subsequently adopted the intervention to manage all patients failing or at risk of failing art with phased implementation in all its cape town facilities starting at the end of 2015. the intervention was designed to provide integrated adherence support and clinical management for all patients in routine clinical care with vls above 400 copies/ml, irrespective of treatment regimen. patients who experienced a single vl > 400 copies/ml were enrolled in an lhcw support group, while those with two consecutive vls > 400 copies/ml experienced more intensive counselling with a nurse trained to provide integrated adherence and clinical management. adherence was managed through structured steps including vl monitoring and switching patients to second-line art regimens in accordance with national guidelines (two consecutive vls > 1000 copies/ml). after suppression (vl < 400 copies/ml) – whether on first line, after switch to second line or on second line – patients were given the choice to enrol directly into an ac or return to routine clinician-led facility-based care. patients who suppressed and enrolled in an ac following the rotf intervention are hereafter referred to as ‘high-risk patients’ as they were regarded to be at a higher risk of interrupting their treatment again.34,35 high-risk patients were enrolled in acs on a rolling basis, and therefore acs are composed of both stable and high-risk patients. data collection and analysis analysis inclusion and exclusion patients who joined acs between february 2012 and february 2014 after suppressing in the rotf intervention were identified retrospectively by comparing the clinic’s electronic monitoring records (emr), which identified patients participating in the rotf and ac programmes. additional data were gathered from ac registers on those patients who were identified as having participated in both programmes. patients were excluded if they were enrolled in an ac before the rotf intervention, enrolled in a family ac (utilised for children and their caregivers), missing from the ac register or confirmed to have never joined an ac (indicating emr ac participation incorrect), never suppressed after rotf or if they never had a vl greater than 400 copies/ml (indicating emr rotf participation incorrect) (figure 1). one ac register could not be found, and all patients referred to that ac were excluded from analysis. this left only high-risk patients confirmed to have joined acs directly after participation and successful suppression following the rotf intervention. figure 1: flow chart of analysis inclusion criteria applied to obtain study sample. data collection data for each patient in the analysis cohort were collected from patient visit and laboratory data from the emr and ac registers. missing vl results were obtained from the national health laboratory service database. patient clinic folders were consulted for patients whose most recent status was missing from the ac registers to confirm their current ac status. key variables collected included art regimen, art start date, rotf enrolment date, last unsuppressed vl and date, first suppressed vl and date, all vls and dates after club enrolment and all clinic and club visits after suppression. statistical analysis patients entered the analysis on their first ac date (between february 2012 and february 2014) and were followed until march 24, 2015. we assessed three outcomes: retention in care, retention in club care and viral suppression. retention in care was defined as having contact with the clinic or ac between march 24 and june 21, 2015, with retention in club care defined as attending an ac in the same period. patients were classified as virally suppressed if their last vl before analysis closure was less than 400 copies/ml. we define viral rebound as an elevated vl above 400 copies/ml after having achieved viral suppression. known deaths and transfers contributed retention time until they were censored at the time of death or transfer. patient characteristics at enrolment into an ac (gender, age at art start, age at ac start, year of art start, treatment regimen) and time from art initiation to rotf participation and from rotf participation to ac enrolment were summarised using medians and interquartile ranges (iqrs) for continuous variables and proportions for categorical variables. cross-sectional retention outcomes are reported at study closure. kaplan–meier methods were used to estimate the survival probabilities of retention, ac retention and viral suppression, and are reported at 3-monthly intervals to 18 months with 95% confidence intervals (cis). data were analysed using stata 13.0 software (stata corporation, college station, tx, us). ethical consideration because of the nature of the study, individual patient consent was not obtained, consistent with the declaration of helsinki. all participants and data were drawn from an ongoing cohort study of routine art outcomes in khayelitsha, cape town, approved by the human research ethics committee of the faculty of health sciences at the university of cape town (hrec 395/2005). only routine clinical service data were used and no identifying patient information was entered into the database. results patient characteristics from february 2012 to february 2014, 165 high-risk patients who completed the rotf intervention and suppressed were immediately enrolled in an ac. the cohort was predominantly female (81.8%) with a median age at art start of 31 years (iqr: 28–37). current treatment regimens were available for 133 patients, and of those 105 (79%) were on second-line therapy (table 1) at the time of ac enrolment. the median time from art initiation to enrolment in the rotf intervention was 3.4 years (iqr: 2.1–5.5), and the median time from rotf intervention to ac enrolment was 1.2 years (iqr: 1.0–1.5). table 1: description of risk of treatment failure patients who suppressed and were referred to an adherence club. cross-sectional outcomes during the study period, two patients (1.2%) died, 15 (7.8%) were lost to follow-up and 40 (24.0%) experienced viral rebound. at the closure of the study, 148 patients (89.0%) were retained in care and 119 patients (72.0%) were virally suppressed. when stratified by known art regimen, 26 patients (93.0%) on first line and 97 patients (92.0%) on second line were retained in care, while 20 patients (71.0%) on first line and 83 patients (79.0%) on second line were virally suppressed. time to event outcomes retention in care was estimated to be 98.8% (95% ci, 94.4–99.4), 94.8% (95% ci, 89.8–97.4) and 89.3% (95% ci, 81.8–93.8) at 6, 12 and 18 months after ac enrolment, respectively (table 2, figure 2a). retention in ac care was estimated to be 98.2% (95% ci, 94.4–99.4), 92.0% (95% ci, 86.3–95.4) and 80.5% (95% ci, 72.0–86.6) over the same time periods (table 2, figure 2b). eighteen months after enrolment in acs, 90% of patients retained in clinic care were still in acs. viral suppression was estimated to be 90.0% (95% ci, 84.1–93.7), 83.9% (95% ci, 76.8–88.9) and 75.0% (95% ci, 66.0–81.9) at 6, 12 and 18 months after ac enrolment, respectively (table 2, figure 2c). figure 2: retention in care (a), retention in adherence club care (b) and viral suppression (c) over the first 18 months in adherence clubs immediately after viral suppression and referral to an adherence club. table 2: kaplan–meier estimates of retention in care, retention in adherence club care and viral suppression by duration of follow-up after first ac meeting. discussion patients who had previously had elevated vls had good treatment outcomes following supported viral suppression and direct referral to acs, a differentiated art delivery model. despite having had recent elevated vl, 75% of patients who joined acs after undergoing a rotf intervention were estimated to maintain viral suppression 18 months after joining the ac. eighteen months after ac enrolment, retention in care was estimated at 89%, and 90% of patients retained in care were still in acs. care was differentiated in the intensified management intervention to target patients failing treatment and in the art delivery model provided immediately after suppression. to date there is limited evidence on the outcomes of high-risk patients in art delivery models differentiated for stable patients. we observed retention and viral suppression outcomes matching or exceeding those of retention benchmarks and meta-analyses from sub-saharan africa through 18 months of follow-up. retention in sub-saharan africa was estimated to be 81% at 12 months,10 significantly less than the 94.8% retention in this cohort of recently suppressed patients. while we report 12-month retention from ac enrolment, not art initiation, this remains significant. twelve-month retention is only slightly lower than the 12-month 97.0% retention observed in stable patients in acs at the same clinic15 and the 99.0% retention observed in stable patients in a similar community ac cohort36 and the 12-month retention in acs across the cape metro.31 in a 2015 systematic review of vl suppression, 12-month suppression in sub-saharan africa was estimated to be 64.2%.37 we observed 83.9% viral suppression at 12 months after ac enrolment. these outcomes also compare well to those of patients switched to second-line regimens. analysis of a cohort in durban, south africa, found 25.0% virological failure every 6 months after switching to second-line regimens.38 in a european cohort of treatment-experienced patients who recently achieved viral suppression, 31.0% of patients experienced viral rebound within 1 year.35 considering 100.0% of the study cohort experienced recent elevated vls and 79.0% had either recently been switched to a second-line regimen within the rotf intervention or entered rotf on a second-line regimen, our results are promising. ninety per cent of patients retained in care after 18 months were still receiving their care in acs, suggesting a high level of satisfaction with the service delivery model. this result is important because patient satisfaction is a strong predictor of adherence to art regimens.39 while patients on art experience elevated vls (including viral rebound) for a variety of reasons, the single largest predictor is sub-optimal treatment adherence.4,40,41,42,43 therefore, it follows that patients have better outcomes in models that better fit their lives. the ac model may support patients struggling with adherence in routine care by reducing or removing barriers to adherence. in addition to the differentiated nature of the acs, the model was also differentiated from routine care, providing more intensified integrated adherence and clinical care through the rotf intervention to meet the needs of patients as they attempted to achieve viral suppression after elevated vls and remain in care. this model of vl-informed differentiated care has been shown to be effective and cost-efficient in supporting patients who experience elevated vls in routine care.44 in other words, it is possible that both the intense support in achieving suppression through the rotf and simplifying ongoing access to care and treatment, with peer support, through the ac model immediately after suppression could be responsible for the positive outcomes. these results should be viewed in light of a number of limitations. firstly, a control group was not obtained, making comparison of these results difficult. because of the retrospective nature of the study and the ability of patients to self-select into ac care or routine clinic care after rotf, any control group chosen would be biased. we chose to compare the outcomes to broader benchmark goals for all art programmes. importantly, our analysis begins at ac enrolment and not art start. because the largest drop in retention occurs immediately after art start, care must be taken when comparing these results to those of newly enrolled patients. secondly, tracing of patients lost to follow-up to identify undocumented transfers was not completed. however, any bias this limitation created would serve to reduce observed retention. thirdly, patients were given the choice to join an ac or return to routine clinic care after completing the rotf intervention. it is therefore possible that only the motivated patients joined acs, and our results are not representative of all patients who have experienced an elevated vl. this scenario is unlikely because fewer than 10.0% of patients chose to return to routine care after achieving suppression. regardless, by allowing patients to self-select into care models, the probability that they will find a model of care that suits their life, and thus maintain adherence, increases. fourthly, it is possible that transmitted resistance to first-line regimens was responsible for the positive response in patients switched to second line. this would only account for a small proportion of patients given the relative infrequency of transmitted resistance in south africa45 and the extensive evidence indicating that non-adherence is the primary cause of an elevated vl.32,46 it is also possible that patients switched to second-line therapy had positive viral suppression results despite continued poor adherence because of a switching effect.47 however, this effect is thought to be minimal as most patients who fail second-line treatment after switching do so within the first 2 years and the outcome would be seen within our follow-up period.48 unfortunately, we are unable to differentiate the patients who entered the rotf intervention on second-line regimens from those who were switched to second line during the intervention and are susceptible to this switching effect. in addition, because of the limited number of patients, there was insufficient power to analyse associations between outcomes and patient demographics. an attempt was made to include all patients who participated in both rotf and acs by cross-referencing both databases; however, it is possible that patients were missed in our sampling approach. in addition, data were collected from routine clinical databases and thus may be subject to data quality error. finally, it is possible that the exclusion criteria that were applied biased the results towards increased retention and viral suppression. this possibility was minimised by cross-checking multiple data sources and excluding the entire ac when information was missing for a selective subset of patients in that ac. despite these limitations, we find these results promising in introducing the idea that patients who experienced a recent elevated vl can have positive outcomes if care is differentiated to meet their specific needs at a particular time point in their treatment pathway. conclusion further research is needed to fully understand how less intense, differentiated art delivery models can collectively support the heterogeneous population of patients currently ineligible for these models. we recommend both small-scale implementation in diverse contexts to assess the generalisability of our findings and randomised control trials to directly compare the outcomes of patients experiencing elevated vls recently suppressed or resuppressed immediately accessing a simplified art delivery model versus routine care. tests of association should be employed to determine the populations who could most benefit. finally, retention in ac care had its sharpest decline between 12 and 18 months, and longer term follow-up is needed to determine if differentiated art delivery models can support patient retention over the long run. in summary, criteria for differentiation must continue to be re-evaluated. using the criteria of proven ‘stability’ may exclude those who have the most to gain from streamlining access to art, including those who have recently suppressed. in conclusion, our findings suggest that patients who struggled to achieve or maintain viral suppression in routine clinic care can have good retention and viral suppression outcomes in differentiated art delivery models, such as acs, immediately following suppression support. these models may remove health system barriers imposed by clinician-led facility-based models. further studies are required to evaluate both retention and viral suppression benefits of expanding access to differentiated art delivery models to patients who have struggled with adherence. acknowledgements the authors thank all the staff at ubuntu clinic and khayelitsha and eastern sub-structure for their ongoing dedication to their patients demonstrated through their continued support for piloting models of care that better suit the needs of their patients. the authors would also like to thank the msf rotf and ac nurses and counsellors who mentor and support their colleagues at ubuntu clinic. competing interests the authors declare that they have no financial or personal relationship(s) that may have inappropriately influenced them in writing this article. authors’ contributions j.s. was responsible for the writing of the article, with statistical analysis completed by j.s. and a.g. j.s. and l.w. collected the data for analysis. j.s., l.w., c.c., g.v.c. and a.g. contributed to the plan of the analysis and interpretation of the data. l.w. and v.c. developed the rotf 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second-line antiretroviral therapy: associations with nucleoside reverse transcriptase inhibitor resistance and subtherapeutic drug concentrations prior to switch. j infect dis. 2014;209 (5):711–720. https://doi.org/10.1093/infdis/jit411 tsegaye a, wubshet m, awoke t, alene k. predictors of treatment failure on second-line antiretroviral therapy among adults in northwest ethiopia: a multicentre retrospective follow-up study. bmj open. 2016;6(12):e0125. https://doi.org/10.1136/bmjopen-2016-012537 hiv 906 forum world health organization guidelines should not change the cd4 count threshold for antiretroviral therapy initiation n geffen centre for social science research, university of cape town n geffen, msc corresponding author: n geffen (nathangeffen@gmail.com ) the world health organization (who) currently recommends that hiv-positive adults start antiretroviral therapy (art) at cd4 counts <350 cells/µl. several countries have changed their guidelines to recommend art irrespective of cd4 count or at a threshold of 500 cd4 cells/µl. consequently, who is currently revising its treatment guidelines and considering recommending art initiation at cd4 counts <500 cells/µl. such decisions are critically important, as who guidelines inform healthcare policies in developing countries and are used by activists in their advocacy work. changing the cd4 initiation point from 350 to 500 cells/µl would, however, be premature and have profound cost implications on global fund, president’s emergency plan for aids relief (pepfar) and developing country health budgets. we should be willing to campaign for such a change in guidelines despite cost implications, if supported by evidence. however, the evidence remains outstanding. s afr j hiv med 2013;14(1):6-7. doi:10.7196/sajhivmed.906 the world health organization (who) currently recommends that adults living with hiv start antiretroviral therapy (art) when their cd4 counts fall below 350 cells/µl. several countries have changed their art guidelines to recommend treatment irrespective of cd4 count or at treatment thresholds of 500 cd4 cells/µl.1 who is currently revising its treatment guidelines and considering recommending that treatment start at 500 cells/µl. the decisions taken by who on art guidelines are extremely important, as these guide healthcare policies in developing countries and are used by activists in their advocacy work. to understand the impact of the who guidelines, it is important to consider that there are more people living with hiv in nigeria alone than in the whole of north america, western europe and australia combined. even a small country such as zimbabwe has more hiv-positive people than in the whole of western europe.2 countries in sub-saharan africa, the caribbean and asia are strongly influenced by the who guidelines, much more so than by the department of health and human services (dhhs) guidelines published in the united states of america. this is especially the case for countries where treatment is primarily provided through funding from the global fund to fight aids, tb and malaria (gfatm) or the united states president’s emergency plan for aids relief (pepfar). the evidence for changing cd4 initiation thresholds when considering changing the cd4 threshold for art initiation, or dispensing a threshold entirely, we need to consider the evidence to support such a change, for both an individual patient’s health and for hiv prevention efforts at a population level. prevention the hptn 052 trial showed that art greatly reduces the risk of an hiv-positive person transmitting hiv to his/her partner. this finding was consistent with compelling observational data. 3 there is also evidence from several places, including san francisco, vancouver and taiwan, that reducing community viral load reduces hiv incidence.4-6 there is also indication from mathematical models that art may be reducing hiv incidence in south africa.7 who subsequently published guidelines regarding the role of art in hiv prevention efforts.8 nevertheless, in many settings it is not clear whether changing the cd4 initiation threshold to 500 cd4 cell/ µl would have a significant effect on hiv incidence. in contrast to places in north america where reduction in community viral load has been shown to reduce incidence, the distribution of hiv in many sub-saharan african cities is characterised largely by heterosexual epidemics of a much broader scale. it is likely that reducing viral load through widespread art use will reduce incidence in sub-saharan africa, but this is not a given. moreover, this approach has to be proven to policy makers, because there are enormous cost implications associated with this type of expanded treatment. studies currently underway in african countries are looking at whether initiating treatment earlier does reduce community incidence. treatment the benefit to the patient should be the salient consideration in the who treatment guidelines (as opposed to guidelines for sero-discordant couples, where preventing infection of the hiv-negative partner is the primary consideration). when empirical data on this question are appraised rigorously, as in the british hiv association’s guidelines, it emerges that the evidence for initiating treatment at a cd4 count >350 cells/µl is poor.9 one widely circulated myth that needs to be discredited is that the hptn 052 trial showed a reduced disease progression when art was initiated above 350 cd4 cells/µl: the initiation threshold was 250 cd4 cells/µl, and not 350 cells/µl. data from clinical trials had previously shown that a treatment threshold of 250 cells/µl was inferior.10 , 11 the question of whether a threshold of 350 cd4 cells/µl is optimal remains unanswered. guidelines in some wealthy countries have changed to-and-fro over the last decade and a half on the issue of when to initiate art: from the ‘hit hard, hit early’ strategy promoted in the 1990s, to postponing art initiation until lower cd4 thresholds more recently. this is precisely why the strategic timing of anti retroviral therapy trial (start) (funded by the united states national institute of health) and the early antiretroviral treatment and/or early isoniazid prophylaxis against tuberculosis in hiv-positive adults trial (temprano) (funded by the french national agency for research on aids and viral hepatitis) are being conducted: to answer once and for all when the best point is for patients to start art. there are three likely outcomes of the start and temprano studies: (i) that earlier treatment reduces disease progression; (ii) that there is no difference between the earlier v. later treatment arms; or (iii) that earlier treatment is harmful due to increased side-effects or reduced adherence. if the latter two outcomes emerge but who has already recommended earlier treatment, it will undermine the who treatment guidelines in general. at best, there would have been serious cost implications for developing country health budgets; and at worst patients might have been harmed. if who keeps its threshold recommendation unchanged and the first of the aforementioned outcomes is validated, then the organisation would have taken the correct action by having waited for the evidence. although clinicians and aids activists have different expectations of the trial results, these personal prejudices do not matter. the evidence is simply not yet available, and in this case, who needs to wait. the issue of cost cost is profoundly important when considering public health interventions, and should always be a concern for activists. to ignore such implications is poor activism, not only because policy makers do not take activists who ignore cost seriously, but also because it is morally problematic. public health policy involves making choices determined by cost. as art becomes more nuanced, the relative cost per disability adjusted life-year (daly) saved becomes higher and the arguments for using the money elsewhere become harder to refute. as an example of how cost has informed activism in a developing country, the treatment action campaign (tac) has been cognisant of cost in its campaigns, despite demanding that the south african (sa) government implements treatment and prevention programmes. in a court case that dealt with prevention of mother-to-child transmission of hiv in 2002, the tac included an affidavit that showed that the intervention would be cost-saving.12 the tac later published research showing that art would be affordable for the sa government. by considering cost, the tac was able to make compelling arguments for the implementation of life-saving interventions. the current who art guidelines for adults and adolescents include two important changes, including provision (i) for art to be initiated at 350 cd4 cells/µl; and (ii) for stavudine (d4t) to be replaced by tenofovir (tdf). both of these changes have cost implications, but are supported by a very strong evidence base. because the campaigns for these changes to be adopted by poor countries have been based on sound science, they have met some success. who guidelines should be seen as an achievable aspiration for poorer countries. nevertheless, even today, several sub-saharan countries initiate art at 200 250 cd4 cells/µl with stavudine, largely due to resource limitations. this proves that cost is a critical factor – perhaps the most critical factor – in getting poorer countries to change their guidelines. conclusion changing the cd4 initiation point from 350 to 500 cells/µl in the new who guidelines would be premature. it would have profound cost implications on global fund, pepfar and developing country health budgets. we should be willing to campaign for such a change in guidelines despite cost implications if it was supported by evidence. but, the evidence is still outstanding. expecting countries to move to a costly new cd4 threshold without sufficient evidence is a mistake. conflict of interest. the author serves on the community advisory board of insight, the organisation that runs the start trial. acknowledgements. the author acknowledges assistance from claire rappoport, simon collins and caroline sabin. references 1. us department of health and human services. guidelines for the use of antiretroviral agents in hiv-1-infected adults and adolescents. http://aidsinfo.nih.gov/contentfiles/lvguidelines/aa_recommendations.pdf (accessed 12 january 2013). 1. us department of health and human services. guidelines for the use of antiretroviral agents in hiv-1-infected adults and adolescents. http://aidsinfo.nih.gov/contentfiles/lvguidelines/aa_recommendations.pdf (accessed 12 january 2013). 2. unaids. report on the global aids epidemic. geneva: unaids, 2012. 2. unaids. report on the global aids epidemic. geneva: unaids, 2012. 3. cohen, ms, chen yq, mccauley m, et al. prevention of hiv-1 infection with early antiretroviral therapy. n engl j med 2011;365(6):493-505. [http://dx.doi.org/10.1056/nejmoa1105243] 3. cohen, ms, chen yq, mccauley m, et al. prevention of hiv-1 infection with early antiretroviral therapy. n engl j med 2011;365(6):493-505. [http://dx.doi.org/10.1056/nejmoa1105243] 4. das m, chu pl, santos g-m, et al. decreases in community viral load are accompanied by reductions in new hiv infections in san francisco. plos one 2010;5(6):e11068;5(6):e11068. [http://dx.doi.org/10.1371/journal.pone.0011068] 4. das m, chu pl, santos g-m, et al. decreases in community viral load are accompanied by reductions in new hiv infections in san francisco. plos one 2010;5(6):e11068;5(6):e11068. [http://dx.doi.org/10.1371/journal.pone.0011068] 5. fang c-t, hsu h-m, twu s-j, et al. decreased hiv transmission after a policy of providing free access to highly active antiretroviral therapy in taiwan. j infect dis 2004;190(5):879-885. [http://dx.doi.org/10.1086/422601] 5. fang c-t, hsu h-m, twu s-j, et al. decreased hiv transmission after a policy of providing free access to highly active antiretroviral therapy in taiwan. j infect dis 2004;190(5):879-885. [http://dx.doi.org/10.1086/422601] 6. montaner js, lima vd, barrios r, et al. association of highly active antiretroviral therapy coverage, population viral load, and yearly new hiv diagnoses in british columbia, canada: a population-based study. lancet 2010;376(9740):532-539. [http://dx.doi.org/10.1371/journal.pmed.1001245] 6. montaner js, lima vd, barrios r, et al. association of highly active antiretroviral therapy coverage, population viral load, and yearly new hiv diagnoses in british columbia, canada: a population-based study. lancet 2010;376(9740):532-539. [http://dx.doi.org/10.1371/journal.pmed.1001245] 7. eaton jw, johnson lf, salomon, ja, et al. hiv treatment as prevention: systematic comparison of mathematical models of the potential impact of antiretroviral therapy on hiv incidence in south africa. plos med 2012;9(7):e1001245. [http://dx.doi.org/10.1371/journal.pmed.1001245] 7. eaton jw, johnson lf, salomon, ja, et al. hiv treatment as prevention: systematic comparison of mathematical models of the potential impact of antiretroviral therapy on hiv incidence in south africa. plos med 2012;9(7):e1001245. [http://dx.doi.org/10.1371/journal.pmed.1001245] 8. world health organization. guidance on couples hiv testing and counselling – including antiretroviral therapy for treatment and prevention in serodiscordant couples: recommendations for a public health approach. geneva: who, 2012. http://www.who.int/hiv/pub/guidelines/9789241501972/en/index.html (accessed 12 january 2013). 8. world health organization. guidance on couples hiv testing and counselling – including antiretroviral therapy for treatment and prevention in serodiscordant couples: recommendations for a public health approach. geneva: who, 2012. http://www.who.int/hiv/pub/guidelines/9789241501972/en/index.html (accessed 12 january 2013). 9. british hiv association. bhiva guidelines for the treatment of hiv-1 positive adults with antiretroviral therapy 2012. hiv med 2012;13(suppl 2):1-85. [http://dx.doi.org/10.1111/j.1468-1293.2012.01029_1.x] 9. british hiv association. bhiva guidelines for the treatment of hiv-1 positive adults with antiretroviral therapy 2012. hiv med 2012;13(suppl 2):1-85. [http://dx.doi.org/10.1111/j.1468-1293.2012.01029_1.x] 10. severe p, juste maj, ambroise a, et al. early versus standard antiretroviral therapy for hiv-infected adults in haiti. n engl j med 2010;363(3):257-265. [http://dx.doi.org/10.1056/nejmoa0910370] 10. severe p, juste maj, ambroise a, et al. early versus standard antiretroviral therapy for hiv-infected adults in haiti. n engl j med 2010;363(3):257-265. [http://dx.doi.org/10.1056/nejmoa0910370] 11. smart study group. cd4+ count-guided interruption of antiretroviral treatment. n engl j med 2006;355(22):2283-2296. [http://dx.doi.org/10.1056/nejmoa062360] 11. smart study group. cd4+ count-guided interruption of antiretroviral treatment. n engl j med 2006;355(22):2283-2296. [http://dx.doi.org/10.1056/nejmoa062360] 12. nattrass n. affidavit in prevention of mother-to-child transmission court case. http://www.tac.org.za/documents/mtctcourtcase/ccmnnatt.txt (accessed 12 january 2013). 12. nattrass n. affidavit in prevention of mother-to-child transmission court case. http://www.tac.org.za/documents/mtctcourtcase/ccmnnatt.txt (accessed 12 january 2013). abstract introduction methods results discussion acknowledgements references about the author(s) leigh f. johnson centre for infectious disease epidemiology and research, university of cape town, south africa rob e. dorrington centre for actuarial research, university of cape town, south africa haroon moolla centre for infectious disease epidemiology and research, university of cape town, south africa citation johnson lf, dorrington re, moolla h. progress towards the 2020 targets for hiv diagnosis and antiretroviral treatment in south africa. s afr j hiv med. 2017;18(1), a694. https://doi.org/10.4102/sajhivmed.v18i1.694 original research progress towards the 2020 targets for hiv diagnosis and antiretroviral treatment in south africa leigh f. johnson, rob e. dorrington, haroon moolla received: 21 sept. 2016; accepted: 04 apr. 2017; published: 27 july 2017 copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the unaids targets for 2020 are to achieve a 90% rate of diagnosis in hiv-positive individuals, to provide antiretroviral treatment (art) to 90% of hiv-diagnosed individuals and to achieve virological suppression in 90% of art patients. objectives: to assess south africa’s progress towards the 2020 targets and variations in performance by province. methods: a mathematical model was fitted to hiv data for each of south africa’s provinces, and for the country as a whole. numbers of hiv tests performed in each province were estimated from routine data over the 2002–2015 period, and numbers of patients receiving art in each province were estimated by fitting models to reported public and private art enrolment statistics. results: by the middle of 2015, 85.5% (95% ci: 84.5% – 86.5%) of hiv-positive south african adults had been diagnosed, with little variation between provinces. however, only 56.9% (95% ci: 55.3% – 58.7%) of hiv-diagnosed adults were on art, with this proportion varying between 50.8% in north west and 72.7% in northern cape. in addition, 78.4% of adults on art were virally suppressed, with rates ranging from 69.7% in limpopo to 85.9% in western cape. overall, 3.39 million (95% ci: 3.26–3.52 million) south africans were on art by mid-2015, equivalent to 48.6% (95% ci: 46.0% – 51.2%) of the hiv-positive population. art coverage varied between 43.0% in gauteng and 63.0% in northern cape. conclusion: although south africa is well on its way to reaching the 90% hiv diagnosis target, most provinces face challenges in reaching the remaining two 90% targets. introduction expanded access to hiv testing and antiretroviral treatment (art) is critical both to reducing levels of aids mortality and to reducing hiv incidence, at a population level. this is therefore the focus of the unaids 2020 targets, which aim to achieve a 90% rate of diagnosis in people living with hiv, a 90% rate of art coverage in hiv-diagnosed individuals and a 90% rate of virological suppression in patients on art.1 however, few african countries have been able to report progress towards these ‘90–90–90’ targets.2,3 most household surveys conducted in african countries do not include questions about whether hiv-positive individuals know they are hiv-positive, which prevents estimation of the fraction of hiv-positive individuals who have been diagnosed. in addition, most african countries have only recently introduced virological monitoring of art patients, and there is thus limited ability to report on progress towards the last 90% target. this means that the few african studies published to date have relied on special surveys for tracking progress towards the 90–90–90 targets,4,5 and almost none have made use of routine monitoring systems.6 in south africa, it has been shown that by triangulating hiv testing data from a number of sources, it is possible to arrive at estimates of the fraction of hiv-positive adults who have been diagnosed positive.7 the south african art programme has also recommended virological monitoring since its inception,8 and systems for reporting rates of virological suppression have been established.9,10 south africa is therefore well placed to track its progress towards the 90–90–90 targets. this article aims to estimate progress towards the targets in the period up to 2015, at national and provincial levels. methods progress towards the 90–90–90 targets is estimated using the thembisa model, a combined demographic and hiv model of the south african population. hiv disease progression prior to art initiation is modelled using a staged model of cd4 decline, with rates of transition between cd4 stages set so that the modelled estimates of the fraction of hiv-positive adults in different cd4 stages match those observed in south african surveys, and hiv mortality assumptions by cd4 stage being set so that the model matches observed trends in mortality by age.11 as described previously, the model was fitted to national age-specific hiv prevalence data from antenatal surveys and household surveys to determine key sexual behaviour and hiv transmission parameters.12 separate versions of the model were then created for each of the nine provinces. key parameters that differed between provinces included the demographic assumptions, marriage rates, initial prevalence of male circumcision, fraction of the population in the ‘high-risk’ and ‘low-risk’ groups, sexual mixing between highand low-risk groups, initial hiv prevalence and uptake of hiv services (hiv testing, prevention of mother-to-child transmission, art, medical male circumcision and condoms). to allow for the uncertainty regarding a number of the behavioural parameters, a bayesian approach was adopted in fitting the model to province-specific hiv prevalence data from antenatal and household surveys.13 the model estimates of hiv prevalence were in reasonable agreement with the provincial hiv prevalence data.13 the uncertainty regarding the behavioural parameters and the level of hiv prevalence in each province is reflected in the confidence intervals around the model estimates of diagnosis levels and art coverage. modelling hiv testing the modelling of hiv testing and diagnosis has been described previously.7 briefly, individuals are assumed to get tested in one of three ways: through antenatal services (women only), through treatment of patients with opportunistic infections (ois) and through other testing services. the model allows for provincial variation in rates of antenatal hiv testing based on data from the district health barometer reports14,15,16 and other surveys.17,18,19 proportions of oi patients tested for hiv are assumed to be the same as assumed in the national model, for all provinces, because of lack of province-specific data. province-specific rates of testing for other reasons are set in such a way that the model estimates of the total number of hiv tests are consistent with estimates of the annual total numbers of hiv tests performed in each province (online appendix figure 4). these province-specific estimates of total hiv tests were derived by disaggregating previously estimated total numbers of hiv tests for the country as a whole.7 the totals were calculated for the public health sector, medical schemes, the life insurance industry and other private providers of hiv testing (e.g. workplace hiv testing programmes). most of the public health sector statistics include provincial disaggregation (from 2004 to 2015), and these were used to calculate the numbers of individuals tested for hiv in the public sector in each province. information is also available on the provincial profile of hiv testing by insurers20 and other private providers.21 in the case of medical schemes, data on the provincial profile of individuals tested were not directly available, but rates of hiv testing by province in the discovery medical scheme22 were assumed to apply to other medical schemes in distributing the total hiv tests in medical schemes between provinces. for all three private sector data sources, the fraction of hiv tests in each province that was estimated was assumed to apply in all years, because of the lack of information on temporal changes in provincial distributions. assumptions about the effect of age, sex and hiv testing history on rates of hiv testing were held constant at the levels estimated previously when the model was fitted to national hiv testing statistics.7 modelling antiretroviral treatment uptake the thembisa model requires as inputs estimates of the total numbers of individuals starting art in each year, split into three categories (children aged < 15 years, adult males and adult females). these estimates are derived from public sector statistics combined with biennial surveys of numbers of individuals treated in the private and ngo sectors.23 public sector statistics included in the modelling are those from the comprehensive care, management and treatment (ccmt) reporting system,24 in the period prior to 2012, and the district health information system (dhis),9,25 in the period from 2012 to 2015. because of frequent ‘self-transfer’,26 many patients who move between art services are incorrectly recorded as new art patients, and reporting of ‘new’ art enrolment is therefore not considered reliable. instead, annual numbers of new art patients are modelled using bayesian b-splines,27,28 with the b-splines being fitted to produce estimates of current art enrolment consistent with reported public and private statistics for each province (online appendix figures 1–3). the model fitting procedure takes into account the change over time in the reporting of art enrolment (from reporting cumulative enrolment in the period up to 2009 to reporting total current enrolment in subsequent periods, with allowance for provincial differences in the timing of the change in reporting). the model fitting procedure also takes into account possible errors in the reporting (e.g. late reporting and double-counting), with the spline functions ‘smoothing out’ fluctuations because of reporting errors, and with the extent of the fluctuations in the reported totals determining the 95% confidence interval widths. a more detailed statistical description of the b-spline fitting procedure is provided in online appendix 1. national art enrolment was calculated by summing the province-specific totals. modelling viral suppression viral suppression is defined in the model as a viral load of less than 400 rna copies/ml. the model input is the annual rate of viral suppression in patients starting art with a cd4 count of < 200 cells/µl, and this rate is adjusted to allow for higher rates of viral suppression in patients starting art at higher cd4 counts.29 the input parameters have been estimated from provincial dhis statistics in 2013/2014, for patients who had been on art for 48 months (viral load data were available for 55% of these patients).9 these rates were 73.4% in eastern cape, 80.1% in free state, 72.5% in gauteng, 84.2% in kwazulu-natal, 67.5% in limpopo, 68.2% in mpumalanga, 84.9% in north west, 75.8% in northern cape and 84.8% in western cape. because of lack of historical data on viral suppression, the same input parameter was assumed to apply in all years. the thembisa model is programmed in c++, and all results presented are based on the c++ version of the model. an excel version of the model, as well as outputs from the excel model, is available for download from the thembisa website (www.thembisa.org). results by the middle of 2015, high levels of hiv diagnosis were achieved in south africa, with an estimated 85.5% (95% ci: 84.5% – 86.5%) of hiv-positive adults diagnosed. rates of hiv diagnosis were similar across provinces, ranging from 82.0% in gauteng to 88.3% in kwazulu-natal (figure 1a). figure 1: provincial progress towards the 90–90–90 targets in 2015: (a) proportion of hiv-positive adults diagnosed; (b) proportion of diagnosed adults on art; (c) proportion of art patients virally suppressed; (d) proportion of hiv-positive adults on art and virally suppressed. table 1 shows that 3.39 million (95% ci: 3.26–3.52 million) south africans were on art by mid-2015, a more than 30-fold increase on the total in 2005 (103 300, 95% ci: 100 900–105 600). approximately 287 000 art patients in 2015 (8.5%) were receiving treatment from the private sector or ngos. over the period from mid-2010 to mid-2013, the annual number of new art patients was relatively stable at around 560 000 per annum, but in the more recent years enrolment declined, reaching 413 000 (95% ci: 342 000–486 000) over the period from mid-2014 to mid-2015 (table 2). the decline in annual new enrolment was particularly pronounced in children: from 39 500 (95% ci: 36 000–43 100) in 2010–2011 to 13 700 (95% ci: 9600–18 900) in 2014–2015. table 1: numbers of patients currently on antiretroviral treatment in south africa. table 2: numbers of patients starting antiretroviral treatment in south africa. expressed as a fraction of all hiv-positive individuals, art coverage in south africa in 2015 was 48.6% (95% ci: 46.0% – 51.2%), more than double the art coverage in 2010 (table 3). art coverage was substantially higher in women (52.0%, 95% ci: 49.3% – 54.7%) than in men (43.2%, 95% ci: 40.2% – 46.2%), with coverage in children being between the two (47.4%, 95% ci: 44.0% – 50.8%). coverage differed substantially by province, ranging from 43.0% (95% ci: 40.9% – 45.2%) in gauteng to 62.0% (95% ci: 58.4% – 64.9%) in northern cape. similar differences were observed when coverage was expressed as a fraction of all hiv-diagnosed adults: 56.9% (95% ci: 55.3% – 58.7%) of all hiv-diagnosed adults were on art, with this proportion varying between 50.8% (95% ci: 47.5% – 54.6%) in north west and 72.7% (95% ci: 68.8% – 75.8%) in northern cape (figure 1b). table 3: antiretroviral treatment coverage (as a fraction of all hiv-positive individuals). the fraction of art patients who were virologically suppressed was 78.4% nationally (figure 1c). rates of virological suppression differed substantially between provinces, ranging from 69.7% in limpopo and 70.3% in mpumalanga to 85.8% in north west and 85.9% in western cape. overall, the fraction of hiv-positive adults who were on art and virologically suppressed in 2015 was 38.2% (95% ci: 36.7% – 39.7%); the proportion varied from 31.8% (95% ci: 29.2%–34.4%) in gauteng to 48.3% (95% ci: 45.4% – 50.7%) in northern cape (figure 1d). expressed as a proportion of new hiv infections, new art enrolment rose to 1.00 (95% ci: 0.94–1.06) in the 2009–2010 period, then continued to increase in the subsequent years as art eligibility criteria were revised and as hiv incidence declined (figure 2a). however, the enrolment ratio dropped from 1.66 (95% ci: 1.48–1.84) in 2012–2013 to 1.37 (95% ci: 1.10–1.67) in 2014–2015. although the drop was not significant in adults, the enrolment ratio declined significantly in children, from 1.26 (95% ci: 1.14–1.39) in 2010–2011 to 0.65 (95% ci: 0.45–0.90) in 2014–2015 (figure 2b). figure 2: art enrolment ratio (new art initiation divided by new hiv infections): (a) national average; (b) comparison of adults and children. discussion this study shows that south africa has made good progress towards the first unaids 90% target, with progress being relatively uniform across provinces. progress towards the 90% diagnosis target is similar to that made in botswana4 and the chiradzulu district in malawi5 (table 4). however, progress towards the second and third unaids 90% targets has been less impressive, with much variation between provinces. despite its success in getting hiv-positive individuals diagnosed, south africa has not achieved the high levels of art coverage and viral suppression seen in botswana, rwanda and malawi (table 4). table 4: comparison with 90–90–90 estimates from other studies. these results are similar to the results of other south african surveys. the model estimate of the art coverage in 2012 (33.7%, 95% ci: 32.3% – 35.2%) is consistent with the results of a national survey in the same year (31.2%, 95% ci: 28.1% – 34.5%).30 the model estimates that 26.0% of all hiv-positive adults were on art and virally suppressed in 2012, which is consistent with an estimate of 24% based on estimates from the national laboratory system,10 as well as a smaller survey in gauteng (table 4). estimates of art coverage in other local household surveys are also consistent with model estimates (table 4), although a survey conducted in mbongolwane and eshowe districts found higher art coverage and viral suppression than expected, probably because special hiv interventions were introduced in these districts prior to the survey.31 provincial differences in the scale-up of hiv testing and art access may be partly explained by differences in budget allocations. in a recent analysis of hiv expenditure by province, it was found that the hiv expenditure per hiv-positive individual was highest in northern cape and free state, and lowest in gauteng and mpumalanga.32 this could explain why progress towards the 90–90–90 targets is greatest in northern cape, whereas progress appears relatively poor in gauteng and mpumalanga (figure 1). it is important that the underfunding of the hiv response in the latter group of provinces is corrected. the slowdown in adult art enrolment in recent years might be considered surprising, given the broadening of art eligibility criteria in august 201133 and january 2015.34 poor linkage to care following diagnosis is likely to be a key explanation; in a recent randomised trial in rural kwazulu-natal, less than half of hiv-positive adults not in care sought hiv care within six months.35 even when linked to hiv care, adults with higher cd4 counts have significantly lower rates of art initiation,36,37,38,39,40,41 and thus the broadening of art eligibility criteria to include patients in higher cd4 categories may have less impact on enrolment than might be expected if patients at higher cd4 counts had the same rates of art initiation as patients at lower cd4 counts. simplified models for art initiation may be required to increase the fraction of hiv-diagnosed adults on art.42,43 in addition, further research is required to better understand the barriers to art initiation in hiv-diagnosed individuals, particularly those at higher cd4 counts. efforts to improve the transition from diagnosis to art initiation should also focus particularly on poorly performing provinces such as north west and gauteng (figure 1b). it is concerning that annual new art enrolment in children has declined so substantially in the last five years. although this is partly because of the success of prevention of mother-to-child transmission programmes, new enrolment has declined even when expressed as a fraction of annual new infections (figure 2b). this might be because of inadequate hiv testing: although great emphasis has been placed on hiv testing in early infancy,44 there has been little focus on hiv testing in children after infancy and in children who are not known to have been exposed to hiv. it is likely that an increasingly high fraction of mother-to-child transmission is postnatal transmission and transmission from mothers who have not been diagnosed positive, and thus an increasingly high fraction of transmission is likely to be missed by the current screening strategy. in addition, national hiv testing statistics and targets until recently excluded testing under the age of 15,45,46 and the absence of any monitoring of hiv testing in the 1–14 year age group means that it has not been possible to produce estimates of the fraction of hiv-positive children who have been diagnosed. a limitation of this study is therefore that it does not assess progress towards the 90–90–90 targets in children – a limitation common to most studies (table 4). it is important that children are not neglected in the scale-up of hiv testing and art,50 and there is an urgent need for better monitoring of hiv testing and diagnosis in children. viral suppression has been identified as the most important determinant of future hiv incidence trends in south africa,12 and it is therefore concerning that rates of viral suppression are as low as 70% in limpopo and mpumalanga. efforts to improve viral suppression could include adherence support interventions,51 community-supported models of care to improve retention,52 better supply chain management to avoid drug stock-outs and potentially new drugs, such as dolutegravir.53 efforts are also required to monitor viral suppression more thoroughly, as the data on which these model estimates are based represent only 55% of adults starting art in 2009–2010 who were followed up in 2013–2014 (the fraction of patients who had viral load results varied between 42% in limpopo and 65% in eastern cape). although viral suppression statistics are also available at other art durations, these are generally similar to the rates at 48 months, and are based on less complete information.9 a limitation of this analysis is that it does not quantify the uncertainty because of the incomplete viral load data, but it is anticipated that it will be possible to produce confidence intervals for the modelled rate of viral suppression in future, as more data become available. to be consistent with the published statistics, we have used a viral load threshold of 400 copies/ml in defining suppression, although guidelines issued by the who54 and global aids response progress reporting55 recommend using a threshold of 1000 copies/ml. the thembisa model estimates that using a threshold of 1000 copies/ml would increase the rate of viral suppression in 2015 from 78.4% to 81.7%. another limitation is that the confidence intervals around the provincial art coverage estimates are too wide to draw firm conclusions about the relative performance of the different provinces. the wide confidence intervals are mainly because of erratic and infrequent reporting of art totals in recent years (see online appendix 1). further work is required to correct anomalies in the dhis data and to integrate more frequent dhis estimates into the thembisa model fitting procedure, which should lead to narrower confidence intervals. an additional limitation is that the art enrolment ratio that we have proposed56 may become meaningless in future if the annual number of new infections (the denominator in the calculation) declines towards zero. a strength of this analysis is that it employs a fully integrated hiv transmission and survival model, unlike previous analyses of art coverage in south africa, which have relied on independent models to estimate hiv incidence and hiv survival.57,58 this study estimates slightly lower levels of art uptake than estimated previously (e.g. 1.72 million on art in 2011 compared to 1.79 million [95% ci: 1.65–1.93 million]57) because the earlier study assumed an immediate transition from reporting cumulative totals to reporting current totals in 2009, when in fact the transition occurred more gradually in some provinces. achieving the 90–90–90 targets will require that at least 73% of hiv-positive individuals are on art and virally suppressed by 2020. with the proportion treated and suppressed at 38% in 2015, south africa still has a long way to go towards meeting the targets. however, the successes seen in botswana, rwanda and malawi offer hope that the targets can be achieved, and south africa needs to learn from these success stories if it is to maximise the impact of its art programme. acknowledgements this research was funded by the south african national aids council. we are grateful to mary-ann davies for providing helpful comments on an earlier version of this article. funding information: south african national aids council. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions l.j. developed the mathematical model, set the epidemiological input parameters for each province and drafted the first version of this article. r.d. set the demographic parameters for each province. h.m. ran the model simulations and assisted in data collection. all authors assisted in the drafting of this manuscript. references unaids. ambitious treatment targets: writing the final chapter of the aids epidemic [homepage on the internet]. geneva; 2014 [cited 2014 aug 19]. available from: http://www.unaids.org/en/media/unaids/contentassets/documents/unaidspublication/2014/jc2670_unaids_treatment_targets_en.pdf kelly sl, wilson dp. hiv cascade monitoring and simple modeling reveal potential for reductions in hiv incidence. j acquir immune defic syndr. 2015;69(3):257–263. https://doi.org/10.1097/qai.0000000000000655 levi j, raymond a, pozniak a, vernazza p, kohler p, hill a. can the unaids 90-90-90 target be achieved? analysis of 12 national level hiv treatment cascades [abstract moad0102]. eighth international aids society conference on hiv pathogenesis, treatment and prevention; 2015 jul 19–22; vancouver, canada. gaolathe t, wirth ke, holme mp, et al. botswana’s progress toward achieving the 2020 unaids 90-90-90 antiretroviral 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https://doi.org/10.1016/s1473-3099(11)70181-5 bemelmans m, baert s, goemaere e, et al. community-supported models of care for people on hiv treatment in sub-saharan africa. trop med int health. 2014;19(8):968–977. https://doi.org/10.1111/tmi.12332 walmsley sl, antela a, clumeck n, et al. dolutegravir plus abacavir-lamivudine for the treatment of hiv-1 infection. n engl j med. 2013;369(19):1807–1818. https://doi.org/10.1056/nejmoa1215541 world health organization. consolidated strategic information guidelines for hiv in the health sector [homepage on the internet]. 2015 [cited 2016 aug 18]. available from: http://apps.who.int/iris/bitstream/10665/164716/1/9789241508759_eng.pdf unaids. global aids response progress reporting 2016: construction of core indicators for monitoring the 2011 united nations political declaration on hiv and aids [homepage on the internet]. geneva; 2016 [cited 2016 aug 18]. available from: https://aidsreportingtool.unaids.org/static/docs/garpr_guidelines_2016_en.pdf johnson lf, boulle a. how should access to antiretroviral treatment be measured? bull world health organ. 2011;89:157–160. https://doi.org/10.2471/blt.10.080911 johnson lf. access to antiretroviral treatment in south africa, 2004–2011. south afr j hiv med. 2012;13(1):22–27. https://doi.org/10.4102/sajhivmed.v13i1.156 adam ma, johnson lf. estimation of adult antiretroviral treatment coverage in south africa. s afr med j. 2009;99(9):661–667. abstract key principles goals of antiretroviral therapy standard of care antiretroviral drugs: classes and mechanisms of action antiretroviral drugs currently available in southern africa indications for initiating antiretroviral therapy investigations prior to starting antiretroviral therapy initial antiretroviral therapy regimens for the previously untreated patient laboratory monitoring for antiretroviral therapy efficacy and safety defining antiretroviral therapy failure indications for changing antiretroviral therapy second-line regimens third-line antiretroviral therapy regimens patients who return after defaulting therapy drug interactions antiretroviral therapy in special populations antiretroviral therapy toxicity monitoring and management immune reconstitution inflammatory syndrome support and counselling prophylaxis in patients receiving antiretroviral therapy acknowledgements references about the author(s) graeme meintjes southern african hiv clinicians society, johannesburg, south africa michelle a. moorhouse southern african hiv clinicians society, johannesburg, south africa sergio carmona southern african hiv clinicians society, johannesburg, south africa natasha davies southern african hiv clinicians society, johannesburg, south africa sipho dlamini southern african hiv clinicians society, johannesburg, south africa cloete van vuuren southern african hiv clinicians society, johannesburg, south africa thandekile manzini southern african hiv clinicians society, johannesburg, south africa moeketsi mathe southern african hiv clinicians society, johannesburg, south africa yunus moosa southern african hiv clinicians society, johannesburg, south africa jennifer nash southern african hiv clinicians society, johannesburg, south africa jeremy nel southern african hiv clinicians society, johannesburg, south africa yoliswa pakade southern african hiv clinicians society, johannesburg, south africa joana woods southern african hiv clinicians society, johannesburg, south africa gert van zyl southern african hiv clinicians society, johannesburg, south africa francesca conradie southern african hiv clinicians society, johannesburg, south africa francois venter southern african hiv clinicians society, johannesburg, south africa citation meintjes g, moorhouse ma, carmona s, et al. adult antiretroviral therapy guidelines 2017. s afr j hiv med. 2017;18(1), a776. https://doi.org/10.4102/sajhivmed.v18i1.776 disclaimer: specific recommendations provided here are intended only as a guide to clinical management, based on expert consensus and best current evidence. treatment decisions for patients should be made by their responsible clinicians, with due consideration for individual circumstances. the most current version of this document should always be consulted. guidelines adult antiretroviral therapy guidelines 2017 graeme meintjes, michelle a. moorhouse, sergio carmona, natasha davies, sipho dlamini, cloete van vuuren, thandekile manzini, moeketsi mathe, yunus moosa, jennifer nash, jeremy nel, yoliswa pakade, joana woods, gert van zyl, francesca conradie, francois venter copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract these guidelines are intended as an update to those published in the southern african journal of hiv medicine in 2014 and the update on when to initiate antiretroviral therapy in 2015. since the release of the previous guidelines, the scale-up of antiretroviral therapy (art) in southern africa has continued. new antiretroviral drugs have become available with improved efficacy, safety and robustness. the guidelines are intended for countries in the southern african region, which vary between lower and middle income. key principles while many antiretroviral therapy (art) guidelines are available internationally, the current guidelines have been written to address issues relevant to southern africa. the following general principles underpinned the writing process: countries in the region vary between middle income and low-income countries; therefore, affordability was taken into account. only treatment and diagnostic options available in southern africa were included. we recognised the need to bridge the gap in treatment recommendations between public and private sector programmes, considering that many patients transition between the two sectors for treatment. while it is acknowledged that certain recommendations are aspirational for poorly resourced settings, the unavailability of diagnostic or monitoring tests should not pose a barrier to providing art to those in need. goals of antiretroviral therapy the goals of art are to: provide maximal and durable suppression of viral load (vl) restore and preserve immune function reduce hiv-related infectious and non-infectious morbidity prolong life expectancy and improve quality of life prevent onward transmission of hiv minimise adverse effects of the treatment. these goals are achieved by suppressing viral replication completely for as long as possible, by using well tolerated and sustainable treatment taken with good adherence. with prolonged viral suppression, the cd4+ lymphocyte count usually increases, which is accompanied by a restoration of pathogen-specific immune function. for most patients, this results in a dramatic reduction in the risk of hiv-associated morbidity and mortality. for patients who start art with preserved cd4+ counts, art is able to prevent the decline in cd4+ count which has been observed in untreated patients and prevent clinical complications of hiv infection. it is still unclear whether immune function ever returns to full normality. long-term cohorts show that patients who adhere well to art have a near-normal life expectancy.1 standard of care maximally suppressive art regimens should be used in the treatment of hiv-infected individuals to obtain the best results and to prevent resistance. antiretroviral drugs: classes and mechanisms of action there are currently five classes of art drugs available in southern africa (table 1). the most commonly used drugs inhibit one of three key hiv enzymes required by the virus for intracellular replication: reverse transcriptase: essential for completion of the early stages of hiv replication. integrase: required for the integration of proviral dna into the host chromosomal dna. protease: required for the assembly and maturation of infectious viral progeny. table 1: classes of antiretroviral agents. antiretroviral drugs currently available in southern africa the antiretroviral (arv) drugs currently available in southern africa are summarised in table 2. a number of two-drug and three-drug fixed dose combinations (fdcs) are available in the region. these fdcs reduce the burden of multiple pills and may improve treatment adherence. table 2: dosage and common adverse drug reactions of antiretroviral drugs available in southern africa. indications for initiating antiretroviral therapy we now advise starting art in all individuals diagnosed with hiv. in general, delays to starting art should be minimised. in particular, patients with profound immunosuppression (cd4+ count < 200 cells/μl) are at significant risk of opportunistic infections (ois) and associated mortality, and should be assessed rapidly and initiated on art within one week once adherence counselling has been initiated. an exception to this is patients presenting with cryptococcal meningitis (cm) or tuberculous meningitis (tbm) – see below. rationale for these guidelines in 2015, two seminal randomised controlled trials (rcts) that addressed the optimal timing of art in hiv-infected patients with high cd4+ counts were published: strategic timing of antiretroviral therapy (start) and temprano anrs 12136 (early antiretroviral treatment and early isoniazid prophylaxis against tuberculosis in hiv-infected adults).3,4 the findings of these two trials were consistent: there was significant individual clinical benefit from starting art immediately in patients with cd4+ counts higher than 500 cells/μl rather than deferring until a certain lower cd4+ threshold or clinical indication was met. benefits of antiretroviral therapy in reducing transmission there is evidence that starting art when hiv-positive people have higher cd4+ counts reduces hiv transmission within couples where one partner is hiv-negative (hptn 052). this trial showed that treating the hiv-positive partner in a serodiscordant relationship with art was associated with a 93% reduction in transmission risk to the uninfected partner.5,6 wider art coverage appears to reduce the risk of hiv transmission at a community level. therefore, early art initiation has the public health benefits of potentially reducing both hiv incidence and morbidity. this led the southern african hiv clinicians society to update its guidelines on starting art in 2015 to advise starting art in all patients diagnosed with hiv infection regardless of cd4+ count or symptoms. commencing antiretroviral therapy in patients with tuberculosis decisions regarding the timing of art in patients with tb should be made on the basis of the cd4+ count. cd4+ count ≤ 50 cells/µl antiretroviral therapy should be regarded as urgent, with the aim to start therapy two weeks following the commencement of tb treatment. a meta-analysis of rcts has demonstrated that this approach reduces mortality.7 it is advised to commence art after it is clear that the patient’s tb symptoms are improving and that tb therapy is tolerated. the exception to this is in the case of cm (see the section ‘starting antiretroviral therapy in patients with other opportunistic infections and acute illnesses’) or tbm. cd4+ count > 50 cells/µl antiretroviral therapy can be delayed until eight weeks after starting tb treatment, but no later. however, if the patient has other who stage 4 conditions, art should also be initiated two weeks after tb treatment is started. the exception to this is in the case of cm (see the section ‘starting antiretroviral therapy in patients with other opportunistic infections and acute illnesses’) or tbm. the longer delay before commencing art in this group is anticipated to reduce the risk of shared toxicity (as the patient will then be receiving fewer tb drugs) and to reduce the risk of immune reconstitution inflammatory syndrome (iris) (see the section ‘immune reconstitution inflammatory syndrome’). the aforementioned meta-analysis of rcts did not show a higher risk of aids progression or mortality in this group when art initiation was delayed until approximately eight weeks after starting tb treatment.7 tuberculous meningitis in patients with tbm, starting art immediately or at two months following diagnosis was shown to have similar high mortality, with more complications in the immediate group.8 we recommend starting art 4–8 weeks after tbm diagnosis. there are important drug interactions and shared side effects when art is co-administered with tb therapy (see the section ‘tuberculosis’). when art is commenced, patients should be warned that tb symptoms or signs may temporarily worsen and new features may occur in the first three months as a result of tb-iris (see the section ‘immune reconstitution inflammatory syndrome’). starting antiretroviral therapy in patients with other opportunistic infections and acute illnesses with most ois and acute illnesses (e.g. pneumocystis or bacterial pneumonia), the clinician should aim to start art within two weeks of commencing treatment for that infection.9 in patients with severe kaposi’s sarcoma and lymphoma, art counselling should be expedited and art should be initiated as soon as possible. in a patient diagnosed with an oi in hospital, it is important to ensure referral and linkage to outpatient services for art initiation without delay. for patients with cm, the optimal time to start art is 4–6 weeks from the time of starting cm treatment. the coat (cryptococcal optimal art timing) trial demonstrated a significantly higher mortality in patients who started art in hospital 1–2 weeks after cm diagnosis than in those starting 5–6 weeks after diagnosis.2 in hiv-infected patients admitted to the intensive care unit (icu), if the patient is receiving art, then this should be continued (through nasogastric tube [ngt], if necessary) and only interrupted if the gastrointestinal tract is not functional (e.g. ileus). if the patient is not yet receiving art, then it should not be commenced if the reason for admission is an acute critical illness or injury. there are several potential problems associated with commencing art in this setting: lack of adequate counselling, gastrointestinal dysfunction, malabsorption and possible development of resistance. there are no intravenous options for an art regimen. in patients admitted to the icu for prolonged periods, art initiation in the unit should be considered after multi-organ failure has resolved. certain art preparations should not be administered via ngt. in general, paediatric syrups can be administered via ngt. a pharmacist should always be consulted regarding which art drugs can be administered via ngt and how to do this. patient readiness for antiretroviral therapy preparing patients for lifelong art with good adherence is a critical component of achieving long-term efficacy and preventing resistance: to accommodate counselling, traditionally two or three visits were required, staggered closely together, either before or during early art (see the section ‘commencing antiretroviral therapy at the first antiretroviral therapy clinic visit’, where same-day initiation may be an option). prolonged delays in commencing art should be avoided. art should be delayed only if concerns about adherence are severe enough to outweigh the risk of hiv disease progression. the patient should be provided with details on the following: the benefits of art that art is a lifelong therapy the importance of good adherence list of art side effects relevant to the drugs they will use, including what to do and who to contact if serious side effects occur. counselling should also ensure that the patient has a good understanding of hiv (the virus, the potential clinical complications and transmission) and should cover safer-sex practices and address issues related to reproductive health (i.e. family planning, contraception, condom use and pregnancy). clinicians should check family planning choices at follow-up visits too and adequate access to safe and effective contraception should be provided. active depression, other mental health issues or substance abuse should actively be detected and treated. a personal treatment plan should be formulated for each patient, specifying drug storage, strategies for missed doses and how to integrate taking medication into their daily routine. the patient must be made aware of scheduling in terms of clinical follow-up. disclosure of hiv status (to a partner or other household members) should strongly be encouraged. this has been shown to be an important determinant of treatment adherence and assists in the provision of patient-directed support. disclosure also identifies exposed contacts for screening and support. this issue needs to be handled sensitively in situations where disclosure may have harmful consequences, particularly for women. the patient should be encouraged to join a support group or identify a treatment ‘buddy’. however, neither disclosure nor support group participation is a prerequisite for good adherence in all patients, and should not be a reason for deferring art. clinicians should ensure that they have the contact details of each patient and their treatment buddy. commencing antiretroviral therapy at the first antiretroviral clinic visit several studies have demonstrated that it is possible to initiate art safely on the same day as hiv diagnosis or receipt of cd4+ count result.10,11,12 these studies have demonstrated less overall loss to follow-up when art is initiated immediately in selected patients. now that treatment is recommended irrespective of cd4+ count this same-day strategy should be considered as a means to improve retention in care. more experience is needed to make firm recommendations, and this approach is being tested in different programmes. until then, the following should be considered for patients newly diagnosed or returning for cd4+ or other test results, when deciding about initiating art on the same day: the patient should be motivated to start immediately. same-day initiation is not an adherence support ‘short cut’; ongoing support can occur in the days and weeks immediately after initiation. patients starting tenofovir (tdf) (which are the majority) should be contactable in the event of a creatinine clearance (crcl) < 50 ml/min, and told to return to the clinic immediately. a serum or plasma crag should be conducted in those with cd4+ < 100 cells/μl; again, the patient should be contactable in the event of a positive crag and must be advised to return to the clinic immediately. symptom screening for tb and cm before initiation of treatment is important. patients with tb symptoms (e.g. cough, night sweats, fever and recent weight loss) should first be investigated for tb before art initiation. likewise in a patient with a headache, meningitis should be considered and investigated if appropriate (i.e. lumbar puncture [lp]) before starting art. table 3 lists the medical reasons for deferring art initiation. table 3: medical reasons to defer initiation of antiretroviral therapy. antiretroviral therapy in primary hiv infection for patients who are diagnosed with hiv during acute seroconversion, we advise that those patients be counselled and initiated on art as soon as possible. this should preferably be expedited art initiation as there is evidence that this may limit the size of the hiv reservoir.13 previously, we suggested that these patients could have art interrupted. rather, once art is started in this situation, this should be lifelong art, and this should be discussed with the patient. additional counselling once the patient is established on art may be required for patients who start art in this acute situation because there is limited time for extensive counselling pre-art, and there is often considerable psychological distress around this time. diagnosing seroconversion is facilitated by having a recent negative hiv test that then becomes positive on a subsequent test. otherwise, the following are suggestive: the compatible clinical syndrome, an indeterminate enzyme-linked immunosorbent assay (elisa) test result that then becomes positive on a subsequent test, and a very high vl. antiretroviral therapy initiation in ‘elite controllers’ a minority of patients (< 1%) have very effective immune control of hiv infection and are able to control hiv viraemia at undetectable levels in the absence of art – termed ‘elite controllers’. an argument could be made that such individuals do not require art if their cd4+ count is > 500 cells/μl. the start and temprano trials did not specifically address the question of whether early art was beneficial in such patients, and it is highly unlikely that any sufficiently powered rct could ever be conducted focused on these individuals. in the absence of such data, we rely on indirect evidence. firstly, elite controllers still have evidence of chronic immune activation and inflammation that may drive non-infectious morbidities.14 secondly, elite controllers have been shown to have a higher rate of hospitalisation than patients who are virologically controlled by art.15 for these reasons, we do advise starting art in elite controllers too, with the same caveats regarding the patient being prepared. one important consideration in such patients is that careful attention should be paid to confirming the diagnosis of hiv before starting art. they are typically patients who have a positive hiv elisa test, undetectable hiv vl, cd4+ count in the normal range and are clinically well. the possibility of a false-positive hiv elisa test should be excluded either by performing a qualitative hiv dna polymerase chain reaction assay or a western blot assay. if the patient at some point previously had a detectable hiv vl, this would also serve as confirmation. such patients should be discussed with a laboratory virologist to assist with confirmation of hiv infection status. investigations prior to starting antiretroviral therapy if hiv diagnosis has been made by using two rapid tests performed outside of a laboratory setting, then we advise confirming the positive serostatus by using a laboratory test prior to commencing lifelong art. a detectable vl result would be sufficient (note that it may be undetectable in < 1% of patients not receiving art, i.e. ‘elite controllers’), but if unaffordable or unavailable, then an elisa should be performed. the following investigations are recommended prior to initiating art: alanine transaminase (alt) full blood count (fbc) if azt being considered: avoid azt if haemoglobin (hb) is < 8 g/dl serum creatinine and calculation of crcl: avoid tdf if crcl is < 50 ml/min; other nucleoside reverse transcriptase inhibitors (nrtis), except abacavir (abc), require dose adjustment if crcl is < 50 ml/min (either by using the estimated glomerular filtration rate [egfr] provided by the laboratory or calculating by using the modified cockgraft–gault equation, table 11) hepatitis b surface antigen (hbsag – see the section ‘hepatitis b co-infection’) cd4+ count baseline vl syphilis serology serum cryptococcal antigen test in patients starting art at a cd4+ count < 100 cells/μl (to screen for early cryptococcal disease and to initiate pre-emptive treatment if positive) we advise a symptom screen for tb (cough, weight loss, fever, night sweats). if any are present then send sputum for xpert and tb culture, and if cd4+ < 100 cells/μl then send urine for lipoarabinomannan (lam) assay. initial antiretroviral therapy regimens for the previously untreated patient the preferred first-line regimens are (see table 4): tdf + emtricitabine (ftc) (or 3tc) + efavirenz (efv) or tdf + emtricitabine (ftc) (or 3tc) + dolutegravir (dtg) or tdf + emtricitabine (ftc) (or 3tc) + rilpivirine (rpv) provided vl < 100 000 copies/ml. table 4: preferred first-line regimen options. rilpivirine cannot be used with rifampicin, and dolutegravir requires dose adjustment with rifampicin. nucleoside reverse transcriptase inhibitor component of first-line regimen the recommended nrti drugs are tdf with ftc (emtricitabine) or 3tc. ftc and 3tc are both co-formulated in two-drug fdcs with tdf, and in three-drug fdcs with tdf and efv. we favour regimens that include fdcs and allow once-daily dosing. tdf is the favoured nrti to use with 3tc or ftc, as it aligns with public sector programmes, is widely available as an fdc and is very well tolerated. however, patients with a crcl < 50 ml/min should not start tdf and should rather start abc. a meta-analysis showed that virological suppression is equivalent with abcand tdf-containing first-line regimens regardless of baseline vl.16 abc has been associated with an increased risk of myocardial infarction in some but not other cohort studies,17,18 but the association was not confirmed in a meta-analysis of rcts.19 nevertheless, caution is recommended when considering abc for patients at significant risk of, or with established ischaemic heart disease. abc, which does not require dose adjustment in renal failure, is specifically recommended for use during chronic renal failure, as tdf is nephrotoxic and azt could aggravate the anaemia of renal failure. we now recommend that azt or short-term stavudine (d4t) is only used in special circumstances in first-line therapy. if both tdf and abc are unavailable or contraindicated, then azt should be used, provided that the hb level is > 8 g/dl. as it is considerably more toxic than other nrtis, d4t is no longer recommended. nonetheless, there is still a role for d4t in selected patients, when it is used in the short-term in patients with contraindications to other nrtis. a common example is a patient with renal dysfunction and anaemia at baseline, who could be initiated on d4t for three months if abc is unavailable, and then switched to azt or tdf depending on resolution of the anaemia or renal dysfunction. patients usually tolerate short-term d4t (≤ 3 months) well. severe d4t side effects, such as hyperlactataemia, lipoatrophy and other mitochondrial toxicities, typically occur after six months, although peripheral neuropathy can develop earlier. if there is a need for concomitant nephrotoxic medications, e.g. aminoglycosides to treat multidrug-resistant (mdr)-tb, then abc or azt is preferable to tdf during the period of exposure to the other nephrotoxic medication. the third drug in the regimen: efavirenz, dolutegravir or rilpivirine the who guidelines currently recommend efavirenz-based first-line art, with efv 600 mg as the preferred option and efv 400 mg as an alternative option. efv 600 mg is available in public sector programmes in most countries in southern africa. efavirenz is thus very widely used in first-line regimens in the region. although efv 400 mg demonstrated non-inferior efficacy with moderately improved tolerability in encore1,20 this reduced dose has not been studied in pregnant women or patients who are receiving rifampicin-based tb treatment. efv 400 mg is currently also not available in fdcs, and for these reasons, we do not recommend the routine use of efv 400 mg in first-line art. dolutegravir is now available as an alternative for first-line art in the private sector, is included in the first-line regimen in the public sector in botswana and is likely to be accessible in public sectors in other countries in the region when affordable generic options become available at scale. dolutegravir has been shown to be superior to efavirenz-based art in the single trial and also has a higher barrier to resistance. the single trial compared dtg/abc/3tc versus efv/tdf/ftc in art-naïve adults in north america, europe and australia (n = 833). at week 48, the proportion of participants with a vl < 50 copies/ml was 88% in the dtg arm versus 81% in the efv arm (p = 0.003). this difference was largely driven by the superior tolerability of the dtg arm: 2% vs 10% on the efv arm had an adverse event leading to discontinuation of study drug.21 in the 144-week results of this trial the dtg arm remained superior: 71% vs 63% maintained vl suppression < 50 copies/ml (p = 0.01). a striking result was that no participants in the dtg/abc/3tc arm developed treatment-emergent integrase or nrti resistance mutations over three years, demonstrating the high barrier to resistance of a dtg-containing first-line regimen.22 dolutegravir may cause a small increase in serum creatinine because of interference with tubular secretion. this does not represent renal damage and is not an indication for switching off the drug. there are currently limited data on the use of dtg in patients being treated for tb and during pregnancy, but trial data on these groups are expected soon. dolutegravir is preferred to the other integrase inhibitor available in southern africa, raltegravir (ral), the major reason being that it has a higher barrier to resistance. in the spring-2 trial, dtgand ral-containing first-line regimens were compared: dtg was found to be non-inferior.23 at week 48, 88% of patients on dtg achieved virological suppression (vl < 50 copies/ml) vs 85% on ral (difference not significant). adverse events were similar between treatment groups. no patients in the dtg arm were found to have developed resistance, whereas, in patients in the ral arm, one developed integrase resistance and four developed nrti resistance. the high barrier to resistance of dtg-containing art regimens has been replicated in other first-line studies and in a study of art-experienced patients in which dtg was compared to ral.22,24,25 in a meta-analysis that included clinical trials and observational studies, the emergence of integrase resistance was more common with ral than with dtg (3.9% vs 0.1%).26 in addition, the emergence of integrase resistance on ral compromises second-generation instis (which otherwise have a very high barrier to resistance) in a proportion of cases. another option in first-line regimens is rpv, a second-generation nnrti. rpv is inexpensive, but drawbacks are that it cannot be used with rifampicin-based tb treatment (subtherapeutic concentrations because of rifampicin induction of its metabolism), and it should not be started in a patient with a vl > 100 000 copies/ml (it is inferior to efv in such patients).27 it is also not yet available in an fdc in the region. we no longer recommend nvp use for new patients starting art because of the severe toxicity that may be associated with its use. in patients currently tolerating nvp, there is no reason to switch for toxicity, which characteristically occurs in the first three months of taking nvp and not later. however, switch for simplification to a once-daily regimen, providing that there is virological suppression, should be considered. for patients transitioning from the private sector on dtg first-line to the public sector and requiring a switch because dtg is unavailable, we recommend doing a vl and switching to efv. if vl < 50 copies/ml then repeat vl in one year. if vl is not suppressed then switch to efv, counsel regarding adherence and repeat vl in 2–3 months. baseline resistance test we recommend a baseline resistance test to guide first-line regimen choice only in the following situations: pre-exposure prophylaxis (prep) received in the previous 6 months history of sexual exposure to a person with known drug-resistant hiv or known to have failed an art regimen. laboratory monitoring for antiretroviral therapy efficacy and safety viral load timing of viral load monitoring viral load monitoring should be performed: at baseline (before commencing art) at three months after the commencement of art (this early vl is desirable to detect adherence problems early, before resistance develops. a subset of patients who start with a very high vl may not be fully suppressed at three months despite 100% adherence, but such patients would have had a > 2 log10 drop in vl from baseline if adherence is optimal and there is no resistance. therefore, the 3-month result should be interpreted in relation to the baseline vl. all patients who have a detectable vl at three months should receive additional adherence interventions.) at six months and thereafter every six months (in patients who have an undetectable vl for > 12 months, and who demonstrate reliable adherence and follow-up, it may be acceptable to reduce the frequency of vl monitoring to 12-monthly.) if the vl is > 50 copies/ml, then the patient should receive counselling, and interventions should be implemented to improve adherence. a repeat measurement of vl should then be done in 2–3 months. we recommend a baseline vl for the following reasons: the 3-month vl can then be compared with the baseline vl to detect > 2 log10 drop, and if this has not occurred it allows early adherence intervention; it may guide nnrti selection (rpv should not be used if vl > 100 000 copies/ml); and it confirms the diagnosis of hiv (antibody tests very rarely may give a false-positive result). interpreting viral load results a vl > 50 copies/ml while receiving art should be an indication for urgent action to improve adherence. a subsequent art change must be considered if the patient meets the criteria for a switch to a second-line art regimen at the subsequent 2–3-month follow-up vl measurement (see the section ‘indications for changing antiretroviral therapy’). vl monitoring is key to the success of art. decisions to change art made on the basis of virological failure, rather than on clinical or immunological failure alone, have been shown to result in better patient outcomes.28 if the vl is undetectable, then the virus cannot mutate and develop resistance. a sustained vl of < 50 copies/ml is associated with the most durable benefit. isolated, detectable hiv vls that are < 1000 copies/ml, which are followed by an undetectable vl, are termed ‘viral blips’ and alone are not a reason to change art regimen. cd4+ counts cd4+ counts should be performed every six months. in patients being monitored with vl measurements, if the cd4+ count at baseline was > 200 cells/μl or it increases above this threshold on art, routine cd4+ testing can be stopped once the vl is suppressed and provided it remains suppressed, as it adds little to management. data to support this have been summarised.29 however, if virological or clinical failure occurs, then a cd4+ count should be repeated, as cotrimoxazole (ctx) prophylaxis should be commenced if the count falls to < 200 cells/μl while receiving art. laboratory monitoring of antiretroviral therapy safety table 5 lists the blood tests and their frequency that we advise for monitoring of art safety. the section ‘antiretroviral therapy toxicity monitoring and management’ provides more details regarding the toxicities of art and their management. table 5: standard laboratory monitoring of patients once commenced on antiretroviral therapy. defining antiretroviral therapy failure in resource-limited settings where vls are unavailable, the who has devised criteria for defining art failure on the basis of cd4+ count responses or clinical disease progression. studies have shown that switching art regimens using these criteria results in a significant proportion of patients switching very late (with progressive accumulation of resistance mutations) and switching inappropriately (as the cd4+ count response may be poor in some patients, despite optimal virological suppression).30 we therefore advocate using the vl for making decisions regarding art failure and the need to switch. virological criteria for treatment success treatment success is defined by a decline in vl to < 50 copies/ml within six months of commencing art, and sustained thereafter. virological criteria for treatment failure treatment failure is defined by a confirmed vl of > 1000 copies/ml on two measurements taken 2–3 months apart. several factors can influence the measurement of the vl. the decision to alter art should, therefore, be based on the results of repeat testing after 2–3 months, following intensive adherence counselling. inadequate patient adherence to the prescribed regimen remains the most common reason for treatment failure. other important causes include: prior use of single-dose nvp for pmtct; drug interactions that decrease art concentrations; and transmitted drug resistance, which is currently increasing in the region (estimated to be around 5– 15%).31,32 cd4+ response typically, the cd4+ count increases rapidly in the first month of art, by approximately 75–100 cells/μl, with a more gradual rise thereafter (50–100 cells/μl/year).33 most, but not all, patients achieve a cd4+ count > 500 cells/μl after several years of art, provided that the vl remains suppressed.34,35,36 however, cd4+ responses are highly variable and may fail to increase despite virological suppression in about 10–20% of patients.37,38 such patients have a delayed or absent cd4+ response to art despite viral suppression, which is termed an ‘immunological discordant response to art’. certain studies suggest that older patients are at higher risk. there is no evidence that such patients benefit from a change in art regimen; therefore, the same regimen should be continued. ctx prophylaxis should be continued if the cd4+ count remains < 200 cells/μl. there is evidence that the prognosis of such patients is worse than in those who have a cd4+ response, but better than that of patients experiencing both virological and immunological failure.38 if patients with an immunological discordant response to art are clinically unwell, then tb or lymphoma should be considered as the cause of persistent cd4+ lymphopenia. cd4+ counts may remain stable in the presence of incomplete viral suppression in patients receiving art until the vl is high (approximately ≥ 10 000 copies/ml).39 indications for changing antiretroviral therapy individual art drugs may be substituted in the event of toxicity (see the section ‘antiretroviral therapy toxicity monitoring and management’), provided that the vl is suppressed or art is initiated within the preceding six months. changing the first-line art regimen to a second-line regimen is a major step. the drugs used in second-line regimens are often not as well tolerated and are more expensive and generally require twice-daily dosing. for this reason, clinicians tend to switch to second-line art after a prolonged period of virological failure, causing a progressive increase in the accumulation of resistance mutations. if the vl is detectable, it is essential to step up adherence interventions, as discussed above. if the patient is on an nnrti-based first-line regimen, we advise a switch to a second-line regimen without undue delay when two vl measurements have been > 1000 copies/ml, preferably with the measurements taken 2–3 months apart, with at least four weeks of an intensified adherence intervention in between. in patients with low cd4+ counts (< 100 cells/μl), this process should be expedited. some patients have persistently detectable vls at low levels (200–1000 copies/ml). if patients have low-level viraemia (i.e. vl detectable but < 1000 copies/ml) for a prolonged period (> 1 year), or persistently low cd4+ counts (< 100 cells/μl) together with low-level viraemia despite adherence interventions, then they should be switched to second-line art. in patients who fulfil the criteria for virological failure on a dolutegravir-based regimen, there is currently an evidence gap with respect to data that inform the approach to switching to second-line art. because of the high barrier to resistance of dtg, it is likely that many such patients will not have resistance and will merely require improved adherence on the same first-line regimen. for that reason, we only recommend switching from first-line dolutegravir-based art to second-line if a resistance test shows resistance. this advice may change as more data on the risks of resistance to dolutegravir-based art in a programmatic setting become available. a similar approach should be applied for patients on a boosted pi first-line regimen. second-line regimens resistance testing for selecting second-line antiretroviral therapy we do not recommend routinely performing a resistance test at first-line failure of nnrti-based regimens. the earnest (europe-africa research network for evaluation of second-line therapy) and select (second-line art in resource-limited settings) trials showed that without the use of a resistance test to decide which nrtis to use in second-line therapy, virological outcomes were good and equivalent to a boosted pi + ral regimen. in addition, in these trials those patients with more extensive nrti resistance at first-line failure were those more likely to achieve virological suppression on second-line.40,41 a potential benefit of a resistance test is that it may be able to differentiate whether failure is because of complete or near complete non-adherence (when the resistance test shows no resistance mutations) and whether there is already established resistance (usually a consequence of sub-optimal adherence). also, if the resistance test at first-line failure shows that there is no tdf resistance mutation, then tdf could be used to accompany 3tc (or ftc) and a ritonavir (rtv)-boosted pi in second-line. when dtg is used in first-line art, reports to date suggest that it is very unlikely that art resistance will develop. there are inadequate data available for making a recommendation on resistance testing at dtg first-line failure, but similar recommendations as for second-line failure should be used until more data are available: patients with unsuppressed vl on a dtg-based first-line regimen should receive intensive adherence counselling and repeated vl measurements. only if the vl remains detectable on several occasions despite this, should resistance testing be considered. recommended second-line antiretroviral therapy regimen we recommend a regimen of two nrtis and a rtv-boosted (/r) pi. boosting of pis involves the addition of low-dose rtv, which inhibits pi metabolism, thereby boosting pi plasma concentration and prolonging half-life. we recommend against the use of unboosted pis. for patients who failed a first-line nnrti + 2 nrti regimen, we do not recommend the use of dtg with 2 nrtis in second-line as there is currently insufficient evidence to support such a regimen. we await results of the dawning trial which will compare such a dtg-based versus lpv/r-based second-line regimen (https://clinicaltrials.gov/ct2/show/nct02227238). ritonavir-boosted protease inhibitor in the second-line regimen based on clinical trials demonstrating superior tolerability, we suggest that the preferred pi in second-line therapy should be ritonavir-boosted atazanavir (atv) 300 mg/rtv 100 mg daily.42,43 the benefits of atv/r over lopinavir (lpv)/r include that it is better tolerated in terms of gastrointestinal side effects, has a more favourable lipid profile and is taken once-daily. drawbacks of atv/r are: it cannot be used with rifampicin (rif)-based tb treatment; and there are important drug interactions with drugs that reduce stomach acidity such as proton pump inhibitors. an alternative rtv-boosted pi rather than atv/r should be used in the following situations: patients who do not tolerate atv/r (e.g. cosmetically unacceptable jaundice): use lpv/r patients receiving rif-based tb treatment: double-dose lpv/r should be used while receiving the tb treatment. other rtv-boosted pi options in second-line therapy are lpv/r and darunavir (drv)/r. lpv is co-formulated with rtv in a heat-stable tablet (aluvia). lpv/r is also an option with rifampicin when double-dosed. darunavir/ritonavir (drv/r) is taken twice-daily, currently, and is more costly. when the appropriate dose tablet becomes available, the 800/100 mg daily dose will be a feasible option in second-line art, with fewer side effects than the twice-daily dosing. drv/r cannot be co-prescribed with rifampicin. saquinavir (sqv) is not recommended. ritonavir capsules are no longer available and have been replaced with rtv heat-stable tablets. selecting second-line dual nucleoside reverse transcriptase inhibitors because boosted pis are robust drugs (i.e. resistance develops slowly) in pi-naive patients, it is very likely that virological suppression will be achieved with good adherence, even if the two nrtis used in second-line therapy are partially compromised by nrti resistance mutations (tables 6 and 7). this is supported by findings of the earnest and select trials, which showed good virological suppression rates of second-line lpv/r and nrti regimens, even in patients with significant nrti resistance.40,41 certain nrti combinations are contraindicated for toxicity reasons (e.g. d4t + didanosine [ddi], or tdf + ddi). a tdf + abc combination is not recommended for second-line art, as these agents share resistance mutations. nrti combinations advised for second-line regimens include either azt + 3tc, or tdf + 3tc (ftc can be substituted for 3tc), depending on the likely mutational profile selected during the patient’s first-line nrti combination. table 6: mutations selected by first-line nucleoside reverse transcriptase inhibitor combinations. table 7: choice of second-line nucleoside reverse transcriptase inhibitors in relation to first-line nucleoside transcriptase inhibitors used. even if 3tc (or ftc) was used in a failed first-line regimen and may, therefore, have selected for the m184v mutation, which confers resistance to the agent, 3tc (or ftc) should be reused in second-line therapy because of the capacity of the m184v mutation to partially restore susceptibility to azt, d4t and tdf in the presence of thymidine analogue mutations (tams), and to partially restore susceptibility to tdf in the presence of the k65r mutation. the m184v mutation also reduces the replicative capacity of the virus. in patients with baseline anaemia or who develop anaemia on second-line art, azt should be switched to abc or tdf. in a minority of patients a second-line regimen of dtg plus a boosted pi may be considered (e.g. broad nrti intolerance). selecting second-line antiretroviral therapy in patients who received a first-line pi-regimen if a patient was receiving a first-line combination of two nrtis and a pi (boosted or unboosted), it is best to discuss the choice of second-line regimen with an experienced hiv clinician, and to perform a genotype resistance test. second-line nnrti + nrti regimens are often not effective in such patients because of nrti resistance mutations. the regimen choice is, therefore, best guided by resistance testing and dtg may have a role in such regimens. third-line antiretroviral therapy regimens third-line art is used when a patient has experienced virological failure on drugs from the nrti, nnrti and pi classes, and has documented pi resistance. before considering third-line therapy, adherence interventions should be intensified, and then adherence checked (e.g. check that pharmacy refills are all collected over a 6-month period). if there is still no viral suppression, then a resistance test should be performed to confirm the presence of resistance to the pi being used in second-line therapy. we advise doing this only after patients have been on a pi-based second-line regimen for a period of longer than one year, as the development of resistance earlier than this is very uncommon, unless there has been a medication error (e.g. giving standard dose lpv/r with rifampicin). the resistance test is expensive and the patient must be receiving the failing art at the time, as ‘wild-type’ hiv is more fit and outgrows the resistant mutant population which therefore cannot be detected within some weeks after cessation of art. however, third-line regimens are also expensive and are not justified if the patient does not have resistance necessitating such a switch. currently, data show that most patients failing second-line regimens in the sa public sector have no pi mutations. in these patients, improved adherence is required rather than third-line regimens. see figure 1.44 figure 1: indications for doing a resistance test on second-line antiretroviral therapy. the decisions regarding treatment choices in third-line therapy are complex and need to be guided by resistance patterns found on resistance testing. it is essential that resistance tests are interpreted by an expert in conjunction with a full art history. a number of drugs are available for use in third-line art: instis (dtg and ral), the newer pi drv and newer nnrtis (etr and rpv)). these provide an opportunity for effective viral suppression with third-line therapy in the majority of patients, provided that adherence is optimal.45,46 regimen choice should be individualised and an expert treater should always be consulted. a few guidelines regarding third-line art regimens are: there is a need for specific adherence counselling in patients preparing to start third-line art, with a frank discussion that this regimen is likely to be their last option for the foreseeable future. first-generation nnrtis (nvp and efv) have no place in third-line therapy as they do not impair viral fitness. a boosted pi with the broadest resistance profile should be selected (this is currently drv). drv must be used twice-daily in this context (600 mg 12-hourly with 100 mg rtv 12-hourly). lpv may be used if the drug is still active based on a resistance test (e.g. if the patient failed second-line atv therapy). the addition of 3tc (or ftc) is recommended as the m184v mutation that it selects for impairs viral replication. other nrtis (the most active based on resistance testing) should also be added. consideration of the addition of other drugs (e.g. dtg and etr or rpv) will depend on the results of genotype resistance testing and cost issues. dtg is preferred because it belongs to an entirely new class with no risk of cross-resistance from prior art exposure in first-line and second-line therapy, and has a higher barrier to resistance than ral.25 because most patients are not receiving an nnrti at the time of failing second-line therapy when a genotype resistance test is typically performed, prior nnrti mutations related to first-line nnrti failure may be archived at this time. therefore, it is difficult to be certain from this genotype whether etr is compromised; however, data from sa suggest that the majority of patients who have failed nvp or efv are still susceptible to etr.47 we advise against double rtv-boosted pis.48 if viral suppression is not achieved, then there is still benefit in continuing failing art, because of the residual partial activity and ‘crippling’ effect of such art. ‘crippling’ describes the fact that mutant viruses often have less replicative capacity. provided that the vl can be maintained at < 10 000 copies/ml, the cd4+ count will usually be maintained or even increase.39 mvc (a ccr5 blocker) is a consideration in third-line therapy; however, it is currently extremely costly and can only be used after a tropism test shows that the patient’s circulating virus has sole tropism for the ccr5 coreceptor. we advise only considering this when there is intermediate-level or high-level resistance to all pis, all nnrtis and all nrtis. an algorithm approach to third-line art can be used. once a genotype resistance test has been performed, stanford scores are used to determine which combination of arvs is most appropriate for third-line regimen for the specific patient. patients are eligible for third-line art if they have demonstrated genotypic resistance to the pi which they are taking, as evidenced by a stanford score ≥ 15, and should receive a drv/r-based third-line regimen. in addition to drv/r, all patients on a third-line regimen should receive two nrtis, 3tc/ftc with either tdf or azt, determined by which of tdf or azt has the lower stanford score. if there is resistance to drv/r (score ≥ 15), or if there is intermediate-level or high-level resistance (score > 29) to the selected nrti (tdf or azt), add dtg to the regimen. if there is both drv/r resistance and intermediate or high (score > 29) level resistance to the selected nrti, then add etr or rpv (whichever score is lower) in addition to dtg, unless both etr and rpv score > 29. see figure 2.49 figure 2: algorithm for choosing drugs in third-line antiretroviral therapy regimen based on stanford database score. the sailing trial compared ral versus dtg in art-experienced patients with at least two class resistance who were integrase inhibitor-naïve. at week 48, dtg was superior to ral (71% vs 64% achieved vl suppression < 50 copies/ml; p = 0.03). significantly fewer patients developed treatment-emergent integrase inhibitor resistance in the dtg arm. we therefore no longer recommend the use of ral in third-line unless dtg is not tolerated or there is a contraindication to using dtg. we also recommend that patients currently using ral in third-line be switched to dtg, because of its higher barrier to resistance.25 if such patients have a suppressed vl then they can be switched to standard dose dtg (50 mg daily), but if they are not virologically suppressed we suggest a resistance test with integrase sequencing before switching. if there are insti mutations present that are associated with reduced susceptibility to dtg then the dtg dose should be 50 mg bd. stopping antiretroviral therapy structured treatment interruptions are not advised as they have been shown to increase mortality (smart study).50 sometimes, patients need to stop therapy for reasons beyond the control of the patient and clinician. if life-threatening toxicity occurs (e.g. hepatitis with liver failure), all drugs should be stopped at once, but in most cases of toxicity, a continuation of art should be attempted while switching the culprit drug(s) to an alternative. if stock-outs occur, it may also be necessary to stop art. with pi and insti regimens, it is possible to stop all drugs simultaneously. with an nnrti regimen, it is necessary to cover the tail with 5–7 days of two nrtis (not needed if tdf/ftc are the nrtis because of the long half-life of tdf and ftc). we strongly advise against 3tc monotherapy ‘holding regimens’ in patients who have virological failure. such regimens can be associated with a rapid fall in cd4+ count. the objective when prescribing art should always be to provide a regimen that is most likely to achieve virological suppression. patients who return after defaulting therapy we recommend restarting the same regimen if patients return to care after defaulting therapy. a vl should preferably be performed before restarting. we then recommend that the vl is measured three months after restarting art; switching to a second-line regimen should be considered if the vl is not < 1000 copies/ml at this point. in patients with multiple episodes of interruption, particularly beyond the first year of art, many clinicians would consider switching to a second-line regimen, making the assumption that the multiple interruptions resulted in first-line resistance. reasons for defaulting should be addressed and adherence support increased. hospitalisation with an aids-defining condition and a cd4+ count < 50 cells/μl represents another scenario in which a patient may be restarted immediately on second-line art when returning to care after defaulting; the reason being that the patient is considered to be at high risk of mortality if restarted on a first-line therapy to which their virus may be resistant, and that they require a guaranteed effective art regimen immediately. this decision should usually be taken by the clinicians at a hospital level. performing a resistance test after the patient has been off art for longer than four weeks is of limited value, as many resistance mutations are overtaken by wild-type virus when art is stopped. drug interactions there are many important drug interactions between arv drugs and other medications, as well as between certain arv drugs themselves. these interactions occur because of the metabolism of arv drugs by cytochrome p450 in the liver and intestine, and the induction or inhibition by arv drugs of this and other enzyme systems and drug transporters. some of these drug interactions are discussed in these guidelines (e.g. the interaction between rifampicin and nnrtis, pis and instis). the list of all potential drug interactions is, however, very long and beyond the scope of this document. knowledge of drug interactions is constantly evolving. clinicians are advised to consult package inserts of arv drugs and concomitant medications to assess for drug interactions, in addition to the following websites, which provide up-to-date information on drug interactions and the actions required to account for them: university of liverpool drug interactions charts: http://www.hiv-druginteractions.org university of cape town medicines information centre antiretroviral (arv) interactions table: http://www.mic.uct.ac.za/?page_id=47 we advise that clinicians assess for potential drug interactions whenever patients start or switch to new arv drugs or start new concomitant medications. this includes contraception. in addition, herbal medications may also have interactions with arv drugs. antiretroviral therapy in special populations tuberculosis the arv regimen should be modified if necessary for compatibility with rifampicin. rifampicin is a critical component of the tb regimen that substantially reduces the risk of relapse after completing tb treatment. efv is the preferred nnrti for use with rifampicin. nvp is an alternative in patients with contraindications for efv (e.g. psychosis), but it carries a higher risk of hepatitis and virological failure when used with rifampicin. rpv and etr cannot be used with rifampicin. dtg can also be used in patients on rifampicin, but a dose adjustment is required (table 8). table 8: antiretroviral therapy interactions with rifampicin and recommendations for co-administration. the plasma concentrations of all boosted pis are reduced to subtherapeutic ranges with rifampicin. dose adjustment of lpv/r can overcome this induction (table 8), but there is a risk of hepatotoxicity: patients require counselling and alt should be monitored frequently. an alternative approach is to replace rifampicin with rifabutin. however, rifabutin is not currently widely available at public sector tb clinics. also, rifabutin is not co-formulated with other tb drugs, and the evidence base for rifabutin in the treatment of tb is much less substantial than that for rifampicin.52 there is also uncertainty regarding the optimal dose of rifabutin with boosted pis; these guidelines recommend 150 mg daily (table 9) for efficacy reasons but careful monitoring for toxicity is required (alt, neutrophil count and visual symptoms at least monthly).53 rifabutin may be considered in patients who are not tolerating co-treatment with lpv/r and rifampicin-based antitubercular therapy (patients unable to tolerate the increased lpv/r dose because of hepatotoxicity or gastrointestinal side effects) or in art-experienced patients on an art regimen that is not compatible with rifampicin (e.g. third-line art with drv/r). if rifabutin is unavailable and adjusted doses of lpv/r are poorly tolerated in patients receiving second-line art, then dtg (50 mg 12-hourly) may be substituted for the pi. however, there is not good evidence regarding the robustness of dtg in second-line with compromised nrtis, as there is for boosted pis. nevertheless, short-term use over six months is probably preferable to treating tb without rifampicin, which has a high risk of failure or relapse. art and tb medication share many side effects (table 10). table 9: dosing of antiretroviral therapy drugs and rifabutin when prescribed concomitantly. table 10: shared side effects of antiretroviral therapy and tuberculosis treatment. pregnancy the aim of art in pregnancy is both to prevent clinical complications of hiv in the mother and to decrease transmission to the child during pregnancy, delivery and breastfeeding. antiretroviral drugs in pregnancy we recommend standard first-line, second-line and third-line regimens be used in pregnancy. based on the accumulated evidence, we endorse the who guidance that efv can be used in pregnancy and in women who intend to fall pregnant.54 their guidance was based on a meta-analysis which found that the incidence of neural tube defects and all congenital abnormalities among women exposed to efv in the first trimester was similar to that of the general population.55 the fda category d classification of efv should be discussed with women, explaining that this was based on animal studies; human cohort studies have not demonstrated an increased risk of congenital abnormalities, but that there is a background low risk of congenital abnormalities in all pregnancies, unrelated to drugs. studies have shown that total lpv concentrations are significantly reduced in pregnancy, but unbound lpv concentrations are not affected.56 therefore, dose adjustment of lpv/r is not recommended in pregnancy. however, once-daily dosing of lpv/r should not be used in pregnancy. similarly, concentrations of boosted atv are reduced in pregnancy, but trough concentrations are adequate and dose adjustments are not recommended in pregnancy.57 an exception is in patients who are also receiving tdf, as tdf may reduce atv concentrations: atv/r dose should be increased to 400 mg/100 mg daily in such patients during the second and third trimester of pregnancy. unboosted atv is not recommended in pregnancy. recommendations for antiretroviral-naïve pregnant patients it is beyond the scope of these adult art guidelines to provide comprehensive guidance for the management of pregnant women. key recommendations are included but providers are encouraged to refer to the complete pmtct guidelines should a woman living with hiv be confirmed pregnant in order to optimise management. all hiv-negative or status unknown pregnant women should be offered an hiv test at confirmation of pregnancy. if the test result is negative, regular retesting should be performed every three months throughout pregnancy and breastfeeding to detect any new infection. seroconversion during pregnancy or breastfeeding is associated with a substantial risk of mtct because of the very high maternal vl during acute infection. the following is recommended: all hiv-infected pregnant women should be initiated on lifelong triple-drug art. the aim should be to initiate all pregnant women on treatment on the same day as pregnancy confirmation. before initiating art, a full history and examination, including tb screen, should be conducted. reasons to defer same-day initiation would include suspected or confirmed active tb, suspected or confirmed cm, suspected renal dysfunction or active psychosis. women who cannot be initiated on tdf/ftc/efv on the same day because of a drug-related contraindication (e.g. active psychosis; renal impairment) should be provided with an alternate three-drug regimen. where an alternative three-drug regimen cannot be provided on the same day, provide azt monotherapy and ensure that a three-drug regimen is started as soon as possible. women who cannot be initiated on tdf/ftc/efv on the same day because of a clinical contraindication (e.g. headache, where cryptococcal or tb meningitis are suspected) should be discussed with an expert to weigh up the benefit of starting art for pmtct versus the risk of iris for the mother. if a woman presents during labour and is newly diagnosed hiv-infected or was known hiv-infected but not yet on art, start triple-drug art immediately, no matter what stage of labour. viral load should be checked at three months on therapy and then 6-monthly thereafter throughout pregnancy and breastfeeding. refer to pmtct guidelines for recommended regimens for the baby. a clear history of previous pmtct exposure should be taken from all women who report they are art-naïve. they may have been exposed to single-dose nvp, azt or even triple therapy during previous pregnancies which was discontinued after delivery or cessation of breastfeeding according to previous guidelines. in this situation, the woman may not perceive herself to have been on art but her risk of first-line failure may be increased. if she received triple therapy in a previous pregnancy or during breastfeeding, which was then discontinued because of a high cd4+ count, then she should be considered as re-initiating art. this would necessitate that a baseline vl be taken on the day of pregnancy confirmation and repeated again after two months to ensure viral suppression is occurring on the first-line regimen. if viral suppression is not confirmed after two months, then treatment failure and non-adherence need to be considered and managed as per existing guidelines. recommendations for antiretroviral-experienced pregnant patients in women currently taking art, check vl on the day of pregnancy confirmation, regardless of when it was last performed. if the vl is suppressed then continue the current regimen and reinforce adherence messaging. if the vl is not suppressed, then provide intensive adherence counselling and repeat the vl in one month. if there has not been > 1 log drop in vl then switch patients on first-line to second-line art. in patients on second-line regimen, if the vl is not suppressed, request an hiv drug resistance test to assess the need for a third-line regimen and continue with adherence support. in women who have previously stopped art and returned to care when pregnant but not on art, check the vl and restart the regimen they were taking previously with intensive adherence counselling. then repeat the vl test in two months. if there has not been > 1 log drop in vl, then switch patients on first-line to second-line art. in patients on second-line regimen, request a resistance test to assess their need for third-line art. if a woman presents in pregnancy and the history suggests previous evidence of virological failure on first-line art or high likelihood thereof before they stopped art, the provider should start the woman on second-line art from the outset to maximise the chances of rapid viral suppression and avoiding the possibility of mtct with resistant virus. refer to pmtct guidelines for recommended prophylaxis regimens for the baby. breastfeeding late mtct during breastfeeding remains a considerable problem. all hiv-positive mothers who are breastfeeding should be maintained on triple art with vl monitoring conducted every six months (if previously virally suppressed) throughout the breastfeeding period. women should be provided with breastfeeding support, where available, including counselling about the importance of exclusive breastfeeding during the first six months of life, followed by the addition of complementary foods up to 24 months of life, in combination with ongoing high levels of adherence to art and regular vl monitoring. hiv-negative women should also seek to breastfeed for 24 months and should access retesting regularly, at least 3-monthly, throughout this time. if an hiv-negative woman tests hiv-positive, or an hiv-positive woman is found to have a high vl (> 1000 copies/ml) during breastfeeding, then a discussion should be undertaken to assess the risks and benefits of continuing breastfeeding in relation to the nutritional benefits versus the increased risk of motherto-child-transmission of hiv. in this situation, the baby should be tested immediately for hiv, as an hiv-positive infant requires urgent treatment and should continue breastfeeding. if breastfeeding is to be discontinued, ensure that a safe, adequate alternative is available. postnatal period retention in care and art adherence often decline in the postnatal period. women who do not attend for their art supply should be tracked, traced and re-engaged in care. if a woman is found to have low adherence or a treatment interruption is suspected or confirmed then a vl should be repeated, regardless of when last done, and the woman should be provided with support. she should be assessed for post-natal depression, gender-based violence, substance abuse and other reasons for low adherence. partner engagement it is important to engage partners of pregnant women: pregnancy indicates condomless sex. encourage partner testing and engagement in care where necessary. male involvement in antenatal and postnatal care has been shown to improve art adherence and maternal and infant outcomes. advise that the couple return to consistent condom use throughout the pregnancy to avoid increased risk of hiv transmission (if serodiscordant couple), reinfection (if concordant) and acquisition of new sexually transmitted infections (stis) during the pregnancy, which can be associated with increased risk of miscarriage, preterm labour and intrauterine growth retardation. renal failure antiretroviral drug dosages renal function is estimated either by the modified cockgraft–gault equation (table 11) or the modification of diet in renal disease (mdrd) method, which most laboratories report as egfr. the results of these formulae differ slightly, but either can be used for clinical management. for peritoneal dialysis, the dose given with a crcl < 10 ml/min should be given daily. for haemodialysis, the dose given with a crcl < 10 ml/min should be given daily. table 11: antiretroviral drug dosage adjustments in the event of renal failure. antiretroviral drug choice and dosing in patients on chronic haemodialysis patients with hiv may develop end-stage renal failure requiring chronic haemodialysis owing to hiv-associated nephropathy or an hiv-unrelated cause. in patients on chronic haemodialysis, there are a number of important art issues that arise. the nrti class is eliminated through the kidneys, and thus doses of most nrti drugs need to be adjusted in patients on dialysis (table 11). although tdf can be used in patients on chronic haemodialysis, dosing is once weekly, which can be difficult for patients to remember. azt is generally avoided because of anaemia associated with renal failure. nnrti drugs do not require dose adjustment. we recommend the following first-line options for patients on chronic haemodialysis: abc 600 mg daily 3tc 50 mg first dose and thereafter 25 mg daily (on the days when haemodialysis is performed, the dose should be given after the haemodialysis session) efv 600 mg nocte. atazanavir concentrations are reduced in patients on haemodialysis to a greater degree than lpv, and thus atv is preferably not used in treatment-experienced patients. lpv/r should be used with twice-daily dosing in patients on haemodialysis. in patients on haemodialysis, we recommend an lpv/r-based second-line regimen with two nrtis in the regimen (selected after consideration of issues related to nrtis discussed above). drv/r and instis may be used at standard dosages. it is suggested that patients on chronic haemodialysis (who generally receive ongoing medical care in a dialysis unit) are reviewed by a clinician experienced in art management at least 6-monthly, to monitor treatment efficacy and side effects and to adjust the regimen when needed. daily dosages or the evening doses of a twice-daily art regimen on the day of haemodialysis should be given after the haemodialysis session to prevent the drug from being dialysed out. antiretroviral therapy in patients with acute kidney injury in patients with acute kidney injury (aki), dosages of nrti drugs should be adjusted based on estimated crcl calculation (table 11).58,59,60 tdf should be interrupted even if it is not thought to be the cause of the aki. once there is clear evidence that renal function is improving (creatinine on downward trend), nrti dosages should be readjusted to standard dosages to avoid underdosing. in patients with aki who are not yet receiving art, initiation is preferably deferred until aki has resolved. see the section ‘nephrotoxicity’ for discussion of art nephrotoxicity. antiretroviral therapy dosages in liver impairment unlike in renal impairment, there is no blood test that can accurately quantify liver impairment. child-pugh class c may require dose adjustment for the relevant art drugs listed in table 12. in general, the combination of tdf with 3tc (or ftc) and dtg or ral (or efv, which can be hepatotoxic) is regarded as the least hepatotoxic. table 12: prescribing antiretrovirals in liver impairment. hepatitis b co-infection hepatitis b is a common co-infection with hiv in southern africa, with significant implications for progression to cirrhosis, as well as for treatment options. clinicians are encouraged to support current efforts in the region to vaccinate all children for hepatitis b, and to extend coverage to eligible adults. access to vaccination, laboratory resources and treatment options are limited to some extent in southern african countries, and the recommendations below should each be considered in the light of the local context. all hiv-infected patients should be screened for active hepatitis b (limiting screening to those with liver function abnormalities will miss many cases, as liver enzymes are often normal in hepatitis b infection). hbsag is an appropriate screening test. hepatitis b vl correlates with disease progression and may be used to monitor antihepatitis b therapy, but it is expensive and availability is limited. hepatitis b/hiv co-infection is associated with: an increased risk of chronic liver disease a higher hepatitis b vl diminished responses to hepatitis b vaccine poorer responses to interferon-alpha treatment an increased incidence of drug-induced hepatotoxicity (particularly with nvp) a flare of hepatitis within three months of commencing art (because of hepatitis b-iris, which is difficult to differentiate from drug hepatotoxicity). drugs directed against hepatitis b that have no or minimal anti-hiv activity (e.g. entecavir and telbivudine) are largely unavailable or extremely expensive in our region. for practical purposes, the only available therapy is to use art drugs that also have antihepatitis b activity (tdf + 3tc/ftc). as with hiv, these drugs suppress hepatitis b, but do not eradicate it. effective treatment prevents or slows progression to cirrhosis. for all hiv-infected hbsag-positive patients the art regimen should include tdf and 3tc (or ftc). using 3tc without including tdf leads to hepatitis b resistance in 80–90% of patients after five years of treatment. if a patient meets the criteria for switching to a second-line art regimen (to treat hiv), this combination (tdf + 3tc/ftc) should be continued to suppress hepatitis b infection, as interruption of tdf or ftc/3tc has been associated with flares of life-threatening hepatitis. the second-line art regimen should be shaped around these two drugs. nvp should be avoided in patients with hepatitis b co-infection. in patients with hepatitis b and renal dysfunction, the use of tdf may be considered with dosing frequency adjustment based on crcl (see package insert) and more frequent creatinine monitoring. if renal dysfunction is severe or renal function deteriorates with tdf, then 3tc monotherapy (with or without pegylated interferon-alpha, which is very costly) or other drugs with antihepatitis b activity should be considered. malaria there are several drug interactions between antimalarials and art drugs: artemether-lumefantrine (coartem) can safely be administered with nvp. efv significantly lowers the concentrations of artemether (and its active metabolite) and lumefantrine, which is likely to increase the risk of failure of antimalarial therapy. there is no clear guideline on how to overcome this interaction, but some experts recommend repeating the 3-day course of artemether-lumefantrine (i.e. treat for six days). boosted pis dramatically increase the plasma concentrations of lumefantrine, but a dose reduction is not recommended, as the toxicity threshold of lumefantrine seems to be high. close monitoring for toxicity is recommended when coadministering artemether-lumefantrine with art. quinine concentrations are significantly decreased by lpv/r, probably owing to induction of metabolism by rtv. it is likely that quinine concentrations will also be reduced by efv and nvp; therefore, quinine should be avoided in patients receiving pis or nnrtis. patients with severe malaria should receive artesunate, if this is available, and those with milder malaria should be treated with artemether-lumefantrine. among drugs used for chemoprophylaxis, there are no clinically significant pharmacokinetic interactions between arvs and mefloquine or doxycycline. however, mefloquine and efv both cause frequent neuropsychiatric side effects; therefore, doxycycline is the preferred chemoprophylactic agent for patients receiving efv. there are several interactions with atovaquone-proguanil (malanil). atovaquone concentrations are reduced by pis and efv. it is also likely that nvp decreases atovaquone concentrations. proguanil concentrations are also reduced by pis and efv. use of atovaquone-proguanil is, therefore, best avoided in patients receiving pis or nnrtis. no significant drug interactions are predicted between instis and antimalarial drugs. antiretroviral therapy toxicity monitoring and management currently recommended art is generally well tolerated. many adverse drug reactions are mild and occur only in the first few weeks of therapy. if toxicity does not resolve or is severe, then the offending drug should be substituted as indicated below. it is important to ensure that the vl is suppressed before substituting a single drug for toxicity; otherwise, resistance may develop to the new drug, consequently compromising future regimens. however, single drug substitutions can be done in the first few months of art without measuring the vl, as the vl may take up to six months to suppress. it is rarely necessary to stop the entire art regimen because of toxicity. it is advised to switch only the culprit drug(s) and continue the rest of the art regimen. in certain life-threatening situations (e.g. hepatitis with liver failure), it may be necessary to cease use of all arvs. haematological toxicity cytopenias occur commonly in hiv infection without exposure to art. patients receiving azt, d4t or ctx may experience abnormalities in their fbcs. significant bone marrow toxicity from ctx generally only occurs with high doses used for treating ois. patients receiving prophylactic ctx rarely develop isolated neutropenia. hb and neutrophil monitoring is necessary with azt; this should be performed monthly for three months, then after six months of therapy and thereafter if clinically indicated (it is unusual to see haematological toxicity developing after six months). the main problem arising from azt use is anaemia and neutropenia; platelet counts generally rise with use of the drug. management guidelines are provided in table 13. macrocytosis is usual with d4t and azt therapy; there is no need to measure vitamin b12 and folate concentrations unless there are other indications that these may be deficient. table 13: guidelines for managing haematological toxicity (mainly zidovudine-induced). pure red cell aplasia, which presents with severe anaemia and low reticulocyte production index, has rarely been associated with 3tc and ftc. a bone marrow examination should be performed to confirm the condition. parvovirus b19 infection should be excluded (a polymerase chain reaction [pcr] test should be requested on blood sent in an ethylenediaminetetra-acetic acid [edta] tube). hepatotoxicity alanine transaminase should be performed at art initiation and repeat alt testing is indicated in patients who develop symptoms or signs suggestive of hepatitis. all art classes have been associated with hepatotoxicity – most commonly nnrtis. nrtis very rarely present with acute hepatitis. mild alt elevations occur very commonly and usually transiently with many drugs in general. alt elevations > 5× the upper limit of normal (uln) are significant in the absence of symptoms. in the presence of symptoms of hepatitis, alt elevations > 2.5× uln are significant. management guidelines are provided in table 14. table 14: guidelines for managing hepatotoxicity: elevation. nevirapine is the arv drug most frequently associated with drug-induced liver injury (dili) and most cases occur in the first three months of starting the drug. ideally, in patients starting nvp, alt should be monitored at 2, 4, 8 and 12 weeks after initiation. if monitoring is performed, a system should be in place to obtain the result and contact the patient. routine alt monitoring makes little sense in settings where the result will only be available when the patient is seen in 2–4 weeks, or where the patient cannot be contacted. it is essential to educate all patients starting nvp about the symptoms of hepatitis (nausea, vomiting, anorexia, malaise, jaundice and right-upper-quadrant pain) and drug rash, which is frequently associated with hepatitis. hepatitis often follows the rash after about 10 days. if such symptoms develop, alt should be determined urgently. hepatotoxic drugs should be discontinued at high levels of lft abnormality or at lower levels if any symptoms of hepatitis appear and an alternative arv drug substituted. rechallenge may be considered in selected cases; a specialist should be consulted. if hepatitis occurs together with a rash or fever, or with other systemic involvement, then rechallenge with nnrtis, abc or ctx should not be attempted. prolonged use of nrtis, especially d4t and ddi, may cause fatty liver. typically, alt concentration is more significantly elevated than ast, and the concentrations of canalicular enzymes (gamma-glutamyl transferase [ggt] and alkaline phosphatase [alp]) are more elevated than those of the transaminases. non-tender hepatomegaly may be present. ultrasound or computed tomography (ct) imaging may show decreased hepatic density. the condition is not benign and fibrosis has been reported with long-term ddi use. patients should be advised to avoid alcohol and switched to alternative dugs with lower potential for causing fatty liver. in patients with severe hepatitis or jaundice, the international normalised ratio (inr) and serum glucose should be assessed, as well as features of hepatic encephalopathy (i.e. features of hepatic failure). if the concentration of canalicular enzymes is more significantly elevated than that of alt, or if conjugated bilirubin is elevated, an ultrasound of the liver should be conducted to exclude biliary obstruction. isolated unconjugated hyperbilirubinaemia (drug-induced gilbert’s syndrome) is associated with atv. in this case, all other lfts are normal and the patient has no other symptoms of hepatitis. although this is a benign condition (it does not reflect liver injury, but isolated competitive inhibition of the enzyme in the liver which conjugates bilirubin), it is often cosmetically unacceptable to patients requiring a switch from atv to an alternative. while efv has been recognised to be an infrequent cause of dili since it first became available, recently a novel pattern of dili associated with efv has been recognised.61 among these patients, many were found to have a particularly severe pattern of liver injury at liver biopsy (termed ‘submassive necrosis’, and associated with severe jaundice and raised inr) and overall mortality was 11%. while severe efv-related dili is likely to be uncommon, clinicians should be aware of the features observed: the diagnosis of dili was generally made after a longer duration on efv than what is seen with dili related to nvp or tb medication: around 3–6 months on efv. the dili was not associated with features of hypersensitivity (e.g. drug rash) and often the first symptom was jaundice rather than abdominal symptoms. once efv was stopped it typically took several months for liver function tests to normalise. median resolution took more than six months. we do not advise routine liver function test monitoring in patients on efv, as there is no evidence that this would lead to earlier detection of this dili or improve outcomes. however, those managing patients on efv should monitor for symptoms and signs of hepatitis (nausea, vomiting, right-sided abdominal pain or jaundice). if these occur, an alt should be requested and the patient examined for jaundice. efv should be switched to an alternative (e.g. dtg) and the patient managed appropriately for dili if there are hepatitis symptoms with alt > 120, or there is jaundice. many other drugs can cause hepatotoxicity, notably antituberculous agents (including prophylactic isoniazid) and azoles. ctx is an uncommon cause of hepatitis, often as part of a systemic hypersensitivity reaction. recommendations for the management of dili in patients receiving tb treatment have been published by the society in 2013.62 hyperlactataemia and lactic acidosis this side effect has become less common with fewer patients starting art with d4t and ddi. it can also occur occasionally with azt. lactic acidosis is a serious, rare, potentially fatal side effect of nrtis, most commonly associated with d4t, particularly when combined with ddi. symptomatic hyperlactataemia without acidosis is more common, but seldom seen with the safer nrtis that are currently recommended. symptoms are nonspecific and include nausea and vomiting, abdominal pain, dyspnoea, fatigue and weight loss. risk factors for hyperlactataemia include female gender, obesity and use of nrtis for more than six months. a raised lactate of > 5 mmol/l together with metabolic acidosis confirms the diagnosis of lactic acidosis. low serum bicarbonate (< 20 mmol/l) is the most sensitive marker of acidosis. the management of symptomatic hyperlactataemia depends on lactate and bicarbonate concentrations: lactate < 5 mmol/l and bicarbonate > 20 mmol/l: nrtis should be switched to agents less frequently associated with hyperlactataemia: tdf/abc + ftc/3tc. symptoms and serial lactate should be monitored for several months (lactate levels decrease slowly over weeks). lactate > 5 mmol/l and bicarbonate > 15 mmol/l: patient should be admitted and nrtis should be discontinued. if the patient is on an nnrti regimen, then a boosted pi should be added. if the patient has already failed an nnrti and is on a boosted pi, then dtg should be added, if available, or the patient should be continued on the boosted pi only. when lactate has normalised, the patient should be switched to tdf/abc + 3tc/ftc, as above. lactate > 5 mmol/l and bicarbonate < 15 mmol/l: the patient should be admitted, preferably to an icu, and nrtis should be discontinued. if the patient is on an nnrti regimen, a boosted pi should be added. if the patient has already failed an nnrti regimen and is receiving a boosted pi, then dtg should be added, if available, or the patient should be continued on a boosted pi only. bicarbonate replacement is controversial, but most experts would use this strategy to partially correct severe acidosis. broad-spectrum antibiotics are recommended as sepsis can mimic nrti-induced lactic acidosis (this can be discontinued if procalcitonin is normal). on recovery, all nrtis should be avoided in future regimens. dyslipidaemia pis can cause hypertriglyceridaemia and elevated low-density lipoprotein (ldl) cholesterol. boosted atv and once-daily boosted drv (800 mg drv/100 mg rtv once-daily) are associated with less severe dyslipidaemia than other boosted pis; d4t and azt can cause mild hypertriglyceridaemia, and efv can cause elevated total cholesterol and mild hypertriglyceridaemia. we suggest routinely assessing lipids after three months on a pi-regimen. if normal at this stage, reassessment should be performed only in those with cardiovascular (cvs) risk factors. diet and lifestyle modification should always be advised. diet is more effective for controlling hypertriglyceridaemia than hypercholesterolaemia. other cvs risk factors should be addressed. clinicians should consider and investigate secondary causes of hypertriglyceridaemia and hypercholesterolaemia (e.g. diabetes, nephrotic syndrome, alcohol abuse and hypothyroidism). if patients on lpv/r develop significant dyslipidaemia, then they should be switched to atv/r, if possible, rather than adding lipid-lowering therapy. however, lipid-lowering therapy is indicated in patients with persistent elevations despite switching to atv/r. switching the pi to dtg is another option, because dtg has a more favourable lipid profile than pis. however, dtg should only be used in a regimen in which at least one other arv drug is known to be fully active. in patients with hyperlipidaemia on efv, switch efv to rpv. marked hypertriglyceridaemia (> 10 mmol/l) can cause pancreatitis and requires urgent treatment with diet modification (restrict total triglyceride intake to < 30 g/day), fibrates and switching lpv/r to atv/r or dtg (fibrates can be stopped after one month, followed by reassessment within 4–6 weeks). indications for statin therapy in hiv-positive patients should be the same as in hiv-negative patients, using the framingham heart disease risk score. as a general rule, in young patients with isolated elevated cholesterol but no other cvs risk factors, a threshold of total cholesterol > 7.5 mmol/l (or ldl cholesterol > 5.0 mmol/l) should be used for initiating statin therapy, and the patient should be referred to a lipid clinic for investigation if feasible. in patients with cvs risk factors (e.g. smoking, diabetes, hypertension) decisions should be made using the framingham heart disease risk score (https://www.mdcalc.com/framingham-coronary-heart-disease-risk-score). all patients with established atherosclerotic disease (coronary, cerebral or peripheral), all patients with familial hypercholesterolaemia and all patients with type 2 diabetes aged > 40 years should be started on statin treatment. many statins have interactions with pis that can lead to potentially toxic statin concentrations, with the exception of pravastatin and fluvastatin. atorvastatin concentrations are significantly raised by pis, but low doses (maximum 10 mg daily) can be used with monitoring for symptoms of myalgia. lovastatin and simvastatin should not be coadministered with pis, as their concentrations are dramatically increased and severe rhabdomyolysis has been reported. we also advise against the use of rosuvastatin with pis because of a complex drug–drug interaction: pis increase the plasma concentrations of rosuvastatin while reducing their efficacy in the liver. lipodystrophy lipodystrophy can present with fat accumulation (visceral obesity, breast enlargement, ‘buffalo hump’ or lipomata) or subcutaneous fat loss (lipoatrophy, most noticeable in the face, limbs and buttocks), or with both forms of lipodystrophy. the thymidine analogue nrtis (azt and especially d4t) are associated with fat loss. lipoatrophy improves when d4t/azt are substituted with tdf or abc, but resolution is very slow and often incomplete; therefore, it is important to recognise lipoatrophy early or, better still, to use nrtis that are not associated with the condition. previously, pis were thought to be the cause of lipohypertrophy. however, more recent studies have shown that all art classes are associated with fat gain to the same extent. furthermore, longitudinal studies comparing hiv-negative people with hiv-positive people on long-term art have demonstrated that the extent and distribution of fat gain are similar. a systematic review of rcts concerning switching art for fat accumulation failed to show any benefit.63 these data indicate that fat gain is a consequence of treating hiv rather than a drug-specific side effect. telling the patient that the art drugs are causing fat gain is not only incorrect, but may result in the patient discontinuing art. the appearance of the fat gain is particularly unsightly when accompanied by lipoatrophy in the face, limbs and buttock. there is no evidence to support the switching of art drugs in patients with fat accumulation. healthy diet and exercise should be advocated, as in the hiv-negative population. surgery should be considered in selected cases with focal fat gain (e.g. those with prominent ‘buffalo humps’). metformin modestly reduces weight and improves insulin resistance in patients with the metabolic syndrome or isolated dysglycaemia. visceral fat accumulation is associated with insulin resistance and dyslipidaemia. other cvs risk factors should be addressed. hypersensitivity rash with nnrtis is common (more severe and frequent with nvp) in the first six weeks of therapy. if the rash is accompanied by systemic features (e.g. fever, elevated alt or hepatitis), mucosal involvement or blistering, then the nnrti should be discontinued immediately and rechallenge must not be performed as these are features of life-threatening reactions. if the rash is mild and occurs without these features, then the nnrti can be continued and the rash can be treated symptomatically with antihistamines, and possibly topical steroids. systemic steroids should not be used. in patients who develop mild rashes during the low-dose nvp lead-in phase (200 mg daily), the dosage must not be increased to 200 mg 12-hourly until the reaction has resolved. this ‘treat-through’ approach is only acceptable if the patient can be observed carefully, otherwise, nvp should be substituted. there is a possible cross-reaction between nvp and efv, although most studies report no evidence of this. it is acceptable to substitute efv for nvp in the event of hypersensitivity, unless the reaction was severe. in addition, if there was a severe reaction to nvp or efv we do not recommend switching to rpv or etr (rather use dtg or pi). there are hardly any data on substituting nvp for efv in the event of hypersensitivity; therefore, this substitution is not recommended. abc hypersensitivity is primarily a systemic reaction occurring within the first eight weeks of therapy in ~3% of cases. fatalities may occur on rechallenge. abc must be discontinued and never reintroduced. the manifestations of hypersensitivity include fever, rash, fatigue and abdominal or respiratory symptoms. if there is any doubt concerning the diagnosis (e.g. if the patient has a cough with fever), then the patient should be admitted for observation of the next dose: symptoms progress if hypersensitivity is present. the hypersensitivity reaction has been shown to occur on a genetic basis, being very strongly associated with the hla-b*5701 allele, which is very uncommon in africans. it is thus less frequent in patients of african descent. if testing is affordable and available, this allele should be excluded prior to using abc. other arv drugs, notably ral and drv, can occasionally cause hypersensitivity rashes, including life-threatening rashes. ctx is a common cause of cutaneous and systemic hypersensitivity reactions, indistinguishable from hypersensitivity reactions to art drugs. ctx should be interrupted when treating mild suspected nnrti cutaneous hypersensitivity rashes, and permanently discontinued if severe hypersensitivity reactions occur. if being given for secondary prophylaxis an alternative should be substituted. nephrotoxicity in a minority of patients, tdf may cause a tubular wasting syndrome (including wasting of phosphate and potassium). if patients receiving tdf develop muscle weakness or other muscle symptoms, then potassium and phosphate levels must be assessed. tdf can also cause acute renal failure, but this is uncommon. tdf should be switched to abc (or an alternative nrti) immediately in patients with acute renal failure as it may exacerbate injury even if it is not the primary cause. consider recommencing tdf with careful monitoring when the creatinine is normal only if an alternative cause of renal failure is established and tdf was considered not to have contributed. we recommend that the crcl should be estimated before commencing tdf, which should not be used if the egfr or crcl is < 50 ml/min. for patients receiving tdf, creatinine should be monitored at three months, six months and then 6-monthly thereafter. in high risk patients (particularly those with coexistent hypertension or diabetes), creatinine should also be checked at one and two months. long-term use of tdf together with other nephrotoxic agents (e.g. aminoglycosides or non-steroidal anti-inflammatory agents [nsaids]) should be avoided. where tdf is avoided because crcl is < 50 ml/min at baseline, it may be possible to switch to tdf at a later point if renal function improves. this is often the case where patients had diarrhoea or other ois at the time of art initiation. neuropsychiatric toxicity zidovudine and raltegravir frequently cause headaches when started, but this usually resolves. efv frequently causes neuropsychiatric effects in the first few weeks of therapy, typically presenting with insomnia, vivid dreams and dizziness. both dysphoria and euphoria may occur. fortunately, these features subside in the majority of patients within the first 4–6 weeks. psychosis may occasionally occur. if the neuropsychiatric effects of efv are not tolerated, then the patient should be switched to rpv, dtg, lower-dose efv or nvp (if the cd4+ count is < 250 cells/μl in women or < 400 cells/μl in men; if virologically suppressed, then efv can be switched to nvp at higher cd4+ counts as this is not associated with increased risk of rash-associated hepatitis), 400 mg daily. patients starting efv should be warned about these symptoms, and reassured that they resolve in most patients continuing the drug, but if not, that an alternative can be substituted. dtg may also cause insomnia, headache and neuropsychiatric side effects. ral has been associated with similar cns side effects. dysglycaemia the older pis, notably idv, may cause diabetes. however, the newer pis (atv, drv and lpv) do not. efv, azt and d4t are associated with small increased risks of dysglycaemia. visceral fat gain, which occurs to a similar extent with all art classes, is associated with insulin resistance. blood glucose should be assessed serially in these patients as part of a cvs risk assessment. gynaecomastia gynaecomastia, which is a benign glandular breast tissue proliferation seen in males, has most consistently been associated with the use of efv, although d4t and ddi have also been implicated.64,65 this is not related to lipodystrophy. the onset occurs several months after initiation of art and it may be bilateral or unilateral. the mechanism appears to be related to oestrogen receptor activation in breast tissues by efv.66 it is important to exclude other common causes of gynaecomastia, such as other medications (including spironolactone, calcium channel blockers, metoclopramide). a serum testosterone is useful in excluding hypogonadism as a cause. if the serum testosterone is low, other appropriate investigations should be performed to identify the cause and manage accordingly. if the serum testosterone level is normal, then efv should be substituted, bearing in mind the general principles of single drug substitutions (patients who are virologically suppressed should be switched to dtg or rpv). resolution of gynaecomastia is generally slow, taking months and may be incomplete in a small percentage.67 it is, therefore, important to manage the expectations of the patient in this regard. immune reconstitution inflammatory syndrome approximately 10%–20% of patients who start art with advanced immunosuppression experience clinical deterioration during the first months because of iris. two forms are recognised: unmasking iris occurs in patients who have an unrecognised oi when art is initiated, and who then present with exaggerated inflammatory features of that infection during early art because of it being ‘unmasked’ by recovering immunity. paradoxical iris occurs in patients who are being treated for an oi when they start art, but who develop an immune-mediated worsening or recurrence of features of that infection after starting art. immune reconstitution inflammatory syndrome is most frequently described in association with tb and cm. skin conditions such as molluscum contagiosum and kaposi’s sarcoma may also worsen because of iris. the diagnosis of iris can be difficult, mainly because there is no confirmatory diagnostic test. diagnosis relies on recognition of the characteristic clinical presentation, ensuring that ois are correctly diagnosed, and excluding alternative causes for deterioration, such as drug resistance (e.g. mdr-tb). case definitions for tb and cryptococcal iris have been published.68,69 it is important to ensure that the underlying oi is treated appropriately. art should be continued, unless iris is life-threatening (e.g. neurological involvement in tb-iris with depressed level of consciousness). corticosteroids have been shown to reduce morbidity and improve symptoms in paradoxical tb-iris,70 and can be used in mycobacterial and fungal forms of iris when other causes for deterioration have been excluded, and particularly when iris features are severe. for paradoxical tb-iris, prednisone can be commenced at a dose of 1.5 mg/kg/day and weaned over four weeks, but a longer course may be required if symptoms recur on weaning.71 steroids should not be used in patients with kaposi’s sarcoma. support and counselling the patient should be informed about the benefits of art and that side effects are usually minor and transient, or manageable. the patient should be given a treatment plan, specifying the drugs to be used (with names and details including the appearance of each drug, when and how they are to be taken and a brief indication of anticipated side effects and toxicity). poor adherence results in the development of drug resistance. there is a bell-shaped relationship between adherence and resistance: patients with very poor resistance may not acquire resistance to certain drugs because of insufficient drug pressure to select for resistance. the patient should be encouraged to discuss drug-related issues with his or her clinician. prophylaxis in patients receiving antiretroviral therapy opportunistic infections the use of appropriate prophylaxis (primary or secondary) is essential in patients initiating art. in general, prophylaxis can be discontinued once the cd4+ count has increased to 200 cells/μl (but certain minimal durations of prophylaxis apply for secondary prophylaxis – local and international guidelines should be consulted). isoniazid preventive therapy clinical trials conducted in sa and cote d’ivoire have shown that isoniazid preventive therapy (ipt) has an additive effect with art in preventing incident tb in hiv-infected patients.4,72 in the sa trial, there was a 37% reduction in incident tb when patients receiving art were prescribed ipt (vs placebo) for 12 months. this benefit applied irrespective of tuberculin skin test (tst) status, and the trial included patients established on art. all patients receiving art should be considered for ipt and screened for active tb by using a symptom screen73 – defer ipt and investigate for active tb if any of the four symptoms (current cough, fever, night sweats or weight loss) are present. consider sputum tb culture in all patients with a cd4+ count < 200 cells/μl before ipt initiation where feasible. in patients receiving ipt, monitor for neuropathy and hepatitis symptoms. routine alt monitoring is not indicated, but request alt if hepatitis symptoms occur. the duration of ipt depends on tst and art status as outlined in table 15. table 15: indications for and duration of isoniazid preventive therapy. acknowledgements this work is supported and funded by the southern african hiv clinicians society. g.m. has received honoraria for speaking engagements from sanofi aventis and janssen pharmaceuticals, serves as a consultant for aid for aids and tb alliance and is on the gilead antifungal advisory board. m.m. is part of the optimize consortium that includes drug donations from gilead and viiv and also includes mylan as part of the consortium. she has received speaker fees and honoraria from sa hiv clinicians society, gilead sciences, abbvie and janssen; has received conference sponsorship from bd, gilead, merck, cipla and mylan; has acted as a consultant to abbvie, gsk, viiv and gilead; and is a member of the johnson and johnson global public health hiv therapeutic area steering committee. s.d. has received honoraria for speaking engagements from msd and pfizer. c.v.v. has received honoraria for speaking engagements from pfizer and msd and has received support to attend conferences from pfizer and msd. t.m. has received support from gilead to attend a conference. m.m. has received support from cipla and aspen to attend conferences and honoraria from johnson & johnson for the development of educational presentations. y.m. has received honoraria for speaking engagements from mylan, msd, abbott laboratories, aspen and gilead and support from gilead to attend conferences. j.n. has received honoraria for speaking engagements from cipla and mylan. f.c. is a board member of the samrc, hiv consultant for discovery medical aid and is employed by clinical hiv research unit; has received support from mylan, aspen and merck to attend conferences; honoraria for speaking engagements from sa hiv clinicians society, mylan, cipla and janssen; and acted as a consultant to abbvie, mylan and viiv. f.v. is part of the optimize consortium that includes drug donations from gilead and viiv and also includes mylan as part of the consortium. he has given talks and participated on advisory boards (all < $1000) for these companies, as well as j&j, roche, merck, aspen, abbott and adcock-ingram in the last 10 years. competing interests the authors declare that they have no financial or personal relationship(s) which may have inappropriately influenced them in writing this article. authors’ contributions all expert panel members have completed and submitted conflict of interest disclosure forms. disclosure information represents the previous 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suppression. j acquir immune defic syndr. 2010;55:451–459. https://doi.org/10.1097/qai.0b013e3181ec28ff tuboi sh, pacheco ag, harrison lh, et al. mortality associated with discordant responses to antiretroviral therapy in resource-constrained settings. j acquir immune defic syndr. 2010;53:70–77. https://doi.org/10.1097/qai.0b013e3181c22d19 ledergerber b, lundgren jd, walker as, et al. predictors of trend in cd4-positive t-cell count and mortality among hiv-1-infected individuals with virological failure to all three antiretroviral-drug classes. lancet. 2004;364:51–62. https://doi.org/10.1016/s0140-6736(04)16589-6 paton ni, kityo c, hoppe a, et al. assessment of second-line antiretroviral regimens for hiv therapy in africa. n engl j med. 2014;371:234–247. https://doi.org/10.1056/nejmoa1311274 la rosa am, harrison lj, taiwo b, et al. raltegravir in second-line antiretroviral therapy in resource-limited settings (select): a randomised, phase 3, non-inferiority study. lancet hiv. 2016;3:e247–e258. https://doi.org/10.1016/s2352-3018(16)30011-x johnson m, grinsztejn b, rodriguez c, et al. 96-week comparison of once-daily atazanavir/ritonavir and twice-daily lopinavir/ritonavir in patients with multiple virologic failures. aids. 2006;20:711–718. https://doi.org/10.1097/01.aids.0000216371.76689.63 molina jm, andrade-villanueva j, echevarria j, et al. once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive hiv-1-infected patients: 96-week efficacy and safety results of the castle study. j acquir immune defic syndr. 2010;53:323–332. https://doi.org/10.1097/qai.0b013e3181c990bf department of health. 2015. national consolidated guidelines for the prevention of mother-to-child transmission of hiv (pmtct) and the management of hiv in children, adolescents and adults. department of health, south africa. yazdanpanah y, fagard c, descamps d, et al. high rate of virologic suppression with raltegravir plus etravirine and darunavir/ritonavir among treatment-experienced patients infected with multidrug-resistant hiv: results of the anrs 139 trio trial. clin infect dis. 2009;49:1441–1449. https://doi.org/10.1086/630210 meintjes g, dunn l, coetsee m, et al. third-line antiretroviral therapy in africa: effectiveness in a southern african retrospective cohort study. aids res ther. 2015;12:39. https://doi.org/10.1186/s12981-015-0081-8 stevens ws, wallis cl, sanne i, venter f. will etravirine work in patients failing nonnucleoside reverse transcriptase inhibitor-based treatment in southern africa? j acquir immune defic syndr. 2009;52:655–656. https://doi.org/10.1097/qai.0b013e3181ba1b00 petersen ml, wang y, van der laan mj, rhee sy, shafer rw, fessel wj. virologic efficacy of boosted double versus boosted single protease inhibitor therapy. aids. 2007;21:1547–1554. https://doi.org/10.1097/qad.0b013e32825a69a8 conradie f, fox m, moorhouse ma, et al. south africa’s national third-line art cohort: descriptive analysis. conference on retroviruses and opportunistic infections (croi); 2017 february 13–16; johannesburg, south africa. university of the witwatersrand; 2017. http://www.croiconference.org/sessions/south-africa%e2%80%99s-national-third-line-art-cohort-descriptive-analysis strategies for management of antiretroviral therapy study group, el-sadr wm, lundgren j, et al. cd4+ count-guided interruption of antiretroviral treatment. n engl j med. 2006;355:2283–2296. grinsztejn b, de castro n, arnold v, et al. raltegravir for the treatment of patients co-infected with hiv and tuberculosis (anrs 12 180 reflate tb): a multicentre, phase 2, non-comparative, open-label, randomised trial. lancet infect dis. 2014;14:459–467. https://doi.org/10.1016/s1473-3099(14)70711-x davies g, cerri s, richeldi l. rifabutin for treating pulmonary tuberculosis. cochrane database syst rev. 2007;(4):cd005159. https://doi.org/10.1002/14651858.cd005159.pub2 hennig s, svensson em, niebecker r, et al. population pharmacokinetic drug-drug interaction pooled analysis of existing data for rifabutin and hiv pis. j antimicrob chemother. 2016;71:1330–1340. https://doi.org/10.1093/jac/dkv470 world health organization. technical update on treatment optimization. use of efavirenz during pregnancy: a public health perspective. switzerland: who press; 2012. ford n, calmy a, mofenson l. safety of efavirenz in the first trimester of pregnancy: an updated systematic review and meta-analysis. aids. 2011;25:2301–2304. https://doi.org/10.1097/qad.0b013e32834cdb71 patterson kb, dumond jb, prince ha, et al. protein binding of lopinavir and ritonavir during 4 phases of pregnancy: implications for treatment guidelines. j acquir immune defic syndr. 2013;63:51–58. https://doi.org/10.1097/qai.0b013e31827fd47e eley t, bertz r, hardy h, burger d. atazanavir pharmacokinetics, efficacy and safety in pregnancy: a systematic review. antivir ther. 2013;18:361–375. https://doi.org/10.3851/imp2473 bartlett jg. medical care of patients with hiv infection. philadelphia, pa: lippincott williams and wilkins; 2010. gilbert dn, moellering jr., rc (editor), eliopoulos gm, editors. the sanford guide to antimicrobial therapy. sperryville, va: antimicrobial therapy inc; 2012. lucas gm, ross mj, stock pg, et al. clinical practice guideline for the management of chronic kidney disease in patients infected with hiv: 2014 update. clin infect dis. 2014;59(9):e96–e138. https://doi.org/10.1093/cid/ciu617 sonderup mw, maughan d, gogela n, et al. identification of a novel and severe pattern of efavirenz drug-induced liver injury in south africa. aids. 2016;30:1483–1485. https://doi.org/10.1097/qad.0000000000001084 jong e, conradie f, berhanu r, et al. consensus statement: management of dili in hiv-positive patients treated for tb. s afr j hiv med 2013;14(3):113–119. https://doi.org/10.4102/sajhivmed.v14i3.63 de waal r, cohen k, maartens g. systematic review of antiretroviral-associated lipodystrophy: lipoatrophy, but not central fat gain, is an antiretroviral adverse drug reaction. plos one. 2013;8:e63623. https://doi.org/10.1371/journal.pone.0063623 manfredi r, calza l, chiodo f. another emerging event occurring during hiv infection treated with any antiretroviral therapy: frequency and role of gynecomastia. infez med. 2004;12:51–59. mira ja, lozano f, santos j, et al. gynaecomastia in hiv-infected men on highly active antiretroviral therapy: association with efavirenz and didanosine treatment. antivir ther. 2004;9:511–517. sikora mj, rae jm, johnson md, desta z. efavirenz directly modulates the oestrogen receptor and induces breast cancer cell growth. hiv med. 2010;11:603–607. https://doi.org/10.1111/j.1468-1293.2010.00831.x njuguna c, swart a, blockman m, et al. cases of antiretroviral-associated gynaecomastia reported to the national hiv & tuberculosis health care worker hotline in south africa. aids res ther. 2016;13:40. https://doi.org/10.1186/s12981-016-0121-z haddow lj, colebunders r, meintjes g, et al. cryptococcal immune reconstitution inflammatory syndrome in hiv-1-infected individuals: proposed clinical case definitions. lancet infect dis. 2010;10:791–802. https://doi.org/10.1016/s1473-3099(10)70170-5 meintjes g, lawn sd, scano f, et al. tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. lancet infect dis. 2008;8:516–523. https://doi.org/10.1016/s1473-3099(08)70184-1 meintjes g, wilkinson rj, morroni c, et al. randomized placebo-controlled trial of prednisone for paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome. aids. 2010;24:2381–2390. https://doi.org/10.1097/qad.0b013e32833dfc68 meintjes g, sonderup mw. a practical approach to the diagnosis and management of paradoxical tuberculosis immune reconstitution inflammatory syndrome. contin med educ. 2011;29(10):410–417. rangaka mx, wilkinson rj, boulle a, et al. isoniazid plus antiretroviral therapy to prevent tuberculosis: a randomised double-blind, placebo-controlled trial. lancet. 2014;384:682–690. https://doi.org/10.1016/s0140-6736(14)60162-8 getahun h, kittikraisak w, heilig cm, et al. development of a standardized screening rule for tuberculosis in people living with hiv in resource-constrained settings: individual participant data meta-analysis of observational studies. plos med. 2011;8:e1000391. https://doi.org/10.1371/journal.pmed.1000391 summer 2008                                                          the southern african journal of hiv medicine                                                   under international trade rules, patent protection for pharmaceuticals lasts 20 years. during this period, competitors are excluded from the market, which generally results in medicine prices that far exceed production costs.2 patent protection is particularly widespread in developing countries with strong pharmaceutical manufacturing capacity, including south africa.3 the main defence of the patent system is based on the argument that it acts as an incentive for investing in research and development. in order to benefit from patent protection, manufacturers need to demonstrate that they have contributed sufficiently to the drug innovation process. in the field of hiv/aids, the public sector – principally universities and large publicly funded government research organisations – have contributed significantly, and sometimes entirely, to the research and development of many key arvs. abacavir, didanosine, stavudine, zalcitabine, zidovudine and the concept of protease inhibition have all received substantial public funding in their discovery and development.4,5 public interest and patient groups have successfully challenged the legitimacy of a number of arv patents, based on the fact that patent holders did nothing significantly inventive to deserve a monopoly. in thailand, bristol-myers squibb’s patent for didanosine was overturned on the grounds that the patent holder manipulated the details of the patent claim, and the fact that most of the research and development was done by the us national institutes of health.6 in india and thailand, civil society groups managed to successfully block a patent application by glaxosmithkline for the combination zidovudine+lamivudine on the grounds that simply combining two known and already patented drugs was not sufficiently inventive to warrant an extended monopoly.7 in south africa, the purchasing of generic stavudine was made possible because of a challenge to the licensing agreement between bristol-myers squibb and the patent owner, yale university.8 each of these initiatives has led to significant cost savings, as is clearly demonstrated by the precipitate fall in the price of branded stavudine in south africa, from more than us$1 539 per adult patient/ year in 2000 to less than us$77 in 2008. generic versions cost even less. tenofovir disoproxil fumarate (tdf) is a desirable arv because it is regarded as safe, requires relatively limited toxicity monitoring, and is administered once daily. at the end of january 2008, the us patent and trademark office revoked four key patents held by gilead sciences for tdf. this followed a challenge by a us public interest organisation (the public patent foundation) that showed that tdf was already a known substance by the time gilead applied for the patents.9 (much of the research work was done by the academy of sciences of the czech republic and the catholic university in leuven, belgium. emtricitabine, which is partnered with tdf in a once-a-day dosage form, truvada, was similarly discovered by public researchers at emory university.) similar patent challenges have been filed by civil society groups in india, and thailand is expected to follow suit. patent challenges have been raised in part because of the unreasonably high cost and significant variation in pricing of tdf. for example, brazil, south africa and thailand have very similar gross domestic products, but the price of tdf tough choices: tenofovir, tenders and treatment patent rights and wrongs opinion nathan ford, bsc, dha médecins sans frontières, johannesburg andy gray, msc (pharm), fps (sa) department of therapeutics and medicines management, nelson r mandela school of medicine, university of kwazulu-natal, durban w d francois venter, fcp (sa) hiv management cluster, reproductive health and hiv research unit, university of the witwatersrand, johannesburg scaling up of antiretroviral therapy (art) in developing countries would not have been possible without market competition, which has driven down the price of standard first-line antiretroviral (arv) drugs from more than us$12 000 per person/year in 2000 to us$99 today. however, access to newer, second-line arvs remains largely restricted to originator (patented) drugs. this causes significant challenges in countries where access to newer medicines is becoming increasingly important as programmes mature and face challenges related to drug toxicity and resistance.1 toxicity in particular has emerged as a major reason for individual drug switches and regimen changes, and is strongly implicated in decreasing adherence. this article focuses on international efforts to reduce the price of tenofovir, and outlines the implications of these dynamics for south africa. challenging the tenofovir monopoly 8 pg8-10.indd 8 4/4/08 9:03:41 am the southern african journal of hiv medicine                                                        summer 2008   in brazil is three times that in thailand and six times that in south africa (table i). in india, the tdf patent has not yet been granted by the indian patent office, but gilead has managed to limit generic competition by entering into voluntary licence agreements with the majority of indian generic manufacturers capable of producing the product or its active pharmaceutical ingredient (including matrix, ranbaxy, hetero, aurobindo and emcure). these voluntary licences impose restrictions so that, for example, manufacturers cannot export to middle-income countries such as south africa and brazil, preventing the option of sourcing alternative price options and limiting access to alternative supplies of drug in the event of shortage. the tdf market for africa has been awarded to aspen pharmacare (gilead has not patented tdf in south africa, but has relied on the licensing agreement with aspen to manage the market).11 however, as gilead itself will not market tdf (or the combination of tdf and emtricitabine) in these countries, the overall result is that tdf remains a monopoly (single-source) product. if gilead’s patents are rejected by the indian patent office, the voluntary licence agreements signed between gilead and indian manufacturers will probably become void. this means that generic manufacturers will be able to freely manufacture and export generic versions of tenofovir without restrictions. the place of tdf in the management of hiv/aids has been variably described in treatment guidelines; this variability is directly influenced by considerations of price when applied to the developing world. for example, the united states department of health and human services guidelines for the use of antiretroviral agents in hiv-1-infected adults and adolescents lists tdf and emtricitabine among its firstline ‘preferred’ choices.12 the 6th edition of aid for aids guidelines (used widely in south africa’s private sector), while noting that tdf was not yet registered in the country in 2007, stated that ‘… [i]ts best current role is in initial therapy, combined with either lamivudine or emtricitabine’.13 in march 2007, the world health organization (who) included tdf in the 15th model essential medicines list.14 in may 2007, a who working group recommended that tdf be included (with lamivudine, considered equivalent to emtricitabine) as the preferred non-nucleoside/nucleotide reverse transcriptase (nrti) background option for secondline arv therapy in developing countries using thymidinebased first-line regimens. a number of countries in southern africa have either moved to using tdf as part of first-line regimens (lesotho) or are considering such a move (zambia). tdf is increasingly needed in all programmes using stavudine as first-line therapy for the growing number of patients who develop toxicity to stavudine (lipoatrophy, peripheral neuropathy, symptomatic hyperlactataemia and lactic acidosis). one study found that 21% of patients starting on a d4t-based regimen required a switch to an alternative arv within 3 years because of toxicity.15 cost is a major factor for considering a move to providing tdf as a first-line art option. a recent cost-effectiveness analysis estimated that, for tdf to replace d4t at a neutral cost, the price of tdf would need to fall to us$72 per person/year – a third of the current price (personal communication – sydney rosen). this is not unrealistic. experts involved in arv price negotiations and forecasting are anticipating significant reductions for tdf. it is expected that tdf is likely to fall to around us$120 per person/year in the next 12 18 months; in the long term, it is certainly possible that prices could fall to well below $100 (personal communication – aaron pattillo, clinton foundation). however, there are two major obstacles to south africa being able to access these prices: the arv tender process for 2008, and the medicines registration process. the department of health is in the process of concluding the arv tender for 2008 2011. the first arv tender, concluded in 2004, locked the government into a 3-year agreement with manufacturers. prices were, as with other medicines tenders, set for the entire period, scheduled for pre-determined price escalations at various time points, or linked to international exchange rate fluctuations. the request for proposals noted that ‘… [a]ll contracts are subjected to the general conditions of contract (gcc) issued in accordance with the regulations in terms of the public finance management act, 1999: framework for supply chain management that was promulgated in the government gazette no. 25767 on 5 december 2003’; it also indicated that ‘special conditions of contract (scc)’ would apply. therefore, while the gcc state that ‘… [t]he supplier shall indemnify the purchaser against all third-party claims of infringement of patent, trademark, or industrial design rights arising from use of the goods or any part thereof by the purchaser’, the scc included the following two clauses (bold text is in the original):16 3.3 bidders must comply with the requirements of the patents act, 1978 (act 57 of 1978) and the trade marks act, 1993 (act 194 of 1993). bidders must submit a copy of the actual patent or an agreement with the patent holder with the bid document at the closing date and time of the request for proposal/quotation. 3.4 bidders must comply with any legal requirements with regard to voluntary licences obtained, and proof of agreements in this regard must be supplied with the bid document at the closing date and time of the request for proposal/quotation. these additional clauses are extraordinary – they are not found in other medicines tenders – and potentially highly restrictive. if a more affordable source of tdf becomes available in a year’s time, it is not clear whether the 2008 country gdp per capita cost of tenofovir brazil us$8 402 us$1 387 india us$3 452 us$199 south africa us$11 110 us$235 thailand us$8 677 us$454 best available price us$195 table i. comparison of tdf prices in selected developing countries, 200710 implications for south africa 9 pg8-10.indd 9 4/4/08 9:03:42 am summer 2008                                                          the southern african journal of hiv medicine                                                   tender will allow for its procurement. it is also not clear whether a generic manufacturer, which holds neither patent nor agreement with the patent holder, will be able to enter the process, even if that generic production is entirely consistent with intellectual property law. two other clauses in the 2004 request for proposals relate to registration and are standard for all medicine tenders: 3.1 bidders offering medicines which require registration in terms of the medicines and related substances act, (act 101 of 1965 as amended), must be in possession of valid registration certificates, issued in terms of the said act at the closing date and time of the request for proposal/ quotation, and must comply with the conditions under which the medicines have been registered. copies of registration certificates for drugs offered must be supplied with the bid document at the closing date and time of the request for proposal/quotation. 3.2 bidders offering medicines must supply proof of positive gmp status with the medicines control council which must be submitted with the bid document at the closing date and time of the request for proposal/quotation. the registration of generic tdf products may therefore present a second obstacle to procuring more affordable versions of this highly desirable arv. tdf was only registered in south africa in mid-2007, even though it has been registered in the usa since 2001 and in europe since 2002. the registration dossier was finally submitted to the south african medicines control council early in 2006. even if affordable, quality-assured, generic versions of tdf become available this year, the registration of these products for use in south africa may take an unnecessarily long time. the popular ‘all-in-one’ single tablet coformulation of tenofovir/emtricitabine/efavirenz, which is widely used in developed countries as one of the safest and most convenient combinations, will probably take years to be registered in south africa because of the complexity of having two pharmaceutical companies owning different patents. that generic versions are needed is amply demonstrated by the lack of price differentials between the tender prices and private sector single-exit prices for products only available from brand manufacturers. ideally, the volumes guaranteed by large-scale programmes in the state sector and the relatively simple product delivery processes should mean that the state should enjoy significant cost reductions. this has not uniformly been the case. for example, efavirenz (efv) 600 mg tablets are sold to the south african public and private sectors at the same price (us$238 per person/ year). in contrast, nevirapine (nvp) 200 mg tablets are provided to the state at us$74.50 per person/year by a generic manufacturer, which sells the same product in the private sector for us$276.84. the branded version sells to the private sector for us$983. nevirapine 50 mg/5 ml suspension provides an object lesson in the consequences of insisting on the existence of concluded voluntary licences at the time of tender submission. the state currently purchases a bottle at us$25.86, whereas the lowest-priced licensed generic sells to the private sector at us$13.13. while a tender provides a measure of stability over time, it may also limit the ability of the state to take advantage of new clinical evidence and/or new generic entrants. arv scale-up in the developing world was made possible because of a simple, affordable first-line regimen using public health principles. as hiv treatment programmes mature, the need for newer medicines to overcome toxicity and resistance is becoming increasingly urgent. faced with rising treatment costs, a number of developing countries have taken strong action against the monopolies on key arv patents, resulting in significant cost savings. for south africa, broader access to tdf has the potential to simplify treatment by offering a more favourable sideeffect profile, an issue that is particularly important in facilitating the provision of care at the primary care level. further potential for simplification is presented by the use of tdf in the once-a-day combination of tenofovir/ emtricitabine/efavirenz (and potentially tenofovir/ lamivudine/nevirapine). internationally, the cost of tdf is set to fall significantly in the coming months. the price that south africa will pay will depend on whether the tender process will allow for the inclusion of new, unpatented medicines and how quickly these new products can be registered. neither of these issues is immutable: they are simple matters of policy choice. dr venter acknowledges support from pepfar. references 1. chien cv. hiv/aids drugs for sub-saharan africa: how do brand and generic supply compare? plos one 2007; 2(3): e278. 2. westerhaus m, castro a. how do intellectual property law and international trade agreements affect access to antiretroviral therapy? plos med 2006; 8: 1230-1236. 3. attaran a, gillespie-white l. do patents for antiretroviral drugs constrain access to aids treatment in africa? jama 2001; 286(15): 1886-1892. 4. chirac p, von schoen-angerer t, kasper t, ford n. aids: patent rights versus patient's rights. lancet 2000; 356: 502. 5. chokshi d, rajkumar r. leveraging university research to advance global health. jama 2007; 298: 1934-1936. 6. ford n, wilson d, bunjumnong o, von schoen-angerer t. the role of civil society in protecting public health over commercial interests: lessons from thailand. lancet 2004; 363: 560-563. 7. ford n, wilson d, costa chaves g, lotrowska m, kijtiwatchakul k. sustaining access to antiretroviral therapy in developing countries: lessons from brazil and thailand. aids 2007; 21(suppl 4): s21-s29. 8. chokshi d. improving access to medicines in poor countries: the role of universities. plos med 2006; 6: 723-726. 9. beasley d. us patent office rejects gilead viread patents. reuters, 23 january 2008. 10. untangling the web of price reductions: a pricing guide for the purchase of arvs for developing countries. 10th ed. geneva: médecins sans frontiéres, 2007. 11. gilead sciences and aspen pharmacare sign letter of intent to establish nonexclusive licensing and distribution agreement for antiretrovirals truvada and viread in developing world countries. business wire, 25 april 2005. http:// findarticles.com/p/articles/mi_m0ein/is_2005_april_25/ai_n13650816 (accessed 10 february 2008). 12. guidelines for the use of antiretroviral agents in hiv-1-infected adults and adolescents. washington, dc: united states department of health and human services, 2006. 13. regensberg l, whitelaw c, eds. aid for aids guideline. 6th ed. howard place: aid for aids, 2007. 14. model essential medicines list. 15th ed. geneva: world health organization, 2007. 15. boulle a, orrell c, kaplan r, et al. substitutions due to antiretroviral toxicity or contraindication in the first 3 years of antiretroviral therapy in a large south african cohort. antiviral therapy 2007; 12: 753-760. 16. request for proposals/quotation. rt71-2004mf. the supply of antiretroviral drugs for the department of health’s comprehensive hiv and aids care, management and treatment plan. pretoria: state tender board, 2004. conclusions 10 pg8-10.indd 10 4/4/08 9:03:43 am hiv 903 progressive hiv infection in the presence of a raised cd4+ count: hiv/htlv-1 co-infection a f haeri mazanderani,1 mb chb; o ebrahim,2 m bchb, md, dtm&h, fccp (sa) 1 department of medical virology, university of pretoria & national health laboratory service, tshwane academic division, pretoria, south africa 2 department of medical microbiology, university of pretoria, pretoria, south africa corresponding author: a f haeri mazanderani (ahmad.haerimazanderani@up.ac.za) there are a number of pathophysiological causes for a normal or raised cd4 count in the context of progressive hiv infection. these include various co-infections, previous splenectomy, and lymphoproliferative disorders. such circumstances can both confound hiv diagnosis and delay initiation of chemoprophylaxis and highly active antiretroviral therapy (haart). we describe the case of a patient co-infected with hiv and human t-cell lymphotropic virus type 1 (htlv-1) who, prior to haart initiation, was found to have progressive immune deficiency associated with a raised cd4 count. s afr j hiv med 2013;14(2):92-94. doi:10.7196/sajhivmed.904 a 51-year-old married man from gauteng province, south africa (sa), originally from the northern cape, tested hiv-positive on an enzyme-linked immunosorbent assay (elisa) in march 2002 as part of a routine medical examination for insurance purposes. his cd4+ count was 794 cells/μl and his hiv viral load was 19 365 copies/ml. he gave no history of any infectious diseases, but was receiving treatment for hypertension. on examination he was generally healthy, with normal vital signs and all systems proved unremarkable. on account of being asymptomatic with a cd4+ count within normal range, he was neither initiated on highly active antiretroviral therapy (haart) nor chemoprophylaxis, and was told to follow-up with his general practitioner for regular immune monitoring (table 1). an abnormally high cd4+ count was detected on follow-up in september 2002 prompting t-cell receptor polymerase chain reaction (pcr) studies, which revealed no evidence of a clonal t-cell lymphoproliferative disorder. a bone-marrow biopsy was also performed and showed non-malignant t-cell hyperplasia. no further studies were conducted and expert opinion from hiv clinicians recommended that no antiretroviral therapy (art) be given at that stage. in january 2009 the patient was referred to us with a history of weight loss, fatigue and night sweats. on examination, he had increased reflexes affecting the right leg, with weakness in both arms; otherwise, examination was essentially normal. magnetic resonance imaging of the spine revealed a collapsed vertebra at t9; a biopsy showed a chronic inflammatory process but no granulomata. on account of the history and clinical presentation, spinal tuberculosis (tb) was considered and tb treatment was commenced. furthermore, despite the high cd4+ count, it was felt that the patient would benefit from art on account of being clinically immune-compromised and having a high hiv viral load. he was initiated on a regimen of truvada (tenofovir/emtricitabine) and efavirenz (efv) to which he responded well with a drop in rna copies/ ml of >2 log10 after three months of treatment and an undetectable hiv viral load six months thereafter. as the cd4+ count remained above normal limits, repeat bone marrow and flow cytometry studies were carried out, identifying a population of t-lymphocytes with abnormal flow characteristics. t-cell receptor pcr showed the presence of a clonal cell population and bone marrow histology revealed infiltration by tumour cells with scattered atypical uninucleated cells and binucleated reed-sternberg cells. immunophenotypic analysis showed no overt evidence of a b-cell lymphoproliferative disorder. antibodies to human t-cell lymphotropic virus type 1/2 (htlv-1/2) were detected by elisa and the patient was diagnosed with a smouldering type of adult t-cell leukaemia/lymphoma (atll) secondary to htlv-1 infection (htlv-2 not being associated with this condition). he was treated with four cycles of infusional chemotherapy consisting of etoposide, vincristine, doxorubicin, cyclophosphamide and prednisone (epoch), which he tolerated well. interferon-alpha therapy was subsequently commenced and mantained three times per week. at the time of writing, the patient is clinically well with no neurological deficits, an undetectable hiv viral load and a cd4+ count of 4 430 cells/μl. discussion htlv-1 was the first retrovirus to be identified in humans and is structurally related to other viruses within the retroviridae family, such as hiv-1 and hiv-2, sharing similar routes of transmission. since its discovery in 1979 three additional human deltaretroviruses (htlv-2, htlv-3 and htlv-4) have been found, but only htlv-1 and htlv-2 have so far been associated with human disease. antibodies to htlv-1 were first identified in sa in 1984 and the first report of isolation of the virus was published in 1988. 1 , 2 subsequently, a number of seroprevalence studies have been conducted in sa, where htlv-1 has been found to be endemic in areas of mpumalanga, the eastern cape, free state and kwazulu-natal (kzn). 3 , 4 however, there are no recent representative data regarding prevalence in the general sa population or specific patient subgroups.5 like other human retroviruses, htlv-1 causes a lifelong infection of t-lymphocytes, in particular cd4+ cells. however, unlike hiv, the immunological hallmark of htlv-1-infected individuals is a sustained proliferation of t-cells driven by the htlv-1-encoded tax protein. 6 the subsequent transactivation of cellular genes by the tax-encoded region can result in malignant transformation, although this is rare.7 in the majority of cases, cytotoxic t-cells effectively control the virus by lysis of infected lymphocytes, which in turn results in the release of inflammatory cytokines that can be pathogenic.6 on account of these various pathophysiological mechanisms, htlv-1 is associated with a diverse range of pathology, including malignant disease, inflammatory syndromes and infective complications.6 a number of these conditions have been described in sa, including atll, htlv-1-associated myelopathy/tropical spastic paraparesis (ham/tsp) and infectious dermatitis.8-10 although the life-time risk for htlv-1-associated diseases in general is considered close to 10%, an indication of a long history of viral-human co-evolution,6 this may be an under-representation when the interaction between htlv-1 and other infective agents is considered. tb has been found to occur more frequently in patients infected with htlv-1 and is also thought to be associated with a worse prognosis. 6 htlv-1 has been shown to up-regulate hepatitis c viral replication and is implicated as a co-factor in the development of hepatocellular carcinoma. furthermore, two studies have demonstrated an increased rate of cervical carcinoma in htlv-1-infected patients.7 whether hiv-1 co-infection with htlv-1 is associated with a faster progression to aids remains a contentious issue, although a number of studies have suggested as much. 11 what is, however, less controversial and perhaps of greater relevance is the effect of htlv-1 on t-lymphocytes, and in particular, its association with cd4+ lymphocytosis in hiv-1 co-infected patients.12 , 13 in general, lymphocytosis can be classified as belonging to one of two groups: either a reactive polyclonal proliferation, which can be caused by a variety of infective agents, hyper­sensitivity reactions, autoimmune conditions and splenectomy, or a clonal expansion as a result of a lymphoproliferative disorder. in the context of hiv co-infection, lympho­cytosis has been described during early sero­conversion associated with cmv, as well as in hiv/htlv-1 co-infection where cd4+ lymphocytosis can be caused by both a reactive or clonal expansion. consequently, patients with untreated hiv-1 who are co-infected with htlv-1 show a dissociation between immunological and virological markers. that is to say, hiv-1/htlv-1 co-infected patients have been found to progress to aids with a high hiv viral load, but in the presence of a normal or higher than normal cd4+ count (both absolute and percentage).12 a recent study in mozambique demonstrated that co-infected pre-haart adult patients were seven times more likely to have cd4+ counts >500 cells/μl (median 525 cells/μl) than hiv mono-infected patients.13 however, as these cd4+ cells are likely to be functionally altered, associated with a loss of naive cells and a higher activation pattern, cd4+ lymphocyte counts in hiv-1/ htlv-1 co-infected patients cannot be considered to be a reliable marker of immunological competence.12 furthermore, cd4+ counts can be dramatically raised on account of atll (i.e. clonal expansion), which occurs in ≤5% of htlv-1 infections.6 as most cases of atll develop in individuals infected early in life through breastfeeding,6 it is probable that our patient was already infected with htlv-1 when he first presented in 2002 with a cd4+ count of 794 cells/μl. whether initiation of haart at this juncture would have prevented the development of atll cannot be determined. however, it is thought that zidovudine (azt) may protect htlv-1-infected peripheral blood mononuclear cells from immortalisation on account of its genotoxic/mutagenic properties. 14 the last sizeable htlv-1 seroprevalence study in sa was conducted in northern kzn in 1993; a prevalence of 2.6% was found among the general population.4 in the same study an hiv-1 prevalence of 3.5% was noted. as the risk factors for htlv-1 and hiv are shared, an epidemiological association between these two retroviruses is to be expected. in 1996, htlv-1 was found in 2% of asymptomatic urban black people in the free state, but in 6% of hiv-seropositive patients from the same region.3 more recently, and alarmingly, in a small retrospective study of 170 hiv-positive plasma specimens collected between 2007 and 2008 from limpopo, 24% of specimens tested positive for htlv-1/2 antibodies by elisa. 15 unfortunately, further testing to confirm the diagnosis or differentiate between htlv-1 and htlv-2 infection was not performed. nevertheless, these findings highlight the evident gap in current knowledge and the need for clinicians to be aware of retroviruses other than just hiv. conclusion a cd4+ lymphocyte count cannot always be considered to be a reliable marker of immunological competence in hiv-infected people, especially in patients co-infected with htlv-1. normal or raised cd4+ counts in such persons can be on account of reactive or clonal expansion of t-lymphocytes and can confound hiv diagnosis and delay initiation of chemoprophylaxis and haart. as we lack up-to-date epidemiological data but know that certain areas in sa are endemic for htlv-1, we suggest maintaining a high index of suspicion of htlv-1 infection in all hiv-positive adult patients in southern africa. in particular, hiv-positive persons who are clinically immune-compromised and have a raised cd4+ count should be tested for htlv-1, as well as patients who present with clinical features in keeping with atll, ham/tsp or infective dermatitis. as locally available serological tests are unable to differentiate htlv-1 and -2, a pcr or western blot analysis may be required subsequent to a positive htlv-1/2 elisa test to confirm the diagnosis and distinguish between htlv-1 and -2. furthermore, the decision to initiate haart in co-infected patients is better determined by clinical stage and hiv viral load than cd4+ count. more research is needed to understand the epidemiology of htlv-1 infection in southern africa; not only with regard to co-infections such as hiv-1/ htlv-1 and tb/ htlv-1, but also in terms of the wider public health impact, including implications for pmtct practices and safety of the blood supply. references 1. saxinger w, blattner wa, levine ph, et al. human t-cell leukemia virus (htlv-1) antibodies in africa. science 1984;225:1473-1476. 1. saxinger w, blattner wa, levine ph, et al. human t-cell leukemia virus (htlv-1) antibodies in africa. science 1984;225:1473-1476. 2. becker wb, botha mc, engelbrecht s, becker mlb. isolation of human t-lymphotropic virus type i (htlv-i) from a black south african with kaposi’s sarcoma. s afr med j 1988;73:481-483. 2. becker wb, botha mc, engelbrecht s, becker mlb. isolation of human t-lymphotropic virus type i (htlv-i) from a black south african with kaposi’s sarcoma. s afr med j 1988;73:481-483. 3. van der ryst e, joubert g, smith ms, et al. htlv-i infection in the free state region of south africa: a sero-epidemiologic study. cent afr j med 1996;42(3):65-68. 3. van der ryst e, joubert g, smith ms, et al. htlv-i infection in the free state region of south africa: a sero-epidemiologic study. cent afr j med 1996;42(3):65-68. 4. bhigjee ai, vinsen c, windsor im, et al. prevalence and transmission of htlv-i infection in natal/ kwazulu. s afr med j 1993;83:665-667. 4. bhigjee ai, vinsen c, windsor im, et al. prevalence and transmission of htlv-i infection in natal/ kwazulu. s afr med j 1993;83:665-667. 5. hlela c, shepperd s, khumalo np, taylor gp. the prevalence of human t-cell lymphotropic virus type 1 in the general population is unknown. aids rev 2009;11:205-214. 5. hlela c, shepperd s, khumalo np, taylor gp. the prevalence of human t-cell lymphotropic virus type 1 in the general population is unknown. aids rev 2009;11:205-214. 6. verdonck k, gonzalez e, van dooren s, et al. human t-lymphotropic virus 1: recent knowledge about an ancient infection. lancet infect dis 2007;7:266-281. [http://dx.doi.org/10.1016/s1473-3099(07)70081-6] 6. verdonck k, gonzalez e, van dooren s, et al. human t-lymphotropic virus 1: recent knowledge about an ancient infection. lancet infect dis 2007;7:266-281. [http://dx.doi.org/10.1016/s1473-3099(07)70081-6] 7. taylor gp. the human t-lymphotropic viruses. in : zuckerman aj, banatvala je, schoub bd, et al, editors. principles & practice of clinical virology. 6th ed. west-sussex: wiley-blackwell, 2009:875-896. 7. taylor gp. the human t-lymphotropic viruses. in : zuckerman aj, banatvala je, schoub bd, et al, editors. principles & practice of clinical virology. 6th ed. west-sussex: wiley-blackwell, 2009:875-896. 8. jogessar vb, de bruyn cc, bhigjee ai, naicker vl, bill pla, tait d. adult t-cell leukaemia/lymphoma associated with htlv-i in natal. s afr med j 1992;81(16):528-529. 8. jogessar vb, de bruyn cc, bhigjee ai, naicker vl, bill pla, tait d. adult t-cell leukaemia/lymphoma associated with htlv-i in natal. s afr med j 1992;81(16):528-529. 9. schutte c-m, townsend t, van coller r, olorunju s. comparison of htlv-associated myelopathy (ham) in hiv-positive and hiv-negative patients at a tertiary south african hospital. s afr med j 2013;103(1):43-46. [http://dx.doi.org/10.7196/samj.5298] 9. schutte c-m, townsend t, van coller r, olorunju s. comparison of htlv-associated myelopathy (ham) in hiv-positive and hiv-negative patients at a tertiary south african hospital. s afr med j 2013;103(1):43-46. [http://dx.doi.org/10.7196/samj.5298] 10. hlela c. human t cell lymphotrophic virus 1 associated infective dermatitis in kwazulu-natal south africa [dissertation]. durban: university of kwazulu-natal, 2008. 10. hlela c. human t cell lymphotrophic virus 1 associated infective dermatitis in kwazulu-natal south africa [dissertation]. durban: university of kwazulu-natal, 2008. 11. beilke ma. retroviral coinfections: hiv and htlv: taking stock of more than a quarter century of research. aids res hum retroviruses 2012;28(2):139-147. [http://dx.doi.org/10.1089/aid.2011.0342] 11. beilke ma. retroviral coinfections: hiv and htlv: taking stock of more than a quarter century of research. aids res hum retroviruses 2012;28(2):139-147. [http://dx.doi.org/10.1089/aid.2011.0342] 12. gudo se, bhatt nb, ramalho bila dr, et al. co-infection by human immunodeficiency virus type 1 (hiv-1) and human t cell leukemia virus type 1 (htlv-1): does immune activation lead to a faster progression to aids? bmc infect dis 2009;9:211. [http://dx.doi.org/10.1186/1471-2334-9-211] 12. gudo se, bhatt nb, ramalho bila dr, et al. co-infection by human immunodeficiency virus type 1 (hiv-1) and human t cell leukemia virus type 1 (htlv-1): does immune activation lead to a faster progression to aids? bmc infect dis 2009;9:211. [http://dx.doi.org/10.1186/1471-2334-9-211] 13. bhatt nb, gudo se, semá c, et al. loss of correlation between hiv viral load and cd4+ t-cell counts in hiv/ htlv-1 co-infection in treatment naïve mozambican patients. int j std aids 2009;20:863-868. [http://dx.doi.org/10.1258/ijsa.2008.008401] 13. bhatt nb, gudo se, semá c, et al. loss of correlation between hiv viral load and cd4+ t-cell counts in hiv/ htlv-1 co-infection in treatment naïve mozambican patients. int j std aids 2009;20:863-868. [http://dx.doi.org/10.1258/ijsa.2008.008401] 14. macchi b, balestrieri e, mastino a. effects of nucleoside-based antiretroviral chemotherapy on human t cell leukaemia/lymphotropic virus type 1 (htlv-1) infection in vitro. j antimicrob chemother 2003;51:1327-1330. [http://dx.doi.org/10.1093/jac/dkg240] 14. macchi b, balestrieri e, mastino a. effects of nucleoside-based antiretroviral chemotherapy on human t cell leukaemia/lymphotropic virus type 1 (htlv-1) infection in vitro. j antimicrob chemother 2003;51:1327-1330. [http://dx.doi.org/10.1093/jac/dkg240] 15. bessong po, mathomu lm. seroprevalence of htlv1/2, hsv1/2 and toxoplasma gondii among chronic hiv-1 infected individuals in rural northeastern south africa. afr j microbiol res 2010;4(23):2587-2591. 15. bessong po, mathomu lm. seroprevalence of htlv1/2, hsv1/2 and toxoplasma gondii among chronic hiv-1 infected individuals in rural northeastern south africa. afr j microbiol res 2010;4(23):2587-2591. southern african hiv clinicians society guidance references about the author(s) michelle a. moorhouse wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa sergio carmona national health laboratory services, south africa natasha davies wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa sipho dlamini department of medicine, university of cape town, south africa cloete van vuuren southern african hiv clinicians society, south africa thandekile manzini southern african hiv clinicians society, south africa moeketsi mathe private practice, vereeniging, south africa yunus moosa department of infectious diseases, university of kwazulu-natal, south africa jennifer nash southern african hiv clinicians society, south africa jeremy nel southern african hiv clinicians society, south africa yoliswa pakade southern african hiv clinicians society, south africa joana woods wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa gert van zyl southern african hiv clinicians society, south africa francesca conradie wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa francois venter wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa graeme meintjes department of medicine and institute of infectious disease and molecular medicine, university of cape town, south africa citation moorhouse ma, carmona s, davies n, et al. southern african hiv clinicians society guidance on the use of dolutegravir in first-line antiretroviral therapy. s afr j hiv med. 2018;19(1), a917. https://doi.org/10.4102/sajhivmed.v19i1.917 guidelines southern african hiv clinicians society guidance on the use of dolutegravir in first-line antiretroviral therapy michelle a. moorhouse, sergio carmona, natasha davies, sipho dlamini, cloete van vuuren, thandekile manzini, moeketsi mathe, yunus moosa, jennifer nash, jeremy nel, yoliswa pakade, joana woods, gert van zyl, francesca conradie, francois venter, graeme meintjes received: 20 sept. 2018; accepted: 20 sept. 2018; published: 17 oct. 2018 copyright: © 2018. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. the southern african hiv clinicians society would like to update all hiv-treating clinicians with regard to the use of dolutegravir in women of childbearing potential (wocp). in preliminary data from the tsepamo study in botswana, it was found that 0.94% (95% confidence interval [ci]: 0.37 – 2.4) of babies (4/426) born to women who were taking dolutegravir periconception had neural tube defects (ntds), compared with 0.1% of babies (14/11 173) of women taking other antiretroviral drugs (arvs) in the periconception period.1 no ntds were observed in pregnancies where dolutegravir was initiated later in pregnancy. further data from the tsepamo study were presented at aids 2018: the updated number of ntds with periconception dolutegravir exposure in the tsepamo cohort is 4/596, 0.67% (95% ci: 0.26 to 1.7). the next formal analysis will occur after 31 march 2019 and will include women exposed to dolutegravir from conception before the recent change in guidance. tsepamo plans to expand the number of study sites, increasing the coverage from 45% to 72% of births in botswana with a projected denominator of over 1200 by march 2019.1 prior to the data from botswana, reproductive toxicology studies had not shown any concerning findings. to date, other data on the use of dolutegravir in pregnancy, including data from the antiretroviral pregnancy registry, clinical trials and post-marketing surveillance, have not indicated a risk of ntds. the world health organization (who) launched new interim guidance on hiv treatment at aids 2018, recommending dolutegravir for everyone aged six years and above. based on limited data, who notes that there are safety concerns regarding the use of dolutegravir periconception.2 world health organization recommendations for wocp include the following: dolutegravir-based first-line antiretroviral therapy (art) is recommended for: all pregnant cent girls2,3 women and adolescent girls with effective contraception or not of childbearing potential. women and adolescent girls of childbearing potential who want to become pregnant or have no effective contraception should use efavirenz-based (600 mg) first-line art.2,3 consider the balance of benefits and risks, including fertility levels, contraceptive availability and coverage, pretreatment resistance to non-nucleoside reverse transcriptase inhibitors at the population level, drug availability and the maternal and infant toxicity profile when selecting the optimal arv drug regimen for wocp.2,3 strengthen the integration of sexual and reproductive health services within hiv treatment programmes to ensure reliable and consistent access to contraception for women and adolescent girls living with hiv.2,3 a woman-centred approach should be adopted: healthcare providers should provide women with information and options to allow for informed choices about using lifelong art regimens.2,3 southern african hiv clinicians society guidance a woman-centred approach should be adopted: healthcare providers should give women information and options to allow for informed choices about using lifelong art regimens. dolutegravir-based first-line art is recommended for: all pregnant (from eight weeks after conception) and breastfeeding women and adolescent girls women and adolescent girls on effective contraception or not of childbearing potential. women and adolescent girls of childbearing potential who want to become pregnant or have no effective contraception should be adequately counselled about the potential risks and benefits of dolutegravirversus efavirenz-based art and should be offered the choice of both treatments. this discussion should be documented, preferably along with consent from those women opting for dolutegravir-based art. if pregnancy is confirmed in the first eight weeks while a woman is taking dolutegravir, she should be adequately counselled about the potential risks and benefits of dolutegravirversus efavirenz-based art and should offered the choice of both treatments. this discussion should be documented, preferably along with consent from those women opting for dolutegravir-based art. the risk and benefits of switching during pregnancy should also be discussed. switching is associated with a small risk of viraemia in a previously virologically suppressed patient, which may result in risk of mother-to-child transmission and resistance. while this is an early signal, it warrants careful pharmacovigilance and further evaluation. as more information becomes available, we will update our guidance. references zash r, holmes l, makhema j, diseko m, jacobson dl, mayondi g, et al. surveillance for neural tube defects following antiretroviral exposure from conception, the tsepamo study (botswana). aids 2018. 2018 jul 23–27. symposium session tusy1. who. what’s new in who treatment guidelines: the role of dolutegravir in firstand second-line and new directions in early infant diagnosis. session mosa26. who policy brief. antiretroviral regimens for treating and preventing hiv infection and update on early infant diagnosis of hiv [homepage on the internet]. july 2018 [cited]. available from: http://apps.who.int/iris/bitstream/handle/10665/273129/who-cds-hiv-18.19-eng.pdf abstract introduction methodology ethical consideration results the participants were also asked to make recommendations discussion conclusion acknowledgements references about the author(s) taurayi a. tafuma fhi 360, zimbabwe nyikadzino mahachi fhi 360, zimbabwe chengetai dziwa fhi 360, zimbabwe tafara moga fhi 360, zimbabwe paul baloyi fhi 360, zimbabwe gladys muyambo plan international, zimbabwe auxilia muchedzi fhi 360, zimbabwe tinashe chimbidzikai fhi 360, zimbabwe getrude ncube ministry of health and child care, zimbabwe joseph murungu ministry of health and child care, zimbabwe tendai nyagura united states agency for international development, zimbabwe katherine lew fhi 360, zimbabwe citation tafuma ta, mahachi n, dziwa c, et al. barriers to hiv service utilisation by people living with hiv in two provinces of zimbabwe: results from 2016 baseline assessment. s afr j hiv med. 2018;19(1), a721. https://doi.org/10.4102/sajhivmed.v19i1.721 original research barriers to hiv service utilisation by people living with hiv in two provinces of zimbabwe: results from 2016 baseline assessment taurayi a. tafuma, nyikadzino mahachi, chengetai dziwa, tafara moga, paul baloyi, gladys muyambo, auxilia muchedzi, tinashe chimbidzikai, getrude ncube, joseph murungu, tendai nyagura, katherine lew received: 13 jan. 2017; accepted: 07 june 2018; published: 09 aug. 2018 copyright: © 2018. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the emergence of antiretroviral therapy (art) transformed hiv from a terminal illness to a chronic disease. however, limited access to health services remains one of many barriers to hiv service utilisation by people living with hiv (plhiv) in low-resource settings. the goal of this study was to describe the barriers to hiv service utilisation in two provinces of zimbabwe. methods: a qualitative descriptive study was conducted with plhiv and village health workers (vhw) in eight districts within the two provinces. convenience sampling was used to select the participants. this sampling was limited to communities supported by health facilities with more than 500 plhiv enrolled into hiv care and treatment. interviews were audio-recorded and transcripts were subjected to thematic content analysis. results: a total of 22 community focus group discussions (fgds) were conducted. barriers to using hiv services cited in plhiv and vhw fgds were similar. these were categorised as health system-related barriers, which include user fees, long waiting times, lack of confidentiality and negative attitudes by healthcare providers, and lack of consistent community-based hiv services. community-related barriers cited were stigma and discrimination, food insecurity, distance to facilities and counterproductive messaging from religious sectors. client-related factors reported were inadequate male involvement in hiv-related activities and defaulting after symptoms improved. conclusion: our assessment has indicated that there are several barriers to the utilisation of hiv services by plhiv in the two provinces of zimbabwe. as new strategies and programmes are being introduced in the current resource-constrained era, efforts should be made to understand the needs of the clients. if programmes are designed with an effort to address some of these challenges, there is a possibility that countries will quickly achieve the 90-90-90 targets set by the joint united nations programme on hiv/aids. introduction an effective community human immunodeficiency virus (hiv) response requires coordination and synergy among actors supporting hiv testing and treatment services, provision of compassionate care for people living with hiv (plhiv), open and non-stigmatising discussions of hiv and concrete strategies to prevent new infections.1 however, with limited access to health services in low-resource settings, communities are not mounting a sufficient response. it has been noted that limited access to health services is recognised as one of the greatest barriers to entry into the healthcare system, hindering hiv testing, treatment and care.2 in areas where services are available plhiv are faced with economic, geographic and social barriers to access those services. this array of setting-specific challenges resulted in the global burden of hiv being unevenly distributed, with sub-saharan africa having the greatest share.3,4 it has become imperative that efforts be made to have healthcare systems evolve and focus on providing patient-centred and high-value care. research has shown that most patients prefer to be involved in medical decisions,5 which should include programming of their services. involving clients in programming begins with developing an understanding of their needs and assessing barriers to the availed services. advances in antiretroviral therapy (art) transformed hiv from a terminal illness to a chronic disease6,7 and resulted in significant decreases in hiv-related morbidity and mortality. in zimbabwe, where there are approximately 1.4 million plhiv, hiv services have been decentralised to increase accessibility for people.8 by june 2015 approximately 842 372 (60%) of plhiv were on art and 94% of health facilities were offering art services.8 despite the massive scale-up in national hiv testing programmes, studies suggest that up to 80% of hiv-infected adults do not know their status in some sub-saharan african settings and only 47% of adults who are eligible are accessing art, although rates vary substantially by country.9 there are many factors that can possibly explain these gaps, and currently most studies on the hiv cascade have been focused on clinic-level data.10 community-level interventions are believed to create an enabling environment for the utilisation of hiv services.10 zimbabwe was one of the first african countries to implement the holistic primary healthcare approach, which was adopted at the alma ata conference of 1978 through the introduction of the village health worker (vhw) programme in 1981.11 a number of improvements have been made to this programme since then as a way of positioning communities to contribute meaningfully in the provision of healthcare, disease prevention and promotion of health and well-being.11 zimbabwe, in its national strategic hiv and aids plan iii (2015–2018),12 recognised that strengthening community participation ensures high standards of transparency, accountability of health service management and community ownership. however, to date, community system engagement and strengthening has been limited. literature reports that most countries’ community response has not been sufficiently defined and prioritised, resulting in lack of cohesion and funding.10 ultimately, this has contributed to the underutilisation of hiv services by plhiv. in order to address some of these gaps in service utilisation, the us agency for international development (zimbabwe) funded fhi 360 for the five-year zimbabwe hiv care and treatment (zhct) project. the main goals of the project are (1) to increase the availability of quality comprehensive care and treatment services for plhiv at community level and (2) to strengthen community-level health systems to monitor, track and maintain plhiv in care. understanding community-level factors in hiv care and treatment contributes to the larger effort in designing multilevel, effective and sustainable programmes and interventions for hiv epidemic control.10 we present here the qualitative findings from a baseline assessment that was designed to determine the barriers to hiv service utilisation by plhiv in eight districts in two provinces of zimbabwe. methodology this was a qualitative descriptive study design that used focus group discussions (fgds) with plhiv and vhws. the study targeted eight districts in manicaland and midlands provinces in zimbabwe, where fhi 360 was to implement the zhct project. these districts have high numbers of plhiv (17 500–34 000) and the hiv prevalence among adults (15–49 years) is in the range of 9% – 20%. the provincial hiv prevalence among adults (15–49 years) in manicaland and midlands is 11% and 15.5%, respectively.13 overall, manicaland province has the largest population of plhiv14 in zimbabwe. convenience sampling was used to select participants for the fgds and limited to communities supported by health facilities with more than 500 plhiv enrolled into hiv care and treatment. plhiv and vhws were grouped into separate fgds. this was to ensure that more fgds were conducted in districts with more clients on art. data were collected from may to june 2016. village health workers (vhw) are the community-based cadres who coordinate activities related to health at village level and act as conduits into formal clinic-based care.11 plhiv are individuals who are receiving hiv services (art or pre-art services) from the selected facilities. participant recruitment was limited to clients 18 years and above and coordinated by field supervisors and representatives of facilities. field supervisors approached selected facilities and informed facility representatives (nurse-in-charge) about the study. plhiv were then informed of the study at the time of drug collection or review and those interested had their names documented as potential participants. vhws who support facilities of interest were also informed about the study during their daily activities. the potential participants were then later contacted by field supervisors. at this stage, these participants were given detailed information describing the purpose of the research, confidentiality and the right to refuse to participate. appointments were then set for the fgds. interviewers explored the existence of stigma and discrimination against plhiv, existence of supporting services at community level and barriers and facilitators to accessing hiv services for plhiv. as for the vhws, we explored the perceived attitude of the community towards them, relations with health facilities and perceived barriers and facilitators in the uptake of hiv services by plhiv. interviewers and field supervisors were trained on how to recruit and obtain consent from prospective participants and how to conduct fgds. a total of eight interviewers were recruited, with four of them being males. all of them had experience in conducting fgds and they had gone through the ethical training under fhi 360. in addition, the field supervisors were trained on organising, coordinating and supervising data collection activities in their respective sites, including data verification and how to remotely transfer data from their site to the provincial and central office. a pretest of the data collection tools was conducted in a district that was not under assessment. a total of 22 fgds, each with 6–12 participants, were conducted (out of 24 planned). the distribution of fgds was based on the number of facilities in a district with more than 500 plhiv on art per district. if more than 50% of the facilities in a district had more than 500 plhiv, they were assigned four fgds while those with below 50% were assigned two fgds. the fgds were conducted in quiet and discreet locations, often a vacant community hall or open space where community gatherings were usually held. these were places that were agreed on by the participants. data analysis was performed manually by three fhi 360 researchers, two from the zimbabwe office and one from headquarters. data from the fgds were translated and transcribed by the interviewers from shona and ndebele to english. transcripts were verified to ensure headings and content were correct. this included multiple readings of the transcripts developed to capture context and meaning, followed by coding and categorisation of recurring concepts and ideas. data verification was done by a third researcher from headquarters, who also coded all transcripts. codes were compared and added or removed based on the agreement between analysts. once data were translated, transcribed and verified, audio recordings were deleted from the recording devices and hardand soft-copy transcripts were stored securely and safely in lockable cabinets and on password-protected computers. common themes were analysed using content analysis, grouped and quantified according to the volume of similar responses. no repeat interviews were carried out. utilisation of hiv services in this case included uptake of hiv testing to staying on art while participating in other community-related hiv activities such as advocacy, health promotion and education. ethical consideration ethical approval was granted by the medical research council of zimbabwe (mrcz) and fhi 360 institutional review board (irb). the study was conducted in compliance with protocol after permission was obtained from the ministry of health and child care (mohcc). further fieldwork clearance was sought from relevant local authorities and leadership at district level. results a total of 22 fgds were conducted in eight districts, 10 with vhws and 12 with plhiv. a total of 106 plhiv and 96 vhws took part in the fgds. most (68%) of plhiv who participated were women and the average age was 43 years (s.d. 10 years). similarly, most of the vhws were female (73%). the average age for vhws was 43 years (s.d. 9 years). the perceived barriers reported by participants were categorised under the following three broad themes: barriers related to the health system; barriers related to clients; barriers in the broader community (these are issues experienced outside health facilities and are perpetuated by members in the community or experienced at community level where people live); and other barriers. the barriers described below were those reported most frequently. health system-related barriers user fees at health facilities: participants in all districts felt that there was no good justification for payment of user fees at different levels of service provision. this was raised by the plhiv fgd: ‘.… at clinic, one has to pay and pays again at referral hospital. what is the justification for these charges?’ (plhiv fgd) long waiting times at health facilities: this was mentioned across all districts and was attributed to inadequate staffing, poor attitudes from healthcare providers and complicated referral processes within health facilities: ‘nurses spend time socialising during working hours.’ (plhiv fgd) ‘some clients might give up accessing services after waiting so long before being served at health facilities.’ (vhw fgd) lack of community-based hiv services: this was mentioned in six districts, and plhiv’s comments focused on vhws being too busy or not active in some communities while vhw highlighted challenges with their voluntary work: ‘vhws … should be monitored so that they provide their services. they also have multiple roles in the community, compromising the quality of their work.’ (plhiv fgd) ‘they [vhws] are not mobile and don’t come to us; if we want a service we go to their residence. we need them to visit us.’ (plhiv fgd) ‘we were given bicycles and scales and they have long since stopped working … we are not paid incentives on time.’ (vhw fgd) vhws indicated that the nature of their work was mainly voluntary; hence they were less prioritised by authorities when payments and resupplies were being made. in one of the districts, respondents complained about the lack of incentives, airtime and transport, which made it difficult to perform their duties. this also contributed to the vhw programme having fewer males: ‘the lack of incentives is a barrier to attracting more men to be vhws.’ (vhw fgd) bad attitude by healthcare providers: nurses were singled out as having bad attitudes in all districts: ‘at clinics/hospitals that’s where all the stigma exists because nurses have attitudes; that’s why you will find some people will collect their pills from facilities away from their places.’ (plhiv fgd) however, not all were in agreement that nurses in some districts had bad attitudes: ‘there has been improvement in services and the way they treat us.’ (plhiv fgd) client-related barriers inadequate male involvement in hiv-related activities: findings from both groups of fdgs were consistent on why men were less involved in hiv activities and were reported in all districts: ‘men don’t participate … they are busy at work; they take time to accept their status; they only seek treatment when very sick; men just don’t like to be gathered around without financial benefit.’ (plhiv fgd) ‘some men are not accommodative; they feel male vhws are lazy to work and thus opt for a female job.’ (vhw fgd) defaulting after feeling better: plhiv reported that there were some individuals who would stop art when they improved and this was reported in five districts: ‘people tend to relax after their health improves.’ (plhiv fgd) distance to health facilities: the challenge of clients accessing care because of distance and related costs (transport) were mentioned in four districts, and this was also highlighted even if community hiv testing was provided: ‘if a person tests positive in the community and is far from health facilities, the linkage to care will be a challenge due to transport needs.’ (vhw fgd) lack of trust: it takes time for vhws to establish themselves as a trusted cadre within the communities. some community members were afraid that vhws would disclose their health problems to the community. this resulted in vhws being abused by some of the community members: ‘… we are verbally abused by those who do not want to disclose that you are the ones who are going to disclose our status to others.’ (vhw fgd) some mentioned that the behaviour of some of the vhws was very bad, resulting in them not being trusted: ‘… their work is put into disrepute by some of their colleagues who display bad behaviour in the community, e.g. husband snatching, drunkenness, dishonesty.’ (plhiv fgd) community-related barriers roles of religious leaders and traditional healers: counterproductive messaging was mentioned in six districts, with traditional or religious healers often convincing plhiv that they do not need art to manage hiv. messages from religious leaders have been counterproductive to the efforts made by the ministry of health and child care (mohcc) in managing hiv. the ‘white garment’ churches were singled out for this practice in two of the fgds: ‘churches are also causing followers to default, saying they have prayed for you and you have been healed.’ (plhiv fgd) ‘others go to prophets and replace their medication with anointed water from prophets.’ (plhiv fgd) ‘we still have some members of white garment churches who are resistant; most members in those families died.’ (vhw fgd) in some cases, people also opt for traditional medicine, rather than modern medicine, believing their hiv infection is a curse: ‘there are still people out there who believe that being hiv positive is a curse and would consult a traditional healer.’ (plhiv fgd) stigma and discrimination in the community: community-level stigma was listed as an important barrier to better treatment outcomes in five districts. plhiv are still seen as unfaithful and are subjected to name-calling, particularly at social events: ‘people in the community pass negative comments once they found that one is hiv positive, and [this] is common at gatherings such as funerals and churches.’ (plhiv fgd) ‘… we [vhws] are verbally abused by plhiv who feel that we disclose their hiv status to the community.’ (vhw fgd) and, worryingly, respondents made a direct link between stigma and art adherence: ‘stigma still exists here, causing people not to go to collect their medications because they don’t want to be known.’ (plhiv fgd) food insecurity: food insecurity was mentioned in four districts, and this was mainly linked to the recent drought that zimbabwe experienced. lack of food was directly linked to art adherence: ‘they also require food since they are supposed to take their drugs after they have eaten something.’ (plhiv fgd) other barriers negative attitudes towards vhws: the vhws mentioned that they were sometimes accused of stealing drugs, pressurising people too much to complete referrals and suspected of having intentions other than providing health education. this was raised in five districts: ‘people in the community give the impression that the health workers are out there to bother people and disturb them.’ (vhw fgd) ‘our worst thing is that people talk bad about us if they find out that we don’t have the resources to assist them.’ (vhw fgd) men as barriers: there were many instances where men were highlighted as a significant barrier, especially within the families: ‘my husband gave me hiv and he did not want to get tested until he died. he was arrogant about getting tested. men have a big problem and they want to keep on spreading hiv.’ (plhiv fgd) ‘… we as females we are always complaining that our partners do not want to use protection when having sex even when they know they are positive.’ (plhiv fgd) ‘the men do not want to visit clinics; this makes it difficult for women to disclose to their husbands … when they tell their husbands they are positive, at times they are blamed.’ (vhw fgd) the participants were also asked to make recommendations village health workers recommended that a system should be developed so that there is improved coordination between health facility staff and vhws. facilities should routinely share review dates with vhws and they should give clients referred from vhws first preference. giving preference to referred clients might improve men’s participation in hiv services: ‘men do not want to be kept waiting for long hours … and they do not want empty promises.’ (vhw fgd) in addition, vhws proposed availing food handouts to clients taking arvs. this was also highlighted in the plhiv fgds: ‘… use the previous strategy where positives are enrolled and get food; this could promote men’s attendance.’ (plhiv fgd) ‘people with hiv need food. we might lose many of them if help does not come.’ (vhw fgd) other recommendations were that x-rays for tb should be free for art clients; user fees upon art refills should also be removed; and health facilities, especially clinics, should have more nurses who are empathetic to clients. to improve male involvement in support groups, plhiv suggested that these groups should carry out income-generating projects such as raising poultry. however, they suggested that these projects should be suggested by people themselves, rather than being dictated: ‘… mostly they would want to work for their families and hence can be lured into groups if there are opportunities for fundraising.’ (plhiv fgd) ‘income-generating projects should be decided by the people themselves and not dictated.’ (plhiv fgd) discussion the above findings describe the perceived barriers to utilisation of hiv services in manicaland and midlands provinces. findings from this assessment provide more information to programmes designed to provide hiv services at community level and strengthening facilitators currently existing with facility-based services. long waiting times at health facilities and the negative attitudes of healthcare providers highlighted above generally reflect the human resource constraints pervasive in busy art clinics in sub-saharan africa.15 long waiting times have been mentioned as a key driver in the attrition of clients on art.16 also of note is that competing activities such as work and social life among clients seeking medical attention tend to interfere with time spent queuing in overburdened health facilities. introduction of flexible working hours is likely to improve uptake of services as has been noted in other studies.17 although zimbabwe has decentralised hiv services, user fees at some facilities are still a barrier to service utilisation, especially with the current economic challenges. plhiv are likely to travel longer distances to access free services but this is not sustainable, as has been indicated in other settings.2,18 community hiv services will address issues of long distances travelled by clients to access services and also decongest health facilities, resulting in shorter waiting times. our finding of a negative attitude among healthcare workers towards plhiv is consistent with other studies and is associated with non-enrolment into care.17 considering the sparsity of health services in rural areas of most of sub-saharan africa2 there is need to train health personnel in the importance of empathy towards patients, as well as engaging patients as partners in the hiv care process. this will enable plhiv to visit their nearest facilities whenever they need hiv services and might indirectly improve adherence to treatment. overall, this will help the country to achieve the second and third 90s of the joint united nations programme on hiv/aids (unaids) targets. studies have shown that stigma is often measured at the individual level but it is a social construct that manifests itself at the community level.10,17 generally, stigma has been associated with poor utilisation of hiv services10 and this was highlighted in five districts in this study. fear of gossip and being called names results in plhiv avoiding hiv services as well as disclosing. this has been reported to be prominent in several countries,10,17 and in zimbabwe there are individuals who cannot confide to vhws. interestingly, underwood et al.10 cited a study where stigma was a motivator of adherence as plhiv took their medications to avoid a sickly appearance, which might draw community attention. however, stigma and discrimination should be discouraged regardless of this finding. the fear of hiv disclosure among women, especially to their husbands, as highlighted, could be because of poor appreciation and utilisation of hiv services by males in these communities. a gender-balanced vhw programme would allow more males to be reached by their counterparts. zimbabwe has embarked on couple testing and counselling also as a mitigating factor to this. however, its impact needs to be continuously assessed. with the introduction of household hiv index case testing in zimbabwe, there is hope of strengthening disclosure of hiv status within households and improving utilisation of hiv services by all, as has been noticed in other studies.17,19 overall, it is important to support strategies that address men’s challenges to access health services. the reports from the fgds that hiv spiritual healing is seen as a better alternative to medical management is not unique to these two provinces in zimbabwe. studies have shown that, at community level, religious organisations are influential social networks that have the power to support or stigmatise plhiv and endorse or reject medical treatment of hiv.20,21 a study in uganda noted that a few (1.2%) individuals discontinued their art because they believed that their pastors’ prayers had cured them of hiv.20 our findings were not quantified, hence we recommend quantitative studies to determine the impact of these counterproductive messages from religious sects. manzou et al.21 highlighted the need for hiv programmes to strengthen collaboration with religious institutions so that appropriate messages are shared with plhiv. laws should be enacted to apprehend religious leaders who propagate spiritual healing of hiv. our participants made some important recommendations that could help address some of the gaps. there is need to increase collaboration between income-generating projects and hiv programmes so that men can be involved in hiv service provision. food handouts for clients on art was also suggested, although it had no effect on art adherence in mozambique.22 however, this could be different in zimbabwe because of the current economic challenges. user fees at facilities should be removed for all hiv-related services. most fgds highlighted the need for personnel providing hiv care services to be trained in the importance of empathy towards plhiv. limitations there are a number of limitations in our findings, including the fact that fgds are known to elicit more views from verbal participants than shy ones. however, our teams were trained to moderate the discussions so as to mitigate this challenge. recruitment of participants was done from sites with more than 500 plhiv, and these were conveniently sampled from those already visiting health facilities, hence our results cannot be generalised. these clients might not have reported all barriers to accessing services, as they were receiving them at the time of recruitment. furthermore, the age of the participants was high and we could have missed valuable information from the younger age groups. while we have made all attempts to maintain the integrity of our data, it is possible that some words or phrases were incorrectly translated, though we believe the substantive viewpoints were correctly inferred. one major strength of our assessment is that it highlights barriers perceived by the clients, who are the plhiv, as well as their supportive cadres at community level. conclusion our assessment has indicated that there are several barriers to the utilisation of hiv services by plhiv in the two provinces of zimbabwe. as new strategies and programmes are being introduced in the current resource-constrained era, efforts should be made to understand the needs of the clients. this will help in providing client-centred services. although the barriers highlighted above could not be generalised, we have confidence that these are likely to be experienced across the country, as they were frequently cited in other settings. as such we recommend that mohcc find ways to be responsive to the needs of plhiv while improving the services of vhws as conduits between communities and health facilities. acknowledgements the authors would like to thank all the participants who took part in the fgds. disclaimer: this study was made possible through the support of the american people through the united states agency for international development (usaid). the contents are the sole responsibility of the authors and do not necessarily reflect the views of usaid or the us government. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions t.a.t. led in the study concept and design and developed the manuscript. c.d., t.m., p.b. and g.m. were responsible for the data acquisition and management. k.l. and n.m. assisted with the critical revision of the manuscript for important intellectual content. a.m., t.c., t.n. and g.n. assisted with proofreading and interpretation of the data. all authors have read and approved the final version of the manuscript. references campbell c, nhamo m, scott k, et al. the role of community conversations in facilitating local hiv competence: case study from rural zimbabwe. bmc public health. 2013;13:354. https://doi.org/10.1186/1471-2458-13-354 akullian an, mukose a, levine ga, babigumira jb. people living with hiv travel farther to access healthcare: a population-based geographic analysis from rural uganda. j int aids soc. 2016;19:20171. https://doi.org/10.7448/ias.19.1.20171 takah nf, awungafac g, aminde ln, et al. delayed entry into hiv care after diagnosis in two specialized care and treatment centres in cameroon: the influence of cd4 count and who staging. bmc public health. 2016;16:529. https://doi.org/10.1186/s12889-016-3258-8 katza it, essienc t, marindad et, et al. antiretroviral refusal among newly diagnosed hiv-infected adults in soweto, south africa. aids. 2011;25(17):2177–2181. https://doi.org/10.1097/qad.0b013e32834b6464 brabers am, de jong jd, groenewegen pp, van dijk l. social support plays a role in the attitude that people have towards taking an active role in medical decision-making. bmc health serv res. 2016;16:502. https://doi.org/10.1186/s12913-016-1767-x sayles jn, wong md, kinsler jj, martins d, cunningham we. the association of stigma with self-reported access to medical care and antiretroviral therapy adherence in persons living with hiv/aids. j gen intern med. 2009;24(10):1101–1108. https://doi.org/10.1007/s11606-009-1068-8 scanlon ml, vreeman rc. current strategies for improving access and adherence to antiretroviral therapies in resource-limited settings. hiv/aids. 2013;5:1–17. https://doi.org/10.2147/hiv.s28912 ministry of health and child care (mohcc). national anti-retroviral therapy program data. mohcc, government of zimbabwe (goz); 2015. world health organization. global hiv/aids response: epidemic update and health sector progress towards universal access – progress report 2011. geneva: world health organization; 2011. underwood c, hendrickson z, van lith lm, et al. role of community-level factors across the treatment cascade: a critical review. j acquir immune defic syndr. 2014;66:s311–s318. https://doi.org/10.1097/qai.0000000000000234 ministry of health and child care (mohcc). the village health worker strategic direction. mohcc, government of zimbabwe (goz); 2010. national aids council (nac) and ministry of health and child care (mohcc). zimbabwe national hiv and aids strategic plan 2015–2018. commitment towards fast tracking ending aids by 2030. mohcc, nac, government of zimbabwe (goz); 2015. zimbabwe national statistics agency and icf international. 2015 zimbabwe demographic and health survey: key findings. rockville, md: zimstat and icf international; 2015. ministry of health and child care (mohcc). hiv estimates 20151. government of zimbabwe (goz); 2015. duff p, kipp w, wild tc, et al. barriers to accessing highly active antiretroviral therapy by hiv-positive women attending an antenatal clinic in a regional hospital in western uganda. j int aids soc. 2010;13:37. https://doi.org/10.1186/1758-2652-13-37 decrooa t, rasschaert f, telfera b, et al. community-based antiretroviral therapy programs can overcome barriers to retention of patients and decongest health services in sub-saharan africa: a systematic review. int health. 2013;5:169–179. https://doi.org/10.1093/inthealth/iht016 nakigozi g, atuyambe l, kamya m, et al. a qualitative study of barriers to enrollment into free hiv care: perspectives of never-in-care hiv-positive patients and providers in rakai, uganda. biomed res int. 2013:470245. https://doi.org/10.1155/2013/470245 gore o, makananga f, muza c, et al. the role of village health workers and challenges faced in providing primary health care in mutoko and mudzi districts in zimbabwe. gjbahs. 2015;4(1):129–135. chimoyi l, tshuma n, muloongo k, et al. hiv-related knowledge, perceptions, attitudes, and utilisation of hiv counselling and testing: a venue-based intercept commuter population survey in the inner city of johannesburg, south africa. glob health action. 2015;8:26950. https://doi.org/10.3402/gha.v8.26950 wanyama j, castelnuovo b, wandera b, et al. belief in divine healing can be a barrier to antiretroviral therapy adherence in uganda. aids. 2007;21:1486–1487. https://doi.org/10.1097/qad.0b013e32823ecf7f manzou r, schumacher c, gregson s. temporal dynamics of religion as a determinant of hiv infection in east zimbabwe: a serial cross-sectional analysis. plos one. 2014;9(1):e86060. https://doi.org/10.1371/journal.pone.0086060 posse m, tirivayi n, saha ur, baltussen r. the effect of food assistance on adherence to antiretroviral therapy among hiv/aids patients in sofala province, in mozambique: a retrospective study. j aids clin res. 2013;4:198. https://doi.org/10.4172/2155-6113.100198 abstract introduction methods results discussion acknowledgements references appendix 1 about the author(s) charlotte schutz wellcome centre for infectious diseases research in africa (cidri-africa), institute of infectious disease and molecular medicine (idm) and department of medicine, university of cape town, cape town, south africa amy ward wellcome centre for infectious diseases research in africa (cidri-africa), institute of infectious disease and molecular medicine (idm) and department of medicine, university of cape town, cape town, south africa rosie burton gf jooste hospital; department of medicine, university of cape town, cape town, south africa mark p. nicol division of medical microbiology, university of cape town and national health laboratory services, cape town, south africa liz blumenthal wellcome centre for infectious diseases research in africa (cidri-africa), institute of infectious disease and molecular medicine (idm) and department of medicine, university of cape town, cape town, south africa graeme meintjes wellcome centre for infectious diseases research in africa (cidri-africa), institute of infectious disease and molecular medicine (idm) and department of medicine, university of cape town, cape town, south africa andrew d. kerkhoff division of hiv, infectious diseases and global medicine at zuckerberg san francisco general hospital and trauma center, department of medicine, university of california, san francisco, united states citation schutz c, ward a, burton r, et al. false rifampicin resistant results using xpert mtb/rif on urine samples in hospitalised hiv-infected patients. s afr j hiv med. 2019;20(1), a978. https://doi.org/10.4102/sajhivmed.v20i1.978 original research false rifampicin resistant results using xpert mtb/rif on urine samples in hospitalised hiv-infected patients charlotte schutz, amy ward, rosie burton, mark p. nicol, liz blumenthal, graeme meintjes, andrew d. kerkhoff received: 05 apr. 2019; accepted: 24 may 2019; published: 28 aug. 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: a small proportion of false rifampicin resistant results have previously been reported using genexpert mtb/rif version g4 on sputum samples; however, this has not been investigated for urine samples in hiv-associated tuberculosis (tb). objectives: we sought to determine the proportion of false rifampicin resistant results using xpert mtb/rif version g4 on urine samples among hiv-infected inpatients investigated for tb. methods: hospitalised hiv-infected patients undergoing systematic tb testing from two cohorts in cape town, south africa, were enrolled. all patients with ≥1 urine xpert result available were included. rifampicin resistant urine xpert results were classified into three mutually exclusive groups: (1) true rifampicin resistance, (2) false rifampicin resistance or (3) unknown after review of available microbiologic and clinical data. results: overall, 1171 patients were included, from whom a total of 1704 urine xpert results were available on unconcentrated and/or concentrated urine samples. there were 416 samples positive for tb (24.4% [95% ci 22.4–26.5]), of which 43/413 (10.4% [95% ci 7.6–13.8]) were rifampicin resistant (after excluding three results that were falsely positive due to contamination). of 43 rifampicin resistant xpert results (among 40 patients), 30 were classified as true resistance, 11 as false resistance and 2 could not be classified. excluding unclassifiable results, 30/41 results were confirmed as true-positive urine xpert rifampicin resistance (positive predictive value: 73.2% [95% ci 57.1–85.8]). conclusion: urine xpert testing showed a high proportion of false rifampicin resistance results. urine xpert rifampicin resistant results should be interpreted cautiously and confirmed when possible. keywords: hiv; aids; tuberculosis; xpert; rifampicin resistance; false resistance. introduction tuberculosis (tb) remains the leading cause of death in people living with hiv, contributing to one-in-three aids-related deaths.1 timely diagnosis of tb in such patients remains challenging because of non-specific presentations and disseminated disease.2,3,4 gene xpert mtb/rif, an automated nucleic acid amplification test, is capable of providing results in a few hours and represents an important breakthrough for diagnosing hiv-associated tb. importantly, xpert also rapidly detects rifampicin resistance, without need for an additional sample or cartridges. it has been endorsed by the world health organization (who) since 2010. sputum xpert (or xpert ultra where available) is currently recommended by the who as the initial diagnostic test in patients with suspected hiv-associated tb or multi-drug resistant (mdr) tb.5 in those with microbiologically confirmed tb, xpert mtb/rif is also recommended by the who as a first-line assay for the rapid detection of rifampicin-resistance. it is therefore an important tool in tackling the growing global health challenge of drug resistant (dr)-tb. however, the who does not currently have a recommendation regarding the use of xpert mtb/rif in urine owing to an insufficient amount of data on the performance and utility of this assay in urine specimens.6 in concordance with who guidelines, sputum xpert was implemented as the initial diagnostic evaluation in those with suspected tb and dr-tb in south africa as well as other countries7 and in south africa, it has now been replaced with the updated xpert ultra cartridge. although xpert has not been associated with a mortality reduction in most trials to date,8,9,10 its implementation has been associated with overall shorter times to starting anti-tb therapy, including dr tb.8,11,12,13 it has also increased the diagnostic yield by 1.4% – 15% (compared to sputum microscopy) in clinical trials in sub-saharan africa, brazil and indonesia. 8,9,10,11,13,14,15,16 against the backdrop of improved case detection, previous studies have reported on false rifampicin resistance results associated with the xpert mtb/rif assay, and meta-analyses found the overall specificity of the xpert for rifampicin-resistance in sputum samples to be 98% (i.e. 2% showed false rifampicin resistant results) and 99% in extra-pulmonary samples.17,18 this however appeared to be associated in part with earlier xpert cartridge generations.19 an implementation study from south africa found the xpert g4 cartridge to have excellent positive predictive value for rifampicin resistance of 99.5% (95% ci 98.5–100) in sputum samples.20 we have previously found that among hiv-patients requiring acute medical hospitalisation, testing of a single concentrated urine sample detected 2.2 times more tb cases than sputum xpert testing, largely because of the inability of sick inpatients to produce a sputum sample.21 additionally, a recent randomised, multi-country trial found that the addition of rapid urine-based assays (including urine xpert) to sputum xpert testing was associated with reduced mortality among hospitalised hiv-infected patients in sub-group analyses.22 this suggests that urine-based testing using xpert may have an important role in the tb diagnostic algorithm among hospitalised patients with advanced hiv, especially those too ill to produce a sputum sample. however, the proportion of false-positive rifampicin resistance results using xpert on urine samples has not been reported. we sought to determine the proportion of urine xpert false rifampicin resistance results among hospitalised hiv-infected patients being investigated for hiv-associated tb in cape town, south africa. methods patients and setting patients from two parent cohort studies were included. in the first, patients were recruited at gf jooste hospital, south africa from june 2012 to october 2013. unselected hiv-infected patients admitted to the medical wards were recruited within 24 h of admission, regardless of tb treatment at the time of admission.21,23 gf jooste hospital was closed at the end of 2013 and two new hospitals (including khayelitsha hospital) were opened serving the same communities at the time the second study was conducted. the second study was undertaken at khayelitsha hospital from january 2014 until october 2016 and recruited hiv-infected patients with a low cd4 t-cell count (< 350 cells/µl) admitted to hospital with a suspected new diagnosis of tb. patients already on tb treatment were excluded from this study. sputum, blood and urine samples were systematically obtained (when possible) as part of both study protocols and submitted for mycobacteriology (tb culture and/or xpert). information about any additional specimens, that were clinically indicated and collected by the medical teams were also recorded – for example, lymph node aspirates, cerebrospinal fluid tb cultures, pleural tb cultures and urine tb cultures. in the first study, two cases of false urine rifampicin resistance occurred 3 months after study initiation (appendix table 1-a1 – patients jtbs097 & jtbs099). both patients’ urine xpert samples were collected after a sample was taken from an mdr patient earlier on the same day. it was determined that both samples were likely contaminated due to inadequate cleaning of the reusable bedpan, although laboratory cross-contamination could not be ruled out. we subsequently introduced single-use disposable bed pans (litha healthcare group, johannesburg, south africa) and these were used for the remainder of the jooste hospital tb study and the duration of the khayelitsha hospital tb study. there were no repeat episodes of suspected cross-contamination. urine was transferred to a polypropylene tube using a sterile syringe. patients from both cohort studies had urine xpert testing performed. demographic details and clinical symptoms were recorded for all patients at study entry. patients were managed by the hospital and clinic staff, and all tb diagnostic test results were made available by study staff and could be utilised to inform patient care. laboratory methods urine xpert testing for both studies was performed at the groote schuur hospital national health laboratory service laboratory using xpert mtb/rif assay g4 version 5. all specimens were processed using standardised protocols and quality assurance procedures as previously described.24 in brief, for the gf jooste hospital study, xpert testing of urine samples was conducted in two ways on each sample. the first method (unconcentrated) utilised 2.0 ml of fresh urine that was centrifuged, resuspended in 0.75 ml phosphate buffer and then tested using xpert.25 the second method (concentrated) used a 30 ml – 40 ml urine sample that was centrifuged at 3000 g for 15 min. the resultant supernatant was removed and the pellet was resuspended in the residual urine volume (without the addition a phosphate buffer); 0.75 ml was then tested using xpert.21 for both methods, xpert sample reagent (1.5 ml) was added to the samples as per manufacturer’s instructions. the khayelitsha hospital study only used xpert testing on concentrated urine samples and was undertaken using the same methods as described above. the reference standard for drug resistance, including rifampicin resistance for both studies, was a molecular line probe assay (mtbdr plus; hain lifescience nehren, germany) undertaken on culture isolates from any clinical specimen (not necessarily urine). analysis patient populations were from overlapping referral areas in the cape town townships and both cohorts included hiv-infected patients requiring medical admission and had detailed tb investigations performed. urine xpert rifampicin resistance results were classified by two authors independently by first assessing all available microbiological results (including culture, xpert and line probe assay) on all clinical samples. in cases where it was not possible to classify urine xpert rifampicin resistance results by assessing microbiological results from other clinical samples, the type of tb treatment, response to treatment and vital status at 12 weeks were also considered. all patients with urine xpert rifampicin resistant results were assigned to one of the three mutually exclusive groups: (1) true rifampicin resistant urine xpert (patients who had rifampicin-resistant tb confirmed by culture or xpert on other clinical samples) (2) false rifampicin resistant urine xpert (patients who did not have rifampicin-resistant tb present on additional clinical samples and had a clinical course that was not compatible with drug-resistant tb), (3) unknown (insufficient microbiological and clinical evidence to classify a patient’s urine xpert rifampicin resistant result). furthermore, patients with true urine xpert rifampicin resistance were classified as having heteroresistance if additional independent sample/s from the same clinical episode demonstrated both a rifampicin-susceptible and a rifampicin-resistant mycobacterium tuberculosis (mtb) isolate, i.e. discordant results from two different clinical specimens in the same patient. two patients (contributing three urine xpert rifampicin resistance results) were determined to have false urine xpert rifampicin resistance; this occurred within 3 months of initiating the first study, and was prior to the introduction of single use disposable bedpans (see details above). this led to the introduction of single-use disposable bedpans and avoided further such cases. ethical consideration approval for both studies was obtained from the university of cape town faculty of health sciences human research ethics committee and patients provided written informed consent according to the approved study protocols. results there were 585 patients from the gf jooste hospital cohort and 586 patients from the khayelitsha hospital cohort with urine xpert results available for a total of 1171 hospitalised hiv-infected patients. overall 1704 urine xpert results were available from 1171 patients, of which 554 were performed on unprocessed urine samples and 1150 on concentrated urine samples (figure 1). baseline characteristics of the two cohorts were similar. (table 1). figure 1: overview of urine xpert rifampicin resistance results from two cohorts of hospitalised hiv-patients in cape town, south africa. table 1: baseline characteristics of jooste hospital tuberculosis study and khayelitsha hospital tuberculosis study patients. among 1704 urine xpert results, there were 416 (24.4% [95% ci 22.4–26.5]) samples that tested positive for mtb and 46 results indicating rifampicin resistance among 42 patients (figure 1). after excluding three results (from two patients) that were determined to be caused by contamination, 43 results from 40 patients remained (n = 43/413; prevalence 10.4% [95% ci 7.6–13.8]) and were further classified. the majority of rifampicin resistance results (n = 30/43; 69.8% [95% ci 53.9–82.8]) were classified as true urine xpert rifampicin resistance based on the results from other independent clinical samples. eleven (11/43, 25.6% [95% ci 13.5–41.2]) results were classified as false rifampicin resistance and two further results (one from each study) could not be classified. thus, by the most conservative estimate (excluding 2 unknown results), n = 30/41 results were confirmed as true urine xpert rifampicin resistant results, for a positive predictive value of 73.2% (95% ci 57.1–85.8). comprehensive details for each patient with urine xpert rifampicin resistance were reported in appendix table 1-a1. false urine rifampicin resistance results were more commonly observed in the jooste hospital study: 9/18 (50%) results compared with 2/25 (8%) in the khayelitsha hospital study (figure 2). the jooste hospital study enrolled not only patients not yet on tb treatment but also those already established on tb treatment, whereas the khayelitsha hospital study excluded patients who were already on tb treatment at the time of admission. in the jooste hospital study, there were n = 14 results (one unknown rifampicin resistant result) from patients on tb treatment at enrolment and n = 4 results from patients not on tb treatment at enrolment and among these, n = 7/13 (53.8%) and n = 2/4 (50%) had false rifampicin resistant urine xpert results, respectively. therefore, in both cohorts and excluding two results that could not be classified, among patients not on tb therapy, n = 24/28 (85.7% [95% ci 67.3–96.0] had true positive urine xpert resistance results compared to n = 7/13 (53.8% [95% ci 25.1–80.8] among those receiving tb therapy at study enrolment. this suggests that the positive predictive value of xpert mtb/rif for rifampicin resistance is higher among those not on tb treatment compared with those who were already established on tb treatment. figure 2: urine xpert rifampicin resistance results separated by cohort and tuberculosis treatment status. twelve-week mortality for patients with urine xpert rifampicin resistant results was 30% (n = 12/40) and 7.5% (n = 3/40) were lost to follow-up. no deaths were observed among the 10 patients (accounting for 11 results) with false urine xpert rifampicin resistance. limited details regarding xpert probe features for the two patients with false rifampicin resistance in the khayelitsha hospital study were available. the clinical microbiologists’ comment for patient kdhtb479 indicated that there was a very low load with a double mutation detected by a delay in probes d and e and that the result was likely false positive. in patient kdhtb439 there was a failure of probe d to bind in the isolate and a repeat sample was requested that demonstrated rif susceptibility. we were unable to obtain information about the probe features for samples of the jtbs study. three patients (n = 3/40, 7.5%) with a confirmed rifampicin resistant urine xpert result had evidence of likely heteroresistant infection. the first patient (appendix table 1-a1 – kdhtb203) cultured a drug susceptible isolate from blood (mycof/lytic bottle), sputum and urine samples but also a rifampicin resistant isolate from sputum during the same admission. the second patient (kdhtb531) cultured a drug-sensitive isolate from blood as well as a drug-resistant isolate from sputum during the same admission. the third patient (jtbs463) was originally started on drug-sensitive tb treatment after a prior sputum xpert and abscess aspirate culture both showed rifampicin susceptible isolates. one month after starting tb treatment, the patient was admitted for tb immune reconstitution inflammatory syndrome (iris). shortly after discharge, the patient was readmitted for gastroenteritis and was clinically deteriorating despite drug-sensitive tb treatment. at this time, two urine xpert results showed rifampicin resistance; however, the patient died shortly after receipt of urine xpert results. discussion in this study, which included hospitalised hiv-infected patients systematically investigated for tb, the overall proportion of urine xpert rifampicin resistance results was 10.4% (n = 43/413); however, the positive predictive value of urine xpert mtb/rif for rifampicin resistance was only 73.2% (n = 30/41). the correct identification of drug-resistant tb has important implications for both the individuals’ health as well as for public health. for the patient, a false rifampicin resistance result may result in not only over-treatment with more toxic drugs that are less efficacious for drug-sensitive tb, but also significantly and unnecessarily prolong treatment times. in high burden, under-resourced settings, a false rifampicin resistance may have important resource implications by resulting in additional drug susceptibility testing, significantly more expensive treatment costs and unnecessary community contact tracing.26 thus, any test that detects dr tb should ideally have very high specificity. under the best-case scenario when results were restricted to those not receiving tb treatment, we found that xpert testing of rifampicin resistance on urine samples did not achieve sufficiently high positive predictive value (86%) to be the sole/definitive test for drug-resistant tb identification. this, however, needs to be evaluated in additional settings. xpert ultra is an updated, next-generation sample cartridge for the xpert platform that is now recommended by the who as a replacement for the current xpert mtb/rif cartridge27,28 and has been implemented in south africa. it provides increased sensitivity for the detection of mtb in sputum (especially smear-negative and pauci-baciliary disease). xpert ultra utilises a new melt curve analysis to detect rif-resistance; however, its diagnostic accuracy (including specificity) for the detection of rifampicin resistance is similar to that of xpert.29 the results of this study suggest that urine xpert ultra rifampicin resistance results should be interpreted cautiously and confirmed by alternative drug susceptibility testing (either phenotypic or alternative genotypic assays) until the specificity of xpert ultra for rifampicin resistance detection has been confirmed to be adequately high to warrant stand-alone testing on urine samples. of interest, in this cohort we describe three patients with a confirmed urine xpert rifampicin resistance result who also had drug-sensitive strains from independent samples during the same admission suggesting likely heteroresistance (either polyclonal infection or acquired heteroresistance). the prevalence of heteroresistance in mtb infections has previously been described.30,31,32 although not well-studied, these are likely associated with increased rates of treatment failure for the individual31 and could complicate tb control efforts at a population level. xpert may miss heteroresistance if used as a stand-alone test for the detection of rifampicin resistance, however, early studies show that xpert ultra may detect heteroresistance when the resistant dna comprises 5% or more of the sample.28 strengths of this study include a large number of urine xpert rifampicin results from two geographically and clinically comparable cohorts where patients were prospectively recruited and underwent systematic testing for tb. additionally, all tb assays including urine xpert testing were performed at the same laboratory according to standard protocols. after an error yielded two likely false xpert rifampicin resistant urine cases due to contamination soon after recruitment initiation, disposable bedpans (single-use) were implemented for the duration of both studies. we therefore recommend that clinicians use single-use specimen collection bedpans and containers when utilising xpert or xpert ultra testing on urine to prevent dna-cross-contamination between samples. the reason(s) for the high proportion of false positive urine rifampicin resistance is not entirely clear, but the proportion was higher among those already receiving tb therapy. a limitation of this study is that we did not have data available to systematically evaluate the xpert probe features associated with our classification of false rifampicin resistance. different methods of drug susceptibility testing could explain discrepant results in some cases.33,34 the majority of drug susceptibility testing on cultured isolates in both studies was pcr-based; however, we also captured results of all tb tests performed in-service and cannot reliably differentiate between drug susceptibility testing performed with other methods such as liquid or solid media for all samples for the duration of the study. because of the early implementation of disposable bedpans, we do not suspect undetected contamination beyond that described above. furthermore, because most patients with positive urine rifampicin results did not have paired urine culture isolates available for further genotypic or phenotypic drug-susceptibility testing, patients classified as having false positive rifampicin results may have had heteroresistance with compartmentalised true rifampicin-resistant urinary tb and rifampicin-susceptible tb at other anatomic sites. however, the favourable clinical course of most of these patients on first-line drug-sensitive tb treatment counts against this possibility. notably, a large proportion of false positive rifampicin results were among those already receiving anti-tb therapy, where 50% of urine xpert rifampicin resistance results were classified as false resistance; this suggests that further caution should be applied when interpreting urine xpert rifampicin resistance results in treatment-experienced patients. an additional limitation of the study is that sequencing of isolates was not performed as part of either study. sequencing of the rpob gene would have been particularly useful in the cases that we could not classify as true or false resistance and the heteroresistant cases. furthermore, urine tb cultures were not routinely performed in either study and it may have been useful to compare drug susceptibility results on isolates cultured from urine samples collected at the same time as the urine xpert samples. in conclusion, urine testing using xpert provides important diagnostic yield for hospitalised hiv-infected patients being investigated for hiv-associated tb, especially in those unable to produce sputum samples. although the overall proportion of patients with urine xpert rifampicin resistance in this cohort was relatively low, the proportion of those classified as false rifampicin resistance was substantially higher than has previously been reported on sputum. urine xpert rifampicin resistant results should therefore be interpreted with caution, repeated on a second sample in patients at low-risk for drug resistant tb (as currently recommended by the who for sputum samples) and confirmed using additional culture-based or molecular assays when possible. whether these findings apply to xpert ultra is an issue that requires further study. acknowledgements the late stephen d. lawn was pi on the jooste hospital study. the investigators are grateful to the clinical and administrative staff of the western cape department of health. competing interests the authors have no conflict of interests. authors’ contributions g.m. r.b., c.s., l.b. a.w. and g.m. were responsible for patient recruitment and overseeing the individual study sites. a.d.k. and c.s. were responsible for the database. c.s. and a.d.k. designed and performed the analyses with input from g.m. and m.p.n. was responsible for the mycobacteriology. c.s. and a.d.k. wrote the first draft of the article and g.m. gave input to further drafts. all other authors commented on a draft and approved the final version of the article. funding information g.m. was supported by the wellcome trust (098316), the south african research chairs initiative of the department of science and technology and national research foundation (nrf) of south africa (grant no 64787), nrf incentive funding (uid: 85858) and the south african medical research council through its tb and hiv collaborating centres programme with funds received from the national department of health (rfa# samrc-rfa-cc: tb/hiv/aids-01-2014). c.s. is funded by the south african medical research council under the national health scholars programme. a.d.k. was supported by the national institute of allergy and infectious diseases (grant no t32 ai060530). the funders had no role in the study design, data collection, data analysis, data interpretation or writing of this report. the opinions, findings and conclusions expressed in this manuscript reflect those of the authors alone. data availability statement the data sets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. disclaimer the views expressed in the article are those of the authors and not an official position of the institution or funder. references global tuberculosis report 2016. geneva: world health organization; 2016. kyeyune r, den boon s, cattamanchi a, et al. causes of early mortality in 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rifampin resistance missed in automated liquid culture system for mycobacterium tuberculosis isolates with specific rpob mutations. j clin microbiol. 2013;51(8):2641–2645. https://doi.org/10.1128/jcm.02741-12 appendix 1 table 1-a1: patients with positive urine xpert rifampicin resistant results – details of additional tuberculosis tests and clinical course. abstract introduction methods findings discussion conclusion acknowledgements references about the author(s) zoe duby desmond tutu hiv centre, department of medicine, university of cape town, south africa busisiwe nkosi desmond tutu hiv centre, department of medicine, university of cape town, south africa andrew scheibe desmond tutu hiv centre, department of medicine, university of cape town, south africa ben brown desmond tutu hiv centre, department of medicine, university of cape town, south africa linda-gail bekker desmond tutu hiv centre, department of medicine, university of cape town, south africa citation duby z, nkosi b, scheibe a, brown b, bekker l-g. ‘scared of going to the clinic’: contextualising healthcare access for men who have sex with men, female sex workers and people who use drugs in two south african cities. s afr j hiv med. 2018;19(1), a701. https://doi.org/10.4102/sajhivmed.v19i1.701 original research ‘scared of going to the clinic’: contextualising healthcare access for men who have sex with men, female sex workers and people who use drugs in two south african cities zoe duby, busisiwe nkosi, andrew scheibe, ben brown, linda-gail bekker received: 30 sept. 2016; accepted: 30 oct. 2017; published: 19 jan. 2018 copyright: © 2018. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: men who have sex with men (msm), sex workers (sw) and people who use drugs (pwud) are at increased risk for hiv because of multiple socio-structural barriers and do not have adequate access to appropriate hiv prevention, diagnosis and treatment services. objective: to examine the context of access to healthcare experienced by these three ‘key populations’, we conducted a qualitative study in two south african cities: bloemfontein in the free state province and mafikeng in the north west province. method: we carried out in-depth interviews to explore healthcare workers’ perceptions, beliefs and attitudes towards key populations. focus group discussions were also conducted with members of key populations exploring their experiences of accessing healthcare. results: healthcare workers described their own attitudes towards key populations and demonstrated a lack of relevant knowledge, skills and training to manage the particular health needs and vulnerabilities facing key populations. female sw, msm and pwud described their experiences of stigmatisation, and of being made to feel guilt, shame and a loss of dignity as a result of the discrimination by healthcare providers and other community. members. our findings suggest that the uptake and effectiveness of health services amongst key populations in south africa is limited by internalised stigma, reluctance to seek care, unwillingness to disclose risk behaviours to healthcare workers, combined with a lack of knowledge and understanding on the part of the broader community members, including healthcare workers. conclusion: this research highlights the need to address the broader healthcare provision environment, improving alignment of policies and programming in order to strengthen provision of effective health services that people from key populations will be able to access. introduction hiv amongst key populations in south africa specific populations are disproportionately affected by, and more vulnerable to, hiv infection and its consequences, largely because of the criminalisation of certain behaviours, combined with societal and individual stigma and discrimination.1,2,3 for public health purposes, these socially marginalised groups are termed ‘key populations’. in this paper, we use this term to refer to people who use drugs (pwud), sex workers (sw) and men who have sex with men (msm). structural and interpersonal barriers, including multiple forms of discrimination and exclusion experienced by these key populations at individual, community, health system and policy levels, impede access to healthcare, and the delivery of appropriate, non-discriminatory and non-judgemental services.4 the south african hiv epidemic is diverse, and within the generalised national epidemic there are several concentrated sub-epidemics.5 in 2015, an estimated 6.19 million people were living with hiv, and hiv prevalence amongst adults aged 15–49 years was estimated to be 16.6%.6 in 2015, approximately 153 000 individuals in south africa made a living in the sex industry, and hiv prevalence amongst female sw in the three major metropolitan cities, johannesburg, cape town and durban, was estimated between 39.7% and 71.8%.5,7 no national msm size estimate exists, and hiv prevalence has been estimated to range between 22.3% and 48.2% amongst msm in the three largest metropolitan areas.8,9 the population of pwud has not been quantified, but a modelling study estimated that in 2010 there were 67 000 people who inject drugs in south africa.10 the only multi-city hiv prevalence survey amongst people who inject drugs, conducted in 2016, found an overall prevalence of 14%.11 in south africa, laws criminalising sex work and drug use, as well as the broader social context of discrimination towards msm, pwud and sw, make it difficult to collect epidemiological data, as people are often reluctant to be counted as members of these populations for fear of arrest or discrimination.12 key population access to healthcare various structural factors limit the ability of key populations to access essential, appropriate and acceptable hiv prevention and treatment services.13 globally, laws that criminalise behaviours such as drug use, sex work and same-sex relationships further marginalise key populations and perpetuate their exclusion from their communities and essential support services.13 members of key populations commonly experience disapproval, rejection and suboptimal services in healthcare settings, to the point of their exclusion from the formal health system altogether.12,14 stigma, a multilevel construct, ranging from individual to structural levels, has been conceptualised as a fundamental cause of health inequities amongst key populations.15 structural or institutional discrimination refers to societal-level conditions such as practices and norms within institutions and social structures that deny rights or constrain the opportunities, resources and well-being of socially marginalised groups.16 structural stigma has been defined as ‘societal-level conditions, cultural norms, and institutional policies that constrain the opportunities, resources, and wellbeing of the stigmatized’.15 in this study, we refer to the structural discrimination that key populations experience in the clinical setting, where human rights abuses and unethical treatment of key populations by healthcare providers are widespread.13 even when key populations manage to access health services, those provided in the public sector health system in south africa are often inappropriate, inadequate or insensitive to their particular needs. examples include clinic opening hours that are unsuitable, particularly for sw; healthcare providers that take an ‘abstinence only’ approach to managing substance use; the lack of harm reduction services such as needle and syringe programmes; the absence of support groups targeted specifically at key populations; and the lack of standard routine risk assessment tools enquiring about penile–anal intercourse.13,17,18 similarly, despite an early focus on preventing hiv and sexually transmitted infections (stis) amongst sw, few scaled-up targeted interventions have been implemented in sex work settings, or amongst pwud.1 evidence shows that timely access to antiretroviral therapy (art) and health services enabling viral suppression for key populations living with hiv is poor.7 while the south african constitution does not discriminate against anyone on grounds of sexual orientation, in reality, gay men and other msm continue to be stigmatised and discriminated largely because their behaviour deviates from social norms, and homoprejudice is widespread.19,20 a key population stakeholder consultation process conducted in south africa in 2011 found that discrimination by healthcare workers towards msm, sw and pwud was a major barrier to accessing health services.21 in a study conducted in south africa’s gauteng province, 44% of the 487 lesbian, gay, bisexual or transgender study respondents reported having experienced heterosexism when accessing healthcare.22 widespread discrimination, prejudice and moral-loading on the part of healthcare workers result in substandard healthcare provision and intensify key populations’ fear of seeking services.2,16,23,24 fear of arrest and discrimination when disclosing particular practices to healthcare workers further limits key populations’ access to hiv prevention, treatment, care and support services.25,26 however, achieving a reduction in hiv incidence necessitates the adoption of approaches grounded in principles of human rights and inclusion, entailing the successful engagement of key populations in the health system to improve reach, uptake, access and utilisation of services, by creating enabling environments where non-discriminatory services are provided.12,21 research context: free state and north west provinces the study was conducted in two provincial capitals in south africa: bloemfontein (free state) and mafikeng (north west). these locations were selected based on lack of published research around these issues and potential scale-up of key population hiv prevention programmes in these areas at the time the research was completed. both provinces share characteristics of being non-major metropolitan areas in rural provinces, with low population density compared to other provinces in south africa. free state contains 5.1% of the national population and north west contains 6.7%.27 north west is poorer than free state, with 8.1% of the national poverty share, compared to 4.9% in free state.27 no hiv prevalence data or population size estimates are available for msm, sw or pwud in these provinces. these provinces are characteristic of the public health system in south africa beyond major metropolitan areas: no pwud outreach programmes or harm reduction services exist,28 and availability of water-based condom-compatible lubricants is poor. limited health services for msm and sw have recently been provided through the red umbrella national sex work programme.14 this article describes the findings from a qualitative baseline assessment of a study evaluating the ‘integrated key populations sensitivity training programme for healthcare workers in south africa’.29 here we present data relating to the context and key populations’ experiences of health service delivery in bloemfontein and mafikeng. evaluation data of the training intervention itself will be presented in a separate paper. methods we used qualitative research methods to conduct a baseline assessment of the context of access to healthcare for msm, sw and pwud in bloemfontein and mafikeng. data collection took place from march to august 2014. in-depth interviews (idis) were conducted with eight healthcare workers purposively sampled from four government health facilities in bloemfontein and four in mafikeng. interviews enquired about healthcare workers’ knowledge, experiences and attitudes around service provision for key populations. in addition, six focus group discussions (fgds) were conducted with 36 members of key populations (13 msm, 13 pwud and 10 female sw). respondents were purposively sampled and recruited through organisations and networks in the respective cities. fgds with msm, pwud and female sw explored experiences of stigma and discrimination in the community, and when accessing health services. all idis and fgds were audio-recorded with permission of the respondents and were later transcribed and translated into english. qualitative data were analysed using an integrated approach, employing a deductive organising framework for code types, as determined by the content of the interview guides, combined with an inductive (ground-up) development of codes as they emerged from the data.30 a codebook was iteratively developed reflecting the key research questions, and the topics covered in the interview guides. the codebook was revised and modified throughout the coding process to ensure that it reflected the emerging themes. qualitative data were coded and thematically analysed using nvivo 10 data analysis software by two analysts, with any identified discrepancies resolved through discussion until consensus was reached. ethical consideration ethical approval for the study was granted by the provincial departments of health in the free state and north west provinces, as well as by the human subjects research ethics committee at the university of cape town. all respondents provided written informed consent prior to their participation. findings respondents in the idis and fgds were similar across both provinces, as shown in table 1. qualitative data from idis and fgds describing respondents’ experiences and perceptions are presented with direct quotations illustrating the key themes. the predominant narrative in the qualitative data pertained to the multiple forms of stigma and discrimination faced by pwud, female sw and msm at: (1) individual, (2) interpersonal (community) and (3) structural (health facility) levels. the data below are presented in relation to these three themes. table 1: baseline respondent sample. individual internalised stigma stigma and discrimination experienced at the interpersonal and structural levels also resulted in feelings of shame and worthlessness, manifested as internalised stigma: you don’t feel alright, as a person you know that is was not your intention to find yourself next to the road as a sex worker. it’s because you don’t have a job and there’s no way you can do anything because there are no jobs.’ [female sw, fgd, free state] key population respondents seeking healthcare described their experiences of being made to feel guilt and shame by healthcare providers. ‘they (healthcare workers) make it like the sickness or the problem is your fault … that the issue you came with is your fault. they make you feel the guilt … you feel that whatever you are getting is deserved.’ [pwud, fgd, free state] the negative health consequences, particularly health-seeking behaviours, related to internalised stigma were apparent in some of the narratives. female sw respondents described situations in which nurses adopted a scolding tone, which caused feelings of embarrassment and shame, resulting in a reluctance to return to the clinic for treatment. ‘they (nurses) embarrass you … you end up telling yourself that you are no longer going to the clinic … they (nurses) make you uncomfortable, you become reluctant to go to the clinic.’ [female sw, fgd, free state] perceived and experienced stigma and discrimination within healthcare settings by key populations, particularly around sexual identity and sexual behaviour, led to internalised stigma which manifested in delayed care-seeking, travel to distant clinics and missed opportunities to receive appropriate services. one female sw respondent explained that she defaulted on her antiretroviral treatment because of the judgemental attitude of healthcare workers, which made her scared of going to the clinic. ‘there’s nowhere else i can go (for healthcare) … it has been three months since i last had my treatment. i take pills (arvs) but because the sisters don’t treat me well i have decided to stay without the treatment (implying hiv). this thing also makes me feel bad because i know that it is my life … they (nurses) just scold at you that you have come to irritate them. “we are not able to help you, go” … nurses don’t treat us like people.’ [female sw, fgd, free state] interpersonal discrimination key population and healthcare worker respondents in both provinces described a context of discrimination at the interpersonal level. this interpersonal level discrimination in their communities was characterised by homoprejudice, discrimination and social exclusion experienced by key populations. the following quote from a healthcare worker in the north west alludes to the denial of the existence of homosexuality in the community, and the belief that homosexuality is a mental illness that should be prevented. ‘from where i come from what i have encountered is that in terms of homosexuality, there are no homosexual people. this thing of same-gender sex usually appears in psychotic patients, patients who are … ill. they are the ones you normally hear cases of them sleeping with one another, but in normal people it doesn’t happen … i don’t think that this facility can provide homosexuals with lubricant … because we do not encourage that kind of sexual intercourse … the aim is to prevent intolerable behaviour, that’s our aim … trying to discourage all the inappropriate behaviours.’ [healthcare worker, idi, north west] another healthcare worker from the north west described how discrimination towards gay and lesbian people extends beyond healthcare facilities, and is evident in the broader community and religious institutions. ‘there is a lot of stigma around gays and lesbians. gays don’t feel comfortable because of us in the community. even in church gay people are not free because we don’t accept them the way they are.’ [healthcare worker, idi, north west] in free state, one healthcare worker attributed the discrimination towards msm and gay men to the ignorance of community members. ‘(people) are ignorant … we know that it (msm) is something that exists. people will tell you that the bible doesn’t agree, but it’s something that exists. people treat them in a different way like they are not human beings. if they get some sickness they say that they brought it on themselves which is not true. what they (community) need is information … they discriminate … there is a gay person on my street and they call him names, ‘isitabane’ and things like that, and it hurts him. that’s not right because he’s a person like us, he was created like that.’ [healthcare worker, idi, free state] a number of gay-identified msm fgd respondents in free state reported experiencing significant discrimination and rejection as a result of their sexual identity. ‘in my community i have a lot of people who don’t actually accept us as being gay … most of them are older people or the elderly, because they don’t understand what is being gay. they think it’s our choice to be this way, that we choose to be this way and we can change to being straight … also our own age groups give us a hell of a problem for being gay. they also think that whatever we do it’s our choice; we were not born this way. we are actually choosing this type of life, this type of sexuality for ourselves … in my community i have experienced a lot of problems … i have to actually go out of my community to feel accepted.’ [msm, fgd, free state] all the key population respondents reported having experienced verbal abuse and being called derogatory names in the general community, and by healthcare workers specifically. some of the gay-identified msm respondents shared their experiences of homophobia and homoprejudice in their communities, manifested in actions such as being verbally abused, shunned and isolated. msm described being called isitabane and moffie, offensive slang terms for homosexuals. ‘they call me a “moffie” … some of them will actually curse at me, give me some nasty words that i won’t even care to mention … especially when you are in the taxis they show by their actions that “i don’t want to sit next to him” or “i don’t want him to touch me because he might infect me, he’s gay and everything”. that’s the type of things i actually experience in my community.’ [msm, fgd, free state] female sw were often called ‘magosha’ (prostitute), a derogatory term for sw in south african slang. the context of discrimination in the community was similar for pwud, who were described by healthcare workers as being subject to stereotyping and assumptions of criminal and violent behaviour. ‘they think they (pwud) are thugs, they mug people, they rape … if they don’t have money to buy drugs they will end up doing those things … so the community doesn’t accept them.’ [healthcare worker, idi, free state] people who use drugs also reported being called derogatory and offensive names and experienced a lack of trust from their families and friends because of their being perceived as untrustworthy and unreliable. respondents from the pwud focus groups described instances in which they had been labelled as being mentally unstable. ‘they treat me like a mad person, when i appear children start to run away. children can run away because their parents tell them that this chap is mad.’ [pwud, fgd, north west] one theme that emerged in healthcare workers’ attitudes towards key populations related to a sense of blame and culpability, and the belief that sw, msm and pwud deserved to get hiv. various key population respondents described the way in which nurses, often middle-aged women, adopt moralising judgemental tones when providing services to them. ‘there’s also discrimination whereby you find these old kinds of nurses who don’t have this knowledge about gays and lesbians … when you go to clinics and then maybe let’s say you have an sti or something. they then start calling you names, and saying “guys don’t sleep with guys, why do you do that? … boys don’t sleep together”.’ [msm, fgd, free state] the narratives from healthcare workers themselves suggested that their moralising, judgemental and homoprejudicial attitudes are a result of religious conviction: ‘those who don’t accept this thing of men sleeping with men, i would say it’s religious people mostly … the bible doesn’t accept that (homosexuality).’ [healthcare worker, idi, free state] several of the healthcare workers cited their religious beliefs and christian values in explanation of their own judgemental attitudes and lack of acceptance of behaviours such as sex work and same-sex partnerships. the following quotation illustrates a healthcare worker’s self-reflection on their own prejudicial attitudes and the need to resolve the conflict between religious beliefs and providing healthcare to those in need: ‘i am a christian, i don’t believe in those things (homosexuality) actually. but because they are happening in a society that i am living in, then somewhere somehow it’s a dilemma i need to understand. even if my religious belief does not allow me. people say this is wrong and we know that it’s wrong and it’s not accepted biblically. so people don’t accept them.’ [healthcare worker, idi, free state] structural discrimination several of the key population respondents narrated their personal experiences of violence, harassment and physical and sexual assault. female sw respondents described their sense of powerlessness and their lack of recourse to bring incidents of discrimination or violence to the authorities because of the criminalisation of sex work; they explained that their lack of access to police protection enhances their vulnerability to violence. in addition to the fear of violence, respondents described their reluctance to disclose themselves as sw, msm or pwud to healthcare workers, or disclose their risk behaviours. as a consequence of this lack of disclosure, healthcare workers are often unaware of such patients’ risk behaviours, vulnerabilities or specific needs: ‘when it comes to health facilities … at the clinics, it’s about keeping it to yourself.’ [msm, fgd, north west] one barrier to disclosure to both police and healthcare workers was the lack of confidentiality: ‘they already know what you are … whether it’s a policeman or a nurse, will go to another colleague and say that you are from work (selling sex) … that one will also relay it (to colleagues) … imagine getting that treatment here at hospital … we are even scared to go there because even if i get injured … they say that i was selling, i am a “magosha”.’ [female sw, fgd, north west] many of the key population respondents described their personal experiences of having their confidentiality breached by nurses in government clinics: ‘healthcare facilities … people who work there are not friendly. when you walk in they stare … (the nurses) will call their friends and tell them that you have an sti and they should come look. they tell you to undress. it will reach a point were you are scared of going to the clinic … they (nurses) call each other every time and about five of them would come. they would say come see, what is this thing? so that’s why some of us don’t go to these places, and that’s why some of us die of hiv/aids. that’s why.’ [msm, fgd, free state] one sw respondent explained that as a consequence of the lack of confidentiality at the clinics, she chose to seek assistance instead from traditional herbalist healers to treat her sti symptoms. ‘i am scared of going to the clinic because we say these things in front of nurses … when she (nurse) leaves you in the room she goes out and tells people that ‘magosha’ are here to irritate them looking for condoms. ‘they are sick, the men they sleep with have given them sores’ … i have problems, i go to the clinic to present that problem, the sister will leave me there and go talk. i can hear that this person is talking about me. i was even shy to leave the sister’s room and go walk past those people (in waiting room) … i once had a problem with a very scary sore (sti) … since i was scared of going to the clinic i took traditional sotho herbs. there was no chance that i would go to the clinic because the sisters talk about us … we are scared. we are terribly scared of nurses.’ [female sw, fgd, free state] notably, some key population respondents commented that healthcare workers are not homogeneous, and some provide services without discrimination or judgement: ‘they are not the same, there is one who will treat you fine … they are not the same; there are those who are fine and those who are not.’ [female sw, fgd, free state] the sentiment that not all healthcare workers are unfriendly was echoed by some of the msm respondents who explained that they had good relationships with healthcare workers and were open about being gay: ‘i have never had experiences like those … they are the friendliest towards gay people. even when i am sick i go there and the service is okay unless they wait for me to leave and speak behind my back. people do that but i have not had such an experience.’ [msm, fgd, north west] in addition to healthcare workers displaying judgemental attitudes, many of the key population respondents shared the view that healthcare workers in government facilities are not equipped with the knowledge and skills to provide them with appropriate services: ‘the last time i went to the clinic there was this lady and she is very old. so she was busy writing and asking questions and stuff, then came the part where i had to take my clothes off. she was like where are you sick and then i had to tell her that my ‘other vagina’ (anus) is sick. she couldn’t understand. “what are you talking about?” “my a-s-s is sick”, and she was like “what happened? did you have sex with your … (anus)?” i am like “yes, i am gay”.’ [msm, fgd, free state] structural barriers to accessing hiv-related commodities were also described by the key population respondents, such as the lack of access to clean injecting equipment for people who inject drugs. one pwud explained that the only way for them to get clean needles is to steal them from the health facility: ‘what you do is that you wait in the sister’s room and when they go out you just take a handful of needles … you steal them … i was too scared to ask (for needles), because i was scared i was going to get a reaction “what do you need them for?”. [pwud, fgd, free state] some healthcare workers expressed the opinion that providing an injecting drug user with clean needles would serve to encourage and condone the behaviour, and thus they were not prepared to do so: ‘i won’t encourage a person to commit a crime by giving them needles it means that i am encouraging them to continue with what they are doing.’ [healthcare worker, idi, free state) the physical environment of health facilities was also described as uninviting and non-inclusive of key populations, for example, the lack of informative and educational materials relating to key populations or their risk behaviours. as a result of the judgemental and discriminatory attitudes of public sector healthcare workers, and the non-conducive clinic environments, key population respondents expressed a preference for health services delivered through community and outreach-based programmes, or by the private sector. discussion these findings highlight the individual, interpersonal and structural barriers impeding access to healthcare for sws, msm and pwud, and the delivery of health services in these two south african cities. our findings support similar evidence from other cities in south africa, such as johannesburg, tshwane, durban, pietermaritzburg and cape town.23,31,32 high levels of stigma and discrimination affecting key populations in communities and at health facilities were described by key population members who participated in the fgds. several healthcare workers described their own judgemental and moralising attitudes towards key populations. this research illustrates prejudiced, discriminatory and judgemental views held by some healthcare workers in the areas in which this research was conducted, shaped by the prevalent social and religious norms and attitudes in their communities. aligning with the experiences reported by members of the key populations, there was high self-reporting of moralistic and judgemental views by healthcare workers, coupled with a belief that healthcare professionals should provide ‘moral guidance’. these findings highlight the need for specific efforts to better align health service provision, especially in the public sector, with the south african constitution, the south african national health act33 and the principles outlined in the batho pele white paper,34 decreeing that healthcare should be impartial, non-judgemental and free of moral-loading. additional key population policies that highlight the need for sensitisation training include the south african national strategic plan for hiv, tb and stis (2017–2022), the south african national sex worker hiv plan (2016–2019), the south african national lgbti hiv plan (2016–2019) and the operational guidelines for hiv, stis and tb programmes for key populations in south africa (2012). in addition, these findings demonstrate the need for specific efforts to address judgemental attitudes amongst healthcare workers, providing them with the skills to provide the necessary support, counselling and services to key populations even when there is marked conflict with personally held moral views. key population respondents in this study described their experiences of being made to feel guilt, shame and a loss of dignity as a result of the discrimination by healthcare providers. evidence has shown that contexts of stigmatisation and discrimination may become internalised by individuals, manifesting at the individual level in psychological distress.15 ‘internalised stigma’ or self-stigma refers to the cognitive, affective and behavioural processes in which stigmatised individuals engage in response to stigma-related stressors and the internalisation of negative societal attitudes about one’s social group.15 the south african hiv stigma index posited that internalised stigma is one of the most prevalent forms of stigma and can lead to reduced self-confidence, loss of motivation, withdrawal from social contact, avoidance of workand health-based interactions, and abandonment of planning for the future.35 ‘oppression illness’ refers to the negative emotional effects of internalising prejudice, social mistreatment and experienced stigma, including psychological or emotional harms, resulting in self-hatred, guilt and accepting blame for one’s suffering as just retribution for someone who does not deserve better treatment.36 individual level stigma is associated with adverse health outcomes, devaluation of the self, poor self-regard, increased risk-taking behaviour, impeded health-seeking behaviour and negative health outcomes.15,30,37,38 key population respondents in this study described their reluctance to seek public sector healthcare and fear of disclosing their behaviours because of lack of confidentiality and concern around negative treatment from healthcare workers. these findings support other evidence showing that despite significant and sometimes urgent hiv treatment and care needs, many key populations do not access health services for several reasons, including fear of discrimination, humiliation, recrimination and breaches of confidentiality from community members, healthcare workers and the state.15,25 fearing likely discrimination, possible legal consequences and even the refusal of services, sw, msm and pwud in these cities are reluctant to disclose risk behaviours and sexual practices to healthcare workers.39 the unwillingness of key populations has been shown to impede access to hiv testing and treatment services, resulting in poor adherence to medication, loss to follow-up, travel to more distant clinics and missed opportunities for appropriate service provision.15,40 the findings of this study provide insights into health service delivery for key populations in south africa from the perspective of healthcare workers in these cities. as seen from some of the narratives of both healthcare workers and key population service users, it is evident that there is some level of engagement with key populations at health facilities; however, healthcare workers do not always have the necessary skills or support for this engagement. in this way, the lack of targeted training to inform health workers of the needs, health issues, strategies and interventions for key populations contributes to marginalisation and leaves healthcare workers ill-equipped to address health needs and perpetuates stigmatising and discriminating practices.41 the south african national strategic plan on hiv (2012–2016)42 recommended appropriate hiv prevention services for msm, sw and pwud and aimed to address discrimination. south african healthcare workers are constitutionally and ethically obliged to provide key populations with equitable, impartial care and treatment. however, as these findings demonstrate, discrimination of key populations by healthcare workers is a reality. evidence has shown that efforts to effect structural change and the creation of ‘enabling’ environments through activities such as the training of healthcare workers to provide high-quality, non-judgemental services can be successful.3,31 one limitation of this research was the small sample size of respondents, and limited recruitment scope, meaning that the views expressed by respondents may not be representative of the broader communities; this limited generalisability is inherent in this type of research. few pwud participated in the study, and only one was female. inclusion of more female pwud, as well as male and transgender sw, would have provided additional insights into healthcare service experiences. it is possible that some of the nuance of respondents’ narratives may have been lost during the process of translation into english. response bias may have been present in the respondents’ narratives, particularly amongst healthcare workers who may have expressed reserved attitudes out of concern for being judged by the researchers. although this may have been the case, judgemental attitudes were described, suggesting that at least some of the healthcare workers openly disclosed their negative opinions towards key populations. despite these limitations, the study findings provide insights with regard to the context of key populations and their access to healthcare in these settings. recommendations sensitisation training of healthcare workers has been proven to be effective in reducing homoprejudice towards msm and increasing knowledge and awareness of the specific vulnerabilities and health needs of key populations.2,43 although sensitisation training on its own is likely to be insufficient, it is an essential step towards fostering enabling environments for effective health service provision for sw, msm and pwud. sensitisation training needs to be combined with clinical competency training, which can improve the ability of healthcare workers to take appropriate medical histories, conduct relevant examinations, develop appropriate differential diagnosis and institute appropriate clinical management in a sensitive and appropriate manner.38 clinical competency training is likely to be more effective amongst healthcare workers who have been ‘sensitised’, do not harbour prejudicial attitudes and are sensitive to the unique issues affecting and needs of sw, msm and pwud. training interventions on their own are not sufficient to address barriers to accessing healthcare; they need to be complemented by demand generation and linkage to appropriate services, as well as the inclusion of mechanisms to monitor and address instances of stigma and discrimination. ongoing provision of resources, support and mentorship to enable the provision of sensitive, appropriate and effective health services is important, particularly as health workers face challenging situations. to ensure that key populations are willing and able to access the relevant healthcare, healthcare workers need to be non-judgemental, supportive, responsive and respectful and should understand the socio-environmental and health issues that key populations face. providing healthcare workers in south africa with sensitisation training and ongoing support would help to reduce discriminatory attitudes, increase compassion, encourage the use of non-judgemental language when working with persons who engage in behaviours that are often stigmatised and enable healthcare workers to carry out sexual risk assessments that do not assume heterosexuality. these changes, coupled with clinical competency training building on existing service provision practices, would enable healthcare workers to respond appropriately and effectively to the needs to key populations.16,38 health service data collection tools and forms should reflect the heterogeneity of sexual and risk behaviour in a gender-neutral and non-judgemental manner, and requisite hiv prevention commodities should be available. conclusion within the healthcare sector, stigma and discrimination take many forms at individual, interpersonal and structural levels. these findings highlight the need to address the policies that perpetuate the stigmatisation of key populations, increase efforts to reduce key population vulnerability to and risk of hiv infection and ensure equitable access to hiv testing, treatment and care. better alignment of policies and programming is needed to strengthen the provision of effective health services that will reach key populations. efforts towards increased hiv and sti testing and treatment, especially amongst key populations, are unlikely to be successful without addressing these issues. the need for sensitisation of healthcare workers through training and skills development is paramount to mitigate the discrimination of key populations, improving their ability to provide non-discriminatory, non-judgemental and appropriate health services to key populations, as well as the broader population. it is imperative that healthcare workers receive sensitisation training as part of an effort to ensure that the national hiv response is effective, and does not contravene the human rights and public health principles of freedom from discrimination and access to health services. acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions z.d. was involved in the project from the outset, inclusive of research design, planning, training and support of field workers, data analysis, and took the lead in the writing of the manuscript. b.n. was involved in the data collection, data analysis and writing of the article. a.s. was involved in the research design, implementation, training and support of field workers, and writing of the article. b.b. was involved in the research design, implementation, training and support of field workers, and writing of the article. l-g.b. was involved in the research conceptualisation and in reviewing the manuscript during 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men: a systematic review. int health. 2015;7(3):151–162. https://doi.org/10.1093/inthealth/ihu101 hiv 884 original article association of hiv prevalence and concurrency of sexual partnerships in south africa’s language groups: an ecological analysis c kenyon sti/hiv unit, institute of tropical medicine, antwerp, belgium, and division of infectious diseases and hiv medicine, faculty of health sciences, university of cape town c kenyon, mb chb, ma, mph, phd, fcp, fcp (cert id) corresponding author: c kenyon (chriskenyon0@gmail.com) background. there is considerable variation in hiv prevalence between different language groups in south africa (sa). sexual partner concurrency has been linked to the spread of hiv, but its effect on differential hiv transmission within sa’s language groups has not been investigated quantitatively. objective. this ecological analysis was intended to explore the degree to which the variation in hiv prevalence according to language group can be explained by differential concurrency rates. method. linear regression was used to assess the association between each language group’s hiv prevalence and four risk factors: the prevalence of concurrency, multiple sexual partners in the preceding year, circumcision, and condom utilisation. results. in multivariate analysis, only the point prevalence of concurrency remained associated with hiv prevalence. conclusion. there is evidence of a high prevalence of point concurrency in sexual partnerships in sa’s most hiv-affected language groups. together with evidence that relatively small decreases in concurrency can lead to large declines in hiv incidence, this provides impetus for interventions to promote having only one sexual partner at a time. s afr j hiv med 2013;14(1):25-28. doi:10.7196/sajhivmed.884 although adult hiv incidence in south africa (sa) has fallen somewhat, it remains alarmingly high – between 1% and 2%.1 it is of great importance to ascertain what is driving this high incidence. one approach that has received little attention is to compare the potential risk factors for hiv in sa’s various language groups. since hiv prevalence varies widely among these groups, this offers an opportunity to determine which population-level factors co-vary most closely with this prevalence. the objective of this analysis was to determine the manner in which hiv prevalence varies according to sa’s 11 major self-defined language groups, and to examine the ecological association of four risk factors (prevalence of concurrency, multiple partners in the preceding year, circumcision, and condom utilisation) with hiv prevalence in these groups. methods two nationally representative surveys were used for this study, namely the south african national hiv prevalence, hiv incidence, behaviour and communication survey of 2008 (sabssm iii) and the national communication survey of 2009 (ncs 2009).2 , 3 in both surveys, respondents were asked to verify which main language they spoke at home; responses were coded into 11 identical language options (table 1). the hiv prevalence (dependent variable) and risk factors (independent variables: prevalence of concurrency, multiple sexual partners in the preceding year, circumcision, and condom utilisation) were calculated for each language group. hiv prevalence the hiv prevalence of each language group (among individuals aged 16 55 years) was obtained from the sabbssm iii survey. 2 this was the third and most recent of the sabssm surveys, which are the only nationally representative hiv sero-surveys of south africans of all ages. the survey used a multi-stage stratified sampling approach. when correctly weighted to account for the complex sampling design and hiv testing non-response, the sample was representative of the population in sa for the main reporting domains of sex, age, race and province.2 structured questionnaires were used to collect demographic, social and behavioural data. dried blood-spot specimens were used for hiv testing using an algorithm that saw all samples initially being tested with an enzyme immuno-assay (vironostika hiv uni-form ii plus o, biomerieux). of 23 369 individuals, 20 826 (89.1%) completed the interviews and 15 031 (64.3%) agreed to provide blood for hiv testing. the mid-point of data collection was september 2008. risk factors the four independent variables were derived from the ncs 20093 – a cross-sectional survey that utilised a multi-stage, stratified sampling approach (comprising three stages). firstly, 400 primary sampling units (psus) were sampled using principles of probability proportional to size. psus comprised small areas from the 2001 national census. the second and third stages, respectively, involved the selection of secondary sampling units or households, and the selection of one individual per household (aged 15 55 years) from eligible household members. the final sample comprised 9 728 individuals aged 16 55 years, who were representative of south africans in this age band. the overall response rate was 58%. data were collected between june and august 2009. see johnson et al.3 for further details of the methodology and possible bias introduced by differential non-response. the four independent variables were defined as follows: • point concurrency: the point prevalence of concurrency (i.e. having two or more overlapping sexual relationships) at the time of the survey was used as the indicator of concurrency, as this has been shown to best capture the effect thereof in increasing a sexual network’s connectivity and, hence, hiv transmissibility.4 , 5 for each language group, the point concurrency was determined by the percentage of persons who reported having two or more partners at the time of the survey. this variable was derived from the question: ‘how many sexual partners do you currently have?’ • multiple partners per year: defined as the proportion of respondents in each language group who reported having two or more sexual partners in the preceding 12 months. • condom utilisation: defined as the proportion of respondents in each language group who reported using a condom the last time they had sexual intercourse. • circumcision: defined as the proportion of male respondents who reported being circumcised (each male respondent was asked whether or not he was circumcised). statistical analyses the hiv prevalence and independent variables were calculated for each self-defined language group using stata version 12.0 (college station, texas, usa) and by applying the survey methodology to account for the multi-stage sampling strategies and varying non-response rates. uniand multivariate linear regression models were used to assess the association between the independent and dependent variables. all analyses were limited to sexually experienced individuals aged 16 55 years. the data were not age-standardised, as the differences in the age structure of each language group were relatively small (table 1). table 1. prevalence of hiv 2 and various risk factors 3 per language group among south africans aged 16 55 years language sabssm iii2 ncs 20093 n age median (iqr) hiv prevalence % (95% ci) n age median (iqr) concurrency % (95% ci) multiple partners per year % (95% ci) circumcision % (95% ci) condom utilisation % (95% ci) isizulu 1 646 28 (21 40) 28.8 (24.3 31.8) 1 973 29 (23 38) 8.9 (7.3 10.9) 16.8 (14.4 19.7) 23.5 (20.0 27.3) 50.5 (46.2 54.7) isizhosa 1 497 28 (20 40) 21.6 (17.6 24.6) 1 351 28 (22 39) 4.9 (3.5 6.9) 11.6 (9.4 14.2) 76.6 (72.3 80.4) 45.8 (42.1 54.7) isindebele 105 28 (21 41) 20.6 (9.4 38.5) 191 27 (22 36) 6.1 (3.0 12.0) 9.4 (5.0 17.0) 68.0 (52.9 80.1) 44.4 (33.7 55.5) isiswati 251 28 (19 41) 23.9 (18.1 30.0) 365 25 (21 34) 5.3 (3.6 7.6) 7.7 (5.3 10.9) 32.9 (19.5 49.8) 51.7 (42.7 60.6) english 1 847 32 (21 43) 1.5 (0.8 2.6) 370 36 (27 44) 1.4 (0.5 3.9) 3.1 (1.4 6.9) 31.9 (22.3 43.4) 22.8 (16.6 30.3) afrikaans 2 568 33 (21 44) 2.5 (1.8 3.3) 1 228 36 (26 44) 1.2 (0.6 2.4) 4.3 (2.8 6.6) 14.8 (10.3 21.0) 21.3 (17.0 26.3) sesotho 783 29 (21 40) 20 (16.6 22.9) 946 31 (23 40) 4.6 (3.0 7.0) 13.2 (9.9 17.5) 49.2 (42.5 56.1) 44.5 (39.6 49.5) sepedi 808 29 (20 42) 16.6 (11.4 21.6) 797 26 (21 35) 5.4 (5.0 7.5) 12.8 (9.1 17.8) 79.5 (72.5 85.0) 54.0 (44.9 62.9) setswana 852 29 (20 41) 18.4 (13.6 22.7) 699 31 (24 40) 4.6 (2.8 7.5) 11.0 (7.5 15.9) 31.6 (23.4 41.2) 49.2 (43.9 54.5) tshivenda 143 27 (20 41) 8.1 (3.2 17.8) 232 28 (22 36) 3.8 (1.5 9.5) 10.9 (6.5 17.5) 89.2 (77.4 95.2) 45.6 (38.1 53.2) xitsonga 331 28 (21 38) 17.6 (10.6 26.3) 374 27 (22 36) 5.4 (2.3 11.9) 11.8 (7.4 18.3) 70.1 (55.4 82.4) 39.5 (30.0 49.8) sabssm iii = south african national hiv prevalence, hiv incidence, behaviour and communication survey of 2008; ncs 2009 = national communication survey of 2009; iqr = interquartile range; ci = confidence interval. results table 1 shows the variation in hiv prevalence between language groups, ranging from 1.5% (95% ci 0.8 2.6) to 28.8% (95% ci 24.3 31.8). these variations remained considerable upon analysis of the nine black language groups alone; ranging from 8.1% (95% ci 3.2 17.8) in tshivenda speakers to 28.8% (95% ci 24.3 31.8) in isizulu speakers. three risk factors were strongly associated with increased hiv prevalence per language group upon univariate analysis: multiple partners per year, point concurrency (fig. 1) and lower condom utilisation rates (table 2). circumcision prevalence rates were not associated with hiv prevalence; however, this may have been driven by the effect of the englishand afrikaans-speaking groups who had low rates of circumcision and hiv prevalence (fig. 2). when the analysis was restricted to the nine black language groups, increasing circumcision rates were correlated with lower hiv prevalence rates (r2=0.48; p=0.04). in multivariate analysis, only point concurrency remained associated with hiv prevalence (β co-efficient=3.5; p=0.03) (table 2). fig. 1. association between hiv prevalence (derived from sabssm iii) and the point prevalence of concurrency (derived from ncs 2009) for 11 language groups in south africa (r2 =-0.84; p< 0.001).[2,3] fig. 2. association between hiv prevalence (derived from sabssm iii) and the prevalence of male circumcision (derived from ncs 2009), for 11 language groups in south africa (r2 =-0.02; p=0.70 for all 11 language groups and r2 =0.48; p=0.04 when analysis restricted to the nine black language groups). [2,3] table 2. univariate and multivariate linear regression analysis of the relationship between hiv prevalence per language group and risk factors2 , 3 risk factor univariate multivariate β co-efficient r2 p -value β co-efficient p -value concurrency 3.79 0.84 0.0001 3.50 0.046 multiple partners/year 2.04 0.55 0.0061 -0.23 0.949 circumcision 0.04 0.02 0.8132 -0.02 0.427 condom utilisation 0.61 0.58 0.0165 0.24 0.267 there was a high degree of overlap between language and self-reported ethnicity within the ncs 2009 sample. the proportion of coloureds, indians and whites who spoke english or afrikaans was 91.9%, 97.9% and 97.8%, respectively. the proportion of blacks who spoke english or afrikaans as their home language was 1.6%. omitting these individuals from the analyses made no difference to the results (data not shown). moreover, it is possible that hiv prevalence may peak in different language groups at different times depending on the stage of the epidemic. to evaluate this, we repeated the analyses using the hiv prevalence rates from the 2002 and 2005 sabssm surveys. the resultant difference to the results was negligible (data not shown). discussion hiv prevalence is known to vary dramatically between south african language and racial groups.2 this heterogeneity offers a useful opportunity to examine the reasons underpinning the country’s generalised hiv epidemic. great caution needs to exercised in the use of ethnic and racial categories in health research. this is especially the case in sa, where the uncritical use of racial categories in the apartheid era, combined with the concomitant lack of controlling for the effects of the widely divergent socio-economic conditions, served to exaggerate racial differentials in various health outcomes. 6-8 however, a wide range of evidence indicates that economic differences are not the predominant drivers of differential hiv spread according to racial group.9 furthermore, it is important to explain the considerable differences in hiv prevalence between language groups among black south africans. there is a high degree of homophilous partnering (like-with-like) among self-defined language groups in sub-saharan africa10 and elsewhere.11 sexual networks would therefore be expected to cluster and segregate to a considerable degree along these lines, as has been demonstrated empirically.10 , 11 these sexual networks may be, more or less, densely interconnected and these differences are believed by many,4 , 12 but not all, epidemiologists13 to be important in explaining differential hiv spread. since network connectivity, as assessed by measures such as concurrency prevalence, is a network-level property, it is necessary and appropriate to investigate it at a network or ecological level. a number of studies from sa, the usa and elsewhere have found that racial or ethnic variations in hiv prevalence are not explained by individual-level risk factors (e.g. multiple partners per year and lifetime number of sexual partners), but rather that network-level factors such as concurrency prevalence are important.4 , 14 , 15 this is commensurate with global reviews of sexual behaviour which have shown that the average number of lifetime sexual partners is, if anything, lower in countries with generalised hiv epidemics than in countries with low hiv prevalence rates such as those in western europe.16 in the data described here, the relationship between circumcision and hiv prevalence is interesting, especially considering the significant association within the black language groups. circumcision cannot, however, explain the low hiv prevalence rates in the english and afrikaans groups, as they have the lowest circumcision rates. this is mirrored globally. eastern and southern africa have considerably higher circumcision rates than latin america, and the non-islamic countries in asia and europe, all of which have very low hiv prevalence rates. 17 , 18 clearly, something else may be driving the higher hiv prevalence rates. the multivariate analyses presented here support findings from elsewhere which suggest that the degree of connectedness of the sexual network (here measured by point prevalence of concurrency) is playing a significant role in this regard.4 , 14 , 15 , 19 , 20 study limitations there are a number of weaknesses in this analysis, including the fact that the data for sexual behaviour and hiv prevalence were derived from different surveys. both surveys were, however, conducted with nationally representative samples. the surveys were designed to provide representative data for the four racial groups in sa, but not for the eleven language groups. ecological analyses, such as this one, assume a high degree of language group homophily as far as sexual partnering is concerned. this has been long been shown to be the case in the usa,11 but only recently so in sa.10 the data are derived from self-reported behaviour and circumcision statuses; however, these are prone to well-described biases.11 in particular, self-described circumcision has been shown to over-estimate circumcision prevalence.21 there is, however, no evidence to indicate that these biases vary between different language groups and, as such, they should not affect the validity of this study. furthermore, ecological studies are susceptible to the ecological inference fallacy. this study, however, makes no inferences from the population to the individual level. further work is necessary to evaluate whether partner concurrency is associated with an increased risk of hiv acquisition in prospective cohorts. lastly, it is possible that the study’s results may have been confounded by unmeasured variables. conclusion in summary, evidence is presented here of a high prevalence of point concurrency in sexual partnerships in sa’s most hiv-affected language groups. other studies have found that these groups may be unaware of the dangers of concurrency.22 these results combined with the evidence that relatively small decreases in concurrency can lead to large declines in hiv incidence provide further impetus for interventions to promote having only one partner at a time.15 , 19 , 20 references 1. unaids. south africa: fact sheet. geneva: unaids, 2012. http://www.unaids.org/en/regionscountries/countries/southafrica/ (accessed 12 october 2012). 1. unaids. south africa: fact sheet. geneva: unaids, 2012. http://www.unaids.org/en/regionscountries/countries/southafrica/ (accessed 12 october 2012). 2. shisana o. south african national hiv prevalence, incidence, behaviour and communication survey, 2008: a turning tide among teenagers? cape town: hsrc press, 2009. 2. shisana o. south african national hiv prevalence, incidence, behaviour and communication survey, 2008: a turning tide among teenagers? cape town: hsrc press, 2009. 3. johnson s, kincaid l, laurence s, et al. second national hiv communication survey, 2009. pretoria: jhhesa, 2010. 3. johnson s, kincaid l, laurence s, et al. second national hiv communication survey, 2009. pretoria: jhhesa, 2010. 4. morris m, epstein h, wawer m. timing is everything: international variations in historical sexual partnership concurrency and hiv prevalence. plos one 2010;5:e14092. 4. morris m, epstein h, wawer m. timing is everything: international variations in historical sexual partnership concurrency and hiv prevalence. plos one 2010;5:e14092. 5. glynn jr, dube a, kayuni n, et al. measuring concurrency: an empirical study of different methods in a large population-based survey and evaluation of the unaids guidelines. aids 2012;26:977-985. 5. glynn jr, dube a, kayuni n, et al. measuring concurrency: an empirical study of different methods in a large population-based survey and evaluation of the unaids guidelines. aids 2012;26:977-985. 6. baldwin-ragaven l, london l. an ambulance of the wrong colour: health professionals, human rights and ethics in south africa. cape town: juta and company ltd, 1999. 6. baldwin-ragaven l, london l. an ambulance of the wrong colour: health professionals, human rights and ethics in south africa. cape town: juta and company ltd, 1999. 7. ncayiyana dj. racial profiling in medical research: what are we measuring? s afr med j 2007;97(12):1225-1226. 7. ncayiyana dj. racial profiling in medical research: what are we measuring? s afr med j 2007;97(12):1225-1226. 8. van niekerk aa. deliberating about race as a variable in biomedical research. s afr med j 2011;101(4):248-250. 8. van niekerk aa. deliberating about race as a variable in biomedical research. s afr med j 2011;101(4):248-250. 9. kenyon c. ‘differential poverty rates are responsible for the racial differentials in hiv prevalence in south africa’: an enduring and dangerous epidemiological urban legend? southern african journal of hiv medicine 2010;11:22. 9. kenyon c. ‘differential poverty rates are responsible for the racial differentials in hiv prevalence in south africa’: an enduring and dangerous epidemiological urban legend? southern african journal of hiv medicine 2010;11:22. 10. kenyon c, colebunders r. birds of a feather; homophily and sexual network structure in sub-saharan africa. int j std aids 2012 (in press). 10. kenyon c, colebunders r. birds of a feather; homophily and sexual network structure in sub-saharan africa. int j std aids 2012 (in press). 11. laumann eo. the social organization of sexuality: sexual practices in the united states. chicago: university of chicago press, 1994. 11. laumann eo. the social organization of sexuality: sexual practices in the united states. chicago: university of chicago press, 1994. 12. mah tl, halperin dt. concurrent sexual partnerships and the hiv epidemics in africa: evidence to move forward. aids behav 2010;14:11-16. 12. mah tl, halperin dt. concurrent sexual partnerships and the hiv epidemics in africa: evidence to move forward. aids behav 2010;14:11-16. 13. sawers l, stillwaggon e. concurrent sexual partnerships do not explain the hiv epidemics in africa: a systematic review of the evidence. j int aids soc 2010;13:34. 13. sawers l, stillwaggon e. concurrent sexual partnerships do not explain the hiv epidemics in africa: a systematic review of the evidence. j int aids soc 2010;13:34. 14. kenyon c, dlamini s, boulle a, et al. a network-level explanation for the differences in hiv prevalence in south africa’s racial groups. afr j aids res 2009;8:243-254. 14. kenyon c, dlamini s, boulle a, et al. a network-level explanation for the differences in hiv prevalence in south africa’s racial groups. afr j aids res 2009;8:243-254. 15. morris m, kurth ae, hamilton dt, et al. concurrent partnerships and hiv prevalence disparities by race: linking science and public health practice. am j public health. 2009;99(6):1023-1031. 15. morris m, kurth ae, hamilton dt, et al. concurrent partnerships and hiv prevalence disparities by race: linking science and public health practice. am j public health. 2009;99(6):1023-1031. 16. wellings k, collumbien m, slaymaker e, et al. sexual behaviour in context: a global perspective. lancet 2006;368(9548):1706-1728. 16. wellings k, collumbien m, slaymaker e, et al. sexual behaviour in context: a global perspective. lancet 2006;368(9548):1706-1728. 17. weiss h. male circumcision: global trends and determinants of prevalence, safety, and acceptability. report no. 9291736333. geneva: world health organization, 2008. 17. weiss h. male circumcision: global trends and determinants of prevalence, safety, and acceptability. report no. 9291736333. geneva: world health organization, 2008. 18. unaids. report on the global aids epidemic. geneva: unaids; 2010. 18. unaids. report on the global aids epidemic. geneva: unaids; 2010. 19. halperin dt, mugurungi o, hallett tb, et al. a surprising prevention success: why did the hiv epidemic decline in zimbabwe? plos med 2011;8:e1000414. 19. halperin dt, mugurungi o, hallett tb, et al. a surprising prevention success: why did the hiv epidemic decline in zimbabwe? plos med 2011;8:e1000414. 20. kirby d. changes in sexual behaviour leading to the decline in the prevalence of hiv in uganda: confirmation from multiple sources of evidence. sex transm dis 2008;84:ii35-ii41. 20. kirby d. changes in sexual behaviour leading to the decline in the prevalence of hiv in uganda: confirmation from multiple sources of evidence. sex transm dis 2008;84:ii35-ii41. 21. thomas ag, tran br, cranston m, et al. voluntary medical male circumcision: a cross-sectional study comparing circumcision self-report and physical examination findings in lesotho. plos one 2011;6:e27561. 21. thomas ag, tran br, cranston m, et al. voluntary medical male circumcision: a cross-sectional study comparing circumcision self-report and physical examination findings in lesotho. plos one 2011;6:e27561. 22. kenyon c, zondo s, badri m. determinants of self-perceived hiv risk in young south africans engaged in concurrent sexual relationship. afr j reprod health 2010;14(3):171-181. 22. kenyon c, zondo s, badri m. determinants of self-perceived hiv risk in young south africans engaged in concurrent sexual relationship. afr j reprod health 2010;14(3):171-181. hiv 894 forum gender inequality: bad for men’s health m cornell centre for infectious disease epidemiology and research, school of public health and family medicine, faculty of health sciences, university of cape town m cornell, mph (epidemiology) corresponding author: m cornell (morna.cornell@uct.ac.za) men’s increased risk of death in art programmes in sub-saharan africa is widely reported but poorly understood. some studies have attributed this risk to men’s poorer health-seeking behaviour, which may prevent them from accessing art, being adherent to treatment, or remaining in care. in a multicentre analysis of 46 201 adults starting art in urban and rural settings in south africa, these factors only partly explained men’s increased mortality while receiving art. importantly, the gender difference in mortality among patients receiving art (31% higher for men than women) was substantially smaller than that among hiv-negative south africans, where men had twice the risk of death compared with women. yet, this extreme gender inequality in mortality, both within and outside of art programmes, has not given rise to widespread action. here it is argued that, despite their dominance in society, men may be subject to a wide range of unfair discriminatory practices, which negatively affect their health outcomes. the health needs of men and boys require urgent attention. s afr j hiv med 2013;14(1):12-14. doi:10.7196/sajhivmed.894 sub-saharan africa is the centre of the hiv epidemic, with an estimated 68% of all people hiv-infected.1 over the past 10 years, largely through international aid programmes, there has been a dramatic increase in the number of hiv-infected individuals who have started antiretroviral therapy (art) in the region. despite early concerns that women may be disadvantaged in art programmes, disproportionately more women than men have accessed art in southern africa.2 in south africa, for example, 60% of eligible women were receiving art by mid-2011 compared with 41% of eligible men.3 men have a higher mortality than women when receiving art.4-8 although the reasons for this are poorly understood, a number of possible explanations have been suggested; some implicitly blame men for their own poorer outcomes. for example, numerous studies have suggested that men’s poorer ‘health-seeking behaviour’ may prevent them from accessing art services, being adherent to treatment or remaining in care. but, is this based on evidence or is it an assumption that has gained currency through widespread usage? to date, there has been no systematic attempt to understand the phenomenon of gender differences on art. in the past year, we explored the issue in an analysis including 46 201 adults initiating art in 8 large urban and rural south african cohorts between 2002 and 2009.5 as 60% of our patients had civil identification (id) numbers, it was possible to confirm their vital status through linkage to the national population register, estimated to capture over 90% of deaths nationally. 9 we were also able to track patients with ids after they were lost to follow-up (ltf) and confirm whether they were alive or dead. men’s increased mortality on art unrelated to hiv/aids at the start of treatment, on average men had lower cd4+ cell counts and more advanced hiv disease than women. after we adjusted for such gender differences at art initiation, men still had a 31% higher risk of mortality than women over 36 months (adjusted hazard ratio (ahr) 1.31, 95% confidence interval (ci) 1.22 1.41). men were more likely to be ltf than women (ahr 1.20, 95% ci 1.12 1.28), but not to die after being ltf (ahr 1.04, 95% ci 0.86 1.25). virological responses to art were similar between men and women and, even among virologically suppressed patients, men were still more likely to die. women had slightly stronger immunological responses than men, but in analyses restricted to patients who had reached cd4+ cell counts ≥200 cells/µl, the gender difference in mortality persisted (ahr 1.37, 95% ci 1.03 1.83). importantly, however, this difference was smaller than the gender difference in death rates (standardised by age) in a hypothetical cohort of hiv-negative south africans, where men were twice as likely to die than women. it appears then that the observed differences in mortality while receiving art may best be explained by background gender differences in mortality in the south african population that are unrelated to hiv/aids. some more equal than others? the gender differences in mortality outside of art programmes suggest a situation of extreme gender inequality. the world health organization (who) defines gender inequality as ‘difference(s) between men and women which systematically empower one group to the detriment of the other’ and which impact negatively on access to healthcare and health status.10 section 9 of the south african bill of rights states unequivocally that ‘everyone is equal before the law’.11 equality includes protection against unfair discrimination (both direct and indirect) on the grounds of gender, and discrimination on any of the grounds mentioned is regarded as unfair unless proven to be fair. but, for many of us, discrimination seems a vague and unmeasurable concept. we have an intuitive sense of what it means, but how do we study it in order to address it? krieger provides a useful framework to conceptualise how unfair discrimination affects population health (table 1). on this basis it appears that, despite their dominance in society, men may be subject to a wide range of unfair discriminatory practices over their entire lives, through multiple pathways, with generally harmful responses. table 1. conceptualising discrimination as a determinant of population health aspects of discrimination type defined in reference to constituent dominant and subordinate groups, and justifying ideology form legal or illegal; institutional, structural, interpersonal; direct or indirect; overt or covert agency perpetrated by state or by non-state actors (institutional or individuals) expression from verbal to violent; mental, physical, or sexual domain for example: at home; within family; at school; getting a job; at work; getting housing; getting credit or loans; getting medical care, purchasing other goods and services; by the media; from the police or in the courts; by other public agencies or social services; on the street or in a public setting level individual, institutional, residential neighbourhood, political jurisdiction, regional economy cumulative exposure to discrimination timing conception; infancy; childhood; adolescence; adulthood intensity frequency (acute, chronic) duration pathways of embodying discrimination (involving exposure, susceptibility and responses to) #1 economic and social deprivation: at home, in the neighbourhood and other socio-economic regions #2 toxic substances and hazardous conditions (pertaining to physical, chemical, and biological agents): at home, at work, and in the neighbourhood #3 socially inflicted trauma (mental, physical or sexual, ranging from verbal to violent): at home, at work, in the neighbourhood, in society at large #4 targeted marketing of legal and illegal psycho-active/other substances (alcohol, smoking, other drugs, junk food) #5 inadequate healthcare, by healthcare facilities and by specific providers (including access to care, diagnosis, treatment) responses to discrimination (protective and harmful) protective active resistance by individuals and communities (involving organising, lawsuits, social networks, social support) creating safe spaces for self-affirmation (social, cultural, sexual) harmful internalised oppression and denial use of psycho-active substances (legal and illegal) effects of discrimination on scientific knowledge theoretical frameworks specific hypotheses data collection data interpretation *from: berkman lf. social epidemiology. london, uk: oxford university press, 2000:42; reproduced with permission from oxford university press. there are few studies exploring the issue of discrimination towards men in health services. in contrast, there is a large body of literature on discrimination and women’s health,12-21 possibly in response to the historic under-representation of women in research informing medical practice. in 1993 the united states national institutes of health (nih) was mandated by law to ensure that ‘women and minority groups’ were included in clinical research.22 while this was a welcome response to an important omission from international research agendas, is it possible that the pendulum has swung too far? it seems probable that we are unable to recognise gender inequality when it affects men. the priorities and programmes of large funders appear to confirm the focus on women in hiv/aids programmes. for example, the global fund for hiv/aids, tuberculosis and malaria – the largest multilateral hiv/aids funding agency – states that equitable access to services is fundamental to its mission but does not include men’s poorer access to art as a key action area. the united states of america, the largest donor on hiv/aids, has provided funding for nearly 2.5 million people living with hiv through its president’s emergency plan for aids relief (pepfar) programme. although disproportionately more women than men have accessed art, pepfar does not prioritise increasing men’s access to treatment. in turn, funders’ priorities may affect national art programmes. in zambia, 54% of those living with hiv, but 63% of adults starting art, are women.23 in south africa, too, there is a gender gap: 55% of those living with hiv, but only an estimated 68% of those starting public sector art, are women.24 yet, the national strategic plans for hiv/aids in both countries do not identify male access to art as a priority, nor do they include action plans to address this gap urgently. the same is true for many other african countries. this apparent lack of concern for men’s needs extends beyond art programmes to other arenas. policy documents define gender as the ‘socially constructed roles, behaviours, activities and attributes’ considered appropriate for men and women in particular settings.10 in practice, however, it seems that gender and women’s issues are still regarded as interchangeable. for instance, south africa has a ministry for women, children and people with disabilities, but nothing comparable for men. similarly, the united nations has an inter-agency network on women and gender equality and the third millennium development goal for 2015 is to ‘promote gender equality and empower women’. the unaids’s operational plan on gender addresses ‘women, girls, gender equality and hiv’, but none of the three action areas refers to the needs of men or boys. clearly the initiatives listed above are vital, as are initiatives to address the health needs of men. in the words of who: ‘no one should be sick or die because of gender inequality’. one last point for readers to consider: many international and national conferences, including the recent conference of the southern african hiv clinicians society, include tracks on women’s health, but not that of men. is this because there are no hiv-related issues specific to men’s health – or is it because the question was not asked? references 1. united nations programme on hiv/aids. how to get to zero: faster. smarter. better. unaids world aids day report. geneva, switzerland: unaids, 2011. 1. united nations programme on hiv/aids. how to get to zero: faster. smarter. better. unaids world aids day report. geneva, switzerland: unaids, 2011. 2. muula a, ngulube t, siziya s, et al. gender distribution of adult patients on highly active antiretroviral therapy (haart) in southern africa: a systematic review. bmc public health 2007;7(1):63. 2. muula a, ngulube t, siziya s, et al. gender distribution of adult patients on highly active antiretroviral therapy (haart) in southern africa: a systematic review. bmc public health 2007;7(1):63. 3. johnson l. access to antiretroviral treatment in south africa, 2004 2011. southern african journal of hiv medicine 2012;13(1):22-27. 3. johnson l. access to antiretroviral treatment in south africa, 2004 2011. southern african journal of hiv medicine 2012;13(1):22-27. 4. auld af, mbofana f, shiraishi rw, sanchez m, alfredo c, nelson lj, et al. four-year treatment outcomes of adult patients enrolled in mozambique's rapidly expanding antiretroviral therapy program. plos one 2011;6(4):e18453. [http://dx.doi.org/10.1371/journal.pone.0018453] 4. auld af, mbofana f, shiraishi rw, sanchez m, alfredo c, nelson lj, et al. four-year treatment outcomes of adult patients enrolled in mozambique's rapidly expanding antiretroviral therapy program. plos one 2011;6(4):e18453. [http://dx.doi.org/10.1371/journal.pone.0018453] 5. cornell m, schomaker m, garone db, et al. gender differences in survival among adult patients starting antiretroviral therapy in south africa: a multicentre cohort study. plos med 2012;9(9):e1001304. 5. cornell m, schomaker m, garone db, et al. gender differences in survival among adult patients starting antiretroviral therapy in south africa: a multicentre cohort study. plos med 2012;9(9):e1001304. 6. desilva m, merry s, fischer p, rohrer j, isichei c, cha s. youth, unemployment and male gender predict mortality in aids patients started on haart in nigeria. aids care 2009;21(1):70-77. 6. desilva m, merry s, fischer p, rohrer j, isichei c, cha s. youth, unemployment and male gender predict mortality in aids patients started on haart in nigeria. aids care 2009;21(1):70-77. 7. druyts e, dybul m, kanters s, et al. male gender and the risk of mortality among individuals enrolled in antiretroviral treatment programs in africa: a systematic review and meta-analysis. aids 2012 (in press). 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[http://dx.doi.org/ 10.1146/annurev.publhealth.18.1.401] 22. united states of america. national institutes of health guidelines on the inclusion of women and minorities as subjects in clinical research. http://grants.nih.gov/grants/guide/notice-files/not94-100.html (accessed 12 june 2012). 22. united states of america. national institutes of health guidelines on the inclusion of women and minorities as subjects in clinical research. http://grants.nih.gov/grants/guide/notice-files/not94-100.html (accessed 12 june 2012). 23. stringer jsa, zulu i, levy j, et al. rapid scale-up of antiretroviral therapy at primary care sites in zambia. jama 2006;296(7):782-793. [http://dx.doi.org/10.1001/jama.296.7.782] 23. stringer jsa, zulu i, levy j, et al. rapid scale-up of antiretroviral therapy at primary care sites in zambia. jama 2006;296(7):782-793. [http://dx.doi.org/10.1001/jama.296.7.782] 24. cornell m, technau k, fairall l, et al. monitoring the south african national antiretroviral treatment programme, 2003 2007: the iedea southern africa collaboration. s afr med j 2009;99(9):653-660. 24. cornell m, technau k, fairall l, et al. monitoring the south african national antiretroviral treatment programme, 2003 2007: the iedea southern africa collaboration. s afr med j 2009;99(9):653-660. hiv 899 a suicide risk screening scale for hiv-infected persons in the immediate post-diagnosis period r d govender,1 bsc, mb chb, mfammed; l schlebusch, 2 ma (clin psych), mmed sc (psychiatry), phd 1 department of family medicine, university of kwazulu-natal, durban, south africa 2 emeritus professor of behavioural medicine, university of kwazulu-natal, durban, south africa corresponding author : r d govender (govenderr1@ukzn.ac.za) background. the risk of suicidal tendencies in hiv-infected persons appears high and may parallel the increasing prevalence of suicidal behaviour in south africa. objective. to construct a brief suicide risk screening scale (srss) as a self-administered instrument to screen for suicidal ideation in recently diagnosed hiv-infected persons. methods. an srss was developed, drawing 14 items from two established screening tests, and assessed using a sample of 150 hiv-infected consenting adults identified at a voluntary counselling and testing (vct) clinic at an academic district level hospital in durban, south africa. participants returned three weeks after their initial assessment for a re-assessment. results. the internal consistency of the srss was good (cronbach’s alpha, 0.87), and its sensitivity (81%) was higher than its specificity (47%). the findings suggest that, despite certain limitations, the srss may be a valuable screening tool for suicidal ideation at vct clinics. conclusion. screening for suicide risk and possible suicidal behaviour in hiv-positive persons may form a routine aspect of comprehensive patient care at vct clinics to assist with effective prevention and treatment. s afr j hiv med 2013;14(2):58-63. doi:10.7196/sajhivmed.899 globally, suicide and hiv/aids remain two of the greatest healthcare issues, particularly in lowand middle-income countries where approximately 85% of suicides occur.1-3 the world health organization (who) predicted that global suicide mortality will increase to 1.53 million per annum by the year 2020.2 suicide mortality rates have changed significantly in south africa (sa) since apartheid, with differences evident across cities, races and gender.4 sa has a relatively high 12-month prevalence of anxiety and mood disorders compared with other countries, which adds to the burden of suicide risk.5 in 2007 the overall rates for suicide in sa were high (0.9/100 000),6 and there is an increasing occurrence of suicide among youth and men, consistent with the international trend.7 at least one suicide is committed every hour in sa, and 20 more unsuccessful attempts are made in the same time-span, with one-third of non-fatal attempts recorded among youth.6-8 the risk factors for suicide are diverse and inter-related, and may be particularly complex in hiv-infected individuals. one systematic literature review showed a high suicidal risk in persons with hiv: 19.7% were described as generally suicidal, 26.9% as having suicidal ideation and 9.4% completed suicides.9 there is also a high rate of lifetime suicide risk associated with depression.10 the prevalence of depression and anxiety in people living with hiv/aids is almost double that of hiv-negative individuals.11 there is growing evidence that this is true in sa and other african countries.12 , 13 the risk of suicide appears to be increasing in the context of the hiv epidemic. 14 , 15 several sa studies have documented a correlation between suicidality and hiv at different points in disease progression,12 , 13-18 including the high prevalence of suicidal ideation among hiv-positive pregnant mothers.16 in a recent study conducted among hiv-positive persons in sa, suicidal ideation increased over a 6-week period and was present in 24% of the hiv-positive participants following hiv counselling and testing.17 this correlated with results of the who multisite intervention study on suicidal behaviours (supre-miss) community survey, where the highest rates of lifetime suicidal thoughts and plans were found in durban (25.4% and 15.6%, respectively).17 , 19 despite the introduction of antiretroviral therapy (art), the suicide rate remains more than 3 times higher among hiv-positive persons than in the general population.20 although the international findings on the correlation between suicide and hiv/aids are diverse,10 the results show compelling evidence to screen for suicide risk and intervene as early as possible.9 , 10-12 despite this, the assessment of suicide risk is not a routine aspect of hiv patient care in sa. the lack of consistent definitions of suicidal behaviour across studies has led to confusion in the field of suicidology. suicidality encompasses a range of suicidal behaviours, which in turn involve degrees of self-destruction that may be fatal or non-fatal. suicidal ideation is defined as having the intent to commit suicide, wanting to take one's own life or thoughts about suicide without actually making plans to commit suicide. to prevent suicides, healthcare professionals need to understand the reasons why people have suicidal thoughts or display suicidal behaviour. while there are a number of psychometric, clinical and biological measures to detect suicide risk,[ 21-23] this risk in itself is difficult to measure and predict with high degrees of accuracy23 because of its multifactorial and multidimensional nature. suicide risk can be assessed by a variety of self-report and interviewer-administered measures. selecting a self-report and/or a structured-interview format to measure suicidal symptoms is a critical decision. for example, although interviewer-administered measures may allow for greater flexibility for conducting appropriate assessments of suicidal behaviour, these measures usually require more time and expense (for administration and training) than self-report measures. in contrast, self-report questionnaires may be inadequate for measuring suicidality in cognitively impaired or highly emotional individuals with concentration difficulties, although findings in this regard are mixed.24 , 25 although self-report measures are often used as screening tools, an adequate evaluation of suicidality should include both self-report and interviewer-administered measures. since its publication in 1974, beck’s hopelessness scale (bhs) has become an internationally-accepted and widely used measure in suicide prevention.26 the scale has been extensively researched and validated as a measure to predict suicide and is still being used worldwide.27 , 28 although depression, hopelessness and suicide correlate closely, hopelessness was identified as one of the most important psychological, predictive and modifiable risk factors.27 , 28 in this context, the aim of the present study was to construct a short, reliable and valid instrument with high screening and clinical utility with which to screen for suicide risk in recently diagnosed hiv-infected persons at a voluntary counselling and testing (vct) clinic in durban. this was intended to identify individuals whose suicidal ideation was severe enough to warrant treatment and suicide prevention. methods participants and setting the sample consisted of 150 hiv-infected adults, presenting for the first time to be tested for hiv at a vct clinic in an academic district-level hospital in durban. all participants who tested hiv-positive following vct were informed about the study by the resident vct counsellor. participants who consented voluntarily were enrolled in the study and were asked to complete the suicide risk screening scale (srss) and the supre-miss instrument at baseline and three weeks later. the study was approved by the biomedical research ethics committee of the university of kwazulu-natal (bf202/09) and permission to conduct the study was granted by the relevant health institution. instruments two well-known and extensively used scales were utilised to assess aspects of suicidality in various population groups, viz. the bhs and the beck depression inventory (bdi). although these items do not directly assess suicidal behaviour, they measure hopelessness and immediate suicide risk. the bhs contains 20 true/false items (11 negatively and 9 positively phrased), with the severity of hopelessness (an indirect indicator of suicide risk) calculated by adding the scores for the 20 items. the total scores range from 0 (no hopelessness) to 20 (maximum level of hopelessness). the bdi, developed as a standardised measurement to assess the grades and severity of depression in order to monitor the change over time, contains 21 behavioural manifestations (items) of depression, which describe the symptoms from low to high. the items are scored individually from 0 to 3; these are added to obtain a total score of 0 63. a value <9 represents no or minimal depression, 17 29 moderate depression and >30 severe depression. co-morbid conditions have been found to affect specificity of severity ratings at both the lowand high-end scores.27 several researchers have used items from both scales to validate the use of shorter versions in specific populations.27 , 29 , 30 for the present study, 14 items were selected from these scales to construct the srss (table 1). the 11 bhs items selected are negatively phrased questions that reflect expectations of failure or motivational components (items v2, v9, v11, v16, v17, v20) and future uncertainty or cognitive components (items v4, v7, v12, v14, v18). item selection was based on patient responses in the related previous studies, by choosing those with the highest and lowest scores at the two time-points using the complete bhs and bdi.17 , 18 what the components measure has been addressed in other research.29 , 31 our rationale for item selection incorporated several additional considerations. firstly, patients with extreme pessimism would endorse the negative items selected and thus be more likely to be scored to have a higher suicide risk. 29 , 30 secondly, the item-size pool is underscored by a theoretical framework that the patients’ perceived hopelessness about their situation and future could be linked to suicide risk. this stems from the premise that cognitions mainly centre around an uncertain future and the loss of perspective in finding solutions to problems, which lead to hopelessness and consequently to suicidal ideation or attempt.26 in line with the bhs scoring, the items of the srss were scored: true = 1; false = 0. in the absence of a gold standard, an instrument previously tested in the general population in durban was used as a proxy: the community survey aspect of supre-miss, based on the european parasuicide study interview schedule, which had been applied in the who/euro multicentre study on suicidal behaviour.19 the following questions were asked: (i) ‘have you ever seriously thought about committing suicide?’; (ii) ‘have you ever made a plan for committing suicide?’; (iii) ‘have you ever attempted suicide?’. the supre-miss instruments were pilot-tested, translated into different languages and validated. since the supre-miss instrument was deemed reliable to predict suicidal behaviour, it was used as the reference to test the validity of the srss. statistical analysis spss version 10.0 was used for data analysis. receiver operating characteristic (roc) analyses were used to determine the sensitivity, specificity and optimal cut-off points of the srss to predict suicidal ideation. inter-item characteristics, internal consistency, reliability and validity analyses were also performed. results the mean age of participants at baseline was 33.5 years (standard deviation (sd) ±9.4). the cut-off points of the srss scores and their corresponding sensitivity and specificity values are shown in table 2. a cut-off score of 4.5 (≥4 being a positive result) achieved 68% sensitivity and 64% specificity in predicting suicidal ideation and is therefore the recommended cut-off for the srss. in establishing cut-off points on the srss that would optimise sensitivity and specificity via roc analysis, it was decided that, ideally, the test should be more sensitive than specific to identify as many probable suicidal patients as possible. sensitivity is paramount to suicide prediction and was our rationale for maximising sensitivity in the present analysis. the area under the curve (auc) in roc analysis was 0.730 at baseline (95% ci 0.64 0.81) and 0.776 at three weeks (95% ci 0.68 0.87) (figs 1 and 2, respectively). fig. 1. roc curve of srss scores for suicidal ideation immediately post-diagnosis (baseline) in hiv-infected adults. fig. 2 roc curve of srss scores for suicidal ideation three weeks post-diagnosis in hiv-infected adults. inter-item characteristics and internal consistency table 3 displays the corrected item-total correlation at baseline and three weeks later. the corrected item total was >0.30 for all items except for v2 (‘i can’t imagine what my life would be like in ten years’). this item had a corrected item-total correlation of 0.333 at baseline and 0.277 three weeks later. due to its potential for ambiguity in some non-clinical samples, it has been described as an outlier; in other studies it represented one of the highest-scoring item responses at different time intervals.13 , 17 , 18 this apparent discrepancy can be explained partially by considering various factors. for example, for some patients, being told that they have a positive hiv status can be an extremely stressful experience that constitutes a life crisis. for many, their psychological response can include the perception of ‘a death image’,7 if they assume that they have been dealt a death sentence. this, along with the myriad of possible other misconceptions, cognitive distortions, psychiatric and life-disruption complications, a shortage of healthcare resources and the fear of not being eligible for, or having access to art,1 makes it difficult for hiv-positive persons to visualise a long-term future. the item-total correlations ranged from 0.318 to 0.675. at baseline, item v10 (‘the future seems vague and uncertain to me’) had the best corrected item total (0.675), while item v11 (‘there’s no use in really trying to get something i want because i probably won’t get it’) had the best corrected item total (0.802) at three weeks. the cronbach’s alpha for a deleted item showed that none of the items were problematic. the level of internal consistency for the srss was, therefore, acceptable for clinical purposes and was consistent with the findings of other studies.27 reliability and validity the overall cronbach’s alpha for the srss at baseline and three weeks was 0.874 and 0.915, respectively. to determine the validity of the srss, it was compared with the accepted instrument for supre-miss. using a cut-off score of 4, the sensitivity for the srss at baseline was 81% with a positive predictive value of 48%, a specificity of 47% and a negative predictive value of 80%. at three weeks, the sensitivity was 79%, the specificity 55%, the positive predictive value 44%, and the negative predictive value 82%. discussion this study demonstrated the potential utility of a simple screening tool to detect suicidality in hiv-infected individuals newly diagnosed through a vct programme. although the sensitivity and specificity of the srss were not very high (around 68%), these compared favourably with those obtained in other research.26 , 29 unlike other studies, where item 7 or the 4 items of the bhs were not administered individually, in our study the full version of the bhs was administered and the responses to the 20 items were used to deduce final scores.29 notably, there was a likelihood of a high level of false-positives through the use of the srss. the results indicate a good sensitivity at both time-periods and a comparatively low rate of false-positives. further research and the incorporation of additional assessment items in the questionnaire are likely to have a more successful result in suicide prevention. equally important for screening instruments to be effective is the prevalence of risk within the population. it is well documented that sa – especially the city of durban, where the research was conducted – has a high prevalence of hiv/aids, and a recent study showed that sero-positivity, age and gender were significantly associated with suicidal ideation.17 , 18 it can therefore be concluded that the srss can be used, in conjunction with a clinical interview, as a valid screening instrument to assess for suicide risk in this setting. the use of a clinical interview, which remains the fundamental basis of suicide risk assessment, should incorporate an understanding of the patient’s suicidal crisis from both an objective/descriptive as well as an experiential perspective.23-25 the former includes objective patient data to assess suicide risk, a clinical (psychiatric/psychological) history and identification of overt suicidal manifestations and risk factors.23-25 the latter perspective goes beyond delineation of clinical symptoms in an attempt to understand the patient’s actual feelings, personal narrative, perspective, sustaining resources and beliefs about suicide.23-25 the assessment of hopelessness is extremely important in clinical practice, since high levels of hopelessness can lead to isolation and the inhibition to seek help timeously. given this, vct offers patients an option to be counselled and tested for the presence of hiv and, at the same time, provides an opportunity to identify any underlying level of hopelessness and suicide risk related to receiving a life-altering diagnosis of hiv-positivity.17 , 18 the self-administered questionnaire can be completed while patients are awaiting their hiv test results. the questionnaire is easily scored and a risk assessment is performed with relative ease. a suicide intervention to be included in the post-test counselling is presently being evaluated, including re-administering the srss at the next clinical visit. this may decrease the rate of false-positives obtained. study limitations the construction of the srss involved selecting items from two sub-scales, which were grouped and analysed as a single scale. the main limitation of this study was that there was no gold standard to use as a baseline reference within the context of the population studied. furthermore, there was no reference to the participants’ views on living with hiv, which can be part of a clinical interview; this should form the focus of further research. conclusion analyses have demonstrated the importance of brief scales with high clinical validity for assessing suicidal risk in daily clinic settings.21 , 22 our research shows that the srss can be a valuable screening tool for suicidality as part of a standard clinical interview and good clinical assessment in hiv/aids vct clinics. suicide risk assessment in patients seen at such clinics should be a routine aspect of comprehensive patient care, to assist with effective management and the prevention of possible suicidal behaviour. the srss is not intended as a stand-alone diagnostic tool to assess suicidal behaviour, but may be used as a triage tool to assist in the identification of high-risk patients. acknowledgements. we thank prenisha pillay for research assistance and mrs t esterhuizen for statistical assistance. rdg was supported by the columbia university/south african fogarty aids international training and research programme (aitrp) funded by the fogarty international center, 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[http://dx.doi.org/10.1177/0306624x08319418] 28. perry ae, olason dt. a new psychometric instrument assessing vulnerability to risk of suicide and self-harm behaviour in offenders: suicide concerns for offenders in prison environment (scope). int j offender ther comp criminol 2009;53:385. [http://dx.doi.org/10.1177/0306624x08319418] 29. american psychiatric association (apa). handbook of psychiatric measures. washington, dc: apa, 2000. 29. american psychiatric association (apa). handbook of psychiatric measures. washington, dc: apa, 2000. 30. yip psf, cheung yb. quick assessment of hopelessness: a cross-sectional study. health qual life out 2006;4(13). [http://dx.doi.org/10.1186/1477-7525-4-13] 30. yip psf, cheung yb. quick assessment of hopelessness: a cross-sectional study. health qual life out 2006;4(13). [http://dx.doi.org/10.1186/1477-7525-4-13] 31. aish am, wasserman d. does beck’s hopelessness scale really measure several components? psychol med 2001;31:367-272. 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[http://dx.doi.org/10.1017/s0033291701003300] abstract introduction basic modelling concepts the core demographic models modelling when to start treatment models targeting particular policy conundrums discussion acknowledgements references appendix 1 competing interests about the author(s) nathan geffen department of computer science, centre for social science research, university of cape town, south africa alex welte south african centre for epidemiological modelling and analysis (sacema), university of stellenbosch, south africa citation geffen n, welte a. modelling the human immunodeficiency virus (hiv) epidemic: a review of the substance and role of models in south africa. s afr j hiv med. 2018;19(1), a756. http://doi.org/10.4102/sajhivmed.v19i1.756 original research modelling the human immunodeficiency virus (hiv) epidemic: a review of the substance and role of models in south africa nathan geffen, alex welte received: 29 mar. 2017; accepted: 07 aug. 2017; published: 21 feb. 2018 copyright: © 2018. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract we review key mathematical models of the south african human immunodeficiency virus (hiv) epidemic from the early 1990s onwards. in our descriptions, we sometimes differentiate between the concepts of a model world and its mathematical or computational implementation. the model world is the conceptual realm in which we explicitly declare the rules – usually some simplification of ‘real world’ processes as we understand them. computing details of informative scenarios in these model worlds is a task requiring specialist knowledge, but all other aspects of the modelling process, from describing the model world to identifying the scenarios and interpreting model outputs, should be understandable to anyone with an interest in the epidemic. introduction no epidemic has received the attention of the ongoing human immunodeficiency virus (hiv) and acquired immune deficiency syndrome (aids) pandemic, and no matter of public health concern has been the subject of so much controversy and policy debate. scenario modelling has been widely employed in attempts to better understand the demographic, health and economic impacts of the epidemic under various interventions, for example, antiretroviral treatment, pre-exposure prophylaxis and condom use. despite modelling being ubiquitous and some models generating intense public debate, with consequences, for example, on world health organization (who) treatment and prevention guidelines, it remains poorly understood by non-specialists. even modellers themselves hold differing views about the principal uses and limitations of models. this article reviews the evolution of models, and their applications, in the context of the south african hiv epidemic. we describe, in terms aimed at a wider audience than just modellers, the basic structure of the modelling process, challenges that modellers face and how this has affected policy debate. in appendix 1, we explore in more detail the social complexities of the particular issues and controversies. basic modelling concepts books, tutorials and reviews of epidemiological modelling are plentiful, including guidance for working with models in the context of policy debate.1,2,3,4 nevertheless, it is useful to review some essential aspects of all scenario modelling. the aim of mathematical modelling is to first identify the key rules that govern the behaviour of a natural world phenomenon, and then to implement those rules in mathematical relations, so that we can learn more about the phenomenon. for models of the hiv epidemic, this may mean understanding how gender, age, location and other sociological factors influence fertility, exposure to ‘infectious contacts’, access to healthcare and mortality. what determines whether and what kind of model is feasible or useful are the questions we want to answer about the ‘real world’ epidemic, coupled with the data available to justify assumptions about precisely stated rules driving critical processes (dynamical rules). mathematical and computational challenges may be substantial and sometimes curtail the ambitions of modellers. it is important to differentiate the specialised technical aspects of model construction and analysis, carried out by mathematical modellers, from the conceptual aspects, which are accessible to anyone with basic insights into the situation being modelled, including doctors, politicians, health system administrators, biologists and activists. this conceptual and technical distinction helps clarify thinking and reminds us that model building should be an inclusive multidisciplinary process rather than the protected domain of specialists. for example, in the early 2000s, members of the activist organisation the treatment action campaign approached the developers of the actuarial society of south africa (assa) models and asked them to incorporate antiretroviral treatment into their model, which they did. an analysis of the cost of rolling out antiretroviral treatment in the public health system, based on the outputs of the assa model, was featured on the front page of the mail & guardian. the assa models were explained by demographers in affidavits in litigation by activists advocating for treatment. the scenarios, assumptions and outputs of the model were debated and understood by a broad range of people: politicians, activists, lawyers, etc. the actual equations in the model spreadsheet were likely of interest to, and understood by, only a handful of specialists.5,6,7,8 to maintain the distinction between concepts and techniques, we use concepts popularised by ecological modeller tony starfield: model world versus model implementation.9 a model world is the conceptual realm in which we explicitly declare the rules – usually some simplification of ‘real world’ processes as we understand them. model implementation then refers to the mathematical and computational details. for example, a model world may be conceptually inhabited by genderless people between the ages of 15 and 49 who all have exactly the same behaviours and mortality. we may declare that in our model world each day brings the same risk of infection or death as the day before, without any notion of individual age, the mechanisms of infection or death. a related model implementation of such a world may consist of some mathematical equations or computer programme. model worlds capture the essential ideas which we then formally analyse and explore in technical investigations, using mathematical and computational tools. a model world has abstracted entities and rules, but no particular history. when we set up initial conditions in a model world, like winding up a clock set to midnight, and then let it run, we produce scenarios – particular realisations of processes and events consistent with the assumptions of the model world. a full-fledged investigation may involve many scenarios located in several model worlds. there are typically two kinds of variables in a model: (1) state variables, that is, scenario-specific accounting indicators, such as the size of population, number of infections and number of deaths, and (2) parameters, that is, model world defining metrics such as, most critically, rates of infection, rates of death and other state transition rules. when the model executes (e.g. as a stand-alone piece of software or as a spreadsheet), state variables evolve over time from given initial conditions, but for this to happen, parameter values must actively be chosen. sometimes parameters are chosen based on pre-existing knowledge or estimates. sometimes they are chosen entirely heuristically, just to see what is implied by their values lying here or there within some plausible range. another option is model calibration, by which parameters are chosen in such a way that the emergent behaviour of the model is consistent with some data. for example, we can try different values of an infectious ‘contact rate’ (how frequently people become infected), and then see whether a suitably narrow range of this parameter produces a time-varying prevalence that is consistent with survey data. for sexually transmitted infections, a key aspect of model worlds is how infections occur. infection can happen for a population group at some rate, without any concern for sexual interactions. there can be a single rate across the population or it could be differentiated by age, risk group and gender. alternately, infection can be conceptualised at a very fine level of detail: a model world could track sexual relationships – or even sexual acts – per individual, with each individual having their own risk of contracting or transmitting the infection. in model worlds, there are no grey areas of the kind we find in the real world, no hidden unknown rules, factors and entities – although the interplay of components may be complex and may require some sophistication to implement, or conceptually untangle. modelling then might be seen as teasing out the implications of hypothetical claims about how the world is composed and governed. if done skilfully, this helps explain some aspect of the real world. it informs real world choices that need to be made, even if the full underlying truth in the real world is much more elusive and ambiguous than in any model world we may have constructed. table 1 highlights key features of the model worlds implemented in the models we review here. table 1: examples of models of the south african hiv epidemic. the crucial point is as follows: everyone with a legitimate interest in the situation being modelled is entitled to a comprehensible description of the model world. they should expect to be part of the model world construction, critique and interpretation processes. modellers need to talk in conceptual terms about this model world, without resorting to jargon or specialised techniques. the core demographic models padayachee and schall, working for johannesburg’s city health department, published the first serious model of the whole south african hiv epidemic in april 1990.10 they cited two earlier models that estimated the number of gay men and antenatal care attendees in what was then southern transvaal with hiv. they also mentioned a who model that estimated the number of aids cases in south africa but noted that the model was based on ‘very little, if any, supporting evidence from south africa’ (p. 330). padayachee and schall actually implemented three simple models, which used antenatal clinic, blood transfusion, sexually transmitted infection and family planning clinic data and population estimates by province to estimate infections for the whole country up to 1992. their model worlds consist of adult (aged 15 to 49 years) black people, possibly living in a particular province or urban or rural area, but with no other identifiable characteristics. their first model fitted clinic and blood transfusion data to estimate a rate at which the epidemic was growing. they extrapolated this to calculate national prevalence and the rate at which it was growing up to 1992. their second model, whose method they called ‘direct’, used various data sets to estimate the number of people with hiv in each province, which they then aggregated for the whole country. their third model, whose method they called back calculation, used the number of known aids cases and an assumption about the time from hiv infection to aids to back-calculate the number of hiv cases, derive an incidence rate and then use this to project the number of hiv cases in the future. they estimated the number of black south africans, aged 15 to 49 years, with hiv for the end of 1989, 1990 and 1991. their model calculated between 45 000 and 63 000 infections by end of 1989, rising to between 317 000 and 446 000 at the end of 1991. clearly there were problems with their methodology: for one thing blood donor hiv prevalence rates were not representative. however, their models provided some idea of the extent of the epidemic using the limited data available then. they wrote: ‘because of the lack of basic data, these forecasts are tentative, but they nevertheless indicate the great seriousness of the hiv epidemic in south africa’ (p. 329). in october 1990, doyle and millar, working for the metropolitan life insurance company, published one of the most influential models of the epidemic.11 they constructed a model world with an adult population comprising four risk groups: (1) people having no sexual contact, or in long-term monogamous relationships, who are not at risk of hiv, (2) people at some risk, conceived as being in stable relationships but with one or the other partner having more than one sexual relationship, (3) people with higher levels of risk, such as those with other sexually transmitted infections, and (4) sex workers and people with large numbers of sexual partners. these four risk groups remained a part of highly cited models derived from or based on the doyle model (as it came to be known) until the late 2000s. model world inhabitants were assigned rates for forming new relationships, within and across risk groups, and rates of transmission within relationships. it allowed for 5-year age groups to be defined, with different levels of hiv prevalence at the beginning of a scenario. it also had parameters for fertility, mother-to-child transmission rate and hiv and non-hiv mortality rates. it could be used for heterosexual or homosexual populations, adapted as needed to populations of interest. doyle applied the model to south africa, leading to prescient predictions that were not obvious in the early 1990s, for example, that the epidemic would kill many young adults, but that the population would not decline (although the growth rate would slow).12 lee et al. applied the model to soweto, estimating that by 2010 it would account for 28% – 52% of all deaths there.13 the model implementation of doyle and millar’s model world was in the form of population counts at discrete time steps, deterministically updated according to the expected values emerging from statistical rules (like probability of infection or death). doyle cites other models developed by the institute of actuaries and society of actuaries at the time but points out that these ‘considered one small homogeneous risk group’ and were inappropriate for modelling the south african epidemic.12 these model implementations are often called deterministic compartmental, frequency-dependent or macro. by contrast, a microsimulation, network or agent-based implementation, possibly of the same underlying model world, proceeds by explicitly tracking a large number of identifiable individual model world inhabitants and subjecting them, usually stochastically, to the different events to which they are exposed. the first microsimulation of the south african epidemic that we can find is a medical research council lecture cited in doyle and millar’s 1990 paper. unfortunately, we can find no further references to this particular one in the literature. doyle’s model was a proprietary one used by metropolitan life, primarily for the purpose of making decisions about employee benefits (pers comm. stephen kramer). it was the progenitor of other models, including those of the assa. given the computing power at the time, the level of detail is impressive, in most respects exceeding the complexity of a widely cited and highly impactful model, published as late as 200914 that stimulated the debate on early treatment as a means of reducing new transmissions. groeneveld and padayachee used a microsimulation implementation of a model world in which each person, based on their age and gender, has an expected number of sexual partners per year, with a specified proportion of ‘short’ relationships, and an estimate of the frequency of sexual contacts with partners who are infected with hiv with a probability dependent on age and gender. the authors also estimated the annual number of immigrants with hiv who entered south africa annually. their goal was to ‘to estimate the extent of hiv infection among black heterosexual south africans’. they attempted to predict new hiv infections for the period 1985–2000 and concluded that there would be 5.7 million people with hiv in south africa by 2000. by comparison, the most comprehensive up-to-date current model of the epidemic, thembisa, estimates that there were 3.3 million people infected in 2000.15 brophy adapted a world bank model for the south african epidemic and investigated demographic effects on the black population under various scenarios.16 the model world divided the population by sex and 5-year age groups. there were also partially overlapping groups: blood transfusion recipients, heterosexual females, heterosexual males and bisexual males. it considered fertility rates, the age pattern of fertility and mortality levels by male and female. the model population was matched to the sex and age structure of the 1985 census. various data sources were used to estimate fertility and life expectancy. some parameters, such as the number of sexual partners, coital frequency, condom use, as well as fertility and life expectancy from 2005 to 2010, were essentially guessed (and various scenarios were tried). they calibrated the model so that it estimated the middle estimate of the number of infections in 1990 of the model by padayachee and schall (described above). brophy predicted substantial reductions in the population and life expectancy in 2000, 2005 and 2010 under three aids scenarios of increasing severity versus a no-aids scenario. in the bleakest scenario, the model estimated that there would be just about 1.9 million people with hiv in the adult black population in 2000 (the actual number was about 3 million). dorrington described the origins of the assa models.17 the first assa model was developed on a spreadsheet by a team led by alan whitelock-jones. it was titled assa500 and was similar to the doyle model with some simplifications. dorrington explains that the motivation for assa to develop a model when the doyle model already existed was that the latter was proprietary and there was a need for a ‘program which the user could alter to his or her needs’ (p. 99). consequently, the model was placed on assa’s website and dorrington wrote: ‘the reader is encouraged to download and play with it’ (p. 101). dorrington also wished to improve the model world of doyle, specifically because it assumed constant fertility and non-hiv mortality over time; the assa model world would include decreasing fertility rates and improving non-hiv mortality. using the same risk groups as the doyle model, it additionally accounted for ‘net national in-migration’ (p. 100). while users of the doyle model needed to set the parameters for the community they were modelling, the assa models are explicitly aimed at modelling the south african epidemic, with later models disaggregating the outputs by province. the starting point of the assa600 model was the 1985 south african population, known from a census conducted that year. the model was calibrated to reported aids cases in 1995 and antenatal hiv prevalence, derived from annual surveys by the department of health for 1994–1997. dorrington described the calibration of the model as ‘perhaps inevitably a little more art than science’. the assa modellers aimed to produce a population estimate for 1996, national mortality rates for 1998, a projection of antenatal clinic hiv prevalence rates and a projection of national fertility rates. over the next decade, assa600 had several successors: assa2000, assa2002 and assa2008. from 2000, the suffix indicates the latest year of the empirical, primarily antenatal survey, data against which the models were calibrated (i.e. not the year they were published). the goal was to fit the known empirical data, estimate past unknown and project future, demographic and hiv outputs, such as population size, non-hiv and hiv mortality, hiv prevalence and incidence. from assa2002, the effects of antiretroviral treatment were incorporated.5,6 the assa models are widely cited. besides being comprehensive, they have also been open and easily accessible. as johnson explains, the ‘excel interface of the publicly-available model is appealing to many non-modellers’.18 the latest assa model has been calibrated with data only as far as 2008. in recent years, the assa models too have been superseded, most notably by the thembisa model.18 this combines the features of three other models, besides the assa model. the model world complexity is substantial, including more realistic sexual behaviour ‘calibrated to marriage data and cross-sectional data on numbers of partners’, ‘more determinants of mother-to-child transmission’ and ‘most of the new strategies for preventing and treating paediatric hiv’. for example, it features cd4 count staging instead of clinical staging as in the assa models and allows for earlier antiretroviral initiation. it includes newer prevention interventions such as male medical circumcision, pre-exposure prophylaxis and ‘who options b and b+ for prevention of mother-to-child transmission’. in contrast to the assa models, it takes into account change in risk behaviour by people over time. the joint united nations programme on hiv and aids (unaids) has also produced widely used models. in the 1990s, unaids used epimodel – developed in 1987 by the global programme on aids – for its global, regional and country hiv projections.19 this was eventually replaced by spectrum, developed by the erstwhile futures group (now avenir health), and the estimation and projection package (epp), since combined into one programme.20,21,22 the model provides a user interface that takes a range of inputs, for example, base year population by age and sex, fertility rates, life expectancy (aids and non-aids), migration rates, number of people on antiretrovirals, number of people on cotrimoxazole and about a dozen or so more (see table 1).22 it then aggregates all cases in the population aged 15 to 49 years and fits a non-age-structured population model to the historical aggregates, thereby inferring incidence and projecting outputs such as hiv infections and deaths. johnson18 writes: the spectrum/epp model is used … in producing estimates of the global distribution of hiv, and therefore has the advantage of benefiting from a substantial body of international expertise in hiv epidemiology. however, the separation of the modelling of hiv incidence and demographic impact in this model does limit the ability of the model to make use of age-specific data in model calibration. [p. 6] spectrum/epp is used to estimate official estimates for every country in the world every two years for the united nations population division; it serves an important purpose, providing rough estimates of hiv prevalence and mortality where none would otherwise be available. the model is also used to analyse the long-term impact and cost of interventions, though as johnson says, it is ‘limited in its ability to evaluate the impact of hiv prevention strategies and make long-term projections’. where countries have developed high-quality specialised models, such as the thembisa model for south africa, it makes more sense to use these. modelling when to start treatment in 2009, granich et al. at the who presented two models.14 the first model is a population-level transmission model (implemented deterministically) that calculated the long-term dynamics of the hiv epidemic based on different treatment strategies. the second model (implemented stochastically) investigated the effect on r0 – ‘the number of secondary infections resulting from one primary infection in an otherwise susceptible population’ – of different treatment strategies applied to an hypothetical person. the paper argued that, in south africa, a policy of universal testing coupled with immediate treatment for adults found to be hiv-positive would effectively eliminate the epidemic. in particular, they estimated that hiv incidence could drop to less than 0.1% per year by 2016. they also costed the strategy. the paper caused great excitement and controversy. it has been cited, according to google scholar, 1640 times (as of 11 march 2017). we know of no other hiv model that has been cited as often, which is extraordinary considering the simplicity of the models: there is no gender or age structure. perhaps this simplicity, coupled with the strongly stated message the authors conveyed, engaged readers across multiple disciplines and accounted for much of the interest taken in the paper. the paper also encouraged a flurry of other models that looked at the same question.23 even 4 years later, a detailed set of microsimulation models by hontelez et al. was published, trying to answer the same question as granich et al.14 the modellers developed ‘nine structurally different mathematical models of the south african hiv epidemic in a stepwise approach of increasing complexity and realism’. the simplest resembled the granich model. the most complex included ‘sexual networks and hiv stages with different degrees of infectiousness’. hontelez et al.24 defined ‘universal test-and-treat’ as annual screening and immediate treatment for all hiv-positive adults, starting at 13% in january 2012 and scaling up to 90% coverage by january 2019. elimination of the hiv epidemic was defined as incidence below 1 per 1000 person-years. it is controversial whether addition of complexity to models improves them. for example, one of the authors of the granich et al. paper, brian williams, has written: hontelez et al. suggest that the [then] current scale-up of art at cd4 cell counts less than 350 [cells/mm3] will lead to elimination of hiv in 30 years. i disagree … and believe that their more complex models rely on unwarranted and unsubstantiated assumptions.25 the granich model and the ensuing attempts by other modellers to verify, refute or improve upon it raise important questions about what we are trying to achieve with modelling. the original paper is the one that was widely debated. even though it could be improved, it answered the question of whether a test-and-treat policy had the potential to massively reduce incidence. most subsequent models agreed with that of granich et al. that universal test-and-treat would substantially reduce new infections but not as quickly as they proposed. the assumption of rapid scale-up of treatment coverage and significant viral suppression in those failing treatment were, perhaps, too optimistic. models targeting particular policy conundrums interventions other than antiretroviral treatments have also been modelled. there are numerous such models, and here we briefly note some without describing their model worlds. the results of a randomised controlled trial that compared infection rates in circumcised versus uncircumcised men in orange farm26 were used to calculate that this intervention could prevent between 1.1 and 3.8 million infections as well as 0.1 to 0.5 million deaths over a 10-year period in sub-saharan africa.27 a comparison of the cost-effectiveness of treatment as prevention, treatment (solely for the benefit of the patient) and circumcision concluded that although treatment as prevention was cost-effective, it was less so than treatment or circumcision.28,29 modelling the introduction of pre-exposure prophylaxis (prep), researchers found that it could avert 30% of new infections in ‘targeted age groups of women at highest risk of infection’. however, they also found that the cost-effectiveness of prep relative to treatment would decrease rapidly as treatment coverage increased.30 another group had more optimistic results modelling prep in serodiscordant couples (although it is unclear how a model can address whether antiretrovirals should be given to the hiv-negative or hiv-positive partner in a relationship).31 they concluded: although the cost of prep is high, the cost per infection averted is significantly offset by future savings in lifelong treatment, especially among couples with multiple partners, low condom use, and a high risk of transmission. [p. 1] another model found that treatment plus prep was more effective than either strategy alone but would also produce high prevalence of drug resistance.32 hallett et al. investigated the use of prep for seronegative partners in stable serodiscordant partnerships, as an alternative or adjunct to treatment for the hiv-positive partner.31 sexual behaviour – such as condom use, number of partners, concurrency, and transactional sex – has been widely modelled.33,34,35,36,37,38 models developed by the assa researchers, for example, estimated that hiv incidence in south africa dropped during the period from 2000 to 2008 and that increased condom use was the ‘most significant factor explaining’ this decline.39 the role of concurrency has however been contentious, with conflicting findings.33,34,40 experimental interventions such as microbicides41 and vaccines have also been considered,42 and so has the role of treating sexually transmitted infections.43 for further references, see johnson.18 currently, models such as thembisa and spectrum are being used to track progress towards national and global objectives, such as the unaids 90-90-90 targets (90% of people with hiv diagnosed, 90% of people diagnosed on treatment and 90% of people on treatment virally undetectable),44 as well as elimination of mother-to-child transmission.45 discussion the distinction between model worlds and the technical implementation of models is useful for demystifying modelling and perhaps allows more people to participate in model construction and critique, and hence reach better informed decisions on the policy implications of models. while models, with their complex equations and computer code, might be impenetrable to all but specialists, the conceptual ingredients – the model world – should be accessible to a wide audience. the earliest models of the south african hiv epidemic projected prevalence and mortality over time, a task that remains useful today. new models were subsequently developed to estimate the effects of interventions, for example, how antiretroviral treatment would reduce mortality (assa2002 interventions model) or how it would reduce new infections (the granich model). the challenge facing modellers was summarised by dorrington5: estimating the exact impact of hiv/aids on mortality is not a simple task since there are many uncertainties surrounding the dynamics of the spread of the virus and subsequent passage to death. in addition there are difficulties in deciding on the level of overall mortality in south africa since not all deaths are registered. however, determining an order of magnitude of the impact is well within the capabilities of a trained demographer. (our emphasis) (para. 7) models, even simple ones, can shed light on ‘big picture’ questions. they cannot be used to provide precise predictions of the long-term future. models can also provide plausible estimates of unobserved epidemic indicators and assist with planning for the short-term future. these benefits and limitations of models should be kept in mind before deciding to add complexity to model worlds, and consequently model implementations. modelling is still an evolving component of biomedical science. perhaps, as we argue in appendix 1, a key factor in advancing consensus in how models are assessed, especially with societal implications, is a more inclusive interdisciplinary approach to defining and debating ‘model worlds’, and ‘model world scenarios’, the conceptual aspects of modelling that should be accessible to everyone with an interest in the hiv epidemic. this should lead to improved models that contribute more robustly to policy discussions. acknowledgements competing interests nathan geffen occupied senior positions, both as a staff and executive member, in the treatment action campaign (tac) from 2000 to 2013. both he and the tac were active participants in the debates described in this article. he has received bursary contributions towards his phd research from the centre for social science research and the south african centre for epidemiological modelling and analysis. alex welte has no disclosures. authors’ contributions n.g. conceived and drafted the article. a.w. proposed including the terminology on model world, model and scenario, and drafted this section of the article. the authors reviewed and edited the article together. references delva w, wilson dp, abu-raddad l, et al. hiv treatment as prevention: principles of good hiv epidemiology modelling for public health decision-making in all modes of prevention and evaluation. plos med. 2012 jul 10;9(7):e1001239. https://doi.org/10.1371/journal.pmed.1001239 vynnycky e, white r. an introduction to infectious disease modelling. 1st ed. new york: oxford university press; 2010. 400 p. garnett g. an introduction to mathematical models in sexually transmitted disease epidemiology. sex transm infect. 2002 feb;78(1):7–12. https://doi.org/10.1136/sti.78.1.7 johnson l. notes: an introduction to the mathematics of hiv/aids modelling. [publisher unknown]; 2004. dorrington re. expert affidavit in tac competition commission complaint [homepage on the internet]. 2002 [cited 2016 may 18]. available from: http://www.tac.org.za/documents/drugcompaniescc/tac_dorrington_final.doc johnson lf, dorrington r. modelling the demographic impact of hiv/aids in south africa and the likely impact of interventions. demogr res. 2006 jun;14(22):541–574. https://doi.org/10.4054/demres.2006.14.22 nattrass n, geffen n. the impact of reduced drug prices on the cost-effectiveness of haart in south africa. afr j aids res. 2005 may;4(1):65–67. https://doi.org/10.2989/16085900509490343 deane n. the price of three million lives. mail guard. 2016 mar;2. starfield t. tony starfield shares his thoughts on modeling [homepage on the internet]. 2012 [cited 2017 aug 17]. available from: http://www.uvm.edu/~tdonovan/modeling/nicetoknow/00_modelthoughts_transcript.pdf padayachee gn, schall r. short-term predictions of the prevalence of human immunodeficiency virus infection among the black population in south africa. s afr med j suid-afr tydskr vir geneeskd. 1990 apr;77(7):329–333. doyle p, millar d. a general description of an actuarial model applicable to the hiv epidemic in south africa. trans actuar soc south afr. 1990;viii(ii):561–593. doyle p. the demographic impact of aids on the south african population. in: cross s, whiteside a, editors. facing up to aids [homepage on the internet]. palgrave macmillan uk; 1993 [cited 2016 feb 19]. p. 87–112. available from: http://link.springer.com/chapter/10.1007/978-1-349-22597-2_5 lee t, esterhuyse t, steinberg m, schneider h. demographic modelling of the hiv/aids epidemic on the soweto population–results and health policy implications. s afr med j suid-afr tydskr vir geneeskd. 1996 jan;86(1):60–63. granich rm, gilks cf, dye c, de cock km, williams bg. universal voluntary hiv testing with immediate antiretroviral therapy as a strategy for elimination of hiv transmission: a mathematical model. lancet. 2009 jan;373(9657):48–57. https://doi.org/10.1016/s0140-6736(08)61697-9 groeneveld h, padayachee n. a stochastic model for medium-term estimation of the prevalence of hiv infection in a south african heterosexual population. s afr med j suid-afr tydskr vir geneeskd. 1992 jan;81(2):67–70. brophy g. modelling the demographic impact of aids: potential effects on the black population in south africa. in: cross s, whiteside a, editors. facing up to aids [homepage on the internet]. palgrave macmillan uk; 1993 [cited 2016 feb 19]. p. 113–134. available from: http://link.springer.com/chapter/10.1007/978-1-349-22597-2_5 dorrington re. assa600: an aids model of the third kind? trans actuar soc south afr. 1998;13(1):99–153. johnson l. thembisa version 1.0: a model for evaluating the impact of hiv/aids in south africa. centre for infectious disease epidemiology and research working paper. thembisa project; 2014. p. 6. [cited 2017 dec 18] available from: http://www.publichealth.uct.ac.za/sites/default/files/image_tool/images/108/thembisa%20version%201.0.pdf unaids, world health organisation. report on the global hiv/aids epidemic [homepage on the internet]. 1998 [cited 2016 may 18]; p. 50–51. available from: http://data.unaids.org/pub/report/1998/19981125_global_epidemic_report_en.pdf unaids. unaids quarterly update on hiv epidemiology/1q 2010: methods for estimating hiv incidence [internet]. 2010 [cited 2016 may 18]. available from: http://www.unaids.org/sites/default/files/media_asset/epi_alert_1stqtr2010_en_3.pdf stover j, brown t, marston m. updates to the spectrum/estimation and projection package (epp) model to estimate hiv trends for adults and children. sex transm infect. 2012 dec;88 suppl 2:i11–16. https://doi.org/10.1136/sextrans-2012-050640 stover j, andreev k, slaymaker e, gopalappa c, sabin k, velasquez c, et al. updates to the spectrum model to estimate key hiv indicators for adults and children. aids lond engl. 2014 nov;28(4):s427–s434. https://doi.org/10.1097/qad.0000000000000483 eaton jw, johnson lf, salomon ja, et al. hiv treatment as prevention: systematic comparison of mathematical models of the potential impact of antiretroviral therapy on hiv incidence in south africa. plos med. 2012 jul 10;9(7):e1001245. https://doi.org/10.1371/journal.pmed.1001245 hontelez jac, lurie mn, bärnighausen t, et al. elimination of hiv in south africa through expanded access to antiretroviral therapy: a model comparison study. plos med. 2013 oct;10(10):e1001534. https://doi.org/10.1371/journal.pmed.1001534 williams b. elimination of hiv in south africa through expanded access to antiretroviral therapy: cautions, caveats and the importance of parsimony. arxiv14037104 q-bio [internet]. 2014 mar 26 [cited 2015 nov 16]; available from: http://arxiv.org/abs/1403.7104 auvert b, sobngwi-tambekou j, cutler e, et al. effect of male circumcision on the prevalence of high-risk human papillomavirus in young men: results of a randomized controlled trial conducted in orange farm, south africa. j infect dis. 2009 jan 1;199(1):14–19. https://doi.org/10.1086/595566 williams bg, lloyd-smith jo, gouws e, et al. the potential impact of male circumcision on hiv in sub-saharan africa. plos med. 2006 jul 11;3(7):e262. https://doi.org/10.1371/journal.pmed.0030262 verguet s. efficient and equitable hiv prevention: a case study of male circumcision in south africa. cost eff resour alloc. 2013;11:1. https://doi.org/10.1186/1478-7547-11-1 bärnighausen t, bloom de, humair s. economics of antiretroviral treatment vs. circumcision for hiv prevention. proc natl acad sci usa. 2012 dec;109(52):21271–21276. https://doi.org/10.1073/pnas.1209017110 pretorius c, stover j, bollinger l, bacaër n, williams b. evaluating the cost-effectiveness of pre-exposure prophylaxis (prep) and its impact on hiv-1 transmission in south africa. plos one. 2010;5(11):e13646. https://doi.org/10.1371/journal.pone.0013646 hallett tb, baeten jm, heffron r, barnabas r, de bruyn g, cremin í, et al. optimal uses of antiretrovirals for prevention in hiv-1 serodiscordant heterosexual couples in south africa: a modelling study. plos med [internet]. 2011 nov [cited 2016 may 12];8(11). available from: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc3217021/ abbas ul, glaubius r, mubayi a, hood g, mellors jw. antiretroviral therapy and pre-exposure prophylaxis: combined impact on hiv transmission and drug resistance in south africa. j infect dis. 2013 jul;208(2):224–234. https://doi.org/10.1093/infdis/jit150 coffee m, lurie mn, garnett gp. modelling the impact of migration on the hiv epidemic in south africa. aids. 2007 jan;21(3):343–350. https://doi.org/10.1097/qad.0b013e328011dac9 mah tl, halperin dt. concurrent sexual partnerships and the hiv epidemics in africa: evidence to move forward. aids behav. 2008 jul;14(1):11–16. https://doi.org/10.1007/s10461-008-9433-x johnson l, dorrington r, bradshaw d, pillay-van wyk v, rehle t. sexual behaviour patterns in south africa and their association with the spread of hiv: insights from a mathematical model. demogr res. 2009 sep;21(11):289–340. https://doi.org/10.4054/demres.2009.21.11 rehle tm, hallett tb, shisana o, et al. a decline in new hiv infections in south africa: estimating hiv incidence from three national hiv surveys in 2002, 2005 and 2008. plos one. 2010 jun;5(6):e11094. https://doi.org/10.1371/journal.pone.0011094 sawers l, stillwaggon e. concurrent sexual partnerships do not explain the hiv epidemics in africa: a systematic review of the evidence. j int aids soc. 2010;13(1):34. https://doi.org/10.1186/1758-2652-13-34 nyabadza f, mukandavire z, hove-musekwa sd. modelling the hiv/aids epidemic trends in south africa: insights from a simple mathematical model. nonlinear anal real world appl. 2011 aug;12(4):2091–2104. https://doi.org/10.1016/j.nonrwa.2010.12.024 johnson lf, hallett tb, rehle tm, dorrington re. the effect of changes in condom usage and antiretroviral treatment coverage on human immunodeficiency virus incidence in south africa: a model-based analysis. j r soc interface r soc. 2012 jul;9(72):1544–1554. https://doi.org/10.1098/rsif.2011.0826 tanser f, bärnighausen t, hund l, garnett gp, mcgrath n, newell m-l. effect of concurrent sexual partnerships on rate of new hiv infections in a high-prevalence, rural south african population: a cohort study. lancet. 2011 jul 22;378(9787):247–255. https://doi.org/10.1016/s0140-6736(11)60779-4 vickerman p, watts c, delany s, alary m, rees h, heise l. the importance of context: model projections on how microbicide impact could be affected by the underlying epidemiologic and behavioral situation in 2 african settings. sex transm dis. 2006 jun;33(6):397–405. https://doi.org/10.1097/01.olq.0000218974.77208.cc gumel ab, mccluskey cc, van den driessche p. mathematical study of a staged-progression hiv model with imperfect vaccine. bull math biol. 2006 nov 1;68(8):2105–2128. https://doi.org/10.1007/s11538-006-9095-7 johnson lf, dorrington re, bradshaw d, coetzee dj. the role of sexually transmitted infections in the evolution of the south african hiv epidemic. trop med int health tm ih. 2012 feb;17(2):161–168. https://doi.org/10.1111/j.1365-3156.2011.02906.x unaids. 90-90-90 an ambitious treatment target to help end the aids epidemic [homepage on the internet]. 2014 [cited 2016 apr 4]. available from: http://www.unaids.org/sites/default/files/media_asset/90-90-90_en_0.pdf south african national aids council. south african national strategic plan on hiv, tb and stis 2017–2022 (draft 2) [homepage on the internet]. 2017 [cited 2017 jul 18]. available from: http://sanac.org.za/wp-content/uploads/2017/03/nsp-draft-2_24-february-2017.pdf appendix 1: a history of controversies involving human immunodeficiency virus (hiv) models in south africa 1. introduction disputes over models of the human immunodeficiency virus (hiv) epidemic have been public, vociferous, fraught and acrimonious. in this article, which supplements our article reviewing the main models of the south african hiv epidemic, we describe these debates. it is perhaps strange that the equations of obscure spreadsheets or highly technical computer code, understood only by a few specialists, should occupy so much attention in the media. but the stakes have been high, with millions of lives at risk. also, as we explain in the main article, while, on the one hand, the technical workings of models might be understood by a few, on the other hand, the model world, that is, the conceptual realm of explicitly declared rules that match, in a simplified way, some aspect of the real world, can be understood by many. 2. the effect of models on policy in the 1990s in 1990, although less than 1% of pregnant women attending public antenatal facilities in south africa tested positive for hiv, modellers had predicted explosive growth during the subsequent decade, unless significant interventions were mounted. indeed, by 2000, antenatal prevalence had increased to over 24%.1 this failure to control the epidemic might suggest that modelling had no useful influence on policy, but in fact the situation was more complex. concern about the growing hiv epidemic, based on modelling data and antenatal survey results, led to the formation of a body called the networking hiv, acquired immune deficiency syndrome (aids) community of south africa (nacosa) in 1991.2 in the transition to democracy in 1994, the african national congress released a national health plan. it cites demographic modelling projections, stating that credible predictions ‘indicate that by the year 2005, between 18% and 24% of the adult population will be infected with hiv’ and that the ‘cumulative death toll will be 2.3 million, and that there will be about 1.5 million aids orphans’ (p. 30).3 but the plan’s recommendations, while cognisant of the rights of people with hiv, were mostly broad and vague, which, to be fair, was largely a reflection of the lack of effective interventions available at the time. the small but growing aids activist movement was also aware of the model projections. the treatment action campaign (tac) was formed in late 1998. there are few early documents of the organisation’s work still available, but a letter to the pharmaceutical manufacturers association on 22 september 1999 notes that the hiv epidemic is an ‘unprecedented health crisis in south africa’ and ‘3.5 million people are already infected with hiv and it is estimated that 150,000 people die of aids related illnesses every year’.4 these figures were likely obtained from a model by the actuarial society of south africa, such as assa600.5 3. the medical research council report a controversy with a model at its centre erupted in 2001. dorrington et al. produced a technical report under the auspices of the south african medical research council (mrc) that analysed mortality data collected by government agencies. the researchers also compared the mortality data with the projections of the assa600 model.6 the preface written by the president of the mrc at the time, malegapuru makgoba, stated there had been a shift in the age pattern of mortality in the country ‘from the old to the young over the last decade particularly for young women – this is a unique phenomenon in biology’, and ‘this shift in mortality fits several aids models’. makgoba wrote that the ‘future burden’ of the epidemic was ‘broadly predictable from the models with reasonable confidence over the next decade’ (p. 4). the study investigated trends in reported deaths until 1996 based on data from statistics south africa (stats sa), compared with more recent data (mid-1997 to september 2000) from the population register of the department of home affairs. these empirical data were then compared with the outputs of the assa600 demographic model ‘to assess the consistency of the empirical data with the model projections’ (pp. 8–9). the authors used standard techniques for adjusting the data to take into account under-reporting of deaths. the data showed a ‘steady increase in adult mortality in the 1990s’. women aged between 25 and 29 years had a 3.5 times higher death rate in 1999/2000 than in 1985 (p. 5). the authors compared the empirical data with the projections of the assa600 demographic model, which they described as a ‘behavioural demographic component projection model, which models the heterosexual epidemic for the country as a whole, ignoring race and geographical heterogeneity’ (p. 19). the model was calibrated to reproduce the results of antenatal hiv surveys up to 1997. the model projected antenatal infections between the values found for the 1999 and 2000 antenatal clinic surveys. it estimated that there would be between 4 and 7 million aids deaths from 2000 to 2010 in the absence of any interventions (behavioural change or treatment). the authors wrote that: ‘given the pattern of deaths exhibited by the assa600 model … the … estimate of non-aids deaths is probably a little on the low side … and the aids deaths a little exaggerated.’ (p. 24) they also considered and critiqued the outputs of three other models: the doyle one discussed in our main article,7 the one by the united nations and the one by the us bureau of census (pp. 24–25). the report noted limitations of both the available data and models. its recommendations included proposals for improving both. it stated: ‘considering these different sources of information, it seems highly probable that about 40% of the adult south african 1999/00 mortality in the 15–49 age group is due to hiv/aids.’ (p. 37). it briefly considered interventions to mitigate the effect of the epidemic: azt for mother-to-child transmission prevention, promoting increased use of condoms and a national campaign to treat sexually transmitted infections. the authors concluded that the interventions ‘can make a significant difference to the course of epidemic, although it will still exact a heavy toll’ (p. 38). they also wrote: ‘unfortunately the assa600 model was not designed to model the impact of antiretroviral therapies. provided these drugs could be implemented successfully they could have a significant impact on the future prevalence levels.’ (p. 38) (note: the interaction between antiretrovirals, incidence, prevalence and mortality is complex and still not fully resolved by today’s models.) the report was written against the background of the acrimonious debate in south africa over the cause of aids, the size of the epidemic and whether antiretrovirals should be introduced in the public health system, both for mother-to-child transmission prevention as well as treatment (for a history of the aids denialist era, see cameron).8 in particular, in march 2001, the presidential aids advisory panel report had been released.9 this panel, constituted by president mbeki, consisted of a roughly equal number of aids denialists and conventional scientists. it was criticised for promoting aids denialism.10 the panel’s report contained a very short section on modelling (p.44), essentially noting a fundamental disagreement on their utility. it also stated in a section on epidemiology that repeated requests for ‘reliable data and statistics on the magnitude of the aids problem or even hiv prevalence’ (p. 45) had not been provided to the panel. yet, the mrc report did provide this, as did many other reports available during the time of the panel’s deliberations, such as the department of health’s annual antenatal clinic studies. the mrc report was carefully researched and showed the growing impact of the epidemic on adult deaths. however, the mrc board, together with the minister of health, stopped or delayed its publication, possibly ‘because it contradicted president thabo mbeki’s view that the epidemic was being vastly exaggerated and that there were other, larger causes of death’.11 however, findings from the report were leaked to the media. it was subsequently officially released in october 2001.12 the tensions surrounding the mrc study are illustrated by a news report: ‘[the study] prompted a whole new furore around aids statistics and the reliability of mrc research. stats sa was then used by government to rubbish the mrc report, a move that was yesterday slammed by one of the authors of the mrc report, university of cape town actuarial science professor rob dorrington. pointing out that he was speaking in his personal capacity, dorrington said it was a great shame that stats sa had decided to trash the report. “it is clear that they have a limited understanding of the estimation process and model. their (stats sa) presentation was riddled with half truths and misunderstandings”.’9 instead of acting on the report’s concerning findings, the state’s response was to try to determine who leaked it. on 17 april 2002, independent newspapers published quotations from a letter obtained by reporter lynne altenroxel and written by the minister of health, manto tshabalala-msimang, to the chair of the mrc board, taole mokoena, on 17 september 2001.13 tshabalala-msimang wrote, ‘this is not the first time that the mrc president has acted against government’. she continued: ‘you will recall that when the president of south africa established a website for the members of the presidential advisory council on aids to debate their different points of view, the mrc president was instrumental in establishing a separate website for the orthodox scientists, under the umbrella of the mrc.’13 she further wrote: ‘the [health department] director-general [ayanda ntsaluba] advised the mrc president and his team not to release the report until the report had been presented to the minister of health and the cabinet.’13 tshabalala-msimang called for ‘corrective action’ to be taken. makgoba was accused of being the source of the leak, but a subsequent investigation cleared him and three other mrc members. an earlier report by independent newspapers alleged that a private consultancy had been paid to find out the source of the leak.13 makgoba soon resigned from the mrc and became the vice-chancellor of the university of kwazulu-natal. dorrington would later write that the only institution that seriously questioned the finding by the mrc study that aids was the largest cause of mortality in south africa by 2000, responsible for 25% of all deaths, was stats sa. but, wrote dorrington, ‘[stats sa] have not produced any statistics of their own and have not claimed that the figure should in fact be lower’.14 stats sa officials attempted to discredit the actuarial society of south africa (assa) model results. the institution released a press statement claiming that the model gave lower projected aids mortality by 2010 (1 to 2 million deaths vs. 5 or 6 million, in the absence of antiretroviral treatment) simply by changing the model’s assumptions. but as dorrington pointed out, stats sa failed to calibrate the model under their assumptions to known prevalence data.14 4. mother-to-child transmission prevention court case when the tac launched with a small protest at st george’s cathedral in cape town, one of the protesters’ demands was for the ministers of health and finance to meet with aids organisations to ‘plan for resources to introduce free azt for pregnant mothers with hiv/aids’.15 over the next 4 years, the tac tried to convince the south african government to implement a countrywide mother-to-child hiv transmission prevention programme. the organisation, along with several others, proceeded with litigation against the national and provincial health ministers, eventually winning a seminal judgement at the constitutional court in july 2002. the court ordered the state to: ‘devise and implement within its available resources a comprehensive and co-ordinated programme to realise progressively the rights of pregnant women and their newborn children to have access to health services to combat mother-to-child transmission of hiv.’16 in this and subsequent tac litigation, we find clear examples of modelling being used to make an argument for policy changes to increase access to antiretroviral medicines. evidence put before the court by the tac included an affidavit by nicoli nattrass, an economist at the university of cape town. she concluded that the: ‘cost to the health sector of [mother-to-child transmission prevention] programmes … is less than the costs of treating all children born hiv+ in the absence of a … programme. this is true for all … of the … programmes discussed here.’17 nattrass performed costing analyses in her affidavit, and cited similar work by other researchers. her model was relatively simple compared with most of those discussed here, but nattrass’s affidavit offered compelling arguments in favour of implementing mother-to-child transmission prevention. although the role of nattrass’s affidavit in the court’s decision is not mentioned explicitly in the court’s judgement, her submission made it practically impossible for the state to offer a coherent financial argument against implementing the programme (p. 31).16 5. competition commission complaints in 2002, the tac lodged a complaint with the competition commission against two pharmaceutical companies, glaxosmithkline and boehringer ingelheim, over what the organisation called the excessive pricing of the antiretroviral medicines zidovudine (azt), lamivudine and nevirapine.18 here again an expert affidavit describing the results of several models was placed on record.14 the affidavit, written by dorrington, explained the impact of hiv: ‘according to the models referred to above, well over five million people are currently infected with the virus and, unless they receive treatment that would increase their life expectancy, most of these people will die within the next 10 years. it is clear that hiv/aids is estimated by all demographers outside government to be having a devastating effect on the population and is undoubtedly the leading cause of death these days in south africa.’ (p. 7) in 2003, the tac reached a settlement with the two companies that allowed generic manufacturers to sell the drugs in competition with them, not only in south africa but also in sub-saharan africa. the tac followed up with other successful complaints and actions to lower antiretroviral prices. the effect on drug prices was profound: when judge cameron began taking antiretrovirals in 1997, the monthly cost of his regimen was r3419. by 2008, the standard regimen in the private sector cost under r240 per month.11 the dorrington affidavit played a small but significant role in this. 6. pushing for the state to treat after the tac won the mother-to-child transmission prevention court case, the organisation stepped up its demand for antiretrovirals to be made generally available in the public health system for the treatment of hiv. to make the case for this much more expensive and vast programme, a tac researcher, with the assistance of the assa model developers, nattrass and others, calculated the cost of a countrywide treatment programme using the outputs of the assa2000 demographic model. the article concluded that implementing treatment would incur substantial direct costs but potentially provide long-term savings from reduced hospitalisations and treatment of opportunistic infections. the publication of this article in 2003 was at the height of the conflict between the tac and government over antiretroviral treatment.19 the lead story in one of the country’s leading weekly newspapers at the time, mail & guardian, describing this work, was ‘counting the cost of three million lives’.20 its findings were debated in subsequent issues of the mail & guardian.21 this was not the first such costing model. in october 2002, boulle et al. modelled eight scenarios of a limited antiretroviral rollout.22 this research did ‘not explicitly link their numbers on treatment to an external demographic model’, but they estimated the number of people needing treatment in their model would be about 10% of new hiv cases in an assa model.23 another case of a model being used to advocate for treatment arose in mid-2003. the government had established the joint health & treasury technical team, which used a model to estimate the cost of implementing an antiretroviral treatment programme in the public health system, and the number of deaths that would be averted by such a programme. the director-general of health, dr ayanda ntsaluba, presented the team’s findings to the health minmec (the national and provincial ministers of health) on 9 may 2003.24,25 the presentation considered an antiretroviral treatment programme scaled up over three years in public hospitals. it showed three scenarios: treating 20%, 50% and 100% of aids cases. in the 50% scenario, 600 000 people would be on treatment by 2008 at a cost of about r10 billion (about $1.3 billion at the 2003 exchange rate). according to slides not shown at the meeting, this scenario would ‘defer’ 733 000 deaths until after 2010, assuming that treatment led to ‘4–5 additional years of relatively illness-free life’ (an extremely conservative assumption, on hindsight). what model was used and how the results were calculated remains out of the public domain. the presentation was supposed to be a secret. however, based on a review of costing models by boulle et al.,23 it appears that this prescient costing model was likely developed by fareed abdullah, an official at the time in the health department, in march 2003. the tac obtained the presentation and leaked it to the media in july 2003. accusations and counter-accusations followed. at the time, following pressure from tac, including a civil disobedience campaign, negotiations for a treatment plan were taking place, at the national economic development and labour council (nedlac), between the state, labour, business and civil society organisations. advocate rams ramashia, the director-general of the department of labour, accused the tac of breaching ‘state security’ and ‘undermining and possibly de-railing the nedlac process’.24 the tac responded: ‘on a matter of such fundamental importance to millions of people’s lives, the constitutional right of access to information and the constitutional duties that govern public administration are paramount. the notion that state security has been breached is ludicrous: in fact it is the personal security of millions affected and infected with hiv that is threatened by government procrastination.’24 by april 2004, the state began providing antiretroviral treatment to people with aids in the public health system. the programme stuttered in its first few years as mbeki and tshabalala-msimang continued to undermine it, for example, by promoting untested remedies as alternatives. eventually, the programme scaled up rapidly and is the largest of its kind in the world. since 2008, there has been considerable debate about the optimal clinical stage at which to start antiretroviral treatment. as described in our main article, models, such as the one by granich et al., have played a central role in this debate.26 following the results of a clinical trial in 2015, the world health organization has recommended, and the south african government has adopted, a policy of universal access to treatment for all people with hiv. 7. aids denialists attack models south africa’s period of state-supported scepticism of the link between hiv and aids under president thabo mbeki lasted from the late 1990s until mbeki was removed from power by his own party in 2008. it’s important to note that the governing party was not unified in its dismissal of the epidemic, and mbeki’s position ultimately delayed rather than entirely prevented the implementation of the public sector antiretroviral treatment programme, which began in 2004. throughout this period, there was a constant battle between the supporters of the scientific position and the aids denialists, with the former slowly becoming ascendant until aids denialism ceased to be a relevant political force in south africa.11 mathematical models were at the centre of this conflict. the aids denialist attack on modelling did not come from a scientist but from a journalist, rian malan. well-known for his best-selling non-fiction book my traitor’s heart,27 malan wrote an article in rolling stone in 2001, disputing that there was a large hiv epidemic in africa including south africa. the article questioned hiv testing methodology on the continent and essentially accused unaids of cynically exaggerating the size of the epidemic.28 he followed this with articles in the british magazine the spectator29 and the south african magazine noseweek.30 a large part of the latter two articles was aimed at mathematical modelling of the epidemic, particularly the assa models. a tac researcher published a detailed rebuttal of malan.31 interestingly, no rebuttal approaching the detail of the tac’s response was written by scientists with recognised expertise in demography, although leigh johnson, one of the main producers of the assa and subsequent models, assisted the tac’s researcher. it appears that academics found malan’s arguments so absurd that they were not worth more than a cursory occasional response in newspaper articles. this despite the fact that his three articles, which appeared in large-circulation popular publications, almost certainly were more widely read than the peer-reviewed publications on aids demographics in sub-saharan africa. malan’s articles had numerous errors. in noseweek, he miscalculated the number of south african hiv deaths from a stats sa report, ignoring that many deaths owing to aids were not officially classified as aids deaths. he therefore reached the incorrect conclusion that they were a small fraction of the assa estimates. the stats sa report in fact made it clear that if physicians wrote the cause of death as, for example, tuberculosis, then this was not classified as an aids death, even though many such deaths are aids-related. the report stated that extricating the hiv-related deaths from the other death categories is where ‘official statistics stop and research begins’ (p. 28).32 the tac added: ‘malan has not bothered with such research, which would be a very complex undertaking’.31 mbeki mentioned malan favourably in his 2004 state of the nation speech, which a tac researcher characterised thus: ‘it was not explicitly about hiv, but to anyone following the debate at the time, it was clear that mbeki was grateful for malan’s support on aids’.33 running battles in print between malan, activists and, to a lesser extent, scientists continued through the 2000s. in 2007, malan published again in noseweek, suggesting that the rise in recorded deaths was primarily owing to improved registration.34 grebe35 pointed out on a website dedicated to refuting aids denialism, https://www.aidstruth.org/, that malan continued to ignore the age pattern of deaths in south africa, in which most recorded deaths were among young adults, as well as ‘the increase in the recorded deaths resulting from causes typically associated with aids’. in the post-mbeki, and thus post-denialist, period, minister of health aaron motsoaledi delivered a presentation in which one of his slides had erroneously substantially overstated the number of 2008 deaths. malan pounced on this in the online news site politicsweb. besides correcting the error, malan wrote, ‘[t]here is no apocalypse. no massive aids -related death surge. if anything, death registrations are stable’.36 malan’s point was petty: motsoaledi’s slide had mistakenly transposed two digits, reporting 756 062 instead of 576 062 aids deaths. the argument continued when malan published his book, resident alien, in 2009.37 it contained a chapter that reaffirmed his position, disputing there was a large hiv epidemic. the daily maverick, a popular south african news site, gave it a favourable review, and then published a critical reply by the tac.38,39 after the removal of mbeki from office, aids denialism no longer had any political force. public debates over the size of the hiv epidemic receded. 8. the impact of aids denialism after the rollout of antiretroviral treatment and the termination of thabo mbeki’s presidency, two studies were conducted that calculated the loss of life owing to aids denialist policies. nattrass40 used the assa2003 demographic model to estimate that if the national government had used antiretrovirals for mother-to-child transmission prevention and treatment of people with hiv at the same rate as the western cape province ‘which defied national policy on arvs’, then 171 000 hiv infections and 343 000 deaths could have been prevented, just between 1999 and 2007. a few months later, chigwedere and colleagues at harvard university used a different methodology but reached similar conclusions.41 they considered what the south african government could have achieved had it scaled up treatment coverage from 5% in 2000 to 50% in 2005 instead of 3% to 23%. these estimates were actually more modest than what was achieved by botswana or namibia. using a unaids model accounting for the period 2000 to 2005, they concluded that delayed treatment caused 2.2 million lost person-years and over 330 000 deaths, and delayed mother-to-child transmission prevention caused over 35 000 excess infections and 1.6 million lost person-years. both studies have been cited in an argument that mbeki and the late south african health minister manto tshabalala-msimang should have been prosecuted.42 9. conclusion this article has shown that mathematical models have been at the centre of policy debates and decision-making in the context of the south african hiv epidemic. in the early 1990s, models acted as a warning sign of the pending mortality that would be caused by the disease. in the late 1990s until the mid-2000s, modelling was a key point of discussion in the aids denialist controversy that characterised the government’s response to the epidemic. modelling also informed discussions on the relative efficacy of treatment and prevention options. but, these examples also show the limitations of the influence of modelling over public policy. despite the warnings of the early 1990s, little was done to stem the rise of hiv infections. and in the 2000s, the models were simply disputed by the aids denialists, so that antiretroviral treatment was delayed until 2004, and then only after an immense conflict between the state and aids activists, of which the dispute over modelling results was but one aspect. also, no aids denialists have been held accountable for their role in hundreds of thousands of avoidable deaths, despite the estimates of nattrass and chigwedere et al. even the granich model, cited an order of magnitude more often than any other model, had a limited effect on public policy. it was not until the publication of the hptn 052 trial that there was consensus that test-and-treat would be effective at reducing new infections,43 and it was not until the results of the start randomised control clinical trial in 2015 that there was consensus that antiretrovirals should be provided to all with hiv irrespective of cd4 count.44 although models have informed these debates, they do not carry the same weight as other forms of evidence in medicine, especially randomised controlled trials. perhaps, if consensus is reached on which modelling techniques produce the most robust estimates of past outputs and future projections – in other words if the science of modelling improves greatly – future models will be more effective at changing policy. we are aware of no developments that suggest this is likely to happen. nevertheless, as a means of exploring future scenarios and understanding the epidemic better, models have played a vital role. 10. acknowledgements competing interests geffen was with the treatment action campaign from 2000 to 2013 and an active participant in some of the debates discussed in this article. authors’ contributions n.g. conceived and drafted the article. n.g. and a.w. reviewed and edited the article. 11. summary of appendix 1 mathematical models have helped describe and project the south african human immunodeficiency virus (hiv) epidemic. they have also informed, and been the subject of, public debates. we describe the main policy debates in which models had a crucial role, explaining how they were used to inform these debates, and we discuss the limits of how they influence policy. in the early 1990s, models were used to warn of the impending epidemic. the models of the early 2000s informed debates on treatment for people with acquired immune deficiency syndrome (aids) and prevention of mother-to-child transmission. models were also at the centre of the aids denialist controversy. in more recent years, models have played a key role in the debate on when to start treatment. 12. references department of health. the national hiv and syphilis prevalence survey south africa 2007 [homepage on the internet]. 2008 [cited 2016 may 19]. available from: https://dl.dropboxusercontent.com/u/193052/primarydocuments/governmentdocs/doh/antenatalsurveyfor2007released2008withincorrectcalculations.pdf mcneil j. a history of hiv/aids in south africa [homepage on the internet]. south africa history online; 2016 [cited 2016 may 19]. available from: http://www.sahistory.org.za/topic/history-official-government-hivaids-policy-south-africa african national congress. a national health plan for south africa. african national congress johannesburg; 1994. jara m. open letter to the pharmaceutical manufacturers association of south africa: join the partnership against aids [homepage on the internet]. 1999 [cited 2016 may 19]. available from: http://www.tac.org.za/community/node/2455 dorrington re. assa600: an aids model of the third kind? trans actuar soc south afr. 1998;13(1):99–153. dorrington re, bourne d, bradshaw d, laubscher r, timaeus im. the impact of hiv/aids on adult mortality in south africa [homepage on the internet]. 2001 [cited 2016 may 22]. available from: http://www.mrc.ac.za/bod/ doyle p. the demographic impact of aids on the south african population. in: cross s, whiteside a, editors. facing up to aids [homepage on the internet]. palgrave macmillan uk; 1993 [cited 2016 feb 19]. p. 87–112. available from: http://link.springer.com/chapter/10.1007/978-1-349-22597-2_5 cameron e. edwin cameron: witness to aids. 1st ed. cape town: tafelberg; 2005. south african government. presidential aids advisory panel report [homepage on the internet]. 2001. [cited 2017 dec 05]. available from: https://www.gov.za/sites/www.gov.za/files/aidspanelpdf_0.pdf geffen n. echoes of lysenko: state-sponsored pseudo-science in south africa. soc dyn. 2005;31(2):183–210. https://doi.org/10.1080/02533950508628713 geffen n. debunking delusions: the inside story of the treatment action campaign. 1st ed. auckland park, south africa: jacana media; 2010. 256 p. health-e news. one in four deaths in sa related to hiv/aids – mrc report [homepage on the internet]. 2001 [cited 2016 may 24]. available from: https://www.health-e.org.za/2001/10/16/one-in-four-deaths-in-sa-related-to-hivaids-mrc-report/ altenroxel l. minister demanded ‘corrective action’ at mrc [homepage on the internet]. iol; 2002 [cited 2016 may 24]. available from: http://www.iol.co.za/news/south-africa/minister-demanded-corrective-action-at-mrc-85131 dorrington re. expert affidavit in tac competition commission complaint [homepage on the internet]. 2002 [cited 2016 may 18]. available from: http://www.tac.org.za/documents/drugcompaniescc/tac_dorrington_final.doc treatment action campaign. hiv/aids treatment action campaign 10 december 1998 – day of action international human rights day [homepage on the internet]. 1998 [cited 2016 feb 11]. available from: http://www.tac.org.za/community/node/2454 constitutional court. minister of health v treatment action campaign (tac) (2002) 5 sa 721 (cc) [homepage on the internet]. 2002 [cited 2016 feb 11]. available from: http://www.tac.org.za/documents/mtctcourtcase/concourtjudgmentorderingmtctp-5july2002.pdf nattrass n. affidavit in treatment action campaign and others versus minister of health and others [homepage on the internet]. treatment action campaign; 2001 [cited 2014 sep 04]. available from: http://www.tac.org.za/documents/mtctcourtcase/affidavit/nattrass.txt tau h, zwedala np, godwana s, et al. statement of complaint in terms of section 49b(2)(b) of the competition act 89 of 1998 [homepage on the internet]. treatment action campaign; 2002 [cited 2016 may 29]. available from: http://www.section27.org.za/wp-content/uploads/2010/10/tauvgskevidenceandlegalsubmissions.pdf geffen n, raubenheimer c, nattrass n. the cost of hiv prevention and treatment interventions in south africa [homepage on the internet]. report no.: 28. centre for social science research; 2003 [cited 2017 dec 05]. available from: https://open.uct.ac.za/handle/11427/19732 deane n. the price of three million lives. mail & guardian 2016 mar 7;2. nattrass n. we need to fight aids and poverty [homepage on the internet]. the m&g online. 2003 [cited 2016 may 31]. available from: http://mg.co.za/article/2003-03-25-we-need-to-fight-aids-iandi-poverty/ boulle a, kenyon c, skordis j, wood r. exploring the costs of a limited public sector antiretroviral treatment programme in south africa. s afr med j. 2002;92(10):811–817. boulle a, kenyon c, abdullah f. a review of antiretroviral costing models in south africa. in: moatti j-p, editor. economics of aids and access to hiv/aids care in developing countries: issues and challenges. paris: anrs; 2003. p. 293–309. treatment action campaign. tac releases details of government costing study [homepage on the internet]. 2003 [cited 2016 jun 04]. available from: http://www.tac.org.za/newsletter/2003/ns14_07_2003.htm treatment action campaign. report of the joint health and treasury task team charged with examining options to supplement comprehensive hiv/aids care in the public health sector [homepage on the internet]. 2003 [cited 2016 jun 04]. available from: http://www.tac.org.za/documents/treatmentplan/slideshowongovernmentcostingstudy.pdf granich rm, gilks cf, dye c, de cock km, williams bg. universal voluntary hiv testing with immediate antiretroviral therapy as a strategy for elimination of hiv transmission: a mathematical model. lancet. 2009;373(9657):48–57. https://doi.org/10.1016/s0140-6736(08)61697-9 malan r. my traitor’s heart: a south african exile returns to face his country, his tribe, and his conscience. reprint edition. new york: grove press, 2000; 368 p. malan r. hiv & aids – aids in africa – in search of the truth [homepage on the internet]. 2001 [cited 2016 jun 04]. available from: http://www.virusmyth.com/aids/hiv/rmafrica.htm malan r. africa isn’t dying of aids [homepage on the internet]. the spectator 2003 dec. [cited 2017 dec 05]. available from: https://www.spectator.co.uk/2003/12/africa-isnt-dying-of-aids/ malan r. apocalypse when [homepage on the internet]. noseweek 2003 dec. [cited 2017 dec 05]. available from: https://www.noseweek.co.za/article.php?current_article=0629 geffen n. rian malan spreads confusion about aids statistics [homepage on the internet]. 2004 [cited 2016 jun 04]. available from: http://www.tac.org.za/newsletter/2004/ns20_01_2004.htm statistics south africa. causes of death in south africa 1997–2001: advance release of recorded causes of death. pretoria: statistics south africa; 2002. geffen n. the shameless rian malan [homepage on the internet]. 2009 [cited 2016 jun 04]. available from: http://www.tac.org.za/community/node/2778 malan r. rian malan’s last ever aids piece – or so he says… noseweek [homepage on the internet]. 2007 [cited 2016 jun 04];(88). available from: http://www.noseweek.co.za/article/1364/rian-malans-last-ever-aids-piece--or-so-he-says grebe e. a response to rian malan’s ‘last ever aids piece’ [homepage on the internet]. 2007 [cited 2016 jun 04]. available from: https://old.aidstruth.org/features/malan malan r. did zuma & motsoaledi get their aids stats wrong? [homepage on the internet]. 2009 [cited 2016 jun 04]. available from: http://www.politicsweb.co.za/opinion/did-zuma--motsoaledi-get-their-aids-stats-wrong malan r. resident alien. 1st ed. johannesburg: jonathan ball publishers sa, 2009; 380 p. bloom k. review: return of rian malan, the aids bore [homepage on the internet]. 2009 [cited 2016 jun 04]. available from: http://www.dailymaverick.co.za/article/2009-12-23-review-return-of-rian-malan-the-aids-bore/#.v1kr2p6ffyq geffen n. tac replies to our review: ‘rian malan is shameless’ [homepage on the internet]. 2009 [cited 2016 jun 04]. available from: http://www.dailymaverick.co.za/article/2009-11-19-tac-replies-to-our-review-rian-malan-is-shameless/#.v1kqoz6ffyq nattrass n. aids and the scientific governance of medicine in post-apartheid south africa. afr aff. 2008;107(427):157–176. https://doi.org/10.1093/afraf/adm087 chigwedere p, seage gr, gruskin s, lee t-h, essex m. estimating the lost benefits of antiretroviral drug use in south africa. j acquir immune defic syndr. 2008;49(4):410–415. https://doi.org/10.1097/qai.0b013e31818a6cd5 geffen n. justice after aids denialism: should there be prosecutions and compensation? j acquir immune defic syndr. 2009;51(4):454–455. https://doi.org/10.1097/qai.0b013e3181ab6da2 cohen ms, chen yq, mccauley m, et al. prevention of hiv-1 infection with early antiretroviral therapy. n engl j med. 2011;365(6):493–505. https://doi.org/10.1056/nejmoa1105243 insight start study group. initiation of antiretroviral therapy in early asymptomatic hiv infection. n engl j med. 2015;373(9):795–807. https://doi.org/10.1056/nejmoa1506816 abstract introduction methods results discussion conclusion acknowledgements references about the author(s) natasha khamisa department of public health, school of engineering, it, science and health, iie msa, johannesburg, south africa maboe mokgobi department of psychology, school of social science, iie msa, johannesburg, south africa tariro basera médecins sans frontières, rustenburg, south africa citation khamisa n, mokgobi m, basera t. knowledge, attitudes and behaviours towards people with hiv and aids among private higher education students in johannesburg, south africa. s afr j hiv med. 2020;21(1), a991. https://doi.org/10.4102/sajhivmed.v21i1.991 project research number: cf15/1095 – 2015000518c original research knowledge, attitudes and behaviours towards people with hiv and aids among private higher education students in johannesburg, south africa natasha khamisa, maboe mokgobi, tariro basera received: 11 june 2019; accepted: 11 dec. 2019; published: 24 mar. 2020 copyright: © 2020. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: human immunodeficiency virus and acquired immunodeficiency syndrome (hiv and aids) is a global health and social problem, with south africa having an estimated overall prevalence rate of 13.5%. compared to young male participants, young female participants have been reported to have less knowledge about hiv and aids, including prevention strategies, and this is associated with risky sexual behaviours and negative attitudes towards condom use. objectives: the study investigated gender differences in knowledge, attitudes and behaviours towards hiv and aids among 542 private higher education students in johannesburg, south africa. method: participants completed an online structured questionnaire measuring knowledge, attitudes and behaviours as well as demographics (including age, gender and relationship status). results: the results indicate that overall there were no significant differences between male and female students in terms of hiv and aids knowledge. however, female students had significantly less knowledge with regard to unprotected anal sex as a risk factor for hiv and aids. in addition, young female students reported condom use at last sex less frequently than male students. nonetheless, both genders reported a positive attitude towards condom use and towards people living with hiv and aids. conclusion: it is recommended that the relevant authorities at the state and the higher education level seriously consider implementing specific strategies for preventing hiv and aids through improved knowledge, attitudes and behaviours among young females. keywords: attitudes about contraception; levels of knowledge; risky sexual behaviours; gender differences; young female students. introduction since the beginning of the epidemic, human immunodeficiency virus and acquired immunodeficiency syndrome (hiv and aids) has affected more than 70 million people globally, accounting for 35 million deaths.1 as of 2018, over 30% of the global hiv and aids prevalence has been among the youth aged 15–25 years, with 5 million young people currently living with hiv and aids.1 the youth between the ages of 15 and 24 years account for 45% of new infections.2 the burden of hiv and aids is concentrated in sub-saharan africa, where 71% of people living with hiv reside and where 65% of new infections reported in 2017 occurred.3 the female population is disproportionately affected by hiv, with three in four new infections reported among girls aged 15–19 years, while the young female population aged 15–24 years is twice as likely to be living with hiv and aids than their male counterparts.4 south africa is known to have one of the highest rates of hiv and aids globally and on the african continent. it is estimated that 7.97 million south africans (13.5%) are living with hiv and aids, and over a fifth of these are females of reproductive age (15–49 years). gauteng province, the most populous province in the country (25.8% of the population), is home to over 2 million young people, the majority of whom are females.5 the high infection rate among the young female population is attributed to a lack of knowledge as well as poor attitudes towards the use of condoms and risky sexual behaviour.6 knowledge regarding hiv and aids infection is necessary to correct negative attitudes towards condom use and to encourage healthy sexual behaviour among the youth by improving their ability to practice safe sex. this is likely to improve the uptake of hiv prevention strategies to address the increase in the prevalence of hiv and aids in vulnerable populations.6,7 young female participants are twice as likely to be infected with hiv and aids, compared to young male participants, with the most common means of transmission being unprotected sex, and the key barriers to prevention being lack of knowledge, negative attitudes and risky sexual behaviour.3,6,8 knowledge facilitates familiarity with and awareness of hiv and aids, which influences attitudes (resulting in support and motivation for prevention) as well as behaviour (safer sex practices), thereby reducing the risk of infection.9 a high prevalence of hiv and aids is associated with lower levels of knowledge about the modes of transmission and condom use, negative attitudes towards condom use and risky sexual behaviours such as unsafe sex and multiple sex partners.10,11 the young female population has been shown to possess significantly lower levels of knowledge as well as misconceptions and erroneous beliefs about hiv and aids, compared to the male population.6,12 this is often associated with negative attitudes to prevention strategies, which have been shown to affect behaviours such as condom use.13 studies have also confirmed that hiv and aids testing attitudes and the intention to use condoms are influenced by knowledge.14,15 charles et al.16 reveal that although the young female population is more concerned about hiv and aids infection, they agree less than the young male population on condom use as a safe sex strategy. the attitudinal gender differences of the young female population with regard to transactional sex are thought to result in risky behaviours such as unprotected sex with older men.17 although it is known that the young female population is more susceptible to hiv and aids infection, there is a paucity of research on gender differences in knowledge, attitudes and behaviours among young people in higher education settings, thereby inhibiting an in-depth understanding of factors contributing to hiv and aids infection among this population in south africa. such a gap in the literature negatively influences policy and practice aimed at reducing hiv and aids rates among vulnerable youth within this context. this study was aimed at identifying gender differences in knowledge, attitudes and behaviours among the youth at a private higher education institution in johannesburg, south africa. it is envisaged that this will allow for the development of specific strategies for preventing hiv and aids infection among the youth at private higher education institutions in south africa. the research question seeks to determine differences between the male and female populations on knowledge, attitudes and behaviours towards hiv and aids. it is hypothesised that knowledge, attitudes and behaviours will differ between the male and the female populations. methods study design this cross-sectional survey was conducted at a private higher education institution in johannesburg, south africa. participants were invited via an online learning platform where they completed and submitted a structured questionnaire assessing sexual risk and sexual prevention behaviours. setting johannesburg is the capital of gauteng province and is considered the largest and the wealthiest city in south africa. with a population estimated at 5.6 million, it is the most populous city in the country, with 66% growth rate in population expected over the next 30 years. racial profiles indicate that 76.4% of the population is black african, 5.6% is mixed race, 12.3% is white or of european descent and 4.9% is of indian or asian descent. approximately, 7% of the population is illiterate, 3.4% have only a primary education, 41% have completed secondary education and 6% have a tertiary qualification.18 study population and sampling random sampling was used to recruit 845 students enrolled at a private higher education institution in johannesburg, south africa. random numbers were generated using a computer program to select participants from the sampling frame – enrolment records. a global email was sent to all potential participants inviting them to participate in the study. of those invited to participate in the study, 542 responded – a response rate of 64%. participants completed an online questionnaire via their online learning platform, which contained study information and instructions for accessing and completing the questionnaire. data collection and analysis an online structured questionnaire measuring knowledge, attitudes and behaviours as well as demographics (including age, gender and relationship status) was completed by the participants. the questionnaire was developed as part of a larger study using existing literature and consisted of 93 questions of which 51 questions were on knowledge about hiv and aids transmission and prevention, attitudes towards hiv and aids, including treatment and prevention methods (six questions), and sexual behaviours (36 questions). data were cleaned and checked for errors before coding and analysing using stata 14.0 (statacorp, college station, tx, usa). to evaluate knowledge and behaviours, respondents were required to provide mostly ‘yes’ or ‘no’ responses. for the knowledge score, a score of 1 was assigned for a correct answer and 0 for a wrong answer. for the attitude questions, a rank was assigned using the relative importance index to obtain an overall rank for each attitude item. for knowledge, attitudes and practice questions (knowledge and awareness of hiv & aids, prevention and control of hiv, students’ attitudes towards condom use and people living with hiv, risky sexual behaviours), the frequency of responses in each category was determined. a chi-square test was used to evaluate the variation in knowledge, attitude and behaviour between male and female students. for all tests, p < 0.05 was considered statistically significant. ethical considerations ethical approval to conduct the study was obtained from monash university human research ethics committee (muhrec) (approval number cf15/1095 – 2015000518). no identifying information was obtained from students when they completed the questionnaire. a unique identifier was generated when the questionnaire was submitted. all the data were de-identified for analysis. data were stored in password-protected files and will be retained for up to 5 years after the study. results socio-demographic characteristics of the students data were collected from 542 students, 374 (69.0%) of whom were female students. the participants had a median age of 19 years (interquartile range [iqr] = 16–30 years), and their average knowledge score of hiv and aids and sexually transmitted infections (stis) was 0.78 (standard deviation [sd] = 0.17); 397 (73.2%) students were black africans, 67 (12.4%) students were whites, 44 (8.1%) students were of indian/asian descent and 29 (5.4%) students were of mixed race; 427 (80.6%) students were single and 88 (16.6%) students were in a stable relationship. most of the students were in the higher certificate, higher education studies’ stream (n = 357, 71.1%), and 145 (28.9%) students were undergraduates (table 1). table 1: socio-demographic characteristics of students. there were high levels of awareness and knowledge about biomedical methods of hiv prevention amongst the sample group. more female (77.1%) than male students (64.1%, p = 0.003) said that they had heard about medication that hiv-positive pregnant women could take to reduce the risk of infecting the baby with hiv, and more female (59.9%) than male students (47.6%, p = 0.015) had heard about medication that could help to reduce the risk of hiv infection if a woman had been raped. a higher proportion of male (95.8%) versus female students (85.7%, p = 0.001) said that they were able to obtain a condom. there was no significant difference between the proportion of male (97.0%) and female students (94.1%) about where to get condoms (table 2). table 2: student’s knowledge of and access to hiv and aids prevention and control. knowledge about hiv transmission was high, with 98.1% of female students and 96.4% of male students knowing that the virus could be passed on through unprotected sex. a high proportion of male students (92.9%) and female students (90.9%) knew that a person can have hiv and pass it on to others without showing symptoms. also, most female students (77.4%) and male students (76.8%) knew that stis put people at greater risk of hiv infection. however, only 33.6% of female students and 39.3% of male students admitted that they knew that anal sex increased the risk of hiv infection. a low proportion of female students (16.9%) and male students (21.4%) knew that people can reduce their chance of getting hiv by using a condom every time they have sex. more female (96.2%) than male students (91.7%) were aware that aids could not be cured. most of the female students (n = 307, 82.5%) and male students (n = 119, 70.8%) indicated that partners could not have sexual intercourse if both partners were hiv-positive (p = 0.002) (table 3). table 3a: frequency and percentage of students’ knowledge and awareness of hiv and aids. table 3b: frequency and percentage of students’ knowledge and awareness of hiv and aids. as illustrated in table 4, a substantial number of students expressed positive attitudes towards condom use. across age and gender groups, a significant majority of students disagreed with the statement that a woman loses a man’s respect if she asks him to use a condom (96.8% of female participants and 91.7% of male participants); that they only use condoms if their sexual partner wants to use them (95.7% female participants and 86.3% of male participants); and that condoms should only be used if having sex with a person who is not the main sexual partner (94.6% of female participants and 83.9% of male participants). about a third of the students and 41.7% of the male students said that condoms felt unnatural, and nearly a quarter of the students aged 20–32 years and 36.3% of the male students said that condoms alter climax or orgasm. table 4a: student’s attitudes related to condom use. table 4b: student’s attitudes related to condom use. most participants had positive attitudes towards hiv-positive people, but 38 (7%) participants were unwilling to be associated with or share living space with people living with hiv. based on the relative importance index score, the most important attitudes towards people living with hiv, ranked in order of relative importance, were: (1) about 83.4% of students indicated that even if a family member had hiv, their relationship with them would remain good; (2) 20% of students said that sharing a house with hiv-positive people would be very difficult for them; and (3) 7.6% of students felt that people who get infected with hiv are promiscuous. forty-one (7.6%) students also said they do not want to be associated with hiv-positive people, and 6.4% of students felt that hiv-negative people should not be allowed to socialise with hiv-positive people. students had positive attitudes towards treatment for hiv and aids. around two-thirds (63.1%) of the students agreed that hiv treatment would keep an hiv-positive person alive (ranked the most important attitude). two hundred and seventy-four (50.8%) students agreed that hiv medication really works (with a relative importance score of 2). most of the respondents (69% students) rejected the notion that antiretroviral (arv) medication is poisonous (table 5). table 5: attitudes of students towards people who are hiv-positive or have aids and hiv and/or aids treatment. condom use at last sex was higher when with a regular partner: female students (n = 147) and male students (n = 93). the difference is statistically significant (p < 0.001). fewer female students (n = 53) and male students (n = 57) reported using condoms consistently with a non-regular partner (p = 0.049). more female students (n = 83) reported consistent condom usage (every time) with regular sex partners than male students (n = 54); however, the difference was not significant (p = 0.240) (table 6). table 6: condom use among students. discussion south africa is battling an hiv and aids pandemic, which remains one of the primary social and health concerns in the country. notwithstanding the outstanding effort by the department of health in implementing hiv and aids prevention strategies, south africa is still the country worst affected by the hiv and aids pandemic, with the youth between the ages of 15 and 24 years being the hardest hit.5 young female students are reported to have higher infection rates owing to a lack of knowledge and poor attitudes towards condom use and risky sexual behaviours,6 making them twice as likely as male students to be infected with hiv.3,6,8 this study was aimed at determining gender differences in knowledge, attitudes and behaviour in relation to hiv and aids among students at a private higher education institution in johannesburg, south africa. findings in this study indicate that there is no significant difference between male and female students in terms of their general knowledge of hiv and aids. however, it is noteworthy that female students had significantly less knowledge of unprotected anal sex as a risk factor for hiv and aids. in addition, a smaller proportion of female students reported condom use at last sex, compared to their male counterparts. this could be attributed to the female population having limited control over male condom usage.19 the complex power imbalance in this scenario, with most females not having the power to negotiate condom use with their partners, is the likely underlying cause.20,21 moreover, 8.3% of male students and 3.8% of female students believed that aids can be cured. although these percentages are comparatively low, they are equally as disconcerting as the results in haroun et al.,22 who found that just over 20% of a sample of university students in the united arab emirates did not know whether hiv and aids could be cured or not. this poor knowledge of basic messages relating to hiv and aids is a likely reason as to why the youth engage in risky sexual behaviour and why the prevalence of hiv infection among them is high.23 regarding risky sexual behaviour, this study revealed notable differences between male and female students, with the latter (57.3%) and the former (37.2%) reporting not having used a condom at last sex with a non-regular partner. as the chi-square test revealed no significant variation in attitudes between male and female students, we opted to investigate the entire sample’s attitudes rather than to compare male and female students. results revealed that the majority of participants (83.4%) had a positive attitude towards people living with hiv and aids. this differs from previous findings where the majority indicated negative attitudes towards people living with hiv and aids.22 positive attitudes such as these have been attributed to parental and social communication aimed at promoting hiv and aids awareness among the youth.24 limitations there were a disproportionate number of female students, compared to male students in this study. it is possible that this might have affected the robustness of the chi-square test and therefore skewed the findings. in addition, the sample came from one private higher education institution in johannesburg, south africa. it would have been ideal for more institutions to be included in the study to get a better picture of the knowledge levels, attitudes and behaviours towards hiv and aids at private higher education institutions in the johannesburg metropolitan area. notwithstanding these limitations, these findings could serve as a springboard for national research that would be more representative of the wider student population in both private and public higher education institutions. recommendations it is recommended that future research should sample students from several private and public higher education institutions with a representative number of both male and female students. this could then inform interventions that reduce hiv infection among the youth in south africa through improved attitudes facilitated by communication at both social and parental levels.24 it is further recommended that sex education in secondary schools should be introduced to close the gender gap in knowledge and prevent risky sexual behaviours. conclusion this study found that the level of hiv and aids knowledge in female students was not significantly different than in male students although risky sexual behaviour in female students was more frequent. in addition to the existing interventions aimed at reducing the prevalence of hiv and aids among the youth in south africa, efforts towards implementing interventions at educational as well as social and family-based levels are imperative. acknowledgements we would like to acknowledge the participants for their participation in this study. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions n.k. and m.m. conceptualised the study, collected data and did the write-up of the introduction, method and discussion sections. t.b. did data analysis and the write-up of the results section. funding information this study was funded by monash south africa research office. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views expressed in this article are the authors’ own and not an official position of the institution or the funder. references who. hiv and aids. who [homepage on the internet]. 2018 [cited 2019 may 17]. available from: https://www.who.int/gho/hiv/en/ miller cl, nkala b, closson k, et al. the botsha bophelo adolescent health study: a profile of adolescents in soweto, south africa. south afr j hiv med. 2017;18(1):1–10. https://doi.org/10.4102/sajhivmed.v18i1.731 dwyer-lindgren l, cork ma, sligar a, et al. mapping hiv prevalence in sub-saharan africa between 2000 and 2017. nature [serial online]. 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https://doi.org/10.1186/s12889-018-5051-3 haroun d, el saleh o, wood l, mechli r, al marzouqi n, anouti s. assessing knowledge of, and attitudes to, hiv and aids among university students in the united arab emirates. plos one. 2016;11(2):1–11. https://doi.org/10.1371/journal.pone.0149920 talwar p, rahman mfba. assessment of hiv knowledge among university students using the hiv-kq-18 scale: a cross-sectional study. south east asia j public heal. 2015;5(1):33–38. https://doi.org/10.3329/seajph.v5i1.24849 adeleke it, azeez ba, aliyu d, ogundiran lm, salami a, adeoye wa. hiv and aids awareness among secondary schools’ adolescents in south-western nigeria: a correlate to strengthen advocacy and strategic sexuality education programs. am j health res. 2015;3(1–1):61–67. https://doi.org/10.11648/j.ajhr.s.2015030101.19 indication southern african hiv clinicians society guidelines using darunavir/ritonavir 800/100 mg once-daily in clinical practice about the author(s) michelle a. moorhouse wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa sergio carmona national health laboratory services, south africa natasha davies wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa sipho dlamini department of medicine, university of cape town, south africa cloete van vuuren southern african hiv clinicians society, south africa thandekile manzini southern african hiv clinicians society, south africa moeketsi mathe private practice, vereeniging, south africa yunus moosa department of infectious diseases, university of kwazulu-natal, south africa jennifer nash southern african hiv clinicians society, south africa jeremy nel southern african hiv clinicians society, south africa yoliswa pakade southern african hiv clinicians society, south africa joana woods wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa gert van zyl southern african hiv clinicians society, south africa francesca conradie wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa francois venter wits reproductive health and hiv institute, faculty of health sciences, university of the witwatersrand, south africa graeme meintjes department of medicine and institute of infectious disease and molecular medicine, university of cape town, south africa citation moorhouse ma, carmona s, davies n, et al. appropriate clinical use of darunavir 800 mg. s afr j hiv med. 2018;19(1), a918. https://doi.org/10.4102/sajhivmed.v19i1.918 guidelines appropriate clinical use of darunavir 800 mg michelle a. moorhouse, sergio carmona, natasha davies, sipho dlamini, cloete van vuuren, thandekile manzini, moeketsi mathe, yunus moosa, jennifer nash, jeremy nel, yoliswa pakade, joana woods, gert van zyl, francesca conradie, francois venter, graeme meintjes received: 20 sept. 2018; accepted: 21 sept. 2018; published: 18 oct. 2018 copyright: © 2018. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. indication darunavir 400 mg tablets were recently approved by the south african health products regulatory authority (sahpra) for the following indication: prezista, in combination with low dose ritonavir (drv/r) and with other antiretroviral medicines, is indicated for the treatment of human immunodeficiency virus (hiv) infection in antiretroviral treatment experienced adult patients who are protease-inhibitor-naïve or after exclusion of darunavir resistance associated mutations (drv-rams: v11i, v32i, l33f, i47v, i50v, i54m, i54l, t74p, l76v, i84v and l89v). genotypic or phenotypic testing should guide the use of drv/r. (prezista package insert) there is no information on the use of darunavir in combination with ritonavir in the paediatric population for the once-daily dose. southern african hiv clinicians society guidelines southern african hiv clinicians society adult antiretroviral therapy (art) guidelines currently recommend ritonavir-boosted atazanavir (atv/r) 300/100 mg as preferred boosted protease inhibitor (pi/r) for second-line art. it was noted in the guidelines that once a suitable tablet for drv/r 800/100 mg dosing became available, drv/r 800/100 mg would be a feasible option in second-line art, with fewer side effects than the drv/r 600/100 mg twice-daily dosing. using darunavir/ritonavir 800/100 mg once-daily in clinical practice in second-line antiretroviral therapy in patients failing first-line non-nucleoside reverse transcriptase inhibitor (nnrti)or integrase strand transfer inhibitor (insti)-based regimens, switch to drv/r 800/100 mg daily with two nucleoside reverse transcriptase inhibitors (nrtis). sequence the nrtis as per guidelines (see figure 1). figure 1: patients failing non-nucleoside reverse transcriptase inhibitoror integrase inhibitor-based first-line antiretroviral therapy. for those patients who are already on a second-line pi/r-based regimen, check the viral load (vl). if the vl is undetectable, then pi/r can be switched to drv/r 800/100 mg daily, retaining the same nrti backbone (see figure 2). figure 2: patients on protease inhibitor-based second-line antiretroviral therapy. if the vl is detectable, intensify adherence interventions and repeat the vl in 2–3 months. if the vl is undetectable, the pi/r can then be switched to drv/r 800/100 mg daily. if vl > 1000 copies/ml, resistance genotype is needed to determine if the patient is eligible for third-line art (see figure 2). using darunavir/ritonavir 800/100 mg in third-line antiretroviral therapy currently, patients on drv/r on third-line art receive drv/r 600/100 mg bid. however, a small proportion of third-line patients have no drv resistance-associated mutations (rams), and in such patients it may be possible to use drv/r 800/100 mg daily instead of drv/r 600/100 mg bid to reduce pill burden, dosing frequency and side effects. for patients initiating third-line art, if the composite drv score (stanford) is zero on all genotypes, drv/r 800/100 mg daily may be initiated (see figure 3). figure 3: patients initiating third-line antiretroviral therapy. for those patients who are already on a third-line regimen, their vl must be checked. if the vl is undetectable, and the composite drv score (stanford) on all genotypes is zero, the patient may switch from drv/r 600/100 mg twice daily to drv/r 800/100 mg once daily. the rest of the regimen should not be changed (see figure 4). if the vl is detectable, manage further as appropriate according to current guidelines. figure 4: third-line patients on darunavir/ritonavir-based third-line antiretroviral therapy (600/100 mg bid). abstract introduction methods ethical considerations results discussion conclusion acknowledgements references about the author(s) sabine l. van elsland department of paediatric infectious diseases and immunology, amsterdam university medical center, vrije universiteit amsterdam, amsterdam, the netherlands department of paediatrics and child health, tygerberg children’s hospital, stellenbosch university, cape town, south africa remco p.h. peters anova health institute, johannesburg, south africa cornelis grobbelaar anova health institute, johannesburg, south africa patiswa ketelo anova health institute, johannesburg, south africa maarten o. kok department of health care governance, erasmus school of health policy and management, erasmus university rotterdam, rotterdam, the nertherlands mark f. cotton fam-cru, department of paediatrics and child health, stellenbosch university, tygerberg hospital, cape town, south africa a. marceline van furth department of paediatric infectious diseases and immunology, amsterdam university medical center, vrije universiteit amsterdam, amsterdam, the netherlands citation van elsland sl, peters rph, grobbelaar c, et al. disclosure of human immunodeficiency virus status to children in south africa: a comprehensive analysis. s afr j hiv med. 2019;20(1), a884. https://doi.org/10.4102/sajhivmed.v20i1.884 original research disclosure of human immunodeficiency virus status to children in south africa: a comprehensive analysis sabine l. van elsland, remco p.h. peters, cornelis grobbelaar, patiswa ketelo, maarten o. kok, mark f. cotton, a. marceline van furth received: 11 july 2018; accepted: 05 feb. 2019; published: 22 aug. 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the extent of disclosure of hiv status to children and adolescents and the context facilitating their disclosure process have received little attention. objectives: to assess disclosure and provide a comprehensive analysis of characteristics associated with disclosure to children (3–14 years) receiving antiretroviral treatment in a south african semi-urban clinic. methods: this cross-sectional study used structured interview administered questionnaires which were supplemented with medical record data. predictors included child, caregiver, clinical and socio-economic characteristics, viral suppression, immune response, adherence, health-related quality of life and family functioning. results: we included 190 children of whom 45 (23.7%) received disclosure about their hiv status, of whom 28 (14.7%) were partially disclosed and 17 (8.9%) were fully disclosed. older age of the child and higher education of the caregiver were strongly associated with disclosure. female caregivers, detectable viral load, syrup formulation, protease inhibitor (pi) regimens with stavudine and didanosine, and self-reported non-adherence were strongly associated with non-disclosure. conclusion: when children do well on treatment, caregivers feel less stringent need to disclose. well-functioning families, higher educated caregivers and better socio-economic status enabled and promoted disclosure. non-disclosure can indicate a sub-optimal social structure which could negatively affect adherence and viral suppression. there is an urgent need to address disclosure thoughtfully and proactively in the long-term disease management. for the disclosure process to be beneficial, an enabling supportive context is important, which will provide a great opportunity for future interventions. keywords: disclosure; child; paediatric; hiv; quality of life; south africa. introduction globally, 36.7 million people live with human immunodeficiency virus (hiv), of whom an estimated 2.1 million are children (0–14 years).1 fifteen per cent (320 000) of these children live in south africa.1,2 south africa has more people receiving antiretroviral therapy (art) than any other country in the world.3 in 2016, the coverage of paediatric art was 55.0%, reaching 172 000 children.2 depending on measure and definition, paediatric art adherence ranges between 20.5% and 89.1%.4 poor adherence to medication is common, which contributes to substantial worsening of disease, death and increased healthcare costs.5 factors associated with art adherence reported in a south african paediatric population include the impact of the condition on daily life, household functioning, socio-economic status (ses), problems administering medication and disclosure.4 non-disclosure of hiv status to the child can lead to a delay in access to treatment, non-adherence and consequent treatment failure.6,7,8,9 although studies have suggested both positive and negative effects of disclosure for children,10 the lack of disclosure of hiv status to children and adolescents ultimately adversely affects their well-being.7 the availability and roll-out of treatment for adults and children highlight the need to address disclosure.7 a review showed that the minority of hiv-infected children in resource-limited settings know their hiv status, and identified child, caregiver, clinical and socio-economic characteristics associated with disclosure.10 these predictors are not all studied within the same population. delaying the initiation of the disclosure process makes it an increasingly difficult process.9 research is needed on effective strategies for disclosure in resource-limited settings.10,11 reported full disclosure to the child in south africa ranges between 7.9% and 9.0%.12,13,14 the south african national department of health has committed to prioritise support and guide primary caregivers and healthcare providers for disclosure. this approach intends to ensure the physical, emotional, cognitive and social well-being of the child.8 a literature review including 17 studies in low-middle-income countries reported a mean age for disclosure as 9.6 years (8.1–15.0), and that 20.4% of children (3.2% – 69.2%) knew their status.15 national guidelines recommend all children from age 3 years to be prepared for disclosure. disclosure is the first step for children transitioning into adolescents and young adults who successfully manage their own hiv care.16 to support the implementation of disclosure guidelines, we assessed the prevalence of disclosure of children’s hiv status to them. in addition, to better understand disclosure, we explored the association between disclosure and child, caregiver, clinical and socio-economic characteristics. methods this cross-sectional study is a sub-analysis of data published elsewhere, which focused on art adherence in a population of active paediatric patients aged 2–14 years who were on treatment at tc newman clinic – a semi-urban art clinic in the western cape, south africa – and their caregivers.4 for this sub-analysis, we included all children aged 3–14 years who were on treatment between september 2012 and september 2013. the age group was based on national disclosure guidelines.9 children and their caregivers who did not meet these inclusion criteria were excluded from the study. for this study, we assessed prevalence of disclosure and explored all possible characteristics associated with disclosure. structured questionnaires were administered in interviews while patients were waiting to see the doctor and supplemented with medical record data. definition of disclosure paediatric disclosure can refer to disclosure of the child’s hiv status to the child, caregivers’ hiv status to children or children’s disclosure of their own hiv status to others. this study focused on disclosure of the child’s hiv status to the child. based on caregiver interview, healthcare provider report and medical files, we categorised disclosure status into non-disclosure (the child is unaware of his or her condition and its effect on the body), partial disclosure (the child is aware of his or her condition without naming hiv) and full disclosure (the child is made aware of his or her condition which is named as hiv).9 when referred to disclosure, we consider both partial and full disclosure unless otherwise specified. measurements to provide a comprehensive analysis of predictor variables (child, caregiver, clinical and socio-economic characteristics) and their association with disclosure, we included general demographic information, supplemented with questionnaires. the validated pedsqltm questionnaires measured health-related quality of life (hrqol) combining caregiver proxy-report and child self-report (all children ≥ 5 years), and the impact of paediatric chronic health conditions on family and caregivers (family impact).17,18,19 socio-economic status was calculated using 21 questions from the census 2011.20 a higher score (%) indicated better hrqol, overall family functioning and ses. a combination of adherence monitoring measures was included. pill count was calculated using the number of pills taken or the volume for liquid formulations (dispensed minus returned) as a percentage of medication prescribed. adherence was defined as 95% – 105% (a score > 100% could be explained by ingestion of more pills than prescribed and lost pills). self-reported adherence for the last 3 days was recorded with the validated paediatric aids clinical trials group (pactg) adherence modules.21 adherence was defined as no missed dosages in the last 3 days for self-report. treatment success was defined by a suppressed viral load (< 50 copies/ml), and immune response defined by cd4 count (> 5 00 cells/mm3). this information was retrieved from medical records (6 months before or 3 months after inclusion). regimen specifications were retrieved from medical records and questionnaires (formulation, prescription, treatment start, progress, complications, difficulties administering medication, side effects). statistical analyses all analyses were done using ibm spss statistics version 25. to describe the association between possible predictor variables and disclosure, univariate logistic regression analyses were conducted presenting odds ratio (or) and 95% confidence interval (ci) unless otherwise specified. multivariate analyses are presented when confounding or effect modification was identified for child’s age or caregiver education. fisher’s exact p-value was presented for cell size below 5. significance was measured at p ≤ 0.05. to describe the relation between multiple possible predictor variables and disclosure, we present a prediction model which was constructed using the forward selection procedure. this method considered all predictors of disclosure by adding the predictor with the lowest p-value under 0.05 to the crude model, which was repeated until no additional predictor had a p-value < 0.05. the overall percentage correct classified cases and hosmer and lemeshow chi-square test with p-value for goodness of fit are presented for each model (good fit is indicated by p-value > 0.05). ethical considerations stellenbosch university’s human research ethics committee approved this study (n11/11/329). in addition, hospital management approved the study in accordance with provincial research policy (40/2009). written informed consent was obtained from all caregivers and assent from children older than 7 with normal cognitive functioning. results at the start of the study, 238 active paediatric patients on art aged 2–14 years attended the clinic. one caregiver refused to participate and 42 patients were missed because caregivers did not visit on the appointment date. with 5 children younger than 3 years of age, this sub-analysis included 190 children. for five households with two children in the study, only the child enrolled first was considered for ses analyses (n = 185). disclosure of human immunodeficiency virus status to the child most of the children (145 of 190, 76.3%) had not received disclosure about their hiv status, 28 children (14.7%) had received partial disclosure and 17 children (8.9%) had full disclosure. none of the children in early childhood (3–5 years) received disclosure (n = 49), 11 of 89 children (12.8%) aged 6–9 years and 34 of 52 (65.4%) young adolescents aged 10–14 years received disclosure. the youngest child disclosed to about their hiv status was 6.6 years and the oldest child who was not disclosed was 12.2 years. child characteristics child characteristics associated with disclosure were age and hrqol. the children were aged 3.2–12.9 years, the majority (74.2%) were of school going age (6 years and older) and 27.4% were young adolescents (10–14 years). older children (young adolescents) were significantly more likely to be disclosed compared to younger children (under 10 years) (odds ratio [or] 21.81; 9.41–50.52). mean self-reported hrqol index was 91.5%. children who rated their hrqol highly were less likely to have received disclosure compared to children who had low hrqol (or 0.29; 0.09–0.91). this association attenuated in multivariate analyses (or 0.58; 0.15–2.30). we did not find significant associations between disclosure and sex of the child, overall hrqol or school functioning (caregiver proxy-report or self-report) (table 1). table 1: associations between disclosure and child characteristics – univariate analyses. caregiver characteristics caregiver characteristics associated with disclosure were sex, education and hrqol. the minority of caregivers were males (7.9%). young children (under 10 years) of male caregivers were more likely to have received disclosure compared to young children of female caregivers (or 5.58; 1.24–25.19). most caregivers had not completed high school education (87.3%). caregivers who completed their high school education were more likely to disclose the child’s hiv status to the child (multivariate or 4.04; 1.26–12.91) than those who had not completed their high school education. caregivers rated their own quality of life index at 90.5% (mean). caregivers who rated their quality of life higher were less likely to disclose the child’s hiv status to the child (or 0.31; 0.10–0.95). this association attenuated in multivariate analyses (or 0.64; 0.16–2.54). we did not find significant associations between disclosure and caregiver’s age, relationship with the child, cultural background, caregiver’s marital status or worry as indicators of caregiver functioning (extent of concern about chil d’s treatment, side effects, reaction of others, child’s condition or effects of illness on family and future) (table 2). table 2: associations between disclosure and caregiver characteristics – univariate analyses. clinical characteristics clinical characteristics associated with disclosure included suppressed viral load, formulation (tablet/syrup), non-nucleoside reverse transcriptase inhibitors (nnrti) in regimen, protease inhibitor (pi) in regimen with stavudine and didanosine, regimens with efavirenz, longer duration on treatment, start of treatment in the first year of life, experiencing difficulties administering treatment and poor adherence to treatment. one-third (32.8%) of children had a detectable viral load and had less likely received disclosure compared to those with a suppressed viral load (multivariate or 0.21; 0.05–0.84). most children were on a regimen with a combination of three medicines (86.3%), consisting of tablets only (62.2%). children whose regimen included syrups (syrups only or combined with tablets) had less likely received disclosure compared to children who were on tablets only (multivariate or 0.28; 0.08–0.92). children on a regimen including an nnrti (35.3%) more likely received disclosure compared to children on a regimen with no nnrtis (or 2.71; 1.37–5.38). this association attenuated in multivariate analyses (or 1.84; 0.78–4.31). children on a pi-based regimen with stavudine and didanosine (16.8%) less likely received disclosure compared to children who were on a non-pi-based regimen (multivariate or 0.19; 0.03–1.00). children on a regimen including efavirenz more likely received disclosure than those with no efavirenz (or 2.90; 1.46–5.77). this association attenuated in multivariate analyses (or 1.91; 0.81–4.48). children on a regimen of lopinavir/ritonavir syrup (79.5%) less likely received disclosure (or 0.14; 0.03–0.59). this association attenuated in multivariate analyses (or 0.54; 0.11–2.62). children were on treatment for 1 month to 9.8 years (mean 5.2 years). children with a longer treatment duration more likely received disclosure compared to those more recently initiating treatment (or3.02; 1.19–7.63). this association attenuated in multivariate analyses (or 1.21; 0.38–3.91). children who started their treatment in the first year of their life (30.5%) less likely received disclosure than those commencing treatment later in life (or 0.12; 0.04–0.40). this association attenuated in multivariate analyses (or 0.49; 0.12–1.94). caregivers who experienced difficulties administering medication (30.5%) less likely disclosed the child’s hiv status to the child compared to caregivers not experiencing difficulties administering medication (or 0.41; 0.18–0.95). this association attenuated in multivariate analyses (or 0.63; 0.23–1.73). non-adherence was 10.1% for self-report and 63.1% for pill count. children who were non-adherent to their treatment had less likely received disclosure than those who were adherent (self-report fisher’s exact p-value 0.008). we did not find any significant associations between disclosure and who clinical staging, cd4 count, complications reported (e.g. running out of medication, flavour, forgetting, multiple caregivers, illness, depression and being away from home), side effects (e.g. fever, rash, sleep disturbance and pain), default on treatment in the past and subsequently restarted, number of medicines in regimen or adherence defined by pill count (95% – 105%) (table 3). table 3: associations between disclosure and clinical characteristics – univariate analyses. socio-economic characteristics socio-economic characteristics associated with disclosure included family functioning, affected daily activities and waterborne sanitation. overall family impact index was 90.4% (mean). children with a high overall family impact scale (good family functioning) had more likely received disclosure than those from a household with low family impact index (or 4.18; 1.54–11.32). this association attenuated in multivariate analyses (or 0.80; 0.22–3.00). the mean score for daily activity index (component of family functioning) was 91.5% and included the extent of activities taking more time and effort, difficulty finding time and energy to finish household tasks or affected daily activities. children from families with a higher family activity index had less likely received disclosure compared to children from families with a low family activity index (activities affected) (or 0.21; 0.04–1.000). this association attenuated in multivariate analyses (or 0.81; 0.30–2.17). the overall mean ses index was 52.0%. the study population had significantly more often waterborne sanitation (73.7%, p < 0.001), owned a tv (89.4%, p < 0.001), fridge (79.9%, p = 0.001) or cell phone (95.2%, p = 0.003) than the general south african population. however, the study population lived with significantly more people in one household (mean 5.2, p < 0.001), more people lived in informal dwellings (39.5%, p < 0.001) and were less likely to own a computer (11.5%, p = 0.001), landline phone (7.1%, p = 0.004) or car (15.3%, p < 0.001) compared to the general south african population (table 4). children from households with waterborne sanitation had more likely received disclosure than those from households with no toilet facilities connected to sewage (or 2.87; 1.13–7.29). this association attenuated in multivariate analyses (or 1.76; 0.58–5.35). we did not find any significant associations between disclosure and overall ses index (table 5). table 4: associations between disclosure and socio-economic characteristics – univariate analyses. table 5: socio-economic status indicators and south african comparison. prediction model the prediction model for disclosure included five variables: age of the child (or 146.56; 20.27–1059.69, p < 0.001), pi regimen with stavudine and didanosine (or 0.01; 0.00–0.22, p = 0.005), marital status (or 7.00; 1.39–35.03, p = 0.018), viral load (or 0.05; 0.01–0.41, p = 0.005) and adherence (pill count 95% – 105%) (or 0.16; 0.03–0.77, p = 0.023). the association with caregiver education attenuated when adding viral load to the model. the overall percentage of correctly classified cases was 91.1% and hosmer and lemeshow’s chi-square test for goodness of fit was 58.7 (p = 0.812). figure 1 provides an overview of the proportion who received children disclosure within the categories of all predictors identified in multivariate analyses and the prediction model. figure 1: predictors of paediatric disclosure. discussion only 17 children (8.9%) in this cohort of 3–14-year-olds received full disclosure. in multivariate analyses, we found that increased age of the child and higher education of the caregiver were strongly associated with disclosure of hiv status to the child. in addition, sex of the caregiver, detectable viral load, syrup formulation, pi regimens with stavudine and didanosine, and self-reported non-adherence were strongly associated with non-disclosure. the prediction model identified age of the child, caregiver’s marital status, viral load, regimen and non-adherence defined by pill count (95% – 105%) as predictors of disclosure. similar to other studies, we found older age of the child to be strongly associated with increased probability of disclosure of the hiv status to the child.14,22,23 literature does not specifically associate better hrqol of the child with non-disclosure; however, health-related factors and a child’s family situation are reported as predictors of disclosure.10 male caregiver, level of education and hrqol were associated with disclosure. while some studies have described not having a biological father as a predictor of disclosure,24,25 we found that children had more likely received disclosure when their main caregiver was their father. both the events of the demise of one’s father and the absence of the mother in the household indicate major life events that are possibly related to hiv. this could explain the association between caregiver’s gender and disclosure, as disclosure is more likely to happen when the caregivers themselves are hiv-positive.26 while some studies have confirmed our finding that caregivers with higher education are more likely to disclose the child’s hiv status to their child,27 other studies have not.14 caregivers feeling worried and unprepared for the process of disclosure and answering questions prevent actual disclosure.22,28 the association we found between educational level and disclosure might be explained by better educated caregivers feeling more equipped to start this process. our finding that caregivers with better hrqol are a predictor of non-disclosure is not reported in other literature, although the child’s family situation and caregiver disclosure-related anxiety are described to affect disclosure.28 we found a strong association between detectable viral load and non-disclosure. a detectable viral load is an indicator of failure of treatment.29 conversely, addressing disclosure could positively affect adherence and viral suppression.6,23 non-adherence was associated with non-disclosure. most likely, this association was reversed where non-disclosure contributed to difficulties remaining adherent.4 similarly, caregivers experiencing difficulties administering medication had less likely disclosed the child’s hiv status. non-disclosure may have contributed to difficulties administering medication. we did not find an association between cd4 count and disclosure. some literature described that children with a cd4 percentage over 15% are more likely to receive disclosure,24 where others did not confirm this association for cd4 percentage or cd4 count.14 children on regimens including syrups were less likely to receive disclosure. although young children were generally on syrup formulations, the association remained when corrected for age. possibly an easier routine with syrups does not require the need to disclose. children on pi-based regimens with stavudine and didanosine had less likely received disclosure. current guidelines recommend replacing stavudine and didanosine with abacavir29 and will therefore not be part of future regimens. multiple clinical characteristics associated with disclosure in univariate analyses attenuated in multivariate analyses, explained by the child’s age (lopinavir/ritonavir syrup, nnrti-based regimens, efavirenz regimens, duration on treatment and starting treatment in the first year of life). children on lopinavir/ritonavir syrup were less likely disclosed. this could be explained by the regimen generally being given to young children and being changed to tablet form for older children. although the general experience of side effects did not affect disclosure, side effects affecting the central nervous system, unusual dreams and trouble sleeping (efavirenz) and severe rash (nevirapine)29 likely contributed to the decision of caretakers to disclose the hiv status to children on regimens including nnrtis. children who were on treatment for longer duration had more likely received disclosure. guidelines in south africa regard all hiv-positive children eligible to initiate art irrespective of cd4 count or clinical staging.29 older children, who are more likely on treatment for longer duration, more often receive disclosure,10 potentially explaining why the association attenuated in multivariate analysis. other studies have confirmed the association we find between longer time on art and disclosure.25 children who started treatment in the first year of life, however, less likely received disclosure. disclosure did not seem as urgent for caregivers when the same routine with their child could be maintained from birth and no failure of treatment occurred. socio-economic characteristics associated with disclosure included family functioning, affected daily activities and waterborne sanitation. although some studies have described an association with disclosure and the child’s family situation,10,14 no specific measures for family functioning or activities were reported in the literature. indicators of ses including financial problems24 and the child being hungry14 are reported in the literature as a predictor of disclosure. although we did not find an association between ses index and disclosure, despite a large number of people living in informal settlements, we found that children from households with access to waterborne sanitation had more likely received disclosure. informal living conditions more often lack waterborne sanitation, are more densely populated and lack privacy required to support the disclosure process. a limitation of our study was the reliance on medical records for viral load and cd4 count results. in addition, the questionnaire did not include topics like experience with or perspectives on disclosure. literature focuses on healthcare providers’ perspective30,31,32 or caregivers’ perspective.12,14,22,33 the child’s perspective on disclosure is rarely or not studied at all. a strength of our study was that our interviews included all children aged 5 years or older when addressing their hrqol. although we suggest doing similar research in other settings to ensure generalisability of the data, another strength of this study was the reasonable sample size. conclusion this cross-sectional study shows a low proportion of children knowing about their hiv status. older age of the child was strongly associated with disclosure. we found a less stringent need for caregivers to disclose the child’s hiv status to the child when art was tolerated well and no condition-related difficulties were experienced (e.g. high hrqol for both the child and the caregiver and family activities not affected by chronic disease). well-functioning families, with caregivers who received higher level of education and children from households with better ses, provided an environment enabling and promoting disclosure of the hiv status to the child. disclosure can only be beneficial when there is a supportive social structure. non-disclosure can indicate a sub-optimal social structure, which could negatively affect adherence and viral suppression. in order to successfully address disclosure, the complex social context needs to be taken into account. when families are in a good space, there is no pressing need to start the disclosure process. however, these circumstances positively enable the disclosure process. targeting these families for disclosure interventions and the support of families to reach such an enabling environment can therefore be especially successful. acknowledgements the authors thank the study participants, the staff at the clinical site, tc newman hospital and anova health institute and also mrs h. lesch for her assistance with the data collection. competing interests the authors have no conflict of interests. authors’ contributions s.l.v.e. and a.m.v.f. conceived this cohort study. s.l.v.e., a.m.v.f., m.f.c. and r.p.h.p. contributed to the conception of design and methodology of the study and prepared the protocol. s.l.v.e. and p.k. contributed to acquisition of data, facilitated by c.g. s.l.v.e. prepared the data sets and conducted the statistical analyses, which were checked by a.m.v.f., r.p.h.p. and m.o.k. all authors contributed substantially to the interpretation of the data. s.l.v.e. drafted the manuscript and all authors revised the manuscript critically for important intellectual content. all authors reviewed and approved the final manuscript. funding information this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views expressed in the article are those of the authors and not an official position of the institution or funder. references joint united nations programme on hiv/aids (unaids), aidsinfo. global factsheets [homepage on the internet]. 2016 [cited 2018 apr 19]. available from: http://aidsinfo.unaids.org/?did=5581277ae9beccab3bd5a44e&r=world&t=2016&tb=q&bt=undefined&ts=0,0&qla=g&qls=allcountries joint united nations programme on hiv/aids (unaids), aidsinfo. country factsheets 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https://doi.org/10.1111/hex.12141 madiba s, mokgatle m. health care workers’ perspectives about disclosure to hiv-infected children; cross-sectional survey of health facilities in gauteng and mpumalanga provinces, south africa. peer j. 2015;3:e893. https://doi.org/10.7717/peerj.893 madiba s, mokwena k. caregivers’ barriers to disclosing the hiv diagnosis to infected children on antiretroviral therapy in a resource-limited district in south africa: a grounded theory study. aids res treat. 2012;2012:402–403. https://doi.org/10.1155/2012/402403 abstract introduction background materials and methods results discussion conclusion acknowledgements references about the author(s) catherine atuhaire department of nursing, faculty of medicine, mbarara university of science and technology, mbarara, uganda kabanda taseera department of nursing, faculty of medicine, mbarara university of science and technology, mbarara, uganda chris spoor faculty of health science, leeds beckett university, leeds, united kingdom rosaline y. cumber faculty of political science, university of kwazulu-natal, durban, south africa samuel n. cumber section for epidemiology and social medicine, department of public health, institute of medicine, the sahlgrenska academy at university of gothenburg, gothenburg, sweden faculty of health sciences, university of the free state, bloemfontein, south africa citation atuhaire c, taseera k, spoor c, cumber ry, cumber sn. knowledge and perceptions of male immigrants in leeds (uk) towards male circumcision as an hiv prevention strategy. s afr j hiv med. 2019;20(1), a823. https://doi.org/10.4102/sajhivmed.v20i1.823 original research knowledge and perceptions of male immigrants in leeds (uk) towards male circumcision as an hiv prevention strategy catherine atuhaire, kabanda taseera, chris spoor, rosaline y. cumber, samuel n. cumber received: 20 dec. 2017; accepted: 05 feb. 2019; published: 31 oct. 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the world health organization has accepted and recommended medical male circumcision (mmc) as an hiv prevention strategy. despite the advantages of mmc, the rate of uptake of this practice among immigrants and the general population in the united kingdom (uk) is low, yet the procedure is provided in public and private health facilities. the role of negative perception and its contribution to low circumcision rates is unknown. objectives: since immigrants are a key group that is vulnerable to hiv in the uk, this study aimed at understanding their knowledge and perceptions with regard to mmc. methods: we enrolled 10 participants who were purposively selected using snowball recruitment methods. data were collected during individual in-depth interviews using semi-structured interview guides. responses were audio recorded, transcribed and analyzed using thematic analysis. appropriate themes were generated from the data collected. results: we found that the majority looked at male circumcision (mc) as a practice to fulfill their cultural and religious obligations rather than as an hiv protection method. few participants showed belief and certainty that mc or mmc was effective in hiv prevention hence limited knowledge. they also expressed perceived danger. this included fear of pain, complications from the procedure and possible infections when carried out through traditional means. these dangers discouraged study participants from accessing mmc. conclusion: male circumcision is mainly practiced to fulfill cultural and religious norms, but is not seen as a credible hiv prevention strategy. keywords: male circumcision; knowledge; perceptions; hiv prevention; united kingdom. introduction medical male circumcision (mmc) is a globally accepted and recommended hiv prevention strategy.1,2 however, the success of this strategy depends on its uptake within the community, something consequent upon cultural acceptance, knowledge and perceptions of its effectiveness in the prevention of hiv transmission. in the united kingdom (uk), the prevalence of hiv among immigrants, especially those from southern and eastern africa, is higher than that of the indigenous population, namely 25 per 1000 men and 50 per 1000 women versus 2.1 per 1000 men and 1 per 1000 women, respectively.3,4 this is partly attributed to the high prevalence rates of hiv infection in the home countries of immigrants and, as some argue, to complacency with regard to hiv prevention.5 behavioural change is an important instrument in the public health promotion of mmc. for change and acceptability to happen, people’s knowledge and perceptions have to change.6 we conducted in-depth interviews to assess the knowledge and perceptions of circumcision as an hiv prevention tool among male immigrants from southern and eastern africa, but currently resident in the uk. background hiv is a major health challenge, especially in sub-saharan africa.2 in 2013, more than 35 million people worldwide were infected and 1.5 million died of hiv and aids.7 male circumcision (mc), which is the surgical removal of the foreskin of the penis, supplements less effective strategies such as abstinence, faithfulness to a partner and the consistent use of condoms as a means to prevent infection.8,9,10 east and southern african countries have implemented mmc as a primary prevention strategy. the widespread introduction of mmc followed compelling evidence of the reduction of hiv acquisition in circumcised, uninfected and exposed men of ≥ 40%.11 the biological plausibility and efficacy of the procedure arises from the fact that the penile foreskin contains many cd4 receptor-bearing langerhans cells and lymphocytes. these cells permit viral (hiv) invasion.12 in addition to the removal of vulnerable tissue, circumcision assists in increasing the thickness (keratinisation) of residual skin, thereby reducing penile abrasions during intercourse.13 circumcision may reduce the incidence of genital ulcer disease and in this way also ‘protect’ from hiv infection.14 in order for rates of mc or mcc to increase, society and the individual’s perceptions must be better understood. indeed, without perception, action, according to gibson,15 is misguided and serves no purpose.16 the promotion of successful health strategies, for example mc and mmc, must influence people’s perceptions.17 although the number of people diagnosed with hiv annually in the uk has been low, namely 5000 in 2001, the number of those living with hiv is increasing and by the end of 2011 was estimated to be 96 000.1,11 disease is not restricted to a geographical region or a specific population group. to reduce or eradicate hiv from the uk, prevention strategies must focus on the needs of key and vulnerable populations such as immigrants. given the political and economic instability of countries in africa, the number of those seeking asylum in the uk is likely to grow. the world health organization (who) has identified 14 countries in east and southern africa with generalised hiv epidemics and with low prevalence rates of mc. these countries have been targeted for the scale-up of mmc programmes.1 in the uk, circumcision of british men is on the decline and currently stands at 15.8% of 16–44-year olds. rates vary: high among jewish men (98.7%), and lower among hindus, sikhs and buddhists (9.8%).18 the overall low rate of circumcision in the uk likely follows on directives from the national health system (nhs) that recommends circumcision only if medically indicated.19 the role of negative perception and its contribution to low circumcision rates is unknown. this study sought to better understand the knowledge base and perceptions of male immigrants from eastern and southern africa now residing in leeds (uk) with regard to the role of mc or mmc as an hiv prevention strategy. materials and methods study population and setting a cross-sectional qualitative research approach was used for the evaluation of the knowledge and perceptions of male immigrants living in leeds, the uk, and originally from southern and eastern africa. all eligible participants had lived in the uk for more than 2 years and had a reasonable command of the english language. the study focused on participants from this part of africa because of the high prevalence of hiv infection in their region of origin.2,20 tools for data collection data were gathered using semi-structured interview guides. the responses were audio recorded, although participants had been offered the option of having their responses hand written in case they felt uncomfortable with recording. each interview took approximately 45–60 min. data collection participants were purposively selected using a snowball recruitment method. data were collected through face-to-face researcher-guided in-depth interviews. during the preliminary stage, an eligible person was identified. the subject was invited to participate in the study and given the participant information sheet to read before consenting to participate. he was then contacted and invited to an interview. after the interview, this person was asked if he knew any potential participants from the region of africa under study and was requested to pass on details to the researcher. this referral process was applied until the sample size was reached. to allow for response diversity, participants from different age groups and nationalities were contacted. the questions required the participants to define circumcision, any benefits and cultural views in support of or against mc or mmc. the research questions were formulated based on the study objectives, and each interview was allocated approximately 45–60 min. data were collected in 2 months. data management data were analysed using a thematic content analysis. in brief, transcripts were read and re-read several times. initial codes were identified, noting repeated issues. each code was checked against the raw data, and emerging ones were developed into categories. the categories were grouped together into overarching themes, based on the understanding of the data. appropriate themes were generated and recorded. when checking the raw information, a description was provided that summarised the theme. these transcripts were analysed manually and checked for consistency. this method of data analysis was used to describe in detail the views, opinions and feelings of respondents. verbatim accounts have been used in the presentation of the data, and results compared with other similar studies so as to contextualise the work. research rigour an assessment of data trustworthiness was undertaken throughout this study that focussed on credibility, transferability, conformability and dependability.21 credibility was ensured through establishing a conducive rapport with participants, while conformability was done by evaluating interview questions to ensure that they were not leading and closed-ended. codes used for each participant allowed for proper matching of each participant’s description. dependability was ensured by careful listening to the recorded responses to explain phrases that were used by the participants and transferability was also achieved by eliciting descriptions of findings, adequate sampling and achieving data saturation. limitations because this study targeted immigrants from southern and eastern africa, the sampling was difficult, as it was not an easily identifiable population. the researcher had to resort to a snowball recruitment technique. consequently, bias is possible as the sampling may have captured a group of like-minded friends. the researcher attempted to limit bias by recruiting respondents from different african countries. it is acknowledged that bias may remain as peers may share the same views or beliefs. the small number of participants is a further limitation as additional views and perceptions were excluded, that is, it is acknowledged that this study cannot represent the views of all citizens of east and southern africa or of all african immigrants. however, the uniformity of the results suggests that the study has captured some important themes. relevant additional demographic data such as the grouping of participants’ age and response, educational (highest educational level achieved) and socio-economic (employment) status were not included in the study, but may have influenced responses of the study members. ethical consideration the leeds metropolitan university approved the conduct of the study and informed consent was obtained from eligible participants. all ethical issues were addressed. efforts were made to build trust and rapport with participants during the interview process. potential risks to the participants included breach of confidentiality, possible sensitivity of the respondents to the research questions and a feeling of uneasiness towards the interviewer. to mitigate these risks, the participants received as much information as possible before the interviews, so that they decide whether or not to participate in the study. results a total of 12 informants were interviewed; however, the data analysis could be performed on only 10 (table 1). table 1: key informants’ demographics. all respondents were between 18 and 65 years of age, and had lived in the uk for more than 2 years. the various geographical backgrounds of the cohort, ages and relationships were thought to provide a wide range of views, opinions and perceptions. results are presented thematically using verbatim reporting. knowledge of male immigrants about male circumcision as an hiv prevention measure to achieve this objective, respondents were asked what they understood mc or mmc was, the benefits and views of the relevance of mc or mmc in the prevention of hiv. meaning of male circumcision all the 10 participants were able to define mc: … my understanding of circumcision is the removal of the foreskin from the penis of a man. that is my understanding … (key informant 2, male, married) … i believe it’s the cutting of the foreskin of the male penis … (key informant 3, male, married) although all the 10 participants understood mc as removal of the foreskin from the penis, one respondent defined mc in a cultural sense: … circumcision i believe is what certain cultures undergo as a culture … (key informant 4, male, single) some respondents understood circumcision from a religious point of view as one participant revealed: … i mean am a christian. circumcision the way i see it was directed by god. ok from the bible … … genesis 18 verse 10 says this is my covenant you shall keep between me and you and thy seed after thee. every male child among you shall be circumcised … i don’t see any medical basis for it. it is just a religious thing … (key informant 10, male, single) the findings show that participants viewed circumcision as being done for medical, cultural and religious purposes. benefits of male circumcision we explored whether participants knew mc as an hiv prevention strategy. responses to this question were spontaneous as we wanted to find how hiv prevention ranked among the benefits of mc. participants gave various benefits of mc and hiv prevention ranked third. male circumcision for cultural purposes culture has been suggested in various studies as both the determinant and predictor of mc. from spontaneous responses, culture was viewed as the major benefit of mc. out of 10 respondents, six mentioned culture as the reason for mc and that the procedure helped fulfil cultural obligations and fitted in with the accepted cultural practices: … firstly, some cultures tend to practice that. when a child is born if he is male, at a certain age he has to get circumcised. it is a way of passing from being a boy into manhood … (key informant 3, male, married) … this is my understanding. perhaps if you are not circumcised, how do you say you are a man because for us we believe that to be a man fully, you have to undergo a knife … (key informant 5, male, married) … well in south africa boys in certain tribes especially in the eastern cape, are expected to go through an initiation into manhood and this initiation starts with circumcision because they believe that the foreskin is a feminine part of the body and so this is removed … (key informant 8, male, single) for most of the participants, circumcision is one way a boy can transit from childhood to adulthood. fulfilling cultural obligations seemed to be the major benefit provided by mc. perceptions towards male circumcision although mc or mcc as an hiv prevention strategy was the core of this study, this aspect was third in importance in the view of respondents and was mentioned by only four subjects. however, only one gave this as of first importance. another mentioned it as of second importance after culture, and two placed it fourth after culture, religion and hygiene: … if you remove the foreskin you also protect yourself from stis and in the same manner i think circumcision helps hiv prevention. it is not 100% to my understanding but it’s to quite a good degree, it helps people from contracting hiv … (participant 2, male, married) the above participant was the only one who mentioned hiv prevention as the first benefit with some level of certainty. in some cases, participants were aware that mc or mcc protects against hiv, but were not sure whether it was true as revealed below: … am also told that one is that in the hiv perspective. i don’t know how true it is … (participant 4, male, single) … i have heard that it helps in hiv/aids prevention and other people do it for religious beliefs, i think … i just read it in one of the magazines that it helps people in hiv prevention but am not sure in the technical details … (participant 1, male, in a relationship) two, however, revealed that mc protects against sexually transmitted infections (stis) but could not mention which: ‘… really, to me, well i feel, it helps to prevent some sexually transmitted diseases … all the sexually transmitted diseases. most of them, you can name them …’ (participant 7, male, married) so based on this study, it was clear that the level of knowledge about mc as an hiv prevention strategy was low, with cultural and religious factors taking precedence over hiv prevention. social factors besides hiv prevention in this study, participants revealed that mc had a social importance. three participants mentioned that mc can help a person fit in his society or peer group: … hmm social aspect, i think as with most things really, many people are taking decisions based on the society. i think if you look at an individual, one is defined by where they belong to a group of people who uphold circumcision then you may want to get circumcised … (participant 3, male, married) the issue of social benefits was also echoed by other participants, showing that it was an important determinant of mc decisions: … i think it is accepted in society, you know. in society, if you are not circumcised, you cannot really fit in. you know, discriminating and all that … (participant 7, male, married) … yes, but it is not something done because of medical reasons. much as it is not done for those reasons, in the long run it will help protect an individual from acquiring stis. it is quite beneficial if it is medical male circumcision … (participant 2, male, married) therefore, based on such views, the decision to undergo mc or mcc or not can be a social decision, not necessarily to prevent hiv. sexual satisfaction furthermore, one participant linked mc to sexual satisfaction revealing that being circumcised gave one increased sexual pleasure: … you really get the feeling of, i wouldn’t call it satisfaction but when you are into sex … in my own view, it is true. … i mean during sexual intercourse. a man can run for longer hours which is advantageous to the women because they enjoy it more … (participant 5, male, married) five participants revealed that they were aware that mc or mmc prevents hiv, but were not sure of how this was possible: … i understand because i read a lot. i understand that there is a link between and it is being practiced in uganda where they are encouraging most people to get circumcised as a prevention of hiv. how it is or the specifications, am not sure … (participant 4, male, single) one participant revealed that he had heard of the link, but could not believe it was possible and showed scepticism: … we have heard always in media but specifically i have not yet believed. (participant 5, male, married) one participant did not have any idea that mc or mcc had any link to hiv prevention: … well i don’t know what exactly the link is. i only know studies that have looked at the link between hiv and circumcision. … i don’t know if there is any proof exactly how it could prevent hiv … (participant 8, male, single) to achieve objective 2, participants were also asked what they thought were the disadvantages or dangers of mc or mmc. pain came up prominently as one of the barriers to circumcision, as was mentioned by five participants: … first and foremost, i would say to human beings, pain is something that is not easy to persevere so perhaps i do think they would fear the pain … (participant 5, male, married) this study found that people do not only fear to face the knife, but also fear possible complications that may arise out of the procedure, especially if it is done traditionally: … hmm i would like to believe that circumcision is a surgical and there is bound to be complications especially traditionally. if you are undergoing through circumcision and then there are complications that could be a disadvantage … (participant 3, male, married) lastly, some participants believed that circumcision of males can actually lead to hiv infection instead of protecting against it, especially when done traditionally: … understanding is that they just use the same instrument to cut all the boys. and there is no sterilising of instruments. because of that i think those are the disadvantages … (participant 1, male, in a relationship) responses presented show that although there is some awareness of mc or mcc as an hiv prevention strategy, most people still view the procedure from a cultural and a social point of view. even among the people who are aware of the positive relevance of mc in hiv prevention, there is limited knowledge of how effective the strategy is, resulting in scepticism. discussion the efficacy of any health strategy relies on how the target population is aware of the strategy and the benefits it can provide. this was made evident in a study carried out22 in botswana, where before the informational session, 68% of respondents were willing to circumcise their male children, but the percentage of those willing to circumcise their children increased to 89% after the session. this study sought to establish the knowledge regarding mc or mcc as an hiv prevention strategy. our study found that there were still gaps in the knowledge of immigrants from east and southern africa. male circumcision is still largely looked at in the light of culture (five participants) and religion (five participants), rather than hiv prevention. regarding culture, other studies have also tried to explain how culture informs health choices and behaviour. shweder suggested that mc often seems to be a social phenomenon, propelled by the need for individuals to fulfil cultural norms and practices, that enables males to acquire the traits of masculinity.23 such cultures are embedded in african societies like the gisu and bakonjo in uganda, kikuyu of kenya, masai of kenya and tanzania. in the modern era, the cultural aspect of mc remains in regions such as east and southern africa. however, in the majority of these areas, most of the rites that used to accompany such ceremonies are no more. in many cases, the procedure is now performed in private, for example one-on-one, in a hospital or doctor’s surgery. local pain relief is often used in such settings. however, this modification is not acceptable to all tribes.24 the antagonists of modernisation insist on circumcision within a group ceremony, without anaesthesia, and as a test of courage at the banks of a river. this traditional approach is common among the meru and kissi tribes of kenya.24 despite the loss of the traditional appeal of circumcision, the physical effects are crucial to personal identity, pride and acceptance in society. uncircumcised men in such communities risk being banished, and subject to ridicule as if they were boys. there have been many reported cases of forced circumcision of men from such communities, who are discovered to have escaped the ritual. culture as the primary reason for mc in this study is largely explained by the fact that the participants came from countries where some cultures continue to practise circumcision. the findings showed that there was uncertainty regarding mc or mcc as an hiv prevention strategy. even after concerted efforts by the who to promote this,2,25 this study suggests that many individuals do not agree. the findings concur with naidoo et al.,26 who suggested that even among educated people such knowledge is limited. the latter study assessed university students in kwazulu-natal, south africa. based on the findings, it is evident that although there has been increased information, especially through the media and peer groups about mmc, little has been done to help people understand how mc protects against hiv. as a result, scepticism about the appropriateness of the procedure remains. this explains why educated people seem to be more likely to accept mc as an hiv prevention strategy (participant 1). this was demonstrated in a study carried out in uganda27 and kenya,28 where it was found that levels of awareness were higher among educated adults in rural areas. male circumcision is often associated with genital hygiene (participants 4, 7, 8). it is believed that when a man undergoes mc or mmc, hygiene is guaranteed. a study by hill et al.,29 from papua new guinea, found that genital hygiene was the second most frequent reason given in support of mc. this study suggests that adult male migrants from east and southern africa may be unlikely to recommend mmc and opt rather for a view in line with culture, religious and social expectations. conclusion this study explored the knowledge and perceptions of male immigrants from southern and eastern africa with regard to mc or mmc as an hiv control measure. the study indicates that the understanding of many immigrants is defective in this respect. it is suggested that attempts to increase awareness of the benefits of mmc be encouraged and that mmc be made more accessible and affordable to the immigrant community in the uk. acknowledgements the authors thank all the participants. competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions c.a., k.t., s.n.c. and c.s. designed the study and were involved in aspects of the study. r.y.c. and s.n.c. contributed to scientifically reviewing the article and intellectual inputs. all authors reviewed the final article and agreed to submission. funding information this research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references world health organization. progress in scale-up of male circumcision for hiv prevention in eastern and southern africa: focus on service delivery-2011 revised. geneva: world health organization; 2011. unicef unaid, world health organization. global hiv/aids response: epidemic update and health sector progress towards universal access: progress report 2011. geneva: world health organization; 2011. unaids. report on the global aids epidemic. nova york: joint united nations program on hiv/aids (un aids); 2008. mcgarrigle c, cliffe s, copas aj, et al. estimating adult hiv prevalence in the uk in 2003: the direct method of estimation. sex transm infect. 2006;82(suppl 3):iii78–iii86. https://doi.org/10.1136/sti.2006.020339 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africa. afr j prim health care fam med. 2012;4(1):1–7. https://doi.org/10.4102/phcfm.v4i1.327 wilcken a, et al. male circumcision for hiv prevention-a cross-sectional study on awareness among young people and adults in rural uganda. bmc public health. 2010;10(1):209. https://doi.org/10.1186/1471-2458-10-209 ngalande rc, et al. acceptability of male circumcision for prevention of hiv infection in malawi. aids behav. 2006;10(4):377–385. https://doi.org/10.1007/s10461-006-9076-8 hill ps, et al. a typology of penile cutting in papua new guinea: results of a modified delphi study among sexual health specialists. aids care. 2012;24(1):77–86. https://doi.org/10.1080/09540121.2011.592812 abstract background methods ethical consideration results discussion conclusion acknowledgements references about the author(s) boniphace m. idindili rti international, tanzania simon j. king rti international, united states kristen stolka rti international, united states irene mashasi independent consultant, tanzania philberth bashosho independent consultant, tanzania happy karungula independent consultant, tanzania florida chintowa independent consultant, tanzania godfrey mwakabole independent consultant, tanzania kimberly ashburn rti international, united states barbara do rti international, united states norman goco center for applied public health research, rti international, united states citation idindili bm, king sj, stolka k, et al. hiv care and treatment clinic performance following president’s emergency plan for aids relief-funded infrastructure improvement in tanzania. s afr j hiv med. 2018;19(1), a777. https://doi.org/10.4102/sajhivmed.v19i1.777 original research hiv care and treatment clinic performance following president’s emergency plan for aids relief-funded infrastructure improvement in tanzania boniphace m. idindili, simon j. king, kristen stolka, irene mashasi, philberth bashosho, happy karungula, florida chintowa, godfrey mwakabole, kimberly ashburn, barbara do, norman goco received: 21 june 2017; accepted: 17 apr. 2018; published: 14 june 2018 copyright: © 2018. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract purpose: to assess how the infrastructure improvements supported by the us centers for disease control and prevention (cdc) and the united states president’s emergency plan for aids relief (pepfar) contributed to facility-level quarterly and annual new patient enrolment in hiv care and treatment and antiretroviral therapy (art) uptake and retention in care. methods: aggregate quarterly and annual facility-based hiv care and treatment data from the cdc-managed pepfar reporting online and management information system database collected between 2005 and 2012 were analysed for the 11 rural and 32 urban facilities that met the eligibility criteria. infrastructure improvements, including both renovations and new construction, occurred on different dates for the facilities; therefore, data were adjusted such that preand post-infrastructure improvements were aligned and date-time was ignored. the analysis calculated the mean (95% confidence interval) number of patients per facility who were (1) newly enrolled in hiv care, (2) patients initiated on art, (3) patients retained in care, defined as alive and on art, and (4) reasons for attrition, defined as transferred out, lost to follow-up, deceased or stopped art. results: the overall mean number of adult patients newly enrolled in hiv care clinics per quarter declined from 187.7 (151.4–223.9) to 135.2 (117.4–152.9) after infrastructure improvements but was not statistically significant (p = 0.20). however, the mean number of patients who were alive and remained on art increased from 193.2 (145.3–241.1) to 273.2 (219.0–327.3) after improvements in both rural and urban facilities, although not significantly (p = 0.59). a similar picture was observed for overall paediatric enrolment and retention in care. health facility-specific case studies show variations in new patient enrolment and retention in care between health facilities depending on the catchment area, population hiv prevalence and coverage of art facilities. regarding attrition, the mean number of adult patients lost to follow-up changed from 76.6 (20.8–132.3) to 139.4 (79.6–199.1) (p = 0.65) among rural facilities, while the mean number of children lost to follow-up increased significantly from 3.4 (0.5–6.3) to 8.7 (5.0–12.3) (p = 0.02) after improvements. conclusion: patient retention in care improved in hiv care and treatment facilities with infrastructure improvements. however, the overall number of patients newly enrolled and initiated on art declined and attrition increased in facilities after improvements. background hiv/aids morbidity and mortality has overburdened the health system in tanzania and other countries in sub-saharan africa for over three decades without effective interventions.1,2,3 because of the high burden of people living with hiv (plhiv) in the early 2000s, tanzania experienced a high demand for hiv care and treatment services but faced challenges such as limited budget for health services, poor infrastructure, shortage of health workers and a fragmented procurement and supply system.4,5 antiretroviral therapy (art) services were provided by a few private hospitals at a price that could not be afforded by the majority of hiv-infected patients. by december 2004, only 3000 hiv patients in tanzania were reported to be receiving art, while the estimated demand at that time was 440 000 patients.2,6 tanzania began providing free access to art in september 2004 under the hiv/aids treatment and care plan 2003–2008.6 hiv/aids care and treatment centres were initially established in four referral hospitals and five regional hospitals. antiretroviral (arv) users travelled long distances and spent a significant amount of money for monthly travel to clinics to seek hiv care and treatment.7 initially, the majority of hiv-positive persons were found in urban areas where the initial hiv epidemic in tanzania was identified. over time, as the epidemic spread to rural areas, the existing health system was unable to meet the art demands of the increased number of people living with hiv/aids.8 unaids and who released the 3 by 5 strategy in 2003, which aimed at mobilising international donor agencies to work together to assist developing countries to fight the hiv/aids pandemic.9 tanzania received funding for hiv/aids care and treatment scale-up from organisations such as the global fund to fight aids, tuberculosis and malaria (the global fund), the us president’s emergency plan for aids relief (pepfar), the clinton foundation, the swedish international development agency and the tanzania multicountry hiv/aids programme.3,10 pepfar, through the us centers for disease control and prevention (cdc), provided financial and technical support to tanzania in the rapid scale-up of hiv/aids prevention, care and treatment programmes, health system strengthening and impact mitigation. as part of health system strengthening, pepfar invested approximately $33 million for renovation and construction of laboratory and hiv care and treatment clinic buildings between 2005 and 2012 in 132 sites across tanzania.11,12 the infrastructure improvements improved work space, accommodated additional services and improved patient flow to access hiv-related services. through pepfar support, tanzania made tremendous achievements in the fight against hiv/aids. hiv prevalence decreased from 7.1% in 2001 to 5.0% in 2011 in adults 15–49 years (tanzania health and malaria indicator survey [thmis] 2011–12). more than 1.1 million pregnant women received hiv testing and counselling. the number of clients who received hiv testing and counselling results was 105 000 in 2004 and increased to 3.37 million in 2012. during the same period, the number of patients on art increased from 1518 to 364 00011 and the number of hiv/aids care and treatment clinics increased from 22 to 729. rationale increased funding from the global fund and pepfar as well as competition from generic manufacturers drastically improved availability of arvs in developing countries, including tanzania.13 as a result, plhiv overcrowded the few available care and treatment centres. health facilities accredited to provide art services experienced structural problems with potential impact on patients’ access and retention in care. most art services were provided in temporary shelters or a single shared room that lacked both confidentiality and privacy, leading to poor quality of care, stigma, and discrimination.7 in addition, poor laboratory services to support patient care were common in almost all hiv care and treatment facilities.12 this study was designed to evaluate the impact of infrastructure investments to support the scale-up of art on the delivery of services, particularly in terms of patient enrolment and uptake of services and retention in care. the results of this evaluation will provide information for future investments in health facility infrastructure improvement. although pepfar has invested in a range of hiv intervention programmes, the contribution of physical infrastructure improvements on patient outcomes in line with the scaling up of art is not documented. infrastructure improvement inputs are postulated to affect the quality of the care environment by providing adequate physical space to offer privacy for confidential patient counselling and examinations, enhanced access to and organisation of patient records, and increased confidence in treatments offered to clients.14 investments in physical buildings may contribute to the efficient use of space as planned for hiv services and possibly for additional hiv or non-hiv services as well. improving infrastructure enhances how patients are able to access services, service utilisation, staff job satisfaction and patient satisfaction with services. we acknowledge that other individual factors contribute to enrolment and retention to care, such as transportation to clinics, financial constraints, social support and stigma, and perception of ‘feeling well’.15 however, we hypothesised that investments in infrastructure improvements were expected to lead to increased numbers of patients coming to the facility for services and ultimately the increased enrolment and retention in hiv care and treatment patients. methods data collection and reporting this infrastructure evaluation was designed as a longitudinal, retrospective evaluation of pepfar-funded, cdc-managed infrastructure improvements completed in selected facilities in mainland tanzania. among 244 pepfar-supported infrastructure improvement sites located in 22 regions of tanzania, we selected 86 health facilities using census sampling using the following eligibility criteria: cdc-managed, us department of state regional procurement service-funded investments in infrastructure in mainland tanzania during 2007–2009 and new construction or renovation fully completed (officially handed over from cdc-managed contract to the responsible partner or agency). these facilities are located in rural and urban settings and range from health centres providing primary care to regional hospitals providing tertiary care. tanzania uses the pepfar records organization management information system (promis) database to collect and aggregate quarterly report data from health facilities providing hiv care and treatment, as well as community-based programmes. this database was established in 2006 to track facility-level data from all cdc-supported hiv care and treatment facilities. at the facility level, patients obtaining hiv/aids care and treatment services are registered in the attendance register; demographic and clinical characteristics and treatment information are recorded on the patient medical card. the data are then entered into a ministry of health microsoft access database, which is maintained at the facility, updated with every patient visit and used for reporting to the national government. the non-governmental organisation providing technical support to the hiv care and treatment facility; ministry of health, community development, gender, elderly and children; and the regional and district health management teams provides regular supportive supervision to the facility-level data entry clerks for quality assurance. the non-governmental organisation implementing partner available at the facility is also responsible for aggregating the facility-level data into quarterly data reports and submitting them to the cdc promis database in the facility-based hiv care and art reporting form. quarterly data submitted to promis between january 2007 and june 2012 were used for this analysis. data analysis time points are presented as quarters before and after infrastructure improvements. the date of completion of infrastructure improvements is considered time point zero. two study periods were analysed: (1) the period of at least four quarters before the improvement of the hiv care and treatment building and (2) the period of at least four quarters after commissioning the improved building for use. in defining the quarters, it was critical to ensure the following: clinics were reporting during both time points. clinics were reporting the indicator of interest during both time points. this process was repeated for all analyses, including subpopulation analyses (e.g. urban vs. rural), and led to the inclusion of 43 health facilities (11 rural and 32 urban) for final analysis. the main outcomes of interest included patients newly enrolled in hiv care; patients initiated on art; patients retained in care, defined as alive and on art; and reasons for attrition, defined as transferred out, lost to follow-up, deceased or stopped art. for each outcome of interest, the mean (95% confidence interval) number of patients was calculated for the four quarters before and four quarters after infrastructure improvements using stata version 12. students’ t-test and corresponding p-values were calculated for the comparison of the before and after means. some indicators are distributed normally, some uniform, some skewed. there is no perfect measure of central tendency to cover this range of score distributions, but because the assumptions of the central limit theorem were not violated, it was decided to use the mean. additionally, a pre-post difference was desired. in addition, we analysed patient data at facility level to present trends in patient enrolment and retention in care before and after improvements. these analyses are presented as health facility-specific case studies. ethical consideration the study received ethical clearance from the tanzania medical research coordinating committee of the national institute for medical research and cdc center for global health associate director for science. results we discuss changes in key indicators before and after infrastructure improvements. overall results are presented by adult (table 1) and child (table 2) patient outcomes, by sex and by location (rural or urban). key indicators are presented in the following order: (1) patients newly enrolled in hiv care and treatment, (2) patients newly initiated on art, (3) patients retained in care (alive and on art) and (4) reasons for attrition such as transferred out, lost to follow-up, deceased or stopped art. these overall results are complemented by health facility-specific case studies and graphs to show the variation in trends in patient outcomes observed at individual health facilities before and after infrastructure improvements. table 1: mean numbers of hiv-positive adults newly enrolled in care, initiated on antiretroviral therapy and retained in care before and after construction of hiv buildings in selected health facilities. table 2: mean numbers of hiv-positive children newly enrolled in care, initiated on antiretroviral therapy and retained in care before and after construction of hiv buildings in selected health facilities. new enrolment to care the overall mean number of adult patients newly enrolled in hiv care per quarter declined from 187.7 (151.4–223.9) to 135.2 (117.4–152.9) patients after infrastructure improvements but was not statistically significant (p = 0.20). however, the urban facilities experienced a significant decrease in the quarterly mean number of patients for both females and males newly enrolled in care after improvements (before: males 81.5 [63.9–99.1], females 149.2 [120.3–178.0]; after: males 58.9 [50.7–67.1], females 104.3 [90.8–117.8]; p = 0.02 and p = 0.01, respectively) (table 1). the overall mean number of children newly enrolled in hiv care per quarter declined significantly from 16.4 (13.1–19.8) to 11.3 (9.8–12.8) after improvements (p = 0.01). this significant drop was seen primarily in urban facilities (before: 19.8 [15.5–23.9]; after: 13.3 [11.5–15.1], p = 0.01) (table 2). newly initiated on antiretroviral therapy the mean number of adult patients newly initiated on art saw an overall decrease after improvements. for the rural health facilities, the mean changed non-significantly from 33.8 (22.2–45.3) before improvements to 26.9 (20.6–33.3) after improvements (p = 0.99). however, there was a significant drop among both males and females after improvements in urban health facilities (p = 0.03 and p = 0.01, respectively) (table 1). overall, the mean number of children newly initiated on art per quarter did not change significantly among rural and urban facilities after improvements (p = 0.34). rural facilities reported no change in the mean number of children who started on art after improvements while urban health facilities recorded a non-significant drop (before: 8.0 [6.3–9.8]; after: 6.9 [5.8–8.0], p = 0.30) (table 2). figure 1: mlandizi health centre patients, new and cumulative on antiretroviral therapy by quarter. figure 2: marangu lutheran hospital patients, new and cumulative on antiretroviral therapy by quarter. figure 3: geita district hospital patients, new and cumulative on antiretroviral therapy by quarter. retention in care overall retention in care did not change significantly for adult patients who were alive and on art in both rural and urban facilities. for the 11 rural facilities that reported for the four quarters before and after improvements, the mean number of patients retained in care changed from 193.2 (145.3–241.1) to 273.2 (219.0–327.3) after improvements. at the same time, for the 32 urban facilities, the mean number of patients alive and on art increased from 668.9 (560.1–777.7) to 895.9 (771.7–1020.0) after improvements. however, these differences were not statistically significant (p = 0.59 and p = 0.64, respectively) (table 1). on the other hand, the mean number of children retained in care increased significantly across both rural and urban health facilities. in rural health facilities, the mean number of children retained in care and active on art increased significantly from 17.5 (13.0–22.0) to 27.5 (21.5–33.5) after improvements (p = 0.01). urban facilities saw an increase from 55.4 (44.4–66.3) to 72.3 (60.0–84.6) (p = 0.04) (table 2). attrition attrition at each facility occurred because of a number of factors including transfers, loss to follow-up, death and stopping art. loss to follow-up accounted for the majority of attrition during this study period. loss to follow-up is defined as patients who do not return to care after a specified period of time because of a variety of reasons, which may include social and economic factors such as lack of transport or stigma, transfer to another clinic or voluntarily dropping out of care.16 this evaluation did not analyse factors associated with retention in care or attrition in this study population. for the six rural facilities that had complete data for all four quarters before and after improvements, the mean number of patients lost to follow-up changed non-significantly from 76.6 (20.8–132.3) to 139.4 (79.6–199.1) (p = 0.65). for the 17 urban facilities, the mean number of patients lost to follow-up changed from 207.7 (147.4–267.9) to 325.8 (258.5–393.1) (p = 0.94). death comprised the next largest reported contribution to adult attrition; the mean number of patient deaths for the rural facilities was 28.4 (15.4–41.3) before and 48.7 (27.7–69.6) after improvements, a non-significant increase across six facilities (p = 0.70). the mean number of adult patient deaths for 17 urban facilities increased non-significantly from 93.6 (79.9–107.3) to 150.2 (127.3–173.1) (p = 0.50) (table 1). for children, loss to follow-up was the leading cause of attrition. the mean number of children lost to follow-up increased significantly in both rural and urban facilities (p = 0.02 and p = 0.004, respectively). the second largest reported contribution to attrition among children was transferring to another facility. the mean number of children who transferred out of rural facilities significantly increased from 2.2 (1.1–3.4) to 5.8 (3.1–8.5) after improvements (p = 0.02). among urban facilities, the mean number of transfers also increased significantly from 11.6 (7.5–15.6) to 22.7 (16.5–28.8) (p = 0.003). in addition, there was a notable increase in deaths among children in urban facilities (before: 7.9 [5.9–9.7]; after: 14.3 [10.6–17.9], p = 0.002) (table 2). impact of infrastructure improvements on performance of health facilities: case studies as a complement to overall results, we present case studies that show health facility-specific variations in trends of patients newly enrolled in care and initiated on art and cumulative number of patients on art, before and after infrastructure improvements. case studies include graphs that show the trend in patient outcomes before and after improvements by quarter. time point zero on the x-axis of the graph indicates the time point at which infrastructure improvements were completed. case study 1: mlandizi health centre experienced an increase in patients newly enrolled and initiated on art. the health centre started providing art services in november 2008 immediately after construction of the hiv care and treatment building. prior to construction of the mlandizi hiv care and treatment clinic, patients had to travel about 40 km to access art care and treatment services. the graph shows that over time there have been progressive increases in the number of patients newly initiated in art and the cumulative number of patients currently on art. the presence of an hiv clinic within the community reduced the travel distance and time to receive services, as well as transport costs for patients. case study 2: marangu lutheran hospital experienced a decrease in the number of newly enrolled patients but a steady increase in cumulative patients on art after improvements. at the beginning of the provision of hiv services in 2007, four quarters prior to construction, there were more than 250 newly enrolled patients on art. this was followed by a sharp drop in enrolment of new patients on art to fewer than 50 patients per quarter, which remained steady even after construction. on the other hand, we observed a progressive increase in cumulative number of patients who remained alive and on art after construction. case study 3: geita district hospital experienced a decrease in enrolment after infrastructure improvements but a steady rise in cumulative patients on art. the decline in enrolment of new patients persisted consistently for more than eight quarters after improvements. the decline can be explained by the effects of establishing new art sites in health centres within the district catchment area. the cumulative number of patients on art continued to increase, which was likely because of the transfer of patients from other clinics. discussion the construction and renovation of hiv care and treatment centres took place during the scale-up of art services in tanzania. hiv care and treatment services were decentralised to lower level health facilities from the initial urban higher level health facilities.17 after infrastructure improvements, the new clinics in rural and peri-urban settings reduced the work load of health workers in urban health facilities. the trends of both adults and children newly enrolled to hiv care and initiated on art show mostly non-significant declines in health facilities after infrastructure improvements. significant declines in new enrolments to care and initiation to art were seen in urban facilities, which we suspect is because of patients enrolling at rural facilities now closer to their homes. for children, this general trend of declines is surprising because of the contribution of prevention of mother-to-child transmission (pmtct) programmes in child entry to hiv care and treatment during the post-infrastructure improvement study period.18,19 pmtct programme efforts were intensified in the country following pepfar funding and have increased pregnant women’s access to art and linking children into hiv care and treatment. it is possible that the successful implementation of pmtct programmes during pregnancy and delivery have reduced the incidence of hiv among infants at birth. our analysis showed an overall decline in patients newly enrolled in hiv care and initiated on art. however, health facility-specific case studies demonstrate both positive and negative trends observed in enrolment of new hiv patients and art initiation following infrastructure improvements. the infrastructure improvements established new hiv care and treatment centres with the aim of increasing coverage and access to art but also coincided with additional training of health workers, improved laboratory services and establishment of new hiv laboratories in lower level health facilities together with art initiation centres. depending on its location, a health facility in a high hiv transmission area and not close to another hiv care treatment clinic experienced a positive change in enrolment after infrastructure improvements. an hiv clinic located in a limited catchment area and close to another clinic experienced negative changes in enrolment or no changes at all. mlandizi health centre, an example of a new facility constructed in an area with high hiv transmission, experienced a positive change in the number of new hiv patients enrolled in care and art. geita district hospital experienced a negative change in enrolment of new hiv patients because a nearby health centre started to provide art services, which was also improved by construction of a new building to accommodate art services. the mean number of adult patients remaining alive and on art increased in both rural and urban facilities after improvements. retention rates varied between rural and urban health facilities, with urban facilities recording the highest number of patients remaining on art after improvements. increased access to art during the scale-up years, greater accessibility to art in dedicated hiv care and treatment clinics and community support organisations active in urban settings may have played a major role in retaining art patients as compared to rural areas. the improved quality of care offered at the improved hiv care and treatment buildings may have been a factor contributing to retention in care. we did not analyse other factors related to retention in care; however, patient retention in care and alive on art improved after pepfar investment in art programmes in sub-saharan africa. studies have estimated that up to 80% of patients remained in care at six month follow-up with gradual decline because of early mortality and loss to follow-up.20,21 the mean retention in care of children on art increased significantly after improvements as compared to before improvements. this may be attributed to improved quality of care for children in general and increased coverage of hiv paediatric services attained after improvements. expansion of early child hiv diagnosis and pmtct services coupled with family-centred childcare helped children to access and remain in hiv care and treatment.22 the problem of attrition observed in this analysis was mostly the result of loss to follow-up and death. overall, attrition increased after infrastructure improvements. there is no single explanation for loss to follow-up and increases in deaths of patients on art after improvements. there is evidence that poor quality of health services and advanced disease at start of art carries a high risk of mortality and loss to follow-up.23,24 we speculate that the increased loss to follow-up observed in this study was the result of unreported deaths, because most patients who started on art during that time had severe immunodeficiency and who stage 3/4 in compliance with tanzania and who art guidelines, which set the threshold for initiation of arvs at cd4+ < 200 cells/µl.9,15 additional evidence shows that there are increased deaths in the first year of art because of opportunistic infections at enrolment, stopping art or persisting immunodeficiency.25,26,27,28 limitations of our study include not being able to link patients between facilities. patients may have been lost to follow-up in one facility but not necessarily in the district. without specific patient level data, we were unable to analyse contributing factors leading to attrition. conclusion patient retention in care improved in hiv care and treatment facilities with infrastructure improvements, whereas the overall number of patients newly enrolled and initiated on art declined and attrition increased, which we suspect is partially because of patients enrolling or transferring to other facilities now closer to their homes. conversely, health facility-specific case studies showed increases in patient enrolment in high hiv transmission areas and decreases in patient enrolment in facilities where additional hiv services were offered at nearby health facilities. infrastructure improvements that provided adequate physical space, enhanced privacy and confidentiality, and greater accessibility to a range of hiv services may have contributed to the improved retention in care of hiv patients on art. acknowledgements competing interests the authors declare no potential conflict of interest. authors’ contributions b.i., k.a. and n.g. lead the conception of the article, research protocol write up and research tools development, data collection, data analysis and article writing. k.s. participated in conception of the article, data analysis and article writing. i.m., p.b., h.k., f.c., g.m, s.k., b.d., k.a., s.k. and n.g. participated in data collection, data analysis and article writing. references buvé a, kalibala s, mcintyre j. stronger health systems for more effective hiv/aids prevention and care. int j health plann manage. 2003;18(s1):s41–s51. https://doi.org/10.1002/hpm.725 united republic of tanzania (urt). report of the 3 by 5 mission to tanzaniaon scaling up antiretroviral treatment as part of the global emergency response to hiv/ aids. 2003 dec 04–12. dar es salaam: ministry of health; 2003. yu d, souteyrand y, banda ma, kaufman j, perriëns jh. investment in hiv/aids programs: does it help strengthen health systems in developing countries? global health. 2008;4(1):8. https://doi.org/10.1186/1744-8603-4-8 kwesigabo g, mwangu ma, kakoko dc, et al. tanzania’s health system and workforce crisis. j public health policy. 2012;33:s35–s44. https://doi.org/10.1057/jphp.2012.55 tibandebage p, wangwe s, mujinja p, bail rn, shepard ds. expenditures on hiv/aids in tanzania. brussels, belgium: the european commission; washington, dc: world bank; 1998. united republic of tanzania. hiv/aids care and treatment plan 2003–2008. dar es salaam: tanzania national aids control program; 2003. hardon a, davey s, gerrits t, world health organization, universiteit van amsterdam, koninklijk instituut voor de tropen, eds. from access to adherence: the challenges of antiretroviral treatment: studies from botswana, tanzania and uganda 2006. geneva: world health organization; 2006. aids strategy & action plan. the hiv epidemic in tanzania mainland: where have we come from, where is it going, and how are we responding? dar es salaam: tanzania ministry of health; 2008. nemes mib, beaudoin j, conway s, kivumbi gw, skjelmerud a, vogel u. evaluation of who’s contribution to ‘3 by 5’. main report. geneva: world health organization (who); 2006. kim jy, gilks c. scaling up treatment – why we can’t wait. n engl j med. 2005;353(22):2392–2394. https://doi.org/10.1056/nejme058261 tanzania operational plan report the united states and tanzania working together to fight hiv and aids. dar es salaam: pepfar;2013. the office of the u.s. global aids coordinator. action today, a foundation for tomorrow: the president’s emergency plan for aids relief, second annual report to congress. pepfar 2006. world health organization (who). joint united nations programme on hiv/aids (unaids)). aids epidemic update. 2003. birungi h. injections and self-help: risk and trust in ugandan health care. soc sci med. 1998;47(10):1455–1462. https://doi.org/10.1016/s0277-9536(98)00194-4 geng eh, nash d, kambugu a, et al. retention in care among hiv-infected patients in resource-limited settings: emerging insights and new directions. curr hiv/aids rep. 2010;7(4):234–244. https://doi.org/10.1007/s11904-010-0061-5 chi bh, yiannoutsos ct, westfall ao, et al. universal definition of loss to follow-up in hiv treatment programs: a statistical analysis of 111 facilities in africa, asia, and latin america. plos med. 2011;8(10):e1001111. https://doi.org/10.1371/journal.pmed.1001111 national aids control program (nacp). national guidelines for the clinical management of hiv and aids. 2nd ed. dar es salaam: the united republic of tanzania ministry of health and social welfare; 2005. nuwagaba-biribonwoha h, kilama b, antelman g, et al. reviewing progress: 7 year trends in characteristics of adults and children enrolled at hiv care and treatment clinics in the united republic of tanzania. bmc public health. 2013;13(1):1016. https://doi.org/10.1186/1471-2458-13-1016 national aids control program (nacp). national guidelines for the clinical management for hiv and aids. 4th ed. dar es salaam: the united republic of tanznia ministry of health and social welfare; 2012. rosen s, fox mp. retention in hiv care between testing and treatment in sub-saharan africa: a systematic review. plos med. 2011;8(7):e1001056. https://doi.org/10.1371/journal.pmed.1001056 braitstein p, brinkhof mwg, dabis f, et al. mortality of hiv-1-infected patients in the first year of antiretroviral therapy: comparison between low-income and high-income countries. lancet. 2006;367(9513):817–824. https://doi.org/10.1016/s0140-6736(06)68337-2 rochat tj, bland r, coovadia h, stein a, newell m-l. towards a family-centered approach to hiv treatment and care for hiv-exposed children, their mothers and their families in poorly resourced settings. future virol. 2011;6(6):687–696. https://doi.org/10.2217/fvl.11.45 kids-art-linc collaboration. low risk of death, but substantial program attrition, in pediatric hiv treatment cohorts in sub-saharan africa. j acquir immune defic syndr. 2008;49(5):523–531. https://doi.org/10.1097/qai.0b013e31818aadce mcnairy ml, lamb mr, carter rj, et al. retention of hiv-infected children on antiretroviral treatment in hiv care and treatment programs in kenya, mozambique, rwanda, and tanzania. j acquir immune defic syndr. 2013;62(3):e70–e81. https://doi.org/10.1097/qai.0b013e318278bcb0 lawn sd, harries ad, anglaret x, myer l, wood r. early mortality among adults accessing antiretroviral treatment programmes in sub-saharan africa. aids. 2008;22(15):1897–1908. https://doi.org/10.1097/qad.0b013e32830007cd lawn sd, myer l, edwards d, bekker l-g, wood r. short-term and long-term risk of tuberculosis associated with cd4 cell recovery during antiretroviral therapy in south africa. aids. 2009;23(13):1717–1725. https://doi.org/10.1097/qad.0b013e32832d3b6d kabue mm, buck wc, wanless sr, et al. mortality and clinical outcomes in hiv-infected children on antiretroviral therapy in malawi, lesotho, and swaziland. pediatrics. 2012;130(3):e591–e599. https://doi.org/10.1542/peds.2011-1187 violari a, cotton mf, gibb dm, et al. early antiretroviral therapy and mortality among hiv-infected infants. n engl j med. 2008;359(21):2233–2244. https://doi.org/10.1056/nejmoa0800971 abstract introduction case description discussion acknowledgements references about the author(s) theresa m. rossouw department of immunology, university of pretoria, pretoria, south africa gisela van dyk department of immunology, university of pretoria, pretoria, south africa gert van zyl division of medical virology, stellenbosch university and national health laboratory service, bellville, south africa citation rossouw tm, van dyk g, van zyl g. rapid emergence of resistance to antiretroviral treatment after undisclosed prior exposure: a case report. s afr j hiv med. 2019;20(1), a965. https://doi.org/10.4102/sajhivmed.v20i1.965 case report rapid emergence of resistance to antiretroviral treatment after undisclosed prior exposure: a case report theresa m. rossouw, gisela van dyk, gert van zyl received: 08 mar. 2019; accepted: 28 mar. 2019; published: 30 july 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract introduction: patients who disengaged from care may present as therapy naïve for antiretroviral treatment (art) initiation at a different site, without being recognised as being at an increased risk of rapid treatment failure and hiv drug resistance. patient presentation: a 43-year-old woman, who gave no prior history of art, was initiated on a standard first-line regimen of tdf, ftc and efv. she had a poor response to treatment with evidence of treatment failure at 12 months. management and outcome: hiv-1 drug resistance tests showed no pre-treatment hivdr mutations, but revealed high-level drug resistance to all component drugs at 12 months. on investigation, viral load (vl) was recorded in 2012 and 2013, providing evidence of prior art use. conclusion: linkage of patient therapy and laboratory information to unique patient identifiers may allow health-care workers to identify patients who previously received art and disengaged from care. this will enable differentiated care when these patients reinitiate art, which should involve expedited vl testing and more rapid transition to definitive second-line art. keywords: hiv drug resistance; antiretroviral therapy; undisclosed prior treatment. introduction hiv drug resistance (hivdr) is a major public health concern, especially in the context of a large treatment programme. patients who disengage from care and then return to the health-care system without disclosing previous antiretroviral therapy (art) are at increased risk of having pre-existing drug resistance. unfortunately, patients rarely report prior art use, and health-care workers do not routinely ask and record this. all drugs in the current first-line regimen (tdf, ftc and efv) have low genetic barriers, and hence, one or two mutations lead to diminished activity, which can affect entire drug classes. hiv drug resistance testing is not currently available in the south african public sector for patients initiating or failing first-line art. here we describe a case of a patient with undisclosed prior exposure to art who had a complex hivdr pattern at treatment failure and highlight potential risk factors for rapid hivdr emergence. case description a 43-year-old woman presented to a clinic in tshwane, south africa, on 23 july 2014. she tested hiv-positive and had a cd4 count of 14 cells/µl and hiv-1 viral load (vl) of 560 000 copies/ml. she gave no prior history of art and was initiated on a first-line regimen of tdf, ftc and efv on 06 august 2014. she attended all her visits on time and reported good adherence, but had a poor response after 12 months of treatment: cd4 53 cells/µl and vl 186 000 copies/ml. the 6-month vl had not been performed. as part of a research project (ethics approval 469/2013), she had a drug resistance test (drt) with a validated in-house sanger-based sequencing method1 before the initiation of art, which showed no hivdr mutations, and again after 12 months, which revealed six nucleoside/nucleotide reverse transcriptase inhibitor (nrti) and three non-nucleoside reverse transcriptase inhibitor (nnrti) mutations (tables 1 and 2). a search of the nhls database for evidence of prior hiv-related testing revealed two vl results (2012 and 2013), which precede her art-initiation date (figure 1). figure 1: hiv viral load results over time. table 1: drug resistance report at 12 months. table 2: mutation-penalty score for the reverse transcriptase inhibitors. ethical consideration this study was part of a research project that had been approved by the research ethics committee of the faculty of health sciences of the university of pretoria (ethics approval number 469/2013). discussion this case study describes the rapid emergence of high-level, dual-class hivdr in a patient with undisclosed prior art use. having nine reverse transcriptase mutations within 12 months is much faster than the reported rate of emergence.4 this together with the unsuppressed vl during 2012 and 2013 suggests prior hivdr mutation selection, which waned to below the detection threshold of population sequencing (± 20%) when drt was performed in 2014. thereafter, it rapidly re-emerged upon reintroduction of art. prior undisclosed use of art is a common problem, requiring vigilance, especially in health sectors where patients are mobile and do not have unique identifiers, as is the case in south africa. recent data from botswana showed that 136/951 (14%) hiv-infected participants who reported no prior art use had a baseline vl of < 400 copies/ml, and of these, 39% had detectable art levels in plasma.5 a study from khayelitsha reported that 23% of patients disengaged from care for at least 6 months and that ~50% of these returned to care in the medium term.6 almost 1/3 of adults restarting first-line art with prior art exposure harbour resistant virus with women twice as likely as men to have resistance because of previous art exposure during pregnancy.7 patients with multiple treatment interruptions and/or pre-treatment drug resistance (pdr) are at an increased risk of virological failure.8,9,10,11 this patient had seven different laboratory numbers, making linking her previous results complicated. patients with prior art may benefit from differentiated care with specialised adherence support, an early vl12 (at 4 months), drt in case of a suboptimal vl response and rapid change to a second-line regimen. the absence of a 6-month vl in this patient made prompt action impossible. she had a number of risk factors for treatment failure, namely previous art, high vl and previous adherence issues, which could have alerted the astute clinician had this information been available. acknowledgements the authors would like to thank sr eileen thompson for assisting with patient recruitment. competing interests the authors declare that they have no financial or personal relationship(s) that may have inappropriately influenced them in writing this article. authors’ contributions g.v.d. performed the laboratory work, namely sanger sequencing, and interpretation of the results; t.m.r. accessed and interpreted the clinical information and prepared the first draft of the manuscript; g.v.z. assisted with the interpretation of the genotype. all authors contributed to and proofread the final manuscript. funding information this work was financially supported by the national research foundation (nrf) (grant number 87876) and the university of pretoria and national health laboratory service (nhls) research trust (grant number 94447). data availability statement the clinical and genotypic data will be made available on request. disclaimer the views expressed in the article are those of the authors and not an official position of the institution or funder. references manasa j, katzenstein d, cassol s, newell ml, de oliveira t, southern africa treatment and resistance network (saturn). primary drug resistance in south africa: data from 10 years of surveys. aids res hum retroviruses. 2012;28(6):558–565. https://doi.org/10.1089/aid.2011.0284 liu tf, shafer rw. web resources for hiv type 1 genotypic-resistance test interpretation. clin infect dis. 2006;42(11):1608–1618. https://doi.org/10.1086/503914 parikh um, barnas dc, faruki h, mellors jw. antagonism between the hiv-1 reverse-transcriptase mutation k65r and thymidine-analogue mutations at the genomic level. j infect dis. 2006;194(5):651–660. https://doi.org/10.1086/505711 rossouw tm, nieuwoudt m, manasa j, et al. hiv drug resistance levels in adults failing first line antiretroviral therapy in urban and rural settings in south africa. hiv med. 2017;18(2):104–114. https://doi.org/10.1111/hiv.12400 moyo s, gaseitsiwe s, powis km, et al. undisclosed antiretroviral drug use in botswana: implication for national estimates. aids 2018;32(11):1543–1546. https://doi.org/10.1097/qad.0000000000001862 kaplan sr, oosthuizen c, stinson k, et al. contemporary disengagement from antiretroviral therapy in khayelitsha, south africa: a cohort study. plos med. 2017;14(11):e1002407. https://doi.org/10.1371/journal.pmed.1002407 who, cdc, global fund. hiv drug resistance report 2017 [homepage on the internet]. geneva: world health organization; 2017 [cited 2019 feb 28]. licence: cc by-nc-sa 3.0 igo. available from: https://apps.who.int/iris/bitstream/handle/10665/255896/9789241512831-eng.pdf?sequence=1 kantor r, smeaton l, vardhanabhuti s, et al. pretreatment hiv drug resistance and hiv-1 subtype care independently associated with virologic failure: results from the multinational pearls (actg a5175) clinical trial. clin infect dis. 2015;60(10):1541–1549. https://doi.org/10.1093/cid/civ102 hamers rl, schuurman r, sigaloff kc, et al. effect of pretreatment hiv-1 drug resistance on immunological, virological, and drug-resistance outcomes of first-line antiretroviral treatment in sub-saharan africa: a multicentre cohort study. lancet infect dis. 2012;12(4):307–317. https://doi.org/10.1016/s1473-3099(11)70255-9 parienti j-j, massari v, descamps d, et al. predictors of virologic failure and resistance in hiv-infected patients treated with nevirapineor efavirenz-based antiretroviral therapy. clin infect dis [serial online]. 2004 [cited 2019 mar 01];38(9):1311–1316. available from: https://academic-oup-com.ez.sun.ac.za/cid/article/38/9/1311/317940 oyugi jh, byakika-tusiime j, ragland k, et al. treatment interruptions predict resistance in hiv-positive individuals purchasing fixed-dose combination antiretroviral therapy in kampala, uganda. aids. 2007;21(8):965–971. https://doi.org/10.1097/qad.0b013e32802e6bfa grimsrud a, barnabas rv, ehrenkranz p, ford n. evidence for scale up: the differentiated care research agenda. j int aids soc. 2017;20(suppl 4):22024. https://doi.org/10.7448/ias.20.5.22024 hiv 855 forum screening for hiv-associated neurocognitive disorders (hands) in south africa: a caution against uncritical use of comparative data from other developing countries c van wijk private practice, simon’s town, cape town c van wijk, ma (clinical psychology) corresponding author: c van wijk (chvanwijk@gmail.com) the prevalence of hiv-associated neurocognitive disorders necessitates community-based screening. in recent years, progress has been made in developing more localised comparative data for use in such screening on the african continent. these studies used measurements that are considered fair, easily accessible, and quick to administer. however, the variance in available international data limits their usefulness and poses a risk to the appropriate streaming of individuals. here, examples are presented of variance in both cross-national and local demographic screening and neuropsychological test scores, with the aim of cautioning practitioners against undue reliance on general african data for classification of individuals. recommendations are provided for the development of appropriate norms, specific to local communities. s afr j hiv med 2013;14(1):17-19. doi:10.7196/sajhivmed.855 south africa (sa) is home to the world’s largest population of people living with hiv and aids (plwha), with an estimated hiv prevalence of 16.9% among sa adults (aged 15 49 years) in 2008.1 recent figures suggest that 17 25% of hiv patients in sa display cognitive impairment,2 , 3 the diagnosis of which is largely dependent on the deviation of test scores from standardised norms. hiv-associated neurocognitive disorders (hands) are diagnosed using the frascati model,4 which requires neuropsychological scores to be compared with normative data using standard deviation (sd) as an indicator of impairment. the classification of neurocognitive impairment requires clinical attention as it influences decisions on treatment initiation, the management of daily living, and so forth. owing to the large number of people affected and the prevalence of impairment, large-scale screening is imperative and streams identified individuals towards further investigation. this process requires measurements that are fair, easily accessible and quick to administer. in this regard, the international hiv dementia scale (ihds) and grooved pegboard (gp) are arguably the most widely used instruments for hand screening in limited-resource communities,5 and these have been shown to differentiate between the hiv statuses of asymptomatic patients in sub-saharan africa.6 , 7 the problem of variance data from the ihds and gp tests, and from the rest of the world health organization (who) hiv battery, have been reported from various sites in sub-saharan africa. this is positive progress, as the developing world norms differ from those of industrialised countries,8 and practitioners may need to use comparative data from africa when no local data are available. however, despite these positive developments, the issue of data variability across countries has not been resolved.9 an example of the range of scores for hiv-negative respondents on the ihds and gp is provided in table 1. table 2 provides an example of the range of scores for hiv-negative respondents for some of the tests used across countries in eastern and southern africa. table 1. scores for ihds and gp-ndh tests conducted among hiv-negative respondents in east and southern africa country test n mean sd zambia10 ihds total 57 10.10   ihds memory recall 57 3.40   gp-ndh 57 97.50 uganda11 ihds 25 11.10 ±0.80 uganda7 ihds total 100 11.00 ±1.00 ihds memory recall 100 3.60 ±0.60 gp-ndh 100 102.70 ±25.20 south africa6 gp-ndh 24 80.83 ±9.20 south africa12 ihds memory recall (female; aged 18 29 years) 3.77 ±0.47 ihds memory recall (male; aged 18 29 years) 3.39 ±0.55 ihds memory recall (female; aged 30 50 years) 3.66 ±0.48 ihds memory recall (male; aged 30 50 years) 3.19 ±0.96 sd = standard deviation; ihds = international hiv dementia scale; gp-ndh = grooved pegboard-non-dominant hand test. table 2. scores for tgt, dsmt, tmt and ds conducted among hiv-negative respondents in east and southern africa country test n mean sd zambia10 tgt 57 12.3   uganda7 dsmt 100 31.10 ±11.30 tgt 100 6.95 ±0.82 dsf 100 5.30 ±0.90 dsb 100 3.50 ±0.90 south africa6 tmt-a 24 43.74 ±12.40 dsmt 24 50.54 ±11.10 south africa12 tmt-a (female; aged 18 29 years) 40.73 ±17.40 tmt-a (male; aged 18 29 years) 35.89 ±8.94 all aged 18 29 years (n=68) tmt-a (female; aged 30 50 years) 48.54 ±18.70 all aged 30 50 years (n=42) tmt-a (male; aged 30 50 years) 50.00 ±13.60 tmt-b (female; aged 18 29 years) 72.57 ±26.00 tmt-b (male; aged 18 29 years) 87.78 ±26.50 tmt-b (female; aged 30 50 years) 89.26 ±28.40 tmt-b (male; aged 30 50 years) 114.25 ±43.10 dsf (female; aged 18 29 years) 6.50 ±1.38 dsf (male; aged 18 29 years) 6.33 ±1.12 dsf (female; aged 30 50 years) 6.14 ±1.40 dsf (male; aged 30 50 years) 6.00 ±1.07 dsb (female; aged 18 29 years) 3.63 ±0.97 dsb (male; aged 18 29 years) 4.56 ±0.73 dsb (female; aged 30 50 years) 3.29 ±0.83 dsb (male; aged 30 50 years) 3.88 ±0.99 tgt = timed gait test; dsmt = digit symbol modalities test; tmt-a = trail making test a; tmt-b = trail making test b; ds = digit span; dsf = digit span forward; dsb = digit span backward. in terms of screening, there are some difficulties when comparing sa scores with other african data for local use. for example, the ihds total score range equals an sd of ±1 across some countries (table 1). given that the recommended cut-off for streaming towards further investigation for possible neurocognitive impairment is ≤10,7 this could have significant implications for individuals across different countries. additionally, the range of the ihds memory recall subtest differs noticeably between different demographic subgroups within one location.12 the gp-non-dominant hand test (gp-ndh) also differs significantly across countries. this is an important hand screening mechanism, and the variance in published data creates difficulties for interpretation and further streaming. similar problems are faced in terms of diagnosis. for example, the range of the trail making test (tmt) scores differs by more than ±1 sd between different demographic subgroups within one location.12 the digit symbol modalities test (dsmt) differs further by an sd of ±2 between countries. digit span (ds) forward and backward scores also display ranges equalling an sd of ±1 between some countries (most notably uganda and south africa) and even within countries, based on demographics. the timed gait test (tgt) score range equals an sd of ±6 between samples in zambia and uganda.7 , 10 this is despite indications in the reported studies suggesting that the samples had broadly similar socio-economic and educational backgrounds. while it is tempting to believe that the variance is simply due to inter-country differences, there may be a number of reasons why it may not reflect true cross-national or cross-cultural differences. firstly, it is not always clear whether psychologists, primary healthcare nursing personnel or highly qualified researchers performed the assessments. some tests (e.g. ihds) were developed to be administered by primary healthcare workers, while others were (at least historically) firmly placed in the neuropsychological domain (e.g. gp, tmt). secondly, there is a lack of demographic reporting. the effects of gender, age, education, and so forth, are well documented,5 , 12 but not equally well-reported across studies, consequently limiting comparison. thirdly, the samples are often small (n<50 in the case of the sa samples), which may not reflect the larger population.13 fourthly, viral subtypes may further limit comparison between hiv-1 clades.8 , 14 using general scores from african samples may, therefore, not be appropriate when placing people in categories of impairment using sd from normative scores. the intention of this article is to caution researchers and practitioners against an over-reliance on cross-national ‘african’ data to create ‘local’ norms, which may result in inappropriate diagnostic classification. looking forward given the incidence of hands in sa, there is a critical requirement for valid norms to guide screening and eventual diagnosis. the problematic nature of comparing across national (and presumably cultural) borders emphasises the need for assessment that is fair to patients. this includes: firstly, the development of localised norms – in terms of specific communities – that, at the very least, are reported in terms of age, gender and education (socio-economic status, ethnicity and testing language may also be valuable); and secondly, the use of larger samples that have reasonable validity.13 there are further concerns about the responsibility of test administration, in light of the possible effects of the tester on outcome variance.15 here, a balance must be struck between making assessment accessible to the community and maintaining the integrity of the neuropsychological nature of the tests. a tiered approach – i.e. screening with the ihds by primary healthcare workers, referral to community-based psychologists for an expanded battery (e.g. who hiv battery), and further referral to specialist clinics for extended neuropsychological assessment – is recommended. references 1. unaids. aids epidemic update: november 2009. geneva, switzerland: world health organization, 2009. 1. unaids. aids epidemic update: november 2009. geneva, switzerland: world health organization, 2009. 2. ganasen ka, fincham d, smit j, seedat s, stein d. utility of the hiv dementia scale (hds) in identifying hiv dementia in a south african sample. j neurol sci 2008;269:62-64. [http://dx.doi.org/10.1016/j.jns.2007.12.027] 2. ganasen ka, fincham d, smit j, seedat s, stein d. utility of the hiv dementia scale (hds) in identifying hiv dementia in a south african sample. j neurol sci 2008;269:62-64. [http://dx.doi.org/10.1016/j.jns.2007.12.027] 3. joska ja, westgarth-taylor j, myer l, et al. characterization of hiv-associated neurocognitive disorders among individuals starting antiretroviral therapy in south africa. aids beh 2011;15(6):1197-1203. [http://dx.doi.org/10.1007/s10461-010-9744-6] 3. joska ja, westgarth-taylor j, myer l, et al. characterization of hiv-associated neurocognitive disorders among individuals starting antiretroviral therapy in south africa. aids beh 2011;15(6):1197-1203. 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[http://dx.doi.org/10.1080/09540260701877894] 6. moshani ml. the exploration of neuropsychological disorders in haartnaïve young adults in south africa. honour’s thesis. cape town: university of cape town, 2009. http://web.uct.ac.za/depts/psychology/postgraduate/hons2009projects/nomakhawuta.moshani.pdf (accessed 28 june 2011). 6. moshani ml. the exploration of neuropsychological disorders in haartnaïve young adults in south africa. honour’s thesis. cape town: university of cape town, 2009. http://web.uct.ac.za/depts/psychology/postgraduate/hons2009projects/nomakhawuta.moshani.pdf (accessed 28 june 2011). 7. sacktor nc, wong m, nakasujja n, et al. the international hiv dementia scale: a new rapid screening test for hiv dementia. aids 2005;19:1367-1374. 7. sacktor nc, wong m, nakasujja n, et al. the international hiv dementia scale: a new rapid screening test for hiv dementia. aids 2005;19:1367-1374. 8. robertson k, liner j, heaton r. neuropsychological assessment of hiv infected populations in international settings. neuropsychol rev 2009;19(2):232-249. [http://dx.doi.org/10.1007/s11065-009-9096-z] 8. robertson k, liner j, heaton r. neuropsychological assessment of hiv infected populations in international settings. neuropsychol rev 2009;19(2):232-249. [http://dx.doi.org/10.1007/s11065-009-9096-z] 9. robertson k, kumwenda j, supparatpinyo k, et al. baseline data from actg 5199: the international neurological study. 15th conference on retroviruses and opportunistic infections, boston, 2008. 9. robertson k, kumwenda j, supparatpinyo k, et al. baseline data from actg 5199: the international neurological study. 15th conference on retroviruses and opportunistic infections, boston, 2008. 10. holguin a, banda m, willen ej, et al. hiv-1 effects on neuropsychological performance in a resource-limited country, zambia. aids beh 2011;15(8):1895-1901. 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[http://dx.doi.org/10.1007/s10461-011-9988-9] 11. nakasujja n, skolasky rl, musisi s, et al. depression symptoms and cognitive function among individuals with advanced hiv infection initiating haart in uganda. bmc psychiatry 2010;10:44. 11. nakasujja n, skolasky rl, musisi s, et al. depression symptoms and cognitive function among individuals with advanced hiv infection initiating haart in uganda. bmc psychiatry 2010;10:44. 12. singh d, joska ja, goodkin k. normative scores for a brief neuropsychological battery for the detection of hiv-associated neurocognitive disorder (hand) among south africans. bmc research notes 2010;3:28. 12. singh d, joska ja, goodkin k. normative scores for a brief neuropsychological battery for the detection of hiv-associated neurocognitive disorder (hand) among south africans. bmc research notes 2010;3:28. 13. mitrushina mn, boone kb, razan j, d’elia lf. handbook of normative data for neuropsychological assessment, 2nd ed. new york: oxford university press, 2005. 13. mitrushina mn, boone kb, razan j, d’elia lf. handbook of normative data for neuropsychological assessment, 2nd ed. new york: oxford university press, 2005. 14. sacktor n, nakasujja n, roberson k, clifford db. hiv-associated cognitive impairment in sub-saharan africa – the potential effect of clade diversity. nat clin pract neurol 2007;3(8):436-443. 14. sacktor n, nakasujja n, roberson k, clifford db. hiv-associated cognitive impairment in sub-saharan africa – the potential effect of clade diversity. nat clin pract neurol 2007;3(8):436-443. 15. breuer e, stoloff k, myer l, seedat s, stein dj, joska j. reliability of the lay adherence counsellor administered substance abuse and mental illness symptoms screener (samiss) and the international hiv dementia scale (ihds) in a primary care hiv clinic in cape town, south africa. aids behav 2012;16(6):1464-1471. 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[http://dx.doi.org/10.1007/s10461-011-0067-z] abstract introduction method ethical consideration results discussion acknowledgements references about the author(s) cait-lynn d. wells department of neurology, greys hospital, university of kwazulu-natal, pietermaritzburg, south africa anand a. moodley department of neurology, universitas hospital, university of the free state, bloemfontein, south africa citation wells cd, moodley aa. hiv-associated cavernous sinus disease. s afr j hiv med. 2019;20(1), a862. https://doi.org/10.4102/sajhivmed.v20i1.862 original research hiv-associated cavernous sinus disease cait-lynn d. wells, anand a. moodley received: 25 apr. 2018; accepted: 05 feb. 2019; published: 20 mar. 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract introduction: the underlying diagnosis of cavernous sinus disease is difficult to confirm in hiv-coinfected patients owing to the lack of histological confirmation. in this retrospective case series, we highlight the challenges in confirming the diagnosis and managing these patients. results: the clinical, laboratory and radiological data of 23 hiv-infected patients with cavernous sinus disease were analysed. the mean age of patients was 38 years. the mean cd4+ count was 390 cells/μl. clinically, patients presented with unilateral disease (65%), headache (48%), diplopia (30%) and blurred vision (30%). third (65%) and sixth (57%) nerve palsies in isolation and combination (39%) were most common. isolated fourth nerve palsy did not occur. tuberculosis (17%) was the most commonly identified disorder followed by high-grade b-cell lymphoma (13%), meningioma (13%), metastatic carcinoma (13%) and neurosyphilis (7%). in 22% of the patients, there was no confirmatory evidence for a diagnosis. the patients were either treated empirically for tuberculosis or improved spontaneously when antiretroviral therapy was started. cerebrospinal fluid was helpful in 4/13 (31%) of patients where it was not contraindicated. only 3/23 (13%) of the patients had a biopsy of the cavernous sinus mass. the outcomes varied, and follow-up was lacking in the majority of patients. conclusion: in hiv-infected patients, histological confirmation of cavernous sinus pathology is not readily available for various reasons. in resource-limited settings, one should first actively search for extracranial evidence of tuberculosis, lymphoma, syphilis and primary malignancy and manage appropriately. only if such evidence is lacking should a referral for biopsy be considered. introduction the cavernous sinus, a venous structure at the base of the skull, contains important neurological and vascular components that are susceptible to opportunistic infections, para-infectious disorders and neoplastic disorders in hiv-infected patients. the cavernous sinuses are two dura-enclosed venous chambers connected by the circular sinus.1 the crossover of pathology between the two sides is therefore not uncommon. each cavernous sinus receives venous blood from the superior and inferior ophthalmic veins and drains via the superior and inferior petrosal sinuses into sigmoid sinuses bilaterally. the involvement of vital structures within the cavernous sinus presents as a double-edged sword. they allow for early detection of cavernous sinus disease, but their presence also heralds the presence of grave pathology. each cavernous sinus contains the carotid artery and the sixth cranial nerve lying within the sinus (figure 1). sympathetic nerves that emerge from the carotid artery wall run along the sixth nerve for a short distance and are then destined for the eye along the nasociliary branch of the fifth cranial nerve. from rostral to caudal, the third, fourth and ophthalmic divisions of the fifth cranial nerve lie within the lateral wall of the sinus and further back is a short encounter with the maxillary division of the fifth nerve, which enters via the foramen rotundum en route to the gasserian ganglion. the cavernous sinus syndrome is defined as involvement of two or more of the third, fourth, fifth and sixth cranial nerves or involvement of any amount of cranial nerves with neuro-imaging confirming the presence of a cavernous sinus lesion. clinically, various combinations of third nerve, fourth nerve, sixth nerve, horner syndrome, ophthalmic and maxillary division sensory loss are localised to the cavernous sinus. the cavernous sinus is also secondarily affected by pathology in surrounding structures, namely, the pituitary gland, the surrounding dura, the optic chiasm, the sphenoid sinus and structures of the floor of the third ventricle. lesions of the cavernous sinus that spread anteriorly to the orbital apex affect the optic nerve.2 figure 1: the cavernous sinus showing cranial nerves iii, iv, ophthalmic division of v (v1) and maxillary division of v (v2) along the lateral wall of the sinus. the vi cranial nerve lies free within the sinus. the sympathetic fibres, which enter the cavernous sinus along the carotid artery, are not shown. causes of cavernous sinus pathology are protean. in a series of 151 patients, keane et al. described the common causes for cavernous sinus lesions to be tumours (30%), trauma (24%) and self-limiting inflammation (23%), while carotid aneurysms, carotico-cavernous fistulae, infection and other causes constituted the remaining 12%. the most common tumour in this series was nasopharyngeal carcinoma (22%), followed by metastases (18%) and lymphoma (18%). the infectious aetiologies comprised one case of bacterial sphenoid sinusitis and three cases of mucormycosis. in this series, there were three patients who were hiv-infected, and all three were diagnosed with lymphoma.3 fernandez et al. in their series of 126 patients found the most common cause for cavernous sinus disease to be tumours (63%), vascular lesions (20%), inflammatory conditions such as tolosa-hunt syndrome (13%) and miscellaneous causes (4%). of the miscellaneous causes, only two were because of infectious aetiologies, namely, aspergillosis and thrombophlebitis from haemophilus influenzae infection. pituitary adenoma and meningioma were the most frequent of the tumours at 36.25% and 31.25%, respectively. in this series, two hiv-infected patients formed part of the cohort – both patients were diagnosed with lymphoma.4 in the hiv population, one would predict that the disease spectrum would coincide with the immunocompromised state of the patient, and opportunistic infections and hiv-associated neoplastic disorders would be commonly encountered. however, epidemiological data regarding cavernous sinus pathology in hiv-infected patients are lacking. the deep skull base location of the cavernous sinus and the fact that most patients are severely immunosuppressed discourage invasive diagnostic procedures unless lesions are easily accessible via the paranasal sinuses. histological confirmation is therefore scant. often, the diagnosis is based on the presence of a systemic disease, or patients are treated empirically for the commonly occurring diseases. the outcome therefore can be unpredictable and catastrophic at times. there is no study that has specifically addressed cavernous sinus pathology in patients coinfected with hiv. the literature in this population consists of mainly case reports (table 1). surprisingly, tuberculosis (tb) of the cavernous sinus has not been described in hiv-infected patients previously. in fact, tb of the cavernous sinus is an uncommon disorder even in an immunocompetent patient.5 the only infection reported is aspergillosis. infection as an infrequent cause of cavernous sinus disease in hiv-infected patients is likely because of poor reporting or lack of confirmatory evidence. table 1: case reports of patients infected with hiv and presenting with cavernous sinus disease. we undertook a retrospective analysis to highlight the pathology and challenges encountered in the diagnosis and management of hiv-infected patients with cavernous sinus disease. non-hiv-infected patients have similar challenges, but despite equity in the management of hiv-infected patients, personal experience shows us that surgeons are more likely to offer biopsies to non-hiv-infected patients for the fear of negative outcomes post-surgery in hiv-infected patients. twenty-three hiv-infected patients with cavernous sinus lesions as their main reason for referral were recruited. their clinical, radiological and biochemical data were analysed. problems encountered in their diagnosis and management will be highlighted. method all hiv-infected patients, from 2010 to 2016, referred to the neurology department of grey’s hospital, pietermaritzburg, with non-traumatic cavernous sinus lesions as their main presenting problem were included for analysis. the data search was done by selecting the keywords of cavernous sinus and hiv in hospital records and patient summaries. clinical, biochemical and radiological data were obtained from hospital records. all data were captured on a spreadsheet for descriptive statistics. averages and standard deviations were obtained for continuous quantitative data and qualitative data were represented in tables and graphs. ethical consideration ethical approval (be370/15) for a retrospective analysis was obtained from the university of kwazulu-natal biomedical research ethics committee. results a total of 23 hiv-infected patients with cavernous sinus disease were recruited for analysis. the mean age of the patients was 38 years (range 22–62 years), and 52% (12/23) were female. eight patients were newly diagnosed with hiv infection. the remainder of the patients were aware of their hiv infection for 1–6 years. the mean cd4+ count was 390 cells/μl ± 227 (s.d.), implying mild-to-moderate immunosuppression. however, two patients had severe immunosuppression with cd4+ counts of 24 cells/μl and 70 cells/μl, respectively. the viral load was not readily obtained owing to inadequate records. four patients had undetectable viral loads. in three patients, viral loads of 54900 copies/ml, 850 copies/ml and 4992 copies/ml were obtained. viral loads for the remaining patients were unknown. acute onset of headache was common, but visual symptoms of diplopia and blurred vision occurred in only 30% of the patients (table 2). proptosis was an uncommon finding, and unilateral disease was present in 65% (15/23) of patients. isolated third nerve and sixth nerve palsies were common (65% and 57%, respectively; figure 2). fifty-two percent (12/23) of the patients had a combination of third, sixth and fourth palsies or third and sixth nerve palsies. isolated fourth nerve palsy did not occur and when present only occurred with combined third and sixth nerve palsy. the involvement of the fifth cranial nerve was found only in 22% (5/23) of the patients. systemic clinical findings occurred in 57% (13/23) of the patients but only contributed to the diagnosis in 35% (8/23) of the patients. figure 2: number of patients presenting with various combinations of third, fourth and sixth cranial nerve palsies. table 2: symptoms, signs and associated findings. figure 3 depicts various diagnoses made, and table 3 shows the radiological features of the 18 patients. in five cases, the diagnosis was unknown owing to the absence of clinical, biochemical or radiological evidence for the underlying pathology. the most commonly identified diagnosis was tb. tuberculosis was confirmed on cerebrospinal fluid (csf) in one patient. the other three patients had positive sputum culture for tb or suggestive chest x-ray and responded neurologically to anti-tb treatment alone making tb of the cavernous sinus highly probable. high-grade b-cell lymphoma, metastatic carcinoma and meningioma were the next most common. figure 3: pie chart showing the number of patients and the spectrum of cavernous sinus disease in hiv-infected patients. table 3: radiological features of 18 patients with confirmed diagnosis (the diagnosis was unknown in five patients). table 3 shows 18 patients (78%) with confirmed diagnosis. representative images of the common groups are shown. in five patients (22%) where no diagnosis was confidently made, two patients were treated empirically for tb and were lost to follow-up after discharge; one patient was treated for pyogenic sinusitis and the patient’s condition subsequently improved; one patient who had acute inflammatory demyelinating polyneuropathy (aidp) and was treated with intravenous immunoglobulin, recovered and was discharged. he had abnormal cavernous sinus enhancement; so, his eye signs were not attributed to an aidp variant such as miller fisher syndrome. the fifth patient had a cavernous sinus syndrome that cleared after the commencement of antiretroviral therapy. we presume the latter two to have been para-infectious in nature. csf was obtained in 13 patients. it was contraindicated or not required in the others. in 31% (4/13) of the cases, the csf was abnormal and pointed to the diagnosis. in only 25% (1/4) of the cases, tb was confirmed on csf findings. abnormal csf findings confirmed the diagnosis of cryptococcal meningitis in one patient and neurosyphilis in two patients. all three patients were treated appropriately but none returned for follow-up csf examination. neurosyphilis was confirmed in two patients by serum rapid plasma regain titres of > 1:32. csf pleocytosis and the positive venereal disease research laboratory tests were confirmatory in both cases. the case of cryptococcal meningitis with pachymeningitis and unilateral cavernous sinus syndrome occurred in a patient with cd4+ count of 338 cells/μl. the csf was mildly pleocytotic (polymorphs = 3 cells/μl and lymphocytes = 113 cells/ μl), protein was 0.81 g/l and glucose was 3.1 mmol/l. diagnosis was made on a positive cryptococcal antigen test. response to amphotericin b and fluconazole was initially promising, but follow-up was absent. the outcomes varied, and the follow-up of patients was lacking. two patients with confirmed tb returned for follow-up and were recovering on treatment. the three patients with high-grade b-cell lymphoma were referred to oncology and lost to follow-up. the three patients with meningioma were referred to neurosurgery for further follow-up. two patients have since received radiotherapy but remain clinically unchanged. the patient with breast carcinoma demised from pulmonary embolism. the patients with nasopharyngeal carcinoma and corneal carcinoma were receiving chemotherapy from oncology, but follow-up showed no change to the cavernous sinus syndrome. the patient with the pituitary macroadenoma had debulking surgery and was commenced on replacement therapy by endocrinology. her visual acuity loss and left-sided ophthalmoplegia have not improved; she is awaiting radiotherapy. the patient with the cavernous sinus aneurysm was still awaiting neurosurgical intervention three months after diagnosis. discussion according to 2016 statistics, south africa has the most high-profile hiv epidemic in the world, having 7.1 million people living with the infection.6 despite having the largest antiretroviral treatment programme globally, the complications from hiv infection continue to burden the limited health resources in south africa. determining the actual duration of hiv infection is difficult for various reasons, which include late presentation and reluctance to know one’s hiv status for the fear of stigmatisation and apathy. despite regular and widely published educational, screening and treatment programmes for hiv infection in south africa, stigmatisation of the illness is still prevalent.7 neurological sequelae of hiv infection are common, and cavernous sinus disease in the setting of hiv infection poses huge challenges both for diagnosis and management. cavernous sinus disease biopsies by neurosurgery even in a tertiary facility are at most times unobtainable. trauma consumes most of their time leaving little to disorders where empirical treatment is the fall-back option. histological diagnosis while indicated becomes unobtainable and if systemic evidence is unavailable then confirmation of the diagnosis is extremely difficult to obtain. in the setting of cavernous sinus disease, even empirical treatment is unsupported as epidemiological data regarding cavernous sinus disease are unavailable in south africa. the different spectrum of disease in developed countries cannot be extrapolated to developing countries. so, management strategies usually fall back on expert opinion. furthermore, despite the excellent hiv education and antiretroviral treatment programme in south africa, non-adherence to treatment by patients is common.8 the follow-up of patients is inconsistent despite the high cost of investigations and treatment initially given to patients at the tertiary facilities. in this study, we have attempted to obtain reliable and perhaps reproducible epidemiological data on cavernous sinus disease in hiv-infected patients but, as expected, were faced with many challenges. of the 23 patients with cavernous sinus disease, the diagnosis was confidently made in 18 patients (78%). the majority had mild-to-moderate immunosuppression. only two patients had severe immunosuppression of cd4+ < 100 cells/μl. histological diagnoses from the biopsy of the cavernous sinus disease was obtained in 13% (3/23) of the patients. systemic evidence and/or expert opinion on radiological findings were used for the other cases. in five patients, the cause was unknown. fortunately, two patients recovered without specific intervention, and one responded to intravenous antibiotics. two patients were treated empirically for tb based solely on radiological findings as their csf findings were unhelpful. both patients did not return for follow-up, and the outcome of their treatment remains unknown. the most commonly identified diagnosis was tb with evidence available from pulmonary tb in all four patients. csf results were only contributory in one patient. high-grade b-cell lymphoma, metastatic carcinoma and meningioma were the next most common. with immunosuppression, the presence of high-grade b-cell lymphoma was plausible, but non-hiv-related metastatic disease and meningioma were probably incidental. two cases of neurosyphilis were identified in this series, which is high as there are only two other cases in the literature of neurosyphilis affecting the cavernous sinus where hiv was negative or the hiv status was unknown.9,10 neurosyphilis is more common in hiv-infected patients, which could account for the higher number found in this series affecting an atypical site. response to treatment was much too early to assess during admission and unfortunately both patients failed to return for follow-up. there were isolated cases of a saccular internal carotid artery aneurysm and a pituitary macroadenoma, which were also probably incidental. the increased incidence of intracranial saccular aneurysms in hiv infection is unsubstantiated; however, dolichoectatic vessels from immune-mediated vessel damage are more plausible.11 in this first case series of cavernous sinus disease in hiv-coinfected patients, we describe hivand non-hiv-related pathology. the third cranial nerve was the commonest cranial nerve affected in this group followed by involvement of the sixth cranial nerve, the ophthalmic division of the fifth cranial nerve and then the fourth cranial nerve. unlike the third and sixth cranial nerve palsies, the fourth nerve palsy did not occur in isolation. the horner syndrome was present in one patient only. this could imply a rare occurrence or difficulty in detection in the presence of other cranial nerve palsies. unilateral disease was present in 65% of the patients despite the connection of the two cavernous sinuses by the circular sinus. proptosis and visual impairment were uncommon implying minimal extension of pathology from the cavernous sinus to the orbital apex. the magnetic resonance imaging and computed tomography findings of cavernous sinus disease were helpful in localising the disorder but not in elucidating the pathology in the majority of cases. the presence of unilateral or bilateral enhancing masses did not provide any clues to the underlying pathology. however, mri was diagnostic in the case of the pituitary adenoma and saccular internal carotid artery disease, which, in all probability, were incidental disorders. csf findings were positive in confirming the diagnosis in 31% (4/13) of the patients, which included one patient with tb, one patient with cryptococcal meningitis and two patients with neurosyphilis. while treatment at the tertiary centre was appropriately initiated, continuation and follow-up care was poor. it is not unusual for patients to ‘disappear’ into a void or be lost in the system after discharge from the tertiary centre. in most instances, the fault lies with the highly prohibitive referral system to tertiary and academic centres in south africa. the apathy and lack of social support are other contributing factors. this study was a retrospective chart review and hence fraught with many limitations as evidenced by a deficiency of appropriate and detailed record-keeping. furthermore, the follow-up of patients was poor, especially when referred to other departments for co-management. in resource-limited developing countries, access to tertiary care is a challenge. neurosurgical services are usually inaccessible, but a rational approach to diagnosis and treatment is achievable. we suggest a management strategy for hiv-infected patients presenting with cavernous sinus disease that can address the common causes at regional level before referral to a tertiary centre (figure 4). figure 4: suggested management algorithm of cavernous sinus disease in an hiv-infected patient. there is a growing need for comprehensive databanks in south africa for epidemiological research and the benefits thereof. in addition, hiv infection as a serious but manageable disorder needs to be revisited and a re-emergence of a rigorous hiv education programme is essential for both the general public and health care workers alike. cavernous sinus disorders, as with many other neurological complications, are preventable. negligence in the preservation of a patient’s immunity can be catastrophic, especially in a disorder that is not easy to diagnose or manage. acknowledgements competing interests the authors declare that they have no financial or personal relationship(s) which may have inappropriately influenced them in writing this article. authors’ contributions c.d.w. and a.a.m. were responsible for conception and design. data collection was done by c.d.w. data analysis and interpretation, drafting of the article and final approval of the version to be published were done by both authors. references standring s. gray’s anatomy: the anatomical basis of clinical practice. 41st ed. book. 2015;1562. lee jh, lee hk, park jk, choi cg, suh dc. cavernous sinus syndrome: clinical features and differential diagnosis with mr imaging. am j roentgenol. 2003;181(2):583–590. https://doi.org/10.2214/ajr.181.2.1810583 keane jr. cavernous sinus syndrome. analysis of 151 cases. arch neurol. 1996;53(10):967–971. https://doi.org/10.1001/archneur.1996.00550100033012 fernández s, godino o, martínez-yélamos s, et al. cavernous sinus syndrome: a series of 126 patients. medicine (baltimore). 2007;86(5):278–281. https://doi.org/10.1097/md.0b013e318156c67f kapadia s pa. extrapulmonary tuberculosis presenting as cavernous sinus syndrome: case report with review of existing literature. id cases. 2014;2014(1):97–100. 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tertiary syphilis: case report and review of the literature. clin neurol neurosurg. 2011;113:65–67 nadgir db, ramdas r, kulkarni rv, oak pj, shah ab. cavernous sinus syndrome due to syphilitic pachymeningitis. neurol india. 2003;51:289–290. blignaut g, loggenberg e, de vries c. the radiological appearance of intracranial aneurysms in adults infected with the human immunodeficiency virus (hiv). south african j radiol [28 january 2018]. 2014;18(1):4. available from: http://www.sajr.org.za/index.php/sajr/article/view/586/724 gross fj, waxman js, rosenblatt ma, tabibzadeh ss, solodnik p. eosinophilic granuloma of the cavernous sinus and orbital apex in an hiv-positive patient. ophthalmology. 1989;96(4):462–467. https://doi.org/10.1016/s0161-6420(89)32855-7 kleinschmidt-demasters bk, mierau gw, sze ci, breeze re, greffe b, lillehei ko, et al. unusual dural and skull-based mesenchymal neoplasms: a report of four cases. hum pathol. 1998;29(3):240–245. https://doi.org/10.1016/s0046-8177(98)90042-9 blumenthal dt, raizer jj, rosenblum mk, bilsky mh, hariharan s a le. primary intracranial neoplasms in patients with hiv. neurology. 1999;52:1648–1651. https://doi.org/10.1212/wnl.52.8.1648 dhillon. ws st. diplopia in a patient with hiv infection. n engl j med. 2010;362(15):362. https://doi.org/10.1056/nejmicm0905333 junior akb, moura fc mm. bilateral cavernous sinus non-hodgkin’s lymphoma as the presenting sign of acquired immunodeficiency syndrome: case report. arq bras oftalmol. 2011;74(2):130–131. meltzer de, gollapelle e, chrysofakis g, modica i, chung m gm. nasopharyngeal carcinoma in an hiv-positive patient with cranial nerve defects. hem onc today. [cited 2012 nov 25]. available from: https://www.healio.com/hematology-oncology/head-neck-cancer/news/print/hemonc-today/%7b771c16c2-52b6-455b-98de-d81bc340414a%7d/nasopharyngeal-carcinoma-in-an-hiv-positive-patient-with-cranial-nerve-defects humphrey jm, walsh tj gr. invasive aspergillus sinusitis in human immunodeficiency virus infection: case report and review of the literature. open forum infect dis. 2016;3(3):1–12. https://doi.org/10.1093/ofid/ofw135 abstract introduction the training intervention methods findings discussion limitations recommendations conclusion acknowledgements references footnotes about the author(s) zoe duby division of social and behavioural sciences, school of public health and family medicine, university of cape town, cape town, south africa desmond tutu hiv centre, department of medicine, university of cape town, cape town, south africa francisco fong-jaen school of public health and family medicine, university of cape town, cape town, south africa busisiwe nkosi desmond tutu hiv centre, department of medicine, university of cape town, cape town, south africa benjamin brown desmond tutu hiv centre, department of medicine, university of cape town, cape town, south africa andrew scheibe desmond tutu hiv centre, department of medicine, university of cape town, cape town, south africa citation duby z, fong-jaen f, nkosi b, brown b, scheibe a. ‘we must treat them like all the other people’: evaluating the integrated key populations sensitivity training programme for healthcare workers in south africa. s afr j hiv med. 2019;20(1), a909. https://doi.org/10.4102/sajhivmed.v20i1.909 original research ‘we must treat them like all the other people’: evaluating the integrated key populations sensitivity training programme for healthcare workers in south africa zoe duby, francisco fong-jaen, busisiwe nkosi, benjamin brown, andrew scheibe received: 07 sept. 2018; accepted: 20 mar. 2019; published: 30 apr. 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: sensitisation training can reduce judgemental and discriminatory attitudes amongst healthcare workers. the ‘integrated key populations sensitivity training programme for healthcare workers in south africa’ aimed to improve access to appropriate and non-judgemental health services for ‘key populations’, specifically men who have sex with men, sex workers and people who use drugs, through the sensitisation of healthcare workers. objectives: the aim of this study was to evaluate the effects of the integrated key population sensitisation training intervention for healthcare workers, conducted between 2013 and 2014 in south africa. methods: this study used a combination of qualitative and quantitative methods. qualitative methods compared attitudes between healthcare workers who received the training intervention and those who did not. quantitative methods were used to compare similar changes in awareness amongst healthcare workers before and after receiving the training. we explored shifts in attitudes towards key populations, changes in awareness of health issues related to stigma, discrimination, and changes in capacity to manage sexual health and hiv risk behaviours, including substance use and anal sex. results: the findings indicate that the training intervention resulted in a shift in attitudes, increased empathy for key populations, a reduction in negative and discriminatory moral-based judgements towards key populations and their behaviours, and increased self-perceived capacity to provide appropriate health services to key populations. over 70% of healthcare workers trained in this programme strongly agreed that this intervention helped to increase awareness of psychosocial vulnerabilities of key populations, and address stigmatising attitudes. conclusion: the findings suggest that sensitisation training increases healthcare workers’ knowledge and awareness about specific hiv-related health needs and psychosocial vulnerabilities of key populations, reduces moralising and judgemental attitudes, and results in healthcare workers feeling more skilled to provide appropriate and sensitive services. keywords: men who have sex with men; sex workers; people who use drugs; sensitisation training; healthcare workers; south africa. introduction globally, ‘key population’ groups such as sex workers, men who have sex with men (msm) and people who use drugs (pwud) are at increased risk of hiv infection compared with the general population.1,2 each year, a significant number of new infections occur amongst these groups, influenced, in part, by the stigmatisation and discrimination experienced in healthcare settings, including refusal of care, patient neglect, provision of differential treatment based on hiv status, breaches of confidentiality, isolation and verbal abuse by staff.2,3,4,5,6 such experiences negatively affect the ability of key populations to engage with both prevention and treatment services, and can lead to delayed treatment, negative effects on retention in care and, ultimately, to poor health outcomes or death.4,6,7,8 in addition to experiences of discrimination, few facilities provide the full range of services (e.g. evidence-based substance use disorder services) and equipment (e.g. clean injecting equipment, condoms and compatible lubricants) that might be required by key populations.9,10,11,12 in the south african context, msm, sex workers and pwud report frequent exclusion from society and high levels of stigma and discrimination in the healthcare setting.6,8,9,13,14 judgemental and moralising views towards sex work, sex between people of the same sex, homosexuality and drug use are frequently expressed within south african communities, and more specifically by individuals working in the healthcare setting, warranting specific attention and address.6,8,15,16 public sector healthcare providers receive scant professional training to support key populations, as highlighted by a review of undergraduate training at one of south africa’s medical schools.17 as such, healthcare workers lack the appropriate skills or knowledge necessary to be adequately equipped to provide these much needed services.5,6,18 in response, south african advocates, service providers and researchers have identified the need for increased healthcare worker awareness of the issues affecting key populations, particularly in the context of hiv, and the need to build capacity to provide evidence-based, competent and appropriate health services.6,17,19,20 in the light of discrimination by service providers being identified as a major barrier to accessing health services, sensitisation training for healthcare workers about key populations has been recommended to reduce stigmatising attitudes and behaviours towards clients, and thus reduce hiv transmission and incidence rates in south africa.21 the south african national strategic plan for hiv, tb and stis (2017–2022) states the objective to: [i]nvest in expanding training and sensitisation programmes to reduce stigma: programmes [to] … protect those affected by hiv against discrimination and violence and to support access to hiv prevention, treatment, care and support. in addition, human rights and ethics training will be provided for healthcare providers … [and] will strengthen the batho pele principles.22 for the purposes of this article, we use the word ‘sensitisation’ to refer to the process of increasing knowledge of an issue to instil empathy, nurture a ‘sensitive’ disposition shaped by increased awareness, and modify negative attitudes and behaviour, with the intention of reducing discrimination and inequality.23,24 sensitisation training can challenge negative beliefs and shift attitudes through providing factual information, enable individuals to engage emotionally and reflect upon and examine their personal attitudes and beliefs, and encourage positive behavioural intentions through role plays and practical exercises.25,26 evidence from a european context indicates that reductions in structural discrimination and homo-negativity require a multilevel intervention approach, one component of which is enabling changes in attitudes and practices amongst individuals, groups and institutions.27 sensitisation-type training have been shown to have the potential for effecting change at each of these levels, shifting attitudes of individual participants directly and positively, and changing normative professional practice amongst health workers.27 sensitisation training for healthcare workers has been shown to be effective in reducing judgemental and discriminatory attitudes towards marginalised groups.28 a mixed-method quantitative and qualitative assessment conducted over a two-year period in kenya found an overall positive effect of sensitisation training for healthcare workers on attitudes and competencies towards serving msm patients.29,30 evaluations of stigma reduction or sensitisation training programmes for healthcare workers addressing msm, transgender or hijra and sex worker populations in india and bangladesh found substantial positive effects of such training; trained healthcare workers were more likely to exhibit positive, kind, respectful and non-judgemental attitudes towards key populations.28,31 local and regional qualitative research evidence on the effects of sensitisation training for healthcare workers comes from interventions focusing on msm.24 published data on the outcomes of similar sensitisation training addressing the needs of pwud and sex workers were not available at the time of writing. early key population training efforts in south africa utilised diverse training methodologies to reach healthcare workers with both sensitisation and medical competency training; however, the training typically focused on individual population groups.1 in 2013, several organisations collaborated to develop the ‘integrated key populations sensitivity training programme for healthcare workers in south africa’ in partnership with the south african national department of health and the south african national aids council to consolidate sensitisation training across population groups and improve training efficiency. the training intervention in 2013, ‘healthcare provision for msm, sex workers, and pwud: an introductory manual for healthcare workers in south africa’ was developed.32,2 the manual was developed with the intention of improving healthcare workers’ knowledge and awareness of health and related issues affecting key populations, and included topics relating to social norms and values; human sexuality and sexual behaviour; the legal and rights context, socio-structural marginalisation and prejudice; and interventions to foster an enabling healthcare environment. notably, this training programme did not focus on clinical skills for health service provision to key populations (beyond sexual history taking and awareness raising). the ‘integrated key populations sensitivity training programme for healthcare workers in south africa’ (key populations’ sensitisation training) was a one-day sensitisation training programme for healthcare workers utilising the training manual, in conjunction with a facilitation guide. a total of 405 healthcare workers (inclusive of nurses, counsellors, social workers and managers) received the sensitisation training between october 2013 and july 2014 across five south african provinces: eastern cape, free state, kwazulu-natal, limpopo and the northern cape. the training was conducted by facilitators with prior key population experience, who also received a comprehensive pre-intervention training on the specific content of the integrated key population training. local government and civil society organisations providing services in the provinces where the training was provided, nominated the healthcare workers who participated in the training. this article presents the findings from a mixed-method study evaluating the outcomes of the key populations’ sensitisation training in selected locations. the evaluation objectives were to (1) assess changes in the perceptions, attitudes and knowledge of healthcare workers regarding hiv-related issues affecting msm, sex workers and pwud, and (2) to assess changes in healthcare workers’ attitudes, for example, stigma and discrimination towards msm, sex workers and pwud who access health and related services. methods background to the evaluation research of the five provinces that received training, two provincial capitals were selected for evaluation: bloemfontein (mangaung metropolitan district, free state province), in which 84 healthcare workers received the sensitisation training, and mafikeng (ngaka modiri molema district municipality, north-west province), in which no training intervention was implemented. these locations were selected because they are characteristic of the public health system outside of major south african metropolitan areas (poor infrastructure, under-resourced, operating with inadequate health personnel, and with significant financial and geographic barriers to accessing healthcare),33,34 and because implementation and scale up of key population hiv programmes in these areas were lacking at the time the research was completed. the number of locations was limited by the resources available for the evaluation. compared to other south africa provinces, both north-west and the free state have low population densities, each containing 7% (n = 3 856 174) and 5% (n = 2 866 678) of the national population, respectively.3 the south african national aids council estimated that in 2018 there were 1228 female sex workers in mangaung and 1753 in the ngaka modiri molema district. msm estimates for these districts are 3655 and 3779, respectively. hiv prevalence for these districts is estimated to be similar: 53% for female sex workers and 18% for msm. pwud estimates have not been developed because of lack of data.4 at the time of the research, health services for msm and sex workers were limited (but have subsequently increased),19 no pwud outreach programmes or harm reduction services existed35 and the availability of water-based condom-compatible lubricants was poor. this study used a combination of qualitative and quantitative methods to evaluate the intervention. we used quantitative preand post-training questionnaires, combined with qualitative interviews, to evaluate the changes linked to the integrated key population sensitisation training. similar methods have been used to assess changes in healthcare workers’ knowledge, attitudes and practices related to training in african contexts, about hiv treatment and also mental health.36,37 quantitative component healthcare workers who received the intervention were invited to complete anonymous paper-based preand post-training assessment questionnaires. the questionnaires assessed previous training and experience working with key populations, knowledge about key populations’ health needs, as well as attitudes, opinions and beliefs pertaining to key populations and their behaviours. all of the completed paper-based questionnaires were entered into an excel spreadsheet and imported into stata 14.5 quantitative analysis included comparison of proportions and frequencies, as well as t tests for independent proportions to determine if there were significant differences between preand post-training responses.38 qualitative component prior to the training intervention, baseline in-depth interviews (idis) were conducted with eight healthcare workers purposively sampled from four government health facilities in bloemfontein and four in mafikeng. three months after the training intervention was implemented in bloemfontein, follow-up idis were conducted with three healthcare workers in bloemfontein and one in mafikeng (the variance in sample size at follow-up was because of respondents declining follow-up interviews). both baseline and follow-up idis explored healthcare workers’ narratives of their experience of working with key populations viz. attitudes and views of the behaviour and social vulnerabilities of this group and of their own capacity to provide appropriate and nonjudgmental services to them. in addition, views with regard to the training of healthcare workers in this field were elicited from the interviewees. interviews were conducted by a female socio-behavioural interviewer and a male research assistant, both competent in english and local languages, and trained in the specific implementation of the research tools. idis were conducted at the health facility of each participant, often in consultation rooms during tea or lunch breaks. idis were conducted in a combination of english and local languages, largely sesotho and setswana, and were audio-recorded with consent from the interviewees. debriefing notes were captured after each idi by the interviewer and research assistant. audio-recordings were transcribed and translated into english, and transcriptions were quality-checked by the multi-lingual lead interviewer. nvivo 10 software6 was used to code and manage qualitative data. two coders read and coded the transcripts independently, and any discrepancies were resolved through inter-coder consensus. predetermined themes and an a priori coding scheme were developed to structure the analysis, and coded data were reviewed to determine final themes and outcomes. comparisons were drawn between the baseline and follow-up evaluation activities per facility, and between facilities. ethical consideration approval for the research and permission to access the healthcare staff and facilities were granted by the free state and north-west provincial departments of health. ethical approval was also granted by the university of cape town’s human subjects research ethics committee.7 findings quantitative findings from preand posttraining questionnaires results from the 401 preand 405 post-training assessment questionnaires are shown in table 1. awareness of the psychosocial vulnerabilities of key populations, such as violence, stigma and lack of access to healthcare, increased between preand post-training assessments. for example, awareness of unfair treatment and discrimination towards sex workers, msm and pwud by staff at health facilities increased to 88% after the training (n = 355), compared to 71% beforehand (n = 286). after the training, 75% (n = 302) of respondents were aware that sex workers, msm and pwud are more likely to be exposed to violence than the general community, compared to 59% (n = 235) prior to training. after the training, 83.5% of trainees (n = 338) agreed that this training increased their awareness of how stigma affecting sex workers, msm and pwud can limit their access to effective healthcare, compared to 69% (n = 276) prior to the training. in the post-training assessments, 67% (n = 273) of trainees felt that it was important for their health services to be friendly towards and supportive of sex workers, msm and pwud, compared to 50% (n = 202) prior to the training. in addition, 56% (n = 219) of healthcare workers also strongly felt that they would be able to address discrimination against sex workers, msm and pwud in their facilities. self-reported moralising and prejudicial attitudes related to selling sex, using drugs and same-sex sex were also reduced as a result of the training. table 1: changes in preand post-training assessment items. qualitative findings in the interviews conducted three months after the training intervention was implemented, there were marked contrasts between opinions expressed by healthcare workers in the intervention group who received training as compared with those in the non-intervention group who did not receive any training. judgmental views towards key populations, for example, moralising attitudes towards sex work, were voiced by healthcare workers in the non-intervention group: ‘selling one’s body is not fine … if someone sells their body in town we feel that they are just doing it deliberately. it’s not right … we feel that the person should not be a part of us [society] because they sell their body.’ (non-intervention group) prejudicial statements about pwud were also made by a healthcare worker in the non-intervention group: ‘people who use drugs … after they smoke the drugs they become crazy, they start to steal, they start to harass us and mug us.’ (non-intervention group) a healthcare worker from the group who did not receive the training described their own lack of skills and knowledge, and perceived capacity to provide services to sex workers and msm, and shared the view that training would be beneficial: ‘men who have sex with men? … i don’t know about those … sex work is illegal in south africa … they [sex workers] don’t speak [disclose that they are sex workers to healthcare workers]. they might come [to the clinic] but you can’t know and can’t ask them … you can’t ask them where they work … [there is a need for training on how to deal with sex workers].’ (non-intervention group) a variety of differences between trained and non-trained healthcare workers later emerged in the follow-up interviews, specifically regarding their judgemental attitudes towards key populations; these are presented below. respondents who received the training intervention felt that the training had addressed their previously judgemental attitudes by increasing their knowledge and understanding of various psychosocial and health issues pertaining to key populations. the comment below illustrates a shift away from homo-prejudicial attitudes: ‘now i can welcome them [key populations patients] properly. because i used to think that they are just naughty before the training. i found out that they are not naughty, at times as a woman you get feelings for other women and as a man you get feelings for other men … i can welcome them because now i know what the problem is. they did not choose … i have learned … not to discriminate them, to end stigma, social stigma.’ (intervention group, post-training) intervention recipients provided further examples of how they perceived the training to have improved their knowledge, specifically in their ability to conduct sexual and risk behaviour history taking. trained healthcare workers described their perceptions of their own capacity to ask appropriate and relevant questions to key populations patients to provide them with effective care: ‘when a sex worker comes to test [for hiv] at the clinic i know what sort of questions to ask.’ (intervention group, post-training) those healthcare workers who received training demonstrated an improved understanding and increased compassion for the challenges, hostility and violence facing key populations in society: ‘these people [key populations] feel rejected because we don’t treat them like people.’ (intervention group, post-training) ‘there are problems, you find that sex workers are beaten and sometimes they are not paid … when they go and report at the police station they tell them off and laugh at them … i have learned a lot about key populations.’ (intervention group, post-training) respondents voiced opinions that the training had enabled them to understand the social marginalisation and discrimination experienced by key populations: ‘i noticed since i went for the [training] course … i found that we stigmatise them [key populations], we don’t treat them well … a man who has sex with man is ridiculed in society for dating another man, that is stigma … social stigma … i learned a lot from the training.’ (intervention group, post-training) some of the trained healthcare workers explained that their improved understanding and compassion was the result of reflecting on and confronting their own prejudicial attitudes during the training, a necessary step to be able to provide services to key population clients in a sensitive, compassionate, and humane manner: ‘after we went for the training [we realised] that … we must treat them [key populations] like this [sensitively]. when they come here [to the health facility] they must feel welcome. they must be like any other patient, we must treat them equally. when a person comes here to share their problems they must not be scared to say that i am a sex worker because they are afraid of how i will react, what i will say to them and if i will judge them. if they say i am a sex worker, i must not even react, i must listen to their story and understand what their problem is … it’s alright because they are also people, we don’t have to isolate them in society, we must treat them like all the other people.’ (intervention group, post-training) the way in which the sensitisation training worked to challenge prejudicial views and beliefs, combined with the provision of information about key populations and their risks and vulnerabilities, resulted in self-reported attitude shifts on the part of the healthcare workers, as well as increased introspection on personally held judgemental views: ‘[after the training] i also know where i stand … the training opened my eyes so that i could introspect … i noticed that my attitude has changed towards those people [key populations] … [before] i would see them [key populations] but i didn’t understand them. the training opened my eyes and my attitude has changed.’ (intervention group, post-training) discussion findings from this evaluation of south africa’s first integrated sex worker, msm and pwud sensitisation programme for healthcare workers demonstrate that training interventions of this nature can be successful in enabling healthcare workers to better understand the social marginalisation and discrimination experienced by these groups, creating space for them to assess and reflect on engrained social norms that inform discriminatory and judgemental attitudes towards these key populations and their behaviour. knowledge pertaining to key factors that contribute to poor health outcomes amongst key populations were improved amongst healthcare workers who received the training. specifically, this evaluation suggests that the sensitisation training improved healthcare workers’ awareness of factors that increase the vulnerability of key populations to hiv infection, including psychosocial issues such as stigma and violence, barriers towards accessing health services, and the consequences of unfair treatment and discrimination by healthcare staff. findings also indicate that the training intervention resulted in a shift in attitudes, expressed through an increased empathy for key populations, and a reduction in negative and discriminatory moral-based judgements of sex workers, msm and pwud and their behaviours. healthcare workers who received the training also self-reported increased comfort and capability in providing appropriate health services to key populations, suggesting that a sensitisation training of this nature could help to improve the ability of healthcare workers to provide sensitive and appropriate health services to stigmatised and marginalised populations. the limited data on similar sensitisation-type training programmes that exist support and are congruent with the findings of this study, suggesting that sensitisation training can be efficacious and can facilitate the creation of more tolerant and respectful workplace norms.25,26,29,30,31 outcomes from our study, as previously published data demonstrate, suggest that healthcare workers at both sites held and expressed judgemental and moralising attitudes towards key populations and also lacked the knowledge and awareness of specific key population health needs.6 these findings show that healthcare workers who received the training intervention reported an increase in both their support of and acknowledgement of evidence-based interventions for key populations. limitations there were limitations to this study that should be considered. firstly, participants in the qualitative component of the study included a small purposively sampled group of healthcare workers, which may have limited the range of data collected. the recruitment and implementation of idis were constrained because of the operational logistics of clinics, limited space and the availability of participants because of staff shortages and heavy workloads. in addition, the follow-up idis had an even smaller sample size because of respondents declining follow-up idis. the participants were not requested to include identifying information on their training questionnaires in order to maximise confidentiality; therefore, preand post-training analyses for individuals were not included in this study. evaluations of future training interventions should include linked preand post-intervention assessments to determine individual changes more precisely (e.g. using a unique code) as well as an assessment of key populations service utilisation statistics preand post-intervention to identify changes in service uptake. in addition, this study included a three-month period between baseline and follow-up data collection; however, a different follow-up interval may have resulted in different long-term changes in shifts in attitude. future evaluations would benefit from a larger qualitative sample, and representation from all cadres of healthcare workers. recommendations despite the stated limitations, this evaluation suggests that a one-day integrated key population sensitisation training course can positively impact the perceptions, attitudes and knowledge of healthcare workers about hiv-related issues affecting msm, sex workers and pwud. such changes may contribute to the reduction in barriers to access health services and the promotion of welcoming and enabling healthcare facilities. evidence of this nature is necessary to inform policy recommendations regarding the need for sensitisation training programmes to be integrated into national preand in-service training for healthcare workers, and contributes to existing data on outcomes of sensitisation training of healthcare workers, particularly in sub-saharan africa where access to sensitised healthcare services for key populations still remains a challenge. future research is needed to determine how best to utilise refresher training and ongoing mentorship to maintain the longevity of positive attitude changes for periods greater than a year.26 additional operational factors that may improve the efficacy or effectiveness of sensitisation training should also be investigated, including types of content (e.g. clinical competency models), delivery modalities (e.g. online vs. in-person) and participant cadres (e.g. social workers and law enforcement). in addition, future training interventions and evaluations should consider the inclusion of transgender people as a key population, given their vulnerability to hiv infection. lastly, future research should explore the impact of sensitisation training on key population service utilisation both as a stand-alone intervention and within the context of integrated programming inclusive of community-driven demand creation. conclusion this evaluation demonstrates that a relatively short (one-day), low-cost training intervention can improve healthcare workers’ levels of knowledge and awareness about the specific hiv-related health needs and psychosocial vulnerabilities of key populations, and reduce levels of prejudice and discrimination.8 acknowledgements the authors would like to acknowledge the support from the funders and implementing partners for this project, and nacosa (global fund), which funded the evaluation. furthermore, they would like to acknowledge the co-investigators of the evaluation: esda van de watt broekman, jacques livingston, machteld busz, hilde roberts, delene van dyk, dawie nel, gordon isaacs, xander flemming, jacqueline mbwana, bram langen, benjamin janse van rense, eva marumo, felistus momedi, coceka nogoduka, jabulile sibeko, steave nemande, manoj kurian and helen savva. the organisations involved in the training and evaluation include icap south africa, mainline, out wellbeing, sex workers education and advocacy taskforce (sweat), amsher, bridging the gaps, coc netherlands, south african national department of health, bonela, south african national aids council, fhi360 and the us centers for disease control and prevention. competing interests the authors declare that they have no financial or personal relationship(s) that may have inappropriately influenced them in writing this article. disclaimer the views and opinions expressed in this article are those of 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london: harm reduction international, 2016; 148 p. arem h, nakyanjo n, kagaayi j, et al. peer health workers and aids care in rakai, uganda: a mixed methods operations research evaluation of a cluster-randomized trial. aids patient care stds. 2011 dec;25(12):719–724. https://doi.org/10.1089/apc.2010.0349 liu g, jack h, piette a, et al. review mental health training for health workers in africa: a systematic review. lancet psychiatry. 2016 jan 30;3:65–76. https://doi.org/10.1016/s2215-0366(15)00379-x fraenkel jr, wallen ne, hyun hh. how to design and evaluate research in education. new york: mcgraw-hill; 2012. footnotes 1. examples include msm trainings by anova health institute/health4men/icap south africa; msm/sex worker/pwud trainings by desmond tutu hiv foundation; lgbt trainings by out lgbt well-being. 2. available at: https://www.researchgate.net/publication/261078875_health_care_provision_for_men_who_have_sex_with_men_sex_workers_and_people_who_use_drugs_-_an_introductory_manual_for_health_care_workers_in_south_africa. 3. statssa. 4. south african national aids council key populations cascade stakeholder group, february 2018. 5. statacorp, college station, tx. 6. nvivo qualitative data analysis software; qsr international pty ltd., version 10, 2014. 7. human subjects research ethics committee reference number: 390/2013. 8. building on this and other sensitisation training projects, i-tech south africa is developing, implementing and evaluating a comprehensive sensitisation and capacity development pilot intervention programme, with the objective of sensitising clinical and non-clinical staff at the primary care and community levels on issues related to stigma and discrimination, as they relate to five key populations (msm, people in prisons and other closed settings, sex workers, pwud and transgender people). https://www.go2itech.org/2017/06/key-populations-sensitization-training-for-health-care-workers-in-south-africa/. hiv message message from the editor this june edition of sajhivmed is being released to coincide with the 6th south african aids conference, held in durban. the conference programme is filled with renowned speakers from a range of backgrounds, and the focus of the meeting – integration of policies and systems in response to hiv – is particularly critical at this stage of our response to the epidemic. paralleling the broad focus of this meeting, the diversity of articles in this issue of the journal emphasises the range of clinical, psychosocial and health systems challenges raised by the hiv epidemic and our responses to it. on the topic of the prevention of mother-to-child transmission (pmtct) of hiv, mnyani and mcintyre1 document the challenges to providing high quality services in soweto; while their research was conducted around previous pmtct guidelines, the results showing the difficulties in delivering pmtct interventions in primary care are especially noteworthy in light of recently revised national policies. in the area of mental health, govender and schlebusch2 present a potentially useful screening tool for identifying patients at risk of suicidality following hiv diagnosis – a critically important but widely neglected concern. rebe and colleagues3 discuss the health service needs of men who have sex with men and suggest a range of approaches to the design and delivery of services. on the topic of the social impact of the epidemic, jury and nattrass4 present unique insights into how the household circumstances of patients initiating art may change over time, suggesting decreased reliance on family members for individuals stable on treatment. meanwhile, there has been great interest in innovative strategies for managing large numbers of stable, relatively healthy art patients in primary care. wilkinson5 reports on the development of ‘adherence clubs’ in cape town, which have the potential to reduce the patient load within clinical services – an approach that certainly warrants greater consideration. this issue also features a rich array of interesting clinical case reports. haeri mazanderani and ebrahim6 discuss a case of hiv/htlv-1 co-infection, and the seemingly paradoxical finding of progressive hiv disease with lymphocyte proliferation. there is widespread concern around the incidence of new hiv infections in pregnant women, and kalk and colleagues7 present two cases of mother-to-child hiv transmission that show the risks associated with acute hiv infection in pregnant and breastfeeding women. meanwhile, barnardt8 presents an unusual case of kaposi’s sarcoma in pregnancy, with complexities in managing concomitant infection, malignancy and pregnancy. complementing these traditional case reports, we present here a new feature of the journal, a critical case review that incorporates perspectives from local and international clinicians. this first instalment from venter and colleagues9 presents a common picture of acute liver failure with multiple potential causes; a special thanks to our discussants, sarah fidler and sarah stacey, for outlining their clinical thinking. ideas for future cases to approach in this format will be most welcome – please send in your suggestions. happy reading. landon myer associate professor school of public health & family medicine university of cape town landon.myer@uct.ac.za 1. mnyani cn, mcintyre ja. challenges to delivering quality care in a prevention of mother-to-child transmission of hiv programme in soweto. southern african journal of hiv medicine 2013;14(2):64-69. [http://dx.doi.org/10.7196/sajhivmed.902] 1. mnyani cn, mcintyre ja. challenges to delivering quality care in a prevention of mother-to-child transmission of hiv programme in soweto. southern african journal of hiv medicine 2013;14(2):64-69. [http://dx.doi.org/10.7196/sajhivmed.902] 2. govender rd, schlebusch l. a suicide risk screening scale for hiv-infected persons in the immediate post-diagnosis period. southern african journal of hiv medicine 2013;14(2):58-63. [http://dx.doi.org/10.7196/sajhivmed.899] 2. govender rd, schlebusch l. a suicide risk screening scale for hiv-infected persons in the immediate post-diagnosis period. southern african journal of hiv medicine 2013;14(2):58-63. [http://dx.doi.org/10.7196/sajhivmed.899] 3. rebe kb, de swardt g, struthers h, mcintyre ja. towards ‘men who have sex with men-appropriate' health services in south africa. southern african journal of hiv medicine 2013;14(2):52-57. [http://dx.doi.org/10.7196/sajhivmed.841] 3. rebe kb, de swardt g, struthers h, mcintyre ja. towards ‘men who have sex with men-appropriate' health services in south africa. southern african journal of hiv medicine 2013;14(2):52-57. [http://dx.doi.org/10.7196/sajhivmed.841] 4. jury c, nattrass n. parental presence within households and the impact of antiretroviral therapy in khayelitsha, cape town. southern african journal of hiv medicine 2013;14(2):70-74. [http://dx.doi.org/10.7196/sajhivmed.921] 4. jury c, nattrass n. parental presence within households and the impact of antiretroviral therapy in khayelitsha, cape town. southern african journal of hiv medicine 2013;14(2):70-74. [http://dx.doi.org/10.7196/sajhivmed.921] 5. wilkinson ls. art adherence clubs: a long-term retention strategy for clinically stable patients receiving antiretroviral therapy. southern african journal of hiv medicine 2013;14(2):48-50. [http://dx.doi.org/10.7196/sajhivmed.924] 5. wilkinson ls. art adherence clubs: a long-term retention strategy for clinically stable patients receiving antiretroviral therapy. southern african journal of hiv medicine 2013;14(2):48-50. [http://dx.doi.org/10.7196/sajhivmed.924] 6. haeri mazanderani af, ebrahim o. progressive hiv infection in the presence of a raised cd4+ count: hiv/htlv-1 co-infection. southern african journal of hiv medicine 2013;14(2):92-94. [http://dx.doi.org/10.7196/sajhivmed.904] 6. haeri mazanderani af, ebrahim o. progressive hiv infection in the presence of a raised cd4+ count: hiv/htlv-1 co-infection. southern african journal of hiv medicine 2013;14(2):92-94. [http://dx.doi.org/10.7196/sajhivmed.904] 7. kalk e, slogrove a, speert dp, bettinger ja, cotton mf, esser m. hiv sero-conversion during late pregnancy – when to retest. southern african journal of hiv medicine 2013;14(2):90-92. [http://dx.doi.org/10.7196/sajhivmed.903] 7. kalk e, slogrove a, speert dp, bettinger ja, cotton mf, esser m. hiv sero-conversion during late pregnancy – when to retest. southern african journal of hiv medicine 2013;14(2):90-92. [http://dx.doi.org/10.7196/sajhivmed.903] 8. barnardt p. managing aids-related kaposi’s sarcoma and pregnancy. southern african journal of hiv medicine 2013;14(2):87-88. [http://dx.doi.org/10.7196/sajhivmed.851] 8. barnardt p. managing aids-related kaposi’s sarcoma and pregnancy. southern african journal of hiv medicine 2013;14(2):87-88. [http://dx.doi.org/10.7196/sajhivmed.851] 9. venter f, masingi n, stacey s, fidler s. clinical challenge: deteriorating liver function in tb and hiv co-treatment. southern african journal of hiv medicine 2013;14(2):95-97. [http://dx.doi.org/10.7196/sajhivmed.927] 9. venter f, masingi n, stacey s, fidler s. clinical challenge: deteriorating liver function in tb and hiv co-treatment. southern african journal of hiv medicine 2013;14(2):95-97. [http://dx.doi.org/10.7196/sajhivmed.927] abstract introduction methods ethical consideration results discussion conclusion acknowledgement references about the author(s) antoinette v. chateau department of dermatology, school of clinical medicine greys hospital, university of kwa-zulu natal, kwazulu-natal, south africa ncoza c. dlova department of dermatology, school of clinical medicine greys hospital, university of kwa-zulu natal, kwazulu-natal, south africa halima dawood department medicine, infectious disease unit, greys hospital and caprisa, university of kwa-zulu natal, kwazulu-natal, south africa colleen aldous department of general medicine, school of clinical medicine, university of kwazulu-natal, kwazulu-natal, south africa citation chateau av, dlova nc, dawood h, aldous c. outcomes of stevens–johnson syndrome and toxic epidermal necrolysis in hiv-infected patients when using systemic steroids and/or intravenous immunoglobulins in pietermaritzburg, south africa. s afr j hiv med. 2019;20(1), a944. https://doi.org/10.4102/sajhivmed.v20i1.944 original research outcomes of stevens–johnson syndrome and toxic epidermal necrolysis in hiv-infected patients when using systemic steroids and/or intravenous immunoglobulins in pietermaritzburg, south africa antoinette v. chateau, ncoza c. dlova, halima dawood, colleen aldous received: 21 jan. 2019; accepted: 13 mar. 2019; published: 04 july 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: stevens–johnson syndrome (sjs) and toxic epidermal necrolysis (ten) are severe life-threatening mucocutaneous reactions. there is an ongoing controversy regarding the use of systemic corticosteroids and intravenous immunoglobulin (ivig) in sjs/ten and their utility in hiv-infected patients. objectives: the objective was to assess the outcome of a combination of intensive supportive care with oral corticosteroids in sjs and a combination of systemic steroids and ivig for 3 consecutive days in hiv-infected patients with ten. in addition, we assessed management in a general dermatology ward without implementing wound debridement. methods: this was a retrospective cohort study of 36 hiv-infected adults with sjs/ten admitted to a tertiary dermatology unit between 1st january 2010 and 31st july 2011. standard-of-care protocols included identification and elimination of the possible causative drug, meticulous wound care without debridement, initiation of oral prednisone (1 mg/kg/day) on admission for 3 consecutive days, and the addition of ivig (1 g/kg/day) for 3 consecutive days to those with ten. results: of the 36 patients in the study, 32 were female. nevirapine was the commonest drug implicated. a diagnosis of tuberculosis did not increase the case fatality rate. complications included infections, anaemia, drug-induced hepatitis, ocular involvement, renal impairment, deep vein thrombosis, respiratory distress, leucopenia, gastritis and hypernatremia. the overall survival rate was 97%. conclusion: hiv-infected sjs and ten patients were treated in a tertiary dermatology ward with a treatment plan of skin care, and a combination of systemic corticosteroids and ivig respectively had a survival rate of 97%. keywords: stevens–johnson syndrome; toxic epidermal necrolysis; systemic steroids; intravenous immunoglobulins. introduction stevens–johnson syndrome (sjs) and toxic epidermal necrolysis (ten) are severe life-threatening mucocutaneous reactions characterised by epithelial sloughing and systemic symptoms.1,2 stevens–johnson syndrome is characterised by mucous membrane erosions and epidermal detachment, which involves less than 10% of the body surface area (bsa) in the bastuji-garin classification. stevens–johnson syndrome–toxic epidermal necrolysis overlap represents 10% – 30% bsa involvement, and ten involves over 30% bsa involvement.3 the worldwide incidence rate of sjs is 1.2–6 per million persons per year with a mortality rate of 5%, while the incidence rate of ten is 0.5–1.2 per million per year with a mortality rate of up to 30%.4 in south africa, there are no published data on the incidence of sjs and ten. with the current hiv epidemic and increased use of hiv treatment in south africa, the number of patients with sjs/ten has increased.5 the incidence of sjs/ten is 1000-fold higher in patients with hiv.6 the high incidence of sjs/ten in immunocompromised patients is likely multifactorial. it may be due to polypharmacy in the management of hiv, slow acetylation of drugs, glutathione deficiency, altered lymphocyte function and cytotoxic sulfamethoxazole metabolites in the case of trimethoprim/sulfamethoxazole.7,8 in addition, the high rates of tuberculosis co-infection in individuals with hiv leads to the use of a vast array of drugs to treat these infections. this results in greater susceptibility to sjs/ten and an associated increase in mortality.9 other factors that contribute to mortality included lymphopenia, neutropenia and hypernatremia, as well as low-serum haemoglobin and hypoalbuminemia.9,10 the use of systemic corticosteroids in the treatment of sjs/ten is controversial.11 systemic steroids in the setting of sjs/ten has immune-modulating anti-apoptotic effects which downregulate fas-fas l binding.12 this results in anti-inflammatory properties which inhibit interleukin 2, tumour necrosis factor (tnf) α and interferon (ifn)γ, and immunosuppressant properties which inhibit t cells.12,13 intravenous immunoglobulins (ivigs) contain anti-fas antibodies that block the fas-fas l interactions on the keratinocyte and thus prevent apoptosis that results in epidermal detachment.14 studies have shown that ivig arrests disease progression and reduces time to skin healing.14,15,16 by combining systemic corticosteroids and ivig, the inflammatory cascade and the undesirable adverse effects are prevented. systemic corticosteroids and ivig abort the inflammatory cascade in sjs/ten and, hence, the deleterious effects that ensue. therefore, this retrospective cohort study assessed the outcomes of intensive supportive care combined with systemic corticosteroids and ivig for 3 consecutive days in hiv-infected patients with ten. in addition, we assessed the outcome of managing these patients in a general dermatology ward without implementing wound debridement. some centres treat sjs/ten as a partial thickness burn17 as the clinical presentation is similar to a burn wound, although it is an immune-mediated hypersensitivity reaction. however, sjs/ten should not be managed strictly as a burn but rather in a specialised dermatology ward without debridement.1,18,19 we believe the treatment of sjs/ten should differ from that of burn treatment because of the different aetiology and pathophysiological mechanism.1,20 methods the study was undertaken at the greys hospital department of dermatology, a tertiary referral centre in pietermaritzburg, kwazulu-natal, south africa. it is a 530-bed tertiary hospital, serving 3.5 million people in the western part of kwazulu-natal. study population the clinical records of all 39 participants with sjs/ten admitted to a general dermatology ward from 01 january 2010 until july 2011 were retrospectively reviewed. three patients were hiv-negative and were thus excluded from the study. all participants were of black african descent. participants who presented with organ failure and fulfilled intensive care admission criteria were referred to the intensive care unit where they were co-managed with critical care specialists and the dermatology team. data collection and classification the review of patient’s clinical records during admission, weekly after discharge for the first month and then monthly for the following 3 months were recorded. demographics, scorten score, drug history, cd4 count, comorbidities and complications were documented from the records. scorten (score of toxic epidermal necrosis) is a score used to assess severity and predict mortality in patients with sjs/ten. it uses seven criteria (table 1). one point is given to each criterion, and this correlates with a predicted mortality rate.10 table 1: scorten score. criteria used to determine drug causality were timing of the skin lesions after the administration of the drugs (temporality), increase of drug dose, previous history of drug reactions and if the drug reaction occurred when the drug was restarted, criteria noted in the naranjo scale.21 score of > 9 = definite adr (adverse drug reaction), 5–8 = probable adr, 1–4 = possible adr, 0 = doubtful adr. treatment plan the standard-of-care protocols included identifying and eliminating the possible causative drug, initiating oral prednisone (1 mg/kg/day) on admission for 3 consecutive days, and adding ivig (1 g/kg) for 3 consecutive days to participants with ten (n = 12). biochemical assessments on admission included a full blood count, glucose level, and renal and liver function tests. vital signs were registered every 4 h, and plasma glucose was monitored every 12 h. a screen for sepsis was done when clinically indicated. fluid depletion and electrolyte abnormalities were corrected, nutritional support was guided by the dietician and pain management was optimised. oral mucosal care included glycothymol irrigation every 6 h, removal of haemorrhagic crusting and the application of a mixture of prednisolone, remicaine, nystatin and sucralfate (8:8:8:1 formulation) to the lips and oral mucosa. genital mucosa was treated with daily potassium permanganate sitz baths and lubricated with petroleum jelly (vaseline ®) to prevent adhesions. pain was controlled with tramadol hydrochloride 50 mg – 100 mg 6 hourly and paracetamol 1 g 6 hourly. pethidine was used to alleviate the pain while dressing the wounds. cutaneous lesions were managed by strict barrier protection nursing and meticulous wound care without debridement using nanocrystalline silver dressings (acticoat®). antibiotics were not used prophylactically unless there was a clinical indication. expert opinion was sought from the ophthalmologists on admission and instructions were carried out as per the ophthalmologist care plan. their management plan entailed the use of a topical steroid (maxitrol®), lubricants and glass rodding to prevent adhesions. obstetricians and physicians were consulted when indicated. data analysis data were analysed using stata 13.0 se (statacorp. 2013. stata statistical software: release 13. college station, tx: statacorp lp). descriptive statistics included means (standard deviations) for continuous variables and frequencies (n [%]) for categorical variables. relationships between continuous predictors and dichotomous outcomes were assessed using the standard t-test or non-parametric wilcoxon rank-sum test if the normality assumptions were violated. similarly, analysis of variance (anova, or non-parametric equivalent, namely the kruskal–wallis equality-of-populations rank test) was employed to compare the means of continuous predictors across the three-drug reaction groups. correlation between continuous variables was assessed using the spearman rank correlation coefficient. differences in frequencies of categorical explanatory variables by drug reaction category were assessed using the pearson chi-square (χ2) test or fisher’s exact test if an expected cell count contained fewer than five observations. a p-value of < 0.05 was deemed statistically significant. ethical consideration ethical approval was obtained from the university of kwazulu-natal biomedical research ethics committee (reference number be417/14). results of the 36 patients in the study, 32 (88.9%) were women. eleven had sjs, 13 had sjs/ten overlap and 12 had ten. the number of days of hospitalisation increased exponentially along the spectrum of the disease (table 2). table 2: demographics of 36 hiv-infected patients presenting with stevens–johnson syndrome–toxic epidermal necrolysis. sixteen (50.0%) women in the study were pregnant. the mean (s.d.) cd4 cell count in the pregnant women was 267.2 (60.6) cells/mm3. a significant number of pregnant women (93.8%) developed sjs/ten secondary to nevirapine, while one was due to isoniazid prophylaxis. the pregnant women presented at a mean (s.d.) of 29.13 (3.76) weeks gestation. five (31.25%) of the women delivered prematurely as a result of foetal distress, and all five of these patients had ten. one of the deliveries was a stillbirth at 34 weeks’ gestation. the other four infants were healthy and showed no signs of any drug reaction. cd4 cell counts were available for all the patients but one (table 3). there was no association between the cd4 cell count and scorten score (spearman rho correlation test of 0.039). there was no significant difference in the mean cd4 cell count by drug type with an anova p-value of 0.594 (data not shown). table 3: cd4, scorten, drugs implicated, co-morbidities and mortality of 36 hiv-infected patients presenting with stevens–johnson syndrome–toxic epidermal necrolysis. the mean (s.d.) cd4 cell count and confidence interval noted in patients with complications were 236.8 (186.4–287.2) cells/mm3. there was no statistical difference across all complications. thus, the complications seen in the patients with sjs/ten were not influenced by the cd4 cell counts and hence the level of immunosuppression in the sample. the average scorten scores for sjs, sjs-ten overlap and ten were 1, 2 and 3, respectively. there was a significant difference in the median scorten score by drug reaction type p < 0.001. thus, the more severe the drug reaction, the higher the scorten score observed. comorbidities included hypertension, tuberculosis and epilepsy (table 3). ten (27.8%) of the patients in the study reacted to the anti-tuberculosis therapy, two due to isoniazid prophylaxis and the other eight to rifafour®. of these eight patients, only three were microbiologically confirmed cases of tuberculosis. the three patients were rechallenged with anti-tuberculosis therapy without further incident. the most common drugs implicated were nevirapine (69.4%), anti-tuberculosis medication (16.7%) and trimethoprim/sulfamethoxazole (8.3%). other drugs included phenytoin (2.8%) and fluconazole (2.8%) (table 3). thirty-two of the study patients had associated complications such as anaemia, drug-induced hepatitis, ocular involvement, renal impairment, deep vein thrombosis, respiratory distress, lichen planus, leucopenia, gastritis and hypernatremia. the number of complications noted increased along the continuum of the drug reactions with seven complications noted in sjs patients, 19 in sjs-ten overlap syndrome and 27 noted in the patients with ten (table 4). ten patients (28.7%) were noted to have infections (table 5). table 4: complications correlated to the various drug reactions. table 5: profile of the 10 patients with infection, organisms isolated and scorten score. there was one death in our study representing a case fatality rate of 2.8%. the patient was pregnant (34 weeks gestation)and was admitted with ten secondary to nevirapine. she had a cd4 count of 185 cells/mm3 and a scorten score of 4 which predicted a poor outcome (expected mortality rate of 58.3%). she experienced preterm labour 2 days after admission and gave birth to a stillborn male. she died 4 days after admission. she presented with poor prognostic factors: scorten score of 4 (tachycardia, bsa involvement of 40% acidosis and elevated urea, as well as hypernatremia and staphylococcus aureus septicaemia). discussion this retrospective cohort study has shown that the use of systemic corticosteroids together with ivigs for the treatment of sjs/tens in hiv-infected patients resulted in a 97.2% survival rate compared to the previous report, which has a mortality rate of 30.0%.4 we observed that cd4 cell counts and scorten score did not impact the mortality rate in hiv-infected patients. the use of systemic corticosteroids in sjs/ten has been an issue of debate for many years, and its use in hiv-infected patients remains highly controversial as it is thought to cause further immunosuppression.22 there have been case reports of hiv-infected patients being treated with systemic steroids and ivig with a favourable outcome.22,23,24,25 systemic corticosteroids in sjs/ten is beneficial if used in the acute stage, that is, within 3–4 days of the disease onset and for short time periods, for less than a week.12,26 hirahara et al. measured pro-inflammatory cytokines ifn ˠ, tnf α, interleukin 6 and 10 before and after high-dose methylprednisone therapy.27 this study showed that there was a significant decrease in the cytokines post therapy which could contribute to the survival of these patients.27 there are a number of other studies that support the use of systemic corticosteroids in sjs/ten.18,28,29,30,31 high-dose corticosteroids early in the course of the disease decrease epidermal damage, shorten the recovery period and prevent permanent sequelae.32 corticosteroids have been noted to decrease the intensity of the reaction, control the extension of necrolysis, decrease fever and discomfort and prevent damage to internal organs.1 this is supported by our findings. kardaun et al. noted that dexamethasone therapy in sjs/ten is more efficacious than long term lower dose therapy with a diminished risk of infection and delayed wound healing.12 those opposing the use of systemic steroids argue that systemic steroids impair the immune system and increase the risk of infections.33,34 however, aberdien et al. noted that systemic steroids are beneficial in the acute stage of infection in hiv-infected patients with pneumocystis jirovecii pneumonia, acute bacterial meningitis, tuberculous pericarditis and meningitis and in patients with septic shock.35 a study by mayosi et al. investigating the role of oral prednisone in hiv-associated tuberculous pericarditis demonstrated an insignificant effect on mortality, cardiac tamponade requiring pericardiocentesis and constrictive pericarditis. however, the incidence of constrictive pericarditis was significantly reduced by adjunctive corticosteroids (4.4% vs. 7.8%; p = 0.009), but this also resulted in an increase in hiv-associated malignancy (kaposi sarcoma).36 the rationale for the use of systemic steroids in sjs/ten is mainly due to anti-inflammatory and anti-apoptotic effects.12,37 there were no adverse effects noted at 3-month follow-up of our patients. we thus contend that this dose and the duration of systemic corticosteroids is unlikely to cause deleterious side effects. studies that have opposed the use of systemic corticosteroids are of the view that systemic corticosteroids are associated with a high rate of sepsis, poor wound healing, prolonged hospital stay and a higher mortality rate.11,33,34,38 rasmussen reported a retrospective analysis of 32 immunocompetent children with sjs, 17 of whom were treated with systemic steroids for an unknown duration and of those treated with systemic steroids, 9 developed complications ranging from severe infections, seizures, gastrointestinal bleeds, pulmonary effusion and cushingoid facies.33 based on the side effects noted by rasmussen, a prolonged use of systemic steroids can be inferred. in a study of 30 patients by helebian et al. all of whom were treated in a burns unit, 15 patients received supportive care alone while the other 15 received dexamethasone at various doses together with supportive care. there was a 66% mortality rate in the dexamethasone group as compared to the 33% mortality rate in the supportive group alone.34 helebian et al. did not stipulate the dose of corticosteroid or the duration of use. this may account for the high mortality noted. their skin care regimen also changed after the high mortality was noted in the group treated with systemic steroids. the positive outcome may not be a result of simply omitting systemic steroids but may also be due to a more intensive skin care regimen. studies have shown that ivig arrests disease progression and reduces the time of skin healing.14 two case reports by tan et al. noted that ivig administered to hiv-infected patients with ten lowered morbidity and shortened the duration of hospital admission.22 in contrast, brown et al. showed that there was no therapeutic benefit in using ivig.39 this study showed a higher mortality rate of patients receiving ivig than in controls and concluded that there is no role of ivig in the setting of ten and this should not be used outside of trials.39 recent studies have shown that a combination of corticosteroids and ivig arrested disease progression, and decreased hospitalisation and mortality in patients with sjs/ten more than the use of corticosteroids as monotherapy.2 jagadeesan et al. noted that combining systemic steroids and ivig may have a synergistic action targeting the different pathways of apoptosis active in sjs/ten.37 thus, combination therapy was noted to arrest disease progression and there was a faster onset of re-epithelialisation with no adverse side effects.37 a systematic review showed that patients who received systemic steroids and ivig had a favourable clinical outcome compared to patients who received supportive care alone.40 local studies oppose the use of systemic steroids and immunoglobulins in patients with sjs/ten. kannenberg et al. conducted a study in which 78.9% of the patients were hiv-infected. all patients in the study received extensive supportive care. there was a mortality rate of 29.8% in the hiv-infected patients and 6.0% in the non-infected patients. the prognostic indicators noted were hiv -tuberculosis co-infection, sepsis and bsa > 40.0%.9 knight et al. implemented similar treatment strategies of extensive supportive care in their study. seventy-eight per cent of their cohort was hiv-infected. the study concluded that the extent of bsa involvement increases the risk of bacterial skin infections and that tuberculosis co-infection and bacterial skin infections increase the mortality rate. this study had a mortality rate of 9%.41 many view ten and major burns as similar entities based on bsa involvement, and hence the general principles of management should be the same.13 however, burns differ in pathophysiology, presentation, long term sequelae; hence, target therapy to counteract the process of apoptosis such as the use of systemic corticosteroids and ivig is indicated for sjs/ten. the admission of patients to specialised dermatology centres has shown good clinical outcomes, and this is illustrated in our cohort.18 none of the patients in this cohort had wound debridement, and this is supported by a number of studies.1,19 blisters act as a natural biological dressing which favours re-epithelialisation.42 fluid management also differs between sjs/ten and burns patients in that sjs/ten patients require only two-thirds to three-quarters of the fluid requirements of burns patients.43 infection is the leading cause of death in patients with sjs/ten and maybe as high as 40% in tertiary centres.41 knight et al. noted that epidermal detachment > 30% in sjs/ten has an increased risk of bacterial infections and mortalities.41 one of our patients with ten had tuberculosis and pseudomonas co-infection with a positive outcome. de prost et al. noted that bsa involvement was the main predictor of infection.44 this group identified staphylococcus aureus, pseudomonas and enterobacteriaceae as the most commonly implicated pathogens leading to mortality.44 these were similar pathogens noted in our patients. complications noted in our patients who died are unlikely to have been due to the administration of systemic corticosteroids and ivig. we receive patients that may have been at more than one health care facility prior to being transferred to our unit. nosocomial infections may have been acquired at the referral centres prior to systemic corticosteroid use. infections noted in the pregnant women included herpes simplex, vaginal discharge and vaginal warts. urinary tract infections are common in pregnancy and may be independent to the use of systemic corticosteroids. cutaneous pseudomonas and staphylococcus aureus infection may have been owing to the immunocompromised pregnancy state and hiv infection and may or may not be dependent on the use of systemic corticosteroids. anaemia in one patient may be due to hiv disease, blood loss from the wounds, pregnancy and renal impairment. drug-induced hepatitis was most likely due to nevirapine and trimethoprim/sulfamethoxazole use as the liver dysfunction returned to normal once the drugs were stopped. infectious hepatitis was excluded in the study population. ocular lesions are the most common and devastating complications in sjs/ten (20% – 79% of patients).45 araki et al. noted that steroid pulse therapy with methylprednisone at the onset of sjs/ten is of great therapeutic importance in preventing ocular complications.46 kim et al. noted that early treatment with systemic steroids and ivig improved ocular outcomes.47 the aetiology of deep vein thrombosis is multifactorial, and in one patient it may have been due to prolonged hospital stay, hiv infection, low cd4 cell count, pregnancy or ivig used.48,49,50 in our study, the high female-to-male ratio may be due to the use of nevirapine which is implicated as the cause of sjs/ten. it was prescribed in pregnant women (who accounted for 44.4% of the study sample) as part of the hiv treatment guidelines at the time of the study. the three drugs most implicated included nevirapine, trimethoprim/sulfamethoxazole and anti-tuberculosis medication – mainly isoniazid and rifampicin. risk factors for nevirapine-induced sjs/ten include female gender, baseline cd4 counts > 250 cells/mm3 in women and > 400 cells/mm3 in men, history of drug allergy, low body weight, high nevirapine serum levels and certain human lymphocyte antigen types.5,51,52 pregnant woman in the study had a mean cd4 count of 267.2 (s.d. 60.6) cells/mm3, a risk factor in keeping with nevirapine-induced sjs/ten as noted in the literature. pregnancy was not a risk factor for developing a drug reaction in our patient profile. this is contrary to what has been suggested in the literature.5,24 pregnancy is associated with immune dysregulation, which may predispose a woman to sjs/ten.24 there was no statistically significant difference between cd4 cell count and scorten score between the pregnant and the non-pregnant women. thus, the severity of immunosuppression and severity of the drug reaction and predicted mortality was not influenced by pregnancy. scorten score directly correlated to the severity of the drug reaction. there was no significant correlation between the cd4 cell count and scorten score, the severity of the drug reaction and the various complications. this could be explained by the fact that cd8 cytotoxic t cells are the main cells resulting in keratinocyte apoptosis.13,53 yang et al. noted that hiv infection depleted the cd4+ regulatory cells (cd4+cd25+), and this resulted in the unregulated activity of the cd8 cytotoxic t cells which resulted in ten.54 marks et al. noted that drug reactions to anti-tuberculosis therapy occurred in 13.0% of the non-hiv-infected patients and 27.0% of the hiv-infected patients.55 patients with sjs/ten are often co-infected with tuberculosis, which further increases the mortality rate.9 ten of the patients in our study group (27.8%) reacted to anti-tuberculosis treatment, and this was very similar to marks et al.’s findings. co-infection with tb was not associated with mortality in our cohort. the limitations of this study are the retrospective study design and the small sample of patients. future recommendations would be for larger randomised controlled studies to confirm the role of short course systemic corticosteroids in the management of hiv-associated sjs/tens. conclusion this retrospective study has shown that an intensive skin care regimen in combination with systemic corticosteroids and/or ivig in hiv-infected sjs and ten patients, respectively, treated in a tertiary dermatology ward resulted in a 97.2% survival rate. short course (3 days) systemic steroids were not associated with significant mortality in this hiv-infected cohort. a randomised controlled study is needed to confirm the results of this study. acknowledgement sincere appreciation to ms p. jika in preparation of this manuscript and to dr peer for reviewing the manuscript. competing interest the authors have declared that no competing interests exist. author contributions a.v.c., n.c.d., h.d and c.a. equally contributed to the writing and research is this article. funding this research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references wolf r, davidovici b. severe cutaneous adverse drug reactions: who should treat, where and how?: facts and controversies. clin dermatol. 2010;28(3):344–348. https://doi.org/10.1016/j.clindermatol.2009.06.020 schwartz ra, mcdonough ph, lee bw. toxic epidermal necrolysis: part i. introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis. j am acad dermatol. 2013;69(2):173.e1–173.e13. https://doi.org/10.1016/j.jaad.2013.05.003 bastuji-garin s, rzany b, stern 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https://doi.org/10.1016/j.jaad.2013.05.002 araki y, sotozono c, inatomi t, et al. successful treatment of stevens-johnson syndrome with steroid pulse therapy at disease onset. am j ophthalmol. 2009;147(6):1004–1011.e1. https://doi.org/10.1016/j.ajo.2008.12.040 kim kh, park sw, kim mk, wee wr. effect of age and early intervention with a systemic steroid, intravenous immunoglobulin or amniotic membrane transplantation on the ocular outcomes of patients with stevens-johnson syndrome. korean j ophthalmol kjo. 2013 oct;27(5):331–340. https://doi.org/10.3341/kjo.2013.27.5.331 govender i, mabuza hl, ogunbanjo ga. the characteristics of hiv and aids patients with deep vein thrombosis at dr. george mukhari academic hospital. afr j prim health care fam med. 2015 mar 27;7(1). https://doi.org/10.4102/phcfm.v7i1.690 momin sb. review of intravenous immunoglobulin in the treatment of stevens-johnson syndrome and toxic epidermal necrolysis. j clin aesthet dermatol. 2009;2(2):51–58. colman-brochu s. deep vein thrombosis in pregnancy. mcn am j matern child nurs. 2004 may–jun;29(3):186–192. https://doi.org/10.1097/00005721-200405000-00010 bera e, mia r. safety of nevirapine in hiv-infected pregnant women initiating antiretroviral therapy at higher cd4 counts: a systematic review and meta-analysis. s afr med j. 2012 oct 8;102(11 pt 1):855–859. https://doi.org/10.7196/samj.5700 dube n, adewusi e, summers r. risk of nevirapine-associated stevens-johnson syndrome among hiv-infected pregnant women: the medunsa national pharmacovigilance centre, 2007–2012. s afr med j. 2013 may;103(5):322–325. https://doi.org/10.7196/samj.6077 tiwari p, panik r, bhattacharya a, ahirwar d, chandy a. toxic epidermal necrolysis: an update. asian pac j trop dis. 2013;3(2):85–92. https://doi.org/10.1016/s2222-1808(13)60051-1 yang c, mosam a, mankahla a, dlova n, saavedra a. hiv infection predisposes skin to toxic epidermal necrolysis via depletion of skin-directed cd4 t cells. j am acad dermatol. 2014 jun;70(6):1096–1102. https://doi.org/10.1016/j.jaad.2013.12.025 marks dj, dheda k, dawson r, ainslie g, miller rf. adverse events to antituberculosis therapy: influence of hiv and antiretroviral drugs. int j std aids. 2009 may;20(5):339–345. https://doi.org/10.1258/ijsa.2008.008361 hiv message from editor message from the editor hiv medicine is a rapidly evolving field, perhaps more so than many other areas of clinical practice. the optimal choice of medicines changes regularly, but more profound changes in strategies to manage (and prevent) hiv infection also emerge at frequent intervals. to keep pace with these changes, guidelines to support different aspects of hiv medicine are updated regularly, and indeed we are in the midsts of another season of international guideline revisions; most notably, at the world health organization (who). given the heavy burden of hiv in south africa, and the major international contributions of south african research to the global evidence base, it is unsurprising that this edition of the journal contains a number of pieces of commentary on key issues facing the who guidelines group. one of the key issues in adult hiv medicine is the ‘best’ cd4 threshold for art initiation – recognising that the ‘best’ can be defined in terms of individual patient management, cost-effectiveness for public health services, and even in terms of impact on hiv prevention efforts. in his commentary, geffen1 touches on each of these concerns and arrives at a sensible position to maintain current cd4 starting points (i.e. with art initiation below 350 cells/µl) until further evidence emerges. meanwhile, the question of the most appropriate prevention of mother-to-child transmission (pmtct) policy for south africa was discussed in the previous issue2 – focusing on the question of 'option b+'. an editorial written in response by coutsoudis and colleagues3 is published here – and the question of whether south africa should shift policy to universal initiation of lifelong art for all hiv-infected women remains open. finally, an issue that is not squarely in the sights of the who guidelines group – but perhaps should be – is the pervasive gender inequities in access to and outcomes of art. as cornell4 notes in her commentary, this inequality favours female patients, in contrast to many of the commonly held assumptions about gender and hiv, raising concerns about men’s health that many health services and policies are ill-equipped to address. there are a number of other exciting contributions in these pages. katusiime and colleagues5 describe the evaluation of a novel ugandan programme to transition hiv-infected adolescents to routine adult care services – one of the first of its kind in africa. given the growing number of adolescents in our care and treatment programmes, examples of south african services that meet this need are urgently required. meanwhile, kenyon6 provides a creative analysis of hiv risk factors across language groups in south africa, providing further indirect evidence for the role of sexual partner concurrency in the spread of the epidemic. furthermore, roussouw and colleagues7 provide a useful overview of hiv-associated liopdystrophy. finally, this issue of the journal is the first since the very successful sa hiv clinicians society conference, held in november 2012 in cape town. we have published several of the best abstracts8 that were presented at the meeting, and look forward to seeing others published in sajhivmed soon. happy reading. landon myer associate professor, school of public health & family medicine university of cape town landon.myer@uct.ac.za 1. geffen n. world health organization guidelines should not change the cd4 threshold for antiretroviral therapy initiation. southern african journal of hiv medicine 2013;14(1):6-7. [http://dx.doi.org/10.7196/sajhivmed.906] 1. geffen n. world health organization guidelines should not change the cd4 threshold for antiretroviral therapy initiation. southern african journal of hiv medicine 2013;14(1):6-7. [http://dx.doi.org/10.7196/sajhivmed.906] 2. besada d, van cutsem g, goemaere e, ford n, bygrave h, lynch s. the case for option b and optional b+: ensuring that south africa’s commitment to eliminating mother-to-child transmission of hiv becomes a reality. southern african journal of hiv medicine 2012;13(4):178-181. [http://dx.doi.org/10.7196/sajhivmed.864] 2. besada d, van cutsem g, goemaere e, ford n, bygrave h, lynch s. the case for option b and optional b+: ensuring that south africa’s commitment to eliminating mother-to-child transmission of hiv becomes a reality. southern african journal of hiv medicine 2012;13(4):178-181. [http://dx.doi.org/10.7196/sajhivmed.864] 3. coutsoudis a, goga a, desmond c, barron p, black v, coovadia h. is option b+ the best choice? southern african journal of hiv medicine 2013;14(1):8-10. [http://dx.doi.org/10.7106/sajhivmed.898] 3. coutsoudis a, goga a, desmond c, barron p, black v, coovadia h. is option b+ the best choice? southern african journal of hiv medicine 2013;14(1):8-10. [http://dx.doi.org/10.7106/sajhivmed.898] 4. cornell m. gender inequality: bad for men's health. southern african journal of hiv medicine 2013;14(1):12-14. [http://dx.doi.org/10.7196/sajhivmed.894] 4. cornell m. gender inequality: bad for men's health. southern african journal of hiv medicine 2013;14(1):12-14. [http://dx.doi.org/10.7196/sajhivmed.894] 5. katusiime c, parkes-ratanshi r, kambugu a. transitioning behaviourally infected hiv-positive young people into adult care: experiences from the young person's point of view. southern african journal of hiv medicine 2012;14(1):20-23. [http://dx.doi.org/10.7196/sajhivmed.885] 5. katusiime c, parkes-ratanshi r, kambugu a. transitioning behaviourally infected hiv-positive young people into adult care: experiences from the young person's point of view. southern african journal of hiv medicine 2012;14(1):20-23. [http://dx.doi.org/10.7196/sajhivmed.885] 6. kenyon c. association of hiv prevalence and concurrency of sexual partnerships in south africa's language groups: an ecological analysis. southern african journal of hiv medicine 2013;14(1):25-28. [http://dx.doi.org/10.7196/sajhivmed.884] 6. kenyon c. association of hiv prevalence and concurrency of sexual partnerships in south africa's language groups: an ecological analysis. southern african journal of hiv medicine 2013;14(1):25-28. [http://dx.doi.org/10.7196/sajhivmed.884] 7. roussow tm, botes me, conradie f. overview of hiv-related lipodystrophy. southern african journal of hiv medicine 2013;14(1):29-33. [http://dx.doi.org/10.7196/sajhivmed.871] 7. roussow tm, botes me, conradie f. overview of hiv-related lipodystrophy. southern african journal of hiv medicine 2013;14(1):29-33. [http://dx.doi.org/10.7196/sajhivmed.871] 8. southern african hiv clinicians society. 'striving for clinical excellence': southern african hiv clinicians society conference, cape town, 25 28 november 2012 (best astracts). southern african journal of hiv medicine 2013;14(1):36-39. [http://dx.doi.org/10.7196/sajhivmed.893] 8. southern african hiv clinicians society. 'striving for clinical excellence': southern african hiv clinicians society conference, cape town, 25 28 november 2012 (best astracts). southern african journal of hiv medicine 2013;14(1):36-39. [http://dx.doi.org/10.7196/sajhivmed.893] the editorial team of southern african journal of hiv medicine recognises the value and importance of the peer reviewer in the overall publication process – not only in shaping the individual manuscript, but also in shaping the credibility and reputation of our journal. we are committed to the timely publication of all original, innovative contributions submitted for publication. as such, the identification and selection of reviewers who have expertise and interest in the topics appropriate to each manuscript are essential elements in ensuring a timely, productive peer review process. we would like to take this opportunity to thank all reviewers who participated in shaping this volume of southern african journal of hiv medicine. in an effort to facilitate the selection of appropriate peer reviewers for southern african journal of hiv medicine, we ask that you take a moment to update your electronic portfolio on http://www. sajhivmed.org.za for our files, allowing us better access to your areas of interest and expertise, in order to match reviewers with submitted manuscripts. if you would like to become a reviewer, please visit the journal website and register as a reviewer. to access your details on the website, you will need to follow these steps: 1. log into the online journal at http://www. sajhivmed.org.za 2. in your ‘user home’ [http://www.sajhivmed. org.za/index.php/ sajhivmed/user] select ‘edit my profile’ under the heading ‘my account’ and insert all relevant details, bio statement and reviewing interest. 3. it is good practice as a reviewer to update your personal details regularly to ensure contact with you throughout your professional term as reviewer to the southern african journal of hiv medicine. please do not hesitate to contact us if you require assistance in performing this task. publisher: publishing@aosis.co.za tel: +27 21 975 2602 fax: +27 21 975 4635 alex welte andre mochan andrew black antonia wadley bernadette gosnell brian g. williams candice fick carel pretorius colin menezes david spencer eitzaz sadiq evan shoul francesca conradie francois venter gary maartens gloria d. maimela jade mogambery james j.c. nuttall jeanette wessels jeremy s. nel joana woods joel dave john stover jonathan stadler kapila hari katherine gill kerry gordon kevin rebe kim roberg lauren jankelowitz lee fairlie leigh f. johnson leon levin louise gilbert lynda graetz maia lesosky mala modi mark sonderup michelle a. moorhouse michelle venter moeketsi mathe mohammed majam mohendran archary nadine harran nataly woollett nesri padayatchi nicola wattrus nicolette naidoo nithendra manickchund nobubelo ngandu nomathemba chandiwana nosisa sipambo paul a. goldberg pino mavengere pooja balani rannakoe lehloenya renee de waal robert freercks robyn eakle rubeshan perumal saiqa mullick samuel gavi sanjay bhagani shayne loubser shenaaz pahad shobna sawry siraaj adams stuart a. ali tanuja gengiah tendesayi k. chakeza tom boyles ute feucht vuyolwethu magasana open accesshttp://www.sajhivmed.org.za page iii of iii reviewer acknowledgementpage 1 of 1 we appreciate the time taken to perform your review successfully. acknowledgement to reviewers http://www.indieskriflig.org.za http://www.indieskriflig.org.za http://www.sajhivmed.org.za http://www.sajhivmed.org.za http://www.sajhivmed.org.za/index.php/sajhivmed/user http://www.sajhivmed.org.za/index.php/sajhivmed/user http://www.sajhivmed.org.za/index.php/sajhivmed/user mailto:publishing@aosis.co.za http://www.sajhivmed.org.za abstract introduction methods results discussion conclusion acknowledgements references about the author(s) bhakti hansoti department of emergency medicine, johns hopkins university, united states sarah e. hill kriegler school of arts and sciences, johns hopkins university, united states madeleine whalen department of emergency medicine, johns hopkins university, united states david stead department of internal medicine, frere hospital, south africa department of medicine, walter sisulu university, south africa andy parrish department of internal medicine, frere hospital, south africa department of medicine, walter sisulu university, south africa richard rothman department of emergency medicine, johns hopkins university, united states yu-hsiang hsieh department of emergency medicine, johns hopkins university, united states thomas c. quinn department of emergency medicine, johns hopkins university, united states division of intramural research, niaid, nih, bethesda, united states citation hansoti b, hill se, whalen m, et al. patient and provider attitudes to emergency department-based hiv counselling and testing in south africa. s afr j hiv med. 2017;18(1), a707. https://doi.org/10.4102/sajhivmed.v18i1.707 original research patient and provider attitudes to emergency department-based hiv counselling and testing in south africa bhakti hansoti, sarah e. hill, madeleine whalen, david stead, andy parrish, richard rothman, yu-hsiang hsieh, thomas c. quinn received: 08 nov. 2016; accepted: 24 mar. 2017; published: 31 may 2017 copyright: © 2017. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: the national south african hiv counselling and testing (hct) guidelines mandate that voluntary counselling and testing (vct) should be offered in all healthcare facilities. emergency departments (eds) are at the forefront of many healthcare facilities, yet vct is not routinely implemented in this setting. methods: we conducted a cross-sectional study that surveyed patients and healthcare providers at a tertiary care ed in the spring and summer of 2016 to ascertain their attitudes to vct in the ed. we also used two previously validated survey instruments to gather data on patients’ hiv knowledge and providers’ stigma against patients living with hiv, as we anticipated that these may have an impact on providers’ and patients’ attitudes to the provision of hiv testing within the ed, and may offer insights for future intervention development. results: a total of 104 patients and 26 providers were enrolled in the study. overall, patients responded more favourably to ed-based hiv testing (92.3%) compared to providers (only 40% responded favourably). when asked about potential barriers to receiving or providing hiv testing, 16.4% of patients and 24% of providers felt that the subject of hiv was too sensitive and 58.7% of patients and 80% of providers indicated that privacy and confidentiality issues would pose major barriers to implementing ed-based hiv testing. conclusion: this study shows that while ed-based hiv testing is overall highly acceptable to patients, providers seem less willing to provide this service. the survey data also suggest that future development of ed-based testing strategies should take into consideration privacy and confidentiality concerns that may arise within a busy emergency care setting. furthermore, every effort should be made to tackle hiv stigma among providers to improve overall attitudes towards hiv-positive individuals that present for care in the ed. introduction hiv infection is a worldwide public health problem that disproportionately affects vulnerable population groups and populations in low-resource settings. in sub-saharan africa, nearly one in every 20 adults is living with hiv, and over 25% of those infected remain unaware of their hiv-positive serostatus.1 this is despite ongoing efforts to bring screening to the general population.1 to address the testing gap, and in accordance with recommendations from the world health organization (who), the south african department of health and the united states centers for disease control and prevention (cdc), public health leaders in south africa have begun to recognise the importance of transitioning hiv testing and linkage to care from traditional outpatient settings, to other components of the healthcare system including high-impact, population rich sectors such as the nation’s emergency departments (eds).2 in 2010, the south african department of health released explicit requirements that provider-initiated counselling and testing (pict) be offered in all healthcare facilities, including emergency care. the relative lack of trained hiv counsellors, coupled with already overburdened clinical resources in settings such as eds, has significantly impeded uptake, such that testing services currently remain focused in community-based clinics, mobile clinics and antenatal centers.3 significant challenges thus remain, to addressing the joint united nations program on hiv/aids (unaids) target, namely that 90% of hiv-positive individuals be diagnosed by 2020. for example, a 2015 south african study found that rates of hiv testing remain exceedingly low among men and older adults.4 in many countries, eds are considered the safety net of the healthcare system since they are required to provide care to all patients with acute and life threatening injury and illness. in south africa, emergency care is enshrined in the constitution as a basic human right2 assuring delivery of care to large volumes of patients. in high-resource settings, such as the united states, eds have proven to be pivotal both for defining the burden of hiv, and developing high yield programmatic testing and linkage to care.5,6 pilot studies from other sub-saharan countries have also identified the ed to be a high yield testing venue.7,8 in uganda, nakanjako et al.9 reported an hiv prevalence among ed patients of 30%. it was also reported that 99% of patients believed hiv testing and counselling should be a part of routine care in the hospital setting.9 based on these results, hiv testing in the ed appears to be a promising and highly acceptable testing intervention. south africa has the largest hiv epidemic in the world.10 the eastern cape region of south africa, in particular, faces a disproportionate burden of hiv infection.11 ed-based testing may be an important setting to help close testing coverage gaps, both in terms of number of patients reached as well as reaching those who may not get tested elsewhere, for example, young men who do not seek routine healthcare.12 the implementation of any new service intervention within an already complex healthcare setting requires an assessment of both acceptability and feasibility. this study forms part of a larger research strategy that focuses on the development of an ed-based hiv testing and linkage to care for the south african emergency care setting. the first component of this evaluation was to gauge local acceptability of ed-based hiv testing to inform intervention implementation. future studies will conduct exploratory evaluations to identify implementation gaps and assess intervention feasibility. in this study, we assessed patient and provider attitudes towards ed-based hiv testing. we also surveyed patients’ knowledge of hiv and providers’ stigma against patients living with hiv, as we hypothesised that these factors may influence patient and healthcare provider attitudes to provision of hiv testing within the ed. methods study design we designed a cross-sectional, observational study that surveyed patients and healthcare providers at a tertiary care ed in the spring and summer of 2016. study setting the study was conducted in the ed of frere hospital located in east london, south africa. frere hospital is a provincial, government funded hospital located in the eastern cape in south africa. the frere hospital ed has 24 hour emergency care coverage, and provides access to all public sector patients in the east london region that present with medical or surgical emergencies. the frere hospital ed sees approximately 120–150 patients per day, at any time there are two physicians, six nurses and six nursing assistants to care for patients in the ed. the average nurse to patient ratio can be as high as 1–10 in certain parts of the ed. enrolment and eligibility a convenience sample of patients and providers was recruited for voluntary and anonymous participation using a verbal consent script. only patients who were over the age of 18 years and spoke english were approached for enrolment. recruitment took place in the waiting room while patients waited for a provider after triage was completed so as not interfere with patient care. an announcement was made to the entire clinical staff team every morning during their routine hand-off session. providers who wished to participate were asked to liaise with a member of the research team during their break period. data collection instruments and strategy following informed consent, patients were asked to complete the patient attitudes to hiv testing (43 questions) and patient knowledge of hiv questionnaires (11 questions), as well as basic demographic details. providers were requested to complete the healthcare provider hiv/aids stigma scale (hpass) questionnaire (30 questions) and a staff attitudes to hiv testing in the ed survey (10 questions) as well as provide demographic details. the hpass questionnaire and the patient knowledge questionnaire have been previously validated.13,14 given the lack of a previously validated survey instrument, the ed attitudes to hiv testing surveys were created by the study team using currently available peer-review published instruments.15,16,17,18,19,20 the study team collected the data using an electronic handheld mobile tablet. each survey contained a brief introduction and a consent script. completion of the survey served as the official record that verbal consent to participate in the study had been obtained. patients and providers were asked each question and then allowed to read it before providing an answer. interviews took place in a private setting to ensure confidentiality for survey administration, and no patient or provider-identifying information was collected. outcome measures and data analysis the primary outcome measure was patient and staff acceptability of an ed-based hiv testing strategy. the secondary outcome measures were patient knowledge of hiv infection and staff stigma towards providing care for patients living with hiv. simple descriptive statistics were derived with microsoft excel (microsoft, redmond, wa) and stata© (stata corporation, college station, tx). data analysis was conducted using cross tabulation. the likert scale responses were collected as ‘strongly agree’, ‘agree’, ‘neither agree nor disagree’, ‘disagree’ and ‘strongly disagree’. a p-value less than 0.05 was considered statistically significant. results demographics a total of 104 patients and 26 providers were enrolled in the study (table 1). basic demographic information from both groups are summarised in table 1. the majority of patients were over the age of 30 years, unemployed, single and had received less than a high school diploma. of the providers who were interviewed, 64% were nurses and 32% were doctors and the remaining 4% identified as ‘other’ (which included hospital administrators, nursing students and clerical staff). the majority of those interviewed were women, had been in practice for over 5 years (88%) and worked in frere hospital for 5–9 years (56%). table 1: distribution of demographic characteristics of patients and providers in frere hospital, east london, south africa. overall, patients responded favourably to ed-based hiv testing (92.3%). however, this attitude was not mirrored by staff with only 40% agreeing with the statement ‘the emergency department should offer hiv testing’. both patients and providers agreed that if testing was implemented, an hiv counsellor would be an acceptable person to deliver the results of an hiv test to a patient. when asked about potential barriers to hiv testing, 16.4% of patients and 24% of providers felt that the subject of hiv was too sensitive and 58.7% of patients and 80% of providers agreed that privacy and confidentiality issues were major barriers to implementing ed-based hiv testing (table 2). table 2: patient and provider response to key questions regarding emergency department-based testing strategy. the majority of patients agreed that the ed should offer hiv testing, and 78.2% agreed that if offered hiv testing, they would prefer to be tested that day (figure 1). patients strongly agreed that hiv testing should be free. almost half of patients (48%) assumed that the hospital already tests every patient for hiv without telling them. patients’ response to the survey indicated that they believed point of care hiv testing is both confidential and accurate (69.5%). fifty one per cent of patients stated that they would not want anyone to know if they decided to be tested for hiv and only half of patients reported that they would trust nurses and hiv counsellors to keep their information private and confidential (figure 1). figure 1: a graphical representation of key patient attitudes towards emergency departments-based hiv testing on a likert scale. the most commonly cited barriers to implementation of routine ed-based hiv testing included privacy and confidentiality concerns (58.7%), that they already knew their hiv status (47.1%) and that this was not the primary purpose of their ed visit (41.3%). while 66.7% of patients would recommend a friend to get an hiv test in the ed, 80.8% of patients reported that they would not be willing to pay for an hiv test. patient knowledge of hiv in general, patient knowledge of hiv varied. when answering general knowledge questions about hiv, 99% of patients answered correctly regarding condom use for preventing hiv and 98% responded correctly that hiv causes aids. patients had less information on vertical transmission (73.7% answered correctly) and asymptomatic hiv infection (73.8% answered correctly). throughout the study, relevant quotes from patients regarding perceptions of hiv testing and stigma towards hiv, were collected. the majority of statements (89%) collected centred around hiv stigma and hiv testing. box 1 provides representative examples of these statements. box 1: patient quotes collected during interviews. impact of hiv knowledge towards testing patients’ level of hiv knowledge (poor knowledge was defined as getting less than 7 out of the 10 validated knowledge questions wrong) had no impact on their attitudes towards ed-based hiv testing. the mean knowledge score was 7.6 of 9 correct (range: 5–9), or 84% (sd: 15%). there was no statistical difference in mean hiv knowledge score between patients who reported strongly agree or agree opinion on the statement ‘the a&e should offer hiv testing’ and patients who reported neutral or disagree opinion (7.6 vs. 7.3 or 84% vs. 81%, p = 0.503). provider attitudes to emergency department-based hiv testing overall, providers did not respond favourably to implementing an ed-based hiv testing strategy, with 80% disagreeing with the statement that the ed should offer hiv testing (figure 2). most (84%) providers agreed that hiv testing would take up too much time and interfere with their job duties. nearly three quarter (72%) of providers disagreed with the statement that they believed they would have adequate support staff for delivery of counselling and referral. only 32% of providers reported being comfortable disclosing the results of a positive hiv test to a patient; however, 56% of providers disagreed with the statement that patients would be offended or upset when offered an hiv test (figure 2). figure 2: a graphical representation of key provider attitudes towards emergency department-based hiv testing on a likert scale. staff stigma towards caring for patients with hiv in general, providers reported varying degrees of stigma. most (76%) providers agreed that most hiv-positive patients acquired the virus through ‘risky’ behaviour, and 54.2% of providers agreed that people would not have hiv if they had sex with fewer people. when it came to working with colleagues who were hiv-positive, 68% of providers reported feeling comfortable working alongside another healthcare provider who had hiv. while 41.7% of providers would avoid conducting certain procedures on hiv-positive patients, only 28% agreed that they have the right to refuse to treat hiv-positive patients if it made them feel uncomfortable. in addition, 72% of providers worry about contracting hiv from hiv-positive patients. providers had many concerns about the implementation of an ed-based hiv testing strategy. box 2 provides representative quotes collected from providers during the interview. among providers, 83% of the responses were unfavourable towards an ed-based hiv testing strategy. box 2: quotes from providers collected during interview. discussion our survey found that patients and providers vary markedly in their attitudes regarding provision of hiv testing and counselling in the ed. this is surprising given the fact that despite having the highest prevalence of hiv infection, south africa also hosts the largest number of programmes, and most advanced infrastructure of any african country to enable linkage to care and treatment for hiv-infected individuals.21 in addition, our study found that many of the traditional barriers to hiv testing (e.g. concerns regarding confidentiality, accuracy of results and stigma in society) still prevail, particularly among providers, suggesting that policymakers and public health professionals must face significant hurdles to address patient and provider attitudes and concerns prior to implementing an ed-based hiv testing strategy. stigma not only affects healthcare providers’ provision of hiv testing, but also a patient’s willingness to accept an hiv test. the impact of stigma on hiv testing acceptance is not new. in a 2003 south african study, kalichman et al. found that when compared with people who had been tested for hiv, individuals who had never been tested for hiv demonstrated greater hiv-related discrimination, ascribing greater guilt, shame and social disapproval to those living with hiv.22 in a study in botswana two years before the implementation of universal access to hiv care, the majority of patients who delayed testing did so because of fear of hiv stigma.23 notably, hiv-related stigma is not limited to developing countries.24 while efforts to reduce stigma have resulted in substantial gains,25,26 concerns regarding stigma persist worldwide and remain one of the most frequently cited barriers to hiv testing and treatment.27,28 in both developed and developing countries, research points to community-based education, as well as increased access to antiretroviral therapy (art,) in reducing hiv stigma among the general community.29,30,31 the results of this study show that significant education efforts will be required to reduce hiv stigma among both healthcare providers and patients. it has been six years since the south african national hiv counselling and testing (hct) guidelines mandated that pict should be offered to all persons attending medical services in both public and private sectors. compliance remains poor because of the significant barriers (such as lack of trained hiv counsellors, time and cost of testing).32 in addition, pict is time consuming and requires availability of trained full-time hiv counsellors to initiate testing, especially difficult in evenings and weekends, times when the majority of patients present for care in the ed.33,34 an alternative strategy may be to perform routine opt-out blood-based laboratory testing, for all patients who have blood drawn for clinical indications. the practical aspects of this concept require less ancillary staff to undertake pre-test counselling, while potentially de-stigmatising the disease by integrating it into the provision of routine care.6 a further complicating factor is that eds are the busiest and most stressful units in hospitals.6,35 in our study, 84% of providers reported that hiv testing would take up too much time and interfere with their job duties. this statement may reflect an overall trend of burnout and job dissatisfaction among emergency service providers which is attributable to a variety of systemic factors, including difficult work schedules and lack of resources.36,37 the connection between hiv stigma and job dissatisfaction has been researched in many low-middle-income countries. notably, one recent study in five african countries (lesotho, malawi, south africa, swaziland and tanzania) indicated that perceived stigma against hiv negatively correlates with job dissatisfaction among nurses caring for hiv-positive individuals.38 studies have found that hiv stigma experienced by nurses is a key contributing factor to their decision to immigrate and may contribute to health workforce shortages.39,40 this study suggests that hiv stigma is not only hindering timely hiv testing and diagnosis in the ed, but may also be a detrimental force in the maintenance of our valuable and finite emergency healthcare workers. to address hiv stigma and discrimination, it has been shown that universal testing and treatment should be integrated into the national response to hiv.25 eds in the united states have made an effort to integrate opt-out hiv testing strategies into routine care to improve hiv testing uptake and de-stigmatise the provision of hiv testing.41,42 in south africa, however, universal population-based opt-out testing will be challenging because the national standards dictate that patients must be provided with extensive testing prior to the offering of testing. although streamlined population-based opt-out testing has the potential to reduce hiv testing stigma and increase testing rates in south africa, pragmatic issues need to be addressed to capitalise on the benefits of this strategy. barriers to these efforts include existing counselling standards, staff and patient hiv stigma, and the establishment of effective and reliable linkages to care programmes.43 limitations a closed question survey instrument that has been previously used in the ed hiv literature was utilised in this study to gather information on patients and provider attitudes to hiv testing. the limitations of closed question survey are that while it enables you to get an overall gist of the current environment and is easily replicable across studies and sites, it does not allow one to explore the underlying reasoning behind the answers to survey questions. in our methodology, we did collect some free-text responses; however, an in-depth qualitative interview methodology will be necessary to explore the presented findings further. in addition, while our study demonstrated that providers in our sample had an overall negative attitude to ed-based hiv testing and there is some provider stigma against people living with hiv, we are unable to prove causation. lastly, the study addresses only one aspect of pre-implementation evaluation; we do not address structural or organisational barriers to the provision of hiv testing and linkage to care within the emergency care context. conclusion emergency department-based hiv testing is rarely implemented in south africa. in this exploratory study, we have identified that while ed-based hiv testing is highly acceptable to patients, providers seem less willing to provide this service. prior to implementing an ed-based testing strategy, it will be necessary to first address provider concerns surrounding resource utilisation, comfort and privacy for testing provision. furthermore, to our surprise, our study sample raises some concerns about provider stigma against hiv-positive patients that warrants further exploration. acknowledgements both dr b. hansoti and s.e. hill are joint first-authors on this manuscript in acknowledgement of the equal partnership in conducting this work. this research was supported by the woodrow wilson fellowship at johns hopkins university, as well as the johns hopkins hospital. the study was also supported in part by the division of intramural research, national institute of allergy and infectious diseases, nih (tcq). additionally, research reported in this publication was supported by the south african medical research council. competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions both b.h. and s.e.h. were responsible for study conception and design, data collection, analysis of data and manuscript drafting. y-h.h. contributed towards data analysis and manuscript revision. r.r. contributed to the drafting and revision of the manuscript. d.s., a.p. and m.w. contributed to the 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clinical trial. bmj. 2016;352:h6895. https://doi.org/10.1136/bmj.h6895 hardwicke r, malecha a, lewis st, grimes rm. hiv testing in emergency departments: a recommendation with missed opportunities. j assoc nurses aids care. 2008;19(3):211–218. https://doi.org/10.1016/j.jana.2008.03.005 perez f, zvandaziva c, engelsmann b, dabis f. acceptability of routine hiv testing (‘opt-out’) in antenatal services in two rural districts of zimbabwe. j acquir immune defici syndr. 2006;41(4):514–520. https://doi.org/10.1097/01.qai.0000191285.70331.a0 introduction challenges of vaccination rationale for the development of national guidelines scope of guideline influenza vaccines pneumococcal vaccines meningococcal vaccines pertussis vaccines diphtheria and tetanus vaccines hepatitis a vaccines hepatitis b vaccines human papilloma virus vaccines poliovirus vaccines live vaccines measles, mumps and rubella vaccine varicella vaccines zoster vaccine conclusion acknowledgements references about the author(s) sipho k. dlamini department of medicine, university of cape town, south africa shabir a. madhi south african medical research council, respiratory and meningeal pathogens research unit, faculty of health sciences, university of the witwatersrand, south africa department of science and national research foundation: research chair: vaccine preventable diseases, faculty of health sciences, university of the witwatersrand, south africa rudzani muloiwa department of paediatrics and child health, university of cape town, south africa anne von gottberg centre for respiratory diseases and meningitis, national institute for communicable diseases, a division of the national health laboratory services, johannesburg, south africa school of pathology, faculty of health sciences, university of the witwatersrand, johannesburg, south africa mahomed-yunus s. moosa department of infectious diseases, division of internal medicine, nelson r. mandela school of medicine, university of kwazulu-natal, south africa susan t. meiring national institute for communicable diseases, division of the national laboratory services, south africa school of public health, university of the witwatersrand, south africa charles s. wiysonge cochrane south africa, south african medical research council, division of epidemiology and biostatistics, department of global health, stellenbosch university, south africa division of epidemiology and biostatistics, school of public health and family medicine, university of cape town, south africa eric hefer private practice, johannesburg, south africa muhangwi b. mulaudzi private practice, rustenburg phomolong medical centre, south africa james nuttall department of paediatrics and child health, university of cape town, south africa michelle moorhouse wits reproductive health and hiv institute, johannesburg, south africa benjamin m. kagina school of public health and family medicine, university of cape town, south africa vaccines for africa initiative, university of cape town, south africa citation dlamini sk, madhi sa, muloiwa r, et al. guidelines for the vaccination of hiv-infected adolescents and adults in south africa. s afr j hiv med. 2018;19(1), a839. https://doi.org/10.4102/sajhivmed.v19i1.839 guidelines guidelines for the vaccination of hiv-infected adolescents and adults in south africa sipho k. dlamini, shabir a. madhi, rudzani muloiwa, anne von gottberg, mahomed-yunus s. moosa, susan t. meiring, charles s. wiysonge, eric hefer, muhangwi b. mulaudzi, james nuttall, michelle moorhouse, benjamin m. kagina received: 12 feb. 2018; accepted: 09 mar. 2018; published: 23 may 2018 copyright: © 2018. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. introduction the introduction of vaccines has been one of the most cost-effective strategies to prevent infectious diseases in humans.1 it is estimated that vaccines save 2–3 million lives globally each year (who and unicef 2005). vaccines are critical in preventing vaccine-preventable diseases (vpds), particularly among immunocompromised individuals such as those with hiv infection. hiv-infected individuals have impaired host defence (cellular and humoral immunity), and hence have a greater risk and severity of vpds than non-immunocompromised populations.2 effective antiretroviral therapy (art) has resulted in hiv infection becoming a chronic manageable illness. despite art, systemic inflammation and immune activation persist in hiv-infected individuals and are associated with adverse health outcomes.3 furthermore, immune reconstitution is incomplete following art initiation, which might include absence of underlying memory responses previously induced through natural infection or early childhood vaccination. vaccination, and possibly revaccination, could be an important complement to art in preventing further complications in this population.4 the impact of vpds in hiv-infected individuals not only relates to the acute phase mortality but also derives from the high prevalence of these diseases in the hiv population, with effects on long-term morbidity and mortality.5 vaccines enhance immunity against infections that may have been compromised following hiv infection. the benefits of vaccination in hiv-infected individuals must be weighed against its risks. however, in the absence of severe immunosuppression, the majority of routine vaccines, including live attenuated vaccines, have been found to be safe for use in hiv-infected individuals.2 at present, the evidence suggests that vaccination of hiv-infected persons with suppressed viral loads and nadir cd4+ counts greater than 200 cells/µl has little or no deleterious effect on immune and inflammatory activation.4,6 the duration of seroprotection for most vaccines has been shown to be shorter in hiv-infected patients compared to uninfected individuals.7 there are insufficient data to guide the optimal timing for revaccination or booster vaccination among hiv-infected individuals.8 there are no national guidelines for the use of vaccines for hiv-infected people in south africa. establishment of guidelines could contribute to improving vaccine uptake in this population. the national guidelines will also help healthcare workers in decision-making towards vaccinating hiv-infected individuals. the use of vaccines in the hiv-infected is generally safe and causes no harm among patients with cd4+ counts above 200 cells/µl and with very low viral load (< 50 copies/ml).9,10 even among hiv-infected individuals who are severely immunocompromised, the majority of non-live vaccines are potentially safe, although the immunogenicity and effectiveness need to be elucidated. as part of a comprehensive approach to the management of hiv-infected individuals, the southern african hiv clinicians society aims to promote the use of vaccines in this group. currently, there are no guidelines on the use of vaccines among the hiv-infected in south africa. furthermore, suboptimal knowledge among hiv-infected individuals and healthcare providers undermines the use of vaccines in a population that could otherwise benefit most from vaccination. challenges of vaccination challenges faced by the healthcare providers wanting to vaccinate hiv-infected individuals include, firstly, a lack of national guidelines and policies. secondly, vaccines are not generally available at settings where hiv-infected adults seek care. furthermore, cost of the vaccines may be a limiting factor in the health system which is already burdened by various other costs. these barriers impact negatively on the uptake of vaccines among hiv-infected adolescents and adults. rationale for the development of national guidelines the epidemiology of hiv disease has changed significantly in the last 10 years in south africa. more people with hiv are living longer as access to art increases. associated with this increase in life expectancy is an increased risk of vpds despite suppressive art. scope of guideline these national guidelines for vaccines available for hiv-infected adolescents and adults in south africa have been developed to address challenges of adolescent and adult immunisation in the setting of hiv. the guidelines specifically focus on the most common vpds in sub-saharan africa among hiv-infected adolescents and adults. the best available evidence has been used to make recommendations on the appropriate use of active and passive immunisation in hiv-infected adolescents and adults. influenza vaccines influenza is a seasonal viral disease that often leads to a high morbidity and mortality both nationally and globally. the mortality from influenza in south africa is between 6000 and 11 000 deaths every year.11 individuals who are hiv-infected have a fourto eight-fold risk of influenza and are 1.5 times more likely to die as a result of this than hiv-uninfected individuals.12,13 there are several types of licensed vaccines against seasonal influenza; only the trivalent inactivated influenza vaccine (tiv) is currently available in south africa. vaccination against influenza has been shown to be an effective preventive strategy, and many international immunisation guidelines recommend vaccination against the seasonal influenza in hiv-infected individuals. evidence suggests that hiv-infected individuals may have reduced immune responses to influenza vaccines, especially when cd4+ cell counts are below 200 cells/µl.14 despite this, influenza vaccination is effective in preventing influenza infection and reducing severity of influenza-associated illnesses among hiv-infected persons.10 inactivated influenza vaccines administered to hiv-infected individuals have been found to be safe with a vaccine efficacy of approximately 75% in south africa, despite a relatively modest immune response as measured by the haemagglutinin inhibition (hai) assay.15 similarly, despite low immunogenicity per hai assay of influenza vaccine in hiv-infected compared to hiv-uninfected pregnant women in south africa, the vaccine efficacy was 73% against influenza confirmed illness among hiv-infected women.16 these studies suggest that the conventional immune read-outs which we use for predicting vaccine efficacy for inactivated influenza vaccine, that is, hai titres ≥ 40, might not be useful and may underestimate vaccine efficacy in this population. the influenza season in south africa is variable. it can start as early as april or as late as july and lasts between 12 and 25 weeks.17 the panel recommends that the trivalentor quadrivalent-inactivated influenza vaccine be administered between march and may each year to all hiv-infected persons, irrespective of cd4+ cell count, hiv viral load or pregnancy status. pneumococcal vaccines invasive pneumococcal disease (ipd) in hiv-infected individuals is a significant cause of morbidity and mortality.18 even with improved and increased access to universal art in south africa, the relative risk of having ipd among the hiv-infected is 35–100 times more than hiv-uninfected individuals.19,20,21 available evidence from africa suggests that pneumococcal conjugate vaccines (pcv) are effective against the vaccine-type pneumococcal disease when given to hiv-infected adults.19,20 in south africa, pcv has been included in the routine childhood immunisation programme since 2009. early post-vaccine impact data from south africa showed a 40% reduction in vaccine-type ipd over non-vaccine-type ipd in hiv-infected adults, indicating that there is some indirect protection to unvaccinated adults.22 however, with such a high burden of disease in the hiv-infected population, there is a need to consider additional or complementary strategies to prevent pneumococcal disease in hiv-infected adults. an example would be a combination vaccine strategy of the 13-valent pneumococcal conjugate vaccine (pcv13) and 23-valent pneumococcal polysaccharide vaccine (ppv23). this directly increases protection to serotypes that are in ppv23 but not in pcv13. broadly, there are two types of vaccine available for use to prevent pneumococcal disease: the pneumococcal polysaccharide vaccines (ppv) and the pcv. the ppv23 is protective against all-cause pneumonia and pneumococcal disease in hiv-infected adults, although data vary as to whether the protective benefit is irrespective of cd4+ count above a particular threshold, or dependent on hiv viral load at time of vaccination.23 results from a randomised placebo-controlled trial of ppv in hiv-infected subjects conducted in uganda found an increase in all-cause pneumonia in the vaccine arm.24 as a result, some international guidelines do not recommend vaccination with ppv among hiv-infected adults with cd4+ counts less than 200 cells/µl. the immunological and clinical efficacy of ppv23 for hiv-infected adults, particularly in the absence of art, remains controversial.19 a randomised double-blind placebo-controlled trial of pcv7 in hiv-infected adults in malawi showed that the vaccine was protective against recurrent ipd.19 other studies have confirmed the safety and immunogenicity of pcv13 in hiv-infected adults.20 the use of pcv in hiv infection is supported by studies showing prevention of pneumococcal pneumonia in children and prevention of recurrent ipd in adults.25 the use of either pcvs or ppvs will be a balance between the resources available to pay for the vaccine and the evidence to support the use of either of the vaccines or even a combination. the evidence suggests that the burden of pneumococcal disease is high in hiv-infected individuals, and vaccination against pneumococcal disease is an important strategy to reduce this.26 globally, various advisory committees on vaccination differ in their recommendations for vaccination against pneumococcus.27 as an example, the united states advisory committee on immunisation practices (acip) and infectious diseases society of america (idsa) guidelines recommend pcv13 followed by ppv23 in hiv-infected adults; however, the evidence supporting this is limited.25 in contrast, the british guideline recommends vaccination with pcv13 only, irrespective of cd4+ count, viral load or art use.28 available evidence suggests that the use of ppv23 or pcv13 is safe in hiv-infected individuals on art or with a cd4+ count greater than 200 cells/µl.8,29 vaccination against pneumococcal disease should be recommended for all hiv-infected individuals regardless of cd4+ count, but ideally when hiv viral load is < 1000 copies/ml.29 this guideline supports the prime-boost immunisation approach of first vaccinating with pcv13 followed by ppv23 eight weeks later. alternatively, pcv13 can be used alone if available. for those who are to receive ppv23 as the primary vaccine, it is suggested that the ppv23 vaccine be given to those who have achieved art-driven virologic suppression, regardless of the cd4+ count. meningococcal vaccines neisseria meningitidis is endemic in south africa, presenting as meningococcal bacteraemia or meningitis. hiv infection is an important risk factor for acquiring invasive meningococcal disease (imd), with a relative risk 5–13 times greater than the general population.30,31,32,33 epidemiological data from south africa show an increased case-fatality rate of imd in hiv-infected patients (20% vs. 11% in hiv-uninfected patients) that could be explained by their increased odds of bacteraemia compared to meningitis.33 currently in south africa, meningococcal disease is a minor contributor to mortality among the hiv-infected, when compared to other infections such as tuberculosis (tb) and pneumococcal disease.34 however, the availability of effective vaccines against meningococcal disease should warrant the use of these vaccines in hiv-infected adults where needed. in 2016, the acip added hiv infection as a high-risk condition for meningococcal disease, based on the growing body of evidence supporting an increased risk of meningococcal disease in hiv-infected individuals.30,35 prospective cohort studies or case-controlled studies are needed to evaluate this association and further clarify the level of immunosuppression at which the increased risk occurs. our recommendation is that, where possible, vaccination should be considered in hiv-infected adults with a cd4+ count above 200 cells/µl. where resources are limited, routine meningococcal vaccination of hiv-infected adults should follow the indications for meningococcal vaccination for the general population. the general indications for vaccine are: functional or anatomic asplenia complement deficiency individuals at risk of exposure through travel or work settings (routine microbiology laboratories) individuals living in hostels, or university or college residences individuals at risk through an outbreak, including men who have sex with men (msm) who may be exposed to outbreak strains because of social interactions within the global msm community. two quadrivalent meningococcal vaccines covering serogroups a, c, w135 and y are currently available in south africa. one is a polysaccharide vaccine and the other is a protein-conjugated polysaccharide vaccine. because of the hypo-immunity associated with repeated doses of the plain polysaccharide vaccine, it is recommended that hiv-infected individuals receive the conjugate vaccine.36 a two-dose primary schedule (given 8–12 weeks apart) is recommended to increase the likelihood of a protective primary immune response. this should be followed by booster doses every five years. hiv-infected persons should ideally be vaccinated before their cd4+ cell percent drops to < 25%.37 pertussis vaccines there are currently two categories of pertussis vaccines, namely, acellular and whole-cell vaccines.38 acellular vaccines are developed from one or more highly purified individual pertussis antigens, and whole-cell vaccines are based on killed bordetella pertussis organisms. although infants below three months of age are at the highest risk of death from bordetella pertussis, current epidemiological evidence shows that it is an important cause of respiratory disease in both adolescents and adults.38,39,40 despite the availability of vaccines and adequate coverage of childhood vaccinations, incidence of the disease continues to increase in adolescents and adults, possibly because of waning immunity. there are very few studies of adolescent and adult pertussis in the hiv-infected population, with most of the data on pertussis coming from children.41 maternal carriage, hiv exposure of young infants, and incomplete vaccination seem to be the most important risk factors for childhood pertussis. available evidence indicates that maternal vaccination offers significant protective benefits to both mothers and infants.39 evidence shows that asymptomatic pertussis infection is more common than symptomatic infection in healthy adolescents and adults.42 more data are needed to understand the epidemiology and the burden of pertussis in countries where hiv/aids is endemic. to date, there are no studies with regard to the immunogenicity or efficacy of pertussis vaccination in hiv-infected adults. evidence from studies in children demonstrates that hiv infection lowers antibody response following vaccination, and high cd4+ counts at vaccination improve antibody response.41 with the lack of data on the burden of disease in hiv-infected adolescents and adults, the recommendation would be that only pregnant women, regardless of cd4+ counts or viral load, be vaccinated (with acellular vaccine) during each pregnancy until there is more evidence to do otherwise. this is mainly to increase their antibody levels, so as to enhance transplacental antibody transfer to their newborns, who are at high risk of pertussis illness.43 diphtheria and tetanus vaccines recommendations for the use of tetanus and diphtheria vaccines in hiv-infected adults mirror that for the general population. both vaccines are inactivated toxoid and are therefore safe for use in hiv-infected individuals. vaccine-induced immune responses following tetanus vaccination appear to be similar in both hiv-infected and hiv-uninfected individuals.44 in contrast, vaccine-induced immune responses following diphtheria vaccination are lower in the presence of hiv infection and are influenced by the cd4+ counts.7 studies show that following primary vaccination with tetanus and diphtheria vaccines among hiv-infected children, there is a quick waning of the vaccine-induced immunity.45 however, as the evidence is lacking on the optimal booster schedule for hiv-infected adults, the recommendation is administration of tetanus and diphtheria vaccines at least every 10 years until more data are available. hepatitis a vaccines hepatitis a virus (hav) is the most common cause of acute viral hepatitis, with approximately 1.4 million clinical cases annually.46 the disease burden is most likely underestimated because of a high incidence asymptomatic infection. the main route of infection is faecal-oral, and infection is driven by poor access to safe water and sanitation services. in africa, data on hav infection are limited but the continent is considered to be a highly endemic setting.47 in such settings, routine vaccination in childhood is not recommended because of immunity acquired following natural infection.47 data from south africa show that antibodies to hav in black african adults are almost 100% by the age of 20 years, whereas only 30% – 40% of white adults are positive for hav antibodies by the age of 20 years.47 men who have sex with men are at a higher risk of acquiring hav infection with reported outbreaks in some parts of the world.7,48 the burden of disease in this population group is 1.5–3 times that of the general population especially in the developed world.49 about 13 studies have reported data on hav vaccination of hiv-infected adults.46 all these studies explored the immune responses to hav vaccination and reported that the vaccine is safe and without effect on the clinical progression of hiv infection among adults on art.46 vaccination at higher cd4+ counts is associated with better vaccine-induced immune responses. however, given the heterogeneity of the methodology and study populations, these results should be interpreted with caution.46 there is no consensus on the benefits of routine vaccination of hiv-infected adults with hav vaccines. advisory groups such as acip and the who strategic advisory group of experts on immunisation (sage) recommend vaccination in the presence of other risk factors (medical, behavioural, epidemiological or occupational risk factors). high risk groups for hav infection typically include msm, injection drug users, people travelling to or working in countries with a high or intermediate endemicity of hav, people with chronic liver disease (including hepatitis b or c), bleeding diathesis, immunosuppressed individuals who have undergone transplantation and contacts of children arriving from countries with high or intermediate hav endemicity.46 we recommend that hav vaccination should be given if there are other medical, behavioural, epidemiological or occupational conditions in addition to hiv infection. the accepted schedule is two doses separated by 6–12 months.46 hepatitis b vaccines hepatitis b virus (hbv) vaccination is highly recommended for individuals with hiv infection. globally, the introduction of routine hbv vaccination has resulted in a significant decrease of hbv infection and the overall disease burden.46,50 co-infection with hbv and hiv is considered endemic in sub-saharan africa, including south africa. both viruses share the same routes of infection, and it is estimated that the prevalence of chronic hbv in hiv-infected individuals ranges from 0.4% to 23% in south africa.51 the overall global prevalence of co-infection is around 10%, but this estimate varies from region to region. the rates of hbv infection among hiv-infected individuals are estimated to be 20 times higher than among hiv-uninfected persons.46,52 in south africa, hbv vaccination has been part of the childhood immunisation programme since april 1995. although vaccination coverage against hbv in childhood is high,53 many adults born before 1995 were not vaccinated earlier in life and remain at high risk of hbv infection.54 the administration of vaccines against hbv among hiv-infected individuals has been shown to be safe in many studies.55 however, immunologic responses are diminished.46 a successful response to hbv vaccination is most frequently associated with an undetectable hiv viral load and a cd4+ count above 200 cells/µl.56 the international recommendation for administration of vaccines against hbv is a four-double-dose regimen of a recombinant hbv vaccine (40 µg) at 0, 1, 2 and 6 months.57 however, the who recommendation is a three-dose regimen of recombinant hbv vaccine (20 µg) at 0, 1 and 6 months.55 the double-dose regimen induces higher peak anti-hbs antibody titres than the standard-dose regimen, but no clear difference in the proportion of adults with protective antibodies up to five years after vaccination.8,58,59,60 the british hiv association (bhiva) and the acip both recommend serologic antibody testing one month and six to eight weeks, respectively, following administration of the last dose of the vaccine.46 the panel supports the four-double-dose regimen hbv vaccine schedule. if this is not possible, then the standard regimen should be administered. the panel does not recommend serologic antibody testing and is only advised for healthcare workers or others at high risk. human papilloma virus vaccines human papilloma virus (hpv) infection is a common infection in hiv-infected adults. the virus is more prevalent and persistent in hiv-infected adults. the persistence of certain serotypes of hpv infection is associated with squamous dysplasia and cancer.61 in 2008, it was estimated that of the 12.7 million new cancers that occurred worldwide, around 5% were attributable to hpv infection.61,62 the highest burden of hpv infection and associated diseases is carried by women.61,63 hpv vaccines are safe and immunogenic in hiv-infected adults.64 as observed with other vaccines, hpv vaccine-induced immune responses are better in hiv-infected subjects with cd4+ cell counts greater than 200 cells/µl and suppressed viral loads. there are limited data on the efficacy and durability of protection provided by hpv vaccines in hiv-infected adults, whether vaccinated before or after acquisition of hiv infection. there is also no evidence to guide booster vaccine dosing in hiv-infected individuals.61 in south africa, hpv vaccination is routinely recommended for preteen girls aged 9–13 years, regardless of hiv status. hpv vaccination is recommended for all hiv-infected adult men and women, and msm aged up to 40 years, regardless of cd4+ count, art use or viral load. in the public sector in south africa, the bivalent vaccine is currently in use. in the private sector, the quadrivalent hpv vaccine (4vhpv) is also available. the 4vhpv was originally tested and approved as a three-dose regimen, with a dosing schedule of 0, 2 and 6 months. more recently, a two-dose schedule (6 or 12 months apart) has been recommended by the world health organization for younger age groups (e.g. 9–14 years at first dose). this is because immunogenicity with two doses in preadolescent and early adolescent girls was noninferior to antibody responses in women aged 16–26 years receiving three doses.65,66 should the vaccine schedule be interrupted, it is recommended that the vaccination series be completed, rather than restarted.28 poliovirus vaccines there are very little data on wild-type poliomyelitis in hiv-infected individuals. poliomyelitis is exceedingly rare in south africa but continues to occur in a few countries in the world. the live attenuated oral polio vaccine should be avoided in immunocompromised hiv-infected individuals because of the potential risk of paralytic polio.67 hence, the inactivated vaccine is recommended. as with many other vaccines, hiv-infected adults have reduced vaccine-induced immune response to inactivated polio vaccine,44,68 which is better if the cd4+ cell count is above 200 cells/µl. we recommend that all unvaccinated hiv-infected adults be vaccinated with the inactivated polio vaccine, regardless of cd4+ count, especially if the individuals are travelling to high-risk regions (such as nigeria, pakistan and afghanistan). three doses should be administered at 0, 1–2 and 6–12 months with a further dose after 10 years if at high risk.69 live vaccines the use of live vaccines is contraindicated in hiv-infected adults, especially if the cd4+ count is below 200 cells/µl, and/or there is clinical evidence of acquired immune deficiency syndrome (aids). there is evidence that for some live vaccines, there is a potential for the proliferation of vaccine-related viruses in the host, varicella as an example.70,71 measles, mumps and rubella vaccine measles, mumps and rubella (mmr) vaccines are live and therefore contraindicated in individuals with cd4+ counts below 200 cells/µl. the acip has since 2013 made recommendation about the use of mmr vaccine in hiv-infected adults, provided the cd4+ counts are above 200 cells/µl, without laboratory evidence of immunity or past disease.72 a retrospective study from the usa assessing the mmr serostatus of hiv-infected adults reported that 15% of hiv-infected adults are seronegative. a seronegative mmr status was associated with a longer duration of hiv infection, younger age and those born after 1957. this study also reported that about 50% of hiv-infected adults seroconverted after mmr vaccination. this study found that mmr vaccination did not lead to progression of hiv disease, nor did it impact on hiv disease control.72 this study therefore demonstrated the safety and efficacy of mmr vaccination in hiv-infected adults with cd4+ counts above 200 cells/µl and undetectable viral loads. most international guidelines recommend mmr vaccination in non-immune adults infected with hiv with a cd4+ cell count above 200 cells/µl.28,72 varicella vaccines it is estimated that 4.2 million cases of severe varicella infection globally result in hospitalisation or death. varicella zoster virus (vzv) infections and related deaths are common in hiv-infected individuals. most hiv-infected adults will have evidence of prior infection or immunity. there is an effective vaccine for varicella which is in use in high-income countries. there are limited data on varicella vaccination in hiv-infected adolescents or adults, although one study has reported on the safety and modest immunogenicity of two doses of varicella vaccine in hiv-infected adults with a cd4+ count above 400 cells/µl with a suppressed viral load.73 at present in africa, there is a lack of varicella epidemiology and socio-economic data on the impact of this disease. therefore, there are no data on which to base recommendations regarding the use of this vaccine in hiv-infected adults.74 zoster vaccine reactivation of latent varicella-zoster virus infection leads to a debilitating condition: herpes zoster (hz; known as shingles). despite the increased uptake and use of art, the incidence of herpes zoster remains increased in hiv-infected adults. the increased uptake of art has also resulted in a greater proportion of hiv-infected people living beyond the age of 50 years.7,75,76 the use of varicella vaccine is recommended in varicella-susceptible adults, as long as they have a cd4+ count above 200 cells/µl; the same cd4+ threshold is used for mmr and yellow fever vaccines. no transmission of vaccine strain vzv has been documented in people with hiv infection with a cd4+ count above this threshold. the administration of live attenuated herpes zoster vaccine (lahzv) to 295 hiv-infected adults with a cd4+ count above 200 cells/µl was found to be safe and immunogenic, with no cases of vaccine strain infection.75,77 at present, there are no epidemiological data to support the use of this vaccine in africa. there is a systematic review underway to assess the morbidity and mortality of vzv infection.74 until more evidence becomes available, we do not recommend this vaccine for hiv-infected adults. conclusion the role out and increased uptake of art has led to improvements in mortality of hiv-infected individuals. a great proportion of individuals are still at risk of vaccine preventable infections. vaccines are an important tool in protecting individuals at risk of vaccine preventable infections. a suppressed viral load and a cd4+ count above 200 cells/µl improve immunogenicity to vaccines. these guidelines are primarily aimed to help clinicians who look after people living with hiv infection. for some vaccines, there may not be enough local evidence to give guidance. it is believed that by producing this guideline, the gaps in our local data will generate research to provide the necessary evidence. this guideline attempts to take into account our local epidemiological situation in formulating our guidance where possible (see table 1). table 1: vaccination guidelines for hiv-infected adolescents and adults. acknowledgements this work was supported and funded by the southern african hiv clinicians society and msd through an educational grant. the funders had no role in the development and preparation of the manuscript. dr john black, dr prashini moodley and dr karl le roux were involved in the discussions at the guideline meeting that guided the development of these guidelines. competing interests the authors declare no potential conflict of interest. authors’ contributions s.k.d. chaired the meeting for the development of guidelines for the use of vaccines for hiv-infected individuals, is the corresponding author and prepared the first draft of the manuscript. all other authors were involved in the discussions that guided the development of the manuscript, contributed to the first draft and reviewed the first draft. all authors developed the recommendations. references eaton ef, kulczycki a, saag m, mugavero m, raper jl. immunization costs and programmatic barriers at an urban hiv clinic. clin infect dis. 2015;61(11):1726–1731. https://doi.org/10.1093/cid/civ637 geretti am, doyle t. immunization for hiv-positive individuals. curr opin infect dis. 2010;23(1):32–38. https://doi.org/10.1097/qco.0b013e328334fec4 slim j, saling cf. a review of management of inflammation in the hiv population. biomed res int. 2016;2016:3420638. https://doi.org/10.1155/2016/3420638 tan dh, szadkowski l, raboud j, et al. effect of intercurrent 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zoster vaccine for hiv-infected adults. hiv med. 2016;17(4):305–310. https://doi.org/10.1111/hiv.12311 berkowitz em, moyle g, stellbrink hj, et al. safety and immunogenicity of an adjuvanted herpes zoster subunit candidate vaccine in hiv-infected adults: a phase 1/2a randomized, placebo-controlled study. j infect dis. 2015;211(8):1279–1287. benson ca, hua l, anderson jw, et al. zostavax® is generally safe and immunogenic in hiv-infected adults with cd4 counts ≥200 cells/μl virologically suppressed on art: results of a phase 2, randomized, placebo-controlled trial. the 19th conference on retroviruses and opportunistic infections (croi); 2012 mar 05–08; seattle, wa; 2012. abstract background case report ethical consideration discussion conclusion acknowledgements references about the author(s) cleophas chimbetete institute of global health, university of geneva, geneva, switzerland newlands clinic, harare, zimbabwe linda chirimuta newlands clinic, harare, zimbabwe margaret pascoe newlands clinic, harare, zimbabwe olivia keiser institute of global health, university of geneva, geneva, switzerland citation chimbetete c, chirimuta l, pascoe m, keiser o. a case report of untreatable hiv infection in harare, zimbabwe. s afr j hiv med. 2019;20(1), a885. https://doi.org/10.4102/sajhivmed.v20i1.885 case report a case report of untreatable hiv infection in harare, zimbabwe cleophas chimbetete, linda chirimuta, margaret pascoe, olivia keiser received: 16 july 2018; accepted: 28 feb. 2019; published: 27 june 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract introduction: zimbabwe, like other resource limited countries, manages hiv infection using the public health approach with standard antiretroviral therapy (art) regimens for first, second and third-line treatment. third-line art is the last available treatment option and is based on dolutegravir and darunavir use after hiv drug resistance testing. patient presentation: we report here a 17-year-old patient on dolutegravir (dtg) and darunavir based third-line antiretroviral therapy (art) previously exposed to raltegravir who develops multidrug resistance hiv to the four art classes available in zimbabwe. management and outcome: a trophism assay revealed that patient has cxcr4 trophic virus and hence will not benefit from maraviroc. patient is currently stable and receiving a holding regimen of abacavir, lamivudine and lamivudine. conclusion: this is the first documented case of multiclass resistance to the four available art classes in zimbabwe. the development and transmission of multiclass hiv drug resistance in resource limited settings has potential to undo the gains of national art programs. there is need to ensure optimum adherence to art even in the era of dtg. keyowrds: dolutegravir; resistance; untreatable hiv; zimbabwe; art programmes. background widespread availability of antiretroviral therapy (art) has transformed a positive hiv diagnosis from being a death sentence into a chronic manageable disease. to date, no cure exists for hiv, and hence patients must remain on effective art for the rest of their lives, that makes the development of drug resistance a major public health concern. sustained viral suppression is of paramount importance if drug resistance is to be prevented. strategies to ensure optimal adherence to art are, therefore, an important component of hiv care and treatment. antiretroviral therapy resistance limits further treatment options, increases treatment programme costs and drug resistance may even be transmitted to others.1 the rising prevalence of hiv drug resistance poses a great threat to the hiv response and has the potential to drive increase in mortality and hiv incidence.2 several risk factors for the development of hiv drug resistance among patients on art have been identified.3 hiv treatment in zimbabwe is based on a public health approach using standard national treatment guidelines.4 treatment guidelines have periodically changed and are guided by the world health organization (who). in 2015, zimbabwe introduced third-line art in the national programme. patients failing second-line art are referred for specialist assessment that includes viral load (vl) and genotype testing prior to recommending third-line medicines. adherence needs to be reinforced at all times.4 we report the first case of documented four-class hiv drug resistance in zimbabwe that highlights the possibility of third-line art failure and transmission of untreatable hiv in resource-limited settings. case report we report the case of an adolescent girl born in july 2000. she tested positive for hiv infection in 2009 and was enrolled into care at newlands clinic on 30 july 2009. she is the last born in a family of three children, a paternal orphan and stays with her mother. she was vertically infected, and her mother is accessing art at the same treatment centre. both her siblings are hiv negative. she commenced first-line art on 28 august 2009. table 1 summarises art regimens received over time and the reasons for regimen changes. table 1: antiretroviral therapy history by regimen. monitoring for art treatment success was done clinically and immunologically since the initiation of treatment. routine vl monitoring was added in january 2014. figure 1 highlights the patient’s cd4, vl and art regimens over time. figure 1: cd4 count, viral load and antiretroviral therapy regimens over time. hiv drug resistance testing and third-line response a genotypic resistance test was performed on 31 march 2015 after second-line art failure. results of the test were interpreted using the stanford hiv drug resistance guide. we found four major protease inhibitor (pi) resistance-associated mutations (rams), that is, m46i, i54v, l76v and v82a. the pi rams conferred high-level resistance to atazanavir (atv), lopinavir, indinavir and saquinavir. there were three nucleoside reverse transcriptase (nrti) rams, that is, m41l, m184v and t215f, and three non-nrti rams, that is, a98g, k103n and e138a. the rams conferred intermediate resistance to abacavir, zidovudine, stavudine, didanosine and rilpivirine. there was high-level resistance to emtricitabine, lamivudine, efavirenz and nevirapine. the virus had low-level resistance to tenofovir and etravirine. table 2 summarises results of the resistance tests conducted during the course of patient management. table 2: hiv drug resistance test results. she was started on third-line art in august 2015. she has had challenges with treatment adherence because of the high pill burden, and received 3tc monotherapy as a holding therapy from march 2017 (vl was 255 397 copies/ml) to january 2018. she was treated for pulmonary tuberculosis (tb) from 08 august 2017 to 23 january 2018. the tb diagnosis was made based on loss of weight and suggestive chest x-ray findings. she improved clinically on tb treatment, and after completing 6 months of therapy, she recommenced third-line therapy with ritonavir-boosted darunavir, lamivudine and dolutegravir (dtg). she came daily to the clinic for a nurse to observe her and to take third-line medicines for 16 weeks, but her vl remained very high. an integrase strand transfer inhibitor (insti) resistance test was then performed on 14 june 2018. results showed three integrase inhibitor major rams, that is, e138k, g140a and q148r. the rams conferred high-level resistance to dtg, raltegravir (ral) and elvitegravir (elv). trophism assay was performed, and results showed that unfortunately the patient is cxcr4 trophic and hence maraviroc is unlikely to work. the recently approved post-attachment inhibitor, ibalizumab, is not available in the country. she was commenced on a holding regimen of abc, 3tc and azt, and her latest vl done on 12 november 2018 was 771 334 copies/ml. her mother is virologically suppressed on a second-line art regimen of atv or ritonavir, azt and 3tc. ethical consideration analysis of routine clinical data is approved by the medical research council of zimbabwe as part of a larger study, international epidemiological databases to evaluate aids (iedea collaboration) (approval no. mrcz/a/1336). verbal assent from adolescent and written informed consent from parent were obtained. discussion to our knowledge, this is the first report of a patient with a virus that has developed multi-class drug resistance to all four standard classes of art, including instis, in zimbabwe. this patient has hiv with high-level resistance to dtg after previous exposure to ral. recently, a case of multi-drug resistant hiv, including resistance to instis, was reported from botswana5 and a similar case was reported earlier in south africa.6 multi-drug resistant hiv could have developed because of a variety of factors, including poor adherence to art and inadequate psychosocial support – issues which are frequently encountered among adolescents living with hiv.7 in this case, poor adherence was mainly because of poor family support and lack of motivation for art when the patient felt clinically well. poor adherence to previous art regimens could have led to exposure to dtg monotherapy. previous studies have shown that monotherapy with dtg has a high rate of resistance selection in the integrase gene through different pathways in case of virologic failure.8 integrase strand transfer inhibitors are one of the newest class of antiretroviral drugs to be approved for hiv treatment and act by inhibiting the essential hiv protein integrase from inserting the viral dna genome into the host cell’s chromatin. raltegravir and evg have been successful in clinical settings, but have low genetic barriers to resistance. dolutegravir is known to have a very high genetic barrier to resistance and retains activity against raland evg-resistant viruses.9,10 zimbabwe has not yet adopted the use of dtg as part of the preferred first-line art regimens. conclusion this is the first case of recorded four-class hiv drug resistance in zimbabwe. this adolescent girl cannot be effectively treated with any of the currently available art regimens in zimbabwe. prevention measures such as family planning intervention and safe sex counselling are being taken to minimise the risk of transmission of this multi-class resistant virus. this case emphasises the need for health workers to continue providing adherence counselling and support for patients who are on art. transmission of four-class-resistant hiv is a potential public health disaster. acknowledgements the authors would like to acknowledge the ruedi luethy foundation for providing all the resources required for medical management of this patient, and also acknowledge the nurses and doctors of newlands clinic who were involved in the care of this patient. competing interests the authors declare that they have no financial or personal relationship(s) that may have inappropriately influenced them in writing this article. authors’ contributions l.c. and m.p. are the physicians looking after the patient. c.c. and l.c. prepared the first draft of the case report. all authors read and approved the final manuscript. references tang mw, shafer rw. hiv-1 antiretroviral resistance: scientific principles and clinical applications. drugs. 2012;72(9):1–25. https://doi.org/10.2165/11633630-000000000-00000 hamers rl, rinke de wit tf, holmes cb. hiv drug resistance in low-income and middle-income countries. lancet hiv. 2018;5(10):e588–e596. https://doi.org/10.1016/s2352-3018(18)30173-5 wallis cl, godfrey c, fitzgibbon je, mellors jw. factors influencing the emergence of human immunodeficiency virus drug resistance in low-and middle-income countries. j inf dis. 2017;216(suppl 9):s851–s856. 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katlama c, martinez e. dolutegravir resistance mutations. curr opin infect dis. 2018;31(3):237–245. https://doi.org/10.1097/qco.0000000000000453 anstett k, brenner b, mesplede t, wainberg ma. hiv drug resistance against strand transfer integrase inhibitors. retrovirology. 2017;14(1):1–16. https://doi.org/10.1186/s12977-017-0360-7 dow de, bartlett ja. dolutegravir, the second-generation of integrase strand transfer inhibitors (instis) for the treatment of hiv. infect dis ther. 2014;3(2):83–102. https://doi.org/10.1007/s40121-014-0029-7 hiv 887 forum hiv/aids and admission to intensive care units: a comparison of india, brazil and south africa k naidoo, j a singh, u g lalloo department of family medicine, school of nursing and public health, nelson r mandela college of medicine, university of kwazulu-natal, durban k naidoo, mb chb, mmed (fam med), llm (medical law) centre for the aids programme of research in south africa (caprisa), doris duke medical research institute, nelson r mandela college of medicine, university of kwazulu-natal, durban j a singh, llm, phd department of pulmonology and critical care, school of clinical medicine, nelson r mandela college of medicine, university of kwazulu-natal, durban u g lalloo, mb chb, md corresponding author: u g lalloo (umeshlalloo@gmail.com) in resource-constrained settings and in the context of hiv-infected patients requiring intensive care, value-laden decisions by critical care specialists are often made in the absence of explicit policies and guidelines. these are often based on individual practitioners’ knowledge and experience, which may be subject to bias. we reviewed published information on legislation and practices related to intensive care unit (icu) admission in india, brazil and south africa, to assess access to critical care services in the context of hiv. each of these countries has legal instruments in place to provide their citizens with health services, but they differ in their provision of icu care for hiv-infected persons. in brazil, some icus have no admission criteria, and this decision vests solely on the ‘availability, and the knowledge and the experience’ of the most experienced icu specialist at the institution. india has few regulatory mechanisms to ensure icu care for critically ill patients including hiv-infected persons. sa has made concerted efforts towards non-discriminatory criteria for icu admissions and, despite the shortage of icu beds, hiv-infected patients have relatively greater access to this level of care than in other developing countries in africa, such as botswana. policymakers and clinicians should devise explicit policy frameworks to govern icu admissions in the context of hiv status. s afr j hiv med 2013;14(1):15-16. doi:10.7196/sajhivmed.887 people living with hiv/aids (plwha) often become ill due to opportunistic infections such as pneumocystis jeroveci pneumonia, necessitating hospitalisation and admission to intensive care units (icus). resources allocated to specialised care in developing countries seldom match their demand, resulting in decisions having to be made about who benefits from treatment and who does not.1 in resource-constrained countries, these value-laden decisions by critical care specialists are often made in the absence of explicit policies and guidelines, and are based on individual knowledge and experience, which may be subject to bias. in south africa the general criteria for icu admission in the public sector include whether the patient is ‘too well or too ill’, and whether there is a realistic prospect of ‘reversibility of organ dysfunction’. this policy is equally applicable to plwha who require icu admission. we reviewed published information on legislation and practices related to icu admission in india, brazil and south africa, to assess access to critical care services in the context of hiv status. according to the 2012 unaids global aids report, the brics countries – brazil, russia, india, china and south africa – increased domestic public spending on hiv by more than 120% between 2006 and 2011. these countries currently fund, on average, more than 75% of their domestic aids responses and have dealt with the hiv pandemic with varying levels of success.2 the three countries reviewed face similar problems regarding resource constraints and the numbers of available icu beds (table 1). india is notable in that icu care in the country is very limited, inaccessible and unaffordable to many citizens.3 table 1. population to icu bed ratio according to country brazil india usa south africa 2012 population 199 million 1.2 billion 313 million 49 million number of icu beds, n 25 367 70 000 94 000 5 500 population : icu bed ratio ~ 1:8 000 ~ 1:14 000 ~ 1:4 000 ~ 1:10 000 the constitutional right to intensive care for plwha the constitutions of brazil, india and south africa enshrine a patient’s right to healthcare and their right not to be refused access to emergency treatment. legal precedents to this effect exist in india and south africa, where this constitutional right has withstood legal review (table 2). these case precedents apply equally to plwha and access to intensive care. table 2. the right to healthcare and access to emergency care: case precedents country case india p rathnam v. union of india 1994 (3); supreme court cases 394 430 gian kaur v. state of punjab 1996 supreme court; 83: 12578 12564 paschim baga khet mansoor samiti v. state of west bengal; air 1996 sc 2426 south africa government of the republic of south africa (rsa) and others v. grootboom and others (judgment: 4 october 2000) minister of health and others v. treatment action campaign (tac) and others (judgment: 5 july 2002) soobramoney v. minister of health (kwazulu-natal) 116 case cct 32/97 (judgement: 27 november 1997) professional ethical guidelines for icu admission the medical associations of india, brazil and south africa subscribe to the international guidelines of the world medical association’s declaration of geneva, which provide a framework for the appropriate conduct of the medical profession globally.4 each country has a professional association that guides and regulates ethical conduct, particularly with regard to plwha. these guidelines protect plwha against stigmatisation and discrimination by health professionals, particularly with regard to access to healthcare, treatment and support programmes. similarly, the siracusa principles5 spell out five criteria concerning human rights and restrictions to public health based on resource limitations. the burden of proof still falls on those who want to restrict rights, and concrete scientific and public health evidence is needed, specifically with response to siracusa principle 5 which states that ‘the restriction of the right of access to public health cannot be unreasonable or discriminatory in its application’.5 lessons to be learnt from brazil and india the regulatory and ethical frameworks of brazil and india provide a useful indication of the varied challenges faced by developing nations regarding plwha and their access to icu care. an important contributor to the success of brazil’s response to the hiv/ aids epidemic is its national health insurance scheme, which has strengthened its public health system, including icu bed availability. in brazil, health services are provided by private-public partnerships, funded by the government and freely accessible to the patient, and extending to specialist and icu care.6 it is therefore evident that an hiv-infected patient in brazil who requires admission to icu would have easy access to such level of care. the brazilian society of intensive care7 speaks of issues of informed consent, the need for comprehensive medical records, humanising the icus by improving communication with patients and their families, and establishing icu admission and discharge criteria in keeping with the ‘existing laws and institutional rules’. as such, failure to comply with the provisions under the resolution will be subject to ‘civil liability, and administrative and criminal sanctions’. there is no comprehensive legislation in india addressing hiv/aids and criteria for icu admission. the number of icu beds available is disproportionately low, in the private and public hospitals, and there is also considerable variation in the allocation and distribution of critical care services across the country, given that 70% of the country is rural.3 , 8 notwithstanding explicit icu admission policy at a macro level in south africa, widespread anecdotal evidence seems to suggest that hiv status may be commonly used as an icu exclusion criterion. this practice results in arbitrary decision-making and has no prognostic evidentiary basis, rendering such decision-making irrational. furthermore, it is contrary to sa’s legal and human rights policy frameworks. given the current state of affairs, policy-makers and clinicians in sa and further afield should devise explicit policy frameworks to govern icu admissions in the context of hiv status. author contributions. kn conducted the study, interpreted the data and drafted the manuscript. jas critically revised the manuscript for intellectual content. ugl conceptualised, designed and supervised the study, analysed and interpreted the data, and critically revised the manuscript for intellectual content. all authors read and approved the manuscript prior to publication. references 1. caldeira vm, silva junior jm, oliveira am, et al. criteria for patient admission to an intensive care unit and related mortality rates. rev assoc med bras 2010;56(5):528-534. 1. caldeira vm, silva junior jm, oliveira am, et al. criteria for patient admission to an intensive care unit and related mortality rates. rev assoc med bras 2010;56(5):528-534. 2. unaids. world aids day report 2012. http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2012/gr2012/jc2434_worldaidsday_results_en.pdf (accessed 17 january 2012). 2. unaids. world aids day report 2012. http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2012/gr2012/jc2434_worldaidsday_results_en.pdf (accessed 17 january 2012). 3. yeolekar me, mehta s. icu care in india – status and challenges. j assoc physicians india 2008;56:221-222. 3. yeolekar me, mehta s. icu care in india – status and challenges. j assoc physicians india 2008;56:221-222. 4. world medical association. wma medical ethics manual, 2005. http://www.wma.net/en/30publications/30ethicsmanual/ (accessed 12 september 2010). 4. world medical association. wma medical ethics manual, 2005. http://www.wma.net/en/30publications/30ethicsmanual/ (accessed 12 september 2010). 5. gruskin s, loff b. do human rights have a role in public health work. lancet 2002;360(9348):1880. [http://dx.doi.org/10.1016/s0140-6736(02)11780-6] 5. gruskin s, loff b. do human rights have a role in public health work. lancet 2002;360(9348):1880. [http://dx.doi.org/10.1016/s0140-6736(02)11780-6] 6. brazilian department of std, aids and viral hepatitis. datasus; sistema de monitoramento de indicadores do programa nacional de dst/aids monitoraids http://www.aids.gov.br (accessed 25 march 2012). 6. brazilian department of std, aids and viral hepatitis. datasus; sistema de monitoramento de indicadores do programa nacional de dst/aids monitoraids http://www.aids.gov.br (accessed 25 march 2012). 7. brazilian society of critical care. resolution no. rdc-7 of 24 february 2010. http://www.medicinaintensiva.com.br/resolucao-07-anvisa-uti.htm (accessed 22 march 2012). 7. brazilian society of critical care. resolution no. rdc-7 of 24 february 2010. http://www.medicinaintensiva.com.br/resolucao-07-anvisa-uti.htm (accessed 22 march 2012). 8. jayaram r, ramakrishnan n. cost of intensive care in india. indian j crit care med 2008;12(2):55-61. [http://dx.doi.org/10.4103/0972-5229.42558] 8. jayaram r, ramakrishnan n. cost of intensive care in india. indian j crit care med 2008;12(2):55-61. [http://dx.doi.org/10.4103/0972-5229.42558] abstract introduction methods results discussion conclusion acknowledgements references about the author(s) kaminie moodley department of neurology, university of kwazulu-natal, durban, south africa pierre l.a. bill department of neurology, university of kwazulu-natal, durban, south africa vinod b. patel department of neurology, university of kwazulu-natal, durban, south africa citation moodley k, bill pla, patel vb. motor lumbosacral radiculopathy in hiv-infected patients. s afr j hiv med. 2019;20(1), a992. https://doi.org/10.4102/sajhivmed.v20i1.992 original research motor lumbosacral radiculopathy in hiv-infected patients kaminie moodley, pierre l.a. bill, vinod b. patel received: 12 june 2019; accepted: 31 july 2019; published: 28 oct. 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: this study is a review of the clinical findings and treatment outcome of 11 hiv-infected patients with motor lumbosacral radiculopathy. objectives: to describe the clinical, laboratory, electrophysiological features and treatment outcome in hiv-infected motor lumbosacral radiculopathy which is a rare manifestation of hiv. method: a retrospective review of hiv-infected patients with motor lumbosacral radiculopathy was performed at inkosi albert luthuli central hospital (ialch), durban, south africa between 2010 and 2015. results: eleven black african patients met the inclusion criteria. there were six women. the median age was 29 years, the interquartile range (iqr) was 23–41 years, the median duration of symptom progression was 6.5 months (iqr 3–7.5 months). the median cd4 count was 327 cells/µl (iqr 146–457). the cerebrospinal fluid (csf) median polymorphocyte count was 0 cells/µl (iqr 0 cells/µl – 2 cells/µl), lymphocyte count was 16 cells/µl (iqr 1 cells/µl – 18 cells/µl), glucose level was 3.1 mmol/l (iqr 2.8 mmol/l – 3.4 mmol/l) and protein level was 1.02 g/dl (iqr 0.98 g/dl – 3.4 g/dl). all patients were treated with corticosteroid therapy. ninety-one per cent recovered fully within 6 months of treatment, the median time for recovery was 3.4 months (iqr 1.8–5.6 months). there were no relapses during the 18-month follow-up. conclusion: hiv-infected patients with motor lumbosacral radiculopathy responded to corticosteroids, with no relapses during the 18-month follow-up period. keywords: hiv; lumbosacral radiculopathy; art; corticosteroids; treatment outcome. introduction progressive lumbosacral polyradiculopathy is a well-described complication of late hiv infection and is usually caused by opportunistic infections such as cytomegalovirus (cmv), herpes simplex virus (hsv), varicella zoster virus (vzv), ebstein-barr virus (ebv), syphilis, tuberculosis (tb), cryptococcus and, less commonly, lymphoma, paraneoplastic polyradiculopathy, chronic inflammatory demyelinating polyradiculopathy (cidp), or diffuse infiltrative lymphocytosis (dils).1,2,3 infective aetiologies, lymphoma and paraneoplastic polyradiculopathy are usually subacute and are progressive unless treated.1,3,4,5,6,7 in 2000, benatar et al. described four hiv-infected patients who presented with acute or subacute weakness with spontaneous recovery.8 infective and inflammatory aetiologies were excluded. this entity was described as a ‘unique’ clinical entity in the setting of hiv or a ‘variant of guillain–barre syndrome (gbs)’.8 since 2000, there were no further documented cases in the literature. between 2010 and 2015, we retrospectively identified a similar cohort of 11 hiv-infected patients who presented with a motor lumbosacral radiculopathy. in this article, we add to the current literature regarding this unusual group of patients by describing the clinical presentation, demographic features, electrodiagnostic, radiological, cerebrospinal fluid (csf) findings and response to therapy. methods patients were identified between 2010 and 2015 in the department of neurology at inkosi albert luthuli central hospital, which is a 1000-bed tertiary hospital in durban, kwazulu-natal province, south africa. the department of neurology attends approximately 8000 patients per year. the inclusion criteria for patient selection were as follows: hiv-infected patients older than 18 years with lower motor neuron weakness involving exclusively the lower limbs, normal sensation, preserved sensory nerve action potentials (snaps) and lumbosacral root enhancement on magnetic resonance imaging (mri). exclusion criteria were as follows: abnormal sensation on clinical examination, upper limb or truncal involvement, upper motor neuron signs, sensory nerve action potential on nerve conduction studies that were less than 70% of normal values, compressive or intra-spinal lesions accounting for the weakness, polyradiculopathies due to infective, malignant or paraneoplastic aetiology, clinical features of dils or raised creatinine kinase levels with electrophysiological or histological features of a myopathy, and electrolyte abnormalities, for example hypokalaemia accounting for weakness and areflexia. data extracted from patient records included clinical findings, laboratory results, electrodiagnostic findings (nerve conduction and needle electromyography), mri of the thoracolumbar and lumbosacral spine, duration of therapy and response to therapy. tests that were conducted to exclude infective or neoplastic causes of a polyradiculopathy included csf polymerase chain reaction (pcr) for vzv, cmv, hsv, ebv; csf ziehl–neelson (zn) stain, culture and gene expert for tb; csf venereal disease research laboratory (vdrl), fluorescent treponemal antibody absorption (fta-abs) for syphilis; csf cytology for malignancy (lymphoma); csf cryptoccocal antigen, india ink stain and cryptococcal culture; chest radiograph for pulmonary tuberculosis (tb), csf cytology, paraneoplastic antibodies and mri spine for structural and inflammatory and/or infective lesions. patients were followed up and scored according to the modified rankin scale (mrs) to assess for relapses and response to therapy at 3-month intervals for 6 months and thereafter 6 monthly up to 18 months. ethical considerations this article followed all ethical standards for research without direct contact with human or animal subjects. results clinical features, cerebrospinal fluid, electrophysiological and magnetic resonance imaging findings eleven patients met the inclusion criteria. there were six women. the median age was 29 years (interquartile range [iqr] 23–41 years). all patients were of black african ancestry. the mean duration of symptom progression (continuous and not stepwise) was 6.5 months (iqr 3–7.5 months). no patients had preceding flu-like illness, sensory complaints or upper limb symptoms. examination revealed that they had flaccid, symmetrical areflexic paraparesis with normal assessment of mental state, cranial nerves and upper limbs. sensory testing for all modalities was normal and sphincters were normal. cd4 counts are listed in table 1 (median cd4 count of 327 cells/µl, iqr 146–457). none of the patients were on antiretroviral therapy (art) at the time of diagnosis. however, all patients were referred to art clinics for monitoring or initiation of arts according to the south african art guidelines applicable during the study period. blood investigations, which included routine tests such as full blood count, urea and electrolytes, autoimmune screen (anti-nuclear factor, anti-neutrophil cytoplasmic antibodies), paraneoplastic antibodies, creatinine kinase, rapid plasma reagin test, vitamin b12 and folate, glucose and serum protein electrophoresis, did not reveal any abnormalities. table 1: demographic, laboratory, and radiological features of motor lumbosacral radiculopathy. the csf median polymorphocyte count and lymphocyte count were 0 cells/µl (iqr 0–2) and 16 cells/µl (iqr 1 cells/µl – 18 cells/µl), respectively. the csf median glucose and protein was 3.1 mmol/l (iqr 2.8 mmol/l – 3.4 mmol/l) and 1.02 g/dl (iqr 0.98 g/dl – 3.4 g/dl), respectively (table 1). the csf tested negative for viruses (cmv, hsv, htlv1, ebv and vzv), tb, syphilis and cryptococcus. csf cytology was negative. five patients had negative antiganglioside antibodies, which were not tested for in the other six patients. motor and sensory electrophysiological tests are listed in tables 2 and 3, respectively. normal values for ialch electrophysiology laboratory are listed in table 4. the compound muscle action potential (cmap) of the tibial and peroneal nerves were reduced in amplitude, with median cmap of 3.6 mv (iqr 2.2–4.2) and 3.5 mv (iqr 2.6–4.2), respectively. the distal motor latency (dml) and conduction velocity (cv) were within the normal range for both the tibial and peroneal nerves. the f responses were either absent or prolonged, with median 62 ms (iqr 59–70.5) and 68 ms (iqr 64–70) for the peroneal and tibial nerves, respectively, compared to the respective f estimates of 53 ms (iqr 50–55) and 54 ms (iqr 52–55). there were no conduction blocks or temporal dispersion. the sural and superficial peroneal snaps were present in all patients, although amplitudes were marginally reduced, most likely because of coexistent hiv peripheral neuropathy. the median sural and superficial peroneal snap was 12.5 µv (iqr 10–13) and 6.5 µv (iqr 5.7–7.1), respectively, which is greater than 80% the expected lower limit of normal (table 4). the peak sensory latencies for both nerves were normal: median 4.1 ms (iqr 3.9–4.2) and 3.1 ms (iqr 2.27–3.3) for the sural and superficial peroneal, respectively. the upper limb motor and sensory nerve conduction tests were performed in 7 of the 11 patients (63%) and were normal (tables 2 and 3). table 2: electrophysiological findings of patients with motor lumbosacral radiculopathy in hiv-infected patients: motor studies. table 3: electrophysiological findings in patients with motor lumbosacral radiculopathy in hiv-infected patients: sensory studies. table 4: normal values for inkosi albert luthuli central hospital electrophysiology laboratory. needle electromyography (emg) findings are listed in table 5. muscles examined included the lumbar paraspinals (lower and mid lumbar), gluteus medius, quadriceps, tibialis anterior and gastrocnemius. these muscles demonstrated neurogenic changes as evidenced by increased insertional activity, positive sharp waves, fibrillation potentials, and reduced or single unit recruitment of polyphasic motor unit potentials with greater involvement of proximal rather than distal muscles. table 5: needle examination. all 11 patients had mri with gadolinium, of the thoracolumbar and lumbosacral spine. imaging revealed root enhancement of the lumbosacral ventral roots in all patients (figure 1). there were no identifiable structural abnormalities and no thoracic root enhancement. figure 1: (a) post-gadolinium sagittal and (b) axial lumbosacral spine images showing ventral root enhancement (arrows). all patients were treated with corticosteroids (prednisone) at an initial dose of 1.5 mg/kg/day at diagnosis for 4–6 weeks or longer if needed. thereafter corticosteroid therapy was tapered and stopped based on side effects or response to therapy. this was done at the discretion of the attending neurologist. sixty-four per cent (7/11) of patients showed a clinical response within the first 4 weeks of treatment and recovered fully by 3 months. in this category, corticosteroids were given at full dose for 4 weeks, then tapered over the subsequent 6–8 weeks and stopped by 3 months. thirty-six per cent (4/11) of patients received initial full-dose corticosteroids for longer periods of 4–6 weeks as they had taken longer to respond, and then corticosteroids were tapered over the subsequent 18 weeks. eighteen per cent (2/11) of patients recovered fully by 4 months and the other 18% (2/11) by 5 months. in this category of ‘slower responders’, corticosteroid therapy was stopped by 6 months. all patients had no residual clinical deficit except patient 11, who despite demonstrating a good response to corticosteroid therapy by 4 months had minimal residual deficit at 18 months follow-up with a mrs of 1. the median time for recovery in all categories was 3.4 months (iqr 1.8–5.6). there were no relapses during the 18-month follow-up. within the period of corticosteroid therapy, there were no documented side effects and no patients required corticosteroid sparing immunosuppressive agents or long-term corticosteroids therapy. six patients had cd4 counts < 350 cells/µl and qualified for art according to art guidelines at that time. hiv titres were not documented. three patients were commenced on art at 4 months after the diagnosis. these three patients had recovered prior to art commencement. the other three patients were commenced on art 6 months after presentation. at 18 months follow-up, seven patients were on art. discussion the 11 patients presented in this article represent an unusual cohort of hiv-infected patients with a subacute motor lumbosacral radiculopathy. sensory, sphincter function and upper limbs were normal in all patients. the mri showed gadolinium enhancement confined to the lumbar ventral roots. in other infective or inflammatory aetiologies, such as syphilis, tb, viral infections or lymphoma, both dorsal and ventral roots are involved, enhancement may be nodular and patchy with coexistent myelitis, intramedullary granulomas, subdural collections or discitis especially in infective aetiologies.9,10,11 the clinical scenario of symmetrical ascending weakness, areflexia and high csf protein is suggestive of gbs.12,13 more recently, the boundaries of gbs have expanded and variations include a paraparetic gbs where the upper limbs and cranial nerves are spared.14 a further variant is associated with hiv seroconversion.15,16 these patients typically have a csf pleocytosis as seen in our cohort, which may reflect hiv viral replication in the csf space rather than immunological changes that occur with the subacute motor lumbosacral radiculopathy.17,18 the axonal variant of gbs, associated with a high rate of preceding campylobacter jejuni infection, may present as a pure motor axonopathy.19 our patients may meet some of the criteria for a ‘variant gbs’.19 benatar et al. described four patients with similar clinical findings. they described these patients as a possible variant of gbs or a distinct clinical entity.8 however, the unusual features include duration of progression, limitation of signs to the lower limbs, csf pleocytosis and response to corticosteroid therapy, which is known not to be of benefit in gbs.20,21 the above cohort may therefore be consistent with a proximal motor variant of cidp involving demyelination of the ventral roots rather than gbs. evidence for the above includes prolonged or absent f responses with normal dmls, neurogenic changes in the paraspinals, ventral root gadolinium enhancement on mri, raised csf protein and rapid response to corticosteroid therapy with no relapses. denervation on needle emg may suggest secondary axonal loss. moodley et al. described cidp in the setting of hiv. in that particular cohort of patients, demyelination was distal rather than proximal, patients had sensory and motor symptoms rather than exclusively motor manifestations, and both upper and lower limbs were involved.22,23 the rapid response to corticosteroid therapy and the predilection for ventral roots may suggest an antibody-mediated process that targets the ventral roots only. the production of these antibodies may be a transient phenomenon during the course of hiv infection as none of the patients relapsed during the 18-month follow-up despite stopping corticosteroid therapy for 6 months or less. we hypothesise that immune reconstitution with art may have prevented relapses by induction of tolerance, by increasing the number of functional t regulatory cells and hence maintaining remission. some diseases associated with hiv may recover with immune reconstitution, for example hiv-associated cidp, hiv-associated motor neuron syndrome or even myasthenia gravis, despite there being insufficient literature to support the above.22,24 therefore, variable or unexpected patterns can occur in hiv immune reconstitution, with exacerbation of some diseases and improvement of others. the wide range of cd4 counts may also support an immune-mediated process, which is independent of the stage of hiv. the high cd4 counts in some patients were not explained by concomitant dils as the patients had no clinical features of dils.1,25 seven of the 11 patients were on arts at 18-month follow-up. however, only three patients started art at 4 months after presentation. these three patients had recovered prior to commencing art on corticosteroid therapy alone. by 6 months all patients had recovered. hence, the recovery was likely induced by corticosteroid therapy as no patients showed spontaneous recovery before corticosteroid therapy. however, it is likely that art-induced immune reconstitution may have prevented relapses as all patients on art at 18 months follow-up had cd4 counts above 350 cells/µl. since the south african government’s rollout programme in 2017 which commenced all hiv-infected patients on art at the time of diagnosis irrespective of cd4 counts, we rarely encounter the above group of patients. this further supports an immune basis for the disease which may improve with changes in tolerance. limitations of this study include retrospective design, small patient numbers and lack of a control arm. conclusion studies are required to understand the pathogenesis of this disease in order to identify the possible antigenic targets. this may help refine therapy in hiv-uninfected patients with pure immune-mediated motor polyradiculopathy, for example paraneoplastic and other immune ventral root radiculopathies.5,6,7,26,27,28 acknowledgements competing interests the authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article. authors’ contributions k.m. developed the study concept, collected and analysed the data, and wrote the manuscript. v.b.p.m. developed the concepts and helped with planning analysis and review of the manuscript. p.l.a.b. was responsible for the review of the manuscript. funding this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the 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guillain-barre syndrome. cochrane database syst rev. 2016;10:cd001446. https://doi.org/10.1002/14651858.cd001446.pub5 wang yz, lv h, shi qg, et al. action mechanism of corticosteroids to aggravate guillain-barre syndrome. sci rep. 2015;5:13931. https://doi.org/10.1038/srep13931 moodley k, bill pl, patel vb. a comparative study of cidp in a cohort of hiv-infected and hiv-uninfected patients. neurol neuroimmunol neuroinflamm. 2017;4:e315. https://doi.org/10.1212/nxi.0000000000000315 mochan a, anderson d, modi g. cidp in a hiv endemic population: a prospective case series from johannesburg, south africa. j neurol sci. 2016;363:39–42. https://doi.org/10.1016/j.jns.2015.11.013 moodley k, bill pla, bhigjee ai, patel vb. a comparative study of motor neuron disease in hiv-infected and hiv-uninfected patients. j neurol sci. 2019;397:96–102. https://doi.org/10.1016/j.jns.2018.12.030 harrison tb, smith b. neuromuscular manifestations of hiv/aids. j clin neuromuscul dis 2011;13:68–84. https://doi.org/10.1097/cnd.0b013e318221256f anderson sc, baquis gd, jackson a, monteleone p, kirkwood jr. ventral polyradiculopathy with pediatric acute lymphocytic leukemia. muscle nerve. 2002;25:106–110. https://doi.org/10.1002/mus.1219 stefurak tl, midroni g, bilbao jm. vasculitic polyradiculopathy in systemic lupus erythematosus. j neurol neurosurg psychiatry. 1999;66:658–661. https://doi.org/10.1136/jnnp.66.5.658 ahn s-w, yoon b-n. motor dominant polyradiculopathy with primary sjögren’s syndrome mimicking motor neuron disease. ann clin neurophysiol. 2019;21:61–65. https://doi.org/10.14253/acn.2019.21.1.61 abstract introduction key opportunities for ward-based outreach teams in south africa’s human immunodeficiency virus programme barriers and challenges to successful ward-based outreach team support perspective conclusion acknowledgements references about the author(s) nireshni naidoo anova health institute, johannesburg & tzaneen, south africaschool of public health, university of the witwatersrand, south africa jean railton anova health institute, johannesburg & tzaneen, south africa geoffrey jobson anova health institute, johannesburg & tzaneen, south africa nthabiseng matlakala anova health institute, johannesburg & tzaneen, south africa gert marincowitz mopani dcst, department of health, limpopo province, south africa james a. mcintyre anova health institute, johannesburg & tzaneen, south africa school of public health & family medicine, university of cape town, south africa helen e. struthers anova health institute, johannesburg & tzaneen, south africadivision of infectious diseases & hiv medicine, department of medicine, university of cape town, south africa remco p.h. peters anova health institute, johannesburg & tzaneen, south africa citation naidoo n, railton j, jobson g, et al. making ward-based outreach teams an effective component of human immunodeficiency virus programmes in south africa. s afr j hiv med. 2018;19(1), a778. https://doi.org/10.4102/sajhivmed.v19i1.778 forum making ward-based outreach teams an effective component of human immunodeficiency virus programmes in south africa nireshni naidoo, jean railton, geoffrey jobson, nthabiseng matlakala, gert marincowitz, james a. mcintyre, helen e. struthers, remco p.h. peters received: 28 june 2017; accepted: 12 feb. 2018; published: 12 apr. 2018 copyright: © 2018. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract the implementation of ward-based outreach teams (wbots), comprised of community health workers (chws), is one of the three interventions of the south african national department of health’s (ndoh) primary health care (phc) re-engineering strategy for improving health outcomes. chws provide a necessary structure to contribute to successful implementation of the human immunodeficiency virus (hiv) programme in four ways: (1) prevention of hiv infection by health education, (2) linkage to care by health education and referrals, (3) adherence support and (4) identification of individuals who are failing treatment. however, chw programme and hiv programme-specific barriers exist that need to be resolved in order to achieve maximum impact. these include a lack of stakeholder and community support for wbots, challenging work and operational environments, a lack of in-depth knowledge and skills, and socio-cultural barriers such as hiv-related stigma. considering its promising structure, documentation of the wbot contribution to healthcare overall, and the hiv programme in particular, is urgently warranted to successfully and sustainably incorporate it into the south african healthcare system. introduction ward-based outreach teams (wbots) are becoming an increasingly important part of primary healthcare (phc) in resource-constrained rural settings across the globe.1 in addition to district clinical specialist teams and integrated school health services, wbots are one of the three components of the phc re-engineering programme introduced in south africa in 2012 to improve communities’ access to health services and the quality of care provided.2 in south africa, each wbot is linked to a phc facility and consists of a team leader, usually a professional nurse, plus five or more community health workers (chws). each chw is allocated 250–400 households to support.3 several approaches have been initiated to improve outcomes of the hiv programme in south africa, including human immunodeficiency virus (hiv) counselling and testing and adherence clubs.4 specifically, these approaches have been either community-based or facility-based. wbots provide a means of bridging the gap between health facilities and the communities they serve, a role which may be especially valuable in rural areas where communities are impoverished and under-served, and where individuals have to travel excessive distances to seek medical care.1 chw’s primary activities include registration of household’s health needs, provision of health education and the provision of adherence support for individuals on antiretroviral therapy (art) or with other chronic illnesses. in this article, we identify and discuss key opportunities for effectively integrating wbots in the hiv response in south africa, while noting various challenges that need to be addressed in order to maximise impact. key opportunities for ward-based outreach teams in south africa’s human immunodeficiency virus programme the wbots are well positioned at the interface of the community and facility to contribute to the hiv programme in the following ways (table 1): provision of information to educate individuals on how to prevent transmission of hiv infection identification of individuals at risk for hiv infection who should be tested for hiv provision of adherence support and tracing of individuals with missed appointments to improve retention in care early identification of individuals with deteriorating health while on art to reduce further morbidity and mortality. table 1: summary of potential contributions of wbots to the hiv programme prevention of human immunodeficiency virus infection and its complications there is evidence showing the effectiveness of using chws in large-scale health promotion and disease prevention programmes in low-income countries such as haiti, ethiopia, uganda and malawi.5,6 this preventative aspect of chws’ work could also play a critical role in south africa’s hiv programme. chws could support the programme specifically not only by providing health education on how to prevent hiv infection but also by distributing condoms and potentially assisting in the identification of individuals that may benefit from pre-exposure prophylaxis (prep).7,8,9,10 chws, through adherence support, could contribute to lowering community viral load (vl) and thereby reducing transmission in the community.11,12 however, it has not yet been documented how well the above roles are performed and whether chws’ efforts positively impact on the reduction of hiv incidence. to our knowledge, there are so far no south african studies undertaken that assess the impact of preventative aspect of chws’ work. identification of human immunodeficiency virus-infected individuals chw’s link between communities and facilities makes them well placed to support and appropriately refer vulnerable individuals to health facilities. amongst those classified as vulnerable by the national department of health (ndoh) are individuals at risk for hiv infection and those already infected.3 as such, discussion of hiv status and hiv risk with individuals, their partners and children is an important component of chw activity. south africa is one of the first countries to formally adopt the universal test and treat approach recommended in the updated world health organization (who) guidelines on hiv treatment. the guidelines state that all hiv-infected individuals should start art within two weeks of an initial cd4 count being performed.13 there are limited data about the feasibility of hiv case identification by chws in south africa, but a study by uys, conducted at seven sites in south africa, shows that community caregivers who provide psychosocial and household support may have a positive impact on hiv case identification through mobilisation and referral of individuals to hiv services for testing.14 chws, on the contrary, focus on providing medical aspects of care. although this study was conducted in the setting of a home-based aids care model, and community caregivers are not the same as chws, the results are encouraging and support the involvement of a structure such as wbot that bridges the gap between the community and the healthcare facility by complementing services provided by community caregivers.15 chws could also make an important contribution to the hiv response by supporting home-based hiv testing. this approach to hiv testing and counselling was used in a cluster randomised controlled trial in kwazulu-natal province, south africa, which found significantly higher rates of hiv testing amongst participants in the home-based testing arm than those testing at facilities (69% vs. 47%; 95% ci 1.32–1.81). other results included a higher uptake of couple counselling and testing as well as a reduction in multiple partners.16 in light of this, to strengthen the impact of chws in the hiv programme, home-based testing by chws should be considered. there is also potential for hiv testing during community-based campaigns17 and hiv self-testing as recommended by the who.18 tracing non-adherent individuals and provision of adherence support to improve retention in care a high level of patient retention on antiretroviral treatment is imperative for good hiv programme outcomes. chws can improve retention in care directly by tracing individuals who missed their appointments or defaulted treatment and linking them back into care at the healthcare facility. although tracing is an important part of the chw’s activities, the effectiveness of this approach remains undocumented. defaulter tracing should not become so time consuming that it prevents chws from effectively undertaking their other duties. in the south african wbot programme, we suggest that defaulter tracing should combine an initial attempt to contact non-adherent individuals telephonically, followed by physical tracing at their homes by chws if they are not reachable via telephone. this was shown to be successful in other studies19, and preliminary data from mopani district, limpopo province, are promising, suggesting that there is value in using a combination of telephone and physical tracing as a routine chw activity (r.p. peters, 2017, n.d., personal communication). another way in which chws could contribute to improving retention in care is through adherence support. grimwood et al.,20 in a multicentre cohort study, demonstrated that community-based adherence support is an effective way to improve patient retention on art. in that study, patient advocates (pas) were tasked with providing adherence support to the community. clinical, virological and immunological outcomes were compared between children who did and did not receive community-based adherence support from pas in western cape, kwazulu-natal, eastern cape and mpumalanga provinces. they showed a significant difference in patient retention after three years: 92% (95% ci: 76.7% – 97.6%) amongst children with pas and 74% (95% ci: 65.4% – 81.0%) amongst children without pa support. in addition, multivariable analyses showed that children with pas had reduced probability of hiv-related programme attrition and mortality.20 similarly, igumbor et al.12 found that a significantly higher proportion of patients (70% vs. 30%) with a community-based adherence supporter had a vl of less than 400 copies/ml at six months of treatment.12 in the context of the wbot programme, adherence support entails regularly visiting patient’s households to supervise medication taking, educating patients about the importance of taking treatment exactly as prescribed by the healthcare workers, provision of tips and tools such as diary record cards to aid in timely treatment taking and referrals of non-adherent individuals to the nearest phc facility for follow-up. the positive value of adherence support in retaining individuals on art in south africa was also documented in the study by igumbor et al.,12 which evaluated the effect of community adherence support on art programme retention. they observed that a significantly higher proportion of patients with a community-based adherence supporter (89%) had a treatment pick-up rate of over 95%.12 adherence support by chws may also play an important role in reducing health facility workloads through monitoring and supporting hiv-infected patients who are stable on art.21,22,23 grimsrud et al.,4 for example, found that task-shifting to chws can successfully support and improve art adherence and encourage patient self-management.4 over a period of 12 months, more than 2000 stable art patients were successfully decentralised from a doctor-driven phc clinic to a community-based model of care including chws, while maintaining art retention rates of 97% after six months and 94% at 12 months.4 the ongoing scale-up of the art programme in south africa, particularly as test and treat becomes routine, makes it increasingly important to find effective ways to involve chws in novel systems of alternative distribution of art and long-term art retention, especially in resource-limited settings. early identification of individuals failing treatment finally, chws have a critical role to play in maintaining hiv viral suppression and hence reducing hiv-related morbidity and mortality through ongoing monitoring of individuals on art. in this role, chws essentially provide a means for the early detection of individuals at risk of defaulting or treatment failure through symptom screening. by enhancing treatment literacy, early identification of art side effects, awareness of psychosocial and poverty-related factors that may impact the likelihood of patient’s virological failure, chws can be an essential link in the hiv treatment cascade. grimwood et al.20 demonstrate this potential by finding that the presence of community-based patient support reduced mortality of children after three years of art: 3.7% of children died in a setting with pas, whereas 8.0% of children died without community-based support.20 barriers and challenges to successful ward-based outreach team support despite the promise of the wbots in improving programme outcomes, there are several key barriers and challenges to their successful implementation in south africa’s healthcare system. these include general operational challenges and hiv programme-specific challenges as discussed below. general challenges varying perceptions of community health worker roles the health system identifies chws as volunteers who manage patients within the community in which they reside and usually receive a stipend for their services.24 some community members perceive chws to be peers, while others are knowledgeable about chw roles in communities such as promoting primary health services and encouraging testing for several health conditions.25 chws generally perceive themselves as being a part of the community, while providing services and making a difference to the lives of people. some even have an elevated perception of their roles as being teachers, social workers and doctors as they are given access to privileged medical information of patients and are linked to the formal health system.26 however, this empowerment may be challenged by difficult working environments. a recent multi-country comparative study shows that chws are often left feeling unsupported and undervalued as organisational and relational challenges hindered their work. therefore, improving organisational support and helping the community better understand and appreciate the roles of chws could possibly mitigate these challenges faced by chws.27 lack of stakeholder and community support a fundamental challenge that limits the effectiveness of wbots in south africa is their poor integration into local health systems, which in turn undermines the role of chws in community healthcare.7 effective integration of wbots requires phc facilities in the chw programme to adopt a coordinating role28 and to facilitate ongoing contact with chws for the purposes of feedback, training and monitoring. a study in uganda, for example, found that creating a bidirectional feedback loop by holding monthly meetings and using data collected timeously improved chw activities and ensured that the continuum of services from community to facility is maintained.29 the integration of chws into a well-established community-based phc system with facility nurses, doctors, a proper referral system and adequate financing and resources is essential in relieving pressures of health service delivery.1,30 in addition, support from community leaders and social workers as well as community acceptance plays an important role in the success of the chw programme. evaluating the interaction of chws and the community from a cultural and gender perspective is therefore imperative; for example, male community members may resist interaction with female chws.31 gender inequalities have also been shown to negatively impact hiv counselling and testing, hiv status disclosure and art adherence, as well as the ability of female chws to work with male community members.32 in this regard, the introduction of male chws may be necessary to address these gender-related challenges and may result in improvement in health outcomes of male community members.33 however, the introduction of male chws may be thwarted by existing norms of hegemonic masculinity, where male chws assert dominance over their clients, limiting male community member’s ability to be open about being sick and vulnerable.34 this could also result in female community members feeling intimidated and withdrawn. when making these decisions to introduce male chws into the programme, it is imperative to adopt an approach that is conducive to developing supportive relationships between chws and community members that improve health-seeking behaviour.34 challenging work environments and operational barriers minimal, inconsistent or irregular payment of stipends remains a critical challenge in maintaining chws interest and involvement in community-based programmes.7,28 common reasons for chws resigning include inadequate compensation for their time, and family members being unsupportive of their workload in light of the minimal incentive received.23,35 limited practical resources can also inhibit the effectiveness of chw programmes. for example, a lack of comfortable footwear and umbrellas to protect chws from harsh weather elements may prohibit them from conducting household visits. the fact the chws have not been provided with official uniforms or name tags may also present a problem with regard to identification and authority of the chws in the community and health systems. funding constraints also mean that chws often lack resources to travel to households, meetings and training sessions.28 evaluations of chw programmes show that chws become overwhelmed by their broad range of tasks, resulting in poor performance and work overload. hermann et al.6 note that chws with a large number of tasks tend to select a few that they perceive as the most important or feasible to prioritise.6 the tasks they prioritise may or may not align with programmatic goals. therefore, clearly defined management and reporting channels are essential to ensure that wbots are effectively used in the south african hiv programme. moreover, the use of mobile technology should be considered to assist chws with their tasks and to improve communication. studies show that the use of mobile technology by chws to collect field-based health data, receive reminders and alerts, facilitate health education and conduct person-to-person communication improved quality of care, service efficiency and programme monitoring.36,37 human immunodeficiency virus programme challenges lack of knowledge and skills in south africa, the ndoh developed a curriculum for chws, with the ultimate goal of national certification.38 chws are currently trained on hiv prevention and treatment, including provision of health education, screening community members for health problems and referrals to local facilities, included in the phase one training. they are therefore expected to have adequate knowledge to do their work. however, sustaining and updating knowledge through continual training is a challenge.28 continuous education and support is therefore a requirement to sustain quality of the programme. phase two training is currently underway, which will address knowledge gaps.38 socio-cultural barriers in a context where hiv is stigmatised, chws may be seen as a marker of hiv or aids as they are known to support individuals who are hiv-positive. this, in turn, can arouse a feeling of stigmatisation in community members which may result in individuals refusing to talk to chws, providing incorrect contact information, pretending to be someone else when visited by chws and asking to change the location of chw visits. for example, there has been a report of chws specifically providing art adherence support, trying to conceal their identities when visiting households by refraining from wearing uniforms given to them by their ngos and pretending to be selling various commodities.31 implementing community awareness and education campaigns aimed at reducing hiv-related stigma may therefore be an important factor facilitating the effectiveness of wbots. this may enable individuals to feel more comfortable to provide accurate medical information to their chws and details regarding treatment options can be shared with them by chws. this will also enable individuals to build relationships with external sources of support such as chws and phc facilities in order to obtain healthcare advice and treatment.31 a formal wbot policy is still in the process of being finalised. the policy may include ethical guidelines governing their roles, such as the requirement of registration with health bodies (currently not required), ethics training and the legal framework in which the chws operate.38 the policy may also stipulate the extent to which chws are qualified to provide health advice. this may improve chws credibility in the community. perspective there is great potential for chws to have a substantial impact on hiv programmes as evidenced above. we have presented several examples of successful chw initiatives. chw efforts can lead to improved health outcomes by improving community access to phc in terms of health education, patient linkage to and retention in care. expanding the chw programme will further increase the potential to address large healthcare gaps. however, health system barriers such as human resource capacity, inconsistent remuneration, lack of nationally recognised training and a failure to mainstream wbots are important factors that limit the effectiveness of the wbot programme. these need to be addressed for wbots to have maximum impact on the hiv and other health programmes.23 a particular point of concern is that chws may be overloaded with expectations and activities. in that regard, it is essential that the workforce size and quality of services provided must match the programme deliverables. further investment in the wbot programme would be essential to expand it; however, this is not easily achieved without a broad-scale documented impact. to our knowledge, there are no comprehensive data available on the impact and contribution of the wbot structure on hiv programme outcomes in south africa. such impact would likely be highest in rural settings with high poverty and low education rates, but at the same time the operational barriers may be larger in those areas.23 several initiatives are currently underway to document the impact that chws have on health programmes in general, and the hiv programme in particular, as well as to assess practical ways to improve their contribution. community healthcare provides an important component of the south african healthcare system with high promise to support the usually overcrowded healthcare facilities, but strengthening of the structure is warranted to obtain maximum impact. conclusion there is evidence that wbots have a positive impact on healthcare. however, despite the strong potential, there are limited data on the impact of wbots on the south african hiv programme. therefore, evaluations to determine operational barriers and opportunities for improvement are urgently warranted. this will provide much needed information to stakeholders regarding areas that need improvement and strengthening in order for wbots to become a sustainable structure in the south african healthcare system. acknowledgements division of epidemiology and biostatistics, school of public health, faculty of health sciences, university of the witwatersrand, johannesburg, south africa. this research project was supported by a postgraduate training scholarship from the fogarty and niaid, the unc-wits aids implementation science and cohort analyses training grant (grant number: 5d43tw009774-02). the content is solely the responsibility of the authors and does not necessarily represent the official views of the fogarty and niaid. anova health institute is supported by the us president’s emergency plan for aids relief (pepfar) programme via the us agency for international development (usaid) under cooperative agreement no. aid-674-a-12-00028. the views expressed in this manuscript do not necessarily reflect those of pepfar or usaid. competing interests the authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article. authors’ contributions n.n. conceptualised the study and undertook the writing of the manuscript. j.r., g.j., n.m., g.m., j.a.m. and h.e.s. contributed to the manuscript review. r.p.h.p. conceptualised the study and contributed to the in-depth review of the manuscript. references lui a, sullivan s, khan m, sachs s, singh p. community health workers in global health: scale and scalability. mt sinai j med. 2011;78:419–435. https://doi.org/10.1002/msj.20260 pillay y, barron p. the implementation of phc re-engineering in south africa [homepage on the internet]. public health association of south africa; 2012 [cited 2017 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d, et al. effect of home based hiv counselling and testing intervention in rural south africa: cluster randomised trial. bmj. 2013;346:f3481. https://doi.org/10.1136/bmj.f3481 reif lk, rivera v, louis b, et al. community-based hiv and health testing for high-risk adolescents and youth. aids patient care stds. 2016;30(8):371–378. https://doi.org/10.1089/apc.2016.0102 who. who recommends hiv self-testing [homepage on the internet]. world health organization; 2016 [cited 2017 mar 29]. available from: http://www.who.int/hiv/pub/vct/alternate_policy-brief_hivst-asia.pdf?ua=1 allen cg, escoffery c, satsangi a, brownstein jn. strategies to improve the integration of community health workers into health care teams: ‘a little fish in a big pond’. prev chronic dis. 2015;12:e154. https://doi.org/10.5888/pcd12.150199 grimwood a, fatti g, mothibi e, malahela m, shea j, eley b. community adherence support improves programme retention in children on antiretroviral treatment: a multicentre cohort study in south africa. j int aids soc. 2012;15:17381. https://doi.org/10.7448/ias.15.2.17381 le roux k, le roux i, mbewu n, davis e. the role of community health workers in the re-engineering of primary health care in rural eastern cape. s afr fam pract. 2015;57(2):116–120. https://doi.org/10.1080/20786190.2014.977063 cohen r, lynch s, bygrave h, et al. antiretroviral treatment outcomes from a nurse-driven community supported hiv/aids treatment programme in rural lesotho: observational cohort assessment at two years. j int aids soc. 2009;12:23. https://doi.org/10.1186/1758-2652-12-23 mwai gw, mburu g, torpey k, frost p, ford n, seeley j. role and outcomes of community health workers in hiv care in sub-saharan africa: a systematic review. j int aids soc. 2013;16:18586. https://doi.org/10.7448/ias.16.1.18586 tsolekile lp, puoane t, schneider h, levitt ns, steyn k. the roles of community health workers in management of non-communicable diseases in an urban township. afr j prim health care fam med. 2014;6(1):e1–e8. rachlis b, naanyu v, wachira j, et al. community perceptions of community health workers (chws) and their roles in management for hiv, tuberculosis and hypertension in western kenya. plos one. 2016;11(2):e0149412. https://doi.org/10.1371/journal.pone.0149412 mlotshwa l, harris b, schneider h, moshabela m. exploring the perceptions and experiences of community health workers using role identity theory. glob health action. 2015;8:28045. https://doi.org/10.3402/gha.v8.28045 naimoli jf, frymus de, wuliji t, franco lm, newsome mh. a community health worker ‘logic model’: towards a theory of enhanced performance in lowand middle-income countries. hum res health. 2014;12:56. https://doi.org/10.1186/1478-4491-12-56 horwood cm, youngleson em, stern af, barker pm. using adapted quality-improvement approaches to strengthen community-based health systems and improve care in high hiv-burden sub-saharan african countries. aids. 2015;29 (suppl 2):s155–s164. https://doi.org/10.1097/qad.0000000000000716 wools-kaloustian kk, sidle je, selke hm, et al. a model for extending antiretroviral care beyond the rural health centre. j int aids soc. 2009;12:22. https://doi.org/10.1186/1758-2652-12-22 bajpai n, dholakai r. improving the performance of accredited social health activists (ashas) in india. new delhi: international advisory panel of the national rural health mission, ministry of health and family welfare, government of india; 2011. masquillier c, wouters e, mortelmans d, van wyk b, hausler h, van damme w. hiv/aids competent households: interaction between a health-enabling environment and community-based treatment adherence support for people living with hiv/aids in south africa. plos one. 2016;11(3):e0151379. https://doi.org/10.1371/journal.pone.0151379 treffry-goatley a, lessells r, sykes p, et al. understanding specific contexts of antiretroviral therapy adherence in rural south africa: a thematic analysis of digital stories from a community with high hiv prevalence. plos one. 2016;11(2):e0148801. https://doi.org/10.1371/journal.pone.0148801 martinez perez g, cox v, ellman t, et al. ‘i know that i do have hiv but nobody saw me’: oral hiv self-testing in an informal settlement in south africa. plos one. 2016;11(4):e0152653. https://doi.org/10.1371/journal.pone.0152653 gittings l. ‘when you visit a man you should prepare yourself’: male community care worker approaches to working with men living with hiv in cape town, south africa. cult health sex. 2016;18(8):936–950. https://doi.org/10.1080/13691058.2016.1150513 unicef. what works for children in south asia, community health workers [homepage on the internet]. regional office for south asia: the united nations children’s fund; 2004 [cited 2016 may 18]. available from: http://www.unicef.org/rosa/community.pdf braun r, catalani c, wimbush j, israelski d. community health workers and mobile technology: a systematic review of the literature. plos one. 2013;8(6):e65772. https://doi.org/10.1371/journal.pone.0065772 schuttner l, sindano n, theis m, et al. a mobile phone-based, community health worker program for referral, follow-up, and service outreach in rural zambia: outcomes and overview. telemed j e health. 2014;20(8):721–728. https://doi.org/10.1089/tmj.2013.0240 national department of health. national health insurance for south africa (white paper). pretoria: ndoh; 2015. hiv 851 managing aids-related kaposi’s sarcoma and pregnancy p barnardt, mb chb, dip onc division of radiation and clinical oncology, department of medical imaging and clinical oncology, stellenbosch university, stellenbosch, south africa corresponding author: p barnardt (pieterb@sun.ac.za) an estimated 30 40% of hiv-infected patients are likely to develop cancer during the progression of their disease. the occurrence of malignancy among these patients represents a difficult challenge in their care. kaposi’s sarcoma (ks) – currently the most common tumour observed with an estimated incidence of 15 20% – represents the first manifestation of aids in 30 40% of patients. any organ may be involved, but the gastrointestinal tract and lung remain the most frequently involved locations. the case described here presented a clinical and ethical dilemma where visceral ks, pregnancy and medical complications required multi-disciplinary management. s afr j hiv med 2013;14(2):87-88. doi:10.7196/sajhivmed.851 a 24-year-old woman was referred to the division of oncology at a large academic hospital. she had presented recently at a local hospital with a history of progressive shortness of breath, and had received treatment for atypical, multilobular pneumonia. she was diagnosed with hiv in 2009 when she presented with severe mucocutaneous kaposi’s sarcoma (ks) as her aids-defining disease. she was pregnant at the time of her initial diagnosis, and received 4 cycles of bleomycin/vincristine chemotherapy after delivering a healthy term infant. this was followed by an additional 14 cycles of chemotherapy, which was discontinued when her ks lesions demonstrated a good clinical response. she returned 6 months later with ks progression and was re-challenged with the abv regime (doxorubicin, bleomycin and vincristine) for 6 cycles. she reached the tolerance dose of bleomycin, and chemotherapy was discontinued. a large lesion behind her left earlobe was treated with a short course of palliative external beam radiotherapy (ebrt). in february 2012, ks progression was visible, this time involving the genital area, mouth and lymph nodes. again, she was challenged with combination chemotherapy containing doxorubicin and vincristine for 4 cycles, with no clinical benefit, and palliative ebrt was offered to problematic lesions of the vulva and left foot. in june 2012 she was admitted to the high-care unit with a 2-month history of progressive, grade iv dyspnoea, intermittent cough, and bleeding from a palatial ks lesion in her mouth. she was 27 weeks pregnant and had been treated at a local hospital for pneumonia and started on anti-tuberculosis (tb) treatment 2 weeks earlier. on inspection, the patient was acutely ill with signs of a hyper-dynamic circulation and peripheral oedema. physical examination revealed bilateral coarse crepitations, wheezes and the use of accessory respiratory muscles. a large, bleeding, nodular ks lesion was observed, involving most of the hard palate and oropharynx. abnormal laboratory studies revealed reduced haemoglobin (7.8 g/dl), raised c-reactive protein (75.0 mg/l), low albumin (26 g/l), raised fibrinogen (4.4 g/l), raised d-dimer (1.34 mg/l) and raised lactate dehydrogenase (368 u/l) levels and a low cd4 count (137 cells/µl). a standard blood culture was negative. a routine chest x-ray (cxr) revealed bilateral opacities infiltrating predominantly the perihilar peribronchovascular interstitium of both lungs (fig. 1). fig. 1. chest x-ray showing bilateral ks opacities infiltrating pre­dominantly the perihilar peribronchovascular interstitium (these may often be mistaken for opportunistic infections). according to the aids clinical trials group (actg) staging system, the patient was classified as a poor-risk stage iv (t1,i1,s1) hiv/aids patient with a problem list of: (i) hiv-infected since 2009, receiving antiretroviral therapy (art); (ii) cd4 count of 137 cells/µl; (iii) 2 weeks of anti-tb treatment; (iv) ks since 2009 (for which she received multiple cycles of chemotherapy and palliative ebrt); (v) current presentation of bilateral, multi-lobular infiltrates on a cxr with a high index of suspicion of lung ks involvement; (vi) early signs of early diffuse intravascular coagulation (dic); and (vii) pregnancy (28 weeks). management a multi-disciplinary team (mdt), comprising a high-care medical team, oncologist, obstetrician and the hiv/infectious diseases personnel, was required for optimal management. intravenous antibiotic therapy (clarithro­mycin), concurrent art (tenofovir, efavirenz and lamivudine) and anti-tb (rifafour) supportive treatment were continued, with the addition of trimetroprim-sulfamethoxazole as pneumocystis jyroveci prophylaxis, as the patient's current cd4 count was <200 cells/ µl. continuous positive airway pressure (cpap) was required as she became entirely dependent on the support system to maintain breathing. sub-cutaneous heparin was administered dur­ing her hospital stay. on day two post admission, she reported no fetal activity and an obstetric consult confirmed an intra-uterine death. she went into spontaneous labour and delivered a premature, stillborn microcephalic fetus (weighing 1 380 g). her bleeding ks mouth lesion was controlled with adrenaline gauze. due to her poor perform­­ance status, low cd4 count, resistant ks, extent of ks disease and poor prognosis, no active chemotherapy management was offered. she died 3 hours post delivery due to extensive ks and respiratory failure. discussion in sub-saharan africa, where many patients access art with advanced hiv disease, aids-related ks presents with a high tumour burden and rapid disease progression, resulting in a life expectancy of <6 months.1 ks involving the lung presents as shortness of breath, fever, cough, chest pain and haemoptysis, or as an incidental finding on a cxr.2 a prognostic index can guide therapeutic options for aids-related ks, including: immune status (cd4 count); patient age; aids-defining disease on presentation; and the presence of co-morbid conditions. patients with a favourable prognostic index can be treated initially with art alone. systemic chemotherapy is warranted in advanced, systemic or rapid, progressive ks disease. several chemotherapeutic agents – e.g. bleomycin, vincristine, vinblastine, and an anthracycline (doxorubicin) – have activity in the treatment of ks, but in the developed world, liposomal doxorubicin and a taxane group constitute the backbone of current systemic chemotherapy against ks.1 , 3 , 4 in all cases, an objective response of 70 80% can be obtained with various combinations of chemotherapy. partial responses and clinical benefit are frequently observed, but relapses often occur when treatment is stopped.3 , 5 our patient initially received a combination of bleomycin and vincristine, and was re-challenged with the abv combination when her ks progressed. unfortunately, treatment with systemic chemotherapy comes at a cost: both bleomycin and doxorubicin have a maximum tolerable dose before long-term complications become evident. in addition, bleomycin may induce alveolitis and pulmonary fibrosis, and there is evidence of accelerated pulmonary dysfunction in lung ks patients who received bleomycin.6 doxorubicin is associated with irreversible cardiac damage (congestive heart failure and cardiomyopathy) when the maximum dose of ≥450 mg/m2 is exceeded. the patient described here had reached the maximum tolerable dose of both bleomycin and doxorubicin. she developed progressive ks during the last 4 cycles of doxorubicin-based therapy; therefore, it may be postulated that her ks became resistant to anthracycline chemotherapy. as both liposomal doxorubicin and the taxane drugs are not available in the public healthcare sector, second-line chemotherapy could not be offered. the incidence of pregnancy-associated malignancy ranges from 0.02 0.10%; the most common malignancies diagnosed during pregnancy are gynaecological, haemato­logical and skin cancers (malignant melanoma). malignancies in pregnancy present the mdt with an ethical conflict between the optimum management of the cancer and preservation of the pregnancy.7 for most of these cancers, chemotherapy is necessary to achieve a cure or efficient palliation of cancer-related symptoms. the consequence of chemotherapy and/or ebrt during the first trimester is high (congenital malformation or spontaneous abortion), and termination of pregnancy v. delayed treatment should be discussed with the patient. chemotherapy treatment during the second and third trimesters follows the standard chemotherapy guidelines, but delivery should be timed during a non-neutropaenic period and care should be taken to time the last cycle of treatment at 32 weeks of gestation. however, patients remain at high risk and this warrants careful monitoring.8 the patient described in this case presented with a 28-week pregnancy, but had received chemotherapy and ebrt during the first trimester when she was unaware of her pregnant status. this resulted in an intra-uterine death and early clinical dic that concluded in a spontaneous delivery, probably due to maternal hypoxia and the abnormal fetus (microcephaly). few studies are available concerning in utero chemotherapy-exposed neonates. in one study, the mean gestational age at delivery was 35.8 weeks, the mean birth weight was 2 647 g, and 4% of infants were born with a congenital abnormality.8 , 9 conclusion this case highlights the clinical complications and ethical dilemma associated with advanced ks in pregnancy. the mdt plays an important role in securing optimal care for patients with advanced hiv disease, malignancy and associated pregnancy. conflict of interest. none. references 1. di lorenzo g, konstantinopoulos pa, pantanowitz l, et al. management of aids-related kaposi’s sarcoma. lancet 2007;8:167-176. [http://dx.doi.org/10.1016/s1470-2045(07)70036-0] 1. di lorenzo g, konstantinopoulos pa, pantanowitz l, et al. management of aids-related kaposi’s sarcoma. lancet 2007;8:167-176. [http://dx.doi.org/10.1016/s1470-2045(07)70036-0] 2. gruden jf, huang l, webb wr, et al. aids-related kaposi’s sarcoma of the lung: radiographic findings and staging system with bronchoscopic correlation. radiology 1995;195:545-552. 2. gruden jf, huang l, webb wr, et al. aids-related kaposi’s sarcoma of the lung: radiographic findings and staging system with bronchoscopic correlation. radiology 1995;195:545-552. 3. spano jp, atlan d, breau jl,farge d. aids and non-aids-related malignancies: a new vexing challenge in hiv-positive patients. eur j int med 2002;13:170-179. 3. spano jp, atlan d, breau jl,farge d. aids and non-aids-related malignancies: a new vexing challenge in hiv-positive patients. eur j int med 2002;13:170-179. 4. friedman-kien a, saltzman b. clinical manifestations of classical, endemic african, and epidemic aids-associated kaposi’s sarcoma. j am acad dermatol 1990;22:1250. 4. friedman-kien a, saltzman b. clinical manifestations of classical, endemic african, and epidemic aids-associated kaposi’s sarcoma. j am acad dermatol 1990;22:1250. 5. tayio m, yaccher e, antinori a, et al. combination chemotherapy with doxorubicin, bleomycin and vindesine for aids-related kaposi’s sarcoma. cancer 1996;77:2117-2122. 5. tayio m, yaccher e, antinori a, et al. combination chemotherapy with doxorubicin, bleomycin and vindesine for aids-related kaposi’s sarcoma. cancer 1996;77:2117-2122. 6. denton as, simpson m, hallam m, spittle mf, miller rf. effects on pulmonary function of two regimes of chemotherapy for aids-related kaposi’s sarcoma. clin oncol 1996;8:48-50. 6. denton as, simpson m, hallam m, spittle mf, miller rf. effects on pulmonary function of two regimes of chemotherapy for aids-related kaposi’s sarcoma. clin oncol 1996;8:48-50. 7. morice p, uzan c, gouy s, verschraegen c, haie-meder c. malignancies in pregnancy. gynaecological cancers in pregnancy. lancet 2012;379:558-569. 7. morice p, uzan c, gouy s, verschraegen c, haie-meder c. malignancies in pregnancy. gynaecological cancers in pregnancy. lancet 2012;379:558-569. 8. cardonick e, iacobucci a. use of chemotherapy during human pregnancy. lancet oncol 2004;5:283-291. [http://dx.doi.org/10.1016/s1470-2045(04)01466-4] 8. cardonick e, iacobucci a. use of chemotherapy during human pregnancy. lancet oncol 2004;5:283-291. [http://dx.doi.org/10.1016/s1470-2045(04)01466-4] 9. cardonic e, usmani a, ghaffar s. perinatal outcomes of a pregnancy complicated by cancer, including neonatal follow-up after in utero exposure to chemotherapy: results of an international registry. j clin oncol 2010;33:221-228. [http://dx.doi.org/10.1097/coc.0b013e3181a44ca9] 9. cardonic e, usmani a, ghaffar s. perinatal outcomes of a pregnancy complicated by cancer, including neonatal follow-up after in utero exposure to chemotherapy: results of an international registry. j clin oncol 2010;33:221-228. [http://dx.doi.org/10.1097/coc.0b013e3181a44ca9] abstract background aim and objectives research methods and design ethical consideration results discussion conclusion recommendations acknowledgements references about the author(s) joana woods wits reproductive health and hiv institute (wrhi), johannesburg, south africa michelle moorhouse wits reproductive health and hiv institute (wrhi), johannesburg, south africa lucia knight school of public health, university of the western cape, cape town, south africa citation woods j, moorhouse m, knight l. a descriptive analysis of the role of a whatsapp clinical discussion group as a forum for continuing medical education in the management of complicated hiv and tb clinical cases in a group of doctors in the eastern cape, south africa. s afr j hiv med. 2019;20(1), a982. https://doi.org/10.4102/sajhivmed.v20i1.982 original research a descriptive analysis of the role of a whatsapp clinical discussion group as a forum for continuing medical education in the management of complicated hiv and tb clinical cases in a group of doctors in the eastern cape, south africa joana woods, michelle moorhouse, lucia knight received: 06 may 2019; accepted: 13 june 2019; published: 01 aug. 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: as south africa’s (sa) hiv programme increases in size, hiv/tb cases occur that are often beyond the clinical scope of primary healthcare clinicians. in sa’s eastern cape (ec) province, health facilities are geographically widespread, with a discrepancy in specialist availability outside of academic institutions. the aim of this study is to describe whatsapp and its use as an alternative learning tool to improve clinicians’ access to specialised management of complicated hiv/tb cases. objectives: to analyse clinicians’ use of the whatsapp chat group as a learning tool; to assess clinicians’ confidence in managing complicated hiv and tb patients after participating in the whatsapp case discussion group; to describe the perceived usefulness of the chat group as a learning tool; to understand clinicians’ knowledge and use of informed consent when sharing patient case details on a public platform such as whatsapp. method: an observational, cross-sectional study was conducted among a group of clinicians from the ec that formed part of a whatsapp hiv/tb clinical discussion group. data were collected using a structured anonymous internet questionnaire and analysed with epi info, using descriptive and analytic statistics. results: the analysis found the majority of participants had gained new clinical confidence from group participation. this was associated with the increased group engagement in group follow-up (odds ratio [or] 48.13 [95% confidence interval [ci] 4.99–464.49]); in posting questions (or 3.81 [95% ci 1.02–18.48]); in reports of ‘new’ clinical insights (or 23.75 [95% ci 3.95–142.88]); in referencing old case material (or 21.42 [95% ci 4.39–104.84]) and in the use of peer guidance to manage cases (or 48.13 [95% ci 4.99–464.49]). however, there was a discrepancy in participants’ knowledge and actual use of informed consent when posting patient details on social media. conclusions: our study findings support the use of whatsapp in a medical setting as an effective means of communication, long distance learning and support between peers and specialists. keywords: continuing medical education; hiv/tb; eastern cape; whatsapp; clinician. background many nations face problems of inequitable access to healthcare services and the shortage of suitably qualified healthcare professionals. an insufficient number of medical graduates; a scarcity of postgraduate education; the migration of healthcare professionals and a critical shortage of teaching faculty demonstrate a need for alternative approaches to improving the retention of the healthcare workforce.1 a possible contributing solution to this problem is found in continuing medical education (cme). countries must retain health professionals by providing them with opportunities for career development, cme, motivation and support.2 the evidence shows that career development and cme strongly motivate health professionals to stay in their own countries and to practise in remote areas.3 however, many health professionals struggle to access cme because of professional isolation, lack of locum relief and heavy workload, and this is seen particularly in rural areas.1 much cme traditionally happens through conferences, seminars and other face-to-face meetings. these are often difficult to attend which limits training to attendees only.1 this is particularly applicable to clinicians working in the eastern cape (ec), a predominantly rural province, where the clinicians enrolled in this study are working. in south africa, 46% of the population live in rural areas, but only 19% of the nursing workforce and 12% of physicians practise in those areas.2 the ec has a population of 7 million and an hiv prevalence of 12.1%.4 approximately 4.1 million of the population live in rural communities.5 in this setting, district hospitals and public health clinics are often geographically widespread, with only three academic or tertiary centres servicing these facilities.6 in addition, the province has only four infectious disease (id) specialists to provide expert care to its seriously ill hiv and tb patients. per population size, south africa (sa) has the largest hiv epidemic in the world. the overall hiv prevalence rate is approximately 12.6%. similarly, the country’s tb burden is large. in 2016, sa recorded 438 000 new tb infections.7 tb was the leading cause of death in the country. hiv treatment and care is often complicated by the emergence of drug resistance, drug–drug interactions and the advanced immune suppression of newly diagnosed patients. the use of smartphone technology and mim platforms in clinical practice is a research topic that is gaining support. since january 2017, there are 1.2 billion active whatsapp users worldwide.8 this service offers users the following features: the transmission of text messages, images and videos to contacts and a chat group feature that allows 256 users to share content simultaneously.9 however, its use in the public health sector has been poorly researched with only a small number of studies published.10 the literature that is available shows that the use of this technology offers an efficient, unobtrusive and portable mode of communication for medical staff.11 not only that, but also medical images that are captured using smartphone devices promote the delivery of medical care in a timely and resource-friendly manner.12 kankane et al., in a study of neurosurgical communication, found that whatsapp enabled cost-effective and quick decision-making, namely 4.06 min from image to registrar report.13 this led to earlier diagnosis and more prompt treatment. nikolic et al. suggest that this technology has the potential to improve patient education and management, and perhaps, to impact significantly on health provision as a whole.11 there are obvious concerns, however, about the transmission of confidential patient information over a social media platform. according to international guidelines, patient confidentiality and guarding their personal health data are a legal requirement under different laws, such as the health information portability and accountability act (hipaa) in the united states, or the data protection directive in the european union.14 there are currently no health professionals council of south africa (hpcsa) guidelines that address the issue of clinicians specifically posting on social media. however, their guidelines address the issue of patient confidentiality, as well as ethical concerns using telemedicine (which have been extrapolated below to the use of social media). clinicians who wish to publish details about specific medical cases or clinical experiences online, which identify or run the risk of identifying a patient, should ensure they follow the guidelines relating to patient consent and disclosure set out by the hpcsa.15 these state that a patient’s express consent must be obtained before publishing case reports, photographs or other images in media that the public can access. whatsapp has improved its end-to-end encryption policies and does not store chat data in a virtual cloud (like facebook), but this form of protection has not been conclusively tested in clinical environments. patient confidentiality is therefore still at risk. the increased use of medical social media, data and information can be very useful, but any abuse of data needs to be prevented.14 a whatsapp messenger chat group was created in 2016 for doctors who had attended an advanced hiv management course, and were working in district hospitals in the ec. the group included medical specialists and members of the district clinical support team. clinicians posted complicated cases. the discussion that followed referenced national and international hiv guidelines and evidence-based clinical care. this provided cumulative medical expertise that assisted the clinician in the management of the case. it is important to know if this intervention is of benefit to doctors, particularly those without onsite specialist support in the south african healthcare context. it is also important to know if clinicians are aware of local occupational governing authority rules relating to patient confidentiality breaches when posting on social media. this would raise awareness of these important ethical and legal obligations in the medical fraternity. the data obtained from this research could be used to motivate for the use of alternative platforms of learning and clinician support across different medical specialist modalities besides id care. this intervention could then support the world health organization’s (who) recommendation that countries can aid in the retention of health professionals by providing them with opportunities for career development, cme, motivation and support.16 aim and objectives aim the aim of this study is to describe the use of a whatsapp clinical discussion group as an alternative learning tool to improve clinician access to specialised clinical management of complicated hiv/tb cases, as part of cme, and their knowledge of informed consent use when posting patient cases on social media. objectives the specific objectives are: to analyse clinicians’ use of the whatsapp chat group as a learning tool to assess clinicians’ confidence in managing complicated hiv/tb patients after participating in the whatsapp case discussion group to describe the perceived usefulness of the chat group as a learning tool to understand clinicians’ knowledge and use of informed consent when sharing patient case details on a public platform such as whatsapp. research methods and design study design an observational, descriptive cross-sectional design was used, with an anonymous internet questionnaire, distributed to the clinicians who formed part of the whatsapp group, as the data source. a quantitative approach was chosen for the study as the responses from the questionnaire were graded and therefore easily quantifiable. study population, setting and sampling the study population that was used in this study were 166 doctors from the ec province that accepted the organiser’s invitation to be part of the whatsapp clinical discussion group from january 2016 to july 2017. the inclusion criteria for the study included doctors from the ec department of health, as well as clinicians from collaborating non-governmental organisations (ngos). all the 166 doctors in the group were included to minimise any non-response, and to improve representation of the clinicians in the group.17 data collection tools and collection data were collected using a structured, anonymous internet questionnaire. this comprised 17 statements or questions, each with a corresponding answer or choice of answers. the main themes for the questionnaire centred on access to the whatsapp or internet; usage of the group; aid in improving clinical confidence; usefulness as a learning tool and the confidentiality of cases posted (doctors’ perceptions). to reduce information bias, the investigator used a standardised tool, and each doctor received the same questionnaire. the questionnaire had been reviewed by a group of three colleagues to ensure clarity and the exclusion of external bias. once ethical approval was received and before distribution to the participants, the questionnaire in its electronic format was piloted with the same colleagues who are a part of the whatsapp group to further improve question clarity and ease of participation. the questionnaire was self-administered, so no measurement bias was introduced by a third party.18 there was a threat to validity in terms of sampling bias when administrating the questionnaire, with the potential of non-responders possibly skewing the results.17 forty-five per cent (74/166) of the participants did, in fact, not submit responses. the investigator attempted to minimise this threat as much as possible by regular email and whatsapp reminders.17 the questionnaire was kept as short as possible and attempts were made to simplify access to it with an easy to use internet link being sent to the participants – all this to minimise non-responses.17 a link to the questionnaire in the google form was initially sent to each clinician in the whatsapp discussion chat group via whatsapp. when the clinicians clicked on the link, they were taken to the electronic google form. google saved each completely filled questionnaire in the investigator’s google drive. this form was completed by the respondent by a click on the most appropriate response. there were no open-ended or continuing questions, making the questionnaire simple and fairly quick to answer; the investigator estimated around 5 to 10 min per form. participants were able to answer the questions within their own time frame, enabling them to have privacy or choice of space. all the completed forms were available to view on the drive, which was password protected, and could be downloaded when needed for analysis. the clinicians were also emailed the link as well. emailing helped to collect data from the clinicians that may have at any stage left the group during the period under investigation. data management and analysis the individual responses saved on google drive were collected and transferred to an excel spreadsheet, where data cleaning occurred. any incompletely answered questionnaire was removed as a data source. text responses were also allocated a numerical key for easier analysis. the data were then imported into epi info statistical programme for analysis and were initially explored using basic frequencies for the categorical data. summary statistics were presented to give a general description of the above responses using analysis tables and graphs. these categorical variables were summarised as the number and percentage of responses in each category or exposure variable. further analysis was done by looking at other possible associations between clinical confidence to group engagement and clinical confidence because of perceived usefulness of the group as a learning tool. in the confidence variable, like–like response options were recorded for ease of analysis. other associations included the recommendation of the group based on the perceived usefulness of the group as a learning tool. for all the above associations, frequency distributions and cross-tabulations of the above-mentioned variables were generated. bivariate analysis was done to determine significant associations between the differing variables using p-values, odds ratios (ors) and 95% cis. the assessment of any significant differences was conducted using a mid-p exact test. this was computed to confirm statistical significance. type i error rate (alpha) for statistical tests was set at 0.05 and 95% ci, and were provided when appropriate. ethical consideration ethics approval was received from: hrec (human research ethics committee) from the university of witwatersrand; bmrec (biomedical research ethics committee) from the university of the western cape. a participant information form (combined with participant consent), along with the link to this internet questionnaire was electronically available and posted on the whatsapp group, as well as emailed to all participants who had at any stage belonged to the group within the reporting period. as the questionnaire was anonymous, no participant name was requested. there was no anticipated harm in the study, but there may have been some discomfort to the doctors in completing the online questionnaire. there was also the risk of identifying the locality of where the doctors worked (i.e. ec) but no risk of identifying individual doctors or patients/cases. results sample description out of the 166 belonging to the whatsapp chat group, a total of 92 participants submitted internet questionnaires. one form was submitted with no answers and was therefore excluded from the analysis. analysing clinicians’ use of the whatsapp group to analyse the usage of the whatsapp group (objective one of the study), the questionnaire included questions that assessed the participant’s internet accessibility and their engagement in the group. satisfaction at the relevance of responses received (by content and timing) was also assessed. lastly, participants were asked what types of cases they posted. only 1% of participants did not have access to a form of internet connectivity. twenty-nine per cent of the remainder had only occasional access. internet connectivity and access was important to permit the receipt and posting of questions on the app. seventy-one per cent of participants had access all the time. the majority (73%) looked on the app every time a case was posted, with only 2% ignoring the group completely. to further assess engagement in the group, participants were also asked how many times they posted cases in the group, and if they posted any responses to a case that had been posted by a colleague. half of the participants reported to have never posted cases; 47% had posted at least 1–5 times and 3% had posted 6–10 times. in terms of posting any medical advice or responses to another colleague’s case, 52% posted occasionally, 4% all the time. to determine the satisfaction of case responses received, participants were asked if the responses to the cases posted came timeously. the participants who had posted cases felt positively about the timely case response. the majority of participants who posted cases also stated that they were satisfied with the content of the case response received. those participants who posted cases were asked what type of cases they presented (figure 1). there was a very similar distribution in reporting paediatric (paeds), adult cases (including opportunistic infections [oi]) and cases of unsuppressed viral loads (unsupp. vl) – making up the bulk of cases at 65% collectively. other cases discussed included dermatological conditions (derm), adverse events (adv ev), maternal cases and prevention of mother-to-child transmission (pmct). figure 1: types of cases discussed (n = 81). lastly, in terms of participants’ perceptions of having obtained greater clinical confidence in managing complicated hiv/tb cases (study objective two), the majority (86%) agreed that it did increase their clinical confidence. perceived usefulness of the chat group as a learning tool the questionnaire also assessed the participants’ perceived usefulness of the group as a learning tool in managing complicated cases after taking part in the group (study objective three), and whether they would recommend this case discussion platform to other colleagues. when participants were asked if they used the clinical guidance posted on the whatsapp doctors group in their own patient management, 52% responded that they used the clinical guidance all the time, 44% used the guidance occasionally. only 4% felt that the guidance given on the group was not relevant to their current patient case management. about a third of the participants reported that they actually referred back to old cases discussed all the time when a complicated clinical case presented at their clinic. out of the remainder, 64% used the previous discussions occasionally, and 8% felt that felt that the guidance given on the group was not relevant to their current patient case management. again, the majority of the participants strongly agreed that the whatsapp group was useful in helping them gain new clinical insights on hiv/tb, that the information discussed in the group chat was according to national guidelines and international best practice principles and they would recommend a similar case discussion platform to other colleagues (table 1) table 1: usefulness of the group as a learning tool (n = 91). clinicians’ knowledge and use of informed consent in the group the last objective was understanding the clinicians’ knowledge of informed consent when sharing patient information on social media. from the responses, 89% of the participants reported that they were aware that according to hpcsa regulations, they needed to obtain documented patient consent when posting a patient-related image on social media. however of those that reported posting questions, only half obtained consent (52%) versus 48% not obtaining consent, when posting patients’ photographs or other medical images on the group (even if patient identity was not revealed). when asked if they obtained documented patient consent when posting patients’ laboratory results on the group (even if patient identity was not revealed), around two-thirds (68%) of participants who had posted said they had in fact not obtained consent, less so than when posting other medical images. bivariate analysis using a bivariate analysis, with cross-tabulation in epi info, any statistically significant associations were looked for in those clinicians who reported feeling more confident in managing their patients after group participation and whether they would recommend the group as a learning platform to other colleagues. table 2 looks at any association between group engagement as an exposure variable, and increased clinician confidence as an outcome. in doctors who followed the group regularly, there was a clinically significant increase in or (8.44, 95% ci 2.33–35.23), participants being 8.44 times more likely to have increased confidence in managing their patients. those who posted questions also had an increase in or, 3.8 times more likely to have an increase in their clinical confidence (95% ci 1.02–18.48). table 2: increased clinician confidence in managing patients and levels of group engagement. other associations were found in increased clinician confidence in managing patients as an outcome, cross-tabulated with participant perceptions of the usefulness of the group as a learning tool (table 3). of statistical significance, participants who used the chat group guidance to manage their patients were 48.13 times more likely to be confident afterwards (or 48.13, 95% ci 4.99–464.49); those who referred to old chat cases were 21.42 times more confident (or 21.42, 95% ci 4.39–104.84); there was also an increase in confidence in participants who reported that they had gained new clinical insights while participating in the group (or 23.75, 95% ci 3.95–142.88). table 3: increased clinician confidence in managing patients based on their perceived usefulness of the group as a learning tool (n = 91). when looking at recommending the group to colleagues as an outcome, participants who report gaining new clinical insights were 17.33 times more likely to recommend the group (95% ci 3.13–96.01). those who reported that the group helped them to practically apply pre-existing knowledge and felt that the guidance given was according to national or international guidelines were also, respectively, 12.82 (95% ci 2.55–64.56) and 20 (95% ci 1.63–245.63) times more likely to recommend the group to other colleagues as a case discussion platform (table 4). table 4: clinician recommendation of the whatsapp group based on their perceived usefulness of it as a learning tool (n = 91). in terms of group engagement and recommending the group to others, those who followed the group regularly were 4.79 times more likely to recommend it (95% ci 1.19–21.10). there was no difference in those who posted questions and responses (table 5). table 5: clinician recommendation of the whatsapp group based on their level of engagement in the group (n = 91) lastly, we looked at whether internet access impacted clinicians’ reported ability to follow the group, but there was no clinically significant association found. discussion group engagement and its usefulness as a learning tool the responses from participants in this study were favourable in the reported use of the whatsapp group and its application as a learning tool. the majority of the participants firstly cited regular internet connectivity, which facilitated the uninterrupted use of the application and communication in real time.19 they also reported using the group discussions as a guide to further manage other patients, referred back to old chat discussions and were satisfied at the timeous response to cases (including the peer responses themselves). group engagement, or participation, measured by following of the group and posting of cases or responses, was regular. the results further demonstrated that there was a statistically significant association between engagement in the group and increased clinical confidence – those who followed the group regularly were 8.44 times more likely to report an increase in clinical confidence and 3.8 times more confident if they posted a case. this correlates with findings by raiman et al., who discussed in their article that the use of mobile applications has been shown to increase student participation and therefore foster improved learning.20 similarly, rambe et al. also reported that whatsapp facilitated, in learners, the ability to more confidently engage with peers and educators.19 this form of engagement and success can be described through the theory of cooperative learning. in cooperative learning, students who maximally engage in a group are able to extend their current knowledge base, as they are in control of the discussion construct.21 in our study’s context, participants posted a case they are most interested in and there develops a close relationship between theory, research and a practical working through the case; this underpins long-term retention of knowledge and maximises student learning.21 furthermore, the participants also reported that the group gave them new clinical insights; helped them to practically apply pre-existing knowledge and felt that the guidance was aligned with international or national guidelines. in a systemic review of medical literature, kamel boulos et al. found collective evidence that whatsapp has been successfully used in health and medical education and learning.9 they also concluded that apps can help to create virtual communities of enquiry and practice, and bridge distances of busy distributed healthcare settings. our research adds to the literature by further clarifying that the knowledge gained (whether from peers or specialists) in belonging to such a group aids in the application of new clinical insights and previous medical knowledge, as well as contributing to clinical confidence by facilitating distance learning. lastly, our study found that participants were more likely to recommend the group to other colleagues if they had followed the group regularly (or 4.79), and in those who reported the group as a useful learning tool. the investigators therefore surmised that the whatsapp group seems to have promoted good group engagement which, in turn, facilitated learning, decreasing professional isolation and produced a recommendation of a similar platform to other colleagues. such a mobile learning platform is therefore an important adjunct to current cme practices. e-learning (of which whatsapp forms a part) can result in greater educational opportunities for participants, while at the same time enhancing student effectiveness and efficiency, as is the reported outcome in our study.22 clinical confidence in managing complicated hiv and tb cases the majority of the participants in the study agreed that they had gained greater clinical confidence in managing their patients after participating in the group. the findings showed that there was also an improvement in clinical confidence among those participants who perceived the group as a useful learning tool (it has been previously mentioned how engagement in the group had a similar effect). participants who used the chat group guidance to manage their patients were 48 times more likely to feel clinically confident. there was an increase in clinical confidence in those who referred to old chat cases (or 21.42) and those who gained new clinical insights while participating in the group (or 23.75). raiman et al. reported similar findings in their study – a whatsapp group provided a unique environment to be able to quickly access learning resources while participating in a discussion facilitated learning. their participants also cited how useful it was to look back at old recorded learning discussions.20 improved clinical confidence among our participants could be because of two main aspects: accessibility and case-based learning. doctors could easily access the application, could easily access old cases in the application and could easily access new knowledge by asking for guidance on the application. wani et al. found that doctors started management of patients quicker after using whatsapp clinician advice because of faster access to that advice, and that they found that management to be more effective.23 it is often laborious trying to find best evidence-based management in medical literature, especially in a time-constrained clinical setting. also, the application of that knowledge is sometimes broad, with medical theory not always correlating clearly to what is found in clinical practice. by providing input on a specific case (in a specific south african clinical setting) and supporting the clinician in managing the case in real time, a clinician’s confidence can be further bolstered. the whatsapp group provides a form of case-based learning, which has been shown to tie theory to practice and promote deeper learning.24 studies that use interactive techniques for cme, such as case discussions, produce a favourable change in professional practices and outcomes.25 this correlates to a similar reported outcome in our study. clinicians’ knowledge and use of informed consent although whatsapp is relatively safe in terms of hacking and leaking of confidential content because of its end-to-end encryption of data, there is still much concern about its use in medical literature and the impact on patient confidentiality.26 the majority of our study participants reported being aware that they needed to obtain documented patient consent when posting a patient-related image (photographs, case report, laboratory report) on social media. however, less than half of participants actually obtained consent. there seems to be a discrepancy in what the clinicians reported to know, and what they did to maintain patient confidentiality in this study. several authors share similar concerns that the use of patient data needs to be regulated when using social media, and that there needs to be a review of the roles and responsibilities of medical professionals when using such platforms.14 mars and escott found few reports of patient consent being regularly sought when sending patient information over whatsapp.26 they concluded that doctors need to be told what steps to take to maintain confidentiality. in our study’s whatsapp group, group rules were posted advising clinicians to remove any patient identifiers from any medical images when posting. this helped in some ways towards preserving patient confidentiality, but further education needs to be iterated to our study group regarding obtaining actual documented consent from the patients themselves. generalisability the results of the study show that whatsapp is perceived as an effective means of learning and clinical support in this study group. this mobile application can then be applied to other clinical disciplines (not only ids), from other health settings (private, district, provincial level), as a learning intervention. the target population groups that could potentially use this intervention include, for example, doctors in other clinical disciplines who need expert advice or access regarding patient management, allied health professionals (such as nurses, physiotherapists, occupational therapists) who need clinical supervision and advice from senior consultants regarding patients they are managing. as this study looks at the use of the whatsapp group in a clinical setting for patient management and further medical learning, it would be difficult to comment if its use would be applicable outside of the medical field. the second outcome of the study was to assess if patient confidentiality breaches had occurred with the posting of cases, and if doctors were aware of the legal obligations they are under when posting patient case details on a social media platform. the findings of this study could definitely be generalised to any health profession. it would aid in raising awareness of the pitfalls of posting cases on social media, and in doing so, protect health professionals from any future litigation as well as protecting their patient’s confidentiality. limitations there are several limitations to this study. although many attempts were made to get responses from the group, only 55% (n = 91) of participants submitted responses; the selection was therefore not random, and could introduce some bias. the small sample size and simple survey framework could affect the overall results, with resultant wide cis. some further bias could have been introduced by the online format of the questionnaire (with possible technical inability to fill it in correctly). a possible bias might have also occurred if any of the collaborating ngo clinicians filled in the questionnaire, although only four were active in the group at the time. we did not collect any demographic data from the respondents. the retrospective nature of the study could also affect the participants’ responses, as recall of their experiences of the chat group over a period of 1 year could vary from their original experiences. the investigators could also not determine from the study if the responses received to posted questions were from peers or specialists. a more accurate observation of the whatsapp group would have been obtained through direct analysis of the chat contents, but this was not approved by local ethical governing bodies without written consent from each doctor (which would be beyond our scope given the study’s retrospective nature). conclusion the initial aim of this study was to show that participating in a whatsapp group was a useful adjunct learning tool that could also clinically support doctors in geographically widespread facilities without onsite specialist support. based on the participant responses from this research, this mobile platform does offer an alternative cme solution that can be easily and successfully implemented in various health fields. by giving healthcare professional opportunities for career development, cme, motivation and support through this novel learning platform, we can perhaps aid in their retention in the public health sector.16 caution needs to be taken to maintain patient confidentiality when posting on social media, but that does not negate whatsapp’s usefulness in a clinical learning setting. recommendations the investigators recommend the use of whatsapp clinical support groups as a long-distance learning platform, based on our findings. to facilitate group success, some further recommendations include a commitment from participants in the group with active participation; a case-based method of discussion (but other learning modalities can be used); cooperative engagement led by students determining the learning construct of the group that will benefit them the most; and a range of different levels of clinical expertise in the group. there needs to be an increased awareness and education among clinicians on the legal implications of posting patient details in social media (not just whatsapp) without proper informed consent, to protect patient confidentiality. we also suggest that further research should be conducted to obtain a more objective analysis as to whether advice given in these mobile platforms improves clinical management in patients or not. these could include auditing clinical advice given on clinician whatsapp groups, according to best practice principles in medical literature, or by directly auditing patient outcomes in those having been managed by doctors who participate in similar mobile learning platforms in south africa. the findings of this study will be posted on the whatsapp group, which is still ongoing. acknowledgements the author (j.w.) would like to acknowledge the university of the western cape: this article was based on her recently submitted mph thesis. she would also like to acknowledge her employer wits rhi, for whom the article premise was also part of her kpis. competing interests the authors have declared that no competing interest exist. authors’ contributions this article was based on a thesis submission for dr j.w. for her mph to the university of the western cape. dr m.m. and prof. l.k. were her supervisors and assisted with conception, formatting and editing. funding information acc grant, sub awarded to wits rhi from beyond zero (funder-cdc). data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. references lygidakis h, mcloughlin c, patel k. achieving universal health coverage: technology for innovative primary health care education. 2016. 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https://doi.org/10.4103/0970-0358.121990 mclean sf. case-based learning and its application in medical and health-care fields: a review of worldwide literature. j med educ curric dev. 2016;3:39–49. https://doi.org/10.4137/jmecd.s20377 davis d, o’brien m, freemantle n, wolf f, mazmanian p, taylor-vaisey a. impact of formal continuing medical education: do conferences, workshop, rounds and other traditional continuing medical education activities change physician behavior or health car outcomes? jama. 1999;282(9):867–874. mars m, escott r. whatsapp in clinical practice: a literature review. stud health technol inform. 2016;231(march):82–90. https://doi.org/10.3233/978-1-61499-712-2-82 abstract introduction study objective material and methods ethical consideration results discussion limitations conclusion and recommendations addendum acknowledgements references about the author(s) melantha coetzee department of paediatrics and child health, steve biko academic hospital, pretoria, south africa faculty of health sciences, university of pretoria, pretoria, south africa suzanne d. delport faculty of health sciences, university of pretoria, pretoria, south africa division of neonatology, department of paediatrics, kalafong provincial tertiary hospital, pretoria, south africa citation coetzee m, delport sd. peripartum hiv infection in very low birth weight infants fed ‘raw’ mother’s own milk. s afr j hiv med. 2019;20(1), a912. https://doi.org/10.4102/sajhivmed.v20i1.912 original research peripartum hiv infection in very low birth weight infants fed ‘raw’ mother’s own milk melantha coetzee, suzanne d. delport received: 15 sept. 2018; accepted: 15 apr. 2019; published: 19 june 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: hiv-exposed very low birth weight (vlbw) infants (≤ 1500 g) are considered at high risk of peripartum mother-to-child hiv transmission (mtct). in the past, they received formula to prevent breast milk related hiv transmission. this denied them the benefits of breast milk, thus exposing the infant to the risk of necrotising enterocolitis (nec). from 2010, ‘raw’ mother’s own milk (rmom) has been recommended for term infants whose mothers’ received antenatal antiretroviral therapy (art). at the same time, the infant received antiretroviral (arv) prophylaxis as per the national prevention of mtct programme. objectives: to determine the cumulative incidence of peripartum hiv infection by 4–6 weeks of age in hiv-exposed vlbw infants, who received rmom and infant arv prophylaxis. method: a retrospective, observational audit over 3 years at a single institution was undertaken. the study population comprised hiv-exposed vlbw infants who received both nevirapine prophylaxis and rmom from birth until discharge. a positive hiv-pcr by 4–6 weeks of life was used to confirm maternal to infant hiv transmission. results: of the 80 eligible infants admitted between 2010 and 2013, 63 (79%) were exposed to antenatal art. seventy-eight (97.5%) tested hiv-pcr negative at 4–6 weeks. of the two infants who tested positive, both presented with features of an acute hiv infection. the absence of mtct in the remaining 78 infants given arv prophylaxis and rmom suggests that rmom is an unlikely source of infection in the two infected infants. conclusion: rmom, in the presence of infant prophylaxis, was a safe feeding option for hiv-exposed vlbw infants. it should be strongly considered for these infants, as rmom likely provides additional maternal and child benefits. keywords: hiv; prevention of mother-to-child transmission; mother-to-child transmission; very low birth weight; peripartum transmission; mother’s own milk; raw breast milk; nevirapine. introduction south africa is the global epicentre of the human immunodeficiency virus (hiv) pandemic, with an antenatal prevalence of 31%.1 human immunodeficiency virus-infected women are at increased risk of delivering low birth weight and/or preterm infants2 and of transmitting infection to their infants. hiv transmission is higher in the absence of maternal antiretroviral therapy (art);3,4,5,6 greater with higher maternal viral load; greater with worsening immunosuppression (low cd4 count);3,4,6 and is increased in the presence of maternal infections such as tuberculosis and sexually transmitted disease.7 increased permeability of the intestinal mucosal barrier in preterm infants further increases the risk of mother-to-child transmission (mtct).4,6 these infants are also at risk of necrotising enterocolitis (nec) if formula feeds are administered in an effort to reduce mtct.8 mother’s own milk (mom) is crucial to the survival of preterm infants.9 the risk and benefit to vlbw hiv-exposed infants receiving prevention of mother-to-child transmission (pmtct) interventions and ‘raw’ mom (rmom) is unclear. preterm and vlbw infants receiving rmom have fewer infections and less nec.8,9 whether this is true for hiv-exposed preterm and vlbw infants has not been studied. pmtct programmes in south africa before 2002 were limited because of governmental aids denialism and concerns related to art toxicity.10 in 2002, a constitutional court ruling mandated rolling-out of a pmtct programme.11 reports of mtct of hiv in vlbw infants followed,12,13,14,15,16,17 but these failed to determine the safest feeding choice in such infants. the feeding regimens in these studies included exclusive formula feeding (eff) in line with the national pmtct programme at the time,18,19 exclusive donor breast milk (dbm) (holder pasteurised) and heat-treated mom (pretoria pasteurised or flash-heated).20,21 annual studies reporting on mtct in infants ≤ 1500 g from 2005 to 2007 noted hiv transmission rates of 14.9%,12 19.0%13 and 10.0%,14 respectively. at this time, the implementation of art for pmtct in south africa was inconsistently applied (table 1). subsequently (2008–2015), mtct declined from 7.6% to 0.0%15,16,17 when pmtct became the standard of care (table 1). this included improved infant regimens at and post-delivery18,19,22,23,24 and the provision of maternal combination art (cart) to pregnant and breastfeeding women.23 no infants included in these studies (n = 289) received rmom from birth.15,16,17 table 1: south african studies reporting on human immunodeficiency virus transmission by postnatal age in infants ≤ 1500 g birth weight. most hiv-exposed preterm infants prior to initiation of modern pmtct programmes received eff, as did their term counterparts.18,19 subsequently, the safety of heat-treated expressed mom was confirmed,20,21 and this became the feeding choice for hospitalised preterm infants in many facilities. although affordable,20,21 heat-treated mom is labour-intensive in a hospital setting and for mothers after discharge. also, it remained unclear whether non-hiv-related benefits of mom were lost through the heat treatment. study objective a retrospective, observational audit was undertaken to determine the cumulative incidence of peripartum hiv transmission at 4–6 weeks of age in hiv-exposed vlbw infants, who received infant prophylaxis according to the national pmtct programme of 201019,22 and ‘predominantly’ raw mom (prmom) (see study population section for the definition of prmom). material and methods setting this study was performed in the neonatal unit of kalafong provincial tertiary hospital, south africa. the neonatal unit comprises 30 beds, which include 6 neonatal intensive care beds. there are approximately 5900 deliveries per year at kalafong provincial tertiary hospital, with a maternal hiv prevalence of approximately 18%. study population the study population was identified from ward registers. the start of this study, 01 march 2010, coincided with the implementation of the national 2010 pmtct guideline. records of patients admitted to the unit in the subsequent 36 consecutive months were audited. breast milk was prescribed to all infants admitted to the neonatal unit and supplemented by dbm if mom was insufficient. infants were included if they were hiv-exposed, that is, born to an hiv-positive mother and received prmom, that is, at least two-thirds of the total enteral volume, over the study period. the remaining one-third enteral fluid volume was dbm and was given with infant antiretroviral prophylaxis. the latter was daily nevirapine from birth until at least 6 weeks of age. a surveillance hiv-pcr was checked at 6 weeks as per the 2010 national pmtct programme.19,22 (table 2). table 2: maternal antiretroviral therapy, infant prophylaxis and feeding regimens recommended by the south african national prevention of mother-to-child transmission programme of 2010 for human immunodeficiency virus-positive women during pregnancy and after delivery and their human immunodeficiency virus-exposed infants. deviations from the surveillance regimen19,22 were indicated in some infants. these included hiv-pcr testing at ‘non-routine’ times, for example, within 72 h after birth to diagnose congenital infection; before 6 weeks of age in the event of clinical signs suggestive of hiv infection; and should discharge occur before 4 weeks of age to minimise the number who might not return and so be lost to follow-up. all hiv-pcr test results were accessed from patient files and the national health laboratory service (nhls) database. definitions congenital infection in utero acquisition of hiv (congenital infection) was diagnosed when an hiv-pcr was positive within 72 h of birth. peripartum infection the mtct of hiv during the peripartum period was defined as hiv acquisition during labour, delivery or while receiving prmom and nevirapine (nvp) prophylaxis. it was diagnosed when an hiv-pcr test was negative within 72 h after birth yet positive at 4–6 weeks. in the absence of an early hiv-pcr, peripartum infection was excluded if the hiv-pcr was negative at 4–6 weeks. exclusion criteria infants were excluded if death occurred before 4 weeks of age, azidothymidine (azt) was used as pmtct, feeds were exclusively dbm or eff, no hiv-pcr result was available at 4–6 weeks of age, admission to the neonatal unit occurred after 72 h of life, hiv was deemed to have been acquired in utero and clinical records were missing or incomplete (figure 1). figure 1: flow chart detailing exclusions. background infant feeding regimens although free tins of formula were provided for hiv-exposed infants who complied with the acceptable, feasible, affordable, safe and sustainable (afass) feeding criteria,21 breastfeeding was officially adopted in august 2011 (tshwane declaration) as the feeding regimen of choice for all infants, including those who were hiv-exposed25 as breast milk was shown to be safe in these infants provided they received pmtct26 (table 2). maternal antiretroviral therapy regimens the national pmtct programme of 2010 used the maternal cd4 count and hiv staging to determine maternal antenatal and postnatal art regimens19,22,27 (table 2). exposure of infants to maternal antenatal antiretroviral therapy duration of exposure to maternal antenatal art (lifelong cart or dual therapy) was defined, for the purpose of this study, as optimal (≥ 4 weeks), suboptimal (< 4 weeks) or no art. infant prophylaxis all infants were initiated on nvp after delivery, which was continued for at least 6 weeks. a weight-based dosing regimen, as recommended by the world health organization,28 was adopted for infants weighing < 1800 g: 2 mg/kg daily for the first 2 weeks of life and 4 mg/kg thereafter.29 data analysis statistical analysis was performed using stata statistical software 2017 (release 15.1, statacorp llc, college station, us). continuous data were expressed as medians and ranges and categorical data as frequencies and percentages. cumulative incidence and 95% confidence intervals were determined using poisson regression. ethical consideration the study protocol was approved by the ethics committee of the faculty of health sciences of the university of pretoria, south africa (ethics approval number 351/2013). results over the 3-year period from 01 march 2010 to 28 february 2013, 3790 newborn infants were admitted to the neonatal unit, of whom 3774/3790 (99.58%) had a documented birth weight. of these infants, 690/3774 (18.28%) had a birth weight ≤ 1500 g; 404/690 (58.55%) of these were not hiv-exposed; 219/690 (31.74%) were hiv-exposed; and a further 67/690 (9.71%) had no documented maternal hiv test result. study population and exclusions the hiv-exposed infants (219/690) were the preliminary study population. as per protocol, 139/219 infants were excluded, as shown in figure 1. a sample of 80/219 hiv-exposed infants remained and formed the final study population. the details of the 39 infants who died and were consequently excluded from the study are also shown in figure 1. maternal data of the study population the maternal population totalled 72 mothers: 8/80 infants were four twin pairs. of these mothers, 61/72 (84.72%) received antenatal care during pregnancy. all had non-reactive rapid plasma reagin (rpr) tests for syphilis, while 7/72 (9.72%) received treatment for tuberculosis (tb). the demographics of the hiv-infected mothers is shown in table 3. the median cd4 count was 272 cells/mm3 (range 8–1097 cells/mm3), and the median hiv viral load was 7191 copies/ml (range 0–68 952 copies/ml). it should be noted that only 77.78% (56/72) of hiv-infected women were receiving art during their pregnancy. table 3: maternal human immunodeficiency virus characteristics clinical characteristics of the study population (n = 80) infant median weight was 1130 g (range 510–1500 g) and the median gestational age was 30 weeks (range 25–38 weeks). additional data are shown in table 4. during pregnancy, only 78.75% (63/80) of infants had any antenatal art exposure. twenty per cent had no exposure. the antenatal art exposure of one infant was undocumented. after delivery, all infants (n = 80) received both postnatal nvp and prmom until discharge (figure 2). table 4: infant characteristics. figure 2: the safety of ‘raw’ mother’s own milk in human immunodeficiency virus-exposed very low birth weight infants. postnatal prophylaxis all 80 infants were hospitalised after birth and received supervised daily nvp until discharge. the majority of infants (67/80) received the first dose of nvp within 24 h of birth. seven infants received it after 24 h (range 30–84 h). the timing of the first dose was not recorded for six infants. just more than half of the infants (41/80) received nvp at the recommended daily dose of 2 mg/kg, with doses varying between 2 mg/kg and 10 mg/kg (median 2 mg/kg), but never exceeding a total daily dose of 10 mg. in addition to nvp, 40/80 (50.0%) infants were also exposed to maternal lifelong cart during breastfeeding. feeding regimen with mother’s own milk in keeping with the exclusive breastfeeding policy of the neonatal unit, mom was prescribed for all infants after birth. three-quarters, viz. 59/80 (73.8%) of infants, received rmom exclusively until discharge. the remainder, viz. 21/80, required supplementation with dbm. the median proportion of the volume of dbm intake of the 21/80 infants was 8.96% (range 1.67% – 33.33%) of the total enteral intake. no infant received formula milk. mother-to-child transmission of human immunodeficiency virus a definitive hiv-pcr was performed on 78/80 infants by 4–6 weeks of age to rule out peripartum acquisition of hiv; n = 45/78 infants tested negative before discharge; 33/78 infants tested negative at follow-up, viz. 67/78 at 6 weeks, 7/78 at 5 weeks and 4/78 at 4 weeks of age. two infants tested positive: one on day 9 and the other on day 20 of life. these hiv-pcr tests were performed earlier because clinical signs suggested active hiv infection. human immunodeficiency virus infection in these two infants was confirmed with a second (follow-up) hiv-pcr, and they were initiated on lifelong cart. neither had an hiv-pcr within 72 h of birth, so in utero hiv infection cannot be excluded. their birth weights were 1120 g and 1400 g, respectively. both were on nvp prophylaxis and prmom from birth. neither had been exposed to maternal art before birth. fourteen (14/78) other hiv-exposed but uninfected (heu) infants remained uninfected despite the absence of exposure to maternal art prior to birth (table 4). the time of hiv acquisition in the two infected infants (namely in utero as opposed to peripartum) could not be determined with certainty. therefore, the cumulative incidence of peripartum hiv transmission by 4–6 weeks of age in the study population is expressed as ranging between 0% and 2.5%. it would be 0% had both these infants acquired hiv in utero, 1.27% (95% ci: 0.2–8.9) had one infant acquired hiv during the peripartum period, and 2.5% (95% ci: 0.6–9.9) had both acquired hiv during the peripartum period (figure 3). figure 3: three scenarios related to cumulative incidence of peripartum human immunodeficiency virus transmission by 4–6 weeks. discussion the cumulative incidence of peripartum hiv infection in vlbw infants by 4–6 weeks receiving the national pmtct programme of 2010 19,22 in addition to prmom is 2.5%. this is comparable to the mtct of 2.7% in a more vulnerable cohort of extremely low birth weight south african infants at 6 weeks.16 this cohort, studied when the national pmtct programme of 201019,22 was operational, did not receive rmom.16 the vlbw infants in our study received prmom and its additional nutritional and immunological advantages with seemingly no increased risk of mtct. this finding lends support for the contention that exclusive breastfeeding of hiv-exposed infants3 and their vlbw counterparts is safe in the context of antiretroviral prophylaxis. as previously documented, 690 of the 3774 infants (18.28%) admitted to the neonatal unit at kalafong provincial tertiary hospital were vlbw, 219 being hiv-exposed. their risk of being already hiv-infected at the time of birth (in utero hiv acquisition) or acquiring the infection during the peripartum period could be minimised by timeous antenatal as well as postnatal maternal art. providing the infant with additional art prophylaxis after birth should further reduce the risk of peripartum hiv transmission, particularly via breast milk. this directive was mandated by the national pmtct programme of 2010,19,22 at the time of this study, however was not reliably applied especially during the antenatal period. at least 15/72 women received no art during pregnancy, which increased the risk of in utero and peripartum infection in 16 infants in the study population (one mother had twins). only two of these 16 infants acquired hiv infection, while none of the infants exposed to antenatal art acquired hiv infection, although receiving prmom in the presence of postnatal nvp prophylaxis (figure 2). these results suggest that nvp prophylaxis may be effective in preventing early transmission of hiv in vlbw infants receiving prmom; however, as this is the first study reporting on the safety of prmom in vlbw infants, this observation should be confirmed by larger studies. limitations although all infants received prophylaxis, it was carried out inconsistently. some infants did not receive the first nvp dose immediately after delivery, and in almost half, the weight-based nvp regimen was not adhered to. notably, only 2/42 infants with suboptimal or no antenatal art exposure acquired hiv infection in the presence of prmom. the inconsistencies in the practical implementation of the national pmtct programme of 201019,22 at clinic and hospital level demonstrate the importance of correct emphasis when training healthcare workers. lack of maternal art may have contributed to hiv transmission in the two hiv-infected infants in this study because neither of the mothers received antenatal or postnatal art before the infants were diagnosed with hiv infection. by virtue of the retrospective nature of this study, limitations exist. reduced infant numbers (n = 80) resulting from various exclusions (figure 1) was the predominant limitation. the largest number of exclusions was for undocumented maternal hiv status (67/690), and no traceable infant hiv-pcr result at ≥ 4 weeks of age (54/219). no long-term follow-up hiv results were available for the 80 included infants, so the overall hiv transmission rate is unknown. although the results may be confounded by the 39 deaths prior to 4 weeks of age, the majority of these deaths occurred before 7 days of life (32/39) and are likely to have been immaturity related. however, the possibility of peripartum hiv infection in the late deaths (7/39) cannot be excluded. other confounding factors include the possibility of false-negative hiv-pcr tests by 4–6 weeks of age as a result of incomplete viral suppression caused by maternal art exposure and/or infant prophylaxis.30 conclusion and recommendations viral suppression by antenatal art followed by infant prophylaxis decreases the risk of mtct in preterm infants in the presence of rmom and is likely to protect from life-threatening infection in this group of special – ‘key population’ – patients. additional personal and public health consequences of breastfeeding such as bonding and long-term successful lactation are of importance to hiv-positive mothers and their children. addendum the latest national pmtct programme (2017)24 differs from the 2010 programme19,22 (table 2) as follows: maternal lifelong cart is initiated immediately at hiv diagnosis, irrespective of the cd4 count or hiv staging. infant pmtct prophylaxis (drugs and duration) is dependent on maternal factors, with risk classified as low or high. ‘low-risk’ infants (maternal cart since conception; cart > 4 weeks prior to delivery with a viral load < 1000 copies/ml) receive nvp for 6 weeks, and ‘high-risk’ infants (newly diagnosed maternal hiv; cart < 4 weeks; viral load > 1000 copies/ml) receive dual therapy (nvp plus azt) for 12 weeks. breastfeeding is recommended for all hiv-exposed infants (‘low risk’ and ‘high risk’), except for those whose mothers are failing second-line or third-line art regimens. acknowledgements the authors thank prof. p.j. becker, research office, university of pretoria, south africa, for his assistance with data analysis and reporting. they also thank the department of research innovation at the university of pretoria for their assistance. competing interests the authors declare that they have no financial or personal relationship(s) that may have inappropriately influenced them in writing this article. authors’ contributions both authors conceptualised and designed the research project, interpreted the data after statistical analysis and drafted the article. m.c. collected and managed the data. s.d.d. revised the article critically for important scientific content. both authors approved the final version to be published. references department of health south africa. the 2015 national antenatal sentinel hiv & syphilis survey report [homepage on the internet]. 2015 [cited 2019 apr 7]. available from: http://www.health.gov.za/index.php/shortcodes/2015-03-29-10-42-47/2015-04-30-08-18-10/2015-04-30-08-21-56?download=2584:2015-national-antenatal-hiv-prevalence-survey-final-23oct17. xiao p, zhou y, chen y, et al. association between maternal hiv infection and low birth weight and prematurity: a meta-analysis of cohort studies. bmc pregnancy childbirth. 2015;15:246. https://doi.org/10.1186/s12884-015-0684-z goga ae, dinh th, jackson dj, et al. population-level effectiveness of pmtct option a on early mother-to-child (mtct) transmission of hiv in south africa: implications for eliminating mtct. j 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from: http://pmg-assets.s3-website-eu-west-1.amazonaws.com/docs/080226pmtct.pdf. department of health south africa. clinical guidelines: pmtct (prevention of mother-to-child transmission) [homepage on the internet]. 2010 [cited 2019 apr 7]. available from: http://www.sahivsoc.org/fileupload/ndoh_pmtct.pdf. jeffery bs, webber l, erasmus d. determination of the effectiveness of inactivation of human immunodeficiency virus by pretoria pasteurisation. j trop pediatr. 2001;47(6):345–349. https://doi.org/10.1093/tropej/47.6.345 israel-ballard k, chantry c, dewey k, et al. viral, nutritional, and bacterial safety of flash-heated and pretoria pasteurised breast milk to prevent mother-to-child transmission of hiv in resource-poor countries. a pilot study. j acquir immune defic syndr. 2005;40(2):175–181. https://doi.org/10.1097/01.qai.0000178929.15904.95 department of health south africa. guidelines for the management of hiv in children [homepage on the internet]. 2nd edition. 2010 [cited 2019 apr 7]. available from: https://sahivsoc.org/files/guidelines_for_management_of_hiv_in_children_2010.pdf. department of health south africa. national consolidated guidelines for the prevention of mother-to-child transmission of hiv (pmtct) and the management of hiv in children, adolescents and adults [homepage on the internet]. 2015 [cited 2019 apr 7]. available from: http://www.sahivsoc.org/files/art%20guidelines%2015052015.pdf. human immunodeficiency virus infection. in: standard treatment guidelines and essential medicines list for south africa. hospital level paediatrics [homepage on the internet]. 4th ed. pretoria, south africa: the national department of health; 2017 [cited 2019 apr 7], p. 274–275. available from: http://www.health.gov.za/index.php/standard-treatment-guidelines-and-essential-medicines-list/category/456-hospital-level-paediatrics. coutsoudis a, pillay k, kuhn l, et al. method of feeding and transmission of hiv-1 from mothers to children by 15 months of age: prospective cohort study from durban, south africa. aids. 2001;15(3):379–387. https://doi.org/10.1097/00002030-200102160-00011 the tshwane declaration of support for breastfeeding in south africa. s afr j clin nutr. 2011;24(4):214. world health organization. antiretroviral drugs for treating pregnant women and preventing hiv infection in infants: recommendation for a public health approach [homepage on the internet]. 2010 [cited 2019 apr 7]. available from: https://apps.who.int/iris/bitstream/handle/10665/75236/9789241599818_eng.pdf?sequence=1. department of health south africa. the south african antiretroviral treatment guidelines [homepage on the internet]. 2010 [cited 2019 apr 7]. available from: http://www.sahivsoc.org/files/summary_the_south_african_antiretroviral_treatment_2010.pdf. kroon m, de waal r, horn a, et al. pmtct guidelines for preterm infants and an interim report of nevirapine trough levels [homepage on the internet]. proceedings of the 30th conference on priorities in perinatal care. south africa; 2011 [cited 2019 apr 7]. available from: https://www.perinatalpriorities.co.za/proceedings-database/. sherman gg. hiv testing during the neonatal period. s afr j hiv med. 2015;16(1), art. #362:3. https://doi.org/10.4102/sajhivmed.v16i1.362 abstract introduction methods measurements and variables definitions statistical analysis ethical consideration results demographic characteristics of respondents who reported multiple sexual partnership demographic characteristics of respondents who reported non-condom use univariate analysis – predictors of multiple sexual partnership univariate analysis – predictors of non-condom use at last sex multivariable analysis – predictors of multiple sexual partnership and non-condom use discussion conclusion and recommendations acknowledgements references about the author(s) patience g. manjengwa south african field epidemiology training programme, national institute of communicable diseases, johannesburg, south africa school of health systems and public health, university of pretoria, pretoria, south africa kerry mangold south african national aids council trust, pretoria, south africa alfred musekiwa south african field epidemiology training programme, national institute of communicable diseases, johannesburg, south africa lazarus r. kuonza south african field epidemiology training programme, national institute of communicable diseases, johannesburg, south africa school of health systems and public health, university of pretoria, pretoria, south africa citation manjengwa pg, mangold k, musekiwa a, kuonza lr. cognitive and behavioural determinants of multiple sexual partnerships and condom use in south africa: results of a national survey. s afr j hiv med. 2019;20(1), a868. https://doi.org/10.4102/sajhivmed.v20i1.868 original research cognitive and behavioural determinants of multiple sexual partnerships and condom use in south africa: results of a national survey patience g. manjengwa, kerry mangold, alfred musekiwa, lazarus r. kuonza received: 07 may 2018; accepted: 14 feb. 2019; published: 10 june 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: human immunodeficiency virus (hiv) risky behaviours including multiple sexual partnership (msp) and non-condom use (ncu) are known to be drivers of the spread of hiv; cognitive factors including perceived susceptibility of hiv, self-efficacy and attitudes play a significant role in influencing risky sexual behaviours. objectives: we sought to investigate personal beliefs, perceptions, thoughts and actions that are associated with msp and ncu in south africa. methods: we analysed nationally representative data from the 2012 national hiv communication survey (ncs) that included about 10 000 participants aged 16–55 years. five constructs were created to measure psychosocial and cognitive determinants. cronbach’s alpha coefficient for internal consistency reliability was calculated. multivariable logistic regression was used to determine factors associated with msp and ncu. results: of the 6061 sexually active respondents, 13% (95% ci: 11.47–13.12) reported msp and 52.7% (n = 3158 of 6039) (95% ci: 51.0–53.55) ncu at last sex. factors associated with msp included perceived benefits, adjusted odds ratio (aor) = 2.16 (95% ci: 1.80–2.58), perceived susceptibility to hiv, aor = 2.22 (95% ci: 1.83–2.69) and engaging in intergenerational sex, aor = 2.14 (95% ci: 1.78–2.56). predictors of ncu were perceived benefits, aor = 1.25 (95% ci: 1.09–1.43); perceived susceptibility to hiv, aor = 1.6 (95% ci: 1.39–1.83); and personal beliefs, aor = 1.35 (95% ci: 1.13–1.62). conclusion: cognitive and behavioural factors were found to be predictors of risky sexual behaviours for hiv. this highlights the importance of considering personal perception and reasoning when attempting to understand and influence an individual’s sexual behaviour. this could be done through enhancing awareness of hiv risk in the general population and by influencing cognitive behaviour change through community mobilisation, advocacy and creating activities to improve self-esteem. keywords: hiv; multiple sexual partnerships; non-condom use; cognitive factor; intergenerational sex; perceived benefits; perceived susceptibility; personal beliefs. introduction globally, human immunodeficiency virus (hiv) poses a major public health concern, causing high rates of mortality and morbidity.1 in 2013, there were 35.3 million people living with hiv, with approximately 2.3 m new hiv infections and more than 1.6 m hiv-related deaths.2 in sub-saharan africa, it was estimated that there were 23.5 m people living with hiv in march 2015.2 in 2012, hiv prevalence in south africa (sa) among all age groups was 12.2%, an increase from 10.6% reported in 2008.2 with an hiv incidence rate of 4.5%, the increased prevalence of hiv in 2012 could be attributed to the combined effects of new infections and a successfully expanded antiretroviral treatment (art) programme.2 numerous societal, cultural and personal intrinsic factors have been identified as important social and structural drivers of the hiv epidemic in sa, including high population mobility and inequalities in wealth and gender.3 other contributing drivers of hiv include attitudes and behaviours of men, intergenerational sex, gender and sexual violence, stigma and untreated viral sexually transmitted infections (stis).3,4,5,6,7 sa is continuing to address social and structural factors that influence hiv and prevent new hiv infections.2,6 one of the goals of the south african national strategic plan on hiv, stis and tb 2012–2016 is to reduce new hiv infections by at least 50%, using a combination of prevention approaches combining biomedical and behavioural interventions.8 in 2012, the south african government made a commitment to address issues related to social and structural factors that influence hiv through scaling up accessibility of services including art, rolling out the hiv counselling and testing campaign, expanding medical male circumcision programmes and provision of basic needs grants.6,7,9 to reduce new hiv infections, a combination of biomedical, behavioural, social and structural interventions have been set in place and are being constantly improved for better alignment.8 multiple and concurrent partnerships, low and inconsistent condom use, alcohol abuse (together termed risky sexual behaviours) and low levels of male circumcision have been shown to be the key drivers of the epidemic.10,11 while hiv risky behaviours are known to be drivers of the spread of hiv, cognitive factors including perceived susceptibility to hiv, perceived monetary or material benefits of having sex for material gain, self-efficacy and attitudes play a significant role in influencing risky sexual behaviours.12,13,14 based on the health belief model, an individual’s personal belief influences their behaviour.12 despite the large number of research studies carried out on risk factors of hiv in sa, which include age of sexual debut, age disparate or intergenerational relationships (5 year age difference), multiple sexual partnerships (msps) and condom use, there have been limited studies of cognitive behaviours that influence risky sexual behaviours. cognitive behaviours include a perceived lack of susceptibility to hiv, perceived benefits, personal beliefs surrounding risky sexual behaviours, condom self-efficacy, social norms and the impact self-esteem has on engaging in risky sexual behaviours.15 a study conducted by tarkang in cameroon in 2013 revealed that only 39% of the sexually active secondary school learners had a high hiv risk perception.16 a study conducted by pettifor et al. in sa reported that only 14.0% of school learners had high hiv risk perception.17 perceptions, ideas and behaviours that determine people’s actions need to be explored further in order to better understand the drivers of risky sexual behaviours in sa. there are a number of psychological concepts that show how ideational and cognitive factors can have an impact on behaviour modification. the acquired immune deficiency syndrome (aids) risk reduction model states that knowledge of hiv and aids is a prerequisite that will enable an individual to take action and change their behaviour. this model links hiv knowledge to behaviour change. however, findings regarding the correlation between knowledge and behaviour have been inconsistent.3 other theories and models of health risk perception assert that cognitive ideational factors that are related to attitudes, beliefs, knowledge, intentions and perceived self-efficacy are sufficient to foster safer sex behaviour.3,12 this study sought to investigate personal beliefs, perceptions and other ideas, thoughts and actions that are associated with msp and non-condom use (ncu) among the south african population aged 16–55 years. methods we analysed secondary data from the third national hiv communication survey (ncs) conducted in all nine provinces in sa between february and may 2012. this survey was designed to be representative of 16–55 years old. the methodology has been previously published,16 but briefly a multi-stage, cluster sampling approach was first used to draw a sample of 400 primary sampling units. secondly, a systematic sampling interval was calculated by probability proportional to size techniques. the third stage of the sampling focused on randomly selected households, followed by individuals. measurements and variables an interviewer-administered structured questionnaire was used to collect data, including socio-demographic characteristics, exposure to television and radio communication messages or programmes on hiv and aids, perception of risk and indicators on knowledge, attitude and behaviour related to hiv and aids. five constructs were created to measure psychosocial and cognitive determinants. responses to the questions that made up the constructs were graded on a five-point likert scale, ranging from strongly disagree to strongly agree. cronbach’s alpha coefficient for internal consistency reliability was used to assess the correlations between the items that made up each construct. values of 60% or higher were considered to indicate acceptable internal consistency. a composite score was obtained for each construct by calculating an average score of the responses to all the questions that made up the construct. we calculated the average scores in percentages. the composite score was used to create a dichotomous variable for the construct, which was graded as either high if the composite score was above 65% or low if the composite score was 65% or lower. this cut-off number was used to accommodate the small number of questions used on other constructs because we used questions from a survey that was intended to measure communication programmes in sa. box 1 shows single-item questions that were used for each behavioural construct. box 1: single-item questions from the questionnaire of the national hiv communication survey 2012 used to create cognitive and social behaviour constructs. definitions the perceived benefits construct was defined as beliefs that there are positive outcomes related to engaging in a specific behaviour. the self-efficacy construct was defined as beliefs that one is capable of completing a certain task on their own. perceived susceptibility was defined as the individual’s belief that they would acquire hiv infection. social norms are beliefs of how the society thinks people should perform or how the society views things. personal beliefs are intrinsic cognitive beliefs that people have on their own. multiple sexual partnerships (msp) refers to having had more than one sexual partner in the past 12 months and ncu is defined as not using either a male or a female condom at last sex. intergenerational sex was defined as having a sexual relationship with someone with a 5 year or more age difference. statistical analysis a descriptive cross-sectional analysis was conducted to describe the demographic and risk factors by age, sex and province. we used weighted data in our analysis to be representative of the sa population with respect to age, sex, province, population group and urban or rural residence. sample weights were corroborated using the 2007 community survey conducted by statistics south africa. chi-squared test was used to test for an association between the outcomes msp and ncu and psychosocial and cognitive constructs. univariate logistic regression was used to determine factors associated with the outcomes msp and ncu. manual forward stepwise procedure was used to select variables for the multivariable model. multi-collinearity tests were performed and only non-collinear variables were analysed. multivariable logistic regression was used to determine independent factors associated with outcome after adjusting for potential confounders such as sex, employment, age, relationship type, geography, settlement type, hiv status, condom use at last sex, intergenerational sex (difference in ages by 5 years) and alcohol use at last sex, perceived susceptibility, personal benefits, personal beliefs, social norms, self-esteem and condom self-efficacy. a p-value of less than 0.05 was considered statistically significant. all analyses were conducted using stata 13.0 (stata corporation, college station, tx, usa). ethical consideration all procedures performed in studies involving human participants were in accordance with ethical standards of the institutional and/or national research committee and with the 1964 helsinki declaration and its later amendments or comparable ethical standards. for this type of study, formal consent was not required. results the socio-demographic characteristics of the sampled population are shown in table 1. of the total sample of 10 034 participants, 6061 reported that they had at least one sexual encounter in the past 12 months. of these sexually active participants, 41% (2467 of 6061) were men. the overall mean age was 31.3 years (s.d.: 11). twenty-three per cent (1378 of 6061) of the participants were aged 20–24 years and 6% (371 of 6061) were aged 45–49 years. overall, 39% (2374 of 6061) lived in urban formal settlements, 37% (2158 of 6061) were from urban informal settlements, 11% (659 of 6061) lived in peri-urban areas and only 2% (286 of 6061) lived in farming settlements. the majority of participants had some form of education, but 1% (56 of 6061) had no schooling. participants with a high socio-economic status were 34.7% (2107 of 6061) and medium socio-economic status was almost similar at 38.5% (2335 of 6061). table 1: background demographic characteristics of participants who had at least one sexual encounter in the past 12 months of the survey in the south african 16–55-year-old population, 2012. demographic characteristics of respondents who reported multiple sexual partnership a total of 13% (744/6061; 95% ci: 11.47–13.12) of the sexually active population aged 16–55 years reported having had msp in the past 12 months. the mean age was 28 years (s.d. 7.62), with the majority (65%) being men (481/744). table 3 shows that the majority (93%) were black people (696/744), 5% (41/744) were mixed race and less than 1% (7/744) were white people or indians. almost half had medium socio-economic status 45% (330/744). the highest percentage of people who engaged in msp was recorded among single respondents 41% (306/744) followed by those not married or living together but in a steady relationship 33% (247/744). table 2: demographic, hiv risk, cognitive and social predictors of multiple sexual partnership in the past 12 months among 16–55-year-old participants in south africa, 2012. table 3: demographic, hiv risk, cognitive and social predictors of non-condom use at last sex among sexually active 16–55-year-old participants in south africa, 2012. demographic characteristics of respondents who reported non-condom use out of the total number of sexually active respondents, more than half reported not using a condom at last sex 53% (3158/6039, 95% ci: 51.03–53.55, p < 0.05). mean age was 33 years (s.d. 10.02). of the people who did not use condoms at last sex, 62% (1956/3158) were women. twenty per cent of the people who reported ncu were from gauteng province (gp) (632/3158) followed by western cape (wc) 18% (568/3158) and kwazulu-natal (kzn) 17% (562/3158). among those with no schooling, 79% (44/56) did not use condoms at last sex. non-condom use at last sex was common among those who had education up to grade 11 (43%; 1355/3158). the prevalence of ncu among people with a high socio-economic status was 54% (1134/2097) and those with a low socio-economic status were 52% (852/1610). of the people who reported not using condoms at last sex, married participants had the highest prevalence of ncu at last sex (35%; 1102/3158), followed by single (22%; 700/3158) and not married or living together but in a steady relationship (21%; 648/3158). univariate analysis – predictors of multiple sexual partnership the odds of reporting msp were two times higher among those engaging in intergenerational sex than those having sex with people in the same generation (or 2.10, 95% ci: 1.79–2.46, p < 0.001). participants who had consumed alcohol before sex were 1.3 times more likely to report msp than those who did not consume alcohol before sex (or 1.33, 95% ci: 1.06–1.67, p < 0.02). people who engaged in transactional sex were almost six times more likely to have msp in the past 12 months than those who did not engage in transactional sex (or 5.97, 95% ci: 4.89–7.29, p < 0.001). people who lived in free state province were nearly four times more likely to report msp (or 3.73, 95% ci: 2.67–5.21, p < 0.001) than people living in wc province. those living in gp were two times more likely to report engaging in msp (or 2.35, 95% ci: 1.74–3.09, p < 0.001) than people living in wc province. students were almost 1.5 times likely to report having engaged in msp than unemployed participants (or 1.47, 95% ci: 1.13–1.89, p < 0.005). univariate analysis – predictors of non-condom use at last sex employed participants were 1.17 times (or 1.17, 95% ci: 1.05–1.31, p < 0.005) more likely to report to have not used condoms at last sex than their unemployed counterparts. people living in farming settlements were almost two times more likely to have not used a condom at last sex than those living in urban formal (or 1.91, 95% ci: 1.35–2.68, p < 0.001). drinking alcohol in the past month was significantly associated with ncu at last sex (or 1.27, 95% ci: 1.07–1.53, p < 0.001). multivariable analysis – predictors of multiple sexual partnership and non-condom use the multivariable analysis showed that perceived benefits (aor 2.16, 95% ci: 1.80–2.58, p < 0.001) and low perceived susceptibility (aor 2.22, 95% ci: 1.83–2.69, p < 0.001) to hiv infection were the two psychosocial and cognitive constructs that were significantly associated with msp. intergenerational sex (aor 2.14, 95% ci: 1.78–2.56, p < 0.001), medium socio-economic status (aor 1.24, 95% ci: 1.01–1.55, p = 0.05) and having tertiary education (aor 2.04, 95% ci: 1.27–3.28, p < 0.005) were additional predictors of msp. results in table 1 show that after adjusting for confounders, personal belief around condoms (aor 1.35, 95% ci: 1.13–1.62, p < 0.005), high perceived benefits (aor 1.25, 95% ci: 1.09–1.43, p < 0.005) and low perceived susceptibility to hiv infection (aor 1.6, 95% ci: 1.39–1.83, p < 0.001) were identified as psychosocial and cognitive factors that influence ncu at last sex. the final multivariable model for ncu, table 3, retained living in farming settlements (aor 2.15, 95% ci: 1.46–3.15, p < 0.001) and age group (30–34) compared to 16–19 year olds (aor 2.28, 95% ci: 1.74–3.01, p < 0.001) together with the psychosocial and cognitive factors mentioned above. discussion in this study, low perceived susceptibility of hiv infection and perceived monetary, material or cognitive benefits were significantly associated with both msp and ncu at last sex. similar associations were found in a study conducted in cameroon in 2012, which revealed the association of msp and low-risk perception of hiv infection.16 it is very concerning to note that people perceive themselves to be at lower risk of acquiring hiv infection despite engaging in risky sexual behaviour. it is generally known that people judge a potential threat through their past experiences and anticipated consequences.12,18 low perceived susceptibility could be partially attributed to the fact that hiv and aids is a highly stigmatised disease. therefore, when a person acknowledges his or her risk of acquiring hiv infection, he or she becomes vulnerable to being stigmatised. because of this risk, people may avoid self-disclosure and by so doing downplay their personal risk. a high proportion of black participants reported engaging in msp, followed by mixed race participants as compared to the indian participants. multiple sexual partnership was significantly higher among men than among women. this is consistent with other studies where generally wealthy men in patriarchal societies like sa are expected to have numerous partners or wives. this follows the polygamous culture in african countries.19 furthermore, women have been found generally to under-report sexual behaviours.8,20 this can be explained by the fact that women want their manner to be viewed favourably by others. msp in women is often viewed in a derogatory sense. the proportion of respondents who had reported not using condoms at last sex was 57%. this was higher among women (62%) than among men (38%). the figure appeared similar to the findings of the south african national hiv prevalence, incidence and behaviour survey, 2012, which reported ncu as 63% in the whole population.2 engaging in msp and having unprotected sex increases hiv risk because of the fact that individuals may be linked through sexual networks and become more vulnerable to high viral load exposure during the early phases of new hiv infection.21 low socio-economic status was predictive of ncu at last sex but there was a significant association with msp. in this study, msp was frequently reported among those with medium socio-economic status and least reported among respondents with a high socio-economic status. similarly, according to a survey conducted on young men and women in sa in 2004, msp was reported least among those with high socio-economic status. an explanation of a similar finding suggested that if people with lower socio-economic status are compared to the ones with a high socio-economic status, those with lower socio-economic status may choose to spend more of their income pursuing various forms of relationships.2,5 another possible explanation could be that respondents in the high socio-economic group may have higher educational attainment and better health information; hence, they reduce risky sexual behaviours.22,23 msp was prevalent among participants who engaged in intergenerational sex. it has been shown in this study and other studies that intergenerational sex fuels the hiv epidemic among the younger generations.19,24 research studies argue that when young women mix with the older generation, their risk for contracting hiv increases.2,25 interventions targeted at reducing intergenerational sex could reduce the prevalence of hiv among younger generations. it is concerning that the highest proportion of msp is among the 20–24-year age groups where both boys and girls are affected. age mixing with older generations further exacerbates this problem because young girls are likely to mix with both older men and young boys.26 in this case, old men infect young girls who then infect young boys. studies have confirmed that sex with older men is more risky than sex with younger men because hiv prevalence among older men is significantly higher than younger men.24 the age differential with older men also introduces a power dynamic into the sexual relationship where younger women are more vulnerable and less likely to successfully negotiate condom use. intergenerational sex is also closely entwined with transactional sex – where economic factors push young girls to engage in various forms of sex in exchange for cash or material benefits.1 it is not surprising then that transactional sex was also associated with msp. almost half of the participants reporting both msp and transactional sex were among those with medium socio-economic status. this implies that these participants were not poor but rather alludes to need for economic gains or advancements and wealth inequalities as a push factor towards engaging in hiv risk behaviours. the need for social upward mobility could explain the need for participants to engage in msp and transactional sex.3 increased hiv incidence has been associated with low socio-economic status in recent studies.1,20 however, the practice of msp is not untouched by employment status. with regard to employment status, students recorded a higher prevalence of msp than the unemployed category. this finding is in contradiction to another study conducted in sa that showed that nearly half of the participants who engaged in msp were unemployed and only 10% were students.24 these differences in findings could be because of the differences in how the studies defined unemployed group. this study considered informal employment as employed, while the other study categorised it as unemployed. the geographical coverage of the two studies could also explain the different findings. this analysis utilised data from a national survey, whereas the other study referred to was only undertaken in two provinces in sa. further research will need to be undertaken to confirm these findings. the high prevalence of non-condom use is exacerbated by the consumption of alcohol.1,9,27 alcohol has adverse side effects that include sexual risk behaviours and these have been documented in various different studies in sa.1 poor judgement and risky sexual behaviours are often exacerbated as a result of alcohol consumption as it impairs judgement and reduces inhibition. these findings emphasise the risks associated with the mix of sexual risk behaviours, msp, transactional sex and alcohol; therefore, interventions better equipped for the complexities of the behaviour mix need to be put in place. perceived material, monetary or cognitive benefits were strongly associated with ncu and this was furthermore compounded by the association found between ncu, engaging in transactional sex and having msp. while perceived benefits could be judged by anticipated rewards, in this study, there was an association with both ncu and msp.28 among those who did not use condoms at last sex, perceived benefits were significantly high. similarly, other studies have found that people engage in a mix of msp, ncu and transactional sex to access a fashionable lifestyle.19,24 this may be also explained why we found that students were more likely to engage in risky sexual behaviours as they are vulnerable to peer pressure and living up to a standard. the findings of this research showed that the participants did not use condoms because of their perception of benefits acquired. they perceived that not wearing condoms will make them get more money as compared to wearing condoms and the risk for hiv infection. the findings of ncu after adjusting for confounders of transactional sex, alcohol use before sex and msps revealed that personal beliefs had an impact on condom use. participants believed that it was unpleasurable to use condoms. this is consistent with other studies that have revealed that attitudes about condoms are predictive of condom use.29 while marital status strongly correlated with ncu and remained stronger after adjusting for confounders, being married was significantly associated with ncu; this is consistent with most studies. this finding is concerning and people in all types of relationships should be encouraged to use condoms, especially in a country where msp is common practice regardless of marital status. living in a rural area or farming settlement was found to be a risk factor for not using condoms at last sex. this could be because of stigma and patriarchal norms which play a larger role in determining behaviour.30 this could also be because of logistical challenges of condom supply because of these areas being in difficult to reach or sparse areas of the country. in our analysis, we had some limitations which included the fact that data used in this study analysis relied on self-reported sexual behaviour on sensitive issues, such as condom use and hiv and aids. self-reported data are prone to social desirability bias where respondents tend to respond to questions in a manner that is viewed favourably by others. there is the possibility that participants could have exaggerated behaviour or under-reported undesirable behaviour. it is, however, unlikely that this bias affected our results because assurance of confidentiality and anonymity was given and the questionnaire was administered in a consistent manner across the whole sample. a further limitation is that the survey was cross-sectional in nature, and hence causality was difficult to establish. to overcome this challenge, we only reported on associations and correlations. conclusion and recommendations our study analysed determinants of msp and ncu and revealed that a low perceived susceptibility to hiv infection and that a high perception of benefit are common cognitive constructs correlated strongly to risky behaviours. our results highlight the need to expand on several initiatives including prevention efforts and changing cognitive and psychosocial thinking. firstly, hiv prevention efforts could be performed through encouraging avoidance of extramarital sex and the importance of condom use in all types of relationships, especially where high-risk sexual behaviour takes place such as msp. secondly, these results show that initiatives need to focus more closely on changing cognitive and psychosocial thinking in terms of personal beliefs and norms including the constructs of perceived benefits and perceived susceptibility. this could be done through enhancing awareness of hiv risk in the general population and other cognitive behaviour change interventions. therefore, community mobilisation, advocacy, creating activities to improve self-esteem and aim to increase risk perception are of paramount importance. multi-sectorial efforts focusing on the social and structural drivers of risky sexual behaviours and hiv need to be prioritised. this includes psychosocial, health, educational and economic interventions. lastly, the findings of this research will contribute to the knowledge about personal intrinsic factors and the psychosocial factors that predispose people to engage in risky sexual behaviours and help close a literature gap in understanding the dynamics of the epidemic. cognitive factors must be prioritised and explored further in terms of the roles they play in hiv incidence. acknowledgements the authors acknowledge access to the analysed data from the third ncs. the ncs is a collaborative survey undertaken by johns hopkins health and education in sa, lovelife and soul city. the survey was managed by health and development africa (had). the johns hopkins bloomberg school of public health center for communication programs (jhu-ccp) provided technical support and oversight at all stages of the study. data were gathered by freshly ground insights (fgi). the authors wish to thank the south african national aids council trust, south african field epidemiology training programme (sa fetp). appreciation is also given to dorothy l. southern for providing scientific writing support and critically reviewing this article. competing interests the authors declare that they have no financial or personal relationship(s) that may have inappropriately influenced them in writing this article. authors’ contributions p.g.m., k.m., a.m. and l.r.k. equally contributed to the writing and research of this article. references johnson skd, figueroa me, delate r, mahlasela l, magni s. the third national hiv communication survey 2012. 2013. https://www.ccisa.org.za/sites/default/files/hiv_survey.pdf simbayi lc, shisana o, rehle t, et al. south african national hiv prevalence, incidence and behaviour survey, 2012. pretoria hum sci res counc [serial online]. 2014 [cited 2015 aug 30]; available from: 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author(s) adegoke o. adefolalu practice of medicine unit (pome), sefako makgatho health sciences university, south africa citation adefolalu ao. cognitive-behavioural theories and adherence: application and relevance in antiretroviral therapy. s afr j hiv med. 2018;19(1), a762. http://doi.org/10.4102/sajhivmed.v19i1.762 original research cognitive-behavioural theories and adherence: application and relevance in antiretroviral therapy adegoke o. adefolalu received: 05 may 2017; accepted: 30 oct. 2017; published: 12 apr. 2018 copyright: © 2018. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: adherence in chronic disease conditions is described as the extent to which a person‘s behaviour corresponds to the prescribed medical advice of the healthcare provider. this is not limited to medication intake only but also includes acts such as following instructions regarding dietary or fluid restrictions and taking medicines at the prescribed times and intervals. although adherence to antiretroviral therapy (art) is a predictor of good clinical outcome among hiv-infected persons on art, it is a major challenge and strict adherence is not very common. this article aims to examine the application and relevance of some cognitive-behavioural theories in antiretroviral therapy adherence methods: after doing a thorough literature review, contemporary theories of health behaviour at the individual and interpersonal levels referred to as cognitive-behavioural theories were explored. this review highlights some aspects of the cognitive perspective of health behaviour theories as a good theoretical framework that could be used for organising thoughts about adherence and other health behaviours among patients on lifelong treatment such as art. results: key concepts of these theories stipulate that behaviour is mediated by cognition i.e. knowledge and attitude affect the person’s action. in addition, cognitive-behavioural theories recognise knowledge alone as being insufficient to produce behavioural change; a person’s perception, motivation, skills and social environment are all influential in the process of behavioural change. conclusion: prediction of medication adherence is complex, and health-related knowledge and beliefs alone are insufficient to achieve behaviour change, especially in chronic conditions such as hiv/aids. however, people can control or influence the events affecting their lives by integrating cognitive, social, and behavioural sub-skills related to beliefs of personal efficacy in performing these skills. introduction the cognitive perspective on health behaviour is based upon the assumption that our thoughts and beliefs influence our emotions and behaviour. it focuses attention on ways in which patients conceptualise health threats and appraises factors that facilitate adherence or serve as barriers to treatment.1 however, this model has consistently been criticised for not adequately addressing the issue of behavioural skills needed for adherence among patients, and for paying little attention to the origin of beliefs and how such beliefs influence other behaviours.2 in general, health behaviour theories provide grounds for target interventions aimed at changing behaviour or establishing good health habits.3 ways in which health behaviour can be modified to achieve a desired outcome is increasingly becoming the focus of research into medication adherence. individual level theories explore behaviour and focus on intrapersonal factors such as knowledge, attitude, beliefs, motivation, self-concept, past experience and skills;2 at the interpersonal level, theories of health behaviour take into consideration that an individual exists within a society and is influenced by the social environment. thoughts, behaviours and opinions of people around an individual influence the feelings and actions of that individual, and in turn the individual has reciprocal effects on those around them.4 health behaviour theories play a crucial role in the planning and implementation of health improvement programmes. successful health programmes are based on health behaviours, which are well understood within a social context. there are several individual-related theories related to health behaviour, which can be used to describe and guide interventions related to cognitive factors and antiretroviral therapy (art) adherence in hiv-infected persons. some of the theories frequently used in behavioural interventions are social cognitive theory (sct), the health belief model (hbm), the beliefs about medicine (bam), the trans-theoretical model, the theory of planned behaviour (tpb), and the precaution adoption process model (papm). social cognitive theory social cognitive theory (sct) explains human behaviour in terms of a dynamic, reciprocal and continuous interaction between the individual and the environment.5 the common theoretical basis of cognitive theory is learning; it posits that human behaviour is learned. therefore, sct proposes that behaviour is the result of cognitive processes that people develop through the social acquisition of knowledge.5 this theory focuses on the concept of behavioural capability, which states that before an individual acts in a given circumstance the person needs to know what to do and how to do it. bandura’s conceptual model of reciprocal determinism addresses the personal determinants of health; he postulates that a person engages in cognitive, vicarious, self-reflective, and self-regulatory processes to achieve a set goal.6-7 he goes further to say people effect change in themselves through their actions in anticipatory and proactive ways by exercising control over their behaviour through their thought processes, motivations, and actions.8 bandura asserts that without aspirations people remain unmotivated and uncertain about their capabilities.9 he further states that individuals who engage in health promoting behaviour possess self-belief, enabling them to exercise control over their thoughts, feelings, and actions.9 therefore, people who engage in self-management of health habits reduce major health risks and live healthier and more productive lives.9 according to bandura, although sct acknowledges that knowledge of health risks and the benefits of treatment are necessary to perform health behaviours, this in itself is not enough. additional self-influences are necessary to achieve changes that will result in the desired health behaviour; and this concept is called self-efficacy.8 the two cognitive processes that influence behaviour in sct are called self-efficacy and outcome expectation. social cognitive theory is relevant during healthcare workers’ counselling of patients with chronic medical diseases such as hiv and aids; it could be used to assist patients in learning relevant information about hiv and aids and the potential courses of action to take in making decisions about the disease and its associated health challenges such as adherence.10 support groups for hiv or aids patients could also use cognitive and behavioural strategies to empower patients to negotiate problems around art adherence and establish supportive relationships which strengthen patients’ ability to adhere; all these would subsequently lead to better adherence and good clinical outcomes.2 issues around disclosure of hiv status, relaxation skills, and anxiety management are skills that could be taught in such support groups, and which could lead to improved treatment adherence.10 self-efficacy self-efficacy, a concept first articulated by bandura, describes one’s belief in one’s own ability to execute a particular behaviour and the confidence that one can perform a specific task to achieve a desired outcome. central to bandura’s work is the self-efficacy model, a process whereby a person engages in a particular behaviour with a desired consequent outcome.6 the self-efficacy model begins with a perception of the existence of a problem followed by the belief that the desired result could be achieved with one’s actions, thus creating an incentive to persevere.8 self-efficacy has become a major focus area in the process of assessing patient performance of certain skills that are required to manage their disease condition with the aim of improving their quality of life. self-efficacy theory has also been increasingly recognised in the study of health behaviour as one of the key constructs of sct. individuals with high self-efficacy to perform certain health behaviour (such as adhering to medication) are more likely to carry out such behaviour.11 self-efficacy influences how a person thinks, feels, acts and is motivated. furthermore, self-efficacy affects a person’s choice of setting, the effort expended on a particular task, and their emotional reactions to situations.12 self-efficacy in terms of behavioural change regarding health and disease describes an individual’s belief that he or she can alter a behaviour or action required to achieve positive health outcomes in managing a specific disease condition. self-efficacy is a known predictor of health behaviour in patients with chronic medical conditions,13–17 and has also been shown to influence adherence to art.18,19 art adherence self-efficacy is an individual’s belief in the ability to continue taking antiretrovirals (arvs) despite the various challenges they may encounter in doing so. behaviour change is said to occur as a result of the person’s belief about how capable they are in performing behaviours that would lead to the desired outcome. hiv-infected patients on art will choose to adhere to their medication if they believe that doing so will result in their getting better and experiencing increased quality of life. self-care, defined as the daily regimen of tasks that an individual performs to manage hiv or aids, is not limited to taking pills; it involves behaviours such as sticking to a healthy diet, regular exercise, avoidance of risky behaviour and medication adherence. maintaining self-care behavioural skill in persons with hiv or aids can be a significant challenge, as it requires high level of self-efficacy. bandura describes four sources of information that influence self-efficacy; these are performance mastery, vicarious experience, verbal persuasion, and physiological symptoms. integration of information from one or more different sources forms a self-efficacy judgment.5 all of these factors are equally applicable in art adherence in an hiv-infected person who is on antiretroviral therapy for a prolonged time. performance mastery this refers to knowledge and skill gained through experience and perseverance.5 this strategy is applicable in art adherence, as it entails teaching patients how to avoid negative self-talk, as well as how to monitor self-defeating thoughts and how to replace them with task-focused ones, so that hopelessness associated with non-adherence to antiretroviral therapy can be avoided. vicarious experience vicarious experience occurs when a person observes other people completing a task successfully. this serves as a way of modelling self-efficacy for the observer.5 vicarious experiences or modelling could be used by adherence counsellors in enhancing art adherence.20 this will be in the form of vicarious reinforcement where a desired behaviour such as adherence is being reinforced by seeing someone else being rewarded for it. verbal persuasion this strategy usually takes the form of encouragement or discouragement from another person and is the most commonly used self-efficacy approach used by healthcare professionals. it is used to attempt to convince someone that they can succeed at a particular task.5 verbal or social persuasion serves to reinforce feelings of self-efficacy when facing the minor failures associated with adherence to art. health workers use verbal persuasion and encouragement to enhance art adherence by expressing confidence in their capabilities. this form of support has been shown to result in patients learning new skills and exploring more self-care behaviours. since self-efficacy develops over time, continuous positive reinforcement would be most likely to enhance adherence among patients. physiological symptoms these also serve as sources of information regarding an individual’s self-evaluation of competence. a person’s physical reaction to difficult situations can influence how prepared that person feels to handle the situation effectively.5 during stressful situations, a person’s perception of the impact of their own distress on their body can alter their self-efficacy. becoming ‘overwhelmed’ when faced with some challenges associated with chronic medical conditions (such as adverse reactions to medications) could be interpreted by someone with low self-efficacy as a sign of their inability to adhere to treatment, thus further decreasing self-efficacy. on the other hand, a person with high self-efficacy may interpret such physiological symptoms as normal and unrelated to their ability to adhere to therapy. it has been shown that it is a person’s belief in the implications of physiological symptoms that alters self-efficacy, and not the physiological response itself.5 outcome expectation an outcome expectation is the belief that a particular behaviour will result in a specified outcome or effect, and outcomes can be either positive or negative. the sct postulates that an individual will choose an action that he or she believes will maximise positive outcomes and minimise negative outcomes.11 cognitive intervention in art patients is aimed at changing the patient’s behaviour and attitude by assisting the individual in changing unrealistic expectations or behaviour. observational learning or modelling other influences that are recognised by sct are observational learning or modelling which describes how a person acquires skills and information through the actions of other people.11 through observation, a person can learn from another’s actions and go further to develop an understanding of such actions and be prepared for the consequences of performing them. an applicable scenario in the context of art adherence would be to find a highly adherent art patient to serve as ‘role models’ for other patients who are not adherent. support groups for hiv-infected patients may also provide good opportunities for modelling as people can learn how to do certain things by observing others within the group.10 all these have the potential to improve the individual’s self-care behaviour and subsequently lead to improved adherence to art. reinforcement this is a foundational concept within cognitive-behavioural theory as a whole. it predates and underlies much of what is in sct; this concept is more basic to how behavioural approaches work. here the response to behaviour can determine whether or not that behaviour will be repeated. reinforcement can be positive (rewards) or negative. when health behaviour is positively reinforced, it makes it more likely that the individual will repeat such behaviour. on the other hand lack of response or negative reinforcement of a person’s behaviour tends to make repetition of such behaviour less likely.11 the behavioural theory of adherence is based on the operant conditioning such as reinforcement of action that leads to adherence. for example, a reward for the completion of medication might be given by a healthcare provider in the form of a compliment, or a natural reward may occur if the patient felt healthier after adhering to their treatment. negative reinforcement is the ceasing of an unpleasant stimulus to reinforce behaviour. negative reinforcement has limited role in art adherence, but may be applicable in patients who continuously fail to adhere and develop a resistant strain of the virus with very few resources available to initiate other regimens of art. in addition, repeated hospital admissions, opportunistic diseases and time lost from work are negative consequences that a non-adherent person could experience. the health belief model this psychosocial approach to explaining health behaviour was introduced by psychologists rosenstock, hockbaum, leventhal and kegels in the 1950s and deals with value expectancies related to health. it is a cognitive interpersonal approach that views humans as rational beings who behave in certain ways to minimise what they perceive as threats (e.g. disease symptoms) and enhance what are perceived as benefits (e.g. adherence to treatment).8 the hbm is comprised of several interactive states of belief, which collectively affect adherence in a disease like hiv/aids. these are referred to as perceived susceptibility, perceived seriousness, perceived benefits and perceived barriers. perceived susceptibility the perceived susceptibility of a disease brings to light the fact that an individual could actually contract the disease.11 this means that a person will seek preventive medical care if the individual believes he or she is at risk of developing a disease. a person who has engaged in an activity that made him or her prone to contracting hiv infection is likely to seek medical intervention to confirm the suspicion. perceived seriousness this implies that people tend to be more proactive in prevention of serious diseases than in preventing those perceived to be less serious. in other words, susceptibility and seriousness combine to form what an individual perceives as a threat of a disease.15 perceived seriousness of hiv/aids are the consequences of being infected with the virus which are pain, infections, disability, lifelong therapy on arvs and ultimately death.21 perceived benefits the perceived benefit derived from health behaviour describes how effective an individual thinks the health behaviour will be. health behaviour that results in an immediate benefit may be perceived as very effective since the effect is rapid and noticeable.11 the immediate benefit of antibiotics in treating an opportunistic disease in hiv/aids may create belief that choosing to adhere to the medication (behaviour) has instant rewards. long-term treatment with art might not provide such instant benefits, and thus there is a chance that a patient may not be as strongly motivated to adhere to art as they would be to antibiotics. perceived barriers these include factors which an individual perceives as obstacles to the health action. an individual may feel that treatment takes too much time, requires too much effort or is too difficult to obtain. when the perceived threat of contracting a disease is very high and perceived benefits of taking action that would prevent one from contracting such disease outweigh the perceived barriers, patients are more likely to take action regarding their health.11 the hbm model also recognises other factors that could influence health behaviour. these include predisposing factors such as the individual’s values, beliefs, attitudes and perception of the disease. enabling factors such as issues around availability and accessibility of health resources also play a role. lastly, reinforcing factors relate to peer-support, feedback and assurance given by healthcare workers to patients to ensure treatment compliance.11 perceived susceptibility to and severity (health consequences) of a disease are postulated to be driven by knowledge, attitudes and practices of individuals.8 similarly, pre-existing beliefs about the disease and the symptoms experienced are said to affect an individual’s perceived susceptibility to and severity of the disease.8 in the context of hiv or aids, the general knowledge of the high prevalence of the disease and the severe health consequences associated with it are also assumed to influence the perceived personal susceptibility to and severity of hiv or aids among the general population.21 medication-use behaviour among patients has been shown to be influenced by experience of previous adverse effects to medication.2 following an adverse reaction to medication, it is likely that the patient will make a causal attribution of the event to one or more of their prescribed medications. therefore, a patient with prior adverse drug reactions to medication may have a pre-existing belief that art would give similar adverse events. in essence, medication-use behaviour of such a patient will ultimately be influenced by belief in potential adverse effects of medications.2 patients’ perception of their relationship with their healthcare provider is also postulated to influence their medication-use behaviour. healthcare providers potentially have substantial influence over patients’ levels of knowledge about the target condition, the adverse health consequences of that condition and the treatments required.10 in addition, the patients’ trust that their healthcare providers are competent and knowledgeable about hiv/aids will influence their acceptance of the advice and education that they receive regarding the threat to their health.10 further to this, patients’ perception of health providers’ concern about their welfare, being involved in decision-making processes regarding management of their health, and good communication with health providers are all influential in patients’ medication use behaviour.22 beliefs about medicines the hbm has been used for a long time in explaining variation in adherence to treatment of chronic medical conditions. more recently, researchers have postulated that bams which consist of questions that have some resemblance to the concepts of the hbm is an important factor influencing medication-use behaviour.23 according to self-regulatory theory, a cognitive-behavioural theory, patients’ treatment perceptions and illness representations influence their adherence to medication.24 therefore, patients on chronic treatment often undertake a cost–benefit analysis, considering whether their beliefs about the necessity of using medications to maintain their health outweigh their concerns about the potential adverse effects of taking the medicines.25-26 this perspective led to the development of the beliefs about medicines questionnaire (bmq),23 whose authors reasoned that a separate, specific measure to gauge patients’ beliefs about medicines would add to the explanatory power of the hbm. the authors further argued that an enhanced understanding of patients’ beliefs about their medications could inform the development of interventions to improve adherence and optimise the benefits they derive from medications.23 the use of medication is strongly influenced by the patient’s perception of the benefits of taking such medication.11,22 however, variables such as medication cost and level of trust in the prescriber may also influence adherence, even in persons with favourable attitudes towards their medications.22 patients often conceptualise the use of medication as necessary to achieve a specific health goal. in the context of hiv and aids, the perceived health benefit of medication is defined as the perceived necessity of art for the target condition. the perceived necessity of medication is also driven by interaction of two variables in patients, namely the perception that they are susceptible to the target condition, and the perceived severity of the condition should it occur.2 each of the two variables is considered to be necessary but insufficient for an individual to perceive that a medication is necessary for their health, and hence the model postulates that the interaction between the two is associated by patients with the necessity for adhering to medicines.2 in terms of patients’ beliefs, the perceived effectiveness of the medication to treat the target condition is a predictor of medication-use behaviour.2, 24 perceived necessity for medication is also influenced by concerns about the long-term safety of that medication. patients’ concerns about medications are often generalised, with some patients thinking that all medications have some negative qualities, and this is also true of art.28,29,30 patients’ beliefs about medicines are dynamic, and these beliefs are often due to patients’ misunderstanding of the role of medications in chronic illnesses. various studies across a range of chronic medical conditions have identified similarities in beliefs that influence medication adherence; these studies have found low rates of adherence to be consistently related to doubts about personal need for medications.31,32,33 given that perceived need for art includes the beliefs that use of a medication is necessary to maintain or improve one’s health, concerns about the long-term harm of medications logically have a negative impact on those beliefs.22 one can therefore expect that if patients on art believe that long-term use of arvs is going to be harmful to their health, they will not fully adhere to their medications. therefore, strategies to change patients’ views can be employed during adherence counselling. patients’ belief about hiv and aids can be modified positively through educational interventions, which aim towards behaviour change. this serves as an opportunity for patients on art to improve their knowledge about the disease condition, gain better understanding of the role of medications and have any misconceptions harboured about their medications clarified.20 addressing the risks and benefits of antiretroviral therapy could reinforce positive medication beliefs (such as perceived need for medication) and assuage negative ones (such as general harm and overuse of medicines). increase in knowledge is expected to lead to a change in the participants’ beliefs about hiv medicines and improved adherence to art. trans-theoretical model (stages of change) this theory was developed by prochaska and diclemente,34 and is also called the stages of change theory. the basic premise of the model is that behaviour change is not a once-off event but a process in which an individual attempting to change a specific behaviour moves along a series of motivational changes, namely: pre-contemplation, contemplation, determination, action, maintenance and relapse.4 the stages of change model is not linear but circular in nature; a person does not progress automatically from one stage to the next, but rather enters the change process at any stage, and can progress or relapse to earlier stages.11 the trans-theoretical model has been used in various behavioural interventions at both individual and organisational levels; persons at different stages in this process often have varying informational needs and only benefit from intervention designed specifically for the stage they are in.4 in the pre-contemplation stage, the person has not thought about the particular health behaviour to be taken and therefore has no intention of adopting such behaviour. at the contemplation stage, the person is said to be seriously considering taking the health behaviour but has not taken any action about it. the person proceeds to make a plan to adopt the health behaviour at the determination stage. during the action phase, the person makes an initial behavioural change; this phase usually covers the first six months of adopting the health behaviour. after a period of six months, the individual enters the maintenance phase and this is sustained for a period of time, say more than six months.11 applying this theory to patients on art can best be described in the context of the patients who started art and often adhere strictly at the early stages but become non-adherent after some time on treatment. the relapse stage describes the reversion to an earlier stage after failing to maintain adherence to medication, dietary instructions and other life style modifications; this is often referred to as a secondary stage of change. the relapse may occur at any time after action is taken to adopt the specified behaviour (in this case strict art adherence). the precaution adoption process model this model comprises seven stages, beginning from lack of awareness and progressing to adoption and maintenance of desired health behaviour. at the first stage, a person is unaware of the health risk; the individual may become aware in stage 2 but remained unengaged. in stage 3 the individual is faced with the decision to act, and may decide to act (stage 4), or decide not to (stage 5). stage 6 is an action stage, and stage 7 is maintenance of the action taken in earlier stage.4 in the precaution adoption process model (papm), an individual moves sequentially through all the stages, and although it is possible to move backwards from some later stages to earlier ones, people do not return to the first two stages once completed. this model recognises that the barriers faced by people who are unaware of health risks or hazards differ from the barriers faced by those who are aware of such risks but decide not to take action.4 in the papm, interventions which target stages that precede active decision making have been asserted to address adherence in medical conditions. in the context of adherence to art, in the first stage of the papm a person might be unaware of the link between non-adherence to art and the development of viral resistance. the individual may then become aware through a medium like health education but decide not to engage in strict adherence to art (stage 2). next, the person faces a decision about strict adherence to art (stage 3); may decide not to adhere strictly (stage 4), or to strictly adhere (stage 5). the stages of strict adherence (stage 6) and maintenance of strict adherence (stage 7) follow. as it is impossible to move backwards to stages 1 and 2 once completed, a person cannot move from being aware of the consequences of non-adherence to art to being unaware of such implications. the theory of reasoned action or planned behaviour the theory of planned behaviour (tpb) and the associated theory of reasoned action (tra) stipulate that behavioural intention is the determinant of behaviour.4 the tra predicts behaviour from intention and explores the relationship between beliefs, attitudes, intentions and behaviour.11 the modified version of the tra is the tpb which includes one additional construct, perceived behavioural control; this construct relates to people’s beliefs that they can control a specific behaviour.11 the perceived control construct was added to the tra to gain better understanding of situations where behaviour or behavioural intention is influenced by factors which are beyond a person’s control.4 in the tra, intention is influenced by three factors: subjective norms, attitudes and self-efficacy.5,6,8,11 according to the tra, behavioural intention is influenced by an individual’s attitude towards such behaviour and by the individual’s beliefs about whether people who are significant to them approve or disapprove of the behaviour (subjective norms). self-efficacy is the confidence a person has that certain behaviour can be performed.11 two beliefs in the tra that influence behavioural intentions are normative and behavioural beliefs. normative beliefs are based on social expectations which are often considered as rules (they influence subjective norms), while beliefs about the behaviour influence attitudes. a person’s attitudes towards health behaviour are said to be determined by the outcome expectations of performing such behaviour and the extent to which the individual values the outcome.6,8,11 according to the tra, an individual will perform a certain health behaviour to reduce health risks if convinced that such a behaviour will prevent the risks. it is also influenced by the extent to which the individual perceives that the benefit of performing the behaviour will outweigh the cost.11 applying this theory to art adherence requires that one take into cognisance the beliefs, attitudes, and intentions that exist within a specified population in terms of adherence to treatment in chronic conditions. this will involve designing a measure to gauge the following variables: previous adherence to medication among the population (behaviour); how likely they are to strictly adhere to art (intention); predisposition towards adherence (attitude); whether or not ‘“most people who are important to me would want me to be strictly adherent to art’” (subjective norm); and whether or not being strictly adherent is ‘under my control’ (perceived behavioural control). comparison of the results of those who are likely to adhere with those who are not likely to adhere to art will assist in identifying beliefs, attitudes, and intentions that predict adherence to art among such populations. conclusion prediction of medication adherence is complex, and health-related knowledge and beliefs alone are insufficient to achieve behaviour change, especially in chronic conditions such as hiv and aids. however, people can control or influence the events affecting their lives by integrating cognitive, social, and behavioural sub-skills related to beliefs of personal efficacy in performing these skills.8 the cognitive perspective on health behaviour focuses on effective self-management of health habits.8 hiv-infected patients need to have confidence in their ability to perform the required self-management activities (self-efficacy) and hold positive beliefs about the benefits of their medications. it is important for them to believe that exhibiting self-care behaviour and holding the right beliefs about their medications would result in adhering to therapy which subsequently leads to good clinical outcomes and quality health. acknowledgements competing interests the author declares 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accepted: 13 july 2019; published: 28 aug. 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract this article presents a case of an hiv-infected paediatric patient with an unusual mycobacterium genavense infection with predominantly abdominal organ involvement. keywords: mycobacterium genavense; non-tuberculous mycobacterium; 16s rrna sequence analysis; line-probe assay; fastidious; retractile mesenteritis. the patient is a chronically ill 8-year-old boy from limpopo province in south africa, living with his adoptive parents. he was born prematurely at 7 months’ gestation, weighing 1.9 kg. there was a history of recent travel to the kruger national park, and to india 6 months prior to admission. all his vaccinations were up to date on history, but this was never confirmed. he was markedly underweight for his age (with weight-for-age and height-for-age z scores of −2 and −1, respectively, and body mass index of 13) with a 2-year history of abdominal distension, diarrhoea, failure to thrive and drenching night sweats. there was no history of chronic cough. his treatment up to the time of admission included nutritional and iron supplements and repeated courses of antibiotics. no clinical improvement was achieved with this management. the patient was referred to a paediatric gastroenterologist in october 2016. he was acutely ill, severely wasted (17 kg) and pyrexial (39 °c). he was clinically pale with a tachycardia and mild oedema of his lower limbs. hepatosplenomegaly was detected, although there was no peripheral lymphadenopathy. his abdomen was severely distended, and he had recurrent diarrhoea and vomiting with marked intolerance of all foods. abdominal computed tomography (ct) scan and ultrasound revealed massively enlarged intra-abdominal lymph nodes (see figure 1) with a moth-eaten appearance of the spleen. prominent collateral circulation was seen, which was suggestive of portal hypertension. figure 1: radiology (computed tomography coronal images of the chest, abdomen and pelvis, a–c). multiple conglomerate nodal masses are seen along the mesenteric, aorta, iliac and para-aortic nodal chains. there are also enlarged nodes in the porta hepatis. several of the upper abdominal mesenteric nodes demonstrate low density, compatible with central necrosis. diffuse hepatomegaly with no discrete lesion is seen. laboratory investigations confirmed that the patient was hiv-infected with a cd4 count of 59 cells/μl (7%) and hiv viral load of 453 780 copies/ml (log10 5.66). further testing revealed mildly elevated liver enzymes. moderate proteinuria was present and the faecal α-1 antitrypsin result was in keeping with a protein-losing enteropathy. his blood count showed microcytic hypochromic anaemia, with the iron function studies reflecting a pattern of reticuloendothelial iron blockade (see table 1). table 1: laboratory results. the differential diagnosis included tuberculosis or lymphoma. over a period of 7 months, endoscopically and surgically obtained biopsy material was submitted for histology (see table 2). histological images of the duodenum and a lymph node are shown in figure 2. the findings were consistent with non-tuberculous mycobacterial infection. figure 2: histological images of the duodenum and lymphnode. (a) histology of the duodenal mucosa showing lamina propria expansion by histiocyte sheets (hematoxylin and eosin, 100×). (b) duodenal villus filled with abundant organism-containing histiocytes (hematoxylin and eosin, 400×). (c) lymph node replaced by sheets of histiocytes with scattered intervening inflammatory cells (hematoxylin and eosin, 100×). (d) lymph node histiocytes revealing finely granular to foamy cytoplasm, engorged with bacilli (hematoxylin and eosin, 400×). (e) ziehl–neelsen stain demonstrating large numbers of acid-fast bacilli in duodenal histiocytes (400×). (f) periodic acid-schiff stain showing granular positivity in the histiocyte intracytoplasmic organisms (400×). table 2: histology results. further testing of the biopsy specimens included mycobacterial cultures, all of which showed no growth. acid-fast bacilli (afb) were noted during the processing of the tissue samples obtained from the intra-abdominal lymph nodes on 12 october 2016, and again in biopsy material obtained on 08 march 2017. microscopy performed on a stool sample on 26 march 2017 also showed acid-fast organisms with a coccoid appearance. the polymerase chain reaction (pcr) assay for mycobacterium avium complex was negative (artus® mycobac. diff. lc pcr from qiagen, germany). numerous pcr assays for mycobacterium tuberculosis complex were negative, which include nanogen (nanogen inc., san diego, ca, usa), bd max (bd diagnostics, sparks, md) and the xpert® mtb/rif assay (cepheid inc., ca, usa). the urinary lipoarabinomannan test conducted on 22 march 2017 was positive. a cytomegalovirus (cmv) viraemia of 3974 copies/ml (log10 3.60) was measured in march 2017 together with a colon biopsy that was pcr positive for cmv. the epstein barr viral load at the time was 9318 copies/ml (log10 3.97). anti-mycobacterial treatment was started (rifampicin, isoniazid, ethambutol, pyrazinamide and clarithromycin) followed 4 weeks later with antiretroviral therapy (abacavir, lamivudine and efavirenz). the patient’s hiv viral load was undetectable at 3 months, and his cd4 count at that stage was 101 cells/μl (6%). clinically and radiologically, however, there was no improvement in his abdominal signs and symptoms. malabsorption and refeeding syndrome was considered, and all treatment, including ganciclovir, was given intravenously. his antiretroviral medication was temporarily suspended until oral feeding could be tolerated. immune reconstitution inflammatory syndrome (iris) was considered, and methylprednisone was initiated (1 mg/kg/dose) for 4 weeks, after which the dosage was tapered and stopped. the patient was given a period of bowel rest and free drainage, after which he was placed on an elemental diet. there was no clinical improvement and liver dysfunction worsened (see table 1), and hence a decision was made to stop rifampicin, isoniazid and pyrazinamide. in may 2017, a diagnosis of mycobacterium genavense was made, based on sequencing of a mycobacterial 16s rrna pcr product. this identity was subsequently confirmed using the hain lifescience genotype (nehren, germany) mycobacterium as assay that was performed directly on a histology specimen from may 2017. as a result of this finding, and in consultation with an infectious disease specialist and microbiologist, treatment was changed to include moxifloxacin, azithromycin and rifabutin for 2 years, with amikacin for the first 3 months. methylprednisone was also restarted. antiretroviral therapy, together with cotrimoxazole prophylaxis, was continued. the patient’s response to the new regimen was slow, and initially he was unable to tolerate food. insertion of a nasogastric tube was required for continuous feeds together with total parenteral nutrition. at the time of writing this article (17 months of treatment completed), his clinical response had improved. he was able to tolerate small regular meals with no nausea, vomiting or diarrhoea. his weight gain had been slow (now up to 20 kg) despite nutritional supplementation. the hepatosplenomegaly and abdominal distension had improved markedly, and his hiv remains virologically suppressed. ethical consideration dr r. de gama obtained consent from the patient’s parents to publish this case report. discussion the first case of m. genavense was described in 1987 in the clinical setting of acquired immunodeficiency syndrome (aids);1 the bacterium is closely related to mycobacterium simiae.2 mycobacterium genavense has been recovered from dogs, cats, rabbits, monkeys, ferrets and a variety of birds (parrots, budgerigars, amazons, flycatchers, zebra finches, hoopers, parakeets, parrotlets and waxwings).1,3 it is the most common cause of psittacine mycobacteriosis.4 it has also been isolated from the respiratory and gastrointestinal tracts of healthy individuals5,6 and from tap water.7 this organism has not been recovered from soil,8 and no human-to-human transmission has been described.9 human isolates have been recovered from cultures of blood, bone marrow, liver, spleen and other tissues.8 faeces may also show a large amount of afb.4,9 mycobacterium genavense is a fastidious non-tuberculous mycobacterium requiring special supplementation with mycobactin j, adjusted ph and incubation temperature of 37 °c – 45 °c for isolation from culture specimens.2,10 use of middlebrook 7h11 solid medium supplemented with sheep blood and charcoal acidified to ph 6.2+/−0.2 has also been noted.11 thompson and colleagues12 used the bactec pyrazinamide test medium and determined ph 5.5 to yield the best growth for susceptibility testing. the duration of incubation is typically 8–12 weeks.8 about 30% – 50% of cases are identified after prolonged incubation.10 clinical presentation most clinical m. genavense isolates have been cultured from patients with advanced hiv infection, especially in the pre-highly active antiretroviral therapy (haart) era.9,10 mycobacterium genavense presents similarly to m. avium complex: it is encountered in patients with cd4 counts < 100 cells/mm3; has a high affinity for the abdomen; and causes abdominal pain, diarrhoea, hepatosplenomegaly, lymph node enlargement and sometimes ascites.6 mycobacterium genavense should be considered in hiv-infected patients with suspected disseminated m. avium complex, but whose routine cultures are negative.8 immune reconstitution inflammatory syndrome may occur in patients on haart infected with this pathogen, and symptoms may paradoxically worsen, leading to severe complications.6 disseminated m. genavense infection account for 4% – 13% of non-tuberculous mycobacteria in hiv-infected patients.13 descriptions of documented clinical cases with m. genavense in patients with hiv and/or aids have been similar to our patient in presentation and course of disease. recently, cases of m. genavense have been described in patients with non-hiv-related immunological pathology.10 risk categories in which clinical disease due to m. genavense occurs include patients with hiv and/or aids,4,5,6,13,14 lymphoproliferative disorders,15,16 solid organ and allogeneic stem cell transplant patients,10,17,18,19 patients receiving chronic steroids in combination with other immunomodulating drugs20 and patients with primary immunodeficiency diseases.21,22,23 other diseases that may be associated with m. genavense infection include sarcoidosis, hyper-ige syndrome and auto-immune disorders (systemic lupus erythematosus and myasthenia gravis).9,24,25,26,27 while most patients with m. genavense infection have immunological pathology, a case of disseminated m. genavense infection in a healthy japanese boy has also been described. computed tomography of the abdomen showed intestinal wall thickening from the ileocecum to the ascending colon, as well as small intestinal dilation and ascites. the only possible risk factor appeared to be exposure to pets, including dogs, rabbits, turtles and tropical fish.28 the clinical presentation of cases with m. genavense appears mostly to be disseminated involving abdominal organs. less common presentations include pleuropulmonary, cutaneous, central nervous system and genital tract involvement.9,29 pulmonary involvement may include cavitations and reticular–nodular infiltrates on chest x-ray. a few cases of pulmonary m. genavense disease have been documented.20 the laboratory diagnosis of m. genavense infections usually relies on detection by molecular methods. mycobacterial 16s rrna sequence analysis is often used for the confirmation of the diagnosis.9,10 the genotype mycobacterium as line probe assay (hain lifescience, nehren, germany) can also be used, but it cannot distinguish between m. genavense and mycobacterium triplex. it is validated for use on cultured material. we ran this line-probe assay method directly on the duodenal biopsy according to the standard genotype mtbdrplus protocol and were able to generate an interpretable banding pattern in our patient. treatment in vitro susceptibility data are limited because of the extreme fastidiousness of the organism, requiring special supplementation, an acid ph and prolonged incubation.8,9 available data suggest that most isolates are susceptible to macrolides, rifamycins, fluoroquinolones and aminoglycosides (amikacin and streptomycin).8 mycobacterium genavense is resistant to isoniazid.9 optimal therapy is not determined.8 in animal models, a reduction in afb burden is seen after 15–30 days with clarithromycin and rifampicin and after 30 days with amikacin and ethambutol.10 a threeor four-drug regimen is typically suggested. in one case series, a regimen including a macrolide, ethambutol and often rifampicin recorded a favourable outcome in 75% of cases (9/12).20 in another case series, the survival rate at 1 year was 72%. in this case series, a treatment regime typically included clarithromycin, ethambutol and rifabutin, and sometimes also a fluoroquinolone or amikacin.27 multidrug therapies that include clarithromycin appear to be more effective than those without clarithromycin.8 ethambutol, despite limited in vitro activity against m. genavense,8,12 is included in treatment regimens of many documented cases of m. genavense infections.20,27 in our patient, ethambutol was given for a total of 10 months as part of the initial treatment. older literature refers to the use of clofazimine.30,31,32 this drug was used less frequently for the treatment of disseminated non-tuberculous mycobacterial disease after a clinical study found that clofazimine in combination with clarithromycin and ethambutol was associated with increased mortality in disseminated m. avium complex infections in patients with aids.33 the use of prednisone has been advocated to reduce local inflammation and compressive effects of the affected organs. in one study, it was used for 10 months.6 a case series where steroid therapy was included did not describe worse outcomes.27 treatment duration and follow-up the documented cases of m. genavense disease indicate that the duration of treatment should be prolonged to more than 12–27 months.10,21 to make recommendations on the termination of treatment for these cases is therefore challenging. due to the fastidious nature of the mycobacterium, treating cases until 12 months culture negativity8 is problematic and treating for as long as the immunodeficiency is present has resulted in life-long treatment in some patients.20 mycobacterial blood culture (with prolonged incubation) and stool afb where appropriate may be of value as markers of treatment response. follow-up radiological investigation, especially if ct is used, increases the risks associated with radiation exposure. some authors suggest an x-ray and high-resolution ct at baseline prior to the commencement of therapy.34 follow-up radiology should be considered together with clinical assessment.34 follow-up with repeat biopsies from the affected organs to compare with initial histology reports might be another option6; although as granulomas persist much longer than the infection/disease, this might be a poor marker of response. rebiopsy for histology and culture may be considered when treatment failure is suspected. complications a poorly understood pathogen-specific syndrome similar to retractile mesenteritis has been described in patients infected with m. genavense where chronic fibrosing inflammation is found in the small bowel mesentery. rarely, chylous ascites may develop.4,6 persistent relapsing infection may occur in patients with profound immunosuppression and high hiv viral loads at initial diagnosis with a large inoculum of m. genavense organisms.6 a case of an hiv-infected paediatric patient with intestinal lymphangiectasia and protein-losing enteropathy has been described. this patient presented with severe hypogammaglobulinaemia and moderate hypoalbuminaemia. lymphatic vessel dilatation, small intestinal wall thickening, ascites as well as retroperitoneal and mesenteric adenopathy were seen on abdominal magnetic resonance imaging. elevated α-1 antitrypsin in stool confirmed the diagnosis of protein-losing enteropathy.13 a similar scenario was reported by tassone and colleagues.21 hyperammonemia was described in a renal transplant case with disseminated m. genavense infection.35 conclusion the patient described in this case report is illustrative of the difficulties encountered in accurately diagnosing and managing disease caused by non-tuberculous mycobacteria, in this case m. genavense. clinicians and laboratory professionals need to be aware of non-tuberculous mycobacterial infections, particularly encountered in immunocompromised patients and use available molecular diagnostic tools to obtain a diagnosis. teaching points mycobacterium genavense should be considered in hiv-infected patients with suspected disseminated m. avium complex, but whose routine cultures are negative. this organism is the most common cause of psittacine mycobacteriosis. the clinical presentation of patients with m. genavense usually includes dissemination involving abdominal organs. available molecular diagnostic tools are used to obtain a diagnosis. a threeor four-drug regimen is typically suggested for treatment. treatment is prolonged to more than 12–27 months. acknowledgements the authors wish to thank prof. mark cotton and prof. helena rabie from the university of stellenbosch and dr carlos perez-velez from the university of arizona for their contributions to the management of this case. competing interests the authors have no conflict of interests. authors’ contributions r.d.g. and c.k. contributed to the clinical information. e.h. was the initial pathologist involved in assisting with work-up of the case. p.e. assisted with the trouble shooting of the diagnostic work-up. c.c. managed to get the primers for the mycobacterial 16s rrna polymerase chain reaction (pcr) and assisted with the running of that pcr. t.s. assisted with the histological work-up of the case. t.m. assisted greatly with integrating the hiv management with that of the mycobacterium genavense. e.h. assisted with checking all the lab data in the article. p.e. did the literature review. j.v.i. assisted with checking the academic content of the document as an international expert in non-tuberculous mycobacteria. t.m. and c.c. assisted with the editing of the final version. all the authors reviewed the document and were satisfied with the final version. funding information this research received no specific grant from any funding agency in the 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literature. acta clin belg. 2013;68(3):220–222. https://doi.org/10.2143/acb.3204 albrecht h, rüsch-gerdes s, stellbrink h-j, et al. treatment of disseminated mycobacterium genavense infection (correspondence). aids. 1995;9(6):659–660. https://doi.org/10.1097/00002030-199506000-00026 pechère m, opravil m, wald a, et al. clinical and epidemiologic features of infection with mycobacterium genavense. arch intern med. 1995;155:400–404. https://doi.org/10.1001/archinte.1995.00430040074009 koehler m, chak a, setrakain s, et al. endoscopic appearance of mycobacterium genavense: a case report and review of the literature (case report). gastrointest endosc. 1996;44(3):331–333. https://doi.org/10.1016/s0016-5107(96)70174-8 egelund ef, fennelly kp, peloquin ca. medications and monitoring in nontuberculous mycobacteria infections. clin chest med. 2015;36:55–66. https://doi.org/10.1016/j.ccm.2014.11.001 philey jv, griffith de. treatment of slowly growing mycobacteria. clin chest med. 2015;36:79–90. https://doi.org/10.1016/j.ccm.2014.10.005 nurmohamed s, weenink a, moeniralam h, et al. hyperammonemia in generalized mycobacterium genavense infection after renal transplantation. am j tranplant. 2007;7:722–723. https://doi.org/10.1111/j.1600-6143.2006.01680.x abstract introduction case report acknowledgements references about the author(s) nithendra manickchund king edward viii hospital, durban, south africa department of infectious diseases, university of kwazulu-natal, durban, south africa camille du plessis king edward viii hospital, durban, south africa department of infectious diseases, university of kwazulu-natal, durban, south africa melanie-anne a. john department of infectious diseases, university of kwazulu-natal, durban, south africa thandekile c. manzini department of infectious diseases, university of kwazulu-natal, durban, south africa bernadett i. gosnell king edward viii hospital, durban, south africa department of infectious diseases, university of kwazulu-natal, durban, south africa richard j. lessells department of infectious diseases, university of kwazulu-natal, durban, south africa kwazulu-natal research and innovation sequencing platform (krisp), university of kwazulu-natal, durban, south africa centre for the aids programme of research in south africa, university of kwazulu-natal, durban, south africa yunus s. moosa king edward viii hospital, durban, south africa department of infectious diseases, university of kwazulu-natal, durban, south africa citation manickchund n, du plessis c, john ma, et al. emtricitabine-induced pure red cell aplasia. s afr j hiv med. 2019;20(1), a983. https://doi.org/10.4102/sajhivmed.v20i1.983 case report emtricitabine-induced pure red cell aplasia nithendra manickchund, camille du plessis, melanie-anne a. john, thandekile c. manzini, bernadett i. gosnell, richard j. lessells, yunus s. moosa received: 10 may 2019; accepted: 10 june 2019; published: 23 sept. 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract introduction: anemia is common in hiv. parvo b19 infection is a well-recognised cause of red cell aplasia. other causes of persistent pure red cell aplasia (prca) include anti-retroviral drugs such as zidovudine and lamivudine. we describe a case of prca that strongly implicates emtricitabine as the probable cause. patient presentation: patient was hiv positive and on treatment with a fixed drug combination consisting of tenofovir, emtricitabine and efavirenz for 3 months when she developed severe transfusion dependent anemia. the anemia, attributed to prca, was persistent and transfusion dependent for about one year. management and outcome: replacement of emtricitabine with abacavir resulted in a prompt, complete and lasting resolution of the anaemia, suggesting an etiologic role of emtricitabine in the prca. conclusion: emtricitibine is a rare cause of pure red cell aplasia. keywords: emtricitabine; pure red cell aplasia; drug induced; rare drug toxicity; adverse drug reaction; antiretroviral. introduction there are 7.9 million people living with hiv in south africa.1 anaemia in the hiv infected is common, affecting 60% – 80% with advanced disease. there are several causes of anaemia, including hiv itself, opportunistic infections, malignancies, drug toxicities and malnutrition.2 often a combination of factors contributes to anaemia. nucleoside reverse transcriptase analogues, such as zidovudine and lamivudine, are well-established causes of red cell aplasia.3,4,5,6 considering the close structural and functional similarity between lamivudine and emtricitabine, it is not surprising that emtricitabine was recently implicated as a cause of pure red cell aplasia (prca) in a case series of four patients.7 we describe a case of prca that strongly implicates emtricitabine as the probable cause. case report a 35-year-old hiv-infected, pregnant woman developed a severe anaemia following initiation of anti-retroviral treatment (art) consisting of a fixed drug combination of tenofovir, emtricitabine and efavirenz (atroiza). she was diagnosed with hiv infection at 17 weeks gestation in august 2014 and was promptly started on art. her baseline cd4 cell count and haemoglobin (hb) were 83 cells/mm3 and 8.2 g/dl respectively. three months later, she was admitted with a symptomatic, normochromic, normocytic anaemia with hb of 2.2 g/dl and a normal white blood cell and platelet count. haemolysis was excluded and an autoimmune screen was negative. there was no suggestion of ongoing blood loss. electrolytes and liver function tests were normal. epstein-barr virus, cytomegalovirus and hepatitis a, b and c serology were all negative. she received six units of packed red cells with post-transfusion hb of 8.9 g/dl. she subsequently required an emergency caesarean section for foetal distress. following surgery, her hb repeatedly dropped, requiring frequent blood transfusions. a bone marrow aspirate and trephine biopsy, done 3 months later, revealed adequately represented myeloid series and megakaryocytes, but a marked reduction in erythropoiesis with maturation arrest at the pronormoblast stage. overall findings were consistent with prca. coupled with a positive qualitative serum parvovirus b19 (pvb19) polymerase chain reaction (pcr) (parvovirus r-gene® assay, argene range, biomérieux s.a., verniolle france), a diagnosis of pvb19-induced prca was made even though giant pronormoblasts, which are pathognomonic for pvb19 marrow infection, were not observed.8 she was treated with a single course of 400 mg/kg/day of intravenous immunoglobulin (ivig) over 5 days, but remained transfusion-dependent. the department of infectious diseases was then consulted for further management. a second positive blood pvb19 qualitative pcr prompted continued treatment for pvb19-induced prca. over the following 11 months, she presented numerous times with symptomatic anaemia and received more than 53 units of packed red blood cells as well as six courses of ivig at doses ranging from 0.4 mg/kg/day to 1 g/kg/day for 5 days. at no point did she demonstrate a reticulocyte response.9 a repeated bone marrow aspirate and trephine biopsy done 7 months after the first bone marrow examination did not contribute anything further. she remained adherent to art and was virologically suppressed throughout. what was striking was that the problem of symptomatic transfusion requiring anaemia arose after starting art, which suggested that the drugs could be playing a role. the close structural relationship between lamivudine and emtricitabine, and the rare but well-accepted fact that lamivudine is associated with prca, led us to implicate emtricitabine in this patient.5,6 a similar case of emtricitabine-induced prca was described in 2015 in a 39-year-old pregnant woman.10 we do not believe pregnancy had any role in the pathogenesis of prca in our patient because resolution occurred 1 year after delivery and promptly after discontinuing emtricitabine. her art regimen was changed to abacavir, tenofovir and efavirenz, resulting in a dramatic change in her condition. her hb spontaneously improved and she became transfusion-independent and remained so for the following 2 years of follow-up (figure 1). figure 1: changes in haemoglobin over time. interestingly, the qualitative pvb19 pcr remained positive a year after recovery of her hb. we suspect our patient has asymptomatic pvb19 viremia, which has been described in < 1% of well blood donors.11 in summary, we describe a case of prca, initially presumed to be secondary to chronic pvb19 infection that failed to respond to multiple courses of ivig, but promptly resolved after discontinuing emtricitabine. this case provides strong circumstantial evidence that emtricitabine played an etiologic role in the prca. this would be the fifth case of prca, implicating emtricitabine, reported from south africa.7 acknowledgements competing interests the authors have no conflict of interests. authors’ contributions n.m. and c.d.p. contributed to the literature search, data collection, analysis, interpretation and writing; y.s.m. and r.j.l. contributed to analysis, interpretation, writing and editing; b.i.g. contributed to data collection, analysis, and writing. m.-a.a.j. and t.c.m. contributed to analysis and interpretation. ethical considerations approval was obtained from the biomedical research and ethics committee on 22 march 2016, since it extended no risk to the patient. brec reference number exm188/16. funding this research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors. data availability statement data sharing is not applicable to this article as no new data were created or analysed in this study. disclaimer the views expressed in the article are those of the authors and not an official position of the institution or funder. references council sana. south african national aids council (sanac) progress report on the national strategic plan for hiv, tb and stis (2013–2106). [cited 2017 apr 05]. available at: http://www.tbfacts.org/hiv-statistics-south-africa/#sthash.unc3knya.dpuf. meidani m, rezaei f, maracy mr, avijgan m, tayeri k. prevalence, severity and related factors of anemia in hiv/aids patients. j res med sci. 2012;17(2):138–142. blanche p, silberman b, barreto l, gombert b, sicard d. reversible zidovudine-induced pure red cell aplasia. aids. 1999;13(12):1586–1587. https://doi.org/10.1097/00002030-199908200-00023 cohen h, williams i, matthey f, miller rf, machin sj, weller iv. reversible zidovudine-induced pure red-cell aplasia. aids. 1989;3(3):177–178. https://doi.org/10.1097/00002030-198903000-00009 majluf-cruz a, luna-castanos g, trevino-perez s, santoscoy m, nieto-cisneros l. lamivudine-induced pure red cell aplasia. am j hematol. 2000;65(3):189–191. https://doi.org/10.1002/1096-8652(200011)65:3%3c189::aid-ajh2%3e3.0.co;2-6 john ma, rhemtula ya, menezes cn, grobusch mp. lamivudine-induced red cell aplasia. j med microbiol. 2008;57(pt 8):1032–1035. https://doi.org/10.1099/jmm.0.47782-0 cohen k, viljoen c, njuguna c, maartens g. emtricitabine-associated red cell aplasia. aids. 2019;33(6):1095–1096. https://doi.org/10.1097/qad.0000000000002136 koduri pr. novel cytomorphology of the giant proerythroblasts of parvovirus b19 infection. am j hematol. 1998;58(2):95–99. https://doi.org/10.1002/(sici)1096-8652(199806)58:2%3c95::aid-ajh1%3e3.0.co;2-v crabol y, terrier b, rozenberg f, et al. intravenous immunoglobulin therapy for pure red cell aplasia related to human parvovirus b19 infection: a retrospective study of 10 patients and review of the literature. clin infect dis. 2013;56(7):968–977. https://doi.org/10.1093/cid/cis1046 bulman j, teo sy, page e. an uncommon cause of anemia in pregnancy: a case report of emtricitabine-induced pure red cell aplasia (abstract). in: 21st annual conference of the british hiv association (bhiva). brighton, uk: hiv medicine; 2015. p. 30. francois kl, parboosing r, moodley p. parvovirus b19 in south african blood donors. j med virol. 2019;91(7):1217–1223. https://doi.org/10.1002/jmv.25450 hiv guidelines_in.indd september 2014, vol. 15, no. 3 sajhivmed 81 g u id e l in e sguideline management of mental health disorders and central nervous system sequelae in hiv-positive children and adolescents by the southern african hiv clinicians society r nassen, k donald, k walker, s paruk, m vujovic, w duncan, b laughton, b moos (panel members) b eley, a lachman, j wilmshurst (reviewers) corresponding author: r nassen (rnassen@sun.ac.za) disclaimer. specific recommendations provided here are intended as only a guide to clinical therapy, based on expert consensus and best current evidence. treatment decisions for patients should be made by their responsible clinicians, with due consideration for individual circumstances. the most current version of this document should always be consulted. hiv-positive children and adolescents are at increased risk of both central nervous system (cns) sequelae and mental disorders owing to a number of factors, including the impact of hiv infection on the brain, social determinants of health (e.g. poverty and orphanhood) and psychosocial stressors related to living with hiv. every effort should be made to identify perinatally hiv-infected children and initiate them on antiretroviral therapy early in life. hiv clinicians should ideally screen for mental health and neurocognitive problems, as part of the routine monitoring of children attending antiretroviral clinics. this guideline is intended as a reference tool for hiv clinicians to support the early identification, screening and management of mental health disorders and/or cns impairment in children and adolescents. this guideline covers mental disorders (section 1) and hiv-associated neurocognitive disorders (section 2) among children and adolescents. s afr j hiv med 2014;15(3):81-96. doi:10.7196/sajhivmed.1091 untreated perinatally hiv-infected (phiv) children are at increased risk of central nervous system (cns) sequelae compared with hiv-infected children who begin antiretroviral therapy (art) in infancy. hiv in vades the developing cns earlier and with greater severity than observed in adults and with a more rapid progression to death. in addition, patients receiving art may remain vulnerable to the effects of hiv on the brain because the cns may be a reservoir for persistent viral replication. initiation of art, therefore, does not fully reverse cns insults, particularly if treatment is not initiated during infancy.[1] psychosocial stressors, such as poverty, orphanhood and parental illness (physical and mental), experienced by hivpositive children living in disadvantaged communities place them at further risk of poor educational and mental health outcomes. furthermore, the onset of adolescence presents new challenges related to adherence issues, the provision of adolescent-friendly clinical environments, academic problems, mental health problems, and sexual and other risk behaviours.[2] 1. mental disorders among hiv-infected children and adolescents phiv children present with high rates of mental disorders that exceed population norms and rates in other chronically ill children.[3] 1.1 overview of mental disorders in children and adolescents prevalence: • in hiv-positive children, prevalence rates of 25 50% • most common: attention deficit hyperactivity disorder (adhd), mood disorders, anxiety disorders, substance use disorders (suds) (adolescents) • less common: psychotic disorders, bipolar mood disorder risk factors: • previous aids-defining diagnosis, lower intelligence quotient, caregiver psychiatric disorder, parental loss, limitsetting problems effects: • untreated psychiatric illness may affect art adherence, and educational and medical outcomes • adolescents vulnerable to depression, non-disclosure, school failure/dropout, sexual risk behaviours and suds 1.2 screening for mental disorders • accurate diagnosis requires a thorough history, and assessment of the mental state of the child and of the family. • collateral information from the educator and/or extended family provides essential additional information. • the objective is to detect and refer suspected cases of children presenting with mental health disorders for a more comprehensive assessment. the detection of psychosocial g u id e l in e 82 sajhivmed september 2014, vol. 15, no. 3 g u id e l in e dysfunction is important as it may contribute to non-adherence and later treatment failure.[4] • when screening for mental health problems, remember multiple interacting factors such as those within the child, home, school and external environment, all of which influence emotions/behaviour. • no brief screening tool has been validated worldwide specifically for the detection of mental health disorders among hiv-positive children and adolescents. table 1 presents some well-validated screening tools that may be utilised in primary care settings. • a rapid screen of the commonly occurring mental disorders should be performed at the art clinic and patients should be referred for a mental health assessment (tables 2 and 3). 1.2.1 referral criteria based on mental health screen refer or discuss the child with a mental health professional (mental health nurse, psychologist, child psychiatrist, psychiatrist) if the child presents with the following: • symptoms of adhd • frequent or daily symptoms of anxiety that have affected functioning at home and at school • frequent or daily symptoms of depression/low mood, which have affected functioning at home and at school • suicidal ideas, intentions, plans or previous attempts • misuse of cannabis, methamphetamine, alcohol or any other illicit substance • confusion or change in behaviour/functioning from baseline refer or discuss with a social worker if additional information reveals the following: • maltreatment of the child (e.g. physical or sexual abuse) • adverse socioeconomic circumstances requiring assistance • limited or no parental care (child-headed household) • substance abuse 1.3 assessment and diagnosis of mental disorders tables 4 and 5 outline the assessment and diagnosis of adhd and major depressive episodes, respectively. 1.4 assessment and diagnosis of anxiety disorders • anxiety may present in children in a variety of ways (table 6): • general symptoms include withdrawal, worries, fears, anticipation of threat and anxiety-themed dreams. these may be associated with vigilance/caution in anticipation of threat and avoidant behaviour. • common physical symptoms include nausea and vomiting, headaches and abdominal cramps. cardiovascular symptoms such as palpitations and dizziness are less common in children. • anxieties may be related to worries about the child’s illness, the parent/caregiver, school, placement insecurity or the general environment. • anxiety disorders that occur more commonly in childhood include separation anxiety disorder, selective mutism and specific phobias. • adolescents may additionally present with social anxiety (social phobia) and panic disorder. the clinical presentation may more closely resemble that of adults. generalised anxiety disorder may occur across the lifespan.[5] 1.5 assessment and diagnosis of psychotic disorders neuropsychiatric symptoms in an hiv-positive child or adolescent include psychosis, severe mood disturbance, delirium or encephalopathy. psychotic symptoms (hallucinations, delusions, formal thought disorder) and mania are less common among hiv-positive children and adolescents compared with adults, and therefore have a high index of suspicion of a comorbid medical condition such as a cns disorder. • consider a psychotic disorder if there is a positive family history of mental illness, particularly schizophrenia or bipolar mood disorder. • suspect delirium if a patient presents with an acute onset of psychotic symptoms associated with confusion and clouding of consciousness that tends to fluctuate. exclude general medical conditions (gmcs) such as seizures, meningitis, encephalitis, brain tumour or stroke. failure to recognise delirium may delay the diagnosis of an underlying medical condition and may lead to an adverse outcome and even death.[5] table 1. validated screening tools for mental disorders in children and adolescents* screening instrument clinical condition source sdq (available in english, afrikaans, xhosa and zulu) psychosocial functioning http://www.sdqinfo.org/py/sdqinfo/b0.py conner’s scales (parent, teacher) adhd http://www.doctorrudy.com/files/teacher_add_adhd_short.pdf http://www.doctorrudy.com/files/add_adhd_parent_long.pdf snap-iv rating scale adhd http://www.adhd.net/snap-iv-form.pdf subscale of sdq depression www.sdqinfo.org/py/sdqinfo/b0.py paediatric symptom checklist psychosocial function http://www.brightfutures.org/mentalhealth/pdf/professionals/ped_sympton_chklst.pdf scared anxiety http://www.psychiatry.pitt.edu/sites/default/files/documents/assessments/scared%20child.pdf http://www.psychiatry.pitt.edu/sites/default/files/documents/assessments/scared%20parent.pdf sdq = strengths and difficulties questionnaire; adhd = attention deficit hyperactivity disorder; snap-iv = swanson, nolan and pelham, 4th revision; scared = screen for child anxiety related disorders. * consult the relevant international academy of child and adolescent psychiatry and allied professions (iacapap) book chapter, which provides an overview of clinical assessment of a child: http://iacapap.org/wp-content/uploads/a.5-clinical-examination-072012.pdf september 2014, vol. 15, no. 3 sajhivmed 83 g u id e l in e 1.5.1 delirium • delirium is a nonspecific neuropsychiatric disorder that occurs in medically ill patients, signifying global encephalopathic dysfunction. it commonly occurs across the age extremes (the very young and geriatric patients). however, it can occur in all ages, particularly in seriously ill patients with limited cognitive reserves and/or cns conditions. it is well recognised in the elderly but underdiagnosed in children. • onset confers a poorer prognosis for an underlying medical condition. • the core features comprise an altered level of consciousness, attention disturbances and diffuse cognitive deficits. symptoms fluctuate and may present with behavioural disturbances (e.g. aggression) and perceptual disturbances, commonly visual hallucinations. 1.6 differential diagnoses to consider • schizophreniform disorder • schizophrenia • bipolar mood disorder: usually a history of a previous episode of elevated mood resulting in abnormal behaviour, e.g. decreased sleep, euphoria, hypersexuality, grandiosity and increased energy • mood or psychotic disorder secondary to gmc: hiv encephalopathy, seizures, tumours (frontal lobe), side-effect of efavirenz • substance-induced psychotic or mood disorder: cannabis, methamphetamine 1.7 mental status examination of the child or adolescent the mental status examination of a child comprises observation of play, quality of caregiver-child interactions, verbalisations and also interpretation of drawings. the mental state of an adolescent more closely resembles that of an adult patient. 1.7.1 recording the mental state examination (mse) the mse is an essential part of the psychiatric evaluation. the objective is to describe the child or adolescent’s appearance, behaviour, symptoms and cognitive functioning during the examination. • physical appearance: age, grooming, clothes, cleanliness, dysmorphic features, bruising, scars • behaviour and manner of relating to caregivers and interviewer: eye contact, ability to co-operate, quality of play, interaction with caregiver • mood and affect: range, type and appropriateness of affect (objectively euthymic, depressed, elevated) • anxiety: fears, separation difficulties, phobias • psychomotor behaviour: activity level, tics, co-ordination • content and form of thinking: delusions, preoccupations, ruminations, violence, anxiety themes, thought disorder • speech and language: fluency, language skills, volume, rate • perceptual abnormalities: evidence of hallucinations (e.g. visual, auditory, olfactory) • overall cognitive ability: developmentally appropriate behaviour and drawings, general knowledge, vocabulary • attention, concentration and memory: attention and concentration, shortand long-term recall • level of consciousness: fluctuation, orientation for time, person and place • insight and judgement into own condition: acknowledgement of problem, attitude to receiving help, willingness to adhere to treatment, ability to judge hypothetical situations 1.8 management of hiv-positive children and adolescents presenting with mental disorders see fig. 1, which summarises the assessment and management of hivpositive children presenting to primary care services. 1.8.1 risk assessment • risk assessment includes evaluation of the following: • risk to self: suicidal thoughts or intent or self-harming behaviour; a patient may require hospitalisation in cases of a serious suicide attempt or intent • risk to others: thoughts or intention to harm others • risk-taking behaviour such as reckless driving, violence, disinhibited sexual behaviour, antisocial behaviour (engaging in unlawful acts) and unprotected sex • additional risk to children is related to adverse child care, e.g. minimal parental/family or social support, neglect, physical, emotional or sexual abuse, abandonment. 1.8.2 referral • be aware of referral pathways in your own facility and local district. communicate with colleagues providing mental health services at primary and district levels, such as a dedicated mental health nurse practitioner, psychiatric registrar, psychologist, occupational therapist and district psychiatrist. • have a high index of suspicion for new-onset psychiatric symptoms that may present as a result of an acute or subacute infection or general medical condition, such as aids-defining infections, intracranial viral or bacterial infections, and delirious states due to substance abuse/withdrawal/infection or medication. • referral for any suspected mental health problems at primary level care should be to a mental health nurse practitioner (or psychiatric registrar, if available). less severe or uncomplicated cases may be children who have not been initiated on art due to adequate cd4+ counts and who have psychiatric symptoms that are poorly responsive to antipsychotics may have detectible/high cns viral loads despite undetectable serum viral loads (due to differing mutations in cerebrospinal fluid (csf) and serum). these children should be initiated on art, which may contribute to the resolution of psychotic symptoms. children already on art who have psychotic symptoms poorly responsive to antipsychotics should be assessed for a comorbid cns disorder and/or have their art regimen reviewed and a cns penetrating regimen considered.[6] the montreal cognitive assessment may be a useful screening instrument to detect cognitive impairment in adolescents. • https://pdbp.ninds.nih.gov/assets/crfs/montreal cognitive assessment (moca)7_1.pdf • https://pdbp.ninds.nih.gov/assets/crfs/montreal%20 cognitive%20assessment%20scoring%20and%20instructions. pdf the child should ideally be interviewed in his/her first language. 84 sajhivmed september 2014, vol. 15, no. 3 g u id e l in e managed at primary level in discussion with the district psychiatrist and mental health team at specialist level. • complex cases (e.g. comorbid psychiatric and medical illness such as seizures, other cns conditions, comorbid substance misuse and psychotic symptoms, catatonia and severe depression) should be referred to the district psychiatrist or specialist child and adolescent mental health (camh) services within the catchment area for assessment and possible hospitalisation. • refer suspected cases of child abuse to the facility social worker, who may refer to an external social worker for statutory intervention. • refer to an occupational therapist at community level, who may do group-based interventions, or adherence groups and functional assessments. • refer to the district psychologist for a psychological evaluation of the child and family. 1.8.3 liaison • communicate with the educator and school psychologist (with the family’s consent) to obtain accurate information. • liaise with relevant adult services if you suspect parent or caregiver mental health problems. 1.8.4 attitude to family • be sensitive and non-judgemental in your attitude. • be aware of and attend to issues about stigma. • comply with the rules of confidentiality at all times. table 2. detecting commonly occurring mental disorders among hiv-infected children interviewee questions parent/ caregiver adhd ask about level of activity, attention and impulsivity, e.g.: • does the child struggle to sit still, move around constantly, fidget? • is he/she able to concentrate on a task, focus on homework? • does he/she wait his/her turn or act without thinking? example answer: when he watches tv, he rocks and moves all the time and then gets up and walks/runs around. he looks around and interrupts conversations while he is doing his homework. he runs over the road without looking. depression/ mood symptoms • is the child tearful, irritable, withdrawn from peers, disinterested in play most of the time? • does the child talk about death or say he/she wants to die? example answer: she is moody and gets angry and cries quickly. she doesn’t want to play with her friends anymore. she used to like to play with her doll but now doesn’t want to. she sometimes says she wants to die. anxiety symptoms • does the child worry excessively, or feel fearful/scared? example answer: she is quiet and is scared of the dark and thunder. she worries that she will fail at school and worries about me (that i will get sick and die) and that there is no money. she talks about it all the time and it makes her not want to play or go to school. child school tell me about school: • what do you like? what don’t you like about school? • have you been in trouble at school? what for? example answer: i like my teacher and playing outside. i don’t like schoolwork (sums, reading out loud in class) and when the other children tease me or hit me. i was in trouble because i didn’t do my homework. mood • what makes you happy or laugh a lot? • what makes you sad or want to cry? example answer: i am happy when i play with my friend and when i go out with my mommy to the shop. i cry when they argue or fight in the house. i feel sad when i stay long in hospital. anxiety • do you have a lot of worries? example answer: yes, i worry that i am sick and that i have to go to hospital and may die. i worry about my mommy because she is sick too. i worry that she won’t be able to work anymore. i worry when it rains hard as the water may flood our house, and then we have nowhere to go. • pick a feeling that you feel almost every day, e.g. happy, sad, scared, worried. (you may present the child with pictures of different faces.) example answer: i feel worried a lot, like every day. caregiver: academic enquiry • ask to see the latest school report • send the teacher conner’s scale (adhd screening tool) • send a written request for information about the child adhd = attention deficit hyperactivity disorder. september 2014, vol. 15, no. 3 sajhivmed 85 g u id e l in e table 3. detecting commonly occurring mental disorders among hiv-infected adolescents interviewee questions parent/ caregiver • is your adolescent very moody, tearful, sad and withdrawn? • does your child ever say he/she wants to die or talk about attempted suicide? • is he/she worried, fearful/scared or complaining of nightmares? • do you know if your adolescent has taken drugs or had unprotected sex? example answers: she locks herself in her room, is irritable, ignores us/doesn’t talk to us. i hear her crying in her room a lot. she worries that she will fail, says she can’t sleep and that she is having bad dreams. she sometimes says she wants to die/will kill herself. he smokes ‘weed’/’ganja’ with his friends. he has a girlfriend but i don’t know if they use condoms. adolescent • do you feel sad or worried, or feel like crying very often (every day or most days)? • do you think about death or wanting to die? • have you experimented with alcohol/drugs or had unprotected sex? example answers: i feel bad, like low/down, so that i don’t feel like getting out of bed. i think all the time of bad stuff, like i’m going to die or be alone. yea, i worry about a lot of stuff, that my boyfriend will leave me if he finds out i’m positive, that i’m going to fail or that i’m going to get sick as i keep forgetting to take the medicine for hiv. i smoke ‘weed’/’ganja’ with my friends and we drink brandy over the weekend. my girlfriend is on the injection so we don’t use condoms. caregiver/adolescent: academic enquiry ask to see the latest school report. ask the adolescent to report on his/her academic function and school, e.g.: • tell me about school, e.g. your likes and dislikes? are you ever in trouble at school? what for? ask the adolescent to report on his/her academic functioning and school, e.g.: • tell me about school, e.g. likes and dislikes? are you ever in trouble at school? what for? send the teacher a copy of conner’s scale or snap-iv to complete and a written request for information about the adolescent. snap-iv = swanson, nolan and pelham, 4th revision. table 4. assessment and diagnosis of adhd[5] dsm-v criteria presentation in children presentation in adolescents persistent inattention and/or hyperactivity/impulsivity inattention symptoms (six or more of following): • poor attention to details, careless mistakes • difficulty sustaining attention • does not listen • does not follow instructions • struggles to organise activities and tasks • task avoidant or dislikes tasks • loses things • easily distracted by external stimuli • forgetfulness as per dsm-v criteria as per dsm-v criteria hyperactivity/impulsivity symptoms (six or more of following): • fidgety • leaves seat • runs or climbs when not appropriate • unable to play or engage in leisure activities • often ‘on the go’, acts ‘like a motor’ • talks excessively • blurts out answers • struggles to wait turn • interrupts or intrudes on others as per dsm-v criteria hyperactivity symptoms may wane but impulsivity persists in some cases to adulthood adhd = attention deficit hyperactivity disorder; dsm-v = diagnostic and statistical manual of mental disorders (5th edition). 86 sajhivmed september 2014, vol. 15, no. 3 g u id e l in e 1.8.5 management of depression and anxiety in hivpositive children and adolescents • conduct a thorough history and clinical assessment. this includes information about functioning at school. • interview the child/adolescent alone and with the caregiver. • initiate first-line psychosocial intervention, i.e. address precipitating or perpetuating stressors, e.g. bullying, stigma. refer the child for play/individual/group therapy if resources are available and according to the child’s intellectual ability; alternatively, refer to the school counsellor. refer parents to local parenting groups and/or for their own psychological or psychiatric interventions as necessary. • for moderate to severe symptoms, initiate selective serotonin re-uptake inhibitor (ssri) in addition to psychosocial management. • initiate with a low dose and titrate slowly, preferably with citalopram 5 mg or 10 mg daily, or fluoxetine 5 mg or 10 mg daily if citalopram is not available. (administer by opening a capsule into 20 ml of orange juice to create a 1 mg/ml solution. use a 5 ml or 10 ml syringe to measure out the daily dose. keep the remainder refrigerated.) • titrate up to the therapeutic dose (as per edl). • monitor adolescents or older children closely for suicidal ideation and ssri side-effects, e.g. behavioural disinhibition or activation. • review in 1 month. titrate up to 10 20 mg (or beyond up to a maximum of 30 40 mg) if indicated and if there are no adverse side-effects. • reassure the patient and parent that most side-effects are transient and dose related. • refer a child with moderate to severe symptoms and with poor response to treatment to a local child psychiatric service if available, or discuss with a psychiatrist (or child psychiatrist if available). • treatment for depression should ideally be for 6 12 months after symptom resolution, after which the patient may be weaned off medication. discuss with a mental health professional or child psychiatrist. • treatment duration for anxiety disorders is usually 6 12 months after symptom resolution. however, treatment duration and discontinuation of medication management should be individualised according to the specific anxiety disorder, severity, recurrence and treatment response. discuss with a mental health professional or child psychiatrist. 1.8.6 management of adhd in hiv-positive children and adolescents • conduct a thorough history and clinical assessment. it is important to include all spheres of the child’s environment (including home, school and peers). • ask the parent and teacher to complete a connor’s or snap report. • establish baseline weight and height, and calculate and plot body mass index (bmi). • initiate psychosocial intervention, including support for parents and teachers, input on positive reinforcement, and establishing structure and routine in the child’s day. refer parents to a local parenting group if available. • if indicated, initiate stimulant medication. the dosage should be based on the child’s age and weight, i.e 1 mg/kg body weight/day. • in children 6 years and older, start with 5 mg short-acting methylphenidate 2 3 times daily (5 mg every 3 3.5 hours), e.g. initiate 5 mg at 07h30, 5 mg at 11h00 and 5 mg at 14h30. increase weekly by 5 10 mg, but do not exceed 30 mg daily. • alternatively, in older children or adolescents, initiate long-acting methylphenidate 20 mg daily at 07h30, if available. • medication should be initiated only after confirmation of the diagnosis by a psychiatry registrar, medical officer or district psychiatrist. fluoxetine or citalopram may be prescribed for moderate to severe depression and anxiety disorders. citalopram is preferable because of potential drug-drug interactions between fluoxetine and certain antiretroviral medications. fluoxetine can increase agitation and impulsivity, so monitor closely. table 5. assessment and diagnosis of major depressive episode[5] dsm-v criteria presentation in children presentation in adolescents • depressed mood almost all day, every day or • loss of interest or enjoyment of usually pleasurable activities for most of the day • irritable mood, tearfulness • loss of interest in play, toys or friends • decline in academic performance • similar to adults • irritability • social withdrawal from peer group and • diminished pleasure or interest in most activities, most of the day • significant weight loss (i.e. >5 kg) • insomnia or hypersomnia (inability to sleep/ excessive sleep) • psychomotor agitation or retardation • loss of energy or fatigue • feelings of worthlessness or inappropriate, excessive guilt • decreased ability to think or concentrate, or indecisiveness (either by subjective account or as observed by others) • thoughts of death that are recurrent, or recurrent suicidal ideation without a specific plan, or a specific plan for committing suicide or a suicide attempt • somatic complaints such as abdominal pain and/or headache • suicide risk may increase dsm-v = diagnostic and statistical manual of mental disorders (5th edition). september 2014, vol. 15, no. 3 sajhivmed 87 g u id e l in e • use the lowest effective dosage. • educate parents about effects and possible side-effects. • review the child in one month. check pulse and blood pressure. if abnormal, do an electrocardiogram (ecg), lower the dosage and continue to monitor. medication should be discontinued if an ecg abnormality is detected and/or cardiovascular disease is observed. refer to a cardiologist if a cardiovascular abnormality is detected. • assess response to methylphenidate through direct observation and feedback from teachers and parents. • assess weight and height and plot bmi at each visit. if there is loss of appetite, encourage the parent to provide additional calories and snacks such as a peanut butter sandwich at night for extra protein. stop treatment if growth curve flattens or there is significant weight loss >5 kg. 1.8.7 management of children presenting with psychotic symptoms and/or mania • complex cases should ideally be referred for neuropsychiatric assessment and further investigation (including cns investigation and neurocognitive testing) at a tertiary-level service. • behaviourally disturbed psychotic adolescents should be referred for admission. • exclude delirium before considering a primary psychotic illness. investigations such as chest x-ray, full blood count, temperature, pulse and urine dipsticks can be used to screen for delirium before referring to secondary level for further investigations such as lumbar punctures and/or neuroimaging. table 6. overview of anxiety disorders in children and adolescents anxiety disorder dsm-v criteria clinical presentation in children separation anxiety disorder • excessive fear of separation from attachment figure that is inappropriate for developmental stage • stays close to parent and refusal to be away from home. could lead to school refusal • becomes very distressed when separated • worries that attachment figure will not come home, or will become ill, become a victim of an accident, or will die selective mutism • failure to speak in situations or environments where there is an expectation for speaking, e.g. school. interferes with normal functioning • not associated with language problem. no associated communication disorder • the child fails to speak or reciprocate with speech when spoken to • the child speaks freely at home or when alone with familiar family figures • child is anxious in social situations • may lead to academic problems and social difficulties specific phobia • marked anxiety or fear about a specific situation or object e.g. animals, injections, heights, blood • fear is out of proportion to the danger posed by the object or situation • persistent and lasts 6 months or longer • causes significant distress and impairment • the object of phobia evokes an immediate and extreme reaction • the fear is expressed by tantrums, crying, clinging or freezing social anxiety disorder (social phobia) • social situations evoke fear or anxiety, when the individual is exposed to scrutiny by others (conversations, being observed, meeting unfamiliar people, delivering a talk in front of class or large group) • the person fears humiliation or embarrassment • the social situation is endured with extreme discomfort or avoided • occurs among peers • the anxiety may be expressed by freezing, tantrums, clingy behaviour, crying or failure to speak panic disorder • feelings of intense discomfort and fear associated with physical symptoms such as sweating, palpitations, shaking, chest pain, nausea, chills or feeling hot, and numbness/tingling sensations • abrupt onset and peaks within minutes • onset may be from a calm or anxious state • intense fears of losing control or death generalised anxiety disorder • excessive uncontrollable worry and anxiety occurring most days for longer than 6 months • requires three of six accompanying symptoms: poor sleep, fatigue, muscle tension, poor concentration, restlessness and irritability • causes distress and significant impairment in functioning • asks constant questions and seeks reassurance • complains of headaches and abdominal cramps • anxiety dreams, e.g. of being chased, storms, wild animals • requires only one of six accompanying symptoms: poor sleep, fatigue, muscle tension, poor concentration, restlessness and irritability dsm-v = diagnostic and statistical manual of mental disorders (5th edition). there are no known drug-drug interactions between methylphenidate and antiretroviral medications. 88 sajhivmed september 2014, vol. 15, no. 3 g u id e l in e • antipsychotics may be initiated at low doses, but with caution and after discussion with a psychiatrist. initiate risperidone 0.5 1 mg daily and increase the dose by 0.25 0.5 mg daily every 1 2 weeks, depending on tolerance and age of the child. refer for admission to tertiary camh or psychiatric unit if doses in excess of 3 mg are required. 1.8.8 medication management • do not prescribe psychotropic medication to children or adolescents if there is diagnostic uncertainty and/or there has not been a thorough psychiatric assessment and consultation with a specialist. • it is important to be cautious about the use of psychotropic medications in the management of behaviour disorders in the context of hiv because of high pill burden and potential drug interactions. if medications are not seen to be working, they should be discontinued and polypharmacy should be avoided. • initiate at lower doses and increase slowly. monitor for untoward side-effects. • be aware of drug-drug interactions between certain antiretroviral and psychotropic medications (particularly ssris) (table 7). • be aware of neurological and psychological side-effects of some antiretroviral medications. 1.8.9 other diagnoses or symptomatology to consider as part of the assessment and management of hiv-positive children and adolescents 1.8.9.1 suicide • definition: deliberate self-harm where the intention is to die. • a suicide risk assessment is essential in the assessment of all patients with hiv presenting with psychiatric symptoms such as depression, anxiety, psychosis or self-harming behaviour. • suicide attempts in children and adolescents may be impulsive and often related to an intercurrent stressor, which may not always be severe. however, the outcome may be fatal. suicide risk assessment high suicide risk is indicated by any one or more of the factors below: • previous suicide attempt • pre-existing mental illness • family history of suicide • substance abuse • gender (adolescent males are at increased risk of completed suicide; adolescent females make more suicide attempts) the following may further contribute to risk: • stressful life events • physical and sexual abuse • poor parent-child communication management of suicidal ideation • assess suicide risk severity. • screen for and treat underlying mental illness, especially depression. • develop a safety plan in collaboration with the patient and family. • consider hospitalisation if assessment indicates high risk. • do not discharge without an adequate psychiatric evaluation if high risk.[7] 1.8.9.2 management of trauma-related disorders in children and adolescents with hiv • psychosocial counselling and support strategies include compassionate early debriefing, family support and psychoeducation. • psychotherapy: cognitive behaviour therapy is useful. table 7. commonly used psychotropic medications and their interactions* class drug possible side-effects possible drug interactions ssris fluoxetine headache, nausea/vomiting, behavioural activation potential increase in efavirenz levels citalopram headache, nausea/vomiting antipsychotics fgas haloperidol epses (dystonia, tremor, akathisia, cogwheeling, bradykinesia), neuroleptic malignant syndrome sgas risperidone epses at higher doses, sedation, weight gain, metabolic syndrome possible interactions with protease inhibitors olanzapine sedation, metabolic syndrome, cvs sideeffects probable interactions with protease inhibitors clozapine best to avoid without specialist support probable interactions with protease inhibitors mood stabilisers lithium carbonate toxicity, which may be life threatening avoid with tenofovir sodium valproate sedation, thrombocytopenia, toxicity lamotrigine stevens-johnson syndrome possible interactions with protease inhibitors ssris = selective serotonin re-uptake inhibitors; fgas = first-generation antipsychotics; epses = extrapyramidal side-effects; sgas = second-generation antipsychotics; cvs = cardiovascular. * source: http://www.druginteractions.org september 2014, vol. 15, no. 3 sajhivmed 89 g u id e l in e • medication such as ssris may be indicated if there is a poor response to treatment or severe symptoms. • check for alcohol and substance abuse in older adolescents. • refer to specialist care if there is a poor response to treatment.[8,9] post-traumatic stress disorder • post-traumatic stress disorder (ptsd) can occur when a person has experienced, witnessed or been confronted with an event that involves actual or threatened death, harm or injury, to themselves or to others, with resultant shock, fear, helplessness or horror. • the prevalence of ptsd in adolescents living with hiv is not known, but studies report a prevalence range of 15 64% in adult samples, suggesting that ptsd may also be common in adolescents.[9] • children may have significant symptoms of ptsd but may not meet full diagnostic and statistical manual of mental disorders (5th edition) (dsm-v) criteria (table 8), as they may have difficulty verbalising their emotions. 1.8.9.3 adjustment disorders • an adjustment disorder is the development of a behavioural or emotional response to an identifiable stressor within 3 months of the stressor, resolving within 6 months of termination of the stressor. • patients may present with depressive, anxiety and/or behavioural symptoms but do not meet criteria for depression, anxiety or disruptive behaviour disorders.[4] • treatment for adjustment disorders includes supportive psychotherapy and improving coping mechanisms. short-term medication may be considered. • children and adolescents with hiv in africa often have multiple psychosocial challenges/stressful life events that make them more emotionally vulnerable and isolated.[10] • the effect of the virus is thus compounded by negative life events that further negatively affect neurocognitive development. common stressful life events for hiv-positive children • ill caregiver who cannot cope with parenting • death of caregiver suspect primary mental disorder adhd depression anxiety identify stressful life events (may impact on mental health and adherence) grief/bereavement: refer for counselling non-adherence in adolescents: refer to adherence group/counsellor substance abuse and risktaking behaviours: refer to social worker/mental health nurse child abuse (physical, emotional, sexual): refer to social worker learning di�culties, cognitive decline: see section 2) address stressors family and parenting individual and/or group therapy • ssri: citalopram • family, group, individual intervention ssri: citalopram • • • • refer to department of education for psychometric testing, remedial teaching • parenting behaviourbased management • stimulant medication • screening primary or art site diagnosis/referral refer to mental health nurse/psychiatry registrar for assessment/diagnosis discuss with district psychiatrist refer to tertiary service if complex presentation/suicide risk/admission refer to adherence group if available management exclude gmcs (encephalopathy, seizures, stroke, cns tumour) and refer appropriately beware misdiagnosis of psychosis may be delirium fig. 1. recognising primary mental disorders in hiv-positive children and adolescents. (art = antiretroviral therapy; adhd = attention de� cit hyperactivity disorder; gmcs = general medical conditions; cns = central nervous system; ssri = selective serotonin re-uptake inhibitor.) table 8. ptsd criteria in children and adolescents dsm-v criteria presentation: preschooler presentation: child presentation: adolescent • onset after experiencing or witnessing a serious traumatic event (e.g. rape, assault, accidents) • symptoms may occur soon after the event or with delayed onset • symptoms: intrusive memories (reliving, flashbacks, nightmares), hyperarousal (increased startle response, anxiety symptoms), avoidance (avoiding situations that remind of the traumatic event, numbing, feeling of foreshortened future) nightmares, inconsolable crying, repetitive play of traumatic content, regression, e.g. bedwetting fearful, repetitive play, traumatic content in drawings, hyperarousal and avoidance of painful stimuli, poor concentration, temper tantrums similar to adults ptsd = posttraumatic stress disorder; dsm-v = diagnostic and statistical manual of mental disorders (5th edition). 90 sajhivmed september 2014, vol. 15, no. 3 g u id e l in e • multiple caregivers or child-headed households • sick siblings • poverty • multiple hospital visits • disrupted schooling • disclosure issues • stigma grief and bereavement • children may lose one or both parents to aids and are then often separated from siblings and moved about in an attempt to continue to provide for their basic physical needs. • these children are often left fearful and anxious or confused. • in addition, hiv-positive children may have fears about their own mortality. • it is important that children be allowed to express their grief. grief reactions are influenced by the child’s developmental age and coping mechanisms (table 9). • very young bereaved children may experience regression such as thumb sucking, have nightmares or become clingy. they may also present with acting-out behaviours. • bereavement in older children may pre sent with aggressive or impulsive behaviour, poor performance at school, and/or poor concentration or emotional outbursts.[11] • supportive therapy/counselling at a developmentally appropriate level of the child and family is the mainstay of treatment. 1.8.9.4 the disruptive and aggressive child and adolescent • a high prevalence of challenging or disruptive behaviours exist in hiv-positive children and adolescents, including adhd, adhd-like impulsivity and hyperactivity, aggression, oppositionality and conduct disturbances.[2] • however, aggression and disruptive behaviours may arise from medical problems in the child or adolescent, or may be a manifestation of a mood or anxiety-related problem. • adolescents in particular struggle with mood and behavioural regulation. • there is no direct link between hiv itself and disruptive behaviour. factors such as poverty, prenatal alcohol and drug exposure, malnutrition, family disruption, social chaos and educational deprivation may play a role. table 10. conduct disorder in children and adolescents dsm-v criteria presentation: child presentation: adolescent aggression towards people and animals • frequent threats, bullying or intimidation of others • frequently initiating physical fights • use of a weapon that can cause serious physical harm to others • physically cruel to people • physically cruel to animals • while confronting a victim, has stolen from him/her (e.g. mugging) • has coerced someone into sexual activity destruction of property • deliberate engagement in fire setting with the intention of causing serious damage • deliberate destruction of others’ property deceitfulness or theft • housebreaking or breaking into a car or building • frequently lying to obtain favours or goods to avoid obligations • theft of items of non-trivial value without confronting a victim serious violations of rules • frequently staying out at night despite parental prohibitions, beginning before the age of 13 years • has more than once run away from home overnight while living in a parental or parental surrogate home, or once without returning for a lengthy period • frequently truant from school • aggression • difficulties adhering to rules and age-appropriate expectations • reluctance to engage positively with authority figures; senseless resistance and/or open hostility and defiance • bullying • conflict with peers • truanting; educational failure • serious violation of societal rules; significant risk-taking behaviour • promiscuity; early sexual debut • substance misuse • mood instability • serious aggression • self-destructive (self-harming) behaviour • move into delinquent and/or criminal behaviour • negative peer associations • truanting; educational failure dsm-v = diagnostic and statistical manual of mental disorders (5th edition). table 9. children’s developmental stages of grief[12] age (years) view of death 0 2 very limited but realises person not there 3 5 thinks loved one will return; no concept of finality of death 6 8 curiosity about death; magical thinking 9 12 understands finality and irreversibility of death 13 18 understands finality of death september 2014, vol. 15, no. 3 sajhivmed 91 g u id e l in e • there is a further association between behaviour disorders and high rates of neurocognitive and neurodevelopmental delay in hivpositive children. • two disorders that require specific consideration are conduct disorder and oppositional defiant disorder. conduct disorder definition: a repetitive and persistent pattern of behaviour that violates the basic rights of others or where major age-appropriate societal norms or rules are transgressed (table 10).[5] oppositional defiant disorder • definition: a pattern of argumentative/defiant behaviour and angry/irritable mood or vindictiveness lasting at least 6 months. • classification requires exhibition of at least four symptoms from any of the categories in table 11 during an interaction with at least one individual who is not a sibling.[5] common co-occurring disorders in children with disruptive or aggressive behaviour aggressive and disruptive behaviour may present with co-occurring difficulties such as: • adhd • learning disorders and language difficulties • intellectual disability • anxiety and depressive disorders • adjustment disorders • substance use disorders • trauma-related disorders • disruptive mood dysregulation disorder • bereavement • epilepsy • sensory integration difficulties • delirium (may be secondary to opportunistic infection or a medication) • psychotic disorders management of behaviour problems in children and adolescents with hiv • explore the family’s circumstances, particu larly parenting practices and harsh discipline. • obtain information from the school and/or recent report cards and any other structures that might be involved with the child or the family (e.g. social services, justice). • establish an alliance with the child and his/her parent/caregiver; try not to get drawn into the anger and power struggle that often arises out of the child’s behaviour. • optimise the management of hiv; ensure adherence to antiretroviral medication, establish extent of health and viral suppression and ensure that no intercurrent opportunistic infections have arisen. • manage co-occurring problems. these may be more responsive to treatment and addressing them may improve the behavioural ‘dyscontrol’, i.e. aggression, impulsivity and risk-taking behaviours. • address learning and educational problems. this may necessitate more formal psycho-educational assessment and/or referral to local educational authorities, and may be as simple as establishing contact with the school and its support structures. • refer to social services if there are concerns of neglect or maltreatment, child-headed households, poverty, household instability or parental illness. • encourage participation in prosocial activities and environments in the local community (e.g. sports and cultural activities). • psychotropic medication may prove useful, but is seldom the only solution in addressing behaviour disorders in hiv-positive children. medications are often more successful in treating comorbid problems, e.g. methylphenidate for adhd, anticonvulsants (sodium valproate, lamotrigine and carbamazepine) for epilepsy, ssris for anxiety and depression. • seek supervision and get support from your colleagues; working with these children and their families can be demoralising and frustrating. management of conduct disorder and oppositional defiant disorder in hiv-positive children and adolescents • assess family functioning and parenting, and establish that the child not been maltreated (physical, emotional or sexual abuse or neglect). • refer family to a parenting support group or parenting skills training. • refer for individual and/or group psychological intervention, depending on the intellectual capacity of the child or adolescent, his/ her capacity to engage in relationship and motivation to participate. • risperidone may be useful in reducing aggression and impulsivity, but will need to be carefully monitored for the occurrence of epse. a dose of 0.5 1 mg/day, with a maximum dose of 1 2 mg daily, is recommended. discuss with a mental health professional if there is a poor response to the maximum dosage. • mood stabilisers may be used to aid behavioural management and affective dysregulation associated with behaviour disorders. these should ideally be prescribed by a specialist and monitored carefully. table 11. overview of oppositional defiant disorder dsm-v criteria clinical presentation • angry/irritable mood • frequently loses temper • easily annoyed or touchy • often resentful and angry • argumentative/defiant behaviour • frequently argues with adults and authority figures • frequently refuses to comply with requests from authority figures or with rules • frequently deliberately annoys others • mistakes or misbehaviour frequently blamed on others • vindictiveness • spiteful or vindictive at least twice within the last 6 months • temper outbursts (sometimes referred to as rage attacks in younger children) • persistent stubbornness; resistance to directions • unwillingness to compromise, give in or negotiate with adults or peers • no need to please • deliberate or persistent testing of limits • verbal (and minor physical) aggression • low self-esteem • mood lability and low frustration tolerance dsm-v = diagnostic and statistical manual of mental disorders (5th edition). 92 sajhivmed september 2014, vol. 15, no. 3 g u id e l in e 1.8.10 psychological interventions 1.8.10.1 psychosocial support for children • psychosocial support can be understood as any type of initiative that seeks to protect or promote the well-being of a child or adolescent, and prevent or treat mental health problems. • it should form part of a broad framework of care that includes the family, parents, school and community, and that encompasses a range of interventions combined to achieve the best possible outcomes. the provision of psychosocial support involves a range of stakeholders: caregivers, family members, teachers, and healthcare providers including psychological and social services. • psychosocial support includes the provision of individual counselling, the availability of facilityand community-based support groups, parenting programmes and peer support initiatives, and information and education workshops.[12] • to be effective, psychosocial intervention should be tailored to the context and take into account the child’s age and stage of development. it is essential that there is focus on enabling an hivpositive child to establish their identity, manage their care, live positively, cope with challenges and work towards a healthy future. • hiv-positive children are particularly vulnerable to psychological and social stressors that can affect their development and well-being. psychosocial support can foster resilience, enabling children and adolescents to bounce back from adverse experiences and to cope better with the multiple stressors related to hiv. their unique psychosocial needs include assistance to deal with their illness, help to cope with loss and changes of caregiver, and support to overcome isolation associated with stigma and discrimination.[12-14] 1.8.10.2 therapeutic support psychosocial intervention can take various forms including referral to support groups, psychotherapy or counselling (table 12).[15] 1.8.10.3 psychosocial support for adolescents • interventions for adolescents fall into three categories: therapeutic support, youth-centred interventions and those aimed at fostering independence. • in the case of the former, support groups, counselling and psychotherapy provide support across a broad range of issues (table 13).[15] • group-based interventions are attractive to the adolescent and are a timeand cost-effective method of delivery.[15] 1.8.10.4 benefits of group interventions for adolescents • enhance self-knowledge and self-acceptance. • empower individuals to make change. • help individuals to develop coping skills. • build communication skills and help in relationships outside of the group. • give individuals freedom to express negative feelings in a safe, nonjudgemental environment. • provide positive reinforcement and emotional support. • provide a platform for education, e.g. adherence to treatment. • foster a sense of belonging to counter feelings of isolation and inadequate social support. 1.8.11 youth-centred interventions • an important aspect of adolescent service provision is ensuring that it is youth friendly. • adolescent and youth-friendly service (ayfs) provision has been identified as an important aspect of service delivery in south africa, and has a strong focus on attracting and retaining young people for ongoing care. • adolescents are particularly vulnerable to the harmful outcomes of risk behaviours, e.g. unprotected sex and substance abuse, but tend not to seek early treatment. there are a number of reasons for this, such as worry about stigma or fear of harsh treatment at the clinic. table 12. psychosocial interventions for children support groups psychotherapy counselling • groups need to be tailored to the child’s age and stage of development, e.g. with younger children play can be combined with opportunities to learn about healthy living • older children can benefit from experiential activities across a range of health-related topics • useful to allow parents and caregivers to talk about their own fears, frustrations and challenges • can address difficulties with disclosure. secrecy can affect the mental health of both child and parent/ caregiver • provides a forum for education, correction of misconceptions and skills building • useful for building parenting skills that can help caregivers to develop effective communication skills, set limits and discipline appropriately • different types of psychotherapy are available to address a wide range of issues ranging from separation anxiety and learning or school problems to excessive shyness and low self-esteem. the choice of therapy will depend on the age and stage of the child’s development • in particular, younger children may benefit from play therapy where the use of play materials such as toys and puppets encourage children to talk about their feelings in order to better understand and cope with their difficulties • the participation of children is an important aspect of counselling but is easily overlooked. children may also be shut out of conversations because they have not been told their status • providing the opportunity to talk about matters that concern them with someone who is empathic, supportive and non-judgemental is important • the following counselling approaches may be useful:[16] • get down to the child’s eye level • speak softly and directly to the child • smile and play • be honest and patient • allow and respect normal emotions • start with the least invasive activities • give the child choices, e.g. would s/he like juice or water with medication • engage the child, e.g. talk about hobbies, friends and so on • support the parent-child relationship. • sit close to the child september 2014, vol. 15, no. 3 sajhivmed 93 g u id e l in e • paying attention to the health needs of adolescents is crucial. as young people become more independent, they are expected to take more responsibility for their own health. knowing where and when to get help and feeling confident that they can rely on a service that they trust and feel is there for them is fundamental to a positive outcome.[16] • a package of services should be available to meet the diverse needs of young people. • it is important to address obstacles that commonly inhibit the use of healthcare services by adolescents. 1.8.11.1 overcoming obstacles to providing afys • providers should be trained to work competently and respectfully with adolescents. • services must be confidential, non-judgemental and private. • clinic hours should be convenient for young people, e.g. after school. • services should be accessible to all adolescents and young people, irrespective of their age, sexual orientation or marital status. • an effective referral system should be in place. • opportunities should be made available for young people to be involved in the design, implementation and evaluation of the programme. • services should seek to involve and gain the support of those important in the lives of young people and in their communities, e.g. partners, parents, school.[16] 1.8.12 adherence in adolescents • helping adolescents to achieve independence is important particularly for those transitioning to adult services. • part of taking increased responsibility for their healthcare involves adhering to the prescribed treatment regimen. 1.8.12.1 improving adherence in adolescents • poor adherence is normal in adolescence, but the risk of drug resistance, limited treatment options, increased viral load and risks to survival mean that adherence needs to be well supported. • reasons for poor adherence among adolescents can be categorised into patient, treatment and socioeconomic factors. • stressful life events can contribute to poor adherence, as can treatment fatigue, substance abuse and mental health problems such as depression. • psychosocial support in the form of counselling, referrals and group participation can help young people who are finding adherence difficult. counselling provides opportunities to develop jointly a workable treatment plan that includes treatment reminders and takes into account lifestyle issues that have the potential to interfere with adherence if not addressed. • ideally, adolescents should know their hiv status. adolescents who have not been disclosed to will be unable to appreciate the importance of adherence to treatment and are less likely to understand the risks associated with engaging in unprotected sex. this makes status disclosure an important aspect of care and support.[19] 2. hiv-associated neurocognitive disorders 2.1 neurocognitive sequelae • in untreated children, cognitive impairment occurs early and progresses over time, with prevalence rates ranging between 8% and 60%. • early invasion of the developing fetal and infant brain is believed to result in the most common primary hiv-related cns complication, hiv encephalopathy (hive), which refers table 13. psychosocial interventions for adolescents support groups psychotherapy counselling • three main types of groups • educational • social and emotional support • peer-led • costand time-effective in a busy clinic • provide a safe space for young people to talk about personal issues, share similar challenges, discuss aspects of treatment (e.g. adherence), explore coping strategies and build a social network • can involve novel and interesting ways to achieve a specific goal, e.g. music, dance, drama, art or storytelling groups • important to understand developmental stage to ensure that groups meet the particular concerns of different age bands, e.g. discussions about puberty (young adolescents), or sexual and reproductive health issues (older adolescents) • support groups conducted for parents and caregivers are important and provide emotional support for carers, opportunities for discussing parenting challenges and fostering communication skills to build positive family relationships • the most common types of psychotherapy are cognitive behavioural therapy, and interpersonal and psychodynamic psychotherapy[17,18] • cognitive behavioural therapy uses techniques to correct distortions of thinking that are seen in emotional disorders • interpersonal psychotherapy is a brief, timelimited treatment based on the premise that depression occurs in the context of relationships. it covers four general areas of difficulty: grief, conflict in significant relationships, difficulties adapting to changes in relationships or life circumstances, and problems stemming from social isolation • psychodynamic psychotherapy is a ‘talk therapy’ for adolescents based on understanding issues that are behind a young person’s behaviour, thoughts and feelings. not all young people benefit from this form of therapy and assessment for suitability is required • other types of psychotherapy include family therapy, which aims to explore patterns of communication in families and to support and educate, and dialectical behaviour therapy, which is useful with older adolescents with chronic suicidal feelings or thoughts • may involve obtaining advice or exploring a personal or social problem • positive change more likely in a relationship of trust where confidentiality is maintained. building trust takes time and is greatly facilitated when the adolescent is able to see the same person at each visit • different types of counselling include grief, substance abuse and adherence counselling • adherence counselling is a form of psychosocial support that is concerned with the identification of effective strategies to promote adherence to antiretroviral treatment. its aim is to enhance the ability of young people to take their treatment as prescribed. it is a process that includes preparation, treatment initiation, consolidation and maintenance 94 sajhivmed september 2014, vol. 15, no. 3 g u id e l in e to the disease, damage or malfunction of the brain caused by hiv. this complication can be present before significant immunosuppression. however, its presence in a child infected with hiv constitutes an aids-defining illness, reflecting the severity of the condition. 2.1.1 prevalence and impact of hiv-associated neurocognitive disorders (hands) in children prevalence: • in untreated hiv-positive children, 8 60% experience cognitive impairment; disorder occurs early and progresses over time. • untreated hiv increases risk of cns sequelae.[17,20,21] impact: • a range of cognitive deficits occur, cognitive scores clustering in low average to borderline range for intellectual functioning. • although cognitive functioning improves after art initiation, scores remain lower than population norms, with poorer academic performance and persistence of language (e.g. verbal fluency), memory, processing speed, visuospatial and attention problems or deficits. remedial educational interventions are important.[18,22,23] • psychosocial stressors (poverty, orphanhood, parental physical/ mental illness or loss) negatively affect adherence, educational and mental health outcomes. • the concept of a milder form of neurocognitive disturbance in hivpositive children, such as the adult condition of hand is recognised but is yet to be defined in children and adolescents. this condition may have significant effects in functional terms on a child’s learning potential.[24] • many hiv-positive children receiving art function within normal limits compared with uninfected peers, but a subset with cns disease follow a distinct pattern of low average cognitive functioning. • the cognitive deficits in these children may be a result of ongoing viral replication in the brain despite virological control in the periphery or from residual effects of static hiv-1 cns disease. • although hiv-positive children receiving highly active antiretroviral therapy appear to exhibit global measures of intelligence comparable with their uninfected peers, deficits may be present in specific areas such as executive functioning and working memory. deficits in these areas can impact significantly on learning. • children with hand may demonstrate few clinical signs, but an index of suspicion should be aroused when history reveals delayed motor milestones and when school reports describe school difficulties. 2.2 specific neuropsychological deficits • neuropsychological testing reveals that executive functioning deficits might be an early indicator of cognitive problems, with deficits in mental processing, sequential processing, comprehension, memory, visuospatial and time orientation tasks. • one or more of the following must be met for diagnosis of hand: • a significant drop in cognitive test scores, but generally still above the delayed range, with or without mild brain imaging abnormalities, with no loss of previously acquired skills and no apparent functional deficits (adaptive behaviour and school performance stable) • cognitive test scores in the borderline range, with no significant functional deficits (and no history of significant drop or previous testing) • cognitive test scores within normal limits (low average range or above) with no significant functional deficits and moderate to severe brain imaging abnormalities consistent with hiv-related changes • abnormal neurological findings but not significantly affecting function.[26] • deficits suggestive of frontal lobe dysfunction (e.g. attention, processing speed, motor speed and visuomotor integration) are also detectible in hiv-positive children and adolescents. • educational interventions to address these problems are essential to improve the overall health literacy (and adherence) in infected youth as they age and assume greater treatment responsibility. • children infected with hiv presenting with cognitive problems may be slow to process information, slow to complete tasks or may be clumsy, and this may affect everyday living. understanding cognition in children is compounded by the fact that developmental milestones with regard to motor function, co-ordination and the elements of cognition occur at various stages in the development of a child. screening tools used in adults such as the international hiv dementia scale in their current form are thus inappropriate in children and adolescents, as each tool must accommodate the different developmental stages from childhood through to adolescence. 2.3 identification and management of neurocognitive disorders • prevention of hive, hand and aids-defining conditions via early art remains the cornerstone of effective management. art has dramatically decreased the prevalence of hive in the us from 35 50% to <2%.[27] • furthermore, early initiation of art results in improved neurodevelopmental outcomes compared with deferred initiation. • ensuring adherence and providing treatment support are key factors in management. • a multidisciplinary, tiered approach is recommended for the management of neurocognitive complications (table 14). • referral for pure neurocognitive decline should immediately be to a paediatrician/physician, according to the age of the child. • however, concern about contributing mental health/behavioural issues may require psychiatric review. centers for disease control and prevention: hiv encephalopathy criteria for classification[25] must include at least one of the following for at least 2 months in the absence of a concurrent illness: • failure to attain or loss of developmental milestones or loss of intellectual ability, verified by standard developmental scale or neuropsychological tests • impaired brain growth or acquired microcephaly evident by head circumference measurements or brain atrophy demonstrated by computed tomography or magnetic resonance imaging; serial imaging is required for children <2 years of age • acquired symmetric motor deficit manifested by two or more of the following: paresis, pathological reflexes, ataxia or gait disturbance cognition refers to a group of mental processes that include attention, memory, producing and understanding language, learning, reasoning, problem-solving and decision-making. september 2014, vol. 15, no. 3 sajhivmed 95 g u id e l in e • if cognitive impairment develops once a child is receiving art, check viral load and adherence. • if a child’s milestones are deteriorating or if an older child has educational or behaviour problems, and there is no obvious explanation, the child should be referred for further evaluation even if hiv infection is well suppressed. • treatable conditions can be diagnosed at a primary healthcare level; routine history, examination and blood tests assist in this regard (table 15). • exclude indirect complications of hiv infection such as opportunistic infections (tuberculous meningitis, cytomegalic virus infection), and intrauterine exposure to alcohol and substances. table 14. management of hiv-positive children at primary, secondary and tertiary care levels primary • document milestones, and measure head circumference at birth, enrolment and 6-monthly thereafter • monitor growth and nutrition • actively investigate and manage treatable conditions, e.g. chronic middle ear infection, epilepsy, iron deficiency anaemia • review copies of school reports, and refer for educational support, if possible • monitor side-effects of medication, e.g. sleep disturbances • refer to secondary level healthcare if complicated epilepsy, positive diagnosis of hive, or if hand, attention or behavioural problems are suspected secondary • paediatricians, psychiatrists, physiotherapists, occupational therapists and speech therapists at secondary level must be made available to all primary healthcare workers for up-referral as necessary • strengthen links between educators (teacher or learning support professionals at the school) and health professionals in order to provide education goals that are realistic and that will ensure the child achieves his/her maximum potential • refer for screening by specialists to decide if tertiary intervention is required and to manage some of the more complex general medical problems tertiary • refer for assessment by a specialist paediatrician (or developmental paediatrician) • refer for neuroimaging • refer to a psychologist for cognitive testing and/or neuropsychological battery (if indicated) • refer for eeg if indicated • refer for occupational therapy, audiology, and assessment of language and speech therapy as needed • referral for audiometry if a language development delay is present hive = hiv encephalopathy; hand = hiv-associated neurocognitive disorder; eeg = electroencephalography. table 15. medical conditions that may affect cognition[28,29] condition diagnosis potential effect on cognition management iron deficiency anaemia history and full blood count attention problems iron supplements nasal obstruction history, sleep studies learning difficulties and attention problems nasal spray, referral to an ent specialist chronic middle ear infection history and examination decreased hearing resulting in learning difficulties audiology, referral to an ent specialist visual impairment history and examination (e.g. use of a snellen chart for older children and small items such as edible ‘100s and 1 000s’ for young children) visuomotor problems and difficulty managing in the classroom refer to an optometrist/ophthalmologist as appropriate malnutrition growth charts specific learning difficulties and attention problems referral to a dietician, medical followup, refer to a nutrition supplementation programme efavirenz side-effects sleep history and colateral from teacher, may sleep at school, high efavirenz level decreased concentration and focus, poor memory detailed history, consider lower dose (discuss with a specialist) emotional problems history and behaviour checklists cognitive problems, attention problems, poor scholastic performance refer to a psychiatric service ent = ear, nose and throat. 96 sajhivmed september 2014, vol. 15, no. 3 g u id e l in e • identify environmental and socioeconomic deprivation (orphans, poverty, malnutrition), as this may further affect cognition. • if other factors (e.g. behavioural, acute illness, other infection) may possibly explain the drop in scores or low cognitive functioning, do not classify as hand or encephalopathy; re-evaluate at a later stage. 2.3.1 screening tools to detect neurocognitive impairment • no international validated screening tools are available to test hivpositive children for neurocognitive impairment. • however, screening tools can be helpful in identifying children at risk for developmental problems. examples of simple tools that can be used are available to download online (http://www. sahivsoc.org/topics?page=1&currentfilter=mental%20health). these include a tool for children younger than 5 years and another for schoolgoing children. these tools have not been validated, but together with the road to health developmental check list (rthdcl) may provide local tools for use at primary and secondary level care. • we recommend that all children be screened 6-monthly and more formally at 3 4 years and again at 5 6 years. this, together with the rthdcl, should enable flagging of children with potential problems. early detection of problems paves the way for interventions that would improve the quality of life of these children. • screening should occur in the context of general hiv clinics across all levels of healthcare. • screening needs to include a history, formal systemic examination and particularly a neurological examination (at least head circumference and motor examination, deep tendon reflexes and gait assessment). • any child with delayed developmental milestones should be referred for further assessment. • it is important to identify contributing factors that can be managed, e.g. nutritional, emotional, poverty and deprivation factors, among others. conflict of interest. all expert panel members have completed and submitted conflict of interest disclosure statements. disclosure information represents the previous 3 years (updated 3 september 2014) and includes relationships with pharmaceutical companies and medical aids: a lachman reports receiving honoraria from cipla medpro and lilly for speaking engagements; r nassen reports receiving an honorarium from astrazeneca for a speaking engagement. all other panel members report no conflict of interest. acknowledgement. this work was supported and funded by the southern african hiv clinicians society through unrestricted educational grants. references 1. donald k ,walker k, riordan g, et al. neurological complications of hiv/aids in childhood. continuing medical education 2011;29(4):156-159. 2. mellins ca, malee k. understanding the mental health of youth living with perinatal hiv infection: lessons learned and current challenges. j int aids soc 2013;16:18593. [http://dx.doi.org/10.7448/ias.16.1.18593] 3. gadow k, angelidou k. longitudinal study of emerging mental health concerns in youth perinatally infected with hiv and peer comparisons. j dev behav pediatr 2012;33(6):456-468. [http://dx.doi.org/10.1097/dbp.0b013e31825b8482] 4. lowenthal e, lawlerc k, hararic n, et al. rapid psychosocial function screening test identified treatment failure in hiv+ african youth. aids care 2012;24(6):722727. [http://dx.doi.org/10.1080/09540121.2011.644233] 5. american psychiatric association. diagnostic and statistical manual of mental disorders, 5th ed. arlington, va, usa: american psychiatric publishing, 2013. 6. canestri a, lescure f, jaureguiberry s, et al. discordance between cerebral spinal fluid and plasma hiv replication in patients with neurological symptoms who are receiving suppressive antiretroviral therapy. clin infect dis 2010:50(5):773-778. 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[http://dx.doi.org/10.1089/108729103771928717] 10. sherr l. young children with hiv/aids: mapping the field. working paper 33 in early childhood development. the hague, netherlands: bernard van leer foundation, 2005. 11. sherr l, mueller j. where is the evidence base? mental health issues surrounding bereavement and hiv in children. j public ment health 2009;7(4):31-39. 12. oneill jf, selwyn pa, schietinger h, eds. a clinical guide to supportive and palliative care for hiv/aids. washington, dc: us department of health and human services, 2003. 13. department of health south africa. psychosocial support for children and adolescents infected and affected by hiv. pretoria: department of health, 2012. 14. anesathasan a, mcleary-sills j, vujovic m, et al. foundation for the future: meeting the psychosocial needs of children living with hiv in africa. arlington, va: usaid’s aids support and technical assistance resources, aidstar-one, task order 1, 2011. 15. cheng k. psychotherapeutic interventions. in: cheng k, myers km, eds. child and adolescent psychiatry: the essentials. philadelphia: lippincott, 2005:439-457. 16. international planned parenthood federation. keys to youth-friendly services: celebrating diversity. london: ippf, 2011. 17. van rie a, harrington pr, dow a, robertson k. neurologic and neurodevelopmental manifestations of pediatric hiv/aids: a global perspective. eur j paediatr neurol 2007;11(1):1-9. [http://dx.doi.org/10.1016/j.ejpn.2006.10.006] 18. walker sy, pierre rb, christie cdc, chang sm. neurocognitive function in hivpositive children in a developing country. int j infect dis 2013;17(10):e862-867. [http://dx.doi.org/10.1016/j.ijid.2013.02.014] 19. williams p, storm d, montepiedra g, et al. predictors of adherence to antiretroviral medications in children and adolescents with hiv infection. pediatrics 2006;118(6);e1745-1757. [http://dx.doi.org/10.1542/peds.2006-0493] 20. laughton b, cornell m, grove d, et al. early antiretroviral therapy improves neurodevelopmental outcomes in infants. aids 2012;26(13):1685. [http://dx.doi. org/10.1097/qad.0b013e328355d0ce] 21. abubakar a, van baar a, van de vijver fj, holding p, newton cr. paediatric hiv and neurodevelopment in sub-saharan africa: a systematic review. trop med int health 2008;13(7):880-887. [http://dx.doi.org/10.1111/j.1365-3156.2008.02079.x] 22. cooper er, hanson c, diaz c, et al. encephalopathy and progression of human immunodeficiency virus disease in a cohort of children with perinatally acquired human immunodeficiency virus infection. women and infants transmission study group. j pediatr 1998;132(5):808-812. 23. laughton b, cornell m, boivin m, van rie a. neurodevelopment in perinatally hiv-infected children: a concern for adolescence. j int aids soc 2013;16:18603. [http://dx.doi.org/10.7448/ias.16.1.18603] 24. donald ka, hoare j, eley b, wilmshurst jm. neurologic complications of pediatric human immunodeficiency virus: implications for clinical practice and management challenges in the african setting. semin pediatr neurol 2014;21(1):3-11. 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[http://dx.doi.org/10.1016/s0140-6736(11)60555-2] 29. stein a, desmond c, garbarino j, et al. predicting long-term outcomes for children affected by hiv and aids: perspectives from the scientific study of children’s development. aids 2014;28(suppl 3):s261-s268. [http://dx.doi.org/10.1097/qad.0000000000000328] hiv 924 art adherence clubs: a long-term retention strategy for clinically stable patients receiving antiretroviral therapy l s wilkinson, ba, llb médecins sans frontières khayelitsha, cape town, south africa corresponding author: l wilkinson (msfocb-khayelitsha-coord@brussels.msf.org) the art-adherence club model described here provides patient-friendly access to antiretroviral therapy (art) for clinically stable patients. it reduces the burden that stable patients place on healthcare facilities, increasing clinical human resources for new patients, and those clinically unstable and at risk of failing treatment. in the model, 30 patients are allocated to an art club. the group meets either at a facility or community venue for less than an hour every 2 months. group meetings are facilitated by a lay club facilitator who provides a quick clinical assessment, referral where necessary, and dispenses pre-packed art. from january 2011 to december 2012, after adoption for phased rollout by the western cape government, more than 600 art clubs were established in cape town, providing art care to over 16 000 patients. this extensive, rapid rollout demonstrates active buy-in from patients and facility staff. south africa should consider a similar model for national rollout. s afr j hiv med 2013;14(2):48-50. doi:10.7196/sajhivmed.924 south africa (sa)’s national strategic plan 2012 2016 aims to ensure that 80% of all hiv-positive patients who are eligible for antiretroviral therapy (art), estimated at more than 3 million, are initiated on such treatment by 2016. it further aims to retain 70% of these patients in care 5 years after treatment initiation. by early 2013, 1.9 million people in sa were initiated on art, with studies estimating retention to be <70% after 3 years of commencing treatment.1 , 2 the growing numbers of patients attending healthcare facilities place increasing pressure on already stretched human-resource capacity, impacting the time taken to deliver services and the quality of care provided. in turn, the cost to patients of having to return to facilities regularly, the long waiting times at facilities, competing demands on time, including work and family responsibilities, and dissatisfaction with the quality of care, all affect long-term retention.3 effective long-term retention models of care are needed that offer quick, inexpensive and patient-friendly access to treatment and care for stable art patients.4 such models should also aim to decrease the burden that stable patients place on healthcare facilities, thereby increasing human resources for new patients and those who are clinically unstable and at risk of failing treatment. the art-adherence clubs piloted by médecins sans frontières (msf) in khayelitsha, sa, represent one such model. art-adherence clubs art-adherence clubs are an option for rapid service delivery; 30 patients are allocated to a group and meet either at a facility or community venue for less than an hour every 2 months. these group meetings are facilitated by a lay club facilitator who provides a quick clinical assessment, with referral to a clinician, where necessary, and dispenses pre-packed art. club members establish a positive group dynamic over time, which renders much-needed peer support for adherence to lifelong treatment. club facilitators refer any patient reporting symptoms or ill health, or who recorded weight loss since their last club visitation. the club is supported by a facility nurse who is available to see patients referred by the facilitator, immediately after a club session. all club patients receive annual blood tests, with scheduling aligned and blood samples taken at the same session. two months later, all members are seen by the club nurse for their annual clinical consultation and repeat prescriptions of art. patients qualify for art club membership if they have been on the same art regimen for longer than 12 months, have two consecutive undetectable viral loads, and do not have any clinical conditions that require regular follow-up. while in the clinic waiting room, patients are encouraged to request their clinician to assess them for club recruitment. club patients are entitled to send a ‘buddy’ to collect their treatment from their art club. however, patients themselves must attend every second club session, including the annual blood investigation and annual clinical consultation sessions. patients can be removed from club care and returned to mainstream care when more intensive clinical or adherence follow-up is required. a patient exits the club when he/she misses a mandatory club session and fails to attend the clinic within 5 days. patients determined by the club nurse to require more regular follow-up and those with elevated viral loads are also returned to mainstream care. club patients are monitored by completion of a simple register by the facilitator. attendance is then captured as club plus clinic attendance in the clinic’s electronic database by the clinic data capturer. art clubs are considered part of the art service at a facility and are managed by a facility-based nurse (called the 'clubs manager') who is responsible for the scheduling of club dates, the smooth running of clubs, clinical governance and club reporting requirements. pilot: experience from khayelitsha msf began with a pilot project of 20 clubs at the ubuntu clinic, site b, khayelitsha in 2007. a retrospective observational evaluation found that retention in clinic care after 40 months was 97% for club patients compared with 85% among those who qualified for clubs but continued to be managed outside of the club model. club participants were also 67% less likely to experience virological rebound, indicating better adherence in clubs than in mainstream care.5 the club model was adapted both during and after the completion of the initial pilot. at first, clubs allowed membership in excess of 50 patients, but this was later limited to 30 patients after lay club facilitators struggled to manage club sessions and it was felt that smaller groups would improve peer support among members. eligibility criteria were also amended from >18 months on art to >12 months on art, at the time when routine viral load testing changed from every 6 months to annually after the first year of art. to obtain buy-in upfront from the facility manager and improve staff participation in the club model, a formalised art club staff organogram was introduced, with clearly defined roles and responsibilities for each team member. most importantly, the clubs manager required the requisite delegated authority from the facility manager to ensure the effective implementation and smooth running of the clubs. while the clubs manager has, in the past, also taken on the role of the full-time club nurse, placing the responsibility entirely on a single clinician, this led to a parallel service with limited capacity to expand. daily rotation of the club nurse function within a facility ensures collective responsibility for the management of club patients. the implementation of clubs and their expansion within a facility is dependent on the clinic pharmacist, as the club model relies on the pre-packing of art. while supplying club patients with pre-packed art adds no additional burden to supplying the same patients as facility patients, the club model does not alleviate overall pharmacy burden. furthermore, the benefits of not seeing each individual patient at the pharmacy window can be overlooked. space limitations can create an obstacle to club implementation or expansion beyond one club a day within a facility. while full decentralisation into the community is the goal, community venues close to the clinic can be utilised without requiring additional logistical support. the ubuntu clinic utilises a room at the local library, approximately 500 metres from the facility, where half of its day clubs meet. it has also started evening clubs at 18h00, utilising extended hours. this has allowed for 3 club meetings a day. allocating patients to a club designated for a specific feeder area makes it easier to move clubs into the community at a later stage. overall, there has been widespread buy-in and participation by clinic staff and patients in the art clubs in khayelitsha. there is a continued, high demand for more art clubs in facilities where club rollout has slowed or stopped. further detail on how to establish clubs, the art club staff organogram, lessons learnt through the khayelitsha implementation experience and tools utilised in the art club model, are available online (http://www.msf.org.za/publication/art-club-toolkit). implementation beyond the pilot in early 2011, the art club model was adopted by the western cape government (wcg) department of health (doh) for phased rollout initially in the cape town metro. a partnership was formed between the wcg doh, city health (city of cape town), msf and the institute for health improvement (ihi), to support implementation.6 fig. 1 illustrates the implementation strategy adopted by the partner­ship. first, a steering committee with representatives from each partner was formed and hiv/aids, sexually transmitted infections (stis) and tuberculosis (tb) (hast) managers or facility-based doctors were identified to become club mentors. the club mentors were trained on the art club model and were tasked with supporting the implementation of art clubs in 1 3 pilot facilities. facilities with the highest patient load were prioritised. the next phase was to invite 10 12 facility club teams (including the clubs manager, club nurse, club facilitator(s), clinic pharmacist and clinic data capturer) to attend a learning session where they were trained by the steering committee and club mentors and supported in making an implementation plan. the facility club mentor supported the team at the facility intensively at first and with routine support visits thereafter. six months later, the same facility club teams attended a second learning session where they reported back on progress. any challenges experienced were discussed with other facilities and the steering committee allowed for the sharing of possible solutions. where club implementation at these pilot facilities continued to face obstacles, a third learning session could be convened. in general, for this process to be successful, it is important to have buy-in and active support from facility management and sub-district management throughout the implementation process. fig. 1. schema for the implementation of art adherence clubs. hast = hiv/aids, sexually transmitted infections (stis) and tuberculosis (tb). fig. 2. patients at an art adherence club meeting. by 31 december 2012, the cape town metro had implemented over 600 clubs with more than 16 000 stable art patients accessing care and treatment accordingly. this amounts to approximately 15% of art patients in care in cape town. the partnership won a 2012 platinum award from the prestigious impumelelo social innovations centre for adopting and implementing this innovative approach to managing large numbers of patients receiving art. resources to operate adherence clubs each facility running art clubs requires a club team. the role of the clubs manager is part time, but does require sufficient time to carry out club-management responsibilities. at least one full-time lay club facilitator is required per 40 art clubs. in addition, a facility nurse needs to be allocated as the club nurse on the clinic roster for each day on which a club session takes places. the nurse can usually continue to see clinic patients as he/she is infrequently required to see a club patient after a club session, other than the annual blood investigation and annual clinical consultation sessions. in the cape town metro, club facilitation has been included in the job profile of facility counsellors. additional counsellor posts have been allocated to facilities – one for facilities with more than 15 clubs and two for facilities with more than 40 clubs. where clubs are run in the community, community-care workers could serve as club facilitators. in addition, resources may be spared by adapting the art club-visit schedule and associated art supply from 2to 3-monthly. pharmacy-related bottlenecks to club rollout can be pre-empted by allocating an additional pharmacy assistant where the number of facility clubs exceeds 15, or alternatively, by utilising a central dispensing service for pre-packing art as demonstrated in the cape town metro. access to fixed-dose combinations (fdcs) is imperative to support accelerated art club rollout. in addition to supporting long-term adherence, fdcs reduce the pre-packing burden on pharmacy staff and make it logistically simpler to transport pre-packed art drugs to art club locations. conclusion the art-adherence club model improves adherence and long-term retention in care among clinically stable art patients, while optimising health resources to manage new art patients and patients at risk of failing treatment. the impressively extensive and quick rollout in the cape town metro demonstrates active buy-in from patients and facility staff by addressing the obvious need for quick, patient-friendly access to care and treatment for clinically stable art patients. it is imperative that sa considers a similar model for national rollout. conflict of interest. the author contributed to the development of the club model and is the msf representative on the wcg doh art club steering committee. acknowledgements. art club steering committee: j mouton (wcg doh), k jennings (city health), m youngleson (ihi), b harley (city health), c cragg (wcg doh), s jacobs (wcg doh), e kriel (wcg doh); and the ubuntu, msf and treatment action campaign (tac) khayelitsha staff who contributed to the development of, and continue to support art clubs. references 1. cornell m, grimsrud a, fairall l, et al. temporal changes in programme outcomes among adult patients initiating antiretroviral therapy across south africa, 2002 2007. aids 2010;24:2263-2270. 1. cornell m, grimsrud a, fairall l, et al. temporal changes in programme outcomes among adult patients initiating antiretroviral therapy across south africa, 2002 2007. aids 2010;24:2263-2270. 2. fox mp, rosen s. patient retention in antiretroviral therapy programs up to three years on treatment in sub-saharan africa, 2007 2009: systematic review. trop med int health. 2010;15(suppl 1):1-15 2. fox mp, rosen s. patient retention in antiretroviral therapy programs up to three years on treatment in sub-saharan africa, 2007 2009: systematic review. trop med int health. 2010;15(suppl 1):1-15 3. ware nc, wyatt ma, geng eh, et al. toward an understanding of disengagement from hiv treatment and care in sub-saharan africa: a qualitative study. plos med 2013;10(1):e1001369. [http://dx.doi.org/10.1371/journal.pmed.1001369] 3. ware nc, wyatt ma, geng eh, et al. toward an understanding of disengagement from hiv treatment and care in sub-saharan africa: a qualitative study. plos med 2013;10(1):e1001369. [http://dx.doi.org/10.1371/journal.pmed.1001369] 4. harries ad, zachariah r, lawn sd, rosen s. strategies to improve patient retention on antiretroviral therapy in sub-saharan africa. trop med int health 2010;15(suppl 1):70-75. [http://dx.doi.org/10.1111/j.1365-3156.2010.02506.x] 4. harries ad, zachariah r, lawn sd, rosen s. strategies to improve patient retention on antiretroviral therapy in sub-saharan africa. trop med int health 2010;15(suppl 1):70-75. [http://dx.doi.org/10.1111/j.1365-3156.2010.02506.x] 5. luque-fernandez ma, van cutsem g, goemaere e, et al. effectiveness of patient adherence groups as a model of care for stable patients on antiretroviral therapy in khayelitsha, cape town, south africa. plos one 2013;8(2):e56088. [http://dx.doi.org/10.1371/journal.pone.0056088] 5. luque-fernandez ma, van cutsem g, goemaere e, et al. effectiveness of patient adherence groups as a model of care for stable patients on antiretroviral therapy in khayelitsha, cape town, south africa. plos one 2013;8(2):e56088. [http://dx.doi.org/10.1371/journal.pone.0056088] 6. institute for healthcare improvement. the breakthrough series: ihi’s collaborative model for achieving breakthrough improvement. ihi innovation series white paper. boston: institute for healthcare improvement, 2003. 6. institute for healthcare improvement. the breakthrough series: ihi’s collaborative model for achieving breakthrough improvement. ihi innovation series white paper. boston: institute for healthcare improvement, 2003. abstract introduction methods ethical consideration results discussion study limitations acknowledgements references about the author(s) sam mndzebele school of public health, sefako makgatho health sciences university, pretoria, south africa lebogang g. matonyane school of public health, sefako makgatho health sciences university, pretoria, south africa citation mndzebele s, matonyane lg. sexual behaviours, awareness and perceptions towards voluntary medical male circumcision among students in dr kenneth kaunda district, south africa. s afr j hiv med. 2019;20(1), a846. https://doi.org/10.4102/sajhivmed.v20i1.846 original research sexual behaviours, awareness and perceptions towards voluntary medical male circumcision among students in dr kenneth kaunda district, south africa sam mndzebele, lebogang g. matonyane received: 28 feb. 2018; accepted: 05 feb. 2019; published: 22 may 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: voluntary medical male circumcision (vmmc) is regarded as the most cost-effective intervention in reducing female-to-male transmission of hiv in countries where heterosexual transmission is the most prevalent mode of infection. objectives: the aim of the study was to determine the awareness, sexual behaviours and perceptions of college students in dr kenneth kaunda district, south africa. method: a cross-sectional design was engaged among a sample of 400 students selected using a stratified random sampling method. descriptive data analysis was engaged to analyse data using stata 13. results: the mean age of the respondents was 23 years. about 50% of the respondents were below the age of 23 years. the majority among the ethnic groups were black people and or african people (87.5%), followed by people of mixed race (8.1%). most of the students belonged to the christian religion (94.7%), and about 91.3% were single, while only 6.0% lived with their partners. among those who were circumcised, a majority (78.0%) had undergone the mmc. about 76.5% of those residing in urban areas, and 80.6% residing in rural areas were circumcised. about 90.3% of the participants had good awareness about vmmc. about 77.3% of the participants disagreed that vmmc reduces the size of the penis, while 57.0% felt that vmmc provides an individual with the status of being a real man in society. only 14.3% felt that vmmc exposes the penis to environmental hazards. while almost half (47.7%) of the cohort had one sexual partner, about 20.9% had three or more sexual partners. conclusion: the findings suggest that there is a high level of awareness on vmmc among college students in relation to its positive role towards reducing stis and the enhancement of penile hygiene. keywords: voluntary medical male circumcision; sexual-behaviours; awareness; perceptions; hiv testing. introduction male circumcision (mc) is regarded as one of the oldest and most common surgical procedures performed worldwide. it is undertaken for religious, cultural, social and medical reasons.1 due to the increased use of surgical procedures in the 19th century and advancement in technology within the health system, in the 20th century mc was introduced to some individuals whose culture did not observe male circumcision. this was based on health-related and social reasons. in recent years, voluntary medical male circumcision (vmmc) has evolved. the practice of circumcision commenced in english-speaking countries only in the 19th century; in 2002, only half of the boys were circumcised in the us, whereas other countries such as england and new zealand had a fairly low circumcision rate.1,2 in north africa and most of west africa, male circumcision is almost universal; this is in contrast to southern africa, which has a low prevalence of circumcision but a high rate of hiv. a study conducted in zimbabwe in 2013 found that 50% of the students were willing to go for vmmc, and 50.0% were willing to think about whether to do it or not.3 the following year, a similar study indicated that only 0.05% of students were willing to go for circumcision whereas around 50.6% had reservations about undergoing the procedure.4 a study among students in the university of botswana found low circumcision prevalence.5 these studies indicate that in countries such as zimbabwe and botswana, there are still some young men who have not been circumcised. in the south african context, there is reportedly moderate prevalence of circumcision among students in higher institutions of learning as indicated by the survey done in 2014 by higher education and training hiv/aids programme (heaids), which showed that 66.0% of the students were circumcised, 79.0% preferred vmmc and the students were willing to encourage others to opt for circumcision.6 this prevalence in south africa is because of massive scale-up of vmmc in different communities and mobilisation through media platforms targeting young people. in december 2014, over 9 million vmmcs were performed in all of the 14 priority countries in sub-saharan africa.7 in 2014, only 3 million vmmcs were performed, which showed that rapid vmmc scale-up has been implemented in most of sub-saharan africa. according to unaids targets, it is expected that by 2020, there should be an additional 27 million vmmcs done; these vmmc targets were based on the statistics obtained in 2014.7 there has been significant progress made in scaling up vmmcs in 14 priority countries; during 2015 ethiopia and kenya exceeded their 80.0% coverage of men performing vmmcs; tanzania was on track to reach the expected target. countries such as lesotho, malawi, rwanda and zimbabwe were still lagging in 2015 with a low coverage of 6.0% – 26.0%. there is also an urgent need to launch vmmc in central african republic and south sudan.7 the voluntary medical male circumcision programme was launched in kenya in 2008 following the who/unaid recommendation in 2007. initially, kenya aimed to circumcise 860 000 by 2013. the number of operations increased every year from 8000 to 190 000 between 2008 and 2013. according to literature, 80.0% of the vmmcs in kenya were conducted in the nyanza province, where half of the uncircumcised men live in kenya.8,9 there is evidence of the overall success of the vmmc programme in kenya, as most young people begin their adolescent state to acknowledge this and ensure they have done vmmc; the kenyan government seeks to ensure that there is sustainability of the programme.10 according to the centers for disease control and prevention (cdc), the next step in kenya is to accelerate vmmc among males under the age of 15 and infants.11 by the end of 2014, in lesotho there were 85 000 men who had vmmc as part of hiv comprehensive prevention services; 56.0% of those men were tested for hiv; while in south africa between 2012 and 2015 250 000 circumcisions were done.7,12 it is now well documented that a significant portion of south africa’s indigenous population has been practicing the culture of male circumcision for centuries. for instance, male circumcision initiation schools in south africa form part of the cultural practice. however, the integration of medical male circumcision with traditional manhood initiation rituals still seems to lack acceptability in these societies. of note, about 70.0% of the men fear being stigmatised if they are circumcised medically in south africa.13 as part of vmmc promotion and awareness in south africa, a number of organisations have been working closely with heaids to assist with comprehensive hiv prevention services by motivating all male students to get circumcised. within the institutions of higher learning, such as colleges, there are health promoters and vmmc mobilisers who continuously interact with students about the implications that can be endured from having unsafe sex and the benefits of vmmc. according to statistics, young people aged 15–24 account for 39.0% of new hiv infections, which is a startling proportion.14 a study conducted in uganda among fishing communities reported that there are several cultural beliefs about vmmc, which include fear that foreskins are sold after removal, the belief that a vmmc recipient’s first sexual partner after the procedure should not be his spouse, and the belief that vaginal fluids aid circumcision wound healing. on that note, some researchers state that the primary motivations of vmmc are religious injunction, hygiene and protection against sexually transmitted infections (stis) (not necessarily hiv).15,16 a study conducted in kenya suggested that there is a need to dispel misconceptions about mc by involving religious leaders and women’s groups, and making circumcision relevant to men who are already practicing an hiv preventative method. another study conducted among university students in zimbabwe revealed that only a minority of them were willing to be circumcised; this was mainly due to the negative attitude that students had about vmmc.4,17 a cross-sectional study was also conducted among adults in rural uganda, which revealed different negative perceptions about vmmc, especially in relation to its hiv protective measure. there is a concern about circumcision that is done after childhood. a study conducted among police officers in dar es salaam, tanzania, raised concerns about circumcision conducted at older ages, as there is a view that pain can be felt more and penile erection post circumcision can delay wound healing.18,19 the integration of male circumcision into mother and child health services can motivate women to allow circumcision of their child at an early age, hence alleviating many negative beliefs that the child can have as they grow older when they are not circumcised. furthermore, a group of researchers indicated that if more health education can be provided about different aspects of vmmc, some of the perceptions can be eliminated and corrected. studies conducted in most african countries indicate that there is a lack of knowledge and awareness about vmmc; while another study that was conducted among university students in botswana revealed varied evidence that there is an increase in the level of awareness of vmmc.5,20 similarly, a study conducted among university students in zimbabwe found that the majority of students were aware about vmmc but failed to provide detailed information about the procedure. despite people being educated through various media platforms and promotion campaigns, literature has revealed that there is a knowledge gap about certain aspects of vmmc.3,18 a study conducted in zimbabwe indicated that exposure to information on vmmc is important in order to increase the awareness. the most cited sources of information were radio, television, newspaper and billboards. another study conducted among university students in zimbabwe showed that the majority of students were aware of vmmc but failed to provide detailed information about the procedure; the only information they had was from public media.3,17 there have been varied views by the general population regarding vmmc since its inception. for instance, there is still a strong belief in southern africa that circumcision decreases natural sexual ability.5 within the context of eastern and southern africa, where hiv prevalence is high, mathematical modelling has shown that circumcising 80.0% of males (aged 15–49) in five years can prevent approximately 3.4 million infections. there has been a belief that post vmmc, sexual behaviours, especially of males, can potentially reduce the expected benefits of the practice.18 a demographic and health survey (dhs), done from 2010 to 2011 in zimbabwe, found no association between mc status and risky sexual behaviour.17 recent studies conducted in zimbabwe and uganda provided varied evidence that mc is sometimes viewed as a complete protection against hiv and stis. some observational studies conducted in the field of vmmc have found that men who are circumcised are more likely to engage in risky sexual behaviour than those who are uncircumcised.15,17,20 in africa there is a strong belief that circumcision improves sexual performance, especially among adults, and there is also a concern that this can increase the risk of hiv transmission. equally so, there is a strong believe that the perceptions that communities hold about vmmc can likely affect their sexual behaviours after undergoing the procedure.18,19 a study conducted among men in western kenya revealed that most men felt that condoms are much easier to use after vmmc as indicated by messages they got during circumcision.21 there is a very strong association between being circumcised and risky sexual behaviour; however, despite the association, men who are circumcised are less likely than those who are uncircumcised to be hiv-positive; this clearly indicates that the benefits of being circumcised outweigh the risk of predicted unwanted sexual behaviour.22 in a study done to examine sexual behaviour change following circumcision among adult men in siaya and bond district hospitals in western kenya, a cohort of men who chose to be circumcised were matched with those who chose not to be circumcised; in the three months of the study, risky sexual behaviour was reported among the circumcised cohort but at the 12 months follow-up there were no significant differences in risky behaviour.1 this kind of study demonstrates that if proper counselling is offered to men on risk reduction, they are more likely not to engage in risky sexual behaviour following circumcision. the study aimed at determining the awareness, sexual behaviours and perceptions of college students in dr. kenneth kaunda district in south africa. methods study population and sampling method through the use of a cross-sectional design, a population comprising male students between the ages of 18 and 49 years were registered at vuselela college. there were estimated 4000 male students registered in 2015 as per the department of higher education report. each campus was estimated to have the following number of male students enrolled: potchefstroom centre for information communication and technology studies (800), jourbeton centre for engineering studies (1800), klerksdorp centre for business studies (1200) and matlosana campus (200). hence, a stratified random sampling method was found suitable, where each campus was stratified based on the number of male students enrolled. the resultant sample size arrived at was 351 participants, which was increased with a buffer of 15.0% to 400. data collection instrument and pretesting a self-administered questionnaire was used as a data collection tool. the questionnaire comprised closed-ended questions. questions were developed in english, as students were in a higher institute of learning. data were collected until a required sample reached. the data collection instrument comprised four sections, which included socio-demographic characteristics, awareness of vmmc, sexual behaviours and perception towards vmmc. good and/or satisfactory awareness, perceptions and practices regarding vmmc were determined through positive or preferred responses to > 75% of the questions in the questionnaire as indicated by the codes. the questionnaire was pretested among 15 students from springfield college, who do not form part of the study sample. data collection process after proper arrangements with the lecturers and college authority, students were approached in classes and briefed about the study. those selected to take part in the study were asked to remain in class to be informed more about the study. those who agreed to participate were asked to sign an informed consent form with detailed information about the purpose of the study and potential risks, such as being asked certain questions that they were comfortable to answer. participants were therefore provided with the questionnaire and instructions on how to complete it. after completion, questionnaires were collected by the researcher. the process took them 20–25 min. validity and reliability the reliability of the data collection tool was enhanced by conducting a pilot study among a few students. sample size was increased by a marginal number to cater for non-responses and incomplete questionnaires. questions were carefully developed in such a way that they address the study objectives, hence ensuring the reliability of the data collection tool. questionnaires were checked by the supervisor to ascertain if they are relevant to the study. to ensure validity of the data collection instrument, questions were structured using simple language that participants understood. questions were simple and explained clearly the aim of the study and its importance, thus minimising non-response. to minimise selection bias, the researcher used a stratified random sampling method, which involved the division of a population into smaller groups known as strata. unavoidable information bias, more specifically recall bias, was expected to be encountered; however, this was borne in mind when interpreting the results of the study. data capture and analysis the completed questionnaires were cross-checked to remove mistakes. data were later entered into an excel spreadsheet and coded, then finally imported into stata 13 (stata corp, tx, usa) for statistical processing and analysis. univariate analyses, including frequency distributions, were run to characterise the sample. bivariate analysis was done to obtain significant association between the awareness and perception of college students in relation to their sexual practice. the chi-square test and odds ratios (or) with 95.0% confidence intervals were used to measure the association. summary measures were used to describe findings, and they were expressed as means (standard deviations), medians (ranges), modes and proportions. ethical consideration permission to conduct the study was granted by sefako makgatho health sciences university school of healthcare sciences research ethics committee with clearance certificate ref. [smurec/h/1112017: pg]. furthermore, approval was granted by the provincial department of higher education and training (dhet), as well as the dean of vuselela college in order to gain access at the institution for data collection. participants were first clearly briefed about the purpose of the study prior to obtaining an informed consent. further, participants were informed that participation in the study was voluntary and that they were free to withdraw from the study at any time without being penalized. participants were also assured of anonymity in the completion of the questionnaires through the use of codes and not their real names or personal details. during the process of the study, confidentiality was ensured and maintained by not sharing participants’ information with anyone, and by keeping all the study material in a secure place. results sample characteristics the mean age of the respondents was 23 years, with a minimum of 18 and a maximum of 42 years of age and a standard deviation of 4.1. about 50.0% of the respondents were below 23 years. those below 23 years were 59.5% (n = 191) as compared to those above 23 years (n = 130; 40.5%). the majority ethnic group in the study was black people or africans (87.5%), followed by mixed race (8.1%). most students belonged to the christian religion (94.7%), and there were also jewish (1.87%) as well as muslim (1.87%) students. a majority of the students were single (91.3%), with around 19 (6%) living with their partners and 187 (n = 187; 58.3%) participants residing in urban areas. about 47.7% of the participants reported one sexual partner, and 35.5% reported two or more sexual partners. of note, students who had undergone circumcision were more likely to have one sexual partner (53.3%). uptake of male circumcision and sexual behaviours the proportion of circumcised men in the cohort was 77.6%. among those circumcised, the majority (78.2%) had undertaken the medical male circumcision; the rest underwent traditional male circumcision. one reason provided by the participants for not being circumcised included fear of complications (21.1%), while about 45.1% had no specific reason for not being circumcised. about 51.8% had a single partner and was circumcised, with 22.3% having three or more partners. participants who resided in the urban areas were mostly circumcised (76.5%), those who were uncircumcised from urban areas were only 23.5%. those who resided in rural areas and were not circumcised constituted 19.4% compared to those who were circumcised (80.6%). a significantly high proportion of the participants rightly acknowledged health benefits of undergoing vmmc as revealed in the following percentages: 82.2% indicated that vmmc increases penile hygiene; 95.6% reported that vmmc reduces the risk of stis; and 92.2% said that vmmc reduces the risk of penile cancer. in terms of sexual behaviours, almost half (47.7%) of the cohort had one sexual partner; about 20.9% had three or more sexual partners. level of awareness the majority of the participants (90.3%) had good awareness about issues surrounding vmmc. participants below the age of 23 years (54.8%) had a poor awareness level. specifically, the majority of participants (97.8%) were aware that vmmc involves the removal of the foreskin. in terms of penile hygiene knowledge regarding vmmc, most participants (82.2%) scored well on this aspect. a very high number of the participants (95.6%) had a strong belief that vmmc reduces the risk of stis. participants who knew that there is a need for abstinence for six weeks after vmmc were about 91.9%. about 30.6% of the respondents reported that they have learnt about vmmc on television, while only a few (1.3%) reported that they have never learnt about vmmc at all. those who learnt from the radio were about 18.4%, from newspaper 15.6%, from clinic and/or hospital 38.3%, from friend 27.1%, from neighbours 10.0%, through posters 13.7%, and from other sources 8.1%. perception of medical male circumcision generally, only 10.6% of the participants had positive perceptions about vmmc. in terms of the following statements: ‘vmmc reduces the size of the penis’, and ‘vmmc decreases sexual satisfaction’; 77.26% of the participants disagreed with the former and 75.63% with the latter. when asked whether circumcised men enjoy sex more than uncircumcised men, about 61.99% agreed with this statement. in terms of whether women prefer circumcised sexual partners to uncircumcised partners, about 58.57% agreed. further, about 54.2% disagreed that vmmc violates the principles of traditional male circumcision (as indicated in table 1). table 1: participants’ perceptions towards voluntary medical male circumcision. discussion uptake and barriers towards voluntary medical male circumcision in our study, a significantly higher (78.2%) proportion of participants had undergone vmmc. this figure is above the one recorded by heaids in southern africa in 2014, which indicated that about 66.0% of the students were circumcised, bearing in mind that our study was conducted three years later. these developments may also be an indication of a rapid scale-up of vmmc promotion and awareness by non-governmental organisations (ngos) targeting young people within the dr. kenneth kaunda district. on another note, around 21.1% participants in our study reported fear of complications, and 16.1% said they fear pain following vmmc. these findings are consistent with findings in most literature of these barriers associated with vmmc. for instance, these barriers (fear of pain, concerns around safety issues, and the costs) were mentioned by participants in related studies.1,20,23,24,25 our findings indicated that about 47.7% of the participants reported one sexual partner, and 35.5% had two or more sexual partners. of note, students who had undergone circumcision were more likely to have one sexual partner (53.3%). this is an indication that there was a limited presence of risky sexual behaviour among the participants in our study. voluntary medical male circumcision awareness among students the high proportion (90.3%) in terms of good awareness on vmmc issues among students in our study seems to be in line with the findings of a study conducted among university students in botswana, where they found that 95.4% had good knowledge about vmmc.5 in terms of vmmc’s protective role against hiv, we noted that participants lacked knowledge (30.8%) on this aspect. this is consistent with related findings in studies, such as those in botswana and uganda, whose findings revealed that there was still a knowledge gap among students about such aspects regarding sexual matters and vmmc.5,18 in contrast, engle and others conducted a study in kenya, which showed increased awareness of vmmc among participants, especially in relation to its role in partial hiv protection.21 in our study, only 18.4% of the participants claimed that they learnt about vmmc from the radio; while about 15.6% learnt from newspapers. about 38.3% learnt about vmmc from clinics/hospitals, and 27.1% and 13.7% from friends and posters, respectively. we also noted that these findings are similar to a study conducted in zimbabwe, which indicated almost the same sources of information to their participants such as radio, television, newspaper and billboards.17 some health benefits associated with voluntary medical male circumcision there are certain health benefits associated with being circumcised, which include the reduced risk of acquiring hiv, cancer, and stis, in addition to an increased level of penile hygiene. in all of these aspects, a significantly high proportion of the participants in our study rightly acknowledged these benefits in the following percentages: 82.2% indicated that vmmc increases penile hygiene; 95.6% reported that vmmc reduces the risk of stis; and 92.2% said that vmmc reduces the risk of penile cancer. these ratings are closely similar to other findings conducted in a number of studies within the african region in terms of vmmc and its health benefits such as in botswana;26 south africa;24,27,28 zimbabwe;29 and kenya.23 perception regarding voluntary medical male circumcision in terms of perception towards vmmc, our study results revealed that only 14.3% of the participants reported that vmmc makes the penis more vulnerable to environmental hazards, while only 10.0% reported that vmmc decreases sexual satisfaction. such perceptions from students are consistent with some studies conducted among university students in zimbabwe, which revealed that only a minority of them were willing to be circumcised.4 further, a cross-sectional study that was conducted among adults in rural uganda revealed some negative perceptions towards vmmc.18 however, there is evidence that such negative perceptions towards vmmc may be minimised in societies through the involvement of community leaders and religious groups in aspects of vmmc education and promotion. our study also revealed that students who were circumcised were more likely to have a positive perception towards vmmc than those who were uncircumcised at 91.8% and 8.2%, respectively. study limitations the study was limited to students in the selected colleges only; there were no other young people from the society included in the study to increase external validity. the study was relying mostly on self-reported information regarding the circumcision status of the participants. there was no physical examination done to confirm the circumcision status. finally, like in most similar studies, there might be some recall bias as some participants may not accurately remember where they have learnt and/or heard about circumcision. acknowledgements competing interests the authors declare that they have no financial or personal relationship(s) which may have inappropriately influenced them in writing this article. authors’ contributions s.m. and l.g.m. equally contributed to the writing and research of this article. references who/unaids. male circumcision: global trends and determinants of prevalence, safety and acceptability. brazzaville: who; 2007. pang mg, kim ds. extra-ordinarily high rates of male circumcision in south korea: history and underlying causes. bju int. 2002;89(1):48–54. https://doi.org/10.1046/j.1464-410x.2002.02545.x jeofrey m, zivanai s, gwendoline s. attitude of midland state university students towards male circumcision as a way of reducing hiv transmission. j hum soc sci. 2013;16(1):1–5. https://doi.org/10.9790/0837-1614549 tsevere m, pedzisai c. attitudes of university students towards male circumcision. int j innov res dev. 2014;3(2):236–242. mndzebele sl, tegegn ga. knowledge, attitude and acceptance of voluntary male medical circumcision among male students attending botswana university. j public health epidemiol. 2015;7(1):6–14. https://doi.org/10.5897/jphe2014.0671 higher education and training hiv/aids programme (heaids). hiv and aids related knowledge, attitudes and behaviours of students and staff at south african technical and vocational education and training colleges in south africa, 2014. avert. voluntary medical male circumcision for hiv prevention [homepage on the internet]. 2015 [cited 2017 jun 30]. available from: https://www.avert.org/professionals/hiv-prevention-programming/voluntary-medical-male-circumcision national aids control council of kenya (nacck). kenya aids response progress report 2014: progress towards zero [homepage on the internet]. 2014 [cited 2017 sep 10]. available from: http://www.unaids.org/sites/default/files/en/dataanalysis/knowyourresponse/countryprogressreports/2014countries/ken_narrative_report_2014.pdf kenya national aids & sti control programme (nascop). kenya aids indicator survey 2007: final report [homepage on the internet]. 2009 [2017 sep 10]. available from: http://www.nacc.or.ke/nacc%20downloads/official_kais_report_2009.pdf galbraith js, ochieng a, mwalili s, et al. status of voluntary medical male circumcision in kenya: findings from 2 nationally representative surveys in kenya, 2007 and 2012. jaids. 2014;10(1097):37–45. https://doi.org/10.1097/qai.0000000000000121 centers for disease control and prevention (cdc). progress in voluntary medical male circumcision service provision – kenya, 2008–2011 [homepage on the internet]. 2012 [cited 2017 sep 10]. available from: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6147a2.htm u.s. agency for international development (usaid). demographic and health survey 2009 [homepage on the internet]. 2010 [cited 2017 sep 10]. available from: http://pdf.usaid.gov/pdf_docs/pnadu407.pdf peltzer k, kanta x. medical circumcision and manhood initiation rituals in the eastern cape, south africa: a post intervention evaluation. cult health sex. 2009;11:83–97. https://doi.org/10.1080/13691050802389777 sabreakingnews. male students urged to get circumcised [homepage on the internet]. 2017 [cited 2017 jul 15]. available from: http://www.sabreakingnews.co.za/2017/03/27/male-students-urged-to-get-circumcised/ nevin pe, pfeiffer j, kibira sps, lubinga sj, mukose a, babigumira jb. perceptions of hiv and safe male circumcision in high hiv prevalence fishing community on lake victoria, uganda. plos one. 2015;10(12):1–16. https://doi.org/10.1371/journal.pone.0145543 toefy y, skinner d, thomsen sc. ‘what do you mean i’ve got to wait for six weeks?!’ understanding the sexual behaviour of men and their female partners after voluntary medical male circumcision in the western cape. plos one. 2015;10(7):1–13. https://doi.org/10.1371/journal.pone.0133156 chikutsa a, maharaj p. social representations of male circumcision as prophylaxis against hiv/aids in zimbabwe. biomed central public health. 2015;15(603):1–9. https://doi.org/10.1186/s12889-015-1967-z mukama t, ndejjo r, musinguzi g, musoke d. perceptions about medical male circumcision and sexual behaviours of adults in rural uganda: a cross sectional study. pan afr med j. 2015;22(354):1–7. https://doi.org/10.11604/pamj.2015.22.354.7125 tarimo eam, francis jm, kakoko d, munseri p, bakari m, sandstrom e. the perceptions of male circumcision as a preventive measure against hiv infection and considerations in scaling up of the services: a qualitative study among police officers in dar es salaam, tanzania. biomed central public health. 2012;12(529):1–12. https://doi.org/10.1186/1471-2458-12-529 naidoo pv, dawood f, driver c, narainsamy m, ndlovu s, ndlovu v. knowledge attitude and perceptions of pharmacy and nursing students towards male circumcision and hiv in a kwazulu natal university, south africa. afr j prim health care fam med. 2012;4(1):1–7. https://doi.org/10.4102/phcfm.v4i1.327 engle kl, lanham m, loolpapit m, oguma i. understanding partial protection and hiv risk and behaviour following voluntary medical male circumcision rollout in kenya. health educ res. 2013;29(1):122–130. https://doi.org/10.1093/her/cyt103 kibira sps, nansubuga e, tumwesigye nm. male circumcision, sexual behavior, and hiv status in uganda. usaid. 2013;100:1–31. mattson cl, bailey rc, muga r, poulussen r, onyango t. acceptability of male circumcision and predictors of circumcision preference among men and women in nyanza province in kenya. aids care. 2005;17(2):182–194. https://doi.org/10.1080/09540120512331325671 scott be, weiss ha, viljoen ji. the acceptability of male circumcision as an hiv intervention among a rural zulu population in kwazulu-natal south africa, aids care. 2005;17(3):304–313. https://doi.org/10.1080/09540120412331299744 skolnik l, tsui s, ashengo ta, kikaya v, lukobo-durrell m. a cross-sectional study describing motivations and barriers to voluntary medical male circumcision in lesotho. biomed central public health. 2014;14(1119):1–10. https://doi.org/10.1186/1471-2458-14-1119 kebaabetswe p, lockman s, mogwe s, et al. male circumcision: an acceptable strategy for hiv prevention in botswana. sex transm infect. 2003;79(3):214–219. https://doi.org/10.1136/sti.79.3.214 lagarde e, dirk t, puren a, reathe rt, bertran a. acceptability of male circumcision as a tool for preventing hiv infection in a highly infected community in south africa. aids. 2003;17(1):89–95. rain-taljaard rc, lagarde e, taljaard dj, et al. potential for an intervention based on male circumcision in a south african town with high levels of hiv infection. aids care. 2003;15(3):315–327. https://doi.org/10.1080/0954012031000105379 halperin dt, fritz k, mcfarland w, woelk g. acceptability of adult male circumcision for sexually transmitted disease and hiv prevention in zimbabwe. sex transm dis. 2005;32(4):238–239. https://doi.org/10.1097/01.olq.0000149782.47456.5b abstract background methodological approach research design study setting research methods selection of respondents data collection process data analysis ethical consideration results discussion limitations, rigour and trustworthiness conclusion acknowledgements references about the author(s) ferdinand c. mukumbang school of public health, university of the western cape, cape town, south africa brian van wyk school of public health, university of the western cape, cape town, south africa sara van belle department of public health, institute of tropical medicine, antwerp, belgium bruno marchal school of public health, university of the western cape, cape town, south africa department of public health, institute of tropical medicine, antwerp, belgium citation mukumbang fc, van wyk b, van belle s, marchal b. ‘at this [adherence] club, we are a family now’: a realist theory-testing case study of the antiretroviral treatment adherence club, south africa. s afr j hiv med. 2019;20(1), a922. https://doi.org/10.4102/sajhivmed.v20i1.922 original research ‘at this [adherence] club, we are a family now’: a realist theory-testing case study of the antiretroviral treatment adherence club, south africa ferdinand c. mukumbang, brian van wyk, sara van belle, bruno marchal received: 03 oct. 2018; accepted: 28 feb. 2019; published: 26 june 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: an estimated 7.9 million people were living with hiv in south africa in 2017, with 63.3% of them remaining in antiretroviral therapy (art) care and 62.9% accessing art. poor retention in care and suboptimal adherence to art undermine the successful efforts of initiating people living with hiv on art. to address these challenges, the antiretroviral adherence club intervention was designed to streamline art services to ‘stable’ patients. nevertheless, it is poorly understood exactly how and why and under what health system conditions the adherence club intervention works. objectives: the aim of this study was to test a theory on how and why the adherence club intervention works and in what health system context(s) in a primary healthcare facility in the western cape province. method: within the realist evaluation framework, we applied a confirmatory theory-testing case study approach. kaplan–meier descriptions were used to estimate the rates of dropout from the adherence club intervention and virological failure as the principal outcomes of the adherence club intervention. qualitative interviews and non-participant observations were used to explore the context and identify the mechanisms that perpetuate the observed outcomes or behaviours of the actors. following the retroduction logic of making inferences, we configured information obtained from quantitative and qualitative approaches using the intervention–context–actor–mechanism–outcome heuristic tool to formulate generative theories. results: we confirmed that patients on art in adherence clubs will continue to adhere to their medication and remain in care because their self-efficacy is improved; they are motivated or are being nudged. conclusion: a theory-based understanding provides valuable lessons towards the adaptive implementation of the adherence club intervention. keywords: antiretroviral treatment; adherence club; medication adherence; retention in care; realist evaluation; south africa. background south africa has the largest aids epidemic in the world, with an estimated 7.9 million people living with hiv (plhiv) as of 2017.1 the south african health system currently runs the largest antiretroviral therapy (art) programme in the world.2 although major successes have been achieved by the south african health system in responding to the hiv epidemic, yet challenges remain. these challenges are reflected in the sustained high hiv incidence rates,3 poor retention in art care and suboptimal adherence to medication.2 poor retention in care and suboptimal adherence to medication threaten the success of the south african national art programme. with an estimated 4.44 million people initiated on art to date1 and the recent adoption of the ‘test and treat’ approach,4 the need for sustainable programmes to improve the retention in care and adherence to art is critical. a consolidated version of the world health organization’s (who’s) 2015 hiv treatment guideline recommends the use of differentiated care models to improve the access and quality of treatment and care services for plhiv.4 differentiated models adapt hiv treatment services to specific patient populations and contexts, rather than adopting a one-size-fits-all approach.5 by tailoring services according to the needs of different patient groups, reducing clinic contact and relying on community-based services for quick medication access for the treatment of mature patients, these models increase the capacity and efficiency of art services. the adherence club intervention is an example of a differentiated care model designed to streamline art care for adults (18+ years), treatment-experienced patients on first-line treatment with a good clinic attendance record and evidence of medication adherence.6,7 through quick group consultations, convenient medication pickup processes and direct access to a clinician when needed, the adherence club drastically reduces the waiting times of the patients. the adherence club intervention also provides a conducive social environment to encourage patient interactions with peers. the adherence club intervention has been described in greater detail elsewhere.8 the evidence supporting the effectiveness of the adherence club intervention9,10,11,12 and its cost-effectiveness13 has prompted plans to roll out the intervention nationwide.2 nevertheless, there is a limited theory-based understanding of how and why the adherence club intervention works and in what health system context(s). to this end, a realist evaluation of the adherence club intervention was commissioned.14 in this article, we report on the process of testing the hypothesis (initial programme theory) of how and why the adherence club intervention is expected to work under real-life implementation conditions. methodological approach the realist evaluation, a theory-driven approach, guided the inquiry.15 the goal of realist evaluation is about learning ‘for whom, in what circumstances, and in what respects a programme works’,15,16 through identifying, testing and refining programme theories. therefore, realist evaluation starts with an initial programme theory and the goal is to obtain a more refined programme theory. programmes work with the acquiescence of participants (actors),17 and provide resources, opportunities or constraints of some kind that influence the target person’s decision-making.18 therefore, understanding why a programme works (or not) rests on the ability of the evaluator to explain the decision-making process of the relevant actors regarding the resources, opportunities and constraints that the programme provides to the relevant actors. identifying the important generative mechanisms (social and psychological drivers) of a programme is not enough to explain how and why a programme works (or not).19 for an intervention to work, it must influence the reasoning (mechanism) of the targeted actors to cause them to adopt an intended behaviour that, in a specific context, will lead to a specific outcome. therefore, realists assume that an outcome (o) is generated by a mechanism (m) being triggered in context (c) through an actor (a) when an intervention (i) is implemented. this captures how, why, for whom and in what circumstances programmes work. formulating realist theories is, therefore, achieved through the formation of intervention–context–actor–mechanism–outcome (icamo) configurations.20,21 the icamo configuration is a modification of context–mechanism–outcome (cmo), originally proposed by pawson and tilley22 as the heuristic tool for the development of realist theories. in the first phase of this project, we elicited an initial programme theory of the adherence club intervention with information obtained from four sources23,24,25 (see figure 1). figure 1: sources of information towards formulating the initial programme theory. we applied the icamo heuristic tool to configure the programme theory by applying the logic of retroduction – mechanism-centred analysis and conceptualisation – to make inferences. testable hypotheses were distilled from the configurational map,8 an approach to causality whereby outcomes are considered to follow from the alignment of a specific combination of attributes,16 using the ‘if … then … because’ phrase (box 1). box 1: initial programme theory of the adherence club intervention represented by two tentative theories (hypotheses). the aim of this study was to test these initial programme theories in a primary healthcare facility running the adherence club programme, with the goal of obtaining a more refined programme theory of the adherence club intervention. in conducting and reporting the findings of the study, we followed the rameses ii reporting standards for realist evaluation developed by wong et al.26 research design this study is framed within the realist evaluation approach. we sought to test the initial programme theory of the adherence club intervention in a real-life implementation situation to verify, refute and/or modify the initial programme theory of the adherence club intervention. to this end, we adopted an explanatory theory-building case approach and the multiple embedded case study design.27 facility y was considered the case and the unit of analysis, with each of its art clubs being sub-units embedded in the case. according to creswell and plano clark,28 cases selected for case study research could be identified as typical, deviant or crucial. facility y was selected as a deviant case, a most likely case shown to be negative with regard to the phenomenon under consideration. to this end, we considered facility y for testing the initial programme theory of the adherence club intervention. this facility has retention in care rates of only 63.0% based on the routine monitoring and evaluation data on the adherence club intervention of 2015. although facility y was selected for the first phase rollout of the adherence club intervention in 2012 along with other clinics in the health sub-districts, the intervention only rolled out in september 2014. reasons were challenges related to lack of physical space and poor buy-in from the facility healthcare providers. study setting facility y is a provincial primary healthcare facility providing primary healthcare to the surrounding communities. staff provide first-level and some second-level care, including a 24-h emergency service. housed in a separate building from the main clinic, is an accredited art initiation and on-going management site, which operates mondays to fridays providing treatment and care services to plhiv and those infected with tuberculosis (tb). patients who are co-infected with hiv and tb can easily access both services, as those with hiv and tb share the same waiting area and are seen by the same counsellors. because of a lack of proper structures such as physical meeting space, the programme could not be implemented at the scheduled time. following the construction of a makeshift building for club activities, the intervention was initiated at the facility. while conducting a preliminary qualitative exploration for the suitability of facility y for our study, we uncovered that the adherence club programme was poorly implemented because of poor buy-in from the staff members, who failed to identify how the intervention would benefit them and/or improve the overall delivery of art services to the patients. they perceived the adherence club intervention as extra work in their already busy schedule. consequently, even when a makeshift building was constructed for the adherence club activities, the programme struggled to function properly. when the sub-district managers identified the problem through routine monitoring and reporting, a nurse was identified and trained in the implementation and execution of the adherence club programme to champion the intervention at facility y. this nurse subsequently ran workshops and meetings with the other art care providers at the facility expounding on the advantages of the intervention to the patients, the healthcare workers themselves and the clinic. this strategy led to an overall improvement of the level of buy-in, uptake and implementation of the adherence club intervention. to date, an estimated 50 clubs with 25–35 patients each have been established at the facility. research methods we combined a retrospective cohort analysis and an explanatory qualitative approach to data collection. using a sequential explanatory approach,29 we first collected the quantitative data, which informed the retention in care and suppressive adherence to medication outcomes at the facility. the quantitative data collection was followed by qualitative methods (non-participant observation, in-depth interviews and focus group discussions) aimed at informing the nature of the outcomes obtained. the combination of qualitative and quantitative methods allowed us to explore the important contextual elements that influence the implementation of that adherence club intervention, the mechanisms that the intervention introduces and the emergent outcome patterns. the multi-method approach also allowed for triangulation. selection of respondents regarding the retrospective cohort arm of the study, our goal was to identify a typical ‘mature’ adherence club, that is, a club that reached its maximum capacity of 30–35 patients. firstly, we selected all the clubs that had opened in 2014, and then identified the clubs that had reached their maximum capacity (35 patients per club) in the same year – seven clubs were identified. we purposefully decided to select two clubs to allow us to compare their retention in care and ability to enhance adherence to medication. these two clubs were randomly selected from the identified seven to conduct the survival analysis using the fishbowl or lottery method – without replacing.30 all the patients in the cohort of each of the selected adherence clubs (35 per club) were included in the cohort analysis. regarding the interview process, we included all the operational staff working on the adherence club programme at the facility, which comprised an adherence club nurse, who heads the adherence club programme, and three lay counsellors. we applied a purposive sampling approach to select six participants to be interviewed from the two adherence clubs sampled for the quantitative retrospective arm of the study. our goal was to obtain at least one male and one female from each of the clubs. we also included two patients who were members of the adherence club, but had been asked to return to the standard care scheme at the main facility because they failed to follow all the club rules. table 1 elaborates on the characteristics of the participants who were interviewed. table 1: characteristics of study participants for the qualitative interviews. data collection process we used the two sampled clubs as the focus of data collection for the observation. the quantitative data were extracted from the adherence club registers at the clinic. in the western cape, information relating to retention in care is registered using the modalities outlined in table 2. table 2: modalities defining adherence club attendance. concerning retention in care, the patients were considered not retained in care if they did not attend a club session or sent a ‘buddy’ and were sent back to the clinic. patients were considered censored if they were transferred out to a different club or clinic, or died. for adherence to medication, when a patient was not attending that club for whatever reason, they were considered censored. the viral load of the patients is used as a proxy indicator of adherence to medication. non-adherence was identified as any reading > 400 copies/cm3 and adherence was represented as ldl (lower than detectable reading). we conducted four non-participant observations31 of the adherence club meetings, where we observed club sessions without interfering in any of the processes. these included two sessions of exclusive medication collection and a blood sample collection plus medication collection. the goal of the non-participant observation was to obtain insights into events and activities and the meanings that the club members attach to the sessions. we captured the dynamics of interactions of the group members with each other and with care providers in our field notes. during each observation session, we took detailed field notes. after the non-participant observations, we conducted realist interviews – a theory-driven approach to interviewing32,33 – to uncover the causal relationship of aspects related to the implementation of the adherence club intervention. the investigation looked at the relevant context, generative mechanisms and emerging outcomes in relation to the patients (actors). pawson32 advises that in applying the realist interviewing approach, the researcher’s theory is the subject matter of the interview, and the subject is there to confirm or falsify and, above all, to refine that theory. he also suggests that the care providers are versed in issues around the context and outcome of the intervention, while the patients, being the principal actors in the intervention, can provide mechanism-related attributes.32 the patient interviews were conducted after the second non-participant observation. the quantitative data were captured using microsoft excel and prepared for analysis using the statistical package for social sciences (ibm spss) version 24. the field notes from the non-participant observations were also developed into transcripts. the audio-recorded interviews were transcribed verbatim by a professional transcriber and prepared for analysis. atlas.ti version 7 was used to manage the field notes and interview transcripts. data analysis to identify and describe the outcome patterns of the adherence club intervention regarding retention in care and adherence to medication, we used the kaplan–meier method – the probability of surviving in a given time while considering time in many small intervals.34 this method was suitable because it allowed us to estimate the rate at which patients remained in care and the rate at which they maintained a viral load lower than detectable (< 400 copies/mm³ of blood) at 6-month intervals, covering a 24-month period. the analysis of the qualitative data involved the coding of the realist interview (semi-structured) transcripts. the coding process was done by the first author who has extensive knowledge on the subject matter,35 with a previously validated coding frame by four authors that was based on the initial programme theory (appendix 1). after the coding process, we classified the themes as a mechanism, context, actors, intervention and outcomes. ethical consideration regarding the study participants, we first provided the participants with an information sheet for the project. this was followed by a verbal explanation of the role of the participants and the significance of their participation. the participants were required to sign an informed consent form. we promised and ensured confidentiality and anonymity by identifying the participants using pseudo names and password-protecting all the study related files. this study is part of a larger project ‘a realist evaluation of the antiretroviral treatment adherence club program in selected primary healthcare facilities in the metropolitan area of western cape province, south africa’, which has received ethical clearance from the higher degree’s committee of the university of the western cape. in addition, we obtained ethical clearance from the provincial department of health of the western cape province. we also obtained permission from the facility heads. results the findings are presented in relation to the two initial programme theories. qualitative findings context context relates to important conditions relevant to the implementation of the adherence club, which includes buy-in from health workers, clinic organisation, the number of clubs run by the facility, staffing dynamics, availability of resources (including human resources), pre-club preparations (including teamwork) done by the club team and individual patients’ attributes. buy-in from health workers although buy-in could be identified as an important mechanism for the implementation of the adherence club intervention, it also constitutes an important context element for its day-to-day functioning. our analysis revealed that buy-in was not always obtained from all the operational managers when the programme was initially rolled out in the facility. one of the counsellors explained the situation below: ‘when the idea of clubs came in 2011, we did not like the idea because we knew that it would be more work for us. it meant that we had to do our normal patient counselling including the tb patients and then still organise the clubs. we were not happy about it … but when sister came, she explained that the clubs will reduce the waiting times of the patients because we were always complaining “we were working so slow, the time periods, waiting periods is long”.’ (counsellor 2, female) our study participants revealed that at the time of the study, there was a good buy-in from the operational staff regarding the implementation of the adherence club programme. this buy-in prompts them to work beyond the call of duty. for instance, a counsellor explained that rather than start the adherence club sessions at 8 am, as originally scheduled, they start the club activities at 7 am to allow the patients to finish at the club and still make it to their workplaces on time. this is what the nurse had to say: ‘we have to have buy-in from everybody, so i also had to speak to the pharmacists, telling them, “this is the plan, this is the reason” and tell them how they are going to benefit by fewer patients waiting in their waiting area.’ (nurse 1, female) integrated care integrated care means providing services relating to not only art, but also services of other non-communicable chronic diseases, such as hypertension, diabetes and epilepsy. patients having any other illness and who are on art in the adherence club are also provided with services to manage the concomitant non-communicable chronic diseases. this context encourages the successful implementation of the adherence club regarding patients with comorbidities. the nurse participant explained how the notion of integrated care provides for a conducive environment for patients with other comorbidities along with living with hiv: ‘what we have also done is now all the patients, because we provide a holistic, integrated service in this department, we have made a chronic club [patients with concomitant hiv and non-infectious chronic diseases]. we have three chronic clubs. if you have hypertension or diabetes, then we will put you together in one club. so, we know when those patients come, we measure their blood pressures, we will test their sugar levels, and we will send them for their yearly eye testing. we also do their feet exam, so that they are also not disadvantaged.’ (nurse 1, female) availability of conducive physical space the availability of appropriate physical space where the adherence club sessions could be conducted is an important context condition. in fact, the lack of a physical structure was one of the main reasons why the adherence club programme at facility y only commenced in 2014 when a makeshift building was constructed. some of the providers suggested that having a separate unit to run the adherence club programme is ideal. this was confirmed by the comments of the adherence club nurse who suggested that having a separate, dedicated space for art adherence clubs provides an air of privacy for the patients: ‘we have a separate space at the back for club activities. so, they have got their own privacy and their own space. they have that freedom and it is not with everybody else.’ (nurse 1, female) availability of a programme champion a champion is someone who is dedicated to the success of a programme and closely monitors the implementation and execution of every aspect of the programme. having a programme champion is identified, therefore, as an important context element for the successful execution of the adherence club intervention. it triggers the required mechanisms to ensure retention in care and adherence to medication. a participant said the following to capture the importance of having a programme champion, especially with regard to initiating and sustaining buy-in from other operational staff: ‘when i came here, i received training and i wanted to find out more about this club. i received training from an ngo and they told us … what the goal of the club is, what is the aim, and then once i got the buy-in and the training, then i realised the benefits of it. i then encouraged my staff and told them “the more patients we put in the club, the fewer patients we have to see”. because the staff is always complaining, “there are many patients”. they are overworked, they are exhausted, there are staff shortages, their morale is low and it is just too much. so, i said okay, i had several meetings with them. i said, “guys, we need to pull together because we are not going to get more staff. the only way to decongest the people waiting in our clinic is to put them in a club because if they are in the club, we will have fewer people waiting here, fewer people that you have to see”. so then, everybody was on board, everybody is excited and then we got a timetable. so, everybody was given a responsibility that we need to fill out the clubs, write out the scripts, fewer patients.’ (nurse 1, female) teamwork working as a team is identified as a favourable condition for the successful implementation and execution of the adherence club programme. this is related to the fact that each member of the team has a role to play, and if any of the team members fail to deliver, then the execution of the intervention is affected, which also affects how the users take up the intervention. one of the counsellors explained how each of the operational staff executing their responsibilities as a team member ensures that the adherence club programme works seamlessly: ‘teamwork is very important because if the sister [nurse] does not prescribe the medication, you cannot get the medication from pharmacy, there are going to be delays or no medication given. then the patients have to go sit in that mainstream, then what is the use of the club because then they have to go back to the waiting area.’ (counsellor 1, female) mechanisms we identified possible mechanisms from the data, based on the two parts of the initial programme theory, and defined a ‘mechanism’ as a process of how subjects interpret and act upon the intervention.19 initial programme theory 1 regarding theory 1 (box 1), we found the following elements in the interviews with the stakeholders. motivation motivation relates to the motive behind an individual’s involvement in an activity. in this case, the outcome of interest relates to ease of receiving art and care services that fit into one’s lifestyle. this is especially applicable for newly diagnosed patients who are not attending adherence clubs as they are not yet eligible to attend, but are aware of the benefits that the adherence club offers. one of the counsellors indicated how patients are usually motivated to join the adherence club for easy access to treatment and care by meeting the adherence club criterion of achieving viral load suppression: ‘when we prepare them [treatment-naïve patients] for arvs, we tell them “in six months if your viral load is suppressed then you are going be a vip which means starting from today you are starting your medication, you need to take your medication very well. you are not going to come to the clinic monthly. you will come maybe four times but it will be less than five times a year to the clinic, we take blood only once a year.” you know so we are starting to buy them in when we are preparing them. this motivates them to achieve a low viral load.’ (counsellor 3, female) perceived benefit the perceived benefit relates to the awareness of the positive impact that the resources of the adherence club could have on fitting their art into their lifestyles. these benefits were related to the prompt service delivery that they received through the adherence club. one of the patients expressed their perceived benefit of having quick access to see a clinician when they have any issue(s) requiring clinician consultations. this is expressed in the quote below: ‘if you are here and you want to see the doctor, one of the nurses goes inside and speaks to a doctor [on your behalf]. then, they will just come and fetch you here and then you go straight to the doctor.’ (patient 1, male) satisfaction satisfaction relates to the fulfilment of the patients’ desires, expectations and needs regarding the service delivery offered through the adherence club. one of the patients expressed their satisfaction with the adherence club by indicating that it is nice to have everything done within the club – a one-stop-shop. this is how some of the patients described the care they experienced in the club: ‘here we are doing everything inside here, so it is nice. it is very nice. so, if someone wants to go back to work, she or he can go back to work. so, it is encouraging for the person to take their medication, it is encouraging for the person to come to the clinic.’ (patient 1, male) according to the providers, the patients’ experiences with the adherence club care leave them satisfied, which makes them potentially remain in care and adhere to their medication. bonding and group identifying formation bonding is the formation of a close relationship, especially through frequent or constant association. the literature says that the bonding process can be facilitated by shared common goals and characteristics.36 the bond formation between the club members is an important mechanism as it fosters sharing among the club patients. one of the patients explained how being in the club and meeting on a regular basis enhances a close association with each other that they are now a family. this is what a patient said about bonding: ‘okay, you see here as we are at this club, we are a family now. we did not know each other, but now, as we are here, we know each other … this is my family. some other people here, they do have families, but they do not tell their families that they have this.’ (patient 2, female) perceived social support perceived social support speaks to the awareness of the positive impact that the moral, psychological or physical support has on the patients receiving care in the adherence club intervention. the nature of the support received in the adherence club is predominantly peer support. according to lee and lok,36 peers can provide companionship, stimulation, physical support, ego support and intimacy. one of the patients indicated the nature of support that he or she receives when they are in the adherence club re moral support through chatting with other club members: ‘when i am here [in the club], i feel de-stressed (relaxed) like i am staying at home. i think the club is the right thing, because we share some talks, “how is the medication you take?” i prefer the club than to talk with friends.’ (patient 1, male) knowledge acquisition knowledge acquisition is an important cognitive mechanism related to the health talks that are provided by the club facilitators during each club meeting session. we found that the acquisition of knowledge by the patients improves their self-efficacy – the perception of their ability to perform activities related to the self-management of their disease.37 in the quote below, a patient explained some of the things that they learn during the adherence club sessions, some related to enhancing medication adherence and others with regard to preventing the spread of hiv: ‘in the club, they are open; they always tell us how to take the tablets, what you are supposed to do. like now, they were telling us that if you have a partner, you must not sleep without a condom. you must always “condomise”. they were telling us about tb [tuberculosis], the side effects of drinking alcohol whilst you are on medication and the side effects of smoking cigarettes.’ (patient 3, female) one of the respondents suggested how this education received by the patients translates into understanding: ‘when they receive the health talks, at least they will have a clear understanding of what to do and how the club will be benefitting them.’ (counsellor 3, female) based on our observation of the club sessions, we noticed that the club facilitators also spent some time to remind the patients during the health talk of the rules and regulations guiding the adherence club. they emphasised the behaviours that could potentially lead to the patient being ousted from the club, indicating that the rules were being reinforced. one of the counsellors confirmed this observation: ‘yes, the health talks have a very big impact, because it reminds them [patients] of the dos and don’ts because if we do not give the talks, patients will forget the rules.’ (counsellor 1, female) trust one of the counsellors explained the unspoken code of conduct or the psychological contract, which exists among the members of the adherence club and the counsellors. that is, club members and counsellors are not meant to disclose the status of patients outside the adherence club meeting or with a non-club member. one of the counsellors explained how the underlying code of conduct to maintain confidentiality in the adherence clubs promotes trust among the members: ‘they know that whatever happens here [in the club], it remains here. we do not go and share things that are discussed here in the community. for example, if one of the club members is a friend or a neighbour or whoever, maybe they go to church together. they know that they are not allowed to go and talk “that we are in the same club”. so, they know that one of the rules is like confidentiality. whatever happens here, remains here.’ (counsellor 2, female) perceived barriers perceived barriers to leave the club are related to the circumstances that cause patients to be aware of the advantages offered by the adherence club intervention in light of the challenges they face in regular clinic care. in the excerpt that follows, a lay counsellor explained how perceived barriers related to seeking permission from work to pick up their monthly art from the healthcare facility. patients in art care, therefore, cherish the two monthly medication pickup and the quick services offered at the club (nullifying the need for asking for permission): ‘when you are in the care of the facility, you only get maybe one month [medication supply]. so, every time you have to ask for a day off, leave, or something for you to get your medication. so [in the club], it is much easier. it saves time and then you do not have to sit in the clinic for the whole day.’ (counsellor 1, female) the following excerpts outline aspects of the regular art clinic that patients perceive as barriers to their art care. because the adherence club is meant to remove these barriers, it encourages them to remain in art care under the clubs: ‘and waiting at the aisles is not so nice like here [in the clubs], because then you have to wait for the doctors and you have to wait for everything, your tablets, even to go to the pharmacy, but here [in the clubs], you can just come and get your medication and weight and that is it.’ (patient 4, male) a patient also identified the potential of being stigmatised, which is part of the environment of the regular art clinics as a perceived barrier. this barrier is minimal or absent in the adherence club: ‘therefore, i have to stay stable, because we do not like to stand there in front [in the regular clinic] so that the people are going to judge us. so, i have to take my medication so that the people do not see me there [in the regular clinic]. i must stay here at the club.’ (patient 5, female) initial programme theory 2 perceived coercion perceived coercion is the awareness of being compelled or pressured to do something. although the club intervention is beneficial to the patients, there are also some managerial benefits, such as decongesting the facility. thus, the club rules are there to ensure the smooth functioning of the intervention as well as to promote the success of the programme. nevertheless, some patients might interpret some of the club rules as being coercive: ‘i know the club [has] got rules and like the one rule. it [club rules] helps a lot because then you must take your medication. it is necessary that you take it [medication]; otherwise, you will go back to where you came [regular art clinic].’ (patient 4, male) our observation revealed that the patients were being reminded of the club rules at every club visit. they are particularly reminded of the circumstances that could lead to being sent back to the main clinic care. fear fear relates to the awareness of the dangers of being returned to the mainstream care and experiencing the barriers that the adherence club intervention addressed. one of the patients explained how the fear of being sent back to the main art scheme, characterised by long waiting times and frequent travels to the clinic, causes them to not afford to miss a club session: ‘so, you do not want to be sent back, because you know you will return to waiting for two hours for tablets. you have to wait there and you go to the pharmacy, there will be a queue. you know that if i miss the appointment with the club, then they might send me back.’ (patient 3, female) nudging nudging is the notion of being guided towards making decisions that are considered beneficial (to the patient), usually by the healthcare providers by presenting options in a specific way. by providing restricted options to the patients receiving care in the adherence club programme, they are nudged to acting in a particular way as guided by the resources and principles that are on offer at the adherence club. a patient suggested they are being made to attend their adherence club sessions and to take their medication through the rules of the club, because if the rules are not abided to, then they are sent back to the main clinic care: ‘they make you come to the clinic, and they make you take your medication, because if you are going back to the main clinic, my dear, you will stay there for the whole day in the main clinic. you come at half past six, you stand in a queue there at the reception, then at eight o’clock, they start giving your folders and then from there you go to the scale.’ (patient 1, male) outcome the outcomes that are identified here are based on the findings of quantitative analysis (retrospective cohort analysis – primary outcomes) and emergent outcomes from the interview process that are challenging or complex to measure (these are not part of the primary outcomes of retention in care and adherence to medication). these outcomes include decongesting the healthcare facility and reducing the workload of the healthcare workers. decongestion of the facility one of the emerging outcomes of the adherence club intervention is that it contributes to decongesting the healthcare facility. one of the participants explained how this is being achieved: ‘it [the club] is decongesting because remember, there are 35 patients per club. there are some days that we have two clubs. so, remember, if it is one day, every day 35 patients from the normal waiting area are being removed. so, they receive their medication and their treatment thus decongesting the waiting area … on days that there are two clubs per day, that is 70 patients out of your waiting area.’ (nurse 1, female) quantitative findings the role of quantitative (extensive) methods in realist research is considered to be predominantly descriptive. to this end, our quantitative findings are mostly descriptive. table 3 illustrates the characteristics of the participants of the two selected adherence clubs. table 3: characteristics of patients in clubs a and b. retention in care the combined retention in care within a 24-month period is 77.8%, with ‘club a’ registering a much lower retention in care rate (71.4%) compared to ‘club b’ (83.8%) (table 4). table 4: retention in care distributions in two adherence clubs at facility y. the survival distributions of the patients receiving care in the two adherence clubs are shown in figure 2. at 6 months, the retention in care rate of club a was 91.4% (95% ci, 75.8–97.8). at 12 months, the retention in care rate dropped to 77.1% (95% ci, 59.4–89). at 24 months, the rate decreased further to 65.7% (95% ci, 47.7–80.3). club b registered better retention in care rates at 6, 12 and 24 months with values of 86.5% (95% ci, 70.4–94.9), 83.8% (95% ci, 67.3–93.2) and 81.1% (95% ci, 64.3–91.4), respectively. fox et al. estimated a 6-year national retention in art care in south africa at 63.3%.38 comparing this value to the overall retention in care value of facility y (77.8%), we suggested the 2-year retention in care rate of the facility is good. figure 2: survival distribution of patient retention in care in two adherence clubs at facility y. we further conducted a log-rank test (mantel–cox) to determine whether the survival distributions of the two adherence clubs were statistically significantly different. a p-value of 0.255 showed that the survival distributions of the two adherence clubs were not statistically different, suggesting some level of constancy regarding retaining patients in care within the 24-month period. nevertheless, club b showed signs of having stabilised, while a projection of club a showed that it had the potential of continuously losing patients. adherence to medication patients in club b showed better adherence to medication behaviours (89.2%) compared to those in club a (77.1%) (table 5). the population-level adherence to medication based on the two sampled clubs was 83.3%. table 5: adherence to medication distribution rates in two adherence clubs at facility y. based on figure 3, the adherence to medication of the club a members at 12 and 24 months was 97.1% (95% ci, 83.3–99.9) and 72.0% (95% ci, 54.0–85.2), respectively. at 12 months, club b members showed a slightly lower adherence rate of 91.7% (95% ci, 76.7–97.8) compared to club a members, but at 24 months, club b members showed a better retention in care rate of 88.4% (95% ci, 72.7–96.0) compared to club a members. according to the human sciences research council report of 2018, only 62.3% of all plhiv in south africa were virally suppressed.1 in comparison to the national art adherence rate, we considered the 83.3% obtained as a ‘good’ adherence rate. figure 3: the survival distributions of the adherence behaviours of patients in the two adherence clubs at facility y. the log-rank test (mantel–cox) showed a value of 0.252, which indicates an overall consistency between the two clubs in enhancing adherence to medication among the patients using the intervention. data synthesis the data synthesis involved merging the data from the descriptive quantitative arm to the findings obtained from the thematic analysis of the qualitative transcripts in an attempt to refute, confirm or modify the initial programme theories. we formulated the icamo matrix following the different modalities of the adherence club intervention. this matrix is outlined in table 6. table 6: intervention–context–actor–mechanism–outcome matrix formulated from the study findings. in constructing the icamo matrix, we applied the configurational mapping approach, in which outcomes are considered to follow from the alignment of various interactive components. the retroduction logic informed this process. retroduction is a form of inference that seeks to identify and verify mechanisms that are theorised to have generated the phenomena under study.39 firstly, we paid attention to the outcomes of interest and then identified the mechanism(s) most associated with each outcome. this transfactual thinking approach40 helped us to identify mechanisms that were associated with the different modalities of the intervention and how these mechanisms relate to the different actors (patients, health professionals). then, we examined the context in which the mechanisms are contingent to perpetuate the observed outcome as informed by the data. thirdly, we confirmed each icamo chain by applying counterfactual thinking (creating possible alternatives) to trace the various pathways (demi-regularities).40,41 while having icamo links, such as in table 6, is useful, we constructed a configurational map to obtain a bigger picture. according to byng et al.42 the bigger picture adds value to understanding the programme theory. the result of this exercise is a model illustrating how adherence clubs contribute to adherence and retention in care (figure 4). figure 4: modified programme theory. our analysis reveals that the two theories identified as initial programme theories complement each other to provide a full picture of how and why the adherence club intervention works (figure 4). this is backed up by the respondents in the realist interviews. most suggested that a combination of both theories could explain how the club intervention works. they used phrases like: ‘it is a combination of both your theories …’ [nurse 1] or ‘i think both [theories]’ (counsellor 2). in the next step, we formulate a modified programme theory of the adherence club intervention based on the analysis of the facility y data set (see box 2). box 2: a modified programme theory of the adherence club intervention. discussion we aimed to confirm, refute or modify the initial programme theory of the adherence club intervention, which we drafted based on literature reviews and exploratory research. we examined the implementation of the adherence club intervention at facility y, chosen as a deviant case – poor performing based on 2014 routine data. our hypothesis suggested two possible explanations of how and why the adherence club intervention improves retention in care and sustains adherence to medication: by motivating and empowering the patients towards adopting the desired behaviours or by nudging them into doing so. these study findings showed that the two initial alternative theories complement each other to explain how and why the intervention works and in what context. although some patients would become motivated and empowered, through improved self-efficacy to remain in care and adhere to their medication, others were made to remain in care by strictly enforcing rules and regulations of the adherence club programme. it is worth mentioning that different patients would respond better to different aspects of care embedded in the adherence club programme. patients who already possess self-motivation would be empowered by the adherence club intervention as it enforces convenience to the patients. other patients who may not be adequately self-motivated could respond better to being ‘told what to do’, which is the role that the rules and regulations of the adherence club programme plays, or fulfills. a combination of these two explanations provides a comprehensive understanding of how and why the adherence club intervention works. in another case study testing the initial programme theory, it was also confirmed that the combined programme theory explains how and why the adherence club enhances adherence to medication and promotes retention in care among stable patients on art.43 although the retention in care and the adherence rates of the patients at the facility seemed to have improved from 2014, as reflected in our current programme theory, it is worth exploring why the intervention failed to take off as intended. this could add value to understanding in what context or circumstances the intervention works or not. this follows the notion that programmes are open systems. by open system, realists argue that programmes cannot be fully isolated or kept constant and that they are affected by various conditions such as physical and technological shifts, personnel movements and learning, organisational imperative and so on.16 such externalities always impact the delivery of a programme, and this entails that they are never quite implemented in the same way. in some instances, these externalities are introduced into the ‘system’ to engender a positive impact and are usually changes made to address the challenges that the intervention previously encountered. the failure of the intervention to kick off was attributed to a myriad of factors, including lack of proper understanding of the adherence club programme, which led to poor buy-in from the healthcare providers and lack of required infrastructure. buy-in, although considered an important mechanism at the level of implementing the intervention in the facility, nevertheless constitutes an important contextual factor regarding the day-to-day running as it affects the way the intervention is organised and delivered to the patients. lack of buy-in was identified by the participants of the study as part of the reasons why the intervention was poorly implemented and executed at this facility. it was also mentioned that the operational staff failed to understand how the adherence club was going to work in their favour, and thus did not welcome the intervention until they were made to understand how it would decongest the healthcare facility. because of the instructions received from sub-structure to roll out the adherence club programme in facility y, the operational staff working on the art programme felt compelled to do something, although they did not share in the vision of the programme. our study unveiled that apart from the lack of a conducive space, impacting the buy-in of the healthcare providers, their understanding that the adherence club intervention would increase their workload also contributed to the diminishing buy-in. the notion of increased workload was compounded by perceived staff shortage. the perceived staff shortage also ties with the contextual factor of not having a programme champion to run the adherence club programme when it was first adopted by the facility in the first phased rollout. another important context element that was identified as a hindrance to the effective implementation and execution of the adherence club intervention at facility y was the lack of a conducive physical space where the meetings could be conducted. our interviews revealed that when the intervention was rolled out at the facility, there was no physical space where the patients could meet to conduct the meetings. it took an intervention from the management to provide a makeshift building at the back of the facility for the intervention to be officially implemented. while exploring the context under which the adherence club is implemented in another facility, the authors found that lack of a conducive space for conducting club activities strongly influences the outcome of the intervention.44 this highlights the important role that context plays in activating the mechanisms that are provided by an intervention. in the absence of a conducive space, the buy-in of the healthcare providers became reduced, and they were not motivated to execute the intervention. this, in turn, affected the way the intervention was executed and the way it was received by the patients, thus impacting the retention in care and adherence outcomes. dudhia and kagee45 also uncovered that lack of resources for operating the club (delivery of care and support for club team) could demotivate the healthcare providers, thus impacting the quality of care delivered to patients. the four important context conditions, lack of buy-in, lack of staff, the absence of a programme champion and lack of physical space for the club meetings, caused the mechanisms that are provided by the adherence club intervention and naturally occurring in the environment not to be triggered. consequently, this led to sustained poor retention in care and suboptimal adherence to medication. while testing the initial programme theory in another context, we found that ‘integrating’ the adherence club programme with the management of patients with other non-communicable diseases (the presence of non-hiv-positive patients) presents a different prevailing context within which the adherence club intervention did not work.44 the context of integrated care was characterised by a lack of resources (adherence club meeting room), different execution models and poor adherence club programme coordination.44 when a nurse was identified and trained to champion the intervention, she exposed the other healthcare providers to the benefits of the intervention and headed the implementation. this engendered buy-in from the care workers. following the buy-in, the pharmacists also reorganised their schedules to prepare medication packages for the club members. once these elements were put in place, the context conditions of the adherence club changed, and the present conditions were favourable to incite the mechanisms provided by the adherence club intervention to cause the expected outcomes. these improved conditions and performance of the adherence club intervention are reflected in the high retention in care and adherence to medication rates, as demonstrated in the retrospective cohort analyses. limitations, rigour and trustworthiness although viral load is commonly used as a proxy for art adherence, it is not considered a perfect benchmark for evaluating how accurately an individual adheres to art. this is especially true because for patients in the adherence club, their viral loads are only measured once a year. thus, the viral load does not offer a real-time measure of adherence, which could be considered a limitation of the study. regarding the retention in care and adherence behaviours of patients in the adherence club, it would have been ideal to obtain the overall rates of the facility. this posed a challenge because the facility actively creates new clubs monthly. this would potentially affect the overall retention in care and adherence rates of patients in the adherence club programme. to this end, we decided to sample two adherence clubs that had reached their maximum capacity and to study the rate at which patients drop out of the club for various reasons – default, transferred out of the clinic, lost to follow-up or died. to improve the rigour of the study, we adopted the mixed-method approach. the use of a multi-method approach to data collection was informed by its ability not only to improve the retroductive inferencing, but also to confirm and complement the information required to test the initial programme theory. in addition, we used a variety of participants to promote the triangulation of the information obtained from the participants as it makes it easy for the researchers to verify facts. frequent debriefing sessions were held among the authors. these sessions took place in all the phases of this study, including the data collection, analysis and synthesis phases. conclusion we conducted a theory-testing case study within the realist approach. we uncovered that patients on art in adherence clubs will continue to adhere to their medication and remain in care because their self-efficacy is improved and they are motivated through the programme modalities and/or because they are being nudged through the club rules and regulations. through the application of the realist evaluation approach, we modified the initial programme theory, which combines alternative theories to formulate a complementary theory. this is a step towards obtaining a refined programme theory of the adherence club intervention. with the adherence clubs currently being rolled out nationwide,46 understanding how, why, for whom and under what health systems context the adherence club programme works could inform its successful implementation to other contexts where it is required. acknowledgements the authors acknowledge the contributions of dr ebrahim kriel through his expert knowledge. this work was supported by the south african medical research council (national health scholars programme). this research was also funded by an african doctoral dissertation research fellowship (addrf) award offered by the african population and health research center (aphrc) in partnership with the international development research centre (idrc). the work was also partly funded by the framework 4 agreement between the belgian directorate general for development cooperation and the university of the western cape (grant number: bbd 0344023272). disclaimer: the views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors. data availability statement: data associated to this study are available upon request from the corresponding author. competing interests the authors declare that they have no financial or personal relationship(s) that may have inappropriately influenced them in writing 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at, et al. estimating retention in hiv care accounting for patient transfers: a national laboratory cohort study in south africa. plos med. 2018;15:30–43. https://doi.org/10.1371/journal.pmed.1002589 wynn d, williams ck. principles for conducting critical realist case study research in information systems. mis q. 2012;36(3):787–810. eastwood jg, jalaludin bb, kemp la. realist explanatory theory building method for social epidemiology: a protocol for a mixed method multilevel study of neighbourhood context and postnatal depression. springerplus. 2014;3:12. https://doi.org/10.1186/2193-1801-3-12 ferraro pj. counterfactual thinking and impact evaluation in environmental policy. environmental program and policy evaluation. new dir eval. 2009;122(112):75–84. https://doi.org/10.1002/ev.297 byng r, norman i, redfern s. using realistic evaluation to evaluate a practice-level intervention to improve primary health care for patients with long-term mental illness. evaluation. 2005;11(1):69–93. https://doi.org/10.1177/1356389005053198 mukumbang fc, van wyk b, van belle s, marchal b. unravelling how and why the antiretroviral adherence club intervention works (or not) in a public health facility: a realist explanatory theory-building case study. plos one. 2019;14(1):e0210565. https://doi.org/10.1371/journal.pone.0210565 mukumbang fc, marchal b, van belle s, van wyk b. ‘patients are not following the [adherence] club rules anymore’: a realist case study of the antiretroviral treatment adherence club, south africa. qual health res. 2018;18(12):1839–1857. https://doi.org/10.1177/1049732318784883 dudhia r, kagee a. experiences of participating in an antiretroviral treatment adherence club. psychol heal med. 2015;20(4):488–494. https://doi.org/10.1080/13548506.2014.953962 mukumbang fc, zaida o, van wyk b. what do the implementation outcome variables tell us about the scaling-up of the antiretroviral treatment adherence clubs in south africa? a document review. health res policy syst. 2019;17:28. https://doi.org/10.1186/s12961-019-0428-z summer 2009                                                          the southern african journal of hiv medicine                                                  42 case presentation a 36-year-old hiv-positive woman with a cd4 count of 13 cells/µl was admitted to the intensive care unit (icu) at king edward viii hospital, durban, with a 3-week history of shortness of breath (new york heart association grade iv) which had progressively worsened 4 days prior to admission. she also had a 2-day history of pleuritic chest pain and cough. there was no past history of tuberculosis (tb) or tb contact. the medical and surgical history was non-contributory. clinically, the patient was noted to be well nourished, with a body mass index >25 kg/m2, febrile and tachypnoeic. there were no herpetic lesions on her lips or mouth. she was in severe respiratory distress and chest auscultation revealed global crepitations with increased intensity at the bases of the lungs. the cardiac and abdominal examinations were normal. the patient was alert and orientated with no features of meningism. arterial blood gas analysis revealed severe type i respiratory failure with a po2 4.5 kpa, pco2 3.5 kpa and oxygen saturation 75%. the chest radiograph showed bilateral homogeneous opacities and a ground-glass appearance. in light of these findings the patient was intubated, ventilated and started empirically on intravenous amoxicillin-clavulanic acid and gentamycin. the haemoglobin concentration was 12.3 g/dl, the white cell count 8.0×109/l and the platelet count 249×109/l. electrolyte levels and renal function were normal. liver function tests showed a decreased albumin level of 19 g/l and an increased gamma-glutaryltransferase (ggt) level of 125 iu/l. a bacterial and fungal septic screen was performed on blood, urine and endotracheal aspirate (eta) samples. the diagnosis of pcp was confirmed by immunofluorescent testing (axis; shield diagnostics ltd, uk) on the eta samples, which were also negative for routine bacterial pathogens and tb. trimethoprim (tmp) 240 mg-sulphamethoxazole (smx) 2 400 mg 6-hourly intravenously and prednisone 40 mg intravenously daily were started; however, over the next few days there was no improvement in her clinical condition. blood and eta samples were obtained to exclude infection with atypical bacteria and viruses. she was started empirically on piperacillin-tazobactam and amikacin for suspected nosocomial sepsis. viral studies revealed a positive hsv-1 dna polymerase chain reaction (pcr) on the eta and two whole-blood samples. eta samples were negative for cytomegalovirus and respiratory syncytial virus. hsv igm serology was negative. the patient was immediately started on acyclovir 800 mg 8-hourly intravenously approximately 1 week after the initiation of tmp-smx and an interesting case of hsv pneumonia and pcp co-infection in a patient with aids: a diagnostic and management challenge adult case study mohammed mitha1, mb chb kriban reddy2, mb chb raveen parboosing1, mb chb, fcpath (virol) yacoob coovadia1, mb chb, fcpath (microbiol) 1department of medical microbiology, university of kwazulu-natal, durban, and national health laboratory service 2department of surgery, university of kwazulu-natal the advent of hiv and aids has brought about many diagnostic and management challenges regarding multiple opportunistic infections. pneumocystis jirovecii pneumonia (pcp) is a common presentation in patients with aids who are not on prophylaxis or highly active antiretroviral therapy (haart). herpes simplex 1 virus (hsv-1) is a ubiquitous virus that mainly causes benign disease during primary infection. however, it is known to cause severe pneumonia and disseminated disease in the immunocompromised.1 we present a case of hsv-1 pneumonitis and pcp co-infection in an hiv-positive patient with respiratory failure. to the best of our knowledge, based on pubmed and google scholar searches, this is the first case to be reported in the english language literature. the southern african journal of hiv medicine                                                        summer 2009   43 prednisone. tmp-smx and prednisone were continued concurrently with acyclovir. the patient remained on maximum ventilatory support and died 22 days after admission. discussion hsv-1 may cause tracheobronchitis or pneumonitis and is associated with significantly increased mortality in critically ill patients.2 it is usually due to reactivation of the virus, which occurs as a result of certain stimuli such as fever and ultraviolet light as well as immunosuppression.1,2 it is a rare cause of respiratory disease in hiv-positive individuals, the likelihood increasing with progression to aids; it is an even rarer cause of respiratory infection in the immunocompetent.3 there are several hypotheses regarding the patho genesis of hsv-1 pneumonia. the virus may reach the lower respiratory tract through contiguous spread, aspiration from the oropharynx or haematogenous spread in the presence of viraemia.1 it is usually due to reactivation and not primary disease.2,4 this was consistent with the findings in our patient, in whom testing for hsv igm m was negative. there are no pathognomonic clinical or radiological features for hsv pneumonia. a high index of clinical suspicion with appropriate laboratory testing is required for the diagnosis. clinically, patients may present with cough, fever, dyspnoea and hypoxaemia and failure to wean off the ventilator.1,5 chest radiographs generally demonstrate a bilateral ground-glass appearance. pleural effusions and patchy consolidation may also be present.6 the virus may be detected by viral isolation or pcr in broncho-alveolar lavage or endotracheal aspirate specimens. however, the significance of detecting hsv in respiratory secretions remains controversial as it may represent shedding rather than active disease.1-3 nevertheless, the presence of hsv in respiratory secretions in severely ill patients has been associated with a poor outcome and prolonged ventilation.3 the demonstration of intranuclear inclusions or cowdry type a bodies in biopsies is highly suggestive of active infection in the lung or in other tissue specimens.1 however, performing a lung biopsy in a ventilated patient is challenging and associated with complications. our patient could not be weaned off the ventilator, and her condition deteriorated despite appropriate antimicrobial therapy for pcp, as well as steroids which are usually beneficial in patients with severe pcp.7,8 it has been reported in the literature that the presence of hsv in blood indicates the inability of the host to limit viral replication, with dissemination occurring particularly in immunosuppressed patients.9 hsv viraemia is typically associated with interstitial pneumonia4,10 which is in keeping with that observed in our patient with two whole blood specimens being positive for hsv-1 dna by pcr. the paucity of literature regarding the diagnosis and management of patients who have co-infection with hsv pneumonia and pcp suggests that this condition is either rare or under-diagnosed. considering that both hsv-1 pneumonia and pcp have similar clinical and radio logical findings, we would recommend that in patients with pcp who do not respond to appropriate therapy, co-infection with hsv-1 pneumonia should be excluded. the demonstration of hsv in blood and in respiratory samples would strongly support such a diagnosis. it is debatable whether steroid therapy exacerbated the underlying hsv pneumonia, or contributed to ventilator dependence and overall clinical deterioration in our patient. in the absence of any other data in the literature, we suggest that if co-infection is suspected an approach would be to delay steroids for 24 48 hours as this immunosuppressive agent may exacerbate the hsv infection. if co-infection is confirmed, acyclovir can be given before initiation of steroids. alternatively empiric treatment with both tmp-smx and acyclovir together with steroids can be initiated and therapy can be modified once laboratory results become available for both pcp and hsv. laboratory results are usually available within 24 48 hours. the diagnosis of hsv-1 pneumonia-pcp co-infection is rare and management is currently speculative. the optimal therapy for this dual infection remains to be determined by means of greater awareness, further research and clinical trials. references 1. simoons-smit am, kraan em, beishuizen a, strack van schijndel rj, vandenbrouckegrauls cm. herpes simplex virus type 1 and respiratory disease in critically-ill patients: real pathogen or innocent bystander? clin microbiol infect 2006; 12(11): 1050-1059. 2. engelmann i, gottlieb j, meier a, et al. clinical relevance of and risk factors for hsv-related tracheobronchitis or pneumonia: results of an outbreak investigation. crit care 2007; 11(6): r119. 3. bruynseels p, jorens pg, demey he, et al. herpes simplex virus in the respiratory tract of critical care patients: a prospective study. lancet 2003; 362: 1536-1541. 4. ramsey pg, fife kh, hackman rc, meyers jd, corey l. herpes simplex virus pneumonia; clinical virologic and pathologic features in 20 patients. ann intern med 1982; 97: 813–820. 5. eisenstein le, cunha ba. herpes simplex virus pneumonia presenting as failure to wean from a ventilator. heart lung 2003; 32(1): 65-66. 6. aquino sl, dunagan dp, chiles c, haponik ef. herpes simplex virus 1 pneumonia: patterns on ct scans and conventional chest radiographs. j comput assist tomogr 1998; 22(5): 795-800. 7. gagnon s, boota am, fischl ma, baier h, kirksey ow, la voie l. corticosteroids as adjunctive therapy for severe pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. a double-blind, placebo-controlled trial. n engl j med 1990; 323: 1444-1450. 8. bozzette sa, sattler fr, chiu j, wu aw, gluckstein, d, kemper c, et al. a controlled trial of early adjunctive treatment with corticosteroids for pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. california collaborative treatment group. n engl j med 1990; 323: 1451-1457. 9. whitley rj. herpes simplex viruses. in: knipe dm, howley pm, eds. fields virology, vol. 2. 4th ed. philadelphia: lippincott williams & wilkins, 2001: 2467-2468. 10. groeneveld ab, vandenbroucke-grauls cm. one swallow does not make a summer: can herpes simplex virus-1 cause pneumonia and acute lung injury? am j respir crit care med 2007; 175(9): 865-866. abstract introduction and background methods ethical consideration results discussion conclusion acknowledgement references about the author(s) deborah j. solomons department of nursing and midwifery, faculty of medicine and health sciences, stellenbosch university, cape town, south africa anita s. van der merwe department of nursing and midwifery, faculty of medicine and health sciences, stellenbosch university, cape town, south africa tonya m. esterhuizen division of epidemiology and biostatistics, department of global health, faculty of medicine and health sciences, stellenbosch university, cape town, south africa talitha crowley department of nursing and midwifery, faculty of medicine and health sciences, stellenbosch university, cape town, south africa citation solomons dj, van der merwe as, esterhuizen tm, crowley t. factors influencing the confidence and knowledge of nurses prescribing antiretroviral treatment in a rural and urban district in the western cape province. s afr j hiv med. 2019;20(1), a923. https://doi.org/10.4102/sajhivmed.v20i1.923 note: this article is based on a master of nursing thesis (stellenbosch university) (http://hdl.handle.net/10019.1/103738). original research factors influencing the confidence and knowledge of nurses prescribing antiretroviral treatment in a rural and urban district in the western cape province deborah j. solomons, anita s. van der merwe, tonya m. esterhuizen, talitha crowley received: 13 oct. 2018; accepted: 25 mar. 2019; published: 02 july 2019 copyright: © 2019. the author(s). licensee: aosis. this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. abstract background: since the introduction of nurse-initiated and managed antiretroviral treatment (nimart) in south africa in 2010, initiation of antiretroviral therapy (art) in primary care has become the responsibility of nurses. the continued success of this approach is dependent on factors such as adequate training and effective support systems. objectives: this study aimed to investigate factors influencing the knowledge and confidence of professional nurses in managing patients living with human immunodeficiency virus (hiv) in primary healthcare settings in a rural and urban district in the western cape. methods: a cross-sectional survey was conducted amongst 77 nimart-trained nurses from 29 healthcare facilities to measure demographic details, influencing factors, hiv management confidence and hiv management knowledge. results: the majority of participants had adequate hiv management knowledge and reported being very confident or expert in the hiv management skills or competencies. participants trained recently on local guidelines (practical approach to care kit) (3 years ago or less) had significantly higher knowledge scores. regular feedback about clinic and personal performance was associated with higher hiv management knowledge. participants who received nimart mentoring over a period of 2 weeks had a higher mean confidence score compared to other periods of mentoring. a higher caseload of patients living with hiv was also associated with higher knowledge and confidence. conclusion: training, mentorship and clinical practice experience are associated with knowledge and confidence. recommendations include the strengthening of current training and mentoring and ensuring that nimart-trained nurses are provided with regular updates and sufficient opportunities for clinical practice. keywords: hiv; nimart; primary healthcare; clinics; nurses. introduction and background south africa has the largest antiretroviral treatment programme in the world.1 antiretroviral treatment guidelines are continuously revised, consequently increasing the threshold for antiretroviral therapy (art) treatment. because of persistent human resource constraints in south africa, task shifting from doctors to nurses to prescribe art became essential to ensure that more patients living with human immunodeficiency virus (hiv) are initiated on life-saving art.2 since the introduction of nurse-initiated and managed antiretroviral therapy (nimart) in south africa in 2010, there has been an increased demand for the training of professional nurses in hiv management in the primary healthcare (phc) setting. the availability of nimart-trained nurses in phc clinics has improved the access of patients to hiv treatment.3 although the shifting of tasks is a timely solution for human resource constraints, the continued success of the approach depends on factors such as adequate training and effective support systems.4 the world health organization (who) recommends that countries should adopt a methodical approach to coordinated, consistent and competency-based education that is needs-driven and approved. this will ensure that all healthcare workers are equipped with the appropriate competencies to undertake the tasks that they perform.5 competency has been described as the knowledge, perceptions, skills, attitudes and standards that an individual develops or acquires through education, training and work experience, which can be used to depict particular occupational roles or functions against which personal performance may be assessed.6 although it is ideal that all health professionals should be competent to undertake the tasks they perform, competency may be difficult to assess. the assessment of competency in the form of subjective, multiple-choice and standardised patient assessments may underemphasise significant domains of professional capability such as the integration of knowledge and skills, the framework of care, cooperation and patient–provider associations.7 it is even more challenging to assess the competency of clinicians in practice. in this study, self-assessment was used to measure how confident nurses are in performing hiv management skills. knowledge questions were used to provide an objective assessment. self-assessment is often used to help practising clinicians to identify their own strengths and weaknesses for continuous professional development. however, the process of assessing oneself is complex and never completely objective. self-assessment can therefore not be used as an accurate measure of competency, but it can be used to help individuals identify gaps in their clinical performance.8 one such study conducted in the eastern cape province of south africa found satisfactory self-efficacy in the clinical performance of nimart amongst 358 trained nurses, with some limitations in their abilities regarding clinical evaluation.9 care provided by providers with low levels of self-rated expertise who treat low numbers of hiv and aids patients tends to lead to less favourable patient outcomes.10 factors such as training, mentoring and clinical experience have been found to influence the competency of healthcare providers. a systematic review revealed better clinical outcomes for patients treated by a provider with more training in hiv and aids care.10 there is very little research available on the evaluation of the different nimart training courses and training outcomes. one study found that 62% of nurses who had been trained in nimart were initiating patients on art in the clinics where they were working, yet some of these nurses did not pass the open book exam after the training.11 in kwazulu-natal province, knowledge scores of nurses increased significantly after nimart training, with a median post-test knowledge score of 77%. however, the majority of nurses were not confident enough to practise their skills, which emphasised the need for continuous mentorship.12 a study in khayelitsha, south africa, showed an increase in the confidence of nurses to manage patients on art after mentorship.13 similarly, a study evaluating 5 years of nimart mentorship in south africa identified improved knowledge, attitudes and confidence perceived by nurses who received nimart mentoring, but highlighted the need for mentoring to continue in light of continuous changes to treatment guidelines.14 in addition to mentoring, provider experience in hiv and aids care has shown to improve the quality of care.10 although there is substantial evidence that nurses can provide high-quality treatment and care, several challenges have been identified, such as shortages of essential drugs, salary concerns, excessive workload, lack of practice standards, access to mentoring and infrastructural barriers.4,11,15,16 this therefore highlights the need for continuous quality assurance in settings where nimart is being implemented.17,18 no published studies could be found that specifically investigated the factors that influence the knowledge and confidence of nurses currently prescribing art. evaluating the hiv management confidence and knowledge of professional nurses who prescribe art may help to improve ongoing nimart training interventions. this study therefore aimed to determine the factors that influence the hiv management confidence and knowledge of professional nurses prescribing art in a rural and urban district in the western cape province. methods research design and setting a quantitative cross-sectional and analytical research design was used because nimart training has been operational for several years and is in its implementation phase.19 the study was conducted in one urban and one rural district – the city of cape town (city health) and the cape winelands districts. population and sample based on a list obtained from the department of health, there were 256 nurses who were authorised to prescribe nimart in the two districts. of the five subdistricts in the cape winelands, three districts gave permission for the research and two declined. the assessable population, determined by contacting facilities, was 146 (67 in the city of cape town and 79 in the cape winelands). all the nurses authorised to prescribe nimart for a period of 1 year were invited to participate in order to account for the clustering effect in the subdistricts. in the cape winelands, 49 (69%) participants completed the questionnaires, 18 (25%) refused to participate and four (6%) were absent, on leave or not available when the research was conducted. in the city of cape town, 28 (42%) participants completed the questionnaires, 22 (33%) refused to participate and 17 (25%) were absent, on leave or not available when the research was conducted. instrumentation a self-completion questionnaire was used that was designed by the researcher based on the literature and previous instruments. the questionnaire measured demographic details, influencing factors, hiv management confidence and hiv management knowledge. the questionnaire was available in english only. in addition, facility statistics related to caseload were collected. pilot test a pilot test was conducted in the stellenbosch sub-district. participants in the sub-district were randomly selected to complete the questionnaire. eight participants completed the questionnaire. after completion of the questionnaire, a few changes were made to the questionnaire. the pilot test data were not included in the main study. validity and reliability reliability and content validity of the instrument were ensured by making use of the literature, a review of the instrument by experts in the field of hiv and the pilot test. content validity was determined by calculating a content validity index (cvi) for each item (called the i-cvi) in the questionnaire based on the feedback of five experts. the i-cvi was calculated by determining the percentage of experts who rated the specific item as relevant. for an item to be considered relevant, four of the five experts had to rate the item as relevant (an i-cvi score of 0.8).20 for six items in the questionnaire, one of the five experts rated the item as not relevant (an i-cvi score of 0.8). however, this is still acceptable according to the literature. for the remaining items, all the experts rated the items as relevant (an i-cvi score of 1). they made suggestions to improve the clarity of items and these suggestions were incorporated in the final instrument. the cronbach’s alpha coefficient was used to establish the reliability of the likert scale items that measured confidence. the previously reported cronbach’s alpha for the confidence items was 0.94.21 in this study, the cronbach’s alpha for the 22 confidence items was 0.95. data analysis data were entered into microsoft excel by the researcher, imported and analysed using the statistical package for social sciences (spss) software.22 hiv management confidence and knowledge were measured as continuous variables by calculating the total scores. the scores were converted to percentages to facilitate interpretation. a higher score indicated more confidence. descriptive statistics were used to describe the data and appropriate statistical tests were used to test for relationships between variables. as the confidence and knowledge scores were normally distributed, the student t-test was used to compare mean scores of two independent groups or categories of influencing factors and analysis of variance (anova) for comparing more than two groups. the spearman rho correlation coefficient was used to test for associations between continuous variables, for example, scores and the patient caseload of the participant (as the caseload was not normally distributed). a level of significance of < 0.05 was used in this study. ethical consideration ethics approval to conduct the study was obtained from the health research ethics committee at stellenbosch university (s14/12/268). permission was further obtained from the department of health, city of cape town (city health), western cape province and the appropriate medical superintendents from the chosen subdistricts. this study adhered to the ethical principles of the declaration of helsinki 2013. the researcher has the ethical responsibility to protect the human rights of the participants, such as their rights to privacy, confidentiality, autonomy, anonymity, fair treatment and protection from discomfort and harm. results biographical data most of the participants were recruited from healthcare facilities (n = 20, 69%) in the cape winelands. the median headcount in facilities was 2496.5 (interquartile range [iqr] 1460.5–5441.5), indicating a high patient load in the facilities with relatively high variability between facilities. the mean age of participants was 43.6 years, with a standard deviation (s.d.) of 9.98 years, the youngest being 25 years of age and the oldest being 64 years of age. table 1 presents the categorical biographical data of the participants. most of the respondents performed clinical work as a professional nurse. participants in the ‘other’ category were providing different services, for example, the prevention of mother-to-child transmission (pmtct) manager from head office prescribed art if there was understaffing in certain clinics. another participant was appointed as a psychiatric nurse but was also nimart-trained and provided art. one participant indicated that she was a clinical mentor but was also allocated to clinics to provide art. table 1: biographical data of the participants. influencing factors the factors influencing confidence and knowledge included: (1) hiv management experience, (2) training, (3) continuous mentoring and support, (4) workload, motivation, facility equipment and general satisfaction, and (5) quality assurance mechanisms (see table 2). table 2: influencing factors. human immunodeficiency virus management confidence the mean hiv management confidence score was 68.7% (95% ci 66.3–71.1), with a minimum score of 45% and a maximum of 85%. the participants reported the highest confidence in the use of art stationery (with 51.9% considering themselves experts) and performing a physical examination (with 50.6% considering themselves experts). they were less confident in identifying drug interactions in commonly used medications, because only 14.3% considered themselves to be experts, and stopping or switching drug treatments (with only 15.5% considering themselves as experts). low confidence was reported in prescribing for concurrent illnesses and in identifying the signs and symptoms of immune reconstitution inflammatory syndrome (fewer than 20% of participants considered themselves experts). the distribution of the hiv management confidence score was the same across categories of district and facility type. bivariate analysis indicated a low to moderate positive correlation between the hiv management confidence score and the average number of patients on art followed up in the last 3 months (r = 0.328, p = 0.004). the distribution of hiv management confidence scores was not the same across categories of how long nimart mentoring lasted (f[df4] = 4.6; p = 0.002). post hoc analysis revealed that participants who received nimart mentoring for 2 weeks had significantly higher confidence scores than those who received mentoring for more than 2 months. none of the other influencing factors has significant associations with hiv management confidence (see table 2). human immunodeficiency virus management knowledge the mean hiv management knowledge score was 72.7% (95% ci 69.8–75.6). the minimum score was 38% and the maximum 100%. participants had high knowledge scores regarding treatment for peripheral neuropathy (97.4% indicated the correct answer) and the side effects of tenofovir, with 89.6% indicating the correct answer. high knowledge scores were also identified for identifying pneumocystis pneumonia (88.3% correct) and art contraindications (88.3% correct). the participants were less knowledgeable regarding the treatment of toxoplasmosis (22.1% correct), oral hairy leukoplakia (39% correct) and tinea capitis (41.6% correct). a few participants (41.6%) demonstrated an understanding of virological failure and only 51.9% provided the correct answer for the question related to drug–drug interactions. there was a significant difference in distribution of the hiv management knowledge score across categories of district (t[df75]= -2.9, p = 0.004). participants in the cape winelands had a lower mean knowledge score (69.6%) compared to the mean knowledge score of participants in the city of cape town (78.2%). participants trained in practical approach to care kit (pack – flowchart-based guidelines designed for assisting nurses manage various conditions in a primary care setting)4 3 years ago or less had significantly higher knowledge scores (t[df70] = -3.5, p = 0.001). those with no training in dispensing had significantly higher knowledge scores, which is an unexpected finding. knowledge scores of participants who indicated that they received regular feedback about their personal performance (t[df75] = 2.45, p = 0.016) and the performance of the clinic related to the provision of art (t[df75] = 3.5, p = 0.001) were significantly higher compared to those who did not. bivariate analysis indicated a low to moderate positive correlation between the hiv management knowledge score and the average number of patients initiated on art in the last 3 months (r = 0.357, p = 0.002) and a moderate positive correlation for the average number of patients on art followed up (r = 0.386, p = 0.001). a significant negative correlation was found between the hiv knowledge score and the average number of other or non-art patients the participants managed in the past 3 months (r = -0.367, p = 0.001). discussion appropriate training is the beginning of the pathway to expertise.5,23 in this study, a variety of hiv management training courses were attended by the participants. all of the participants were trained in pack, completed an hiv management course and participated in nimart training as per the nimart guidelines of the western cape.13 only 57.1% of participants had completed a dispensing course, although this did not affect confidence and was associated with lower knowledge scores. a dispensing certificate is not a requirement for nimart in the western cape and most clinics have either a pharmacy assistant or a pharmacist who can dispense medication. cameron et al.11 found that 79% of the nurse participants in their study had previous formal training in hiv management and 55% had formal training in phc, which is comparable to the 57.1% of participants in the present study who had completed a postgraduate diploma in phc. a qualification in phc (health assessment, treatment and care [r48]) and a dispensing certificate are therefore not requirements to prescribe art in the study context, but the pack training and completing an hiv management course are. although no cause and effect can be inferred, it can be deduced from the results that recent pack training (3 years or less) is likely to improve the hiv management knowledge of nurses. clinical mentoring is depicted alongside clinical practise and continuous assessment on the pathway to competency and proficiency.22 the purpose of mentoring is to acquire skills to competently initiate, but also manage patients according to established clinical protocols.17 the western cape department of health guideline advises a minimum of 40 h of nimart one-on-one mentorship following didactic training.13 in a study in the health districts of tshwane (gauteng province), nkangala (mpumalanga province) and capricorn and vhembe (limpopo province), the median mentoring period was 25 months.14 it therefore appears that there is no set period for mentoring. a total of 80 cases are required to be seen by a nurse in consultation with a mentor, according to the clinical mentorship guideline for integrated services, in order for the nurse to be authorised in nimart.22 in the present study, all nurses had received nimart mentoring. the findings from this study support a 2-week nimart mentoring period. it may be that a 2-week mentoring period is more intense. perhaps those who were mentored for a longer period, for example, for more than 2 months, did not have intensive contact sessions and case studies or the contact sessions may have been too far apart. a study conducted by orner et al.16 found that nurses and doctors were too busy for mentoring, which may result in less frequent contact sessions. a longer period of mentoring may therefore not translate to the acquisition of more knowledge and confidence in practice. this, however, needs to be explored further. having an assigned mentor or the frequency of contact sessions with the mentor were not associated with the participants’ level of confidence or knowledge. however, other studies have found mentoring to improve nurses’ confidence, improving institutional barriers and the quality of patient care.13,14 although mentoring was not associated with the participants’ knowledge in the present study, participants who received regular feedback about their personal and clinical performance (classified in this study as part of quality assurance) had significantly higher knowledge scores (75.2%) compared to those with limited or no feedback (67.9%). feedback was mostly received from the clinic manager or hiv and aids, stis and tb coordinator. regular feedback provided about individual and clinic performance related to the provision of art is likely to influence nurses’ hiv management confidence.4 however, the clinical mentorship manual for integrated services22 distinguishes between clinical mentorship and supportive supervision. although both have similar goals and some overlapping activities, supervision tends to emphasise health facility management and is more hierarchical, whereas mentoring is more focused on the enhancement of the skills of the mentee. mentoring should therefore be more effective in improving the confidence and knowledge of nurses than feedback from supervisors. the above mentioned results may mean that mentoring is not currently being implemented or practised effectively. knowledge and confidence of the clinicians should increase as they gain experience.22 in this study, the hiv management confidence and knowledge scores were the same across all categories of experience. however, the average number of patients living with hiv seen or the caseload may be an indication of the intensity of experience and was associated with both hiv management confidence and knowledge. it therefore appears that the total years of experience does not influence confidence and knowledge, rather it is more clinical practice experience, for example, the patients living with hiv caseload, that influences confidence and knowledge. none of the other health system influencing factors were associated with hiv management confidence and knowledge. these may nonetheless still have an impact on overall service delivery and quality of patient care. recommendations based on the study findings include regular guideline updates to reinforce hiv management knowledge. methods to strengthen mentoring should be engaged such as dedicated roving mentors or access to telephonic consultations.14 dedicated mentoring may be costly and therefore non-governmental organisation support may be required to ensure mentor capacity.13 nimart-trained nurses should be offered sufficient opportunities to practise their skills. as not all nurses may be exposed to a high caseload because of the phc approach of providing integrated services, especially in rural settings, those with low caseloads need access to updated guidelines and mentors to assist them when they initiate patients or encounter complex cases. limitations study limitations include the small sample size and high refusal rate, which limits the generalisability of the findings. the small sample size further limits the power of the statistical tests to detect significant differences. as mentioned before, self-assessment may not accurately measure confidence. the cross-sectional nature of the study implies that no cause and effect relationships between the variables explored can be inferred. further, the knowledge and competency items assessed were delimited to adult hiv care. conclusion this study investigated various factors that influence the knowledge and confidence of professional nurses prescribing art in an urban and rural setting, and gave an account of what is currently happening at the healthcare facilities that partook in the study. the majority of participants had adequate hiv management knowledge and reported being very confident or experts in the hiv management skills and competencies. training, mentorship and clinical practice experience are associated with knowledge and confidence. recommendations include the strengthening of current training and mentoring programmes and ensuring that nimart-trained nurses are provided with regular updates and sufficient opportunities for clinical practice. acknowledgement competing interest the authors have declared that no competing interests exist. author contributions d.j.s. wrote the proposal and conducted the study as part of her master of nursing degree. t.c. supervised the study and developed the initial draft of the article. a.s.v.d.m. cosupervised the study, and 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